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Semiconductor memory element, production method and operational method |
A semiconductor memory element has a substrate, in which a source region and a drain region are formed, a floating gate electrically insulated from the substrate, and a tunnel barrier arrangement, via which charging or discharging of the floating gate can be performed. It is possible to alter the conductivity of a channel between source and drain regions by charging or discharging the floating gate. A source line is electrically conductively connected to the source region and controls the charge transmission of the tunnel barrier arrangement. |
1. A semiconductor memory element, comprising: a substrate, in which at least one source region and at least one drain region are formed; floating gate electrically insulated from the substrate; tunnel barrier arrangement, via which electrical charge can be fed to the floating gate or dissipated from the latter, it being possible to alter the conductivity of a channel between the source and drain regions by charging or discharging the floating gate; means for controlling the charge transmission of the tunnel barrier arrangement; and wherein the means for controlling the charge transmission of the tunnel barrier arrangement has a source line which is electrically conductively connected to the source region extending from the source region parallel to the stack direction of the layer stack of the multiple tunnel barrier. 2. The semiconductor memory element of claim 1, the tunnel barrier arrangement having a layer stack with an alternating layer sequence of semiconducting and insulating layers for the purpose of forming a multiple tunnel barrier. 3. The Semiconductor memory element of claim 1, the source line having doped polysilicon or a metal. 4. The semiconductor memory element of claim 2, the semiconducting layers of the layer stack having undoped polysilicon. 5. The semiconductor memory element of claims 2, the insulating layers of the layer stack having silicon nitride or silicon dioxide. 6. The semiconductor memory element of claim 2, the semiconducting layers of the layer stack having a thickness in the range of 10 to 100 nm and the insulating layers having a thickness in the range of 2 to 10 nm. 7. The semiconductor memory element of claim 6, the semiconducting layers of the layer stack having a thickness in the range of 30 to 50 nm and the insulating layers having a thickness in the range of 2 to 6 nm. 8. The Semiconductor memory element of claim 1t,the tunnel barrier arrangement being electrically connected to a word line on its side remote from the floating gate, by means of which word line a voltage pulse can be applied via the tunnel barrier arrangement to the floating gate for the purpose of charging the latter and for the purpose of inverting the channel between source region and drain region. 9. The semiconductor memory element of claim 1 and at least one additional like semiconductor memory element arranged in a matrix-like manner in a plurality of rows and columns, the semiconductor memory elements belonging to a column having a common source line which is electrically conductively connected to the source regions of said semiconductor memory elements and via which the charge transmission of the tunnel barrier arrangements belonging to said semiconductor memory elements can be controlled. 10. The semiconductor memory element arrangement of claim 9, the source line respectively assigned to a semiconductor memory element in a row forming a bit line of a semiconductor memory element that is adjacent in the same row. 11. The semiconductor memory element arrangement of claim 9, a common source line being assigned in each case to two semiconductor memory elements that are arranged adjacent in the same row. 12. A method for fabricating a semiconductor memory element comprising: forming at least one source region and at least one drain region in a substrate; forming a floating gate that is electrically insulated from the substrate; forming a tunnel barrier arrangement, via which electrical charge can be fed to the floating gate or dissipated from the latter, it being possible to alter the conductivity of a channel between the source and drain regions by charging or discharging the floating gate; and providing a source line that is electrically conductively connected to the source region and serves for controlling the charge transmission of the tunnel barrier arrangement being formed adjacent to the tunnel barrier arrangement, said source line being formed from the source region parallel to the stack direction of the layer stack of the multiple tunnel barrier. 13. The method of claim 12, the tunnel barrier arrangement being formed as a layer stack with an alternating layer sequence of semiconducting and insulating layers for the purpose of forming a multiple tunnel barrier. 14. The method of claim 12, the step of formation of a source line that is electrically conductively connected to the source region comprising: application of a first semiconducting layer on an insulating layer that covers the tunnel barrier arrangement and the source region; performance of a directional implantation for doping that region of the first semiconducting layer which is applied on the insulating layer that covers the multiple tunnel barrier; uncovering of the source region by partial removal of the first semiconducting layer that covers the source region and of the insulating layer; removal of the non-doped regions of the first semiconducting layer with the insulating layer being partially uncovered; and selective application of a second semiconducting layer to the source region and the doped region of the first semiconducting layer. 15. The method of claim 14, the first and second semiconducting layers being formed from polysilicon and the insulating layer being formed from silicon dioxide. 16. A method for operating a semiconductor memory element which has a substrate with at least one source region formed therein and at least one drain region formed therein, a floating gate electrically insulated from the substrate, and a tunnel barrier arrangement, comprising: feeding an electrical charge to the floating gate or dissipated from the latter via the tunnel barrier arrangement; altering the conductivity of a channel between source and drain regions by charging or discharging the floating gate; and controlling the charge transmission of the tunnel barrier arrangement via a source line that is electrically conductively connected to the source region, the source line being formed from the source region parallel to the stack direction of the layer stack of the multiple tunnel barrier. 17. The method of claim 16, for writing data of the semiconductor memory element further comprising: applying a voltage in the range of +(2-3) volts to the source line; and applying a voltage of at most ±1 volt to a word line which is electrically connected to the tunnel barrier arrangement on its side remote from the floating gate. 18. The method of claim 16, for reading data of the semiconductor memory element further comprising: applying a voltage in the range of +(0.5-1) volt to a bit line that is electrically conductively connected to the drain region; and applying a voltage in the range of +(3-5) volts to a word line which is electrically connected to the tunnel barrier arrangement on its side remote from the floating gate. |
<SOH> BACKGROUND <EOH>The invention relates to a semiconductor memory element, a semiconductor memory element arrangement, a method for fabricating a semiconductor memory element and a method for operating a semiconductor memory element. Some essential parameters of a semiconductor memory element are the retention time for which the memory content stored in the semiconductor memory element is preserved, the write time required for programming in the memory content, and the write voltages required for programming in the memory content. A known semiconductor memory element is the DRAM memory element (DRAM=Dynamic Random Access Memory) which, although having relatively fast write times of a few nanoseconds, has only short retention times on account of unavoidable leakage currents, so that the RAM memory element has to be recharged at regular time intervals of about 100 ms. By contrast, although the so-called EEPROM memory element (EEPROM=Electrically Erasable Programmable Read Only memory) enables relatively long retention times of a number of years, the write times required for programming in the memory content are significantly longer than in the case of the RAM memory element. There is therefore a need for semiconductor memory elements in which fast write times (of about 10 nanoseconds) are combined with long retention times (of more than one year) and low write voltages. K. K. Likharev, “Layered tunnel barriers for non-volatile memory devices”, Applied Physics Letters Vol. 73, pages 2137-2139 has proposed a so-called “crested barrier” memory element, in which a floating gate is charged or discharged via a serial arrangement of (typically three) tunnel barriers, the tunnel barriers having a profiled (=“crested”) form. In this case, the tunnel barriers are not formed in the customary manner in the form of a square-wave potential with a constant height of the potential barrier, but rather are profiled by means of “peaks”. Since, compared with a conventional tunnel barrier, such a “profiled” tunnel barrier has a greater charge transmission and a greater sensitivity for the voltage present, relatively fast write times can be achieved theoretically in any case with such a “crested barrier” semiconductor memory element. However, the write voltages required for writing are relatively large, i.e. approximately greater than 10 V. K. Nakazato et al., “PLED—Planar Localized Electron Devices”, IEDM pages 179-182 has disclosed a proposal for a so-called PLED memory element (PLED=Planar Localized Electron Device). In this case data is written or erased by fast charging or discharging of a floating gate via a multiple tunnel barrier (MTJ=Multiple Tunnel Junction), the transmission of the multiple tunnel barrier being controlled by means of a side gate electrode. For reading data, depending on the conductivity state of the channel running below the floating gate between a source terminal and a drain terminal, a current flow is detected in the channel (corresponding to a “1” bit) or is not detected (corresponding to a “0” bit). In the case of the PLED memory element, it is possible to achieve short write times (similar to those of a RAM memory element) and long retention times (similar to those of an EEPROM memory element). Moreover, the required write voltages are significantly lower than in the case of the “crested barrier” memory element mentioned above. However, since a further terminal is required for the side gate electrode for controlling the transmission of the tunnel barrier in addition to the source, drain and data terminals, the PLED memory element is a 4-terminal arrangement. On account of this 4-terminal arrangement, the PLED memory element has relatively 2 5 large dimensions and, consequently, is not ideal for ULSI applications (ULSI=Ultra Large Scale Integration). |
<SOH> SUMMARY <EOH>One embodiment of, the invention addresses the problem of providing a semiconductor memory element, a semiconductor memory element arrangement, a method for fabricating a semiconductor memory element and a method for operating a semiconductor memory element that has better suitability for ULSI applications in conjunction with enabling fast write times, long retention times and low write voltages. In one embodiment of the invention, semiconductor memory element has a substrate, in which at least one source region and at least one drain region are formed. A floating gate is electrically insulated from the substrate. Furthermore, a tunnel barrier arrangement is provided, via which electrical charge can be fed to the floating gate or can be dissipated from the latter, it being possible to alter the conductivity of a channel between the source and drain regions by charging or discharging the floating gate. Moreover, means for controlling the charge transmission of the tunnel barrier arrangement is provided, which has a source line that is electrically conductively connected to the source region. By virtue of the fact that the means for controlling the charge transmission of the tunnel barrier arrangement has a source line that is electrically conductively connected to the source region, the source line can be used, on the one hand, for current transport when writing to or reading from the semiconductor memory element and, on the other hand, for controlling the charge transmission of the multiple tunnel barrier. Consequently, unlike in the case of the PLED memory element described above, there is no need for an additional terminal for a side gate which controls the charge transmission. In other words, by virtue of the fact that the charge transmission of the tunnel barrier arrangement is controlled via the source line, it suffices, in the case of the invention's construction of the semiconductor memory element, to provide, for operation, a source line, a data line and a word line to which different voltages can be applied in each case for writing, reading and erasing. The semiconductor memory element according to one embodiment of the invention thus has a 3-terminal arrangement and, on account of the associated narrower construction, is better suited in particular to ULSI applications than a 4-terminal arrangement, as represented e.g. by the PLED memory element described above. At the same time, the semiconductor memory element according to the invention manages with significantly lower write voltages than, for instance, the abovementioned “crested barrier” memory element. The tunnel barrier arrangement in one embodiment has a layer stack with an alternating layer sequence of semiconducting and insulating layers for the purpose of forming a multiple tunnel barrier. In this case, the source line extends from the source region parallel to the stack direction of the layer stack of the multiple tunnel barrier. The source line additionally has doped polysilicon. As an alternative, the source line may have metal of aluminium, copper, or titanium nitride. In accordance with one embodiment, the semiconducting layers of the layer stack have undoped polysilicon, and the insulating layers have silicon nitride or silicon dioxide. In this case, the semiconducting layers may have a thickness in the range of typically 10 to 100 nm, and more specifically, in the range of 30 to 50 nm. The insulating layers may have a thickness in the range of typically 2 to 10 nm, and more specifically, in the range of 2 to 6 nm. As an alternative, the semiconducting layers may also have amorphous silicon. The tunnel barrier arrangement may be electrically connected to a word line on its side remote from the floating gate, by means of which word line a voltage pulse can be applied via the tunnel barrier arrangement to the floating gate for the purpose of charging the latter and for the purpose of inverting the channel between source region and drain region. In a semiconductor memory element arrangement according to one embodiment of the invention, a plurality of semiconductor memory elements according to the invention are arranged in a matrix-like manner in a plurality of rows and columns, the semiconductor memory elements belonging to a column having a common source line which is electrically conductively connected to the source regions of said semiconductor memory elements and via which the charge transmission of the tunnel barrier arrangements belonging to said semiconductor memory elements can be controlled. In this case, the source line respectively assigned to a semiconductor memory element in a row may form a bit line of a semiconductor memory element that is adjacent in the same row. In this way, it is possible to realize particularly high storage densities of 4×f 2 (f=“minimum feature size”). However, it is also possible for a common source line to be assigned in each case to two semiconductor memory elements that are arranged adjacent in the same row. In this case, the source line is arranged symmetrically, i.e. at the same distance with respect to the layer stacks that are adjacent on the left and right of the source line, for forming the tunnel barrier arrangement, as a result of which the fabrication process of the semiconductor memory element arrangement is simplified. A method for fabricating a semiconductor memory element in accordance with one embodiment of the invention has the following steps: formation of at least one source region and at least one drain region in a substrate; formation of a floating gate that is electrically insulated from the substrate; formation of a tunnel barrier arrangement, via which electrical charge can be fed to the floating gate or dissipated from the latter, it being possible to alter the conductivity of a channel between the source and drain regions by charging or discharging the floating gate; and a source line that is electrically conductively connected to the source region and serves for controlling the charge transmission of the tunnel barrier arrangement being formed adjacent to the tunnel barrier arrangement. In one embodiment, the tunnel barrier arrangement is formed as a layer stack with an alternating layer sequence of semiconducting and insulating layers for the purpose of forming a multiple tunnel barrier. The source line is formed from the source region parallel to the stack direction of the layer stack of the multiple tunnel barrier. In one embodiment, the step of formation of a source line that is electrically conductively connected to the source region has the following steps: application of a first semiconducting layer on an insulating layer that covers the tunnel barrier arrangement and the source region; performance of a directional implantation for doping that region of the first semiconducting layer which is applied on the insulating layer that covers the multiple tunnel barrier; uncovering of the source region by partial removal of the first semiconducting layer that covers the source region and of the insulating layer; removal of the non-doped regions of the first semiconducting layer with the insulating layer being partially uncovered; and selective application of a second semiconducting layer to the source region and the doped region of the first semiconducting layer. In one embodiment, the first and second semiconducting layers are formed from polysilicon and the insulating layer is preferably formed from silicon dioxide (SiO 2 ) or silicon nitride (Si 3 N 4 ). In one method for operating a semiconductor memory element which has a substrate with at least one source region formed therein and at least one drain region formed therein, a floating gate electrically insulated from the substrate, and a tunnel barrier arrangement, electrical charge being fed to the floating gate or dissipated from the latter via the tunnel barrier arrangement, the conductivity of a channel between source and drain regions being altered by charging or discharging the floating gate, and the charge transmission of the tunnel barrier arrangement being controlled via a source line that is electrically conductively connected to the source region. In one embodiment of writing data to the semiconductor memory element, a voltage in the range of +(2-3) volts is applied to the source line and a voltage of at most ±1 volt is applied to a word line which is electrically connected to the tunnel barrier arrangement on its side remote from the floating gate. The voltage of +(2-3) volts present on the source line exponentially increases the transmission of the tunnel barrier arrangement formed by the layer stack and enables electrical charge to be fed to or dissipated from the floating gate and thus an inversion of the channel situated between source and drain regions. For reading data of the semiconductor memory element a voltage in the range of +(0.5-1) volt is applied to a bit line that is electrically conductively connected to the drain region; and a voltage in the range of +(3-5) volts is applied to a word line which is electrically connected to the tunnel barrier arrangement on its side remote from the floating gate. On account of the capacitive coupling, the voltage of +(3-5) volts present on the word line corresponds to a voltage of typically about +1.5 volts between floating gate and the channel between source region and drain region, so that the capacitive punch-through from the word line to the floating gate and the channel between source and drain regions suffices to put the read-out transistor into the on state. Consequently, when a low voltage of +(0.5-1) volt is applied to the bit line, depending on inverted or non-inverted state of the channel, a current flow is detected in the channel (corresponding to a “1” bit) or is not detected (corresponding to a “0” bit). Exemplary embodiments of the invention are illustrated in the figures and are explained in more detail below. |
Ethylenic copolymer and film comprising the same |
The ethylene base copolymer of the present invention having a density d falling in a range of 940 to 970 kg/m3, a polydispersion index PDI falling in a range of 25 to 50 and a long chain branch index LCBI falling in a range of 0.6 to 2.0 has a high impact strength and few fish eyes and is excellent in a high extruding characteristic, a high-speed moldability, a bubble stability and a tear strength in molding, and it can be produced via at least two steps of reaction by a slurry polymerization method using a Ziegler catalyst. |
1. An ethylene base copolymer having a density d falling in a range of 940 to 970 kg/m3, a polydispersion index PDI falling in a range of 25 to 50 and a creep distortion γ0 of 100% or less. 2. An ethylene base copolymer having a density d falling in a range of 940 to 970 kg/m3, a polydispersion index PDI falling in a range of 25 to 50 and a critical shear stress of 0.21 MPa or more. 3. An ethylene base copolymer having a density d falling in a range of 940 to 970 kg/m3, a polydispersion index PDI falling in a range of 25 to 50 and a long chain branch index LCBI falling in a range of 0.6 to 2.0. 4. An ethylene base copolymer having a density d falling in a range of 940 to 970 kg/m3, a polydispersion index PDI falling in a range of 25 to 50, a creep distortion γ0 of 100% or less, a critical shear stress of 0.21 MPa or more and a long chain branch index LCBI falling in a range of 0.6 to 2.0. 5. The ethylene base copolymer as described in claim 1, wherein a boiling hexane-soluble component amount is 1.0% by weight or less. 6. The ethylene base copolymer as described in claim 1, wherein a relation of an amount Y (% by weight) of a component having an elution temperature of 90° C. or lower obtained by a cross fractionation method and a molecular weight of 50,000 or more with a density d (kg/m3) satisfies the following equation: log Y≧56.80−0.0595d 7. A production process for the ethylene base copolymer as described in claim 1, wherein it is produced via at least two continuous steps by a slurry polymerization method using a Ziegler catalyst. 8. The production process for the ethylene base copolymer as described in claim 7, wherein it is produced by continuous polymerization of two or more kinds of polyethylenes, and polyethylene produced at the first step has a melting enthalpy ΔH of 200 J/g or more and a molecular weight distribution (weight average molecular weight Mw/number average molecular weight Mn) of 5 to 30. 9. The production process for the ethylene base copolymer as described in claim 7, wherein it is produced by introducing the powdery polyethylene resin obtained by polymerization into an extruding machine without being exposed even once to the air. 10. The production process for the ethylene base copolymer as described in claim 9, wherein the extruding machine is a double shaft screw extruding machine. 11. The production process for the ethylene base copolymer as described in claim 7, wherein an antioxidant is added to the powdery polyethylene resin in a proportion of 4000 ppm or less. 12. A film obtained by subjecting the ethylene base copolymer as described in claim 1 to inflation molding. 13. The ethylene base copolymer as described in claim 2, wherein a boiling hexane-soluble component amount is 1.0% by weight or less. 14. The ethylene base copolymer as described in claim 2, wherein a relation of an amount Y (% by weight) of a component having an elution temperature of 90° C. or lower obtained by a cross fractionation method and a molecular weight of 50,000 or more with a density d (kg/m3) satisfies the following equation: log Y≧56.80−0.0595d 15. A production process for the ethylene base copolymer as described in claim 2, wherein it is produced via at least two continuous steps by a slurry polymerization method using a Ziegler catalyst. 16. The production process for the ethylene base copolymer as described in claim 15, wherein it is produced by continuous polymerization of two or more kinds of polyethylenes, and polyethylene produced at the first step has a melting enthalpy ΔH of 200 J/g or more and a molecular weight distribution (weight average molecular weight Mw/number average molecular weight Mn) of 5 to 30. 17. The production process for the ethylene base copolymer as described in claim 15, wherein it is produced by introducing the powdery polyethylene resin obtained by polymerization into an extruding machine without being exposed even once to the air. 18. The production process for the ethylene base copolymer as described in claim 17, wherein the extruding machine is a double shaft screw extruding machine. 19. The production process for the ethylene base copolymer as described in claim 15, wherein an antioxidant is added to the powdery polyethylene resin in a proportion of 4000 ppm or less. 20. A film obtained by subjecting the ethylene base copolymer as described in claim 2 to inflation molding. 21. The ethylene base copolymer as described in claim 3, wherein a boiling hexane-soluble component amount is 1.0% by weight or less. 22. The ethylene base copolymer as described in claim 3, wherein a relation of an amount Y (% by weight) of a component having an elution temperature of 90° C. or lower obtained by a cross fractionation method and a molecular weight of 50,000 or more with a density d (kg/m3) satisfies the following equation: log Y≧56.80−0.0595d 23. A production process for the ethylene base copolymer as described in claim 3, wherein it is produced via at least two continuous steps by a slurry polymerization method using a Ziegler catalyst. 24. The production process for the ethylene base copolymer as described in claim 23, wherein it is produced by continuous polymerization of two or more kinds of polyethylenes, and polyethylene produced at the first step has a melting enthalpy ΔH of 200 J/g or more and a molecular weight distribution (weight average molecular weight Mw/number average molecular weight Mn) of 5 to 30. 25. The production process for the ethylene base copolymer as described in claim 23, wherein it is produced by introducing the powdery polyethylene resin obtained by polymerization into an extruding machine without being exposed even once to the air. 26. The production process for the ethylene base copolymer as described in claim 25, wherein the extruding machine is a double shaft screw extruding machine. 27. The production process for the ethylene base copolymer as described in claim 23, wherein an antioxidant is added to the powdery polyethylene resin in a proportion of 4000 ppm or less. 28. A film obtained by subjecting the ethylene base copolymer as described in claim 3 to inflation molding. 29. The ethylene base copolymer as described in claim 4, wherein a boiling hexane-soluble component amount is 1.0% by weight or less. 30. The ethylene base copolymer as described in claim 4, wherein a relation of an amount Y (% by weight) of a component having an elution temperature of 90° C. or lower obtained by a cross fractionation method and a molecular weight of 50,000 or more with a density d (kg/m3) satisfies the following equation: log Y≧56.80−0.0595d 31. A production process for the ethylene base copolymer as described in claim 4, wherein it is produced via at least two continuous steps by a slurry polymerization method using a Ziegler catalyst. 32. The production process for the ethylene base copolymer as described in claim 30, wherein it is produced by continuous polymerization of two or more kinds of polyethylenes, and polyethylene produced at the first step has a melting enthalpy ΔH of 200 J/g or more and a molecular weight distribution (weight average molecular weight Mw/number average molecular weight Mn) of 5 to 30. 33. The production process for the ethylene base copolymer as described in claim 30, wherein it is produced by introducing the powdery polyethylene resin obtained by polymerization into an extruding machine without being exposed even once to the air. 34. The production process for the ethylene base copolymer as described in claim 32, wherein the extruding machine is a double shaft screw extruding machine. 35. The production process for the ethylene base copolymer as described in claim 30, wherein an antioxidant is added to the powdery polyethylene resin in a proportion of 4000 ppm or less. 36. A film obtained by subjecting the ethylene base copolymer as described in claim 4 to inflation molding. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The present invention relates to an ethylene base copolymer suited for producing a film and a film comprising the same, more specifically to polyethylene for a film in which an impact strength is high and fish eyes (FE) are few and which is excellent in a high extruding characteristic, a high-speed moldability, a bubble stability and a tear strength in molding and the same film. |
Tetrazoyl oxime derivative and agricultural chemical containing the same as active ingredient |
The present invention provides a tetrazoyloxime derivative which is less likely to cause chemical injury to useful plants and is also superior in chemical efficacy to a conventional hetero ring-substituted oxime derivative. A tetrazoyloxime derivative represented by the general formula (1): X represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a cyano group, a methanesulfonyl group, a nitro group, a trifluoromethyl group, or an aryl group; A represents a 1-alkyltetrazoyl-5-yl group or a 5-alkyltetrazoyl-1-yl group; and Het represents a pyridyl group having a substituent or a thiazoyl group having a substituent, and a plant disease controlling agent containing the same as an active ingredient are disclosed. |
1. A tetrazoyloxime derivative represented by the general formula (1): wherein X represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a cyano group, a methanesulfonyl group, a nitro group, a trifluoromethyl group, or an aryl group; A represents a tetrazoyl group represented by the general formula (2): (wherein Y represents an alkyl group) or a tetrazoyl group represented by the general formula (3): (wherein Y represents an alkyl group); and Het represents a pyridyl group represented by the general formula (4): (wherein R represents a hydrogen atom or a halogen atom; Z represents a hydrogen atom, an amino group, the general formula QC(═O)NH— (Q represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with a halogen atom, a cycloalkyl group having 3 to 6 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, a cycloalkyloxy group having 3 to 6 carbon atoms, a benzyloxy group, a 2-phenylethyloxy group, a thioalkyl group substituted with an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 2 carbon atoms substituted with an alkoxyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with an acylamino group having 1 to 4 carbon atoms, an alkoxy group having 1 to 6 carbon atoms substituted with an acylamino group having 1 to 4 carbon atoms, an alkylamino group having 1 to 8 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an aralkyl group, or a phenyl group)), or a thiazoyl group represented by the general formula (5): (wherein R and Z are as defined in the general formula (4). 2. The tetrazoyloxime derivative according to claim 1, wherein Z is a group represented by the general formula: QC(═O)NH— (wherein Q represents an alkyl group having 1 to 8 carbon atoms or an alkoxyl group having 1 to 8 carbon atoms) and Het is a pyridyl group represented by the general formula (4). 3. The tetrazoyloxime derivative according to claim 2, wherein X is a hydrogen atom or a halogen atom. 4. The tetrazoyloxime derivative according to claim 2, wherein Y is a methyl group. 5. The tetrazoyloxime derivative according to claim 1, wherein Z is a group represented by the general formula: QC(═O)NH— (wherein Q represents an alkyl group having 1 to 8 carbon atoms or an alkoxyl group having 1 to 8 carbon atoms) and Het is a thiazoyl group represented by the general formula (5). 6. The tetrazoyloxime derivative according to claim 5, wherein X is a hydrogen atom or a halogen atom. 7. The tetrazoyloxime derivative according to claim 5, wherein Y is a methyl group. 8. A tetrazoylhydroxyimino derivative represented by the general formula (6): wherein X1 represents a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group; and Y1 represents an alkyl group. 9. A tetrazoylhydroxyimino derivative represented by the general formula (7): wherein X2 represents an alkyl group, an alkoxy group, a cyano group, a methanesulfonyl group, a nitro group, a trifluoromethyl group, or an aryl group; and Y2 represents an alkyl group. 10 (canceled): 11 (canceled): 12. The tetrazoyloxime derivative according to claim 3, wherein Y is a methyl group. 13. The tetrazoyloxime derivative according to claim 6, wherein Y is a methyl group. 14. An agricultural chemical comprising the tetrazoyloxime derivative of any one of claims 1 to 7 and 12 to 13 as an active ingredient. 15. A plant disease controlling agent comprising the tetrazoyloxime derivative of any one of claims 1 to 7 and 12 to 13 as an active ingredient. |
<SOH> BACKGROUND ART <EOH>Japanese Unexamined Patent Application, First Publication No. Hei 11-269176 (WO99/29689, EP-A-1038874) and Japanese Unexamined Patent Application, First Publication No. 2001-55387 (WO00/75138, EP-A-1184382) according to an invention of the present inventors disclose that hetero ring-substituted oxime derivatives act as plant disease controlling agents. Specifically, Japanese Unexamined Patent Application, First Publication No. Hei 11-269176 (WO99/29689, EP-A-1038874) discloses oxime derivatives represented by the general formula (A): wherein R 1 represents a hydrogen atom or a lower alkyl group; X represents a halogen atom, a nitro group, a hydroxy group, a cyano group, a carboxyl group, an alkoxycarbonyl group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfonyl group, an aryl group, an aryloxy group, or an amino group; n represents an integer of 0 to 3; Het A represents a six-membered nitrogen-containing aromatic ring having one or more nitrogen atoms, which may be substituted with one or more substituents selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkoxy group, a trifluoromethyl group and a cyano group, or a benzo condensed ring type nitrogen-containing aromatic ring; and Het B represents a group represented by an one of the ring structures of the general formula: the general formula: and the general formula: (wherein Y represents a hydrogen atom, a halogen atom, or a lower alkyl group). Also Japanese Unexamined Patent Application, First Publication No.2001-55387 (WO00/75138, EP-A-1184382) discloses oxime derivatives represented by the general formula (B): wherein Het A represents a group represented by any one of the following three formulas: (wherein Q represents a hydrogen atom, a halogen atom, or a lower alkyl group; R 1 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkenyl group, a lower alkynyl group, an aralkyl group, or an aryl group; and R 2 represents a hydrogen atom or a lower alkyl group); Het B represents a group represented by any one of the following nine formulas: (wherein Y represents a hydrogen atom or a lower alkyl group; and R 3 represents a hydrogen atom or a lower alkyl group); and Het C represents a group represented by any one of the following nine formulas: (wherein R 4 represents a hydrogen atom or a lower alkyl group; X represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a cyano group; Z represents a hydrogen atom, a halogen atom, or a lower alkyl group, and n represents an integer of 0 to 3). Although the respective compounds described in Japanese Unexamined Patent Application, First Publication No. Hei 11-269176 (WO99/29689, EP-A-1038874) and Japanese Unexamined Patent Application, First Publication No. 2001-55387 (WO00/75138, EP-A-1184382) exhibit considerable control activity, it is particularly necessary to develop chemicals which exert superior control activity. The document (Bull. Soc. Chim. Belg., Vol. 96, page 675, 1987) discloses only compounds similar to tetrazoylhydroxime derivatives represented by the general formula (7) described in claim 9 of the present invention, which are suited for use as an intermediate for synthesis of tetrazoyloxime derivatives described in claim 1 of the present invention, for example, compound of the general formula (7) X 2 is a hydrogen atom and Y 2 is a methyl group, compound wherein X 2 is a hydrogen atom and Y 2 is an isopropyl group, and compound wherein X 2 is a chlorine atom and Y 2 is a methyl group. These three compounds were synthesized during research for the purpose of elucidation of a reaction mechanism. The document does not disclose the utility of these compounds, for example, tetrazoyloxime derivatives represented by the general formula (1) described in claim 1 of the present invention can be synthesized by using the compounds and the compounds are suited for use as an intermediate for preparation of an agricultural chemical. |
Semiconductor manufacturing method and apparatus |
The present invention aims to provide processes and equipments for manufacturing semiconductors, according to which oxidation of wafer surfaces can be controlled by simple means and contaminants promoting oxidation and contaminants inviting a decreased yield of wafers can also be totally controlled. To achieve the object above, the present invention provides a process for manufacturing a semiconductor, characterized in that a substrate is treated while exposing the surface of the substrate with a negative ion-enriched gas; and an equipment for manufacturing a semiconductor comprising a gas channel through which a gas to be treated is passed; a negative ion-enriched gas generator consisting of a gas cleaner located at an upstream part of said gas channel and a negative ion generator located at a downstream part thereof: and means for supplying the resulting negative ion-enriched gas to the surface of each substrate. |
1-8. (canceled) 9. A process for manufacturing a semiconductor, comprising: treating a substrate while exposing a surface of the substrate with a negative ion-enriched gas. 10. The process of claim 9, wherein said negative ion-enriched gas is prepared by passing a clean gas freed of microparticles and/or chemical contaminant through a negative ion generator. 11. The process of claim 10, wherein said chemical contaminant is one or more selected from the group consisting of ionic components, inorganic matters, and organic matters. 12. The process of claim 10, wherein said negative ion-enriched gas is prepared by passing a gas having a microparticle concentration of class 100 or less, an ionic component concentration of 10 μg/m3 or less, and an organic matter concentration of 10 μg/m3 or less through a negative ion generator. 13. The process of claim 9, wherein the concentration of negative ions in said negative ion-enriched gas is 1,000 negative ions/mL or more. 14. The process of claim 9, wherein the concentration of negative ions in said negative ion-enriched gas is 5,000 negative ions/mL or more. 15. The process of claim 9, wherein the concentration of negative ions in said negative ion-enriched gas is 10,000 negative ions/mL or more. 16. The process of claim 9, wherein the concentration of negative ions in said negative ion-enriched gas is 50,000 negative ions/mL or more. 17. An equipment for manufacturing a semiconductor comprising: a gas channel through which a gas to be treated is passed; a negative ion-enriched gas generator including a gas cleaner located at an upstream part of said gas channel and a negative ion generator located at a downstream part of said gas channel; and means for supplying resulting negative ion-enriched gas to a surface of a substrate. 18. The equipment of claim 17, wherein said gas cleaner prepares a gas having a microparticle concentration of class 100 or less, an ionic component concentration of 10 μg/m3 or less, and an organic matter concentration of 10 μg/m3 or less. 19. The equipment of claim 17, wherein said negative ion-enriched gas generator prepares a negative ion-enriched gas having a negative ion concentration of 1,000 negative ions/mL or more. 20. The process of claim 17, wherein the concentration of negative ions in said negative ion-enriched gas is 5,000 negative ions/mL or more. 21. The process of claim 17, wherein the concentration of negative ions in said negative ion-enriched gas is 10,000 negative ions/mL or more. 22. The process of claim 17, wherein the concentration of negative ions in said negative ion-enriched gas is 50,000 negative ions/mL or more. |
<SOH> BACKGROUND ART <EOH>Air cleaning in the working environment Is very important for the manufacture of semiconductors, which normally takes place in an air-conditioned space called clean room. A conventional air cleaning technique in a semiconductor factory (clean room) is explained with reference to FIG. 8 . In FIG. 8 , ambient air 1 first passes through a prefilter 2 where coarse particles are eliminated and then the temperature and humidity are conditioned in an air conditioner 3 and then dusts are collected by a medium-performance filter 4 . Then, fine particles are collected by an HEPA filter 6 at the ceiling of a clean room 5 . Such an air cleaning system maintains a microparticle concentration of class 10,000 in the-clean room. In FIG. 8 , references 7 - 1 and 7 - 2 represent fans and arrows indicate air streams. The air cleaning system in conventional clean rooms for the purpose of removing microparticles is designed as shown in FIG. 8 and effective for removing microparticles but not effective for removing gaseous hazardous components. As improvements in the quality and precision of products increasingly advance in the recent semiconductor industry, not only microparticles (particulate substances) but also gaseous substances have come to participate in contamination of semiconductors. However, conventional dust filters for clean rooms (e.g., HEPA filters, ULPA filters, etc.) as shown in FIG. 8 can collect only microparticles, but gaseous hazardous components from ambient air are not collected and but introduced into clean rooms. Such gaseous hazardous components include e.g. gases called hydrocarbons (HCs) derived from automobile emissions and outgassing (gas release) from polymer resin products widely used as consumer products; and basic (alkaline) gases such as NH 3 and amine. Among them, hydrocarbons (HCs) must be completely eliminated because they cause pollution even at very low concentrations as gaseous hazardous components in normal air (indoor and outdoor air). Recently, outgassing from the materials of clean rooms or polymer resins of manufacturing equipments or appliances used has become a problem as a source of hydrocarbons (HCs). These gaseous substances in question also include those generated during operations in clean rooms. That is, typical clean rooms contain gaseous substances not only introduced from ambient air (those having passed through microparticle-collecting filters for clean rooms to enter the clean rooms) but also generated in the clean rooms so that they contain higher concentrations of gaseous substances than ambient air, which increase the possibility of contaminating semiconductor substrates. When microparticulate contaminants are deposited on the surfaces of semiconductor substrates, they cause breakage or short in circuits (patterns) on the substrate surfaces, resulting in failure. When gaseous hazardous components, especially hydrocarbons (HCs) are deposited on the surfaces of semiconductor substrates, they increase the contact angle to adversely affect e.g. substrate-resist affinity (compatibility). The lowered substrate-resist affinity adversely affects the film thickness of the resist or adhesion of the resist to the substrate. Hydrocarbons (HCs) also have the disadvantage that they deteriorate the pressure resistance of oxide films on the surfaces of semiconductor substrates (lowered reliability). The contact angle here means the contact angle of wetting with water and indicates the degree of contamination on substrate surfaces. That is, substrate surfaces stained with hydrophilic (oily) contaminants repel water and resist wetting. This increases the contact angle between the substrate surfaces and water drops. Thus, contamination is more serious at larger contact angles, while contamination is weaker at smaller contact angles. NH 3 causes production of ammonium salts or the like to invite haze (resolution failure) in semiconductor substrates. For these reasons, the productivity (yield) of semiconductor products Is lowered by not only microparticles but also gaseous contaminants as described above. Especially, the above gaseous substances as gaseous hazardous components are generated from the sources described above and more concentrated in clean rooms than ambient air so that they are deposited on substrates to contaminate their surfaces because air circulation is recently increased in clean rooms for saving energy. To address these contamination problems, we have previously proposed various space cleaning methods using photoelectrons or photocatalysts. For example, methods for removing microparticulate substances using photoelectrons are described in JP-B-HEI-3-5859, JP-B-HEI-6-74909, JP-B-HEI-8-211 and JP-B-HEI-7-121367. Methods for removing gaseous hazardous components using photocatalysts are described in Japanese Patent No. 2863419 and Japanese Patent No. 2991963. A method for removing microparticles and gaseous substances at the same time by combining photoelectrons and photocatalysts is described in Japanese Patent No. 2623290. It is thought that current Al wirings will not suffice for patterns on wafer surfaces of semiconductor products with higher quality (microfabricated products) in future and will be replaced by Cu wirings. Thus, it will be necessary in future to use Cu wirings and interlayer dielectrics with low dielectric constant (low-k) to shorten the delay because the combination of current Al wirings and SiO 2 dielectrics requires a long wiring delay under compact wiring-and design rules for future ultra large scale Integrated circuits (ULSIs). However, Cu materials are more susceptible to oxidation than conventional Al or W. Thus, it will be also important in future to controls gaseous substances, especially those oxidizing wafer surfaces (wiring surfaces and interfaces) though it was sufficient in the past to pay attention to removal of only microparticles in semiconductor manufacturing environments. Possible materials promoting oxidation of wafer surfaces include water (moisture) and organic matters (HCs) in clean room air, but it is difficult to control moisture present at about 45-50% (RH) in clean room air. This is because excessive reduction of moisture in the air adversely affects the health of operators working in the clean room. Thus, it would be desirable to provide a novel method for controlling (inhibiting) oxidation of wafer surfaces by controlling materials in clean rooms including moisture and HCs. In view of the circumstances described above, the present invention aims to provide processes and equipments for manufacturing semiconductors, according to which oxidation of wafer surfaces can be controlled by simple means and contaminants promoting oxidation and contaminants inviting a decreased yield of wafers can also be totally controlled. |
Aqueous dispersion comprising stable nonoparticles of a water-insoluble active and an excipient like middle chain triglycerides (mct) |
A process for the preparation of a stable dispersion of solid particles, in an aqueous medium comprising combining (a) a first solution comprising a substantially water-insoluble substance, a water-miscible organic solvent and an inhibitor with (b) an aqueous phase comprising water and optionally a stabiliser, thereby precipitating solid particles comprising the inhibitor and the substantially water-insoluble substance; and optionally removing the water-miscible organic solvent; wherein the inhibitor is a non-polymeric hydrophobic organic compound as defined in the description. The process provides a dispersion of solid particles in an aqueous medium, which particles exhibit reduced or substantially no particle growth mediated by Ostwald ripening. |
1. A process for the preparation of a stable dispersion of solid particles in an aqueous medium, the process comprising: combining (a) a first solution comprising a substantially water-insoluble substance, a water-miscible organic solvents and an inhibitor; with (b) an aqueous phase comprising water and optionally a stabiliser, thereby precipitating solid particles comprising the inhibitor and the substantially water-insoluble substance; and optionally removing the water-miscible organic solvent from the dispersion; wherein: (i) the inhibitor is a non-polymeric hydrophobic organic compound that is substantially insoluble in water; (ii) the inhibitor is less soluble in water than the substantially water-insoluble substance; and (iii) the inhibitor is not a phospholipid. 2. The process according to claim 1, wherein the substantially water-insoluble substance is a substantially water-insoluble pharmacologically active compound. 3. The process according to claim 1, wherein the inhibitor is a mixture of triglycerides obtainable by esterifying glycerol with a mixture of medium chain fatty acids. 4. The process according to claim 3, wherein the inhibitor is a mixture of triglycerides containing acyl groups with 8 to 12 carbon atoms. 5. The process according to claim 1, wherein the first solution further comprises a co-inhibitor which is a long chain aliphatic alcohol containing 6 or more carbon atoms. 6. The process according to claim 1, wherein the inhibitor is sufficiently miscible with the substantially water-insoluble substance to form solid particles in the dispersion, wherein the particles comprise a substantially single phase mixture of the substance and the inhibitor. 7. The process according to claim 1, wherein the miscibility of the inhibitor and the substantially water-insoluble substance is sufficient to give an interaction parameter, χ, of less than 2.5. 8. The process according to claim 1, wherein the aqueous phase contains a stabiliser. 9. The process according to claim 8 wherein the stabiliser comprises a polymeric dispersant and a surfactant. 10. A process according to claim 1 for the preparation of a stable dispersion of solid particles of a substantially water-insoluble pharmacologically active substance in an aqueous medium, the process comprising: combining (a) a first solution comprising the substantially water-insoluble pharmacologically active substance, a water-miscible organic solvent and an inhibitor; with (b) an aqueous phase comprising water and optionally a stabiliser; thereby precipitating solid particles comprising the inhibitor and the substantially water-insoluble pharmacologically active substance; and optionally removing the water-miscible organic solvent from the dispersion; wherein the inhibitor is less soluble in water than the pharmacologically active substance, and wherein the inhibitor is one or more substances selected from the group consisting of: (i) a mono-, di- or a tri-glyceride of a fatty acid; (ii) a fatty acid mono- or di-ester of a C2-10 diol; (iii) a fatty acid ester of an alkanol or a cycloalkanol; (iv) a wax; (v) a long chain aliphatic alcohol; and (vi) a hydrogenated vegetable oil. 11. The process according to claim 1, wherein the mean particle size of the solid particles is less than 1 μm. 12. The process according to claim 1, further comprising the step of isolating the solid particles from the dispersion. 13. A stable aqueous dispersion prepared according to any one of claims 1-12 or 20-22 wherein the dispersion comprises a continuous aqueous phase and solid particles dispersed in the continuous aqueous phase, wherein the solid particles comprise an inhibitor and a substantially water-insoluble substances and wherein: (i) the inhibitor is a non-polymeric hydrophobic organic compound that is substantially insoluble in water; (ii) the inhibitor is less soluble in water than the substantially water-insoluble substance; and (iii) the inhibitor is not a phospholipid. 14. A solid particle comprising an inhibitor and a substantially water-insoluble substance prepared by the process according to any one of claims 1-12 or 20-22. 15. The solid particle according to claim 14, wherein the substantially water-insoluble substance is a substantially water-insoluble pharmacologically active substance. 16. (Canceled) 17. A pharmaceutical formulation comprising the solid particle according to claim 15 in association with a pharmaceutically acceptable carrier or diluent. 18. A method for inhibiting Ostwald ripening in a dispersion of solid substantially water-insoluble particles in an aqueous medium the method comprising: combining (a) a first solution comprising a substantially water-insoluble substance, a water-miscible organic solvent, and an inhibitor; with (b) an aqueous phase comprising water and optionally a stabiliser, thereby precipitating solid particles comprising the inhibitor and the substantially water-insoluble substance to give a dispersion of the solid substantially water-insoluble particles in an aqueous medium; and optionally removing the water-miscible organic solvent from the dispersion; wherein: (i) the inhibitor is a non-polymeric hydrophobic organic compound that is substantially insoluble in water; (ii) the inhibitor is less soluble in water than the substantially water-insoluble substance; and (iii) the inhibitor is not a phospholipid. 19. (Canceled) 20. The process according to claim 10, wherein the mean particle size of the solid particles is less than 1 μm. 21. The process according to claim 10, further comprising the step of isolating the solid particles from the dispersion. 22. The process according to claim 1, wherein the first solution comprises two or more inhibitors. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a graph of the (mean particle diameter) 3 (nm 3 ) against time (minutes) for particles of felodipine prepared with and without the use of an inhibitor (Miglyol 812N). The open circles in FIG. 1 represent the felodipine particles prepared with the inhibitor (Miglyol 812N) and the solid circles felodipine particles prepared without an inhibitor. FIG. 1 clearly shows that the presence of the inhibitor eliminated Ostwald ripening in the felodipine particles and the particle size remains constant. Whereas the felodipine particles prepared without an inhibitor grew rapidly with time. detailed-description description="Detailed Description" end="lead"? |
Flexible connector module and modular system for measuring and transferring sensor signals |
The invention relates to a connector module for a measuring system, which connector module comprises:—a number of sensor connections placed mutually adjacently in a single row;—a connecting cable having at least one plug and connected to the sensor connections; wherein the sensor connections and at least a part of the connecting cable are embedded in a flexible material. The invention further relates to a modular system for measuring and transferring sensor signals to a monitor unit, which system comprises; —a basic module for connecting to the monitor unit; and at least one amplifier module for amplifying the sensor signals; wherein the modules are electrically connected to each other by means of a bus system. |
1-12. (cancelled). 13. A connector module for a measuring system, which connector module comprises: a) a number of sensor connections placed mutually adjacently in a single row; and b) a connecting cable having at least one plug and connected to the sensor connections, wherein the sensor connections and at least a part of the connecting cable are embedded in a flexible material. 14. The connector module as claimed in claim 13, comprising at least one amplifier arranged in the connector module. 15. The connector module as claimed in claim 13, comprising a modular system for measuring and transferring sensor signals to a monitor unit, which system comprises: a basic module for connecting to the monitor unit; and at least one amplifier module for amplifying the sensor signals, wherein the modules are electrically connected to each other by means of a bus system, and wherein the at least one plug is connected to the at least one amplifier module. 16. The connector module as claimed in claim 15, comprising a storage module connectable to the basic module for storing the measured sensor signals. 17. The connector module as claimed in claim 15, comprising a battery module connectable to the basic module to supply the modular system temporarily with power. 18.The connector module as claimed in claim 15, comprising a transfer module which can be connected to the basic module for wireless connection of the basic module to the monitor unit. 19. A modular system for measuring and transferring sensor signals to a monitor unit, which system comprises: a) a basic module for connecting to the monitor unit; and b) at least one amplifier module for amplifying the sensor signals, wherein the modules are electrically connected to each other by means of a bus system. 20. The modular system as claimed in claim 19, comprising a storage module connectable to the basic module for storing the measured sensor signals. 21. The modular system as claimed in claim 19, comprising a battery module connectable to the basic module to supply the modular system temporarily with power. 22. The modular system as claimed in claim 19, comprising a transfer module which can be connected to the basic module for wireless connection of the basic module to the monitor unit. 23. The modular system as claimed in claim 13, comprising at least one connector module for connecting each of the sensors individually to the system. 24. The modular system as claimed in claim 23, wherein the connector module comprises: c) a number of sensor connections placed mutually adjacently in a single row; and d) a connecting cable having at least one plug and connected to the sensor connections, wherein the sensor connections and at least a part of the connecting cable are embedded in a flexible material. 25. The modular system as claimed in claim 19, comprising at least one connector module for connecting each of the sensors individually to the system. 26. The modular system as claimed in claim 25, wherein the connector module comprises: c) a number of sensor connections placed mutually adjacently in a single row; and d) a connecting cable having at least one plug and connected to the sensor connections, wherein the sensor connections and at least a part of the connecting cable are embedded in a flexible material. |
Rigid track |
The invention relates to rigid track consisting of concrete, in particular of pre-cast concrete components, comprising a slab (1) with traversing fixing elements (4), or a plurality of fixing elements arranged thereon, of rails (3) for track-borne vehicles. The inventive rigid track is characterised in that a pre-cast concrete component constitutes a protuberance (5) that is positioned on the slab (1), parallel to at least one rail (3) and located on at least one side of the rail (3), to act as a guard and a guide for the vehicle during a derailment. |
1. A rigid track bed of concrete, in particular, of precast concrete components, with a slab (1) and with a continuous or a multiplicity of fastenings (4) for rails (3) to accommodate track guided vehicles, therein characterized, in that on the slab (1), parallel to least one rail (3) on at least one side of a rail (3) a curb (5) is placed as a precast concrete component for the protection of and for guidance during a derailment of the said vehicle. 2. A rigid track bed in accord with claim 1, therein characterized, in that the curb (5) acts as a uniform guide element for a derailed wheel (13′). 3. A rigid track bed in accord with one of the foregoing claims, therein characterized, in that the rail fastening (4) is installed at support points, especially at raised protuberances of the slab (1). 4. A rigid track bed in accord with one of the foregoing claims, therein characterized, in that the curb (5) is integrated in the slab (1). 5. A rigid track bed in accord with one of the foregoing claims, therein characterized, in that the curb (5) is located on that side of the rail (3) which is proximal to the centerline of the tracks. 6. A rigid track bed in accord with one of the foregoing claims, therein characterized, in that the curb (5) is furnished with at least one slot (10) extending transverse to the longitudinal axis of the slab (1). 7. A rigid track bed in accord with one of the foregoing claims, therein characterized, in that the slot (10) extends into the slab (1). 8. A rigid track bed in accord with one of the foregoing claims, therein characterized, in that the slot (10) is placed proximal to a fissure-blocking position (11) of the slab (1). 9. A rigid track bed in accord with one of the foregoing claims, therein characterized, in that the upper edge (6) of the curb (5) is above the upper edge (7) of the rail (3) by a distance of approximately 20 mm. 10. A rigid track bed in accord with one of the foregoing claims, therein characterized, in that the longitudinal side of the curb (5) proximal to the rail (3) has a separating distance from the top of said rail, which said distance corresponds to an appropriate space to accept a derailed wheel (13′) of a vehicle, wherein the said separating distance is about 180 mm. 11. A rigid track bed in accord with one of the foregoing claims, therein characterized, in that the curb (5) is made of high strength concrete. 12. A rigid track bed in accord with one of the foregoing claims, therein characterized, in that in the curb (5) metallic reinforcement is installed. 13. A rigid track bed in accord with one of the foregoing claims, therein characterized, in that the curb (5) is made of fiber reinforced concrete. 14. A rigid track bed in accord with one of the foregoing claims, therein characterized, in that the longitudinal side of the curb (5) proximal to the rail (3) possesses a structural metal member (15), especially an angle iron. 15. A rigid track bed in accord with one of the foregoing claims, therein characterized, in that the structural metal member (15) in the area of the slots (10) is interrupted. 16. A rigid track bed in accord with one of the foregoing claims, therein characterized, in that a structural metal member (15) can be fastened to effect a longitudinal prestress on the curb (5). 17. A rigid track bed in accord with one of the foregoing claims, therein characterized, in that rail fastening (4) is protected from damage by the curb (5). |
Low density fibre-reinforced cement composition |
A fibre-reinforced, low density cement system for the control of lost circulation during the drilling of subterranean wells, generally comprising a cement particle mixture having a specific granulometric characterization and alkaline resistant fibres, such as fibres composed of glass having a high zirconia concentration or organic fibres composed of a phenolic polymer or other polymeric system. |
1. A cement slurry having a density of 0.9 g/cm3 to 1.3 g/cm3, and comprising a solid fraction and a liquid fraction with a porosity (volume ratio of liquid fraction over solid fraction)of 38% to 50%, the solid fraction comprising: 60% to 90% (by volume) of lightweight particles having a mean size of 20 microns (μm) to 350 μm; 10% to 30% (by volume) of micro-cement having a mean particle diameter of 0.5 μm to 5 μm; 0% to 20% (by volume) of Portland cement, having particles with a mean diameter of 20 μm to 50 μm; 0% to 30% (by volume) of gypsum; and at least one alkali-resistant fibre present in an amount of less than 2% (by weight) and having a length of less than 6 cm and an aspect ratio of greater than 10. 2. A system as claimed in claim 1, wherein the fibres comprise glass having a high zirconia concentration or organic fibres composed of a phenolic polymer or other polymeric system. 3. A cement slurry as claimed in claim 1 or 2, wherein the porosity is less than 45%. 4. A cement slurry as claimed in claim 1, 2 or 3, wherein the lightweight particles have a density of less than 2 g/cm3. 5. A cement slurry as claimed in claim 4, wherein the lightweight particles have a density of less than 0.8 g/cm3. 6. A cement slurry as claimed in any preceding claim, wherein the lightweight material is selected from hollow microspheres, synthetic materials, ceramic microspheres, or beads of plastics material. 7. A slurry as claimed in any preceding claim, further comprising one or more additives including dispersants, antifreeze, water retainers, cement setting accelerators or retarders, and foam stabilizers. 8. A slurry as claimed in any preceding claim, wherein the fibres have a length of 2 mm to 6 cm and diameters of 6 microns to 200 microns. 9. A slurry as claimed in any preceding claim, wherein the fibres are added to the slurry at a concentration of 0.5 to 1.5 pounds of fibre per barrel of slurry 10. A method of controlling lost circulation in a well being drilled, comprising placing, adjacent a zone of lost circulation, a plug of a fibre-reinforced, low density cement system for the control of lost circulation during the drilling of subterranean wells, generally comprising a cement slurry having a density of 0.9 g/cm3 to 1.3 g/cm3, and comprising a solid fraction and a liquid fraction with a porosity (volume ratio of liquid fraction over solid fraction) of 38% to 50%, the solid fraction comprising: 60% to 90% (by volume) of lightweight particles having a mean size of 20 microns (μm) to 350 μm; 10% to 30% (by volume) of micro-cement having a mean particle diameter of 0.5 μm to 5 μm; 0% to 20% (by volume) of Portland cement, having particles with a mean diameter of 20 μm to 50 μm; 0% to 30% (by volume) of gypsum; and at least one alkali-resistant fibre present in an amount of less than 2% (by weight) and having a length of less than 6 cm and an aspect ratio of greater than 10. 11. A cement slurry having a density of 0.9 g/cm3 to 1.3 g/cm3, and comprising a solid fraction and a liquid fraction with a porosity (volume ratio of liquid fraction over solid fraction)of 38% to 50%, the solid fraction comprising: 60% to 90% (by volume) of lightweight particles having a mean size of 20 microns (μm) to 350 μm; 10% to 30% (by volume) of micro-cement having a mean particle diameter of 0.5 μm to 5 μm; 0% to 20% (by volume) of Portland cement, having particles with a mean diameter of 20 μm to 50 μm; 0% to 30% (by volume) of gypsum; and at least one alkali-resistant fibre present in an amount of less than 2% (by weight) and having a length of less than 6 cm and an aspect ratio of greater than 10. 12. A system as claimed in claim 11, wherein the fibres comprise glass having a high zirconia concentration or organic fibres composed of a phenolic polymer or other polymeric system. 13. A cement slurry as claimed in claim 11, wherein the porosity is less than 45%. 14. A cement slurry as claimed in claim 11, wherein the lightweight particles have a density of less than 2 g/cm3. 15. A cement slurry as claimed in claim 12, wherein the porosity is less than 45%. 16. A cement slurry as claimed in claim 15, wherein the lightweight particles have a density of less than 2 g/cm3. 17. A cement slurry as claimed in claim 11, wherein the lightweight particles have a density of less than 0.8 g/cm3. 18. A cement slurry as claimed in claim 11, wherein the lightweight material is selected from hollow microspheres, synthetic materials, ceramic microspheres, or beads of plastics material. 19. A slurry as claimed in claim 11, further comprising one or more additives including dispersants, antifreeze, water retainers, cement setting accelerators or retarders, and foam stabilizers. 20. A slurry as claimed in claim 11, wherein the fibres have a length of 2 mm to 6 cm and diameters of 6 microns to 200 microns. 21. A slurry as claimed in claim 11, wherein the fibres are added to the slurry at a concentration of 0.5 to 1.5 pounds of fibre per barrel of slurry. 22. A cement slurry having a density of 0.9 g/cm3 to 1.3 g/cm3, and comprising a solid fraction and a liquid fraction with a porosity (volume ratio of liquid fraction over solid fraction)of 38% to 50%, the solid fraction comprising: 60% to 90% (by volume) of lightweight particles having a mean size of 20 microns (Jum) to 350 μm; 10% to 30% (by volume) of micro-cement having a mean particle diameter of 0.5 μm to 5 μm; 0% to 20% (by volume) of Portland cement, having particles with a mean diameter of 20 μm to 50 μm; 0% to 30% (by volume) of gypsum; and at least one alkali-resistant fibre present in an amount of less than 2% (by weight) and having a length of less than 6 cm and an aspect ratio of greater than 10, wherein the fibres comprise glass having a high zirconia concentration or organic fibres composed of a phenolic polymer or other polymeric system. 23. A cement slurry as claimed in claim 22, wherein the porosity is less than 45%. 24. A cement slurry as claimed in claim 22, wherein the lightweight particles have a density of less than 2 g/cm3. 25. A cement slurry as claimed in claim 22, wherein the lightweight particles have a density of less than 0.8 g/cm3. 26. A cement slurry as claimed in claim 22, wherein the lightweight material is selected from hollow microspheres, synthetic materials, ceramic microspheres, or beads of plastics material. 27. A slurry as claimed in claim 22, further comprising one or more additives including dispersants, antifreeze, water retainers, cement setting accelerators or retarders, and foam stabilizers. 28. A slurry as claimed in claim 22, wherein the fibres have a length of 2 mm to 6 cm and diameters of 6 microns to 200 microns. 29. A slurry as claimed in claim 22, wherein the fibres are added to the slurry at a concentration of 0.5 to 1.5 pounds of fibre per barrel of slurry. 30. A method of controlling lost circulation in a well being drilled, comprising placing, adjacent a zone of lost circulation, a plug of a fibre-reinforced, low density cement system for the control of lost circulation during the drilling of subterranean wells, generally comprising a cement slurry having a density of 0.9 g/cm3 to 1.3 g/cm3, and comprising a solid fraction and a liquid fraction with a porosity (volume ratio of liquid fraction over solid fraction)of 38% to 50%, the solid fraction comprising: 60% to 90% (by volume) of lightweight particles having a mean size of 20 microns (μm) to 350 μm; 10% to 30% (by volume) of micro-cement having a mean particle diameter of 0.5 μm to 5 μm; 0% to 20% (by volume) of Portland cement, having particles with a mean diameter of 20 μm to 50 μm; 0% to 30% (by volume) of gypsum; and at least one alkali-resistant fibre present in an amount of less than 2% (by weight) and having a length of less than 6 cm and an aspect ratio of greater than 10. |
Device controller |
A device controller is used for controlling PCI devices or card devices on an add-inboard. To install multiple devices including a master device on the add-in board, and to build a multifunction PCI device or card device by smoothly controlling their operation, a device controller (1) is provided with a bus arbiter circuit (17) for handling bus mastering request from devices (D1-D8). The device controller causes the bus arbiter circuit (17) and a target detect circuit (16) to detect an initiator and a target, and a bus sequencer (2) to control signal issuing operation in a bus mastering cycle, for example, by an appropriate procedure based on the result of the detecting operation. An add-in board (30) is recognized as a single multifunction device. |
1. A device controller comprising: a communications control unit for controlling communications between a host device and multiple devices having their own functions which are provided on an add-in board connected to a PCI slot or a card bus slot of the host device; a storage unit for storing a relationship between the individual functions of the multiple devices and multiple functions allocated to the add-in board; a determination circuit for determining which one of the devices is the device which should become the destination of access in a configuration access based on the relationship stored in the storage unit when the configuration access is made from the host device to the add-in board; and a header information supply circuit for substituting information conforming to the operation of the add-in board for information not conforming to the operation of the add-in board among information on the configuration space headers in a configuration space of the device specified by the determination circuit as the destination of the configuration access and then supplying the substituted information to the host device. 2. The device controller according to claim 1 further comprising: an arbiter circuit which, upon detecting that a bus mastering request has been issued from one of the devices provided on the add-in board, issues a bus mastering request in place of the device to the host device and authorizes the bus mastering request from the device upon receiving authorization of the bus mastering request from the host device; wherein the communications control unit detects a master device and a target device in a bus cycle of the host device and the device and performs communications between the host device and the device by a procedure based on the result of the detecting operation. |
<SOH> BACKGROUND ART <EOH>A method generally used when extending functional capabilities of a PCI bus or a card bus is to plug in an add-in board on which a device having necessary functions is mounted into a slot, for example. This method has a drawback, however, in that add-in boards that can be added are limited by the number of slots provided in a host device. Particularly because the number of PCI slots and card bus slots provided on the host device, such as a personal computer, tends to be reduced recently, an alternative method has sometimes been used for achieving the aforementioned extension of the functional capabilities. This method has been to install a bridge like a PCI-PCI bridge on an add-in board to configure hierarchized buses so that a plurality of PCI devices, for example, can be connected to secondary buses. This approach has a problem, however, in that a large amount of circuitry is needed when a hierarchized bus structure is produced by adding a bridge like the PCI-PCI bridge on the add-in board. Another problem of this approach is that there is the need for software for controlling the bridge installed on the add-in board to ensure proper functioning of the add-in board. Among conventional techniques directed to the solution of this problem is the use of a PCI bridge device which reduces the amount of circuitry while complying with the PCI standards, as described in Japanese Laid-open Patent Publication No. H11-288400, for example. It has so far been said that it becomes possible with this kind of PCI bridge device to build a multifunction add-in board while achieving a reduction in the amount of circuitry as the PCI bridge device properly relays signals between primary and secondary sides. In the conventional techniques including the one described in Japanese Laid-open Patent Publication No. H11-288400, the only subject that is controllable by a PCI bridge device is a target device. Therefore, when a master device is connected to the secondary side of the PCI bridge device and this master device works as an initiator, for instance, there would arise a problem that an operational error could occur. This means that it has not been possible with prior art technology to realize a multifunction capability when the master device (initiator) is mounted on the PCI bridge device. Furthermore, as the PCI bridge device needs to acquire configuration information from individual devices on the secondary side and store that information in the PCI bridge device, there has been a problem that it is necessary to provide a separate storage unit in the bridge for storing all information on a configuration space including unused field information of the devices (e.g., base address space and interrupt pins), for instance. It is an object of the present invention to provide a device controller which makes it possible to build a multifunction PCI device or card device by installing a plurality of general-purpose devices including a master device while achieving as much a reduction as possible in the amount of circuitry and by smoothly controlling the operation of these general-purpose devices. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a diagram showing the configuration of an add-in board to which the present invention is applied; FIG. 2 is a diagram showing the configuration of a device controller according to the present embodiment; FIG. 3 is a flowchart showing an operating sequence of the device controller according to the present embodiment; FIG. 4 is a chart showing an example of device setup information; and FIG. 5 is a chart showing common signals and dedicated signals of this embodiment. detailed-description description="Detailed Description" end="lead"? |
Oral pharmaceutical composition containing a combination pparalpha and a hmg-coa reductase inhibitor |
Oral pharmaceutical composition containing, in the same pharmaceutical form, effective amounts of a HMG-CoA reductase inhibitor derivative and of a PPARa, especially fenofibrate. Also described is the use of some inactive ingredients which allow to improve the dissolution and/or bioavailability of the drugs from the said composition. |
1-33. cancelled 34. A pharmaceutical composition comprising in a same dosage form an effective amount of at least one peroxisome proliferator activated compound (PPARα), an effective amount of at least one HMG-CoA reductase inhibitor compound of the statin family, and at least one polyglycolized glyceride. 35. The pharmaceutical composition of claim 34, wherein the PPARα compound agent is contained in a semi-solid vehicle comprising at least least one polyglycolized glyceride, and the statin compound is formulated as a tablet, the formulations of both being filled into one single pharmaceutically acceptable capsule. 36. The pharmaceutical composition of claim 34, wherein the PPARα compound is contained in a semi-solid vehicle comprising at least least one polyglycolized glyceride, and the statin compound is formulated as a coated tablet, the formulations of both being filled into one single pharmaceutically acceptable capsule. 37. The pharmaceutical composition of claim 34, which comprises at least one hydrophilic disintegrating compound. 38. The pharmaceutical composition of claim 34, wherein the PPARα compound is a compound of the fibrate family. 39. The pharmaceutical composition of claim 34, wherein the PPARα compound is fenofibrate. 40. The pharmaceutical composition of claim 34, wherein the pharmaceutical composition is administered orally. 41. The pharmaceutical composition of claim 40, wherein the polyglycolised glyceride has an HLB balance above 10. 42. The pharmaceutical composition of claim 34, wherein the melting point of the composition is below 90° C. 43. The pharmaceutical composition of claim 34, containing at least one further compound selected from the group consisting of antioxidants and preservatives. 44. The pharmaceutical composition of claim 34, further comprising a vitamin E compound. 45. The pharmaceutical composition of claim 34, containing a methoxyphenol compound. 46. The pharmaceutical composition of claim 43, where a combination of a vitamin E compound and a methoxyphenol compound is used as antioxidant and preservative agent, respectively. 47. The pharmaceutical composition of claim 34, wherein the composition contains a wetting compound. 48. The pharmaceutical composition of claim 37, wherein the disintegrating compound is sodium starch glycolate. 49. The pharmaceutical composition of claim 37, wherein the at least one hydrophilic disintegrating compound selected from the group consisting of sodium croscarmellose, crospovidone, starch, and colloidal silicone dioxide. 50. The pharmaceutical composition of claim 34, further comprising polyethylene glycol. 51. The pharmaceutical composition of claim 34, further comprising a suspension stabilizer. 52. The pharmaceutical composition of claim 51, wherein the suspension stabilizer is a cellulose compound. 53. The pharmaceutical composition of claim 52, wherein the cellulose compound is hydropropylcellulose. 54. The pharmaceutical composition of claim 34, wherein the amount of PPARα compound per dose is between 30 and 400 mg, while the amount of statin per dose is between 5 and 100 mg. 55. The pharmaceutical composition of claim 35, wherein the pharmaceutically-acceptable capsule is selected from the group consisting of hard gelatin capsules, and hypromellose capsules. 56. The pharmaceutical composition of claim 36, wherein the pharmaceutically-acceptable capsule is selected from the group consisting of hard gelatin pharmaceutical capsules, and hypromellose capsule. 57. The pharmaceutical composition of claim 34, with the proviso that the PPARα compound is not co-micronized. 58. The pharmaceutical composition of claim 34, comprising at least one disintegrating compound, in which the weight ratio of PPAR α compound+statin/hydrophilic disintegrating agent is between 100 and 0.1. 59. The pharmaceutical composition of claim 35, in which the weight ratio of PPARα compound+statin agent/polyglycolized glyceride(s) is between 10 and 0.1. 60. The pharmaceutical composition of claim 34, wherein the at least one HMG-CoA reductase inhibitor compound of the statin family is selected from the group consisting of pravastatin, simvastatin, lovastatin, fluvastatin, atorvastatin and cerivastatin. simvastatin, lovastatin, pravastatin and mixtures thereof. 61. The pharmaceutical composition of claim 34, which further comprises a polyethyleneglycol compound. 62. The pharmaceutical composition of claim 34, which further comprises one or more antioxidant or preservative compounds, or both a polyethylene compound, and a hydrophilic wetting compound. 63. A method of treating hyperlipidemia or hypercholesterolemia or both in human in need thereof, which comprises administering orally substantially simultaneously, an effective amount of at least one peroxisome proliferator activated compound (PPARα), an effective amount of at least one HMG-CoA reductase inhibitor compound of the statin family, and at least one glyceride compound. 64. The method of claim 63, wherein the at least one glyceride compound is polyglycolized glyceride. 65. The method of claim 63, which further comprises administering at least one hydrophilic disintegrating compound. 66. The method of claim 63, wherein the PPARα compound is a compound of the fibrate family. 67. The method of claim 66, wherein the PPARα compound is selected from the group consisting of fenofibrate, cipofibrate, clofibrate, gemfibrate, bezafibrate and combination thereof. 68. The method of claim 63, wherein the PPARα compound is fenofibrate. 69. The method of claim 63, wherein at least one HMG-CoA reductase inhibitor compound of the statin family is selected from the group consisting of pravastatin, simvastatin, lovastatin, fluvastatin, atorvastatin and cerivastatin. simvastatin, lovastatin, pravastatin and mixtures thereof. 70. The pharmaceutical composition of claim 34, wherein the PPARα compound is a compound selected from the group consisting of fenofibrate, ciprofibrate, clofibrate, gemfibrozil, bezafibrate and mixtures thereof. 71. The pharmaceutical composition of claim 34, wherein the polyglycolized glyceride has an HLB balance above 11. 72. The pharmaceutical composition of claim 71, wherein the polyglycolized glyceride has an HLB balance above 12. 73. The pharmaceutical composition of claim 34, wherein the melting point of the composition is below 80° C. 74. The pharmaceutical composition of claim 34, wherein the melting point of the said composition is below 70° C. 75. The pharmaceutical composition of claim 34, further containing a mixture of polyethylene glycols having different molecular masses. 76. The pharmaceutical composition of claim 34, wherein the amount of PPARα compound per dose is between 30 and 400 mg, while the amount of statin per dose is between 5 and 100 mg, the amount of statin per dose being lower than the amount of PPARα compound per dose. 77. The pharmaceutical composition of claim 34, wherein the amount of PPARα compound per dose is between 30 and 400 mg, while the amount of statin per dose is between 5 and 100 mg, the amount of statin per dose being between 0.1 and 0.5 times the amount of PPARα compound per dose. 78. The pharmaceutical composition of claim 34, wherein the amount of fenofibrate per dose is between 30 and 400 mg, while the amount of statin per dose is between 5 and 100 mg. 79. The pharmaceutical composition of claim 34, wherein the amount of fenofibrate per dose is between 30 and 400 mg, while the amount of statin per dose is between 5 and 100 mg, the amount of statin per dose being preferably lower than the amount of fenofibrate per dose. 80. The pharmaceutical composition of claim 34, wherein the amount of fenofibrate per dose is between 30 and 400 mg, while the amount of statin per dose is between 5 and 100 mg, the amount of statin per dose being between 0.1 and 0.5 times the amount of fenofibrate per dose. 81. The pharmaceutical composition of claim 34, with the proviso that the PPARα compound is not co-micronized, and with the proviso that the statin is not co-micronized. 82. The pharmaceutical composition of claim 34, with the proviso that fenofibrate is not co-micronized, and with the proviso that the statin is not co-micronized. 83. The pharmaceutical composition of claim 34, comprising at least one disintegrating compound, in which the weight ratio PPARα compound+statin/hydrophilic disintegrating compound is between 50 and 2. 84. The pharmaceutical composition of claim 34, comprising at least one disintegrating compound, in which the weight ratio PPARα compound+statin/hydrophilic disintegrating compound is between 40 and 4. 85. The pharmaceutical composition of claim 34, comprising at least one disintegrating compound, in which the weight ratio PPARα compound+statin/hydrophilic disintegrating compound is between 6 and 25. 86. The pharmaceutical composition of claim 34, comprising at least one disintegrating compound, in which the weight ratio PPARα compound+statin/hydrophilic disintegrating compound is between 50 and 2. 87. The pharmaceutical composition of claim 34, comprising at least one disintegrating compound, in which the weight ratio PPARα compound+statin/hydrophilic disintegrating compound is between 40 and 4. 88. The pharmaceutical composition of claim 34, comprising at least one disintegrating compound, in which the weight ratio PPARα compound+statin/hydrophilic disintegrating compound is between 6 and 25. 89. The pharmaceutical composition of claim 34, in which the weight ratio PPARα compound+statin compound/polyglycolized glyceride(s) is between 5 and 0.2. 90. The pharmaceutical composition of claim 34, in which the weight ratio PPARα compound+statin compound/polyglycolized glyceride(s) is between 0.8 and 0.3. 91. The method of claim 63, wherein the PPARα compound is a compound selected from the group consisting of fenofibrate, ciprofibrate, clofibrate, gemfibrozil, bezafibrate and mixtures thereof. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Hypercholesterolaemia plays a crucial role in the development of atherosclerosis diseases in general and coronary heart disease in particular. The risk of progression of the atherosclerosis process to coronary heart diseases increases progressively with increasing levels of total serum cholesterol or low density lipoproteins (LDL) cholesterol at both the individual and the population level. The HMG-CoA reductase inhibitors are reversible inhibitors of the microsomal enzyme HMG-CoA reductase, which converts HMG-COA to mevalonate. This is an early rate-limiting step in cholesterol biosynthesis. Inhibition of HMG-CoA reductase by HMG-CoA reductase inhibitors decreases intracellular cholesterol biosynthesis, which then leads to transcriptionnally upregulated production of microsomal HMG-CoA reductase at cell surface LDL receptors. Subsequently, additional cholesterol is provided to the cell by de novo synthesis and by receptor-mediated uptake of LDL-cholesterol from the blood. This resets intracellular cholesterol homeostasis in extrahepatic tissues, but has little effect on the overall cholesterol balance (Clin. Pharmacokinet. 1997, May, 32(5), 403-425). The main HMG-COA reductase inhibitors currently used in therapeutics are: pravastatin, simvastatin, lovastatin, fluvastatin, atorvastatin and cerivastatin. simvastatin, lovastatin and pravastatin are derived from fungi (14,15). simvastatin reductase inhibitor is a clinically modified 2,2-dimethyl-butyrate analogue of lovastatin. Fibrates are old hypolipidemic drugs with pleitropic effects on lipid metabolism. Their intimate molecular mechanisms of action have been mysterious for a long time. Recently, it has been shown that the pharmacological effect of fibrates depends on their binding to “Peroxisome Proliferator Activated Receptor alpha” (PPAR alpha). The binding of fibrates to PPAR induces the activation of the inhibition of multiple genes involved in lipid metabolism through the binding of the activated PPAR alpha to “Peroxisome Proliferator Response Element” (PPRE) located in the gene promoters. Furthermore, it was recently demonstrated that fibrates are potent antiinflammatory molecules through an indirect modulation of the nuclear-factor-Kappa B activity. Fenofibrate or P-(4-chlorobenzoyl)-phenoxy isobutyrate isopropyl ester is useful for the treatment of adult patients with very high elevations of serum triglyceride levels and/or cholesterol levels. The usual daily dosage is 100 to 300 mg which is administered in two or three doses. Fenofibrate is absorbed as fenofibric acid which is responsible for the pharmacological activity. Fenofibric acid resulting from the hydrolysis of fenofibrate is extensively bound to plasma albumin. The plasma half-life is about 20 hours. Fenofibric acid is excreted predominantly in the urine, mainly as the glucuronide conjugate, but also as a reduced form of fenofibric acid and its glucuronides. It has been demonstrated that the combination of a HMG-CoA reductase inhibitor and fenofibrate (administered in two separate dosage forms) was better tolerated and as efficient as a higher dose of the HMG-CoA reductase inhibitor derivative. The main disadvantage of this double administration is that it complicates the posology for the patients and hence it increases the risk of mistakes or omissions in the intake of drugs. The patient's compliance is then decreased. Consequently, there is still a need for patients suffering from hypercholesterolemia and/or lipidemia to dispose of a pharmaceutical dosage form containing effective amounts of at least one HMG-CoA reductase inhibitor derivative and of fenofibrate and allowing to obtain a good bioavailability of both drugs. Some patents describing association of hypolipidemiant agents are already described. For instance, U.S. Pat. No. 6,180,660 describes methods for preventing or reducing the risk of a first occurrence of a cardiovascular event using an HMG-COA reductase inhibitor alone or in combination with another lipid altering agent. Subjects to be treated are those having an average serum total cholesterol level, an average to mildly elevated serum low-density lipoprotein cholesterol level, and a below average serum high-density lipoprotein cholesterol level, with no history of clinically evident coronary disease. The U.S. Pat. No. 6,264,938 relates to methods for treating hypercholesterolemia and atherosclerosis, and reducing serum cholesterol in a mammal. The methods of the invention comprise administering to a mammal a first amount of a bile acid sequestrant compound which is an unsubstituted polydiallylamine polymer and a second amount of an HMG CoA reductase inhibitor compound. The first and second amounts together comprise a therapeutically effective amount. The invention further relates to pharmaceutical compositions useful for the treatment of hypercholesterolemia and atherosclerosis, and for reducing cholesterol. The WO 01/37831 describes a pharmaceutical combination comprising separate dosage form in a common blister card of an inhibitor of the HMG-CoA reductase and a fibric acid derivative useful in the treatment at different ways of dyslipidemia of diabetics and non-diabetics. U.S. Pat. No. 5,545,628 describes an advantageous oral pharmaceutical composition containing fenofibrate while the patent PCT/BE 01/00098 describes an advantageous semi-solid oral pharmaceutical composition containing an HMG-CoA reductase. Not described is an oral semi-solid pharmaceutical composition containing, in the same pharmaceutical form, a combination of an effective amount of a HMG-CoA reductase inhibitor derivative together with an effective amount of a PPARa agent, especially fenofibrate. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention relates to an oral pharmaceutical composition, containing a combination of effective amounts of at least one HMG-CoA reductase inhibitor derivative and of PPARα agent, especially fenofibrate, in the same dosage form, allowing to obtain a high bioavailability of all drugs. The invention also relates to a process for manufacturing the same. detailed-description description="Detailed Description" end="lead"? |
Carboxylic acid derivative compounds and drugs comprising these compounds as the active ingredient |
A carboxylic acid derivative of formula (I): wherein R1 is —COOH, —COOR6, etc.; A is a single bond, alkylene, etc.; R2 is alkyl, alkoxy, etc.; B is a carbocyclic ring or a heterocyclic ring; Q is alkylnene-Cyc2, etc.; D is a linking chain; and R3 is alkyl, a carbocyclic ring or a heterocyclic ring, or a non-toxic salt thereof. The compound of formula (I) binds to PGE2 receptor, especially subtypes EP3 and/or EP4 and show the antagonizing activity, are useful for the prevention and/or treatment of diseases induced pain, itch, urticaria, allergy, urinary frequency, urinary disturbance, Alzheimer's disease, cancer, dysmenorrhea, endometriosis, etc. |
1. A carboxylic acid derivative of formula (I): wherein R1 is —COOH, —COOR4, —CH2OH, —CONR5SO2R6, —CONR7R8, —CH2NR5SO2R6, —CH2NR9COR10, —CH2NR9CONR5SO2R6, —CH2SO2NR9COR10, —CH2OCONR5SO2R6, tetrazole, 1,2,4-oxadiazol-5-one, 1,2,4-oxadiazol-5-thione, 1,2,4-thiadiazol-5-one, 1,3-thiazolidin-2,4-dione or 1,2,3,5-oxathiadiazol-2-one, R4 is C1-6 alkyl or —(C1-4 alkylene)-R11, R11 is hydroxy, C1-4 alkoxy, —COOH, C1-4 alkoxycarbonyl or —CONR7R8, R5 is hydrogen or C1-6 alkyl, R6 is (i) C1-6 alkyl, (ii) a C3-15 mono-, bi- or tri-carbocyclic ring or a 3- to 15-membered mono-, bi- or tri-heterocyclic ring which is substituted with 1-5 of R12 or unsubstituted, (iii) C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl substituted with a C3-15 mono-, bi- or tri-carbocyclic ring or a 3- to 15-membered mono-, bi- or tri-heterocyclic ring which is substituted with 1-5 of R12 or unsubstituted, R7 and R8 each independently, is (i) hydrogen, (ii) C1-6 alkyl, (iii) hydroxy, (iv) —COR17, (v) a C3-15 mono-, bi- or tri-carbocyclic ring or a 3- to 15-membered mono-, bi- or tri-heterocyclic ring which is substituted with 1-5 of R12 or unsubstituted, or (vi) C1-4 alkyl substituted with a C3-15 mono-, bi- or tri-carbocyclic ring or a 3- to 15-membered mono-, bi- or tri-heterocyclic ring which is substituted with 1-5 of R12 or unsubstituted, R9 is hydrogen or C1-6 alkyl, R10 is (i) hydrogen, (ii) C1-6 alkyl, (iii) a C3-15 mono-, bi- or tri-carbocyclic ring or a 3- to 15-membered mono-, bi- or tri-heterocyclic ring which is substituted with 1-5 of R12 or unsubstituted, or (iv) C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl substituted with a C3-15 mono-, bi- or tri-carbocyclic ring or a 3- to 15-membered mono-, bi- or tri-heterocyclic ring which is substituted with 1-5 of R12 or unsubstituted, R12 is (a) C1-6 alkyl, (b) C1-6 alkoxy, (c) C1-6 alkylthio, (d) halogen, (e) CF3, (f) cyano, (g) nitro, (h) hydroxy, (i) —COOR13, (j) —NHCOR13, (k) —SO2R14, (l) —NR15R16, (m) a C3-7 mono-carbocyclic ring which is substituted with C1-4 alkyl or oxo or unsubstituted, (n) a 3- to 7-membered mono-heterocyclic ring which is substituted with C1-4 alkyl or oxo or unsubstituted, or (o) C1-4 alkyl substituted with hydroxy, —COOR13, —NHCOR3, —SO2R14 or —NR15R16, R13 is hydrogen, C1-4 alkyl, phenyl, or phenyl-(C1-4) alkyl, R14 is C1-4 alkyl, R15 and R16 each independently, is hydrogen, C1-4 alkyl, phenyl, or phenyl-(C1-4) alkyl, R17 is C1-4 alkyl or phenyl, A is (i) a single bond, (ii) C1-6 alkylene, (iii) C2-6 alkenylene, (iv) C2-6 alkynylene, (v) —O—(C1-3 alkylene), (vi) —S—(C1-3 alkylene), (vii) —NR20—(C1-3 alkylene), (viii) —CONR21—(C1-3 alkylene), (ix) —(C1-3 alkylene)-O—(C1-3 alkylene), (x) —(C1-3 alkylene)-S—(C1-3 alkylene), (xi) —(C1-3 alkylene)-NR20—(C1-3 alkylene), (xii) —(C1-3 alkylene)-CONR21—(C1-3 alkylene), (xiii) -Cyc1, (xiv) —(C1-4 alkylene)-Cyc1 or (xv) -Cyc1-(C1-4 alkylene), the alkylene, alkenylene and alkynylene in A may be substituted with 1-6 of the following substituents of (a)-(i): (a) C1-6 alkyl, (b) C1-6 alkoxy, (c) halogen, (d) CHF2, (e) CF3, (f) OCHF2, (g) OCF3, (h) hydroxy, (i) hydroxy-(C1-4) alkyl, R20 is hydrogen, C1-4 alkyl, —SO2—(C1-4) alkyl or C2-5 acyl, R21 is hydrogen or C1-4 alkyl, Cyc1 is a C3-7 mono-carbocyclic ring or a 3- to 7-membered mono-heterocyclic ring which is substituted with 1-4 of C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C2-6 alkenyl, C2-6 alkynyl, halogen, CHF2, CF3, nitro or cyano, or unsubstituted, B ring is a C3-12 mono- or bi-carbocyclic ring or a 3- to 12-membered mono- or bi-heterocyclic ring, R2 is C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C2-6 alkenyl, C2-6 alkynyl, halogen, CHF2, CF3, nitro, cyano, phenyl or oxo, m is 0, 1 or 2, n is 1 or 2 when -D-R3 binds to B ring at the ortho position based on -A-R1, n is 0, 1 or 2 when -D-R3 binds to B ring at the non-ortho position based on -A-R1, Q is (1)(i) —(C1-4 alkylene, C2-4 alkenylene or C2-4 alkynylene)-Cyc2, (ii) —(C1-4 alkylene)-Z-Cyc3, (iii) C1-4 alkyl substituted with a substituent(s) selected from —NR24R25, —S(O)pR26, cyano, —NR23COR27, —NR23SO2R28 and —NR23CONR24R25, (iv) C1-4 alkoxy(C1-4) alkoxy, —NR23COR27, —COR28, —OSO2R28, —NR23SO2R28 or —NR23CONR24R25, (v) a C3-7 mono-carbocyclic ring or a 3- to 6-membered mono-heterocyclic ring which is substituted with 1-5 of R30, wherein one R30 of them always binds to the ring at the non 1-position, (vi) a C8-15 mono-, bi- or tri-carbocyclic ring or a 7- to 15-membered mono-, bi- or tri-heterocyclic ring which is substituted with 1-5 of R30 or unsubstituted, (vii) -T-Cyc5, (viii) -L-Cyc6-1, -L-(C3-6 cycloalkyl), -L-CH2—(C3-6 cycloalkyl), -L-(C2-4 alkylene)-Cyc6-2 or -L-(C1-4 alkylene)q-Cyc6-3, wherein the cycloalkyl is substituted with 1-5 of R30 or unsubstituted, (2)(i) phenoxy, (ii) benzyloxy, (iii) hydroxy(C1-4) alkyl, (iv) C1-4 alkoxy(C1-4) alkyl, or (v) —(C1-4 alkylene)-O-benzyl, or (3)(i) C2-6 alkenyl, (ii) C2-6 alkynyl, (iii) C1-6 alkyl substituted with 1-3 halogen(s), (iv) cyano, (v) nitro, (vi) —NR33R34, (vii) —CONR33R34, (viii) —S(O)p—(C1-4) alkynyl, (ix) —S(O)p—CHF2, (x) —S(O)p—NR33R34, (xi) —O—(C3-6) alkynyl, (xii) —O—CHF2, or (xiii) C3-7 cycloalkyl, R22 is hydrogen, C1-4 alkyl, —SO2—(C1-4) alkyl or C2-5 acyl, R23 is hydrogen, C1-4 alkyl, phenyl or phenyl(C1-4) alkyl, R24 and R25 each independently, is hydrogen, C1-4 alkyl, Cyc4 or (C1-4 alkylene)-Cyc4, R26 is C1-4 alkyl or Cyc4, R27 is hydrogen, C1-4 alkyl, —OR29 or Cyc4, R28 is C1-4 alkyl, Cyc4 or —(C1-4 alkylene)-Cyc4, R29 is hydrogen, C1-4 alkyl, Cyc4 or (C1-4 alkylene)-Cyc4, R30 is C1-8 alkyl, C1-8 alkoxy, C1-8 alkylthio, halogen, CF3, OCF3, SCF3, CHF2, SCHF2, hydroxy, cyano, nitro, —NR31R32, —CONR31R32, formyl, C2-5 acyl, hydroxy(C1-4) alkyl, C1-4 alkoxy(C1-4) alkyl, C1-4 alkylthio(C1-4) alkyl, —(C1-4 alkylene)-CONR31R32, —SO2(C1-4) alkyl, —NR23CO—(C1-4) alkyl, —NR23 SO2—(C1-4) alkyl, benzoyl, oxo, a C3-7 mono-carbocyclic ring, a 3- to 7-membered mono-heterocyclic ring, —(C1-4 alkylene)-NR31R32, -M-(C3-7 mono-carbocyclic ring), or -M-(3- to 7-membered mono-heterocyclic ring), the C3-7 mono-carbocyclic ring and 3- to 7-membered mono-heterocyclic ring in R30 may be substituted with 1-5 of the following substituents (a)-(l): (a) C1-6 alkyl, (b) C2-6 alkenyl, (c) C2-6 alkyl, (d) c1-6 alkoxy, (e) C1-6 alkylthio, (f) halogen, (g) CHF2, (h) CF3, (I) nitro, (j) cyano, (k) hydroxy, (l) amino; M is —O—, —S—, C1-4 alkylene, —O—(C1-4 alkylene)-, —S—(C1-4 alkylene)-, —(C1-4 alkylene)-O— or —(C1-4 alkylene)-S—, R31 and R32 each independently, is hydrogen or C1-4 alkyl, Cyc2 is a C3-15 mono-, bi- tri-carbocyclic ring or a 3- to 15-membered mono-, bi- tri-heterocyclic ring which is substituted with 1-5 of R30 or unsubstituted, Z is —O—, —S(O)p—, —NR22—, —NR23CO—, —NR23SO2—, —NR22—(C1-4 alkylene)-, —S(O)p—(C1-4 alkylene)-, —O—(C2-4 alkylene)-, —NR23CO—(C1-4 alkylene) or —NR23 SO2—(C1-4 alkylene), p is 0, 1 or 2, Cyc3 is a C3-15 mono-, bi- tri-carbocyclic ring or a 3- to 15-membered mono-, bi- tri-heterocyclic ring which is substituted with 1-5 of R30 or unsubstituted, Cyc4 is a C3-12 mono-, bi-carbocyclic ring or a 3- to 12-membered mono-, bi-heterocyclic ring which is substituted with 1-5 of R30 or unsubstituted, T is —O—, —NR22—, —O—(C1-4 alkylene)-, —S(O)p—(C1-4 alkylene)- or —NR22—(C1-4 alkylene)-, Cyc5 is a 3- to 15-membered mono-, bi- tri-heterocyclic ring which is substituted with 1-5 of R30 or unsubstituted, q is 0 or 1, L is —O— or —NR23—, Cyc6-1 is phenyl or benzyl which is substituted with one or more R30, Cyc6-2 is a C3-6 mono-carbocyclic ring which is substituted with 1-5 of R30 or unsubstituted, Cyc6-3 is a C7-15 mono-, bi- or tri-carbocyclic ring which is substituted with 1-5 of R30 or unsubstituted, R33 and R34 each independently, is hydrogen, C1-4 alkyl, phenyl or benzyl, or NR33R34 is a 3- to 6-membered mono-heterocyclic ring containing one nitrogen and optionally containing one hetero atom selected from nitrogen, oxygen and sulfur, D is (1) a 1- or 2-membered linking chain comprising an atom(s) selected from carbon, nitrogen, oxygen and sulfur, which may contain a double bond or a triple bond in the chain and may be substituted with 1-4 of R40, (2) a 3- to 6-membered linking chain comprising atoms selected from carbon, nitrogen, oxygen and sulfur, which may contain a double bond or a triple bond and may be substituted with 1-12 of R40, wherein R40 substituted on the atom bound to R3, and R42 which is a substituent of R3, taken together may form —(CH2)y—, in which y is 1-4, or (3) a 7- to 10-membered linking chain comprising atoms selected from carbon, nitrogen, oxygen and sulfur, which may contain a double bond or a triple bond and may be substituted with 1-20 of R40, wherein R40 substituted on the atom bound to R3, and R42 which is a substituent of R3, taken together may form —(CH2)y—, R40 is (a) C1-8 alkyl, (b) C2-8 alkenyl, (c) C2-8 alkynyl, (d) oxo, (e) halogen, (f) CF3, (g) hydroxy, (h) C1-6 alkoxy, (i) C2-6 alkenyloxy, (j) C2-6 alkynyloxy, (k) OCF3, (l) —S(O)p—(C1-6) alkyl, (m) —S(O)p—(C2-6) alkenyl, (n) —S(O)p—(C2-6) alkynyl, (o) C2-5 acyl, (p) Cyc9, (q) C1-4 alkoxy(C1-4) alkoxy, or (r) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with 1 or 2 of substituents selected from halogen, CF3, OCF3, hydroxy, cyano, C1-4 alkoxy, —S(O)p—(C1-6) alkyl, Cyc9 and C1-4 alkoxy(C1-4) alkoxy or two R40's taken together with the atom of a linking chain to which they bind, may form a C3-15 mono-, bi- or tri-carbocyclic ring or a 3- to 15-membered mono-, bi- or tri-heterocyclic ring containing 1-2 hetero atom(s) selected from O, S, SO2 and N, wherein the carbocyclic ring and the heterocyclic ring may be substituted with 1-3 substituent(s) selected from C1-4 alkyl, C1-4 alkoxy, C2-5 acyl, SO2(C1-4 alkyl), phenyl and phenyl(C1-4) alkyl, Cyc9 is a C3-6 mono-carbocyclic ring or a 3- to 6-membered mono-heterocyclic ring, which is substituted with 1-5 of R41 or unsubstituted, R41 is C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkoxy(C1-4) alkyl, halogen, CF3, OCF3, SCF3, hydroxy, cyano, formyl, C2-5 acyl, —SO2—(C1-4) alkyl, —NR23CO—(C1-4) alkyl, benzoyl or oxo, R3 is (1) C1-6 alkyl or (2) a C3-15 mono-, bi- or tri-carbocyclic ring or a 3- to 15-membered mono-, bi- or tri-heterocyclic ring which is substituted with 1-5 of R42 or unsubstituted, R42 is (a) C1-6 alkyl, (b) C1-6 alkoxy, (c) C1-6 alkylthio, (d) halogen, (e) cyano, (f) CF3, (g) CHF2, (h) OCF3, (i) OCHF2, (j) SCF3, (k) —NR43R44, (l) —SO2R45, (m) —NR46COR47, (n) hydroxy, (o) oxo, (p) C1-4 alkoxy(C1-4) alkyl, (q) Cyc10, (r) C1-6 alkylene-Cyc10, (s) —CO-Cyc10, (t) —W-Cyc10, (u) —(C1-6 alkylene)-W-Cyc10, (v) —W—(C1-6 alkylene)-Cyc10 or (w) —(C1-6 alkylene)-W—(C1-6 alkylene)-Cyc10, R43 and R44 each independently, is hydrogen or C1-4 alkyl, R45 is C1-4 alkyl, R46 is hydrogen or C1-4 alkyl, R47 is hydrogen or C1-4 alkyl, Cyc10 is a C3-12 mono- or bi-carbocyclic ring or a 3- to 12-membered mono- or bi-heterocyclic ring which is substituted with 1-5 of substitutes of the following (a)-(j) or unsubstituted, (a) C1-4 alkyl, (b) C2-5 acyl, (c) 1-4 alkoxy, (d) halogen, (e) hydroxy, (f) nitro, (g) cyano, (h) amine, (i) CF3, (j) OCF3, W is —O—, —S(O)p— or —NR48—, R48 is hydrogen or C1-4 alkyl; or a non-toxic salt thereof. 2. The compound according to claim 1, wherein, in formula (I), n is 1 or 2, Q is (1)(i) —(C1-4 alkylene, C2-4 alkenylene or C2-4 alkynylene)-Cyc2, (ii) —(C1-4 alkylene)-Z-Cyc3, (iii) C1-4 alkyl substituted with —NR24R25, —S(O)pR26, cyano, —NR23COR27, —NR23SO2R28 or —NR23CONR24R25, (iv) C1-4 alkoxy(C1-4) alkoxy, —NR23COR27, —COR28, —OSO2R28, —NR23SO2R28 or —NR23CONR24R25, (v) a C3-7 mono-carbocyclic ring or 3- to 6-membered mono-heterocyclic ring which is substituted with 1-5 of R30, wherein one R30 is always substituted on the ring at the non 1-position, (vi) a C8-15 mono-, bi- or tri-carbocyclic ring or 7- to 15-membered mono-, bi- or tri-heterocyclic ring which is substituted with 1-5 of R30 or unsubstituted, (vii) -T-Cyc5, (viii) -L-Cyc6-1, -L-(C2-4 alkylene)-Cyc6-2 or -L-(C1-4 alkylene)q-Cyc6-3, and D is (1) a 1- or 2-membered linking chain comprising an atom(s) selected from carbon, nitrogen, oxygen and sulfur, which may contain a double bond or a triple bond in the chain and may be substituted with 1-4 of R40, (2) a 3- to 6-membered linking chain comprising atoms selected from carbon, nitrogen, oxygen and sulfur, which may contain a double bond or a triple bond in the chain and may be substituted with 1-12 of R40, wherein R40 substituted on the atom bound to R3, and R42 which is a substituent of R3, taken together may form —(CH2)y—. 3. The compound according to claim 2, wherein D is (1) a 1- or 2-membered linking chain comprising an atom(s) selected from carbon, nitrogen, oxygen and sulfur, which may contain a double bond or a triple bond in the chain and may be substituted with 1-4 of R40. 4. The compound according to claim 2, wherein D is (2) a 3- to 6-membered linking chain comprising atoms selected from carbon, nitrogen, oxygen and sulfur, which may contain a double bond or a triple bond in the chain and may be substituted with 1-12 of R40, wherein R40 substituted on the atom bound to R3, and R42 which is a substituent of R3, taken together may form —(CH2)y—. 5. The compound according to claim 1, wherein, in formula (I), n is 1 or 2, Q is (2)(i) phenoxy, (ii) benzyloxy, (iii) hydroxy(C1-4) alkyl, (iv) C1-4 alkoxy(C1-4) alkyl, or (v) —(C1-4 alkylene)-O—(C1-4 alkylene)-Cyc7, and D is (2) a 3- to 6-membered linking chain comprising atoms selected from carbon, nitrogen, oxygen and sulfur, which may contain a double bond or a triple bond in the chain and may be substituted with 1-12 of R40, wherein R40 substituted on the atom bound to R3, and R42 which is a substituent of R3, taken together may form —(CH2)y—. 6. The compound according to claim 1, wherein, in formula (I), n is 1 or 2, Q is (3)(i) C2-6 alkenyl, (ii) C2-6 alkynyl, (iii) C1-6 alkyl substituted with 1-3 halogen(s), (iv) cyano, (v) nitro, (vi) —NR33R34, (vii) —CONR33R34, (viii) —S(O)p—(C2-4) alkynyl, (ix) —S(O)p—CHF2, (x) —S(O)p—NR33R34, (xi) —O—(C3-6) alkynyl, (xii) —O—CHF2, or (xiii) C3-7 cycloalkyl, and D is (1) a 1- or 2-membered linking chain comprising an atom(s) selected from carbon, nitrogen, oxygen and sulfur, which may contain a double bond or a triple bond in the chain and may be substituted with 1-4 of R40. 7. The compound according to claim 1, wherein, in formula (I), n is 0, and D is (1) a 1- or 2-membered linking chain comprising an atom(s) selected from carbon, nitrogen, oxygen and sulfur, which may contain a double bond or a triple bond in the chain and may be substituted with 1-4 of R40, (2) a 3- to 6-membered linking chain comprising atoms selected from carbon, nitrogen, oxygen and sulfur, which may contain a double bond or a triple bond in the chain and may be substituted with 1-12 of R40, wherein R40 substituted on the atom bound to R3, and R42 which is a substituent of R3, taken together may form —(CH2)y—. 8. The compound according to claim 1, wherein, in formula (I), n is 0, 1 or 2, Q is (1)(i) —(C1-4 alkylene, C2-4 alkenylene or C2-4 alkynylene)-Cyc2, (ii) —(C1-4 alkylene)-Z-Cyc3, (iii) C1-4 alkyl substituted with —NR24R25, —S(O)pR26, cyano, —NR23COR27, —NR23SO2R28 or —NR23CONR24R25, (iv) C1-4 alkoxy(C1-4) alkoxy, —NR23COR27, —COR28, —OSO2R28, —NR23SO2R28 or —NR23CONR24R25, (v) a C3-7 mono-carbocyclic ring or 3- to 6-membered mono-heterocyclic ring which is substituted with 1-5 of R30, wherein one R30 is always substituted on the rings at the non 1-position, (vi) a C8-15 mono-, bi- or tri-carbocyclic ring or 7- to 15-membered mono-, bi- or tri-heterocyclic ring which is substituted with 1-5 of R30 or unsubstituted, (vii) -T-Cyc5, (viii) -L-Cyc6-1, -L-(C2-4 alkylene)-Cyc6-2 or -L-(C1-4 alkylene)q-Cyc6-3, (2)(i) phenoxy, (ii) benzyloxy, (iii) hydroxy(C1-4) alkyl, (iv) C1-4 alkoxy(C1-4) alkyl, or (v) —(C1-4 alkylene)-O—(C1-4 alkylene)-Cyc7, or (3)(i) C2-6 alkenyl, (ii) C2-6 alkynyl, (iii) C1-6 alkyl substituted with 1-3 halogen(s), (iv) cyano, (v) nitro, (vi) —NR33R34, (vii) —CONR33R34, (viii) —S(O)p—(C1-4) alkynyl, (ix) —S(O)p—CHF2, (x) —S(O)p—NR33R34, (xi) —O—(C3-6) alkynyl, (xii) —O—CHF2, or (xiii) C3-7 cycloalkyl, and D is (3) a 7- to 10-membered linking chain comprising atoms selected from carbon, nitrogen, oxygen and sulfur, which may contain a double bond or a triple bond in the chain and may be substituted with 1-20 of R40, wherein R40 substituted on the atom bound to R3, and R42 which is a substituent of R3, taken together may form —(CH2)y—. 9. The compound according to the claim 3, which is selected from (1) (2E)-3-(2-(naphthalen-2-ylmethoxy)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (2) 3-(2-phenylsulfonylamino-4-phenoxymethylphenyl)propanoic acid, (3) (2E)-3-(2-(naphthalen-2-ylmethyl)-4-phenoxymethylphenyl)-2-propenoic acid, (4) (2E)-3-(2-(naphthalen-2-ylmethyl)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (5) (2E)-3-(2-benzyl-4-phenoxymethylphenyl)-2-propenoic acid, (6) 3-(2-(naphthalen-2-ylmethyl)-4-phenoxymethylphenyl)propanoic acid, (7) 3-(2-(naphthalen-2-ylmethyl)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (8) (2E)-N-phenylsulfonyl-3-(2-(naphthalen-2-ylmethyl)-4-phenoxymethylphenyl)-2-propenamide, (9) (2E)-N-(5-bromo-2-methoxyphenylsulfonyl)-3-(2-(naphthalen-2-ylmethyl)-4-phenoxymethylphenyl)-2-propenamide, (10) (2E)-N-phenylsulfonyl-3-(2-(naphthalen-2-ylmethyl)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenamide, (11) (2E)-N-(5-bromo-2-methoxyphenylsulfonyl)-3-(2-(naphthalen-2-ylmethyl)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenamide, (12) (2E)-N-(5-bromo-2-methoxyphenylsulfonyl)-3-(2-benzyl-4-(pyrazol-1-ylmethyl)phenyl)-2-propenamide, (13) (2E)-N-(5-bromo-2-methoxyphenylsulfonyl)-3-(2-benzyl-4-phenoxymethylphenyl)-2-propenamide, (14) N-(5-bromo-2-methoxyphenylsulfonyl)-3-(2-(naphthalen-2-ylmethyl)-4-phenoxymethylphenyl)propanamide, (15) N-(5-bromo-2-methoxyphenylsulfonyl)-3-(2-(naphthalen-2-ylmethyl)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (16) 2-(5-(pyrazol-1-ylmethyl)-2-(naphthalen-2-ylmethyl)isoindolin-3-one-1-yl)acetic acid, (17) 2-(5-phenoxymethyl-2-(naphthalen-2-ylmethyl)isoindolin-3-one-1-yl)acetic acid, (18) 2-(5-(4-cyanophenoxymethyl)-2-(naphthalen-2-ylmethyl)isoindolin-3-one-1-yl)acetic acid, (19) 2-(5-(pyrazol-1-ylmethyl)-2-(naphthalen-1-ylmethyl)isoindolin-3-one-1-yl)acetic acid, (20) 2-(5-phenoxymethyl-2-(3-methyl-1-phenylbutyl)isoindolin-3-one-1-yl)acetic acid, (21) N-(3,4-difluorophenylsulfonyl)-2-(5-(pyrazol-1-ylmethyl)-2-(naphthalen-1-ylmethyl)isoindolin-3-one-1-yl)acetamide, (22) N-(3,4-difluorophenylsulfonyl)-2-(5-phenoxymethyl-2-(3-methyl-1-phenylbutyl)isoindolin-3-one-1-yl)acetamide, (23) 3-(2-((3-methylbutyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (24) N-phenylsulfonyl-3-(2-((3-methylbutyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, methyl ester thereof, ethyl ester thereof or non-toxic salts thereof. 10. The compound according to the claim 4, which is selected from (1) (2E)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (2) (2E)-3-(2-(2-(2,5,7,8-tetramethyl-6-methoxychroman-2-yl)ethoxy)-4-(imidazol-1-ylmethyl)phenyl)-2-propenoic acid, (3) (2E)-3-(2-(2-(2,5,7,8-tetramethylchroman-2-yl)ethoxy)-4-(imidazol-1-ylmethyl)phenyl)-2-propenoic acid, (4) (2E)-3-(2-(2-(2,5,7,8-tetramethyl-6-hydroxychroman-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (5) (2E)-3-(2-(3-phenoxypropoxy)-4-(imidazol-1-ylmethyl)phenyl)-2-propenoic acid, (6) (2E)-3-(2-(4-phenoxybutoxy)-4-(imidazol-1-ylmethyl)phenyl)-2-propenoic acid, (7) (2E)-3-(2-(2-(chroman-2-yl)ethoxy)-4-(imidazol-1-ylmethyl)phenyl)-2-propenoic acid, (8) (2E)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(imidazol-1-ylmethyl)phenyl)-2-propenoic acid, (9) (2E)-3-(2-(2-(benzofuran-2-yl)ethoxy)-4-(imidazol-1-ylmethyl)phenyl)-2-propenoic acid, (10) (2E)-3-(2-(2-(2,5,7,8-tetramethyl-6-hydroxychroman-2-yl)ethoxy)-4-(2-methylimidazol-1-ylmethyl)phenyl)-2-propenoic acid, (11) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (12) (2E)-3-(2-(2-(2,5,7,8-tetramethyl-6-hydroxychroman-2-yl)ethoxy)-4-(2H-1,2,3-triazol-2-ylmethyl)phenyl)-2-propenoic acid, (13) (2E)-3-(2-(2-(2,5,7,8-tetramethyl-6-hydroxychroman-2-yl)ethoxy)-4-(1H-1,2,3-triazol-1-ylmethyl)phenyl)-2-propenoic acid, (14) (2E)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-benzylphenyl)-2-propenoic acid, (15) (2E)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(thiophen-2-ylmethyl)phenyl)-2-propenoic acid, (16) (2E)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(thiophen-3-ylmethyl)phenyl)-2-propenoic acid, (17) 4-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)butanoic acid, (18) (2E)-3-(2-(2-(naphthalen-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (19) (2E)-3-(2-(3-(naphthalen-2-yl)propoxy)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (20) (2E)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-phenoxymethylphenyl)-2-propenoic acid, (21) 2-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)acetic acid, (22) (2E)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(2-oxopyrrolidin-1-yl)phenyl)-2-propenoic acid, (23) 2-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenoxy)acetic acid, (24) (2E)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-dimethylaminomethylphenyl)-2-propenoic acid, (25) (2E)-3-(2-(2-phenylethoxy)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (26) (2E)-3-(2-(naphthalen-2-ylmethoxymethyl)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (27) (2E)-3-(2-((3E)-4-phenyl-3-butenyloxy)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (28) (2E)-3-(2-(2-hydroxy-3-phenoxypropoxy)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (29) (2E)-3-(2-(2-(1,4-benzodioxan-6-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (30) (2E)-3-(2-(2-(1,4-benzodioxan-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (31) (2E)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-cyanomethylphenyl)-2-propenoic acid, (32) (2E)-3-(2-(2-(naphthalen-2-yloxy)ethyl)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (33) (2E)-3-(2-(2-(N-benzoyl-N-methylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (34) (2E)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-phenylthiomethylphenyl)-2-propenoic acid, (35) (2E)-3-(2-(2-(benzoylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (36) (2E)-3-(2-(2-methoxy-3-phenoxypropoxy)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (37) (2E)-3-(2-(2-methoxy-2-(naphthalen-2-yl)ethoxy)-4-(pyrazol 1-ylmethyl)phenyl)-2-propenoic acid, (38) (2E)-3-(2-(pyrazol-1-ylmethyl)-3-(2-(naphthalen-2-yl)ethoxy)thiophen-4-yl)-2-propenoic acid, (39) (2E)-3-(3-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)thiophen-2-yl)-2-propenoic acid, (40) (2E)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(N-mesyl-N-phenylaminomethyl)phenyl)-2-propenoic acid, (41) (2E)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(N-acetyl-N-phenylaminomethyl)phenyl)-2-propenoic acid, (42) (2E)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(N-benzoyl-N-methylaminomethyl)phenyl)-2-propenoic acid, (43) (2E)-3-(2-(2-(naphthalen-2-yl)propoxy)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (44) 3-(2-((naphthalen-2-yl)carbonylmethoxy)-4-(pyrazole-1-methyl)phenyl)propanoic acid, (45) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrrol-1-ylmethyl)phenyl)propanoic acid, (46) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(4-methylpyrazol-1-ylmethyl)phenyl)propanoic acid, (47) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(3,5-dimethylpyrazol-1-ylmethyl)phenyl)propanoic acid, (48) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-phenylsulfonylmethylphenyl)propanoic acid, (49) 3-(2-(2-(1,1′-biphenyl-4-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (50) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-benzoylaminophenyl)propanoic acid, (51) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(N-benzoyl-N-methylamino)phenyl)propanoic acid, (52) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(N-mesyl-N-methylamino)phenyl)propanoic acid, (53) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-mesylaminophenyl)propanoic acid, (54) 3-(2-(2-(1,1′-biphenyl-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (55) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(benzimidazol-1-ylmethyl)phenyl)propanoic acid, (56) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(3-methyl-2-oxoimidazolidin-1-ylmethyl)phenyl)propanoic acid, (57) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(2-oxopyridin-1-ylmethyl)phenyl)propanoic acid, (58) 3-(2-(2-(1,1′-biphenyl-3-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (59) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-phenylsulfonylaminophenyl)propanoic acid, (60) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-acetylaminophenyl)propanoic acid, (61) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(2-methylpyridin-3-yloxymethyl)phenyl)propanoic acid, (62) 3-(2-(4-methyl-2-(naphthalen-1-yl)pentyloxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (63) 3-(2-(2-(benzothiophen-3-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (64) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyridin-3-yloxymethyl)phenyl)propanoic acid, (65) 3-(2-(2-(indol-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (66) 3-(2-(2-(1-methylindol-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (67) 3-(2-(2-(benzothiophen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (68) 3-(2-(2-(benzofuran-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (69) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(2-methylpyridin-5-yloxymethyl)phenyl)propanoic acid, (70) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyridin-2-yloxy)phenyl)propanoic acid, (71) 3-(2-(2-(naphthalen-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (72) 3-(2-(2-(chroman-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (73) 3-(2-(2-(1-methylindol-3-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (74) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(4-methylimidazol-1-ylmethyl)phenyl)propanoic acid, (75) 3-(2-(4-methyl-2-(naphthalen-2-yl)pentyloxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (76) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(2-cyanopyridin-3-yloxymethyl)phenyl)propanoic acid, (77) 3-(2-(2-methoxy-2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (78) 3-(2-(4-methyl-2-phenylpentyloxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (79) 3-(2-(4-methyl-2-phenylpentyloxy)-4-phenoxymethylphenyl)propanoic acid, (80) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-phenoxymethylphenyl)propanoic acid, (81) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-phenylaminomethylphenyl)propanoic acid, (82) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(N-phenyl-N-methylaminomethyl)phenyl)propanoic acid, (83) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(N-ethyl-N-phenylaminomethyl)phenyl)propanoic acid, (84) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(3-(pyrazol-1-yl)propyl)phenyl)propanoic acid, (85) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(2-chloro-5-methylphenoxymethyl)phenyl)propanoic acid, (86) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(3-cyanophenoxymethyl)phenyl)propanoic acid, (87) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(2-methoxyphenoxymethyl)phenyl)propanoic acid, (88) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(2-methylphenoxymethyl)phenyl)propanoic acid, (89) 3-(2-(2-phenylethoxy)-4-phenoxymethylphenyl)propanoic acid, (90) 3-(2-(2-phenylethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (91) 3-(2-(4-methyl-2-(3,5-dimethylphenyl)pentyloxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (92) 3-(2-(4-methyl-2-(4-fluoro-3-methylphenyl)pentyloxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (93) 2-(2-(2-phenylethoxy)-4-(pyrazol-1-ylmethyl)benzyl)benzoic acid, (94) 2-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)benzyl)benzoic acid, (95) 2-(2-(4-methyl-2-phenylpentyloxy)-4-(pyrazol-1-ylmethyl)benzyl)benzoic acid, (96) 2-(2-(4-methyl-2-(3,5-dimethylphenyl)pentyloxy)-4-(pyrazol-1-ylmethyl)benzyl)benzoic acid, (97) 3-(2-(4-methyl-2-(4-methoxy-1,3-dioxaindan-6-yl)pentyloxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (98) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(3-cyanophenylaminomethyl)phenyl)propanoic acid, (99) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(2-methylphenylaminomethyl)phenyl)propanoic acid, (100) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyridin-3-ylaminomethyl)phenyl)propanoic acid, (101) 3-(2-(2-(benzoylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (102) 3-(2-(2-(phenylsulfonylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (103) 3-(2-(2-(N-methyl-N-phenylsulfonylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (104) 3-(2-(2-methoxy-3-phenoxypropoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (105) 3-(2-(2-ethoxy-3-phenoxypropoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (106) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)-5-chlorophenyl)propanoic acid, (107) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)-5-methoxyphenyl)propanoic acid, (108) 3-(2-(2-(benzimidazol-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (109) 3-(2-(4-methyl-2-(4-fluoro-3-methylphenyl)pentyloxy)-4-(3-cyanophenoxymethyl)phenyl)propanoic acid, (110) 3-(2-(4-methyl-2-(4-fluoro-3-methylphenyl)pentyloxy)-4-phenoxymethylphenyl)propanoic acid, (111) 3-(2-(2-(2-methylbenzimidazol-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (112) 3-(2-(2-(1H-indazol-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (113) 3-(2-(2-(2H-benzotriazol-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (114) 3-(2-(2-(1H-benzotriazol-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (115) 3-(2-(2-((3-methylbenzoyl)amino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (116) 3-(2-(2-((3-methoxybenzoyl)amino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (117) 3-(2-(2-((naphthalen-2-ylcarbonyl)amino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (118) 3-(2-(2-((4-methoxybenzoyl)amino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (119) 3-(2-(2-((4-chlorobenzoyl)amino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (120) 3-(2-(4-methyl-2-benzoylaminopentyloxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (121) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(4-acetylpiperazin-1-ylmethyl)phenyl)propanoic acid, (122) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(morpholin-4-ylmethyl)phenyl)propanoic acid, (123) 3-(2-(2-(4-methylbenzoylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (124) 3-(2-(2-(naphthalen-1-ylcarbonylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (125) 3-(2-(2-(2-benzylcarbonylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (126) 3-(2-(2-(2-methylbenzoylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (127) 3-(2-(2-(2-chlorobenzoylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (128) 3-(2-(2-(2-methoxybenzoylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (129) 3-(2-phenylcarbamoylmethoxy-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (130) 3-(2-(naphthalen-1-ylcarbamoylmethoxy)-4-(pyrazol 1-ylmethyl)phenyl)propanoic acid, (131) 3-(2-(naphthalen-2-ylcarbamoylmethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (132) 3-(2-(3-phenylpropoxy)-4-phenoxymethylphenyl)propanoic acid, (133) 3-(2-(4-phenylbutoxy)-4-phenoxymethylphenyl)propanoic acid, (134) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(4-methylpiperazin 1-ylmethyl)phenyl)propanoic acid, (135) 2-((2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)benzyl)amino)acetic acid, (136) 2-(N-methyl-N-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)benzyl)amino)acetic acid, (137) 2-(N-mesyl-N-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)benzyl)amino)acetic acid, (138) 2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)benzoic acid, (139) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyridin-2-ylaminomethyl)phenyl)propanoic acid, (140) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(thiazol-2-ylaminomethyl)phenyl)propanoic acid, (141) 3-(2-(2-cyclohexyloxyethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (142) 3-(2-(benzylcarbamoylmethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (143) 3-(2-((1-phenylethyl)carbamoylmethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (144) 3-(2-(2-(3-chlorobenzoylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (145) 2-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)benzyloxy)acetic acid, (146) 3-(2-(2-(1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (147) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(2-(pyrazol-1-yl)ethyl)phenyl)propanoic acid, (148) 3-(2-(2-(thiophen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (149) 3-(2-(2-(thiophen-3-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (150) 3-(2-(3-cyclohexylpropoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (151) 3-(2-(2-phenoxyethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (152) 3-(2-(2-(N-methyl-N-phenylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (153) 3-(2-(2-phenylethoxy)-4-(3-cyanophenoxymethyl)phenyl)propanoic acid, (154) 3-(2-(2-phenylethoxy)-4-(2-chloro-4-methylphenoxymethyl)phenyl)propanoic acid, (155) 3-(2-(3-phenylpropoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (156) 3-(2-(4-phenylbutoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (157) (2E)-3-(2-(2-(2,5,7,8-tetramethyl-6-hydroxychroman-2-yl)ethoxy)-4-(imidazol-1-ylmethyl)phenyl)-2-propenoic acid, (158) 3-(2-(3,3-diphenylpropoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (159) 3-(2-(2-(N,N-diphenylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (160) 3-(2-(2-(4-phenylpiperazin-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (161) 3-(2-(2-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (162) 3-(2-(2-(4-phenylpiperidin-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (163) 3-(2-(2-(phenoxazin-10-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (164) 4-(2-(2-phenylethoxy)-4-(3-cyanophenoxymethyl)phenyl)butanoic acid, (165) 4-(2-(2-(naphthalen-2-yl)ethoxy)-4-(3-cyanophenoxymethyl)phenyl)butanoic acid, (166) 2-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)benzoylamino)acetic acid, (167) 3-(2-(2-(2-methylimidazol-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (168) 3-(2-(5-phenylpentyloxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (169) 3-(2-(3-(N-methyl-N-phenylamino)propoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (170) 3-(2-(2-(N-ethyl-N-phenylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (171) 3-(2-(2-(N-(2-hydroxyethyl)-N-phenylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (172) 3-(2-(2-(3-(piperidin-1-yl)phenyl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (173) 3-(2-(2-(3-(morpholin-4-yl)phenyl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (174) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propynoic acid, (175) 3-(2-(2-hydroxy-2-(naphthalen-2-yl)ethoxy)-4-(3-cyanophenoxymethyl)phenyl)propanoic acid, (176) 3-(2-(2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (177) 3-(2-(2-(9-methylcarbazol-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (178) 3-(2-(2-(3-(4-methylpiperazin-1-yl)phenyl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (179) 3-(2-(2-(3-(4-acetylpiperazin-1-yl)phenyl)ethoxy)-4-(pyrazol 1-ylmethyl)phenyl)propanoic acid, (180) 3-(2-(2-phenylaminoethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (181) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(N-acetyl-N-methylaminomethyl)phenyl)propanoic acid, (182) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(N-ethoxycarbonyl-N-methylaminomethyl)phenyl)propanoic acid, (183) 3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(2-methylphenoxymethyl)phenyl)propanoic acid, (184) (2E)-3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (185) 3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (186) (2E)-3-(2-((naphthalen-2-ylmethyl)carbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (187) (2E)-3-(2-(N-(naphthalen-2-ylmethyl)-N-methylcarbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (188) (2E)-3-(2-((naphthalen-2-ylmethyl)carbamoyl)-4-phenoxymethylphenyl)-2-propenoic acid, (189) (2E)-3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-phenoxymethylphenyl)-2-propenoic acid, (190) 3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (191) (2E)-3-(2-(1-(naphthalen-1-yl)ethyl)carbamoyl)-4-phenoxymethylphenyl)-2-propenoic acid, (192) 3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(2,5-dimethylphenoxymethyl)phenyl)propanoic acid, (193) 3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(2,5-dichlorophenoxymethyl)phenyl)propanoic acid, (194) 3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(2-chloro-5-methylphenoxymethyl)phenyl)propanoic acid, (195) 3-(2-((3-methyl-1-(naphthalen-1-yl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (196) 3-(2-((1-methyl-1-(naphthalen-1-yl)ethyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (197) 3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(2,6-dimethylphenoxymethyl)phenyl)propanoic acid, (198) 3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(2-chloro-6-methylphenoxymethyl)phenyl)propanoic acid, (199) 3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(3-cyanophenoxymethyl)phenyl)propanoic acid, (200) 3-(2-(((1R)-1-(naphthalen-1-yl)ethyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (201) 3-(2-((1-(naphthalen-1-yl)propyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (202) 3-(2-(((1S)-1-(naphthalen-1-yl)ethyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (203) 3-(2-((1-(naphthalen-2-yl)ethyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (204) 3-(2-((4-methoxynaphthalen-1-ylmethyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (205) 3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(2-methylthiophenoxymethyl)phenyl)propanoic acid, (206) 3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(2-mesylphenoxymethyl)phenyl)propanoic acid, (207) 4-(2-((3-methyl-1-(naphthalen-1-yl)butyl)carbamoyl)-4-phenoxymethylphenyl)butanoic acid, (208) 3-(2-((4-fluoronaphthalen-1-ylmethyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (209) 3-(2-((quinolin-4-ylmethyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (210) 3-(2-((3-methyl-1-(naphthalen-1-yl)butyl)carbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (211) 3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(2-cyanophenoxymethyl)phenyl)propanoic acid, (212) 3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(2-chlorophenoxymethyl)phenyl)propanoic acid, (213) 3-(2-((3-methyl-1-(naphthalen-1-yl)butyl)carbamoyl)-4-(pyridin-3-yloxymethyl)phenyl)propanoic acid, (214) 3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(2-formylphenoxymethyl)phenyl)propanoic acid, (215) 3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(2-hydroxymethylphenoxymethyl)phenyl)propanoic acid, (216) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (217) 3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(2-acetylaminophenoxymethyl)phenyl)propanoic acid, (218) 3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(2-methoxyphenoxymethyl)phenyl)propanoic acid, (219) 3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(2-methoxymethylphenoxymethyl)phenyl)propanoic acid, (220) 3-(2-((3-methyl-1-(4-methoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (221) 3-(2-(((1R)-1-(naphthalen-1-yl)ethyl)carbamoyl)-4-(pyridin-2-yloxy)phenyl)propanoic acid, (222) 3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (223) 3-(2-((3-methyl-1-(4-methylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (224) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(pyridin-3-yloxymethyl)phenyl)propanoic acid, (225) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(pyridin-4-yloxymethyl)phenyl)propanoic acid, (226) 3-(2-((1-phenylethyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (227) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(pyridin-2-yloxymethyl)phenyl)propanoic acid, (228) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-phenylaminomethylphenyl)propanoic acid, (229) 2-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-phenoxymethylphenoxy)acetic acid, (230) 3-(2-((1-phenylpropyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (231) 3-(2-((1-phenylbutyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (232) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(pyrimidin-2-yloxymethyl)phenyl)propanoic acid, (233) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(pyrazin-2-yloxymethyl)phenyl)propanoic acid, (234) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(2-methylpyridin-3-yloxymethyl)phenyl)propanoic acid, (235) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-phenylthiomethylphenyl)propanoic acid, (236) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(thiazol-2-ylthiomethyl)phenyl)propanoic acid, (237) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(1-methylimidazol-2-ylthiomethyl)phenyl)propanoic acid, (238) 3-(2-((2-cyclopropyl-1-phenylethyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (239) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(2-methylphenoxymethyl)phenyl)propanoic acid, (240) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(2-methoxyphenoxymethyl)phenyl)propanoic acid, (241) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(2-hydroxyphenoxymethyl)phenyl)propanoic acid, (242) 3-(2-((2-phenylethyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (243) 3-(2-benzylcarbamoyl-4-phenoxymethylphenyl)propanoic acid, (244) 3-(2-((3-methyl-1-phenyl-3-butenyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (245) 3-(2-phenylcarbamoyl-4-phenoxymethylphenyl)propanoic acid, (246) 3-(2-((3-methyl-1-(4-trifluoromethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (247) 3-(2-((3-methyl-1-(4-ethoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (248) 3-(2-((3-methyl-1-(3-methylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (249) 3-(2-((3-methyl-1-(3-chlorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (250) 3-(2-((3-methyl-1-(4-chlorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (251) 3-(2-((3-methyl-1-(3-trifluoromethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (252) 3-(2-((3-methyl-1-(3-chloro-4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (253) 3-(2-((3-methyl-1-(3-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (254) 3-(2-((3-methyl-1-(3,4,5-trifluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (255) 3-(2-((3-methyl-1-(3,5-ditrifluoromethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (256) 3-(2-((3-methyl-1-(3-methoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (257) 3-(2-((3-methyl-1-(4-ethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (258) 3-(2-((3-methyl-1-(4-butylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (259) 3-(2-((3-methyl-1-(4-fluoro-3-methylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (260) 3-(2-((3-methyl-1-(3-fluoro-4-methoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (261) 3-(2-((3-methyl-1-(3-fluoro-4-methylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (262) 3-(2-((3-methyl-1-(4-chloro-3-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (263) 3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-(2-methylphenoxymethyl)phenyl)propanoic acid, (264) 3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-(2-chlorophenoxymethyl)phenyl)propanoic acid, (265) 3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-(2-methoxyphenoxymethyl)phenyl)propanoic acid, (266) 3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-(3-cyanophenoxymethyl)phenyl)propanoic acid, (267) 3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-(2-chloro-5-methylphenoxymethyl)phenyl)propanoic acid, (268) 3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-(pyridin-3-yloxymethyl)phenyl)propanoic acid, (269) 3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (270) 3-(2-((3-methyl-1-(4-t-butylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (271) 3-(2-((3-methyl-1-(2-methoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (272) 3-(2-((3-methyl-1-(4-fluoro-2-methylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (273) 3-(2-((3-methyl-1-(3-ethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (274) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (275) 3-(2-((3-methyl-1-(3,5-dimethyl-4-methoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (276) 3-(2-((3-methyl-1-(5-methyl-2-methoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (277) 3-(2-((3-methyl-1-(4-propylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (278) 3-(2-((3-methyl-1-(3-trifluoromethoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (279) 3-(2-((3-methyl-1-(3-isopropylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (280) 3-(2-((3-methyl-1-(3-isopropyloxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (281) 3-(2-((3-methyl-1-(1,3-dioxaindan-5-yl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (282) 3-(2-((3-methyl-1-(4-propoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (283) 3-(2-((3-methyl-1-(2-fluoro-4-trifluoromethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (284) 3-(2-((3-methyl-1-(4-trifluoromethoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (285) 3-(2-((3-methyl-1-(2,5-dimethoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (286) 3-(2-((3-methyl-1-(1,4-benzodioxan-6-yl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (287) 3-(2-((3-methyl-1-(4-difluoromethoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (288) 3-(2-((3-methyl-1-(3,4,5-trimethoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (289) 3-(2-((3-methyl-1-(2-chloro-3,4-dimethoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (290) 3-(2-((3-methyl-1-(4-isobutylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (291) 3-(2-((3-methyl-1-(2-fluoro-5-trifluoromethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (292) 3-(2-((3-methyl-1-(2-chloro-6-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (293) 3-(2-((3-methyl-1-(2-chloro-5-trifluoromethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (294) 3-(2-((3-methyl-1-(2-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (295) 2-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(2-methylphenoxymethyl)phenoxy)acetic acid, (296) 2-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(2-methoxyphenoxymethyl)phenoxy)acetic acid, (297) 3-(2-((3-methyl-1-(4-acetylaminophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (298) 3-(2-((3-methyl-1-(3-fluoro-4-trifluoromethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (299) 3-(2-((3-methyl-1-(4,5-dimethoxy-2-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (300) 3-(2-((3-methyl-1-(2-fluoro-4-methoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (301) 3-(2-((3-methyl-1-(3,4-difluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (302) 3-(2-((3-methyl-1-(4-methoxy-1,3-dioxaindan-6-yl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (303) 3-(2-((3-methyl-1-(3-ethoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (304) 3-(2-((3-methyl-1-(4-trifluoromethylthiophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (305) 3-(2-((3-methyl-1-(2-difluoromethoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (306) 3-(2-((3-methyl-1-(2,3,5,6-tetrafluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (307) 3-(2-((3-methyl-1-(2-trifluoromethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (308) 3-(2-((3-methyl-1-(2,5-difluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (309) 3-(2-((3-methyl-1-(2-fluoro-5-methoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (310) 3-(2-((3-methyl-1-(3,4-dimethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (311) 3-(2-((3-methyl-1-(2,4-difluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (312) 3-(2-((3-methyl-1-(2,3,6-trifluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (313) 3-(2-((3-methyl-1-(4-chloro-2-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (314) 3-(2-((3-methyl-1-(2,4,5-trifluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (315) 3-(2-((3-methyl-1-(2,3-difluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (316) 3-(2-((3-methyl-1-(2-chloro-4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (317) 3-(2-((3-methyl-1-(2,4,6-trifluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (318) 3-(2-((3-methyl-1-(2,3-dimethoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (319) 3-(2-((3-methyl-1-(4-diethylaminophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (320) 3-(2-((3-methyl-1-(2,3,4,5,6-pentafluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (321) (2E)-3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-phenoxymethylphenyl)-2-propenoic acid, (322) 3-(2-((3-methyl-1-(4-mesylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (323) 3-(2-((3-methyl-1-(3-fluoro-2-methylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (324) 3-(2-((3-methyl-1-(2,3,4-trifluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (325) 3-(2-((3-methyl-1-(4-(pyrrolidin-1-yl)phenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (326) 3-(2-((3-methyl-1-(4-dimethylaminophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (327) 3-(2-((3-methyl-1-(4-dimethylamino-2-methoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (328) 3-(2-((3-methyl-1-(2,4-dimethoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (329) 3-(2-((3-methyl-1-(4-butoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (330) 3-(2-((3-methyl-1-(4-ethoxy-3-methoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (331) 3-(2-((3-methyl-1-(4-isopropyloxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (332) 3-(2-((3-methyl-1-(3,4-diethoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (333) 3-(2-((3-methyl-1-(2,3,4-trimethoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (334) 3-(2-((3-methyl-1-(2,4-dimethoxy-3-methylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (335) 3-(2-((3-methyl-1-(thiophen-2-yl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (336) 3-(2-((3-methyl-1-(2,4,5-trimethoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (337) 3-(2-((3-methyl-1-(3-methylthiophen-2-yl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (338) 3-(2-((3-methyl-1-(2,3-dimethyl-4-methoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (339) 3-(2-((3-methyl-1-(2,5-dimethyl-4-methoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (340) 3-(2-((3-methyl-1-(4-methoxy-3-methylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (341) 3-(2-((3-methyl-1-(5-methylfuran-2-yl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (342) 3-(2-((3-methyl-1-(2,4-diethoxy-3-methylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (343) 3-(2-((3-methyl-1-(1-methylpyrrol-2-yl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (344) 3-(2-((3-methyl-1-(4-ethylthiophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (345) 3-(2-((3-methyl-1-(3-trifluoromethylthiophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (346) 3-(2-((3-methyl-1-(4-methylthiophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (347) 3-(2-((3-methyl-1-(4-cyanophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (348) 3-(2-((3-methyl-1-(thiophen-3-yl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (349) 3-(2-((3-methyl-1-(2,5-dimethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (350) 3-(2-((3-methyl-1-(3,4-dimethoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (351) 3-(2-((3-methyl-1-(1,3-dioxaindan-4-yl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (352) 3-(2-(N-benzyl-N-methylcarbamoyl)-4-phenoxymethylphenyl)propanoic acid, (353) 3-(2-(N-benzyl-N-propylcarbamoyl)-4-phenoxymethylphenyl)propanoic acid, (354) 3-(2-((3-methyl-1-(3-fluoro-5-trifluoromethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (355) 3-(2-((3-methyl-1-(4-fluoro-2-trifluoromethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (356) 3-(2-((3-methyl-1-(2,4-dimethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (357) 3-(2-((3-methyl-1-(2,4-ditrifluoromethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (358) 3-(2-((3-methyl-1-(2-methylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (359) 3-(2-((3-methyl-1-(2,3-dimethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (360) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(furan-2-ylcarbonylaminomethyl)phenyl)propanoic acid, (361) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (362) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(2-phenylethyl)phenyl)propanoic acid, (363) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-cyanophenoxymethyl)phenyl)propanoic acid, (364) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-methylphenoxymethyl)phenyl)propanoic acid, (365) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-chloro-5-methylphenoxymethyl)phenyl)propanoic acid, (366) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(pyridin-3-yloxymethyl)phenyl)propanoic acid, (367) 3-(2-((3-methyl-1-(4-methoxy-1,3-dioxaindan-6-yl)butyl)carbamoyl)-4-(2-chloro-5-methylphenoxymethyl)phenyl)propanoic acid, (368) 3-(2-((3-methyl-1-(4-methoxy-1,3-dioxaindan-6-yl)butyl)carbamoyl)-4-(3-cyanophenoxymethyl)phenyl)propanoic acid, (369) 3-(2-((3-methyl-1-(4-methoxy-1,3-dioxaindan-6-yl)butyl)carbamoyl)-4-(2-methylphenoxymethyl)phenyl)propanoic acid, (370) 3-(2-((3-methyl-1-(3,5-dichlorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (371) 3-(2-((3-methyl-1-(3-chloro-5-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (372) 3-(2-((3-methyl-1-(4-fluoro-3-methylphenyl)butyl)carbamoyl)-4-(2-methylphenoxymethyl)phenyl)propanoic acid, (373) 3-(2-((3-methyl-1-(4-fluoro-3-methylphenyl)butyl)carbamoyl)-4-(2-chloro-5-methylphenoxymethyl)phenyl)propanoic acid, (374) 3-(2-((3-methyl-1-(3,5-difluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (375) 3-(2-((3-methyl-1-(3,5-dimethoxyphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (376) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(1-phenoxyethyl)phenyl)propanoic acid, (377) 3-(2-((2-methoxy-2-phenylethyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (378) 3-(2-((2-phenylpropyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (379) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(2-phenoxyethyl)phenyl)propanoic acid, (380) 3-(2-(3-phenylmorpholin-4-ylcarbonyl)-4-phenoxymethylphenyl)propanoic acid, (381) 3-(2-(4-phenoxypiperidin-1-ylcarbonyl)-4-phenoxymethylphenyl)propanoic acid, (382) 3-(2-((2-methoxy-1-(3,5-dimethylphenyl)ethyl)carbamoyl)-4-(2-chloro-5-methylphenoxymethyl)phenyl)propanoic acid, (383) 3-(2-((4-methyl-2-phenylpentyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (384) 3-(2-diphenylmethylcarbamoyl-4-phenoxymethylphenyl)propanoic acid, (385) 3-(2-((2-cyclopropyl-1-(3,5-dimethylphenyl)ethyl)carbamoyl)-4-(2-chloro-5-methylphenoxymethyl)phenyl)propanoic acid, (386) 3-(2-((1-(3,5-dimethylphenyl)ethyl)carbamoyl)-4-(2-chloro-5-methylphenoxymethyl)phenyl)propanoic acid, (387) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-phenoxymethyl-5-methoxyphenyl)propanoic acid, (388) 3-(2-((1-methyl-2-phenylethyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (389) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(benzothiazol-2-yl)phenyl)propanoic acid, (390) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(1,3-dioxaindan-2-yl)phenyl)propanoic acid, (391) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(indol-1-ylmethyl)phenyl)propanoic acid, (392) 3-(2-((4-methyl-1-phenylpentan-2-yl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (393) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-phenoxymethyl-5-methylphenyl)propanoic acid, (394) 3-(2-((naphthalen-2-ylmethyl)carbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (395) 3-(2-((3-methyl-1-phenylbutyl)sulfamoyl)-4-phenoxymethylphenyl)propanoic acid, (396) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (397) 3-(2-((3-methyl-1-(3,5-dimethoxyphenyl)butyl)carbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (398) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-3-methyl-4-phenoxymethylphenyl)propanoic acid, (399) 2-(2-(3-methyl-1-phenylbutyl)carbamoyl-4-phenoxymethylbenzyloxy)acetic acid, (400) 3-(2-((3-hydroxy-3-methyl-1-phenylbutyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (401) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-ethoxyphenoxymethyl)phenyl)butanoic acid, (402) (2E)-3-(2-((2-(naphthalen-2-yl)acetyl)amino)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (403) 2-(2-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-4-mesyloxybenzyl)benzoic acid, (404) 2-(2-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-4-acetylaminobenzyl)benzoic acid, (405) 2-(2-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-4-mesylaminobenzyl)benzoic acid, (406) 2-(2-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-4-(N-mesyl-N-methylamino)benzyl)benzoic acid, (407) 2-(2-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-4-(pyrazol-1-ylmethyl)benzyl)benzoic acid, (408) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-phenoxymethylphenyl)butanoic acid, (409) 2-(2-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-4-mesylmethylbenzyl)benzoic acid, (410) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-methylthiomethylphenyl)butanoic acid, (411) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-methylsulfinylmethylphenyl)butanoic acid, (412) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-mesylmethylphenyl)butanoic acid, (413) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-aminomethylphenyl)butanoic acid, (414) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-acetylaminomethylphenyl)butanoic acid, (415) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-mesylaminomethylphenyl)butanoic acid, (416) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(N-mesyl-N-methylaminomethyl)phenyl)butanoic acid, (417) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-benzoylaminophenyl)butanoic acid, (418) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-phenylsulfonylaminophenyl)butanoic acid, (419) 4-(2-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-4-phenoxymethylphenyl)butanoic acid, (420) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-oxopyridin-1-ylmethyl)phenyl)butanoic acid, (421) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(pyridin-3-yloxymethyl)phenyl)butanoic acid, (422) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-phenylthiomethylphenyl)butanoic acid, (423) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-phenylaminomethylphenyl)butanoic acid, (424) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-phenylsulfinylmethylphenyl)butanoic acid, (425) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-phenylsulfonylmethylphenyl)butanoic acid, (426) 3-(2-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-4-phenoxymethylphenyl)propanoic acid, (427) 4-(2-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-4-(pyrazol-1-ylmethyl)phenyl)butanoic acid, (428) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-benzoylaminomethylphenyl)butanoic acid, (429) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(pyridin-4-yloxymethyl)phenyl)butanoic acid, (430) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-phenoxyethyl)phenyl)butanoic acid, (431) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(pyridin-2-yloxymethyl)phenyl)butanoic acid, (432) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(N-methyl-N-phenylaminomethyl)phenyl)butanoic acid, (433) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(N-benzoyl-N-methylamino)phenyl)butanoic acid, (434) 4-(2-((2-(4-fluoronaphthalen-1-yl)propanoyl)amino)-4-phenoxymethylphenyl)butanoic acid, (435) 4-(2-((2-phenylpropanoyl)amino)-4-phenoxymethylphenyl)butanoic acid, (436) 3-(2-((4-methyl-2-phenylpentanoyl)amino)-4-phenoxymethylphenyl)propanoic acid, (437) 3-(2-((2-phenylpentanoyl)amino)-4-phenoxymethylphenyl)propanoic acid, (438) 3-(2-((2-phenylpropanoyl)amino)-4-phenoxymethylphenyl)propanoic acid, (439) 3-(2-((2-phenylbutanoyl)amino)-4-phenoxymethylphenyl)propanoic acid, (440) 4-(2-((2-phenylpropanoyl)amino)-4-phenylaminomethylphenyl)butanoic acid, (441) 4-(2-((2-phenylpropanoyl)amino)-4-benzoylaminomethylphenyl)butanoic acid, (442) 4-(2-((2-(4-fluoronaphthalen-1-yl)propanoyl)amino)-4-benzoylaminomethylphenyl)butanoic acid, (443) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-phenylsulfonylaminomethylphenyl)butanoic acid, (444) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-benzylaminomethylphenyl)butanoic acid, (445) 4-(2-((2-(4-fluoronaphthalen-1-yl)propanoyl)amino)-4-phenylaminomethylphenyl)butanoic acid, (446) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-cyanophenoxymethyl)phenyl)butanoic acid, (447) 4-(2-((2-(benzothiophen-3-yl)propanoyl)amino)-4-phenylaminomethylphenyl)butanoic acid, (448) 2-(2-((2-phenylpropanoyl)amino)-4-phenoxymethylbenzyl)benzoic acid, (449) 2-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-phenoxymethylbenzyl)benzoic acid, (450) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-ethoxycarbonylaminomethylphenyl)butanoic acid, (451) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(furan-2-ylcarbonylaminomethyl)phenyl)butanoic acid, (452) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-fluorobenzoylaminomethyl)phenyl)butanoic acid, (453) 3-(2-(N-benzylsulfonyl-N-methylamino)-4-phenoxymethylphenyl)propanoic acid, (454) (2E)-3-(2-(N-benzylsulfonyl-N-methylamino)-4-phenoxymethylphenyl)-2-propenoic acid, (455) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-methoxybenzoylaminomethyl)phenyl)butanoic acid, (456) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-cyclopropylcarbonylaminomethylphenyl)butanoic acid, (457) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(thiophen-2-ylcarbonylaminomethyl)phenyl)butanoic acid, (458) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-methylbenzoylaminomethyl)phenyl)butanoic acid, (459) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-chlorobenzoylaminomethyl)phenyl)butanoic acid, (460) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-cyanobenzoylaminomethyl)phenyl)butanoic acid, (461) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-fluorobenzoylaminomethyl)phenyl)butanoic acid, (462) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-fluorobenzoylaminomethyl)phenyl)butanoic acid, (463) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-chloro-4-fluorobenzoylaminomethyl)phenyl)butanoic acid, (464) 4-(2-((2-(2-chlorophenyl)propanoyl)amino)-4-phenoxymethylphenyl)butanoic acid, (465) 4-(2-((2-(3-chlorophenyl)propanoyl)amino)-4-phenoxymethylphenyl)butanoic acid, (466) 4-(2-((2-(4-chlorophenyl)propanoyl)amino)-4-phenoxymethylphenyl)butanoic acid, (467) 4-(2-((2-(4-fluorophenyl)propanoyl)amino)-4-phenoxymethylphenyl)butanoic acid, (468) 4-(2-((2-(4-methoxyphenyl)propanoyl)amino)-4-phenoxymethylphenyl)butanoic acid, (469) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-ethoxybenzoylaminomethyl)phenyl)butanoic acid, (470) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3,5-difluorobenzoylaminomethyl)phenyl)butanoic acid, (471) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-fluorophenoxymethyl)phenyl)butanoic acid, (472) 4-(2-((2-(4-methylphenyl)propanoyl)amino)-4-phenoxymethylphenyl)butanoic acid, (473) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-cyano-2-methoxyphenoxymethyl)phenyl)butanoic acid, (474) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-acetylphenoxymethyl)phenyl)butanoic acid, (475) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-isopropyl-5-methylphenoxymethyl)phenyl)butanoic acid, (476) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2,4,6-trifluorophenoxymethyl)phenyl)butanoic acid, (477) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-trifluoromethylthiophenoxymethyl)phenyl)butanoic acid, (478) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-bromophenoxymethyl)phenyl)butanoic acid, (479) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-methoxyphenoxymethyl)phenyl)butanoic acid, (480) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-methoxyphenoxymethyl)phenyl)butanoic acid, (481) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-methylbenzothiazol-5-yloxymethyl)phenyl)butanoic acid, (482) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-(1,2,4-triazol-1-yl)phenoxymethyl)phenyl)butanoic acid, (483) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-ethoxyphenoxymethyl)phenyl)butanoic acid, (484) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-methoxy-5-methylphenoxymethyl)phenyl)butanoic acid, (485) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3,5-dimethoxyphenoxymethyl)phenyl)butanoic acid, (486) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-fluoro-6-methoxyphenoxymethyl)phenyl)butanoic acid, (487) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-isopropyloxyphenoxymethyl)phenyl)butanoic acid, (488) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-acetyl-5-methoxyphenoxymethyl)phenyl)butanoic acid, (489) 2-(2-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-4-phenoxymethylbenzyl)benzoic acid, (490) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-chloro-4,5-dimethylphenoxymethyl)phenyl)butanoic acid, (491) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(1-oxo-1,2,3,4-tetrahydronaphthalen-6-yloxymethyl)phenyl)butanoic acid, (492) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-cyanophenoxymethyl)phenyl)butanoic acid, (493) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-chloro-5-methoxyphenoxymethyl)phenyl)butanoic acid, (494) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-ethyl-2-methoxyphenoxymethyl)phenyl)butanoic acid, (495) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-acetylamino-2-chlorophenoxymethyl)phenyl)butanoic acid, (496) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-methylthiophenoxymethyl)phenyl)butanoic acid, (497) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-butanoylphenoxymethyl)phenyl)butanoic acid, (498) (2E)-3-(2-((4-methyl-2-phenylpentanoyl)amino)-4-phenoxymethylphenyl)-2-propenoic acid, (499) 4-(2-((2-(4-fluoronaphthalen-1-yl)propanoyl)amino)-4-(pyrazol-1-ylmethyl)phenyl)butanoic acid, (500) 3-(2-((2-(4-fluoronaphthalen-1-yl)propanoyl)amino)-4-phenoxymethylphenyl)propanoic acid, (501) 3-(2-((2-(4-fluoronaphthalen-1-yl)propanoyl)amino)-4-phenylaminomethylphenyl)propanoic acid, (502) 3-(2-((2-(4-fluoronaphthalen-1-yl)propanoyl)amino)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (503) 2-(2-((2-(4-fluoronaphthalen-1-yl)acetyl)amino)-4-phenoxymethylbenzyl)benzoic acid, (504) 2-(2-((2-(4-fluoronaphthalen-1-yl)propanoyl)amino)-4-phenoxymethylbenzyl)benzoic acid, (505) 2-(2-((4-methyl-2-phenylpentanoyl)amino)-4-phenoxymethylbenzyl)benzoic acid, (506) 2-(2-((4-methyl-2-(3,5-dimethylphenyl)pentanoyl)amino)-4-phenoxymethylbenzyl)benzoic acid, (507) 2-(2-((2-(naphthalen-1-yl)acetyl)amino)-4-phenoxymethylbenzyl)benzoic acid, (508) 3-(2-((4-methyl-2-(4-fluoro-3-methylphenyl)pentanoyl)amino)-4-phenoxymethylphenyl)propanoic acid, (509) 3-(2-((4-methyl-2-(3,5-dimethylphenyl)pentanoyl)amino)-4-phenoxymethylphenyl)propanoic acid, (510) 3-(2-((4-methyl-2-(4-methoxy-1,3-dioxaindan-6-yl)pentanoyl)amino)-4-phenoxymethylphenyl)propanoic acid, (511) 2-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-methylphenoxymethyl)benzyl)benzoic acid, (512) 2-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-chloro-5-methylphenoxymethyl)benzyl)benzoic acid, (513) 2-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-cyanophenoxymethyl)benzyl)benzoic acid, (514) 2-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(pyridin-3-yloxymethyl)benzyl)benzoic acid, (515) (2E)-3-(2-(3-phenylpropyl)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid, (516) 2-(2-(3-(naphthalen-2-yl)propyl)-4-(pyrazol-1-ylmethyl)phenoxy)acetic acid, (517) N-mesyl-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (518) N-phenylsulfonyl-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (519) N-phenylsulfonyl-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (520) N-methyl-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (521) N-(pyridin-2-yl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (522) N-(4-trifluoromethylphenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (523) N-(naphthalen-2-ylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (524) N-(3-chloro-4-methylphenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (525) N-(4-ethylphenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (526) N-isopropylsulfonyl-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (527) N-(4-mesylphenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (528) N-((1,1′-biphenyl-4-yl)sulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (529) N-((1,1′-biphenyl-2-yl)sulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (530) N-(3,4-difluorophenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (531) N-(2,6-difluorophenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (532) N-(2,5-difluorophenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (533) N-(2,5-dimethoxyphenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (534) N-((E)-2-phenylethenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (535) N-(furan-2-ylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (536) N-(thiophen-2-ylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (537) N-(7-chlorobenzofurazan-4-ylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (538) N-(3,4-dichlorophenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (539) N-(4-methoxyphenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (540) N-(3-methylphenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (541) N-(2-fluorophenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (542) N-(4-cyanophenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (543) N-(3-cyanophenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (544) N-(2-chloro-4-cyanophenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (545) N-(3-methoxyphenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (546) N-(4-butoxyphenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (547) N-(4-fluorophenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (548) N-(2-chloro-6-methylphenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (549) N-(2-trifluoromethylphenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (550) N-(3-trifluoromethylphenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (551) N-(4-propylphenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (552) N-(4-isopropylphenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (553) N-(naphthalen-1-ylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (554) N-(4-butylphenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (555) N-(5-benzoylaminomethylthiophen-2-ylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (556) N-phenylsulfonyl-2-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-phenoxymethylphenoxy)acetamide, (557) N-phenylsulfonyl-2-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(2-methylphenoxymethyl)phenoxy)acetamide, (558) N-phenylsulfonyl-2-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(2-methoxyphenoxymethyl)phenoxy)acetamide, (559) N-(5-methylfuran-2-ylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (560) N-(thiophen-3-ylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (561) N-(furan-3-ylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (562) N-(1-methylpyrrol-2-ylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (563) N-(3,5-dimethylisoxazol-4-ylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (564) N-benzylsulfonyl-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (565) N-(5-dimethylaminonaphthalen-1-ylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (566) N-(4-acetylaminophenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (567) N-(4-chlorophenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (568) N-(2-methoxycarbonylphenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (569) N-(3-(3-methyl-5-oxopyrazol-1-yl)phenylsulfonyl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (570) N-(tetrazol-5-yl)-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (571) (2E)-N-phenylsulfonyl-3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-phenoxymethylphenyl)-2-propenamide, (572) N-(pyridin-2-yl)-3-(2-(4-methyl-2-phenylpentyloxy)-4-phenoxymethylphenyl)propanamide, (573) N-(tetrazol-5-yl)-3-(2-(4-methyl-2-phenylpentyloxy)-4-phenoxymethylphenyl)propanamide, (574) N-phenylsulfonyl-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-phenoxymethylphenyl)propanamide, (575) N-phenylsulfonyl-3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (576) N-(tetrazol-5-yl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (577) N-(tetrazol-5-yl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-phenoxymethylphenyl)propanamide, (578) N-phenylsulfonyl-3-(2-(2-phenylethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (579) N-(tetrazol-5-yl)-3-(2-(2-phenylethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (580) N-(5-bromo-2-methoxyphenylsulfonyl)-3-(2-(2-phenylethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (581) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (582) N-(7-chlorobenzofurazan-4-ylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (583) N-(3,4-dichlorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (584) N-(3-cyanophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (585) N-(3-chloro-4-methylphenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (586) N-(3-chloro-4-fluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (587) N-(5-bromo-2-methoxyphenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (588) N-(5-bromo-2-methoxyphenylsulfonyl)-3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (589) N-phenylsulfonyl-3-(2-(2-phenylethoxy)-4-phenoxymethylphenyl)propanamide, (590) N-(3-chloro-4-fluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(3-cyanophenoxymethyl)phenyl)propanamide, (591) N-(3-cyanophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(3-cyanophenoxymethyl)phenyl)propanamide, (592) N-(3,4-dichlorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(3-cyanophenoxymethyl)phenyl)propanamide, (593) N-(3-chloro-4-methylphenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(3-cyanophenoxymethyl)phenyl)propanamide, (594) N-(7-chlorobenzofurazan-4-ylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(3-cyanophenoxymethyl)phenyl)propanamide, (595) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(3-cyanophenoxymethyl)phenyl)propanamide, (596) N-(5-bromo-2-methoxyphenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(3-cyanophenoxymethyl)phenyl)propanamide, (597) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-phenylethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (598) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(benzimidazol-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (599) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(benzoylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (600) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(2H-benzotriazol-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (601) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(1H-benzotriazol-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (602) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(2-methylbenzimidazol-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (603) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(1H-indazol-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (604) (2E)-N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenamide, (605) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(4-methylpiperazin-1-ylmethyl)phenyl)propanamide, (606) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(4-acetylpiperazin-1-ylmethyl)phenyl)propanamide, (607) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(morpholin-4-ylmethyl)phenyl)propanamide, (608) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyridin-3-yloxymethyl)phenyl)propanamide, (609) N-phenylsulfonyl-2-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)acetamide, (610) N-phenylsulfonyl-4-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)butanamide, (611) N-(3,4-difluorophenylsulfonyl)-4-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)butanamide, (612) N-(pyridin-3-ylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol 1-ylmethyl)phenyl)propanamide, (613) N-(1-methylpyrrol-2-ylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (614) N-(4-methylthiazol-2-ylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (615) N-(3,5-dimethylisoxazol-4-ylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (616) N-(pyridin-2-ylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol 1-ylmethyl)phenyl)propanamide, (617) N-hydroxy-3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (618) N-(1-methyl imidazol-2-ylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (619) N-phenylsulfonyl-2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)benzamide, (620) N-(5-methylfuran-2-ylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (621) N-(furan-3-ylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol 1-ylmethyl)phenyl)propanamide, (622) N-(thiophen-3-ylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (623) N-(2,5-dimethoxyphenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (624) N-(4-methoxyphenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (625) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-cyclohexyloxyethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (626) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(piperidin-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (627) N-phenylsulfonyl-3-(2-(2-(3-methoxybenzoylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (628) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(3-methoxybenzoylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (629) N-(3,4-difluorophenylsulfonyl)-3-(3-(3-phenylpropoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (630) N-(3,4-difluorophenylsulfonyl)-3-(3-(3-(naphthalen-1-yl)propoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (631) N-phenylsulfonyl-3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (632) N-(3,4-difluorophenylsulfonyl)-3-(2-((naphthalen-1-ylmethyl)carbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (633) N-phenylsulfonyl-3-(2-((naphthalen-2-ylmethyl)carbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (634) N-(3,4-difluorophenylsulfonyl)-3-(2-((naphthalen-2-ylmethyl)carbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (635) N-phenylsulfonyl-3-(2-(benzylcarbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (636) N-(3,4-difluorophenylsulfonyl)-3-(2-(benzylcarbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (637) N-(3,4-difluorophenylsulfonyl)-3-(3-(3-(naphthalen-2-yl)propoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (638) N-phenylsulfonyl-3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (639) N-(3,4-difluorophenylsulfonyl)-3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (640) N-phenylsulfonyl-3-(2-((3-methyl-1-(3,5-dimethoxyphenyl)butyl)carbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (641) N-(3,4-difluorophenylsulfonyl)-3-(2-((3-methyl-1-(3,5-dimethoxyphenyl)butyl)carbamoyl)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (642) (2E)-N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(4-acetylpiperazin-1-ylmethyl)phenyl)-2-propenamide, (643) (2E)-N-phenylsulfonyl-3-(2-(N-benzylsulfonyl-N-methylamino)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenamide, (644) (2E)-N-(3,4-difluorophenylsulfonyl)-3-(2-(N-benzylsulfonyl-N-methylamino)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenamide, (645) N-(3,4-difluorophenylsulfonyl)-3-(2-((2-(naphthalen-1-yl)acetyl)amino)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (646) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(thiophen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (647) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(thiophen-3-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (648) N-(tetrazol-5-yl)-3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-chloro-5-methylphenoxymethyl)phenyl)propanamide, (649) N-(3,4-difluorophenylsulfonyl)-3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-chloro-5-methylphenoxymethyl)phenyl)propanamide, (650) N-(3,4-difluorophenylsulfonyl)-2-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)benzyloxy)acetamide, (651) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-dimethylaminomethylphenyl)propanamide, (652) N-(3,4-difluorophenylsulfonyl)-3-(2-(3-cyclohexylpropoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (653) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-phenoxyethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (654) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(3-methyl-2-oxoimidazolidin-1-ylmethyl)phenyl)propanamide, (655) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-benzoylaminophenyl)propanamide, (656) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-phenylsulfonylaminophenyl)propanamide, (657) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-mesylaminophenyl)propanamide, (658) N-(3,4-difluorophenylsulfonyl)-3-(2-(naphthalen-1-ylcarbamoylmethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (659) N-(3,4-difluorophenylsulfonyl)-3-(2-(benzylcarbamoylmethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (660) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(3-methylbenzoylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (661) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(3-chlorobenzoylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (662) N-(3,4-difluorophenylsulfonyl)-3-(2-(3-phenylpropoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (663) N-(3,4-difluorophenylsulfonyl)-3-(2-(4-phenylbutoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (664) (2E)-N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(2-oxopyrrolidin-1-ylmethyl)phenyl)-2-propenamide, (665) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(3-(piperidin-1-yl)phenyl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (666) (2E)-N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-cyanomethylphenyl)-2-propenamide, (667) N-(3,4-difluorophenylsulfonyl)-3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(morpholin-4-ylmethyl)phenyl)propanamide, (668) N-(3,4-difluorophenylsulfonyl)-3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-cyanophenoxymethyl)phenyl)propanamide, (669) N-(3,4-difluorophenylsulfonyl)-2-(2-(3-(naphthalen-2-yl)propyl)-4-(pyrazol-1-ylmethyl)phenoxy)acetamide, (670) (2E)-N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(thiophen-3-ylmethyl)phenyl)-2-propenamide, (671) (2E)-N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-benzylphenyl)-2-propenamide, (672) (2E)-N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(N-benzoyl-N-methylaminomethyl)phenyl)-2-propenamide, (673) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-phenylethoxy)-4-(2-chloro-5-methylphenoxymethyl)phenyl)propanamide, (674) N-(3,4-difluorophenylsulfonyl)-2-(N′-methyl-N′-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)amino)acetamide, (675) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(N′-acetyl-N′-methylaminomethyl)phenyl)propanamide, (676) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(N′-ethoxycarbonyl-N′-methylaminomethyl)phenyl)propanamide, (677) N-(3,4-difluorophenylsulfonyl)-3-(2-((2E)-3-phenyl-2-propenyloxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (678) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(N′-methyl-N′-phenylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (679) (2E)-N-(3,4-difluorophenylsulfonyl)-3-(2-(3-phenylpropyl)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenamide, (680) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-phenylethoxy)-4-(3-cyanophenoxymethyl)phenyl)propanamide, (681) N-benzyl-N-hydroxy-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (682) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(thiazol-2-ylaminomethyl)phenyl)propanamide, (683) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyridin-2-yloxy)phenyl)propanamide, (684) N-(3,4-difluorophenylsulfonyl)-5-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)pentanamide, (685) (2E-N-(3,4-difluorophenylsulfonyl)-3-(2-(pyrazol-1-ylmethyl)-3-(2-(naphthalen-2-yl)ethoxy)thiophen-4-yl)-2-propenamide, (686) (2E)-N-(3,4-difluorophenylsulfonyl)-3-(4-(pyrazol-1-ylmethyl)-3-(2-(naphthalen-2-yl)ethoxy)thiophen-2-yl)-2-propenamide, (687) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(4-phenylpiperazin-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (688) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (689) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(4-phenylpiperidin-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (690) N-(3,4-difluorophenylsulfonyl)-4-(2-(2-phenylethoxy)-4-(3-cyanophenoxymethyl)phenyl)butanamide, (691) N-(3,4-difluorophenylsulfonyl)-4-(2-(2-(naphthalen-2-yl)ethoxy)-4-(3-cyanophenoxymethyl)phenyl)butanamide, (692) N-(3,4-difluorophenylsulfonyl)-3-(2-(5-phenylpentyloxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (693) N-(3,4-difluorophenylsulfonyl)-2-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenoxy)acetamide, (694) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(pyrazol-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (695) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(2-methylimidazol-1-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (696) N-(3,4-difluorophenylsulfonyl)-2-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)benzoylamino)acetamide, (697) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(N-ethyl-N-phenylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (698) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(N-(2-hydroxyethyl)-N-phenylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (699) N-(3,4-difluorophenylsulfonyl)-3-(2-(3-(N-methyl-N-phenylamino)propoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (700) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propynamide, (701) N-phenylsulfonyl-3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-phenoxymethylphenyl)propanamide, (702) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-hydroxy-2-(naphthalen-2-yl)ethoxy)-4-(3-cyanophenoxymethyl)phenyl)propanamide, (703) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(3-(morpholin-4-yl)phenyl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (704) 3-(2-(5-methyl-3-phenylhexanoyl)-4-phenoxymethylphenyl)propanoic acid, (705) 3-(2-((3-methyl-1-(4-fluorophenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanol (706) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-phenoxymethylphenyl)propanol (707) N-(3-methyl-1-(4-fluorophenyl)butyl)-2-(3-mesylaminopropyl)-5-phenoxymethylbenzamide, (708) N-(3-methyl-1-(4-fluorophenyl)butyl)-2-(3-phenylsulfonylaminopropyl)-5-phenoxymethylbenzamide, (709) N-(3-methyl-1-(4-fluorophenyl)butyl)-2-(3-benzoylaminopropyl)-5-phenoxymethylbenzamide, (710) N-(3-methyl-1-(4-fluorophenyl)butyl)-2-(3-formylaminopropyl)-5-phenoxymethylbenzamide, (711) N-phenylsulfonyl-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)benzyl)aminocarboxamide (712) N-(3,4-difluorophenylsulfonyl)-N′-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)benzyl)urea (713) 3-[4-phenoxymethyl-2-[1-(4-fluorophenyl)-3-methylbutylaminocarbonyl]phenyl]propanamide, (714) N-(3-methyl-1-(4-fluorophenyl)butyl)-2-(2-(tetrazol-5-yl)ethyl)-5-phenoxymethylbenzamide, (715) 1-(2-(tetrazol-5-yl)ethyl)-2-(4-methyl-2-phenylpentyloxy)-4-phenoxymethylbenzene (716) N-(2-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)ethylsulfonyl)benzamide, (717) 3-[2-[2-(naphthalen-2-yl)ethyloxy]-4-(1-pyrazolylmethyl)phenyl]propanamide, (718) 3-(2-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)ethyl-1,2,4-oxadiazole-5-thione (719) 3-(2-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)ethyl-1,2,4-oxadiazole-5-one (720) 3-(2-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)ethyl-1,2,4-thiadiazole-5-one (721) 4-(2-(2-(2-(naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)ethyl-1,2,3,5-oxathiadiazole-2-one (722) 3-(2-(N-methyl-N-(2-(naphthalen-2-yl)ethyl)amino)-4-phenoxymethylphenyl)propanoic acid, (723) 3-(2-(N-acetyl-N-(2-(naphthalen-2-yl)ethyl)amino)-4-phenoxymethylphenyl)propanoic acid, (724) 3-(2-(2-(naphthalen-2-yl)ethylthio)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (725) 3-(2-(2-(naphthalen-2-yl)ethylsulfonyl)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (726) 3-(2-(2-(N-benzyl-N-methylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (727) 3-(2-(2-(N-benzyl-N-ethylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (728) 3-(2-(2-(N-phenyl-N-propylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (729) 3-(2-(2-(6-methoxy-naphthalen-2-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (730) 3-(2-(2-(carbazol-9-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (731) 3-(2-(2-(9,10-dihydroacridin-9-one-10-yl)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (732) 3-(2-(5-phenylpentyl)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (733) 3-(2-(5-phenyl-1-pentenyl)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (734) 3-(2-(5-phenyl-1-pentynyl)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (735) 3-(4-(pyrazol-1-ylmethyl)-2-(naphthalen-2-ylcarbonylaminomethyl)phenyl)propanoic acid, (736) 3-(2-(2-(N-phenyl-N-methylsulfonylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (737) 3-(2-(2-(N-acetyl-N-phenylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (738) 3-(2-(2-(N-benzyl-N-phenylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (739) 3-(2-(2-(N-(2-cyanoethyl)-N-phenylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (740) 3-(2-(3-(phenoxazin-10-yl)propoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (741) N-(3,4-difluorophenylsulfonyl)-3-(2-(5-phenylpentyl)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (742) N-(3,4-difluorophenylsulfonyl)-3-(2-(5-phenyl-1-pentenyl)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (743) N-(3,4-difluorophenylsulfonyl)-3-(2-(5-phenyl-1-pentynyl)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (744) 3-(2-(N-benzoylpiperazin-1-yl)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (745) N-(3,4-difluorophenylsulfonyl)-3-(2-(N-benzoylpiperazin-1-yl)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (746) 3-(2-(2-(3-methyl-1-phenylbutylcarbamoyl)-4-phenoxymethyl)phenyl)ethyl-1,2,4-oxadiazole-5-one (747) 2-(1-benzyl-3-(3-methyl-1-phenylbutylcarbamoyl)indol-4-yl)acetic acid, (748) 3-(1-benzyl-3-(3-methyl-1-phenylbutylcarbamoyl)indol-4-yl)propanoic acid, (749) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(3-cyanobenzyloxy)phenyl)propanoic acid, (750) 1-benzyl-3-(3-methyl-1-phenylbutylcarbamoyl)-5-indolecarboxylic acid, (751) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-cyanobenzyloxy)phenyl)propanoic acid, (752) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-methylsulfonylaminophenyl)propanoic acid, (753) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(N-methyl-N-methylsulfonylamino)phenyl)propanoic acid, (754) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-methoxycarbonylaminophenyl)propanoic acid, (755) N-(3,4-difluorophenylsulfonyl)-3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-methylsulfonylaminophenyl)propanamide, (756) N-(3,4-difluorophenylsulfonyl)-3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-(N-methyl-N-methylsulfonylamino)phenyl)propanamide, (757) N-(3,4-difluorophenylsulfonyl)-3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-methoxycarbonylaminophenyl)propanamide, (758) 3-(2-(2-(3-methyl-1-phenylbutylcarbamoyl)-4-phenoxymethyl)phenyl)ethyl-1,2,4-oxadiazole-5-thione (759) 3-(2-((3-methyl-1-(3-methylphenyl)butyl)carbamoyl)-4-(3-cyanophenoxymethyl)phenyl)propanoic acid, (760) 3-(2-((3-methyl-1-(3-methoxyphenyl)butyl)carbamoyl)-4-(3-cyanophenoxymethyl)phenyl)propanoic acid, (761) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-phenylsulfonyloxyphenyl)propanoic acid, (762) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-isopropylsulfonyloxyphenyl)propanoic acid, (763) N-(3,4-difluorophenylsulfonyl)-3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-isopropylsulfonyloxyphenyl)propanamide, (764) 3-(1-benzyl-3-(3-methyl-1-(3,5-dimethylphenyl)butylcarbamoyl)indol-4-yl)propanoic acid, (765) 3-(1-(3-cyanobenzyl)-3-(3-methyl-1-(3,5-dimethylphenyl)butylcarbamoyl)indol-4-yl)propanoic acid, (766) 3-(2-((3-methyl-1-(3,4-dimethoxyphenyl)butyl)carbamoyl)-4-(3-cyanophenoxymethyl)phenyl)propanoic acid, (767) 3-(3-benzyl-1-(3-methyl-1-phenylbutylcarbamoylmethyl)indol-7-yl)propanoic acid, (768) 3-(2-((3-methyl-1-(3-methyl-4-fluorophenyl)butyl)carbamoyl)-4-(3-cyanophenoxymethyl)phenyl)propanoic acid, (769) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-methylsulfonyloxyphenyl)propanoic acid, (770) 3-(2-((3-methyl-1-(3,5-dimethoxyphenyl)butyl)carbamoyl)-4-(3-cyanophenoxymethyl)phenyl)propanoic acid, (771) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-benzyloxycarbonylaminophenyl)propanoic acid, (772) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(isoindolin-2-yl)phenyl)propanoic acid, (773) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-phenoxycarbonylaminophenyl)propanoic acid, (774) 3-(2-((3-methyl-1-(3,5-difluorophenyl)butyl)carbamoyl)-4-(3-cyanophenoxymethyl)phenyl)propanoic acid, (775) N-(3-fluorophenylsulfonyl)-3-(2-(2-(3-methoxyphenylcarbonylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (776) N-(4-fluorophenylsulfonyl)-3-(2-(2-(3-methoxyphenylcarbonylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (777) N-(4-methylphenylsulfonyl)-3-(2-(2-(3-methoxyphenylcarbonylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (778) N-(3-nitrophenylsulfonyl)-3-(2-(2-(3-methoxyphenylcarbonylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (779) N-(3-cyanophenylsulfonyl)-3-(2-(2-(3-methoxyphenylcarbonylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (780) N-(3-methylphenylsulfonyl)-3-(2-(2-(3-methoxyphenylcarbonylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (781) N-(3-methoxyphenylsulfonyl)-3-(2-(2-(3-methoxyphenylcarbonylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (782) N-(3-trifluoromethylphenylsulfonyl)-3-(2-(2-(3-methoxyphenylcarbonylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (783) N-(3-methoxycarbonylphenylsulfonyl)-3-(2-(2-(3-methoxyphenylcarbonylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (784) N-(3-carboxyphenylsulfonyl)-3-(2-(2-(3-methoxyphenylcarbonylamino)ethoxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, (785) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-benzoylaminophenyl)propanoic acid, (786) 2-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenoxy)acetic acid, (787) 2-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-cyanophenoxymethyl)phenoxy)acetic acid, (788) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(N-acetyl-N-benzylamino)phenyl)propanoic acid, (789) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-((N-phenylamino)carbonylamino)phenyl)propanoic acid, (790) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-phenylsulfonylaminophenyl)propanoic acid, (791) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(N-benzyl-N-methylsulfonylamino)phenyl)propanoic acid, (792) 3-(3-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-5-(3-cyanophenoxymethyl)phenyl)propanoic acid, (793) 3-(3-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-5-(3-cyanophenoxymethyl)phenyl)propenoic acid, (794) 4-(3-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-5-(3-cyanophenoxymethyl)phenyl)butanoic acid, (795) 3-(2-(1-(3,5-dimethylphenyl)butylcarbamoyl)-4-(3-cyanophenoxymethyl)phenyl)propanoic acid, (796) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(pyrazol-1-ylmethylcarbonyl)phenyl)propanoic acid, (797) 3-(2-((1-(3,5-dimethylphenyl)propyl)carbamoyl)-4-(3-cyanophenoxymethyl)phenyl)propanoic acid, (798) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-phenylvinyl)phenyl)propanoic acid, (799) 3-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(2-cyanophenoxy)phenyl)propanoic acid, (800) 3-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(4-cyanophenoxy)phenyl)propanoic acid, (801) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-(pyrazol-1-yl)ethyl)phenyl)propanoic acid, (802) 3-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(4-methylphenoxy)phenyl)propanoic acid, (803) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-methylbenzyloxy)phenyl)propanoic acid, (804) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-fluorobenzyloxy)phenyl)propanoic acid, (805) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-cyanobenzyloxy)phenyl)propanoic acid, (806) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-methoxybenzyloxy)phenyl)propanoic acid, (807) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-chlorobenzyloxy)phenyl)propanoic acid, (808) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-phenylbenzyloxy)phenyl)propanoic acid, (809) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-methylbenzyloxy)phenyl)propanoic acid, (810) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-fluorobenzyloxy)phenyl)propanoic acid, (811) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-ethylbenzyloxy)phenyl)propanoic acid, (812) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-trifluoromethylbenzyloxy)phenyl)propanoic acid, (813) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,3-dimethoxybenzyloxy)phenyl)propanoic acid, (814) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-fluorophenoxymethyl)phenyl)propanoic acid, (815) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-chlorophenoxymethyl)phenyl)propanoic acid, (816) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,4-difluorophenoxymethyl)phenyl)propanoic acid, (817) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-fluorophenoxymethyl)phenyl)propanoic acid, (818) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (819) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-chloro-5-fluorophenoxymethyl)phenyl)propanoic acid, (820) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,6-dimethylbenzyloxy)phenyl)propanoic acid, (821) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-cyanophenoxymethyl)phenyl)propanoic acid, (822) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-cyanophenoxymethyl)phenyl)propanoic acid, (823) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-methoxyphenoxymethyl)phenyl)propanoic acid, (824) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-methoxyphenoxymethyl)phenyl)propanoic acid, (825) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-methylphenoxymethyl)phenyl)propanoic acid, (826) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-methoxy-5-cyanophenoxymethyl)phenyl)propanoic acid, (827) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-chlorobenzyloxy)phenyl)propanoic acid, (828) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-fluorobenzyloxy)phenyl)propanoic acid, (829) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-trifluoromethylbenzyloxy)phenyl)propanoic acid, (830) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-trifluoromethyloxybenzyloxy)phenyl)propanoic acid, (831) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-isopropylbenzyloxy)phenyl)propanoic acid, (832) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(naphthalen-1-yl)methyloxyphenyl)propanoic acid, (833) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-butylbenzyloxy)phenyl)propanoic acid, (834) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-methoxyphenoxymethyl)phenyl)propanoic acid, (835) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-acetylphenoxymethyl)phenyl)propanoic acid, (836) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-t-butylbenzyloxy)phenyl)propanoic acid, (837) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-phenylbenzyloxy)phenyl)propanoic acid, (838) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-benzylbenzyloxy)phenyl)propanoic acid, (839) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-chloro-4-fluorophenoxymethyl)phenyl)propanoic acid, (840) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-methyl-4-fluorophenoxymethyl)phenyl)propanoic acid, (841) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,5-dimethylphenoxymethyl)phenyl)propanoic acid, (842) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-carbamoylmethylphenoxymethyl)phenyl)propanoic acid, (843) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-methoxy-5-methylphenoxymethyl)phenyl)propanoic acid, (844) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-methylphenoxymethyl)phenyl)propanoic acid, (845) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-fluorophenoxymethyl)phenyl)propanoic acid, (846) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-chloro-6-fluorobenzyloxy)phenyl)propanoic acid, (847) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,5-difluorobenzyloxy)phenyl)propanoic acid, (848) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-chlorobenzyloxy)phenyl)propanoic acid, (849) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-fluoro-5-trifluoromethylbenzyloxy)phenyl)propanoic acid, (850) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,4-difluorobenzyloxy)phenyl)propanoic acid, (851) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3,5-dimethylbenzyloxy)phenyl)propanoic acid, (852) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(1-ethyl-3-methylpyrazol-5-yl)methoxyphenyl)propanoic acid, (853) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-fluoro-6-trifluoromethylbenzyloxy)phenyl)propanoic acid, (854) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,3-difluorobenzyloxy)phenyl)propanoic acid, (855) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,6-difluorobenzyloxy)phenyl)propanoic acid, (856) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-chloro-4-fluorobenzyloxy)phenyl)propanoic acid, (857) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3,5-difluorobenzyloxy)phenyl)propanoic acid, (858) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,4-bis(trifluoromethyl)benzyloxy)phenyl)propanoic acid, (859) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3,4-difluorobenzyloxy)phenyl)propanoic acid, (860) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-trifluoromethyloxybenzyloxy)phenyl)propanoic acid, (861) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3,4-dimethylbenzyloxy)phenyl)propanoic acid, (862) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-methoxynaphthalen-1-ylmethyloxy)phenyl)propanoic acid, (863) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,3,6-trifluorobenzyloxy)phenyl)propanoic acid, (864) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(4-nitrophenoxy)phenyl)butanoic acid, (865) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(4-aminophenoxy)phenyl)butanoic acid, (866) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(4-methylsulfonylphenoxy)phenyl)butanoic acid, (867) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-thienylmethyloxy)phenyl)propanoic acid, (868) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(1,3-dioxyindan-4-yl)methyloxyphenyl)propanoic acid, (869) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,4-dimethylbenzyloxy)phenyl)propanoic acid, (870) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-methylbenzyloxy)phenyl)propanoic acid, (871) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-methylthiobenzyloxy)phenyl)propanoic acid, (872) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,5-dimethylbenzyloxy)phenyl)propanoic acid, (873) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-fluoro-4-trifluoromethylbenzyloxy)phenyl)propanoic acid, (874) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-fluoro-3-trifluoromethylbenzyloxy)phenyl)propanoic acid, (875) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-fluoro-5-trifluoromethylbenzyloxy)phenyl)propanoic acid, (876) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-fluoro-3-chlorobenzyloxy)phenyl)propanoic acid, (877) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-fluoro-4-methylbenzyloxy)phenyl)propanoic acid, (878) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-fluoro-5-methoxybenzyloxy)phenyl)propanoic acid, (879) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-isobutylbenzyloxy)phenyl)propanoic acid, (880) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,4,5-trimethylbenzyloxy)phenyl)propanoic acid, (881) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-(4-methoxyphenoxy)benzyloxy)phenyl)propanoic acid, (882) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-methoxybenzyloxy)phenyl)propanoic acid, (883) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,3,4-trimethoxybenzyloxy)phenyl)propanoic acid, (884) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(4-cyanophenoxy)phenyl)butanoic acid, (885) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(4-acetylaminophenoxy)phenyl)butanoic acid, (886) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(4-methylsulfonylaminophenoxy)phenyl)butanoic acid, (887) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-methoxy-5-cyanophenoxymethyl)phenyl)propanoic acid, (888) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-fluoro-3-methoxybenzyloxy)phenyl)propanoic acid, (889) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-methoxynaphthalen-1-ylmethyloxy)phenyl)propanoic acid, (890) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-methoxy-3,5-di(t-butyl)benzyloxy)phenyl)propanoic acid, (891) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-phenoxybenzyloxy)phenyl)propanoic acid, (892) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(4-acetylphenoxy)phenyl)butanoic acid, (893) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-furylmethyloxy)phenyl)propanoic acid, (894) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-chloro-3-fluorobenzyloxy)phenyl)propanoic acid, (895) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-((3,5-dimethyl-4-benzyloxy)benzyloxy)phenyl)propanoic acid, (896) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(2,3,4,5,6-pentafluorophenoxy)phenyl)butanoic acid, (897) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(benzo[e]1,4-dioxan-6-yl)methyloxy)phenyl)propanoic acid, (898) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,4,6-trifluorobenzyloxy)phenyl)propanoic acid, (899) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-chloro-4,5-difluorobenzyloxy)phenyl)propanoic acid, (900) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-fluoro-4-trifluoromethylbenzyloxy)phenyl)propanoic acid, (901) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-chloro-5-trifluoromethylbenzyloxy)phenyl)propanoic acid, (902) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,5-diethoxybenzyloxy)phenyl)propanoic acid, (903) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-cyano-4-fluorobenzyloxy)phenyl)propanoic acid, (904) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-ethoxybenzyloxy)phenyl)propanoic acid, (905) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-benzyloxybenzyloxy)phenyl)propanoic acid, (906) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,3,4,5,6-pentafluorobenzyloxy)phenyl)propanoic acid, (907) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,5-bis(trifluoromethyl)benzyloxy)phenyl)propanoic acid, (908) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-methyl-5-fluorobenzyloxy)phenyl)propanoic acid, (909) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-((4-methylnaphthalen-1-yl)methyloxy)phenyl)propanoic acid, (910) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4′-trifluoromethyl-1,1′-biphenyl-2-yl)methyloxy)phenyl)propanoic acid, (911) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-phenylethoxy)phenyl)propanoic acid, (912) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-phenylpropoxy)phenyl)propanoic acid, (913) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoic acid, (914) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-methyl-3-chlorobenzyloxy)phenyl)propanoic acid, (915) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-trifluoromethyloxybenzyloxy)phenyl)propanoic acid, (916) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,4-bis(trifluoromethyl)benzyloxy)phenyl)propanoic acid, (917) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-ethoxybenzyloxy)phenyl)propanoic acid, (918) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-chlorophenoxymethyl)phenyl)propanoic acid, (919) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-fluoro-5-methylphenoxymethyl)phenyl)propanoic acid, (920) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,3,4,5,6-pentafluorophenoxymethyl)phenyl)propanoic acid, (921) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,6-difluorophenoxymethyl)phenyl)propanoic acid, (922) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-methylsulfonylbenzyloxy)phenyl)propanoic acid, (923) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-chlorophenoxymethyl)phenyl)propanoic acid, (924) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,3,5,6-tetrafluorobenzyloxy)phenyl)propanoic acid, (925) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-chloro-3,6-difluorobenzyloxy)phenyl)propanoic acid, (926) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-hexylbenzyloxy)phenyl)propanoic acid, (927) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3,4-diethoxybenzyloxy)phenyl)propanoic acid, (928) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-trifluoromethylthiobenzyloxy)phenyl)propanoic acid, (929) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(6-chloro-2-fluoro-3-methylbenzyloxy)phenyl)propanoic acid, (930) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-trifluoromethylthiobenzyloxy)phenyl)propanoic acid, (931) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-chloro-6-fluoro-3-methylbenzyloxy)phenyl)propanoic acid, (932) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-(4-chlorophenylthio)benzyloxy)phenyl)propanoic acid, (933) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(4-carbamoylphenoxy)phenyl)butanoic acid, (934) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(4-N-methylcarbamoylphenoxy)phenyl)butanoic acid, (935) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(4-N,N-dimethylcarbamoylphenoxy)phenyl)butanoic acid, (936) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-pentylbenzyloxy)phenyl)propanoic acid, (937) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-(4-methylphenoxy)benzyloxy)phenyl)propanoic acid, (938) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-chloro-2-fluoro-6-trifluorobenzyloxy)phenyl)propanoic acid, (939) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-difluoromethoxybenzyloxy)phenyl)propanoic acid, (940) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(fluoren-2-ylmethyloxy)phenyl)propanoic acid, (941) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-chloro-3-trifluoromethylbenzyloxy)phenyl)propanoic acid, (942) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-fluoro-2-methylbenzyloxy)phenyl)propanoic acid, (943) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,3,5-trifluorobenzyloxy)phenyl)propanoic acid, (944) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-(pyridin-2-yl)benzyloxy)phenyl)propanoic acid, (945) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-(4-t-butylphenoxy)benzyloxy)phenyl)propanoic acid, (946) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-ethylthiobenzyloxy)phenyl)propanoic acid, (947) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-(4-fluorobenzyloxy)benzyloxy)phenyl)propanoic acid, (948) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,3-difluorophenoxymethyl)phenyl)propanoic acid, (949) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3,5-difluorophenoxymethyl)phenyl)propanoic acid, (950) 3-(2-((3-methyl-1-(naphthalen-1-yl)butyl)carbamoyl)-4-(4-fluorophenoxymethyl)phenyl)propanoic acid, (951) 3-(2-((3-methyl-1-(naphthalen-1-yl)butyl)carbamoyl)-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (952) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(2-cyanophenoxy)phenyl)butanoic acid, (953) 3-(2-((3-methyl-1-(naphthalen-1-yl)butyl)carbamoyl)-4-(3-cyanophenoxymethyl)phenyl)propanoic acid, (954) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3,4-difluorophenoxymethyl)phenyl)propanoic acid, (955) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-methyl-4-fluorophenoxymethyl)phenyl)propanoic acid, (956) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-fluoro-6-methoxyphenoxymethyl)phenyl)propanoic acid, (957) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-(3-trifluoromethylphenoxy)benzyloxy)phenyl)propanoic acid, (958) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-chloro-2-fluoro-5-trifluoromethylbenzyloxy)phenyl)propanoic acid, (959) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,3-dimethylbenzyloxy)phenyl)propanoic acid, (960) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,3-difluoro-4-methylbenzyloxy)phenyl)propanoic acid, (961) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-chloro-2-fluorobenzyloxy)phenyl)propanoic acid, (962) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-chloro-2,6-difluorobenzyloxy)phenyl)propanoic acid, (963) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3,4,5-trifluorobenzyloxy)phenyl)propanoic acid, (964) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-fluoro-3-methylbenzyloxy)phenyl)propanoic acid, (965) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-(4-chlorophenoxy)benzyloxy)phenyl)propanoic acid, (966) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,3,6-trifluorophenoxymethyl)phenyl)propanoic acid, (967) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,3,5,6-tetrafluorophenoxymethyl)phenyl)propanoic acid, (968) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-fluoro-4-cyanophenoxymethyl)phenyl)propanoic acid, (969) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-(4-propylphenyl)benzyloxy)phenyl)propanoic acid, (970) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-phenoxybenzyloxy)phenyl)propanoic acid, (971) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(5-chloro-2-methoxybenzyloxy)phenyl)propanoic acid, (972) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-dimethylaminobenzyloxy)phenyl)propanoic acid, (973) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-chloro-5-methylthiobenzyloxy)phenyl)propanoic acid, (974) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-carbamoylphenoxymethyl)phenyl)propanoic acid, (975) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-methylcarbamoylphenoxymethyl)phenyl)propanoic acid, (976) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-dimethylcarbamoylphenoxymethyl)phenyl)propanoic acid, (977) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-hydroxymethylphenoxymethyl)phenyl)propanoic acid, (978) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(2-nitrophenoxy)phenyl)butanoic acid, (979) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(2-aminophenoxy)phenyl)butanoic acid, (980) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(2-acetylaminophenoxy)phenyl)butanoic acid, (981) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(2-methylsulfonylaminophenoxy)phenyl)butanoic acid, (982) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(4-methoxyphenoxy)phenyl)butanoic acid, (983) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(4-fluorophenoxy)phenyl)butanoic acid, (984) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(3-fluorophenoxy)phenyl)butanoic acid, (985) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(3-methoxyphenoxy)phenyl)butanoic acid, (986) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-chloro-2,6-difluorobenzyloxy)phenyl)propanoic acid, (987) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-ethylbenzyloxy)phenyl)propanoic acid, (988) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-chloro-2-methoxybenzyloxy)phenyl)propanoic acid, (989) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-methyl-3-methoxybenzyloxy)phenyl)propanoic acid, (990) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-methyl-4-methoxybenzyloxy)phenyl)propanoic acid, (991) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-methoxymethylphenoxymethyl)phenyl)propanoic acid, (992) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(2-fluorophenoxy)phenyl)butanoic acid, (993) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (994) 3-(2-(((1S)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (995) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-cyclohexyloxyphenyl)butanoic acid, (996) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(pyridin-2-yl)oxyphenyl)butanoic acid, (997) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-(2-acetylphenoxy)phenyl)butanoic acid, (998) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-methoxyphenoxy)phenyl)butanoic acid, (999) 2-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-phenylethyl)phenoxy)acetic acid, (1000) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-fluorophenoxymethyl)phenyl)propanoic acid, (1001) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(4-fluorophenoxymethyl)phenyl)propanoic acid, (1002) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-methoxyphenoxymethyl)phenyl)propanoic acid, (1003) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-methylphenoxymethyl)phenyl)propanoic acid, (1004) 3-(2-diphenylmethylcarbamoyl-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (1005) 3-(2-((1-(3,5-dimethylphenyl)cyclohexyl)carbamoyl)-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (1006) 3-(2-((1-(3,5-dimethylphenyl)cyclopentyl)carbamoyl)-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (1007) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-fluorophenoxymethyl)phenyl)propanoic acid, (1008) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-ethoxyphenoxymethyl)phenyl)propanoic acid, (1009) 3-(2-((N-(2-methylpropyl)-N-(3,5-dimethylphenyl)amino)carbamoyl)-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (1010) 3-(2-(1-ethyl-1-(3,5-dimethylphenyl)propyl)carbamoyl)-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (1011) 3-(2-(4-(3,5-dimethylphenyl)perhydropyran-4-yl)carbamoyl)-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (1012) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-cyanophenoxymethyl)phenyl)propanoic acid, (1013) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,4-difluorophenoxymethyl)phenyl)propanoic acid, (1014) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,5-dimethylphenoxymethyl)phenyl)propanoic acid, (1015) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-chlorophenoxymethyl)phenyl)propanoic acid, (1016) 3-(2-(1-methyl-1-(3,5-dimethylphenyl)ethyl)carbamoyl)-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (1017) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (1018) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(benzothiazol-2-yl)oxyphenyl)propanoic acid, (1019) 3-(2-((4-(3,5-dimethylphenyl)perhydropyran-4-yl)carbamoyl)-4-(2-chloro-6-fluorobenzyloxy)phenyl)propanoic acid, (1020) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-ethylphenoxymethyl)phenyl)propanoic acid, (1021) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(3-chlorophenoxymethyl)phenyl)propanoic acid, (1022) 3-(2-(4-(3,5-dimethylphenyl)perhydrothiopyran-4-yl)carbamoyl)-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (1023) 3-(2-(1-benzyl-4-(3,5-dimethylphenyl)piperidin-4-yl)carbamoyl)-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (1024) 3-(2-(1,1-dione-4-(3,5-dimethylphenyl)perhydrothiopyran-4-yl)carbamoyl)-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (1025) 3-(2-((4-(3,5-dimethylphenyl)perhydropyran-4-yl)carbamoyl)-4-(3-cyanophenoxymethyl)phenyl)propanoic acid, (1026) 3-(2-((2,6-dimethyl-4-(3,5-dimethylphenyl)-4-heptyl)carbamoyl)-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (1027) 3-(2-((4-(3,5-dimethylphenyl)perhydropyran-4-yl)carbamoyl)-4-(2,3,6-trifluorobenzyloxy)phenyl)propanoic acid, (1028) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-chloro-6-fluorobenzyloxy)phenyl)propanoic acid, (1029) 3-(2-((4-(3,5-dimethylphenyl)perhydropyran-4-yl)carbamoyl)-4-(2-chloro-5-fluorophenoxymethyl)phenyl)propanoic acid, (1030) 3-(2-((4-(3,5-dimethylphenyl)perhydropyran-4-yl)carbamoyl)-4-(2-chloro-5-methylphenoxymethyl)phenyl)propanoic acid, (1031) 3-(2-((4-(3,5-dimethylphenyl)perhydropyran-4-yl)carbamoyl)-4-(2,5-dichlorophenoxymethyl)phenyl)propanoic acid, (1032) 3-(2-((4-(3,5-dimethylphenyl)perhydropyran-4-yl)carbamoyl)-4-phenoxymethylphenyl)propanoic acid, (1033) 3-(2-((4-(3,5-dimethylphenyl)perhydropyran-4-yl)carbamoyl)-4-(3-chlorophenoxymethyl)phenyl)propanoic acid, (1034) 3-(2-((4-(3,5-dimethylphenyl)perhydropyran-4-yl)carbamoyl)-4-(3-fluorophenoxymethyl)phenyl)propanoic acid, (1035) 3-(2-((4-(3,5-dimethylphenyl)perhydropyran-4-yl)carbamoyl)-4-(2,5-dimethylphenoxymethyl)phenyl)propanoic acid, (1036) 3-(2-((1-methylsulfonyl-4-(3,5-dimethylphenyl)piperidin-4-yl)carbamoyl)-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (1037) 3-(2-((4-(3,5-dimethylphenyl)perhydropyran-4-yl)carbamoyl)-4-(2-fluorophenoxymethyl)phenyl)propanoic acid, (1038) 3-(2-((4-(3,5-dimethylphenyl)perhydropyran-4-yl)carbamoyl)-4-(2-chlorophenoxymethyl)phenyl)propanoic acid, (1039) 3-(2-((4-(3-methylphenyl)perhydropyran-4-yl)carbamoyl)-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (1040) 3-(2-((4-(naphthalen-1-yl)perhydropyran-4-yl)carbamoyl)-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (1041) 3-(2-((1-methyl-4-(3,5-dimethylphenyl)piperidin-4-yl)carbamoyl)-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (1042) 3-(2-((1-ethyl-4-(3,5-dimethylphenyl)piperidin-4-yl)carbamoyl)-4-(2,5-difluorophenoxymethyl)phenyl)propanoic acid, (1043) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2,3,6-trifluorobenzyloxy)phenyl)propanoic acid, (1044) 2-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(2-chloro-6-fluorobenzyloxy)phenoxy)acetic acid, methyl ester thereof, ethyl ester thereof or non-toxic salts thereof. 11. The compound according to the claim 5, which is selected from (1) (2E)-3-(2-(2-(2,5,7,8-tetramethyl-6-hydroxychroman-2-yl)ethoxy)-4-hydroxymethylphenyl)-2-propenoic acid, (2) (2E)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-benzyloxyphenyl)-2-propenoic acid, (3) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-phenoxyphenyl)propanoic acid, (4) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-hydroxymethylphenyl)propanoic acid, (5) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(1-hydroxy-1-methylethyl)phenyl)propanoic acid, (6) 3-(2-(((1R)-1-(naphthalen-1-yl)ethyl)carbamoyl)-4-phenoxyphenyl)propanoic acid, (7) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-benzyloxyphenyl)propanoic acid, (8) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-benzyloxymethylphenyl)propanoic acid, (9) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-cyclopropylmethoxymethylphenyl)propanoic acid, (10) 2-(2-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-4-hydroxymethylbenzyl)benzoic acid, (11) 2-(2-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-4-methoxymethylbenzyl)benzoic acid, (12) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-hydroxymethylphenyl)butanoic acid, (13) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-methoxymethylphenyl)butanoic acid, (14) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-benzyloxyphenyl)butanoic acid, (15) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-phenoxyphenyl)butanoic acid, (16) 3-(2-((4-methyl-2-phenylpentanoyl)amino)-4-phenoxyphenyl)propanoic acid, (17) 4-(2-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-4-phenoxyphenyl)butanoic acid, (18) 4-(2-((4-methyl-2-phenylpentanoyl)amino)-4-phenoxyphenyl)butanoic acid, (19) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-benzyloxymethylphenyl)butanoic acid, (20) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-phenoxyphenyl)propanamide, (21) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-hydroxymethylphenyl)propanamide, (22) N-(3,4-difluorophenylsulfonyl)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(1-hydroxy-1-methylethyl)phenyl)propanamide, (23) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-methoxymethylphenyl)propanoic acid, (24) N-(3,4-difluorophenylsulfonyl)-3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-methoxymethylphenyl)propanamide, (25) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-benzyloxyphenyl)propanoic acid, (26) 3-(2-(naphthalen-1-ylmethylcarbamoyl)-4-phenoxyphenyl)propanoic acid, (27) 3-(2-(1-(naphthalen-2-yl)ethylcarbamoyl)-4-phenoxyphenyl)propanoic acid, (28) 3-(2-((3-methyl-1-(naphthalen-1-yl)butyl)carbamoyl)-4-phenoxyphenyl)propanoic acid, (29) 3-(2-(4-methyl-2-phenylpentyl)carbamoyl)-4-phenoxyphenyl)propanoic acid, (30) 3-(2-((1R)-1-phenylethylcarbamoyl)-4-phenoxyphenyl)propanoic acid, (31) 4-(2-((1R)-1-(naphthalen-1-yl)ethylcarbamoyl)-4-phenoxyphenyl)butanoic acid, (32) 3-(2-((1R)-1-(4-methylphenyl)ethylcarbamoyl)-4-phenoxyphenyl)propanoic acid, (33) 3-(2-(1-(4-fluorophenyl)ethylcarbamoyl)-4-phenoxyphenyl)propanoic acid, (34) 3-(2-((1R)-1-indan-1-yl)carbamoyl-4-phenoxyphenyl)propanoic acid, (35) 3-(2-(1-methyl-3-phenylpropyl)carbamoyl-4-phenoxyphenyl)propanoic acid, (36) 3-(2-((1R)-1-(4-nitrophenyl)ethylcarbamoyl)-4-phenoxyphenyl)propanoic acid, (37) 3-(2-diphenylmethylcarbamoyl-4-phenoxyphenyl)propanoic acid, (38) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-phenoxyphenyl)propanoic acid, (39) 3-(2-((1R)-1-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl-4-phenoxyphenyl)propanoic acid, (40) 3-(2-((1R)-1-(1,1′-biphenyl-4-yl)ethylcarbamoyl)-4-phenoxyphenyl)propanoic acid, (41) 3-(2-(cyano-phenylcarbamoyl)-4-phenoxyphenyl)propanoic acid, (42) 4-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-benzyloxyphenyl)butanoic acid, (43) 4-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-phenoxyphenyl)butanoic acid, (44) 4-(2-(3-methyl-1-phenylbutyl)carbamoyl)-4-phenoxyphenyl)butanoic acid, (45) 4-(2-(1-(naphthalen-1-yl)propylcarbamoyl)-4-phenoxyphenyl)butanoic acid, (46) 4-(2-(1-(naphthalen-1-yl)butylcarbamoyl)-4-phenoxyphenyl)butanoic acid, (47) 4-(2-((3-methyl-1-(naphthalen-1-yl)butyl)carbamoyl)-4-phenoxyphenyl)butanoic acid, (48) 4-(2-((3-methyl-1-(4-fluoro-3-methylphenyl)butyl)carbamoyl)-4-phenoxyphenyl)butanoic acid, (49) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-phenoxyphenyl)propanoic acid, (50) 3-(2-((4-(3,5-dimethylphenyl)perhydropyran-4-yl)carbamoyl)-4-phenoxyphenyl)propanoic acid, (51) 3-(2-((4-(3,5-dimethylphenyl)perhydropyran-4-yl)carbamoyl)-4-benzyloxyphenyl)propanoic acid, (52) 3-(2-(((1R)-3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-benzyloxyphenyl)propanoic acid, (53) 3-(2-((4-(naphthalen-1-yl)perhydropyran-4-yl)carbamoyl)-4-phenoxyphenyl)propanoic acid, (54) 4-(2-((4-(naphthalen-1-yl)perhydropyran-4-yl)carbamoyl)-4-phenoxyphenyl)butanoic acid, (55) 4-(2-((4-(3,5-dimethylphenyl)perhydropyran-4-yl)carbamoyl)-4-phenoxyphenyl)butanoic acid, (56) 2-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-benzyloxyphenoxy)acetic acid, methyl ester thereof, ethyl ester thereof or non-toxic salts thereof. 12. The compound according to the claim 6, which is selected from (1) 4-(2-(naphthalen-1-yl)carbonylamino-4-cyanophenyl)butanoic acid, (2) 3-(6-cyano-1-(2-(naphthalen-1-yl)propionyl)indol-3-yl)propanoic acid, (3) N-(3,4-difluorophenylsulfonyl)-3-(6-cyano-1-(1-(naphthalen-1-yl)ethylcarbonyl)indol-3-yl)propanamide, methyl ester thereof, ethyl ester thereof or non-toxic salts thereof. 13. The compound according to the claim 7, which is selected from (1) 4-(3-methyl-1-phenylbutylcarbamoyl)-2-benzofurancarboxylic acid, (2) 7-(3-methyl-1-phenylbutylcarbamoyl)-2-benzofurancarboxylic acid, (3) 2-(7-(3-methyl-1-phenylbutylcarbamoyl)indol-1-yl)acetic acid, (4) 2-(7-(3-methyl-1-phenylbutylcarbamoyl)indol-3-yl)acetic acid, (5) 7-(3-methyl-1-phenylbutylcarbamoyl)naphthalenecarboxylic acid, (6) 2-(7-(3-methyl-1-phenylbutylcarbamoyl)indolin-1-yl)acetic acid, (7) 3-(7-(3-methyl-1-phenylbutylcarbamoyl)indolin-1-yl)propanoic acid, (8) 3-(8-(3-methyl-1-phenylbutylcarbamoyl)-1,2,3,4-tetrahydroquinolin-1-yl)propanoic acid, (9) 2-(8-(3-methyl-1-(3,5-dimethylphenyl)butylcarbamoyl)-1,2,3,4-tetrahydroquinolin-1-yl)acetic acid, (10) 2-(7-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)indolin-1-yl)acetic acid, (11) 8-(3-methyl-1-(3,5-dimethylphenyl)butylcarbamoyl)-2-naphthalenecarboxylic acid, (12) 7-(3-methyl-1-(3,5-dimethylphenyl)butylcarbamoyl)-2-benzofurancarboxylic acid, (13) 2-(7-(3-methyl-1-(3,5-dimethylphenyl)butylcarbamoyl)benzofuran-2-yl)acetic acid, (14) 7-((2-(naphthalen-1-yl)acetyl)amino)-2-benzofurancarboxylic acid, (15) 7-((2-(naphthalen-1-yl)propanoyl)amino)-2-benzofurancarboxylic acid, (16) 7-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-2-benzofurancarboxylic acid, (17) 2-(1-(2-(naphthalen-1-yl)propionyl)indol-3-yl)acetic acid, (18) 2-(2-methyl-1-(2-(naphthalen-1-yl)propionyl)indol-3-yl)acetic acid, (19) 3-(1-(2-(naphthalen-1-yl)propionyl)indol-3-yl)propanoic acid, (20) 3-(2-methyl-1-(2-(naphthalen-1-yl)propionyl)indol-3-yl)propanoic acid, (21) N-(3,4-difluorophenylsulfonyl)-2-(1-(1-(naphthalen-1-yl)ethylcarbonyl)indol-3-yl)acetamide, (22) N-(3,4-difluorophenylsulfonyl)-2-(2-methyl-1-(1-(naphthalen-1-yl)ethylcarbonyl)indol-3-yl)acetamide, (23) N-(3,4-difluorophenylsulfonyl)-3-(1-(1-(naphthalen-1-yl)ethylcarbonyl)indol-3-yl)propanamide, methyl ester thereof, ethyl ester thereof or non-toxic salts thereof. 14. The compound according to the claim 8, which is selected from (1) (2E)-3-(2-(6-phenoxyhexyloxy)-4-(imidazol-1-ylmethyl)phenyl)-2-propenoic acid, (2) 3-(2-(6-phenylhexyloxy)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid, (3) N-(3,4-difluorophenylsulfonyl)-3-(2-(6-phenylhexyloxy)-4-(pyrazol-1-ylmethyl)phenyl)propanamide, methyl ester thereof, ethyl ester thereof or non-toxic salts thereof. 15. A compound according to the claim 1 selected from (1) (2E)-3-(2-(2-(naphthalen-2-yl)ethoxy)-4-phenylcarbamoylphenyl)-2-propenoic acid, (2) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-phenylphenyl)butanoic acid, (3) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-benzylcarbamoylphenyl)butanoic acid, (4) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-phenylcarbamoylphenyl)butanoic acid, (5) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-cyanophenyl)propanoic acid, (6) N-(3,4-difluorophenylsulfonyl)-3-(4-cyano-2-((3-methyl-1-phenylbutyl)carbamoyl)phenyl)propanamide, (7) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-dibenzylaminophenyl)propanoic acid, (8) 3-(2-((3-methyl-1-phenylbutyl)carbamoyl)-4-benzylaminophenyl)propanoic acid, (9) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-benzylaminophenyl)propanoic acid, (10) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-(N-benzyl-N-methylamino)phenyl)propanoic acid, (11) 3-(2-(2-(naphthalen-2-yl)ethoxy)-4-(N-phenylcarbamoyl)phenyl)propanoic acid, (12) 3-(2-((3-methyl-1-(3,5-dimethylphenyl)butyl)carbamoyl)-4-phenylcarbamoylphenyl)propanoic acid, methyl ester thereof, ethyl ester thereof or non-toxic salts thereof. 16. A pharmaceutical composition, which comprises the compound of formula (I) according to claim 1, or a non-toxic salt thereof. 17. A therapeutic and/or preventive agent for diseases induced by activation of EP3 and/or EP4 acceptor, which comprises the compound of formula (I) according to claim 1, or a non-toxic salt thereof. 18. The therapeutic and/or preventive agent according to claim 1, wherein the disease is pain, allodynia, hyperalgesia, itch, urticaria, atopic dermatitis, contact dermatitis, poison ivy dermatitis, allergic conjunctivitis, various symptoms in dialysis, asthma, rhinitis, allergic rhinitis, nasal obstruction, sneeze, psoriasis, urinary frequency, urinary disturbance, dysspermia, fever, systemic inflammatory response syndrome, learning disability, Alzheimer's disease, angiogenesis, canceration, cancer proliferation, cancer metastasis into organ, cancer metastasis into bone, hypercalcemia accompanying cancer metastasis into bone, retinosis, red spot, erythema, leukoma, skin spot, burn, ambustion, steroid burn, renal insufficiency, nephropathy, acute nephritis, chronic nephritis, blood electrolyte imbalance, threatened premature delivery, threatened abortion, epimenorrhagia, dysmenorrhea, endometriosis, premenstrual syndrome, adenomyosis uteri, reproductive disturbance, stress, anxiety, depression, psychosomatic disorder, mental diseases, thrombosis, embolism, transient ischemic attack, brain infraction, atheroma, organ transplantation, myocardial infarction, heart failure, hypertension, arteriosclerosis, circulatory disturbance and ulcer accompanying the same, nerve disorder, vascular dementia, edema, diarrhea, constipation, biliary discharge disorder, ulcerative colitis, Crohn's disease, irritable colitis, relieving rebound phenomena after using steroids, accelerating reduction and elimination of steroids, bone diseases, systemic granuloma, immune diseases, pyorrhea alveolaris, gingivitis, periodontal disease, nerve cell death, lung injury, liver injury, acute hepatitis, myocardial ischemia, Kawasaki's disease, multiple organ failure, chronic headache, angiitis, venous insufficiency, varicose vein, anal fistula, diabetes insipidus, newborn patent ductus arteriosus, cholelithiasis, sleep disturbance or platelet aggregation. 19. A method for treating and/or preventing diseases induced by activation of EP3 and/or EP4 acceptor, which comprises administering the compound of formula (I) according to claim 1 or a non-toxic salt thereof. 20. The method according to claim 19, wherein the disease is pain, allodynia, hyperalgesia, itch, urticaria, atopic dermatitis, contact dermatitis, poison ivy dermatitis, allergic conjunctivitis, various symptoms in dialysis, asthma, rhinitis, allergic rhinitis, nasal obstruction, sneeze, psoriasis, urinary frequency, urinary disturbance, dysspermia, fever, systemic inflammatory response syndrome, learning disability, Alzheimer's disease, angiogenesis, canceration, cancer proliferation, cancer metastasis into organ, cancer metastasis into bone, hypercalcemia accompanying cancer metastasis into bone, retinosis, red spot, erythema, leukoma, skin spot, burn, ambustion, steroid burn, renal insufficiency, nephropathy, acute nephritis, chronic nephritis, blood electrolyte imbalance, threatened premature delivery, threatened abortion, epimenorrhagia, dysmenorrhea, endometriosis, premenstrual syndrome, adenomyosis uteri, reproductive disturbance, stress, anxiety, depression, psychosomatic disorder, mental diseases, thrombosis, embolism, transient ischemic attack, brain infraction, atheroma, organ transplantation, myocardial infarction, heart failure, hypertension, arteriosclerosis, circulatory disturbance and ulcer accompanying the same, nerve disorder, vascular dementia, edema, diarrhea, constipation, biliary discharge disorder, ulcerative colitis, Crohn's disease, irritable colitis, relieving rebound phenomena after using steroids, accelerating reduction and elimination of steroids, bone diseases, systemic granuloma, immune diseases, pyorrhea alveolaris, gingivitis, periodontal disease, nerve cell death, lung injury, liver injury, acute hepatitis, myocardial ischemia, Kawasaki's disease, multiple organ failure, chronic headache, angiitis, venous insufficiency, varicose vein, anal fistula, diabetes insipidus, newborn patent ductus arteriosus, cholelithiasis, sleep disturbance or platelet aggregation. |
<SOH> BACKGROUND ART <EOH>Prostaglandin E 2 (PGE 2 ) has been known as a metabolite in the arachidonic acid cascade. It has been known that PGE 2 possesses cyto-protective activity, uterine contractile activity, a pain-inducing effect, a promoting effect on digestive peristalsis, an awaking effect, a suppressive effect on gastric acid secretion, hypotensive activity, and diuretic activity. In the recent study, it was found that PGE 2 receptor was divided into some subtypes, which possesses different physical roles from each other. At present, four receptor subtypes are known and they are called EP 1 , EP 2 , EP 3 and EP 4 respectively [ J. Lipid Mediators Cell Signaling, 12, 379-391 (1995)]. Among these subtypes, EP 3 receptor was believed to be involved in signal transduction of peripheral nerve, control of exothermal reaction in central nerve, formation of memory by expressing in cerebral neuron, vascularization, reabsorption of urine by expressing in renal tubular, uterine contraction, production of ACTH, platelet aggregation. Besides, it was expressed in vascular smooth muscle, heart and gastrointestinal tract also. EP 4 receptor was believed to be involved in suppression of TNF-α production and induction of IL-10 production. So the compounds which can bind to EP 3 receptor and/or EP 4 receptor strongly and show the antagonizing activity, are useful for the prevention and/or treatment of diseases induced by excess activation of EP 3 receptor and/or EP 4 receptor, for example, pain such as cancerous pain, fractural pain, pain following surgical and dental procedures; allodynia, hyperalgesia, pruritus, urticaria, atopic dermatitis, contact dermatitis, rhus dermatitis, allergic conjunctivitis, various symptoms by treating with dialysis, asthma, rhinitis, sneeze, urinary frequency such as neurogenic bladder, neurogenic bladder, irritant bladder, unstable bladder, urinary frequency that originate with prostate-gland enlargement; urinary disturbance, ejaculatory failure, fever, systemic inflammatory response syndrome, learning disturbance, Alzheimer's disease, angiogenesis, cancer such as formulation of cancer, growth of cancer and metastasis of cancer; retinopathy, patch of red, erythematous patches, achromoderma, pigmented spot, scald, burn, burn by steroid, renal failure, nephropathy, acute nephritis, chronic nephritis, abnormal blood levels of electrolytes, threatened premature delivery, abortion threatened, hypermenorrhea, dysmenorrhea, uterine fibroids, premenstrual syndrome, reproductive disorder, stress, anxiety disorders, depression, psychosomatic disorder, mental disorder, thrombosis, embolism, transient ischemia attack, cerebral infarction, atheroma, organ transplant, myocardial infarction, cardiac failure, hypertension, arteriosclerosis, circulatory failure and circulatory failure induced ulcer, neuropathies, vascular dementia, edema, various arthritis, rheumatism, diarrhea, constipation, disorder of bilious excretion, ulcerative colitis, Crohn's disease, irritable bowel syndrome, alleviation of rebound phenomenon after steroid, dose reduction of steroid and adjunct for steroid withdrawal and/or bone diseases such as osteoporosis, rheumatoid arthritis, osteoarthritis, abnormal bone formation; cancer such as formation of cancer, proliferation of cancer, metastasis of cancer to organs and to bones and hypercalcemia induced metastasis to bones of cancer; systemic granuloma, immunological diseases such as ALS, multiple sclerosis, Sjoegren's syndrome, systemic lupus erythematosus, AIDS; allergy such as allergic conjunctivitis, allergic rhinitis, contact dermatitis, psoriasis; atopy such as atopic dermatitis; asthma, pyorrhea, gingivitis, periodontitis, neuronal cell death, Alzheimer's disease, pulmonary injury, hepatopathy, acute hepatopathy, nephritis, renal failure, myocardial ischemia, Kawasaki disease, scald, ulcerative colitis, Crohn's disease, multiple organ failure, chronic headache such as migraine headache, tension-type headache or mixed headache thereof, cluster headache; pain, angiogenesis, angiitis, venous insufficiency, varicose veins, anal fistula, diabetes insipidus, stress, endometriosis, adenomyosis of the uterus, neonatal patent ductus arteriosus, cholelithiasis etc. Moreover, it relates to sleeping disorder and platelet aggregation, so the compounds are considered to be useful for them. As a compound useful for a treatment of a disease related prostaglandin E receptor, for example, (A) in a specification of WO 99/47497, a compound of formula (A): wherein HET a is a 5- to 12-membered mono- or bi-aromatic ring; A a is a group of one or two atoms; X a is 5- to 10-membered mono- or bi-aryl, heteroaryl, and the rings may be substituted with R 14a and R 15a ; B a is —(C(R 18a ) 2 ) pa —Y a —C(R 18a ) qa —; R 1a , R 2a and R 3a are hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, etc.; and (B) in a specification of WO 00/20371, a compound of formula (B) wherein Ar 1b is aryl or heteroaryl; W b is a 3- to 6-membered linking chain containing 0-2 of a hetero atom(s); Ar 2b is aryl or heteroaryl which may be substituted with R 3b ; R 3b is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, CHF 2 , CF 3 , halogen, halo(C1-6) alkyl, N(R 5b ) 2 , cyano, nitro, C(R 6b ) 3 ; X b is a linking chain; Q b is COOH, tetrazole, SO 3 H, hydroxamic acid, CONHSO 2 R 12b , SO 2 NHCOR 12b ; were described |
Cd44 variants carrying heparan sulfate chains and uses thereof |
Modulation of the activity of a heparin-binding growth factor (HBGF) by enhancing or inhibiting high affinity binding of said HBGF to its receptor, can be achieved with an agent selected from: (i) a soluble CD44 isoform carrying at least one chain of a heparan sulfate; (ii) a recombinant chimeric fusion protein comprising the amino acid sequence of a soluble CD44 isoform fused to a tag suitable for proteoglycan purification, said fusion molecule being post-translationally glycosylated to carry at least one chain of a heparan sulfate; and (iii) a sugar molecule being a heparan sulfate derived from a CD44 isoform, or a fragment thereof. The agents (i) and (ii) when the soluble CD44 isoform is the soluble CD44 variant expressed in synovial cells of rheumatoid arthritis patients (CD44vRA), and the heparan sulfate of (iii), are novel. |
1-7: (canceled) 8: An agent capable of modulating the activity of a heparin-binding growth factor (HBGF) by enhancing or inhibiting high affinity binding of said HBGF to its receptor, said agent being selected from the group consisting of: (i) the soluble CD44vRA variant expressed in synovial cells of rheumatoid arthritis (RA) patients (herein CD44vRA), carrying at least one chain of a heparan sulfate; (ii) a recombinant chimeric fusion protein comprising the amino acid sequence of soluble CD44vRA variant fused to a tag suitable for proteoglycan purification, said fusion molecule being post-translationally glycosylated to carry at least one chain of a heparan sulfate; and (iii) a sugar molecule being a heparan sulfate derived from a CD44 isoform, or a fragment thereof. 9: A recombinant chimeric fusion protein of claim 8 wherein the amino acid sequence of the soluble CD44vRA (SEQ ID NO:2) is fused to a tag selected from the group consisting of the Fc region of the gamma globulin heavy chain, glutathione S-transferase (GST) or polyHis. 10: The recombinant chimeric fusion protein of claim 9 wherein soluble CD44vRA is fused to the Fc region of the gamma globulin heavy chain (CD44vRA-Fc). 11: A heparan sulfate of claim 8 derived from a CD44 isoform carrying at least one chain of a heparan sulfate, or a fragment thereof. 12: A heparan sulfate of claim 11, derived from a CD44 isoform selected from the group consisting of CD44s, CD44v3-v10, and CD44vRA. 13: A heparan sulfate of claim 12, wherein said CD44 variant is CD44vRA. 14: An agent according to claim 8, wherein said at least one heparan sulfate chain has at least one highly sulfated domain. 15: An agent according to claim 8, wherein said at least one heparan sulfate chain contains at least 2 monosaccharide residues. 16: An agent according to claim 26, wherein said heparan sulfate chain contains 10-16 monosaccharide residues. 17: An inhibitor of a heparan sulfate agent as defined in claim 8(iii), being selected from the group consisting of an antibody, a peptide, an oligosaccharide or a polysaccharide mimetic. 18: A method for diagnosis of rheumatoid arthritis in an individual comprising: (i) obtaining a sample from the joints of the individual; (ii) contacting said sample with a FGFR conjugated to a detection system; (iii) detecting the presence of CD44vRA expressed by the joint cells in the sample through binding of an endogenous or exogenous FGF and the conjugated receptor by adding a substrate for the detection system, whereby development of color indicates the presence of CD44vRA expressed by the joint cells and a high probability of rheumatoid arthritis. 19-25: (canceled) 26: An agent according to claim 8, wherein said at least one heparan sulfate chain contains at least 6 monosaccharide residues. 27: A method for modulation of the activity of a heparin-binding growth factor (HBGF) by enhancing or inhibiting high affinity binding of said HBGF to its receptor, which comprises administering to an individual in need an agent selected from the group consisting of: (i) a soluble CD44 isoform carrying at least one chain of a heparan sulfate; (ii) a recombinant chimeric fusion protein comprising the amino acid sequence of a soluble CD44 isoform fused to a tag suitable for proteoglycan purification, said fusion molecule being post-translationally glycosylated to carry at least one chain of a heparan sulfate; and (iii) a sugar molecule being a heparan sulfate derived from a CD44 isoform, or a fragment thereof, in an amount effective to enhance or inhibit high affinity binding of said HBGF to its receptor in said individual. 28: A method according to claim 27, wherein said HBGF is a growth factor selected from the group consisting of a member of the fibroblast growth factor (FGF), colony-stimulating factor (CSF), transforming growth factor beta (TGF-β), interleukin (IL), or bone morphogenetic protein (BMP) families, heparin-binding epidermal-like growth factor (HB-EGF), insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), macrophage inflammatory protein-1β (MIP-1β), regulated on activation, normally T cell expressed and secreted (RANTES), and hepatocyte growth factor (HGF). 29: A method according to claim 27, for modulating heparin-dependent growth factor activity relevant for promoting tissue-specific cell proliferation, migration and differentiation. 30: A method according to claim 29, for induction of angiogenesis and blood vessel formation, bone fracture healing, enhancement of wound healing, treatment of ischemic heart diseases and peripheral vascular diseases, neuronal regeneration, and promotion of tissue regeneration. 31: A method according to claim 30 wherein the promotion of tissue regeneration consists in promotion of liver regeneration, or promotion of tissue regeneration after transplantation of myocytes into heart tissues or of dopaminergic/neuronal cells into brain tissue. 32: A method according to claim 30, comprising the administration of said agent together with a compound selected from the group consisting of a FGF, a CSF, a TGF-β, an IL, VEGF, MIP-1β, BMP, IGF, HB-EGF, RANTES and HGF. 33: A method according to claim 27 for prevention and treatment of infectious and other inflammatory diseases, autoimmune diseases and CD44-dependent cancer. 34: A method for the treatment of rheumatoid arthritis comprising administering to a patient in need the soluble CD44vRA variant expressed in synovial cells of rheumatoid arthritis (RA) patients (herein CD44vRA), carrying at least one chain of a heparan sulfate, in an amount effective to treat rheumatoid arthritis in said patient. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The cell surface adhesion glycoprotein, designated CD44, formerly known as lymphocyte homing receptor has been shown to be involved in multiple cellular functions, such as cell-matrix interactions, cell migration, delivery of signals for apoptosis or, conversely, for cell survival and proliferation. In addition, CD44 variants were shown to exert some of their functions through docking and presentation of cytokines, chemokines, enzymes and growth factors to their relevant cell surface receptors or substrates (Naor et al., 1997). Hyaluronic acid is the principal ligand of CD44, but other cell surface or extracellular matrix (ECM) components, such as osteopontin, fibrinogen, fibronectin, collagen and laminin can interact with this glycoprotein. This multifunctionality of CD44 is possible due to the tremendous structural variability of this receptor derived from its highly complex genetic construction. CD44 is a single-chain type I transmembrane glycoprotein comprising a conserved extracellular domain (exons 1-5, 15, 16), a nonconserved membrane proximal region, a variable region expressing various combinations of variant exons, a conserved transmembrane segment (exon 17) and a conserved cytoplasmic tail (exon 19). The genomic map of CD44 includes 5 constant exons at the 5′ terminus and 5 constant exons in the 3′ end. In addition to the 10 constant exons, the mouse CD44 gene includes 10 variant exons in the middle of the molecule, designated V 1 -V 10 , resulting in a total of 20 exons. The human CD44 gene comprises only 9 of these 10 variant exons (V 2 -V 10 ) thus comprising a total of 19 exons (Screaton et al., 1992). Differential alternative splicing of the variant exons generates many isoforms of CD44 that express various combinations of variant exons (designated Exon Vx, x=1-10), which are inserted in the membrane proximal extracellular domain and constitute the variable region of the molecule. These CD44 variant isoforms (CD44v) are designated by the variant exons that they include, e.g. CD44v3, CD44v6, CD44v8, CD44v8,9, CD44v9, CD44v10, CD44v3-v10, etc. Theoretically, hundreds of CD44 isoforms can be generated by alternative splicing of the 10 (mouse) or the 9 (human) variant exons inserted in different combinations between the two constant exon regions, 5 exons in each end of the molecule. However, the number of the known CD44 variants (CD44v) has so far been limited to a few dozen, detected mostly on epithelial cells, keratinocytes, activated leukocytes and many types of tumor cells. Differential utilization of the 10 (mouse) or the 9 (human) variant exons as well as variations in N-glycosylation, O-glycosylation, and glycosaminoglycanation (by heparan sulfate or chondroitin sulfate), generate multiple isoforms of different molecular sizes (85-230 kDa). The smallest CD44 molecule (85-95 kDa), which results from direct splicing of constant exon 5 to constant exon 16 and thus lacks the entire variant region, is standard CD44 (CD44s), expressed mainly by hematopoietic cells and is also known as hematopoietic CD44 (CD44H). Soluble isoforms of CD44 (sCD44), the shed ectodomain of transmembrane CD44, lack the transmembrane and the cytoplasmatic tail of CD44 (Stickeler et al., 2001). The soluble form of CD44H has a molecular weight of 70-80 kDa. Although serum concentrations of soluble CD44 vary widely in healthy individuals, elevated levels of soluble CD44 have been identified in synovial fluid from rheumatoid arthritis patients and in patients with non-Hodgkin's lymphoma. The involvement of CD44 protein and variants thereof in autoimmune diseases is known, and several anti-CD44 monoclonal antibodies (mAbs) directed against the constant (anti-pan CD44 mAbs) or other regions of CD44 have been suggested as agents for treatment of various autoimmune diseases, particularly diseases of the rheumatic type (EP 538754, EP 501233, WO 9500658, WO 9409811). Marked accumulation of CD44, and sometimes hyaluronic acid, is detected in areas of intensive cell migration and cell proliferation as in wound healing, tissue remodeling, inflammation (including autoinflammation), morphogenesis and carcinogenesis. The involvement of CD44 in malignant processes has also been described by the present inventors (Naor et al., 1997). Anti-CD44 mAbs injected into mice were shown to inhibit or prevent infiltration of various lymphoma and carcinoma cells into their target organs. It has been reported that mAbs directed against the constant epitopes shared by all CD44 isoforms (anti-pan CD44 mAbs), induced resistance to several experimental inflammatory autoimmune diseases, such as collagen-induced arthritis (Nedvetzki et al., 1999), experimental allergic encephalomyelitis (EAE) (Brocke et al., 1999) and insulin-dependent diabetes mellitus (IDDM) (Weiss et al., 2000). However, targeting of CD44 constant epitopes with anti-pan CD44 mAbs may also limit the CD44-dependent physiological commitment of normal cells expressing such epitopes. In contrast, targeting of CD44 alternatively spliced variant epitopes or products of CD44 sequence alterations generated by “inaccurate” alternative splicing (as found in some cancer cells and in synovial fluid cells of RA patients) with specific mAbs could restrictively block the activity of pathological cells, i.e. the inflammatory cells found in autoimmune diseases or of cancer cells. This is conceivable because normal cells may express CD44s, CD44 isoforms expressing different variant exons or CD44 lacking the sequence alteration. Proteoglycans (PGs) are large and complex macromolecules comprised of numerous molecules of a core protein and long chains of modified sugars called glycosaminoglycans (GAGs). More specifically, GAGs are large complexes of polysaccharide chains associated with a core protein in which the polysaccharide makes up most of the mass, often 95% or more. These compounds have the ability to bind large amounts of water, thereby producing a gel-like matrix that forms the body's ground substance. GAGs stabilize and support cellular and fibrous components of tissue while maintaining the water and salt balance of the body. The combination of insoluble protein and the ground substance forms connective tissue. For example, cartilage is rich in ground substance while tendon is composed primarily of fibers. GAGs are long chains composed of repeating disaccharide units of monosaccharides (aminosugar-acidic sugar repeating units). The aminosugar, typically N-acetylglucosamine or N-acetylgalactosamine, may also be sulfated. The acidic sugar may be D-glucuronic acid or L-iduronic acid. GAGs, with the exception of hyaluronic acid, are covalently bound to a protein, forming proteoglycan monomers. The covalent attachments between GAGs and a core protein are glycosidic bonds between sugar residues and the hydroxyl groups of Ser residues in the protein. The carbohydrate structure of GAGs varies markedly among different tissues and proteoglycans, with differing patterns of sulfation, carboxyl groups, and N-acetylation on uronic acid or other carbohydrate structures. All GAGs contain hexosamine or uronic acid derivative products of the glucose pathway and from exogenous glucosamine, for example: hyaluronic acid (HA) contains N-acetylglucosamine+glucuronic acid; keratan sulfate contains sulfated N-acetylglucosamine+galactose; chondroitin sulfate (CS) contains glucuronic acid+sulfated N-acetylgalactosamine; heparan sulfate (HS) contains sulfated glucosamine+glucuronic or iduronic acid; dermatan sulfate contains sulfated iduronic acid+galactosamine. Heparin and heparan sulfate consist of alternate sequences of an uronic acid (iduronic or glucuronic) and N-acetylglucosamine, variously sulfated depending on the tissue and the animal species from which they have been obtained and, to a certain extent, on the isolation processes too. Heparan sulfate GAGs are found in many tissues—some are located in connective tissue and basal lamina, while others are moieties of surface proteins that are either integral to membranes, or extracellular, anchored to the cell by a glycosylphosphatidylinositol (GPI) linkage. Heparan sulfates, as components of proteoglycans, probably play important roles in cell-cell interactions. A number of growth factors including members of the fibroblast growth factor (FGF), colony-stimulating factor (CSF), transforming growth factor beta (TGF-β), interleukin (IL), and bone morphogenetic protein (BMP) families, heparin-binding epidermal-like growth factor (HB-EGF), insulin-like growth factor, vascular endothelial growth factor (VEGF), macrophage inflammatory protein-1β (MIP-1β), regulated on activation, normally T cell expressed and secreted (RANTES) and hepatocyte growth factor (HGF), have been shown to bind to ECM and HS. For example. FGFs bind avidly to heparin and to heparan sulfate proteoglycans (HSPGs) found on cells and in the ECM. Studies on the mode of action of FGF-2 identified a novel role for heparin-like molecules in the formation of distinct FGF-2-heparin complexes that are essential for binding of FGF-2 to its cognate receptor (Yayon et al., 1991) and subsequent signal transduction (Rapraeger et al., 1991). The crucial role of the cell surface HS was revealed by the finding that high affinity receptor binding of FGF-2 was abolished in Chinese hamster ovary (CHO) mutant cell lines defective in their metabolism of glycosaminoglyans, and that receptor binding was restored upon addition of exogenous heparin (Yayon et al., 1991). In the case of CD44, while alternative splicing is a most efficient machinery for the enrichment of the genetic information stored in a single gene, post-translation modifications by glycosylation and GAG attachments further modifies the CD44 protein, thus allowing further expansion of its functions. To this end, it was found that HS attached to the v3 exon of v3-containing CD44 PGs can bind HS-binding chemokines and growth factors. The binding of HS-binding growth factors to the CD44 proteoglycan allows frequent attachments between low affinity, high density HS-ligand complexes and their unoccupied, less abundant high affinity receptors expressed on the same cell, or more oriented and efficient presentation of the growth factor to the relevant receptor expressed on a different cell, resulting in input of transduced signals and output of cell activity (e.g., cell proliferation). The growth factor binding function of v3-containing CD44 can support both physiological (e.g. embryonic limb outgrowth) and pathological (e.g. tumor cell motility and growth) activities. As mentioned above, we and others have shown that CD44 targeting by anti-CD44 mAbs can reduce experimental tumor growth as well as pathological activities in experimental autoimmune diseases, possibly by interfering with CD44-dependent growth factor presentation, as well as disruption of other CD44-dependent functions (for example, cell migration). However, in most cases, the mAbs were directed against standard CD44 epitopes, shared by all CD44 isoforms, resulting in targeting of cells engaged in both physiological and pathological activities. On the other hand, if cells engaged in pathological activities express CD44 isoforms that are not expressed on normal cells, mAbs exclusively recognizing the CD44 variants associated with the pathological activities may reduce the disease activity with minimal damage to innocent normal cells. To test the hypothesis that disease-specific CD44 is expressed on cells involved in pathogenesis, the present inventors have previously analyzed the CD44 repertoire of synovial cells from RA patients by flow cytometry and the reverse transcriptase-polymerase chain reaction (RT-PCR). The CD44 RT-PCR products were isolated and sequenced to define the pathological CD44 mRNA. As disclosed in PCT Publication WO 00/75312, herein incorporated by reference as if fully disclosed herein, the mRNA of synovial cells from inflamed joints includes a dominant isoform, CD44v3-v10, which is also present in normal keratinocytes. The CD44v3-v10 transcript was detected in 44 of 47 patients. When the CD44v3-v10 isoform of RA synoviocytes was sequenced and its sequence was compared with the published sequence of CD44v3-v10 (Screaton et al., 1992 and 1993), it was found that it included an extra trinucleotide sequence (CAG), that was illegitimately transcribed from the end of the intron bridging exon v4 to exon v5 and inserted at the 5′ end of exon v5, allowing it to encode the hydrophobic amino acid alanine, without interfering with the entire reading frame. The translation at both sides of the new insert is not changed, as the original GAT codon (which encodes aspartic acid) is preserved as are all the other codons of exons v4 and v5. The location of the extra CAG in the CD44 transcript of the RA patient's synoviocytes is shown below: Normal CD44: Exon V4 . . . GGATGACTG ATGTAGACA . . . Exon V5 RA CD44: Exon V4 . . . GGATGACTG CA G ATGTAGACA . . . Exon V5 Ala A transcript with identical CAG insertion was detected in synovial cells of 20 out of 26 RA patients who displayed the CD44v3-v10 transcript. This CD44v of the RA patients was, therefore, designated CD44vRA. This CD44 variant is a naturally occurring molecule which has not been detected in cells of healthy individuals but only in those of RA patients. As disclosed in the above-mentioned WO 00/75312, the expressed CD44vRA enables production of CD44vRA-specific mAbs, that can be used for prevention and treatment of infectious and other inflammatory diseases, cancer and autoimmune diseases, particularly rheumatoid arthritis. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention relates, in one aspect, to a pharmaceutical composition for modulation of the activity of a heparin-binding growth factor (HBGF) by enhancing or inhibiting high affinity binding of said HBGF to its receptor, comprising a pharmaceutically acceptable carrier and an agent selected from: (i) a soluble CD44 isoform carrying at least one chain of a heparan sulfate; (ii) a recombinant chimeric fusion protein comprising the amino acid sequence of a soluble CD44 isoform fused to a tag suitable for proteoglycan purification, said fusion molecule being post-translationally glycosylated to carry at least one chain of a heparan sulfate; and (iii) a sugar molecule consisting of a heparan sulfate derived from a CD44 isoform or a fragment thereof. In another aspect, the present invention relates to the use of an agent (i), (ii) or (iii) as defined above for the preparation of a pharmaceutical composition for modulation of the activity of a heparin-binding growth factor (HBGF) by enhancing or inhibiting high affinity binding of said HBGF to its receptor. In a further aspect, the invention relates to novel agents (i) and (ii) as defined above wherein the soluble CD44 isoform is the soluble CD44vRA, and to the novel sugar molecules as defined in (iii) above wherein the heparan sulfate is derived from any CD44 isoform, preferably from the CD44vRA, or a fragment thereof, said heparan sulfate and fragments being capable of modulating the activity of a heparin-binding growth factor (HBGF). In one embodiment, the HBGF is a member of the FGF family, for example, FGF-2, and the agent of the invention can either enhance or inhibit FGF receptor binding, depending on the structure of said HS. In the proteoglycan CD44vRA, as in all heparan sulfate proteoglycans (HSPGs), there are several linear HS chains covalently attached to a protein core. According to one embodiment, the invention relates to a sugar molecule being a heparan sulfate derived from CD44vRA, that may have for example at least one highly sulfated domain. In one embodiment, said at least one HS chain isolated from the proteoglycan CD44vRA is not associated with the core protein of said CD44vRA. In another embodiment, the said at least one HS chain may be associated with the core protein of said CD44vRA. In another embodiment, the invention relates to a heparan sulfate as defined above or a fragment thereof, preferably containing at least 2, more preferably at least 5 or 6, most preferably 10-16, monosaccharide residues. In a further aspect, the invention further relates to an inhibitor of a heparan sulfate or a fragment thereof as defined above such as an antibody, a peptide or an oligosaccharide or polysaccharide mimetic. These inhibitors will, for example, inhibit angiogenesis thus being useful for inhibition of cell proliferation and migration in the treatment of primary tumors and metastasis, or in treatment of destructive inflammatory disorders. |
Method and device for integrated biomolecular analyses |
A method whereby first biological entities are recognized by way of second biological entities able to bind to the first (or the first to the second), including the steps of binding first biological entities to a surface comprising an array of first electrodes selectively energizable and addressable at least in part, positioned facing at least one second electrode, bringing the second biological entities into contact with the first, these second biological entities and possibly the first being moved by means of dielectrophoretic cages generated between the electrodes, and sensing any binding activity between at least a portion of the first and of the second biological entities, preferably utilizing radiation at a first frequency to excite fluorophore groups bound to the second biological entities and detecting the emission of fluorescence at a second frequency by means of optical sensors integrated into the electrodes, the biological entities preferably being concentrated on the electrodes by the fusion of dielectrophoretic cages. |
1-31. (Canceled) 32. A method of conducting integrated biomolecular analyses on a biological sample including unknown biological entities, with the aid of known biological entities capable of binding to the unknown biological entities, comprising the steps of immobilizing first biological entities directly or indirectly on a support, bringing second biological entities into contact with said first biological entities and detecting any binding activity between at least a proportion of said first biological entities and at least a proportion of said second biological entities; said first or said second biological entities being said unknown entities and said second or said first biological entities being said known entities; characterized: (A)—in that said support is provided by a surface consisting in an array of first electrodes (LIJ) selectively energizable and addressable at least in part, disposed facing and distanced by means of a spacer from at least one second electrode (M2), in such a manner that said second electrode, said spacer and said array of first electrodes (LIJ) combine to establish a test chamber such as will compass a liquid or semi-liquid environment (L) in which closed dielectrophoretic cages (S1) are generated selectively by means of said first electrodes (LIJ) and said second electrode (M2) for the purpose of trapping and moving at least said second biological entities in said chamber; (B)—in that said surface is treated beforehand in such a way as to promote binding with said first biological entities at said first electrodes (MIJ). 33. A method as in claim 32, wherein the immobilizing step comprises the single steps of: a. introducing a suspension of said first biological entities into said chamber compassing said liquid or semi-liquid environment (L); b. trapping and levitating said first biological entities within dielectrophoretic potential cages (S1, DEP) generated between selected first electrodes (LIJ) and said second electrode (M2); c. selectively directing said dielectrophoretic cages (S1), with said first biological entities trapped within them, toward selected first electrodes (MIJ); d. moving said cages (S1) in such a way as to bring about said binding between said first biological entities and said selected first electrodes (MIJ) and consequently immobilizing said first biological entities on said electrodes, according to a predetermined patterning sequence. 34. A method as in claim 33, further comprising the step of concentrating said first biological entities at selected first electrodes (MIJ) by bringing together and fusing two or more said dielectrophoretic cages (S1) containing one or more said first biological entities trapped within them. 35. A method as in claim 32, wherein said first biological entities are said known biological entities, and said second biological entities are said unknown biological entities, further comprising the steps of: e. introducing a suspension of populations of second biological entities, conceivably of two or more different types, into said chamber; f. concentrating at least one first part of the population of said second biological entities by attracting them into a dielectrophoretic cage (S1) generated between said electrodes (LIJ,M2); g. moving said at least one first part of the population of said second biological entities and causing it to interact with at least part of a population of said known first biological entities immobilized on said surface at a selected first electrode (LIJ); h. sensing any binding activity between at least one part of the population of unknown second biological entities and at least one part of the population of said known first biological entities immobilized on the first electrodes (LIJ). 36. A method as in claim 35, wherein said binding activity is verified by seeking to separate said populations of first and/or second biological entities one from another and/or from said first electrodes dielectrophoretically, trapping them within dielectrophoretic cages (S1) and distancing the cages from selected first electrodes (LIJ). 37. A method as in claim 36, wherein said binding activity is sensed by means of optical type sensors either located externally of said chamber or integrated into said array of first electrodes (LIJ). 38. A method as in claim 36, wherein said binding activity is sensed by means of capacitive type sensors. 39. A method as in claim 37, comprising a step of immobilizing said unknown second biological entities on microbeads having predetermined physical and chemical characteristics, such as will increase the capacitive or optical detectability of said binding activity. 40. A method as in claim 38, comprising a step of immobilizing said unknown second biological entities on microbeads having predetermined physical and chemical characteristics, such as will increase the capacitive or optical detectability of said binding activity. 41. A method as in claim 37, wherein use is made of optical sensors integrated into said array of first electrodes (LIJ), comprising the steps of: treating said second biological entities that will be bound to said first biological entities immobilized on the first electrodes (LIJ), with a substrate including fluorophore groups; exciting said fluorophores associated with the unknown first biological entities by exposing them to light emitted at a first wavelength (UV); sensing the emission of fluorescence at a second wavelength (LIG) different to the first by means of said integrated optical sensors in such a way as to determine the presence of the second biological entities bound to the first in close proximity to each first electrode (LIJ). 42. A method as in claim 32, wherein said first biological entities are said unknown biological entities, and said second biological entities are said known biological entities, further comprising the steps of: i. immobilizing populations of second biological entities, conceivably of two or more different types, on microsupports having predetermined physical and chemical characteristics, conceivably different one to another; l. introducing microsupports of at least one first type carrying said immobilized known second biological entities, into said chamber, and trapping them in dielectrophoretic cages (S1); m. causing said microsupports trapped in said dielectrophoretic cages (S1) to interact with said surface consisting in said array of first electrodes (LIJ) occupied by immobilized populations of said unknown first biological entities conceivably different one from another; n. verifying the force of any binding that occurs by seeking to separate said microsupports from said surface dielectrophoretically, trapping the microsupports within dielectrophoretic cages (S1) and distancing the cages from selected first electrodes (LIJ); p. sensing a possible presence of the microsupports where binding occurs with said selected first electrodes (LIJ) to determine whether or not said binding is still occurring. 43. A method as in claim 42, wherein said microsupports are selected from a group including microbeads of synthetic material, cells and liposomes. 44. A method as in claim 43, wherein the microsupports are microbeads of at least two types distinguishable one from another on the basis of one or more physical parameters including dielectric constant, colour, transparency or fluorescence, further comprising the step of identifying the microsupport before implementing steps (n) and (p). 45. A method as in claim 42, wherein the step of causing interaction (m) is effected by shifting the dielectrophoretic cages (S1) toward the surface. 46. A method as in claim 42, wherein the step of causing interaction (m) is effected by eliminating the dielectrophoretic cages (S1) and causing the microsupports to precipitate onto the surface. 47. A method as in claim 42, wherein the step of causing interaction (m) is effected by changing the excitation frequency of said electrodes (LIJ) so as to generate a positive dielectrophoretic force (pDEP) such as will repel the microsupports from the respective dielectrophoretic cages (S1) and thus direct them into contact with the surface. 48. A method as in claim 42, wherein the step of verifying binding force (n) dielectrophoretically is effected by distancing the dielectrophoretic cages from the surface. 49. A method as in claim 46, wherein the step of verifying binding force (n) dielectrophoretically is effected by reactivating the dielectrophoretic cages (S1) to raise the microsupports from the surface. 50. A method as in claim 47, wherein the step of verifying binding force (n) dielectrophoretically is effected by restoring the initial excitation frequency so as to attract the microsupports toward the dielectrophoretic cages (S1). 51. A method as in claim 42, wherein the step of verifying binding force (n) dielectrophoretically is replaced with a verification step (n′) effected by exposing the microsupports to a flow of buffer solution directed through said chamber. 52. A method as in claim 42, wherein the step of sensing the presence of the microsupport (p) in the position of a selected electrode (LIJ) is effected utilizing a capacitive sensor associated with the electrode (LIJ). 53. A method as in claim 42, wherein the step of sensing the presence of the microsupport (p) at the site of a selected electrode (LIJ) is effected utilizing an optical sensor associated with the electrode (LIJ). 54. A method as in claim 53, wherein said optical sensor detects radiation emitted at a first frequency (LIG) from fluorophore groups associated with said microsupport, excited by radiation emitted at a second frequency (UV) not detectable by said optical sensor. 55. A method as in claim 53, wherein said optical sensor detects the variation in incident radiation accompanying the absorption or reflection by said microsupport of a measure of radiation originating externally to said test chamber. 56. A method as in claim 42, wherein the presence of said microsupport is sensed by an optical sensor located externally to said test chamber. 57. A device for carrying out molecular biological analyses performed with the aid of movable dielectrophoretic cages (S1, DEP) as claimed in the method according to anyone of the foregoing claims, comprising a surface afforded by an array (M1) of first electrodes (LIJ) selectively energizable and addressable at least in part and arranged on an insulating support (O1); at least one second electrode (M2) positioned opposite and facing at least a part of said array (M1) of first electrodes (LIJ); and a spacer serving to distance the first electrodes (LIJ) from said at least one second electrode (M2) in such a way that said second electrode, said spacer and said array (M1) of first electrodes combine to establish a test chamber encompassing a liquid or semi-liquid environment (L); and further comprising integrated optical sensors located beneath or in close proximity to at least one of said first electrodes (LIJ); characterized in that said integrated optical sensors consist in junction photodiodes (CPH) located at a given depth (DEP) from a surface of a semiconductor substrate (C) such as to render them substantially insensitive to radiation of a first predetermined wavelength (UV) and sensitive to radiation of a second predetermined wavelength. |
<SOH> BACKGROUND ART <EOH>A great many immunological methods have been developed in recent years allowing the determination of antigens and antibodies, both for purely scientific and for diagnostic purposes. Immunoassays Immunological tests, or immunoassays, utilize a number of notably powerful methods for identifying and measuring antigens and antibodies. Specific antibodies are available for an increasing number of antigens, soluble, immobilized (on plates, resins or membranes), conjugated and otherwise. Moreover, with the range of systems for analyzing antigen-antibody complexes becoming steadily wider, and their sensitivity continuing to be improved, the potential and the range of applications for immunological reactions and techniques have been extended conspicuously. In the case of soluble antigens and antibodies, assays are based on the labelling of one of the reagents, on the formation and precipitation of immunocomplexes, or on the measurement of an effector function expressed by the antibody. For some time, the most sensitive system available was radioimmunoassay (RIA), developed by Yarlow and Benson in 1960. This method betrays numerous drawbacks at all events, including the need for special equipment, also for special precautions against radiation (and for specially trained staff), and the limited average life of the radioactive isotopes used for labelling purposes. Such constraints soon led to the notion of replacing isotopes with enzymes as the labelling medium. The first studies on Enzyme Immunoassay (EIA) were conducted by Schuurs et al. and disclosed in a series of patents: U.S. Pat. Nos. 3,654,090; 3,791,932 and successive references. EIA methods include ELISA (Enzyme-Linked ImmunoadSorbent Assay) and its numerous variations, which currently are the methods of choice in the art fields of research and diagnostics. EIA-ELISA procedures are categorized as competitive and non-competitive, which in turn can be homogeneous or heterogeneous. Whilst homogeneous assays require no physical separation, heterogeneous assays require separation of the free antigen fraction from the fraction bound to the antibody, obtained by means of a solid phase system consisting generally in polystyrene, cellulose or nylon substrates to which the antibodies are bound. The substrates are usually 96- and 384-well microtiter plates or microstrips having 8, 12 and 16 wells, though they can also consist in single elements known as microbeads, on which the antigens or antibodies are immobilized. Competitive enzyme immunoassays are those where the antibody is present in a limited concentration. In non-competitive or immunometric assays, on the other hand, a notable excess of the antibody is used, conjugated with the enzyme, so as to maximize the antigen signal. Among non-competitive enzymatic immunoassays, the system most widely adopted involves capturing antigens from the sample on the walls of microsites coated with antibodies, generally monoclonal (mAb). The captured antigen is marked by coating it with a second layer of specific antibodies (secondary antibodies) with or without further amplification steps. The secondary antibody is often conjugated with an enzyme, the conversion of the enzyme demonstrating the presence of a given antigen: this is known as a sandwich ELISA assay. With a wide range of substrates available for marker enzymes, it is possible to choose between different detection methods. The substrates are reagents that allow of displaying, qualifying and/or quantifying an analyte of interest in an enzyme immunoassay. Substrates can be chromogenic, chemiluminescent or fluorescent. Chromogenic substrates produce a coloured compound that can be identified visually and quantified with a spectrophotometer. Chemiluminescent substrates produce light that can be measured with a luminometer or recorded permanently on X-ray film. Fluorescent substrates on the other hand emit fluorescence that is measured with a fluorometer. Chromogenic and chemiluminescent substrates are excellent media for the detection of conjugates labelled with enzymes bound indirectly to a solid support. The enzymes commonly used for the purpose are peroxidase, generally Horse Radish Peroxidase (HRP), which catalyzes the fission of H 2 O 21 Alkaline Phosphatase (AP), which removes the phosphate from phosphorylate molecules, and β-galactosidase (β-Gal), which hydrolyzes lactose. The conversion of numerous substrate molecules by a single enzyme molecule produces a notable amplification of the signal, though if a luminogenic or fluorogenic substrate is used, the signal/mass is still greater, comparable to that obtained with Radioimmunoassays. EIA methods are powerful, but affected by the serious limitation of low productivity (given the difficulty of conducting significant numbers of analyses in parallel), due mainly to the scant possibilities for integration afforded by the various items of equipment needed to carry out the procedure. This makes it all but impossible to process thousands of samples simultaneously or at least in a short time, whereas speed is becoming more and more a fundamental aspect of modern research and diagnostics. In addition, EIA can involve a relatively heavy consumption of costly reagents. Labelled Microbeads Not least in order to overcome the aforementioned drawbacks, the use of microbeads labelled selectively employing various fluorescence methods is gaining more and more importance in the art field of biotechnologies. Especially pertinent in this field are the following patents: WO 00/68692 in the name of Quantum Dot Corporation, which discloses various assay methods utilizing semiconductor nanocrystals, each emitting at distinct wavelengths, as specific markers for different microbeads; WO 01/13120 A1 in the name of Luminex Corporation, which discloses microparticles emitting multiple fluorescence signals and methods for their use in a cytofluorometric system. Molecular Sensors Based on Surface Plasmon Resonance U.S. Pat. No. 5,641,640 in the name of BIAcore AB, discloses a system for the analysis of biological samples using surface plasmon resonance. Molecules of a sample held in suspension are directed into a chamber, of which the surface carries immobilized molecules potentially capable of binding with those of the sample. The binding of the molecules is sensed by indirect measurement of the variation in the refraction index caused by the binding of the molecules with the surface, observing the reflection from the surface of a suitable light source. Dielectrophoresis Dielectrophoresis relates to the physical phenomenon whereby dielectric particles subject to spatially non-uniform d.c. and/or a.c. electric fields undergo a net force directed toward those regions of space characterized by increasing (pDEP) or decreasing (nDEP) field strength. If the strength of the resulting forces is comparable to the force of gravity, it is possible in essence to create an equilibrium of forces enabling the levitation of small particles. The strength, direction and orientation of the dielectrophoretic force are heavily dependent on the dielectric and conductive properties of the body and of the medium in which it is immersed, and these properties in turn vary with frequency. Studies analyzing the effects of dielectrophoretic forces on particles (the term “particles” is used hereinafter to indicate dielectrophoretically manipulated bodies or elements) consisting in biological entities (the term “biological entities” is used hereinafter to indicate cells and microorganisms, or parts thereof, namely DNA, proteins, etc.) or artificial objects consisting of inorganic matter, have suggested for some time the notion of exploiting these forces as a means of selecting a particular body from a sample containing a plurality of microorganisms, characterizing the physical properties of microorganisms and in general allowing their manipulation. Accordingly, it has been found advantageous to utilize systems comparable in size to those of the microorganisms being manipulated, and thus reduce the magnitude of the voltages used to create the field distributions needed to reveal the aforementioned effects. Particles exposed to the phenomenon of dielectrophoresis are subject to forces dependent on the volume of the particle; this being the case, it has been assumed for some time that there must be a lower limit for particle size, beneath which dielectrophoretic force would be defeated by Brownian movement. It was considered that there would be a need for electric fields of magnitude such that local warming of the fluid would increase local flow and effectively prevent dielectrophoretic manipulation. Pohl (1978) speculated that the electric fields needed to trap particles smaller than 500 nm subject to Brownian movement would be too strong. The first group to overcome this obstacle was that of Washizu (Washizu et al., Trans. Ind. Appl. 30:835-843, 1994), who used positive dielectrophoresis to precipitate small proteins down to 25 kDa. This lowering of the threshold was favoured by improvements in electrode manufacturing technologies, notably the use of electron beams in manufacture. Thereafter, Fuhr et al. (Fuhr, 1995, Proc. St Andrews Meeting of Society for Experimental Biology p.77; Mueller et al., 1996 , J. Phys. D: Appl. Phys. vol.29:340-349) and Green et al. (Green et al., 1995, Proc. St Andrews Meeting of Society for Experimental Biology p.77; Green et al., 1997 , J. Biochem. Biophys. Methods vol.35:89-102) demonstrated that viruses of 100 nm diameter could be manipulated employing negative dielectrophoresis. It was also shown that latex microbeads of 14 nm diameter could be trapped both with positive and with negative dielectrophoresis (Mueller et al., 1996, J. Phys. D: Appl. Phys. vol.29:340-349). Subsequent studies showed that 68 kDa molecules of the protein avidin can be concentrated from solution using both positive and negative dielectrophoresis (Bakewell et al., 1998, Proc. 20th Ann. Int. Conf. IEEE Eng. Med. Biol. Soc. 20, 1079-1082). Patent application PCT/WO 00/47322 discloses an apparatus and a method for manipulating particles utilizing closed dielectrophoretic potential cages, generated by singly and selectively addressable and mutually energizable adjacent electrodes making up an array. Patent application PCT/WO 00/69565, filed by the same applicant, discloses a more efficient apparatus than that mentioned above and describes various methods of manipulating particles utilizing closed dielectrophoretic potential cages. The device described in this second PCT application is illustrated in FIG. 1 and comprises two basic modules; the first such module consists in a regularly distributed array. M of electrodes LIJ arranged on an insulating support (O 1 in FIG. 1 ). The electrodes LIJ can be of any given conductive material, preference being given to metals compatible with electronic integration technology, whereas the insulating medium O 1 can be silicon oxide or any other insulating material. The electrodes of the array can be of any given shape; in the example of FIG. 1 , the electrodes are square. Each element of the array M 1 consists in an electrode LIJ that is selectively addressable and energizable in such a way as to generate a dielectrophoretic cage S 1 ( FIG. 1 ) by means of which to manipulate a particle, generally a biological entity (BIO in FIG. 1 ), all of which occurring in a liquid or semi-liquid environment denoted L in FIG. 1 . The region beneath the electrodes (C in FIG. 1 ) can be occupied by sensing means, and more exactly integrated circuits incorporating sensors of various types, able to detect the presence of single particles in potential cages generated by the electrodes. In a preferred embodiment, the second main module appears substantially as a single large electrode M 2 , covering the device in its entirety. Finally, the device may also include an upper support structure (O 2 in FIG. 1 ). The simplest form for the second electrode M 2 is that of a plain flat and uniform surface; other forms of greater or lesser complexity are possible (for example a grid of given mesh size through which light is able to pass). The most suitable material for the upper electrode M 2 will be a transparent conductive material. Besides allowing the inclusion of sensing circuits as outlined previously, this will also allow the use of traditional optical inspection means (microscope and TV camera) located above the device. Among the singular aspects of the invention disclosed in patent application PCT PCT/WO 00/69565, parts of which are incorporated into the present specification where necessary for reference purposes, is that the one substrate can accommodate both the elements capable of manipulating the particles (biological entities), and the sensing devices. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a schematic three-dimensional view showing part of a prior art device for the manipulation of a sample, which presents a modular structure composed of a support containing the electrodes, and a lid; FIG. 2 illustrates one possible embodiment of an integrated optical sensor according to the present invention; FIG. 3 is a detailed step-by-step illustration of the method according to the invention; FIG. 4 illustrates a test procedure in which the sample containing the protein to be identified is immobilized on the electrodes, whereupon dielectrophoretic cages are generated above the electrodes; FIG. 5 shows another way of conducting an immunological assay according to the invention, in which there is no need to move the cages; FIG. 6 shows the spectral emission response of certain fluorescent molecules excited by a monochrome laser source emitting ultraviolet radiation at 405 nm; FIG. 7 illustrates an enlarged detail of FIG. 2 , viewed schematically and representing a cross section through a planar MOS device associated with a well diffusion; FIG. 8 shows the spectral responses, calculated mathematically on the basis of the semiconductor device equations, interpolated with silicon related experimental absorption data, of the two junctions of FIG. 7 for a typical CMOS device with detail definition of 0.7 μm. detailed-description description="Detailed Description" end="lead"? |
Remedies for heart diseases |
This invention aims at providing a method of searching for substances that can selectively suppress apoptosis in cardiovascular cells. This objective is attained by providing a method of screening for therapeutic and/or prophylactic agents of cardiac disease, which comprises the steps of inducing apoptosis in cultured myocardial cells and/or cultured vascular endothelial cells; treating the cells with a Cl− channel blocker under test; and evaluating the therapeutic and/or prophylactic effect of the blocker under test on cardiac disease by checking to see if it can suppress apoptotic cell death in the cardiovascular cells or vascular endothelial cells. |
1. A method of screening for therapeutic and/or prophylactic agents of cardiac disease, which comprises the steps of: inducing apoptosis in cardiovascular cells; treating the cells with a Cl− channel blocker under test; and evaluating the therapeutic and/or prophylactic effect of the blocker under test on cardiac disease by checking to see if it can suppress apoptotic cell death in the cardiovascular cells. 2. The method according to claim 1, wherein the cardiovascular cells are cultured myocardial cells and/or cultured vascular endothelial cells. 3. The method according to claim 1, wherein the ability to suppress apoptotic cell death is assessed by decreased cell viability, decreased cell volume, cytochrome c release, caspase activation, DNA fragmentation, the formation of apoptotic bodies, or the expression of an apoptosis-related specific antigen. 4. The method according to claim 1, wherein apoptosis induction and the treatment of the blocker under test are performed simultaneously. 5. The method according to claim 1, wherein apoptosis induction and the treatment of the blocker under test are performed consecutively. 6. The method according to claim 1, wherein the cardiac disease is ischemic heart disease. 7. (canceled) 8. The method according to claim 2, wherein the ability to suppress apoptotic cell death is assessed by decreased cell viability, decreased cell volume, cytochrome c release, caspase activation, DNA fragmentation, the formation of apoptotic bodies, or the expression of an apoptosis-related specific antigen. 9. The method according to claim 8, wherein apoptosis induction and the treatment of the blocker under test are performed simultaneously. 10. The method according to claim 8, wherein apoptosis induction and the treatment of the blocker under test are performed consecutively. 11. The method according to claim 10, wherein the cardiac disease is ischemic heart disease. 12. The method according to claim 9, wherein the cardiac disease is ischemic heart disease. 13. A therapeutic composition for the treatment of cardiac disease, comprising an amount sufficient for said treatment of a Cl− channel blocker as active ingredient, and a pharmaceutically acceptable excipient or carrier therefor. |
<SOH> BACKGROUND ART <EOH>Most cases of cardiac disease are primarily due to structural or functional damage to the coronary artery which causes imbalance between blood supply from the coronary artery and its demand by the myocardium, eventually leading to acute or chronic ischemic myocardial dysfunction. If myocardial cells become ischemic, it is believed apoptosis consequently occurs in them. Once apoptosis has been triggered off, myocardial cells are incapable of avoiding apoptosis and cell death occurs, leading to serious conditions of symptomatic cardiac disease such as angina pectoris, myocardial infarction and heart failure. In the process of apoptosis which is known as physiological cell death, it is known that progressive cell shrinkage first occurs, then followed by cell fragmentation (formation of apoptotic bodies). At the very early stage in the course of this apoptotic cell death which is prior to the formation of apoptotic bodies, there occurs normotonic cell shrinkage called apoptotic volume decrease (AVD) (Maeno, E. et al., Proc. Natl. Acad. Sci. U.S.A., Vol. 97, 9487-9492, 2000). Induction of AVD under normotonic conditions is associated with facilitation of regulatory volume decrease (RVD) which occurs after cell swelling has been physicochemically compelled by extracellular hypotonic stresses. Both the AVD induction and the RVD facilitation are known to occur at the very early stage of apoptosis, preceding cytochrome c release from mitochondria, caspase (e.g. caspase-3) activation, DNA ladder formation and ultrastructural alterations. AVD and RVD have been closely studied in many cell types including epithelial cell lines (e.g. human derived epithelial HeLa cell), lymphoid cell lines (e.g. human derived lymphoid U937 cell) and neuronal cell lines (e.g. rat pheochromocytoma PC12 cell and mouse neuroblastoma x rat glioma hybrid NG108-15 cell). As a result, it has been found that the aforementioned RVD is primarily caused by KCl efflux owing to parallel activation of the Ca 2+ -dependent K + channel and the volume-sensitive outwardly rectifying Cl − channel (VSOR-ClC, also called the volume regulated anion channel (VRAC) or the volume-sensitive organic osmolyte and anion channel (VSOAC)). Also it is known that if the AVD induction and RVD facilitation are inhibited by blocking the volume-regulatory Cl − channel or K + channel, the above-mentioned cells do not undergo any biochemical or morphological changes that accompany apoptosis and apoptotic cell death itself can be prevented. It is known in many cells that the K + channel is always activated if the cell is at quiescence state whereas the Cl − channel is not activated unless it is necessary, except in limited cell types including skeletal muscle and erythrocyte. Therefore, VSOR-ClC is considered to play a more important role in the AVD induction and the RVD facilitation but its entity is yet to be unraveled. Many studies have shown that different kinds of tissues as cell sources express different volume-regulatory Cl − channels. For example, it has been suggested that ClC-3 is the entity of VSOR-ClC in myocardial cells (Duan et al., Nature 1997;390:417-421; Britton et al., Am J Physiol Heart Circ Physiol 2000;279:H2225-2233; and Duan et al. J Physiol 2001;531:437-444). Specifically known are the following: a study in which gpClC-3 clones were cloned from guinea pig hearts, expressed in the atria and ventricles by the detection using Northern blot and transfected into cultured cells (NIH/3T3 cells), which were used to detect current activity of similar nature to VSOR-ClC current found in myocardium (Duan et al. Nature 1997;390:417-421); a study in which ClC-3 specific antibodies were used to show immunohistochemically that ClC-3 existed in both sarcolemmal membranes and cytoplasmic regions (Britton et al. Am J Physiol Heart Circ Physiol 2000;279:H2225-2233); and a study in which VSOR-ClC-like currents were shown to be suppressed in gpClC-3 transfected NIH/3T3 cells by injecting them with an anti-ClC-3 antibody (product of Alomone) and which further showed that VSOR-ClC currents inherently observed in guinea-pig myocardium were similarly suppressed by injection of the same antibody, thus concluding that endogenous ClC-3 is an entity responsible for VSOR-ClC inherently observed in myocardium (Duan et al. J Physiol 2001;531:437-444). On the other hand, it was suggested in experiments employing cells from tissues other than the myocardium that ClC-3 was not the entity of VSOR-ClC (Stobrawa et al. Neuron 2001;29:185-196; and Weylandt et al. J Biol Chem 2001;276:17461-17467). Specifically known are the following: a study in which a knockout mouse with a deletion of exon 3 from the ClC-3 gene was created for the first time and which, in view of the fact that in the knockout mouse, ClC-3 was absent from the membrane protein, there was no enhancement of ClC-4 and ClC-5 expression and that VSOR-ClC currents were not affected in hepatocytes and pancreatic acinar cells, suggested that the entity of VSOR-ClC was other than ClC-3, and which further showed that ClC-3 existed in intracellular endosomal membranes and that the homo-knockout mouse had only poor postnatal growth (weight gain), suffering from degeneration of the hippocampus and the retina (Stobrawa et al. Neuron 2001;29:185-196); and a study using HEK293 cells with stable expression of any one of several hClC-3 variants demonstrated that the ClC-3 protein which was predominantly located on intracellular organelles such as Golgi body was also found in the plasma membranes, but concluded that hClC-3 is not VSOR-ClC since both the control (untransfected) cells and a series of transfected cells showed no significant difference in VSOR-ClC current activity and RVD (Weylandt et al. J Biol Chem 2001;276:17461-17467). Thus, it is not completely clear if VSOR-ClC can similarly suppress apoptosis in cells or tissues other than the heretofore studied cell lines, for example, in myocardial cells. In addition, little has been known about the mechanism behind apoptosis in myocardial cells and which compounds are capable of selectively suppressing apoptosis in myocardial cells. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a graph showing how SITS was effective at 125, 250 and 500 μM in suppressing the 1 μM staurosporine (STS-1) induced decrease in viability of primary cultures of rat myocardial cells (cultured rat myocardial cells) on 24-well multiwell plates; each column represents a mean value and each bar, ± standard error (SE), and these definitions will apply in the following figures; FIG. 2 is a graph showing how SITS was effective at 500 and 1000 μM in suppressing the STS-1 induced decrease in viability of cultured rat myocardial cells on 24-well multiwell plates; FIG. 3 is a graph showing how SITS was effective at 250 and 500 μM in suppressing the STS-1 induced decrease in viability of cultured rat myocardial cells on 96-well multiwell plates; FIG. 4 is a graph showing how DIDS was effective at 62.5, 125 and 250 μM in suppressing the STS-1 induced decrease in viability of cultured rat myocardial cells on 24-well multiwell plates; FIG. 5 is a graph showing how DIDS was effective at 250 μM in suppressing the STS-1 induced increase in the caspase-3 activity of cultured rat myocardial cells on 12-well multiwell plates; FIG. 6 is a graph showing that even in an HCO 3 − -free culture solution, the STS-1 induced a decrease in the viability of cultured rat myocardial cells on 24-well multiwell plates and also showing how DIDS was effective at 62.5, 125 and 250 μM in suppressing the STS-1 induced decrease in cell viability; FIG. 7 is a graph showing that even in an HCO 3 − -free culture solution, the STS-1 induced a decrease in the viability of cultured rat myocardial cells on 96-well multiwell plates and also showing how SITS was effective at 125, 250 and 500 μM in suppressing the STS-1 induced decrease in cell viability; FIG. 8 is a graph showing how SITS was effective at 125, 250 and 500 μM in suppressing the STS-1 induced decrease in viability of a cell line from bovine arterial endothelial cells on 24-well multiwell plates; and FIG. 9 is a graph showing how SITS was effective at 500 μM in suppressing the 1 μM or 3 μM staurosporine (STS-1 or STS-3) induced decrease in viability of a cell line from bovine arterial endothelial cells on 24-well multiwell plates. detailed-description description="Detailed Description" end="lead"? |
Fusion proteins for insect control |
A fusion protein comprising a translocating moiety and a toxic moiety wherein the translocating moiety comprises a plant protein that is capable of acting as a carrier to translocate the toxic moiety across the gut wall of at least one plant pathogen, wherein the toxic moiety is adapted to be effective as a toxic agent following translocation; composition comprising the protein, methods for preparation thereof; polynucleotide encoding the fusion protein, vector comprising the polynucleotide, host cell and transgenic plant cell or plant that is resistant to pathogen, expressing the fusion protein, and uses thereof in combatting plant pathogens and in insect control. |
1. A fusion protein comprising a translocating moiety and a toxic moiety wherein the translocating moiety comprises a plant protein that is capable of acting as a carrier to translocate the toxic moiety across the gut wall of at least one plant pathogen, wherein the toxic moiety is adapted to be effective as a toxic agent following translocation and wherein a toxic agent is a natural or synthetic pest insect or related arthropod-derived peptide or protein or neuropeptide or metabolite or analogue thereof, capable of causing deleterious effects on growth, development, reproduction or mortality in pest insects or related arthropods. 2. A fusion protein as claimed in claim 1 wherein a toxic agent is an allatostatin, chitinase or diuretic hormone, metabolitic or analogue thereof. 3. A fusion protein as claimed in claim 1 wherein a toxic agent is derived from insects such as cockroach, blowfly, mosquito, webworm, beetle, or related arthropods such as antipede, millipede, crab, lobster, shrimp, prawn, spider, scorpion, mite, tick and the like. 4. A fusion protein as claimed in claim 1 wherein insect peptides for inclusion in the fusion protein include any one or more of the following neuropeptides and their natural or synthetic metabolites or analogues: Manduca sexta allatostatin (Manse-AS); cockroach allatostatin such as those found in either of the following species Diplotera punctata or Periplaneta americana or blowfly allatostatin such as in the species Calliphora vomitaria; alternatively insect specific enzymes such as an insect chitinase for example, those found in M. sexta; Bombyx mori; the mosquito Anopheles gambiae; fall webworm Hyphantria cunea; beetle Phaedon cochleariae; or Lacanobia oleracea; alternatively, peptides comprising, or derived from, insect diuretic hormones such as those isolated from any one or more of the aforementioned species, or related arthropod hormones. 5. A fusion protein as claimed in claim 1 wherein a toxic agent is selected from the following group of toxic proteins and their metabolites and analogues: Manduca sexta Manse-AS (16, 17); Diploptera punctata allatostatin (38); Periplaneta americana allatostatin (39); Calliphora vomitaria allatostatin (40); or insect chitinase such as M. sexta chitinase (37, 34, 35); Bombyx mori chitinase (34, 37); Anopheles gambiae chitinase (36); Hyphantria cunea chitinase (34); Phaedon cochleariae chitinase (33) or Lacanobia oleracea chitinase; or insect diuretic hormone such as that isolated from M. sexta (32). 6. A fusion protein as claimed in claim 1 wherein a toxic agent is selected from an insect protein selected from the group consisting of SEQ ID NOS: 3-8 and 14-17, and natural or synthetic metabolites or analogues or effective fragment thereof. 7. A fusion protein as claimed in claim 1 wherein a plant protein comprises a plant lectin. 8. A fusion protein as claimed in claim 1 wherein a plant protein for inclusion in the novel compound is selected from any one or more of the following plant lectins: snowdrop lectin (GNA), pea lectin Pisum sativum (P-lec), peanut lectin Arachis hypogaea, French bean lectin (PHA, phytohaemo glutinin), and analogues thereof. 9. A fusion protein as claimed in claim 1 wherein the moieties of the fusion protein are linked together by genetic or biochemical means and so, in the first instance, by at least one linking peptide or, in the second instance, by a covalent or non-covalent bond or linking moiety. 10. A fusion protein as claimed in claim 1 which is capable of destroying, or at least debilitating, any one or more classes of insect or related arthropods, preferably pathogens, selected from: Coleopterans, Lepidopterans and Homopteran pests, more preferably Coleopterans eg. Southern corn rootworm (Diabrotica undecimpunctata); cowpea bruchid (Callosobruchus maculatus); Lepidopterans eg. European cornborer (Ostinia nubilalis); tobacco hornworm (Manduca sexta); stem borer (Chilo partellus): Homopteran pests eg. Rice brown plant hopper (Nilaparvata lugens); rice green leaf hopper (Nephotettix cinciteps); potato leaf hopper (Empoasca fabae); peach potato aphid (Myzus persicae). 11. A fusion protein as claimed in claim 1 which comprises the protein of SEQ ID NO:1 which is a fusion of GNA (snowdrop lectin) and Manse-AS (Manduca sexta allatostatin). 12. A pesticidal composition comprising a fusion protein as claimed in claim 1 in the form of a solution, emulsion, spray, suspension, powder, foam, paste, granule, aerosol, capsule or other finely or coarsely divided material or impregnant for natural or synthetic material, in admixture with suitable carriers, diluents, adjuvants, preservatives, dispersants, solvents, emulsifying agents or the like suitable for physically or chemically associating with plants or their locus, and for oral uptake by pathogens. 13. Composition as claimed in claim 12 comprising fusion protein in an amount of between 0.1 and 99% by weight, preferably between 0.5 and 98% by weight, more preferably between 1.0 and 95% by weight. 14. Method for administering a fusion protein as claimed in claim 1 or a composition including said fusion protein to a plant or its locus for combating insect pests. 15. A process for the preparation of a composition as claimed in claim 12 which comprises the admixture of an amount of a fusion protein and carrier, diluents, adjuvants, preservatives, dispersants, solvents, emulsifying agents or the like, in effective pesticidal amount for the oral administration of an effective pesticidal amount of the fusion protein. 16. Process for the preparation of a fusion protein as claimed in claim 1 by biochemical or chemical synthesis, expression, coupling or modification or the like. 17. A polynucleotide encoding a fusion protein as claimed in claim 1. 18. The nucleotide sequence as claimed in claim 17 comprising SEQ ID NO:1. 19. A vector comprising at least one polynucleotide as claimed in claim 17. 20. A vector as claimed in claim 19 comprising one polynucleotide which is one of two vectors each comprising one of said separate polynucleotides; or comprising two or more separate polynucleotides wherein each polynucleotide encodes a different moiety of said fusion protein. 21. At least one vector as claimed in claim 19 wherein each polynucleotide is provided with a complementary binding domain whereby the polynucleotides can be linked together, pre or post translationally, to form a functional fusion protein. 22. At least one vector as claimed in claim 19 wherein the at least one polynucleotide(s) is/are operatively linked to regulatory sequences allowing expression of said fusion protein in a host cell. 23. At least one vector as claimed in claim 19 which is selected from plasmids, cosmids, viruses, bacteriophages or other vectors used in genetic engineering. 24. A host cell comprising at least one polynucleotide and/or vector and regulatory sequences as claimed in claim 17. 25. A host cell as claimed in claim 24 which is prokaryotic or eukaryotic such as bacterial, insect, fungal, plant or animal wherein regulatory sequences are adapted accordingly to enable expression of said polynucleotide(s) in said host species. 26. A method for the production of a fusion protein comprising: culturing a host cell comprising at least on polynucleotide and/or vector and regulatory sequences as claimed in claim 17 under conditions suitable for expression of the fusion protein; and harvesting the fusion protein from the culture. 27. A method for the production of transgenic plant cells or plants that are resistant to disease comprising: transforming a selected plant genome with the at least one vector as claimed in claim 19. 28. A transgenic plant cell or plant, or their progeny, including in its genome a polynucleotide encoding the fusion protein as claimed in claim 1. 29. A transgenic plant cell or plant, or their progeny produced by the method of claim 27. 30. Use of a fusion protein as claimed in claim 1 in the manufacture of a pesticide or a transgenic plant cell or plant. 31. Use of the pesticide as claimed in claim 30 to destroy, or debilitate one or more pathogens. 32. A fusion protein, composition, vector, polynucleotide, host cell, transgenic plant, or methods for the preparation or use thereof substantially as herein described in the description or sequences or illustrated in the Figures. |
Process for producing polymer |
A process for producing an olefin polymer with high polymerization activity without using an expensive co-catalyst or using a limited amount of the co-catalyst, more particularly a process for producing a high molecular weight (co)polymer with high polymerization activity even at a high polymerization temperature which is more practical. At least one olefin is polymerized by means of a polymerization catalyst comprising at least one transition metal compound selected from transition metal compounds which have a substituted indenyl group, represented by a certain specific chemical formula, and an organoaluminum compound represented by the formula Al(R)3. |
1. A process for producing an olefin polymer, characterized by polymerizing at least one olefin by means of a polymerization catalyst comprising at least one transition metal compound selected from transition metal compounds represented by the following formula (1) and an organoaluminum compound represented by the following formula (2): wherein each A is a substituted indenyl group, or one of A is a substituted indenyl group and the other is a group selected from groups which have a nitrogen atom or an oxygen atom coordinated or directly bonded to metal M and, if necessary, a C1-20 hydrocarbon group (said groups may further contain from 1 to 3 boron, silicon, phosphorus, selenium, sulfur, chlorine or fluorine atoms), and in a case where each A is a substituted indenyl group, the two A may be the same or different; Y is a substituted methylene group, a substituted 1,2-ethanediyl group, a substituted 1,3-propanediyl group, a substituted silicon group, a substituted boron group, a substituted germylene group or a substituted aluminum group, which has bonds to the two A and further has hydrogen or a C1-20 hydrocarbon group as a substituent, and the substituent in Y may contain from 1 to 5 nitrogen, boron, silicon, phosphorus, selenium, oxygen, sulfur, chlorine or fluorine atoms, or may have a cyclic structure; X each independently is hydrogen, halogen, a C1-15 alkyl group, a C3-20 alkenyl group, a C6-10 aryl group, a C8-12 alkylaryl group, a silyl group having a C1-4 hydrocarbon substituent, a C1-10 alkoxy group, or an amido or amino group having hydrogen or a C1-22 hydrocarbon substituent; n is 0, 1 or 2; and when a plurality of X are present, they may be bonded to one another, and M is zirconium, hafnium or titanium; Al(R)3 Formula (2) wherein R each independently is hydrogen or C2-20 hydrocarbon, provided that among these R, one or two may be halogen; R may have a cyclic structure; when these R are hydrocarbon groups, they may contain from 1 to 5 nitrogen, silicon, phosphorus or halogen atoms; a plurality of R in the formula may have a bonding structure; and a plurality of such organoaluminum compounds may be bonded via R. 2. The process for producing an olefin polymer according to claim 1, characterized in that the substituted indenyl group is a substituted indenyl group represented by the following formula (3-1) or (3-2): in the formulae (3-1) and (3-2), Ra each independently is a substituent of hydrogen, halogen, a hydroxyl group, an amine group or a C1-20 hydrocarbon group; the hydrocarbon group may contain from 1 to 3 halogen, silicon, phosphorus, oxygen, boron, nitrogen, sulfur or selenium atoms; and they may have a structure of an OSiR3 group, a SiR3 group, an NR2 group, an OH group, an SR group, a SeR group, an OR group or a PR2 group (each R is a C1-10 hydrocarbon group); and Rb each independently is a substituent of hydrogen, halogen, a hydroxyl group, an amine group or a C1-20 hydrocarbon group; the hydrocarbon group may contain from 1 to 3 halogen, silicon, phosphorus, oxygen, boron, nitrogen, sulfur or selenium groups; they may have a structure of an OSiR3 group, a SiR3 group, an NR2 group, an OH group, an SR group, a SeR group, an OR group or a PR2 group (each R is a C1-10 hydrocarbon group); and further, adjacent substituents of such hydrocarbons may be united to form a single or plural 5- to 8-membered cyclic aromatic rings or aliphatic rings; provided that at least one of Ra is not hydrogen, or at least one of Rb is not hydrogen. 3. The process for producing an olefin polymer according to claim 2, characterized in that the two A in the formula 1 are substituted indenyl groups represented by the formula (3-1) or (3-2), and in this case, the two A may be the same or different. 4. The process for producing an olefin polymer according to claim 1, characterized in that at least one A or the two A in the formula 1 are any one of substituted benzoindenyl groups which may have substituents, represented by the formulae (4-1) to (4-3), and in this case, the two A may be the same or different: in the above formulae (4-1) to (4-3), R1a, R1b, R2a, R2b, R3a and R3b each independently is a substituent of hydrogen, halogen, a hydroxyl group, an amine group or a C1-20 hydrocarbon group; these hydrocarbon groups may contain from 1 to 3 halogen, silicon, phosphorus, oxygen, boron, nitrogen, sulfur or selenium atoms; they may have a structure of a OSiR3 group, a SiR3 group, an NR2 group, an OH group, an OR group, an SR group, a SeR group or a PR2 group (each R is a C1-10 hydrocarbon group); these R1a each other, R1-b one another, R2a each other, R2b one another, R3a each other and R3b one another, may be the same or different; and further, adjacent such substituents may be united to form a single or plural 5- to 8-membered cyclic aromatic rings or aliphatic rings. 5. The process for producing an olefin polymer according to claim 1, characterized in that the transition metal compound is one represented by the formula (1) wherein Y is a substituted silicon group or a substituted boron group, which has bonds to the two A and further has hydrogen or a C1-20 hydrocarbon group as a substituent, provided that the substituent in Y may contain from 1 to 5 nitrogen, boron, silicon, phosphorus, selenium, oxygen, sulfur, chlorine or fluorine atoms, or may have a cyclic structure. 6. The process for producing an olefin polymer according to claim 1, characterized in that the transition metal compound is one represented by the formula (1) wherein Y is a substituted boron group, which has bonds to the two A and further has hydrogen or a C1-20 hydrocarbon group as a substituent, provided that the substituent in Y may contain from 1 to 5 nitrogen, boron, silicon, phosphorus, selenium, oxygen, sulfur, chlorine or fluorine atoms, or may have a cyclic structure. 7. The process for producing an olefin polymer according to claim 1, characterized in that the organoaluminum compound is triisobutyl aluminum. 8. The process for producing an olefin polymer according to claim 1, characterized in that the amount of aluminum in the organoaluminum compound is within a range of from 10 to 100,000 times by molar ratio to the transition metal in the transition metal compound. 9. The process for producing an olefin polymer according to claim 1, characterized in that at least one olefin is polymerized by means of a polymerization catalyst having an alumoxane in an amount to satisfy the following condition added to the polymerization catalyst comprising a transition metal compound represented by the formula (1) and an organoaluminum compound represented by the formula (2): the molar amount of aluminum derived from the alumoxane to be used is at most 80% to the molar amount of aluminum derived from the organoaluminum compound to be used. 10. The process for producing an olefin polymer according to claim 1, characterized in that at least one olefin is polymerized by means of a polymerization catalyst having no alumoxane added to the polymerization catalyst comprising a transition metal compound represented by the formula (1) and an organoaluminum compound represented by the formula (2). 11. The process for producing an olefin polymer according to claim 1, characterized in that the relation between the molecular weight distribution (Mw/Mn) obtained by GPC (gel permeation chromatography) and the ratio (I10/I2) of the melt flow rates measured by changing the load to 10 kg and 2 kg, satisfies the following formulae: 30≧MFI≧1.25m+6.25, 10≧m≧2 where MFI: the ratio (I10/I2) of MFR under loads of 10 kg and 2 kg, and m: the molecular weight distribution (Mw/Mn) by GPC. 12. The process for producing an olefin polymer according to claim 1, characterized in that the amount of a Lewis basic substance in the polymerization solution is at most 30 ppm. |
<SOH> BACKGROUND ART <EOH>Metallocene Catalyst and Process for Producing Olefin Polymer Since Kaminski, Sinn, et al. discovered that a polymerization catalyst comprising a metallocene compound having a ligand having two cyclopentadienyl ring structures and a methylalumoxane synthesized from trimethylaluminum and water, is capable of polymerizing ethylene with high activity (Angew, Chem., Int. Ed. Engl., 19, 390 (1980)), olefin polymerization by means of a so-called single-site polymerization catalyst has been actively researched and practically used. Particularly, olefin polymerization catalysts constituted by transition metal compounds activated by a cocatalyst comprising a methylalumoxane or a boron compound, have been widely used as catalysts for producing polyolefins. Among them, polymerization catalysts containing a metallocene compound having a structure in which two ligands are crosslinked by carbon or silicon, are known particularly as catalysts for producing LLDPE, or isotactic or syndiotactic polypropylenes. However, they have a problem that the methylalumoxane or the boron compound to be used as a cocatalyst, is expensive. JP-A-3-197513 discloses a polymerization catalyst constituted by an alkyl aluminum and a certain specific transition metal compound (a metallocene compound) without using the methyl alumoxane or the boron compound as a cocatalyst. However, with the transition metal compound employed, the activity is low, and the molecular weight of the obtainable polymer is low, whereby it is still poor in practical applicability. Even if it is attempted to improve the activity at a higher polymerization temperature, it is considered that at a polymerization temperature condition higher than the polymerization temperature of 50° C. specifically disclosed, the molecular weight tends to decrease, such being poor in practical applicability. Further, JP-A-7-62012 discloses a method for polymerization under such a condition that the aluminum/transition metal ratio of a transition metal compound and an alkyl aluminum compound is from 1 to 500 by molar ratio calculated as atoms. However, by such a ratio and with such a transition metal compound employed, it is considered that the activity is low, and such is poor in practical applicability. Further, with the transition metal compound employed, even if it is attempted to improve the activity at a higher polymerization temperature, it is considered that at a polymerization temperature condition higher than the polymerization temperature specifically disclosed, the molecular weight tends to be low, such being poor in practical applicability. It is an object of the present invention to provide a process for producing an olefin polymer with higher polymerization activity without using an expensive co-catalyst or using such a cocatalyst within a limited range, more particularly a process for producing a high molecular weight (co)polymer with high polymerization activity even at a high polymerization temperature which is more practical. |
Digital equalization process and mechanism |
A filter is created by sampling noise during an inter-frame gap (110) of a received signal, sampling a data frame preamble (115) from within a data frame (105) of the received signal, and computing filter coefficients based on the noise sampled during the inter-frame gap (110) and the data frame preamble (115) sampled from within the data frame (105). |
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