text
stringlengths 0
1.67M
|
|---|
Audio-video communication device for computer users |
The invention relates to gathering, processing and exchanging audio-video information with the aid of an audio-video communication between computer users and can be used for teaching and controlling the knowledge of trainable computer users, in particular for teaching a foreign language and informatics. Said invention enables the computer users to perform an audio and video communication therebetween and between the grouped computer users. The number of computer users who can be united into audio-video groups in random manner is not limited and depends on the number of connected audio and video switches. For example, 16 users can be get together for setting 8 audio groups and one video group with the aid of one audio switch and one video switch. The industrial multimedia linguaphone complex RINEL LINGO AUDIO-VIDEO makes it possible to connect 16 audio-video switches, provide with the communication 240 users and set 128 audio groups and 1 video group. Said Complex . . . is controlled with the aid of RINEL LINGO software. |
1. (canceled) 2. An audio-video communication apparatus for computer users, comprising a tutor's central computer having a software for arranging for an educational process, and learners'computers connected thereto via communication channels; characterized in that said apparatus comprises: at least two audio cards, to each of which cards connected are a microphone and headphones of the computer users; and at least two video cards; each one of the audio and video cards being inserted in ICA-, or PCI-slots in each one of the computers; at least one video commutator and at least one audio commutator that establish the audio and video communication among the computer users; the learners'computers and the tutor's central computer being connected via the audio and video cards, respectively, to the audio commutator and video commutator; and the central computer—via a control channel, using control cables—being connected to the audio commutator, and—via the audio commutator—to the video commutator; and said central computer, using an appropriate software, controls the formation and transformation of learners'groups, and the switching of the sound from the individual communication to the common loudspeaker communication; whereas the audio and video signals are transmitted by hardware means without use of the hard- and software resources of |
<SOH> BACKGROUND OF THE INVENTION <EOH>Regarding the set of its essential features, the claimed invention's most pertinent art is “A complex for monitoring students' knowledge” according to RF Patent N 2001.204, 64/28, IPC G 09 B 7/07. A disadvantage of said complex is its orientation to the applications for use with a certain group of learners and for use with pre-programmed reference replies. Further, said complex does not allow to set up a group of learners who are trained using the audio-video communication, by discretion of a tutor. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>The invention further is explained by description of embodiments thereof, with reference to the accompanying drawings, in which drawings: FIG. 1 shows a general block diagram of an audio communication device for computer users, according to the invention; FIG. 2 shows a diagram for connecting a computer via an audio card—LINGO-card (a LINGO-card is to be inserted in PCI-, or ISA-slot of a computer); FIG. 3 shows a general view of the LINGO-video card plane to be inserted in PCI- or ISA-slots in a computer; FIG. 4 shows a scheme of interconnections among audio commutators and video commutators for increasing a number of the users included into the audio and video communication; FIG. 5 shows a block diagram of an audio card; FIG. 6 shows a block diagram of an audio commutator; FIG. 7 shows a block diagram of a video card; FIG. 8 shows a block diagram of a video commutator; FIG. 9 shows a block diagram of a video card, wherein used is one channel for transmitting the video signal from a computer to a video commutator, and from the video commutator to the computer; FIG. 10 a shows a block diagram of a video commutator, using one channel for transmitting the video signal from a computer to a video commutator, and from a video commutator to a computer; FIG. 10 b shows a block diagram of a video commutator implemented as a passive mixer; FIG. 10 c shows a block diagram, wherein a monophonic channel is used; FIG. 11 a - 11 d show a block-diagram of a user circuit board; FIG. 12 a - 12 c show a block-diagram of an audio card (LINGO-card); FIG. 13 a - 13 f show a block diagram of a mother board. detailed-description description="Detailed Description" end="lead"? |
Remedies for mammary cancer |
Provided is a remedy for cancer which remedy is specific to cancer tissue and has therapeutic effects on mammary cancer. The remedy is available by associating an antitumor substance with a human monoclonal antibody having amino acid sequences of SEQ. ID. NOS. 1, 2 and 3 of Sequence Listing in hypervariable regions of a heavy chain and amino acid sequences of SEQ. ID. NOS. 4, 5 and 6 of Sequence Listing in hypervariable regions of a light chain by attaching the antibody to a liposome having the antitumor substance encapsulated therein. |
1. A remedy for mammary cancer comprising a human monoclonal antibody having amino acid sequences of SEQ. ID. NOS. 1, 2 and 3 of Sequence Listing in hypervariable regions of a heavy chain and amino acid sequences of SEQ. ID. NOS. 4, 5 and 6 of Sequence Listing in hypervariable regions of a light chain; and an antitumor substance associated with the antibody. 2. A remedy for mammary cancer of claim 1, wherein the monoclonal antibody has a heavy chain variable region containing an amino acid sequence of SEQ. ID No. 7 of Sequence Listing and a light chain variable region containing an amino acid sequence of SEQ. ID No. 8 of Sequence Listing. 3. A remedy for mammary cancer of claim 1, wherein the antitumor substance has been associated with the antibody by binding the antibody to the surface of a liposome having the antitumor substance encapsulated therein. 4. A mammary cancer of claim 3, wherein the antibody has been bound to the surface of the liposome by attaching via a thioether group the antibody to the liposome having a lipid end partially maleimidated. 5. A remedy for mammary cancer of claim 4, wherein 0.1 to 2 mole % of the antibody has been bound to 1 mole of the maleimidated lipid. 6. A remedy for mammary cancer of claim 4, wherein the antibody has been bound to the surface of the liposome by causing the maleimide-containing liposome to react with a sulfur-containing group derived from the antibody to form a thioether bond. 7. A remedy for mammary cancer of claim 3, wherein to the surface of the liposome, a compound containing a polyalkyleneglycol portion has been bound further. 8. A remedy for mammary cancer of claim 7, wherein 15 to 50 mole % of the compound containing a polyalkyleneglycol portion has been bound to 1 mole of the maleimidated lipid contained in the liposome. 9. A remedy for mammary cancer of claim 7, wherein the compound containing a polyalkyleneglycol portion has been bound to the surface of the liposome by causing the maleimide group of the maleimidated lipid to react with the compound containing a polyalkyleneglycol portion added with a thiol group. 10. A remedy for mammary cancer of claim 7, wherein the polyalkyleneglycol portion is a polyethyleneglycol portion. 11. A remedy for mammary cancer of claim 10, wherein the compound containing a polyalkyleneglycol portion has two polyethyleneglycol portions. 12. A remedy for mammary cancer of claim 10, wherein the polyethyleneglycol portion has a molecular weight of from 2,000 to 7,000 daltons. 13. A remedy for mammary cancer of claim 1, wherein the antibody is an F(ab′)2 fragment. |
<SOH> BACKGROUND ART <EOH>A method of administering a medicament such as antitumor substance as a complex with an antibody by making use of the specific reactivity of the antibody and thereby accumulating the antitumor substance in cancer tissues has been developed. For example, an antibody-bound liposome, that is, a liposome having a medicament encapsulated therein and an antibody bound to the surface of the liposome is proposed as means for carrying a large amount of the medicament without modification has been proposed and excellent antitumor effects of it have been reported (Konno, et al., Cancer Research, 47, 4471(1987), Hashimoto, et al, Japanese Patent Application Laid-Open No. Sho 58-13404). As an antibody against cancer tissues, a GAH antibody which is a human monoclonal antibody screened for reactivity with gastric cancer and colorectal cancer is known (Japanese Patent Application Laid-Open No. Hei 4-346918 and Japanese Patent Application Laid-Open No. Hei 5-304987). Antibodies generally have markedly high specificity to antigens so that it is difficult even for those skilled in the art to forecast the reactivity of the GAH antibody, which has been screened for the reactivity with gastric cancer and lower bowel cancer, with another cancer. As an antibody drug targeting to mammary cancer, an antibody (refer to International Publication W089/6692) against HER2 (human epidermal growth factor receptor 2) is developed now, but this antibody is originally a mouse-derived monoclonal antibody and is humanized by genetic recombination so that its hypervariable region is derived from mouse. When an antibody is obtained by immunizing a known antigen to a mouse, it is easy to identify the cancer type by studying the distribution of the antigen itself by, for example, in situ hybridization, but in the case of a purely human-derived monoclonal antibody, it is difficult to know the distribution of the antigen itself or identify the cancer type, different from the mouse-derived antibody. |
<SOH> BRIEF DESCRIPTION OF THE DRAWING <EOH>FIG. 1 illustrates the investigation results of the effects of a GAH antibody on the proliferation inhibition of cancer cell lines. detailed-description description="Detailed Description" end="lead"? |
Cancer diagnostics |
Provided is a diagnostic comprising a peptide or protein capable of recognizing at least a portion of a tissue section and a fluorescent substance having the below-described characteristics: i) having, in a predetermined excitation wavelength, an emission wavelength not adjacent to a wavelength region of nonspecific autofluorescence which the tissue section has; and ii) permitting simultaneous observation of the image of the peptide or protein and the image of the tissue section. A diagnostic method and diagnostic kit each of which uses the peptide or protein, and the fluorescent substance is provided. A therapeutic agent administered to a disease after selection of the appropriate agent for the disease by using the above-described method. Also, a tissue section stained by the peptide or protein and the fluorescent substance is provided. In addition, a method of analyzing expression and/or behavior of a protein by using the fluorescent substance is provided. |
1. A diagnostic comprising a peptide or protein capable of recognizing at least a portion of a tissue section and a fluorescent substance having the below-described characteristics i) and ii): i) having, in a predetermined excitation wavelength, an emission wavelength not adjacent to a wavelength region of nonspecific autofluorescence which the tissue section has; ii) having fluorescence properties permitting simultaneous observation of the image of the peptide or protein and the image of the tissue section. 2. A diagnostic of claim 1, wherein in a predetermined excitation wavelength, the fluorescent substance shows a Stokes shift thereof on a long wavelength side not adjacent to the wavelength region of nonspecific autofluorescence which the tissue section has. 3. A diagnostic of claim 1, wherein the tissue section is a human-derived paraffin section or human-derived formalin-fixed paraffin section. 4. A diagnostic of claim 1, wherein the peptide or protein is an antibody. 5. A diagnostic of claim 4, wherein the antibody is a monoclonal antibody. 6. A diagnostic of claim 5, wherein the monoclonal antibody is a cancer-reactive monoclonal antibody. 7. A diagnostic of claim 6, wherein the cancer is gastric cancer, breast cancer, colorectal cancer or esophagus cancer. 8. A diagnostic of claim 5, wherein the monoclonal antibody has amino acid sequences of SEQ. ID NOS. 1, 2 and 3 of Sequence Listing in a hypervariable region of a heavy chain and amino acid sequences of SEQ. ID NOS. 4, 5 and 6 of Sequence Listing in a hypervariable region of a light chain. 9. A diagnostic of claim 5, wherein the monoclonal antibody has a heavy chain variable region containing an amino acid sequence of SEQ. ID No. 7 of Sequence Listing and a light chain variable region containing an amino acid sequence of SEQ. ID No. 8 of Sequence Listing. 10. A diagnostic of claim 5, wherein the monoclonal antibody is a biotin-labeled monoclonal antibody. 11. A diagnostic of claim 2, wherein the Stokes shift of the fluorescent substance has a wavelength longer by at least about 80 nm than that of the tissue section. 12. A diagnostic of claim 11, wherein the Stokes shift of the fluorescent substance has a wavelength longer by at least about 150 nm than that of the tissue section. 13. A diagnostic of claim 1, wherein the excitation wavelength ranges from about 450 nm to about 500 nm. 14. A diagnostic of claim 13, wherein the excitation wavelength ranges from about 480 nm to about 500 nm. 15. A diagnostic of claim 13, wherein the excitation wavelength is about 490 nm. 16. A diagnostic of claim 1, wherein the fluorescent substance is a peridinin chlorophyll protein or a fragment of the protein containing the fluorescent group portion thereof. 17. A diagnostic of claim 16, wherein the peridinin chlorophyll protein is streptavidin-bound peridinin chlorophyll protein. 18. A diagnostic of claim 1, which is a diagnostic for pathologic tissue. 19. A diagnostic method, which comprises performing tissue staining with the diagnostic as claimed in claim 1. 20. A diagnostic method of claim 19, for diagnosing the reactivity between cancer and the diagnostic. 21. A therapeutic agent appropriate for a disease, which has been selected by using a diagnostic method as claimed in claim 19. 22. A therapeutic agent of claim 21, wherein the disease is cancer. 23. A therapeutic agent of claim 22, wherein the cancer is gastric cancer, breast cancer, colorectal cancer or esophagus cancer. 24. An analysis method, which comprises using a fusion protein available by fusing a fluorescent substance having the below-described characteristics with a protein, i) having, in a predetermined excitation wavelength, an emission wavelength not adjacent to a wavelength region of nonspecific autofluorescence which a tissue section has; ii) having fluorescence properties permitting simultaneous observation of the image of the peptide or protein and the image of the tissue section. 25. An analysis method of claim 24, wherein in a predetermined excitation wavelength, the fluorescent substance shows a Stokes shift thereof on a long wavelength side not adjacent to the wavelength region of nonspecific autofluorescence which the tissue section has. 26. An analyzing method of claim 24, wherein the Stokes shift of the fluorescent substance has a wavelength longer by at least about 80 nm than that of the tissue section. 27. An analyzing method of claim 24, wherein the Stokes shift of the fluorescent substance has a wavelength longer by at least about 150 nm than that of the tissue section. 28. An analyzing method of claim 24, for analyzing the expression and/or behavior of the protein in a cell. 29. A tissue section which has been subjected to tissue staining with a diagnostic as claimed in claim 1. 30. A diagnostic kit, comprising a diagnostic as claimed in claim 1. 31. A diagnostic kit of claim 30, for judging the reactivity of the therapeutic agent with cancer. 32. A therapeutic agent for a disease, which is to be administered after selection of a medicament appropriate to the disease by using the diagnostic kit as claimed in claim 30. 33. A therapeutic agent of claim 32, wherein the disease is cancer. 34. A therapeutic agent of claim 33, wherein the cancer is gastric cancer, breast cancer, colorectal cancer or esophagus cancer. |
<SOH> BACKGROUND ART <EOH>With a view to imparting anticancer agents with higher effects and safety, researches have been pursued on cancer targeting agents using antibodies against cancer cells. It is known that corresponding to a variety of cells which become cancerous, there are many different kind of antibodies capable of recognizing them. For example, a human monoclonal antibody screened for the reactivity with gastric cancer and colorectal cancer is known as a GAH antibody (Japanese Patent Application Laid-Open No. Hei 4-346918, Japanese Patent Application Laid-Open No. Hei 5-304987). It is presumed that upon administration of such a cancer targeting agent to a patient, higher effects and safety can be accomplished by diagnosing the reactivity with the antibody in advance by using the clinical tissue of the patient. The reactivity of an antibody with cancer cells has conventionally been detected by a method of analyzing isolated cells through flow cytometry, or a method of analyzing a tissue section stained by the enzyme antibody method or fluorescence antibody assay without isolating cancer cells. Flow cytometry is very useful for detecting blood-related cells or cultured cells, but the tissue section cannot be observed directly. When applied to detecting tissue sections, this method needs a cumbersome operation, and a tissue piece having a relatively large size to isolate cells from the tissue. In addition, an apparatus for flow cytometry costs high and lacks versatility. Fluorescence antibody assay or enzyme antibody method is known as a method of analyzing a tissue section, particularly a formalin-fixed paraffin embedded section (paraffin section) which is popularly used because of convenient formation and long-term storage stability in a clinical site. The enzyme antibody method is a method of detecting the reactivity of an antibody by reacting a section with a complex between the antibody and an enzyme such as horseradish peroxidase (HRP) and then developing an insoluble pigment derived from an enzyme substrate such as 3,3′-diaminobenzidine (DAB). In this case, however, the staining intensity depends on the conditions for the enzymatic reaction. When the reaction occurs excessively, it is sometimes difficult to judge the staining degree correctly because excessive deposition of the pigment occurs nonspecifically. It is therefore necessary to severely manage and standardize the reaction time or evaluation criteria in order to obtain highly reliable diagnostic results. Fluorescence antibody assay, on the other hand, is a method capable of actualizing a vivid contrast and excellent from the viewpoint of quantitative determination. When a paraffin section is subjected to fluorescence observation, however, a stained antibody image cannot easily be detected because of a high autofluorescence background of the section itself. Several attempts have been made with a view to developing a fluorescence antibody assay which has the above-described features, that is, vivid contrast and excellent quantitative determination and in addition, can be used for the observation of a paraffin section. For example, reported is a method of staining a section with a fluorescein isothiocyanate (FITC) labeled antibody, followed by counterstaining with an azo pigment to change the autofluorescence into a color utterly different from green fluorescence of FITC (Hall, C. T. Bakteriol. 184: 548-555, 1962. Hokenson, E. O. Stain Technology, 41: 9-14, 1966. Fey, H. Microbiol. 38: 271-277, 1972. Schenk, E. A. Cytochem. 22: 962-966, 1974. Hoff, H. F. Artery 6(4): 328-339, 1980). In the case of a fluorescent substance showing Stokes shift (difference (Em-Ex) between an emission wavelength (Em) available by exposing a fluorescent substance and an excitation wavelength (Ex)) longer than the excitation wavelength, to same extent, for example, R-Phycoerythrin (R-PE) or 7-amino-4-coumarin-3-acetic acid (AMCA), it is possible to separate and detect target fluorescence by installing a proper filter to a microscope, blocking fluorescence on the short wavelength side including the autofluorescence in an excitation wavelength region. Richard, et al., used a complex of Europium, one of lanthanides having a longer Stokes shift than R-PE and reduced the influence of autofluorescence of a section by the Time-Resolved Fluorescence Imaging method (Haas, R. R., J. Histochem. Cytochem. 44(10): 1091-1099, 1996). The influence of autofluorescence can be reduced by the techniques described above, while they lead to observe only the target fluorescence as an image in a dark field. It is therefore necessary to judge it checking with information about a tissue morphology, important in diagnosis, obtained by a separate technique. As described above, various investigations have been made to make use of the advantages of the fluorescence antibody assay for a clinical section, but there are still some problems to be resolved from the viewpoints of convenience, quantitative determination and observation of a tissue morphology. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is an image of gastric cancer tissue stained with a GAH antibody; FIG. 2 is an image of gastric cancer tissue stained with a GAH antibody (method using HRP-labeled antibody); FIG. 3 is an image of breast cancer tissue stained with a GAH antibody; FIG. 4 is an image of colorectal cancer tissue stained with GAH F(ab′) 2 ; FIG. 5 is an image of esophagus cancer tissue stained with GAH F(ab′) 2 ; FIG. 6 is a stained image, with a GAH antibody, of tumor grown by implantation of colorectal cancer cell line; FIG. 7 illustrates in vivo antitumor effects for tumor grown by implantation of colorectal cancer cell line; FIG. 8 illustrates the comparison between an image stained with FITC and that stained with PerCP; FIG. 9 illustrates the autofluorescence spectrum analysis of a tissue section; FIG. 10 illustrates the spectrum analysis of each of various fluorescent substances; FIG. 11 illustrates the study on fluorescence quantification of an image stained with PerCP; and FIG. 12 illustrates the comparison between an image stained with Alexa fluor 546 and that stained with PerCP. detailed-description description="Detailed Description" end="lead"? |
Attachment to a hydroponic conduit |
A hydroponic conduit can be converted to drainage conduit by providing an attachment on which a plant container can be supported. The attachment comprises a circular plate on which the plant containers sits, drainage means (ribs, grooves etc.) and a central aperture in the circular plate to allow water to drain from the circular plate, and a short collar or spout on the bottom of the circular plate which passes into an opening in the hydroponic conduit to allow water to drain into the conduit. A second support means can be provided which is attached to the hydroponic conduit and which provides additional support to the attachment. |
1. An attachment for a hydroponic conduit of the type which has an at least partially rigid wall, the attachment comprising a support means to support a plant container and the like, drainage means adapted to collect water passing out of the container, and communication means to communicate the water from the drainage means into the hydroponic conduit. 2. The attachment as claimed in claim 1, wherein the support means comprises a drainage tray adapted to support the plant container. 3. The attachment as claimed in claim 2, wherein the drainage means comprises part of the drainage tray. 4. The attachment as claimed in claim 3, wherein the drainage means comprises at least one projection extending from the drainage tray and adapted to support the plant container thereby allowing water to pass between the bottom of the plant container and the drainage tray. 5. The attachment as claimed in claim 3, wherein the drainage means comprises at least one recess in the drainage tray to allow water to pass along the drainage tray. 6. The attachment as claimed in claim 2, wherein the drainage tray is provided with a drain opening. 7. The attachment as claimed in claim 6, wherein the communication means comprises the collar on a bottom wall of the drainage tray and extending about the drain opening, the collar adapted to pass into an opening in the hydroponic conduit to allow water to drain from the drainage tray into the hydroponic conduit. 8. The attachment as claimed in claim 1 comprising a second support means to assist in supporting the support means. 9. The attachment as claimed in claim 8, wherein the second support means comprises a platform, the platform being provided with an opening through which the communication means can pass, and at least one attachment means to attach the second support means to the hydroponic conduit. 10. The attachment as claimed in claim 1, wherein the support means comprises a circular plate having a top wall and a bottom wall and formed with a peripheral rim, the plate being dish shaped and having a central aperture, at least one radially extending rib extending from the top wall and on which the plant container is supported in use, the communication means comprising an integrally formed collar depending from the bottom wall and extending about the central aperture to drain water from the circular plate. |
<SOH> BACKGROUND ART <EOH>Hydroponics involves growing plants in the absence of soil. Typically, the required nutrient and water is delivered to the plant root system in the form of an aqueous nutrient solution that passes over the root ball of the plant. Hydroponic techniques have certain advantages over more conventional agriculture that includes the ability to carefully control optimum feeding, the elimination of weeds, and improved control of pests and diseases. Typically, a channel or conduit is provided through which the nutrient solution passes. The channel or conduit may comprise a closed pipe or tube, a closed channel or drain and the like. If a pipe or tube is provided, this may have various shapes including circular, oval, rectangular, square, irregular configurations and the like. The pipe or tube may be formed of a semirigid material such as PVC plastic, or may be formed from a very flexible plastic bag-like material. If the material is very flexible, it is generally required to fill the bag with a medium other than soil. These mediums can include sand, gravel, fibre mediums and the like. The medium will provide dimensional stability to the bag, but can interfere with flow-through of nutrient solution and the like. Therefore, it is generally preferable to have a semi rigid conduit typically formed of polyvinyl chloride, such that a growing medium is not required to provide shape and stability to the conduit. In our earlier U.S.A patent application Ser. No. 09/196,638, there is described an elliptical conduit for use with a hydroponic apparatus. The elliptical conduit provided an ideal cross-section for root growth that was similar to normal root growth in soil. It was found that the elliptical conduit provided a faster and better growth of plants. Some plants are best grown in pots or planter bags as opposed to in a hydroponic system. For instance, the plant might be too large to grow properly in a hydroponic system. Alternatively, the plant may not be suited for growing in a medium devoid of soil. A disadvantage of growing and maintaining plants in pots or planter bags is in dealing with the used water that drains from the pot or bag. In some countries, this water can contaminate aquifers, creeks, streams and rivers. In other countries, water is precious and should not be merely drained away. Many countries have introduced legislation to penalise growers who contaminate ground water with run-off. A hydroponic system efficiently reuses and recycles water. Therefore, there would be an advantage if part of a hydroponic system could be used for plants grown in pots or planter bags. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>An embodiment of the invention will be described with reference to the following drawings in which: FIG. 1 . Illustrates the separate components of an attachment according to an embodiment of the invention. FIG. 2 . Illustrates the attachment of FIG. 1 attached to a hydroponic conduit. FIG. 3 . Illustrates an underneath view of a second support means which forms part of the attachment according to the embodiment. FIG. 4 . Illustrates a plan view of the support means/drainage means. FIG. 5 . Illustrates an underneath view of the support means/drainage means of FIG. 4 . FIG. 6 . Illustrates a part length of a typical known hydroponic conduit. FIG. 7 . Illustrates a drainage tray according to a second embodiment and which allows several trays to nest into each other. FIG. 8 . Illustrates the tray of FIG. 7 in plan view and illustrating raised ribs on which the pot/bag can sit. detailed-description description="Detailed Description" end="lead"? |
Composition based on lipid lamellar vesicles incorporating at least a dhea compound |
The present invention relates to a composition comprising: a dispersion, in an outer aqueous phase, of vesicles formed by lipid lamellar phases comprising at least one amphiphilic lipid and encapsulating an inner hydrophilic phase, the said lamellar phases not comprising succinic and/or hemisuccinic derivatives, and at least one DHEA-based compound included in the said lamellar phases. The incorporation of the DHEA-based compound into the lamellar phases of vesicles makes it possible to avoid its recrystallization in the outer aqueous phase and to improve its bioavailability. |
1. A composition comprising a dispersion of an outer aqueous phase, an inner hydrophilic phase and at least one DHEA compound, wherein the outer aqueous phase comprises vesicles of lipid lamellar phases comprising at least one amphiphilic lipid, wherein the lipid lamellar phases encapsulate the inner hydrophilic phase, wherein the lamellar phases do not comprise a succinic derivative, or a hemisuccinic derivative or both, and wherein the at least one DHEA compound is present in the lamellar phases. 2. The composition according to claim 1, wherein the DHEA compound is selected from the group consisting of DHEA, a DHEA precursor and a DHEA derivative. 3. The composition according to claim 2, comprising at least one of Δ5-pregnenolone, 17α-hydroxypregnenolone or 17 α-hydroxypregnenolone sulphate. 4. The composition according to claim 2, comprising at least one DHEA chemical precursor selected from the group consisting of a sapogenin, a natural extract of fenugreek and an extract of a Dioscorea plants 5. The composition according to claim 2, comprising at least one DHEA derivative selected from the group consisting of Δ5-androstene-3,17-diol, Δ4-androstene-3,17-dione, 7α-OH DHEA, 7β-OH DHEA, 11α-OH DHEA, 7-keto-DHEA, 3-acetoxy-7-keto-DHEA, DHEA sulphate, a hydroxycarboxylic acid ester of DHEA, DHEA salicylate, DHEA acetate, DHEA valerate, DHEA enanthate, a DHEA carbamate, a 2-hydroxymalonate ester of DHEA and an amino acid ester of DHEA. 6. The composition according to claim 2, comprising a DHEA derivative is represented by formula (1) in which: R1 and R2 are independently: a saturated or unsaturated, linear, branched or cyclic C1-C12 alkyl group optionally containing one or more hetero atoms, and optionally substituted with one or more of an OR′, —SR6′, —COOR′, —NR′R′, halogen, sulphate, phosphate, aryl, or heterocycle group, an alkylcarbonyl group, the C1-C24 alkyl portion of which is saturated or unsaturated, linear, branched or cyclic, and optionally substituted with one or more of a —OR′, —SR′, —COOR′, —NR′R, halogen, sulphate, phosphate, aryl, or heterocycle group, an arylcarbonyl group, or an arylalkylcarbonyl group, optionally substituted with one or more groups of a —OR′, —SR′, —COOR′, —NR′R′, halogen, aryl or heterocycle group; a group O═P(OH)OR′; a group (O)2SOR′; a trialkylsilyl group of formula SiR′3 in which the 3 groups R′ may be identical or different; a carbonyloxyalkyl group of formula R′OCO; a carbonylaminoalkyl group of formula R′NHCO; in which R′ is a hydrogen atom, a saturated or unsaturated, linear, branched or cyclic C1-C12 group optionally containing one or more hetero atoms, optionally functionalized with one or more of a —OR″, —COOR″, halogen, —NR″R″, or aryl group, and optionally functionalized with one or more of a —OR″, —COOR″, halogen or —NR″R″ group; R″ representing a hydrogen atom or a saturated or unsaturated, linear, branched or cyclic alkyl chain, wherein each of the groups —NR′R′ and —NR″R″, the substituents R′ or R″, respectively, are identical or different. 7. The composition according to claim 6, comprising 3-O-acetyl-7-benzoyloxy-dehydroepiandrosterone. 8. The composition according to claim 1, wherein the DHEA compound represents from 0.1% to 50% by weight of the lipid lamellar phases. 9. The composition according to claim 1, wherein the lamellar phases comprise at least one nonionic amphiphilic lipid selected from the group consisting of an alkyl ester of a polyol, a polyalkyl ester of a polyol, an alkyl ether of a polyol, a polyalkyl ether of a polyol and oxyalkylerated compounds thereof, with a melting point of at least 40° C. 10. The composition according to claim 9, comprising a nonionic amphiphilic lipid comprising a mixture of polyol esters of at least one acid with a saturated hydrocarbon-based chain containing at least 14 carbon atoms. 11. The composition according to claim 9, comprising a nonionic amphiphilic lipid comprising a polyol ether of at least one alcohol with a saturated hydrocarbon-based chain containing at least 14 carbon atoms. 12. The composition according to claim 9, comprising at least one nonionic amphiphilic lipid consisting of a mixture of esters of at least one polyol selected from the group consisting of a polyethylene glycol comprising from 1 to 60 ethylene oxide units, sorbitan, sorbitan bearing 2 to 60 ethylene oxide units, glycerol bearing 2 to 30 ethylene oxide units, a polyglycerol comprising 2 to 15 glycerol units, a sucrose, a glucose bearing 2 to 30 ethylene oxide units, and a fatty acid comprising a saturated or unsaturated, linear or branched C14-C20 hydrocarbon-based chain. 13. The composition according to claim 1, wherein the lamellar phases comprise an ionic amphiphilic lipid. 14. The composition according to claim 13, wherein the ionic amphiphilic lipid is selected from the group consisting of an alkali metal salt of dicetyl, an alkali metal salt of dimyristyl phosphate; an alkali metal salt of cholesteryl sulphate; an alkali metal salt of cholesteryl phosphate; a monosodium acylglutamate; a disodium acylglutamate; a sodium salt of phosphatidic acid; a phospholipids; an acylgutamate, a alkylsulphonic derivative, and an ammonium salt represented by formula (II): in which the radicals R1 to R4, which may be identical or different, represent a linear or branched aliphatic radical containing from 1 to 30 carbon atoms, an aromatic aryl radical, an aromatic radical, an alkylaryl radical; X is an anion selected from the group consisting of a halide, a phosphate, an acetate, a lactate, a (C2-C6)alkyl sulphate, an alkyl sulphonate and a alkylaryl sulphonate, an quaternary ammonium salts of imidazolinium, represented, by formula (III): in which R5 represents an alkenyl or alkyl radical containing from 8 to 30 carbon atoms, R6 represents a hydrogen atom, an alkyl radical containing from 1 to 4 carbon atoms or an alkenyl or alkyl radical containing from 8 to 30 carbon atoms; R7 represents an alkyl radical containing from 1 to 4 carbon atoms; R8 represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms; X is an anion selected from the group consisting of a halide, a phosphate, an acetate, a lactate, an alkyl sulphate, and an alkyl sulphonate and an alkylaryl sulphonate, and diquaternary ammonium salts represented by formula (IV): in which R6 denotes an aliphatic radical containing from 16 to 30 carbon atoms approximately; R7, R8, R9, R10 and R11, which may be identical or different, may be a hydrogen or an alkyl radical containing from 1 to 4 carbon atoms; and X is an anion selected from the group consisting of a halide, an acetate, a phosphate, a nitrate and a methyl sulphate. 15. The composition according to claim 9, wherein the lamellar phases contain comprise at least one additive selected from the group consisting of sterols, fatty-chain alcohols, fatty chain diols, fatty-chain amines and quaternary ammonium derivatives thereof. 16. The composition according to claim 15, comprising cholesterol. 17. The composition according to claim 16, wherein the lamellar phases comprise from 35% to 90% by weight of nonionic amphiphilic lipid, from 0 to 20% by weight of ionic amphiphilic lipid, from 5% to 50% by weight of cholesterol and from 0.1% to 50% by weight of the DHEA-compound relative to the total weight of the lipids comprising the lamellar phase. 18. The composition according to claim 1, wherein the lamellar phases comprise at least one phospholipids, combined either with cholesterol and optionally with an ionic surfactant, or with an oxyethylenated phytosterol comprising from 2 to 50 ethylene oxide units. 19. The composition according to claim 18, wherein the lamellar phase comprises lecithin. 20. The composition according to either claim 18, wherein the lipid vesicles comprise from 50% to 99% by weight of lecithin, from 50% to 1% by weight of a mixture of cholesterol and the DHEA compound, and from 0 to 20% by weight of one or more ionic surfactant relative to the total weight of the lipids comprising the lamellar phase. 21. The composition according to claim 18 wherein the lipid vesicles comprise from 40% to 80% by weight of lecithin and from 20% to 60% by weight of a mixture of oxyethylenated phytosterol and the DHEA compound relative to the total weight of the lipids comprising the lamellar phase. 22. The composition according to claim 1, wherein the lipids are in the vesicles and represent from 1% to 20% of the total weight of the composition. 23. The composition according to claim 1 in gel form. 24. The composition according to claim 1, further comprising an oily phase dispersed in the outer aqueous phase or a phase in which the outer aqueous phase is dispersed. 25. The composition according to claim 1, comprising at least one water-soluble, amphiphilic or liposoluble active agent. 26 (Canceled). 27 (Canceled). 28. The composition according to claim 4, comprising at least one sapogenin selected from the group consisting of diosgenin, hecogenin, smilagenin, sarsapogenin, tigogenin, yamogenin and yuccagenin. 29. The composition according to claim 6, wherein at least one of R1 or R2 is a group substituted with a heterocycle group selected from the group consisting of indole, a pyrimidine, a piperidine, a morpholine, a pyran, a furan, a piperazine and a pyridine. 30. The composition according to claim 1, wherein at least one of R1 or R2 is a phenylcarbonyl group. 31. The composition according to claim 6, wherein at least one of R1 or R2 is a benzylcarbonyl group. 32. The composition according to claim 6, wherein at least one of R1 or R2 is substituted with a C1-C6 alkyl group. 33. The composition according to claim 6, wherein at least one of R1 or R2 is substituted with a R′ group functionalized with a phenyl group. 34. The composition of claim 6, wherein at least one of R1 or R2 is substituted with a R′ group which is functionalized with a group containing a R″ group that is a C1-C6 alkyl chain. 35. The composition according to claim 1, comprising a DHEA compound present in an amount of from 1% to 25% by weight of the lipid lamellar phases. 36. The composition according to claim 18, wherein the lamellar phase comprises hydrogenated lecithin. 37. The composition according to claim 1, wherein the lipids are in vesicles and the lipids are present in an amount of from 1% to 10% of the total weight of the composition. 38. A cosmetic method comprising administering the composition of claim 1 to a mammal to prevent or treat the signs of at least one of intrinsic aging of the skin or photo-induced aging of the skin. 39. A composition comprising the composition of claim 1 and a physiologically or dermatologically acceptable diluent, excipient or carrier. |
Method for measuring withstand voltage of semiconductor epitaxial wafer and semiconductor epitaxial wafer |
A measurement-facilitating method of measuring the breakdown voltage of a semiconductor epitaxial wafer, and a semiconductor epitaxial wafer whose breakdown voltage is superior are realized. In a method of measuring the breakdown voltage of a semiconductor epitaxial wafer having to do with the present invention, the breakdown voltage between contacts 12, 12 is measured only through the Schottky contacts, without need for ohmic contacts. Inasmuch as the manufacturing process of forming ohmic contacts is accordingly omitted, the semiconductor epitaxial wafer 10 may be readily used in a breakdown-voltage measurement test. The measurement of the wafer 10 breakdown voltage thus may be readily carried out. Likewise, because the inter-contact breakdown voltage V2 of a wafer 10 can be measured prior to manufacturing a working device from it, unsuitable wafers 10 can be excluded before they are cycled through the working-device fabrication process. Reduction in losses can accordingly be counted upon, in contrast to conventional measuring methods, by which inter-contact breakdown voltage V2 is measured following fabrication of the working devices. |
1. A method of measuring the breakdown voltage of a semiconductor epitaxial wafer, comprising: a step of applying a voltage to a least one pair of contacts among a plurality of Schottky contacts formed onto a semiconductor epitaxial wafer; and a step of measuring the breakdown voltage across the contacts. 2. A semiconductor epitaxial wafer breakdown-voltage measurement method as set forth in claim 1, wherein in forming the Schottky contacts the semiconductor epitaxial wafer is superficially flat. 3. A semiconductor epitaxial wafer breakdown-voltage measurement method as set forth in claim 2, wherein the Schottky contacts are formed onto the same surface. 4. A semiconductor epitaxial wafer breakdown-voltage measurement method as set forth in claim 1, wherein the Schottky contact materially contains one selected from the group consisting of Au, Pt, Pd, W, Ti, Al and Ni. 5. A semiconductor epitaxial wafer breakdown-voltage measurement method as set forth in claim 1, wherein before said step of applying a voltage, the semiconductor epitaxial wafer is superficially cleaned with a cleaning solution containing at least one of: hydrochloric acid, phosphoric acid, ammonia, sulfuric acid, and hydrogen peroxide. 6. A semiconductor epitaxial wafer breakdown-voltage measurement method as set forth in claim 1, wherein the structure of the semiconductor epitaxial wafer is one in which the contact layer has been removed from a high-electron-mobility-transistor epitaxial structure. 7. A semiconductor epitaxial wafer breakdown-voltage measurement method as set forth in claim 1, wherein the semiconductor epitaxial wafer materially is a compound expressed by: AlxGayIn1-x-yN (0≦x≦1, 0≦y≦1, x+y≦1); AlxGayIn1-x-yAs (0≦x≦1, 0≦y≦1, x+y≦1); or AlxGayIn1-x-yP(0≦x≦1, 0≦y≦1, x+y≦1). 8. A semiconductor epitaxial wafer breakdown-voltage measurement method as set forth in claim 1, wherein as the Schottky contacts a first contact, a second contact and a third contact, corresponding respectively to a working-device gate, source and drain are formed onto the semiconductor epitaxial wafer. 9. A semiconductor epitaxial wafer breakdown-voltage measurement method as set forth in claim 8, wherein angled portions of said first contact and second contact where they oppose each other have a curved form. 10. A semiconductor epitaxial wafer breakdown-voltage measurement method as set forth in claim 8, wherein the first contact is 0.8 μm or more, 5 μm or less in width; and the distance separating the first contact and the second contact, and the distance separating the first contact and the third contact, is 0.8 μm or more, 20 μm or less. 11. A semiconductor epitaxial wafer breakdown-voltage measurement method as set forth in claim 8, wherein a constant current is applied between the first contact and the second contact before step of applying a voltage. 12. A semiconductor epitaxial wafer utilized as a substrate for FETs in which the gate-to-drain distance is L1 and for which the breakdown voltage V1 between the gate and the drain is sought, the semiconductor epitaxial wafer characterized in that: wherein the distance separating the first contact and the second contact is L2, the breakdown voltage V2 between the first contact and the second contact, measured by the breakdown-voltage-measurement method set forth in claim 8 satisfies the following relation (1) V2≧V1×L2/L1 (1) |
<SOH> BACKGROUND ART <EOH>Recently, even higher output from power FETs (field-effect transistors) that are employed in base stations for mobile communications and in satellite communications has been sought. While one way to realize higher power output from an FET is to raise the operating voltage that is applied to it, owing to the fact that the operating voltage is limited by the gate-to-drain breakdown voltage (BV gd ) of the FET, measuring the BV gd is a must. Here, “gate-to-drain breakdown voltage” is for example a voltage value defined as, “voltage at which a current of 1 mA per 1 mm gate width flows between gate-drain when a reverse voltage is applied across the two terminals.” Then to date, an appropriate film has been built on a wafer as a substrate; the working device including a Schottky contact (gate) and ohmic contacts (source, drain) has been fabricated; and voltage has been applied across the Schottky contact-ohmic contact. Nonetheless, with methods of measuring the breakdown voltage of the conventional epitaxial semiconductor wafer just described, issues such as the following have persisted. In particular, if after fabricating a working device onto a wafer the wafer is determined not to be up to standard for carrying out the breakdown-voltage measurement, a great deal of time and expense ends up being lost. Moreover, even cases in which the breakdown-voltage measurement is carried out using a readily-fabricated “large device” (a device, larger than a working device, from which measurements are taken), there has been a problem in that with at least two patterning cycles being necessary—patterning for the Schottky contact serving as the gate, and patterning for the ohmic contacts serving as the source/drain—the fabricating process ends up costing a great deal of time and trouble. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a plan view depicting a wafer involving an embodiment of the present invention; FIG. 2 is diagrams representing steps in the course of fabricating the wafer depicted in FIG. 1 ; FIG. 3 is a section view through line III-III in FIG. 1 ; FIG. 4 is a graph illustrating the relationship between voltage and current in a circuit; and FIG. 5 is a graph illustrating the relationship between voltage and current in a circuit following oxide-film removal. detailed-description description="Detailed Description" end="lead"? |
Cyclopenta'b! indole derivatives as spla inhibitors |
A novel class of tricyclic compounds of the following formula (I) is disclosed together with the use of such compounds for inhibiting sPLA2 mediated release of fatty acids for treatment of Inflammatory Diseases such as septic shock. |
1. A tricyclic compound represented by the formula (I), or a pharmaceutically acceptable salt, or solvate thereof; wherein; R1 is an amide, thioamide or hydrazone group represented by the formulae, wherein X is oxygen or sulfur; Ra and Ra′ are independently selected from hydrogen, (C1-C8)alkyl, or aryl; Ra″ is hydrogen, NH2, (C1-C8)alkyl, aryl, (C1-C8)alkylaryl, or arylalkyl; and n is 0, 1, or 2. R2, and R3 are independently selected from the group consisting of hydrogen, (C1 -C4)alkyl, (C2-C4)alkenyl, —O—(C1-C3 alkyl), —S—(C1-C3 alkyl), (C3-C4)cycloalkyl, —CF3, halo, —NO2, —CN, or —SO3; R4 is the group (C1-C20)alkyl, (C1-C20)haloalkyl, (C2-C20)alkenyl, (C2-C20)alkynyl, (C1-C10)alkylaryl, (C1 -C5)alkylcyclohexyl, (C1-C5)alkylcyclopentyl, (C1-C5)alkylcycloheptyl, phenyl, benzyl, methylnaphthyl, (C1-C5)alkylheterocyclic, carbocyclic radical, or heterocyclic radical, or aryl; R5, R6, and R7 are independently selected from hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8) alkynyl, (C7-C12)arylalkyl, (C7-C12)alkylaryl, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, phenyl, toluyl, xylenyl, benzyl, biphenyl, (C1-C8)alkoxy, (C2-C8)alkenyloxy, (C2-C8)alkynyloxy, (C2-C12)alkoxyalkyl, (C2-C12)alkoxyalkyloxy, (C2-C12)alkylcarbonyl, (C2-C12)alkylcarbonylamino, (C2-C12)alkoxyamino, (C2-C12)alkoxyaminocarbonyl, (C1-C12)alkylamino, (C1-C6)alkylthio, (C2-C12)alkylthiocarbonyl, (C1-C8)alkylsulfinyl, (C1-C8)alkylsulfonyl, (C2-C8)haloalkoxy, (C1-C8)haloalkylsulfonyl, (C2-C8)haloalkyl, C1-C8)hydroxyalkyl, —C(O)O(C1-C8 alkyl), —(CH2)n-O—(C1-C8)alkyl), benzyloxy, phenoxy, phenylthio, —(CONHSO2R), —CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, —(CH2)n-CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, —SO3H, thioacetal, thiocarbonyl, and carbonyl; where n is from 1 to 8, and R is (C1-C4)alkyl, phenyl or (C7-C12)aryl.; R8 is the group, -(La)-(acidic group) wherein -(La)-, is an acid linker having an acid linker length of 1 to 8; 2. The compound of claim 1 wherein R2 and R3 are each independently selected from hydrogen, (C1-C4)alkyl, (C2-C4)alkenyl, —O—(C1 -C3 alkyl), —S—(C1-C3 alkyl), (C3-C4)cycloalkyl, and —CF3. 3. The compound of claim 1 wherein R8 is the group, -(La)-(acidic group) and wherein the (acidic group) is selected from the group: —COOH -5-tetrazolyl, —SO3H, 4. The compound of claim 1 wherein R1 is the group represented by the formula; 5. The compound of claim 1 wherein R1 is the group 6. The compound of claim 1 wherein R1 is the group 7. The compound of claim 1 wherein, for R5 or R6 or R7, the non-interfering substituent is independently selected from hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8) alkynyl, (C7-C12)arylalkyl, (C7-C12)alkylaryl, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, phenyl, toluyl, xylenyl, benzyl, biphenyl, and (C1-C8)alkoxy. 8. The compound of claim 1 wherein R8 is the group, -(La)-(acidic group) and wherein the (acidic group) is selected from the group consisting of —COOH, —COONa, and —COOK. 9. The compound of claim 1 wherein the prodrug is the methyl or ethyl or N-methylmorpholino ester of a compound of formula (I). 10. A compound selected from the group consisting of: (4-benzyl-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(cyclopropylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(cyclobutylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(cyclopentylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(cycloheptylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3 -trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-furyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-furyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-thienyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-thienyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(1-napthyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-napthyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2,3-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2,4-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2,5-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2,6-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3,4-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3,5-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3,6-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2,3-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2,4-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2,5-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2,6-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3,4-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3,5-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-benzyl-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(cyclopropylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(cyclobutylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(cyclopentylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(cycloheptylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-furyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-furyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-thienyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-thienyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(1-napthyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-napthyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2,3-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2,4-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2,5-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2,6-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol -8-yloxy)-acetic acid, methyl ester, (4-[(3,4-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3,5-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3,6-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, 2,3-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2,4-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2,5-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2,6-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3,4-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3,5-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(phenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, morpholinoethyl ester, (4-[(cyclohexyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, morpholinoethyl ester, (4-[(cyclopentyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, morpholinoethyl ester, (4-[(phenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, N,N-diethylacetamido ester, (4-[(cyclohexyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, N,N-diethylacetamido ester, and (4-[(cyclopentyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, N,N-diethylacetamido ester. 11. A tricyclic compound represented by the formulae (C1), (C2), or (C3): 12. A pharmaceutical formulation comprising a tricyclic compound of formula (I) together with a pharmaceutically acceptable carrier or diluent. 13. A method of inhibiting sPLA2 mediated release of fatty acid comprising contacting sPLA2 with a therapeutically effective amount of tricyclic compound of formula (I). 14. A method of treating a mammal, including a human, to alleviate the pathological effects of Inflammatory Diseases wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula (I). 15. A pharmaceutical formulation comprising a therapeutically effective amount of the compound of formula (I) useful for the treatment and/or amelioration of Inflammatory Diseases. 16. A pharmaceutical formulation comprising a therapeutically effective amount of the compound of formula (I) useful for inhibiting sPLA2 mediated release of fatty acid. 17. Use of a pharmaceutical composition comprising a therapeutically effective amount of sPLA2 inhibitor compounds according to formula (I) and mixtures thereof for the manufacture of a medicament for the treatment of Inflammatory Diseases. 18. (Canceled) 19. (Canceled) |
<SOH> BACKGROUND OF THE INVENTION <EOH>The structure and physical properties of human non-pancreatic secretory phospholipase A 2 (hereinafter called, “sPLA 2 ”) has been thoroughly described in two articles, namely, “Cloning and Recombinant Expression of Phospholipase A 2 Present in Rheumatoid Arthritic Synovial Fluid” by Seilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.; The Journal of Biological Chemistry , Vol. 264, No. 10, Issue of April 5, pp. 5335-5338, 1989; and “Structure and Properties of a Human Non-pancreatic Phospholipase A 2 ” by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry , Vol. 264, No. 10, Issue of April 5, pp. 5768-5775, 1989; the disclosures of which are incorporated herein by reference. It is believed that sPLA 2 is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids. Thus, it is important to develop compounds, which inhibit sPLA 2 mediated release of fatty acids (e.g., arachidonic acid). Such compounds would be of value in the general treatment of conditions induced and/or maintained by overproduction of sPLA 2 ; such as sepsis or pain. There is a dearth of effective treatment for diseases associated with sPLA 2 mediated release of fatty acids, particularly sepsis. Therefore, it is desirable to develop new compounds and treatments for sPLA 2 induced diseases. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or enantiomers thereof, useful for the treatment or prevention of Inflammatory Diseases: wherein; R 1 is an amide, thioamide or hydrazone group represented by the formulae, wherein X is oxygen or sulfur; R a and R a′ , are independently selected from hydrogen, (C 1 -C 8 )alkyl, or aryl; R a″ is hydrogen, NH 2 , (C 1 -C 8 )alkyl, aryl, (C 1 -C 8 )alkylaryl, or arylalkyl; and n is 0, 1, or 2. R 2 , and R 3 are independently hydrogen, or a group containing 1 to 10 non-hydrogen atoms plus any required hydrogen atoms; R 4 is the group (C 1 -C 20 )alkyl, (C 1 -C 20 )haloalkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 1 -C 10 )alkylaryl, (C 1 -C 5 )alkylcyclohexyl, (C 1 -C 5 )alkylcyclopentyl, (C 1 -C 5 )alkylcycloheptyl, phenyl, benzyl, methylnaphthyl, (C 1 -C 5 )alkylheterocyclic, carbocyclic radical, or heterocyclic radical, or aryl; R 5 , R 6 , and R 7 are independently selected from hydrogen and non-interfering substituents; R 8 is the group, -(La)-(acidic group) wherein -(L a )-, is an acid linker having an acid linker length of 1 to 8; The present invention provides novel tricyclic compounds of formula I having potent and selective effectiveness as inhibitors of mammalian sPLA 2 . The present invention also relates to the use of novel tricyclic compounds of formula I useful in the treatment and/or prevention of Inflammatory Diseases. The present invention also relates to the use of a novel tricyclic compound of formula I to inhibit mammalian sPLA 2 mediated release of fatty acids. The present invention provides a pharmaceutical composition containing any one of the tricyclic compounds of the invention. The present invention also relates to the use of a formulation comprising a compound of formula I, and a carrier or diluent for the treatment or prevention of sepsis The present invention relates to the use of a pharmaceutical composition comprising a therapeutically effective amount of sPLA 2 inhibitor compounds of formula I and mixtures thereof for the manufacture of a medicament for the treatment of Inflammatory Diseases. The present invention relates to a of a pharmaceutical composition comprising a therapeutically effective amount of sPLA2 inhibitor compounds according to claim 1 and mixtures thereof for the manufacture of a medicament for the treatment of Inflammatory Diseases. The present invention relates to the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of Inflammatory Diseases comprising administering a therapeutically effective amount of a tricyclic compound of formula (I), or a pharmaceutically acceptable salt, solvate or prodrug thereof: wherein; R 1 is an amide, thioamide or hydrazone group represented by the formulae, wherein X is oxygen or sulfur; R a and R a′ are independently selected from hydrogen, (C 1 -C 8 )alkyl, or aryl; R a″ is hydrogen, NH 2 , (C 1 -C 8 )alkyl, aryl, (C 1 -C 8 )alkylaryl, or arylalkyl; and n is 0, 1, or 2. R 2 , and R 3 are independently hydrogen, or a group containing 1 to 10 non-hydrogen atoms plus any required hydrogen atoms; R 4 is the group (C 1 -C 20 )alkyl, (C 1 -C 20 )haloalkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 1 -C 10 )alkylaryl, (C 1 -C 5 )alkylcyclohexyl, (C 1 -C 5 )alkylcyclopentyl, (C 1 -C 5 )alkylcycloheptyl, phenyl, benzyl, methylnaphthyl, (C 1 -C 5 )alkylheterocyclic, carbocyclic radical, or heterocyclic radical, or aryl; R 5 , R 6 , and R 7 are independently selected from hydrogen and non-interfering substituents; R8 is the group, -(La)-(acidic group) wherein -(L a )-, is an acid linker having an acid linker length of 1 to 8; The present invention relates to the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of Inflammatory Diseases comprising administering a therapeutically effective amount of a tricyclic compound represented by the formulae (C1), (C2), or (C3): I. Definitions: The terms, “mammal” and “mammalian” include human and domesticated quadrupeds. The term, “Inflammatory Diseases” refers to diseases such as inflammatory bowel disease, sepsis, septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, asthma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, spondylarthropathris, ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, enteropathric spondylitis, prostrate cancer, Juvenile arthropathy or juvenile ankylosing spondylitis, Reactive arthropathy, infectious or post-infectious arthritis, gonoccocal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with “vasculitic syndromes”, polyarteritis nodosa, hypersensitivity vasculitis, Luegenec's granulomatosis, polymyalgin rheumatica, joint cell arteritis, calcium crystal deposition arthropathris, pseudo gout, non-articular rheumatism, bursitis, tenosynomitis, epicondylitis (tennis elbow), carpal tunnel syndrome, repetitive use injury (typing), miscellaneous forms of arthritis, neuropathic joint disease (charco and joint), hemarthrosis (hemarthrosic), Henoch-Schonlein Purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, arthritis associated with certain diseases, surcoilosis, hemochromatosis, sickle cell disease and other hemoglobinopathries, hyperlipoproteineimia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behat's Disease, systemic lupus erythrematosis, or relapsing polychondritis and related diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula I in an amount sufficient to inhibit sPLA 2 mediated release of fatty acid and to thereby inhibit or prevent the arachidonic acid cascade and its deleterious products. The term, “tricyclic”, or “tricyclic nucleus” as used herein refers to a nucleus (having numbered positions) with the structural formula (X): The tricyclic compounds of the invention employ certain defining terms as follows: The term, “alkyl” by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, sec-butyl, n-pentyl, and n-hexyl. The term, “alkenyl” employed alone or in combination with other terms means a straight chain or branched monovalent hydrocarbon group having the stated number ranges of carbon atoms, and typified by groups such as vinyl, propenyl, crotonyl, isopentenyl, and various butenyl isomers. The term, “hydrocarbyl” means an organic group containing only carbon and hydrogen. The term, “halo” means fluoro, chloro, bromo, or iodo. The term, heterocyclic radical, refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nuclei having 5 to 14 ring atoms and containing from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur. Typical heterocyclic radicals are pyrrolyl, pyrrolodinyl, piperidinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, benzo(b)thiophenyl, carbazolyl, norharmanyl, azabenzo(b)thiophenyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, indazolyl, imidazo(1.2-A)pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pyridinyl, dipyridylyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl, morpholino, thiomorpholino, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, oxacanyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrahydrothiophenyl, pentamethylenesulfadyl, 1,3-dithianyl, 1,4-dithianyl, 1,4-thioxanyl, azetidinyl, hexamethyleneiminium, heptamethyleneiminium, piperazinyl and quinoxalinyl. The term “(C 1 -C 5 )alkylcyclopentyl,” “(C 1 -C 5 )alkylcyclohexyl,” or “(C 1 -C 5 )alkylheterocyclic” represent a (C l -C 5 )alkyl group attached respectively to a cylopentyl, cyclohexyl, and heterocyclic group wherein the entire group is attached to the tricyclic nucleus (X) at the alkyl terminus. Therefore the mass of the entire group is the mass of the (C 1 -C 5 )alkyl group plus the cyclopentyl, cyclohexyl or heterocyclic group to which it is attached. The term, “carbocyclic radical” refers to radicals derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered organic nucleus whose ring forming atoms (other than hydrogen) are solely carbon atoms. Typical carbocyclic radicals are cycloalkyl, cycloalkenyl, phenyl, benzyl, spiro[5.5]undecanyl, naphthyl, norbornanyl, bicycloheptadienyl, toluyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, and anthracenyl, biphenyl, dibenzylyl and related dibenzylyl homologues represented by the formula (a): where n′ is a number from 1 to 8. The terms, “non-interfering substituent”, or “non-interfering groups” refer to radicals suitable for substitution at positions 2, 3, 5, 6, and/or 7 of the tricyclic nucleus and on other nucleus substituents (as hereinafter described for Formula I), and radicals suitable for substitution on the heterocyclic radical and carbocyclic radical as defined above. Illustrative non-interfering radicals are (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 7 -C 12 )arylalkyl, (C 7 -C 12 )alkylaryl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkenyl, phenyl, benzyl, toluyl, xylenyl, biphenyl, (C 1 -C 8 )alkoxy, C 2 -C 8 )alkenyloxy, C 2 -C 8 alkynyloxy, (C 2 -C 12 )alkoxyalkyl, (C 2 -C 12 )alkoxyalkyloxy, C 2 -C 12 alkylcarbonyl, (C 2 -C 12 )alkylcarbonylamino, (C 2 -C 12 )alkoxyamino, (C 2 -C 12 )alkoxyaminocarbonyl, (C 1 -C 12 )alkylamino, (C 1 -C 6 )alkylthio, (C 2 -C 12 )alkylthiocarbonyl, (C 1 - 8 )alkylsulfinyl, (C 1 -C 8 )alkylsulfonyl, (C 2 -C 8 )haloalkoxy, (C 2 -C 8 )haloalkylsulfonyl, (C 2 -C 8 )haloalkyl, (C 2 -C 8 )hydroxyalkyl, —C(O)O((C 2 -C 8 )alkyl), —(CH 2 ) n -O—(C 1 -C 8 alkyl), benzyloxy, phenoxy, phenylthio, —(CONHSO 2 R), —CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, —(CH 2 ) n -CO 2 H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, —SO 3 H, thioacetal, thiocarbonyl, and carbonyl; where n is from 1 to 8; and R is (C 1 -C 8 )alkyl. The term “substituted group” is an organic group substituted with one or more non-interfering substituents. As used herein the terms “group”, “radical” or “fragment” are synonymous and are intended to indicate functional groups or fragments of molecules attachable to a bond or other fragments of molecules. For example acetamide group represent the acetamide fragment or radical. Structures of groups, radicals or fragments attached to the tricyclic nucleus have been drawn to show the first line as a connecting bond only. Thus, the group represents the acetamide radical or group, not the propanamide radical unless otherwise indicated. The term, “(acidic group)” means an organic group which when attached to a tricyclic nucleus at the 8-position, through suitable linking atoms (hereinafter defined as the “acid linker”), acts as a proton donor capable of hydrogen bonding. Illustrative of an (acidic group) are the following: The term, “amine”, includes primary, secondary and tertiary amines. The term, “alkylene chain of 1 or 2 carbon atoms” refers to the divalent radicals, —CH 2 —CH 2 — and —CH 2 —. The term, “acid linker length” refers to the number of groups or atoms directly connecting from the tricyclic nucleus to the acidic group. For example, the group —OCH 2 — has an acid linking length of 2. The term, “group containing 1 to 10 non-hydrogen atoms” refers to relatively small groups which form substituents at the designated position of the tricyclic nucleus, said groups may contain non-hydrogen atoms alone, or non-hydrogen atoms plus hydrogen atoms as required to satisfy the unsubstituted valence of the non-hydrogen atoms, for example; (i) groups absent hydrogen which contain no more than 4 non-hydrogen atoms such as —CF 3 , —Cl, —Br, —NO 2 , —CN, —SO 3 ; and (ii) groups having hydrogen atoms which contain less than 4 non-hydrogen atoms such as —CH 3 , —C 2 H 5 , and —CH═CH 2 . The term “spiro[5.5]undecanyl” refers to the group represented by the formula; II. The tricyclic Compounds of the Invention: The present invention provides a novel class of tricyclic compounds useful as sPLA 2 inhibitors for the treatment and/or prophylaxis of inflammation attendant to Inflammatory Diseases The compounds of the invention are represented by the general formula (I) and include pharmaceutically acceptable salts, racemates, enantiomers, or solvates thereof; wherein; R 1 is an amide, thioamide or hydrazone group represented by the formulae, wherein X is oxygen or sulfur; R a and R a′ are independently selected from hydrogen, (C 1 -C 8 )alkyl, or aryl; R a″ is hydrogen, NH 2 , (C 1 -C 8 )alkyl, aryl, (C 1 -C 8 )alkylaryl, or arylalkyl; and n is 0, 1, or 2. R 2 , and R 3 are independently hydrogen, or a group containing 1 to 10 non-hydrogen atoms plus any required hydrogen atoms; R 4 is the group (C 1 -C 20 )alkyl, (C 1 -C 20 )haloalkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 1 -C 10 )alkylaryl, (C 1 -C 5 )alkylcyclohexyl, (C 1 -C 5 )alkylcyclopentyl, (C 1 -C 5 )alkylcycloheptyl, phenyl, benzyl, methylnaphthyl, (C 1 -C 5 )alkylheterocyclic, carbocyclic radical, or heterocyclic radical, or aryl; R 5 , R 6 , and R 7 are independently selected from hydrogen and non-interfering substituents; R 8 is the group, -(La)-(acidic group) wherein -(L a )-, is an acid linker having an acid linker length of 1 to 8; Preferred Subgroups of Compounds of Formula (I): Preferred R 1 Substituents: A preferred subgroup of R 1 is an amide, thioamide or hydrazone group represented by the formula, wherein X is oxygen or sulfur; R a and R a′ are independently selected from hydrogen, (C 1 -C 8 )alkyl, or aryl; R a″ is hydrogen, NH 2 , (C 1 -C 8 )alkyl, aryl, (C 1 -C 8 )alkylaryl, or arylalkyl; and n is 0, 1, or 2. A more preferred subclass of compounds of formula (I) are those wherein X is oxygen. Also more preferred is a subclass of compounds of formula I wherein R 1 is an amide group represented by Preferred R 2 Substituents: R 2 is preferably selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, —O—((C 1 -C 4 )alkyl), —S—((C 1 -C 3 )alkyl), —(C 3 -C 10 )cycloalkyl, —CF 3 , halo, —NO 2 , —CN, —SO 3 . Particularly preferred R 7 groups are selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, —F, —CF 3 , —Cl, —Br, or —O—CH 3 . Preferred R 3 Substituents: R 3 is preferably selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, —O—((C 1 -C 4 )alkyl), —S—((C 1 -C 3 )alkyl), —(C 3 -C 10 )cycloalkyl, —CF 3 , halo, —NO 2 , —CN, —SO 3 . Particularly preferred R 6 groups are selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, —F, —CF 3 , —Cl, —Br, or —O—CH 3 . Preferred R 4 Substituents: Preferred R 4 groups are selected from the group consisting of (C 1 -C 20 )alkyl, (C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkylaryl, cyclohexylmethyl, cyclopentylmethyl, ethylcyclohexyl, ethylcyclopentyl, methylcycloheptyl, phenyl, benzyl, methylnaphthyl,and aryl radicals. Preferred R 5 , R 6 , and R 7 Groups A preferred R 5 or R 6 or R 7 group is a group independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, —OCH 3 , —OCH 2 CH 3 , halogen, phenyl and phenoxy. Preferred R 8 Substituents: A preferred subgroup of R8 is the group -(La)-(acidic group) wherein -(L a )-, is an acid linker having an acid linker length of 1, 2 or 3 atoms; Also preferred is a subclass of compounds of formula I wherein -(L a )- is an acid linker selected from the group consisting of; A most preferred subgroup of R8 is the group, -(La)-(acidic group) wherein -(L a )-, is an acid linker represented by O—CH 2 . A preferred compound of the invention is a compound selected from the group consisting of: (4-benzyl-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(cyclopropylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(cyclobutylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(cyclopentylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(cycloheptylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-furyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-furyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-thienyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-thienyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(4-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(1-napthyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2-napthyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2,3-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2,4-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2,5-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2,6-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3,4-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3,5-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3,6-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2,3-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2,4-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2,5-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(2,6-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3,4-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-[(3,5-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, (4-benzyl-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(cyclopropylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(cyclobutylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(cyclopentylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(cycloheptylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-furyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-furyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-thienyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-thienyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(4-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(1-napthyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2-napthyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2,3-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2,4-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2,5-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2,6-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3,4-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3,5-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3,6-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, 2,3-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2,4-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2,5-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(2,6-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3,4-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(3,5-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester, (4-[(phenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, morpholinoethyl ester, (4-[(cyclohexyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, morpholinoethyl ester, (4-[(cyclopentyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, morpholinoethyl ester, (4-[(phenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, N,N-diethylacetamido ester, (4-[(cyclohexyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, N,N-diethylacetamido ester, and (4-[(cyclopentyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, N,N-diethylacetamido ester. Preferred compounds of the invention are represented by the formulae (C1), (C2), or (C3): The salts of the tricyclic compounds represented by formula (I), are an additional aspect of the invention. In those instances when the compound of the invention possesses acidic or basic functional groups, various salts may be formed which are more water soluble and more physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts, include but are not limited to, the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin. Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Phar. Sci., 66: 1-19 (1977)). Moreover, the basic group(s) of the compound of the invention may be reacted with suitable organic or inorganic acids to form salts such as acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, hydrobromide, camsylate, carbonate, chloride, clavulanate, citrate, chloride, edetate, edisylate, estolate, esylate, fluoride, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrochloride, hydroxynaphthoate, hydroiodide, isothionate, lactate, lactobionate, laurate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate, pantothenate, phosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, tosylate, trifluoroacetate, trifluoromethane sulfonate, and valerate. Certain compounds of the invention may possess one or more chiral centers, and thus, may exist in optically active forms. Likewise, when the compounds contain an alkenyl or alkenylene group, there exist the possibility of cis- and trans-isomeric forms of the compounds. The R- and S-isomers and mixtures thereof, including racemic mixtures as well as mixtures of cis- and trans-isomers, are contemplated by this invention. Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. All such isomers as well as the mixtures thereof are intended to be included in the invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art by using stereo-specific reactions with starting materials which contain the asymmetric centers and are already resolved or, alternatively by methods which lead to mixtures of the stereoisomers and subsequent resolution by known methods. For example, a racemic mixture may be reacted with a single enantiomer of some other compound. This changes the racemic form into a mixture of stereoisomers and diastereomers, because they have different melting points, different boiling points, and different solubilities and can be separated by conventional means, such as crystallization. Prodrugs are derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Derivatives of the compounds of this invention have activity in both their acid and base derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs , pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic or aromatic esters derived from acidic groups pendent on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Particularly preferred esters as prodrugs are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, morpholinoethyl, and N,N-diethylglycolamido. N,N-diethylglycolamido ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) with 2-chloro-N,N-diethylacetamide (available from Aldrich Chemical Co., Milwaukee, Wis. USA; Item No. 25,099-6). Morpholinylethyl ester prodrugs may be prepared by reaction of the sodium salt of a compound of formula (I) (in a medium such as dimethylformamide) with 4-(2-chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4, 220-3). (III) Method of Preparing the Tricyclic Compound: The tricyclic compounds of the present invention are prepared by following a scheme such as Scheme 1 shown below: Scheme 1 depicts a protocol for preparing tricyclic-compounds of the invention starting from 6-chloro-m-anisidine (1) (available from Aldrich Chemical Co. Milwaukee U.S.A, and other fine chemical suppliers) or substituted analogs thereof. As shown, the starting material (1) is reductively aminated with benzaldehyde using a mixture of zinc chloride and sodium cyanoborohydride as reducing agents to form the compound (2). One of skill in the art is aware that the reaction to prepare (2) may be accomplished with other reducing agents including but not limited to NaBH 4 , HCl/Zn, and NaCNBH 3 . The choice of aldehyde or ketone to be reductively aminated with compound (1) determines the structure of the group R 4 . For example, the use of formaldehyde in the reductive amination steps would form the N-methyl analog of (2) and ultimately a compound of formula I wherein R 4 is methyl. Similarly, the use of cyclohexylacetaldehyde in the reductive amination steps would form the cyclohexylmethyl analog of (2) and ultimately a compound of formula I wherein R 4 is cyclohexylmethyl. A solution of compound (2) is deprotonated at the nitrogen using a base to form a nucleophile to which is added 2-carbomethoxy-5-bromocyclopentanone. When substitution is desired at positions 2 and/or 3, an appropriately substituted analog of 2-carbomethoxy-5-bromocyclopentanone is employed. The reaction of (2) with 2-carbomethoxy-5-bromocyclopentanone results in a tertiary amine substitution product (compound 3). 2-carbomethoxy-5-bromocyclopentanone and analogs thereof may be prepared by a method similar to that reported by Marx et al. J. Org. Chem. 1972, 37, 4489. Strong bases are preferred for de-protonating the nitrogen atom of compound 2. Most preferred is a base selected from potassium(bistrimethylsilyl)amide, lithium diisopropyl amide, and n-butyllithium. After the initial base addition at about −60 to −10° C., the reaction is preferably performed at ambient temperatures for about 4 to 24 hours. The product (3) is isolated by aqueous work-up and extraction from organic solvents such as, for example, ethyl acetate. The product (3) may be used directly or further purified by chromatography and/or crystallization by methods known to one of skill in the art. To prepare compound (4), compound (3) dissolved in toluene or other suitable solvent is heated with zinc chloride at reflux temperature over a period of 10 to 60 hours, preferably about 48 hours, to afford an intermediate tricyclic compound. The intermediate compound is reduced by hydrogenation using palladium-on-carbon as catalyst. Preferably, the hydrogenation is performed in ethanol or other protic solvent with triethylamine as acid scavenger. While other reducing catalysts may be used, 10% palladium-on-carbon is preferred. The catalyst is also preferably wetted with ethanol before use. The methyl ester at the 1-position of compound (4) is converted to the amide by reaction of compound (4) with excess ammonia solution. Other methods for the conversion of esters to amides are known to one of skill in the art and may be found in general reference texts (see J. March, Advanced Organic Chemistry, 3 rd ed., Wiley Interscience Publishers, New York, N.Y., 1985). The compound (5) is de-methylated by reaction with boron tribromide or sodium thioethoxide in a suitable solvent such as dichloromethane. About 1.0 to 12.0 equivalents of boron tribromide is typically sufficient to effect complete de-methylation. The de-methylation reaction temperature is from about −12° C. to about 10° C. Work-up is initiated by stirring with methyl alcohol or other suitable protic solvent. The stirring in methyl alcohol is followed by neutralization with a base such as sodium bicarbonate. This is followed by extraction and purification of the organic phase by methods known to one of skill in the art. The product (6) is then dissolved in N,N-dimethylformamide followed by addition of a slight excess (about 1.05 mole equiv. based on (5)) of TRITON-B™ (Aldrich Chemical Company, Milwaukie, USA), cesium carbonate or other mild base, and methyl bromoacetate. The mixture is stirred at ambient temperature to afford compound (7) after about 1 to 6 hours of reaction. Compound (7) is isolated by aqueous wash followed by chromatography of the organic layer. Other 2-substituted haloacetates i.e. benzyl bromoacetate may be used to prepare, for example, the benzyl analog of (7). The free acid (8) is obtained by acidifying the saponification product of (7) or other basification reaction product, e.g. with potassium or lithium hydroxide. Most strong inorganic acids are suitable for acidification as described previously. However, the use of dilute HCl is preferred. The free acid (8) may be extracted into an organic phase if soluble, and dried by common laboratory methods or dried by removing water from the aqueous phase. Alternatively the saponification reaction (sodium hydroxide reaction with (8a)) product, itself a compound of the invention, may be isolated. Preparation of homologous amide derivatives of (I) may be accomplished by methods known to one of skill in the art as shown for example for the propanamide derivative below in Scheme 2. Compound (4) from Scheme 1 is reduced to the alcohol (9), for example by lithium hydride reductions or by other methods known to one of skill in the art. The resulting alcohol (9) may be converted to the halide, preferably chloride (10). The halogenation of the alcohol (9) may be accomplished by use of a thionyl halide or other methods known to one of skill in the art. The halide (10) may be activated by halogen-metal exchange reaction using for example, n-butyllithium. The activated product of (10) is then reacted with ethylene oxide, for example, to afford the terminal alcohol compound (11). Conversion of the terminal alcohol (11) to an ester via an intermediate acid may be accomplished, for example, by oxidation of the alcohol (11) with sodium hypochlorite in buffered t-butanol followed by esterification of the incipient acid to the ester (12). Methods for these conversions are known to one of skill in the art and may also be found in general reference texts that have been discussed previously. The ester (12) may be converted to the corresponding amide derivative (13) or other substituted amide compound. For example, the reaction of the ester (12) with methylchloroaluminum amide in benzene or other suitable solvent or solvent mixtures affords an intermediate amide (See Levin, J. I.; Turos, E.; Weinreb, S. M. An alternative procedure for the aluminum-mediated conversion of esters to amides. Syn.Comm., 1982, 12, 989-993). The intermediate amide from (12) is then de-protected at the 8-position by the use of boron tribromide as described previously to afford the amide (13). The amide (13) acetylated by reaction with methylbromo acetate and TRITON-B™ (Aldrich Chemical Company, Milwaukee, USA) to afford compound (14). The conversion of compound (14) to the oxyacetic acid (15), salt or ester derivative is accomplished as described previously for Scheme 1. In an alternate and preferred procedure, the ester (12) may be prepared in a sequence as shown in Scheme 3 below According to Scheme 3, the alcohol (9) may be oxidized to the aldehyde (10a). Oxidation of alcohol (9) to the aldehyde (10a) may be accomplished for example, by the use of sodium hypochlorite in buffered t-butanol, or the use of pyridinium sulfur trioxide complex with diisopropyl ethylamine as base in dimethyl sulfoxide solvent (see Tetrahedron Letters, 28, 1603 (1987)). The aldehyde (10a) is then subjected to a Horner-Emmons modification of the Wittig reaction to afford the α,β-unsaturated ester (11a). Preferably, a reagent for forming the α,β-unsaturated methyl ester (i.e. trimethylphosphonoacetate) is used to react with the aldehyde in the presence of a base. Preferred bases for the Wittig type reactions include n-butyllithium, sodium hydride and sodium ethoxide. The E regio-isomer of α,β-unsaturated methyl ester or a preponderance of the E regio-isomer may be obtained. A general review of Wittig and modified Wittig reactions is provided in Chem. Rev., 89 863 (1989). However, the regio-isomerism of the modified Wittig reaction is irrelevant because of the subsequent reduction step. The unsaturated ester (11a) is reduced to afford compound (12), preferably by hydrogenation techniques such as use of hydrogen with Palladium-on-carbon catalysts. The saturated ester (12) is then converted to the amide (13) and ultimately to compound (15) and analogs thereof as shown in Scheme 3, and described previously for Scheme 1. Compounds of formula (I) wherein for R 1 n is 1, may be prepared by a Scheme such as Scheme 4 below: For example, the halide (10) prepared according to Scheme 2 may be cyanated using sodium cyanide or a soluble source of cyanide ion to afford the cyano compound (11b). The cyano compound (11b) may be hydrolyzed to afford the amide compound (16). The amide (16) is converted to compound (18) or analogs such as the oxyacetic acid methyl ester (17), or oxyacetic acid, sodium salt derivatives as discussed previously. A preferred procedure for the conversion of (11b) to (16) is the use of a hydrogen peroxide/potassium carbonate mixture in dimethyl sulfoxide solvent. The reaction is typically performed at ambient temperatures and the product is worked up by acidic aqueous quench followed by extraction. Other procedures for the conversion of the cyano group to the amide group may be found in previously disclosed general reference texts. To prepare compound of formula (I) wherein R 4 is a halo-substituted group, i.e. R 4 is halosubstituted benzyl or (C 1 -C 20 )haloalkyl wherein the halo group is chloro, bromo, fluoro or iodo, the process as shown in Scheme 5 below may be utilized. Scheme 5 in addition to its utility in preparing compounds of formula I also provides the the advantage of allowing alkylation of the tricyclic nitrogen (4-position of tricyclic nucleus) with haloaryl, haloalkylaryl, or haloalkyl groups after formation of the tricycle to avoid dehalogenation of such groups as may obtain following the procedure of Scheme 1. According to Scheme 5, the 6-chloro-m-anisidine is BOC-protected using t-butyloxycarbonyl anhydride (BOC anhydride) or other protecting group to form compound (19). Compound (19) is then substituted with 2-carbomethoxy-5-bromocyclopentanone at the nitrogen to form compound (20), using a base as described for Scheme 1. The product (20) is deprotected with trifluoroacetic acid in a suitable solvent to afford an intermediate compound which is then reductively cyclized using zinc chloride in a suitable solvent e.g. toluene at reflux to form compound (21). Compound (21) is dehalogenated using 10% palladium-on-carbon to afford compound (22) similar to the procedure of Scheme 1. The dehalogenated product (22) is then arylated or alkylated at the tricyclic nitrogen using a suitable base (in the absence, or presence, of a catalyst) and an appropriately halo-substituted arylhalide or alkylhalide. Arylation of amines can be accomplished by a wide variety of known methods and catalysts and are known to one of skill in the art and may be found in general reference texts (see March's Advanced Organic Chemistry, 5th ed., Wiley Interscience Publishers, New York, N.Y., 2001, page 501-502), for example, according to the general procedures of Watanabe, M.; Nishiyama, M.; Yamamoto, T.; Koie, Y.; Tetrahedron Lett 2000, 41 (4), 481-483; Wolfe, J. P.; Buchwald, S. L.; J. Org. Chem. 1996, 61, 1133; Morita, S.; Kitano, K.; Matsubara, J.; Ohtani, T.; Kawano, Y.; Otsubo, K.; Uchida, M.; Tetrahedron [TETRAB] 1998, 54 (19), 4811-4818; Smith W. J., Sawyer J. S., Tetrahedron Lett 37(3), 299-302 (1996); and related references. The resulting haloaryl or haloalkyl compound (23) is subjected to procedures similar to that shown in Scheme 1 (see compound 4 of Scheme 1) to afford the desired halosubstituted compound (24). IV. Methods of Using the Compounds of the Invention: The tricyclic compounds described herein are believed to achieve their beneficial therapeutic action principally by direct inhibition of mammalian (including human) sPLA 2 , and not by acting as antagonists for arachidonic acid, nor other active agents below arachidonic acid in the arachidonic acid cascade, such as 5-lipoxygenases, cyclooxygenases, and etc. The method of the invention for inhibiting sPLA 2 mediated release of fatty acids comprises contacting mammalian sPLA 2 with a therapeutically effective amount of tricyclic compounds of Formulae (I) as described herein including a salt or a prodrug derivative thereof. Another aspect of this invention relates to a method for treating Inflammatory Diseases such as inflammatory bowel disease, septic shock, adult respiratory distress syndrome, pancreatitis, trauma, asthma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, osteoarthritis, and related diseases which comprises administering to a mammal (including a human) a therapeutically effective dose of a tricyclic compound of the invention. As previously noted the compounds of this invention are useful for inhibiting sPLA 2 mediated release of fatty acids such as arachidonic acid. By the term, “inhibiting” is meant the prevention or therapeutically significant reduction in release of sPLA 2 initiated fatty acids by the compounds of the invention. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The specific dose of a compound administered according to this invention to obtain therapeutic or prophylactic effect will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration and the condition being treated. Typical daily doses will contain a non-toxic dosage level of from about 0.01 mg/kg to about 50 mg/kg of body weight of an active compound of this invention. Preferably compounds of the invention per Formula (I) or pharmaceutical formulations containing these compounds are in unit dosage form for administration to a mammal. The unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these. The quantity of Active ingredient in a unit dose of composition may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. The compound can be administered by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Pharmaceutical formulations of the invention are prepared by combining (e.g., mixing) a therapeutically effective amount of the tricyclic compound of the invention together with a pharmaceutically acceptable carrier or diluent therefor. The present pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients. In making the compositions of the present invention, the Active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), or ointment, containing, for example, up to 10% by weight of the active compound. The compounds of the present invention are preferably formulated prior to administration. For the pharmaceutical formulations any suitable carrier known in the art can be used. In such a formulation, the carrier may be a solid, liquid, or mixture of a solid and a liquid. For example, for intravenous injection the compounds of the invention may be dissolved in at a concentration of 2 mg/ml in a 4% dextrose/0.5% Na citrate aqueous solution. Solid form formulations include powders, tablets and capsules. A solid carrier can be one or more substance, which may also act as flavoring agents, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating material. Tablets for oral administration may contain suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, together with disintegrating agents, such as maize, starch, or alginic acid, and/or binding agents, for example, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid, or talc. A preferred tablet formulation for oral administration is one that affords rapid dissolution in the mouth of a patient in need thereof. In powders the carrier is a finely divided solid which is in admixture with the finely divided Active ingredient. In tablets the Active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about 1 to about 99 weight percent of the Active ingredient which is the novel compound of this invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethyl cellulose, low melting waxes, and cocoa butter. Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs. The Active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both. The Active ingredient can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol. Other compositions can be made by dispersing the finely divided Active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil. The following pharmaceutical formulations 1 through 8 are illustrative only and are not intended to limit the scope of the invention in any way. “Active ingredient”, refers to a compound according to Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof. |
Protective undergarment configured for improved handling |
A protective undergarment is provided according to exemplary aspects of this invention. The undergarment includes a waist portion adapted to encircle the waist of a user. The undergarment also includes a crotch portion having an end segment extending from the waist portion, a central segment, and a terminal end segment attachable to the waist portion. The terminal end segment of the crotch portion extends substantially perpendicular to the waist portion. |
1. A protective undergarment comprising: a waist portion adapted to encircle the waist of a user; and a crotch portion comprising an end segment extending from said waist portion, a central segment, and a terminal end segment attachable to said waist portion, said terminal end segment extending substantially perpendicular to said waist portion. 2. The protective undergarment of claim 1 wherein said waist portion comprises end segments each being configured for engagement to at least one of said terminal end segment of said crotch portion and the other of said end segments of said waist portion; and wherein, upon engagement, said end segments of said waist portion and said terminal end segment of said crotch portion engage one another in a common region. 3. The protective undergarment of claim 2 wherein, upon engagement, said end segments of said waist portion and said terminal end segment of said crotch portion overlap one another in said common region. 4. The protective undergarment of claim 2 wherein each of said end segments of said waist portion and said terminal end segment of said crotch portion comprises a surface configured for engagement to at least one of said other end segments and a surface configured to be engaged by at least one of said other end segments. 5. The protective undergarment of claim 4 wherein at least one of said end segments of said waist portion and said terminal end segment of said crotch portion comprises hooks on said surface configured for engagement, and said surface configured to be engaged is configured for engagement by hooks. 6. The protective undergarment of claim 4 wherein each of said end segments of said waist portion and said terminal end segment of said crotch portion comprises hooks on said surface configured for engagement, and said surface configured to be engaged is configured for engagement by hooks. 7. The protective undergarment of claim 4 wherein said surface configured for engagement and said surface configured to be engaged on of each of said end segments of said waist and crotch portions are positioned such that said end segments can be engaged in any order. 8. The protective undergarment of claim 2 wherein said end segments of said waist portion are configured for engagement to one another and said terminal end segment of said crotch portion is configured for engagement to at least one of said end segments of said waist portion. 9. The protective undergarment of claim 1 wherein said terminal end segment of said crotch portion is narrower than said central segment of said crotch region. 10. The protective undergarment of claim 1 wherein said waist portion comprises end segments each being configured for engagement to at least one of said terminal end segment of said crotch portion and the other of said end segments of said waist portion; wherein, upon engagement, said end segments of said waist portion and said terminal end segment of said crotch portion engage one another in a common region; and wherein said terminal end segment of said crotch portion is narrower than said central segment of said crotch portion. 11. A protective undergarment comprising: a waist portion adapted to encircle the waist of a user, wherein said waist portion comprises end segments; and a crotch portion comprising an end segment extending from said waist portion, a s central segment, and a terminal end segment attachable to said waist portion, said terminal end segment extending substantially perpendicular to said waist portion, wherein said terminal end segment of said crotch portion is no wider than said central segment; each of said end segments of said waist portion being configured for engagement to at least one of said terminal end segment of said crotch portion and the other of said end segments of said waist portion; and wherein, upon engagement, said end segments of said waist portion and said terminal end segment of said crotch portion engage one another in a common region. 12. The protective undergarment of claim 11 wherein each of said end segments of said waist portion and said terminal end segment of said crotch portion comprises a surface configured for engagement to at least one of said other end segments and a surface configured to be engaged by at least one of said other end segments. 13. The protective undergarment of claim 12 wherein each of said end segments of said waist portion and said terminal end segment of said crotch portion comprises hooks on said surface configured for engagement, and said surface configured to be engaged is configured for engagement by hooks. 14. The protective undergarment of claim 12 wherein said surface configured for engagement and said surface configured to be engaged on of each of said end segments of said waist and crotch portions are positioned such that said end segments can be engaged in any order. 15. The protective undergarment of claim 12 wherein said end segments of said waist portion are configured for engagement to one another and said terminal end segment of said crotch portion is configured for engagement to at least one of said end segments of said waist portion. 16. The protective undergarment of claim 12, wherein said waist and crotch portions form a substantially “T” shaped configuration when said end segments of said waist and crotch portions are disengaged and said waist and crotch portions are extended. 17. The protective undergarment of claim 2, wherein said waist and crotch portions form a substantially “T” shaped configuration when said end segments of said waist and crotch portions are disengaged and said waist and crotch portions are extended. 18. The protective undergarment of claim 1, said waist portion and said crotch portion together defining leg openings when said terminal end segment of said crotch portion is attached to said waist portion, said protective undergarment further comprising at least one member for engagement between said crotch portion and said waist portion, said engagement member being positioned to adjust the size of at least one of said leg openings. 19. The protective undergarment of claim 18, said protective undergarment comprising an engagement member positioned to adjust the size of each of said leg openings. 20. The protective undergarment of claim 18, said engagement member extending from said crotch portion of said protective undergarment. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The use of absorbent articles, such as protective undergarments, has increased steadily for many years. Early uses, such as diapers for babies and sanitary products for women, have in recent years been joined by an increasing demand for products designed to deal with incontinence issues for adults, frequently brought on by advanced age, obesity, or a variety of medical conditions. At the same time, markets have grown in all of these areas for both disposable and reusable products, depending on the preferences of the consumer. Disposable absorbent articles, such as diapers and pads for example, are in widespread use throughout the world as a result of their convenience. They provide substantial advantages and convenience over absorbent articles that have to be laundered and reused, particularly when the absorbent articles are used away from home. In recent years, many different disposable absorbent articles have been proposed and some have been very successful in the marketplace. However, even current successful products leave room for improvement. To promote preservation of the environment, some consumers desire to return to the use of reusable, rather than disposable, absorbent articles such as infant and adult diapers. A recent improvement to reusable diapers is in the replacement of pin fasteners by fasteners of filamentary material, such as hook and loop filamentary materials manufactured by Velcro Corporation and Aplix Corporation. In this regard, reference is made to U.S. Pat. No. 4,537,591 to Coates, incorporated herein by reference, which discloses a cloth diaper having filamentary fasteners together with a self-closing tab cover that protects the fasteners from buildup of lint during washing. Whether for reusable or disposable products, various fastening systems have been employed for fastening the absorbent products to the wearer or to the clothing of the wearer. For example, the waistband of a diaper is preferably fastened around the waist of the wearer, and the fastening system is generally intended to hold the diaper in snug encircling fashion on the wearer's torso. After the diaper is soiled, it is removed by unfastening the tabs, thereby opening the waist. The configuration of reusable and/or disposable products for adults, especially the infirm or obese, and/or those with limited dexterity, is additionally made difficult by the size and weight of the person wearing the garment. These factors hinder the donning and doffing of protective undergarments having traditional configurations. For example, it is extremely inconvenient for a caregiver to be required to remove an undergarment just to see if a change is needed, particularly if the undergarment is being worn by a large and/or immobile person. Thus there continues to be a need for undergarments affording easier access for checking, and greater facility of donning and doffing. |
<SOH> SUMMARY OF THE INVENTION <EOH>A protective undergarment is provided according to exemplary aspects of this invention. The undergarment includes a waist portion adapted to encircle the waist of a user. The undergarment also includes a crotch portion having an end segment extending from the waist portion, a central segment, and a terminal end segment attachable to the waist portion. The terminal end segment of the crotch portion extends substantially perpendicular to the waist portion. According to another aspect of this invention, a protective undergarment is provided including a waist portion adapted to encircle the waist of a user, wherein the waist portion comprises end segments. The protective undergarment also includes a crotch portion comprising an end segment extending from the waist portion, a central segment, and a terminal end segment attachable to the waist portion. The terminal end segment extends substantially perpendicular to the waist portion, and the terminal end segment of the crotch portion is no wider than the central segment. Each of the end segments of the waist portion is configured for engagement to at least one of the terminal end segment of the crotch portion and the other of the end segments of the waist portion. Upon engagement, the end segments of the waist portion and the terminal end segment of the crotch portion engage one another in a common region. |
Substituted isoxazoles and their use as antibiotics |
Compounds of formula (I), wherein X is O, S, NH, OCO, NH—CO, NH—COO, NH—CO—NH, NH—CS or NH—CS—NH; R4 is H, (C1-C3)-alkyl optionally substituted by halogen, or a C-linked heterocyclic radical selected from several possibilities; R1 and R3 are H or F; and R2 is an N-linked or C-linked heterocyclic radical, are useful in the treatment of microbial infections in human or animal body. |
1. A (3,5)-disubstituted isoxazolinic type compound of formula (I), stereoisomers, mixtures of stereoisomers, polymorphic forms, mixtures of polymorphic forms, N-oxides, solvates and pharmaceutically acceptable salts thereof, wherein X is a biradical selected from the group consisting of O, S, NH, OCO, NH—CO, NH—COO, NH—CS, NH—CO—NH and NH—CS—NH; R4 is a radical selected from the group consisting of: hydrogen, (C1-C3)-alkyl, optionally substituted by 1, 2 or 3 halogen radicals selected from F, Cl or Br; and a C-linked heterocyclic radical HET1 that is: either a C-linked radical of a 5-membered heterocycle of 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S, optionally substituted by a radical selected from the group consisting of (C1-C4)-alkyl, amino, (C1-C4)-alkylamino, (C1-C4)-alkoxyl, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylcarbonyl, (C1-C4)-amido, amido, CN, NO2, F, Cl, and Br; or a C-linked radical of a 6-membered heterocycle with 1, 2 or 3 atoms of nitrogen, optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of (C1-C4)-alkyl, amino, (C1-C4)-alkylamino, (C1-C4)-alkoxyl, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylcarbonyl, (C1-C4)-amido, amido, CN, NO2, F, Cl and Br; R1 and R3 each independently represent H or F; R2 is an N-linked or C-linked radical selected from the group consisting of: wherein: R5 is a non cyclic radical selected from the group consisting of: —(CH2)n—C0-R7, and SO2—R7 wherein: R7 is (C1-C4)-alkyl, (C1-C3)-alkenyl (straight or branched), —(CH2)p—R2, —(CH2)m-Y—(CH2)q-R8 or HET2; n, p, q and m are integers from 0 to 8; Y is O, S or NH; R2 is as defined above, excluding Q20, Q21, Q22, Q23 and Q24. R8 is H or a C-linked radical selected from the group consisting of (C1-C3)-alkyl, vinyl, allyl, ethinyl, propargyl, phenyl and a C-linked radical of an aromatic system constituted by a 5- or 6-membered ring, or by two 5- or 6-membered fused rings; containing the aforementioned aromatic system from one to three heteroatoms independently selected from O, N and S; and being the aforementioned aromatic system optionally mono-, di- or trisubstituted by radicals independently selected from the group consisting of H, (C1-C4)-alkyl (straight or branched), (C1-C4)-alkoxyl, (C1-C4)-alkylsulfanyl, NHCO—R9, NHCOO—R9, CO—R9, COO—R9, CN, NO, NO2, CH═N—R10, F, Cl and Br; R9 is H, (C1-C3)-alkyl or N(R11)(R12), wherein R11 and R12 are independently selected from the group consisting of H and (C1-C3)-alkyl; R10 is H, (C1-C3)-alkyl, phenyl, benzyl, OH or (C1-C3)-alkyloxy; HET2 is a C-linked heterocyclic radical selected from the group consisting of: wherein R13, R14 and R15 are radicals independently selected from the group consisting of (C1-C4)-alkyl (straight or branched), (C1-C4)-alkoxyl, (C1-C4)-alkylsulfanyl, NHCO—R9, NHCOO—R9, CO—R9, COO—R9, CN, NO, NO2, CH═N—R10, F, Cl and Br, wherein R9 and R10 are as defined above; alternatively, R5 is C-linked heterocyclic radical selected from the group consisting of: wherein R16, R17 and R18 are independently selected from the group consisting of CO—R9, COO—R9, CN, NO, NO2, and CH═N—R10; R6 is selected from the group consisting of H, F, Cl, Br, trifluoromethyl, CN, NO2, CHO, CH2OH, (C1-C3)-alkyl, (C1-C3)-alkoxyl, (C1-C3)-alkoxycarbonyl, (C1-C3)-alkoxy-(C1-C3)-alkyl, benzyloxy-(C1-C3)-alkyl, (C1-C3)-alkylcarbonyl, CO—NR19R20, NR19R20, (C1-C3)-alkylamino, (C1-C3)-alkyl-CH═N—O—R21, CH═N—O—R21, CH═CR22R23, (CH2)5NHR19, and CH═NR19; wherein R19 and R20, are independently selected from the group consisting of H, (C1-C3)-alkyl, CO—R24 and an aromatic system constituted by a 5- or 6-membered ring, or by two 5- or 6-membered fused rings; optional containing the aforementioned aromatic system from one to three heteroatoms independently selected from the group consisting of O, N and S; and being the aforementioned aromatic system optionally mono-, di- or trisubstituted by radicals independently selected from the group consisting of H, (C1-C4)-alkyl (straight or branched), (C1-C4)-alkoxyl, (C1-C4)-alkylsulfanyl, NHCO—R9, NHCOO—R9, CO—R9, COO—R9, CN, NO, NO2, CH═N—R10, F, Cl and Br; R21 is H or (C1-C3)-alkyl; R22 and R23, are independently selected from the group consisting of H, CN, NO2, (C1-C3)-alkylcarbonyl, (C1-C3)-alkoxycarbonyl, CHO, CONR19R20 and CH2OH; and R24 is H, (C1-C3)-alkyl, (C1-C3)-alkoxyl or HET2, wherein HET2 is as defined above; s is a integer comprised from 0 to 4. 2. The compound according to claim 1, wherein: X is NH or NH—CS; R4 is methyl or a C-linked isoxazole or isothiazole radical optionally substituted by a methyl moiety in any of their substitutable positions; R1 is H and R3 is F; R2 is a radical selected from the group consisting of: R5 is CO—R7; R7 is selected from (CH2)m—Y—R8 and HET2, wherein m=1; Y is O or NH; R8 is selected from the group consisting of H, phenyl and 2-, 3-, 4-pyridyl, being the last four optionally substituted by CHO, CN, NO2, CH3 or F; HET2 is selected from the group consisting of: wherein R13, R14 and R15 are independently selected from the group consisting of CN, NO2 and CHO; and R6 is selected from the group consisting of H, CH3, CN, CHO, CH2OH, CH═N—OH, CH═CHCN, CO—CH3 and CH2NH-phenyl, said phenyl being substituted by a radical selected from the group consisting of F, CN, CHO and NO2. 3. The compound according to claim 1, for use in the therapeutic treatment of human or animal body. 4. The compound according to claim 1, for use in the treatment of microbial infections. 5. The compound according to claim 4, wherein the treatment is carried out by oral, parenteral, or topical administration. 6. Use of the compound defined in claim 1, for the manufacture of a medicament for the treatment of microbial infections. 7. Use according to claim 6, wherein the medicament can be administered by oral, parenteral or topical route. 8. The compound according to claim 1, for use in the treatment of cancerous and precancerous pathologies. 9. The compound according to claim 8, wherein the treatment is carried put by oral, parenteral, or topical administration. 10. Use of the compound defined in claim 1, for the manufacture of a medicament for the treatment of cancerous and precancerous pathologies. 11. Use according to claim 10, wherein the medicament is administered by oral, parenteral or topical route. 12. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in claim 1, and pharmaceutically acceptable excipients or solvents. |
<SOH> BACKGROUND OF THE ART <EOH>The international microbiological community continues to express serious concern in view of the alarming increase of resistance to commercially available antibiotics, which reduces the range of possibilities of treatment of the different infectious processes. In general, bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity. The compounds of the present invention exhibit activity against both Gram-positive and Gram-negative pathogens. Gram-positive pathogens, for example staphylococci, enterococci, and streptococci, are particularly important because of the development of the resistant strains which are both difficult to treat and difficult to eradicate from the hospital environment. Examples of such strains are methicillin resistant staphylococci, methicillin resistant coagulase negative staphylococci, penicillin resistant Streptococcus pneumoniae and multiply vancomycin resistant enterococci. The best clinically effective antibiotic for treatment of such resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with nephrotoxicity an ototoxicity. Nevertheless, antibacterial resistance to vancomycin and other glycopeptides is also appearing and this resistance is increasing, rendering these agents less and less effective in the treatment of infections produced by Gram-positive pathogens. Between 1989 and 1992, certain antibacterial compounds containing an oxazolidinone ring with a 5-acetamidomethyl side chain have been described (see for example, W. A. Gregory et al., J. Med. Chem. 1989, 32, 1673-1681; W. A. Gregory et al., J. Med. Chem. 1990, 33, 2569-2578; Chung-Ho Park et al. J. Med. Chem. 1992, 35, 1156-1165). Some examples of this compounds are DuP 105 and DuP 721, which reached the clinical state of development. Afterwards, different modifications of certain substituents of the oxazolidinonic structure were made, rendering several compounds from which especially notable are U-100592 (eperezolid) and U-100766 (linezolid), both from Pharmacia Corporation (see for example, S. J. Brickner et al., J. Med. Chem. 1996, 39, 673-679). From them, only linezolid is commercially available at the moment. Nevertheless, though the discovery of the mentioned oxazolidinones means a clear advance in the treatment of infections produced by Gram-positive pathogens, it is as well to remember that bacterial resistance to known antibacterial agents may develop, for example, by the evolution of active binding sites in the bacteria rendering a decrease or total loss of activity of pharmacophore previously active. Therefore, it is useful to obtain new antibacterial agents with other pharmacophores different to the ones containing an oxazolidinone ring. In this respect, Pharmacia Corporation has described the use of an isoxazoline central ring to obtain compounds with antibacterial activity (cf. WO 9807708, WO 9941244 and WO 9943671), which can be described by the following general structure: Bayer has described (cf. DE 19909785 A1) the use of an isoxazoline ring in compounds which have an A ring consisting of two fused rings. AstraZeneca has described (cf. WO 01/40222 A1) the use of an isoxazoline central ring for the preparation of compounds with antibacterial activity with the following general structure: The aforementioned compounds have, at least, a chiral center in the carbon 5 of the isoxazoline ring. Nevertheless, it has been observed that only compounds with R configuration have antibacterial activity, what represents a drawback under a synthetic point of view. On the other hand, Bristol-Myers Squibb (cf. WO 00/10566 A1) describes how to obtain antibacterial compounds containing an isoxazolinone central ring without any chiral center, with the following general structure: In the light of the background art, it is obvious the present interest in providing new compounds with antibacterial activity against both Gram-positive and Gram-negative pathogens, especially if they do not present chirality in the five membered ring. |
<SOH> SUMMARY OF THE INVENTION <EOH>An aspect of the present invention relates to the provision of new (3,5)-disubstituted isoxazolinic type compounds of formula (I), and stereoisomers, mixtures of stereoisomers, polymorphic forms, mixtures of polymorphic forms, N-oxides, solvates and pharmaceutically acceptable salts thereof, wherein X is a biradical selected from the group consisting of O, S, NH, OCO, NH—CO, NH—COO, NH—CS, NH—CO—NH and NH—CS—NH; R4 is a radical selected from the group consisting of hydrogen, a straight or branched (C 1 -C 3 )-alkyl, optionally substituted in any of their carbon atoms by 1, 2 or 3 atoms of F, Cl or Br; and a Clinked heterocyclic radical HET1 that is: either a C-linked radical of a 5-membered heterocycle of 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S, optionally substituted by a radical selected from the group consisting of (C 1 -C 4 )-alkyl, amino, (C 1 -C 4 )alkylamino, (C 1 -C 4 )alkoxyl, (C 1 -C 4 )-alkoxycarbonyl, (C 1 -C 4 )-alkylcarbonyl, (C 1 -C 4 )-amido, amido, CN, NO 2 , F, Cl, and Br; or a C-linked radical of a 6-membered heterocycle with 1, 2 or 3 atoms of nitrogen, optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, amino, (C 1 -C 4 )-alkylamino, (C 1 -C 4 )-alkoxyl, (C 1 -C 4 {alkoxycarbonyl, (C 1 -C 4 )-alkylcarbonyl, (C 1 -C 4 )amido, amido, CN, NO 2 , F, Cl and Br; R1 and R3 each independently represent H or F; R2 is an N-linked or Clinked radical selected from the following group: wherein: R5 is a non cyclic radical selected from the group consisting of: —(CH 2 ) r —COR7, and SO 2 —R7 wherein: R7 is (C 1 -C 4 )-alkyl, (C 1 -C 3 )-alkenyl (straight or branched), —(CH 2 ) p —R2. —(CH 2 ) m —Y—(CH 2 ) q -R8 or HET2; n, p, q and m are integers from 0 to 8; Y is O, S or NH; R2 is as defined above, excluding Q20, Q21, Q22, Q23 and Q24; R8 is H or a Clinked radical selected from (C 1 -C 3 )-alkyl, vinyl, allyl, ethynyl, propargyl, phenyl and a C-linked radical of an aromatic system constituted by a 5- or 6-membered ring, or by two 5- or 6-membered fused rings; containing the aforementioned aromatic system from one to three heteroatoms independently selected from O, N and S; and being the aforementioned aromatic system optionally mono-, di- or trisubstituted by radicals independently selected from the group consisting of H, (C 1 -C 4 )-alkyl (straight or branched), (C 1 C 4 )-alkoxyl, (C 1 -C 4 )-alkylsulfanyl, NHCO—R9, NHCOO—R9, CO—R9, COO—R9, CN, NO, NO 2 , CH═N—R10, F, Cl and Br; R9 is H. (C 1 -C 3 )-alkyl or N(R11)(R12), wherein R11 and R12 are independently selected from the group consisting of H and (C 1 -C 3 )-alkyl; R10 is H, (C 1 -C 3 )-alkyl, phenyl, benzyl, OH or (C 1 -C 3 )-alkyloxy; HET2 is a Clinked heterocyclic radical selected from the group consisting of wherein R13, R14 and R15 are radicals independently selected from the group consisting of (C 1 -C 4 )alkyl (straight or branched), (C 1 -C 4 )-alkoxyl, (C 1 -C 4 )-alkylsulfanyl, NHCO—R9, NHCOO—R9, CO—R9, COO—R9, CN, NO, NO 2 , CH═N—R10, F, Cl and Br, wherein R9 and R10 are as defined above; alternatively, R5 is Clinked heterocyclic radical selected from the group consisting of: wherein R16, R17 and R18 are independently selected from the group consisting of CO—R9, COOR9, CN, NO, NO 2 , and CH═N—R10; R6 is selected from the group consisting of H, F, Cl, Br, trifluoromethyl, CN, NO 2 , CHO, CH 2 OH, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkoxyl, (C 1 -C 3 )-alkoxycarbonyl, (C 1 -C 3 )-alkoxy-(C 1 -C 3 )-alkyl, benzyloxy-(C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkylcarbonyl, CO—NR19R20, NR19R20, (C 1 -C 3 {alkylamino, (C 1 -C 3 )-alkyl-CH═N—O—R21, CH═N—O—R21, CH═CR22R23, (CH 2 ) s NHR19, and CH═NR19; wherein R19 and R20, are independently selected from the group consisting of H. (C 1 -C 3 )-alkyl, CO—R24 and an aromatic system constituted by a 5- or 6-membered ring, or by two 5- or 6-membered fused rings; optionally containing the aforementioned aromatic system from one to three heteroatoms independently selected from O, N and S; and being the aforementioned aromatic system optionally mono-, di- or trisubstituted by radicals independently selected from the group consisting of H, (C 1 -C 4 )-alkyl (straight or branched), (C 1 -C 4 )-alkoxyl, (C 1 -C 4 )-alkylsulfanyl, NHCO—R9, NHCOO—R9, CO—R9, COO—R9, CN, NO, NO 2 , CH═N—R10, F, Cl and Br, R21 is H or (C 1 -C 3 )-alkyl; R22 and R23, are independently selected from the group consisting of H, CN, NO 2 , (C 1 -C 3 )-alkylcarbonyl, (C 1 -C 3 )-alkoxycarbonyl, CHO, CONR19R20 and CH 2 OH; and R24 is H, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkoxyl or HET2, wherein HET2 is as defined above; s is a integer comprised from 0 to 4. Pharmaceutically acceptable salts include acid addition salts, such as mesilates, fumarates, hydrochlorides, citrates, maleates and tartrates. Also physiologically acceptable are salts formed with phosphoric and sulfuric acids. Likewise, suitable salts are basic salts, such as an alkaline metal salt, for example sodium, or an alkaline earth metal salt, for example calcium or magnesium. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. Some compounds of the formula (I) of the present invention may have one or several chiral centres. The present invention includes each of the stereoisomers, and racemic mixtures thereof. Optically active compounds can be prepared by commonly used processes, for example by resolution of the racemic mixture by recrystallisation techniques, by chiral synthesis, by enzymatic resolution, by biotransformation or by chromatographic resolution. Certain compounds of the formula (I) of the present invention can exist in unsolvated as well as solvated forms such as, for example, hydrated forms. The present invention encompasses all such aforementioned forms which are pharmaceutically active. Some compounds of the general formula (I) may exist as N-oxides of any of the oxidizable nitrogens of the mentioned compounds, encompassing the instant invention all N-oxides of the described compounds. Certain compound of the general formula (I) may exhibit polymorphism, encompassing the present invention all the possible polymorphic forms. In a particular embodiment, compounds of the present invention are those of formula (I) wherein: X is NH or NH—CS; R4 is methyl or a C-linked isoxazole or isothiazole radical optionally substituted by a methyl moiety in any of their substitutable positions; R1 is H and R3 is F; R2 is a radical selected from the following group: R5 is CO—R7; R7 is selected from (CH 2 ) m —Y—R8 and HET2, wherein m=1; Y is O or NH; R8 is selected from the group consisting of H, phenyl and 2-, 3, 4-pyridyl, being the last four optionally substituted by CHO, CN, NO 2 , CH 3 or F; HET2 is selected from the group consisting of: wherein R13, R14 and R15 are independently selected from the group consisting of CN, NO 2 and CHO; and R6 is selected from the group consisting of H, CH 3 , CN, CHO, CH 2 OH, CH═N—OH, CH═CHCN, CO—CH 3 and CH 2 NH-phenyl, said phenyl being substituted by a radical selected from the group consisting of F, CN, CHO and NO 2 . Subsequently, processes used for the preparation of the compounds of general structure (I), or for the preparation of pharmaceutically acceptable salts or in vivo hydrolyzable esters are described. The following schemes illustrate the processes carried out. In Scheme 1, the process of synthesis of structures with a methanosulfonylmethylen radical in C5 is illustrated, said structures being used as precursors of several subclasses of final compounds. By reaction of the conveniently substituted 4-fluorobenzaldehyde 1 with hydroxylamine hydrochloride, aldoxyme 2 is obtained. Aldoxyme 2 is reacted with N-chlorosuccinimide to give the corresponding N-hydroxybenzimidoyl chloride 3, from which the nitrile oxide is formed in situ by reaction with triethylamine. Isoxazolic structure 4 is obtaining by a 1,3-dipolar cycloaddition type reaction between propargyl alcohol and the mentioned nitrile oxide to give an hydroxymethyl radical in C5 which is subsequently derivatized to the mesilate 5. In Scheme 2 the process of synthesis used to obtain the precursors with a methylencarbamate 8, amido 7, thiourea 9 orthioamide 10 radical in C5 is illustrated. In all cases, treatment of mesilate 5 with an ammonia alcoholic solution gives the aminomethylenic compound 6. Carbamates 8 are obtained by treatment of amine 6 with the corresponding chloroformate. Amides 7 are obtained by reaction of 6 with the corresponding anhydride or hydrochloric acid, and thioureas 9 are obtained by reaction of 6 with ammonium thiocyanate. Finally, treatment of amides 7 with Lawesson reagent gives thioamides 10. Scheme 3 illustrates the process to get precursors with an alkoxymethylenic moiety in C5 by Williamson reaction of mesilates 5. According to Scheme 4, acylation of alcohol 4 with the corresponding anhydride or acid chloride allows the introduction of alkoxycarbonylic functionality in C5. Finally, according to Scheme 5, introduction of secondary amine radicals (from weak nucleophilic amines) is carried out by activation of the amines through the corresponding t-Boc derivative, generation of the corresponding anion with a strong base (e.g. NaH) and nucleophilic attack of the anion over the mesilate 5. Subsequently, deprotection of the corresponding t-Boc derivative 13 is carried out by treatment with an acid (e.g. CFRCOOH) giving aminomethylen substituted compounds 14. Subsequently, two general processes to obtain the final compounds of general formula (I) are disclosed. According to Scheme 6, nucleophilic aromatic substitution through the attack of the fluorine derivative by the corresponding azolic type nucleophile, allows introduction of radicals of the characteristics mentioned in the last synthetic step giving azoles (Ia). In this reaction strong bases such as NaH, K 2 CO 3 and potassic tert-butoxide in solvents such as DMF, DMSO or N-methylpyrrolidone are used, being the temperature range very broad. Introduction of alicyclic secondary amines such as morpholine, piperazine, or pyrrolidine is carried out in a similar way. In several cases, a great excess of nucleophilic agent is used, being the reaction carried out in a pressure reactor in such conditions that the amine is melt, and, in some cases, in the presence of an inorganic base such as anhydrous K 2 CO 3 . When the amine is piperazine, functionalization of the NH free radical is produced by nucleophilic displacement of the corresponding R5 radical linked to a good leaving group (“Lg”) as being attacked by the secondary piperazinic radical, to give final compounds (Ib). Nevertheless, when a C—C bond between the phenylic ring and the new bounded ring is sought, the process carried out substantially differs from those previously shown. As shown in Scheme 7, in such cases the starting compound is the bromine derivative 15 obtained by one of the processes described above, to give the organometallic derivative 16, which reacts with the corresponding triflate radical in the presence of metal palladium by a Stille reaction to give the (t-Boc) derivative 17. Subsequent functionalization steps are equal to those described in some of the preceding processes. Compounds of the present invention are useful in human and animal therapy, especially in the treatment of microbial infections and in the treatment of cancerous and precancerous pathologies. Preferably, they are administered by oral, parenteral or topical route. Therefore, according to other aspects of the invention there are provided the use of compounds of formula (I) for the preparation of a medicament for the treatment of the aforementioned pathologies, and the pharmaceutical compositions comprising at least a therapeutically effective quantity of the compound defined in any of claims 1 or 2 , as the active principle, and pharmaceutically acceptable excipients or solvents. The invention will be illustrated by the following non-limiting examples. Examples of Antimicrobial Activity In order to assess the antimicrobial activity of the compounds of the present invention a method of microdilution in microtiter plate was used. The compounds were diluted in a nutritious medium and, subsequently, distributed by two-fold serial dilutions in 96 well plates. Then, plates were inoculated with a bacterial suspension. After incubation for 24 h at 35° C. the minimum inhibitory concentration (MIC) of the drug in jig/mL was determined as the lowest concentration of compound which inhibits the growth of the bacterium. Results included in Table 1 illustrate the antimicrobial activity of some of the compounds of the present invention in comparison with thus obtained with two compounds (linezolid and eperezolid) of a known antimicrobial activity. The antimicrobial activity of the compound versus Streptococcus faecalis (BCM-010, strain designation as for SALVAT collection) Staphylococcus aureus (BCM-012, strain designation as for SALVAT collection) and Moraxella catarrhalis (BCM-015, strain designation as for SALVAT collection), respectively, is shown in the different columns. TABLE 1 BCM- BCM- BCM- 010 012 015 MIC MIC MIC COMPOUND (μg/mL) (μg/mL) (μg/mL) 4 2 4 Linezolid 4 2 8 Eperezolid 4 2 8 Example 1 4 2 Example 2 4 2 Example 3 4 2 Example 4 1 1 8 Example 5 4 2 >16 Example 6 4 2 Example 7 4 2 Example 8 4 2 >16 Example 9 4 2 >16 Example 10 4 2 Example 11 2 2 Example 12 2 1 Example 13 2 1 Example 14 4 2 Example 15 4 2 Example 16 2 2 Example 17 4 2 Example 18 0.5 1 Example 19 1 0.5 4 Example 22 1 0.5 4 Example 23 0.5 0.5 16 Example 24 0.5 0.5 16 Example 25 1 0.5 4 Example 26 2 0.5 4 Example 27 1 0.5 4 Example 28 1 0.5 4 Example 29 1 0.5 16 Example 30 1 0.5 — Example 31 1 1 — Example 32 2 0.5 4 Example 33 1 1 4 Example 34 Antitumoral Activity Examples Antitumoral activity of the compounds of the present invention was evaluated by determining in vitro cell growth inhibition of 2 human colon adenocarcinome cell lines. The SBR (Sulphorhodamine B) protein dye assay described by the NCI (National Cancer Institute) was used. Results of Table 2 illustrate the antiproliferative activity of some of the compounds of the present invention versus the one obtained with exisulind (sulindac sulfone). TABLE 2 Cell viability percentage at 100 μM COMPOUND HT-29 HCT-116 38.1 44.1 Exisulind 66.1 57.1 Example 4 71.2 64.7 Example 28 14.3 77.1 Example 36 <5 18.9 Example 37 53.3 48.6 Example 38 Intermediate 1. Preparation of 3,4-difluorobenzaldoxime A solution of 74.8 g (1.845 mol) of sodium hydroxide in 330 mL of deionized water was prepared and allowed to cool down. To the solution 150.0 g (1.049 mol) of 3,4-difluorobenzaldehyde were added and, then, 78.0 g (1.222 mol) of hydroxylamine hydrochloride were added dropwise, while an increase of the temperature over 22-25° C. was avoided by refrigeration of the system with a water bath. The mixture was stirred mechanically at room temperature during 30 minutes, poured over 2.5 L of water, acidified with an aqueous solution of hydrochloric acid 6N to pH 6, and extracted with diethyl ether (3×1 L). The organic extracts were dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residual solid was broken up with hexane to give 122.1 g (yield=84%) of a yellow solid corresponding to the title compound. IR (KBr): 3327, 1694 cm 1 . Mass spectrum (m/e): 157 (M + ). Intermediate 2. Preparation of 3,4-difluoro-N-hydroxybenzenecarboxiimidoyl chloride A solution of 17.0 g (0.108 mol) of 3,4-difluorobenzaldoxime (Intermediate 1) in 1.7 L of N,N-dimethylformamide was prepared and externally cooled down with an ice bath to an internal temperature comprised between 0 and 5° C. Then, 26.0 g (0.195 mol) of N-chlorosuccinimide were added under nitrogen atmosphere. The mixture was heated at 50° C. during 3 h, allowed to cool down at room temperature, and then poured over 1.7 kg of ice while keeping mechanical stirring during 30 minutes. The mixture was extracted three times with 1 L of toluene. The organic extracts were washed with 1 L of water, and then three times with 1 L of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure. The residual solid was broken up with hexane to give 17.6 g (yield=85%) of a yellow solid corresponding to the title compound. IR (KBr): 3435, 1618 cm −1 . Mass spectrum (m/e): 192 (M + ). Intermediate 3. Preparation of [3-(3,4-difluorophenyl)isoxazol-5-yl]methanol A solution of 71 g (0.37 mol) of 3,4-difluoro-N-hydroxybenzenocarboximidoyl chloride (Intermediate 2) in 1 L of toluene was prepared and cooled down with an ice bath. After adding 45 mL of triethylamine dropwise and with stirring, a solution of 41.5 g (0.74 mol) of propargylic alcohol in 200 mL of toluene was added. The mixture was stirred at room temperature for 48 h. Then, 650 mL of water were added and the organic layer was separated, dried over anhydrous sodium sulfate and evaporated to dryness. The resulting solid was broken up with hexane. 56 g (yield=71%) of a beige solid were obtained. IR (KBr): 3380, 1612, 1600, 1500 cm −1 . Mass spectrum (m/e): 211 (M + ). Intermediate 4. Preparation of 3-(3.4-difluorophenyl)isoxazol-5-methyl methylsulfonate A solution of 32 g (0.151 mol) of [3(3,4-difluorophenyl)isoxazol-5-yl]methanol (Intermediate 3) in 1200 mL of dichloromethane was prepared and cooled down with an ice bath to a temperature comprised between 0 and 5° C. 35 mL of triethylamine were added, and then a solution of 17.5 mL (25.9 g, 0.226 mol) of methanesulfonyl chloride in 20 mL of dichloromethane was added dropwise. The reaction mixture was stirred and allowed to warm to room temperature for 2 h. The crude product was poured over 1.5 L of water/ice, and the mixture was placed in a separatory funnel. The organic layer was separated, washed three times with 1 L of a 5% sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure and the residual solid broken up with hexane. 42 g (yield=96%) of a beige solid were obtained. IR (KBr): 1620, 1600, 1500, 1320, 1180 cm −1 . Mass spectrum (m/e): 289 (M + ). Intermediate 5. Preparation of isoxazol-3-ylcarbamic acid, tert-butyl ester A mixture of 28.5 g (0.338 mol) of 3-aminoisoxazole in 950 mL of dichloromethane was prepared, and 2.8 g (0.023 mol) of 4-dimethylaminopyridine, and 147.7 g (0.677 mol) of di-ert-butyl dicarbonate were added. The mixture was stirred at room temperature for 18 h, and the solvent was distilled off under reduced pressure. The residue was dissolved in 570 mL of methanol, and 180 mL of a 2 N sodium hydroxide aqueous solution were added. The mixture was stirred for 2 h, and then 450 mL of an 10% citric acid aqueous solution were added to adjust pH between 4 and 5. Stirring was continued for some minutes and the solution was poured over 2.8 L of water. The solid was filtered and dissolved in 500 mL of dichloromethane. The solution was dried over anhydrous sodium sulfate, and filtered, and the solvent was distilled off under reduced pressure. The residual solid was broken up with hexane. 42.9 g (yield=69%) of a yellow solid were obtained. IR (KBr): 3257, 1732 cm −1 . Mass spectrum (m/e): 184 (M+). Intermediate 6. Preparation of isoxazol-3-yl[3-(3,4-difluorophenyl)isoxazol-5-ylmethyl]carbamic acid, tert-butyl ester A solution of 34.4 g (0.186 mol) of isoxazol-3-ylcarbamic acid, tert-butyl ester (Intermediate 5) in 750 mL of N,N-dimethylformamide was prepared and cooled down with an ice bath to a temperature comprised between 0 and 5° C. 7.5 g (0.187 mol) of a 60% sodium hydride suspension in paraffin were added under inert atmosphere, and the mixture was stirred at low temperature for 45 minutes. Then, 34.1 g (0.12 mol) of 3-(3,4-difluoro-phenyl)isoxazol-5-methyl methylsulfonate (Intermediate 4) were added. The mixture was stirred at 40° C. for 16 h, and then allowed to cool down at room temperature. The reaction crude was poured over 5 L of a 5% sodium bicarbonate aqueous solution and the final solution was extracted three times with 1.5 L of ethyl acetate. The organic layer was washed five times with 1 L of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered, and the solvent was distilled off under reduced pressure. The residual solid was broken up with hexane. 39 g (yield=88%) of a yellow solid was obtained. IR (KBr): 1717 cm −1 . Mass spectrum (m/e): 391 (M+). Intermediate 7. Preparation of isoxazol-3-yl[3(3.4-difluorophenyl)isoxazol-5-ylmethyl]amine To 300 mL of a 10% w/v solution of concentrated sulfuric acid in dioxane, 10 g (0.0255 mol) of isoxazol-3-yl[3-(3,4-difluorophenyl)isoxazol-5-ylmethyl]-carbamic acid tert-butyl ester were added. The mixture was stirred at 30° C. for 1 h and, then, allowed to cool down at room temperature. The solvent was distilled off under reduced pressure, and the residue was dissolved in 200 mL of water. The resulting solution was basified with concentrated ammonia, and extracted three times with 200 mL of dichloromethane. The extracts were washed twice with 200 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residual solid obtained was broken up with hexane. 4.95 g (yield=79%) of a white solid were obtained. IR (KBr): 3380, 1620, 1600, 1500 cm −1 . Mass spectrum (m/e): 277 (M + ). Intermediate 8. Preparation of [3(3,4-difluorophenyl)isoxazol-5-yl]-methylamine A solution of 17.5 g (0.060 mol) of 3-(3,4-difluorophenyl)isoxazol-5-methyl methylsulfonate (Intermediate 4) in 200 mL of methanol, and 100 mL of concentrated ammonia was prepared. After stirring for 48 h, the solvent was distilled off under reduced pressure. The residue was treated with 300 mL of ethyl acetate, and 100 mL of a saturated sodium chloride aqueous solution. The organic layer was washed twice with 100 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the residual solid obtained was broken up with hexane. 9.4 g (yield=74%) of a yellow solid were obtained. IR (KBr): 3400, 3100, 1620, 1600, 1480 cm −1 . Mass spectrum (m/e): 210 (M+). Intermediate 9. Preparation of N-[3-(3,4-difluorophenyl)isoxazol-5-ylmethyl]-acetamide A solution of 1.2 g (5.68 mmol) of [3(3,4-difluorophenyl)isoxazol-5-yl]-methylamine (Intermediate 8) in 100 mL of dichloromethane, and 10 mL of triethylamine was prepared. After cooling down the solution at a temperature comprised between 0 and 5° C. with an ice bath, a solution of 0.5 g (6.36 mmol) of acetyl chloride in 5 mL of dichloromethane was added dropwise. The mixture was stirred at room temperature for 1 h. Then, 100 mL of dichloromethane were added and the solution was washed three times with 100 mL of a 5% sodium bicarbonate aqueous solution, then with water, and eventually was dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure. The residual solid obtained was broken up with diethyl ether. 900 mg (yield=62%) of a white solid were obtained. IR (KBr): 3180, 1660 cm −1 . Mass spectrum (m/e): 253 (M + ). Intermediate 10. Preparation of [3-(3-fluoro-4-piperazin-1-ylphenyl)isoxazol-5-ylmethyl]isoxazol-3-ylamine In a pressure reactor, a mixture, previously ground in a mortar, of 8.2 g (0.03 mol) of isoxazol-3-yl[3-(3,4-difluoro-phenyl)isoxazol-5-ylmethyl]-amine (Intermediate 7), 44 g de piperazine, and 6.8 g of anhydrous potassium carbonate were placed. The mixture was heated at a temperature comprised between 130 and 135° C. for 6 h, and then allowed to cool down. The reaction crude was treated with 500 mL of chloroform, and 500 mL of water. The organic layer was washed three times with 100 mL of water, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was filtered through a short pad of silica gel with elution by a mixture of dichloromethane:ethyl acetate (5:1). 4.2 g (yield=42%) of a white solid. IR(KBr): 3206, 1613 cm −1 . Mass spectrum (m/e): 343 (M + ). 1 H-NMR (200 MHz, d 6 -DMSO, δ ppm): 8.42 (s, 1H), 7.70-7.60 (m, 2H), 7.25-6.90 (m, 3H), 6.00 (s, 1H), 4.45 (s, 2H), 3.40-3.25 (m, 8H). Intermediate 11. Preparation of 2-chloro-1-(442-fluoro-4-[5-(isoxazol-3-ylaminomethyl)isoxazol-3-yl]phenyl}piperazin-1-yl)ethanone A solution of 1.75 g (5.09 mmol) of [3-(3-fluoro-4-piperazin-1-ylphenyl)isoxazol-5-ylmethyl]isoxazol-3-ylamine (Intermediate 10) in 40 mL of dichloromethane was prepared and cooled down to a temperature comprised between 0 and 5° C. with an ice bath. After adding 1.2 mL of triethylamine, a solution of 1 g (8.84 mmol) of acetyl chloride in 5 mL of dichloromethane was added dropwise. The mixture was stirred at room temperature for 1 h and diluted with 40 mL of dichloromethane. The solution was washed three times with 50 mL of a 5% sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was filtered over silica gel with a mixture of dichloromethane/ethyl acetate (1:1) as eluanteluant. 1.1 g (yield=51%) of a slightly yellow solid was obtained. IR (KBr): 3300, 1650 cm 1 . Mass spectrum (m/e): 420 (M + ). Intermediate 12. Preparation of 3.4.5-trifluorobenzaldoxime Following an analogous process to that described in preparation of Intermediate 1, 1.54 g (yield=80%) of a yellow solid corresponding to the title compound were obtained. IR (KBr): 3324, 1705 cm −1 . Mass spectrum (m/e): 175 (M + ). Intermediate 13. Preparation of 3.4.5-difluoro-N-hydroxybenzene-carboxiimidoyl chloride Following an analogous process to that described in preparation of Intermediate 2, 19 g (yield=64%) of a yellow oil corresponding to the title compound were obtained. IR (KBr): 3350, 1707 cm −1 . Intermediate 14. Preparation of [3-(3,4,5-trifluorophenyl)isoxazol-5-yl]methanol Following an analogous process to that described in preparation of Intermediate 3, 18 g (yield=83%) of a brown solid were obtained. Mass spectrum (m/e): 229 (M + ). Intermediate 15. Preparation of 3-(3.4.5-trifluorophenyl)isoxazol-5-methyl methylsulfonate Following an analogous process to that described in preparation of Intermediate 4, 28 g (yield=66%) of a beige solid were obtained. IR (KBr): 1351, 1183 cm −1 . Intermediate 16. Preparation of isoxazol-3-yl[3-(3,4,5-trifluorophenyl)isoxazol-5-ylmethyl]carbamic acid, tert-butyl ester Following an analogous process to that described in preparation of Intermediate 6, 30 g (yield=93%) of a brown oil were obtained. IR (KBr): 1730 cm −1 . Intermediate 17. Preparation of isoxazol-3-yl[3-(3,4,5-trifluorophenyl)isoxazol-ylmethyl]amine Following an analogous process to that described in preparation of Intermediate 7, 1.8 g (yield=60%) of an orange solid were obtained. IR (KBr): 3264. Intermediate 18. Preparation of [3-(3,5-difluoro-4-piperazin-1-ylphenyl)-isoxazol-5-ylmethyl]isoxazol-3-ylamine Following an analogous process to that described in preparation of Intermediate 10, 1.3 g (yield 23%) of a white solid were obtained. IR(KBr): 3386, 3287, 1597 cm −1 . 1 H-NMR (200 MHz, d 6 -DMSO, δ ppm): 8.11 (d, 1H), 7.41 (s, 1H), 7.38 (s, 1H), 6.57 (s, 1H), 6.42 (t, 1H), 5.89 (d, 1H), 4.46 (d, 2H), 3.40-2.9 (m, 8H). Intermediate 19. Preparation of 3-methylisothiazol-5-ylcarbamic acid, tert-butyl ester A mixture of 5.0 g (33.2 mmol) of 5-amino-3-methylisothiazole hydrochloride, and 4.3 g (33.3 mmol) of N1N-diisopropylethylamine in 100 mL of dichloromethane was prepared and stirred at room temperature for 30 minutes. 0.30 g (2.43 mmol) of 4-methylaminopyridine, and 15.69 g (71.9 mmol) of di-tert-butyl dicarbonate were added. The mixture was stirred at room temperature for 18 h, and the solvent was distilled off under reduced pressure. The residue was dissolved in 62 mL of methanol and 20 mL of a 2 N sodium hydroxide solution was added. The mixture was stirred during 2 h. 50 mL of a 10% citric acid solution was added to adjust pH between 4 and 5, and the mixture was stirred again for some minutes, poured over 130 mL of water, and filtered. The solid obtained was dissolved in 50 mL of dichloromethane. The solution was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to give a crude oil which crystallizes slowly. 2.57 g (yield=36%) of a yellow solid were obtained. Mass spectrum (m/e): 215 (M + ). Intermediate 20. Preparation of [3-(3,4-difluorophenyl)isoxazol-5-ylmethyl]-(3-methylisotiazol-5-yl)carbamic acid, tert-butyl ester Following an analogous process to that described in preparation of Intermediate 6, 2.21 g (yield=92%) of an orange solid corresponding to the title compound were obtained. IR (KBr): 1695 cm −1 . Intermediate 21. Preparation of [3-(3,4-difluorophenyl)isoxazol-5-ylmethyl]-(3-methylisotiazol-5-yl)amine Following an analogous process to that described in preparation of Intermediate 7, 1.06 g (yield=63%) of an orange solid corresponding to the title compound were obtained. IR (KBr): 3374 cm −1 . Intermediate 22. Preparation of isoxazol-3-ylmethanol To a solution of 30 g (0.306 mol) of ethyl propiolate in 600 mL of ethanol, 85 g (1.223 mol) of hydroxylamine hydrochloride in 1.1 L of a 10% sodium hydroxide solution were added in an argon atmosphere. The mixture was stirred at room temperature for 48 h, and then acidified to a pH=2-3 by addition of concentrated hydrochloric acid. The reaction mixture was extracted three times with diethyl ether, and the combined extracts were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was extracted with hot hexane, and then the solvent was evaporated under reduced pressure. 9.0 g (yield=35%) of a white crystalline solid corresponding to the title compound was obtained. Mass spectrum (m/e): 83 (M + ). Intermediate 23. Preparation of 3-(3,4-difluorophenyl)-5-(isoxazol-3-yloximethyl)isoxazole In 55 mL of N,N-dimethylformamide a suspension of 2.12 g (53 mmol) of 60% sodium hydride in paraffin was prepared under argon atmosphere. After cooling to 0° C., a solution of 4.5 g (53 mmol) of isoxazol-3-ylmethanol (Intermediate 22) in 50 mL of N,N-dimethylformamide was added dropwise. The mixture was stirred at 40° C. for 15 minutes, and then allowed to cool down at room temperature. A solution of 15.2 g (52.4 mmol) of 3-(3,4-difluoro-phenyl)isoxazol-5-methyl methylsulfonate (Intermediate 4) in 110 mL de N,N-dimethylformamide was added dropwise. The mixture was stirred at 70° C. for 1 h, cooled, poured over 1.7 L of a 5% sodium bicarbonate solution, and extracted three times with ethyl acetate. The combined organic extracts were washed with 1.7 L of deionized water, and with 1.7 L of a saturated solution of sodium chloride, then dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was chromatographed on a silica gel column, eluting with dichloromethane. Relevant fractions were combined to give, once evaporated the solvent, 14.5 g (quantitative yield) of a white solid. Mass spectrum (m/e): 278 (M+). detailed-description description="Detailed Description" end="lead"? |
Baked goods having extended shelf life |
In one aspect, the present invention provides partially waxy wheat flour comprising starch comprising amylose in an amount of from 10 weight percent to 20 weight percent, and amylopectin in an amount less than 90%. In another aspect, the present invention provides flour blends comprising one or more partially waxy wheat flours of the invention. The present invention also provides baked goods prepared from a flour or flour blend of the invention. The baked goods of the invention possess an extended shelf life. In other aspects, the present invention provides methods for making baked goods. |
1. A partially waxy wheat flour comprising starch, said starch comprising amylose in an amount of from 10 weight percent to 20 weight percent, and amylopectin in an amount less than 90 weight percent. 2. A partially waxy wheat flour of claim 1 comprising starch comprising amylose in an amount of from 15 weight percent to 20 weight percent, and amylopectin in an amount from 80 weight percent to 85 weight percent. 3. A partially waxy wheat flour of claim 1 comprising starch comprising amylose in an amount of from 15 weight percent to 18 weight percent, and amylopectin in an amount from 82 weight percent to 85 weight percent. 4. A partially waxy hard wheat flour of claim 1 further comprising protein in an amount of from 11 weight percent to 18 weight percent. 5. A partially waxy soft wheat flour of claim 1 further comprising protein in an amount of from 8 weight percent to 12 weight percent. 6. A baked good prepared from partially waxy wheat flour comprising amylose in an amount of from 10 weight percent to 20 weight percent, and amylopectin in an amount less than 90 weight percent. 7. A baked good of claim 6 wherein said partially waxy wheat flour comprises amylose in an amount of from 15 weight percent to 20 weight percent, and amylopectin in an amount from 80 weight percent to 85 weight percent. 8. A baked good of claim 6 wherein said partially waxy wheat flour comprises amylose in an amount of from 15 weight percent to 18 weight percent, and amylopectin in an amount from 82 weight percent to 85 weight percent. 9. A baked good of claim 6 wherein said partially waxy wheat flour further comprises yeast and protein, said protein being present in an amount of from 5 weight percent to 16 weight percent. 10. A baked good of claim 9 wherein said protein is present in an amount of from 8 weight percent to 12 weight percent. 11. A baked good of claim 6 wherein said baked good is bread. 12. A baked good of claim 6 wherein said baked good is cake. 13. A flour blend comprising partially waxy wheat flour, wherein said partially waxy wheat flour comprises starch comprising amylose in an amount greater than 10 weight percent. 14. A flour blend of claim 13 further comprising protein in an amount of from 5 weight percent to 16 weight percent. 15. A baked good prepared from a flour blend comprising partially waxy wheat flour, wherein said partially waxy wheat flour comprises starch comprising amylose in an amount greater than 10 weight percent. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Edible baked goods, such as bread, bagels, raised doughnuts, cakes, and other baked products can be made from flour prepared from the seeds of common, hexaploid wheats, although a lower proportion of flours from a wide variety of other cereals, including oats, barley, millet and rye, are often included to obtain products with different flavors, or with more fiber, but most baked goods are prepared from wheat flour, because wheat is unique among cereals for its content and composition of gluten protein. Gluten is comprised of two types of proteins, gliadins and glutenins, which together are responsible for the dough-forming properties of wheat flours. Wheat flour is made by milling wheat seeds, which are sometimes referred to as wheat grains or wheat kernels, and the seed coat is commonly separated as part of the bran, from the endosperm, to make flour. Wheat seeds include an outer, protective, seed coat, which along with the outer layers of endosperm cells, the aleurone layer, make up the bran portion, an embryo (usually called the wheat germ) and starchy endosperm that provides food for the embryo which develops from these. The endosperm makes up more than 80% of the weight of a wheat grain seed and typically contains from 62-67% starch and about 11% gluten protein. Gluten protein is the principal protein component of the endosperm. Wheats are divided into two main classes—hard and soft, and within these, varieties differ by the color of their seed coat, as hard or soft ‘red’ or hard or soft ‘white’ Market Classes. The soft varieties yield flours that are often relatively low in protein content, and usually have weaker mixing strength gluten proteins, while the hard endosperm varieties usually are selected to yield flours that are relatively higher in gluten having stronger mixing properties, but those relationships are more traditional than necessary, since soft wheat varieties with the stronger proteins required for bread making can easily be developed by recombination breeding. The core ingredients that are used to make baked goods are flour and water. Usually salt, and a leavening agent, such as yeast, are also added. Additional ingredients can include sugar, eggs, butter and fruits. For example, when making bread from wheat flour, salt, water and yeast, the ingredients are mixed to yield a dough that is sufficiently strong and extensible to rise as gas is produced by yeast fermentation during the dough-development, proofing, and baling processes, and that provides a sponge-like network or matrix stable enough to hold the starch and to contribute support to the crumb structure when baking is complete. The amount and composition of gluten proteins in wheat flours are mainly responsible for the spongy network (matrix) developed in wheat flour doughs. The spongy-network of doughs is formed during the dough-mixing process, and during the fermentation process, the gluten matrix traps the gas bubbles formed by the yeast, resulting in the dough expansion (rising). Then, the dough is shaped into subunits, which are allowed to rise for a short period (proofing), then are baked. During the fermentation process the yeast grow and convert carbohydrates (sugars) to ethanol and carbon dioxide. The sugars, usually sucrose, may be added as such, and/or malt (containing amylases) often may be added to convert some of the starches to sugars, which then are metabolized by the yeast. During baking, the gases formed by the yeast inside the dough expand, causing the dough to rise further, most of the alcohol evaporates, and the starch granules begin to swell after about 60° C. is reached. In the presence of water, the starch gelatinizes, forming a thick paste within the protein matrix. The amylose molecules in the starch paste phase separate from the amylopectin molecules, and during cooling after baking, the amylose molecules retrograde (recrystallize) within the gluten protein matrix, to form the crumb structure of the baked product. At about 74° C., the gluten matrix is denatured, contributing further strength to the crumb structure. However, the main contributor supporting the crumb structure of baked bread is retrograded amylose. Instead of using yeast as a leavening agent, some baked goods can be leavened with chemicals that produce carbon dioxide. A commonly used leavening agent is baking powder, which includes sodium bicarbonate and an acid salt, such as Cream of Tartar (potassium bitartrate). Some baked goods are unleavened, such as unleavened, flat, or pita breads. It is common knowledge that baked goods, such as bread and cakes, lose moisture, and harden rapidly during storage after baking. This process is commonly referred to by the baking industry as “staling”. Staling reduces the consumer appeal of the baked goods, which are then difficult to sell. The staling process is accelerated at refrigerator temperatures of about 4-5° C., as is the retrogradation of starch molecules of the gel/paste formed during baking. Although baked goods can become stale due to infection by molds, staling usually results from starch retrogradation, or the reduction of starch solubility. Retrogradation is the process by which starch molecules associate with each other, and recrystallize after baking. When starch is cooked, its granular structure is changed, and all of the crystalline structures of the starch granules are degraded. During storage after baking, the amylopectin molecules in the crumb gradually retrograde, and this process is believed to cause the baked goods to “stale”. Emulsifiers, such as monoglycerides, calcium and sodium steroyl lactate are often used as softeners in breads to delay staling, but they have limited effectiveness. Starch is composed both of linear amylose molecules and branched amylopectin molecules. Wheat starch typically contains about 25-28% amylose and about 72-75% amylopectin. Amylopectin absorbs and retains water more strongly than amylose, presumably because of the branched molecular structure of amylopectin. Consequently, attempts have been made to reduce the staling rate of baked goods by increasing the amount of amylopectin starch. For example, flour blends have been prepared in which some wheat flour is replaced with waxy barley flour, which does not include amylose. Gluten protein must be added, however, to compensate for the reduction in protein caused by the substitution of wheat flour by the waxy barley flour, which does not contain gluten. Wheat mutants exist, which when recombined, produce fully waxy grains that comprise starch containing very little, or no amylose (usually 0-4%). These mutant-derived grains are termed waxy, because of the waxy appearance of their grains. However, the term is a misnomer, since the trait has no relation to plant waxes for which the same term is used. Cultivated wheat plants are polyploids, i.e., possess two or three sets of chromosomes, and the so-called common, or ‘bread’ wheats are hexaploid (having three sets of chromosomes). The amylopectin debranching enzyme protein, granule-bound starch synthase (GBSS), encoded in each set of chromosomes may be functionally inactive, due to a deleted gene, to a DNA base alteration, or to mutation-induced reduction in the activity of the GBSS enzyme, causing the enzyme to be partially active, or inactive, in waxy mutants. Although waxy grains contain elevated levels of amylopectin, which binds water better than amylose and would therefore be expected to retard the staling process, bread made from the flour of fully waxy wheats, or induced mutant waxy wheats, does not possess reduced staling characteristics. Indeed, bread made from waxy wheat flour is filled with large, open spaces, due to the absence of amylose molecules, which normally form the crumb structure, and the crumb texture is soggy due to the retention of too much water by the amylopectin starch. The present inventor has developed novel, partially waxy wheat genetic recombinant selections, which produce starch with less amylose than non-waxy wheat (i.e., wheat, in which all of the GBSS genes produce fully functional GBSS enzyme proteins), but more amylose than fully waxy wheats (i.e., wheats that do not produce any GBSS protein, or which produce one or more, non-functional, or less functional GBSS proteins). In one embodiment of the invention, partially waxy wheat plants of the present invention include at least one pair of functional GBSS or Wx genes. Baked goods made from flour obtained from the plants of the present invention possess an extended shelf life, i.e., have a reduced rate of staling. Thus, in one aspect, the present invention provides partially waxy wheat flour, and flour blends, including partially waxy wheat flours, from which baked (or boiled, or fried) goods may be made that have an extended shelf-life, due to their reduced staling properties. |
<SOH> SUMMARY OF THE INVENTION <EOH>In one aspect, the present invention provides partially waxy wheat flour comprising starch comprising amylose in an amount from at least 10% up to 20%, and amylopectin in an amount less than 90%. In some embodiments, the partially waxy wheat flour of the invention comprises starch comprising amylose in an amount of from 15% to 20%, and amylopectin in an amount of from 80% to 85%. In other embodiments, the partially waxy wheat flour of the invention comprises starch comprising amylose in an amount of from 15% to 18%, and amylopectin in an amount of from 82% to 85%. Some partially waxy wheat flours of the invention further comprise protein in an amount of from 5% to 16%. Typically, the protein content of soft wheat is from 8% to 12%. Typically, the protein content of hard wheat is from 11% to 18%. The prime starch fraction of the partially waxy starch of the partially waxy wheat flours of the invention has a Brabender amylograph peak viscosity temperature of from 93° C. to 96.5° C. In another aspect, the present invention provides a flour blend comprising one or more partially waxy wheat flours of the invention. The flour blends of the present invention can include a mixture of waxy and/or partially waxy and/or non-waxy flours. In another aspect, the present invention provides baking mixes comprising a partially waxy wheat flour of the invention. The present invention also provides baked goods prepared from a partially waxy wheat flour and/or flour blend and/or baking mix of the invention. The baked goods possess an extended shelf life as described herein. In another aspect, the present invention provides methods for making baked goods. The methods comprise the steps of (a) preparing a baking mix comprising a partially waxy wheat flour of the invention; and (b) baking the baking mix to form a baked product. In one embodiment, the methods comprise the steps of (a) preparing a baking mix comprising flour consisting of partially waxy wheat flour comprising starch comprising amylose in an amount of from 10% to 20%, and amylopectin in an amount less than 90%; and (b) baking the baking mix to form a baked product. In some embodiments, the flour further comprises protein in an amount of from 5% to 16%. The flour, flour blends, and baking mixes of the invention are useful, for example, for making baked goods. The baked goods of the invention are useful, for example, as foodstuffs. The methods of the invention are useful, for example, for making the baked goods of the invention. detailed-description description="Detailed Description" end="lead"? |
Content transfer |
The present invention provides a method of transferring content from a file and a database. In this case, the file includes content instances, each content instance being associated with a respective field, and each field having a respective type. The transfer is achieved by determining the type of each field, and then storing each content instance in a store in accordance with the determined field type of the associated field. Each content instance can then be transferred to the database in accordance with the determined field type. A similar procedure is provided for creating XML files based on content within the database. |
1-30. (canceled) 31. A method of transferring content from a file to a database, the file including content instances, each content instance being associated with a respective field, and each field having a respective type, the method including: a) determining the type of each field; b) generating store fields in a store, each store field having a respective store field type; c) storing each content instance in a respective store field in accordance with the field type of the associated field; and, d) transferring each content instance to the database in accordance with the store field type. 32. A method according to claim 31, the file being an XML file, each content instance being a respective node in the XML file. 33. A method according to claim 32, the method including determining the field type from a document definition file. 34. A method according to claim 31, the database being a relational database having a number of database fields, each having a respective type, the method including transferring each content instance into a respective database field in accordance with the database field type and the store field type. 35. A method according to claim 34, the method including storing each content instance in database using a respective query, the query being generated in accordance with the field type and the database field type. 36. A method according to claim 35, the query being an SQL query. 37. A method according to claim 35, the method of transferring each content instance to the database including: a) creating one or more vacant locations in the query in accordance with the store field type; b) transferring each content instance into a respective vacant location; and, c) applying the query to the database to thereby transfer the content instance(s) to the database. 38. A method according to claim 34, the method including storing each content instance in a store by: a) determining a mapping between each field type of the associated field and each database field type; b) creating store fields corresponding to each content instance, each store field being determined in accordance with the field type of the associated field and the mapping; and, c) transferring the content instance to the respective store field. 39. A method according to claim 38, the method including determining the mapping from a predetermined mapping stored in a store. 40. A method according to claim 31, the content instances being arranged hierarchically in the file, the method including: a) selecting a respective content instance; b) determine any child content instances to the respective content instance; c) transferring the content instance and any child content instances to the store; d) transferring the content instances from the store to the database; and, e) Repeating steps (a) to (d) for any other content instances within the file. 41. A method according to claim 31, the method including using a processing system, the processing system having a processor coupled to a store, the processor being adapted to: a) receive the file; b) determine the field type of each field; c) generate the store fields in the store; d) store each content instance in the respective store field; and, e) transfer each content instance from the store to the database. 42. A processing system adapted to transfer content from a file to a database, the file including content instances, each content instance being associated with a respective field, and each field having a respective type, the processing system including a processor adapted to: a) determine the type of each field; b) generate store fields in a store, each store field having a respective store field type; c) store each content instance in a respective store field in accordance with the field type of the associated field; and, d) transfer each content instance to the database in accordance with the determined store field type. 43. A processing system according to claim 42, the processing system including a memory, the processor being adapted to create the store in the memory. 44. A processing system according to claim 42, the processing system being adapted to perform the method of transferring content from a file to a database, the file including content instances, each content instance being associated with a respective field, and each field having a respective type, the method including: a) determining the type of each field; b) generating store fields in a store, each store field having a respective store field type; c) storing each content instance in a respective store field in accordance with the field type of the associated field; and, d) transferring each content instance to the database in accordance with the store field type. 45. A computer program product for transferring content from a file to a database, the computer program product including computer executable code which when executed by a suitably programmed processing system causes the processing system to perform the method of claim 31. 46. A method of transferring content from a database to a file, the database including content instances, each content instance being associated with a respective database field, and each database field having a respective type, the method including: a) retrieving each content instance from the database; b) generating store fields in a store, each store field having a respective store field type; c) storing each content instance in a respective store field in accordance with the database field type of the associated database field; d) creating a file including a number of fields, each field having a respective type; and, e) transferring each content instance into a respective field within the file, in accordance with the store field type. 47. A method according to claim 46, the file being an XML file, each content instance being a respective node in the XML file. 48. A method according to claim 47, the method including generating the field type of each field using a document definition file. 49. A method according to claim 46, the database being a relational database, the method including transferring each content instance to the store using a respective query, the query determining the database field type. 50. A method according to claim 49, the query being an SQL query. 51. A method according to claim 49, the method including: a) creating the query including one or more vacant locations; b) applying the query to the database to thereby transfer each content instance into a respective vacant location; and, c) transferring the content instance to the store. 52. A method according to claim 51, the method including: a) determining a mapping between each database field type of the associated database field and each field type; b) creating store fields corresponding to each content instance, each store field being determined in accordance with the field type of the associated database field and the mapping; and, c) transferring each content instance into a respective store field. 53. A method according to claim 52, the method including:, a) generating fields in the file in accordance with the database field type of each associated database field and the mapping; and, b) transferring each content instance from the store field to the respective field. 54. A method according to claim 52, the method including determining the mapping from a predetermined mapping stored in a store. 55. A method according to claim 46, the method including: a) performing at least one query, the query being adapted to extract content instances from the database as a number of reports; b) for a respective report: i) determine the number of content instances in the report; ii) generate a respective store field for each content instance in the report, the store field type being determined in accordance with the database field type; and, iii) determine a parent content instance; iv) transfer the parent content instance to a respective file field; v) determine any child content instances; and, vi) transfer the child content instances to respective file fields; and, c) repeating steps (i) to (vi) for each report. 56. A method according to claim 46, the method including using a processing system, the processing system having a processor coupled to a store, the processor being adapted to: a) retrieve each content instance from the database: b) store each content instance in the store; and, c) generate the file. 57. A processing system adapted to transfer content from a database to a file, the database including content instances, each content instance being associated with a respective database field, and each database field having a respective type, the processing system including a processor adapted to: a) retrieve each content instance from the database; b) generate store fields in a store, each store field having a respective store field type; c) store each content instance in a respective store field in accordance with the database field type of the associated database field; d) generate a file, the file including a number of fields, each field having a respective type; and, e) transferring each content instance into a respective field within the file. 58. A processing system according to claim 57, the processing system including a memory, the processor being adapted to create the store in the memory. 59. A processing system according to claim 57, the processing system being adapted to perform the method of transferring content from a database to a file, the database including content instances, each content instance being associated with a respective database field, and each database field having a respective type, the method including: a) retrieving each content instance from the database; b) generating store fields in a store, each store field having a respective store field type; c) storing each content instance in a respective store field in accordance with the database field type of the associated database field; d) creating a file including a number of fields, each field having a respective type; and, e) transferring each content instance into a respective field within the file, in accordance with the store field type. 60. A computer program product for transferring content from a file to a database, the computer program product including computer executable code which when executed by a suitably programmed processing system causes the processing system to perform the method of claim 46. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The present invention relates to a method and a processing system for transferring content between a file and a database. |
<SOH> SUMMARY OF THE PRESENT INVENTION <EOH>In a first broad form the present invention provides a method of transferring content from a file to a database, the file including content instances, each content instance being associated with a respective field, and each field having a respective type, the method including: a) Determining the type of each field; b) Storing each content instance in a store in accordance with the field type of the associated field; and, c) Transferring each content instance to the database in accordance with the determined field type. Typically the file is an XML file, with each content instance being a respective node in the XML file. However, the techniques can also be applied to other files, and in particular, files having a hierarchical structure. Typically, when the file is an XML file, the method includes determining the field type from a document definition file. However, the field type may be determined in other manners as appropriate to the type of file. The database is typically a relational database having a number of database fields, each having a respective type. In this case, the method usually includes transferring each content instance into a respective database field in accordance with the database field type. Typically the method includes storing each content instance in database using a respective query, the query being generated in accordance with the field type and the database field type. In this case, the query is typically an SQL query. The method of transferring each content instance to the database can include: a) Creating one or more vacant locations in the query in accordance with the field type; b) Transferring each content instance into a respective vacant location; and, c) Applying the query to the database to thereby transfer the content instance(s) to the database. The method generally includes storing each content instance in a store by: a) Determining a mapping between each field type of the associated field and each database field type; b) Creating a store field corresponding to each content instance, each store field being determined in accordance with the field type of the associated field and the mapping; and, c) Transferring the content instance to the respective store field. The method typically includes determining the mapping from a predetermined mapping stored in a store. The method generally includes using a processing system, the processing system having a processor coupled to a store, the processor being adapted to: a) Receive the file; b) Determine the field type of each field; c) Store each content instance in the store; and, d) Transfer each content instance from the store to the database. In a second broad form the present invention provides a processing system adapted to transfer content from a file to a database, the file including content instances, each content instance being associated with a respective field, and each field having a respective type, the processing system including a processor adapted to: a) Determine the type of each field; b) Store each content instance in a store in accordance with the field type of the associated field; and, c) Transfer each content instance to the database in accordance with the determined field type. In this case, the processing system generally includes a memory, with the processor being adapted to create the store in the memory. The processing system is generally adapted to perform the method of the first broad form of the invention. In a third broad form the present invention provides a computer program product for transferring content from a file to a database, the computer program product including computer executable code which when executed by a suitably programmed processing system causes the processing system to perform the method of the first broad form of the invention. In a fourth broad form the present invention provides a method of transferring content from a database to a file, the database including content instances, each content instance being associated with a respective database field, and each database field having a respective type, the method including: a) Retrieving each content instance from the database; b) Storing each content instance in a store in accordance with the database field type of the associated database field; c) Creating a file; and, d) Transferring each content instance into the file, each field having a respective type determined in accordance with the associated database field type. In this case, the file is typically an XML file, with the database being a relational database as described above. Accordingly, the method typically includes: a) Creating the query including one or more vacant locations; b) Applying the query to the database to thereby transfer each content instance into a respective vacant location; and, c) Transferring each content instance to the store. The method generally includes: a) Determining a mapping between each database field type of the associated database field and each field type; b) Transferring each content instance into a respective store field, the type of the store field being determined in accordance with the database field type; and, c) Generating fields in the file in accordance with the database field type of each associated database field and the mapping; and, d) Transferring each content instance from the store field to the respective field. The method generally includes determining the mapping from a predetermined mapping stored in a store. The method generally includes using a processing system, the processing system having a processor coupled to a store, the processor being adapted to: a) Retrieve each content instance from the database: b) Store each content instance in the store; and, c) Generate the file. In a fifth broad form the present invention provides a processing system adapted to transfer content from a database to a file, the database including content instances, each content instance being associated with a respective database field, and each database field having a respective type, the processing system including a processor adapted to: a) Retrieve each content instance from the database; b) Store each content instance in a store in accordance with the database field type of the associated database field; and, c) Generate a file, the file including each content instance associated with a respective field, and each field having a respective type determined in accordance with the associated database field type. The processing system generally includes a memory, the processor being adapted to create the store in the memory. The processing system is preferably adapted to perform the method of the fourth broad form of the invention. In a sixth broad form the present invention provides a computer program product for transferring content from a file to a database, the computer program product including computer executable code which when executed by a suitably programmed processing system causes the processing system to perform the method of the fourth broad form of the invention. |
Antibodies specific for nanotubes and related methods and compositions |
This invention provides two compositions. The first composition comprises a nanotube and at least one anti-nanotube antibody, wherein the anti-nanotube antibody is bound to the nanotube. The second composition comprises a fullerene and at least one anti-fullerene antibody, wherein the anti-fullerene antibody is bound to the fullerene. Finally, this invention provides methods and kits relating to the antibody and compositions of matter. |
1. A composition comprising a nanotube and at least one anti-nanotube antibody, wherein the anti-nanotube antibody is bound to the nanotube. 2. A composition comprising a fullerene and at least one anti-fullerene antibody, wherein the anti-fullerene antibody is bound to the fullerene. 3. The composition of claim 1 or 2, wherein the antibody is a monoclonal antibody or an antigen-binding portion thereof. 4. The composition of claim 3, wherein the monoclonal antibody or antigen-binding portion thereof binds to the same epitope on the nanotube as the monoclonal antibody produced by the hybridoma designated 1-10F-8A (ATCC Number PTA-279). 5. The composition of claim 3, wherein the monoclonal antibody or antigen-binding portion thereof competitively inhibits the binding to the nanotube of the monoclonal antibody produced by the hybridoma designated 1-10F-8A (ATCC Number PTA-279). 6. The composition of claim 4 or 5, wherein the monoclonal antibody or antigen-binding portion thereof is the monoclonal antibody produced by the hybridoma designated 1-10F-8A (ATCC Number PTA-279) or the antigen-binding portion thereof. 7. The composition of claim 1 or 2, wherein the antibody is a polyclonal antibody. 8. The composition of claim 1 or 2, wherein the composition is immobilized. 9. The composition of claim 1, wherein the nanotube has bound thereto a plurality of anti-nanotube antibodies. 10. The composition of claim 2, wherein the fullerene has bound thereto a plurality of anti-fullerene antibodies. 11. The composition of claim 1 or 2 further comprising a moiety, wherein the moiety is bound to the antibody. 12. The composition of claim 11, wherein the moiety is selected from the group consisting of a detectable marker, a probe, a small molecule, a polypeptide, an antibody and a nucleic acid. 13. The composition of claim 12, wherein the detectable marker is selected from the group consisting of a radioactive label, and a calorimetric., luminescent, or fluorescent marker. 14. The composition of claim 12, wherein the probe permits the detection of ion concentration. 15. The composition of claim 14, wherein the ion is Ca+2. 16. The composition of claim 14, wherein the probe is C-3010 or B-8610. 17. A method for introducing the composition of claim 1 or 2 into a cell comprising contacting the composition with the cell under conditions permitting entry of the composition into the cell. 18. The method of claim 17, wherein the conditions permitting entry of the composition into the cell comprises the use of an atomic force microscope. 19. A method for determining whether an agent is present in a sample comprising contacting the sample with the composition of claim 11, wherein the moiety of the composition permits the detection of the agent, and detecting any agent present in the sample via the moiety, thereby detecting whether the agent is present in the sample. 20. A method for introducing a moiety into a sample comprising introducing into the sample the composition of claim 11, wherein the moiety being introduced into the sample is the moiety of the composition. 21. A kit comprising the composition of claim 1 or 2 and instructions for use. 22. A kit comprising the composition of claim 11 and instructions for use. 23. A kit comprising a nanotube, an anti-nanotube antibody, and instructions for making and/or using the composition of claim 1. 24. A kit comprising a fullerene, an anti-fullerene antibody, and instructions for making and/or using the composition of claim 2. 25. A kit comprising the composition of claim 1 or 2, a moiety, and instructions for binding the moiety to the antibody of the composition. 26. A method for immobilizing a nanotube on a solid support comprising contacting the composition of claim 1 with a solid support having affixed thereto an agent that binds to the antibody of the composition, under conditions permitting such binding, thereby immobilizing the nanotube. 27. A method for immobilizing a nanotube on a solid support comprising contacting the composition of claim 11 with a solid support havinq affixed thereto an agent that binds to the moiety of the composition, under conditions permitting such binding, thereby immobilizing the nanotube. 28. A method for immobilizing a fullerene on a solid support comprising contacting the composition of claim 2 with a solid support having affixed thereto an agent that binds to the antibody of the composition, under conditions permitting such binding, thereby immobilizing the fullerene. 29. A method for immobilizing a fullerene on a solid support comprising contacting the composition of claim 11 with a solid support having affixed thereto an agent that binds to the moiety of the composition, under conditions permitting such binding, thereby immobilizing the fullerene. 30. The method of claim 26, 27, 28, or 29, wherein the solid support has the agent affixed thereto at one or more discrete loci. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The recent interest in using Buckminster fullerene (fullerene) derivatives in biological systems raises the possibility of their assay by immunological procedures. This, in turn, leads to the question of the ability of these unprecedented polygonal structures, made up solely of carbon atoms, to induce the Production of specific antibodies. Immunization of mice with a C 60 fullerene derivative conjugated to bovine thyroglobulin yielded a population of fullerene-specific antibodies of the IgG isotype, showing that the immune repertoire was diverse enough to recognize and process fullerenes as protein conjugates. The population of antibodies included a subpopulation that crossreacted with a C 70 fullerene as determined by immune precipitation and ELISA procedures. These assays were made possible by the synthesis of water-soluble fullerene derivatives, including bovine and rabbit serum albumin conjugates and derivatives of trilysine and pentalysine, all of which were characterized as to the extent of substitution and their UV-Vis spectra. Possible interactions of fullerenes with the combining sites of IgG are discussed based on the physical chemistry of fullerenes and previously described protein-fullerene interactions. They remain to be confirmed by the isolation of monoclonal antibodies (mAbs) for X-ray crystallographic studies. Until 1985 there were only two known allotropic forms of carbon: graphite and diamond. In 1985, a novel allotrope was reported in which 60 carbon atoms were arranged as a truncated icosahedron, with 60 vertices and 32 faces, 12 of which were pentagonal and 20 hexagonal (1). It was dubbed Buckminsterfullerene (usually shortened to fullerene) because of its geodesic character, a name that has held through the present day. A detailed background of metallofullerenes is provided in “Fourth Series of Experiments”, section I (A) (infra). Considerable activity followed this discovery particularly after procedures were developed to prepare fullerenes in workable quantities (2, 3). Various fullerene-based compounds have been prepared, and diverse uses were sought for them. Some were incorporated into photovoltaic cells (4) and nanotubes (5). Others were tested for biological activity (6), including antiviral (7, 8), antioxidant (9, 10), and chemotactic activities (11), and as neuroprotective agents in a mouse model of amyotrophic lateral sclerosis (12). Practical application of fullerenes as biological or pharmacological agents requires that dosage and serum levels be capable of measurement, preferably by sensitive, simple immunological procedures. This, in turn, requires that specific antibodies to fullerenes be produced. The clonal selection theory tells us that antigens elicit the production of antibodies by selecting for specific antibody producing cells already present in the repertoire of immunized animals (13). Although there is debate about the size of the “available” repertoire (14, 15), immunologists usually work on the assumption that the repertoire is diverse enough to be counted on to produce antibodies to “any” molecule a researcher may choose. This is, of course, an unreliable assumption, as experimental failures rarely find their way into the literature. The question that arises, therefore, is whether the immune repertoire is “complete” enough (15) to recognize and respond to the unprecedented geodesic structure of the fullerenes or sufficient aspects of it-more particularly, whether the immune system can process a fullerene-protein conjugate and display the processed peptides for recognition by T cells to yield IgG antibodies. We report here that it does. |
<SOH> SUMMARY OF THE INVENTION <EOH>This invention provides two compositions. The first composition comprises a nanotube and at least one anti-nanotube antibody, wherein the anti-nanotube antibody is bound to the nanotube. The second composition comprises a fullerene and at least one anti-fullerene antibody, wherein the anti-fullerene antibody is bound to the fullerene. This invention also provides seven methods using the two compositions. The first is for introducing the first and second compositions into a cell comprising contacting the composition with the cell under conditions permitting entry of the composition into the cell. The second method is for determining whether an agent is present in a sample comprising contacting the sample with the composition comprising the antibody which has a moiety bound thereto, wherein the moiety of the composition permits the detection of the agent, and detecting any agent present in the sample via the moiety, thereby detecting whether the agent is present in the sample. The third method is for introducing a moiety into a sample comprising introducing into the sample the composition comprising the antibody which has a moiety bound thereto, wherein the moiety being introduced into the sample is the moiety of the composition. The fourth method is for immobilizing a nanotube on a solid support comprising contacting the first composition with a solid support having affixed thereto an agent that binds to the antibody of the composition, under conditions permitting such binding, thereby immobilizing the nanotube. The fifth method is for immobilizing a nanotube on a solid support comprising contacting the first composition comprising the antibody which has a moiety bound thereto with a solid support having affixed thereto an agent that binds to the moiety of the composition, under conditions permitting such binding, thereby immobilizing the nanotube. The sixth method is for immobilizing a fullerene on a solid support comprising contacting the second composition with a solid support having affixed thereto an agent that binds to the antibody of the composition, under conditions permitting such binding, thereby immobilizing the fullerene. The seventh method is for immobilizing a fullerene on a solid support comprising contacting the second composition comprising the antibody which has a moiety bound thereto with a solid support having affixed thereto an agent that binds to the moiety of the composition, under conditions permitting such binding, thereby immobilizing the fullerene. Finally, this invention provides five kits for using the two compositions. The first kit comprises the first and second compositions and instructions for use. The second kit comprises the composition comprising the antibody which has a moiety bound thereto and instructions for use. The third kit comprises a nanotube, an anti-nanotube antibody, and instructions for making and/or using the first composition. The fourth kit comprises a fullerene, an anti-fullerene antibody, and instructions for making and/or using the second composition. The fifth kit comprises the first and second compositions, a moiety, and instructions for binding the moiety to the antibody of the compositions. |
Reception method and reception device estimating reception quality and communication system using the reception device |
Variation in received signal qualities at positions in a frame is estimated so as to improve a communication quality. In communication from a transmitting station to a receiving station, a received signal quality is estimated per data position in a data frame received by the receiving station, thus to grasp situations of the received signal quality varied depending on a position which is caused by various factors of property deterioration in a process from transmitting communication data from the transmitting station to receiving it by the receiving station via a transmission path. Further, an estimating result is supplied to a data processing unit and used at a latter stage. The estimating result is notified to the transmitting station and arrangement of transmitting data is reconstructed on the transmitting station side. The arrangement of the transmitting data is properly changed in accordance with importance of the communication data. Further, the rearranged transmitting data is properly restored on the receiving station side, thereby obtaining received data and improving a quality of a communication service. |
1. A receiving method comprising: a step of estimating a received signal quality per position in a string of received data from a result of demodulating a received signal and outputting a result of estimating the quality per position. 2. The receiving method according to claim 1, further comprising a received data processing step of processing received data by use of said result of estimating the quality per position and said result of demodulating the received signal. 3. The receiving method according to claim 2, wherein in said received data processing step, data at a position where the received signal quality is lower than a predetermined received signal quality, which is estimated based on the result of estimating the quality per position, is canceled. 4. The receiving method according to claim 2, wherein in said received data processing step, soft determining information on a receiving and demodulating result is weighted based on the result of estimating the quality per position. 5. A receiving apparatus comprising means for estimating a quality per position which estimate a received signal quality per position in a string of received data from a result of demodulating a received signal and output a result of estimating the quality per position. 6. The receiving apparatus according to claim 5, further comprising received data processing means which process the received data by use of said result of estimating the quality per position and said result of demodulating the received signal. 7. The receiving apparatus according to claim 6, wherein said received data processing means cancel the data at a position where the received signal quality is lower than a predetermined received signal quality, which is estimated based on the result of estimating the quality per position. 8. The receiving apparatus according to claim 6, wherein said received data processing means weight soft determining information on a receiving and demodulating result based on the result of estimating the quality per position. 9. A communication system for transferring data from a first communication station to a second communication station, wherein said second communication station comprises the receiving apparatus according to claim 6, and further comprises: means for notifying quality information per position which notify said first communication station of quality information per position which is outputted from means for estimating a quality per position in said receiving apparatus, and said first station comprises means for extracting quality information per position which receive the quality information per position from said second communication station and extract it. 10. The communication system according to claim 9, wherein said first station further comprises, as said means for notifying quality information per position, return link transmitting means which perform transmission processing of a radio communication link from said second communication station to said first communication station, and said return link transmitting means transmit transmitting data and the quality information per position. 11. The communication system according to claim 9, wherein said means for notifying quality information per position comprise: a transmitting data processing unit which forms a transmitting data frame and outputs it by use of the transmitting data from said second communication station to said first communication station and said quality information per position; and a second transmitting and modulating unit which processes predetermined modulation processing of said transmitting data frame and transmits it. 12. The communication system according to claim 9, wherein said means for extracting quality information per position comprise: second receiving and demodulating means which receive and demodulate a signal transmitted from said second communication station and output a receiving and demodulating result; and a second received data processing portion which extracts the quality information per position estimated from said receiving and demodulating result in said second communication station and supplies the extracted quality information per position to data rearranging means. 13. The communication system according to claim 9, wherein said first communication station comprises: transmitting data processing means which generate a string of transmitting data and simultaneously output importance information of the data; and data rearranging means which rearrange a sequence of the string of transmitting data and output the transmitting data frame based on the quality information per position notified from said second communication station, said string of transmitting data, and said importance information; and first transmitting and modulating means which perform predetermined modulation processing of the transmitting data frame outputted from said data rearranging means and transmit it. 14. The communication system according to claim 9, wherein said second communication system comprises: receiving and demodulating means which receive and demodulate a modulated signal received based on a frame unit from said first communication station and outputs a receiving and demodulating result; data arrangement information extracting means which extract data arrangement information notified from said first communication station; and data arrangement restoring means which perform restoring processing of arrangement of a string of receiving and demodulating data based on said extracted data arrangement information. 15. The communication system according to claim 13, wherein in said first communication station, codec processing of the transmitting data is performed by said transmitting data processing means or said first transmitting and modulating means, interleave processing in said codec processing is performed by said data rearranging means, and a pattern of said interleaves is dynamically changed in accordance with the quality information per position. 16. The communication system according to claim 14, wherein in said second communication station, codec processing of the received data is performed by said receiving and demodulating means, deinterleave processing in said codec processing is performed by said data arrangement restoring means, a pattern of said deinterleave is set based on the data arrangement information notified from said first communication station by said data arrangement information extracting means. 17. A first communication station in the communication system according to claim 13. 18. A second communication station in the communication system according to claim 14. 19. The communication system according to claim 13, wherein said first communication station further comprises MIMO transmitting means, as said first transmitting and modulating means, which separate the transmitting data into a plurality of transmitting systems and demodulate and transmit the separated data. 20. The communication system according to claim 14, wherein said second communication station further comprises MIMO receiving means which receive a signal transmitted from said MIMO transmitting means and output a receiving result obtained by the separating processing. 21. The communication system according to claim 19, wherein said MIMO transmitting means comprise: a data separating unit which separates the string of transmitting data to be inputted into a plurality of systems under a predetermined rule; transmission processing units of plural systems which output a high-frequency signal that is obtained by predetermined transmission and modulation processing of the transmitting data inputted from said data separating unit; and transmitting antennas of plural systems which transmit said high-frequency signal. 22. The communication system according to claim 20, wherein said MIMO receiving means comprise: receiving antennas of plural systems which receive a transmitted high-frequency signal; reception processing units of plural systems which select a predetermined signal from the high-frequency signal received by said receiving antenna and performs frequency conversion and amplification processing of the signal; channel condition estimating units of plural systems which estimate an equivalent property of a propagation path from said MIMO transmitting means to said receiving antenna by use of a received signal supplied from said reception processing unit; a signal separating unit which performs separation processing of transmitting signals of the plural systems transmitted from said MIMO transmitting means by use of the received signal and a result of estimating the property of the propagation path obtained by said reception processing unit and said channel condition estimating unit; data detecting units of plural systems which determine a bit of the received signal and outputs a result of determination by use of a signal separated by said signal separating unit; and a data synthesizing unit which synthesizes strings of bit data of plural systems to be inputted under a predetermined rule and outputs a result as a one-system string of the bit data. 23. The communication system according to claim 13, wherein said first communication station further comprises data arrangement information transmitting means which transmit the data arrangement information concerning a rearranging rule of the string of transmitting data determined by said data rearranging means by use of a communication link different from a communication link for data transmission to said second communication station from said first communication station. 24. The communication system according to claim 14, wherein said second communication station further comprises receiving and demodulating means which receive and demodulate the modulated signal received based on a frame unit via a communication link for data transmission from said first communication station and output the receiving and demodulating result; data arrangement information receiving means which receive the data arrangement information that is transmitted by use of another communication link from said first communication station; and data arrangement restoring means which perform the restoring processing of the arrangement of the string of the receiving and demodulating data based on said received data arrangement information. 25. The communication system according to claim 23, wherein said other communication link is a communication link using infrared communication. 26. The communication system according to claim 23, wherein said other communication link is a communication link having a personal area network (PAN). 27. The communication system according to claim 23, wherein said communication link for data transmission is a radio LAN. 28. A communication system for transmitting data from a first communication station to a second communication station, comprising: a receiving property inspecting device which estimates a received signal quality per position in a string of received data and temporarily stores a result of inspecting the quality per position upon receiving a signal transmitted from said first communication station by said second communication station, wherein said receiving property inspecting device previously estimates said received signal quality per position, and supplies information on said received signal quality to said first communication station, and said first communication station uses said supplied information on the received signal quality per position in rearranging a sequence of transmitting data. 29. The communication system according to claim 28, wherein said receiving property inspecting device comprises: means for estimating a quality per in-frame position which estimate a received signal quality per bit position in a frame by use of a receiving and demodulating result of a predetermined number of frames outputted from said second communication station and output information of the estimated quality per in-frame position; and means for writing quality information per in-frame position which temporarily store quality information per in-frame position to be inputted from said means for estimating a quality per in-frame position and transmits and stores said temporarily-stored quality information per position to said first communication station. 30. The communication system according to claim 28, wherein said first communication station comprises: transmitting data processing means which generate a string of data to be transmitted and simultaneously output importance information on the data; means for storing quality information per in-frame position which store quality information per in-frame position supplied from said receiving property inspecting device; data rearranging means which rearrange the sequence of the string of transmitting data and output the data arrangement information and a transmitting data frame based on the string of transmitting data to be inputted from said transmitting data processing means, the importance information per portion of the string of transmitting data, and the quality information per position from said means for storing quality information per in-frame position; and transmitting and modulating means which perform predetermined modulation processing of the transmitting data frame outputted from said data rearranging means, and transmit the data frame. 31. The communication system according to claim 28, wherein said second communication system comprises: receiving and demodulating means which receive and demodulate a modulated signal received based on a frame unit from said first communication station and output a receiving and demodulating result; data arrangement information extracting means which extract the data arrangement information notified from said first communication station; data arrangement restoring means which perform restoring processing of arrangement of a string of receiving and demodulating data based on said extracted data arrangement information; and received data processing means which perform data processing by use of said string of the receiving and demodulating data. 32. The communication system according to claim 28, wherein said receiving property inspecting device comprises: means for estimating a quality per in-frame position which estimate a received signal quality per bit position in a frame by use of a receiving and demodulating result of the predetermined number of frames to be outputted from said second communication station and output the estimated quality information per in-frame position; data-arranging rule determining means which determines a data-arranging rule upon transmitting the data from said first communication station and output the data arrangement information; and means for writing quality information per in-frame position which temporarily store said quality information per in-frame position and said data arrangement information, and transmit and store said temporarily-stored information to said first communication station and said second communication station. 33. The communication system according to claim 32, wherein said first communication station comprises: data processing means which generate the string of transmitting data and simultaneously output importance information on the data; data arrangement information storing means which store the quality information per in-frame position and said data arrangement information that are supplied from said receiving property inspecting device; data rearranging means which rearrange the sequence of the string of transmitting data and outputs a transmitting data frame based on the string of transmitting data to be inputted from said transmitting data processing means and said quality information per in-frame position and said data arrangement information that are from said data arrangement information storing means; and transmitting and modulating means which perform predetermined modulation processing of a transmitting data frame to be outputted from said data rearranging means and transmit a result. 34. The communication system according to claim 32, wherein said second communication station comprises: receiving and demodulating means which receive and demodulate a modulated signal received based on a frame unit from said first communication station and output a receiving and demodulating result; data arrangement information storing means which store the quality information per in-frame position and said data arrangement information that are supplied from said receiving property inspecting device; data arrangement restoring means which perform restoring processing of arrangement of the string of the receiving and demodulating data based on said stored data arrangement information; and received data processing means which perform data processing by use of said string of the receiving and demodulating data. 35. A first communication station in the communication system according to claim 19. 36. A second communication station in the communication system according to claim 20. 37. A first communication station in the communication system according to claim 23. 38. A second communication station in the communication system according to claim 24. 39. A receiving property inspecting device in the communication system according to claim 29. 40. A first communication station in the communication system according to claim 30. 41. A second communication station in the communication system according to claim 31. 42. A receiving property inspecting device in the communication system according to claim 32. 43. A first communication station in the communication system according to claim 33. 44. A second communication station in the communication system according to claim 34. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The present invention relates to a receiving method and a receiving apparatus for estimating the received signal quality, and a communication system using the receiving apparatus. 2. Description of the Prior Art Various technologies are introduced to conventional communication systems, in particular, a radio communication system, for the purpose of the high efficiency of a transfer method and the increase in transfer capacity. For example, the abovementioned technologies include a multivalue modulating technology, e.g., a quadrature amplitude modulating (QAM) method serving as a modulating method, an orthogonal frequency division multiplexing (OFDM) method serving as a multiplexing method, punctured convolution coding which is obtained by combining convolution coding and punctured processing serving as codec processing, and turbo coding, and the like. Further, one of the abovementioned conventional technologies is disclosed in a book titled “WAVE SUMMIT COURSE (Ido Tsushin in Japanese)” written and edited by SASAOKA Shuichi and published by Ohmsha, Ltd. on Mar. 25, 1998. Hereinbelow, a description is given of an example of the configuration and the operation of a receiving station in the conventional high-efficient communication system with reference to FIG. 1 . Here, it is assumed to use the punctured convolution coding as the codec processing, a 64-level QAM method whereby the signal point is arranged by a gray code as the modulating method, and the OFDM as the modulating method. A signal transmitted from a transmitting station 10 is subjected to the to the orthogonal frequency division multiplexing, and the resultant signal is received and demodulated by an OFDM receiving unit 21 . Consequently, a receiving station 20 obtains a modulating result every sub-carrier. A multivalue-QAM demodulating unit 22 performs the 64-level QAM demodulation processing of the sub-carriers, thereby obtaining a demodulating result. The transmitting station 10 performs the so-called punctured convolution coding processing of transmitting data, that is, deletes data at a predetermined position thereof. Then, in a codec unit 23 , a de-puncturing processing portion 24 depunctures the data and thereafter a Viterbi decoding portion 25 Viterbi-decodes the data at the predetermined position which is subjected to the puncturing processing, thereby restoring the data transmitted from the transmitting station 10 . With the abovementioned configuration, the efficiency for frequency use is improved and the communication with a large capacity is possible between the transmitting station 10 and the receiving station 20 . When the communication capacity is highly efficient with the abovementioned configuration, various factors in the processing cause the communication quality to vary depending on the position of bit data in a frame. For example, the communication quality in the OFDM method varies depending on the position of the sub-carrier due to the property of a transmission path between the transmitting station 10 and the receiving station 20 and due to a deteriorating factor in an analog processing unit for filter processing and the like in the transmitting station 10 and the receiving station 20 . Further, since the average distance between signal points of bits is essentially different in the reception and demodulation of the 64-level QAM with the arrangement of the signal points shown in FIG. 4 , the obtained communication quality varies. Specifically, it is known that the qualities of bits b 0 and b 1 are the highest and the qualities of bits b 4 and b 5 are the lowers. Further, it is generally well-known that data is subjected to the interpolation processing of phase and amplitude by use of a previously-inserted well-known pilot symbol in the QAM demodulation and the data is subjected to the compensation of phase and amplitude. However, the symbol apart from the pilot symbol is not fully interpolated and the quality might deteriorate depending on the precision of interpolation processing. Further, a code through the punctured convolution coding might essentially vary the distance between the codes. As mentioned above, since the communication quality might vary in the processing units, the communication qualities at the positions in a finally-obtained received data frame are not uniform and are varied. Generally, in order to reduce the variation in communication quality, the codec processing unit makes the communication quality uniform by combining the interleave processing and the error correction in many cases. As the data communication using the above high-efficient transfer method, recently, the data is communicated by increasing use of the packet transfer of an IP (Internet Protocol) and the transfer of multi-media as upgrade transfer thereof, e.g., a moving image, audio information, and text information with the large capacity. It is assumed that moving image data through the MPEG coding is transferred. A data sequence generated by the coding contains various header portions (a sequence header and a picture header) and image data. (DCT coding data portion). The degree of influence upon decoding the image varies depending on the portions of the data sequence when an error is caused upon communication. Specifically, the occurrence of communication error at the sequence header portion or the picture header potion influences the entire sequence block and picture header portion, thus excessively deteriorating the image quality. However, the occurrence of the communication error in a DCT encoding data unit doe not exert the influence only on the DCT block. The encoding processing uses a variable code and, therefore, the occurrence of the communication error at the header portion in the data sequence does not enable the decoding of the subsequent portions up to the position at which the next start position of the well-known variable code is inserted and this exerts the serious influence on the image reading. The above-generated data sequence includes many services in which the influence on the quality of the communication service varies depending on the component of the data sequence. In transmitting the data with the large capacity, the data sequence generated by the updating processing is basically generated regardless of the transfer method of a physical layer. Further, the data sequence is generally supplied to a processing system of the physical layer by a fixing method in accordance with a predetermined procedure, and the procedure is not dynamically changed. In this case, upon transmitting MPEG moving image data, data in header information portions (sequence header, picture header, etc.) with high influence on the original image quality is fixedly allocated at the position with the low quality in the physical layer, and the image quality is not fully obtained. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention is devised in consideration of the above circumstances and it is an object of the present invention to provide a receiving method and a receiving apparatus for estimating the received signal quality per position in a frame received by a receiving station, and a communication system for notifying a transmitting station side of the received signal quality per position and for rearranging transmitting data on the transmitting station side by use of information on the received signal quality per position. In order to solve the above problems, according to the present invention, there is provided a receiving method including: a step of estimating a received signal quality per position in a string of received data from a result of demodulating a received signal and of outputting a result of estimating the quality per position; and a received data processing step of processing the received data by use of the result of estimating the quality per position and the result of demodulating the received signal. Further, according to the present invention, there is provided a receiving apparatus which has means to realize the processing steps in the receiving method. With the receiving method and receiving apparatus, it is possible to estimate the variation in received signal quality at positions in a frame, which is due to various property deteriorating factors in the process from the transmission of the communication data from the transmitting station to the reception in the receiving station via a transmission path. Further, it is possible to improve the quality of communication services by processing, e.g., for deleting data with the weighting of soft decision value according to the quality and at the position having excessively deteriorated quality in error correction processing and image decoding at the latter stage. Further, according to the present invention, there is provided a communication system for transferring data from a first communication station to a second communication station, wherein the first communication station includes: data processing means which generate a string of transmitting data and simultaneously output importance information of the data; and data rearranging means which rearrange the sequence of the string of transmitting data and output the transmitting data frame based on the quality information per position notified from the second communication station, the string of transmitting data, and the importance information; and transmitting and modulating means which perform predetermined modulation processing of the transmitting data frame outputted from the data rearranging means and transmit it, and the second communication system includes: means for estimating quality per position which estimates received signal quality per position; means for notifying quality information per position which notify the first communication station of the quality information per position which is outputted from the means for estimating the quality per position; data arrangement information extracting means which extract the data arrangement information notified from the first station; and data arrangement restoring means which perform restoring processing of the arrangement of the string of receiving and demodulating data based on the extracted data arrangement information. With the above configuration, it is possible to arrange the transmitting data with the higher importance information at the position with the higher communication reliability and communicate it in accordance with the variation in received signal quality depending on the in-frame position due to various factors in a down-link communication system. Consequently, the communication services are improved. According to the present invention, it is possible to estimate the variation in received signal quality depending on the position in the frame which is caused by various property deteriorating factors in the processing from transmitting the transmitting data from the transmitting station to receiving the data by the receiving station via the transmission path, and to efficiently use the estimating result in the data processing unit at the latter stage. With the foregoing configuration and advantages, the levels of received signal qualities at the specific position in the frame can be detected and the data processing unit at the latter state can improve the precision of the processing based on the quality information. For example, the data with the low quality can be deleted. Further, it is possible to arrange the transmitting data with the higher importance information at the position with the higher communication reliability and communicate it in accordance with the variation in received signal quality depending on the in-frame position due to various factors in a down-link communication system. Thus, it is possible to improve a communication service. In addition, in the communication from the transmitting station to the receiving station, a received signal quality is estimated every data position in a data frame received by the receiving station, thus to estimate situations of the received signal quality varied depending a position which is caused by various factors of property deterioration in a process from transmitting communication data from the transmitting station to receiving it by the receiving station via a transmission path. Further, an estimating result is supplied to a data processing unit and used at a latter stage. The estimated result is notified to the transmitting station and arrangement of the transmitting data is reconstructed on the transmitting station side. The arrangement of the transmitting data is properly changed in accordance with importance of the communication data. Furthermore, the rearranged transmitting data is properly restored on the receiving station side, thereby obtaining received data and improving a quality of a communication service. |
Novel transformed cell, method of screening antiaging agent and antiaging agents |
This invention provides a novel transformed cell useful in constructing an anti-aging agent screening system, a screening method which uses the same and an anti-aging agent, and it relates to a transformed cell in which a gene coding for (a) a protein capable of phosphorylating p38 protein, or (b) p38 protein, a mutant of p38 protein, a kinase domain of p38 protein, a kinase domain of p38 protein mutant or a fusion protein containing them is transformed into a normal cell, a screening method which uses this transformed cell and an anti-aging agent which uses a compound obtained by the screening method as the active ingredient. |
1. A transformed cell in which a gene coding for (a) a protein capable of phosphorylating p38 protein, or (b) p38 protein, a mutant of p38 protein, a kinase domain of p38 protein, a kinase domain of p38 protein mutant or a fusion protein containing them is transformed into a normal cell. 2. A method for screening a compound, which comprises (1) a step for allowing a normal cell introduced with a gene capable of inducing cellular senescence to contact with a substance to be tested, and (2) a step for analyzing an aging index of the cell by the activation of p38. 3. The screening method according to claim 2, wherein the step for analyzing an aging index of the cell is a step in which an aging index of the cell is analyzed by comparing with a control cell which is not contacted with a substance to be tested. 4. The screening method according to claim 2 or 3, wherein the aging index is a change in the ratio of S phase cell, an ability. 5. The screening method according to any one of claims 2 to 4, wherein the normal cell introduced with a gene capable of inducing cellular senescence is the transformed cell according to claim 1 or a transformed cell prepared by transforming a normal cell with a gene coding for (c) a protein positioned at the upstream of a MAPKK protein of the p38 pathway, a mutant of the protein positioned at the upstream of the MAPKK protein of the p38 pathway, the kinase domain of the protein positioned at the upstream of the MAPKK protein of the p38 pathway, or a fusion protein containing them, or (d) a protein which activates the p38 MAPK pathway or a fusion protein thereof. 6. An anti-aging agent which comprises a compound obtained by the screening method of any one of claims 2 to 5. 7. The anti-aging agent according to claim 6, wherein the compound obtained by the screening method of any one of claims 2 to 5 is a compound having the activity to inhibit a p38 protein or a molecule positioned at the downstream of the p38 protein in the p38 MAPK pathway. 8. The anti-aging agent according to claim 7, wherein the inhibitor is a p38 protein inhibitor. 9. An anti-aging pharmaceutical composition which comprises, as an active ingredient, a compound obtained by the screening method of any one of claims 2 to 5 which is an inhibitor of a p38 protein or a molecule positioned at the downstream of the p38 protein in the p38 MAPK pathway. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Cellular senescence is conditions under which a cell that should originally carry out cell growth cannot perform cell division in response to growth stimulation. A senescent cell is characterized by its large flat nucleus and a cellular senescence-specific β-galactosidase (senescence-associated β-galactosidase; SA-β-galactosidase) activity. In addition to morphological changes, the cellular senescent cell (senescent cell) shows characteristic changes in the gene expression patterns and the like. There are many causes which trigger cellular senescence. For example, human normal fibroblast is a cell most generally used in the studies on cellular senescence. It is known that cellular senescence is induced when this is exposed to ionizing radiation or cultured under a high oxygen partial pressure. Also, in recent years, it has been reported that cellular senescence is rapidly induced after about 1 week when an activated oncognic RAS is expressed by force in human normal fibroblast. However, the cellular senescence most thoroughly studied is a cellular senescence by the replicative life span (telomere-dependent) in which a normal cell reaches an aging cell after a finite number of cell divisions. Since the cellular senescence generated by these different causes finally shows the same phenotype, it is considered that it occurs by the same molecular mechanism, but its details are not clear. The cellular senescence based on the replicative life span is a phenomenon in which a normal cell becomes senescent cell after a certain number of cell divisions which vary depending on the kind of the cell. In the case of the most frequently used human normal fibroblast, a fetal cell shows an aging phenotype after about 60 to 80 times of cell division. This phenomenon was reported by Hayflick in 1962. However, it has been unclear for a long time that intracellular mechanism of the recording of the number of cell divisions. In recent years, it has been shown that DNA replication of the chromosomal terminal telomere is not complete due to the so-called “end replication problem”, and the telomere length is shortened from about 50 to 200 base pairs per cell division, and that a cellular senescence is induced when this shortening reaches its threshold value. However, it is not clear that in what manner the cellular senescence occurs by the shortening of telomere length and whether or not its molecular mechanism is identical to cellular senescence caused by other causes. On the other hand, MAPK (Mitogen-activated protein kinase) pathway is a cascade of protein kinases which exist in the cytoplasm and are activated by the intracellular and extracellular stimuli and thereby phosphorylate and activate downstream inactive protein kinases. The final target kinase MAPK phosphorylates and activates a specific transcription factor, and the cell responds to stimuli through the induction of the expression of a group of genes by the transcription factor. The upstream kinase which phosphorylates the final target kinase MAPK is called MAPKK (MAPK2K), and the upstream kinase which phosphorylates the aforementioned MAPKK is called MAPKKK (MAPK3K). Two or more of the MAPK pathway are present, and MAPK, MAPKK and MAPKK are known as each of them. The classical MAPK pathway which was discovered and analyzed earliest in the history comprises Raf-Mek-Erk, and it responds to mainly extracellular stimuli, such as growth factor and the like and is activated via Ras. PD98059 is known as a specific inhibitor of Mek. On the other hand, JNK (c-Jun N-terminal kinase) and p38 protein are known as the MAPK which is induced by cytokine of tumor necrosis factor (TNF) and the like that induce stress and apoptosis. Also, the MAPKK and MAPKKK of JNK and p38 protein are not single, but two or more of them are respectively known. SB203580 is known as a compound which specifically inhibits the function of the p38 protein, and it is known that this compound inhibits production of inflammatory cytokines interleukin-1, interleukin-6, interleukin-8 or TNF and therefore is useful a therapeutic agent of inflammatory diseases (WO 97/33883). |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a photomicrograph which is a substitute for a drawing, showing the presence or absence of β-galactosidase activity in a juvenile cell and a senescent cell of human normal fibroblast WI-38. FIG. 2 is a photograph which is a substitute for a drawing, showing a result of western blotting of each of the cell lysates shown in FIG. 1 using an anti-p38 antibody. FIG. 3 is a graph showing cell growth curves of a juvenile cell and a senescent cell of human normal fibroblast WI-38 in the presence or absence of a p38 protein inhibitor, SB203580. FIG. 4 is a graph showing the ratio of S phase cell in a juvenile cell and a senescent cell of human normal fibroblast WI-38 in the presence or absence of a p38 protein inhibitor, SB203580. FIG. 5 is a graph showing cell growth curve of the transformed cell of the present invention in the absence (graph (a)) or presence [graph (b)] of a p38 protein inhibitor, SB203580. FIG. 6 is a graph showing the ratio of S phase cell in the transformed cell of the present invention, by FACS analysis. FIG. 7 is a photomicrograph which is a substitute for a drawing, showing the presence or absence of β-galactosidase activity in the transformed cell of the present invention. FIG. 8 is a graph showing a result of the determination of β-galactosidase activity in the transformed cell of the present invention. FIG. 9 is a photograph which is substitute for a drawing, showing a result of western blotting of the transformed cell of the present invention. FIG. 10 is a photomicrograph which is a substitute for a drawing, showing morphological changes of the transformed cell of the present invention by varied concentration of added tamoxifen. FIG. 11 is a graph showing variation per day in the growth ratio of the transformed cell of the present invention by varied concentration of added tamoxifen. FIG. 12 is a graph showing variation per day in the growth ratio of the transformed cell of the present invention in the presence or absence of added tamoxifen and PD98059. FIG. 13 is a graph showing a result of the quantitation of β-galactosidase in the transformed cell of the present invention in the presence or absence of added tamoxifen and PD98059. FIG. 14 is a graph showing variation per day in the growth ratio of the transformed cell of the present invention in the presence or absence of added tamoxifen and SB203580. FIG. 15 is a graph showing a result of the quantitation of β-galactosidase in the transformed cell of the present invention in the presence or absence of added tamoxifen and SB203580. detailed-description description="Detailed Description" end="lead"? |
Lactic acid production |
The present invention relates to a bacterium capable of converting sugars into lactic acid or a salt thereof. The invention also relates to a method for producing lactic acid or a salt thereof comprising culturing the bacterium of the present invention. In particular, the present invention provides a thermophilic bacterium capable of converting at least 70% (w/w) of a monosaccharide sugar and a disaccharide sugar into lactic acid or a salt thereof. |
1. A thermophilic bacterium capable of converting a monosaccharide sugar and a disaccharide sugar into lactic acid or a salt thereof, when grown in a defined medium, wherein at least 60% (w/w) of the monosaccharide sugar and the disaccharide sugar are converted into lactic acid or a salt thereof. 2. The bacterium of claim 1, wherein the monosaccharide sugar is a pentose and/or a hexose sugar. 3. The bacterium of claim 1 or claim 2, wherein the monosaccharide sugar is selected from the group consisting of arabinose, fructose, glucose, and xylose. 4. The bacterium of claim 3, wherein the monosaccharide sugar is selected from the group consisting of glucose and xylose. 5. The bacterium of anyone of the previous claims claim 1, wherein the disaccharide sugar is selected from the group consisting of sucrose, lactose, and cellobiose. 6. The bacterium of claim 5, wherein the disaccharide sugar is sucrose. 7. The bacterium of claim 1, which is capable of utilising simultaneously two different sugars. 8. The bacterium of claim 7, wherein the two different sugars are xylose and glucose. 9. The bacterium of claim 1, which is capable of growth in a medium comprising lactate and/or acetate as the sole carbon source. 10. The bacterium of claim 1, wherein the bacterium is a Bacillus sp. bacterium. 11. The bacterium of claim 10, wherein the Bacillus is selected from B. stearothermophilus; B. caldovelox; B. caldotenax; B. thermoglucosidasius; B. coagulans; B. licheniformis; B.thermodenitrificans; B. caldolyticus; B. smithii; and B. fumarioli. 12. The bacterium of anyone claim 1, which is capable of converting the monosaccharide and the disaccharide sugar to lactic acid or a salt thereof at a pH of 5 to 9. 13. The bacterium of claim 12, which is capable of converting the monosaccharide and the disaccharide sugar to lactic acid or a salt thereof at a pH of 6 to 8. 14. The bacterium of claim 1, which is capable of growth at a pH of less than 7.0. 15. The bacterium of claim 1, wherein at least 70% w/w of monosaccharide and disaccharide sugars are converted into lactic acid or salt thereof. 16. The bacterium of claim 1, wherein at least 80% w/w of the monosaccharide and disaccharide sugars are converted into lactic acid or salt thereof. 17. The bacterium of claim 1, wherein at least 95% w/w of the monosaccharide and disaccharide sugars are converted into lactic acid or salt thereof. 18. The bacterium of claim 1, which has an exponential growth rate (μ) greater than 1 h−1 in a defined medium. 19. The bacterium of claim 1, wherein at least 99% of the lactic acid produced is the L-optical isomer. 20. The bacterium of claim 1, which is sporulation deficient. 21. The bacterium of claim 1, wherein the bacterium is a facultative anaerobe. 22. A bacterial strain selected from the group consisting of strain LN (NCIMB Accession number 41038; strain J44 (NCIMB Accession number 41111); strain J30 (NCIMB Accession number 41113); and strain SCM6 (NCIMB Accession number 41112). 23. A method of producing lactic acid or a salt thereof comprising culturing the bacterium of claim 1 in a culture medium under suitable conditions. 24. The method of claim 23, wherein the culturing is performed in a continuous fermentation process. 25. The method of claim 23, wherein the culture medium is sparged with air and the culture is microaerobic. 26. The method of claim 23, wherein the culturing is at a temperature of between 40 and 70° C. 27. The method of claim 23, wherein the culturing is at a temperature of between 50 to 65° C. 28. The method of claim 23, wherein the culturing is at a temperature of between 52 and to 60° C. 29. The method of anyone of claim 23, wherein the bacterium produces at least 4.2 g/litre of culture/hour of lactic acid or a salt thereof. 30. The method of anyone of claim 23, wherein the culture medium comprises lactate and/or acetate as the sole carbon source. |
Basic cell for fuel cell with helical structure, production method thereof and fuel cell comprising numerous basic cells |
The invention concerns an elementary cell (1) for a fuel cell comprising two electrodes between which an ion exchange membrane (20) is positioned. According to the invention, one of the two electrodes has a threaded surface carrying the ion exchange membrane (20), the assembly formed by this electrode and the ion exchange membrane (20) being able to be assembled by screwing onto a threaded surface belonging to the other of the two electrodes. The invention also concerns a fuel cell provided with a plurality of elementary cells (1). |
1. Elementary cell (1) for fuel cell (100) comprising two electrodes (8,14) between which an ion exchange membrane (20) is positioned, characterized in that one of said two electrodes (14) has a threaded surface (18) carrying ion exchange membrane (20), the assembly formed by this electrode (14) and the ion exchange membrane (20) being able to be assembled by screwing onto a threaded surface (10) belonging to the other of said two electrodes (8). 2. Elementary cell (1) as in claim 1, characterized in that the ion exchange membrane (20) has two threaded surfaces (22,26) able to cooperate respectively with the threaded surfaces (18,10) of said two electrodes (14,8). 3. Elementary cell (1) as in claim 2, characterized in that the threaded surfaces (10,18,22,26) of said two electrodes (8,14) and of ion exchange membrane (20) have the same pitch. 4. Elementary cell (1) as in any of the preceding claims, characterized in that the ion exchange membrane (20) is a preformed film. 5. Elementary cell (1) as in any of the preceding claims, characterized in that one of said two electrodes (14) consists of a coating deposited on a screw (12), and in that the other of said two electrodes (8) consists of a coating deposited on a nut (4) formed in a substrate (2). 6. Elementary cell (1) as in claim 5, characterized in that screw (12) and substrate (2) are made in a porous material able to allow diffusion of the reagents in direction of electrodes (8,14). 7. Elementary cell (1) as in claim 5 or claim 6, characterized in that screw (12) is provided with at least one orifice (42) in which at least one reagent is able to be injected. 8. Elementary cell (1) as in any of claims 5 to 7, characterized in that substrate (2) is provided with at least one orifice (48) in which at least one reagent is able to be injected. 9. Elementary cell (1) as in claim 8, characterized in that the ion exchange membrane (20) is carried by electrode (14) deposited on said screw (12), and in that each orifice (48) provided in substrate (2) leads directly into a space (50) delimited at least in part by threaded surface (10) of electrode (8) deposited on nut (4), allowing the passage of each reagent inside interstices (51) of a helical connection between threaded surface (10) of electrode (8) deposited on nut (4) and the ion exchange membrane (20). 10. Fuel cell (100), characterized in that it comprises a plurality of elementary cells (1) as in any of the preceding claims, said cells (1) being electrically connected together. 11. Fuel cell (110) as in claim 10, characterized in that the elementary cells (1) comprise a common substrate (2) in which nuts (4) are made so as to be arranged matrix fashion. 12. Method for manufacturing an elementary cell (1) for fuel cell (100) as in any of claims 1 to 9, characterized in that it comprises the following steps: preforming the ion exchange membrane (20) using a screw (12); depositing a coating on screw (12) so as to create an electrode (14); machining the coating made so as to obtain the threaded surface (18) of this electrode (14); depositing a coating on nut (4) so as to create another electrode (8); tapping the coating made so as to obtain the threaded surface (10) of this other electrode (8); screwing the ion exchange membrane (20) onto the threaded surface (18) of electrode (14) carried by screw (12); screwing the assembly consisting of ion exchange membrane (20), screw (12) and electrode (14) carried by screw (12) onto the threaded surface (10) of the other electrode (8). |
<SOH> TECHNICAL FIELD <EOH>The present invention relates to a fuel cell comprising as electrolyte a membrane of ion exchange type, and more specifically a proton exchange membrane. More particularly, the invention concerns elementary cells for fuel cells and their methods of manufacture, the elementary cells also called “electrode-membrane-electrode” assemblies conventionally comprising two electrodes between which the ion exchange membrane is positioned. By way of example, the invention finds application in the area of fuel cells of PEMFC-type (“Proton Exchange Membrane Fuel Cell), of DMFC-type (“Direct Methanol Fuel Cell”) or further of alkaline anion exchange type. |
Asymmetric gel-filled microporous membranes |
The invention provides asymmetric membranes composed of a microporous substrate whose pores contain a crosslinked gel, the density of the crosslinked gel being greater at or adjacent to one major surface of the membrane than the density at the other major surface. The membranes are useful for separating matter from liquids and display good flux and good rejection at low pressure. |
1. An asymmetric membrane comprising a microporous membrane substrate, in at least some of whose pores is contained a crosslinked gel which forms a continuous or substantially continuous layer, the density of the crosslinked gel being greater at or adjacent to a first major surface of the membrane than the density at or adjacent to a second major surface of the membrane. 2. A membrane according to claim 1, wherein at least some of the pores contain a cross-linked gel such that it forms a continuous or substantially continuous layer whose thickness is less than that of the support membrane and is adjacent to the first major surface of the microporous membrane substrate. 3. A membrane according to claim 1, wherein the gel forming the continuous pore-filling band is not chemically bonded to the microporous support substrate but is entangled with the structural elements of the support. 4. A membrane according to claim 1, wherein the density of crosslinked gel polymer is at a maximum at or adjacent to the first major surface of the membrane and decreases gradually towards the second major surface of the membrane. 5. A membrane according to claim 1, wherein the membrane substrate is a microporous polyethylene, polypropylene, poly(vinylidenedifluoride), poly(tetrafluoroethylene), cellulose, cellulose acetate, nylon, poly(ester), polysulfone, or polycarbonate, or a porous ceramic or glass membrane support having a thickness of from 1 to 500 μm, preferably in the range of 10 to 200 μm, more preferably in the range 20 to 150 μm, a pore diameter in the range of 0.05 to 20 μm, preferably in the range 0.1 to 10 μm, more preferably 0.2 to 2 μm, and a pore volume of about 25% to about 95%, preferably in the range of 60 to 85%. 6. A membrane according to claim 1, wherein pores are of different sizes, with larger pores adjacent to one of the major surfaces of the substrate and smaller pores adjacent to the other major surface. 7. A membrane according to claim 1, wherein the crosslinked gel is a polyelectrolyte gel. 8. A membrane according to claim 7, wherein the crosslinked polyelectrolyte is based on one or more of 4-vinylpyridine, 2-vinylpyridine, acrylic acid, methacrylic acid, styrenesulfonic acid, vinylsulfonic acid, acrylamidomethylpropanesulfonic acid, diallylamine, N,N-dimethyldiallylamine, allylamine, N(dimethylaminoethyl)-acrylamide, N,N-dimethylaminopropyl-methacrylamide), vinylbenzylamine or polyethyleneimine and their derivatives. 9. A membrane according to claim 1, wherein the crosslinked gel is a hydrogel. 10. A membrane according to claim 9, wherein the crosslinked hydrogel is based on crosslinked poly(vinyl alcohol), poly(acrylamide), poly(N-vinylpyrrolidone), poly(ethylene glycol) or poly(propylene glycol). 11. A membrane according to claim 1, which displays a rejection ratio of 1.5 or greater. 12. A process for preparing an asymmetric membrane according to claim 1, wherein the pores of the microporous substrate are filled with a solution of a polymer, or a polymerizable monomer, that bears functional groups and a crosslinking agent, whereafter some of the solvent is allowed to evaporate and crosslinking or polymerization and crosslinking, is allowed to proceed in the pores to form the asymmetric membrane. 13. A process according to claim 12, wherein the functional groups present on the polymer or on the polymerizable monomer are ionically charged groups or groups that can be rendered ionically chargeable. 14. A process according to claim 12, wherein evaporation from one major surface of the substrate is permitted while the other major surface is sealed to prevent evaporation. 15. A process according to claim 12, wherein the microporous substrate has pores of different sizes, with larger pores adjacent to one major surface of the substrate and smaller pores adjacent to the other major surface of the substrate. 16. A process according to claim 12, wherein evaporation is permitted from that major surface to which the larger pores are adjacent. 17. A process according to claim 15, wherein evaporation from both major surfaces of the microporous substrate is permitted. 18. A process according to claim 12, wherein the polymer is poly(4-vinylpyridine) or poly(acrylic acid) and the solvent is N,N-dimethylformamide or N-methylpyrrolidone. 19. A process according to claim 18, wherein the solvent is N,N-dimethylformamide, in admixture with methanol. 20. A process according to claim 12, wherein the polymer is a polyamine and the crosslinking agent is a dihalide or a diepoxide. 21. A process according to claim 20, wherein the polyamine is poly(4-vinylpyridine) or poly(ethylimine) and the crosslinking agent is α, α′-dibromoxylene, α, α′-dichloroxylene or 1,3-dibromopropane. 22. A process according to claim 20, wherein the polymer is poly(ethyleneimine) and the solvent is an isopropanol/methanol mixture. 23. A process according to claim 12, wherein the polymer is poly(vinylbenzylchloride) and the crosslinking agent is a di- or polyamine. 24. A process according to claim 23, wherein the di- or polyamine is 1,6-diaminohexane, piperazine or 1,4-diazabicyclo[2.2.3]octane. 25. A process according to claim 12, wherein the polymer is poly(vinyl alcohol) and the crosslinking agent is glutaraldehyde. 26. A process for preparing an asymmetric membrane according to claim 1, which comprises filling the pores of the microporous substrate with a solution of a polymerizable monomer that bears functional groups, a crosslinking agent, a photoinitiator for polymerization and a photoblocker, and irradiating to cause polymerization to form the asymmetric membrane. 27. A process according to claim 26, wherein the functional groups are ionically charged groups or groups that can be rendered ionically chargeable. 28. A process according to claim 26, wherein the polymerizable monomer is 4-vinylpyridine or acrylic acid, the photoinitiator is 2,2′-dimethoxy-2-phenylacetophenone, the photoblocker is 2′,2-dihydroxy-4,4′-dimethoxybenzophenone and the solvent is N,N-dimethylformamide. 29. A separation process which comprises passing a liquid containing matter through a membrane according to claim 1 to separate some or all of the matter from the liquid. 30. A process according to claim 29, wherein multivalent cations are separated from the liquid. 31. A process according to claim 29, wherein monovalent cations are separated from the liquid. 32. A process according to claim 29, which is operated at pressure below 300 kPa. 33. A process according to claim 29, which is operated at a pressure below 100 kPa. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Membranes are used, for instance, in separation processes as selective barriers that allow certain chemical species to pass, i.e., the permeate, while retaining other chemical species, i.e., the retentate. Membranes are used in many applications, for example as biosensors, heparinized surfaces, facilitated transport membranes utilizing crown ethers and other carriers, targeted drug delivery systems including membrane-bound antigens, catalyst-containing membranes, treated surfaces, sharpened resolution chromatographic packing materials, narrow band optical absorbers, and in various water treatments which involve removal of a solute or contaminant, for example, dialysis, electrodialysis, microfiltration, ultrafiltration, reverse osmosis, nanofiltration and in electrolysis and in fuel cells and batteries. There are many materials or substrates for membranes. Specific physical and chemical characteristics to be considered when selecting a substrate include: porosity, surface area, permeability, solvent resistance, chemical stability, hydrophilicity, flexibility and mechanical integrity. Other characteristics may be important in certain applications. The rate of transport through a membrane is inversely related to the thickness of the membrane. However, reduction in thickness is normally accompanied by a loss of mechanical strength. Loeb and Sourirajan prepared a membrane which contained a thin dense layer at one surface and a less dense, more open structure through the rest of the membrane. The thin, dense layer provides the separating function of the membrane while the more porous component assists in providing mechanical strength. Loeb and Sourirajan formed the skinned membranes using a casting, partial evaporation and subsequent phase inversion. These and comparable membranes typically are made from a single polymer using some kind of phase separation process in the production of the film. A further important type of membrane involves the formation of a thin layer on the surface of a supporting membrane in which the thin film has a different composition to that of the support. Such membranes are generally known as thin film composite membranes. Typically, the thin dense layers consist of a crosslinked polyamide that is made using an interfacial polymerization step. Essentially all commercially available membranes used in reverse osmosis and nanofiltration applications are of a thin film construct with most being based on the thin film composite approach. The present invention is concerned with pore-filled membrances, not thin film membranes. It should be stressed that there is a fundamental difference in membrane construction between thin film and pore-filled membranes. The separating or active layer in thin film membranes is typically a dense layer that is formed on the top of a support membrane. This dense layer faces the feed solution. In pore-filled membranes a low density, cross-linked gel is contained within the pores of a microporous substrate and serves as the separating “layer”. Because of the nature of the gel it has to be prevented from excessive swelling in contact with water or other gel-swelling solvents by the physical constraint imposed upon it by the microporous host. As a result, in pore-filed membranes attempts are made to avoid having gel surface layers but instead to ensure that the gel is held within the pores of the host. In Mika et al., J. Membr. Sci., 108 (1995) pp 37 to 56, there is described a procedure for modifying microporous polypropylene and polyethylene membranes wherein 4-vinylpyridine is in-situ graft-polymerized into the pores of the membrane. The teaching of this article is incorporated by reference. U.S. Pat. No. 6,258,276, the disclosure of which is incorporated by reference, teaches that by cross-linking the membranes described by Mika et al. with a suitable cross-linking agent, such as divinylbenzene (DVB), there are provided charged membranes comprising porous microfiltration substrate membranes whose pores have anchored therein a cross-linked polyelectrolyte or hydrogel which exhibit novel effects in a variety of membrane applications. In particular, the membranes are said to exhibit significant ion rejection properties, enabling water softening to be effected, particularly at ultra-low pressure, such as the pressure of tap water, by removing multivalent ions, such as calcium and magnesium, in preference to monovalent ions, such as sodium. The membranes further exhibit electrochemical separator properties which make them suitable for a wide variety of applications, including electrodialysis, battery separators, fuel cell separators and electrochemical synthesis. In addition, the membrane may be used for Donnan dialysis, diffusion dialysis and pervaporation. Table 1 shows performance data of some symmetric pore-filled membranes at a driving pressure of 100 kPa with a municipal tap water feed, and one commercially available thin-film or non-pore filled membrane (DESAL-51). In each case the pore-filled membranes were made using a poly(propylene) microporous host membrane. TABLE 1 Mass- Cross- FLUX at REJECTION INCORPORATED gain linking 100 kPa (%) GEL (%) (%) kg/m 2 h Na Mg Ca Poly(vinylbenzyl 42 5 12 35 79 80 ammonium)/Piperazine Poly(vinylbenzyl 53 9 7 24 78 62 ammonium)/DABCO Poly(vinylpyridine)/α, 66 11 8 20 74 61 α′-dichloro-p-xylene DESAL-51 8 21 71 54 DESAL-51 is a commercially available high performance, flat-sheet nanofiltration membrane produced by Osmonics. The data shown for DESAL-51 in Table 1 were obtained under identical conditions to the pore-filled membranes. In these pore-filled membranes transport of matter such as solvent or solutes occurs only through the incorporated gel phase and not through the microporous support material. The microporous support simply provides mechanical support for the incorporated gel. These polyelectrolyte gel-filled membranes have a more or less even distribution of the incorporated polyelectrolyte gel-throughout the thickness of the membrane. This means that the thickness of the active layer, i.e., the thickness of the polyelectrolyte gel layer, is approximately the same as the thickness of the starting host membrane, typically in the range 80 to 120 μm. Plasma induced graft polymerization techniques, which are well known as a surface modification method, could, in principle, be used to prepare asymmetrically filled porous membranes. Yamaguchi et al. [J. Polym. Sci. Part A. Polymer Chem. 34, 1203-1208 (1996), Macromolecules 24, 5522-5527, (1991) and Ind. Eng. Chem. Res. 32, 848-853 (1993).] have described the plasma graft polymerization of poly(methylacrylate) onto a microporous high density poly(ethylene) membrane, pore size 0.02 μm. It was found that the grafted polymer was distributed symmetrically through the membrane cross-section. The graft polymerization rate was, however, affected by changing the monomer diffusivity relative to the reactivity of activated sites with change of the solvent. This in principle could lead to control of the grafted polymer location in the substrate. The present inventors have found that it is very hard to control the location of the grafted polymer using plasma activation techniques. In particular, with the large pore-sized and high porosity substrates preferred for high performance pore filled nanofiltration membranes experience in introducing poly(acrylic acid) has been that grafting largely occurs throughout the thickness of the membrane. The grafted polymers introduced by this method were not crosslinked. Porous hollow fibre membranes filled with hydrogels having mesh size asymmetry are disclosed by Dai and Barbari [J. Membrane Science, 171, 79-86, (2000)]. The hollow fibre was first impregnated with a solution of poly(vinyl(alcohol) and gluteraldehyde as a cross-linker so as to form an incorporated gel evenly distributed across the thickness of the membrane. After the cross-linking reaction was completed in the pores, the pore-filling hydrogel was modified to create mesh size asymmetry in the gel phase within the wall of the fibre. A gradient cross-linking was used to create the asymmetry in cross-linking. While there was an asymmetry in cross-linking density through the wall of the fibres the overall gel density did not significantly alter. |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.