Providing a semiconductor device for use in a ignition circuit, which prevents an increase in clamp voltage and allows application of a constant voltage across an ignition plug. In a semiconductor device which comprises a transistor and a zener diode connected between a collector and a gate of the transistor, a glass coat layer coating the zener diode is made of silicon oxide.

The present invention relates to a semiconductor device for controlling an ignition coil for an automobile or the like, and more particularly, to a semiconductor device comprising a transistor and a zener diode.
FIG. 4 shows an ignition circuit of an internal combustion engine of an automobile or the like. The ignition circuit comprises a semiconductor device 21 for controlling an ignition coil. An induction coil 22 and a power source 23 are connected to a cathode terminal (C) of the semiconductor device 21. A resistor 25 is connected to a gate terminal (G) of the semiconductor device 21. The gate terminal (G) receives a control signal 26 of the semiconductor device 21. An emitter terminal (E) of the semiconductor device 21 is grounded.
The semiconductor device 21 comprises an insulated gate bipolar transistor (hereinafter referred to as xe2x80x9cIGBTxe2x80x9d) 27. A zener diode 28 and a diode 29 are connected in series between a gate and a cathode of the IGBT 27.
In the ignition circuit, as the control signal 26 changes the IGBT 27 from the ON-state to the OFF-state, a predetermined voltage is developed on the primary side of the induction coil 22. Due to the zener diode 28, the voltage is always a constant voltage (hereinafter referred to as xe2x80x9cclamp voltagexe2x80x9d). As a result, a constant induced voltage is generated also on the secondary side of the induction coil 22, and this induced voltage is applied across an ignition plug 24. This sets sparks flying between the terminals, igniting an internal combustion engine or the like. In order to realize stable ignition, it is necessary to always apply a constant voltage across the ignition plug 24.
FIG. 5 is a cross sectional view of a conventional semiconductor device generally denoted at 150 for use in an ignition circuit. In the semiconductor device 150, a p-type well 2 is formed in an n-type silicon semiconductor substrate 1, and an n-type source region 3 is formed in the well 2. A gate electrode layer 9 is formed on the well 2 through an insulation layer 8. Meanwhile, an emitter electrode 10 electrically connected with the well 2 is formed on the well 2.
Further, a field oxide film 6 is formed on the semiconductor substrate 1, and a zener diode 7 of polycrystalline silicon is formed on the field oxide film 6. The zener diode 7 has a plurality of pn junction surfaces, and each pn junction surface is approximately perpendicular to a surface of the semiconductor substrate 1.
In FIG. 5, a diode (denoted at 29 in FIG. 4) is formed in series with the zener diode 7. In addition, the insulation layer 8 is formed on the zener diode 7, and a gate electrode 11 and a collector electrode 12 are electrically connected with the zener diode 7 through a hole formed in the insulation layer 8. The gate electrode 11 and the gate electrode layer 9 are electrically connected with each other.
Further, a p-type guard ring layer 4 is formed on the semiconductor substrate 1 below the zener diode 7.
A glass coat layer 33 of silicon nitride is formed as a protection film on a top surface of the semiconductor substrate 1.
On the other hand, an n-type buffer layer 14 and a p-type collector layer 15 are stacked one atop the other in this order on a back surface of the semiconductor substrate 1.
At last, a collector electrode 16 is formed on the p-type collector layer 15.
However, in an ignition circuit in which the semiconductor device 150 shown in FIG. 5 is used in the semiconductor device 21 shown in FIG. 4, if the semiconductor device 150 is switched (on/off) over a few million cycles, for example, the clamp voltage increases, and therefore, the voltage applied across the ignition plug 24 changes largely.
The present invention aims at providing a semiconductor device for preventing an increased clamp voltage and applying a constant voltage across an ignition plug in an ignition circuit.
As a result of intensive research, the inventor of the present invention discovered that while a semiconductor device is heated in the presence of hydrogen while forming a glass coat layer of the semiconductor device, hydrogen enters into the glass coat layer, and in turn the hydrogen diffuses in a zener diode during switching and a zener voltage accordingly changes.
In short, the present invention is directed to a semiconductor device comprising a transistor whose collector is connected to an induction coil and a zener diode connected between said collector and a gate of said transistor, wherein a constant induced voltage is generated in said induction coil in accordance with a signal supplied to said gate, said semiconductor device comprising: a semiconductor substrate; a transistor formed on said semiconductor substrate; a zener diode formed on said semiconductor substrate such that a pn junction surface is approximately perpendicular to a surface of said semiconductor substrate; and a glass coat layer formed on said semiconductor substrate so as to coat said zener diode, wherein said glass coat layer is an silicon oxide film.
Since the glass coat layer is made of silicon oxide, it is not necessary, unlike customarily practiced, to execute a step of forming the glass coat layer in a hydrogen-reduced atmosphere. This prevents diffusion of hydrogen in the zener diode during switching, and hence, to reduce a change in clamp voltage within the semiconductor device.
In addition, the present invention is directed to a semiconductor device comprising a transistor whose collector is connected to an induction coil and a zener diode connected between said collector and a gate of said transistor, wherein a constant induced voltage is generated in said induction coil in accordance with a signal supplied to said gate, said semiconductor device comprising: a semiconductor substrate; a transistor formed on said semiconductor substrate; a zener diode formed on said semiconductor substrate such that a pn junction surface is approximately perpendicular to a surface of said semiconductor substrate; and a glass coat layer of silicon nitride formed on said semiconductor substrate, wherein said glass coat layer is formed except for an area above said pn junction surface of said zener diode.
With this structure as well, it is possible to prevent diffusion of hydrogen in the zener diode and reduce a change in clamp voltage within the semiconductor device.
The glass coat layer of silicon nitride may be formed except for at least in an area above the pn junction surface of the zener diode, so that a change in clamp voltage within the semiconductor device is effectively suppressed.
The zener diode may include a plurality of pn junction surfaces.
It is preferable that an n-type region of said zener diode is connected to said gate of said transistor and a p-type region of said zener diode is connected to said collector of said transistor.
The zener diode is formed preferably on a field oxide film formed on said semiconductor substrate, and an insulation film is formed preferably between said zener diode and said glass coat layer.
The zener diode may be made of polycrystalline silicon.
Further, in the semiconductor device, a diode of a forward direction opposite to said zener diode may be disposed in series with said zener diode between said collector and said gate of said transistor.
The transistor is preferably an insulated gate bipolar transistor.
As described clearly above, application of the semiconductor device according to the present invention to an ignition circuit makes it possible to repeat stable ignition.

Semiconductor device for preventing an increased clamp voltage in an ignition circuit


A two-wire load control device, such as a dimmer, is operable to control the amount of power delivered to an electrical load, such as a magnetic low-voltage (MLV) load, and comprises a bidirectional semiconductor switch, a timing circuit, a trigger circuit having a variable voltage threshold, and a clamp circuit. When a timing voltage signal of the timing circuit exceeds an initial magnitude of the variable voltage threshold, the trigger circuit is operable to render the semiconductor switch conductive, reduce the timing voltage signal to a predetermined magnitude less than the initial magnitude, and to increase the variable voltage threshold to a second magnitude greater than the first magnitude. The clamp circuit limits the magnitude of the timing voltage signal to a clamp magnitude between the initial magnitude and the second magnitude, thereby preventing the timing voltage signal from exceeding the second magnitude. Accordingly, multiple attempted firings of the semiconductor switch are avoided, and the MLV dimmer is prevented from conducting asymmetric current when an MLV transformer of the MLV load is unloaded.

1. Field of the Invention
The present invention relates to load control devices for controlling the amount of power delivered to an electrical load. More specifically, the present invention relates to a drive circuit for a two-wire analog dimmer that includes a trigger circuit having a variable voltage threshold for preventing multiple attempted firings of a bidirectional semiconductor switch of the dimmer.
2. Description of the Related Art
A typical lighting dimmer is coupled between a source of alternating-current (AC) power (typically 50 or 60 Hz line voltage AC mains) and a lighting load. Standard dimmers use one or more semiconductor switches, such as triacs or field effect transistors (FETs), to control the amount of power delivered to the lighting load and thus the intensity of the light emitted by the load. The semiconductor switch is typically coupled in series between the source and the lighting load. Using a phase-control dimming technique, the dimmer renders the semiconductor switch conductive for a portion of each line half-cycle to provide power to the lighting load, and renders the semiconductor switch non-conductive for the other portion of the line half-cycle to disconnect power from the load.
Some dimmers are operable to control the intensity of low-voltage lighting loads, such as magnetic low-voltage (MLV) and electronic low-voltage (ELV) loads. Low-voltage loads are generally supplied with AC power via a step-down transformer, typically an isolation transformer. These step-down transformers step the voltage down to the low-voltage level, for example 12 to 24 volts, necessary to power the lamp or lamps. One problem with low-voltage lighting loads employing a transformer, specifically MLV loads, is that the transformers are susceptible to any direct-current (DC) components of the voltage provided across the transformer. A DC component in the voltage across the transformer can cause the transformer to generate acoustic noise and to saturate, increasing the temperature of the transformer and potentially damaging the transformer.
FIG. 1A is a simplified schematic diagram of a prior art magnetic low-voltage dimmer 10. The prior art dimmer 10 is coupled to an AC power source 12 via a HOT terminal 14 and an MLV load 16 via a DIMMED HOT terminal 18. The MLV load 16 includes a transformer 16A and a lamp load 16B. The dimmer 10 further comprises a triac 20, which is coupled in series electrical connection between the source 12 and the MLV load 16 and is operable to control the power delivered to the MLV load. The triac 20 has a gate (or control input) for rendering the triac conductive. Specifically, the triac 20 becomes conductive at a specific time each half-cycle and becomes non-conductive when a load current iL through the triac becomes substantially zero amps, i.e., at the end of the half-cycle. The amount of power delivered to the MLV load 16 is dependent upon the portion of each half-cycle that the triac 20 is conductive. An inductor L22 is coupled in series with the triac 20 for providing noise filtering of electromagnetic interference (EMI) at the HOT terminal 14 and DIMMED HOT terminal 18 of the dimmer 10.
A timing circuit 30 includes a resistor-capacitor (RC) circuit coupled in parallel electrical connection with the triac 20. Specifically, the timing circuit 30 comprises a potentiometer R32 and a capacitor C34. As the capacitor C34 charges and discharges each half-cycle of the AC power source 12, a voltage vC develops across the capacitor. A plot of the voltage vC across the capacitor C34 and the load current iL through the MLV load 16 is shown in FIG. 2. The capacitor C34 begins to charge at the beginning of each half-cycle (i.e., at time to in FIG. 2) at a rate dependent upon the resistance of the potentiometer R32 and the capacitance of the capacitor C34.
A diac 40, which is employed as a trigger device, is coupled in series between the timing circuit 30 and the gate of the triac 20. As soon as the voltage vC across the capacitor C34 exceeds a break-over voltage VBR (e.g., 30V) of the diac 40, the voltage across the diac quickly decreases in magnitude to a break-back voltage VBB. The quick change in voltage across the diac 40 and the capacitor C34 causes the diac to conduct a gate current iGATE to and from the gate of the triac 20. The gate current iGATE flows into the gate of the triac 20 during the positive half-cycles and out of the gate of the triac during the negative half-cycles.
FIG. 1B is a plot of the voltage-current characteristic of a typical diac. The values of the break-over voltage VBR and the break-back voltage VBB may differ slightly during the positive half-cycles and the negative half-cycles. Thus, the voltage-current characteristic of FIG. 1B shows the positive break-over voltage VBR+ and the positive break-back voltage VBB+ occurring during the positive half-cycles and the negative break-over voltage VBR− and the negative break-back voltage VBB− occurring during the negative half-cycles.
The charging time of the capacitor C34, i.e., the time constant of the RC circuit, varies in response to changes in the resistance of potentiometer R32 to alter the times at which the triac 20 begins conducting each half-cycle of the AC power source 12. The magnitude of the gate current iGATE is limited by a gate resistor R42. The gate current iGATE flows for a period of time TPULSE, which is determined by the capacitance of the capacitor C34, the difference between the break-over voltage VBR and the break-back voltage VBB of the diac 40, and the magnitude of the gate current iGATE. After the voltage vC across the capacitor C34 has exceeded the break-over voltage VBR of the diac 40 and the gate current iGATE has decreased to approximately zero amps, the voltage vC decreases by substantially the break-back voltage VBB of the diac 40.
While the gate current iGATE is flowing through the gate of the triac 20, the triac will begin to conduct current through the main load terminals, i.e., between the source 12 and the MLV load 16 (as shown at time t1 in FIG. 2). In order for the triac 20 to remain conductive after the gate current iGATE ceases to flow, the load current iL must exceed a predetermined latching current ILATCH of the triac before the gate current reaches zero amps. When the MLV lamp 16B is connected to the MLV transformer 16A, the load current iL through the main load terminals of the triac 20 is large enough such that the load current exceeds the latching current ILATCH of the triac. Thus, when the magnitude of the gate current iGATE falls to substantially zero amps after the gate current period TPULSE, the triac 20 remains conductive during the rest of the present half-cycle, i.e., until the load current iL through the main load terminals of the triac 20 nears zero amps (e.g., at time t2 in FIG. 2).
When the MLV lamp 16B is not connected to the MLV transformer 16A, i.e., the MLV transformer is unloaded, the MLV load 16 will have a larger inductance than when the MLV lamp is connected to the MLV transformer. The larger inductance L causes the load current iL through the main load terminals of the triac 20 to increase at a slower rate since the rate of change of the current through an inductor is inversely proportional to the inductance, i.e., diL/dt=vL/L (assuming the instantaneous voltage vL across the inductor remains constant). Accordingly, when the MLV lamp 16B is not connected, the load current iL may not rise fast enough to exceed the latching current of the triac 20, and the triac may stop conducting when the gate current iGATE falls to substantially zero amps.
FIG. 3 is a plot of the voltage vC across the capacitor C34 and the load current iL when the MLV transformer 16A is unloaded. After the voltage vC exceeds the break-over voltage VBR of the diac 40 (as shown by a peak A1), the load current iL begins to increase slowly (as shown by a peak B1). However, the load current iL does not reach the latching current ILATCH of the triac 20 before the gate current IGATE stops flowing, and thus the triac 10 does not latch on and the load current iL will begin to decrease. Because the triac 20 did not latch and becomes non-conductive, the voltage across the timing circuit 20 will be a substantially large voltage, i.e., substantially equal to the voltage of the AC power source 12, and the capacitor C34 will begin to charge again (as shown by a peak A2). Note that the load current iL does not have enough time to drop to zero amps. When the voltage vC exceeds the break-over voltage VBR for the second time in the present half-cycle, the gate current iGATE flows through the gate and the triac 20 will once again attempt to fire (as shown by a peak B2). Because the load current iL is not zero amps when the gate current iGATE begins to flow, the load current rises to a greater value than was achieved at peak B1. Nonetheless, the load current iL does not reach the latching current ILATCH, and thus the cycle repeats again (as shown by peaks A3 and B3). A similar, but complementary, situation occurs during the negative half-cycles. As shown in FIG. 3, the load current iL does not exceed the latching current ILATCH during any of the AC line half-cycles.
As the situation of FIG. 3 repeats for multiple half-cycles, i.e., the triac 20 attempts to repeatedly fire from one half-cycle to the next, the load current iL through the main load terminals of the triac may acquire either a positive or a negative DC component. Eventually, the DC component will cause the load current iL to exceed the latching current ILATCH during some half-cycles, e.g., the negative half-cycles as shown in FIG. 4. Thus, an asymmetric load current iL will flow through the MLV load 16, causing the MLV transformer 16A to generate acoustic noise and to overheat, which can potentially damage the MLV transformer.
Thus, there exists a need for an MLV dimmer that prevents the conduction of asymmetric currents through an MLV load when the MLV transformer is unloaded.

Load control device having a trigger circuit characterized by a variable voltage threshold


An encoding apparatus compresses a stereo signal using a sum signal and a difference signal of a left component signal and a right component signal of the stereo signal. The encoding apparatus includes a calculating unit that calculates complexity of the sum signal and complexity of the difference signal; a setting unit that sets, based on the complexity, an allocation rate of bits to be allocated in quantizing the sum signal and the difference signal; and a quantizing unit that quantizes the sum signal and the difference signal based on the allocation rate.

1. Field of the Invention
The present invention relates to a technology for encoding a stereo signal to compress an audio signal.
2. Description of the Related Art
Conventionally, as a scheme of encoding a frequency spectrum obtained by orthogonally transforming an audio signal such as those of voice and music, an advanced audio coding (AAC) that is an audio standard of ISO/IEC 13818-7 has been used. The AAC is applied to a surface digital radio broadcasting, and a mid-side (MS) stereo encoding is further applied to improve efficiency of compression of the stereo signal.
FIG. 12 is a schematic for illustrating an encoding procedure in the MS stereo encoding. An MS stereo encoding apparatus 1200 shown in FIG. 12 first orthogonally transforms a left channel audio signal (L) by an L-orthogonally transforming unit 1201 and orthogonally transforms a right channel audio signal (R) by an R-orthogonally transforming unit 1202. The L and R after the transformation are input into an MS stereo transforming unit 1203 and the MS stereo transforming unit 1203 generates respectively a sum signal M (M=(L+R)/2) and a difference signal S (S=(L−R)/2) from the input L and R. The sum signal M is encoded by a sum signal quantizer 1204 (code word 1). The difference signal S is encoded by a difference signal quantizer 1205 (code word 2).
In MS stereo encoding, in the MS stereo transforming unit 1203, when L and R are highly correlated with each other, that is, L and R are highly similar to each other, the electric power of the difference signal S is smaller than that of the sum signal M. Therefore, the efficiency of the encoding can be improved by decreasing the number of encoding bits of the difference signal S and increasing the number of encoding bits of the sum signal M.
In addition to the transformation by the MS stereo encoding, as a method of improving the efficiency of encoding, for example, Japanese Patent Application Laid-Open Publication No. 2001-255892 discloses a technique that transforms adaptively a difference signal into a monaural state. FIG. 13 is schematic for explaining an adaptive transformation into the monaural state. Charts 1310 and 1320 show the spectrums of audio signals L and R. Charts 1330 and 1340 show the spectrums of a sum signal M and a difference signal S generated using the L and R. A spectrum 1311 of the L and a spectrum 1321 of the R are transformed respectively into a spectrum 1331 of the sum signal M and a spectrum 1341 of the difference signal S.
In the transformation from the L and R into the sum signal M and the difference signal S, a signal at a frequency "f" is noted. In the monaural transformation, similarity between the L and the R is obtained, and when the similarity between the L and the R is high, the difference signal S is silenced or is deformed into a signal having small amplitude. When the similarity between the L and the R is high, the number of bits of the difference signal S is decreased to zero because the difference signal S becomes S=(L−R)/2≈0. That is, for the spectrum 1341 representing the difference signal S, the signal at the frequency f becomes zero and the bits for this signal is allocated to the signal at the frequency f of the spectrum 1331 representing the sum signal M. Therefore, the number of bits of the sum signal M is increased and distortion of the audio signal associated with the quantization can be reduced.
However, in the surface digital radio broadcasting, the bit rate allocated to sound is very low as 32 kilo bits per second (kbps) to 64 kbps to realize high-quality sound (music) at the quality level of a CD and video images at around 330 kbps in total. Therefore, in the conventional MS stereo encoding, sound quality is degraded due to shortage of the number of quantization bits.
If the adaptive transformation into the monaural state is applied, in a band of the difference signal S being zero, which is a band that has been transformed into the monaural state, the number of quantization bits of the difference signal S can be decreased. However, in a band that can not be transformed into the monaural state, the number of quantization bits of the difference signal S can not be decreased. Therefore, sufficient sound quality can not be obtained under the condition of a low bit rate.

Encoding apparatus, encoding method, and computer product


A glass for press molding, containing substantially no lead, consisting substantially of, as represented by mol % based on oxides:

The material of optical glass to be used for an instrument utilizing light, such as a lens, is desired to have characteristics such that it has a refractive index as high as possible and a deformation point as low as possible. If the material has a high refractive index, the optical design can advantageously be made, and if the deformation point is low, a lens can be produced at a low cost by press molding. Here, the deformation point is the temperature at which expansion of glass along with the temperature rise stops and shrinkage starts, and it substantially corresponds to the temperature at which glass becomes moldable. In recent years, in addition to these characteristics, the material is desired to be composed of components containing substantially no lead with a view to facilitating e.g. disposal of waste materials.
However, many of conventional glasses for press molding have been developed on the premise that they will be used mainly in a visible light range, and no glass has been found which satisfies three conditions i.e. a no lead content, a low deformation point and a high refractive index to a light having a long wavelength, particularly a wavelength at a level of from 0.8 to 1.8 μm. Among conventional glass materials for press-molded lenses, there have been some which have reached to a level of a deformation point of 543° C. and a refractive index of about 1.88 to a wavelength of about 0.8 μm, with no lead content. However, there has been no glass material which satisfies both a refractive index higher than this and a deformation point lower than this on the premise that it contains no lead.
The first object of the present invention is to provide a glass for press molding which contains substantially no lead and which has a low deformation point and a refractive index of at least 1.9 to a light having a wavelength of 0.8 μm, and the second object is to present a lens prepared by press molding such a glass.

Abstract: Bi2O325 to 70%,B2O3 + SiO2 5 to 75%,CeO2 0 to 10%,Al2O3 0 to 20%,Ga2O3 0 to 20%,Al2O3 + Ga2O3 0 to 30%, andZnO + TeO2 + BaO + WO3 0 to 40%,and having a refractive index of at least 1.9 to a light having a wavelength of 0.8 μm.


The present invention relates to phosphoric acid derivatives represented by general formula (I), wherein each symbol is as defined in the description and nontoxic salts thereof.

This invention relates to phosphoric acid derivatives. More particularly, this invention relates to
1) phosphoric acid derivatives of the formula (I)
wherein all symbols are the same meaning as hereinafter defined and non-toxic salts thereof,
2) processes for the preparation thereof, and
3) pharmaceutical compositions containing them as active ingredient.
Tumor necrosis factor a (TNFxcex1) was discovered found as a factor that induces tumor hemorrhagic necrosis. TNFxcex1 is produced by macrophages as well as various other cells, including lymphocytes (CD4+ T cells, CD8+ T cells, B cells), neutrophils, stellate cells, endothelial cells and smooth muscle cells. TNFxcex1 showed various physiological activities by affecting various cells. TNFxcex1 is believed to play an important role especially in inflammatory reactions as a biophylactic response. Macrophages and neutrophils are deeply involved in development and progress of inflammatory reaction. TNFxcex1 stimulates vulnerary activities of macrophages and increases release of inflammatory cytokines, including TNFxcex1, interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8) etc. Also TNFxcex1 is associated with activation of neutrophils such as phagocytosis, degranulation, chemotaxis and expression of adhesion molecules and enhances production of platelet activating factor and active oxygen by neutrophils. TNFxcex1 stimulates growth, induction of interleukin-2 (IL-2) receptor and production of interferon xcex3 and colony-stimulating factor in T cells, which play an important role in immune response. Besides TNFxcex1 provides help to B lymphocytes for antibody production and cell division.
It is reported below that TNFxcex1 is involved in variety of diseases. p0 (1) It may be a cause of fulminant hepatitis that TNFxcex1 levels in serum of the patients with fulminant hepatitis were higher than that of the patients with the severe form of acute hepatitis [H. Iwai et. al., Crit. Care. Med., 26, 873 (1998)].
(2) TNFxcex1 contents in intestinal mucosa from inflammatory bowel disease were markedly increased [Z. Kmiec, Arch. Immunol. Ther. Exp., 4, 143 (1998)].
(3) In the patients with Crohn""s disease, anti TNFxcex1 antibody was effective endoscopically [D. W. Hommes et. al., Haemostasis, 27, 269 (1997)].
(4) There was a correlation between TNFxcex1 and glucose level in serum of the patients with insulin dependent diabetes [M. Muc-Wierzgon et. al., Pol. Arch. Med. Wewn., 97, 426 (1998)].
(5) In the patients with interstitial pneumonia, ability to produce TNFxcex1 by alveolar macrophages are enhanced than in controls [J. Ancochea et. al., Arch. Bronconeumol., 33, 335 (1997)].
(6) Anti-TNFxcex1 antibody was effective on experimental autoimmune uveitis in mice [G. Sartani et. al., Invest. Ophthalmol. Vis. Sci., 37, 2211 (1996)].
(7) Thalidomide, which is a TNFxcex1 production inhibitor, diminished mechanical allodynia and thermal hyperalgesia in bennet model and improved the pathologic vascular injury [C. Sommer et. al., Pain, 74, 83 (1998)].
(8) Thalidomide was effective for diarrhea and weight loss in HIV patients [D. Sharpstone et. al., Gastroenterol, 112, 1823 (1997)].
(9) Anti-TNFxcex1 antibody reduced infarct volume in middle cerebral artery ischemia-reperfusion model [G. Yang et. al., Neuroreport, 9, 2131 (1998)].
Therefore inhibitors of TNFxcex1 production may be considered useful as preventives and/or remedies of various diseases induced by inflammatory cytokines including TNFxcex1. In view of physiological activity and involvement of TNFxcex1 with diseases, these inhibitors may be useful for rheumatoid arthritis, ulcerative colitis, Crohn""s disease, hepatitis, sepsis, hemorrhagic shock, multiple sclerosis, cerebral infarction, diabetes, interstitial pneumonia, uveitis, pain, glomerulonephritis, HIV-associated diseases, cachexia, myocardial infarction, chronic heart failure, oral aphtha, Hansen""s disease, infection, etc.
For example, it is disclosed in JP kokai 55-118494 that the phosphorylcholine type compound of the formula (A)
wherein R1A and R2A are the same or different to represent hydrogen atom, optionally substituted by alkyl, alkenyl, aralkyl, aryl, acyl, alkoxycarbonyl, alkoxycarbonylalkyl, aralkoxycarbonyl, alkoxycarbonylaminoalkyl, carbamoyl, thiocarbamoyl, or heterocyclic ring, R3A and R5A are the same or different to represent hydrogen atom, carboxyl, optionally substituted by alkyl, alkenyl, aralkyl, aryl, alkoxycarbonyl, or heterocyclic ring, R4A represents hydrogen atom, alkyl, alkenyl, aralkyl, or aryl etc., AA represents oxygen atom, sulfur atom, or xe2x80x94NR8Axe2x80x94 (wherein R8A repersents hydrogen atom, etc.), R6A is the same or different to represent hydrogen atom, or optionally substituted by alkyl, aralkyl, R7A represents alkyl, aralkyl, X1A and X2A represent oxygen atom or sulfur atom, IA and mA each, is 0, 1 or 2, and nA is 2 or 3 is useful as antitumor agent.
It is disclosed in WO 96/22966 that the compound of the formula (B)
wherein XB represents xe2x80x94COOH, xe2x80x94Pxe2x88x92O3H, xe2x80x94SO2R5B, xe2x80x94SO3H, xe2x80x94OPxe2x88x92O3H, xe2x80x94COOR4B or xe2x80x94CON(R4B)2, YB repersents xe2x80x94COxe2x80x94, xe2x80x94SO2xe2x80x94, or xe2x80x94PO2xe2x80x94, R1B represents alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocyclyl etc., R2B represents hydrogen atom, aryl, alkyl, alkenyl, alkynyl, or cycloalkyl etc., R3B represents alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl etc., or R2B and R3B, taken together with the atom to which they are attached, represent heterocyclyl, R4B represents aryl, alkyl, or cycloalkyl etc., and nB is 0, 1 or 2 is useful as a cell adhesion inhibitor.
Energetic investigations have been carried out to find new compounds having TNFxcex1 production inhibitory activity. As a result, the present inventor have found that these aims may be accomplished by a phosphoric acid derivatives of the formula (I).
The phosphoric acid derivatives of the formula (I) have not been known as TNFxcex1 production inhibitor at all.
The present invention relates to
1) Phosphoric acid derivatives of the formula (I)
wherein R1 is
(1) C1-20 alkyl,
(2) C1-20 alkyl which one carbon atom is replaced by an oxygen atom, a sulfur atom, xe2x80x94S(O)xe2x80x94 or S(O)2xe2x80x94 (with the proviso that, a carbon atom which attached with E is not replaced by these groups),
(3) C2-20 alkenyl,
(4) C2-20 alkynyl,
(5) Cyc1 (wherein Cyc1 is C5-15 membered mono-, bi- or tricarbocyclic ring or 5-15 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom),
(6) C1-20 alkyl, C2-20 alkenyl or C2-20 alkynyl substituted by Cyc1 (wherein all symbols are the same meaning as hereinbefore defined), Cyc1 may be substituted by one or more substituents selected from the following (a)-(r):
(a) C1-8 alkyl,
(b) C1-8 alkoxy,
(c) nitro,
(d) halogen atom,
(e) trifluoromethyl,
(f) trifluoromethyloxy,
(g) hydroxy,
(h) cyano,
(i) NR10R11 (wherein R10 and R11 each, independently, is a hydrogen atom, C1-8 alkyl, C1-8 hydroxyalkyl, C2-5 acyl or C1-8 alkylsulfonyl),
(j) COOR20 (wherein R20 is a hydrogen atom or C1-4 alkyl),
(k) CONR30R31 (wherein R30 and R31 each, independently, is a hydrogen atom or C1-4 alkyl),
(l) xe2x80x94S(O)mxe2x80x94R32 (wherein m is 0, 1 or 2, R32 is 1-8 alkyl or C1-8 alkyl substituted by C1-8 alkoxy, COOR20 (wherein R20 is the same meaning as hereinbefore defined) or CONR30R31 (wherein R30 and R31 each, independently, is a hydrogen atom or C1-4 alkyl)),
(m) xe2x80x94Oxe2x80x94Cyc2 (wherein Cyc2 is C3-8 cycloalkyl or phenyl),
(n) xe2x80x94Sxe2x80x94Cyc2 (wherein Cyc2 is the same meaning as hereinbefore defined),
(o) C1-8alkyl substituted by one substituent selected from C1-8 alkoxy, COOR20 (wherein R20 is the same meaning as hereinbefore defined), CONR30R31 (wherein R30 and R31 are the same meaning as hereinbefore defined), phenyl or hydroxy.
(p) C1-8alkoxy substituted by one substituent selected from C1-8 alkoxy, COOR20 (wherein R20 is the same meaning as hereinbefore defined), CONR30R31 (wherein R30 and R31 are the same meaning as hereinbefore defined), phenyl or hydroxy,
(q) C3-15 membered mono-, bi- or tricarbocyclic ring,
(r) 5-15 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom,
E is
(a) xe2x80x94NR7COxe2x80x94,
(b) xe2x80x94NR7SO2xe2x80x94,
(c) xe2x80x94NR7CONR8xe2x80x94,
(d) xe2x80x94NR7COOxe2x80x94,
(e) xe2x80x94CONR7xe2x80x94,
(f) xe2x80x94NR7CSxe2x80x94,
(g) xe2x80x94NR7CSNR8xe2x80x94,
(h) xe2x80x94NR7CSxe2x80x94Oxe2x80x94,
(i) xe2x80x94CSNR7xe2x80x94 or
(j) xe2x80x94NR7xe2x80x94 (wherein R7 and R8 each, independently, is a hydrogen or C1-4 alkyl), A ring is C3-15 membered mono-, bi- or tricarbocyclic ring or 5-15 membered mono-, bi- or trycyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom,
R2 is the same meaning as hereinbefore defined substituents (a)-(r), R3 and R4
i) each, independently, is a hydrogen atom, C1-8 alkyl, C1-8 alkoxy, C1-8 hydroxyalkyl or phenyl, or
ii) taken together represents C2-6 alkylene, or
iii) one of R3 or R4, taken together with R2, represent C1-5 alkylene, and the other one is a hydrogen atom, C1-8alkyl or C1-8alkoxy,
n is an integer of 0, 1 or more,
R5 and R6 each, independently, is a hydrogen atom, C1-8 alkyl, phenyl, C1-4 alkyl substituted by phenyl, C1-4 alkyl substituted by cyano or C1-4 alkyl substituted by trihalomethyl,
Y and Z each, independently, is an oxygen atom or a sulfur atom,
xe2x80x83with the proviso that,
(1) when n is 2 or more integer, then R2 is the same or different,
(2) when R1 and R2 represent contains a sulfur atom, then Y is an oxygen atom, and R1 and R2 do not represent contains a sulfur atom at the same time or a non-toxic salt thereof,
2) processes for the preparation thereof, and
3) pharmaceutical composition containing them as active ingredient.
In the present specification, C1-4 alkyl means methyl, ethyl, propyl, butyl and isomers thereof.
In the present specification, C1-8 alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof.
In the present specification, C1-20 alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl and isomers thereof.
In the present specification, C2-20 alkenyl means vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, icosenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl, undecadienyl, dodecadienyl, tridecadienyl, tetradecadienyl, pentadecadienyl, hexadecadienyl, heptadecadienyl, octadecadienyl, nonadecadienyl, icosadienyl, hexatrienyl, heptatrienyl, octatrienyl, nonatrienyl, decatrienyl, undecatrienyl, dodecatrienyl, tridecatrienyl, tetradecatrienyl, pentadecatrienyl, hexadecatrienyl, heptadecatrienyl, octadecatrienyl, nonadecatrienyl, icosatrienyl and isomers thereof.
In the present specification, C2-20 alkynyl means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl, hexadecynyl, heptadecynyl, octadecynyl, nonadecynyl, icosynyl, butadiynyl, pentadiynyl, hexadiynyl, heptadiynyl, octadiynyl, nonadiynyl, decadiynyl, undecadiynyl, dodecadiynyl, tridecadiynyl, tetradecadiynyl, pentadecadiynyl, hexadecadiynyl, heptadecadiynyl, octadecadiynyl, nonadecadiynyl, icosadiynyl, hexatriynyl, heptatriynyl, octatriynyl, nonatriynyl, decatriynyl, undecatriynyl, dodecatriynyl, tridecatriynyl, tetradecatriynyl, pentadecatriynyl, hexadecatriynyl, heptadecatriynyl, octadecatriynyl, nonadecatriynyl, icosatriynyl and isomers thereof.
In the present specification, C1-8 alkoxy means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and isomers thereof.
In the present specification, C1-5 alkylene means methylene, ethylene, trimethylene, tetramethylene, pentamethylene and isomers thereof.
In the present specification, C2-6 alkynene means ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and isomers thereof.
In the present specification, C2-5 acyl means acetyl, propionyl, butyryl, valeryl and isomers thereof.
In the present specification, a halogen atom is chlorine, bromine, fluorine or iodine.
In the present specification, C3-8 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
In the present specification, C1-8 hydroxyalkyl means hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, hydroxyheptyl, hydroxyoctyl and isomers thereof.
In the present specification, C1-4 alkyl substituted by phenyl means phenylmethyl, phenylethyl, phenylpropyl and phenylbutyl.
In the present specification, C1-4 alkyl substituted by cyano means cyanomrethyl, cyanoethyl, cyanopropyl and cyanobutyl.
In the present specification, C1-4 alkyl substituted by trihalomethyl means methyl, ethyl, propyl or butyl substituted by trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl.
In the present specification, C3-15 membered mono-, bi- or tricarbocyclic ring includes a C3-15 membered mono-, bi- or tricarbocyclic aryl, partially saturated or fully saturated one; for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene, pentalene, indene, naphthalene, azulene, fluorene, phenanthrene, anthracene, acenaphthylene, biphenylene, perhydropentalene, perhydroindene, perhydronaphthalene, perhydroazulene, perhydrofluorene, perhydrophenanthrene, perhydroanthracene, perhydroacenaphthylene, perhydrobiphenylene, adamantane etc.
In the present specification, 5-15 membered mono-, bi- or tricyclic heterocyclic ring containing 1-4 of nitrogen, 1-2 of oxygen and/or 1 of sulfur includes 5-15 membered mono-, bi- or tricyclic heterocyclic aryl, partially saturated or fully saturated one containing 1-4 of nitrogen, 1-2 of oxygen and/or 1 of sulfur.
Above-mentioned 5-15 membered mono-, bi- or tricyclic heterocyclic aryl containing 1-4 of nitrogen, 1-2 of oxygen and/or 1 of sulfur represents pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, oxazepine, thiophene, thiin (thiopyran), thiepin, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, carbazole, acridine, etc.
Above-mentioned 5-15 membered mono-, bi- or tricyclic heterocyclic ring which is partially saturated or fully saturated, containing 1-4 of nitrogen, 1-2 of oxygen and/or 1 of sulfur represents pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiine (dihydrothiopyran), tetrahydrothiine (tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, benzoxazepine, benzoxadiazepine, benzothiazepine, benzothiadiazepine, benzazepine, benzodiazepine, indoloxazepine, indolotetrahydrooxazepine, indolooxadiazepine, indolotetrahydrooxadiazepine, indolothiazepine, indolotetrahydrothiazepine, indolothiadiazepine, indolotetrahydrothiadiazepine, indoloazepine, indolotetrahydroazepine, indolodiazepine, indolotetrahydrodiazepine, benzofurazan, benzothiadiazole, benzotriazole, camphor, imidazothiazole, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, tetrahydroacridine, perhydroacridine, dioxolane, dioxane, dioxazine, etc.
In the present invention, as may be easily understood by those skilled n the art, the symbol:

indicates that the substituent attached thereto is in front of the sheet (xcex2-position), unless otherwise specified, the symbol:

indicates that the substituent attached thereto is behind the sheet (xcex1-position), unless otherwise specified, the symbol:

indicates that the substituent attached thereto is xcex2-position or xcex1-position (though it is single isomer that it attached thereto is either xcex2-position or xcex1-position, the structure is not determined), the symbol:

indicates the mixture of the compounds that the substituent attached thereto is xcex2-position and xcex1-position.
In the formula (I), ring A is preferably C3-15 membered mono-, bi- or tricarbocyclic ring, more preferably C3-7 membered monocarbocyclic ring, even more preferably benzene, cyclopentane, cyclohexane or cycloheptane, most preferably benzene.
In the formula (I), R3 and R4 are preferably that each, independently, is hydrogen atom or C1-8 alkyl, more preferably C1-4 alkyl, and most preferably that each, independently, is hydrogen atom and methyl.
In the formula (I), when one of R3 and R4 is a hydrogen atom and the ther is not a hydrogen atom, then the former is preferably attached to the xcex1-position (behind the sheet), and the latter is preferably attached to the xcex2-position (in front of the sheet).
In the formula (I), E is preferably xe2x80x94NR7COxe2x80x94, xe2x80x94NR7SO2xe2x80x94, xe2x80x94NR7CONR8xe2x80x94, or xe2x80x94NR7COOxe2x80x94, more preferably xe2x80x94NR7COxe2x80x94 or xe2x80x94NR7COOxe2x80x94 (wherein all symbols are the same meaning as hereinbefore defined), and most preferably xe2x80x94NHCOxe2x80x94 or xe2x80x94NHCOOxe2x80x94.
In the formula (I), E may be attached xcex1-position or xcex2-position, preferably xcex2-position (in front of the sheet).
In the formula (I), R1 is preferably C1-20 alkyl, more preferably C5-10 alkyl, and most preferably heptyl.
In the formula (I), R2 is prepreably C1-8 alkyl, C1-8 alkoxy, C1-8 alkylthio or COOR20 (R20 is the same meaning as hereinbefore defined), more preferably C1-4 alkoxy, C1-4 alkylthio, COOR200 (R200 is C1-4alkyl), and most preferably methoxy, isopropyloxy, methylthio or methoxycarbonyl.
In the formula (I), when benzene ring is substituted by R2, then the position of substitution is preferably 3-position.
In the formula (I), n is preferably 0-5, and more preferably 0-2.
Concretely, the compounds that hereinafter described in the examples and the compounds in the following tables 1-89 are preferably. Besides, in the following tables, the numbers described before each group represent the position of substitution, Me is methyl group, Et is ethyl group, Ph is phenyl group and Py is pyridyl group.
Unless otherwise specified, all isomers are included in the present invention. For example, alkyl, alkoxy, alkylthio, alkenyl, alkynyl and alkylene include straight and branched isomers. Isomers in the double bonds, rings, fused rings (E, Z, cis, trans isomers), isomers generated by the existence of asymmetric carbon atom(s) (R, S isomers, xcex1, xcex2 isomers, enantiomers, diastereomers), optically active isomers having optically rotatory power (D, L, d, I isomers, +, xe2x88x92 isomers), polar isomers separated by chromatography (more polar, less polar isomers), equilibrium compounds, arbitrary ratios of these compounds, racemic mixtures are all included in the present invention. Optically active isomers of formula (I) in the present invention may be obtained by general methods of optically separation (for example, separation by gas chromatography or high performance liquid chromatography, separation by crystallization as diastereomeric salts or clathrates, separation by prior crystallization etc.) or may be prepared by general methods of asymmetric synthesis.
[Salt]
The compounds of formula (I) of the present invention may be converted into the corresponding salts by conventional method. Non-toxic and water-soluble salts are preferred. Suitable salts, for example, include: salts of alkali metals (e.g. potassium, sodium, etc.), salts of alkaline earth metals (e.g. calcium, magnesium, etc.), ammonium salts, salts of pharmaceutically acceptable organic amines (e.g. tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine, N-methyl-D-glucamine, etc.). Salts of alkali metals are preferably.
The compounds of formula (I) of the present invention and salts thereof may be converted into the corresponding hydrates by conventional means.
[Processes for the Preparation of the Compound of the Present Invention]
The compounds of formula (I) of the present invention may be prepared by following, described in example or known methods.
(1) In the compounds of the formula (I), the compounds in which all of R1 and R2 do not contain carboxyl, hydroxy or amino, and all of R3 and R4 do not contain hydroxy, that is the compounds of the formula (IA)
wherein R1a and R2a are the same meaning as R1 and R2 respectively, provided that, when at least one of R1 and R2 represent contain carboxyl, hydroxy or amino, then each carboxyl, hydroxy or amino is protected by protective group, R3a and R4a are the same meaning as R3 and R4 respectively, provided that, when at least one of R3 and R4 represent contain hydroxy, then the hydroxy is protected by protective group, and the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by following method (1-1), (1-2) or (1-3).
(1-1) In the compounds of the formula (IA), the compounds in which all of R5 and R6 do not represent a hydrogen atom, that is the compounds of the formula (IA-1)
wherein R50 and R60 each, independently, is C1-8 alkyl, phenyl, C1-4 alkyl substituted by phenyl, C1-4 alkyl substituted by trihalomethyl or C1-4 alkyl substituted by cyano,
xe2x80x83may be prepared by reacting the formula (X-1)
wherein all symbols are the same meaning as hereinbefore defined
xe2x80x83with the compound of the formula (X-2)
wherein X is a halogen atom or hydroxy, and the other symbols are the same meaning as hereinbefore defined.
The reaction of the compound of the formula (X-1) with the compound of the formula (X-2) is known per se, for example, when X is a halogen atom, then the reaction may be carried out in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine , etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.), at a temperature of from 0xc2x0 C. to 40xc2x0 C. When X is hydroxy, then the reaction may be carried out in the presence of an azo compound (diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1xe2x80x2-(azodicarbonyl)dipiperidine, 1,1xe2x80x2-azobis(N,N-dimethylformamide), etc.) and a phosphine compound (triphenylphosphine, tributylphosphine, trimethylphosphine, etc.) in an inert organic solvent (methylene chloride, diethyl ether, tetrahydrofuran, acetone, benzene, toluene, etc. ), at a temperature of from 0xc2x0 C. to 60xc2x0 C.
In the compounds of the formula (IA-1), the compounds in which all of R1a and R2a do not contain xe2x80x94Sxe2x80x94 or xe2x80x94S(O)xe2x80x94, that is the compounds of the formula (IA-1-X)
wherein R1a-x and R2a-x are the same meaning as R1a and R2a, with the proviso that, all of R1a and R2a do not contain xe2x80x94Sxe2x80x94 and xe2x80x94S(O)xe2x80x94, and other symbols are the same meaning as hereinbefore defined
may be prepared by reacting the compound of the formula (X-1-X),
wherein all symbols are the same meaning as hereinbefore defined
which in the compound of the formula (X-1), all of R1a and R2a do not contain xe2x80x94Sxe2x80x94 and xe2x80x94S(O)xe2x80x94 with the compound of the formula (X-3)
wherein R12 and R13 each, independently, is C1-8 alkyl, and the other symbols are the same meaning as hereinbefore defined
followed by oxidation.
The reaction of the compound of the formula (X-1-X) with the compound of the formula (X-3) may be carried out in the presence of tetrazole in an inert organic solvent (acetonitrile, tetrahydrofuran, diethyl ether, methylene chloride, chloroform, etc.), at a temperature of from 0xc2x0 C. to 40xc2x0 C.
Above-mentioned oxidation may be carried out in a solvent (acetonitrile, methylene chloride, water, etc.) in the presence of oxidant (3-chloroperoxybenzoic acid, iodine, hydrogen peroxide, t-butyl hydroperoxide, 3H-1,2-benzothiol-3-one 1,1-dioxide, etc.) at a temperature of from 0xc2x0 C. to 40xc2x0 C.
(1-2) In the compounds of the formula (IA), in which R5 and R6 are a hydrogen atom, that is the compounds of the formula (IA-2)
wherein all symbols are the same meaning as hereinbefore defined may be prepared by subjecting to a deprotection reaction of the protective group for phosphoric acid.
The deprotection reaction of the protective group for phosphoric acid is known per se, for example,
(a) Elimination of C1-2 alkyl may be carried out in an organic solvent (chloroform, etc.) in the presence of trimethylsilyl halide (trimethylsilyl chloride, trimethylsilyl bromide or trimethylsilyl iodide, etc.) in the presence or absence of alkali metal iodide (sodium iodide or potassium iodide, etc.) at a temperature of from 0xc2x0 C. to 40xc2x0 C.
(b) Elimination of phenyl may be carried out under an atmosphere of hydrogen, in an organic solvent (methanol, ethanol or tetrahydrofuran, etc.) or without a solvent in the presence of catalyst (platinum dioxide, etc.), and in the presence or absence of organic acid (acetic acid, etc.) or inorganic acid (hydrochloric acid, etc.) for 24 hours to 3 days at a temperature of from 0xc2x0 C. to 50xc2x0 C.
(c) Elimination of benzyl may be carried out under an atmosphere of hydrogen, in an organic solvent (methanol, ethanol, tetrahydrofuran, pyridine or acetic acid, etc.) in the presence of catalyst (palladium-carbon, palladium black or palladium hydroxide, etc.) at a temperature of from 0xc2x0 C. to 50xc2x0 C.
(d) Elimination of 2,2,2-trichloroethyl may be carried out in an organic solvent (methanol, ethanol or tetrahydrofuran, etc.) or without a solvent, using zinc powder and organic acid (acetic acid, etc.) or inorganic acid (hydrochloric acid, etc.) at a temperature of from 0xc2x0 C. to 50xc2x0 C.
The compounds in which R1a represent contains alkenyl or alkynyl ay be prepared by subjecting to a deprotection reaction that above-mentioned method (a) or (d).
The compound in which R1a dose not contain alkenyl or alkynyl may be prepared by subjecting to a deprotection reaction that above-mentioned method from (a) to (d). With the proviso that, when Cyc1 and/or A ring represented by R1 is carbocyclic aryl or heterocyclic aryl, then the compound may be prepared by subjecting to a deprotection reaction that above-mentioned method (a) or (c)xcx9c(d), and when nitro is containing in R1 or R2, then the compound may be prepared by subjecting to a deprotection reaction that above-mentioned method (a) or (d).
(1-3) In the compounds of the formula (IA), the compounds in which one of R5 or R6 is a hydrogen atom and the other is not a hydrogen atom, that is the compounds of the formula (IA-3)
wherein one of R51 or R61 is a hydrogen atom and the other is C1-8 alkyl, phenyl, C1-4 alkyl substituted by phenyl, C1-4 alkyl substituted by trihalomethyl or C1-4 alkyl substituted by cyano, and the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by following method (1-3-a) or (1-3-b).
(1-3-a) The compound of the formula (IA-3) may be prepared by subjecting to a deprotection reaction of the protective group for phosphoric acid of the compound of the formula (IA-1) hereinbefore described.
This deprotection reaction of the protective group for phosphoric acid may be carried out under some condition hereinafter described, and depends on the protective group, for example,
(1) in organic solvent (diethyl ether, methanol, tetrahydrofuran or dioxane, etc.) using hydroxide of alkali metal (sodium hydroxide or potassium hydroxide, etc.) or an aqueous solution thereof or a mixture thereof at a temperature of from 0xc2x0 C. to 40xc2x0 C.,
(2) in organic solvent (tetrahydrofuran or pyridine, etc.), using t-butylamine or tetrabutylammonium hydroxide at a temperature of from 0xc2x0 C. to 100xc2x0 C., or
(3) in organic solvent (2-ethoxyethanol or acetone, etc.), using lithium halide (lithium chloride or lithium bromide, etc.) under reflux condition.
(1-3-b) In the compounds of formula (IA-3), the compounds in which one of R51 or R61 is a hydrogen and the other is phenyl, R1a does not contain alkenyl or alkynyl, that is the compounds of the formula (IA-3-B)
wherein Ph is phenyl, R1a-b is the same meaning as R1a, provided that, R1a does not contain alkenyl or alkynyl, and the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by subjecting to a deprotection reaction of the protective group for phosphoric acid of the compound of the formula (IA-1-B)
wherein all symbols are the same meaning as hereinbefore defined.
The elimination reaction of protective group for phosphoric acid may be carried out under an atmosphere of hydrogen, in an organic solvent (methanol, ethanol, tetrahydrofuran, etc.) or without a solvent in the presence of catalyst (platinum dioxide, etc.), in the presence or absence of organic acid (acetic acid, etc.) or inorganic acid (hydrochloric acid, etc.) for 1-3 hours at a temperature of from 0xc2x0 C. to 50xc2x0 C.
(I-4) In the compound of formula (IA), the compounds in which one of R1a or R2a represent contains xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94, that is the compounds of the formula (IA-4)
wherein R1a-c and R2a-c are the same meaning as R1a and R2a, respectively, provided that, one of R1a or R2a represent contains xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94, and the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by oxidation among the compound of formula (IA-1), (IA-2) or (IA-3) hereinbefore described, the compounds in which one of R1a or R2a represent contains xe2x80x94Sxe2x80x94, that is the compounds of the formula (IA-5).
wherein R1a-d and R2a-d are the same meaning as R1a and R2a, respectively, provided that, one of R1a or R2a represent contains xe2x80x94Sxe2x80x94, and the other symbols are the same meaning as hereinbefore defined.
The oxidation is known per se, and may be carried out, for example, in suitable organic solvent (methylene chloride, chloroform, benzene, hexane, t-butylalcohol, etc.) in the presence of oxidant (hydrogen peroxide, sodium periodate, acyl nitrites, sodium perborate, a peroxide (for example, 3-chloroperbenzoic acid or peroxiacetic acid, etc.), potassium peroxomonosulfate, potassium permanganate, chromic acid, etc.) at a temperature of from 20xc2x0 C. to 60xc2x0 C.
Above-mentioned the compounds of the formula (X-1) may be prepared by the method described in the following reaction scheme 1.
In the scheme, all symbols are the same meaning as hereinbefore defined, and all reaction may be carried out as the methods hereinafter described in (1A-1-a), (1A-1-b), (1A-1-c), (1A-1-d-1), (1A-1-d-2), (1A-1-e) and (1A-1-f).
In the compounds of the formula (IA-1), the compounds in which E is not xe2x80x94CONR7xe2x80x94 or xe2x80x94CSNR7xe2x80x94, i.e. xe2x80x94NR7COxe2x80x94, xe2x80x94NR7SO2xe2x80x94, xe2x80x94NR7CONR8xe2x80x94, xe2x80x94NR7COOxe2x80x94, xe2x80x94NR7CSxe2x80x94, xe2x80x94NR7CSNR8xe2x80x94, xe2x80x94NR7CSxe2x80x94Oxe2x80x94 or xe2x80x94NR7xe2x80x94 may be prepared by the method described in the following (1A-1-a), (1A-1-b), (1A-1-c), (1A-1-d-1), (1A-1-d-2), (1A-1-e) or (1A-1-f.
(1A-1-a) In the compounds of the formula (IA-1), the compounds in which E is xe2x80x94NR7COxe2x80x94, that is the compounds of the formula (IA-1-A)
wherein E1 is xe2x80x94NR7COxe2x80x94, the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by amidation of the compound of the formula (X-5)
wherein all symbols are the same meaning as hereinbefore defined with the compound of the formula (X-6A)
R1axe2x80x94COOHxe2x80x83xe2x80x83(X-6A)
xe2x80x83wherein all symbols are the same meaning as hereinbefore defined.
The amidation is known per se and can be carried out by methods for example:
1) using an acid halide,
2) using a mixed acid anhydride,
3) using a condensing agent (EDC, DCC, etc.), etc.
These methods are explained as follows.
1) The method using an acid halide may be carried out, for example, by reacting a carboxylic acid with an acid halide (oxalyl chloride or thionyl chloride, etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.) or without a solvent at from xe2x88x9220xc2x0 C. to the reflux temperature of the solvent, and then by reacting the acid halide obtained with a corresponding amine in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine, etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.), at a temperature of from 0xc2x0 C. to 40xc2x0 C.
Besides, the reaction may be carried out in an organic solvent (dioxane, tetrahydrofuran, etc.), using aqueous solution of hydroxide or carbonate of alkali metal (an aqueous solution of sodium bicarbonate, an aqueous solution of sodium hydroxide, etc.) with acid halide at a temperature of from 0xc2x0 C. to 40xc2x0 C.
2) The method using a mixed acid anhydride may be carried out, for example, by reacting a carboxylic acid and an acid halide (pivaloyl chloride, tosyl chloride or mesyl chloride, etc.) or an acid derivative (ethyl chloroformate or isobutyl chloroformate, etc.) in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine, etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.) or without a solvent at a temperature of from 0xc2x0 C. to 40xc2x0 C., and then by reacting the mixture of acid anhydride obtained with a corresponding amine in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.), at a temperature of from 0xc2x0 C. to 40xc2x0 C.
3) The method using a condensing agent may be carried out, for example, by reacting a carboxylic acid with a corresponding amine using a condensing agent (1,3-dicyclohexyl carbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1xe2x80x2-carbonyldiimidazole (CDI) or 2-chloro-1-methylpyridinium iodide, etc.) in the presence or absence of a tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine, etc.) in an inert organic solvent (chloroform, methylene chloride, dimethyl formamide, diethyl ether or tetrahydrofuran, etc.) or without a solvent, in the presence or absence of 1-hydroxybenztriazole (HOBt) at a temperature of from 0xc2x0 C. to 40xc2x0 C.
These reactions 1), 2) and 3) hereinbefore described may be preferably carried out in an atmosphere of inert gas (argon or nitrogen , etc.) under anhydrous conditions.
(1A-1-b) In the compounds of the formula (IA-1), the compounds in which E is xe2x80x94NR7COOxe2x80x94, that is the compounds of the formula (IA-1-B)
wherein E2 is xe2x80x94NR7COOxe2x80x94, the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by reaction for forming urethane of the compounds of the formula (X-5) with the compounds of the formula (X-6B)
R1axe2x80x94OCOxe2x80x94X1xe2x80x83xe2x80x83(X-6B)
wherein X1 is a halogen atom, the other symbols are the same meaning as hereinbefore defined.
The reaction for forming urethane of the compounds of (X-5) with the compounds of the formula (X-6B) may be carried out as the same methods which above-mentioned 1) using an acid halide of amidation.
(1A-1-c) In the compounds of the formula (I), the compounds in which E is xe2x80x94NR7SO2xe2x80x94, that is the compounds of the formula (IA-1-C)
wherein E3 is xe2x80x94NR7SO2xe2x80x94, the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by sulfonamidation of the compounds of the formula (X-5) hereinbefore described with the compounds of the formula (X-6C)
R1axe2x80x94SO2Clxe2x80x83xe2x80x83(X-6C)
xe2x80x83wherein all symbols are the same meaning as hereinbefore defined.
The sulfonamidation is known per se and can be carried out, for example, using sulfonyl halide in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine, etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.) at a temperature of from 0xc2x0 C. to 40xc2x0 C.
(1A-1-d-1) In the compounds of the formula (I), the compounds in which E is xe2x80x94NR7CONR8xe2x80x94 or xe2x80x94NR7CSNR8xe2x80x94, that is the compounds of the formula (IA-1-D-1)
wherein E4 is xe2x80x94NR7CONR8xe2x80x94 or xe2x80x94NR7CSNR8xe2x80x94, the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by reacting the compounds of the formula (X-5) hereinbefore described with the compounds of the formula (X-6D-A)
R1axe2x80x94NHR8xe2x80x83xe2x80x83(X-6D-A)
xe2x80x83wherein all symbols are the same meaning as hereinbefore defined and the compound of the formula (X-6D-B)
wherein T is an oxygen atom or a sulfur atom.
The reaction using the compounds of the formulae (X-5), (X-6D-A) and (X(-6D-B) can be carried out by known method, for example, in an organic solvent (N,N-dimethylformamide, methylene chloride or tetrahydrofuran, etc.) in the presence or absence of an amine (triethylamine, pyridine, dimethylaniline or dimethylaminopyridine, etc.) at a temperature of from 0xc2x0 C. to 80xc2x0 C.
(1A-1-d-2) In the compounds of the formula (I), the compounds in which E is xe2x80x94NR7CONR8xe2x80x94, that is the compounds of the formula (IA-1-D-2)
wherein E44 is xe2x80x94NR7CONR8xe2x80x94, the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by reacting the compounds of the formula (X-5) hereinbefore described with the compounds of the formula (X-6D-C)
R1axe2x80x94Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83(X-6D-C)
xe2x80x83wherein all symbols are the same meaning as hereinbefore defined or the compounds of the formula (X-6D-D)
wherein X2 is a halogen atom, the other symbols are the same meaning as hereinbefore defined.
The reaction of the compounds of the formula (X-5) and (X-6D-C), or the reaction of the compounds of the formula (X-5) and (X-6D-D) are known per se, and can be carried out, for example, in an organic solvent (acetone, chloroform, methylene chloride, benxene or tetrahydrofuran, etc.) in the presence or absence of a tertiary amine (triethylamine, pyridine, dimethylaniline, dimethylaminopyridine, etc.) at a temperature of from 0xc2x0 C. to 80xc2x0 C., or as the same methods which above-mentioned 1) using an acid halide of amidation.
(1A-1-e) In the compounds of the formula (I), the compounds in which E is xe2x80x94NR7xe2x80x94, that is the compounds of the formula (IA-1-E)
wherein E5 is xe2x80x94NR7xe2x80x94, the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by reacting the compounds of the formula (X-5) hereinbefore described with the compounds of the formula (X-6E)
X3xe2x80x94R1axe2x80x83xe2x80x83(X-6E)
xe2x80x83wherein X3 is a halogen atom or hydroxy, the other symbols are the same meaning as hereinbefore defined.
The reaction of the compounds of the formula (X-5) with the compounds of the formula (X-6E) is N-alkylation or corresponding one. For example, when X3 is a halogen atom, then the reaction may be carded out in an organic solvent (N,N-dimethylformamide or tetrahydrofuran, etc.) in the presence of a base (sodium hydride, butyl lithium, lithium diisopropylamide, etc.) at a temperature of from 0xc2x0 C. to 80xc2x0 C. And when X3 is hydroxy, then the reaction may be carried out in an organic solvent (methylene chloride, diethyl ether, tetrahydrofuran, acetone, benzene, toluene, etc.) in the presence of an azo compound (diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1xe2x80x2-(azodicarbonyl)dipiperidine, 1,1xe2x80x2-azobis(N,N-dimethylformamide), etc.) and a phosphine compound (triphenylphosphine, tributylphosphine, trimethylphosphine, etc.) at a temperature of from 0xc2x0 C. to 60xc2x0 C.
(1A-1-f) In the compounds of the formula (I), the compounds in which E is xe2x80x94NR7CSxe2x80x94, xe2x80x94NR7CSxe2x80x94Oxe2x80x94 or xe2x80x94NR7CSNR8xe2x80x94, that is the compounds of the formula (IA-1-F)
wherein E6 is xe2x80x94NR7CSxe2x80x94, xe2x80x94NR7CSxe2x80x94Oxe2x80x94 or xe2x80x94NR7CSNR8xe2x80x94, the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by reacting the compounds of the formula (IA-1-A), (IA-1-B) or (IA-1-D-2) hereinbefore described, that is the compounds of the formula (IA-1-FF)
wherein E66 is xe2x80x94NR7COxe2x80x94, xe2x80x94NR7COOxe2x80x94 or xe2x80x94NR7CONR8xe2x80x94, the other symbols are the ame meaning as hereinbefore defined
xe2x80x83with Lawesson""s Reagent of the formula (X-6F)
The reaction using Lawesson""s Reagent is known per se, and can be carried out in an organic solvent (dioxane, benzene, toluene or xylene, etc.), using Lawesson""s reagent at a temperature of from 20xc2x0 C. to 150xc2x0 C. This reaction may be preferably carried out in an atmosphere of inert gas (argon or nitrogen, etc.) under anhydrous conditions.
(2) In the compounds of the formula (I), the compounds in which at least one of R1, R2, R3 or R4 represent contains carboxyl, hydroxy or amino, that is the compound of the formula (IB)
wherein R1b, R2b, R3b or R4b is the same meaning as R1, R2, R3 or R4, respectively, provided that, at least one of them is a group containing carboxyl, hydroxy or amino
xe2x80x83may be prepared by the method described in the following (2-1), (2-2) or (2-3).
(2-1) In the compounds of the formula (IB), the compounds in which all of R5 and R6 is hydrogen atom, that is the compounds of the formula (IB-1)
wherein all symbols are the same meaning as hereinbefore defined may be prepared by subjecting to a deprotection reaction a compound, among the compound of the formula (IA-1), which contains at least one protected carboxyl, hydroxy or amino, i.e. the compound of the formula (IA-1-Y)
wherein R1a-y, R2a-y, R3a-y and R4a-y is the same meaning as R1a, R2a, R3a and R4a, provided that, at least one of them represent contains protected carboxyl, hydroxy or amino, the other symbols are the same meaning as hereinbefore defined.
Each deprotection reaction of protective group for phosphoric acid, carboxyl, hydroxy or amino is known well and means a comprehensive deprotection reaction easily understood by those skilled in the art, for example, alkali hydrolysis, deprotection reaction under acidic condition, deprotection reaction by hydrogenation or deprotection reaction of a group containing silyl. The desired compounds of the present invention can be easily prepared by these reactions.
Each deprotection reaction of protective group for phosphoric acid, carboxyl, hydroxy or amino are explained.
As should be easily understood by those skilled in the art, for example, methyl, ethyl, t-butyl and benzyl are included in the protective groups for carboxyl, but other groups that can be easily and selectively eliminated may also be used instead. For example, the groups described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991 may be used.
For example, methoxymethyl, tetrahydropyranyl, t-butyldimethylsilyl, acetyl and benzyl are included in the protective groups for hydroxy, but other groups that can be easily and selectively eliminated may also be used instead. For example, the groups described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991 may be used.
For example, benzyloxycarbonyl, t-butoxycarbonyl and trifluoroacetyl are included in the protective groups for amino but other groups that can be easily and selectively eliminated may also be used instead. For example, the groups described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991 may be used.
Deprotection reaction by alkali hydrolysis is known, for example, it is carried out in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.) using hydroxide of alkali metal (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), hydroxide of alkaline earth metal (barium hydroxide, calcium hydroxide, etc.) or carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof at a temperature of from 0xc2x0 C. to 40xc2x0 C.
Deprotection reaction under acidic conditions is known, for example, it is carried out in an organic solvent (methylene chloride, chloroform, dioxane, ethyl acetate, anisole, etc.), in organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, trimethylsilyl iodide etc.) or inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrobromic acid-acetic acid etc.) at a temperature of from 0xc2x0 C. to 100xc2x0 C.
Deprotection reaction by hydrogenation is known, for example, it is carried out in an inert solvent [ether (e.g. tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol (e.g. methanol, ethanol, etc.), benzene (e.g. benzene, toluene, etc.), ketone (e.g. acetone, methylethylketone, etc.), nitrile (e.g. acetonitrile etc.), amide (e.g. dimethylformamide etc.), water, ethyl acetate, acetic acid or a mixture of two or more thereof], in the presence of hydrogenating catalyst (e.g. palladium-carbon, palladium black, palladium hydroxide, platinum dioxide, Raney-nickel, etc.) under normal atmosphere or suppressed atmosphere of hydrogen or in the presence of ammonium formate, at a temperature of from 0xc2x0 C. to 200xc2x0 C.
Deprotection reaction of silyl group is known, for example, it is carried out in a water-soluble organic solvent (tetrahydrofuran, acetonitrile, etc.), using tetrabutylammonium fluoride at a temperature of from 0xc2x0 C. to 40xc2x0 C.
(2-2) In the compounds of the formula (IB), the compound in which all of R5 and R6 are hydrogen atom, that is the compound of the formula (IB-2)
wherein all symbols are the same meaning as hereinbefore defined may be prepared by subjecting to a deprotection reaction a compound, among the compound of the formula (IA-2) hereinbefore described, which contains at least one protected carboxyl, hydroxy or amino, i.e. the compound of the formula (IA-2-Y)
xe2x80x83all symbols are the same meaning as hereinbefore defined.
The deprotection reaction is carried out as the same method hereinbefore described.
(2-3) In the compounds of the formula (IB), the compounds in which one of R5 and R6 is a hydrogen atom, and the other is not a hydrogen atom, that is the compounds of the formula (IB-3)
wherein all symbols are the same meaning as hereinbefore defined may be prepared by subjecting to a deprotection reaction a compound, among the compound of the formula (IA-3) hereinbefore described, which contains at least one protected carboxyl, hydroxy or amino, i.e. the compound of the formula (IA-3-Y)
xe2x80x83all symbols are the same meaning as hereinbefore defined.
The deprotection reaction is carried out as the same method hereinbefore described.
The compounds of the formula (X-5) may be prepared by the method described in the following reaction scheme 2.
In the scheme, X4 is a halogen atom or hydroxy, Q is a protective group for amino, the other symbols are the same meaning as hereinbefore defined.
In the reaction scheme 2, the compounds in which R2a does not contain xe2x80x94Sxe2x80x94 or xe2x80x94S(O)xe2x80x94, among the compound of the formula (X-10), that is the compounds of the formula (X-10-A)
wherein R2a-a is the same meaning as R2a, provided that its does not contain xe2x80x94Sxe2x80x94 or xe2x80x94S(O)xe2x80x94, the other symbols are the same meaning as hereinbefore defined.
In the scheme, all symbols are the same meaning as hereinbefore defined.
In each reaction described in the present specification, reaction products may be purified by conventional techniques. For example, purification may be carried out by distillation at atmospheric or reduced pressure, by high performance liquid chromatography, thin layer chromatography or column chromatography using silica gel or magnesium silicate, by washing or by recrystallization, etc. Purification may be carried out after each reaction, or after a series of reactions.
The starting materials and agents in the present invention are known per se (commercially available), or may be prepared by conventional method.
For example, in the compound of the formula (X-8), 2-amino-2-phenylethanol ((R)-(xe2x88x92)-2-phenyl glycinol, (S)-(+)-2-phenyl glycinol) is known as CAS No. 56613-80-0 (R form) and 20989-17-7(S form), and (1R,2S)-(+)-cis-1-amino-2-indanol and (1S,2R)-(xe2x88x92)-cis-1-amino-2-indanol are known as CAS No. 136030-00-7 and 126456-43-7, respectively.
Besides, 2-amino-2-phenyl-1,1-propanoethanol may be prepared according to the method described in the literature (Larry R. Kpepski et al., SYNTHESIS, 301,(1986)) from cyclobutanone as a starting material.
(1S,2R)-1-methyl-2-phenylethanol, (1R,2S)-1-methyl-2-phenylethanol, (1R,2R)-1-methyl-2-phenylethanol, and (1S,2S)-1-methyl-2-phenylethanol may be prepared according to the method described in the literatures ( K. Barry Sharpless et al., Tetrahedron Lett. 37(19), 3219(1996), von Vladimir Prelog et.al., Helvetica Chimca Acta 66(7), 2274,(1983), Christian R. Noe et.al., Monatsh Chem., 122(4), 283(1991)).
Pharmacological Activities
Because of having a TNFxcex1 production inhibitory effect, the compounds represented by general formula (I) are useful as preventives and/or remedies of various diseases induced by inflammatory cytokines including TNFxcex1 (example for rheumatoid arthritis, ulcerative colitis, Crohn""s disease, hepatitis, sepsis, hemorrhagic shock, multiple sclerosis, cerebral infarction, diabetes, interstitial pneumonia, uveitis, pain, glomerulonephritis, HIV-associated diseases, cachexia, myocardial infarction, chronic heart failure, oral aphtha, Hansen""s disease, infection, etc.). It has been confirmed that the compounds of the present invention of the formula (I) possess a TNFxcex1 production inhibitory effect by the following experimental results.
(i) Measure of TNFxcex1 Production Inhibitory Activity
Measure of TNFxcex1 production inhibitory activity was prepared according to procedures described previously (Kazuo Ohuchi, SEIBUTSUKAGAKUJIKKENKOZA, 12, 707 (1994) Hirokawa, Tokyo). Female mice (BALB/c, 7 weeks) were injected with test compounds via intravenous administration and with LPS (100 xcexcg/mouse) (Bacto W. E. coli 055:B5; DIFCO Lab.) via in traperitoneal administration. At 90 minutes after LPS challenge, blood with heparin was obtained from abdominal aorta, and serum was stored at xe2x88x9280xc2x0 C. Serum level of TNFxcex1 was determined by mouse cytokine ELISA kit (Genzyme). Inhibition and 50% effective dose (ED50) of test compounds were calculated as 100% of the difference of serum level of TNFxcex1 between in control and in LPS. ED50 of some compounds produced by the following examples were 0.01-100 mg/kg. For examples, ED50 of (2R)-2-phenyl-2-(N-octanoylamino)ethylphosphate.2Na (the compound of example 8) was 2.6 mg/kg.
Toxicity
The toxicity of the compounds of the present invention is very low and therefore the compounds may be considered safe for pharmaceutical use.
Application for Pharmaceuticals
Because of having a TNFxcex1 production inhibitory effect, the compounds represented by general formula (I) are useful as preventives and/or remedies for rheumatoid arthritis, ulcerative colits, Crohn""s disease, hepatitis, sepsis, hemorrhagic shock, multiple sclerosis, cerebral infarction, diabetes, interstitial pneumonia, uveitis, pain, glomerulonephritis, HIV-associated diseases, cachexia, myocardial infarction, chronic heart failure, oral aphtha, Hansen""s disease, infection, etc.
For the purpose above described, the compounds of formula (I) of the present invention and non-toxic salts thereof, acid addition salts thereof and hydrates thereof may normally be administered systemically or locally, usually by oral or parenteral administration.
The doses to be administered are determined depending upon age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment etc. In the human adult, the doses per person per dose are generally between 1 mg and 1000 mg, by oral administration, up to several times per day, and between 0.1 mg and 100 mg, by parenteral administration (preferred into vein) up to several times per day, or continuous administration between 1 and 24 hrs. per day into vein.
As mentioned above, the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.
The compounds of the present invention may be administered as inner solid compositions or inner liquid compositions for oral administration, or as injections, liniments or suppositories etc. for parenteral administration.
Inner solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders and granules etc. Capsules contain hard capsules and soft capsules.
In such inner solid compositions, one or more of the active compound(s) is or are, admixed with at least one inert diluent (lactose, mannitol, glucose, microcrystalline cellulose, starch etc.), connecting agents (hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium metasilicate aluminate etc.), disintegrating agents (cellulose calcium glycolate etc.), lubricating agents (magnesium stearate etc.), stabilizing agents, assisting agents for dissolving (glutamic acid, asparaginic acid etc.) etc. to prepare pharmaceuticals by known methods. The pharmaceuticals may, if desired, be coated with material such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropyl cellulose phthalate etc., or be coated with two or more films. And further, coating may include containment within capsules of absorbable materials such as gelatin.
Inner liquid compositions for oral administration include pharmaceutically-acceptable water-agents, suspensions, emulsions, syrups and elixirs etc. In such liquid compositions, one or more of the active compound(s) is or are comprised in inert diluent(s) commonly used in the art (purified water, ethanol or mixture thereof etc.). Besides inert diluents, such compositions may also comprise adjuvants such as wetting agents, suspending agents, emulsifying agents, sweetening agents, flavouring agents, perfuming agents, preserving agents and buffer agents etc.
Injections for parenteral administration include solutions, suspensions and emulsions and solid injections which are dissolved or suspended in solvent when it is used. One or more active compound(s) is or are dissolved, suspended or emulsified in a solvent when such compositions are used. Aqueous solutions or suspensions include distilled water for injection and physiological salt solution, plant oil, propylene glycol, polyethylene glycol and alcohol such as ethanol etc., and mixture thereof. Such compositions may comprise additional diluents such as stabilizing agent, assisting agents for dissolving (glutamic acid, asparaginic acid, POLYSOLBATE80 (registered trade mark) etc.), suspending agents, emulsifying agents, dispersing agents, buffer agents, preserving agents etc. They may be sterilized for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile solid compositions and which can be dissolved in sterile water or some other sterile diluent for injection immediately before use.
Other compositions for parenteral administration include liquids for external use, ointments, endermic liniments, aerosols, spray compositions, suppositories and pessaries for vaginal administration etc. which comprise one or more of the active compound(s) and may be prepared by known methods.
Spray compositions may comprise additional substances other than inert diluents: e.g. stabilizing agents such as sodium hydrogen sulfate, stabilizing agents to give isotonicity, isotonic buffer such as sodium chloride, sodium citrate, citric acid. For preparation of such spray compositions, for example, the method described in the U.S. Pat. No. 2,868,691 or 3,095,355 may be used.

Drugs containing phosphoric acid derivatives as the active ingredient

Abstract: Because of having a TNFxcex1 production inhibitory effect, the compounds represented by general formula (I) are useful as preventives and/or remedies for rheumatoid arthritis, ulcerative colitis, Crohn""s disease, hepatitis, sepsis, hemorrhagic shock, multiple sclerosis, cerebral infarction, diabetes, interstitial pneumonia, uveitis, pain, glomerulonephritis, HIV-associated diseases, cachexia, myocardial infarction, chronic heart failure, oral aphtha, Hansen""s disease, infection, etc.


There is provided an information processing apparatus that makes it possible to supply power only for a function desired by the user. A CPU causes a display unit to display a plurality of functions of the information processing apparatus in a manner being selectable. Information on at least one function selected from the plurality of functions via a screen displayed by the display unit is input. The CPU controls power supply relating to the input at least one function, based on the information on the at least one function.

1. Field of the Invention
The present invention relates to an information processing apparatus, a power supply control method for the same, and a power supply control program.
2. Description of the Related Art
Conventionally, a power supply control technique for an image forming apparatus has been known in which the power status of the image forming apparatus is monitored at a remote location, and the turning-on/off of power supply to the image forming apparatus is remotely controlled.
Also, a power supply control technique has been known in which the turning-on/off of power supply only to a designated local part of an image forming apparatus (refer to Japanese Laid-Open Patent Publication (Kokai) No. 6-183102, for example).
On the other hand, a so-called multifunction digital copying machine has been known as an image forming apparatus for inputting/outputting images. The multifunction digital copying machine is comprised mainly of a scanner which reads an original image recorded on e.g. a sheet, a printer which outputs the read image or an image transmitted from a host computer to a medium such as a sheet, a device controller which controls the operations of the scanner and the printer or performs various kinds of image processing, an operating section through which the user can operate the machine, and a memory and a hard disk which temporarily or permanently store image data, processing programs, and so forth.
The multifunction digital copying machine constructed as described above is capable of not only copying an original image but also transferring image data read by the scanner to the host computer via a LAN (network) and, on the other hand, causing the printer to print out documents prepared on the host computer using a word processor or the like. Further, as is known, the multifunction digital copying machine has a variety of functions such as a facsimile function of transmitting an original image to a facsimile apparatus at a remote location.
According to the conventional techniques, however, although instructions for turning-on/off power supply to the image forming apparatus can be given from a remote location, such instructions are only related to turning-on/off of power supply to the image forming apparatus as a whole, and hence power supply cannot be controlled in a manner satisfying user's needs.
For example, the multifunction digital copying machine has the problem that even when it is desired to use only a printing function, power is supplied for not only the printing function but also the facsimile function in response to an instruction for turning on power supply.
Further, when power supply for the printing function is desired to be turned off, power supply for not only the printing function but also the facsimile function is turned off, and hence it is necessary to turn on power supply again when using the facsimile function.
Further, due to complicated functions of the multifunction digital copying machine, the user is required to carry out such a complicated operation as designating as to which part is to be subjected to power supply control to carry out turning on/off of power supply in a manner satisfying his/her needs.

Remote power configuration of functions within multifunction apparatus using status and setting screens displayed on external apparatus


A circuit and method for compensating for the output phase delay of an external clock signal utilizes a phase-locked loop that includes an output port of an integrated circuit device. In the phase-locked loop, a phase detecting circuit compares the external clock signal with an output signal from the output port, producing a phase error signal. The phase error signal is applied to a skew compensator to generate an internal clock signal. The internal clock signal is fed back through the output port to the phase detecting circuit. Clock jitter is reduced by reducing the gain of the skew compensator after a phase lock condition occurs in the compensation circuit.

In a computer system with a plurality of devices interconnected by a communications channel, such as a bus, the overall achievable system speed is determined by the clock period of the communications channel. With reference to FIG. 1(a), device 100 and device 102 are interconnected by channel 110. Device 100 communicates with device 102 by sending output signal Q1 through channel 110 where it is received as data signal D2 by device 102.
The total time budget, T, for the channel clock period is described by the following equation: T=T.sub.CTO +T.sub.Z +T.sub.SU +T.sub.SKEW, where T.sub.CTO is the input clock to output phase delay of the source device; T.sub.SU is the set up time requirement of the destination device; T.sub.SKEW is the input clock skew between devices; and T.sub.Z is the transmission settling time of the communication channel.
T.sub.CTO, the input clock to output phase delay of a source device, is the amount of time taken between the beginning of a clock cycle as determined by clock input signal CLK and when output data signal Q1 is first available at an output port of the source device.
There are several factors responsible for the output phase delay of a device including the time required for the input clock signal to reach an output buffer of the device, the time required to pass a signal through the output buffer, and the delay introduced by a capacitive load on the output port of the device, driven by the output buffer. These factors are difficult to precisely predict because they vary significantly with process, temperature, and supply voltage differences. As a result, T.sub.CTO is determined by a tolerance for the maximum acceptable input to output phase delay under a variety of possible operating environments.
T.sub.Z, the transmission settling time of the communications channel, is the amount of time between a change in data signal Q1 and the corresponding change in D2. T.sub.SU, the setup time requirement of the destination device, is how long D2 must be valid before device 102 can read signal D2 at clock signal CLK'. Finally, T.sub.SKEW is the input clock skew between devices due to the inherent delay in delivering a clock signal to a plurality of devices. In FIG. 1(a), a clock signal is supplied to device 100 as signal CLK and to device 102 as signal CLK'. As illustrated in FIG. 1 (b), each of these delays contributes to the total clock period, T, as T.sub.CTO +T.sub.Z +T.sub.SU +T.sub.SKEW.
For a communications channel such as a PC bus, the output phase delay contribution, T.sub.CTO, accounts for much of the total time budget for the bus. For example, a typical bus timing specification for a 66 MHz bus allocates 7 ns for T.sub.CTO or nearly 50% of the 15 ns time budget. A 15 ns clock period for a 32-bit bus has a peak data bandwidth of 267 megabytes per second (MB/s). If the maximum T.sub.CTO amount can be reduced to 4 ns, then the clock period for the bus can be reduced to only 12 ns. The data bandwidth for 12 ns bus is about 333 MB/s for an improvement of about 25%. If the maximum output phase delay of a source device can be further reduced to 2 ns, then the resulting data bandwidth is about 400 Mb/s, an improvement of about 50% over specification.
Therefore, it is desirable to tighten the tolerance for the amount of output delay of a semiconductor device.

Adaptable output phase delay compensation circuit and method thereof


The apparatus for removal of bone-cement comprises means to generate an ultrasonic signal and a tool element including an elongate stem (1) to transmit the signal to a distal end:. A plurality of spoke members (3), preferably four or eight, extend radially from adjacent the distal end to connect with an annular member (2) surrounding and spaced from the distal end. A plurality of openings (4) are each defined by the stem (1), the annular member (2) and two of the spokes (3). The annular member (2) is provided with a distally facing cutting edge. The spokes (3) are so configured as to transmit to and allow axial movement of the annular member (2) with respect to the stem (1), with an enhanced displacement relative to that of the stem (1).

It is known from our UK Patent No. 2229660B and our copending European patent Application No. 92917959.6 and from Engelbrecht U.S. Pat. No. 4,248,232 and Hood U.S. Des 341,202 that the local heating effect associated with the application of ultrasound to plastics materials can be employed to soften and effect the removal of bone cement during revision arthroplasty. Specifically, it has been shown in our previous patent and patent applications that a fundamental requirement of the cement removal technique is to influence the flow of softened material so that a small quantity of cement can be isolated and retained to be captured in the head of the activated instrument in order to extract it efficiently from the operating site, over a series of penetrating cycles. An important characteristic of such instruments is the presence of an axisymmetric disc close to the distal end of the instrument, and critically, of one or more connecting ports or passages parts between the distal face and an annular cavity proximal to said disc.
It is also known from our application No. EP 92917959.6 that the flow of softened cement is encouraged by the use of an annular cutting edge optionally incorporating a taper either towards or away from the distal end of the probe.

Apparatus for removal of plastics cement