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WO2005063736A1 - Derive d'aminoalkylpyrazole - Google Patents

Derive d'aminoalkylpyrazole Download PDF

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Publication number
WO2005063736A1
WO2005063736A1 PCT/JP2004/019310 JP2004019310W WO2005063736A1 WO 2005063736 A1 WO2005063736 A1 WO 2005063736A1 JP 2004019310 W JP2004019310 W JP 2004019310W WO 2005063736 A1 WO2005063736 A1 WO 2005063736A1
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Prior art keywords
group
pyridyl
methoxy
salt
compound
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English (en)
Japanese (ja)
Inventor
Haruhiko Horino
Naoaki Kanaya
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Daiichi Pharmaceutical Co Ltd
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Daiichi Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a pyrazole derivative having a platelet aggregation inhibitory action.
  • Platelets play an important role in preventing bleeding by aggregating during blood vessel damage to form a hemostatic thrombus, but on the other hand, as seen in arteriosclerosis, vascular endothelium may be damaged or blood may be damaged. If the vessel is stenotic, it may aggregate to induce thrombus or embolism, causing ischemic disease such as myocardial infarction, angina, ischemic cerebrovascular disorder, or peripheral vascular disorder. It has been known. Therefore, platelet aggregation inhibitors have been administered for the prevention and treatment of ischemic diseases.
  • aspirin has long been used as a platelet aggregation inhibitor, and its effects have been proven by the APT (Antiplatelet Trialists' Collaboration), which meta-analyzed the results of multiple clinical trials administered to 100,000 patients. (See Non-Patent Document 1).
  • APT Antiplatelet Trialists' Collaboration
  • aspirin is known to cause gastrointestinal bleeding and so-called aspirin ulcer side effects, which occur in 1 in 100 patients without depending on the dose ( Non-Patent Document 2).
  • Cyclooxygenases include cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), and aspirin selectively inhibits COX-1 at low doses to aggregate platelets. Inhibition of COX-1 is also a cause of aspillin ulcer (see Non-Patent Documents 3 and 4). It is known that non-steroid anti-inflammatory drugs selectively inhibit COX-2 and exhibit an anti-inflammatory effect.
  • aspirin is useful as a platelet aggregation inhibitor, but it has a gastrointestinal disorder as a side effect due to its mechanism of action, COX-1 inhibitory action. Aggregation inhibitors are required.
  • pyrazole derivatives having an antithrombotic effect so far include compound (A) (specifically, Patent Document 1 and Non-Patent Document 5) or compound (B) (see Patent Document 2) are known.
  • Patent Document 1 Patent No. 2586713
  • Patent Document 2 W09729774
  • Non-Patent Document 1 BMJ, 308, 81-106, 1994
  • Non-Patent Document 2 BMJ, vol.
  • Non-Patent Document 3 Neurology, Vol. 57, Suppl. 2, S5—S7, 2001
  • Non-Patent Document 4 Drugs Today, Vol. 35, pp. 251-265, 1999
  • Non-Patent Document 5 Chem. Pharm. Bull., Vol. 45, pp. 987-995, 1997
  • an object of the present invention is to provide a potent platelet aggregation inhibitor that does not inhibit COX-1 and COX-2.
  • the present inventors have conducted intensive studies for such a platelet aggregation inhibitor and as a result, The present inventors have found that the pyrazole derivative represented by the general formula (I) exhibits a potent platelet aggregation inhibitory action without inhibiting COX-1 and COX-2, and thus completed the present invention.
  • the present invention provides a compound represented by the general formula (I)
  • Ar and Ar may each independently have 1 to 3 substituents
  • R 1 and R 2 each independently represent a hydrogen atom or a lower alkyl group
  • R 3 represents a hydrogen atom or a lower alkyl group which may have a substituent
  • R 4 has a substituent May have a lower alkyl group, an amino group that may have a substituent, a lower alkoxy group that may have a substituent, a carbamoyl group that may have a substituent, or may have 1 to 3 substituents.
  • n shows the number of 0 or 1.
  • the present invention also provides a medicine containing the compound represented by the general formula (I), a salt thereof, or a solvate thereof.
  • the present invention further provides a preventive and / or therapeutic agent for ischemic disease containing a compound represented by the general formula (I), a salt thereof, or a solvate thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the general formula (I), a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides a compound represented by the general formula (I), a salt thereof, or a solvent thereof.
  • the present invention provides a use of the Japanese product for the manufacture of a medicament.
  • the present invention provides a use of the compound represented by the general formula (I), a salt thereof, or a solvate thereof for prevention of ischemic disease and production of Z or a therapeutic agent. It is.
  • the present invention provides a method for treating ischemic disease, which comprises administering an effective amount of a compound represented by the general formula (I), a salt thereof, or a solvate thereof. It is a thing.
  • the compound (I) of the present invention a salt or solvate thereof, or a solvate of the salt strongly inhibits platelet aggregation without inhibiting COX-1 and COX-2, and forms thrombus. It has a strong inhibitory effect.
  • myocardial infarction myocardial infarction, angina (chronic stable angina, unstable angina, etc.), ischemic cerebrovascular disorder (transient cerebral ischemic attack (TIA), cerebral infarction, etc.), peripheral vascular disorder, artificial Occlusion after vascular replacement, thrombotic occlusion after coronary intervention (coronary artery bypass graft (C AGB), percutaneous transluminal coronary angioplasty (PTCA), stent placement, etc.), diabetic retinopathy 'nephropathy, heart valve replacement
  • ischemic diseases caused by thrombosis / embolism, such as temporal occlusion.
  • it is useful as a prophylactic and / or therapeutic agent for thrombus emboli associated with vascular surgery, extracorporeal blood circulation, and the like.
  • Ar and the aromatic heterocyclic group represented by Ar represent a 5- or 6-membered aromatic heterocyclic group.
  • pyridyl group pyridazinyl group, pyrimidinyl group, pyrazuryl group, furyl group, chenyl group, pyrrolyl group, pyrazolyl group, imidazolyl group, triazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, and pyrazolyl group.
  • a 5- or 6-membered aromatic heterocycle having 13 nitrogen atoms as a hetero atom such as a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazuryl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, and a triazolyl group.
  • the group is more preferably a 6-membered aromatic heterocyclic group having one to three nitrogen atoms, more preferably a pyridyl group, a pyridazyl group or a pyrazur group, and particularly preferably a pyridyl group.
  • Ar and the aryl group having 6 to 14 carbon atoms represented by Ar include a phenyl group and a naphthyl
  • a phenol group is preferable.
  • Those substituents for Ar and Ar include a lower alkyl group, a halogeno group, and a hydroxyl group.
  • substituents will be described.
  • Ar and a lower alkyl group as a substituent on Ar are straight-chain, branched
  • Means Jo or cyclic alkyl group, a methyl group Specific examples, Echiru group, a propyl group, an isopropyl group, butyl group, isobutyl group, t-butyl group, a pentyl group, an isopentyl group, a cyclopropyl group, a cyclopentyl group, Hexyl group, cyclopropylmethyl group
  • halogeno group examples include a fluoro group, a chloro group, and a bromo group.
  • the lower alkoxy group means a linear, branched or cyclic alkoxy group having 16 carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, and an isobutoxy group. Pentoxy group, cyclopentyloxy group and the like.
  • the aralkyl group of the aralkyl group refers to an aryl group having 6 to 14 carbon atoms and a group capable of cooperating with the lower alkyl group.
  • Specific examples of the aralkyl group include a benzyloxy group and a phenethyloxy group. Can be.
  • the lower alkylthio group means a group having an alkylthio group having 1 to 16 carbon atoms, and specific examples thereof include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a pentylthio group, A cyclopentylthio group and the like can be mentioned.
  • the lower alkoxycarbol group means an alkoxycarbol group having a total of 2 to 7 carbon atoms, and specific examples thereof include a methoxycarbyl group, an ethoxycarbol group, a propoxycarbonyl group, Butoxycarbonyl group and the like.
  • lower alkylsulfur group means an alkylsulfur group having 1 to 6 carbon atoms, Specific examples include a methanesulfol group, an ethanesulfol group, and a trifluoromethanesulfol group.
  • the amino group which may have 1 or 2 substituents means an unsubstituted amino group, an amino group substituted with 1 or 2 lower alkyl groups, or a lower alkanoylamino group.
  • a group means a lower alkoxycarboramino group or a ureido group which may be replaced by one or two of the above lower alkyl groups.
  • amino group substituted with one or two lower alkyl groups include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a cyclopropylamino group, a butylamino group, an isobutylamino group, and a cycloalkyl group.
  • Pentylmethylamino, dimethylamino getylamino, dipropylamino, dibutylamino, N-methyl-N-ethylamino, N-ethyl-propylamino, N-methyl-N-cyclopentylmethylamino,
  • the lower alkanoylamino group means an amino group substituted with a linear or branched alkanoyl group having 2 to 6 carbon atoms, and specific examples thereof include an acetylamino group and a propionylamino group. it can.
  • the lower alkoxycarbonylamino group means an amino group substituted with a linear or branched lower alkoxycarbonyl group having 2 to 6 carbon atoms, and specific examples thereof include a methoxycarbolamino group and an ethoxycarbo group. -A lumino group.
  • examples thereof include an aminocarbo-amino group, an Nl, N1-dimethylaminocarbo-amino group, an Nl, N3-dimethylaminocarbo-amino group, an N1 methyl N3-ethylaminocarbo-amino group, and the like.
  • a carbamoyl group which may be substituted with one or two lower alkyl groups is a carbamoyl group substituted with one or two lower alkyl groups in addition to an unsubstituted carbamoyl group.
  • specific examples include a methylcarbamoyl group, an ethylcarbamoyl group, a dimethylcarbamoyl group, and a methylethylcarbamoyl group.
  • the aminosulfol group which may be substituted with one or two lower alkyl groups refers to an aminosulfo group substituted with one or two lower alkyl groups in addition to an unsubstituted aminosulfol group. And specific examples thereof include a methylaminosulfol group and an ethylamino group.
  • Examples include an aminosulfol group, a cyclohexylaminosulfol group, a cyclopentylmethylaminosulfol group, a dimethylaminosulfol group, a getylaminosulfol group, and the like.
  • the substituent on Ar is preferably substituted para to the substitution position of the pyrazole ring.
  • R 1 and R 2 a linear or branched alkyl group having 16 carbon atoms can be mentioned. Of these, a methyl group and an ethyl group are preferred, and a methyl group is particularly preferred.
  • R 1 is preferably a hydrogen atom.
  • R 2 is preferably a hydrogen atom or a lower alkyl group. It is particularly preferable that R 1 is a hydrogen atom and R 2 is a hydrogen atom or a methyl group.
  • carboxyl group is a linear or branched alkyl group having a carbon number of 1 one 6 which is also be substituted. Specific examples include a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a carboxymethyl group, a carboxyethyl group, and the like.
  • R 3 is preferably a hydrogen atom, a lower alkyl group or a carboxy lower alkyl group, and particularly preferably a hydrogen atom, a methyl group, an ethyl group, a carboxymethyl group, and a carboxyethyl group.
  • carboxyl group is a linear or branched alkyl group having a carbon number of 1 one 6 which is also be substituted.
  • Specific examples include a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a t-butyl group, a propyloxymethyl group, and a carboxyl group.
  • a methyl group, an ethyl group, an isopropyl group and a t-butyl group are particularly preferred.
  • the amino group which may have a substituent represented by R 4 includes an amino group, a lower alkylamino group, a di (lower alkyl) amino group, and an arylamino group having 6 to 14 carbon atoms.
  • the lower alkylamino group include a c alkylamino group, and a di (lower alkyl
  • Le) amino groups include di (C alkyl) amino groups, and aryl groups having 6 to 14 carbon atoms.
  • Examples of the lumino group include a fluoramino group.
  • Specific examples of the amino group that may have the substituent include an amino group, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a t-butylamino group, a dimethylamino group, a acetylamino group, a phenylamino group, and the like. Is mentioned.
  • lower alkoxy group which may have a substituent represented by R 4, a lower alkoxy group, and a halogeno lower alkoxy group and the like.
  • examples of the lower alkoxy group include straight-chain or branched-chain alkoxy groups having 116 carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group, and an isopropoxy group.
  • force Rubamoiru group which may be substituted represented by R 4
  • force Rubamoiru group include lower alkyl force Rubamoiru group. Specific examples of this group include a carbamoyl group, a methylcarbamoyl group, an ethylcarbamoyl group, and an isopropyl rubamoyl group.
  • heterocyclic group which may have 1 to 3 substituents represented by R 4 include a 5- or 6-membered saturated heterocyclic group, and specifically, a morpholino group and a thiomorpholino Group, pyrrolidinyl group, piberidyl group, piperazino group, N-methylbiperazino group and the like.
  • the salt of the compound (I) of the present invention not all of the compounds of the present invention form a salt, but when the compound has a carboxyl group, an amino group, or the like, or when Z or Ar or Ar is a pyridine ring In such a case, a salt can be formed, and the salt can form a solvate.
  • the salt mentioned here includes salts of organic acids such as methanesulfonic acid, p-toluenesulfonic acid, fumaric acid, and trifluoroacetic acid, in addition to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and nitric acid. And salts with alkali metal or alkaline earth metal ions such as sodium, potassium and calcium.
  • the solvate of the compound (I) of the present invention or the solvate of a salt thereof refers to a solvate to which a solvent used for crystal crystallization or the like is added, or a solvate in the air. Includes those formed by absorbing water.
  • the solvent include lower alcohols such as methanol and ethanol, organic solvents such as acetone and acetonitrile, and water.
  • the compound (la) in which n is 0 in the general formula (I) is synthesized using a virazoamine derivative (6) obtained by the following production method as a production intermediate.
  • Compound (2) is prepared by dissolving dimethyl cyanomethylphosphonate in an appropriate solvent such as tetrahydrofuran, treating the mixture with sodium hydride at 20-20 ° C. in an argon stream, and then converting aldehyde (1). It can also be produced by adding and stirring.
  • an appropriate solvent such as tetrahydrofuran
  • aldehyde (1) a commercially available product or a product produced by the method described in Reference Example or a method analogous to that method may be used.
  • the compound (2) is dissolved in ethanol or methanol, and after adding the hydrazine derivative (4) or a salt thereof at room temperature, an appropriate amount of sodium methoxide is added and the mixture is heated under reflux.
  • compound (5) can be produced.
  • the pyrazoleamine derivative (6) can be produced by dissolving the compound (5) in a suitable solvent such as methylene chloride and treating with a dimanganese diacid.
  • the reaction temperature is preferably 0-50 ° C
  • hydrazine derivative (4) a commercially available product may be used or described in Reference Examples. As described above, a method in which hydrazine is reacted with halogenated Ai ⁇ or a substance produced by a method according to the method may be used. As the amine (3), the ability to use a commercially available compound, or the method described in Reference Examples or a method produced by a method similar thereto, may be used.
  • the hydrazine derivative (4) or a salt thereof used in the above-mentioned pyrazole ring-forming reaction is obtained by dissolving an amine (3) in concentrated hydrochloric acid and adding sodium nitrite under ice cooling to induce a diazo compound. After that, it can be manufactured by treating with tin chloride (II).
  • the reaction temperature is preferably -10 to 20 ° C.
  • the present compound (la) By subjecting the pyrazoleamine derivative (6) obtained by the above production method to acylation, the present compound (la) can be obtained.
  • the above-mentioned acylation reaction may be based on a condensation reaction generally used as a peptide synthesis method.
  • Commonly used peptide synthesis methods include, for example, an azide method, an acid chloride method, an acid anhydride method, a DCC (dicyclocarbodiimide) method, an active ester method, a rubodiimidazole method, and a DCCZHOBT (l- (Hydroxybenzotriazole) method, a method using water-soluble carbodiimide, a method using getyl cyanophosphate, and the like. These methods are described in M. Bodanszky, YS Klausner and MA On de ci Peptide Snthesis.
  • the compound (lb) in which n is 1 can be produced using the following pyrazolecarboxylic acid derivative (14) as a production intermediate.
  • Compound (11) is obtained by treating compound (9) and dialkyl oxalate (10) in an alcohol (methanol or ethanol) solution in the presence of sodium alkoxide (methoxide or ethoxide). Can also be manufactured.
  • the reaction temperature is preferably from -10 to 100 ° C.
  • compound (11) is dissolved in an inert solvent such as tetrahydrofuran of compound (9), and treated with a base such as lithium bis (trimethylsilyl) amide under cooling at ⁇ 78 ° C. It can also be produced by adding ethyl ester and stirring.
  • the reaction temperature is preferably -78-20 ° C.
  • ketone (9) a commercially available product or a product produced by the method described in Reference Example or a method analogous thereto may be used.
  • the compound (11) is dissolved in ethanol, the hydrazine derivative (4) or a salt thereof is added at room temperature, and then an appropriate amount of acetic acid is added, followed by heating under reflux to convert the compound (12). Can be manufactured. At this time, the positional isomer (13) is produced as a by-product, but the compound (12) can be easily separated and purified by silica gel column chromatography.
  • the hydrazine derivative (4) or a salt thereof used in the above-mentioned pyrazole ring-forming reaction may be a commercially available one, or may be made to react hydrazine with Ar halide as described in Reference Examples.
  • a method manufactured by a method or a method according to the method may be used.
  • the hydrazine derivative (4) or a salt thereof is prepared by dissolving the amine (3) in concentrated hydrochloric acid, adding sodium nitrite under ice-cooling to form a diazo compound, and then tin chloride (-10-20 ° C). It can be manufactured by processing in ⁇ ).
  • As the amine (3) a commercially available compound may be used, or a compound produced by a method described in Reference Example or a method analogous thereto may be used.
  • hirazole carboxylic acid derivative (14) By hydrolyzing compound (12) by a conventional method, hirazole carboxylic acid derivative (14) can be produced.
  • This hydrolysis reaction can be performed in the presence of a base or a Lewis acid.
  • the base include hydroxides of alkali metals (eg, lithium, sodium, potassium, etc.).
  • the Lewis acid include boron tribromide.
  • the reaction temperature is preferably from -20 to 100 ° C, more preferably from 5 to 50 ° C.
  • the Ar substituent is a S methoxy group
  • a compound (12) in which the Ar substituent is a halogeno group such as a chloro group or a bromo group is dissolved in methanol, sodium methoxide is added, and the mixture is heated to reflux.
  • compound (12) substituted with a methoxy group as a substituent of Ar can be produced.
  • the substituent of Ar is The compound (12), which is a halogeno group, and sodium methoxide are dissolved in a mixed solvent of methanol and toluene, a catalyst such as copper (I) bromide is added, and the mixture is heated to reflux to obtain a substituent S of Ar.
  • the compound (12) substituted with a toxic group can also be produced.
  • a pyrazolemethylamine derivative (18), which is an intermediate for producing the compound of the present invention (lb), is obtained. Can be manufactured.
  • the ester (12) is reduced to an alcohol (15), and the Z group is a leaving group (for example, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, chloro group, bromo group or
  • the compound (16) is a compound (16).
  • Ester (12) force The reduction reaction to alcohol (15) is carried out, for example, in an inert solvent such as tetrahydrofuran at 78-50 ° C, preferably at -20-30 ° C, by using lithium aluminum hydride, hydrogen It can be achieved by treatment with lithium boron oxide or the like.
  • an inert solvent such as tetrahydrofuran at 78-50 ° C, preferably at -20-30 ° C
  • lithium aluminum hydride hydrogen It can be achieved by treatment with lithium boron oxide or the like.
  • the alcohol (15) is produced by reacting the carboxylic acid (14) with lithium aluminum hydride, borane-tetrahydrofuran complex or the like in an inert solvent such as tetrahydrofuran at -78 to 50 ° C, preferably This can be done by treating at 20-30 ° C.
  • the alcohol (15) is converted to the compound (16) by a methanesulfonate at 50-50 ° C in the presence of a base such as pyridine in the case of a Z-based methanesulfonoxy group when the methanesulfonyloxy group is used.
  • a base such as pyridine
  • Z group is p-toluenesulfonyloxy group
  • Compound (16) such as trifluoromethanesulfonyloxy group can be produced under the same conditions.
  • a chloro derivative (16) or a bromo derivative (16) is produced from the alcohol (15) using thionylc-lid liditol bromide, Further, by treating them with sodium iodide, an oxide derivative (16) can be obtained.
  • the conditions and reagents for these reactions should be appropriately selected based on ordinary knowledge of organic chemistry.
  • the azide compound (17) can be produced by dissolving the compound (16) in a suitable solvent such as N, N-dimethylformamide and treating with azide sodium.
  • the reaction temperature is preferably 50-100 ° C.
  • the pyrazole methylamine derivative (18) can be produced by dissolving the azide compound (17) in a solvent such as ethanol, and catalytically reducing the catalyst with 10% sodium-carbon as a catalyst. In this catalytic reduction, a Lindlar catalyst may be used. In addition, the reduction reaction of the azide conjugate (17) with a metal hydride such as sodium borohydride, and the reduction reaction of the azide conjugate (17) with triphenylphosphine, thiol, sulfide, diborane, etc. Alternatively, the pyrazole methylamine derivative (18) can be produced.
  • the compound (23) in which the methylene group of the pyrazolemethylamine derivative (18) is substituted with a lower alkyl group can be produced by the following production method or a method analogous thereto.
  • the reaction can be carried out by dissolving in an inert solvent such as butane and treating with methyllithium at 78-50 ° C, preferably -20-30 ° C.
  • the ketone (19) is reduced to alcohol (20), and the Z group is a leaving group (for example, p-toluenesulfonoxy, methanesulfonoxy, trifluoromethanesulfonoxy), Group, a bromo group or an odo group).
  • the Z group is a leaving group (for example, p-toluenesulfonoxy, methanesulfonoxy, trifluoromethanesulfonoxy), Group, a bromo group or an odo group).
  • Ketone body (19) force The reduction reaction to alcohol (20) is carried out, for example, in an inert solvent such as tetrahydrofuran at 78-50 ° C, preferably -20-30 ° C, by using lithium aluminum hydride. And sodium borohydride.
  • the alcohol (20) is converted to the compound (21) by a methanesulfonate at 50-50 ° C in the presence of a base such as pyridine in the case of a Z-group cata-sulfo-oxy group. It can be produced by reacting with luchloride.
  • the Z group is a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, or the like, it can be converted to the conjugate (21) under the same conditions.
  • the chloro derivative (21) or the bromo derivative (21) is derived using thionyl chloride or thionyl bromide and the like. By the treatment, an odode derivative (21) can be obtained. Conditions and reagents for these reactions may be appropriately selected based on ordinary knowledge of organic chemistry.
  • the azide compound (22) can be produced by dissolving the compound (21) in an appropriate solvent such as N, N-dimethylformamide and treating with azide sodium.
  • the reaction temperature is preferably from 50 to 150 ° C, more preferably from 50 to 100 ° C.
  • the amine compound (23) can be produced by dissolving the azide compound (22) in a solvent such as ethanol, and catalytically reducing the solution using a 10% palladium carbon or Lindlar catalyst.
  • the amine compound can also be obtained by a reduction reaction of the azide compound (22) with a metal hydride such as sodium borohydride or a reduction reaction of the azide compound (22) with triphenylphosphine, thiol, sulfide or diborane. (23) can be manufactured.
  • the compound of the present invention (lb) in which n is 1 is converted to an amide compound (lb) by condensing the above-mentioned amine compound (23) with acid chloride (8) or carboxylic acid (7). Can be manufactured.
  • the amine compound (23) has the ability to produce the compound (24) and react with the amine (25) to produce urea.
  • a compound (lb) can be produced.
  • R 7 and R 8 are each independently hydrogen, a lower alkyl group which may have a substituent, an aryl group which may have a substituent, and a complex ring group which may have a substituent
  • W represents a leaving group.
  • the present invention provides a method for treating a pyrazole methylamine derivative (18) or (23) produced by the above-mentioned production method with an acid chloride (8) in a solvent such as methylene chloride in the presence of an organic amine such as triethylamine.
  • Compound (I) can be produced.
  • the reaction temperature is preferably -10 to 50 ° C.
  • the compound (lb) of the present invention is also produced by condensing a pyrazole methylamine derivative (18) or (23) with a carboxylic acid (7).
  • peptide synthesis methods include, for example, azide method, acid chloride method, acid anhydride method, DCC (dicyclocarbodiimide) method, active ester method, carpoimidazole method, and DCCZHOBT (1-hydroxybenzoate).
  • Triazole) method a method using water-soluble carbodiimide, a method using getyl cyanophosphate, and the like. These methods are described in “Peptide Snthesis ⁇ by M. Bodanszky, YS Klausner and MA Ondetti.
  • the compound (lb) in which R 4 is a substituted rubamoyl group which may have a substituent may be a pyrazolemethylamine derivative (18) or (23) in a solvent such as methylene chloride or the like.
  • the reaction temperature is preferably 10-50 ° C.
  • the compound (lb) having a sorbamoyl group can also be produced by treating a pyrazolemethylamine derivative (18) or (23) with an alkyl isocyanate in a solvent such as methylene chloride. It is possible.
  • the compound (I) of the present invention produced by the above method can be further modified to give another compound (I) of the present invention based on ordinary knowledge of organic chemistry. it can.
  • the compound (I) of the present invention a salt or solvate thereof, or a solvate of the salt thereof has a strong antiplatelet effect, and is also effective in a thrombosis model induced by high shear stress. did.
  • the compound (1) of the present invention, a salt or solvate thereof, or a solvate of the salt thereof is useful in mammals including humans for myocardial infarction, angina pectoris (chronic stable angina pectoris, anxiety Constant angina pectoris, etc.), ischemic cerebral vascular disease (transient cerebral ischemic attack (TIA), cerebral infarction, etc.), peripheral vascular disorder, occlusion after artificial blood vessel replacement, coronary artery intervention (coronary artery bypass graft (CAG B ), Percutaneous transluminal coronary angioplasty (PTCA), stent placement, etc.), ischemic diseases caused by thrombosis / embolism, such as diabetic retinopathy 'nephropathy, obstruction at the time of heart valve replacement, etc. It is useful as a prophylactic and Z or therapeutic agent. Alternatively, it is useful as a prophylactic and / or therapeutic agent for thrombus emboli, for example, associated with vascular surgery and extracorporeal blood
  • the dosage varies depending on the age, sex, symptoms, etc., of the patient. 1 dose per person, preferably 0.1 mg-lg power, 0.5 mg-more preferred than 500 mg! / ⁇ . In this case, the daily dose can be divided into several doses and, if necessary, the daily dose can be exceeded.
  • the medicament containing the compound (I) of the present invention, a salt thereof or a solvate thereof can be used according to an administration method and a dosage form as required.
  • an administration method and dosage form There is no particular limitation on the administration method and dosage form as long as a pharmaceutically acceptable carrier is added as necessary in the preparation of the drug product and a dosage form that matches the administration method is selected. .
  • oral preparations include solid preparations such as tablets, powders, granules, pills, and capsules, and liquid preparations such as solutions, syrups, elixirs, suspensions, and emulsions. Can be mentioned.
  • compound (I), a salt or solvate thereof, or a solvate of the salt thereof may be dissolved and filled into a container. It may be prepared as a preparation.
  • compositions such as a binder, a disintegrant, a dissolution promoter, a lubricant, a filler, and an excipient are selected as necessary. It is easy to use.
  • the reaction mixture was acidified by adding 1N hydrochloric acid (180 ml), and water and ethyl acetate were added to carry out liquid separation.
  • the organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 4-phenyl 2,4-dioxobutanoic acid ethyl ester (22.96 g, quantitative) as an oil. It was used for the next reaction without further purification.
  • the aqueous layer was made acidic with 1N hydrochloric acid aqueous solution (140 ml), extracted with ethyl acetate, and the organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound (13.88 g, 92%) as an individual.
  • Manganese dioxide (10.7 g) was added to a solution of the above 1- (6-methoxy-3-pyridyl) 5-phenyl-4,5-dihydro-1H-pyrazonole-3-ylamine (8.27 g) in dichloromethane (165 ml) at room temperature. Stirred for hours. Insolubles were separated from the reaction solution by filtration using celite, and water and black form were added to the filtrate, and the mixture was separated. The organic layer was dried with anhydrous sodium sulfate.
  • Triethylamine (20) was added to a solution of [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methylamine (33 mg) in Reference Example 9 in dichloromethane (2 ml). 1) and N, N-dimethylcarbamoyl chloride (131) were stirred at room temperature for 18 hours. The residue obtained by evaporating the reaction solvent under reduced pressure was purified by silica gel thin-layer chromatography (formaldehyde methanol) to give the title compound (34 mg, 82%) as an oil.
  • Triethylamine (14) was added to a solution of [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methylamine (25 mg) in Reference Example 9 in dichloromethane (3 ml). 1) and methyl chloroformate (8 ⁇ l) were stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (form-form methanol) to give the title compound (27 mg, 90%) as an oil.
  • Triethylamine (0.1 ml) was added to a solution of 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazole-3-ylamine (100 mg) in Reference Example 7 in dichloromethane (2 ml) at room temperature. ) And Shioi-Dani Pivaloyl (44 mg) were stirred for 1 day. Water and dichloromethane were added to the reaction mixture, and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (dichloromethane / methanol) to give the title compound (95 mg, 72%) as an individual.
  • reaction buffer heme, arachidonic acid, SnCl, EIA buffer, washing buffer,
  • PG screening EIA standard solution PG screening acetylcholinesterase (AchE), tracer (chromogenic enzyme HRP conjugate), PG screening EI A antiserum were prepared.
  • reaction solution containing the compound of the example (50 ⁇ M) and COX-1 or COX-2 was allowed to stand at 37 ° C. for 10 minutes, and then arachidonic acid 101 was added and allowed to stand at 37 ° C. for 2 minutes. After the reaction, add 1N-hydrochloric acid 501 to stop the reaction, add SnCl solution 1001, and leave it at room temperature for 5 minutes
  • the diluted solution 501 and the AchE tracer 501 were collected in sequence and allowed to stand at room temperature for 18 hours. Each well was washed five times with a washing buffer to remove excess AchE tracer, and then supplemented with 200 / zl of Ellman reagent. After standing in a dark room for 60 minutes, measure the absorbance at 405 nm.
  • the production amount of PGF ⁇ obtained using the reaction solution containing no example compound was defined as 100%.
  • the compound (1) of the present invention, a salt or solvate thereof, or a solvate of the salt has a strong platelet aggregation inhibitory action. And did not show COX-1 and COX-2 inhibitory effects.

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Abstract

L'invention pore sur un inhibiteur de l'agrégation plaquettaire n'inhibant ni COX-1 et ni COX-2 et comprenant un composé de la formule générale (I), ou un sel ou un solvate de celui-ci, (dans laquelle chacun de Ar1 et Ar2 représente, indépendamment, un hétérocycle aromatique à 5 ou 6 éléments possédant éventuellement un à trois substituants, ou un aryle C6 C14 possédant éventuellement un à trois substituants ; chacun de R1 et de R2 représentent indépendamment hydrogène ou un alkyle inférieur ; R3 représente hydrogène ou un alkyle inférieur éventuellement substitué ; R4 représente un alkyle inférieur éventuellement substitué, un amino éventuellement substitué, un alcoxy inférieur éventuellement substitué, un carbamoyle éventuellement substitué ou un hétérocycle possédant éventuellement un à trois substituants ; et n représente 0 ou 1).
PCT/JP2004/019310 2003-12-26 2004-12-24 Derive d'aminoalkylpyrazole Ceased WO2005063736A1 (fr)

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WO2009041447A1 (fr) * 2007-09-28 2009-04-02 Takeda Pharmaceutical Company Limited Composé hétérocyclique à 5 chaînons
US7622471B2 (en) 2003-02-07 2009-11-24 Daiichi Pharmaceutical Co., Ltd. Pyrazole derivatives having a pyridazine and pyridine functionality
WO2010126580A1 (fr) * 2009-04-27 2010-11-04 Dow Agrosciences, Llc Composés pyridine insecticides
US8242117B2 (en) 2003-06-26 2012-08-14 Novartis Ag 5-membered heterocycle-based p38 kinase inhibitors
US9193738B2 (en) 2012-01-24 2015-11-24 Laboratorios Del Dr. Esteve S.A. Substituted pyrano and furanoquinolines, their preparation and use as medicaments

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JPH0673014A (ja) * 1992-06-23 1994-03-15 Elf Sanofi 新規なピラゾール誘導体、それらを調製する方法、及びこれらを含有する薬学的組成物
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JPH03141261A (ja) * 1989-09-22 1991-06-17 Fujisawa Pharmaceut Co Ltd ピラゾール誘導体、その製造法およびそれを含有する医薬組成物
JPH0673014A (ja) * 1992-06-23 1994-03-15 Elf Sanofi 新規なピラゾール誘導体、それらを調製する方法、及びこれらを含有する薬学的組成物
JP2003513064A (ja) * 1999-11-05 2003-04-08 ユニバーシティ カレッジ ロンドン 可溶性グアニル酸シクラーゼのアクチベーター
US6649638B1 (en) * 2002-08-14 2003-11-18 Ppd Discovery, Inc. Prenylation inhibitors and methods of their synthesis and use
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7622471B2 (en) 2003-02-07 2009-11-24 Daiichi Pharmaceutical Co., Ltd. Pyrazole derivatives having a pyridazine and pyridine functionality
US8242117B2 (en) 2003-06-26 2012-08-14 Novartis Ag 5-membered heterocycle-based p38 kinase inhibitors
US8410160B2 (en) 2003-06-26 2013-04-02 Novartis Ag 5-membered heterocycle-based P38 kinase inhibitors
US8580838B2 (en) 2003-06-26 2013-11-12 Novartis Ag 5-membered heterocycle-based p38 kinase inhibitors
WO2009041447A1 (fr) * 2007-09-28 2009-04-02 Takeda Pharmaceutical Company Limited Composé hétérocyclique à 5 chaînons
US8334301B2 (en) 2007-09-28 2012-12-18 Takeda Pharmaceutical Company Limited 5-Membered heterocyclic compound
WO2010126580A1 (fr) * 2009-04-27 2010-11-04 Dow Agrosciences, Llc Composés pyridine insecticides
US8604199B2 (en) 2009-04-27 2013-12-10 Dow Agrosciences, Llc. Insecticidal pyridine compounds
US9131694B2 (en) 2009-04-27 2015-09-15 Dow Agrosciences Llc Insecticidal pyridine compounds
US9193738B2 (en) 2012-01-24 2015-11-24 Laboratorios Del Dr. Esteve S.A. Substituted pyrano and furanoquinolines, their preparation and use as medicaments

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