WO2005063736A1 - Aminoalkylpyrazole derivative - Google Patents

Abstract

A platelet aggregation inhibitor not inhibiting COX-1 and COX-2, comprised of a compound of the general formula: (I) (wherein each of Ar1 and Ar2 independently represents a 5-membered or 6-membered aromatic heterocycle optionally having one to three substituents, or a C6-C14 aryl optionally having one to three substituents; each of R1 and R2 independently represents hydrogen or a lower alkyl; R3 is hydrogen or an optionally substituted lower alkyl; R4 is an optionally substituted lower alkyl, an optionally substituted amino, an optionally substituted lower alkoxy, an optionally substituted carbamoyl or a heterocycle optionally having one to three substituents; and n is 0 or 1), or its salt or a solvate thereof.

Description

 Specification

 Aminoalkylpyrazole derivatives

 Technical field

 The present invention relates to a pyrazole derivative having a platelet aggregation inhibitory action.

 Background art

 [0002] 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. In particular, 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). However, 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).

 [0003] It is known that the inhibitory action of aspirin on platelet aggregation is based on the inhibitory action of cyclooxygenase. 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.

 [0004] As described above, 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.

[0005] On the other hand, 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.

[0006] [Formula 1]

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

 Disclosure of the invention

 Problems to be solved by the invention

[0007] However, the IC value of compound (Α) for collagen-induced platelet aggregation is 5.3 X 10-6 ⁶

 50

, And the exhibit a strong inhibitory activity than this for COX 2 (IC value 2. 4 X 10- ⁷ M). same

 50

 Similarly, the platelet aggregation inhibitory effect of compound (B) is not as strong as its inhibitory activity on COX-2. As described above, the inhibitory effect of COX-2 leads to an anti-inflammatory effect, —2 It is not necessarily preferred as a platelet aggregation inhibitor to have inhibitory activity. Therefore, an object of the present invention is to provide a potent platelet aggregation inhibitor that does not inhibit COX-1 and COX-2.

 Means for solving the problem

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.

 That is, the present invention provides a compound represented by the general formula (I)

 [0010] [Formula 2]

(Wherein, Ar and Ar may each independently have 1 to 3 substituents

 1 2

 A 5- or 6-membered aromatic heterocyclic group or a C 6-14 aryl group which may 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. Represents a certain heterocyclic group;

 n shows the number of 0 or 1. )

 Or a salt thereof or a solvate thereof.

[0012] The present invention also provides a medicine containing the compound represented by the general formula (I), a salt thereof, or a solvate thereof.

[0013] 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.

Further, the present invention provides a pharmaceutical composition comprising a compound represented by the general formula (I), a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier. .

[0015] Furthermore, 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.

 Further, 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.

 [0017] Furthermore, 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 invention's effect

 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. Therefore, 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 It is useful as a prophylactic and / or therapeutic agent for ischemic diseases caused by thrombosis / embolism, such as temporal occlusion. Alternatively, it is useful as a prophylactic and / or therapeutic agent for thrombus emboli associated with vascular surgery, extracorporeal blood circulation, and the like.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0019] The substituents in the above general formula (I) will be described below.

[0020] Ar and the aromatic heterocyclic group represented by Ar represent a 5- or 6-membered aromatic heterocyclic group.

 1 2

Specific examples include 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. Can be mentioned. Of these, 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. [0021] Ar and the aryl group having 6 to 14 carbon atoms represented by Ar include a phenyl group and a naphthyl

1 2

 And among them, a phenol group is preferable.

 [0022] Those substituents for Ar and Ar include a lower alkyl group, a halogeno group, and a hydroxyl group.

 1 2

 A group, a cyano group, a lower alkoxy group, an aralkyloxy group, a lower alkylthio group, a lower alkoxycarbol group, a carboxyl group, a lower alkylsulfol group, an amino group which may have one or two substituents, 1 or Examples thereof include a rubamoyl group which may be substituted with two lower alkyl groups, and an aminosulfol group which may be substituted with one or two lower alkyl groups. Hereinafter, these substituents will be described.

[0023] Ar and a lower alkyl group as a substituent on Ar are straight-chain, branched

 1 2

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

And a cyclopentylmethyl group.

[0024] Examples of the halogeno group include a fluoro group, a chloro group, and a bromo group.

[0025] 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.

[0026] 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.

[0027] 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.

 [0028] 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.

[0029] The term "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.

 [0030] 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. Specific examples of the 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, and the like. Can be. 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. Specific examples of the ureido group which may be substituted with one or two lower alkyl groups include an aminocarbo-lamino group, an N1-methylaminocarbo-lamino group, an N1-ethylaminocarbo-lamino group, an N3-methyl 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.

 [0031] 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. And specific examples include a methylcarbamoyl group, an ethylcarbamoyl group, a dimethylcarbamoyl group, and a methylethylcarbamoyl group.

[0032] 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. Nosulfol group, propylaminosulfur group, isopropylaminosulfur group, primary or tertiary butylaminosulfur group, cyclopropylaminosulfur group, cyclobutylaminosulfur group, cyclopentyl Examples include an aminosulfol group, a cyclohexylaminosulfol group, a cyclopentylmethylaminosulfol group, a dimethylaminosulfol group, a getylaminosulfol group, and the like.

 [0033] As these Ar and the substituent on Ar, a C alkyl group and a C alkoxy group are preferable.

 1 2 1-6 1-6

 Particularly preferred are a methyl group and a methoxy group.

 [0034] The substituent on Ar is preferably substituted para to the substitution position of the pyrazole ring.

As the lower alkyl group represented by 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.

As also lower alkyl group which may have a substituent represented by [0037] R ^3, 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.

As also lower alkyl group which may have a substituent represented by [0039] R ^4, 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. Of these, 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. This Here, examples of the lower alkylamino group include a c alkylamino group, and a di (lower alkyl

 1-6

 Le) amino groups include di (C alkyl) amino groups, and aryl groups having 6 to 14 carbon atoms.

 1-6

 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.

[0041] As also 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. Here, 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.

[0042] As also 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.

Examples of the 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.

 As 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.

2

 It may be formed. 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.

[0045] 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. Examples of the solvent include lower alcohols such as methanol and ethanol, organic solvents such as acetone and acetonitrile, and water. The

 Hereinafter, a typical method for producing the compound (I) of the present invention will be described.

 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.

[0048]

(1) Ar, ~ NH ₂

 (3)

(In the above formula, Ar and Ar represent the same as described above.)

 1 2

 Sodium hydride is suspended in a suitable solvent such as tetrahydrofuran at 20 to 20 ° C under an argon stream, getyl cyanomethylphosphonate is added dropwise, and then compound (1) is added and stirred to give compound (2). ) Can be obtained.

 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. As the 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.

 Next, 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. Thus, compound (5) can be produced.

 [0052] 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

As the 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.

 [0055] By subjecting the pyrazoleamine derivative (6) obtained by the above production method to acylation, the present compound (la) can be obtained.

[0056] [Formula 4]

(6) R—COGI (I _a )

 (8)

(In the above formula, Ar, Ar and R ⁴ are the same as described above.)

 1 2

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. (A Wiley-mterscience publication, New York, 1976), "Synthetic Peptides" by GR Pettit (Elsevier Scientific Publication Company, New York, 1976), edited by The Chemical Society of Japan, 4th Ed. , Organic Synthesis IV "(Maruzen Co., Ltd., 1991). This condensation reaction Examples of the solvent used include solvents such as N, N-dimethylformamide, pyridine, chloroform, methylene chloride, tetrahydrofuran, dioxane, and acetonitrile, and a mixed solvent thereof. The reaction temperature is preferably 20-50 ° C, more preferably 10-30 ° C. As the carboxylic acid (7) and the acid chloride (8), commercially available compounds may be used, or the methods described in Reference Examples or those produced according to those methods may be used.

 [0058] Among the compound (I) of the present invention, the compound (lb) in which n is 1 can be produced using the following pyrazolecarboxylic acid derivative (14) as a production intermediate.

[0059] [Formula 5]

 (14)

(In the above formula, Ar and Ar represent the same as described above, and IT represents a methyl group or an ethyl group.

 1 2

 Indicates. )

 Dissolve or suspend ketone (9) and dialkyl oxalate (10) in an appropriate solvent such as N, N-dimethylformamide, add sodium hydride at 20-20 ° C under argon stream, and stir. Thereby, compound (11) can be obtained.

[0061] 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.

Further, 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.

 As the 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.

 Next, 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.

 [0065] In the above-mentioned pyrazole ring formation reaction, instead of adding acetic acid, an appropriate amount of triethylamine or concentrated hydrochloric acid may be added, followed by heating under reflux. In some cases, acetic acid, triethylamine or concentrated hydrochloric acid may be added. Without this, compound (12) can be obtained.

 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 Π). 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.

 [0067] 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. Examples of the base include hydroxides of alkali metals (eg, lithium, sodium, potassium, etc.). Examples of the Lewis acid include boron tribromide. The reaction temperature is preferably from -20 to 100 ° C, more preferably from 5 to 50 ° C.

 [0068] Further, based on ordinary knowledge of organic chemistry, substitution of Ar or Ar on compound (12)

12 groups can be modified. For example, when 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. As a result, compound (12) substituted with a methoxy group as a substituent of Ar can be produced. In addition, 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.

From the pyrazolecarboxylic acid derivative (14) obtained by the above method or an ester (12) as a precursor thereof, a pyrazolemethylamine derivative (18), which is an intermediate for producing the compound of the present invention (lb), is obtained. Can be manufactured.

[0070]

 (1 4) (1 8)

(In the formula, Ar, Ar and R ⁵ are the same as described above, and Z represents a leaving group.)

 1 2

 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.

 [0073] 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.

[0074] Next, 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. -It can be produced by reacting with ruchloride. Z group is p-toluenesulfonyloxy group Compound (16) such as trifluoromethanesulfonyloxy group can be produced under the same conditions. When the Z group is a chloro group, a bromo group or an odo group, 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.

[0075] 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.

 [0076] 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.

 [0078] [Formula 7]

 (23) (22)

(In the formula, Ar and Ar represent the same as described above, and Z represents a leaving group.)

 1 2

Conversion of carboxylic acid (14) to ketone (19) 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.

 [0080] 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).

 [0081] 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.

 [0082] Next, 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. When 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. When the Z group is a chloro group, a bromo group or an odo group, etc., 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.

 [0083] 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.

[0085] 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. In addition, 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.

[0086] [Formula 8]

(Wherein, Ar, Ar and R ² are the same as those described above, and R ° is low which may have a substituent.

 1 2

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 And 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. Further, the compound (lb) of the present invention is also produced by condensing a pyrazole methylamine derivative (18) or (23) with a carboxylic acid (7).

[0088] In the above condensation reaction, a method generally used as a peptide synthesis method may be applied mutatis mutandis. Commonly used 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. A Wiley— mterscience publication, New York, l9 / o ), "Synthetic Peptides" by GR Pettit (Elsevier Scientific Publication Company, New York, 1976), edited by The Chemical Society of Japan, "4th Edition Experimental Chemistry Course, Vol. 22, Organic Synthesis IV" (Maruzen Co., Ltd., 1991), etc. It is described in. Examples of the solvent used for this condensation reaction include solvents such as N, N-dimethylformamide, pyridine, chloroform, methylene chloride, tetrahydrofuran, dioxane, and acetonitrile, and a mixed solvent thereof. The reaction temperature is preferably from 20 to 50 ° C, more preferably from 10 to 30 ° C. As the carboxylic acid (7) and the acid chloride (8), commercially available compounds may be used, or the methods described in Reference Examples or those produced according to those methods may be used.

Further, among the compounds of the present invention, 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. Of the compound (24) in which the leaving group W is a 412-trophenyl-oxy group by treating with 4-trophenol-chloroformate in the presence of an organic amine such as triethylamine. It can be produced by adding 25). The reaction temperature is preferably 10-50 ° C.

 [0090] 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.

 [0091] The carboxylic acid (7), acid chloride (8) and amine compound (25) used in the above-mentioned production method are commercially available, or the methods described in Reference Examples or a method analogous thereto. You can use the one made in.

 [0092] In the above reaction, it may be necessary to protect the functional group. Protecting groups and their cleavage conditions can be selected appropriately based on ordinary knowledge of organic chemistry!

 [0093] Further, 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.

[0094] 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. Therefore, 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 circulation.

 [0095] When the compound (I) of the present invention, a salt or solvate thereof, or a solvate of a salt thereof is used as a medicament, 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! / ヽ. In this case, the daily dose can be divided into several doses and, if necessary, the daily dose can be exceeded.

 [0096] 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. 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. .

 [0097] Examples of 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.

 [0098] As an injection, 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.

 [0099] In preparing these preparations, pharmaceutically acceptable additives 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.

 Example

[0100] Hereinafter, a method for producing specific compounds in the present invention will be described, and it will be shown that those compounds exhibit a potent platelet aggregation inhibitory action without inhibiting COX-1 and COX-2. Shown in a specific test.

 [Reference Example 1] 5-hydrazino 2-methoxypyridine hydrochloride

[0101] [Formula 9]

[0102] A solution of sodium nitrite (3.795 g) in water (20 ml) was added dropwise to a solution of 5-amino-2-methoxypyridine (6.21 g) in concentrated hydrochloric acid (50 ml) under ice cooling over 60 minutes. The mixture was stirred at warm for 30 minutes. To the reaction solution, a solution of tin (II) chloride dihydrate (39.5 g) in concentrated hydrochloric acid (30 ml) was added dropwise at an internal temperature of about 10 ° C over 30 minutes, and the mixture was stirred at room temperature for 2 hours. Under ice-cooling, a solution of sodium hydroxide (75 g) in water (300 ml) and getyl ether were added to the reaction solution, followed by separation. The aqueous layer was extracted twice with getyl ether. After that, the aqueous layer was saturated with sodium chloride, extracted with getyl ether, and the combined organic layers were dried over anhydrous sodium sulfate. After filtration, a 1M-ethanol solution (50 ml) was added to the filtrate, and the mixture was stirred. The precipitated solid was collected by filtration, washed with getyl ether, and dried to give the title compound (5.02 g, 57%).

 'H-NMR (400MHz, DMSO-d) δ: 3.81 (3Η, s), 6.82 (1Η, d, J = 8.8Hz

 6

 ), 7.57 (1H, dd, J = 8.8, 2.9Hz), 7.97 (1H, d, J = 2.9Hz), 8.55-9.20 (1H, br), 10 13-10. 50 (3H, br).

 MS (ESI) m / z: 140 (M + H) +.

[Reference Example 2] 5-hydrazino 2-methoxypyridine [0103] [Formula 10]

A solution of sodium nitrite (3.795 g) in water (20 ml) was added dropwise to a solution of 5-amino-2-methoxypyridine (6.207 g) in concentrated hydrochloric acid (50 ml) under ice cooling over 80 minutes. The mixture was stirred at warm for 30 minutes. A solution of tin (II) chloride dihydrate (39.5 g) in concentrated hydrochloric acid (30 ml) was added dropwise to the reaction solution at an internal temperature of about 10 ° C over 60 minutes, and the mixture was stirred at room temperature for 12.5 hours. The reaction solution was cooled under ice-cooling, a solution of sodium hydroxide (54 g) in water (200 ml) and a porcelain form were filtered off to remove insolubles from the liquid, and then separated. Further, the aqueous layer was extracted twice with a black form, and the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound (4.23 g, 60%) as an individual. 'H-NMR (400MHz, CDC1) δ: 3.50-3.68 (2Η, br), 3.88 (3Η, s), 4.86

 Three

 -5. 03 (1H, br), 6.66 (1H, d, J = 8.8 Hz), 7.20 (1H, dd, J = 8.8, 2.9 Hz), 7.77 (1H, d, J = 2.9Hz).

 MS (ESI) m / z: 140 (M + H) +.

 [Reference Example 3] 1- (6-Methoxy-3-pyridyl) -5-phenyl 1H-pyrazole-3-capronic acid

 [0105] [Formula 11]

[0106] 1) 1- (6-Methoxy-3-pyridyl) -5-phenyl 1H-pyrazole-3-potassium ribonate To a solution of acetophenone (9.85 g) in N, N-dimethylformamide (80 ml) was added 60% sodium hydride (6.56 g) at 0 ° C, and the mixture was stirred for 30 minutes. To the reaction solution, a solution of getyl oxalate (23.97 g) in N, N-dimethylformamide (80 ml) was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 13 hours. 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 obtained 4-phenyl 2,4-dioxobutanoic acid ethyl ester was dissolved in ethanol (200 ml), and 5 hydrazino 2-methoxypyridine (11.39 g) of Reference Example 2 was heated and refluxed for 4 hours. After air cooling, the reaction solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to give 1- (6-methoxy-3-pyridyl) -5-phenyl-2-H-pyrazole-3. —Ethyl rubonate (16.37 g, 61%) was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 1.42 (3Η, t, J = 7.OHz), 3.93 (3H, s), 4.

 Three

 45 (2H, q, J = 7.OHz), 6.73 (1H, d, J = 8.8Hz), 7.04 (1H, s), 7.19-7.

26 (2H, m), 7.30-7.37 (3H, m), 7.57 (1H, dd, J = 8.8, 2.6 Hz), 8.11 (

1H, d, J = 2.6Hz).

 MS (ESI) m / z: 324 (M + H) +.

 2) Title compound

 To a solution of the above 1- (6-methoxy-3-pyridyl) -5-phenyl 1H-pyrazole-3-capillic acid ethyl ester (16.37 g) in methanol (250 ml) was added a 1N aqueous solution of sodium hydroxide (126 ml). The mixture was stirred for 30 minutes. The reaction solvent was distilled off under reduced pressure, and water and getyl ether were separated into a residue and a residue. 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.

 'H-NMR (400MHz, CDC1) δ: 3.94 (3Η, s), 6.75 (1Η, d, J = 8.8Hz), 7

 Three

.10 (1H, s), 7.21-7.27 (2H, m), 7.32-7.39 (3H, m), 7.58 (1H, dd, J = 8.8, 2.6Hz), 8.12 (1H, d, J = 2.6Hz).

 MS (ESI) m / z: 296 (M + H) +.

 [Reference Example 4] [1- (6-Methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] methylamine

[0107] [Formula 12]

[0108] 1) [1- (6-Methoxy-3-pyridyl) 5-phenyl-1H-pyrazole-3-yl] methanol Reference Example 3 1- (6-methoxy-3-pyridyl) -5 phenol-1H-pyrazole 3 To a solution of carboxylic acid (1.181 g) in tetrahydrofuran (20 ml) was added dropwise a solution of 1.08 M borane-tetrahydrofuran complex in tetrahydrofuran (9.2 ml) under an argon atmosphere and ice cooling over 10 minutes, followed by stirring at room temperature for 7 hours. . Water and ethyl acetate were added to the reaction solution, and the mixture was stirred. The precipitated insoluble material was removed by filtration, and the organic layer was separated. 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, and the residue obtained was purified by silica gel column chromatography (hexane ethyl acetate) and purified with [1- (6-methoxy-3-pyridyl) 5-phenyl-1H-pyrazole-3-yl. [Methanol] (682 mg, 60%) as an oil

'H-NMR (400MHz, CDC1) δ: 3.92 (3Η, s), 4.79 (2Η, s), 6.52 (1H, s)

 Three

 , 6.72 (1H, d, J = 8.5Hz), 7.18-7.27 (2H, m), 7.29-7.37 (3H, m), 7.52 (1H, dd, J = 8.5, 2.7Hz), 8.07 (1H , d, J = 2.7Hz).

 MS (ESI) m / z: 282 (M + H) +.

2) [1- (6-Methoxy-3-pyridyl) 5-phenyl-1H-pyrazol-3-yl] methyl methanesulfonate Triethylamine (611) was added to a solution of the above [1- (6-methoxy-3-pyridyl) 5-phenyl-1H-pyrazol-3-yl] methanol (112 mg) in methylene chloride (4 ml) at room temperature. And methanesulfoyl chloride (341) were stirred and stirred for 15 minutes. Water and ethyl acetate were added to the reaction solution to carry out liquid separation. 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 to give [1 (6-methoxy-3-pyridyl) 5-fluoro-1H-pyrazol-3-yl] methyl methanesulfonate (138 mg, 96%) as an oil. Was.

 MS (ESI) m / z: 360 (M + H) +.

 3) [1- (6-Methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] methylazide,

 To a solution of the above [1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] methyl methanesulfonate (138 mg) in N, N-dimethylformamide (4 ml) was added sodium azide (130 mg). ) And stirred at 80 ° C. for 13 hours. After air cooling, 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 distilled off under reduced pressure to obtain [1- (6-methoxy-3-pyridyl) -5-phenyl-1H-virazol-3-yl] methyl azide (105 mg, 89%) as an oil.

ESI-MSm / z: 307 (M + H) ⁺ .

 4) Title compound

 To a solution of the above [1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] methyl azide (105 mg) in ethanol (10 ml) was added 10% palladium on carbon (50% wet, 20 mg). The mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The catalyst was removed by filtration, and the mother liquor solvent was distilled off under reduced pressure to obtain the title compound (96 mg, quantitative) as an oil.

ESI-MSm / z: 281 (M + H) +.

[Reference Example 5] 1- (6-Methoxy-3-pyridazyl) -5- (2-pyridyl) -1H-pyrazole-3 monoester rubonic acid methyl ester [0109] [Formula 13]

[0110] 1) 4- (2-pyridyl) -2,4-dioxobutanoic acid methyl ester

 Under an argon atmosphere, to a solution of dimethyl oxalate (5.0 OOg) and sodium methoxide (2.29 g) in methanol (26 ml), add a solution of acetylviridine (2.56 g) in methanol (26 ml) at room temperature and add it for 15 minutes. After stirring, the mixture was stirred at 60 ° C. for 45 minutes. After air cooling, water was added to the reaction solution, which was washed with ethyl ether. To the aqueous layer were added a saturated aqueous solution of sodium chloride and ammonium chloride, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain methyl 4- (2-pyridyl) 2,4-dioxobutanoate (3.44 g, 79%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.94 (3Η, s), 7.54--7.50 (1Η, m), 7.64

 Three

 (1H, s), 7.93-7. 89 (1H, m), 8.19-8.16 (1H, m), 8.74-8.72 (1H, m) EI-MSm / z: 207 (M +).

 2) 1— (6—Mouth—3 pyridazyl) —5— (2-pyridyl) —1H—pyrazole—3—pyruvonic acid methyl ester

A solution of the above 4- (2-pyridyl) -2,4-dioxobutanoic acid methyl ester (4.143 g) and 3-chloro-6 hydrazinopyridazine (2.891 g) in methanol (100 ml) was heated under reflux for 109 hours. . Concentrated hydrochloric acid (2 ml) was added to the reaction solution, and the mixture was further heated under reflux for 6 hours. After air cooling, a saturated aqueous solution of sodium hydrogen carbonate 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 then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and 1- (6-chloro-3-pyridazyl) -5- (2-pyridyl) -1H-pyrazole-3-pyruvonic acid The chill ester (3.169 g, 50%) was obtained as a solid.

 'H-NMR (400MHz, CDCl) δ: 4.00 (3Η, s), 7.24-7.28 (1Η, m), 7.24

 Three

 (1H, s), 7.64 (1H, dt, J = 7.8, 1.2Hz), 7.70 (1H, d, J = 9.0Hz), 7.79 (1H, td, J = 7.8, 1.7Hz), 8.09 (1H, d, J = 9.0Hz), 8.38-8.41 (1H, m). ESI-MSm / z: 316 (M + H) +.

3) Title compound

 In a methanol (190 ml) solution of the above 1- (6-cyclomouth-3 pyridazyl) -5- (2 pyridyl) -1H-pyrazole-3 carboxylate (2.98 lg) was added sodium methoxide (1.530 g) at room temperature. g) was added and stirred for 19 hours. A 1N aqueous hydrochloric acid solution (19 ml) was added to the reaction solution, and methanol was distilled off under reduced pressure. Water was added to the resulting residue, and the insoluble solid was collected by filtration and dried to give the title compound (2.571 g, 87%). %) As a solid.

 'H-NMR (400MHz, CDCl) δ: 3.99 (3Η, s), 4.10 (3Η, s), 7.15 (1H, d,

 Three

 J = 9.3Hz), 7.21-7.23 (1H, m), 7.24 (1H, s), 7.58-7.61 (1H, m), 7.73-7.78 (1H, m), 7.93 (1H, d, J = 9.3Hz), 8.40-8.41 (1H, m).

LC-MSm / z: 312 (M + H) +.

 [Reference Example 6] 1- (6-Methoxy-3-pyridyl) -5-phenyl-1H-pyrazole-3-ylamine

[Formula 14]

1) 1- (6-Methoxy-3-pyridyl) 5-ferruo 4,5-dihydro-1H-pyrazole-3-ylamine

Under an argon atmosphere, 5 hydrazino 2-methoxypyridine (6. Og) and cinnamic acid in Reference Example 2 Sodium methoxide (4.66 g) was added to a solution of nitrile (5.57 g) in ethanol (120 ml) at room temperature, and the mixture was heated under reflux for 13 hours. After air cooling, water and chloroform were added to the reaction solution to carry out liquid separation. The organic layer was dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The resulting residue was washed with getyl ether, and the resulting solid was collected by filtration, dried and dried to give the 4,5-dihydro-1H-pyrazolyl-3-ylamine (8.28 g). , 71%).

 'H-NMR (400MHz, CDC1) δ: 2.82-2.88 (1Η, m), 3.28-3.32 (1H, m

 Three

 ), 3.81 (3H, s), 4.02 (2H, m), 4.70-4.76 (1H, m), 6.57 (1H, d, J = 8.8 Hz), 7.26-7.42 (6H, m), 7.61 (1H , d, J = 2.8Hz).

MS (El) m / z: 268 (M ⁺ ).

2) Title compound

 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. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform ethyl acetate) to obtain the title compound (6.92 g, 84%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.79 (2Η, br s), 3.91 (3H, s), 5.92 (1H

 Three

 , s), 6.69 (1H, d, J = 8.8Hz), 7.20-7.32 (5H, m), 7.49 (1H, dd, J = 8.

8, 2.8Hz), 8.00 (1H, d, J = 2.8Hz).

MS (El) m / z: 266 (M ⁺ ).

[Reference Example 7] 1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazole-3-ylamine [0113] [Formula 15]

[0114] 1) 3— (2 Pyridyl) acrylonitrile

 To a suspension of 60% sodium hydride (3.7 g) in tetrahydrofuran (120 ml) was added dropwise ethyl cyanomethylphosphonate (10.Og) under ice cooling, followed by stirring for 20 minutes. A solution of 2-pyridincarboxaldehyde (9. Og) in tetrahydrofuran (30 ml) was added dropwise to the reaction solution, and the mixture was stirred for 24 hours. A saturated aqueous solution of sodium chloride and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane) to obtain 3- (2-pyridyl) acrylonitrile (3.9 g, 35%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 6.59 (1Η, d, J = 16.1Hz), 7.31-7.35 (2

 Three

 H, m), 7.40 (1H, d, J = 16.1Hz), 7.72-7.77 (1H, m), 8.63-8.65 (1H, m).

MS (El) m / z: 130 (M ⁺ ).

 2) 1- (6-Methoxy-3-pyridyl) 5- (2-pyridyl) -4,5-dihydro-1H-pyrazonole 3-ylamine

 Using 5 hydrazino 2-methoxypyridine (4.17 g) of Reference Example 2 and the above 3- (2-pyridyl) atali-tolyl (3.9 g), 1- (6) was obtained in the same manner as 1) of Reference Example 6. —Methoxy-3-pyridyl) -5- (2-pyridyl) 4,5-dihydro-1H-pyrazole-3-ylamine (4.5 g, 55%) was obtained as a solid.

MS (El) m / z: 269 (M ⁺ ).

3) Title compound Manganese dioxide (5.3 g) was added at room temperature to a solution of 1 (6-methoxy-3-pyridyl) -5- (2-pyridyl) 4,5-dihydro-1H-pyrazol-3ylamine (4.5 g) in dichloromethane (100 ml) at room temperature. The mixture was stirred for 3 hours. The reaction mixture was filtered using Celite and Florisil to remove insolubles, and the organic solvent in the filtrate was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to give the title compound (3. 06g, 38%) as a solid.

 'H-NMR (400 MHz, CDC1) δ: 3.84 (2Η, br s), 3.92 (3H, s), 6.17 (1H

 Three

 , s), 6.72 (1H, d, J = 8.8 Hz), 7.19-7.24 (2H, m), 7.57-7.65 (2H, m), 8.01 (1H , d, J = 2.7 Hz), 8.52—8.5.55 (1H, m).

 MS (FAB) m / z: 268 (M + H) +.

 [Reference Example 8] 1- (6-Methoxy-3-pyridazyl) -5- (2-pyridyl) -1H-pyrazole-3-ylamine

[0115] [Formula 16]

[0116] To a solution of 6-hydrazide pyridine (3.61 g) and 3- (2-pyridyl) attril nitrile (3.25 g) of 1) of Reference Example 7 in methanol (75 ml) was added sodium methoxide. (2.70 g) was heated and refluxed for 75 hours under an argon atmosphere. After air cooling, water and black-mouthed form were added to the reaction mixture, and the mixture was separated. The organic layer was dried with anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was dissolved in dichloromethane (75 ml), manganese dioxide (3.0 Og) was added, and the mixture was heated under reflux for 8 hours. After air cooling, a solid was filtered off from the reaction solution, and the filtrate solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol (25 ml), sodium methoxide (1.08 g) was added, and the mixture was heated under reflux for 1 hour. After air cooling, water and chloroform were added to the reaction solution to carry out liquid separation. Organic layer anhydrous sulfur Dried over sodium acid. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-form methanol) to give the title compound (0.878 g, 13%) as a solid.

 'H-NMR (400 MHz, CDC1) δ: 3.87 (2Η, br s), 4.06 (3H, s), 6.16 (1H

 Three

 , s), 7.06 (1H, d, J = 9.2 Hz), 7.16-7.27 (1H, m), 7.43-7.50 (1H, m), 7.66-7 .74 (1H, m), 7.80 (1H, d, J = 9.2Hz), 8.43-8.52 (1H, m) .MS (ESI) m / z: 269 (M + H) +.

 [Reference Example 9] [1 (6-Methoxy-3-pyridyl) 5- (2-pyridyl) 1H-pyrazol-3-yl] methylamine

[0117] [Formula 17]

[0118] 1) 1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazole-3-Rubonic acid methyl ester

 Reference Example 5 1) 4 (2-pyridyl) -2,4-dioxobutanoic acid methyl ester (4.12 g) in N, N-dimethylformamide (20 ml) solution was added to Reference Example 2 5-hydrazino-2-methoxypyridine. A solution of (2.767 g) in N, N-dimethylformamide (10 ml) was collected, stirred at 80 ° C. for 16 hours, further stirred at 110 ° C. for 5 hours. After air cooling, water and ethyl acetate were added to the reaction mixture, 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 column chromatography (ethyl acetate) to give 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) 1H virazole. 3-Rubonic acid methyl ester (1.097 g, 17%) was obtained as a solid.

'H-NMR (400MHz, CDC1) δ: 3.95 (3Η, s), 3.98 (3Η, s), 6.76 (1H, d, J = 8.8Hz), 7.21-7.28 (1H, m), 7.28 (1H, s), 7.36 (1H, d, J = 8.0Hz), 7.64-7.73 (2H, m), 8.10 (1H, d, J = 2.7Hz), 8.52 (1H, d, J = 4.1Hz)

ESI-MSm / z: 311 (M + H) +.

 2) [1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) 1H-pyrazol-3-yl] methano

 To a solution of the above 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazole-3 carboxylic acid methyl ester (1.097 g) in tetrahydrofuran (15 ml) at room temperature was added lithium borohydride (154 mg). ) And stirred for 6 hours. 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 distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroformumethanol) to give [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) 1H —Pyrazol-3-yl] methanol (581 mg, 58%) was obtained as amorphous.

'H-NMR (400MHz, CDC1) δ: 2.07 (1Η, t, J = 5.8Hz), 3.94 (3Η, s), 4.

 Three

 80 (2Η, d, J = 5.8Hz), 6.75 (1H, d, J = 8.8Hz), 6.77 (1H, s), 7.18-7.24 (1H, m), 7.28-7.33 (1H, m), 7.61 (1H, dd, J = 2.7, 8.8Hz), 7.64-7.70 (1H, m), 8.07 (1H, d, J = 2.7Hz), 8.51-8.56 (1H, m).

ES MSm / z: 283 (M + H) +.

 3) [1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methyl methanesulfonate

Using [1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methanol (581 mg), [1— ( 6-Methoxy-3-pyridyl) -5- (2-pyridyl) 1H-pyrazol-3-yl] methyl methanesulfonate (754 mg, quantitative) was obtained as an oil. It was used for the next reaction without further purification. ESI-MSm / z: 361 (M + H) ⁺ .

 4) [1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methylazide

The above [1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] me [11- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazole-3-yl was prepared in the same manner as in 3) of Reference Example 4 using tyl methanesulfonate (498 mg). ] Methyl azide (341 mg, 80%) was obtained as an oil.

 'H-NMR (400MHz, CDCl) δ: 3.94 (3Η, s), 4.46 (2Η, s), 6.76 (1H, d,

 Three

 J = 8.8Hz), 6.78 (1H, s), 7.20-7.26 (1H, m), 7.31 (1H, d, J = 7.8Hz), 7.62 (1H, dd, J = 8.8, 2.7 Hz), 7.64-7.71 (1H, m), 8.08 (1H, d, J = 2.7Hz), 8.52-8.57 (1H , m).

ESI-MSm / z: 308 (M + H) +.

5) Title compound

 Using the above [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methylazide (341mg) in the same manner as in 4) of Reference Example 4 The compound (314 mg, quantitative) was obtained as an oil.

ESI-MSm / z: 282 (M + H) ⁺ .

 [Reference Example 10] 1- [1- (6-methoxy-3-pyridyl) -5-phenyl 1H-pyrazole-3-yl] ethylamine

[Formula 18]

1) 1— [1— (6-Methoxy-3-pyridyl) -5-phenyl 1H-pyrazol-3-yl] ethanone

To a solution of 1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazole-3-carbonic acid (1.181 g) in Reference Example 3 in tetrahydrofuran (20 ml) was added 1.14 M methyllithium under ice cooling. A getyl ether solution (7 ml) was added dropwise over 15 minutes, and the mixture was stirred at room temperature for 4 hours. Reaction liquid A saturated aqueous sodium chloride solution and ethyl acetate were separated into aqueous and organic layers, and the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 1- [1- (6-methoxy-13-pyridyl) 5-phenyl-1-H —Pyrazole-13-yl) ethanone (352 mg, 30%) was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 2.65 (3Η, s), 3.95 (3Η, s), 5.10-5.20 (

 Three

 1H, br), 6.75 (1H, d, J = 8.8 Hz), 7.00 (1H, s), 7.20-7.26 (2H, m), 7.32-7.37 ( 3H, m), 7.53 (1H, dd, J = 8.8, 2.7 Hz), 8.15 (1H, d, J = 2.7 Hz).

 ESI-MSm / z: 294 (M + H) +.

 2) l— [1— (6-methoxy-3 pyridyl) -5-ferro 1H—pyrazol-3-yl] etano

 Sodium borohydride (45 mg) was added to a solution of the above 1- [1- (6-methoxy-3-pyridyl) -5 phenol-1H-pyrazol-3-yl] ethanone (353 mg) in methanol (6 ml) at room temperature. 1. Stirred for 5 hours. 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 then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 1- [1- (6-methoxy-3-pyridyl) 5phenyl-1H-pyrazol-3-yl] ethanol (348 mg, 98%) as an individual.

 'H-NMR (400MHz, CDC1) δ: 1.62 (3Η, d, J = 6.6Hz), 2.39 (1H, d, J =

 Three

 4.4 Hz), 3.92 (3H, s), 5.04 (1H, qd, J = 6.6, 4.4 Hz), 6.48 (1H, s), 6.71 (1H, d, J = 8.8Hz), 7.19-7.27 (2H, m), 7.28-7.36 (3H, m), 7.52 (1H, dd, J = 8.8, 2.7 Hz ), 8.07 (1H, d, J = 2.7Hz).

ES G MSm / z: 296 (M + H) +.

 3) 3- (1-Chloroethyl) -1- (6-methoxy-3-pyridyl) -5 Feru 1H-Pyrazol

To a solution of the above 1- [1- (6-methoxy-3-pyridyl) -5 phenol-1H-pyrazol-3-yl] ethanol (345 mg) in dichloromethane (10 ml) was added triethynoleamine (179 mg) under ice-cooling. μ1) and methanesulfonyl chloride (991) were added, and the mixture was stirred at room temperature for 3 hours. Sarako, the reaction solution Triethylamine (147 μl) and methanesulfoyl chloride (82 μl) were added and stirred for 5 hours. The reaction solvent was evaporated under reduced pressure, water and ethyl acetate were added to the obtained residue, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to give 3- (1-chloroethyl) -1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazole (448 mg) as an oil.

ESI-MSm / z: 314 (M + H) ⁺ .

 4) 1— [1— (6-Methoxy-3-pyridyl) -5 phenyl 1H—pyrazol-3-yl] ethyl azide

 Using the above 3- (1-chloroethyl) -1- (6-methoxy-3-pyridyl) -5 feruyl 1H pyrazole (448 mg) and sodium azide sodium (380 mg), refer to Reference Example 4-3). In a similar manner, 1- [1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] ethyl azide (312 mg, 83% in two steps from an ethanol compound) was obtained as an oil.

'H-NMR (400MHz, CDC1) δ: 1.65 (3Η, d, J = 7.OHz), 3.93 (3H, s), 4

 Three

 .74 (1H, q, J = 7.OHz), 6.50 (1H, s), 6.72 (1H, d, J = 8.8Hz), 7.20-7.26 (2H, m), 7.30-7.37 (3H, m), 7.53 (1H, dd, J = 8.8, 2.7Hz), 8.07 (1H, d, J = 2.7Hz).

ESI-MSm / z: 321 (M + H) ⁺ .

 5) Title compound

 Using the above 1- [1- (6-methoxy-3-pyridyl) -5 phenol-1H-pyrazol-3-yl] ethylazide (312 mg) in the same manner as 4) of Reference Example 4 (298 mg, quantitative) was obtained as an oil.

ES MSm / z: 295 (M + H) +.

[Reference Example 11] [1- (6-Methoxy-3-pyridazyl) -5- (2-pyridyl) -1H-pyrazole-3-yl] methylamine [0121] [Formula 19]

[0122] 1) [1- (6-Methoxy-3-pyridazyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methanol

 Hydrogenation of 1- (6-methoxy-3-pyridazyl) -5- (2-pyridyl) -1H-pyrazole-3-capillonic acid methyl ester (2.567 g) in tetrahydrofuran (80 ml) of Reference Example 5 Lithium boron (1.077 g) was added, and the mixture was stirred at room temperature for 46 hours. The reaction solvent was evaporated under reduced pressure, water and ethyl acetate were added to the obtained residue, and the mixture was separated, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give [1- (6-methoxy-3-pyridazyl) -5- (2-pyridyl). ) —1H-Pyrazol-3-yl] methanol (1.141 g, 48%) was obtained as amorphous.

 'H-NMR (400MHz, CDC1) δ: 2.04—2.15 (1Η, br), 4.09 (3H, s), 4.82

 Three

 (2H, s), 6.74 (1H, s), 7.11 (1H, d, J = 9.3Hz), 7.19-7.23 (1H, m), 7.51--7.55 (1H, m), 7.72 (1H, td, J = 7.8, 1.9 Hz), 7.83 (1H, d, J = 9.3 Hz), 8.42-8.45 (1H , m).

 ESI-MSm / z: 284 (M + H) +.

 2) [1- (6-Methoxy-3-pyridazyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methyl methanesulfonate

Using [1- (6-methoxy-3-pyridazyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methanol (1.097 g) described above, in the same manner as in 2) of Reference Example 4, [1- (6-Methoxy-3-pyridazyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methyl methanesulfo Nart (1.078 g, 77%) was obtained as an individual.

ESI-MSm / z: 362 (M + H) ⁺ .

 3) [1- (6-Methoxy-3-pyridazyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methylazide

 Using the above [1- (6-methoxy-3-pyridazyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methyl methanesulfonate (1.078mg) and sodium azide (969mg), [1 (6-Methoxy-3-pyridazyl) -5- (2-pyridyl) 1H-pyrazol-3-yl] methylazide (790 mg, 85%) was obtained as an individual in the same manner as in 3) of Reference Example 4.

'H-NMR (400MHz, CDCl) δ: 4.10 (3Η, s), 4.46 (2Η, s), 6.75 (1H, s)

 Three

 , 7.13 (1H, d, J = 9.3Hz), 7.20-7.24 (1H, m), 7.54 (1H, d, J = 7.8Hz), 7.73 (1H, td, J = 7.8, 1.8Hz), 7.85 ( 1H, d, J = 9.3Hz), 8.43-8.46 (1H, m).

 ES MSm / z: 309 (M + H) +.

 4) Title compound

 To a solution of the above [1- (6-methoxy-3-pyridazyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methylazide (254 mg) in methanol (25 ml) at room temperature was added 10% palladium-carbon ( (50% wet, 51 mg) and stirred under a hydrogen atmosphere for 2 hours. After filtering off the catalyst, the mother liquor solvent was distilled off under reduced pressure to obtain the title compound (228 mg, 98%) as a solid.

ES MSm / z: 283 (M + H) +.

[Reference Example 12] N— [1 (6-Methoxy-3-pyridyl) -5— (2-pyridyl) -1H-pyrazonole-3-yl] methyl-N-methylamine

[0123] [Formula 20]

[0124] Reference example 9-3) [1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazole-3-yl] methyl methanesulfonate (214 mg) in tetrahydrofuran (5 ml) To the solution was added a 2.OM methylamine-tetrahydrofuran solution (1.48 ml), and the mixture was stirred at room temperature for 45 hours. Getyl ether was added to the reaction solution, and the insoluble material was filtered off. The filtrate solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel thin-layer chromatography (chloroform-methanol) to give the title compound (52 mg). , 29%) as an oil.

 ES G MSm / z: 296 (M + H) +.

 [Example 1] N- [1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazole-3-ylmethyl] acetamide

[0125] [Formula 21]

[1- (6-Methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] of Reference Example 4 To a solution of methylamine (96 mg) in dichloromethane (5 ml) at room temperature was added triethylamine (95 μ1) and sodium chloride. Dashi acetyl (36a1) was added and stirred for 1 hour. Water and ethyl acetate were added to the reaction After washing, 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, and the obtained residue was purified by silica gel thin-layer chromatography (form: methanol) to give the title compound (93 mg, 84%) as an amorphous substance.

'H-NMR (400 MHz, CDC1) δ: 2.05 (3Η, s), 3.93 (3Η, s), 4.54 (2H, d,

 Three

 J = 5.2Hz), 6.07-6.17 (1H, br), 6.46 (1H, s), 6.72 (1H, d, J = 8.8Hz), 7.19-7. 26 (2H, m), 7.30-7.37 (3H, m), 7.50 (1H, dd, J = 8.8, 2.7 Hz), 8.07 (1H, d, J = (2.7 Hz).

ES MSm / z: 323 (M + H) +.

 [Example 2] 3- [1- (6-Methoxy-3-pyridyl) -5 phenol-1H-pyrazole-3-ylmethyl] -1-methylperyl

[Formula 22]

In a dichloromethane (4 ml) solution of chloroformic acid (412 mg) (87 mg) in dichloromethane (4 ml), [1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] methyla of Reference Example 4 was added under ice cooling. A solution of min (121 mg) and triethylamine (44 μl) in dichloromethane (4 ml) was added dropwise over 1 minute, and the mixture was stirred at room temperature for 1 hour. Under ice-cooling, a methanol solution of 40% methylamine (85 1) and triethylamine (44 μl) were added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The reaction solvent was evaporated under reduced pressure, water and ethyl acetate were added to the obtained residue, and the mixture was partitioned. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel thin-layer chromatography (chloroform-form methanol) to give the title compound (100 mg, 68%) as an amorphous product.

'H-NMR (400MHz, CDC1) δ: 2.80 (3Η, d, J = 4.9Hz), 3.93 (3H, s), 4 .46 (2H, d, J = 5.5Hz), 4.47--4.56 (IH, br), 4.90--4.98 (IH, br), 6.47 (1H, s), 6.71 (IH, d, J = 8.8Hz) , 7.17-7.23 (2H, m), 7.28-7.33 (3H, m), 7.49 (1H, dd, J = 2.7, 8.8Hz), 8.07 (1H, d, J = 2.7Hz).

 ES MSm / z: 338 (M + H) +.

 [Example 3] 3- [1- (1- (6-Methoxy-3-pyridyl) -5-phenyl-1H-pyrazole-3-yl] ethyl] -1-methylperyl

 [0129] [Formula 23]

[0130] The title compound was prepared in the same manner as in Example 2 using 1- [1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazole-3-yl] ethylamine (152 mg) of Reference Example 10. An individual (119 mg, 63%) was obtained as an individual.

 'H-NMR (400MHz, CDCl) δ: 1.56 (3Η, d, J = 6.6Hz), 2.78 (3H, d, J =

 Three

 4.6Hz), 3.92 (3H, s), 4.68--4.77 (1H, br), 4.98 (IH, qd, J = 6.8, 6.6 Hz), 5.10 (1H, d, J = 6.8Hz), 6.41 (IH, s), 6.71 (IH, d, J = 8.8Hz), 7.17-7.23 (2H, m), 7.28-7.33 (3H, m), 7.48 (IH, dd, J = 8.8, 2.4Hz), 8.07 (1H, d, J = 2.4Hz).

ESI-MSm / z: 352 (M + H) ⁺ .

[Example 4] 3- [1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazonole-3-ylmethyl] -1-methylperyl [0131] [Formula 24]

[0132] A method similar to that of Example 2 using [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methylamine (121 mg) of Reference Example 9 As a result, a title compound (36 mg, 23%) was obtained as an individual.

 'H-NMR (400MHz, CDCl) δ: 2.79 (3Η, d, J = 4.9Hz), 3.94 (3H, s), 4

 Three

 .47 (2H, d, J = 5.6Hz), 4.54-4.68 (IH, br), 5.00-5.12 (1H, br), 6.7 2 (1H, s), 6.74 (IH, d, J = 8.8Hz) , 7.17-7.23 (1H, m), 7.30 (1H, d, J = 8.OHz), 7.58 (IH, dd, J = 8.8, 2.7Hz), 7.61-7.68 (IH, m), 8.06 ( 1 H, d, J = 2.7Hz), 8.49-8.55 (IH, m).

 ES MSm / z: 339 (M + H) +.

[Example 5] 1-isopropyl 3- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazole-3-ylmethyl] メ チ ル rea

[0133] [Formula 25]

[0134] In a dichloromethane (3 ml) solution of [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methylamine (28 mg) of Reference Example 5, isopropyl isocyanate was added. (111) was added and the mixture was stirred at room temperature for 1 hour. The residue obtained by evaporating the reaction solvent under reduced pressure was crystallized from ethyl acetate and filtered to obtain the title compound (28 mg, 77%).

 'H-NMR (400MHz, CDC1) δ: 1.15 (6Η, d, J = 6.6Hz), 3.83-3.93 (1H

 Three

 , m), 3.94 (3H, s), 4.29-4.36 (1H, br), 4.47 (2H, d, J = 5.6Hz), 4.77 -4.83 (1H, br), 6.72 (1H, s), 6.75 ( 1H, d, J = 8.8Hz), 7.17-7.23 (1H, m), 7.28-7.33 (1H, m), 7.58 (1H, dd, J = 8.8, 2.7Hz), 7.63-7.69 (1H, m), 8.06 (1H, d, J = 2.7Hz), 8.49--8.55 (1H, m).

ESI-MSm / z: 367 (M + H) ⁺ .

[Example 6] 3- [1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazonoles-3-ylmethyl] -1-phen-perurea

Using [1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methylamine (28mg) of Reference Example 9 and isocyanate phenol (121), The title compound (24 mg, 60%) was obtained as an individual in the same manner as in Example 5.

 'H-NMR (400MHz, CDCl) δ: 3.94 (3Η, s), 4.55 (2Η, d, J = 5.6Hz), 5

 Three

 .31-5.38 (IH, br), 6.53--6.61 (IH, br), 6.74 (IH, s), 6.74 (IH, d, J = 8.8Hz), 7.04-7.11 (IH, m), 7.18-7.23 (IH, m), 7.26-7.35 (5H, m), 7.57 (1H, dd, J = 8.8, 2.7Hz), 7.62-7.69 (1H, m), 8.05 (1H, d, J = 2.7Hz), 8.49-8.54 (IH, m).

ESI-MSm / z: 401 (M + H) +.

[Example 7] 1,1 dimethyl-3- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) 1H-pyrazol-3-ylmethyl] ゥ rea

[0137] [Formula 27]

[0138] 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.

 'H-NMR (400MHz, CDCl) δ: 2.94 (6Η, s), 3.94 (3Η, s), 4.53 (2H, d,

 Three

 J = 5.3Hz), 4.95-5.05 (1H, br), 6.74 (1H, s), 6.75 (1H, d, J = 8.8Hz), 7.17-7.23 (1H, m), 7.30 (1H, d, J = 7.8Hz), 7.59 (1H, dd, J = 8.8, 2.7Hz), 7.61-7.68 (1H, m), 8.07 (1H, d, J = 2.7Hz), 8.49-8.54 (1H, m).

 ES MSm / z: 353 (M + H) +.

Example 8 1,3-Dimethyl-3- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-ylmethyl] メ チ ル rea

[0139] [Formula 28]

[0140] In Reference Example 12, N- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) 1H-pyrazole-3-yl] methyl-N-methylamine (52 mg) and methyl isocyanate (16 μl ) To give the title compound (51 mg, 82%) as an oil in the same manner as in Example 2.

 'H-NMR (400MHz, CDC1) δ: 2.82 (3Η, d, J = 4.6Hz), 3.00 (3H, s), 3

 Three

 .94 (3H, s), 4.52 (2H, s), 4.77—4.86 (IH, br), 6.71 (IH, s), 6.75 (IH, d, J = 8.8 Hz), 7.18-7.23 (1H, m ), 7.30 (1H, d, J = 8. OHz), 7.59 (1H, dd, J = 8.8, 2.7Hz), 7.63-7.70 (1H, m), 8.07 (1H, d, J = 2.7Hz), 8.50-8.55 (IH, m).

 ES MSm / z: 353 (M + H) +.

[Example 9] N- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -IH-pyrazole-3-ylmethyl] methyl rubamidate

[0141] [Formula 29]

[0142] 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 μl) 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.

 'H-NMR (400MHz, CDC1) δ: 3.71 (3Η, s), 3.94 (3Η, s), 4.49 (2H, d,

 Three

 J = 5.3Hz), 5.18-5.31 (1H, br, NH), 6.72 (1H, s), 6.75 (1H, d, J = 8.8Hz), 7.18-7.24 (1H, m), 7.28 (1H, d, J = 7.8Hz), 7.60 (1H, dd, J = 8.8, 2.7Hz), 7.62-7.69 (1H, m), 8.05 (1H, d, J = 2.7Hz), 8.50-8.56 (1H , m).

 ESI-MSm / z: 340 (M + H) +.

[Example 10] morpholine 4-monorubic acid [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methylamide [0143] [Formula 30]

[0144] Reference Example 10 [1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methylamine (32 mg) and 4 morpholinecarbol chloride (16 μl) were used. The title compound (41 mg, 93%) was obtained as an oil in the same manner as in Example 2.

 'H-NMR (400MHz, CDCl) δ: 3.38 (4Η, t, J = 4.9Hz), 3.69 (4H, t, J =

 Three

 4.9Hz), 3.94 (3H, s), 4.55 (2H, d, J = 5.1Hz), 5.05-5.15 (1H, br), 6.73 (1H, s), 6.75 (1H, d, J = 8.8 Hz), 7.17-7.23 (1H, m), 7.29 (1H, d, J = 7.8Hz), 7.58 (1H, dd, J = 8.8, 2.7Hz), 7.61-7.68 (1H, m), 8.07 (1H , d, J = 2.7Hz), 8.49-8.55 (1H, m).

 ES MSm / z: 395 (M + H) +.

 [Example 11] 3- [1- (6-Methoxy-3-pyridazyl) -5- (2-pyridyl) 1H-pyrazol-3-ylmethyl] -1-methylperyl

[0145] [Formula 31]

[0146] Reference Example 11 [1- (6-Methoxy-3-pyridazyl) -5- (2-pyridyl) -1H-pyrazole Using [3-yl] methylamine (228 mg), the title compound (18 Omg, 64%) was obtained as an individual in the same manner as in Example 2.

 'H-NMR (400MHz, CDC1) δ: 2.79 (3Η, d, J = 4.9Hz), 4.10 (3H, s), 4

 Three

 .48 (2H, d, J = 5.6Hz), 4.70-4.79 (1H, br m), 5.18-5.25 (1H, br m), 6.70 (1H, s), 7.09 (1H, d, J = 9.3Hz), 7.19 (1H, ddd, J = 7.6, 4.9, 1.2Hz), 7.48-7.52 (1H, m), 7.70 (1H, dt, J = 7.6, 1.7Hz), 7.72 (1H, d, J = 9.3Hz), 8.38-8.41 (1H, m).

 ESI-MSm / z: 340 (M + H) +.

 Elemental analysis: C H N O -0.5H O

 16 17 7 2 2

 Theory: C, 55.17; H, 5.21; N, 28.14.

 Found: C, 55.33; H, 5.00; N, 28.14.

 [Example 12] N- [1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] -2,2-dimethylpropionamide

[0147] [Formula 32]

[0148] 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.

'H-NMR (400MHz, CDC1) δ: 1.33 (9Η, s), 3.94 (3Η, s), 6.74 (1H, dd , J = 8.8, 0.5Hz), 7.18-7.20 (1H, m), 7.27 (2H, d, J = 5.1Hz), 7.47-7.49 (IH, m), 7.55-7.59 (IH, m), 7.67 --7.70 (1H, m), 8.05 (IH, d, J = 2.7Hz), 8.45-8.47 (1H, m).

FAB-MSm / z: 352 (M + H) ⁺ .

 [Example 13] N- [1- (6-methoxy-3-pyridazyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] -2,2-dimethylpropionamide

[Formula 33]

Using 1- (6-methoxy-3-pyridazyl) -5- (2-pyridyl) -1H-pyrazole-3 (440 mg) of Reference Example 8, the title compound was prepared in the same manner as in Example 12. 42 lmg, 79%) was obtained as an individual.

 'H-NMR (400MHz, CDCl) δ: 1.34 (9Η, s), 4.10 (3Η, s), 7.07 (1H, d,

 Three

 J = 9.03Hz), 7.17-7.21 (IH, m), 7.30 (1H, s), 7.61-7.76 (3H, m), 8.00 (IH, br s), 8.37-8.39 (IH, m).

EI-MSm / z: 352 (M +).

[Example 14] N-tert-butyl-N,-[1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] oxamide [0151] [Formula 34]

[0152] 1) N- [1- (6-Methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] oxamic acid ethyl ester

 In a solution of 1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazole-3-ylamine (500 mg) of Reference Example 6 in dichloromethane (10 ml), triethylamine (0.33 ml) and salted glyoxylic acid were added at room temperature. The ethyl ester (280 mg) was stirred for 16 hours. Water and dichloromethane were added to the reaction solution, and the mixture was separated, and 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 column chromatography (dichloromethane / ethanol) to give N- [1- (6-methoxy-3-pyridyl) -5-phenyl-1H- Pyrazol-3-yl] oxamic acid ethyl ester (680 mg, quantitative) was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 1.44 (3Η, t, J = 7.1Hz), 3.94 (3H, s), 4.

 Three

 43 (2H, q, J = 7.1 Hz), 6.72 (1H, d, J = 8.8 Hz), 7.10 (1H, s), 7.25-7.28 (5H, m), 7.47-7.51 (1H, m), 8.07 (1H, d, J = 2.5Hz), 9.40 (1H, br s).

 EI-MSm / z: 366 (M +).

 2) N— [1- (6-Methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] oxamic acid

To a solution of the above N- [1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] oxamic acid ethyl ester (680mg) in ethanol (5ml), tetrahydrofuran (5ml) and water (lml) A 6N aqueous sodium hydroxide solution (0.2 ml) was stirred at room temperature for 24 hours. The reaction solvent was evaporated under reduced pressure, concentrated hydrochloric acid was added to the obtained residue for neutralization, dichloromethane was added, and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent is decompressed Under reduced pressure, N- [l- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] oxamic acid (560 mg, 89%) was obtained. It was used for the next reaction without further purification. EI-MSm / z: 338 (M +).

3) Title compound

 N- [1- (6-Methoxy-3-pyridyl) -5 phenol-1H-pyrazol-3-yl] oxamic acid (560mg), 1-hydroxybenzotriazole (340mg), 1-ethyl-3- (3-dimethyl) Triethylamine (0.4 ml) was stirred at room temperature in a solution of (aminopropyl) carbodiimide hydrochloride (475 mg) and tert-butylamine (133 mg) in dichloromethane (10 ml) for 16 hours at room temperature. Water and dichloromethane were added to the reaction solution, and the mixture was separated, and 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 / acetone) to give the title compound (55 mg, 7.4%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.44 (9Η, s), 3.93 (3Η, s), 6.72 (1H, d,

 Three

 J = 8.8Hz), 7.02 (1H, s), 7.24-7.39 (5H, m), 7.45-7.59 (1H, m), 8.06 (1H, d, J = 2.7 Hz), 9.76 (1H, br s).

EI-MSm / z: 393 (M +).

[Test Example 1] Platelet aggregation inhibitory effect

 Human blood was collected using 1Z10 volumes of 3.13% sodium citrate as an anticoagulant, and centrifuged at 180 g for 10 minutes to separate platelet-rich plasma (PRP). After collecting the upper layer of PRP, the lower layer was centrifuged at 1600 g for 10 minutes to collect the upper layer of platelet poor plasma (PPP). 1 μl of the solution of the example compound was added to 200 μl of PRP, allowed to stand at 37 ° C. for 2 minutes, and then added with 2 μl of collagen to induce platelet aggregation. The platelet aggregation rate was measured using ΡΑΜ-12C (SSR Engineering). Using the light transmittance of と し as the 100% aggregation value, the aggregation ratio at each concentration of the example compound was determined, and the IC value was calculated. The results are shown in Table 1.

 50

 [Test Example 2] Cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (CO X-2) inhibitory action

To measure the COX-1 and COX-2 inhibitory activities of the compounds of the examples, a Cayman Chemical Company COX inhibitor screening assay kit (catalog number 560101, 560121) was used.

 [0153] Before the measurement, the reaction buffer, heme, arachidonic acid, SnCl, EIA buffer, washing buffer,

 2

 Staglandin (PG) screening EIA standard solution, PG screening acetylcholinesterase (AchE), tracer (chromogenic enzyme HRP conjugate), PG screening EI A antiserum were prepared.

 (1) Production of PGFα by COX-1 or COX-2

 2

 A reaction solution containing the compound of the example (50 μM) 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

 2

 did.

 (2) Quantification of PGF α by ELISA

 2

 After each mouse well of a 96-well (panel) plate coated with mouse anti-panther IgG was coated with 50 ^ 1 of an antiserum (panthera anti-PGFα antibody), the above PGFα production reaction solution was increased by 2000 times.

 twenty two

 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.

 (3) Calculation of inhibitory activity of example compounds

 PG screening A standard curve was prepared using an EIA standard solution, and the absorbance power was also used to determine the amount of PGFa produced. Example Compound Inhibition of COX-1 or COX-2 in 50 μΜ

2

 The harm rate was calculated. The results are shown in Table 1.

[0154] In the calculation of the inhibition rate, the production amount of PGFα obtained using the reaction solution containing no example compound was defined as 100%.

 2

[0155] [Table 1] Collagen-induced platelets at 50 μΜ at 50 μΜ

 Compound

 Agglutination inhibitory action COX-1 inhibitor COX-2 inhibitor

 (Example number)

For IC ₅₀ (μΜ) (% inhibition) (Inhibition./.)

 1 0.0 9 2 2.3 9.5

 2 0. 0 1 9 9. 2 — 2. 9

 3 0.1 8 ND ND

 4 0.0 9 2 ND ND

 5 0.0 34 6.6.8.4

 7 0.093 ND ND As apparent from Table 1, 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.

Claims

Claims [1] General formula (I)

 [Chemical 1]

(Wherein, Ar and Ar each independently may have 1 to 3 substituents

 1 2

 A 5- or 6-membered aromatic heterocyclic group or a C 6-14 aryl group which may 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. Represents a certain heterocyclic group;

 n shows the number of 0 or 1. )

 Or a salt thereof, or a solvate thereof.

[2] Ar and Ar forces each independently may have 1 to 3 substituents, nitrogen

 1 2

 The compound according to claim 1, which is a 5- or 6-membered aromatic heterocyclic group having 1 to 3 atoms or a phenyl group which may have 1 to 3 substituents, a salt thereof, or a solvate thereof. object.

[3] The compound according to claim 1 or 2, wherein R ³ is a hydrogen atom, a lower alkyl group or a carboxy lower alkyl group, a salt thereof or a solvate thereof.

[4] R ⁴ is a lower alkyl group, a lower alkylamino group, a di (lower alkyl) amino group, a carbon number

6-14 arylamino group, lower alkoxy group, morpholino group or lower alkylcarno 14. The compound according to claim 1, which is a moyl group, a salt thereof or a solvate thereof.

 [5] A medicament comprising the compound according to any one of claims 1-4, a salt thereof, or a solvate thereof.

 [6] An agent for preventing and / or treating ischemic disease, comprising the compound according to any one of claims 1-4, a salt thereof, or a solvate thereof.

[7] A pharmaceutical composition comprising the compound according to any one of claims 1-4, a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.

[8] Use of the compound according to any one of claims 14 to 14, a salt thereof, or a solvate thereof for the manufacture of a medicament.

[9] Use of the compound according to any one of claims 1-4, a salt thereof, or a solvate thereof for the prevention of ischemic disease and the production of a Z or therapeutic agent.

[10] A method for treating ischemic disease, which comprises administering an effective amount of the compound according to any one of claims 1-4, a salt thereof, or a solvate thereof.