JP2007084437A - Aminoalkylpyrazole derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a platelet coagulation inhibitor not inhibiting COX-1 and COX-2. <P>SOLUTION: This aminoalkylpyrazole derivative is a compound expressed by general formula (I) [wherein, Ar<SB>1</SB>, Ar<SB>2</SB>are each independently a 5-or 6-membered aromatic heterocyclic ring which may have 1-3 substituents or a 6-14C aryl which may have 1-3 substituents; R<SP>1</SP>, R<SP>2</SP>are each independently H or a lower alkyl; R<SP>3</SP>is H or a lower alkyl which may have a substituent; R<SP>4</SP>is a lower alkyl which may have a substituent, an amino which may have a substituent, a lower alkoxy which may have a substituent, a carbamoyl which may have a substituent or a heterocyclic ring which may have 1-3 substituents; and (n) is 0 or 1 number], or its salt or their solvated compound. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

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

  Platelets have an important role in preventing bleeding by agglutinating and forming a hemostatic thrombus at the time of vascular injury. On the other hand, as seen in arteriosclerosis, vascular endothelium is damaged and blood vessels are constricted. It is known that it causes aggregation and induces thrombus and embolism to cause ischemic diseases such as myocardial infarction, angina pectoris, ischemic cerebrovascular disorder, and peripheral vascular disorder. Therefore, platelet aggregation inhibitors are administered for the prevention and treatment of ischemic diseases. Among them, aspirin has been used as a platelet aggregation inhibitor for a long time, and its effect has been proved by 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 or the like, a so-called aspirin ulcer, and the side effect occurs at a rate of 1 out of 100 people regardless of the dose (Non-patent Document 2). reference).

  It is known that the platelet aggregation inhibitory action of aspirin is based on the inhibitory action of cyclooxygenase. Cyclooxygenase includes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Aspirin selectively inhibits COX-1 and suppresses platelet aggregation at low doses. Inhibition of is also a cause of aspirin ulcers (see Non-Patent Documents 3 and 4). Nonsteroidal anti-inflammatory drugs are known to selectively inhibit COX-2 and exhibit an anti-inflammatory action.

  As described above, aspirin is useful as a platelet aggregation inhibitor. However, since a gastrointestinal disorder due to COX-1 inhibitory action, which is the mechanism of action, is accompanied as a side effect, a platelet aggregation inhibitor without COX-1 inhibitory action is It has been demanded.

  On the other hand, compound (A) (see Patent Literature 1 and Non-Patent Literature 5) or Compound (B) (see Patent Literature 2) is known as a pyrazole derivative having an antithrombotic action so far.

Japanese Patent No. 2586713 WO9729774 BMJ, 308, 81-106, 1994 BMJ, 321 volumes, 1183-1187, 2000 Neurology, Vol. 57, Suppl. 2, pages S5-S7, 2001 Drugs Today, 35, 251-265, 1999 Chem. Pharm. Bull. 45, 987-995, 1997

However, the IC ₅₀ value for collagen-induced platelet aggregation of the compound (A) is 5.3 × 10 ⁻⁶ M, and it exhibits a stronger inhibitory activity against COX-2 (IC ₅₀ value 2.4 × 10 6). ^-7 M). Similarly, the platelet aggregation inhibitory action of compound (B) is not as strong as its inhibitory activity against COX-2. As described above, since the inhibitory action of COX-2 leads to an anti-inflammatory action, COX- 2 Having inhibitory activity is not always preferable as a platelet aggregation inhibitor. Therefore, an object of the present invention is to provide a powerful platelet aggregation inhibitor that does not inhibit COX-1 and COX-2.

As a result of earnest research for the present inventors to find such a platelet aggregation inhibitor, the pyrazole derivative represented by the following general formula (I) is a powerful platelet without inhibiting COX-1 and COX-2. The present invention was completed by finding that it exhibits an aggregation-inhibiting action.
That is, the present invention relates to the general formula (I)

(In the formula, Ar ₁ and Ar ₂ each independently have a 5- or 6-membered aromatic heterocyclic group or 1 to 3 substituents which may have 1 to 3 substituents. Or an aryl group having 6 to 14 carbon atoms;
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 is a lower alkyl group which may have a substituent, an amino group which may have a substituent, a lower alkoxy group which may have a substituent, a carbamoyl group which may have a substituent, or 1 to 3 A heterocyclic group which may have a substituent of
n represents a number of 0 or 1. )
The compound represented by these, its salt, or those solvates are provided.

  Moreover, this invention provides the pharmaceutical containing the compound represented by general formula (I), its salt, or those solvates.

  Furthermore, the present invention provides a prophylactic and / or therapeutic agent for ischemic diseases containing a compound represented by the general formula (I), a salt thereof, or a solvate thereof.

The compound (I) of the present invention, a salt or solvate thereof, or a solvate of the salt strongly suppresses platelet aggregation without inhibiting COX-1 and COX-2, and potently inhibits thrombus formation. Has an inhibitory effect. Therefore, myocardial infarction, angina pectoris (chronic stable angina pectoris, unstable angina pectoris, etc.), ischemic cerebrovascular disorder (transient cerebral ischemic attack (TIA), cerebral infarction, etc.), peripheral vascular disorder, artificial Occlusion after vascular replacement, coronary intervention (coronary artery bypass grafting (CAGB), percutaneous transluminal coronary angioplasty (PTCA), stent placement, etc.), thrombotic occlusion, diabetic retinopathy / nephropathy, heart valve replacement occlusion It is useful as a preventive and / or therapeutic agent for ischemic diseases caused by thrombus / emboli. Alternatively, it is useful as a prophylactic and / or therapeutic agent for thrombus / embolism associated with, for example, vascular surgery or extracorporeal blood circulation.

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

The aromatic heterocyclic group represented by Ar ₁ and Ar ₂ represents a 5- or 6-membered aromatic heterocyclic group, and specific examples thereof include pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, furyl group, thienyl group. Pyrrolyl group, pyrazolyl group, imidazolyl group, triazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, pyrazolyl group and the like. Among these, 5- or 6-membered aromatic heterocycles having 1 to 3 nitrogen atoms as heteroatoms, such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, and triazolyl groups A 6-membered aromatic heterocyclic group having 1 to 3 nitrogen atoms, more preferably a pyridyl group, a pyridazinyl group and a pyrazinyl group, and particularly preferably a pyridyl group.

Examples of the aryl group having 6 to 14 carbon atoms represented by Ar ₁ and Ar ₂ include a phenyl group and a naphthyl group, and among these, a phenyl group is preferable.

Examples of the substituent in Ar ₁ and Ar ₂ include a lower alkyl group, a halogeno group, a hydroxyl group, a cyano group, a lower alkoxy group, an aralkyloxy group, a lower alkylthio group, a lower alkoxycarbonyl group, a carboxyl group, a lower alkylsulfonyl group, An amino group which may have one or two substituents, a carbamoyl group which may be substituted by one or two lower alkyl groups, an aminosulfonyl which may be substituted by one or two lower alkyl groups Groups and the like. These substituents will be described below.

The lower alkyl group is a substituent on Ar ₁ and Ar _2, the number 1 to 6 linear carbon atoms, means a branched or cyclic alkyl groups of a methyl group Specific examples, an ethyl group, a propyl group Isopropyl group, butyl group, isobutyl group, t-butyl group, pentyl group, isopentyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group, cyclopropylmethyl group, cyclopentylmethyl group and the like.

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

  The lower alkoxy group means a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, and specific examples include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, and a pentoxy group. And cyclopentyloxy group.

The aralkyl group of the aralkyloxy group means a group consisting of an aryl group having 6 to 14 carbon atoms and the above lower alkyl group, and specific examples of the aralkyloxy group include benzyloxy group and phenethyloxy group. Can do.
The lower alkylthio group means an alkylthio group having 1 to 6 carbon atoms, and specific examples include methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, pentylthio group, cyclopentylthio group. Groups and the like.
The lower alkoxycarbonyl group means an alkoxycarbonyl group having 2 to 7 carbon atoms in total, and specific examples include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and a butoxycarbonyl group.
The lower alkylsulfonyl group means an alkylsulfonyl group having 1 to 6 carbon atoms, and specific examples thereof include a methanesulfonyl group, an ethanesulfonyl group, and a trifluoromethanesulfonyl group.

  The amino group which may have one or two substituents is an amino group substituted with one or two lower alkyl groups, a lower alkanoylamino group, a lower alkoxycarbonyl in addition to an unsubstituted amino group. It means an ureido group which may be substituted with an amino group and one or two lower alkyl groups. Specific examples of the amino group substituted with one or two lower alkyl groups include methylamino group, ethylamino group, propylamino group, isopropylamino group, cyclopropylamino group, butylamino group, isobutylamino group, Cyclopentylmethylamino group, dimethylamino group, diethylamino group, dipropylamino group, dibutylamino group, N-methyl-N-ethylamino group, N-ethyl-N-propylamino group, N-methyl-N-cyclopentylmethylamino Groups and the like. 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. Specific examples thereof include a methoxycarbonylamino group and an ethoxycarbonylamino group. Can be mentioned. Specific examples of the ureido group which may be substituted with one or two lower alkyl groups include aminocarbonylamino group, N1-methylaminocarbonylamino group, N1-ethylaminocarbonylamino group, N3-methylaminocarbonyl Amino group, N1, N1-dimethylaminocarbonylamino group, N1, N3-dimethylaminocarbonylamino group, N1-methyl-N3-ethylaminocarbonylamino group and the like can be mentioned.

  The carbamoyl group which may be substituted with one or two lower alkyl groups means a carbamoyl group substituted with one or two lower alkyl groups in addition to the unsubstituted carbamoyl group, and specific examples Examples thereof include a methylcarbamoyl group, an ethylcarbamoyl group, a dimethylcarbamoyl group, and a methylethylcarbamoyl group.

  The aminosulfonyl group which may be substituted with one or two lower alkyl groups means an aminosulfonyl group substituted with one or two lower alkyl groups in addition to the unsubstituted aminosulfonyl group. Specific examples include methylaminosulfonyl group, ethylaminosulfonyl group, propylaminosulfonyl group, isopropylaminosulfonyl group, primary to tertiary butylaminosulfonyl group, cyclopropylaminosulfonyl group, cyclobutylaminosulfonyl group, Examples thereof include a cyclopentylaminosulfonyl group, a cyclohexylaminosulfonyl group, a cyclopentylmethylaminosulfonyl group, a dimethylaminosulfonyl group, and a diethylaminosulfonyl group.

As the substituent on Ar ₁ and Ar ₂ , a C _1-6 alkyl group and a C _1-6 alkoxy group are preferable, and a methyl group and a methoxy group are particularly preferable.

The substituent on Ar ₁ is preferably substituted at the para position relative to the substitution position of the pyrazole ring.

Examples of the lower alkyl group represented by R ¹ and R ² include linear or branched alkyl groups having 1 to 6 carbon atoms. Of these, a methyl group, an ethyl group, and the like are preferable, and a methyl group is particularly preferable.

R ¹ is preferably a hydrogen atom, and R ² is preferably a hydrogen atom or a lower alkyl group. Moreover, it is particularly preferable that R ¹ is a hydrogen atom and R ² is a hydrogen atom or a methyl group.

Examples of the lower alkyl group which may have a substituent represented by R ³ include a linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted by a carboxyl group. Specific examples include methyl group, ethyl group, isopropyl group, isobutyl group, carboxymethyl group, carboxyethyl group and the like.

R ³ is preferably a hydrogen atom, a lower alkyl group or a carboxy lower alkyl group, particularly preferably a hydrogen atom, a methyl group, an ethyl group, a carboxymethyl group or a carboxyethyl group.

Examples of the lower alkyl group which may have a substituent represented by R ⁴ include a linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted by a carboxyl group. Specific examples include a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a t-butyl group, a carboxymethyl group, and a carboxyethyl group. Among these, a methyl group, an ethyl group, an isopropyl group, and a t-butyl group are particularly preferable.

Examples of the amino group that may have a substituent represented by R ⁴ include an amino group, a lower alkylamino group, a di (lower alkyl) amino group, and an arylamino group having 6 to 14 carbon atoms. Here, the lower alkylamino group includes a C _1-6 alkylamino group, and the di (lower alkyl) amino group includes a di (C _1-6 alkyl) amino group, and has 6 to 14 carbon atoms. A phenylamino group is mentioned as an arylamino 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 diethylamino group, and a phenylamino group. Groups and the like.

Examples of the lower alkoxy group which may have a substituent represented by R ⁴ include a lower alkoxy group and a halogeno lower alkoxy group. Here, examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms, and specific examples include a methoxy group, an ethoxy group, and an isopropoxy group.

Examples of the carbamoyl group that may have a substituent represented by R ⁴ include a carbamoyl group and a lower alkylcarbamoyl group. Specific examples of this group include a carbamoyl group, a methylcarbamoyl group, an ethylcarbamoyl group, and an isopropylcarbamoyl group.

Examples of the heterocyclic group which may have 1 to 3 substituents represented by R ⁴ include a 5-membered or 6-membered saturated heterocyclic group, and specifically include a morpholino group, a thiomorpholino group, a pyrrolidinyl group. Group, piperidinyl group, piperazino group, N-methylpiperazino 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 having a carboxyl group, an amino group or the like, and / or Ar ₁ or Ar ₂ is a pyridine ring or the like In this case, a salt can be formed, and the salt can also form a solvate. Examples of the salt herein include 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 ions of alkali metals or alkaline earth metals such as sodium, potassium and calcium.

  The solvate of the compound (I) of the present invention, or the solvate of the salt thereof, refers to the solvate added by the solvent used for crystallization of the crystal, as well as moisture in the air. Including those formed by absorption. Examples of the solvent include lower alcohols such as methanol and ethanol, organic solvents such as acetone and acetonitrile, water, and the like.

  Hereinafter, representative production methods of the compound (I) of the present invention will be described.

Compound (Ia) in which n in general formula (I) is 0 is synthesized using a pyrazoleamine derivative (6) obtained by the following production method as a production intermediate.

(In the above formula, Ar ₁ and Ar ₂ are the same as described above.)

Under a stream of argon, sodium hydride is suspended in a suitable solvent such as tetrahydrofuran at -20 to 20 ° C., diethyl cyanomethylphosphonate is added dropwise, and then compound (1) is added and stirred to give compound (2). Obtainable.
Compound (2) is prepared by dissolving diethyl cyanomethylphosphonate in a suitable solvent such as tetrahydrofuran, treating with sodium hydride at −20 to 20 ° C. under an argon stream, and then adding aldehyde (1) and stirring. Can also be manufactured. In addition, what is necessary is just to use what was manufactured by the method according to the method as described in a reference example, or its method, using a commercially available aldehyde (1).

Next, compound (2) is dissolved in ethanol or methanol, hydrazine derivative (4) or a salt thereof is added at room temperature, and then an appropriate amount of sodium methoxide is added and heated to reflux to produce compound (5). it can.
The pyrazole amine derivative (6) can be produced by dissolving the compound (5) in a suitable solvent such as methylene chloride and treating with manganese dioxide. The reaction temperature is preferably 0 to 50 ° C.

As the hydrazine derivative (4), a commercially available product may be used, or as described in Reference Examples, a method of reacting hydrazine with a halogenated Ar ₁ or a method produced by a method according to the method may be used. Good. In addition, what is necessary is just to use what was manufactured by the method according to the method as described in a reference example, or its method, using a commercially available compound for amine (3).
The hydrazine derivative (4) or a salt thereof used in the above-mentioned pyrazole ring formation reaction is prepared by dissolving amine (3) in concentrated hydrochloric acid and adding sodium nitrite under ice cooling to derive a diazo compound, followed by tin chloride (II ). The reaction temperature is preferably −10 to 20 ° C.

  The present compound (Ia) can be obtained by acylating the pyrazoleamine derivative (6) obtained by the above production method.

(In the above formula, Ar ₁ , Ar ₂ and R ⁴ are the same as described above.)

  For the acylation reaction, a condensation reaction generally used as a peptide synthesis method may be applied. Commonly used peptide synthesis methods include, for example, the azide method, acid chloride method, acid anhydride method, DCC (dicyclocarbodiimide) method, active ester method, carbodiimidazole method, DCC / HOBT (1- Hydroxybenzotriazole) method, a method using water-soluble carbodiimide, a method using diethyl cyanophosphate, and the like. Bodanszky, Y.M. S. Klausner and M.M. A. Ondetti, “Peptide Synthesis” (A Wiley-interscience publication, New York, 1976), G.C. R. It is described in “Synthetic Peptides” written by Pettit (Elsevier Scientific Publication Company, New York, 1976), “The 4th edition, Experimental Chemistry Course Vol. 22, Organic Synthesis IV” (Maruzen Co., Ltd., 1991) edited by the Chemical Society of Japan. Yes. Examples of the solvent used in this condensation reaction include solvents such as N, N-dimethylformamide, pyridine, chloroform, methylene chloride, tetrahydrofuran, dioxane, acetonitrile, and mixed solvents thereof. The reaction temperature is preferably -20 to 50 ° C, more preferably -10 to 30 ° C. As the carboxylic acid (7) and the acid chloride (8), commercially available compounds may be used, and methods described in Reference Examples or those produced according to these methods may be used.

Among the compounds (I) of the present invention, the compound (Ib) in which n is 1 can be produced using the following pyrazole carboxylic acid derivative (14) as a production intermediate.

(In the above formula, Ar ₁ and Ar ₂ are the same as described above, and R ⁵ represents a methyl group or an ethyl group.)

Dissolve or suspend ketone (9) and oxalic acid dialkyl ester (10) in a suitable solvent such as N, N-dimethylformamide, add sodium hydride at −20 to 20 ° C. under argon flow, and stir. Thus, compound (11) can be obtained.
Compound (11) can also be produced by treating compound (9) and oxalic acid dialkyl ester (10) in an alcohol (methanol or ethanol) solution in the presence of sodium alkoxide (methoxide or ethoxide). The reaction temperature is preferably −10 to 100 ° C.

Furthermore, compound (11) is dissolved in an inert solvent such as tetrahydrofuran of compound (9), treated with a base such as lithium bis (trimethylsilyl) amide under cooling to −78 ° C., and diethyl oxalate is added. Can also be produced by stirring. The reaction temperature is preferably -78 to 20 ° C.
In addition, what is necessary is just to use what was manufactured by the method according to the method as described in a reference example, or its method as a ketone (9).

Next, compound (11) can be produced by dissolving compound (11) in ethanol, adding hydrazine derivative (4) or a salt thereof at room temperature, then adding an appropriate amount of acetic acid and heating to reflux. At that time, the regioisomer (13) is by-produced, but the compound (12) can be easily separated and purified by silica gel column chromatography.
In the above pyrazole ring formation reaction, instead of adding acetic acid, an appropriate amount of triethylamine or concentrated hydrochloric acid may be added and heated to reflux. In some cases, the compound may be added without adding acetic acid, triethylamine or concentrated hydrochloric acid. (12) can be obtained.

As the hydrazine derivative (4) or a salt thereof used in the above-mentioned pyrazole ring formation reaction, a commercially available product may be used, or a method of reacting hydrazine with a halogenated Ar ₁ as described in Reference Examples or a method thereof You may use what was manufactured by the method. 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 induce diazo compound, and then converting it to tin (II) chloride at −10 to 20 ° C. It can manufacture by processing. In addition, what is necessary is just to use what was manufactured by the method according to the method as described in a reference example, or its method, using a commercially available compound for amine (3).
By hydrolyzing the compound (12) by a conventional method, the hydrazole carboxylic acid derivative (14) can be produced. This hydrolysis reaction can be carried out in the presence of a base or a Lewis acid. Examples of the base include alkali metal hydroxides (eg, lithium, sodium, potassium, etc.). Examples of the Lewis acid include boron tribromide. The reaction temperature is preferably -20 to 100 ° C, more preferably -5 to 50 ° C.

Moreover, the substituent on Ar < ₁ > or Ar < ₂ > of a compound (12) can be modified based on the general knowledge of organic chemistry. For example, when the substituent of Ar ₁ is a methoxy group, the compound (12) in which the substituent of Ar ₁ is a halogeno group such as a chloro group or a bromo group is dissolved in methanol, and sodium methoxide is added and heated to reflux. Thus, a compound (12) in which the substituent of Ar ₁ is substituted with a methoxy group can be produced. Further, a compound (12) in which Ar ₁ is substituted with a chloro or bromo halogeno group and sodium methoxide are dissolved in a mixed solvent of methanol and toluene, and a catalyst such as copper (I) bromide is added and heated. By refluxing, the compound (12) in which the substituent of Ar ₁ is substituted with a methoxy group can also be produced.

  From the pyrazole carboxylic acid derivative (14) obtained by the above method or the ester (12) that is a precursor thereof, a pyrazole methylamine derivative (18) that is an intermediate for the production of the compound (Ib) of the present invention can be produced. it can.

(In the formula, Ar ₁ , Ar ₂ and R ⁵ are the same as described above, and Z represents a leaving group.)

Ester (12) is reduced to alcohol (15), and Z group is a leaving group (for example, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, chloro group, bromo group or iodo group). To the compound (16).
The reduction reaction from the ester (12) to the alcohol (15) is carried out, for example, in an inert solvent such as tetrahydrofuran at −78 to 50 ° C., preferably −20 to 30 ° C., lithium aluminum hydride, lithium borohydride, etc. This can be achieved by processing.
The alcohol (15) is produced by using the carboxylic acid (14) in an inert solvent such as tetrahydrofuran, such as lithium aluminum hydride, borane-tetrahydrofuran complex, -78 to 50 ° C, preferably -20 to 30 ° C. This can be done by processing.
Subsequently, the conversion from the alcohol form (15) to the compound (16) is carried out by reacting with methanesulfonyl chloride at −50 to 50 ° C. in the presence of a base such as pyridine when the Z group is a methanesulfonyloxy group. Can be manufactured. A compound (16) in which the Z group is a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group or the like can also be produced under the same conditions. When the Z group is a chloro group, a bromo group or an iodo group, a chloro derivative (16) or a bromo derivative (16) is produced from the alcohol (15) using thionyl chloride or thionyl bromide, and further iodinated. Iodo derivatives (16) can be obtained by treating them with sodium. The conditions and reagents for these reactions may 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 sodium azide. The reaction temperature is preferably 50 to 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 it using 10% palladium-carbon as a catalyst. In this catalytic reduction, a Lindlar catalyst may be used. The pyrazole methylamine derivative (18) can also be obtained by a reduction reaction of the azide compound (17) with a metal hydride such as sodium borohydride or a reduction reaction of the azide compound (17) using triphenylphosphine, thiol, sulfide, diborane or the like. ) Can be manufactured.

  Moreover, the compound (23) in which the lower alkyl group is substituted on the methylene group of the pyrazole methylamine derivative (18) can be produced by the following production method or a method analogous thereto.

(In the formula, Ar ₁ and Ar ₂ are the same as described above, and Z represents a leaving group.)

Conversion from carboxylic acid (14) to ketone body (19) is carried out by dissolving carboxylic acid (14) in an inert solvent such as tetrahydrofuran, and using methyllithium to -78 to 50 ° C, preferably -20 to 30 ° C. This can be done by processing.
The ketone body (19) is reduced to alcohol (20), and the Z group is a leaving group (for example, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, chloro group, bromo group or iodo group). ) Which is a compound (21).

The reduction reaction from the ketone body (19) to the alcohol (20) is carried out in, for example, an inert solvent such as tetrahydrofuran at −78 to 50 ° C., preferably −20 to 30 ° C., lithium aluminum hydride, boron hydride. This can be achieved by treatment with sodium or the like.
Subsequently, the conversion from the alcohol form (20) to the compound (21) is carried out by reacting with methanesulfonyl chloride at −50 to 50 ° C. in the presence of a base such as pyridine when the Z group is a methanesulfonyloxy group. Can be manufactured. Even when the Z group is a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, or the like, it can be converted to the compound (21) under the same conditions. When the Z group is a chloro group, a bromo group, an iodo group or the like, it is led to a chloro derivative (21) or a bromo derivative (21) using thionyl chloride or thionyl bromide, and further treated with sodium iodide. By doing so, an iodo derivative (21) can be obtained. The 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 a suitable solvent such as N, N-dimethylformamide and treating with sodium azide. The reaction temperature is preferably 50 to 150 ° C, more preferably 50 to 100 ° C.
The amine body (23) can be prepared by dissolving the azide compound (22) in a solvent such as ethanol, and catalytic reduction using 10% palladium-carbon or Lindlar catalyst. The amine body (23) 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) using triphenylphosphine, thiol, sulfide, diborane or the like. Can be manufactured.

The compound (Ib) of the present invention in which n is 1 can produce an amide type compound (Ib) by condensing the amine body (23) with an acid chloride (8) or a carboxylic acid (7). it can. Moreover, a urea type compound (Ib) can be manufactured by manufacturing a compound (24) from an amine body (23), and making it react with an amine (25).

(In the formula, Ar ₁ , Ar ₂ and R ² are the same as described above, R ⁶ is a lower alkyl group which may have a substituent, and R ⁷ and R ⁸ are each independently hydrogen, substituent. A lower alkyl group which may have a substituent, an aryl group which may have a substituent, a heterocyclic group which may have a substituent, and W represents a leaving group.)

  The pyrazole methylamine derivative (18) or (23) produced by the above production method is treated 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 (Ib) of the present invention can also be produced by condensing a pyrazole methylamine derivative (18) or (23) and a carboxylic acid (7).

  For the above condensation reaction, a method generally used as a peptide synthesis method may be applied. Commonly used peptide synthesis methods include, for example, the azide method, acid chloride method, acid anhydride method, DCC (dicyclocarbodiimide) method, active ester method, carbodiimidazole method, DCC / HOBT (1- Hydroxybenzotriazole) method, a method using water-soluble carbodiimide, a method using diethyl cyanophosphate, and the like. Bodanszky, Y.M. S. Klausner and M.M. A. Ondetti, “Peptide Synthesis” (A Wiley-interscience publication, New York, 1976), G.C. R. It is described in “Synthetic Peptides” written by Pettit (Elsevier Scientific Publication Company, New York, 1976), “The 4th edition, Experimental Chemistry Course Vol. 22, Organic Synthesis IV” (Maruzen Co., Ltd., 1991) edited by the Chemical Society of Japan. Yes. Examples of the solvent used in this condensation reaction include solvents such as N, N-dimethylformamide, pyridine, chloroform, methylene chloride, tetrahydrofuran, dioxane, acetonitrile, and mixed solvents thereof. The reaction temperature is preferably -20 to 50 ° C, more preferably -10 to 30 ° C. As the carboxylic acid (7) and the acid chloride (8), commercially available compounds may be used, and methods described in Reference Examples or those produced according to these methods may be used.

Further, among the compounds of the present invention, the compound (Ib) in which R ⁴ is a carbamoyl group which may have a substituent is obtained by removing the pyrazole methylamine derivative (18) or (23) in a solvent such as methylene chloride, triethylamine, etc. After the compound (24) in which the leaving group W is a 4-nitrophenyloxy group by treating with 4-nitrophenyl chloroformate in the presence of an organic amine, the amine body (25) is added. Can be manufactured. The reaction temperature is preferably −10 to 50 ° C.
The compound (Ib) having a carbamoyl group can also be produced by treating the pyrazole methylamine derivative (18) or (23) with an alkyl isocyanate in a solvent such as methylene chloride.
The carboxylic acid (7), acid chloride (8) and amine compound (25) used in the above production method are commercially available, or produced by the method described in Reference Examples or a method according to the method. What is necessary is just to use.

In the above reaction, it may be necessary to protect the functional group. The protecting group and its cleavage conditions may be appropriately selected based on ordinary knowledge of organic chemistry.
Moreover, this invention compound (I) manufactured by said method can be guide | induced to another compound (I) of this invention by further modifying based on the general knowledge of organic chemistry.

  The compound (I) of the present invention, a salt or solvate thereof, or a solvate of the salt has a potent antiplatelet action, and has shown effectiveness in a thrombosis model induced by high shear stress. Therefore, the compound (I) of the present invention, a salt or solvate thereof, or a solvate of the salt thereof is used in mammals including humans in myocardial infarction, angina pectoris (chronic stable angina pectoris, unstable angina pectoris). ), Ischemic cerebrovascular disorder (transient ischemic attack (TIA), cerebral infarction, etc.), peripheral vascular disorder, occlusion after artificial blood vessel replacement, coronary artery intervention (coronary artery bypass grafting (CAGB), percutaneous Prevention and / or treatment of ischemic diseases caused by thrombus / embolism such as thrombotic occlusion after diabetic coronary angioplasty (PTCA), stent placement, etc., diabetic retinopathy / nephropathy, occlusion at the time of cardiac valve replacement, etc. Useful as a medicine. Alternatively, it is useful as a prophylactic and / or therapeutic agent for thrombus / embolism associated with, for example, vascular surgery and extracorporeal blood circulation.

When the compound (I) of the present invention, a salt or solvate thereof, or a solvate of the salt is used as a pharmaceutical, the dose varies depending on the age, sex, symptoms, etc. of the patient, but 1 per adult The daily dose is preferably from 0.1 mg to 1 g, more preferably from 0.5 mg to 500 mg. In this case, the daily dose can be administered in several divided doses, and if necessary, the daily dose can be administered in excess of the above-mentioned daily dose.
The medicament containing the compound (I) of the present invention, a salt thereof or a solvate thereof can be used according to the administration method and dosage form as required, and the preparation thereof is a preparation of various commonly used preparations. According to the method, if necessary, a pharmaceutically acceptable carrier may be blended and a dosage form suitable for the administration method may be selected, and the administration method and dosage form are not particularly limited.
Examples of oral preparations include liquid preparations such as liquids, syrups, elixirs, suspensions, and emulsions in addition to solid preparations such as tablets, powders, granules, pills, and capsules. .
As an injection, compound (I), a salt or solvate thereof, or a solvate of the salt may be dissolved and filled in a container, and the preparation prepared as a solid by lyophilization or the like It is good.
In preparing these preparations, pharmaceutically acceptable additives such as binders, disintegrants, dissolution accelerators, lubricants, fillers, excipients, and the like are selected and used as necessary. be able to.

  In the following, specific methods for producing the compounds in the present invention are shown, and specific tests show that these compounds exhibit a strong platelet aggregation inhibitory action without inhibiting COX-1 and COX-2. .

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

  To a concentrated hydrochloric acid (50 ml) solution of 5-amino-2-methoxypyridine (6.21 g), a solution of sodium nitrite (3.795 g) in water (20 ml) was added dropwise over 60 minutes under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Stir for 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 30 minutes, followed by stirring at room temperature for 2 hours. A solution of sodium hydroxide (75 g) in water (300 ml) and diethyl ether were added to the reaction solution under ice-cooling to separate the layers. The aqueous layer was extracted twice with diethyl ether. Further, the aqueous layer was saturated with sodium chloride and extracted with diethyl ether, and the organic layers were combined and dried over anhydrous sodium sulfate. After separation by filtration, 1M hydrochloric acid-ethanol solution (50 ml) was added to the filtrate and stirred. The precipitated solid was collected by filtration, washed with diethyl ether and dried to give the title compound (5.02 g, 57%). .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.81 (3H, s), 6.82 (1H, d, J = 8.8 Hz), 7.57 (1H, dd, J = 8. 8, 2.9 Hz), 7.97 (1 H, d, J = 2.9 Hz), 8.55-9.20 (1 H, br), 10.13-10.50 (3 H, br).
MS (ESI) m / z: 140 (M + H) ^<+> .

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

  To a concentrated hydrochloric acid (50 ml) solution of 5-amino-2-methoxypyridine (6.207 g), a solution of sodium nitrite (3.795 g) in water (20 ml) was added dropwise over 80 minutes under ice-cooling, and at the same temperature. Stir 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 then stirred at room temperature for 12.5 hours. A solution of sodium hydroxide (54 g) in water (200 ml) and chloroform were added to the reaction solution under ice-cooling, and the insoluble material was removed by filtration. Further, the aqueous layer was extracted twice with chloroform, and the organic layers were combined and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (4.23 g, 60%) as a solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.50-3.68 (2H, br), 3.88 (3H, s), 4.86-5.03 (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 = 2.9 Hz).
MS (ESI) m / z: 140 (M + H) ^<+> .

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

1) 1- (6-Methoxy-3-pyridyl) -5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester To a solution of acetophenone (9.85 g) in N, N-dimethylformamide (80 ml) at 0 ° C. 60% sodium hydride (6.56 g) was added and stirred for 30 minutes. To the reaction solution, a solution of diethyl oxalate (23.97 g) in N, N-dimethylformamide (80 ml) was added dropwise over 10 minutes and stirred at room temperature for 13 hours. The reaction mixture was acidified with 1N hydrochloric acid (180 ml), and water and ethyl acetate were added to separate the layers. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure to give 4-phenyl-2,4-dioxobutanoic acid ethyl ester (22.96 g, quantitative) as an oil. The product was subjected to the next reaction without further purification. The obtained 4-phenyl-2,4-dioxobutanoic acid ethyl ester was dissolved in ethanol (200 ml), 5-hydrazino-2-methoxypyridine (11.39 g) of Reference Example 2 was added, and the mixture was heated to reflux for 4 hours. After air cooling, the reaction solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazole-3. Carboxylic acid ethyl ester (16.37 g, 61%) was obtained as an oil.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.42 (3H, t, J = 7.0Hz), 3.93 (3H, s), 4.45 (2H, q, J = 7.0Hz) 6.73 (1H, d, J = 8.8 Hz), 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 = 2.6 Hz).
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-carboxylic acid ethyl ester (16.37 g) in methanol (250 ml), 1N aqueous sodium hydroxide solution (126 ml) was added and stirred for 30 minutes. The reaction solvent was distilled off under reduced pressure, and water and diethyl ether were added to the resulting residue for liquid separation. The aqueous layer was acidified with 1N aqueous hydrochloric acid (140 ml), extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (13.88 g, 92%) as a solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.94 (3H, s), 6.75 (1H, d, J = 8.8 Hz), 7.10 (1H, s), 7.21-7 .27 (2H, m), 7.32-7.39 (3H, m), 7.58 (1H, dd, J = 8.8, 2.6 Hz), 8.12 (1H, d, J = 2.6 Hz).
MS (ESI) m / z: 296 (M + H) ^<+> .

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

1) [1- (6-Methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] methanol 1- (6-methoxy-3-pyridyl) -5-phenyl-1H- of Reference Example 3 To a solution of pyrazole-3-carboxylic acid (1.181 g) in tetrahydrofuran (20 ml) was added dropwise a tetrahydrofuran solution (9.2 ml) of 1.08 M-borane-tetrahydrofuran complex under argon atmosphere and ice cooling over 10 minutes, and then room temperature. For 7 hours. Water and ethyl acetate were added to the reaction solution and stirred, the precipitated insoluble matter was removed by filtration, and the organic layer was separated. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain [1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazole-3. -Yl] methanol (682 mg, 60%) was obtained as an oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.92 (3H, s), 4.79 (2H, s), 6.52 (1H, s), 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, 2.7 Hz), 8 .07 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 282 (M + H) ^<+> .

2) [1- (6-Methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] methyl methanesulfonate Above [1- (6-methoxy-3-pyridyl) -5-phenyl- 1H-pyrazol-3-yl] methanol (112 mg) in methylene chloride (4 ml) was added with triethylamine (61 μl) and methanesulfonyl chloride (34 μl) at room temperature and stirred for 15 minutes. Water and ethyl acetate were added to the reaction solution for liquid separation. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and [1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] methyl methanesulfonate (138 mg, 96%) was obtained as an oil. Got as.
MS (ESI) m / z: 360 (M + H) ^<+> .

3) [1- (6-Methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] methyl azide The above [1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazole- Sodium azide (130 mg) was added to a solution of 3-yl] methyl = methanesulfonate (138 mg) in N, N-dimethylformamide (4 ml), and the mixture was stirred at 80 ° C. for 13 hours. After air cooling, water and ethyl acetate were added to the reaction solution and the phases were separated. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure to obtain [1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] methyl azide (105 mg, 89%) as an oil.
ESI-MS m / 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-carbon (50% wet). , 20 mg), and stirred at room temperature for 1 hour under a hydrogen atmosphere. The catalyst was removed by filtration, and the mother liquor was evaporated under reduced pressure to give the title compound (96 mg, quantitative) as an oil.
ESI-MS m / z: 281 (M + H) ⁺ .

Reference Example 5 1- (6-Methoxy-3-pyridazinyl) -5- (2-pyridyl) -1H-pyrazole-3-carboxylic acid methyl ester

1) 4- (2-Pyridyl) -2,4-dioxobutanoic acid methyl ester A solution of dimethyl oxalate (5.00 g) and sodium methoxide (2.29 g) in methanol (26 ml) under an argon atmosphere at room temperature -A solution of acetylpyridine (2.56 g) in methanol (26 ml) was added and stirred for 15 minutes, and then stirred at 60 ° C for 45 minutes. After air cooling, water was added to the reaction solution and washed with diethyl ether. A saturated aqueous ammonium chloride solution and chloroform were added to the aqueous layer for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain 4- (2-pyridyl) -2,4-dioxobutanoic acid methyl ester (3.44 g, 79%) as a solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.94 (3H, s), 7.54-7.50 (1H, m), 7.64 (1H, s), 7.93-7.89 (1H, m), 8.19-8.16 (1H, m), 8.74-8.72 (1H, m).
EI-MS m / z: 207 (M ^<+> ).

2) 1- (6-Chloro-3-pyridazinyl) -5- (2-pyridyl) -1H-pyrazole-3-carboxylic acid methyl ester 4- (2-pyridyl) -2,4-dioxobutanoic acid methyl ester ( A solution of 4.143 g) and 3-chloro-6-hydrazinopyridine (2.891 g) in methanol (100 ml) was heated to reflux for 109 hours. Concentrated hydrochloric acid (2 ml) was added to the reaction solution, and the mixture was further heated to reflux for 6 hours. After air cooling, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, and the mixture was separated. 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 1- (6-chloro-3-pyridazinyl) -5- (2-pyridyl) -1H-pyrazole-3-carboxylic acid methyl ester (3.169 g, 50%). Obtained as a solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.00 (3H, s), 7.24-7.28 (1H, m), 7.24 (1H, s), 7.64 (1H, dt , J = 7.8, 1.2 Hz), 7.70 (1H, d, J = 9.0 Hz), 7.79 (1H, td, J = 7.8, 1.7 Hz), 8.09 ( 1H, d, J = 9.0 Hz), 8.38-8.41 (1H, m).
ESI-MS m / z: 316 (M + H) ⁺ .

3) Title compound To a solution of 1- (6-chloro-3-pyridazinyl) -5- (2-pyridyl) -1H-pyrazole-3-carboxylic acid methyl ester (2.981 g) in methanol (190 ml) at room temperature Sodium methoxide (1.530 g) was added and stirred for 19 hours. 1N aqueous hydrochloric acid (19 ml) was added to the reaction mixture, methanol was distilled off under reduced pressure, water was added to the resulting residue, the insoluble solid was collected by filtration, and dried to give the title compound (2.571 g, 87%). Obtained as a solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.99 (3H, s), 4.10 (3H, s), 7.15 (1H, d, J = 9.3 Hz), 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 = 9.3 Hz), 8.40-8.41 (1H, m).
LC-MS m / z: 312 (M + H) ^<+> .

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

1) 1- (6-Methoxy-3-pyridyl) -5-phenyl-4,5-dihydro-1H-pyrazol-3-ylamine Under argon atmosphere, 5-hydrazino-2-methoxypyridine (6. 0 mg) and cinnamate nitrile (5.57 g) in ethanol (120 ml) were added sodium methoxide (4.66 g) at room temperature and heated to reflux for 13 hours. After air cooling, water and chloroform were added to the reaction solution for liquid separation. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, diethyl ether was added to the resulting residue, and the resulting solid was collected by filtration and dried to give 4,5-dihydro-1H-pyrazol-3-ylamine (8.28 g, 71%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.82-2.88 (1H, m), 3.28-3.32 (1H, m), 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 = 2.8 Hz).
MS (EI) m / z: 268 (M ^<+> ).

2) Title compound To a solution of 1- (6-methoxy-3-pyridyl) -5-phenyl-4,5-dihydro-1H-pyrazol-3-ylamine (8.27 g) in dichloromethane (165 ml) at room temperature Manganese (10.7 g) was added and stirred for 3 hours. Insolubles were filtered off from the reaction solution using Celite, and water and chloroform were added to the filtrate for liquid separation. The organic layer was dried over anhydrous sodium sulfate. After separation by 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.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.79 (2H, brs), 3.91 (3H, s), 5.92 (1H, s), 6.69 (1H, d, J = 8.8 Hz), 7.20-7.32 (5 H, m), 7.49 (1 H, dd, J = 8.8, 2.8 Hz), 8.00 (1 H, d, J = 2.8 Hz) ).
MS (EI) m / z: 266 (M ^<+> ).

[Reference Example 7] 1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-ylamine

1) 3- (2-Pyridyl) acrylonitrile Diethyl cyanomethylphosphonate (10.0 g) was added dropwise to a suspension of 60% sodium hydride (3.7 g) in tetrahydrofuran (120 ml) under ice cooling, and the mixture was stirred for 20 minutes. To the reaction solution, a solution of 2-pyridinecarboxaldehyde (9.0 g) in tetrahydrofuran (30 ml) was added dropwise and stirred for 24 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution, and the mixture was partitioned. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (dichloromethane) to obtain 3- (2-pyridyl) acrylonitrile (3.9 g, 35%) as a solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.59 (1H, d, J = 16.1 Hz), 7.31-7.35 (2H, m), 7.40 (1H, d, J = 16.1 Hz), 7.72-7.77 (1 H, m), 8.63-8.65 (1 H, m).
MS (EI) m / z: 130 (M ^<+> ).

2) 1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -4,5-dihydro-1H-pyrazol-3-ylamine 5-hydrazino-2-methoxypyridine of Reference Example 2 (4. 17-g) and 3- (2-pyridyl) acrylonitrile (3.9 g) described above and 1- (6-methoxy-3-pyridyl) -5- (2- Pyridyl) -4,5-dihydro-1H-pyrazol-3-ylamine (4.5 g, 55%) was obtained as a solid.
MS (EI) m / z: 269 (M ^<+> ).

3) Title compound To a solution of 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -4,5-dihydro-1H-pyrazol-3-ylamine (4.5 g) in dichloromethane (100 ml) Then, manganese dioxide (5.3 g) was added at room temperature and stirred for 3 hours. Insolubles were filtered off from the reaction solution using Celite and Florisil, the organic solvent in the filtrate was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to give the title compound (3.06 g, 38%) as a solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.84 (2H, brs), 3.92 (3H, s), 6.17 (1H, s), 6.72 (1H, d, J = 8.8 Hz), 7.19-7.24 (2 H, m), 7.57-7.65 (2 H, m), 8.01 (1 H, d, J = 2.7 Hz), 8.52- 8.55 (1H, m).
MS (FAB) m / z: 268 (M + H) ^<+> .

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

  Sodium methoxide (2.70 g) was added to a solution of 3-chloro-6-hydrazide pyridine (3.61 g) and 3- (2-pyridyl) acrylonitrile (3.25 g) of Reference Example 7) in methanol (75 ml). And heated under reflux for 75 hours under an argon atmosphere. After air cooling, water and chloroform were added to the reaction solution for liquid separation. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in dichloromethane (75 ml), manganese dioxide (3.0 g) was added, and the mixture was heated to reflux for 8 hours. After air cooling, the 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 to reflux for 1 hour. After air cooling, water and chloroform were added to the reaction solution for liquid separation. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.878 g, 13%) as a solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.87 (2H, brs), 4.06 (3H, s), 6.16 (1H, 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 = 9.2 Hz), 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

1) 1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazole-3-carboxylic acid methyl ester 4- (2-pyridyl) -2,4 of Reference Example 5-1) A solution of 5-hydrazino-2-methoxypyridine (2.767 g) of Reference Example 2 in N, N-dimethylformamide (10 ml) in a solution of N, N-dimethylformamide (20 ml) in dioxobutanoic acid methyl ester (4.12 g) And stirred at 80 ° C. for 16 hours, and further stirred at 110 ° C. for 5 hours. After air cooling, water and ethyl acetate were added to the reaction solution and the phases were separated. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H. -Pyrazole-3-carboxylic acid methyl ester (1.097 g, 17%) was obtained as a solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.95 (3H, s), 3.98 (3H, s), 6.76 (1H, d, J = 8.8 Hz), 7.21-7 .28 (1H, m), 7.28 (1H, s), 7.36 (1H, d, J = 8.0 Hz), 7.64-7.73 (2H, m), 8.10 (1H) , D, J = 2.7 Hz), 8.52 (1H, d, J = 4.1 Hz).
ESI-MSm / z: 311 ( M + H) +.

2) [1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methanol Above 1- (6-methoxy-3-pyridyl) -5- (2- To a solution of pyridyl) -1H-pyrazole-3-carboxylic acid methyl ester (1.097 g) in tetrahydrofuran (15 ml) was added lithium borohydride (154 mg) at room temperature, and the mixture was stirred for 6 hours. Water and ethyl acetate were added to the reaction solution and the phases were separated, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl)- 1H-pyrazol-3-yl] methanol (581 mg, 58%) was obtained as amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.07 (1H, t, J = 5.8 Hz), 3.94 (3H, s), 4.80 (2H, d, J = 5.8 Hz) , 6.75 (1H, d, J = 8.8 Hz), 6.77 (1H, s), 7.18-7.24 (1H, m), 7.28-7.33 (1H, m) 7.61 (1H, dd, J = 2.7, 8.8 Hz), 7.64-7.70 (1H, m), 8.07 (1H, d, J = 2.7 Hz), 8. 51-8.56 (1H, m).
ESI-MS m / z: 283 (M + H) ⁺ .

3) [1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methyl methanesulfonate [1- (6-methoxy-3-pyridyl)- 5- (2-Pyridyl) -1H-pyrazol-3-yl] methanol (581 mg) and [1- (6-methoxy-3-pyridyl) -5-5- (2-Pyridyl) -1H-pyrazol-3-yl] methyl = methanesulfonate (754 mg, quantitative) was obtained as an oil. The product was subjected to the next reaction without further purification.
ESI-MS m / z: 361 (M + H) ⁺ .

4) [1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methyl azide [1- (6-methoxy-3-pyridyl) -5- (2 -Pyridyl) -1H-pyrazol-3-yl] methyl = methanesulfonate (498 mg) and [1- (6-methoxy-3-pyridyl) -5- 5 in the same manner as in Reference Example 4 3) (2-Pyridyl) -1H-pyrazol-3-yl] methyl azide (341 mg, 80%) was obtained as an oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.94 (3H, s), 4.46 (2H, s), 6.76 (1H, d, J = 8.8 Hz), 6.78 (1H , S), 7.20-7.26 (1H, m), 7.31 (1H, d, J = 7.8 Hz), 7.62 (1H, dd, J = 8.8, 2.7 Hz) 7.64-7.71 (1H, m), 8.08 (1 H, d, J = 2.7 Hz), 8.52-8.57 (1 H, m).
ESI-MS m / z: 308 (M + H) ⁺ .

5) Title compound Using [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methyl azide (341 mg) as in 4) of Reference Example 4 Gave the title compound (314 mg, quantitative) as an oil.
ESI-MS m / z: 282 (M + H) ⁺ .

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

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

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.65 (3H, s), 3.95 (3H, s), 5.10-5.20 (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-MS m / z: 294 (M + H) ^<+> .

2) 1- [1- (6-Methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] ethanol 1- [1- (6-Methoxy-3-pyridyl) -5-phenyl- [1H-pyrazol-3-yl] ethanone (353 mg) in methanol (6 ml) was added sodium borohydride (45 mg) at room temperature and stirred for 1.5 hours. Water and ethyl acetate were added to the reaction solution and the phases were separated, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain 1- [1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] ethanol (348 mg, 98%) as an individual. .

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.62 (3H, d, J = 6.6 Hz), 2.39 (1H, d, J = 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 = 8.8 Hz), 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) .7 Hz).
ESI-MS m / z: 296 (M + H) ⁺ .

3) 3- (1-Chloroethyl) -1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazole The above 1- [1- (6-methoxy-3-pyridyl) -5-phenyl-1H -Pyrazol-3-yl] To a solution of ethanol (345 mg) in dichloromethane (10 ml) was added triethylamine (179 μl) and methanesulfonyl chloride (99 μl) under ice cooling, and the mixture was stirred at room temperature for 3 hours. Further, triethylamine (147 μl) and methanesulfonyl chloride (82 μl) were added to the reaction solution and stirred for 5 hours. The reaction solvent was distilled off under reduced pressure, and water and ethyl acetate were added to the resulting residue for liquid separation. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure to give 3- (1-chloroethyl) -1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazole (448 mg) as an oil.
ESI-MS m / z: 314 (M + H) ⁺ .

4) 1- [1- (6-Methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] ethyl azide Above 3- (1-chloroethyl) -1- (6-methoxy-3-pyridyl) 1- [1- (6-Methoxy-3-pyridyl) -5 was prepared in the same manner as in Reference Example 4 3) using -5-phenyl-1H-pyrazole (448 mg) and sodium azide (380 mg). -Phenyl-1H-pyrazol-3-yl] ethyl azide (312 mg, 83% from ethanol in 2 steps) was obtained as an oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.65 (3H, d, J = 7.0 Hz), 3.93 (3H, s), 4.74 (1H, q, J = 7.0 Hz) 6.50 (1H, s), 6.72 (1H, d, J = 8.8 Hz), 7.20-7.26 (2H, m), 7.30-7.37 (3H, m) 7.53 (1H, dd, J = 8.8, 2.7 Hz), 8.07 (1H, d, J = 2.7 Hz).
ESI-MS m / z: 321 (M + H) ⁺ .

5) Title compound The same method as 4) in Reference Example 4 using 1- [1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] ethyl azide (312 mg) Gave the title compound (298 mg, quantitative) as an oil.
ESI-MS m / z: 295 (M + H) ⁺ .

[Reference Example 11] [1- (6-Methoxy-3-pyridazinyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methylamine

1) [1- (6-Methoxy-3-pyridazinyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methanol 1- (6-methoxy-3-pyridazinyl) -5 of Reference Example 5 To a solution of (2-pyridyl) -1H-pyrazole-3-carboxylic acid methyl ester (2.567 g) in tetrahydrofuran (80 ml) was added lithium borohydride (1.077 g), and the mixture was stirred at room temperature for 46 hours. The reaction solvent was distilled off under reduced pressure, and water and ethyl acetate were added to the resulting residue for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) -1H. -Pyrazol-3-yl] methanol (1.141 g, 48%) was obtained as amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.04-2.15 (1H, br), 4.09 (3H, s), 4.82 (2H, s), 6.74 (1H, s ), 7.11 (1H, d, J = 9.3 Hz), 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-pyridazinyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methyl = methanesulfonate Above [1- (6-methoxy-3-pyridazinyl)- [1- (6-Methoxy-3-pyridazinyl)-] in the same manner as in Reference Example 4 2) using 5- (2-pyridyl) -1H-pyrazol-3-yl] methanol (1.097 g) 5- (2-Pyridyl) -1H-pyrazol-3-yl] methyl methanesulfonate (1.078 g, 77%) was obtained as an individual.
ESI-MS m / z: 362 (M + H) ⁺ .

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

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.10 (3H, s), 4.46 (2H, s), 6.75 (1H, s), 7.13 (1H, d, J = 9) .3 Hz), 7.20-7.24 (1 H, m), 7.54 (1 H, d, J = 7.8 Hz), 7.73 (1 H, td, J = 7.8, 1.8 Hz) 7.85 (1H, d, J = 9.3 Hz), 8.43-8.46 (1H, m).
ESI-MS m / z: 309 (M + H) ⁺ .

4) Title compound 10% of the above [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methyl azide (254 mg) in methanol (25 ml) at room temperature Palladium-carbon (50% wet, 51 mg) was added and stirred for 2 hours under a hydrogen atmosphere. After removing the catalyst by filtration, the mother liquor solvent was distilled off under reduced pressure to obtain the title compound (228 mg, 98%) as a solid.
ESI-MS m / z: 283 (M + H) ⁺ .

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

A solution of [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methyl = methanesulfonate (214 mg) in tetrahydrofuran (5 ml) of Reference Example 9 3) 2.0M methylamine-tetrahydrofuran solution (1.48ml) was added thereto, and the mixture was stirred at room temperature for 45 hours. Diethyl ether was added to the reaction mixture, insolubles were filtered off, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (chloroform-methanol) to give the title compound (52 mg, 29%). Obtained as an oil.
ESI-MS m / z: 296 (M + H) ⁺ .

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

  To a solution of [1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] methylamine (96 mg) in Reference Example 4 in dichloromethane (5 ml) at room temperature with triethylamine (95 μl) and chloride. Acetyl (36 μl) was added and stirred for 1 hour. Water and ethyl acetate were added to the reaction solution and the phases were separated, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (chloroform-methanol) to obtain the title compound (93 mg, 84%) as amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.05 (3H, s), 3.93 (3H, s), 4.54 (2H, d, J = 5.2 Hz), 6.07-6 .17 (1H, br), 6.46 (1H, s), 6.72 (1H, d, J = 8.8 Hz), 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).
ESI-MS m / z: 323 (M + H) ⁺ .

[Example 2] 3- [1- (6-Methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-ylmethyl] -1-methylurea

  To a solution of 4-nitrophenyl chloroformate (87 mg) in dichloromethane (4 ml) under ice cooling, [1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] methyl of Reference Example 4 was added. A solution of amine (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, 40% methylamine in methanol (85 μl) and triethylamine (44 μl) were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the resulting residue for separation. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (chloroform-methanol) to obtain the title compound (100 mg, 68%) as amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.80 (3H, d, J = 4.9 Hz), 3.93 (3H, s), 4.46 (2H, d, J = 5.5 Hz) 4.47-4.56 (1H, br), 4.90-4.98 (1H, br), 6.47 (1H, s), 6.71 (1H, d, J = 8.8 Hz). 7.17-7.23 (2H, m), 7.28-7.33 (3H, m), 7.49 (1H, dd, J = 2.7, 8.8 Hz), 8.07 ( 1H, d, J = 2.7 Hz).
ESI-MSm / z: 338 ( M + H) +.

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

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

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.56 (3H, d, J = 6.6 Hz), 2.78 (3H, d, J = 4.6 Hz), 3.92 (3H, s) 4.68-4.77 (1H, br), 4.98 (1H, qd, J = 6.8, 6.6 Hz), 5.10 (1H, d, J = 6.8 Hz), 6. 41 (1H, s), 6.71 (1H, d, J = 8.8 Hz), 7.17-7.23 (2H, m), 7.28-7.33 (3H, m), 7. 48 (1H, dd, J = 8.8, 2.4 Hz), 8.07 (1H, d, J = 2.4 Hz).
ESI-MS m / z: 352 (M + H) ⁺ .

Example 4 3- [1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-ylmethyl] -1-methylurea

  Using [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methylamine (121 mg) of Reference Example 9 in the same manner as in Example 2. The title compound (36 mg, 23%) was obtained as an individual.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.79 (3H, d, J = 4.9 Hz), 3.94 (3H, s), 4.47 (2H, d, J = 5.6 Hz) , 4.54-4.68 (1H, br), 5.00-5.12 (1H, br), 6.72 (1H, s), 6.74 (1H, d, J = 8.8 Hz) 7.17-7.23 (1H, m), 7.30 (1H, d, J = 8.0 Hz), 7.58 (1H, dd, J = 8.8, 2.7 Hz), 7. 61-7.68 (1H, m), 8.06 (1H, d, J = 2.7 Hz), 8.49-8.55 (1H, m).
ESI-MSm / z: 339 ( M + H) +.

Example 5 1-Isopropyl-3- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-ylmethyl] urea

  To a solution of [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methylamine (28 mg) in Reference Example 5 in dichloromethane (3 ml), isopropyl isocyanate ( 11 μl) was added and stirred at room temperature for 1 hour. The reaction solvent was evaporated under reduced pressure, and the resulting residue was crystallized from ethyl acetate-hexane and collected by filtration to give the title compound (28 mg, 77%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.15 (6H, d, J = 6.6 Hz), 3.83-3.93 (1H, m), 3.94 (3H, s), 4 29-4.36 (1H, br), 4.47 (2H, d, J = 5.6 Hz), 4.77-4.83 (1H, br), 6.72 (1H, s), 6 .75 (1H, d, J = 8.8 Hz), 7.17-7.23 (1H, m), 7.28-7.33 (1H, m), 7.58 (1H, dd, J = 8.8, 2.7 Hz), 7.63-7.69 (1 H, m), 8.06 (1 H, d, J = 2.7 Hz), 8.49-8.55 (1 H, m).
ESI-MS m / z: 367 (M + H) ⁺ .

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

  Using [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methylamine (28 mg) and phenyl isocyanate (12 μl) in Reference Example 9 The title compound (24 mg, 60%) was obtained as an individual in the same manner as in Example 5.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.94 (3H, s), 4.55 (2H, d, J = 5.6 Hz), 5.31-5.38 (1H, br), 6 53-6.61 (1H, br), 6.74 (1H, s), 6.74 (1H, d, J = 8.8 Hz), 7.04-7.11 (1H, m), 7 18-7.23 (1H, m), 7.26-7.35 (5H, m), 7.57 (1H, dd, J = 8.8, 2.7 Hz), 7.62-7. 69 (1H, m), 8.05 (1H, d, J = 2.7 Hz), 8.49-8.54 (1H, m).
ESI-MS m / z: 401 (M + H) ⁺ .

Example 7 1,1-Dimethyl-3- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-ylmethyl] urea

  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) was added triethylamine (20 μl). And N, N-dimethylcarbamoyl chloride (13 μl) were added and stirred at room temperature for 18 hours. The reaction solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (chloroform-methanol) to obtain the title compound (34 mg, 82%) as an oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.94 (6H, s), 3.94 (3H, s), 4.53 (2H, d, J = 5.3 Hz), 4.95-5 .05 (1H, br), 6.74 (1H, s), 6.75 (1H, d, J = 8.8 Hz), 7.17-7.23 (1H, m), 7.30 (1H) , D, J = 7.8 Hz), 7.59 (1H, dd, J = 8.8, 2.7 Hz), 7.61-7.68 (1H, m), 8.07 (1H, d, J = 2.7 Hz), 8.49-8.54 (1H, m).
ESI-MS m / z: 353 (M + H) ^<+> .

Example 8 1,3-Dimethyl-3- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-ylmethyl] urea

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

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.82 (3H, d, J = 4.6 Hz), 3.00 (3H, s), 3.94 (3H, s), 4.52 (2H , S), 4.77-4.86 (1H, br), 6.71 (1H, s), 6.75 (1H, d, J = 8.8 Hz), 7.18-7.23 (1H M), 7.30 (1 H, d, J = 8.0 Hz), 7.59 (1 H, dd, J = 8.8, 2.7 Hz), 7.63-7.70 (1 H, m) , 8.07 (1H, d, J = 2.7 Hz), 8.50-8.55 (1H, m).
ESI-MS m / z: 353 (M + H) ^<+> .

Example 9 N- [1- (6-Methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-ylmethyl] carbamic acid methyl ester

  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) was added triethylamine (14 μl). And methyl chloroformate (8 μl) were added and stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution and the phases were separated, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (chloroform-methanol) to obtain the title compound (27 mg, 90%) as an oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.71 (3H, s), 3.94 (3H, s), 4.49 (2H, d, J = 5.3 Hz), 5.18-5 .31 (1H, br, NH), 6.72 (1H, s), 6.75 (1H, d, J = 8.8 Hz), 7.18-7.24 (1H, m), 7.28 (1H, d, J = 7.8 Hz), 7.60 (1H, dd, J = 8.8, 2.7 Hz), 7.62-7.69 (1H, m), 8.05 (1H, d, J = 2.7 Hz), 8.50-8.56 (1H, m).
ESI-MS m / z: 340 (M + H) ⁺ .

[Example 10] Morpholine-4-carboxylic acid [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-yl] methylamide

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

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.38 (4H, t, J = 4.9 Hz), 3.69 (4H, t, J = 4.9 Hz), 3.94 (3H, s) , 4.55 (2H, d, J = 5.1 Hz), 5.05-5.15 (1H, br), 6.73 (1H, s), 6.75 (1H, d, J = 8. 8 Hz), 7.17-7.23 (1 H, m), 7.29 (1 H, d, J = 7.8 Hz), 7.58 (1 H, dd, J = 8.8, 2.7 Hz), 7.61-7.68 (1H, m), 8.07 (1H, d, J = 2.7 Hz), 8.49-8.55 (1H, m).
ESI-MS m / z: 395 (M + H) ⁺ .

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

  In the same manner as in Example 2 using [1- (6-methoxy-3-pyridyl) -5- (2-pyridazinyl) -1H-pyrazol-3-yl] methylamine (228 mg) in Reference Example 11 The title compound (180 mg, 64%) was obtained as an individual.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.79 (3H, d, J = 4.9 Hz), 4.10 (3H, s), 4.48 (2H, d, J = 5.6 Hz) , 4.70-4.79 (1H, br m), 5.18-5.25 (1H, br m), 6.70 (1H, s), 7.09 (1H, d, J = 9. 3 Hz), 7.19 (1 H, ddd, J = 7.6, 4.9, 1.2 Hz), 7.48-7.52 (1 H, m), 7.70 (1 H, dt, J = 7) .6, 1.7 Hz), 7.72 (1H, d, J = 9.3 Hz), 8.38-8.41 (1H, m).
ESI-MS m / z: 340 (M + H) ⁺ .
Elemental analysis: C ₁₆ H ₁₇ N ₇ O ₂ .0.5H ₂ O Theoretical values: 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

  To a solution of 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -1H-pyrazol-3-ylamine (100 mg) in Reference Example 7 in dichloromethane (2 ml) at room temperature, triethylamine (0.1 ml). And pivaloyl chloride (44 mg) were added and stirred for 1 day. Water and dichloromethane were added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (dichloromethane-methanol) to obtain the title compound (95 mg, 72%) as a solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.33 (9H, s), 3.94 (3H, s), 6.74 (1H, dd, J = 8.8, 0.5 Hz), 7 .18-7.20 (1H, m), 7.27 (2H, d, J = 5.1 Hz), 7.47-7.49 (1H, m), 7.55-7.59 (1H, m), 7.67-7.70 (1H, m), 8.05 (1H, d, J = 2.7 Hz), 8.45-8.47 (1H, m).
FAB-MS m / z: 352 (M + H) ⁺ .

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

  Using 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) -1H-pyrazole-3 (440 mg) of Reference Example 8 in the same manner as in Example 12, the title compound (421 mg, 79 %) As individuals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.34 (9H, s), 4.10 (3H, s), 7.07 (1H, d, J = 9.03 Hz), 7.17-7 .21 (1H, m), 7.30 (1H, s), 7.61-7.76 (3H, m), 8.00 (1H, br s), 8.37-8.39 (1H, m).
EI-MS m / z: 352 (M ^<+> ).

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

1) N- [1- (6-Methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] oxamic acid ethyl ester 1- (6-methoxy-3-pyridyl) -5 of Reference Example 6 -To a solution of phenyl-1H-pyrazol-3-ylamine (500 mg) in dichloromethane (10 ml) at room temperature were added triethylamine (0.33 ml) and ethyl glyoxychloride (280 mg), and the mixture was stirred for 16 hours. Water and dichloromethane were added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting 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.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.44 (3H, t, J = 7.1 Hz), 3.94 (3H, s), 4.43 (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 = 2.5 Hz), 9.40 (1H, br s).
EI-MS m / z: 366 (M ^<+> ).

2) N- [1- (6-Methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] oxamic acid N- [1- (6-Methoxy-3-pyridyl) -5-phenyl 1N-pyrazol-3-yl] oxamic acid ethyl ester (680 mg) in ethanol (5 ml), tetrahydrofuran (5 ml) and water (1 ml) was added 6N aqueous sodium hydroxide solution (0.2 ml) for 24 hours at room temperature. Stir. The reaction solvent was evaporated under reduced pressure, concentrated hydrochloric acid was added to the resulting residue for neutralization, dichloromethane was added for liquid separation, and the organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain N- [1- (6-methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] oxamic acid (560 mg, 89%). The product was subjected to the next reaction without further purification.
EI-MS m / z: 338 (M ^<+> ).

3) Title compound N- [1- (6-Methoxy-3-pyridyl) -5-phenyl-1H-pyrazol-3-yl] oxamic acid (560 mg), 1-hydroxybenzotriazole (340 mg), 1-ethyl Triethylamine (0.4 ml) was added at room temperature to a solution of -3- (3-dimethylaminopropyl) carbodiimide hydrochloride (475 mg) and tert-butylamine (133 mg) in dichloromethane (10 ml), and the mixture was stirred for 16 hours. Water and dichloromethane were added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (dichloromethane-acetone) to obtain the title compound (55 mg, 7.4%) as a solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.44 (9H, s), 3.93 (3H, s), 6.72 (1H, d, J = 8.8 Hz), 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-MS m / z: 393 (M ^<+> ).

[Test Example 1] Platelet aggregation inhibitory action Human blood was collected using 1/10 volume of 3.13% sodium citrate as a blood coagulation inhibitor, and centrifuged at 180 g for 10 minutes to separate platelet-rich plasma (PRP). . After separating the upper layer PRP, the lower layer was centrifuged at 1600 g for 10 minutes to separate the upper layer platelet poor plasma (PPP). 1 μl of the solution of the example compound was added to 200 μl of PRP and allowed to stand at 37 ° C. for 2 minutes, and then 2 μl of collagen was added to induce platelet aggregation. Platelet aggregation rate was measured using PAM-12C (SSR Engineering). The light transmittance of PPP was taken as the 100% aggregation value, the aggregation rate at each concentration of the Example compound was determined, and the IC ₅₀ value was calculated. The results are shown in Table 1.

[Test Example 2] Cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibitory activity For the measurement of the COX-1 and COX-2 inhibitory activities of the Example compounds, the screening of COX inhibitors by Cayman Chemical Company was conducted. An assay kit (catalog numbers 560101, 560121) was used.
Reaction buffer before measurement, heme, arachidonic acid, SnCl _2, EIA buffer, washing buffer,
Prostaglandin (PG) screening EIA standard solution, PG screening acetylcholinesterase (AchE), tracer (chromogenic enzyme HRP conjugate), and PG screening EIA antiserum were prepared.
(1) Production of PGF ₂ α by COX-1 or COX-2 The reaction solution containing Example Compound (50 μM) and COX-1 or COX-2 was allowed to stand at 37 ° C. for 10 minutes, and then 10 μl of arachidonic acid was added. It left still at 37 degreeC for 2 minutes. After the reaction, 50 μl of 1N hydrochloric acid was added to stop the reaction, 100 μl of SnCl ₂ solution was added, and the mixture was allowed to stand at room temperature for 5 minutes.
(2) Quantification of PGF ₂ α by ELISA After adding 50 μl of antiserum (rabbit anti-PGF ₂ α antibody) to each well of a 96-well (well) plate coated with mouse anti-rabbit IgG, the above PGF ₂ α production reaction 50 μl of a solution obtained by diluting the solution 2000 times and 50 μl of AchE tracer were sequentially added, and left at room temperature for 18 hours. Each well was washed 5 times with wash buffer to remove excess AchE tracer and then 200 μl Ellman reagent was added. After standing in a dark room for 60 minutes, the absorbance was measured at 405 nm.
(3) Calculation of inhibitory activity of Example compounds A standard curve was prepared using the PG screening EIA standard solution, and the production amount of PGF ₂ α was determined from the absorbance described above. The inhibition rate of COX-1 or COX-2 in Example Compound 50 μM was calculated. The results are shown in Table 1.
In calculating the inhibition rate, the production amount of PGF ₂ α obtained using the reaction solution not containing the Example compound was defined as 100%.

As is apparent from Table 1, the compound (I) of the present invention, a salt or solvate thereof, or a solvate of the salt has a potent platelet aggregation inhibitory action, and COX-1 and COX- 2 showed no inhibitory effect.

Claims (6)

Formula (I)

(In the formula, Ar ₁ and Ar ₂ each independently have a 5- or 6-membered aromatic heterocyclic group or 1 to 3 substituents which may have 1 to 3 substituents. Or an aryl group having 6 to 14 carbon atoms;
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 is a lower alkyl group which may have a substituent, an amino group which may have a substituent, a lower alkoxy group which may have a substituent, a carbamoyl group which may have a substituent, or 1 to 3 A heterocyclic group which may have a substituent of
n represents a number of 0 or 1. )
Or a salt or solvate thereof. Ar ₁ and Ar ₂ are each independently a 5- to 6-membered aromatic heterocyclic group having 1 to 3 nitrogen atoms or 1 to 3 The compound according to claim 1, a salt thereof or a solvate thereof, which is a phenyl group which may have a substituent. ^3. The compound, salt or solvate thereof according to claim 1 or 2, wherein R3 is a hydrogen atom, a lower alkyl group or a carboxy lower alkyl group. R ⁴ is a lower alkyl group, a lower alkylamino group, a di (lower alkyl) amino group, an arylamino group having 6 to 14 carbon atoms, a lower alkoxy group, a morpholino group, or a lower alkylcarbamoyl group. The compound of any one, its salt, or its solvate.   The pharmaceutical containing the compound of any one of Claims 1-4, its salt, or those solvates.   A prophylactic and / or therapeutic agent for ischemic disease comprising the compound according to any one of claims 1 to 4, a salt thereof, or a solvate thereof.