JP2009184925A - 5-(1h-1,2,3-triazol-4-yl)-1h-pyrazole derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound that exhibits an inhibitory action on plasma coagulation and is excellent in safety as well as in vivo kinetics. <P>SOLUTION: Disclosed are a compound represented by formula (I), its salt, and its solvate. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

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

  Platelet plays an important role in preventing bleeding by agglutinating and forming a hemostatic thrombus at the time of vascular injury, but on the other hand, the site where the vascular endothelium in the blood vessel is damaged, the stenotic site etc. Aggregates to induce thrombi and emboli. These thrombi and emboli cause ischemic diseases such as myocardial infarction, angina pectoris, ischemic cerebrovascular disorder, and peripheral vascular disorder. Therefore, platelet aggregation inhibitors are used for the prevention and treatment of ischemic diseases. Among them, low-dose aspirin has long been used as a platelet aggregation inhibitor, and its effect has been demonstrated by APT (Antiplatelet Trialist's Collaboration), a meta-analysis of the results of multiple clinical trials administered to 100,000 patients. (See Non-Patent Document 1).

  However, aspirin is known to have a side effect of causing bleeding in the gastrointestinal tract 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).

  It is known that aspirin's inhibitory action on platelet aggregation is based on the inhibitory action of cyclooxygenase. Cyclooxygenase includes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Aspirin selectively and irreversibly inhibits COX-1 at a low dose, thereby suppressing platelet aggregation. However, inhibition of COX-1 also causes aspirin ulcers (see Non-Patent Documents 3 and 4). Non-steroidal anti-inflammatory drugs are known to selectively inhibit COX-2 and exhibit an anti-inflammatory action.

  As described above, although aspirin is useful as a platelet aggregation inhibitor, it has a gastrointestinal disorder as a side effect based on its action mechanism, COX-1 inhibitory action, and therefore has no COX-1 inhibitory action. Is required.

  On the other hand, compound (A) (see Patent Document 1 and Non-patent Document 5) and compound (B) (see Patent Document 2) are known as pyrazole derivatives having antithrombotic activity.

However, the IC ₅₀ value for collagen-induced platelet aggregation of Compound (A) is 5.3 × 10 ⁻⁶ M, and it shows a stronger inhibitory activity against COX-2 (IC ₅₀ value 2.4 × 10). ^-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 inhibition of COX-2 leads to an anti-inflammatory action, having COX-2 inhibitory activity is not necessarily preferable as a platelet aggregation inhibitor.

  On the other hand, Patent Document 3 discloses a compound (C) that is a platelet aggregation inhibitor that does not inhibit COX-1 and COX-2, but the difluoro group at the 4-position on the piperidine ring constituting this compound is disclosed. Since the compound (D) obtained by converting into a methoxy group exhibits nephrotoxicity, it is difficult to say that the platelet aggregation inhibitor disclosed in Patent Document 3 is certainly superior in terms of safety.

Japanese Patent No. 2586713 WO 97/29774 pamphlet International Publication 2006/014005 Pamphlet BMJ, 308, 81-106, 1994 BMJ, 321 (1183-1187), 2000 Neurology, 57, Suppl. 2, pages S5-S7 Drugs Today, 35, 251-265, 1999 Chem. Pharm. Bull. 45, 987-995, 1997

  The present invention is to provide a potent platelet aggregation inhibitor that does not inhibit COX-1 and COX-2 and does not exhibit nephrotoxicity.

  As a result of diligent research for such a platelet aggregation inhibitor, the present inventors have found that a pyrazole derivative represented by the following general formula (I) does not inhibit COX-1 and COX-2, The present invention was completed by finding that it exhibits a strong platelet aggregation inhibitory action without showing toxicity.

  That is, the present invention relates to the general formula (I)

Wherein R ² is a hydrogen atom, a lower alkyl group that may be substituted, a lower alkynyl group, a carbamoyl group that may be substituted, a cyano group, an amino group that may be substituted, or a substituent. Or a group or atom selected from a lower alkoxy group and a lower alkanoyl group; wherein X is a group of the general formula (II)

(The cyclic structure in the formula represents a 4- to 7-membered alicyclic heterocyclic ring which may have a nitrogen atom or an oxygen atom as a constituent atom in addition to the nitrogen atom described in the formula, and R ¹ represents the cyclic structure. May be substituted lower alkyl group, may be substituted carbamoyl group, may be substituted amino group, hydroxyl group, lower alkoxy group, oxo group, lower alkanoyl group, lower alkylsulfonyl group and halogen atom A group represented by 1 to 2 groups or atoms selected from the above. ), A salt thereof, or a solvate thereof.

The present invention also provides a pharmaceutical composition containing the above compound, its salt or a solvate thereof; a medicament containing the above compound, its salt or their solvate; the above compound, its salt or their solvate The present invention provides a prophylactic and / or therapeutic agent for ischemic diseases comprising as an active ingredient a platelet aggregation inhibitor comprising a solvate as an active ingredient; the above compound, a salt thereof or a solvate thereof.
The present invention also provides a method for preventing and / or treating an ischemic disease, comprising administering an effective amount of the above-mentioned compound, a salt thereof or a solvate thereof as an active ingredient.
The present invention further provides the use of the above-mentioned compound, its salt or a solvate thereof for the manufacture of a medicament; the above-mentioned compound, its salt or their for the manufacture of a prophylactic and / or therapeutic agent for ischemic disease. Provide the use of solvates.

  The compound (I), a salt thereof or a solvate thereof of the present invention has an action of strongly suppressing platelet aggregation and inhibiting thrombus formation without inhibiting COX-1 and COX-2. 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 (CABG), percutaneous transluminal coronary angioplasty (PTCA), stent placement, etc.), thrombotic occlusion, diabetic retinopathy / nephropathy, occlusion at heart valve replacement It is useful for the prevention and / or treatment of ischemic diseases caused by thrombus / embolism such as acute coronary syndrome. It is also useful for the prevention and / or treatment of thrombi and emboli associated with vascular surgery and extracorporeal blood circulation. Furthermore, it is useful for the improvement of ischemic symptoms such as ulcer, pain and cold feeling associated with chronic arterial occlusion.

  The general formula (I) will be described below.

R ² is 1) a lower alkyl group which may be substituted, 2) a lower alkynyl group, 3) a carbamoyl group which may be substituted, 4) a cyano group, 5) an amino group which may be substituted, 6 It represents a group selected from a lower alkoxy group which may be substituted) and a lower alkanoyl group.

  The “lower alkyl group” in the present specification means a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms. Specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, cyclopropyl group, cyclobutyl Group, cyclopentyl group, cyclohexyl group, cyclopropylmethyl group and cyclopentylmethyl group.

  In the present specification, the “lower alkoxy group” means an alkoxy group containing a lower alkyl group in its structure. Specific examples include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, n-pentoxy group, and cyclopentyloxy group.

  In the present specification, the “lower alkynyl group” means a linear, branched or cyclic alkynyl group having 2 to 6 carbon atoms. Specific examples include ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 1-pentynyl group, and 2-pentynyl group.

  In the present specification, the “lower alkanoyl group” means a linear or branched alkanoyl group having 1 to 6 carbon atoms. Specific examples include formyl group, acetyl group, n-propionyl group, n-butyryl group and isobutyryl group.

  In the present specification, the “lower alkylsulfonyl group” means a sulfonyl group substituted with a lower alkyl group. Specifically, methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, isobutylsulfonyl group, tert-butylsulfonyl group, n-pentylsulfonyl group, isopentylsulfonyl group, A cyclopropylsulfonyl group and a cyclohexylsulfonyl group can be exemplified.

Further, the above 1) to 7) will be described.
1) “Substituted lower alkyl group” is substituted with one or the same or different two or three substituents or atoms selected from the substituent group consisting of the following a) to e) Means a lower alkyl group which may be substituted. These substituents or atoms may be substituted with the same carbon atom in the lower alkyl group as long as they can be substituted, or may be substituted with different carbon atoms. As the lower alkyl group which may be substituted, a methyl group, an ethyl group or an n-propyl group is preferable, and a methyl group is particularly preferable.

  a) a carbamoyl group which may be substituted by one or two identical or different lower alkyl groups: the carbamoyl group is an unsubstituted carbamoyl group or a carbamoyl substituted by 1 to 2 lower alkyl groups Means group. Specific examples include a methylcarbamoyl group, an ethylcarbamoyl group, a dimethylcarbamoyl group, and an N-methyl-N-ethylcarbamoyl group. Of these, an unsubstituted carbamoyl group, a methylcarbamoyl group or a dimethylcarbamoyl group is preferred.

  b) an amino group which may be substituted with one or two identical or different substituents selected from a lower alkyl group, a lower alkanoyl group and a lower alkylsulfonyl group: the amino group is an unsubstituted amino group Or an amino group substituted by one or two identical or different substituents selected from a lower alkyl group, a lower alkanoyl group and a lower alkylsulfonyl group. Specifically, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, cyclopropylamino group, n-butylamino group, isobutylamino group, cyclopentylmethylamino group, dimethylamino group, diethylamino group, Di-n-propylamino group, di-n-butylamino group, N-methyl-N-ethylamino group, N-ethyl-Nn-propylamino group, N-methyl-N-cyclopentylmethylamino group, formylamino group Acetylamino group, n-propionylamino group, N-methyl-N-acetylamino group, N-ethyl-N-acetylamino group, methylsulfonylamino group, ethylsulfonylamino group, isopropylsulfonylamino group, n-butylsulfonyl Amino group, cyclopropylsulfonylamino group, cyclobut Emissions sulfonylamino group, N- methyl -N- methylsulfonylamino group, and an N- ethyl -N- methylsulfonylamino group.

c) Hydroxyl group:
d) Lower alkoxy group: A methoxy group or an ethoxy group is preferable, and a methoxy group is particularly preferable.
e) Halogen atom: fluorine, chlorine, bromine and iodine can be mentioned, fluorine or chlorine is preferred, and fluorine is particularly preferred.

  2) As the lower alkynyl group, an ethynyl group, a 1-propynyl group or a 2-propynyl group is preferable, and an ethynyl group is particularly preferable.

3) The “carbamoyl group which may be substituted” means an unsubstituted carbamoyl group or a carbamoyl group substituted with one or two lower alkyl groups which are the same or different. Specific examples include a methylcarbamoyl group, an ethylcarbamoyl group, an n-propylcarbamoyl group, a dimethylcarbamoyl group, a diethylcarbamoyl group, and an N-methyl-N-ethylcarbamoyl group.
4) “Cyano”

  5) “Amino group that may be substituted” means an unsubstituted amino group or an amino group substituted by one or two identical or different lower alkyl groups. Specific examples include a methylamino group, an ethylamino group, an n-propylamino group, a dimethylamino group, a diethylamino group, and an N-methyl-N-ethylamino group. Among these, an unsubstituted amino group, a methylamino group, or a dimethylamino group is preferable.

  6) “Alkoxy group which may be substituted” means an unsubstituted alkoxy group, or one selected from the group of substituents consisting of a) to e) in the above 1), or the same or different 2-3 Means an alkoxy group which may be substituted with a single substituent or atom. The alkoxy group which may be substituted is preferably an unsubstituted lower alkoxy group or a lower alkoxy group substituted with a carbamoyl group, more preferably a methoxy group, an ethoxy group or a carbamoylmethoxy group, and most preferably a methoxy group or a carbamoylmethoxy group. preferable.

  7) As the “lower alkanoyl group”, an acetyl group or an n-propionyl group is preferable, and an acetyl group is particularly preferable.

Among these substituents 1) to 7), R ² is preferably a lower alkyl group that may be substituted, more preferably an unsubstituted lower alkyl group, and most preferably a methyl group.

  Next, X will be described. X represents a group represented by the general formula (II). In the general formula (II), in addition to the nitrogen atom described in the general formula (II), a nitrogen atom or an oxygen atom may be a constituent atom. Means a 7-membered alicyclic heterocyclic group;

  As a 4- to 7-membered alicyclic heterocyclic group, azetidinyl group, pyrrolidinyl group, pyrazolidinyl group, piperidinyl group, piperazinyl group, hexahydropyridazinyl group, hexahydropyrimidinyl group, imidazolidinyl group, homopiperazinyl group, morpholinyl group, An oxazepanyl group can be mentioned. Among these, azetidinyl group, pyrrolidinyl group, pyrazolidinyl group, piperidinyl group, piperazinyl group, hexahydropyridazinyl group, morphonyl group or oxazepanyl group are preferable, and piperazinyl group, piperidinyl group, morpholinyl group or pyrrolidinyl group are particularly preferable. .

R ¹ is a group that substitutes for a carbon atom or a nitrogen atom constituting the alicyclic heterocyclic ring in the 4- to 7-membered alicyclic heterocyclic group, and is selected from the following (i) to (ix): Means group.

(I) Lower alkyl group which may be substituted: The same as the lower alkyl group which may be substituted in the above R ² ). That is, it means a lower alkyl group which may be substituted with one or the same or different 2 to 3 substituents or atoms selected from the substituent group consisting of a) to e). Furthermore, the lower alkyl group which may be substituted may be a lower alkyl group substituted by an oxo group alone. Further, the lower alkyl group which may be substituted may be a lower alkyl group which is substituted in combination with a group or atom selected from the above a) to e). As the lower alkyl group, a methyl group or a cyclopropyl group is preferable. Further, the group or atom substituted on the lower alkyl group is preferably a halogen atom, a hydroxyl group, a lower alkoxy group or an amino group. Accordingly, the substituted lower alkyl group substituted with the cyclic structure in formula (II) is preferably a halogeno lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group or an amino lower alkyl group. The halogeno lower alkyl group means a lower alkyl group substituted with a halogen atom. Examples of the halogeno lower alkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, and a trichloromethyl group, and among these, a fluoromethyl group, a difluoromethyl group, or a trifluoromethyl group. Group is preferred, and a fluoromethyl group is particularly preferred. A hydroxy lower alkyl group means a lower alkyl group substituted with a hydroxyl group. Examples of the hydroxy lower alkyl group include a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydroxypropyl group, a 2-hydroxypropyl group, and a 3-hydroxypropyl group. The lower alkoxy lower alkyl group means a lower alkyl group substituted with a lower alkoxy group, and examples thereof include a methoxymethyl group, an ethoxymethyl group, a methoxyethyl group, and an ethoxyethyl group. Of these, a methoxymethyl group is preferred. An amino lower alkyl group means a lower alkyl group substituted with an amino group, and specific examples include an aminomethyl group, a 2-aminoethyl group, and a 1-aminocyclopropyl group. A cyclopropyl group is preferred.

(Ii) Carbamoyl group that may be substituted: The carbamoyl group that may be substituted means the same group as the carbamoyl group that may be substituted in R ² . As the carbamoyl group which may be substituted, an unsubstituted carbamoyl group, a methylcarbamoyl group or a dimethylcarbamoyl group is preferable, and an unsubstituted carbamoyl group is particularly preferable.

(Iii) Amino group that may be substituted: The amino group that may be substituted means the same group as the amino group that may be substituted in R ² . The amino group which may be substituted is preferably an unsubstituted amino group, a methylamino group, a dimethylamino group, an ethylamino group or a diethylamino group, particularly preferably an unsubstituted amino group or a dimethylamino group.

(Iv) Hydroxyl group (v) Lower alkoxy group: As the lower alkoxy group, a methoxy group or an ethoxy group is preferable, and a methoxy group is particularly preferable.
(Vi) an oxo group,
(Vii) Lower alkanoyl group: Examples of the lower alkanoyl group include formyl group, acetyl group, n-propionyl group, n-butyryl group, isobutyryl group, and pivaloyl group. Among these, formyl group is particularly preferable.

  (Viii) Lower alkylsulfonyl group: As lower alkylsulfonyl group, methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, isobutylsulfonyl group, tert-butylsulfonyl group, n- A pentylsulfonyl group, an isopentylsulfonyl group, a cyclopropylsulfonyl group, and a cyclohexylsulfonyl group can be exemplified. Of these, a methylsulfonyl group, an ethylsulfonyl group, or an n-propylsulfonyl group is preferable.

(Ix) Halogen atom: The halogen atom is preferably fluorine or chlorine.
One of the groups or atoms selected from (i) to (ix) may be substituted with the alicyclic heterocyclic group, and 2 or 4 groups that are the same or different as long as they can be substituted. It may be substituted with a cyclic heterocyclic group. Further, when a plurality of groups are substituted, they may be substituted with the same element of the alicyclic heterocyclic group or may be substituted with different elements.

  As the alicyclic heterocyclic ring in the 4- to 7-membered alicyclic heterocyclic group, a piperazine ring, a piperidine ring or a morpholine ring is preferable.

  X is preferably a piperazinyl group, piperidinyl group, morpholinyl group, 4-methyl-piperazinyl group, 4-cyclopropyl-piperazinyl group, (2-fluoromethyl) pyrrolidinyl or 4-methoxy-piperidinyl group, and 4-methoxy-piperidinyl group 4-methyl-piperazinyl, 4-cyclopropyl-piperazinyl, morpholinyl or (2-fluoromethyl) pyrrolidinyl are particularly preferred.

As the compound of the present invention, a compound in which R ² is a methyl group; X is a piperazinyl group, piperidinyl group, morpholinyl group, 4-methyl-piperazinyl group, 4-cyclopropyl-piperazinyl group or 4-methoxy-piperidinyl group Is preferred. Further, particularly compounds in which R ² is a methyl group; and X is a 4-methoxy-piperidinyl group, 4-methyl-piperazinyl group, 4-cyclopropyl-piperazinyl group, morpholinyl group or (2-fluoromethyl) pyrrolidinyl group preferable.

  Not all of the compounds of the present invention form a salt, but may form a salt when the compound of the present invention has a carboxyl group or an amino group. In addition, the salts may form solvates. The salt here is a salt of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or nitric acid; a salt of an organic acid such as methanesulfonic acid, p-toluenesulfonic acid, fumaric acid or trifluoroacetic acid; sodium or potassium And salts with alkali metal or alkaline earth metal ions such as calcium.

  The solvate in the solvate of the compound of the present invention or a salt thereof includes not only a solvate added with a solvent used for crystallization of crystals but also those formed by absorbing moisture in the air. Including. Examples of the solvent include water, lower alcohols such as methanol or ethanol, and organic solvents such as acetone or acetonitrile.

  As the compounds of the present invention, salts thereof or solvates thereof, the following formulas (Ia) to (Ie)

Of these, a compound represented by the formula I, a salt thereof, or a solvate thereof can be preferably exemplified. Furthermore, the compound represented by the formula (Ib), a salt thereof or a solvate thereof can be most preferably exemplified.

  The compound of the present invention, a salt thereof or a solvate thereof does not inhibit COX-1 and COX-2, and does not exhibit nephrotoxicity, exhibits a potent platelet aggregation inhibitory action, and has a main drug efficacy and safety. From the viewpoints of oral absorption, pharmacokinetics and solubility, it is extremely excellent as a pharmaceutical product.

  The compound of the present invention, a salt thereof or a solvate thereof can be produced by the following method.

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

(In the above formula, R ² represents the same group as R ^2, and R ³ represents a methyl group or an ethyl group.)

  Compound (3) is prepared by dissolving compound (1) in an inert solvent such as tetrahydrofuran and treating with a base such as lithium bis (trimethylsilyl) amide under cooling at −78 ° C. to give an oxalic acid dialkyl ester (oxalic acid dimethyl ester or Acid diethyl ester) (2) can be added and stirred. The reaction temperature is preferably -78 ° C to room temperature.

  Also, compound (1) and oxalic acid dialkyl ester (dimethyl oxalate or diethyl oxalate) (2) are treated in an alcohol (methanol or ethanol) solution in the presence of sodium alkoxide (sodium methoxide or sodium ethoxide). By doing this, the compound (3) can also be obtained. The reaction temperature is preferably −10 to 100 ° C.

  The aromatic ketone (1) is S.I. It may be produced and used by the method of Ohta et al. (Chem. Pharm. Bull., 1997, 45 (7), 1140), the method described in Reference Examples or a method according to the method.

  When the aromatic ketone (1) has a functional group such as a hydroxyl group or an amino group, it may be necessary to protect these functional groups with an appropriate protective group in advance. Examples of the hydroxyl-protecting group include a tert-butyl group and a benzyl group, and examples of the amino group-protecting group include a trifluoroacetyl group, a tert-butoxycarbonyl group, and a benzyloxycarbonyl group. These protecting groups can be removed under conditions suitable for each protecting group.

  Next, the compound (3) and the hydrazine derivative ((4) WO2004 / 069824) are dissolved in alcohol (methanol or ethanol) and heated and stirred for 30 minutes to 5 hours. Compound (5) can be produced by stirring with heating overnight. The reaction temperature is preferably 10 to 110 ° C. At that time, positional isomers are by-produced, but the compound (5) can be easily separated and purified by silica gel column chromatography or crystallization.

  Next, the ester body (6) can be produced by heating and stirring a suspension of the compound (5) and Raney nickel in alcohol (methanol or ethanol). The reaction temperature is preferably 50 to 110 ° C. The reaction conditions, reagents and the like may be appropriately selected based on ordinary knowledge of organic chemistry.

  Moreover, ester body (6a) can also be guide | induced from the following compound (8).

(In the above formula, R ² represents the same group as R ^2, and R ³ represents a methyl group or an ethyl group.)

  Treating compound (8) and dialkyl oxalate (dimethyl oxalate or diethyl oxalate) (2) in an alcohol (methanol or ethanol) solution in the presence of sodium alkoxide (sodium methoxide or sodium ethoxide); Thus, compound (9) can be obtained. The reaction temperature is preferably −10 to 100 ° C.

  Compound (9) was prepared by dissolving compound (8) in an inert solvent such as tetrahydrofuran and treating with a base such as lithium bis (trimethylsilyl) amide under cooling at −78 ° C. to give an oxalic acid dialkyl ester (oxalic acid dimethyl ester). Alternatively, it can also be produced by adding oxalic acid diethyl ester) (2) and stirring. The reaction temperature is preferably -78 ° C to room temperature.

  Next, the compound (9) and the hydrazine derivative ((4) WO2004 / 069824) are dissolved in alcohol (methanol or ethanol), heated and stirred for 30 minutes to 5 hours, and then added with an appropriate amount of acetic acid to further add 1 Compound (6a) can be produced by stirring with heating overnight. At that time, positional isomers are by-produced, but the compound (6a) can be easily separated and purified by silica gel column chromatography or crystallization.

  The aromatic ketone (8) can be derived from the following compound (1a). Further, a method described in the literature (Erik Van der Ecken et al., Org. Lett. 2004, 6 (23), 4223-4225) is applied to use a commercially available acetylene derivative (10 or 12) and an azide compound 1, It can also be produced by a 2,3-triazole ring formation reaction.

  The compound (8) can be produced by heating and refluxing an alcohol (methanol or ethanol) suspension of the compound (1) and Raney nickel. The reaction conditions, reagents and the like may be appropriately selected based on ordinary knowledge of organic chemistry.

  By stirring a mixed suspension of 3-butyn-2-ol (10), sodium azide, dimethyl sulfate, and copper iodide in t-butanol and water at room temperature, 1- (1-methyl-1H— 1,2,3-triazol-4-yl) ethanol (11) can be prepared. The reaction conditions, reagents and the like may be appropriately selected based on ordinary knowledge of organic chemistry.

  Compound (8) can also be produced by adding manganese dioxide to a dichloromethane solution of compound (11) and stirring at room temperature. The reaction conditions, reagents and the like may be appropriately selected based on ordinary knowledge of organic chemistry.

  Further, compound (8) is produced by stirring a mixed suspension of 3-butyn-2-one (12), sodium azide, dimethyl sulfate, and copper iodide in t-butanol and water at room temperature. You can also. The reaction conditions, reagents and the like may be appropriately selected based on ordinary knowledge of organic chemistry.

  Next, ester body (6) can be hydrolyzed by a conventional method to lead to carboxylic acid body (7).

(In the above formula, R ² and R ³ are the same groups as R ² and R ³ )

  The hydrolysis reaction can be performed 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.

  Compound (I) of the present invention can be obtained by subjecting the carboxylic acid compound (7) obtained by the above production method to the following treatment.

(In the above formula, R ¹ and R ² are the same groups as R ¹ and R ² , respectively.)
The compound (I) of the present invention can be produced by condensing the carboxylic acid form (7) and the amine form (13).

  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 (dicyclohexylcarbodiimide) method, active ester method, carbonyldiimidazole method, DCC / HOBT (1-hydroxy). Benzotriazole) 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. "Synthetic Peptides" written by Pettit (Elsevier Scientific Publication Company, New York, 1976), edited by The Chemical Society of Japan, 4th edition, Laboratory Chemistry Vol. 22, Organic Synthesis IV "(Maruzen Co., 1992), etc. 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. A commercially available compound may be used for the amine body (13), and the method described in the literature, the method described in the production example, or the one produced according to those methods may be used.

  Based on ordinary knowledge of organic chemistry, the compound (I) of the present invention produced by the above method can be further modified to lead to another compound (I) of the present invention.

  The compound (I) of the present invention, a salt thereof or a solvate thereof has a strong antiplatelet action and strongly inhibits thrombus formation even in a thrombosis model induced by high shear stress. Further, the compound of the present invention is particularly excellent in terms of safety due to extremely weak nephrotoxicity as compared with the compound (B) described in Patent Document 3. Such safety is extremely important in consideration of long-term administration of platelet aggregation inhibitors. Therefore, the compound (I), a salt thereof or a solvate thereof of the present invention is used in mammals including humans such as myocardial infarction, angina pectoris (chronic stable angina pectoris, unstable angina pectoris, etc.), ischemic brain. Vascular disorders (transient cerebral ischemic attack (TIA), cerebral infarction, etc.), peripheral vascular disorders, occlusion after artificial blood vessel replacement, coronary artery intervention (coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA) It is useful as a prophylactic and / or therapeutic agent for ischemic diseases caused by thrombosis / embolism such as thrombotic occlusion, diabetic retinopathy / nephropathy, occlusion at the time of cardiac valve replacement, etc. In addition, it is useful as a preventive and / or therapeutic agent for thrombus / embolism associated with vascular surgery, extracorporeal blood circulation, and the like. Furthermore, it is useful for the improvement of ischemic symptoms such as ulcer, pain and cold feeling associated with chronic arterial occlusion.

  When the compound (I) of the present invention, a salt thereof or a solvate thereof is used as a pharmaceutical, the dosage varies depending on the age, sex, symptoms, etc. of the patient, but the daily dose per adult is 0.1 mg to 1 g is preferable, and 0.5 mg to 500 mg is particularly preferable. 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 comprising the compound (I) of the present invention, a salt thereof or a solvate thereof as an active ingredient can be used according to the administration method and dosage form as required. What is necessary is just to mix | blend a pharmacologically acceptable support | carrier as needed with a preparation method, and should just select the dosage form corresponding to an administration method, and an administration method and a dosage form are not specifically 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, cheek granules, pills and capsules. it can.

  As an injection, the compound (I) of the present invention, a salt thereof or a solvate thereof may be dissolved and filled in a container, or it may be prepared as a solid preparation by lyophilization or the like. .

  When preparing these preparations, select pharmaceutically acceptable additives such as binders, disintegrants, dissolution accelerators, lubricants, fillers, excipients, etc., as necessary. Can be used.

Next, the present invention will be described in detail with reference examples, examples and test examples.
Reference example 1
Ethyl 1- (6-methoxypyridin-3-yl) -5- [1-methyl-5- (phenylthio) -1H-1,2,3-triazol-4-yl] -1H-pyrazole-3-carboxylate ester

1) 4- [1-Methyl-5- (phenylthio) -1H-1,2,3-triazol-4-yl] -2,4-dioxobutanoic acid ethyl ester 1- [1-methyl-5 under argon atmosphere -(Phenylthio) -1H-1,2,3-triazol-4-yl] ethanone (1.84 g, S. Ohta et al., Chem. Pharm. Bull., 1997, 45 (7), 1140) in tetrahydrofuran (37 ml ) Lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 8.68 ml) was added dropwise to the solution while cooling at −78 ° C., and the mixture was stirred for 80 minutes. To the reaction solution, diethyl oxalate (2.14 ml) was added dropwise at the same temperature for 15 minutes and then at 0 ° C. for 30 minutes. The mixture was further stirred at room temperature for 3 hours. Water and diethyl ether were added to the reaction solution, and the mixture was separated. A saturated aqueous ammonium chloride solution was added to the aqueous layer, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and 4- [1-methyl-5- (phenylthio) -1H-1,2,3-triazol-4-yl] -2,4-dioxobutanoic acid ethyl ester (1 .60 g, 61%) as a solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.38-1.42 (3H, m), 3.95 (3H, s), 4.36-4.42 (2H, m), 7.22 -7.35 (5H, m), 7.52 (1H, s).
MS (EI) m / z: 333 (M ^<+> ).

2) Title compound 4- [1-Methyl-5- (phenylthio) -1H-1,2,3-triazol-4-yl] -2,4-dioxobutanoic acid ethyl ester (1.59 g) and 5-hydrazino- A suspension of 2-methoxypyridine (0.730 g, WO2004 / 0669824) in ethanol (32 ml) was heated to reflux for 45 minutes. Acetic acid (1.37 ml) was added to the reaction mixture, and the mixture was further heated to reflux for 18 hours. After air cooling, saturated sodium hydrogen carbonate and chloroform were added to the reaction solution and the phases were separated, 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 (hexane-ethyl acetate) to obtain the title compound (1.08 g, 52%) as a solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.39-1.43 (3H, m), 3.93 (3H, m), 3.96 (3H, s), 4.41-4.47 (2H, m), 6.72 (1H, d, J = 8.8 Hz), 6.90-6.93 (2H, m), 7.21-7.26 (4H, m), 7.66 −7.69 (1H, m), 8.10 (1H, d, J = 2.7 Hz).
MS (EI) m / z: 436 (M ^<+> ).

Reference example 2
1- (6-Methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazole-3-carboxylic acid

1) 1- (6-Methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazole-3-carboxylic acid ethyl ester Raney nickel (NIKKO) RICA R-100, 20 g) was washed with ethanol (decane was removed by decantation), and the resulting residue in ethanol (40 ml) was suspended in 1- (6-methoxypyridine-3-yl under an argon atmosphere. Yl) -5- [1-methyl-5- (phenylthio) -1H-1,2,3-triazol-4-yl] -1H-pyrazole-3-carboxylic acid ethyl ester (1.07 g) in ethanol (60 ml) ) The suspension was added and heated to reflux for 3.5 hours. After air cooling, the solid in the reaction solution was filtered off through celite. The solvent of the obtained filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-acetone) to give 1- (6-methoxypyridin-3-yl) -5- (1-methyl). -1H-1,2,3-triazol-4-yl) -1H-pyrazole-3-carboxylic acid ethyl ester (0.607 g, 75%) was obtained as a solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.40-1.44 (3H, m), 3.99 (3H, s), 4.07 (3H, s), 4.42-4.48 (2H, m), 6.83 (1H, d, J = 8.8 Hz), 7.21 (1H, s), 7.31 (1H, s), 7.70 (1H, dd, J = 8) .8, 2.7 Hz), 8.22 (1H, d, J = 2.7 Hz).
MS (EI) m / z: 328 (M ^<+> ).

2) Title compound 1- (6-Methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazole-3-carboxylic acid ethyl ester ( To a mixed solution of 0.600 g) of methanol (12 ml) and tetrahydrofuran (12 ml), 1N aqueous sodium hydroxide solution (4.57 ml) was added at room temperature and stirred for 1 hour. The reaction mixture was neutralized with 1N aqueous hydrochloric acid (4.57 ml), and then water and a mixed solvent of chloroform and methanol (10 to 1) were added to separate the layers. The solvent of the organic layer was distilled off under reduced pressure to obtain the title compound (0.540 g, 98%) as a solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.93 (3H, m), 4.04 (3H, m), 6.94 (1H, d, J = 8.8 Hz), 7.16 (1H, m), 7.80-7.83 (1H, m), 8.09 (1H, m), 8.27 (1H, d, J = 2.7 Hz), 13.03 (1H, br ).
MS (EI) m / z: 300 (M ^<+> ).

Reference example 3
1- (6-Methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazole-3-carboxylic acid ethyl ester 1) 1- ( 1-methyl-1H-1,2,3-triazol-4-yl) ethanone Raney nickel (NIKKO RICA R-100, 50 g) was washed with ethanol (ethanol was removed by decantation), and the resulting residue ethanol ( 100 ml) suspension into 1- [1-methyl-5- (phenylthio) -1H-1,2,3-triazol-4-yl] ethanone (5.00 g, S. Ohta et al., Chem.) Under an argon atmosphere. Pharm.Bull., 1997, 45 (7), 1140) in ethanol (100 ml) was added and heated to reflux for 4 hours. After air cooling, the solid in the reaction solution was filtered off through celite. The solvent of the obtained filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1- (1-methyl-1H-1,2,3-triazole-4. -Yl) ethanone (0.685 g, 26%) was obtained as a solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.69 (3H, s), 4.16 (3H, s), 8.05 (1H, s).
MS (ESI) m / z: 126 (M + H) ^<+> .

2) 4- (1-Methyl-1H-1,2,3-triazol-4-yl) -2,4-dioxobutanoic acid ethyl ester Sodium ethoxide (20% ethanol solution, 3.70 g) under argon atmosphere To a solution of ethanol (6.8 ml), diethyl oxalate (1.48 ml) was added at room temperature and stirred for 15 minutes. To the reaction solution, a solution of 1- (1-methyl-1H-1,2,3-triazol-4-yl) ethanone (0.680 g) in ethanol (13.6 ml) was added and stirred for 2 hours. Water and diethyl ether were added to the reaction solution, and the mixture was separated. A saturated aqueous ammonium chloride solution was added to the aqueous layer, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and 4- (1-methyl-1H-1,2,3-triazol-4-yl) -2,4-dioxobutanoic acid ethyl ester (0.904 g, 74%) Was obtained as a solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.39-1.42 (3H, m), 4.20 (3H, s), 4.37-4.42 (2H, m), 7.42 (1H, s), 8.16 (1H, s).
MS (EI) m / z: 225 (M ^<+> ).

3) Title compound 4- (1-Methyl-1H-1,2,3-triazol-4-yl) -2,4-dioxobutanoic acid ethyl ester (0.896 g) and 5-hydrazino-2-methoxypyridine (0 .554g, WO2004 / 069824) in ethanol (18 ml) was heated to reflux for 30 minutes. To the reaction solution was added 5-hydrazino-2-methoxypyridine (0.111 g), and the mixture was heated to reflux for 1 hour. Furthermore, acetic acid (1.14 ml) was added to the reaction solution, and the mixture was heated to reflux for 19 hours. After air cooling, saturated sodium hydrogen carbonate and chloroform were added to the reaction solution and the phases were separated, 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 (toluene-acetone) to obtain the title compound (0.881 g, 67%) as a solid.

Reference example 4
2-Methoxy-5- [3-[(4-methoxypiperidin-1-yl) carbonyl] -5- (1-methyl-1H-1,2,4-triazol-3-yl) -1H-pyrazole-1 -Yl] pyridine

1- (6-Methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,4-triazol-3-yl) -1H-pyrazole-3-carboxylic acid (184 mg, WO 2006/014005) , 4-methoxypiperidine hydrochloride (185 mg, WO2004 / 094407), 1-hydroxybenzotriazole (16 mg), triethylamine (425 μl), and 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride (176 mg) The dichloromethane (30 ml) solution was stirred overnight at room temperature. Water and 10% methanol-chloroform were added to the reaction solution, and the solution was separated. 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 thin layer chromatography (chloroform-methanol) to obtain the title compound (109 mg, 45%) as a solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.66 (2H, brs), 1.93 (2H, brs), 3.37 (3H, s), 3.49 (2H, brs), 3. 69 (1H, brs), 3.90 (3H, s), 3.98 (3H, s), 4.07 (1H, s), 4.23 (1H, s), 6.80 (1H, d , J = 8.79 Hz), 7.22 (1H, d, J = 0.49 Hz), 7.71 (1H, dd, J = 8.79, 2.20 Hz), 7.99 (1H, s) , 8.23 (1H, d, J = 2.69 Hz).
MS (ESI) m / z: 398 (M + H) ^<+> .

Reference Example 5
1- (1-Methyl-1H-1,2,3-triazol-4-yl) ethanone A method)
To a solution of t-butanol (1.5 ml) and water (1.5 ml) was added 3-butyn-2-one (82 μl), sodium azide (65 mg), dimethyl sulfate (97 μl), and copper (I) iodide ( 38 mg) was added and stirred at room temperature for 17 hours. After filtering the solid of the reaction solution, the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (dichloromethane-methanol) to obtain the title compound (21 mg) as a solid.
MS (EI) m / z: 125 (M ^<+> ).

Method B)
1) 1- (1-Methyl-1H-1,2,3-triazol-4-yl) ethanol In a solution of t-butanol (1.5 ml) and water (1.5 ml), 3-butyn-2-ol ( 81 μl), sodium azide (65 mg), dimethyl sulfate (97 μl), and copper (I) iodide (38 mg) were added and stirred at room temperature. After filtering the solid of the reaction solution, the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (dichloromethane-methanol) to obtain 1- (1-methyl-1H-1,2,3-triazol-4-yl) ethanol (54 mg) as an oily substance. .
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.59 (3H, d, J = 6.62 Hz), 2.38 (1H, d, J = 4.17 Hz), 4.09 (3H, s) , 5.09 (1H, dt, J = 12.01, 5.21 Hz), 7.46 (1H, s).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ: 23.1, 36.6, 62.9, 121.1, 152.7.
MS (ESI) m / z: 128 (M + H) ^<+> .

2) Title compound Manganese dioxide (4.9 g) was added to a solution of 1- (1-methyl-1H-1,2,3-triazol-4-yl) ethanol (635 mg) in dichloromethane (10 ml) at room temperature for 15 hours. Stir. The reaction solution was filtered through Celite, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane-methanol) to obtain the title compound (627 mg).

Example 1
2-Methoxy-5- [3-[(4-methoxypiperidin-1-yl) carbonyl] -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazole-1 -Yl] pyridine

1- (6-Methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazole-3-carboxylic acid of Reference Example 2 (0. 254 g), 4-methoxypiperidine hydrochloride (0.192 g, WO 2004/094407), 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride (0.178 g), and 1-hydroxybenzotriazole (0. 126 g) in dichloromethane (5.1 ml) was added triethylamine (0.307 ml) at room temperature and stirred for 21 hours. Water and chloroform were added to the reaction solution for liquid separation, and the solvent of the organic layer was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.239 g, 71%) as a solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.71 (3H, m), 1.94 (2H, m), 3.38 (3H, s), 3.47-3.56 (2H, m ), 3.68-3.74 (1H, m), 3.98 (3H, s), 4.09 (3H, s), 4.21-4.26 (1H, m), 6.81 ( 1H, d, J = 8.5 Hz), 7.07 (1H, s), 7.32 (1H, s), 7.68-7.70 (1H, m), 8.22 (1H, d, J = 2.4 Hz).
MS (EI) m / z: 397 (M ^<+> ).

Example 2
4-{[1- (6-Methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazol-3-yl] carbonyl} morpholine

(Method A)
1- (6-Methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazole-3-carboxylic acid of Reference Example 2 (0. 260 g), 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride (0.183 g), and 1-hydroxybenzotriazole (0.129 g) in dichloromethane (5.2 ml) at room temperature with morpholine ( 90.5 μl) and triethylamine (0.133 ml) were added and stirred for 17 hours. Water and chloroform were added to the reaction solution for liquid separation, and the solvent of the organic layer was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give the title compound (0.277 g, 87%) as a solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.73-3.82 (6H, m), 3.98 (3H, s), 4.09 (3H, s), 4.10 (2H, m ), 6.82 (1H, d, J = 8.8 Hz), 7.14 (1H, s), 7.33 (1H, s), 7.66-7.69 (1H, m), 8. 22 (1H, d, J = 2.4 Hz).
MS (EI) m / z: 369 (M ^<+> ).

(Method B)
1- (6-Methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazole-3-carboxylic acid of Reference Example 2 (9. 00 g), 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride (6.32 g), and 1-hydroxybenzotriazole (4.45 g) in dichloromethane (180 ml) at room temperature at morpholine (3. 13 ml) and triethylamine (4.60 ml) were added and stirred for 17 hours. Water and chloroform were added to the reaction solution and the phases were separated, 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 the title compound as a solid. The obtained solid methanol suspension was dissolved with heating under reflux. The reaction solution was stirred under ice cooling, and the precipitated crystals were collected by filtration. Further, the solvent of the filtrate was distilled off under reduced pressure, methanol was added to the obtained solid, and the reaction solution was dissolved under heating under reflux. The reaction mixture was stirred under ice-cooling, and the precipitated crystals were collected by filtration and combined with the previously obtained fraction to give the title compound (10.2 g, 92%).

Example 3
1-{[1- (6-Methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazol-3-yl] carbonyl}- 4-methylpiperazine

1- (6-Methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazole-3-carboxylic acid of Reference Example 2 (0. 200 g), 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride (0.140 g), and 1-hydroxybenzotriazole (99.0 mg) in dichloromethane (4 ml) at room temperature in 1-methylpiperazine (0.111 ml) and triethylamine (0.102 ml) were added and stirred for 15 hours. Water and chloroform were added to the reaction solution for liquid separation, and the solvent of the organic layer was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give the title compound (0.176 g, 69%) as a solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.34 (3H, s), 2.47-2.53 (4H, m), 3.86 (2H, m), 3.98 (3H, s ), 4.07 (2H, m), 4.09 (3H, s), 6.80-6.82 (1H, m), 7.10 (1H, s), 7.32 (1H, s) , 7.67-7.70 (1H, m), 8.22 (1H, m).
MS (EI) m / z: 382 (M ^<+> ).

Example 4
1-cyclopropyl-4-{[1- (6-methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazole-3- Yl] carbonyl} piperazine

1- (6-Methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazole-3-carboxylic acid of Reference Example 2 (250. 0 mg) in a solution of N, N-dimethylformamide (5 ml), 1-cyclopropylpiperazine hydrochloride (245.8 mg, WO2004 / 069824), 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride (192) 0.2 mg), 1-hydroxybenzotriazole (112.9 mg), and triethylamine (0.350 ml) were added and stirred for 15 hours. To the reaction solution are added a saturated aqueous sodium hydrogen carbonate solution and chloroform, and the mixture is separated, and the organic layer is washed with water and dried over anhydrous sodium sulfate. After separation by filtration, the organic 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 (250.7 mg, 74%) as a solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.46 (4H, m), 1.62-1.67 (1H, m), 2.64-2.72 (4H, m), 3.75 -3.81 (2H, m), 3.94-4.01 (5H, m), 4.09 (3H, s), 6.81 (1H, d, J = 8.8 Hz), 7.10 (1H, s), 7.32 (1H, s), 7.69 (1H, dd, J = 8.8, 2.7 Hz), 8.22 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 409 (M + H) ^<+> .

Example 5
4-{[1- (6-Methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazol-3-yl] carbonyl} morpholine 1) 1-methyl-1H-1,2,3-triazole With cooling to 0 ° C., a solution of 1H-1,2,3-triazole (150 g) and methyl iodide (189 ml) in tetrahydrofuran (2.25 l) 1,8-diazabicyclo [5.4.0] -7-undecene (389 ml) was added dropwise over 2 hours. The reaction was stirred at room temperature for 16 hours. Insoluble matter in the reaction solution was filtered off, the solvent in the filtrate was distilled off under reduced pressure, and the resulting residue was distilled under reduced pressure (72 ° C. at 6 mmHg) to give 1-methyl-1H-1,2,3-triazole (117 g). , 65%) as an oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.13 (3H, s), 7.56-7.56 (1 H, m), 7.70-7.71 (1 H, m).

2) 1-methyl-5- (phenylthio) -1H-1,2,3-triazole Under cooling to −50 ° C., 1-methyl-1H-1,2,3-triazole (117 g) in anhydrous tetrahydrofuran (1. 2l) To the solution, n-butyllithium (1.59 M n-hexane solution, 1.06 l) was added dropwise over 1.5 hours, followed by stirring for 2 hours. A solution of diphenyl disulfide (369 g) in anhydrous tetrahydrofuran (1.2 l) was added dropwise to the reaction solution over 2 hours, and the reaction solution was stirred at room temperature for 18 hours. Water (1 l) was added to the reaction mixture, and the mixture was extracted 4 times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After separation by filtration, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to give 1-methyl-5- (phenylthio) -1H-1,2,3-triazole. (224 g, 83%) was obtained as an oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.97 (3H, s), 7.11-7.14 (2H, m), 7.23-7.32 (3H, m), 7.86 (1H, s).
MS (ESI) m / z: 192 (M + H) ^<+> .

3) 1- [1-Methyl-5- (phenylthio) -1H-1,2,3-triazol-4-yl] ethanone Under cooling to −50 ° C., 2,2,6,6-tetramethylpiperidine (237 ml) N-butyllithium (1.60 M n-hexane solution, 878 ml) was added dropwise over 30 minutes to an anhydrous tetrahydrofuran (2 l) solution. Furthermore, 1-methyl-5- (phenylthio) -1H-1,2,3-triazole (224 g) in anhydrous tetrahydrofuran (1.5 l) was added dropwise to the reaction solution over 1.5 hours, followed by stirring for 2 hours. did. N-methoxy-N-methylacetamide (133 g) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. Water (1.3 l) and ethyl acetate (5 l) were added to the reaction solution and the phases were separated, and the organic layer was washed with water (1.3 l). The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to give 1- [1-methyl-5- (phenylthio) -1H-1,2, 3-Triazol-4-yl] ethanone (236 g, 86%) was obtained as an oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.72 (3H, s), 3.92 (3H, s), 7.21-7.33 (5H, m).

4) 4- [1-Methyl-5- (phenylthio) -1H-1,2,3-triazol-4-yl] -2,4-dioxobutanoic acid ethyl ester Sodium ethoxide (82.6 g) in ethanol (1 l) ) To the solution was added diethyl oxalate (177 g). To the reaction solution was added dropwise a solution of 1- [1-methyl-5- (phenylthio) -1H-1,2,3-triazol-4-yl] ethanone (236 g) in ethanol (750 ml) over 15 minutes. Stir for 5 hours. The reaction mixture was neutralized with 1N aqueous hydrochloric acid (1.2 l), and the precipitated solid was collected by filtration to give 4- [1-methyl-5- (phenylthio) -1H-1,2,3-triazole-4. -Yl] -2,4-dioxobutanoic acid ethyl ester (254 g, 76%) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.40 (3H, t, J = 7.1 Hz), 3.95 (3H, s), 4.39 (2H, q, J = 7.1 Hz) , 7.21-7.25 (2H, m), 7.29-7.34 (3H, m), 7.52 (1H, s).

5) 1- (6-Methoxypyridin-3-yl) -5- [1-methyl-5- (phenylthio) -1H-1,2,3-triazol-4-yl] -1H-pyrazole-3-carbon Acid ethyl ester 4- [1-methyl-5- (phenylthio) -1H-1,2,3-triazol-4-yl] -2,4-dioxobutanoic acid ethyl ester (147 g) and 5-hydrazino-2-methoxy A suspension of pyridine (67.8 g, WO2004 / 069824) in ethanol (1.48 l) was stirred at an internal temperature of 75 ° C. for 4.5 hours. Acetic acid (133 g) was added dropwise to the reaction solution over 10 minutes, and the mixture was further stirred at an internal temperature of 75 ° C. for 4.5 hours. After air cooling, ethanol (1 l) was added to the reaction mixture and stirred, and the precipitated crystals were collected by filtration to give 1- (6-methoxypyridin-3-yl) -5- [1-methyl-5- (phenylthio) -1H- 1,2,3-triazol-4-yl] -1H-pyrazole-3-carboxylic acid ethyl ester (152 g, 79%) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.41 (3H, t, J = 7.1 Hz), 3.93 (3H, s), 3.96 (3H, s), 4.44 (2H , Q, J = 7.1 Hz), 6.72 (1H, d, J = 8.8 Hz), 6.89-6.93 (2H, m), 7.21-7.27 (4H, m) 7.68 (1H, dd, J = 8.8, 2.7 Hz), 8.10 (1H, d, J = 2.7 Hz).

6) 1- (6-Methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazole-3-carboxylic acid ethyl ester 1- ( 6-methoxypyridin-3-yl) -5- [1-methyl-5- (phenylthio) -1H-1,2,3-triazol-4-yl] -1H-pyrazole-3-carboxylic acid ethyl ester (152 g ) Was added a suspension of Raney nickel (1 kg) in ethanol (1.5 l) and stirred at an internal temperature of 74 ° C. for 1 hour. After air cooling, chloroform was added to the reaction solution and stirred, and the reaction solution was filtered through Celite. The organic solvent in the filtrate was washed twice with water. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (acetone-chloroform) to give 1- (6-methoxypyridin-3-yl) -5- (1-methyl). -1H-1,2,3-triazol-4-yl) -1H-pyrazole-3-carboxylic acid ethyl ester (101 g, 88%) was obtained as a solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42 (3H, t, J = 7.1 Hz), 3.99 (3H, s), 4.07 (3H, s), 4.45 (2H , Q, J = 7.1 Hz), 6.83 (1H, d, J = 8.8 Hz), 7.21 (1H, s), 7.30 (1H, s), 7.71 (1H, dd) , J = 8.8, 2.7 Hz), 8.22 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 329 (M + H) ^<+> .

7) 1- (6-Methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazole-3-carboxylic acid 1- (6- Methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazole-3-carboxylic acid ethyl ester (101 g) in methanol (1 l) and tetrahydrofuran To the mixed suspension of (1 l), 1N aqueous sodium hydroxide solution (768 ml) was added at room temperature and stirred for 2.5 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the insoluble matter was separated by filtration when the amount was about half. To the filtrate was added 1N hydrochloric acid (768 ml), and the resulting solid was collected by filtration, and 1- (6-methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazole-4- Yl) -1H-pyrazole-3-carboxylic acid (88.4 g, 96%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.93 (3H, s), 4.04 (3H, s), 6.96 (1H, d, J = 8.8 Hz), 7.17 (1H, s), 7.83 (1H, dd, J = 8.8, 2.7 Hz), 8.12 (1H, s), 8.28 (1H, d, J = 2.7 Hz), 13 .05 (1H, brs).
MS (ESI) m / z: 301 (M + H) ^<+> .

8) Title compound Under ice cooling, 1- (6-methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazole-3-carboxyl To a suspension of acid (88.4 g), 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride (62.1 g) and 1-hydroxybenzotriazole (43.8 g) in dichloromethane (1.8 l) Morpholine (30.8 g) and triethylamine (32.8 g) were added and stirred for 15 minutes, and then the reaction solution was stirred at room temperature for 23 hours. Saturated aqueous sodium hydrogen carbonate solution (1.5 l) was added to the reaction mixture, and the mixture was separated. The aqueous layer was further extracted with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate. After separation by filtration, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol-chloroform) to obtain the title compound as a solid. The obtained solid methanol suspension was dissolved with heating under reflux. The reaction mixture was filtered while hot, the filtrate was allowed to cool in air, and the precipitated crystals were collected by filtration to give the title compound (58.8 g, 54%).

Example 6
5- [3-{[(2S) -2- (fluoromethyl) pyrrolidin-1-yl] carbonyl} -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H- Pyrazol-1-yl] -2-methoxypyridine

1- (6-Methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazole-3-carboxylic acid of Reference Example 2 (0. 200 g), (2S) -fluoromethylpyrrolidine hydrochloride (0.139 g, WO 2006/004027), 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride (0.140 g), and 1-hydroxybenzotriazole (99.0 mg) in dichloromethane (4 ml) was added triethylamine (0.241 ml) at room temperature and stirred for 63 hours. Water and chloroform were added to the reaction solution for liquid separation, and the solvent of the organic layer was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.178 g, 69%) as a solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.88-2.15 (4H, m), 3.67-4.16 (8H, m), 4.36-5.18 (3H, m) 6.80-6.82 (1H, m), 7.21-7.23 (1H, m), 7.35-7.40 (1H, m), 7.66-7.71 (1H, m) m), 8.21-8.24 (1H, m).
MS (EI) m / z: 385 (M ^<+> ).

[Test Example 1] Platelet aggregation inhibitory action Human blood was collected using 1/10 volume of 3.8% 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 a test compound solution was added to 200 μl of PRP and heated 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 (MC Medical). The light transmittance of PPP was taken as the 100% aggregation value, the aggregation rate at each concentration of the 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 Action The COX inhibitor screening activity of Cayman Chemical Company was used to measure the COX-1 and COX-2 inhibitory activities of test compounds. A kit (catalog numbers 560101, 560121) was used.
Reaction buffer before measurement, heme, arachidonic acid, SnCl _2, EIA buffer, wash buffer, prostaglandin (PG) screening EIA standard solution, PG screening acetylcholinesterase (AchE), tracer (chromogenic enzyme HRP conjugate) PG screening EIA antiserum was prepared.
(1) Production of PGF ₂ α by COX-1 or COX-2 The reaction solution containing the test 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 to the reaction mixture. The mixture was allowed to stand at 2 ° C 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 test compound 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 at each concentration of the test compound was calculated, and IC ₅₀ was determined. The results are shown in Table 1.
In calculating the inhibition rate, the production amount of PGF ₂ α obtained using a reaction solution not containing the test compound was defined as 100%.

Test Example 3 Male Rat Oral Single-Dose Toxicity Test Each test substance (Examples 1 and 2 and Reference Example 4) was orally administered at 200 mg / kg to male rats and sacrificed on the next day by examining the toxicity. In the control group, 0.5% methylcellulose was administered in the same manner (20 ml / kg).

<Method>
(1) Rat The test was conducted using male rats (Crl: CD (SD), 6 weeks old, Charles River Japan Co., Ltd.). The animals were allowed to freely take food and water, but fasted until about 2 hours after the evening of administration. On the day before administration, the animals were assigned to 5 animals in each group so that the average body weights were approximated between groups by randomized stratification based on body weight [safety test computer system (Fujitsu)].

(2) Reagent used i) 0.5% w / v Methyl Cellulose 400cP Solution, Sterilized (0.5% MC, Wako Pure Chemical Industries, Ltd.)
ii) 10% neutral buffered formalin solution (Wako Pure Chemical Industries, Ltd.)
(3) Test design A test substance was orally administered to rats once and sacrificed on the next day to examine toxicity.
(4) Adjustment of chemical solution The chemical solution was adjusted at the time of use. The test substances (Examples 1 and 2 and Reference Example 4) were suspended in 0.5% MC to a concentration of 10 mg / ml.
(5) Control group To the control group, 0.5% MC was orally administered (20 ml / kg).

(6) Administration method i) Route of administration: Oral
ii) Frequency: single
iii) Dosing volume: 20 ml / kg
iv) Equipment used for administration: Disposable gastric sonde for rats (Fuchigami Co., Ltd.) and disposable syringe (Terumo)
v) Administration of solvent control group: 0.5% MC was administered in the same manner (20 ml / kg).
vi) Fasting treatment: All animals were fasted from the evening before the administration until about 2 hours after the administration.

(7) Examination i) Symptom observation: The presence or absence of death and nephrotoxicity from immediately after administration to the time of sacrifice were observed.
ii) Body weight: Body weight was measured using a balance (LP-4200, Sartorius) before administration and at the time of sacrifice.
iii) Necropsy: After the carotid artery was cut and the animal was lethal to death, the major organs in the thoracoabdominal cavity were observed with the naked eye.
iv) Histopathological examination: After collecting liver, spleen, kidney, heart, lung and gastrointestinal tract, and fixing with 10% neutral buffered formalin solution, HE (Hematoxylin and eosin) stained specimens were pathohistologically examined. Observed.

<Result>
i) Symptom observation: Death and toxic symptoms were not observed in the test substance (Examples 1 and 2 and Reference Example 4) administration groups.
ii) Body weight: No change was observed in the test substance (Examples 1, 2 and Reference Example 4) administration groups.
iii) Necropsy: No dosing-related changes were observed in the test substance (Examples 1 and 2 and Reference Example 4) administration groups.
iv) Histopathological examination:

  From the results in Table 2, it can be seen that the compounds of the present invention have less nephrotoxicity and higher safety than the compounds described in WO 2006/014005 having a 1,2,4-triazole ring.

[Test Example 4] Male rat oral single dose toxicity test of Example 2 (high dose)
The test substance (Example 2) was orally administered to male rats at 500, 1000 and 2000 mg / kg and sacrificed on the next day to examine the toxicity. In the control group, 0.5% methylcellulose was administered in the same manner (20 ml / kg).

<Method>
(1) Rat The test was conducted using male rats (Crl: CD (SD)), 6 weeks old, Charles River Japan Co., Ltd. The animals were allowed to freely take food and water, but fasted until about 2 hours after the evening of administration. On the day before administration, the animals were assigned to 5 animals in each group so that the average body weights were approximated between groups by randomized stratification based on body weight [safety test computer system (Fujitsu)].
(2) Reagent used i) 0.5% w / v Methyl Cellulose 400cP Solution, Sterilized (0.5% MC, Wako Pure Chemical Industries, Ltd.)
ii) 10% neutral buffered formalin solution (Wako Pure Chemical Industries, Ltd.)

(3) Test design A test substance was orally administered to rats once and sacrificed on the next day to examine toxicity.
(4) Adjustment of chemical solution The chemical solution was adjusted at the time of use. The test substance (Example 2) was suspended in 0.5% MC to a concentration of 25, 50 and 100 mg / ml.
(5) Control group To the control group, 0.5% MC was orally administered (20 ml / kg).
(6) Administration method i) Route of administration: Oral
ii) Frequency: single
iii) Dosing volume: 20 ml / kg
iv) Equipment used for administration: Disposable gastric sonde for rats (Fuchigami Co., Ltd.) and disposable syringe (Terumo)
v) Administration of solvent control group: 0.5% MC was administered in the same manner (20 ml / kg).
vi) Fasting treatment: All animals were fasted from the day before administration until about 2 hours after administration.

(7) Examination i) Symptom observation: The presence or absence of death and toxic symptoms were observed immediately after administration until the time of sacrifice.
ii) Body weight: Body weight was measured using a balance (LP-4200, Sartorius) before administration and at the time of sacrifice.
iii) Necropsy: After the carotid artery was cut and the animal was lethal to death, the major organs in the thoracoabdominal cavity were observed with the naked eye.
iv) Histopathological examination: After collecting liver, spleen, kidney, heart, lung and gastrointestinal tract and fixing with 10% neutral buffered formalin solution, HE (Hematoxylin and eosin) -stained specimens were pathohistologically examined. Observed. In the tissues other than the gastrointestinal tract (cecum), no change based on medication was observed in the 2000 mg / kg group, so the 500 and 1000 mg / kg groups were not examined. The gastrointestinal tract (cecum) was not examined in the 500 mg / kg group because no change based on medication was observed in the 1000 mg / kg group.

<Result>
i) Symptom observation: No death was observed in the test substance (Example 2) administration group. There was no toxic symptom other than transient fluency in one patient in the 500 mg / kg group.
ii) Body weight: No change was observed in the test substance (Example 2) administration group.
iii) Autopsy: No changes related to medication were observed in the test substance (Example 2) administration group.
iv) Histopathological examination:

Claims (14)

Formula (I)

Wherein R ² is a hydrogen atom, a lower alkyl group that may be substituted, a lower alkynyl group, a carbamoyl group that may be substituted, a cyano group, an amino group that may be substituted, or a substituent. Or a group or atom selected from a lower alkoxy group and a lower alkanoyl group; wherein X is a group of the general formula (II)

(The cyclic structure in the formula represents a 4- to 7-membered alicyclic heterocyclic ring which may have a nitrogen atom or an oxygen atom as a constituent atom in addition to the nitrogen atom described in the formula, and R ¹ represents the cyclic structure. May be substituted lower alkyl group, may be substituted carbamoyl group, may be substituted amino group, hydroxyl group, lower alkoxy group, oxo group, lower alkanoyl group, lower alkylsulfonyl group and halogen atom A group represented by 1 to 2 groups or atoms selected from the above. ), A salt thereof, or a solvate thereof. The compound according to claim 1, a salt thereof, or a solvate thereof, wherein R ² is a lower alkyl group which may be substituted. The compound according to claim 1, a salt thereof, or a solvate thereof, wherein R ² is a methyl group.   X is an optionally substituted lower alkyl group, an optionally substituted carbamoyl group, an optionally substituted amino group, a hydroxyl group, a lower alkoxy group, an oxo group, a lower alkanoyl group, a lower alkylsulfonyl group and a halogen. The compound according to any one of claims 1 to 3, which is a piperazinyl group, a piperidinyl group, or a morpholinyl group, which may be substituted with 1 to 2 groups selected from atoms or atoms, or a salt thereof, or a group thereof Solvates.   X is a piperazinyl group, piperidinyl group, morpholinyl group, pyrrolidinyl group, 4-methyl-piperazinyl group, 4-cyclopropyl-piperazinyl group, 4-methoxy-piperidinyl group or (2-fluoromethyl) pyrodinyl group, The compound of any one of 1-4, its salt, or those solvates. R ² is a methyl group; X is a piperazinyl group, piperidinyl group, morpholinyl group, pyrrolidinyl group, 4-methyl-piperazinyl group, 4-cyclopropyl-piperazinyl group, 4-methoxy-piperidinyl group or 2-fluoromethylpyrrole The compound according to any one of claims 1 to 5, a salt thereof, or a solvate thereof, which is a dinyl group. Formulas (Ia) to (Ie)

Or a salt thereof or a solvate thereof. Formula (Ib)

Or a salt or a solvate thereof.   4-{[1- (6-Methoxypyridin-3-yl) -5- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-pyrazol-3-yl] carbonyl} morpholine , Salts thereof, or solvates thereof.   The pharmaceutical containing the compound of any one of Claims 1-9, its salt, or those solvates.   A prophylactic and / or therapeutic agent for ischemic diseases comprising the compound according to any one of claims 1 to 9, a salt thereof or a solvate thereof as an active ingredient.   The platelet aggregation inhibitor which also uses the compound of any one of Claims 1-9, its salt, or those solvates as an active ingredient.   A method for preventing and / or treating an ischemic disease, comprising administering an effective amount of the compound, salt or solvate thereof according to any one of claims 1 to 9 as an active ingredient.   Use of the compound according to any one of claims 1 to 9, a salt thereof, or a solvate thereof for the manufacture of an agent for preventing and / or treating an ischemic disease.