WO2008053602A1 - 5-(1h-1,2,3-triazol-4-yl)-1h-pyrazole derivative - Google Patents

Abstract

Disclosed are: a compound represented by the formula (I), a salt thereof, or a solvate of the compound or the salt; and a pharmaceutical agent comprising the compound, the salt or the solvate. The compound has an inhibitory activity on platelet aggregation, and is therefore excellent in safety and in vivo kinetics.

Description

 Specification

 5— (1 H-1, 2, 3— Triazol, 4 yl) 1 Η-virazole derivatives

 Technical field

 [0001] The present invention relates to a pyrazole derivative having a platelet aggregation inhibitory action.

 Background art

 [0002] 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, sites where vascular endothelium in the blood vessels is damaged, stenotic sites, etc. It aggregates and induces blood clots 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. In particular, low-dose aspirin has long been used as a platelet aggregation inhibitor, and its effect is a meta-analysis of the results of several clinical trials administered to 100 million patients. I atelet Trial ι sts and ollaboration) (see Non-Patent Document 1).

 [0003] However, aspirin is known to cause gastrointestinal bleeding, a so-called aspirin ulcer, and the side effect occurs at a rate of 1 in 100 without depending on the dose. (See Non-Patent Document 2).

[0004] It is known that the inhibitory action of aspirin on platelet aggregation is based on the inhibitory action of cyclooxygenase. Cyclooxygenases include cycloxygenase _ 1 (COX-1) and cyclooxygenase _2 (COX-2), but aspirin selectively and irreversibly inhibits CO X-1 at low doses. Although platelet aggregation is suppressed, 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. 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 so far. .

[0006] [Chemical 1]

[0007] However, the IC ₅₀ value for collagen-induced platelet aggregation of Compound (A) is 5.3 X 10- 6 M, indicating a stronger inhibitory activity against COX-2 (IC ₅₀ value 2 4 X 1 0-7 M). Similarly, the platelet aggregation inhibitory action of compound (B) is not as strong as its inhibitory activity against CO X — 2.

 [0008] On the other hand, Patent Document 3 discloses a compound (C) which is a platelet aggregation inhibitor, and is a compound obtained by converting a difluoro group at the 4-position on the piperidine ring constituting this compound into a methoxy group. Since (D) shows nephrotoxicity, it is difficult to say that the platelet aggregation inhibitor disclosed in Patent Document 3 is certainly superior in terms of safety.

 [0009] [Chemical 2]

 Patent Document 1: Japanese Patent No. 25867 13 Specification

 Patent Document 2: International Publication No. 97/29774 Pamphlet

 Patent Document 3: International Publication 2006/01 4005 Pamphlet

Non-Patent Document 1: BMJ, 308, 81— 106, 1 994 Non-Patent Document 2: BMJ, 32 1, 1 1 83—1 1 87, 2000 Non-Patent Document 3: N eurology, 57, Supp 2, S 5—S 7 Non-Patent Document 4: D rugs Today, 35, 25 1 —265, 1 99 9 years

 Non-Patent Document 5: Ch em. Pharm m. Bui, 45, 987-995, 1 997

 Disclosure of the invention

 Problems to be solved by the invention

 [0011] The present invention is to provide a powerful platelet aggregation inhibitor with high safety.

 [0012] 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) strongly inhibits COX-1 and COX_2. And the present invention was completed by finding that it exhibits potent platelet aggregation inhibitory activity without nephrotoxicity.

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

 [0014] [Chemical 3]

 (I)

(In the formula, R ² is a hydrogen atom, a lower alkyl group that may be substituted, a lower alkynyl group, a rubamoyl group that may be substituted, a cyano group, or an amino group that may be substituted. Represents a group or an atom selected from a lower alkoxy group and a lower alkanol group which may be substituted; wherein X represents the general formula (II)

[0016] One ^N ~ ^R1

[0017] (The cyclic structure in the formula represents a 4- to 7-membered alicyclic heterocycle in which a nitrogen atom or an oxygen atom may be a constituent atom in addition to the nitrogen atom described in the formula, and R ¹ is The cyclic structure may be a lower alkyl group that may be substituted, a carbamoyl group that may be substituted, an amino group that may be substituted, a hydroxyl group, a lower alkoxy group, an oxo group, a lower alkanol group, a lower alkylsulfonyl group It indicates that the group may be substituted with 1 to 2 groups or atoms selected from a group and a halogen atom. And a salt thereof or a solvent thereof.

 [0018] The present invention also provides a pharmaceutical composition containing the above compound, salt or solvate thereof; a pharmaceutical containing the compound, salt or solvate thereof; the above compound, salt thereof Or a platelet aggregation inhibitor comprising the solvate thereof as an active ingredient; and a prophylactic and / or therapeutic agent for ischemic disease comprising the compound, salt thereof or solvate thereof as an active ingredient.

 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.

 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 invention's effect

[0019] The compound (I), a salt thereof or a solvate thereof of the present invention has an action of strongly inhibiting platelet aggregation and inhibiting thrombus formation while maintaining high safety. Therefore, myocardial infarction, angina (chronic stable angina, unstable angina, etc.), ischemic cerebral vascular disorder (transient cerebral ischemic attack (TIA), cerebral infarction, etc.), peripheral vascular disorder, artificial Occlusion after vascular replacement, coronary artery intervention (coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA), stent placement, etc.) after thrombotic occlusion, diabetic retinopathy "nephropathy, heart valve replacement Thrombus such as obstruction, acute coronary syndrome etc. • Useful for prevention and / or treatment of ischemic diseases caused by embolism, and Thrombus associated with vascular surgery, extracorporeal blood circulation, etc. ■ Prevention and / or treatment of embolism In addition, it is useful for the improvement of ischemic symptoms such as ulcer, pain, and cold feeling associated with chronic arterial occlusion.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0020] The general formula (I) will be described below.

[0021] R ² is 1) a lower alkyl group which may be substituted, 2) a lower alkynyl group, 3) a rubamoyl group which may be substituted, 4) a cyano group, or 5) which may be substituted. A group selected from an amino group, 6) a lower alkoxy group which may be substituted, and 7) a lower alkanol 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 A cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclopropylmethyl group, and a 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 a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a tert-butoxy group, an n-pentoxy group, and a 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 thereof include a formyl group, an acetyl group, an n-propionyl group, an n_petityl group, and an isoptylyl 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_ptylsulfonyl group, isobutylsulfonyl group, tert_butylsulfonyl group, n-pentylsulfonyl group, isopentylsulfonyl group Group, cyclopropylsulfonyl group, and cyclohexylsulfonyl group.

 [0027] Furthermore, the above 1) to 7) will be described.

 1) The “lower alkyl group which may be substituted” is substituted with 1 or the same or different 2 to 3 substituents or atoms selected from the following substituent group consisting of 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. The lower alkyl group which may be substituted is preferably a methyl group, an ethyl group or an n_propyl group, and particularly preferably a methyl group.

 [0028] a) A force rubamoyl group that may be substituted with one or two lower alkyl groups that are the same or different: The force rubamoyl group is an unsubstituted force rubamoyl group or 1 to 2 lower rubamoyl groups. This means a cal / moyl group substituted with an alkyl group. Specific examples include a methylcarbamoyl group, an ethylcarbamoyl group, a dimethyl-powered rubermoyl group, and an N-methyl-1-N-ethylcarbamoyl group. Of these, an unsubstituted force ruberamoyl group, a methylcarbamoyl group or a dimethylcal / moyl group is preferred.

[0029] b) Substituted by one or two identical or different substituents selected from a lower alkyl group, a lower alkanol group and a lower alkylsulfonyl group In some cases, the amino group is an unsubstituted amino group, or is substituted with one or two identical or different substituents selected from a lower alkyl group, a lower alkanol group, and a lower alkylsulfonyl group. Means an amino group. Specifically, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, cyclopropylamino group, n_butylamino group, isoptilamino group, cyclopentylmethylamino group, dimethylamino group, jetylamino group, di-n —Propylamino group, di n_ptylamino group, N-methyl-1-N-ethylamino group, N_ethyl_N_n-propylamino group, N-methyl-1-N-cyclopentylmethylamino group, formylamino group, acetylamino group , N-propionylamino group, N-methyl-1-N-acetylamino group, N-ethyl-1-N-acetylamino group, methylsulfonylamino group, ethylsulfonylamino group, isopropylsulfonylamino group, n_propyl Sulfonylamino group, cyclopropylsulfonylamino group, cyclobuta And N-methyl-1-N-methylsulfonylamino groups and N-ethyl_N-methylsulfonylamino groups.

[0030] 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.

 [0031] 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.

[0032] 3) "Substantially substituted rubermoyl group" refers to an unsubstituted rubermoyl group, or a rubermoyl group substituted by one or two lower alkyl groups that are the same or different. Means. Specific examples include a methylcarbamoyl group, an ethylcarbamoyl group, an n-propyl-powered rubamoyl group, a dimethylcarbamoyl group, a jetylcarbamoyl group, and an N_methyl_N-ethylcarbamoyl group. 4) "Cyan group"

 [0033] 5) The "amino group which may be substituted" means an unsubstituted amino group or an amino group substituted with one or two lower alkyl groups which are the same or different. Specific examples include a methylamino group, an ethylamino group, an n-propylamino group, a dimethylamino group, a jetylamino group, and a 1 \ 1_methyl_1 \ 1_ethylamino group. Of these, an unsubstituted amino group, a methylamino group or a dimethylamino group is preferred.

 [0034] 6) The "optionally substituted alkoxy group" is an unsubstituted alkoxy group, or one selected from the group of substituents consisting of a) to e) in 1) above, or the same or different It means an alkoxy group which may be substituted with 2 to 3 substituents or atoms. As the alkoxy group which may be substituted, an unsubstituted lower alkoxy group or a lower alkoxy group substituted with a strong rubermoyl group is preferable, a methoxy group, an ethoxy group or a strong ruberamoyl methoxy group is more preferable, and a methoxy group or The strong rubermoyl methoxy group is most preferred.

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

[0036] Of 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. preferable.

 [0037] Next, X will be described. X represents a group represented by the general formula (II), but the general formula (II) may contain a nitrogen atom or an oxygen atom in addition to the nitrogen atom described in the general formula (II). It means a 4- to 7-membered alicyclic heterocyclic group which may have a substituent.

[0038] 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, oxazolidinyl group, oxazepanyl group be able to. Among these, a azetidinyl group, a pyrrolidinyl group, a birazidinyl group, a piperidinyl group, a piperazinyl group, a hexahydropyridazinyl group, a morpholinyl group, an oxazolidinyl group or an oxazepanyl group are preferable, a piperazinyl group, a piperidinyl group, a morpholinyl group, An oxazolidinyl group, an oxazepanyl group or a pyrrolidinyl group is particularly preferred.

[0039] R ¹ is a group substituted with a carbon atom or a nitrogen atom constituting the alicyclic heterocycle in the 4- to 7-membered alicyclic heterocyclic group, and the following (i) to (i X) means a group selected from

[0040] (i) Lower alkyl group which may be substituted: The same as the lower alkyl group which may be substituted. 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 above-mentioned substituent group consisting of a) to e). Furthermore, the lower alkyl group that may be substituted may be a lower alkyl group that is independently substituted by an oxo group. 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). The lower alkyl group is preferably a methyl group or a cyclopropyl group. 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. Therefore, the substituted lower alkyl group substituted on 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 them, a fluoromethyl group, a difluoromethyl group, or a trifluoromethyl group. Of these, a fluoromethyl group is particularly preferred. A hydroxy lower alkyl group means a lower alkyl group substituted with a hydroxyl group. As a hydroxy lower alkyl group, Examples include a loxymethyl 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 methoxycetyl group, and an ethoxyethyl group. Of these, a methoxymethyl group is preferred. The amino lower alkyl group means a lower alkyl group substituted with an amino group, and specifically includes an aminoamino group, a 2_aminoethyl group, and a 1_aminocyclopropyl group. An oral propyl group is preferred.

(Ii) Forced rubamoyl group that may be substituted: The force rubamoyl group that may be substituted means the same group as the force rubamoyl group that may be substituted in R ² . As the force rubamoyl group which may be substituted, an unsubstituted force rubamoyl group, a methylcarbamoyl group or a dimethylcarbamoyl group is preferable, and an unsubstituted force rubamoyl 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 jetylamino group, particularly preferably an unsubstituted amino group or a dimethylamino group.

 [0043] (i V) 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.

 (v i) oxo group,

 (V ii) Lower alkanoyl group: As the lower alkanoyl group, a formyl group, an acetyl group, an n-propionyl group, an n_petityl group, an isoptylyl group, and a pivalol group can be exemplified, and among these, a formyl group is particularly preferable. Preferred

[0044] (viii) Lower alkylsulfonyl group: Lower alkylsulfonyl group Methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n_ptylsulfonyl group, isoptylsulfonyl group, tert-butylsulfonyl group, n-pentylsulfonyl group, isopentylsulfonyl group, cyclopropyl A sulfonyl group and a cyclohexyl sulfonyl group can be mentioned. Of these, a methylsulfonyl group, an ethylsulfonyl group or an n_propylsulfonyl group is preferred.

[0045] (ix) Halogen atom: As the halogen atom, fluorine or chlorine is preferred.

 As for the group or atom selected from these (i) to (iX), one may be substituted with the alicyclic heterocyclic group, and 2 to 4 which are the same or different as long as they can be substituted. An alicyclic heterocyclic group may be substituted. 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.

 [0046] The alicyclic heterocyclic ring in the 4- to 7-membered alicyclic heterocyclic group is preferably a piperazine ring, piperidine ring, oxazolidine ring, oxazepan ring, pyrrolidine ring or morpholine ring.

 [0047] As X, piperazinyl group, piperidinyl group, morpholinyl group, 4-methylpiperazinyl group, 4-cyclopropyl monopiperazinyl group, 2_fluoromethylpyrrolidinyl group, 2, 4_dimethylbiperazinyl group, 2 _Fluoromethylpyrrolidinyl group, oxazepanyl group, 4,4-dimethyloxazolidinyl group, 2_force rubamoylbiperidinyl group or 4-methoxy-1-piperidinyl group, 2_force rubamoylbiperidinyl group, 4-methyoxypiperidinyl group, 4-methyl-piperazinyl group, 4-cyclopropylpipirazinyl group, morpholinyl group, oxazepanyl group, 4, 4_dimethyloxazolidinyl group or 2_fluoromethyl A pyrrolidinyl group is particularly preferred.

In the compound of the present invention, R ² is a methyl group; X is a piperazinyl group, a piperidinyl group, a morpholinyl group, a 4-methyl-piperazinyl group, a 4-cyclopropylmonopiperazinyl group, 2_full O-methylpyrrolidinyl group, 2, 4- Dimethylbiperazinyl group, 2_Fluoromethylpyrrolidinyl group, Oxazepanyl group, 4,4-Dimethyloxazolidinyl group, 2_Force ruberamoylbiberidinyl group or 4-Methoxy group Compounds that are piperidinyl groups are preferred. In addition, R ² is a methyl group; X is a 2_strength rubamoylbiperidinyl group, 4-methoxy-piperidinyl group, 4-methyl-piperazinyl group, 4-cyclopropyl-piperazinyl group, morpholinyl Particularly preferred are compounds which are a group, an oxazepanyl group, a 4,4-dimethyloxazolidinyl group or a 2_fluoromethylpyrrolidinyl group.

 [0049] Not all of the compounds of the present invention form a salt, but when the compound of the present invention has a strong lpoxyl group or an amino group, it may form a salt. In addition, the salt may form a solvate. 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; And salts with alkali metal or alkaline earth metal ions such as potassium and calcium.

 [0050] The solvate in the solvate of the compound of the present invention or a salt thereof is formed by absorbing moisture in the air in addition to the solvate to which the solvent used for crystallization of crystals is added. Hydrates. Examples of the solvent include water, lower alcohols such as methanol or ethanol, and organic solvents such as aceton or acetonitrile.

 [0051] As a compound of the present invention, a salt thereof or a solvate thereof, the following formula (Ia) to

 (I k)

[0052] Five]

[0053] Preferred examples include a compound represented by any one of the formulas, a salt thereof, or a solvate thereof. Furthermore, the compound represented by the formula (Ib), a salt thereof, or a solvate thereof can be most preferably exemplified.

 [0054] The compound of the present invention, a salt thereof or a solvate thereof has a potent platelet aggregation inhibitory action without strongly inhibiting COX-1 and C OX — 2 and without showing nephrotoxicity. From the viewpoints of main drug efficacy, safety, oral absorption, pharmacokinetics, solubility, it is extremely excellent as a pharmaceutical product.

 [0055] The compound of the present invention, a salt thereof, or a solvate thereof can be produced by the following method.

 [0056] Hereinafter, representative production methods of the compound (I) of the present invention will be described.

[0057] [Chemical 6]

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

 [0059] 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 at 78 ° C cooling to obtain a dialkyl ester of oxalic acid ( Succinic acid dimethyl ester or oxalic acid jetyl ester) (2) can be added and stirred. The reaction temperature is preferably _78 ° C to room temperature.

 [0060] Further, the compound (1) and dialkyl oxalate (dimethyl ester oxalate or cetyl oxalate) (2) are mixed with an alcohol (methanol or ethanol) in the presence of sodium alkoxide (natrium methoxide or sodium methoxide). ) Compound (3) can also be obtained by treating in solution. The reaction temperature is preferably _10 to 1 oo ° c.

 [0061] It should be noted that the aromatic ketone (1) is S. Ohtha et al. (Chem. Pharm.

B ui may be manufactured and used by the method of 1 997, 45 (7), 1 1 40), the method described in Reference Examples or a method according to the method. [0062] When the aromatic ketone (1) has a functional group such as a hydroxyl group or an amino group, it may be necessary to protect the functional group with an appropriate protecting group in advance. Examples of the protecting group for the hydroxyl group include a tert_butyl group and a benzyl group. Examples of the protecting group for the amino 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) WO 2004/069 824) are dissolved in alcohol (methanol or ethanol), heated and stirred for 30 minutes to 5 hours, and then an appropriate amount of acetic acid is added to the reaction solution. The compound (5) can be produced by adding 1 to the mixture and stirring with heating for 1 hour. The reaction temperature is preferably 10 to 110 ° C. At that time, positional isomers are by-produced, but it is possible to easily separate and purify compound (5) by silica gel column chromatography or crystallization.

 [0064] Next, the ester (6) is composed of the compound (5) and Raney-nickel alcohol.

 (Methanol or ethanol) Can be produced by heating and stirring the suspension. 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.

 [0065] The ester form (6a) can also be derived from the following compound (8).

 [0066] [Chemical 7]

 (Four)

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

[0068] Compound (8) and oxalic acid dialkyl ester (oxalic acid dimethyl ester) Alternatively, the compound (9) can be obtained by treating the oxalic acid jetyl ester (2) in an alcohol (methanol or ethanol) solution in the presence of sodium alkoxide (sodium methoxide or sodium ethoxide). . The reaction temperature is preferably _10 to 100 ° C.

 [0069] Compound (9) was prepared by dissolving compound (8) in an inert solvent such as tetrahydrofuran and treating it with a base such as lithium bis (trimethylsilyl) amide at 78 ° C under cooling to obtain a dialkyl oxalate. It can also be produced by adding an ester (succinic acid dimethyl ester or oxalic acid jetyl ester) (2) and stirring. The reaction temperature is preferably _78 ° C to room temperature.

 [0070] Next, the compound (9) and the hydrazine derivative ((4) WO 2004/069 824) are dissolved in alcohol (methanol or ethanol), heated and stirred for 30 minutes to 5 hours, and then an appropriate amount of acetic acid is added to the reaction solution. The compound (6a) can be produced by adding and stirring for 1 hour with heating. At that time, positional isomers are by-produced, but it is possible to easily separate and purify the compound (6a) by silica gel column chromatography or crystallization.

 [0071] The aromatic ketone (8) can be derived from the following compound (1a). Further, by applying the method described in the literature (E rik V ander E ycken et al., Org. Lett. 2004, 6 (23), 4223-4225), a commercially available acetylene derivative (10 or 1 2) and It can also be produced by a 1, 2, 3_triazol ring formation reaction using an azide compound.

[0072]

[Chemical 8]

 (11)

[0073] Compound (8) can be produced by heating and refluxing an alcohol (methanol or ethanol) suspension of compound (1a) and Raney-nickel. The reaction conditions and reagents may be selected as appropriate based on ordinary knowledge of organic chemistry.

 [0074] 3-Butin_2_ol (1 0), sodium azide, dimethyl sulfate, and copper iodide in a mixed suspension of t-butanol and water were stirred at room temperature to produce 1_ (1 _Methyl _ 1 H— 1, 2, 3_Triazol 4 _yl) Ethanol (1 1) can be produced. The reaction conditions and reagents may be selected as appropriate based on ordinary knowledge of organic chemistry.

 [0075] 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, etc. may be appropriately selected based on ordinary knowledge of organic chemistry.

 [0076] Furthermore, a mixed suspension of 3-butyne-2-one (12), sodium azide, dimethyl sulfate, and copper iodide in t-butanol and water was stirred at room temperature to obtain a compound. (8) can also be manufactured. The reaction conditions, reagents, etc. may be appropriately selected based on ordinary knowledge of organic chemistry.

Next, the ester form (6) can be hydrolyzed by a conventional method to lead to the carboxylic acid form (7). [0078] [Chemical 9]

[0079] (wherein, R ² and R ³ represent the same groups as the R ² and R ³⁾

[0080] The hydrolysis reaction can be carried out in the presence of a base or a Lewis acid. Examples of the base include hydroxides of alkali metals (for example, 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.

 [0081] The 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.

[0082] [Chemical 10]

(In the above formula, R ¹ and R ² are the same groups as R ¹ and R ² , respectively.) By condensing the carboxylic acid form (7) and the amine form (1 3), Compound (I) can be produced.

[0084] 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, azide method, acid chloride method, acid anhydride method, DCC (dicyclohexyl carbonate) method, active ester method, force sulfonyl diimidazole. Method, DCC / HOB T (1-Hydroxybenzotriazol) method, water-soluble calpositimide And methods that use jetyl cyanophosphate, such as those described by M. B odanszky, YS K lausner and MA O ndetti "P eptide Synthesis" (AW iley—intersciencepublicati on, N ew Y ork, 1 976), GR Pettit, "Synthetic P eptides (E lsevier Scientific Publication Com pany, N ew Y ork, 1 976), edited by the Chemical Society of Japan" 4th edition Lecture Vol. 22, Organic Synthesis IV "(Maruzen Co., Ltd., 1 992), etc. Solvents used in this condensation reaction include N, N-dimethylformamide, pyridine, black mouth form, and methyl chloride. And solvents such as tetrahydrofuran, dioxane, and acetonitrile, and mixed solvents thereof The reaction temperature is preferably _20 to 50 ° C, more preferably _10 to 30 ° C. 1 3) may be a commercially available compound. , The method according to the method or preparation examples described in the literature, Oh Rui may be used and one produced according to these methods.

[0085] Based on ordinary knowledge of organic chemistry, the compound (I) of the present invention produced by the above-described method can be further modified to lead to another compound (I) of the present invention. .

[0086] 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. In addition, the compound of the present invention is extremely superior in terms of safety because it has extremely low nephrotoxicity compared to the compound (B) described in Patent Document 3. Such safety is extremely important considering the long-term administration of platelet aggregation inhibitors. Therefore, the compound (I) of the present invention, a salt thereof, or a solvate thereof 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 surgery (CABG), percutaneous transluminal coronary angioplasty PT CA), stent placement, etc.) It is useful as a prophylactic and / or therapeutic agent for ischemic diseases caused by thrombosis ■ embolism such as thrombotic occlusion, diabetic retinopathy ■ nephropathy, and obstruction at the time of cardiac valve replacement. It is also useful as a prophylactic and / or therapeutic agent for blood clots and emboli associated with vascular surgery and extracorporeal blood circulation. It is also useful for improving ischemic symptoms such as ulcers, pain, and cold feeling associated with chronic arterial occlusion.

 [0087] When the compound (I) of the present invention, a salt thereof or a solvate thereof is used as a medicine, 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 divided into several doses, and if necessary, the daily dose can be exceeded.

 [0088] A pharmaceutical 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, and the preparation is usually used. The dosage form and dosage form are not particularly limited as long as a pharmaceutically acceptable carrier is blended as necessary in the preparation methods of various preparations and a dosage form that matches the administration method is selected.

 [0089] 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. Can be mentioned.

 [0090] 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 solidified by freeze-drying or the like. It is good also as a formulation.

 [0091] When preparing these preparations, pharmaceutically acceptable additives such as binders, disintegrants, dissolution promoters, lubricants, fillers, excipients and the like are added as necessary. You can select and use.

 Next, the present invention will be described in detail with reference examples, examples and test examples.

 Reference example 1

1-(6-Methoxypyridine _ 3 _yl) _5_ [1 -Methyl _5_ (phenylthio) 1 H 1, 2, 3 -Triazol 1 4-yl] — 1 H-villa Zole 3 _ Carponic acid ethyl ester

 [0093] [Chemical 11]

[0094] 1) 4- [1 -Methyl-1 5- (phenylthio) 1 1H— 1, 2, 3-triazol _ 4 _yl] —2, 4-Dioxobutanoic acid ethyl ester

 1_ [1_methyl_5_ (phenylthio) 1 1H—1, 2,3-triazol 1-4-yl] ethanone (1.84 g, S. Ohta et al., C B ui, 1 997, 45 (7), 1 1 40) in tetrahydrofuran (37 ml) solution at _78 ° C under cooling with lithium bis (trimethylsilyl) amide (1.0M Tetrahydrofuran solution, 8.68 ml) was added dropwise and stirred for 80 minutes. To the reaction solution, jetyl oxalate (2.14 ml) was added dropwise at the same temperature, stirred for 15 minutes, and stirred at 0 ° C for 30 minutes. The mixture was further stirred at room temperature for 3 hours. Water and jetyl 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 black mouth form. 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-1,5- (phenylthio) 1-1H-1,2,3-triazol-4-yl] —2,4-dioxobutane The acid ethyl ester (1.60 g, 61%) was obtained as a solid.

H-NMR (400 MHz, CDC I ₃ ) δ: 1. 38- 1. 42 (3 Η, m), 3. 95 (3 H, s), 4. 36-4. 42 (2 H, m) , 7. 22-7. 35 (5 H, m), 7. 52 (1 H, s).

[0095] 2) Title compound

4- [1-Methyl-1-5- (phenylthio) -1-H-1,2,3-Triazol-4-yl] —2,4-Dioxobutanoic acid ethyl ester (1.59 g ) And 5_hydrazino_2-methyoxypyridine (0.730 g, WO2204 / 0 6 9 8 2 4) in ethanol (32 ml) were heated to reflux for 45 minutes. Acetic acid (1.37 ml) was added to the reaction mixture, and the mixture was further heated under reflux for 18 hours. After air cooling, saturated sodium hydrogen carbonate and black mouth form were added to the reaction liquid 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 monoethyl acetate) to give the title compound (1.08 g, 52 / o) as a solid. It was.

H-NMR (400 MHz, CDCI ₃ ) δ: 1.3 9-1.4 ₃ (3 Η, m), 3. 9 3 (3 H, m), 3. 9 6 (3 H, s), 4. 4 1-4. 4 7 (2 H, m), 6. 7 2 (1 H, d, J = 8.8 H z), 6. 90-6. 9 3 (2 H , m), 7. 2 1-7. 2 6 (4 H, m), 7. 6 6-7. 6 9 (1 H, m), 8. 1 0 (1 H, d, J = 2. 7 H z).

 [0096] Reference Example 2

 1-(6-methoxypyridine 1-3 yl) 1 5-(1-methyl 1 1 H- 1 2, 3 _triazol _ 4 _yl) _ 1 H-pyrazol 1 3 _ carpon acid

[0097] [Chemical 12]

 1) 1-(6-methoxypyridine _ 3 _yl) _ 5 _ (1 _ methyl _ 1 1 ~ 1 _ 1, 2, 3 _triazol 1 _ 4 _il) _ 1 H-pyrazo 1_Carponate ethyl ester

Rane-nickel (NIK KO RICA R- 100, 20 g) was washed with ethanol (decane was removed by decantation), and the resulting residue was suspended in ethanol (40 ml). 1 _ (6-methoxypyridine _ 3 _yl) _ 5 _ [1 —methyl _ 5 _ (phenylthio) 1 H -1, 2, 3 _ Triazol 4 _ 1] _ 1 Η _ Pyrazol 1 _ Forced Laponate Ethyl Ester (1.0 7 g) in ethanol (60 ml) 3.5 Heated to reflux for 5 hours. After air cooling, the solid in the reaction solution was filtered off with celite. The solvent of the obtained filtrate was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform 1aceton), and 1_ (6-methoxypyridine 1-yl) 1 5— (1 -Methyl Mono 1 H- 1, 2, 3,3-Triazol _ 4 _yl) _ 1 H-Pyrazol-3 _Carponic acid ethyl ester (0.6 0 7 g, 7 5%) as a solid Got as.

H - NMR (4 0 0 MH z, CDCI 3) δ:.. 1 4 0 - 1 4 4 (3 Η, m), 3. 9 9 (3 H, s), 4. 0 7 (3 H, s), 4.4 2-4. 4 8 (2 H, m), 6. 8 3 (1 H, d, J = 8.8 H z), 7. 2 1 (1 H, s), 7 3 1 (1 H, s), 7. 70 (1 H, dd, J = 8. 8, 2. 7 H z), 8. 2 2 (1 H, d, J = 2.7 H z ).

2) Title compound

 1-(6-Methoxypyridine 1-yl) 1 5- (1 -Methyl 1 1 H— 1, 2, 3 _Triazol _ 4 _yl) _ 1 H-Pyrazol 1 3 _ To a mixed solution of carboxylic acid ethyl ester (0.600 g) in methanol (1 2 ml) and tetrahydrofuran (1 2 ml), 1 N aqueous sodium hydroxide solution (4.57 m I) was added at room temperature for 1 hour. Stir. The reaction mixture was neutralized with 1 N 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.

H - NMR (4 0 0 MH z, DM S O_ d 6) δ: 3. 9 3 (3 Η, m), 4. 0 4 (3 Η, m), 6. 9 4 (1 Η, d, J = 8. 8 Η ζ), 7. 1 6 (1 Η, m), 7. 8 0-7. 8 3 (1 Η, m), 8. 0 9 (1 Η, m), 8.2 7 (1 Η, d, J = 2. 7 ζ ζ), 1 3. 0 3 (1 Η, br).

MS (EI)

z: 3 0 0 (M +). [0100] Reference Example 3

 1-(6-Methoxypyridine 1-yl) 1 5- (1 -Methyl 1 1 H— 1, 2, 3_Triazol _4_ Gil) _ 1 H-Pyrazol 1 3_Carpon Acid ester

 1) 1 — (1-Methyl 1 H 1, 2, 3 3-Triazol 4 4-yl) Ethanone

 Raney nickel (NI KKO RI CA R-1 00, 50 g) was washed with ethanol (ethanol removed with decantation), and the resulting residue ethanol (100 ml) suspension In an argon atmosphere, 1_ [1-methyl-1-5- (phenylthio) -1- 1H--1,2,3-triazol-4-yl] ethanone (5.00 g, S.O A suspension of 1 997, 45 (7), 1 1 40) in ethanol (100 ml) was added to hta et al., Chem. Pharm. Bui, and heated to reflux for 4 hours. After air cooling, the solid in the reaction solution was filtered off with 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 monoethyl acetate), and 1 _ (1 _ methyl _ 1 H-1, 2, 3— Triazol 4-yl) Ethanone (0.685 g, 26%) was obtained as a solid.

¹ H-NMR (400 MHz, CDCI ₃ ) (5: 2.69 (3 H, s), 4. 16 (3 H, s), 8. 05 (1 H, s).

[0101] 2) 4— (1—Methyl-1-H 1, 2,3-Triazol-1-4-yl) 1,2-Dioxobutanoic acid ethyl ester

Under an argon atmosphere, sodium ethoxide (20% ethanol solution, 3.70 g) in ethanol (6.8 ml) was added with ethyl oxalate (1.48 ml) at room temperature and stirred for 15 minutes. To the reaction mixture, add 1_ (1-methyl_1H-1,2,3-triazol-4-yl) ethanone (0.680 g) in ethanol (13.6 ml) 2 Stir for hours. To the reaction solution are added water and diethyl ether, and the mixture is separated. A saturated aqueous ammonium chloride solution is added to the aqueous layer, and Extracted with mouth form. 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_1 1 ~ 1_1,2,3_triazol-4-yl) 1,2,4-dioxobutanoic acid ethyl ester (0.904 g) , 7 4%) as a solid.

H-NMR (400 MHz, CDC I ₃ ) δ: 1. 39- 1. 42 (3 Η, m), 4. 20 (3 H, s), 4. 37 -4. 42 (2 H, m) , 7. 42

(1 H, s), 8. 1 6 (1 H, s).

 [0102] 3) Title compound

 4— (1 — Methyl 1 H— 1, 2, 3 — Triazol 1 4 — yl) 1, 2, 4-Dioxobutanoic acid ethyl ester (0. 896 g) and 5_hydrazino 1 2-methoxypyridine ( A suspension of 0.55 g, WO 2004/069824) in ethanol (18 ml) was heated to reflux for 30 minutes. To the reaction solution, 5_hydrazino_2-methoxypyridine (0.11 1 1 g) was added, 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 mixture was separated. 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 1aceton) to obtain the title compound (0.881 g, 67%) as a solid.

 [0103] Reference Example 4

 2—Methoxy _5_ [3-[(4-Methoxypiperidine 1 _yl) carbonyl] _5_ (1 _Methyl _ 1 1 ~ 1_ 1, 2, 4_Triazol _3—yl) _ 1 H—Pyrazol 1 1 _yl] Pyridine

[0104] [Chemical 13]

[0105] 1-(6-Methoxypyridine _ 3 _yl) _5_ (1 _Methyl _ 1 1 ~ 1_ 1, 2, 4_Triazol _3_ yl) _ 1 H-Pyrazol 1 3 _Carponic acid (1 84 mg, WO 2006/01 4005), 4-Methoxypiperidine hydrochloride (1 85 mg, WO 2004/094407), 1-Hydroxybenzotriazol (16 mg), Triethylamine (425 I ), And 3_ (3-dimethylaminopropyl) _ 1_ethyl carpositimide hydrochloride (1 76 mg) in dichloromethane (30 ml) were stirred at room temperature overnight. To the reaction solution were added water and 10% methanol-chloroform and separated. 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 thin layer chromatography (chloroform form-methanol) to obtain the title compound (109 mg, 45%) as a solid.

H-NMR (400 MHz, CDC I ₃ ) δ: 1. 66 (2 H, brs), 1. 93 (2 H, brs), 3. 37 (3 H, s), 3. 49 (2 H, brs), 3.69 (1 H, brs), 3. 90 (3 H, s), 3. 98 (3 H, s), 4. 07 (1 H, s), 4. 23 (1 H, s), 6. 80 (1 H, d, J = 8. 79 H z), 7. 22 (1 H, d, J = 0.49 H z), 7. 7 1 (1 H, dd, J = 8. 79, 2.20 H z), 7. 99 (1 H, s), 8. 23 (1 H, d, J = 2. 69 H z).

 MS (ES I) m / z: 398 (M + H) +.

 [0106] Reference Example 5

 1— (1-methyl 1 H 1, 2, 3-triazol 1 4-yl)

 Method)

in a solution of t-butanol (1.5 ml) and water (1.5 ml), 3-butyne-2-one (82 I), sodium azide (65 mg), dimethyl sulfate (97 7 I), and Copper iodide (I) (38 mg) was added, and the mixture was 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 subjected to silica gel thin layer chromatography (dichloromethane / methanol). Purification gave the title compound (21 mg) as a solid.

[0107] Method B)

 1) 1 — (1-Methyl 1 H 1, 2, 3 3-Triazol 4 4-yl) Ethanol

 In a solution of t-butanol (1.5 ml) and water (1.5 ml), 3-butyn-2-ol (8 1 I), sodium azide (65 mg), dimethyl sulfate (97 I), and Copper (I) iodide (38 mg) was added and stirred at room temperature. After filtering the reaction solid, the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (dichloromethane-methanol), and 1 _ (1 _ methyl _ 1 H— 1, 2, 3_triazol 1 4 _yl) ethanol

(54 mg) was obtained as an oil.

1 H-NMR (400 MHz, CDC I ₃ ) δ: 1.59 (3 H, d, J = 6.62 H z), 2.38 (1 H, d, J = 4. 1 7 H z) , 4. 09 (3 H, s), 5. 09 (1 H, dt, J = 1 2. 0 1, 5. 2 1 H z), 7. 46 (1 H, s).

¹³ C-NMR (40 OMH z, CDCI ₃ ) (5: 23.1, 36. 6, 62. 9, 1 2 1.1, 1 52. 7.

[0108] 2) Title compound

 1 — (1 —Methyl 1 H— 1, 2, 3—Triazol 1 4 —yl) Ethanol (635 mg) in dichloromethane (10 ml) and manganese dioxide (4.9 g) And stirred at room temperature for 15 hours. 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).

[0109] Reference Example 6

(3 R) _ 3 _Methylmorpholine hydrochloride [0110] [Chemical 14]

[0111] 1) t e r t —Butyl (3 R) _3_ Methylmorpholine _4_ Carpoxylate

 (R) _2-Aminopropanol (3.4 ml) was added to tetrahydrofuran (

Dissolved in 200 ml), sodium hydride (55% in mineral oil, 2.1 g) was added and stirred at room temperature for 30 minutes. In the reaction solution

(4.7 ml) was added and heated to reflux for 7 hours. After the reaction solvent was distilled off under reduced pressure, the resulting residue was suspended in ethyl acetate. Insoluble matter was removed by filtration through Celite, and the filtrate solvent was distilled off under reduced pressure to obtain crude (R) _5_methylmorpholin-3_one (3.5 g). This was dissolved in tetrahydrofuran (250 ml), lithium aluminum hydride (2.3 g) was added, and the mixture was heated to reflux for 7 hours. After cooling to room temperature and adding methanol to complete the reaction, celite (

30 g) and sodium sulfate decahydrate (30 g) were added and stirred for 2 hours. The reaction solution was filtered through Celite, and di-tert-ptyl dicarbonate (6.6 g) was added to the filtrate, followed by stirring for 17 hours. The reaction solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexyl monoacetate), then tert butyl (3 S) _ 3 _methylmorpholine _ 4 _carboxylate (1

5 g, 25%) as an oil.

H-NMR (400 MHz, CDC I ₃ ) δ: 1.24 (3 H, d, J = 6.6 H z), 1. 47 (9 H, s), 3. 1 1 -3. 1 9 (1 H, m), 3.40-3. 46 (1 H, m), 3.56-3.70 (3 H, m), 3. 8 2-3. 87 (1 H, m), 4. 08-4. 0 1 (1 H, m).

MS (ES I)

z: 202 (M + H) +.

[0112] 2) Title compound

Above tert —butyl (3 S) _3_methylmorpholine _4_carpoxy Silate (1.5 g) was dissolved in ethyl acetate (30 ml), 4N hydrochloric acid-ethyl acetate solution (5 ml) was added, and the mixture was stirred for 18 hours. The precipitate was collected by filtration to give the title compound (0.82 g, 80%) as a solid.

¹ H-NMR (400MH z, DMSO_D ₆ ) (5: 1. 1 6 (3 H, d, J = 6. 6 H z), 2. 97-3. 04 (1 H, m), 3.1 4-3. 1 9 (1 H, m), 3. 21 -3. 29 (1 H, m), 3. 42 (1 H, dd, J = 1 2. 3, 1 0. OH z), 3. 65-3. 72 (1 H, m), 3. 83 —3. 89 (2 H, m), 9. 56 (2 H, brs).

 MS (ES I) m / z: 1 02 (M + H) +.

 [0113] Reference Example 7

 (3 S)-3 —Methylmorpholine

[0114] [Chemical 15]

[0115] 1) t tert-Butyl (3 S) _3_ methylmorpholine

 (S) _2-Aminopropanol (3.4 ml) from tert-butyl (3 S) — 3_methylmorpholine _4_ force lupoxylate (3.9 g, 76%) as an oil.

1 H-NMR (40 OMH z, CDC I ₃ ) δ ^. 24 (3 H, d, J = 6.6 H z), 1. 47 (9 H, s), 3.1 1 1 -3. 1 9 (1 H, m), 3. 40-3. 46 (1 H, m), 3. 56-3. 70 (3 H, m), 3.8 3-3. 87 (1 H, m) , 4. 08-4. 01 (1 H, m).

 MS (ES I) m / z: 202 (M + H) +.

[0116] 2) Title compound

From the above tert-butyl (3 S) _3_methylmorpholine-4 carboxylate (3.9 g), the title compound (1. 6 g, 60%) was obtained as a solid.

 H-N M R (4 0 0 M H z, DM S O— (5: 1.1 8 (3 H, d,

= 6. 6 H z), 2. 9 6-3. 0 3 (1 m), 3. 1 3-3. 1 8

1 H, m), 3. 2 0-3. 2 9 (1 H,, 3. 4 2-3. 4 7 (1

, m), 3. 6 8-3. 7 4 (1 H, m). 8 3-3. 8 9 (2 H,

), 9. 7 2 (2 H, b rs).

MS (ESI)

z: 1 0 2 (M + H)

 [0117] Reference Example 8

 3_dimethylbiperazine

[0118] [Chemical 16]

 1) Benzyl 2, 4_dimethylbiperazine 1 1-carpoxylate benzyl 2-methylbiperazine 1 1_carpoxylate (WO 2 0 3/0 2 2 2 1 4, 1.8 g) methanol (4 To the 0 ml) solution were added sodium triacetoxyborohydride (2.1 g), acetic acid (0.4 3 ml) and 37 o / o aqueous formaldehyde solution (2. O ml) at 0 ° C. After stirring at room temperature for 1 hour, a saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added to separate the layers. The organic layer was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (black-form form-methanol) to obtain benzyl 2,4_dimethylbiperazine_1_carboxylate (1.8 g, 9 4%) as an oil.

¹ H-NMR (400 MHz, CDCI ₃ ) δ: 1.27 (3 H, d, J = 6.6 H z), 1.8 9-1.96 6 (1 H, m) , 2. 0 9-2. 1 3 (1 H, m), 2. 2 4 (3 H, s), 2. 5 7-2. 6 1 (1 H, m), 2. 7 0— 2 7 4 (1 H, m), 3. 1 4-3. 2 2 (1 H, m), 3. 8 8-3. 9 3 (1 H, m), 4. 2 7-4.3 4 (1 H, m), 5. 1 0-5. 1 7 (2 H, m), 7. 37-7.30 (5 H, m).

MS (ES I)

z: 249 (M + H) +.

 [0120] 2) Title compound

 The above benzyl 2,4_dimethylbiperazine 1_carboxylate (1.8 g) and palladium on carbon (1 · 0 g) in ethanol (1 Om I) and 1 N hydrochloric acid in 1 ethanol (20 ml) And stirred for 7 hours in a hydrogen atmosphere. The palladium was removed by Celite filtration, and the filtrate solvent was evaporated under reduced pressure to give the title compound (1.3 g, 100%) as an oily substance.

H-NMR (400 MHz, DMSO_D ₆ ) δ: 1. 29- 1. 30 (3 H, m), 2. 80 (3 H, s), 3. 09-4. 1 5 (7 H, m) , 1 0 .07 (2 H, brs), 1 1. 85 (1 H, m).

 [0121] Example 1

 2—Methoxy _5_ [3-[(4-Methoxypiperidine 1 _yl) carbonyl] _5_ (1 _Methyl _ 1 1 ~ 1_ 1, 2, 3_Triazol _4—yl) _ 1 H—Pyrazol 1 1 _yl] Pyridine

[0122] [Chemical 17]

1_ (6-Methoxypyridine _3_yl) of Reference Example 2 _5_ (1-Methyl-1 H- 1, 2, 3-Triazol 4-yl) 1 1 H-Pyrazol 3- — Carponic acid (0.254 g), 4-Methoxypiperidine hydrochloride (0.192 g, WO 2004/094407), 3- (3-Dimethylaminopropyl) _ 1 _Ethylcarpoimide hydrochloride To a solution of salt (0.178 g) and 1-hydroxybenzotriazol (0.126 g) in dichloromethane (5.1 ml) was added triethylamine (0.307 ml) at room temperature and stirred for 21 hours. did. To the reaction solution are added water and chloroform, and the mixture is separated. The solvent in the organic layer is distilled off under reduced pressure. did. The obtained residue was purified by silica gel column chromatography (black mouth form-methanol) to give the title compound (0.239 g, 71%) as a solid.

H-NMR (400 MHz, CDCI ₃ ) (5: 1. 7 1 (3 H, m), 1. 94 (2 H, m), 3. 38 (3 H, s), 3. 47-3. 56 (2 H, m), 3.68-3. 74 (1 H, m), 3.98 (3 H, s), 4. 09 (3 H, s), 4. 21 -4. 26 ( 1 H, m), 6. 81 (1 H, d, J = 8.5 H z), 7. 07 (1 H, s), 7. 32 (1 H, s), 7. 68- 7. 70 (1 H, m), 8. 22 (1 H, d, J = 2.4 H z) MS (EI) m / z: 397 (M +).

 [0124] Example 2

 4- {[1-(6-Methoxypyridine _ 3 _yl) _5_ (1 -Methyl 1 1 H- 1, 2, 3 -Triazol 1 4 -yl) 1 1 H-Pyrazoyl 1 3-yl] carponyl} morpholine

 [0125] [Chemical 18]

 [0126] (Method A)

1_ (6-Methoxypyridine _3_yl) of Reference Example 2 _5_ (1-Methyl-1 H- 1, 2, 3-Triazol 4-yl) 1 1 H-Pyrazol 3- — Carponic acid (0.260 g), 3- (3-dimethylaminopropyl) _ 1 _ ethyl carbodiimide hydrochloride (0.183 g), and 1-hydroxybenzotriazole (0. To a solution of 1 29 g) in dichloromethane (5.2 ml), morpholine (90. 5 I) and triethylamine (0.13 ml) were added at room temperature, and the mixture was stirred for 17 hours. To the reaction solution, water and chloroform were added for liquid separation, and the solvent in the organic layer was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography. Purification with raffii (black-form-form-methanol) gave the title compound (0.277 g, 87%) as a solid.

H-NMR (400 MHz, CDCI ₃ ) (5: 3. 73-3. 82 (6 H, m), 3. 98 (3 H, s), 4. 09 (3 H, s), 4.1 0 (2 H, m), 6. 82 (1 H, d, J = 8.8 H z), 7. 14 (1 H, s), 7. 33 (1 H, s), 7. 66 -7. 69 (1 H, m), 8. 22 (1 H, d, J = 2.4 H z).

 MS (E I) m / z: 369 (M +).

[0127] (Method B)

 1_ (6-Methoxypyridine _3_yl) of Reference Example 2 _5_ (1-Methyl-1 H- 1, 2, 3-Triazol 4-yl) 1 1 H-Pyrazol 3- — Carponic acid (9.00 g), 3- (3-dimethylaminopropyl) _ 1-ethylcarbodiimide hydrochloride (6.32 g), and 1-hydroxybenzotriazole (4.45 g) Morpholine (3.13 ml) and triethylamine (4.60 ml) were added to a dichloromethane (180 ml) solution at room temperature 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 residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform form-methanol) to obtain the title compound as a solid. The obtained solid methanol suspension was dissolved by 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 and 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%).

[0128] Example 3

 1-{[1-(6-Methoxypyridine _ 3 _yl) _5_ (1—Methyl 1 1 H- 1, 2, 3—Triazol 1 4 —yl) 1 1 H—Pyrazol 1 3-yl] carponyl} _ 4-methylbiperazine

[0129] [Chemical 19]

[0130] 1_ (6-Methoxypyridine _ 3 _yl) of Reference Example 2 _ 5 _ (1 —Methyl-1 H-1, 2, 2, 3-triazol 4-yl) 1 H —Pyrazolol 3—Carponic acid (0.200 g), 3- (3-dimethylaminopropyl) _ 1 _ ethylcarbodiimide hydrochloride (0.140 g), and 1 —Add 1-methylbiperazine (0.1 1 1 m I) and triethylamine (0.1 0 2 ml) at room temperature to a solution of hydroxybenzotriazole (9 9. O mg) in dichloromethane (4 ml). Stir for 5 hours. To the reaction solution, water and chloroform were added 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 (chromoform monomethanol) to obtain the title compound (0.176 g, 69%) as a solid.

H-NMR (400 MHz, CDCI ₃ ) (5: 2. 3 4 (3 H, s), 2. 4 7-2.5 3 (4 H, m), 3. 8 6 (2 H , m), 3. 9 8 (3 H, s), 4.0 7 (2 H, m), 4.0 9 (3 H, s), 6. 8 0-6. 8 2 (1 H, m), 7. 1 0 (1 H, s), 7. 3 2 (1 H, s), 7. 6 7-7.70 (1 H, m), 8. 2 2 (1 H, m ).

[0131] Example 4

 1-Cyclopropyl 1 _ {[1-(6 -Methoxypyridine _ 3 _yl)-5-(1 -Methyl 1 1 H— 1, 2, 3 -Triazol 1 4 -yl) 1 1 H —Virazol _ 3 _yl] Carponyl} Piperazine

[0132] [Chemical 20]

[0133] 1_ (6-Methoxypyridine_3_yl) of Reference Example 2 _5_ (1—Methyl-1H-1,2,2,3-triazol-4-yl) 1H —Pyrazolol 1—— 1-cyclopropylpiperazine hydrochloride (2 4 5. 8 mg) in N, N-dimethylformamide (5 m I) solution of carponic acid (2 5 0. O mg) , WO 2 0 0 4/0 6 9 8 2 4), 3-(3 -dimethylaminopropyl) _ 1 _ethyl sulfidochloride hydrochloride (1 9 2. 2 mg), 1-hydroxybenzotriazo — (11.29 mg) and triethylamine (0.350 ml) were added and stirred for 15 hours. To the reaction solution were added a saturated aqueous sodium hydrogen carbonate solution and chloroform, and the phases were separated. The organic layer was washed with water and then 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 (black mouth form methanol) to give the title compound (2 5 0.7 mg, 7 4%). Obtained as a solid.

H - NMR (4 0 0 MH z, CDCI 3) (5:.. 0. 4 6 (4 H, m), 1 6 2 - 1 6 7 (1 H, m), 2. 6 4 - 2. 7 2 (4 H, m), 3. 7 5-3. 8 1 (2 H, m), 3. 9 4-4. 0 1 (5 H, m), 4.0 9 (3 H, s ), 6. 8 1 (1 H, d, J = 8.8 H z), 7. 1 0 (1 H, s), 7. 3 2 (1 H, s), 7. 6 9 (1 H , dd, J = 8. 8, 2. 7 H z), 8. 2 2 (1 H, d, J = 2. 7 H z).

MS (ESI)

z: 4 0 9 (M + H) +.

[0134] Example 5

4-{[1-(6-methoxypyridine _ 3 _yl) _ 5 _ (1-methyl 1 1 H-1, 2, 3 -triazol 1 4 -yl) 1 1 H-pyrazo 1 1-3] Carponyl} Morpholine 1) 1_Methyl_ 1 1 ~ 1_ 1, 2, 3_Triazol

 Under cooling to 0 ° C, 1 H— 1, 2, 3_triazol (1 50 g) and methyl iodide (1 8 9 ml) in tetrahydrofuran (2. 25 I) —Zazabicyclo [5.4.0] _7_undecene (3 8 9 ml) was added dropwise over 2 hours. The reaction was stirred at room temperature for 16 hours. The insoluble material 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 mm Hg) to give 1-methyl-1 1H-1, 2 , 3-Triazol (1 1 7 g, 65%) was obtained as an oil.

H-NMR (4 00 MHz, CDCI ₃ ) (5: 4. 1 3 (3 H, s), 7.5 6-7.5 6 (1 H, m), 7. 70-7. 7 1 (1 H, m).

 [0135] 2) 1_Methyl_5_ (Phenylthio) _1H_1,2,3_Triazol

 _Butyllithium (1.2 I) solution of 1_methyl_ 1 1 ~ 1 _ 1, 2, 3_triazol (1 1 7 g) in anhydrous tetrahydrofuran (1.2 I) 1.59 M n-hexane solution, 1.0 6 I) was added dropwise over 1.5 hours, followed by stirring for 2 hours. A solution of diphenyldisulfide (369 g) in anhydrous tetrahydrofuran (1.21) was added dropwise to the reaction solution over 2 hours, and the reaction solution was stirred at room temperature for 18 hours. Water (1 I) was added to the reaction solution, followed by extraction four times with ethyl acetate, and the combined 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 monoethyl acetate). 1 _methyl_ 5 _ (phenylthio) 1 1 H— 1, 2 , 3-Triazol (2 2 4 g, 8 3%) was obtained as an oil.

H - NMR (4 0 0 MH z, CDCI 3) (5: 3. 9 7 (3 H, s), 7. 1 1 - 7. 1 4 (2 H, m), 7. 2 3 - 7. 3 2 (3 H, m), 7. 8 6 (1 H, s).

 [0136] 3) 1-[1-Methyl 1 5-(Phenylthio) 1 1 H— 1, 2, 3-Triazol 1 4 _l] Ethanone

2, 2, 6, 6-Tetramethylpiperidine (2 3 7 m I) in anhydrous tetrahydrofuran (2 1) solution with n_butyllithium (1.

6 OM n-hexane solution, 878 ml) was added dropwise over 30 minutes. Furthermore, 1_methyl_5_ (phenylthio) _1H—1,2,3_triazole (224 g) in anhydrous tetrahydrofuran (1.5 1) was added to the reaction mixture over 1.5 hours. And then stirred for 2 hours. To the reaction solution was added N-methoxy-1-N-methylacetamide (133 g), and the mixture was stirred at room temperature for 3 hours. In the reaction solution, water (

1. 3 I) and ethyl acetate (5 I) were added for liquid separation, and the organic layer was washed with water (1.3 1). 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 monoethyl acetate). 1 _ [1 _methyl_5_ (phenylthio) _ 1 H_

1,2,3-Triazol-4-yl] Ethanone (236 g, 86%) was obtained as an oil.

¹ H-NMR (400 MHz, CDCI ₃ ) (5: 2.72 (3 H, s), 3.

92 (3 H, s), 7. 21 -7. 33 (5 H, m).

4) 4— [1-Methyl-1 5- (Phenylthio) -1-H 1, 2, 3-Triazol _ 4 _Il] —2, 4-Dioxobutanoic acid ethyl ester

 To a solution of sodium ethoxide (82.6 g) in ethanol (1 1) was added jetyl oxalate (1 77 g). 1_ [1_methyl_5_ (phenylthio) 1 1H—1, 2, 3-triazol 1-4-yl] Ethanone (236 g) in ethanol (750 ml) was added to the reaction solution. Drip over 5 minutes, 2.

Stir for 5 hours. The reaction mixture was neutralized by adding 1 N aqueous hydrochloric acid (1.2 I), and the precipitated solid was collected by filtration. 4_ [1 _methyl_5_ (phenylthio) 1 H 1,

2,3_Triazol _4-yl] —2,4-dioxobutanoic acid ethyl ester (254 g, 76%) was obtained.

H-NMR (400 MHz, CDC I ₃ ) δ: 1.40 (3H, t, J = 7.1 Hz), 3.95 (3H, s), 4.39 (2H, q, J = 7. 1 H z), 7. 21 -7. 25 (2 H, m), 7. 29-7. 34 (3 H, m), 7. 52 (1 H, s). [0138] 5) 1-(6-Methoxypyridine _ 3 _yl) _5_ [1 _Methyl_5_ (phenylthio) 1 H 1, 2, 3-Triazol 1 4 yl] — 1 H-Pyrazole 1_Carponate ester

 4- [1—Methyl mono 5— (phenylthio) mono 1 H— 1, 2, 3-triazol —_4_yl] —2, 4-dioxobutanoic acid ethyl ester (1 47 g) and 5 —hydrazino _ A suspension of 2-methoxypyridine (67.8 g, WO 2004/069824) in ethanol (1.48 I) was stirred at an internal temperature of 75 ° C for 4.5 hours. Acetic acid (133 g) was added dropwise to the reaction mixture over 10 minutes, and the mixture was further stirred at an internal temperature of 75 ° C. for 4.5 hours. After cooling with air, ethanol (1 I) was added to the reaction mixture and stirred. The precipitated crystals were collected by filtration. 1_ (6-Methoxypyridine_3_yl) 1-5- (1-methyl-1-5-phenyl) ) 1 1 H—1, 2, 3—Triazol _4_yl] — 1 H—Pyrazol—3_Carponic acid ethyl ester (1 5 2 g, 79%) was obtained.

¹ H-NMR (400 MHz, CDC I ₃ ) δ: 1. 41 (3 H, t, J = 7.1 H z), 3. 93 (3 H, s), 3. 96 (3 H, s ), 4.44 (2

H, q, J = 7.1 Hz), 6. 72 (1 H, d, J = 8.8 H z), 6. 89-6. 93 (2 H, m), 7. 21 -7 27 (4 H, m), 7. 68

(1 H, d d, J = 8. 8, 2. 7 H z), 8. 1 0 (1 H, d, J = 2. F H z).

 [0139] 6) 1-(6-Methoxypyridine _ 3 _yl) _5_ (1—Methyl _ 1 H_

 I, 2, 3_Triazol 4_yl) _ 1 H_Pyrazol 3_Carponic acid ethyl ester

1-(6-Methoxypyridine _ 3 _yl) _5_ [1—Methyl _5_ (phenylthio) 1 H 1, 2, 3 -Triazol 1 4-yl] — 1 H-Vilazo 1 A suspension of Raney-nickel (1 kg) in ethanol (1.5 I) was added to ru_3_carponic acid ethyl ester (152 g), and the mixture was stirred at an internal temperature of 74 ° C for 1 hour. After cooling with air, 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. Dry the organic layer over anhydrous sodium sulfate Dried. 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 monochloroform). 1_ (6-Methoxypyridine 1-yl) 1 5 — (1 —Methyl 1 H— 1, 2, 3—Triazol 1 4 _yl) _ 1 H—Pyrazol 1 3 _Carponic acid ethyl ester (1 0 1 g, 8 8%) Obtained as a solid.

. H - NMR (4 0 0 MH z, CDCI 3) δ: 1 4 2 (3 H, t, J = 7

1 H z), 3. 9 9 (3 H, s), 4.0 7 (3 H, s), 4.4 5 (2

H, q, J = 7. 1 H z), 6. 8 3 (1 H, d, J = 8.8 H z), 7. 2 1 (1 H, s), 7. 3 0 (1 H , s), 7.71 (1 H, dd, J = 8.8, 2. 7 H z), 8. 2 2 (1 H, d, J = 2. 7 H z).

MS (ESI)

z: 3 2 9 (M + H) +.

7) 1-(6-Methoxypyridine _ 3 _yl) _ 5 _ (1 _Methyl _ 1 1 ~ 1 _

1, 2, 3 _Triazol 1 4 _yl) _ 1 H-Pyrazol 1 3 _Carponic acid

 1-(6-Methoxypyridine 1-yl) 1 5- (1 -Methyl 1 1 H— 1, 2, 3 _Triazol _ 4 _yl) _ 1 H-Pyrazol 1 3 _ To a mixed suspension of carponic acid ethyl ester (101 g) in methanol (1 I) and tetrahydrofuran (1 I), 1 N aqueous sodium hydroxide solution (76.68 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 material was filtered off when the amount was about half. To the filtrate, 1 N hydrochloric acid (76 8 8 m I) was added and the resulting solid was collected by filtration. 1 _ (6-methoxypyridine _ 3 _yl) _ 5 _ (1-methyl 1 1 H— 1 , 2, 3-Triazol 4-yl) 1 1 H-Pyrazol 3-Carbonic acid (88.4 g, 96%).

H - NMR (4 0 0 MH z, DM S O_ d 6) δ: 3. 9 3 (3 Η, s), 4. 0 4 (3 Η, s), 6. 9 6 (1 Η, d, J = 8. 8 Η ζ), 7. 1 7 (1 Η, s), 7. 8 3 (1 Η, dd, J = 8. 8, 2. 7 ζ ζ), 8. 1 2 (1 Η , s), 8. 2 8 (1 Η, d, J = 2. 7 Η ζ), 1 3. 0 5 (1 Η, brs). MS (ES I) m / z: 301 (M + H) +.

 [0141] 8) Title compound

 1 _ (6-Methoxypyridine _ 3 _yl) _5_ (1—Methyl 1 1 H-1, 2, 3—Triazol 1 4—yl) 1 1 H—Pyrazol 1 3-Force Luponic acid (88.4 g), 3- (3-Dimethylaminopropyl) _ 1-ethylcarbodiimide hydrochloride (62.1 g) and 1-hydroxybenzotriazole (43.8) g) suspension of morpholine in dichloromethane (1.8 I)

(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. A saturated aqueous sodium hydrogen carbonate solution (1.5 I) was added to the reaction solution, and the mixture was separated. The aqueous layer was 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 (methanoyl 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%).

 [0142] Example 6

 5- [3-{[(2 S)-2-(Fluoromethyl) pyrrolidine 1-yl] carbonyl} -5- (1 _methyl_ 1 1 ~ 1_ 1, 2, 3_triazol _4 — _ 1 H—Pyrazol 1 _il] _ 2—Methoxypyridine

[0143] [Chemical 21]

1_ (6-Methoxypyridine _3_yl) of Reference Example 2 _5_ (1-Methyl-1 H- 1, 2, 3-Triazol 4-yl) 1 1 H-Pyrazol 3- — Carponic acid (0.200 g), (2 S) — Fluoromethylpyrrolidine hydrochloride (0.13 g, WO 2006/004027), 3- (3-dimethylamino Tripropyl ether at room temperature in a solution of 1-ethyl carbodiimide hydrochloride (0.140 g) and 1-hydroxybenzotriazol (99. Omg) in dichloromethane (4 m I). Min (0.241 ml) was added and stirred for 63 hours. Water and chloroform were added to the reaction solution and the phases were separated, and the solvent of the organic layer was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform monomethanol) to obtain the title compound (0.178 g, 69%) as a solid.

H-NMR (400 MHz, CDC I ₃ ) δ: 1. 88-2. 1 5 (4 Η, m), 3. 67-4. 1 6 (8 H, m), 4. 36-5. 1 8 (3 H, m)

, 6. 80-6. 82 (1 H, m), 7. 21-23 (1 H, m)

35-7. 40 (1 H, m), 7. 66-7. 7 11 ((11 HH ,, mm)),, 88. 2 1—8. 24 (1 H, m).

[0145] Example 7

 (3 R) -4- {[1-(6-Methoxypyridine _ 3 _yl) _5_ (1 —Methyl 1 H— 1, 2, 3—Triazol 1 4 —yl) 1 1 H —Pyrazol _3_yl] Carponyl} _ 3 _Methylmorpholine

[0146] [Chemical 22]

[0147] 1_ (6-Methoxypyridine _ 3 _yl) of Reference Example 2 _5_ (1-Methyl-1 H-1, 2, 3-Triazol one 4-yl) One 1 H-pyrazo 3-N-N-dimethylformamide (4 ml) solution of 1- force luponic acid (1 30 mg) was added to (3 R) _ 3 _methylmorpholine (1 20 mg), 4-( 4,6-dimethyoxy-1,3,5-triazine-2-yl) 4-methylmorpholine chloride (155 mg) and triethylamine (180 I) And stirred at room temperature for 4 hours. To the reaction solution are added water and ethyl acetate, and the mixture is separated, the organic layer is evaporated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (chloroform form-methanol) to give the title compound (1 2 1 mg, 73%) was obtained as a solid.

H - NMR (4 0 0 MH z, CDCI 3) δ:. 1 4 3 (. 3 H, d, J = 6 6 H z), 3. 3 8 - 3. 2 1 (1 H, m), 3. 5 3-3. 7 6 (3 H, m), 3. 8 4-3. 9 6 (1 H, m), 3. 9 8 (3 H, s), 4.0 9 (3 H , s), 4. 4 0-4. 6 2 (1 H, m), 4. 7 4-4. 9 5 (1 H, m), 6. 8 2 (1 H, d, J = 9. OH z), 7. 1 1 (1 H, s), 7. 3 3 (1 H, s), 7. 6 6-7. 6 9 (1 H, m), 8. 2 2 (1 H, d, J = 2.7 H z).

MS (ESI)

z: 3 8 4 (M + H) +.

[0148] Example 8

 (3 S)-4-{[1-(6-methoxypyridine _ 3 _yl) _ 5 _ (1 —methyl 1 1 H— 1, 2, 3—triazol 1 4 —yl) 1 1 H-pyrazole _ 3 _yl] carbonyl} _ 3 _methylmorpholine

[0149] [Chemical 23]

 1_ (6-Methoxypyridine_3_yl) of Reference Example 2 _5_ (1—Methyl-1H-1,2,2,3-triazol 4-alkyl) 1 1H-pyrazo In the same manner as in Example 7, the title compound (1 12 mg, 1 12 mg) was prepared from the same as in Example 7 using 3-carponic acid (120 mg) and (3 S) _ 3 _methylmorpholine (11 O mg) 73%) was obtained as a solid.

H - NMR (4 0 0 MH z, CDCI 3) δ:. 1 4 3 (. 3 H, d, J = 6 6 H z), 3. 2 0 - 3. 3 8 (1 H, m), 3. 5 3-3. 7 4 (3 H , m), 3. 8 5-3. 9 4 (1 H, m), 3. 9 8 (3 H, s), 4. 1 0 (3 H, s), 4. 4 0-4.6 3 (1 H, m), 4. 7 3-4. 9 3 (1 H, m), 6. 8 2 (1 H, d, J = 9.00 H z), 7. 1 2 (1 H , s), 7. 3 2 (1 H, s), 7. 68 (1 H, dd, J = 9.00, 2. 7 H z), 8. 2 2 (1 H, d, J = 2. 7 H z).

MS (ESI)

z: 3 8 4 (M + H) +.

 [0151] Example 9

 4-{[1-(6-methoxypyridine _ 3 _yl) _ 5 _ (1-methyl 1 1 H-1, 2, 3 -triazol 1 4 -yl) 1 1 H-pyrazo 1 1-yl] Carponil}-1, 4-oxazepane

 [0152] [Chemical 24]

 [0153] 1_ (6-Methoxypyridine_3_yl) of Reference Example 2 _5_ (1—Methyl-1H-1,2,2,3-triazol-4-yl) —Pyrazol-l 3-- Carponic acid (1 3 0 mg) and 1,4-oxazeze hydrochloride (WO 2 0 0 4/9 4 4 0 7, 1 2 0 mg) were used in the same manner as in Example 7. Gave the title compound (92. 7 mg, 56%) as a solid.

H-NMR (4 00 MHz, CDCI ₃ ) (5: 2. 0 0-2. 1 0 (2 H, m), 3. 7 9-3. 8 9 (6 H, m), 3. 9 8 (3 H, s), 4.0 0 4-4. 1 3 (2 H, m), 4.0 9 (3 H, s), 6. 8 1 (1 H, d, J = 9. 0 H z), 7. 1 3 (1 H, d, J = 4.3 Hz), 7. 3 4-7. 3 6 (1 H, m), 7. 6 5-7. 6 9 ( 1 H, m), 8. 2 3-8. 2 0 (1 H, m).

MS (ESI)

z: 3 8 4 (M + H) +.

[0154] Example 1 0 5- {3- [(4,4-Dimethyl _ 1, 3 _oxazolidine 1 3 _yl) Forced Luponyl] _5_ (1 _Methyl _ 1 H— 1, 2, 3_Triazol 1 4 _il) _ 1 H—Pyrazol _ 1—yl} _ 2—Methoxypyridine

 [0155] [Chemical 25]

 [0156] 1_ (6-Methoxypyridine _ 3 _yl) of Reference Example 2 _5_ (1-Methyl-1 H-1, 2, 3, 3-triazol 4-yl) 1 H-pyrazo The title compound (1 24 mg, 75%) was prepared in the same manner as in Example 7 from 3-carponic acid (1 30 mg) and 4,4-dimethyloxazolidine (75% aqueous solution, 120 I). ) Was obtained as a solid.

H-NMR (400 MHz, CDC I ₃ ) δ: 1.62 (6 H, s), 3. 79 (2 H, s), 3. 98 (3 H, s), 4. 1 0 (3 H , s), 5.4 7 (2 H, s), 6. 81 (1 H, d, J = 9. OH z), 7. 21 (1 H, s), 7. 38 (1 H, s ), 7. 66-7. 69 (1 H, m), 8. 2 2-8. 1 8 (1 H, m).

MS (ES I)

z: 384 (M + H) +.

[0157] Example 1 1

 1-{[1-(6-Methoxypyridine _ 3 _yl) _5_ (1—Methyl 1 1 H- 1, 2, 3—Triazol 1 4 —yl) 1 1 H—Pyrazol 1 3-yl] carponyl} piperidine _ 2 _carboxamide

[0158] [Chemical 26]

1_ (6-Methoxypyridine _3_yl) of Reference Example 2 _5_ (1-Methyl-1 H- 1, 2, 3-Triazol 4-yl) 1 1 H-Pyrazol 3- — The title compound (1 30 mg, 85%) was obtained as a solid in the same manner as in Example 7 from carponic acid (1 20 mg) and piperidine _2 _ force lupoxamide hydrochloride (WO 2006/004027, 1 32 mg). .

H-NMR (400 MHz, CDC I ₃ ) δ: 1. 52- 1. 85 (5 Η, m), 2. 2 9 2 4 1 (1 H, m), 2. 7 8-2. 86 ( 1/2 H, m), 3. 1 3-3 2 1 (1/2 H, m), 3.98 (3 H, s), 4.

1 0 (3 H, s) 4 68-4. 73 (1 H, m), 5.3 3 2-5.45

(2 H, m) 6 3 4 -6. 39 (1/2 H, m), 6. 8 0-6.84

(1 H, m) 7 0 2-7. 07 (1/2 H, m), 7. 1 2-7. 1 6

(1 H, m) 7 2 8-7. 36 (1 H, m), F. 63-7. 7 0 (1

H, m), 8 23 ― 8. 1 8 (1 H, m).

 [0160] Example 1 2

 1-{[1-(6-Methoxypyridine _ 3 _yl) _5_ (1—Methyl 1 1 Η-1, 2, 3—Triazol 1 4-yl) 1 1 Η—Pyrazol 1 3-yl] carbonyl} -2, 4 _dimethylbiperazine

[0161] [Chemical 27]

1 _ (6-Methoxypyridine _3_yl) of Reference Example 2 _5_ (1-Methyl-1 Η-1, 2, 3-Triazol 1 4-yl) 1 1 Η-Pyrazoyl 1 3 — The title compound (1 15 mg, 73%) was converted to amorphous form from carponic acid (1 2 Omg) and 1,3_dimethylbiperazine hydrochloride (1 49 mg) in Reference Example 8 in the same manner as in Example 7. Got as.

H-NMR (400 MHz, CDC I ₃ ) δ: 1. 42 (3 H, d, J = 6 3 H z), 2. 0 1-2. 08 (1 H, m), 2. 20-2. 24 (1 H, m), 2. 2 7 (3 H, s), 2. 59- 2. 8 8 (2 H, m), 3. 4 3-3. 58 (1 H, m), 3. 9 8 (3 H, s), 4. 09 (3 H, s), 4. 53 -4. 58 (1 H, m), 4. 90 (1 H, brs), 6. 80-6. 8 3 (1 H, m), 7. 07 (1 H, s), 7. 3 2 (1 H, s), 7. 6 7-7. 70 (1 H, m), 8. 2 3-8. 2 2 (1 H, m). MS (ESI) m / z: 3 9 7 (M + H) +.

[0163] [Test Example 1] Inhibition of platelet aggregation

Human blood was collected using 1/10 volume of 3.8% sodium quenate as an anticoagulant and centrifuged at 180 g for 10 minutes to separate platelet-rich plasma (PRP). After separating the upper PRP, the lower layer was centrifuged at 1 600 g for 10 minutes to separate the upper platelet poor plasma (PPP). Add test compound solution 1 I to PRP 200 I 3 7. After heating for 2 minutes at C, collagen 2 I was added to induce platelet aggregation. Platelet aggregation rate was measured using PAM-12C (MC Medical). The light transmittance was 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.

[0164] [Test Example 2] Cyclooxygenase _ 1 (CO X— 1) and Cyclooxygena _ Ze _ 2 (CO X-2) inhibitory action

 For the measurement of the CO X-1 and CO X-2 inhibitory activities of the test compounds, C a y C n c hem i c a l C o m p a n y C O X inhibitor screening assay kit (catalog numbers 560 100 1, 560 1 2 1) was used.

Reaction buffer before measurement, heme, Arakidon acid, S n CI _2, EIA buffer, wash buffer, prostaglandin (PG) screening EIA standard solution, PG screening acetylcholinesterase (A ch E), Torre colonel 1 (Coloring enzyme HRP conjugate), PG screening EIA antiserum was prepared.

(1) Production of PGF ₂ by CO X-1 or CO X-2

Reaction mixture containing test compound (50; UM) and CO X_ 1 or CO X-2 Was allowed to stand at 37 ° C. for 10 minutes, 10 μI of arachidonic acid was added, and the mixture was allowed to stand at 37 ° C. for 2 minutes. After the reaction, 1 N_hydrochloric acid 50 UI was added to stop the reaction, and then SnCI ₂ solution 100 I was added and left at room temperature for 5 minutes.

[0165] (2) Quantification of PGF ₂ by ELISA

After adding 50 I of antiserum (rabbit anti-PGF ₂ antibody) to each well of a 96-well plate that was coated with mouse anti-rabbit I g G, the above PGF ₂ production reaction solution was increased 2000 times. Diluted solution 50 I, A ch E tracer

I was sequentially added and allowed to stand at room temperature for 18 hours. Each well was washed 5 times with wash buffer to remove excess Ac h E tracer and then Ellman (E I I m a n) reagent 200 I was added. After standing in a dark room for 60 minutes, the absorbance was measured at 405 nm.

[0166] (3) Calculation of inhibitory activity of test compound

PG screening A standard curve was prepared using the EIA standard solution, and the production amount of PGF ₂ was determined from the above absorbance. Calculate the inhibition rate of CO X-1 or CO X-2 at each concentration of the test compound, IC ₅ . Asked. The results are shown in Table 1. In calculating the inhibition rate, the production amount of PGF ₂ obtained using a reaction solution containing no test compound was set to 100%.

[0167] [Table 1]

[Result 1]

*: Compounds within the scope of the claims of ^{WO 200 6/0 005 (D} )

 NT: Not Tested

[0168] [Test Example 3] Male rat oral single dose toxicity study

Test substances (Examples 1 and 2 and Reference Example 4) were each orally administered with 200 _mg Z kg to male rats and sacrificed on the next day to examine toxicity. The control group was similarly administered 0.5% methylcellulose (2 Om IZ kg). [0169] <Method>

 (1) Rat

 The test was carried out using male rats (C r I: CD (SD), 6 weeks old, Nippon Chirasu River Co., Ltd.). The animals were allowed to freely take food and water, but fasted until about 2 hours after the evening before the administration. On the day before administration, animals were assigned to 5 animals in each group so that the average body weight was approximated between groups by randomized stratification based on body weight [Safety test computer system (Fujitsu)]

[0170] (2) Reagents used

 i) 0.5% w / V Me t h y l C e l l u l o s e 400 c P S o u u t i o n, S t e r i I i z e d (0.5% Mc, Wako Pure Chemical Industries, Ltd.)

 i i) 10% neutral buffered formalin solution (Wako Pure Chemical Industries, Ltd.)

 (3) Exam design

 Rats were given a single oral dose of the test substance and sacrificed the next day for toxicity.

(4) Preparation of chemical solution

 The chemical solution was prepared 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 1 Omg / mI.

 (5) Control group

 In the control group, 0.5% MC was orally administered (2 Oml / kg).

[0171] (6) Administration method

 i) Route of administration: Oral

 i i) Frequency: Single

 i i i) Dose volume: 20 m I / k g

 i v) Apparatus used for administration: Disposable gastric sonde for rats (Fuchigami apparatus store) and disposable syringe (Terumo)

V) Solvent control group administration: 0.5 <½MC in the same way (2 Om I / k g)

 v i) Fasting treatment: All animals were fasted from the evening before the administration until about 2 hours after the administration.

 [0172] (7) Inspection

 i) Symptom observation: The presence of death and nephrotoxicity were observed immediately after administration until the time of sacrifice.

 ii) Body weight: Body weight was measured using a balance (L P — 4200, Zarius) before administration and at the time of sacrifice.

 i i i) Necropsy: After the carotid artery was cut and the animal was exsanguinated, the major organs in the thoracoabdominal cavity were observed with the naked eye.

 iv) Histopathological examination: The liver, spleen, kidney, heart, lung and gastrointestinal tract are collected, fixed with 10% neutral buffered formalin solution, and then HE (Hema toxy I inandeosin) stained specimen is pathological tissue. Observed scientifically.

[0173] <Result>

 i) Symptom observation: Test substance (Examples 1 and 2 and Reference Example 4) No death or toxic symptoms were observed in the administration group.

 i i) Body weight: Test substance (Examples 1 and 2 and Reference Example 4) No change was observed in the administration group.

 i i i) Necropsy: Test substance (Examples 1 and 2 and Reference Example 4) No changes related to drug administration were observed in the administration group.

 i V) Histopathological examination:

[0174] Ho 2]

From the results of Table 2, the compound of the present invention has less nephrotoxicity and safety compared to the compound described in WO 2006/0 1 4005 having a 1,2,4-triazole ring. Is high.

 [0176] [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, 1 000 and 2000 mg / kg, and then sacrificed on the next day to examine the toxicity. The control group was similarly administered with 0.5% me t h y l c e l l u l o s e (20 m I / kg).

 [0177] <Method>

 (1) Rat

 The test was conducted using male rats (C r I: CD (SD)), 6 weeks of age, Nippon Chirasu Co., Ltd. ■ River Co., Ltd. The animals were allowed to freely take food and water. They were fasted for about 2 hours after the evening before the administration. On the day before administration, 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)

] o

 (2) Reagents used

 i) 0.5% w / V M e t h y l C e l l u l o s e 400 c P S o l u t i o n, S t e r i I i z e d (0.5% M C, Wako Pure Chemical Industries, Ltd.)

 i i) 10% neutral buffered formalin solution (Wako Pure Chemical Industries, Ltd.)

[0178] (3) Exam design

 Rats were given a single oral dose of the test substance and sacrificed the next day for toxicity.

(4) Adjustment of chemicals

 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 10 Omg / mI.

 (5) Control group

 In the control group, 0.5% MC was orally administered (2 Oml / kg).

(6) Administration method

 i) Route of administration: Oral

ii) Frequency: single iii) Dosage volume: 20 m I / kg

 i v) Apparatus used for administration: Disposable gastric sonde for rats (Fuchigami apparatus store) and disposable syringe (Terumo)

 V) Administration of vehicle control group: 0.5 <½ MC was administered in the same manner (2 Om I / kg).

 v i) Fasting treatment: All animals were fasted from the day before administration until about 2 hours after administration.

[0179] (7) Inspection

 i) Symptom observation: We observed the presence of death and toxic symptoms immediately after administration until the time of sacrifice.

 ii) Body weight: Body weight was measured using a balance (L P_4200, Sartorius) before administration and at the time of sacrifice.

 i i i) Necropsy: After the carotid artery was cut and the animal was exsanguinated, the major organs in the thoracoabdominal cavity were observed with the naked eye.

 iv) Histopathological examination: The liver, spleen, kidney, heart, lung and gastrointestinal tract are collected, fixed with 10% neutral buffered formalin solution, and then HE (Hema toxy I inandeosin) stained specimen is pathological tissue. Observed scientifically. In tissues other than the gastrointestinal tract (cecum), no changes were observed in the 200 Omg / kg group, so the 500 and 100 Omg / kg groups were not tested. The gastrointestinal tract (cecum) was not examined in the 50 Omg / kg group because no change was observed in the 100 Omg / kg group.

[0180] <Result>

 i) Symptom observation: Test substance (Example 2) No death was observed in the administration group. There were no toxic symptoms other than transient fluency in one patient in the 500 mg / kg group.

 i i) Body weight: test substance (Example 2) No change was observed in the administration group. i i i) Necropsy: Test substance (Example 2) No administration-related changes were observed in the administration group.

i V) Histopathological examination: 3] Kidney histological examination of test substance (Example 2) Histological examination of other organs Dose (mg "kg)

 No medication-related changes (cecum only

1000 Not implemented

 Implementation)

 2000 No medication-related changes Cecal fistula and cell infiltration (2/5 cases)

Claims

Claims [1] General formula (I)

 [Chemical 1]

 (I)

(Wherein R ² represents a hydrogen atom, a lower alkyl group which may be substituted, a lower alkynyl group, a rubamoyl group which may be substituted, a cyano group, an amino group which may be substituted, a substituted A group or atom selected from a lower alkoxy group and a lower alkanol group, which may be represented by the general formula (II):

C I I)

(The cyclic structure in the formula represents a 4- to 7-membered alicyclic heterocycle, which may contain a nitrogen atom or an oxygen 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 alkanol group, lower alkylsulfonyl group and halogen It indicates that the group may be substituted with 1 to 2 groups or atoms selected from atoms. Or a salt thereof or a solvent thereof.

[2] The compound, salt or solvate thereof according to claim 1, wherein R ² is a lower alkyl group which may be substituted.

[3] The compound according to claim 1, wherein R ² is a methyl group, a salt thereof, or a solvate thereof.

 [4] X force Lower alkyl group which may be substituted, carbamoyl group which may be substituted, amino group which may be substituted, hydroxyl group, lower alkoxy group, oxo group, lower alkanoyl group, lower alkylsulfonyl A piperazinyl group, a piperidinyl group, an oxazolidinyl group, an oxazepanyl group, a pyrrolidinyl group, or a morpholinyl group, which may be substituted with 1 to 2 groups or atoms selected from a group and a halogen atom, The compound, its salt, or those solvates as described in any one of these.

 [5] X is a piperazinyl group, piperidinyl group, oxazolidinyl group, morpholinyl group, oxazepanyl group, pyrrolidinyl group, 4-methyl-piperazinyl group, 4-cyclopropylmonopiperazinyl group, 2, 4-methyl-piperazinyl group A 4-methyloxypiperidinyl group, 2_strong ruberamoylbiperidinyl group, 4,4-dimethyloxazolidinyl group or 2_fluoromethylpyrrolidinyl group, 5. The compound according to any one of 4, a salt thereof, or a solvate thereof.

[6] R ² is a methyl group; X is an oxazolidinyl group, a morpholinyl group, an oxazepanyl group, a pyrrolidinyl group, a 4-methyl-piperazinyl group, a 4-cyclopropylmonopiperazinyl group, 2, 4-methyl It is a loopiperazinyl group, 4-methoxypiperidinyl group, 2_force rubamoylbiperidinyl group, 4,4-dimethyloxazolidinyl group, or 2_fluoromethylpyrrolidinyl group. 6. The compound according to any one of 5, a salt or a solvate thereof.

[7] The following equations (I a) to (I k) [Chemical 3]

Compound, a salt thereof, or a solvate _c represented by any of formulas of

[8] The following formula (l b)

 [Chemical 4]

 A compound represented by (lb), a salt thereof or a solvate thereof.

 [9] 4- {[1-(6-Methoxypyridine _ 3 _yl) _5_ (1-Methyl

 1 H- 1, 2, 3-triazol 4-yl) 1 H-pyrazol 3-yl] carbonyl} morpholine, its salts, or solvates thereof.

[10] A medicament comprising the compound according to any one of claims 1 to 9, a salt thereof, or a solvate thereof.

[1 1] A prophylactic and / or therapeutic agent for ischemic disease comprising the compound according to any one of claims 1 to 9, a salt thereof or a solvate thereof as an active ingredient.

[12] A platelet aggregation inhibitor comprising the compound according to any one of claims 1 to 9, a salt thereof, or a solvate thereof as an active ingredient.

[13] A method for preventing and / or treating an ischemic disease, comprising administering an effective amount of the compound according to any one of claims 1 to 9, a salt thereof, or a solvate thereof.

 [14] 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 ischemic diseases.