JPH10182615A - New pyrazole derivative and its medicinal use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound useful for preventing and treating diseases caused by cell proliferation of smooth muscle such as blood vessel restenosis and arteriosclerotic diseases, having a specific structure, capable of suppressing the proliferation of smooth muscle cells. SOLUTION: This new compound is shown by formula I (R<1> is H, a 2-6C alkyl, etc.; R<2> is H, a 1-6C alkyl, etc.; R<3> is H, a 1-6C alkyl, etc.; R<4> and R<5> are each H, a 1-6C alkyl, etc.; X is O or S) such as N-propyl-N'-(1-benzyl-4- ethoxycarbonylpyrazol-3-yl)urea. 3-Ethoxy-2-cyanopropenioc acid of formula II is subjected to a ring formation reaction with a hydrazine of the formula R<1> -NH-NH2 in a lower alcohol-based solvent at a room temperature to the heating temperature with reflex to give an intermediate compound of formula III. Then the compound of formula III is reacted with an alkylating agent in the presence of a base to give a 1-substituted-3-amino-4-alkoxycarbonylpyrazole type compound of formula IV. The compound of formula IV is reacted with an isocyanate of the formula R<4> -N=C=X to give the objective pyrazole derivative of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel pyrazole derivative and a pharmaceutical use thereof, and more specifically, a smooth muscle cell growth inhibitor containing the pyrazole derivative as an active ingredient, and a pyrazol derivative. Diseases caused by smooth muscle cell proliferation containing a derivative as an active ingredient, in particular, vascular restenosis occurring after percutaneous coronary dilatation, vascular restenosis occurring after percutaneous arterial dilatation, membrane proliferative nephritis, The present invention relates to a pharmaceutical composition for preventing or treating arteriosclerotic diseases, hypertension, diabetes and the like.

[0002]

BACKGROUND OF THE INVENTION Ischemic heart diseases such as myocardial infarction and angina
Obstructive coronary artery disease, which occurs as a result of coronary artery narrowing due to cholesterol deposition and the like. For these obstructive coronary artery diseases, treatment with thrombolytic drugs such as t-PA or percutaneous coronary dilatation (Percutaneous Trauma)
Reopening by nsluminal coronary angioplasty or percutaneous transluminal angioplasty is applied, and in particular, the latter reopening by a physical method has recently become widespread due to its immediate clinical effect. In these arterial dilatation procedures, a balloon catheter is inserted from a femoral artery or the like, and the balloon is inflated at the stenosis site to physically dilate the blood vessel at the stenosis site. However, a significant problem with this method is that 3-6
Months, restenosis often occurs (Circulation, 8
4 , 1426-1436 (1991); Drugs, 46 , 259-262 (1993), etc.).

[0003] In this chronic restenosis, immediately after reopening, there is a microscopic injury to the blood vessels accompanying dilatation, and thrombotic reocclusion due to excessive adhesion and aggregation of platelets to the inner surface,
In other words, unlike acute occlusion, when the injury reaches the vascular tunica media, abnormal proliferation / migration of smooth muscle cells and intimal hyperplasia constituted by the intercellular matrix produced by smooth muscle cells are the main causes. It is said. Intimal hyperplasia resulting from the proliferation of vascular smooth muscle cells, migration to the intima, and matrix deposition is a major factor in the onset of diseases such as membranoproliferative nephritis, atherosclerotic disease, diabetes, and hypertension. ing. Platelet-derived growth factor (PDGF) is a factor that induces smooth muscle cell proliferation.
th Factor), epidermal growth factor (EGF)
wth Factor), insulin-like growth factor (IGF; Ins)
ulin-like growth factors) are known, and antagonists to these growth factors are smooth muscle cell growth inhibitors, but none of them have been put to practical use in clinical settings. For example, trapidil having inhibitory activity on PDGF (see Life Sciences, 28 , 1641-1646 (1981)) has been reported to be effective in animal restenosis models (Circulation, 81 , 1089-). 1093 (1
990)), the activity is not sufficient, and it has not been put to practical use. In addition, tranilast, which has already been clinically used as an antiallergic agent, also has an effect of inhibiting smooth muscle cell proliferation in recent years (Atherosclerosis, 107 , 179-185 (19
94)), and has been reported to have a vascular restenosis-preventing effect after percutaneous arterial dilatation (clinical medicine,
12 , 65-85 (1996)). It has been known that tranilast has a high rate of side effects on liver function, and its medicinal effects are clear, but its administration requires careful attention.

[0004] Under these circumstances, there is a demand for the development of a new drug excellent in the action of inhibiting and suppressing smooth muscle cell proliferation induced by growth factors such as PDGF. Furthermore, vascular restenosis after percutaneous coronary dilatation and vascular restenosis after percutaneous dilatation are associated with ischemic heart disease such as myocardial infarction and angina. In addition, since these heart diseases are chronic, there is a demand for a low-toxicity drug that does not cause severe side effects upon long-term or repeated administration of such inhibitors and inhibitors for smooth muscle cell proliferation. Further, needless to say, there is a similar demand for diseases such as membrane hyperplasia nephritis, arteriosclerosis, diabetes, and hypertension.

[0005]

An object of the present invention is to provide a novel compound having a smooth muscle cell growth inhibitory action, a smooth muscle cell growth inhibitor containing the compound as an active ingredient, and a smooth muscle cell growth. It is intended to provide a pharmaceutical composition for use in the prevention or treatment of diseases caused by. That is, an object of the present invention is to provide a novel compound having an excellent action of inhibiting smooth muscle cell proliferation, and to provide a pharmaceutical composition containing the compound as an active ingredient.

[0006]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, a novel pyrazole derivative having a specific structure has an effect of inhibiting smooth muscle cell proliferation. And found that the present invention was completed. The novel pyrazole derivative of the present invention has the following general formula (I):

[0007]

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Or the following general formula (II):

[0009]

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(In the formulas (I) and (II), R ¹ represents a hydrogen atom, a linear or branched alkyl group having 2 to 6 carbon atoms, a benzyl group or a phenyl group, and R ² represents Represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms or a benzyl group, and R ³ represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms or a benzyl group. R ⁴ and R ⁵ are a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkenyl group having 3 to 6 carbon atoms, X represents a cycloalkyl group, a benzyl group or a phenyl group, respectively, and X represents an oxygen atom or a sulfur atom.

When R ¹ is a benzyl group, R ² is an ethyl group, R ³ is a hydrogen atom, and R ⁴ is a hydrogen atom, R ⁵ has a hydrogen atom, straight chain or branched. An alkyl group having 2 to 6 carbon atoms, a linear or branched alkenyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms or a benzyl group is selected. ) Or a pharmacologically acceptable salt thereof.

Further, the invention of the pharmaceutical use of the present invention relates to a smooth muscle cell proliferation inhibitor containing the above-mentioned pyrazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient and a disease caused by smooth muscle cell proliferation. It is a pharmaceutical composition for prophylactic or therapeutic use.
The pharmaceutical composition of the present invention is used for the prevention or treatment of diseases caused by smooth muscle cell proliferation. Representative examples of the diseases caused by smooth muscle cell proliferation include percutaneous coronary artery dilatation. Examples include vascular restenosis occurring after surgery, vascular restenosis occurring after percutaneous arterial dilatation, membrane proliferative nephritis, arteriosclerotic disease, hypertension, and diabetes. That is, the pharmaceutical composition of the present invention is a drug for use in treating or preventing the above-mentioned diseases.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION In the pyrazole derivative of the present invention, that is, in the pyrazole derivative represented by the above general formula (I) or (II), a straight-chain or branched carbon atom having 1 to 1 carbon atoms. As the alkyl group of 6, specifically, a linear alkyl group such as a methyl group, an ethyl group, a propyl group,
Butyl group, pentyl group, hexyl group, and branched alkyl groups such as isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, 1-methylbutyl group, 2-methylbutyl group, and 3-methylbutyl group , 1,1
-Dimethylpropyl group, 2,2-dimethylpropyl group,
1,2-dimethylpropyl group, 1-ethylpropyl group,
1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 1- Examples include an ethylbutyl group, a 2-ethylbutyl group, and a 1-ethyl-2-methylpropyl group. The straight-chain or branched alkyl group having 2 to 6 carbon atoms refers to the aforementioned straight-chain or branched alkyl group having 1 to 6 carbon atoms.
Of the above alkyl groups except for the methyl group. The straight-chain or branched alkenyl group having 3 to 6 carbon atoms has a carbon skeleton corresponding to the straight-chain or branched alkyl group having 3 to 6 carbon atoms.
It means a compound having a carbon double bond, and examples thereof include an allyl group (2-propenyl group), a 1-propenyl group, an isopropenyl group, a 2-butenyl group, and a 2-pentenyl group. An alkenyl group having no double bond at the position, specifically, an allyl group (2-propenyl group), 2-butenyl group, 2-pentenyl group, etc. can be used without any inferiority to the corresponding alkyl group. it can. That is, when an unsaturated hydrocarbon group having no double bond at the carbon atom at position 1 is used, the effect of the substituent is the same as that when a saturated alkyl group is used. The cycloalkyl group having 3 to 8 carbon atoms includes a monocyclic cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and a monocyclic cycloalkyl group as a side chain. It also includes those having a linear or branched alkyl group having a total carbon number of 8 or less.

In the pyrazole derivative of the present invention, which is represented by the general formula (I), an alkyl group or a benzyl group having 2 to 6 carbon atoms is selected for R ¹ on the nitrogen atom on the pyrazole ring. More preferred. On the other hand, in the compound represented by the general formula (II), R ¹ substituted on the nitrogen atom on the pyrazole ring is selected from a phenyl group in addition to the above-mentioned alkyl group or benzyl group having 2 to 6 carbon atoms. Is also a preferred embodiment. In addition, in the general formula (I) or the general formula (II), it is preferable that at least one of R ⁴ and R ⁵ substituted on the nitrogen atom of the urea or thiourea structure other than a hydrogen atom is selected.

Some compounds structurally similar to the pyrazole derivative represented by the general formula (I) or (II) of the present invention have already been reported in the literature (Chem. Ph.
arm. Bull., 20 (2), 391-397 (1972), etc.). However, the report was made solely of synthetic interest, and the biological activity of these known compounds, particularly, the effect of suppressing or inhibiting the proliferation of smooth muscle cells,
No mention is made. The method for preparing the pyrazole derivative of the present invention will be briefly described below. First, the following general formula (III):

[0016]

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(Wherein R ² represents a group having the same meaning as R ^{2 in} formulas (I) and (II)), for example, 3-ethoxy-2-cyanopropenoic acid esters, for example, 3
-Ethoxy-2-cyanopropenoic acid ethyl ester and the like, and the following general formula (IV):

[0018]

(In the formula, R ¹ is. Representing the R ¹ group having the same meaning as in the general formula ^{(II)) R 1 -NH-} NH 2 (IV) cyclization with hydrazine or mono-substituted hydrazine represented by And reacting with the following general formula (V):

[0019]

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[0020] (wherein, R ² represents an R ² group having the same meaning as in formula (I).) 3- amino-4-alkoxycarbonyl pyrazole type intermediate compound of represented by, for example, 3
-Amino-4-ethoxycarbonylpyrazole or the like, or the following general formula (VIb):

[0021]

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[0022] (wherein, R ^1, R ² is, R ^1, represents a R ² group having the same meaning. Each formula (II)) 1-substituted-5-amino-4-alkoxycarbonyl pyrazole represented by An intermediate compound of the type is obtained. This cyclization reaction uses a lower alcohol solvent such as methanol and ethanol,
The reaction temperature is selected between room temperature and the reflux heating temperature, and the cyclization proceeds. Subsequently, an intermediate compound represented by the general formula (V) is reacted with an alkylating agent or the like in the presence of a base to give the following general formula (VIa):

[0023]

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[0024] (wherein, R ^1, R ² is, R ^1, represents a R ² group having the same meaning. Each formula (I)) 1-substituted-3-amino-4-alkoxycarbonyl pyrazole represented by Type of compound. The newly introduced substituent R ¹ is a hydrocarbon group derived from an alkylating agent or the like, and a reagent such as benzyl halide may be used in addition to a general-purpose alkylating agent such as an alkyl halide or an alkyl sulfate. it can. On the other hand, examples of the base include sodium hydroxide, alkoxide (sodium methoxide, sodium ethoxide, etc.), sodium hydride and the like, and can be appropriately selected according to the type of reagent such as an alkylating agent to be used. it can.

The N-substitution reaction, such as N-alkylation,
As the solvent, a suitable solvent is selected from water, alcohol, dimethylformamide and the like according to both the base and the reagent such as the alkylating agent. Further, the reaction temperature can be selected from room temperature to a temperature at which the solvent is refluxed. Depending on the selection of the reagent such as the alkylating agent and the reaction temperature, N-
In addition to the main product of the general formula (VIa) obtained by the substitution reaction, a by-product represented by the general formula (VIb) or the like may be obtained. These can be separated and purified by a method such as recrystallization or column chromatography.

Further, the introduction of the substituent R ³ into the amino group of the intermediate compound represented by the general formula (V), (VIa) or (VIb) is carried out by reacting an alkylating agent or a benzylating agent in the presence of a base. It can be done by doing. The newly introduced substituent R ³ is a hydrocarbon group derived from an alkylating agent or a benzylating agent, and an alkylating agent such as an alkyl halide or an alkyl sulfate, or a benzylating agent such as a benzyl halide can be used. Examples of the base include sodium hydroxide, alkoxide (such as sodium methoxide and sodium ethoxide), and sodium hydride. Further, as the solvent, a suitable solvent is selected from alcohol, dimethylformamide and the like according to both the base and the alkylating agent, the benzylating agent, and the reaction can be carried out at a temperature between room temperature and the reflux temperature of the solvent. . The 1-substituted-3-amino-4-alkoxycarbonylpyrazole type compound of the general formula (VIa) has the following general formula (VII) at the 3-position amino group in the presence of a base:

[0027]

R ⁴ —N ＝ C ＝ X (VII) (wherein, R ⁴ represents a group having the same meaning as R ^{4 in} formula (I), and X represents an oxygen atom or a sulfur atom.) Is reacted to form a urea structure or a thiourea structure of the general formula (I) (provided that a hydrogen atom is selected for R ⁵ ). As the base, it is preferable to use trialkylamines such as tertiary amines such as triethylamine and dipropylethylamine. As a solvent to be used, aromatic hydrocarbon solvents such as toluene and benzene, tetrahydrofuran, 1,4 And aprotic solvents that dissolve the above-mentioned tertiary amine bases, such as cyclic ether solvents such as -dioxane. The temperature of the reaction can be appropriately selected from room temperature to the temperature at which the solvent is refluxed, but it is desirable to carry out the reaction while heating under high pressure using a sealed tube or the like.

The 1-substituted-3-amino-4-alkoxycarbonylpyrazole type compound of the general formula (VIa) is prepared by adding triphosgene; CO (OCCl ₃ ) ₂ to the 3-position amino group in the presence of a base. Once reacted, once the following general formula (VIIIa) or (VIIIb):

[0029]

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(Wherein R ¹ and R ² each represent a group having the same meaning as R ¹ and R ^{2 in} formula (I)). Then, the following general formula (IX):

[0031]

Embedded image R ⁴ -NH ₂ (IX) (wherein, R ⁴ represents a R ⁴ group having the same meaning as in formula (I).) In further reacted with primary amines represented, general It can also lead to a urea structure of the formula (I) (provided that a hydrogen atom is selected for R ⁵ ). The compound of the general formula (VIIIa) or (VIIIb) is represented by the following general formula (X):

[0032]

Embedded image R ⁴ —NH—R ⁵ (X) (wherein, R ⁴ and R ⁵ are each independently R ⁴ ,
Represents a group having the same meaning as R ⁵ . ) Can be further reacted with a secondary amine represented by the formula (I) to lead to the urea structure of the general formula (I).

When a hydrogen atom is selected for R ² , that is, when a carboxyl group is formed, the carboxyl group is protected in advance by a benzyl group, and after performing the above-described series of steps, the benzyl ester is converted to Pd. The benzyl group may be deprotected by catalytic hydrogenolysis using a catalyst such as / C 2.

Further, instead of the 1-substituted-3-amino-4-alkoxycarbonylpyrazole type compound of the general formula (VIa), 1-substituted-5-amino-4-alkoxycarbonylpyrazole of the general formula (VIb) Use of a compound of the type can lead to a urea structure of the general formula (II) in a similar manner.

In the pyrazole derivative represented by the general formula (I) or (II) produced by the above method,
In each case, the substituents R ¹ , R ² , R
³ , R ⁴ and R ⁵ are derived from the respective starting compounds, and their introduction positions are also defined. It is easily confirmed that the compound is the target compound by referring to the ¹ H-NMR spectrum and the like. be able to. Formula (I) or Formula (II)
Specific examples of the pyrazole derivative represented by are shown below.

A pyrazole derivative of the general formula (I)
As those having a urea structure, N-phenyl-N'-
(4-ethoxycarbonyl-1-phenylpyrazole-
3-yl) urea, N-phenyl-N '-(1-butyl-
4-ethoxycarbonylpyrazol-3-yl) urea, N-isopropyl-N '-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) urea, N-ter
t-butyl-N '-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) urea, N-2-propenyl-N'-(1-benzyl-4-ethoxycarbonylpyrazol- 3-yl) urea, N-benzyl-N '-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) urea, N-propyl-N'-(1-benzyl-4-
Ethoxycarbonylpyrazol-3-yl) urea, N
-Butyl-N '-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) urea, N-hexyl-N'-
(1-benzyl-4-ethoxycarbonylpyrazole-
3-yl) urea, N-cyclohexyl-N '-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) urea, N-propyl-N'-(1-ethyl-4-ethoxycarbonylpyra Zol-3-yl) urea, N-
Butyl-N '-(1-ethyl-4-ethoxycarbonylpyrazol-3-yl) urea, N-hexyl-N'-(1
-Ethyl-4-ethoxycarbonylpyrazol-3-yl) urea, N-cyclohexyl-N '-(1-ethyl-
4-ethoxycarbonylpyrazol-3-yl) urea, N-propyl-N '-(4-ethoxycarbonyl-1
-Propylpyrazol-3-yl) urea, N-butyl-N '-(4-ethoxycarbonyl-1-propylpyrazol-3-yl) urea, N-hexyl-N'-(4-ethoxycarbonyl-1 -Propylpyrazol-3-yl) urea, N-cyclohexyl-N '-(4-ethoxycarbonyl-1-propylpyrazol-3-yl) urea, N-propyl-N'-(1-butyl-4- Ethoxycarbonylpyrazol-3-yl) urea, N-butyl-
N ′-(1-butyl-4-ethoxycarbonylpyrazol-3-yl) urea, N-hexyl-N ′-(1-butyl-4-ethoxycarbonylpyrazol-3-yl) urea, N-cyclohexyl-N '-(1-butyl-4-ethoxycarbonylpyrazol-3-yl) urea, N-propyl-N'-(1-benzyl-4-carboxypyrazo-
Ru-3-yl) urea, N-butyl-N ′-(1-benzyl-4-carboxypyrazol-3-yl) urea, N
-Hexyl-N '-(1-benzyl-4-carboxypyrazol-3-yl) urea, N-cyclohexyl-N'-
(1-benzyl-4-carboxypyrazol-3-yl) urea, N-propyl-N ′-(4-carboxy-1
-Ethylpyrazol-3-yl) urea, N-butyl-
N '-(4-carboxy-1-ethylpyrazol-3-yl) urea, N-hexyl-N'-(4-carboxy-1
-Ethylpyrazol-3-yl) urea, N-cyclohexyl-N '-(4-carboxy-1-ethylpyrazol-3-yl) urea, N-propyl-N'-(4-carboxy-1-propylpyrazo -Ru-3-yl) urea, N
-Butyl-N '-(4-carboxy-1-propylpyrazol-3-yl) urea, N-hexyl-N'-(4-carboxy-1-propylpyrazol-3-yl) urea, N-cyclohexyl -N '-(4-carboxy-1-
Propylpyrazol-3-yl) urea, N-propyl-N '-(1-butyl-4-carboxypyrazol-3-
Yl) urea, N-butyl-N '-(1-butyl-4-carboxypyrazol-3-yl) urea, N-hexyl-N'-(1-butyl-4-carboxypyrazol- 3-
Yl) urea, N-cyclohexyl-N ′-(1-butyl-4-carboxypyrazol-3-yl) urea, N,
N-dimethyl-N '-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) urea, N, N-dipropyl-N'-(1-benzyl-4-ethoxycarbonylpyrazol- 3-yl) urea, N, N-dibutyl-N'-
(1-benzyl-4-ethoxycarbonylpyrazole-
3-yl) urea, N, N-diphenyl-N '-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) urea, N, N-dicyclohexyl-N'-(1-benzyl-4 -Ethoxycarbonylpyrazol-3-yl) urea, N, N-dimethyl-N '-(4-ethoxycarbonyl-1-propylpyrazol-3-yl) urea, N, N-dipropyl-N'- (4-ethoxycarbonyl-1-propylpyrazol-3-yl) urea, N,
N-dibutyl-N '-(4-ethoxycarbonyl-1-propylpyrazol-3-yl) urea, N, N-diphenyl-N'-(4-ethoxycarbonyl-1-propylpyrazol-3-yl) Urea, N, N-dicyclohexyl-N '-(4-ethoxycarbonyl-1-propylpyrazol-3-yl) urea, N, N-dimethyl-N'-
(1-butyl-4-ethoxycarbonylpyrazole-3
-Yl) urea, N, N-dipropyl-N '-(1-butyl-4-ethoxycarbonylpyrazol-3-yl) urea, N, N-dibutyl-N'-(1-butyl-4- Ethoxycarbonylpyrazol-3-yl) urea, N, N
-Diphenyl-N '-(1-butyl-4-ethoxycarbonylpyrazol-3-yl) urea, N, N-dicyclohexyl-N'-(1-butyl-4-ethoxycarbonylpyrazol-3) -Yl) urea, N-propyl-N'-
(1-benzyl-4-ethoxycarbonylpyrazole-
3-yl) -N'-methylurea, N-propyl-N'-benzyl-N '-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) urea and the like.

A pyrazole derivative of the general formula (I)
As those having a thiourea structure, N-phenyl-
N ′-(1-butyl-4-ethoxycarbonylpyrazol-3-yl) thiourea, N-propyl-N ′-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) thiourea, N-butyl-N ′-(1-benzyl-4
-Ethoxycarbonylpyrazol-3-yl) thiourea, N-hexyl-N '-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) thiourea, N-cyclohexyl-N'-(1 -Benzyl-4-ethoxycarbonylpyrazol-3-yl) thiourea, N-propyl-N '-(1-ethyl-4-ethoxycarbonylpyrazol-3-yl) thiourea, N-butyl-N '-(1-
Ethyl-4-ethoxycarbonylpyrazol-3-yl) thiourea, N-hexyl-N '-(1-ethyl-4
-Ethoxycarbonylpyrazol-3-yl) thiourea, N-cyclohexyl-N '-(1-ethyl-4-ethoxycarbonylpyrazol-3-yl) thiourea, N
-Propyl-N '-(4-ethoxycarbonyl-1-propylpyrazol-3-yl) thiourea, N-butyl-
N '-(4-ethoxycarbonyl-1-propylpyrazo-
Ru-3-yl) thiourea, N-hexyl-N ′-(4-
Ethoxycarbonyl-1-propylpyrazol-3-yl) thiourea, N-cyclohexyl-N '-(4-ethoxycarbonyl-1-propylpyrazol-3-yl)
Thiourea, N-propyl-N ′-(1-butyl-4-ethoxycarbonylpyrazol-3-yl) thiourea,
N-butyl-N '-(1-butyl-4-ethoxycarbonylpyrazol-3-yl) thiourea, N-hexyl-
N '-(1-butyl-4-ethoxycarbonylpyrazol-3-yl) thiourea, N-cyclohexyl-N'-
(1-butyl-4-ethoxycarbonylpyrazole-3
-Yl) thiourea, N-propyl-N '-(1-benzyl-4-carboxypyrazol-3-yl) thiourea, N-butyl-N'-(1-benzyl-4-carboxypyrazol) -3-yl) thiourea, N-hexyl-
N '-(1-benzyl-4-carboxypyrazole-3-
Yl) thiourea, N-cyclohexyl-N '-(1-benzyl-4-carboxypyrazol-3-yl) thiourea, N-propyl-N'-(4-carboxy-1-ethylpyrazol-3- Yl) thiourea, N-butyl-
N '-(4-carboxy-1-ethylpyrazol-3-yl) thiourea, N-hexyl-N'-(4-carboxy-1-ethylpyrazol-3-yl) thiourea, N-
Cyclohexyl-N '-(4-carboxy-1-ethylpyrazol-3-yl) thiourea, N-propyl-N'-
(4-carboxy-1-propylpyrazol-3-yl) thiourea, N-butyl-N ′-(4-carboxy-
1-propylpyrazol-3-yl) thiourea, N-
Hexyl-N '-(4-carboxy-1-propylpyrazol-3-yl) thiourea, N-cyclohexyl-
N '-(4-carboxy-1-propylpyrazole-3-
Yl) thiourea, N-propyl-N ′-(1-butyl-
4-carboxypyrazol-3-yl) thiourea, N
-Butyl-N '-(1-butyl-4-carboxypyrazo-
Ru-3-yl) thiourea, N-hexyl-N ′-(1-
Butyl-4-carboxypyrazol-3-yl) thiourea, N-cyclohexyl-N '-(1-butyl-4-carboxypyrazol-3-yl) thiourea, N, N-
Dimethyl-N '-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) thiourea, N, N-dipropyl-N'-(1-benzyl-4-ethoxycarbonylpyrazol-3- Yl) thiourea, N, N-dibutyl-
N '-(1-benzyl-4-ethoxycarbonylpyrazo-
Ru-3-yl) thiourea, N, N-diphenyl-N'-
(1-benzyl-4-ethoxycarbonylpyrazole-
3-yl) thiourea, N, N-dicyclohexyl-
N '-(1-benzyl-4-ethoxycarbonylpyrazo-
Ru-3-yl) thiourea, N, N-dimethyl-N'-
(4-ethoxycarbonyl-1-propylpyrazole-
3-yl) thiourea, N, N-dipropyl-N ′-(4
-Ethoxycarbonyl-1-propylpyrazole-3-
Yl) thiourea, N, N-dibutyl-N '-(4-ethoxycarbonyl-1-propylpyrazol-3-yl)
Thiourea, N, N-diphenyl-N '-(4-ethoxycarbonyl-1-propylpyrazol-3-yl) thiourea, N, N-dicyclohexyl-N'-(4-ethoxycarbonyl-1-propylpyrazol- 3-yl) thiourea, N, N-dipropyl-N ′-(1-butyl-4
-Ethoxycarbonylpyrazol-3-yl) thiourea, N, N-dibutyl-N '-(1-butyl-4-ethoxycarbonylpyrazol-3-yl) thiourea, N,
N-diphenyl-N '-(1-butyl-4-ethoxycarbonylpyrazol-3-yl) thiourea, N, N-dicyclohexyl-N'-(1-butyl-4-ethoxycarbonylpyrazol- 3-yl) thiourea, N-propyl-N '-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) -N'-methylthiourea, N-propyl-N'-benzyl-N'- (1-benzyl-4-ethoxycarbonylpyrazol-3-yl) thiourea and the like.

Further, a pyrazole derivative of the general formula (II) having a urea structure may be selected from N-propyl-
N '-(1-benzyl-4-ethoxycarbonylpyrazo-
Ru-5-yl) -N'-methylurea, N-propyl-
N'-benzyl-N '-(1-benzyl-4-ethoxycarbonylpyrazol-5-yl) urea, N-phenyl-
N '-(1-benzyl-4-ethoxycarbonylpyrazo-
Ru-5-yl) urea, N-propyl-N '-(1-benzyl-4-ethoxycarbonylpyrazol-5-yl)
Urea, N-phenyl-N '-(4-ethoxycarbonyl-1-phenylpyrazol-5-yl) urea, N-propyl-N'-(4-ethoxycarbonyl-1-phenylpyrazol-5-yl) Urea and the like can be mentioned.

A pyrazole derivative of the general formula (II),
As those having a thiourea structure, N-propyl-
N '-(1-benzyl-4-ethoxycarbonylpyrazo-
-5-yl) -N'-methylthiourea, N-propyl-N'-benzyl-N '-(1-benzyl-4-ethoxycarbonylpyrazol-5-yl) thiourea, N-phenyl-N '-(1-benzyl-4-ethoxycarbonylpyrazol-5-yl) thiourea, N-propyl-N'-
(1-benzyl-4-ethoxycarbonylpyrazole-
5-yl) thiourea, N-phenyl-N '-(4-ethoxycarbonyl-1-phenylpyrazol-5-yl)
Thiourea, N-propyl-N '-(4-ethoxycarbonyl-1-phenylpyrazol-5-yl) thiourea and the like can be mentioned.

The pharmacologically acceptable salts of these pyrazole derivatives include, for example, hydrochloride, sulfate, nitrate, methanesulfonate, toluenesulfonate, sodium salt, potassium salt, calcium salt and the like. Can be mentioned.

The pharmaceutical composition of the present invention for preventing or treating diseases caused by smooth muscle cell proliferation comprises a pyrazole derivative having an inhibitory effect on the smooth muscle cell proliferation described above as an active ingredient, , Additives and the like are mixed to form a preparation. Diseases to which the pharmaceutical composition is applied, that is, vascular restenosis occurring after the operation of percutaneous coronary dilatation, vascular restenosis occurring after the operation of percutaneous arterial dilatation, membrane proliferative nephritis, arteriosclerotic disease, etc. Although the symptoms gradually appear, the pharmaceutical composition of the present invention is mainly administered for the purpose of suppressing its progress. From the point of view of such usage, it is the most expedient to prepare an orally administered drug. Therefore,
For oral administration, it is preferable to use commonly used dosage forms, carrier substances, and additives. For example, the composition may be in the form of a powder, tablet, or capsule together with an excipient such as lactose. The dose of the pyrazole derivative as an active ingredient is appropriately selected according to the age, sex, and weight of the patient, as well as the purpose of administration and the severity of the disease. In general, in adult males, the dose of the pyrazole derivative per day may be selected from the range of 0.1 to 100 mg / kg, and the entire dose is usually administered once or in multiple doses.

[0042]

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to these examples.

Example 1 Synthesis of N-propyl-N '-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) urea 2-ethoxymethylene-2-cyanoacetic acid ethyl ester
Dissolve 10 g in 100 ml of ethanol and add hydrazine
2.87 ml of hydrate was added, and the mixture was heated under reflux for 12 hours. The solvent ethanol was distilled off under reduced pressure.
Was added, and pale yellow crystals of precipitated 3-amino-4-ethoxycarbonylpyrazole (7.68 g, yield: 84%) were separated by filtration and separated.

1.9 g of metallic sodium was added to anhydrous ethanol 1
The solution was dissolved in 00 ml to prepare sodium ethoxide.
To this solution, 12.4 g of 3-amino-4-ethoxycarbonylpyrazole and 10 g of benzyl chloride were added, and the mixture was heated under reflux for 1 hour. The mixture was filtered while hot, and the filtrate was concentrated to about 1/4 volume. After cooling, the precipitated crystals were separated. The crude product was recrystallized from a mixture of ether-water to give 3-amino-1-benzyl-4-ethoxycarbonylpyrazo-
A purified product (10.7 g, yield 44%) was obtained. Next, 0.2 g of this 3-amino-1-benzyl-4-ethoxycarbonylpyrazole was dissolved in 30 ml of dry toluene, and n-
0.307 ml of propyl isocyanate and triethylamine
0.11 ml was added, and the mixture was refluxed and heated in a sealed tube for 8 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (toluene: ethyl acetate = 20: 1) to obtain 0.129 g (yield: 48%) of the title compound.

¹ H-NMR (CDCl ₃ ) δ ppm: 0.92 (3H, t, J = 7H
z, CH ₂ CH ₂ CH ₃ ), 1.32 (3H, t, J = 7Hz, COOCH ₂ CH ₃ ), 1.57
(2H, 6th, CH ₂ CH ₂ CH ₃ ), 4.28 (2H, q, J = 7Hz, COO CH ₂ CH ₃ ),
_{5.14 (2H, s, CH 2} -Ph), 7.25 (5H, m, CH 2 - Ph), 7.91 (2H,
brs, -NH-), 8.00 (1H, s, C5-H) Mass (m / z): 330 (M ⁺ ) Anal.: C ₁₇ H ₂₂ N ₄ O ₃ calcd. C; 61.80, H; 6.71, N; 16.96 found. C; 61.66, H; 6.85, N; 16.99 Melting point: 100-101 ° C

Example 2 Synthesis of N-phenyl-N ′-(1-n-butyl-4-ethoxycarbonylpyrazol-3-yl) urea According to the method of Example 1, the title compound was prepared. Synthesized (yield
18%).

¹ H-NMR (CDCl ₃ ) δ ppm: 1.00 (3H, t, J = 8H
z, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.25 (6H, t + 6th, CH ₂ CH ₂ CH ₂ CH ₃ + COOC
H ₂ CH ₃ ), 1.84 (2H, 5th, CH ₂ CH ₂ CH ₂ CH ₃ ), 4.05 (2H, t, J =
7Hz, CH ₂ CH ₂ CH ₂ CH ₃ ), 4.30 (2H, q, J = 7Hz, COO CH ₂ CH ₃ ),
7.20 (5H, m, Ph), 7.75 (1H, s, C5-H), 8.20 (1H, brs, -N
H-), 10.15 (1H, brs , -NH-) Mass (m / z): 330 (M +) Anal:.. C 17 H 22 N 4 O 3 calcd C; 61.80, H; 6.71, N; 16.96 found. C; 61.89, H; 6.71, N; 16.95 Melting point: 118-120 ° C

Example 3 Synthesis of N-phenyl-N ′-(1-n-butyl-4-ethoxycarbonylpyrazol-3-yl) thiourea The title compound was prepared according to the method of Example 1. Synthesized (yield
58%).

¹ H-NMR (CDCl ₃ ) δ ppm: 0.95 (3H, t, J = 7H
z, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.40 (6H, t + 6th, J = 7Hz, CH ₂ CH ₂ CH ₂ C
H ₃ + COOCH ₂ CH ₃ ), 1.85 (2H, 5th, CH ₂ CH ₂ CH ₂ CH ₃ ), 4.05
(2H, t, J = 7Hz, CH ₂ CH ₂ CH ₂ CH ₃ ), 4.35 (2H, q, J = 7Hz, COO CH
₂ CH ₃ ), 7.30 (5H, m, Ph), 7.77 (1H, s, C5-H), 9.53 (1
H, brs, -NH-) Mass ( m / z): 346 (M +) Anal:... C 17 H 22 N 4 O 2 S calcd C; 58.93, H; 6.41, N; 16.18 found C; 58.74 , H; 6.36, N; 16.20 Melting point: 93-95 ° C

Reference Example 1 Synthesis of N-phenyl-N '-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) urea 35.7 mg of triphosgene (CO (OCCl ₃ ) ₂ ) was added to THF 2 The solution was dissolved in an aliquot of each solution and placed under a stream of argon. To this solution was added 3-amino-1-benzyl-4-ethoxycarbonylpyrazole.
0 mg and 0.0936 ml of diisopropylethylamine in THF
The mixed solution dissolved in 1 ml was slowly added using a syringe over 15 minutes, and heated and stirred at 40 ° C. for 5 hours. Aniline 11.1 μl and diisopropylethylamine 0.093
A solution obtained by adding 6 ml to 1 ml of THF was added to the above solution, followed by stirring. After the reaction was completed, water was added, and the solvent was distilled off under reduced pressure. Ether was added to the obtained residue, and 32 mg of precipitated crystals were separated by filtration (yield 71%). ¹ H of this product
-NMR data were consistent with the reference compound synthesized according to the method described in the literature (see Chem. Pharm. Bull., 20 (2), 391-397 (1972)), and it was confirmed to be the title compound. .

Example 4 Synthesis of N-phenyl-N ′-(1-benzyl-4-benzyloxycarbonylpyrazol-3-yl) urea According to the procedure of Example 1, 3-amino- 4-Benzyloxycarbonylpyrazole was synthesized. Then, from 3-amino-4-benzyloxycarbonylpyrazole,
The title compound was prepared in the same manner as in Reference Example 1 (yield: 80%).

¹ H-NMR (CDCl ₃ ) δ ppm: 5.22 (2H, s, COO
CH ₂ Ph), 5.47 (2H, s, N- CH ₂ Ph), 7.50 (15H, m, N-CH ₂ Ph +
3-NHCONH Ph + COOCH ₂ Ph ), 7.88 (1H, s, C5-H) Mass (m / z): 426 (M ⁺ ) Anal.: C ₂₅ H ₂₂ N ₄ O ₃ calcd. C; 70.41, H ; 5.20, N; 13.14 found. C; 70.20, H; 5.18, N; 13.16

Example 5 Synthesis of N-phenyl-N '-(1-benzyl-4-carboxypyrazol-3-yl) urea 300 mg (0.7 mmol) of the compound of Example 4 was added to 5 ml of DMF. After dissolving, 40 ml of methanol was added. Add 5% Pd / C
30 mg was added, and the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere. The reaction solution was filtered, and the obtained filtrate was distilled off under reduced pressure to obtain 203 mg of the title compound (yield: 86%).

¹ H-NMR (DMSO-d ₆ ) δ ppm: 5.37 (2H, s, N
-CH ₂ Ph), 7.90 (10H, m, N-CH ₂ Ph + 3-NHCONH Ph ), 7.89 (1
H, s, C5-H), 8.59 (1H, brs, -NH-), 9.92 (1H, brs, -NH
-) Mass (m / z): 336 (M ⁺ ) Anal .: C ₁₈ H ₁₆ N ₄ O ₃ calcd. C; 64.28, H; 4.79, N; 16.66 found. C; 64.17, H; 4.94, N; 16.61

Reference Example 2 Synthesis of N-phenyl-N '-(4-ethoxycarbonyl-1-methylpyrazol-5-yl) urea Ethyl 3-ethoxy-2-cyanopropenoate
5.14 g was dissolved in 50 ml of ethanol, 1.61 ml of methylhydrazine was added, and the mixture was refluxed for 12 hours. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 50: 1), and 5-amino-4-ethoxycarbonyl- as an intermediate material was purified.
1-Methylpyrazole (4.31 g, 84% yield) was obtained.

Next, 0.845 g of 5-amino-4-ethoxycarbonyl-1-methylpyrazole as an intermediate material was dissolved in 50 ml of benzene, and phenyl isocyanate was added to this solution.
0.543 ml and 0.70 ml of triethylamine were added, and the mixture was refluxed and heated in a sealed tube for 3 hours. The solvent was distilled off under reduced pressure, and ether was repeatedly added to the obtained residue to obtain 0.36 g (yield: 25%) of crystals of the title compound precipitated.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.31 (3H, t, J = 7H
z, COOCH ₂ CH ₃ ), 3.82 (3H, s, N-CH ₃ ), 4.26 (2H, q, J = 7H
z, COOCH ₂ CH ₃ ), 7.40 (5H, m, Ph), 7.79 (1H, s, C3-H),
8.73 (2H, brs, -NH- × 2) Mass (m / z): 288 (M +) HRMS m / z:. C 14 H 16 N 4 O 3 calcd 288.1222, found 288.1288 mp: 151-153 ° C.

Example 6 Synthesis of N-phenyl-N ′-(4-ethoxycarbonyl-1-phenylpyrazol-5-yl) urea According to the method of Reference Example 2, the title compound was synthesized. rate
50%).

¹ H-NMR (CDCl ₃ ) δ ppm: 1.33 (3H, t, J = 7H
z, COOCH ₂ CH ₃ ), 4.27 (2H, q, J = 7Hz, COO CH ₂ CH ₃ ), 7.40
(10H, m, Ph × 2), 7.80 (1H, s, C3-H) Mass (m / z): 350 (M ⁺ ) HRMS m / z: C ₁₉ H ₁₈ N ₄ O ₃ calcd. 350.1379, found 350.1475 Melting point: 184-185 ℃

Example 7 Synthesis of N-propyl-N ′-(4-ethoxycarbonyl-1-phenylpyrazol-5-yl) urea The title compound was synthesized according to the method of Reference Example 2. rate
16%).

¹ H-NMR (CDCl ₃ ) δ ppm: 0.83 (3H, t, J = 7H
z, CH ₂ CH ₂ CH ₃ ), 1.32 (3H, t, J = 7Hz, COOCH ₂ CH ₃ ), 1.45
(2H, 6th, CH ₂ CH ₂ CH ₃ ), 3.15 (2H, q, J = 5Hz, CH ₂ CH ₂ CH ₃ ),
4.29 (2H, q, J = 7Hz, COO CH ₂ CH ₃ ), 6.79 (2H, brs, -NH−
× 2), 7.46 (5H, m, Ph), 8.21 (1H, s, C3-H) Mass (m / z): 316 (M ⁺ ) HRMS m / z: C ₁₆ H ₂₀ N ₄ O ₃ calcd. 316.1535, found 316.1601 Melting point: 117-118 ° C

Example 8 Synthesis of N-isopropyl-N ′-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) urea The title compound was synthesized in the same manner as in Reference Example 1. (Yield 84%).

¹ H-NMR (CDCl ₃ ) δ ppm: 1.19 (6H, d, J = 7H
z, -CH (CH ₃ ) ₂ ), 1.31 (3H, t, J = 7Hz, COOCH ₂ CH ₃ ), 3.99
(1H, m, -CH (CH ₃ ) ₂ ), 4.27 (2H, q, J = 7Hz, COO CH ₂ CH ₃ ),
5.13 (2H, s, N- CH ₂ Ph), 7.39 (5H, m, N-CH ₂ Ph ), 7.67
(1H, s, C5-H), 7.78 (1H, brs, -NH-), 7.93 (1H, brs,-
NH-) Mass (m / z): 330 (M ⁺ ) Anal .: C ₁₇ H ₂₂ N ₄ O ₃ calcd. C; 61.80, H; 6.71, N; 16.96 found. C; 61.87, H; 6.73, N ; 16.96 Melting point: 111-112 ° C

Example 9 Synthesis of Nn-butyl-N ′-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) urea The title compound was prepared in the same manner as in Reference Example 1. It was synthesized (yield 66%).

¹ H-NMR (CDCl ₃ ) δ ppm: 0.92 (3H, t, J = 7H
z, -CH ₂ CH ₂ CH ₂ CH ₃ ), 1.42 (7H, m, -CH ₂ CH ₂ CH ₂ CH ₃ + COO
CH ₂ CH ₃ ), 3.32 (2H, m, -CH ₂ CH ₂ CH ₂ CH ₃ ), 5.14 (2H, s, N
-CH ₂ Ph), 7.28 (5H, m, N-CH ₂ Ph ), 7.67 (1H, s, C5-H),
7.99 (1H, brs, -NH-) , 8.03 (1H, brs, -NH-) Mass (m / z): 344 (M +) Anal:.. C 18 H 24 N 4 O 3 calcd C; 62.77, H; 7.02, N; 16.27 found. C; 62.63, H; 7.01, N; 16.27 Melting point: 104-105 ° C

Example 10 Synthesis of N-tert-butyl-N ′-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) urea The title compound was prepared in the same manner as in Reference Example 1. It was synthesized (yield 85%).

¹ H-NMR (CDCl ₃ ) δ ppm: 1.31 (3H, t, J = 7H
z, COOCH ₂ CH ₃ ), 1.37 (9H, s, -C (CH ₃ ) ₃ ), 4.26 (2H, q, J
= 7Hz, COO CH ₂ CH ₃ ), 5.11 (2H, s, N- CH ₂ Ph), 7.38 (5H,
m, N-CH ₂ Ph ), 7.68 (1H, s, C5-H), 7.82 (1H, brs, -NH
-), 7.88 (1H, brs , -NH-) Mass (m / z):. 344 (M +) HRMS m / z: C 18 H 24 N 4 O 3 calcd 344.1848, found 344.1857 mp: 130-131 ° C.

Example 11 Synthesis of N-2-propenyl-N ′-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) urea By the same procedure as in Reference Example 1, the title compound was obtained. It was synthesized (yield 82%).

¹ H-NMR (CDCl ₃ ) δ ppm: 1.32 (3H, t, J = 7H
_{z, COOCH 2 CH 3),} 3.98 (2H, t, J = 2Hz, - CH 2 -CH = CH 2), 4.2
8 (2H, q, J = 7Hz, COO CH ₂ CH ₃ ), 5.10 (1H, dd, J = 9Hz, 1Hz,
-CH ₂ -CH = C Ha (Hb)), 5.15 (2H, s, N- CH ₂ Ph), 5.20 (1H, d
d, J = 6Hz, 1Hz, -CH ₂ -CH = CHa ( Hb )), 5.92 (1H, m, -CH ₂ - CH
= CH ₂ ), 7.50 (5H, m, N-CH ₂ Ph ), 7.66 (1H, s, C5-H), 8.
02 (1H, brs, -NH-) , 8.07 (1H, brs, -NH-) Mass (m / z): 328 (M +) HRMS m / z:. C 17 H 20 N 4 O 3 calcd 328.1535, found 328.1526 Melting point: 77-78 ° C

Example 12 Synthesis of N-cyclohexyl-N ′-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) urea The title compound was synthesized in the same manner as in Reference Example 1. (Yield 76%).

¹ H-NMR (CDCl ₃ ) δ ppm: 1.27 (4H, m, ch
ex), 1.31 (3H, t, J = 7Hz, COOCH ₂ CH ₃ ), 1.57 (4H, m, c-he
x), 1.90 (2H, m, c-hex), 3.80 (1H, m, c-hex), 4.27
(2H, q, J = 7Hz, COO CH ₂ CH ₃ ), 5.13 (2H, s, N- CH ₂ Ph), 7.3
9 (5H, m, N-CH ₂ Ph ), 7.68 (1H, s, C5-H), 7.94 (2H, br
s, each -NH-) Mass (m / z): 370 (M +) HRMS m / z:. C 20 H 26 N 4 O 3 calcd 370.2005, found 370.2020 mp: 94-95 ° C.

Example 13 Synthesis of N-benzyl-N ′-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) urea The title compound was synthesized by the same operation as in Reference Example 1. (63% yield).

¹ H-NMR (CDCl ₃ ) δ ppm: 1.32 (3H, t, J = 7H
z, COOCH ₂ CH ₃ ), 4.29 (2H, q, J = 7Hz, COO CH ₂ CH ₃ ), 4.56
(2H, d, J = 5Hz , 3-NH-CO-NH- CH 2 Ph), 5.09 (2H, s, N- CH 2 P
h), 7.27 (10H, m, N-CH ₂ Ph + 3-NH-CO-NH-CH ₂ Ph ), 7.66
(1H, s, C5-H), 8.11 (1H, s, -NH-), 8.31 (1H, brs, -N
H-) Mass (m / z): 378 (M ⁺ ) Anal .: C ₂₁ H ₂₂ N ₄ O ₃ Mw = 378.434 calcd. C; 66.65, H; 5.86, N; 14.80 found. C; 66.86, H; 5.87, N; 14.80 Melting point: 82-83 ° C

Example 14 Synthesis of N, N-dimethyl-N ′-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) urea The title compound was prepared in the same manner as in Reference Example 1. It was synthesized (63% yield).

¹ H-NMR (CDCl ₃ ) δ ppm: 1.30 (3H, t, J = 7H
z, COOCH ₂ CH ₃ ), 3.05 (6H, s, -N (CH ₃ ) ₂ ), 4.24 (2H, q, J
= 7Hz, COO CH ₂ CH ₃ ), 5.26 (2H, s, N- CH ₂ Ph), 7.42 (5H,
m, N-CH ₂ Ph), 7.51 (1H, s, C5-H), 8.71 (1H, brs, -NH
-) Mass (m / z): 316 (M ⁺ ) Melting point: 125-126 ° C

Example 15 Synthesis of N, N-dipropyl-N ′-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) urea The title compound was prepared in the same manner as in Reference Example 1. It was synthesized (72% yield).

¹ H-NMR (CDCl ₃ ) δ ppm: 0.95 (6H, t, J = 7H
z, -CH ₂ CH ₂ CH ₃ × 2), 1.29 (3H, t, J = 7Hz, COOCH ₂ CH ₃ ),
1.70 (4H, m, -CH ₂ CH ₂ CH ₃ × 2), 3.30 (4H,
t, J = 7 Hz, −CH ₂ CH ₂ CH ₃ × 2),
4.24 (2H, q, J = 7 Hz, COO CH ₂ C
_{H 3), 5.26 (2H,} s, N- CH 2 P
h), 7.36 (5H, m , N-CH 2 Ph),
7.48 (1H, s, C5-H), 8.72
(1H, brs, -NH-) Mass (m / z): 372 (M +) mp: 114-115 ℃ Anal:.. C 20 H 28 N 4 O 3 calcd C; 64.49, H; 7.58, N; 15.04 found. C; 64.20, H; 7.60, N; 14.82

Example 16 Synthesis of N, N-diphenyl-N ′-(1-benzyl-4-ethoxycarbonylpyrazol-3-yl) urea The title compound was prepared in the same manner as in Reference Example 1. It was synthesized (3.3% yield).

¹ H-NMR (CDCl ₃ ) δ ppm: 1.12 (3H, t, J = 7H
z, COOCH ₂ CH ₃ ), 4.02 (2H, q, J = 7Hz, COO CH ₂ CH ₃ ), 5.25
(2H, s, N- CH ₂ Ph), 7.30 (15H, m, N-CH ₂ Ph & N (Ph) ₂ ), 7.
51 (1H, s, C5-H), 8.36 (1H, brs, -NH-) Mass (m / z): 440 (M ⁺ ) Melting point: 164-165 ° C

Example 17 N-phenyl-N ′-(4-ethoxycarbonylpyrazo-
Synthesis of l-3-yl) urea 3-amino-4-ethoxycarbonylpyrazole 1.0 g
Was dissolved in 10 ml of THF, and 2.2 g of (Boc) ₂ O was added.
Stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (toluene / ethyl acetate = 15/1) to give 3-amino-1- (te
0.59 g of (rt-butoxycarbonyl) -4-ethoxycarbonylpyrazole was obtained. Using this intermediate raw material, N-phenyl-N ′-(1- (tert-
(Butoxycarbonyl) -4-ethoxycarbonylpyrazol-3-yl) urea was obtained (yield 75%). Then, 0.5 g of this N-phenyl-N '-(1- (tert-butoxycarbonyl) -4-ethoxycarbonylpyrazol-3-yl) urea was dissolved in 7 ml of a 10% trifluoroacetic acid / dichloromethane solution, Stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and ether was added to the residue to give the title compound 0.3
04 g were obtained (yield 83%).

¹ H-NMR (CDCl ₃ ) δ ppm: 1.37 (3H, t, J = 7H
z, COOCH ₂ CH ₃ ), 4.34 (2H, q, J = 7Hz, COO CH ₂ CH ₃ ), 7.14
(1H, t, J = 7Hz, p-Ph), 7.40 (2H, t, J = 8Hz, m-Ph), 7.56
(2H, d, J = 7Hz, o-Ph), 7.86 (1 / 2H, brs, C5-H, D ₂ O
1H), 10.09 (3 / 4H, brs, -NH-) Mass (m / z): 274 (M ⁺ ) Melting point: 257-258 ° C Anal .: C ₁₃ H ₁₄ N ₄ O ₃ calcd. C; 56.93, H; 5.14, N; 20.43 found. C; 56.93, H; 5.11, N; 20.42

Example 18 N-phenyl-N′-benzyl-N ′-(1-benzyl-4)
Synthesis of -ethoxycarbonylpyrazol-3-yl) urea 0.5 g of 3-amino-1-benzyl-4-ethoxycarbonylpyrazole was dissolved in 10 ml of DMF, and 60% NaH 0.082
g was added and stirred at room temperature for 5 minutes. Benzyl bromide
0.307 ml was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
(Toluene / ethyl acetate = 50/1) to obtain 0.3 g of an intermediate raw material, 3-benzylamino-1-benzyl-4-ethoxycarbonylpyrazole. Using the intermediate raw material, the title compound was synthesized in the same manner as in Reference Example 1 (yield 31%).

¹ H-NMR (CDCl ₃ ) δ ppm: 1.26
(3H, t, J = 7 Hz, COOCH ₂ CH ₃ ),
4.20 (2H, q, J = 7 Hz, COO CH _{2
CH 3), 5.04 (2H,} s, 3-N- CH 2
Ph), 5.23 (2H, s , 1- CH 2 P
h), 7.30 (15H, m, N-Ph + 3
_{-N-CH 2 Ph + 1-} CH 2 Ph), 7.90
(1H, s, C5-H) Mass (m / z): 454 (M ⁺ ) Melting point: 116-117 ° C Anal .: C ₂₇ H ₂₆ N ₄ O ₃ calcd. C; 71.35, H; 5.77, N; 12.33 found. C; 71.26, H; 5.83, N; 12.21

Example 19 Synthesis of N-phenyl-N ′-(1-benzyl-4-ethoxycarbonylpyrazol-5-yl) urea The title compound was synthesized according to the method of Reference Example 1. (yield
60%).

¹ H-NMR (CDCl ₃ ) δ ppm: 1.28 (3H, t, J = 7H
z, 4-COOCH ₂ CH ₃ ), 4.20 (2H, q, J = 7Hz, 4-COO CH ₂ CH ₃ ), 5.
48 (2H, s, N- CH ₂ Ph), 7.23 (10H, m, N-CH ₂ Ph + N-Ph),
7.84 (1H, brs, -NH-) , 7.87 (1H, s, C3-H) Mass (m / z): 364 (M +) Anal:.. C 20 H 20 N 4 O 3 calcd C; 65.92, H; 5.53, N; 15.37 found. C; 65.82, H; 5.54, N; 15.29 Melting point: 178-179 ° C

Example 20 Synthesis of N-cyclohexyl-N ′-(1-benzyl-4-ethoxycarbonylpyrazol-5-yl) urea The title compound was synthesized according to the method of Reference Example 1. (yield
96%).

¹ H-NMR (CDCl ₃ ) δ ppm: 0.87
-1.13 (6H, m, c-hex), 1.33
(3H, t, J = 7 Hz, 4-COOCH ₂ C
_{H 3), 1.67 (2H,} m, c-hex),
1.93 (2H, m, c-hex), 3.57
(1H, m, c-hex), 4.25 (2H, q,
_{J = 7Hz, 4-COO CH} 2 CH 3), 5.45
_{(2H, s, N- CH 2} Ph), 7.24 (5
_{H, m, N-CH 2} Ph), 7.51 (1H, s,
—NH—), 7.80 (1H, s, C3-H) Mass (m / z): 370 (M ⁺ ) Melting point: 182-183 ° C.

Example 21 N- (1-benzyl-4-ethoxycarbonylpyrazo-
Synthesis of l-3-yl) urea The title compound was synthesized in the same manner as in Reference Example 1 (96% yield).

¹ H-NMR (CDCl ₃ ) δ ppm: 1.32 (3H, t, 4-C
OOCH ₂ CH ₃ ), 4.29 (2H, q, 4-COO CH ₂ CH ₃ ), 5.16 (2H, s, N
-CH ₂ Ph), 7.45 (5H, m, N-CH ₂ P h ), 7.67 (1H, s, C5-H),
8.15 (1H, brs, -NH-) Mass (m / z): 288 (M +) Anal:.. C 14 H 16 N 4 O 3 · 1/5 H 2 O calcd C; 57.61, H; 5.66, N; 19.19 found. C; 57.73, H; 5.56, N; 19.19 Melting point: 156-157 ° C

Example 22 Inhibitory Effect on Cell Proliferation Stimulated by PDGF Stimulation In order to verify that the pyrazole derivative of the present invention is excellent in the effect of inhibiting cell proliferation induced by PDGF stimulation, PDGF was inhibited similarly to smooth muscle cells. Using fibroblasts in which cell proliferation was induced by stimulation, the inhibition / inhibition rate of cell proliferation induced by PDGF was evaluated by the following method.

[Test Method] B was previously placed in a 96-well plate.
ALB / c 3T3 cells were seeded at ³ to 5 × 10 ³ cells / well, and as a culture medium, Dulbecco's modified Eagle's medium (DME medium) with high glucose and + 10% fetal bovine serum (FBS) were added. The cells were cultured for 3 days to confluence. After removing the medium, the medium was replaced with a high glucose-added DME medium supplemented with 0.5% platelet-poor plasma (PPP), and the cells were further cultured for 24 hours.

To remove the medium and induce cell proliferation upon PDGF stimulation, 10 ng / ml of PDGF-AA or PDGF-AA
The medium was replaced with a high glucose DME medium supplemented with BB. Also, add a predetermined amount of the test substance previously dissolved in DMSO, and add
The cells were cultured for 6 hours. Then, ³ H-thymidine (1 mCi / ml) was added.
A solution diluted 20-fold with phosphate buffered saline containing no Ca ²⁺ and Mg ²⁺ was added at 20 μl / well, followed by culturing for 4 hours. The final concentration of DMSO was adjusted to 0.25% or less.

Thereafter, the ³ H-thymidine remaining in the medium was washed away, the cells on the plate were detached with trypsin / EDTA, and the cells were harvested with a cell harvester. Using the harvested sample, the total amount of ³ H-thymidine incorporated into the cells was counted using a liquid scintillation counter.

As a reference group, the same culture was performed under the condition that only an equal amount of DMSO was added, that is, the test substance was not added, and the total amount of ³ H-thymidine incorporated in the cells was measured. Based on the total amount of ³ H-thymidine incorporation when the test substance was not added, and the difference between this and the measured value when the test substance was added, the growth inhibition rate was calculated.

Table 1 shows an example of the evaluation results for the pyrazole derivative of the present invention. Trapidyl (5-methyl-7-diethylamino) has been reported to exhibit an inhibitory / inhibitory effect on smooth muscle cell proliferation induced by PDGF stimulation.
-s-triazole [1,5-a] pyrimidine; Life Scie
nces, 28 , 1641-1646 (1981), etc.) and tranilast (N- (3,4-dimethoxycinnamoyl) anthranilic acid; see Clinical Medicine, 12 , 65-85 (1996), etc.). The compound was used as a positive control, and the results are shown in Table 1.
Shown in

[0096]

[Table 1]  

The pyrazole derivative of the present invention is PDGF
It was also separately confirmed that, when no stimulation was induced by cell growth factors such as those described above, the effect of suppressing natural cell growth was not exhibited at an added concentration of 100 μM or less.

(Example 23) [Preparation Example] As the smooth muscle cell proliferation inhibitor of the present invention, a tablet can be produced as follows. Using the compound of Example 1 as an active ingredient, it was uniformly mixed with lactose, corn starch, and polyvinylpyrrolidone in the composition shown in Table 2 below, and formed into 100 mg tablets according to a conventional method.

[0099]

[Table 2] Formulation composition  Compound of Example 1 10 g Lactose 100 g Corn starch 50 g Polyvinylpyrrolidone 20 g

Example 24 Inhibitory Effect on PDGF Stimulated Proliferation of Smooth Muscle Cells The pyrazole derivative of the present invention has an excellent effect of inhibiting cell proliferation induced by PDGF stimulation on smooth muscle cells. For the purpose of verifying that, the inhibition / inhibition rate of the proliferation of coronary artery smooth muscle cells induced by PDGF was evaluated by the following method.

[Test Method] Human coronary artery smooth muscle cells were previously placed in a 96-well plate.
scle cells) at 2 × 10 ⁴ cells / well, FBS (5%), E in basal medium (SmGM-2: Iwaki Glass Co., Ltd.)
GF (0.5 ng / ml), insulin (5 μg / ml) and bas
The cells were cultured for 24 hours using a complete medium supplemented with ic-FGF (2 ng / ml) to bring the cells to confluence. After removing the above-mentioned medium, the cells were replaced with a basal medium containing no various additives and cultured for 24 hours to introduce the cells into the stationary phase.

The medium was removed and replaced with a basal medium supplemented with 20 ng / ml PDGF-BB to induce cell growth upon PDGF stimulation. Further, a predetermined amount of a test substance previously dissolved in DMSO was added, and the cells were cultured for 16 hours. Then, similarly using ³ H- thymidine in Example 22, as an indicator gene DNA synthesis associated with cell proliferation was assessed inhibition rate for cell growth. From the evaluation results, the addition concentration IC ₅₀ value for suppressing the cell proliferation rate by PDGF stimulation to 50% of the reference group to which no test substance was added was calculated. Table 3 shows an example of the evaluation results for the pyrazole derivative of the present invention. As a positive control, the results of the same evaluation for tranilast are also shown.

[0103]

Table 3 Test substance IC ₅₀ value (μM) Example 1 2.3 Example 2 3.1 Example 3 1.5 Example 8 1.3 Example 15 2.2 Example 16 1.1 Example 18 3.0 Tranilast 5.0

Incidentally, the pyrazole derivative of the present invention is
It was also separately confirmed that the effect of suppressing natural cell growth in the presence of% FBS was scarcely exhibited at an added concentration of 10 μM or less.

[0105]

The pyrazole derivative of the present invention is
It exhibits excellent inhibitory effects on smooth muscle cell proliferation induced by cell growth factors such as, for example, vascular restenosis after percutaneous coronary dilatation, percutaneous arterial dilatation Suitable and useful for the prevention and treatment of diseases in which proliferation of smooth muscle cells induced by cell growth factors is a fundamental factor, such as vascular restenosis, membrane proliferative nephritis, arteriosclerotic disease, diabetes, hypertension, etc. It is.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/415 ADP A61K 31/415 ADP AED AED (72) Inventor Yoichi Oba 3-17-3 Nisominami, Toda City, Saitama Prefecture Shares Japan Energy Co., Ltd. (72) Inventor Hiroyuki Morita 2-10-1, Toranomon, Minato-ku, Tokyo Co., Ltd. Japan Energy Co., Ltd. (72) Inventor Haruo Takaku 3--17-17 Nishinamiminami, Toda City, Saitama Japan Inside Energy (72) Inventor Shinsuke Chiba 3-17-35 Niisominami, Toda City, Saitama Japan Inside Japan Energy Co., Ltd.

Claims (4)

[Claims] 1. The following general formula (I): Or the following general formula (II): (In the formulas (I) and (II), R ¹ represents a hydrogen atom, a linear or branched alkyl group having 2 to 6 carbon atoms, a benzyl group or a phenyl group, R ² represents a hydrogen atom, R ³ represents a linear or branched alkyl group having 1 to 6 carbon atoms or a benzyl group; R ³ represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms or a benzyl group, ⁴ and R ⁵ are a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkenyl group having 3 to 6 carbon atoms, or a cycloalkyl group having 3 to 8 carbon atoms , A benzyl group or a phenyl group, and X represents an oxygen atom or a sulfur atom, provided that R ¹ is a benzyl group, R ² is an ethyl group, and R ³
When selecting a hydrogen atom for R ⁴ and a hydrogen atom for R ⁴ , R
⁵ is a hydrogen atom, a straight-chain or branched C2-C2
6 alkyl groups, linear or branched, having 3 to 3 carbon atoms
An alkenyl group of 6, a cycloalkyl group having 3 to 8 carbon atoms or a benzyl group is selected. Or a pharmacologically acceptable salt thereof. 2. A smooth muscle cell proliferation inhibitor comprising the pyrazole derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 3. A pharmaceutical composition for preventing or treating diseases caused by proliferation of smooth muscle cells, comprising the pyrazole derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 4. Diseases caused by smooth muscle cell proliferation are vascular restenosis occurring after percutaneous coronary dilation, vascular restenosis occurring after percutaneous arterial dilatation, membrane proliferative nephritis,
The pharmaceutical composition according to claim 3, which is any of arteriosclerotic diseases, hypertension and diabetes.