JPH10101672A - Adenosine enhancer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare an adenosine enhancer utilizable as a preventing and curing agent for cardiac infarction or cerebral infarction or a preventing agent for angina pectoris by containing a pyrazolo[1,5-a] pyrimidine derivative as an active component together with a carrier. SOLUTION: This enhancer is obtained by containing at least one kind selected from a pyrazolo[1,5-a]pyrimidine derivative expressed by the formula I [R<1> is H, a (substituted) lower alkyl, a (substituted) phenyl, etc.; R<2> is naphthyl, a cycloalkyl, furyl, etc.; R<3> is H, phenyl or a lower alkyl; R<4> is H, a lower alkyl, a (substituted) phenyl, etc.; R<5> is H or a lower alkyl; R<6> is H, a lower alkyl, etc.; Q is a carbonyl or sulfonyl; A is a single bond, a lower alkylene, etc.; (n) is 0 or 1] and the one expressed by the formula II (R<11> is a lower alkyl; R<22> is a lower alkoxy-substituted phenyl; R<33> , R<44> and R<55> are each H; Z is a lower alkylene) as an active component together with a non-toxic carrier.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel adenosine enhancer.

[0002]

2. Description of the Related Art Myocardial infarction and cerebral infarction are known as diseases that increase with aging. It is said that these diseases are caused by the tissue becoming ischemic due to occlusion or narrowing of blood vessels.In general, when the tissue, especially the heart, enters an ischemic state, the blood flow pressure is reduced. The microvessels dilate and exert their autoregulatory ability to maintain a constant blood flow. It has been elucidated that adenosine plays an important role in this autoregulatory function as a regulator (J. Physio).
l., 204, 317 (1963)].

That is, in the ischemic myocardium, adenosine is produced from ATP (adenosine triphosphate), which is an energy source, and this adenosine expands arterioles.

[0004] Adenosine is also known to exhibit an angiogenesis effect and a platelet aggregation inhibitory effect in addition to the above-mentioned arteriole dilatation effect, and also plays a role in protecting ischemic myocardium and reducing reperfusion injury. .

[0005] Regenerated adenosine is taken up by erythrocytes and cardiomyocytes, and is rapidly destroyed by enzymatic degradation, but it suppresses this and maintains the adenosine concentration in the interstitial space. Adenosine enhancer
Recently developed. Typical examples thereof include dipyridamole and dilazep, which are used as adjuvants such as nitrites and calcium antagonists, and are being studied for use as preventive agents for angina attack. .

[0006]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel adenosine enhancing action which is structurally unrelated to the above-mentioned known compounds having an adenosine enhancing action and which has almost no side effects observed in these compounds. And to provide an adenosine enhancer using the same.

The research group of the present inventors has long been engaged in the synthesis of various compounds and the study and elucidation of their pharmacological actions for the purpose of developing active compounds for pharmaceutical preparations. Have succeeded in synthesizing a series of pyrazolopyrimidine derivatives having a powerful analgesic effect, and filed a patent application for an invention relating to these compounds (WO95 / 3).
No. 5298 and WO 97/11946).

[0008] In subsequent studies, the present inventors have found that the above series of compounds has an adenosine potentiating action independently of and independently of their analgesic action, and they have marked side effects. It is newly found that it is reduced,
Here, the present invention has been completed.

[0009]

That is, according to the present invention, at least one selected from pyrazolo [1,5-a] pyrimidine derivatives represented by the following general formulas (1) and (2) is used as an active ingredient. Is provided.

[0010]

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In the above formula (1), R ¹ is a hydrogen atom, a lower alkyl group which may have a thienyl group, a lower alkoxy group, a lower alkylthio group, an oxo group, a carboxyl group or a hydroxyl group as a substituent, a cycloalkyl group. group, a thienyl group, a furyl group, a lower alkyl group as a lower alkenyl group or a substituted group, a lower alkoxy group, a phenyl group which may have 1 to 3 groups selected from phenylthio group and a halogen atom, R ² is naphthyl Group, a cycloalkyl group, a furyl group, a thienyl group, a pyridyl group that may be substituted with a halogen atom, a phenoxy group that may be substituted with a halogen atom or a lower alkyl group, a lower alkoxy group, a halogen atom, Nitro group, halogen-substituted lower alkyl group, halogen-substituted lower alkoxy group, lower alkyl A phenyl group having from 1 to 3 groups selected from a carbonyl group, a hydroxyl group, a phenyl lower alkoxy group, an amino group, a cyano group, a lower alkanoyloxy group, a phenyl group and a di-lower alkoxyphosphoryl lower alkyl group. R ³ is a hydrogen atom, a phenyl group or a lower alkyl group, R ⁴ is a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, a phenyl lower alkyl group, a phenyl group or a halogen which may have a phenylthio group as a substituent. Atom to R ⁵
Represents a hydrogen atom or a lower alkyl group, and R ⁶ has 1 to 3 hydrogen atoms, a lower alkyl group, a phenyl lower alkyl group or a group selected from a lower alkoxy group, a halogen-substituted lower alkyl group, and a halogen atom as a substituent. A benzoyl group; R ¹ and R ⁵ may combine with each other to form a lower alkylene group; Q represents a carbonyl group or a sulfonyl group; and A represents a single bond, a lower alkylene group or a lower alkenylene group, respectively. , N represents 0 or 1.

[0012]

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In the general formula (2), R ¹¹ is a lower alkyl group, R ²² is a phenyl group having 1 to 3 lower alkoxy groups as substituents, and R ³³ , R ⁴⁴ and R ⁵⁵ are each hydrogen. And Z represents a lower alkylene group.

Each of the derivatives represented by the above general formulas (1) and (2) exhibits an excellent adenosine enhancing action, and furthermore, nausea and headache, which are apt to occur in conventional substances having this kind of adenosine enhancing action. It is characterized in that it hardly shows any side effects such as dizziness and hot feeling.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION As each group in the general formula (1) representing an active ingredient of the adenosine enhancer of the present invention, for example, the following groups can be exemplified. That is, examples of the lower alkyl group include linear or branched lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl groups.

Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Examples include cycloheptyl and cyclooctyl groups.

Examples of the lower alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy and the like.

Examples of the lower alkylthio group include a methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio group and the like.

The halogen atom includes fluorine, chlorine, bromine and iodine atoms.

Examples of the halogen-substituted lower alkyl group include trifluoromethyl, pentafluoroethyl, heptafluoropropyl, nonafluorobutyl, undecafluoropentyl, and tridecafluorohexyl.

The halogen-substituted lower alkoxy group includes
Examples thereof include trifluoromethoxy, pentafluoroethoxy, heptafluoropropoxy, nonafluorobutoxy, undecafluoropentyloxy, and tridecafluorohexyloxy groups.

Examples of the lower alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

Examples of the di-lower alkoxyphosphoryl lower alkyl group include dimethoxyphosphorylmethyl, diethoxyphosphorylmethyl, dipropoxyphosphorylmethyl, diisopropoxyphosphorylmethyl, dibutoxyphosphorylmethyl, dipentyloxyphosphorylmethyl, dihexyloxyphosphorylmethyl, (Dimethoxyphosphoryl) ethyl, 2- (diethoxyphosphoryl) ethyl,
Examples thereof include a 3- (diethoxyphosphoryl) propyl group.

The naphthyl group includes 1-naphthyl and 2-naphthyl groups.

Examples of the lower alkylene group include a methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene group and the like.

As the lower alkenylene group, vinylene,
Examples thereof include a propenylene group.

Examples of the pyridyl group which may be substituted with a halogen atom include 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-chloro-2-pyridyl, 5-chloro-2-
Pyridyl, 4-chloro-2-pyridyl, 3-chloro-2
-Pyridyl, 6-chloro-3-pyridyl, 5-chloro-
3-pyridyl, 4-chloro-3-pyridyl, 2-chloro-3-pyridyl, 2-chloro-4-pyridyl, 3-chloro-4-pyridyl, 6-fluoro-3-pyridyl, 6-
Examples thereof include a bromo-3-pyridyl group and a 6-iodo-3-pyridyl group.

Examples of the phenoxy group which may be substituted by a halogen atom include phenoxy, 2-chlorophenoxy, 3-chlorophenoxy, 4-chlorophenoxy,
-Fluorophenoxy, 4-bromophenoxy, 4-iodophenoxy and the like.

The thienyl group includes 2-thienyl and 3-thienyl groups, and the furyl group includes 2-furyl and 3-furyl groups.

The lower alkenyl group includes vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3
-Butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl group and the like.

Examples of the phenyl lower alkyl group include a benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl group and the like.

Examples of the phenyl lower alkoxy group include benzyloxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy and the like.

Examples of the lower alkanoyloxy group include acetoxy, propionyloxy, butyryloxy, valeryloxy, pivaloyloxy, hexanoyloxy, heptanoyloxy and the like.

The lower alkyl group which may have a thienyl group, a lower alkoxy group, a lower alkylthio group, an oxo group, a carboxyl group or a hydroxyl group as a substituent includes 2-thienyl in addition to the unsubstituted lower alkyl group. Methyl, 3-thienylmethyl, 1- (2-thienyl) ethyl, 1- (3-thienyl) ethyl, 2- (2-
Thienyl) ethyl, 2- (3-thienyl) ethyl, 3-
(2-thienyl) propyl, 4- (2-thienyl) butyl, 5- (2-thienyl) pentyl, 6- (2-thienyl) hexyl, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, pentyloxymethyl, Hexyloxymethyl, 1-methoxyethyl, 2-
Methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl, 6-methoxyhexyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl , 3-hydroxybutyl, 4-hydroxypentyl, 5-hydroxyhexyl, methylthiomethyl, ethylthiomethyl, propylthiomethyl, butylthiomethyl, pentylthiomethyl, hexylthiomethyl, 2-methylthioethyl, 3-
Methylthiopropyl, 4-methylthiobutyl, 5-methylthiopentyl, 6-methylthiohexyl, formyl,
Formylmethyl, acetyl, 2-formylethyl, 2-
Oxopropyl, propionyl, 3-formylpropyl, 3-oxobutyl, 2-oxobutyl, butyryl,
4-formylbutyl, 4-oxopentyl, 3-oxopentyl, 2-oxopentyl, valeryl, 5-formylpentyl, 5-oxohexyl, 4-oxohexyl, 3-oxohexyl, 2-oxohexyl, hexanoyl, carboxy Methyl, 2-carboxyethyl, 3
-Carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl and the like.

The phenyl group which may have 1 to 3 groups selected from a lower alkyl group, a lower alkoxy group, a phenylthio group and a halogen atom as a substituent includes:
Phenyl, 2-methylphenyl, 3-methylphenyl,
4-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-butylphenyl, 4-t-butylphenyl, 4-pentylphenyl, 4-hexylphenyl,
2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2-methoxyphenyl, 3-methoxy Phenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4
-Propoxyphenyl, 4-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl,
2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxy Phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-fluorophenyl, 4- (phenylthio) phenyl, 3- (phenylthio) phenyl, 2- (phenylthio) phenyl group Etc. can be exemplified.

As a substituent, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, a halogen-substituted lower alkyl group, a halogen-substituted lower alkoxy group, a lower alkoxycarbonyl group, a hydroxyl group, a phenyl-lower alkoxy group, an amino group, a cyano group Examples of the phenyl group which may have 1 to 3 groups selected from a lower alkanoyloxy group, a phenyl group and a di-lower alkoxyphosphoryl lower alkyl group include the following groups.

That is, phenyl, 2-methylphenyl, 3
-Methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-butylphenyl,
4-t-butylphenyl, 4-pentylphenyl, 4-
Hexylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 2,3-dimethoxy Phenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6
-Dimethoxyphenyl, 3,4-dimethoxyphenyl,
3,5-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl, 2,
3,6-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 2,4,6-trimethoxyphenyl,
3,4,5-trimethoxyphenyl, 3,4,5-triethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromo Phenyl, 3-bromophenyl, 4-bromophenyl, 4-iodophenyl, 2,3-dichlorophenyl,
2,4-dichlorophenyl, 2-nitrophenyl, 3-
Nitrophenyl, 4-nitrophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,
4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-heptafluoropropylphenyl, 4-nonafluorobutylphenyl, 4-undecafluoropentylphenyl, 4-tridecafluorohexylphenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 4-ethoxycarbonylphenyl, 4-propoxycarbonylphenyl, 4-butoxycarbonylphenyl, 4-pentyloxycarbonylphenyl, 4-hexyloxycarbonylphenyl, 2-biphenyl,
-Biphenyl, 4-biphenyl, 2- (diethoxyphosphorylmethyl) phenyl, 3- (diethoxyphosphorylmethyl) phenyl, 4- (diethoxyphosphorylmethyl) phenyl, 4- (dimethoxyphosphorylmethyl) phenyl, 4- (dimethoxyphosphorylmethyl) phenyl Isopropoxyphosphorylmethyl) phenyl, 3,5-dimethoxy-4-ethoxyphenyl,
3,5-dimethoxy-4-propoxyphenyl, 4-butoxy-3,5-dimethoxyphenyl, 3,5-dimethoxy-4-pentyloxyphenyl, 3,5-dimethoxy-4-hexyloxyphenyl, 2,3- Bis (trifluoromethyl) phenyl, 2,4-bis (trifluoromethyl) phenyl, 2,5-bis (trifluoromethyl) phenyl, 2,6-bis (trifluoromethyl) phenyl, 3,4-bis ( Trifluoromethyl) phenyl, 3,5-bis (trifluoromethyl) phenyl,
3,5-dimethoxy-4-hydroxyphenyl, 3,5
-Diethoxy-4-hydroxyphenyl, 3,5-dipropoxy-4-hydroxyphenyl, 4-benzyloxy-3,5-dimethoxyphenyl, 4-benzyloxy-3,5-diethoxyphenyl, 3,5-dimethoxy-
4- (2-phenylethoxy) phenyl, 4-acetoxy-3,5-dimethoxyphenyl, 3,5-dimethoxy-4-propionyloxyphenyl, 2-chloro-3,
5-dimethoxyphenyl, 4-chloro-3,5-dimethoxyphenyl, 4-bromo-3,5-dimethoxyphenyl, 3,5-dimethoxy-4-iodophenyl, 3,5
-Dichloro-4-methoxyphenyl, 3,5-dichloro-4-ethoxyphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, -Trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 4-
Pentafluoroethoxyphenyl, 4-heptafluoropropoxyphenyl, 4-nonafluorobutoxyphenyl, 4-undecafluoropentyloxyphenyl, 4
-Tridecafluorohexyloxyphenyl, 3,5-
Bis (trifluoromethoxy) phenyl, 3,4,5-
A tris (trifluoromethoxy) phenyl group and the like can be exemplified.

The phenyl group which may have a phenylthio group as a substituent includes phenyl, 4- (phenylthio) phenyl, 3- (phenylthio) phenyl, 2- (phenylthio) phenyl,
A (phenylthio) phenyl group can be exemplified.

The benzoyl group having 1 to 3 groups selected from a lower alkoxy group, a halogen-substituted lower alkyl group and a halogen atom as a substituent includes 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, -Fluorobenzoyl, 2-bromobenzoyl,
2-iodobenzoyl, 2,4-dichlorobenzoyl,
3,4-dichlorobenzoyl, 2,5-dichlorobenzoyl, 2,6-dichlorobenzoyl, 2-trifluoromethylbenzoyl, 3-trifluoromethylbenzoyl, 4-trifluoromethylbenzoyl, 3,5-bis (trifluoro Methyl) benzoyl, 3,4,5-tris (trifluoromethyl) benzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 2,3-dimethoxybenzoyl, 2,4-dimethoxybenzoyl, 3,5 -Dimethoxybenzoyl,
Examples thereof include 3,4,5-trimethoxybenzoyl, 2-ethoxybenzoyl, 2-propoxybenzoyl, 2-butoxybenzoyl, 2-pentyloxybenzoyl, and 2-hexyloxybenzoyl groups.

As each group in the general formula (2) representing the active ingredient of the adenosine enhancer of the present invention, for example, the following groups can be exemplified. That is, as the lower alkyl group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Examples thereof include linear or branched lower alkyl groups such as tert-butyl, pentyl, and hexyl groups.

The lower alkylene group includes methylene, ethylene, ethylidene, trimethylene, tetramethylene,
Pentamethylene, hexamethylene and the like can be exemplified.

The phenyl group having 1 to 3 lower alkoxy groups as a substituent includes 2-methoxyphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 2,4-dimethoxyphenyl, 3,
4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,4,5-trimethoxyphenyl, 3,4,5-
Examples thereof include a trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 4-ethoxy-3,5-dimethoxyphenyl group and the like.

The pyrazolo [1,5-a] pyrimidine derivatives represented by the general formulas (1) and (2) are useful as adenosine enhancers, for example, in the treatment and prevention of myocardial infarction and cerebral infarction. In addition, the derivative does not have side effects that are common to conventional adenosine enhancers, and does not cause hallucinations, confusion, or cause addiction or habit.

The pyrazolo [1,5-a] pyrimidine derivative which is preferable as the adenosine enhancer active ingredient is a compound represented by the general formula (2), wherein R ⁴ , R ⁵ and R ⁶ are a hydrogen atom, Q is a carbonyl group, Compounds of the general formula (1) wherein A is a single bond and n is 0 can be exemplified.

Among these preferred pyrazolo [1,5-a] pyrimidine derivatives, (a) a compound of the general formula (1) wherein R ² is a phenyl group having three lower alkoxy groups as substituents, and Compounds of the general formula (2) in which R ²² is a phenyl group having three lower alkoxy groups as substituents are more preferred, and among them, compounds in which R ¹ is an n-propyl group or an n-butyl group Compounds of the formula (1) and compounds of the general formula (2) in which R ¹¹ is n-butyl are particularly preferred.

Specific examples of the most preferred pyrazolo [1,5-a] pyrimidine derivative include 5-n-butyl-7-
(3,4,5-trimethoxybenzoylamino) pyrazolo [1,5-a] pyrimidine, 5-n-propyl-7-
(3,4,5-trimethoxybenzoylamino) pyrazolo [1,5-a] pyrimidine, 5-n-butyl-2-methyl-7- (3,4,5-trimethoxybenzoylamino) pyrazolo [1, 5-a] pyrimidine, and 5-n-
Butyl-7- (3,4,5-trimethoxybenzoyloxy) pyrazolo [1,5-a] pyrimidine can be exemplified, and among them, 5-n-butyl-7- (3,4,
5-trimethoxybenzoylamino) pyrazolo [1,5
-A] pyrimidine is optimal.

The active ingredient compound of the present invention represented by the general formula (1) can be produced by various methods, and specific examples thereof include the method described in the above-mentioned WO 95/35298. it can.

Typically, an appropriate carboxylic acid ester is condensed with a 3-aminopyrazole to obtain 7-hydroxypyrazolo [1,5-a] pyrimidine, which is then halogenated to give 7-hydroxypyrazolo [1,5-a] pyrimidine. Halogenopyrazolo [1,5-
a) Pyrimidines, which are further treated with aqueous ammonia or hydrazine to be converted into the 7-amino form, and reacted with a halide to obtain the active ingredient compound of the present invention.

The active ingredient compound of the present invention represented by the general formula (2) can also be produced by various methods. As a specific example, for example, the aforementioned WO 97/119
The method described in JP-A-46-46 can be exemplified.

Typically, 7-halogenopyrazolo [1,5-a] pyrimidines are obtained in the same manner as in the above-mentioned compound of the general formula (1), and an appropriate alcohol derivative is reacted therewith to obtain a compound of the general formula (1). The active ingredient compound of the present invention represented by (2) can be obtained.

Specific examples of the active ingredient compounds of the adenosine enhancer of the present invention thus obtained include the compounds shown in Examples 1 to 136 in Tables 1 to 6 below.

[0052]

[Table 1]

[0053]

[Table 2]

[0054]

[Table 3]

[0055]

[Table 4]

[0056]

[Table 5]

[0057]

[Table 6]

[0058]

[Table 7]

[0059]

[Table 8]

[0060]

[Table 9]

[0061]

[Table 10]

[0062]

[Table 11]

[0063]

[Table 12]

[0064]

[Table 13]

[0065]

[Table 14]

[0066]

[Table 15]

[0067]

[Table 16]

[0068]

[Table 17]

[0069]

[Table 18]

Each of the compounds represented by the general formulas (1) and (2) can be pharmaceutically acceptable acid addition salts, and these salts are also used as the active ingredient compounds of the adenosine enhancer of the present invention. Is included. Examples of the acid capable of forming the acid addition salt include inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, tartaric acid, and citric acid. The salt formation reaction can be performed according to a conventional method.

In the compounds represented by the general formula (1), those in which R ⁶ is a hydrogen atom can be converted into an alkali metal salt such as a sodium salt, a potassium salt or the like according to a conventional method.
Alkaline earth metal salts, for example, calcium salts, magnesium salts, etc., and other copper salts, etc., are also included in the active ingredient compound of the adenosine enhancer of the present invention.

In the compound represented by the general formula (1),
Some of the compounds in which A is an alkenylene group and some of the compounds in which R1 is a lower alkenyl group can have a cis or trans isomer structure, and the adenosine enhancer of the present invention requires any of these as an active ingredient. Can be.

Some of the compounds represented by the general formula (1) have optical isomers having an asymmetric center at a carbon atom, and the adenosine enhancer of the present invention is an optically active substance and a racemic substance. Any of these can be the active ingredient.

The adenosine enhancer of the present invention has the general formula (1)
And at least one compound selected from the compounds represented by general formula (2) as an active ingredient, which is used together with a suitable non-toxic pharmaceutical carrier to form a general pharmaceutical preparation composition and Is done.

The above-mentioned pharmaceutical carriers used in the pharmaceutical preparation of the present invention include fillers, extenders, binders, humectants, disintegrants, surfactants and the like which are usually used depending on the use form of the preparation.
Diluents or excipients such as lubricants can be exemplified, and these are appropriately selected and used depending on the dosage unit form of the obtained preparation.

As the dosage unit form of the pharmaceutical preparation, various forms can be selected according to the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, Capsules, suppositories, injections (solutions, suspensions, etc.),
Ointments and the like.

In the case of molding into a tablet form, the above-mentioned preparation carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, potassium phosphate and the like.
Water, ethanol, propanol, single syrup, glucose solution, starch solution, gelatin solution, binders such as carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, dried Disintegrants such as starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, surfactants such as polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, and monoglyceride stearate; sucrose, stearin, cocoa butter; Disintegration inhibitors such as hydrogenated oil, quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, glycerin, starch and the like Moisturizers, starch, lactose, kaolin, bentonite, adsorbent such as colloidal silicic acid, purified talc, stearates, boric acid powder, a lubricant such as polyethylene glycol can be used. Further, the tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double tablets or multilayer tablets.

In the case of molding into the form of pills, pharmaceutical carriers such as glucose, lactose, starch, cocoa butter,
Excipients such as hardened vegetable oil, kaolin and talc, gum arabic powder, tragacanth powder, binders such as gelatin and ethanol, and disintegrants such as laminaran and agar can be used.

For shaping in the form of suppositories, for example, polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides and the like can be used as pharmaceutical carriers.

Capsules are prepared by mixing the active ingredient compound of the present invention with the various pharmaceutical carriers exemplified above and filling the mixture into hard gelatin capsules, soft capsules and the like according to a conventional method.

When prepared as injections such as solutions, emulsions, suspensions, etc., they are preferably sterilized and isotonic with blood. When formed into such a form, for example, Water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, a sufficient amount of salt, glucose or glycerin to adjust the isotonic solution may be contained in the drug of the present invention, and ordinary solubilizers, buffers, soothing agents and the like are added. May be.

Further, the pharmaceutical composition of the present invention may contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent and the like, if necessary.

For shaping into the form of an ointment such as a paste, cream or gel, for example, white vaseline, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like can be used as a diluent.

The amount of the active ingredient compound represented by the general formula (1) or (2) to be contained in the drug of the present invention is not particularly limited and may be appropriately selected from a wide range. It is preferable to contain about 1 to 70% by weight.

The method of administration of the pharmaceutical preparation is not particularly limited, and is determined according to various preparation forms, age, sex and other conditions of the patient, degree of disease, and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are orally administered, and injections are administered intravenously, alone or as a mixture with ordinary replenishers such as glucose and amino acids. Intramuscularly, intradermally, subcutaneously or intraperitoneally, and suppositories may be administered rectally alone.

The dose of the above pharmaceutical preparation is appropriately selected depending on the usage, age, sex and other conditions of the patient, the degree of the disease and the like.
The dosage is preferably about 0.5 to 20 mg per kg of body weight per day, and the preparation can be administered in 1 to 4 times a day.

[0087]

EXAMPLES Hereinafter, in order to explain the present invention in more detail, preparation examples of the adenosine enhancer of the present invention will be described, followed by pharmacological test examples.

[0088]

Preparation Example 1 Preparation of Capsule As an active ingredient compound, 5-n-butyl-7- (3,
Using 4,5-trimethoxybenzoylamino) pyrazolo [1,5-a] pyrimidine, a hard gelatin capsule (1000 mg per capsule) containing 250 mg per capsule.
Was prepared according to the following formula.

Active ingredient compound 250 g Microcrystalline cellulose (Japanese Pharmacopoeia product) 30 g Corn starch (Japanese Pharmacopoeia product) 17 g Talc (Japanese Pharmacopoeia product) 2 g Magnesium stearate (Japanese Pharmacopoeia product) 1 g That is, each component is finely powdered. After thoroughly mixing the mixture into a homogeneous mixture, the mixture was filled into gelatin capsules for oral administration having desired dimensions to prepare the desired capsule.

[0090]

Preparation Example 2 Preparation of Tablet As an active ingredient compound, 5-n-butyl-7- (3,
Using 4,5-trimethoxybenzoylamino) pyrazolo [1,5-a] pyrimidine, 300 tablets per tablet
Tablets containing 2000 mg (2000 tablets) were prepared according to the following formulation.

Active ingredient compound 600 g Lactose (Japanese Pharmacopoeia) 67 g Corn starch (Japanese Pharmacopoeia) 33 g Carboxymethylcellulose calcium (Japanese Pharmacopoeia) 25 g Methylcellulose (Japanese Pharmacopoeia) 12 g Magnesium stearate (Japanese Pharmacopoeia) 3g That is, according to the above formula, the active ingredient compound, lactose, corn starch and carboxymethylcellulose calcium were sufficiently mixed, the mixture was granulated with an aqueous methylcellulose solution, passed through a 24-mesh sieve, and mixed with magnesium stearate. The target tablets were prepared by pressing the tablets.

[0092]

[Pharmacological Test Example 1] A male Hartley guinea pig (10 weeks old, 400 to 450 g) was sacrificed by cervical dislocation, the ileum was taken out, and the surrounding tissue was peeled off. The ileum was cut into 3-4 cm lengths, and Krebs-Henseleit solution (NaCl 118 mM, KCl 4.7 mM, C
aCl ₂ 2.5 mM, KH ₂ PO ₄ 1.2 mM, Mg
The suspension was suspended under a pressure of 1 g in an organ bath containing 10 ml of SO _{4 (} 1.2 mM, NaHCO ₃ 25 mM, glucose 11 mM), and an O ₂ / CO ₂ (95% / 5%) mixed gas was continuously ventilated.

The ileum was subjected to 25 V electrical stimulation at 0.1 Hz.
Adenosine in the organ bath at 10 ^-8 M
Is added cumulatively from, and the contraction-like contraction due to electrical stimulation is 1
The adenosine concentration that was suppressed by 00% was determined (control group).

The contraction-like contraction was measured by an isotonic transducer (manufactured by Nihon Kohden, TD-
111T) and measure with a recorder (NIHON DENSI KAGA
KU, U-228).

On the other hand, 30 minutes before adding adenosine,
5-n-butyl-7- (3,4,5-trimethoxybenzoylamino) pyrazolo [1,5-a] pyrimidine
0 ⁻⁶ M (the present invention group 1) or 3 × 10 ⁻⁶ M (the present invention group 2) was added to the organ bath, and the concentration of adenosine at which the contraction-like contraction due to electrical stimulation was inhibited by 100% was determined. Was determined in the same manner.

As a result, the adenosine concentration at which the contraction was suppressed by 100% was 10 ⁻⁶ M in the present invention group 1 and 3 ⁻⁶ M in the present invention group 2.
× 10 ^-7 M, which were reduced to 1/3 and 1/10, respectively, compared to the control group. From this, it became clear that the active ingredient compound of the present invention exhibited an excellent adenosine enhancing action.

[0097]

Pharmacological Test Example 2 Male Hartley guinea pigs (10 weeks old, 400 to 450 g) were sacrificed by cervical dislocation, the heart was taken out, and the atrium was separated. After confirming that the atrium is contracting spontaneously, this is
Henselite solution (NaCl 118 mM, KCl 4.
7 mM, CaCl ₂ 2.5 mM, KH ₂ PO ₄ 1.2
mM, MgSO ₄ 1.2 mM, NaHCO ₃ 25 m
M, glucose 11 mM) was suspended under a pressure of 1 g in an organ bath containing 10 ml of O ₂ / CO ₂ (95% / 5%).
The gas mixture was continuously vented.

Adenosine was cumulatively added to the organ bath from 3 × 10 ⁻⁷ M, and the adenosine concentration at which the spontaneous contraction of the atrium began to be suppressed was determined (control group).

Incidentally, the spontaneous contraction of the atria was measured by an isotonic transducer (manufactured by Nihon Kohden,
TD-111T) and measured with a biological amplifier (Nihon Kohden,
After amplification with TB-611T), the recorder (NIHON DE
NSI KAGAKU, U-228).

On the other hand, 10 minutes before adding adenosine,
5-n-butyl-7- (3,4,5-trimethoxybenzoylamino) pyrazolo [1,5-a] pyrimidine was added to 3
× 10 ⁻⁶ M (the present invention group 1) or 10 ⁻⁵ M (the present invention group 2) was added to the organ bath, and the adenosine concentration at which spontaneous contraction of the atrium was suppressed was determined in the same manner as described above. Was.

[0102] As a result, adenosine concentrations shrinkage begins to be 100% inhibition, 3 × 10 ^-7 M in the present invention group 1, in the present invention group 2 10 ^-7 M, and the respectively compared to the control group 1 /
It decreased to 10 and 1/30. From this, it became clear that the active ingredient compound of the present invention exhibited an excellent adenosine enhancing action.

[0102]

Pharmacological Test Example 3 Male Hartley guinea pigs (10 weeks old, 350 to 400 g) were sacrificed by cervical dislocation, the ileum was taken out, the contents and unnecessary tissues were removed, and the longitudinal muscle was exfoliated. The exfoliated longitudinal muscle was attached to the cannula to which the electrode was fixed, and the O ₂ / CO ₂ (95% / 5)
%) Krebs-Henseleit solution (NaCl 118.3 mM, KCl
4.7 mM, CaCl ₂ 2.5 mM, KH ₂ PO ₄
1.2 mM, MgSO ₄ 1.2 mM, NaHCO ₃ 2
(5.0 mM, glucose 11.1 mM). Note that the longitudinal muscles were not directly touched by the electrodes.

The above longitudinal muscles were subjected to electrical stimulation of a rectangular wave having a period of 0.1 Hz and a duration of 0.5 ms by using a stimulator (DPS-06, manufactured by Dia Medical Systems Co., Ltd.), and contracted nerve stimulation. When was stabilized, adenosine was cumulatively added from 0.1 μM to the Krebs-Henseleit solution to determine the IC ₅₀ of the nerve stimulation contraction inhibitory action.

The above IC ₅₀ value was calculated from the adenosine concentrations at two points around 50% inhibition and the inhibition. The nerve stimulation contraction is performed by using an FD pickup (TB-611, manufactured by Nihon Kohden Co., Ltd.).
T type) and amplifier (AP-601G type, manufactured by Nihon Kohden Corporation)
It measured using.

On the other hand, 5 minutes before the addition of adenosine, the compounds shown in the above tables were added as test compounds at a concentration of 1 μM as a dimethyl sulfoxide solution. It was determined the IC _50. Then, the ratio of the IC ₅₀ without addition of the test compound to this value was calculated to calculate the enhancement.

The results are shown in Table 7 below.

[0107]

[Table 19]

From the above table, it was revealed that the active ingredient compound of the present invention exhibited an excellent adenosine enhancing action.

Claims (8)

[Claims] 1. A compound of the general formula [In the formula, R ¹ is a hydrogen atom, a thienyl group, a lower alkoxy group, a lower alkylthio group, an oxo group, a lower alkyl group which may have a carboxyl group or a hydroxyl group as a substituent, a cycloalkyl group, a thienyl group, a furyl group. A lower alkenyl group or a phenyl group which may have from 1 to 3 groups selected from a lower alkyl group, a lower alkoxy group, a phenylthio group and a halogen atom as a substituent, wherein R ² is a naphthyl group, a cycloalkyl group, a furyl. Group, thienyl group, pyridyl group which may be substituted with a halogen atom, phenoxy group which may be substituted with a halogen atom or a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, a halogen-substituted lower alkyl group Group, halogen-substituted lower alkoxy group, lower alkoxycarbonyl group, hydr Roxyl group, a phenyl lower alkoxy group, an amino group, a cyano group, a lower alkanoyloxy group, a phenyl group which may have 1 to 3 groups selected from a phenyl group and a di-lower alkoxyphosphoryl lower alkyl group, R ³ A hydrogen atom, a phenyl group or a lower alkyl group, R ⁴ represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, a phenyl lower alkyl group, a phenyl group or a halogen atom which may have a phenylthio group as a substituent, R ⁵ Represents a hydrogen atom or a lower alkyl group, and R ⁶ has 1 to 3 hydrogen atoms, a lower alkyl group, a phenyl lower alkyl group or a group selected from a lower alkoxy group, a halogen-substituted lower alkyl group, and a halogen atom as a substituent. indicates a benzoyl group, also form a lower alkylene group attached R ¹ and R ⁵ are mutually May be, Q is a carbonyl group or a sulfonyl group, A is indicated a single bond, a lower alkylene group or a lower alkenylene group, respectively, n represents 0 or 1. A pyrazolo [1,5-a] pyrimidine derivative represented by the general formula: Wherein R ¹¹ is a lower alkyl group, R ²² is a phenyl group having 1 to 3 lower alkoxy groups as substituents,
³³ , R ⁴⁴ and R ⁵⁵ each represent a hydrogen atom, and Z represents a lower alkylene group. Pyrazolo [1,5-
a) An adenosine enhancer characterized by containing an effective amount of at least one selected from pyrimidine derivatives as an active ingredient together with a non-toxic carrier. 2. The compound according to claim 1, wherein the active ingredient is a compound of the general formula (2), and R ⁴ , R ⁵ and R ⁶ are hydrogen atoms,
The compound selected from the compound of the general formula (1) according to claim 1, wherein Q is a carbonyl group, A is a single bond and n is 0.
2. The adenosine enhancer according to item 1. 3. The compound according to claim 1, wherein R ² is a phenyl group having three lower alkoxy groups as substituents, and R ²² is lower alkoxy as a substituent. The adenosine enhancer according to claim 2, which is selected from the compounds of the general formula (2) according to claim 1, which is a phenyl group having three groups. 4. The compound according to claim 1, wherein R ¹ is an n-propyl group or an n-butyl group, and R ¹¹ is n-butyl. The adenosine enhancer according to claim 3, which is selected from the compounds represented by the general formula (2). 5. The method according to claim 5, wherein the active ingredient is 5-n-butyl-7-.
(3,4,5-trimethoxybenzoylamino) pyrazolo [1,5-a] pyrimidine, 5-n-propyl-7-
(3,4,5-trimethoxybenzoylamino) pyrazolo [1,5-a] pyrimidine, 5-n-butyl-2-methyl-7- (3,4,5-trimethoxybenzoylamino) pyrazolo [1, 5-a] pyrimidine, and 5-n-
The adenosine enhancer according to claim 4, which is selected from butyl-7- (3,4,5-trimethoxybenzoyloxy) pyrazolo [1,5-a] pyrimidine. 6. The active ingredient is 5-n-butyl-7-
The adenosine enhancer according to claim 5, which is (3,4,5-trimethoxybenzoylamino) pyrazolo [1,5-a] pyrimidine. 7. An effective amount of at least one pyrazolo [1,5-a] pyrimidine derivative represented by the general formula (1) or (2) according to claim 1 together with a nontoxic carrier. A preventive and therapeutic agent for myocardial infarction and / or cerebral infarction, characterized in that: 8. An effective amount of at least one pyrazolo [1,5-a] pyrimidine derivative represented by the general formula (1) or (2) according to claim 1 together with a nontoxic carrier. An agent for preventing angina pectoris.