JP3163413B2 - Painkillers - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel pyrazolo [1,5
-A] relates to an analgesic containing a pyrimidine derivative as an active ingredient.

[0002]

2. Description of the Related Art A pyrazolo [1,5-a] pyrimidine derivative as an active ingredient in the present invention is a novel compound which has not been described in any literature.

[0003]

An object of the present invention is to provide a new analgesic containing the above novel compound as an active ingredient.

[0004]

According to the present invention, there is provided an analgesic comprising a novel pyrazolo [1,5-a] pyrimidine derivative represented by the following general formula (1) as an active ingredient.

[0005]

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In the above general 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 or a hydroxyl group as a substituent, a cycloalkyl group, a thienyl group. Group,
R ² represents a naphthyl group, a cycloalkyl group, a furyl group, a lower alkenyl group or a 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. , A furyl group, a thienyl group, a pyridyl group which may be substituted with a halogen atom, a 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, or a halogen substitution. One of groups selected from a 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, a lower alkanoyloxy group, a phenyl group and a di-lower alkoxyphosphoryl lower alkyl group; A phenyl group which may have up to 3 , 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 atom which may have a phenylthio group as a substituent, R ⁵ is a hydrogen atom or a lower alkyl group, R ⁶ is a hydrogen atom, a lower alkyl group, a phenyl lower group; Alkyl or a 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, and R ¹ and R ⁵ are bonded to each other to form a lower alkylene group. Q may be a carbonyl group or a sulfonyl group,
A represents a single bond, a lower alkylene group or a lower alkenylene group, and n represents 0 or 1.

As the respective groups in the general formula (1), 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.

The cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Examples include cycloheptyl and cyclooctyl groups.

The lower alkoxy group includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy and the like.

The lower alkylthio group includes, for example, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio and the like.

Halogen atoms include 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.

Examples of the lower alkenylene group include 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 with 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.

Examples of the lower alkyl group which may have a thienyl group, a lower alkoxy group, a lower alkylthio group, an oxo group or a hydroxyl group as a substituent include 2-thienylmethyl,
-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, -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-oxo Pentyl, 3-oxopentyl, 2-
Oxopentyl, valeryl, 5-formylpentyl, 5
Examples thereof include -oxohexyl, 4-oxohexyl, 3-oxohexyl, 2-oxohexyl, and a hexanoyl group.

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-
A (phenylthio) phenyl group can be exemplified.

Examples of 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 include 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.

The pyrazolo [1,5-a] pyrimidine derivative represented by the general formula (1) has a strong analgesic action, and is used as an analgesic, for example, postoperative pain, migraine, gout, cancer pain, It is useful for alleviating pain symptoms such as chronic pain and neuropathic pain. In addition, the derivative does not have side effects that are common in conventional analgesics, does not cause hallucinations, confusion, and does not cause indulgence or addiction.

Pyrazolo [1,1] which is preferable as the above-mentioned analgesic
5-a] Pyrimidine derivatives are preferably those represented by the general formula (1)
Wherein Q is a carbonyl group and n is 0, Q is a carbonyl group, n is 1 and R1 is a lower alkyl group or a phenyl group, and R2 is a lower alkoxy group or a halogen-substituted lower alkyl group as a substituent. 1 to 1 of the groups selected from
Three phenyl group having, R3, R4, R5 and R6 each are a hydrogen atom and A is the compound represents a single bond, and Q is n is 0 sulfonyl group and R1 is a lower alkyl group, R ² is a halogen atom And R3, R4, R5 and R6 are each selected from a hydrogen atom and a compound in which A represents a single bond.

Among these preferred pyrazolo [1,5-a] pyrimidine derivatives, the following are particularly preferred.

(1) R1 is a lower alkyl group which may have a lower alkylthio group as a substituent or a phenyl group which may have a phenylthio group as a substituent;
2 is a phenyl group having 1 to 3 groups selected from a lower alkoxy group, a halogen atom and a halogen-substituted lower alkyl group as a substituent, R3 is a hydrogen atom or a phenyl group, and R4 is a hydrogen atom, a halogen atom or a phenyl group. Based on
R5 is a hydrogen atom; R6 is a hydrogen atom or a benzoyl group having a halogen-substituted lower alkyl group as a substituent;
Is a carbonyl group and A is a single bond, (2) R
3, R4 and R6 are each a hydrogen atom, n is 0, R1 is an n-butyl group and R2 is a phenyl or halogen-substituted lower alkyl group having 2 to 3 lower alkoxy groups; A compound in which R1 is a phenyl group and R2 is a phenyl group having three lower alkoxy groups; and (3) R2 is a 2,4-dimethoxyphenyl group, 3,4 A compound which is a 2,5-trimethoxyphenyl group, a 2-trifluoromethylphenyl group or a 2,5-bis (trifluoromethyl) phenyl group.

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 and 5-n-butyl-7-
(2-trifluoromethylbenzoylamino) pyrazolo [1,5-a] pyrimidine can be exemplified.

The derivative represented by the above general formula (1) is
It can be manufactured by various methods. Specific examples thereof will be described below with reference to reaction schemes.

[0038]

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Wherein R2, R3, R5, n, Q and A
Is the same as above. R ¹ a hydrogen atom, a thienyl group as a substituent, a lower alkyl group which may have a lower alkoxy group or a lower alkylthio group, a cycloalkyl group, a thienyl group, a furyl group, a lower alkyl group as a lower alkenyl group or a substituent, a lower alkoxy group, a phenyl group which may have 1 to 3 groups selected from phenylthio group and a halogen atom, and R ¹ a may also form a lower alkylene group bonded together with R5, R ⁴ a is a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, a phenyl group which may have a phenylthio group as a phenyl lower alkyl group or a substituent, each X and Y is a halogen atom, Z is a lower alkyl group, Shown respectively. In the above reaction scheme 1, the condensation reaction between the compound (2) and the compound (3) is carried out in a suitable inert solvent at a temperature ranging from room temperature to the boiling point of the solvent. As the inert solvent used here, acetic acid, ethanol, benzene, toluene, xylene, tetrahydrofuran (TH
F) and the like. In general, the ratio of the compound (2) to the compound (3) is preferably about equimolar,
The reaction is completed in about 2 to 5 hours, and thus the desired compound (4) can be obtained.

The subsequent halogenation reaction of compound (4) is carried out in the presence of a suitable deoxidizing agent such as N, N-dimethylaniline, N, N-diethylaniline, triethylamine, etc. For example, using phosphorus oxychloride, phosphorus oxybromide and the like. Since the halogenating agent also serves as a solvent, it is not necessary to use a solvent in the reaction, but other inert solvents such as benzene, toluene, and xylene can be used. The amount of the deoxidizing agent to be used is usually about 1 to 10 times the amount of the compound (4), and the reaction requires about 0.5 to 12 hours at room temperature to about 150 ° C. It will be implemented.

The halide (5) obtained by the above reaction can be converted to the compound (6) by treating it with aqueous ammonia or hydrazine. This process
No particular solvent is required, and the compound (5) is usually heated at about 100 to 150 ° C for about 1 to 12 hours with an excess amount of aqueous ammonia, or the compound (5) is heated at about 0 ° C with an excess amount of hydrazine. It can be carried out by treating at room temperature for about 5 to 30 hours.

The compound (6) thus obtained is then reacted with an acid halide (7) to give
It can be converted to the compound (1) of the present invention. This reaction can be carried out in a suitable solvent in the presence of a deoxidizing agent. Examples of the solvent include aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene and petroleum ether, diethyl ether, dimethoxyethane, tetrahydrofuran (TH
F) linear or cyclic ethers such as 1,4-dioxane; ketones such as acetone, ethyl methyl ketone and acetophenone; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane. Can be illustrated. Preferred examples of the deoxidizing agent include tertiary amines such as triethylamine, N, N-diethylaniline, N-methylmorpholine, pyridine and 4-methylaminopyridine.

The amounts of the acid halide (7) and the deoxidizing agent used in the above reaction with respect to the compound (6) are not particularly limited, but usually the acid halide is about equimolar, and the deoxidizing agent is usually equimolar. The reaction is completed in about 0.5 to 20 hours under the conditions of room temperature to the reflux temperature of the solvent.

The compound (6 ') wherein n is 0 among the above compounds (6) can also be produced by the method described in the following reaction scheme-1'.

[0045]

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Wherein R ¹ a, R 3, R ⁴ a and R 5 are the same as above. In the above, the nitrile derivative (2 ′) and the compound (3)
Is carried out in an inert solvent such as benzene, toluene, xylene, acetic acid, and ethanol under conditions of room temperature to reflux temperature for about 2 to 10 hours. The ratio of the two compounds used is generally about equimolar.

[0047]

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[Wherein R2, R3, R5, X, Y, A,
Q, Z and n are the same as above. Ψ is a lower alkyl group having a protected oxo group, Φ is a lower alkyl group having an oxo group, Σ is a lower alkyl group having an acyloxy group, and Ω is a lower alkyl group having a tri-lower alkylsilyloxy group. , R ¹ b represents a hydroxy lower alkyl group,
R ⁴ b is hydrogen atom, a lower alkyl group, a phenyl group which may have a phenylthio group as a phenyl lower alkyl group or a substituent, respectively. The condensation reaction between the compound (8) and the compound (9) in the above reaction scheme-2 can be carried out in the same manner as the reaction between the compound (2) and the compound (3) in the above reaction scheme-1.

In the compound (8), examples of the lower alkyl group having a protected oxo group defined by Ψ include dimethyl acetal, methyl ethyl acetal, diethyl acetal, dipropyl acetal, dibutyl acetal, dipentyl acetal, Di-lower alkyl acetal such as dihexyl acetal, a lower alkyl group having a protected oxo group, or a cyclic acetal residue such as ethylene acetal, trimethylene acetal, tetramethylene acetal, and the protected oxo group. Can be exemplified.

Next, the hydrolysis reaction of the compound (10) according to the above reaction step formula-2 is carried out by acetic acid, propionic acid, p-
It can be carried out using an organic acid such as toluenesulfonic acid. Among the above organic acids, carboxylic acids such as acetic acid and propionic acid also serve as a solvent.Therefore, it is not necessary to use another solvent when using these or the like, but when using such or the like, other organic acids may be used. As in the case of using, other suitable inert solvents such as benzene, toluene and xylene can be used. The reaction is carried out at room temperature to around the reflux temperature of the solvent.
It can be carried out in about 80 hours, and thus the compound (1
1) can be obtained.

In the above compound (11), the lower alkyl group having an oxo group defined by Φ may be a protecting group having a “lower alkyl group having a protected oxo group” defined by Ψ. Such as formyl, formylmethyl, acetyl, 2-formylethyl, 2-oxopropyl, propionyl, 3-formylpropyl, 3-oxobutyl, 2-oxobutyl,
Butyryl, 4-formylbutyl, 4-oxopentyl,
3-oxopentyl, 2-oxopentyl, valeryl,
Examples include 5-formylpentyl, 5-oxohexyl, 4-oxohexyl, 3-oxohexyl, 2-oxohexyl, and hexanoyl groups.

The subsequent reduction reaction of compound (11) can be carried out using an appropriate reducing agent in an inert solvent.
As the reducing agent, for example, boron hydride compounds such as sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triethylborohydride, lithium aluminum hydride, tributoxyaluminohydride Examples thereof include lithium aluminum hydride such as lithium. As the inert solvent, when a borohydride compound is used as the reducing agent, it is preferable to use an alcohol-based solvent such as methanol or ethanol, or a mixed solvent of the alcohol-based solvent and dichloromethane, diethyl ether, or the like, When lithium aluminum hydride is used as the reducing agent, it is preferable to use ethers such as diethyl ether and THF. The amount of the reducing agent to be used is preferably at least about equimolar to compound (11). Reaction is 0 ° C
It can be performed at a temperature of about room temperature to about 30 minutes to 3 hours.

The acylation reaction of the compound (12) thus obtained is carried out without solvent or in an inert solvent such as pyridine, lutidine, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA). It can be performed using an agent. As the acylating agent, for example, acid anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, hexanoic anhydride, and heptanoic anhydride can be used.
These can be used usually in 1 to 10 equivalents to the compound (12). The reaction conditions are preferably appropriately selected from a temperature of 0 ° C. to room temperature and a time of about 30 minutes to 2 hours so that the hydroxyl group at the 7-position of the compound (12) is not acylated.

The halogenation reaction of the compound (13) obtained above can be carried out in the same manner as the halogenation reaction of the compound (4) in the reaction scheme 1.

The conversion reaction of the obtained compound (14) into the compound (15) can also be carried out under the same conditions as in the conversion reaction of the compound (5) into the compound (6) in the reaction step formula-1. By the above reaction, the lower alkyl group having an acyloxy group defined by Σ in the compound (14) is hydrolyzed and converted to a hydroxy lower alkyl group.

The silylation reaction of the compound (15) obtained above can be carried out using a halogenated trialkylsilane in a suitable inert solvent such as THF or dichloromethane in the presence of a deoxidizing agent. Examples of the deoxidizing agent include sodium carbonate, potassium carbonate, triethylamine, N,
N-dimethylaminopyridine and the like can be exemplified. Examples of the halogenated trialkylsilane include trimethylsilane, triethylsilane, tripropylsilane, tributylsilane, and butyldiethylsilane. These can be used generally in an equimolar amount to an excess molar amount with respect to compound (15), and the reaction is completed in about 5 to 30 hours under a temperature condition near room temperature.

Finally, the desired compound (1b) of the present invention can be obtained by reacting the compound (16) obtained above with an acid halide (7). This reaction can also be carried out in the same manner as the reaction using the acid halide (7) in the reaction scheme 1. Incidentally, 5-position substituent Ω compound (16), due during the reaction and subsequent hydrolysis can be easily converted to the corresponding R ¹ b group (hydroxy-lower alkyl group).

[0058]

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[0059] [in the ^{formula, R2, R3, R 4 a} , R5, X,
Y, Z, Q, A, n and Ψ are the same as above. R ¹ c represents a lower alkyl group having an oxo group. In the above Reaction Scheme 3, the reaction between the compound (17) and the nitrile derivative (18) is carried out in an inert solvent such as DMF, DMA, and dimethylformamide (DMSO) in a base such as sodium hydride or potassium hydride. Can be carried out in the presence of The amount of the nitrile derivative (18) and the base to be used is each usually 1 to an excess equivalent relative to the compound (17), and the reaction is carried out under a temperature condition of 0 ° C. to room temperature.
It takes time.

Next, the condensation reaction between the compound (2 ″) and the compound (3) can be carried out in the same manner as in the reaction in the reaction step formula-1 ′.

The hydrolysis reaction of the compound (19)
It can be carried out in the same manner as in the hydrolysis reaction in the reaction step formula-2.

Further, the reaction between compound (20) and compound (7) can be carried out in the same manner as in the reaction in the reaction scheme 1.

[0063]

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Wherein R 2, A, Q and Y are as defined above. As shown in the above reaction process formula-4,
The acid halide (7) used in 1, 2, and -3 can be obtained by halogenating the compound (21). The halogenation reaction can be carried out according to a method commonly used. For example, compound (21) can be prepared without solvent or in an inert solvent such as chloroform or diethyl ether by using thionyl chloride or thionyl bromide. And the like. In this method, the halogenating agent is generally used in an excess amount, and the reaction can usually be performed at a temperature of about room temperature to about 150 ° C. for about 0.5 to 5 hours.

[0065]

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Wherein R 2, R 3, R 5, A and n are as defined above. R ¹ d is a hydrogen atom, a lower alkyl group which may have a lower alkoxy group or a lower alkylthio group as a substituent, a cycloalkyl group, a thienyl group, a furyl group or a lower alkyl group or a lower alkoxy group as a substituent;
1 to 3 groups selected from a phenylthio group and a halogen atom
It represents a phenyl group which may have three, R ¹ d and R 5 may combine with each other to form a lower alkylene group, and R ⁴ c represents a halogen atom. The halogenation reaction of the compound (1d) shown in the reaction step formula-5 is carried out in an inert solvent such as benzene, carbon tetrachloride, and chloroform by using N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS) Can be carried out using a halogenating agent. The amount of the halogenating agent used is the same as that of the compound (1d)
The reaction is generally carried out in an amount of 1 equivalent to a small excess, and the reaction is carried out under a temperature condition of about room temperature to about the reflux temperature of the solvent.
This can take 5-5 hours.

[0067]

Embedded image

Wherein R 3, R 4, R 5 and Y are as defined above. R ¹ e is a hydrogen atom, a thienyl group as a substituent, a lower alkoxy group, a lower alkyl group which may have a lower alkylthio group or an oxo group, a cycloalkyl group, a thienyl group, a furyl group, a lower alkenyl group or a substituent. A lower alkyl group, a lower alkoxy group, a phenylthio group and a phenyl group which may have 1 to 3 groups selected from a halogen atom, and R ¹ e and R 5 are bonded to each other to form a lower alkylene group; at best, R ² a naphthyl group, a cycloalkyl group, a furyl group, a thienyl group,
A pyridyl group which may be substituted with a halogen atom, a 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, a halogen-substituted lower group; A phenyl group which may have 1 to 3 groups selected from an alkoxy group, a lower alkoxycarbonyl group, a phenyl lower alkoxy group, a cyano group, a lower alkanoyloxy group, a phenyl group and a di-lower alkoxyphosphoryl lower alkyl group, ⁶ a is 1 group selected from phenyl-lower alkyl group or a lower alkoxy group as a substituent, halogen-substituted lower alkyl group and a halogen atom
Shows a benzoyl group having three. In the reaction step formula-6, the compound (1g) is obtained by reacting the compound (1f) with the compound (2f) in an inert solvent in the presence of a base.
It can be obtained by reacting with 2). Here, when R ⁶ a is a phenyl-lower alkyl group, examples of the inert solvent, DMF, DMA, and DMSO, and as the base, can be exemplified sodium hydride, potassium hydride and the like. On the other hand, if the benzoyl group having 1 to 3 groups R ⁶ a is selected from a lower alkoxy group, halogen-substituted lower alkyl group and a halogen atom as a substituent,
Examples of the inert solvent include chloroform and dichloromethane, and examples of the base include triethylamine and N, N-dimethylaniline. Compound (2
The amount of 2) is generally 1 to a small excess equivalent,
The amount of the base used is preferably 1 to an excess equivalent. The reaction is carried out at a temperature of about 0 ° C. to room temperature for 3 to 30 hours.

[0069]

Embedded image

Wherein R ¹ a, R 2, R 3, R ⁴ a, R 5
, X, Y, Q and A are the same as above. R ⁶ b is a lower alkyl group or a phenyl-lower alkyl group. Compound (5) and Compound (23) in Reaction Scheme-7
Is carried out in an inert solvent such as methanol or ethanol in the presence of a deoxidizing agent such as sodium hydrogen carbonate, sodium carbonate or potassium carbonate under a temperature condition of about reflux temperature.
It takes about 5 hours.

The reaction between the obtained compound (24) and compound (7) can be carried out in the same manner as the corresponding reaction shown in the reaction scheme 1. Thus, the compound (1h) can be obtained.

[0072]

Embedded image

Wherein R ¹ e, R 3, R ⁴ a, R 5 and Y are the same as above. R ² b is a phenyl group having 1 to 3 groups selected from a lower alkoxy group, a halogen atom and a halogen-substituted lower alkyl group as a substituent, and R ⁶ c is a lower alkoxy group or a halogen-substituted lower alkyl group as a substituent. And a benzoyl group having 1 to 3 groups selected from halogen atoms. In the reaction step formula-8, the compound (25) and the compound (2
The reaction with 6) is carried out by reacting the compound (6) shown in the reaction scheme 1.
And compound (7). At this time, a by-product (1j) is obtained together with the main product (1i).

The compound represented by the general formula (1) can be a pharmaceutically acceptable acid addition salt, and these salts are also included in the active ingredient compound of the analgesic of the present invention. 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.

The target compound obtained in each of the above steps can be easily isolated by ordinary separation and purification means. As the isolation means, any of various commonly used means can be employed, and examples thereof include, for example, adsorption chromatography, preparative thin-layer chromatography, recrystallization, and solvent extraction. it can.

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 analgesic of the present invention can use any of these as an active ingredient. it can.

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

The analgesic of the present invention is used in the form of a general pharmaceutical composition by using the compound represented by the general formula (1) as an active ingredient and using it together with a suitable non-toxic pharmaceutical carrier. You.

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 tablets, 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 a pill form, for example, 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.

In shaping into a suppository, for example, polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glyceride and the like can be used as pharmaceutical carriers.

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

When prepared as injections such as liquids, emulsions, suspensions, etc., it is preferable that they are sterilized and isotonic with blood. 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 drug of the present invention may contain a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent and the like and other pharmaceuticals as required.

For shaping in the form of an ointment such as paste, cream, gel or the like, for example, white vaseline, paraffin, glycerin, cellulose derivative, 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) 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 preferred that the content be contained to a certain degree.

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-mentioned pharmaceutical preparation is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but the amount of the compound of the present invention, which is usually an active ingredient, is 1%.
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 divided doses per day.

[0091]

EXAMPLES Hereinafter, in order to explain the present invention in more detail, a production example of a starting compound for producing a compound as an active ingredient in the present invention will be cited as a reference example. As

[0092]

Reference Example 1 Production of 7-amino-5-n-butylpyrazolo [1,5-a] pyrimidine Step (1) A solution of 100 g of 3-aminopyrazole and 190 g of methyl 3-oxoheptanoate in 120 ml of toluene was mixed with 1
The mixture was heated and refluxed at 00 ° C. for 3 hours. After cooling, toluene was distilled off under reduced pressure, diethyl ether was added to the residue, and the precipitated crystals were collected by filtration, washed sequentially with diethyl ether and acetonitrile, and washed with 5-n-butyl-7-hydroxypyrazolo [1,5. -A] 184 g of colorless crystals of pyrimidine were obtained.

Step (2) 40 g of the crystals obtained in the above step (1) and toluene 400
80 ml of phosphorus oxychloride and 44 ml of triethylamine were added to the ml suspension, and the mixture was heated under reflux for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, the residue was poured into ice water, the mixture was neutralized with sodium acetate, extracted with ethyl acetate, and the organic layer was collected. This was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane = 1: 9) to give 5-n-butyl-7-chloropyrazolo [1,5-a] pyrimidine as a pale yellow oil. Object 4
1 g was obtained.

Step (3) 21 g of the compound obtained in the above step (2) and 100 ml of 25% aqueous ammonia were sealed in a stainless steel sealed tube.
Heated at 10 ° C. for 12 hours. After cooling, the precipitated crystals were collected by filtration, washed with water, and recrystallized from chloroform-n-hexane to give 7-amino-5-n-butylpyrazolo [1,5-
a] 18.4 g of colorless crystals of pyrimidine (melting point: 124-
126 ° C).

The following compounds were prepared in the same manner as described above.

(1) 7-amino-5-ethylpyrazolo [1,5-a] pyrimidine (melting point: 175-177 ° C.,
Recrystallization solvent: ethyl acetate-n-hexane) (2) 7-amino-5-n-propylpyrazolo [1,5-
a] Pyrimidine (melting point: 138 to 140 ° C, recrystallization solvent: ethyl acetate-n-hexane) (3) 7-amino-5-cyclopropylpyrazolo [1,5
-A] pyrimidine (melting point: 206 to 209 ° C, recrystallization solvent: chloroform-n-hexane) (4) 7-amino-5-n-pentylpyrazolo [1,5-
a] Pyrimidine (melting point: 125-126 ° C, recrystallization solvent: ethyl acetate-n-hexane) (5) 7-amino-5-phenylpyrazolo [1,5-a]
Pyrimidine (melting point: 207-209 ° C, recrystallization solvent: ethyl acetate-n-hexane).

(6) 7-amino-5- (4-methoxyphenyl) pyrazolo [1,5-a] pyrimidine (melting point: 19)
4-196 ° C, recrystallization solvent: ethanol-n-hexane) (7) 7-amino-5- (2-thienyl) pyrazolo [1,
5-a] pyrimidine (melting point: 227 to 229 ° C., recrystallization solvent: ethanol-n-hexane) (8) 7-amino-5- (3-thienyl) pyrazolo [1,
5-a] pyrimidine (melting point: 203-205 ° C, recrystallization solvent: ethanol-n-hexane) (9) 7-amino-5-methylpyrazolo [1,5-a] pyrimidine (melting point: 220-222 ° C, re- Crystallizing solvent: chloroform-n-hexane) (10) 7-amino-5-n-butyl-2-methylpyrazolo [1,5-a] pyrimidine (melting point: 176-178 ° C,
Recrystallization solvent: chloroform-n-hexane).

(11) 7-amino-5- (2,4-dimethylphenyl) pyrazolo [1,5-a] pyrimidine (melting point:
168-170 ° C, recrystallization solvent: chloroform-n-hexane) (12) 7-amino-5- (3,5-dimethylphenyl) pyrazolo [1,5-a] pyrimidine (melting point: 180-18)
2 ° C, recrystallization solvent: ethanol-n-hexane) (13) 7-amino-5- (2-methoxyphenyl) pyrazolo [1,5-a] pyrimidine (melting point: 201-203)
° C, recrystallization solvent: ethanol-n-hexane) (14) 7-amino-5- (3-methoxyphenyl) pyrazolo [1,5-a] pyrimidine (melting point: 195-197)
° C, recrystallization solvent: ethanol-n-hexane) (15) 7-amino-5- (3,4,5-trimethoxyphenyl) pyrazolo [1,5-a] pyrimidine (melting point: 19)
8-200 ° C, recrystallization solvent: ethanol-n-hexane).

(16) 7-amino-5- (2-chlorophenyl) pyrazolo [1,5-a] pyrimidine (melting point: 208
-210 ° C, recrystallization solvent: chloroform-n-hexane) (17) 7-amino-5- (2-furyl) pyrazolo [1,5
-A] pyrimidine (melting point: 204-206 ° C, recrystallization solvent: ethanol-n-hexane) (18) 7-amino-5- (3-furyl) pyrazolo [1,5
-A] pyrimidine (melting point: 208 to 210 ° C, recrystallization solvent: ethanol-n-hexane) (19) 7-amino-5- (2-thienylmethyl) pyrazolo [1,5-a] pyrimidine (melting point: 188) ~ 190 ° C,
Recrystallization solvent: ethanol-n-hexane) (20) 7-amino-5- (3,5-dimethoxyphenyl)
Pyrazolo [1,5-a] pyrimidine (melting point: 207-2
(09 ° C., recrystallization solvent: ethanol-n-hexane) Further, the following compounds were produced in the same manner as described above.

(21) 7-amino-5- (3-butenyl) pyrazolo [1,5-a] pyrimidine (22) 7-amino-5-ethoxymethylpyrazolo [1,5
-A] pyrimidine (23) 7-amino-5- (2-methylphenyl) pyrazolo [1,5-a] pyrimidine (24) 7-amino-5- (3-methylphenyl) pyrazolo [1,5-a Pyrimidine (25) 7-amino-5- (4-methylphenyl) pyrazolo [1,5-a] pyrimidine.

(26) 7-amino-5- (3-chlorophenyl) pyrazolo [1,5-a] pyrimidine (27) 7-amino-5- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine ( 28) 7-aminopyrazolo [1,5-a] pyrimidine (29) 7-amino-5-n-butyl-3-ethoxycarbonyl-2-methylpyrazolo [1,5-a] pyrimidine (mp: 178-180 ° C. Recrystallization solvent: methylene chloride-n-hexane) (30) 7-amino-2,5-di-n-butyl-3-methylpyrazolo [1,5-a] pyrimidine (melting point: 123 to 1)
25 ° C, recrystallization solvent: diethyl ether-n-hexane).

(31) 7-amino-5-n-butyl-2-phenylpyrazolo [1,5-a] pyrimidine (melting point: 20
6-208 ° C, recrystallization solvent: ethyl acetate-n-hexane) (32) 7-amino-3-benzyl-5-n-butyl-2-
Phenylpyrazolo [1,5-a] pyrimidine (melting point: 1
06-108 ° C, recrystallization solvent: chloroform-n-hexane) (33) 7-amino-5-n-butyl-2-phenyl-3-
[4- (phenylthio) phenyl] pyrazolo [1,5-
a) Pyrimidine (melting point: 139 to 141 ° C., recrystallization solvent: diethyl ether-n-hexane) (34) 7-amino-3,5-di-n-butylpyrazolo [1,5-a] pyrimidine (melting point: 58) -60 ° C, recrystallization solvent: ethyl acetate-n-hexane) (35) 7-amino-5-n-butyl-3-phenylpyrazolo [1,5-a] pyrimidine (melting point: 113-115)
° C, recrystallization solvent: ethyl acetate-n-hexane).

(36) 7-amino-5-ethylthiomethylpyrazolo [1,5-a] pyrimidine (melting point: 109 to 11)
1 ° C, recrystallization solvent: chloroform-n-hexane) (37) 7-amino-5- (2-methylthioethyl) pyrazolo [1,5-a] pyrimidine (melting point: 77-79 ° C, recrystallization solvent: acetic acid) Ethyl-n-hexane) (38) 7-amino-5- [4- (phenylthio) phenyl] pyrazolo [1,5-a] pyrimidine (melting point: 182)
１８184 ° C., recrystallization solvent: chloroform-diethyl ether) (39) 9-amino-5,6,7,8-tetrahydropyrazolo [5,1-b] quinazoline (melting point: 230-233)
° C, recrystallization solvent: ethyl acetate-n-hexane) (40) 7-amino-2,5-di-n-butylpyrazolo [1,5-a] pyrimidine (melting point: 105-107 ° C,
Recrystallization solvent: diethyl ether-n-hexane).

[0104]

Reference Example 2 Production of 5-n-butyl-7-hydrazinopyrazolo [1,5-a] pyrimidine 5-n-butyl-7- obtained in step (2) of Reference Example 1
Chloropyrazolo [1,5-a] pyrimidine 21.0 g
Then, 50 ml of hydrazine monohydrate was slowly added dropwise at room temperature, and the mixture was stirred at room temperature for 10 hours. After the reaction, the precipitated crystals were collected by filtration, washed with water, and recrystallized from chloroform-n-hexane to obtain 12.6 g of the target compound as colorless crystals (melting point: 126 to 129 ° C).

In the same manner as described above, 7-hydrazino-5
-Phenylpyrazolo [1,5-a] pyrimidine was produced.

[0106]

Reference Example 3 Production of 7-amino-5- (3-oxobutyl) pyrazolo [1,5-a] pyrimidine In a suspension of 2.3 g of 60% sodium hydride in 10 ml of DMF, 2-methyl-1,3 was added. -Dioxolane-2-propionic acid methyl ester 5.0 g of acetonitrile 1
A 0 ml solution was added dropwise, and the mixture was stirred at room temperature for 4 hours. The reaction solution was placed in ice water, acidified with a saturated aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: n-hexane: ethyl acetate = 3:
Purification in 2) to give oily 2-methyl-β-oxo-1,
3.0 g of 3-dioxolan-2-pentanenitrile was obtained.

Next, 3.0 g of the compound obtained above and 3 g of the compound
A solution of 1.4 g of aminopyrazole in 1.6 ml of toluene was stirred at 115 ° C. for 10 hours. The reaction solution was concentrated under reduced pressure,
The residue was subjected to silica gel column chromatography (eluent ...
Purified with chloroform: methanol = 20: 1) and further recrystallized from chloroform-n-hexane to give 7-amino-5- [2- (2-methyl-1,3-dioxolane-
2.1 g of colorless crystals of 2-yl) ethyl] pyrazolo [1,5-a] pyrimidine were obtained.

Next, 1.0 g of the crystals obtained above was dissolved in 500 ml of acetic acid-water (4: 1) and stirred at 80 ° C. overnight. After completion of the reaction, the mixture was concentrated under reduced pressure, the remaining acetic acid-water was distilled off azeotropically with benzene, and the residue was recrystallized from ethanol-n-hexane to obtain 0.7 g of colorless crystals of the title compound.

Melting point: 164-166 ° C., recrystallization solvent: ethanol-n-hexane

[0110]

Reference Example 4 Production of 7-amino-5-n-butyl-6-methylpyrazolo [1,5-a] pyrimidine 1.8 g of 3-aminopyrazole and 3 g of 2-methyl-3-oxoheptanenitrile in toluene 2 The 0.5 ml solution was heated at 115 ° C. for 3.5 hours. The toluene was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate. The obtained crystals were further washed with diethyl ether to obtain 2.4 g of the title compound as colorless crystals.

Melting point: 153-155 ° C., recrystallization solvent: ethyl acetate

[0112]

Example 1 Preparation of 5-n-butyl-7- (3,4,5-trimethoxybenzoylamino) pyrazolo [1,5-a] pyrimidine 7-amino-5-n-butylpyrazolo [1,5- a) Pyrimidine (1.90 g) and pyridine (20 ml) were dissolved in dry dichloromethane (20 ml).
A solution of 2.6 g of 4,5-trimethoxybenzoyl chloride in 10 ml of dry dichloromethane was slowly added dropwise,
Stirred at room temperature for 10 hours. 50 ml of a 10% aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was collected, washed with 10% hydrochloric acid and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane = 1: 2), and further recrystallized from diethyl ether-n-hexane to obtain 2.4 g of the target compound as colorless crystals. Table 1 shows the structure and melting point of the obtained compound.

[0113]

Examples 2 to 46 The compounds shown in Table 1 were obtained in the same manner as in Example 1. Table 1 also shows the structure and melting point of each compound obtained. For oily substances, 1H-N
3 shows MR spectrum data.

[0114]

Embodiments 47 to 99 The second embodiment is similar to the first embodiment.
The compounds shown in the table were obtained. Table 2 shows the structure and melting point of each compound obtained. In addition, 1H-
2 shows NMR spectrum data.

[0115]

Example 100 5- (3-hydroxybutyl) -7-
Production of (3,4,5-trimethoxybenzoylamino) pyrazolo [1,5-a] pyrimidine Step (1) 0.90 g of 3-aminopyrazole and 2-methyl-β-oxo-1,3-dioxolan-2 A solution of 1.90 g of pentanoic acid methyl ester in 2 ml of toluene was heated and refluxed at 115 ° C. for 1 hour. After allowing to cool, the mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and the precipitated crystals were collected by filtration, washed with diethyl ether, and treated with 7-hydroxy-5- [2- (2
-Methyl-1,3-dioxolan-2-yl) ethyl]
1.85 of colorless crystals of pyrazolo [1,5-a] pyrimidine
g was obtained.

Step (2) 2.2 g of the crystals obtained above were treated with 50% acetic acid-water (4: 1).
It was dissolved in 0 ml and stirred at 50 ° C. for 3 days. After completion of the reaction, the mixture was concentrated under reduced pressure, the remaining acetic acid-water was distilled off by azeotropic distillation with benzene, and the residue was recrystallized from ethanol-n-hexane to give 7-hydroxy-5- (3-oxobutyl) pyrazolo [ 1,1.0 g of colorless crystals of 1,5-a] pyrimidine
I got

Step (3) 5.7 g of the crystals obtained in step (2) were dissolved in methanol 120
Dissolve in ice-cold solution and add 0.53 g of sodium borohydride under ice-cooling
Was added and stirred at 0 ° C. for 2 hours. After completion of the reaction, diluted hydrochloric acid was added dropwise to make the mixture acidic, and the mixture was extracted with chloroform. The organic layer was collected, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol-n-hexane to obtain 4.16 g of colorless crystals of 7-hydroxy-5- (3-hydroxybutyl) pyrazolo [1,5-a] pyrimidine.

Step (4) 4.16 g of the crystals obtained in step (3) were added to 40 m of acetic anhydride.
and 40 ml of pyridine and stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol-diethyl ether to obtain 4.2 g of 5- (3-acetoxybutyl) -7-hydroxypyrazolo [1,5-a] pyrimidine as colorless crystals. Was.

Step (5) 4.2 g of the crystals obtained in step (4) in 40 ml of toluene
6.4 ml of phosphorus oxychloride and 3.5 ml of triethylamine were added to the suspension, and the mixture was heated under reflux for 6 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, the residue was poured into ice water, the mixture was neutralized with sodium acetate, and extracted with ethyl acetate. The organic layer was collected, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 4: 1). 4.3 g of a pale yellow oil of 5- (3-acetoxybutyl) -7-chloropyrazolo [1,5-a] pyrimidine was obtained.

Step (6) 4.3 g of the compound obtained in the step (5) and 50 ml of 25% aqueous ammonia were sealed in a stainless steel sealed tube.
Heated at 5 ° C. for 14 hours. After standing to cool, the precipitated crystals were collected by filtration, washed with water, and dried to obtain 3.2 g of 7-amino-5- (3-hydroxybutyl) pyrazolo [1,5-a] pyrimidine as pale yellow crystals. .

Step (7) To a solution of 500 mg of the crystals obtained in step (6) in 5 ml of THF were added 400 μl of triethylamine and 680 μl of trimethylsilane chloride, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. The organic layer was collected, washed with water and saturated saline in this order, dried over anhydrous sodium sulfate and concentrated under reduced pressure. N- in the residue
Hexane was added, and the precipitated crystals were collected by filtration to obtain 520 mg of colorless crystals of 7-amino-5- (3-trimethylsilyloxybutyl) pyrazolo [1,5-a] pyrimidine.

1 H-NMR (δ: ppm) [CDCl 3
0.12 (9H, s), 1.20 (3H, d, J = 5.
9), 1.8-1.9 (2H, m), 2.6-2.9
(2H, m), 3.8-3.9 (1H, m), 5.61
(2H, brs), 5.99 (1H, s), 6.41
(1H, d, J = 2.0), 7.99 (1H, d, J =
2.0) Step (8) 520 mg of the crystals obtained in step (7) in 5 ml of pyridine
To the solution was slowly added dropwise a solution of 650 mg of 3,4,5-trimethoxybenzoyl chloride in 5 ml of dry dichloromethane, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. The organic layer was collected, washed with 1N hydrochloric acid until the pH of the aqueous layer became about 1, and allowed to stand for 2 hours. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue was recrystallized from dichloromethane-n-hexane,
480 mg of colorless crystals of the target compound were obtained. Table 2 shows the structure and melting point of the obtained compound.

[0123]

Examples 101 and 102 The compounds shown in Table 2 were obtained in the same manner as in Example 100. Table 2 shows the structure and melting point of each compound obtained.

[0124]

Example 103 Preparation of 5-n-butyl-3-chloro-2-methyl-7- (3,4,5-trimethoxybenzoylamino) pyrazolo [1,5-a] pyrimidine 5-n-butyl- 0.78 g of 2-methyl-7- (3,4,5-trimethoxybenzoylamino) pyrazolo [1,5-a] pyrimidine (the compound of Example 53) was dissolved in 10 ml of chloroform, and 0.28 g of NCS was added. Heated to reflux for an hour. After allowing to cool, water was added to the reaction solution, and extracted with chloroform. The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate: n-hexane =
1: 2), and further recrystallized from ethanol-n-hexane to obtain 0.61 g of colorless crystals of the target compound.
Table 3 shows the structure and melting point of the obtained compound.

[0125]

Examples 104 to 106 The compounds shown in Table 3 were obtained in the same manner as in Example 103. Table 3 shows the structure and melting point of each compound obtained.

[0126]

Examples 107 to 128 The compounds shown in Table 4 were obtained in the same manner as in Example 1. Table 4 shows the structure and melting point of each compound obtained.

[0127]

Working Example 129 5-N-butyl-7- [N-methyl-
N- (3,4,5-trimethoxybenzoyl) amino]
Production of pyrazolo [1,5-a] pyrimidine 5-n-butyl-7-chloropyrazolo [1,5-a] pyrimidine (compound produced in step (2) of Reference Example 1)
8.60 g, 3.44 g of sodium bicarbonate and 40%
3.18 g of methylamine was added to 50 ml of ethanol, and heated at 120 ° C. for 2 hours. After completion of the reaction, ethanol was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1: 2) to give 5-n-butyl-7. 2.33 g of crystals of -methylaminopyrazolo [1,5-a] pyrimidine were obtained.

Using the obtained crystals and 3,4,5-trimethoxybenzoyl chloride, the target compound was obtained in the same manner as in Example 1. Table 5 shows the structure and melting point of the obtained compound.

[0129]

Example 130 The compounds shown in Table 5 were obtained in the same manner as in Example 129. The structure and melting point of the obtained compound are also shown in Table 5.

[0130]

Example 131 Production of 5-n-butyl-7- [N, N-bis (3,4,5-trimethoxybenzoyl) amino] pyrazolo [1,5-a] pyrimidine Obtained in Example 1. 1.92 g of the compound and 1.02 g of triethylamine were dissolved in 10 ml of chloroform, and 3,4,5-trimethoxybenzoyl chloride 1.2
A solution of 8 g of chloroform in 10 ml was added at room temperature, and the mixture was stirred at room temperature for 10 hours. After the reaction, the organic layer was washed with diluted hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1: 2), and further recrystallized from ethyl acetate-n-hexane to obtain 1.10 g of the target compound as colorless crystals.

The structure and melting point of the obtained compound are also shown in Table 5.

[0132]

Example 132 5-n-Butyl-7- [N, N-bis (2-chlorobenzoyl) amino] pyrazolo [1,5-
a] Production of pyrimidine In Example 23, the above fraction obtained by silica gel column chromatography was purified again by silica gel column chromatography (eluent: dichloromethane) and further recrystallized to obtain colorless crystals of the target compound. . The structure and melting point of the obtained compound are also shown in Table 5.

[0133]

Examples 133 and 134 In the same manner as in Example 132, the compounds shown in Table 5 were obtained from the preceding fractions of the silica gel column chromatography in Examples 32 and 52. Table 5 also shows the structures and melting points of the obtained compounds.

Further, the same compound as the compound of Example 131 was obtained in the same manner from the preceding fraction of the silica gel column chromatography in Example 1.

[0135]

[Table 1]

[0136]

[Table 2]

[0137]

[Table 3]

[0138]

[Table 4]

[0139]

[Table 5]

[0140]

[Table 6]

[0141]

[Table 7]

[0142]

[Table 8]

[0143]

[Table 9]

[0144]

[Table 10]

[0145]

[Table 11]

[0146]

[Table 12]

[0147]

[Table 13]

[0148]

[Table 14]

[0149]

[Table 15]

[0150]

[Table 16]

Examples of pharmacological tests performed on the active ingredient compounds obtained above and examples of preparation of the analgesic of the present invention are described below.

[0152]

[Pharmacological Test Example 1] 6-week-old Wistar male rats 1 group 7
First, the pain threshold of the left hind footpad of each rat was measured using a pressure-stimulated analgesic effect measuring device (manufactured by Unicom) using the Randall-Selit method [Randall, LO and Sellitto, JJ,
Arch.Int.Pharmacodyn., 111, 409 (1957)]. The obtained value is referred to as “previous value”.

One hour after the above measurement, 0.1 ml of a 20% yeast suspension was subcutaneously injected into the left hind footpad of each rat, and the experimental group was further treated with a 5% gum arabic suspension of the compound of the present invention. The suspension was orally administered to the control group at a rate of 10 ml / kg immediately after the yeast injection, with a 5% gum arabic suspension (not containing the compound of the present invention).

Next, every hour after the yeast injection, the pain threshold value of the left hind footpad of each group of rats was measured in the same manner as described above, and this was defined as “post-value”.

The pain threshold recovery rate (%) was calculated from the measured value (post-value) and the pre-value of each group according to the following equation.

Pain threshold recovery rate (%) = [(average value of experimental group) − (average value of control group)] / [(average value of control group) −
(Average after control group)] × 100 The obtained results (maximum recovery rate) are shown in Table 6 below.

[0157]

[Table 17]

[0158]

[Pharmacological Test Example 2] 6-week-old male Wistar rats 7 per group
First, the pain threshold of the left hind footpad of each rat was measured using a pressure-stimulated analgesic effect measuring device (manufactured by Unicom) using the Randall-Selit method [Randall, LO and Sellitto, JJ,
Arch.Int.Pharmacodyn., 111, 409 (1957)]. The obtained value is referred to as “previous value”.

One hour after the measurement of the previous value, the experimental group contained:
Further, a 5% gum arabic suspension of the compound of the present invention and a control group of a 5% gum arabic suspension (not containing the compound of the present invention) were each administered at a dose of 1 mg / kg at a rate of 10 ml / kg. Orally administered as such, and one hour later, a physiological saline solution of substance P (25 ng / 0.
1 ml) was injected subcutaneously into the left hind footpad of each rat.

Next, a predetermined time after the substance P injection,
The pain threshold of the left hind footpad of each group of rats was measured in the same manner as described above, and this was defined as "post-value".

The pain threshold recovery rate (%) was calculated from the measured value (post-value) and the pre-value of each group according to the following equation.

Pain threshold recovery rate (%) = [(average value of experimental group) − (average value of control group)] / [(average previous value of control group) −
(Average after control group)] × 100 The results obtained (maximum recovery rate) are shown in Table 7 below.

[0163]

[Table 18]

From the above Tables 6 and 7, it is clear that the active ingredient compounds of the present invention exhibit excellent analgesic action.

[0165]

Formulation Example 1 Preparation of Tablet Using the compound of the present invention obtained in Example 1 as an active ingredient,
Tablets containing 300 mg per tablet (2000 tablets)
Was prepared according to the following formula.

Compound of the present invention obtained in Example 1 600 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 product) 3 g That is, the compound of the present invention obtained in Example 1 according to the above-mentioned formulation,
Lactose, corn starch and carboxymethylcellulose calcium are thoroughly mixed, the mixture is granulated with an aqueous methylcellulose solution, passed through a 24 mesh sieve, mixed with magnesium stearate, and pressed into tablets to obtain the desired tablet. Was.

[0167]

Formulation Example 2 Preparation of Capsules Using the compound of the present invention obtained in Example 32 as an active ingredient, hard gelatin capsules (2000 tablets) containing 200 mg per capsule were prepared according to the following formulation.

Compound of the present invention obtained in Example 32 400 g Microcrystalline cellulose (Japanese Pharmacopoeia product) 60 g Corn starch (Japanese Pharmacopoeia product) 34 g Talc (Japanese Pharmacopoeia product) 4 g Magnesium stearate (Japanese Pharmacopoeia product) 2 g According to the above formula, each component was finely powdered, mixed to form a uniform mixture, and then filled into a gelatin capsule for oral administration having desired dimensions to obtain a desired capsule.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Kenji Hashimoto 7-8, east of Kitahama-Ju, Nadu-cho, Naruto-shi, Tokushima (72) Inventor Masayuki Ohara Nakase Nakanogoshi Nakakirai, Matsuki-cho, Itano-gun, Tokushima Prefecture 11-28 (72) Inventor Tsuneo Yasuda Hama43, Benzaitenten, Nadu-cho, Naruto City, Tokushima Prefecture (56) References JP-A-3-204877 (JP, A) Mazur, I. A. , Synthesis and biological activity of N- (4-quinzolyl-and 5-imidazopyrimidinyl-) sulfanilamides, Farm. Zh. (Kiev), 1987.1, p. 58-60 (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/435-31/529 A61P 29/00 C07D 471 / 04,487 / 04 CA (STN) REGISTRY (STN) WPI (DIALOG)

Claims (7)

(57) [Claims] 1. A compound of the general formula Wherein R ¹ is a hydrogen atom, a thienyl group, a lower alkoxy group, a lower alkylthio group, a oxo group or a lower alkyl group which may have a hydroxyl group as a substituent, a cycloalkyl group, a thienyl group, a furyl group, a lower alkenyl. R ² represents a 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 group or a substituent; R ² represents a naphthyl group, a cycloalkyl group, a furyl group, a thienyl group; 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, a nitro group, a halogen-substituted lower alkyl group, Substituted lower alkoxy group, lower alkoxycarbonyl group,
A phenyl group which may have 1 to 3 of a group selected from 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 represents a hydrogen atom, a phenyl group or a lower alkyl group;
⁴ is 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 is a hydrogen atom or a lower alkyl group, R ⁶ is A hydrogen atom, a lower alkyl group, a phenyl lower alkyl group or a 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, and R ¹ and R ⁵ are It may combine with each other to form a lower alkylene group, Q represents a carbonyl group or a sulfonyl group, A represents a single bond, a lower alkylene group or a lower alkenylene group, and n represents 0 or 1. An analgesic, characterized by containing an effective amount of a pyrazolo [1,5-a] pyrimidine derivative represented by the formula (1) together with a non-toxic carrier. 2. The compound according to claim 1, wherein Q is a carbonyl group and n is 0, Q is a carbonyl group,
n is 1, and R ¹ is a lower alkyl group or a phenyl group, R ² is a phenyl group having 1 to 3 groups selected from a lower alkoxy group and a halogen-substituted lower alkyl group as substituents, R ³ and R ⁴ , R ⁵ and R ⁶ are each a hydrogen atom and A is a single bond, and Q is a sulfonyl group, n is 0 and R ¹ is a lower alkyl group, and R ² has 1 to 3 halogen atoms. The analgesic according to claim 1, wherein the active ingredient is a compound in which a phenyl group, R ³ , R ⁴ , R ^5, and R ⁶ each may be a hydrogen atom and A is a single bond. 3. In the general formula according to claim 1, R ¹ is a lower alkyl group which may have a lower alkylthio group as a substituent or a phenyl group which may have a phenylthio group as a substituent, and R ² is A phenyl group having 1 to 3 groups selected from a lower alkoxy group, a halogen atom and a halogen-substituted lower alkyl group as a substituent, wherein R ³ is a hydrogen atom or a phenyl group, and R ⁴ is a hydrogen atom, a halogen atom or a phenyl group; A compound in which R ⁵ is a hydrogen atom, R ⁶ is a hydrogen atom or a benzoyl group having a halogen-substituted lower alkyl group as a substituent, Q is a carbonyl group, and A is a single bond. 3. The analgesic according to 2. 4. The general formula according to claim 1, wherein R ³ , R ⁴
And R ⁶ are each a hydrogen atom, n is 0, and R ¹
Is an n-butyl group and R ² is a lower alkoxy group of 2-3
Or a phenyl group having 1 to 2 halogen-substituted lower alkyl groups or a phenyl group wherein R ¹ is a phenyl group and R ² is a phenyl group having 3 lower alkoxy groups. The analgesic according to claim 3, which is an active ingredient. 5. The general formula according to claim 1, wherein R ² is 2,
The compound which is a 4-dimethoxyphenyl group, 3,4,5-trimethoxyphenyl group, 2-trifluoromethylphenyl group or 2,5-bis (trifluoromethyl) phenyl group as an active ingredient. Painkillers. 6. 5-n-butyl-7- (3,4,5-trimethoxybenzoylamino) pyrazolo [1,5-a]
6. A compound selected from pyrimidine and 5-n-butyl-7- (2-trifluoromethylbenzoylamino) pyrazolo [1,5-a] pyrimidine as an active ingredient.
The analgesic according to the above. 7. N-butyl-7- (3,4,5-trimethoxybenzoylamino) pyrazolo [1,5-a]
The analgesic according to claim 6, comprising pyrimidine as an active ingredient.