JPH05125079A - Pyrazolo(1,5-a)pyrimidine derivative - Google Patents

Abstract

PURPOSE:To provide a new compound useful as an antiinflammatory agent, antirheumatic agent antiallergic agent, antipyretic agent, analgesic agent, etc. CONSTITUTION:A compound of formula I [R<1> is (lower alkyl-substituted) heterocyclic group; R<2> is H, halogen-substituted phenyl; A is group of formula II or III (R<3>, R<4> are H, lower alkyl, cycloalkyl, phenyl, etc.; R<5> is lower alkyl, lower alkoxycarbonyl, etc.; R<6> is hydroxy, lower alkyl); but when R<2> is halogen- substituted phenyl, R<3> is not carboxyl and lower alkoxycarbonyl]. For example, 7-hydroxy-5-methyl-2-[2-(1-methyl)pyrrolyl] pyrazolo[1,5-a]pyrimidine. The compound of formula I is obtained by subjecting a compound of formula V and a compound of formula V1 to a cyclization reaction in a solvent such as ethanol at room component to the boiling point of the solvent. The compound of formula V is obtained by reacting a compound of formula IV with hydrazine.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel pyrazolo [1,5
-A] pyrimidine derivatives.

[0002]

BACKGROUND OF THE INVENTION The pyrazolo [1,5-a] pyrimidine derivative of the present invention is a novel compound which has not been published in the literature.

[0003]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a compound useful as a medicine as described below.

The present invention provides a pyrazolo [1,5-a] pyrimidine derivative represented by the following general formula (1).

[0005]

[Chemical 4]

[In the formula, R ¹ is a heterocyclic group which may have a lower alkyl group as a substituent, R ² is a hydrogen atom or a halogen-substituted phenyl group, and A is a group.

[0007]

[Chemical 5]

Or

[0009]

[Chemical 6]

(In each group, R ³ and R ⁴ are the same or different and each is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a halogen-substituted lower alkyl group, a phenyl group, a carboxyl group,
R ⁵ represents a lower alkoxycarbonyl group or a halogen atom or is bonded to each other to form a lower alkylene group;
Represents a lower alkyl group, a lower alkoxycarbonyl group or a group -B-CO-Z (wherein B represents a lower alkylene group, Z represents a di-lower alkylamino group, 1-piperidinyl group or 1-pyrrolidinyl group), R ⁶ represents a hydroxy group or a lower alkyl group). However, when R ² is a halogen-substituted phenyl group, R ³ is not a carboxyl group or a lower alkoxycarbonyl group. ] As each group of the said General formula (1), each following each group can be specifically illustrated. That is, as the lower alkyl group, for example, methyl, ethyl, propyl, isopropyl,
Examples thereof include linear or branched lower alkyl groups such as butyl, isobutyl, tert-butyl, pentyl and hexyl groups.

Examples of the heterocyclic group which may have a lower alkyl group include 2- (1-methyl) pyrrolyl, 2-
Pyrrolyl, 2-thienyl, 2-furyl, 2-pyridyl,
Examples include 5-membered or 6-membered heterocyclic groups such as 3-pyridyl, 4-pyridyl, 4- (2-methyl) pyridyl, and 2-pyrazinyl groups.

Examples of the halogen-substituted phenyl group include 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 4-bromophenyl and 4-iodophenyl groups.

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

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

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

Examples of the lower alkylene group include methylene, ethylene, propylene, butylene, pentylene and hexylene groups.

Examples of the di-lower alkylamino group include dimethylamino, diethylamino, dipropylamino,
Examples thereof include dibutylamino, dipentylamino and dihexylamino groups.

The halogen atom includes a fluorine atom, a chlorine atom,
A bromine atom and an iodine atom are included.

The pyrazolo [1,5-a] pyrimidine derivative of the present invention represented by the above general formula (1) has various anti-inflammatory, anti-rheumatic, anti-allergic, antipyretic, analgesic and other pharmacological actions. Therefore, it is useful as a medicine such as an anti-inflammatory agent, an anti-rheumatic agent, an anti-allergic agent, an antipyretic agent, and an analgesic agent.

The pyrazolo [1,5-a] pyrimidine derivative of the present invention can be produced by various methods. A specific example thereof is shown in the following reaction process formula.

[0021]

[Chemical 7]

[Where R¹And R²Is the same as above. R^3aOver
And R^4aAre the same or different and are a hydrogen atom, a lower alkyl group,
Cycloalkyl group, halogen-substituted lower alkyl group,
Nyl group or halogen atom, or linked to each other
Forming a lower alkylene group, R ⁷Is a lower alkyl group
You ] In the above reaction process formula-1, a nitrile derivative
The reaction between (2) and hydrazine is ethanol, propanol
, Isoamyl alcohol, acetic acid, acetic acid-benzene,
5 in an inert solvent such as acetic acid-toluene or acetic acid-xylene
For heat treatment in the temperature range from 0 ° C to the boiling point of the solvent
Will be carried out more. The reaction is completed in about 1 to 48 hours.
It

The target compound (1a) can be obtained by subjecting the compound (3) thus obtained to a cyclization reaction with the compound (4). The cyclization reaction is ethanol,
In an inert solvent such as propanol, acetic acid, acetic acid-benzene, acetic acid-toluene, etc., at a temperature from room temperature to the boiling point of the solvent, about 2
It can take ~ 12 hours.

[0024]

[Chemical 8]

[In the formula, R ¹ , R ² , R ^3a and R ^4a are the same as defined above. R ^6a represents a lower alkyl group. The cyclization reaction of the compound (3) and the compound (5) shown in the above reaction process formula-2 is carried out in an inert solvent such as methanol or ethanol in the presence of a base such as pyridine, piperidine or triethylamine,
It is carried out by heat treatment. The amount of the compound (5) used is usually 1 to 2 times the molar amount of the compound (3), and the heating condition is generally 40 to 60 ° C. for about 2 to 12 hours, and thus the target compound ( 1b) can be obtained.

[0026]

[Chemical 9]

[Wherein R ¹ is the same as above. R ^2a represents a hydrogen atom, and R ⁸ and R ⁹ are the same or different and represent a lower alkyl group. ] As shown in the above reaction process formula-3, the compound (3
a) can be converted to compound (1c) by subjecting compound (6) to a cyclization reaction. The cyclization reaction comprises acetic acid,
The compound (6) is used in an inert solvent such as methanol or ethanol in an amount of 1 to 2 times the molar amount of the compound (3a) under the temperature condition of 80 to 120 ° C. and about 3 to 5 hours. Be seen.

[0028]

[Chemical 10]

[In the formula, R ¹ , R ² and R ⁵ are the same as defined above.
R ^3b and R ^4b are the same or different and represent a hydrogen atom, a lower alkyl group, a cycloalkyl group, a halogen-substituted lower alkyl group, a phenyl group, a lower alkoxycarbonyl group or a halogen atom, or they are bonded to each other to form a lower alkylene group. X represents a halogen atom. However, when R ² is a halogen-substituted phenyl group, R ^3b is not a lower alkoxycarbonyl group. The reaction of the compound (1d) shown in the above reaction scheme-4 with the compound (7) is carried out in the presence of a deoxidizing agent in a suitable inert solvent. Examples of the inert solvent include dichloromethane, benzene, acetone, methyl ethyl ketone, N, N-dimethylformamide (DMF), tetrahydrofuran (THF), 1,4
-Dioxane etc. can be illustrated. The amount of the compound (7) used is usually about 1 to 2 times the molar amount of the compound (1d). As the deoxidizing agent, for example, sodium hydride, sodium ethoxide, potassium carbonate, sodium carbonate, triethylamine and the like can be preferably used. The amount used is 1-2 with respect to the compound (1d).
A double molar amount can be adopted. The reaction is completed in about 3 to 12 hours under the temperature condition of about 50 to 100 ° C., and thus the compound (1e) can be obtained.

[0030]

[Chemical 11]

[In the formula, R ¹ , R ^2a , R ⁵ and R ⁸ are the same as defined above. ] The hydrolysis reaction of the compound (1c) and the compound (1g) shown in the above-mentioned reaction step formula-5 is carried out in an inert solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, an aqueous sodium hydroxide solution, and a hydroxide. It is carried out using an aqueous alkaline solution such as an aqueous potassium solution. The reaction is carried out at room temperature to a temperature around the boiling point of the solvent for about 1 to 15 hours to obtain the corresponding compounds (1f) and (1h).

Among the pyrazolo [1,5-a] pyrimidine derivatives of the present invention, the compound represented by the following general formula (1i) is a tautomer of (1j) and (1k) shown in the following formula. It is possible that they are present and the present invention also includes these compounds.

[0033]

[Chemical 12]

The target compound in each step shown in the above reaction schemes can be easily isolated and purified by a usual separation means. Examples of the means include adsorption chromatography,
Examples thereof include preparative thin layer chromatography, recrystallization, solvent extraction and the like.

Further, the compound of the present invention can be easily converted into a pharmaceutically acceptable acid addition salt by addition reaction with a suitable acidic compound according to a conventional method, and the acid addition salt is in a free form. It has the same pharmacological activity as the compound of the present invention, and the present invention also includes such an acid addition salt. Examples of the acidic compound capable of forming the acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, and maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid and benzenesulfonic acid. Examples thereof include organic acids.

Further, certain compounds included in the present invention can be easily treated pharmaceutically by treating them with an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide by a conventional method. Can be used as the alkali metal salt, which has the same pharmacological activity as the compound of the present invention in a free form, and the salt is also included in the present invention.

[0037]

EXAMPLES In order to explain the present invention in more detail, production examples of the compound of the present invention will be given below as Examples.

[0038]

Example 1 7-Hydroxy-5-methyl-2- [2-
Production of (1-methyl) pyrrolyl] pyrazolo [1,5-a] pyrimidine To 360 ml of isoamyl alcohol, 36.8 g of 2-cyanoacetyl-1-methylpyrrole and 36.4 ml of hydrazine hydrate were added, and the mixture was heated at 120 ° C. The mixture was heated and stirred for 48 hours. Then, the solvent was distilled off and the mixture was allowed to cool, and ethyl acetate and diethyl ether were added to the residue. The resulting crystals were collected by filtration, washed with diethyl ether, and 5-amino-3-
30.3 g of yellow crystals of [2- (1-methyl) pyrrolyl] pyrazole were obtained.

3.2 g of the crystals obtained above and 2.7 g of ethyl acetoacetate were added to 30 ml of acetic acid, and the mixture was stirred at 90 ° C. for 1 hour.
The mixture was heated and stirred for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, ethanol and diethyl ether were added to the residue, and the generated crystals were collected by filtration. This was further recrystallized from chloroform-methanol-diethyl ether to obtain 4.2 g of the target compound as pale yellow crystals. The structure and physical properties of the obtained compound are
Described in the table.

[0040]

Examples 2 to 21 In the same manner as in Example 1, each compound shown in Table 1 was produced. The structure and physical properties of the obtained compound are also shown in Table 1.

[0041]

Example 22 Preparation of 5,7-dimethyl-2- [2- (1-methyl) pyrrolyl] pyrazolo [1,5-a] pyrimidine 5-amino-3- [2- (1
-Methyl) pyrrolyl] pyrazole (see Example 1) 5.
4 g, acetylacetone 4.0 g and piperidine 4 drops were added, and the mixture was heated under reflux for 12 hours. After allowing to cool, the reaction solution was poured into water, and the precipitated crystals were collected by filtration. This was further recrystallized from chloroform-diethyl ether-n-hexane to obtain 6.3 g of a yellow crystal of the target compound. The structure and physical properties of the obtained compound are shown in Table 1.

[0042]

Examples 23 to 25 In the same manner as in Example 22, each compound shown in Table 1 was prepared. The structure and physical properties of the obtained compound are also shown in Table 1.

[0043]

Example 26 Preparation of 6-ethoxycarbonyl-7-hydroxy-2- [2- (1-methyl) pyrrolyl] pyrazolo [1,5-a] pyrimidine 5-amino-3- [2- (1-methyl) ) Pyrrolyl] pyrazole (see Example 1) (8.1 g) and diethyl ethoxymethylene malonate (12.8 g) were dissolved in 100 ml of acetic acid, and the mixture was heated with stirring at 100 ° C for 12 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the precipitated crystals were collected by filtration and washed successively with ethanol and diethyl ether to obtain 10.6 g of green crystals of the desired compound. The structure and physical properties of the obtained compound are shown in Table 1.

[0044]

Example 27 Sodium 5-methyl-2- [2-
Production of (1-methyl) pyrrolyl] pyrazolo [1,5-a] pyrimidine-7-oleate 175 mg of sodium hydroxide was added to 20 ml of methanol, and the mixture was refluxed for several minutes. 1 g of the compound obtained in Example 1 was added thereto, and the mixture was heated under reflux for 5 minutes. The reaction solution was filtered to remove impurities, the filtrate was concentrated, and diethyl ether was added to the residue. The generated crystals were collected by filtration and washed with diethyl ether to obtain 0.99 g of the target compound.

[0045]

Example 28 4,7-Dihydro-4-ethyl-2-
[2- (1-methyl) pyrrolyl] pyrazolo [1,5-
a] Production of pyrimidin-7-one 7.0 g of the compound obtained in Example 2, 6.2 g of anhydrous potassium carbonate and 4.9 g of ethyl bromide were added to 100 ml of DMF, and the mixture was heated with stirring at 60 ° C. for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (developing solvent: chloroform) and recrystallized from chloroform-diethyl ether to obtain 6.1 g of the target compound. .. Table 2 shows the structure and physical properties of the obtained compound.

[0046]

Examples 29 to 41 In the same manner as in Example 28, each compound shown in Table 2 was produced. Table 2 shows the structures and physical properties of the obtained compounds.

[0047]

Example 42 6-carboxy-4,7-dihydro-4
-Methyl-2- [2- (1-methyl) pyrrolyl] pyrazolo [1,5-a] pyrimidin-7-one Preparation Example 3
1.0 g of ethanol obtained in Example 7 (20 ml)
To the suspension was added 5 ml of 5% aqueous sodium hydroxide solution,
The mixture was heated under reflux for 1 hour. After cooling, dilute hydrochloric acid was added to make the mixture acidic, and the precipitated crystals were collected by filtration, washed successively with ethanol and diethyl ether, and then recrystallized from chloroform-methanol to obtain 0.33 g of yellow crystals of the desired compound. .. Table 2 shows the structure and physical properties of the obtained compound.

[0048]

[Table 1]

[0049]

[Table 2]

[0050]

[Table 3]

[0051]

[Table 4]

[0052]

[Table 5]

[0053]

[Table 6]

[0054]

[Table 7]

[0055]

[Table 8]

[0056]

[Table 9]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical indication location A61K 31/505 ABG (72) Inventor Hashimoto Sajiji East 7 of Kitahama, Miyake, Senyo-cho, Naruto City, Tokushima Prefecture Address 8

Claims (1)

[Claims] 1. A general formula: [Wherein R ¹ is a heterocyclic group which may have a lower alkyl group as a substituent, R ² is a hydrogen atom or a halogen-substituted phenyl group, and A is a group Or the group (In each group, R ³ and R ⁴ are the same or different and represent a hydrogen atom, a lower alkyl group, a cycloalkyl group, a halogen-substituted lower alkyl group, a phenyl group, a carboxyl group, a lower alkoxycarbonyl group or a halogen atom, or are bonded to each other. To form a lower alkylene group, R ⁵ is a lower alkyl group, a lower alkoxycarbonyl group or a group —B—CO—
Z (in the formula, B represents a lower alkylene group, Z represents a di-lower alkylamino group, 1-piperidinyl group or 1-pyrrolidinyl group), and R ⁶ represents a hydroxy group or a lower alkyl group). However, when R ² is a halogen-substituted phenyl group, R ³ is not a carboxyl group or a lower alkoxycarbonyl group. ] The pyrazolo [1,5-a] pyrimidine derivative represented by these.