JPH05112571A - Pyrimidine derivative - Google Patents

Abstract

PURPOSE:To provide the subject new compound having excellent action to inhibit the development of action of androgen and exhibiting excellent effect for the treatment of prostatic hypertrophy, female polytrichia and male bald, pimple, etc. CONSTITUTION:The compound of formula [R<1> is H or OH; R<2> is H, lower alkoxycarbonyl, halogen, lower alkyl, (substituted)phenyl, etc.; R<3> is H, OH, lower alkyl, 3-8C cycloalkyl, phenyl, etc.; R<4> is H, lower alkyl or lower alkoxy; R<5> is H, lower alkyl, lower alkoxy-lower alkyl, etc.], e.g. 3-(4-phenylthiophenyl) pyrazolo[1,5-a]pyrimidine. The compound of formula I can be produced e.g. by reacting a compound of formula II with a compound of formula III (R<8>, R<9> and R<14> are lower alkyl; R<7> is H or lower alkyl) in the presence of an acid such as anhydrous aluminum chloride optionally in a solvent such as pyridine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel pyrimidine derivative which inhibits the expression of androgen action.

[0002]

2. Description of the Related Art Androgens (male hormones) are mainly synthesized in the testes of adult males, and maintain the functions of reproductive organs and accessory reproductive organs (prostate, seminal vesicles) and sperm. It has functions such as formation. It is known that when the balance between these androgens and estrogens (female hormones) is lost and the action of androgens is accelerated, enlargement of the prostate gland, female hirsutism, and male baldness or acne occur. Prostate enlargement is 60
Approximately 30% of men over the age of 50 have symptoms of benign prostatic hyperplasia, such as difficulty urinating.

Known as androgens are testosterone, androstenedione, dehydroepiandrosterone and the like. It is also known that 85% of the androgens synthesized in the testes of adult males are testosterone. In the cells of the prostate, the testosterone becomes 5α-dihydrotestosterone (5α-DHT) by 5α-reductase, then binds to the receptor and enters the nucleus, activates the gene, and expresses the above-mentioned action. To do.

Chlormadinone acetate, flutamide, hydroxyflutamide and the like are known as substances which inhibit the expression of the action of androgens. However,
The inhibitory activity of androgen activity by these compounds is not fully satisfactory, and therefore the therapeutic effect on prostatic hypertrophy, female hirsutism, male baldness or acne is not sufficient.

Therefore, an object of the present invention is to provide a novel compound which is excellent in inhibiting the action expression of androgen, and which is excellent in the therapeutic effect on benign prostatic hyperplasia, female hirsutism, male pattern baldness or acne.

[0006]

Means and Actions for Solving the Problems As a result of intensive studies aimed at achieving the above object, the present inventors have found that a pyrimidine derivative represented by the following general formula (1) and a pharmaceutically acceptable derivative thereof. The present invention has been completed by obtaining new knowledge that salts are excellent in the effect of inhibiting the action expression of androgen.

[0007]

[Chemical 2]

[Wherein R ¹ represents a hydrogen atom or a hydroxyl group, R ² represents a hydrogen atom, a lower alkoxycarbonyl group, a lower alkoxy group, a halogen atom, a lower alkyl group, a cycloalkyl group having 3 to 8 carbon atoms, Lower alkoxycarbonyl lower alkyl group, carboxyl group, carboxy lower alkyl group, group: -CONHR ⁶ (R ⁶ represents a hydrogen atom, a phenyl group which may have a halogen atom or a lower alkyl group), a cyano group, a substituent A phenyl group which may have a group selected from the group consisting of a hydroxyl group, a halogen atom, a lower alkyl group, a lower alkoxy group and a phenylthio group, and a group selected from the group consisting of a hydroxyl group and a lower alkoxy group as a substituent on the phenyl ring. Phenyl lower alkyl groups that may have, lower alkanoyloxy lower alkyl Group, a benzoyl group, a certain hydroxy lower alkyl group which may have a lower alkanoyl group or a group selected from the group consisting of phenyl group and a halogen atom as a substituent which may have a halogen atom, R ³ is a hydrogen atom, A hydroxyl group, a lower alkyl group, a cycloalkyl group having 3 to 8 carbon atoms, a halogen lower alkyl group or a phenyl group, R ⁴ represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and R ⁵ represents a hydrogen atom, a lower group An alkyl group, a lower alkoxy lower alkyl group or a halogen lower alkyl group is shown. However, R ² and R ³ may be bonded together to form a lower alkylene group having 3 to 5 carbon atoms. ] Such a pyrimidine derivative of the present invention
(1) and its pharmaceutically acceptable salts are novel compounds that have not been described in the literature, and highly inhibit the binding of intracellular receptors to 5α-DHT, the binding of intracellular receptors to mibolerone, etc. Have activity.

Therefore, the pyrimidine derivative of the present invention
(1) and pharmaceutically acceptable salts thereof can inhibit the action expression of androgen, and are excellent for treating prostatic hypertrophy caused by accelerated action of androgen, hirsutism in women, male baldness or acne, etc. Show the effect. The lower alkyl group in the above general formula (1) includes, for example, methyl, ethyl, butyl, propyl, isopropyl, butyl, t-butyl, pentyl and hexyl having 1 to 6 carbon atoms.
The alkyl group of

As the lower alkoxycarbonyl group, for example, the alkoxy moiety such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl group has 1 to 10 carbon atoms. 6 is an alkoxycarbonyl group.

Examples of the lower alkoxy group include alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy and hexyloxy groups. Examples of the halogen atom include chlorine, bromine, iodine and fluorine. As the cycloalkyl group having 3 to 8 carbon atoms,
Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, cyclooctyl and the like.

Examples of the lower alkoxycarbonyl lower alkyl group include methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, propoxycarbonylmethyl, propoxycarbonylethyl, isopropoxycarbonylmethyl, butoxycarbonylmethyl, t-butoxycarbonyl. Alkoxy having 1 to 6 carbon atoms in the alkoxy portion and 1 to 6 carbon atoms in the alkyl portion such as methyl, pentyloxycarbonylmethyl, hexyloxycarbonylmethyl, 1-ethyl-2-methoxycarbonylbutyl, and hexyloxycarbonylhexyl. Examples thereof include a carbonylalkyl group.

As the carboxy lower alkyl group, for example, carboxymethyl, carboxyethyl, 3-carboxypropyl, 1-methyl-2-carboxyethyl, 4-
Examples thereof include a carboxy lower alkyl group having 1 to 6 carbon atoms in the alkyl portion such as carboxybutyl, 1,1-dimethyl-2-carboxyethyl, 5-carboxypentyl, 6-carboxyhexyl and the like.

As the phenyl group which may have a halogen atom, for example, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3
-Bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2
-Fluorophenyl, 4-fluorophenyl, 2,4-
Dichlorophenyl, 2,3-dichlorophenyl, 3,5
-Dichlorophenyl, 2,6-dichlorophenyl, 2,
4-dibromophenyl, 2,3-dibromophenyl,
3,5-dibromophenyl, 2,4-diiodophenyl, 3,5-diiodophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 2,3,4-trichlorophenyl, 3,4 5-trichlorophenyl,
2,3,4-tribromophenyl, 3,4,5-tribromophenyl, 2,3,4-triiodophenyl, 3,
Examples thereof include a phenyl group which may have 1 to 3 halogen atoms such as 4,5-triiodophenyl, 2,3,4-trifluorophenyl and 3,4,5-trifluorophenyl.

As the phenyl group which may have a group selected from the group consisting of a hydroxyl group, a halogen atom, a lower alkyl group, a lower alkoxy group and a phenylthio group as a substituent, for example, phenyl; 2-hydroxyphenyl,
3-hydroxyphenyl, 4-hydroxyphenyl,
3,4-dihydroxyphenyl, 3,4,5-trihydroxyphenyl; 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3 -Bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 2-bromo-4-chlorophenyl,
3,4,5-trichlorophenyl; o-tolyl, m-tolyl, p-tolyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-propylphenyl,
3-propylphenyl, 4-propylphenyl, 2-butylphenyl, 3-butylphenyl, 4-butylphenyl, 4-t-butylphenyl, 2-pentylphenyl,
3-pentylphenyl, 4-pentylphenyl, 2-hexylphenyl, 3-hexylphenyl, 4-hexylphenyl, 2,4-dimethylphenyl, 3,5-dimethylphenyl, 2,4-dibutylphenyl, 3,5- Dibutylphenyl, 3,4,5-trimethylphenyl, 2,
3,4-trimethylphenyl; 2-methoxyphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 3-t-butoxyphenyl, 4-ethoxyphenyl, 4-hexyloxyphenyl, 2,3-dipropoxyphenyl, 3-chloro- 4-ethylphenyl; 2-hydroxy-3-pentylphenyl, 3-methyl-4-bromo-5-methoxyphenyl; phenylthiophenyl, and other hydroxyl groups, halogen atoms, alkyl groups having 1 to 6 carbon atoms, and 1 carbon atom A phenyl group which may have 1 to 4 substituents selected from the group consisting of alkoxy groups of ~ 6 and phenylthio groups.

Examples of the phenyl lower alkyl group which may have a substituent selected from the group consisting of a hydroxyl group and a lower alkoxy group on the phenyl ring include, for example, benzyl, α-methylbenzyl, phenethyl, trityl, 3
-Phenylpropyl, phenylhexyl; 2-hydroxyphenylmethyl, 3-hydroxyphenylmethyl, 4
-Hydroxyphenylmethyl, 2- (2-hydroxyphenyl) ethyl, 2- (3-hydroxyphenyl) ethyl, 2- (4-hydroxyphenyl) ethyl, 3- (4
-Hydroxyphenyl) hexyl, 3- (3,4-dihydroxyphenyl) propyl; 2-methoxyphenylmethyl, 3-methoxyphenylmethyl, 4-methoxyphenylmethyl, 4-ethoxyphenylmethyl, 3-propoxyphenylbutyl, 2- Butoxyphenylhexyl,
4-hexyloxyphenylpropyl, 2,4-dibutoxyphenylpropyl, 3,5-dimethoxyphenylmethyl, 3,5-diethoxyphenylbutyl, 2,3,4
-The alkyl moiety, which may have 1 to 3 groups selected from the group consisting of a hydroxyl group and an alkoxy group having 1 to 6 carbon atoms on the phenyl ring, such as trimethoxyphenylmethyl, has 1 carbon atom. A phenyl lower alkyl group which is ˜6.

As the lower alkanoyloxy lower alkyl group, for example, acetoxymethyl, 2-acetoxyethyl, propionyloxymethyl, 2-propionyloxyethyl, 1-hexanoyloxy-2-methylpentyl, and the like lower alkyl having 2 to 6 carbon atoms. Examples include groups having an alkanoyl moiety and a lower alkyl moiety having 1 to 6 carbon atoms.

Examples of the hydroxy lower alkyl group include hydroxymethyl, 2-hydroxyethyl, 1,1-
Dimethyl-2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-hydroxybutyl,
5-hydroxypentyl, 1-hydroxypentyl, 6
Examples thereof include groups having a lower alkyl moiety having 1 to 6 carbon atoms, such as -hydroxyhexyl.

Examples of the halogen lower alkyl group include a monochloromethyl group, monobromomethyl, monoiodomethyl, monofluoromethyl, dichloromethyl, dibromomethyl, diiodomethyl, difluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, trifluoro. 1 to 3 carbon atoms substituted with 1 to 3 halogen atoms such as methyl, monochloroethyl, monobromoethyl, monofluoroethyl, dichlorobutyl, dibromobutyl, diiodobutyl, difluorobutyl, chlorhexyl, bromohexyl, iodohexyl and fluorohexyl ~ 6 alkyl groups.

As the lower alkoxy lower alkyl group,
For example, an alkoxy moiety such as methoxymethyl, methoxyethyl, methoxybutyl, methoxyhexyl, ethoxymethyl, propoxyethyl, isopropoxymethyl, methoxypropyl, butoxyethyl, t-butoxyhexyl, pentyloxyethyl, hexyloxymethyl, hexyloxypropyl. And a lower alkoxy lower alkyl group in which each of the alkyl moieties has 1 to 6 carbon atoms.

Examples of the lower alkanoyl group which may have a halogen atom include acetoxy, propionyl, butyryl, hexanoyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl, dibromoacetyl, tribromoacetyl, monoiodoacetyl, triiodo. Acetyl, monofluoroacetyl, difluoroacetyl, trifluoroacetyl, 3-
Chloropropionyl, 2,3-dichloropropionyl,
It may have 1 to 3 halogen atoms such as 3,3,3-trichloropropionyl, 4-chlorobutyryl, 4-chloropentanoyl, 6-chlorohexanoyl, 3-fluoropropionyl and 4-fluorobutyryl. Examples thereof include alkanoyl groups having 2 to 6 carbon atoms.

Examples of the hydroxy lower alkyl group which may have a group selected from the group consisting of a phenyl group and a halogen atom as a substituent include, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2
-Hydroxy-1,1-dimethylethyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl, 1
-Hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 3-hydroxypentyl, 5-hydroxypentyl, 1-hydroxyhexyl, 3-hydroxyhexyl, 5-hydroxyhexyl, 6-hydroxyhexyl; α-hydroxybenzyl, 2 -Phenyl-2-
Hydroxyethyl, 2,2-diphenyl-1-hydroxyethyl, 2,2,2-triphenyl-1-hydroxyethyl, 3-phenyl-1-hydroxypropyl, 3,
3-diphenyl-2-hydroxypropyl, 4-phenyl-2-hydroxypentyl, 5-phenyl-5-hydroxypentyl, 6,6,6-triphenyl-1-hydroxyhexyl, 1-phenyl-6-hydroxyhexyl; 1-hydroxy-2-chloroethyl, 1-chloro-
2-hydroxyethyl, 2-hydroxy-2-chloroethyl, 1-hydroxy-2,2-dichloroethyl, 1-
Hydroxy-2,2,2-trichloroethyl, 1-hydroxy-2-bromoethyl, 1-bromo-2-hydroxyethyl, 1-hydroxy-2,2-dibromoethyl,
1-hydroxy-2,2,2-tribromoethyl, 2-
Hydroxy-2-iodoethyl, 1-hydroxy-2,
2-diiodoethyl, 1-hydroxymethyl-2,2
2-triiodoethyl, 1-fluoro-2-hydroxyethyl, 1-hydroxy-2,2,2-trifluoroethyl, 2-hydroxy-3-chloropropyl, 2-hydroxy-3,3-dichloropropyl, 1 -Chloro-3-
Hydroxypropyl, 1-hydroxy-2,3-dibromopropyl, 2,2-dibromo-3-hydroxypropyl, 2-iodo-3-hydroxypropyl, 1-fluoro-3-hydroxypropyl, 2-hydroxy-3,
3,3-trifluoropropyl, 2-hydroxymethyl-3,3,3-trifluoropropyl, 2-chloro-2
-Methyl-3-hydroxypropyl, 3-hydroxy-
4-chlorobutyl, 2-hydroxy-4-bromobutyl, 2-hydroxy-3,4-dichlorobutyl, 2-hydroxy-4,4-difluoropentyl, 4-hydroxy-5-chloropentyl, 3-hydroxy-4-bromo Pentyl, 2-hydroxy-5-iodopentyl, 4-
Hydroxy-6-chlorohexyl, 3-hydroxy-
4,4-dichlorohexyl, 3,4-dichloro-6-hydroxyhexyl, 3-hydroxy-6-fluorohexyl, 5,5-difluoro-6-hydroxyhexyl,
1-hydroxy-2-chloro-3-phenylpropyl,
Examples thereof include 1-hydroxy-3-phenyl-4-bromobutyl and the like, which may have 1 to 3 phenyl groups or a halogen atom and have an alkyl moiety having 1 to 6 carbon atoms.

The compounds represented by the general formula (1) include, for example, the following compounds. 3- (4-phenylthiophenyl) pyrazolo [1,5-
a] pyrimidine, 7-hydroxy-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 5
-Hydroxy-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 6-ethoxycarbonyl-3- (4-phenylthiophenyl) pyrazolo [1,
5-a] pyrimidine, 6-ethoxycarbonyl-7-hydroxy-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 6-methoxy-7-hydroxy-3- (4-phenylthiophenyl) ) Pyrazolo [1,5-a] pyrimidine, 6-fluoro-7-hydroxy-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 6-chloro-5-ethyl-
7-Hydroxy-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 6-phenyl-7-
Hydroxy-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 6-methyl-7-hydroxy-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 6- Cyclohexyl-7-
Hydroxy-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 6-phenethyl-7-hydroxy-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 6- Benzyl-7-hydroxy-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 6- (2-methoxyphenylmethyl) -7-hydroxy-3- (4-phenylthiophenyl) pyrazolo [ 1,5-a] pyrimidine, 6-
(3,5-Dimethoxyphenylmethyl) -7-hydroxy-3- (4-phenylthiophenyl) pyrazolo [1,
5-a] pyrimidine, 6-ethoxycarbonylmethyl-
7-Hydroxy-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 6-ethoxycarbonylpropyl-7-hydroxy-3- (3-methoxy-
4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 6-carboxy-7-hydroxy-3- (3
-Methoxy-4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 6-carboxyethyl-7
-Hydroxy-3- (3-methoxy-4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 6-carboxy-7-hydroxy-3- (4-phenylthiophenyl) pyrazolo [1,5-a ] Pyrimidine, 6-carbamoyl-7-hydroxy-2-methyl-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 6- (N-phenylcarbamoyl) -7-hydroxy-3- ( 4-phenylthiophenyl) pyrazolo [1,
5-a] pyrimidine, 6- (N-3,4,5-trichlorophenyl) carbamoyl-7-hydroxy-3- (4
-Phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 6- (N-ethyl) carbamoyl-7-hydroxy-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 6-cyano -7-Hydroxy-3- (4-phenylthiophenyl) pyrazolo [1,
5-a] pyrimidine, 6-ethoxycarbonyl-5-hydroxy-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 5,7-dihydroxy-3
-(4-phenylthiophenyl) pyrazolo [1,5-
a] pyrimidine, 6-methoxycarbonyl-3- (4-
Phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 5-hydroxy-6-methoxycarbonyl-3-
(4-Phenylthiophenyl) pyrazolo [1,5-a]
Pyrimidine, 5-isopropyl-6-isopropoxycarbonyl-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 5-hydroxy-6-hexyloxycarbonyl-3- (4-phenylthiophenyl) Pyrazolo [1,5-a] pyrimidine, 7-hydroxy-5-cyclohexyl-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 6-hexyloxycarbonyl-3- (4-phenylthio) (Phenyl) pyrazolo [1,5-a] pyrimidine, 7-hydroxy-3- (3-methoxy-4-phenylthiophenyl)
Pyrazolo [1,5-a] pyrimidine, 7-hydroxy-
6-Ethoxycarbonyl-3- (3-methoxy-4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 7-hydroxy-3- (3,5-dimethoxy-4-)
Phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 3- (2-ethoxy-4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 7-hydroxy-2-methyl-3- (4- Phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 7-hydroxy-6
-Ethoxycarbonyl-2-methyl-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine,
7-Hydroxy-2-methoxymethyl-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 7-hydroxy-2-trifluoromethyl-3-
(4-Phenylthiophenyl) pyrazolo [1,5-a]
Pyrimidine, 5-methyl-2-ethoxymethyl-3-
(3-Methoxy-4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 7-hydroxy-6-ethoxycarbonyl-2-methoxymethyl-3- (4-phenylthiophenyl) pyrazolo [1,5- a] Pyrimidine, 7-hydroxy-6-ethoxycarbonyl-2-trifluoromethyl-3- (4-phenylthiophenyl)
Pyrazolo [1,5-a] pyrimidine, 5,7-dihydroxy-6-ethoxycarbonyl-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 5,
7-dihydroxy-6-butoxycarbonyl-3- (4
-Phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 5,7-dihydroxy-6-t-butoxycarbonyl-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 5,7 -Dihydroxy-6
-Hexyloxycarbonyl-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 7-hydroxy-5-methyl-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine , 7-hydroxy-5-cyclopropyl-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 7-hydroxy-5-chloromethyl-3- (4-phenylthiophenyl) pyrazolo [1, 5-a] pyrimidine, 7-hydroxy-5-phenyl-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 5H-6,7
-Dihydro-8-hydroxy-3- (4-phenylthiophenyl) -cyclopenta [d] pyrazolo [1,5-
a] pyrimidine, 5-ethyl-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 7-hydroxy-5-trifluoromethyl-3- (4-phenylthiophenyl) pyrazolo [1, 5-a] pyrimidine,
5-Methyl-6-ethoxycarbonyl-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 6-acetyl-7-hydroxy-3- (4-phenylthiophenyl) pyrazolo [1,5 -A] pyrimidine,
6-benzoyl-7-hydroxy-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 7
-Hydroxy-3- (4-phenylthiophenyl) -6
-Trifluoroacetylpyrazolo [1,5-a] pyrimidine, 7-hydroxy-6- (1-hydroxyethyl)
-3- (4-phenylthiophenyl) pyrazolo [1,5
-A] pyrimidine, 7-hydroxy-6- (α-hydroxybenzyl) -3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 7-hydroxy-6
-(1-Hydroxy-2,2,2-trifluoroethyl) -3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine, 7-hydroxy-6- (3
-Bromo-4-methoxyphenyl) -3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine The compound of the present invention represented by the above general formula (1) can be produced by various methods. For example, the following reaction process formula-1
It can be manufactured by the method shown in -18. Reaction process formula-1

[0024]

[Chemical 3]

(Wherein R ²¹ represents a lower alkoxycarbonyl group, R ⁸ , R ⁹ and R ¹⁴ are the same or different and represent a lower alkyl group, R ⁷ represents a hydrogen atom or a lower alkyl group, and R ¹ , R ³ , R ⁴ and R ⁵ are the same as above.) In the above reaction, the compound represented by the formula (2) and the compound represented by the general formula (3) are used in the absence of solvent or in a suitable solvent. By reacting in the presence of an acid to obtain the compound of the present invention represented by the general formula (1-a).

Examples of the solvent include halogenated hydrocarbons such as pyridine, chloroform and dichloromethane, ethers such as dioxane and tetrahydrofuran (THF), aromatic hydrocarbons such as benzene and toluene, and N, N-.
Examples include aprotic polar solvents such as dimethylformaldehyde (DMF), dimethylsulfoxide (DMSO) and acetonitrile. Examples of the acid include anhydrous aluminum chloride, stannic chloride, titanium tetrachloride,
Boron trichloride, boron trifluoride-ethyl ether complex,
Examples thereof include Lewis acids such as zinc chloride, inorganic acids such as phosphoric acid, hydrochloric acid, nitric acid and sulfuric acid, and organic acids such as trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid and acetic acid.

The ratio of the compound (3) to the compound (2) used is at least equimolar, preferably 1 to 1.5 times the molar amount. The ratio of the acid used to the compound (2) is 1 to 50 times, preferably 1 to 20 times the molar amount. The reaction is usually 50 to 150 ° C,
It is preferably carried out at 80 to 120 ° C. and is completed in about 1 to 6 hours.

In the above reaction, the compound of the general formula (1-a)
R ¹ is a hydrogen atom, and R ³ is a compound represented by
A compound in which R is a hydroxyl group and a compound in which R ¹ is a hydroxyl group and R ³ is a hydrogen atom are simultaneously obtained. These separations can be performed by various conventionally known methods, for example, by utilizing the difference in the solubility of each alcohol or the like in a solvent. Reaction process formula-2

[0029]

[Chemical 4]

(In the formula, R ³¹ represents a lower alkyl group,
⁴ , R ⁵ , R ⁸ and R ⁹ are the same as above. ) The above reaction is carried out by reacting the compound represented by the formula (2) with the compound represented by the general formula (4) in the presence of an acid in the absence of a solvent or a suitable solvent, the general formula (1-b) The compound of the present invention represented by is obtained.

As the solvent and the acid used in this reaction, those shown in the above reaction process formula-1 can be mentioned. The ratio of the compound (4) to the compound (2) used is at least equimolar, preferably 1 to 1.5 times the molar amount. The ratio of the acid to the compound (2) used is 1 to 100 times, preferably 1 to 50 times the molar amount. The reaction is usually 50 to 150 ° C,
It is preferably carried out at 80 to 120 ° C. and is completed in about 1 to 5 hours. Reaction process formula-3

[0032]

[Chemical 5]

(In the formula, R ⁴ and R ⁵ are the same as above.) This reaction is carried out from the compound represented by the above formula (5):
The compound of the formula (2) is obtained in the presence of a base in the absence of a solvent or a suitable solvent. Examples of the base used in this reaction include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium hydrogen carbonate,
Examples thereof include inorganic bases such as alkali metal hydrogencarbonates such as potassium hydrogencarbonate.

As the solvent, any solvent can be used as long as it does not affect the reaction, and examples thereof include lower alcohols such as methanol and ethanol, mixed solvents of lower alcohol and water, and the like. When using the above mixed solvent, the mixing ratio of the lower alcohol and water is
The range may be about 1: 1 to 10: 1. Compound (5)
The basic compound is used in a molar ratio of 1 to 50 times, preferably 1 to 20 times. The reaction temperature is room temperature to 100 ° C., preferably 30 to 10
It is better to set it to 0 ° C. The reaction time is about 10 minutes to 2 hours. Reaction process formula-4

[0035]

[Chemical 6]

(In the formula, R ⁴ and R ⁵ are the same as above.) In this reaction, at least equimolar amount of a semicarbazide / mineral salt is added to a compound represented by the formula (6) under ice cooling, Preferably, the compound represented by the formula (5) is obtained by dropwise adding about 1 to 1.2 times the molar amount and then reacting at room temperature for about 4 to 15 hours. As the solvent used in this reaction, any solvent that does not affect the reaction can be used, and examples thereof include lower alcohols such as methanol and ethanol, and mixed solvents of lower alcohol and water. .. When the above mixed solvent is used, the mixing ratio of lower alcohol and water may be in the range of about 1: 1 to 10: 1. Reaction process formula-5

[0037]

[Chemical 7]

(In the formula, R ¹⁰ represents a lower alkyl group,
⁴ and R ⁵ are the same as above. ) This reaction has the formula
The compound of formula (6) is obtained by reacting the acetonitrile derivative represented by (7) with a specific ester. When a formate ester is used as the ester, the group R ⁵ becomes a hydrogen atom. Examples of the formate ester include methyl formate and ethyl formate.

This reaction is carried out in an inert solvent. Examples of the inert solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and dioxane,
N, N-dimethylformamide, dimethylsulfoxide, etc. can be illustrated. The ratio of the ester used to the compound (7) may be at least equimolar amount,
It is preferably 1.05 to 1.25 times the molar amount. The reaction is usually carried out under ice-cooling for about 5 to 20 minutes and then at room temperature for about 4 to 15 hours. In order to allow the reaction to proceed sufficiently, it is preferable that sodium alkoxide such as sodium methoxide and metal hydride such as sodium hydride are present at least in an equimolar amount with respect to the ester.

The reaction product (6) is precipitated by adding water to the reaction solution to separate the aqueous layer and adjusting the pH of the aqueous layer to 3 to 4 with a mineral acid such as hydrochloric acid. Reaction process formula-6

[0041]

[Chemical 8]

(In the formula, X represents a halogen atom, R ¹¹ represents a lower alkyl group, and R ⁴ is the same as the above.) This reaction is carried out by hydrogenating the compound represented by the general formula (8). By reducing with a reducing agent, a compound represented by the formula (9) is obtained, and then the compound represented by the formula (9) is reacted with a halogenating agent to produce a compound represented by the general formula (10). The compound (7), which is the starting material of reaction formula-5, is obtained by obtaining the compound described above and further reacting the compound (10) with a cyanide compound.

The reaction for obtaining the compound (9) from the compound (8) is
It is carried out in a suitable solvent. Examples of the solvent include ethers such as diethyl ether, tetrahydrofuran, dioxane and diglyme; aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene and toluene. Examples of the hydrogenation reducing agent used in this reaction include lithium aluminum hydride, aluminum hydride, diisopropyl aluminum hydride, lithium borohydride, sodium borohydride-aluminum chloride, diborane and the like. The amount of the hydrogenating / reducing agent to be used with respect to the compound (8) is at least 0.5-fold molar amount, preferably 0.6 to 1.2-fold molar amount. The reaction is usually performed under ice cooling to 100 ° C, preferably about 0 to 50 ° C, and is completed in about 30 minutes to 10 hours.

The reaction for obtaining the compound (10) from the compound (9) is
It is carried out without solvent or in a suitable solvent. As the solvent used in this reaction, ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane,
Examples thereof include aromatic hydrocarbons such as benzene and toluene.
Examples of the halogenating agent used in this reaction include thionyl halides such as thionyl chloride and thionyl bromide, hydrogen halides such as hydrogen chloride, hydrogen bromide and hydrogen iodide, phosphorus trichloride and phosphorus tribromide. And the like. The amount of halogenating agent used with respect to compound (9) is
The amount is at least equimolar, preferably 1 to 1.3 times. The reaction is carried out under ice cooling to 100 ° C., preferably 0 to 50.
It is carried out at about C and is completed in about 30 minutes to 5 hours.

The reaction for obtaining the compound (7) from the compound (10) is
It is carried out in a suitable solvent. Solvents used in this reaction include lower alcohols such as methanol, ethanol and propanol, aprotons such as acetone, N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO) and hexamethylphosphoric triamide (HMPA). Examples include polar solvents and mixed solvents of these with water. Further, examples of the cyan compound used in this reaction include potassium cyanide, sodium cyanide, silver cyanide, copper cyanide, calcium cyanide and the like. The amount of the cyanating agent used with respect to the compound (10) is at least an equimolar amount, preferably 1 to 1.3 times the molar amount.
The reaction is carried out at room temperature to 150 ° C., preferably at room temperature to 100 ° C. and is completed in about 1 to 24 hours. Reaction process formula-7

[0046]

[Chemical 9]

(In the formula, R ¹¹ and R ⁴ are the same as described above.) This reaction is carried out by subjecting the compound represented by the general formula (11) to a general esterification reaction,
The compound represented by the general formula (8), which is the starting material of 6, is obtained. The above esterification reaction is carried out, for example, by reacting the compound (11) with an alcohol represented by the general formula: R ¹¹ —OH (wherein R ¹¹ is the same as above) in the presence of a catalyst. Done. As the catalyst used, a conventional catalyst for the esterification reaction is used, and specifically, inorganic acids such as hydrogen chloride, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride, perchloric acid, and trifluoroacetic acid. , Organic acids such as trichloromethanesulfonic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid and ethanesulfonic acid, acid anhydrides such as trichloromethanesulfonic anhydride and trifluoromethanesulfonic anhydride, thionyl chloride and the like The catalyst is. A cation exchange resin (acid type) can also be used. The above esterification reaction is carried out without solvent or in the presence of a suitable solvent. As the solvent used, any solvent commonly used in esterification reactions can be used, for example, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform, diethyl ether. , Ethers such as tetrahydrofuran, dioxane, and the like. The acid may be used in an equimolar to 100-fold molar amount, preferably 10 to 30-fold molar amount with respect to the compound (11). The reaction temperature is −20 ° C. to 200 ° C., preferably 0 to 150 ° C.

The compound (8) can be prepared by adding an alkali metal salt of the compound (11) (for example, sodium salt, potassium salt, etc.) to the compound of the general formula: R ¹¹ —X (wherein R ¹¹ and X are the same as above). The method of reacting a halide compound represented by the above, a method of reacting compound (11) with a diazoalkane such as diazomethane, diazoethane, diazopropane, etc. (Anhydrous),
It can also be obtained by a method of reacting an alcohol represented by the general formula: R ¹¹ —OH (wherein R ¹¹ is the same as above). These esterification reactions can be performed according to a conventional method. Reaction process formula-8

[0049]

[Chemical 10]

(In the formula, X and R ⁴ are the same as above.) In this reaction, a benzoic acid derivative represented by the general formula (12) and a phenylthio derivative represented by the general formula (27) are obtained. After the reaction, the general formula which is the starting material of the above reaction process formula-7
The compound represented by (11) is obtained. This reaction is
It is carried out in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent. As the solvent used,
N, N-dimethylformamide (DMF), N, N-dimethylacetamide, dimethyl sulfoxide (DMS)
Examples thereof include aprotic polar solvents such as O) and hexamethylphosphoric triamide (HMPA).

The ratio of the compound (27) to the compound (12) is at least an equimolar amount, preferably a slight excess. Further, the basic compound forms a salt of the compound (12) and the compound (27), and therefore it is preferable to use at least a 2-fold molar amount, preferably a slight excess, with respect to the compound (12). The reaction is usually performed at room temperature to 180 ° C. and is completed in about 30 minutes to 24 hours. Reaction process formula-9

[0052]

[Chemical 11]

(Wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ^5
21 is the same as above. ) This reaction is represented by the general formula (1-c) by removing the lower alkoxycarbonyl group represented by the group R ²¹ from the compound (1-a) obtained in the above reaction process formula-1. To obtain the compound. The reaction is carried out in the presence of an acid without solvent or in a suitable solvent. As the solvent, any solvent can be used as long as it does not adversely affect this reaction, and examples thereof include ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated carbonization such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride. Hydrogen, aromatic hydrocarbons such as benzene, toluene and xylene, amines such as pyridine, piperidine and triethylamine, aliphatic hydrocarbons such as hexane and heptane, alcohols such as methanol, ethanol and propanol, dimethylformamide ( DMF),
Hexamethylphosphoric triamide (HMPA), aprotic polar solvent such as dimethylsulfoxide (DMSO),
Examples thereof include carbon disulfide and water.

As the acid used, the above reaction process formula-
The one shown in 1 is given. The acid or base is used in a molar amount of 1 to 200 times, preferably 1 to 100 times the molar amount of the compound (1-a). The reaction may be performed at room temperature to 200 ° C., preferably 50 to 200 ° C. for 5 minutes to 5 hours, preferably 10 minutes to 3 hours. Reaction process formula-10

[0055]

[Chemical 12]

(Wherein R ¹ , R ³ , R ⁴ , R ⁵ and R
¹¹ is the same as above. ) In this reaction, the compound represented by the general formula (13) is hydrolyzed to obtain the compound represented by the general formula (14). The reaction is carried out in the presence of a basic compound or an acidic compound in a suitable inert solvent. Examples of the inert solvent include alcohols such as methanol and ethanol, ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, and anisole. Examples of the basic compound include trialkylamines such as triethylamine and tributylamine, pyridine, picoline, 1,5-diazabicyclo [4.3.0] nonene-5,1,4-diazabicyclo [2.2.2]. Octane, organic bases such as 1,8-diazabicyclo [5.4.0] undecene-7, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, carbonic acid Examples thereof include inorganic bases such as alkali metal hydrogen carbonates such as sodium hydrogen and potassium hydrogen carbonate. Examples of the acidic compound include anhydrous aluminum chloride and second chloride
Lewis acids such as tin, titanium tetrachloride, boron trichloride, hydrochloric acid,
Inorganic acids such as hydrobromic acid, nitric acid, sulfuric acid, trichloroacetic acid,
Examples thereof include organic acids such as trifluoroacetic acid, methanesulfonic acid, acetic acid and formic acid, and acid type ion exchange resins.

These basic compounds or acidic compounds are used in a molar amount 1 to 100 times, preferably 1 to 100 times that of the compound (13).
It is suitable to use in a molar ratio of up to 20 times. The reaction may be performed under temperature conditions of -20 to 100 ° C, preferably -10 to 80 ° C for about 30 minutes to 48 hours, preferably about 1 to 24 hours. Alternatively, a deesterification reaction by a catalytic reduction method may be used. Reaction process formula-11

[0058]

[Chemical 13]

(In the formula, R ¹ , R ³ , R ⁴ and R ⁵ are the same as described above.) The general formula obtained in the above reaction process formula-10
The compound represented by the general formula (15) is obtained by decarboxylation from the compound represented by (14). The reaction is carried out in the presence of a basic compound of compound (14) without solvent or in a suitable solvent. Further, the reaction may be carried out in a sealed tube if necessary. Examples of the basic compound include aniline, N, N-
Dimethylaniline, N, N-diethylaniline, N-methylaniline, N-ethylaniline, pyridine, α-picoline, β-picoline, γ-picoline, 2,3-lutidine, 2,4-lutidine, 2,5- Examples thereof include lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, triethylamine, diethylamine, ethylamine, methylamine and ammonia.

The reaction is carried out at 0 to 150 ° C., preferably 30 to
It may be performed under a temperature condition of 100 ° C. for about 10 minutes to 12 hours, preferably for about 30 minutes to 6 hours. Reaction process formula-12

[0061]

[Chemical 14]

(In the formula, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ¹¹ are the same as described above.) The amine compound R ⁶ NH ₂ is added to the compound represented by the general formula (13). After reaction, the general formula (1
The compound represented by 6) is obtained. The reaction is carried out without solvent or in a suitable solvent. When aniline is used as the amine compound, for example, a compound (16) in which R ⁶ is an N-phenylcarbamoyl group can be obtained. The amine compound is used in an equimolar amount to 100-fold molar amount, preferably 10- to 50-fold molar amount, with respect to the compound (13).

The reaction is carried out at 0 to 200 ° C., preferably 100
It may be carried out under a temperature condition of ~ 180 ° C for about 10 minutes to 5 hours, preferably about 30 minutes to 3 hours. Reaction process formula-13

[0064]

[Chemical 15]

(Wherein R ¹ , R ³ , R ⁴ , R ⁵ and R
⁶ is the same as above. ) In this reaction, the carboxyl group of the compound represented by the general formula (14) is converted to a chloroformyl group with thionyl chloride, and then the amine compound R ⁶
A compound represented by the general formula (17) having a group: R ⁶ NHCO— is obtained by reacting NH ₂ . The reaction is carried out without solvent or in a suitable solvent.

The amount of thionyl chloride used is
4) equimolar amount to 100 times molar amount, preferably 2 to
It is used in a 10-fold molar amount ratio. The reaction is -10 to 1
It may be performed under a temperature condition of 00 ° C., preferably −5 to 25 ° C., for about 5 minutes to 10 hours, preferably about 10 minutes to 3 hours.
Note that phosphorus trichloride, phosphorus pentachloride, or the like may be used instead of thionyl chloride.

The amount of the above amine compound used relative to the product obtained by chloroformizing the carboxyl group is equimolar to 5
The molar ratio may be 0 times, preferably 1 to 3 times.
The reaction is carried out under the temperature condition of -10 to 100 ° C, preferably -5 to 25 ° C for about 5 to 20 hours, preferably about 10 minutes to 3
It takes about an hour. Reaction process formula-14

[0068]

[Chemical 16]

(In the formula, R ¹ , R ³ , R ⁴ and R ⁵ are the same as above.) In this reaction, the carbamoyl group of the compound represented by the general formula (18) is converted to a cyano group with thionyl chloride. It is converted to obtain the compound represented by the general formula (19). The reaction is carried out without solvent or in a suitable solvent. The amount of thionyl chloride used is an equimolar amount to 50-fold molar amount, preferably 2 to 10-fold molar amount relative to compound (18). The reaction may be performed at -10 to 100 ° C, preferably 0 ° C to room temperature for about 5 minutes to 20 hours, preferably about 10 minutes to 5 hours.

As the usable solvent, for example, the same solvents as mentioned in the reaction process formula-1 can be mentioned. In addition, instead of thionyl chloride, phosphorus pentachloride, phosphoryl chloride,
Phosphorus pentoxide or the like may be used. Reaction process formula-15

[0071]

[Chemical 17]

(Wherein R ² , R ⁴ , R ⁵ , R ¹¹ and R
¹² is the same as above, and Ph is a phenyl group. ) This reaction is a compound in which a formyl group is introduced at the α-position by reacting an ester compound represented by the general formula (20) with a formate ester.
(21) is obtained, and the compound (21) is reacted with the compound represented by the general formula (2) to obtain the compound of the present invention represented by the general formula (23).

The reaction for introducing the formyl group is carried out in the presence of sodium hydride in a suitable inert solvent. The amount of the formic acid ester used is 1 to the ester compound (20).
It is a 5-fold molar amount, preferably a 1-2-fold molar amount. Also,
The amount of sodium hydride used is 1 to 5 times, preferably 1 to 2 times the molar amount. As the usable solvent, for example, the same solvents as those mentioned in the reaction process formula-1 can be mentioned. The reaction may be performed at 0 to 100 ° C., preferably 0 to 40 ° C. for about 1 to 48 hours, preferably about 5 to 24 hours.

The produced compound (21) can be used in the reaction with the next compound (2) with or without isolation from the reaction solution. The compound (2) is used in a molar ratio of 0.1 to 1 times, preferably 0.5 to 1 with respect to the compound (21).
It is a double molar amount. The reaction may be carried out at 30 to 120 ° C., preferably 80 to 120 ° C. for about 30 minutes to 10 hours, preferably about 3 to 5 hours. Reaction process formula-16

[0075]

[Chemical 18]

(In the formula, R ⁴ and R ⁵ are the same as above.) This reaction is for directly obtaining the compound represented by the general formula (2) from the compound represented by the general formula (6). is there. That is, the compound (6) is reacted with hydrazine NH ₂ NH ₂ .H ₂ O or its dihydrochloride or sulfate in the presence of acetic acid or a mineral acid. The hydrazine is preferably 1 to 2
It may be used in a double molar equivalent, preferably at room temperature to 100 ° C. Further, acetic acid or mineral acid is preferably used in 1 to 2 molar equivalents with respect to hydrazine NH ₂ NH ₂ . Reaction process formula-17

[0077]

[Chemical 19]

(Wherein R ³ , R ⁴ , R ⁵ , R ⁹ and R
¹⁴ is the same as above, and R ¹³ is a lower alkyl group. ) This reaction proceeds from a compound represented by the general formula (2) to a compound represented by the general formula (25) and then a compound represented by the general formula (1
-d) to obtain the compound. The reaction of the compound (2) to the compound (25) can be carried out basically in the same manner as in the above reaction scheme-1. That is, the compound (24) is reacted with the compound (2) in the absence of a solvent or in a suitable solvent in the presence of an acid to precipitate the compound (25). The usable solvent, the acid, and the ratio of the compound (2) to the compound (24) used may be the same as those in the reaction process formula-1. The reaction is usually at room temperature to 1
The reaction is completed at 50 ° C., preferably room temperature to 80 ° C., for about 5 minutes to 2 hours.

After the reaction, the produced compound (25) is separated from the reaction solution, washed and then reacted in a solvent in the presence of a base to obtain a compound (1-d). Examples of the solvent include lower alcohols such as methanol, ethanol and isopropanol, ethers such as dioxane and tetrahydrafuran (THF), aromatic hydrocarbons such as benzene and toluene, N and N.
-Dimethylformamide (DMF), dimethyl sulfoxide
Examples include aprotic polar solvents such as (DMSO).

Examples of usable bases include sodium alkoxide such as sodium methoxide, sodium hydride and the like. The base is used in an equimolar amount, preferably 1 to 3 times the molar amount of the compound (25). The reaction is usually performed at 0 to 100 ° C., preferably 0 to 50 ° C. for about 1 to 72 hours, preferably 1
It will be completed in about 0 to 48 hours. Reaction process formula-18

[0081]

[Chemical 20]

(In the formula, R ³ , R ⁴ , R ⁵ and R ¹³ are the same as above.) In this reaction, the compound represented by the general formula (1-d) is reduced to give the general formula (1- The compound represented by 1-e) is obtained. The reaction is carried out in a solvent in the presence of a reducing agent. Examples of the solvent include lower alcohols such as methanol, ethanol and isopropanol, ethers such as diethylene glycol dimethyl ether, aromatic hydrocarbons such as benzene and toluene, N, N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO). Examples include aprotic polar solvents and water.

Examples of the reducing agent include lithium aluminum hydride, sodium borohydride, diborane, diisobutylaluminum hydride and the like.
When sodium borohydride is used as the reducing agent, it is preferable to use a mixed solvent of water and a lower alcohol such as methanol or ethanol as the solvent. The mixing ratio of lower alcohol and water is preferably about 1: 1 to 10: 1. Also, it is preferable to add a base for the stability of sodium borohydride. Examples of such bases include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. The ratio of the base to be used is appropriately 1 to 50 times, preferably 1 to 10 times the molar amount of sodium borohydride.

The reaction is completed under ice-cooling to 150 ° C., preferably 30 to 100 ° C., for about 30 minutes to 5 hours. Reaction process formula-19

[0085]

[Chemical 21]

(In the formula, X represents a halogen atom, and R ¹ ,
R ³ , R ⁴ and R ⁵ are the same as above. ) In this reaction, a compound represented by the general formula (1-c) is reacted with a halogenating agent in the absence of solvent or in a solvent to obtain a compound represented by the general formula (1-f). Is. As the solvent, the solvents exemplified in Reaction Process Formula-1 can be used. Further, as the halogenating agent, for example, N-bromosuccinimide,
Examples thereof include N-chlorosuccinimide, N-bromocaprolactam, 1,3-dibromo-5,5-dimethylhydantoin, bromine, chlorine and sulfuryl chloride.

The amount of the halogenating agent used is 1 to 2 times the molar amount of the compound represented by the general formula (1-c), preferably 1 time.
It is suitable that the molar amount is about 1.5 times. The reaction is 0
The reaction is completed at 50 ° C., preferably 0 ° C. to room temperature for about 30 minutes to 5 hours. Reaction process formula-20

[0088]

[Chemical formula 22]

(In the formula, R ³⁰ is a lower alkyl group, R ² and R
⁴ and R ⁵ are the same as above. ) This reaction is carried out on a compound represented by the general formula (2) without solvent or in a solvent,
A compound represented by the general formula (1-g) is obtained by reacting an acetal derivative of malondialdehyde represented by the general formula (26). As the solvent, the solvents exemplified in Reaction Process Formula-1 can be used. It is suitable that the acetal derivative of malondialdehyde represented by the general formula (26) is at least an equimolar amount, preferably 1 to 20 times the molar amount of the compound (2).

The reaction is carried out at 50 to 150 ° C., preferably 80
Finish at ~ 130 ° C in about 2-24 hours. The above general formula
The compound represented by (1) can easily form a salt by reacting with a pharmaceutically acceptable acid. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, acetic acid, p-toluene sulfone. Examples thereof include acids and organic acids such as ethanesulfonic acid.

The compound (1) of the present invention naturally includes optical isomers and syn isomers and anti isomers. These isomers can be obtained by conventional resolution methods, for example,
It can be separated by a method using an optical resolving agent, a method using an enzyme, or the like. The compound (1) of the present invention is usually
It is used in the form of a general pharmaceutical preparation. The preparation is prepared using diluents or excipients such as fillers, fillers, binders, moisturizers, disintegrants, surfactants and lubricants which are usually used. Various forms of this pharmaceutical preparation can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules,
In addition to suppositories, injections (solutions, suspensions, etc.), external preparations such as lotions, creams, ointments, etc. can be used. In the case of molding in the form of tablets, as the carrier, any of those conventionally widely used in this field can be used, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin,
Excipients such as crystalline cellulose, silicic acid, water, ethanol,
Propanol, simple syrup, glucose solution, starch solution,
Gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl sulfate Disintegrators such as sodium, stearic acid monoglyceride, starch, lactose, sucrose, stearin, cocoa butter, disintegration inhibitors such as hydrogenated oils, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, glycerin, starch, etc. Examples thereof include humectants, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, purified talc, stearates, boric acid powders and lubricants such as polyethylene glycol. Further, the tablet may be a tablet coated with a usual coating as necessary, for example, a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet or a multilayer tablet.

In the case of molding in the form of pills, those conventionally known in this field can be widely used as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin and talc. , Gum arabic powder,
Examples thereof include tragacanth powder, a binder such as gelatin and ethanol, a disintegrating agent such as laminaran and agar. In the case of molding in the form of suppositories, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. You can Further, when prepared as an injection, the solution, emulsion and suspension are preferably sterilized and isotonic with blood, and when molded into the form of these solution, emulsion and suspension, Any of those conventionally used in this field as a diluent can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. it can. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. may be further added. Coloring agents, preservatives, fragrances, flavors, if necessary,
Sweeteners and other pharmaceutical agents may be included in the therapeutic agent. When forming into a paste, cream or gel, white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like can be used as a diluent.

The amount of the pyrimidine derivative (1) of the present invention or a salt thereof to be contained in the pharmaceutical preparation is not particularly limited and may be selected in a wide range, but is usually 1 to 70% by weight in the whole composition.
It is good to say The administration method of the pharmaceutical preparation according to the present invention is not particularly limited, and may be administered according to various preparation forms, patient age, sex and other conditions, degree of disease and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are orally administered.

In the case of an injection, it may be administered intravenously alone or in a mixture with a normal replacement fluid such as glucose or amino acid, and if necessary, it may be administered intramuscularly, intradermally, subcutaneously or intraperitoneally alone. It In the case of suppositories, it will be administered rectally. Furthermore, in the case of external preparations such as lotions, creams and ointments, they are applied and administered. The dose of the above-mentioned pharmaceutical preparation is appropriately selected depending on the usage, age of the patient, sex and other conditions, degree of disease, etc., but the amount of the compound of the present invention is usually 1 to 100 mg, preferably 5 to 20 mg per 1 kg of body weight per day.
The dosage is preferably 2 to 4 times a day.

[0095]

The present invention will be described in more detail below with reference to reference examples and examples. Reference Example 1 3-amino-4- (4-phenylthiophenyl) pyrazo
Lumpur sodium methoxide (2.79 g) in toluene (10
4-phenylthiophenylacetonitrile (8.9 ml).
7 g), ethyl formate (3.83 g) and toluene (5
0 ml) of the mixture was added dropwise. After 20 minutes, ice cooling was stopped, and after 2 hours, ice water was added, and the aqueous layer was separated.

Then, the organic layer was washed with 0.5N sodium hydroxide.
It was washed twice with 100 ml of each aqueous solution of water. Water layer and wash
Combine the purified solutions, adjust the pH to 3-4 with concentrated hydrochloric acid, and under ice cooling.
It was stirred at. After 1 hour, the precipitate was collected by filtration, washed with water, and α
-Formyl-4-phenylthiophenylacetonitrile
Got The obtained α-formyl-4-phenylthiophene
Nylacetonitrile without drying the semicarb
Methanol (50 m) with zido hydrochloride (4.43 g)
l) and water (10 ml) in a mixture and ice-cooled 1
Stir for 0 minutes. Then stop the ice cooling and leave it for 19 hours
After that, the pH is adjusted to 9 with 5N sodium hydroxide aqueous solution.
The mixture was stirred at room temperature for 1 hour while keeping at -10. At this time, the reaction
The temperature of the liquid was kept below 25 ° C. Water (200m)
l) was added, the mixture was stirred for 30 minutes under ice cooling, and the precipitate was collected by filtration.
It was The obtained precipitate was treated with a 5N sodium hydroxide aqueous solution (1
5 ml) and methanol (150 ml) for 25 minutes
Heated to reflux. Turn off the heat, add water (300 ml),
Stir for 30 minutes under ice cooling, wash the deposited material with water, dry
This gave 8.53 g of the title compound. mp: 120-121 ° C NMR (DMSO-d₆) Δ: 7.74 (s, 1H), 7.2 to 7.6 (m, 10)
H), 6.69 (bs, 2H) Reference Example 2α-acetyl-4-phenylthiophenylacetonitri
Le 60% sodium hydride in a nitrogen atmosphere with stirring under ice cooling
Tetrahydrofuran (10 ml) suspension of (144 mg)
In addition, ethyl acetate (396mg) and 4-phenylthiophene
Nylacetonitrile (675 mg) and tetrahydrofuran
A mixture with benzene (5 ml) was added dropwise. Remove the ice bath after 30 minutes
Left. After 17 hours, evaporate the tetrahydrofuran under reduced pressure.
Removed, 2N hydrochloric acid (10 ml) and dichloromethane (20 ml)
And the mixture was partitioned and the aqueous layer was extracted twice more with dichloromethane.
It was extracted with (20 ml). Combine the organic layer and the extract,
Dry over anhydrous magnesium sulfate and concentrate under reduced pressure.
Rica gel chromatography (eluent is hexane: acetic acid
Separated with a mixed solvent of ethyl 4: 1 (v / v)
Purification gave the title compound (587 mg). NMR (CDCl₃) Δ: 7.26 to 7.38 (m, 9H), 4.63 (s, 1)
H), 2.25 (s, 3H) Reference Example 3α-fluoroacetyl-4-phenylthiophenylacetate
Tonitrile The title compound was obtained according to Reference Example 2. NMR (CDCl₃) Δ: 7.23 to 7.45 (m, 9H), 5.36 (d, J =
46.2 Hz, 2H), 4.63 (s, 1H) Reference Example 4α-trifluoroacetyl-4-phenylthiophenyl
Acetonitrile The title compound was obtained according to Reference Example 2. NMR (CDCl₃) Δ: 7.20 to 7.35 (m, 9H), 4.16 (s, 1)
H) Reference example 53-amino-5-methyl-4- (4-phenylthiophene
Nyl) pyrazole α-acetyl-4-phenylthiophenylacetonitri
(520 mg) and semicarbazide hydrochloride (217 mg)
And are mixed solutions of methanol (15 ml) and water (3 ml).
The mixture was stirred in the medium under ice cooling for 10 minutes. Then remove the ice bath
40 hours after leaving, using 2N sodium hydroxide aqueous solution
Then, the mixture was stirred at room temperature for 1 hour so as to maintain pH 9 to 10.
After that, add water (50 ml) and stir for 30 minutes under ice cooling.
After that, the precipitate was collected by filtration. This is as it is 2N hydroxy
Aqueous sodium chloride solution (5 ml) and methanol (50 m
l) into the mixture and stir at room temperature for 4 hours, then
Water (80 ml) was added, and the mixture was stirred under ice cooling for 30 minutes, then the precipitate
By filtering off, washing with water and drying, the title compound (50
0 mg) was obtained. NMR (CDCl₃) Δ: 7.23 to 7.44 (m, 10H), 5.01 (br
s, 2H), 2.27 (s, 3H) Reference Example 63-amino-5-methoxymethyl-4- (4-phenyl
Thiophenyl) pyrazole Using the compound obtained in Reference Example 3, the same procedure as in Reference Example 5 was carried out.
The above compound was obtained. NMR (CDCl₃) Δ: 7.26 to 7.48 (m, 10H), 5.76 (br
s, 2H), 4.46 (s, 2H), 3.36 (s, 3)
H) Reference example 73-amino-4- (4-phenylthiophenyl) -5-
Trifluoromethylpyrazole α-trifluoroacetyl-4-phenylthiophenyl
Acetonitrile (410 mg), hydrazine monohydrate (7
7 mg), acetic acid (1 ml) and benzene (10 ml)
The product was heated to reflux while dehydrating azeotropically.
After 1 hour, cool and add 6N hydrochloric acid (15 ml) to add organic
Layer and water layer, the water layer was further extracted with ethyl acetate (20 m
l), extract twice, combine with the previous organic layer, and add anhydrous magnesium sulfate.
After drying with nesium, concentrate under reduced pressure and record as a crude product.
A compound (400 mg) was obtained. Do not purify this
It was used for the next reaction. Example 16-ethoxycarbonyl-7-hydroxy-3- (4-
Phenylthiophenyl) pyrazolo [1,5-a] pyrimi
gin 3-Amino-4- (4-phenylthiofate obtained in Reference Example 1
Phenyl) pyrazole (2.97 g), ethoxymethylene
Malonic acid diethyl ester (2.16 g) and acetic acid
Heat the mixture (20 ml) to 90-110 ° C in a heating bath.
Stirring for 2 hours, then ethoxymethylene malonic acid
Add diethyl ester (0.21g) and heat for 10 minutes
The bath was removed and the mixture was allowed to cool. The deposited material is collected by filtration and methano
The extract was washed with water and dried to give the title compound (1.69 g). mp: 251-252.5 ° C NMR (DMSO-d₆) Δ: 8.37 (s, 1H), 8.26 (s, 1H), 7.6
3 (d, J = 8.13 Hz, 2H), 7.42 (d, J
= 8.13 Hz, 2H), 7.38 (s, 5H), 4.
27 (q, J = 7.03 Hz, 2H), 1.31 (t,
J = 7.03 Hz, 3H) Example 26-ethoxycarbonyl-5-hydroxy-3- (4-
Phenylthiophenyl) -pyrazolo [1,5-a] pyri
Mijin 3-amino-4- (4-phenylthiophenyl) pyrazo
Using the alcohol (8.53 g) in the same manner as in Example 1.
Then, the precipitate was washed with ethanol. Got
Allow the filtrate and ethanol wash to stand for 20 hours at room temperature
After that, the precipitate is collected by filtration, washed with ethanol and dried.
Thus, the title compound (0.45 g) was obtained. mp: 206-207.5 ° C NMR (DMSO-d₆) Δ: 9.07 (s, 1H), 8.37 (s, 1H), 7.7
0 (d, J = 8.57 Hz, 2H), 7.36 (d, J
= 8.13 Hz, 2H), 7.34 (s, 5H), 4.
27 (q, J = 7.03 Hz, 2H), 1.31 (t,
J = 7.03 Hz, 3H) Example 37-hydroxy-3- (4-phenylthiophenyl) pi
Lazolo [1,5-a] pyrimidine 6-ethoxycarbonyl-7-hydroxy obtained in Example 1
Ci-3- (4-phenylthiophenyl) -pyrazolo
[1,5-a] pyrimidine (3.91 g) and 85% phosphorus
Heat the mixture with acid (30 ml) to 170 ° C in a heating bath.
After stirring for 30 minutes, foaming gradually occurs and foaming
When the reaction stopped, the reaction solution became deep red. Heating bath
Therefore, add water (200 ml) and leave it for 30 minutes while cooling with ice.
After that, the precipitate is collected by filtration, washed with water and dried to give the title.
A compound (2.55 g) was obtained. mp: 232-236 ° C (silica gel column purification) NMR (DMSO-d₆) Δ: 8.22 (s, 1H), 7.81 (d, J = 7.47H)
z, 1H), 7.61 (d, J = 8.57Hz, 2
H), 7.40 (d, J = 8.57 Hz, 2H), 7.
29-7.41 (m, 5H), 5.79 (d, J = 7.
47 Hz, 1H) Example 45-hydroxy-3- (4-phenylthiophenyl) pi
Lazolo [1,5-a] pyrimidine 6-ethoxycarbonyl-5-hydroxy obtained in Example 2
Ci-3- (4-phenylthiophenyl) -pyrazolo
[1,5-a] pyrimidine (0.39 g) and 85%
Same as Example 3 except that phosphoric acid (5 ml) was used.
The title compound (0.16 g) was obtained. mp: 214-216 ° C (silica gel column purification) NMR (DMSO-d₆) Δ: 8.57 (d, J = 7.92 Hz, 1H), 8.20
(S, 1H), 7.72 (d, J = 8.13Hz, 2
H), 7.36 (d, 2H, J = 8.13Hz, 2
H), 7.27 to 7.42 (m, 5H), 6.12
(D, J = 7.91 Hz, 1H) Example 57-hydroxy-5-methyl-3- (4-phenylthio
Phenyl) pyrazolo [1,5-a] pyrimidine 3-amino-4- (4-phenylthiophenyl) pyrazo
(0.34 g), ethyl acetoacetate (0.165
g) and acetic acid (2 ml) at 100-110 ° C.
Heated and stirred. After 2 hours, the reaction mixture was placed under reduced pressure.
Concentrate with, add ethanol (20 ml) to the residue, and under reduced pressure.
Concentrated in. Furthermore, the same operation as above was repeated to obtain
Ethyl acetate (20 ml) was added to the residue and solidified.
The solid is filtered off, washed with ethyl acetate, dried and
The title compound (0.31 g) was obtained. mp: 233-234 ° C NMR (DMSO-d₆) Δ: 8.09 (s, 1H), 7.59 (d, J = 8.57H)
z, 2H), 7.39 (d, J = 8.13Hz, 2
H), 7.36 (s, 5H), 5.65 (s, 1H),
2.50 (s, 3H) Example 67-hydroxy-5-ethyl-3- (4-phenylthio
Phenyl) pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 5. mp: 222-224 ° C NMR (CD₃OD-CDCl₃) Δ: 7.90 (s, 1H), 7.30 to 7.40 (m, 9)
H), 5.71 (s, 1H), 2.70 (q, J = 7.
42Hz, 2H), 1.32 (t, J = 7.42Hz,
3H) Example 77-hydroxy-5-isopropyl-3- (4-phenyl
Luthiophenyl) pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 5. mp: 260-261 ° C. (decomposition) NMR (CD₃OD-CDCl₃) Δ: 7.91 (s, 1H), 7.30 to 7.37 (m, 9)
H), 5.75 (s, 1H), 2.95 (Heptet, J =
6.93 Hz, 1H), 1.33 (d, J = 6.93H
z, 6H) Example 87-hydroxy-5-cyclopropyl-3- (4-phen
Nylthiophenyl) pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 5. mp: 238-241 ° C (decomposition) NMR (CD₃OD-CDCl₃) Δ: 7.92 (s, 1H), 7.32 to 7.41 (m, 9)
H), 5.37 (s, 1H), 1.91 to 2.01
(M, 1H), 1.11 to 1.19 (m, 2H), 0.
91 to 0.98 (m, 2H) Example 97-Hydroxy-5-chloromethyl-3- (4-phenyl
Luthiophenyl) pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 5. mp: 190-191 ° C NMR (CD₃OD-CDCl₃) Δ: 7.97 (s, 1H), 7.28 to 7.43 (m, 9)
H), 5.95 (s, 1H), 4.54 (s, 2H) Example 107-hydroxy-5-phenyl-3- (4-phenylthio)
Ophenyl) pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 5. mp: 253-255 ° C. (decomposition) NMR (CD₃OD-CDCl₃) Δ: 8.02 (s, 1H), 7.69 (d, J = 8.56H)
z, 2H), 7.28 to 7.57 (m, 12H), 6.
09 (s, 1H) Example 115H-6,7-dihydro-8-hydroxy-3- (4-
Phenylthiophenyl) -cyclopenta [d] pyrazolo
[1,5-a] pyrimidine According to Example 5, the title compound of the following formula was obtained. mp: 274 ° C (decomposition) NMR (CD₃OD-CDCl₃) Δ: 7.92 (s, 1H), 7.25 to 7.43 (m, 9)
H), 2.96 to 3.02 (m, 2H), 2.81
2.87 (m, 2H), 2.14 to 2.20 (m, 2)
H) Example 129-hydroxy-3- (4-phenylthiophenyl)-
5,6,7,8-Tetrahydropyrazolo [5,1-b]
Quinazoline According to Example 5, the title compound of the following formula was obtained. mp: 271-272 ° C NMR (DMSO-d₆) Δ: 8.11 (s, 1H), 7.59 (d, J = 8.2H)
z, 2H), 7.3-7.5 (m, 7H), 2.7-
2.8 (m, 2H), 2.4-2.5 (m, 2H),
1.6-1.8 (m, 4H) Example 137-hydroxy-5-trifluoromethyl-3- (4-
Phenylthiophenyl) pyrazolo [1,5-a] pyrimi
gin 3-amino-4- (4-phenylthiophenyl) pyrazo
Solution (1.07 g) in acetic acid (8 ml)
-Add ethyl trifluoroacetoacetate (0.6 ml),
The mixture was stirred at 100 ° C for 2 hours. After allowing to cool, add ether,
The precipitate is collected by filtration and dried to give the title compound (200 mg, 13
%) Was obtained. mp: 270-273 ° C NMR (DMSO-d₆) Δ: 8.93 (s, 1H), 8.73 (d, J = 8.35H)
z, 2H), 7.42 (d, J = 8.35Hz, 2
H), 7.34 (s, 5H), 6.32 (s, 1H) Example 147-hydroxy-6-ethoxycarbonyl-3- (3-
Methoxy-4-phenylthiophenyl) pyrazolo [1,
5-a] pyrimidine The title compound was obtained according to Example 1. mp: 256-258 ° C NMR (DMSO-d₆) Δ: 8.36 (s, 1H), 8.30 (s, 1H), 7.1
3 to 7.39 (m, 8H), 4.26 (q, J = 7.0)
4Hz, 2H), 3.91 (s, 3H), 1.29
(T, J = 7.04 Hz, 3H) Example 157-hydroxy-3- (3-methoxy-4-phenylthio
Ophenyl) pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 3. mp: 220-260 ° C NMR (DMSO-d₆) Δ: 8.25 (s, 1H), 7.80 (d, J = 6.81H)
z, 1H), 7.03 to 7.44 (m, 8H), 5.6.
9 (d, J = 6.81 Hz, 1H), 3.88 (s, 3
H) Example 167-hydroxy-6-ethoxycarbonyl-2-methyl
-3- (4-phenylthiophenyl) pyrazolo [1,5
-A] pyrimidine The title compound was obtained according to Example 1. NMR (CDCl₃) Δ: 8.28 (s, 1H), 7.42 (bs, 9H), 4.
24 (q, J = 7.03 Hz, 2H), 2.33 (s,
3H), 1.32 (t, J = 7.04Hz, 3H) Example 177-hydroxy-6-ethoxycarbonyl-2-methoxy
Cimethyl-3- (4-phenylthiophenyl) pyrazolo
[1,5-a] pyrimidine The title compound was obtained according to Example 1. NMR (DMSO-d₆) Δ: 8.32 (s, 1H), 7.27 to 7.63 (m, 9)
H), 4.47 (s, 2H), 4.25 (q, J = 7.
03Hz, 2H), 3.26 (s, 3H), 1.28
(T, J = 7.03 Hz, 3H) Example 187-hydroxy-2-methyl-3- (4-phenylthio
Phenyl) pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 3. mp: 218-235 ° C NMR (DMSO-d₆) Δ: 7.69 (d, J = 7.26 Hz, 1 H), 7.36-
7.47 (m, 9H), 5.71 (d, J = 7.25H
z, 1H), 2.32 (s, 3H) Example 197-Hydroxy-2-methoxymethyl-3- (4-phen
Nylthiophenyl) pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 3. mp: 164-167 ° C Example 207-hydroxy-6-ethoxycarbonyl-3- (4-
Phenylthiophenyl) -2-trifluoromethylpyra
Zoro [1,5-a] pyrimidine The title compound was obtained according to Example 1. NMR (DMSO-d₆) Δ: 8.40 (s, 1H), 7.31 to 7.45 (m, 9)
H), 4.26 (q, J = 7.03 Hz, 2H), 1.
29 (t, J = 7.04 Hz, 3H) Example 217-hydroxy-6-methoxy-3- (4-phenylthio)
Ophenyl) pyrazolo [1,5-a] pyrimidine 60% sodium hydride (480 mg) tetrahydrof
Into a orchid suspension, under a nitrogen atmosphere, ethyl formate (2 ml) and
And ethyl methoxyacetate (1.0 g) were added, and at room temperature
It was stirred for 16 hours. Then, 3-amino-4 (4-phen)
Add nylthiophenyl) pyrazole (1.0 g) and add
The mixture was stirred for 4 hours under flowing. After cooling, add water and add 10% hydrochloric acid.
Neutralized. Further, remove water, add ethyl acetate, and
The melt was collected by filtration. Add this to ethyl acetate and ether
Wash with water and dry to give the title compound (100 mg, 8%).
It was mp: 267-272 ° C NMR (DMSO-d₆) Δ: 8.24 (s, 1H), 7.70 (s, 1H), 7.6
3 (d, J = 8.57 Hz, 2H), 7.40 (d, J
= 8.57 Hz, 2H), 7.35 (s, 5H), 3.
78 (s, 3H) Example 227-hydroxy-6-fluoro-3- (4-phenylthio
Ophenyl) pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 21. mp: 278-281 ° C NMR (DMSO-d₆) Δ: 8.32 (d, J = 5.0 Hz, 1H), 8.30
(S, 1H), 7.63 (d, J = 8.35Hz, 2
H), 7.40 (d, J = 8.35 Hz, 2H), 7.
36 (s, 5H) Example 237-hydroxy-6-phenyl-3- (4-phenylthio)
Ophenyl) pyrazolo [1,5-a] pyrimidine 60% sodium hydride (480 mg) tetrahydrof
Into a orchid suspension, under a nitrogen atmosphere, ethyl formate (2 ml) and
And ethyl phenylacetate (1.64 g) were added, and at room temperature
It was stirred for 19 hours. Then, 3-amino-4- (4-
Phenylthiophenyl) pyrazole (1.0 g) was added.
Then, the mixture was stirred under reflux for 4 hours. After cooling, water and 10% salt
Acid was added and extracted with ethyl acetate. After washing with water, dry sodium sulfate
The organic layer was dried with thorium and the solvent was distilled off. Vinegar residue
Dissolve in acid (5ml) and heat at 120 ℃ for 2-20 hours
It was stirred. After allowing to cool, ethyl acetate was added and the precipitate was collected by filtration.
It was Wash this with ethyl acetate and ether and dry
This gave the title compound (270 mg, 18%). mp:> 300 ° C NMR (DMSO-d₆) Δ: 8.28 (s, 1H), 7.97 (s, 1H), 7.6
0 to 7.80 (m, 4H), 7.20 to 7.57 (m,
10H) Example 247-hydroxy-6-methyl-3- (4-phenylthio
Phenyl) pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 23. mp: 270-275 ° C NMR (DMSO-d₆) Δ: 8.22 (s, 1H), 7.75 (s, 1H), 7.5
1 (d, J = 8.35 Hz, 2H), 7.40 (d, J
= 8.35 Hz, 2H), 7.35 (s, 5H), 2.
04 (s, 3H) Example 257-hydroxy-6-ethyl-3- (4-phenylthio
Phenyl) pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 23. mp: 268-272 ° C NMR (DMSO-d₆) Δ: 8.18 (s, 1H), 7.80 (d, J = 8.35H)
z, 2H), 7.72 (s, 1H), 7.37 (d, J
= 8.35 Hz, 2H), 7.31 (s, 5H), 2.
50 (q, J = 7.10 Hz, 2H), 1.14 (t,
J = 7.10 Hz, 3H) Example 267-hydroxy-6-isopropyl-3- (4-phenyl
Luthiophenyl) pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 23. mp: 238-242 ° C NMR (DMSO-d₆) Δ: 8.22 (s, 1H), 7.88 (s, 1H), 7.6
6 (d, J = 8.57 Hz, 2H), 7.39 (d, J
= 8.57 Hz, 2H), 7.36 (s, 5H), 2.
80-3.30 (m, 1H), 1.21 (d, J = 6.
82 Hz, 6 H) Example 277-hydroxy-6-cyclohexyl-3- (4-phen
Nylthiophenyl) pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 23. mp: 213-216 ° C NMR (DMSO-d₆) Δ: 8.19 (s, 1H), 7.65 (d, J = 8.07H)
z, 2H), 7.52 (s, 1H), 7.39 (d, J
= 8.10 Hz, 2H), 7.34 (s, 5H), 1.
00-2.00 (m, 11H) Example 287-hydroxy-6-phenethyl-3- (4-phenyl)
Thiophenyl) pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 23. mp: 278-285 ° C NMR (DMSO-d₆) Δ: 8.21 (s, 1H), 7.60 (d, J = 8.36H)
z, 2H), 7.59 (s, 1H), 7.39 (d, J
= 8.36 Hz, 2H), 7.35 (s, 5H), 7.
24 (s, 5H), 2.60 to 3.00 (m, 4H) Example 297-hydroxy-6-benzyl-3- (4-phenylthio)
Ophenyl) pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 23. mp: 254-256 ° C NMR (DMSO-d₆) Δ: 8.21 (s, 1H), 7.79 (s, 1H), 7.6
1 (d, J = 8.35 Hz, 2H), 7.39 (d, J
= 8.35 Hz, 2H), 7.36 (s, 5H), 7.
20 to 7.40 (m, 5H), 3.81 (s, 2H) Example 307-hydroxy-6- (2-methoxyphenylmethyl)
-3- (4-phenylthiophenyl) pyrazolo [1,5
-A] pyrimidine The title compound was obtained according to Example 23. mp: 219-221 ° C NMR (DMSO-d₆) Δ: 8.24 (s, 1H), 7.70 (d, J = 8.35H)
z, 2H), 7.57 (s, 1H), 7.37 (d, J
= 8.35 Hz, 2H), 7.35 (s, 5H), 6.
85-7.32 (m, 4H), 3.81 (s, 3H),
3.75 (s, 2H) Example 317-hydroxy-6- (3-methoxyphenylmethyl)
-3- (4-phenylthiophenyl) pyrazolo [1,5
-A] pyrimidine The title compound was obtained according to Example 23. mp: 240-242 ° C NMR (DMSO-d₆) Δ: 8.21 (s, 1H), 7.74 (s, 1H), 7.6
1 (d, J = 8.57 Hz, 2H), 7.39 (d, J
= 8.57 Hz, 2H), 7.35 (s, 5H), 7.
14 (d, J = 7.91 Hz, 1H), 6.79 to 7.
00 (m, 3H), 3.77 (s, 2H), 3.72
(S, 3H) Example 327-hydroxy-6- (4-methoxyphenylmethyl)
-3- (4-phenylthiophenyl) pyrazolo [1,5
-A] pyrimidine The title compound was obtained according to Example 23. mp: 271-273 ° C NMR (DMSO-d₆) Δ: 8.20 (s, 1H), 7.73 (s, 1H), 7.5
9 (d, J = 8.14 Hz, 2H), 7.39 (d, J
= 8.14 Hz, 2H), 7.35 (s, 5H), 7.
23 (d, J = 8.35 Hz, 2H), 6.83 (d,
J = 8.35Hz, 2H), 3.73 (s, 2H),
3.71 (s, 3H) Example 337-hydroxy-6-ethoxycarbonylmethyl-3-
(4-Phenylthiophenyl) pyrazolo [1,5-a]
Pyrimidine The title compound was obtained according to Example 23. mp: 240-243 ° C NMR (DMSO-d₆) Δ: 8.22 (s, 1H), 7.87 (s, 1H), 7.6
1 (d, J = 8.13 Hz, 2H), 7.40 (d, J
= 8.13 Hz, 2H), 7.35 (s, 5H), 4.
09 (d, J = 7.25 Hz, 2H), 3.52 (s,
2H), 1.20 (t, J = 7.25Hz, 3H) Example 347-hydroxy-6-ethoxycarbonylethyl-3-
(4-Phenylthiophenyl) pyrazolo [1,5-a]
Pyrimidine The title compound was obtained according to Example 23. mp: 212-216 ° C NMR (DMSO-d₆) Δ: 8.21 (s, 1H), 7.73 (d, J = 5.49H)
z, 1H), 7.61 (d, J = 8.35Hz, 2
H), 7.38 (d, J = 8.35 Hz, 2H), 7.
35 (s, 5H), 4.05 (q, J = 7.03Hz,
2H), 2.73 to 2.47 (m, 4H), 1.16.
(T, J = 7.03 Hz, 3H) Example 357-hydroxy-6-bromo-3- (4-phenylthio
Phenyl) pyrazolo [1,5-a] pyrimidine 7-hydroxy-3- (4-phenylthiophenyl) pi
Dimethyi of Lazolo [1,5-a] pyrimidine (320mg)
N-Bromosuccinine in a solution of ruformamide (2 ml)
Mido (200 mg) was added, and the mixture was stirred at room temperature for 3 hours. Just
Then, water is added, the precipitate is collected by filtration, washed with water and washed with ether.
Then, it was dried to obtain the title compound (370 mg, 93%). mp:> 300 ° C NMR (DMSO-d₆) Δ: 8.25 (s, 2H), 7.63 (d, J = 8.35H)
z, 2H), 7.40 (d, J = 8.35Hz, 2
H), 7.36 (s, 5H) Example 367-hydroxy-6-chloro-3- (4-phenylthio
Phenyl) pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 35. mp: 180 to 195 ° C. (decomposition) NMR (DMSO-d₆) Δ: 8.28 (s, 1H), 8.22 (s, 1H), 7.2
0 to 7.65 (m, 9H) Example 377-hydroxy-6-chloro-5-methyl-3- (4-
Phenylthiophenyl) pyrazolo [1,5-a] pyrimi
gin The title compound was obtained according to Example 5. mp: 259-261 ° C (decomposition) NMR (CD₃OD-CDCl₃) Δ: 7.90 (s, 1H), 7.27 to 7.38 (m, 9)
H), 2.57 (s, 3H) Example 387-hydroxy-6-carboxy-3- (4-phenyl
Thiophenyl) pyrazolo [1,5-a] pyrimidine 7-hydroxy-6-ethoxycarbonyl-3- (4-
Phenylthiophenyl) pyrazolo [1,5-a] pyrimi
Gin (10.30 g), sodium hydroxide (6.59)
g), ethanol (300 ml) and water (300 ml)
The mixture was heated with stirring and allowed to react for 2 hours to give a reaction mixture.
Add water (400 ml) and add hydrochloric acid under ice cooling to adjust the pH to 1
2) After stirring for 30 minutes, the precipitate is collected by filtration, washed with water and dried.
The title compound (9.42 g) was obtained. NMR (DMSO-d₆) Δ: 8.46 (s, 1H), 8.36 (s, 1H), 7.7
6 (d, J = 8.35 Hz, 2H), 7.40 (d, J
= 8.35 Hz, 2H), 7.35 (s, 5H) Example 397-hydroxy-6-carboxyethyl-3- (4-phenyl)
Phenylthiophenyl) pyrazolo [1,5-a] pyrimidi
The 7-hydroxy-6-ethoxycarbonylethyl-3-
(4-Phenylthiophenyl) pyrazolo [1,5-a]
2N water in a suspension of pyrimidine (200 mg) in methanol
Add sodium oxide (2ml) and stir at room temperature for 3 days.
It was The reaction solution was made acidic with 10% hydrochloric acid, and the precipitate was collected by filtration.
It was washed with water and dried to obtain the title compound (quantitative). mp: 250-253 ° C NMR (DMSO-d₆) Δ: 8.21 (s, 1H), 7.72 (s, 1H), 7.6
1 (d, J = 8.35 Hz, 2H), 7.39 (d, J
= 8.35 Hz, 2H), 7.35 (s, 5H), 3.
27 (s, 2H), 2.46 to 2.70 (m, 4H) Example 407-hydroxy-6-carboxymethyl-3- (4-phenyl)
Phenylthiophenyl) pyrazolo [1,5-a] pyrimidi
The The title compound was obtained according to Example 39. mp: 244-246 ° C NMR (DMSO-d₆) Δ: 8.23 (s, 1H), 7.85 (s, 1H), 7.6
2 (d, J = 8.57 Hz, 2H), 7.41 (d, J
= 8.57 Hz, 2H), 7.36 (s, 5H), 3.
45 (s, 2H) Example 417-hydroxy-6-carboxy-3- (3-methoxy
-4-Phenylthiophenyl) pyrazolo [1,5-a]
Pyrimidine 7-hydroxy-6-ethoxycarbonyl-3- (3-
Methoxy-4-phenylthiophenyl) pyrazolo [1,
5-a] pyrimidine (340 mg) in dioxane (15 m
l) and 2N aqueous sodium hydroxide solution (2 ml) were added.
Then, the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure,
Water (30 ml) was added to the residue and neutralized with acetic acid. Deposit
It is collected by filtration, washed with water and dried to obtain the title compound (260 mg).
It was mp: 234-236 ° C NMR (DMSO-d₆) Δ: 8.46 (s, 1H), 8.41 (s, 1H), 7.1
7 to 7.39 (m, 8H), 3.90 (s, 3H) Example 427-hydroxy-6- (N-phenylcarbamoyl)-
3- (4-phenylthiophenyl) pyrazolo [1,5-
a] Pyrimidine 7-hydroxy-6-ethoxycarbonyl-3- (4-
Phenylthiophenyl) pyrazolo [1,5-a] pyrimi
Gin (280 mg) was dissolved in aniline (3 ml) and
The mixture was stirred at 0 ° C for 3 hours. After cooling, add 10% hydrochloric acid and analyze
The product was collected by filtration, washed with water and dried to give the title compound (220 mg,
68%). mp:> 300 ° C NMR (DMSO-d₆) Δ: 8.57 (s, 1H), 8.40 (s, 1H), 7.0
0 to 7.80 (m, 14H) Example 436-carbamoyl-7-hydroxy-3- (4-phenyl
Luthiophenyl) pyrazolo [1,5-a] pyrimidine 7-hydroxy-6-carboxy-3- (4-phenyl
Thiophenyl) pyrazolo [1,5-a] pyrimidine (1
20 mg) under ice cooling, thionyl chloride (0.5 ml)
Was added and stirred for 1 hour. Then, concentrate under reduced pressure, and
Loloformyl-7-hydroxy-3- (4-phenylthio)
Ophenyl) pyrazolo [1,5-a] pyrimidine was obtained.
It was 28% ammonia water was added to the obtained compound under stirring with ice cooling.
(0.3 ml) and pyridine (2 ml) were added. Three
After 0 minutes, the reaction mixture was concentrated under reduced pressure and the residue was washed with water.
Then, the title compound (97 mg) was obtained by drying. mp: 262-273 ° C NMR (DMSO-d₆) Δ: 8.42 (s, 1H), 8.31 (s, 1H), 7.3
3 to 7.89 (m, 9H) Example 446-carbamoyl-7-hydroxy-3- (3-methoxy)
Ci-4-phenylthiophenyl) pyrazolo [1,5-
a] Pyrimidine The title compound was obtained according to Example 43. NMR (DMSO-d₆) Δ: 8.47 (s, 1H), 8.37 (s, 1H), 7.0
0 to 7.38 (m, 8H), 3.91 (s, 3H) Example 457-hydroxy-3- (4-phenylthiophenyl)-
6- (N-3,4,5-trichlorophenyl) carbamo
Ilpyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 43. mp: 272-285 ° C NMR (DMSO-d₆) Δ: 11.31 (s, 1H), 8.55 (s, 1H), 8.
39 (s, 1H), 8.05 (s, 2H), 7.37-
7.78 (m, 9H) Example 467-hydroxy-3- (4-phenylthiophenyl)-
6- (N-t-butyl) carbamoylpyrazolo [1,5
-A] pyrimidine The title compound was obtained according to Example 43. mp: 222-250 ° C NMR (DMSO-d₆) Δ: 9.41 (s, 1H), 8.54 (d, J = 5.49H)
z, 1H), 8.34 (d, J = 13.85Hz, 1
H), 7.26 to 8.21 (m, 9H), 1.15
1.38 (m, 9H) Example 477-hydroxy-6-cyano-3- (4-phenylthio
Phenyl) pyrazolo [1,5-a] pyrimidine 7-hydroxy-6-carbamoyl-3- (4-phenyl
Luthiophenyl) pyrazolo [1,5-a] pyrimidine
(36 mg) was dissolved in dimethylformamide and stirred with ice-cooling.
Thionyl chloride (0.05 ml) was added with stirring. Three
After 0 minutes, the ice bath was removed. After 17 hours, add ice water and analyze
The product is collected by filtration, washed with water and dried, and the preparative silica gel is
Plate (chloroform: methanol: acetic acid 80:
Separation and purification with a developing solvent mixed at 25: 2),
The title compound (13 mg) was obtained. mp: 300 ° C. or higher NMR (DMSO-d₆) Δ: 8.55 (s, 1H), 8.34 (s, 1H), 7.3
6 to 7.73 (m, 9H) Example 487-hydroxy-3- (4-phenylthiophenyl) pi
Lazolo [1,5-a] pyrimidine 7-hydroxy-6-carboxy-3- (4-phenyl
Thiophenyl) pyrazolo [1,5-a] pyrimidine
80 parts of a mixture of (9.32 g) and aniline (68 ml)
The mixture was reacted by heating and stirring at 1.5 ° C. for 1.5 hours. Reaction mixture
Add water (300 ml) to and add hydrochloric acid under ice-cooling to pH 1
~ 2. Add methanol (100 ml), and under ice cooling,
Stir for 30 minutes, collect the precipitate by filtration, and use cold water-methanol.
Wash with (3: 1), dry and dry the title compound (8.17 g).
Got NMR (CDCl₃) Δ: 8.22 (s, 1H), 7.80 (d, J = 7.47H)
z, 1H), 7.60 (d, J = 8.13Hz, 2
H), 7.40 (d, J = 8.13 Hz, 2H), 7.
36 (s, 5H), 5.79 (d, J = 7.47Hz,
1H) Example 493- (4-phenylthiophenyl) pyrazolo [1,5-
a] Pyrimidine 3-amino-4- (4-phenylthiophenyl) pyrazo
(0.26g) and malondialdehyde tetramethyl
Add the mixture with acetal (3 ml) at 120 ℃ for 30 hours.
The mixture was reacted with stirring under heat. After concentration under reduced pressure, silica gel column
Purified with (chloroform), the title compound (0.17 g)
Got mp: 72-72.5 ° C NMR (CDCl₃) Δ: 8.67 (dd, J = 1.76 Hz, 7.04 Hz, 1
H), 8.54 (dd, J = 1.76 Hz, 4.17H
z, 1H), 8.42 (s, 1H), 8.00 (d, J
= 8.57 Hz, 2H), 7.45 (d, J = 8.57)
Hz, 2H), 7.18 to 7.37 (m, 5H), 6.
83 (dd, J = 4.17 Hz, 7.03 Hz, 1H) Example 507-hydroxy-6-methyl-3- (4-phenylthio
Phenyl) pyrazolo [1,5-a] pyrimidine 60% Sodium hydride (480mg) in benzene suspension
Into, under a nitrogen atmosphere, ethyl formate (2 ml) and propionate.
Add ethyl onate (1.2 ml) and stir at room temperature for 16 hours.
I stirred. After distilling off benzene under reduced pressure, acetic acid was added to the residue.
(5 ml) was added, followed by 3-amino-4- (4-phenyl).
Ruthiophenyl) pyrazole (1.0 g) was added, and 12
The mixture was heated and stirred at 0 ° C for 5 hours. After allowing to cool, add ethyl acetate.
The precipitate was collected by filtration, washed with ethyl acetate and water, and dried.
The title compound (1.0 g, 81%) was obtained.

Its melting point and NMR are shown in Example 24.
Was almost the same. Example 51 7-Hydroxy-6- (4-methylphenyl) -3-
(4-Phenylthiophenyl) pyrazolo [1,5-a]
The title compound was obtained according to Pyrimidine Example 50. mp:> 300 ° C NMR (DMSO-d ₆ ) δ: 8.26 (s, 1H), 7.91 (s, 1H), 7.6.
4 (d, J = 8.1 Hz, 2H), 7.36 to 7.60
(M, 4H), 7.36 (s, 5H), 7.22 (d,
J = 8.1 Hz, 2H), 2.34 (s, 3H) Example 52 7-Hydroxy-6- (4-methoxyphenyl) -3-
(4-Phenylthiophenyl) pyrazolo [1,5-a]
Ethyl formate (2 ml) and ethyl 4-methoxyphenylacetate (2.0 g) were added to a benzene suspension of pyrimidine 60% sodium hydride (480 mg) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 16 hours. Then, 3-amino-4- (4
-Phenylthiophenyl) pyrazole (1.0 g) was added, and the mixture was stirred under reflux for 4 hours. After allowing to cool, water and 10% hydrochloric acid were added to neutralize, the mixture was extracted with ethyl acetate, washed with water, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in acetic acid (5 ml) and heated with stirring at 120 ° C. for 6 hours. After cooling, ethyl acetate was added and the precipitate was collected by filtration.
It was washed with ethyl acetate and ether and dried to obtain the title compound (400 mg, 25%). mp:> 300 ° C. NMR (DMSO-d ₆ ) δ: 8.27 (s, 1H), 7.89 (s, 1H), 7.6
5 (d, J = 8.6 Hz, 2H), 7.60 (d, J =
8.8Hz, 2H), 7.44 (d, J = 8.6Hz,
2H), 7.37 (s, 5H), 6.99 (d, J =
8.8 Hz, 2H), 3.79 (s, 3H) Example 53 7-Hydroxy-6- (2-methoxyphenyl) -3-
(4-Phenylthiophenyl) pyrazolo [1,5-a]
The title compound was obtained according to Pyrimidine Example 52. mp:> 300 ° C NMR (DMSO-d ₆ ) δ: 8.25 (s, 1H), 7.77 (s, 1H), 7.6.
7 (d, J = 8.4 Hz, 2H), 7.41 (d, J =
8.4 Hz, 2H), 7.36 (s, 5H), 7.26
~ 7.52 (m, 3H), 6.85 to 7.12 (m, 1
H), 3.75 (s, 3H) Example 54 7-Hydroxy-6- (3-methoxyphenyl) -3-
(4-Phenylthiophenyl) pyrazolo [1,5-a]
The title compound was obtained according to Pyrimidine Example 52. mp:> 300 ° C NMR (DMSO-d ₆ ) δ: 8.27 (s, 1H), 7.97 (s, 1H), 7.6.
4 (d, J = 8.6 Hz, 2H), 7.41 (d, J =
8.6 Hz, 2H), 7.36 (s, 5H), 7.20
~ 7.34 (m, 3H), 6.83-6.96 (m, 1
H), 3.80 (s, 3H) Example 55 7-Hydroxy-6- (4-fluorophenyl) -3-
(4-Phenylthiophenyl) pyrazolo [1,5-a]
The title compound was obtained according to Pyrimidine Example 52. mp:> 300 ° C NMR (DMSO-d ₆ ) δ: 8.27 (s, 1H), 7.97 (s, 1H), 7.6.
5 (d, J = 8.8 Hz, 2H), 7.55 to 7.69
(M, 1H), 7.41 (d, J = 8.8Hz, 2
H), 7.37 (s, 5H), 7.18 (d, J = 9.
0 Hz, 2H) Example 56 7-Hydroxy-6- (3-fluorophenyl) -3-
(4-Phenylthiophenyl) pyrazolo [1,5-a]
The title compound was obtained according to Pyrimidine Example 52. mp:> 300 ° C NMR (DMSO-d ₆ ) δ: 8.29 (s, 1H), 8.07 (s, 1H), 7.6.
5 (d, J = 8.4 Hz, 2H), 7.42 (d, J =
8.4 Hz, 2H), 7.37 (s, 5H), 7.02
~ 7.78 (m, 4H) Example 57 7-Hydroxy-6- (2-fluorophenyl) -3-
(4-Phenylthiophenyl) pyrazolo [1,5-a]
The title compound was obtained according to Pyrimidine Example 52. mp:> 300 ° C NMR (DMSO-d ₆ ) δ: 8.29 (s, 1H), 7.94 (s, 1H), 7.1
0-7.80 (m, 13H) Example 58 7-Hydroxy-3,6-bis (4-phenylthiophe)
Nyl) pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 52. mp: 278-280 ° C NMR (DMSO-d ₆ ) δ: 8.27 (s, 1H), 8.00 (s, 1H), 7.7.
1 (d, J = 8.4 Hz, 2H), 7.64 (d, J =
8.4 Hz, 2 H), 7.41 (d, J = 8.4 Hz,
2H), 7.37 (d, J = 8.4Hz, 2H), 7.
32-7.39 (m, 10H) Example 59 6- (2-acetoxyethyl) -7-hydroxy-3-
(4-Phenylthiophenyl) pyrazolo [1,5-a]
Ethyl formate (4 ml) and γ-butyrolactone (1.6 ml) were added to a benzene suspension of pyrimidine 60% sodium hydride (1.0 g) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 24 hours. Then add water and neutralize with 10% hydrochloric acid,
The mixture was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in acetic acid (10 ml), 3-amino-4- (4-phenylthiophenyl) pyrazole (2.0 g) was added, and the mixture was heated with stirring at 120 ° C. for 6 hours. After cooling, ethyl acetate was added, the precipitate was collected by filtration, washed with ethyl acetate and ether, and dried to obtain the title compound (400 mg, 13%). mp: 265~270 ℃ NMR (DMSO- d 6) δ: 8.22 (s, 1H), 7.78 (s, 1H), 7.6
1 (d, J = 8.6 Hz, 2H), 7.40 (d, J =
8.6 Hz, 2H), 7.36 (s, 5H), 4.20
(T, J = 6.6 Hz, 2H), 2.78 (t, J =
6.6 Hz, 2H), 1.99 (s, 3H) Example 60 7-Hydroxy-6- (2-hydroxyethyl) -3-
(4-Phenylthiophenyl) pyrazolo [1,5-a]
Pyrimidine 6- (2-acetoxyethyl) -7-hydroxy-3-
(4-Phenylthiophenyl) pyrazolo [1,5-a]
2N- into a suspension of pyrimidine (180 mg) in methanol
Sodium hydroxide (2 ml) was added, and the mixture was stirred at room temperature for 21 hours. Then, acidify with 10% hydrochloric acid, collect the precipitate by filtration, wash with water and dry to give the title compound (150 mg, 93%).
Got mp: 244-247 ° C NMR (DMSO-d ₆ ) δ: 8.20 (s, 1H), 7.68 (s, 1H), 7.6.
0 (d, J = 8.6 Hz, 2H), 7.40 (d, J =
8.6Hz, 2H), 7.35 (s, 5H), 3.56
(T, J = 6.8 Hz, 2H), 2.61 (t, J =
6.4 Hz, 2H) Example 61 7-Hydroxy-6- (2-hydroxyphenylmethyl)
) -3- (4-Phenylthiophenyl) pyrazolo
[1,5-a] pyrimidine 7-hydroxy-6- (2-methoxyphenylmethyl)
-3- (4-phenylthiophenyl) pyrazolo [1,5
-A] To a suspension of pyrimidine (150 mg) in dichloroethane, boron tribromide (0.1 ml) was added under ice cooling, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution and stirred for 1 hour. The precipitate was collected by filtration, washed with water and methanol, and dried to give the title compound (70 mg, 48%). mp: 283~287 ℃ NMR (DMSO- d 6) δ: 9.42 (s, 1H), 8.22 (s, 1H), 7.6
0 (d, J = 8.6 Hz, 2H), 7.56 (s, 1
H), 7.39 (d, J = 8.6 Hz, 2H), 7.3
5 (s, 5H), 6.95 to 7.20 (m, 2H),
6.71 to 6.84 (m, 2H), 3.71 (s, 2
H) Example 62 7-Hydroxy-6- (3-hydroxyphenylmethyi)
) -3- (4-Phenylthiophenyl) pyrazolo
[1,5-a] pyrimidine The title compound was obtained according to Example 61. mp: 235-237 ° C NMR (DMSO-d ₆ ) δ: 9.17 (bs, 1H), 8.21 (s, 1H), 7.
70 (d, J = 1.1 Hz, 1H), 7.60 (d, J
= 8.6 Hz, 2H), 7.39 (d, J = 8.6H)
z, 2H), 7.35 (s, 5H), 7.06 (t, J
= 8.0 Hz, 1H), 6.51 to 6.75 (m, 3
H), 3.71 (s, 2H) Example 63 7-Hydroxy-6- (4-hydroxyphenylmethyi)
) -3- (4-Phenylthiophenyl) pyrazolo
[1,5-a] pyrimidine The title compound was obtained according to Example 61. mp: 287-293 ° C NMR (DMSO-d ₆ ) δ: 9.10 (bs, 1H), 8.20 (s, 1H), 7.
65 (s, 1H), 7.60 (d, J = 8.6Hz, 2
H), 7.39 (d, J = 8.6 Hz, 2H), 7.3
5 (s, 5H), 7.10 (d, J = 8.4Hz, 2
H), 6.66 (d, J = 8.4 Hz, 2H), 3.6
8 (s, 2H) Example 64 7-Hydroxy-6- (2-hydroxyphenyl) -3
-(4-phenylthiophenyl) pyrazolo [1,5-
a] Pyrimidine The title compound was obtained according to Example 61. mp:> 300 ° C. NMR (DMSO-d ₆ ) δ: 9.32 (bs, 1H), 8.26 (s, 1H), 7.
83 (s, 1H), 7.65 (d, J = 8.4Hz, 2
H), 7.42 (d, J = 8.4 Hz, 2H), 7.3
7 (s, 5H), 7.10 to 7.52 (m, 2H),
6.76-6.94 (m, 2H) Example 65 7-Hydroxy-6- (3-hydroxyphenyl) -3
-(4-phenylthiophenyl) pyrazolo [1,5-
a] Pyrimidine The title compound was obtained according to Example 61. mp:> 300 ° C NMR (DMSO-d ₆ ) δ: 9.37 (bs, 1H), 8.26 (s, 1H), 7.
69 (s, 1H), 7.63 (d, J = 8.6Hz, 2
H), 7.41 (d, J = 8.6 Hz, 2H), 7.3
6 (s, 5H), 7.00 to 7.22 (m, 3H),
6.66-6.80 (m, 1H) Example 66 7-Hydroxy-6- (4-hydroxyphenyl) -3
-(4-phenylthiophenyl) pyrazolo [1,5-
a] Pyrimidine The title compound was obtained according to Example 61. mp:> 300 ° C NMR (DMSO-d ₆ ) δ: 9.42 (s, 1H), 8.26 (s, 1H), 7.8.
3 (s, 1H), 7.64 (d, J = 8.4Hz, 2
H), 7.42 (d, J = 8.4 Hz, 2H), 7.4
7 (d, J = 8.4 Hz, 2H), 7.36 (s, 5
H), 6.81 (d, J = 8.4 Hz, 2H) Example 67 7-Hydroxy-6-acetyl-3- (4-phenylthio)
A mixture of ophenyl) pyrazolo [1,5-a] pyrimidine 3-amino-4- (4-phenylthiophenyl) pyrazole (534 mg), ethoxymethylene acetoacetic acid ethyl ester (484 mg) and acetic acid (15 ml) was stirred at room temperature. did. After 30 minutes, the precipitate was collected by filtration and washed with n-hexane. A mixture of the obtained precipitate, sodium methoxide (290 mg) and toluene (50 ml) was concentrated under reduced pressure, 2N hydrochloric acid, methylene chloride and ethyl acetate were added to the residue, and after separation, the organic layer was dried over anhydrous magnesium sulfate. , Concentrated under reduced pressure. The residue was recrystallized from methylene chloride-ethyl acetate (= 1: 1) to give the title compound (350 mg). mp: 275~283 ℃ NMR (DMSO- d 6) δ: 8.32 (s, 1H), 8.31 (s, 1H), 7.3
8-7.69 (m, 9H), 2.60 (s, 3H) Example 68 7-Hydroxy-6-benzoyl-3- (4-phenyl)
Thiophenyl) pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 67. mp: 277~290 ℃ NMR (DMSO- d 6) δ: 8.32 (s, 1H), 8.18 (s, 1H), 7.3
8-7.84 (m, 14H) Example 69 7-Hydroxy-6-trifluoroacetyl-3- (4
-Phenylthiophenyl) pyrazolo [1,5-a] pyri
Example 67 except that ethanol was used instead of midine toluene.
The title compound was obtained according to. mp: 265-286 ° C NMR (DMSO-d ₆ ) δ: 8.46 (s, 1H), 8.31 (s, 1H), 8.1
2 (d, J = 8.13 Hz, 2H), 7.39 (d, J
= 8.13 Hz, 2H), 7.29 (s, 5H) Example 70 7-Hydroxy-6- (1-hydroxyethyl) -3-
(4-Phenylthiophenyl) pyrazolo [1,5-a]
Pyrimidine 7-hydroxy-6-acetyl-3- (4-phenylthiophenyl) pyrazolo [1,5-a] pyrimidine (10
8 mg), sodium borohydride (46 mg), 2N aqueous sodium hydroxide solution (2.3 ml), ethanol (5 ml)
The mixture was heated to reflux. After 1 hour, the reaction mixture was concentrated under reduced pressure, water (4 ml) was added to the residue, and the mixture was neutralized with 2N hydrochloric acid. The precipitate was collected by filtration, washed with water, and dried to obtain the title compound (87 mg). mp: 262~285 ℃ NMR (DMSO- d 6) δ: 8.24 (s, 1H), 7.29~7.67 (m, 10
H), 4.84 (q, J = 6.37 Hz, 1H), 1.
36 (d, J = 6.15 Hz, 3H) Example 71 7-Hydroxy-6- (α-hydroxybenzyl) -3
-(4-phenylthiophenyl) pyrazolo [1,5-
a] Pyrimidine The title compound was obtained according to Example 70. mp: 192-198 ° C NMR (DMSO-d ₆ ) δ: 8.20 (s, 1H), 8.17 (d, J = 8.35H)
z, 2H), 7.88 (s, 1H), 7.19 to 7.6.
1 (m, 12H), 5.96 (d, J = 4.83Hz,
1H), 5.49 (d, J = 5.05 Hz, 1H) Example 72 7-Hydroxy-6- (1-hydroxy-2,2,2-
Trifluoroethyl) -3- (4-phenylthiophene
Ru) Pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 70. mp: 265~290 ℃ NMR (DMSO- d 6) δ: 8.28 (s, 1H), 7.85 (s, 1H), 7.3
7 to 7.71 (m, 9H), 6.89 (d, J = 6.1)
5 Hz, 1H), 5.17-5.47 (m, 1H) Example 73 6- (3-Bromo-4-methoxyphenyl) -7- hydr
Roxy-3- (4-phenylthiophenyl) pyrazolo
[1,5-a] pyrimidine 7-hydroxy-6- (4-methoxyphenyl) -3-
(4-Phenylthiophenyl) pyrazolo [1,5-a]
Bromine (0.1 ml) was added to a suspension of pyrimidine (420 mg) in nitrobenzene (2 ml), the mixture was stirred at room temperature for 1 hour, water and ether were added, and the precipitate was collected by filtration. This was washed with water, methanol, ethyl acetate and ether and then dried to obtain the title compound (270 mg, 54%). mp:> 300 ° C NMR (DMSO-d ₆ ) δ: 8.29 (s, 3H), 7.10 to 8.00 (m, 12)
H), 3.89 (s, 3H) Example 74 6-Ethoxycarbonyl-7-hydroxy-3- (3-
Methyl-4-phenylthiophenyl) pyrazolo [1,5
-A] Pyrimidine The title compound was obtained according to Example 1. NMR (DMSO-d ₆ ) δ: 8.37 (s, 1H), 8.28 (s, 1H), 7.2
2 to 7.59 (m, 8H), 4.28 (q, J = 7.0)
3Hz, 2H), 2.39 (s, 3H), 1.29
(T, J = 7.03 Hz, 3H) Example 75 6-carboxy-7-hydroxy-3- (3-methyl-)
4-phenylthiophenyl) pyrazolo [1,5-a] pi
The title compound was obtained according to Limidine Example 38. NMR (DMSO-d ₆ ) δ: 8.48 (s, 1H), 8.39 (s, 1H), 7.2
4-7.75 (m, 8H), 2.38 (s, 3H) Example 76 7-Hydroxy-3- (3-methyl-4-phenylthio)
Phenyl) pyrazolo [1,5-a] pyrimidine The title compound was obtained according to Example 48. mp: 267~271 ℃ _{(decomposition) NMR (DMSO-d 6)} δ: 8.23 (s, 1H), 7.77~7.87 (br, 1
H), 2.23 to 8.0 (m, 8H), 5.79 (d,
J = 7.47 Hz, 1H), 2.38 (s, 3H) Next, formulation examples are shown. Formulation Example 6-Ethoxycarbonyl-7-hydroxy-3- (4-phenylthiophenyl) -pyrazolo [1,5-a] pyrimidine 100 g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40 g Corn starch 30 g Stearic acid Magnesium 2 g TC-5 (trade name, hydroxypropylmethylcellulose manufactured by Shin-Etsu Chemical Co., Ltd.) 10 g polyethylene glycol-6000 3 g castor oil 40 g ethanol 40 g 6-ethoxycarbonyl-7-hydroxy-3- (4 −
Phenylthiophenyl) -pyrazolo [1,5-a] pyrimidine, Avicel, corn starch and magnesium stearate were mixed and polished, and then tableted with a sugar coated R10 mm kine. The obtained tablets were coated with a film coating agent consisting of TC-5, polyethylene glycol-6000, castor oil and ethanol to produce a film coated tablet having the above composition.

For each test compound obtained in the examples, the following pharmacological tests A and B were conducted. The pharmacological test A was conducted based on JBC256 (15) 7998-8005,1981. A. ³ H-5α- on rat prostate androgen receptor
Binding of dihydrotestosterone ⁽³ H-5α-DHT)
And剖殺the cytoplasmic fraction of the preparation rats from the measurement (1) rat prostate inhibitory activity 24 hours after castration for, removed ventral prostate, 3 volumes of 0.25M Sucrose-TME buffer (50 mM
In Tris-HCl (pH 7.4), 0.5 mM mercaptoethanol and 0.1 mM EDTA-2Na), a Potter homogenizer was used to gently homogenize under ice cooling. The obtained homogenate was filtered with double gauze and ultracentrifuged at 4500C for 10500 xg x 60 minutes, and the supernatant was used as a cytoplasmic fraction. (2) ³ H-5α- to the prostatic cytoplasmic androgen receptor
Measurement of DHT-specific binding To the cytoplasmic fraction obtained in (1) above, ³ H-5α-DHT (4
7.8 Ci / mmol) was added so as to have a final concentration of 1 nM, and the mixture was reacted with 0.25 M Sucrose-TME buffer at a final volume of 0.5 ml at 0 ° C. for about 20 hours. After completion of the reaction, ammonium sulfate solution dissolved in 0.25 M Sucrose-TME buffer was mixed to achieve 35% saturation, and the mixture was allowed to stand at 0 ° C for 90 minutes and then at 4 ° C for 10000.
The precipitate was obtained by centrifugation at × g × 10 minutes.

This precipitate was resuspended in 0.8 ml of the above buffer, and 0.2 ml of dextran-carbon powder suspension (4% activated carbon, 0%) was added in order to remove free ³ H-5α-DHT. 1% dextran T-70 and 0.1% gelatin dissolved in the above buffer) were added and mixed,
It was left at 0 ° C. for 10 minutes. Then, at 4 ° C., 3000 ×
Centrifugation was performed for 10 minutes, and 0.5 ml of the obtained supernatant was collected, transferred to a vial, 10 ml aquazol-2 was added, and the radioactivity was measured to the prostate cytoplasmic androgen receptor. The total amount of ³ H-5α-DHT bound was determined. In addition, the amount of non-specific binding was the unlabeled 5α in the reaction solution.
-DHT was added so that the final concentration was 1 µM, and the concentration was determined in the same manner as above. Then, the difference between the total binding amount and the non-specific binding amount was defined as the specific binding amount bound to the androgen receptor. (3) Inhibitory activity of test compound on ³ H-5α-DHT specific binding Each test compound obtained in the example was changed in concentration to ³ H-5α
-DHT was added at the same time and reacted in the same manner as in (2) above, and in this case, the specific binding amount of ³ H-5α-DHT bound to the androgen receptor was determined. And with this value
The IC ₅₀ value of the inhibitory activity of each test compound for ³ H-5α-DHT specific binding was determined by comparing with the value determined in (2). The results are shown in Table 1. The following compounds were used as comparative examples. Comparative Example 1: Flutamide Comparative Example 2: Hydroxyflutamide

[0100]

[Table 1]

B. To rat prostate androgen receptor
Measurement of inhibitory activity against binding of ³ H-mibolerone (1) Preparation of cytoplasmic fraction from rat prostate 24 hours after castration, the rat was sacrificed and the abdominal lobe of the prostate was taken out and 3 times amount of buffer A (1.5 mM EDTA, 2 mM dithiothreitol, 10 mM sodium molybdate,
Using polytroon in 10 vol% glycerol, 10 mM NaF, 25 mM sodium phosphate, pH 7.2), then using a Potter homogenizer,
Gently homogenized under ice cooling. The resulting homogenate was filtered through double gauze and 105,000 at 4 ° C.
Ultracentrifugation was performed for 60 minutes at x g, and the supernatant was used as a cytoplasmic fraction. (2) Measurement of specific binding of ³ H-mibolerone to prostate cytoplasmic androgen receptor The cytoplasmic fraction obtained in (1) above contained ³ H-mibolerone (8
7.0 Ci / mmol) to a final concentration of 1 nM, and at the same time, triamcinolone acetonide was added to a final concentration of 5 μM for the purpose of suppressing binding to ³ H-mibolerone progestin receptor. The final volume of A was 0.4 ml and the reaction was carried out for 20 hours in an environment of 0 ° C. After completion of the reaction, 0.5 ml of 60% hydroxylapatite slurry (wash and equilibrate with buffer B (10 m
MNaH ₂ PO ₄ , 20 mM Tris-HCl, pH 7.
2) was added, and the mixture was allowed to stand at 0 ° C. for 10 minutes and then suction-filtered using a glass fiber. The buffer was washed 5 times with 5 ml of a buffer solution B containing ³ parts by volume to remove free ³ H-mibolerone. Then, the glass fiber is transferred to a vial, and Aquasol-2 is used.
Was added to measure the radioactivity, and the total amount of ³ H-mibolerone bound to the prostatic cytoplasmic androgen receptor was determined.

The amount of non-specific binding was determined in the same manner as above by adding unlabeled 5α-DHT to the reaction solution so that the final concentration was 1 μM. Then, the difference between the total binding amount and the non-specific binding amount was defined as the specific binding amount bound to the androgen receptor. (3) Inhibitory activity of test compound for ³ H-mibolerone-specific binding Each test compound obtained in Example was added at the same time with ³ H-mibolerone, and reacted in the same manner as in (2) above. Let
In this case, the specific binding amount of ³ H-mibolerone bound to the androgen receptor was determined. Then, this value was compared with the value determined in (2) to determine the IC ₅₀ value of the inhibitory activity of each test compound on ³ H-mibolerone-specific binding. The results are shown in Tables 2 to 4. Comparative Example 1: Flutamide Comparative Example 2: Hydroxyflutamide

[0103]

[Table 2]

[0104]

[Table 3]

[0105]

[Table 4]

[0106]

INDUSTRIAL APPLICABILITY The pyrimidine derivative of the present invention or a pharmaceutically acceptable salt thereof has an activity of inhibiting the expression of the action of androgen, and causes hypertrophy of the prostate caused by accelerated action of androgen, hirsutism of female, and male type. It has an excellent effect on the treatment of baldness or acne.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Masatoshi Inai, 554, Tozai-cho, Itano-gun, Tonari-cho, 554, Oza-machi (72) Inventor, Makoto Inoue, Otsu-machi, Naruto, Tokushima Prefecture, Nogami Nokoshi 112-3

Claims (1)

[Claims] 1. General formula (1): [In the formula, R ¹ represents a hydrogen atom or a hydroxyl group, R ² represents a hydrogen atom, a lower alkoxycarbonyl group, a lower alkoxy group, a halogen atom, a lower alkyl group, a cycloalkyl group having 3 to 8 carbon atoms, a lower alkoxycarbonyl. Lower alkyl group, carboxyl group, carboxy lower alkyl group,
Group: -CONHR ⁶ (R ⁶ represents a hydrogen atom, a phenyl group which may have a halogen atom or a lower alkyl group), a cyano group, a hydroxyl group as a substituent, a halogen atom,
A phenyl group which may have a group selected from the group consisting of a lower alkyl group, a lower alkoxy group and a phenylthio group, and a phenyl which may have a group selected from the group consisting of a hydroxyl group and a lower alkoxy group as a substituent on the phenyl ring. A lower alkyl group, a lower alkanoyloxy lower alkyl group, a benzoyl group, a lower alkanoyl group which may have a halogen atom or a hydroxy lower alkyl group which may have a group selected from the group consisting of a phenyl group and a halogen atom as a substituent. Shows, R ³
Is a hydrogen atom, a hydroxyl group, a lower alkyl group, and has 3 to 8 carbon atoms.
Represents a cycloalkyl group, a halogen lower alkyl group or a phenyl group, R ⁴ represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and R ⁵ represents a hydrogen atom, a lower alkyl group, a lower alkoxy lower alkyl group or a halogen lower alkyl Indicates a group. However, R ² and R ³ may be bonded together to form a lower alkylene group having 3 to 5 carbon atoms. ] The pyrimidine derivative represented by these, or its pharmaceutically acceptable salt.