JPH06316578A - Pyrazolotriazine derivative and xanthine oxidase inhibitor containing the derivative - Google Patents

Abstract

PURPOSE:To provide a new compound having excellent xanthine oxidase inhibiting activity and useful as treating agent for gout, etc. CONSTITUTION:The compound is expressed by formula I [R<1> is hydroxy or a lower alkanoyloxy; R<2> is H, hydroxy or mercapto; R<3> is thiochromanyl, benzothienyl, 2,3-dihydrobenzothienyl, (halogen-substituted) thienyl, etc.], e.g. 4-hydroxy-8-phenylpyrazolo[1, 5-a]-1,3,5-triazine. The compound of formula I is obtained, for example, by reacting a compound of formula II with orthoformic acid alkyl.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pyrazolotriazine derivative and a xanthine oxidase inhibitor containing the same.

[0002]

2. Description of the Related Art As a xanthine oxidase inhibitor, J. Heterocycl.
Various heterocyclic compounds disclosed in m., 22 (3), 601-34, 1985 are known, but their xanthine oxidase inhibitory activity was not sufficient.

[0003]

Means and Actions for Solving the Problems The present invention provides a novel pyrazolotriazine derivative represented by the following general formula, which has not been described in the literature, and a salt thereof.

[0004]

[Chemical 7]

[In the formula, R ¹ represents a hydroxyl group or a lower alkanoyloxy group. R ² represents a hydrogen atom, a hydroxyl group, or a mercapto group. R ³ represents (1) an unsaturated heterocyclic group having a nitrogen atom or a sulfur atom as a hetero atom, and the heterocyclic group has a substituent selected from the group consisting of a halogen atom, a nitro group and a phenylthio group. (2) a naphthyl group which may have 1 or 2 groups, or (3) a phenyl group which may have 1 to 3 substituents consisting of the following groups. i lower alkyl group; ii phenyl group; iii lower alkoxycarbonyl group; iv cyano group; v nitro group; vi lower alkoxy group; vii phenyl lower alkoxy group; viii phenylthio lower alkyl group; ix phenoxy group; x group

[0006]

[Chemical 8]

(Wherein R is a lower alkyl group, a halogen-substituted lower alkyl group, 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group as a substituent on the phenyl ring. A phenyl group which may have, or a pyridyl group, t represents an integer of 0, 1 or 2.); xi halogen atom; xii phenyl lower alkyl group; xii carboxy group; xiv lower alkanoyl group; xv substituted on the phenyl ring A benzoyl group which may have 1 to 3 halogen atoms, phenyl lower alkoxy groups and / or hydroxyl groups as groups; xvi amino group; xvii hydroxyl group; xviii lower alkanoyloxy group; xix group

[0008]

[Chemical 9]

(In the formula, R ⁴ and R ⁵ are the same or different and each is a hydrogen atom; a cycloalkyl group;
A lower alkyl group which may have a substituent selected from the group consisting of a hydroxyl group, a furyl group, a thienyl group, a tetrahydrofuranyl group and a phenyl group; a lower alkyl group which may have a hydroxyl group as a substituent, a lower alkanoyl group, A phenyl group which may have 1 to 3 substituents selected from the group consisting of a cyano group, a carboxy group, a lower alkoxycarbonyl group, a hydroxyl group, a lower alkoxy group and a halogen atom; pyridyl, pyrimidinyl, thiazolyl,
Represents a heterocyclic group selected from the group consisting of isoxazolyl and pyrazolyl, which may have a lower alkyl group, an amino group or a lower alkanoylamino group as a substituent; and R ⁴ and R ⁵ are each Alternatively, a saturated 5-membered or 6-membered ring may be formed by bonding with a nitrogen atom to be bonded via an oxygen atom or not. ); And xx groups

[0010]

[Chemical 10]

(In the formula, A represents a lower alkylene group.) The pyrazolotriazine derivative of the present invention represented by the general formula (1) has a xanthine oxidase inhibitory activity and is extremely useful as an anti-gout agent. It is a compound. The above general formula
Each group shown in (1) will be described in more detail below.

Examples of the lower alkyl group include alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl and hexyl groups. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

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 lower alkanoyl group and the lower alkanoyl moiety of the lower alkanoyloxy group and the lower alkanoylamino group include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl groups and the like having 1 to 6 carbon atoms. Can be illustrated.

The unsaturated heterocyclic group having a nitrogen atom or a sulfur atom as a hetero atom includes, for example, pyrrolyl, pyridyl, thienyl, thiopyranyl, indolyl, benzothienyl, 2,3-dihydrobenzothienyl, thiochromanyl, dibenzothienyl and the like. And monocyclic and fused ring heterocyclic groups containing a nitrogen atom or a sulfur atom. This heterocyclic group has a halogen atom as a substituent, a nitro group,
1 to 2 substituents selected from the group consisting of phenylthio groups
Specific examples of the heterocyclic group which may have one or more such substituents include, for example, 2-pyrrolyl and 3
-Pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 2-thiopyranyl,
3-thiopyranyl, 4-thiopyranyl, 5-chloro-2
-Thienyl, 5-bromo-2-thienyl, 4-bromo-
2-thienyl, 2-bromo-3-thienyl, 2,5-dichloro-3-thienyl, 2,5-dibromo-3-thienyl, 4,5-dibromo-2-thienyl, 4,5-dibromo-3- Thienyl, 2-chloro-5-pyridyl, 2,3
-Dibromo-5-pyridyl, 5-nitro-2-thienyl, 4-nitro-2-thienyl, 3-nitro-2-thienyl, 2-nitro-3-thienyl, 2-nitro-4-pyridyl, 6-nitro -2-pyridyl, 3-phenylthio-2-thienyl, 5-phenylthio-2-thienyl, 5
-Phenylthio-3-thienyl, 4-phenylthio-2
-Pyridyl, 5-phenylthio-2-pyridyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-benzothiophen-2-yl, 1- Benzothiophen-3-yl, 1-benzothiophen-4-yl, 1-benzothiophen-5-yl, 1-benzothiophen-6-yl, 1-benzothiophen-7-yl,
2,3-dihydro-1-benzothiophen-4-yl,
2,3-dihydro-1-benzothiophen-5-yl,
2,3-dihydro-1-benzothiophen-6-yl,
2,3-dihydro-1-benzothiophen-7-yl,
Thiochroman-5-yl, thiochroman-6-yl, thiochroman-7-yl, thiochroman-8-yl, dibenzothiophen-1-yl, dibenzothiophen-2-
Pyrrolyl, which may have 1 or 2 substituents selected from the group consisting of a halogen atom, a nitro group and a phenylthio group as a substituent, such as yl, dibenzothiophen-3-yl and dibenzothiophen-4-yl groups, Pyridyl,
Heterocyclic groups such as thienyl, thiopyranyl, indolyl, benzothienyl, 2,3-dihydrobenzothienyl, thiochromanyl and dibenzothienyl can be exemplified.

Examples of the naphthyl group include 1-naphthyl and 2-naphthyl groups. As the lower alkoxycarbonyl group, for example, a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl group or the like having an alkoxy moiety having 1 to 6 carbon atoms. An alkoxycarbonyl group can be illustrated.

As the phenyl lower alkoxy group, for example, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, 2-phenyl-1-methylethoxy, 4-phenylbutoxy, 2-phenyl-1, Examples include 1-dimethylethoxy, 5-phenylpentyloxy, 6-phenylhexyloxy and other phenylalkoxy groups having 1 to 6 carbon atoms in the alkoxy moiety.

As the phenylthio lower alkyl group, for example, phenylthiomethyl, 1-phenylthioethyl,
2-phenylthioethyl, 3-phenylthiopropyl,
2-phenylthio-1-methylethyl, 4-phenylthiobutyl, 2-phenylthio-1,1-dimethylethyl, 5-phenylthiopentyl, 6-phenylthiohexyl, etc. having an alkyl moiety having 1 to 6 carbon atoms A phenylthioalkyl group can be exemplified.

As the halogen-substituted lower alkyl group, for example, chloromethyl, bromomethyl, 1-chloroethyl, 2-chloroethyl, 2-bromoethyl, 3-chloropropyl, 2-chloro-1-methylethyl, 2-bromobutyl, 4- Examples thereof include halogen-substituted alkyl groups having 1 to 6 carbon atoms in the alkyl moiety such as bromobutyl, 2-chloro-1,1-dimethylethyl, 5-chloropentyl, and 6-bromohexyl groups.

Examples of the phenyl group which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group on the phenyl ring include, for example, phenyl and 2- Chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 4-iodophenyl, 2,
4-dibromophenyl, 2,6-dibromophenyl,
2,4,6-tribromophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 4-ethylphenyl, 3-propylphenyl, 4- (t-butyl) phenyl, 4 -Pentylphenyl, 4-hexylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2-methyl-4-ethylphenyl, 2,4,6-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl , 4-methoxyphenyl, 2-ethoxyphenyl, 4-ethoxyphenyl, 3-propoxyphenyl, 4- (t-butoxy) phenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 2,6-dimethoxyphenyl, 2 -Methoxy-4-ethoxyphenyl, 2,4,6-trimethoxyphenyl, 2-ku B-4-methylphenyl, 2,6
-Dibromo-4-methylphenyl, 2-chloro-4-methoxyphenyl, 2,6-dichloro-4-methoxyphenyl, 2-bromo-4-methoxyphenyl, 2,6-dibromo-4-methoxyphenyl, 2, 6-dibromo-4
-Halogen atom such as ethoxyphenyl group, having 1 to 6 carbon atoms
Examples thereof include a phenyl group which may have an alkyl group and an alkoxy group having 1 to 6 carbon atoms.

Examples of the phenyl lower alkyl group include benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenyl-1-methylethyl, 4-phenylbutyl, 2-phenyl-1,1. −
Examples thereof include phenylalkyl groups having 1 to 6 carbon atoms in the alkyl moiety such as dimethylethyl, 5-phenylpentyl and 6-phenylhexyl groups.

Examples of the benzoyl group which may have 1 to 3 halogen atoms, phenyl lower alkoxy groups and / or hydroxyl groups on the phenyl ring as a substituent include, for example, benzoyl, 3-bromobenzoyl, 4-benzyloxybenzoyl, 4-hydroxybenzoyl, 3,5
-Dibromobenzoyl, 3-bromo-4-benzyloxybenzoyl, 3-chloro-4-hydroxybenzoyl, 3,5-dibromo-4-benzyloxybenzoyl, 3,5-dibromo-4- (1-phenethyloxy)
Benzoyl, 3,5-dibromo-4- (2-phenethyloxy) benzoyl, 3,5-dibromo-4- (3-phenylpropoxy) benzoyl, 3,5-dibromo-4
-(4-phenylbutoxy) benzoyl, 3,5-dibromo-4- (5-phenylpentyloxy) benzoyl, 3,5-dibromo-4- (6-phenylhexyloxy) benzoyl, 3,5-dichloro-4 -A halogen atom such as benzyloxybenzoyl, 3,5-dichloro-4-hydroxybenzoyl, 3,4-dichloro-5-hydroxybenzoyl group;
Examples thereof include a benzoyl group which may have 1 to 3 substituents selected from the group consisting of the phenylalkoxy group of 6 and a hydroxyl group.

Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and other cycloalkyl groups having 3 to 8 carbon atoms. Examples of the furyl group include 2-furyl and 3-furyl groups. Examples of the thienyl group include 2-thienyl and 3-
An example is a thienyl group.

Examples of the tetrahydrofuranyl group include 2-tetrahydrofuranyl and 3-tetrahydrofuranyl groups. Examples of the lower alkyl group that may have a hydroxyl group as a substituent include, for example, hydroxymethyl, 1-hydroxyethyl, 2-
Examples thereof include an alkyl group having 1 to 6 carbon atoms in the alkyl moiety which may have a hydroxyl group as a substituent such as hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, and 6-hydroxyhexyl groups.

As the lower alkyl group which may have a substituent selected from the group consisting of a hydroxyl group, a furyl group, a thienyl group, a tetrahydrofuranyl group and a phenyl group as the substituent, for example, the above-mentioned phenyl lower alkyl group, In addition to a lower alkyl group which may have a hydroxyl group as a substituent, 2-furfuryl, 3-furylmethyl, 1-
(2-furyl) ethyl, 2- (3-furyl) ethyl, 3
-(2-furyl) propyl, 4- (3-furyl) butyl, 3- (2-furyl) pentyl, 6- (2-furyl)
Hexyl, 2-thienylmethyl, 3-thienylmethyl,
1- (2-thienyl) ethyl, 2- (3-thienyl) ethyl, 3- (2-thienyl) propyl, 4- (3-thienyl) butyl, 4- (2-thienyl) pentyl, 6-
(2-thienyl) hexyl, 2-tetrahydrofuranylmethyl, 3-tetrahydrofuranylmethyl, 1- (2-
Tetrahydrofuranyl) ethyl, 2- (3-tetrahydrofuranyl) ethyl, 3- (2-tetrahydrofuranyl) propyl, 4- (3-tetrahydrofuranyl) butyl, 5- (2-tetrahydrofuranyl) pentyl, 6-
Examples of the substituent such as (2-tetrahydrofuranyl) hexyl group include a hydroxyl group, a furyl group, a thienyl group, a tetrahydrofuranyl group or a phenyl group, and an alkyl group having 1 to 6 carbon atoms.

As the substituent, a substituent selected from the group consisting of a lower alkyl group which may have a hydroxyl group, a lower alkanoyl group, a cyano group, a carboxy group, a lower alkoxycarbonyl group, a hydroxyl group, a lower alkoxy group and a halogen atom. As the phenyl group which may have 1 to 3, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-isopropyl Phenyl, 3-isopropylphenyl, 4-isopropylphenyl, 3-propylphenyl, 4-butylphenyl, 2- (t-butyl) phenyl, 3- (t-butyl)
Phenyl, 4- (t-butyl) phenyl, 4-pentylphenyl, 4-hexylphenyl, 4-hydroxymethylphenyl, 2- (1-hydroxyethyl) phenyl,
3- (1-hydroxyethyl) phenyl, 4- (1-hydroxyethyl) phenyl, 2- (2-hydroxyethyl) phenyl, 4- (2-hydroxyethyl) phenyl, 3- (3-hydroxypropyl) phenyl, 4-
(4-hydroxybutyl) phenyl, 4- (5-hydroxypentyl) phenyl, 4- (6-hydroxyhexyl) phenyl, 2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl, 3-propionylphenyl, 4- Butyrylphenyl, 3-valerylphenyl,
4-hexanoylphenyl, 2-cyanophenyl, 3-
Cyanophenyl, 4-cyanophenyl, 2-carboxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-ethoxycarbonylphenyl, 4-propoxy Carbonylphenyl, 4- (t-butoxycarbonyl)
Phenyl, 4-pentyloxycarbonylphenyl, 4
-Hexyloxycarbonylphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,4,6-tri Methoxyphenyl, 3,4,5-
Trimethoxyphenyl, 4-ethoxyphenyl, 4-t
-Butoxyphenyl, 4-hexyloxyphenyl, 2
-Chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 3,4.
5-trichlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-iodophenyl, 2-hydroxy-4-carboxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-hydroxy-3-carboxyphenyl, 2-hydroxy -4-methoxycarbonylphenyl, 3-hydroxy-4-methoxycarbonylphenyl, 4-hydroxy-3-methoxycarbonylphenyl, 2-methoxy-4-methoxycarbonylphenyl,
3-methoxy-4-methoxycarbonylphenyl, 4-
A phenyl group such as a methoxy-3-methoxycarbonylphenyl group (this phenyl group is an alkyl group having 1 to 6 carbon atoms which may have a hydroxyl group as a substituent, 1 to 6 carbon atoms).
1 to 3 substituents selected from the group consisting of an alkanoyl group, a cyano group, a carboxy group, an alkoxycarbonyl group having 1 to 6 carbon atoms of an alkoxy moiety, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms and a halogen atom. You may have. ) Can be illustrated.

A heterocyclic group selected from the group consisting of pyridyl, pyrimidinyl, thiazolyl, isoxazolyl and pyrazolyl, on which a lower alkyl group, an amino group or a lower alkanoylamino group is substituted as a substituent. As the heterocyclic group which may be present, for example,
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-
Thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-methyl-4-pyridyl, 4-methyl-3-
Pyridyl, 3-amino-5-pyridyl, 4-amino-2
-Pyridyl, 2-acetylamino-4-pyridyl, 3-
Propanoylamino-5-pyridyl, 2-methyl-4-
Pyrimidinyl, 4-methyl-6-pyrimidinyl, 5-ethyl-2-pyrimidinyl, 2-amino-5-pyrimidinyl, 2-amino-4-pyrimidinyl, 4-acetylamino-2-pyrimidinyl, 4-acetylamino-6- Pyrimidinyl, 4-propanoylamino-2-pyrimidinyl, 2-methyl-4-thiazolyl, 2-ethyl-5-thiazolyl, 4-methyl-2-thiazolyl, 2-amino-
4-thiazolyl, 4-amino-5-thiazolyl, 2-acetylamino-4-thiazolyl, 5-acetylamino-
2-thiazolyl, 5-methyl-3-isoxazolyl,
4-methyl-3-isoxazolyl, 4-methyl-5-
Isoxazolyl, 5-ethyl-3-isoxazolyl, 5-propyl-4-isoxazolyl, 4-isopropyl-3-isoxazolyl, 5-butyl-3-isoxazolyl, 5-pentyl-4-isoxazolyl,
5-hexyl-3-isoxazolyl, 3-amino-4
-Isoxazolyl, 4-amino-5-isoxazolyl, 3-acetylamino-4-isoxazolyl, 5-
Acetylamino-3-isoxazolyl, 1-methyl-
3-pyrazolyl, 3-methyl-5-pyrazolyl, 4-ethyl-1-pyrazolyl, 5-amino-1-pyrazolyl,
4-amino-1-pyrazolyl, 3-amino-1-pyrazolyl, 5-amino-3-pyrazolyl, 5-acetylamino-1-pyrazolyl, 4-acetylamino-1-pyrazolyl, 3-acetylamino-1-pyrazolyl , 5-acetylamino-3-pyrazolyl, 5-propanoylamino-1-pyrazolyl, 4-butyrylamino-1-pyrazolyl, 5-isobutyrylamino-1-pyrazolyl, 5-valerylamino-1-pyrazolyl, 5-hexa Pyridyl, pyrimidinyl, thiazolyl which may have an alkyl group having 1 to 6 carbon atoms as a substituent such as a noylamino-1-pyrazolyl group, an amino group, or an alkanoylamino group having 1 to 6 carbon atoms in the alkanoyl moiety. And a heterocyclic group selected from the group consisting of isoxazolyl and pyrazolyl groups.

Examples of the saturated 5-membered or 6-membered heterocyclic group formed by combining R ⁴ and R ⁵ with the nitrogen atom to which they are bonded via an oxygen atom or not include, for example, pyrrolidinyl and piperidinyl. , Tetrahydro-1,2-oxazinyl, tetrahydro-1,3-oxazinyl, morpholino group and the like. Examples of the lower alkylene group include alkylene groups having 1 to 6 carbon atoms such as methylene, ethylene, trimethylene, dimethylmethylene, tetramethylene, pentamethylene and hexamethylene groups.

The following formula

[0029]

[Chemical 11]

Examples of the group represented by the formula (A is the same as above) include phenylmethylenedioxymethyl, phenylethylenedioxymethyl, phenylpropylenedioxymethyl groups and the like. The compound of the present invention can be produced by various methods, for example, the method shown in the following reaction scheme. Reaction process formula-1

[0031]

[Chemical 12]

(In the formula, R ³ is the same as the above.) The compound of the present invention represented by the general formula (1-a) is a compound of the general formula (2) and an ortho-gelatin such as methyl orthoformate and ethyl orthoformate. Obtained by reacting with an alkyl acid salt. The above reaction can be carried out in a solvent that does not adversely affect the reaction, but the solvent is not always necessary because the alkyl orthoformate also functions as a solvent. The above reaction uses about 15 times mole of alkyl orthoformate with respect to the compound represented by the general formula (2), and usually about 2
It is completed by reacting for about 15 hours. Reaction process formula-2

[0033]

[Chemical 13]

(In the formula, R ³ is the same as above, and R ⁶ is a lower alkyl group.) The compound represented by the general formula (1-b) is obtained by adding the compound of the general formula (3) to sodium hydroxide, It can be obtained by reacting a base such as a hydroxide of an alkali metal such as potassium hydroxide or calcium hydroxide or a hydroxide of an alkaline earth metal to cause ring closure. As the solvent used in the above reaction, a solvent which does not influence the reaction, for example, methanol-
Examples thereof include lower alcohols such as alcohol and ethanol. The ratio of the above base to the general formula (3) is about 4
It is about a double molar amount, and the reaction is usually -10 ° C to 5 ° C.
It takes about 5 to 40 minutes to finish. Reaction process formula-3

[0035]

[Chemical 14]

(In the formula, R ¹ and R ³ are the same as above.) In the above reaction, the 2-mercapto group of the pyrazolotriazine compound of the general formula (1-b) is converted into a hydroxyl group, and the general formula (1 In the reaction for obtaining the compound of -c), water is used as a solvent,
It can be carried out by reacting the compound of the general formula (1-b) with hydrogen peroxide and a hydroxide of an alkali metal such as sodium hydroxide or potassium hydroxide. The ratio of hydrogen peroxide to the compound of general formula (1-b) is
Usually, the molar amount is about 20 times, and the formula (1-
The ratio of the alkali metal hydroxide used to the compound b) is about twice the molar amount. The above reaction is carried out under ice cooling.
It will be finished in about 3 hours. Reaction process formula-4

[0037]

[Chemical 15]

(In the formula, R ³ is the same as the above, R ¹ a is a lower alkanoyl group, R ² a is a hydrogen atom, a hydroxyl group or a mercapto group.) The above reaction is a compound of the general formula (1-d). Is a reaction for acylating the 4-position hydroxyl group to obtain a compound of the general formula (1-e), and the conditions of ordinary acylation reaction can be widely applied, and examples thereof include an acid halide method, an acid anhydride method, and a mixed acid anhydride. Law, N, N
Any of the ′ -dicyclohexylcarbodiimide method (DCC method) and the like can be applied, and particularly the acid anhydride method and the acid halide method are advantageously applied.

The above acid anhydride method is carried out by reacting the compound of formula (1-d) with an acid anhydride in a suitable solvent. As the acid anhydride, a compound represented by the general formula (1-d)
An acid anhydride corresponding to the acyl group to be introduced into the hydroxyl group at the 4-position of the compound is used. Specific examples thereof include acetic anhydride, propionic anhydride, butyric anhydride, and the like. These acid anhydrides are preferably used in at least an equimolar amount, preferably about 1 to 3 times the molar amount of the compound of the general formula (1-d). As the solvent in the above reaction, various inert solvents, for example, halogenated hydrocarbons such as pyridine, chloroform and dichloromethane, ethers such as dioxane and tetrahydrofuran (THF), aromatic hydrocarbons such as benzene and toluene, N, N-dimethylformamide (DMF), dimethylsulfoxide (DM
SO), acetonitrile and the like can be used. The above reaction is
Usually, the reaction temperature is about -30 ° C to 100 ° C, preferably room temperature to about 80 ° C, and the reaction is completed in about 20 minutes to 20 hours. Further, the above reaction is advantageously carried out in the presence of a basic compound. Examples of the basic compound include organic bases such as tertiary amines such as pyridine, triethylamine and N, N-dimethylaniline, and inorganic basic compounds such as sodium hydrogen carbonate, potassium carbonate and sodium acetate.

In the above acid halide method, an acid halide (eg, acid chloride, acid bromide, etc.) corresponding to the acyl group introduced into the compound of the general formula (1-d) is appropriately prepared in the presence of a basic compound. It is carried out by acting in a different solvent. Examples of the solvent and basic compound used in this reaction include the solvents and basic compounds exemplified in the above acid anhydride method, and the reaction is −30 ° C. to 80 ° C.
℃, preferably at 0 ℃ ~ room temperature, usually 5
It takes about 10 minutes to finish.

The compounds of the present invention have the above reaction schemes 1 to 4
In addition, the reaction of introducing a substituent onto a phenyl group present at the 8-position of the compound of the present invention and an unsaturated heterocyclic group having a nitrogen atom or a sulfur atom as a hetero atom, and the mutual reaction of the substituents. It can also be obtained by a conversion reaction. Hereinafter, these reactions will be described. In the following description, only the substituent to be converted will be described, but various substituents described in the claims may be present on the phenyl ring and unsaturated heterocycle. Conversion reaction-1 When a lower alkyl group is present on the phenyl ring, the lower alkyl group can be converted to a carboxy group with an oxidizing agent such as potassium permanganate or chromic acid. Water can be used as a solvent, for example, and the above conversion reaction can be advantageously carried out under ice cooling for about 5 to 24 hours. The molar ratio of the oxidizing agent to the compound having a lower alkyl group is preferably 1 to 2 times. Conversion reaction-2 In the compound having a carboxy group on the phenyl ring, the carboxy group can be converted to a corresponding ester group by a usual esterification reaction. In the above conversion reaction, for example, sulfuric acid, hydrogen chloride or the like is used as a catalyst, and a lower alcohol such as methanol or ethanol is reacted with a compound having a carboxy group at a boiling point thereof for about 24 hours. Can be more advantageously implemented. In the conversion reaction, the lower alcohol is preferably used in a molar amount of about 100 to 500 times that of the compound having a carboxy group. Conversion Reaction-3 A compound in which a lower alkyl group having a methylene group is substituted on the phenyl ring can be converted to a carbonyl group by subjecting the compound to a conventional oxidation reaction. The conversion reaction can be advantageously carried out, for example, by using selenium dioxide, chromic acid or the like as an oxidizing agent, acetic acid or a mixed solvent of acetic acid and water as a solvent, and reacting at room temperature for about 10 to 18 hours. In the above conversion reaction,
The ratio of the oxidizing agent used to the compound having a methylene group is preferably about 5 times the molar amount. Conversion Reaction-4 A compound having a lower alkylenedioxy group in which a carbonyl group is protected by a lower alkylene group as a substituent on a phenyl ring can be converted into a carbonyl group by subjecting the above lower alkylenedioxy group to a general deprotection reaction. Can be converted to. In the above conversion reaction, for example, a compound having a lower alkylenedioxy group is treated with a mineral acid such as hydrochloric acid or sulfuric acid at 10
It can be advantageously carried out by adding a double molar amount and reacting at 40 to 60 ° C. for about 1 to 3 hours. As the solvent used in the above conversion reaction, methano-
Examples thereof include a mixed solvent of water and lower alcohol such as ethanol and ethanol. Conversion Reaction-5 The compound of the present invention having a phenyl ring or an unsaturated heterocycle having a nitrogen atom or a sulfur atom as a hetero atom (hereinafter referred to as an unsaturated heterocycle) can be subjected to the above-mentioned nitration reaction to give the above compound. A nitro group can be introduced on the phenyl ring or on the unsaturated heterocycle. The above reaction is
The conditions of ordinary nitration reaction can be widely applied, for example, acetic acid is used as a solvent, and concentrated nitric acid, fuming nitric acid, or a mixed acid of concentrated nitric acid-concentrated sulfuric acid is used at room temperature to about 60 ° C.
It can be advantageously carried out by reacting for about 1 hour.
In particular, when introducing a nitro group on the unsaturated heterocycle,
The reaction is preferably carried out at room temperature. Conversion Reaction-6 A compound having a nitro group on the phenyl ring can be converted into an amino group by converting the nitro group into a compound by ordinary catalytic reduction or the like. This conversion reaction can be advantageously carried out, for example, by carrying out hydrogenation at room temperature for about 14 hours using palladium carbon in a mixed solvent of methanol-water. Conversion Reaction-7 A compound having an alkoxy group which may be substituted with a phenyl group on the phenyl ring can be converted to a hydroxyl group by subjecting it to a reaction with aluminum halide. The above conversion reaction is carried out using an aromatic compound such as nitrobenzene or chlorobenzene as a solvent and using aluminum halide such as aluminum chloride or aluminum bromide in a molar amount of about 6 times that of the compound having an alkoxy group. . The above reaction can be advantageously carried out by carrying out the reaction at a reaction temperature of room temperature to about 60 ° C. for about 1 to 5 hours. Particularly, when the alkoxy group is a benzyloxy group, the above reaction is preferably carried out at room temperature, and the reaction is completed in about 1 hour. Conversion reaction-8 A compound having a hydroxyl group on the phenyl ring is subjected to a reaction with a lower fatty acid anhydride or a lower fatty acid halide in the same manner as in the acylation reaction of the above Reaction Scheme-4,
The hydroxyl group can be converted into an acyloxy group.
In the conversion reaction, for example, the lower fatty acid anhydride or the lower fatty acid halide is used in an amount of at least about 1 molar amount, preferably about 1.1 to 1.5 times the molar amount of the compound having a hydroxyl group on the phenyl ring. It is carried out by reacting. The above reaction can be advantageously carried out at room temperature for about 45 minutes. Conversion Reaction-9 A compound having a lower alkylthio group on the phenyl ring is
The lower alkylthio group can be converted into a lower alkylsulfinyl group by subjecting it to a reaction with an oxidizing agent such as periodate or hydrogen peroxide. The conversion reaction is
For example, a mixed solvent (40: 1) of lower alcohol such as methanol or ethanol and water is used as a solvent, and a periodate such as sodium periodate or potassium periodate is mixed with the above lower alkylthio group. 2 for compounds with groups
It is performed using a double molar amount. The above reaction can be advantageously carried out at room temperature for about 40 hours. In addition, the above reaction is
It can be advantageously carried out under the same conditions as in the above conversion reaction-3 except that the above solvent is used.

Further, the compound having a phenylthio group on the phenyl ring can be converted into the phenylsulfinyl group in the same manner. Conversion Reaction-10 A compound having a lower alkylthio group or a lower alkylsulfinyl group on the phenyl ring can be converted to the lower alkylsulfonyl group or a lower alkylsulfinyl group by subjecting it to a reaction with hydrogen peroxide. it can. The conversion reaction is carried out, for example, by using acetic acid as a solvent and reacting hydrogen peroxide in an amount of about 30 times the molar amount of the compound having a lower alkylthio group or a lower alkylsulfinyl group on the phenyl ring. The above reaction can be advantageously carried out by carrying out the reaction at about 70 to 80 ° C. for about 1 hour. Conversion Reaction-11 To introduce a phenylthio group onto an unsaturated heterocycle, for example, a compound having an unsaturated heterocycle group may be subjected to a reaction with halogenothiobenzene. The above reaction is carried out by reacting a compound having an unsaturated heterocyclic group with mercaptobenzene, N-chlorosuccinimide and N- in an aprotic polar solvent such as N, N-dimethylformamide and N, N-dimethylacetamide. It can be carried out by reacting halogenothiobenzene obtained by reacting with an N-halogenated succinimide such as bromosuccinimide in a molar amount of about 1.2 times. The above reaction can be advantageously carried out by reacting at 0 ° C. to room temperature for about 2 hours. Conversion Reaction-12 Group on the phenyl ring:

[0043]

[Chemical 16]

(In the formula, R ⁴ and R ⁵ are the same as above.)
Can be introduced by reacting a compound having a phenyl group with a halogenosulfonic acid to introduce a sulfonic acid group on the phenyl ring, and then subjecting it to a usual amide bond forming reaction. Examples of the halogenosulfonic acid in the above reaction include chlorosulfonic acid and bromosulfonic acid. In the above reaction, for example, a compound having a phenyl group is reacted with halogenosulfonic acid in a molar amount of about 20 to 25 times, and the reaction is performed at about 80 ° C. for about 1 to 3 hours to give a chloro compound on the phenyl ring. A sulfonyl group can be introduced, and then the compound represented by the general formula can be used in the absence of a solvent or in the presence of an organic base such as pyridine or triethylamine.

[0045]

[Chemical 17]

(In the formula, R ⁴ and R ⁵ are the same as above.)
It can be advantageously carried out by reacting the amine of 1) under the condition of 50 to 100 ° C. for about 2 to 15 hours. Conversion Reaction-13 A halogen atom can be introduced onto the phenyl ring by a conventional halogenation reaction. The halogenation reaction can be carried out, for example, by using an aromatic compound such as nitrobenzene, chlorobenzene, or bromobenzene as a solvent and reacting the halogen molecule in a molar amount of about 5 times that of the compound having a phenyl group. The above reaction is
In the presence or absence of a catalyst such as aluminum chloride,
It can be advantageously carried out by reacting at about 50 to 60 ° C. for about 4 hours.

Further, the compound having a phenylthio group on the phenyl ring is subjected to the above-mentioned halogenation reaction at room temperature for about 12 hours to give a compound having a phenylthio group on the phenyl ring with a halogen-substituted phenylthio group on the phenyl ring. It can be converted into a compound having a group. Further, by subjecting the compound having an unsaturated heterocyclic group to the above halogenation reaction at room temperature for about 1 hour, a halogen atom can be introduced onto the unsaturated heterocycle of the compound having an unsaturated heterocyclic group.

In the above reaction schemes 1 and 2, the compounds represented by the general formulas (2) and (3) as starting materials are
It can be obtained by the following reaction. Reaction process formula-5

[0049]

[Chemical 18]

(In the formula, R ³ is the same as the above.) In the above reaction, the acetonitrile derivative of the general formula (4) is reacted with the formate ester to obtain the compound of the general formula (5), and then the above-mentioned general formula (5) By reacting the compound of 5) with a semicarbazide hydrochloride such as a semicarbazide hydrochloride or a sulfate, a compound of the general formula (2)
Is a reaction for producing the compound of.

The solvent used in the reaction of the compound of the general formula (4) with the formate ester is a solvent which does not influence the reaction, for example, aromatic hydrocarbons such as benzene, toluene, xylene, N, N. Examples thereof include dimethylformamide and dimethyl sulfoxide. General formula (4)
The use ratio of the formate ester such as methyl formate and ethyl formate to the compound is at least equimolar amount, and preferably 1.05 to 1.25 times the molar amount. In this reaction, it is preferable to carry out the reaction usually under ice cooling for about 5 to 20 minutes, and then under room temperature for about 4 to 12 hours. Further, in the above reaction, it is preferable that sodium alkoxide such as sodium methoxide be present at least in an equimolar amount with respect to the formic acid ester in order to allow the reaction to proceed sufficiently. After completion of the reaction, water is added to separate the aqueous layer, and the pH is adjusted to 3 to 4 with a mineral acid such as hydrochloric acid to obtain precipitated crystals of the general formula (5).

Next, to the obtained compound of the general formula (5), at least equimolar amount, preferably about 1 to 1.2 times molar amount of semicarbazide / mineral salt is added dropwise under ice cooling, followed by room temperature. The reaction is carried out for about 4 to 15 hours to obtain the compound of general formula (2). Examples of the solvent used in the above reaction include solvents that do not influence the reaction, for example, lower alcohols such as methanol and ethanol, or mixed solvents of these lower alcohols and water. When the above mixed solvent is used, the mixing ratio of lower alcohol and water is from 1: 1 to
The range of about 10: 1 can be used. Reaction process formula-6

[0053]

[Chemical 19]

(In the formula, R ³ and R ⁶ are the same as above.) In the above reaction, the compound of the general formula (5) and anhydrous hydrazine or hydrazine monohydrate, or hydrazines such as hydrazine hydrochloride are used. To obtain the compound of the general formula (6), the compound of the general formula (6) is reacted with the lower alkoxycarbonyl isothiocyanate of the general formula (7) to obtain the compound of the general formula (3). Is a reaction to obtain.

The solvent used in the reaction of the compound of the general formula (5) with the hydrazines is a solvent which does not influence the reaction, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc., and acetic acid (10). It is possible to exemplify what is added by about% (v / v). The ratio of the hydrazines used to the compound of the general formula (5) is about 1.1 to 1.5 times the molar amount, and the reaction is completed in about 1 to 4 hours near the boiling point of each solvent used. .

Examples of the solvent used in the reaction between the compound of the general formula (6) obtained in the above reaction and the compound of the general formula (7) include aromatic hydrocarbons such as benzene, toluene, xylene, and chlorides. Examples thereof include halogenated hydrocarbons such as methylene and chloroform, and acetic acid esters such as ethyl acetate, and preferably, mixed solvents of the above acetic acid ester and aromatic hydrocarbons or halogenated hydrocarbons can be mentioned. . The mixing ratio of the above-mentioned acetic ester and aromatic hydrocarbons or halogenated hydrocarbons is 1: 1 to
It is preferably about 2: 1. The ratio of the compound of the general formula (7) to the compound of the general formula (6) is about at least equimolar amount, preferably 1 to 1: 1 with respect to the compound of the general formula (6). It is preferable that the molar amount is twice. Ethoxycarbonyl isothiocyanate is preferably used as the compound of the above general formula (7). The above reaction is completed in about 10 to 20 hours at room temperature. Reaction process formula-7

[0057]

[Chemical 20]

(In the formula, R ³ is the same as above. X represents a halogen atom.) In the above reaction, the compound of the general formula (5) and anhydrous hydrazine or hydrazine monohydrate, hydrazine hydrochloride, etc. The compound of the general formula (6) is reacted with the hydrazines of the formula (6), and then the compound of the general formula (6) is reacted with a compound of the general formula (N- (chlorocarbonyl) isocyanate, N- (bromocarbonyl) isocyanate, etc. N- represented by 8)
This is a reaction in which a compound of the general formula (1-f) is obtained by reacting with (carbonyl halide) isocyanate.

As the solvent used in the reaction of the compound of the general formula (5) with the above-mentioned hydrazines, a solvent which does not influence the reaction, for example, aromatic hydrocarbons such as benzene, toluene and xylene, and acetic acid are added. It can be exemplified by adding about% (v / v). The ratio of the hydrazines used to the compound of the general formula (5) is about 1.1 to 1.5 times the molar amount, and the reaction is completed in about 1 to 4 hours near the boiling point of each solvent used. .

Examples of the solvent used in the reaction between the compound of the general formula (6) obtained by the above reaction and the compound of the general formula (8) include aromatic hydrocarbons such as benzene, toluene and xylene, Examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform, acetic acid esters such as ethyl acetate, and tertiary amines such as pyridine and triethylamine, with preference given to pyridine and triethylamine. As the base used, tertiary amines such as pyridine and triethylamine are preferable. The ratio of the compound of general formula (8) to the compound of general formula (6) is
The amount is at least about equimolar to the compound of (6), preferably 1 to 1.2 times. The ratio of the base used is about 10 to 100 times, preferably 20 to 30 times the molar amount of the compound of the general formula (6). The above reaction is completed in about 1 to 10 hours at room temperature.

General formula (4) which is a starting material of reaction process formula 5
The compound of can also be manufactured by the following reaction process formulas-8 to 13. Reaction process formula-8

[0062]

[Chemical 21]

[Wherein X is the same as above, R ⁷ is selected from the group consisting of a lower alkyl group, a halogen-substituted lower alkyl group, a halogen atom as a substituent on the phenyl ring, a lower alkyl group and a lower alkoxy group. A phenyl group which may have 1 to 3 substituents and R ⁸ represents a substituent selected from the following group. i lower alkyl group; ii phenyl group; iii lower alkoxycarbonyl group; iv cyano group; v nitro group; vi lower alkoxy group; vii phenyl lower alkoxy group; viii phenylthio lower alkyl group; ix phenoxy group; x group

[0064]

[Chemical formula 22]

(Wherein R and t are the same as above); xi halogen atom; xii phenyl lower alkyl group; xii carboxy group; xiv lower alkanoyl group; xv halogen atom as a substituent on the phenyl ring, phenyl lower alkoxy group And / or a benzoyl group which may have 1 to 3 hydroxyl groups; xvi amino group; xvii hydroxyl group; xviii lower alkanoyloxy group; xix group

[0066]

[Chemical formula 23]

(Wherein R ⁴ and R ⁵ are the same as above); xx group

[0068]

[Chemical formula 24]

(Wherein A is the same as above); and xxi hydrogen atom. m represents an integer of 1 or 2. The compound of general formula (11) can be obtained by reacting the compound of general formula (9) with the compound of general formula (10) in the presence of a basic compound in an inert solvent. As the inert solvent used in the above reaction, any solvent can be used as long as it does not adversely influence the reaction, and lower solvents such as water, methanol, ethanol and propanol, N, N-dimethylformamide. , N, N-dimethylacetamide, hexamethylphosphoric triamide, and other aprotic polar solvents, and mixed solvents thereof. As the basic compound used, sodium hydroxide, alkali metal hydroxide such as potassium hydroxide,
Examples thereof include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal alkoxides such as sodium methoxide and sodium ethoxide, and the like. You may use together 1 or more types.

The ratio of the compound of the general formula (10) to the compound of the general formula (9) is at least an equimolar amount, preferably a slight excess. The basic compound has the general formula
In order to form a salt of the compound of the formula (9) and the compound of the general formula (10), it is preferable to use at least a 2-fold molar amount, preferably a slight excess with respect to the compound of the general formula (9). The above reaction is usually carried out at room temperature to 180 ° C, the reaction is completed in about 30 minutes to 24 hours, and the target product is obtained in a substantially quantitative manner.

In the compound of the general formula (11), the compound in which R ⁸ is a nitro group is converted to a compound in which R ⁸ is an amino group by subjecting to a general reduction reaction for converting the nitro group into an amino group. be able to. Furthermore, the compound having an amino group obtained by the above reaction can be converted to a compound in which R ⁸ is a hydroxyl group by subjecting it to a Sandmeyer type reaction. Reaction process formula-9

[0072]

[Chemical 25]

(Wherein R ⁶ , R ⁷ , R ⁸ and m are the same as above) The ester compound of the general formula (12) can be obtained by subjecting the compound of the general formula (11) to a general esterification reaction. be able to. The above esterification reaction is carried out, for example, in the presence of a catalyst,
It is carried out by reacting the compound represented by the general formula (11) with an alcohol represented by the general formula R ⁶ —OH (wherein R ⁶ is the same as above). The catalyst used is an esterification reaction. Conventional catalysts are used. Specifically, inorganic acids such as hydrogen chloride, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride, perchloric acid, trifluoroacetic acid, trichloromethanesulfonic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, benzene. Examples thereof include organic acids such as sulfonic acid and ethanesulfonic acid, acid anhydrides such as trichloromethanesulfonic anhydride, trifluoromethanesulfonic anhydride, and thionyl chloride. 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 of the conventional solvents for the esterification reaction can be used,
Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform, ethers such as diethyl ether, tetrahydrofuran and dioxane. 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 of the general formula (11). The reaction temperature is -20 ° C to 200 ° C.
C., preferably 0 to 150.degree. C.

Further, the compound of the general formula (12) has the following formula:
The alkali metal salts of the compounds (e.g., sodium salt, potassium salt, etc.), the general formula R ⁶ -X (wherein, R ⁶ and X
Is the same as the above), a method of reacting a halide compound represented by the general formula (11), a method of reacting a compound of the general formula (11) with a diazoalkane such as diazomethane, diazoethane, diazopropane, a compound of the general formula (11) It can also be obtained by a method of reacting with an alcohol represented by the general formula R ⁶ —OH (in the formula, R ⁶ is the same as above) after conversion into a reactive derivative at the carboxy group. These esterification reactions can be performed according to a conventional method. Reaction process formula-10

[0075]

[Chemical formula 26]

(In the formula, R ⁶ and R ⁷ are the same as described above, R ^6
9 represents a lower alkyl group. The compound of general formula (14) can be obtained by subjecting the compound of general formula (13) to an alkylation reaction. The reaction can be applied to any of the conventional alkylation reaction for alkylating a phenolic hydroxyl group, for example, the general formula (1
3) compound, di (lower) alkyl sulfuric acid (for example, dimethyl sulfuric acid, diethyl sulfuric acid, etc.), lower alkyl halide (for example, methyl iodide, methyl bromide, ethyl iodide,
Ethyl bromide, propyl iodide, etc.), diazo (lower) alkane (eg, diazomethane, diazoethane, etc.) and the like are reacted.

When the above reaction is carried out using di (lower) alkylsulfuric acid, the reaction is carried out in a lower alcohol such as methanol or ethanol, or an inert solvent such as acetone with respect to the compound of the general formula (13). The reaction is carried out by using an approximately equimolar amount of alkylsulfuric acid at 50 ° C. to the boiling point of the solvent for about 3 to 10 hours, preferably about 6 hours. The above reaction is preferably carried out in the presence of a basic compound in order to form a salt of the compound of the general formula (13) to accelerate the reaction rate and to neutralize mono (lower) alkyl sulfuric acid formed after the reaction. . Examples of the basic compound used include the basic compounds exemplified in the above Reaction Scheme-8. The basic compound is used in an equimolar amount, preferably in a slight excess, with respect to the compound of the general formula (13). Reaction process formula-11

[0078]

[Chemical 27]

(In the formulae, R ⁶ , R ⁷ , R ⁸ , X and m are the same as above.) The compound of the general formula (12) is lithium aluminum hydride,
Aluminum hydride, diisopropyl aluminum hydride, lithium borohydride, sodium borohydride-
The compound of the general formula (15) can be obtained by subjecting it to a general reduction reaction using a hydrogenating reducing agent such as aluminum chloride or diborane. This reduction reaction is carried out in a 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. The hydrogenation reducing agent is used in an amount of at least 0.5 times, preferably 0.6 to 1.2 times the molar amount of the compound of the general formula (12). The reaction is usually under ice cooling to 100
C., preferably 0 to 50.degree. C., and the reaction is completed in 30 minutes to 10 hours.

The compound of general formula (16) can be obtained by reacting the compound of general formula (15) with a halogenating agent in the absence of a solvent or a suitable solvent. Examples of the solvent include ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane, and aromatic hydrocarbons such as benzene and toluene. Examples of the halogenating agent used include thionyl halides such as thionyl chloride and thionyl bromide, hydrogen halides such as hydrogen chloride, hydrogen bromide and hydrogen iodide, and phosphorus halides such as phosphorus trichloride and phosphorus tribromide. Etc.

The amount of the halogenating agent used is at least an equimolar amount with respect to the compound of the general formula (15), preferably 1 to
It is recommended to use 1.3 times the amount. The reaction is carried out under ice-cooling to 10
The compound of the general formula (17), which is carried out at 0 ° C., preferably about 0 to 50 ° C. and is usually completed in about 30 minutes to 5 hours, is obtained by reacting the compound of the general formula (16) with a cyanide compound in a suitable solvent. Can be obtained. Solvents used in this reaction include lower alcohols such as methanol, ethanol and propanol, aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide and hexamethylphosphoric triamide, mixed solvents of them and water. Etc. are illustrated.

Examples of the cyan compound used in the above reaction include potassium cyanide, sodium cyanide,
Silver cyanide, copper cyanide, calcium cyanide and the like, and the cyan compound is a compound of the general formula (16),
It is preferable to use at least an equimolar amount, preferably about 1 to 1.3 times the molar amount. The above reaction is usually carried out at room temperature to 150.
℃, preferably at room temperature to 100 ℃, usually 1-2
It will be finished in about 0 hours. Reaction process formula-12

[0083]

[Chemical 28]

(In the formula, R ⁷ , R ⁸ and m are the same as above,
X ′ represents a hydrogen atom or a halogen atom, and X ″ represents a halogen atom.) In the above reaction, the halogen atom represented by X ″ in the compound of the general formula (18) is replaced by a group —SR, and This is a reaction for obtaining the compound of (20). In the above reaction, an excess amount of magnesium is added to the compound of the general formula (18) in ether such as diethyl ether or tetrahydrofuran to produce a Grignard reagent,
Then, it is carried out by reacting the disulfide compound of the general formula (19). Iodine when producing Grignard reagent,
It is preferable that a catalytic amount of an iodine compound such as methyl iodide be present. The reaction between the generated Grignard reagent and the compound of the general formula (19) is carried out at room temperature to the boiling point of the solvent, and 1 to 10
It will finish in about time. The proportion of the compound of general formula (19) used is at least an equimolar amount, preferably about 1 to 1.2 times the molar amount of the compound of general formula (18). Reaction process formula-13

[0085]

[Chemical 29]

(In the formula, R ⁷ , R ⁸ , X, X'and m are the same as described above.) In the above reaction, the compound of the general formula (20) to the general formula (21)
The reaction for obtaining the compound of (1) is a reaction for halomethylating the compound of general formula (20) to obtain the compound of general formula (21), and the conditions of ordinary halomethylation reaction can be widely applied. The above reaction is carried out, for example, in the presence of a catalyst in an inert solvent, represented by the general formula (20):
It is carried out by reacting the compound of (1) with a halomethylating agent. The inert solvent used is methylene chloride,
Examples thereof include halogenated hydrocarbons such as chloroform, dichloroethane, carbon tetrachloride, carbon disulfide and the like. Examples of the catalyst used include aluminum chloride, iron chloride,
Examples thereof include Lewis acids such as zinc chloride, antimony pentachloride, tin tetrachloride and boron trifluoride, and protonic acids such as hydrogen fluoride and concentrated sulfuric acid. As the halomethylating agent, for example,
Examples thereof include chloromethyl methyl ether, bromomethyl methyl ether, dichloromethyl ether, dibromomethyl ether and the like. In the above reaction, the catalyst is used in an equimolar to 3-fold molar amount, preferably 2-fold molar amount with respect to the compound of the general formula (20). The halomethylating agent is used in an equimolar to 3-fold molar amount, preferably 2-fold molar amount, relative to the compound of the general formula (20). The above reaction is carried out at room temperature to under heating and is usually completed in about 1 to 5 hours.

In this reaction, the substitution position of the halomethyl group depends on the kind and the number of substituents of the compound (21), such as the electron density and steric hindrance of the carbon atom at the substitutable position on the benzene ring. When the reaction product is a mixture, it can be separated and purified by a conventional means such as distillation or column chromatography. The reaction for obtaining the compound of the general formula (22) from the compound of the general formula (21) is the same method as the reaction for converting the compound of the general formula (16) of the above reaction step formula-11 to the compound of the general formula (17), and It can be done under conditions.

In the compound of the general formula (4), R ³
Is 1 to 3 groups -SR '(R' is selected from the group consisting of a lower alkyl group, a halogen-substituted lower alkyl group, a halogen atom as a substituent on the phenyl ring, a lower alkyl group and a lower alkoxy group. In the case of a phenyl group having a phenyl group which may have 1 to 3 substituents), R ³ is a group having 1 to 3 groups by oxidizing the compound in the same manner as in the conversion reaction-9. A compound of the general formula (4) which is a phenyl group having —SO—R ′ (R ′ is as defined above) can be derived. When hydrogen peroxide is used as an oxidizing agent in this reaction, the amount of hydrogen peroxide used is about 1 to 3 times, preferably 1.5 to 2.5 times the molar amount of the compound of the general formula (4). Used in quantity. The reaction is completed at room temperature for about 4 to 24 hours, preferably about 10 hours.

The compound of the general formula (4) in which R ³ obtained by the above-mentioned method is a phenyl group having 1 to 3 groups —SO—R ′ (R ′ is the same as above) can be obtained by the reaction step described above. Formula-5
In the formula (4) a method similar reactions leading to compounds of general formula (5) from the compound represented by, R ³ is 1 to 3 groups -S
A compound of the general formula (5), which is a phenyl group having O-R '(R' is the same as above), can be obtained, and the compound of the general formula (5), 2), compounds of general formula (3) and general formula (1-f) can be obtained. Among the compounds represented by the general formula (1) of the present invention, the compound having a basic group is reacted with a pharmaceutically acceptable acid, and the compound having an acidic group is a pharmaceutically acceptable basic compound. A salt can be easily formed by reacting a compound. 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 and p-toluene. Examples thereof include organic acids such as sulfonic acid and ethanesulfonic acid, and examples of the basic compound include metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate. Examples thereof include alkali metal carbonates and bicarbonates.

The salt of the compound of the present invention naturally includes an inner salt. The compound of the present invention thus obtained is
It can be easily isolated and purified by an ordinary separation means. As the separating means, for example, a solvent extraction method, a dilution method, a recrystallization method, a column chromatography, a preparative thin layer chromatography and the like can be adopted. The compound represented by the general formula (1) of the present invention naturally includes optical isomers. These isomers can be separated by a conventional resolution method such as a method using an optical resolving agent.

The compound of the present invention is usually used in the form of a general pharmaceutical preparation. The preparation is prepared by using diluents or excipients which are usually used such as fillers, fillers, binders, moisturizers, disintegrants, surfactants and lubricants. As this pharmaceutical preparation, various forms can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, liquids,
Suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.) and the like can be mentioned. In the case of molding in the form of tablets, as a carrier, those conventionally known in this field can be widely used, for example, lactose, sucrose, sodium chloride,
Excipients such as glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate , Binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar-free, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose , Sucrose, stearin, cacao butter, disintegration inhibitor such as hydrogenated oil, quaternary ammonium base, absorption enhancer such as sodium lauryl sulfate, humectant such as glycerin and starch, starch, milk , Kaolin, bentonite, adsorbents such as colloidal silicic acid, purified talc, stearates, boric acid powder, such as lubricants such as polyethylene glycol can be exemplified. Further, the tablet may be a tablet which is coated with a usual coating, if necessary, such as a sugar coating, a gelatin-coated tablet, an enteric coated tablet, a film-coated tablet, a double tablet or a multilayer tablet. When molding in the form of pills,
As the carrier, those conventionally known in this field can be widely used, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, tragacanth powder, gelatin, ethanol and the like. Examples include binders, disintegrators 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. . When prepared as an injection,
Liquids, emulsions and suspensions are preferably sterilized and isotonic with blood, and when formed into the form of these liquids, emulsions and suspensions, those commonly used as diluents in this field Can all be used, for example water,
Examples thereof include ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. 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. If necessary, coloring agents, preservatives, fragrances, flavors, sweeteners, and other pharmaceuticals may be included in the therapeutic agent. When forming into paste, cream and gel form,
As a diluent, for example, white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol,
Silicon, bentonite, etc. can be used.

The amount of the compound represented by the general formula (1) or a salt thereof to be contained in the pharmaceutical preparation of the present invention is not particularly limited and may be selected in a wide range, but is usually 1 to 70 in the total composition.
It is good to set it as the weight%. The administration method of the pharmaceutical preparation of the present invention is not particularly limited, and it 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, may be administered intramuscularly, intradermally, subcutaneously or intraperitoneally alone. In the case of suppositories, it will be administered rectally.

The dose of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, age of the patient, sex and other conditions, degree of disease and the like, but usually the amount of the compound of the present invention is 1 kg of body weight per day.
The dose may be 1 to 100 mg, preferably 5 to 20 mg, and the preparation may be administered in 2 to 4 divided doses per day. <Example> Hereinafter, the present invention will be described in detail based on Reference Examples, Examples and pharmacological tests.

The NMR spectrum was measured at 60 MHz unless otherwise specified. Reference Example 1 1) Under a nitrogen stream, 4-chloro-3-nitrobenzoic acid (241.88 g), sodium hydrogen carbonate (100.8).
0 g) and 50% hydrous methanol (900 ml) were stirred at room temperature to give thiophenol (128.35).
ml), and 50 of sodium hydroxide (49.6 g)
% Hydrous methanol (200 ml) solution was added sequentially. After the addition, the mixture was refluxed for 1 hour under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled with ice water, and concentrated hydrochloric acid was added to adjust the pH to 2
3, and the yellow precipitate was filtered and washed with water to give 3-nitro-4.
-Phenylthiobenzoic acid was obtained. This was used as such for the next reaction. 2) To a mixture of 3-nitro-4-phenylthiobenzoic acid obtained above, iron powder (201.0 g) and 50% hydrous ethanol (800 ml) under reflux, with stirring, concentrated hydrochloric acid (20 ml) in ethanol ( 40 ml) solution was added slowly. After refluxing for 15 hours with stirring, the reaction mixture was cooled, and the precipitate was collected by filtration and washed with water. Sodium hydroxide (50 g) and water (1.95 liters) were added to the obtained precipitate, which was dissolved by heating and the insoluble matter was filtered off. Then, while cooling with ice, dilute sulfuric acid was added to the filtrate to adjust the pH to 2-3. did. The precipitate was collected by filtration, washed with water, and dried to give 3-amino-4-phenylthiobenzoic acid (218.28 g). 3) 3-amino-4-phenylthiobenzoic acid (11
0.27 g) was added to a heated solution of concentrated sulfuric acid (81 ml) in water (400 ml), and the mixture was heated with stirring for 2 hours and then cooled to -5 ° C in an ice-salt bath. To this, water (80 m) of sodium nitrite (36.25 g) which had been ice-cooled separately was added.
l) The solution was added over about 1 hour. Further, after stirring for 30 minutes at 0 to 5 ° C., urea (2 g) was added and stirred for 30 minutes to decompose unreacted nitrous acid. The resulting mixture was concentrated sulfuric acid (121 ml) and anhydrous sodium sulfate (16 ml).
8 g) and water (112 ml) under stirring,
The mixture was added little by little at 100 to 110 ° C over 1 hour and 15 minutes. After the addition was completed, the mixture was stirred at the same temperature for 1 hour. The reaction mixture was cooled, the brown granular precipitate that precipitated was collected by filtration, washed with water, and then dried at 50 ° C. overnight. The product obtained was treated with methanol (1.4 liters) and concentrated sulfuric acid (70
ml) and refluxed for 2 hours with stirring.
After the reaction was completed, the reaction mixture was concentrated under reduced pressure, water (1.5 liter) was added to the residue, and ethyl acetate (500 ml x
Extracted in 3). The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was extracted with hot hexane (4.2 liters), cooled, and the precipitated yellow precipitate was collected by filtration to obtain methyl 3-hydroxy-4-phenylthiobenzoate (49.37 g).

NMR (CDCl ₃ ) δ: 7.13-7.
71 (m, 8H), 6.47 (bs, 1H), 3.92
(S, 3H) Reference Example 2 Methyl 3-hydroxy-4-phenylthiobenzoate (4
9.11 g), potassium carbonate (27.33 g) and acetone (627 ml) in a mixture of dimethyl sulfate (1
7.85 ml) was added and the mixture was refluxed for 6 hours with stirring. The reaction mixture was cooled, the precipitate was collected by filtration, and washed with acetone. The filtrate and washings were combined and concentrated under reduced pressure to give methyl 3-methoxy-4-phenylthiobenzoate.

NMR (CDCl ₃ ) δ: 7.35-7.
51 (m, 7H), 6.79 (d, J = 8.57Hz,
1H), 3.96 (s, 3H), 3.88 (s, 3H) Reference Example 3 1) Dry diethyl ether (744m) of methyl 3-methoxy-4-phenylthiobenzoate (30.67g).
1) Lithium aluminum hydride (4.32 g) was added to the solution little by little while stirring with ice cooling. After stirring for 1 hour,
Ethyl acetate, methanol and water were sequentially added to the reaction mixture to decompose unreacted lithium aluminum hydride.
After separating the organic layer, the aqueous layer was washed with ethyl acetate (300 ml x 2)
It was extracted with. The extract was combined with the above organic layer, washed with saturated saline (300 ml × 2), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 1-hydroxymethyl-3-.
Methoxy-4-phenylthiobenzene was obtained.

NMR (CDCl ₃ ) δ: 7.20 to 7.
37 (m, 5H), 7.04 (d, J = 7.69 Hz,
1H), 6.95 (bs, 1H), 6.84 (bd, J
= 7.91 Hz, 1H), 4.68 (s, 2H), 3.
87 (s, 3H) 2) The 1-hydroxymethyl-3-methoxy-4-phenylthiobenzene obtained above was treated with methylene chloride (37
2 ml) and thionyl chloride (9.1
2 ml) was added. After stirring for 1 hour, the reaction mixture was washed with ice water (500 ml × 2) and washed with ethyl acetate (500 m
l) was added. The mixture was mixed with 5% aqueous sodium hydrogen carbonate solution (20 ml), water (200 ml) and saturated brine (2 ml).
00 ml × 2), washed successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 1-chloromethyl-3-
Methoxy-4-phenylthiobenzene was obtained.

NMR (CDCl ₃ ) δ: 7.25 to 7.
32 (m, 5H), 6.89 to 6.94 (m, 3H),
4.55 (s, 2H), 3.89 (s, 3H) 3) 1-chloromethyl-3-methoxy-4-phenylthiobenzene obtained above was added to N, N-dimethylformamide (200 ml). Sodium cyanide (7.34 g) that had been dissolved and finely crushed was added, and the mixture was stirred at 30 ° C for 14 hours. Saturated saline (300 ml) and ice water (300 ml) were added to the reaction mixture, and ethyl acetate (300 ml x
Extracted in 3). The extract was saturated saline (200 ml x
It was washed with 3) and dried over anhydrous sodium sulfate to obtain 1-cyanomethyl-3-methoxy-4-phenylthiobenzene.

NMR (CDCl ₃ ) δ: 7.25 to 7.
41 (m, 5H), 7.01 (d, J = 7.70, 1
H), 6.83 (s, 1H), 6.79 (d, J = 7.
47 Hz, 1H), 3.89 (s, 3H), 3.72
(S, 2H) Reference Example 4 A solution of potassium hydroxide (20.86 g) in N, N-dimethylacetamide (70 ml) was heated to 150 ° C., and thiophenol (1
9.52 ml) and 4-bromobenzoic acid (25.47 ml).
g) was added. After refluxing for 20 hours under a nitrogen atmosphere, the reaction mixture was poured into ice water (400 ml), and benzene (40 ml) was added.
0 ml) was added and washed, and the aqueous layer was separated. Furthermore, the benzene layer is 2.5N-sodium hydroxide (100 ml x 4)
It was extracted with. The extract was combined with the above aqueous layer, adjusted to pH 1-2 with concentrated hydrochloric acid, and the precipitate was collected by filtration, washed with water and dried to give 4-
Phenylthiobenzoic acid (26.29 g) was obtained.

NMR (DMSO-d6) δ: 7.95
(D, J = 8.57 Hz, 2H), 7.34 to 7.48
(M, 5H), 7.20 (d, J = 8.57Hz, 2
H) Reference Example 5 A mixture of 4-phenylthiobenzoic acid (26.29 g), concentrated sulfuric acid (5 ml) and methanol (400 ml) was refluxed for 10 hours with stirring. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and ethyl acetate (400 ml) was added to the residue.
Was added, and the mixture was washed with saturated brine (200 ml × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give methyl 4-phenylthiobenzoate (27.44 g).

NMR (CDCl ₃ ) δ: 7.89 (d,
J = 8.58 Hz, 2H), 7.32 to 7.53 (m,
5H), 7.20 (d, J = 8.79Hz, 2H),
3.88 (s, 3H) Reference Example 6 1) To a solution of methyl 4-phenylthiobenzoate (27 g) in dry diethyl ether (500 ml), lithium aluminum hydride (2.5 g) was added little by little under ice-cooling stirring. . After stirring for 1 hour, ethyl acetate and water were sequentially added to the reaction mixture to decompose unreacted lithium aluminum hydride. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 ml × 2). The extract was combined with the organic layer, washed with saturated brine (100 ml × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-hydroxymethyl-4-phenylthiobenzene (25 g). It was

NMR (CDCl ₃ ) δ: 7.19 to 7.
40 (m, 9H), 4.67 (s, 2H) 2) 1-hydroxymethyl-4-phenylthiobenzene (3.0 g) was dissolved in methylene chloride (15 ml),
Thionyl chloride (1.5 ml) was added with stirring under ice cooling. 1
After stirring for an hour, the reaction mixture was washed with ice water (10 ml × 3), and methylene chloride (50 ml) was added. The mixture was washed successively with 5% aqueous sodium hydrogen carbonate solution (5 ml x 3) and saturated brine (30 ml x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-chloromethyl-4-phenylthio. Benzene (3.0 g) was obtained.

NMR (CDCl ₃ ) δ: 7.25 to 7.
35 (m, 9H), 4.54 (s, 2H) 3) 1-chloromethyl-4-phenylthiobenzene (3.0 g) was added to N, N-dimethylformamide (15 m).
l) dissolved in finely ground sodium cyanide (1.0
g) was added, and the mixture was stirred at room temperature for 17 hours. Saturated saline (50 ml) and ice water (50 ml) were added to the reaction mixture, followed by extraction with ethyl acetate (100 ml × 3). The extract was washed with saturated brine (50 ml × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-cyanomethyl-4-phenylthiobenzene (2.9 g).

NMR (CDCl ₃ ) δ: 7.29 to 7.
38 (m, 9H), 3.71 (s, 2H) Reference Example 7 Potassium hydroxide (1.368 g) was dissolved in N, N-dimethylacetamide (20 ml) under heat, and thiophenol (1 0.16 ml) was added. Next, 4-chloro-3-methylbenzoic acid was added, and the mixture was refluxed for 2 days in a nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled, poured into ice water (about 100 ml), washed with benzene (50 ml), and then the aqueous layer was separated. The benzene layer was further extracted with a 5% aqueous sodium hydroxide solution (50 ml), the extract and the above aqueous layer were combined, adjusted to pH 2-3 with hydrochloric acid, and the precipitate was collected by filtration, washed with water and dried to give 3-methyl. -4-Phenylthiobenzoic acid (1.55 g) was obtained. Reference Example 8 A mixture of 3-methyl-4-phenylthiobenzoic acid (85 g), concentrated sulfuric acid (20 ml) and methanol (1.2 l) was refluxed for 4 hours with stirring. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and ethyl acetate (1.5 l) was added to the residue.
Was added, the mixture was washed with saturated brine (400 ml × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 3-methyl-4-phenylthiobenzoate (80.33 g).

NMR (CDCl ₃ ) δ: 7.85 (b
s, 1H), 7.70 (bd, J = 8.13Hz, 1
H), 7.37 (bs, 5H) 7.00 (d, J = 8.
13 Hz, 1H) Reference example 9 1) Dry diethyl ether (900 m) of methyl 3-methyl-4-phenylthiobenzoate (80.33 g).
1) Lithium aluminum hydride (7.08 g) was added to the solution little by little while stirring with ice cooling. After stirring for 1 hour,
Ethyl acetate, methanol and water were sequentially added to the reaction mixture to decompose unreacted lithium aluminum hydride.
After separating the organic layer, the aqueous layer was washed with ethyl acetate (300 ml x 2)
The extract was combined with the above organic layer, washed with saturated brine (300 ml × 2), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 1-hydroxymethyl-3-.
Methyl-4-phenylthiobenzene was obtained.

NMR (CDCl ₃ ) δ: 7.04 to 7.
36 (m, 8H), 4.62 (s, 2H), 2.37
(S, 3H) 2) 1-hydroxymethyl-3-methyl-4-phenylthiobenzene obtained above was converted into methylene chloride (100
ml), and thionyl chloride (23.3
4 ml) was added. After stirring for 1 hour, the reaction mixture was washed with ice water (100 ml × 3) and washed with ethyl acetate (500 m).
l) was added. The mixture was mixed with 5% aqueous sodium hydrogen carbonate solution (50 ml x 4) and saturated saline solution (100 ml x 2).
After that, the extract was sequentially washed with, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1-chloromethyl-3-methyl-4-phenylthiobenzene.

NMR (CDCl ₃ ) δ: 7.16-7.
25 (m, 8H), 4.53 (s, 2H), 2.37
(S, 3H) 3) 1-chloromethyl-3-methyl-obtained above
4-Phenylthiobenzene was dissolved in N, N-dimethylformamide (56 ml), finely crushed sodium cyanide (18.16 g) was added, and the mixture was stirred at room temperature overnight. Saturated saline (300 ml) and ice water (30 ml) were added to the reaction mixture.
After adding 0 ml), the mixture was extracted with ethyl acetate (300 ml × 3). The extract was washed with saturated brine (200 ml × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-cyanomethyl-3-methyl-4-phenylthiobenzene (45.95 g). .

NMR (CDCl ₃ ) δ: 7.10-7.
37 (m, 8H), 3.69 (s, 2H), 2.38
(S, 3H) Reference Example 10 Magnesium (for Grignard reagent, 7 g) was added to a solution of 2-bromo-4-fluorotoluene (45 g) in anhydrous diethyl ether (500 ml), and the mixture was refluxed with stirring. Methyl iodide (1 ml) was added to the reaction mixture, the reaction started violently, the heating bath was removed, and the mixture was stirred for 30 minutes. The reaction was then mild so it was heated to reflux for 30 minutes. After allowing to cool, the reaction mixture was mixed with dimethyl disulfide (2
4 ml) was added and the mixture was refluxed for 3 hours. After allowing to cool, water and 10% hydrochloric acid were added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with water (500 ml × 3), dried over anhydrous sodium sulfate, the solvent was evaporated, and the obtained residue was distilled under reduced pressure to give 4-fluoro-2-methylthiotoluene (30 g). .

Bp ₁₅ : 95 ° C. NMR (CDCl ₃ ) δ: 6.60 to 7.14 (m, 3
H), 2.45 (s, 3H), 2.27 (s, 3H) Reference Example 11 Carbon disulfide (300 m) of aluminum chloride (29 g)
l) To the suspension, chloromethyl methyl ether (17m
1) was added and stirred for 30 minutes. 4-Fluoro-2-methylthiotoluene (17.2 g) is added thereto, and the mixture is stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with diethyl ether. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-chloromethyl-4-fluoro-2-methylthiotoluene (21
g) was obtained.

NMR (CDCl ₃ ) δ: 7.30 (d,
J = 9.0 Hz, 1H), 7.13 (d, J = 8.0H
z, 1H), 6.83 (d, J = 10.5Hz, 1
H), 4.57 (s, 2H), 2.45 (s, 3H),
2.26 (s, 3H) Reference Example 12 5-chloromethyl-4-fluoro-2-methylthiotoluene (21 g) was added to N, N-dimethylformamide (90
ml) and crushed finely into sodium cyanide (6.0
3 g) was added, and the mixture was stirred at room temperature for 18 hours. Saturated saline (300 ml) and ice water (300 ml) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 ml × 3). The extract was washed with saturated brine (200 ml × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-cyanomethyl-4-fluoro-2-methylthiotoluene.

NMR (CDCl ₃ ) δ: 7.30 (d,
J = 9.0 Hz, 1H), 7.14 (d, J = 8.0H
z, 1H), 6.85 (d, J = 10.5Hz, 1
H), 3.68 (s, 2H), 2.45 (s, 3H),
2.27 (s, 3H) Reference Example 13 Ethyl formate (8.14) was added to a suspension of sodium methoxide (5.56 g) in benzene (200 ml) with stirring under ice cooling.
A mixture of g) and phenylacetonitrile (11.7 g) was added dropwise and after 30 minutes the ice bath was removed. After 3 hours, ice water was added to separate the aqueous layer, and the organic layer was washed with 0.5N-sodium hydroxide aqueous solution (50 ml × 3). The aqueous layer and the washing solution were combined and the pH was adjusted to 3 with concentrated hydrochloric acid. It was set to ~ 4.
The mixture was stirred for 20 minutes under ice cooling, and the precipitated crystals were collected by filtration, washed with water, and α
-Formylphenylacetonitrile was obtained. This is used as it is in the next reaction. The obtained α-formylphenylacetonitrile was added to methanol-water (1: 1 to 10: 1,
(200 ml) as a solution and semicarbazide hydrochloride (9.95 g) was added under ice-cooling stirring. The ice bath was removed, and after 12 hours, the mixture was neutralized with a 5N sodium hydroxide aqueous solution.
After stirring for 20 minutes, the precipitated crystals were collected by filtration, washed with water and dried to give 3-amino-2-carbamoyl-4-phenylpyrazole (16.82 g). This was used without purification. Reference Example 14 Ethyl formate (16.28) was added to a suspension of sodium mexide (10.8 g) in benzene (300 ml) with stirring under ice cooling.
A mixture of g) and phenylacetonitrile (23.4 g) was added dropwise. After 30 minutes, the ice bath was removed. After 3 hours, ice water was added and the aqueous layer was separated, and the organic layer was washed with a 0.5N sodium hydroxide aqueous solution (100 ml × 3). The aqueous layer and the washing solution were combined, adjusted to pH 3 to 4 with concentrated hydrochloric acid, and stirred under ice cooling. After 20 minutes, the precipitated crystals were collected by filtration, washed with water and dried to obtain α-formylphenylacetonitrile (21.13).
g) was obtained. This was directly used for the next reaction. The obtained α-formylphenylacetonitrile (18.85
g), hydrazine hydrate (8.46 g), acetic acid (1
A mixture of 6.9 ml) and benzene (200 ml) was heated to reflux while dehydrating azeotropically. After 2 hours, it was cooled and 6N-hydrochloric acid (28.5 ml and 12.7).
It was washed with ml × 2), and the washings were combined and neutralized by adding 28% aqueous ammonia. After stirring for 20 minutes, the precipitated crystals were collected by filtration, washed with water and dried to give 3-amino-4-phenylpyrazole (1
5.16 g) was obtained. This was directly used in the next reaction without further purification. A suspension of 3-amino-4-phenylpyrazole (3.97 g) in ethyl acetate (15 ml) -benzene (75 ml) was stirred with cooling at 5 ° C. and ethoxycarbonylisothiocyanate (3.28 g) in benzene (2.
5 ml) solution was added. Then the cooling bath is removed, 15
After stirring for an hour, the reaction mixture was concentrated under reduced pressure, the residue was recrystallized from ethyl acetate, and N-carbethoxy-N '-[3-
(4-Phenyl) pyrazolyl] thiourea (3.34 g)
Got Example 1 4-Hydroxy-8-phenyl-pyrazolo [1,5-
a] -1,3,5-triazine 3-amino-2-carbamoyl-4-phenylpyrazo-
(4.8 g) and ethyl orthoformate (30 ml) were heated and stirred at 100 to 110 ° C. for 13 hours, methanol or ethyl acetate was added, and the precipitated crystals were collected by filtration to remove methanol or methanol. It was washed with ethyl acetate and dried to obtain the desired product (2.08 g).

Mp: 292-299 ° C. (decomposition) NMR (DMSO-d6) δ: 8.54 (s, 1H),
8.10 (s, 1H), 7.96 to 8.06 (m, 2
H), 7.24 to 7.52 (m, 3H) carried out in the same manner as in Example 1, using suitable starting materials.
The compounds of Examples 2-65 were obtained. Example 2 4-hydroxy-8- (3-methylphenyl) pyrazolo
[1,5-a] -1,3,5-triazine mp: 262.5-265.0 ° C NMR (DMSO-d6) δ: 8.55 (s, 1H),
8.12 (s, 1H), 7.85 (bs, 1H) 7.8
2 (d, J = 8.40 Hz, 1H), 7.31 (t, J
= 8.40 Hz, 1H), 7.17 (d, J = 9.01)
Hz, 1H), 2.36 (s, 3H) Example 3 4-hydroxy-8- (4-methylphenyl) pyrazolo
[1,5-a] -1,3,5-triazine mp:> 300 ° C NMR: (DMSO-d6) δ: 8.52 (s, 1)
H), 8.08 (s, 1H), 7.90 (d, J = 8.
19Hz, 2H), 7.22 (d, J = 8.19Hz,
2H), 2.32 (s, 3H) Example 4 8- (4-Ethylphenyl) -4-hydroxypyrazolo
[1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.54 (s, 1H),
8.09 (s, 1H), 7.92 (d, J = 8.4H
z, 2H), 7.26 (d, J = 8.4Hz, 2H),
2.56 (q, J = 3.7Hz, 2H), 1.20
(T, J = 3.7 Hz, 3H) Example 5 8- (4-t-butylphenyl) -4-hydroxypyra
Zoro [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.49 (s, 1H),
8.07 (s, 1H), 7.91 (d, J = 8.35H
z, 2H), 7.42 (d, J = 8.35Hz, 2
H), 1.30 (s, 9H) Example 6 8-p-biphenyl-4-hydroxypyrazolo [1,5
-A] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.62 (s, 1H),
8.13 (s, 1H), 8.13 (d, J = 8.35H
z, 2H), 7.73 (d, J = 8.35Hz, 2
H), 7.6 to 7.9 (m, 2H), 7.2 to 7.6.
(M, 3H) Example 7 4-hydroxy-8- (3-methoxycarbonylphenyi
Le) pyrazolo [1,5-a] -1,3,5-triazine mp: 273 to 275 ° C NMR (DMSO-d6) δ: 8.65 (s, 2H),
8.24 (dt, J = 7.9 and 1.5 Hz, 1
H), 8.18 (s, 1H), 7.86 (dt, J =
7.7 and 1.5 Hz, 1H), 7.57 (t, J =
7.7 Hz, 1H), 3.89 (s, 3H) Example 8 8- (4-α, α-ethylenedioxybenzylphenyi
) -4-hydroxypyrazolo [1,5-a] -1,
3,5-triazine mp: 291-291.5 ° C (decomposition) NMR (DMSO-d6) δ: 8.51 (s, 1H),
8.08 (s, 1H), 7.96 (d, J = 8.35H
z, 2H), 7.26 to 7.51 (m, 7H), 4.0
0 (s, 4H) Example 9 8- (4-Cyanophenyl) -4-hydroxypyrazolo
[1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.70 (s, 1H),
8.24 (d, J = 8.8 Hz, 2H), 8.18
(S, 1H), 7.87 (d, J = 8.8Hz, 2H) Example 10 4-hydroxy-8- (3-nitrophenyl) pyrazolo
[1,5-a] -1,3,5-triazine mp: 295-299 ° C NMR: (DMSO-d6) δ: 8.96 (t, J =
1.87, 1H), 8.73 (s, 1H), 8.42
(D, J = 7.91 Hz, 1H), 8.22 (s, 1
H), 8.12 (dd, J = 7.03 and 2.30H
z, 1H), 7.71 (t, J = 8.02 Hz, 1H) Example 11 4-hydroxy-8- (2-methoxyphenyl) pyrazo
B [1,5-a] -1,3,5-triazine mp: 298 to 299 ° C (decomposition) NMR (DMSO-d6) δ: 8.44 (s, 1H),
8.03 (s, 1H), 8.0-8.1 (m, 1H),
6.91-7.37 (m, 3H) Example 12 4-Hydroxy-8- (3-methoxyphenyl) pyrazo
B [1,5-a] -1,3,5-triazine mp: 288-290 ° C NMR (DMSO-d6) δ: 8.59 (s, 1H),
8.12 (s, 1H), 7.59 to 7.65 (m, 2
H), 7.33 (t, J = 7.1 Hz, 1H), 6.8
4 (ddd, J = 7.0, 1.5 and 1.0 Hz, 1
H), 3.81 (s, 3H) Example 13 4-Hydroxy-8- (4-methoxyphenyl) pyrazo
B [1,5-a] -1,3,5-triazine mp: 297.5-305 ° C NMR (DMSO-d6) δ: 8.48 (s, 1H),
8.06 (s, 1H), 7.92 (d, J = 9.01H
z, 2H), 6.98 (d, J = 9.01 Hz, 2
H), 3.78 (s, 3H) Example 14 8- (4-Benzyloxyphenyl) -4-hydroxy
Pyrazolo [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.48 (s, 1H),
8.05 (s, 1H), 7.93 (d, J = 8.79H
z, 2H), 7.33 to 7.42 (m, 5H), 7.0.
7 (d, J = 8.79 Hz, 2H), 5.12 (s, 2
H) Example 15 4-hydroxy-8- (3-methylthiophenyl) pyra
Zoro [1,5-a] -1,3,5-triazine mp: 240-243 ° C NMR (DMSO-d6) δ: 8.61 (s, 1H),
8.12 (s, 1H), 7.84 (t, J = 1.5H
z, 1H), 7.80 (dt, J = 7.7 and 1.5)
Hz, 1H), 7.37 (t, J = 7.7Hz, 1
H), 7.15 (dt, J = 7.7 and 1.4 Hz,
1H), 2.52 (s, 3H) Example 16 4-hydroxy-8- (4-methylthiophenyl) pyra
Zoro [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.56 (s, 1H),
8.10 (s, 1H), 7.97 (d, J = 8.6H
z, 2H), 7.32 (d, J = 8.6Hz, 2H),
2.50 (s, 3H) Example 17 8- (4-Ethylthiophenyl) -4-hydroxypyra
Zoro [1,5-a] -1,3,5-triazine mp: 288-289 ° C NMR (DMSO-d6) δ: 8.56 (s, 1H),
8.11 (s, 1H), 7.98 (d, J = 8.6H
z, 2H), 7.37 (d, J = 8.6Hz, 2H),
3.00 (q, J = 7.4 Hz, 2H), 1.25
(T, J = 7.4 Hz, 3H) Example 18 8- [4-β-Chloroethylthiophenyl] -4-hydr
Roxypyrazolo [1,5-a] -1,3,5-triazi
Mp: 249 ° C. (decomposition) NMR (DMSO-d6) δ: 8.58 (s, 1H),
8.11 (s, 1H), 8.00 (d, J = 8.6H
z, 2H), 7.46 (d, J = 8.6Hz, 2H),
3.68-3.85 (m, 2H), 3.20-3.43
(M, 2H) Example 19 4-Hydroxy-8- (4-phenylthiophenyl) pi
Lazolo [1,5-a] -1,3,5-triazine mp: 297-298 ° C NMR (DMSO-d6) δ: 8.58 (s, 1H),
8.12 (s, 1H), 8.04 (d, J = 8.4H
z, 2H), 7.41 (d, J = 8.5Hz, 2H),
7.34 (s, 5H) Example 20 4-Hydroxy-8- [4- (2-methylphenylthio)
E) Phenyl] pyrazolo [1,5-a] -1,3,5-
Triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.55 (s, 1H),
8.10 (s, 1H), 8.00 (d, J = 8.35H
z, 2H), 7.27 (d, J = 8.35Hz, 2
H), 7.20-8.29 (m, 4H) Example 21 4-hydroxy-8- [4- (4-methylphenylthio).
E) Phenyl] pyrazolo [1,5-a] -1,3,5-
Triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.56 (s, 1H),
8.11 (s, 1H), 7.99 (d, J = 8.6H
z, 2H), 7.32 (d, J = 8.6Hz, 2H),
7.30 (d, J = 8.8 Hz, 2H), 7.18
(D, J = 8.8 Hz, 2H), 2.31 (s, 3H) Example 22 8- (2-Fluorophenyl) -4-hydroxypyrazo
B [1,5-a] -1,3,5-triazine mp: 293-294 ° C NMR (DMSO-d6) δ: 8.37 (d, J = 3.
30Hz, 1H), 8.14 (s, 1H), 8.11-
8.24 (m, 1H), 7.22 to 7.40 (m, 3)
H) Example 23 8- (3-Fluorophenyl) -4-hydroxypyrazo
B [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.64 (s, 1H),
8.15 (s, 1H), 7.82 to 7.94 (m, 2
H), 7.33 to 7.58 (m, 1H), 6.95 to
7.18 (m, 1H) Example 24 8- (4-Fluorophenyl) -4-hydroxypyrazo
B [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.56 (s, 1H),
8.11 (s, 1H), 8.05 (dd, J = 5.0
And 9.01 Hz, 2H), 7.25 (dd, J = 8.
61 and 9.01 Hz, 2H) Example 25 8- (2-chlorophenyl) -4-hydroxypyrazolo
[1,5-a] -1,3,5-triazine mp: 293-295 ° C NMR (DMSO-d6) δ: 8.38 (s, 1H),
8.08 (s, 1H), 7.33 to 7.75 (m, 4
H). Example 26 8- (3-Chlorophenyl) -4-hydroxypyrazolo
[1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.62 (s, 1H),
8.15 (s, 2H), 7.96 (bd, J = 7.21)
Hz, 1H), 7.2-7.5 (m, 2H) Example 27 8- (4-chlorophenyl) -4-hydroxypyrazolo
[1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.60 (s, 1H),
8.13 (s, 1H), 8.06 (d, J = 8.6H
z, 2H), 7.49 (d, J = 8.6Hz, 2H) Example 28 8- (3,4-Dimethylphenyl) -4-hydroxypi
Lazolo [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-b6) δ: 8.52 (s, 1H),
8.09 (s, 1H), 7.78 (bs, 1H), 7.
74 (dd, J = 8.4 and 1.8 Hz, 1H),
7.17 (d, J = 8.4 Hz, 1H), 2.27
(S, 3H), 2.24 (s, 3H) Example 29 4-Hydroxy-8- (4-methoxy-3-methylphene)
Nyl) pyrazolo [1,5-a] -1,3,5-triazi
Mp: 279.5 to 280.5 ° C. (decomposition) NMR (DMSO-d6) δ: 8.45 (s, 1H),
8.06 (s, 1H), 7.75 to 7.82 (m, 2
H), 6.95 (d, J = 9.23 Hz, 1H), 3.
81 (s, 3H), 2.21 (s, 3H) Example 30 4-Hydroxy-8- (3-methyl-4-methylthiof)
Phenyl) pyrazolo [1,5-a] -1,3,5-tria
Gin mp: 273-276 ° C NMR (DMSO-d6) δ: 8.54 (s, 1H),
8.09 (s, 1H), 7,85 (d, J = 9.0H)
z, 1H), 7.83 (s, 1H), 7, 25 (d, J
= 9.0 Hz, 1H), 2.48 (s, 3H), 2.3
0 (s, 3H) Example 31 8- (4-Ethylthio-3-methylphenyl) -4-hi
Droxypyrazolo [1,5-a] -1,3,5-tria
Zin mp: 260-263 ° C NMR (DMSO-d6) δ: 8.50 (s, 1H),
8.08 (s, 1H), 7.77 to 7.94 (m, 2
H), 7.31 (d, J = 9.01 Hz, 1H), 2.
96 (q, J = 7.26 Hz, 2H), 2.33 (s,
3H), 1.28 (t, J = 7.26 Hz, 3H) Example 32 8- (4-benzylthio-3-methylphenyl) -4-
Hydroxypyrazolo [1,5-a] -1,3,5-tri
Azine mp: 234-236 ° C NMR (DMSO-d6) δ: 8.55 (s, 1H),
8.10 (s, 1H), 7.86 (s, 1H), 7.8
2 (dd, J = 8.0 and 1.7 Hz, 1H), 7.
20 to 7.45 (m, 6H), 4.21 (s, 2H),
2.28 (s, 3H) Example 33 4-Hydroxy-8- (3-methyl-4-fernithio)
Phenyl) pyrazolo [1,5-a] -1,3,5-tri
Azine mp: 274-276 ° C NMR (DMSO-d6) δ: 8.59 (s, 1H),
8.13 (s, 1H), 8.01 (bs, 1H), 7.
89 (dd, J = 8.1 and 1.5 Hz, 1H),
7.36 (d, J = 8.0 Hz, 1H), 7.11
7.42 (m, 5H), 2.36 (s, 3H) Example 34 4-Hydroxy-8- [3-methyl-4- (2-methyl)
Phenylthio) phenyl] pyrazolo [1,5-a]-
1,3,5-triazine mp: 246 to 251 ° C. (decomposition) NMR (DMSO-d6) δ: 8.56 (s, 1H),
8.11 (s, 1H), 7.98 (bs, 1H), 7.
84 (bd, J = 8.13 Hz, 1H), 6.9 to 7.
4 (m, 5H), 2.36 (s, 3H), 2.33
(S, 3H) Example 35 4-hydroxy-8- [3-methyl-4- (3-methyl)
Phenylthio) phenyl] pyrazolo [1,5-a]-
1,3,5-triazine mp: 270-273 ° C NMR (DMSO-d6) δ: 8.59 (s, 1H),
8.13 (s, 1H), 7.99 (s, 1H), 7, 8
7 (dd, J = 7.9 and 1.7 Hz, 1H), 7.
32 (d, J = 8.0 Hz, 1H), 6.90 to 7.4
0 (m, 4H), 2.36 (s, 3H), 2.26
(S, 3H) Example 36 4-hydroxy-8- [3-methyl-4- (4-methyl)
Phenylthio) phenyl] pyrazolo [1,5-a]-
1,3,5-triazine mp: 287-290 ° C NMR (DMSO-d6) δ: 8.56 (s, 1H),
8.12 (s, 1H), 7.97 (d, J = 1.5H
z, 1H), 7.82 (dd, J = 9.3 and 2.0)
Hz, 1H), 7.23 (d, J = 9.3Hz, 1
H), 7.15 (s, 4H), 2.35 (s, 3H),
2.28 (s, 3H) Example 37 4-hydroxy-8- [4- (3-methoxyphenylthio)
E) -3-Methyl] phenylpyrazolo [1,5-a] -1,3,5-triazine mp: 245-249 ° C NMR (DMSO-d6) δ: 8.60 (s, 1H),
8.13 (s, 1H), 8.02 (bs, 1H), 7.
91 (dd, J = 7.9 and 1.6 Hz, 1H),
7.39 (d, J = 8.4 Hz, 1H), 7.20
(D, J = 8.1 Hz, 1H), 6.67 to 6.85
(M, 3H), 3.70 (s, 3H), 2.36 (s,
3H) Example 38 4-hydroxy-8- [4- (4-methoxyphenylthio)
E) -3-Methyl] phenylpyrazolo [1,5-a] -1,3,5-triazine mp: 283 to 287 ° C NMR (DMSO-d6) δ: 8.53 (s, 1H),
8.10 (s, 1H), 7.92 (d, J = 1.5H
z, 1H), 7.77 (dd, J = 8.1 and 1.7).
Hz, 1H), 7.31 (d, J = 9.0Hz, 2
H), 7.03 (d, J = 8.1 Hz, 1H), 6.9.
7 (d, J = 9.0 Hz, 2H), 3.77 (s, 3
H), 2.36 (s, 3H) Example 39 8- (3-Ethyl-4-methylthiophenyl) -4-hi
Droxypyrazolo [1,5-a] -1,3,5-tria
Zin mp: 289-294 ° C (decomposition) NMR (DMSO-d6) δ: 8.46 (s, 1H),
8.05 (s, 1H), 7.77 to 7.87 (m, 2
H), 7.25 (d, J = 9.01 Hz, 1H), 2.
71 (q, J = 7.25 Hz, 2H), 2.52 (s,
3H), 1.24 (t, J = 7.25 Hz, 3H) Example 40 8- (3,4-dimethoxyphenyl) -4-hydroxy
Pyrazolo [1,5-a] -1,3,5-triazine mp: 250 ° C. (decomposition) NMR (DMSO-d6) δ: 8.55 (s, 1H),
8.09 (s, 1H), 7.62 (s, 1H), 7.5
7 (bd, J = 8.13 Hz, 1H), 6.99 (d,
J = 8.13 Hz, 1H), 3.83 (s, 3H),
3.79 (s, 3H) Example 41 8-[(3,4-bismethylthio) phenyl] -4-hi
Droxypyrazolo [1,5-a] -1,3,5-tria
Gin mp: 286-292 ° C NMR (DMSO-d6) δ: 8.63 (s, 1H),
8.12 (s, 1H), 7.91 (d, J = 1.76H
z, 1H), 7.85 (dd, J = 8.13 and 1.
76 Hz, 1 H), 7.29 (d, J = 8.13 Hz,
1H), 2.53 (s, 3H), 2.48 (s, 3H) Example 42 8- (3,4-Difluorophenyl) -4-hydroxy
Pyrazolo [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.61 (s, 1H),
8.15 (s, 1H), 7.2-8.2 (m, 3H) Example 43 8- (3-chloro-4-methylthiophenyl) -4-hi
Droxypyrazolo [1,5-a] -1,3,5-tria
Gin mp: 282-286 ° C NMR (DMSO-d6) δ: 8.63 (s, 1H),
8.15 (d, J = 2.0 Hz, 1H), 8.14
(S, 1H), 7.99 (dd, J = 8.3 and 2.
0Hz, 1H), 7.36 (d, J = 8.3Hz, 1
H), 2.52 (s, 3H) Example 44 8- (3,4-Dichlorophenyl) -4-hydroxypyr
Lazolo [1,5-a] -1,3,5-triazine mp: 296.5-297.5 ° C NMR (DMSO-d6) δ: 8.63 (s, 1H),
8.31 (d, J = 1.98 Hz, 1H), 8.15
(S, 1H), 8.01 (dd, J = 8.57 and
1.98 Hz, 1H), 7.64 (d, J = 8.57H
z, 1H) Example 45 8- (2,4-Difluorophenyl) -4-hydroxy
Pyrazolo [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.61 (s, 1H),
8.15 (s, 1H), 7.7 to 8.2 (m, 2H),
7.2-7.6 (m, 1H) Example 46 8- (2,4-Dichlorophenyl) -4-hydroxypyro
Lazolo [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.39 (s, 1H),
8.09 (s, 1H), 7.75 (d, J = 8.13H
z, 1H), 7.70 (d, J = 2.19Hz, 1
H), 7.49 (dd, J = 2.19 and 8.13H)
z, 1H) Example 47 8- (3,5-Dimethylphenyl) -4-hydroxypyr
Lazolo [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.52 (s, 1H),
8.11 (s, 1H), 7.63 (s, 2H), 6.9
0 (s, 1H), 2.31 (s, 6H) Example 48 8- (3,5-dimethoxyphenyl) -4-hydroxy
Pyrazolo [1,5-a] -1,3,5-triazine mp: 280 ° C (decomposition) NMR (DMSO-d6) δ: 8.61 (s, 1H),
8.12 (s, 1H), 7.23 (d, J = 2.4H
z, 2H), 6.42 (t, J = 2.4Hz, 1H),
3.79 (s, 6H) Example 49 8- (3,5-Dichlorophenyl) -4-hydroxypyrpy
Lazolo [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.68 (s, 1H),
8.18 (s, 1H), 8.09 (d, J = 1.98H
z, 2H), 7.39 (t, J = 1.98Hz, 1H) Example 50 8- (2-Fluoro-4-methylthiophenyl) -4-
Hydroxypyrazolo [1,5-a] -1,3,5-tri
Azine mp: 270-272 ° C NMR (DMSO-d6) δ: 8.33 (d, J = 3.
5 Hz, 1H), 8.13 (s, 1H), 8.11
(T, J = 8.5 Hz, 1H), 7.21 (dd, J =
12.0 and 1.7 Hz, 1H), 7.19 (dd,
J = 8.6 and 1.6 Hz, 1H), 2.53 (s,
3H) Example 51 4-Hydroxy-8- (3,4,5-trimethoxyphen)
Nyl) pyrazolo [1,5-a] -1,3,5-triazi
Mp: 262-265 ° C NMR (DMSO-d6) δ: 8.63 (s, 1H),
8.12 (s, 1H), 7.35 (s, 2H), 3.8
5 (s, 6H), 3.70 (s, 3H) Example 52 8- (4-benzyloxy-3,5-dichlorophenyi)
) -4-hydroxypyrazolo [1,5-a] -1,
3,5-triazine mp: 273-273.5 ° C. (decomposition) NMR (DMSO-d6) δ: 8.66 (s, 1H),
8.17 (s, 3H), 7.2 to 7.7 (m, 5H),
5.03 (s, 2H) Example 53 4-Hydroxy-8- (3,4,5-trichlorophenyl)
Le) pyrazolo [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.56 (s, 1H),
8.34 (s, 2H), 8.08 (s, 1H) Example 54 8- (2-Fluoro-5-methyl-4-methylthiophe)
Nyl) -4-hydroxypyrazolo [1,5-a] -1,
3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.32 (d, J = 3.
3 Hz, 1H), 8.13 (s, 1H), 7.94
(D, J = 7.9 Hz, 1H), 7.11 (d, J = 1
2.0 Hz, 1H), 2.51 (s, 3H), 2.24
(S, 3H) Example 55 4-Hydroxy-8- (3-thienyl) pyrazolo [1,
5-a] -1,3,5-triazine mp: 292-293 ° C (decomposition) NMR (DMSO-d6) δ: 8.48 (s, 1H),
8.07 (s, 1H), 7.90 (dd, J = 1.32)
And 2.86 Hz, 1 H), 7.73 (dd, J =
1.32 and 5.05 Hz, 1H), 7.58 (d
d, J = 2.86 and 5.05 Hz, 1H) Example 56 4-Hydroxy-8- (2-thienyl) pyrazolo [1,
5-a] -1,3,5-triazine mp: 267-277 ° C (decomposition) NMR (DMSO-d6) δ: 8.44 (s, 1H),
8.10 (s, 1H), 7.47 (dd, J = 5.05
And 1.10 Hz, 1H), 7.53 (dd, J =
3.52 and 1.10 Hz, 1H), 7.10 (d
d, J = 3.52 and 5.05 Hz, 1H) Example 57 4-Hydroxy-8- (2-pyridyl) pyrazolo [1,
5-a] -1,3,5-triazine mp: 265-267 ° C. MNR (DMSO-d6) δ: 8.58 (bs, 2)
H), 8.27 (d, J = 8.13 Hz, 1H), 8.
17 (s, 1H), 7.83 (dt, J = 7.70 and
And 1.76 Hz, 1H), 7.15 to 7.31 (m, 1
H) Example 58 4-Hydroxy-8- (3-pyridyl) pyrazolo [1,
5-a] -1,3,5-triazine mp: 241 to 243.5 ° C NMR (DMSO-d6) δ: 9.19 (d, J = 2.
20 Hz, 1H), 8.64 (s, 1H), 8.28-
8.49 (m, 2H), 8.14 (s, 1H), 7.4
2 (dd, J = 7.91 and 4.83 Hz, 1H) Example 59 4-Hydroxy-8- (4-pyridyl) pyrazolo [1,
5-a] -1,3,5-triazine mp:> 300 ° C. NMR (DMSO-d6) δ: 8.68 (s, 1H),
8.57 (d, J = 8.57 Hz, 2H), 8.18
(S, 1H), 8.00 (d, J = 8.57Hz, 2
H) Example 60 8- (3-Indolyl) -4-hydroxypyrazolo
[1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 11.31 (s, 1
H), 8.55 (s, 1H), 8.05 (s, 1H),
8.00-8.10 (m, 1H), 7.84 (d, J =
2.4 Hz, 1 H), 7.40 to 7.50 (m, 1
H), 7.05 to 7.25 (m, 2H) Example 61 8- (3-benzo [b] thienyl) -4-hydroxypyr
Lazolo [1,5-a] -1,3,5-triazine mp: 289-292 [deg.] C NMR (DMSO-d6) [delta]: 8.51 (s, 1H),
8.10 (s, 1H), 8.00 to 8.08 (m, 2
H), 7.96 (s, 1H), 7.38 to 7.48.
(M, 2H) Example 62 8- (2-benzo [b] thienyl) -4-hydroxypyr
Lazolo [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.55 (s, 1H),
8.16 (s, 1H), 7.85 (s, 1H), 7.7
7 to 8.00 (m, 2H), 7.27 to 7.39 (m,
2H) Example 63 4-Hydroxy-8- (6-thiochromanyl) pyrazolo
[1,5-a] -1,3,5-triazine mp: 260 ° C. (decomposition) NMR (DMSO-d6) δ: 8.51 (s, 1H),
8.08 (s, 1H), 7.72 (d, J = 8.8H
z, 1H), 7.70 (s, 1H), 7.09 (d, J
= 8.8 Hz, 1H), 3.05 (t, J = 5.6H
z, 2H), 2.81 (t, J = 5.6Hz, 2H),
1.90-2.10 (m, 2H) Example 64 8-[(2,3-Dihydrobenzo [b] thiophene)-
5-yl] -4-hydroxypyrazolo [1,5-a]-
1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.53 (s, 1H),
8.08 (s, 1H), 7.91 (d, J = 1.3H
z, 1H), 7.79 (dd, J = 8.0 and 1.5)
Hz, 1H), 7.27 (d, J = 7.9Hz, 1
H), 3.35 (s, 2H), 3.26 (s, 2H) Example 65 4-Hydroxy-8-β-naphthylpyrazolo [1,5-
a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.68 (s, 1H),
8.53 (bs, 1H), 8.1 to 8.3 (m, 1
H), 8.16 (s, 1H), 7.8 to 8.0 (m, 4)
H), 7.4-7.6 (m, 2H) Example 66 8- (4-Carboxyphenyl) -4-hydroxypyra
Zolo [1,5-a] -1,3,5-triazine 4-hydroxy-8- (4-methylphenyl) pyrazolo
[1,5-a] -1,3,5-triazine (1.13
g) in 1N-sodium hydroxide aqueous solution (50 ml).
Turbid and cool potassium permanganate (1.58 g) with cooling.
Add gradually with stirring. The ice bath was removed after 10 minutes. 5 hours
After that, potassium permanganate (2.3 g) was gradually added.
I got it. After 5 hours, the produced manganese dioxide was filtered.
The pH of the filtrate was adjusted to 2-3 with dilute hydrochloric acid, and the precipitated crystals were collected by filtration.
Then, wash with water and dry to obtain the desired product (0.56g)
Got

Mp:> 300 ° C. NMR (DMSO-d6) δ: 8.65 (s, 1H),
8.16 (s, 1H), 8.16 (d, J = 8.57H
z, 2H), 7.98 (d, J = 8.57Hz, 2H) Example 67 8- (3-Carboxyphenyl) -4-hydroxypyrazolo [1,5-a] -1,3,5- Triazine The target product was obtained in the same manner as in Example 66.

Mp:> 300 ° C. NMR (DMSO-d6) δ: 8.67 (bs, 1)
H), 8.63 (s, 1H), 8.20 (dt, J =
7.69 and 1.53 Hz, 1H), 8.17 (s,
1H), 7.85 (dt, J = 7.69 and 1.43)
Hz, 1H), 7.54 (t, J = 7.69Hz, 1
H) Example 68 4-Hydroxy-8- (4-methoxycarbonylphenyl) pyrazolo [1,5-a] -1,3,5-triazine 8- (4-carboxyphenyl) -4-hydroxypyrazolo [1 , 5-a] -1,3,5-triazine (145
mg), concentrated sulfuric acid (4 ml) and methanol (4 ml)
The mixture was heated to reflux with stirring for 24 hours. After cooling, the precipitated crystals were collected by filtration, washed with methanol and dried to obtain the desired product (74 mg). mp:> 300 ° C. (decomposition) NMR (DMSO-d6) δ: 8.63 (s, 1H),
8.17 (d, J = 8.24 Hz, 2H), 8.15
(S, IH), 7.98 (d, J = 8.24 Hz, 2
H) Example 69 8- (4-Acetylphenyl) -4-hydroxypyrazolo [1,5-a] -1,3,5-triazine 8- (4-ethylphenyl) -4-hydroxypyrazolo [1 , 5-a] -1,3,5-triazine (240 m
g) in a suspension of acetic acid (5 ml) with chromium trioxide (50 ml).
0 mg) and water (1 ml) were added, and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution, the insoluble material was collected by filtration, washed with water, and dried to obtain the desired product (150 mg).

Mp:> 300 ° C. NMR (DMSO-d6) δ: 8.68 (s, 1H),
8.19 (d, J = 8.6 Hz, 2H), 8.18
(S, 1H), 7.99 (d, J = 8.6Hz, 2
H), 2.58 (s, 3H) Example 70 8- (4-benzoylphenyl) -4-hydroxypyrazolo [1,5-a] -1,3,5-triazine 8- (4-α, α-ethylenedioxybenzylphenyl) -4-hydroxypyrazolo [1,5-a] -1,
3,5-triazine (0.20g), concentrated hydrochloric acid (0.5m
A mixture of 1), water (1 ml), methanol (4 ml) and acetone (1 ml) was heated with stirring at 45 to 60 ° C for 2 hours. After cooling, the precipitated crystals were collected by filtration, washed with water and dried to obtain the desired product (0.15 g). mp:> 300 ° C NMR (DMSO-d6) δ: 8.67 (s, 1H),
8.22 (d, J = 8.35 Hz, 2H), 8.17
(S, 1H), 7.5-8.0 (m, 7H) Example 71 8- [4- (4-Benzyloxy-3,5-dibromobenzoyl) phenyl] -4-hydroxypyrazolo [1.5
-A] -1,3,5-Triazine The target ethylene ketal form obtained according to Example 1 was treated by the method of Example 70 to obtain the target.

Mp: 273-274 ° C NMR (DMSO-d6) δ: 8.71 (s, 1H),
8.25 (d, J = 8.6 Hz, 2H), 8.19
(S, 1H), 7.98 (s, 2H), 7.84 (d,
J = 8.6 Hz, 2H), 7.39 to 7.62 (m, 5
H), 5.10 (s, 2H) Example 72 4-Hydroxy-8- (4-nitrophenyl) pyrazolo [1,5-a] -1,3,5-triazine Concentrated sulfuric acid (0.5 ml), 4-Hydroxy-8-phenylpyrazolo [1,5-a] -1,3,5-triazine (310 mg) was added to a mixed solution of concentrated nitric acid (0.5 ml) and acetic acid (2 ml) to give a mixture of 50- The mixture was heated and stirred at 60 ° C.
After 1 hour, water was added, the insoluble matter was filtered off, and water and hot methanol were added.
After being washed with water, it was dried to obtain the desired product (210 mg).

Mp:> 300 ° C. NMR (DMSO-d6) δ: 8.75 (s, 1H),
8.30 (s, 4H), 8.23 (s, 1H) In the same manner as in Example 72, using the appropriate starting materials, the compounds of Examples 73 to 76 were obtained. Example 73 4-Hydroxy-8- (3-methyl-4-nitrophenyl) pyrazolo [1,5-a] -1,3,5-triazine mp: 280 ° C. (sublimation) NMR (DMSO-d6) δ: 8.73 (s, 1H),
8.22 (s, 1H), 8.12 (d, J = 1.5H
z, 3H), 2.60 (s, 3H) Example 74 4-Hydroxy-8- (3-methoxy-4-nitrophenyl) pyrazolo [1,5-a] -1,3,5-triazine mp: > 300 ° C NMR (DMSO-d6) δ: 8.79 (s, 1H),
8.22 (s, 1H), 7.99 (d, J = 8.8H
z, 1H), 7.93 (d, J = 1.7Hz, 1H),
7.83 (dd, J = 8.8 and 1.5 Hz, 1
H), 4.01 (s, 3H) Example 75 8- (3-Chloro-4-nitrophenyl) -4-hydroxypyrazolo [1,5-a] -1,3,5-triazine mp: 265 C. (sublimation) NMR (DMSO-d6) .delta .: 8.79 (s, 1H),
8.44 (d, J = 1.3 Hz, 1H), 8.26
(S, 1H), 8.19 (s, 2H) Example 76 8- (3,5-Dimethyl-4-nitrophenyl) -4-
Hydroxypyrazolo [1,5-a] -1,3,5-triazine mp: 270 ° C. (sublimation) NMR (DMSO-d6) δ: 8.64 (s, 1H),
8.18 (s, 1H), 7.95 (s, 2H), 2.3
1 (s, 6H) Example 77 8- (4-aminophenyl) -4-hydroxypyrazolo [1,5-a] -1,3,5-triazine hydrochloride 4-hydroxy-8- (4- Nitrophenyl) pyrazolo [1,5-a] -1,3,5-triazine (660 m
g) and 5% -palladium on carbon (500 mg), 80%
-Suspended in hydrous methanol (100 ml) and stirred at room temperature under hydrogen atmosphere. After 46 hours, concentrated hydrochloric acid (5 ml) was added, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to dryness.
The target product (450 mg) was obtained. mp:> 300 ° C NMR (DMSO-d6) δ: 8.59 (s, 1H),
8.13 (s, 1H), 8.09 (d, J = 8.6H
z, 2H), 7.39 (d, J = 8.6Hz, 2H) Example 78 4-hydroxy-8- [2- (5-nitrothienyl)]
Pyrazolo [1,5-a] -1,3,5-triazine In a mixed solution of concentrated sulfuric acid (0.2 ml), concentrated nitric acid (0.2 ml) and acetic acid (3 ml), 4-hydroxy-8- (2
After adding -thienyl) pyrazolo [1,5-a] -1,3,5-triazine (440 mg) under ice cooling, the mixture was stirred at room temperature. After 3 hours, water was added, the insoluble matter was filtered off, washed with hot methanol and dried to obtain the desired product (190 mg).

Mp: 250 ° C. (sublimation) NMR (DMSO-d6) δ: 8.72 (s, 1H),
8.28 (s, 1H), 8.13 (d, J = 4.4H
z, 1H), 7.63 (d, J = 4.4Hz, 1H) Example 79 4-Hydroxy-8- [3- (2-nitrothienyl)]
Pyrazolo [1,5-a] -1,3,5-triazine The above compound was obtained in the same manner as in Example 78 by using appropriate starting materials.

Mp:> 300 ° C. NMR (DMSO-d6) δ: 8.51 (s, 1H),
8.15 (s, 1H), 8.02 (d, J = 5.5H
z, 1H), 7.55 (d, J = 5.5Hz, 1H) Example 80 4-Hydroxy-8- (2-hydroxyphenyl) pyrazolo [1,5-a] -1,3,5-triazine 4-Hydroxy-8- (2-methoxyphenyl) pyrazolo [1,5-a] -1,3,5-triazine (242m
A mixture of g), aluminum chloride (799 mg) and nitrobenzene (3 ml) was heated with stirring at 80 to 90 ° C for 5 hours. The reaction solution was cooled, poured into ice water, and the precipitated crystals were collected by filtration, washed with water and dried to obtain the desired product (140 mg).

Mp: 293-297 ° C. (decomposition) NMR (DMSO-d6) δ: 9.85 (s, 1H),
8.55 (s, 1H), 8.07 (s, 1H), 7.9
7 to 8.07 (dd, J = 1.98 Hz, 1H), 6.
76 to 7.14 (m, 3H) In the same manner as in Example 80, using the appropriate starting materials, the compounds of Examples 81 to 83 were obtained. Example 81 4-hydroxy-8- (3-hydroxyphenyl) pyrazolo [1,5-a] -1,3,5-triazine mp: 262-266 [deg.] C. (decomposition) NMR (DMSO-d6) [delta]: 8. 46 (s, 1H),
8.08 (s, 1H), 7.44 to 7.49 (m, 1
H), 7.35 (bs, 1H), 7.19 (t, J =
7.58 Hz, 1H), 6.67 (dd, J = 7.69)
Example 82 4-Hydroxy-8- (4-hydroxyphenyl) pyrazolo [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ. : 8.43 (s, 1H),
8.03 (s, 1H), 7.80 (d, J = 8.57H
z, 2H), 6.81 (d, J = 8.57Hz, 2H) Example 83 8- (4-Bromo-3-hydroxyphenyl) -4-hydroxypyrazolo [1.5-a] -1, 3,5-triazine mp: 277-279 ° C. (decomposition) NMR (DMSO-d6) δ: 10.23 (s, 1)
H), 8.45 (s, 1H), 8.10 (s, 1H),
7.69 (d, J = 1.87 Hz, 1H), 7.49
(D, J = 8.13 Hz, 1H), 7.33 (dd, J
= 8.13 and 1.75 Hz, 1H) Example 84 8- (3,5-dichloro-4-hydroxyphenyl)-
4-hydroxypyrazolo [1,5-a] -1,3,5-
Triazine In the same manner as in Example 80, 8- (4-benzyloxy-
3,5-Dichlorophenyl) -4-hydroxypyrazolo [1,5-a] -1,3,5-pyrimidine was reacted at room temperature for 1 hour to obtain the desired product.

Mp:> 300 ° C. NMR (DMSO-d6) δ: 8.60 (s, 1H),
8.14 (s, 1H), 8.04 (s, 2H) Example 85 8- (3,5-dibromo-4-hydroxyphenyl)-
4-hydroxypyrazolo [1,5-a] -1,3,5-
Triazine The benzyl compound of the desired product obtained according to Example 1 was treated in the same manner as in Example 80 to obtain the desired product.

Mp:> 300 ° C. NMR (DMSO-d6) δ: 8.63 (s, 1H),
8.24 (s, 2H), 8.15 (s, 1H) Example 86 8- (3,5-dimethoxy-4-hydroxyphenyl)
-4-hydroxypyrazolo [1,5-a] -1,3,5
-Triazine In the same manner as in Example 80, using the appropriate starting materials, the target product was obtained.

Mp: 250 to 270 ° C. (decomposition) NMR (DMSO-d6) δ: 8.55 (s, 1H),
8.37 (bs, 1H), 8.07 (s, 1H), 7.
31 (s, 2H), 3.79 (s, 6H) Example 87 8- (3-acetoxyphenyl) -4-hydroxypyrazolo [1,5-a] -1,3,5-triazine 4-hydroxy -8- (3-Methoxyphenyl) pyrazolo [1,5-a] -1,3,5-triazine (242m
A mixture of g), aluminum chloride (799 mg) and nitrobenzene (3 ml) was heated with stirring at 80 to 90 ° C for 5 hours. Add acetyl chloride (0.12 ml) to 4
After 5 minutes, the mixture was cooled, poured into ice water, and the precipitated crystals were collected by filtration, washed with water and dried to obtain the desired product (8 mg).

Mp: 244-249 ° C. (decomposition) NMR (DMSO-d6) δ: 8.58 (s, 1H),
8.13 (s, 1H), 7.79 to 7.96 (m, 2)
H), 7.45 (t, J = 7.91 Hz, 1H), 7.
01 (bd, J = 7.91 Hz, 1H) Example 88 8- [4- (3,5-Dibromo-4-hydroxybenzoyl) phenyl] -4-hydroxypyrazolo [1,5-
a] -1,3,5-Triazine The target benzyl compound obtained according to Example 71 was treated in the same manner as in Example 80 to obtain the target.

Mp:> 300 ° C. NMR (DMSO-d6) δ: 8.70 (s, 1H),
8.23 (d, J = 8.0 Hz, 2H), 8.19
(S, 1H), 7.88 (s, 2H), 7.79 (d,
J = 8.1 Hz, 2H) Example 89 4-hydroxy-8- (4-methylsulfinylphenyl) pyrazolo [1,5-a] -1,3,5-triazine 4-hydroxy-8- (4-methylthio) Phenyl) pyrazolo [1,5-a] -1,3,5-triazine (258
mg) and sodium metaperiodate (430 mg) in methanol (20 ml) suspension, water (0.5 ml) was added, and the mixture was stirred at room temperature for 40 hours. Insoluble matter is filtered off, washed with water,
It was dried to obtain the desired product (180 mg).

Mp: 285-286 ° C NMR (DMSO-d6) δ: 8.66 (s, 1H),
8.22 (d, J = 8.6 Hz, 2H), 8.16
(S, 1H), 7.73 (d, J = 8.6Hz, 2
H), 2.76 (s, 3H) Example 90 4-Hydroxy-8- (3-methyl-4-methylsulfinylphenyl) pyrazolo [1,5-a] -1,3,5.
-Triazine In the same manner as in Example 89, the target product was obtained using the appropriate starting materials.

Mp: 281-282 ° C. MNR (DMSO-d6) δ: 8.64 (s, 1H),
8.16 (s, 1H), 8.13 (dd, J = 8.2 and 1.6Hz, 1H), 7.95 (d, J = 1.6H)
z, 1H), 7.83 (d, J = 8.2Hz, 1H),
2.70 (s, 3H), 2.39 (s, 3H) Example 91 4-Hydroxy-8- (4-methanesulfonylphenyl) pyrazolo [1,5-a] -1,3,5-triazine 4 -Hydroxy-8- (4-methylthiophenyl) pyrazolo [1,5-a] -1,3,5-triazine (260
35% hydrogen peroxide solution (3 ml) was added to a suspension of (mg) in acetic acid (5 ml), and the mixture was heated with stirring at 70 to 80 ° C. 1
After the lapse of time, water was added, the insoluble material was collected by filtration, washed with water, and dried to obtain the desired product (250 mg).

Mp:> 300 ° C. NMR (DMSO-d6) δ: 8.71 (s, 1H),
8.30 (d, J = 8.6 Hz, 2H), 8.20
(S, 1H), 7.96 (d, J = 8.6Hz, 2
H), 3.27 (s, 3H) Example 92 4-Hydroxy-8- [2- (5-phenylthiothienyl)] pyrazolo [1,5-a] -1,3,5-triazine thiophenol. (130 ml) in dimethylformamide (2 ml) solution, N-bromosuccinimide (16
0 mg) was added, and the mixture was stirred at room temperature. After 5 minutes, 4-hydroxy-8- (2-thienyl) pyrazolo [1,5-a]-.
1,3,5-Triazine (218 mg) was added, and the mixture was stirred at room temperature for 2 hours. Diethyl ether was added to the reaction solution, and the precipitate was collected by filtration, ethanol, ethyl acetate, diethyl ether.
It was washed with tel successively and dried to obtain the desired product (120 mg). mp: 295-298 ° C NMR (DMSO-d6
) Δ: 8.54 (s, 1H), 8.12 (s, 1)
H), 7.56 (d, J = 3.7 Hz, 1H), 7.4
0 (d, J = 3.7 Hz, 1H), 7.19 to 7.35
(M, 5H) Example 93 4-Hydroxy-8- [4- (2-phenylthiothienyl)] pyrazolo [1,5-a] -1,3,5-triazine Suitable as in Example 92. The starting material was used to obtain the desired product.

Mp: 278-281 ° C NMR (DMSO-d6) δ: 8.45 (s, 1H),
8.12 (s, 1H), 7.91 (s, 2H), 7.0
4-7.36 (m, 5H) Example 94 4-Hydroxy-8- (4-phenylaminosulfonylphenyl) pyrazolo [1,5-a] -1,3,5-triazine 4-hydroxy-8-phenyl. Pyrazolo [1,5-a]
A mixture of -1,3,5-triazine (420 mg) and chlorosulfonic acid (3 ml) was heated with stirring at 80 ° C.
After 1 hour, water was added to the reaction solution, the precipitate was collected by filtration, washed with water,
Dried. Then, aniline (10 ml) was added to the above collected material
Was added, and the mixture was heated with stirring at 80 ° C. After 2 hours, 2N-hydrochloric acid was added to acidify the reaction solution, and the precipitate was collected by filtration, washed with water and dried to obtain the desired product (420 mg).

Mp: 274-277 ° C. NMR (DMSO-d6) δ: 10.21 (s, 1)
H), 8.62 (s, 1H), 8.17 (d, J = 8.
6 Hz, 2H), 8.16 (s, 1H), 7.78
(D, J = 8.6 Hz, 2H), 6.92 to 7.34
(M, 5H) In the same manner as in Example 94, using the appropriate starting materials, the compounds of Examples 95 to 140 were obtained. Example 95 4-Hydroxy-8- [4- (4-methylphenylaminosulfonyl) phenyl] pyrazolo [1,5-a]-
1,3,5-triazine mp: 262-265 ° C NMR (DMSO-d6) δ: 10.05 (s, 1
H), 8.63 (s, 1H), 8.17 (d, J = 8.
6 Hz, 2H), 8.16 (s, 1H), 7.76
(D, J = 8.6 Hz, 2H), 7.01 (s, 4
H), 2.18 (s, 3H) Example 96 8- [4- (4-Ethylphenylaminosulfonyl) phenyl] -4-hydroxypyrazolo [1,5-a]-
1,3,5-triazine mp: 285-290 ° C NMR (DMSO-d6) δ: 10.09 (s, 1)
H), 8.63 (s, 1H), 8.17 (s, 1H),
8.17 (d, J = 8.6 Hz, 2H), 7.78
(D, J = 8.6 Hz, 2H), 7.04 (s, 4
H), 2.25 (q, J = 7.3 Hz, 2H), 1.1
7 (t, J = 7.3 Hz, 3H) Example 97 8- [4- (3-Ethylphenylaminosulfonyl) phenyl] -4-hydroxypyrazolo [1,5-a]-
1,3,5-triazine mp: 240-248 ° C NMR (DMSO-d6) δ: 10.15 (s, 1)
H), 8.63 (s, 1H), 8.18 (d, J = 8.
6 Hz, 2H), 8.16 (s, 1H), 7.79
(D, J = 8.6 Hz, 2H), 6.70 to 7.50.
(M, 4H), 2.20 to 2.60 (m, 2H), 1.
08 (t, J = 7.2Hz, 3H) Example 98 8- [4- (2-Ethylphenylaminosulfonyl) phenyl] -4-hydroxypyrazolo [1,5-a]-
1,3,5-triazine mp: 250-254 ° C NMR (DMSO-d6) δ: 9.51 (s, 1H),
8.67 (s, 1H), 8.21 (d, J = 8.6H
z, 2H), 8.18 (s, 1H), 7.71 (d, J
= 8.6 Hz, 2H), 7.07 to 7.25 (m, 4
H), 2.46 to 2.57 (m, 2H), 0.97
(T, J = 7.7 Hz, 3H) Example 99 4-hydroxy-8- [4- (4-isopropylphenylaminosulfonyl) phenyl] pyrazolo [1,5-
a] -1,3,5-triazine mp: 290 to 295 ° C NMR (DMSO-d6) δ: 10.10 (s, 1)
H), 8.63 (s, 1H), 8.18 (d, J = 8.
6 Hz, 2H), 8.16 (s, 1H), 7.78
(D, J = 8.6 Hz, 2H), 7.00 to 7.20
m, 4H), 2.46 to 2.52 (m, 1H), 1.1
1 (d, J = 6.8 Hz, 6H) Example 100 8- [4- (4-t-Butylphenylaminosulfonyl) phenyl] -4-hydroxypyrazolo [1,5-
a] -1,3,5-triazine mp: 275-279 [deg.] C NMR (DMSO-d6) [delta]: 10.13 (s, 1)
H), 8.63 (s, 1H), 8.18 (d, J = 8.
6 Hz, 2H), 8.17 (s, 1H), 7.80
(D, J = 8.6 Hz, 2H), 7.25 (d, J =
8.8Hz, 2H), 7.02 (d, J = 8.8Hz,
2H), 1.19 (s, 9H) Example 101 4-Hydroxy-8- [4- (4-α-hydroxyethylphenylaminosulfonyl) phenyl] pyrazolo [1,5-a] -1,3,5. -Triazine mp: 236-239 ° C NMR (DMSO-d6) δ: 8.54 (s, 1H),
8.18 (d, J = 8.6 Hz, 2H), 8.12
(S, 1H), 7.78 (d, J = 8.6Hz, 2
H), 7.21 (d, J = 8.6 Hz, 2H), 7.0
6 (d, J = 8.6 Hz, 2H), 4.61 (q, J =
6.6 Hz, 1 H), 1.24 (d, J = 6.4 Hz,
3H) Example 102 8- [4- (4-acetylphenylaminosulfonyl)
Phenyl] -4-hydroxypyrazolo [1,5-a]-
1,3,5-triazine mp: 260-262 ° C NMR (DMSO-d6) δ: 10.82 (s, 1
H), 8.63 (s, 1H), 8.21 (d, J = 8.
8Hz, 2H), 8.16 (s, 1H), 7.88
(D, J = 8.8 Hz, 2H), 7.84 (d, J =
8.8Hz, 2H), 7.24 (d, J = 8.8Hz,
2H), 3.42 (s, 3H) Example 103 8- [4- (4-cyanophenylaminosulfonyl) phenyl] -4-hydroxypyrazolo [1,5-a]-
1,3,5-triazine mp: 272-274 ° C NMR (DMSO-d6) δ: 11.01 (s, 1
H), 8.64 (s, 1H), 8.22 (d, J = 8.
6 Hz, 2H), 8.18 (s, 1H), 7.88
(D, J = 8.6 Hz, 2H), 7.70 (d, J =
9.0 Hz, 2H), 7.28 (d, J = 9.0 Hz,
2H) Example 104 8- [4- (4-Carboxyphenylaminosulfonyl) phenyl] -4-hydroxypyrazolo [1,5-
a] -1,3,5-triazine mp: 200 to 202 ° C NMR (DMSO-d6) δ: 10.75 (s, 1)
H), 8.62 (s, 1H), 8.20 (d, J = 8.
6Hz, 2H), 8.15 (s, 1H), 7.86
(D, J = 8.6 Hz, 2H), 7.80 (d, J =
8.6 Hz, 2 H), 7.22 (d, J = 8.8 Hz,
2H) Example 105 4-hydroxy-8- [4- (4-methoxycarbonylphenylaminosulfonyl) phenyl] pyrazolo [1,
5-a] -1,3,5-triazine mp: 241-243 ° C NMR (DMSO-d6) δ: 10.81 (s, 1)
H), 8.63 (s, 1H), 8.21 (d, J = 8.
8Hz, 2H), 8.17 (s, 1H), 7.86
(D, J = 8.8 Hz, 2H), 7.83 (d, J =
8.8Hz, 2H), 7.25 (d, J = 8.8Hz,
2H), 3.78 (s, 3H) Example 106 4-Hydroxy-8- [4- (4-hydroxyphenylaminosulfonyl) phenyl] pyrazolo [1,5-a].
-1,3,5-triazine mp: 175-177 ° C NMR (DMSO-d6) δ: 9.69 (s, 1H),
8.63 (s, 1H), 8.17 (s, 1H), 8.1
6 (d, J = 8.6 Hz, 2H), 7.70 (d, J =
8.6 Hz, 2 H), 6.89 (d, J = 9.0 Hz,
2H), 6.61 (d, J = 9.0 Hz, 2H) Example 107 4-hydroxy-8- [4- (3-hydroxyphenylaminosulfonyl) phenyl] pyrazolo [1,5-a].
-1,3,5-triazine mp: 166 to 169 ° C NMR (DMSO-d6) δ: 10.10 (s, 1)
H), 8.64 (s, 1H), 8.18 (d, J = 8.
6 Hz, 2H), 8.16 (s, 1H), 7.79
(D, J = 8.6 Hz, 2H), 6.90 (t, J =
8.4 Hz, 1H), 6.37-6.61 (m, 3H) Example 108 4-Hydroxy-8- [4- (3,4,5-trimethoxyphenylaminosulfonyl) phenyl] pyrazolo [1, 5-a] -1,3,5-triazine mp: 280-282 ° C NMR (DMSO-d6) δ: 10.06 (s, 1)
H), 8.64 (s, 1H), 8.20 (d, J = 8.
6 Hz, 2H), 8.16 (s, 1H), 7.82
(D, J = 8.6 Hz, 2H), 6.42 (s, 2
H), 3.65 (s, 6H), 3.56 (s, 3H) Example 109 8- [4- (4-Chlorophenylaminosulfonyl) phenyl] -4-hydroxypyrazolo [1,5-a]. −
1,3,5-triazine mp: 189-193 ° C NMR (DMSO-d6) δ: 10.38 (s, 1
H), 8.64 (s, 1H), 8.20 (d, J = 8.
6 Hz, 2H), 8.17 (s, 1H), 7.79
(D, J = 8.6 Hz, 2H), 7.31 (d, J =
9.0Hz, 2H), 7.12 (d, J = 9.0Hz,
2H) Example 110 4-Hydroxy-8- [4- (3,4,5-trichlorophenylaminosulfonyl) phenyl] pyrazolo [1,
5-a] -1,3,5-triazine mp: 280-283 ° C NMR (DMSO-d6) δ: 10.91 (bs, 1)
H), 8.66 (s, 1H), 8.25 (d, J = 8.
8Hz, 2H), 8.19 (s, 1H), 7.87
(D, J = 8.8 Hz, 2H), 7.32 (s, 2H) Example 111 8- [4- (4-Carboxy-3-hydroxyphenylaminosulfonyl) phenyl] -4-hydroxypyrazolo [1 , 5-a] -1,3,5-triazine mp: 213-216 ° C NMR (DMSO-d6) δ: 10.81 (s, 1)
H), 8.65 (s, 1H), 8.23 (d, J = 8.
6 Hz, 2H), 8.18 (s, 1H), 7.89
(D, J = 8.6 Hz, 2H), 7.65 (d, J =
9.2 Hz, 1H), 6.67-6.77 (m, 2H) Example 112 4-hydroxy-8- [4- (3-hydroxy-4-methoxycarbonylphenylaminosulfonyl) phenyl] pyrazolo [1, 5-a] -1,3,5-triazine mp: 269-273 ° C NMR (DMSO-d6) δ: 10.84 (bs, 1)
H), 10.55 (bs, 1H), 8.64 (s, 1)
H), 8.22 (d, J = 8.6 Hz, 2H), 8.1
8 (s, 1H), 7.88 (d, J = 8.6Hz, 2
H), 7.64 (d, J = 9.0 Hz, 1H), 6.6
9-6.79 (m, 2H), 3.81 (s, 3H) Example 113 4-hydroxy-8- [4- (3-methoxy-4-methoxycarbonylphenylaminosulfonyl) phenyl]
Pyrazolo [1,5-a] -1,3,5-triazine mp: 160-163 ° C NMR (DMSO-d6) δ: 10.73 (s, 1)
H), 8.64 (s, 1H), 8.22 (d, J = 8.
8 Hz, 2H), 8.17 (s, 1H), 7.89
(D, J = 8.8 Hz, 2H), 7.58 (d, J =
8.4 Hz, 1 H), 6.90 (d, J = 1.8 Hz,
1H), 6.79 (dd, J = 8.4 and 1.8H)
z, 1H), 3.74 (s, 3H), 3.71 (s, 3)
H) Example 114 4-Hydroxy-8- [4- (3-pyridylaminosulfonyl) phenyl] pyrazolo [1,5-a] -1,3.
5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.64 (s, 1H),
8.20 (d, J = 8.6 Hz, 2H), 8.17
(S, 1H), 8.14 to 8.33 (m, 2H), 7.
30 to 7.50 (m, 4H) Example 115 4-Hydroxy-8- [4- (pyrimidin-2-ylaminosulfonyl) phenyl] pyrazolo [1,5-a]-.
1,3,5-triazine mp: 267 to 269 ° C NMR (DMSO-d6) δ: 8.66 (s, 1H),
8.52 (d, J = 4.8 Hz, 2H), 8.23
(D, J = 8.8 Hz, 2H), 8.19 (s, 1
H), 8.03 (d, J = 8.8 Hz, 2H), 7.0
5 (t, J = 4.8Hz, 1H) Example 116 4-hydroxy-8- [4- (thiazol-2-ylaminosulfonyl) phenyl] pyrazolo [1,5-a]-.
1,3,5-triazine mp: 242-245 ° C. MNR (DMSO-d6) δ: 8.64 (s, 1H),
8.18 (d, J = 8.6 Hz, 2H), 8.17
(S, 1H), 7.84 (d, J = 8.6Hz, 2
H), 7.24 (d, J = 4.6 Hz, 1H), 6.8
2 (d, J = 4.6 Hz, 1H) Example 117 4-hydroxy-8- [4- (5-methylisoxazol-3-ylaminosulfonyl) phenyl] pyrazolo [1,5-a] -1. , 3,5-Triazine mp: 273 ° C (decomposition) NMR (DMSO-d6) δ: 11.40 (bs, 1)
H), 8.67 (s, 1H), 8.24 (d, J = 8.
8Hz, 2H), 8.19 (s, 1H), 7.89
(D, J = 8.8 Hz, 2H), 6.16 (d, J =
0.9Hz, 1H), 2.30 (d, J = 0.9Hz,
3H) Example 118 4-Hydroxy-8- [4- (pyrazol-3-ylaminosulfonyl) phenyl] pyrazolo [1,5-a]-.
1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.63 (s, 1H),
8.18 (d, J = 8.6 Hz, 2H), 8.16
(S, 1H), 7.80 (d, J = 8.6Hz, 2
H), 7.52 (d, J = 2.4 Hz, 1H), 5.9
7 (d, J = 2.2 Hz, 1H) Example 119 8- [4- (3-Aminopyrazol-2-ylsulfonyl) phenyl] -4-hydroxypyrazolo [1,5-
a] -1,3,5-triazine mp: 190-194 ° C NMR (DMSO-d6) δ: 8.67 (s, 1H),
8.24 (d, J = 8.4 Hz, 2H), 8.20
(S, 1H), 8.00 (d, J = 2.8Hz, 1
H), 7.86 (d, J = 8.8 Hz, 2H), 5.8
8 (d, J = 2.8 Hz, 1H) Example 120 8- [4- (3-acetylaminopyrazol-2-ylsulfonyl) phenyl] -4-hydroxypyrazolo [1,5-a] -1, 3,5-triazine mp: 239-242 ° C NMR (DMSO-d6) δ: 10.89 (s, 1
H), 8.69 (s, 1H), 8.53 (d, J = 2.
9 Hz, 1 H), 8.29 (d, J = 8.6 Hz, 2
H), 8.21 (s, 1H), 7.95 (d, J = 8.
6Hz, 2H), 6.86 (d, J = 2.9Hz, 1
H), 1.98 (s, 3H) Example 121 4-Hydroxy-8- (4-N-methyl-phenylaminosulfonylphenyl) pyrazolo [1,5-a] -1,
3,5-triazine mp: 252-255 ° C NMR (DMSO-d6) δ: 8.68 (s, 1H),
8.22 (d, J = 8.6 Hz, 2H), 8.19
(S, 1H), 7.54 (d, J = 8.6Hz, 2
H), 7.10 to 7.40 (m, 5H), 3.17.
(S, 3H) Example 122 8- (4-Dimethylaminosulfonylphenyl) -4-
Hydroxypyrazolo [1,5-a] -1,3,5-triazine mp: 283 to 284 ° C NMR (DMSO-d6) δ: 8.70 (s, 1H),
8.29 (d, J = 8.6 Hz, 2H), 8.20
(S, 1H), 7.79 (d, J = 8.6Hz, 2
H), 2.64 (s, 6H) Example 123 8- (4-di-n-butylaminosulfonylphenyl).
-4-hydroxypyrazolo [1,5-a] -1,3,5
-Triazine mp: 136-140 ° C NMR (DMSO-d6) δ: 8.51 (s, 1H),
8.26 (d, J = 8.6 Hz, 2H), 8.08
(S, 1H), 7.77 (d, J = 8.6Hz, 2
H), 2.80 to 3.10 (m, 4H), 0.95
1.61 (m, 8H), 0.78 to 0.95 (m, 6
H) Example 124 4-Hydroxy-8- (4-piperidinosulfonylphenyl) pyrazolo [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8 .61 (s, 1H),
8.28 (d, J = 8.6 Hz, 2H), 8.14
(S, 1H), 7.74 (d, J = 8.6Hz, 2
H), 2.50-3.10 (m, 4H), 1.00
1.80 (m, 6H) Example 125 4-Hydroxy-8- (4-pyrrolidinosulfonylphenyl) pyrazolo [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO- d6) δ: 8.69 (s, 1H),
8.27 (d, J = 8.6 Hz, 2H), 8.19
(S, 1H), 7.84 (d, J = 8.6Hz, 2
H), 3.10 to 3.24 (m, 4H), 1.59 to
1.73 (m, 4H) Example 126 4-Hydroxy-8- (4-morpholinosulfonylphenyl) pyrazolo [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) ) Δ: 8.71 (s, 1H),
8.31 (d, J = 8.6 Hz, 2H), 8.20
(S, 1H), 7.78 (d, J = 8.6Hz, 2
H), 3.59 to 3.64 (m, 4H), 2.90 to
3.00 (m, 4H) Example 127 4-Hydroxy-8- (4-methylaminosulfonylphenyl) pyrazolo [1,5-a] -1,3,5-triazine mp: 296-298 ° C NMR (DMSO). -D6) δ: 8.68 (s, 1H),
8.24 (d, J = 8.4 Hz, 2H), 8.19
(S, 1H), 7.82 (d, J = 8.4Hz, 2
H), 7.39 (q, J = 5.1 Hz, 1H), 2.4
4 (d, J = 4.8Hz, 3H) Example 128 8- (4-aminosulfonylphenyl) -4-hydroxypyrazolo [1,5-a] -1,3,5-triazine mp: 297-300 ° C NMR (DMSO-d6) δ: 8.67 (s, 1H),
8.22 (d, J = 8.6 Hz, 2H), 8.17
(S, 1H) 7.86 (d, J = 8.6Hz, 2H),
7.31 (s, 2H) Example 129 8- (4-cyclohexylaminosulfonylphenyl)
-4-hydroxypyrazolo [1,5-a] -1,3,5
-Triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.68 (s, 1H),
8.23 (d, J = 8.6 Hz, 2H), 8.18
(S, 1H), 7.86 (d, J = 8.6Hz, 2
H), 7.59 (d, J = 7.0 Hz, 1H), 2.7
0 to 3.00 (m, 1H), 1.00 to 1.62 (m,
10H) Example 130 4-Hydroxy-8- (4-tetrahydrofurfurylaminosulfonylphenyl) pyrazolo [1,5-a]-
1,3,5-triazine mp: 258-262 ° C NMR (DMSO-d6) δ: 8.68 (s, 1H),
8.24 (d, J = 8.6 Hz, 2H), 8.19
(S, 1H), 7.84 (d, J = 8.6Hz, 2
H), 7.80 to 8.06 (m, 1H), 3.60 to
3.80 (m, 3H), 2.51 (t, J = 2.0H
z, 2H), 1.68 to 1.82 (m, 4H) Example 131 4-hydroxy-8- (4-β-hydroxyethylaminosulfonylphenyl) pyrazolo [1,5-a] -1,
3,5-triazine mp: 268-270 ° C NMR (DMSO-d6) δ: 8.68 (s, 1H),
8.24 (d, J = 8.6 Hz, 2H), 8.19
(S, 1H), 7.84 (d, J = 8.6Hz, 2
H), 7.54 (t, J = 6.1 Hz, 1H), 3.3
8 (t, J = 6.8 Hz, 2H), 2.70 to 3.00
(M, 2H) Example 132 8- (4-benzylaminosulfonylphenyl) -4-
Hydroxypyrazolo [1,5-a] -1,3,5-triazine mp: 283 to 286 ° C NMR (DMSO-d6) δ: 8.68 (s, 1H),
8.23 (d, J = 8.6 Hz, 2H), 8.19
(S, 1H), 8.10 (t, J = 6.4 Hz, 1
H), 7.85 (d, J = 8.6 Hz, 2H), 7.2
6 (s, 5H), 4.02 (d, J = 6.4Hz, 2
H) Example 133 8- (4-furfurylaminosulfonylphenyl) -4
-Hydroxypyrazolo [1,5-a] -1,3,5-triazine mp: 214 ° C (decomposition) NMR (DMSO-d6) δ: 8.68 (s, 1H),
8.22 (d, J = 8.6 Hz, 2H), 8.19
(S, 1H), 8.12 (t, J = 5.9Hz, 1
H), 7.82 (d, J = 8.6 Hz, 2H), 7.4
8 (dd, J = 2.0 and 0.9 Hz, 1H), 6.
31 (dd, J = 3.3 and 2.0 Hz, 1H),
6.19 (dd, J = 3.1 and 0.7 Hz, 1
H), 4.04 (d, J = 5.9 Hz, 2H) Example 134 4-hydroxy-8- [4- (2-thienylmethylaminosulfonyl) phenyl] pyrazolo [1,5-a]-
1,3,5-triazine mp: 240-245 ° C NMR (DMSO-d6) δ: 8.69 (s, 1H),
8.24 (d, J = 8.6 Hz, 2H), 8.23
(T, J = 5.9 Hz, 1H), 8.19 (s, 1
H), 7.84 (d, J = 8.6 Hz, 2H), 7.3
8 (dd, J = 4.0 and 2.4 Hz, 1H), 6.
92 (d, J = 4.2 Hz, 1H), 6.90 (t, J
= 2.4 Hz, 1H), 4.21 (d, J = 5.9H)
z, 2H) Example 135 8- (2-Dimethylaminosulfonyl-5-methoxyphenyl) -4-hydroxypyrazolo [1,5-a]-
1,3,5-triazine mp: 246-248 ° C NMR (DMSO-d6) δ: 8.15 (s, 1H),
8.02 (s, 1H), 7.89 (d, J = 8.8H
z, 1H), 7.14 (dd, J = 8.8 and 2.6).
Hz, 1H), 7.04 (d, J = 2.6Hz, 1
H), 3.85 (s, 3H), 2.40 (s, 6H) Example 136 8- (3-chloro-4-dimethylaminosulfonylphenyl) -4-hydroxypyrazolo [1,5-a] -1,
3,5-triazine mp: 291-294 ° C NMR (DMSO-d6) δ: 8.76 (s, 1H),
8.38 (d, J = 1.5 Hz, 1H), 8.24
(S, 1H), 8.19 (dd, J = 8.4 and 1.
5 Hz, 1 H), 7.97 (d, J = 8.4 Hz, 1
H), 2.82 (s, 6H) Example 137 8- (4-aminosulfonyl-3-chlorophenyl)-
4-hydroxypyrazolo [1,5-a] -1,3,5-
Triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.74 (s, 1H),
8.34 (d, J = 1.3 Hz, 1H), 8.23
(S, 1H), 8.06 (dd, J = 8.4 and 1.
3Hz, 1H), 7.99 (d, J = 8.4Hz, 1
H), 7.55 (s, 2H) Example 138 8- (4-Dimethylaminosulfonyl-3-methylphenyl) -4-hydroxypyrazolo [1,5-a] -1,
3,5-triazine mp: 256-258 ° C NMR (DMSO-d6) δ: 8.68 (s, 1H),
8.19 (s, 1H), 8.05 to 8.13 (m, 2
H), 7.80 (d, J = 8.8 Hz, 1H), 2.7
4 (s, 6H), 2.50 (s, 3H) Example 139 4-Hydroxy-8- [4- (4-t-butylphenylaminosulfonyl) -3-methylphenyl] pyrazolo [1,5-a ] -1,3,5-Triazine mp: 258-260 ° C NMR (DMSO-d6) δ: 10.24 (s, 1)
H), 8.63 (s, 1H), 8.17 (s, 1H),
7.99 (bs, 3H), 7.23 (d, J = 8.8H
z, 2H), 7.00 (d, J = 8.8Hz, 2H),
2.50 (s, 3H), 1.18 (s, 9H) Example 140 8- (4-chloro-3-dimethylaminosulfonylphenyl) -4-hydroxypyrazolo [1,5-a] -1,
3,5-triazine mp: 294-299 ° C NMR (DMSO-d6) δ: 8.70 (s, 2H),
8.23 (s, 1H), 8.20 (dd, J = 8.6 and 2.2 Hz, 1H), 7.75 (d, J = 8.6H
z, 1H), 2.87 (s, 6H) Example 141 8- (4-Bromophenyl) -4-hydroxypyrazolo [1,5-a] -1,3,5-triazine 4-hydroxy-8. -Phenylpyrazolo [1,5-a]
Bromine (0.5 ml) was added to a nitrobenzene (2 ml) suspension of -1,3,5-triazine (420 mg) and aluminum chloride (1.6 g), and the mixture was heated with stirring at 60 ° C. After 15 hours, water was added, and the precipitate was collected by filtration and washed with hot methanol to obtain the desired product (340 mg).

Mp:> 300 ° C. NMR (DMSO-d6) δ: 8.60 (s, 1H),
8.13 (s, 1H), 8.00 (d, J = 8.6H
z, 2H), 7.61 (d, J = 8.6 Hz, 2H) In the same manner as in Example 141, using appropriate starting materials, the compounds of Examples 142 to 147 were obtained. Example 142 8- (4-Bromo-3-methylphenyl) -4-hydroxypyrazolo [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8 .59 (s, 1H),
8.14 (s, 1H), 8.00 (d, J = 1.5H
z, 1H), 7.77 (dd, J = 8.3 and 1.5)
Hz, 1H), 7.61 (d, J = 8.3Hz, 1
H), 2.39 (s, 3H) Example 143 8- (4-Bromo-3-chlorophenyl) -4-hydroxypyrazolo [1,5-a] -1,3,5-triazine mp:> 300 C. NMR (DMSO-d6) .delta .: 8.68 (s, 1H),
8.32 (d, J = 1.8 Hz, 1H), 8.18
(S, 1H), 7.95 (dd, J = 8.6 and 2.
0Hz, 1H), 7.79 (d, J = 8.6Hz, 1
H) Example 144 8- (4-Bromo-3,5-dimethylphenyl) -4-
Hydroxypyrazolo [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.57 (s, 1H),
8.14 (s, 1H), 7.84 (s, 2H), 2.4
1 (s, 6H) Example 145 8- (4-Bromo-3-methoxyphenyl) -4-hydroxypyrazolo [1,5-a] -1,3,5-triazine mp: 288-291 ° C (decomposition) ) NMR (DMSO-d6) δ: 8.65 (s, 1H),
8.13 (s, 1H), 7.70 (s, 1H), 7.5
9 (s, 2H), 3.92 (s, 3H) Example 146 8- (3-Bromo-4-methylthiophenyl) -4-hydroxypyrazolo [1,5-a] -1,3,5- Triazine mp: 292-293 ° C NMR (DMSO-d6) δ: 8.63 (s, 1H),
8.31 (d, J = 1.8 Hz, 1H), 8.15
(S, 1H), 8.02 (dd, J = 8.4 and 2.
0Hz, 1H), 7.31 (d, J = 8.4Hz, 1
H), 2.51 (s, 3H) Example 147 8- [4- (4-Bromophenylthio) -3-methylphenyl] -4-hydroxypyrazolo [1,5-a]-.
1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.61 (s, 1H),
8.14 (s, 1H), 8.03 (d, J = 2.0H
z, 1H), 7.93 (dd, J = 8.1 and 2.0)
Hz, 1H), 7.50 (d, J = 8.8Hz, 2
H), 7.43 (d, J = 8.1 Hz, 1H), 7.1
0 (d, J = 8.6 Hz, 2H), 2.36 (s, 3
H) Example 148 8- [2- (5-Bromothienyl)]-4-hydroxypyrazolo [1,5-a] -1,3,5-triazine 4-hydroxy-8- (2-thienyl) pyrazolo [1,
Bromine (0.11 ml) was added to a suspension of 5-a] -1,3,5-triazine (440 mg) in nitrobenzene (4 ml) under ice cooling, followed by stirring at room temperature. After 30 minutes, diethyl ether was added, the precipitate was collected by filtration, and recrystallized from N, N-dimethylformamide-methanol to obtain the desired product (280 mg).
mp: 286 ° C. (decomposition) NMR (DMSO-d6) δ: 8.50 (s, 1H),
8.14 (s, 1H), 7.36 (d, J = 3.8H)
z, 1H), 7.21 (d, J = 3.8Hz, 1H) In the same manner as in Example 148, using appropriate starting materials,
The compounds of Examples 149-151 were obtained. Example 149 8- [2- (4,5-dibromothienyl)]-4-hydroxypyrazolo [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ : 8.66 (s, 1H),
8.18 (s, 1H), 7.35 (s, 1H) Example 150 8- [3- (2-Bromothienyl)]-4-hydroxypyrazolo [1,5-a] -1,3. 5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.57 (s, 1H),
8.11 (s, 1H), 7.69 (d, J = 5.7H
z, 1H), 7.54 (d, J = 5.7Hz, 1H) Example 151 8- [3- (2,5-Dibromothienyl)]-4-hydroxypyrazolo [1,5-a]- 1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.57 (s, 1H),
8.14 (s, 1H), 7.68 (s, 1H) Example 152 4-Hydroxy-2-mercapto-8-phenylpyrazolo [1,5-a] -1,3,5-triazine N- Carboethoxy-N '-[3- (4-phenyl) pyrazolyl] thiourea (2.90 g) in methanol (90
(ml) solution under stirring with ice-cooling under stirring with sodium hydroxide (1.80
A solution of g) in methanol (60 ml) is added. After 20 minutes, adjust the pH to 1-2 with concentrated hydrochloric acid and water (100 ml).
Was added and stirred for 30 minutes, and the precipitated crystals were collected by filtration, washed with water, and recrystallized from methanol to obtain the desired product (1.60 g).

Mp: 251 ° C. NMR (DMSO-d6) δ: 12.73 (bs, 1)
H), 8.13 (s, 1H), 7.33 to 7.52
(M, 5H) In the same manner as in Example 152, using appropriate starting materials,
The compounds of Examples 153-155 were obtained. Example 153 8- (3-chlorophenyl) -4-hydroxy-2-mercaptopyrazolo [1,5-a] -1,3,5-triazine mp: 221-222 [deg.] C NMR (DMSO-d6) [delta]: 12. .76 (bs, 1
H), 8.14 (s, 1H), 7.31 to 7.57
(M, 4H) Example 154 8- (2,4-difluorophenyl) -4-hydroxy-2-mercaptopyrazolo [1,5-a] -1,3,5
-Triazine mp: 239 ° C NMR (DMSO-d6) δ: 12.79 (bs, 1)
H), 8.03 (s, 1H), 7.00 to 7.67
(M, 3H) Example 155 4-hydroxy-2-mercapto-8- (3-methyl-
4-Methylthiophenyl) pyrazolo [1,5-a]-
1,3,5-triazine mp: 226.5-229 ° C. (decomposition) NMR (DMSO-d6) δ: 12.74 (bs, 1)
H), 8.08 (s, 1H), 7.15 to 7.39.
(M, 3H), 2.48 (s, 3H), 2.30 (s,
3H) Example 156 2,4-dihydroxy-8-phenylpyrazolo [1,5
-A] -1,3,5-triazine 4-hydroxy-2-mercapto-8-phenylpyrazolo [1,5-a] -1,3,5-triazine (130 m
To a mixture of g), 0.25N-sodium hydroxide (4 ml) and methanol (3 ml), 30% aqueous hydrogen peroxide (1 ml) was added under ice-cooling stirring. After 1 hour, the pH was adjusted to 1-2 with concentrated hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, washed with methanol and dried to obtain the desired product (25.8 mg).

NMR (DMSO-d6) δ: 8.08
(S, 1H), 7.2-7.6 (m, 5H) In the same manner as in Example 156, the compounds of Examples 157 to 159 were obtained using appropriate starting materials. Example 157 8- (3-chlorophenyl) -2,4-dihydroxypyrazolo [1,5-a] -1,3,5-triazine mp: 246-249 [deg.] C NMR (DMSO-d6) [delta]: 12.07. (Bs, 1
H), 11.75 (bs, 1H), 8.14 (s, 1
H), 7.20 to 7.58 (m, 4H) Example 158 8- (2,4-difluorophenyl) -2,4-dihydroxypyrazolo [1,5-a] -1,3,5- Triazine mp: 271-272 ° C NMR (DMSO-d6) δ: 11.77 (bs, 1)
H), 7.96 (s, H), 7.05 to 7.65 (m,
3H) Example 159 4-hydroxy-2-mercapto-8- (3-methyl-
4-Methylsulfinylphenyl) pyrazolo [1,5-
a] -1,3,5-triazine mp: 275-277.5 ° C NMR (DMSO-d6) δ: 11.8 (bs, 1)
H), 8.19 (s, 1H), 7.90 (d, J = 8.
79 Hz, 1H), 7.56 to 7.63 (m, 2H),
3.18 (s, 3H), 2.68 (s, 3H) Example 160 4-acetoxy-8- (3-methyl-4-methylthiophenyl) pyrazolo [1,5-a] -1,3,5. -Triazine 4-hydroxy-8- (3-methyl-4-methylthiophenyl) pyrazolo [1,5-a] -1,3,5-triazine (0.100 g), triethylamine (0.1 m
Acetyl chloride (0.1 ml) was added dropwise to a solution of 1) and methylene chloride (10 ml) at room temperature. After 10 minutes, add methylene chloride (90 ml) and wash with water (20 ml x 3)
The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the desired product (0.110 g).

Mp: 213 ° C. NMR (CDCl ₃ ) δ: 8.63 (s, 1H), 8.
30 (s, 1H), 7.70 (bd, J = 8.36H
z, 1H), 7.65 (bs, 1H), 7.21 (d,
J = 8.79 Hz, 1H), 2.92 (s, 3H),
2.49 (s, 3H), 2.39 (s, 3H) In the same manner as in Example 1, using appropriate starting materials, the compounds of Examples 162 to 168 were obtained. Example 162 4-Hydroxy-8- (4-phenylthiomethylphenyl) pyrazolo [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.54 ( s, 1H),
8.10 (s, 1H), 7.68 (d, J = 8.3H
z, 2H), 7.39 (d, J = 8.3Hz, 2H),
7.14 to 7.34 (m, 5H), 4.24 (s, 2
H) Example 163 4-hydroxy-8- (3-phenoxyphenyl) pyrazolo [1,5-a] -1,3,5-triazine mp: 292-293 [deg.] C NMR (DMSO-d6) [delta]: 8.59. (S, 1H),
8.10 (s, 1H), 7.7 to 7.8 (m, 2H),
7.3 to 7.5 (m, 3H), 6.8 to 7.2 (m, 4)
H) Example 164 4-hydroxy-8- [3-methyl-4- (pyridine-
2-ylthio) phenyl] pyrazolo [1,5-a]-
1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.64 (s, 1H),
8.38 (ddd, J = 4.8, 2.0 and 1.0H
z, 1H), 8.16 (s, 1H), 8.08 (d, J
= 1.7 Hz, 1H), 7.97 (dd, J = 8.0 and 1.7 Hz, 1H), 7.61 (d, J = 8.0H)
z, 1H), 7.61 (ddd, J = 8.5, 8.1 and 2.0 Hz, 1H), 7.11 (ddd, J = 8.
5,4.8 and 1.0 Hz, 1H), 6.84 (d
t, J = 8.1 and 1.0 Hz, 1H), 2.37
(S, 3H) Example 165 4-hydroxy-8- (3-methoxy-4-methylthiophenyl) pyrazolo [1,5-a] -1,3,5-triazine mp: 284-285 ° C NMR (DMSO- d6) δ: 8.61 (s, 1H),
8.11 (s, 1H), 7.66 (dd, J = 8.13)
And 1.54 Hz, 1H), 7.61 (bs, 1
H), 7.18 (d, J = 8.13 Hz, 1H), 3.
89 (s, 3H), 2.40 (s, 3H) Example 166 4-hydroxy-8- (3-methoxy-4-phenylthiophenyl) pyrazolo [1,5-a] -1,3,5- Triazine mp: 247-248 ° C NMR (DMSO-d6) δ: 8.64 (s, 1H),
8.13 (s, 1H), 7.74 (d, J = 1.75H
z, 1H), 7.63 (dd, J = 7.91 and 1.
75Hz, 1H), 7.22 to 7.35 (m, 5H),
7.15 (d, J = 7.91 Hz, 1H) Example 167 8- (3-chloro-4-phenylthiophenyl) -4-
Hydroxypyrazolo [1,5-a] -1,3,5-triazine mp: 290-293 ° C NMR (DMSO-d6) δ: 8.62 (s, 1H),
8.27 (d, J = 2.0 Hz, 1H), 8.15
(S, 1H), 7.92 (dd, J = 8.4 and 2.
0Hz, 1H), 7.41 (s, 5H), 7.16
(D, J = 8.4 Hz, 1H) Example 168 8- (2-Fluoro-3-methyl-4-methylthiophenyl) -4-hydroxypyrazolo [1,5-a] -1,
3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.33 (d, J = 3.
5Hz, 1H), 8.12 (s, 1H), 7.99
(T, J = 8.3 Hz, 1H), 7.14 (d, J =
8.1 Hz, 1H), 2.51 (s, 3H), 2.23
(S, 3H) In the same manner as in Example 89, using the appropriate starting materials, the compounds of Examples 169 to 173 were obtained. Example 169 8- (2-Fluoro-5-methyl-4-methylsulfinylphenyl) -4-hydroxypyrazolo [1,5-
a] -1,3,5-triazine mp:> 300 ° C. NMR (DMSO-d6) δ: 8.41 (d, J = 3.
5Hz, 1H), 8.19 (s, 1H), 8.08
(D, J = 7.5 Hz, 1H), 7.62 (d, J = 1
0.5Hz, 1H), 2.74 (s, 3H), 2.35
(S, 3H) Example 170 4-hydroxy-8- (4-phenylsulfinylphenyl) pyrazolo [1,5-a] -1,3,5-triazine mp: 290-291 ° C (decomposition) NMR (DMSO- d6) δ: 8.60 (s, 1H),
8.17 (d, J = 8.57 Hz, 2H), 8.13
(S, 1H) 7.75 (d, J = 8.57Hz, 2
H), 7.64 to 7.74 (m, 2H), 7.47 to
7.60 (m, 3H) Example 171 4-hydroxy-8- (3-methyl-4-phenylsulfinylphenyl) pyrazolo [1,5-a] -1,3.
5-triazine mp: 243-245.5 ° C NMR (DMSO-d6) δ: 8.60 (s, 1H),
8.14 (s, 1H), 8.11 (bd, J = 8.35)
Hz, 1H), 7.93 (bs, 1H), 7.84
(D, J = 8.35 Hz, 1H), 7.47 to 7.67
(M, 5H) Example 172 4-Hydroxy-8- (3-methoxy-4-methylsulfinylphenyl) pyrazolo [1,5-a] -1,3.
5-triazine mp: 259-260 ° C NMR (DMSO-d6) δ: 8.70 (s, 1H),
8.16 (s, 1H), 7.92 (bd, J = 7.91)
Hz, 1H), 7.75 (bs, 1H), 7.66
(D, J = 8.13 Hz, 1H), 3.95 (s, 3
H), 2.73 (s, 3H) Example 173 4-hydroxy-8- (3-methoxy-4-phenylsulfinylphenyl) pyrazolo [1,5-a] -1,
3,5-triazine monohydrate mp: 173 to 175 ° C NMR (DMSO-d6) δ: 8.66 (s, 1H),
8.15 (s, 1H), 7.45 to 7.95 (m, 8)
H), 3.88 (s, 3H) In addition, the above monohydrate was dried under reduced pressure at 80 ° C. for 12 hours to obtain an anhydride.

Mp: 258-266 ° C. (decomposition) In the same manner as in Example 91, using the appropriate starting materials, the compound of Example 174 was obtained. Example 174 8- (2-Fluoro-5-methyl-4-methylsulfonylphenyl) -4-hydroxypyrazolo [1,5-a]
-1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.44 (d, J = 3.
7 Hz, 1 H), 8.27 (d, J = 7.0 Hz, 1
H), 8.24 (s, 1H), 7.75 (d, J = 1
0.0Hz, 1H), 3.28 (s, 3H) 2.54
(S, 3H) In the same manner as in Example 141, using appropriate starting materials,
The compounds of Examples 175-176 were obtained. Example 175 8- [4- (3-Bromo-4-methoxyphenylthio)
-3-Methylphenyl] -4-hydroxypyrazolo [1,5-a] -1,3,5-triazine mp: 280-285 ° C NMR (DMSO-d6) δ: 8.56 (s, 1H),
8.12 (s, 1H), 7.87 (d, J = 1.6H
z, 1H), 7.83 (dd, J = 7.9 and 1.6)
Hz, 1H), 7.48 (d, J = 2.0Hz, 1
H), 7.32 (dd, J = 8.4 and 2.2 Hz,
1H), 7.19 (d, J = 8.1Hz, 1H), 7.
13 (d, J = 8.5 Hz, 1H), 3.85 (s, 3
H), 2.37 (s, 3H) Example 176 8- [4- (2,4-dibromo-5-methoxyphenylthio) -3-methylphenyl] -4-hydroxypyrazolo [1,5-a ] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.64 (s, 1H),
8.15 (s, 1H), 8.12 (d, J = 1.5H
z, 1H), 8.00 (dd, J = 8.1 and 1.5)
Hz, 1H), 7.87 (s, 1H), 7.46 (d,
J = 7.9 Hz, 1H), 6.47 (s, 1H), 3.
53 (s, 3H), 2.38 (s, 3H) Example 177 2,4-dihydroxy-8- (2-fluoro-5-methyl-4-methylthiophenyl) pyrazolo [1,5-a].
-1,3,5-Triazine 3-amino-4- (2-fluoro-5-methyl-4-methylthiophenyl) pyrazole (2.74 g) was dissolved in pyridine (20 ml) and cooled to 0 ° C. N- (chlorocarbonyl) isocyanate (1.03 ml) was added, the mixture was stirred at room temperature for 4 hours, 10% hydrochloric acid was added to the reaction mixture under ice cooling to acidify the reaction mixture, and the precipitate was collected by filtration and washed with water, The target substance (3.4 g) was obtained by drying.

Mp: 250-253 ° C. NMR (DMSO-d6) δ: 7.94 (d, J = 1.
3Hz, 1H), 7.26 (d, J = 7.9Hz, 1
H), 7.08 (d, J = 11.5 Hz, 1H), 2.
50 (s, 3H), 2.23 (s, 3H) Example 178 4-hydroxy-8- (3-methoxy-4-phenylsulfinylphenyl) pyrazolo [1,5-a] -1,
3,5-Triazine monohydrate 4-hydroxy-8- (3-methoxy-4-phenylthiophenyl) pyrazolo [1,5-a] -1,3,5-triazine (11.21 g) in acetic acid A 30% aqueous hydrogen peroxide solution (10.24 ml) was added to the (384 ml) suspension over about 3.5 hours. After stirring at room temperature for 28 hours, water (400 ml) was added to the reaction mixture, the precipitate was collected by filtration, washed with water and dried to obtain the desired product (11.31 g).

NMR (DMSO-d6) δ: 8.66
(S, 1H), 8.15 (s, 1H), 7.45 to 7.
95 (m, 8H), 3.88 (s, 3H) The monohydrate obtained above was dried under reduced pressure at 80 ° C for 12 hours to obtain an anhydride. mp: 25
8-266 ° C (decomposition) In the same manner as in Example 1, using the appropriate starting materials, the compound of Example 179 was obtained. Example 179 8- (dibenzothiophen-2-yl) -4-hydroxypyrazolo [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.94 (D, J = 1.
1 Hz, 1 H), 8.80 (s, 1 H), 7.98-
8.45 (m, 4H), 8.18 (s, 1H), 7.4
9-7.59 (m, 2H) In analogy to Example 178, using the appropriate starting materials,
The compound of Example 180 was obtained. Example 180 4-hydroxy-8- [3-methyl-4- (pyridine-
2-ylsulfinyl) phenyl] pyrazolo [1,5-
a] -1,3,5-triazine mp: 172-174 ° C NMR (DMSO-d6) δ: 8.58 (s, 1H),
8.55 (dt, J = 4.83 and 1.10 Hz, 1
H), 8.13 (s, 1H), 7.93 to 8.10.
(M, 4H), 7.71 (d, J = 8.13Hz, 1
H), 7.47 (ddd, J = 6.59, 4.56 and 2.20 Hz, 1H), 2.61 (s, 3H) In the same manner as in Example 91, using appropriate starting materials, The compounds of Examples 181-184 were obtained. Example 181 4-hydroxy-8- (4-phenylsulfonylphenyl) pyrazolo [1,5-a] -1,3,5-triazine mp:> 300 ° C NMR (DMSO-d6) δ: 8.66 (s) , 1H),
8.26 (d, J = 8.79 Hz, 2H), 8.18
(S, 1H), 7.99 (d, 2H), 7.92-8.
01 (m, 2H), 7.59 to 7.71 (m, 3H) Example 182 4-Hydroxy-8- (3-methyl-4-phenylsulfonylphenyl) pyrazolo [1,5-a] -1, 3,5
-Triazine mp: 297-298 ° C (decomposition) NMR (DMSO-d6) δ: 8.66 (s, 1H),
8.18 (s, 1H), 8.17 (s, 1H), 8.1
6 (s, 1H), 8.02 (bs, 1H), 7.82-
7.93 (m, 2H), 7.60 to 7.73 (m, 3)
H) Example 183 4-hydroxy-8- (3-methoxy-4-phenylsulfonylphenyl) pyrazolo [1,5-a] -1,3.
5-triazine mp: 286-287 ° C NMR (DMSO-d6) δ: 8.71 (s, 1H),
8.18 (s, 1H), 8.04 (d, J = 8.35H
z, 1H), 7.56-7.96 (m, 7H) Example 184 4-hydroxy-8- [3-methyl-4- (3-methylphenylsulfonyl) phenyl] pyrazolo [1,5-.
a] -1,3,5-triazine mp: 278 to 280 ° C. (decomposition) NMR (DMSO-d6) δ: 8.65 (s, 1H),
8.18 (s, 1H), 8.15 (s, 2H), 8.0
2 (bs, 1H) 7.46 to 7.66 (m, 4H),
2.42 (s, 3H), 2.39 (s, 3H) Example 185 4-hydroxy-8- (3-methoxy-4-phenylsulfinylphenyl) pyrazolo [1,5-a] -1,
3,5-triazine dihydrate 4-hydroxy-8- (3-methoxy-4-phenylsulfinylphenyl) pyrazolo [1,5-a] -1,
3,5-Triazine monohydrate (80 g) was dissolved in N, N-dimethylformamide (600 ml), the insoluble material was filtered off, water (3 l) was added to the filtrate, and the formed precipitate was filtered off. I took it. This was added to acetone (1.6 l), heated under reflux for 2 hours, cooled, and the precipitate was collected by filtration. Then, chloroform-methanol (1: 1) mixed solvent (800 m
In 1), the mixture was heated under reflux for 2 hours, cooled, and the precipitate was collected by filtration. Further add to 50% ethanol (1.5 l),
After heating under reflux for 3 hours, the mixture was cooled, the precipitate was collected by filtration, and dried under reduced pressure (80 ° C., 10 hours) to obtain the desired product (60.
5 g) was obtained.

Mp: 226-235 ° C. NMR * (DMSO-d6) δ: 8.66 (s, 1
H), 8.15 (s, 1H), 7.46 to 7.94.
(M, 8H), 3.88 (s, 3H) *: The measurement was performed at 90 MHz.

Elemental analysis: calculated as C ₁₈ H ₁₄ N ₄ O ₃ S · 2H ₂ O; C: 53.72, H: 4.51, N: 13.92 measured value; C: 54.10, H: 4.70, N: 13.96 or more The results confirm that the compound obtained is a dihydrate. Example 186 4-hydroxy-8- (3-methoxy-4-phenylsulfinylphenyl) pyrazolo [1,5-a] -1,
3,5-Triazine / 1/2 hydrate 4-hydroxy-8- (3-methoxy-4-phenylsulfinylphenyl) pyrazolo [1,5-a] -1,
3,5-Triazine dihydrate (3 g) was suspended in ethanol (70 ml), heated under reflux for 3 hours, cooled, and the precipitate was collected by filtration. The obtained precipitate was again suspended in ethanol (70 ml), heated under reflux for 3 hours, cooled, filtered, and dried under reduced pressure (110 ° C, 20 hours).
By doing so, the target product (2.8 g) was obtained.

Mp: 245-246 ° C. (decomposition) NMR * (DMSO-d6) δ: 8.69 (s, 1)
H), 8.18 (s, 1H), 7.90 (d, J = 8.
1 Hz, 1 H), 7.76 (d, J = 8.2 Hz, 1
H), 7.50 to 7.71 (m, 6H), 3.89.
(S, 3H) *: The measurement was performed at 270 MHz.

Elemental analysis: calculated as C ₁₈ H ₁₄ N ₄ O ₃ S · 1/2 H ₂ O; C: 57.59, H: 4.03, N: 14.93 measured value; C: 57.46, H: 4.06, N: 14.81 From the above results, it is confirmed that the obtained compound is a hemihydrate. Example 187 4-hydroxy-8- (3-methoxy-4-phenylsulfinylphenyl) pyrazolo [1,5-a] -1,
3,5-triazine 4-hydroxy-8- (3-methoxy-4-phenylsulfinylphenyl) pyrazolo [1,5-a] -1,
3,5-Triazine dihydrate (15 g) was suspended in ethyl acetate (450 ml), heated under reflux for 3 hours, cooled, and the precipitate was collected by filtration. The obtained precipitate was suspended again in ethyl acetate (400 ml), and the mixture was heated under reflux for 3 hours,
After cooling, the precipitate was collected by filtration and dried under reduced pressure (120 ° C., 50 hours) to obtain the target product (13.7 g).

NMR * (DMSO-d6) δ: 8.69
(S, 1H), 8.18 (s, 1H), 7.90 (d,
J = 8.1 Hz, 1H), 7.77 (d, J = 8.2H)
z, 1H), 7.50 to 7.70 (m, 6H), 3.8
9 (s, 3H) *: The measurement was performed at 270 MHz.

Elemental analysis: Calculated value as C ₁₈ H ₁₄ N ₄ O ₃ S; C: 59.01, H: 3.85, N: 15.29 Measured value; C: 59.07, H: 3.85, N: 15.09 Obtained from the above results. It is confirmed that the obtained compound is an anhydride. Next, formulation examples are shown. Formulation example 4-Hydroxy-8- [4- (4-methylphenylthio) phenyl] pyrazolo [1,5-a] -1,3,5-
Triazine, Avicel, corn starch and magnesium stearate are mixed and polished, and then tableted with a sugar coated R10 mm kine. The obtained tablets are 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.

The pharmacological test methods and the results thereof are shown below. Pharmacological test-1 (in vitro measurement method) 1) Preparation of xanthine oxidase solution After slaughtering ICR mice, the small intestine was removed and washed with cold saline, and then four times the amount of cold phosphate buffered saline (PBS).
After homogenizing in it, it was centrifuged at 105,000 xg for 60 minutes.
The supernatant fraction was dialyzed overnight in PBS. The obtained dialysate was stored at -20 ° C until used. 2) Preparation of test compound To the test compound, 200 μl of DMSO and 100 μl of 2 were added.
Add N-NaOH to dissolve, add PBS, add 10 ^-3 M
An aqueous solution (25 ml) was made. In addition, ^10-4 , ^10-5 , ^10-6 , ^10-7 , ^10-8 , 10 were prepared by diluting with PBS.
^-9 , 10 ^-10 and 10 ^-11 M aqueous solutions were prepared. 3) Measuring method A solution having the following composition is reacted at 37 ° C. for 5 minutes,
Inactivate the enzyme under the conditions of 00 ° C for 1 minute, then
Liquid high performance chromatography (H
It was measured by PLC). Solution composition HPLC conditions Column: Cosmosil packed column φ 4.6 × 150 mm 5C ₁₈ -300 Eluent: 10 mM phosphate buffer (pH 6.0) flow
Speed: 1.0 ml / min Detector: UV 292 nm Sample size: 20 μl Retention time: Uric acid 2.4 min 4) The inhibition rate was determined by the following formula.

[0145]

[Equation 1]

The inhibition rate (%) was determined for each of the test compounds prepared in 2), and the xanthine oxidase (XO) inhibition IC ₅₀ value was calculated from the obtained rate. The results are shown in Tables 1 and 2.

[0147]

[Table 1]

[0148]

[Table 2]

Pharmacological test-2 (oral administration measurement method) 1) Animal and administration, collection of serum Test in which 0.5% CMC-Na was suspended in normal ICR male mice weighing about 30 g and fed ad libitum. The compound (dose 5 mg / kg) was orally administered by gavage using a stomach probe. About 6 ml of blood was collected from the posterior vena cava under ether anesthesia 4 hours after the administration, with 6 groups. Serum was separated by a conventional method. 2) Measurement of uric acid level in serum 100 μl of 10% perchloric acid was added to 200 μl of serum,
After centrifugation, 100 μl of the supernatant was added with 0.2 M Na ₂ HPO _4.
After adding 200 μl, 20 μl thereof was analyzed by HPLC to measure uric acid. The HPLC conditions are as follows.
Column: Cosmosil packed column φ 4.6 × 150 mm 5C ₁₈ -300 Eluent: 10 mM phosphate buffer (pH 6.0) flow
Speed: 1.0 ml / min Detector: UV 292 nm Sample size: 20 μl Retention time: Uric acid 2.4 min 3) Uric acid reduction rate was calculated by the following formula.

[0150]

[Equation 2]

The results obtained are shown in Table 3.

[0152]

[Table 3]

 ─────────────────────────────────────────────────── ─── Continuation of front page (31) Priority claim number Japanese Patent Application Sho 62-159437 (32) Priority date Sho 62 (1987) June 25 (33) Priority claim country Japan (JP)

Claims (8)

[Claims] 1. A general formula: [In the formula, R ¹ represents a hydroxyl group or a lower alkanoyloxy group, R ² represents a hydrogen atom, a hydroxyl group or a mercapto group, and R ³ represents (1) thiochromanyl group, benzothienyl group, 2,3-dihydrobenzothienyl group. Group, a thienyl group substituted with 1 to 2 halogen atoms, a 5-nitrothienyl group, or 5-
Phenylthiothienyl group, (2) Substituted phenyl group selected from the following groups (however, phenylsulfonyl group alone as a substituent on the phenyl ring, combination of phenylsulfonyl group and lower alkyl group, phenylsulfonyl group and lower alkoxy group And a combination of a phenylsulfinyl group and a lower alkoxy group are excluded.) (I) 3,4-dimethylphenyl group, 3,5
-Dimethylphenyl group, 3-methylphenyl group, 4-ethylphenyl group or 4-t-butylphenyl group, (i
i) 4-lower alkoxycarbonylphenyl group, (iii)
4-cyanophenyl group, (iv) nitrophenyl group, (v)
3-methyl-4-nitrophenyl group, 3-chloro-4
-Nitrophenyl group or 3,5-dimethyl-4-nitrophenyl group, (vi) 3-methoxyphenyl group, 4-
Methoxyphenyl group, 3,5-dimethoxyphenyl group,
3,4-dimethoxyphenyl group, 3,4,5-trimethoxyphenyl group, 3-methoxy-4-nitrophenyl group or 4-methoxy-3-methylphenyl group (vii) phenyl lower alkoxyphenyl group or 4-phenyl Lower alkoxy-3,5-dichlorophenyl group, (viii)
Phenylthio lower alkylphenyl group, (ix) phenoxyphenyl group, (X) 4-bromo-3,5-dimethylphenyl group, 4-bromo-3-methoxyphenyl group, 4-
Bromophenyl group, 3,4-dichlorophenyl group, 3-
Chlorophenyl group, 4-chlorophenyl group, 3,5-dichlorophenyl group, 3,4,5-trichlorophenyl group, 4-bromo-3-chlorophenyl group, 4-bromo-
3-methylphenyl group, 3,4-difluorophenyl group, 4-bromo-3-hydroxyphenyl group, 3,5-
Dichloro-4-hydroxyphenyl group or 3,5-
A dibromo-4-hydroxyphenyl group, (xi) 4-carboxyphenyl group, (xii) lower alkanoylphenyl group; (xiii) a halogen atom, a phenyl lower alkoxy group and / or a hydroxyl group as a substituent on the phenyl ring of the benzoyl group. 1 to 3 benzoylphenyl group, (xiv) 3-hydroxyphenyl group, 4-hydroxyphenyl group or 3,5-dimethoxy-4-hydroxyphenyl group, (xv) lower alkanoyloxyphenyl group, or ( xvi) nitro group, phenyl lower alkoxy group, phenylthio lower alkyl group, phenoxy group, lower alkanoyl group, benzoyl which may have 1 to 3 halogen atoms, phenyl lower alkoxy groups and / or hydroxyl groups as substituents on the phenyl ring 1 to 3 groups or lower alkanoyloxy groups Having a phenyl group (3) One of the groups (I) and (II) represented by the following formula must be substituted by one and the following substituents i-xix
A phenyl group having 0 to 2 substituents selected from the group consisting of: (Wherein R has 1 to 3 substituents selected from the group consisting of a lower alkyl group, a halogen-substituted lower alkyl group and a halogen atom, a lower alkyl group and a lower alkoxy group as a substituent on the phenyl ring. Certain phenyl group, phenyl lower alkyl group or pyridyl group, t is 0, 1
Or an integer of 2 is shown. ) [Chemical 3] (In the formula, R ⁴ and R ⁵ are the same or different and each is a hydrogen atom; a cycloalkyl group; a substituent selected from the group consisting of a hydroxyl group, a furyl group, a thienyl group, a tetrahydrofuranyl group and a phenyl group. A lower alkyl group which may have; a lower alkyl group which may have a hydroxyl group, a lower alkanoyl group, a cyano group, a carboxy group, a lower alkoxycarbonyl group, a hydroxyl group, a lower alkoxy group and a halogen atom as a substituent A phenyl group which may have 1 to 3 substituents selected from the following; represents a heterocyclic group selected from the group consisting of pyridyl, pyrimidinyl, thiazolyl, isoxazolyl and pyrazolyl, the heterocyclic group being a substituent lower alkyl group, which may have an amino group or a lower alkanoylamino group; and R ⁴ And R ⁵ are linked without via or through an oxygen atom together with the nitrogen atom to which they are attached may form a 5- or 6-membered saturated ring)] i lower alkyl group;. Ii phenyl group; iii lower alkoxy Carbonyl group; iv cyano group; v nitro group; vi lower alkoxy group; vii phenyl lower alkoxy group; viii phenylthio lower alkyl group; ix phenoxy group; x group embedded image (Wherein R has 1 to 3 substituents selected from the group consisting of a lower alkyl group, a halogen-substituted lower alkyl group and a halogen atom, a lower alkyl group and a lower alkoxy group as a substituent on the phenyl ring. A phenyl group or a pyridyl group, t represents an integer of 0, 1 or 2.); xi halogen atom; xii carboxy group; xiii lower alkanoyl group; xiv halogen atom as a substituent on the phenyl ring, phenyl lower alkoxy group And / or 1 to 3 hydroxyl groups
Xv amino group; xvi hydroxyl group; xvii lower alkanoyloxy group; xiii group (In the formula, R ⁴ and R ⁵ are the same or different and each is a hydrogen atom; a cycloalkyl group; a substituent selected from the group consisting of a hydroxyl group, a furyl group, a thienyl group, a tetrahydrofuranyl group and a phenyl group. A lower alkyl group which may have; a lower alkyl group which may have a hydroxyl group as a substituent, a lower alkanoyl group, a cyano group, a carboxy group, a lower alkoxycarbonyl group, a hydroxyl group, a lower alkoxy group and a halogen atom. A phenyl group which may have 1 to 3 selected substituents; a heterocyclic group selected from the group consisting of pyridyl, pyrimidinyl, thiazolyl, isoxazolyl and pyrazolyl, wherein the heterocyclic group is a lower substituent An alkyl group,
It may have an amino group or a lower alkanoylamino group; and R ⁴ and R ⁵ are combined with the nitrogen atom to which they are bonded via an oxygen atom or not to form a saturated 5-membered or 6-membered ring. May be. ); And the xix group (In the formula, A represents a lower alkylene group.) A pyrazolotriazine derivative and a salt thereof. 2. R ³ always has one group represented by the general formula (I) as a substituent on the phenyl ring, and as another substituent, a lower alkyl group, a lower alkoxy group or a halogen. The pyrazolotriazine derivative or a salt thereof according to claim 1, which is a phenyl group having 0 to 2 atoms. 3. A substituent on the phenyl ring is (a) a lower alkylthio group alone or a combination of a lower alkylthio group and a substituent selected from a lower alkyl group, a lower alkoxy group and a halogen atom, (b) ) A combination of a phenyl lower alkylthio group and a lower alkyl group, (c) a lower alkyl group as a substituent, a lower alkoxy group or a phenylthio group which may have a halogen atom alone, or a combination of this phenylthio group and a lower alkyl group, (d) a combination of a pyridylthio group and a lower alkyl group, (e) a lower alkylsulfinyl group alone or a combination of a lower alkylsulfinyl group and a substituent selected from a lower alkyl group and a lower alkoxy group, (f) a lower alkyl A combination of a sulfinyl group, a lower alkyl group and a halogen atom, (g) phenylsulfinyl And a substituent selected from a pyridylsulfinyl group alone, or a combination of this substituent and a lower alkyl group, (h) a lower alkylsulfonyl group alone or a lower alkylsulfonyl group, and a substituent selected from a lower alkyl group and a halogen atom. Or a combination of (i) a lower alkyl group-substituted phenylsulfonyl group and a lower alkyl group, and the pyrazolotriazine derivative or a salt thereof according to claim 2. 4. The R ³ is a compound represented by the general formula (I) as a substituent.
A pyrazolotriazine derivative or a salt thereof according to claim 1, which is a phenyl group having two groups represented by the following formula on the phenyl ring. 5. A pyrazolotriazine derivative or a salt thereof according to claim 4, which is a phenyl group having two methylthio groups. 6. The pyrazolotriazine derivative according to claim 3 (c), which has a phenylthio group alone whose substituent may have a lower alkyl group or a lower alkoxy group, or a combination of this phenylthio group and a lower alkyl group. And its salt. 7. R ³ always has one group represented by the above formula (4) as a substituent on the phenyl ring, and has a lower alkyl group, a lower alkoxy group or a halogen atom as another substituent. The pyrazolotriazine derivative or a salt thereof according to claim 1, which has 0 to 2 phenyl groups. 8. A xanthine oxidase inhibitor containing the pyrazolotriazine derivative according to claim 1 or a salt thereof as an active ingredient.