JPH02221280A - Benzothiepine derivative - Google Patents

Abstract

NEW MATERIAL:The benzothiepine derivative of formula I [R<1> is H, halogen, lower alkyl or lower alkoxy; n is 0, 1 or 2; ring A is group of formula II, formu la III, formula IV or formula V (R<2> is lower alkyl, pyridyl or substituted phenyl; R<3> is lower alkyl, pyridyl, phenyl or substituted phenyl; R<4> is halogen)] and its acid addition salt. EXAMPLE:2-(4-Chlorophenyl)-2,3,4,5-tetrahydro-1H-[1]benzothiepine[5,4- C]pyrazol-3- one. USE:Useful as a cerebral function activating agent, antianxiety agent, etc. PREPARATION:The compound of formula I can be produced e.g. by reacting a compound of formula VI (R<5> is H or lower alkyl) with a compound of formula VII in a solvent (e.g. benzene) at a temperature between room temperature and the refluxing temperature of the solvent in the presence or absence of an acid acceptor.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel and pharmaceutically useful benzothiepine derivative or a pharmaceutically acceptable acid addition salt thereof.

(Prior art) Many compounds having a benzothiepine skeleton have various pharmacological effects, and many are under development for clinical use.
hem.

Co+u+un,, Vol, 37. p, 1195~
1206 (1972), 2-phenyl-2,3a,
4.5-tetrahydro-38-(1)benzothiepino
(5,4-c)pyrazol-3-one has been reported, but it is only suggested that it has an anticonvulsant action as a pharmacological action.

[Problem to be solved by the invention]

An object of the present invention is to provide a novel benzothiepine derivative or a pharmaceutically acceptable acid addition salt thereof useful as a brain function stimulant, an anxiolytic, or the like.

[Means to solve the problem]

(0).

(In the formula, R1 represents hydrogen, halogen, lower alkyl or lower alkoxy, n represents 0.1 or 2, and the ring represents the following (a) (b) (C) (d), where: R1 is lower alkyl, pyridyl or phenyl having a substituent, R3 is lower alkyl, pyridyl, phenyl or phenyl having a substituent, R4
represents a halogen, or a pharmaceutically acceptable acid addition salt thereof.

In this specification, halogen refers to chlorine, bromine, fluorine,
Lower alkyl refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, etc., and lower alkoxy refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butyl, etc.
pyridyl refers to 2-pyridyl, 3-pyridyl, or 4-pyridyl, and substituted phenyl refers to phenyl having at least one substituent such as halogen, lower alkyl, or lower alkoxy.

Among the compounds of the present invention represented by the general formula (2), the compounds in which the ring is the pyrazolone ring of the above (a) also include compounds represented by the ring A.

Pharmaceutically acceptable acid addition salts of the compound of the present invention with the general formula (R) include acid addition salts with inorganic or organic acids (hydrochloride, hydrobromide, sulfate, phosphate, maleic acid salt, fumarate, tartrate, citrate, succinate, etc.).

In the present invention, the compound of general formula (1) can be synthesized, for example, by the method shown below.

(In the formula, R5 represents hydrogen or lower alkyl, and the other symbols have the same meanings as above.) A compound represented by the general formula % formula % ((In the formula, triple has the same meaning as above.) By reacting a compound represented by the formula (1-a) with a compound represented by the formula (1-a) and a salt thereof, a compound of the general formula (1-a) and 2-phenyl-2,3
a, 4,5-tetrahydro-3H-(1)benzothiepino(5,4-C)pyrazol-3-one is reacted with a halogen molecule to form a compound of the general formula (wherein, each symbol has the same meaning as above). ) is obtained.

The reaction is usually carried out in a suitable solvent (benzene, toluene, xylene, methanol, ethanol, isopropyl alcohol, butanol, chloroform, dichloroethane, dimethylformamide, tetrahydrofuran, etc.) with a deoxidizer (sodium hydroxide, triethylamine, pyridine, sodium methoxide, etc.). , potassium carbonate, sodium hydrogen carbonate, sodium acetate, etc.) in the presence or absence of
The reaction proceeds from room temperature to reflux of the solvent used for 1 to 24 hours.

A compound represented by "Naoju" - (in the formula, each symbol has the same meaning as above) is obtained.

The reaction proceeds for several minutes to several hours in a solvent such as dichloromethane, chloroform, dichloroethane, benzene, toluene, tetrahydrofuran, acetic acid, etc. under water cooling or under reflux of the solvent.

1. A compound represented by the broad general formula (wherein R1 has the same meaning as above) is reacted with a compound represented by the general formula (wherein R2 has the same meaning as above) or a salt thereof. By doing this, a compound represented by the general formula (in the formula, each symbol has the same meaning as above) is obtained.

The reaction is usually carried out in a suitable solvent (benzene, toluene, xylene, methanol, ethanol, isopropyl alcohol, butanol, chloroform, dimethylformamide,
Dioxane, etc.) in the presence or absence of a deoxidizing agent at room temperature to reflux for 1 to 24 hours.

Legislation ↓ Compounds represented by the general formula (in the formula, Z represents halogen, and other symbols have the same meanings as above); and compounds represented by the general formula (in the formula, R1 has the same meanings as above). By reacting, a compound represented by the general formula (in the formula, each symbol has the same meaning as above) is obtained.

The reaction usually proceeds in a suitable solvent (methanol, ethanol, isopropyl alcohol, butanol, ethylene glycol monomethyl ether, benzene, toluene, xylene, dimethylformamide, etc.) from room temperature to reflux of the solvent used for 1 to 24 hours.

1.1 By subjecting to an oxidation reaction the compound represented by the general formula (in the formula, each symbol has the same meaning as above) obtained by Methods 1 to 4, n=1゛ or 2 compounds are obtained, namely oxide or dioxide compounds.

The reaction is usually carried out in an appropriate solvent (dichloromethane, chloroform, acetic acid, etc.) with an oxidizing agent (hydrogen peroxide, peracetic acid, metachloroperbenzoic acid, sodium metaperiodate, lead tetrasate, etc.) under water cooling. Under reflux of solvent, 1-2
It will proceed in 4 hours.

The compounds of the general formula of the present invention are inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, maleic acid, fumaric acid,
An acid addition salt can be obtained by treating with an organic acid such as tartaric acid, citric acid, or succinic acid in a conventional manner.

[Action and effect of the invention]

The compounds of the present invention have shown affinity for benzodiazepine receptors in receptor binding tests using tritiated diazepam, and have also shown affinity for benzodiazepine receptors in tests using the NPN (N-phenyl-1-naphthylamine) fluorescent probe method. Since it has calmodulin inhibitory activity, it is useful as a brain function stimulant and an anxiolytic drug, and is also useful as an antidote for overdose of diazepam drugs.

When the compound of the present invention is used as a medicine, a carrier,
It can be safely administered to patients in the form of tablets, powders, granules, capsules, injections, drips, etc. by mixing with excipients, diluents, solubilizing agents, etc.

Although the dosage varies depending on the patient's symptoms, weight, age, etc., it is usually administered at 1 to 500 μl per day for adults, either once or in divided doses.

〔Example〕

EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited thereto.

Example 1 Ethyl 2,3,4.5-tetrahydro-5-oxo-
[1] Henzochepine-4-carboxylate 8g, 4
-8.5 g of chlorophenylhydrazine hydrochloride and 4 g of sodium acetate are added to 100 g of butanol and heated under reflux for 18 hours. Concentrate under reduced pressure and add a little water to the residue. The resulting crystals were collected by filtration, washed with water, and then recrystallized from ethanol to give 2-(4-chlorophenyl)-2,3,4,5-tetrahydro-IH-[ with a melting point of 222-224°C.
1] Obtain 6 g of benzothiepino (5,4-Cl pyrazol-3-one).

Example 2 In place of the 4-chlorophenylhydrazine salt 1 salt used in Example 1, 4-methoxyphenylhydrazine hydrochloride was used for the same reaction treatment, and the resulting crystals were recrystallized from ethanol, resulting in a melting point of 191- 2-(4-methoxyphenyl)-213,4,5-tetrahydro-I at 192°C
H-(1)penzothiepino (5,4-C)pyrazol-3-one is obtained.

Example 3 Ethyl 2,3,4.5-tetrahydro-5-oxo-
[1] Benzothiepine-4-carboxylate 4.2g
and 2 g of 2-pyridylhydrazine in 40 d of butanol.
After the completion of the reaction, heat and reflux for 18 hours and let it cool.
The precipitated crystals are collected by filtration. Recrystallization from chloroform-methanol yields 2-(2-pyridyl)-2,3,4,5-tetrahydro-IH-(1
) 1.6 g of benzothiepino (5,4-c)pyrazol-3-one are obtained.

Example 4 2-(4-chlorophenyl')-2,3,4,5-tetrahydro-IH-(1) Benzothiepino [5,4-
c) Add 3.3 g of pyrazol-3-one to 33 d of acetic acid and, with stirring, add 1.8 g of bromine. After stirring at 40°C for 1 hour, the reaction solution was poured into ice water.

The precipitated crystals were collected by filtration and recrystallized from isopropyl alcohol to give 3a-bromo-2-(4-chlorophenyl)-2,3a as pale yellow crystals with a melting point of 146-148°C.
, 2.3 g of 4,5-tetrahydro-3H-(1)benzothiepino (5,4-c)pyrazol-3-one are obtained.

Example 5 3.4-dihydro-4-dimethylaminomethylene-(1
3benzothiepin-5(2H)-one 5.5 and 4-
5g of chlorophenylamidine hydrochloride in 100ml of methanol
In addition to -, a methanol solution of sodium methoxide (containing 1.6 g of sodium in 40 d of methanol) was added at room temperature, and then heated under reflux for 1 hour. After the reaction, the precipitated crystals were collected by filtration and reconstituted from chloroform-ethanol. When crystallized, 2
-(4-chlorophenyl)-5,6-sihydro (1)
5.0 g of benzothiepino C5,4-d) pyrimidine are obtained.

Example 6 When the reaction and treatment were carried out in the same manner using phenylamidine instead of 4-chlorophenylamidine hydrochloride used in Example s, 2-chlorophenylamidine with a melting point of 166-168°C was obtained.
Phenyl-5,6-sihydro(1)benzothiepino
(5,4-d)pyrimidine is obtained.

Example 7 When the reaction and treatment were carried out in the same manner using methylamidine instead of 4-chlorophenylamidine hydrochloride used in Example 5, 2-methyl-5,6-cyhydro( 1) Benzothiepino (5
, 4-d) obtain a pyrimidine.

Example 8 4-bromo2. 3. 4. 5-tetrahydro-(
1) Add 7.5 g of benzothiepin-5-one and 10 g of parachlorophenylthioamide to 200 g of ethanol, and heat under reflux for 23 hours. The solvent is concentrated, isopropyl alcohol is added to the residue, and the precipitated crystals are collected by filtration.

This was purified by silica gel column chromatography, and the resulting crystals were recrystallized from ethanol, with a melting point of 1.
2-(4-chlorophenyl)-4,5-dihydro-(1)benzothiepino (
5,4-d) 1.5 g of thiazole are obtained.

Example 9 When the reaction and treatment were carried out in the same manner using pyridine-3-thioamide instead of parachlorophenylthioamide used in Example 8, 2-(3-pyridyl)-4, having a melting point of 115-116°C, was obtained. 5-dihydro-[1]benzothiepino (5,4-d)thiazole is obtained.

Example 10 2-(4-chlorophenyl)-2,3,4,5-tetrahydro-IH-(1) Benzothiepino [5,4-c)
4 g of pyrazol-3-one is added to 150 m of acetic acid and 2.4 wd of 30% hydrogen peroxide solution.

After reacting at room temperature for 6 hours, the reaction solution was poured into ice water and the precipitated crystals were collected by filtration. When this is recrystallized from ethanol-isopropyl ether, the melting point is 198-199℃ (decomposition).
2-(4-chlorophenyl)-2 as white crystals of
, 3.2 g of benzothiepino (5,4-C) pyrazol-3-one 6-oxide are obtained.

Example 11 2-(4-chlorophenyl)-4,5-dihydro-(1
) benzothiepino (5,4-d) 1 g of thiazole and 50 methylene chloride in hemetachloroperbenzoic acid o,
After washing the reaction solution with water and purifying it with silica gel column chromatography, 2-(4-chlorophenyl)-4, 5-dihydro-(
1) Benzothiepino (5,4-d)thiazole 6.
0.4 g of 6 dioxide is obtained.

Example 12 2.9 g of 2-phenyl-5,6-cyhydro(1)benzothiepino(5,4-d)pyrimidine is added to 150-acetic acid and 2.9 g of 35% hydrogen peroxide.

After reacting at room temperature for 4 hours, pour into ice water. When the precipitated crystals are filtered and recrystallized from ethanol-water, the melting point is 208.
2.3 g of 2-phenyl-5,6-sihydro(1)benzothiepino(5,4-d)pyrimidine 7-oxide are obtained as white crystals at 0.degree. C. (decomposition).

Similarly, the following compounds are produced.

◎ 2-(4-chlorophenyl)-4,5-dihydro-
(1) Benzothiepino (5,4-d)thiazole 6
-Oxide ◎ 2-(4-chlorophenyl)-5,6-sihydro (1) benzothiepino (5,4-d) pyrimidine 7
-oxide ◎ 9-methoxy-2-phenyl-5,6-dihydro (1) benzothiepino (5,4-d) pyrimidine ◎ 9-chloro-2-phenyl-4,5-dihydro-[
1] Henzothiepino (5,4-d)thiazole◎ 9-fluoro-2-(3-pyridyl) -4,5dihydro-(1)benzothiepino (5,4-d)thiazole◎ 2-(4-chlorophenyl)- 10-fluoro-5
,6-sihydro(1)benzothiepino (5,4-d
]Pyrimidine 7-oxide◎ 10-methyl-2-phenyl-5,6-sihydro[1]Benzothiepino (
5,4-d) pyrimidine ◎ 2-ethyl-5,6-sihydro(1) benzothiepino(5,4-d) pyrimidine

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 represents hydrogen, halogen, lower alkyl or lower alkoxy, n represents 0, 1 or 2, and ring A is the following ▲ There are mathematical formulas, chemical formulas, tables, etc.▼ where R^2 is lower alkyl, pyridyl, or phenyl with a substituent, R^3 is lower alkyl,
Pyridyl, phenyl or phenyl having a substituent,
R^4 represents halogen. ) or a pharmaceutically acceptable acid addition salt thereof.