JPS5811876B2 - Ikokankagobutsu no Seizouhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention has a central nervous system depressing effect and is useful as a pharmaceutical, using the general formula (1) [wherein R1 and R2 are the same or different and represent a hydrogen atom or an alkyl group, and the adjacent morpholine may be formed together with the nitrogen atom.

False indicates a hydrogen atom.

Rings A and B may be substituted with halogen atoms].

More specifically, the present invention relates to a compound of the general formula (I) characterized in that a compound represented by the general formula (■) [rings A, B and R1-R3 in the formula have the same meanings as defined above] is treated with phosphorus sulfide. ) is a method for producing a heterocyclic compound.

In the above general formula, the alkyl group represented by R1 and R2 is preferably a straight chain, branched or cyclic lower alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, 5ec-butyl,
Examples include tert-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, and cyclopropylmethyl groups.

When mA and B are substituted with a halogen atom, one or more of the same or different substituents may be appropriately substituted at any substitutable position on A or Bi.

Examples of the halogen atoms substituted for A and Bi include fluorine, chlorine, bromine, and iodine.

The present invention is carried out by reacting the compound of general formula (■) with phosphorus sulfide.

Examples of the phosphorus sulfide used in the present invention include phosphorus trisulfide, phosphorus trisulfide, and elevated phosphorus, among which phosphorus trisulfide is practically preferred.

The amount of phosphorus sulfide used is usually about 1 to 5 moles per mole of the compound of general formula (■).

The reaction is usually preferably carried out in an inert organic solvent, and examples of such solvents include tertiary amines such as pyridine, aromatic hydrocarbons such as toluene and xylene, and mixed solvents thereof.

This reaction is usually advantageously carried out at a temperature near the boiling point of the solvent used, but the reaction may be carried out at a temperature higher or lower depending on the case.

The target compound (■) thus produced can be collected at any purity by means of separation and purification known per se, such as recrystallization and chromatography.

In addition, since the target compound (I) has a basic nitrogen atom in the nucleus, it can be used with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or organic acids (e.g., oxalic acid, succinic acid, etc.). , malonic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, p-1-luenesulfonic acid, etc.) by a method known per se (e.g., adding these acids in a suitable solvent). Can be made into an addition salt.

The target compound (I) or its acid addition salt produced in this manner exhibits significant pharmacological effects such as remarkable central nervous system depressant effects, such as muscle relaxation, anticonvulsant, antianxiety, and hypnotic effects, and It is useful as a medicine such as a relaxant, anticonvulsant, tranquilizer, tranquilizer, and hypnotic agent.

When compound (1) or its acid addition salt is used as a pharmaceutical, it can be prepared as a powder, granules, tablets, capsules, or suppositories by itself or mixed with appropriate pharmacologically acceptable carriers, excipients, and diluents. It can be administered orally or parenterally in the form of a drug or injection.

The dosage varies depending on the type and symptoms of the target disease, but in the case of oral administration, it is usually about 0.5 to 501,119 doses per day for adults.

Furthermore, compound (I) is also useful as a synthetic intermediate for other pharmaceuticals.

For example, a compound obtained by subjecting compound (I) to a reductive desulfurization reaction as described below has the same pharmacological action as compound (I) and is a useful compound as a medicine.

The compound of general formula (II), which is a raw material compound of the present invention, can be produced from compound (B) by a process shown in the following formula.

[X represents a halogen atom (eg, chlorine, bromine), and all other symbols and rings A and B have the same meanings as above.

] The reactive derivative at the carboxyl group of compound (B) is, for example, the corresponding alkyl ester, halide, or mixed acid anhydride.

By the method of the present invention, for example, the following 4H-s-)lyazolo[1,5-a][1,4]benzodiazepine-2
-Thiocarboxamide derivatives are respectively corresponding 2-
It can be produced from carboxamide derivatives.

8-chloro-6-phenyl-4H-s-triazolo(1
,5-a)(1,4:]]]]dibenzazepine-2-
Thiocarboxamichloro-6-phenyl-4H-5-triazolo[1
,5-a) (1,4)benzodiazepine-2-(N-methyl)thiocarboxamide 8-chloro-6-phenyl-
4H-s-triazolo(1,5-a)[1,4,)benzodiazepine-2-(N-ethyl)thiocarboxamide 8-chloro-6-phenyl-4H-s-)riazo(1
,5-a)(1,,4)benzodiazepine-2-(N-
propyl)thiocarboxamide 8-chloro-6-phenyl-4H-s-triazolo(1,,5a)(1,4)benzodiazepine-2-(N-butyl)thiocarboxamide 8-chloro-6-phenyl-4H-s - triazolo (1
,5-a) [1,4) Benzodiazepine-2-(N,N
-dimethyl)thiocarboxamide 8-chloro-6-phenyl-4H--s-)riazolo(1,5-a)(1,4
) Benzodiazepine-2-(N,N-diethyl)thiocarboxamide 8-chloro-6-phenyl-4H-s-triazolo(1,5-a)(1,4)benzodiazepine-
2-(N,N-dipropyl)thiocarboxamide 8-chloro-6-phenyl-4H-s-triazolo(1
,5-a)(1,4)benzodiazepine-2-(N,N
-dibutyl)thiocarboxamide 8-chloro-6-phenyl-4H-s-triazolo(1,5-a) (1,4)
Benzodiazepine-2-(N-methyl-N-isopropyl)thiocarboxamide 4-(8-chloro-6-phenyl-4H-s-triazolo(1,5-a)(1,4,)benzodiazepine-2-
yl)thiocarbonylmorpholine 8-chloro-6-(2
-chlorophenyl)-4H-5-triazolo(1,5-
a) (1,4) Benzodiazepine-2-thiocarboxamide 8-chloro-6-(2-chlorophenyl)-4H-5-
Triazo node (1,5-a)(1,4)benzodiazepine-2-(N-ethyl)thiocarboxamide 8-chloro-6-(2-chlorophenyl)-4H-8-
Triazo section CI, 5-a) (], , 4) Benzodiazepine-2-(N,N-dimethyl)thiocarboxamide 8-chloro-6-(2-chlorophenyl)-4H-8-
Triazolo[1,5-a)(1,4)ben[zodiazepine-2-(N,N-diethyl)thiocarboxamidrophenyl-4H-s-triazolo[1,5-a)(
1,4) Benzodiazepine-2-thiocarboxamidrophenyl-4H-s-triazolo[1,5-a)(
1,4) Benzodiazepine-2-(N.

N-diethyl)thiocarboxamide (2-chlorophenyl)-4H-s'triazo-C
1,s-a,l(1,,4)benzodiazepine-2-thiocarboxamido(2-chlorophenyl)-4H-s-)liazolo(
1,5-a) [1,4) Benzodiazepine-2-(N,
N-diethyl)thiocarboxamide Example 1 8-chloro-6-phenyl-4H-5-triazolo(1
,5-a,](1,4)benzodiazepine-2-(N,
N-dimethyl) carboxamide 194~, phosphorus pentasulfide 2
1. Add a mixture of 22■, 4 ml of toluene, and 2 ml of pyridine.
After heating under reflux for 5 hours, the solvent was distilled off under reduced pressure, water was added, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, then the solvent was distilled off, the residue was dissolved in a small amount of acetone, and 20% ethanolic hydrogen chloride was added. The precipitate was collected by filtration and washed with acetone to give 8-chloro-6-phenyl-4H-s-triazolo[1°5-
a) (1,4)benzodiazepine-2-(N.

Crystals of N-dimethyl)thiocarboxamide hydrochloride are obtained.

Recrystallization from methanol gives yellow prismatic crystals.

Melting point 182-187℃ Elemental analysis C1, H16CIN,
5-HC1 calculated value C54, 55, H4, 10, N16
．． 74 experimental value C54, 32, H4, 06, N16.8
4 Example 2 4-(8-chloro-6-phenyl-4H-s-triazolo(1,5-a)(1,4)benzodiazepin-2-yl)carbonylmorpholine 1.41 Phosphorous pentasulfide 1,52
After heating and refluxing a 21 ml solution of pyridine-toluene (1:2) for 1 hour while stirring, the solvent was distilled off, water was added, and extracted with chloroform. The chloroform layer was washed with water and diluted with NaSO.
4 After drying, the solvent was distilled off to give 4-(8-chloro-6-phenyl-4H-5-triazolo(1,5-a)(1,4)
Benzodiazepin-2-yl)thiocarbonylmorpholine is obtained.

When this is dissolved in a small amount of acetone and 20% ethanolic hydrogen chloride is added, 2-monohydrochloride crystals are obtained.

When this hydrochloride is recrystallized from acetone, it becomes yellow prism crystals.

Melting point 161°-164°C Elemental analysis C21F■13CIN50・2HC1 Calculated value C54,26,H4,34,N15.07 Experimental value C
54,28, H4,15, Nl 5.10 Example 1
, 2 or a method similar thereto, the following compounds can be produced.

8-Chloro-6-phenyl-4H-s l-riazolo(1,5-al(1,4)benzodiazepine-2-(N
-Methyl) thiocarboxamide, when recrystallized from acetone, an acetone adduct [C13H14C1N5S.
(CH3)2C0: pale yellow platelet crystals, melting point 138-140
°C].

Claims (1)

[Scope of Claims] 1 General formula [In the formula, R1 and R2 are the same or different and represent a hydrogen atom or an alkyl group, and may form a morpholine ring together with the adjacent nitrogen atom. R3 represents a hydrogen atom. Rings A and B may be substituted with halogen atoms. A method for producing a heterocyclic compound represented by the general formula [wherein rings A, B and R1-R3 have the same meanings as above], which comprises treating the compound represented by the following with phosphorus sulfide.