DE1445073C - 3H-1,4-Benzodiazepine-4-oxides - Google Patents

Description

The invention relates to 3 H-1,4-benzodiazepine-4-oxides the general formula

NH-R ₁

CH,

in which R _{1 represents} a hydrogen atom or a lower alkyl group and one of R ₂ and R _{3 represents} a hydrogen atom and the other represents a trifluoromethyl group, and salts thereof, a process for the preparation of these compounds and a pharmaceutical preparation.

The lower alkyl group R ₁ can be either straight-chain or branched and z. B. a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, amyl or hexyl radical.

The compounds mentioned are prepared by in a manner known per se Quinazoline-3-oxide of the general formula

CH ₂ -X

in which X is a halogen atom and R ₂ and R _{3 have} the meanings given above, with a compound of the general formula

H ₂ NR ₁

in which R _{1 has} the meaning given above, is reacted and, if appropriate, the base obtained is then converted into a salt with an acid. Upon treatment with ammonia and a primary amine, a structural change occurs in the molecule, whereby the pyrimidine ring is expanded to a 1,4-diazepine ring.

The process is preferably carried out at room temperature in, water or an organic solvent, such as lower aliphatic alcohols, dioxane or tetrahydrofuran. The primary amine is preferably a lower alkylamine such as methylamine, ethylamine, propylamine or isopropylamine.

The salt formation can, for. B. with mineral acids such as hydrohalic acids, e.g. B. hydrochloric acid, or sulfuric acid, nitric acid or phosphoric acid.

The compounds required as starting materials corresponding to the above formula II are new. The processes for their production can be found in the following exemplary embodiments. No protection is claimed for the specified process for the production of the starting materials. The compounds according to the invention are low-toxicity compounds that have sedative properties exhibit. They can be used as tranquilizers and muscle relaxants. They are also suitable as an anticonvulsant. The bases and salts are administered in the pharmaceutical Practice usual way. When checking on

ίο anticonvulsant effect according to that of S wi η yar d. Goodman and Brown in J. Pharmacol. Exp. Therap., 106, 319 (1952), the measurement of the minimal electric shock showed that the ED ₅₀ value for 7-trifluoromethyl-2-amino-5-phenyl-3 H-1,4-benzodiazepine -A - oxide is about 10 times and for 7 - trifluoromethyl - 2 - methylamino-5 - phenyl - 3 H - 1,4 - benzodiazepine - 4 - oxide about 15 times smaller than for 5,5-diphenylhydantoin sodium. The two compounds of the invention also show, compared to 7 - chloro - 2 - methylamino-5 - phenyl - 3H-1,4-benzodiazepine -A- oxide, 3 - methyl 5 - phenyl - 5 - ethyl - hydantoin and especially 5- ( 3-phenanthryl) -5-methyl-hydantoin has superior properties in the maximum or minimum electric shock test.

The following examples illustrate the process according to the invention. All temperatures are given in degrees Celsius.

B e i s ρ i e 1 1

A saturated solution of ammonia is trifluormethylchinazolin-3-oxide treated in methanol with 10 ml - 0.5 g of 2 - chloromethyl -A- phenyl -. 6 The reaction mixture is left to stand for 5 hours at room temperature, then it is diluted with ether and washed 3 times with water. The ether solution is separated off and dried over sodium sulfate. The solvent is evaporated off in vacuo and the residue is recrystallized from benzene-hexane.

This gives 385 mg of 7-trifluoromethyl-2-amino-5-phenyl - 3 H -1,4-benzodiazepin -A- oxide in the form of white needles melting at 229-231 °.

The starting material can be prepared as follows: 80 g of sodium nitrite are added with stirring slowly added to 460 ml of concentrated sulfuric acid. After heating to 70 °, a clear one is obtained Solution. This solution is cooled and slowly with 200 g at a temperature between 10 and 20 ° 2-chloro-5-trifluoromethyl aniline was added. The reaction mixture is stirred for one hour at 20 ° and then poured into a mixture of 200 g of sodium chloride and poured 1.6 kg of ice. The excess sodium chloride is filtered off and the filtrate is added with a solution of 280 g of zinc chloride in 300 ml of water, a zinc chloride double salt being the The resulting diazonium compound is deposited. After standing overnight at 0 °, the double salt is filtered off and wash with a cold saturated saline solution.

A solution of 120 g of sodium cyanide and 72 g of cuprocyanide in 300 ml of water is added with stirring and cooling with ice to add 291 g of wet zinc chloride double salt. After adding 24 g of sodium carbonate the reaction mixture is stirred first for 1 hour at 20 ° and then for a further half hour at 70 °. The reaction mixture is cooled and extracted with ether, taking crude 2-chloro-5-trifluoromethylbenzonitrile receives. This is done by steam distillation

Purified tion and crystallization of the organic part of the distillate from hexane. The pure connection melts at 39 to 40 °.

To a solution of phenyl magnesium bromide. which one consists of 9.5 g of magnesium, 58.5 g of bromobenzene and 500 ml of anhydrous ether are prepared, a solution of 39 g of 2-chloro-5-trifluoromethyl-benzonitrile is added with stirring in 200 ml of benzene. 400 ml of the solvent are distilled off and heated Reaction mixture under reflux for 16 hours. The Grignard complex is decomposed with 40 g of ammonium chloride and 200 g of ice and extract the mixture with benzene. The benzene solution becomes through addition of 40 ml of concentrated hydrochloric acid, the 2-chloro-5-trifluoromethyl-benzophenonimine hydrochloride failed. It is filtered off, washed with benzene and dried in vacuo; F. 248 to 251 °.

60 g of 2 - chloro - 5 - trifluoromethyl - benzophenone imine hydrochloride are mixed with a mixer overnight of 300 ml of toluene and 300 ml of 25% strength sulfuric acid with stirring for binding under reflux heated. The toluene layer is separated off, washed with water, dried and evaporated in vacuo. The residue is crystallized from hexane, pure 2-chloro-5-trifluoromethyl-benzophenone being obtained obtained from the melting point 39 to 40 °.

50 g of 2 - chloro - 5 - trifluoromethyl - benzophenone and 500 ml of concentrated aqueous ammonia are in a closed vessel for 10 hours at 140 ° reacted with one another in the presence of 10 g of cuprous chloride as a catalyst. The reaction product is extracted with ether, the ether extract evaporated in vacuo and the residue dissolved in hexane. The solution obtained is chromatographed on ten times the amount of neutral aluminum oxide (Brockmann activity II). By eluting with. a hexane-ether mixture (1: 1) and evaporation the solvent gives 2-amino-5-trifluoromethyl-benzophenone, which, recrystallized from hexane, forms yellowish crystals with a melting point of 81 to 82 °.

13.3 g of 2 - amino - 5 - trifluoromethyl - benzophenone in 60 ml of ethanol are refluxed with 6 g of hydroxylamine hydrochloride for 24 hours. the Reaction mixture is by adding a solution of 12 g of sodium acetate in 100 ml of water to a pH adjusted to about 6. The mixture is extracted with ether to give an oil which by repeated crystallization from a mixture of ether and hexane, solid 2-amino-5-trifluoromethylbenzophenone oxime from melting point 175 to 177 provides.

2.8 g of 2 - amino - 5 - trifluoromethyl - benzophenone oxime are dissolved in 15 ml of acetic acid and the solution after adding 1.5 ml of chloroacetyl chloride for 1 hour at 20 ° and then held for 2 hours at 70 °. The mixture is diluted with ether and washed with water. The ether solution is in a vacuum evaporated to give a solid residue which is recrystallized from methylene chloride-ether. Man receives pure yellow 2-chloromethyl-4-phenyl-6-trifluoromethyl-quinazoline-3-oxide with a melting point of 149 up to 150 °.

B e i s ρ i e 1 2

500 mg of 2-chloromethyl -4-phenyl-6-trifluoromethyl 1-quinazoline-3-oxide are treated for 5 hours at 25 ° with 10 ml of a 40% solution of methylamine in methanol. The reaction mixture is diluted with water and then extracted with ether. The ether solution is concentrated in vacuo and the crude reaction product obtained by crystallization purified from ether-hexane. 418 m - trifluoromethyl - 2 - methylamino - 5 - phenyl-H- 1,4-benzodiazepine-4-oxide in the form of colorless crystals which melt at 257 to 258 °.

100 mg of this compound are dissolved in 5 ml of methanol and the solution then with 3 ml of 0.1N hydrochloric acid treated at 25 °. The reaction mixture is evaporated at 40 ° and the residue is crystallized out Methanol — ether. The pure hydrochloride is obtained of 7 - trifluoromethyl - 2 - methylamino - 5 - phenyl-H- 1,4-benzodiazepine-4-oxide in the form of white Prisms; 222 ° F. (decomposition).

Claims (3)

Patent claims: 1. 3H-1,4-Benzodiazepine-4-oxides of the general formula NH-R ₁ in which R _{1 is} a hydrogen atom or a lower alkyl group and one of the radicals R ₂ and R _{3 is} a hydrogen atom and the other is a trifluoromethyl group, and salts thereof. 2. Process for making the compounds according to claim 1, characterized in that a quinazoline-3-oxide is used in a manner known per se the general formula CH ₇ X in which X is a halogen atom and R ₂ and R _{3 have} the meanings given above, with a compound of the general formula H ₂ N - R ₁ in which R _{1 has} the meaning given above, is reacted and, if appropriate, the base obtained is then converted into a salt with an acid. 3. A pharmaceutical preparation consisting of a compound according to claim 1 and usual pharmaceutical carriers and / or diluents.