NO129524B - - Google Patents

Description

This invention relates to a process for the preparation of new, therapeutically active compounds of the general formula I where R, means hydrogen, a linear or branched, saturated or unsaturated alkyl residue with 1-6 carbon atoms, or a formyl group; 1*2 is hydrogen or halogen; and means one bromine atom or a trifluoromethyl, nitro or cyano group; and their physiologically compatible acid addition salts•

The new compounds of formula I are prepared according to the invention by

a) a benzodiazepine of the general formula II

where R^ has the meaning given above, excluding formyl, and

R 1 has the above meaning, is reacted with a compound of the general formula III

where R 2 has the meaning given above and X means a halogen atom.

The reaction is carried out in the presence of copper and alkali acetate by heating, possibly in an autoclave. It has proved advantageous to add copper (I) salts, CuO, a weak organic base, such as pyridine, and/or to use a solvent which does not react with the reaction components, e.g. xylene.

b) Compounds of the general formula IV

where R 1 , R 2 and R 2 have the meaning indicated above, are activated, and the activated intermediates are ring-closed.

The compounds of formula IV are then transferred by usual methods of carboxylic acid activation (e.g. Schroder, Lubke; The Pep-tides, Vol. I, p.76 ff; Academic Press, N.Y. and London) to reactive derivatives, e.g. the corresponding esters, acid chlorides or mixed acid anhydrides, which upon heating, possibly in the presence of basic condensing agents, are transferred to the benzodiazepinones.

c) Compounds of the general formula V

where R^f R 2 and R^ have the meanings given above, and Y means

a vinyl or 2-haloethyl group, is ring-closed by means of basic or acidic condensing agents.

The compounds of formula V are cyclized in the presence of an organic or inorganic base or under the catalytic influence of acidic compounds, such as dilute mineral acids, p-toluenesulfonic acid, AlCl^» Zn, etc., optionally in the presence of a suitable solvent, preferably lower alcohols and carboxylic acids, tetrahydrofuran, etc. under elevated pressure in an autoclave or under reflux.

d) Compounds of the general formula VI

where R_ and R^ have the meanings given above, are converted to

an alkylating agent of formula VII

where R^ has the meaning given above, excluding hydrogen, and X means an anionic, easily cleavable acid residue, or, for the preparation of 1-formyl compounds, is heated with formic acid. X can e.g. means a halogen atom or a toluenesulfonic acid residue, and the alkylation is optionally carried out in the presence of basic condensing agents, such as sodium amide or sodium alcoholate.

The end products obtained according to one of the methods indicated above are optionally transferred to their physiologically acceptable acid addition salts.

The starting compounds for methods a - d are partly known and partly they can be produced according to the methods described below.

The compounds of formula II can be prepared from compounds of formula VIII where the residues and R^ have the above-mentioned meanings, by reducing the compound's nitro group with Zn/hydrochloric acid, whereby the diazepine ring is usually closed at the same time. When other reducing agents are used, the ring closure can be carried out afterwards, possibly according to the method described under b). Such compounds of formula VIII in which R 1 denotes a nitro group can be selectively reduced with ammonium sulphide.

The compounds of formula VIII can in turn be prepared by addition of acrylic acid to the correspondingly substituted 2-nitraniline.

The compounds of formula IV can be prepared from arylamino-2-nitrobenzenes of formula IX

where R 2 and R 1 have the meanings given above, by addition of acrylic acid to the amino group, which is obtained by reduction of the nitro group.

The starting material of formula V is obtained by acylation of the correspondingly substituted 2-amino-diarylamino derivatives of formula X protected on nitrogen atom 1 where R^, R^ and R^ have the meanings given above, and Besk means a hydrolytic or also - with exception for compounds in which R 1 means a nitro group - a hydrogenolytically easily removable protecting group, such as a benzyl, acyl or carboxyalkyl group, and subsequent removal of the protecting group.

For the production of the starting compounds with formula VI for method d), the methods described under a-c can be suitably used, if R^ in the thereby formed products with formula I

means hydrogen.

The compounds of formula I - except the 1-formyl compounds -

can, according to its amine-amide structure, form monobasic acid addition salts. Acid components that are suitable for this are e.g. hydrohalic acids, sulfuric acid and methanesulfonic acid.

The new compounds of formula I and their physiologically compatible acid addition salts are valuable drugs with predominantly sedative action, and are also intermediates for their preparation. Especially good are such compounds where R^ means a hydrogen atom, an alkyl or alkenyl group with 1-5 carbon atoms or a formyl residue, R^ means a phenyl or o-chlorophenyl group and R^ means a chlorine or bromine atom or a nitro-, cyano or trifluoromethyl group.

As a dose for the use of the new compounds of the general formula I, 0.5 - 50, preferably 1 - 25 mg as a single dose and 5 - 150 mg as a daily dose are suggested.

The new compounds can be used alone or in combination with other compounds, produced according to the invention, possibly also in combination with other pharmacologically active compounds, such as spasmolytics or psychopharmaceuticals.

The following examples shall serve to further illustrate the invention.

EXAMPLE 1

1-(2'-butenyl)-7-nitro-5-phenyl-1H-2,3>4,5-tetrahydro-1,5-benzodiazepine-4-one

(according to procedure d)

6 g of 7-nitro-5-phenyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepine-4-one are dissolved in 20 ml of dry dimethylformamide and 30 ml of absolute tetrahydrofuran, and 1.5 g of sodium amide is added . Stir at room temperature for 1 hour, add 12 g of crotyl bromide and allow the mixture to react for 2 hours at room temperature and then for 3 hours at 40°C. To work up the reaction mixture, add 5 ml of methanol, neutralize with glacial acetic acid, evaporate in vacuo, dilute with 50 ml of water and shake off with methylene chloride. The oily product is separated from the starting material by ion chromatography on silica gel, using ethyl acetate/cyclohexane = 70/30 as eluent. The product is crystallized with isopropyl ether.

Yield: 4.5 g (63%). Sm.p. 135 -137°C.

EXAMPLE 2

7-bromo-1-formyl-5-phenyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepine-4-one 4 g 7-bromo-5-phenyl-1H-2,3,4 ,5-tetrahydro-1,5-benzodiazepine-4-one is heated in 50 ml of 85% formic acid for 3 hours under reflux cooling. The solution is then diluted with ice water, neutralized with ammonia and shaken out with methylene chloride. After drying with magnesium sulphate, the solution is evaporated and crystallized from ether.

Yield: 3.4 g (78%). Sm.p. 158 - 159°C.

(from acetone/isopropyl ether)

According to these examples, the following compounds are prepared:

EXAMPLE 33

(method a)

7- trifluoromethyl- 5- phenyl- 1H- 2, 3, 4, 5- tetrahydro- 1, 5- benzodiazepine-4- one

15 g of 7-trifluoromethyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepine-

4-one is heated together with 40 ml of bromobenzene, 70 ml of pyridine, 10 g of copper powder, 1 g of copper (I) chloride and 15 g of potassium acetate for 8 hours in an autoclave to 150 - 160°C. The reaction mixture is filtered off with suction over diatomaceous earth, washed with methylene chloride, and the solvent is evaporated in vacuo. The residue is taken up in 100 ml of concentrated ammonia, shaken out with methylene chloride, the solution is dried over magnesium sulphate, the solvent is evaporated in vacuo, and the residue is recrystallized from methylene chloride/isopropyl ether.

Yield: 14.1 g = 71.5% of the theoretical with m.p. 152-153°C.

EXAMPLE 34

(method b)

7-nitro-5-phenyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepine-4-one Dissolve 5 g of N-(2-anilino-4-nitrophenyl)-13-alanine in 55 ml thionyl chloride and heated for 4 hours under reflux. The thionyl chloride is distilled off, the remaining oil is stirred in cold water, ammonia is added and methylene chloride is shaken. The residue that remains after distilling off the solvent is crystallized from acetone.

Yield: 3.1 g 45% of the theoretical with m.p. 241°C.

EXAMPLE 35

(method c)

1- methyl- 7- nitro- 5- phenyl- 1H- 2, 3, 4, 5- tetrahydro- 1, 5- benzodiazepine-4-one 10 g of methylamino-5-nitro-N-(bromopropionyl)-diphenylamine are dissolved in 200 ml of methanol, 0.5 g of sodium iodide and 5 g of potassium bicarbonate are added and heated for 12 hours with stirring and reflux cooling. The reaction mixture is evaporated in vacuo, the residue is taken up in methylene chloride, shaken with water, dried over magnesium sulfate, and the solvent is evaporated in vacuo. The remaining oil is purified over a silica gel column (developing agent cyclohexane/ethyl acetate = 60/40).

Yield: 4.2 g = 53% of the theoretical with m.p. 123-12 5°C.

Claims (1)

Analogous method for the preparation of therapeutically active compounds of the general formula I where R means hydrogen, a linear or branched, saturated or unsaturated alkyl radical with 1-6 carbon atoms, or a formyl group; R? is hydrogen or halogen; and R 3 means a bromine atom or a trifluoromethyl, nitro or cyano group; and their physiologically compatible acid addition salts, characterized in that a) a benzodiazepine of the general formula II where R^ has the above meaning, except formyl, and R^ has the above meaning, is reacted with a compound of the general formula III where R2 has the meaning given above and X means a halogen atom, or b) compounds of the general formula IV where R 1 , R 2 and R 2 have the above meaning, are activated, and the activated intermediates are ring-closed, or c) compounds of the general formula V where R 1 , R 2 and R 2 have the meanings given above, and Y means a vinyl or 2-haloethyl group, is ring-closed by means of basic or acidic condensing agents, or d) compounds of the general formula VI where R 2 and R 1 have the meanings given above, is reacted with an alkylating agent of formula VII where R has the above meaning, excluding hydrogen, and X means an anionic, easily cleavable acid residue, or, for the production of 1-formyl compounds, is heated with formic acid, and the end products obtained according to one of the above methods are optionally transferred to its physiologically acceptable acid addition salts.