GB2095674A

GB2095674A - Imidazobenzodiazepines

Info

Publication number: GB2095674A
Application number: GB8208933A
Authority: GB
Original assignee: Roussel Uclaf SA
Current assignee: Sanofi Aventis France
Priority date: 1981-03-27
Filing date: 1982-03-26
Publication date: 1982-10-06
Also published as: PT74669B; DE3211243C2; FR2502621A1; MA19416A1; ES8302712A1; AU549222B2; DK153404B; IT8248036A0; FI71152C; ES509284A0; CH651565A5; ZA821141B; CA1175823A; DE3211243A1; FI821058L; HU185092B; FR2502621B1; NL8201208A; SE448731B; DK138682A

Abstract

Compounds of the general formula (I), <IMAGE> (in which R1 represents a hydrogen atom, a halogen atom, a nitro radical or a trifluoromethyl radical, R2 represents a hydrogen atom or a halogen atom and R3 and R4, together with the nitrogen atom to which they are attached, represent a 4-alkyl- piperazin-1-yl, 4-cycloalkyl-alkyl- piperazin-1-yl, 4-phenyl-piperazin-1-yl or piperidino radical) as well as their addition salts with mineral or organic acids, are prepared by reacting a compound of formula (II), <IMAGE> with an amine of formula III, <IMAGE> (in which alk and alk' represent alkyl radicals containing from 1 to 3 carbon atoms) in the presence of an organic solvent followed, if desired by salt formation.

Description

SPECIFICATION New process for preparing imidazobenzodiazepines as well as their salts The present invention relates to a new process for preparing certain imidazobenzodiazepines and their addition salts with acids.

In French Patent Specification No. 2,300,569 there are described compounds of general formula (1),

in which R1 represents a hydrogen atom, a halogen atom, a nitro radical or a trifluoromethyl radical, R2 represents a hydrogen atom or a halogen atom and R3 and R4, together with the nitrogen atom to which they are attached, represent a 4-alkyl-piperazin-1 -yl, 4-cycloalkyl a Ikyl-piperazin-l -yl, 4-phenyl-piperazin- 1 -yl or piperidino radical, as well as their addition salts with mineral and organic acids.

In the above formula (I): when R1 represents a halogen atom, this is preferably a fluorine, chlorine or bromine atom and, more particularly, a chlorine atom; when R2 represents a halogen atom, this is preferably a fluorine, chlorine or bromine atom and, more particularly, a fluorine or chlorine atom; in addition, when R2 is a halogen atom, it is preferably in the ortho position; when R3 and R4, together with the nitrogen atom to which they are attached, represent a 4 alkyl-piperazin-1-yl radical, this is preferably a 4 methyl-piperazin-1 -yl, 4-ethyl-piperazin-1 -yl or 4propyl-piperazin-1-yl radical and, more particularly, a 4-methyl-piperazin-1-yl radical and when R3 and R4, together with the nitrogen atom to which they are attached, represent a 4 cycloalkyl-alkyl-piperazin-1 -yl radical, the cycloalkyl radical is preferably one containing from 3 to 6 carbon atoms, such as a cyclopropyl, cyclobutyl or cyclopentyl radical.Among the 4 cycloalkyl-alkyl-piperazine-1-yl radicals there may be considered, more particularly, the 4 cyclopropyl-methyl-piperazin-1-yl radical.

The addition salts with mineral or organic acids can be, for example, the salts formed with hydrochloric, hydrobromic, hydriodic, nitric, sulphuric, phosphoric, propionic, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic and aspartic acids; alkanesulphonic acids such as e.g. methane sulphonic acid; and arylsulphonic acids such as e.g. benzene-sulphonic acid.

As mentioned in French Patent Specification No. 2,300,569, the compounds of general formula (I) and their salts, possess interesting sedative, hypnotic, anxiolytic, tranquillizing, anticonvulsive and myorelaxant properties.

We have now discovered a new process which enables the compounds of formula (I) and their acid addition salts to be prepared with good yields and in a number of stages which is less than that required in the processes described in the aforementioned French patent.

According to the present invention, therefore, we provide a process for the preparation of compounds of general formula (I) as hereinbefore defined as well as their addition salts with mineral or organic acids, which comprises reacting a compound of formula (II),

(in which R1 and R2 are as hereinbefore defined), with an amine of formula (ill),

(in which alk and alk' which may be the same or different each represents an alkyl radical containing from 1 to 3 carbon atoms and R3 and R4 are as hereinbefore defined), in the presence of an organic solvent followed, if desired, by conversion of the compound of formula (I) thus obtained into an acid addition salt thereof.

Under preferred conditions for carrying out the process of the invention, the reaction of the compound of formula (II) with the compound of formula (III) is carried out in the presence of an organic solvent such as methylene chloride. Also preferred is the presence of an amine such as e.g.

triethylamine.

The addition salts with acids of the compounds of formula (I) can be prepared in conventional manner, preferably by reacting the compound of formula (I) with a stoichiometric amount of the mineral or organic acid. Such salt formation is preferably carried out in an organic solvent such as e.g. an alcohol, for example methanol or ethanol, or an alkyl halide, for example methylene chloride or mixtures thereof.

As indicated in French Patent Specification No.

2,300,569, the compounds of formula (II) can be prepared starting with a compound of formula (lav),

(in which R1 and R2 are as hereinbefore defined), by reaction with glycine, to obtain a compound of formula (V)

(in which R1 and R2 are as hereinbefore defined), which may then be dehydrated to obtain the desired compound of formula (II). The dehydration can advantageously be carried out by means of a carbodiimide such as dicyclohexylcarbodiimide.

The compounds of formula (III), when they are not known, can be prepared by reacting a compound of formula (VI),

(in which R3 and R4 are as hereinbefore defined), with an appropriate alkyiketal of dimethylformamide. An example of such a preparation appears in the experimental part.

There will now be given, not by way of limitation, an example of carrying out the invention.

Example 8-Nitro-1 ,2-dihydro-2-(N-methyl-piperazin-1 yl)-methylene-6-(o-chlorophenyl) 1 H,4Himidazo [1,2-a] [1 ,4]benzodiazepin-1-one.

Stage A: 2-carboxymethylamino-7-nitro-5-(ochlorophenyl) 3H-[1 .4]-benzodiazepine.

Into 3 litres of demineralized water are introduced 1.360 kg of glycine followed, gradually, by 1.450 kg of sodium bicarbonate.

The resultant mixture is agitated for 30 minutes at ambient temperature and then 1 5 litres of ethanol are introduced therein followed, over about 5 minutes, by 3 kg of 7-nitro-1 ,3-dihydro-5-(o- chlorophenyl)-2H-[1 ,4]-benzodiazepine-2-thione.

The mixture obtained is taken to reflux for 1 hour, 30 minutes and then distilled under reduced pressure. 1 5 litres of demineralised water are then added in 2 portions followed by 7.5 litres of methylene chloride. The phases are subsequently separated.

The aqueous phase is reextracted with 3x6 litres of methylene chloride then the chloromethylenic phases are washed with water and all the aqueous phases are combined. 18 litres of methylene chloride are added thereto followed at 0 to +5 CC, by 1.3 litres of 220 B6 hydrochloric acid. A chloromethylenic solution of 2-carboxy-methylamino-7-nitro-5-(o chlorophenyl)-3H-[1 ,4]-benzodiazepine is obtained and used directly in the following stage.

Stage B: 8-nitro-1 ,2-dihydro-6-(o- chlorophenyl)-1 H,4H-imidazo[1,2-a] [1 .4]benzodiazepin-l -one.

To the chloromethylenic solution of 2-carboxymethylamino 7-nitro 5-(o-chlorophenyl) 3H-[1,4]- benzodiazepine obtained above is added, at +50C over about 2 minutes, a solution of 1.865 kg of dicyclohexyl-carbodiimide in 3 litres of methylene chloride. The mixture obtained is agitated for 30 minutes, left to stand for one night then separated. The resultant product is washed twice with 3 litres of methylene chloride and the chloromethylenic solution of 8-nitro-1 ,2-dihydro- 6-(o-chlorophenyl)-1 H,4H-imidazo[1 2-a] [1 ,4]benzodiazepin-l -one thus obtained is used in the following stage.

Stage C: 8-nitro 1,2-dihydro 2-(Nmethylpiperazin-1 -yl)-methylene-6-(ochlorophenyl)-1 H,4H-imidazo[1,2-a] [1,4]- benzodiazepin-1 -one.

To the chloromethylenic solution of 8-nitro 1 ,2-dihydro-6-(o-chlorophenyl)-1 H,4H imidazo[1,2-a] [1,4]-benzodiazepin-1-one obtained above are added, over about 5 minutes and at ambient temperature, 650 g of triethylamine followed by 2.4 kg of a solution of the dimethylketal of N-formyl-N-methylpiperazine (prepared as described hereinafter).

The resultant mixture is agitated for 1 hour, 30 minutes and then concentrated to dryness under reduced pressure. 6 litres of ethanol are added to the residue and the mixture obtained is distilled, the volume being kept constant by the addition of ethanol, until vapours are obtained at 780C. The mixture is then cooled to 0 to +2 CC, agitated for 2 hours and separated. The recovered product is washed with ethanol. 4.260 kg of crude product are collected and purified by treating with active charcoal then with ethanol.

Finally 3.362 kg of 8-nitro-1 ,2-dihydro-2-(N- methyl-piperazin-yl)-methylene-6-(o chlorophenyl)-H,4H-imidazo-[l ,2-a] [1 ,4]benzodiazepin-1 -one are collected.

The product obtained is identical to that described in Example 30 of the aforementioned French Patent Specification No.2,300,569.

The solution of the dimethylketal of N-formyl N-methyl piperazine can be prepared as follows: Into 2 kg of the dimethylketal of dimethylformamide are introduced 3.3 kg of Nmethyl piperazine and the mixture obtained is taken to reflux for 1 5 hours. The uncombined Nmethyl-piperazine is subsequently distilled off under reduced pressure and the remainder is agitated for 1 hour under reduced pressure at 1 1 5--1200C then cooled to 200C. 3.920 kg of a brown solution of the dimethyl-ketal of N-formyl N-methyl piperazine are obtained.

Claims

1. A process for the preparation of compounds of general formula (I),

(in which R, represents a hydrogen atom, a halogen atom, a nitro radical or a trifluoromethyl radical, R2 represents a hydrogen atom or a halogen atom and R3 and R4, together with the nitrogen atom to which they are attached, represent a 4-alkyl-piperazin-1-yl, 4-cycloalkyl- alkyl-piperazin- -yl, -yl,4-phenyl-piperazin- 1 -yl or piperidino radical) as well as their addition salts with mineral or organic acids, which comprises reacting a compound of formula (II),

(in which R, and R2 are as defined above), with an amine of formula III,

(in which alk and alk' which may be the same or different each represents an alkyl radical containing from 1 to 3 carbon atoms and R3 and R4 are as defined above), in the presence of an organic solvent, followed, if desired, by conversion of the compound of formula (I) thus obtained into an acid addition salt thereof.

2. A process as claimed in claim 1 wherein the organic solvent is methylene chloride.

3. A process as claimed in any preceding claim wherein the reaction is carried out in the presence of an amine.

4. A process as claimed in claim 3 wherein the amine is triethylamine.

5. A process as claimed in claim 1 substantially as herein described.

6. A process for the preparation of compounds of general formula (I) as defined in claim 1 substantially as herein described in the Example.

7. Compounds of general formula (I) as defined in claim 1 whenever prepared by a process as claimed in any one of claims 1 to 6.