GB2046254A

GB2046254A - Benzodiazepines

Info

Publication number: GB2046254A
Application number: GB8007841A
Authority: GB
Original assignee: Synthelabo SA
Current assignee: Synthelabo SA
Priority date: 1979-03-09
Filing date: 1980-03-07
Publication date: 1980-11-12
Also published as: JPS55122770A; FR2450825A1; FR2450825B1; DE3008852A1

Abstract

Benzodiazepine derivatives of formula (I> <IMAGE> (R1 = C4-6-cycloalkyl; R2 = H or halogen) and acid addition salts thereof are anxiolytics.

Description

SPECIFICATION Benzodiazepine derivatives The present invention relates to benzodiazepine derivatives, their preparation and use in therapy, especially for treatment of anxiety.

The invention provides compounds of the general formula (I)

in which R1 is a cycloalkyl radical having 4 to 6 carbon atoms and R2 is a hydrogen or halogen atom, and their pharmaceutically acceptable acid addition salts. Preferably R2 is a chlorine atom.

According to the invention, the compounds (I) can be prepared by reacting a benzodiazepine (II)

R2 as being defined above, with a compound of the formula (Ill)

R, being as defined above. The reaction usually requires sodium hydride, and is preferably carried out in a solvent, such as dimethylformamide (DMF), at a temperature ranging from 50 to 1 50on.

The compounds (11) are known and are described in French Patent 73.43341 of Synthelabo.

The compounds (III) can be obtained in accordance with the following reaction scheme:

(R, is defined above. Et = ethyl) The following Examples illustrate the invention.

The analyses and the IR and NMR spectra confirmed the structure of the compounds.

Example 1 7-Chloro-1 -(2-cyclobutylmethoxy-ethyl)-5-(2- chlorophenyl)-2, 3-dihydro- 1 H- 1 ,4-benzodia- zepine-2-one and its hydrochloride.

0.72 g (0.015 mol) of a 50% strength suspension of sodium hydride and 20 ml of anhydrous DMF are introduced into a 100 ml Erlenmeyer flask. A solution of 4.58 g (0.015 mol) of 5-(2-chlorophenyl)-7-chloro-2,3-dihydro-1 H-1 ,4-benzodiazepine-2-one in 20 ml of anhydrous DMF is introduced slowly. The mixture is then stirred until the evolution of hydrogen has ended. A solution of 6.1 g (0.021 mol) of 1 -(para-toluenesulphonyloxy)- 2-(cyclobutylmethoxy)-ethane in 20 ml of DMF is then introduced slowly. The mixture is then heated for 3 hours at 60"C and left to stand overnight and 1 litre of water is poured in. Extraction is carried out with 3 times 500 ml of chloroform and the chloroform phase is washed with water, dried over MgSO4 and evaporated to dryness.

This yields an oil which is purified by pass ing it through a silica column, using a 95/5 chloroform/acetone mixture as the eluent.

The valuable fractions are collected and evaporated to dryness, the residue is taken up in ether, the mixture is filtered through paper and the hydrochloride is precipitated by add ing a solution of hydrogen chloride in ether.

The mixture if evaporated to dryness. The residue is taken up in ether and the mixture is filtered through a frit. This yields the crude hydrochloride. It is recrystallised from a meth anol/ether mixture with vegetable charcoal treatment.

Melting point = 177'C.

Example 2 7-Chloro-1 -(2-cyclopentylmethoxy-ethyl)-5- (2-chlorophenyl)-2, 3-dihydro-1 H- 1 ,4-benzodia- zepine-2-one and its hydrochloride.

The procedure followed is the same as in Example 1, 4.58 g of the starting compound (II) being reacted with 6.5 of 1-(para-toluenesu I phonyloxy)-2-(cyclopentyl-methoxy)-ethane in the presence of 0.72 g of NaH. After recrystallisation from a methanol/ether mixture, the hydrochloride of the compound, which melts at 165-1 66 C, is obtained.

The compounds of the invention were subjected to pharmacological experiments which demonstrated their anxiolytic properties.

The compounds have a low toxicity.

The anxiolytic activity of the compounds is demonstrated using the "Eating test" (reference: R. J. Stephens, Brit. J. Pharmacol.

1973, 49, 146).

At a dose of 3 mg/kg, administered orally, the % increase in the food intake is 50 to 90% for the compounds of the invention.

These results show that the compounds of the invention can be used for the treatment of the various states of anxiety.

The invention consequently includes all pharmaceutical compositions containing a compound of the present invention, in association with an excipient. They are preferably formulated with an excipient suitable for oral or parenteral administration.

The preferred methods of administration are oral and parenteral. The daily dosage will usually be from 20 to 200 mg, administered orally.

Claims

1. Benzodiazepine derivatives having the general formula (I)

in which R, is a cycloalkyl radical having 4 to 6 carbon atoms and R2 is a hydrogen or halogen atom, and their pharmaceutically ac ceptable acid addition salts.

2. 7-Chloro-1 -(2-cyclobutylmethoxy-ethyl)- 5-(2-chlorophenyl)-2,3-dihydro-1 H-1 ,4-benzo- diazepine-2-one and its hydrochloride.

3. 7-chloro- 1 -(2-cyclopentylmethoxy-ethyl) 5-(2-chlorophenyl)-2, 3-dihydro-1 H-1.4-benzo- diazepine-2-one and its hydrochloride.

4. A process for the preparation of a com pound claimed in Claim 1, which process comprises reacting a bezodiazepine of general formula (II)

R2 being as defined in Claim 1, with a compound of the formula (III)

R, being as defined in Claim 1, and when the product is obtained in free base form, if desired converting the free base into a pharmaceutically acceptable acid addition salt.

5. A process according to Claim 4, carried out in sodium hydride and at a temperature of from 50 to 1 50"C.

6. A process according to Claim 4 substantially as described in Example 1 or 2.

7. A benzodiazepine derivative claimed in Claim 1 when obtained by a process claimed in Claim 4, 5 or 6.

8. Benzodiazepine derivatives claimed in Claim 1, 2, 3 or 7 for use in therapy.

9. A pharmaceutical composition comprising a benzodiazepine derivative claimed in Claim 1, 2, 3 or 7 in association with a pharmaceutically acceptable excipient.