DE1795771C3 - 1 -Cyclopropylmethyl-S- (o-halophenyl) -7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-ones - Google Patents

Description

CH ₂ -NH ₂

in which Rt and X have the same meaning as in claim 1, or its salt in acidic Medium and in a solvent with chromium trioxide or ozone in at least stoichiometric Treated crowd.

3. The method according to claim 2, characterized in that the oxidation with chromium trioxide in

2 to 3 times the stoichiometric amount in the presence of acetic acid at room temperature performs.

4. Medicines with neuroleptic effects, characterized by a content 'of one A compound according to claim 1 as an active ingredient.

The invention relates to the subject matter characterized in the claims.

The salts of the compounds of the general formula I are derived from inorganic or organic acids rule. Examples are hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, furmar acid. Succinic acid. Formic acid and acetic acid.

In general , the process of the invention is carried out at room temperature, but sometimes higher or lower operating temperatures give better results. Examples of solvents that can be used are water, acetone, carbon tetrachloride. Acetic acid and sulfuric acid. When carrying out the oxidation with chromium trioxide in the presence of acetic acid, the chromium trioxide is preferably used in 2 to 3 times the stoichiometric amount and the reaction is carried out at room temperature. The 2-amine methylindole compound or its salt is dissolved or suspended in a solvent and the oxidizing agent is added with stirring. The reaction is generally complete within 24 hours. The benzodiazepine formed can either be extracted from the reaction mixture, which is optionally neutralized, or the reaction mixture is evaporated to dryness and the product is isolated from the residue. The product can be further purified by recrystallization from solvents such as ethanol or isopropanol.

The 2-aminomethylindoles of general formula II used in the process of the invention are new compounds that can be prepared in a manner known per se.

6s The compounds of general formula 1 are valuable psychotropic drugs with neuroleptic (anxiety-suppressing) effects. This has been shown by pharmacological studies.

Connections examined:
Connection A:

1-Cydopropytaetoyl-7-chloro-5- (o-fluorophenyI) -1,3-dihydro-2H-1,4-benzodiazepin-2-one

Connection B:

1-Cydopropylmethyl ^ -chlor-S-io-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one

Comparison compounds:
Diazepam:

1-methyl ^ -chloro-S-phenyl-U-dihydro ^ H-1,4-benzodiazepin-2-one

Prazepaxn:

l-Cyclopropylmethyl-7-chloro-5-phenyl-13-dihydro-2H-1,4-benzodiazepin-2-one.

The pharmacological activity of the compounds of the invention when administered orally to mice is shown from Table I.

Table I.

connection

Electric shock test ')
ED »

(mg / kg)

Tensile test *) EDso

(mg / kg)

Anti-pentamethylene LDso tetrazole effect ³ ) EDso (mg / kg) (mg / kg) 0.2 980 0.5 > 3000 0.7 940 1.8 910

A. 0.9 B. 2.0 Diazepam 5.0 Prazepam 6.2

6 13

2.3 11

According to R.ETedeschi and colleagues, J. Pharmacol, exp. Therap, Vol. 122 (1958). 85 A. ) After S. Courvoisier, Psychotropic Drugs, Elsevier Publ. Co, Amsterdam - London. 1957, p. 373 ff. 3) According to E A. S w i η y a r d, J Am. Pharm. Assoc. (Sci. Ed.), 38 (1949). 201

The following conclusions can be drawn from the values given in Table 1:

It is known that influencing aggression (Electric shock test) and the anticonvulsant effect (anti-pentamethylene tetrazole effect) closely related related to clinical anti-anxiety effects. In this regard, those according to the invention Compounds A and B are superior to the known comparison compounds diazepam and prazepam.

In the case of anxiety-suppressing drugs, the muscle-relaxing effect (tensile test) is an undesirable one Side effect. Accordingly, anti-anxiety drugs should have the highest possible ED »at Exhibit tensile test. In this regard, compounds A and B have less activity than Diazepam. Compared to prazepan, compound A has a stronger and compound B has one weaker effect.

The anti-anxiety effect of compound A is 6 to 9 times greater than that of prazepam. the the superior effect of compound A over prazepam is evident when comparing the Ratio of EDso in the tensile test to EDso in the electric shock test or the anti-pentamethylene tetrazole test.

The toxicity of compound A is practically the same as that of diazepam and prazepam, while the Compound B has a much lower toxicity.

The examples illustrate the invention.

B is ρ ic 1 1 _{& 5}

A solution of 3 g of chromium trioxide in 3 ml of water is added dropwise to a suspension of 3.6 g of l-cyclopropylmethyl-2-aminomethyl-3- (o-fluorophenyl) -5-chloroindole hydrochloride in 36 ml of acetic acid at a temperature below 25 ⁰ C given. The mixture is then stirred at room temperature overnight, then poured into ice water, made alkaline with aqueous ammonia solution and extracted with methylene chloride. The methylene chloride extract is dried over sodium sulfate, the solvent is distilled off under reduced pressure and the residue is purified by chromatography. Yield 2.43 g (72% of theory) 1-cyclopropylmethyl-S-io-fluorophenyl) -? - chloro-l _r 3-dihydro- 2H-1,4-benzodiazepin-2-one from m.p. 86.0 to 87.5 ° C. ν ** 3080.1670 cm- '.

Example 2

A solution of 1.6 g of chromium trioxide in 1.6 ml of water is added dropwise to a suspension of 2.0 g of 1-cyclopropylmethyl-2-aminomethyl-3- (o-fluorophenyl) -5-chloroindole hydrochloride in 10 ml of acetic acid Given room temperature. The mixture is then stirred overnight at room temperature and then a 30 percent strength aqueous sodium hydroxide solution is added dropwise to a pH of the reaction mixture of 5. The mixture is then extracted with carbon tetrachloride. The organic phase is washed with water and dried over sodium sulfate. The solvent is then distilled off under reduced pressure. 2.2 g of an oily residue are obtained, from which a crystalline precipitate is precipitated after the addition of a solution of hydrogen chloride in diethyl ether. The crystals are filtered off and washed with diethyl ether. Yield 1.55 g (75% of theory) of l-cyclopropylmethyl-5- (ofluorophenyl) -7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one hydrochloride, melting point 203 up to 205 ⁰ C,

Preparation of the examples 1 and 2
used starting compounds

(a) 5-chloro-1-cyclopropylr-diethyl-2-cyano-

3- (o-fluorophenyl) indole

In a mixture of 52 g of anhydrous dimethylformamide and 250 g of anhydrous toluene, 26 g of 5-chloro-2-cyano-3- (o-nuophenyl) indole are dissolved in this solution 3.8 g of 67 percent sodium hydride are added at room temperature. After stirring for 1 hour, the mixture is stirred the mixture with 143 g of cyclopropylmethyl bromide added and then heated under reflux for 2 hours. After cooling, the mixture is ir. Poured ice water and extracted with toluene. The organic phase is washed with water and washed over Sodium sulfate dried. The solvent is distilled off under reduced pressure. After recrystallization of the oily residue from isopropyl alcohol, 26.2 g (84.0% of theory) of 5-chloro-1-cyclopropylmethyl-2-cyano-3- (o-fluorophenyl) indole are obtained in the form of colorless prisms from 153 to 155 ° C.

(b) 5-chloro-1-cyclopropylmethyl-2-aminomethyl-3- (o-fluorophenyl) indole hydrochloride

A suspension of 0.88 g of lithium aluminum hydride in 50 ml of anhydrous diethyl ether is added at room temperature with stirring with 5.0 g of 5-chloro-1-cyclopropylmethyl-2-cyano-3- (o-fluorophenyl) indole. The resulting mixture is refluxed for 2 hours. It is then cooled with ice water and water is added dropwise. The ether phase is separated off and 3.2 g of concentrated hydrochloric acid are added dropwise. The mixture is then stirred for 3 hours while cooling. The precipitated crystals are filtered off and washed with diethyl ether. (Th 81.1% d..) To obtain 4.56 g of 5-chloro-1-cyclopropylmethyl ^ -aminomethyl-S-fo-fluorphenylJ-indole hydrochloride, mp 235-240 ⁰ C.

Example 3

A solution of 1.2 g of chromium trioxide in 1 ml of water is added dropwise to a at room temperature Suspension of 1.2 g of l-cycloptopylmethyl-2-aminomethyl-S-io-chlorophenylJ-S-chloroindole hydrochloride given in 20 ml of acetic acid. The mixture is then stirred overnight at room temperature and then a 30 percent aqueous solution of sodium hydroxide dropwise to bring the mixture to pH of 5 added. The mixture is then extracted with carbon tetrachloride. The organic phase is washed with water and dried over sodium sulfate. The solvent is reduced under reduced pressure Distilled off under pressure The oily residue is made from a mixture of methanol and isopropyl ether crystallized and the crystals are filtered off. 0.84 g (75% ITh.) of l-Cyclopropyünethyl-5- (o-

chlorophenyl) -7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one, mp 153.5 to 154.5 ⁰ C

Preparation of those used in Example 3
Output compound

(a) 5-Chloro-1-cyclopropylmethyl-2-cyano-3- (o-chlorophenyl) indole

3.0 g of 5-chloro-2-cyano-3- (o-chlorophenyl) indole are dissolved in a mixture of 35 ml of anhydrous dimethylformamide and 10 ml of anhydrous toluene. 0.48 g of 6Z5 per cent sodium hydride are added to this solution at room temperature After stirring for 1 hour, 145 g of cyciopropylmethyl bromide are added, and the reaction mixture is heated under reflux for 2 hours. After cooling, the mixture is poured into ice water and extracted with toluene. The organic phase is washed with water and dried over sodium sulfate Distilled off under pressure The oily residue is crystallized from benzene. 3.55 g (99.6% of theory) of 5-chloro-1-cyclopropylmethyl-2-cyano-3- (o-chlorophenyl) indole are obtained in the form of colorless ones Prisms from 160 to 161 ° C

(b) 5-chloro-1-cyclopropylmethyl-2-aminomethyl-3- (o-chlorophenyl) indole hydrochloride

A suspension of 0.45 g of lithium aluminum hydride in 40 ml of anhydrous diethyl ether is added at room temperature with stirring with 2.0 g of 5-chloro-1-cyclopropylmethyl-2-cyano-3- (o-chlorophenyl) indole Refluxed for hours. It is then cooled with ice water and water is added dropwise. The ether phase is separated off and concentrated hydrochloric acid is added dropwise. The resulting mixture is stirred for 3 hours with cooling. The precipitated crystals are filtered off and washed with diethyl ether. 1.74 g (78% of theory) of 5-chloro-1-cyclopropylmethyl-2-aminomethyl-3- (o-chlorophenyl) indole hydrochloride are obtained
from 206 to 209 ° C.

Claims (1)

Patent claims: 1. l-Cydopropylmethyl-S-io-halogenphenyD-J-chlor-U-dihydro ^ H-l ^ faenzodiazepin ^ -one of the general formula! in the Rt a cyclopropylmethyl group and X a Means fluorine or chlorine atom, and their salts with acids. 2. Process for making the compounds the general cn formula 1 according to claim 1, characterized characterized in that one is a 2-aminomethylindole of the general formula II