DE2150091B2 - 1,3-DIHYDRO-5-PHENYL-2H-1,4-BENZODIAZEPINE-2-ONE DERIVATIVES - Google Patents

Description

in which Ri and R _{2 are} fluorine or chlorine atoms and R3 is a hydrogen atom, a methyl or ethyl group, and their salts with acids.

2. Medicament, consisting of a compound according to claim 1 and customary carriers and / or diluents and / or solids.

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

The salts can be from inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, Sulfuric acid, phosphoric acid, nitric acid, acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, Citric acid, camphor sulfonic acid, ethanesulfonic acid, Derive ascorbic acid or lactic acid.

Compounds of the general formula I can be prepared in a manner known per se, for example by reaction of the corresponding benzodiazepine unsubstituted in the 1-position with a compound of the general Formula II

CH ₂ -CH-CH ₂ -OR ₃
O

(II)

50

be prepared, in which R _{3 has} the preceding meaning. The reaction is carried out in the presence of a base, or the benzodiazepine unsubstituted in the 1-position is reacted with a basic metal compound and the metal salt obtained is then condensed with the compound of the general formula II. Examples of basic compounds that can be used are sodium hydroxide, potassium hydroxide, Sodium amide, potassium amide, lithium amide, lithium hydride, sodium hydride, butyllithium, phenyllithium, Natfiummethylät, Nutriümäthylat UHd ₁ KaliunHert-butylät The reaction is generally carried out in a solvent or solvent mixture. Examples of solvents that can be used are toluene, xylene, benzene, dimethylformamide, dimethylsulfoxyl methanol , Isopropanol and tert-butanol and mixtures thereof.

25 The method according to the preceding herstellbarat benzodiazepines of general formula I can be prepared from. separated from the reaction mixture by extraction with or without prior neutralization. Thereafter

the extract is evaporated to dryness The product can by recrystallization from a suitable solvent such as methylene chloride, isopropanol or isopropyl ether or their equipment can be further cleaned according to the usual procedures.

, o The salt formation takes place λ in the usual way shower Reaction with an inorganic or organic acid.

The benzodiazepines of the general formula I and their salts with acids are valuable medicinal substances. she

These are particularly valuable muscle relaxants emerges from the following pharmacological tests:

1. Connections examined

l- ^ O'-DihydroxypropylJ-S-io-fluorophenyl) -

7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one l- (JJ-Hydroxy-y-methoxypropyl) -5- (o-fluoro-

phenyl) -7-chloro-13-dihydro-2H-1,4-benzodiazepin-2-one,

2-methyl-2 · propyl-13-propenedioldicarbamate (Meprobamat)

7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide (Chlordiazepoxide)

:>. Experimental methods a) Torsion bar test

This test records the muscle relaxation and the influence on the ability to coordinate movements.

A horizontally arranged cylindrical rod with a diameter of 3 cm is used, the is rotated about its longitudinal axis at 5 rpm. Each test group consists of 10 male albino mice with a body weight of 20 ± 2g. Only those animals are selected for the experiment which can hold on to the rotating rod before the start of the experiment. The EDso, that's the dose at which 50% of the animals can no longer hold on to the rotating rod, is calculated by probit analysis

b) Acute toxicity

The acute toxicity is assessed on groups of 10 male albino mice each with a body weight of 20 ± 2g in 3 different doses determined The LDm is the dose of a compound that is 50% of the Test animals within 10 days of oral administration kills

The results are summarized in the table. 55

60

Test connection Torsion bar test Acute EDw toxicity (p. o.) LDso (p. O.) mg / kg mg / kg Connection »A« 2.8 > 1500 Connection "B" 4.4 > 1500 2-methyl'2-propyl- 125 980 1,3-propendiol- ^{1 f} carbamate Chlordiazepoxide 24 960 -

The benzodiazepines or their salts in general Formula I can be used parenterally or orally in usual ^

Administration fora. for example as tablets, coated tablets, capsules, suspensions, solutions and elixirs.
The example illustrates the invention.

example

A solution of 5 g of 5- (o-fluorophenyl) -7-chloro-13-dihydro-2H-1,4-benzodiazepin-2-one in 40 ml of dimethylformamide is added to a suspension of 13 g of sodium methylate ic 40 ml of dimethylformamide. The mixture is heated to 50 to 60 ^° C. for one hour. The mixture is then treated with a solution of 4 g of 2-hydroxy-3-methoxypropyl chloride in 20 ml of dimethylformamide and heated to 120 ° C. for 9 hours and stirred. After cooling, the mixture is poured into ice water and extracted with diethyl ether combined ether extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The residue is dissolved in chloroform and chromatographed on silica gel. A mixture of equal parts by volume of chloroform and ethyl acetate is used as the mobile phase

φ
2-one as a colorless viscous oil;

v ^ ^taöl 3450cm- ¹ (-OH), 1660cm- ¹ (> N-CO-).

ίο In a similar way, the following connections are obtained:

l - (^ - Hydroxy-y-ethoxypropyl) -5- (o-fluorophenyl) - / - chloro-l ^ -dihydro ^ H-l ^ benzodiazepin ^ -one.oil;

ν JS ,? ¹ * ¹⁶¹ 3450cm ^-1 (-OH), 1660cm ^-1 (> N-CO-).

l - (/ ?, y-dihydroxypropyl} -5- (o-fluorophenyl) -7-chloro, 3-draydro-2H-1,4ien-todiazepin-2-one,
123 to l25 ° C

Claims (1)

Patent claims: 1. 1. ißDihydroSphenyla
2-ones of the general formula I. OH
CH ₂ -CH-CH ₂ -OR ₃