CS208510B1 - 1- [3- (4-Phenylpiperazino) propyl derivative of 7-chloro-5-phenyl-1,3-dihyro-1,4-benzodiazepin-2-one and its salts - Google Patents

Abstract

The invention relates to a new derivative of 7-chloro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one, specifically 7-chloro-5-phenyl-1-/3-(4-phenyl-piperazino)propyl/-1,3-dihydro-1,4-benzodiazepin-2-one of formula I, which in animal tests exhibits centrally depressant, hypnotic and anticonvulsant effects. These properties make it a potential drug for states of restlessness, anxiety, sleep disorders and epilepsy. The embodiment example describes a method for preparing substance I by alkylation of 7-chloro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one with 3-(4-phenyl-piperazino)propyl chloride in a mixture of dimethylformamide and toluene in the presence of sodium hydride.

Description

1- / 3- (4-Phenylpiperazino) propyl 7-chloro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one derivative and its salts

The present invention relates to a novel 7-chloro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one derivative, in particular 7-chloro-5-phenyl-1- [3- (4-phenylpiperazino)]. propyl] -1,3-dihydro-1,4-henzodiazepin-2-one of formula I which exhibits centrally depressing, hypnotic and anticancer activity in animal tests. These properties make it a potential remedy for restlessness, anxiety, sleep disorders and epilepsy. An exemplary embodiment describes a process for preparing Compound I by alkylating 7-chloro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one 3- (4-phenylpiperazino) propyl chloride in a mixture of dimethylformamide and toluene in the presence of a hydride sodium.

208 510

208 S10

The present invention relates to a novel 7-chloro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one derivative, in particular its 1- (3- (4-phenylpiperazino) propyl) derivative of carboxylic acid I,

and pharmaceutically acceptable salts thereof with inorganic or organic acids.

The compound of formula I and its salts have centrally depressant, antispasmodic and hypnotic drug properties. These properties can be demonstrated in tesetches in experimental animals and the hydrochloride of the compound of formula I has been used for this demonstration. This substance is of low toxicity since it does not act orally lethal to the 1 g / kg dose in the acute toxicity test in mice.

From a dose of 200 mg / kg it causes sedation, sleep and loss of righting reflex. Also in rats oral doses up to 1 g / kg are non-lethal. Even at lower doses, the substance causes sedation, decreased locomotor activity and decreased muscle tone. In dogs, an oral dose of 50 mg / kg tame, but not hypnotic. In monkeys (M.mulatta), the 10 mg / kg dose does not affect behavior; a dose of 100 mg / kg reduces locomotor activity 1 h after administration (mostly oral); a dose of 200 mg / kg strongly reduces locomotion and induces ataxia; after 400 mg / kg ataxia lasts for 18 h, after 40 h muscle tone is normal again. To evaluate the hypnotic effect, the loss of righting reflex in mice was monitored; ED50 values ranging from 1.5-4 h range from 200 to 220 mg / kg. The maximum effect is 2-3 h after application; higher doses have an effect lasting longer than 30 h. Phenobarbital is somewhat more effective in this test, but at the dose of 200 mg / kg it is already toxic. In the rotating rod test, the compound of formula I induces ataxia in mice; median effective dose ΕΒ ^ θ = 31 mg / kg (90 min after administration). In assessing the effect on the overall activity of mice according to the Thera test, the ED50 of the compound of formula I is 60 mg / kg (interval 2-4 h after administration); phenobarbital is approximately equally potent and nitrazepam is more effective in 2 hours after administration, but its effect subsides quickly. In the mouse pentetrazole seizure antagonism test, a dose of ΡΒ θ = 7.0 mg / kg is effective for the compound of Formula I; phenobarbital is 2-3 times less effective. When evaluating the effect on corneal electroshock in mice, a dose of ΡΒ ^ θ = 91.5 mg / kg is effective for the compound of formula I. Eo doses of 60 mg / kg do not induce catalepsy in rats.

The compound of formula (I) is considered as a psychotropic and neurotrophic drug with a depressant effect (states of restlessness and pre-brownness, sleep disorders, anxioslta) and an anticonvulsant effect (epilepsy).

The compound of formula I is accessible as described in the exemplary embodiment. Starting from the known 7-Chloro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (LHSternbach et al., J. Org. Chem. 27, 3788, 1962; H. Rohnert et al., GDR Pat. No. 57,126) of formula II, which is alkylated on the nitrogen of the lactam group with 3- (4-phenylpiperazino) propyl chloride (FLBach jr. And

208,510 et al., J. American Chemical and dimethylformamide, 22 2222, 1957). The alkylation is preferably carried out in a toluene mixture

and using sodium hydride as the amide anion forming agent. In a conventional manner, the compound of formula (I) isolated is of a basic nature and neutralization with inorganic and organic acids yields the corresponding salts, partially well crystallizing. With respect to salts with non-toxic acids, they are more suitable than the free base for pharmacological testing even in the preparation of dosage forms and form part of the present invention.

Exemplary embodiment

A mixture of 23.1 g of 7-chloro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (literature cited), 100 ml of dimethylformamide and 2.4 g of sodium hydride is stirred for 25 min and then with stirring over 10 min, a solution of 22.4 g of 3- (4-phenylpiperazino) propyl chloride (literature cited) in 20 ml of toluene is added dropwise and the mixture is refluxed at 120-125 ° C for 1.5 h. After cooling, it is quenched by the slow addition of 200 ml of water and the product is extracted with toluene. The extract was dried with potassium carbonate, filtered with charcoal and the filtrate evaporated under reduced pressure. The remainder is the crude base of roll I; Dissolve in 100 ml of ethanol and acidify with 7 ml of hydrochloric acid. The hydrochloride formed is filtered, washed with ethanol and dried in vacuo. 30 g (69%) of crude product with m.p. 251-257 ° C. The analytically pure product was obtained by crystallization from aqueous ethanol; m.p. Mp 254-257 ° C.

Claims (1)

SUBJECT OF THE INVENTION 1- (3- (4-phenylpiperazino) propyl) 7-chloro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one derivative of the formula I and its pharmaceutically acceptable salts with inorganic or organic acids, preferably hydrochloride. Price: 2,40 Kčs Printed by Moravian Printing Works, plant 12, Leninova 21, Olomouc