CS207620B2 - Method of making the new derivatives of 5,11-dihydro-6h-pyrido-2,3-b 1,4 benzodiazepin-6-on - Google Patents

Description

The invention relates to novel 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one derivatives of the general formula I

and their physiologically tolerable salts with inorganic or organic acids, processes for their preparation and pharmaceutical compositions consisting of one or more of the aforementioned compounds and customary and / or auxiliary substances.

In the above general formula (I), R 1 is C 1 -C 3 alkyl, allyl, 2-methylallyl, 3-methyl-2-butenyl, farnesyl, phytyl, benzyl or 2-phenylethyl,

R 2 represents a hydrogen atom or a methyl group and 5,11-dihydro-BH-pyrido [2,3-b] [1,4] 2 derivatives

A represents a straight or branched alkylene group having 2 to 5 carbon atoms.

In accordance with the invention, these novel compounds can be prepared by 5,11-dihydro-11 - [(1-piperazinyl) acyl] -6H-pyrido [2,3-b] [1,4] benzodiazepine-6- he of formula II

in which

R2 and A, as defined above, are reacted with a halide of formula III

Rl — Hal (ΙΠ) in which

R1 is as defined above and

Hal represents a halogen atom.

The reaction is carried out in an indifferent solvent, preferably an alcohol such as ethanol, n-propanol or isopropanol, an ether such as dioxane or tetrahydrofuran, or a ketone such as acetone at elevated temperature, preferably boiling the reaction mixture. It is recommended to bind the liberating hydrogen halide with a hydrogen halide binding agent such as an alkali metal carbonate, an alkali metal bicarbonate or a tertiary organic amine such as triethylamine, pyridine or dimethylaniline,

The compounds of the formula I obtained can be converted into physiologically tolerated salts by reaction with inorganic or organic acids by methods known per se. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, tartaric acid, furnaric acid, citric acid, maleic acid, succinic acid or oxalic acid.

The starting materials of the formula (II) are possible. prepare by 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one of formula IV

^H (IV) wherein

Ra is as defined above, reacted with a haloacyl halide of formula V ₍ II

Hal — C — A — Hal (V), in which:

A is as defined above and each of Hal and HaV, which may be the same or different, represents a halogen atom such as chlorine, bromine or iodine to form a compound of formula VI

O = C- <4-Hal (Vf) in which

A, Ra and Hal are as defined above.

The reaction is conveniently carried out in an inert solvent, in the presence of a hydrogen halide-binding agent, at elevated temperature, preferably boiling the reaction mixture. As solvents, aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as diethyl ether or dipropyl ether, or preferably cyclic ethers such as dioxane, can be used. Suitable hydrogen halide binding agents are tertiary organic amines, such as triethylamine, Ν, Ν-dimethylaniline and pyridine, or else inorganic bases, such as alkali metal carbonates or alkali metal hydrogen carbonates. Working up of the reaction mixture is carried out in the usual manner and yields are in the range of 90 o / _o theory. The resulting halogenated derivatives of the general formula (VI) are mostly well-crystallizable substances which can be used in the subsequent reaction without further purification, i.e. in the crude state.

Compounds of formula IV are known from the literature (see, for example, DE 1,179,943 and 1,204,680 J.

The starting materials of formula II are most conveniently prepared from compounds of formula VI by reaction with N-benzylpiperazine in a solvent such as dioxane, ether, ethanol, propanol or benzene under reflux. After removal of the solvent, a crystalline precipitate consisting of a compound of formula VII is obtained

in which

Ra is as defined above.

This compound is then dissolved in an alcohol such as methanol or ethanol and hydrogenated in the presence of palladium on carbon at a temperature of 20 to 80 ° C, preferably 50 ° C and under a hydrogen pressure of from 1 to 10 MPa, preferably 5 MPa. The corresponding compound of formula (II) is then isolated from the reaction mixture.

The novel compounds of the formula I and their salts have valuable therapeutic properties. In particular, they act as agents for inhibiting ulceration and for suppressing secretion.

The following compounds were tested for their potency in inhibiting stress-induced ulceration in rats and for their spiasmolytic effect relative to atropine, taking into account acute toxicity:

11- [3- (4-benzyl-1-piperazinyl) propionyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one (A);

5,11-dihydro-11β- [4- (2-phenylethyl) -1-piperazinyl] propionyl} -6 H -pyrido [2,3- b] [1,4] benzodiazepin-6-one (B).

The inhibitory effect on the formation of stress-induced ulcers in rats was determined by the procedure described by K. Takagi and S. Okabe in Jap. Journ. Pharmac. 18, pp. 9-18 (1968). Fed female rats weighing between 220 and 260 g are individually placed in small wire cages, which are then immersed vertically in a water bath at a constant temperature of 23 ° C for 16 hours so that only the head and chest protrude above the water surface. . Roughly 5 to 10 minutes before the start of the experiment, animals are orally administered the test compound. Each substance was tested on 5 animals. Control animals receive in the same way only 1 ml 0.9% saline or 1 ml 1% tylose solution. After 18 hours, the rats were sacrificed by a high dose of chloroethyl and their stomachs were killed

Tested Inhibition of ulceration (in%) in rats after oral dosing, (mg / kg)

25 12.5 cuts, cuts along a large curvature and stretches to a cork wheel. The evaluation of the experiment was carried out as described by Marazzi-Uberti and Turba in Med. Exp., 4, pp. 284-292 (1961), and Takagi and Okabe, supra.

The spasmolytic effect is determined in vitro on guinea pig colon using the assay described by R. Magnus in Pflugers Archiv, 102, 123 (1904). Acetylcholine, as the comparator atropine sulfate, is used to induce convulsions. The spastic drug is added 1 minute before the addition of the spasmolytic, time. the action of the spasmolytic is 1 minute. It is also observed in the experimental rats that side effects of the atropine type, such as inhibition of saliva secretion, are completely absent or significantly less when A and B are administered.

Acute toxicity is determined in fasted white mice weighing 18-20 g after oral administration of the active substances. The observation period is 14 days.

The values are summarized as follows:

Spasmolytic effect of DL 50 in mg / kg (acetylcholine) relative to atopicin = 1 mice after oral administration ·

90 90 58

. B 87 56 34

Legend:

*) at 5 mg / kg one out of 5 animals **) at 1500 mg / kg three out of 6 animals died

The spasmolytic effect of Compounds A and B is considerably lesser than that of atropine sulfate, as are the side effects of the atropine type.

Substances A and B are practically non-toxic.

The invention is illustrated by the following non-limiting Examples.

Example 1 and 1

5,11-Dihydro-11- [3- (4-prenyl-1-piperazinyl) propionyl] -6H-pyrido (2,3-b] [1,4] benzodiazepin-6-one

3.5 g of 5,11-dihydro-11- [3- (1-piperazinyl) propioinyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one, 1.1 g of triethylamine and 2 g of prenylbromide in refluxing n-propanol (50 ml) was heated at reflux for 3 hours. The reaction mixture is evaporated to dryness in vacuo, the residue is stirred with water and the insoluble material is recrystallized from isopropanol.

The product resulting in a yield of 38% of theory melts at 199 to 201 ° C.

1/43> 3000

1/700 -1500 **)

Example 2

11- (3- (4-Benzyl-1-piperazinyl) propionyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-oin

3,51 g of 5,11-dihydro-11- [3- (1-piperazinyl) propionyl] -6H-pyrido [2,3-bj [1,4] benzodiazepin-6-om and 1,6 g of sodium carbonate 2.14 g of benzyl bromide are added in 100 ml of absolute ethanol, the reaction mixture is heated under reflux for 6 hours, then filtered off with suction while hot, the filtrate is evaporated to dryness and the residue is purified by silica gel column chromatography. and the residue was recrystallized from xylene.

The product resulting in a yield of 42% of theory melts at 205-207 ° C.

Chromatographic purification of the crude products was carried out in all examples by silica gel column chromatography using a 68: 15: 15: 2 mixture of chloroform, methanol, cyclohexane and concentrated ammonia as solvent or eluent.

In analogy to Examples 1 and 2, the compounds of Examples 3 to 9 are also summarized in the following table:

Example R 1 R 2 A Melting point (crystallization yield Preparation No. solvent) (% of theory) according to example no.

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The compounds of formula (I) and their salts can be formulated in conventional manner into conventional dosage forms, such as solutions, suppositories, tablets or tea preparations. The unit dose for adults for oral administration is 5 to 50 mg, preferably 10 to 30 mg, daily dose 20 to 100 mg, preferably 30 to 100 mg.

Claims (3)

Subject A process for the preparation of the novel 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one derivatives of the general formula I wherein R1 represents an alkyl group having 1 to 3 atoms carbon, allyl, 2-methyl-allyl, 3-methyl-2-butenyl, farnesyl, phytyl, benzyl or 2-phenylethyl, R2 represents a hydrogen atom or a methyl group and A represents a straight or branched alkylene group having 2 to 5 carbon atoms, and their addition salts with inorganic or organic acids, characterized in that 5,11-dihydro-11 - [(1-piperazinyl) acyl] -6H- pyrido [2,3-b] [1,4] benzodiazepin-6-one of formula (II) wherein: R2 and A, as defined above, are reacted with a halide of formula III Ri — Hal (III) in which · R1 is as defined above and Hal represents a halogen atom, in an indifferent solvent, whereupon the compound of formula (I) thus obtained is converted into an addition salt with an inorganic or organic acid, 2. A process according to claim 1, wherein the reaction is carried out under reflux and the hydrogen halide liberating is removed by means of a hydrogen halide binding agent. 3. The process according to claim 1, wherein the solvents used are alcohols, ketones, ethers or aromatic hydrocarbons and the hydrogen halide binding agents are alkali metal carbonates, alkali metal acid carbonates or tertiary organic amines.