CS207618B2 - Method of making the new derivatives of 5,11-dihydro-6h-pyrido 2,3-b 1,4 benzodiazepin-6-on - Google Patents

Description

The present invention relates to novel 5,11-dihydro-OH-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 their use as medicaments.

In the above general formula (I), R1 is a straight or branched alkyl group having 3 to 12 carbon atoms, an unsaturated, straight or branched aliphatic hydrocarbon radical having 3 to 20 carbon atoms and 1 to 3 double bonds and / or a single triple bond, phenylalkyl. C 2 -C 4 straight or branched alkylene, methylenedioxybenzyl, chlorobenzyl, 5- or 3-indanylmethyl, C 2 -C 4 alkenylene, C 5 -C 7 cycloalkyl, cycloalkylmethyl a (C 3 -C 10) cycloalkyl ring which may optionally be further substituted by a methyl group in the cycloalkyl ring, or a morpholino- or 4-methylpiperazinoalkyl group having 2 or 3 carbon atoms in the alkylene moiety,

R 2 represents a hydrogen atom or a methyl group, and each of R 3 and R 1, which may be the same or different, represents a hydrogen atom or a methyl group, and when R 5 and / or R 4 represents a methyl group, R 1 may also be methyl or ethyl group.

By straight or branched alkyl groups R 1 is, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, neopentyl, isopentyl, n-pentyl, 1-methylbutyl, 3-methylbutyl , n-hexyl, 4-methylpentyl, 2-ethylbutyl, 3,3-dimethylbutyl, heptyl, octyl, no207818 nyl, decyl, undecyl or dodecyl. Unsaturated straight or branched aliphatic hydrocarbon radicals within the meaning of this symbol may be, for example, 2-methylallyl, allyl, 2-butenyl, 1-methylallyl, 4-pentenyl, 3-methyl-2-butenyl, n-hex-5 -enyl, n-hept-6-enyl, farnesyl, neryl, geranyl, citronellyl, phytyl or pnopargyl. Suitable R-phenylalkyl groups include, for example, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, phenylisopropyl or 4-phenylbutyl, and phenylalkenyl groups include, for example, cinnamyl, phenylethylene, 4-phenyl-2-butenyl or -3-butenyl, or isomeric groups having a phenyl moiety attached at the 2 or * 3 position, such as cycloalkyl groups are cyclopentyl, cyclohexyl or cycloheptyl and, for example, adamiantyl, cycloheptyl cyclohexyl-, cyclopentyl-, cyclo-butyl-, cyclopropyl or bicyclo [2.2.1] hept-2-ylmethyl.

The novel compounds of the formula I can be obtained according to the invention by 5,11-dihydrci-11 - [(1-piperazinyl) acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepine-6- he of formula II

Rif (ID 'in which

R 2, R 1 and R 4 are as defined above, reacted with a halide of formula III

R 1 -Hal, (III) wherein

R 1 is as defined above, and

Hal represents a halogen atom.

This 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 at the boiling point of the solvent used. It is recommended to bind the liberating hydrogen halide with a hydrogen halide binding agent, for example 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 treatment with inorganic or organic acids in a known manner. Suitable acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, tartaric acid, fum, aric citric acid, butyric acid, succinic acid or oxalic acid.

The starting compounds of formula (II) may be prepared by reacting 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one of formula (IV)

IV (IV) in which

R2 is as defined above, reacted with a haloacetyl halide of formula (V '), (II)

Hal — C — CH2 — Hal, (V) wherein each of Hal and Hal ¹ , which may be the same or different, represents a chlorine, bromine or iodine atom to form a compound of formula VI

O = C-CH £ poured (VI) in which

R 2 and Hal are as defined above. This reaction is preferably carried out in an inert solvent in the presence of a hydrogen halide binding agent, at an elevated temperature, preferably at the boiling point of the solvent used. Solvents which may be used are aromatic hydrocarbons, for example benzene, toluene or xylene, ethers such as diethyl ether or dipropyl ether, or preferably cyclic ethers such as dioxane. Suitable hydrogen halide binding agents are tertiary organic bases such as triethylamine, Ν, Ν-dimethylaniline. and pyridine, or else inorganic bases such as alkali metal carbonates and alkali metal hydrogencarbonates. Working up of the reaction mixture is carried out in the usual manner and yields are in the range of 90% of theory. The resulting haloacetyl derivatives of the general formula (VI) are predominantly well-crystallizable substances (see also DE-A-1795 183).

The compounds of the formula IV are known from the literature (see DE-A-1 179 943 and 1 204 680).

As described above, as compound of the general formula VI is reacted with ^N-1 benzylpiperazi, dimethoxypropane in a solvent such as ether, dioxane, ethanol, propanol or benzene under reflux. In this reaction, a crystalline precipitate is formed which is filtered off with suction and isolated, for example, as hydrochloride. The compound of formula (VII) thus formed

in which*

Rz, R3 and R4 have the abovementioned meaning, then the free base is dissolved in an alcohol, for example methanol, in the presence of palladium on charcoal is hydrogenated at 20-80 ³ C, preferably 50 ° C, under a hydrogen pressure of 0.1 up to 10 MPa, preferably 5 MPa. The corresponding compound of formula (II) is then isolated from the reaction mixture.

The novel compounds and their salts according to the invention have valuable therapeutic properties. In particular, they act as ulcer inhibiting agents and secretion suppressors.

The compounds listed below were tested for their potency in inhibiting stress-induced ulceration in rats and for their atropine-related spiasmolytic effect with respect to acute toxicity.

5,11-dihydro-11j [4- (2-methylallyl) -1-piperazinyl] acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one (A),

5.11-Dihydro-11j [4- (3-methylbut-2-enyl) -1-piperazinyl] acetyl} -6H-pyrido [2,3-bj [1,4] benzodiazepin-6-one dihydrochloride (Bj ,

5.11-Dihydro-11 {(4- (2,2-dimethyl-propyl) -1-pipenazinyl] acetyl) -1H-pyrido (2,3-b) (1,4) benzodiazepin-6-one

11-j [4- (1-adamantylmethyl) -1-piperazinyl] acetyl} -5,11-dibydro-6H-pyridino [2,3-b] [1,4] bemzodiazepin-6-one (D) ,

5.11-Dihydro-11 '{[4- (3,4-methylenedioxybenzyl) -1-piperazinyl] acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one (E), 5,11-dihydro-11 - [(2,4-dimethyl-1-piperazinyl) acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one hydrochloride (F),

5.11-Dihydro-5-methyl-11 - {[4- (3,4-methylenedioxybenzyl) -1-piperazinyl] acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one (G),

11 - ((4-dimethylamino-1-piperazinyl) acetyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one (H).

The inhibitory effect on the formation of stress-induced ulcers in rats is determined by the procedure described by K. Takagi and S. Okahe in Jap. Journ. Pharmac. 18, pp. 9-18 (1968). The fed female rats having a body weight between 220 and 260 g are individually placed in small wire cages, which are then placed on. 16 hours vertical immersion in a water bath at a constant temperature of 23 ° C so that the rat protrudes mad surface water only head and chest. About 5 to 10 minutes before the start of the experiment, the animals are orally administered the test compound. Each substance was tested on 5 animals. Control animals receive in the same way only 1 ml of 0.9% saline or 1 ml of a 1% tylose solution. After 18 hours, the rats are sacrificed with a high dose of chloroethyl, their stomach is removed, slit along a large kurvatura and stretched onto a cork disc. The evaluation of the experiment is carried out as described by Marazzi-Uberti and Turba, in Med, Exp., 4, pp. 284-292 (1961), and by Takagi and Okabe, supra.

The spasmolytic effect was determined by guinea pig colon imitations 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, the duration of action of the spasmolytic is 1 minute.

It was also observed in the experimental rats that side effects of the atropine type, such as inhibition of saliva secretion, were completely absent from the administration of test substances A to H, or. they are considerably lower.

Acute toxicity was determined in fasted white mice weighing 18-20 g after oral administration of test substances. The observation period is 14 days. Each dose was tested in n * and a group of 6 mice.

The values obtained are summarized in. the following tables:

Test substance

Inhibition of ulceration (% in rats after oral administration (mg / kg)

Spasmolytic effect (acetylcholine) based on atroDL 50 in mg / kg after oral administration to mice

50 25 12.5 pin = 1 AND 90 52 32 1/330 > 3000 (B) 84 63 52 1/200 > 3000 C 95 61 39 1/70 > 1500 *) D 79 47 26 1/86 > 3000 E 95 73 37 1/78 > 3000 ***) F 95 90 84 1/130 > 3000 **) G 90 58 21 1/290 > 1500 ***) H 95 69 53 1/700 ~ 3000 **** Legend: 6-one, 3.45 ml triethylamine and 10.5 g far- *) ze 6 animals did not die nesylbromidu se in 140 ml of n-propanol 6 ··) of 6 animals died 1 hours of heating to i / aru under reflux- ***) ze 6 animals died 2 čem. The reaction mixture was evaporated, the residue was evaporated ****) ze 6 animals died 4. dissolved in the mixture chloroform and water, or- ganic phase se dried with sodium sulphate, Spasmolytic effect of substances And to H is the chloroform was distilled off and the residue was purified compared to atropine sulfate considerably slab- chromatography on silica gel column. Gets-

as well as side effects of atropine or type.

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

He did

11 - [(4-cyclohexylmethyl-1-piperazinyl) acetyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one dihydrate

5.05 g of 5,11-dihydro-11 - ((1-piperazinyl) acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one, 2.07 ml of triethylamine and 2.5 ml The residue was purified by silica gel column chromatography and recrystallized from ethanol to give the desired dihydrate (33%), m.p. 222-224 ° C.

Example 1 a d 2

5,11-dlhydro-11 - [(4-fat'nesyl-1-piperazinyl) acetyl] 6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one dihydrochloride

8.4 g of 5,11-dlhydro-11 - [(1-piperazinyl) acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepine base was dissolved in isopropanol and concentrated hydrochloric acid was added to the solution. The crystallized dihydrochloride is recrystallized from absolute ethanol.

The product resulting in a yield of 29% _of theory melts at 164-170 ° C (decomposition).

Example 3

11 - [(4-cinnamyl-1-piperazinyl) acetyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] azodiazin-6-one

5.05 g of 5,11-dihydro-11 - [(1-piperazinyl) acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one, 1.6 g of sodium carbonate and 3, 7 g of cinnatoyl bromide are taken up in 80 ml of n-propanol

Heat to reflux for 3.5 hours. After evaporation of the reaction mixture, the residue is dissolved in a mixture of chloroform and water, the organic phase is dried over sodium sulfate and the chloroform is distilled off. The residue was purified by silica gel column chromatography.

The product resulting in a yield of 41% of theory melts after recrystallization from ethyl acetate at 198-198 ° C.

In a similar manner to Examples 1 to 3, the compounds in the other examples summarized in the following summary are also prepared:

207B18

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In all examples, purification of vine products by silica gel column chromatography was performed using a mixture of chloroform, cyclohexane / hexane and concentrated ammonia in a ratio of 68: 15: 15: 2 as both solvent and eluent.

Compounds of formula (I) and salts thereof

Claims (3)

SUBJECT A process for the preparation of the novel 5,11-dihydro-BH-pyridioph 2,3-b '] [1,4] benzodiazepin-6-one derivatives of the general formula I in which: R1 represents a straight or branched alkyl group having from 3 to 12 carbon atoms, an unsaturated, straight or branched aliphatic hydrocarbon radical having from 3 to 20 carbon atoms and 1 to 3 double bonds and / or one triple bond, a phenylalkyl group having 2 to 4 carbon atoms straight or branched alkylene moieties, methylenedioxybenzyl, chloro-orbenzyl, 5- or 3-indanylraethyl, phenylalkenyl of 2 to 4 carbon atoms in the alkenylene moiety, cycloalkyl of 5 to 7 carbon atoms, cycloalkylmethyl of 3 to 10 the carbon atoms in the cycloalkyl ring which may optionally be further substituted in the cycloalkyl ring by a methyl group or a morpholino- or 4-methylpiperazinoalkyl group having 2 or 3 carbon atoms in the alkylene moiety, R 2 is hydrogen or methyl, and each of R 5 and R 6, which may be the same or different, is hydrogen or methyl, and when R 3 and / or R 1 is methyl, R 1 may also be methyl or ethyl, and their pharmaceutical formulations may 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 90 mg. CLAIMS OF THE INVENTION with the use of inorganic or organic acid addition salts, characterized in that 5,11-dihydro-11 - [(1-piperazinyl) acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepine -6-one of formula II wherein:. R 2, R 3 and R 4 are as described above, reacted with a halide of formula III R1-Hai, (III) wherein R 1 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 its addition salts with inorganic or organic acids. 2. The process according to claim 1, wherein the reaction is carried out at a temperature up to the boiling point of the reaction mixture and the hydrogen halide liberating agent is removed with the 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 bicarbonates or tertiary organic bases.