KR810001174B1 - Process for preparing dithiepino [1,4] [2,3-C] pyrrole derivatives - Google Patents

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Description

Method for preparing dithiepino [1,4] [2,3-C] pyrrole derivatives

The present invention relates to novel, therapeutic and useful dithiepino [1,4] [2,3-C] pyrrole derivatives of the general formula (I) and methods for preparing acid addition salts thereof.

Wherein A is a phenyl, pyrid-2-yl, quinol-2-yl or 1,8-naphthyridin-2-yl group, each of which is a halogen atom (preferably a chlorine atom), an alkyl group of C _1-4 (preferably Is a methyl group) C _1-4 alkoxy group (preferably methoxy group), cyano group or nitro group may be optionally substituted and R is a hydrogen atom or C _1-4 alkyl group (preferably methyl group), C _{2- 4} is an alkenyl group (preferably allyl group) or a C _1-4 alkanoyl group (for example, propionyl or butyryl group).

According to a feature of the invention, piperazine of the following general formula (II)

(Wherein R is as described above.) A compound of formula (I) is prepared by reacting the mixed carbonate of formula (III).

(Wherein A is as defined above and Ar is an optionally substituted phenyl group of a C _1-4 alkyl group or nitro group)

The reaction can generally be carried out in anhydrous organic solvents such as acetonitrile at 0-50 ° C.

The mixed carbonates of the general formula (III) are chloroformate of the following general formula (IV)

(Ar is as described above) can be prepared by reacting with a dithi epino [1,4] [2,3-C] pyrrole derivative of the general formula (V).

(A is as described above)

This reaction can generally be carried out in a basic organic solvent such as pyridine or in an organic solvent such as tetrahydrofuran in the presence of an alkaline condensing agent.

Dithiepino [1,4] [2,3-C] pyrrole derivatives of the general formula (V) can be prepared by partially reducing the imide of the following general formula (VI).

(A is as described above)

Reduction is generally effected effectively with alkali metal borohydrides in organic solvents or in water-organic solutions such as, for example, dioxane-tetrahydrofuran or dioxane-methanol or dioxane-water or methanol-water or ethanol-water mixtures. can do.

Amides of the general formula (VI) are amine compounds of the following general formula (VII)

(A is as described above)

It can be prepared by reacting with anhydrides of 6,7-dihydro-5H-1,4-dithiene-2,3-dicarboxylic acid. The reaction is usually carried out in a carbohydrate such as dicyclohexylcarbodiimide or 3- (3-diethylaminopropyl) -1-isopropylcarbodiimide, in acetic acid, dimethyl formamide, acetonitrile or diphenyl ether or mixtures of these solvents. This can be done by heating the reactants in the presence or absence of bodyimide.

The anhydrides of 6,7-dihydro-5H-1,4-dithiene-2,3-dicarboxylic acid are 6,7-dihydro-5H-1,4-dithiene-2, It can be prepared by hydrolysis of 3-dicarbonitrile.

In general, this reaction can be performed better in about 20N sulfuric acid at 100-125 ℃.

6,7-dihydro-5H-1,4-dithipine-2,3-dicarbonitrile acts on 1,3-dibromopropane to disodium salt of 2,3-dimercaptomalonitrile Can be prepared. This reaction can generally be carried out in an inert organic solvent such as 1,2-dimethoxyethane or dimethylformamide at temperatures between 20 ° C. and the boiling point of the reaction mixture.

The disodium salt of 2,3-dimercaptomalenitrile is Helv. Chim. It may be prepared according to the method of Age Alsch visor described in Acta 52,2228 (1969).

Piperazine derivatives of the general formula II wherein R is an alkanoyl group are represented by the acid of the general formula

R ₂ -COOH (VIII)

(Wherein R ₂ is a hydrogen atom or an alkyl group of C _1-3 )

Or a known method itself in the production of amides, such as by the action of derivatives of acids such as halides, esters, anhydrides, mixed anhydride amides or azides. The piperazine derivatives of formula (II) can be separated from the disubstituted piperazine produced simultaneously by physical or chemical methods.

The dithiepino [1,4] [2,3-C] pyrido derivatives of the general formula I obtained by the above-mentioned methods may be used in chemical methods such as the formation of salts, crystallization of salts and decomposition of salts in alkaline media, or physical methods such as crystallization or chromatography. It can be purified by the method. The nature of the anions of the salts is not critical to the practice of the above-mentioned chemical methods, and the only requirement is that the salts be outlined and easily crystallized.

Compounds of formula (I), more particularly wherein R is a hydrogen atom or an alkyl or alkenyl group, can be converted into acid addition salts by known methods themselves.

The dithiepino [1,4] [2,3-C] pyrido derivatives of the general formula (I) obtained by the above-described method may be obtained by physical methods such as crystallization or chromatography or salt formation, salt crystallization and decomposition of salts in alkaline media. It can be purified by the same chemical method. The nature of the anions of the salts is not critical to the practice of the above-mentioned chemical methods and the only requirement is that the salts are contoured and easily crystallized.

Compounds of general formula (I), in which R in particular is a hydrogen atom or an alkyl or alkenyl group, can be converted into acid addition salts by known methods.

Acid addition salts can be prepared by reacting the acid with the new compound in a suitable solvent. Alcohols, ketones, ethers or chlorinated hydrocarbons can be used as the organic solvent. The resulting salt precipitates out and the solution is concentrated and, if necessary, separated by filtration or decantation.

The derivatives of dithiepino [1,4] [2,3-C] blood of the present invention and, where appropriate, their acid addition salts have important pharmacological properties. They are particularly powerful as mental stabilizers, anticonvulsants, relaxers and sleeping pills. In animals (or rats), oral administration at a dose of 1-100 mg / kg (animal weight) showed a particularly strong effect in the following tests;

(i) when an electrical struggle is made according to a technique similar to that of Tedeshi et al. described in J. Pharmacol 125,28 (1959),

(ii) when pentetrazole-induced convulsions are developed according to techniques similar to those of Everett and Richard et al., described in J. Pharmacol, 81,402 (1994);

(iii) when a stimulus of more than a minimum was given according to the technique of Swinyard et al. described in J. Pharmacol, 106,319 (1952),

And (iii) mortality upon treatment with striknin according to techniques similar to those of F. Barzaghi et al., Described in Arzneimittel Forschung 23,683 (1973).

(V) Convores des Medecins Alienistes et Neurologistes Tours, 8th-13th June 1959, the description of the Cour voisier, and Julou described in Bulletin de la societe de Pharmacie de Lille NO.2, Jan 1967.p.7. Mobility test according to the technique of).

Furthermore, the compounds of the invention are low in toxicity; When administered orally to rats, the LD ₅₀ was generally greater than 900 mg / kg body weight.

In the present invention, a better dithiepino [1,4] [2,3-C] pyridine derivative is A in which pyrid-2-yl or a halogen atom (preferably chlorine) or a C _1-4 alkoxy group. Is a 1,8-naphthyridin-2-yl group optionally substituted with a (methoxy group is better) and R is a C _1-4 alkyl group (preferably a methyl group) or a C _2-4 alkenyl group (preferably an allyl group) ) Is a compound of formula (I). Of particular interest are derivatives of dithiepino [1,4] [2,3-C] pis of general formula (I) obtained as products in the following examples 2, 10, 11 and 15.

For therapeutic purposes, the salts of dithiepino [1,4] [2,3-C] blood of formula (I), as they are or that contain relatively negative anions, which are relatively harmless to animal organs in therapeutic amounts of salts (hydrochlorides, sulfates) , Nitrates, phosphates, acetates, propionates, succinates, benzoates, butyrates, maleates, tartarates, theophylan-acetates, salicylates, phenolphthalinates and methylenebis-β-hydroxynaproates) In the form of, it can be used in the form of non-toxic acid addition salt so that the useful physiological properties originally possessed by the base group are not lowered by side effects caused by anions.

The invention is illustrated by the following infinite examples.

EXAMPLE

1-Methylpiperazin (1.1 g) was added 7- (5-chloropyrid-2-yl) -8-oxo-phenoxycarbonyloxy-3,4,7,8-tetrahydro-2H, 6H-diti It is added to acetonitrile (20 cc) suspension of epino [1,4] [2,3-C] pyrrole (1.6 g).

The resulting suspension is stirred at about 20 ° C. for 20 hours. Acetonitrile is evaporated under reduced pressure (20 mmHg). Crystalline residue (2.4 g, melting point about 150 ° C.) is dissolved in methylene chloride (40 cc).

The methylene chloride solution is washed with N-sodium hydroxide solution (40 cc) and extracted twice with 0.1 N aqueous methanesulfonic acid solution (200 cc total). The acidic aqueous extract is made alkaline by adding about 10N sodium hydroxide solution. The oil to be separated is extracted twice with methylene chloride (80 cc in total). The organic solution is washed twice with distilled water (total 100 cc), dried over anhydrous magnesium sulfate and evaporated. The product (1.6 g; melting point 153 ° C.) is dissolved in boiling acetonitrile (4 cc) and boiling ethanol (14 cc) is added. After cooling for 2 hours at 2 ° C., the resulting crystals are spared, washed with ice-filled ethanol (5 cc) and dried under reduced pressure (0.2, mmHg). 7- (5-chloropyrid-2-yl) -6- (4-methylpiperazin-1-yl) -carbonyloxy-8-oxo-3,4,7,8-tetrahydro soluble at 156 ° C -2H, 6H-dithiino [1,4] [2,3-C] pyrrole (0.7 g) is obtained.

7- (5-chloropyrid-2-yl) -8-oxo-6-phenoxycarbonyloxy-3,4,7,8-tetrahydro-2H, 6H-dithi epino [1,4] [ 2,3-C] pyrrole was added phenylchloroformate (3.14g) at -10 ° -20 ° C and 7- (5-chloropyrid-2-yl) -6-hydroxy-8-oxo-3,4 , 7,8-tetrahydro-2H, 6H-dithiepino [1,4] [2,3-C] pyrrole (210 g) can be prepared by acting on anhydrous pyridine (25 cc) solution.

7- (5-chloropyrid-2-yl) -8-oxo-6-phenoxycarbonyloxy-3,4,7,8-petrahydro- soluble at 173 ° C. after recrystallization with acetonitrile (50 cc) 2H, 6H-dithi epino [1,4] [2,3-C] pyrrole (1.73 g) is obtained.

According to the procedure of the foregoing embodiments, using appropriate starting materials of the general formulas (II) and (III), the product of the following general formula (I) is also obtained:

6- (4-Methylpiperazin-1-yl) carbonyloxy-7- (4-nitrophenyl) -8-oxo-3,4, 7,8-tetrahydro-2H, 6H-dithiino [1 , 4] [2,3-C] pyrrole, dissolved at 149 ° C.

7- (5-chloropyrid-2-yl) -6- (4-ethylpiperazin-1-yl) carboxyloxy-8-oxo-3,4,7,8-tetrahydro-2H, 6H-diti Epino- [1,4] [2,3-C] pyrrole, dissolved at 130 ° C.

6- (4-allylpiperazin-1-yl) carbonyloxy-7- (5-chloropyrid-2-8-oxo-3,4,7,8-tetrahydro-2H, 6H-dithiino -[1,4] [2,3-C] pyrrole, dissolved at 139 ° C.

6- (4-methylpiperazin-1-yl) carbonyloxy-7- (5-methylpyrid-2-yl) -8-oxo-3,4,7,8-tetrahydro-2H, 6H- Dithiepino [1,4] [2,3-C] pyrrole, dissolved at 145 ° C.

6- (4-Methylpiperazin-1-yl) carbonyloxo-7- (5-nitropyridyl-2-yl) -8-oxo-3,4,7,8-tetrahydro-2H, 6H- Dithiepino- [1,4] [2,3-C] pyrrole, dissolved at 182 ° C.

7- (7-chloroquinol-2-yl) -6- (4-methylpiperazin-1-yl) carbonyloxy-8-oxo-3,4,7,8-tetrahydro-2H, 6H-diti Epino- [1,4] [2,3-C] pyrrole and hydrochloride decompose at 255 ° C and dissolve.

7- (7-methyl-1,8-naphthyridin-2-yl) -6- (4-methylpiperazin-1-yl) carbonyloxy-8-oxo-3,4,7,8-tetrahydro -2H, 6H-dithiino [1,4] [2,3-C] pyrrole, dissolved at 230 ° C.

7- (7-methoxy-1,8-naphthyridin-2-yl) -6- (4-methylpiperazin-1-yl) carbonyloxy-8-oxo-3,4,7,8-tetra Hydro-2H, 6H-dithiepino [1,4] [2,3-C] pyrrole, dissolved at 215 ° C.

7- (7-chloro-1,8-naphthyridin-2-yl) -6- (4-methylpiperazin-1-yl) carbonyloxy-8-oxo-3,4,7,8-tetrahydro -2H, 6H-dithiino [1,4] [2,3-C] pyrrole, dissolved at 283 ° C.

7- (7-chloro-1,8-naphthyridin-2-yl) -6- (4-ethylpiperazin-1-yl) carbonyloxy-8-oxo-3,4,7,8-tetrahydro -2H, 6H-dithiino [1,4] [2,3-C] pyrrole, dissolved at 254 ° C.

7- (7-chloro-1,8-naphthyridin-2-yl) -8-oxo-6- (4-propyl piperazin-1-yl) carbonyloxy-3,4,7,8-tetrahydro -2H, 6H-dithiino [1,4] [2,3-C] pyrrole-dissolved at 225 ° C.

7- (7-chloro-1,8-naphthyridin-2-yl) -6- (4-isopropylpiperazin-1-yl) carbonyloxy-8-oxo-3,4,7,8-tetra Hydro-2H, 6H-dithiepino [1,4] [2,3-C] pyrrole, dissolved at 230 ° C.

6- (4-allylpiperazin-1-yl) carbonyloxy-7- (7-chloro-1,8-naphthyridin-2-yl) -8-oxo-3,4,7,8-tetrahydro -2H, 6H-dithiino [1,4] [2,3-C] pyrrole, dissolved at 226 ° C.

6- (4-butyrylpiperazin-1-yl) carbonyloxy-7- (7-chloro-1,8-naphthyridin-2-yl) -8-oxo-3,4,7,8-tetra Hydro-2H, 6H-dithiepino [1,4] [2,3-C] pyrrole, dissolved at 210 ° C and 230 ° C.

7- (7-chloro-1,8-naphthyridin-2-yl) -8-oxo-6- (4-propionylpiperazin-1-yl) carbonyloxy-3,4,7,8-tetra Hydro-2H, 6H-dithiepino [1,4] [2,3-C] pyrrole, dissolved at 246 ° C.

Claims (1)

Dithiepino [1,4] [2,3-C] pyrrole derivatives of the following general formula (I) characterized by reacting piperazine of the following general formula (II) with a mixed carbonate of the following general formula (III) And a method for producing the acid addition salt thereof.

Wherein A is phenyl, pyrid-2-yl, quinol-2-yl or 1,8-naphthyridin-2-yl group and each halogen atom, an alkoxy group of the alkyl group, C _1-4 of C _1-4, a cyano group or a nitro group can be optionally substituted, and R is an alkenyl group of Al or an alkyl group of C _1-4, C _2-4 a hydrogen atom or a C _1-4 alkanoyl group, and Ar is a C _1-4 alkyl or nitro It is an optionally substituted phenyl group.