CS227050B2 - Method of preparing new benzodiazepines - Google Patents

Description

The invention relates to processes for the preparation of novel benzodiazepines.

Various tricyclic compounds with pharmaceutical properties have been investigated, in particular compounds of the type containing two benzene cores. A new compound of the following general formula has now been found

The present invention provides a process for the preparation of the novel benzodiazepines of formula (I)

R ³

I in which

R @ ¹ and R @ ² each represent a halogen atom and R @ ³ and R ^{@ 4} each represent C1-4 alkyl, or their acid addition salts. It is an object of the invention to cyclize the anilinotriazole derivative of the formula II

in which

R ¹ , R ² , R ³ and R ⁴ are as defined above, and the product obtained is optionally converted into an acid addition salt.

The compounds of formula (I) have been found to possess useful biological properties so that they can be used as therapeutic agents for the treatment of central nervous system disorders.

As mentioned above, the compounds of the invention are useful both in the form of the free base and in the form of acid addition salts. Acid addition salts are preferably pharmaceutically acceptable salts, non-toxic acid addition salts such as salts with inorganic acids such as hydrochloric, hydrobromic, nitric, sulfuric, or phosphoric acid, or with organic acids such as organic carboxylic acids such as acid glycolic, maleic, hydroxymaleinic, fumaric, malic, tartaric, citric or lactic, or organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, toluene-p-sulfonic acid or naphthalene-2-sulfonic acid. In addition to the pharmaceutically acceptable acid addition salts, the acid addition salts include other salts, for example picric or oxalic acid salts, as they may serve as intermediates in the purification of compounds or in the preparation of other, for example, pharmaceutically acceptable acid addition salts, or for the identification, characterization or purification of bases.

In the reaction, compounds of formula II may be cyclized using, for example, titanium tetrachloride as a catalyst and toluene as a solvent, preferably at a temperature of from 150 ° C to 200 ° C. The compounds of formula (II) may also be prepared in situ without isolation.

The compounds of formula I prepared as described above may be isolated per se or converted into their corresponding acid addition salts using conventional methods.

Necessary starting materials may be prepared by condensation of a triazole derivative of formula ^{R 9} 2 ° ^C; V ^{x N x} \

N - R ⁴ where

R ⁹ is C ^1-4 alkyl and R ⁴ is as defined above, with the ortho-halonitrobenzene as mentioned above, to form a nitro ester which can be reduced to the aminoester of formula

catalytically using, for example, hydrogen and palladium on carbon, or chemically using, for example, stannous chloride and hydrogen chloride in an aqueous solution of ethanol or ammonium polysulfide.

Finally, the compounds of formula II may be prepared in situ, without isolation, by reacting the amino ester with N-alkylpiperazine, for example by heating to a temperature of between 30 to 120 ° C, for example 100 ° Ό, in a suitable solvent such as using titanium tetrachloride as a catalyst, or by conventional amino ester methods, followed by cyclization to provide the compounds of the invention.

The triazole starting materials used in the above process are either known, see for example Chem. Indian. (1970) 92, J. Am Chem Soc (1956) 78 5832, J. Chem Soc (C) (1968) 2076, J. Chem Soc Perkin 1 (1972) 461, J. Chem. Soc., Perkin 1 (1973) 1634; J. Chem. Soc. (C) (1968) 344; J. Am. Chem. Soc. (1957) 79 490; J. Appl. Chem. (1957) 7,109; Chem. Soc., (C) (1969) 152, J. Chem. Soc., (C) (1969) 2379, or may be prepared by known methods from known compounds. prepared from commercially available substances.

As noted above, the compounds of the invention act on central nervous system activity. Their effects have been demonstrated on animals using known procedures. For example, in a study of mouse behavior, a decrease in activity was observed over the dose range of 12.5 to 200 mg / kg after. - 749 (1976 J) and have, for example, an IC50 (concentration of compound required to reduce bound spiroperidol to 50 percent) of less than 2 μΜ, which are therefore active centrally acting substances with neuroleptic, sedative or relaxing, anxiolytic or antiemetic properties. in conjunction with the high therapeutic index makes them useful in the treatment of mild anxiety and certain types of psychiatric conditions such as schizophrenia and acute mania.

The compounds of the invention are effective over a wide dosage range and the actual substance administered will depend on such factors as the species of use of the compound, the condition of the subject being treated and the species and size of the mammal being treated. However, commonly required doses fall within the range of 0.5 to 50 mg / kg per day, for example, doses ranging from 5 to 500 mg per day may be used to treat adults.

The compounds of the invention may conveniently be administered orally or by injection, and for this purpose the compounds are usually formulated into a pharmaceutical formulation. Such formulations are prepared in a manner conventional in the pharmaceutical art and comprise at least one active ingredient.

In the manufacture of a preparation containing the active compound according to the invention, the active compounds are usually mixed with a carrier or diluted in a carrier or enclosed in a carrier, which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material that acts as a vehicle, excipient, or medium for the intended ingredient. Examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, syrup, methylcellulose, methyl- and propylhydroxybenzoate, talc, magnesium stearate or mineral oil. The compositions of the invention may, if desired, be formulated so as to provide rapid, uniform or delayed release of the active ingredient after administration to the patient.

Depending on the route of administration, the above compositions may be formulated as tablets, capsules or suspensions for oral use and injectable solutions for parenteral use or as suppositories. Preferred formulations are formulated in a unit dosage form, each dosage containing from 1 to 200 mg, usually 5 to 100 mg, of the active ingredient.

The following example illustrates the process of the invention in more detail.

Example 1 a) 4- (4-Fluoro-2-nitrophenylamino} -2-methyl-1,2,3-triazole-5-carboxylic acid

4- (4-Fluoro-2-nitrophenylamino) -2-methyl-2,3,3-triazole-5-carbonitrile (0.5 g) was added to a mixture of ethanol (10 mL) and aqueous potassium hydroxide (2.5N) ( 20 ml] and refluxed overnight The suspension was cooled, diluted with water and filtered and the organic extract was washed with water, dried over magnesium sulfate and evaporated under reduced pressure.

An orange solid was obtained, which crystallized from ethanol to give orange crystals (0.5 gj, m.p. > 250 ° C).

b) Methyl 4- (4-fluoro-2'-nitrophenylamino] -2-methyl-1,2,3-triazole-5-carboxylate

The above carboxylic acid (0.3 g) was dissolved in methanol (20 ml) at 0 ° C and then concentrated sulfuric acid (0.5 ml) was added dropwise and the solution was refluxed overnight. . The cooled solution was neutralized with sodium bicarbonate, filtered and the filtrate evaporated to dryness under reduced pressure. The resulting yellow solid was extracted with chloroform, filtered and the filtrate was evaporated. The resulting orange solid (0.3 g) (EtOH) has a melting point of 208.5 to 210.5 ° C, i.e. 7-Fluoro-2-methyl-10- (4-methyl-1-piperazinyl) -4H-1. 2,3-triazolo [4,5-b] [1,5] benzodiazepine

The above nitroester (0.23 g) was dissolved in absolute ethanol (50 mL) and a slurry of palladium on charcoal (10%) (0.2 g) in ethanol was added and the solution was hydrogenated at 4.223 MPa at room temperature. The solution was then filtered through a Celite filter and evaporated to dryness under reduced pressure to give a white solid, 4- (4'-fluoro-2'-aminophenylamino) -2-methyl-1,2,3- triazole-5-carboxylate.

The white aminoester, N-methylpiperazine (0.5 mL) and anlsol (10 mL) were placed in a three necked flask equipped with nitrogen inlet, thermometer, dropping funnel and stirrer and stirred under nitrogen in an ice water bath at 0 ° C. slowly titanium tetrachloride (0.5 mL) in anisole (10 mL), then the mixture was heated and maintained at 90 ° C overnight. Thin layer chromatography showed no starting compound but all product as 4- (4'-). fluoro-2-aminophenylamino} -1,2,3-triazole-5- (4-methyl-1-piperazinyl) carboxamide, m.p. 148-149 ° C.

This product was further heated to 150 ° C and the reaction mixture was allowed to stand for 72 hours. The cooled reaction mixture was poured into a mixture of water with ammonia and ethyl acetate with stirring and then filtered through a celite filter. The organic layer was separated, washed twice with water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure to give a brown oil. This oil is chromatographed on a 5: 95 column of magnesium silicate using methanol / chloroform. The desired fractions are evaporated under reduced pressure to give a yellow crystalline solid (0.03 g (ethyl acetate-hexane) corresponding to 7-fluoro-). 2-methyl-10- (4-methyl-1-piperazinyl) -4H-1,2,3-triazolo [4,5-b] [1,5] benzodiazepine, m.p. 193-195 ° C.

Example 2

Tablets containing each 50 mg of active ingredient were prepared as follows

active substance starch microcrystalline cellulose polyvinylpyrrolidone (as a 10% solution in water) Na-carboxymethyl-starch magnesium stearate 50 mg 120 mg 100 mg 13 mg 14 mg 3 mg total 300 mg

The active ingredient, starch and cellulose are mixed.

The polyvinylpyrrolidone solution is mixed with the resulting powder and passed through a sieve. The granules so formed are dried and sieved again. The na-carboxymethyl starch and magnesium stearate are then added to the granules and, after mixing, are tabletted to give tablets weighing 300 mg each.

Example 3

Capsules containing 100 mg of active ingredient per capsule are prepared as follows. by:

active substance 100 mg dried starch 98 mg magnesium stearate 2 mg total 200 mg

The active ingredient, starch and magnesium stearate are passed through a sieve and filled into hard gelatin capsules of 200 mg per capsule.

Example 4

Suppositories containing 100 mg of active ingredient per suppository are prepared as follows:

active substance 100 mg of saturated fatty acid glycerides into

2000 mg.

Claims (1)

pRedmEt v A process for the preparation of the novel benzodiazepines of the general formula I in which: R ¹ and R ^{2 are} each a halogen atom and The active ingredient is sieved and suspended in saturated fatty acid glycerides previously melted at the lowest possible temperature. The mixture is then poured into a suppository form with a nominal capacity of 2 g and allowed to cool. Example 5 A suspension containing 50 mg of active ingredient in a 5 ml dose is prepared as follows: active substance 50 mg ' Na-carboxymethylcellulose 50 mg sucrose 1.25 g p-hydroxybenzoates 0.5 mg flavor q. with. dye q. with. purified water up to 5 ml The active ingredient is sieved and mixed with Na-carboxymethylcellulose and sugar (dissolved in water) to form a fine paste. The p-hydroxybenzoates, flavors and color are dissolved in a smaller amount of water and added to the paste with stirring. Sufficient water is then added to make up to the desired volume. ynAlezu R ³ and R ^{4 are} each C ^1-4 alkyl or their acid addition salts, characterized in that the anilinotriazole derivative of the general formula II is cyclized in which: R ¹ , R ² , R ³ and R ⁴ are as defined above, and the product obtained is optionally converted into an acid addition salt. Severography, n. p “závod t, Most