SU584772A3 - Method of preparing benzodiazepine derivatives or salts thereof - Google Patents

Description

NH-SaNgp. de RJ, RI, R.3, R and p are as defined above, they are reacted with the 2,5-dione derivative of formula 11L, -sn-e. X NH-e, where RJ is as defined above, and X is oxygen or sulfur, in the presence of an organic solvent, for example carbon tetrachloride, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran or dioxane, and mineral acid, for example hydrogen chloride, hydrogen bromide or sulfuric acid at room temperature. The target product is isolated in a free state or in the form of Benzodiazepine derivatives, described by formula D or their salts possess valuable pharmacological properties, in particular, they are powerful trunk muscles, sedatives, muscle relaxants (relax muscles), increase the activity of hexobarbital. . The invention captures new benzodiazepine derivatives, methods for their preparation, and pharmaceutical preparations containing them. This invention relates specifically to the production of new diazepine derivatives described by the formula (iH-Hj - (OU where RJ, R, Rj, R4,, n and n are as defined above. In the compounds described by the formula. I, halogen atoms mean chlorine, bromine, iodine, and fluorine atoms; alkoxy groups with 1-4 carbon atoms include methoxy, ethoxy SI-, p-propoxy, isopropoxy, p-butoxy, isobutoxy- and tert.-butoxy groups; alkyl groups with 1-4 carbon atoms include methylethyl, p-propyl, isopropyl, butyl, isobutyl, and tert-butyl groups, examples of the groups of apoxyalco xy include meroxymethoxy, methoxyethoxy, metho and pro-, ethoxymethoxy, ethoxyethoxy and ethoxypropoxy groups. -CnHgn groups are straight chain or branched chain groups with 1-4 carbon atoms and include, for example , methylene, ethylene, 1-methylethylene, 2-methylethylene, trimetipena, 1-methyltrimetipena and 2-methyltrimetipena groups. Although the molar ratio of 2,5-dione derivative to benzofonon derivative is not critical, it is preferable to use at least stoichiometric amount reagent Properties. In most cases, it is more preferable to use an excess of the 2,5-ration derivative. I The target benzocyazepine derivative can be isolated from the reaction mixture in its crude form by extraction with or without prior neutralization and evaporation to dryness. Further, the product, if desired, is purified by recrystallization from a suitable solvent, such as ethanol, isopropane, isopropyl ether, or mixtures thereof according to standard procedures. The benzodiazepine derivative obtained according to the above method can also be isolated as a salt resulting from the addition of an acid when treated with an acid, for example a mineral acid, such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid, or an organic acid, as maleic, fumaric, amber, formic or acetic acid. Example 1. To a solution of 1 g of 2 - (/ - phenoxyethyl) amino-5-chlorobenzophenone in 30 ml of anhydrous methylene chloride was added 1.2 g of oxazolid-2,5-dione. To the mixture was added 10 ml of a solution of hydrogen chloride in diethyl ether while cooling with ice, and the mixture was stirred at room temperature. The reaction mixture was poured into water, basified with aqueous ammonia, and extracted with methylene chloride. The extracts are combined, washed with a saturated solution of sodium chloride and the solvent is removed. The residue is crystallized and recrystallized from isopropano / -chloroform to obtain 1- {ji-phenoxyethyl) -phenyl-7-chloro-1, 3-dihydro-2H-1,4-benzopiazepin-2-one, melting at 165-166 ° C. Example 2. To a solution of 1, O5 g of 2 (α-phenoxyethyl) amino-5-chloro-2-fluorobenzophenone in 30 ml of dry ethylene dichloroporide was added 1.2 g of oxazolyl-3,5-dione. To the mixture was added 10 ml of an ethereal solution of hydrogen chloride while cooling with ice and

the mixture is heated under reflux overnight. After cooling, the reaction mixture is poured into water, made basic with an aqueous solution of ammonia and extracted with ethylenedichloride. The extracts are combined, washed with a saturated solution of sodium chloride and the solvent is evaporated off under reduced pressure. The residue is crystallized and recrystallized from the isopropanode - xnopcxfopNi mixture to form 1- (-phenoxy-etip) -5- {c-fluoro4 "1I1i) -7-hpor-1, 3-dihydro-2H-1,4-bezoa-zepine. 2-she, t. Pl, 131-132 ° C, vyhop 86%.

In a similar way, G1T compounds are given in the table.

Starting materials. and the amount used, g

2- (-Phenoxyethyl) -amino-5-chloro-Oxazolidobenzophenone, 1-2,5-dione,

1.2

2- (in -Phenoxyethyl) -amino-5-chloro-2-fluorobenzophenone, 1, O5

2- (-Benzipoxyethyl) -amino-5-xporbenzophenone, 1, O4

2- (-Benzyloxyethyl) -amino-5-chloro-2-fluorobenzophenone, 1, OS

2- -Methoxyethoxy -) - ethyl-amino-5-chlorobenzophenone, 0.95

 -; 8 (Metoxyethoxy) -ethylZ-amino-5-chloro-2-fluorobenzophenone, 1

(-Ethoxyethoxy) -ethyl-amino-5-chlorobenzophenone, 0.99

 -Ethoxyethoxy) ethyl-amino-5-chloro -2-fluorobenzophenone, 1.04

Product and its output, g

l- (j8-phenoxyethyl) -5-phenyl-7-chloro-1, 3-dihydro-2H-1,4-benzodiazepi -2-one, t. pl. 165-166 ° С 0.99

l (yg -Phenoxyethyl) -5- (o-fluorophenyl l) -7-chloro-1,3-digi dro-2 I-1,4-benzodiazepin-2-one, so pl. 131132 ° C, 1

1 - {; 6 -Benzyloxyethyl) -5-phenyl-7-hpor-, 3-dihydro-2H-1,4-benzodiazepin-2-one (mp 133-135 ° C), 1.05

1 - (/ -Benzyloxyethyl) -5- (o-fluorophenip) -7-chloroph-, 3-dihydro-2H-, 4-benzodiazepin-2-one (t. Pp. 114-I5,5 ° C), 1.06

 - (-Metoxie, tox} -ethyl-5-phenyl-7-chloro-1, 3-digi-dro-2H-1,4-benzodiazepin-2-one (t. I. 9394 ° C), 0, 9

1-jS, f -Methoxyethoxy) ethyl 4-5- (o-fluorophenyl) -7-chloro-1,3-digi dro-2H-1, 4-benzodiazepin-2-one (mp. 7O-72 ° C ), Oh, 94

1-f / - {D-ethoxyethoxy) -etip-t (o-fluorophenyl) -7-hpor-1,3-dihydro-2H-1,4-benzodiazepin-2-one (t. Pl. 78-79 ° C), 0.97

Claims (4)

1-yg - (Ub-ETOXYETOXYETHYL-5) -o-fluorophenip-7-chloro-1, 3-dihydro-2H-1,4-benzoiazepin-2-one (mp. 76-77 ° С), 0.99 7 Claims 1. Method for preparing benzodiazepine derivatives of general formula 1 Cr, H2P O N C., CHO R: where Rt denotes a hydrogen atom, a hapoid, no ro-, Ci-C4-anKOKCH-, cyano- or trifluorime of the group , RJ is the group where RS and RU denote a hydrogen atom, halogen, C1-C4-alkyl, benzyl; benzyl substituted by halogen or C4-C4-alkyl; ethoxyphenyl or ethoxyphenyl, substituted by halogen or C, -C-alkyl, or trifluoromethyl; RJ is a hydrogen atom, C-C4-alkyl, benzyl, benzyl, substituted by halogen or Cd-C-alkyl-M | ethoxyphenyl, or ethoxyphenyl, substituted by halogen or C-C-alkyl; R; means tetrahydropyranyloxy-, tetrahydrofuranyloxy-, phenoxy-, halo-substituted phenoxy- and alkyl-substituted phenoxy-, benzyloxy-, halo- or alkyl-substituted benzyloxy-, phenetyloxy-, halo, or apkil-substituted phenethyloxy- -Cyro -Cy -Cy -Cy -Cy -Cy -Cy -Cyroxy-, phenoxy-, phenyloxy-, halogeno-, phenyloxy-, halogenoxy-, phenoxy-, alkyl-substituted phenoxy-, alkyl-substituted phenoxy-, alkyl-substituted phenoxy-, alkyl-substituted phenoxy-, alkyl-substituted phenoxy-, alkyl-substituted phenoxy-, alkyl-substituted phenoxy-, and l means an integer from 1 to 4, or their salts, characterized in that the benzophenone derivative of the general formula KH-SpNgp where Rf, RJ, R and t are as defined above, is reacted with. a derivative of 2,5-dione common forcixl NH-d O RJ is as defined above, and X is oxygen or sulfur, in the presence of an organic solvent and mineral acid at a temperature ranging from room temperature to 85 ° C, followed by isolating the desired product as a base or as a salt. 2. The method according to claim 1, wherein the treatment is carried out at room temperature with a stoichiometric amount of reagents, preferably using an excess of 2,5-dione, 3. Method according to paragraphs. 1, 2, about 1 ml and with the fact that carbon tetrachloride, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran or dioxane are used as the organic solvent. 4. Method according to paragraphs. 1-3, characterized in that hydrogen chloride, hydrogen bromide or sulfuric acid is used as the mineral acid. Sources of information taken into account in the examination: 1. Patent of England No. 1.116.918, cl. C 2 C, 1966.