5-(- aminoacyl)-5,10-dihydro-11h-dibenzo[b, e] [1,4]- diazepin-11-ons or their salts, possess antiarrhythmic activity

 

(57) Abstract:

The invention relates to heterocyclic substances, in particular 5-( w-aminoacyl)-5,10-dihydro-11H-dibenzo [b, c] [1,4] diazepin-11-ones of General formula where 1) R1=H, R2= R3= CH3n = 5, X = Cl, m = 1; 2) R1=H, R2= R3= C2H5n = 3 or 5 m = 0; 3) R1=H, R2= R3= C2H5n = 5 m = 1, X = Cl; 4) R1=Cl, R2= R3= C2H5n = 3 - 6, n = 0; 5) R1=Cl n = 5 or 6, m = 0; 6) R1=Cl, n = 5, m = 0; 7) R1= Cl, H; R2= H, R3= C2H5n = 5, X = Cl, m = 1; 8) R1=Cl, R2=H, n = 5, m = 1, X = Cl ; 9) R1=H; n = 5, m = 1; X = Cl; 10) R1= R2= h; n = 5, m = 1, X = Br, 11) R1=H, R2= R3= -CH(CH3)2n = 5, m = 0; 12) R1=Cl, n = 3, m = 0, possess antiarrhythmic activity, which can be used in medicine. Goal - the creation of new active in a wide range of substances specified class. The synthesis are, for example, by reaction of the corresponding diazepinone 11 dialkylamino in the environment of dimethylformamide at 2°C, followed by slow heating to 30°C, distillation of the solvent, by treatment with a solution of NH3and CHCl3, extraction with HCl (1:1), alkalinization of acidic phase extraction CHCl3its distillation, mixed with acetophenone. New substances two times less toxic than lidocaine ( LD50=28 - 144 mg/kg to 18 mg/kg) and more active (therapeutic range of 12 - 1810 vs 5.8). table 1.

The invention relates to the field of chemistry, particularly to the new series of compounds - 5-(-aminoacyl)-5,10-dihydro-11N - dibenzo [b,e]-[1,4]-diazepin-11-Onam General formula

where R1is a hydrogen atom or chlorine;

R2is a hydrogen atom or a C1-C2-alkyl;

R3- C1-C2-alkyl or cyclohexyl, or R2and R3together with the nitrogen atom can be morpholinyl or N-methylpiperazine balance; provided that, if R2is a hydrogen atom, R3can be1-C3-alkyl or cyclohexyl,

n=3-6;

m = 0-1; X=Cl or Br.

Famous 5, 10-dihydro-11N-dibenzo[b,e][1,4] diazepin-11-ons that are in the fifth position aminoallyl (n=1) or aminopropionitrile (n=2) residue. These compounds possess antiulcer and antisecretory activity.

As comparative drugs were used lidocaine and quinidine. Lidocaine is widely used in clinical practice as an antiarrhythmic agent, used for ventricular ectopic rhythms. In addition, it is known that lidocai is Kim antiarrhythmic agent and a number of patients may cause anticholinergic properties. As lidocaine, and quinidine may not be actually the prototype for the studied group of compounds, as they are not structural analogues dibenzodiazepine. However, atropine as cholinolytic, does not possess antiarrhythmic properties, cannot be the prototype for the investigated compounds. And strong side effects of atropine: dry mouth, thirst, constipation, mydriasis, and, as a consequence, blurred vision, tachycardia, complicate its use in combination therapy of bradyarrhythmia.

The aim of the invention is new derivatives of dibenzodiazepine with pronounced antiarrhythmic properties for the treatment of severe cardiac arrhythmias, as bradycardia in cross section with arrhythmia.

The compounds of formula I get the following manner.

5,10-Dihydro-11N-dibenzo[b, e][1,4]dia - seen-11-ons are subjected to interaction with gelegenheid-halogen-substituted aliphatic acid in inert organic solvents (aromatic hydrocarbons, hydrogen halides)) when 60-140aboutC. Intermediate 5-(-halogenated)-5,10-dihydro-11N-dibenzo[b, e] [1,4]di - azepin-11-ons are crystalline substance, insoluble in water and soluble ESCWA I, 1-18 receive out of 5--halogenating derived their aminating inert organic solvent or in an excess of amine. As inert organic solvents can be used aromatic hydrocarbons, dipolar aprotic solvent is dimethylformamide or dimethylsulfoxide. To retrieve the target soedinenii I in high yields choose optimal process conditions amination using monitoring by TLC on plates "Silufol" UV254 and Kieselgel" 60F254 in the system of benzene: methanol: ammonia. Detection is performed using UV light or iodine vapours. It is shown that to obtain the target compounds I preferably use-brauzernye derivatives as reactivity-bromatum, higher than-haratama that allows the process of obtaining them in more mild conditions and thereby significantly reduce or completely eliminate side process, removal of the N-acyl group. Were selected process conditions under which the target substance is obtained with a yield of 60-80%.

Received aminoaniline of compound I represented either crystalline or resinous substance, insoluble in water and rangitoto.

The method is illustrated by the following examples.

P R I m e R 1. 5-(6-Dimethylaminopropyl)-5,10-dihydro-11N-dibenzo [b,e] [1,4]-diazepin-11-he(I. 1).

of 7.75 g (0.02 mol) of 5-(6-bromopropyl)-5,10-dihydro-11N-dibenzo-[b,e] [1,4] diazep - in-11-she dissolved in 50 ml of dimethylformamide at room temperature, cooled to 2aboutC, add 10 ml of the solution of dimethylamine in dimethylformamide (72%, contains 0.16 mol dimethylamine) and slowly heated in a closed vessel to room temperature and then 0.5 h at 40aboutC (bath temperature). Then add 10 ml of the solution of dimethylamine, and the heating continues as described above. The dimethylformamide is distilled off in vacuum, the remaining oil is shaken with 30 ml of dilute ammonia solution and 50 ml of chloroform, separated ammonia phase is shaken out 2 more times with 20 ml of chloroform and the combined chloroform phase is extracted with 3 times 20 ml of diluted hydrochloric acid 11. Acidic phase is alkalinized with 10 ml of concentrated ammonia solution and extracted with 2 times 10 ml of chloroform. The combined chloroform solution is dried with sodium sulfate. After separation of the sodium sulfate distilled chloroform, the residue is mixed with 40 ml of acetone and passed into a solution of HCl to pH 1. The solution is evaporated, Spinola. The output is 4.7 (61% of theory); so pl. 183aboutC.

Found%: C 64,69; N Is 6.78; N Of 10.73; Cl 9,29.

WITH21H25N3O2HCl.

Calculated, %: C 65,02; N 6,76; N 10,83; Cl 9,14.

The necessary starting material 5(6-bromopropyl)-5,10-dihydro-11N-dibenzo [b,e][1,4]diazepin-11-he will receive in the following way.

14.4 g (0.07 mol) of 5,10-dihydro-11N-dibenzo[b,e][1,4]diazepin-11-she dissolved in 100 ml of toluene and to the solution is slowly added to 18.8 g (0,088 mol) of the hydrochloride of 6-bromophenol acid. The reaction mixture is stirred 5 hours at the boil under reflux, was added 2 g of activated charcoal, boiled for 15 min under reflux, filtered and leave the filtrate to crystallize. The crystalline precipitate is filtered off, washed with a small amount of toluene and, after drying, recrystallized from isopropanol.

The output of 17.8 g (65,6% of theory); so pl. 138-139aboutC.

Found, %: C 59,08; N 4,94; N 7,24.

WITH19H19BrN2O2.

Calculated,%: C 58,92; H 4,94; N 7.23 Percent.

P R I m m e R 2. 5-(4-Diethylaminophenyl)-5,10-dihydro-11N-dibenzo [b,e] [1,4] diazepin-11-he (I. 2).

3,59 g (0.01 mol) of 5-(4-bromobutyryl)-5,10-dihydro-11N-dibenzo[b,e][1,4] diazepin-11-she RA who headed the remainder of 15 ml of water and 5 ml of ammonia solution. The reaction product is extracted with dichloroethane. Declaratively solution is shaken 3 times with diluted hydrochloric acid 1:2. Acidic phase is alkalinized with aqueous ammonia and extracted with dichloroethane. The dichloroethane is distilled off and the residue is recrystallized from toluene. Output 2,95 g (84% of theory); so pl. 166-167aboutC.

Found, %: C 71,56; N 7,31; N 11,96.

WITH21H25N3ABOUT2.

Calculated %: C 71,77; H 7,17; N 11,96.

The necessary starting material 5-(4-bromobutyryl)-5,10-dihydro-11N-dibenzo [b,e][1,4]diazepin-11-he will receive in the following way:

A mixture of 8.4 (0,04 mol) 5,10-dihydro-11N-dibenzo [b,e][1,4]diazepin-11-she, 9.6 g (0,052 mol) of acid chloride of 4-pamakani acid in 40 ml of dry toluene is refluxed for 5 hours, add 2 g of activated charcoal, boiled for 15 minutes under reflux, filtered and allowed to crystallize. The crystalline precipitate is filtered off and dried. After recrystallization from toluene obtain 10.7 g (74.3% of theory) of white crystalline substance with so pl. 159-161aboutC.

Found,%: C 56,98; N 4,30; N 7,72; Br 22,02;

WITH17H15BrN2O2.

Calculated, %: C 56,84; H 4,21; N 7,80; Br 22,24.

P R I m e R 3. 5(6 Diethylam the Idro-11N-dibenzo[b,e] [1,4] dia - seen-11-she and 50 ml of diethylamine heated for 5 hours under reflux. The reaction mixture was evaporated, to the residue add 30 ml of water and 10 ml of concentrated ammonia solution, and then shaken 3 times with benzene. The combined benzene solution is extracted 3 times with diluted hydrochloric acid 1:2. Acidic phase is alkalinized with concentrated ammonia solution and extracted released oil 3 times with benzene. The benzene is distilled off and the oily residue of the base (7 g) is dissolved by heating in 30 ml of toluene. After cooling, the precipitated precipitate is filtered and washed with toluene and ether. Yield 5 g (65,9% of theory); so pl. 104-105aboutC.

Found,%: C 72,63; H Of 7.68; N 11,20.

WITH23H29N3O2.

Calculated, %: C 72,79; H Of 7.70; N 11,07.

The hydrochloride. 7 g of oily residue grounds (see above) is dissolved by heating in 50 ml of isopropyl alcohol and cooled to room temperature, the solution is passed hydrogen chloride to pH 1. The solution is evaporated in vacuum to dryness, add another 50 ml of isopropyl alcohol and again evaporated. The residue is recrystallized from acetonitrile with addition of charcoal. The output of the hydrochloride of 3.8 g (45.7% of theory, counting by 5-(4-bromopropyl)-5,10-dihydro-11N-dibenzo[b,e][1,4]diazepin-11-he; so pl. 179-183aboutC.

Found, %: C 6652.

P R I m e R 4. 8-Chloro-5-(4-diethylaminophenyl)-5,10-dihydro-11N-dibenzo[b,e][1,4]diazepin-1 1-he (I. 4).

3,94 (0.01 mol) of 5-(4-bromobutyryl)-8-chloro-5,10-dihydro-11N-dibenzo [b, e] [1,4] diazepin-11-she dissolved in 25 ml of diethylamine, the solution is heated with stirring 5 h under reflux, the excess diethylamine distilled off and the residue is treated with 15 ml of water and 5 ml of concentrated ammonia solution. The mixture is extracted 3 times with diluted (1:2) hydrochloric acid, alkalinized with concentrated ammonia solution and extracted with separated oil 3 times with chloroform. Then the chloroform is distilled off and the residue is stirred with a small amount of dry benzene, and the product crystallized. After recrystallization from toluene; yield 2.85 g (73,8% of theory); so pl. 163-164aboutC.

Found, %: C 65,53; H 6,41; Cl 9,01.

WITH21H24lN3ABOUT2.

Calculated, % : C 65,36; H 6,27; Cl 9,19. 5-(4-Bromobutyryl)-8-chloro-5,10-dihydro-11N-dibenzo[b, e] [1,4]diazepin-11-it is used as an initial matter, get as similar to the starting material in example 1 from 8-chloro-5,10-dihydro-11N-dibenzo[b,e][1,4]diazepin-11-she 4-bromo-butyrylcholine. Output 83.1% of theory; so pl. 176-177aboutC.

Found,%: 51,77; N 3,65.

acylaminoalkyl)-5,10-dihydro-11N-dibenzo-[b,e] [1,4]-diazepin-11-he (I. 5).

4,07 g (0.01 mol) 5-5-bromovaleryl)-8-chloro-5,10-dihydro-11N-dibenzo[b, e][1,4]di - azepin-11-she dissolved in 25 ml of diethylamine, boiled for 5 hours under reflux, then the excess diethylamine distilled off, to the residue is added 15 ml of water and 5 ml of concentrated ammonia solution and the base is extracted with benzene. The benzene solution is shaken out twice with diluted hydrochloric acid (1:2), alkalinized with concentrated ammonia solution and extracted with benzene. After distillation of the benzene, the residue is recrystallized from toluene.

Yield 3.25 g (81.3% of theory); so pl. 159-160aboutC.

Found,%: C Of 66.00; H 6,63; Cl 8,65.

WITH22H26ClN3ABOUT2.

Calculated, % : C 66,07; H 6,55; Cl 8,86. 5-(5-Bromovaleryl)-8-chloro-5,10-dihydro-11N-dibenzo[b, e][1,4]-diazepin-11-it is used as the starting material, is obtained as similar to the starting material in example 1 from 8-chloro-5,10-dihydro-11N-dibenzo[b, e][1,4]diazepin-11-it 5-bromovalerate. Yield 87% of theory; so pl. 180-181aboutC.

Found, %: C 53,26; H Was 4.02; N 7,14.

WITH18H16BrClN2ABOUT2.

Calculated, %: C 53,03; H 3,96; N 6,37.

P R I m e R 6. 8-Chloro-5-(6-diethylaminopropyl)-5,10-dihydro-11N-dibenzo[b,e] [1,4]diazepin-11-he (1,6).

Found, %: C 66,72; H 7,02; N 10,08; Cl 8,54.

WITH23H28lN3ABOUT2.

Calculated, %: C 66,74; H 6,82; N 10,15; Cl 8,55.

5-(6-Bromopropyl)-8-chloro-5,10-dihydro - 11N-dibenzo[b,e][1,4]diazepin-11-it is used as an initial matter, get as similar to the starting material in example 1 from 8-chloro-5,10-dihydro-11N-dibenzo[b,e][1,4] diazepin-11-it 6-Brommapojkarna. Output 76.6% of theory; so pl. 170-171aboutC (from toluene).

Found, %: C 54,01; H 4.26 Deaths.

WITH15H18BrClN2ABOUT2.

Calculated, %: C 54,11; N 4,30.

P R I m e R 7. 8-Chloro-5-(7-diethylaminoethyl)-5,10-dihydro-11N-dibenzo[b,e][1,4]diazepin - 11-he (1,7).

A mixture of 4.35 g (0.01 mol) of 5-(7-bromine the excess diethylamine evaporated to a residue, add 15 ml of water and 5 ml of concentrated ammonia solution and extracted with the mixture 3 times with benzene. The combined benzene solution is shaken out three times with diluted hydrochloric acid (1:2), alkalinized acidic phase concentrated ammonia solution, shaken 3 times with benzene, the benzene is distilled off, the residue is dissolved by heating in toluene and allowed to stand until crystallization. The crystalline precipitate is filtered and washed successively with toluene and ether. Yield 2.8 g (66,6% of theory); so pl. 145-146aboutC.

Found, %: C 67,30; N 7,08; N 9,77; Cl 8,17.

WITH24H30ClN3ABOUT2.

Calculated, %: C 67,35; H 7,06; 9,81 N; Cl By 8.22.

5-(7-Brominator)-8-chloro-5,10-dihydro-11N-dibenzo [b,e][1,4]-diazepin-11-it is used as an initial matter, get as similar to the starting material in example 1 from 8-chloro-5,10-dihydro - 11N-dibenzo [b, e] [1,4]diazepin-11-she and 7 of ramanantoanina. Output for 71.5% of theory; so pl. 159-161aboutC (toluene).

Found, %: C 55,02; 4 H;68; N 6,40.

WITH20H20BrClN2ABOUT2.

Calculated, %: C 55,13; H 4,63; N To 6.43.

P R I m e R 8. 8-Chloro-5(6-N-morpholinoethyl)-5,10-dihydro-11N-dibenzo[b,e]-[1,4]-diazepin - 11-he (I,8).

A mixture of 5.9 g (0.015 mol) of 5-(6-bromopropyl)-8-chloro-5,10-dihydro-11N-dibenzo[b, e] [1,4]diazepin-11-she 5,23 g (0.06 mol) of the research by Kilani acid (1:2), alkalinized solution concentrated solution of ammonia and shaken with benzene. After washing the benzene phase with water, the benzene is distilled off, the oily residue is dissolved when heated to 120 mol of toluene, allowed to cool, filtered off the precipitate, wash it successively with toluene and ether and dried. Yield 3.7 g (59.6% of theory); so pl. 135-136aboutC.

Found,%: C 64,40; N 6,11; N 9,90; Cl 8,23;

WITH23H26ClN3ABOUT3.

Calculated, %: C 64,55; N 6,12; N 9,82; Cl 8,28.

P R I m e R 9. 8-Chloro-5-(7-N-morpholinomethyl)-5,10-dihydro-11N-dibenzo[b,e] [1,4]diazepin-11-he (I. 9).

A mixture of 3.27 g (0,0075 mol) 5-(7-brominator)-8-chloro-5,10-dihydro-11N-dibenzo[b, e][1,4]diazepin-11-she and 2 g (0,0225 mol) of the research in 25 ml of toluene is refluxed 5 hours After cooling, the reaction is extracted with a solution of diluted hydrochloric acid, alkalinized solution of concentrated ammonia and extracted 3 times with dichloromethane. Washed declaratively solution of water, distilled dichloromethane, the residue is recrystallized from a mixture of heptane-toluene (1:1), the crystalline precipitate is filtered off, washed with ether and dried. Output 2 g (60.7% of theory); so pl. 102-103aboutC.

Found is 1; Cl 8,02.

P R I m e R 10. 8-Chloro-5,10-dihydro-5-[6-(4-methylpiperazin-1-yl)caproyl]-hibe - site, located between[b,e][1,4]diazepin-11-he (I. 10).

The mixture 8.44 grams (0.02 mol) of 5-(6-bromopropyl)-8-chloro-5,10-dihydro-11N-dibenzo [b,e][1,4]diazepin-11-she is 4.21, (0,042 mol) of N-methylpiperazine and 50 ml of toluene is refluxed. Toluene solution is shaken with 20 ml of water. Toluene phase was extracted with 2 times 10 ml of diluted hydrochloric acid (1: 1), United acidic phase is alkalinized solution of concentrated ammonia, shaken once with 30 ml and 2 times with 10 ml of chloroform and the chloroform phase is evaporated. To the residue was added 2 times in 50 ml isopropanol and evaporated each time. In conclusion, add 10 ml of toluene, slightly heated and filtered crystalline precipitate. Yield 6 g (68% of theory); so pl. 142-147aboutC.

Found, %: C 65,47; H 6,67; N 12,31; Cl 7,98.

C24H29ClN4ABOUT2.

Calculated, %: C 65,37; N. Of 6.68; N 12,71; Cl 8,04.

P R I m e R 11. 5,10-Dihydro-[6-(4-methylpiperazin-1-yl)-caproyl]-11N-dibenzo[b,e] [1,4]diazepin-11-he (I. 11).

A mixture of 5.8 g (0.015 mol) of 5-(6-bromopropyl)-5,10-dihydro-11N-dibenzo[b, e] [1,4] di-azepin-11-she, 3.2 g (to 0.032 mol) of N-methylpiperazine and 40 ml of toluene is boiled for 4 times with a reflux condenser,two more times with 20 ml of diluted hydrochloric acid (1:1), add to the combined acidic phase, 20 ml of chloroform, alkalinized with concentrated ammonia solution, shaken and separated chloroform phase. Ammonia solution is shaken for a further 2 times with 20 ml of chloroform, the combined chloroform solutions are dried under Na2SO4and evaporated. The oily residue is boiled with 20 ml of isoprenaline, evaporated and zakristallizuetsya product when heated with 20 ml of toluene. Yield 4.7 g (77% of theory); so pl. 129aboutC (with decomp.).

Found, %: C 70,52; N 7,37; N 13,46.

C24H30N4O2.

Calculated, %: C 70,91; H 7,44; N 13,78.

P R I m e R 12. 8-Chloro-5(6-ethylaminomethyl)-5,10-dihydro-11N-dibenzo[b,e][1,4] diazepin-11-he (I. 12).

To a solution of 8.44 grams (0.02 mol) of 5-(6-bromopropyl)-8-chloro-5,10-dihydro-11N-dibenzo [b, e][1,4]diazepin-11-she's in 50 ml of dimethylformamide are added at the 2aboutWith 75% solution 10 ml of ethylamine (0.77 mol) in dimethylformamide, heated the mixture for 0.5 h at 50aboutC in a closed vessel, again cooled to 2aboutC, add another 5 ml of the above solution of ethylamine is heated for another 0.5 h at 50aboutC, stirred under heating with 10% (by weight of the original product) activated charcoal, filtered and evaporated in vacuum to dryness. The remainder smesi the s and miss in the HCl solution to pH 1.

The acidic solution is evaporated in vacuum to dryness, again add isopropanol, again evaporated to dryness, and crystallized with coal from isopropanol and boil the residue with 30 ml of acetonitrile. Yield 3.0 g (35,4% of theory); so pl. 190-193aboutC (with decomp.).

Found, %: C 59,40; H 5,94; N 9,96; Cl 16,97.

WITH21H24ClN3O2HCl.

Calculated, %: C 59,72; H 5,97; N 9,95; Cl 16,79.

P R I m e p 13. 5-(6-Ethylaminomethyl)-5,10-dihydro-11N-dibenzo[b,e] [1,4]Diaz - pin 11-he (I. 13).

Dissolve to 7.8 g (0.02 mol) of 5-(6-bromopropyl)-5,10-dihydro-11-dibenzo[b, e] [1,4] diazepin-11-she's in 50 ml of dimethylformamide, added with 2aboutWith 10 ml of 75% aqueous solution of ethylamine (to 0.17 mol), heated the mixture for half an hour at 50aboutC in a closed vessel, add in 2aboutWith another 10 ml of ethylamine and heated with 10% (by weight of the original product) of activated charcoal and evaporated in vacuum to dryness. The residue is dissolved in 30 ml of chloroform, shaken twice with 20 ml of aqueous HCl (1:1) was added to the United acidic extracts 20 ml of chloroform and alkalinized with concentrated ammonia solution. The ammonia layer extracted twice with 20 ml of chloroform, United chloroform extracts are dried with sodium sulphate with the addition of a small amount of the asset is put through a solution of Hcl to pH 1, evaporated in vacuum to dryness, again add 50 ml of isopropanol, evaporated to dryness and boil the residue with 25 ml of acetonitrile. The output of 5.1 g (65.4% of theory); so pl. 189,5-196,5aboutC (with decomp.).

Found, %: C 65,23; N Is 6.54; N 10,89; Cl 8,91.

WITH21H25N3O2HCl.

Calculated, %: C 65,02; H 6,76; N 10,83; Cl 9,14.

P R I m e R 14. 8-Chloro-5-(6-cyclohexylamino)-5,10-dihydro-11N-dibenzo- [b,e][1,4]diazepin-11-he (I. 14).

The mixture 8.44 grams (0.02 mol) of 8-chloro-5-(6-bromopropyl)-5,10-dihydro-11N-dibenzo [b, e][1,4]diazepin-11-it, 4 g (0.04 mol) of cyclohexylamine and 50 ml of toluene is refluxed for 5 hours To the reaction mixture is added 25 ml of toluene and 50 ml of water and the mixture is stirred to dissolve the oily layer formed in the reaction. Toluene solution is washed 3 times with water. The toluene is distilled off in vacuum. To the residue are added 50 ml of toluene and re-evaporated in a vacuum. The residue is dissolved in 90 ml of acetone. To the filtered acetone solution add 3 ml of concentrated hydrochloric acid. The precipitated oil is dissolved under stirring. From the resulting solution upon standing gradually falls crystalline precipitate. The precipitate is recrystallized from absolute alcohol and lysostaphin-11-it; so pl. 174-175aboutC.

Found, %: C 61,56; H 6,57; 8,66; Cl 14,67.

WITH25H30ClN3ABOUT2l1/2 H2O.

Calculated, %: C 61,85; H 6,64; N 8,65; Cl 14,61.

P R I m e R 15. 5-(6-Morpholinoethyl)-5,10-dihydro-11N-dibenzo[b,e] [1,4]Diaz-pin 11-he (1,15).

A mixture of 5.8 g (0.015 mol) of 5-(6-bromopropyl)-5,10-dihydro-11N-dibenzo[b, e] [1,4] -dia - seen-11-she, 2.8 g (to 0.032 mol) of the research and 40 ml of toluene is refluxed and stirred for 4 h the Reaction mixture, after cooling, treated with an aqueous ammonia solution, an aqueous solution is separated and the toluene solution is treated with water. The target product is extracted from toluene twice with diluted hydrochloric acid (1:1). To the acidic aqueous solution was added 30 ml of toluene and the mixture is alkalinized with an aqueous solution of ammonia. In toluene solution is separated, washed with water and dried with sodium sulfate. The drying agent is filtered off, the toluene is distilled off. The balance in the amount of 4.9 g dissolved in 10 ml of toluene and the solution allowed to stand until crystallization. The crystalline precipitate is filtered off, dried, dissolved in 30 ml of isopropyl alcohol, the solution is boiled with coal within 5 minutes the Charcoal is filtered through the filtrate miss gaseous chlorite is Ute. Yield 4.1 g (63,6% of theory); so pl. 206-209aboutC (decomp.).

Found, %: C 64,18; H 6,67; N 9,75; Cl Of 8.37.

WITH23H27N3O3HCl.

Calculated, %: C 64,25; H 6,56; N 9,77; Cl 8,25.

P R I m e R 16. 5-(6-Cyclohexylamino)-5,10-dihydro-11N-dibenzo-[b,e] [1,4]diazepin-11-he (I. 16).

Mix a 3.87 g (0.01 mol) of 5-(6-bromopropyl)-5,10 dihydro-11N-dibenzo[b, e][1,4] diazepin-11-she, 2.5 g (0,025 mol) cyclohexylamine and 25 ml of toluene is refluxed for 5 hours To the reaction mixture add a solution of 2.3 ml of Hydrobromic acid in 20 ml of water to all the major substances to translate in salt. Water-toluene solution merge with decantation of the lower layer (a mixture of a crystalline precipitate with butter). To the bottom layer, add 30 ml of acetone, the mixture is ground and boiled in a reverse refrigerator 15 minutes the Precipitate is filtered off, thoroughly washed with water. To the precipitate was added 50 ml of acetone and the suspension is refluxed for 1 hour the Precipitate is filtered off, washed with acetone and dried. The output of bromhidrosis 5-(6-cyclohexylamino)-5,10-dihydro-11N-dibenzo[b,e][1,4] diazepin-11 - she 2.6 g (52.5% of theory); so pl. 250-251aboutC.

Found, %: C 60,92; H 6,63; N 8,65; Br 16,00.

WITH25H31N3

A mixture of 5.8 g (0.015 mol) of 5-(6-bromopropyl)-5,10-dihydro-11N-dibenzo[b, e] [1,4] -dia - seen-11-she and 20 mol Diisopropylamine refluxed for 21 hours, the Excess Diisopropylamine distilled off, the residue is dissolved in 50 ml of chloroform and treated with 2 times 20 ml of dilute ammonia solution (1: 1). The target product is extracted 3 times with 20 ml of concentrated hydrochloric acid. The combined acidic extracts alkalinized with an aqueous solution of ammonia and the liberated base extracted with chloroform. The chloroform solution is washed with water and the chloroform is distilled off. The residue is dissolved by heating in toluene. When standing from toluene falls crystalline precipitate. The precipitate is filtered, dried. Yield 1.7 g (25,6% of theory); so pl. 100-106aboutC (with decomp).

Found, %: C 73,66; N. Of 7.93; N The 10.40.

WITH25H32N3O2.

Calculated, %: C 73,68; N 8,16; N 10,31.

P R I m e R 18. 8-Chloro-5-(4-morpholinomethyl)-5,10-dihydro-11N-dibenzo[b,e][1,4]diazepin-11 - he (1.18).

A mixture of 7 g (0.02 mol) of 8-chloro-4(chlorobutyryl)-5,10-dihydro-11N-dibenzo[b, e] [1,4] diazepin-11-it, 4 g (0.04 mol) of the research and 50 ml of toluene is refluxed with stirring for 5 hours the Reaction mixture after cooling, ol(1:1) three times with 20 ml. The combined acidic extracts alkalinized with an aqueous solution of ammonia and the product is extracted with chloroform. The chloroform solution is washed with water, dried with sodium sulfate and the chloroform is distilled off. The residue (5.8 g) gradually zakristallizuetsya and recrystallized from 15 ml of isopropanol with the addition of activated charcoal. Yield 3.8 g (47.5% of theory); so pl. 154-157aboutC.

Found, %: C 63,17; H 5,15; N 10,49; Cl 8,67.

WITH21H22lN3ABOUT3.

Calculated, %: C 63,08; H Of 5.55; N 10,51; Cl 8,87.

The necessary starting material 8-chloro-5-(4-chlorobutyryl)-5,10-dihydro-11N-dibenzo [b,e][1,4]diazepin-11-he will receive in the following way:

A mixture of 37.5 g (0.15 mol 8-chloro-5,10-dihydro-11N-dibenzo[b,e][1,4]diazepin-11 - she, 27 g (0.25 mol) of chlorotyrosine and 250 ml of toluene is refluxed under stirring for 6 hours Then add 4 g of activated charcoal and boil another 15 minutes the Charcoal is filtered off. From the filtrate upon cooling roll a crystalline precipitate. The precipitate is filtered off and dried; after recrystallization from toluene and drying the product yield is 44 g (81.9% of theory; so pl. 166-168aboutC).

Found,%: C 58,58; N Is 4.03; N 8,09; Cl 19,97.

WITH17H14

A solution of 10 g (0,029 mol) 5-(6-chloropropyl)-5,10-dihydro-11N-dibenzo[b, e] [1,4]dia - seen-11-she and 50 ml of diethylamine in 100 ml of dimethylformamide is stirred at a temperature of 65aboutwith over 33 hours, the Reaction mixture is evaporated to dryness, the residue is treated by heating a mixture of 120 ml of toluene, 70 ml of water and 40 ml of concentrated ammonia solution. Toluene layer is separated, the aqueous layer was re-extracted with toluene. The target product is extracted from the combined toluene solutions three times with diluted hydrochloric acid (1:1). The combined acidic solution is alkalinized with concentrated ammonia solution and the desired product extracted with toluene. Toluene solution pomeshivayut water and the toluene is distilled off. The residue is 2 times recrystallized from a mixture of toluene cyclohexane with the addition of activated charcoal.

Yield 3.1 g (27,2%) of theory); so pl. 100-103aboutC.

Found,%: C 72,62; H A 7.62; N 11,08.

C23H29N3ABOUT2.

Calculated,%: C 72,79; H Of 7.70; N 11,07.

Pharmacological results obtained in the study of derivatives dibenzodiazepine

The compounds of formula I have a number of advantages. A number of compounds of the formula 1 inhibition of ectopic activity bookstudy vitellinae chronotropic action of a substance in combination with anti-arrhythmic can be very useful in the clinic. Bradycardia, acute arrhythmia, in the clinic, especially in patients with myocardial infarction, represent a significant challenge for treatment. Currently these tools are virtually absent in clinical practice. Therefore, the creation of this type of drugs is very important.

As can be seen from the table, in the study of acute toxicity derived dibenzodiazepine when administered intravenously in rats toxicity ranges from 38 to 144 mg/kg, i.e., the toxicity of the most toxic compounds in 2 times smaller than that of lidocaine, a drug that is widely used by patients with myocardial infarction. In experiments on dogs of all substances were well tolerated by the animals, was not observed vomiting, anxiety is typical for most antiaritmikov. Antiarrhythmic activity of the compounds was studied in experiments on animals on three models of arrhythmias: aconitine in rats, potassium chloride in rats, two-stage ligation of the coronary artery by Harris in dogs.

The table presents two models of arrhythmias the most informative (potassium chloride arrhythmia in rats and the model of Harris in dogs). You can see that the active substances varies from 0.02 mg/kg to 5.8 mg/kg, which in most cases snales their significant therapeutic range, expressed in relation to LD50/ED50that gives the doctor an opportunity to manipulate doses. As can be seen from the table, therapeutic range of these compounds ranges from 12 to 1810. This is much better than antiarrhythmic indexes lidocaine (5,8) and quinidine (18).

The most interesting data were obtained in experiments on dogs. As can be seen from the tables, substance at a dose of 2.5 to 5 times smaller than that of lidocaine and quinidine, suppress ectopic activity, due to experimental myocardial infarction. Especially valuable was the fact long duration antiarrhythmic effects of substances. The maximum duration of effect of lidocaine and quinidine 10-15 min, then the arrhythmia recurs again. Duration of dibenzodiazepine ranges from 30 to 360 minutes This is especially valuable in the clinic, as it does not require frequent repeated injections of drugs. In the table shown in the last column of the positive chronotropic effect of a +. As can be seen from the discussed material, most of the compounds of formula I in equimolar doses tend to increase heart rate, which may be one of the manifestations of anticholinergic properties of the investigated substances. Thus, the compounds of formula I have is sustained fashion chronotropic effect. The obtained data allow to hope for in this series of original medicines for the treatment of bradyarrythmia.

5 - (A - AMINOACYL)-5,10-DIHYDRO-11H-DIBENZO[B, E] [1,4]-DIAZEPIN-11-ONS OR THEIR SALTS, POSSESS ANTIARRHYTHMIC ACTIVITY.

5-( w-Aminoacyl)-5,10-dihydro-11N-dibenzo [b,e] - [1,4]-diazepin-11-ons or their salts of General formula

< / BR>
where R1H, R2= R3- CH3n = 5, X Is Cl, m = 1;

R1- H, R2= R3- C2H5n = 3, m = 0;

R1- H, R2= R3- C2H5n = 5, X Is Cl, m = 1;

R1- Cl; R2= R3- C2H5n = 3, m = 0;

R1- Cl; R2= R3- C2H5n = 4, m = 0,

R1- Cl, R2= R3- C2H5n = 5, m = 0;

R1- Cl, R2= R3- C2H5, n = 6, m = 0;

< / BR>
< / BR>
< / BR>
< / BR>
R1- Cl; R2- H; R3- - C2H5; n = 5 ; X Is Cl; m = 1,

R1-H; R2- H; R3- C2H5n = 5; X Is Cl; m = 1;

< / BR>
< / BR>
< / BR>
R1- H; R2= R3- - CH(CH3)2; n = 5;m = 0;

< / BR>
possess antiarrhythmic activity.

 

Same patents:

The invention relates to new biologically active chemical compounds, namely, to derive a cyclic amide of the formula I

R1-(CH2)n-Z,

where R1group cyclic amide, such as 2H-3,4-dihydro-1,3-benzoxazin-2-she, 2H-3,4-dihydro-1,3-benzoxazin-2,4-dione, and 1,2,3,4-tetrahydroquinazoline-2,4-dione, and 1,2,3,4-tetrahydroquinazolin-2-it, 1,2,3,4-tetrahydropyrido(3,2-d)-pyrimidine-2,4 - dione, and 1,2,3,4-tetrahydropyrido(3,2-d)pyrimidine-2-it, 1,2,3,4-tetrahydropyrimidine-2,4-dione, pyrrolidin-2-it, 1,2,3,4 - tetrahydropyridine-2-it, 5H-6,7,8,9-tetrahydropyrido(3,2-b)azepin-6-she N-5,6,7,8-tetrahydropyrido(2,3-b)azepin - 8-she, 2H-3,4-dihydropyrido(2,3-e)-1, 3-oxazin-2-thione or 2-she pyrrolidine (3,4-b)-pyrazin-5-she 1H-2,3,4,5-tetrahydrothieno(2,3-b)indol-2-it, 8H-4,5,6,7-tetrahydrothieno(2,3-b)thiophene-7-she 4H-pyrazolo(5,4-f)benzazepin-9-it, isoindoline-1,3-dione, benzoxazolyl-2-it, unsubstituted or substituted lower alkyl, lower alkoxy, halogen, the nitro-group, carboxy, benzoyl or benzyl, n is zero or an integer from 1 to 6, Z is a group of formula (A) or (B):

N-(CH2)mR2(A) or -(CH2)p, dioxolane, furan, tetrahydrofuran, methylfuran or thiophene, m is an integer from 1 to 3; R3is lower alkyl; R4is phenyl or a radical of dioxolane, furan or thiophene, p = 1, provided that when R1radical 1,2,3,4-tetrahydrobenzo-2-or 1,2,3,4-tetrahydroquinazoline-2,4-dione, R2and R4are not phenyl or substituted by a halogen phenyl, or their pharmacologically acceptable salts with antiacetylcholinesterase activity

The invention relates to new chemical compounds having valuable pharmacological properties and relates to new pharmacologically active N-substituted derivatives of (3R, 4R)-3-ethyl-4- [(1-methyl-1H-imidazol-5-yl)methyl] -2-Pierre - oligonu that have antiglaucoma action and can find application in medicine

- aminopropionic)-5h-dibenz[b, f] azepine with antiarrhythmic activity" target="_blank">

The invention relates to new chemical compounds of a number of dibenz (b, f) azepine, namely 3-carbalkoxy-5- (-aminopropionic)-5H-dibenz (b, f) azepine General formula

where (a) X=-CH2-CH2-, R1=R2=CH3, R3=H, n=1;

b) X=-CH2-CH2-, R1=CH3, R2=CH2CH2OH, R3=H, n=1;

C) X=-CH2-CH2-, R1=C2H5, R2=R3=H, n=1;

g) X=-CH2-CH2-, R1=C2H5, R2=CH3, R3=H, n=0 or 1;

d) X=-CH2-CH2-, R1=R2=C2H5, R3=H, n=1;

e) X=-CH2-CH2-, R1=C2H5, R2=H-C3H7, R3=H, n=1;

W) X=-CH2-CH2-, R1=C2H5, R2=R3=CH3n=1;

C) X=-CH2-CH2-, R1=R2=R3=C2H5n=1;

and) X=-CH2-CH2-, R1=C2H5, R2and R3together = -(CH2)2O(CH2)2-, n=1;

K) X=-CH2-CH2-, R1=ISO-C3H7, R2=CH3, R3=H, n=0;

l) X=-CH2-CH2-5, R2=CH3, R3=H, n=0;

n) X=-CH=CH-, R1=R2=C2H5, R3=H, n=1,

that possess antiarrhythmic effect and can find application in medicine

The invention relates to medicine, namely to obstetrics

The invention relates to new biologically active pyridyl - or pyrimidinediamine derivative of piperazine or 1,4-disallocation, or their pharmacologically active acid additive salts with psychotropic action
The invention relates to medicine, namely to psychiatry

The invention relates to new derivatives of benzodiazepine, specifically tricyclic compounds of General formula Iwhere RI- phenyl, possibly substituted by fluorine,

X - CH2or CHR3where R3- C1-C4alkyl, and R2- 2-indolocarbazole; phenyl (lower) alkanoyl, which can be substituted by amino or lower alkanolamine; or R2- phenylcarbamoyl, which may be substituted with halogen or lower alkoxygroup, or their pharmaceutically acceptable salts

FIELD: veterinary science.

SUBSTANCE: a sow should be twice injected with oxytocin and, additionally, intramuscularly about 2-4 h after afterbirth detachment one should introduce clathroprostin at the dosage of 1 ml. The innovation suggested is very efficient in preventing metritis-mastitis-agalactia and endometritis in sows, as well.

EFFECT: higher efficiency of prophylaxis.

1 ex, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 1 tbl, 30 ex

FIELD: medicine, cardiology.

SUBSTANCE: patient with stenocardia should be introduced with efficient quantity of omapathrylate or its pharmaceutically acceptable salt either separately or in combination with another pharmaceutically active agent. Another pharmaceutically active substance could be represented by organic nitrate, beta-adrenergistic blocking agent, blocking agent of calcium supply or antithrombocytic preparation. It is suggested to apply omapathrylate or its pharmaceutically acceptable salt to prepare medicinal preparations for treating and/or decreasing stenocardial symptoms.

EFFECT: higher efficiency.

16 cl, 2 dwg, 2 ex, 8 tbl

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of pyridothienodiazepine. Invention describes derivatives of pyridothienodiazepine of the general formula (I):

as a racemate or in form of enantiomers or diastereomers, or their mixture wherein R1 represents hydrogen atom or radical of the formula: R'1-NH-C(Y)- wherein R' represents phenyl radical optionally substituted with one or more similar or different substitutes taken among lower alkyl, lower alkoxy-group, lower alkylthio-group, lower alkoxycarbonyl, lower alkylsulfonyl, halogen atom, trifluoromethyl, trifluoromethyloxy-group, hydroxy-, nitro-, cyano-group, phenyl, phenoxy-group, cycloalkyl or heterocycloalkyl; R2 represents lower alkyl, trifluoromethyl or phenyl radical optionally substituted with one or more similar or different substitutes taken among hydroxy-group, halogen atom, lower alkyl or lower alkoxy-group; X and Y represent independently oxygen (O) or sulfur (S) atom; R3a represents hydrogen atom, lower alkyl, hydroxy-group or radical of the formula -OC(O)R'3a wherein R'3a represents alkyl radical comprising from 1 to 10 carbon atoms optionally substituted with radical of the formula: NR''3aR'''3a wherein NR''3a and R'''3a represent independently hydrogen atom, lower alkyl, phenyl, lower phenylalkyl, alkylcarbonyl or alkoxycarbonyl; R3b represents hydrogen atom or lower alkyl radical; R4 represents radical of the formula: -(CH2)n-CHR'4R''4 wherein n represents a whole number 0, 1, 2, 3, 4, 5 or 6; R'4 and R''4 represent independently hydrogen atom, lower alkyl, cycloalkyl, lower cycloalkylalkyl, phenyl, pyridyl, phenylcarbonyl or adamantyl wherein indicated radicals are substituted optionally with one or more similar or different substitutes taken among hydroxy-group, halogen atom, trifluoromethyl, lower alkyl or lower alkoxy-group; A----B represents -C=N- or -C-N(R5)- wherein R5 represents hydrogen atom, amino-radical, lower alkylamino-group, di-(lower alkyl)-amino-group, cycloalkyl, heterocycloalkyl, guanidyl optionally substituted with nitro- or cyano-group, phenyl optionally substituted with one or more similar or different substitutes taken among alkyl or alkoxyalkyl wherein indicated alkyl or alkoxyalkyl are substituted optionally with oxy- or amino-group; indolyl or radical of the formula: -NH-C(O)-(CH2)c-NH-C(O)(CH2)d-NH2; p represents a whole number 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; c and d represent independently a whole number 0, 1, 2 or 3; or salts of these compounds. Also, invention describes methods for preparing compounds of the general formula (I), pharmaceutical composition based on compounds of the general formula (I) eliciting activity to inhibit binding somatostatin-14 and an intermediate compound of the formula (2) given in the invention description. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

17 cl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: medicine.

SUBSTANCE: method involves administering typical tricyclic antidepressants combined with selective reverse serotonin capture inhibitors. Anxious version of subpsychotic level depressive syndrome of endogenous genesis being treated, intravenous drop-by-drop infusion of 2.-4.0 ml of 1% amitriptiline solution per 200 ml of physiologic saline is applied in 12-14 procedures combined with selective reverse serotonin capture inhibitor given per os, Zoloft is per os administered as the inhibitor at a dose of 50-100 mg. Then, supporting Zoloft therapy is applied at a dose of 100 mg during 3 months. Atypic version of depressive syndrome of subpsychotic level and endogenous genesis is treated with intravenous drop-by-drop infusion of 1.25% Melipramine solution at a dose of 2.0-4.0 ml per 200 ml of power supply source in 12-14 infusions combined with a reverse serotonin capture inhibitor. Paxyl is taken at a peroral dose of 40-60 mg as the inhibitor. Then, supporting Paxyl therapy is applied at a dose of 40-60 mg during 3 months.

EFFECT: enhanced effectiveness of treatment; reduced risk of complications; accelerated depressive syndrome relief.

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: biochemistry.

SUBSTANCE: invention relates to method for production of synthetic chlorophyll (Chl) or bacteriochlorophyll (Bchl) derivatives of general formula I , wherein X is O;. Claimed method includes interaction under anaerobic conditions of Chl, Bchl derivatives containing COOCH3-group in C-132-position and COOR3-group in C-172-position in presence of tetraethyl orthotitanate. Further compounds of formula I wherein R1 and R2 are different radicals are obtained in aproton solvent such as peroxide-free tetrahydrofurane and dimethyl formamide, and compounds of formula I wherein R1 and R2 are the same ones are produced by using R1OH as a solvent. Derivatives of present invention are useful as stabilizers, linkage/spacer for binding another acceptable molecules to Chl/Bchl macrocycle.

EFFECT: simplified method for production of various chlorophyll or bacteriochlorophyll derivatives.

13 cl, 3 ex, 2 tbl, 8 dwg

FIELD: animals science.

SUBSTANCE: the present innovation deals with intramuscular injection of sodium salt preparation cloprostenol 30-45 min before placing at the dosage of 750 mcg/animal. The method provides increased reproductive function, enhances sexual reflex, increases the volume of ejaculate, concentration, activity and quality of spermatozoa.

EFFECT: higher efficiency of breeding.

2 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: described is a novel crystalline β-modification of 7-bromo-1,3-dihydro-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one (phenazepam) and synthesis method thereof, which can be used in pharmaceutical industry and medicine as a tranquilliser. Said novel crystalline β-modification of 7-bromo-1,3-dihydro-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one is characterised by certain interplanar spacing (A0) and corresponding intensity and parameters of the crystal lattice, given in the claims.

EFFECT: marked muscle relaxant, soporific, anticonvulsant and anxiolytic action.

2 cl, 7 ex, 2 tbl, 9 dwg

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 1 tbl, 30 ex

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