3 carbalkoxy-5-(- aminopropionic)-5h-dibenz[b, f] azepine with antiarrhythmic activity


C07D223/24 - with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom

 

(57) Abstract:

The invention relates to heterocyclic substances, in particular 3-carbalkoxy-5-( a-aminopropionic)-5H-dibenz[b, f] azepino, General formula , where X = -(CH2)2and R1= R2= CH3, R3n = 1; b) R1= CH3, R2= C2H5OH, n = 1; R1= C2H5, R2= R3= CH3n = 1; R1= C2H5, R2= CH3, R3= H, n = 0 or 1; d) R1= R2= C2H5, R3=H, n = 1; f) R1= C2H5, R2= n-C3H7, R3= H, n = 1, W) R1= C2H5, R2= R3= CH3n = 1; C) R1R2= R3= C2H5n = 1, and R1= C2H5, (R2+R3) = -(CH2)2-O-(CH2)2-, n = 1; R1= ISO-C3H7, R2= CH3, R3=H, n = 0, l) R1-ISO-FROM3H7, R2=C2H5, R3=H n = 1; when X = -CH= CH - m) R1=C2H5, R2=CH3, R3=H n = 0, n) R1= R2= C2H5, R3=H, n = 1, which possess antiarrhythmic activity, which can be used in medicine. Goal - the creation of new, more active and less toxic substances decree is ω inert solvent(benzene) in the presence of an HCl acceptor(pyridine) at the boiling reaction mixture. The product is then treated with the appropriate amine: other2R3in the environment of the solvent at boiling. New substances, in comparison with bennekom, higher activity with less toxicity. table 1.

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- , THE H2-CH2-, R1=ISO-C3H7, R2=C2H5, R3=H, n=1;

m) X=-CH=CH-, R1=C2H5, R2=CH3, R3=H, n=0;

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

that possess antiarrhythmic effect and can be used in medicine.

The aim of the invention is the finding in a series of dibenz (b, f) azepine new compounds with higher antiarrhythmic activity, less toxicity, better absorption than bonnekor.

The invention is illustrated by the following examples.

P R I m e R 1.

a) 3-Carbomethoxyamino-5--bromopropionyl-10,11-dihydro-5H-dibenz (b, f) azepin.

To a solution of 13.5 g (0.05 mol) of 3-carbomethoxyamino-10,11-dihydro-5H-dibenz (b, f) azepine in 200 ml of toluene was added 12 g (0.05 mol) of acid chloride of bromopropionic acid. The reaction mixture is stirred while heating to 70-80aboutWith 2 hours and then boil for 3 h, cooled, filtered off the precipitation. Weight 14 g; so pl. 158-159aboutC (from toluene); Rf0,40 (in a mixture of chloroform-acetone 12:1).

Found, %: N 7,31; 7,27; Br 20,17; 20,24.

WITH19H19BrN2O3.

Calculated, %: N 6,94; Br 19,81.

aboutWith, then 4 hours at 100-120aboutC. After cooling, the reaction mixture is shaken out with water, the toluene layer is separated, the toluene is distilled off, the residue is dissolved in 5% hydrochloric acid, treated with charcoal and adding 10% sodium hydroxide solution, allocate basis. Weight 2 g

The base is dissolved in toluene and the addition of an ethereal solution of hydrogen chloride allocate hydrochloride. Yield 1.8 g (67%); so pl. 225-227aboutC (with decomp. from acetone).

Found, %: CL 8,95; 8,75; N 10,59; 10,51.

WITH20H23N3O3HCl.

Calculated, %: CL Is 9.09; N 10,77.

P R I m m e R 2. 3 Carbomethoxyamino-5- - (-acetylamino)propionyl 10,11-dihyd-ro-5H-dibenz (b, f) azepin (IB).

A mixture of 4.0 g (0.01 mol) of 3-carbomethoxyamino-5--bromopropionyl-10,11-dihydro-5H - dibenz (b, f) azepine, 3.3 grams (by 0.055 mol) ethanolamine, 70 ml of toluene and 5 ml of ethanol is heated 3 h at 70-80aboutAnd then 3 hours at the boil. The solvent is distilled off, the residue is treated with water, dissolved in 5% hydrochloric acid solution lighten coal, the addition of sodium hydroxide solution, isolated ground, dissolve it in pl. 163-164aboutC (with decomp. from acetone).

Found, %: CL 7,69; To $ 7.91; N 9,46; 9,43.

WITH21H25N3O4HCl H2O.

Calculated, %: CL 8,10; N 9,59.

P R I m e R 3. a) 3-Carbamaxepine-5-(-chloropropionyl)-10,11-dihydro-5H-dibenz (b, f) azepin get similar to the synthesis of Sh-derived in example Ia.

Yield 94%. So pl. 180-182aboutC (from ethanol).

Found, %: C 64,52; N 5,73; N 7,65; Cl 9,72.

WITH20H21N2O3Cl.

Calculated, %: C 64,43; N. Of 5.68; N 7,51; Cl 9,51.

b) 3-Carbamaxepine-5-(-aminopropionic)-10,11-dihydro-5H-dibenzazepine (Ie).

Saturate the mixture of 18.6 g (0.05 mol) of 3-carbamaxepine-5-(-chloropropionyl)-10,11 - dihydro-5H-dibenz (b, f) azepine, 250 ml of 96% ethanol and 200 ml of an aqueous solution of ammonia at room temperature with gaseous ammonia, after which the mixture is heated with stirring in a laboratory autoclave 18 h at 60-65aboutC. Then in vacuum at 70aboutTo remove the solvent, the viscous residue is dissolved in dilute hydrochloric acid, treated with activated carbon, the addition of concentrated ammonia solution allocate the basis and extracted with him methylene chloride. After drying of the extract with sodium sulfate priba is. ) azepine.

Yield 73% of theory; so pl. 193-195aboutC.

Found, %: C 61,31; N 6,11; Cl 9,00.

WITH20H23N3O3HCl.

Calculated, %: C 61,61; N 6,20; Cl Is 9.09.

P R I m e R 4.

a) 3-Carbamaxepine-5--bromopropionyl-10,11-dihydro-5H-dibenz (b, f) azepin.

To a solution of 56 g (0.2 mol) of 3-carbamaxepine-10,11-dihydro-5H-dibenz (b, f) azepine in 300 ml of toluene at boiling and stirring was added 53 g (0.22 mol) of bromopropionitrile. The reaction is over 3 hours the Toluene is distilled off, the oily residue is treated with water, forms a crystalline precipitate. Weight 75 g (80%); so pl. 126-130aboutC. After recrystallization from aqueous isopropanol and then from toluene mass of 54 g (58%); so pl. 140-142aboutC.

Found, %: Br 18,92; 18,87; N 6,82.

WITH20H21BrN2O3.

Calculated, %: Br 19,15; N Of 6.71.

b) 3-Carbamaxepine-5-(-methylamino)propionyl 10,11-dihydro-5H-dibenz (b, f) azepin (Iك).

Suspended 20,9 g (0.05 mol) of 3-carbamaxepine-5-(-bromopropionyl)-10,11-di - hydro-5H-dibenz (b, f) azepine in 150 ml of 96% ethanol. Add 30 ml of 35% aqueous solution of methylamine, stirred the mixture for 16 h at 50-70aboutC and left overnight at room temperature is more at 100aboutC. Obtain 15 g of 3-carbamaxepine-5-( -methylaminopropyl)-10,11 - dihydro-5H-dibenz (b, f) azepine, which is cleaned and then rinsed with acetone and recrystallization from n-butanol; so pl. 201-203aboutC.

Found, %: C 68,58; N. Of 6.96; N 11,32.

WITH21H25N3O3.

Calculated, %: C 68,64; N 6,86; N 11,44.

Dissolve 10 g of the obtained base in 40 ml of methylene chloride, is passed through a solution of gaseous hydrogen chloride to pH 2, add ether, precipitated hydrochloride is filtered off. Yield 81%; so pl. 168aboutC.

P R I m e R 5. 3 Carbamaxepine-5-(ethylamino)propionyl 10,11-dihydro-5H - dibenz (b. (f) azepin (Ia).

Obtained in the conditions of example 4B. Yield 73%; so square hydrochloride 172aboutC.

Found, %: C 60,86; N 7,00; N 9,58; CL 8,13.

WITH22H27N3O3HCl H2O.

Calculated, %: 60,61; N 6,94; N For 9.64; CL 8,13.

P R I m e R 6. 3 Carbamaxepine-5-(n ' propylamino)propionyl 10,11-dihydro-5H - dibenz (b, f) azepin (Ie).

Obtained in the conditions of example 4B. Yield 66%, so square hydrochloride 177-178aboutC.

Found, %: C 60,89; N To 7.09; N To 9.32; CL 7,69.

WITH23H29N3O3HCl H2O.

Calculated, %: C 61,39; N 7,17; N 9,34; CL 7,="ptx2">

To a solution of 2.1 g (0,005 mol) bromo derivatives (get it, see example 4A) in 5 ml of toluene was added a solution of 0.05 m of dimethylamine in toluene. The mixture was stirred with heating ( 40aboutC) for 9 h, then filtered 0.55 g drawn bromhidrosis dimethylamine (theory of 0.7 g). After cooling of the filtrate drops the basis weight of 1.5 g (68%); so pl. 167-168aboutSince it is dissolved in toluene and adding ether saturated hydrogen chloride, allocate hydrochloride. After crystallization from acetone so pl. 240-243aboutC.

Found, %: N 9,63; 9,42; Cl 8,62; 8,56.

WITH22H27N3O3HCl.

Calculated, %: N Of 10.05; CL 8,48.

P R I m e R 8. 3 Carbamaxepine-5-(diethylamino)propionyl 10,11-dihydro-5H - dibenz (b. (f) azepin (Z).

A mixture of 4.17 g (0.01 mol) -bromopropionyl derived (get it, see example 4A) and 1.75 g of diethylamine heated at boiling in 50 ml of xylene for 6 hours In the reaction falls to 1.25 g bromhidrosis of diethylamine (theory 1.5 g). Toluene solution is washed 2 times with water, then the base is extracted with 5% hydrochloric acid, the acidic solution lighten the coal and the addition of dilute sodium hydroxide solution allocate basis. The substance is extracted e is. the HP 147aboutC (with decomp. from acetone).

Found, %: C 64,28; N 7,76; Cl 8,01; 8,13; N 9,19; The Remaining 9.08.

WITH24H31N3O3HCl.

Calculated, %: C 64,64; N 7,93; Cl To 7.93; N 9,43.

P R I m e R 9. 3 Carbamaxepine-5-(morpholino)propionyl 10,11-dihydro-5H-dibenz (b, f) azepin (AI).

A mixture of 4.17 g (0.01 mol) -bromopropionyl derived (get it, see example 4A) 2,03 g (0,022 mol) of the research is heated at the boil for 5 hours Cooled, filtered 1.55 g of bromhidrosis of the research (theory 1.68 g). Distilled in vacuum 1/3 of the volume of xylene and to the residue is added ether saturated with hydrogen chloride, receive hydrochloride weight 3.5 g (73%); so pl. 161-163aboutC (from isopropanol).

Found, %: C 59,40; N 6,66; CL 7,30; N2About 3,60.

WITH24H30N3O4HCl H2O.

Calculated, %: C 60,30; N 6,75; CL 7,46; N2About 3,76.

P R I m e R 10. a) 3-Carisoprodolsoma-5-(bromo)propionyl 10,11-dihydro - 5H-dibenz (b. (f) azepin.

Obtained in the conditions of example 1A. Yield 84%; so bales. 170-174aboutC.

Found, %: C 58,67; N 5,52; N 6,38; Br 19,04.

WITH21H23BrN2O3.

Calculated, %: 58,48; N Lower Than The 5.37; N 6,50; Br 18,53.

b) 3-Carisoprodolsoma-5-(-methylamino)propionyl 10,11-dihydro-5 is="ptx2">

Found, %: C At 69,39; N 7,17; N Of 10.93.

WITH22H27N3O3.

Calculated, %: C 69,25; N 7,13; N 11,02.

P R I m e R 11. 3 Carisoprodolsoma-5-(ethylamino)propionyl 10,11-dihyd - ro-5H-dibenz (b, f) azepin (Il).

Obtained in the conditions of example 1B. Yield 59%; so pl. 210-212aboutWith (hydrochloride).

Found, %: C 62,35; N. Of 7.23; N 7,66. Cl 7,78.

WITH23H29N3O3HCl 1/2 H2O.

Calculated, %: C 62,64; N 7,09. N At 9.53; Cl 8,04.

P R I m e R 12. a) 3-Carbamaxepine-5-(bromo)propionyl 5H-dibenz (b, f) azepin.

A mixture of 28 g (0.1 mol) 3-carbamaxepine-5H-dibenz (b, f) azepine, 300 ml of benzene and 20 g (0.11 mol) -bromopropionyl-chloride is stirred at the boiling temperature of the solvent for 3 hours, the Reaction mixture is evaporated in vacuum to dryness, the viscous residue is treated with water and triturated with ether. The resulting crystals are filtered and recrystallized from triple amount of isopropanol. Yield 35 g; so so pl. pl. 163-165aboutC.

Found, %: C 58,67; N 5,52; N 6,38; Br 19,04.

WITH20H19N2O3Br.

Calculated, %: 58,48; N Lower Than The 5.37; N 6,57; Br 18,53.

b) 3-Carbamaxepine-5-(-methylamino)propionyl 5H-dibenz (b, f) azepin (Ei).

Received from bromopropyl is prohibited, %: 68,56; N 6,32; N 11,47.

WITH21H23N3O3.

Calculated, %: From 69.02; H 6,34; N 11,50.

P R I m e p 13. 3 Carbamaxepine-5-(ethylamino)propionyl 5H-dibenz (b, f) azepin (In).

Obtained in the conditions of example 12B. Yield 58%; so pl. 209-211aboutWith (hydrochloride).

Found, %: C 62,14; N 6,46; N Becomes 9.97; Cl To 8.41.

WITH22H25N3O3HCl 1/2 H2O.

Calculated, %: C 62,18; N 6,41; N 9,89; Cl To 8.34.

For pharmacological tests used aqueous solutions of salts or solutions of bases in the calculated quantity of hydrochloric acid.

The results of the pharmacological study of the derivatives of 5H-dibenz (b, f) azepine I in experiments on animals show that they have a pronounced antiarrhythmic effect.

The study of their antiarrhythmic activity was conducted on the model of aconitine arrhythmia in anesthetized rats. Control preparations were injected for 2 min intravenously or 60 min oral to aconitine (50 µg/kg). For the effective dose in this method take a dose, reducing the fibrillation in the middle to separate cases of ventricular extrasystoles. The calculation is conducted by the method of probit regression analysis with confidence the boundaries of P=0.05. Opredelyali activity of compounds I spent with bennekom (hydrochloride 3-carbomethoxyamino-5-dimethylaminoacetyl-10,11-dihydro-5H-dibenz (b, f) azepine). The obtained data are given in the table.

As can be seen from the presented data, the compounds IB, g exceed bonnekor on antiarrhythmic index. Connection Iك, d, e have a lower value of U73(i.e., more active) than bonnekor on the model of aconitine arrhythmia.

Compounds Ia, b, C, d, g, h, I, K, m, n are of lower toxicity than bonnekor. Compounds IB, g, d, e, K, l have a higher index of absorption (i.e., have greater bioavailability) than bonnekor.

3 CARBALKOXY-5-( - AMINOPROPIONIC)-5H-DIBENZ[B, F]AZEPINE WITH ANTIARRHYTHMIC ACTIVITY.

3 Carbamaxepine a-aminopropionic)-5H-dibenz-[B, f] azepine General formula

< / BR>
where X = -CH2CH2-, R1= R2= CH3, R3- H, n = 1;

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

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

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

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

X-CH2CH2-, R1- CH2H5, R2 - CH3n = 1;

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

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

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

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

X IS-CH = CH-, R1- C2H5, R2= CH3, R3- H, n = 0;

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

possess antiarrhythmic activity.

 

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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

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