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