Rihlokain - anticonvulsant pharmacological tool
The invention relates to medicine, to use rihanana as anti-convulsants, excelling activity reference drugs and does not cause allergic reactions. table 2. The invention relates to the field of medicine, specifically, to the preparation of rihlokain, benzoic ether, 1-allyl-2,5-dimethylpiperidine-4 hydrochloride, which can find application in medical practice as anti-convulsants.Proposed drug rihlokain possessing anticonvulsant activity, according to the breadth of therapeutic action superior to many reference of this group of drugs with low toxicity, non-toxic and allergic reactions, side effects and highly portable sick.Analogues of rihanana on anticonvulsant action are drugs diazepam, carbamazepine, phenobarbital, chlordiazepoxide, primidone. However, their application is limited due to severe side effects: changes in the blood, the emergence of mental disorders, allergic reactions, etc. (M. D. Mashkovsky. Medicinal product. - Vilnius, 1994, T. 1, page 24, 61-63).The closest (prototype) to rhipiphoridae, possessing antiarrhythmic, local anesthetic, antinecrotic and anticonvulsant activity (USSR author's certificate 18234441, CL 07 D 211/48, a 61 K 31/445, 1990).It has a pronounced anticonvulsant action is superior to phenobarbital in terms of maximal electroshock 9.1 times, comparable with phenobarbital in terms Karasyova seizures. However, the breadth of therapeutic action he is behind many of the reference drugs. This compound is toxic in comparison with relocaion 2 times.The objective of the invention is to expand the Arsenal of anticonvulsants.The technical result is achieved by the fact that the proposed drug rihlokain as anticonvulsant pharmacological tools.Rihlokain - benzoic ester of 1-allyl-2,5-dimethylpiperidine-4 hydrochloride chemical formula:Rihlokain is a white or white to slightly yellowish crystalline powder, odorless, soluble in water, isotonic sodium chloride solution. In solutions of the drug is very strong, does not lose its activity during long-term storage (over 10 years), sterilized for 30 min in an autoclave at 120oRihlokain as usual means registered in the Republic of Kazakhstan (RK 5-000860) and the Russian Federation ( 95/250/2 and 95/250/8) included in the State register of drugs permitted for medical use and industrial production.The invention is illustrated by the following examples: Determination of acute toxicity (median lethal dose LD substances). 0.5% solution intravenously, conducted experiments on awake white mice intraperitoneally on rabbits, rats and anesthetized with atenalol sodium 40 mg/kg cats (1. C. B. Prozorovsky. Using the method of least squares for probit analysis of the mortality curves // Pharmacology and toxicology. - 1962. , 25, 1. - S. 115-119. 2. C. B. Prozorovskii, M. P. Prozorovskaya. Tabular method for determining ED. LD substances with low biological activity // Pharmacology and toxicol. - 1980, - so-43, 6. - S. 733-735).Indicators of toxicity LD in rats, rabbits, cats when administered intravenously are shown in table 1.Anticonvulsant activity (PSA) of rihanana and comparative drugs (phenobarbital, hlordiazepoksida, carbamazepine, diazepam) was studied using maximal electroshock and Karasyova seizures. The data are shown in table 2.
In experiments using Karasyova seizures of rihlokain 2.2; 4,8 and 15.0 times on the DOG phenobarbital, carbamazepine and primidone, however, 5.0 and 2.3 times lower than the diazepam and hlordiazepoksida respectively. When taking into account the LD rihlokain 5.5; of 3.8 and 6.4 times has a great STD than phenobarbital, carbamazepine and primidone, however 6.9 and 1.6 times inferior in this respect to diazepam and hlordiazepoksida and accounting TD 8.3; 23,4; 92,6; 5.3 and 9.4 times that of phenobarbital, chlordiazepoxide, carbamazepine, diazepam and primidone.For DOG and STD in experiments on mice of rihlokain and Comparators anticellulite can be placed in the following range: maximum electroshock - rihlokain > diazepam > carbamazepine > phenobarbital > chlordiazepoxide > primidone, STD: DT50/ED50- rihlokain > phenobarbital > primidone > carbamazepine = diazepam > chlordiazepoxide, LD50/ED50- rihlokain > diazepam > carbamazepine > chlordiazepoxide > phenobarbital > primidone; y is one, STD:DT50/ED50- rihlokain > diazepam > primidone = phenobarbital > chlordiazepoxide > carbamazepine, LD50/ED50diazepam > chlordiazepoxide > rihlokain > carbamazepine > phenobarbital > primidone.Thus, rihlokain has a strong anticonvulsant effect in terms of maximal electroshock and Karasyova seizures. On the first model (Grand Mal seizures) is superior to PSA and STD phenobarbital, chlordiazepoxide, carbamazepine, diazepam and primidone, on the second (small seizures) - shows more pronounced anticonvulsant properties than phenobarbital, carbamazepine and primidone, however, inferior to the diazepam and hlordiazepoksida, has a large STD compared with phenobarbital, carbamazepine and geksamidinom inferior to diazepam and hlordiazepoksida.Thus, the claimed drug anticonvulsant activity exceeds the reference drugs, does not cause allergic and toxic reactions, good move, for many indicators and therapeutic properties superior to known drugs of similar action and may find application in medical practice.
The formula imageas anticonvulsant pharmacological tools.
< / BR>where denotes the number 0, 1, 2 or 3; R1represents an alkyl group, phenyl group or a monocyclic heterocyclic group containing as the heteroatom N or O, and these groups may be substituted once or more than once, by substituents selected from alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cyano, amino and nitro; or R1represents cyano or a group of formula-alkyl-CO2R2alkenyl-CO2R2, -CO-R2, -CO2(CH2)mR2or-C(R3)=N-OR2where m denotes the number 0, 1, 2 or 3; R2represents hydrogen, alkyl, phenyl, benzyl, 5 - or 6-membered heterocyclic group, which 5 - or 6-membered heterocyclic group may be substituted once or more than once by alkyl or alkoxy; or R2may represent a group of the formula -(CH2)q-NR4R5, -(CH2)q-CON(R4R5), -(CH2)q-CO2R4or-alkyl-CO2R4where R4and R5independently представляюUP> represents a group of General formula-CO2-R9where R9represents an alkyl or R9can represent a 6-membered heterocyclic group, and this 6-membered heterocyclic group may be substituted once or more than once by alkyl or alkoxy; or R9represents a group of General formula-alkyl-N(R10R12), where R10and R12independently represent hydrogen or alkyl; or R11represents a group of General formula II
< / BR>where n denotes the number 0, 1, 2 or 3; R' and R" together with the N atom to which they are attached, form a heterocyclic ring with the number of members from 5 to 7, and this heterocyclic ring can contain as a ring member, one oxygen atom and/or one additional nitrogen atom; and in this formula, a heterocyclic ring with the number of members from 5 to 7, formed by R' and R", may be substituted once or more than once by a group of the formula -(CH2)px, where p denotes the number 0, 1, 2 or 3; X represents hydrogen, hydroxyl, alkyl or alkenyl, and these alkyl and alkenyl can be possibly substituted by one or more the>R6or-CON-R6R7where R6and R7independently represent hydrogen or alkyl; or R11may represent a group of General formula III
< / BR>where n denotes the number 1; R' represents hydrogen or alkyl; R'" and R" 'together with the atoms to which they are attached, form a heterocyclic ring with the number of members from 5 to 7, and this heterocyclic ring can contain as a ring member one chain-CH=CH-; and in this formula, a heterocyclic ring with the number of members from 5 to 7, formed R'" and R"", may be substituted once or more than once by a group of the formula -(CH2)pX, where p denotes the number 0, 1, 2 or 3; X represents hydrogen, alkyl; or its pharmaceutically acceptable salt; provided that if R11is morpholinyl, R1may not represent tert-butyl; pharmaceutical compositions having the properties of the modulator of the GABAANDreceptors and the treatment of disorders and diseases of the living organism, and it is a disorder or disease responsive to modulation of GABAAND-receptor complex of the Central nervous
< / BR>methods for their preparation and their use in pharmaceutical compositions
in which R1denotes a hydroxy or an aliphatic, analiticheskii or aromatic residue; X is a divalent aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, analiticheskii, heteroaromatics or aromatic residue; R2is hydrogen or aliphatic or analiticheskii balance; alk - (ness.)alkylidene; R3, R4and R5independently from each other hydrogen, (ness.)alkyl, halogen, trifluoromethyl, cyano or nitro, and their salts
< / BR>where R and R are independently selected from the group consisting of hydroxyl and a moiety that can be converted in vivo in hydroxyl, such as acyloxy, -OR4, -OC(O)R7or-OC(O)OR4(where R4represents alkyl, alkenyl, quinil or aryl; and R7represents amino, alkylamino, aminoalkyl and alkylsulfonyl); and R3represents-CH2- or-CH2CH2-; or its pharmaceutically acceptable salt, where the specified compound or salt is optically active because they contain more than 50% (by weight relative to all stereoisomers) 2S stereoisomers
< / BR>or its non-toxic salt or its hydrate, the pharmaceutical composition having inhibitory effect on calcium channel iv-type; the inhibitor calcium channel N-type; a pharmaceutical composition for prevention and/or treatment of cerebral infarction and pharmaceutical compositions for the treatment of pain
FIELD: organic chemistry, biochemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):
their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.
EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.
14 cl, 36 ex