Antiepileptic agent with neuroprotective action
(57) Abstract:The invention relates to medicine and can be used for the treatment of epilepsy. The invention consists of the application -(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid or its potassium salt as antiepileptic drugs with neuroprotective action. The proposed invention has no side effects and helps to improve memory, learning and reasoning. 3 Il., table 4. The invention relates to medicine, namely to protevoepilepticeski means with nootropic effects.Modern drug therapy of epilepsy are mainly imported drugs, among which are derivatives of barbituric acid (phenobarbital, pentobarbital), derived as (phenytoin), derived iminostilbena (carbamazepine), valproic acid and its salts and certain other . When adequate control of seizures, many of them can cause a significant reduction in the responses of the Central nervous system, resulting in increased drowsiness, lethargy, incoordination, memory impairment and learning. This significantly reduces the capacity degrades the quality of life is surrounding brain activity. The high cost of drugs and the necessity of their long reception makes the treatment very expensive.We were tasked with developing a national drug combining anticonvulsant activity with nootropic effect and does not exhibit pronounced negative side effects.Portablindataportafinestrablindata-(3,5-di-tert-butyl-4-hydroxy-phenyl)propionic acid or its potassium salt of General formula
< / BR>where R = H(Ia)
or R = N(IB).Compounds Ia and IB according to the mechanism of action are inhibitors of lipid peroxidation and can be produced from domestic raw materials by hydrolysis of the ester of compound I (R=Me), obtained by the method . Non-toxic in pharmacologically active doses of the compounds Ia and IB have the same physiological effect, and represent various different solubility in water forms of the same drug.The proposed drug has diverse biological activity. Known application forms Ia and IB in agriculture as stimulants for the treatment of seeds of grain crops , as well as the application form Ia in medicine in the quality of what was shown, that the drug in the notoriously non-toxic doses has antiepileptic activity, does not have a sedative side effect, improves learning, memory and reasoning in animals.Example 1. Anticonvulsant properties of the proposed drug is studied on the model audiogenic epilepsy rats KM, which is genetically determined epileptiform seizures can be called with sound effects without the introduction of chemicals or other influences. The drugs were injected pills in pill form (form Ia - 0.1, starch - 0,197, calcium stearate - 0,03) or intraperitoneally for 1-1,5 hours before the sound of impact. The results presented in table. 1, show that both forms of the drug have a pronounced antispasmodic activity. For example, the introduction intraperitoneally 120 mg/kg of the form Ia has prevented the development of a convulsive seizure in 5 of 6 animals, and developed in one animal attack had a long latent period was two and had a weak intensity. Application form IB intraperitoneally at a dose of 80 mg/kg prevented the development of seizures in 100% of cases.The use of the drug in the studied doses were not accompanied by any of the on-line rats KM calls after audiogenic seizure sudden arousal of the brain, accompanied by motor and vegetative disorders and leading to the development of acute cardiovascular disease and mortality 10-15% of the animals from hemorrhages in the brain. The results presented in table. 2, show that the introduction of the form IB 1.5 hours before the sound of impact not only weakens the intensity of epileptiform seizures (in the experimental group fits with a maximum intensity of 4 points developed in 6% of cases versus 70% in the control), but also prevents bleeding in the brain.Example 3. The results of the study anticonvulsant activity of the drug on different underlying models (tests of antagonism with carazolol and thiosemicarbazides, the test is maximal electroshock), are presented in table. 3, showing significantly anticonvulsant effect.Example 4. The effect of the drug on epileptiform activity (EPA) in various brain structures caused by the introduction bemegrida shown in Fig.1. Application form Ia in doses of 100 and 200 mg/kg one hour before the injection bemegrida reduces the amplitude and duration of discharges EPA (grouped complexes sharp and slow waves in the sensorimotor areas of the cortex and hippocampus of rat brain), and at a dose of 200 mg/kg reduces the number of bits and, thus, p is LASS="ptx2">Neuroprotective properties of compounds I studied the behavior of rats KM, which is due to a genetically determined increased excitability reduced ability to solve the extrapolation task, reduced locomotor activity and estimated reaction, i.e. they can be considered as models of certain pathological conditions of the Central nervous system (CNS). Testing of pharmacological agents in these animals allows us to evaluate their potential therapeutic properties for correction of behavior.Example 5. The effect of the drug on the ability of rats KM to basic intellectual activities shown in the table. 4 for example, solutions of extrapolation task. Form IB was administered intraperitoneally at a dose of 30 mg/kg once for 1.5 hours before the experiment.The results obtained when the pills injection mold Ia at a dose of 100 mg/kg, similar to the results of intraperitoneal administration form IB: first presentation in the experimental group correctly solved the problem 60% of the animals against 49% in the control group. The successful solution of extrapolation tasks at the first presentation shows the presence of elementary rational activity. Multiple testiomonials solved the problem, conducted change the stereotype. Experimental group rats had previously reached this criterion and better cope with the task to change the stereotype that confirms the stimulating effect of the drug on reasoning.Example 6. The effect of the drug on learning, memory and behaviour of rats KM, is studied on the example form IB model 8-beam radial maze, shown in Fig.2. Form IB was administered intraperitoneally at a dose of 30 mg/kg for 1-1,5 hours before the experiment daily for 20 days. Then the drug was stopped, and animal testing continued for another 13 days. From the first day of administration of the drug the number of errors in the control group exceeded the number of errors in the experimental group on average 3.5 times. To 10-15 days the number of errors in the experimental group was almost equal to zero. A sharp decrease in the number of errors in the experimental group was observed after withdrawal of the drug until the termination of the experiment. In addition, under the influence of the drug the animals choose the best tactic, ensuring fewer errors. These results indicate the positive effect of the drug on memory and learning in animals.Example 7. The effect of PR is intraperitoneally at a dose of 40 mg/kg 1.5 hours before the start of the experiment. Compared with the control group in the experimental group decreased the number of failed reactions (Fig.3A). In addition, in the experimental group with the increase of the training period significantly decreased the latent period, while in the control group was observed the opposite effect (Fig.3b).Sources of information
1. Anticonvulsants in psychiatric and neurological practice. Edited by Professor A. Wayne M. and D. M. N. S. N. Mosolova, chief 1, S. 6. Medical news Agency, St. Petersburg, 1994.2. Copyright certificate 938532 on the application 2630386 from 21.04.78.3. Copyright certificate 1417218 on the application 4106032 from 31.07.86.4. Copyright certificate 1547101 on the application 4181624 from 12.01.87. Application -(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid or its potassium salt as antiepileptic drugs with neuroprotective action.
< / 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
FIELD: organic chemistry, medicine, immunology.
SUBSTANCE: invention proposes applying 2,4-dichlorophenoxyacetic acid tris-(2-oxyethyl)-ammonium salt as an immunomodulating agent. The newly found properties provide the development on its base medicinal agents for treatment of inflammatory, autoimmune and lymphoproliferative diseases.
EFFECT: valuable medicinal properties of agent, expanded assortment of agents of indicated designation.
4 tbl, 4 ex