Inhibitor of intimal hypertrophy, application oxendolone derived to obtain an inhibitor of intimal hypertrophy, a composition for inhibiting intimal hypertrophy, method of prevention and treatment of intimal hypertrophy

 

(57) Abstract:

The invention relates to medicine, the inhibitor of intimal hypertrophy, containing as the active ingredient oxindole derivative represented by formula I, or its salt, where R represents a hydrogen atom, phenyl group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxyl group, amino group, lower alkylamino or halogen atom, or pyridyloxy group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxyl group, amino group, lower alkylamino, a halogen atom, a lower alkoxycarbonyl group or a carboxyl group, a represents a phenyl group, which may be substituted, or pyridyloxy group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxy-group, amino group, lower alkylamino, a halogen atom, a lower alkoxycarbonyl group or a carboxyl group, a represents a hydrogen atom, a lower alkyl group, benzyl group, or benzosulfimide is, halogen atom, an amino group, a lower alkylamino, karboksilnuyu group, lower alkoxycarbonyl group, phenylcarbamoyl group which may be substituted, or triptorelin group represents CH or N; n represents an integer from 0 to 4, inclusive, that indicates the number of substituents and double dotted/solid line represents a simple bond or double bond, which has an excellent inhibitory action against intimal hypertrophy, and used as an agent for prevention (treatment) attenuation of proliferative vascular diseases such as restenosis after RTSA, arteriosclerosis, peripheral embolism and angia, use oxendolone derived to obtain an inhibitor of intimal hypertrophy, compositions for inhibiting intimal hypertrophy and method of prevention and treatment of hypertrophy of the intima. This inhibitor is an effective means of preventing restenosis of blood vessels after angioplasty for the treatment of arteriosclerosis. 4 C. and 5 C.p. f-crystals, 24 tab., 2 Il.

The invention relates to inhibitors of hypertrophy of the intima (inner lining of blood vessels) containing oxendolone derived as activepresenter occurrence of various pathological conditions, such as angina and myocardial infarction, and is the main reason. Narrowing of the lumen of blood vessels caused by atherosclerosis, and loss of elasticity of blood vessels lead to lack of nutrition and oxygen supply to the heart tissue, which causes the above-mentioned pathological conditions. It is believed that the main reason for the narrowing of the vessel lumen is the accumulation of "foamy" macrophages and cholesterol on the inner wall of the vessel, as well as cellular fibrous intimal hypertrophy, caused by the migration of smooth muscle cells of the middle shell of the vessel intima and proliferation of intimal cells. To alleviate symptoms in the treatment of angina and myocardial infarction, mainly using antithrombotic agents, vasodilator, etc. However, these agents cannot serve as a radical means of narrowing of the lumen of blood vessels and loss of elasticity caused by arteriosclerosis. It is therefore imperative to obtain such pharmaceutical agents that could be used for the prevention or treatment of hypertrophy of the intima caused by angiostenosis.

In recent years, applied surgical treatment of angiostenosis using reseter-cylinder injected by remote control to narrow the affected area through, for example, the femoral artery without holding thoracotomy, after which the bag is inflated in situ and, thereby, achieve physical expansion of the lumen of the vessel. Due to the success of modern robotics used in PTCA, in more than 90% of cases symptoms of immediately after PTCA. In addition, cases of fatal PTCA or the occurrence of severe complications, such as myocardial infarction, are extremely rare. Therefore, PTCA is a highly effective therapy. However, approximately 30-40% of cases after conducting PTCA observed re-stricture formation in the same portion of the vessel, and if it occurs, it is necessary to repeat the procedure, PTCA, or, alternatively, there should be a bypass of aorta. Such cases are a serious problem in the field of clinical medicine. The autopsy carried out in cases of death caused by repeated obturation of the vessel after PTCA showed that intimal hypertrophy occurred in that part, where he carried out the expansion vessel, and brought, as a result, re-blocking of this area (see , for example, British Heart Journal, 58, 635-643 (1987), Human Pathology, 477-485 (1989)).

Hence it was concluded that inhibition of intimal hypertrophy can stat">

Accordingly, studies have been conducted of pharmaceutical preparations, which, as expected, could open the way to getting money for treatment of the above diseases in preclinical and clinical stage (American Heart Journal, 122, 171-187 (1991)). Such preparations candidates were anticoagulants, such as heparin; platelet aggregation inhibitors such as aspirin, dipyridamole, ticlopidine, prostacyclin and derivatives thereof; inhibitors of thromboxane A2, such as trapidil; inhibitors of cell proliferation, such as ketanserin; calcium antagonists such as diltiazem and nifedipine; agents that reduces the content of lipids, such as fish oil, eicosapentaenoic acid and lovastatin; and anti-inflammatory drugs, such as steroids. However, due to practical studies conducted in clinical settings, it was found that none of the above drugs has no explicit efficiency.

The most modern of the currently developed inhibitors of intimal hypertrophy is tranilast (published patent application Japan (kokai) N 6-135829). However, because of its weak activity, the medicine may not be dostatochnykh any effective medicines against intimal hypertrophy, and, therefore, the need for such clinically effective pharmaceutical drugs is extremely important.

The active ingredients of the present invention, namely oxindole derivatives are partly known compounds. Such known compounds are synthesized intermediate compounds described in the publication of the Japan patent (kokoku) N 43-3195, lined the patent Hungary N 65452, in U.S. patent N 4002749, Chem. Ber. 91, 2095 and 91, 1898 (1958), and in U.S. patent N 3413299; absorbers of UV radiation as described in U.S. patent N 3428649; antidepressants or tranquilizers disclosed in laid Noah the patent application of Japan (kokai) N 47-8628; antimetropia agents disclosed in WO 91/01306; drugs for the treatment of diseases of the Central nervous system or gastric ulcers, disclosed in WO 92/07830; and medicines to treat asthma, rheumatoid arthritis and allergic rhinitis disclosed in WO 95/14667. In addition, the additional positive effect of these compounds in acute myocardial infarction is described in European Journal of Medicinal Chemistry, 25(2), 187 (1990), there 27(2), 167 (1992), and ibid 28, 653 (1993). However, it is not yet known whether these compounds to act as inhibitors of hypertrophy and kryvutsa in tiled applications to the Japan patent (kokai) NN 62-29570, 6-501494 and 7-108900; and in tiled applications for the Japan patent (kokai) NN 62-29570 and 6-501494 disclosed activity, inhibiting tyrosinekinase, and posted in the patent application of Japan (kokai) N 7-108900 revealed the antioxidant action of these compounds. However, in these publications do not mention anything about the action of these compounds as inhibitors of intimal hypertrophy.

In line with this, the aim of the present invention to provide effective means inhibits intimal hypertrophy.

Description of the invention

Taking into consideration the above facts, the authors of the present invention conducted a thorough investigation, which found that oxindole derivative of a certain class have a high degree of activity, aimed at the inhibition of intimal hypertrophy, and this fact was the basis of the present invention.

Accordingly, the present invention relates to an inhibitor of intimal hypertrophy, containing as the active ingredient oxindole derivative represented by the formula (1) or its salt:

< / BR>
where R1represents a hydrogen atom; a phenyl group which may be substituted by lower ALK is her alkylaminocarbonyl, or a halogen atom; or pyridyloxy group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxy-group, amino group, lower alkylamino, a halogen atom, a lower alkoxycarbonyl group, or a carboxyl group;

where: (a) in the case when R1represents a hydrogen atom:

R2represents a phenyl group which may be substituted by a hydroxyl group or a lower alkoxygroup; or pyridyloxy group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxyl group, amino group, lower alkylamino, a halogen atom, a lower alkoxycarbonyl group, or a carboxyl group; each of R3and R4represents a hydrogen atom; X represents CH; and double dotted/solid line means a double bond;

(b) in the case when R1represents a phenyl group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxy-group, amino group, lower alkylamino, or a halogen atom; or pyridyloxy group, which is syruppy, amino group, a lower alkylamino, a halogen atom, a lower alkoxycarbonyl group, or a carboxyl group;

R2represents a phenyl group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, lower alkoxycarbonyl group, a carboxyl group, a hydroxy-group, amino group, lower alkylamino, or a halogen atom; or pyridyloxy group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxy-group, amino group, lower alkylamino, a halogen atom, a lower alkoxycarbonyl group, or a carboxyl group; R3represents a hydrogen atom; a lower alkyl group which may be substituted; benzyl group which may be substituted; benzosulfimide group which may be substituted; or acyl group; R4represents a halogen atom, lower, alkoxygroup, halogen atom, amino group, carboxyl group, lower alkylamino, lower alkoxycarbonyl group, phenylcarbamoyl group which may be substituted, or triptorelin group; X represents CH or N; n Predna line means a single or double bond.

The present invention also relates to a method for prevention or treatment of intimal hypertrophy, characterized by administration to a patient suffering from hypertrophy of the intima oxindole derivative (1) or its salt.

In addition, the present invention relates to compositions inhibiting intimal hypertrophy, and characterized in that it contains the above oxindole derivative (1) or its salt and a pharmaceutically acceptable carrier.

The present invention also relates to the use of the above oxindole derivative (1) or its salt to obtain an inhibitor of intimal hypertrophy.

Brief description of drawings

Fig. 1 represents the infrared spectrum oxendolone derived (Crystal 1) used in the present invention.

Fig. 2 represents the infrared spectrum oxendolone derived (Crystal 2) used in the present invention.

The best ways of carrying out the invention

If oxindole derivative of formula (1), symbol (called below the dotted/solid double line) represents a simple bond, due to the presence of two asymmetric carbon atoms, this derivative can exist as optical is de geometrical isomers. The present invention includes both types of isomers oxendolone derived.

Examples of the lower alkyl groups as the substituents on substituted phenyl or peredelnyh groups represented by R1and R2are straight or branched C1-C6is an alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl and n-hexyl; however, the preferred are methyl, ethyl or tert-butyl, and more preferred is methyl. Examples of the lower alkoxygroup are straight or branched C1-C6-alkoxygroup, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentane and n-hexyloxy; preferred are methoxy or ethoxypropan, and more preferred is a methoxy group. Examples of the lower acylaminoalkyl are mono - or di-lower alkylaminocarbonyl containing C1-C6-the alkyl part, such as methylaminomethyl, methylenedioxy, methylaminopropane, methylaminorex, methylaminomethyl, methylenedioxy, Ethylenedioxy, ethylaminomethyl, dimethylaminoethoxy, dimethylaminopropoxy, dimethylaminoethoxy, dimethylaminopropoxy, dimethylaminoethoxy, diethylaminoethoxy, diethylaminoethoxy, diethylaminopropyl, diethylaminoethoxy, diethylaminoethoxy, diethylaminoethoxy. Of them, preferred are methylaminorex, methylenedioxy, dimethylaminoethoxy, diethylaminoethoxy, ethylaminomethyl, ethyleneoxy, and more preferred is dimethylaminoethoxide. Examples of the lower alkylamino are mono - or di-lower alkylamino containing C1-C4-the alkyl part, such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, dimethylamino, diethylamino, dipropylamino. Of them, preferred is dimethylaminopropyl. Examples of halogen atoms are fluorine atoms, chlorine, iodine or bromine; however, preferred is a chlorine atom.

Examples of the lower alkoxycarbonyl groups, which serve as substituents on the substituted phenyl group represented by R2or substituted peredelnyh groups represented by R1and R2are straight or branched C2-C7-alkoxycarbonyl groupselection, second-butoxycarbonyl, tert-butoxycarbonyl, pentyloxybenzoyl and hexyloxybenzoyl; of which preferred are Methocarbamol and etoxycarbonyl.

If R1or R2represent substituted phenyl group or substituted pyridyloxy group, the number of substituents is preferably from 1 to 3, inclusive. In the case of phenyl ring substituents may be present in ortho-, meta - or para-positions, and in the case peredelnyh rings, the substituents can be in any of the 1-6 provisions. Preferred substituents are lower alkyl groups or lower alkoxygroup, and more preferred are methyl or methoxy.

In the formula (1) examples of the lower alkyl group which may be substituted and which is represented by R3are the groups listed above as examples of substituents of the lower alkyl groups are lower alkoxycarbonyl group, lower alkylamino, lower alkylcarboxylic group and carboxyl group.

Examples of the lower alkoxycarbonyl groups are the groups listed below.

Examples of the lower alkylamino are mono - or di - lower alkylamino, sod is ethylamino, dimethylamino, diethylamino and di propylamino.

Examples of the lower alkylcarboxylic groups are carbamoyl group, mono - or disubstituted by lower C1-C6-alkyl groups, such as methylcarbamoyl, ethylcarbitol, propellerblades, butylcarbamoyl, intercalator, exaltabitur, dimethylcarbamoyl and diethylcarbamoyl; however, the preferred group is dimethylcarbamoyl.

As for the benzyl group, which is represented by R3in the formula (1) and which may be substituted, examples of the substituents on the phenyl ring are lower alkoxygroup and lower alkoxycarbonyl group. Specific examples include groups penicilline above.

Acyl group represented by R3in the formula (1) can serve as aliphatic acyl and aromatic acyl groups a wide range, examples of which include lower alcoholnye group, arylcarbamoyl group, heterocyclic carbonyl group, aryloxyalkyl group, lower alkoxycarbonyl group and acyloxyacyl group.

Examples of the lower alkanoyl groups are C1-C6-alcoholnye groups, such as formyl, acetyl what I benzoline and nattermannallee group, which may be substituted by lower alkyl groups, lower alkoxycarbonyl, lower alkoxycarbonyl groups, halogen atoms, carboxyl groups, nitro groups and cyano groups. As specific examples may be mentioned benzoyl, naphthyl-carbonyl, -afterburner, 2-methylbenzoyl, 3-methylbenzoyl, 4-methylbenzoyl, 2,4-dimethylbenzoyl, 4-ethylbenzyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 2,4-dimethoxybenzoyl, 4-ethoxybenzoyl, 2-methoxy-4-ethoxybenzoyl, 4-methoxycarbonylbenzyl, 2,4-dimethoxybenzoyl, 4-ethoxycarbonylbutyl, 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 2,3-dichlorobenzoyl, 2-bromobenzoyl, 4-perbenzoic, 2-carboxybenzoyl, 3-carboxybenzoyl, 4-carboxybenzoyl, 2-cyanobenzoyl, 4-cyanobenzoyl, 2-nitrobenzoyl, 4-nitrobenzoyl or 2,4-dinitrobenzoyl.

Examples of the heterocyclic carbonyl groups are 2 - fornicator, 4-thiazolidinone, 2-hinolincarbonova, 2-pyrazinecarboxamide, 2-pyridylcarbonyl, 3-pyridylcarbonyl and 4-pyridylcarbonyl.

Examples aryloxyalkyl groups are phenoxy-carbonyl, -naphthalocyanine-naphthalocyanines, 2-methylphenoxyacetic, 3-methylfentanyl, 4-methylphenoxyacetic, 2,4-dim is oxycarbonyl, 2,4-dimethoxyphenethylamine, 4-ethoxyphenoxy, 2-methoxy-4-ethoxyphenoxy, 2-chlorphenoxamine, 3-chlorphenoxamine, 4-chlorophenoxyacetic, 2,3-dichlorophenoxyacetic, 2-bromophenanthrene, 4-pertenecieron, -methyl--naphthalocyanines and-chlorine-naphthalocyanine.

Examples of the lower alkoxycarbonyl groups are the groups listed above.

Examples acyloxyacyl groups are acetylacetonates, propionylacetate, -(atomic charges)propionyl and(propionyloxy) propionyl.

Substituents on the phenyl ring of each benzolsulfonate group which may have a substituent and which is represented by R3in the formula (1) may be lower alkyl groups, specific examples of which include the groups listed above.

Examples of the lower alkoxygroup, halogen atoms, lower alkylamino and lower alkoxycarbonyl groups can serve groups and atoms listed above. Substituents on the phenyl ring of each phenylcarbamoyloxy group which may have a Deputy, may be lower alkoxygroup, specific examples of which include the groups listed above.

From oxendolone proizvoditeley the hydrogen atom:

R2represents preferably a phenyl group which may be substituted by a hydroxy-group or a lower alkoxygroup; or pyridyloxy group which may be substituted by lower alkoxygroup; each of R3and R4represents a hydrogen atom; X represents CH; and the dotted/solid double line denotes a double bond; however, the preferred group represented by R2is pyridyl, 4-methoxyphenyl or 3,5-dimethoxy-4-hydroxyphenyl.

(b') when R1is not a hydrogen atom:

R1and R2may be the same or different and each preferably represents a phenyl group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxy-group, amino group, lower alkylamino or a halogen atom; or pyridyloxy group which may be substituted by lower alkoxygroup; R3represents a hydrogen atom, a lower alkyl group which may be substituted by lower alkoxycarbonyl group, a lower alkylamino or lower alkylcarboxylic group; benzyl group which may be substituted on the phenyl Colman on the phenyl ring by lower alkoxygroup; or benzosulfimide group which may be substituted on the phenyl ring, a lower alkyl group; R4represents a hydrogen atom, amino group, carboxyl group, lower alkylamino or lower alkoxycarbonyl group. More preferably, if R1and R2are the same or different, and each represents pyridyloxy group; or phenyl group which may be substituted stands, ethyl, bootrom, methoxy, hydroxy, amino, dimethylamino, dimethylaminoethoxy or chlorine; R3represents a hydrogen atom; a lower alkyl group which may be substituted by methoxycarbonyl, etoxycarbonyl, dimethylamino or dimethylcarbamoyl; benzyl group which may be substituted on the phenyl ring methoxycarbonyl group; or benzosulfimide group which may be substituted on the phenyl ring by methyl group; and R4represents a hydrogen atom, amino group, carboxyl group, di-lower alkylamino or lower alkoxycarbonyl group; X represents CH; and the dotted/solid double line denotes a double bond. Especially preferred are compounds in which R1or R2represent predstavljaet a hydrogen atom, methyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, dimethylaminoethyl group, dimethylcarbamoyl group, methoxycarbonyl - benzyl group or toluensulfonyl group; R4represents a hydrogen atom, amino group, carboxyl group, dimethylaminopropyl or ethoxycarbonyl group; X is CH; n is 1 or 2; and the dotted/solid double line denotes a double bond.

Oxindole derivatives of formula (1) of the present invention can be obtained by a method of synthesis as described, for example, in the publication of Japanese patent (kokoku) 43-3195, posted in the patent application of Japan (kokai) N 47-8628, WO 91/01306 and in WO 92/07830. For example, these derivatives can be obtained in accordance with the following reaction scheme provided in the end of the description (where R1, R2, R3, R4, X and n are as defined above; R3arepresents lower alkyl, benzyl or benzosulfimide group, each of which may have a substituent; or an acyl group; Z represents a halogen atom).

Examples of the halogen atom represented by Z in the above reaction scheme, are halogen atoms, PE is rmula (2) and other well-known compound of the formula (3) is subjected to reaction in an appropriate solvent in the presence of a condensing agent, in the result, get the connection formula (1a). This can be used any solvent, provided that it does not adversely affect the reaction. Examples of such solvents are toluene, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, dioxane, acetic acid, t-amyl alcohol, t-butyl alcohol. Examples of the condensing agent are inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate and sodium carbonate; organic bases such as triethylamine, piperazine, piperidine, pyrrolidine, pyridine and t-piperonyl potassium; ammonium acetate; and sodium acetate. The reaction is preferably carried out using 1-3 mol of compound of the formula (3) and 1-10 mol condensing agent per 1 mol of compound of the formula (2). The reaction temperature is preferably from room temperature to 200oC, and the reaction time is preferably 1-24 hours.

The compounds of formula (2) can be obtained by the methods described, for example, Journal of Medicinal Chemistry, 37, 2033 (1994), Tetrahedron Letters, 2587 (1979), in Journal of American Chemical Society, 5508 (1974), Journal of American Chemical Society, 5512 (1974), Tetrahedron, 24, 6093 (1968), or in lined Synthesis Collection, vol.1, p.95, in Journal of Chemical Society, 529 (1951), Monatsh. Chem. , 119, 1427 (1988), Rec. Trav. Chim. Pays-Bas Belg., 70, 1054 (1951).

(Stage B)

The compound of formula (1a) obtained in Stage A, is subjected to reaction with a known compound of the formula (4) in a suitable solvent in the presence of a base, resulting in the receive connection of the formula (1b). This can be used any solvent, provided that it does not adversely affect the reaction. Examples of such solvents are dimethylformamide, dimethylsulfoxide, tetrahydrofuran and dioxane. Examples of the base are sodium hydride, sodium bicarbonate, potassium carbonate and sodium carbonate. This reaction is preferably carried out using 1-3 mol of compound of the formula (4) and 1 to 3 mol of base per 1 mol of the compounds of formula (1a). The reaction temperature is from room temperature to 100oC, and the reaction time is preferably 1-24 hours.

(Stage C)

The compound of formula (1a) obtained in Stage A, or a compound of the formula (1b) obtained in Stage B, is subjected to catalytic hydrogenation in a suitable solvent in the presence of a suitable catalyst and in the stream of hydrogen, resulting in a receive connection f is provided that it does not adversely affect the reaction. Examples of such a solvent is tetrahydrofuran, dioxane, benzene, toluene, methanol, ethanol, ethyl acetate and acetic acid. Examples of the catalyst are palladium, palladium-on-charcoal, rhodium, platinum and ruthenium. The reaction is preferably carried out using 0.01-0.1 mol of catalyst per 1 mole of the compounds of formula (1a) or the compound of formula (1b). The flow pressure of hydrogen is preferably 1-3 ATM. The reaction is carried out at about room temperature and the reaction time is preferably from 10 minutes to 24 hours.

Of the compounds of formula (1) obtained in the above stage, the compounds in which R1or R2represent phenyl group, substituted carboxyl group, can be, using known techniques, tarifitsirovana the carboxy group on the phenyl ring.

The compound of formula (1) obtained in accordance with the above scheme can be easily separated in the form of crystals or in the form of an oily substance using standard equipment selection/purification such as recrystallization, distillation, column chromatography, etc.

Inhibitors of intimal hypertrophy of the present invention can be manufactured, in accordance with the standard method, in the form of pharmaceutical preparations using appropriate pharmaceutical carriers. These drugs can be introduced in various media, such as fillers, binder, disintegrator, lubricant, dye, corrigentov, fragrances and surfactants, which are widely used in pharmaceutical practice.

When using the inhibitor of intimal hypertrophy of the present invention as a drug for administration to a mammal, the Ana in accordance with the set therapeutic goals. As example can be mentioned parenteral forms such as injections, suppositories, preparations for local application (ointments, plasters, etc.,) and aerosols; and oral forms such as tablets, coated tablets, powders, granules, capsules, solutions, pills, suspensions and emulsions.

The above medicines may be obtained by methods well known to specialists.

In the manufacture of solid oral preparations such as tablets, powders and granules can be used by carriers, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, methylcellulose, glycerin, sodium alginate and the Arabian gum; binders such as simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, hydroxypropylcellulose, water, ethanol and potassium phosphate; dezintegriruetsja agents, such as starch, sodium alginate, powdered agar, powder laminaran, sodium bicarbonate, calcium carbonate, polyoxyethylenesorbitan aliphatische as sucrose, stearic acid, cacao butter and hydrogenated oil; absorption improvers, such as Quaternary ammonium bases and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbing agents such as starch, lactose, kaolin, bentonite and colloidal silica; and lubricants such as purified talc, stearates, powdered boric acid and polyethylene glycol. If necessary, the tablets may be coated with an appropriate coating such as sugar coating, gelatin coating, intersolubility coating, film coating, double coating and multi-layer coating.

In the manufacture of pills can be used by carriers, including excipients such as glucose, starch, cacao butter, hydrogenated vegetable oils, kaolin and talc; binders such as powdered Arabian gum, powdery tragacanth gum, gelatin and ethanol; and dezintegriruetsja agents, such as powdery laminaran and agar.

Capsules are prepared by mixing the compounds with the above-mentioned various media with subsequent filling of hard, soft, or etc., gelatin capsules obtained mixture.

P is mportant esters of higher alcohols, gelatin, semisynthetic glycerides or Witepsol (Witepsole is a registered trademark, Dynamite-Nobel), used in combination with the relevant stimulants absorption.

In the manufacture of drugs for injection can be used in a variety of media, including diluents, such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearoyl alcohol, polyoxyethelene alcohol and polyoxyethylenesorbitan aliphatic acids; pH regulators and buffers such as sodium citrate, sodium acetate and sodium phosphate; and stabilizers such as sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolate acid and tomalachka acid. In this case, the pharmaceutical composition may also contain Sodium chloride, glucose or glycerin in amounts sufficient to obtain isotonic. In addition, this solution may be added the usual solutions-adjuvants, sedatives and local analgesics. Preparations for subcutaneous, intramuscular and intravenous injection is obtained using the above media standard methods.

Liquid preparations may be aqueous or oily suspensions, solutions, For the manufacture of ointments, for example, pastes, creams or gels are usually used, if necessary, appropriate ointment bases, stabilizers, moisturizers, preservatives, etc. that are mixed with the active ingredients, and in accordance with standard techniques get drugs. Examples of ointment bases are white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite, etc., Examples of preservatives can be methylparahydroxybenzoate, metilparagidroksibenzoat and propylparabens.

In the manufacture of plasters of the above ointments, creams, gels, pastes, etc. , applied to an appropriate substrate, usually used for such purposes, in accordance with standard techniques. Examples of suitable substrates can serve as a woven or non-woven materials made of cotton, staple fiber or synthetic fibers; films and foams, made of soft vinyl chloride, polyethylene, polyurethane, etc.

A number of compounds of the present invention, the input in any of the above drugs may vary depending on the form of preparation, method of administration and dosage regimen and can be defined in fairly broad diape on total weight of the preparation.

The method of introduction is not critical and may be selected depending on the form of the drug, age, sex and health of the patient, the severity of the disease of the patient, etc., for example, drugs can be injected parenterally, orally, rectally, via the mouth and transcutaneous. For oral administration can be used for tablets, coated tablets, solutions, suspensions, emulsions, granules and capsules; and for rectal injection can be used suppositories. Preparations for injection can be introduced as such or in combination with commonly used adjuvants, such as glucose and amino acids. If necessary, preparations for injection can be used exclusively for intra-arterial, intramuscular, intradermal, subcutaneous, or intraperitoneal administration. The ointment is usually applied on the skin, on mucous membranes of the mouth, etc.

The amount of the active ingredient of the present invention is determined depending on the method of administration; age, sex and severity of illness of the patient; specifically selected compounds of the present invention; and other factors. However, usually this amount is in the range of 0.1-300 mg/kg/day, and prepact the ideal single dose or 2-4 times per day in the form of fractional doses.

Examples

The present invention is illustrated in more detail by the following Examples which are presented for purposes of illustration, and therefore, cannot be considered as a limitation of the present invention.

EXAMPLE OBTAIN 1

Synthesis of 3-[bis(4-methoxyphenyl)methylene]-oxindole (Compound 1):

10.0 g of oxindole was dissolved in 100 ml of tetrahydrofuran, and then added 21.8 g of 4,4'-dimethoxybenzophenone at room temperature. Then the temperature of the reaction mixture was brought to 0oC. After adding 9.0 g of 60% sodium hydride hydrogen evolution ceased and the reaction mixture was heated under reflux for 12 hours. After completion of the reaction, the reaction mixture was cooled. To this reaction mixture were added saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline and then dried with sodium sulfate and evaporated. The crude product was recrystallized from methanol, resulting in a received 22.8 g (yield = 85%) target compound as yellow crystals (Crystal 1). The melting point and the data elementno the tion shown in Fig. 1.

20 g of compound (Crystal 1) obtained in the Example of obtaining 1, suspended in 200 ml of n-undecane. The resulting suspension was heated for four hours at approximately 160oC, and then cooled to 0oC, resulting in a received 19.6 g (yield 98%) orange polymorphic crystals (Crystal 2) connection 1. In Fig. 2 shows a graph of the infrared spectrum of the obtained compound. Melting point 203.5-205.5oC.

EXAMPLE OF GETTING 2

Connections 2-15 listed in Tables 1-4, synthesized by a method similar to that described in Example Obtain 1 using suitable starting products.

EXAMPLE OF GETTING 3

Synthesis of hydrochloride of 1-dimethylaminoethyl-3-[bis(4-methoxyphenyl) methylene] oxindole (Compound 16):

5.0 g of 3-[bis(4-methoxyphenyl)methylene]oxindole received in the Sample Receiving 1, was dissolved in 50 ml of tetrahydrofuran, and then added 4.0 grams of the hydrochloride of dimethylaminoethoxide at room temperature. After that, the temperature of the reaction mixture was brought to 0oC. To this mixture was added 2.2 g of 60% sodium hydride, and after formation of hydrogen the reaction mixture was heated under reflux for 12 hours. After preceremony, and then was extracted with ethyl acetate. The extract was washed with water and saturated saline and then dried with sodium sulfate and evaporated. The crude product was purified by column chromatography on silica gel (chloroform:methanol = 100:1), resulting in the obtained yellow crystals. After the reaction of the obtained compound with a solution of 4 n HCl/ethyl acetate there was obtained 4.6 g (yield 70%) of target compound as yellow crystals. The melting point and elemental analysis data are shown in Table 5, and the NMR and MS data are shown in Table 6.

EXAMPLE 4

Connection 17-24, are presented in Tables 5 and 6, was synthesized by the method described in the Example of a 3, using suitable starting materials.

EXAMPLE OF GETTING 5

Synthesis of 1-paratoluenesulfonyl-3-[bis(4-methoxyphenyl) methylene] oxindole (Compound 25):

5.0 g of 3-[bis(4-methoxyphenyl)methylene] oxindole received in the Sample Receiving 1, was dissolved in 50 ml of tetrahydrofuran, and then added 3.2 g of para-toluensulfonate at room temperature. After that the reaction temperature was brought to 0oC. To the reaction mixture were added 2.2 g of 60% sodium hydride and after clicks is eacli the reaction mixture was cooled. To the mixture was added saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The extract obtained was washed with water and saturated saline and then dried with sodium sulfate and finally evaporated. The crude product was recrystallized from methanol, which was obtained 3.9 g (yield 60%) of target compound as yellow crystals. The melting point and elemental analysis data are given in Table 7, and the NMR and MS data are shown in Table 8.

AN EXAMPLE OF OBTAINING 6

The connection 26 is provided in Tables 7 and 8, was synthesized the same way as described in Example Receiving 5, using suitable starting products.

EXAMPLE OF GETTING 7

Synthesis of 3-[bis(4-methoxyphenyl)methyl]oxindole (Compound 27):

5.0 g of 3-[bis(4-methoxyphenyl)methylene] oxindole received in the Sample Receiving 1, was dissolved in 100 ml of methanol and the resulting solution was restored in the presence of 10% palladium on coal for 12 hours at room temperature under hydrogen pressure of 3 atmospheres. After completion of the reaction the catalyst was removed by filtration through zerit, and then the filtrate is evaporated under reduced pressure and cooled. Received neocidin is received 5.1 g (yield 100%) of target compound as white crystals. The melting point and elemental analysis data are presented in Table 9, and the NMR and MS data are presented in Table 10.

EXAMPLE OBTAIN 8

The connection 28 is provided in Tables 9 and 10, was synthesized by the method described in Example Receiving 7, using suitable starting products.

EXAMPLE OF GETTING 9

Synthesis of 3-(4-ethoxycarbonylphenyl-4'-were)methylene-oxindole (Compound 30):

3-(4-carboxyphenyl-4'-were)methylisoxazole (Compound 29) (32.0 g, yield 82%) was synthesized by the method described in Example Obtain 1 using suitable starting products. The melting point and elemental analysis data are presented in Table 11, and the NMR and MS data are presented in Table 12.

The Compound obtained 29 (22.0 g) was added to 1000 ml of methanol and the mixture was heated under reflux for 8 hours while adding 50 ml of concentrated sulfuric acid. After completion of the reaction, the reaction mixture was cooled and, after evaporation of methanol were extracted with ethyl acetate. The extract was washed with water, saturated sodium bicarbonate, again with water and finally with saturated brine. Then, the extract was dried with sodium sulfate and evaporated. The floor is those which received 5.0 g (yield = 21.9%) of the E-isomer of the target compound in the form of orange crystals and 16.7 g (yield 73.2%) Z-isomer of the target compound as yellow crystals. The melting point and elemental analysis data are presented in Table 11, and the NMR and MS data are presented in Table 12.

EXAMPLE 10

Synthesis of 3-(4-methoxybenzylidene)-oxindole (Compound 31):

2.0 g of oxindole was dissolved in 40 ml of ethanol and then added 2.0 g of para-anisaldehyde at room temperature. After adding 1.5 ml of piperidine and the mixture was heated under reflux for 13 hours. After completion of the reaction, the reaction mixture was cooled. Precipitated crystals were collected by filtration. The crude product was washed with methanol, and was obtained 2.6 g (yield 71%) of target compound as yellow crystals. The melting point and elemental analysis data are presented in Table 13, and the NMR and MS data are presented in Table 14.

EXAMPLE OF GETTING 11

The connection 32, are presented in Tables 13 and 14, synthesized by the method described in Example 10, using acceptable source products.

EXAMPLE 12

Synthesis of 3-[bis(4-AMINOPHENYL)methylene]-oxindole (Compound 33):

In 200 ml of tert-amyl alcohol was poured 12.9 g 97% oxindole, 20.0 g of 4,4'-diaminobenzophenone and 26.43 g of tert-butoxide potassium. The mixture of gratzii. After 12 hours of heating under reflux, the reaction mixture was cooled. Then added an aqueous solution obtained by diluting 25 g of 35% hydrochloric acid in 200 g of water. The resulting reaction mixture was stirred for one and a half hours under ice cooling, and then the precipitated yellow crystals were collected by filtration. The crude product was washed with acetone and obtained 4.6 g (yield 15%) of target compound as yellow crystals. The melting point and elemental analysis data are presented in Table 15, and the NMR and MS data are presented in Table 16.

EXAMPLE OF GETTING 13

3-[bis(4-dimethylaminophenyl)methylene] -oxindole (Compound 34) specified in Tables 15 and 16, was synthesized by the method described in Example 12, using suitable starting products.

EXAMPLE OF GETTING 14

Synthesis of 3-(di-2-pyridylmethylene)-oxindole (Compound 35):

In 50 ml of acetic acid was poured 4.2 g 97% oxindole, 5.0 g of di-2-pyridylketone and 20.9 g of ammonium acetate. The resulting mixture was heated for 12 hours at a temperature of 100oC. After evaporation of the solvent the residue was extracted with ethyl acetate. The extract was washed with water, saturated bicarb the purified product was purified by column chromatography on silica gel (ethyl acetate), the result that was obtained 6.4 g (yield 78.8%) of target compound as yellow crystals. The melting point and elemental analysis are presented in Table 17, and the NMR and MS data are presented in Table 18.

EXAMPLE GET 15

3-(di-2-pyridylmethylene)-5-ethoxycarbonylmethyl (Compound 36), are presented in Tables 17 and 18, was synthesized by the method described in the Example of a 14, using a suitable source products.

EXAMPLE OF 16

Synthesis of 3-(di-2-pyridylmethylene)-5-carboxyamide (Compound 37):

5.0 g of the synthesized compounds (3-(di-2-pyridylmethylene)- 5-ethoxycarbonylmethyl) was added to 50 ml of a mixture (1:1) methanol in water and 2.5 g of 96% NaOH. The resulting mixture was stirred for six hours at room temperature. After completion of the reaction the pH of the reaction mixture is brought to 5 by adding 10% hydrochloric acid in an ice bath and the precipitated crystals were collected by filtration. These crystals were washed with water and was obtained 2.2 g (yield 47.5%) of target compound in the form of orange crystals. The melting point and elemental analysis indicated in Table 17, and the NMR and MS data are shown in Table 18.

EXAMPLE OF GETTING 17

Connection 38-40 specified in Troduction.

EXAMPLE OF GETTING 18

Connection 41-44, are presented in Tables 21 and 22, synthesized by the method described in Example receiving 7, using the compounds obtained in the Examples of the preparation of 17 and 10.

EXAMPLE TEST 1

Pharmacological test (activity, inhibiting intimal hypertrophy in rats)

With the use of various compounds, which serve as the active ingredients of the present invention, and in accordance with the methods described in the Journal of Clinical Investigation, 85 (1990) 2004, were carried out the following tests (1) and (2):

(1) test Method

In the test used groups of 14-15 weeks of male rats S. D. Each rat under ether anesthesia is injected with a catheter-balloon 3F through the right iliac artery into the aorta. When the balloon inflation was performed by the denudation of the endothelium of the thoracic aorta. Then the catheter balloon was removed and the abdominal cavity through the drop was injected antibiotic followed by saturation. Each drug suspended in 0.5% methylcellulose and 2 hours after Dendarii aorta is the drug orally was administered at a dose of 10 ml/kg / day. As a control were administered 0.5% methylcellulose.

14 days after Dendarii rats were killed. Grosely 6 segments and processed by the standard method of obtaining paraffin sections. Six samples of histological sections from each rat were stained with hematoxylin-eosin. Then measured the thickness increased intima at its maximum hypertrophy and the average thickness of the shell of the vessel in the same place, and then calculated the ratio of intimal thickness to the average thickness of the shell. Then on the calculated relationship of intimal thickness to the average thickness of the shell using as standards the data from groups that were not injected drugs, assessed the inhibition of intimal hypertrophy, expressed as a percentage. The results are presented in Table 23.

As comparative compounds were used four different following compounds (a) to (d):

(a) the compound described in application laid on the Japan patent (kokai) N 6-135829 (Tranilast);

(b) the compound described in application laid on the Japan patent (kokai) N 62-29570;

(c) the compound described in the publication of Japanese patent (kokoku) N 7-108900; and

(d) the compound described in application laid on the Japan patent (kokai) N 6-501494.

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< / BR>
< / BR>
< / BR>
(2) test Method

In the test used group 13-14 weeks of male rats S. D. Each rat under ether anesthesia Actulaly the denudation of the endothelium of the left carotid artery. Then the catheter balloon was removed and the abdominal cavity through the drop was injected antibiotic followed by saturation. Each drug suspended in 0.5% methylcellulose and 2 hours after Dendarii this drug orally was administered at a dose of 10 ml/kg once a day. As a control were administered 0.5% methylcellulose.

14 days after Dendarii rats were killed. The left carotid artery was removed and fixed by perfusion of 10% buffered formalin. Each sample was divided into six segments, and these segments were treated with the standard method, resulting in a received paraffin sections. Six samples of slices from each rat were stained with hematoxylin-eosin. Then measured the surface area of the thickened intima and the surface area of the middle shell and the computed relations of intimal area to the square of the average shell using as standards the data from groups who did not enter drug, evaluated the inhibition of intimal hypertrophy, expressed as a percentage. The results are presented in Table 24.

As shown by the results of the above tests, the compound of formula (1), i.e. the active ing the first example (a)), which is currently at the stage of clinical development and detects the high activity in the inhibition of intimal hypertrophy compared with other comparative compounds (b)-(d), which are analogues of the compounds of the present invention. Thus, the compound of formula (1) can be used as an inhibitor of intimal hypertrophy.

EXAMPLE 1. TABLET:

Connection 1 (Crystal 1) 200 mg

Corn starch 50 mg

Microcrystalline cellulose 50 mg

Hydroxypropylcellulose 15 mg

Lactose - 47 mg

Talc 2 mg

Magnesium stearate 2 mg

Ethylcellulose 30 mg

The monoglyceride Sterol acid 4 mg

The above composition is treated by the standard method and get the pills, each of which has a mass of 400 mg.

EXAMPLE 2. GRANULES:

Connection 2 - 300 mg

Lactose - 540 mg

Corn starch 100 mg

Hydroxypropylcellulose 50 mg

Talc 10 mg

The above composition is treated by the standard method and get packing with beads, where each package weighs 1000 mg.

EXAMPLE 3. CAPSULES:

The connection 200 mg

Lactose 30 mg

Corn starch 50 mg

Meanderthal method and receive capsules, each of which weighs 293 mg.

EXAMPLE 4. SOLUTION FOR INJECTION:

The connection 23 to 100 mg

Sodium chloride 3.5 mg

Distilled water for injection Appropriate number (2 mg per vial)

The above composition is treated by the standard method and get the solution for injection.

EXAMPLE 5. SYRUP:

The connection 29 200 mg

Purified sucrose - 60g

Ethyl-p-hydroxybenzoate-sucrose, 5 mg

Propyl-p-hydroxybenzoate-sucrose, 5 mg

Flavor - a good number of

Dye - a good number of

Purified water Appropriate amount

The above composition is treated by the standard method and get the syrup.

EXAMPLE 6. SUPPOSITORIES:

The connection 33 300 mg

Witepsol W-35 (Registered trademark Dinamite-Nobel; a mixture of mono-, di - and triglycerides of saturated fatty acids from lauric acid to stearic acid) - 1400 mg

The above composition is treated by the standard method and get suppositories.

Industrial application

Inhibitor of intimal hypertrophy of the present invention containing as the active ingredient oxindole derivative or its salt, has high the program/treatment/attenuation of proliferative vascular diseases, such as restenosis after PTCA (percutaneous intraluminal angioplasty), arteriosclerosis, peripheral embolism and angia.

1. Inhibitor of intimal hypertrophy, containing as the active ingredient oxindole derivative represented by formula I or its salt

< / BR>
where R1represents a hydrogen atom, phenyl group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxy-group, amino group, lower alkylamino or halogen atom, or pyridyloxy group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxy-group, amino group, lower alkylamino, a halogen atom, a lower alkoxycarbonyl group or a carboxyl group;

where (a) in the case when R1represents a hydrogen atom, R2represents a phenyl group which may be substituted by a hydroxy-group or a lower alkoxygroup, or pyridyloxy group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxyl group, amino group, lower alkylamino, atomo is SUP> represents a hydrogen atom;

X represents CH;

double dotted/solid line means a double bond;

(b) in the case when R1represents a phenyl group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxy-group, amino group, lower alkylamino or halogen atom, or pyridyloxy group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxy-group, amino group, lower alkylamino, a halogen atom, a lower alkoxycarbonyl group or a carboxyl group;

R2represents a phenyl group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, lower alkoxycarbonyl group, a carboxyl group, a hydroxy-group, amino group, lower alkylamino or halogen atom, or pyridyloxy group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxy-group, amino group, lower alkylamino, a halogen atom, a lower alkoxycarbonyl group or CT is mesena, benzyl group which may be substituted, benzosulfimide group which may be substituted, or acyl group;

R4represents a hydrogen atom, a lower alkoxygroup, halogen atom, amino group, carboxyl group, lower alkylamino, lower alkoxycarbonyl group, phenylcarbamoyl group which may be substituted, or triptorelin group, X represents CH or N;

n represents an integer from 0 to 4, inclusive, that indicates the number of substituents and double dotted/solid line means a single or double bond.

2. Inhibitor of intimal hypertrophy under item 1, where in formula (I) R1represents a hydrogen atom; R2represents a phenyl group which may be substituted by a hydroxy-group or a lower alkoxygroup, or pyridyloxy group which may be substituted by lower alkoxygroup, each R3and R4represents a hydrogen atom, X represents CH and double dotted/solid line means a double bond.

3. Inhibitor of intimal hypertrophy under item 2, where in the formula (I) R2is pyridyloxy group, 4-metoksifenilny group or 3,5-dimethoxy-4-hydroxyphenyl group.

4. Ingiriya of R1and R2represents a phenyl group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxy-group, amino group, lower alkylamino or halogen atom, or pyridyloxy group which may be substituted by lower alkoxygroup; R3represents a hydrogen atom, a lower alkyl group which may be substituted by lower alkoxycarbonyl group, a lower alkylamino or lower alkylcarboxylic group, benzyl group which may be substituted on the phenyl ring by lower alkoxygroup or lower alkoxycarbonyl group, benzoyloxy group which may be substituted on the phenyl ring of the lower alkoxycarbonyl group, or benzosulfimide group which may be substituted on the phenyl ring, a lower alkyl group, and R4represents a hydrogen atom, amino group, carboxyl group, lower alkylamino or lower alkoxycarbonyl group.

5. Inhibitor of intimal hypertrophy under item 4, where in the formula (I) R1and R2may be the same or different and each of R1and R2is pyridyloxy group or phenyl group, XI or chlorine; R3represents a hydrogen atom, a lower alkyl group which may be substituted by methoxycarbonyl, etoxycarbonyl, dimethylamino or dimethylcarbamoyl, benzyl group which may be substituted on the phenyl ring methoxycarbonyl group, or benzosulfimide group which may be substituted on the phenyl ring by methyl group; R4represents a hydrogen atom, amino group, carboxyl group, lower dialkylamino or lower alkoxycarbonyl group; X represents CH and double dotted/solid line means a double bond.

6. Inhibitor of intimal hypertrophy under item 5, where in the formula (I) R1and R2may be the same or different and each represents pyridyloxy group, phenyl group, taillow group, butylphenyl group, metoksifenilny group, hydroxyphenyl group or dimethylaminoacetyl group; R3represents a hydrogen atom, methyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, dimethylaminoethyl group, dimethylcarbamoyl group, methoxycarbonylamino group or toluensulfonyl group; R4represents a hydrogen atom, amino 2, and double dotted/solid line means a double bond.

7. Application oxindole derivative according to any one of paragraphs.1 to 6, or its salt to obtain an inhibitor of intimal hypertrophy.

8. Composition for inhibiting intimal hypertrophy, characterized in that it contains oxindole derivative according to any one of paragraphs.1 to 6, or its salt and a pharmaceutically acceptable carrier.

9. Method of prevention and treatment of intimal hypertrophy, characterized in that the patient is suffering from hypertrophy of the intima enter oxindole derivative or its salt.

 

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71 cl, 2 tbl, 3 ex

FIELD: organic chemistry, pharmaceutical composition.

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3 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmaceutical chemistry.

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3 cl, 6 tbl, 9 ex

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FIELD: organic chemistry, biochemistry.

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3 cl, 3 tbl, 29 ex

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11 cl, 1 tbl, 9 ex

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2 cl, 7 tbl, 9 ex

FIELD: pharmaceutics.

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EFFECT: higher efficiency.

21 cl, 6 dwg, 5 ex, 5 tbl

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

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

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacology, pharmacy.

SUBSTANCE: invention relates to a medicinal agent used for prophylaxis and treatment of diseases and disorders associated with dysfunction of benzodiazepine receptors. This medicinal agent comprises compound of the formula (I)

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EFFECT: valuable medicinal properties of compounds.

5 cl, 1 tbl, 1 ex

FIELD: medicine, narcology.

SUBSTANCE: method involves alternating comatose therapy and electroshock therapy every other day. In day carrying out the comatose therapy eserine ointment is placed in conjunctival sacs to patient and in 30 min 2-2.5 mg scopolamine hydrobromide solution is administrated as its 0.5% solution. Then in 3-5 h of comatose state patient is recovered from coma and 15-30 mg of physostigmine, 6 g of pyracetam, 7.5 g of magnesium sulfate and 400 ml of sodium hypochlorite are administrated by intravenous drops. In each next séance of comatose therapy dose of scopolamine hydrobromide is increased by 0.5 mg and brought about to 5-6 mg. In day carrying out electroshock therapy 1 ml of 0.1% solution of atropine sulfate and 2 ml of cordiamine are administrated and preliminary narcosis is carried out by intravenous administration of 200-300 mg of sodium thiopental or 100 mg of ketamine with simultaneous administration of 3-4 ml 2% ditiline solution and electroshock therapy is carried out followed by artificial lungs ventilation. Method provides enhancing effectiveness of treatment and to prolong the remission period.

EFFECT: enhanced effectiveness of treatment.

3 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: method involves intravenous administration of metypred in every other day being in the 1-st and 3-d days the dose is by 500.0 mg, in 5-th and 7-th day - by 250.0 mg, and in 9-th and 10-th day - by 125 mg. In onset of metypred administration dexamethasone in the dose 1.0 ml is administrated by retrobulbar route every day for 10 days. Also, method involves pterygopalatine blockade including dexamethasone, ketorol, emoxipine, lidocaine, dalargin in doses 1.0; 1.0; 1.0; 2.0 ml and 0.001 g every day for 5 days and then 3 blockades in every other day, one blockade per a day. Method expands assortment of therapeutic approaches in treatment of acute optical neuritis in patients with cerebrospinal sclerosis.

EFFECT: improved and enhanced treatment method.

1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: method involves carrying out radical surgical intervention. Abdominal cavity lavage is carried out using lavage solutions during 15-20 min after having accomplished all surgical intervention stages. The lavage solution is removed from abdominal cavity. Draining silicon tubes are set into the right subdiaphragmal space, into the right subhepatic space and into the right lateral canal, into the left subdiaphragmal space, into the right lateral canal and into small pelvis. Abdominal reservoir is formed by suspending laparotomic wound edges by means of Seagal retractor. Polyethylene film having cruciform cut in its center is fixed on laparotomic wound edges. The abdominal reservoir is filled with isotonic solution on sodium chloride bases or on dialysis solution base or on Ringer-Lock solution base as perfusate. The solution contains primary and additional chemopreparations. Perfusion solution has Cysplatin or Platinol or Carboplatin at a dose of 50 mg/m2 of patient skin area or Mytomicin C at a dose of 20 mg/m2 of patient skin area as the primary preparation and 5-Fluorouracyl as the additional preparation at a dose of 1 mg/m2 of patient skin area. The perfusion solution is introduced via draining tubes at 44-46°C into upper regions of the abdominal cavity. The solution is evacuated from it at a temperature not lower than 42.5°C via draining tubes arranged in pelvic cavity and iliac regions. Perfusion solution chemopreparations temperature control is carried out by means of heat sensor transducers mounted in draining tubes. Chemotherapy is carried out with closed perfusion solution chemopreparations circulation during 60-120 min in abdominal cavity at a rate of 500-2000 ml/min concurrently manually mixing the chemopreparation solution. The abdominal cavity is tightly sutured after having applied the hyperthermic intraoperative intraperitoneal chemotherapy. Intraperitoneal chemotherapy is carried out in postoperative period daily from the first to the fifth day after the operation. To do it, chemotherapy preparation based on physiologic sodium chloride solution or on dialysis solution or on Ringer-Lock solution, containing 5-Fluorouracyl at a dose of 1 mg/m2 of patient skin area is introduced via retained draining tubes with its exposure time being equal to 8-12 h. Then the draining tubes are removed.

EFFECT: enhanced effectiveness of treatment; prevented abdominal cavity and small pelvis region from being inseminated; prolonged survival period; improved life quality.

9 cl

FIELD: medicine.

SUBSTANCE: method involves carrying out radical surgical intervention. Abdominal cavity lavage is carried out using lavage solutions during 15-20 min after having accomplished all surgical intervention stages. The lavage solution is removed from abdominal cavity. Draining silicon tubes are set into the right subdiaphragmal space, into the right subhepatic space and into the right lateral canal, into the left subdiaphragmal space, into the right lateral canal and into small pelvis. Abdominal reservoir is formed by suspending laparotomic wound edges by means of Seagal retractor. Polyethylene film having cruciform cut in its center is fixed on laparotomic wound edges. The abdominal reservoir is filled with isotonic solution on sodium chloride bases or on dialysis solution base or on Ringer-Lock solution base as perfusate. The solution contains primary and additional chemopreparations. Perfusion solution has Cysplatin or Platinol or Carboplatin at a dose of 50 mg/m2 of patient skin area or Mytomicin C at a dose of 20 mg/m2 of patient skin area as the primary preparation and 5-Fluorouracyl as the additional preparation at a dose of 1 mg/m2 of patient skin area. The perfusion solution is introduced via draining tubes at 44-46°C into upper regions of the abdominal cavity. The solution is evacuated from it at a temperature not lower than 42.5°C via draining tubes arranged in pelvic cavity and iliac regions. Perfusion solution chemopreparations temperature control is carried out by means of heat sensor transducers mounted in draining tubes. Chemotherapy is carried out with closed perfusion solution chemopreparations circulation during 60-120 min in abdominal cavity at a rate of 500-2000 ml/min concurrently manually mixing the chemopreparation solution. The abdominal cavity is tightly sutured after having applied the hyperthermic intraoperative intraperitoneal chemotherapy. Intraperitoneal chemotherapy is carried out in postoperative period daily from the first to the fifth day after the operation. To do it, chemotherapeutic solution based on physiologic sodium chloride solution or on dialysis solution or on Ringer-Lock solution, containing 5-Fluorouracyl at a dose of 1 mg/m2 of patient skin area is introduced via retained draining tubes with its exposure time being equal to 8-12 h. Then the draining tubes are removed.

EFFECT: enhanced effectiveness of treatment; prevented abdominal cavity and small pelvis region from being inseminated; prolonged survival period; improved life quality.

9 cl

FIELD: medicine.

SUBSTANCE: method involves carrying out radical surgical intervention. Abdominal cavity lavage is carried out using lavage solutions during 15-20 min after having accomplished all surgical intervention stages. The lavage solution is removed from abdominal cavity. Draining silicon tubes are set into the right subdiaphragmal space, into the right subhepatic space and into the right lateral canal, into the left subdiaphragmal space, into the right lateral canal and into small pelvis. Abdominal reservoir is formed by suspending laparotomic wound edges by means of Seagal retractor. Polyethylene film having cruciform cut in its center is fixed on laparotomic wound edges. The abdominal reservoir is filled with isotonic solution on sodium chloride bases or on dialysis solution base or on Ringer-Lock solution base as perfusate. The solution contains primary and additional chemopreparations. Perfusion solution has Cysplatin or Platinol or Carboplatin at a dose of 50 mg/m2 of patient skin area or Mytomicin C at a dose of 20 mg/m2 of patient skin area as the primary preparation and 5-Fluorouracyl as the additional preparation at a dose of 1 mg/m2 of patient skin area. The perfusion solution is introduced via draining tubes at 44-46°C into upper regions of the abdominal cavity. The solution is evacuated from it at a temperature not lower than 42.5°C via draining tubes arranged in pelvic cavity and iliac regions. Perfusion solution chemopreparations temperature control is carried out by means of heat sensor transducers mounted in draining tubes. Chemotherapy is carried out with closed perfusion solution chemopreparations circulation during 60-120 min in abdominal cavity at a rate of 500-2000 ml/min concurrently manually mixing the chemopreparation solution. The abdominal cavity is tightly sutured after having applied the hyperthermic intraoperative intraperitoneal chemotherapy. Intraperitoneal chemotherapy is carried out in postoperative period daily from the first to the fifth day after the operation. To do it, chemotherapeutic solution based on physiologic sodium chloride solution or on dialysis solution or on Ringer-Lock solution, containing 5-Fluorouracyl at a dose of 1 mg/m2 of patient skin area is introduced via retained draining tubes with its exposure time being equal to 8-12 h. Then the draining tubes are removed.

EFFECT: enhanced effectiveness of treatment; prevented abdominal cavity and small pelvis region from being inseminated; prolonged survival period; improved life quality.

9 cl

FIELD: medicine.

SUBSTANCE: method involves carrying out radical surgical intervention. Abdominal cavity lavage is carried out using lavage solutions during 15-20 min after having accomplished all surgical intervention stages. The lavage solution is removed from abdominal cavity. Draining silicon tubes are set into the right subdiaphragmal space, into the right subhepatic space and into the right lateral canal, into the left subdiaphragmal space, into the right lateral canal and into small pelvis. Abdominal reservoir is formed by suspending laparotomic wound edges by means of Seagal retractor. Polyethylene film having cruciform cut in its center is fixed on laparotomic wound edges. The abdominal reservoir is filled with isotonic solution on sodium chloride bases or on dialysis solution base or on Ringer-Lock solution base as perfusate. The solution contains primary and additional chemopreparations. Perfusion solution has Cysplatin or Platinol or Carboplatin at a dose of 50 mg/m2 of patient skin area or Mytomicin C at a dose of 20 mg/m2 of patient skin area as the primary preparation and 5-Fluorouracyl as the additional preparation at a dose of 1 mg/m2 of patient skin area. The perfusion solution is introduced via draining tubes at 44-46°C into upper regions of the abdominal cavity. The solution is evacuated from it at a temperature not lower than 42.5°C via draining tubes arranged in pelvic cavity and iliac regions. Perfusion solution chemopreparations temperature control is carried out by means of heat sensor transducers mounted in draining tubes. Chemotherapy is carried out with closed perfusion solution chemopreparations circulation during 60-120 min in abdominal cavity at a rate of 500-2000 ml/min concurrently manually mixing the chemopreparation solution. The abdominal cavity is tightly sutured after having applied the hyperthermic intraoperative intraperitoneal chemotherapy. Intraperitoneal chemotherapy is carried out in postoperative period daily from the first to the fifth day after the operation. To do it, chemotherapeutic solution based on physiologic sodium chloride solution or on dialysis solution or on Ringer-Lock solution containing 5-Fluorouracyl at a dose of 1 mg/m2 of patient skin area is introduced via retained draining tubes with its exposure time being equal to 8-12 h. Then the draining tubes are removed.

EFFECT: enhanced effectiveness of treatment; prevented abdominal cavity and small pelvis region from being inseminated; prolonged survival period; improved life quality.

9 cl

FIELD: medicine.

SUBSTANCE: method involves intramuscularly introducing 100 mg of Ketonal before transporting patient to operating room. Then, regional block of femoral and sciatic nerve is carried out by introducing 40 mg of 0.2% Naropin solution. The patient is transported to operating room next to it.

EFFECT: enhanced effectiveness of anesthesia.

FIELD: organic chemistry, medicine, gerontology.

SUBSTANCE: invention relates to using hydrogenated pyrido[4,3-b]indoles of the formula (1) and the formula (2) as an agent for prophylaxis of premature aging. Also, invention relates to a pharmacological agent based on thereof possessing with the geroprotective activity and to a method for prophylaxis of premature aging.

EFFECT: valuable medicinal properties of agents.

20 cl, 6 dwg, 5 tbl, 2 ex

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