Derivatives of quinoline, the way they are received and anti-inflammatory agent

 

(57) Abstract:

Derivatives of quinoline General formula I, in which Y is a group C-G; G is carboxy or alkoxycarbonyl; imidazole, benzimidazole, pyrazole, triazole, 1,2-dihydropyridines, indolyl, optionally substituted alkyl, amino-, hydroxy-, oxo - or formyl group; each of rings A and B may substituted by 1 to 3 substituents selected from halogen, hydroxy, oxo, alkyl, alkoxy and the group-O(CH2)1; l is an integer of 1 to 3, n is an integer of 1 to 4; k = 0 or 1; or their pharmaceutically acceptable salts are anti-inflammatory agent. 3 S. and 18 C.p. f-crystals, 10 PL.

The present invention relates to new quinoline derivative or hintline or its salt, which is an anti-inflammatory agent, particularly a therapeutic tool in the treatment of arthritis.

Arthritis, inflammatory joint disease, is manifested in various forms, such as rheumatoid arthritis and related diseases accompanied by inflammation of a joint.

Rheumatoid arthritis, also called chronic rheumatism, is, in particular, rheumatoid arthritis, which is characterized by inflammatory changes in the Sina is assiduously diseases and lead to the development of disorders in the joint, such as deformity and ankylosis, which often leads to serious physical disorders due to the lack of effective treatment and subsequent destruction.

Traditionally, these forms of arthritis is treated with chemotherapy ways using various means, including steroids, such as cortisone and other adrenal cortex hormones, non-steroidal anti-inflammatory means, such as aspirin, piroxicam and indomethacin, gold funds, such as aurothiomalate, Antirheumatic means, such as drugs based on chloroquine, D-penicillamine, anti-gout, such as colchicine, immunosuppressants, such as cyclophosphamide, azathioprine, methotrexate and levamisole.

However, these drugs have a number of disadvantages, such as severe harmful side effects, adverse reactions, which impedes long-term courses of treatment using these drugs, the low efficiency and low impact on already developed arthritis.

Thus, there is a need to develop drugs that would have excellent preventive/therapeutic effect on arthritis and low toxicity when used the quinoline or hintline. Known compounds having aminomethyl group in position 2 of the skeleton 4-phenylindolin or 4-phenylindolin include 2-dimethylaminomethylene derivative and 2-morpholinomethyl derivative described in Synthesis, Vol. 9, p. 718 (1979), and its derivative 2-alkilaminometilen described in Farmaco, Vol. 44, 555 (1989). However, nowhere are any compounds in which the position of the 2 - skeleton of 4-phenylindolin or 4-phenylindolin through alkylenes group attached to the nitrogen atom of nitrogen-containing unsaturated heterocycle as described in the present invention.

The purpose of the invention

The aim of the invention is new derivatives of quinoline or hintline that can be used as anti-inflammatory remedies.

The next aim of the invention is a method of obtaining the above quinoline derivatives or hintline.

Another objective of the present invention is a new anti-inflammatory agent, containing a quinoline derivative or hintline.

These and other objectives and advantages of the present invention will become more clear to the specialists from the following description.

The authors of the present invention have found that compounds in which p is containing unsaturated heterocycle, possess anti-inflammatory action and are a good means to suppress the processes of destruction of the joints. The authors have conducted studies on the basis of this discovery, and developed the present invention.

Thus, the present invention relates to

(1) the compound represented by the General formula (I)

< / BR>
where Y is a nitrogen atom or a fragment of the C-G (G denotes the carboxyl group, which can be etherification); ring R is a nitrogen-containing unsaturated heterocycle, which may be substituted; each of rings A and B may have a Deputy; n is an integer from 1 to 4; k is 0 or 1, or its salts;

(2) the method of obtaining compounds of General formula (I)

< / BR>
where Y is a nitrogen atom or a fragment of the C-G (G is a carboxyl group which may be etherification); ring R is a nitrogen-containing unsaturated heterocycle which may have substituents; each of rings A and B may have a Deputy; n is an integer from 1 to 4; k is 0 or 1, or its salt by reacting compounds represented by the General formula (II)

< / BR>
where Q denotes a leaving group, and other symbols have the above values,

the inflammatory agent, containing the compound represented by the General formula I

< / BR>
where Y is a nitrogen atom or a fragment of the C-G (G is a carboxyl group which may be etherification); ring R is a nitrogen-containing unsaturated heterocycle which may have substituents; each of rings A and B may have a Deputy; n is an integer from 1 to 4; k is 0 or 1, or its salt.

The above General formula and various symbols included in the scope of claims of the present invention will be hereinafter considered in detail together with typical examples.

With regard to General formula (I) and (III), the nitrogen-containing unsaturated heterocyclic group for a ring R, which may have substituents, can be represented unsaturated heterocyclic compounds containing in the ring one or more nitrogen atoms, predominantly from 1 to 4 nitrogen atoms. Preferred unsaturated heterocyclic groups include 5-membered nitrogen-containing unsaturated heterocyclic group, such as imidazole-1-ilen, pyrazole-1-ilen, 1,2,4-triazole-1-ilen, 1,2,4-triazole-4-ilen, 1,2,3-triazole-1-ilen, 1,2,3-triazole-2-ilen, pyrrol-1-ilen and tetrazol-1-ilen, 2-pyrrolin-1-ilen, 3-pyrrolin-1-ilen, 2 is generowanie ring (in particular, the benzimidazole-1-ilen, indol-1-ilen, 1H-indazol-1-ilen, benzotriazol-1-ilen, benzotriazol-2-ilen, isoindole-2-ilen, 7-parinello, 1H-pyrrolo[1,2-b][1,2,4]triazole-1 - ilen, a 1,8-dihydroimidazo[1,2-a] pyridine-1-ilen, a 1,8-dihydro[1,2,4] triazolo[1,5-a] pyridine-1-ilen, a 3,3-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-3-ilen, a 1,8-dihydroimidazo[1,2-a] - pyrimidine-1-ilen, 1H-pyrazolo[4,3-d] oxazol-2-ilen, 4H-imidazo- [4,5-d]thiazole-4-ilen group, and so on), and 6-membered nitrogen-containing heterocyclic groups, such as 1,4-dihydropyridines-1-ilen, 1,2-dihydropyridines-1-ilen group. These unsaturated heterocyclic group may contain from 1 to 3 substituents at any position. These substituents can be represented hydrocarbon groups with aliphatic chain, alicyclic hydrocarbon groups, aryl groups, aromatic heterocyclic groups, non-aromatic heterocyclic groups, halogen atoms, nitro groups, amino groups which may have substituents, allname groups which may have substituents, hydroxy groups which may have substituents, thiol groups which may have substituents, and carboxyl groups, which can be etherification groups with aliphatic chain, such as alkyl groups having predominantly from 1 to 10 carbon atoms, alkeline group, mainly containing from 2 to 10 carbon atoms, and alkyline group.

Preferred alkyl groups are methyl, ethyl, sawn, ISO-propyl, bucilina, isobutylene, second-bucilina, tert-bucilina, pentilla, isopentyl, neopentyl, tert-pencilina, 1-ethylpropyl, hexeline, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylethylene, 3,3-dimethylbutyl, 2-ethylbutyl, hexeline, pencilina anjilina, Danilina and decile group.

Preferred alkenylamine groups are vinyl, allyl, Isopropenyl, 1-protanilla, 2-methyl-1-protanilla, 1-bucinellina, 2-bucinellina, 3-bucinellina, 2-ethyl-1-bucinellina, 3-methyl-2-bucinellina, 1-penttila, 2-penttila, 3-penttila, 4-penttila, 4-methyl-3-penttila, 1-examilia, 2-examilia, 3-examilia, 4-examilia and 5-examilia group.

Preferred alkenylamine groups are etinilnoy, 1-proponila, 2-proponila, 1-Butyrina, 2-Butyrina, 3-Butyrina, 1-penicilina, 2-penicilina, 3-penicilina, 4-penicilina, 1-hexenyl groups include saturated and unsaturated alicyclic hydrocarbons, such as cycloalkyl group, cycloalkenyl group and cycloalkenyl group.

Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentamine, tsiklogeksilnogo, cyclopentamine, cyclooctyl, bicyclo[2.2.1] heptylene, bicyclo[2.2.2]anjilina, bicyclo[3.2.1] anjilina, bicyclo[3.2.2]Danilina, bicyclo[3.3.1]Danilina, bicyclo[4.2.1] Danilina and bicyclo[4.3.1]decile group.

Preferred cycloalkenyl groups are 2-cyclopenten-1-ilen, 3-cyclopenten-1-ilen, 2-cyclohexen-1-ilen, 3-cyclohexen-1-ilen group.

Preferred cycloalkenyl groups include 2,4-cyclopentadiene-1-ilen, 2,4-cyclohexadiene-1-ilen, 2.5-cyclopentadiene-1-ilen group.

Such aryl groups are monocyclic or condensed polycyclic aromatic hydrocarbon groups, predominantly phenyl, naftilos, untilnow, phenanthrolines, acenaphtylene, or other groups, the greatest preference is given to phenyl, 1-naftilos, 2-naftilos group and others.

Preferred aromatic heterocyclic group include aromatic minociclina, thiazolidine, isothiazolinone, imidazolidine, pyrazolidine, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazolidine, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazoline, 1,2,4-triazoline, tetrataenia, perederina, pyridinoline, pyrimidinyl, piratininga and trainline group, and an aromatic condensed heterocyclic groups such as benzofuranyl, isobenzofuranyl, benzo[b] thienyl, indayla, isoindolyl, 1H-indazolinone, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazole, benzothiazoline, 1,2-benzisothiazolinone, 1H-benzotriazolyl, kinolinna, izochinolina, indolenine, chinadaily, khinoksalinona, phthalazinone, naphthylethylene, polylina, peridiniella, carbazolyl, alpha carbonilla, beta-carbonilla, gamma carbonilla, accidenily, phenoxystyrene, phenothiazinyl, pensinula, phenoxystyrene, centrailia, phenanthridinone, phenanthroline, indolizinyl, pyrrolo[1,2-b] pyridazinyl, pyrazolo[1,5-a] pyridinoline, imidazo[1,5-a] Peregrina, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]piramidalnaya, 1,2,4-triazolo[4,3-a] periasami groups are oxalanilide, azetidinone group, acetanilide, titanilla, pyrrolidinyl, tetrahydrofuranyl, milaninia, piperideine, tetrahydropyranyl, morpholinyl, thiomorpholine and piperazinilnom group.

Such atoms include halogen atoms ftory, chlorine, bromine and iodine, with preference given to fluorine atoms and chlorine.

Such amino groups are amino groups (- NH2), substituted by one or two alkyl groups having from 1 to 10 carbon atoms, alkenylamine groups having from 2 to 10 carbon atoms, aromatic groups, and acyl groups having from 1 to 10 carbon atoms (for example, methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamine, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionamido, benzoylamino and so on).

Such acyl groups include formyl group and a group formed by attaching alkyl groups having from 1 to 10 carbon atoms, alkenylphenol group having from 2 to 10 carbon atoms, or an aromatic group, and carbonyl group (e.g. acetyl, propionyl, butyryloxy, isobutyryloxy, valerino, isovaleryl, pivaloyl, heptanoyl, crotonylene, 2-cyclohexanecarbonyl, benzoyloxy, nicotinoyl group).

Such hydroxy-group include a hydroxy-group and a hydroxy-group, with appropriate substituents, in particular substituents used as protective groups for the hydroxy-group, such as alkoxy, alkenylacyl, arancelaria acyloxy and alloctype. Specified alkoxygroup preferably is alkoxygroup containing from 1 to 10 carbon atoms (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentox, isopentane, neopentane, hexyloxy, heptyloxy, nonyloxy, CYCLOBUTANE, cyclopentane, cyclohexyloxy). An example of the specified alkenylacyl are alkenylacyl containing from 2 to 10 carbon atoms, such as allyloxy, krotylov, 2-pentyloxy, 3 hexenoate, 2-cyclopentyloxy, and 2-cyclohexylmethoxy. An example of the specified aralkylated are phenyl(C1-C4)alkyloxy (for example, benzyloxy, penetratiegraad). Specified alloctype preferably is alkanoyloxy containing from 2 to 4 carbon atoms (for example, atomic charges, propionyloxy, n-butyryloxy) is up tillnow group and tirinya group, having the appropriate substituents, in particular substituents used to protect Tilney groups, such as alkylthio, Uralkali, atillio. Specified alkylthiophene preferably is allylthiourea containing from 1 to 10 carbon atoms (for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, sec-butylthio, tert-butylthio, pentylthio, isopentyl, neopentyl, hexylthio, Reptilia, nonillion, cyclobutyl, cyclopentyl, cyclohexylprop). An example of the specified arkitip are phenyl(C1-C4)allylthiourea (for example, benzylthio, venatici). An example of the specified alltihopa mainly is Alcantara having from 2 to 4 carbon atoms (for example, acetylthio, propositio, n-butylthio, isobutyrate).

Such carboxyl group include carboxyl group, allyloxycarbonyl group and aracelikarsaalyna group.

Example of the alkyl groups in these allyloxycarbonyl groups are alkyl groups having from 1 to 6 carbon atoms, such as methyl, ethyl, sawn, ISO-propyl, bucilina, isobutylene, second-bucilina and tert-bucilina group.

Aralkyl is Italia aryl group (arylalkyl group). The example mentioned aryl groups are phenyl and naftalina groups, each of which may have the same substituents listed previously for the aryl group in the ring R. the Specified alkyl group primarily is a lower alkyl group having from 1 to 6 carbon atoms. Preferred kalkilya groups include benzyl, fenetylline, 3-phenylpropyl, (1-naphthyl)methyl and (2-naphthyl)methyl group, preference is given to benzyl, fenetylline group and others.

The above hydrocarbon group with alifaticescoe chain, alicyclic hydrocarbon groups, aryl groups, heterocyclic groups, and other groups can contain one or more, preferably from 1 to 3 suitable substituents. These substituents include lower alkyl, lower alkeneamine, lower alkyline, cycloalkyl, aryl, aromatic heterocyclic, non-aromatic heterocyclic, kalkilya, amino, N-monosubstituted amino, N,N-disubstituted amino group, amidinopropane, acyl, carbamoyl, N-monosubstituted carbamoyl, N,N-disubstituted carbamoyl, sulfamoyl, N-monosubstituted sulfamoyl, N,N-disubstituted of sulfamoyl is aralkylated, aryloxy, mercapto, lower alkylthio, Uralkali, aaltio, sulfo, cyano, azide, nitro, nitrosopropane and halogen atoms.

With regard to General formula (I) and (II), provided that Y quinoline derivative is a fragment of C-G, the example carboxyl group G, which can be etherification is a carboxyl group, allyloxycarbonyl group and aracelikarsaalyna group. Example alkyl groups in the specified allyloxycarbonyl group are alkyl groups containing from 1 to 6 carbon atoms, such as methyl, ethyl, sawn, ISO-propyl, bucilina, isobutylene, second-bucilina and tert-bucilina group.

Aranceles group in the specified aracelikarsaalyna group is an alkyl group containing as a substituent aryl group (arylalkyl group). The example mentioned aryl group are phenyl group and naftalina group which may have the same substituents, and the aryl group ring R shown above. The specified alkyl group primarily is a lower alkyl group containing from 1 to 6 carbon atoms. Such kalkilya group mainly include benzyl, penecilin the Oh group, fenetylline group and others.

With regard to General formula (II), examples of the leaving group Q include halogen atoms, preferably chlorine atoms, bromine and iodine, hydroxy-group, esterified residue organosulfate acid (in particular, p-toluensulfonate, methysulfonylmethane) and residues of organophosphorus acids, such as diphenylphosphoryl, dibenzofurans and dimethylthiochroman.

With regard to General formula (I) and (II), the rings A and B may have substituents. Examples of these substituents include halogen atoms, nitro group, alkyl group which may have substituents, a hydroxy-group, which may have substituents, tirinya group which may have substituents, an amino group which may have substituents, an acyl group which may have substituents, a carboxyl group, which can be tarifitsirovana, and aromatic ring which may have substituents. Such halogen atoms as substituents include fluorine atoms, chlorine, bromine, iodine, with preference given to fluorine atoms and chlorine. Example alkyl groups which may have substituents, is any linear, branched or cycle bucilina, isobutylene, second-bucilina, tert-bucilina, pentilla, isopentyl, neopentyl, hexeline, heptylene, anjilina, Danilina, decile, cyclopropyl, cyclobutyl, cyclopentamine, tsiklogeksilnogo and cycloheptyl group. An example of a hydroxy-group, which may have substituents is hydroxy-group and a hydroxy-group, having the appropriate substituents, in particular substituents used to protect the hydroxy-group, such as alkoxy, alkenylacyl, aralkylated, alloctype and alloctype. Specified alkoxygroup preferably is alkoxygroup containing from 1 to 10 carbon atoms (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentox, isopentane, neopentane, hexyloxy, heptyloxy, nonyloxy, CYCLOBUTANE, cyclopentane, cyclohexyloxy). Examples of these alkenylacyl are alkenylacyl having from 2 to 10 carbon atoms, such as allyloxy, krotylov, 2-pentyloxy, 3 hexenoate, 2-cyclopentyloxy and 2-cyclohexylmethoxy. An example of raloxiupe are phenyl(C1-C4)alkyloxy (in particular, benzyloxy, penetrometry is Yes (e.g., the atomic charges, propionyloxy, n-butyryloxy, isobutyryloxy). An example of the specified alloctype is phenoxy and 4-chlorphenoxy. Example Tilney group which may have substituents, are Tolna group and tirinya group, having the appropriate substituents, in particular substituents used as a cover for Tilney groups, such as alkylthio, Uralkali and alltihopa. This allylthiourea is mainly alkylthiol having from 1 to 10 carbon atoms (for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, sec-butylthio, tert-butylthio, pentylthio, isopentyl, neopentyl, hexylthio, Reptilia, nonillion, cyclobutyl, cyclopentyl, cyclohexylprop). An example of the specified arkitip are phenyl(C1-C4)allylthiourea (in particular, benzylthio, penitenciaria). This alltihopa, is mainly alkanoyloxy having from 2 to 4 carbon atoms (for example, acetylthio, propositio, n-butylthio, Isobutyraldehyde). Examples of amino groups which may have substituents are amino groups (- NH2), substituted by one or two alkyl groups, containing and, containing from 1 to 10 carbon atoms (in particular, methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamine, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionamido, benzoylamine and so on). Example acyl group which may have substituents, is a formyl group and a group formed from it by attaching alkyl groups having from 1 to 10 carbon atoms, alkenylphenol groups, groups having from 2 to 10 carbon atoms or an aromatic group, and a carbonyl group (in particular, acetyl, propylaniline, Butyrina, isobutylene, valerina, isovaleryl, bialoleka, hexanoyl, heptanoyl, actinaria, cyclobutanone, Cyclopentanone, cyclohexanone, cycloheptanone, crotonylene, 2-cyclohexanecarbonyl, benzoline, nicotinoyl group). Example carboxyl groups, which can be etherification are carboxyl groups, allyloxycarbonyl group and aralkylamines group. Examples of the alkyl group in the specified allyloxycarbonyl group are alkyl groups having from 1 to 6 carbon atoms, such as methyl, ethyl, sawn, ISO-propyl, bucilina, karbonilnoj group is an alkyl group, containing as a substituent aryl group (arylalkyl group). The example mentioned aryl group is a phenyl group and naftalina group which may have the same substituents, and the aryl group ring R shown above. The specified alkyl group primarily is a lower alkyl group containing from 1 to 6 carbon atoms. Such kalkilya group mainly include benzyl, fenetylline, 3-phenylpropyl, (1-naphthyl)methyl and (2-naphthyl)methyl group, preference is given to benzyl, fenetylline group and others. Examples of the aromatic cyclic group which may have substituents, are the remains of aromatic heterocycles, such as perederina, furilla, thienyl, imidazolidine, and thiazolidine group, as well as the remains of the C6-C14aromatic hydrocarbons, such as phenyl, naftalina and antanella group.

These substituents for rings A and B may be present in any position of each ring, and each ring can be from 1 to 4 identical or different substituents. In that case, if the substituents in the rings A and B are in adjacent positions, they can communicate with each other , slice-O-(CH2)l-O- (where l is an integer from 1 to 3), while the ring may be 5 - and 7-membered rings formed with the participation of carbon atoms of the benzene ring.

The salt of compound (I), the target compounds of the present invention, preferably is a pharmaceutically acceptable salt, such as salt formed with inorganic bases, organic bases, inorganic acids, organic acids, and salts formed with basic or acidic amino acids. Salts with inorganic bases preferably include alkali metal salts such as sodium salt and potassium, salts of alkaline earth metals such as calcium salt, magnesium salt and aluminum salt and ammonium. Salts with organic bases mainly include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, and N,N'-dibenziletilendiaminom. Salts with inorganic acids mainly include salts with hydrochloric, Hydrobromic, nitric, sulfuric and phosphoric acids. The preferred salts with organic acids are salts with formic acid, acetic acid, triperoxonane, op-toluensulfonate acid. Salts of basic amino acids mainly include salts with arginine, disina and ornithine. Salts of acidic amino acids mainly include salts with aspartic acid and glutamic acid.

The compound (I), which is the target compound of the present invention, it is possible to assign orally or nearline together with a pharmaceutically acceptable carrier, in the form of solid preparations such as tablets, capsules, granules and powders, or liquid preparations such as syrups or injections.

Pharmaceutically acceptable carriers include various organic or inorganic compounds that are commonly used as pharmaceutical materials, including fillers, softeners, binding or leavening agents for solid preparations, and solvents, substances that contribute to dissolving, dispersing funds, isotonic means, buffer additives and softeners for liquid preparations. If necessary can be used in other pharmaceutical additives such as preservatives, antioxidants, colorants. The preferred fillers are lactose, sucrose, D-mannitol, starch, kristallicheskie, calcium stearate, talc or colloidal silica. Preferred binders are crystalline cellulose, sucrose, D-mannitol, dextrin, oxypropylation, oksipropilmetiltselljuloza and polyvinylpyrrolidone. Preferred loosening means include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium salt croscamellose and sodium salt of carboxymethyl amylum. Preferred solvents are water for injection, alcohol, propylene glycol, macrogol, Kungaeva oil and corn oil. Preferred substances that promote dissolution, are polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trilaminate, cholesterol, triethanolamine, sodium carbonate and sodium citrate. Preferred dispersing means are surface-active substances, such as steartrimonium, sodium salt of lauryl sulphate, lauramidopropyl acid, lecithin, benzalkonium chloride, chloride benzathine and glycerol monostearate and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methylcellulose, Oxymetazoline, acetylcellulose net. The preferred buffer additives are phosphate, acetate, carbonate and citrate buffer solutions. The preferred softening agent is benzyl alcohol. Preferred preservatives are p-oxybenzoates, chlorobutanol, benzyl alcohol, finitely alcohol, dehydroacetic acid and sorbic acid. Preferred antioxidants include sulfites and ascorbic acid.

The compound (I) can be obtained as follows:

How A

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where the symbols have the above values.

In this way the compound (II) interacts with the compound (III) in the presence of a base to form compound (I). The reaction between compounds (II) and (III) proceeds in a suitable solvent. An example of such a solvent may serve as aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, alcohols, such as methanol, ethanol or propanol, ethyl acetate, acetonitrile, pyridine, N, N-dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane, acetone, 2-butanone and mixtures of these solvents. The interaction of the compounds (II) and (III) is carried out in the ATA potassium, sodium carbonate and sodium bicarbonate, amines, such as pyridine, triethylamine and N,N-dimethylaniline, sodium hydride and potassium hydride. The amount of these bases is preferably from 1 to 5 mol per one mol of compound (II). The above reaction is usually carried out at a temperature of from about -20 to 150oC, preferably from approximately -10 to 100oC.

Obtained in this way quinoline derivative or hintline you can select and clear the known methods of separation and purification such as evaporation at atmospheric pressure, evaporation under reduced pressure, extraction with solvent, crystallization, recrystallization, re-dissolution and chromatography.

The original compound (II) according to the present invention can, for example, be obtained as follows:

Method B

< / BR>
where G' represents esterified carboxyl group; the value of the other characters mentioned above. Example esterified carboxyl group can serve the same esterified carboxyl groups specified above for G.

In the specified way derived 2-aminobenzophenone (IV) reacts with the compound (V) in the presence of acid, the rum of such a solvent may serve as aromatic hydrocarbons, such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, N,N-dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane and acetic acid. The interaction of compounds (IV) and (V) is carried out in the presence of a suitable acid such as a Lewis acid, e.g. aluminum chloride or zinc chloride, or sulfuric acid, or triperoxonane acid. The amount of these acids is about 0.01 to 2.0 mol, preferably from about 0.05 to 0.5 mol per 1 mol of compound (IV). The above reaction is usually carried out at a temperature of from about 20 to 200oC, preferably from about 30 to 150oC. the Time of reaction is from 0.5 to 20 hours, mostly from 1 to 10 hours

Obtained by the above method, the compound (II-1) can be extracted and cleaned known methods of separation and purification such as evaporation at atmospheric pressure, evaporation under reduced pressure, extraction with solvent, crystallization, recrystallization, re-dissolution and chromatography.

Method C

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< / BR>
where the meaning of the symbols listed above.

In the specified way p and acid with the formation of compound (VII), which further bromilow, getting derived 2-bromoethylene (P-2). The reaction of interaction of the compounds (IV) and (VI) is carried out analogously to method B. Bromination of the compound (VII) is carried out by conventional means in a suitable solvent. An example of such a solvent are galoidoproizvodnykh hydrocarbons such as carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachlorethane. Bromination of compound (VII) is carried out in the presence of a radical reaction initiator such as benzoyl peroxide or 2,2'-azobis(isobutyronitrile). The number of these initiators of radical reactions is preferably approximately 0.001 to 0.01 equivalents per 1 mol of compound (VII). The above reaction is usually carried out at a temperature of from about 20 to 150oC, preferably from about 30 to 100oC. the Time of reaction is from 0.5 to 20 hours, mostly from 1 to 10 hours

Obtained by the above method, the compound (II-2) can be extracted and cleaned known methods of separation and purification such as evaporation at atmospheric pressure, evaporation under reduced pressure, extraction with solvent, crystallization, recrystallization, to repeat what the rest of the characters listed above.

As for formulas (VIII) and (P-3), examples of the halogen atom or Q' are chlorine atoms, bromine or iodine.

In the specified way derived 2-aminobenzophenone (IV) interacts with a derivative of ganodermanontriol (VIII) with the formation of a derivative of 2-haloidoargentum (P-3). The reaction of interaction of the compounds (IV) and (VIII) is conducted with an excess of compounds (VIII), which serves as a solvent, in the presence of acid. An example of this acid can serve as the acid, which was cited above in the description of method B. the Amount of these acids is from about 1 to 5 equivalents per mole, preferably from about 1 to 2 mol per 1 mol of compound (IV). The time of reaction is from 0.5 to 30 hours, mostly from 1 to 10 including the above reaction is usually carried out at a temperature of from about 20 to 200oC, preferably from about 30 to 150oC.

Obtained by the above method was derived hintline (P-3) you can select and clear the known methods of separation and purification such as evaporation at atmospheric pressure, evaporation under reduced pressure, extraction with solvent, crystallization, recrystallization, re-dissolving nom method derived 2-aminobenzophenone (IV) reacts with acetonitrile with the formation of a derivative of 2-methylinosine (IX), which further bromilow, getting derived 2-bromoethylene (P-4). The reaction of interaction of the compound (IV) and acetonitrile carried out analogously to method B. Bromination of the compound (IX) carry out as well as bromination of the compound (VII) in method C.

Obtained by the above method was derived hintline (P-4) you can select and clear the known methods of separation and purification such as evaporation at atmospheric pressure, evaporation under reduced pressure, extraction with solvent, crystallization, recrystallization, re-dissolution and chromatography.

Method F

< / BR>
where the meaning of the symbols listed above.

In the specified way derived 2-aminobenzophenone (IV) interacts with the derived ester tsianuksusnogo acid (X) with the formation of the derived hintline (XI). The reaction of interaction of the compounds (IV) and (X) perform similarly to D.

Obtained by the above method was derived hintline (XI) can be extracted and cleaned known methods of separation and purification such as evaporation at atmospheric pressure, evaporation under reduced pressure, extraction with solvent, crystallization, recrystallization, re-dissolution and XP is the be derived 2-aminobenzophenone (IV) interacts with the derived ester aacondicionado acid (XII) with the formation of the derived hintline (XIII). The reaction of interaction of the compound (IV) and (XII) is carried out analogously to method B.

Obtained by the above method was derived hintline (XIII) can be extracted and cleaned known methods of separation and purification such as evaporation at atmospheric pressure, evaporation under reduced pressure, extraction with solvent, crystallization, recrystallization, re-dissolution and chromatography.

Method H

< / BR>
where Y' denotes a nitrogen atom or a fragment of the C-G'; the values of the other characters listed previously.

In the specified method of the compound (XI) and (XIII) are obtained, respectively, by methods F and G, is subjected to reduction reaction of the formation of alcohol (XIV). This recovery can hold well-known methods, such as the restoration of the hydrides of metals, recovery metallovedenie complex compounds, recovery of the DIBORANE or substituted DIBORANE and catalytic reduction. In other words, the reaction is carried out, subjecting compound (XI) and (XIII) the recovery action of the agent. Recovery agents include metallovedenie complex compounds, such as borhydride alkali metal (in particular sodium borohydride, lithium borohydride) and is particularly triphenylamine), compounds Nickel compounds zinc and other metals or metal salts, catalytic reductive agents, a combination of hydrogen and of a catalyst based on a transition metal, such as palladium, platinum or rhodium, or DIBORANE. The reaction is carried out in an organic solvent, which does not prevent its occurrence. An example of such a solvent are aromatic hydrocarbons such as benzene, toluene and xylene, galoidoproizvodnykh hydrocarbons, such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachlorethane, ethers, such as diethyl ether, tetrahydrofuran and dioxane, alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol, amides such as N,N-dimethylformamide and suitable mixture of these solvents, prepared in accordance with the type of restorative agent. This reaction is usually conducted in the temperature range from -20 to 150oC, mainly from 0 to 100oC, the time of reaction is from 1 to 24 hours

The method I

< / BR>
where the meaning of the symbols listed above.

In the mentioned method, the compound (XIV) interacts with palodiruyut agent and soluce are chloride thionyl and trichromacy phosphorus. When using these agents receive the compound (P-5) in which Q denotes chlorine or bromine. The above reaction is carried out in a suitable inert solvent (e.g. benzene, toluene, xylene, chloroform, dichloromethane) or in excess halogenous agent that plays the role of solvent, at a temperature of -10 to 80oC. the Number of used halogenous agent is from 1 to 20 mol per 1 mol of compound (XIV). Preferred sulfanilimide agents in this case are mesitylene, Teilhard and benzosulphochloride. If you are using sulfonylurea agents receive the compound (P-5) in which Q denotes respectively methyloxirane, tailorshop and benzolsulfonate. The above reaction is carried out in a suitable inert solvent (e.g. benzene, toluene, xylene, ethyl ether, ethyl acetate, tetrahydrofuran, chloroform, dichloromethane) in the presence of a base (such as triethylamine, N-methylmorpholine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate) at a temperature of from -10 to 30oC. the Number of used sulfonylurea agent or the base is from 1 to 1.2 mol per 1 mol of compound (X where Q is a chlorine atom, bromine or sulfonyloxy, 1-1,5 mol of sodium iodide or potassium iodide. In this case, the reaction can be carried out in a solvent such as acetone, methyl ethyl ketone, methanol or ethanol, at temperatures from 20 to 80oC.

Method J

< / BR>
where the meaning of the symbols listed above.

In this method, compound (P-1), (P-2), (P-3), (a-4) and (a-5) obtained, respectively, by methods B, C, D, E and I, are oxidized with the formation of compound (P-6). This oxidation is carried out with known methods in the presence of an oxidizing agent such as m-chlormadinone acid, hydrogen peroxide, nadair or metaperiodate sodium. The oxidation reaction is preferably carried out in an organic solvent which is inert under the reaction conditions, such as a halogenated hydrocarbon (e.g. methylene chloride, chloroform, dichloroethane), hydrocarbons (e.g. benzene, toluene) or an alcohol (e.g. methanol, ethanol, propane). The amount of oxidizing agent is from 1 to 5 equivalents, per 1 mol, mostly from 1 to 3 equivalents per 1 mol of compound (P-1), (P-2), (P-3), (a-4) or (a-5). The reaction temperature is from -10 to 150oC, preferably from about 0 to 100oC, reaction time obion 1-oxide (II-6) you can select and clear the known methods of separation and purification, such as evaporation at atmospheric pressure, evaporation under reduced pressure, extraction with solvent, crystallization, recrystallization, re-dissolution and chromatography.

The compound (I) can also be obtained by the methods of K, L and m

Method K

< / BR>
< / BR>
where the meaning of the symbols listed above.

In the mentioned method, the compound (IV) initially interacts with the compound (XV) with the formation of compound (I-1). The reaction of interaction of the compounds (IV) and (XV) is carried out analogously to method B.

Further, the compound (I-1) is oxidized to compound (I-2). This oxidation reaction is carried out analogously to method J.

Method L

< / BR>
where the meaning of the symbols listed above.

In the specified method of compound (I-1) and (I-2) hydrolyzing with the formation of the carboxylic acid derivative (I-3). The hydrolysis reaction is conducted by conventional methods in water or hydrated solvent. Specified hydrated solvent is a mixture of water and alcohol (e.g. methanol, ethanol), a simple ether (e.g. tetrahydrofuran, dioxane), N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile or acetone.

The above reaction is carried out in the presence of a base, such taxlot, sulfuric acid, acetic acid or Hydrobromic acid. Acid or base is preferably used in excess (from 1.2 to 6 equivalents of base and from 2 to 50 equivalents of acid per 1 mol of compound (I-1) or (I-2). The above reaction is carried out at a temperature of from -20 to 150oC, mainly from -10 to 100oC.

Method M

In this method, compound (I) in which ring A and B contain as a substituent isopropoxide, is treated with titanium tetrachloride, trichloride titanium, trichloride boron, silicon tetrachloride, etc., with the aim of turning isopropoxide in the hydroxy-group, and receive the compound (I-4), in which rings A and B contain as a substituent a phenolic hydroxy-group.

The reaction is carried out in a suitable solvent. Examples of such solvents are carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane and acetonitrile, and mixtures of these compounds. The amount of titanium tetrachloride, trichloride boron, silicon tetrachloride, etc. is from 1 to 10 molar equivalents, mainly from 1 to 6 molar equivalents per isopropylacetate. This reaction is carried out at tempera the salt of the present invention, possessing anti-inflammatory action, as well as antipyretic and analgesic effect, also shows excellent antiarthritic properties in an experimental model of adjuvant arthritis, which manifest symptoms similar to the symptoms of rheumatoid arthritis in humans. The compound of the present invention has low toxicity; for example, not a single documented death in the appointment of rats oral doses of the compounds according to example 2 or 16 in the amount of 100 mg/kg or in the appointment of oral compound in example 16 in the amount of 200 mg/kg Possessing these properties, the target compound of the present invention can be used in the treatment of all forms of arthritis, in which there are symptoms of inflammation of the joints.

Although the dose of compound (I) of the present invention may vary depending on the destination path and symptoms of the patient, it can be for adults from 5 to 1000 mg for oral destination or from 1 to 100 mg for not oral assignments, and this daily dose can be divided into 1-3 servings.

The following describes a method of testing pharmacological action of compound (I) of the present invention. Readjusted arthritis in rats

Male Lewis rats (aged 7 weeks old, Clea Japan) was injected subcutaneously injection of 0.05 ml of complete Freund adjuvant (a 0.5% suspension of dead cells tubercular granuloma in liquid paraffin) in the right hind paw. The test drug (12.5 mg/kg) in the form of a suspension in 5% gum Arabic is administered orally once a day for 14 days, starting immediately before the injection (day 0). At day 0 and day 14 measure the volume of the rear left legs, and the body weight of animals and determine the percentage of the degree of suppression of the formation of tumors and the growth of body weight relative to control group of rats, which were subjected to vaccination, but did not receive medication.

The results, expressed by the average value of the S. E. for 6 animals in each group, compare and statistically processed by Dunnet test. The significance level is below 5%. As can be seen from the table. 1 (see the end of the description), the compound of the present invention effectively suppresses the swelling of the paws of animals and improve their General condition, as evidenced by the increase in body weight.

Reference example 1

To a mixture of 2-amino-3',4'-dimethoxy-4,5-ethylenedioxythiophene (6.5 g), ethyl 4-chloroacetoacetate (3.7 g) and acetic acid (60 ml) was added Concei reduced pressure, the residue is poured into water, alkalinized 2 N. NaOH solution and extracted with chloroform. The chloroform layer is separated, washed with water and dried (over magnesium sulfate), and then the solvent is distilled off under reduced pressure. The residue is purified column chromatography on silica gel and elute with a mixture of chloroform - ethyl acetate (7: 3, V/V) to give ethyl ester of 2-chloromethyl-4-(3,4-acid)-6,7-ethylenedioxythiophene-3 - carboxylic acid (5.5 g, 60%) which is recrystallized from acetone, and produce colorless prismatic crystals with so pl. 197-198oC.

Elemental analysis (for C23H22NO6Cl):

Calculated: C 62,24; H 5,00; N 3,16

Found: C of 61.95; H 5,15; N 3,01

Reference examples 2 to 12

A methodology similar to that shown in reference example 1, is used to obtain the compounds shown in the table. 2 and 3.

Reference example 13

To a mixture of 2-amino-4,5,3', 4'-tetramethoxybenzene, ethyl 4-chloroacetoacetate and acetic acid was added concentrated sulfuric acid and conduct all operations similar to reference example 1, obtaining the ethyl ester of 6,7-dimethoxy-4-(3,4-acid)-2 - methylinosine-3-carboxylic acid (83%), which is then recrystallized from ethanol, and vitamino-4,5,3',4'-tetramethoxybenzene, propyl 4-chloroacetoacetate and acetic acid was added concentrated sulfuric acid and conduct all operations similar to reference example 1, obtaining the propyl ester of 6,7-dimethoxy-4-(3,4-acid)-2 - methylinosine-3-carboxylic acid (79%), which is then recrystallized from a mixture of ethyl acetate - isopropyl ether, and produce colorless prismatic crystals with so pl. 153 to 155oC.

Reference example 15

To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzene, butyl 4-chloroacetoacetate and acetic acid was added concentrated sulfuric acid and conduct all operations similar to reference example 1, obtaining the butyl ester of 6,7-dimethoxy-4-(3,4-acid)-2 - methylinosine-3-carboxylic acid (53%), which is then recrystallized from a mixture of ethyl acetate - hexane, and produce colorless prismatic crystals with so pl. 119-120oC.

Reference example 16

A mixture of ethyl ester of 6,7-dimethoxy-4-)3,4-acid)-2 - methylinosine-3-carboxylic acid (411 mg), N-bromosuccinimide (214 mg), 2,2'-azobis(isobutyronitrile) (10 mg) and carbon tetrachloride (10 mg) is stirred while boiling under reflux for 5 hours the reaction mixture is Washed with water and dried (over Sul is via on silica gel, elwira a mixture of chloroform-ethyl acetate (10:1, V/V), and receive the ethyl ester of 2-methyl bromide-6,7-dimethoxy-4-(3,4 - acid)quinoline-3-carboxylic acid (285 mg, 58%) which is recrystallized from a mixture of ethyl acetate - hexane, and produce colorless prismatic crystals with so pl. 135-136oC.

Elemental analysis for (C23H24NO6Br):

Calculated: C 56,34; H is 4.93; N 2,88

Found: C 55,98; H 5,23; N 2,62

Reference example 17

Carry out the same operations as in reference example 16, and receive propyl ester 2-methyl bromide-6,7-dimethoxy-4-(3,4-acid)quinoline-3-carboxylic acid (48%), which is recrystallized from a mixture of ethyl acetate - isopropyl ether, and produce colorless prismatic crystals with so pl. 144-145oC.

Elemental analysis (for C24H26NO6Br)

Calculated: C 57,15; H 5,20; N 2,78

Found: C 56,75; H and 5.30; N 2,68

Reference example 18

Carry out the same operations as in reference example 16, and receive butyl ester 2-methyl bromide-6,7-dimethoxy-4-(3,4-acid)quinoline-3-carboxylic acid (56%), which is recrystallized from a mixture of ethyl acetate - ether, and produce colorless prismatic crystals with so pl. 160-161oC.

Elemental analysis (DLR 19

A mixture of ethyl ester of 2-chloromethyl-4-(3,4-acid)- 6,7-ethylenedioxythiophene-3-carboxylic acid (3.0 g), m-chlormadinone acid (85%, 2.3 g) and methanol (40 ml) stirred at the boil under reflux for 2 hours, the Reaction mixture is subjected to removal of solvent distillation under reduced pressure. The residue is poured into chloroform. The chloroform layer is washed with water and dried (over magnesium sulfate), and then the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, elwira a mixture of chloroform - ethyl acetate (6:4, V/V), and receive 1-oxide, ethyl ester 2-chloromethyl-6,7-dimethoxy-4-(3,4-acid)quinoline-3-carboxylic acid (2.0 g, 65%) which is recrystallized from a mixture of acetone - isopropyl ether, and produce colorless prismatic crystals with so pl. 193-194oC.

Elemental analysis (for C23H24NO7Cl):

Calculated: C 59,81; H 5,24; N 3,03

Found: C 59,69; H 5,32; N 3,05

Reference example 20

To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzene (8.0 g) and chloroacetonitrile (25 ml) was added powdered aluminium chloride and stirred at 100oC for 2 hours Pour the reaction mixture into water and extracted with spruce evaporated. The residue is purified column chromatography on silica gel and elute with a mixture of chloroform - ethyl acetate (10:1, V/V) to give 2-chloromethyl-6,7-dimethoxy-4-(3,4-acid)hinzelin (4.9 g, 52%), which is then recrystallized from acetone, and produce colorless prismatic crystals with so pl. 183-184oC.

Reference example 21

To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzene (50.0 g), diethyl ether aacondicionado acid (35,0 g) and acetic acid (400 ml) was added concentrated sulfuric acid (1.5 ml) and stirred while heating to 100oC for 2.5 hours Evaporated mixture under reduced pressure, the residue is poured into water, neutralized with saturated aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform layer is separated, washed with water and dried (over magnesium sulfate), and then the solvent is distilled off under reduced pressure. The obtained solid is recrystallized from ethanol and receive the ethyl ester of 6,7-dimethoxy-4-(3,4-acid)-3-ethoxycarbonylphenyl-2 - acetic acid (55,6 g, 73%) as colorless prismatic crystals with so pl. 146-147oC.

Reference example 22

To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzene (6.3 g) and methyl is within 2.5 hours Pour the reaction mixture into water and extracted with ethyl acetate. The ethyl acetate layer is separated, washed with water and dried (over magnesium sulfate), and then the solvent evaporated. The residue is purified column chromatography on silica gel, elwira a mixture of hexane - ethyl acetate (4: 1, V/V), and obtain methyl ester of 6,7-dimethoxy-4-(3,4-acid)hinzelin-2-acetic acid (4.4 g, 55%), which is then recrystallized from isopropyl ether, and produce colorless prismatic crystals with so pl. 152-153oC.

Reference example 23

A mixture of sodium iodide (1.68 g) and 2-butanone (15 ml) was stirred at 80oC for 1 h, add ethyl ester of 2-chloromethyl-4-(3,4-acid)-6,7-ethylenedioxythiophene-3 - carboxylic acid (2.58 g) and stirred the mixture at 80oC for 12 h, the Reaction mixture was evaporated under reduced pressure, the residue is poured into water and extracted with ethyl acetate. The ethyl acetate layer is separated, washed with water and dried (over magnesium sulfate), and then the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, elwira a mixture of chloroform - ethyl acetate (1:1, V/V) to give ethyl ester of 6,7-dimethoxy-4- (3,4-acid)-2-otmetili.otlichnye prismatic crystals with so pl. 170-171oC.

Reference example 24

A solution of ethyl ester of 6,7-dimethoxy-4-(3,4-acid)- 3-ethoxycarbonylphenyl-2-acetic acid (5.8 g) in tetrahydrofuran (100 ml) was added dropwise at 0oC to a suspension of socialogical (0,455 g) in tetrahydrofuran (50 ml). Stir the mixture at 0oC for 1 h, slowly add dropwise water (2.5 ml) and then stirred for further 30 min Insoluble matter is removed by filtration, the filtrate is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, elwira a mixture of chloroform - ethyl acetate (1:1, V/V), and receive the ethyl ester of 6,7-dimethoxy-4-(3,4-acid)-2- (2-oxyethyl)quinoline-3-carboxylic acid (1.75 g, 33%) which is then recrystallized from a mixture of ethyl acetate - hexane, and produce colorless prismatic crystals with so pl. 150-151oC.

Reference example 25

To a solution of ethyl ester of 6,7-dimethoxy-4-(3,4-acid)- 2-(2-oxyethyl)quinoline-3-carboxylic acid (1.7 g) in benzene (50 ml) at room temperature was added dropwise trichromacy phosphorus (1.0 g). After stirring at a temperature of 80oC for 1 h, the reaction mixture was poured into ice water, neutralizuoti and dried (over magnesium sulfate), then the solvent is evaporated. The residue is purified column chromatography on silica gel, elwira a mixture of chloroform - ethyl acetate (1: 1, V/V), and receive the ethyl ester of 2-(2-bromacil)- 6,7-dimethoxy-4-(3,4-acid)-2-iodothyrin-3-carboxylic acid (0,49 g, 26%), which is then recrystallized from a mixture of ethyl acetate - hexane, and produce colorless prismatic crystals with so pl. 132-133oC.

Reference examples 26 - 32

A methodology similar to that shown in reference example 1, is used to obtain the compounds shown in the table. 4.

Reference example 33

A mixture of benzyl ester 4-pamakani acid (23.7 g), imidazole (8,1 g), potassium carbonate (14.0 g) and acetone (400 ml) is stirred while boiling under reflux for 6 hours After the mixture has cooled to room temperature, insoluble matter is filtered off and the filtrate evaporated. The remaining oily substance is purified column chromatography on silica gel, elwira a mixture of ethyl acetate - methanol (20,1, V/V) with the formation of the benzyl ester of 4-(1-imidazolyl)butyric acid (7,3 g, 33%) as an oily substance.

An NMR spectrum ( M. D. in CDCl3): 2,11 (2H, multiplet), was 2.34 (2H, triplet, J = 6,8 Hz) to 3.99 (2H,EP 34

A methodology similar to that shown in reference example 33, is used to produce benzyl ester 4-(1,2,4-triazo-1-yl)butyric acid (yield 88%) as an oily substance.

An NMR spectrum ( M. D. in CDCl3): 2,14-to 2.42 (4H, multiplet), 4,24 (2H, triplet, J = 6.4 Hz), 5,13 (2H, singlet), 7,30-the 7.43 (5H, multiplet), 7,94 (1H, singlet), to 7.99 (1H, singlet).

Reference example 35

A methodology similar to that shown in reference example 33, is used to produce benzyl ester 5-(1-imidazol-1-yl)valerianic acid as an oily substance by the reaction of 5-bombalurina acid and imidazole.

An NMR spectrum ( M. D. in CDCl3): 1,55 - 1,90 (4H, multiplet), of 2.38 (2H, triplet, J = 6.8 Hz), 3,93 (2H, triplet, J = 7.0 Hz), 5,11 (2H, singlet), 6,87 (1H, singlet), 7,05 (1H, singlet), 7,25 is 7.50 (5H, multiplet), 7,94 (1H, singlet), to 7.99 (1H, singlet).

Reference example 36

A mixture of benzyl ester of 4-(1-imidazolyl)butyric acid (7.4 g), 5% palladium on coal (1.0 g) and ethanol (400 ml) catalytically restore at room temperature under a pressure of 1 ATM. The catalyst is filtered off, the filtrate is evaporated under reduced pressure and the resulting solid is recrystallized from ethanol, receiving 4-(1-imidazolyl)butyric acid (3.4 g, 75%) in the form of fir 4-(1,2,4-triazole-1-yl)butyric acid catalytically restore similar to reference example 36 and receive a 4-(1,2,4-triazole-1-yl)butyric acid, which is then recrystallized from ethanol, and produce colorless prismatic crystals with so pl. 137 - 138oC.

Reference example 38

Benzyl ether of 5-(1-imidazol-1-yl)valerianic acid catalytically restore similar to reference example 36 and receive 5-(1-imidazol-1-yl)valeric acid, which is then recrystallized from ethanol, and produce colorless prismatic crystals with so pl. 157-158oC.

Reference example 39

To a suspension of 4-(1-imidazolyl)butyric acid (0.5 g) in tetrahydrofuran (35 ml) was added 1,1'-carbonyldiimidazole (0,578 g) and stirred at room temperature for 6 hours Then add the magnesium salt of monoethylene ester of malonic acid [Mg(OCOCH2COOC2H5)2] (1,02 g) and the mixture is stirred at room temperature for 18 hours the Mixture is evaporated under reduced pressure and the residue is dissolved in dichloromethane. The dichloromethane layer is washed with water and dried (over magnesium sulfate) and the solvent is then distilled off. The remaining oily substance is purified column chromatography on silica gel, elwira a mixture of chloroform - methanol (30:1, V/V), and receive the ethyl ester of 6-(1-imidazolyl)-3 - oxohexanoate acid (0.3 plet, J = 6.6 Hz), to 3.41 (2H, singlet), of 4.00 (2H, triplet, J = 6.6 Hz), 4,19 (2H, Quartet, J = 7.4 Hz), 6,91 (1H, singlet), 7,07 (1H, singlet), 7,46 (1H, singlet).

Reference example 40

A methodology similar to that shown in reference example 39, is used to produce 4-(1,2,4-triazole-1-yl)butyric acid ethyl ester 6-(1,2,4-triazole-1-yl)-3-oxohexanoate acid as an oily substance.

An NMR spectrum ( M. D. in CDCl3): of 1.28 (3H, triplet, J = 7,2 Hz), 2,19 (2H, multiplet), of 2.50 (2H, triplet, J = 6.6 Hz), 3,43 (2H, singlet), 4,19 (2H, Quartet, J = 7,2 Hz), to 4.23 (2H, triplet, J = 6.6 Hz), 7,94 (1H, singlet), 8,07 (1H, singlet).

Reference example 41

A methodology similar to that shown in reference example 39, is used to produce 5-(1-imidazol-1-yl)valerianic acid ethyl ester 7-(1-imidazol-1-yl)-3-exogamous acid as an oily substance.

An NMR spectrum ( M. D. in CDCl3): of 1.27 (3H, triplet, J = 7.4 Hz), 1,50-1,90 (4H, multiplet), 2,58 (2H, triplet, J = 6.6 Hz), to 3.41 (2H, singlet), of 3.95 (2H, triplet, J = 7.0 Hz), 4,19 (2H, Quartet, J = 7.4 Hz), make 6.90 (1H, singlet), 7,06 (1H, singlet), 7,47 (1H, singlet).

Reference example 42

A methodology similar to that shown in reference example 1, is used to obtain the ethyl ester of 2-chloromethyl-6,7-dimethoxy - 4-(4-methoxy-3-propoxyphenyl)Hino crystals with so pl. 126-128oC.

Example 1

Sodium hydride in oil (60%, 0,323 g) was added to a solution of 2-ethylimidazole (0,776 g) in N,N-dimethylformamide (30 ml) and stirred at room temperature for 15 minutes Then add ethyl ester of 2-chloromethyl-6,7-dimethoxy-4-(3,4 - acid)quinoline-3-carboxylic acid (3.0 g). The resulting mixture was stirred 1 h at a temperature of 80oC and poured into water. The crystals formed are separated by filtration and recrystallized from ethanol, obtaining the ethyl ester of 6,7-dimethoxy-4-(3,4 - acid)-2-(2-ethylimidazole-2-ylmethyl)quinoline-3-carboxylic acid (2.5 g, 74%) as colorless prismatic crystals with so pl. 163-164oC.

Examples 2 through 11

The same methodology as that in example 1, is used to obtain the compounds shown in table. 5 and 6.

Example 12

Sodium hydride in oil (60%, 0,044 g) was added to a solution of imidazole (0.075 g) in N,N-dimethylformamide (5 ml) and stirred at room temperature for 15 minutes Then add ethyl ester 2-(2-bromacil-6,7-acid)quinoline-3-carboxylic acid (0.4 g). The resulting mixture was stirred 1 h at a temperature of 80oC, poured into water and extracted with ethyl acetate. The ethyl acetate layer is separated, promavia on silica gel, elwira a mixture of ethyl acetate - methanol (10:1, V/V), and obtain ethyl ester 2-[2-(1-imidazolyl)ethyl]- 6,7-dimethoxy-4-(3,4-acid)quinoline-3-carboxylic acid (0,295 g, 66%), which is then recrystallized from a mixture of ethyl acetate - hexane and produce colorless prismatic crystals with so pl. 173-174oC.

Examples 13 to 15

The same methodology as that in example 12, is used to obtain the compounds shown in table. 6.

Example 16

Sodium hydride in oil (60%, 0,323 g) was added to a solution of 1H-1,2,5-triazole (0,558 g) in N,N-dimethylformamide (30 ml) and stirred at room temperature for 15 minutes Then add ethyl ester of 2-chloromethyl-6,7-dimethoxy-4-(3,4 - acid)quinoline-3-carboxylic acid (3.0 g). The resulting mixture was stirred 1 h at a temperature of 80oC, poured into water and extracted with ethyl acetate. The ethyl acetate layer is separated, washed with water and dried (over magnesium sulfate), and then the solvent evaporated. The residue is purified column chromatography on silica gel, elwira a mixture of chloroform - methanol (40: 1, V/V), and receive the ethyl ester of 6,7-dimethoxy-4-(3,4-acid)-2-(1,2,4-triazole-1-ylmethyl)quinoline-3-carboxylic acid (1.7 g, 53%), which is then recrystallized from CME is 17

From the second fraction after column chromatography in example 16 emit ethyl ester of 6,7-dimethoxy-4-(3,4-acid)-2- (1,2,4-triazole-4-ylmethyl)quinoline-3-carboxylic acid (0.07 g, 2%), which is then recrystallized from a mixture of ethyl acetate - hexane, and produce colorless prismatic crystals with so pl. 226-227 of theoC.

Example 18

A methodology similar to that shown in example 16, is used to produce ethyl ester of 6,7-dimethoxy-4-(4-methoxyphenyl)-2- (1,2,4-triazole-1-ylmethyl)quinoline-3-carboxylic acid, which is then recrystallized from a mixture of ethyl acetate - hexane, and produce colorless prismatic crystals with so pl. 150 - 151oC.

Example 19

From the second fraction after column chromatography in example 18 emit epilobii ester of 6,7-dimethoxy-4-(4-methoxyphenyl)-2-(1,2,4 - triazole-4-ylmethyl)quinoline-3-carboxylic acid, which is then recrystallized from a mixture of ethyl acetate - hexane, and produce colorless needle crystals with so pl. 218 - 219oC.

Examples 20 - 28

The same methodology as that in example 12, is used to obtain the compounds shown in table. 7.

Example 29

To a solution of ethyl ester of 6,7-dimethoxy-4-(4-isopropoxy-3 - methoxyphenyl)-2-orig titanium (125 mg) and stirred at the same temperature for 6 hours The reaction mixture was poured into water and extracted with chloroform. The chloroform layer was separated and sequentially washed with saturated aqueous sodium bicarbonate solution and water and dried (over magnesium sulfate) and the solvent is then evaporated. The remaining oily substance is purified column chromatography on silica gel, elwira a mixture of ethyl acetate - chloroform (3:2, V/V), and receive the ethyl ester of 6,7-dimethoxy-4-(4-hydroxy-3-methoxyphenyl)-2-(1,2,4 - triazole-1-ylmethyl)quinoline-3-carboxylic acid (24.5 mg, 48%), which is then recrystallized from a mixture of ethyl acetate - hexane and produce colorless prismatic crystals with so pl. 176 - 178oC.

An NMR spectrum ( M. D. in CDCl3): to 0.88 (3H, triplet, J = 7,2 Hz), of 3.80 (3H, singlet), 3,88 (3H, singlet), of 3.96 (2H, Quartet, J = 7,2 Hz), of 4.05 (3H, singlet), 5,73 (2H, singlet), 5,80 (1H, Shir. singlet), 6,80-7,06 (4H, multiplet), 7,42 (1H, singlet), 7,94 (1H, singlet), of 8.27 (1H, singlet).

Examples of 30 - 32

The same methodology as that in example 29, is used to obtain the compounds shown in table. 8.

Example 33

To a solution of ethyl ester of 4-(3,4-diisopropylphenyl)-6,7 - dimethoxy-2-(1,2,4-triazole-1-ylmethyl)quinoline-3-carboxylic acid (116,0 mg) in dichloromethane (2.5 ml) was added at 0oC titanium tetrachloride (228 mg) and om. The chloroform layer was separated and sequentially washed with saturated aqueous sodium bicarbonate solution and water and dried (over magnesium sulfate) and the solvent is then evaporated. The remaining oily substance is purified column chromatography on silica gel, elwira a mixture of ethyl acetate - chloroform (3:7, V/V), and receive the ethyl ester of 4-(3,4-dioksifenil)-6,7-dimethoxy-2-(1,2,4-triazole-1-ylmethyl)quinoline - 3-carboxylic acid (20.0 mg, 21%), having so pl. 122-124oC.

An NMR spectrum ( , memorial plaques in CDCl3): 0,78 (3H, triplet, J = 7.0 Hz), of 3.78 (3H, singlet), 3,86 (2H, Quartet, J = 7.0 Hz), 4.00 points (3H, singlet), 5,71 (2H, singlet), 6,60 (1H, Shir. singlet), 6,68-6,79 (2H, multiplet), 6,92 (1H, singlet), 6,97 (1H, doublet, J = 8.0 Hz), 7,37 (1H, singlet), 7,95 (1H, singlet), 8,35 (1H, singlet), to 8.70 (1H, Shir.the singlet).

Example 34

To a solution of ethyl ester of 4-(3,4-diisopropylphenyl)-6 - isopropoxy-7-methoxy-2-(1,2,4-triazole-1-ylmethyl)quinoline-3 - carboxylic acid (96.0 mg) in dichloromethane (1.0 ml) was added at 0oC titanium tetrachloride (316 mg) and stirred at the same temperature for 10 hours, the Reaction mixture was poured into water and extracted with chloroform. The chloroform layer was separated and sequentially washed with saturated aqueous sodium bicarbonate solution and water and dried (over magnesium sulfate), and is barely, elwira a mixture of ethyl acetate - methanol (10:1, V/V), and receive the ethyl ester of 4-(3,4-dioksifenil)-6-hydroxy-7-methoxy-2- (1,2,4-triazole-1-ylmethyl)quinoline-3-carboxylic acid (19,0 mg, 26%), having so pl. 264-266oC.

An NMR spectrum ( M. D. in CDCl3): to 0.88 (3H, triplet, J = 7.0 Hz), 3,93 (2H, Quartet, J = 7.0 Hz), of 3.94 (3H, singlet), 5,63 (2H, singlet), of 6.52 (1H, doublet of doublets, J = 8,2 and 2.2 Hz), to 6.67 (1H, doublet, J = 2.2 Hz), 6,85 (1H, doublet, J = 8,2 Hz), 6,98 (1H, singlet), 7,29 (1H, singlet), 7,94 (1H, singlet), to 8.57 (1H, singlet), of 9.21 (1H, singlet), of 9.21 (1H, singlet).

Reference example 35

To a mixture of 2-amino-4,5,3', 4'-tetramethoxybenzene (453 mg), ethyl ester of 6-(1-imidazolyl)-3-oxohexanoate acid (320 mg) and acetic acid (5 ml) was added concentrated sulfuric acid (0,03 ml) and stirred while heating to 100oC for 2 hours Evaporated mixture under reduced pressure, the residue is poured into water, alkalinized 2 N. NaOH solution and extracted with chloroform. The chloroform layer is separated, washed with water and dried (over magnesium sulfate), and then the solvent is distilled off under reduced pressure. The obtained oily substance is purified column chromatography on silica gel, elwira a mixture of chloroform - methanol (50:1, V/V), and receive the ethyl ester of 6,7-dimethoxy-4-(3,4-dimethoxyphenylacetic - hexane, and produce colorless prismatic crystals with so pl. 164 - 165oC.

Example 36

The same methodology as that in example 35, is used to obtain the ethyl ester of 6,7-dimethoxy-4-(3,4-acid)-2-[3-(1,2,4- triazole-1-yl)propyl] quinoline-3-carboxylic acid, which is recrystallized from ethanol, and produce colorless prismatic crystals with so pl. 141-142oC.

Example 37

The same methodology as that in example 35, is used to obtain the ethyl ester of 6,7-dimethoxy-4-(3,4-acid)-2-[4-(1- imidazolyl)butyl]quinoline-3-carboxylic acid, which is recrystallized from a mixture of ethyl acetate - hexane, and produce colorless prismatic crystals with so pl. 119 - 120oC.

Example 38

A mixture of ethyl ester of 6,7-dimethoxy-4-(3,4-acid)- 2-(1,2,4-triazole-1-ylmethyl)quinoline-3-carboxylic acid (3.0 g), 2 n sodium hydroxide solution (15.6 ml) and ethanol (50 ml) stirred at the boil under reflux for 8 hours, the Reaction mixture is cooled with ice and the pH adjusted to 5 with 2 n hydrochloric acid, after which the mixture is evaporated under reduced pressure. The residue is dissolved in ethanol and filtered off the insoluble substances. The filtrate is evaporated and the resulting Matlab), and receive the ethyl ester of 6,7-dimethoxy-4-(3,4-acid)-2-(1,2,4-triazole-1-ylmethyl)quinoline-3-carboxylic acid (1.3 g, 46%) which is recrystallized from a mixture of dichloromethane - ethanol, and produce colorless prismatic crystals with so pl. 270 - 271oC (with decomp.).

Example 39

Sodium hydride in oil (60%, 0.156 g) was added to a solution of 1H-1,2,4-triazole (0.27 g) in N,N-dimethylformamide (20 ml) and stirred at room temperature for 15 minutes Then add ethyl ester 1-oxide 2-chloromethyl-6,7-dimethoxy-4- (3,4-acid)quinoline-3-carboxylic acid (1.5 g). The resulting mixture was stirred 45 min at a temperature of 80oC, poured into water and extracted with dichloromethane. The organic layer is separated, washed with water and dried (over magnesium sulfate), and then the solvent evaporated. The remaining oily substance is purified column chromatography on silica gel, elwira a mixture of chloroform - methanol (30:1, V/V), and obtain ethyl ester 1-oxide 6,7-dimethoxy-4-(3,4-acid)-2-(1,2,4-triazole-1-ylmethyl)quinoline-3-carboxylic acid (0.8 g, 50%), which is then recrystallized from a mixture of dichloromethane - hexane, and produce colorless prismatic crystals with so pl. 221 - 222oC.

Example 40

TA yl)-2- (1,2,4-triazole-1-ylmethyl)quinoline-3-carboxylic acid, which is recrystallized from ethanol and produce colorless prismatic crystals with so pl. 127 - 128oC.

Example 41

The same technique as in example 16, is used to obtain the ethyl ester of 6,7-dimethoxy-4-(3-propoxy-4-methoxyphenyl)-2- (1,2,4-triazole-4-ylmethyl)quinoline-3-carboxylic acid, which is recrystallized from ethanol, and produce colorless prismatic crystals with so pl. 154 - 155oC.

Example 42

The same methodology as that in example 16 is used to obtain the ethyl ester of 4-(3,4-acid)-6,7-Ethylenedioxy-2-(1,2,4 - triazole-1-ylmethyl)quinoline-3-carboxylic acid, which is recrystallized from ethanol, and produce colorless prismatic crystals with so square 138 - 140oC.

Example 43

From the second fraction after column chromatography in example 42 emit ethyl ester of 4-(3,4-acid)-6,7-Ethylenedioxy-2- (1,2,4-triazole-4-ylmethyl)quinoline-3-carboxylic acid, which is then recrystallized from ethanol, and produce colorless prismatic crystals with so pl. 237 - 239oC.

Example 44

The same methodology as that in example 16, is used to obtain the ethyl ester of 6,7-dimethoxy-4-(3,4-acid)-2-(1,2,3 - triazole-1-ylmethyl)ripristina crystals with so pl. 195 - 196oC.

Elemental analysis (for C25H26N4O61/4 C2H5OH):

Calculated: C 62,50; H 5,66; N 11,43

Found: C 62,29; H of 5.53; N 11,30

Example 45

From the second fraction after column chromatography in example 44 emit ethyl ester of 6,7-dimethoxy-4-(3,4-acid)-2- (1,2,3-triazole-2-ylmethyl)quinoline-3-carboxylic acid, which is recrystallized from a mixture of ethanol - dichloroethane, and produce colorless prismatic crystals with so pl. 163 - 164oC.

Elemental analysis (for C25H26N4O61/2 C2H5OH):

Calculated: C 62,27; H of 5.83; N 11,17

Found: C 61,98; H 5,69; N 11,10

Example 46

From the second fraction after column chromatography in example 25 emit ethyl ester of 6,7-dimethoxy-4-(3-isopropoxy-4 - methoxyphenyl)-2-(1,2,4-triazole-4-ylmethyl)quinoline-3-carboxylic acid, which is recrystallized from a mixture of ethyl acetate - hexane, and produce colorless prismatic crystals with so pl. 170-171oC.

Example 47

From the second fraction after column chromatography in example 25 emit ethyl ester of 6,7-dimethoxy-4-(4-isopropoxy-3 - methoxyphenyl)-2-(1,2,4-triazole-4-ylmethyl)quinoline-3-carboxylic acid, which is precrystallization/P> Example 48

Sodium hydride in oil (60%, 0,323 g) was added to a solution of 2-oksipiridina (0,277 g) in N,N-dimethylformamide (10 ml) and stirred at room temperature for 15 minutes Then add ethyl ester 2-iodomethyl-6,7-dimethoxy-4-(3,4 - acid)quinoline-3-carboxylic acid (1.2 g). The resulting mixture was stirred at room temperature for 8 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer is separated, washed with water and dried (over magnesium sulfate), and then the solvent evaporated. The residue is purified column chromatography on silica gel, elwira a mixture of ethyl acetate - chloroform (10:1, V/V), and receive the ethyl ester of 2-(1,2-dihydro-2-oxopyridine-1-ylmethyl)-6,7 - dimethoxy-4-(3,4-acid)quinoline-3-carboxylic acid (0.64 g, 57%), which is then recrystallized from ethanol, and produce colorless prismatic crystals with so pl. 154 - 156oC.

Reference example 43

To a mixture of methyl ester of 6,7-dimethoxy-4-(3,4-acid)hinzelin-2-acetic acid (4.0 g), sodium borohydride (1.9 g) and tetrahydrofuran (80 ml) was added dropwise while boiling under reflux methanol (15 ml) and stirred under the same conditions for a further 2 hours Pour the mixture into the water and extragear the second pressure, getting 6,7-dimethoxy-4-(3,4-acid)-2-(2-oxyethyl)hinzelin (3.0 g, 81%), which is then recrystallized from ethyl acetate, and produce colorless needle crystals with so pl. 165-166oC.

Reference example 44

A methodology similar to that shown in reference example 25, is used to produce 2-(2-bromacil)-6,7-dimethoxy-4-(3,4 - acid)hintline, which is then recrystallized from ethyl acetate, highlighting colorless needle crystals with so pl. 166-167oC.

Example 49

A methodology similar to that shown in example 12, is used to produce 2-[2-(1-imidazolyl)ethyl] -6,7-dimethoxy-4-(3,4 - acid)hintline, which is then recrystallized from ethyl acetate, highlighting colorless prismatic crystals with so pl. 147-148oC.

Example 50

A methodology similar to that shown in example 1 is used to obtain the ethyl ester of 2-(benzimidazole-1-ylmethyl)-6,7-dimethoxy - 4-(3,4-acid)quinoline-3-carboxylic acid by the interaction of the ethyl ester of 2-methyl bromide-6,7-dimethoxy-4-(3,4-acid)quinoline-3-carboxylic acid with a benzimidazole, which is then recrystallized from ethanol, and produce colorless prismatic crystals with so pl. 99 - 100oC.

Example 52

A methodology similar to that shown in example 1 is used to produce propyl ester of 6,7-dimethoxy-4-(3,4-acid)-2- (imidazol-1-ylmethyl)quinoline-3-carboxylic acid interaction propyl ester 2-methyl bromide-6,7-dimethoxy-4-(3,4-acid)quinoline-3-carboxylic acid with imidazole, which is then recrystallized from ethanol, and produce colorless prismatic crystals with so pl. 166 - 168oC.

Example 53

A methodology similar to that shown in example 1 is used to produce butyl ester of 6,7-dimethoxy-4-(3,4-acid)- 2-(imidazol-1-ylmethyl)quinoline-3-carboxylic acid interaction butyl ester 2-methyl bromide-6,7-dimethoxy-4-(3,4-acid)quinoline-3-carboxylic acid with imidazole, which is then recrystallized from ethanol, and produce colorless prismatic crystals with so pl. 140 - 141oC.

Example 54

A methodology similar to that shown in example 16, is used to obtain the ethyl ester of 6-chloro-7-phenyl-2-(1,2,4-triazole-1-ylmethyl)quinoline-3-carboxylic acid by the interaction of ethyl shall agree from ethanol, and produce colorless prismatic crystals with so pl. 114-116oC.

Examples 55 - 62

The same methodology as that in example 1, is used to obtain the compounds shown in table. 9.

Example 63

A solution of hydrogen chloride in ethanol (23%, 0.172 g) was added dropwise to a suspension of ethyl ester of 6,7-dimethoxy-4-(3-isopropoxy - 4-methoxyphenyl)-2-(1,2,4-triazole-1-ylmethyl)quinoline-3-carboxylic acid (0.5 g) in a mixture of ethanol (10 ml) - dichloromethane (2 ml) at room temperature. The mixture is stirred at the same temperature for 15 min and evaporated under reduced pressure. The residue is treated with isopropyl ether and receive solid, which is recrystallized from ethanol, and allocate hydrochloride ethyl ester of 6,7-dimethoxy-4-(3-isopropoxy-4 - methoxyphenyl)-2-(1,2,4-triazole-1-ylmethyl)quinoline-3-carboxylic acid (0,211 g, 39%) as yellow crystals with so pl. 93-95oC.

Screening test

Screening test compounds for activity determination was carried out according to the same procedure as described in example test 1. The results of the tests are presented in the accompanying table, in which the symbol "+" means about 30% of the tumor suppression, "++" - about 31 which, presented in table. 10, these compounds have an inhibitory effect on swelling or edema (Eden) in tests on rats with adjuvant arthritis.

1. Derivatives of quinoline General formula I

< / BR>
in which Y represents the group C - G, in which G represents carboxy or C1-6alkoxycarbonyl group;

the group represents a nitrogen-containing unsaturated heterocyclic group selected from imidazol-1-yl, benzimidazole-1-yl, pyrazole-1-yl, 1,2,4-triazole-1-yl, 1,2,4-triazole-4-yl, 1,2,3-triazole-1-yl, 1,2-dihydropyridines-1-yl, indol-1-yl, optionally substituted C1-6-alkyl, amino-, hydroxy-, oxo - or formyl group;

each of rings A and B may be independently substituted by same or different 1 to 3 substituents selected from the group consisting of halogen, hydroxy, oxo-, C1-6-alkyl, C1-6-alkoxy and a group of the formula-O-(CH2)1-O-, in which 1 represents an integer of 1 to 3;

n represents an integer from 1 to 4;

k represents an integer 0 or 1;

or their pharmaceutically acceptable salts.

2. Connection on p. 1, in which n represents 1, or their salts.

3. Connection on p. 1, in which G represents C1-6-aldoxycarb

5. Connection on p. 1, in which each of rings A and B may be independently substituted by same or different 1 to 3 substituents selected from the group consisting of C1-6-alkoxy-, hydroxy-, oxo-, and groups of formula-O-(CH2)1-O-, in which 1 represents an integer of 1 to 3.

6. Connection on p. 5, in which the alkoxy is methoxy group, or their salts.

7. Connection on p. 6, in which one of the substituents is hydroxy, or their salts.

8. Connection on p. 1, in which the Deputy ring A is methoxy in the 6-or 7-position of the quinoline ring, or their salts.

9. Connection on p. 1, in which the Deputy ring B is methoxy in the 3 or 4 position of the benzene ring, or their salts.

10. Connection on p. 1, which is:

ethyl ester of 6,7-dimethoxy-4-(3,4-acid)-2-(1,2,4-triazole-1-ylmethyl)quinoline-3-carboxylic acid,

ethyl ester of 6,7-dimethoxy-4-(3,4-acid)-2-(2-ethylimidazole-1-ylmethyl)quinoline-3-carboxylic acid,

ethyl ester of 6,7-dimethoxy-4-(3,4-acid)-2-(2-pyrazole-1-ylmethyl)quinoline-3-carboxylic acid,

ethyl ester of 6,7-dimethoxy-4-(4-methoxyphenyl)-2-(1,2,4-triazole-1-ylmethyl)quinoline-3-carboxylic acid, or ethoxyphenyl)-2-(1,2,4-triazole-1-ylmethyl)quinoline-3-carboxylic acid,

ethyl ester of 6,7-dimethoxy-4-(4-hydroxy-3-methoxyphenyl)-2-(1,2,4-triazole-1-ylmethyl)quinoline-3-carboxylic acid,

ethyl ester of 6,7-dimethoxy-4-(4-isopropoxy-3-methoxyphenyl)-2-(1,2,4-triazole-1-ylmethyl)quinoline-3-carboxylic acid,

or their salts.

12. Connection on p. 1, which is ethyl ester of 6,7-dimethoxy-4-(3,4-acid)-2-(1,2,4-triazole-1-ylmethyl)quinoline-3-carboxylic acid, or its salt.

13. The method of obtaining quinoline derivatives of General formula I

(I)

in which Y, group , substituents in the rings A and B, k and n have the meanings given in paragraph 1,

or their pharmaceutically acceptable salts, characterized in that the compound of formula II

< / BR>
in which Q represents a leaving or delete the group, and other symbols have the definitions indicated above,

subjected to interaction with the compound of the formula III

< / BR>
in which the group has the definition indicated above.

14. The method according to p. 13, wherein Q is halogen or a hydroxyl group esterified with an organic sulfonic acid or organic phosphoric acid.

15. The method according to p. 14, wherein Q is chlorine, bromine, iodine, p-toluensulfonate on p. 15, wherein Q is chlorine or bromine.

17. Anti-inflammatory agent comprising the compound of formula I, as described in paragraph 1, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

18. Anti-inflammatory agent for p. 17 for the prevention or treatment of inflammatory diseases of the joints.

19. Anti-inflammatory agent for p. 17 for promotion of antipyretic and analgesic actions.

20. Anti-inflammatory agent for p. 17 for the prevention and treatment of arthritis.

21. Anti-inflammatory agent for p. 17 for the prevention and treatment of rheumatoid arthritis.

Priority points:

18.01.93 - PP.1 - 10, 12 - 21;

20.08.93 - p. 11.

 

Same patents:

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The invention relates to a new compound N,N-dimethyl-2-[5-(1,2,4-triazole-1-yl methyl)-1H-indol-3-yl] ethylamine sulphate salt (2:1) structural formula I and its pharmaceutically acceptable hydrate

The invention relates to new derivatives of 3(2H)-pyridazinone General formula I, where R1is hydrogen, phenyl, methyl, substituted CH3O or CH3SO2NH, C2-C4-alkyl, substituted R8R9N; C3-C5alkenyl, substituted phenyl, which is optionally substituted by halogen, one of A and B is hydrogen and the other a group of formula II, where R2and R3is independently hydrogen, C1-C4-alkyl or together with the adjacent group-N(CH2)nN - form pieperazinove or homopiperazine ring; R4is hydrogen or C1-C4-alkyl, R5, R6and R7is hydrogen, C1-C4-alkoxy, CH3SO2NH, X is a simple valence bond, an oxygen atom or the group-CH= CH-, m = 0-1, n = 2-3; R8and R9- independently C1-C4-alkyl, or together with the nitrogen atom to which they are attached, form morpholino - or 4-R10- piperazinone, where R10- C1-C4-alkyl, substituted phenoxypropane, or C3-C5alkenyl, substituted phenyl group, or an acid additive salts, which possess antiarrhythmic activity, pharmaceutical compositions containing an effective amount of the compounds in the mixture

The invention relates to a method for indole derivatives of General formula I, where F denotes a straight or branched C1-C4-alkylenes chain; R is a group of formula-CH2-CHR1-NR2R3where R1hydrogen; R2and R3the same and mean C1-C6-alkyl

The invention relates to piperazine derivatives or its salts, which are used as therapeutic agents for diseases of the circulatory organs and areas of the brain

The invention relates to new derivatives of carbazole formula

< / BR>
where

A represents a group of the formula

-CH2-R (V)

where

R1denotes hydroxyl or 2-methyl-1H-imidazol-1-yl;

B represents a group of the formula

< / BR>
where

R1denotes hydrogen, methyl or ethyl group,

or

A and B form a group of the formula

< / BR>
where

R2denotes a methyl or ethyl group,

A and B form a group of the formula

< / BR>
The invention also provides a method of obtaining the above-mentioned compounds

The invention relates to a derivative of asola used as antifungal therapeutic agents and their use

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The invention relates to novel 1,2,4-substituted piperidines formula 1, where R1is unsubstituted or substituted with halogen and/or trifluoromethyl phenyl or diphenyl-C1-C4-alkyl, ; 9-fluorenyl, pyridil-C1-C4-alkyl; chinolin-C1-C4-alkyl; 5-chloro-2-[1H-1,2,4-triazolyl-1-yl]-phenoxy-C1-C4-alkyl, unsubstituted or substituted C1-C4-alkyl, C1-C4-alkoxyl, hydroxyl, halogen, trifluoromethyl, di-C1-C4-alkylamino-group and/or cyano benzoyl; naphtol; 2-fluorenyl; phenyl - or diphenyl-C2-C4-alkanoyl; naphthyl-C2-C4-alkanoyl; dimethylcyclohexanols; hinolincarbonova; pyridyl-C2-C4-alkanoyl; benzyloxycarbonyl, unsubstituted or substituted by acetyl or 4-carboxymethylation phenylalanine or phenylcarbamoyl; 2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indol-3-yl-carbonyl; R2is unsubstituted or substituted with halogen phenyl or naphthyl; R3is hydrogen, C1-C4-alkyl, cyclohexyl or phenylcarbamoyl, or 3-aminocarbonylmethyl; R4- if necessary substituted C1-C4-alkyl or C1-C4-alkoxyl phenyl, naphthyl, benzyl, pyridyl, if necessary, C-Zam the sludge; if necessary substituted C1-C4the alkyl benzothiophenes, dihydrobenzofuranyl or aniline group, X1- simple bond, methylene, hydroxymethylene or carbonyl, X2- a simple link, X3- simple bond, methylene, ethylene, benzylidene or carbonyl or their salts

The invention relates to new indolinone derived formula, method of production thereof and to pharmaceutical compositions based on

The invention relates to new derivatives of arylsulfonamides having, in particular, valuable pharmacological properties, more particularly to a derivative of arylsulfonamides General formula (I)

< / BR>
where R1benzyl, thienyl, chloranil, tetramethylene pentamethylbenzyl, phenyl, unsubstituted or monosubstituted by a halogen atom, a nitro-group, stands, metaxylem or trifluoromethyl, phenyl, disubstituted by chlorine atoms or methoxypropane,

R2a hydrogen atom, methyl,

R3pyridyl,

R4and R5hydrogen atoms or together denote a carbon-uglerodnoi communication,

R6hydroxyl, methoxyl,

A group of the formula

< / BR>
where R7and R8a hydrogen atom or together denote a methylene or ethylene group

X N-methyl-aminogroup or sulfur atom, and the group-CHR7associated with the group-NR2-,

B a carbon-carbon bond or unbranched Allenova group with 2-4 carbon atoms,

their mixtures, isomers or individual isomers and physiologically tolerated additive salts with bases, if R6means hydroxyl, which

The invention relates to novel condensed heterocyclic compounds or their salts

The invention relates to novel 3,5-dihydroimidazo[2,1-b] hinzelin-2 (1H)-it is a derivative of the formula I

O

(I) where R is a hydrogen atom, a C1-6-alkyl, phenyl, possibly substituted by 1-3 substituents, independently from each other selected from halogen atoms, hydroxy - C1-6-alkyloxy-FROM1-6is an alkyl or triptorelin groups, pyridinyl, or thienyl, unsubstituted or substituted with halogen or1-6by alkyl;

R1the atom of hydrogen or C1-6-alkyl;

R2a hydrogen atom, a C1-6-alkyl, hydroxy-C1-6alkyl or phenyl, or R1and R2together can form WITH1-5-alcander;

X is the radical of the formula

0 (a)

N-O-R3(b) or

SN-R4(c);

R3a hydrogen atom, three (C1-6-alkyl)-silyl or1-6-alkyl which may be substituted by COOH, SOOS1-4-alkyl, СОNR5R6or SOON2-CONR7R8;

R4COOH, COOC1-4-alkyl, СОNR5R6, COOCH2CONR7R8or1-6-alkyl which may be substituted by COOH, SOOS1-4-alkyl, CONR5R6or COOCH2CONR7R8;

RIS-C1-4-alkyl, C1-4-algological - Nile-C1-4-alkyl;

R6a hydrogen atom, a C1-5-alkyl, hydroxy-C1-4-alkyl or C3-7-cycloalkyl, or R5and R6together with the nitrogen atom to which they are bound, can form pyrrolidinyl, morpholinyl or piperazinil, which can be substituted at the nitrogen atom WITH1-4-alkyl or hydroxy-C1-4-alkyl;

R7and R8independently from each other mean a hydrogen atom, a C1-4-alkyl or hydroxy-C1-4-alkyl, and their pharmaceutically acceptable salts and stereoisomers
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