Derivative amide, the method of production thereof and pharmaceutical composition based on them

 

The invention relates to amide derivative of the formula Iwhere R3represents (1-6C)alkyl or halogen; m is 0, 1, 2 or 3; R1represents hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino etc. or R1represents aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaromatic, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclyl-(1-6C)alkyl or heterocyclic, p is 0, 1 or 2; R2represents hydroxy, halogen, trifluoromethyl, (1-6C)alkyl or (1-6C)alkoxy; R4represents amino, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, etc. or R4is heteroaryl, heteroaryl-(1-6C)alkyl, heteroaromatic, heteroaryl-(1-6C)alkoxy, heterocyclyl and so on, q is 0, 1, 2, 3 or 4 and Q2is heteroaryl, heteroaromatic or heteroaryl-(1-6C)alkoxy and Q2optionally substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, trifloromethyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)-alkoxy, amino-(1-6C)alkyl, and so on, and amide. Also proposed pharmaceutical composition having inhibitory cytokine action and containing an active ingredient and a pharmaceutically acceptable diluent or carrier. As the active ingredient, the composition includes an effective amount of an amide derivative of the formula I, or its pharmaceutically acceptable salt or in vivo-split ether. The technical result - amide derivative of the formula I, useful as inhibitors of cytokine-mediated diseases. 4 C. and 10 C. p. F.-ly, 6 PL.

Description text in facsimile form (see graphic part)and

Claims

1. Amide derivative of the formula I

where R3- (1-6C)alkyl or halogen;

m = 0, 1, 2 or 3;

R1hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl]amino-(2-6C)alkylamino, N-(1-6C)alkylamino-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino, N-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(2-6C)alkylamino, amino-(2-6S)-alkanolamine, (1-6C)alkylamino-(2-6C)alkanolamine or di-[(1-cloxi, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclyl-(1-6C)alkyl or heterocyclic, and where any aryl or heteroaryl heterocyclyl substituent R1may optionally have 1 or 2 substituent selected from halogen, (1-6C)alkyl, (1-6C)alkoxy and (1-6C)alkoxycarbonyl;

p = 0, 1, or 2;

R2hydroxy, halogen, trifluoromethyl, (1-6C)alkyl or (1-6C)alkoxy;

R4- amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C) alkoxy, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl]amino-(2-6C)alkylamino, N-(1-6C) -alkylamino-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino, N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6S)-alkylamino or R4- heteroaryl, heteroaryl-(1-6C)alkyl, heteroaromatic, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclyl-(1-6C)alkyl, heterocyclic, heterocyclic-(1-6C)alkoxy, heterocyclisation, N-(1-6C)alkyldiethanolamine, heterocyclyl-(1-6C)alkylamino, N-(1-6C)alkylglycerol-(1-6C)alkylamino, heterocyclyl-(1-6C)alkoxy-(1-6C)alkyl, heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl or N-(1-6C)alkylglycerol-(1-6C)alkylamino-(1-6C)Eiaeeneea to two carbon atoms, or CH3group that is attached to a carbon atom may optionally have on each of the specified CH2or CH3group Deputy selected from amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and where any heteroaryl or heterocyclyl substituent R4may optionally have 1 or 2 substituent selected from hydroxy, halogen, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)the alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl;

q = 0, 1, 2, 3 or 4;

Q2- heteroaryl, heteroaromatic or heteroaryl-(1-6C)alkoxy and Q2optionally substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, trifloromethyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, halogen-(2-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-6C)alkoxy(2-6C)alkoxy, aryl, aryl-(1-6C)alkyl, aryl-(1-6C)alkoxy, arylamino, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclyl-(1-6C)alkyl and heterocyclyl-(1-6C)alkoxy, and where any aryl, heteroaryl or heterocyclyl is-6C)alkyl, (1-6C)alkoxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl,

or its pharmaceutically acceptable salt or in vivo-split the air.

2. Amide derivative of the formula I on p. 1, where Q2- heteroaromatic 5 - or 6-membered monocyclic ring or 9 - or 10-membered bicyclic ring containing up to 5 heteroatoms in the ring selected from oxygen, nitrogen and sulfur, which are the main Deputy, selected from amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C) alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclyl-(1-6C)alkyl and heterocyclyl-(1-6C)alkoxy, and where any heteroaryl or heterocyclyl group principal Deputy Q2may optionally have 1 or 2 substituent selected from halogen, (1-6C)alkyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino.

3. Amide derivative of the formula I on p. 1, where Q2- heteroaromatic 5 - or 6-membered monocyclic ring or 9 - or 10-membered bicyclic ring or a 13 - or 14-membered tricyclic ring, each containing up to 5 heteroatoms in the ring selected from oxygen, nitrogen and sulfur, (1-6C)alkoxy.

4. Amide derivative of the formula I on p. 1, where R4- amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl] amino-(2-6C) alkoxy, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6S)-alkylamino, di-[(1-6C)alkyl]amino-(2-6C)alkylamino, N-(1-6C)alkylamino-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino, N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino, pyridyl, imidazolyl, pyridyl-(1-6C)alkyl, imidazolyl-(1-6C)alkyl, pyridyl-(1-6C)alkoxy, imidazolyl-(1-6C)alkoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 4-(1-6C)alkylpiperazine, homopiperazine, 4-(1-6C)acylhomoserine, pyrrolidinyl-(1-6C)alkyl, piperidinyl-(1-6C)alkyl, morpholinyl-(1-6C)alkyl, piperazinil-(1-6C)alkyl, 4-(1-6C)alkylpiperazine-(1-6C)alkyl, homopiperazine-(1-6C)alkyl, 4-(1-6C)acylhomoserine-(1-6C)alkyl, pyrrolidinyloxy, piperidinyloxy, 1-(1-6C)alkylpiperidines, pyrrolidinyl-(2-6C)alkoxy, piperidinyl-(2-6C)alkoxy, morpholinyl-(2-6C)alkoxy, piperazinil-(2-6C)alkoxy or 4-(1-6C)alkylpiperazine-(2-6C)alkoxy.

5. Amide derivative of the formula I on p. 1, where R3is methyl, ethyl, chlorine or bromine; m = 0 or 1; R1hydroxy, fluorine, chlorine, bromine, drift is - the Mino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3 aminopropoxy, 2-methylaminoethanol, 2-ethylaminoethanol, 3 methylaminopropane, 3 Ethylenedioxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminopropyl, pyridyl, pyridylmethyl, pyridyloxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 4-methylpiperazine, pyrrolidinyl, piperidinylmethyl, morpholinylmethyl, piperidinylmethyl, 4-methylpiperazine, piperidinyloxy, 1 methylpiperidine, 2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy, 2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinil)ethoxy, 3-(piperazinil)propoxy, 2-(4-methylpiperazine)ethoxy or 3-(4-methylpiperazine)propoxy; q=0 and Q2- furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiophene, benzoxazole, benzimidazole, benzothiazole, indazole, benzofurazanyl, hinely, ethanolic, hintline, honokalani or naphthyridine that do not have 1 or 2 substituent, vibrationally, dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy, 3 hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3 methoxypropane, 3 ethoxypropane, pyridyl, pyridylmethyl, pyridyloxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 4-methylpiperazine, pyrrolidinyl, piperidinylmethyl, morpholinylmethyl, piperidinylmethyl, 4-methylpiperazine, 2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy, 2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinil)ethoxy, 3-(piperazinil)propoxy, 2-(4-methylpiperazine)ethoxy and 3-(4-methylpiperazine)propoxy, or its pharmaceutically acceptable salt.

6. Amide derivative of the formula I on p. 1, where R3is methyl; m = 0 or 1 and R1hydroxy, fluorine, chlorine, amino, methyl, methoxy, methylamino or dimethylamino; each of p and q = 0; R4is in the 3rd or 4th position and is selected from diethylaminomethyl, diethylaminoethyl, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminopropyl, 2-aminoethylamino, 3 aminopropylene, 4-aminoethylamino, 3 methylaminopropyl, 2-diethylaminoethylamine, 2-diethylaminoethylamine, 3 dimethylaminopropylamine, 4-diethylaminoethylamine, N-(2-dimethylene the La, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, 4-methyl-homopiperazin-1-yl, piperazine-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-methylhomopiperazine-1-ylmethyl, morpholinomethyl, 3-aminopyrrolidine-1-ylmethyl, 3-hydroxypyrrolidine-1-ylmethyl, 4-(2-hydroxyethyl)piperazine-1-ylmethyl, piperidine-4-yloxy, 1 methylpiperidin-4-yloxy, 2-pyrrolidin-1 ylethoxy, 3-pyrrolidin-1 ipropose, 2-piperidinoethyl, 3 piperidinyloxy, 2-morpholinoethoxy, 3 morpholinopropan, 2-piperazine-1-ylethoxy, 3-piperazine-1-ylpropionic, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-hydroxy-3-pyrrolidin-1 ipropose, 2-hydroxy-3-piperidinyloxy, 2-hydroxy-3-morpholinopropan, piperidine-4-ylamino, 1 methylpiperidin-4-ylamino, 2-pyrrolidin-1 ylethylamine, 3-pyrrolidin-1 iproplatin, 2-morpholinoethyl, 3 morpholinopropan, 2-piperidinoethyl, 3 piperidinophenyl, 2-piperazine-1-ylethylamine, 3-piperazine-1-ylpropionic, 2-(4-methylpiperazin-1-yl)ethylamino, 3-(4-methylpiperazin-1-yl)propylamino, 2-(1-methylpyrrolidine-2-yl)ethylamino, 3-(1-methylpyrrolidine-2-yl)propylamino, 2-dimethylaminoethanol, 3-dimethylamino-propylaminoethyl, 3-dimethylamino-2,2-dimethylpropylene, 2-(1-methylpyrrole who said; " the, 2-piperazine-1-ylethylamine, 3-(4-methylpiperazin-1-ylpropyl)aminomethyl and 2 pyridyloxy; and Q2- 2-pyridyl, 3-pyridyl or 4-pyridyl, which have a Deputy selected from pyrrolidin-1-yl, 3-hydroxypyrrolidine-1-yl, 2-hydroxyethylpyrrolidine-1-yl, morpholino, piperidino, 4-hydroxypiperidine-1-yl piperazine-1-yl, or its pharmaceutically acceptable salt.

7. Amide derivative of the formula I on p. 1, where R3is methyl;

m = 0 or 1 and R1is nitro or amino; each of p and q = 0; R4is in the 3rd or 4th position and is selected from diethylaminomethyl, N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazine-1-yl, 4-methylpiperazin-1-yl, 4-methylhomopiperazine-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazine-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl, 4-methylhomopiperazine-1-ylmethyl, 3-aminopyrrolidine-1-ylmethyl, 3-hydroxypyrrolidine-1-ylmethyl, 4-(2-hydroxyethyl)piperazine-1-ylmethyl, pyrrolidin-3-yloxy, N-methylpyrrolidine-3-yloxy, piperidine-4-yloxy, N-methylpiperidin-4-yloxy, N-ethylpiperidine-4-yloxy, N-isopropylpiperazine-4-yloxy, homopiperazin-4-yloxy, N-methylhomopiperazine-4-yloxy, 3-pyrrolidin-1-improvisational, 2-(1-methylpyrrole)aminomethyl, pyrid-2-ylethoxy, thiazole-4-ylethoxy and 2-methylthiazole-4-ylethoxy; and Q2- 2-pyridyl, 3-pyridyl or 4-pyridyl, which have a Deputy selected from pyrrolidin-1-yl, 2-hydroxyethylpyrrolidine-1-yl, morpholino and piperidino, and where any of the last 4 substituents can optionally having 1 or 2 methyl groups, or Q2- 2 - or 4-dibenzofuran; or its pharmaceutically acceptable salt.

8. Amide derivative of the formula I on p. 1, where R3is methyl; m = 0 or 1 and R1is nitro or amino; each of p and q = 0; R4is in the 3rd or 4th position and is selected from diethylaminomethyl, N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazine-1-yl, 4-methylpiperazin-1-yl, 4-methylhomopiperazine-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazine-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl, 4-methylhomopiperazine-1-ylmethyl, 3-aminopyrrolidine-1-ylmethyl, 3-hydroxypyrrolidine-1-ylmethyl, 4-(2-hydroxyethyl)piperazine-1-ylmethyl, pyrrolidin-3-yloxy, piperidine-4-yloxy, 3-pyrrolidin-1-improvisational, 2-(1-methylpyrrolidine-2-retil)aminomethyl, 2-morpholinosydnonimine, 3-morpholinepropanesulfonic, 3-(4-methylpiperazin-1-ylpropyl)aminomethyl or pdin-1-yl, 2-hydroxyethylpyrrolidine-1-yl, morpholino and piperidino, or its pharmaceutically acceptable salt.

9. Amide derivative of the formula I on p. 1, where R3is methyl; each of m, p and q = 0;

R4is in the 3rd or 4th position and is selected from diethylaminomethyl, 4-methylpiperazin-1-yl, morpholinomethyl, piperazine-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-methylhomopiperazine-1-ylmethyl, 3-hydroxypyrrolidine-1-ylmethyl, pyrrolidin-3-yloxy, piperidine-4-yloxy, N-methylpiperidin-4-yloxy, N-isopropylpiperazine-4-yloxy, N-methylhomopiperazine-4-yloxy, 2-(N-methylpyrrolidine-2-yl)ethoxy, 3-dimethylamino-2,2-dimethylpropanamide, N-(3-dimethylaminopropyl)-N-methylaminomethyl, 3-morpholinepropanesulfonic and 2-methylthiazole-4-ylethoxy; and2- 4-pyridyl, which has a Deputy selected from morpholino, piperidino, 3 methylpiperidin-1-yl and homopiperazin-1-yl, or Q2is a 4-dibenzofuran, or its pharmaceutically acceptable salt.

10. Amide derivative of the formula I on p. 1, selected from

N-{4-methyl-3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]phenyl}furan-2-carboxamide;

N-{4-methyl-3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]phenyl} isoxazol-5-carboxamide;

N-[3-(4-diethylaminoethylamine)-4-were]-2-morph the Jn-4-carboxamide;

N-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-were}-2-morpholinopropan-4-carboxamide;

N-{3-[3-(4-methylhomopiperazine-1-ylmethyl)benzamido]-4-were}-2-morpholinopropan-4-carboxamide;

N-{3-[4-(4-methylhomopiperazine-1-ylmethyl)benzamido]-4-were}-2-morpholinopropan-4-carboxamide;

N-[3-(3-piperazine-1-ylmethylamino)-4-were]-2-morpholinopropan-4-carboxamide;

N-{3-[4-(3-hydroxypyrrolidine-1-ylmethyl)benzamido]-4-were}-2-morpholinopropan-4-carboxamide;

N-{3-[3-(3-pyrrolidin-1-improvisationally)benzamido]-4-were}-2-morpholinopropan-4-carboxamide;

N-{3-[4-(3-morpholinepropanesulfonic)benzamido]-4-were}-2-morpholinopropan-4-carboxamide;

N-[3-(3-diethylaminoethylamine)-4-were]-2-morpholinopropan-4-carboxamide;

N-[3-(4-diethylaminoethylamine)-4-were]-5-morpholinomethyl-3-carboxamide;

N-[3-(4-diethylaminoethylamine)-4-were]-2-piperidinomethyl-4-carboxamide;

N-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-were}-2-(3-methylpiperidin-1-yl)pyridine-4-carboxamide;

N-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-were}-2-homopiperazin-1-espiridion-4-carboxamide;

N-[4-methyl-3-(4-morpholinosydnonimine)phenyl]-2-morpholinopropan is n-4-carboxamide;

N-{3-[4-(3-dimethylamino-2,2-dimethylpropanoyl)-benzamido]-4-were}-2-morpholinopropan-4-carboxamide;

N-(3-{4-[N-(3-dimethylaminopropyl)-N-methylaminomethyl]-benzamido]-4-were)-2-morpholinopropan-4-carboxamide;

N-[4-methyl-3-(3-piperidine-4-roxianne)phenyl]-2-morpholinopropan-4-carboxamide;

N-[4-methyl-3-(3-pyrrolidin-3-roxianne)phenyl]-2-morpholinopropan-4-carboxamide;

N-{3-[3-(N-methylhomopiperazine-4-yloxy)benzamido]-4-were}-2-morpholinopropan-4-carboxamide;

N-(3-{3-[2-(N-methylpyrrolidine-2-yl)ethoxy]benzamido}-4-were)-2-morpholinopropan-4-carboxamide;

N-{4-methyl-3-[4-(2-methylthiazole-4-ylethoxy)benzamido]phenyl}-2-morpholinopropan-4-carboxamide and

N-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-were}dibenzofuran-4-carboxamide,

or its pharmaceutically acceptable salt.

11. The way to obtain an amide derivative of the formula I, or its pharmaceutically acceptable salt or in vivo-split ether under item 1, which includes the interaction of aniline of the formula II

with the acid of formula III

or its active derivative

in standard conditions of formation of amide linkages, where different grapetree group and (ii) optional form pharmaceutically acceptable salt or in vivo-degradable ester; and then (a) for obtaining the compounds of formula I, where R1, R4or Deputy Q2represents (1-6C)alkoxy or substituted (1-6C)alkoxygroup, (1-6C)alkylamino, di-[(1-6C)alkyl]amino or substituted (1-6C)alkylamino, the alkylation, conveniently in the presence of a suitable base, of an amide derivative of the formula I, where1, R4or Deputy Q2represent, respectively, hydroxy or amino; (b) to obtain the compounds of formula I, where Deputy Q2is a N-linked heterocyclyl group interaction, conveniently in the presence of a suitable base, of an amide derivative of the formula I, where Deputy Q2represents the right of the deleted group, with the appropriate amine; (C) to obtain the compounds of formula I, where R1, R4or Deputy Q2represents (1-6C)alkanolamine or substituted (2-6C)alkanolamines, the acylation of compounds of formula I, where R1, R4or Deputy Q2represent amino.

12. The way to obtain an amide derivative of the formula I, or its pharmaceutically acceptable salt or in vivo-split ether under item 1, which includes the interaction of the acid of formula V or the 92264.gif">

in standard conditions of formation of amide linkages, where different groups are previously defined in paragraph 1 and where any functional group is optionally protected, (i) remove any protective group and

(ii) optional form pharmaceutically acceptable salt or in vivo-split the air, and then (a) for obtaining the compounds of formula I, where R1, R4or Deputy Q2represents (1-6C)alkoxy or substituted (1-6C)alkoxygroup, (1-6C)alkylamino, di[(1-6C)alkyl]amino or substituted (1-6C)alkylamino, the alkylation, conveniently in the presence of a suitable base, of an amide derivative of the formula I, where R1, R4or Deputy Q2represent, respectively, hydroxy or amino; (b) to obtain the compounds of formula I, where Deputy Q2is a N-linked heterocyclyl group interaction, conveniently in the presence of a suitable base, of an amide derivative of the formula I, where Deputy Q2represents the right of the deleted group, with the corresponding amidon; (C) to obtain the compounds of formula I, where R1, R4or Deputy Q2represents (1-6C)alkanolamine or substituted (1-6C)Alcano is an amino.

13. Pharmaceutical composition having inhibitory cytokine action and containing an active ingredient and a pharmaceutically acceptable diluent or carrier, wherein the active ingredient composition comprises an effective amount of an amide derivative of the formula I or its pharmaceutically acceptable salt or in vivo degradable ester according to any one of paragraphs.1-10.

14. Amide derivative of the formula I under item 1 or its pharmaceutically acceptable salt or in vivo-split the air as an active ingredient of a medicinal product for treatment of medical conditions caused by cytokines.

Priority items:

25.09.1998 on PP.2, 5, 10, 11, 12, 13 and 14;

09.12.1998 on PP.1, 6 and 10;

17.03.1999 on PP.4 and 8.

 

Same patents:

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The invention relates to novel polycyclic to dihydrothiazolo General formula (I), where Y is a simple bond; X is CH2; R1 is H, F, Cl, NO2, CN, COOH, (C1-C6)-alkyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine; (CH2)n-phenyl, SO2-(C1-C6)-alkyl, and n = 0 and the phenyl residue up to twice may be substituted by F, Cl, CF3, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; O-(CH2)n-phenyl, and n = 0 and phenyl cycle can be one - to twofold substituted by Cl, (C1-C6)-alkyl; 1 - or 2-naphthyl, 2 - or 3-thienyl; R1' is hydrogen; R2 is H, (C1-C6)-alkyl, R3 is hydrogen; R4 - (C1-C8)-alkyl, (C3-C7-cycloalkyl, (CH2)n-aryl, and n = 0-1, and aryl can be phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, indol-3-yl, indol-5-yl, and aryl or heteroaryl residue up to twice may be substituted by F, Cl, HE, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, 2-, 3-, 4-pyridium, pyrrol-1-yl, with peregrinae ring may be substituted CF3; and their physio is

The invention relates to 5-[4-(6-methoxy-1-methyl-1H-benzimidazole-2-ylethoxy)benzyl] thiazolidin-2,4-dione hydrochloride

The invention relates to new derivatives of benzothiazole General formula (I) or its salt, where p denotes 1; X1and X2together form =O; R1denotes hydrogen, halogen, alkyl, alkoxy; R2denotes hydrogen; R3denotes a-Z4-R6, -Z13-NR7R8; Z4denotes a-Z11-C(O)-Z12-, -Z11-C(O)-O-Z12-; Z11and Z12represent a simple bond or alkylene; Z13denotes a-Z11-C(O)-Z12-; R4denotes hydrogen; R5denotes phenyl, substituted groups Z1, Z2selected from alkyl, halogen, nitro, -HE, hydroxyalkyl, -C(O)Z6, -C(O)OZ6-Z4-NZ7Z8where Z4represents a simple bond; biphenyl, substituted alkyl; naphthalenyl, which optionally can be substituted-HE; chinoline, substituted alkyl; heterocyclics; Z6denotes alkyl which may be optionally substituted by a group-Z4-NZ7Z8, morpholinium; Z7, Z8each independently represents alkyl; R6denotes alkyl optionally substituted by cyano, methoxy, phenyl, -Z4-NZ7Z8and so on; R7denotes hydrogen, alkyl; R8denotes alkyl, the long is Z4-NZ7Z8; and t

The invention relates to new derivatives of aminothiazole formula I and their pharmaceutically acceptable salts, where R1and R2independently of one another denote hydrogen, fluorine or lower alkyl; R3denotes heteroaryl selected from oxazolyl, which is substituted by one or more substituents selected from lower alkyl, halogen, carbamoyl, allyloxycarbonyl, alkylcarboxylic; or benzoxazole; R4denotes hydrogen;-alkyl which can be optionally substituted with halogen, alkoxy, hydroxy, allyloxycarbonyl, alkylcarboxylic, amino, carbamoyl; CO-cycloalkyl; CO-aryl, where aryl represents phenyl which may be optionally substituted with halogen, lower alkyl, alkoxy, amino, cyano or naphthyl, and so on; or COO-alkyl; COO-cycloalkyl; soo-phenyl; COO-alkyl-phenyl; SO2-alkyl; SO2-phenyl, C(NCN)NH-phenyl, where phenyl may be optionally substituted with halogen; R5denotes hydrogen; m is an integer from 0 to 2; n is 0

The invention relates to amino acid derivatives of the formula I

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or its non-toxic salt or its hydrate, the pharmaceutical composition having inhibitory effect on calcium channel iv-type; the inhibitor calcium channel N-type; a pharmaceutical composition for prevention and/or treatment of cerebral infarction and pharmaceutical compositions for the treatment of pain

The invention relates to a derivative of sulfoaluminate and sulphoniumhydroxide acid of formula I, its pharmaceutically acceptable salts, where W is-HE-or-NHOH; X denotes (a) a heterocyclic radical selected from the group comprising imidazolines, dihydrobenzofuranyl and so on, b) -NR1SO2R2where R1denotes a hydrogen atom, R2denotes an unsubstituted phenylalkyl and so on; Y represents carbon or sulfur, with the proviso that when Y represents carbon, n is equal to 2; Z represents phenyl, optionally substituted with halogen, unsubstituted alkoxy, phenyloxy, optionally substituted with halogen, phenylacetonitrile, 4-methylpiperazine, 4-phenylpiperidine, pyridyloxy, -NR'1COR'2, -SO2R'2where R'1denotes a hydrogen atom, R'2denotes phenyl, optionally substituted by hydroxy or phenyl, pyridinyl, substituted-CF3; m denotes an integer from 1 to 4, n represents an integer of 1 or 2

The invention relates to new cyclic diamine compounds of the formula I, where

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represents an optionally substituted divalent residue of benzene, where the substituents are selected from unsubstituted lower alkyl groups, unsubstituted lower alkoxygroup, unsubstituted lower acyl group, a lower allylthiourea, lower alkylsulfonyl group, halogen atom, etc. or unsubstituted pyridine; Ar represents a phenyl group which may be substituted by one to four groups selected from unsubstituted lower alkyl group, the unsubstituted alkoxygroup, low allylthiourea, lower alkylsulfonyl group, and so on, optional substituted amino group, alkylenedioxy; X is-NH-, oxygen atom or sulfur atom; Y is a sulfur atom, sulfoxide or sulfon; Z represents a single bond or-NR2-; R2- the atom of hydrogen or unsubstituted lower alkyl group; l = 2 or 3; m = 2 or 3; n = 1, 2, or 3, or their salts, or their solvate

The invention relates to new derivatives isothiazolinones acid of the formula I, where R stands for a group-OR1or-SR2in which R1means alkyl with 1-6 carbon atoms, a substituted once residues selected from the group comprising halogenoalkanes with 1-6 carbon atoms and 1 to 5 halogen atoms, dialkylamino with 1-6 carbon atoms in each alkyl part, phenylalkyl with 1-4 carbon atoms in the CNS parts and pyrrolidinyloxyl with 1-4 carbon atoms in the CNS part, and twice by hydroxyl, or so, m and n is 2, R3means phenyl, R4means alkyl with 1-4 carbon atoms, R2means alkyl with 1-6 carbon atoms, or R2means phenylalkyl with 1-2 carbon atoms in the alkyl part, with the phenyl portion may be substituted with halogen

The invention relates to new derivatives of phenyl - and aminobenzenesulfonamide formula

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where a denotes (R1SO2NR2-), (R3R60NSO2NR2-); X represents-NH-, -CH2- or-OCH2-; Y represents 2-imidazoline, 2-oxazoline or 4-imidazole; R1means (NISS

The invention relates to compounds of formula (1), where X and Y Is N or O; R1substituted alkyl, substituted arylalkyl or cycloalkyl; R2and R3Is h or alkyl; And a Is-C(O)-, -OC(O)-, -S(O)2-; R4- alkyl, cycloalkyl or (C5-C12)aryl; compounds of the formula (2), where X and Y are O, S or N; R1- alkyl, optionally substituted arylalkyl; R2and R3Is h or alkyl;- C(O)-; R6- Deputy, including the condensed heterocyclic rings; and compounds of the formula (3), where X and Y are O, S or N; R1- alkyl, alkylsilane, (C5-C12)arylalkyl, (C5-C12)aryl; R2and R3Is h or alkyl; R2' and R3' - N; R11, R12and E together form a mono - or bicyclic ring which may contain heteroatoms

The invention relates to new derivatives oksiminoalkil acid of the formula (I), where R1is oxazolyl, optionally substituted with 1-2 substituents selected from lower alkyl, phenyl, teinila, furil; thiazolyl, optionally substituted with 1-2 substituents selected from lower alkyl, phenyl; unsubstituted chinoline and so on; X represents a bond or the group-NR6- where R6represents hydrogen or C1-4alkyl; n represents an integer from 1 to 3; Y represents an oxygen atom or the group-NR7- where R7is hydrogen; ring a represents a benzene ring, optionally substituted by one or two1-4alkoxy; p is an integer from 1 to 3; R2represents phenyl, optionally substituted lower alkyl, halogen, and so on; unsubstituted furyl; unsubstituted pyridyl; pyridinyl-1-oxide; q is an integer from 0 to 6; m represents 0 or 1; R3represents a hydroxy-group, lower alkoxy or-NR9R10where R9and R10represent identical or different groups selected from hydrogen, lower alkyl and lower alkylsulfonyl; R4and R5represent identical or different groups selected from hydrogen or

The invention relates to new cyclic diamine compounds of the formula I, where

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represents an optionally substituted divalent residue of benzene, where the substituents are selected from unsubstituted lower alkyl groups, unsubstituted lower alkoxygroup, unsubstituted lower acyl group, a lower allylthiourea, lower alkylsulfonyl group, halogen atom, etc. or unsubstituted pyridine; Ar represents a phenyl group which may be substituted by one to four groups selected from unsubstituted lower alkyl group, the unsubstituted alkoxygroup, low allylthiourea, lower alkylsulfonyl group, and so on, optional substituted amino group, alkylenedioxy; X is-NH-, oxygen atom or sulfur atom; Y is a sulfur atom, sulfoxide or sulfon; Z represents a single bond or-NR2-; R2- the atom of hydrogen or unsubstituted lower alkyl group; l = 2 or 3; m = 2 or 3; n = 1, 2, or 3, or their salts, or their solvate

The invention relates to a derivative of benzamidine formula I, where R1denotes-C(=NH)-NH2; R2denotes H; R3refers to -[C(R5)2]m-СООR5, R3and X together represent well-CO-N-, form a 5-membered ring, with R3refers to - C = O, and X denotes N, R4means And, cycloalkyl, -[C(R5)2]mAr; X represents O, NR5or CH2Y represents O, NR5N[C(R5)2]m-Ar, N[C(R5)2]m-Het, - N[C(R5)2]m-СООR5W represents a bond, -SO2-, -CO - or-СОNR5-

The invention relates to substituted 3-cyanohydrins formula (1), where R1, R2, R3, R4, Y and X are such as defined in the claims

The invention relates to 2-(iminomethyl)aminoaniline derivative of General formula I, And where the aromatic residue of the formula Ia, R1and R2independently H, halogen, HE, linear or branched C1-C6alkyl, linear or branched C1-C6alkoxyl, R3-H, linear or branched C1-C6alkyl, or-COR4where R4-C1-C6alkyl or the residue IC, linear or branched C1-C6the five-membered alkyl or a heterocycle containing 1-4 heteroatoms selected from O, S, N, and in particular: thiophene, furan, pyrrole or thiazole, carbon atoms which is unsubstituted or substituted by one or more groups selected from linear or branched C1-C6of alkyl, C1-C6alkoxyl or halogen; X is-CO-N(R3)-X'-, -NH-CO-X'-, -CH=,-CO -, or a bond, and X' represents -(CH2)n- where n = 0-6; Y means Y'-, -Y'-NH-CO-, -CO-Y', Y'-CO-, -N(R3)-Y'-, -Y,-N(R3)-, Y'-CH2-N(R3)-CO-, -Y'-O-, -Y'-O-Y' - or a bond, and Y' is -(CH2)n- where n = 0-6; Неt-pyrrole, pyrrolidine, furan, thiophene, imidazole, imidazoline, oxazole, isoxazol, oxazoline, isoxazole, thiazole, thiazoline, thiazolidine, thiazolidine, azetidine, piperidine, imidazolidine, they

The invention relates to a new derivative of solidilin formula (I) where one of X, Y and Z represents C=O or C=S, and one of the remaining X, Y and Z denotes a group With=, and the other group C=S; R1, R2and R3are Deputy or X, Y and Z, or nitrogen atom and may be the same or different and denote hydrogen, halogen, hydroxy, nitro, etc., the group -(CH2)n-O - and may be joined through the nitrogen atom, or X, Y, Z, n is 1-4, Ar denotes a phenylene or naftilan, R4denotes hydrogen or forms a bond with group a, And denotes nitrogen or CR5, R5denotes hydrogen, halogen or forms a bond with R4In means O or S, when a is CR5and means that, when a is N, its tautomeric forms, stereoisomers, polymorphic forms, pharmaceutically acceptable salt and solvate

The invention relates to the field of organic chemistry, namely to new derivatives of amides heterylamine butenova acids that have anti-inflammatory activity

The invention relates to derivatives of cyclic amines and their use as pharmaceuticals, particularly to a compound represented by the General formula (I), its pharmaceutically acceptable acid additive salts or its pharmaceutically acceptable C1-C6alcaldicios salt, R1-phenyl, C3-8-cycloalkyl, aromatic heterocycle with 1-3 heteroatoms selected from O, S, N, or combinations thereof, and these groups may be condensed with benzene ring or an aromatic heterocyclic group with heteroatoms, selected from O, S or N, or combinations thereof, and may also have different substituents
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