Oxazolidinone compounds possessing antibacterial activity, method for preparing (variants) and pharmaceutical composition based on thereof

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1 represents azido, -OR4, -NHR4 wherein R4 represents hydrogen atom or unsubstituted groups chosen from acyl, thioacyl, (C1-C6)-alkoxycarbonyl, (C3-C6)-cycloalkoxythiocarbonyl, (C2-C6)-alkenyloxycarbonyl, (C2-C6)-alkenylcarbonyl, (C1-C6)-alkoxythiocarbonyl, (C2-C6)-alkenyloxythiocarbonyl, -C(=O)-C(=O)-(C1-C6)-alkoxy, -C(C=S)-S-(C1-C6)-alkyl, -(C=S)-NH2, -(C=S)-NH-(C1-C6)-alkyl, -C(=S)-N-((C1-C6)-alkyl)2, -C(=S)-NH-(C2-C6)-alkenyl, -C(C=S)-(C=O)-(C1-C6)-alkoxy, thiomorpholinylthiocarbonyl; R2 and R3 can be similar or different and represent independently hydrogen atom, halogen atom, (C1-C6)-alkyl group, halogen-(C1-C6)-alkyl; heterocyclic moiety represents 5-membered heterocycle wherein Z represents sulfur (S), oxygen (O) atom or -NRb wherein Rb represents hydrogen atom or unsubstituted (C1-C6)-alkyl, (C3-C6)-cycloalkyl, aryl or aryl-(C1-C6)-alkyl; Y1 represents group =O or =S ; Y2 and Y3 represent independently hydrogen atom, and if Y2 and Y3 present in common on adjacent carbon atoms then they form 6-membered aromatic cyclic structure substituted if necessary with (C1-C6)-alkyl, or to its pharmaceutically acceptable salt. Also invention relates to a pharmaceutical composition possessing antibacterial activity and containing as an active compound the compound of the formula (I) taken in the effective dose and a pharmaceutically acceptable carrier, diluting agent, excipient. Also, invention relates to method for synthesis of compound of the formula (I). Method for synthesis of compound of the formula (I) wherein R1 represents group -NHR4 wherein R4 means acyl, (C1-C6)-alkoxycarbonyl, (C2-C6)-alkenyloxycarbonyl, (C2-C6)-alkenylcarbonyl, -C(=O)-C(=O)-(C1-C6)-alkoxy and -(C=S)-S-(C1-C6)-alkyl involves acetylation of compound of the formula (I) wherein R1 represents -NHR4 group wherein R4 represents hydrogen atom and all symbols are given above and using halide. Method for synthesis of compound of the formula (I) wherein R1 represents -NHR4 group wherein R4 means thioacyl, (C3-C6)-cycloalkoxythiocarbonyl, (C1-C6)-alkoxythiocarbonyl, (C2-C6)-alkenyloxythiocarbonyl involves the following steps: (i) conversion of compound of the formula (I) wherein R1 represents -NHR4 wherein R4 represents hydrogen atom, and all symbols are given above to compound of the formula (I) wherein R1 represents isothiocyanate group by reaction with thiophosgene, and (ii) conversion of compound of the formula (I) wherein R1 represents isothiocyanate group to compound of the formula (I) wherein R1 represents -NHR4 wherein R4 represents -C(=S)-OR4d wherein R4d represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C2-C6)-alkenyl, and all symbols are given above, in reaction with alcohol. Compounds of the formula (I) are used in treatment of bacterial infection that involves administration of compound of the formula (I) in a patient needing in this treatment. Invention provides synthesis of oxazolidinone compounds possessing antibacterial activity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

7 cl, 1 tbl, 144 ex

 

The text descriptions are given in facsimile form.

Caetanina formula (I)

where R1represents azido, OR4, Other4where R4represents a hydrogen atom or unsubstituted groups selected from acyl, thioacyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkylcarbonyl, (C2-C6)alkenylcarbazoles, (C2-C6)alkenylboronic, (C1-C6)alkoxysilane, (C2-C6)alkenylcarbazoles, -C(=O)-C(=O)-(C1-6)alkoxy, -(C=S)-S-(C1-6)alkyl, -(C=S)-NH2-(C=S)-NH-(C1-6)alkyl, -C(=S)-N-((C1-6)alkyl)2-C(=S)-NH-(C2-6)alkenyl, (C=S)-(C=O)-(C1-6)alkoxy, thiomorpholine;

R2and R3may be the same or different and independently represent hydrogen, halogen atom, (C1-C6)alkyl group, halogen(C1-C6)alkyl,heterocyclic part in whichrepresents a 5-membered heterocycle, and where Z represents S, O or NRbwhere Rbrepresents hydrogen or unsubstituted (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl or aryl(C1-6)alkyl;

Y1represents =O or =S group,

and Y2and Y3independently represent hydrogen; or

if Y2and Y3there are mestena adjacent carbon atoms they

form a 6-membered aromatic cyclic structure, optionally substituted (C1-6)alkyl; or its pharmaceutically acceptable salt.

2. The compound of formula (I) according to claim 1, which is selected from the group consisting of

(5R)-3-[3-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-5-hydroxymethyl-1,3-oxazolin-2-one or its salts;

(5R)-3-[3-fluoro-4-(2-thioxo-1,3-oxazolin-3-yl)phenyl]-5-hydroxymethyl-1,3-oxazolin-2-one or its salts;

(5R)-3-[3-fluoro-4-(2-thioxo-1,3-thiazolin-3-yl)phenyl]-5-hydroxymethyl-1,3-oxazolin-2-one or its salts;

(5R)-3-[3-fluoro-4-(3-methyl-2-thioxo-1-imidazolidinyl)phenyl]-5-hydroxymethyl-1,3-oxazolin-2-one or its salts;

3-{2-fluoro-4-[(5R)-5-hydroxymethyl-2-oxo-1,3-oxazolin-3-yl]phenyl}-2,3-dihydrobenzo[d][1,3]oxazol-2-one or its salts;

3-{2-fluoro-4-[(5R)-5-hydroxymethyl-2-oxo-1,3-oxazolin-3-yl]phenyl}-6-methyl-2,3-dihydrobenzo[d][1,3]oxazol-2-one or its salts;

3-{2-fluoro-4-[(5R)-5-hydroxymethyl-2-oxo-1,3-oxazolin-3-yl]phenyl}-5-methyl-2,3-dihydrobenzo[d][1,3]oxazol-2-one or its salts;

(5R)-5-hydroxymethyl-3-[4-(2-oxo-1,3-oxazolin-3-yl)-3-triptoreline]-1,3-oxazolin-2-one or its salts;

(5R)-3-[2-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-5-hydroxymethyl-1,3-oxazolin-2-one or its salts;

(5R)-3-[3,5-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-5-hydroxymethyl-1,3-oxazolin-2-one or its salts;

(5R)-5-hydroxymethyl-3-[4-(2-oxo-1,3-oxa is olan-3-yl)phenyl]-1,3-oxazolin-2-one or its salts;

3-{4-[(5R)-5-hydroxymethyl-2-oxo-1,3-oxazolin-3-yl]phenyl}-2,3-dihydrobenzo[d][1,3]oxazol-2-one or its salts;

(5R)-3-[3-fluoro-4-(3-methyl-4-oxo-1-imidazolidinyl)phenyl]-5-hydroxymethyl-1,3-oxazolin-2-one or its salts;

(5R)-3-[3-fluoro-4-(3-methyl-2-oxo-1-imidazolidinyl)phenyl]-5-hydroxymethyl-1,3-oxazolin-2-one or its salts;

(5R)-5-hydroxymethyl-3-[4-(3-methyl-2-oxo-1-imidazolidinyl)phenyl]-1,3-oxazolin-2-one or its salts;

(5R)-5-hydroxymethyl-3-[4-(3-benzyl-2-oxo-1-imidazolidinyl)phenyl]-1,3-oxazolin-2-one or its salts;

(5R)-3-[3-fluoro-4-(2-oxo-3-phenyl-1-imidazolidinyl)phenyl]-5-hydroxymethyl-1,3-oxazolin-2-one or its salts;

(5R)-azidomethyl-3-[3-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-1,3-oxazolin-2-one or its salts;

(5R)-azidomethyl-3-[3-fluoro-4-(3-methyl-2-thioxo-1-imidazolidinyl)phenyl]-1,3-oxazolin-2-one or its salts;

3-{4-[(5R)-5-azidomethyl-2-oxo-1,3-oxazolin-3-yl]-2-forfinal}-6-methyl-2,3-dihydrobenzo[d][1,3]oxazol-2-one or its salts;

3-{4-[(5R)-5-azidomethyl-2-oxo-1,3-oxazolin-3-yl]-2-forfinal}-5-methyl-2,3-dihydrobenzo[d][1,3]oxazol-2-one or its salts;

(5R)-5-azidomethyl-3-[4-(2-oxo-1,3-oxazolin-3-yl)-3-triptoreline]-1,3-oxazolin-2-one or its salts;

(5R)-5-azidomethyl-3-[2-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-1,3-oxazolin-2-one or its salts;

(5R)-azidomethyl-3-[3,5-debtor-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-1,3-oxazolin-2-one or the th salt;

(5R)-5-azidomethyl-3-[4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-1,3-oxazolin-2-one or its salts;

3-{4-[(5R)-5-azidomethyl-2-oxo-1,3-oxazolin-3-yl]phenyl}-2,3-dihydrobenzo[d][1,3]oxazol-2-one or its salts;

(5R)-5-azidomethyl-3-[3-fluoro-4-(3-methyl-4-oxo-1-imidazolidinyl)phenyl]-1,3-oxazolin-2-one or its salts;

(5R)-5-azidomethyl-3-[3-fluoro-4-(3-phenyl-2-oxo-1-imidazolidinyl)phenyl]-1,3-oxazolin-2-one or its salts;

(5R)-aminomethyl-3-[3-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-1,3-oxazolin-2-one or its salts;

(5R)-aminomethyl-3-[3-fluoro-4-(3-methyl-2-thioxo-1-imidazolidinyl)phenyl]-1,3-oxazolin-2-one or its salts;

(5R)-5-aminomethyl-3-[4-(2-oxo-1,3-oxazolin-3-yl)-3-triptoreline]-1,3-oxazolin-2-one or its salts;

(5R)-5-aminomethyl-3-[4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-1,3-oxazolin-2-one or its salts;

(5R)-5-aminomethyl-3-[3-fluoro-4-(3-methyl-4-oxo-1-imidazolidinyl)phenyl]-1,3-oxazolin-2-one or its salts;

(5R)-5-aminomethyl-3-[3-fluoro-4-(3-benzyl-4-oxo-1-imidazolidinyl)phenyl]-1,3-oxazolin-2-one or its salts;

N-{(5S)-3-[3-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}metaname or its salt;

N-(5S)-3-[3,5-debtor-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}metaname or its salt;

N1-{(5S)-3-[3-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}ndimethylacetamide or its salt;

N1-{(5S)-3-[3-fluoro-4-(2-oxo-13-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}propanamide or its salts;

N1-{(5S)-3-[3-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}butanamide or its salt;

N1-{(5S)-3-[3-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}pentanone or its salt;

N1-{(5S)-3-[3-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}heptanoic or its salt;

N1-{(5S)-3-[3-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}acrylamide or its salt;

ethyl(5S)-3-[3-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl carbamoylmethyl or its salt;

N1-{(5S)-3-[3-fluoro-4-(2-thioxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}ndimethylacetamide or its salt;

N1-{(5S)-2-oxo-3-[4-(2-thioxo-1,3-oxazolin-3-yl)phenyl]-1,3-oxazolin-5-ylmethyl}ndimethylacetamide or its salt;

N1-{(5S)-2-oxo-3-[3-fluoro-4-(2-thioxo-1,3-thiazolin-3-yl)phenyl]-1,3-oxazolin-5-ylmethyl}ndimethylacetamide or its salt;

N1-{(5S)-3-[3-fluoro-4-(3-methyl-2-thioxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}ndimethylacetamide or its salt;

N1-{(5S)-3-[3-fluoro-4-(2-oxo-2,3-dihydrobenzo[d][1,3]oxazol-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}ndimethylacetamide or its salt;

N1-{(5S)-3-[3-fluoro-4-(6-methyl-2-oxo-2,3-dihydrobenzo[d][1,3]oxazol-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}ndimethylacetamide or its salt;

N1-{(5S)-3-[3-fluoro-4-(5-methyl-2-oxo-2,3-dihydrobenzo[d][1,3]oxazol-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl)ndimethylacetamide Il is its salts;

N1-{(5S)-2-oxo-3-[4-(2-oxo-1,3-oxazolin-3-yl)-3-triptoreline]-1,3-oxazolin-5-ylmethyl}ndimethylacetamide or its salt;

N1-{(5S)-2-oxo-3-[4-(2-oxo-1,3-oxazolin-3-yl)-3-triptoreline]-1,3-oxazolin-5-ylmethyl}propanamide or its salt;

N1-{(5S)-2-oxo-3-[4-(2-oxo-1,3-oxazolin-3-yl)-3-triptoreline]-1,3-oxazolin-5-ylmethyl}heptanoic or its salt;

N1-{(5S)-2-oxo-3-[4-(2-oxo-1,3-oxazolin-3-yl)-3-triptoreline]-1,3-oxazolin-5-ylmethyl}acrylamide or its salt;

N1-{(5S)-3-[2-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}ndimethylacetamide or its salt;

N1-{(5S)-3-[3,5-debtor-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}ndimethylacetamide or its salt;

N1-{(5S)-3-[3,5-debtor-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}propanamide or its salt;

N1-{(5S)-2-oxo-3-[4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-1,3-oxazolin-5-ylmethyl}ndimethylacetamide or its salt;

N1-{(5S)-2-oxo-3-[4-(2-oxo-2,3-dihydrobenzo[d][1,3]oxazol-3-yl)phenyl]-1,3-oxazolin-5-ylmethyl}ndimethylacetamide or its salt;

N1-{(5S)-3-[3-fluoro-4-(3-methyl-4-oxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}ndimethylacetamide or its salt;

N1-{(5S)-3-[3-fluoro-4-(3-benzyl-4-oxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}ndimethylacetamide or its salt;

N1-{(5S)-3-[3-fluoro-4-(3-methyl-2-oxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}ndimethylacetamide or its salt;

N1-{(5S)-3[4-(3-methyl-2-oxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}ndimethylacetamide or its salt;

N1-{(5S)-3-[4-(3-benzyl-2-oxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}ndimethylacetamide or its salt;

N1-{(5S)-3-[3-fluoro-4-(3-phenyl-2-oxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}ndimethylacetamide or its salt;

(5S)-3-[3-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-5-(1-dioxoimidazolidin)-1,3-oxazolin-2-one or its salts;

(5S)-3-[3-fluoro-4-(3-methyl-2-thioxo-1-imidazolidinyl)phenyl]-5-(1-dioxoimidazolidin)-1,3-oxazolin-2-one or its salts;

3-{2-fluoro-4-[(5S)-2-oxo-5-(1-dioxoimidazolidin)-1,3-oxazolin-3-yl]phenyl}-2,3-dihydrobenzo[d][1,3]oxazol-2-one or its salts;

(5S)-3-[4-(2-oxo-1,3-oxazolin-3-yl)-3-triptoreline]-5-(1-dioxoimidazolidin)-1,3-oxazolin-2-one or its salts;

(5S)-3-[3,5-debtor-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-5-(1-dioxoimidazolidin)-1,3-oxazolin-2-one or its salts;

(5S)-3-[3,5-debtor-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-5-(1-dioxopiperazinyl)-1,3-oxazolin-2-one or its salts;

(5S)-3-[4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-5-(1-dioxoimidazolidin)-1,3-oxazolin-2-one or its salts;

(5S)-3-[3-fluoro-4-(3-methyl-4-oxo-1-imidazolidinyl)phenyl]-5-(1-dioxoimidazolidin)-1,3-oxazolin-2-one or its salts;

(5S)-3-[3-fluoro-4-(3-phenyl-2-oxo-1-imidazolidinyl)phenyl]-5-(1-dioxoimidazolidin)-1,3-oxazolin-2-one or its salts;

N1-{(5S)-3-[3-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}methylcarbamate or its salt;

N1-{(5S)-2-oxo-3-[4-(2-oxo-1,3-oxazolin-3-yl)-3-triptoreline]-1,3-oxazolin-5-ylmethyl}methylcarbamate or its salt;

N1-{(5S)-3-[3,5-debtor-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}methylcarbamate or its salt;

N1-{(5S)-3[4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}methylcarbamate or its salt;

N1-{(5S)-3-[3-fluoro-4-(3-methyl-4-oxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}methylcarbamate or its salt;

(5S)-5-methylethoxy(thioxo)methylaminomethyl-3[4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-1,3-oxazolin-2-one or its salts;

N1-{(5S)-3-[3,5-debtor-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}methylthiocarbamate or its salt;

N1-{(5S)-3-[3-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}methylthiocarbamate or its salt;

N1-{(5S)-3-[3-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}etildiocolmain or its salt;

(5S)-5-cyclohexyloxy(thioxo)methylaminomethyl-3-[4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-1,3-oxazolin-2-one or its salts;

N1-{(5S)-3-[3-fluoro-4-(2-thioxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}methylthiocarbamate or its salt;

N1-{(5S)-3-[3-fluoro-4-(3-methyl-2-thioxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin--ylmethyl}etildiocolmain or its salts;

N1-{(5S)-3-[3-fluoro-4-(3-methyl-2-thioxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}-1-prophylthiolcarbamate or its salt;

N1-{(5S)-3-[3-fluoro-4-(3-methyl-2-thioxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}methylthiocarbamate or its salt;

N1-{(5S)-3-[3-fluoro-4-(3-methyl-2-thioxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}-2-prophylthiolcarbamate or its salt;

N1-{(5S)-2-oxo-3-[4-(2-oxo-1,3-oxazolin-3-yl)-3-triptoreline]-1,3-oxazolin-5-ylmethyl}methylthiocarbamate or its salt;

N1-{(5S)-2-oxo-3-[4-(2-oxo-1,3-oxazolin-3-yl)-3-triptoreline]-1,3-oxazolin-5-ylmethyl}etildiocolmain or its salt;

N1-{(5S)-3-[3,5-debtor-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}methylthiocarbamate or its salt;

N1-{(5S)-3-[4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}methylthiocarbamate or its salt;

N1-{(5S)-3-[4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}etildiocolmain or its salt;

N1-{(5S)-3-[4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}-1-prophylthiolcarbamate or its salt;

N1-{(5S)-3-[4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}allylthiourea or its salt;

N1-{(5S)-3-[4-(2-oxo-1,3-oxazolin-3-yl)phenyl)]-2-oxo-1,3-oxazolin-5-ylmethyl}-2-prophylthiolcarbamate or its salt;

N1-{(5S)-2-oxo-3-[4-(2-oxo-2,3-dihydrobenzo[d][1,oxazol-3-yl)phenyl]-1,3-oxazolin-5-ylmethyl}methylthiocarbamate or its salts;

N1-{(5S)-2-oxo-3-[4-(2-oxo-2,3-dihydrobenzo[d][1,3]oxazol-3-yl)phenyl]-1,3-oxazolin-5-ylmethyl}etildiocolmain or its salt;

N1-{(5S)-3-[3-fluoro-4-(3-methyl-4-oxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}methylthiocarbamate or its salt;

N1-{(5S)-3-[4-(3-methyl-2-oxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}methylthiocarbamate or its salt;

N1-{(5S)-3-[4-(3-methyl-4-oxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}methylthiocarbamate or its salt;

N1-{(5S)-3-[3-fluoro-4-(3-methyl-2-oxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}methylthiocarbamate or its salt;

N1-{(5S)-3-[4-(3-benzyl-2-oxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}methylthiocarbamate or its salt;

N1-{(5S)-3-[4-(3-benzyl-2-oxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}etildiocolmain or its salt;

N1-{(5S)-3-[3-fluoro-4-(3-phenyl-2-oxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}methylthiocarbamate or its salt;

N1-((5S)-3-{3-fluoro-4-[3-benzyl-4-oxo-1-imidazolidinyl]phenyl}-2-oxo-1,3-oxazolin-5-ylmethyl)etildiocolmain or its salt;

N1-((5S)-3-{3-fluoro-4-[3-benzyl-4-oxo-1-imidazolidinyl]phenyl)-2-oxo-1,3-oxazolin-5-ylmethyl)isopropylcarbamate or its salt;

N1-((5S)-3-{3-fluoro-4-[4-oxo-1-imidazolidinyl]phenyl}-2-oxo-1,3-oxazolin-5-ylmethyl)methylthiocarbamate or its salt;

N1-{(5S)-3-[3-f the PR-4-(3-methyl-4-thioxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolin-5-ylmethyl}methylthiocarbamate or its salts;

(5S)-5-diethylamino(thioxo)methylaminomethyl-3-[4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-1,3-oxazolin-2-one or its salts;

(5S)-5-allylamino(thioxo)methylaminomethyl-3-[4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-1,3-oxazolin-2-one or its salts;

(5S)-5-methylamino(thioxo)methylaminomethyl-3-[4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-1,3-oxazolin-2-one or its salts;

(5S)-3-[4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-5-[1,4-diazinon-4-yl(thioxo)methylaminomethyl]-1,3-oxazolin-2-one or its salts;

(5S)-5-amino(thioxo)methylaminomethyl-3-[3-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-1,3-oxazolin-2-one or its salts;

(5S)-3-[3-fluoro-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-5-methylamino(thioxo)methylaminomethyl-1,3-oxazolin-2-one or its salts;

(5S)-5-amino(thioxo)methylaminomethyl-3-[3,5-debtor-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-1,3-oxazolin-2-one or its salts;

(5S)-3-[3,5-debtor-4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-5-methylamino(thioxo)methylaminomethyl-1,3-oxazolin-2-one or its salts.

3. Pharmaceutical composition having antibacterial activity comprising as active compounds, the compound of formula (I) according to claim 1 or 2 in the effective number

and pharmaceutically acceptable carrier, diluent, filler.

4. The pharmaceutical composition according to claim 3 in the form of tablets, capsules, powder, syrup, solution or with whom spencie.

5. The method of obtaining the compounds of formula (I)

where R1represents a group other4and R4is acyl, (C1-C6)alkoxycarbonyl, (C2-C6)alkanolammonium, (C2-C6)alkenylboronic, -C(=O)-C(=O)-(C1-C6)alkoxy and -(C=S)-S-(C1-C6)alkyl;

R2and R3may be the same or different and independently represent hydrogen, halogen atom, (C1-C6)alkyl group, halogen(C1-C6)alkyl,

heterocyclic part in whichrepresents a 5-membered heterocycle, and where Z represents S, O or NRbwhere Rbrepresents hydrogen or unsubstituted (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl or aryl(C1-6)alkyl;

Y1represents =O or =S group, and

Y2and Y3independently represent hydrogen; or

if Y2and Y3are present together on adjacent carbon atoms they form a 6-membered aromatic cyclic structure, optionally substituted (C1-6)alkyl,

including acetylation of compounds of formula (I)in which R1represents other 4where R4represents hydrogen; Y1, Y2, Y3, R2, R3and Z have the meanings as defined above, using a halogen.

6. The method of obtaining the compounds of formula (I)

where R1represents a group other4and R4is diazelam, (C3-C6)cycloalkylcarbonyl, (C1-C6)alkoxyaryl, (C2-C6)alkanolammonium;

R2and R3may be the same or different and independently represent hydrogen, halogen atom, (C1-C6)alkyl group, halogen(C1-C6)alkyl,

heterocyclic part in whichrepresents a 5-membered heterocycle, and where Z represents S, O or NRbwhere Rbrepresents hydrogen or unsubstituted (C1-C6)alkyl, (C2-C6)cycloalkyl, aryl or aryl(C1-6)alkyl;

Y1represents =O or =S group, and

Y2and Y3independently represent hydrogen; or

if Y2and Y3are present together on adjacent carbon atoms they form a 6-membered aromatic cyclic structure, optionally substituted (C1-6)alkyl,including

(i) the conversion of compounds of formula (I), where R1represents other4where R4represents a hydrogen atom; Y1, Y2, Y3, R2, R3and Z have the meanings as defined above, in the compound of formula (I)in which R1represents isothiocyanate group and all other symbols are as defined above, by reaction with thiophosgene, and

(ii) the conversion of compounds of formula (I), where R1represents isothiocyanate group in the compound of formula (I)in which R1represents other4where R4represents-C(=S)-OR4dwhere R4dis a (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl, and all symbols are as defined above, by reaction with alcohol.

7. A method of treating a bacterial infection comprising introducing the compound of the formula (I) according to claim 1 or a compound according to any one of claim 1 or 2 or a composition according to claim 3 or 4 to a patient in need of it.



 

Same patents:

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 4-phenyltetrahydroisoquinoline of the general formula (I): wherein R1, R2, R3 and R4 mean independently of one another hydrogen (H), fluorine (F), chloride (Cl), bromine (Br) atoms, CaH2a+1 wherein one or more atoms H are substituted with F, -NR11R12 or -SOj-R15 wherein a = 1-8; R11 and R12 mean independently of one another H, CeH2e+1 or CrrH2rr-1 wherein e = 1-4; rr = 3, 4, or in common with nitrogen atom to which they are bound form a cycle chosen from group consisting of pyrrolidinyl, piperidinyl, N-methylpiperazinyl, piperazinyl or morpholine; j = 1 or 2; R15 means CkH2k+1 wherein k = 1-8; R5 means CpH2p+1 or CssH2ss-1; p = 1-8; ss = 3-8; R6 means H; R7, R8 and R9 mean independently of one another mean -SOwR23, -NR32COR30, NR32CSR30, -NR32SObbR30, H, F, Cl, Br, -OH, -NH2, CeeH2ee+1, -NR40R41, -CONR40R41 or -COOR42 wherein w = 0, 1 or 2; bb = 2 or 3; R23 means NR25R26 wherein R25 and R26 mean independently of one another H or CzH2z+1, CzzH2zz-1 wherein z = 1-8; zz = 3-8 wherein in CzH2z+1 and CzzH2zz-1 one or more H atoms are substituted with fluorine atom and one or more CH2-groups are substituted with -C(=O) or NR27 wherein R27 means H or CaaH2aa+1 wherein aa = 1-4; or R25 and R26 in common with nitrogen atom to which they are bound form 5-, 6- or 7-membered cycle; R30 means H, CccH2cc+1, CyyH2yy-1, pyrrolydinyl, piperidinyl wherein in their cycles CH2-group can be substituted with oxygen atom (O) or -NR33; R32 and R33 mean independently of one another H or ChH2h+1 wherein cc = 1-8; yy = 3-8; h = 1-8 wherein in the group ChH2h+1 one or more hydrogen atoms are substituted with fluorine atom, and in the groups CccH2cc+1 and CyyH2yy-1 one or more hydrogen atoms can be substituted with fluorine atom, and CH2-group can be substituted with O or -NR31 wherein NR31 means H, methyl, ethyl, acetyl or -SO2CH3; or R30 means 6-membered heteroaryl with 1-4 nitrogen atoms, 0 or 1, S-atoms or 0, or 1 O-atom that represents unsubstituted or substituted with up to three substitutes chosen from group consisting of F, Cl, Br, J, CooH2oo+1 wherein one or more hydrogen atoms can be substituted with fluorine atom, -NO2 or -NR70R71 wherein oo = 1-8; R70 and R71 mean independently of one another H, CuuH2uu+1 or -COR72 wherein uu = 1-8; R72 means H, CvvH2vv+1 wherein vv = 1-8; ee = 1-8; R40 and R41 mean independently of one another H, CttH2tt+1 or -C(NH)NH2 wherein tt = 1-8 and wherein in the group CttH2tt+1 one or more CH2-groups can be substituted with NR44 wherein R44 means CggH2gg+1 wherein gg = 1-8; R42 means H or ChhH2hh+1 wherein hh = 1-8 being, however, two substitutes from group R7, R8 and R9 can't mean -OH simultaneously, and at least one residue from R7, R8 and R9 must be chosen from group consisting of -CONR40R41, -OvSOwR23, -NR32COR30, -NR32CSR30 and -NR32SObbR30. Also, invention relates to using above given compounds for preparing a medicinal agent. Also, invention considers a medicinal agent representing inhibitor of sodium-proton exchange of subtype III (NHE3) based on proposed compounds. Invention provides synthesis of novel compounds, a medicinal agent based on thereof for aims of treatment of such diseases as nervous system ischemia, insult and brain edema, in treatment of snore, shock, impaired respiratory impulse, as purgative agents, as agents against extoparasites, for prophylaxis of gall stones formation, as anti-atherosclerotic agents, agents against diabetes mellitus later complications, cancer diseases, fibrous diseases, endothelial dysfunction, hypertrophies and hyperplasia of organs and others.

EFFECT: valuable medicinal properties of compounds and medicinal agents.

21 cl, 15 tbl, 221 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (1): wherein Y means -O-, -S- or -N(R2)- wherein R2 means hydrogen atom, (C1-C10)-alkyl or aralkyl; Z means 2,5-furanyl, 2,5-thiophenyl, 4,4'-stilbenyl or 1,2-ethyleneyl residue; R1 means hydrogen or halogen atom, (C1-C10)-alkyl, (C1-C10)-alkoxy-group, cyano-group, -COOM or -SO3M wherein M means hydrogen atom or alkaline or alkaline-earth metal atom. Method for synthesis involves carrying out the reaction of compound of the formula (2): with dicarboxylic acid of the formula: HOOC-Z-COOH (3) or with it ester wherein Y, Z and R1 have values given above in N-methylpyrrolidone or N,N-dimethylacetamide medium in the presence of an acid catalyst and optionally in the presence of an accessory solvent able to remove water from the reaction mixture.

EFFECT: improved method of synthesis.

11 cl, 7 ex

FIELD: organic chemistry, technology of organic compounds.

SUBSTANCE: invention relates to heterocyclic o-dicarbonitriles. Invention describes heterocyclic o-dicarbonitriles of the general formula: wherein R means the following compounds: . Heterocyclic o-dicarbonitriles can be used for preparing hexazocyclanes-fluorophores as a donor-fragment used for preparing hexazocyclanes-bifluorophores and hexazocyclanes-trifluorophores. Invention provides preparing new compounds possessing valuable properties.

EFFECT: valuable properties of compounds.

2 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of dihydrobenzo[b][1,4]diazepine-2-one. Invention describes derivatives of dihydrobenzo[b][1,4]diazepine-2-one of the general formula (I): wherein X means a simple bond or ethynediyl group wherein if X means a simple bond then R1 means cyano-group, halogen atom, lower alkyl, (C1-C3)-cycloalkyl, (lower)-alkoxyl, fluoro-(lower)-alkyl or it means pyrrole-1-yl that may be free or substituted with 1-3 substitutes taken among the group consisting of fluorine, chlorine atom, cyano-group, -(CH2)1-4-hydroxyl group, fluoro-(lower)-alkyl, lower alkyl, -(CH2)n-(lower)-alkoxyl, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'', hydroxy-(lower)-alkoxyl and -(CH2)n-COR'R'', or it means free phenyl or phenyl substituted with one or two substitutes taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, fluoro-(lower)-alkoxyl and cyano-group; if X means ethynediyl group then R1 means free phenyl or phenyl substituted with 1-3 substituted taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (C3-C6)-cycloalkyl, (lower)-alkoxyl and fluoro-(lower)-alkoxyl; R2 means -NR'R'', fluoro-(lower)-alkoxyl or 3-oxopiperazin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl wherein their rings are substituted optionally with R''; R' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl or 2-(lower)-alkoxy-(lower)-alkyl; R'' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl, 2-(lower)-alkoxy-(lower)-alkyl, -(CH2)2-4-di-(lower)-alkylamino-group, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy-(lower)-alkyl; Y means -CH= or =N-; R3 means halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, cyano-group, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'' or it means optionally substituted 5-membered aromatic heterocycle that can be substituted with halogen atom, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxyl, cyano-group, -(CH2)n-NR'R'', -(CH2)n-C(O)OR'', -(CH2)n-C(O)NR'R'', -(CH2)n-SO2NR'R'', -(CH2)n-C(NH2)=NR'', hydroxyl, (lower)-alkoxyl, (lower)-alkylthio-group or lower alkyl that is optionally substituted with fluorine atom, hydroxyl, (lower)-alkoxyl, cyano-group or carbamoyloxy-group; n means 0, 1, 2, 3 or 4, and their pharmaceutically acceptable additive salts. Also, invention describes a medicinal agent as antagonist of mGlu receptors of group II based on compounds of the formula (I). Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 496 ex

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 a derivative of 1,2,4-thiadiazole, substituted in the 5-position of General formula I, in which X Is N; R1- C1-6alkyl; R2is hydrogen, R3, R4and R5each independently selected from hydrogen; trifloromethyl;is Ar2, Ar2CH2or Het2; AG2is phenyl; Het2is a monocyclic heterocycle selected from thiadiazolyl, pyridinyl, pyrimidinyl or pyrazinyl, their N-oxide forms, the pharmaceutically acceptable acid additive salts and stereochemical isomeric forms

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel pyrrolidine-2-ones of the formula (I): , wherein R1 means group chosen from the following formulae:

wherein each of them comprises optionally additional nitrogen (N) atom as a heteroatom; Z means optional substitute halogen atom, -CH2NH2, -NRaRb or -CN; Z' means optional substitute halogen atom, -CH2NH2 or -CN; alk means alkylene or alkenylene; T means sulfur atom (S), oxygen atom (O); R2 means hydrogen atom (H), -(C1-C3)-alkyl-CONRaRb, -(C1-C3)-alkyl-CO2-(C1-C4)-alkyl, -(C1-C3)-alkylmorpholino-group, -CO2-(C1-C4)-alkyl or -(C1-C3)-alkyl-CO2H; X means phenyl or 5- or 6-membered aromatic or nonaromatic heterocyclic group comprising one or two heteroatoms chosen from O, N or S wherein each of them is substituted optionally with 0-2 groups chosen from halogen atom, -CN, -(C1-C4)-alkyl, -(C2-C4)-alkenyl, -CF3, -NRaRb, -NO2, -N-(C1-C4)-alkyl-(CHO), -NHCO-(C1-C4)-alkyl, -NHSO2Rc, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc and -S(O)2NRaRb; Y means: (i) a substitute chosen from H, halogen atom, -CN, -(C1-C4)-alkyl, -(C2-C4)-alkenyl, -CF3, -NRaRb, -NO2, -N-(C1-C4)-alkyl-(CHO), -NHCO-(C1-C4)-alkyl, -NHSO2Rc, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc and -S(O)2NRaRb, or (ii) phenyl or 5- or 6-membered aromatic or nonaromatic heterocyclic group comprising one or two heteroatoms, chosen from O, N or S and wherein each of them is substituted optionally with 0-2 groups chosen from halogen atom, -CN, -(C1-C4)-alkyl, -(CH2)nNRaRb, -(CH2)nN+RaRbCH2CONH2, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc, -S(O)2NRaRb, =O, oxide at N atom in cycle, -CHO, -NO2 and -N-(Ra)(SO2Rc) wherein Ra and Rb mean independently H, -(C1-C6)-alkyl; Rc means -(C1-C6)-alkyl; Rd means H, -(C1-C6)-alkyl; n means 0-2, and to their pharmaceutically acceptable salts or solvates. Compounds inhibit Xa factor that allows their using as components of pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 144 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: organic chemistry, chemical technology, biology.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (11): wherein X2 represents a leaving group; R3 and R4 represent substitutes chosen independently from group consisting of hydrogen atom, aromatic group and aliphatic group, or taken in common -NR3R4 form 4-11-membered aliphatic ring, but R3 and R4 can't means hydrogen atom simultaneously. Method involves interaction of compound of the formula (10): wherein X1 represents a leaving group with amine of the formula (3): (HNR3R4) in the presence of Lewis acid and a non-nucleophilic base and wherein groups X1 and X2 are similar. Compounds of the formula (11) can be used in treatment of anomalous growth of cells.

EFFECT: improved method of synthesis, valuable biological property of compound.

14 cl, 5 sch, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formulae (I) and (II) and their pharmaceutically acceptable salts and esters wherein each Z1, Z2 and Z3 is chosen from series of (C1-C6)-alkoxy-group, -CH2OCH3 and -CH2OCH2CH3, or one Z1, Z2 or Z3 means hydrogen atom, and each of two others is chosen independently from series (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -Cl, -Br, -F, -CF3, -CH2OCH3, -CH2OCH2CH3, -OCH2CH2R1, -CH2-morpholino, -OR2, -OCH2CF3, -OCH(CH3)CH2OH and -COOQ wherein Q is chosen from series hydrogen atom and (C1-C6)-alkyl, or one of Z1, Z2 or Z3 means hydrogen atom, and two others in common with carbon atoms and in combination with bonds between them and benzene cycle to which they are bound for a cycle chosen from 5- and 6-membered unsaturated cycles and 5- and 6-membered saturated cycles that comprise at least one oxygen atom as heteroatom, and wherein R1 is chosen from series -F, -OCH3, -N(CH3)2 and unsaturated 5-membered cycles comprising at least one nitrogen or oxygen atom as heteroatom, and wherein R2 means 3-6-membered saturated cycle, and each Y1 and Y2 is chosen independently from series -Cl, -Br, -NO2, -C≡N and -C≡CH, and their pharmaceutically acceptable salts and esters and wherein Z4 is chosen from series (C1-C2)-alkyl, (C1-C6)-alkoxy-group, -OH, -SCH3, -CF3, -NO2, -COOQ2, -N(CH3)2, -OCH2-phenyl, -Cl, -Br, -F, -OCH2COQ1, saturated 5- and 6-membered cycles comprising at least one heteroatom wherein heteroatom is chosen from nitrogen (N) and oxygen (O) atom, and wherein Q1 is chosen from series, -OH, -NH2 and -O(C1-C6)-alkyl; Q2 is chosen from series hydrogen atom and (C1-C6)-alkyl; Y1 and Y2 are chosen independently from series -Cl, -Br, -NO2, -C≡N and -C≡CH under condition that if both Y1 and Y2 means -Cl then Z4 doesn't means -Cl, and if both Y1 and Y2 mean -NO2 then Z4 doesn't mean -NO2, and if both Y1 and Y2 mean -CN then Z4 doesn't mean -CN. Also, invention relates to a pharmaceutical composition possessing inhibitory activity with respect to MDM2. Invention provides synthesis of novel biologically active compounds and preparing pharmaceutical compositions based on thereof possessing inhibitory activity with respect to MDM2.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

14 cl, 50 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): their pharmaceutically acceptable salts or solvates, or stereoisomers possessing properties of agonists of β2-adrenoreceptors, to pharmaceutical composition based on thereof, using the claimed compounds in manufacturing a medicinal agent, and to a method for modulation of β2-adrenergic receptors. In the formula (I) each among R1-R5 is chosen independently from group comprising hydrogen atom, (C1-C4)-alkyl and Ra wherein alkyl is substituted optionally with substituted chosen from Rb; or R4 and R5 are combined to form group of the formula: -NRdC(=O)C(Rd)=C(Rd)-; R6, R7 and R8 represent hydrogen atom; R9 represents (C1-C4)-alkyl; R10 represents hydrogen atom or (C1-C4)-alkyl; each among R11, R12 and R13 is chosen independently from group including hydrogen atom, (C1-C4)-alkyl, vinyl, cyclohexyl, phenyl, halogen atom, -CO2Rd, -ORd, -S(O)mRd, -N(NRdRe)Rd or -S(O)2NRdRe, 5-6-membered monocyclic heteroaryl comprising 1 or 2 heteroatoms chosen from nitrogen (N), sulfur (S) atoms, 9-membered bicyclic heteroaryl comprising N as a heteroatom and 5-membered heterocycle comprising N as a heteroatom; or R11 and R12 in common with atoms to which they are bound form 6- or 7-membered heterocyclic ring comprising oxygen (O) atom as a heteroatom and wherein for R11-R13 each phenyl or heteroaryl is substituted optionally with 1 or 2 substitutes chosen independently from Rc, and each heterocyclyl is substituted optionally with 1 or 2 substitutes chosen from Rb and Rc; alkyl is substituted optionally with substitute chosen from Rb, and vinyl is substituted optionally with substitute chosen from Rm; w = 0, 1, 2, 3 or 4. Values Ra, Rb, Rc, Rd, Rm and m are given in the invention claim.

EFFECT: improved method for modulation, valuable medicinal properties of compounds and pharmaceutical composition.

22 cl, 225 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (1): wherein Y means -O-, -S- or -N(R2)- wherein R2 means hydrogen atom, (C1-C10)-alkyl or aralkyl; Z means 2,5-furanyl, 2,5-thiophenyl, 4,4'-stilbenyl or 1,2-ethyleneyl residue; R1 means hydrogen or halogen atom, (C1-C10)-alkyl, (C1-C10)-alkoxy-group, cyano-group, -COOM or -SO3M wherein M means hydrogen atom or alkaline or alkaline-earth metal atom. Method for synthesis involves carrying out the reaction of compound of the formula (2): with dicarboxylic acid of the formula: HOOC-Z-COOH (3) or with it ester wherein Y, Z and R1 have values given above in N-methylpyrrolidone or N,N-dimethylacetamide medium in the presence of an acid catalyst and optionally in the presence of an accessory solvent able to remove water from the reaction mixture.

EFFECT: improved method of synthesis.

11 cl, 7 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (1): wherein R1 means (C1-C6)-alkyl that can be substituted with phenyl; R2, R3, R4 and R5 represent independently each of other hydrogen halogen atom, nitro-group, (C1-C4)-alkyl, (C6-C10)-aryl-(C1-C4)-alkyloxy-, (C6-C10)-aryloxy-group, (C6-C10)-aryl that can be mono-, di- or tri-substituted with halogen atom; 2-oxopyrrolidine-1-yl, 2,5-dimethylpyrrole-1-yl or -NR6-A-R7 under condition that R2, R3, R4 and R5 can't mean simultaneously hydrogen atom and at least one residue among R2, R3, R4 and R5 represents 2-oxopyrrolidine-1-yl, 2,5-dimethylpyrrole-1-yl or -NR6-A-R7 at value R6 - hydrogen atom, (C1-C4)-alkyl or (C6-C10)-aryl-(C1-C4)-alkyl wherein aryl can be substituted with halogen atom; A means a simple bond, -COn, -SOn or -CONH; n = 1 or 2; R7 means hydrogen atom; (C1-C18)-alkyl or (C2-C18)-alkenyl that can be substituted from one to three times with (C1-C4)-alkyl, (C1-C4)-alkyloxy-group, -N-((C1-C4)-alkyl)2-group, -COOH, (C1-C4)-alkyloxycarbonyl, (C6-C12)-aryl, (C6-C12)-aryloxy-group, (C6-C12)-arylcarbonyl, (C6-C10)-aryl-(C1-C4)-alkoxy-group, halogen atom, -CF3 or oxo-group wherein aryl, in turn, can be substituted with halogen atom, (C1-C)-alkyl, aminosulfonyl- or methylmercapto-group; (C6-C10)-aryl-(C1-C4)-alkyl, (C5-C8)-cycloalkyl-(C1-C4)-alkyl, (C5-C8)-cycloalkyl, (C6-C10)-aryl-(C2-C6)-alkenyl, (C6-C10)-aryl, diphenyl, diphenyl-(C1-C4)-alkyl, indanyl that can be mono- or di-substituted with (C1-C18)-alkyl, (C1-C18)-alkyloxy-group, (C3-C8)-cycloalkyl, hydroxy-group, (C1-C4)-alkylcarbonyl, (C6-C10)-aryl-(C1-C4)-alkyl, (C6-C10)-aryl-(C1-C4)-alkyloxy-group, (C6-C10)-aryloxy-group, nitro-, cyano-group, (C6-C10)-aryl, fluorosulfonyl, (C1-C6)-alkyloxycarbonyl, (C6-C10)-arylsulfonyloxy-group, pyridyl, -NHSO2-(C6-C10)-aryl, halogen atom, -CF3 or -OCF3 wherein alkyl can be substituted once again with halogen atom, -CF3 or (C1-C4)-alkyloxy-group; or group Het-(CH2)r wherein r = 0, 1, 2 or 3 wherein Het means saturated or unsaturated 5-7-membered heterocycle comprising atoms nitrogen (N), oxygen (O) or sulfur (S) and can be condensed with benzene and substituted with (C1-C4)-alkyl, (C6-C10)-aryl, halogen atom, (C1-C4)-alkyloxy-group, (C6-C10)-aryl-(C1-C4)-alkyl, (C6-C10)-aryl-(C1-C)-alkylmercapto- or nitro-group and wherein aryl condensed with benzene can be, in turn, substituted with halogen atom, (C1-C4)-alkyloxy-group; and to their pharmacologically acceptable salts and additive salts of acids, and to a method for their preparing. Proposed compounds show inhibitory effect on activity of hormone-sensitive lipase.

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

14 cl, 199 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to bicyclic heterocyclic substituted phenyloxazolidinones that represent compounds of the formula (I): wherein R is taken from the group consisting of -OH, O-heteroaryl, -N3, -OSO2R'', -NR'''R'''', or the formula: wherein: (ii) R'' represents direct or branched alkyl comprising up to 5 carbon atoms; (iii) R''' and R'''' are taken independently from the group consisting of hydrogen atom (H), -CO2-R1, -CO-R1, -CS-R1 and -SO2-R4 wherein R1 is taken among the group consisting of cycloalkyl comprising from 3 to 6 carbon atoms and direct or branched alkyl comprising up to 6 carbon atoms; R4 is taken from direct or branched alkyl comprising up to 4 carbon atoms; and R4a represents -CN or -NO2; R4b represents -SR4c, amino-group, -NHR4c or -NR4cR4d wherein R4c and R4d are taken independently from hydrogen atom (H) or alkyl; X represents from 0 to 4 members taken independently from the group consisting of halogen atom; and Y represents radical of the formula (II): or (III): wherein R5, R6, R7 and R8 represent independently hydrogen atom (H), or R and R6 and/or R7 and R8 form in common oxo-group; R9 and R10 represent independently hydrogen atom (H); A, B, C and D are taken from carbon atom (C) and nitrogen atom (N) to form phenyl ring or 5-6-membered heteroaromatic ring wherein the indicated heteroaromatic ring comprises from 1 to 4 members taken from the group consisting of nitrogen atom (N); Z is taken from alkyl, heteroaryl comprising nitrogen atom (N); and m represents 0 or 1. These compounds are useful as antibacterial agents and can be used for treatment of patient with the state caused the bacterial infection or with the bacterial infection caused by S. aureus and E. faecium.

EFFECT: valuable medicinal properties of compounds.

45 cl, 1 tbl, 50 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of dihydrobenzo[b][1,4]diazepine-2-one. Invention describes derivatives of dihydrobenzo[b][1,4]diazepine-2-one of the general formula (I): wherein X means a simple bond or ethynediyl group wherein if X means a simple bond then R1 means cyano-group, halogen atom, lower alkyl, (C1-C3)-cycloalkyl, (lower)-alkoxyl, fluoro-(lower)-alkyl or it means pyrrole-1-yl that may be free or substituted with 1-3 substitutes taken among the group consisting of fluorine, chlorine atom, cyano-group, -(CH2)1-4-hydroxyl group, fluoro-(lower)-alkyl, lower alkyl, -(CH2)n-(lower)-alkoxyl, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'', hydroxy-(lower)-alkoxyl and -(CH2)n-COR'R'', or it means free phenyl or phenyl substituted with one or two substitutes taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, fluoro-(lower)-alkoxyl and cyano-group; if X means ethynediyl group then R1 means free phenyl or phenyl substituted with 1-3 substituted taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (C3-C6)-cycloalkyl, (lower)-alkoxyl and fluoro-(lower)-alkoxyl; R2 means -NR'R'', fluoro-(lower)-alkoxyl or 3-oxopiperazin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl wherein their rings are substituted optionally with R''; R' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl or 2-(lower)-alkoxy-(lower)-alkyl; R'' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl, 2-(lower)-alkoxy-(lower)-alkyl, -(CH2)2-4-di-(lower)-alkylamino-group, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy-(lower)-alkyl; Y means -CH= or =N-; R3 means halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, cyano-group, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'' or it means optionally substituted 5-membered aromatic heterocycle that can be substituted with halogen atom, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxyl, cyano-group, -(CH2)n-NR'R'', -(CH2)n-C(O)OR'', -(CH2)n-C(O)NR'R'', -(CH2)n-SO2NR'R'', -(CH2)n-C(NH2)=NR'', hydroxyl, (lower)-alkoxyl, (lower)-alkylthio-group or lower alkyl that is optionally substituted with fluorine atom, hydroxyl, (lower)-alkoxyl, cyano-group or carbamoyloxy-group; n means 0, 1, 2, 3 or 4, and their pharmaceutically acceptable additive salts. Also, invention describes a medicinal agent as antagonist of mGlu receptors of group II based on compounds of the formula (I). Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 496 ex

FIELD: medicine, chemical-pharmaceutical industry, microbiology, pharmacy.

SUBSTANCE: invention relates to an adjuvant composition comprising antibacterial agent azalid tulathromycin wherein azalid acts as adjuvant. Also, invention relates to vaccine comprising some components and involving: (A) at least one antigen wherein antigen is chosen from group consisting of M. haemolytica antigen, M. haemolytica leukotoxin, M. haemolytica capsule antigen, M. haemolytica soluble antigen, or their mixture, and (b) at least one azalid, for example, tulathromycin wherein azalid acts as adjuvant. Adjuvant or vaccine compositions are used for prophylaxis and treatment of diseases caused by pathogenic factor, cancer cell or allergen in animal but not in human. Proposed adjuvant provides enhancing effectiveness of the vaccine composition.

EFFECT: improved and valuable medicinal properties of composition.

10 cl, 16 tbl, 2 dwg, 5 ex

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