3-aza-bicyclo[3,3,0]octane compounds

FIELD: chemistry.

SUBSTANCE: invention relates to 3-aza-bicyclo[3.3.0]octane derivatives of formula , where R1 and R2 are hydrogen, C1-4alkyl or fluorine; R3 is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl, trifluoromethoxy group and halogen; 2,3-dihydrobenzofuranyl; 2,3-dihydrobenzo[1,4]dioxynyl; or isoxazolyl, pyridyl, indazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, pyrrolo[2,1b]thiazolyl, imidazo[ 1,2-a]pyridinyl or imidazo[2,1-b]thiazolyl, where said groups are unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, halogen and trifluoromethyl; A is or ; R4 is C1-4alkyl or -NR6R7; R6 is hydrogen or C1-4alkyl; R7 is hydrogen or C1-4alkyl; and D is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl and halogen; or a pharmaceutically acceptable salt of such a compound. 3-aza-bicyclo[3.3.0]octane derivatives or a pharmaceutically acceptable salt thereof are used as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: novel 3-aza-bicyclo[3,3,0]octane derivatives as nonpeptide antagonists of human orexin receptors.

9 cl, 1 tbl, 85 ex

 

The text descriptions are given in facsimile form.

1. The compound of formula (I), where the absolute configuration is the same as it the image is on in the formula (I)

where R1represents hydrogen, C1-4alkyl or fluorine;
R2represents hydrogen, C1-4alkyl or fluorine;
R3represents phenyl, which is unsubstituted, mono - or disubstituted where the substituents independently of one another selected from the group including1-4alkyl, C1-4alkoxygroup, trifluoromethyl, cryptometer and halogen; 2,3-dihydrobenzofuranyl; 2,3-dihydrobenzo[1,4]dioxines or isoxazolyl, pyridyl, indazoles, benzofuranyl, benzoxazolyl, benzisoxazole, benzothiazole, benzisothiazole, pyrrolo[2,1-b]thiazolyl, imidazo[1,2-a]pyridinyl or imidazo[2,1-b]thiazolyl, where these groups are unsubstituted, mono - or disubstituted where the substituents independently of one another selected from the group including1-4alkyl, C1-4alkoxygroup, halogen and trifluoromethyl;
But a
or;
R4represents a C1-4alkyl or-NR6R7;
R6represents hydrogen or C1-4alkyl;
R7represents hydrogen or C1-4alkyl; and
D represents phenyl, which is unsubstituted, mono - or disubstituted where the substituents independently of one another selected from the group including1-4al the sludge, With1-4alkoxygroup, trifluoromethyl and halogen;
or pharmaceutically acceptable salt of such compounds.

2. The compound of formula (I) according to claim 1, where
R1represents hydrogen or C1-4alkyl and
R2represents hydrogen or C1-4alkyl;
or pharmaceutically acceptable salt of such compounds.

3. The compound of formula (I) according to claim 1 or 2, where
R4represents methyl or-NH2;
or pharmaceutically acceptable salt of such compounds.

4. The compound according to claim 3, where
R3represents phenyl, which is unsubstituted, mono - or disubstituted where the substituents independently of one another selected from the group including1-4alkyl, C1-4alkoxygroup, trifluoromethyl, cryptometer and halogen; 2,3-dihydrobenzofuranyl; 2,3-dihydrobenzo[1,4]dioxines or isoxazolyl, pyridyl, indazoles, benzofuranyl, benzoxazolyl, benzisoxazole, benzisothiazole or imidazo[2,1-b]thiazolyl, where these groups are unsubstituted, mono - or disubstituted where the substituents independently of one another selected from the group including1-4alkyl, C1-4alkoxygroup, halogen and trifluoromethyl; or a pharmaceutically acceptable salt of such compounds.

5. The compound according to claim 1, selected from the group comprising (1S,2S,5R)-[3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicy the lo[3.3.0]Oct-2-ylmethyl]amide 2,3-dihydrobenzo[1,4]dioxin-5-carboxylic acid,
(1S,2S,5R)-[3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide benzo[(1]isothiazol-3-carboxylic acid,
(1S,2S,5R)-3-bromo-N-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]benzamide,
(1S,2S,5R)-3-chloro-N-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]benzamide,
(1S,2S,5R)-3-fluoro-N-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]benzamide,
(1S,2S,5R)-3-methoxy-N-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]benzamide,
(1S,2S,5R)-N-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]-3-cryptomelane,
(1S,2S,5R)-3-methyl-N-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]benzamide,
(1S,2S,5R)-N-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]-3-cryptomaterial,
(1S,2S,5R)-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-triptorelin-2-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methoxypyridine-2-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide 4-bromopyridin-2-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide 4-chloropyridin-2-carboxylic what islote,
(1S,2S,5R)-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide 4-methylpyridin-2-carboxylic acid,
(1S,2S,5R)-5-bromo-N-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl] nicotinamide,
(1S,2S,5R)-5-chloro-N-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]nicotinamide,
(1S,2S,5R)-5-methyl-N-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]nicotinamide,
(1S,2S,5R)-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]the amide benzofuran-4-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide 2-methylbenzofuran-4-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide 2-methylbenzothiazol-4-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide 2,3-dihydrobenzo[1,4]dioxin-5-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3,0]Oct-2-ylmethyl]amide 1-methylindol-3-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide 3,5-dimethylisoxazol-4-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide benzo[d]isoxazol-3-carboxylic acid,
(1S,2S,5R)-2-ethyl-N-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]isonicotinamide,
(1S,2S,5R)-[3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide benzo[d]isoxazol-3-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide benzo[d]isoxazol-3-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of imidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-[3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of imidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of imidazo[2,1-b]thiazole-6-carboxylic acid,
(1S,2S,5R)-[3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylpyridin-2-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[5-(3-methoxyphenyl)-2-methylthiazole-4-carbonyl]-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[5-(3-methoxyphenyl)-2-methylthiazole-4-carbonyl]-7-methyl-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[2-methyl-5-(3-triptoreline)thiazole-4-arbonyl]-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{7-methyl-3-[2-methyl-5-(3-triptoreline)thiazole-4-carbonyl]-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[5-(3-forfinal)-2-methylthiazole-4-carbonyl]-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[5-(3-forfinal)-2-methylthiazole-4-carbonyl]-7-methyl-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(2-methyl-5-p-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-[3-(2-methyl-5-p-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[5-(3-chlorophenyl)-2-methylthiazole-4-carbonyl]-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[5-(3-chlorophenyl)-2-methylthiazole-4-carbonyl]-7-methyl-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[5-(4-methoxyphenyl)-2-methylthiazole-4-carbonyl]-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[5-(4-methoxyphenyl)-2-methylthiazole-4-carbonyl]-7-methyl-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[5-(4-ethylphenyl)-2-methylthiazole-4-carbonyl]-7-methyl-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-matrimid the AOR[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{7-methyl-3-[2-methyl-5-(4-triptoreline)thiazole-4-carbonyl]-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[5-(4-forfinal)-2-methylthiazole-4-carbonyl]-7-methyl-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{7-methyl-3-[2-methyl-5-phenylthiazol-4-carbonyl]-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[5-(3,4-dimetilfenil)-2-methylthiazole-4-carbonyl]-7-methyl-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[5-(3,4-dimetilfenil)-2-methylthiazole-4-carbonyl]-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[5-(3,4-differenl)-2-methylthiazole-4-carbonyl]-7-methyl-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo [2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[5-(3,4-differenl)-2-methylthiazole-4-carbonyl]-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-[3-(2-amino-5-phenylthiazole-4-carbonyl)-7-methyl-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-[3-(biphenyl-2-carbonyl)-7-methyl-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(3'-methylbiphenyl-2-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylimidazo[2,1-b]enous is l-5-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(4'-methylbiphenyl-2-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(4'-forbiden-2-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(3'-methoxybiphenyl-2-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-[7-methyl-3-(4'-chlorobiphenyl-2-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-[3-(biphenyl-2-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-[3-(4'-forbiden-2-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-[3-(3'-methylbiphenyl-2-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-[3-(3'-methoxybiphenyl-2-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-[3-(2-methyl-5-phenylthiazol-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[5-(4-forfinal)-2-methylthiazole-4-carbonyl]-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[5-(4-ethylphenyl)-2-methylthiazole-4-carbonyl]-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-Mitilini the azo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[5-(4-chlorophenyl)-2-methylthiazole-4-carbonyl]-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[2-methyl-5-(4-triptoreline)thiazole-4-carbonyl]-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[2-amino-5-(3-were)thiazole-4-carbonyl]-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{3-[2-amino-5-(3-forfinal)thiazole-4-carbonyl]-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-[3-(2-amino-5-phenylthiazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{7-methyl-3-[2-amino-5-(3-were)thiazole-4-carbonyl]-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{7-methyl-3-[2-amino-5-(4-forfinal)thiazole-4-carbonyl]-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-{7-methyl-3-[2-amino-5-(3-forfinal)thiazole-4-carbonyl]-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid,
(1S,2S,5R)-[3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of imidazo[2,1-b]thiazole-6-carboxylic acid,
(1S,2S,5R)-[7,7-debtor-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-3-ylmethyl]amide 2-methylbenzofuran-4-carboxylic acid,
(1S,2S,5R)-[7,7-debtor-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide 2,3-dihydrobenzofuran-4-carboxylic acid,
(1S,2S,5R)-[7,7-debtor-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide 2,3-dihydrobenzo[1,4]dioxin-5-carboxylic acid,
(1S,2S,5R)-[7,7-debtor-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]nebensaison-7-carboxylic acid,
(1S,2S,5R)-[7,7-debtor-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylpyrrole[2,1-b]thiazole-7-carboxylic acid,
(1S,2S,5R)-[7,7-debtor-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]aminimides[1,2-a]pyridine-3-carboxylic acid,
(1S,2S,5R)-[7,7-debtor-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide 1-methylindol-3-carboxylic acid and
(1S,2S,5R)-[7,7-debtor-3-(2-methyl-5-m-tolyltriazole-4-carbonyl)-3-Aza-bicyclo[3.3.0]Oct-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
or pharmaceutically acceptable salt of such compounds.

6. Pharmaceutical composition having activity of the antagonists orexin receptor containing as an active component a compound of the formula (I) according to claim 1 or 5, or its pharmaceutically acceptable salt and at least one therapeutically inert excipient.

7. The compound according to claim 1 or 5 or its pharmaceutically reception who will be Sol for use as medicines possessing activity of the antagonists orexin receptor.

8. The compound according to claim 1 or 5, or its pharmaceutically acceptable salt for the treatment of sleep disorders.

9. The use of compounds according to claim 1 or 5, or its pharmaceutically acceptable salt for a medicinal product for the treatment of sleep disorders.



 

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wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

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13 cl, 2 tbl, 25 ex

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EFFECT: composition improvement.

8 cl, 6 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: method is realised by mixing a compound of formula (B) with p-toluenesulphonic acid or a monohydrate of toluenesulphonic acid in less than 1 molar equivalent with respect to the compound of formula (B), in a solvent while heating. An additional amount of p-toluenesulphonic acid or monohydrate of p-toluenesulphonic acid is then added to the mixed solution while cooling in such an amount that their total molar equivalent with p-toluenesulphonic acid or monohydrate of p-toluenesulphonic acid at the mixing step is equal to 1 molar equivalent or more with respect to the compound of formula (B). At the last step, the obtained solution is crystallised to separate a compound of formula (A).

EFFECT: obtaining a compound of formula (A) with stable high output.

12 cl, 1 dwg, 3 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes the pyrrolo- and thiazolopyridinium compounds and their pharmaceutically acceptable salts covered by general structural formula I: wherein the values A, B, R1, R2, R3, R4, R5, R6, R7 and R8 are those as presented in cl.1, and a pharmaceutical composition based on the given compound for inhibition of hypoxia-inducible factor (HIF) hydroxylase activity.

EFFECT: there are produced and described new compounds able to modulate hypoxia-inducible factor (HIF) stability and/or activity.

29 cl, 178 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , and pharmaceutically acceptable salts thereof, where L denotes O, S, or CH2; Y denotes N or CH; Z denotes CR3; G denotes CH; R1 denotes a heteroaryl ring of formula , where D1 denotes S, O; D2 denotes N or CR12; D3 denotes CR12; R2 denotes (C6-C10)-aryl; 5-9-member mono- or bicyclic heteroaryl with 1 or 2 heteroatoms independently selected from N or S; a saturated or partially saturated (C3-C7)-cycloalkyl; or a saturated 5-6-member heteocyclyl with 1 heteroatom selected from N, where said aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with one or two groups independently selected from (C1-C6)-alkyl, F, Cl, Br, CF3, CN, NO2, OR6, C(-O)R6, C(=O)OR6, C(=O)NR6R7, saturated 6-member heterocyclyl with 2 heteroatoms independently selected from N or O, and S(O)2R6, and where said alkyl is optionally substituted with one -OR8 group; R3 denotes H; (C1-C6)-alkyl; (C2-C6)-alkenyl; Cl; Br; OR6; SR6; phenyl; or a 6-member heteroaryl with 1 heteroatom selected from N, where said alkyl and alkenyl are optionally substituted with one group selected from C(=O)OR8, -OR8, -NR8R9; or a saturated 6-member heterocyclyl with 1 heteroatom selected from N or O.

EFFECT: disclosed compounds are used in treating and preventing diseases mediated by insufficient level of glucokinase activity, such as sugar diabetes.

16 cl, 479 ex

FIELD: chemistry.

SUBSTANCE: described are novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side with considerable absorption in the region up to 410-420 nm, having general formulae (a)-(k) (structural formula and values of radicals are given in the description), composition which is stabilised with respect to UV radiation and containing novel UV-absorbers, and use of the novel compounds as UV light stabilisers for organic materials.

EFFECT: obtaining novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side.

13 cl, 23 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives, having HIV replication inhibiting properties, or pharmaceutically acceptable salts thereof. In formula (1): R1 denotes hydrogen; R2 and R3 independently denote hydrogen; R7 and R8 denote C1-6alkyl; R4 denotes cyano; R9 denotes C1-6alkyl optionally substituted with cyano, C2-6alkenyl substituted with cyano, C2-6alkynyl optionally substituted with cyano; R5 denotes C1-6alkyl optionally substituted with Ar or Het; C2-6alkenyl optionally substituted with Ar or Het; C2-6alkynyl optionally substituted with Ar or Het; C3-7cycloalkyl; Ar; Het; R6 denotes H, Het; Y denotes -OR11, -NR12R13; R11 denotes hydrogen or C1-6alkyl optionally substituted with hydroxy, C1-6alkoxy or pyridyl; R12 denotes hydrogen or C1-6alkyl; R13 denotes hydrogen or C1-6alkyl; or R12 and R13 together with a nitrogen atom, which is substituted by said two substitutes, form a morpholinyl; imidazolyl; X denotes -NR1-; Het denotes 5- or 6-member completely saturated ring, where one or two ring members are heteroatoms, each independently selected from nitrogen and sulphur, and where the rest of the ring members are carbon atoms; and where any member of the heterocycle with a nitrogen heteroatom can optionally be substituted with C1-6alkyl; where the 5- or 6-member ring can optionally be annelated with a benzene or thiophene ring; each aryl independently denotes phenyl or phenyl substituted with one substitute selected from C1-6alkoxy.

EFFECT: high efficiency of using said compounds.

7 cl, 4 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: there are described substituted imidazo[2,1-b]thiazoles of general formula the R1, R1, R3 R4, M1, M2 radical values are presented in the patent claim cl. 1, as well as methods for making them, drug preparations containing these compounds and application of these compounds for making the drug preparations.

EFFECT: higher efficacy.

23 cl, 3 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula

wherein: m, n, R0, R1, R2, R3 and R4 have the values presented in clause 1 of the patent claim provided the compound of formula (I) cannot represent N-methyl-1-(phenylsulphonyl)-1H-indole-4-methanamine.

EFFECT: compounds show 5-NT6 receptor antagonist activity that that allows them being used in the pharmaceutical composition.

19 cl, 3 tbl, 192 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel agents for controlling plant fungal diseases, specifically 3,7-dithia-1,5-diazabicyclo[3,3,0]octane as an agent against Bipolaris sorokiniana, Aspergillus fumigates, Aspergillus niger, synthesis of which takes place in a single step using readily available reactants in contrast to multi-step synthesis of existing agents used for controlling fungal diseases of plants and materials.

EFFECT: obtaining novel agents for controlling plant fungal diseases.

1 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel tricyclic derivative of chemical formula 1 or pharmaceutically acceptable salts thereof: formula 1, where Y1, Y2 and Y3 independently denote H, C1-C10 alkyl with a straight or branched chain, hydroxy, C1-C10 alkoxy, -CCOR1, -NR2R3 or -A-B; A denotes -O-, -CH2-, -CH(CH3)-, -CH-N- or -CONH-; B denotes -(CH2)n1-Z, -(CH2)n2-NR2R3 or -(CH2)n3-OR1; Z denotes C5-C20 aryl, unsubstituted or substituted with R5 and selectively R6, C3-C10 cycloalkyl, unsubstituted or substituted with R5 and selectively R6, C1-C20 heterocyclic compound, unsubstituted or substituted with R5 and selectively R6; R1 denotes H or C1-C10 alkyl with a straight or branched chain; R2 and R3 independently denote H, C1-C10 alkyl with a straight or branched chain or -(CH2)n4R7; R5 denotes H, C1-C10 alkyl with a straight or branched chain, C5-C20 aryl or C1-C20 heterocyclic compound; R6 denotes H or C1-C10 alkyl with a straight or branched chain; R7 denotes -NR8R9, -COOR1, -OR1, -CF3, -CN, halogen or Z; R8 and R9 independently denote H or C1-C10 alkyl with a straight or branched chain; n1-n4 respectively denote an integer from 0 to 15; Y denotes H or C1-C10 alkyl with a straight or branched chain. The invention also relates to methods of producing a compound of formula 1, compositions containing the described compound and with effective inhibiting activity on poly(ADP-ribose)polymerase (PARP).

EFFECT: obtaining and describing novel compounds which can be suitable for preventing or treating diseases caused by excess PARP activity, especially neuropathic pain, neurodegenerative diseases, cardiovascular diseases, diabetic neuropathy, inflammatory diseases, osteoporosis and cancer.

23 cl, 123 ex, 7 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 4-aryl-1,4-dihydro-1,6-naphthyridine-3-carboxamides, method for production thereof, use thereof to produce a medicinal agent which inhibits MR activity.

EFFECT: improved method.

11 cl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) where values of substituents are given in description, possessing inhibiting activity with respect to cathepsin K as well as to pharmaceutical compositions for treating diseases, associated with cysteine protease activity and to methods of inhibiting cathepsin K in mammals, requiring such treatment by introduction of efficient amount of compound to mammal.

EFFECT: claimed is application of formula (I) compound or its pharmaceutically acceptable salt in manufacturing medication for application in cathepsin K inhibition in a warm-blooded animal.

10 cl, 45 ex, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of antibiotics, which represent compounds of formula (I) and their pharmaceutically acceptable salts, where U, V, W, X, R1, R2, R3, R4, R5, R6, A, B, D, E, G, m and n are determined in description. Invention also relates to pharmaceutical composition, containing said compounds and their application for obtaining medication for prevention or treatment of bacterial infections.

EFFECT: obtaining useful antimicrobial agents, efficient against various pathogens of people and animals.

23 cl, 1 tbl, 186 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazopyridine compounds of formula (I) and pharmaceutically acceptable salts thereof, which inhibit kinase activity, selected from IGF-1R, IR, EGFR and Erb2 and have cell proliferation inhibitor properties. In formula (I) halogeno denotes a halogen; X1 is H or halogen, R1 is H, halogen or halogen-C1-C4alkyl; R2 is H or O-C1-C4alkyl; each R3 is identical or different and is independently selected from H, halogen, C1-C4alkyl, halogen-C1-C4alkyl and O-C1-C4alkyl; one of R4 and R5 is selected from H, halogen, C1-C4alkyl and O-C1-C4alkyl; and the other is a group selected from: (i), (ii) and (iii) where:(1) each R7 is H; a equals 0, 1, 2 or 3; R8 is selected from NH2, N(H)C1-C4alkyl, N(C1-C4alkyl)2 and a group of formula (iv): (iv), where: ring D is a 5-6-member saturated N-heterocycle, possibly containing 1 or 2 additional heteroatoms selected from N and O. Other values of radicals are given in the claim.

EFFECT: compounds can be used in treating different types of cancer.

4 tbl, 250 ex

Chemical compounds // 2469034

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes compounds of formula (I) wherein: R1 means C1-6alkyl or C3-6cycloalkyl; wherein R1 may be optionally carbon-substituted by one or more R6; R2 means hydrogen; R3 and R4 are carbon substitutes, and each is independently specified in carboxy, carbamoyl, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, N-(C1-6alkoxy)carbamoyl, phenyl-R9 - or heterocyclyl-R10-; wherein R3 and R4 may be independently carbon-substituted by one or more R11; and wherein provided said heterocyclyl contains -NH - residue, then nitrogen may be optionally substituted by a group specified in R12; m has the value of 0, 1 or 2; wherein the values R3 may be equal or different; p has the value of 0, 1 or 2; wherein the values R4 may be equal or different; the ring A means nitrogen-containing 5- or 6-member heterocyclic group; wherein drawn nitrogen represents = N- and is found in an ortho-position to R1R2NC(O)NH group in formula (I); the ring B means phenyl or heterocyclyl; wherein provided said heterocyclyl contains -NH- residue, then nitrogen may be optionally substituted by a group specified in R14; R5 is specified in hydroxy, C1-6alkoxy or -N(R15)(R16); R6 and R11 are carbon substitutes and each is independently specified in halo, C1-6alkyl or C1-6alkoxy; R15 and R16 are independently specified in hydrogen, C1-6alkyl, C1-6alkoxy, cyclopropyl or cyclopentyl; R12 and R14 mean C1-6alkyl; wherein R14 may be optionally carbon specified by one or more R23; R9 and R10 mean a direct link; and R23 means halo or methoxy; wherein said heterocyclyl means pyridine, imidazole, triazole, thiazole, benzothiazole, imodazolepyridine, dihydroquinoline or thiadiazole, or its pharmaceutically acceptable salt; provided said compound represents other than ethyl ester of 5-[2-[[(ethylamino)carbonyl]amino]pyridin-4-yl]-4-methyl-4H-1,2,4-triazole-3-carboxylic acid or their pharmaceutically acceptable salts. There are also described pharmaceutical compositions on the basis of said compounds, a method for bacterial DNA-hydrase and/or bacterial topoisomerase IV inhibition in a homoiothermal animal, as well as a method of treating an infection in a homoiothermal animal.

EFFECT: there are prepared and described new compounds showing antibacterial activity.

24 cl, 165 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to fluorinated compounds of formula , where: D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more halogen atoms; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: halogen, C1-C10 alkyl; E denotes aryl which can be substituted with one or more fluoro-substitutes or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more fluoro-substitutes, and where Q denotes O; m denotes a number from 1 to 2; under the condition that: R3 is a fluoro-substitute, or group E includes a fluoro-substitute, or group Z includes a fluoro-substitute, with the condition that E does not denote 4-fluorophenyl or a compound of formula , where D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more of the following substitutes: chlorine, bromine, iodine; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: chlorine, bromine, iodine, C1-C10 alkyl; E denotes aryl which can be substituted with one or more chlorine, bromine or iodine atoms, and/or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more substitutes selected from chlorine, bromine, iodine or hydroxy, where Q denotes O, wherein when E denotes phenyl, E does not contain, as a substitute, iodine which is directly bonded to it at position 4; m denotes a number from 1 to 2; wherein at least one of Z, E and R3 includes iodine; under the condition that E does not denote 4-iodophenyl and under the condition that said compound is not a compound of formula (Ia), defined in the following table:

The invention also relates to a pharmaceutical composition based on the compound of formula (I) or (Ia), a diagnosis method, a method of treating said disorders, based on use of the compound of formula (I) or (Ia), and use of the compound of formula (I) or (Ia).

EFFECT: obtaining novel compounds useful in treating disorders in mammals, characterised by anomalous density of peripheral benzodiazepine receptors.

24 cl, 13 dwg, 9 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: compounds, which have formula I , in which A, B, R1, R1a, R2, R3, R4, R5 R6, R7 and R8 have values given in description and are inhibitors of receptor tyrosinkinases, useful in treatment of diseases, mediated by class 3 and class 5 receptor tyrosinkinases. It has been also discovered that specific compounds of the claimed invention are Pim-1 inhibitors. Also claimed is method of obtaining formula I compound.

EFFECT: increase of compound efficiency.

27 cl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of [1,8]naphthyridine, described by formula I(a), where Z represents -NR41-; A represents phenyl; each R10, R17, R31, R33, R35 and R41 in each case is independently selected from group, consisting of hydrogen, C1-C6alkyl, C1-C6haligenalkyl, phenyl, C3-C6cycloalkyl, -Ls-O-Rs, -Ls-C(O)Rs, -Ls-C(O)ORs and LE-Q-LE-(morpholine); X is selected from group, consisting of bond, -Ls-O-, -Ls-S- and -Ls-C(O)N(Rs)-; R22 is selected from group, consisting of halogen, C1-C6alkyl, phenyl, and phenyl C1-C2alkyl, and, optionally, is substituted with one R26, where R26 in each case is independently selected from group, consisting of halogen, hydroxy, nitro, C1-C6alkyl, -Ls-OSO2Rs; Y is selected from group, consisting of bond, -Ls-O-, -Ls-S(O)-, -Ls-C(O)N(R15) - and -Ls-S-, where R15 represents hydrogen; R50 represents -L1-A1, where A1 is selected from group, consisting of C1-C6alkyl and phenyl and L1 is selected from group, consisting of bond and C1-4alkylene, where A1 is optionally substituted with from one to three R30, and R30 in each case is independently selected from group, consisting of halogen, hydroxy, amino, azido, C1-C6alkyl, -Ls-O-Rs, -Ls-C(O)ORs, -LS-N(RSRS), -Ls-C(=NRs)RS', -Ls-C(O)N(RsRsO, -Ls-N(Rs)C(O)Rs', -LE-Q-LE'- (phenyl or naphthyl) and -LE-Q-LE'-(M5-M6heterocyclyl, which represents pyridine, pyrazine, pyrrolodine, furan, thiophene, piperidine); Ls in each case is independently selected from group, consisting of bond and C1-4alkylene; each RS and Rs' in each case is independently selected from group, consisting of hydrogen, C1-C6alkyl, C3-6alkenyl, C1-6alkoxy, C1-6alkoxyC1-C6alkyl and C1-6alkoxycarbonylC1-C6alkyl; each LE and LE' in each case is independently selected from group, consisting of bond, C1-4alkylene, -C1-4alkylene-NC(O)-C1-4alkylene-; Q in each case is independently selected from group, consisting of bond, -O-, -N(Rs)C(O)-, -C(O)N(Rs)- and -O-SO2-; each R17 and R30 in each case is optionally independently substituted with from one to three substituent(s), selected from group, consisting of halogen and hydroxy; and each heterocyclyl group in -LE-Q-LE'-(M5-M6heterocyclyl) in each case is optionally independently substituted with at least one or two substituents, selected from group, consisting of hydrogen, hydroxy, C1-C6alkyl, C1-6alkoxy, C1-6alkoxycarbonyl, phenyloxy and phenylC1-6alkoxycarbonyl, or to their pharmaceutically acceptable salts. Invention also relates to compounds of formula II(a), pharmaceutical composition based on claimed compounds, application of claimed compounds, method of inhibition of HCV virus replication, method of treating HCV infection.

EFFECT: obtained are novel derivatives, useful in treatment of HCV infection.

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of antibiotics, which represent compounds of formula (I) and their pharmaceutically acceptable salts, where U, V, W, X, R1, R2, R3, R4, R5, R6, A, B, D, E, G, m and n are determined in description. Invention also relates to pharmaceutical composition, containing said compounds and their application for obtaining medication for prevention or treatment of bacterial infections.

EFFECT: obtaining useful antimicrobial agents, efficient against various pathogens of people and animals.

23 cl, 1 tbl, 186 ex

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