US 2002/0165227 A1 · Antibacterial chiral 8-(substituted piperidino)-benzo [i,j] quinolizines, processes, compositions and methods of treatment

Abstract

The present invention relates to optically pure 8-(substituted piperidino)-benzo[i,j]quinolizines, their isomers, derivatives, salts, pseudopolymorphs, polymorphs prodrugs and hydrates thereof, to processes for their preparation, and to pharmaceutical compositions comprising 8-(substituted piperidino)-benzo[i,j]quinolizines their isomers, derivatives, salts, pseudopolymorphs, polymorphs and hydrates thereof. These compounds and compositions possess potent activity in treating local and systemic infections, particularly infections caused by sensitive and resistant Gram-positive organism infections, Gram-negative organism infections, mycobacterial infections and nosocomial pathogens, and particularly those belonging to the staphylococcus, streptococcus and enterococcus groups. Methods for treating the diseases and disorders arising from the foregoing infections in humans and animals are described by administering the compounds of the invention to said humans and animals.

Claims16

Dependent claims

A compound of formula I

5
X is hydrogen, X is C1-C20 alkyl, aralkyl, —(CH2)n—CHR10O—OCOR11, or (CH2)—CHR10—OCO2R11 wherein R10 is H, or CH3;
n is 0-3 and R11 is C1-C20 alkyl or substituted C1-C6 alkyl, or aralkyl or R11 is
6
or X is acetoxymethyl, acetoxyethyl, carbethoxymethyl, pivaloyloxymethyl, or pivaloyloxyethyl group;
or X is
7
wherein A is CH or N, and when A is CH, Z is NH or NCH3, and when A is N, Z is CH2, O, NH, S, or NCH3;
p is 0-2;
and q is 0-2;
R1=R2=H, C1-4 alkyl, aralkyl, amino alkyl, trifluoroalkyl, or halogen, except that when R1=H, R2 is not equal to H;
R3 is hydrogen, C1-C20 alkyl, glycosyl, aralkyl, C1-C6 alkanoyl;
or aminoalkanoyl derived from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine, or the optically active isomers thereof, or the racemic mixtures thereof, or 1-aminocyclohexylcarbonyl or COOR11 wherein R11 is as defined above, or —(CH2)n—CHR10—OCOR11 or —(CH2)n—CHR10—OCOOR11 where n, R10 and R11 are as defined above, or C6H11O6, PO2(CH3)H, PO3H2, PO2(OCH3)H or SO3H, provided that R1, R2 and R3 are not equal to H at the same time;
R4 is H, C1-4 alkyl, CF3, phenyl, F, substituted at one or more of the positions of 2-, 4-, 5-, or 6- of the piperidine ring, or an optical isomer, diastereomer or enantiomer thereof, or polymorphs and pseudopolymorphs, and prodrugs thereof or pharmaceutically acceptable salts and hydrates thereof.

11 more elements

A compound selected from the group selected from:

S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxy-3-methylpiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (mixture of cis racemate and trans racemate);
S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxy-3-methylpiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid sodium salt (mixture of cis racemate and trans racemate);
S-(−)-9-fluoro-6,7-dihydro-8-(4-methoxy-3-methylpiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (mixture of cis racemate and trans racemate);
S-(−)-9-fluoro-6,7-dihydro-8-(4-ethoxy-3-methylpiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (mixture of cis racemate and trans racemate);
S-(−)-9-fluoro-6,7-dihydro-8-(4-acetoxy-3-methylpiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (mixture of cis racemate and trans racemate);
S-(−)-9-fluoro-6,7-dihydro-8-(3-methyl-4-pivaloyloxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (mixture of cis racemate and trans racemate);
S-(−)-9-fluoro-6,7-dihydro-8-{trans-4-(RS)-hydroxy-3-(RS)-methylpiperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, isomers, prodrugs and salts thereof;
S-(−)-9-fluoro-6,7-dihydro-8-{trans-(−)-4-R-hydroxy-3-R-methylpiperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;
S-(−)-9-fluoro-6,7-dihydro-8-{trans-(−)-4-R-hydroxy-3-R-methylpiperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt;
S-(−)-9-fluoro-6,7-dihydro-8-{trans-(+)-4-S-hydroxy-3-S-methylpiperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;
S-(−)-9-fluoro-6,7-dihydro-8-{trans-(+)-4-S-hydroxy-3-S-methylpiperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt;
S-(−)-9-fluoro-6,7-dihydro-8-{trans-(+)-4-S-hydroxy-3-S-methylpiperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid histidine salt;
S-(−)-9-fluoro-6,7-dihydro-8-{trans-(+)-4-S-hydroxy-3-S-methylpiperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid lysine salt;
S-(−)-9-fluoro-6,7-dihydro-8-{trans-(+)-4-S-hydroxy-3-S-methylpiperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid arginine methyl ester salt;
S-(−)-9-fluoro-6,7-dihydro-8-{trans-(+)-4-S-hydroxy-3-S-methylpiperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid histidine methyl ester salt;
S-(−)-9-fluoro-6,7-dihydro-8-{cis-4-(RS)-hydroxy-3-(RS)-methylpiperidin-1-yl-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, isomers, prodrugs and salts thereof;
S-(−)-9-fluoro-6,7-dihydro-8-{cis-(−)-4-R-hydroxy-3-S-methylpiperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, prodrugs and salts thereof;
S-(−)-9-fluoro-6,7-dihydro-8-{cis-(+)-4-S-hydroxy-3-R-methylpiperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, prodrugs and salts thereof;
S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxy-3-trifluoromethylpiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers (mixture of cis racemate and trans racemate);
S-(−)-9-fluoro-6,7-dihydro-8-(3,3-dimethyl-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-11H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(4-acetoxy-3,3-dimethylpiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(3,3-dimethyl-4-pivaloyloxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(3-ethyl-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid mixture of cis racemate and trans racemate;
S-(−)-9-fluoro-6,7-dihydro-8-(4-acetoxy-3-ethylpiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid mixture of cis racemate and trans racemate;
S-(−)-9-fluoro-6,7-dihydro-8-(3-ethyl-4-pivaloyloxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(3,3-diethyl-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(3-ethyl-4-hydroxy-3-methylpiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(4-acetoxy-3-ethyl-3-methylpiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(3-ethyl-4-pivaloyloxy-3-methylpiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(3,5-dimethyl-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid mixture of cis racemate and trans racemate;
S-(−)-9-fluoro-6,7-dihydro-8-(trans-3,5-dimethyl-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, isomers, prodrugs and salts thereof;
S-(−)-9-fluoro-6,7-dihydro-8-(cis-3,5-dimethyl-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, isomers, salts and prodrugs thereof;
S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxy-3-n-propylpiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(3,3-di-n-propyl-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxy-3-isopropylpiperidin-1-yl)-5-methyl-I-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(3-n-butyl-4-hydroxypiperidin-1-yl)-5-methyl-I-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(3,3-di-n-butyl-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxy-3-iso-butylpiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(3-benzyl-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxy-4-methylpiperidin-1-yl)-5-methyl-1-oxo-1H, 5H-benzo[i,j]quinolizine-2-carboxylic acid;
S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxy-4-trifluoromethylpiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;
S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxy-4-phenylpiperidin-1-yl)-5-methyl-1-oxo-1H, 5H-benzo[i,j]quinolizine-2-carboxylic acid;
S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxy-3-methyl-4-trifluoromethyl piperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(3-fluoro-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H, 5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(3-aminomethyl-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxy-3,3,5-trimethylpiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(3,5-dimethyl-3-ethyl-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(3,5-diethyl-4-hydroxy-3-methylpiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its isomers;
Pivaloyloxymethyl S-(−)-9-fluoro-6,7-dihydro-8-{trans-4-(RS)-hydroxy-3-(RS)-methylpiperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate;
Acetoxymethyl S-(−)-9-fluoro-6,7-dihydro-8-{trans-4-(RS)-hydroxy-3-(RS)-methylpiperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate;
Carbethoxymethyl S-(−)-9-fluoro-6,7-dihydro-8-{trans-4-(RS)-hydroxy-3-(RS)-methylpiperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate;
2-Piperazino-ethyl S-(−)-9-fluoro-6,7-dihydro-8-{trans-4-(RS)-hydroxy-3-(RS)-methylpiperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate;
2-Morpholino-ethyl S-(−)-9-fluoro-6,7-dihydro-8-{trans-4-(RS)-hydroxy-3-(RS)-methylpiperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate;
2-Pyrrolidino-ethyl S-(−)-9-fluoro-6,7-dihydro-8-{trans-4-(RS)-hydroxy-3-(RS)-methyl piperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate;
or 4-(N-methyl)-piperidinyl S-(−)-9-fluoro-6,7-dihydro-8-{trans-4-(RS)-hydroxy-3-(RS)-methyl piperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate.

52 more elements

Dependencies are inferred from the claim text.

Antibacterial chiral 8-(substituted piperidino)-benzo [i,j] quinolizines, processes, compositions and methods of treatment

Life of this patent

Antibacterial chiral 8-(substituted piperidino)-benzo [i,j] quinolizines, processes, compositions and methods of treatment

Life of this patent

Abstract

Claims16