US 6,608,078 B2Granted

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

AssigneeWockhardt Limited

InventorsNoel John De Souza, Mahesh Vithalbhai Patel, Shiv Kumar Agarwal, Shirkant V Gupte, Dilip J Upadhyay, Satish B Bhawsar, Mohammad A Jafri

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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.

Claims15

Dependent claims

A compound of formula I

X is hydrogen, X is C1-C20 alkyl, aralkyl, —(CH2)n-CHR10—OCOR11, or (CH2)n—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
or X is acetoxymethyl, acetoxyethyl, carbethoxymethyl, pivaloyloxymethyl, or pivaloyloxyethyl group;
or X is heterocyclic amino or heterocyclic aminoalkyl of the formula
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 is hydrogen, C1-4 alkyl, aralkyl, aminoalkyl, trifluoroalkyl, or halogen,
R2 is hydrogen, C1-4 alkyl, aralkyl, aminoalkyl, trifluoroalkyl, or halogen with the proviso that when R1 is hydrogen R2 is not hydrogen;
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 polymorph or pseudopolymorph or prodrug thereof or pharmaceutically acceptable salt or hydrate thereof.

9 more elements

A compound selected from the group consisting of

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, optical 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, optical 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 optical 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-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and its optical 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 optical 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 optical isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(3ethyl-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (mixture of cis racemate and trans racemate) and its optical isomers;
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 and its optical isomers;
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 optical 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 optical 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, its diastereomers and its optical 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, its diastereomers and its optical 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, its diastereomers and its optical 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);
and its optical isomers;
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, optical 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, optical 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, its diastereomers and its optical 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 optical isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxy-3-isopropylpiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, its diastereomers and its optical isomers;
S-(−)-9-fluoro-6,7-dihydro-8-(3-n-butyl-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, its diastereomers and its optical 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 optical 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, its diastereomers and its optical 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, its diastereomers and its optical 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, its diastereomers and its optical 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, its diastereomers and its optical 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, its diastereomers and its optical 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, its diastereomers and its optical 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, its diastereomers and its optical 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, its diastereomers and its optical 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.

54 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/850,669Filed 7 May 2001 · us provisional application
Priority: 8 May 2000
Published: US 2002/0165227 A17 Nov 2002
Granted: 19 Aug 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 451/04
Containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic…:…
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents
C07D
Heterocyclic compounds