WO2001085728A2 - Piperidino-benzo [i, j] quinolizines a substitution de piperidino en 8 chirales antibacteriennes, procedes, compositions et methodes de traitement - Google Patents

Piperidino-benzo [i, j] quinolizines a substitution de piperidino en 8 chirales antibacteriennes, procedes, compositions et methodes de traitement Download PDF

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Publication number
WO2001085728A2
WO2001085728A2 PCT/IN2001/000100 IN0100100W WO0185728A2 WO 2001085728 A2 WO2001085728 A2 WO 2001085728A2 IN 0100100 W IN0100100 W IN 0100100W WO 0185728 A2 WO0185728 A2 WO 0185728A2
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Prior art keywords
methyl
benzo
oxo
quinolizine
fluoro
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PCT/IN2001/000100
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English (en)
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WO2001085728A3 (fr
Inventor
Noel John De Souza
Mahesh Vithalbhai Patel
Shiv Kumar Agarwal
Shrikant Vinayak Gupte
Dilip Jatashankar Upadhyay
Satish Baliram Bhawsar
Mohammad Alam Jafri
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Wockhardt Limited
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Priority claimed from US09/566,875 external-priority patent/US7247642B2/en
Application filed by Wockhardt Limited filed Critical Wockhardt Limited
Priority to AU78667/01A priority Critical patent/AU7866701A/en
Priority to EP01958373A priority patent/EP1305048A2/fr
Priority to CA002417799A priority patent/CA2417799A1/fr
Priority to PCT/IN2001/000139 priority patent/WO2002009758A2/fr
Priority to AU2001280091A priority patent/AU2001280091A1/en
Publication of WO2001085728A2 publication Critical patent/WO2001085728A2/fr
Publication of WO2001085728A3 publication Critical patent/WO2001085728A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine

Definitions

  • This invention relates to 8-(substituted piperidino)-benzo [i,j] quinolizines, to processes for their preparation and to pharmaceutical compositions comprising 8-(substituted piperidino)-benzo [i j] quinolizines.
  • These compounds and compositions possess potent activity in treating local and systemic infections, particularly infections caused by sensitive and resistant Gram-positive organisms, Gram-negative organisms, mycobacterial and nosocomial pathogens, and particularly those belonging to the staphylococcus, streptococcus and enterococcus groups. Also, disclosed are methods for treating the diseases and disorders arising from the foregoing infections in humans and animals by administering the compounds of the invention to said humans and animals.
  • the active compounds of this invention are related to and derived from the fluoroquinolone antibiotic [( ⁇ )-9-fluoro-8-(4-hydroxypiperidin-l-yl)-5-methyl-6,7-dihydro-l-oxo-lH-5H-benzo [i,j]quinolizine-2-carboxylic acid disclosed in JP Patent No. 58,90,511 and US Patent No. 4,399, 134.
  • 9-Fluoro-8-(4-hydroxypiperidin-l-yl)-5-methyl-6,7-dihydro-l-oxo-lH-5H-benzo [i,j] quinolizine-2-carboxylic acid has an asymmetric carbon atom at the 5-position thereof.
  • RS-( ⁇ )- 9-fluoro-8-(4-hydroxypiperidin-l-yl)-5-methyl-6,7-dihydro-l-oxo-lH-5H-benzo [ij] quinolizine -2-carboxylic acid comprises two optically active isomers.
  • R and S or D and L are used to denote the absolute configuration of the molecule about its chiral centre(s).
  • the prefixes (+) and (-) or d and 1 are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • optically active S-(-)-9-fluoro-8-(4- hydroxypiperidin-l-yl)-5-methyl-6,7-dihydro-l-oxo-lH-5H-benzo[i,j]quinolizine-2-carboxylic acid [ ⁇ ] 20 D -312.0 is obtained as disclosed in Chem. Pharm. Bull 44 (1996), page nos. 642-5 and Jpn. Kokai Tokyo Koho JP 63,192,753.
  • optically active R-(+)-9-fluoro-8-(4- hydroxypiperidin-l-yl)-5-methyl-6,7-dihydro-l-oxo-lH-5H-benzo[i,j]quinolizine-2-carboxylic acid, [ ⁇ ] 20 D +312.0, is obtained as disclosed in Jpn.Kokai Tokyo Koho JP 63,192,753.
  • Pharmaceutical compositions of RS-( ⁇ )-9-fluorb-8-(4-hydroxypiperidin-l-yl)-5-methyl-6,7- dihydro-l-oxo-lH-5H-benzo[i,j]quinolizine-2-carboxylic acid are disclosed in US Patent No. 4,399,134 and US Patent No. 4,552,879.
  • the compounds of the invention which are derived from S-(-)-9-fluoro-6,7-dihydro-8- (substituted piperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid have one asymmetric centre which is fixed, viz. the 5(S)-methyl substituent Additional asymmetric centres arise depending on the positions of the substituents in the 8-substituted piperidin-1-yl moiety of the title compounds of this invention.
  • the compounds may comprise a mixture of four diastereomers of S-(- )-9-fluoro-6,7-dihydro-8-(4-hydroxy-3-methylpiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j] quinolizine-2-carboxylic acid, in proportions that can range from a 100% mixture of 5S-trans isomers (4R,3R) and (4S,3S) to a 100% mixture of the 5S-cis isomers (4R,3S) and (4S,3R).
  • the two sets of cis and trans isomers are diastereomers, they can be separated on the basis of chemical properties such as solubility and crystallisation in achiral media, or by chromatography if need be, but there is no need to do so. Furthermore, the mixture of cis isomers or the mixture of trans isomers can be separated into pure optically active isomers by any one of the chiral techniques known to those skilled in the art.
  • the compounds may comprise a mixture of four diastereomers of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxy-3-methylpiperidin-l-yl)-5-methyl-l- oxo-lH,5H-benzo[i,j] quinolizine-2-carboxylic acid, in proportions that can range from a 100% mixture of 5S-trans isomers (3R,5S) and (3S,5R) to a 100% mixture of the 5S-cis isomers (3R,5S) and (3S,5R).
  • the two sets of cis and trans isomers are diastereomers, they can be separated on the basis of chemical properties such as solubility and crystallisation in achiral media, or by chromatography if need be, but there is no need to do so. Furthermore, the mixture of cis isomers or the mixture of trans isomers can be separated into pure optically active isomers by any one of the chiral techniques known to those skilled in the art.
  • Streptococci of various groups such as Group A, Group B and Niridans groups are frequent causes of respiratory and other infections in human as well as animals.
  • Streptococcus pyogenes group A streptococcus
  • group A streptococcus is one of the most common and ubiquitous human pathogens. It is responsible for the majority of cases of sore throat in pediatric patients, and it is also a causative agent of severe life-threatening infections (sepsis, necrotising faciitis, toxic shock syndrome and non-suppurative sequelae such as rheumatic fever and acute glomerulonephritis).
  • fluoroquinolone antibiotics such as ciprofloxacin, ofloxacin, pef ⁇ oxacin and lomefloxacin are only marginally active against streptococci and pneumococci.
  • fluoroquinolones such as Levofloxacin, Gatifloxacin and Moxifloxacin although having improved potency against streptococci and pneumococci, suffer from the deficiencies that then- potency against QRSA and MRSA is therapeutically inadequate.
  • novel S-(-)-9-fluoro- 6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo [i,j]quinolizine-2- carboxylic acid derivatives, salts and hydrates thereof described therein have excellent potency and potent rapid bactericidal action against staphylococci including MRSA and QRSA strains, Gram-negative pathogens E.coli, Klebsiella, Proteus, Serratia, Citrobacter and Pseudomonas, mycobacteria and nosocomial pathogens.
  • enterococcal bacteremia usually encountered with high incidence in large medical centres, is associated with high mortality. Enterococci can also cause serious urinary tract infections.
  • the attributes found for the compounds of the invention are not encompassed with the same potency and cidal action quality by S-(-)-9-fluoro-6,7- ⁇ ydro-8-(4-hydroxypiperi ⁇ n-l-yl)-5-methyl-l-oxo-lH,5H-benzo[ij] quinolizine-2-carboxylic acid itself and its salts, pseudopolymorphs, polymorphs and hydrates thereof.
  • the present invention also includes processes for the preparation of compounds of this invention and pharmaceutical compositions of the compounds of the invention.
  • the present invention furthermore includes methods for treating local and systemic infections caused by different pathogens belonging to the staphylococcus, streptococcus and enterococcus groups by administering a compound of the invention and more particularly those compounds of the invention bearing the 5S-methyl isomer of the fluoroquinolone core to said human or animal.
  • This invention relates to optically active 8-(substituted piperidino)-benzo [ij] quinolizines of the formula I.
  • X hydrogen, or X is C 1 -C 2 0 alkyl, such as straight chain or branched chain aliphatic residues such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl or their branched chain isomers; or X is aralkyl such as benzyl or X is -(CH 2 )n-CHRio-OCORn, or X is wherein R 10 is H, or CH 3 ; n is
  • Rn is C1-C20 alkyl as hereinbefore defined or substituted Ci-C ⁇ alkyl such as hydroxybutyl or aralkyl such as benzyl; orR ⁇ is
  • X is a group such as acetoxymethyl, acetoxyethyl, carbethoxymethyl, pivaloyloxymethyl or pivaloyloxyethyl group; or Xis
  • A is CH or N, and when A is CH, Z is NH or NCH 3 , and when A is N, Z is CH2, O, NH, S, or NCH 3 ; p is 0 - 2 ; q is 0 - 2, wherein X is a group such as N-methylpiperidin-4-yl, pyrrolidin-2-yl-ethyl, piperidin-2-yl-ethyl, or mo holin-2-yl-ethyl.
  • R 3 is hydrogen, or C1-C20 alkyl as hereinbefore defined, or glycosyl, or aralkyl such as benzyl, or Ci-C ⁇ alkanoyl such as acetyl, propionyl, pivaloyl, stearoyl, or nonadecanoyl or aminoalkanoyl such as amino acid residues derived from one of the 20 naturally occurring amino acids viz.
  • R3 is 1-aminocyclohexylcarbonyl or R3 is COORn wherein Rn is as hereinbefore defined or -
  • the compounds of the invention may have one or more chiral centers.
  • one optical isomer including diastereomer and enantiomer
  • another optical isomer for example by use of chiral starting materials, catalysts or solvents
  • the compounds of the invention may exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, or stereoisomers, they may be separated using known methods, such as chiral resolution, chiral chromatography and the like.
  • one optical isomer including diastereomer and enantiomer, or stereoisomer may have favorable properties over the other.
  • both optical isomers including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.
  • Prefeired salts include cationic salts include the alkali metal salts (such as sodium and potassium), alkaline earth metal salts (such as magnesium and calcium), inorganic salts, such as ammonium, substituted ammonium, choline and organic base salts from basic amines such as diethanolamine, n-methylglucamine, ethylenediamine, guanidine or heterocyclic amines such as piperidine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, morpho ⁇ ne, piperazine, N-methyl piperazine and the like or basic amino acids such as optically pure and racemic isomers of arginine, lysine, histidine, tryptophan and the like.
  • alkali metal salts such as sodium and potassium
  • alkaline earth metal salts such as magnesium and calcium
  • inorganic salts such as ammonium, substituted ammonium, choline and organic base salts from basic amines such as diethanolamine,
  • acids addition salts include, but are not limited to acetate, adipate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bitartarate, butyrate, calcium edetate, camsylate, carbonate, citrate, cyclohexanesulfamate, dodecyl sulfate, edetate, edisylate, estolate, esylate, furnarate, formate, gluceptate, gluconate, glutamate, glycollylarsanilate, glutarate, hexylresorcinate, hydrabamine, hydroxynaphthoate, hydrochloride, hydrobromide, hydroiodide, hydrogensulfate, isethionate, lactate, malate, maleate, mandelate, malonate, methanesulfonate, methylbromide, methylnitrate, methylsulphate,
  • amino acid may be selected from one of the 20 naturally occurring amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine or valine or the optically active isomers thereof or the racemic mixtures thereof or dipeptides, tripeptides and polypeptides derived from the monoaminoacid units thereof.
  • Preferred compounds of the invention are those wherein:
  • X Acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, 2-piperazinoethyl, 2- morpholinoethyl, 2-pyrrolidinoethyl, or 4-N-methyl piperidinyl;
  • Ri CH3, C2H5, n-C3H7, i-C3H7, n-C4H9, ⁇ -C4H9, CF3, CH2C6H5, CH2NH2, or F;
  • R2 H, CH3, C2H5, n-C3H7, or n-C4H9 ⁇
  • R3 H, CH3, C2H5, COCH3, or COC(CH3)3;
  • R4 H, 5-CH3, 5-C2H5, 4-CH3, 4-CF3, 4-C6H5 or an optical isomer, diastereomer or enantiomer thereof, or polymorphs and pseudopolymorphs or prodrugs thereof or pharmaceutically acceptable salts and hydrates thereof.
  • Specific compounds of the invention are:
  • Another embodiment of the invention encompasses a process to make the compounds of the invention, which comprise the following general methods.
  • This invention also includes a method for preparing S-(-)-9-fiuoro-6,7-dihydro-8 ⁇ (3- or 4- or 5- substituted-4-alkanoyloxy ⁇ iperidin- 1 -yl)-5 -methyl- 1 -oxo- 1 H, 5H-benzo [i j ]quinolizine-2- carboxylic acid comprising the steps of stirring a mixture of S-(-)-9-fluoro-6,7-dihydro-8-(3- or 4- or 5 -substituted-4-hydroxypiperidin- 1 -yl)-5-methyl- 1 -oxo- lH,5H-benzo[i,j ]quinolizine-2- carboxylic acid with an appropriate alkanoylating agent in presence of a base in the presence or absence of an organic solvent at 0°— 100°C for 0.5 - 8 hr.
  • S-(-)-9-fluoro-6,7-dihydro-8-(3- or 4- or 5-substituted-4-acetoxypiperidin-l-yl)-5-methyl-l-oxo- lH,5H-benzo[i,j]quinolizine-2-carboxylic acid was prepared by stirring a mixture of S-(-)-9- fluoro-6,7-dihydro-8-(3- or 4- or 5-substituted-4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H- benzo[i,j]quinolizine-2-carboxylic acid with acetic anhydride in presence of a base preferably pyridine or triethyl amine in the presence or absence of an organic solvent at 0° - 100°C for 0.5 - 8 hr preferably 2 hrs.
  • a base preferably pyridine or triethyl amine
  • This invention also incldudes a method for preparing alkanoyloxymethyl S-(-)-9-fluoro-6,7- dihydro-8- ⁇ trans-4-hydroxy-3-methylpiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo [ij] quinolizine-2-carboxylate comprising the steps of treating S-(-)-9-fluoro-6,7-dihydro-8-(4- hydroxy-3-methylpiperidin- 1 -yl)-5-methyl- 1 -oxo- lH,5H-benzo [ij ]quinolizine-2-carboxylic acid with halomethyl alkanoate presence of a base potassium carbonate in the presence or absence of an organic solvent at 0° - 100°C for 2 - 24 hrs.
  • Pivaloyloxymethyl S-(-)-9-fluoro-6,7-dihydro-8- ⁇ trans-4-hydroxy-3-methylpiperidin- 1 -yl)-5- methyl-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylate was prepared by treating S-(-)-9- fluoro-6,7-dihydro-8-(4-hydroxy-3-methylpiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo [ij] quinolizine-2-carboxylic acid with chloromethyl pivalate in presence of a base preferably potassium carbonate in the presence or absence of an organic solvent at 0° - 100°C preferably 50°C for 2 - 24 hr preferably 18 hr.
  • This invention also includes a method for preparing hetero cyclic amino/hetero cyclic aminoalkyl S-(-)-9-fluoro-6,7-dihydro-8- ⁇ trans-4-hydroxy-3-methylpiperidin- 1 -yl)-5 -methyl- 1 - oxo-lH,5H-benzo[ij]quinolizine-2-carboxylate comprising the steps of treating S-(-)-9-fluoro- 6,7-dihydro-8-(4-hydroxy-3-methylpiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo [ij] quinolizine-2-carboxylic acid with hydroxy heterocyclicamine/hydroxyalkyl heterocyclic amine in presence of a base in the presence of a condensing agent and in the presence or absence of an organic solvent at 50° - 100°C for 2 - 48 hr.
  • the pharmaceutically acceptable cationic salts of compounds I may be prepared by conventional methods from the corresponding acids e.g. by reaction with about one equimolar amount of a base.
  • suitable cationic salts are those of alkali metals such as sodium or potassium, alkaline earth metals such as magnesium or calcium and ammonium or organic amines such as diethanolamine or N-methylglucamine, ethylenediamine, guanidine or heterocyclic amines such as piperidine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, morpholine, piperazine, N- methyl piperazine and the like or basic amino acids such as optically pure and racemic isomers of arginine, lysine, histidine, tryptophan and the like.
  • the present invention also encompasses the process of making the intermediate amines, as illustrated in the detailed preparations that are used in the condensation with the fluoroquinolone nucleus.
  • the 3-substituted-4-hydroxy piperidine intermediates can exist as a mixture of cis and trans isomers. Each cis and trans isomer is a racemic mixture and can be resolved into optically active enantiomeric forms.
  • Each cis or trans isomer, optionally debenzylated and/or deacetylated can be resolved into their optically active enantiomers by conventional methods known to those skilled in the art of resolving racemic mixtures by fractional crystallisation of their salts with appropriate resolving agents or by chromatography or by enzymatic techniques.
  • the methods for preparation of the mixture of cis and trans isomers and their resolution into enantiomeric forms is exemplified for instance by the following example of 3-methyl-4-hydroxy piperidine l-Benzyl-4-acetoxy-3-methylpiperidine (a mixture of cis and trans isomers) was prepared according to the literature procedure [A.F.Casy and
  • the compounds of the invention can be prepared by condensing the respective 3- methyl-4-hydroxypiperidine with (O-B)-diacetoxy-[S-(-)-8,9-difluoro-5-methyl-l-oxo-lH,5H- benzo [i.,] quinolizine-carboxy] borane, as exemplified in the section on examples described later in this specification.
  • the present invention also encompasses an antiinfectrve composition for the treatment of humans and animals in need of therapy for systemic or topical infections especially resistant Gram-positive organism infections, Gram-negative organism infections, mycobacterial infections and nosocomial pathogen infections, which comprises an amount of optically pure compounds of the invention the derivatives, salts, hydrates, pseudopolymorphs and polymorphs thereof, preferably, substantially free of the compounds of the invention bearing the 5R-mehyl enantiomer of the fluoroquinolone core, said amount being sufficient to eradicate said infection.
  • the composition should provide a therapeutic dose, which is insufficient to cause the toxic effects associated with the comparable compositions comprised of compounds of the invention bearing the 5RS-isomeric mixture of the fluoroquinolone core.
  • the compounds of the invention have superior bactericidal activity against pneumococci, streptococci and enterococci of various groups. Cidal features available in such molecules add to their clinical attractiveness as it would offer clinicians a valuable treatment option to treat a broader range of infections caused by staphylococci, MRSA, MRSE, pneumococci, streptococci and enterococci in a situation such as patients allergic to ⁇ -lactam or possibility of infections due to macrolide resistant strains of streptococci, pneumococci and enterococci or MRSA/QRSA/NRE.
  • the compounds of the invention have potential not only to suppress the growth of NRE strains but also a dual advantage of reducing or curtailing vacomycin usage for the treatment of MRSA infections and thereby not creating circumstances favourable for NRE emergence.
  • the molecules of the invention also retain the other valuable features of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo- lH,5H-benzo[ij]quinolizine-2-carboxylic acid its derivatives, salts, pseudopolymorphs, polymorphs and hydrates thereof, of being bactericidal to fluoroquinolone resistant staphylococci (QRSA with resistant gyrase) and even to staphylococcal isolates possessing Nor
  • diseases which can thus be prevented, alleviated and/or cured by the formulations according to the invention are meningitis, otitis externa, otitis media; pharyngitis; pneumonia; life-threatening bacteremia, peritonitis; pyelonephritis; cystitis; endocarditis; systemic infections; bronchitis; arthritis; local infections; septic diseases.
  • enterococcal diseases are specially enterococcal bacteremia and urinary tract infections.
  • compositions are prepared according to conventional procedures used by persons skilled in the art to make stable and effective compositions.
  • an effective amount of the active compound or the active ingredient is any amount, which produces the desired results.
  • the pharmaceutical compositions may contain the active compounds of the invention, their derivatives, salts and hydrates thereof, in a form to be administered alone, but generally in a form to be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • Suitable carriers which can be used are, for example, diluents or excipients such as fillers, extenders, binders, emollients, wetting agents, disintegrants, surface active agents and lubricants which are usually employed to prepare such drugs depending on the type of dosage form. Any suitable route of administration may be employed for providing the patient with an effective dosage of the compound of the invention their derivatives, salts and hydrates thereof.
  • Dosage forms include (solutions, suspensions, etc) tablets, pills, powders, troches, dispersions, suspensions, emulsions, solutions, capsules, injectable preparations, patches, ointments, creams, lotions, shampoos and the like.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
  • Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • compositions of the present invention include compositions such as suspensions, solutions, elixirs, aerosols, and solid dosage forms.
  • Carriers as described in general above are commonly used in the case of oral solid preparations (such as powders, capsules and tablets), with the oral solid preparations being preferred over the oral liquid preparations.
  • the most preferred oral solid preparation is tablets.
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed.
  • suitable carriers include excipients such as lactose, white sugar, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, binders such as water, ethanol, prepanol, simple syrup, glucose, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and polyvinyl pyrrolidone, disintegrants such as dried starch, sodium alginate, agar powder, laminaria powder, sodium hydrogen carbonate, calcium carbonate, Tween (fatty acid ester of polyoxyethylenesorbitan), sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose, disintegration inhibitors such as white sugar, stearic acid glyceryl ester, cacao butter and hydrogenated oils, absorption promoters such as
  • the tablet if desired, can be coated, and made into sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or tablets comprising two or more layers.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a wide variety of conventional carriers known in the art can be used.
  • suitable carriers are excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oils, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaria and agar.
  • a wide variety of carriers known in the art can be used.
  • suitable carriers include polyethylene glycol, cacao butter, higher alcohols, gelatin, and semi-synthetic glycerides.
  • a second preferred method is parenterally for intramuscular, intravenous or subcutaneous administration.
  • a third preferred route of administration is topically, for which creams, ointments, shampoos, lotions, dusting powders and the like are well suited.
  • an effective amount of the compound according to this invention in a topical form 0.1% composition is to about 10% by weight of the total composition.
  • the effective amount is 1% of the total composition.
  • each tablet contains from about 200 mg to about 1500 mg of the active ingredient.
  • the tablet, cachet or capsule contains either one of three dosages, about 200 mg, about 400 mg, or about 600 mg of the active ingredient.
  • diluents customarily used in the art can be used.
  • suitable diluents are water, ethyl alcohol, polypropylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters.
  • Sodium chloride, glucose or glycerol may be incorporated into a therapeutic agent.
  • the antimicrobial pharmaceutical composition may further contain ordinary dissolving aids, buffers, pain-alleviating agents, and preservatives, and optionally coloring agents, perfumes, flavors, sweeteners, and other drugs.
  • viscous to semi-solid or solid forms comprising a carrier compatible with topical application and having a dynamic viscosity preferably greater than water.
  • suitable formulations include but are not limited to solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, aerosols, etc., which are, if desired, sterilized or mixed with auxiliary agents, e.g. preservatives, antioxidants, stabilizers, wetting agents, buffers or salts for influencing osmotic pressure, etc.
  • auxiliary agents e.g. preservatives, antioxidants, stabilizers, wetting agents, buffers or salts for influencing osmotic pressure, etc.
  • sprayable aerosol preparations wherein the active ingredient preferably in combination with a solid or liquid inert carrier material.
  • a specific embodiment of the invention is the preparation of storage stable compositions of the compounds of the invention of formula I. Such stable compositions can be advantageously made through the use of selective stabilizers. Different stabilizers are known to those skilled in the art of making pharmaceutical compositions. Of special utility for making storage stable compositions of the compound of the invention of formula L stabilizers such as disodium EDTA, tromethamine, cyclodextrins such as gamma-cyclodextrin, hydroxy-propyl-gamma- cyclodextrin have been found to be useful.
  • a specific embodiment of the invention utilises arginine as an excipient in compositions to facilitate the aqueous solubility of the compounds of the invention which comprises utilising an appropriate molar amount of arginine with a specific compound of the invention.
  • the pharmaceutical compositions contain an effective amount of the active compounds of the invention, its derivatives, salts or hydrates thereof described in this specification as hereinbefore described in admixture with a pharmaceutically acceptable carrier, diluent or excipients, and optionally other therapeutic ingredients.
  • the prophylactic or therapeutic dose of the compounds of the invention, their derivatives, salts or hydrates thereof, in the acute or chronic management of disease will vary with the severity of condition to be treated, and the route of administration. In addition, the dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of the individual patient.
  • the total daily dose range, for the compounds of the invention, the derivatives, salts or hydrates thereof, for the conditions described herein, is from about 200 mg to about 1500 mg, in single or divided doses.
  • a daily dose range should be between about 400 mg to 1200 mg, in single or divided dosage, while most preferably a daily dose range should be between about 500 mg to about 1000 mg in divided dosage.
  • intravenous administration may be a single dose or upto 3 divided doses
  • intravenous administration can include a continuous drip. It may be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient's response. The term "an amount sufficient to eradicate such infections but insufficient to cause said toxic effect" is encompassed by the above - described dosage amount and dose frequency schedule.
  • trans-4-(RS)-acetoxy-3-(RS)-methylpiperidine (4.41 g) was refmxed with aqueous NaOH (25 ml, 10%) for 5 hr, cooled and extracted with ethyl acetate (2 X 50 ml). The extract was washed with water, dried (sodium sulphate), concentrated to furnish trans-4-(RS)-hydroxy- 3-(RS)-methylpiperidine as colourless oil.
  • the resulting stirred borane complex was decomposed with aqueous NaOH solution (10 %) and hydrogen peroxide (7 ml, 30 %) respectively at 0°C over a period of 1 hr.
  • the reaction mixture was extracted with ethyl acetate (2 X 250 ml), ethyl acetate extract was washed with brine solution, dried (Na 2 SO 4 ) and concentrated to give a crude mixture of cis- and trans- 1 -benzyl-4- hydroxy-3-methylpi ⁇ eridine as oil. Yield 21 g (82 %), C 13 H ⁇ 9 NO, m/z 206 (M+l).
  • Acetic anhydride (12.54 ml, 122.0 mmole) was added dropwise to the stirred solution of the above obtained crude mixture of cis- /trans-l-benzyl-4-hydroxy-3-methylpi ⁇ eridine (21 g, 102.0 mmole) and 4-N,N-dimethylpyridine (0.25 g) in pyridine (50 ml) at 0 - 5°C.
  • the reaction mixture was stirred for 2 hr at ambient temperature and concentrated to dryness.
  • Method 1 A solution of l-benzyl-3-methylpiperidin-4-one (15.0 g, 0.073 mole) in dry tetrahydrofuran (125 ml) was added to the stirred solution of (+)-diisopinocampheyl borane (20.8 g, 0.075 mole ⁇ prepared according to the procedure described in HC.Brown, J.Org.Chem., 49 (1984), 945 ⁇ ) in dry tetrahydrofuran (125 ml) at -78°C over a period of 1 hr under nitrogen atmosphere. The stirring was continued for 2 hr at -78°C and stirring continued for 24 at ambient temperature.
  • the resulting stirred borane complex was decomposed with aqueous NaOH solution (10%) and hydrogen peroxide (10 ml, 30%) respectively at 0°C over a period of 1 hr.
  • the reaction mixture was extracted with ethyl acetate (2 X 100 ml), ethyl acetate extract was washed with brine solution, dried (Na 2 SO 4 ) and concentrated to give a mixture of cis- and trans- l-benzyl-4- hydroxy-3-methylpiperidine as oil. Yield 6.9 g (82%), C 13 H 19 NO, m/z 206 (M+l).
  • Acetic anhydride (4.08 ml, 0.04 mole) was added dropwise to the stirred solution of the obtained mixture of cis- / trans- l-benzyl-4-hydroxy-3-methylpiperidine (6.9 g, 0.033 mole) and 4-N,N- dimethylpyridine (0.05 g) in pyridine (20 ml) at 0 - 5°C.
  • the reaction mixture was stirred for 2 hr at ambient temperature and concentrated to dryness.
  • the residue thus obtained was dissolved in ethyl acetate, washed with water, dried (Na 2 SO ) and concentrated to dryness to furnish a mixture of cis- and trans-4-acetoxy-l-benzyl-3-methylpiperidine as oil.
  • Dibenzoyl cis-(-)-4S-acetoxy-3R-methylpiperidine-L-tartrate (1.8 g, 3.495 mmole) was suspended in ethyl acetate (10 ml) and basified (pH 8.5) with 10% sodium carbonate solution. Ethyl acetate layer was separated, washed with water, dried (Na 2 SO 4 ) and concentrated to dryness to furnish cis-(+)-4S-acetoxy-3R-methylpiperidine as colourless oil.
  • Cis-(-)-4R-acetoxy-3S-methylpiperidine A solution of dibenzoyl D-(+)-tartaric acid (4.19 g, 11.78 mmole) in ethyl acetate (10 ml) was added to the stirred solution of cis-4-(RS)-acetoxy-3-(SR)-methylpiperidine (3.7 g, 23.56 mole) in ethyl acetate (10 ml). The salt thus separated was filtered, washed with ethyl acetate (10 ml) and recrystallized from methanol to give dibenzoyl cis-(+)-4R-acetoxy-3S-methyl piperidine-D- tartrate.
  • trans-4-acetoxy-l-benzyl-3,5-dimethylpiperidine (9.2 g, 0.035 mole) was refluxed with a mixture of ethanol (10 ml) and aqueous 5 N NaOH (50 ml) for 24 hr, cooled, diluted with water and extracted with ethyl acetate (2 X 50 ml).
  • trans-l-benzyl-3, 5-dimethyl-4-hydroxypiperidine (7.72 g, 0.0353 mole) and 20% palladium hydroxide (1.0 g) in methanol (80 ml) was stirred at room temperature in hydrogen atmosphere (3 atm.) for 15 hr. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give trans-3, 5-dimethyl-4-hydroxypiperidine. Yield 4.54 g (100 %), m.p.
  • Cis-3. 5 -Dimethyl-4-hydroxypiperidine The obtained cis-4-acetoxy-l-benzyl-3,5-dimethylpiperidine (4.9 g, 0.0188 mole) was refluxed with a mixture of ethanol (8 ml) and aqueous 5 N NaOH (40 ml) for 24 hr, cooled, diluted with water and extracted with ethyl acetate (2 X 50 ml). The extract was washed with water, dried (sodium sulphate), concentrated to furnish cis-l-benzyl-4-hydroxy-3,5-dimethylpiperidine. Yield 4.11 g (100 %), m.p.
  • Trifiuoroacetic acid (10 ml) was added dropwise to the stirred solution of the above obtained mixture of two distereomeric l-t-butoxycarbony-3-fluoro-4-hydroxypiperidine (2.4 g, 10.95 mmole) in dichloromethane (7 ml) at 0 °C over a period of 15 min.
  • the reaction mixture was stirred at ambient temperature for 1 hr, concentrated to dryness in vacuum, methanol (2 ml) was added and again dried in vacuum.
  • the residue was dissolved in aqueous 10% NaOH solution (10 ml) and extracted with ethyl acetate (3 X 50 ml). Ethyl acetate extract was washed with water dried (Na 2 SO 4 ) and concentrated to give quantitatively 3-fluoro-4-hydroxypiperidine.
  • Ether extract was dried (Na 2 SO 4 ) and concentrated in vacuum to give l-benzyl-3-methyl-4-hydroxy-4- trifluoromethylpiperidine. Yield 5.1 g (95 %), Ci ⁇ Fs O, m/z 274 (M+l).
  • Example 3 S-r- 9-fluoro-6.7-dihydro-8-(trans-4-rRSVhvdroxy-3-(RS)-methylpiperidin-l-yl ⁇ -5-methyl-l- oxo-lH5H-benzo[ij]quinolizine-2-carboxylic acid It was prepared in a similar manner as described in example 2, where trans-4-(RS)-hydroxy-3- (RS)-methylpiperidine was used in place of 4-hydroxy-3 -methylpiperidine. Yield 0.8 g (89.6%), m.p.
  • Example 11 S-(- -9-fluoro-6.7-dihydro-8-(4-hydroxy-3-trifluoromethylpiperidin-l-yl)-5-methyl-l-oxo- lH,5H-benzo[i, j]quinolizine-2-carboxylic acid It was prepared in a similar manner as described above in Example 2, where 4-hydroxy-3- trifluoromethylpiperidine was used in place of 4-hydroxy-3 -methyl piperidine. Yield 0.15 g (58%), m.p. 130-35°C, C 2 oH 2 oF4N 2 O 4 , m/z 429 (M+l).
  • Example 12 S-(- -9-fluoro-6.7-dihydro-8-(4-hydroxy-3-trifluoromethylpiperidin-l-yl)-5-methyl-l-oxo- lH,5H-benzo[i, j]quinolizine-2-carboxylic acid It was prepared in a similar manner as described above
  • Example 13 S-(-)-9-fluoro-6.7-dihydro-8-(4-hydroxy-3-n-propylpiperidin-l-yl)-5-methyl-l-oxo-lH,5H- benzofl, j]quinolizine-2-carboxylic acid It was prepared in a similar manner as described in Example 2, where 4-hydroxy-3-n- propylpiperidine was used in place of 4-hydroxy-3-methylpiperidine. Yield 0.2 g (41 %), m.p.
  • Example 16 S-(-)-9-fluoro-6.7-rahydro-8-(4-hv ⁇ Voxy-3-isobutylpiperidin-l-yl)-5-methyl-l-oxo-lli5H- benzo[i. jlquinolizine-2-carboxylic acid It was prepared in a similar manner as described in Example 2, where 4-hydroxy-3-isobutpyl piperidine was used in place of 4-hydroxy-3-methylpiperidine. Yield 0.75 g (45 %), m.p.
  • Example 18 S-(-)-9-fluoro-6.7-dihydro-8-(3 -fluoro-4-hydroxypiperidin- 1 -yl)-5-methyl- 1 -oxo- Hi 5H- benzo[ijlquinolizine-2-carboxylic acid It was prepared in a similar manner as described in Example 2, where 3-fluoro-4-hydroxy- piperidine was used in place of 4-hydroxy-3 -methylpiperidine. Yield 0.1 g (25 %), m.p. 180 X (decompose), C19H20F2N2O4, m/z 379 (M+l).
  • Example 19 S-(-)-9-fluoro-6.7-dihydro-8-(3.3-dimethyl-4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H- benzo[ij] quinolizine-2-carboxylic acid It was prepared in a similar manner as described in Example 2, where 3,3-dimethyl-4-hydroxy piperidine was used in place of 4-hydroxy-3 -methylpiperidine. Yield 0.25g (80 %), m.p.
  • Example 22 S-(-)-9-fluoro-6.7-dihydro-8- ⁇ cis-3.5-dimethyl-4-hydroxypiperidin-l-yl)-5-methyl-l-oxo- lH,5H-benzo[ij] quinolizine-2-carboxylic acid It was prepared in a similar manner as described in Example 2, where cis-3,5-dimethyl-4- hydroxypiperidine was used in place of 4-hydroxy-3 -methylpiperidine. Yield 0.48 g (50 %), m.p.
  • Example 24 S-(-)-9-fluoro-6.7-dihydro-8-(3-ethyl-4-hydroxy-3-methylpiperidin-l-yl)-5-methyl-l-oxo- lH,5H-benzo[ij]quinolizine-2-carboxylic acid It was prepared in a similar manner as described in Example 2, where 3-ethyl-4-hydroxy-3- methyl piperidine was used in place of 4-hydroxy-3 -methylpiperidine. Yield 0.153 g (81 %), m.p.
  • Example 31 S-(-)-9-fluoro-6.7-dihydro-8- ⁇ trans-(-)-4-R-hydroxy-3-R-methylpiperidin-l-yl ⁇ -5-methyl-l-oxo- lH.5H-benzo[ij]quinolizine-2-carboxylic acid arginine salt 3.5 hydrate
  • Aqueous L-arginine solution (0.441 g, 2.54 mmole, 15 ml) was added to a stirred solution of S-(- )-9-fluoro-6,7-dihydro-8- ⁇ trans-(-)-4-R-hydroxy-3-R-methylpiperidin-l-yl ⁇ -5-methyl-l-oxo-lH, 5H-benzo[i,j]quinolizine-2-carboxylic acid (0.95 g, 2.54 mmole) in methanol (40 ml).
  • Example 36 S-(-)-9-fluoro-6 -dihydro-8-(4-acetoxy-3-methylpiperidin-l-yl)-5-methyl-l-oxo-lB5H- benzo[ij]quinolizine-2-carboxylic acid
  • Acetic anhydride (0.217 ml, 2.13 mmole) was added to a stirred solution of S-(-)-9-fluoro-6,7- dihydro-8-(4-hydroxy-3-methylpiperidin-l-yl)-5-methyl-l-oxo-lB,5H-benzo[ij] quinolizine-2- carboxylic acid (0.2 g, 0.534 mmole) in pyridine (3 ml) at 0°C.
  • Example 37 S-(-)-9-fluoro-6 -dihydro-8-(4-acetoxy-3.3-dimethylpiperidin-l-yl)-5-methyl-l-oxo-lB5H- benzo[ij]quinolizine-2-carboxylic acid It was prepared in a similar manner as described in example 36, where S-(-)-9-fluoro-6,7- dihydro-8-(4-hydroxy-3,3-dimethylpiperidin-l-yl)-5-methyl-l-oxo-lB,5H-benzo[ij] quinolizine-2-carboxylic acid was used in place of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxy-3- methylpiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid.
  • Example 38 S-(-)-9-fluoro-6.7-dihydro-8-(4-acetoxy-3 -ethylpiperidin- 1 -yl)-5-methyl- 1 -oxo- IB 5B- benzo[ij]quinolizine-2-carboxylic acid It was prepared in a similar manner as described Example 36, where S-(-)-9-fluoro-6,7-dihydro- 8-(4-hydroxy-3-ethylpiperidin-l-yl)-5-methyl-l-oxo-lB,5B-benzo[ij]quinolizine-2-carboxylic acid was used in place of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxy-3-methylpiperidin-l-yl)-5- methyl-l-oxo-lB,5B-benzo[i,j]quinolizine-2-carboxylic acid.
  • Example 39 S-(-)-9-fluoro-6, 7-dihydro-8- (4-acetoxy-3 -ethyl-3 -methylpiperidin- 1 -yl)-5-methyl- 1 -oxo- lB5B-benzo[ij]quinolizine-2-carboxylic acid It was prepared in a similar manner as described in Example 36, where S-(-)-9-fluoro-6,7- dihydro-8-(3 -ethyl-4-hydroxy-3 -methylpiperidin- 1 -yl)-5-methyl- 1-oxo- lB,5B-benzo[i j] quinolizine-2-carboxylic acid was used in place of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxy-3- methyl piperidin-l-yl)-5-methyl-l-oxo-lB,5H-benzo[i,j]quinolizine-2-carboxylic acid.
  • Example 40 S-(-)-9-fluoro-6,7-dihydro-8-(3-methyl-4-pivaloyloxypiperidin-l-yl)-5-methyl-l-oxo-lB5B- benzo[ij]quinolizine-2-carboxylic acid
  • Pivaloyl chloride (0.0128 ml, 1.06 mmole) was added to a stirred solution of S-(-)-9-fluoro-6,7- dihydro-8-(4-hydroxy-3 -methylpiperidin- 1 -yl)-5 -methyl- 1 -oxo- IH, 5H-benzo[i j] quinolizine-2- carboxylic acid (0.2 g, 0.534 mmole) in pyridine (3 ml) at 0°C.
  • Example 41 S- (-)-9-fluoro-6. 7-dihydro-8- (3-ethyl-4-pivaloyloxypiperidin-l-yl)-5-methyl-l-oxo-lB, 5B- benzo[i j] quinolizine-2-carboxylic acid It was prepared in a similar manner as described Example 40, where S-(-)-9-fluoro-6,7-dihydro- 8-(3 -ethyl-4-hydroxypiperidin- 1 -yl)-5-methyl- 1 -oxo- IB, 5B-benzo [i j]quinolizine-2-carboxylic acid was used in place of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxy-3-methylpiperidin-l-yl)-5- methyl-l-oxo-lB,5B-benzo[ij]quinolizine-2-carboxylic acid.
  • Example 43 S-(-)-9-fluoro-6.7-dihydro-8-(3-ethyl-3-methyl-4-pivaloyloxypiperidin-l-y ⁇ -5-methyl-l-oxo- lB.5B-benzo[ij]quinolizine-2-carboxylic acid It was prepared in a similar manner as described Example 40, where S-(-)-9-fluoro-6,7-dihydro-
  • Powdered anhydrous potassium carbonate (0.055 g, 0.4 mmole) was' added to a stirred solution of S-(-)-9-fluoro-6,7-dihydro-8- ⁇ trans-4-(RS)-hydroxy-3-(RS)-methylpiperidin-l-yl ⁇ -5-methyl- l-oxo-lB,5B-benzo[ij]quinolizine-2-carboxylic acid (0.15 g, 0.4 mmole) in N,N-dimethyl formamide (5 ml) at 50X and stirring was continued for 6 hr at 50X.
  • Example 45 Acetoxymethyl S-(-)-9-fluoro-6.7-dihydro-8- ⁇ trans-4-(RS)-hydroxy-3 -(RS)-methylpiperidin- 1 - yl ⁇ -5-methyl- 1 -oxo- 1 5B-benzo[i j] quinolizine-2-carboxylate It was prepared according to procedure described in Example 44, where chloro methyl acetate was used in place of chloro methyl pivalate. Yield 0.128 g (72 %), m.p 178-80°C, [ ⁇ ] D 25 - 165°C (0.1 % CBCI3 solution), C23B2 7 FN2O6, m/z 447 (M+l).
  • Example 46
  • Example 50 4- TS-methyl)- ⁇ i ⁇ eridinyl S-(-V9-fluoro-6.7-dihvdro-8-(trans-4-(RSVhvdroxy-3-(RS)-methyl piperidin-l-yl ⁇ -5-methyl-l-oxo-lB5B-benzo[ij]quinolizine-2-carboxylate It was prepared according to procedure described in example 48, where 4-hydroxy-N- methylpiperidine was used in place of 2-hydroxyethyl-N-4-morpholine.
  • Example 53 S-(- -9-fluoro-6.7-dihvdro-8-(4-hvdroxy-3 -trimethylpiperidin-l-ylV5-methyl-l-oxo-lB.5B- benzo[i j] quinolizine-2-carboxylic acid It was prepared in a similar manner as described in example 2, where 4-hydroxy-3,3,5-trimethyl piperidine was used in place of 4-hydroxy-3-methylpiperidine. Yield 0.035 g (30 %), m.p. 178- 80 X , C 22 B27FN2O 4 , m/z 403 (M+l).
  • Example 54 S-(- -9-fluoro-6.7-dihvdro-8-(4-hvdroxy-3 -trimethylpiperidin-l-ylV5-methyl-l-oxo-lB.5B- benzo[i j] quinolizine-2-carboxylic acid It was prepared in a similar
  • Example 55 S-(-)-9-fluo ⁇ o-6 -dihydro-8-(4-hyd ⁇ oxy-3 -diethyl-3-methylpiperidin-l-yl)-5-methyl-l-oxo- lB5B-benzo[ij]quinolizine-2-carboxylic acid It was prepared in a similar manner as described in example 2, where 4-hydroxy-3,5-diethyl-3- methylpiperidine was used in place of 4-hydroxy-3 -methylpiperidine. Yield 0.04 g (40 %), m.p. 180-82X , C2 4 H31FN2O , m/z 431 (M+l).
  • Microbiological and pharmacological studies can be used to determine the relative potency, and the profile of specificity of the optically pure compounds of the invention as antibacterial agents with a spectrum of activity as described in the specification above.
  • the comparative antimicrobial activity of the compounds of the invention against various microorganisms is given in Table 1.
  • the test method was in accordance with the standard
  • a typical compound of the invention is S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxy-3- methylpiperidin-l-yl)-5-methyl-l-oxo-lB,5B-benzo[i, j]quinolizine-2-carboxylic acid (mixture of cis racemate and trans racemate).

Abstract

L'invention concerne des piperidino-benzo [i,j] quinolizines dont le groupe piperidino est substitué en 8, optiquement pures, les isomères, dérivés, sels, pseudopolymorphes, polymorphes, promédicaments et hydrates de celles-ci, ainsi que des procédés permettant de préparer ces composés et des compositions pharmaceutiques comprenant ces piperidino-benzo [i,j] quinolizines à substitution de piperidino en 8, leur isomères, leurs dérivés, leurs sels, leurs pseudopolymorphes, leurs polymorphes ou leurs hydrates. Ces composés et compositions présentent une efficacité élevée pour le traitement d'infections locales ou systémiques, notamment le traitement d'infections causées par des organismes sensibles ou résistants Gram-positifs, Gram-négatifs, des mycobactéries et des pathogènes nosocomiaux, et en particulier des infections causées par des pathogènes des groupes staphylocoques, streptocoques et entérocoques. L'invention concerne en outre des méthodes permettant de traiter les pathologies et les troubles résultant des infections ci-dessus chez l'homme et chez l'animal, consistant à administrer les composés décrits aux hommes ou aux animaux concernés.
PCT/IN2001/000100 2000-05-08 2001-05-08 Piperidino-benzo [i, j] quinolizines a substitution de piperidino en 8 chirales antibacteriennes, procedes, compositions et methodes de traitement WO2001085728A2 (fr)

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AU78667/01A AU7866701A (en) 2000-05-08 2001-05-08 Antibacterial chiral 8-(substituted piperidino)-benzo (i, j) quinolizines, processes, compositions and methods of treatment
EP01958373A EP1305048A2 (fr) 2000-08-01 2001-07-31 Inhibiteurs de pompes d'efflux cellulaire de microbes
CA002417799A CA2417799A1 (fr) 2000-08-01 2001-07-31 Inhibiteurs de pompes d'efflux cellulaire de microbes
PCT/IN2001/000139 WO2002009758A2 (fr) 2000-08-01 2001-07-31 Inhibiteurs de pompes d'efflux cellulaire de microbes
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INPCT/IN00/00054 2000-05-08
PCT/IN2000/000054 WO2000068229A2 (fr) 1999-05-07 2000-05-08 Acides carboxyliques de benzoquinolizine antibacteriens optiquement purs, procedes, compositions et procedes de traitement

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US6608078B2 (en) 2000-05-08 2003-08-19 Wockhardt Limited Antibacterial chiral 8-(substituted piperidino)-benzo [i,j] quinolizines, processes, compositions and methods of treatment
US7098219B2 (en) 2000-08-01 2006-08-29 Wockhart Limited Inhibitors of cellular efflux pumps of microbes
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