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Title:
(S)-BENZOQUINOLIZINE CARBOXYLIC ACIDS AND THEIR USE AS ANTIBACTERIAL AGENTS
Document Type and Number:
WIPO Patent Application WO/2000/068229
Kind Code:
A2
Abstract:
The present invention relates to S-(-)-optically pure benzoquinolizine carboxylic acid of formula I, and their pharmaceutically acceptable salts, derivatives, pseudopolymorphs, and hydrates, substantially free of their R-(+)-isomers, to processes for their preparation and to pharmaceutical compositions comprising an active compound of the invention. The compounds have excellent antibacterial activity. The compounds and compositions can be used for the treatment of local and systemic bacterial infections, diseases and disorders caused by antibiotic-sensitive and antibiotic-resistant microbial strains, without the concomitant liability of adverse effects associated with the racemic mixture of the active compound of the invention.

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Inventors:
PATEL M V (IN)
GUPTE S V (IN)
CHUGH Y (IN)
SAOJI D G (IN)
AGARWAL S K (IN)
DE SOUZA N J (IN)
KHORAKIWALA H F (IN)
Application Number:
PCT/IN2000/000054
Publication Date:
November 16, 2000
Filing Date:
May 08, 2000
Export Citation:
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Assignee:
PATEL M V (IN)
GUPTE S V (IN)
CHUGH Y (IN)
SAOJI D G (IN)
AGARWAL S K (IN)
SOUZA N J DE (IN)
KHORAKIWALA H F (IN)
International Classes:
A61K31/4745; C07C279/14; C07D455/04; (IPC1-7): C07D455/00
Other References:
DATABASE WPI Week 198838 Derwent Publications Ltd., London, GB; AN 1988-266538 XP002131774 & JP 63 192753 A (OTSUKA PHARM CO LTD), 10 August 1988 (1988-08-10) cited in the application
DATABASE WPI Week 199404 Derwent Publications Ltd., London, GB; AN 1994-031789 XP002131775 & JP 05 339238 A (OTSUKA PHARM CO LTD), 10 June 1992 (1992-06-10)
HASHIMOTO, K. ET AL: "A practical synthesis of (S)-(-)-nadifloxacin: Novel acid-catalyzed racemization of tetrahydroquinaldine derivative" CHEM. PHARM. BULL., vol. 44, no. 4, 1996, pages 642-645, XP000877125 cited in the application
TAKAHASHI, N. ET AL: "Reduction of in vitro clastogenicity induced by the mixture of optical isomers of nadifloxacin during storage" ARZNEIMITTEL-FORSCHUNG, vol. 45, no. 2, 1995, pages 195-197, XP000877120
MORITA, S. ET AL: "An efficient synthesis of a key intermediate towards (S)-(-)-nadifloxacin" TETRAHEDRON ASYMMETRY, vol. 6 , no. 1, 1995, pages 245-254, XP004048518
KIDO, M. ET AL: "Crystal structures of nadifloxacin anhydride and its hemihydrate" CHEM. PHARM. BULL., vol. 42, no. 4, 1994, pages 872-876, XP000960588 cited in the application
MORITA, S. ET AL: "Synthesis and antibacterial activity of the metabolites of 9-fluoro-6,7-dihydro-8(4-hydroxy-1-piperid yl)-5-methyl-1-oxo-1H,5H-benzo(i,j)quinoli zine-2-carboxylic acid (OPC-7251)" CHEM. PHARM. BULL., vol. 38, no. 7, 1990, pages 2027-2029, XP000877122
ISHIKAWA, H. ET AL: "Studies on antibacterial agents. I. Synthesis of substituted 6,7-dihydro-1-oxo-1H,5H-benzo(i,j)-quinoli zine-2-carboxylic acids" CHEM. PHARM. BULL., vol. 37, no. 8, 1989, pages 2103-2108, XP000877246
NISHIJIMA, S. ET AL: "Activiy of eight fluoroquinolones against both methicillin-susceptible and -resistant Staphylococcus aureus isolated from skin infections" THE JOURNAL OF DERMATOLOGY, vol. 22, no. 2, 1995, pages 153-155, XP000884341
NISHIJIMA, S. ET AL: "Sensitivity of Staphylococcus aureus, isolated from skin infections in 1994, to 19 antimicrobial agents" THE JOURNAL OF INTERNATIOAL MEDICAL RESEARCH, vol. 23, no. 5, 1995, pages 328-334, XP000884323
NISHIJIMA, S. ET AL: "Activity of nadifloxacin against methicilllin resistant Staphylococcus aureus isolated from skin infections: Comparative study with seven other fluoroquinolones" THE JOURNAL OF INTERNATIONAL MEDICAL RESEARCH, vol. 24, no. 1, 1996, pages 12-16, XP000884325
DATABASE WPI Week 198327 Derwent Publications Ltd., London, GB; AN 1983-702951 XP002131776 & JP 58 090511 A (OTSUKA PHARM CO LTD), 30 May 1983 (1983-05-30)
Attorney, Agent or Firm:
De Souza N. J. (D-4 MIDC Are, Chikalthana Aurangabad 0, IN)
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Claims:
CLAIMS:
1. A S ()optically pure benzoquinolizine carboxylic acid, its derivatives, its pharmaceutically acceptable salts, derivatives, pseudopolymorphs, polymorphs or hydrates thereof of formula I, Formula I Wherein X is OR,, wherein R1 is hydrogen, a pharmaceutically acceptable cation, aluminum, ammonium or substituted ammonium salts, choline, an organic amine, a heterocyclic amines, a basic amino acid; or Ri is ClC6 alkyl ; or Ri is (CH2) nCHR4OOCR^, wherein R4=H, CH3; n=03 and RC2H5, C (CH3) 3; isorR1 wherein A=CH or N, and when A=CH, Z=NH or NCH3, and when A=N, Z = CH, O, N, S, NCH3; p=02 ; and q = 02; X is NHR2, wherein R2 is hydrogen or NHRz is the residue of one of the 20 naturally occurring amino acids or the optically active isomers thereof, or the racemic mixtures thereof; y denotes an integer from 0 to 3 and any fractional numbers therein depending on the moles of acid added to the basic molecule; z denotes moles of water ; HA represents an acid of an acid addition salts. R3 is hydrogen, ClC6 alkyl, glycosyl, aralkyl, or ClC6 alkanoyl, or aminoalkanoyl or R3 is an ester of gluconic acid, a phosphoric acid derivative, or a sulphuric acid derivative; substantially free of their R (+)isomers.
2. The compound of claim 1 wherein the pharmaceutically acceptable cation is selected from lithium, sodium, potassium, magnesium or calcium.
3. The compound of formula I as defined in claim 1 wherein the basic amino acid is an optically pure or mixture of racemic isomers of arginine, lysine, histidine or tryptophan.
4. The compound of formula I as defined in claim 1 wherein z is 0,0.2,0.25,0.5,0.75,1, 2 or 3.
5. The compound of formula I as defined in claim 1 selected from S ()9fluoro6, 7dihydro8 (4hydroxypiperidin1ylE5methyl1oXolH, 5Hbenzo [i,j]quinolizine2carboxylicacid; S()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5methyloxo1H,5Hbenzo lijlquinolizine2carboxylic acid 0.2 H20; S()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5methyloxo1H,5Hbenzo [ijiquinolizine2carboxylic acid 0.5 H20. S()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5methyt1oxolH, SHbenzo li, jlquinolizine2carboxylic acid 0.75 H20. S ()9fluoro6, 7dihydro8 (4hydroxypiperidin1yl)5methyl1oxolH, SH benzo [i,j]quinolizine2carboxylic acid, sodium salt. S()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5methyl1oxo1H,5H benzo [i,j]quinolizine2carboxylic acid, sodium salt monohydrate. S ()9fluoro6, 7dihydro8 (4hydroxypiperidin1yt)5methyl1oxolH, SH benzo [i,j]quinolizine2carboxylic acid, potassium salt monohydrate. S()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5methyl1oxo1H,5H benzo [i, jlquinolizine2carboxylic acid, arginine salt S ()9fluoro6, 7dihydro8(4hydroxypiperidin1yl)5methyl1oxolH, SH benzo [i,j]quinolizine2carboxylic acid, arginine salt 0.25 H20. S()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5methyl1oxo1H,5H benzo [i, jlquinolizine2carboxylic acid, arginine salt 0.75 H20. S()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5methyl1oxo1H,5H benzo[i,j]quinolizine2carboxylic acid, lysine salt monohydrate. S ()9fluoro6, 7dihydro8 (4hydroxypiperidin1yt)5methyt1oxolH, SH benzo [i, jlquinolizine2carboxylic acid, histidine salt 0.2 H2O. S ()9fluoro6, 7dihydro8 (4hydroxypiperidin1yt)5methyl1oxolH, SH benzo [i,j]quinolizine2carboxylic acid, hydroyethyl pyrrolidine salt. S()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5methyl1oxo1H,5H benzo [i,j]quinolizine2carboxylic acid, diethanolamine salt. S ()9fluoro6, 7dihydro8 (4hydroxypiperidin1yl)5methyl1oxo1H, 5H benzo [i, j] quinolizine2carboxylic acid, choline salt and its hydrates. <BR> <BR> <P>Carboxymethyl S ()9fluoro6, 7dihydro8 (4hydroxypiperidin1yl)5methyt1 oxolH, 5Hbenzo [iJlquinolizine2carboxylate sodium salt. AcetoxymethylS()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5methyl1 oxo1H,5Hbenzo[i,j]quinolizine2carboxylic. PropionoxymethylS()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5methyl1 oxolH, 5Hbenzo [ij] quinolizine2carboxylate. PivaloyloxyS()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5methyl1 oxo1H,5Hbenzo[i,j]quinolizine2carboxylic. PivaloyloxyethylS()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5methyl1 <BR> <BR> oxolH, SHbenzo [i, jlquinolizine2carboxylate.<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>Nmethylpiperidin4yl S ()9fluoro6, 7dihydro8 (4hydroxy piperidin1yl)5 methyl1oxo1H,5Hbenzo[i,j]quinolizine2carboxylic. Pyrrolidin2ylethyl S ()9fluoro6, 7dihydro8 (4hydroxy piperidin1yl)5 methyl1oxo1H,5Hbenzo[i,j]quinolizine2carboxylic. Piperidin2ylethylS()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5methyl loxolH, SHbenzo [i, jlquinolizine2carboxylate. Morpholin2ylethylS()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5 <BR> <BR> methylloxolH, SHbenzo [ij] quinolizine2carboxylate.<BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>9fluoro8 (4hydroxypiperidin1yl)5 (S} methyl6, 7dihydro1oxolH, SHbenzo [i quinolizine2 [2 (S)amino1,5pentanedioic acid] carboxamide, disodium salt. 9fluoro8{4hydroxypiperidin1yl}5(S)methyl6,7dihydro1oxo1H,5H carboxamidebenzo[i,j]quinolizine2[2(S)amino3imidazolylpropionicacid] hydrochloride. S()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5methyl1oxo1H,5H benzo[i,j]quinolizine2carboxylicacid. S()9fluoro6,7dihydro8(4[ßDtetraacetylglucopyranosyl)oxy]piperidin1yl) 5methyl1oxo1 H, SHbenzoli, j] quinolizine2carboylic acid. S()9fluoro6,7dihydro8(4[ßDtetraacetylglucopyranosyl)oxy]piperidin1yl)5methyl1 oxo1H,5Hbenzo[i,j]quinolizine2carboxylicacid. S()9nuoro6,7dihydro8(4acetoxypiperidin1yl)5methyl1oxolH, SH benzo[i,j]quinolizine2carboxylicacid. S()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5methyl1oxo1H,5H benzo [ijlquinolizine2carboxylic acid. S()9fluoro8[4(phosphonoxy)1piperidin1yl)5methyl1oxo1H,5Hbenzo [i,j]quinolizine2carboxylicacid. 8{4[2(S)Aminopropionyloxy]piperidin1yl}9fluoro5(S)methyl6,7dihydro1 oxo1H,5Hbenzo[i,j]quinolizine2carboxylicacid.
6. 8{4 [2 (S)Aminopropionyloxy] piperidin1yl}9fluoro5 (S)methyl6, 7dihydrol oxolH, 5Hbenzo[i,j]quinolizine2carboxylic acid, hydrochloride. 8{4[2(R)Aminopropionyloxy]piperidin1yl}9fluoro5(S)methyl6,7dihydro1 <BR> <BR> oxo1H,5Hbenzoli, j] quinolizine2carboxylic acid.<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>8 {4 [2 (R)Aminopropionyloxy] piperidin1yl}9fluoro5 (S)methyl6, 7dihydrol acetate.oxo1H,5Hbenzo[i,j]quinolizine2carboxylicacid, 8{4[2(RS)Aminopropionyloxy]piperidin1yl}9fluoro5(S)methyl6,7dihydro1 oxo1H,5Hbenzo[i,j]quinolizine2carboxylicacid. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>8 {4 [ (2S)ammopropionyI (2S)ammopropionytoxy] piperidinlyI}9fIuoro5 (S) methyl6,7dihydro1oxo1H,5Hbenzo[i,j]quinolizine2carboxylicacid hydrochloride. 8{4[(2R)Aminopropionyloxy(2R)aminopropionyloxy]piperidin1yl}9fluoro5(S) methyl6,7dihydro1oxo1H,5Hbenzo[i,j]quinolizine2carboxylicacid. 8{4[(2S)Aminopropionyloxy(2R)aminopropionyloxy]piperidin1yl}9fluoro5(S) methyl6,7dihydroloxolH, 5Hbenzo[i,j]quinolizine2carboxylic acid hydrochloride. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>814 [ (2R)Aminopropionoyl (2R)aminopropionyloxyl piperidin1yi)9fluoro5 (S) methyl6,7dihydroloxolH, 5Hbenzo[i,j]quinolizine2carboxylic acid acetate. 8{4[(2S)Methylaminopropionyloxy]piperidin1yl}9fluoro5(S)methyl6,7 dihydro1oxo1H,5Hbenzo[i,j]quinolizine2carboxylicacid. 814 [ (2S)Methylaminopropionyloxyl piperidin1yll9fluoro5 (S)methyl6,7 andhydrochloride.dihydro1oxo1H,5Hbenzo[i,j]quinolizine2carboxylicacid 8{4[2(S)amino3carboxypropionyloxy]piperidin1yl}9fluoro5(S)methyl 6,7dihydroloxolH, 5Hbenzo[i,j]quinolizine2carboxylic acid hydrochloride. 8{4[2(S)amino3phenylpropionyloxy]piperidin1yl}9fluoro5(S)methyl hydrochloride.6,7dihydro1oxo1H,5Hbenzo[i,j]quinolizine2carboxylicacid 8{4[2(S)amino3phenylpropionyloxy]piperidin1yl}9fluoro5(S)methyl 6,7dihydroloxolH, SHbenzoli, j] quinolizine2carboylic acid hydrochloride. 8{4[2(S)amino3phenylpropionyloxy]piperidin1yl}9fluoro5(S)methyl 6,7dihydroloxolH, SHbenzop, j] quinolizine2carboylic acid acetate. 8{4[(2S)Amino3methylbutanoyloxy]piperidin1yl}9fluoro5(S)methyl6,7 dihydro1oxo1H,5Hbenzo[i,j]quinolizine2carboxylicacid. 8{4[(2S)Amino3methylbutanoyloxy]piperidin1yl}9fluoro5(S)methyl6,7 dihydro 1oxo1H, 5Hbenzo [i, j] quinolizine2carboxyGc acid and hydrochloride.
7. 8{4l2 (S)Amino4methylpentanoyloy] piperidin1yl}9fluoro5 (S)methyl6,7 dihydro1oxo1H,5Hbenzo[i,j]quinolizine2carboxylicacid.
8. 8{4l2 (S)Amino4methylpentanoyloy] piperidin1yl}9fluoro5 (S)methyl6,7 dihydroloxolH, SHbenzoli, j] quinolizine2carboylic acid, hydrochloride. 8{4[(2R)Amino4methylbutanoyloxy]piperidin1yl}9fluoro5(S)methyl6,7 dihydro1oxo1H,5Hbenzo[i,j]quinolizine2carboxylicacid. 8{4[(2R)Amino4methylbutanoyloxy]piperidin1yl}9fluoro5(S)methyl6,7 andhydrochloride.dihydro1oxo1H,5Hbenzo[i,j]quinolizine2carboxylicacid 8 {4 [2 (S), 6Diaminohexanoyloy] piperidinlyl}9fluoro5 (S)methyl6,7dihydro loxolH, SHbenzoli, j] quinolizine2carboxylic acid. 8{412 (S), 6Diaminohexanoyloxy] piperidin1yl}9fluoro5 (S)methyl6,7dihydro dihydrochloride.1oxo1H,5Hbenzo[i,j]quinolizine2carboxylicacid, 8{4[(2S)Amino5nitroguanidinobutanoyloxy]piperidin1yl}9fluoro5(S) methyl6,7 dihydro1oxo1H, SHbenzoli, j] quinolizine2carboylic acid. 8{4[(2S)Amino5nitroguanidinobutanoyloxy]piperidin1yl}9fluoro5(S) methyl6,7 dihydroloxolH, SHbenzo [i, j] quinolizine2carboxylic acid and hydrochloride. 8{4[(2S)Amino5guanidinobutanoyloxy]piperidin1yl}9fluoro5(S)methyl6,7 dihydro1oxo1H,5Hbenzo[i,j]quinolizine2carboxylicacid. 8{4[(2S)Amino5guanidinobutanoyloxy]piperidin1yl}9fluoro5(S)methyl6,7 dihydro1oxo1H, SHbenzoli, j] quinolizine2carboylic acid and hydrochloride. 8{4[(2S)Amino5nitroguanidinobutanoyl(2S)amino5nitroguanidino butanoyloy] piperidin1yl}9fluoro5 (S)methyl6, 7dihydro1oxolH, 5H benzo [ij] quinolizine2carboxylic acid.
9. 8{4 [ (2S)Amino5nitroguanidinobutanoyl (2S)amino5nitroguanidino butanoyloxy] piperidin1yl}9fluoro5(S)methyl6,71oxo1H,5H benzoli, j] quinolizine2carboylic acid and hydrochloride. 8{4[(2S)Amino5guanidinobutanoyl(2S)amino5guanidinobutanoyloxy] piperidin1yl}9fluoro5(S)methyl6,7dihydro1oxo1H,5Hbenzo[i,j]quinolizine 2carboxyUc acid. 8{4[(2S)Amino5guanidinobutanoyl(2S)amino5guanidinobutanoyloxy] piperidin1yl}9fluoro5(S)methyl6,7dihydro1oxo1H,5Hbenzo[i,j]quinolizine 2carboylic acid and hydrochloride.
10. A compound of claim 5 selected from S()9fluoro6, 7dihydro8(4hydroxypiperidin1ylE5methyl1oxolH,()9fluoro6, 7dihydro8(4hydroxypiperidin1ylE5methyl1oxolH, 5Hbenzo [i,j]quinolizine2carboxylic acid 0.2 hydrate; S()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5methyl1oxo1H,5H benzoli, j] quinolizine2carboylic acid, sodium salt monohydrate; 8{4[2(R)Aminopropionyloxy]piperidin1yl}9fluoro5(S)methyl6,7dihydro1 oxolH, 5Hbenzop, j] quinolizine2carboxylic acid, acetate; 8{4[2(S)Aminopropionyloxy]piperidin1yl}9fluoro5(S)methyl6,7dihydro1 oxo1H, 5Hbenzoli, j] quinolizine2carboylic acid, hydrochloride; S()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5methyl1oxo1H,5H benzoli, j] quinolizine2carboylic acid, arginine salt; S()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5methyl1oxo1H,5H benzoli, j] quinolizine2carboxylic acid, arginine salt 0.25 H2O ; or S ()9fluoro6, 7dihydro8 (4hydroxypiperidin1yl)5methyl1oxolH, SH benzoli, j] quinolizine2carboylic acid, arginine salt. 0.75 H20.
11. S()9fluoro6,7dihydro8(4hydroxypiperidin1yl)5methyl1oxo1H,5Hbenzo [i, j] quinolizine2carboylic acid 0.2 H2O, wherein the moisture content varies from 0.9% to 1.1 %.
12. A process for the preparation of the S ()9Fluoro8 (4hydroxypiperidin1yl)5 acid0.2H2Omethyl6,7dihydro1oxo1H,5Hbenzo[i,j]quinolizine2carboxylic which comprises dissolving S ()9Fluoro8 (4hydroxypiperidin1yl)5methyl6,7 dihydro1oxo1H, 5Hbenzo [ij] quinolizine2carboxylic acid in a minimum volume of organic solvent, at an elevated temperature, adding an amount of water sufficient to bring about crystallisation after cooling in high yields, filtering and drying the separated crystals at temperatures up to 4050°C for 36 hours, in vacuo upto 50 mm of Hg to a constant weight.
13. A process for the preparation of the S ()9Fluoro8 (4hydroxypiperidin1yl)5 methyl6,7dihydro1oxolH, 5Hbenzo[i,j] quinolizine2carboxylic acid 0.5 hydrate which comprises dissolving S ()9Fluoro8 (4hydroxypiperidin1yl}5methyl6,7 dihydro1oxo1H, 5Hbenzo[i,j]quinolizine2carboxylic acid in a minimum volume of organic solvent at reflux temperature, adding an amount of water at ambient temperature, sufficient to bring about crystallisation after cooling in high yields, filtering and drying the separated crystals at temperatures up to < 40°C for 36 hours 10. A process for the preparation of the S 9Fluoro8(4hydroypiperidin1yl)5 methyl6,7dihydro1oxolH, 5Hbenzoli, j] quinolizine2carboxylic acid 0.
14. 75 hydrate which comprises suspending S ()9Fluoro8(4hydroxypiperidin1yl} 5methyl6, 7 dihydroloxolH, 5Hbenzo [i, j] quinolizine2carboxylic acid in water, formulating into slurry by stirring with an organic solvent at 5 °C for 12 hours, filtering and drying the product at temperatures <40°C for 36 hours.
15. A method for treating bacterial infections, mycobacterial infections or nosocomial pathogen infections in humans and animals, which comprises administering to a human or an animal in need of such antiinfective therapy an amount of a compound of the formula I, as defined in claim 1 or a pharmaceutically acceptable salt, derivative, hydrate, pseudopolymorph or polymorph thereof, substantially free of its R (+)enantiomer said amount being sufficient to eradicate said infections.
16. Formula I.
17. The method of claim 11 wherein, the compound of formula I, or a pharmaceutically acceptable derivative, salt, pseudopolymorph, polymorph or hydrate thereof is administered by intravenous infusion, transdermal delivery, orally or topically.
18. The method of claim 11 wherein, the amount administered is from about 200 mg to about 1500 mg per day.
19. The method of claim 11 wherein, the amount of the compound of formula I or a pharmaceutically acceptable derivative, pseudopolymorph, polymorph, salt or hydrate thereof is greater than approximately 90 % by weight of the total weight of S()isomer.
20. The method of claim 11 wherein, the amount of said compound of formula I or a pharmaceutically acceptable derivative, polymorph, pseudopolymorph, salt or hydrate thereof, substantially free of its R (+)enantiomer, is administered together with a pharmaceutically acceptable carrier.
21. An antiinfective composition for the treatment of a human or animal in need of therapy for a systemic or topical antibacterial infection, specially against resistant Grampositive organism infections, Gramnegative organism infections, mycobacterial infections or nosocomial pathogen infections, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable derivative, salt, pseudopolymorph, polymorph or hydrate thereof, substantially free of its R (+)enantiomer.
22. A composition according to claim 16 comprising: % w/v S ()9fluoro8 (4hydroxypiperidin1yl) 5methyl6,7dihydroloxolH, 5Hbenzo [i, j] Upto 10; quinolizine2carboxylic acid or an optically pure compound of the invention of formula L Iarginine 0.110; Sodium citrate 03.5; Sodium hydroxide to adjust pH between 8.09.9 q. s; Disodium edetate 00.5; and Water for injection q. s. to 100.
Description:
INTERNATIONALSEARCHREPORT Intern. alApplication PCT/IN00/00054 C.(Continuation)DOCUMENTSCONSIDEREDTOBERELEVANT Categorv o CnatiOn ofdocument,withindication,whereappropriate,ottherelevantpass agesRelevanttoclaimNo. XHASHIMOTO,K.ETAL:"Apractical1,4,5 synthesisof(S)- (-)-nadifloxacin:Novel acid-catalyzedracemizationof tetrahydroquinaldine derivative" CHEM.PHARM.BULL., vol.44,no.4,1996,pages642-645, XP000877125 citedintheapplication thewholedocument Y11-16 XTAKAHASHI,N.ETAL:"Reductionofin1,4,5 vitroclastogenicityinducedbythe mixtureofopticalisomersofnadifloxacin duringstorage" ARZNEIMITTEL-FORSCHUNG, vol.45,no.2,1995,pages195-197, XP000877120 thewholedocument XMORITA,S.ETAL:"Anefficientsynthesis1,4,5 ofakeyintermediatetowards (S)- (-)-nadifloxacin" TETRAHEDRONASYMMETRY, vol.6,no.1,1995,pages245-254, XP004048518 Y11-16 page245,firstparagraph,line6-7 AKIDO,M.ETAL:"Crystalstructuresof1,4-6,9, nadifloxacinanhydrideandits11-16 hemihydrate" CHEM.PHARM.BULL., vol.42,no.4,1994,pages872-876, XP000960588 citedintheapplication thewholedocument AMORITA,S.ETAL:"Synthesisand1,5,6, antibacterialactivityofthemetabolites11-16 of 9-fluoro-6,7-dihydro-8(4-hydroxy-1-piperid yl)-5-methyl-1-oxo-lH,5H-benzo(i,j)quinoli zine-2-carboxylicacid(OPC-7251)" CHEM.PHARM.BULL., vol.38,no.7,1990,pages2027-2029, XP000877122 thewholedocument especiallycompound4 1 1 INTERNATIONALSEARCHREPORT Internal ApplicationNo PCT/IN00/00054 C.(Continuation)DOCUMENTSCONSIDEREDTOBERELEVANT CategoryCitationofdocument,withindication,whereappropriate,o ftherelevantpassagesRelevanttoclaimNo. AISHIKAWA,H.ETAL:"Studieson11-16 antibacterialagents.I.Synthesisof substituted 6,7-dihydro-1-oxo-lH, 5H-benzo(i,j)-quinoli zine-2-carboxylicacids" CHEM.PHARM.BULL., vol.37,no.8,1989,pages2103-2108, XP000877246 thewholedocument especiallypage2105,TableI,compounds 34,35,36 YNISHIJIMA,S.ETAL:"Activiyofeight11-16 fluoroquinolonesagainstboth methicillin-susceptibleand-resistant Staphylococcusaureusisolatedfromskin infections" THEJOURNALOFDERMATOLOGY, vol.22,no.2,1995,pages153-155, XP000884341 thewholedocument YNISHIJIMA,S.ETAL:"Sensitivityof11-16 Staphylococcusaureus,isolatedfromskin infections in1994,to19antimicrobial agents" THEJOURNALOFINTERNATIOALMEDICAL RESEARCH, vol.23,no.5,1995,pages328-334, XP000884323 thewholedocument YNISHIJIMA,S.ETAL:"Activityof11-16 nadifloxacinagainstmethicilllin resistantStaphylococcusaureusisolated fromskininfections:Comparativestudy withsevenotherfluoroquinolones" THEJOURNALOFINTERNATIONALMEDICAL RESEARCH, vol.24,no.1,1996,pages12-16, XP000884325 thewholedocument ADATABASEWPI11-16 Week198327 DerwentPublicationsLtd.,London,GB; AN1983-702951 XP002131776 &JP58090511A(OTSUKAPHARMCOLTD), 30May1983(1983-05-30) abstract 1 International Application No. PCT/IN 00 b0054 FURTHERINFORMATIONCONTINUEDFROMPCT/ISA/210 ContinuationofBox1.2 Presentclaims-4and11-17relatetoaratherelevatednumberof possiblecompounds.SupportwithinthemeaningofArticle6PCTand disclosurewithinthemeaningofArticle5PCTistobefound,however, foronlyaverysmallproportionofthecompoundsclaimed.Inthepresen t case,theclaimssolacksupport,andtheapplicationsolacks disclosure,thatameaningfulsearchoverthewholeoftheclaimedscop e isimpossible.Consequently,thesearchhasbeencarriedoutforthose partsoftheclaimswhichappeartobesupportedanddisclosed,namely thosepartsrelatingtothecompoundsspecificallynamedinclaims5-1 0 andtheexampleswithdueregardtothegeneralideaunderlyingthe application. SincetheclaimsaredirectedexclusivelytopureS- (-) benzoquinolizine carboxylicacidsitisnotknownwhatismeantbyclaim14,whichrefers toanamountofthecompoundofformulaIdefinedas "........ approximately90%byweightofthetotalweightofthe S- (-)-isomer." Furthermore,atpage10,ofthedescriptioninthelast line,oneoftheobjectsoftheinvention isstatedastoprovide compositionscontainingRS- (+-)-nadifloxacin(racaemicnadifloxacin)for userelatedtothetreatmentofinfections.Thisdiscrepancybetweent he claimsandthedescriptionleadstoalackofclarity(Article6PCT). Forsearchpurposesthesubject-matteroftheapplicationhasbeentak en tobeS- (-)-benzoquinolizinecompoundsandtheiruserelatedtothe treatmentofinfections. Theapplicant'sattentionisdrawntothefactthatclaims,orpartsof claims,relatingtoinventionsinrespectofwhichnointernational searchreporthasbeenestablishedneednotbethesubjectofan internationalpreliminaryexamination(Rule66.1(e)PCT).Theappli cant isadvisedthattheEPOpolicywhenactingasanInternational PreliminaryExaminingAuthorityisnormallynottocarryouta preliminaryexaminationonmatterwhichhasnotbeensearched.Thisis thecaseirrespectiveofwhetherornottheclaimsareamendedfollowin g receiptofthesearchreportorduringanyChapterIIprocedure. INTERNATIONALSEARCHREPORT lnterni al ApplicationNo Information on patent family members PCT/IN00/00054 PatentdocumentPublicationPatentfamilyPublication citedinsearchreportdatemember(s)date JP63192753A10-08-1988NONE JP5339238A21-12-1993NONE JP58090511A30-05-1983JP1041127B04-09-1989 JP1558409C16-05-1990



 
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