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Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments Number:7,393,957 from the United States Patent and Trademark Office (PTO) owispatent

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Title: Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments

Abstract: This invention relates to new generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, to their optical isomers, diastereomers or enantiomers, as well as pharmaceutically acceptable salts, hydrates, prodrugs, polymorphs and pseudopolymorphs thereof, to their preparation, to their compositions and to their use.

Patent Number: 7,393,957 Issued on 07/01/2008 to De Souza,   et al.

Inventors: De Souza; Noel John (Mumbai, IN), Patel; Mahesh Vithalbhai (Aurangabad, IN), Deshpande; Prasad Keshav (Aurangabad, IN), Agarwal; Shiv Kumar (Cidco Aurangabad, IN), Sreenivas; Kandepu (Aurangabad, IN), Nair; Sheela Chandrasekharan (Cidco Aurangabad, IN), Chugh; Yati (Cidco Aurangabad, IN), Shukla; Milind Chintaman (Aurangabad, IN)
Assignee: Wockhardt Limited (Aurangabad, IN)
Appl. No.: 10/945,504
Filed: September 20, 2004

Related U.S. Patent Documents
Application NumberFiling DatePatent NumberIssue Date
10318367Dec., 20026878713
10128996Apr., 20026964966
60341165Dec., 2001
60286291Apr., 2001
Foreign Application Priority Data
Apr 24, 2002 [WO] PCT/IN02/00111

Current U.S. Class: 546/156
Current International Class: C07D 215/38 (20060101); A61K 31/47 (20060101)
Field of Search: 546/156 514/312

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Primary Examiner: Seaman; D. Margaret
Attorney, Agent or Firm: Ladas & Parry LLP
Parent Case Text


This is a divisional of application Ser. No. 10/318,367 filed on Dec. 12, 2002 now U.S. Pat. No. 6,878,713, which is a CIP of application No. 10/128,996 filed Apr. 23, 2002 now U.S. Pat. No. 6,964,966, which claims the benefit of U.S. Provisional Applications Nos. 60/286,291 filed Apr. 25, 2001 and 60/341,165 filed Dec. 13, 2001.
Claims


The invention claimed is:

1. A compound selected from the group consisting of: a) crystalline polymorphic form of (.+-.)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimeth- yl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid hydrochloride-Polymorph A1, said polymorph characterized by the following analytical data: Differential Scanning Colorimetry (DSC): Endotherm at 252.33.degree. C. (onset at 246.19.degree. C.) exotherm at 205.0 (onset at 200.68.degree. C.) and 259.00.degree. C. (onset at 255.83.degree. C.); X-ray powder diffraction; (2.theta. values): 11.16.+-.0.2, 12.06.+-.0.2, 13.74.+-.0.2, 15.06.+-.0.2, 16.46.+-.0.2, 18.60.+-.0.2, 21.72.+-.0.2, 22.44.+-.0.2, 23.72.+-.0.2, 24.66.+-.0.2, 25.90.+-.0.2, 30.08.+-.0.2, 32.58.+-.0.2; and IR values (cm.sup.-1): 3442, 2957, 1728, 1623, 1512, 1460, 1318, 1277, 1184, 1056, 938; b) crystalline polymorphic form of (.+-.)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimeth- yl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid hydrochloride-Polymorph A2, said polymorph characterized by the following analytical data: Differential Scanning Colorimetry (DSC): Endotherm at 144.66 (onset 115.25) and 254.83.degree. C. (onset at 251.00.degree. C.), exotherm at 211.33 (onset at 208.35.degree. C.) and 259.66.degree. C. (onset at 257.18.degree. C.); X-ray powder diffraction: (2.theta. values): 8.58.+-.0.2, 13.08.+-.0.2, 14.9.+-.0.2, 16.72.+-.0.2, 1834.+-.0.2, 22.68.+-.0.2, 25.38.+-.0.2, 25.92.+-.0.2, 27.6.+-.0.2, 28.18.+-.0.2; and IR values (cm.sup.-1): 3476, 3332, 2880, 1712, 1619, 1528, 1448, 1329, 1273, 1234, 1180, 1066, 1035, 989; c) crystalline polymorphic form of (-)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-- 1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid hydrocloride-Polymorph A1, said polymorph characterized by the following analytical data: Differential Scanning Colorimetry (DSC): Endotherm at 126.5.degree. C. (onset 93.94.degree. C.) and 252.50.degree. C. (onset at 245.14.degree. C.), exotherm at 202.83 (onset at 200.02.degree. C.) and 257.17.degree. C. (onset at 255.66.degree. C.). X-ray powder diffraction: (2.theta. values): 11.30.+-.0.2, 12.06.+-.0.2, 13.64.+-.0.2, 14.4.+-.0.2, 15.16.+-.0.2, 16.48.+-.0.2, 18.52.+-.0.2, 21.48.+-.0.2, 22.72.+-.0.2, 23.94.+-.0.2, 24.76.+-.0.2, 26.42.+-.0.2, 30.24.+-.0,2, 30.60.+-.0.2; and IR values (cm.sup.-1): 3363, 2957, 1727, 1625, 1512, 1461, 1377, 1323, 1289, 1183, 1056, 942; d) crystalline polymorphic form of (-)-1-cyclopropyl-6-fluoro-1,4-dihydro -8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carbo- xylic acid hydrochloride-Polymorph A2, said polymorph characterized by the following analytical data: Differential Scanning Colorimetry (DSC): Endotherm at 123.5 (onset 101.7) and 201,83.degree. C. (onset at 189.84.degree. C.), 244.83.degree. C. (onset at 230.73.degree. C.) exotherm at 210.5 (onset at 206.6.degree. C.) and 253.17.degree. C. (onset at 249.50.degree. C.); and X-ray powder diffraction (2.theta. values): 6.70.+-.0.2, 7.06.+-.0.2, 7.72.+-.0.2, 8.24.+-.0.2, 12.40.+-.0.2, 13.66.+-.0.2, 14.96.+-.0.2, 18.62.+-.0.2, 19.40.+-.0.2, 23.24.+-.0.2, 24.90.+-.0.2, 27.86.+-.0.2; e) crystalline polymorphic form of (+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimeth- yl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid hydrochloride-Polymorph A1, said polymorph characterized by the following analytical data: Differential Scanning Colorimetry (DSC): Endotherm at 131.5.degree. C. (onset 92.32.degree. C.) and 253.33.degree. C. (onset at 248.280.degree. C.), exotherm at 204.0.degree. C. (onset at 200.8.degree. C.) and 258.0.degree. C. (onset at 256.83.degree. C.); X-ray powder diffraction: (2.theta. values): 11.34.+-.0.2, 12.08.+-.0.2, 13.68.+-.0.2, 14.44.+-.0.2, 15.18.+-.0.2, 16.50.+-.0.2, 18.56.+-.0.2, 21.50.+-.0.2, 22.76.+-.0.2, 23.98.+-.0.2, 24.78.+-.0.2, 26.24.+-.0.2, 30.28.+-.0.2, 30.64.+-.0.2, 32.52.+-.0.2; and IR values (cm.sup.-1): 3653, 3369, 2960, 1727, 1627, 1511, 1465, 1377, 1331, 1279, 1183, 1058, 940; and f) crystalline polymorphic form of (+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3 -dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid hydrochloride-Polymorph A2, said polymorph characterized by the following analytical data; Differential Scanning Colorimetry (DSC): Endotherm at 136.66.degree. C. (onset 101.0.degree. C.) and 256.83.degree. C. (onset at 251.92.degree. C.) exotherm at 201.50.degree. C. (onset at 198.60.degree. C.) and 261.16.degree. C. (onset at 259.83.degree. C.); X-ray powder diffraction: (2.theta. values): 7.00.+-.0.2, 7.66.+-.0.2, 8.00.+-.0.2, 12.32.+-.0.2, 12.72.+-.0.2, 13.58.+-.0.2, 14.88.+-.0.2, 15.36.+-.0.2, 16.08.+-.0.2, 18.38.+-.0.2, 19.36.+-.0.2, 20.58.+-.0.2, 23.18.+-.0.2, 25.40.+-.0.2, 26.72.+-.0.2, 72.82.+-.0.2, 29.80.+-.0.2, 30.60.+-.0.2, 32.28.+-.0.2, 36.94.+-.0; and IR values (cm.sup.-1): 3401, 2845, 2632, 1711, 1621, 1537, 1458, 1378, 1321, 1275, 1207, 1061, 989, 806.
Description


FIELD OF THE INVENTION

The present invention relates to novel antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives and pharmaceutically acceptable salts thereof. Methods of preparation of the compounds of the invention, compositions of compounds of the invention and their use are also described.

BACKGROUND OF THE INVENTION

The fluoroquinolone group of antibiotics available since the early 1960s are valuable as antibacterial agents. There have been synthesized, developed and marketed quinolone carboxylic acid derivatives having various chemical structures. Nalidixic acid, the progenitor of the series, was used primarily as a urinary tract antiseptic. Later development provided agents with broader activity, increased potency against selected pathogens and improved pharmacokinetic and pharmacodynamic properties.

From a medical utility viewpoint, the quinolones are classified as first-, second-, and third-generation compounds (Gootz T D et al, Chemistry & Mechanism of Action of the Quinolone Antibacterials. In Andriole VT ed. The Quinolones, San Francisco, Academic Press, 1998, 28-80). First-generation compounds like piromidic acid and pipemidic acid provided coverage for gram negative Enterobacteriaceae. The second-generation compounds are divided into those with enhanced but predominant gram-negative activity, against pathogens like Escherischia coli and Pseudomonas aeruginosa, and those with balanced broad-spectrum activity (norfloxacin, pefloxacin, enoxacin, fleroxacin, lomefloxacin, ciprofloxacin, ofloxacin, rufloxacin, nadifloxacin). Norfloxacin, ofloxacin and ciprofloxacin have, therefore, been used mainly for treatment of diseases including urinary tract infections, gastrointestinal infections, sexually transmitted diseases and the like. Third-generation drugs (levofloxacin, pazufloxacin, sparfloxacin, clinafloxacin, sitafloxacin, trovafloxacin, tosufloxacin, temafloxacin, grepafloxacin, balofloxacin, moxifloxacin, gatifloxacin) are those with enhanced activity against gram-positive cocci (notably clinafloxacin, sitafloxacin, trovafloxacin for Streptococcus pneumoniae) and, for essentially all the third-generation quinolones, activity also against gram-negative Haemophilus influenzae and Legionella pneumophila, and against anaerobes and atypical pathogens (Ball P, The Quinolone. History and Overview. In Andriole VT ed. The Quinolones, San Francisco, Academic Press, 1998, 1-28). Levofloxacin, moxifloxacin and gatifloxacin have, therefore, found use for community-acquired infections such as those of the upper and lower respiratory tract infections (RTI) like pneumonia, sinusitis and pharyngitis, and for skin and soft tissue infections (SSI) caused by gram-positive strains of staphylococci, pneumococci, streptococci and enterococci.

The improvements seen in most of the third-generation drugs in current use are generally attributed to their uniqueness in inhibiting the bacterial targets, DNA gyrase and topoisomerase IV. Three categories of quinolone inhibition have been suggested. Type I quinolones (norfloxacin, enoxacin, fleroxacin, ciprofloxacin, lomefloxacin, trovafloxacin, grepafloxacin, ofloxacin and levofloxacin) indicated a preference for topoisomerase IV inhibition. Type II quinolones (nadifloxacin and sparfloxacin) indicated a preference for DNA gyrase inhibition. Type III quinolones to which some of the third-generation quinolones belong (gatifloxacin, pazufloxacin, moxifloxacin and clinafloxacin) display, however, a dual-targeting property, and equally influence DNA gyrase inhibition and topoisomerase IV inhibition. (Takei M et al, Antimicrobial Agents and Chemotherapy, 2000; 45:3544-49). DNA gyrase is the primary target in bacteria, and thus is explained the weaker activity in gram-positive bacteria of the preferred topoisomerase IV-targeting second-generation quinolones like norfloxacin, ciprofloxacin, ofloxacin, and levofloxacin. The unusual activity of nadifloxacin described by others, and further significantly elaborated for S-(-)-nadifloxacin by us (cf: our pending U.S. application Ser. Nos. 09/566,875, 09/850,669, WO 00/68229 and WO 01/85728), specially against gram positive S. aureus, is now better understood in view of its being shown to be DNA-gyrase targeting, which is the first such report for a quinolone in S. aureus (Oizumi N et al, J. Infect. Chemother, 2001; 7: 191-194). Some, but not all, third generation quinolones being primarily topoisomerase IV-targeting in gram-positive staphylococci, and DNA gyrase-targeting in gram-positive S. pneumoniae, explains the advantages provided by the dual-targeting third-generation quinolones like moxifloxacin and gatifloxacin.

The evolution of quinolones from first-generation to second-generation to third-generation compounds has also been guided by structure-activity relationship studies. It has been determined by those in the art that certain structures with specific sites on the quinolone ring functionalised have distinct advantages over others. Structure-activity relationships of the quinolones have been the subject of detailed study for more than a decade (Asahina Y et al, Recent Advances in Structure Activity Relationships in New Quinolones, Prog. Drug Res., 1992, 38, 57-106) As a result of these studies, it has been determined by those in the art that certain structures, with specific sites on the quinolone ring functionalised, have distinct advantages over others. The structural feature that remains constant throughout the drug class is the bicyclic aromatic core consisting of 2 fused 6-membered rings. This core can contain a carbon at the 8-position, yielding a true quinolone, or a nitrogen which provides a ring system technically termed a naphthyridone, or an additional fused ring across the N-1 and C-8 positions yielding tricyclic heterocycles, such as pyridobenzoxazines and benzoquinolizidines.

In the context of the current invention, the nature of the amine group at the 7-position takes on special relevance. It is notable that in the cited second-generation quinolones the piperazine ring remains relatively constant and undisturbed as a 7-substituent, except for alkylation on the distal nitrogen, or less frequently on the ring carbons. In the third-generation quinolones, the continuing trend of use of a C-7 cyclic amino group is also almost universal. The presence of a second amine, in addition to the nitrogen bonded to C-7 of the quinolone nucleus has been found to be important. However, amongst these new quinolones, too, the frequent employment of mainly a C-7 piperazino or pyrrolidino variant is to be noted, but with only one example of a C-7 piperidino substituent.

Only two of the above-cited quinolones, the second-generation nadifloxacin and the third-generation balofloxacin, have a C-7 piperidino substituent. Nadifloxacin with a hydroxypiperidine substituent at the C-7 position is notable for its being the sole marketed modern quinolone without a distal amino group, but is merely a topical agent. Balofloxacin has an unusual 3-methylaminopiperidino substituent, which is, however, said to be the contributing element to its lower activity against Enterobacteriaceae and Mycoplasma pneumoniae. Among the recent fluoroquinolones which have been introduced commercially are moxifloxacin and gatifloxacin. Both these antibacterial agents have an 8-methoxy substituent in the fluoroquinolone core. As 7-substituents in the core, there is for moxifloxacin a bicyclic pyrollidine as the amino moiety, and for gatifloxacin a substituted pyrollidine as the amino moiety. A more recently described olamufloxacin, which has been shown to have activity in murine models of system infections and urinary tract infections, has an 8-methyl substituent in its fluoroquinolone core in which the C-7 substituent is also a substituted pyrollidine. No commercially introduced fluoroquinolone or one that has commercial potential is known in which a piperidino group, substituted or unsubstituted, is introduced at the 7-position of the quinolone structure also having a methoxy group or methyl group at the 8-position.

Since the 1960s, in an enormous worldwide effort, well more than 10,000 structurally-related fluoroquinolone agents have been described in many hundreds of patents and journal articles. Despite the understanding of the need of a cyclic amine at the C-7 position, the prior art appears to have discounted the value of having a piperidino moiety, unsubstituted or substituted, as a C-7 substituent. For instance, a 1992 review article (Asahina Y et al, vide infra) indicates the comparative low prior art interest in C-7 piperidino substituents, wherein there are only 21 piperidino moieties cited in comparison to 188 piperazino moieties, and 74 pyrollidino moieties out of a total of 578 C-7 amino moieties.

Just as there are structure-activity relationships, there are also structure-side effect relationships that have been determined. Side effects and adverse events related to N-1, C-5, C-8 variants of the quinolone core are generally those that contribute to increase in theophylline interactions, clastogenicity, phototoxicity, hepatotoxicity, cardiotoxicity, arthropathy and tendonitis. Notable is the pattern of (a) the N-1 cyclopropyl and C-8 fluorine, chlorine or methoxy substituted quinolone reported to show heightened cytotoxicity (Domagala J M, J. Antimicrob. Chemother., 1994; 33: 655-706), which can be modulated, however, by further structural manipulation (Gootz T D et al, vide infra), (b) the presence of halogen atoms (fluorine or chlorine) at the C-8 position (sparfloxacin, clinafloxacin) enhancing the tendency to induce photosensitivity, (c) the N-1 difluorophenyl substituent in trovafloxacin and temafloxacin associated with hepatotoxicity and hemolytic anemia and (d) the C-5 methyl (grepafloxacin) and C-8 methoxy substituent (moxifloxacin, gatifloxacin) contributing to prolongation of the QT interval and the development of a form of ventricular tachycardia known as torsade de pointes.

As important, if not more so, than the above-mentioned substituents of the fluoroquinolone core is the amine substituent at the C-7 site. C-7 pyrrolidines tend to show increased cytotoxicity over piperazino substituents, with the combination of 3-substituted pyrrolidines at C-7 and halogens at C-8 providing the most cytotoxic compounds.(Suto N J et al, J Med Chem 1992; 35:4745-50; Mundell L A et al, Clin Infect Dis, 2001; 32(Suppl): S74) In the second most frequently encountered form of quinolone toxicity, namely adverse events involving the CNS, it is the unsubstituted piperazines which correlate best with the degree of GABA-binding inhibition, closely followed by the pyrrolidinyl quinolones.

The incremental improvements that have resulted in moving from first-to second-and third-generation quinolones are a consequence of the understanding of the modulation brought about by a combination of a fluoroquinolone core moiety with a C-7 amino substituent. Although certain substituents can impart improvements, whether on one hand in antibacterial potency or on the other in a minimised potential for adverse effect, it is the overall characteristics of each molecule derived from the interaction of all the substituents with each other and with the specific nucleus employed that brings newer gains. Furthermore, characteristics in addition to those of activity and side effects are central to the development of improved human theraputants such as selective molecular mechanisms of action, broader antibacterial coverage to include anaerobes, atypical and resistant pathogens, improved pharmacokinetics and pharmacodynamics, and devoid of class-identified toxicity features.

It is, thus, clear that the art has focussed on identifying new quinolones to progress from earlier generation compounds to the next generation compounds. Despite the progress made, the full promise of the quinolones has not yet been exploited.

Examples of bacterial infections resistant to antibiotic therapy have been reported in the past; they are now a significant threat to public health in the developed world. The development of microbial resistance is of increasing concern in medical science. "Resistance" can be defined as existence of organisms, within a population of a given microbial species, that are less susceptible to the action of a given antimicrobial agent. This resistance is of particular concern in environments such as hospitals and nursing homes, where relatively high rates of infection and intense use of antibacterials are common. Recent international conferences in 2002 on infectious diseases organised by the Centres for Disease Control and Prevention, USA, World Health Organisation and other groups have highlighted emerging infectious diseases, in which the word "emerging" refers to newly discovered infectious diseases or old ones that have rebounded, turned up in new places, or become drug resistant.

The mechanisms of bacterial resistance to fluoroquinolones is generally believed to function by two principal categories, both resulting from chromosomal mutations (D C Hooper, Drug Resis Updat 1999; 2:38-55). One category is the alterations in drug target enzymes. Fluoroquinolone resistance mutations generally occurring stepwise have been localized to specific regions of the parC and parE genes (grlA and grlB in S. aureus) encoding topoisomerase IV, and the gyrA and gyrB genes encoding DNA gyrase. This clustering of mutations has defined the quinolone resistance determining regions (QRDRs) of these genes that are in proximity to the apparent enzyme active site and are thought likely to constitute a domain at which quinolones interact directly with the enzyme-DNA complex. The manner by which the emergence of resistant mutants can be prevented is receiving attention, but is as yet insufficiently understood and continues to be speculative. Studies with the C-8 methoxy fluoroquinolones bearing a C-7 unsubstituted or 3-alkyl substituted piperazino substituent provide support to the concept that attack of both gyrase and topoisomerase IV equally would be ideal. In cases where single point mutation already exists, then a quinolone that would preferably potently inhibit the primary more essential target, whether gyrase or topoisomerase IV, would be better to prevent the resistance (Zhao et al, Proc. Natl. Acad. Sc. 1997; 94: 13991-13996). No similar study, to our knowledge, is available for compounds with a C-7 piperidino substituent, whether unsubstituted or substituted, in any quinolone core. The second category for bacterial resistance to develop is alterations that limit permeation of drug to the target. In S. aureus the elevated expression of the norA gene is responsible for efflux-mediated resistance to quinolones. Factors influencing the decrease in activity of quinolones in efflux-mediated resistant mutants of S. aureus have been suggested not to be hydrophobicity of the whole quinolone molecule, but rather the bulkiness at the C-7 substituent, and bulkiness and hydrophobicity at the C-8 substituent (Takenouchi T et al, 1996; 40:1835-42). Only two of forty quinolones included in this analysis bore a C-7 amino-substituted piperidino substituent. The effect of efflux was more pronounced with the compound bearing the 4-amino substituted piperidino substituent, its MIC value being 8 times more with an efflux pump-bearing strain than with a non-efflux pump-bearing strain, as compared with a 2 times more value for the 3-amino substituted piperidino substituent. Surprisingly, unlike this precedent, the present invention shows that appropriately substituted 4-amino piperidine substituents on different fluoroquinolone cores display potent efflux pump inhibitory/uptake facilitatory properties.

Stereochemistry-activity relationships are also of importance in considerations regarding the advancement of quinolones that can exist as isomers. For instance, S-(-)-levofloxacin, as an example of a compound in which the chiral centre is close to the quinolone nucleus, is from 8-128 fold as potent as the R-(+)-enantiomer. Earlier work and our pending U.S. patent application Ser. Nos. 09/566,875 and 09/850,669, WO 00/68229 and WO 01/85728 on nadifloxacin, which like levofloxacin has a relatively similar chiral centre, also disclose the superior profile of S-(-)-nadifloxacin over the R-(+)-enantiomer. Chiral centres at C-7 that are at some distance from the quinolone nucleus are said to contribute less significantly to biological activity. However, the relative orientation of the methyl groups on the C-7 piperazine of sparfloxacin is important for bacterial enzymes versus mammalian enzyme selectivity. Sparfloxacin, bearing methyl groups with a cis-stereochemistry essential for its antibacterial activity, displays dramatic differential effects on mammalian topoisomerase-II with no or less interaction with the mammalian enzyme, in contrast to the trans-isomer which does interact with the mammalian enzyme, while however retaining its antibacterial activity (Gootz T D et al., vide infra). Unlike this prior art, the present invention once again surprisingly shows that stereochemical differences of substituents on the C-7 piperidino moiety, while dramatically affecting antibacterial activity, do not significantly influence cytotoxicity of mammalian cell lines, irrespective of whether the differences are enantiomeric or diastereomeric.

Both of the third-generation fluoroquinolone market introductions of moxifloxacin and gatifloxacin with improved activity against gram-positive pathogens, have an 8-methoxy substituent in the core fluoroquinolone nucleus. Even their coverage, however, of staphylococci is considered partial, as they possess weak antibacterial activity against most of the methicillin-resistant strains. Moreover, moxifloxacin and gatifloxacin have failed to show therapeutically relevant potency for recent widely reported ciprofloxacin-resistant and levofloxacin-resistant strains of pneumococci. In addition, the potency of newer fluoroquinolones such as moxifloxacin against gram-negative pathogenic bacteria such as E. coli and P. aeruginosa has considerably diminished.

Therefore, there is a need for newer orally effective fluoroquinolone antibacterials with superior potency not only against methicillin-resistant, macrolide-resistant and fluoroquinolone-resistant strains, viz. multidrug-resistant strains of gram-positive staphylococci and pneumococci, but also against gram-negative strains with potency comparable to ciprofloxacin and levofloxacin, and against the now so called emerging infectious diseases. Accordingly, numerous studies are being continuously conducted to address the disadvantages of the fluoroquinolones having an 8-methoxy substituent or 8-alkyl substituent or other 8-substituents to make them considerably more potent against bacterial pathogens, to increase their spectrum coverage to include the insufficiently addressed pathogens like mycobacteria, anaerobes, and atypicals, to optimise their action towards bacterial molecular targets, to reduce their efflux or facilitate their cellular uptake, and to improve their oral bioavailability and toxicity profile.

Some 1,4-dihydroquinolone related moieties bearing an 8-methoxy substituent are known in the art to have antimicrobial activity and are described in the following references:

U.S. Pat. No. 4,638,067 to Culbertson, et al. on Jan. 20, 1987; U.S. Pat. No. 4,665,079 to Culbertson, et al. on May 12, 1987; European Patent Application 0230295A2 of Kyorin Pharmaceutical Co. pub. Jul. 29, 1987; European Patent Application 0241206A2 of Ube Ind pub. Oct. 14, 1987; U.S. Pat. No. 4,822,801 to Domagala et al. on Apr. 18, 1989; U.S. Pat. No. 5,097,032 to Domagala et al. on Mar. 17, 1992; U.S. Pat. No. 5,051,509 to Nagano et al. on Sep. 24, 1991; European Patent Application 0541086A1 of Kaken Pharmaceutical Co. published May 12, 1993; European Patent Application 0572259A1 of Ube Ind. Published Dec. 1, 1993; WO 1993-JP 1925 of Japan Tobacco, Inc., dated Dec. 28, 1993; European Patent Specification 0342675B1 of Chugai Seiyaku Kabushiki Kaisha published Jan. 25, 1995; Japanese Patent 6-145167 published May 24, 1994; U.S. Pat. No. 5,607,942 of Clive Petersen et al. on Mar. 4, 1997; PCT Patent Application No. PCT/KR94/00005 to Korea Research Institute of Chemical Technology published Jul. 21, 1994; U.S. Pat. No. 5,677,316 to Hideki et al. on Oct. 14, 1997; World Patent WO98/58923A1 to Hagano et al. on Jun. 23, 1998; U.S. Pat. No. 4,777,175 to Warner-Lambert Co. on Oct. 11, 1988; European Patent Application 0919553A1 of Daiichi Pharma Co. published Jun. 2, 1999; U.S. Pat. No. 6,121,285 to Takemura et al., on Sep. 19, 2000; U.S. Pat. No. 6,329,391 B1 to Benoit Ledoussel et al. On Dec. 11, 2001.

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