Antimicrobial quinolones, their compositions and uses

Details Antimicrobial quinolones, their compositions and uses Antimicrobial quinolones, their compositions and uses

2001-12-14

2003-11-11

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S156000

Reexamination Certificate

active

06645981

ABSTRACT:

FIELD OF THE INVENTION
The subject invention relates to novel antimicrobial compounds, their compositions and their uses.
BACKGROUND
The chemical and medical literature describes compounds that are said to be antimicrobial, i.e., capable of destroying or suppressing the growth or reproduction of microorganisms, such as bacteria. For example, such antibacterials and other antimicrobials are described in
Antibiotics, Chemotherapeutics and Antibacterial Agents for Disease Control
(M. Grayson, editor, 1982), and E. Gale et al.,
The Molecular Basis of Antibiotic Action
2d edition (1981).
The mechanism of action of these antibacterials vary. However, they are generally believed to function in one or more of the following ways: by inhibiting cell wall synthesis or repair; by altering cell wall permeability; by inhibiting protein synthesis; or by inhibiting synthesis of nucleic acids. For example, beta-lactam antibacterials act through inhibiting the essential penicillin binding proteins (PBPs) in bacteria, which are responsible for cell wall synthesis. As another example, quinolones act, at least in part, by inhibiting synthesis of DNA, thus preventing the cell from replicating.
The pharmacological characteristics of antimicrobials, and their suitability for any given clinical use, vary. For example, the classes of antimicrobials (and members within a class) may vary in 1) their relative efficacy against different types of microorganisms, 2) their susceptibility to development of microbial resistance and 3) their pharmacological characteristics, such as their bioavailability, and biodistribution. Accordingly, selection of an appropriate antibacterial (or other antimicrobial) in a given clinical situation requires analysis of many factors, including the type of organism involved, the desired method of administration, the location of the infection to be treated and other considerations. there is a continuing need for broad spectrum antimicrobials, which are effective against resistant microbes.
Some 1,4-dihydroquinolone, naphthyridine or related heterocyclic moieties are known in the art to have antimicrobial activity and are described in the following references: R. Albrecht,
Prog. Drug Research,
Vol. 21, p. 9 (1977); J. Wolfson et al., “The Fluoroquinolones: Structures, Mechanisms of Action and Resistance, and Spectra of Activity In Vitro”,
Antimicrob. Agents and Chemother.,
Vol. 28, p. 581 (1985); G. Klopman et al.,
Antimicrob. Agents and Chemother.,
Vol. 31, p. 1831 (1987); M. P. Wentland et al.,
Ann. Rep. Med. Chem.,
Vol. 20, p. 145 (1986); J. B. Cornett et al.,
Ann. Rep. Med. Chem.,
Vol. 21, p. 139 (1986); P. B. Fernandes et al.,
Ann. Rep. Med. Chem.,
Vol. 22, p. 117 (1987); A. Koga, et al., “Structure-Activity Relationships of Antibacterial 6,7- and 7,8-Disubstituted 1-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxylic Acids”,
J. Med. Chem.,
Vol. 23, pp. 1358-1363 (1980); J. M. Domagala et al.,
J. Med. Chem.,
Vol. 31, p. 991 (1988); T. Rosen et al.,
J. Med. Chem.,
Vol. 31, p. 1586 (1988); T. Rosen et al.,
J. Med. Chem.,
Vol. 31, p. 1598 (1988); B. Ledoussal et al., “Non 6-Fluoro Substituted Quinolone Antibacterials: Structure and Activity”,
J. Med Chem.,
Vol. 35, p. 198-200 (1992); J. M. Domagala et al., “Quinolone Antibacterials Containing the New 7-[3-(1-Aminoethyl)-1-pyrrolidinyl] Side Chain: The Effects of the 1-Aminoethyl Moiety and Its Stereochemical Configurations on Potency and in Vivo Efficacy”,
J. Med. Chem.,
Vol. 36, pp. 871-882 (1993); Hagen et al., “Synthesis and Antibacterial Activity of New Quinolones Containing a 7-[3-(1-Amino-1-methylethyl)-1-pyrrolidinyl] Moiety. Gram Positive Agents with Excellent Oral Activity and Low Side-Effect Potential”,
J. Med. Chem.
Vol. 37, pp. 733-738 (1994); V. Cecchetti et al., “Studies on 6-Aminoquinolines: Synthesis and Antibacterial Evaluation of 6-Amino-8-methylquinolones”,
J. Med. Chem.,
Vol. 39, pp. 436-445 (1996); V. Cecchetti et al., “Potent 6-Desfluoro-8-methylquinolones as New Lead Compounds in Antibacterial Chemotherapy”,
J. Med. Chem.,
Vol. 39, pp. 4952-4957 (1996); Hong et al., “Novel 5-Amino-6-methylquinolone Antibacterials: a New Class of Non-6-fluoroquinolones”,
Bioorg. of Med. Chem. Let.,
Vol. 7, pp. 1875-1878 (1997); U.S. Pat. No. 4,844,902 to Grohe on Jul. 4, 1989; U.S. Pat. No. 5,072,001 to Hagen & Suto on Dec. 10, 1991; U.S. Pat. No. 5,328,908 to Demuth & White on Jul. 12, 1994; U.S. Pat. No. 5,457,104 to Bartel et al. on Oct. 10, 1995; U.S. Pat. No. 5,556,979 to Philipps et al. on Sep. 17, 1996; European Patent Appl. 572,259 of Ube Ind. pub. Dec. 1, 1993; European Patent Appl. 775,702 of Toyama Chem. Co. pub. May 28, 1997; Japanese Patent Pub. 62/255,482 of Kyorin Pharm. Co. pub. Mar. 1, 1995.
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 (perhaps as a result of the intense use of antibacterials over extended periods of time) 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. See, e.g., W. Sanders, Jr. et al., “Inducible Betalactamases: Clinical and Epidemiologic Implications for Use of Newer Cephalosporins”,
Reviews of Infectious Diseases,
p. 830 (1988).
Pathogenic bacteria are known to acquire resistance via several distinct mechanisms including inactivation of the antibiotic by bacterial enzymes (e.g., b-lactamases hydrolyzing penicillin and cephalosporins); removal of the antibiotic using efflux pumps; modification of the target of the antibiotic via mutation and genetic recombination (e.g., penicillin-resistance in
Neiserria gonorrhoeae
); and acquisition of a readily transferable gene from an external source to create a resistant target (e.g., methicillin-resistance in
Staphylococcus aureus
). There are certain Gram positive pathogens, such as vancomycin-resistant
Enterococcus faecium,
which are resistant to virtually all commercially available antibiotics.
Hence existing antibacterials have limited capacity in overcoming the threat of resistance. Thus it would be advantageous to provide quinolones with useful properties that can be used against resistant microbes.
SUMMARY OF THE INVENTION
Applicants have found a novel series of quinolones and related compounds that are effective against resistant microbes, and provide significant activity advantages over the art. In particular, the invention relates to compounds having a structure according to Formula (I)
wherein:
(A)
(1) A
1
is selected from —N— and —C(R
8
)—, where R
8
is selected from hydrogen, halo, lower alkoxy, lower alkylthio, lower alkyl, lower alkene and lower alkyne;
(2)
(a) X is selected from —C— and —N—, where (i) if X is —C—, a is a double bond and b is a single bond, and (ii) if X is —N—, a is a single bond and b is a double bond; and
(b) Y is selected from —N(R
1
)— and —C(R
1
)—;
(c) provided that Y is N(R
1
) only if X is —C— and Y is —C(R
1
)— only if X is —N—;
(3) R
1
is selected from C
3
to about C
6
cycloalkyl, C
4
to about C
6
heterocycloalkyl, lower alkyl, lower alkene, a 6-membered aryl and a 6-membered heteroaryl;
(4) R
2
is hydrogen;
(5) R
3
is selected from hydrogen and hydroxy;
(6) R
5
is selected from hydrogen, hydroxy, amino, halo, lower alkyl, lower alkene and lower alkoxy;
(7) R
6
is selected from fluoro and chloro;
(8) R
7
is —Q—C(R
11
)(R
11′
)(R
11″
), where Q is selected from —S—, —O— and —C(R
12
)(R
12
)—, where R
12
and R
12
are each independently selected from hydrogen and fluoro; where R
11
, R
11′
and R
11″
are each independently selected from hydrogen, hydroxy and halo; and where R
11
and R
12
may also bot

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