7-Substituted quinazolin-2,4-diones useful as antibacterial...

Details 7-Substituted quinazolin-2,4-diones useful as antibacterial... 7-Substituted quinazolin-2,4-diones useful as antibacterial...

2001-10-04

2004-11-30

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S279000, C514S258100

Reexamination Certificate

active

06825199

ABSTRACT:

BACKGROUND OF THE INVENTION
Antibiotic resistance is a worldwide problem (
J. Med. Chem
., 1996;39:3853) with catastrophic potential (
Southern Med. J
., 1995;88:797). In 1995, the American Society of Microbiology Task Force issued a report defining the resistance problem and calling for new antibacterial agents with novel structures or mechanisms to offer alternatives to existing therapeutic choices.
The quinolone antibacterials as exemplified by ciprofloxacin 1 represent a significant addition to the therapeutic options currently available. The quinolones are potent, inhibit gram positive and gram negative bacteria, and may be administered orally or IV. The quinolones also have several significant side effects (
J. Antimicrob. Chemother
., 1994;33:685), and significant resistance has been frequently noted (Gootz,
Medicinal Research
, 1996;Rev. 16:433).
The quinolones have a distinct structure activity relationship which has been defined by several thousands of analogs prepared over the last 30 years (
Progress in Drug Research
, Editor S. Mitsuhashi, 1992;38:11-147). In the quinolone SAR, it is well-established that the N
1
group with the C
3
-carboxyl and the C
4
carbonyl are essential for activity and that any substituents at C
2
detract from activity (
J. Antimicrob. Chemother
., 1994;33:685 and Gootz, supra., 1996). It is also well-established that R
6
is ideally fluorine, and that R
7
is a nitrogen containing heterocycle. R
1
is ideally a small alkyl, cycloalkyl, or a phenyl group.
The quinolones inhibit bacterial growth by inhibition of DNA gyrase and Topoisomerase IV (Gootz, supra., 1996). The gyrase interaction appears to rely on the N
1
—C
4
-carbonyl-C
3
-carboxyl relationship.
Attempts to design novel quinolone mimics have focused on the N
1
—C
4
-carbonyl-C
3
-carboxyl relationship. Compounds of type 3 were designed to keep an all planar relationship and to have the NH of the isothiazole ring be as acidic as the quinolone CO
2
H (
Chu, Drugs Exptl. Clin. Res
., 1990;16:215). While maintaining excellent quinolone activity, these compounds also showed antitumor and mammalian topoisomerase activity (
Drugs of the Future
, 1992;17:1101) which is undesired in an antibacterial agent.
Several publications (U.S. Pat. No. 5,283,248
; J. Med. Chem
., 1992;35:1358
; Antimicrob. Agents Chemother
., 1995;39:163) cite compounds of type 4 as having antibacterial activity and inhibition of DNA gyrase. In compounds 4, the relationship of the N
1
to the C
4
carbonyl has been skewed. Compounds of type 4 were also ineffective against bacteria that were quinolone resistant.
Compounds of type 5 have also been revealed as quinolone mimics (JP 4,091,090 March 1992; Interscience Conference on Antimicrobial Agents and Chemotherapy 1991, Abstract 1494). These agents were reported to possess antibacterial and gyrase activity. While the ideal N
1
—C
4
-carbonyl relationship is maintained in 5, the C
2
region where substitution is undesirable in the quinolones is filled with a major part of the ring. None of the quinolone mimics 3-5 exactly mimics the quinolone parent structure because all contain an extra third ring used to deliver the acidic H group required for activity.
WO 96/04288 describes a series of benzoheterocycles 6 which are glycine receptor antagonists. X, Y, and Z are chosen to provide hydrogen bond acceptor and donator groups. Among the compounds depicted are some N-hydroxy-quinazoline-2,4-diones 7, where R
1
-R
4
may be hydroxy, amino, nitro, a variety of alkyls, esters, and amides. In all cases, the substituent on N
1
is hydrogen. None of the substituents R
1
-R
4
are nitrogen containing heterocycles. No antibacterial activity is revealed.
U.S. Pat. No. 5,155,110 (October 1992) reveals certain N
1
-aryl-N-hydroxy-quinazoline-2,4-diones 8 as cyclooxygenase and lipoxygenase inhibitors. R may be halo, cyano, hydroxy, and substituted amino. Amino heterocycles are not included in R, and no antibacterial activity is described.
SUMMARY OF THE INVENTION
Described are compounds of Formula I which are new:
or a pharmaceutically acceptable salt thereof wherein:
R
1
is H, a straight or branched alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons, a heterocycle of 4 to 6 atoms having 1 to 2 heteroatoms, or a phenyl group, each is optionally substituted by R, F, Cl, OR, or N(R)
2
wherein R is H, a straight or branched alkyl of 1 to 6 atoms having 0 to 1 degrees of unsaturation, a ring of 3 to 6 atoms having 0 to 2 heteroatoms, or a phenyl group, each may be substituted by F, Cl, CN, NO
2
, OH, NH
2
; also, two R's may form a 3- to 7-membered ring with the atom to which it is attached which ring may have 0 to 1 heteroatoms;
R
5
, R
6
, and R
8
are each independently H, F, Cl, Br, NO
2
, CN, CF
3
, (C(R)
2
)
n
OR, (C(R)
2
)
n
CO
2
R, (C(R)
2
)
n
CON(R)
2
, (C(R)
2
)
n
N(R)
2
, (C(R)
2
)
n
NRCOR, a straight or branched alkyl of 1 to 4 carbons containing 0 to 1 degrees of unsaturation, a cycloalkyl of 3 to 6 carbons, each optionally substituted by F, Cl, OR, or N(R)
2
wherein R is as defined above;
R
1
and R
8
may form a ring of 6 to 7 atoms having 1 to 2 heteroatoms which ring may be substituted by one or more R's wherein R is as defined above;
R
7
is selected from R
5
, R
6
, R
8
, a carbocycle of 3 to 7 carbons, a phenyl, or a heterocyclic ring of 4 to 7 atoms, a fused heterocyclic ring of 8 to 10 atoms, a bicyclic heterocycle of 6 to 9 atoms, or a spiro heterocycle of 7 to 12 atoms each having 1 to 4 heteroatoms, and each of which is optionally substituted by one or more of R′, F, Cl, (C(R)
2
)
n
N(R)
2
, (C(R)
2
)
n
OR, O, (C(R)
2
)
n
CON(R)
2
, (C(R)
2
)
n
COR, (C(R)
2
)
n
NRCOR, (C(R)
2
)
n
CO
2
R, wherein R is defined above and R′ is defined as R which is defined above; any of the adjacent groups R
5
-R
8
may together form a 5- to 7-membered ring having 0 to 2 heteroatoms, which rings may be substituted by any of the groups described for R
7
;
n is an integer of from 0 to 3; and
X and Y are each independently carbon or nitrogen with the understanding that if X or Y is nitrogen, no substituent R
6
or R
8
is attached.
The invention is also a pharmaceutical composition of the above compounds and methods of using the compounds as pharmaceuticals useful in the treatment of bacterial infection.


REFERENCES:
patent: 5283248 (1994-02-01), Hubschwerlen et al.
patent: 1068263 (1959-11-01), None
patent: 0316630 (1989-05-01), None
patent: 491090 (1992-03-01), None
Ghoneim et al. Novel 2-substituted aminonicotinhydroxaminc acids, Egypt. J. Pharm., 1987.*
Eckstein et al. A facile rearrangement of pyridinecarbohydroxamic acids in formamide, Heterocycles, 20: 1899-1901.*
Cianci et al., “Identification of N-hydroxamic acid and N-hydroxy-imide compounds that inhibit the influenza virus polymerase”,Antiviral Chemistry&Chemotherapy, vol. 7, No. 6, 1996, pp 353-360.
Ghoneim et al., “Nove l 2-Substituted Aminonicotinhydroxamide Acids”,Egypt J. Pharm, vol. 28, No. 1-4, 1987, pp 9-16.
Eckstein, et al., “A fa cile rearrangement ofHeterocycles, pyridinecarbohydroxamic acids in formamide”, vol. 20, No. 10, 1983, pp 1899-1901.
Tserng, et al., “El ectron-Impact Induced Fragmentation of 3-Hydroxy Quinazoline-2,4(1H,3H)dione, Pyridopyrimidine-2,4(1H,3H)diones, Lumazine and Alloxazine”,J. Het Chem., vol. 12, No. 1, 1975, pp 79-83.
Schapira and Lamdan, “C yclic Hydroxamic Acids Derived from Quinazoline”,I. Het. Chem., vol. 9, No. 3, 1972, pp 569-576.
Reddy, et al., “Une xpected formation of cyclic hydroxamic acids from O-(2-aminobenzoyl)hydroxylamine”,Synth. Commun., vol. 26, No. 15, 1996, pp 2843-2846.
Grochowski and Boles awska, “Appl ication of quaternary phosphonium salts in alkylation and acylation of N-hydroxylactams”,Pol I Chem, vol. 55, No. 3, 1981, pp 615-621.
Kobashi et al., “Effe ct of acyl residues of hydroxamic acids on urease inhibition”,Biochim. Biophys. Acta, vol. 227, No. 2, 1971, pp 429-441.
Kühl e and Wegler, “Zur Ke nntnis der N-hydroxy-dicarbonsäuerimide und ihrer O-Sulfonylverbindungen, einer neuen Klasse organisher Fungizide”,Ann. (Jutus Li

Affiliated with

Also associated with

Rating

7-Substituted quinazolin-2,4-diones useful as antibacterial... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with 7-Substituted quinazolin-2,4-diones useful as antibacterial..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 7-Substituted quinazolin-2,4-diones useful as antibacterial... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3363078