Benzoquinoline derivatives useful as antibacterial agents

Details Benzoquinoline derivatives useful as antibacterial agents Benzoquinoline derivatives useful as antibacterial agents

1999-10-06

2001-08-14

Weddington, Kevin E. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S317000, C514S324000

Reexamination Certificate

active

06274596

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions comprising benzoquinoline derivatives and methods for using benzoquinoline derivatives as antibacterial agents. The invention also relates to novel benzoquinoline derivatives, their preparation, to pharmaceutical compositions containing them, and to methods of using them to alleviate bacterial infections.
BACKGROUND OF THE INVENTION
New classes of antibacterial agents are needed to address both the growing resistance of bacteria to present therapies and the general lack of efficacy of existing antibiotics against slow-growing organisms. Although bacterial infections were once considered well controlled, the threat posed by the emergence of multidrug-resistant organisms is now well accepted. Desirable characteristics for new antibacterial products include activity against drug resistant organisms, reduced propensity for resistance development, greater biological half-life in humans, reduced liability for allergic reactions, and broad spectrum antibacterial activity.
SUMMARY OF THE INVENTION
The present invention provides pharmaceutical compositions and formulations comprising benzoquinoline compounds having the generic formula (I):
wherein:
X is selected from the group consisting of O, S, CH
2
, CH
2
-CH
2
, C═O or NR
B
;
Y is C or N;
R
1
, R
2
, R
3
and R4 are independently selected from the group consisting of hydrogen, halogen, linear or branched chain lower alky, alkenyl, alkynyl, alkoxy or acyl; and
X-R
A
and R
3
, or R
3
and R
4
, are optionally linked together to form a C
3
-C
4
alkylene bridge wherein X is CH
2
or C═O
provided that:
when X is NR
B
, then
(a) R
B
is hydrogen, and R
A
is a linear or branched chain lower alkyl, alkenyl, alkynyl, aryl, heteroaryl or cycloalkyl, cycloalkenyl, optionally interrupted by at least one heteroatom, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or cycloalkenyl being optionally substituted singly or plurally by at least one of a linear or branched chain lower alkyl, alkenyl, alkynyl, acyl, alkoxy, cycloalkyl or cycloalkenyl optionally interrupted by at least one heteroatom and optionally substituted by at least one linear or branched chain lower alkyl, alkenyl, alkynyl, acyl, or alkoxy, an amino group wherein said amino group is substituted at one or two positions with a linear or branched chain lower alkyl, alkenyl, or alkynyl, (linear or branched chain lower alkyl N-mono- or N,N-dialkylamino)(lower alkyl), (linear or branched chain lower alkyl N-mono- or N,N-dialkyl)carbamyl, aryl or heteroaryl; or
(b) X, R
A
and R
B
together form a ring system comprising from about five to about twelve linked carbon atoms, said system being optionally interrupted by at least one heteroatom, optionally mono- or polyunsaturated and optionally substituted singly or plurally by at least one of a linear or branched chain lower alkyl, alkenyl, alkynyl, acyl, alkoxy, a linear or branched chain lower alkyl N-mono- or N,N-dialkylamino, (linear or branched chain lower alkyl N-mono- or N,N-dialkylamino)(lower alkyl), halogen, cyano, trifluoromethyl, nitro, aryl or heteroaryl; and
when X is O, S, CH
2
, CH
2
—CH
2
or C═O, then
(a) R
A
is hydrogen or a linear or branched chain lower alkyl, alkenyl, alkynyl, aryl or heteroaryl, said alkyl, alkenyl, alkynyl, aryl or heteroaryl being optionally substituted singly or plurally by at least one of a linear or branched chain lower alkyl, alkenyl, alkynyl, acyl, or alkoxy, a linear or branched chain lower alkyl N-mono- or N,N-dialkylamino, (linear or branched chain lower alkyl N-mono- or N,N-dialkylamino)(lower alkyl), halogen, cyano, trifluoromethyl, nitro, aryl or heteroaryl; and
(b) R
3
is a linear or branched chain lower alkyl, alkenyl, alkynyl, substituted by hydroxyphenyl, or is a linear or branched chain lower alkoxyphenyl singly or plurally substituted by CH
2
NR
C
R
D
wherein N, R
C
and R
D
together form a ring system comprising from about five to about twelve linked carbon atoms, said system being optionally interrupted by at least one heteroatom, optionally mono- or polyunsaturated and optionally substituted singly or plurally by at least one of a linear or branched chain lower alkyl, alkenyl, alkynyl, acyl, or alkoxy, a linear or branched chain lower alkyl N-mono- or NN-dialkylamino, (linear or branched chain lower alkyl N-mono- or N,N-dialkylamino)(lower alkyl), halogen, cyano, trifluoromethyl, nitro, aryl or heteroaryl;
and further provided that when Y is N, R
2
is absent;
or a salt thereof, and a pharmaceutically acceptable carrier or diluent.
In an additional embodiment, the invention also comprises pharmaceutical compositions and formulations comprising a compound having the generic formula (II):
wherein:
R
1
, R
2
and R
3
are independently selected from the group consisting of hydrogen, halogen, linear or branched chain lower alkyl, alkoxy or acyl; and
X is O, S, CH
2
, CH
2
-CH
2
, C═O or NR
B
;
provided that:
when X is NR
B
, then
(a) R
B
is hydrogen, and R
A
is a linear or branched chain lower alkyl, aryl, heteroaryl or cycloalkyl optionally interrupted by at least one heteroatom, said alkyl, aryl, heteroaryl or cycloalkyl being optionally substituted singly or plurally by at least one of a linear or branched chain lower alkyl, acyl, alkoxy, or cycloalkyl optionally interrupted by at least one heteroatom and optionally substituted by at least one linear or branched chain lower alkyl, acyl, or alkoxy, or a linear or branched chain lower alkyl mono- or dialkylamino, (linear or branched chain lower alkyl N-mono- or N,N-dialkylamino)(lower alkyl), (linear or branched chain lower alkyl N-mono- or N,N-dialkyl)carbamyl, aryl or heteroaryl, said aryl or heteroaryl being optionally substituted by at least one alkyl, alkenyl, or alkynyl, wherein said alkyl, alkenyl or alkynyl is optionally substituted by at least one hydroxy; or
(b) X, R
A
and R
B
together form a ring system comprising from about five to about twelve linked carbon atoms, said system being optionally interrupted by at least one heteroatom, optionally mono- or polyunsaturated and optionally substituted singly or plurally by at least one of a linear or branched chain lower alkyl, acyl, or alkoxy, a linear or branched chain lower alkyl N-mono- or N,N-dialkylamino, (linear or branched chain lower alkyl N-mono- or N,N-dialkylamino)(lower alkyl), halogen, cyano, trifluoromethyl, nitro or aryl or heteroaryl; and
when X is O, S, CH
2
CH
2
-CH
2
or C═O, then
(a) R
A
is hydrogen or a linear or branched chain lower alkyl, alkenyl, alkynyl, aryl or heteroaryl, said alkyl, aryl or heteroaryl being optionally substituted singly or plurally by at least one of a linear or branched chain lower alkyl, alkenyl, alkynyl, acyl, or alkoxy, a linear or branched chain lower alkyl N-mono- or N, N-dialkylamino, (linear or branched chain lower alkyl N-mono- or N,N-dialkylamino)(lower alkyl), halogen, cyano, trifluoromethyl, nitro or aryl or heteroaryl; and
(b) R
3
is a linear or branched chain lower alkyl substituted by hydroxyphenyl or linear or branched chain lower alkoxyphenyl singly or plurally substituted by CH
2
NR
C
R
D
wherein N, R
C
and R
D
together form a ring system comprising from about five to about twelve linked carbon atoms, said system being optionally interrupted by at least one heteroatom, optionally mono- or polyunsaturated and optionally substituted singly or plurally by at least one of a linear or branched chain lower alkyl, alkenyl, alkynyl, acyl, or alkoxy, a linear or branched chain lower alkyl N-mono- or N,N-dialkylamino, (linear or branched chain lower alkyl N-mono- or N,N-dialkylamino)(lower alkyl), halogen, cyano, trifluoromethyl, nitro, aryl or heteroaryl;
or a salt thereof, and a pharmaceutically acceptable carrier or diluent.
The present invention also provides methods for inhibiting microbial replication and preventing and/or treating microbial infections in an animal, comprising administering an antibacterial effective amount of the pharmaceutical formulations of the invention to an a

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