Antibacterial compounds

Details Antibacterial compounds Antibacterial compounds

2003-03-12

2004-11-16

Davis, Zinna Northington (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

06818654

ABSTRACT:

TECHNICAL FIELD
This invention is directed to compounds having antibacterial activity, processes for making the compounds and intermediates used in the processes, compositions containing the compounds, and methods for prophylaxis and treatment of bacterial infections using the compounds.
BACKGROUND OF THE INVENTION
Because the effectiveness of many drugs currently available for prophylaxis and treatment of bacterial infections is being compromised by the emergence of drug-resistant bacteria, the introduction of novel antibacterials would be beneficial for their therapeutic value and their contribution to the antibacterial arts.
SUMMARY OF THE INVENTION
Accordingly, the first embodiment of this invention is directed to compounds, and salts, prodrugs, and salts of prodrugs thereof, which are useful as antibacterials, the compounds having formula (I)
in which
one of A
1
or R
4
is OH or OR
11
and the other is C(O)OH or C(O)OR
60
;
R
1
and R
2
are hydrogen or taken together are ═O;
R
3
is hydrogen, C(CH
3
)
3
, O—CH
2
CH═CH
2
, or methyl substituted with 2,4-dimethoxyphenyl;
R
5
is hydrogen, alkyl, halo, OH, CF
3
, CH
2
CF
3
, CF
2
CF
3
, or OR
11
;
R
6
is hydrogen, halogen, alkyl, CN, NO
2
, C(O)H, C≡CH, C≡C(alkyl), C≡CCCl
3
, C≡CCF
3
, CH═CH
2
, or OR
11
;
R
7
is halo, aryl, heteroaryl, heterocyclyl, bicyclic heterocyclyl, NH(R
12
), or N(R
13
) (R
14
);
R
11
is alkyl, C(O)R
70
, or alkyl substituted with a substituent selected from the group consisting of halo, aryl, —NH
2
, —NH(alkyl), and —N(alkyl)
2
;
R
12
, R
13
, and R
14
are independently alkyl or alkyl substituted with a substituent selected from the group consisting of heterocyclyl, —NH
2
, —NH(alkyl), and —N(alkyl)
2
; and
R
60
and R
70
are independently alkyl, aryl, or alkyl substituted with a substituent selected from the group consisting of halo, aryl, —NH
2
, —NH(alkyl), and —N(alkyl)
2
;
in which, for the foregoing,
each aryl, heteroaryl, heterocyclyl, and bicyclic heterocyclyl is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of alkyl, halo, —CN, —OH, ═O, —CF
3
, —OR
30
, —C(O)R
35
, —C(O)OH, —C(O)OR
35
, —NH
2
, —NH(R
35
), —N(R
35
) (R
36
), —C(O)NH
2
, —C(O)NH(R
35
), and —C(O)N(R
35
)(R
36
);
in which
R
30
is alkyl or alkyl substituted with a substituent selected from the group consisting of halo and —OR
45
;
R
35
and R
36
are independently alkyl or alkyl substituted with phenyl; and
R
45
is alkyl.
A second embodiment is directed to a process for making the compounds of the invention.
A third embodiment is directed to intermediates which are useful in the second embodiment.
A fourth embodiment is directed to compositions for the prophylaxis and treatment of bacterial infections in a fish or a mammal comprising the compounds of the invention and an excipient.
In a preferred fourth embodiment, the bacterial infection is quinoline-resistant bacterial infection.
A fifth embodiment is directed to a method for prophylaxis and treatment of bacterial infection in a fish or a mammal comprising administering thereto a therapeutically effective amount of a compound of the first embodiment.
In a more preferred fifth embodiment, the bacterial infection is quinolone-resistant bacterial infection.
A sixth embodiment of this invention is directed to a method for inhibiting bacterial protein synthesis in a fish or a mammal comprising administering thereto a therapeutically effective amount of a compound, or salt, prodrug, or salt of prodrug thereof, having formula (I)
in which
one of A
1
or R
4
is OH or OR
11
and the other is C(O)OH or C(O)OR
60
;
R
1
and R
2
are hydrogen or taken together are ═O;
R
3
is hydrogen, C(CH
3
)
3
, O—CH
2
CH═CH
2
, or methyl substituted with 2,4-dimethoxyphenyl;
R
5
is hydrogen, alkyl, halo, OH, CF
3
, CH
2
CF
3
, CF
2
CF
3
, or OR
11
;
R
6
is hydrogen, halogen, alkyl, CN, NO
2
, C(O)H, C≡CH, C≡C(alkyl), C≡CCCl
3
, C≡CCF
3
, CH═CH
2
, or OR
11
;
R
7
is halo, aryl, heteroaryl, heterocyclyl, bicyclic heterocyclyl, NH(R
12
), or N(R
13
)(R
14
);
R
11
is alkyl, C(O)R
70
, or alkyl substituted with a substituent selected from the group consisting of halo, aryl, —NH
2
, —NH(alkyl), and —N(alkyl)
2
;
R
12
, R
13
, and R
14
are independently alkyl or alkyl substituted with a substituent selected from the group consisting of heterocyclyl, —NH
2
, —NH(alkyl), and —N(alkyl)
2
; and
R
60
and R
70
are independently alkyl, aryl, or alkyl substituted with a substituent selected from the group consisting of halo, aryl, —NH
2
, —NH(alkyl), and —N(alkyl)
2
;
in which, for the foregoing,
each aryl, heteroaryl, heterocyclyl, and bicyclic heterocyclyl is unsubstituted or subatotuted with one, two, or three substituents independently selected from the group consisting of alkyl, halo, —CN, —OH, ═O, —CF
3
, —OR
30
, —C(O)R
35
, —C(O)OH, —C(O)OR
35
, —NH
2
, —NH(R
35
), —N(R
35
) (R
36
), —C(O)NH
2
, —C(O)NH(R
35
), and —C(O)N(R
35
)(R
36
), in which
R
30
is alkyl or alkyl substituted with a substituent selected from the group consisting of halo and —OR
45
;
R
35
and R
36
are independently alkyl or alkyl substituted with phenyl; and
R
45
is alkyl.


REFERENCES:
patent: 4774246 (1988-09-01), Chu
patent: 5385900 (1995-01-01), Konno et al.

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