Antibacterial compounds

Details Antibacterial compounds Antibacterial compounds

2000-02-10

2002-06-25

Soloau, T. A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S254050, C514S341000, C514S380000, C544S140000, C544S371000, C546S211000, C546S274100, C546S275400, C548S364700, C548S370400, C548S372500

Reexamination Certificate

active

06410533

ABSTRACT:

BACKGROUND OF THE INVENTION
The development of antimicrobial chemotherapeutic agents has significantly reduced the morbidity and mortality associated with bacterial infections over the last century, particularly in developed countries. However, the emergence of drug-resistant bacterial strains threatens the resurgence of diseases long thought to have been conquered. For example, a growing number of cases of drug-resistant tuberculosis have been reported since the mid-1980s, and a recent increase in multiple drug resistant
Staphylococcus aureus
infections has been observed. As the prevalence of drug-resistant bacteria increases, there is a growing need for new antibacterial agents which are suitable for use against a variety of bacterial targets.
SUMMARY OF THE INVENTION
The present invention relates to compounds which are useful as antimicrobial agents, and, in particular, as antibacterial agents.
In one embodiment, the invention provides compounds of Formula I,
where R
1
is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkyl, perfluoroalkyl, heteroaryl, carboxy, substituted or unsubstituted carboxamido, substituted or unsubstituted amino or alkoxycarbonyl. R
2
and R
3
are, independnetly, hydrogen; substituted or unsubstituted, linear, cyclic or branched alkyl; substituted or unsubstituted aminoalkyl; substituted or unsubstituted arylalkyl; substituted or unsubstituted heteroarylalkyl; or substituted or unsubstituted heteroarylcarbonyl and R
3
is hydrogen. R
2
and R
3
can also together form ═N—OH or a substituted or unsubstituted alkylidene group. R
1
and R
2
can also together form —(CH
2
)
m
—, where m is 3 or 4. R
4
is a substituted or unsubstituted phenyl group.
In another embodiment, the compounds of the invention are of Formula II,
where R
5
is hydrogen; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted arylalkyl; substituted or unsubstituted heteroarylalkyl; substituted or unsubstituted alkyl; carboxy; alkoxycarbonyl; substituted or unsubstituted aminoalkyl; or substituted or unsubstituted heterocycloalkyl-alkyl. R
6
is substituted or unsubstituted phenyl; R
7
is substituted or unsubstituted phenyl, substituted or unsubstituted alkyl or fluoroalkyl; and R
8
is halogen, phenyl, hydrogen or alkoxycarbonyl. R
5
and R
8
can also together form a substituted or unsubstituted alkylene group.
In yet another embodiment, the compounds of the invention are of Formula III,
where n is 0 or 1. R
9
is hydrogen; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted linear, branched or cyclic alkyl, alkoxy, alkoxycarbonyl, alkenyl or alkoxycarbonylcarbonyl; substituted or unsubstituted heterocycloalkyl; substituted or unsubstituted arylalkyl; substituted or unsubstituted heteroarylalkyl; substituted or unsubstituted heterocycloalkylalkyl. R
10
is substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted arylalkyl; or substituted or unsubstituted heteroarylalkyl; and R
11
is hydrogen, alkyl or alkylcarbonyl. R
9
and R
11
can also together form a substituted or unsubstituted alkylene group.
The invention also includes pharmaceutically acceptable salts of the compounds of Formulas I, II and III, and pharmaceutical compositions comprising one or more of these compounds and/or the salts thereof.
In another embodiment, the invention provides a method for treating a microbial infection in a patient. The method comprises administering to the patient a therapeutically effective amount of one or more compounds of Formula I, II or III.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to antimicrobial compounds and salts thereof, pharmaceutical compositions comprising these compounds and methods of use thereof.
For the purposes of the present invention, the term “alkyl” refers to a straight chain or branched saturated hydrocarbyl group. Preferred alkyl groups include C
1
-C
12
-alkyl groups, while more preferred alkyl groups include C
1
-C
6
-alkyl groups. The term “cycloalkyl” refers to a mono-, bi- or polycyclic alkyl group. Preferred cycloalkyl groups include C
3
-C
8
-cycloalkyl groups. The term “alkoxy” refers to an alkyl-O— group or a cycloalkyl-O— group, where the preferred alkyl and cycloalkyl groups are those given above. The term “alkenyl” refers to a straight chain or branched hydrocarbyl group which includes one or more double bonds. Preferred alkenyl groups include C
2
-C
12
-alkenyl groups. The term “cycloalkenyl” refers to a cyclic hydrocarbyl group which includes one or more double bonds but is not aromatic. Preferred cycloalkenyl groups include C
5
-C
8
-cycloalkenyl groups.
The term “aryl” refers to an aromatic carbocyclic group, such as a phenyl group, a naphthyl group or a phenyl or naphthyl group which is fused with a a five or six-membered carbocyclic or heterocyclic ring.
The terms “heterocycle” and “heterocyclic group” refer to a saturated, aromatic or partially unsaturated ring system which includes at least one heteroatom, such as one or more oxygen, nitrogen or sulfur atoms or a combination thereof. Saturated heterocyclic groups (“heterocycloalkyl groups”) include piperidyl, pyrollidyl, piperazyl tetrahydrofuranyl and morpholyl.
The term “heteroaryl” refers to an aromatic heterocyclic group. Suitable heteroaryl groups include, but are not limited to, pyridyl, pyrimidyl, quinolyl, isoquinolyl, pyrrolyl, quinoxalyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, furanyl, pyrazolyl, thiadiazolyl, oxadiazolyl, indazolyl, thiazolyl, isothiazolyl, and tetrazolyl. Heteroaryl groups also include ring systems in which a carbocyclic aromatic ring, carbocyclic non-aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings (e.g., benzo(b)thienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, indazolyl, quinolinyl, imidazopyridyl, puryl, pyrrolo[2,3-d]pyrimidyl, pyrazolo[3,4-d]pyrimidyl).
The term “arylalkyl” refers to an alkyl group which is substituted by one or more substituted or unsubstituted aryl groups. Preferred arylalkyl groups include benzyl, diphenylmethyl and 2-phenethyl groups. The term “heteroarylalkyl” refers to an alkyl group which is substituted by a substituted or unsubstituted heteroaryl group.
Alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkoxy groups can be substituted or unsubstituted. Substituted groups of this type can include, for example, one or more substituents such as halo, including fluoro, chloro, bromo and iodo; alkyl, such as C
1
-C
6
-alkyl; nitro; cyano; aryl groups, cycloalkyl groups and heterocyclic groups.
Aryl and heterocyclic, such as heteroaryl, groups can be substituted or unsubstituted. Suitable substituents include one or more substituents independently selected from halo, such as fluoro, chloro, bromo or iodo; alkyl, preferably C
1
-C
3
-alkyl; alkoxy, preferably C
1
-C
3
-alkoxy; nitro; methylenedioxo; aryl groups and heterocyclic groups.
In one embodiment, the invention provides compounds of Formula I,
In one embodiment, R
1
is selected from the group consisting of carboxy, substituted and unsubstituted amino, substituted and unsubstituted phenyl; substituted and unsubstituted benzyl; linear and branched C
1
-C
6
-alkyl; trifluoromethyl; and substituted and unsubstituted pyridyl. For example, suitable identities for R
1
include phenyl, 4-methylphenyl, 2-methylphenyl, 3-methylphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, methyl, trifluoromethyl, ethyl, n-propyl, 2-propyl, n-pentyl, 2-pentyl, 3-pentyl, 4-(1-morpholinyl)phenyl, 4-(4-carboxy-1-piperazinyl)phenyl; 2-pyridylcarbonyl; amino, carboxy and benzyl.
R
2
and R
3
are preferably selected from the group consisting of hydrogen, dimethylaminomethyl, methyl, ethyl, 2-propyl, 1-pyrrolidinyl-C
1
-C
4
-alkyl; pyridyl-C
1
-C
4
-alkyl; 3-carboxyphenylmethyl, 4-carboxyphenylmethyl, 3-(1-morpholinylcarbony

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