Pyrazole antimicrobial agents

Details Pyrazole antimicrobial agents Pyrazole antimicrobial agents

2001-05-02

2004-01-06

Ramsuer, Robert W. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C544S140000, C544S371000, C546S211000, C548S377100, C514S236500

Reexamination Certificate

active

06673923

ABSTRACT:

BACKGROUND OF THE INVENTION
Resistance to currently available antibiotics has created a need for new antibiotic agents. Infections, caused by organisms such as
Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecium
and
Enterococcus faecalis,
have become increasingly resistant to currently approved antibiotics. For example, significant clinical problems include methicillin-resistant strains of
S. aureus,
which are resistant to all current antibiotics except vancomycin (a drug of last resort because of severe side effects), and a vancomycin-resistant strain of
E. faecium enterococci,
which is now found world-wide. Even community-acquired organisms such as
Streptococcus pneumoniae
are increasingly resistant to antimicrobial agents, with a significant number of isolates being resistant to penicillin and extended-spectrum cephalosporins.
The emergence and spread of resistant bacterial organisms are primarily caused by acquisition of drug resistance genes, resulting in a broad spectrum of antibiotic resistance (e.g., extended-spectrum cephalosporin-resistant mutant &bgr;-lactamases found in several bacterial organisms). Genetic exchange of multiple-resistance genes, by transformation, transduction and conjugation, combined with selective pressures in settings such as hospitals where there is heavy use of antibiotic therapies, enhance the survival and proliferation of antimicrobial agent-resistant bacterial strains occurring by, e.g., spontaneous mutation. Although the extent to which bacteria develop resistance to antimicrobial drugs and the speed with which they do so vary with different types of drugs, resistance has inevitably developed to all antimicrobial agents (see, Gold and Moellering, Jr., 1996,
New Eng. J Med.,
335(19):1445-1453).
To prevent or delay the buildup of a resistant pathogen population, different chemicals that are effective against a particular disease-causing bacterium must be available. Thus, there is a need to identify compounds which can penetrate and specifically kill the pathogenic bacterial cell, or arrest its growth without also adversely affecting its human, animal, or plant host.
One avenue for accomplishing this task involves the use of compounds targeting bacterial RNA polymerase. Accordingly, what is needed in the art are new compounds which are effective inhibitors of bacterial RNA polymerase and useful as antimicrobial agents. The present invention provides such compounds along with methods for their use.
SUMMARY OF THE INVENTION
In a first aspect, the present invention provides compounds having the formula:
wherein R
1
is selected from H, OR′ and NR′R″, wherein R′ and R″ are independently selected from H and substituted or unsubstituted lower alkyl. R
2
and R
3
are independently selected from substituted or unsubstituted aryl, substituted or unsubstitued heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl-heteroalkyl, and substituted or unsubstituted aryl-heteroalkyl.
Unless otherwise indicated, the compounds provided in the above formulas are meant to include pharmaceutically acceptable salts and prodrugs thereof.
In another aspect, the present invention provides pharmaceutical compositions comprising a compound of formula I or II in admixture with a pharmaceutically acceptable carrier or excipient.
In still another aspect, the present invention provides methods for treating or preventing bacterial growth in a subject by administering to the subject a therapeutically effective amount of a compound of formula I or II.
In yet another aspect, the present invention provides methods for modulating bacterial growth on a surface comprising contacting the surface with a compound of formula I or II.
Other objects and advantages of the present invention will be apparent from the detailed description that follows.
DETAILED DESCRIPTION OF THE INVENTION
Abbreviations and Definitions
The abbreviations used herein are conventional, unless otherwise defined.
The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multi-valent radicals, having the number of carbon atoms designated (i.e. C
1
-C
10
means one to ten carbons). Examples of saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)ethyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The term “alkyl,” unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below as “heteroalkyl,” “cycloalkyl” and “alkylene.” The term “alkylene” by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by —CH
2
CH
2
CH
2
CH
2
—. Typically, an alkyl group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
The terms “alkoxy,” “alkylamino” and “alkylthio” refer to those groups having an alkyl group attached to the remainder of the molecule through an oxygen, nitrogen or sulfur atom, respectively. Similarly, the term “dialkylamino” is used in a conventional sense to refer to —NR′R″ wherein the R groups can be the same or different alkyl groups.
The term “acyl” or “alkanoyl” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and an acyl radical on at least one terminus of the alkane radical.
The term “alkoxycarbonyl” denotes —C(O)OR wherein R is alkyl as defined herein.
The term “alkylcarbamoyl” denotes —C(O)NR′R″ wherein R′ and R″ are independently selected alkyl groups as defined herein.
The term “sulfonyl” denotes —SO
2
—.
The term “sulfamoyl” denotes —SO
2
NH
2
.
The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. The heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. Examples include —CH
2
—CH
2
—O—CH
3
, —CH
2
—CH
2
—NH—CH
3
, —CH
2
—CH
2
—N(CH
3
)—CH
3
, —CH
2
—S—CH
2
—CH
3
, —CH
2
—CH
2
—S(O)—CH
3
, —CH
2
—CH
2
—S(O)
2
—CH
3
, —CH═CH—O—CH
3
, —Si(CH
3
)
3
, —CH
2
—CH═N—OCH
3
, and —CH═CH—N(CH
3
)—CH
3
. Up to two heteroatoms may be consecutive, such as, for example, —CH
2
—NH—OCH
3
and —CH
2
—O—Si(CH
3
)
3
. Also included in the term “heteroalkyl” are those radicals described in more detail below as “heteroalkylene” and “heterocycloalkyl.” The term “heteroalkylene” by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by —CH
2
—CH
2
—S—CH
2
CH
2
— and —CH
2
—S—H
2
—CH
2
—NH—CH
2
—. For heteroalkylene groups, heteroatoms can also occupy either o

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