Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-01-09
2004-01-06
Stockton, Laura L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S311700, C548S343500, C548S346100, C548S335100, C514S396000, C514S397000
Reexamination Certificate
active
06673941
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to pharmaceutically active compounds which are useful for the treatment of bacterial infections.
BACKGROUND OF THE INVENTION
There is a medical need for novel antibiotics and a market opportunity for new antibacterial agents. Thus, the object of this invention is to identify novel compounds having antibiotic activity.
While the overall pathway of saturated fatty acid biosynthesis is similar in all organisms, the fatty acid synthase (FAS) systems vary considerably with respect to their structural organization. Vertebrates and yeast possess a FAS in which all the enzymatic activities are encoded on one or two polypeptide chains, respectively, and the acyl carrier protein (ACP) is an integral part of the complex. In contrast, in bacterial FAS, each of the reactions is catalyzed by a distinct, mono-functional enzyme and the ACP is a discrete protein. Therefore, there is considerable potential for the selective inhibition of the bacterial system by antibacterial agents.
Fab I (previously designated EnvM) functions as an enoyl-ACP reductase (Bergler, et al, (1994),
J. Biol. Chem.
269, 5493-5496) in the final step of the four reactions involved in each cycle of bacterial fatty acid biosynthesis. In this pathway, the first step is catalyzed by &bgr;-ketoacyl-ACP synthase, which condenses malonyl-ACP with acetyl-CoA (FabH, synthase III). In subsequent rounds, malonyl-ACP is condensed with the growing-chain acyl-ACP (FabB and FabF, synthases I and II, respectively). The second step in the elongation cycle is ketoester reduction by NADPH-dependent &bgr;-ketoacyl-ACP reductase (FabG). Subsequent dehydration by &bgr;-hydroxyacyl-ACP dehydrase (either FabA or FabZ) leads to trans-2-enoyl-ACP, which in turn is converted to acyl-ACP by NADH-dependent enoyl-ACP reductase (Fab I). Further rounds of this cycle, adding two carbon atoms per cycle, eventually lead to palmitoyl-ACP (16C), where upon the cycle is stopped largely due to feedback inhibition of Fab I by palmitoyl-ACP (Heath, et al, (1996),
J. Biol. Chem.
271, 1833-1836). Thus, Fab I is a major biosynthetic enzyme and is a key regulatory point in the overall synthetic pathway of bacterial fatty acid biosynthesis. Therefore, Fab I is an ideal target for antibacterial intervention.
Studies have shown that diazaborine antibiotics inhibit fatty acid, phospholipid and lipopolysaccharide (LPS) biosynthesis and that the antibacterial target of these compounds is Fab I. For example, derivative 2b18 from Grassberger, et al (1984)
J. Med Chem
27 947-953 has been reported to be a non-competitive inhibitor of Fab I (Bergler, et al, (1994),
J. Biol. Chem.
269, 5493-5496). Also, plasmids containing the Fab I gene from diazaborine resistant
S. typhimurium
conferred diazaborine resistance in
E. coli
(Turnowsky, et al, (1989),
J. Bacteriol.,
171, 6555-6565). Furthermore, inhibition of Fab I either by diazaborine or by raising the temperature in a Fab I temperature sensitive mutant is lethal. These results demonstrate that Fab I is essential to the survival of the organism (Bergler, et al, (1994),
J. Biol. Chem.
269, 5493-5496).
Recent studies have shown that Fab I is also the target for the broad spectrum antibacterial agent triclosan (McMurry, et al, (1998)
Nature
394, 531-532). A crystal structure of the
E. Coli
Fab I complexed with AND and triclosan shows that triclosan acts as a site-directed, very potent inhibitor of Fab I by mimicking its natural substrate (Levy, et al, (1999)
Nature
398, 383-384). Ward, et al ((1999)
Biochem.
38, 12514-12525) have shown that there is no evidence for the formation of a covalent complex between Fab I and triclosan, which would be analogous to the diazaborines; triclosan differs from these compounds in that it is a reversible inhibitor of Fab I. The structural data for the complex of Fab I with NAD and triclosan provides important information about Fab I as a therapeutic target.
Importantly, it has now been discovered that certain compounds have antibacterial activity and some of these antibacterial compounds are Fab I inhibitors. Therefore, the compounds of the present invention may be useful for the treatment of bacterial infections in mammals, particularly in man.
SUMMARY OF THE INVENTION
This invention comprises compounds of formula (I) and formula (II), as described hereinafter, which are useful in the treatment of bacterial infections.
This invention is also a pharmaceutical composition comprising a compound according to formula (I) or formula (II) and a pharmaceutically acceptable carrier.
This invention is also a method of treating bacterial infections by inhibiting Fab I. In a particular aspect, the compounds of this invention are useful as antibacterial agents.
DETAILED DESCRIPTION
This invention comprises compounds of formula (I) or formula (II):
wherein:
R
1
is C
1-4
alkyl, Ar or 2-thienyl or 3-thienyl;
R
2
is C
1-4
alkyl or Ar; and
n is 0-3;
or a pharmaceutically acceptable salt thereof.
Also included in this invention are pharmaceutically acceptable addition salts and complexes of the compounds of this invention. In cases wherein the compounds of this invention may have one or more chiral centers, unless specified, this invention includes each unique racemic compound, as well as each unique nonracemic compound. These compounds may be synthesized and resolved by conventional techniques.
In cases in which compounds have unsaturated carbon—carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, such as
and
each tautomeric form is contemplated as being included within this invention, whether existing in equilibrium or locked in one form by appropriate substitution with R′. The meaning of any substituent at any one occurrence is independent of its meaning, or any other substituent's meaning, at any other occurrence.
Also included in this invention are prodrugs of the compounds of this invention. Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) or in formula (II) in vivo.
The compounds of formula (I) and formula (II) may be useful in the treatment of bacterial infections. Also, the compounds of this invention may be useful as antifungal agents. Additionally, the compounds may be useful in combination with known antibiotics.
Preferably, the compounds of the invention comprise compounds of the formula (I):
wherein:
R
1
is C
1-4
alkyl, Ar or 2-thienyl or 3-thienyl;
R
2
is C
1-4
alkyl or Ar; and
n is 0-3;
or a pharmaceutically acceptable salt thereof.
With respect to formula (I):
Suitably, R
2
is Ar. Preferably, R
2
is phenyl, unsubstituted or substituted by one or two substituents selected from the group consisting of C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkoxy, CF
3
, F, Cl, Br and I, or methylenedioxy. Preferably, n is 1
Suitably, R
1
is Ar or Het. Preferably, R
1
is 2- or 3-thienyl or phenyl, unsubstituted or substituted by one or two substituents selected from the group consisting of C
1-4
alkyl, C
1-4
alkoxy, CF
3
, F, Cl, Br and I.
Alternately, the compounds of the invention comprise compounds of the formula (II):
wherein:
R
1
is C
1-4
alkyl, Ar or 2-thienyl or 3-thienyl;
R
2
is C
1-4
alkyl or Ar; and
n is 0-3;
or a pharmaceutically acceptable salt thereof.
With respect to formula (II):
Suitably, R
2
is Ar. Preferably, R
2
is phenyl, unsubstituted or substituted by one or two substituents selected from the group consisting of C
1-4
alkyl, C
1-4
alkoxy, CF
3
, F, Cl, Br, I and phenyl, or methylenedioxy. Preferably, n is 1
Suitably, R
1
is Ar. Preferably, R
1
is phenyl or naphthyl, unsubstituted or substituted by one or two substituents selected from the group consisting of C
1-4
alkyl, C
1-4
alkoxy, CF
3
, F, Cl, Br, I and phenyl.
Representative of the novel compounds of this invention are the compounds named in Examples 1-91.
Representative of the antibacterial compounds having Fab I inhibitory activity are th
Heerding Dirk
Newlander Kenneth A.
Affinium Pharmaceuticals, Inc.
Foley & Hoag LLP
Stockton Laura L.
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