Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-16
2003-04-29
Padmanabhan, Sreeni (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S419000, C514S311000, C514S314000, C514S315000, C514S317000, C514S326000, C514S330000, C514S210190, C514S210200
Reexamination Certificate
active
06555569
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the use of certain glycogen phosphorylase inhibitors in the treatment of infections.
BACKGROUND OF THE INVENTION
Glycogenolysis in tissues, whereby glycogen is cleaved to release glucose-1-phosphate, is catalyzed by glycogen phosphorylase (GP). In humans, three isoforms of this enzyme have been identified: the liver isoform (HLGP), the muscle isoform (HMGP), and the brain isoform (HBGP). These isoforms are products of three separate genes and have 80-83% amino acid identity (C. B. Newgard, D. R. Littman, C. van Gendered, M. Smith, and R. J. Fletterick, J. Biol. Chem.263:3850-3857, 1988). Glycogen phosphorylase is also present in bacteria.
Glycogen phosphorylase inhibitors that have been reported to date include glucose and glucose analogs (e.g., Martin, J. L. et al., Biochemistry 1991, 30, 10101), caffeine and other purine analogs (e.g., Kasvinsky, P. J. et al. J. Biol. Chem. 1978, 253, 3343-3351 and 9102-9106), and inhibitors of the type described by Oikonomakos, N. G. et al., Protein Sci. 1999, 8, 1930-1945.
Glycogen phosphorylase inhibitors are useful in the treatment of diabetes mellitus. For example, International Patent publications WO 96139384 and WO 96/39385, both published Dec. 12, 1996, describe use of substituted N-(indole-2-carbonyl-) amides and derivatives for treatment of diabetes. These compounds are also described as useful in treatment of atherosclerosis, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipidemia, and in prevention of myocardial ischemic injury.
U.S. Pat. No. 5,952,322 describes the use of glycogen phosphorylase inhibitors, such as those described in WO 96/39384 and WO 96/39385, to reduce tissue damage associated with non-cardiac ischemia.
U.S. Pat. No. 5,882,885, issued Mar. 16, 1999 refers to antagonists and agonists of streptococcal glycogen phosphorylase as useful in the treatment of otitis media, conjunctivitis, pneumonia, bacteremia, meningitis, sinusitis, pleural empyema and endocarditis.
SUMMARY OF THE INVENTION
The present invention relates to a method of treating or preventing infection, e.g., bacterial, fungal, parasitic, or viral infection, comprising administering an amount of a compound of Formula I or Formula IA that is effective in treating or preventing said infection.
Compounds of the Formula I and Formula IA have the following structures:
and the pharmaceutically acceptable salts and prodrugs thereof;
wherein:
the dotted line (---) is an optional bond;
A is —C(H)═, —C((C
1
-C
4
)alkyl)═ or —C(halo)═ when the dotted line (---) is a bond, or A is methylene or —CH((C
1
-C
4
)alkyl)— when the dotted line (---) is not a bond;
R
1
, R
8
or R
9
are each independently H, halo, 4-, 6- or 7-nitro, cyano, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, fluoromethyl, difluoromethyl or trifluoromethyl;
R
2
is H;
R
3
is H or (C
1
-C
5
)alkyl;
R
4
is H, methyl, ethyl, n-propyl, hydroxy(C
1
-C
3
)alkyl, (C
1
-C
3
)alkoxy(C
1
-C
3
)alkyl, phenyl(C
1
-C
4
)alkyl, phenylhydroxy(C
1
-C
4
)alkyl, phenyl(C
1
-C
4
)alkoxy(C
1
-C
4
)alkyl, thien-2- or -3-yl(C
1
-C
4
)alkyl or fur-2- or -3-yl(C
1
-C
4
)alkyl wherein said R
4
rings are mono-, di- or tri-substituted independently on carbon with H, halo, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, trifluoromethyl, hydroxy, amino or cyano; or
R
4
is pyrid-2-, -3- or -4-yl(C
1
-C
4
)alkyl, thiazol-2-, -4- or -5-yl(C
1
-C
4
)alkyl, imidazol -1-, -2-, -4- or -5-yl(C
1
-C
4
)alkyl, pyrrol-2- or -3-yl(C
1
-C
4
)alkyl, oxazol-2-, -4- or -5-yl-(C
1
-C
4
)alkyl pyrazol-3-, -4- or -5-yl(C
1
-C
4
)alkyl, isoxazol-3-, -4- or -5-yl(C
1
-C
4
)alkyl, isothiazol-3-, -4- or -5-yl(C
1
-C
4
)alkyl, pyridazin-3- or -4-yl-(C
1
-C
4
)alkyl, pyrimidin-2-, -4-, -5- or -6-yl(C
1
-C
4
)alkyl, pyrazin-2- or -3-yl(C
1
-C
4
)alkyl or 1,3,5-triazin-2-yl(C
1
-C
4
)alkyl, wherein said preceding R
4
heterocycles are optionally mono- or di-substituted independently with halo, trifluoromethyl, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, amino or hydroxy and said mono-or di-substituents are bonded to carbon;
R
5
is H, hydroxy, fluoro, (C
1
-C
5
)alkyl, (C
1
-C
5
)alkoxy, (C
1
-C
6
)alkanoyl, amino(C
1
-C
4
)alkoxy, mono-N- or di-N,N-(C
1
-C
4
)alkylamino(C
1
-C
4
)alkoxy, carboxy(C
1
-C
4
)alkoxy, (C
1
-C
5
)alkoxy-carbonyl(C
1
-C
4
)alkoxy, benzyloxycarbonyl(C
1
-C
4
)alkoxy, or carbonyloxy wherein said carbonyloxy is carbon-carbon linked with phenyl, thiazolyl, imidazolyl, 1H-indolyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl and wherein said preceding R
5
rings are optionally mono-substituted with halo, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, hydroxy, amino or trifluoromethyl and said mono-substituents are bonded to carbon;
R
7
is H, fluoro or (C
1
-C
5
)alkyl; or
R
5
and R
7
can be taken together to be oxo;
R
6
is C(O)R
10
;
R
10
is piperazin-1-yl, 4-(C
1
-C
4
)alkylpiperazin-1-yl, 4-formylpiperazin-1-yl, morpholino, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxo-thiomorpholino, thiazolidin-3-yl, 1 -oxo-thiazolidin-3-yl, 1,1-dioxo-thiazolidin-3-yl, 2-(C
1
-C
6
)alkoxycarbonylpyrrolidin-1-yl, oxazolidin-3-yl or 2(R)-hydroxymethylpyrrolidin-1-yl; or
R
10
is 3- and/or 4-mono-or di-substituted oxazetidin-2-yl, 2-, 4-, and/or 5- mono- or di-substituted oxazolidin-3-yl, 2-, 4-, and/or 5- mono- or di- substituted thiazolidin-3-yl, 2-, 4-, and/or 5- mono- or di- substituted 1-oxothiazolidin-3-yl, 2-, 4-, and/or 5- mono- or di-substituted 1,1-dioxothiazolidin-3-yl, 3- and/or 4-, mono- or di-substituted pyrrolidin-1-yl, 3-, 4-and/or 5-, mono-, di- or tri-substituted piperidin-1-yl, 3-, 4-, and/or 5- mono-, di-, or tri-substituted piperazin-1-yl, 3-substituted azetidin-1-yl, 4- and/or 5-, mono- or di-substituted 1,2-oxazinan-2-yl, 3-and/or 4-mono- or di-substituted pyrazolidin-1-yl, 4- and/or 5-, mono- or di-substituted isoxazolidin-2-yl, 4- and/or 5-, mono- and/or di-substituted isothiazolidin-2-yl wherein said R
10
substituents are independently H, halo, (C
1
-C
5
)-alkyl, hydroxy, amino, mono-N- or di-N,N-(C
1
-C
5
)alkylamino, formyl, oxo, hydroxyimino, (C
1
-C
5
)alkoxy, carboxy, carbamoyl, mono-N-or di-N,N-(C
1
-C
4
)alkylcarbamoyl, (C
1
-C
4
)alkoxyimino, (C
1
-C
4
)alkoxymethoxy, (C
1
-C
6
)alkoxycarbonyl, carboxy(C
1
-C
5
)alkyl or hydroxy(C
1
-C
5
)alkyl;
R
12
is H, methyl, ethyl, n-propyl, hydroxy(C
1
-C
3
)alkyl, (C
1
-C
3
)alkoxy(C
1
-C
3
)alkyl, phenyl(C
1
-C
4
)alkyl, phenylhydroxy(C
1
-C
4
)alkyl, (phenyl)((C
1
-C
4
)-alkoxy)(C
1
-C
4
)alkyl, thien-2- or - 3-yl(C
1
-C
4
)alkyl or fur-2- or -3-yl(C
1
-C
4
)alkyl wherein said R
12
rings are mono-, di- or tri-substituted independently on carbon with H, halo, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, trifluoromethyl, hydroxy, amino, cyano or 4,5-dihydro-1H-imidazol-2-yl; or
R
12
is pyrid-2-, -3- or -4-yl(C
1
-C
4
)alkyl, thiazol-2-, -4- or -5-yl(C
1
-C
4
)alkyl, imidazol-2-, -4- or - 5-yl(C
1
-C
4
)alkyl, pyrrol-2- or -3-yl(C
1
-C
4
)alkyl, oxazol-2-, -4- or -5-yl(C
1
-C
4
)alkyl, pyrazol-3-, -4- or -5-yl(C
1
-C
4
)alkyl, isoxazol-3-, -4- or -5-yl(C
1
-C
4
)alkyl, isothiazol-3-, 4- or -5-yl(C
1
-C
4
)alkyl, pyridazin-3- or -4-yl(C
1
-C
4
)alkyl, pyrimidin-2-, -4-, -5- or -6-yl(C
1
-C
4
)alkyl, pyrazin-2-or - 3-yl(C
1
-C
4
)alkyl, 1,3,5-triazin-2-yl(C
1
-C
4
)alkyl or indol-2-(C
1
-C
4
)alkyl, wherein said preceding R
12
heterocycles are optionally mono- or di-substituted independently with halo, trifluoromethyl, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, amino, hydroxy or cyano and said substituents are bonded to carbon; or
R
12
is R
11
-carbonyloxymethyl, wherein said R
11
is phenyl, thiazolyl, imidazolyl, 1H-indolyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl and wherein said preceding R
11
rings are optionally mono- or di-substituted independently with halo, amino, hydroxy, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy or trifluoromethyl and said mono- or di-substituents are bonded to carbon;
R
13
is H, methyl, ethyl, n-propyl, hydroxymethyl, or hydroxyethyl;
R
14
C(O)
Sutcliffe Joyce A.
Treadway Judith Lee
Benson Gregg C.
Jacobs Seth H.
Jiang S.
Padmanabhan Sreeni
Pfizer Inc.
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