| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | April 29, 2003 |
| PATENT TITLE |
Use of heteroaryl substituted N-(indole-2-carbonyl-) amides for treatment of infection |
| PATENT ABSTRACT | A pharmaceutical composition containing a glycogen phosphorylase inhibitor of Formula I or IA as defined herein is administered to a mammal to treat infection. ##STR1## ##STR2## |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | February 16, 2001 |
| PATENT REFERENCES CITED |
Berkow, R., The Merck Manual of Diagnosis and Therapy (16th ED) (1992).* Berrs et al., The Merck Manual of Diagnosis and Therapy (17th ED) (1999).* Martin et al., Discovery of a human liver glycogen phosphorylase inhibitor that lowers blood glucose in vivo, Proc. Natl. Acad. Sci. USA, vol. 95, pp. 1776-1781, Feb. 1998. Letter from Prof. Dr. W. Goebel to Dr. Judith Treadway dated Mar. 25, 1998. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
Claims -------------------------------------------------------------------------------- What is claimed is: 1. A method of treating a Chiamydia pneumoniae or a Chlamydia trachomatis infection in a mammal comprising administering an effective amount of a glycogen phosphorylase inhibitor of Formula I or Formula IA ##STR7## and the pharmaceutically acceptable salts and prodrugs thereof; wherein: the dotted line (---) is an optional bond; A is --C(H).dbd., --C((C.sub.1 -C.sub.4)alkyl).dbd. or --C(halo).dbd. when the dotted line (---) is a bond, or A is methylene or --CH((C.sub.1 -C.sub.4)alkyl)- when the dotted line (---) is not a bond; R.sub.1, R.sub.8 or R.sub.9 are each independently H, halo, 4-, 6- or 7-nitro, cyano, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, fluoromethyl, difluoromethyl or trifluoromethyl; R.sub.2 is H; R.sub.3 is H or (C.sub.1 -C.sub.5)alkyl; R.sub.4 is H, methyl, ethyl, n-propyl, hydroxy(C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3)alkoxy(C.sub.1 -C.sub.3)alkyl, phenyl(C.sub.1 -C.sub.4)alkyl, phenylhydroxy(C.sub.1 -C.sub.4)alkyl, phenyl(C.sub.1 -C.sub.4)alkoxy(C.sub.1 -C.sub.4)alkyl, thien-2- or -3-yl(C.sub.1 -C.sub.4)alkyl or fur-2- or - 3-yl(C.sub.1 -C.sub.4)alkyl wherein said R.sub.4 rings are mono-, di- or tri-substituted independently on carbon with H, halo, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, trifluoromethyl, hydroxy, amino or cyano; or R.sub.4 is pyrid-2-, -3- or -4-yl(C.sub.1 -C.sub.4)alkyl, thiazol-2-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, imidazol -1-, -2-, -4- or - 5-yl(C.sub.1 -C.sub.4)alkyl, pyrrol-2- or -3-yl(C.sub.1 -C.sub.4)alkyl, oxazol-2-, - 4- or -5-yl-(C.sub.1 -C.sub.4)alkyl, pyrazol-3-, -4- or -5- yl(C.sub.1 -C.sub.4)alkyl, isoxazol-3-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, isothiazol-3-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, pyridazin-3- or -4-yl-(C.sub.1 -C.sub.4)alkyl, pyrimidin-2-, -4-, -5- or -6- yl(C.sub.1 -C.sub.4)alkyl, pyrazin-2- or -3-yl(C.sub.1 -C.sub.4)alkyl or 1,3,5-triazin-2-yl(C.sub.1 -C.sub.4)alkyl, wherein said preceding R.sub.4 heterocycles are optionally mono- or di-substituted independently with halo, trifluoromethyl, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, amino or hydroxy and said mono-or di- substituents are bonded to carbon; R.sub.5 is H, hydroxy, fluoro, (C.sub.1 -C.sub.5)alkyl, (C.sub.1 -C.sub.5)alkoxy, (C.sub.1 -C.sub.6)alkanoyl, amino(C.sub.1 -C.sub.4)alkoxy, mono-N- or di-N,N- (C.sub.1 -C.sub.4)alkylamino(C.sub.1 -C.sub.4)alkoxy, carboxy(C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.5)alkoxy-carbonyl(C.sub.1 -C.sub.4)alkoxy, benzyloxycarbonyl(C.sub.1 -C.sub.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.sub.5 rings are optionally mono-substituted with halo, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, hydroxy, amino or trifluoromethyl and said mono-substituents are bonded to carbon; R.sub.7 is H, fluoro or (C.sub.1 -C.sub.5)alkyl; or R.sub.5 and R.sub.7 can be taken together to be oxo; R.sub.6 is C(O)R.sub.10 ; R.sub.10 is piperazin-1-yl, 4- (C.sub.1 -C.sub.4)alkylpiperazin-l-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.sub.1 -C.sub.6)alkoxycarbonylpyrrolidin-1-yl, oxazolidin-3-yl or 2(R) -hydroxymethylpyrrolidin-1-yl; or R.sub.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.sub.10 substituents are independently H, halo, (C.sub.1 -C.sub.5)-alkyl, hydroxy, amino, mono-N- or di-N,N- (C.sub.1 -C.sub.5)alkylamino, formyl, oxo, hydroxyimino, (C.sub.1 -C.sub.5)alkoxy, carboxy, carbamoyl, mono-N-or di-N,N-(C.sub.1 -C.sub.4)alkylcarbamoyl, (C.sub.1 -C.sub.4)alkoxyimino, (C.sub.1 -C.sub.4)alkoxymethoxy, (C.sub.1 -C.sub.6)alkoxycarbonyl, carboxy (C.sub.1 -C.sub.5)alkyl or hydroxy(C.sub.1 -C.sub.5)alkyl; R.sub.12 is H, methyl, ethyl, n-propyl, hydroxy(C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3)alkoxy(C.sub.1 -C.sub.3)alkyl, phenyl(C.sub.1 -C.sub.4)alkyl, phenylhydroxy(C.sub.1 -C.sub.4)alkyl, (phenyl) ((C.sub.1 -C.sub.4)-alkoxy) (C.sub.1 -C.sub.4)alkyl, thien-2- or -3-yl(C.sub.1 -C.sub.4)alkyl or fur-2- or -3-yl(C.sub.1 -C.sub.4)alkyl wherein said R.sub.4 rings are mono-, di- or tri-substituted independently on carbon with H, halo, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, trifluoromethyl, hydroxy, amino, cyano or 4,5-dihydro-1H-imidazol-2-yl; or R.sub.12 is pyrid-2-, -3- or -4-yl(C.sub.1 -C.sub.4)alkyl, thiazol-2-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, imidazol-2-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, pyrrol-2- or -3-yl(C.sub.1 -C.sub.4)alkyl, oxazol-2-, 4- or -5-yl(C.sub.1 -C.sub.4)alkyl, pyrazol-3-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, isoxazol-3-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, isothiazol-3-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, pyridazin-3-or -4-yl(C.sub.1 -C.sub.4)alkyl, pyrimidin-2-, -4-, -5- or -6-yl(C.sub.1 -C.sub.4)alkyl, pyrazin-2- or -3-yl(C.sub.1 -C.sub.4)alkyl, 1,3,5-triazin-2-yl(C.sub.1 -C.sub.4)alkyl or indol-2-(C.sub.1 -C.sub.4)alkyl, wherein said preceding R.sub.12 heterocycles are optionally mono- or di-substituted independently with halo, trifluoromethyl, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, amino, hydroxy or cyano and said substituents are bonded to carbon; or R.sub.12 is R.sub.11 -carbonyloxymethyl, wherein said R.sub.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.sub.11 rings are optionally mono- or di-substituted independently with halo, amino, hydroxy, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy or trifluoromethyl and said mono- or di-substituents are bonded to carbon; R.sub.13 is H; R.sub.14 C(O)R.sub.15 ; R.sub.15 is morpholino, thiomorpholino, 1-oxothiomorpholino, 1, 1-dioxothiomorpholino, thiazolidin-3-yl, 1-oxothiazolidin-3-yl, 1,1-dioxothiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, piperazin-4-yl, azetidin-1-yl, 1,2-oxazinan-2-yl, pyrazolidin-1-yl, isoxazolidin-2-yl, isothiazolidin-2-yl, 1,2-oxazetidin-2-yl, oxazolidin-3-yl, 3,4-dihydroisoquinolin-2-yl, 1,3-dihydroisoindol-2-yl, 3,4-dihydro-2H-quinol-1-yl, 2,3-dihydro-benzo[1,4]oxazin-4-yl, 2,3-dihydro-benzo[1,4]-thiazine-4-yl, 3,4-dihydro-2H-quinoxalin-1-yl, 3,4-dihydro-benzo[c][1,2]oxazin-1-yl, 1,4-dihydro-benzo[d][1,2]oxazin-3-yl, 3,4-dihydro-benzo[e][1,2]-oxazin- 2-yl, 3H-benzo[d]isoxazol-2-yl, 3H-benzo[c]isoxazol-1-yl or azepan-1-yl, wherein said R.sub.15 rings are optionally mono-, di- or tri-substituted independently with halo, (C.sub.1 -C.sub.5)alkyl, (C.sub.1 -C.sub.5)alkoxy, hydroxy, amino, mono-N- or di-N,N-(C.sub.1 -C.sub.5)alkylamino, formyl, carboxy, carbamoyl, mono-N- or di-N,N- (C.sub.1 -C.sub.5)alkylcarbamoyl, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.3)alkoxy, (C.sub.1 -C.sub.5)alkoxycarbonyl, benzyloxycarbonyl, (C.sub.1 -C.sub.5)alkoxycarbonyl (C.sub.1 -C.sub.5)alkyl, (C.sub.1 -C.sub.4)alkoxycarbonylamino, carboxy(C.sub.1 -C.sub.5)alkyl, carbamoyl(C.sub.1 -C.sub.5)alkyl, mono-N- or di-N,N-(C.sub.1 -C.sub.5)alkylcarbamoyl(C.sub.1 -C.sub.5)alkyl, hydroxy(C.sub.1 -C.sub.5)alkyl, (C.sub.1 -C.sub.4)alkoxy(C.sub.1 -C.sub.4)alkyl, amino(C.sub.1 -C.sub.4)alkyl, mono-N- or di-N,N- (C.sub.1 -C.sub.4)alkylamino(C.sub.1 -C.sub.4)alkyl, oxo, hydroxyimino or (C.sub.1 -C.sub.6)alkoxyimino and wherein no more than two substituents are selected from oxo, hydroxyimino or (C.sub.1 -C.sub.6)alkoxyimino and oxo, hydroxyimino or (C.sub.1 -C.sub.6)alkoxyimino are on nonaromatic carbon; and wherein said R.sub.15 rings are optionally additionally mono- or di-substituted independently with (C.sub.1 -C.sub.5)alkyl or halo. 2. A method according to claim 1 wherein: R.sub.1 is 5-H, 5-halo, 5-methyl or 5-cyano; R.sub.8 and R.sub.9 are each independently H or halo; A is --C(H).dbd.; R.sub.2 and R.sub.3 are H; R.sub.4 is phenyl(C.sub.1 -C.sub.2)alkyl wherein said phenyl groups are mono-, di- or tri-substituted independently with H or halo or mono- or di- substituted independently with H, halo, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, trifluoromethyl, hydroxy, amino or cyano; or R.sub.4 is thien-2- or -3-yl(C.sub.1 -C.sub.2)alkyl, pyrid-2-, -3- or -4-yl(C.sub.1 -C.sub.2)alkyl, thiazol-2-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, imidazol -1-, -2-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1 -C.sub.2)alkyl, pyrrol-2- or -3-yl(C.sub.1 -C.sub.2)alkyl, oxazol-2-, -4- or -5-yl-(C.sub.1 -C.sub.2)alkyl, pyrazol-3-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, isoxazol-3-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl wherein said preceding R.sub.4 heterocycles are optionally mono- or di-substituted independently with halo, trifluoromethyl, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, amino or hydroxy and said mono- or di-substituents are bonded to carbon; R.sub.5 is hydroxy; and R.sub.7 is H. 3. A method according to claim 2 wherein: the carbon atom labelled a has (S) stereochemistry; the carbon atom labelled b has (R) stereochemistry; R.sub.4 is phenyl(C.sub.1 -C.sub.2)alkyl, thien-2-yl-(C.sub.1 -C.sub.2)alkyl, thien-3-yl-(C.sub.1 -C.sub.2)alkyl, fur-2-yl-(C.sub.1 -C.sub.2)alkyl or fur-3-yl-(C.sub.1 -C.sub.2)alkyl wherein said rings are mono- or di- substituted independently with H or fluoro; and R.sub.10 is morpholino, 4-(C.sub.1 -C.sub.4)alkylpiperazin-1-yl, 3-substituted azetidin-1-yl, 3- and/or 4-, mono- or di-substituted pyrrolidin-1-yl, 4- and/or 5- mono- or di-substituted isoxazolidin-2-yl, 4- and/or 5-, mono- or di-substituted 1,2-oxazinan-2-yl wherein said substituents are each independently H, halo, hydroxy, amino, mono-N- or di-N,N-(C.sub.1 -C.sub.6)alkylamino, oxo, hydroxyimino or alkoxy. 4. A method according to claim 1 wherein the compound is of Formula I and wherein: R.sub.1 is H, halo, methyl or cyano; R.sub.8 and R.sub.9 are each independently H or halo; A is --C(H).dbd.; R.sub.2 and R.sub.3 are H; R.sub.4 is phenyl(C.sub.1 -C.sub.2)alkyl wherein said phenyl groups are mono-, di- or tri-substituted independently with H or halo or mono- or di- substituted independently with H, halo, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, trifluoromethyl, hydroxy, amino or cyano; or R.sub.4 is thien-2- or -3-yl(C.sub.1 -C.sub.2)alkyl, pyrid-2-, -3- or -4-yl(C.sub.1 -C.sub.2)alkyl, thiazol-2-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, imidazol -1-, -2-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1 -C.sub.2)alkyl, pyrrol-2- or -3-yl(C.sub.1 -C.sub.2)alkyl, oxazol-2-, -4- or -5-yl-(C.sub.1 -C.sub.2)alkyl, pyrazol-3-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, isoxazol-3-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl wherein said preceding R.sub.4 heterocycles are optionally mono- or di-substituted independently with halo, trifluoromethyl, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, amino or hydroxy and said mono- or di-substituents are bonded to carbon; R.sub.5 is fluoro, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.5)alkoxy, amino(C.sub.1 -C.sub.4)alkoxy, mono-N- or di-N,N-(C.sub.1 -C.sub.4)alkylamino(C.sub.1 -C.sub.4)alkoxy, carboxy(C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.5)alkoxy-carbonyl(C.sub.1 -C.sub.4)alkoxy, benzyloxycarbonyl(C.sub.1 -C.sub.4)alkoxy; and R.sub.7 is H, fluoro or (C.sub.1 -C.sub.6)alkyl. 5. A method according to claim 1 wherein said compound is selected from the group consisting of: 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-(4-methylpiperazin-1-yl)-3-oxo-propyl]-amide hydrochloride, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-(3-hydroxyazetidin-1-yl)-3-oxo-propyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-(2R)-hydroxy-3-isoxazolidin-2-yl-3-oxo-propyl)-amide, 5-Chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-(2R)-hydroxy-3-[1,2]oxazinan-2-yl-3-oxo-propyl)-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-((3S)-hydroxypyrrolidin-1-yl)-3-oxo-propyl]-am ide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-3-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-prop yl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-3-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-prop yl]-amide; and 5-Chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-(2R)-hydroxy-3-morpholin-4-yl-3-oxo-propyl)-amide. 6. A method according to claim 1 wherein the compound is of the Formula IA, and wherein: R.sub.1 is 5-H, 5-halo, 5-methyl, 5-cyano or 5-trifluoromethyl; R.sub.8 and R.sub.9 are each independently H or halo; A is --C(H).dbd.; R.sub.2 and R.sub.3 are H; and R.sub.12 is H, methyl, phenyl(C.sub.1 -C.sub.2)alkyl, wherein said phenyl groups are mono- or di-substituted independently with H, halo, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, trifluoromethyl, hydroxy, amino or cyano and wherein said R.sub.12 groups are optionally additionally mono- substituted with halo; or R.sub.12 is thien-2- or -3-yl(C.sub.1 -C.sub.2)alkyl, pyrid-2-, -3- or -4-yl(C.sub.1 -C.sub.2)alkyl, thiazol-2-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, imidazol-2-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1 -C.sub.2)alkyl, pyrrol-2- or -3-yl(C.sub.1 -C.sub.2)alkyl, oxazol-2-, - 4- or -5-yl(C.sub.1 -C.sub.2)alkyl, pyrazol-3-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, isoxazol-3-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, isothiazol-3-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, pyridazin-3- or -4-yl(C.sub.1 -C.sub.2)alkyl, pyrimidin-2-, -4-, -5- or -6-yl(C.sub.1 -C.sub.2)alkyl, pyrazin-2- or -3-yl(C.sub.1 -C.sub.2)alkyl or 1,3,5-triazin-2-yl(C.sub.1 -C.sub.2)alkyl wherein said preceding R.sub.12 heterocycles are optionally mono- or di-substituted independently with halo, trifluoromethyl, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, amino or hydroxy and said mono- or di- substituents are bonded to carbon. 7. A method according to claim 1 wherein said compound is selected from the group consisting of: 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(3-hydroxyimino-pyrrolidin-1 -yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [2-(cis-3,4-dihydroxy-pyrrolidin-1 -yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [2-(1,1-dioxo-thiazolidin-3-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid (2-oxo-2-thiazolidin-3-yl-ethyl)-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-(4-fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-((3RS)-hydroxy-piperidin-1 -yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [2-oxo-2-((1RS)-oxo-1-thiazolidin-3-yl)-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-(2-fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1 S)-benzyl-2-(3-hydroxyimino-azetidin-1-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(4-hydroxyimino-piperidin-1-yl)-2-oxo-ethyl]-amide, and 5-Chloro-1H-indole-2-carboxylic acid [1-benzyl-2-(3-hydroxypyrrolidin-1-yl)-2-oxo-ethyl]amide. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
Description -------------------------------------------------------------------------------- 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: ##STR3## ##STR4## and the pharmaceutically acceptable salts and prodrugs thereof; wherein: the dotted line (---) is an optional bond; A is --C(H).dbd., --C((C.sub.1 -C.sub.4)alkyl).dbd. or --C(halo).dbd. when the dotted line (---) is a bond, or A is methylene or --CH((C.sub.1 -C.sub.4)alkyl)-- when the dotted line (---) is not a bond; R.sub.1, R.sub.8 or R.sub.9 are each independently H, halo, 4-, 6- or 7-nitro, cyano, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, fluoromethyl, difluoromethyl or trifluoromethyl; R.sub.2 is H; R.sub.3 is H or (C.sub.1 -C.sub.5)alkyl; R.sub.4 is H, methyl, ethyl, n-propyl, hydroxy(C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3)alkoxy(C.sub.1 -C.sub.3)alkyl, phenyl(C.sub.1 -C.sub.4)alkyl, phenylhydroxy(C.sub.1 -C.sub.4)alkyl, phenyl(C.sub.1 -C.sub.4)alkoxy(C.sub.1 -C.sub.4)alkyl, thien-2- or -3-yl(C.sub.1 -C.sub.4)alkyl or fur-2- or -3-yl(C.sub.1 -C.sub.4)alkyl wherein said R.sub.4 rings are mono-, di- or tri-substituted independently on carbon with H, halo, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, trifluoromethyl, hydroxy, amino or cyano; or R.sub.4 is pyrid-2-, -3- or -4-yl(C.sub.1 -C.sub.4)alkyl, thiazol-2-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, imidazol -1-, -2-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, pyrrol-2- or -3-yl(C.sub.1 -C.sub.4)alkyl, oxazol-2-, -4- or -5-yl-(C.sub.1 -C.sub.4)alkyl pyrazol-3-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, isoxazol-3-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, isothiazol-3-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, pyridazin-3- or -4-yl-(C.sub.1 -C.sub.4)alkyl, pyrimidin-2-, -4-, -5- or -6-yl(C.sub.1 -C.sub.4)alkyl, pyrazin-2- or -3-yl(C.sub.1 -C.sub.4)alkyl or 1,3,5-triazin-2-yl(C.sub.1 -C.sub.4)alkyl, wherein said preceding R.sub.4 heterocycles are optionally mono- or di-substituted independently with halo, trifluoromethyl, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, amino or hydroxy and said mono-or di-substituents are bonded to carbon; R.sub.5 is H, hydroxy, fluoro, (C.sub.1 -C.sub.5)alkyl, (C.sub.1 -C.sub.5)alkoxy, (C.sub.1 -C.sub.6)alkanoyl, amino(C.sub.1 -C.sub.4)alkoxy, mono-N- or di-N,N-(C.sub.1 -C.sub.4)alkylamino(C.sub.1 -C.sub.4)alkoxy, carboxy(C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.5)alkoxy-carbonyl(C.sub.1 -C.sub.4)alkoxy, benzyloxycarbonyl(C.sub.1 -C.sub.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.sub.5 rings are optionally mono-substituted with halo, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, hydroxy, amino or trifluoromethyl and said mono-substituents are bonded to carbon; R.sub.7 is H, fluoro or (C.sub.1 -C.sub.5)alkyl; or R.sub.5 and R.sub.7 can be taken together to be oxo; R.sub.6 is C(O)R.sub.10 ; R.sub.10 is piperazin-1-yl, 4-(C.sub.1 -C.sub.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.sub.1 -C.sub.6)alkoxycarbonylpyrrolidin-1-yl, oxazolidin-3-yl or 2(R)-hydroxymethylpyrrolidin-1-yl; or R.sub.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.sub.10 substituents are independently H, halo, (C.sub.1 -C.sub.5)-alkyl, hydroxy, amino, mono-N- or di-N,N-(C.sub.1 -C.sub.5)alkylamino, formyl, oxo, hydroxyimino, (C.sub.1 -C.sub.5)alkoxy, carboxy, carbamoyl, mono-N-or di-N,N-(C.sub.1 -C.sub.4)alkylcarbamoyl, (C.sub.1 -C.sub.4)alkoxyimino, (C.sub.1 -C.sub.4)alkoxymethoxy, (C.sub.1 -C.sub.6)alkoxycarbonyl, carboxy(C.sub.1 -C.sub.5)alkyl or hydroxy(C.sub.1 -C.sub.5)alkyl; R.sub.12 is H, methyl, ethyl, n-propyl, hydroxy(C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3)alkoxy(C.sub.1 -C.sub.3)alkyl, phenyl(C.sub.1 -C.sub.4)alkyl, phenylhydroxy(C.sub.1 -C.sub.4)alkyl, (phenyl)((C.sub.1 -C.sub.4)-alkoxy)(C.sub.1 -C.sub.4)alkyl, thien-2- or - 3-yl(C.sub.1 -C.sub.4)alkyl or fur-2- or -3-yl(C.sub.1 -C.sub.4)alkyl wherein said R.sub.12 rings are mono-, di- or tri-substituted independently on carbon with H, halo, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, trifluoromethyl, hydroxy, amino, cyano or 4,5-dihydro-1H-imidazol-2-yl; or R.sub.12 is pyrid-2-, -3- or -4-yl(C.sub.1 -C.sub.4)alkyl, thiazol-2-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, imidazol-2-, -4- or - 5-yl(C.sub.1 -C.sub.4)alkyl, pyrrol-2- or -3-yl(C.sub.1 -C.sub.4)alkyl, oxazol-2-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, pyrazol-3-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, isoxazol-3-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, isothiazol-3-, 4- or -5-yl(C.sub.1 -C.sub.4)alkyl, pyridazin-3- or -4-yl(C.sub.1 -C.sub.4)alkyl, pyrimidin-2-, -4-, -5- or -6-yl(C.sub.1 -C.sub.4)alkyl, pyrazin-2-or - 3-yl(C.sub.1 -C.sub.4)alkyl, 1,3,5-triazin-2-yl(C.sub.1 -C.sub.4)alkyl or indol-2-(C.sub.1 -C.sub.4)alkyl, wherein said preceding R.sub.12 heterocycles are optionally mono- or di-substituted independently with halo, trifluoromethyl, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, amino, hydroxy or cyano and said substituents are bonded to carbon; or R.sub.12 is R.sub.11 -carbonyloxymethyl, wherein said R.sub.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.sub.11 rings are optionally mono- or di-substituted independently with halo, amino, hydroxy, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy or trifluoromethyl and said mono- or di-substituents are bonded to carbon; R.sub.13 is H, methyl, ethyl, n-propyl, hydroxymethyl, or hydroxyethyl; R.sub.14 C(O)R.sub.15 ; R.sub.15 is morpholino, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, thiazolidin-3-yl, 1-oxothiazolidin-3-yl, 1,1-dioxothiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, piperazin-4-yl, azetidin-1-yl, 1,2-oxazinan-2-yl, pyrazolidin-1-yl, isoxazolidin-2-yl, isothiazolidin-2-yl, 1,2-oxazetidin-2-yl, oxazolidin-3-yl, 3,4-dihydroisoquinolin-2-yl, 1,3-dihydroisoindol-2-yl, 3,4-dihydro-2H-quinol-1 -yl, 2,3-dihydro-benzo[1,4]oxazin4-yl, 2,3-dihydro-benzo[1,4]-thiazine-4-yl, 3,4-dihydro-2H-quinoxalin-1 -yl, 3,4-dihydrobenzo[c][1,2]oxazin-1-yl, 1,4-dihydro-benzo[d][1,2]oxazin-3-yl, 3,4-dihydro-benzo[e][1,2]-oxazin-2-yl, 3H-benzo[d]isoxazol-2-yl, 3H-benzo[c]isoxazol-1-yl or azepan-1-yl, wherein said R.sub.15 rings are optionally mono-, di- or tri-substituted independently with halo, (C.sub.1 -C.sub.5)alkyl, (C.sub.1 -C.sub.5)alkoxy, hydroxy, amino, mono-N- or di-N,N-(C.sub.1 -C.sub.5)alkylamino, formyl, carboxy, carbamoyl, mono-N- or di-N,N-(C.sub.1 -C.sub.5)alkylcarbamoyl, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.3)alkoxy, (C.sub.1 -C.sub.5)alkoxycarbonyl, benzyloxycarbonyl, (C.sub.1 -C.sub.5)alkoxycarbonyl(C.sub.1 -C.sub.5)alkyl, (C.sub.1 -C.sub.4)alkoxycarbonylamino, carboxy(C.sub.1 -C.sub.5)alkyl, carbamoyl(C.sub.1 -C.sub.5)alkyl, mono-N- or di-N,N-(C.sub.1 -C.sub.5)alkylcarbamoyl(C.sub.1 -C.sub.5)alkyl, hydroxy(C.sub.1 -C5)alkyl, (C.sub.1 -C.sub.4)alkoxy(C.sub.1 -C.sub.4)alkyl, amino(C.sub.1 -C.sub.4)alkyl, mono-N- or di-N,N-(C.sub.1 -C.sub.4)alkylamino(C.sub.1 -C.sub.4)alkyl, oxo, hydroxyimino or (C.sub.1 -C.sub.6)alkoxyimino and wherein no more than two substituents are selected from oxo, hydroxyimino or (C.sub.1 -C.sub.6)alkoxyimino and oxo, hydroxyimino or (C.sub.1 -C.sub.6)alkoxyimino are on nonaromatic carbon; and wherein said R.sub.15 rings are optionally additionally mono- or di-substituted independently with (C.sub.1 -C.sub.5)alkyl or halo. A group of preferred compounds of Formula I consists of those compounds wherein: R.sub.1 is 5-H, 5-halo, 5-methyl or 5-cyano; R.sub.8 and R.sub.9 are each independently H or halo; A is --C(H).dbd.; R.sub.2 and R.sub.3 are H; R.sub.4 is phenyl(C.sub.1 -C.sub.2)alkyl wherein said phenyl groups are mono-, di- or tri-substituted independently with H or halo or mono- or di- substituted independently with H, halo, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, trifluoromethyl, hydroxy, amino or cyano; or R.sub.4 is thien-2- or -3-yl(C.sub.1 -C.sub.2)alkyl, pyrid-2-, -3- or -4-yl(C.sub.1 -C.sub.2)alkyl, thiazol-2-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, imidazol -1-, -2-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1 -C.sub.2)alkyl, pyrrol-2- or -3-yl(C.sub.1 -C.sub.2)alkyl, oxazol-2-, 4- or -5-yl-(C.sub.1 -C.sub.2)alkyl, pyrazol-3-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, isoxazol-3-, 4- or -5-yl(C.sub.1 -C.sub.2)alkyl wherein said preceding R.sub.4 heterocycles are optionally mono- or di-substituted independently with halo, trifluoromethyl, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, amino or hydroxy and said mono- or di-substituents are bonded to carbon; R.sub.5 is hydroxy; and R.sub.7 is H. Within the above group of preferred compounds of Formula I is a second group of especially preferred compounds wherein the carbon atom labelled a has (S) stereochemistry; the carbon atom labelled b has (R) stereochemistry; R.sub.4 is phenyl(C.sub.1 -C.sub.2)alkyl, thien-2-yl-(C.sub.1 -C.sub.2)alkyl, thien-3-yl-(C.sub.1 -C.sub.2)alkyl, fur-2-yl-(C.sub.1 -C.sub.2)alkyl or fur-3-yl-(C.sub.1 -C.sub.2)alkyl wherein said rings are mono- or di- substituted independently with H or fluoro; and R.sub.10 is morpholino, 4-(C.sub.1 -C.sub.4)alkylpiperazin-1-yl, 3-substituted azetidin-1-yl, 3- and/or 4-, mono- or di-substituted pyrrolidin-1-yl, 4- and/or 5- mono- or di-substituted isoxazolidin-2-yl, 4- and/or 5-, mono- or di-substituted 1,2-oxazinan-2-yl wherein said substituents are each independently H, halo, hydroxy, amino, mono-N- or di-N,N-(C.sub.1 -C.sub.6)alkylamino, oxo, hydroxyimino or alkoxy. Within the above group of especially preferred compounds are the particularly preferred compounds: 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-(4-methylpiperazin-1-yl)-3-oxo-propyl]-amide hydrochloride, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-(3-hydroxyazetidin-1-yl)-3-oxo-propyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-(2R)-hydroxy-3-isoxazolidin-2-yl-3-oxo-propyl)-amide, 5-Chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-(2R)-hydroxy-3-[1,2]oxazinan-2-yl-3-oxo-propyl)-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-((3S)-hydroxypyrrolidin-1-yl)-3-oxo-propyl]-am ide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-3-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-prop yl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-3-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-prop yl]-amide; and 5-Chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-(2R)-hydroxy-3-morpholin-4-yl-3-oxo-propyl)-amide. Within the above group of especially preferred compounds of Formula I are compounds wherein: a. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; R.sub.4 is benzyl; and R.sub.10 is 4-methylpiperazin-1-yl; b. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; R.sub.4 is benzyl; and R.sub.10 is 3-hydroxyazetidin-1-yl; c. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; R.sub.4 is benzyl; and R.sub.10 is isoxazolidin-2-yl; d. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; R.sub.4 is benzyl; and R.sub.10 is (1,2)-oxazinan-2-yl; e. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; R.sub.4 is benzyl; and R.sub.10 is 3(S)-hydroxypyrrolidin-1-yl; f. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; R.sub.4 is benzyl; and R.sub.10 is (3S,4S)-dihydroxypyrrolidin-1-yl; g. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; R.sub.4 is benzyl; and R.sub.10 is cis-3,4-dihydroxypyrrolidin-1-yl; and h. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; R.sub.4 is benzyl; and R.sub.10 is morpholino. Another group of preferred compounds of Formula I are those wherein: R.sub.1 is H, halo, methyl or cyano; R.sub.8 and R.sub.9 are each independently H or halo; A is --C(H).dbd.; R.sub.2 and R.sub.3 are H; R.sub.4 is phenyl(C.sub.1 -C.sub.2)alkyl wherein said phenyl groups are mono-, di- or tri-substituted independently with H or halo or mono- or di- substituted independently with H, halo, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, trifluoromethyl, hydroxy, amino or cyano; or R.sub.4 is thien-2- or -3-yl(C.sub.1 -C.sub.2)alkyl, pyrid-2-, -3- or -4-yl(C.sub.1 -C.sub.2)alkyl, thiazol-2-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, imidazol -1-, -2-, -4- or -5-yl(C.sub.1 -C.sub.2)aikyl, fur-2- or -3-yl(C.sub.1 -C.sub.2)alkyl, pyrrol-2- or -3-yl(C.sub.1 -C.sub.2)alkyl, oxazol-2-, -4- or -5-yl-(C.sub.1 -C.sub.2)alkyl, pyrazol-3-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, isoxazol-3-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl wherein said preceding R.sub.4 heterocycles are optionally mono- or di-substituted independently with halo, trifluoromethyl, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, amino or hydroxy and said mono- or di-substituents are bonded to carbon; R.sub.5 is fluoro, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.5)alkoxy, amino(C.sub.1 -C.sub.4)alkoxy, mono-N- or di-N,N-(C.sub.1 -C.sub.4)alkylamino(C.sub.1 -C.sub.4)alkoxy, carboxy(C.sub.1 -C.sub.4)aIkoxy, (C.sub.1 -C.sub.5)alkoxy-carbonyl(C.sub.1 -C.sub.4)alkoxy, benzyloxycarbonyl(C.sub.1 -C.sub.4)alkoxy; and R.sub.7 is H, fluoro or (C.sub.1 -C.sub.6)alkyl. A group of preferred compounds of Formula IA consists of those compounds wherein: R.sub.1 is 5-H, 5-halo, 5-methyl, 5-cyano or 5-trifluoromethyl; R.sub.8 and R.sub.9 are each independently H or halo; A is --C(H).dbd.; R.sub.2 and R.sub.3 are H; R.sub.12 is H, methyl, phenyl(C.sub.1 -C.sub.2)alkyl, wherein said phenyl groups are mono- or di-substituted independently with H, halo, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, trifluoromethyl, hydroxy, amino or cyano and wherein said R.sub.12 groups are optionally additionally mono-substituted with halo; or R.sub.12 is thien-2- or -3-yl(C.sub.1 -C.sub.2)alkyl, pyrid-2-, -3- or -4-yl(C.sub.1 -C.sub.2)alkyl, thiazol-2-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, imidazol-2-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1 -C.sub.2)alkyl, pyrrol-2- or -3-yl(C.sub.1 -C.sub.2)alkyl, oxazol-2-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, pyrazol-3-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, isoxazol-3-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, isothiazol-3-, -4- or -5-yl(C.sub.1 -C.sub.2)alkyl, pyridazin-3- or -4-yl(C.sub.1 -C.sub.2)alkyl, pyrimidin-2-, -4-, -5- or -6-yl(C.sub.1 -C.sub.2)alkyl, pyrazin-2- or -3-yl(C.sub.1 -C.sub.2)alkyl or 1,3,5-triazin-2-yl(C.sub.1 -C.sub.2)alkyl wherein said preceding R.sub.12 heterocycles are optionally mono- or di-substituted independently with halo, trifluoromethyl, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, amino or hydroxy and said mono- or di-substituents are bonded to carbon; and R.sub.13 is H. Within the above group of preferred compounds of Formula IA is a group of especially preferred compounds wherein: R.sub.12 is H, phenyl(C.sub.1 -C.sub.2)alkyl, thien-2- or -3-yl(C.sub.1 -C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1 -C.sub.2)alkyl wherein said R.sub.12 rings are mono- or di-substituted independently with H or fluoro; and R.sub.15 is morpholino, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, thiazolidin-3-yl, 1-oxothiazolidin-3-yl, 1,1-dioxothiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, piperazin-4-yl, azetidin-1-yl, 1,2-oxazinan-2-yl, isoxazolidin-2-yl, isothiazolidin-2-yl, 1,2-oxazetidin-2-yl, oxazolidin-3-yl, 1,3-dihydroisoindol-2-yl, or azepan-1-yl, wherein said R.sub.15 rings are optionally mono- or di-substituted independently with halo, (C.sub.1 -C.sub.5)alkyl, (C.sub.1 -C.sub.5)alkoxy, hydroxy, amino, mono-N-or di-N,N-(C.sub.1 -C.sub.5)alkylamino, formyl, carboxy, carbamoyl, mono-N- or di-N,N-(C.sub.1 -C.sub.5)alkylcarbamoyl, (C.sub.1 -C.sub.5)alkoxycarbonyl, hydroxy(C.sub.1 -C.sub.5)alkyl, amino(C.sub.1 -C.sub.4)alkyl, mono-N- or di-N,N-(C.sub.1 -C.sub.4)alkylamino(C.sub.1 -C.sub.4)alkyl, oxo, hydroxyimino or (C.sub.1 -C.sub.6)alkoxyimino with the proviso that only the R.sub.15 heterocycles thiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, piperazin-4-yl, azetidin-1-yl, 1,2-oxazinan-2-yl, isoxazolidin-2-yl, or oxazolidin-3-yl are optionally mono- or di-substituted with oxo, hydroxyimino, or (C.sub.1 -C.sub.6)alkoxyimino; and wherein said R.sub.15 rings are optionally additionally mono- or di-substituted independently with (C.sub.1 -C.sub.5)alkyl. Within the above group of especially preferred compounds are the compounds: 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(3-hydroxyimino-pyrrolidin-1 -yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [2-(1,1 -dioxc-thiazolidin-3-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid (2-oxo-2-thiazolidin-3-yl-ethyl)-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-(4-fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-((3RS)-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [2-oxo-2-((1RS)-oxo-1-thiazolidin-3-yl)-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-(2-fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(3-hydroxy-azetidin-1 -yi)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(3-hydroxyimino-azetidin-1 -yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(4-hydroxyimino-piperidin-1 -yl)-2-oxo-ethyl]-amide, and 5-Chloro-1H-indole-2-carboxylic acid [1 -benzyl-2-(3-hydroxypyrrolidin-1-yl)-2-oxo-ethyl]amide. Within the above group of especially preferred compounds of Formula IA is a group of particularly preferred compounds wherein: R.sub.12 is H; and R.sub.15 is thiazolidin-3-yl, 1-oxo-thiazolidin-3-yl, 1,1-dioxo-thiazolidin-3-yl or oxazolidin-3-yl or said R.sub.15 substituents optionally mono- or di-substituted independently with carboxy, (C.sub.1 -C.sub.5)alkoxycarbonyl, hydroxy(C.sub.1 -C.sub.3)alkyl, amino(C.sub.1 -C.sub.3)alkyl, mono-N- or di-N,N-(C.sub.1 -C.sub.3)alkylamino(C.sub.1 -C.sub.3)alkyl or R.sub.15 is mono- or di-substituted pyrrolidin-1-yl wherein said substituents are independently carboxy, (C.sub.1 -C.sub.5)alkoxycarbonyl, (C.sub.1 -C.sub.5)alkoxy, hydroxy, hydroxy(C.sub.1 -C.sub.3)alkyl, amino, amino(C.sub.1 -C.sub.3)alkyl, mono-N- or di-N,N-(C.sub.1 -C.sub.3)alkylamino(C.sub.1 -C.sub.3)alkyl or mono-N- or di-N,N-(C.sub.1 -C.sub.4)alkylamino; and the R.sub.15 rings are optionally additionally independently disubstituted with (C.sub.1 -C.sub.5)alkyl. Preferred compounds within the immediately preceding group of compounds are those wherein: a. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; and R.sub.15 is cis-3,4-dihydroxy-pyrrolidin-1-yl; b. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; and R.sub.15 is (3S,4S)-dihydroxy-pyrrolidin-1-yl; c. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; and R.sub.15 is 1,1 -dioxo-thiazolidin-3-yl; d. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; and R.sub.15 is thiazolidin-3-yl; and e. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; and R.sub.15 is 1-oxo-thiazolidin-3-yl. Within the above group of especially preferred compounds of Formula IA is another group of particularly preferred compounds wherein: R.sub.15 is phenylmethyl, thien-2- or -3-ylmethyl wherein said R.sub.15 rings are optionally mono- or di-substituted with fluoro; and R.sub.15 is thiazolidin-3-yl, 1-oxo-thiazolidin-3-yl, 1,1-dioxo-thiazolidin-3-yl or oxazolidin-3-yl or said R.sub.15 substituents optionally mono- or di-substituted independently with carboxy or (C.sub.1 -C.sub.5)alkoxycarbonyl, hydroxy(C.sub.1 -C.sub.3)alkyl, amino(C.sub.1 -C.sub.3)alkyl or mono-N- or di-N,N-(C.sub.1 -C.sub.3)alkylamino(C.sub.1 -C.sub.3)alkyl or R.sub.15 is mono- or di-substituted azetidin-1-yl or mono- or di-substituted pyrrolidin-1-yl or mono- or di-substituted piperidin-1-yl wherein said substituents are independently carboxy, (C.sub.1 -C.sub.5)alkoxycarbonyl, hydroxy(C.sub.1 -C.sub.3)alkyl, amino(C.sub.1 -C.sub.3)alkyl, mono-N- or di-N,N-(C.sub.1 -C.sub.3)alkylamino(C.sub.1 -C.sub.3)alkyl, hydroxy, (C.sub.1 -C.sub.5)alkoxy, amino, mono-N- or di-N,N-(C.sub.1 -C.sub.5)alkylamino, oxo, hydroxyimino or (C.sub.1 -C.sub.5)alkoxyimino; and the R.sub.15 rings are optionally additionally mono- or di-substituted independently with (C.sub.1 -C.sub.5)alkyl. Preferred compounds within the immediately preceding group of particularly preferred compounds of Formula IA are compounds wherein a. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; R.sub.12 is 4-fluorobenzyl; R.sub.15 is 4-hydroxypiperidin-1-yl; and the stereochemistry of carbon (a) is (S); b. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; R.sub.12 is benzyl; R.sub.15 is 3-hydroxypiperidin-1-yl; and the stereochemistry of carbon (a) is (S); c. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; R.sub.12 is benzyl; R.sub.15 is cis-3,4-dihydroxy-pyrrolidin-1-yl; and the stereochemistry of carbon (a) is S; d. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; R.sub.12 is benzyl; R.sub.15 is 3-hydroxyimino-pyrrolidin-1-yl; and the stereochemistry of carbon (a) is (S); e. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; R.sub.12 is 2-fluorobenzyl; R.sub.15 is 4-hydroxypiperidin-1-yl; and the stereochemistry of carbon (a) is (S); f. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; R.sub.12 is benzyl; R.sub.15 is (3S,4S)-dihydroxy-pyrrolidin-1-yl; and the stereochemistry of carbon (a) is (S); g. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; R.sub.12 is benzyl; R.sub.15 is 3-hydroxy-azetidin-1-yl; and the stereochemistry of carbon (a) is (S); h. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; R.sub.12 is benzyl; R.sub.15 is 3-hydroxyimino-azetidin-1-yl; and the stereochemistry of carbon (a) is (S); and i. R.sub.1 is 5-chloro; R.sub.8 and R.sub.9 are H; R.sub.12 is benzyl; R.sub.15 is 4-hydroxyimino-piperidin-1-yl; and the stereochemistry of carbon (a) is (S). The glycogen phosphorylase inhibitor of formula I or IA is employed to treat bacterial infections and protozoa infections and disorders related to such infections that include the following: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, or Peptostreptococcus spp.; pharynigitis, rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Clostridium diptheriae, or Actinobacillus haemolyticum; respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae; uncomplicated skin and soft tissue infections, abscesses and osteomyelitis, and puerperal fever related to infection by Staphylococcus aureus, coagulase-positive staphylococci (i.e., S. epidermidis, S. hemolyticus, etc.), Streptococcus pyogenes , Streptococcus agalactiae, Streptococcal groups C-F (minute-colony streptococci), viridans streptococci, Corynebacterium minutissimum, Clostridium spp., or Bartonella henselae; uncomplicated acute urinary tract infections related to infection by Staphylococcus saprophyticus or Enterococcus spp.; urethritis and cervicitis; and sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrheae; toxin diseases related to infection by S. aureus (food poisoning and Toxic shock syndrome), or Groups A, B, and C streptococci; ulcers related to infection by Helicobacter pylori; systemic febrile syndromes related to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitis related to infection by Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, or H. influenzae; disseminated Mycobacterium avium complex (MAC) disease related to infection by Mycobacterium avium, or Mycobacterium intracellulare; gastroenteritis related to infection by Campylobacter jejuni; intestinal protozoa related to infection by Cryptosporidium spp.; odontogenic infection related to infection by viridans streptococci; persistent cough related to infection by Bordetella pertussis; gas gangrene related to infection by Clostridium perfringens or Bacteroides spp.; atherosclerosis related to infection by Helicobacter pylori, Chlamydia pneumoniae, or Mycoplasma pneumoniae, dysentery related to infection by Shigella dysenteriae, and symptoms of infection by enterotoxigenic E. coli or Mycobacterium tuberculosis. Bacterial infections and protozoa infections and disorders related to such infections that may be treated or prevented in animals include the following: bovine respiratory disease related to infection by Pasteurella haemolyticus, P. multocida, Mycoplasma bovis, or Bordetella spp.; cow enteric disease related to infection by E. coli or protozoa (i.e., coccidia, cryptosporidia, etc.); dairy cow mastitis related to infection by Staph. aureus, Strep. uberis, Strep. agalactiae, Strep. dysgalactiae, Klebsiella spp., Corynebacterium, or Enterococcus spp.; swine respiratory disease related to infection by Actinobaciflus pleuropneumoniae, P. multocida, or Mycoplasma spp.; swine enteric disease related to infection by E. coli, Lawsonia intracellularis, Salmonella, or Serpulina hyodysenteriae; cow footrot related to infection by Fusobacterium spp.; cow metritis related to infection by E. coli; cow hairy warts related to infection by Fusobacterium necrophorum or Bacteroides nodosus; cow pink-eye related to infection by Moraxella bovis; cow premature abortion related to infection by protozoa (i.e. neosporium); urinary tract infection in dogs and cats related to infection by E. coli; skin and soft tissue infections in dogs and cats related to infection by Staph. epidermidis, Staph intermedius, coagulase neg. Staph. or P. multocida; and dental or mouth infections in dogs and cats related to infection by Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella. The invention also encompasses treatment of bacteremia, meningitis, pleural empyema, malaria, river blindness, toxoplasmosis, and endocarditis. Other bacterial infections and protozoa infections and disorders related to such infections that may be treated or prevented in accord with the method of the present invention are referred to in J. P. Sanford et al., "The Sanford Guide To Antimicrobial Therapy," 26th Edition, (Antimicrobial Therapy, Inc., 1996). In one embodiment, the infection that is treated according to the invention is mediated by an organism that requires glycogen, or glucose that results from the breakdown of glycogen, as a source of energy and/or carbon supply. In another embodiment, the glycogen phosphorylase inhibitor is administered in an amount that reduces or eliminates infection sufficiently to reduce complications, including long-term complications, that can be associated with the infection. These complications include, but are not limited to asthma, and cerebrovascular disease. In an alternative embodiment, the present invention relates to a pharmaceutical composition for the treatment of bacterial infection comprising an amount of a compound of Formula I or IA effective to treat said infection in combination with a pharmaceutically acceptable carrier. In another embodiment, a glycogen phosphorylase inhibitor is administered to treat Chiamydia pneumoniae infection |
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