Therapeutic use of alpha-2-delta ligands

Abstract

The instant invention relates to the use of an alpha-2-delta ligand in the treatment of chronic obstructive pulmonary disease (COPD) and diseases associated with a diagnosis of COPD, and particularly to the treatment of chronic cough, which may be unrelated to COPD.

1 . A method of treating COPD or a disease, disorder or condition associated with a diagnosis of COPD in a mammal, which method comprises administering to said mammal in need of such treatment a therapeutically effective amount of a compound comprising an alpha-2-delta ligand or a pharmaceutically acceptable salt thereof.  
     
     
         2 . The method of  claim 1  wherein the alpha-2-delta ligand is a compound of formula (I),  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is a carboxylic acid or carboxylic acid bioisostere;  
 n is 0, 1 or 2; and  
 R 1 , R 1a , R 2 , R 2a , R 3 , R 3a , R 4  and R 4a  are independently selected from H and C 1 -C 6  alkyl, or  
 R 1  and R 2  or R 2  and R 3  are taken together with the carbon atoms to which they are attached to form a C 3 -C 7  cycloalkyl ring, which ring is optionally substituted with one or two C 1 -C 6  alkyl; a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug.  
 
     
     
         3 . The method of  claim 2  wherein the alpha-2-delta ligand compound is 3-(1-aminomethyl-cyclohexylmethyl)-4H-[ 1,2,4]oxadiazol-5-one; [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid; (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid; or (1α,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, a stereoisomer or prodrug prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug.  
     
     
         4 . The method of  claim 1  wherein the alpha-2-delta ligand is a compound of formula (II),  
       
         
           
           
               
               
           
         
       
       wherein: 
 n is 0 or 1,  
 R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  are independently H or C 1 -C 6  alkyl;  
 with the proviso that compounds of formula (IIa) are excluded:  
                     
  wherein R 11  is a straight or branched alkyl of from 1 to 6 carbons, phenyl, or cycloalkyl having from 3 to 6 carbon atoms; R 12  is hydrogen or methyl; and R 13  is hydrogen methyl or carboxyl; a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug.  
 
     
     
         5 . The method of  claim 4  wherein the alpha-2-delta ligand compound is (3S,5R)-3-aminomethyl-5-methyl-octanoic acid; (3S,5R)-3-amino-5-methyl-heptanoic acid; (3S,5R)-3-amino-5-methyl-nonanoic acid; or (3S,5R)-3-amino-5-methyl-octanoic acid; a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug.  
     
     
         6 . The method of  claim 1  wherein the alpha-2-delta ligand is a compound of formula (III),  
       
         
           
           
               
               
           
         
       
       wherein: 
 either (a) X is O, S, NH or CH 2  and Y is CH 2  or a direct bond; or (b) Y is O, S or NH and X is CH 2 ; and  
 R is a 3-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, aryl or heteroaryl, where any ring may be optionally substituted independently with one or more halogen, hydroxy, cyano, nitro, amino, hydroxycarbonyl, C 1 -C 6  alkyl, C 1 -C 6  alkenyl, C 1 -C 6  alkynyl, C 1 -C 6  alkoxy, hydroxyC 1 -C 6  alkyl, C 1 -C 6  alkoxyC 1 -C6 alkyl, perfluoro C 1 -C 6  alkyl, perfluoroC 1 -C 6  alkoxy, C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, aminoC 1 -C 6  alkyl, C 1 -C 6  alkylaminoC 1 -C 6  alkyl, di-C 1 -C 6  alkylaminoC 1 -C 6  alkyl, C 1 -C 6 acyl, C 1 -C 6 acyloxy, C 1 -C 6 acyloxyC 1 -C 6  alkyl, C 1 -C 6  acylamino, C 1 -C 6  alkylthio, C 1 -C 6  alkylthiocarbonyl, C 1 -C 6  alkylthioxo, C 1 -C 6  alkoxycarbonyl, C 1 -C 6  alkylsulfonyl, C 1 -C 6  alkylsulfonylamino, aminosulfonyl, C 1 -C 6  alkylaminosulfonyl, di-C 1 -C 6  alkylaminosulfonyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, phenyl and monocyclic heteroaryl; a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug.  
 
     
     
         7 . The method of  claim 6  wherein the alpha-2-delta ligand is (2S, 4S)-4-(3-chloro-phenoxy)-pyrrolidine-2-carboxylic acid; (2S,4S)-4-(3-fluoro-benzyl)-pyrrolidine-2-carboxylic acid; (2S,4S)-4-(2,3-difluoro-benzyl)-pyrrolidine-2-carboxylic acid; or (2S,4S)-4-(3-fluoro-phenoxymethyl)-pyrrolidine-2-carboxylic acid; a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug.  
     
     
         8 . A method of treating chronic cough in a mammal, which method comprises administering to said mammal in need of such treatment a therapeutically effective amount of an alpha-2-delta ligand, or a pharmaceutically acceptable salt thereof.  
     
     
         9 . The method of  claim 8  wherein the alpha-2-delta ligand is a compound of formula (I),  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is a carboxylic acid or carboxylic acid bioisostere;  
 n is 0, 1 or 2; and  
 R 1 , R 1a , R 2 , R 2a , R 3 , R 3a , R 4  and R 4a  are independently selected from H and C 1 -C 6  alkyl, or  
 R 1  and R 2  or R 2  and R 3  are taken together with the carbon atoms to which they are attached to form a C 3 -C 7  cycloalkyl ring, which ring is optionally substituted with one or two C 1 -C 6  alkyl; a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug.  
 
     
     
         10 . The method of  claim 9  wherein the alpha-2-delta ligand compound is selected from 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one; [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid; (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid; or (1α,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug.  
     
     
         11 . The method of  claim 8  wherein the alpha-2-delta ligand is a compound of formula (II),  
       
         
           
           
               
               
           
         
       
       wherein: 
 n is 0 or 1,  
 R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  are independently H or C 1 -C 6  alkyl;  
 with the proviso that compounds of formula (IIa) are excluded:  
                     
  wherein R 11  is a straight or branched alkyl of from 1 to 6 carbons, phenyl, or cycloalkyl having from 3 to 6 carbon atoms; R 12  is hydrogen or methyl; and R 13  is hydrogen methyl or carboxyl; a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug.  
 
     
     
         12 . The method of  claim 11  wherein the alpha-2-delta ligand compound is (3S,5R)-3-aminomethyl-5-methyl-octanoic acid; (3S,5R)-3-amino-5-methyl-heptanoic acid; (3S,5R)-3-amino-5-methyl-nonanoic acid; or (3S,5R)-3-amino-5-methyl-octanoic acid; a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug.  
     
     
         13 . The method of  claim 8  wherein the alpha-2-delta ligand is a compound of formula (III),  
       
         
           
           
               
               
           
         
       
       wherein: 
 either (a) X is O, S, NH or CH 2  and Y is CH 2  or a direct bond; or (b) Y is O, S or NH and X is CH 2 ; and  
 R is a 3-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, aryl or heteroaryl, where any ring may be optionally substituted independently with one or more halogen, hydroxy, cyano, nitro, amino, hydroxycarbonyl, C 1 -C 6  alkyl, C 1 -C 6  alkenyl, C 1 -C 6  alkynyl, C 1 -C 6  alkoxy, hydroxyC 1 -C 6  alkyl, C 1 -C 6  alkoxyC 1 -C 6  alkyl, perfluoro C 1 -C 6  alkyl, perfluoroC 1 -C 6  alkoxy, C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, aminoC 1 -C 6  alkyl, C 1 -C 6  alkylaminoC 1 -C 6  alkyl, di-C 1 -C 6  alkylaminoC 1 -C 6  alkyl, C 1 -C 6 acyl, C 1 -C 6 acyloxy, C 1 -C 6 acyloxyC 1 -C 6  alkyl, C 1 -C 6  acylamino, C 1 -C 6  alkylthio, C 1 -C 6  alkylthiocarbonyl, C 1 -C 6  alkylthioxo, C 1 -C 6  alkoxycarbonyl, C 1 -C 6  alkylsulfonyl, C 1 -C 6  alkylsulfonylamino, aminosulfonyl, C 1 -C 6  alkylaminosulfonyl, di-C 1 -C 6  alkylaminosulfonyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, phenyl and monocyclic heteroaryl; a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug.  
 
     
     
         14 . The method of  claim 13  wherein the alpha-2-delta ligand is (2S, 4S)-4-(3-chloro-phenoxy)-pyrrolidine-2-carboxylic acid; (2S,4S)-4-(3-fluoro-benzyl)-pyrrolidine-2-carboxylic acid; (2S,4S)-4-(2,3-difluoro-benzyl)-pyrrolidine-2-carboxylic acid; or (2S,4S)-4-(3-fluoro phenoxymethyl)-pyrrolidine-2-carboxylic acid; a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug.  
     
     
         15 . The method of any one of claims  1 - 7  wherein said COPD is the COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated therewith, or said COPD is characterized by irrerversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS) or exacerbation of airways hyper-reactivity consequent to other drug therapy.  
     
     
         16 . The method of either  claim 1  or  8 , wherein the alpha-2-delta ligand compound is gabapentin; pregabalin; [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid; 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one; (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid; (1α,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid; (3S,5R)-3-aminomethyl-5-methyl-octanoic acid; (3S,5R)-3-amino-5-methyl-heptanoic acid; (3S,5R)-3-amino-5-methyl-nonanoic acid; (3S,5R)-3-amino-5-methyl-octanoic acid; (2S, 4S)-4-(3-Chloro-phenoxy)-pyrrolidine-2-carboxylic acid; (2S,4S)-4-(3-fluoro-benzyl)-pyrrolidine-2-carboxylic acid; (2S,4S)-4-(2,3-difluoro-benzyl)-pyrrolidine-2-carboxylic acid; or (2S,4S)-4-(3-fluoro-phenoxymethyl)-pyrrolidine-2-carboxylic acid; a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer, or prodrug.  
     
     
         17 . The method of  claim 16  wherein the alpha-2-delta ligand compound comprises (1α,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer, or prodrug.  
     
     
         18 . The method of  claim 15  wherein the alpha-2-delta ligand compound is gabapentin; pregabalin; [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid; 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one; (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid; (1α,3α,5α) (3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid; (3S,5R)-3-aminomethyl-5-methyl-octanoic acid; (3S,5R)-3-amino-5-methyl-heptanoic acid; (3S,5R)-3-amino-5-methyl-nonanoic acid; (3S,5R)-3-amino-5-methyl-octanoic acid; (2S, 4S)-4-(3-Chloro-phenoxy)-pyrrolidine-2-carboxylic acid; (2S,4S)-4-(3-fluoro-benzyl)-pyrrolidine-2-carboxylic acid; (2S,4S)-4-(2,3-difluoro-benzyl)-pyrrolidine-2-carboxylic acid; or (2S,4S)-4-(3-fluoro-phenoxymethyl)-pyrrolidine-2-carboxylic acid; a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer, or prodrug.  
     
     
         19 . The method of  claim 18  wherein the alpha-2-delta ligand compound comprises (1α,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer, or prodrug.  
     
     
         20 . A method of treating COPD or a disease, disorder or condition associated with a diagnosis of COPD in a mammal, which method comprises administering to said mammal in need of such treatment a pharmaceutical composition comprising an alpha-2-delta ligand, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle or diluent.  
     
     
         21 . A method of treating chronic cough in a mammal, which method comprises administering to said mammal in need of such treatment a pharmaceutical composition comprising an alpha-2-delta ligand, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle or diluent.