Spiro-oxindole compounds and their use as therapeutic agents

Abstract

This invention is directed to spiro-oxindole compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment and/or prevention of sodium channel-mediated diseases or conditions, such as pain.

1 .- 2 . (canceled) 
     
     
         3 . A compound of formula (VI): 
       
         
           
           
               
               
           
         
       
       wherein:
 Z is —O— or —N(H)—; 
 R 10  is hydrogen, 3-methylbutyl, 4-methoxybenzyl, 2-(2-methoxyethoxy)ethyl, 4-isoxazol-5-ylbenzyl, 2-(trifluoromethyl)benzyl, [3-(trifluoromethyl)pyridin-2-yl]methyl, [4-(hydroxycarbonyl)oxazol-2-yl]methyl, [4-(N,N-dimethylaminocarbonyl)oxazol-2-yl]methyl, (4-cyanomethylcarbonyl)benzyl, [5-(trifluoromethyl)furan-2-yl]methyl, (2R)-tetrahydrofuran-2-ylmethyl, (3-fluoropyridin-2-yl)methyl, [4-(methoxycarbonyl)oxazol-2-yl]methyl, 4-(3-amino-1H-pyrazol-5-yl)benzyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl or pyrazin-2-ylmethyl; and 
 R 10a  is hydrogen, methyl or —NH 2 ; 
 as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof; 
 
       or a pharmaceutically acceptable salt, solvate or prodrug thereof. 
     
     
         4 .- 11 . (canceled) 
     
     
         12 . The compound of  claim 3  wherein Z is —O— or —N(H)— and R 10a  is hydrogen or methyl. 
     
     
         13 . The compound of  claim 12  selected from:
 1′-[2-(trifluoromethyl)benzyl]-1H-spiro[furo[3,2-f]indazole-5,3′-indol]-2′(1′H)-one; 
 1′-(pyridin-2-ylmethyl)-1H-spiro[furo[3,2-f]indazole-5,3′-indol]-2′(1′H)-one; 
 1′-((3-(trifluoromethyl)pyridin-2-yl)methyl)-1,6-dihydrospiro[furo[3,2-f]indazole-5,3′-indolin]-2′-one; 
 1′-(4-methoxybenzyl)-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one; 
 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one; 
 3-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one; 
 3-methyl-1′-(pyridin-2-ylmethyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one; 
 3-methyl-1′-(pyridin-3-ylmethyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one; 
 3-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one; 
 1′-(4-isoxazol-5-ylbenzyl)-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one; 
 3-methyl-1′-[2-(trifluoromethyl)benzyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one; 
 3-methyl-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one; 
 1′-[2-(2-methoxyethoxy)ethyl]-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one; 
 3-methyl-1′-(3-methylbutyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one; 
 3-methyl-1′-(pyrazin-2-ylmethyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one; 
 1′-[(3-fluoropyridin-2-yl)methyl]-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one; 
 methyl 2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate; 
 2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylic acid; 
 N,N-dimethyl-2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide; 
 3-{4-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]phenyl}-3-oxopropanenitrile; or 
 1′-[4-(3-amino-1H-pyrazol-5-yl)benzyl]-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one hydrochloride. 
 
     
     
         14 . The compound of  claim 3  wherein R 10a  is —NH 2 . 
     
     
         15 . The compound of  claim 14  selected from:
 3-amino-1′-(4-methoxybenzyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one; 
 3-amino-1′-(pyridin-2-ylmethyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one; 
 3-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one; or 
 3-amino-1′-[2-(trifluoromethyl)benzyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one. 
 
     
     
         16 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of any one of  claims 3  and  12 - 15 , as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof. 
     
     
         17 . A method of treating, preventing or ameliorating a disease or a condition in a mammal selected from the group consisting of pain, hypercholesterolemia, benign prostatic hyperplasia, pruritis, cancer, depression, cardiovascular diseases, respiratory diseases, and psychiatric diseases, and combinations thereof, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of any one of  claims 3  and  12 - 15 , as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof.