6-AMIDO DERIVATIVES OF 4, 5-a EPOXYMORPHINANS FOR THE TREATMENT OF PAIN

Abstract

Compounds of formula: in which R 4 is chosen from substituted phenyl, optionally substituted naphthylene, optionally substituted anthracene and optionally substituted aromatic heterocycle, are useful as analgesics.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is chosen from
 (a) C 2 -C 10  hydrocarbon other than cyclopropylmethyl; and 
 (b) —CH 2 -Het, wherein Het is a five- or six-membered heterocycle; 
 
         R 2  is chosen from hydrogen, (C 1 -C 6 )acyl, (C 1 -C 6 )oxaalkyl, and (C 1 -C 6 )acyloxaalky; 
         R 3  is chosen from hydrogen and (C 1 -C 6 )alkyl; 
         R 4  is chosen from 
         (a) phenyl substituted at other than 2 or 6 with from one to three substituents chosen from amino, bromo, chloro, iodo, hydroxy, nitro, cyano, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )alkoxy and R 10 ; 
         (b) optionally substituted naphthylene; 
         (c) optionally substituted anthracene; 
         (d) optionally substituted aromatic heterocycle; 
         R 8  is chosen from hydrogen and (C 1 -C 6 )alkyl; 
         R 10  is optionally substituted phenyl, optionally substituted aromatic heterocycle or optionally substituted non-aromatic oxygen or sulfur heterocycle; 
         wherein the substituents on naphthylene, anthracene, heterocycle or R 10  are chosen independently from halogen, hydroxy, nitro, cyano, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )acyl and (C 1 -C 3 )alkoxy. 
       
     
     
         2 . A compound according to  claim 1  wherein
 R 1  is cyclobutylmethyl or allyl; 
 R 3  is hydrogen or methyl; 
 R 4  is chosen from 
 (a) phenyl substituted at other than 2 or 6 with from one to three substituents chosen from amino, bromo, chloro, iodo, hydroxy, nitro, cyano, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )alkoxy and R 10 ; 
 (b) optionally substituted naphthylene; 
 (c) optionally substituted anthracene; 
 (d) aromatic heterocycle chosen from pyridine, thiophene, furan and pyrrole optionally substituted with from one to three substituents chosen from bromo, chloro, iodo, hydroxy, nitro, cyano, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy and (C 1 -C 3 )alkoxy; and R 8  is hydrogen. 
 
     
     
         3 . A compound of formula II 
       
         
           
           
               
               
           
         
         wherein 
         R 2  is chosen from hydrogen, (C 1 -C 6 )acyl, (C 1 -C 6 )oxaalkyl, and (C 1 -C 6 )acyloxaalkyl; 
         R 3  is chosen from hydrogen and (C 1 -C 6 )alkyl; 
         R 4a  is chosen from 
       
       
         
           
           
               
               
           
         
       
       wherein R 5a  is chosen from amino, bromo, chloro, iodo, cyano, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, (C 2 -C 3 )alkoxy and R 10 ; 
       
         
           
           
               
               
           
         
       
       wherein R 6a  is chosen from hydroxy, nitro, cyano, (C 2 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )alkoxy and R 10 ; 
       
         
           
           
               
               
           
         
       
       wherein R 5  is chosen from halogen, hydroxy, nitro, cyano, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )alkoxy and R 10 ; and R 6b  is chosen from halogen, hydroxy, nitro, cyano, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )alkoxy and R 10 , or, taken together, R 5  and R 6b  are alkylenedioxy, with the proviso that both R 5  and R 6b  are not chloro or fluoro; 
       
         
           
           
               
               
           
         
       
       wherein R 5b  is chosen from bromo, chloro, iodo, hydroxy, nitro, cyano, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )alkoxy and R 10 ; R 6  is chosen from hydrogen, halogen, hydroxy, nitro, cyano, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )alkoxy and R 10 ; R 7  is chosen from halogen, hydroxy, nitro, cyano, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )alkoxy and R 10 ; and
 (e) napthylene substituted with from one to three substituents chosen from halogen, hydroxy, nitro, cyano, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )alkoxy and R 10 ; 
 (f) anthracene optionally substituted with from one to three substituents chosen from halogen, hydroxy, nitro, cyano, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )alkoxy and R 10 ; 
 (g) aromatic heterocycle other than unsubstituted pyridine, quinoline or isoquinoline, optionally substituted with from one to three substituents chosen from halogen, hydroxy, nitro, cyano, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )alkoxy and R 10 ; 
 R 8  is chosen from hydrogen and (C 1 -C 6 )alkyl; and 
 R 10  is optionally substituted phenyl, optionally substituted aromatic heterocycle or optionally substituted non-aromatic oxygen or sulfur heterocycle; 
 wherein the substituents on naphthylene, anthracene, heterocycle or R 10  are independently chosen from halogen, hydroxy, nitro, cyano, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )acyl and (C 1 -C 3 )alkoxy. 
 
     
     
         4 . A compound according to  claim 1  wherein the amide substituent at the oxymorphone 6 position is in the β configuration and R 8  is hydrogen: 
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound according to  claim 4  wherein R 2  is H. 
     
     
         6 . A compound according to  claim 4  wherein R 2  is chosen from CH 3 , acetyl, acetoxymethyl, —CH 2 C(═O)C(CH 3 ) 3  and —CH 2 C(═O)OCH 3 . 
     
     
         7 . A compound according to  claim 4  wherein R 3  is H. 
     
     
         8 . A compound according to  claim 4  wherein R 3  is CH 3 . 
     
     
         9 . A compound according to  claim 4  wherein R 4  is 
       
         
           
           
               
               
           
         
       
       wherein R 5a  is chosen from bromo, chloro, iodo, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, (C 2 -C 3 )alkoxy and R 10 . 
     
     
         10 . A compound according to  claim 9  wherein R 5a  is chosen from bromo, chloro, iodo, trifluoromethyl, trifluoromethoxy and R 10 , and R 10  is chosen from phenyl, furanyl and thiophenyl optionally substituted with one to three substituents independently chosen from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy and acetyl. 
     
     
         11 . A compound according to  claim 4  wherein R 4  is 
       
         
           
           
               
               
           
         
       
       wherein R 5  is chosen from halogen, nitro, cyano, methyl, trifluoromethyl, trifluoromethoxy, methoxy, phenyl, thiophenyl, furanyl; and R 6b  is chosen from halogen, nitro, cyano, methyl, trifluoromethyl, trifluoromethoxy, methoxy, phenyl, thiophenyl, furanyl, with the proviso that both R 5  and R 6b  are not phenyl or heteroaryl. 
     
     
         12 . A compound according to  claim 11  wherein R 4  is 3,4-diiodophenyl. 
     
     
         13 . A compound according to  claim 2  wherein the amide substituent at the oxymorphone 6 position is in the β configuration and R 4  is phenyl substituted at other than 2 or 6 with from one to three substituents chosen from bromo, chloro, iodo, hydroxy, nitro, cyano, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )alkoxy and R 10 . 
     
     
         14 . A compound according to  claim 13  wherein R 4  is phenyl substituted at the 3- and 4-positions with two substituents chosen independently from bromo, chloro, iodo, methyl, trifluoromethyl, methoxy and trifluoromethoxy. 
     
     
         15 . A compound according to  claim 14  wherein R 1  is allyl; R 2  is H; R 3  is hydrogen and R 4  is 3,4-diiodophenyl. 
     
     
         16 . A compound according to  claim 13  wherein R 4  is phenyl substituted at the 3- or 4-position with a substituent chosen from bromo, chloro, iodo, methyl, trifluoromethyl, methoxy, trifluoromethoxy and R 10 , and R 10  is chosen from phenyl, furanyl and thiophenyl optionally substituted with one to three substituents independently chosen from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy, methylenedioxy and acetyl. 
     
     
         17 . A compound according to  claim 10  wherein R 4  is 3-iodophenyl. 
     
     
         18 . A compound according to  claim 2  wherein the amide substituent at the oxymorphone 6 position is in the β configuration and R 4  is optionally substituted quinoline. 
     
     
         19 .- 21 . (canceled) 
     
     
         22 . A method for reducing pain comprising administering to a subject suffering from pain an amount of a compound according to  claim 1  effective to reduce pain. 
     
     
         23 .- 25 . (canceled) 
     
     
         26 . A method for assaying for the kappa3 receptor comprising exposing a tissue to a radiolabeled compound according to  claim 1 , rinsing said tissue and measuring the amount and/or location of said radiolabeled compound in said tissue. 
     
     
         27 . A method for assaying for an opioid-like receptor comprising exposing a labeled compound according to  claim 12  to a source of receptor in vitro or in vivo, and measuring the amount and/or location of said labeled compound bound to the receptor. 
     
     
         28 .- 30 . (canceled)