Novel morphinans useful for treating medical disorders

Abstract

The present invention related to novel morphinans, compositions comprising the novel morphinans, and their uses as agonists of the kappa opioid receptor.

What is claimed is: 
     
         1 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R is hydrogen, methyl, allyl, cyclopropylmethyl, 1-hydroxylcyclopropylmethyl, or cyclobutylmethyl; 
         R 1  and R 2  independently are hydrogen, halogen, hydroxy, alkoxy, or aryloxy; 
         R 3  is hydrogen, hydroxy, alkoxy, or alkanoate; 
         R 7  and R 8  independently are hydrogen, alkyl, or substituted alkyl; 
         R 10  is hydrogen, hydroxy, alkyoxy, or keto; 
         R 14  is hydrogen, hydroxy, or alkoxy; 
         one of R 20 , R 21 , R 22 , and R 23  is represented by the compound of Formula (II) and the rest are chosen from hydrogen or halogen, and R 24  is hydrogen; 
       
       
         
           
           
               
               
           
         
         R 25  is hydrogen, alkyl, substituted aryl, alkylaryl, substituted alkylaryl, heterocycle, or substituted heterocycle; 
         R 26  and R 27  independently are H, Cl, Br, F, CF 3 , CN, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, aryl, substituted aryl, or heterocycle; 
         R 28  is hydrogen or halogen; 
         R 29  is absent, hydrogen, or C 1 -C 6  alkyl; 
         X is nitrogen; 
         Y is selected from a group consisting of O, S, and N; 
         and 
         the dashed line represents an optional double bond; 
         wherein the substitution on R 26  and R 27  independently are Cl, Br, F, CF 3 , CN, C 1 -C 6  alkyl, or C 3 -C 6  cycloalkyl. 
       
     
     
         2 . The compound of  claim 1 , wherein the carbons attached to R 20 -R 24  on the cyclopropyl ring independently have an R or S configuration. 
     
     
         3 . The compound of  claim 1 , wherein heterocycle is chosen from a group consisting of furyl, benzofuryl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, purinyl, quinolinyl, isoquinolinyl, thienyl, phenol, and imidazopyridyl. 
     
     
         4 . The compound of  claim 1 , wherein; R 3  is hydroxy, C 1 -C 4  alkyoxy, or alkanoate; R 7  and R 8  are each hydrogen, R 14  is hydrogen or hydroxy; R 20 , R 21 , R 23 , and R 24  are hydrogen, R 22  is furyl, substituted furyl, thienyl, substituted thienyl, pyrrole or substituted pyrrole; and R 25  is C 1 -C 4  alkyl. 
     
     
         5 . The compound of  claim 1 , wherein R is cyclopropylmethyl; R 3  is hydroxy; R 14  is hydroxy; and R 25  is methyl; R 26  is hydrogen; R 27  is Cl; and Y is O. 
     
     
         6 . The compound of  claim 1 , wherein R is cyclopropylmethyl; R 3  is hydroxy; R 14  is hydroxy; and R 25  is methyl; R 26  and R 27  are Cl; and Y is O. 
     
     
         7 . The compound of  claim 1 , wherein R is cyclopropylmethyl; R 3  is hydroxy; R 14  is hydroxy; and R 25  is methyl; R 26  is hydrogen; R 27  is CF 3 ; and Y is O. 
     
     
         8 . The compound of  claim 1 , which has an optical activity of (−) or (+); and carbons C-5, C-13, C-14, and C-9, respectively, have a configuration chosen from RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, or SSSS, provided that the C-15 and the C-16 carbons are both either on the alpha face of the molecule or the beta face of the molecule. 
     
     
         9 . The compound of  claim 1 , wherein carbon C-6 has an alpha configuration or a beta configuration. 
     
     
         10 . A pharmaceutical composition comprising a compound of  claim 1  and at least one pharmaceutically acceptable excipient. 
     
     
         11 . A method for treating a kappa opioid receptor-related disease or disorder, the method comprising administering a pharmaceutically effective amount of the pharmaceutical composition of  claim 10  to an individual in need thereof;
 wherein the wherein the kappa opioid receptor-related disease or disorder is pain, pruritis, or an addiction. 
 
     
     
         12 . The method of  claim 10 , wherein addiction is substance abuse addiction. 
     
     
         13 . The method of  claim 10 , wherein pain is chronic pain, visceral pain, neuropathic pain, and post-surgical pain. 
     
     
         14 . The method of  claim 10 , wherein the individual is a human.