Substituted 1-Arylalkyl-4-Acylaminopiperidine Compounds and Methods of Producing and Using the Same

Abstract

to treat various clinical conditions including, but not limited to, hemorrhagic shock, nicotine withdrawal symptoms, gastrointestinal side effects of opioids, cancer therapy, epithelial wounds, herpes zoster infection, or opioid-induced pruritus. In compound of Formula I, R1 is C1-10 alkyl, C1-10 haloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R2 is C1-6 alkylene; Y is optionally substituted aryl, optionally substituted heteroaryl, or a moiety of the formula —C(═O)—X1, wherein X1 is —OR3 or —NR4R5, where each of R3, R4 and R5 is H or C1-10 alkyl.

1 . A method for treating a clinical condition associated with α 2B  adrenoreceptor activation, said method comprising administering a therapeutically effective amount of an α 2B  adrenoreceptor antagonist to a patient in need of such a treatment, wherein said α 2B  adrenoreceptor antagonist is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is C 1-10  alkyl, C 1-10  haloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 R 2  is C 1-6  alkylene; 
 Y is optionally substituted aryl, optionally substituted heteroaryl, or a moiety of the formula —C(═O)—X 1 , wherein X 1  is —OR 3  or —NR 4 R 5 , where each of R 3 , R 4  and R 5  is H or C 1-10  alkyl, 
 
       and wherein said clinical condition associated with α 2B  adrenoreceptor activation is selected from the group consisting of hemorrhagic shock, nicotine withdrawal symptoms, gastrointestinal side effects of opioids, cancer therapy, epithelial wounds, herpes zoster infection, and opioid-induced pruritus. 
     
     
         2 . The method of  claim 1 , wherein R 1  is selected from the group consisting of ethyl, 7-bromoheptyl, fur-2-yl, fur-3-yl, and phenyl. 
     
     
         3 . The method of  claim 1 , wherein R 2  is ethylene. 
     
     
         4 . The method of  claim 1 , wherein Y is selected from the group consisting of phenyl, thiophen-2-yl, and a moiety of the formula —C(═O)—OR 3 , where R 3  is C 1-10  alkyl. 
     
     
         5 . The method of  claim 1 , wherein said α 2B  adrenoreceptor antagonist compound is selected from the group consisting of N-(1-phenethylpiperidin-4-yl)propionamide, methyl 3-(4-propionamidopiperidin-1-yl)propanoate, N-(1-phenethylpiperidin-4-yl)furan-2-carboxamide, N-(1-phenethylpiperidin-4-yl)furan-3-carboxamide, N-(1-(2-(thiophen-2-yl)ethyl)piperidin-4-yl)propionamide, 8-bromo-N-(1-phenethylpiperidin-4-yl)octanamide, and N-(1-phenethylpiperidin-4-yl)benzamide. 
     
     
         6 . A method for treating hemorrhagic shock, nicotine withdrawal symptoms, gastrointestinal side effects of opioids, cancer therapy, epithelial wounds, herpes zoster infection, or opioid-induced pruritus in a subject, said method comprising administering a therapeutically effective amount of an N-substituted piperidin-4-yl compound to a subject in need of such a treatment, wherein said N-substituted piperidin-4-yl compound is of the Formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is C 1-10  alkyl, C 1-10  haloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 R 2  is C 1-6  alkylene; 
 Y is optionally substituted aryl, optionally substituted heteroaryl, or a moiety of the formula —C(═O)—X 1 , wherein X 1  is —OR 3  or —NR 4 R 5 , where each of R 3 , R 4  and R 5  is H or C 1-10  alkyl. 
 
     
     
         7 . The method of  claim 6 , wherein R 1  is selected from the group consisting of ethyl, 7-bromoheptyl, fur-2-yl, fur-3-yl, and phenyl. 
     
     
         8 . The method of  claim 6 , wherein R 2  is ethylene. 
     
     
         9 . The method of  claim 6 , wherein Y is selected from the group consisting of phenyl, thiophen-2-yl, and a moiety of the formula —C(═O)—OR 3 , where R 3  is C 1-10  alkyl. 
     
     
         10 . The method of  claim 6 , wherein said α 2B  adrenoreceptor antagonist compound is selected from the group consisting of N-(1-phenethylpiperidin-4-yl)propionamide, methyl 3-(4-propionamidopiperidin-1-yl)propanoate, N-(1-phenethylpiperidin-4-yl)furan-2-carboxamide, N-(1-phenethylpiperidin-4-yl)furan-3-carboxamide, N-(1-(2-(thiophen-2-yl)ethyl)piperidin-4-yl)propionamide, 8-bromo-N-(1-phenethylpiperidin-4-yl)octanamide, and N-(1-phenethylpiperidin-4-yl)benzamide.