Nicotinic acetylcholine receptor silent agonists

Abstract

Derivatives of N,N-diethyl-N′-phenyl-piperazine, a silent agonist of the mammalian α7 nicotinic acetylcholine receptor, are provided. These silent agonists control the desensitization state of the receptor. Further provided are pharmaceutical compositions that allow the administration of the silent agonists of the disclosure to a subject animal or human in need of treatment for a pathological condition arising from such as inflammation. The novel silent agonists also may be co-administered to a patient simultaneously or consecutively with a type II positive allosteric modulator to modulate the activity of the receptor.

1 - 20 . (canceled) 
     
     
         21 . A compound having the formula III, or IV: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Y is: 
 
       
         
           
           
               
               
           
         
         Z is 
       
       
         
           
           
               
               
           
         
         n is 2, 3, 4, or 5; 
         R 1 , R 2 , and R 3  is each independently a hydrogen, an alkyl group, cyano, an alkoxy group, a halogen, a trihaloalkyl, a carboxamide, pentafluorosulfanyl, or hydroxyl, and wherein the halogen is fluorine, chlorine or bromine; and 
         R 5  is a hydrogen or a carboxytrifluoromethyl. 
       
     
     
         22 . The compound of  claim 21 , wherein R 1 , R 2 , and R 3  is each independently a hydrogen, a methyl, cyano, methoxy, a halogen, trihaloalkyl, a carboxamide, pentafluorosulfanyl, or hydroxyl. 
     
     
         23 . The compound of  claim 21 , wherein R 1 , R 2 , and R 3  is each independently a hydrogen, a methyl, cyano, methoxy, a halogen, a trihaloalkyl, a carboxamide, pentafluorosulfanyl, or hydroxyl, and R 5  is hydrogen. 
     
     
         24 . The compound of  claim 21 , wherein:
 when R 1  is a methyl or a CN, R 2  and R 3  are each hydrogen;   when R 1  is a methoxy, R 2  is hydrogen R 3  is hydrogen or methoxy;   when R 1  is a halogen, R 2  and R 3  are each hydrogen;   when R 1  is a trifluoromethyl, R 2  and R 3  are each hydrogen;   when R 1  is a carboxamide, pentafluorosulfanyl, R 2  and R 3  are each hydrogen;   when R 1  and R 3  are each hydrogen, R 2  is a methyl, a CN, a methoxy, a halogen, a trifluoromethyl, or a carboxamide, or OH; and   when R 1  and R 2  are each hydrogen, R 3  is a methyl or Cl.   
     
     
         25 . A pharmaceutical composition comprising a compound having the formula III, or IV: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Y is: 
 
       
         
           
           
               
               
           
         
         Z is 
       
       
         
           
           
               
               
           
         
         n is 2, 3, 4, or 5; 
         R 1 , R 2 , and R 3  is each independently a hydrogen, an alkyl group, cyano, an alkoxy group, a halogen, a trihaloalkyl, a carboxamide, pentafluorosulfanyl, or hydroxyl, and wherein the halogen is fluorine, chlorine or bromine; 
         R 4  is a hydrogen or an ethyl group; and 
         R 5  is a hydrogen or a carboxytrifluoromethyl; and a pharmaceutically acceptable carrier. 
       
     
     
         26 . The pharmaceutical composition of  claim 25 , wherein R 1 , R 2 , and R 3  is each independently a hydrogen, a methyl, cyano, methoxy, a halogen, trihaloalkyl, a carboxamide or hydroxyl. 
     
     
         27 . The pharmaceutical composition of  claim 25 , wherein R 1 , R 2 , and R 3  is each independently a hydrogen, a methyl, cyano, methoxy, a halogen, a trihaloalkyl, a carboxamide, pentafluorosulfanyl, or hydroxyl, and R 5  is hydrogen. 
     
     
         28 . The pharmaceutical composition of  claim 25 , wherein:
 when R 1  is a methyl or a CN, R 2  and R 3  are each hydrogen;   when R 1  is a methoxy, R 2  is hydrogen R 3  is hydrogen or methoxy;   when R 1  is a halogen, R 2  and R 3  are each hydrogen;   when R 1  is a trifluoromethyl, R 2  and R 3  are each hydrogen;   when R 1  is a carboxamide, pentafluorosulfanyl, R 2  and R 3  are each hydrogen;   when R 1  and R 3  are each hydrogen, R 2  is a methyl, a CN, a methoxy, a halogen, a trifluoromethyl, or a carboxamide, or OH; and   when R 1  and R 2  are each hydrogen, R 3  is a methyl or Cl.   
     
     
         29 . The pharmaceutical composition of claim  6 , wherein said composition is formulated to deliver to a human or animal subject in need thereof, an amount of the compound therapeutically effective in modulating the activity of a nicotinic acetylcholine receptor in the recipient patient, and wherein the therapeutically effective amount is delivered as a single dose or as a series of doses. 
     
     
         30 . The pharmaceutical composition of  claim 25 , further comprising a therapeutically effective amount of a nicotinic acetylcholine receptor positive allosteric modulator (PAM). 
     
     
         31 . The composition of  claim 30 , wherein the nicotinic acetylcholine receptor positive allosteric modulator (PAM) is a type II PAM. 
     
     
         32 . The composition of  claim 31 , wherein the nicotinic acetylcholine receptor positive allosteric modulator (PAM) is the type II PAM 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea (PNU-120596). 
     
     
         33 . A method of modulating the activity of a nicotinic acetylcholine receptor in an animal or human subject by administering to said subject therapeutically effective doses of a silent agonist of the nicotinic acetylcholine receptor and a nicotinic acetylcholine receptor positive allosteric modulator (PAM). 
     
     
         34 . The method of  claim 33 , wherein the silent agonist of the nicotinic acetylcholine receptor and the nicotinic acetylcholine receptor positive allosteric modulator (PAM) are administered to the subject simultaneously or as consecutive doses. 
     
     
         35 . The method of  claim 33 , wherein the silent agonist of the nicotinic acetylcholine receptor is a compound having the formula I, II, III, or IV: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Y is: 
 
       
         
           
           
               
               
           
         
         Z is 
       
       
         
           
           
               
               
           
         
         n is 2, 3, 4, or 5; 
         R 1 , R 2 , and R 3  is each independently a hydrogen, an alkyl group, cyano, an alkoxy group, a halogen, a trihaloalkyl, a carboxamide, pentafluorosulfanyl, or hydroxyl, and wherein the halogen is fluorine, chlorine or bromine; and 
         R 5  is a hydrogen or a carboxytrifluoromethyl. 
       
     
     
         36 . The method of claim  15 , wherein the nicotinic acetylcholine receptor positive allosteric modulator (PAM) is a type II PAM. 
     
     
         37 . The method of claim  18 , wherein the nicotinic acetylcholine receptor positive allosteric modulator (PAM) is the type II PAM 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea (PNU-120596).