Amide derivatives and nociceptin antagonists

Abstract

The present invention relates to a compound of the formula [1′] wherein R 2 is lower alkyl optionally substituted by hydroxy, amino and the like, ring B is phenyl, thienyl and the like, E is a single bond, —O—, —S— and the like, ring G is aryl, heterocyclic group and the like, R 5 is halogen atom, hydroxy, lower alkyl optionally substituted by halogen atom etc., and the like, t is 0 or an integer of 1 to 5, when t is an integer of 2 to 5, each R 5 may be the same or different, m is 0 or an integer of 1 to 8, and n is 0 or an integer of 1 to 4, and a nociceptin antagonist containing compound [1′] as an active ingredient. The compound [1′] shows, due to nociceptin antagonistic action, analgesic effect against sharp pain such as postoperative pain and the like. The present invention also relates to the use of certain amide derivative inclusive of compound [1′] as a nociceptin antagonist or analgesic.

1 . A nociceptin antagonist containing an amide derivative of the formula [1] 
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  and R 2  are the same or different and each is hydrogen atom, lower alkyl optionally substituted by hydroxy, amino, lower alkylamino or di(lower)alkylamino;  
 R 3  and R 4  are the same or different and each is hydrogen atom, halogen atom or-lower alkyl;  
 ring A is aryl or heterocyclic group;  
 ring B is phenyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl or cyclohexenyl; and  
 X is hydrogen atom, halogen atom, lower alkyl optionally substituted by lower alkoxy, lower alkenyl, amino, cyano or a group of the formula  
                     
 wherein E is a single bond, carbonyl, sulfinyl,  
 —O—, —S—, —NHCO—, —CH═CR 6 — wherein R 6  is hydrogen atom or aryl or —NR 7 — wherein R 7  is hydrogen atom, lower alkyl or lower alkoxycarbonyl;  
 ring G is aryl, heterocyclic group, cycloalkyl or condensed aryl;  
 R 5  is halogen atom, hydroxy, lower alkyl Optionally substituted by any of halogen atom, hydroxy, lower alkanoyloxy and lower alkoxy optionally substituted by lower alkoxy, lower alkoxy optionally substituted by lower alkoxy, amino, lower alkylamino, di(lower)alkylamino, nitro, cyano, lower alkanoyl, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, lower alkylsulfonyl or phenyl;  
 t is 0 or an integer of 1 to 5, which indicates the number of substituents on the ring G,  
 wherein when t is an integer of 2 to 5, each R 5  may be the same or different;  
 m is 0 or an integer of 1 to 8; and  
 n is 0 or an integer of 1 to 4, or a pharmaceutically acceptable salt thereof as an active ingredient.  
 
   
   
       2 . A nociceptin antagonist containing the amide derivative of  claim 1 , wherein the ring A is quinolyl or a pharmaceutically acceptable salt thereof as an active ingredient.  
   
   
       3 . A nociceptin antagonist containing the amide derivative of  claim 1 , wherein the ring B is phenyl and X is a group of the formula  
     
       
         
         
             
             
         
       
     
     wherein E, ring G, R 5 , t, m and n are as defined in  claim 1 , or a pharmaceutically acceptable salt thereof as an active ingredient.  
   
   
       4 . A nociceptin antagonist containing the amide derivative of  claim 3 , wherein the ring A is  
     
       
         
         
             
             
         
       
     
     wherein R 8  is lower alkylthio, or a pharmaceutically acceptable salt thereof as an active ingredient.  
   
   
       5 . An amide derivative of the formula [1′] 
     
       
         
         
             
             
         
       
     
     wherein R 2 , ring B, E, ring G, R 5 , t, m and n as defined in  claim 1 , or a pharmaceutically acceptable salt thereof.  
   
   
       6 . The amide derivative of  claim 5 , wherein the ring B is phenyl and R 2  is lower alkyl, or a pharmaceutically acceptable salt thereof.  
   
   
       7 . The amide derivative of  claim 6 , wherein the amino substitutes at the 4-position on a quinoline skeleton, R 2  is methyl substituting at the 2-position on the quinoline skeleton, E is —O— and the ring B of phenyl has a substituent of the formula  
     
       
         
         
             
             
         
       
     
     wherein ring G, R 5 , t, m and n as defined in  claim 1 , at the 2-position, or a pharmaceutically acceptable salt thereof.  
   
   
       8 . The amide derivative of  claim 7  or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of 
 N-(4-amino-2-methyl-6-quinolyl)-2-[(4-ethylphenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(2,4-dichlorophenoxy)-methyl]benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-(phenoxymethyl)benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-methoxyphenoxy)-methyl]benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(3,5-dimethylphenoxy)-methyl]benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(3,4-dimethoxyphenoxy)-methyl]benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-nitrophenoxy)methyl]-benzamide,    N-(4-amino-2-methyl-6-quinolyl)-2-[(2,3-dimethoxyphenoxy)-methyl]benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(3-methylphenoxy)-methyl]benzamide,    N-(4-amino-2-methyl-6-quinolyl)-2-[(3,5-dimethoxyphenoxy)-methyl]benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-chlorophenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-acetylphenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-hydroxyphenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-methoxymethoxyphenoxy)-methyl]benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(3-methoxyphenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-cyanophenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-methylphenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-trifluoromethylphenoxy)methyl]benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(3-nitrophenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(2-nitrophenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-acetoxyphenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(2-methoxyphenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-aminophenoxy)methyl]-benzamide dihydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[-(3-chlorophenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-fluorophenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(3,4-dichlorophenoxy)-methyl]benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(2-chlorophenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-dimethylaminophenoxy)-methyl]benzamide dihydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-tert-butylphenoxy)-methyl]benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-(4-biphenylyloxymethyl)-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-isopropylphenoxy)-methyl]benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-nitrophenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-bromophenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-propylphenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(3-fluorophenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(3-trifluoromethylphenoxy)methyl]benzamide hydrochloride,    methyl 4-[2-{N-(4-amino-2-methyl-6-quinolyl)carbamoyl}-benzyloxylbenzoate hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-iodophenoxy)methyl]-benzamide,    N-(4-amino-2-methyl-6-quinolyl)-2-(3-pyridyloxymethyl)-benzamide hydrochloride,    4-[2-{(4-amino-2-methyl-6-quinolyl)carbamoyl}benzyloxy]-benzoate hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(3-cyanophenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-mesylphenoxy)methyl]-benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(2-chloro-4-ethylphenoxy)-methyl]benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-chloro-3-methylphenoxy)methyl]benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(2-chloro-4-methylphenoxy)methyl]benzamide hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-ethylphenoxy)methyl]-benzamide,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-chloro-3-methylphenoxy)methyl]benzamide,    4-[2-{(4-amino-2-methyl-6-quinolyl)carbamoyl}benzyloxy]benzyl acetate hydrochloride,    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-hydroxymethylphenoxy)-methyl]benzamide hydrochloride and    N-(4-amino-2-methyl-6-quinolyl)-2-[(4-ethylphenoxy)methyl]-benzamide hydrochloride monohydrate.    
   
   
       9 . An amide derivative of the formula [1″] 
     
       
         
         
             
             
         
       
     
     wherein the ring A, R 2 , R 5  and t are as defined in  claim 1 , or a pharmaceutically acceptable salt thereof.  
   
   
       10 . A pharmaceutical composition comprising the amide derivative of any of  claims 5  to  9  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.  
   
   
       11 . A nociceptin antagonist containing the amide derivative of any of  claims 5  to  9  or a pharmaceutically acceptable salt thereof as an active ingredient.  
   
   
       12 . An analgesic containing the amide derivative of any of  claims 1  to  9  or a pharmaceutically acceptable salt thereof as an active ingredient.  
   
   
       13 . A method for expressing a nociceptin antagonistic action, comprising administering the amide derivative of any of  claims 1  to  9  or a pharmaceutically acceptable salt thereof.  
   
   
       14 . A method for treating pain, comprising administering the amide derivative of any of  claims 1  to  9  or a pharmaceutically acceptable salt thereof.  
   
   
       15 . Use of the amide derivative of any of  claims 1  to  9  or a pharmaceutically acceptable salt thereof for the production of a nociceptin antagonist.  
   
   
       16 . Use of the amide derivative of any of  claims 1  to  9  or a pharmaceutically acceptable salt thereof for the production of an analgesic.  
   
   
       17 . A pharmaceutical composition for antagonizing nociceptin, which comprises the amide derivative of any of  claims 1  to  9  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.  
   
   
       18 . A commercial package comprising the pharmaceutical composition of  claim 17  and a written matter associated therewith, the written matter stating that the pharmaceutical composition can be or should be used for antagonizing nociceptin.  
   
   
       19 . A pharmaceutical composition for analgesic use, which comprises the amide derivative of any of  claims 1  to  9  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.  
   
   
       20 . A commercial package comprising the pharmaceutical composition of  claim 19  and a written matter associated therewith, the written matter stating that the pharmaceutical composition can be or should be used for analgesia.