Kappa agonist compounds and pharmaceutical formulations thereof

Abstract

Compounds having kappa opioid agonist activity, compositions containing them and method of using them as analgesics are provided. The compounds of formulae I, II, IIA, III, IIIA, IIIB, IIB-i, IV and IVA have the structure: wherein R 1 , R 2 , R 3 , R 4 ; and X, X 4 , X 5 , X 7 , X 9 ; Y, Z and n are as described in the specification.

1 - 19 . (canceled)  
     
     
         20 . A compound of the formula IIIA or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 n is 1 to 3;  
 R 1  and R 2  are independently CH 3  or together form —(CH 2 ) m —, —CH 2 CH(OR)(CH 2 ) 2 —, —CH 2 CH(F)(CH 2 ) 2 —, —(CH 2 ) 2 O(CH 2 ) 2 — or —(CH 2 ) 2 CH═CHCH 2 —;  
 R is H, alkyl, acyl or aroyl;  
 Ar is mono- or di-substituted phenyl, wherein said substituents are selected from the group consisting of halogen, OCH 3 , OH, SO 2 CH 3 , CF 3 , NH 2 , alkyl, CN, unsubstituted and substitued sulfamoyl groups;  
 Ar may also be substituted with NH(CH 2 ) u CO 2 R′, NH(CH 2 ) u (CH═CH) u (CH 2 )CO 2 R′, NHCO(CH 2 ) u (CH═CH) u (CH 2 ) u CO 2 R′, NHP(O)(OBn) 2 , NHP(O)(OR′) 2 , (CH 2 ) u NHSO 2 CH 3 , (CH 2 ) u NHC(S)NHCH(CO 2 R′)(CH 2 ) u CO 2 R′, CONHOH, or (CH 2 ) u CONHOH;  
 or Ar is substituted with  
                     
 R 6  is H or Ac;  
 R 7  is NH(CH 2 ) v CO 2 H, NH(CH 2 ) v CH(NH 2 )(CO 2 H), NHCH(CO 2 H)(CH 2 ) v NH 2 . NH(CH 2 ) v SO 3 H, NH(CH 2 ) v PO 3 H, NH(CH 2 ) v NHC(NH)NH 2 , or NHCH(CO 2 H)(CH 2 ) v CO 2 H;  
 R′ is H or lower alkyl;  
 X 7  is H, halogen, OH, OCH 3 , CF 3 , NO 2 , NH 2 , amino substituted with acyl, carbamate, alkyl or aryl sulfonates, or COR″;  
 R″ is OH, amide, alkoxy, aryloxy or heteroaryloxy;  
 X 8  is CO 2 H, NHSO 2 CH 3 , NHP(O)(OBn) 2 , NHP(O)(OH) 2 , OP(O)(OBn) 2 , or OP(O)(OH) 2 ;  
 m is 4 to 8;  
 u is 0 to 5; and  
 v is 1 to 20.  
 
     
     
         21 . A compound which is selected from the group consisting of 
 N-[(4-Trifluoromethylphenyl)-N-methyl-{[1S-1-phenyl-2-[1-pyrrolidinyl)]ethyl}-acetamido]glycine hydrochloride;    2-(3,4-Dichlorophenyl)-N-methyl-N-[(1R,S)-1-(3-sulfamidophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide hydrochloride;    2-(4-Trifluoromethylphenyl)-N-methyl-N-{[1 S]-1-[3-[(methylsulfonyl)amino]-phenyl]-2-[1-pyrrolidinyl]ethyl}acetamide hydrochloride;    2-(4-Methanesulfonylphenyl)-N-methyl-N-{[1S]-1-[3-[(methylsulfonyl)amino]-phenyl]-2-[1-pyrrolidinyl]ethyl}acetamide methanesulfonate;    2-(3,4-Dichlorophenyl)-N-methyl-N-{[1S]-1-[3-[(methylsulfonyl)amino]phenyl]-2-[1-pyrrolidinyl]ethyl}acetamide hydrochloride;    2-(3,4-Dichlorophenyl)-N-methyl-N-[(1S)-1-[3-(diethyl phosphoryl)amino]phenyl)-2-(1-pyrrolidinyl)ethyl]acetamide hydrochloride;    2-(3,4-Dichlorophenyl)-N-methyl-N-[(1S)-1-[3-[(4-oxo-butenoate)]amino]phenyl)-2-(1-pyrrolidinyl)ethyl]acetamide;    2-(3,4-Dichlorophenyl)-N-methyl-N-{(1S)-1-[3-(3-(((iso-butoxycarbonyl)-methyl)aminocarbonyl)propionamido)phenyl]-2-(1-pyrrolidinyl)ethyl}acetamide hydrochloride;    2-(3,4-Dichlorophenyl)-N-methyl-N-{(1R,S)-1-[3-(3-(((hydroxycarbonyl)-methyl)aminocarbonyl)propionamido)phenyl]-2-(1-pyrrolidinyl)ethyl}acetamide hydrochloride;    2-[(2-N-Phenylsulfonamido)phenyl)]-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide methane sulfonate;    2-[3-(N-Methylsulfamoyl)-4-chlorophenyl]-N-methyl-N-{[1 S]-1-phenyl-2-[1-pyrrolidinyl]ethyl}acetamide hydrochloride;    2-(3-Sulfamoyl-4-chlorophenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-pyrrolidinyl]-ethyl}acetamide methanesulfonate;    2-(3-Sulfamoyl-4-chlorophenyl)-N-methyl-N-{[1S]-1-[3-[(methylsulfonyl)amino]-phenyl]-2-[1-pyrrolidinyl]ethyl}acetamide methanesulfonate;    2-[3-(N-Methylsulfamoyl)-4-fluorophenyl]-N-methyl-N-{[1S]-1-phenyl-2-[1-pyrrolidinyl]ethyl}acetamide hydrochloride;    2-[2&4-(N-Methylsulfamoyl)phenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-pyrrolidinyl)-ethyl]acetamide hydrochloride;    3-(N-Methylsulfamoyl)phenyl-N-methyl-N-[(1S)-phenyl-2-(1-pyrrolidinyl)ethyl]-acetamide hydrochloride;    2-[N-Methylsulfamoyl)-4-bromophenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-pyrrolidinyl]ethyl acetamide hydochloride;    2-[2&4-(N-Methylsulfamoyl)phenyl]-N-methyl-N-{[1 S]-1-phenyl-2-[1-(3S)-3-hydroxypyrrolidinyl]ethyl}acetamide hydrochloride;    2-[2-Methoxy-3-(N-methylsulfamoyl)phenyl]-N-methyl-N-{[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl}acetamide hydrochloride;    (Z)-4-[2-(2-Aminophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-(3S)-3-hydroxypyrrolidinyl]ethyl]acetamido]-4-oxo-2-butenoic acid;    (Z)-4-[2-(2-Amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-pyrrolidinyl]ethyl]acetamido]-4-oxo-butanoic acid;    (Z)-4-[2-(2-Amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-pyrrolidinyl]ethyl]acetamido]-4-oxo-2-butenoic acid;    (E) Ethyl 4-[2-(2-amino-4,5-dichorophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-pyrrolidinyl]ethyl]acetamido]-4-oxo-2-butenoate hydrochloride;    (Z)-4-[2-(2-Amino-4-trifluoromethylphenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-pyrrolidinyl]ethyl]acetamido]-4-oxo-2-butenoic acid;    (Z)-4-[2-(2-Aminophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-pyrrolidinyl]-ethyl]acetamido]-4-oxo-2-butenoic acid hemimaleate;    2-(N,N-Bisacetic acid-2-amino-α,α,α,-trifluoro-4-tolyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide hydrochloride;    3-[2-N-Methylsulfonamido)phenyl]-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)-ethyl]acetamide hydrochloride;    2-(O-Butylacetate)phenyl-N-methyl-N-[(1S)-1-phenyl-2-[1-pyrrolidinyl]ethyl acetamide hydrochloride;    2-[Phenoxy-acetyl]methylamino(1-pyrrolidinyl) ethyl]acetamide]hydrochloride;    2-[4-Trifluoromethylphenyl]-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-3-hydroxy-pyrrolidinyl]ethyl}acetamide hydrochloride;    2-(2-Pyridyl)-N-methyl-N-{[1 S]-1-phenyl-2-[1-(3S)-3-hydroxypyrrolidinyl]ethyl}-acetamide dihydrochloride;    2-(5-Bromo-3-pyridyl)-N-methyl-N-[(1S)-1-phenyl-2-pyrrolidinyl ethyl]acetamide hydrochloride;    2-(5-Bromo-3-pyridyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-3-hydroxy-pyrrolidinyl]ethyl}acetamide hydrochloride;    2-(9-Anthracenyl)-N-methyl-N-{[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl}acetamide hydrochloride;    2-(2-Carboxyphenyl)-N-methyl-N-{[1 S]-1-phenyl-2-(1-pyrrolidinyldethyl}acetamide hydrochloride;    [2-(2-Phenyl)-N-methyl-N-{[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl}acetamido]-2-oxo-glycine hydrochloride;    Methyl N-[2-(2-phenyl)-N-methyl-N-{[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl}-acetamido]-2-oxo-glycinate hydrochloride;    2-(3,4-Dihydroxyphenyl)-N-methyl-N-{[1 S]-1-phenyl-2-(1-pyrrolidinyl)ethyl}-acetamide hydrochloride;    2-(3,4-Dimethoxyphenyl)-N-methyl-N-{[1 S]-phenyl-2-(1-pyrrolidinyl)ethyl}-acetamide hydrochloride;    2-(2-Methanesulfonamidophenyl-N-methyl-N-[(1S)-1-(3-methanesulfonamidophenyl-2-(1-pyrrolidinyl)ethyl]acetamide hydrochloride;    2-(2-Iso-butyramidophenyl)-N-methyl-N-[(1S)-1-(3-isobutyramido-phenyl)-2-(1-pyrrolidinyl)ethyl]acetamide methanesulfonic acid salt;    4-[4-N-Methylsulfonamido-phenyl]-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)-ethyl]acetamide hydrochloride;    2-(3,4-Dichlorocinnamyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)-ethyl]acetamide hydrochloride;    2-(2-Nitrocinnamyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl) ethyl]acetamide hydrochloride;    (R,S)-1-[2-(Methanesulfonylamino)-phenyl-N-methylacetamido]-1-(3-methoxy-phenyl)-2-(1-pyrrolidino)-ethane, methanesulfonic acid salt;    (R,S)-1-[2-(Methanesulfonylamino)-phenyl-N-methylacetamido]-1-(3-hydroxy-phenyl)-2-(1-pyrrolidino)ethane, methanesulfonic acid salt;    2-(3-Indolyl)-N-methyl-N-[(1S)-1-phenyl-2-[(3S)-1-pyrrolidin-3-ol]ethyl]-acetamide hydrochloride;    2-(2-N-Benzyl-2-N-methylsulfamoyl-3,4-dimethoxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide hydrochloride;    2-(N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-[(1R)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide methane sulfonate;    (R,S)-1-(4-Trifluoromethylphenyl-N-methylacetamido)-1-(3-methoxyphenyl)-2-(1-pyrrolidino)-ethane, methanesulfonic acid salt;    (R,S)-1-(4-Trifluoromethylphenyl-N-methylacetamido)-1-(3-hydroxyphenyl)-2-(1-pyrrolidino)-ethane, methanesulfonic acid salt;    2-Fluorophenyl-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]-acetamide hydrochloride;    4-Fluorophenyl-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide hydrochloride; and    (E)-4-[2-(2-Amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-pyrrolidinyl]ethyl]acetamido]-4-oxo-2-butenoic acid hydrochloride.    
     
     
         22 . A pharmaceutical composition comprising a compound of  claim 20  in a pharmaceutically acceptable carrier.  
     
     
         23 . A pharmaceutical composition comprising a compound of  claim 21  in a pharmaceutically acceptable carrier.  
     
     
         24 . A method of treating hyperalgesia in a patient comprising administereing to said patient an effective amount of a compound of  claim 20 .  
     
     
         25 . A method of treating hyperalgesia in a patient comprising administereing to said patient an effective amount of a compound of  claim 21 .  
     
     
         26 . A method of treating hyperalgesia in a patient comprising administereing to said patient an effective amount of the pharmaceutical composition of  claim 22 .  
     
     
         27 . A method of treating hyperalgesia in a patient comprising administereing to said patient an effective amount of the pharmaceutical composition of  claim 23 .  
     
     
         28 . A pharmaceutical composition comprising a compound of  claim 20  and an antibiotic, antiviral, antifungal, anti-inflammatory agent, or a mixture thereof in a pharmaceutically acceptable carrier.  
     
     
         29 . A pharmaceutical composition comprising a compound of  claim 21  and an antibiotic, antiviral, antifungal, anti-inflammatory agent, or a mixture thereof in a pharmaceutically acceptable carrier.  
     
     
         30 . A compound of the formula IVA or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 n is 1 to 3;  
 R 1  and R 2  are independently CH 3  or together form —(CH 2 ) m —, —CH 2 CH(OR)(CH 2 ) 2 —, —CH 2 CH(F)(CH 2 ) 2 —, —(CH 2 ) 2 O(CH 2 ) 2 — or —(CH 2 ) 2 CH═CHCH 2 —;  
 R is H, alkyl, acyl or aroyl;  
 R 3  and R 4  are independently H, OCH 3 , alkyl or —O(CH 2 ) 2 —;  
 each X 9  is independently selected from the group consisting of halogen, CF 3 , OH, OCH 3 , SO 2 NH(CH 2 ) q CH 3 , NH(CH 2 ) q CO 2 R′, NH(CH 2 ) q (CH═CH) q (CH 2 ) q CO 2 R′, NH(CH 2 ) q (CH≡CH) q (CH 2 ) q CO 2 R′, NHCO(CH 2 ) q (CH═CH) q (CH 2 ) q CO 2 R′, and NHCO(CH 2 ) q (CH≡CH) q (CH 2 ) q CO 2 R′;  
 R′ is OH, lower alkyl, aryl ester or aryl amide;  
 q is 0 to 20; and  
 y is 1 to 4.  
 
     
     
         31 . A compound which is selected from the group consisting of 
 (Z)-4-[2-((±)-trans-2-Amino-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]phenylaetamido)]-4-oxo-2-butenoic acid;    (Z)-4-[2-((±)-trans-2-Amino-4-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-phenylaetamido)]-4-oxo-2-butenoic acid;    (±)-trans-2-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-pyridylacetamide dihydrochloride;    (±)-trans-3-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-5-bromo-pyridylacetamide hydrochloride;    (±)-trans-3,5-Di-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide hydrochloride;    (±)-trans-3-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-(trans-3-furyl)acetamide hydrochloride;    (±)-trans-2-Methoxy-3-methylsulfamoyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide hydrochloride;    (±)-trans-3-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]indoleacetamide hydrochloride;    (±)-trans-4-Fluoro-3-methylsulfamoyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide hydrochloride;    N-[1 S,2S-trans-4-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamido]glycine hydrochloride; and    N-[1 R,2R-trans-4-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamido]glycine hydrochloride.    
     
     
         32 . A pharmaceutical composition comprising a compound of  claim 30  in a pharmaceutically acceptable carrier.  
     
     
         33 . A pharmaceutical composition comprising a compound of  claim 31  in a pharmaceutically acceptable carrier.  
     
     
         34 . A method of treating hyperalgesia in a patient comprising administering to said patient an effective amount of a compound of  claim 30 .  
     
     
         35 . A method of treating hyperalgesia in a patient comprising administering to said patient an effective amount of a compound of  claim 31 .  
     
     
         36 . A method of treating hyperalgesia in a patient comprising administering to said patient an effective amount of the pharmaceutical composition of  claim 32 .  
     
     
         37 . A method of treating hyperalgesia in a patient comprising administering to said patient an effective amount of the pharmaceutical composition of  claim 33 .  
     
     
         38 . A pharmaceutical composition comprising a compound of  claim 30  and an antibiotic, antiviral, antifungal, anti-inflammatory agent, or a mixture thereof in a pharmaceutically acceptable carrier.  
     
     
         39 . A pharmaceutical composition comprising a compound of  claim 31  and an antibiotic, antiviral, antifungal, anti-inflammatory agent, or a mixture thereof in a pharmaceutically acceptable carrier.