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, III and IV have the structure:wherein:X, X4, X5, X7, X9;R1, R2, R3, R4; andY, Z and n are as described in the specification.

What is claimed is:  
     
       1. A compound of the formula III or a pharmaceutically acceptable salt thereof                    
       wherein 
       n=1-3;  
       R 1  and R 2  are independently ═CH 3 ; —(CH 2 ) m , where m=4-8, —CH 2 CH(OH)(CH 2 ) 2 —; —CH 2 CH(F) (CH 2 ) 2 —;  
       —(CH 2 ) 2 O(CH 2 ) 2 —; or —(CH 2 ) 2 CH═CHCH 2 —;  
       Ar=unsubstituted or mono-, or di-substituted phenyl wherein said substituents are selected from the group consisting of halogen, OCH 3 , SO 2 CH 3 , CF 3 , amino, alkyl, and 3,4-dichloro; benzothiophenyl; benzofuranyl; naphthyl; diphenyl methyl; or 9-fluorene; or Ar=heteroaromatic groups having 1-3 heteroatoms selected from the group consisting N, O and S and bearing 1-4 substituents selected from the group consisting of chlorobenzoyl, Br, Cl, F, alkyl, alkoxy, carboxy, carboxamided, amine, amide and sulfonamide;  
       X 7  is 
       —NHSO 2 CH 3 ; —NHP(O)(OBn) 2 ; —NHP(O)(OH) 2 ; —(CH 2 ) u NHSO 2 CH 3 ; —(CH 2 ) u NHC(S)NHCH (CO 2 H)(CH 2 ) u CO 2 H; —CONHOH; or —(CH 2 ) u  CONHOH;  
       wherein 
       u=1-5;  
       or X y  is                    
       R 6 =—H or -Ac;  
       X 8 =—CO 2 H; —NHSO 2 CH 3 ; —NHP(O)(OBn) 2 ;  
       —NHP(O)(OH) 2 ; —OP(O)(OBn) 2 ; or  
       —OP(O)(OH) 2 ;  
       R 7 =—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 2 ; —NH(CH 2 ) v NHC(NH)NH 2 ; or  
       —NHCH(CO 2 H)(CH 2 ) v CO 2 H; and  
       v=1-20.  
     
     
       2. The compound according to  claim 1  selected from the group consisting of: 2-(3,4-dichlorophenyl)-N-methyl-N-{1-[3-(N-2-acetic acid)carboxamido]phenyl-2-(1-pyrrolidinyl)ethyl}acetamide; 2-(3,4-dichlorophenyl)-N-methyl-N-{1-[3-(N-methanesulfonamido)aminomethyl] phenyl-2-(1-pyrrolidinyl)ethyl}acetamide; 2-(3,4-dichlorophenyl)-N-methyl-N-{1-[3-(N-succinic acid-2S-thioureido)aminomethyl]phenyl-2-(1-pyrrolidinyl) ethyl}acetamide; and 2-(3,4-dichlorophenyl)-N-methyl-N-{1-[3-(N-2-acetic acid)sulfonamido]phenyl-2-(1-pyrrolidinyl)ethyl}acetamide. 
     
     
       3. The compound according to  claim 1 A compound selected from the group consisting of: 
       2-(3,4-Dichlorophenyl)-N-methyl-N-{[1S]-1-[N-(S-aspartic acid-a-amide-S-aspartic acid-a-amido)-3-aminophenyl]-2-[1-pyrrolidinyl]ethyl}acetamide;  
       2-(3,4-Dichlorophenyl)-N-methyl-N-{[1S]-1-[N-(bis-methylsulfonamido)-3-aminophenyl]-2-]1-pyrrolidinyl]ethyl}acetamide; 2 -(   3 , 4   - Dichlorophenyl )- N - methyl - N - {[ 1 S] -   1   - [N -( bis - methylsulfonamido )-   3   - aminophenyl] -   2   - [ 1   - pyrrolidinyl]ethyl}acetamide;   
       2-(2-Nitrophenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(2-Aminophenyl)-N-methyl-N-[(1S)-1-(3-aminophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(N-Diethyl phosphoramidate-2-aminophenyl)-N-methyl-N-[(1S)-1-(N-diethyl phosphoramidate-3-aminophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(N-Bis-sulfonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-(N-bis-sulfonamido-3-aminophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(2-Nitro-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(4-Methylsulfonylphenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(N-butyloxycarbonyl-4-aminophenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(4-Aminophenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(N-Bis-sulfonamido-4-aminophenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(N-B is-sulfonamido-4-aminophenyl)-N-methyl-N-[(1S)-1-(3-aminophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide; 2 -( N - Bis - sulfonamido -   4   - aminophenyl )- N - methyl - N -[(   1 S )-   1   -(   3   - aminophenyl )-   2   -(   1   - pyrrolidinyl ) ethyl]acetamide;   
       2-(N-Bis-sulfonamido-4-aminophenyl)-N-methyl-N-[(1S)-1-(N-diethyl phosphoramidate-3-aminophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(2-Nitrophenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)[ethyl}acetamide;  
       2-(2-Nitro-4,5-dichlorophenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)[ethyl}acetamide;  
       2-(4-Methylsulfonylphenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)[ethyl}acetamide;  
       2-(2-Nitro-4-trifluoromethylphenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)[ethyl}acetamide;  
       2-(2-Amino-4-trifluoromethylphenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)[ethyl}acetamide;  
       2,2-Diphenyl-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       N′,N′-Diphenyl-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]urea;  
       2-(2-Nitrophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(2-Nitro-4,5-dichlorophenyl)-N-methyl-N-[1S]-1-phenyl-2-(1-pyrrolidinyl) ethyl]acetamide;  
       2-(4-Methylsulfonylphenyl)-N-methyl-N-[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(2-Methoxyphenyl)-N-methyl-N-[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(3-Indolyl)-N-methyl-N-[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(α,α,α-Trifluoro-p-tolyl)-N-methyl-N-[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(2-Nitro-α,α,α-Trifluro-4-tolyl)-N-methyl-N-[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(1-[4-Chlorobenzoyl)-5-methoxy-2-methyl indole)-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(4-Nitrophenyl)-N-methyl-N-[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(3-Nitrophenyl)-N-methyl-N-[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(2-Pyridyl)-N-methyl-N-[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(3-Pyridyl)-N-methyl-N-[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-((+)-6-Methoxy-a-methyl-2-naphthalene)-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl) ethyl]acetamide; 2 -((+)-   6   - Methoxy - a - methyl -   2   - naphthalene )- N -[(   1 S )-   1   - phenyl -   2   -(   1   - pyrrolidinyl )  ethyl]acetamide;   
       2-(α,α,α-Trifluoro-3-tolyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(4-Pyridyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(α,α,α-Trifluoro-2-tolyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-((S)-(+)-4-Isobutyl-a-methylphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(3,4,5-Trimethoxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(2-Aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(2-N,N-Dimethylsulfonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(2-Amino4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide; 2 -(   2   - Amino -   4 , 5   - dichlorophenyl )- N - methyl - N -[(   1 S )-   1   - phenyl -   2   -(   1   - pyrrolidinyl ) ethyl]acetamide;   
       2-(N,N-Dimethylsulfonamido-2-amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(2-Amino,α,α,α-Trifluoro-4-toly)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(2-N,N-Dimethylsulfonamido-2-amino-α,α,α-trifluoro-4-tolyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(N-Methylsulfonamido-2-amino-α,α,α-trifluro-4-tolyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(2-Aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(4-Aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(N,N-Dimethylsulfonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(N,N-Dimethylsulfonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       2-(2-Hydroxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;  
       N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethyl]-3,4,5-trimethoxyphenylacetamide.  
     
     
       4. A pharmaceutical composition comprising a compound of  claim 1  in a pharmaceutically acceptable carrier. 
     
     
       5. A pharmaceutical composition comprising a compound of  claim 2  in a pharmaceutically acceptable carrier. 
     
     
       6. A pharmaceutical composition comprising a compound of  claim 3  in a pharmaceutically acceptable carrier. 
     
     
       7. A method of treating hyperalgesia in a patient comprising administering to said patient an effective amount of a compound of  claim 1 . 
     
     
       8. A method of treating hyperalgesia in a patient comprising administering to said patient an effective amount of a compound of  claim 2 . 
     
     
       9. A method of treating hyperalgesia in a patient comprising administering to said patient an effective amount of a compound of  claim 3 . 
     
     
       10. A method of treating hyperalgesia in a patient comprising administering to said patient an effective amount of a compound of  claim 4 . 
     
     
       11. A method of treating hyperalgesia in a patient comprising administering to said patient an effective amount of a compound of  claim 5 . 
     
     
       12. A method of treating hyperalgesia in a patient comprising administering to said patient an effective amount of a compound of  claim 6 . 
     
     
       13. A pharmaceutical composition comprising a compound of  claim 1  and an antibiotic, antiviral, antifungal, anti-inflammatory agent or a mixture thereof in a pharmaceutically acceptable carrier. 
     
     
       14. A pharmaceutical composition comprising a compound of  claim 2  and an antibiotic, antiviral, antifungal, anti-inflammatory agent or a mixture thereof in a pharmaceutically acceptable carrier. 
     
     
       15. A pharmaceutical composition comprising a compound of  claim 3  and an antibiotic, antiviral, antifungal, anti-inflammatory agent or a mixture thereof in a pharmaceutically acceptable carrier.