Kappa agonist compounds, pharmaceutical formulations and method of prevention and treatment of pruritus therewith

Abstract

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

What is claimed is:  
     
         1 . A pharmaceutical composition for the prevention or treatment of pruritus comprising a compound of formula I or a pharmaceutically acceptable salt thereof  
       
         
           
           
               
               
           
         
       
       wherein 
 n=1-3;  
 R 1  and R 2  are independently ═CH; —(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;  
 Z is —P(O)(OBn) 2 ; —P(O)(OH) 2 ; —(CH 2 ) p C(O)NHOH; —(CH 2 ) p CO 2 H; —SO 2 CH 3 ; —SO 2 NH 2 ; —CO(CH 2 ) p CH(NH 2 )(CO 2 H); —COCH(NH 2 )(CH 2 ) p CO 2 H; —CO 2 CH 3 ; —CONH 2 ; —(CH 2 ) p O(CH 2 ) p CO 2 H; —(CH 2 ) p O(CH 2 ) p CONHOH; —(CH 2 ) p NHSO 2 CH 3 ; —(CH 2 ) p NHC(S)NHCH(CO 2 H)(CH 2 ) p CO 2 H; —(CH 2 ) p SO 3 H; or  
 or Z is  
                     
 wherein  
                     
 p=0-20;  
 R 3 =—H or —Ac  
 X 2 =—CO 2 H; —NHSO 2 CH 3 ; NHP(O)(OBn) 2 ; NHP(O)(OH) 2 —; OP(O)(OBn) 2 ; or OP(O)(OH) 2    
 X and Y and independently —CH 2 NHSO 2 CH 3 , —CH 2 NHP(O)(OBn) 2 , —CH2NHP(O)(OH) 2 , —CH 2 OP(O)(OBn) 2 , CH 2 OP(O)(OH) 2 , (CH 2 ) q O(CH 2 ) q CO 2 H, (CH 2 ) q O(CH 2 ) q SO 3 H, (CH 2 ) q O(CH 2 ) q CHNHOH, CH 2 NHC(S)NHCH(CO 2 H)(CH 2 ) q CO 2 H, or  
                     
 wherein  
 q=1-20  
 r=1-20  
 R 4 =—H or —Ac  
 X 3 =—C 2 H; —NHSO 2 CH 3 ; —NHP(O)(OBn) 2 ; —NHP(O)(OH) 2 ; —OP(O)(OBn) 2 ; or —OP(O)(OH) 2    
 in a pharmaceutically acceptable carrier.  
 
     
     
         2 . The pharmaceutical composition according to  claim 1  wherein said compound is selected from the group consisting of: (4-[1-(3,4-Dichlorophenyl)acetyl-2R-(1-pyrrolidinyl)-methyl]piperazinyl)acetic acid; [1-(3,4-Dichlorophenyl)acetyl-4-methanesulfonyl-2R-(1-pyrrolidinyl)methyl]piperazine; [4-S-Aspartic acid-α-amido-1-(3,4-dichlorophenyl)acetyl-2R-(1-pyrrolidinyl)methyl]piperazine; Methyl-[2R-(O-2-acetic acid)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-3R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate; Methyl-[2R-(O-S-aspartic acid-α-acetyl)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-3R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate; Methyl-[4-(3,4-dichlorophenyl)acetyl-2R-(N-methanesulfonamido)aminomethyl-3R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate; Methyl-{4-[3,4-dichlorophenyl]acetyl-3R-[1-pyrrolidinyl]methyl-2R-[N-(succiinicc acid-2S-thioureido)}aminomethyl-1-piperazinecarboxylate; Methyl-[2S-(O-2-acetic acid)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate; Methyl-[2S-(O-S-aspartic acid-a-acetyl)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate; Methyl-[4-(3,4-dichlorophenyl)acetyl-2S-(N-methanesulfonamido)aminomethyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate; Methyl-{4-[3,4-dichlorophenyl]acetyl-5R-[1 -pyrrolidinyl]methyl-2S-[N-(succinic acid-2S-thioureido)]aminomethyl-1-piperazinecarboxylate; Methyl-[2R-(O-2-acetic acid)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate; Methyl-[2R-(O-S-aspartic acid-α-acetyl)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate; Methyl-[4-(3,4-dichlorophenyl)acetyl-2R-(N-methanesulfonamido)aminomethyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate; and Methyl-{4-[3,4-dichlorophenyl]acetyl-5R-[1-pyrrolidinyl]methyl-2R-[N-(succinic acid-2S-thioureido)]aminomethyl}-1-piperazinecarboxylate.  
     
     
         3 . The pharmaceutical composition according to  claim 1  wherein said compound is selected from the group consisting of: 
 (R)-4-(Phenylmethyl)-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrolidinyl)methyl]piperazine hydrochloride;  
 (R)-1-[(3,4-Dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]piperazine hydrochloride;  
 (R)-4-Methanesulfonyl-1-[(3,4-dichlorophenyl)acetyl]-2-[(1 -pyrrolidinyl)methyl]-piperazine hydrochloride;  
 (R)-4-t-Butyl-acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]-piperazine;  
 (R)-4-(3,4-Dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazineacetic acid dihydrochloride;  
 (R)-4-N-t-Boc-D-aspartic acid-β-benzyl ester-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]-piperazine;  
 (R)-4-Aspartic acid-1-[(3,4-dichlorophenyl)acetyl}-2-[(1 -pyrrolidinyl)methyl]-piperazine dihydrochioride;  
 (R)-4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]-piperazine hydrochloride;  
 (R)-4-(Diethoxyphosphonate)-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]-piperazine hydrochloride;  
 (R)-4-Trifluoroacetyl-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]-piperazine hydrochloride;  
 (R)-4-[(3,4-Dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxamide hydrochloride;  
 (R)-4-[(3,4-Dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl}-1-piperazinecarboxaldehyde hydrochloride;  
 (R)-4-[(3,4-Dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazine-sulfonamide hydrochloride;  
 (R)-4-(4-Methylphenylsulfonyl)-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]-piperazine hydrochloride;  
 (R,S)-4-Methanesulfonyl-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]-piperazine hydrochloride;  
 (R,S)-4-Methanesulfonyl-1-[(4-methylsulfonylphenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]piperazine hydrochloride;  
 (R,S)-4-Methanesulfonyl-1-[(2-nitrophenyl)acetyl]-2-[(1-pyrrolidinyl)-methyl]piperazine hydrochloride;  
 (R,S)-4-Methanesulfonyl-1-[(4-trifluoromethylphenyl)acetyl]-2-[(1-pyrrolidinyl)-30 methyl]piperazine hydrochloride;  
 (R,S)-4-Methanesulfonyl-1-[(3-indolylacetyl]-2-[(1-pyrrolidinyl)-methyl]piperazine hydrochloride;  
 (R,S)-Methyl 4-[(4-methylsulfonylphenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]-1-piperazinecarboxylate hydrochloride;  
 (R,S)-Methyl 4-[(4-trifluoromethylphenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]-1-piperazinecarboxylate hydrochloride;  
 (R,S)-Methyl 4-[(3-indolyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]-1-piperazine-carboxylate hydrochloride;  
 (R,S)-Methyl 4-[(2-nitrophenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]-1-piperazine-carboxylate hydrochloride;  
 (R,S)-Methyl 4-[(2-methoxyphenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl)-1-piperazinecarboxylate hydrochloride;  
 (R,S)-Methyl 4- [(2-aminophenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]-1-piperazinecarboxylate dihydrochloride;  
 (R,S)-4-Acetyl-1-[(4-methylsulfonylphenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]-piperazine hydrochloride;  
 (R,S)-4-Acetyl-1-(4-trifluoromethylphenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]piperazinecarboxylate hydrochloride;  
 (R,S)-4-Acetyl-1-[(2-trifluoromethylphenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]piperazinecarboxylate hydrochloride;  
 (R,S)-4-Acetyl-1-[(3-nitrophenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]piperazine-carboxylate hydrochloride;  
 (R,S)-4-Acetyl-1-[(2-nitrophenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]piperazine-carboxylate hydrochloride;  
 (R,S)-4-Acetyl-1-[(4-nitrophenyl)acetyl]-3-[(1-pyrrolidinyl)-methylpiperazine; carboxylate hydrochloride; and  
 (R,S)-4-(Phenylmethyl)-1-[(4,5,-dichloro-2-nitrophenyl)acetyl]-2-[ 
                     
 (1-pyrrolidinyl)methyl]piperazine dihydrochloride.  
 
     
     
         4 . A method for the prevention or treatment of pruritus in a patient comprising administering to said patient an effective amount of a composition according to  claim 1 .  
     
     
         5 . A method for the prevention or treatment of pruritus in a patient comprising administering to said patient an effective amount of a composition according to  claim 2 .  
     
     
         6 . A method for the prevention or treatment of pruritus in a patient comprising administering to said patient an effective amount of a composition according to  claim 3 .  
     
     
         7 . A pharmaceutical composition for the prevention or treatment of pruritus comprising a compound of formula II 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; benizofuranyl; naphthyl; diphenyl methyl; or 9-fluorene;    X 4  and X 5  are independently —OP(O)(OBn) 2 -OP(O)(OH),; —CO 2 H; —SO 3 H; —O(CH 2 ) n CO 2 H; —NHSO 2 CH 3 ; —CONH(CH 2 ) s CO 2 H; or —SO 2 NH(CH 2 ) s CO 2 H; wherein s=1-5 or X 4  and X 5  are independently                          wherein    t=1-20    R 5 =—H or —Ac    X 6 =—CO 2 H; —NHSO 2 CH 3 ; —NHP(O)(OBn) 2 ; —NHP(O)(OH) 2 ; —OP(O)(OBn) 2 ; or —OP(O)(OH) 2  in a pharmaceutically acceptable carrier.    
     
     
         8 . The pharmaceutical composition according to  claim 7  wherein said compound is selected from the group consisting of: (±)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-5-(O-2-acetic acid)-hydroxy-2-(1-pyrrolidinyl)naphthyl]acetamide; (±)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-7-(O-2-acetic acid)-hydroxy-2-(1-pyrrolidinyl)naphthyl]acetamide; (±)-2-(3,4-dichlorophenyl)-N-methyl-N-1[1,2,3,4-tetrahydro-7-(N-methanesulfonamido)-amino-2-(1-pyrrolidinyl)naphthyl]acetamide; (±)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-5-(N-methanesulfonamido)-amino-2-(1-pyrrolidinyl)naphthyl]acetamide; (±)-2-(3,4-dichlorophenyl)-N-methyl-N 1-[1,2,3,4-tetrahydro-5-(N-2-acetic acid)-carboxamido-2-(1-pyrrolidinyl)naphthyl]acetamide; (±)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-5-(N-2-acetic acid)-sulfonamido-2-(1-pyrrolidinyl)naphthyl]acetamide; (±)-2-(3,4-dichlorophenyl)-N-methyl-N-141,2,3,4-tetrahydro-7-(N-2-acetic acid)-carboxamido-2-(1-pyrrolidinyl)naphthyl]acetamide; and (±)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-7-(N-2-acetic acid)-sulfonamido-2-(1-pyrrolidinyl)naphthyl]acetamide.  
     
     
         9 . The pharmaceutical composition according to  claim 7  wherein said compound is selected from the group consisting of: 
 2-(7-[(±)-trans-1-(N-3,4-dichlorophenylacetamido-N-methylamino)-2-(1-pyrrolidinyl)-1,2,3,4-tetrahydronaphthoxy]}acetic acid;  
 2,2-Diphenyl-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-7-methoxy-1,2,3,4-tetrahydronaphth-1-yl]acetamide;  
 2,2-Diphenyl-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-7-hydroxy-1,2,3,4-tetrahydronaphth-1-yl]acetamide;  
 2-(2-Nitro-4,5-dichlorophenyl)-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-7-nitro-1,2,3,4-tetrahydronaphth-1-yl]acetamnide;  
 2-(3,4-Dichlorophenyl)-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-7-nitro-1,2,3,4-tetrahydronaphth-1-yl]acetamide;  
 2-(3,4-Dichlorophenyl)-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-7-amino-1,2,3,4-tetrahydronaphth-1-yl]acetamide;  
 2-(4-Methylsulfonylphenyl)-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-7-nitro-1,2,3,4-tetrahydronaphth-1-yl]acetamide;  
 2-(3,4-Dichlorophenyl)-N-methyl-N-([±]-trans-2-[1-pyrrolidinyl]-7-[N,N-bis-(t-butoxycarbonylmethyl)-amino]-1,2,3,4-tetrahydronaphth-1-yl]acetamide;  
 2-(3,4-Dichlorophenyl)-N-methyl-N-([±]-trans-2-[1-pyrrolidinyl]-7-[N,N-bis-(carboxymethyl)amino]-1,2,3,4-tetrahydronaphth-1-yl]acetamnide;  
 2-(3,4-Dichlorophenyl)-N-methyl-N-([±]-trans-2-[1-pyrrolidinyl]-7-[N,N-bis-(ethoxycarbonylmethyl)-amino]-1,2,3,4-tetrahydronaphth-1-yl]acetamide;  
 2-(3,4-Dichlorophenyl)-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-7-(N-diethylphosphoramidato-amino)-1,2,3,4-tetrahydronaphth-1-yl]acetamide;  
 2-(3,4-Dichlorophenyl)-N-methyl-N-([±]-trans-2-[1-pyrrolidinyl]-7-[N-2-(diethylphosphoryl)ethyl-amino]-1,2,3,4-tetrahydronaphth-1-yl]acetamide;  
 2-(3,4-Dichlorophenyl)-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-6-methoxy-7-(N-benzyl-N-methylaminosulfonyl)-1,2,3,4-tetrahydronaphth-1-yl]acetamide;  
 2-(3,4-Dichlorophenyl)-N-methyl-N-[(±)-trans-2-(1-pyrrolidiuyl)-7-(N-benzyl-N-methylaminosulfonyl)-1,2,3,4-tetrahydronaphth-1-yl]acetamide;  
 2-(2-Nitro-4,5-dichlorophenyl)-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-indan-1-yl]acetamide;  
 2-(2-Nitro-4-trifluoromethylphenyl)-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-indan-1-yl]acetamide;  
 2,2-Diphenyl-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-indan-1-yl]acetamide; and  
 2-(4-Methylsulfonylphenyl)-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-indan-1-yl]acetamide.  
 
     
     
         10 . A method for the prevention or treatment of pruritus in a patient comprising administering to said patient an effective amount of a composition according to  claim 7 .  
     
     
         11 . A method for the prevention or treatment of pruritus in a patient comprising administering to said patient an effective amount of a composition according to  claim 8 .  
     
     
         12 . A method for the prevention or treatment of pruritus in a patient comprising administering to said patient an effective amount of a composition according to  claim 9 .  
     
     
         13 . A pharmaceutical composition for the prevention or treatment of pruritus comprising 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 substituted 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;  
         X 7  is —NHSO 2 CH 3 ; —NHP(O)(OBn) 2 ; —NBP(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 7  is  
         
           
             
             
                 
                 
             
           
         
         R 6 =—H or —Ac;  
         X 8 =—CO 2 H; —NHSO 2 CH 3  —NHP(O)(OBn) 2 ; —NBP(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 2 ; —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; in a pharmaceutically acceptable carrier.  
       
     
     
         14 . The pharmaceutical composition according to  claim 13  wherein said compound is 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.  
 
     
     
         15 . The pharmaceutical composition according to  claim 13  wherein said compound is selected from the group consisting of: 
 2-(3,4-Dichlorophenyl)-N-methyl-N-{[1S]-1-[N-(S-aspartic acid-α-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-(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]acetarnide;  
 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]acetamnide;  
 2-(N-Bis-sulfonamido-4-aminophenyl)-N-methyl-N-[(1S)-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-pyrroidinyl)ethyl]acetamide;  
 2-(2-Nitro-α,α,α-Trifluoro-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-napthalene)-N-[(1S)-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-x-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-Amino 4,5-dichlorophenyl)-N-methyl-N-[(1S)-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,x,x,x-Trifluoro-4-tolyl)-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-trifluoro-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-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide; and  
 N-Methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethyl]-3,4,5-trimethoxyphenylacetamide.  
 
     
     
         16 . A method for the prevention or treatment of pruritus in a patient comprising administering to said patient an effective amount of a composition according to  claim 13 .  
     
     
         17 . A method for the prevention or treatment of pruritus in a patient comprising administering to said patient an effective amount of a composition according to  claim 14 .  
     
     
         18 . A method for the prevention or treatment of pruritus in a patient comprising administering to said patient an effective amount of a composition according to  claim 15 .  
     
     
         19 . A pharmaceutical composition for the prevention or treatment of pruritus comprising a compound of the formula IV 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 —;  
         R 3  and R 4  are independently H; OCH 3  alkyl; or c-O(CH 2 ) 2  X 9 =1-4 substituents selected from the groups consisting of —halogen; —CF 3 ; —OCH 3 ; —SO 2 NH(CH 2 ) q CO 2 H; CONH(CH 2 ) q CO 2 H; —NH 2 ; —NHSO 2 CH 3 ; —NHP(O)(OBn) 2 ; —NHP(O)(OH) 2 ; NH(CH 2 ) q CO 2 H; —SO 2 CH 3  —OP(O)(OBn) 2 ; —OP(O)(OH) 2 ; —CO 2 H; O(CH 2 ) q CO 2 H; —O(CH 2 ) q SO 3 H,; —O(CH 2 ) q OPO 3 H 2 ; wherein  
         q=1-20;  
         or X 9  is  
         
           
             
             
                 
                 
             
           
         
         wherein  
         t=1-20;  
         R 5 =—H or —Ac;  
         X 5 =—CO 2 H; —NHSO 2 CH 3 ; —NBP(O)(OBn) 2 ; —NBP(O)(OH) 2 ; —OP(O)(OBn) 2 ; or —OP(O)(OH) 2    
         in a pharmaceutically acceptable vehicle.  
       
     
     
         20 . The pharmaceutical composition according to  claim 19  wherein said compound is selected from the group consisting of: 
 (−)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro-[4,5]dec-8-yl]-3-(N-methanesulfonamido)aminophenylacetamide; (−)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro-[4,5]dec-8-yl]-3-(N-2-acetic acid)sulfonamidophenylacetamide; and (−)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro-[4,5]dec-8-yl]-3-(N-2-acetic acid)carboxamidophenylacetamide.  
 
     
     
         21 . The pharmaceutical composition according to  claim 19  wherein said compound is selected from the group consisting of: 
 (±)-trans-2-Nitro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]phenylacetamide Hydrochloride;  
 (±)-trans-2-Amino-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]phenylacetamide Hydrochloride;  
 (±)-trans-2-Nitro-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide Hydrochloride;  
 (±)-trans-2-Amino-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide Hydrochloride;  
 (±)-trans-2-Methanesulfonamido-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide Hydrochloride;  
 N-[2-(±)-trans-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamido]glycine Hydrochloride;  
 (±)-trans-4-Trifuoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide Hydrochloride;  
 (±)-trans-2-Nitro-4-trifluoromethyl-N-methyl-N-[2-(l -pyrrolidinyl)cyclohexyl]-phenylacetamide Hydrochloride;  
 (±)-trans-2-Amino-4-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide Hydrochloride;  
 (±)-trans-2-Bismethanesulfonamido-4-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide Hydrochloride;  
 (±)-trans-2-Methanesulfonamido-4-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide Hydrochloride;  
 N-[2-(±)-trans-4-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamido]glycine Hydrochloride;  
 (±)-trans-3-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide Hydrochloride;  
 (±)-trans-5-Nitro-3-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide Hydrochloride;  
 (±)-trans-2-Nitro-3-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide Hydrochloride;  
 (±)-trans-2-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide Hydrochloride;  
 (±)-trans-4-Nitro-2-tiifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide Hydrochloride;  
 (±)-trans-4-Amino-2-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide Hydrochloride;  
 (±)-trans-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]2,2-diphenylacetamide Hydrochloride; and  
 (±)-trans-4-Methylsulfonyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]phenylacetamide Hydrochloride.  
 
     
     
         22 . A method for the prevention or treatment of pruritus in a patient comprising administering to said patient an effective amount of a composition according to  claim 19 .  
     
     
         23 . A method for the prevention or treatment of pruritus in a patient comprising administering to said patient an effective amount of a composition according to  claim 20 .  
     
     
         24 . A method for the prevention or treatment of pruritus in a patient comprising administering to said patient an effective amount of a composition according to claim  21 .