Back to results
US 6,486,165 B2Granted
Kappa agonist compounds, pharmaceutical formulations and method of prevention and treatment of pruritus therewith
AssigneeAdolor Corporation
InventorsWei Yuan Zhang, Alan L. Maycock, Michael Anthony Marella, Virendra Kumar, Forrest Gaul, Deqi Guo
Life of this patent
Estimating the term…
Abstract
Method for the prevention or treatment of pruritus with anti-pruritic compounds is provided. The compounds of formula I
Claims2
A method for the treatment of pruritus in a patient comprising administering to said patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof
- wherein
- n=1-3;
- R1 and R2 are independently=CH3;
- —(CH2)m, where m=4-8, —CH2CH(OH)(CH2)2—;
- —CH2CH(F)(CH2)2—;
- —(CH2)2O(CH2)2—;
- or —(CH2)2CH═CHCH2—;
- Ar=unsubstituted or mono-, or di-substituted phenyl wherein said substituents are selected from the group consisting of halogen, OCH3, SO2CH3, CF3, amino, alkyl, and 3,4-dichloro;
- benzothiophenyl;
- benzofuranyl;
- naphthyl diphenyl methyl;
- or 9-fluorene;
- Z is
- —P(O)(OBn)2;
- —P(O)(OH)2;
- —(CH2)pC(O)NHOH;
- —(CH2)pCO2H;
- —SO2CH3;
- —SO2NH2;
- —CO(CH2)pCH(NH2)(CO2H);
- —COCH(NH2)(CH2)pCO2H;
- —CO2CH3;
- —CONH2;
- —(CH2)pO(CH2)pCO2H;
- —(CH2)pO(CH2)pCONHOH;
- —(CH2)pNHSO2CH3;
- —(CH2)pNHC(S)NHCH(CO2H)(CH2)pCO2H;
- —(CH2)pSO3H;
- or
- or Z is
- wherein
- p=0-20;
- R3=—H or —Ac;
- X2=—CO2H;
- —NHSO2CH3;
- NHP(O)(OBn)2;
- NHP(O)(OH)2;
- —OP(O)(OBn)2;
- or OP(O)(OH)2;
- X and Y are independently
- —CH2NHSO2CH3, —CH2NHP(O)(OBn)2, —CH2NHP(O)(OH)2, —CH2OP(O)(OBn)2, —CH2OP(O)(OH)2, —(CH2)qO(CH2)qCO2H, —(CH2)qO(CH2)qSO3H, —(CH2)qO(CH2)CHNHOH, —CH2NHC(S)NHCH(CO2H)(CH2)qCO2H, or
- wherein
- q=1-20
- r=1-20
- R4=—H or —Ac
- X3=—CO2H;
- —NHSO2CH3;
- —NHP(O)(OBn)2;
- —NHP(O)(OH)2;
- —OP(O)(OBn)2;
- or —OP(O)(OH)2
- in a pharmaceutically acceptable carrier.
49 more elements
A compound which is selected from the group consisting of:
- Methyl-4-[-2-glycyl-4-(trifluoromethylphenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)-methyl]-1-piperazinecarboxylate;
- Methyl-4-[(2-[N,N-bis-methylsulfonamido]-4-trifluoromethyphenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)-methyl]-1-piperazinecarboxylate dihydrochloride;
- Methyl-4-[(2-[N-methylsulfonamido]phenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate hydrochloride;
- Methyl-4-[(2-[N,N-bis-methylsulfonamido]phenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate hydrochloride;
- Methyl-4-[(2-[N-methylamino)sulfamyl]phenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl) methyl]-1-piperazinecarboxylate hydrochloride;
- Methyl-4-[-4-[N-methylamino)sulfamyl]phenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl) methyl]-1-piperazinecarboxylate hydrochloride;
- 4-Trifluoroacetyl-1-[(trans-3-furanacyrlate]-2-(R,S)-(1-pyrrolidinyl)methyl]piperazine hydrochloride;
- 4-Trifluoroacetyl-1-[(-4-trifluoromethylphenyl)acetyl]-2-(R,S)-(1-pyrrolidinyl)methyl]piperazine hydrochloride;
- Methyl-4-[(3,4-dichlorophenyl)acetyl]-3-(R,S)-[(4′-methylpiperazinecarboxylate)methyl]-1-piperazinecarboxylate hydrochloride;
- Methyl-4-[(4-a,a,a-trifluoromethylphenyl)acetyl]-3-(R,S)-[3-(S)-(4′-a,a,a-trifluoro methylphenylacetate)-1-(pyrrolidinyl)methyl]-1-piperazinecarboxylate hydrochloride;
- Methyl-4-[(3,4-dichlorophenyl)acetyl]-3-(R,S)-[(2-(S)-pyrrolidinemethyl-3′,4′-dichlorophenyl acetate)methyl]-1-piperazinecarboxylate hydrochloride;
- Methyl-4-[(3,4-dichlorophenyl)acetyl]-3-(R)-[(2-(S)-pyrrolidinemethanol)methyl]-1-piperazinecarboxylate hydrochloride;
- Methyl-4-[(2-nitro-4-a,a,a-trifluoromethylphenyl)acetyl]-3-(R,S)-[(2-(S)-pyrrolidine methanol)methyl]-1-piperazinecarboxylate hydrochloride;
- Methyl-4-[(4-methylsulphonylphenyl)acetyl]-3-(R,S)-[(2-(S)-pyrrolidinemethyl-4′-methylsulphonylphenylacetate)methyl]-1-piperazinecarboxylate hydrochloride;
- Methyl-4-[(4-methylsulphonylphenyl)acetyl]-3-(R,S)-[(2-(S)-pyrrolidinemethanol) methyl]-1-piperazinecarboxylate hydrochloride;
- Methyl-4-[(2-amino-4-a,a,a-trifluoromethylphenyl)acetyl]-3-(R,S)-[(2-(S)-pyrrolidine methanol)methyl]-1-piperazinecarboxylate hydrochloride;
- Methyl-4-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[3-(S)-(3′,4′-dichlorophenylacetate)-1-(pyrrolidinyl)methyl]-1-piperazinecarboxylate hydrochloride;
- 4-Acetyl-1-[3-(N-methylsulfonamido)phenyl]acetyl-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine hydrochloride;
- 4-Acetyl-1-[(2-acetylamidophenyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine hydrochloride;
- 4-Acetyl-1-[(4-acetylamidophenyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine hydrochloride;
- 4-Acetyl-1-[(4-methylsulfonyl]phenyl)acetyl]-2-(R,S)-[3-(S)-(4′-methylsulfonyl phenyl acetate)-1-(pyrrolidinyl)methyl]piperazine hydrochloride;
- 4-Acetyl-1-[(4-a,a,a-trifluoromethylphenyl)acetyl]-2-(R,S)-[3-(S)-(4′-a,a,a-trifluoromethylphenyl acetate)-1-(pyrrolidinyl)methyl]piperazine hydrochloride;
- 4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[3-(S)-(3′,4′-dichlorophenylacetate)-1-(pyrrolidinyl)methyl]piperazine hydrochloride;
- 4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[(2-(S)-pyrrolidinemethyl-3′,4′-dichlorophenylacetate)methyl]piperazine hydrochloride;
- 4-Acetyl-1-[(4-trifluoromethylphenyl)acetyl]-2-(R,S)-[2-(S)-pyrrolidinemethyl-4′-trifluoromethylphenylacetate)methyl]piperazine hydrochloride;
- 4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[(2-(S)-pyrrolidinemethanol)methyl]piperazine hydrochloride;
- 4-Acetyl-1-[(4-methylsulphonylphenyl)acetyl]-2-(R,S)-[(2-(S)-pyrrolidinemethyl-4′-methylsulphonylphenylacetate)methyl]piperazine hydrochloride;
- 4-Acetyl-1-[(4-methylsulphonylphenyl)acetyl]-2-(R,S)-[(2-(S)-pyrrolidinemethanol) methyl]piperazine hydrochloride;
- 4-Acetyl-1-[(4-trifluoromethylphenyl)acetyl]-2-(R,S)-[(2-(S)-pyrrolidinemethanol) methyl]piperazine hydrochloride;
- 4-Formyl-1-[(2-N-methylsulfamylphenyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine hydrochloride;
- 4-Carbonylimidazole-1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(1-pyrrolidinyl)methyl]piperazine hydrochloride;
- 4-Allyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(1-pyrrolidinyl)methyl]piperazine hydrochloride;
- 4-Acetyl-1-[(2-pyridyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine hydrochloride;
- 4-Formyl-1-[(2-pyridyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine hydrochloride;
- Methyl-4-[(3,4-dichlorophenyl)acetyl]-3-(S)-[(2-(S)-pyrrolidinemethanol)methyl]-1-piperazinecarboxlate hydrochloride;
- 4-Methanesulfonyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[3-(S)-methanesulfonate-1-(pyrrolidinyl) methyl]piperazine hydrochloride;
- 4-Methylsulphonyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[3-(S)-(3′,4′ dichloro phenyl acetate)-1-(pyrrolidinyl)methyl]piperazine hydrochloride;
- 4-Methylsulphonyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[(3-(S)-hydroxy-1-pyrrolidinyl) methyl]piperazine hydrochloride;
- 4-Methylsulphonyl-1-[(4-α,α,α-triflouromethylphenyl)acetyl]-2-(R,S)-[3-(S)-(4′-a,a,a-triflouro methylphenyl acetate)-1-(pyrrolidinyl)methyl]piperazine hydrochloride;
- 4-Methylsulphonyl-1-[(4-α,α,α-triflouromethylphenyl)acetyl]-2-(R,S)-[(3-(S)-hydroxy-1-pyrrolidinyl)methyl]piperazine hydrochloride;
- 4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(S)-[(3′-(S)-hydroxy-1-pyrrolidine)methyl]-piperazine hydrochloride;
- 4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(3′-(R)-hydroxy-1-pyrrolidine)methyl]-piperazine hydrochloride;
- and
- 4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(S)-[(3′-(R)-hydroxy-1-pyrrolidine)methyl]-piperazine hydrochloride.
41 more elements
Dependencies are inferred from the claim text.