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US 2003/0144272 A1Published application
Kappa agonist compounds and pharmaceutical formulations thereof
AssigneeAdolor Corporation
InventorsVirendra Kumar, Deqi Guo, Michael Anthony Marella, Alan L. Maycock
Life of this patent
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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, IIIB-i, IV and IVA have the structure: 1 2 wherein R1, R2, R3, R4; and X, X4, X5, X7, X9; Y, Z and n are as described in the specification.
Claims19
A compound of the formula IIIB or a pharmaceutically acceptable salt thereof:
- 363
- wherein:
- n is an integer from 1 to 3;
- R1 and R2 are together alkylene of about 4 to about 8 carbons, optionally substituted with a group R′, where R′ is selected from —OH, halogen, —NRaRb, in which Ra and Rb are independently selected from hydrogen, —C(═O)Rc, —SO2Rd and —C(═O)(CH2)mCO2Re, in which Rc and Rd are independently selected from alkyl, aryl and heteroaryl, Re is hydrogen or alkyl and m is an integer from 1 to 3;
- Ar is unsubstituted phenyl or mono-, di-, tri-, or tetra-substituted phenyl, wherein said substituents are independently selected from halogen;
- alkyl;
- alkoxy;
- aryloxy;
- aralkyloxy;
- alkylene dioxide;
- —OH;
- —SO2Rf in which Rf is alkyl or aryl;
- —CN;
- haloalkyl;
- —NRgRh, in which Rg and Rh are independently selected from hydrogen, alkyl, —C(═O)Rf, —C(═O)—N(Re)2, —S(O)2Rf, and —(CH2)y—CO2Re in which y is an integer from 1 to 3;
- —S(O)2N(Ri)(Rj), in which Ri and Rj are each independently selected from hydrogen, alkyl optionally substituted with —CO2Re, aryl and aralkyl;
- or Ri and Rj together form —(CH2)2X(CH2)2—, where X is a direct bond, —CH2—, —NRe—, S or O;
- R is hydrogen, halogen, —OH, alkoxy, or —NRkRl, where Rk and Rl are independently selected from hydrogen and alkyl.
15 more elements
A compound of the formula IIIB-i or a pharmaceutically acceptable salt thereof:
- 365
- wherein:
- x is an integer from 0 to 4;
- R″ is hydrogen, fluoro, —OH, —NHC(═O)Rc, —NHSO2Rd and —NHC(═O)(CH2)mCO2Re, in which Rc and Rd are independently selected from alkyl, aryl and heteroaryl, Re is hydrogen or alkyl and m is an integer from 1 to 3
- R3 is independently selected from halogen;
- alkyl;
- alkoxy;
- aryloxy;
- aralkyloxy;
- alkylene dioxide;
- —OH;
- —SO2Rf in which Rf is alkyl or aryl;
- —CN;
- haloalkyl;
- —NRgRh, in which Rg and Rh are independently selected from hydrogen, alkyl, —C(═O)Rf, —C(═O)—N(Re)2, —S(O)2Rf in which Rf is alkyl or aryl, and —(CH2)y—CO2Re in which y is an integer from 1 to 3;
- —S(O)2N(Ri)(Rj), in which Ri and Rj are each independently selected from hydrogen, alkyl optionally substituted with —CO2Re, aryl and aralkyl;
- or Ri and Rj together form —(CH2)2X(CH2)2—, where X is a direct bond, —CH2—, —NRe—, S or O/
- R is hydrogen, halogen, —OH, alkoxy, or —NRkRl, where Rk and Rl are independently selected from hydrogen and alkyl.
15 more elements
A compound selected from the group consisting of:
- 2-(3-N-Methylsulfonamido-3-amino-4-methoxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide methane sulfonate;
- 2-(3-N-Methylsulfonamido-3-amino-4-benzyloxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;
- 2-(3-N-Methylsulfonamido-3-amino-4-hydroxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;
- 2-(2-N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide;
- 2-(2-N-Methylsulfonamido-2-amino-4-trifluoromethylphenyl)-N-methyl-N-[(1S)-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide;
- 2-(3-N-Methylsulfonamido-3-amino-4-metoxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide;
- 2-(2-N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-1-(4-methoxyphenyl)-2-(1-pyrrolidinyl) ethyl]acetamide;
- (R,S)-2-(2-N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-1-(4-hydroxyphenyl)-2-(1-pyrrolidinyl)ethyl]acetamide;
- (S)-2-(2-N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-1-(4-hydroxyphenyl)-2-(1-pyrrolidinyl)ethyl]acetamide;
- 2-(3-N-Bis-methylsulfonamido-3-amino-4-hydroxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;
- 2-[2-(N-Benzyl-N-methylsulfamoyl)-4,5-methylenedioxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide;
- 2-[2-(N-Dimethylsulfamoyl)-4,5-methylenedioxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide;
- 2-[2-(N-Dimethylsulfamoyl)-4,5-methylenedioxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide;
- 2-[2-(N-Pyrrolidinesulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide;
- 2-[2-(N-Pyrrolidinesulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide;
- 2-[2-(N-Dimethylsulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide;
- 2-[2-(N-Dimethylsulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1l-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide;
- 2-[2-[N-(4-Methylpiperazine)]sulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-(pyrrolidinyl)ethyl]]acetamide;
- 2-[2-[N-(4-Methylpiperazine)]sulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide;
- 2-[2-N-(Morpholinesulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-(pyrrolidinyl)ethyl]]acetamide;
- 2-[2-N-(Morpholinesulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide;
- N-Methyl-[[2-(N-sulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-(pyrrolidinyl)ethyl]]acetamido]glycine;
- 2-[2-(N-Pyrrolidinesulfamoyl)-3,4,5-trimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide;
- 2-[2-(N-t-Butylsulfamoyl)-3,4,5-trimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide;
- 2-[2-(N-Methylsulfamoyl)-4-methoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide;
- 2-[4-N-(Methylsulfamoyl)-phenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide;
- 2-[2-(N-Methylsulfamoyl)-phenyl]-N-,methyl-N-[1-(2-fluorophenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide;
- and
- 2-[2-(N-Benzyl-N-methylsulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide;
- or a pharmaceutically acceptable salt thereof.
27 more elements
Dependencies are inferred from the claim text.