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US 2004/0110795 A1Published application
Use of iminosugar derivatives to inhibit ion channel activity
AssigneeUnited Therapeutics Corporation
InventorsNicole Zitzmann, Raymond Allen Dwek Frs
Life of this patent
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Abstract
Disclosed are methods to treat HCV infection by administering an iminosugar derivative compound that is effective to inhibit the activity of HCV p7 protein, and methods by which to screen for compounds that inhibit the activity of p7 protein or variants thereof. The disclosed N-substituted imino compounds, and pharmaceutical compositions thereof, inhibit the capacity of HCV p7 to permeabilize membranes. Particularly efficacious compounds are imino sugars derived from N-alkylated piperidines of the formulas: 1
Claims57
A method of treating a hepatitis C virus (HCV) infection comprising:
- administering to a subject in need thereof a compound selected from a group consisting of compounds of formula 1 or 11, related isomers, pharmaceutically acceptable salts, and solvates thereof:
- 35
- wherein each substituent R11, R11′, R12, R12′, R13, R13′, R14, R14′, R15 R15′, R31, R31′, R32, R32′, R33, R33′, R34, and R34′ is selected, independently from each other, from a group consisting of —H;
- —OH;
- —F;
- —Cl;
- —Br;
- —I;
- —NH2;
- alkyl- and dialkylamino;
- linear or branched C1-6 alkyl, C2-6 alkenyl and alkynyl;
- aralkyl;
- linear or branched C1-6 alkoxy;
- aryloxy;
- aralkoxy;
- -(alkylene)oxy(alkyl);
- —CN;
- —NO2;
- —COOH, —COO(alkyl);
- —COO(aryl);
- —C(O)NH(C1-6 alkyl);
- —C(O)NH(aryl);
- sulfonyl;
- (C1-6 alkyl)sulfonyl;
- arylsulfonyl;
- sulfamoyl, (C1-6 alkyl)sulfamoyl;
- (C1-6 alkyl)thio;
- (C1-6 alkyl)sulfonamide;
- arylsulfonamide;
- —NHNH2;
- —NHOH;
- aryl;
- and heteroaryl, wherein each substituent may be the same or different;
- wherein each alkyl, alkenyl, alkynyl, aryl, and heteroaryl moiety may be optionally substituted with one or more groups independently selected from —OH;
- —F;
- —Cl;
- —Br;
- —I;
- —NH2;
- alkyl- and dialkylamino;
- linear or branched C1-6 alkyl, C2-6 alkenyl and alkynyl;
- aralkyl;
- linear or branched C1-6 alkoxy, aryloxy;
- aralkoxy;
- -(alkylene)oxy(alkyl);
- —CN, —NO2, —COOH, —COO(alkyl);
- —COO(aryl);
- —C(O)NH(C1-6 alkyl);
- —C(O)NH(aryl);
- sulfonyl;
- (C1-6 alkyl)sulfonyl;
- arylsulfonyl;
- sulfamoyl, (C1-6 alkyl)sulfamoyl;
- (C1-6 alkyl)thio;
- (C1-6 alkyl)sulfonamide;
- arylsulfonamide;
- —NHNH2;
- and —NHOH;
- and
- R2 and R4 are substituents selected independently of each other from a group consisting of linear C7-18 alkyl, substituted C1-18 alkyl, branched C3-18 alkyl, C2-18 alkenyl and alkynyl, and aralkyl;
- wherein each linear C7-18 alkyl, branched C3-18 alkyl, C2-18 alkenyl and alkynyl, and aralkyl optionally may be substituted, and each substituted C1-11 alkyl is substituted with one or more groups independently selected from a group consisting of —OH;
- —F;
- —Cl;
- —Br;
- —I;
- —NH2;
- alkyl- and dialkylamino;
- linear or branched C1-6 alkyl, C2-6 alkenyl and alkynyl;
- aralkyl;
- linear or branched C1-6 alkoxy, aryloxy;
- aralkoxy;
- —CN, —NO2, —COOH, —COO(alkyl);
- —COO(aryl);
- —C(O)NH(C1-6 alkyl);
- —C(O)NH(aryl);
- sulfonyl;
- (C1-6 alkyl)sulfonyl;
- arylsulfonyl;
- sulfamoyl, (C1-6 alkyl)sulfamoyl;
- (C1-6 alkyl)thio;
- (C1-6 alkyl)sulfonamide;
- arylsulfonamide;
- —NHNH2;
- and —NHOH.
81 more elements
A method of screening for a potential HCV antiviral agent comprising:
- incorporating at least one of a p7 protein and a variant into a membrane to create a p7-containing membrane, wherein the p7-containing membrane has an increased permeability relative to a membrane that does not contain p7;
- contacting one or more components of the p7-containing membrane with a test compound;
- comparing the permeability of the p7-containing membrane, wherein one or more components have been contacted with a test compound, to the permeability of a p7-containing membrane, wherein none of the components have been contacted with a test compound.
A kit for treating a hepatitis C virus (HCV) infection comprising:
- (A) a compound of formula I or II, related isomers, pharmaceutically acceptable salts, or solvates thereof:
- 67
- wherein each substituent R11, R11′, R12, R12′, R13, R13′, R14, R14′, R15, R15′, R31, R31′, R32, R32′, R33, R33′, R34, and R34′ is selected, independently from each other, from a group consisting of —H;
- —OH;
- —F;
- —Cl;
- —Br;
- —I;
- —NH2;
- alkyl- and dialkylamino;
- linear or branched C1-6 alkyl, C2-6 alkenyl and alkynyl;
- aralkyl;
- linear or branched C1-6 alkoxy;
- aryloxy;
- aralkoxy;
- -(alkylene)oxy(alkyl);
- —CN;
- —NO2;
- —COOH, —COO(alkyl);
- —COO(aryl);
- —C(O)NH(C1-6 alkyl);
- —C(O)NH(aryl);
- sulfonyl;
- (C1-6 alkyl)sulfonyl;
- arylsulfonyl;
- sulfamoyl, (C1-6 alkyl)sulfamoyl;
- (C1-6 alkyl)thio;
- (C1-6 alkyl)sulfonamide;
- arylsulfonamide;
- —NHNH2;
- —NHOH;
- aryl;
- and heteroaryl, wherein each substituent may be the same or different;
- wherein each alkyl, alkenyl, alkynyl, aryl, and heteroaryl moiety may be optionally substituted with one or more groups independently selected from —OH;
- —F;
- —Cl;
- —Br;
- —I;
- —NH2;
- alkyl- and dialkylamino;
- linear or branched C1-6 alkyl, C2-6 alkenyl and alkynyl;
- aralkyl;
- linear or branched C1-6 alkoxy, aryloxy;
- aralkoxy;
- -(alkylene)oxy(alkyl);
- —CN, —NO2, —COOH, —COO(alkyl);
- —COO(aryl);
- —C(O)NH(C1-6 alkyl);
- —C(O)NH(aryl);
- sulfonyl;
- (C1-6 alkyl)sulfonyl;
- arylsulfonyl;
- sulfamoyl, (C1-6 alkyl)sulfamoyl;
- (C1-6 alkyl)thio;
- (C1-6 alkyl)sulfonamide;
- arylsulfonamide;
- —NHNH2;
- and —NHOH;
- and
- R2 and R4 are substituents selected independently of each other from a group consisting of linear C7-18 alkyl, substituted C1-18 alkyl, branched C3-18 alkyl, C2-18 alkenyl and alkynyl, and aralkyl;
- wherein each linear C7-18 alkyl, branched C3-18 alkyl, C2-18 alkenyl and alkynyl, and aralkyl optionally may be substituted, and each substituted C1-18 alkyl is substituted with one or more groups independently selected from a group consisting of —OH;
- —F;
- —Cl;
- —Br;
- —I;
- —NH2;
- alkyl- and dialkylamino;
- linear or branched C1-6 alkyl, C2-6 alkenyl and alkynyl;
- aralkyl;
- linear or branched C1-6 alkoxy, aryloxy;
- aralkoxy;
- —CN, —NO2, —COOH, —COO(alkyl);
- —COO(aryl);
- —C(O)NH(C1-6 alkyl);
- —C(O)NH(aryl);
- sulfonyl;
- (C1-6 alkyl)sulfonyl;
- arylsulfonyl;
- sulfamoyl, (C1-6 alkyl)sulfamoyl;
- (C1-6 alkyl)thio;
- (C1-6 alkyl)sulfonamide;
- arylsulfonamide;
- —NHNH2;
- and —NHOH;
- and
- (B) instructions for treating HCV infection.
83 more elements
A composition of formula I or II, related isomers, pharmaceutically acceptable salts, or solvates thereof:
- 68
- wherein each substituent R11, R11′, R12, R12′, R13, R13′, R14, R14′, R15, R15′, R31, R31′, R32, R32′, R33, R33′, R34, and R34′ is selected, independently from each other, from a group consisting of —H;
- —OH;
- —F;
- —Cl;
- —Br;
- —I;
- —NH2;
- alkyl- and dialkylamino;
- linear or branched C1-6 alkyl, C2-6 alkenyl and alkynyl;
- aralkyl;
- linear or branched C1-6 alkoxy;
- aryloxy;
- aralkoxy;
- -(alkylene)oxy(alkyl);
- —CN;
- —NO2;
- —COOH, —COO(alkyl);
- —COO(aryl);
- —C(O)NH(C1-6 alkyl);
- —C(O)NH(aryl);
- sulfonyl;
- (C1-6 alkyl)sulfonyl;
- arylsulfonyl;
- sulfamoyl, (C1-6 alkyl)sulfamoyl;
- (C1-6 alkyl)thio;
- (C1-6 alkyl)sulfonamide;
- arylsulfonamide;
- —NHNH2;
- —NHOH;
- aryl;
- and heteroaryl, wherein each substituent may be the same or different;
- wherein each alkyl, alkenyl, alkynyl, aryl, and heteroaryl moiety may be optionally substituted with one or more groups independently selected from —OH;
- —F;
- —Cl;
- —Br;
- —I;
- —NH2;
- alkyl- and dialkylamino;
- linear or branched C1-6 alkyl, C2-6 alkenyl and alkynyl;
- aralkyl;
- linear or branched C1-6 alkoxy, aryloxy;
- aralkoxy;
- -(alkylene)oxy(alkyl);
- —CN, —NO2, —COOH, —COO(alkyl);
- —COO(aryl);
- —C(O)NH(C1-6 alkyl);
- —C(O)NH(aryl);
- sulfonyl;
- (C1-6 alkyl)sulfonyl;
- arylsulfonyl;
- sulfamoyl, (C1-6 alkyl)sulfamoyl;
- (C1-6 alkyl)thio;
- (C1-6 alkyl)sulfonamide;
- arylsulfonamide;
- —NHNH2;
- and —NHOH;
- and R2 and R4 are 10-oxaundecyl.
55 more elements
Dependencies are inferred from the claim text.