Methods for modulating bladder function
AssigneeAmerican Home Products Corporation
InventorsThomas Michael Argentieri, Jeffrey Howard Sheldon, Mark R. Bowlby
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Abstract
This invention provides methods and pharmaceutical compositions for maintaining bladder control or treating urinary incontinence in a mammal utilizing agonists of KCNQ potassium channels, including KCNQ2, KCNQ3, KCNQ4 and KCNQ5 potassium channels, alone or in combination. Compounds useful in these methods include the 1,2,4-triamino-benzene derivatives described in U.S. Pat. No. 5,384,330 (Dieter et al.) and the substituted 3-phenyl oxindole compounds described in U.S. Pat. No. 5,565,483 (Hewawasam et al.). Among the preferred compounds of this invention is N-[2-amino-4-(4-fluorobenzylamino)-phenyl]carbamic acid ethyl ester, also referred to as retigabine.
Claims32
A method of inducing or maintaining bladder control in a mammal, the method comprising administering to a mammal in need thereof a pharmacologically effective amount of a KCNQ potassium channel agonist.
A method of treatment or prevention of urinary incontinence in a mammal, the method comprising administering to a mammal in need thereof a pharmacologically effective amount of a KCNQ potassium channel agonist.
A method of treatment or prevention of urinary incontinence in a mammal, the method comprising administering to a mammal in need thereof a pharmacologically effective amount of a compound of the formula:
- wherein:
- R1 is selected from hydrogen, C1-C6-alkyl, C2-C6-alkanoyl or the radical Ar;
- R2 is selected from hydrogen or C1-C6-alkyl;
- R3 is selected from C1-C6-alkoxy, NH2, C1-C6-alkylamino, C1-C6-dialkylamino, amino substituted by the radical Ar, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, the radical Ar or the radical ArO—;
- R4 is selected from hydrogen, C1-C6-alkyl or the radical Ar;
- R5 is selected from hydrogen or C1-C6-alkyl or the radical Ar;
- Alk:
- a straight or branched alkylene group with 1-0 carbon atoms, which can also be substituted by the radical Ar;
- Ar is a phenyl radical substituted by the radicals R6, R7 and/or R8 where these radicals R6, R7 and R8 are the same or different and represent C1-C6-alkyl, C3-C7-cycloalkyl, hydroxy, C1-C6-alkoxy, C2-C6-alkanoyloxy, halogen, hydroxy, C1-C6-halogenoalkyl, —CN, —NH2, —NH—C1-C6-alkyl, —N(C1-C6-alkyl)2, —CO2H, —CO—C1-C6-alkyl, —CO—O—C1-C6-alkyl, —COAr, —CO—OAr, —CONH2, —CONH—C1-C6-alkyl, —CON(C1-C6-alkyl)2, —CONHAr, —NH—CO—C1-C6-alkyl, —NHCO—Ar, —NHCO—C1-C6-alkoxy, —N—H—CO—Ar, —NHCO—NH2, —NHCO—N(—C1-C6-alkyl)2, —NHCO—NHAr, —NH—SO2—C—1—C6-alkyl, —NH—SO2Ar, —NH—SO2-nitrophenyl, —SO2—OH, —SO2-C1-C6-alkyl, —SO2—Ar, —SO2-C1-C6-alkoxy, —SO2—OAr, —SO2—NH2, —SO2—NH—C1-C6-alkyl, —SO2—N(C1-C6-alkyl)2, —SO2—NHAr, —SO2—C2-C6-alkoxy;
- n is 0 or 1;
- or a pharmaceutically acceptable salt thereof.
A method of treatment or inhibition of urinary incontinence in a mammal, the method comprising administering to a mammal in need thereof a pharmacologically effective amount of N-[2-amino4-(4-fluorobenzylamino)-phenyl]carbamic acid or a pharmaceutically acceptable salt or ester form thereof.
A method of treatment or inhibition of urinary incontinence in a mammal, the method comprising administering to a mammal in need thereof a pharmacologically effective amount of a compound of the formula:
- wherein:
- R is hydrogen, hydroxy or fluoro;
- R1, R2, R3 and R4 each are independently hydrogen, C1-4 alkyl, halogen, trifluoromethyl, phenyl, p-methylphenyl or p-trifluoromethylphenyl;
- or R1 and R2, R2 and R3 or R3 and R4 are joined together to form a benzo fused ring;
- R5 is hydrogen or C1-4 alkyl;
- and
- R6 is chlorine or trifluoromethyl;
- or a nontoxic pharmaceutically acceptable salt, solvate or hydrate thereof.
Dependencies are inferred from the claim text.