Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor
AssigneeAbbott Laboratories
InventorsChih-Hung Lee, Erol K. Bayburt, Stanley DiDomenico JR., Irene Drizin, Arthur R. Gomtsyan, John R. Koenig, Richard J. Perner, Robert G. Schmidt JR., Sean C. Turner, Tammie K. White, Guo Zhu Zheng
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Abstract
Compound of formula (I) 1 are novel VR1 antagonist that are useful in treating pain, inflammatory thermal hyperalgesia, urinary incontinence and bladder overactivity.
Claims84
A compound of formula (I)
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- or a pharmaceutically acceptable salt or prodrug thereof, wherein
- - - - is absent or a single bond;
- X1 is selected from the group consisting of N and CR1;
- X2 is selected from the group consisting of N and CR2;
- X3 is selected from the group consisting of N, NR3, and CR3;
- X4 is a bond or selected from the group consisting of N and CR4;
- X5 is selected from the group consisting of N and C;
- provided that at least one of X1, X2, X3, and X4 is N;
- Z1 is selected from the group consisting of O, NH, and S;
- Z2 is a bond or selected from the group consisting of NH and O;
- L is selected from the group consisting of alkenylene, alkylene, alkynylene, cycloalkylene,
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- —(CH2)mO(CH2)n—, and N(RY), wherein the left end of —(CH2)mO(CH2)n— is attached to Z2 and the right end is attached to R9;
- m and n are each independently 0-6;
- RY is selected from the group consisting of hydrogen and alkyl;
- R1, R3, R5, R6, and R7 are each independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, (CF3)2(HO)C—, —NRAS(O)2RB, —S(O)2ORA, —S(O)2RB, —NZAZB, (NZAZB)alkyl, (NZAZB)carbonyl, (NZAZB)carbonylalkyl and (NZAZB)sulfonyl, wherein ZA and ZB are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, formyl, aryl, and arylalkyl;
- R2 and R4 are each independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, (CF3)2(HO)C—, —NRAS(O)2RB, —S(O)2ORA, —S(O)2RB, —NZAZB, (NZAZB)alkyl, (NZAZB)alkylcarbonyl, (NZAZB)carbonyl, (NZAZB)carbonylalkyl, (NZAZB)sulfonyl, (NZAZB)C(═NH)—, (NZAZB)C(═NCN)NH—, and (NZAZB)C(═NH)NH—;
- RA is selected from the group consisting of hydrogen and alkyl;
- RB is selected from the group consisting of alkyl, aryl, and arylalkyl;
- R8a is selected from the group consisting of hydrogen and alkyl;
- R8b is absent when X5 is N or R8b is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonylalkyl, alkyl, alkylcarbonyloxy, alkylsulfonyloxy, halogen, and hydroxy when X5 is C;
- and
- R9 is selected from the group consisting of hydrogen, aryl, cycloalkyl, and heterocycle.
A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
A method of treating a disorder wherein the disorder is ameliorated by inhibiting vanilloid receptor subtype 1 (VR1) receptor in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
A method of treating bladder overactivity in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
A method of treating urinary incontinence in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.