Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor
OwnerChih-Hung Lee, Erol K. Bayburt +9inventors
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
Compounds of formula (I) are novel VR1 antagonists that are useful in treating pain, inflammatory thermal hyperalgesia, urinary incontinence and bladder overactivity.
Claims68
A compound of formula (I)
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- or a pharmaceutically acceptable salt or prodrug thereof, wherein
- - - - is absent or a covalent 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 absent or selected from the group consisting of N and CR4
- X5 is selected from the group consisting of N and CH2;
- 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 absent 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—, —N(H)O—, and —NHNH— wherein the left end of —(CH2)mO(CH2)n— and —N(H)O— is attached to Z2 and the right end is attached to R9;
- provided that when Z2 is NH or O then L is other than —N(H)O— or —NHNH—;
- m and n are each independently 1-6;
- 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, ethylenedioxy, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, methylenedioxy, 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, ethylenedioxy, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, methylenedioxy, 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;
- R8 is absent or selected from the group consisting of hydrogen and alkyl;
- provided that R is absent when X5 is CH2 and R8 is selected from selected from the group consisting of hydrogen and alkyl when X5 is N;
- and
- R9 is selected from the group consisting of hydrogen, aryl, 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 (L) or a pharmaceutically acceptable salt thereof.
A method of treating pain in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
A method of treating inflammatory thermal hyperalgesia in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.