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US 8,026,256 B2Granted
Fused compounds that inhibit vanilloid subtype 1 (VR1) receptor
AssigneeAbbott Laboratories
InventorsArthur Gomtsyan, Erol K. Bayburt, John R. Koenig, Chih-Hung Lee
Life of this patent
Estimating the term…
Abstract
Compounds of formula (I) are novel VR1 antagonists that are useful in treating pain, inflammatory thermal hyperalgesia, urinary incontinence, or bladder overactivity.
Claims6
A method of treating a disorder by inhibiting vanilloid receptor subtype 1 in a mammal wherein the disorder is selected from the group consisting of pain, bladder overactivity, urinary incontinence, and inflammatory thermal hyperalgesia, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof
- wherein
- --- is a single bond;
- X1 is N or CR1;
- X2 is N or CR2;
- X3 is N, NR3, or CR3;
- X4 is N or CR4;
- X5 is N or C;
- provided that at least one of X1, X2, X3, and X4 is N;
- Z1 is O, NH, or S;
- Z2 is a bond, NH, or O;
- Ar1 is dihydro-1H-indenyl, 1H-indenyl, tetrahydronaphthalenyl, or dihydronaphthalenyl, wherein the Ar1 group is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, 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, (NZAZR)carbonylalkyl, or (NZAZB)sulfonyl, wherein ZA and ZB are each independently hydrogen, alkyl, alkylcarbonyl, formyl, aryl, or arylalkyl;
- R1, R3, R5, R6, and R7 are each independently 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 or (NZAZB)sulfonyl;
- R2 and R4 are each independently 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—, or (NZAZB)C(═NH)NH—;
- RA is hydrogen or alkyl;
- RB is alkyl, aryl, or arylalkyl;
- R8a is hydrogen or alkyl;
- and
- R8b is absent, hydrogen, alkoxy, alkoxycarbonylalkyl, alkyl, alkylcarbonyloxy, alkylsulfonyloxy, halogen, or hydroxy;
- provided that R8b is absent when X5 is N.
16 more elements
A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof
- wherein
- --- is absent or a single bond;
- X1 is N or CR1;
- X2 is N or CR2;
- X3 is N, NR3 or CR3;
- X4 is a bond, N, or CR4;
- X5 is N or C;
- provided that at least one of X1, X2, X3 and X4 is N;
- Z1 is O, NH, or S;
- Z2 is NH or O;
- Ar1 is dihydro-1 H-indenyl, 1 H-indenyl, tetrahydronaphthalenyl, or dihydronaphthalenyl, wherein the Ar1 group is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, 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, or (NZAZB)sulfonyl, wherein ZA and ZB are each independently hydrogen, alkyl, alkylcarbonyl, formyl, aryl, or arylalkyl;
- R1, R3, R5, R6, R7 are each independently 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, or (NZAZB)sulfonyl;
- R2 and R4 are each independently 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, or (NZAZB)sulfonyl, (NZAZB)C(═NH)—, (NZAZB)C(═NCN)NH—, or (NZAZB)C(═NH)NH—;
- RA is hydrogen or alkyl;
- RB is alkyl, aryl, or arylalkyl;
- R8a is hydrogen or alkyl;
- and
- R8b is absent, hydrogen, alkoxy, alkoxycarbonylalkyl, alkyl, alkylcarbonyloxy, alkylsulfonyloxy, halogen, or hydroxy;
- provided that R8b is absent when X5 is N.
16 more elements
Dependencies are inferred from the claim text.