US 7,375,126 B2
Fused compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor
Arthur R. Gomtsyan, Vernon Hills, Ill. (US); Erol K. Bayburt, Gurnee, Ill. (US); Chih-Hung Lee, Vernon Hills, Ill. (US); John R. Koenig, Chicago, Ill. (US); Robert G. Schmidt, Waukegan, Ill. (US); Kirill A. Lukin, Vernon Hills, Ill. (US); Margaret Chi-Ping Hsu, Vernon Hills, Ill. (US); Marvin R. Leanna, Grayslake, Ill. (US); Russell D. Cink, Grayslake, Ill. (US); and Gilles Chambournier, Ann Arbor, Mich. (US)
Assigned to Abbott Laboratories, Abbott Park, Ill. (US)
Filed on Jun. 09, 2004, as Appl. No. 10/864,068.
Claims priority of provisional application 60/477894, filed on Jun. 12, 2003.
Prior Publication US 2005/0043351 A1, Feb. 24, 2005
Int. Cl. A61K 31/403 (2006.01); A61K 31/416 (2006.01)
U.S. Cl. 514—403  [514/412; 548/241; 548/469] 8 Claims
 
1. 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, inflammatory pain, osteoarthritic pain, chronic lower pain, and migraine, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof

OG Complex Work Unit Drawing
wherein
---is absent;
X1 is CR1;
X2 is N or CR2;
X3 is N, NR3, or CR3;
X4 is a bond;
provided that at least one of X2 and X3 is N;
Z1 is O;
Z2 is NH;
Ar1 is selected from the group consisting of

OG Complex Work Unit Drawing
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—, RB(SO)2RAN—, RAO(SO)2—, RBO(SO)2—, ZAZBN—, (ZAZBN)alkyl, (ZAZBN)carbonyl, (ZAZBN)carbonylalkyl, and (ZAZBN)sulfonyl;
R2 is 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—, RB(SO)2RAN—, RAO(SO)2—, RBO(SO)2—, ZAZBN—, (ZAZBN)alkyl, (ZAZBN)alkylcarbonyl, (ZAZBN)carbonyl, (ZAZBN)carbonylalkyl, (ZAZBN)sulfonyl, (ZAZBN)C(═NH)—, (ZAZBN)C(═NCN)NH— and (ZAZBN)C(═NH)NH—;
R8a is hydrogen or alkyl;
R8b is absent;
R9, R10, R11, and R12 are each individually selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, aryl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, heteroaryl, heterocycle, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, (CF3)2(HO)C—, RB(SO)2RAN—, RAO(SO)2—, RBO(SO)2—, ZAZBN—, (ZAZBN)alkyl, (ZAZBN)carbonyl, (ZAZBN)carbonylalkyl, and (ZAZBN)sulfonyl, wherein ZA and ZB are each independently hydrogen, alkyl, alkylcarbonyl, formyl, aryl, or arylalkyl, provided that at least one of R9, R10, R11, or R12 is other than hydrogen, or R10 and R11 taken together with the atoms to which they are attached form a cycloalkyl, cycloalkenyl, or heterocycle ring;
R13 is selected from the group consisting of alkyl, aryl, heteroaryl and halogen;
RA is hydrogen or alkyl; and
RB is alkyl, aryl, or arylalkyl.