US 2006/0217372 A1 · Diaryl ethers as opioid receptor antagonist

Diaryl ethers as opioid receptor antagonist

AssigneeEli Lilly and Company

InventorsMaria-Jesus Blanco-Pillado, Mark Chappell, Marta De La Torre, Nuria Diaz Buezo, James Fritz, William Holloway, James Matt, Charles Mitch, Concepcion Pedregal-Tercero, Steven Wuimby, Miles Siegel, Dana Smith, Russell Stucky, Kumiko Takeuchi, Elizabeth Thomas, Chad Wolfe

Life of this patent

Estimating the term…

Abstract

A compound of the formula (I) wherein the variables X1 to X10, R1 to R7 including R3′, E, v, y, z, A and B are as described, or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixtures thereof, useful for the treatment, prevention or amelioration of obesity and Related Diseases is disclosed.

A compound of formula (I)

wherein
each of X1, X2, X3, X4, X5, X6, X7, X8, X9 and X10 is C, CH, or N;
provided that each of rings A or B has no more than 2 nitrogen atoms;
E is O or NH;
v is 1, 2, or 3;
R1 and R2 are independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C3-C8 cycloalkyl, —C1-C10 alkylaryl, heterocyclyl, —C1-C10 alkylheterocyclic, -arylheterocyclyl, —C3-C8 cycloalkylheterocyclyl, —C1-C8 alkylC(O)C1-C8 alkyl, aryl C(O)C1-C8 alkyl-, C3-C8 cycloalkylC(O)(CH2)n-, C1-C8 alkylC(O)heterocyclic, —C1-C8 alkylC(O)aryl, aryloxyC1-C8 alkyl-, benzhydryl, fused bicyclic, C1-C8 alkylfused bicyclic, phenylC(O)—, phenylC(O)C1-C8 alkyl-, C1-C8 alkoxyC1-C8 alkyl-, —CO(O)C1-C8alkyl, —SO2C1-C8alkyl, —SO2C1-C10 alkylaryl, —SO2C1-C8 alkylheterocyclic, —C1-C8 alkylcycloalkyl, —(CH2)nC(O)OR8, —(CH2)mC(O)NR8R8, and —(CH2)mNSO2R8;
wherein each of the alkyl, alkenyl, cycloalkyl, heterocyclic, and aryl groups are optionally substituted with one to five groups independently selected from halo, C1-C8 haloalkyl, C1-C8 thioalkyl, C1-C8 alkyl, C2-C8 alkenyl, aryl, —C1-C8 alkylaryl, —C(O)C1-C8 alkyl, —SO2C1-C8 alkyl, —SO2C1-C8 alkylaryl, —SO2C1-C8 alkylheterocyclic, —C1-C8 alkylcycloalkyl, —(CH2)nC(O)OR8, and —(CH2)nC(O)R8;
and wherein R1 and R2 may optionally combine with each other, or with 1, or 2 atoms adjacent to the nitrogen atom to form a 4, 5, 6, or 7-membered nitrogen-containing heterocycle which nitrogen-containing heterocycle may further have substituents selected from the group consisting of amino, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C1-C8 alkylaryl, —C(O)C1-C8 alkyl, —CO(O)C1-C8 alkyl, halo, oxo, and C1-C8 haloalkyl;
and wherein R1 and R2 may independently attach to the A ring to form a 4, 5, 6, or 7-member nitrogen-containing bicyclic heterocycle which nitrogen-containing bicyclic heterocycle may further have substituents selected from the group consisting of oxo, amino, —C1-C8 alkyl, —C2-C8 alkenyl, —C2-C8 alkynyl, aryl, —C1-C8 alkylaryl, —C(O)C1-C8 alkyl, —CO(O)C1-C8 alkyl, halo, and C1-C8 haloalkyl;
and wherein R1 and R2 are not simultaneously hydrogen;
and provided that when one of R1 and R2 is hydrogen the other is not C1-C8 alkyl;
and provided that the group NR1R2 is not —NHCH2Ph;
and further provided that when one of R1 or R2 is —CH2CH2-optionally substituted phenyl or —CH2CH2)-optionally substituted naphthyl, or —CH2CH2-optionally substituted 5 or 6 member monocyclic heterocyclic aromatic, and v is 1, then R6 and R7 are not simultaneously hydrogen;
R3 and R3′ are each independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, —C1-C8 alkylcycloalkyl, and —C1-C8 alkylaryl;
R4 and R5 are each independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, —C2-C8 alkynyl, —C1-C8 alkoxyalkyl, C1-C8 thioalkyl, halo, C1-C8 haloalkyl, —C1-C8 alkoxyhaloalkyl, aryl, —C1-C8 alkylaryl, —C(O)C1-C8 alkyl, or —C(O)OC1-C8 alkyl, -C1-C8 alkylamino, —C1-C8 alkylcycloalkyl, —(CH2)mC(O)C1-C8 alkyl, and (CH2)nNR8R8, wherein each R4 or R5 is attached to its respective ring only at carbon atoms, and wherein y is 0, 1, 2, or 3;
and wherein z is 0, 1, 2, or 3;
R6 and R7 are each independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —C(O)C1-C8 alkyl, hydroxy, C1-C8 alkoxy, —SO2C1-C8 alkyl, SO2C1-C8 alkylaryl, —SO2C1-C8 alkylheterocyclic, aryl, —C1-C8 alkylaryl, C3-C7 cycloalkyl, —C1-C6 alkylcycloalkyl, —(CH2)nC(O)R8, —(CH2)mC(O)NR8R8, and —(CH2)mNSO2R8;
wherein each of the alkyl, alkenyl, and aryl groups are optionally substituted with one to five groups independently selected from C1-C8 alkyl, C2-C8 alkenyl, aryl, and C1-C8 alkylaryl;
and wherein R6 and R7 may independently combine with each other, and with the nitrogen atom to which they are attached or with 1, or 2 atoms adjacent to the nitrogen atom to form a 4, 5, 6, or 7-membered nitrogen containing heterocycle which nitrogen-containing heterocycle may optionally have substituents selected from the group consisting of oxo, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, —C1-C8 alkylaryl, —C(O)C1-C8 alkyl, —CO(O)C1-C8 alkyl, hydroxy, C1-C8 alkoxy, —C1-C8 alkylamine, amino, halo, and haloalkyl;
R8 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylaryl, —C(O)C1-C8 alkyl, or —C(O)OC1-C8 alkyl;
and wherein n is 0, 1, 2, 3 or 4 and m is 1, 2, or 3;
or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers thereof.

19 more elements

Abstract

Claims42