Opioid receptor antagonists
AssigneeEli Lilly and Company
InventorsHoward Broughton, Nuria Diaz Buezo, Charles Mitch, Concepcion Pedregal-Tercero
Life of this patent
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Abstract
A compound of the formula (I) (I) wherein the variables X1 to X6, Ra, Rb, R1 to R7 including R3′, E, p, j, y, z, A, B and C 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.
Claims22
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The compound according to claim 22 wherein the A-ring is selected from the group consisting of phenyl, pyridine, pyrimidine and pyrazine.
A compound according to claim 22 wherein the C-ring is selected from the group consisting of phenyl and pyridine.
A compound according to claim 22 wherein the A-ring is phenyl and the C ring is pyridine.
A compound according to claim 22 wherein both A and C rings are phenyl.
A compound according to claim 22 wherein p is 2 and both Ra and Rb are hydrogen.
A compound according to claim 22 wherein (CRaRb)p— is —CH═CH—.
A compound according to claim 22 wherein E is an oxygen atom.
A compound according to claim 22 wherein y is 0 or 1, and R4 is independently selected from the group consisting of fluoro, chloro, bromo, methoxy, ethoxy, methyl, ethyl, isopropyl, trifluoromethyl, phenyl, benzyl and ethoxy.
A compound according to claim 22 wherein z is 0 or 1, and R5 is independently selected from the group consisting of fluoro, chloro, bromo, methoxy, ethoxy, methyl, ethyl, isopropyl, trifluoromethyl, phenyl, and benzyl.
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The compound according to claim 22 wherein R6 and R7 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, and phenyl.
A compound according to claim 22 wherein E is an oxygen atom, wherein both R6 and R7 are hydrogen atoms.
A compound selected from the group consisting of:
- 8-[(3-Methyl-butylamino)-methyl]-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-(Isobutylamino-methyl)-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-[(4-Methyl-pentylamino)-methyl]-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-[(2-Thiophen-2-yl-ethylamino)-methyl]-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-Pentylaminomethyl-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-Hexylaminomethyl-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-[(Cyclohexylmethyl-amino)-methyl]-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-Cyclooctylaminomethyl-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-Cycloheptylaminomethyl-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-[(Cycloheptylmethyl-amino)-methyl]-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide trifluoroacetate salt,
- 8-{[2-(Tetrahydro-pyran-4-yl)-ethylamino]-methyl}-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-[(3,3-Dimethyl-butylamino)-methyl]-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-[(2-Cyclopentyl-ethylamino)-methyl]-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-[(3-Morpholin-4-yl-propylamino)-methyl]-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-[(3-Ethoxy-propylamino)-methyl]-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-[(2-Diethylamino-ethylamino)-methyl]-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-[(3-Methoxy-propylamino)-methyl]-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide, and
- 8-[(3-Phenyl-propylamino)-methyl]-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-(3-Phenyl-pyrrolidin-1-ylmethyl)-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-(3-Phenyl-piperidin-1-ylmethyl)-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-[2-(4-Chloro-phenyl)-pyrrolidin-1-ylmethyl]-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-(2-Phenyl-pyrrolidin-1-ylmethyl)-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-(2-Phenyl-piperidin-1-ylmethyl)-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-(2-Phenyl-azepan-1-ylmethyl)-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-(2-Benzyl-pyrrolidin-1-ylmethyl)-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide,
- 8-[(3-Methyl-butylamino)-methyl]-dibenzofuran-2-carboxylic acid amide,
- 8-[(3-Methyl-butylamino)-methyl]-10,11-dihydro-dibenzo[b,j]oxepine-2-carboxilic acid amide,
- 8-[(3-Methyl-butylamino)-methyl]-10,11-dihydro-5-oxa-4-aza-dibenzo[a,d]cycloheptene-2-carboxylic acid amide,
- 8-[(3-Methyl-butylamino)-methyl]-5-oxa-4-aza-dibenzo[a,d]cycloheptene-2-carboxylic acid amide,
- or a pharmaceutically acceptable salt or solvate thereof.
A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 22, or a pharmaceutically acceptable salt or solvate thereof in association with a carrier, diluent and/or excipient.
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A compound of formula (I)
- wherein:
- j is 1 or 2;
- y is 0, 1, or 2;
- andzis 0, 1, or 2;
- p is 0, 1, or 2;
- E is O or NH;
- and wherein each of
- X1, X2, X3, X4, X5, or X6, is C, CH, or N;
- provided that each of rings A or C has no more than 2 nitrogen atoms;
- and provided that Ring B has 0 or 1 double bond excluding tautomeric bonds from rings A and C;
- R1 and R2 are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, 2-methylpentyl, t-butyl, cyclopropyl, phenyl,
- and wherein R1 and R2 may optionally combine with each other 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 oxo, amino, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, phenyl, C1-C8 alkylaryl, C(O)C1-C8 alkyl, CO(O)C1-C8 alkyl, halo, C1-C8 haloalkyl;
- R3 and R3 are each independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, phenyl, aryl, C1-C8 alkylcycloalkyl, and C1-C8 alkylaryl;
- Ra and Rb are each independently selected from hydrogen, and C1-C3 alkyl or combine with their respective carbon atoms to form the vinyl diradical —CH═CH—;
- R4 and R5 are each independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, halo, C1-C8 haloalkyl, phenyl, aryl, C1-C8 alkylaryl, (CH2)mNSO2C1-C8 alkyl, (CH2)mNSO2phenyl, (CH2)mNSO2aryl, —C(O)C1-C8 alkyl, and —C(O)OC1-C8 alkyl;
- wherein each R4 and R5 is attached to its respective ring only at carbon atoms;
- wherein m is 1 or 2;
- and n is 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, SO2C1-C8 alkyl, SO2C1-C8 alkylaryl, SO2C1-C8 alkylheterocyclic, aryl, C1-C8 alkylaryl, C3-C7 cycloalkane, C1-C6 alkylcycloalkane, (CH2)nC(O)OR8, (CH2)nC(O)R8, (CH2)mC(O)NR1R8, 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, phenyl, 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 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, amino, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, phenyl, and C1-C8 alkylaryl;
- R8 is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, phenyl, benzyl, and C5-C8 alkylaryl;
- or a compound selected from 8-cyclooctylaminomethyl-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide;
- 8-cycloheptylaminomethyl-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide;
- 8-[(cycloheptylmethyl-amino)-methyl]-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide;
- 8-{[cyclopropylmethyl-(3-methyl-butyl)-amino]-methyl}-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide;
- 8-[2-(4-chloro-phenyl)-pyrrolidin-1-ylmethyl]-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide;
- 8-(2-phenyl-azepan-1-ylmethyl)-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide;
- and 8-(2-benzyl-pyrrolidin-1-ylmethyl)-10,11-dihydro-dibenzo[b,f]oxepine-2-carboxylic acid amide;
- or a pharmaceutically acceptable salt or solvate thereof.
Dependencies are inferred from the claim text.