US 2004/0106645 A1 · Antagonists of melanin concentrating hormone receptor

Antagonists of melanin concentrating hormone receptor

AssigneeMillennium Pharmaceuticals, Inc.

InventorsChristopher Blackburn, Su-Jen Lai, Jennifer L. Che, Martin P. Maguire, Michael A. Patane, Matthew J. LaMarche, Courtney A. Cullis, James Brown, Anil Vasudevan, Jennifer C. Freeman, Mathew M. Mulhern, John K. Lynch, Ju Gao, Dariusz Wodka, Andrew J. Souers, Rajesh Iyengar, Mary Katherin Verzal, Philip R. Kym

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Abstract

This invention provides compounds that are antagonists of melanin concentrating hormone receptor-1 (MCH-R1). The compounds are represented by formula I: 1 where m is zero or one, n is zero to two, Y is oxygen or —N(R9)—, R1, R2, R3, R4, R5, R9 and Ring A are defined in the specification. Coumarin and quinolone compounds where R1 and R2 together form a fused benzo ring are preferred. The invention also provides compounds of formula VI where the coumarin moiety is replaced by a quinazolinone ring. The compounds are useful for treating MCH-R1-related disorders, particularly overweight conditions including obesity.

A compound of formula I:

310
or a pharmaceutically-acceptable salt or prodrug thereof,
wherein:
m is zero or one;
n is zero, one or two;
Ring A is selected from the group consisting of phenyl, C3-8 carbocyclyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, wherein said Ring A is optionally fused to a 5-7 membered saturated, unsaturated or partially unsaturated ring having 0-2 heteroatoms selected from N, O, or S, and wherein the Ring A system is substituted or unsubstituted;
Y is oxygen or —N(R9)—;
Q is absent or is a C3-6 cycloalk-1,2-diyl, —CHN(R8)2—, or a saturated or unsaturated carbon chain having 1-5 chain atoms, wherein each hydrogen-bearing carbon of said chain is optionally and independently substituted by a C1-6 aliphatic group, and one saturated carbon of said chain along with the hydrogen atoms attached thereto is optionally replaced by —C(R7)2—, —O—, —S—, —S(O)—, —S(O)2—, or —N(R8)—;
R1 is selected from R, —CN, CO2R, —C(O)R, or —CON(R8)2;
R is hydrogen, C1-10 aliphatic, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl;
R2 is selected from hydrogen, C1-10 aliphatic, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, or R1 and R2 taken together with their intervening atoms form a fused, unsaturated or partially unsaturated, substituted or unsubstituted, 5-7 membered ring having 0-2 heteroatoms selected from O, N or S;
R3 is selected from R, —CN, CO2R, —C(O)R, —CH2N(R8)2, or —C(O)N(R8 )2, heterocyclyl;
R4 is selected from hydrogen, C1-10 aliphatic, —CN, —CO2R, —C(O)R, or —C(O)N(R8)2;
each R5 is independently selected from the group consisting of hydrogen, C1-6 aliphatic, —CN, —CO2R, —C(O)R, and —CON(R8)2, or two R5 groups taken together with their intervening carbon form an optionally substituted 3-6 membered ring having 0-2 heteroatoms selected from O, N, or S;
Ring B is optionally substituted by one or more R6;
each R6 is independently selected from C1-6 aliphatic, hydroxyl, alkoxy, oxo, halo, —SR, —CN, —N(R8)2, —NHC(O)R, —N(R8)CON(R8)2, —N(R8)COR, —NHCO2(C1-8 aliphatic), —CO2R, —C(O)R, —CON(R8)2, —S(O)2R, —S(O)R, —SO2N(R8)2, or —N(R8)S(O)2R, or two R6 taken together with their intervening atoms form a 5-7 membered ring having 0-2 heteroatoms selected from N, O, or S;
each R7 is independently selected from hydrogen, C1-10 aliphatic, halo, —OR, —SR, —CN, —N(R8)2, —NHC(O)R, —N(R8)CON(R8)2, —N(R8)COR, —NHCO2R—, —CO2R, —C(O)R, —CON(R8)2, —S(O)2R, —S(O)R, —SO2N(R8)2, or —N(R8)S(O)2R, or two R7 groups taken together form ═O, ═N—OR, ═N—N(R8)2, ═N—NHC(O)R, ═N—NHCO2R, or two R7 groups taken together with their intervening carbon form an optionally substituted 3-6 membered ring having 0-2 heteroatoms selected O, N, or S;
each R8 is independently selected from R, —CO2R, —C(O)R, —C(O)N(C1-6 aliphatic)2, —C(O)NH(C1-6 aliphatic), —S(O)2R, —S(O)R, or —SO2N(C1-6 aliphatic)2, —SO2NH(C1-6 aliphatic), or two R8 groups on the same nitrogen taken together with the nitrogen form a 5-7 membered heterocyclyl ring;
and
R9 is hydrogen, C1-10 aliphatic, aralkyl, heteroaralkyl, or heterocyclylalkyl.

17 more elements

Facts

Application

10/459,682Filed 11 Jun 2003

Priority

12 Jun 2002

Published

3 Jun 2004

Term ends

Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 405/14
Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having…:…
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Abstract

Claims39