US 6,660,752 B2 · 2,6-Substituted chroman derivatives useful as beta-3 adrenoreceptor agonists

Abstract

This invention relates to novel 2,6-substituted chroman derivatives which are useful in the treatment of beta-3 adrenoreceptor-mediated conditions.

A compound of Formula I:

wherein,
R is independently
hydroxy,
oxo,
halo,
cyano,
nitro,
C1-C10 alkyl,
C1-C10 haloalkyl,
CF3,
NR1R1,
SR1,
OR1,
SO2R2,
OCOR2,
NR1COR2,
COR2,
NR1SO2R2,
phenyl, or
a 5- or 6-membered heterocycle with from 1 to 4 heteroatoms selected from O, S, and N;
each cyclic moiety being optionally substituted with
hydroxy,
R1,
halo,
cyano,
NR1R1,
SR1,
CF3,
OR1,
C3-C8 cyoloalkyl,
NR1COR2,
COR2,
SO2R2,
OCOR2,
NR1SO2R2,
C1-C10 alkyl, or
C1-C10 alkoxy;
R1 is
hydrogen,
(CH2)d—O—(CH2)dR5 where each d is selected independently, or
C1-C10 alkyl optionally substituted with 1 to 4 substituents each independently selected from
hydroxy,
halo,
CO2C1-C4-alkyl,
CO2H,
C1-C10 alkoxy,
S(O)b-phenyl optionally substituted with halo, C1-C4 alkyl, C1-C4 alkoxy, SO2—C1-C4alkyl, or CO2 C1-C4alkyl;
or
phenyl optionally substituted with CO2—C1-C4-alkyl, CO2H, halo, or C1-C10 alkyl;
or
C3-C8 cycloalkyl, phenyl, or naphthyl, each optionally substituted with 1 to 4 substituents each independently selected from halo, nitro, oxo, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, CO2C1-C4-alkyl, and CO2H, and
when two R1 groups are attached to N as NR1R1, these R1 groups may form together with the nitrogen to which they are attached, a heterocyclic ring containing 4 to 7 C atoms, 1 to 2 N atoms, and 0 to 1 O or S atoms;
R2 is
R1,
OR1,
NR1R1,
NHS(O)bphenyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halo or nitro;
NHS(O)bnaphthyl,
NHS(O)bC1-C10 alkyl optionally substituted with fluoro up to the perfluoro level, or
a 5- or 6-membered heterocycle with one or more heteroatoms selected from O, S, and N, said heterocyclic moiety being optionally substituted with R1;
R3 is hydrogen, C1-C10 alkyl, or COR2;
R4 is hydrogen, C1-C10 alkyl, C1-C10 alkyl-phenyl, or C1-C10 alkyl-pyridyl;
R5 is hydrogen or COOH;
R6 is
hydrogen,
C1-C10 alkyl optionally substituted with 1 to 4 substituents each independently selected from halo, phenyl, or phenyl-COR2, or
C1-C10 alkyl-S(O)bC1-C10 alkyl optionally substituted with COR2 or C3-C8 cycloalkyl;
Ar is pyridine:
Y is
halo,
NO2,
R6,
SR1,
S(O)b-phenyl-CO2R1,
where, when the two R4 groups attached to the same C are both alkyl, they optionally may be joined so that, when taken together with the C to which they are attached, they form a spiro ring of 3, 5, or 6 C atoms, or where the R4 attached to N and one R4 attached to the adjacent C are both alkyl, they optionally may be joined so that, taken together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclic ring;
with the proviso that when e is 1, at least one R4 group must be C1-C10 alkyl-phenyl or C1-C10 alkyl-pyridyl, or two R4 groups must form one of said spiro or heterocyclic ring moieties;
phenyl optionally fused to one or two phenyl rings, or to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, or
a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S and O, optionally fused to a phenyl ring, each cyclic moiety being optionally substituted with one or more substituents independently selected from
COR2,
CONR1S(O)2R9,
COCH2SO2-thiazolyl optionally substituted with alkyl or amino,
halo,
NO2,
OR1,
R1,
SR1,
O—C1-C6-alkyl substituted by C3-C6-cycloalkyl,
O-phenyl optionally substituted by SO2CH3,
SO2NH2,
SO2NR1R7,
NR1R1,
NR1COC1-C6alkyl,
C1-C10COR2,
phenyl optionally substituted with halo, C1-C4 alkyl, or C1-C4 alkoxy,
tetrazolo;
R7 is
phenyl or heteroaryl containing 3-6 C and 1-3 O, N, or S atoms, each optionally substituted by C1-C4 alkyl, CN, NO2, C0-C1-C4alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl,
C0-R8,
R8 is
C1-C6 alkyl optionally substituted with C1-C4 alkoxy, N(CH3)2, or one or two CF3,
C3-C6-cycloalkyl,
phenyl optionally substituted with C1-C4 alkoxy, halo, or C1-C4 alkyl,
NH-phenyl optionally substituted with C1-C4 alkyl, halo, C1-C4 alkoxy, or C1-C4 haloalkoxy,
NH-cyclohexyl;
R9 is
C3-C6-cycloalkyl,
thienyl optionally substituted with C1-C4 alkyl or isoxazolyl,
pyridyl optionally substituted with —SO2—C1-C4alkyl,
pyrazolyl optionally substituted with halo or C1-C4 alkyl,
isoxazolyl optionally substituted with C1-C4 alkyl, or
a is 0, 1, 2, 3, 4, or 5;
b is 0, 1, or 2;
d is 1, 2, or 3;
e is 1 or 2;
and pharmaceutically acceptable salts and esters thereof.

112 more elements

2,6-Substituted chroman derivatives useful as beta-3 adrenoreceptor agonists

Life of this patent

2,6-Substituted chroman derivatives useful as beta-3 adrenoreceptor agonists

Life of this patent

Abstract

Claims30