2,6-Substituted chroman derivatives useful as beta-3...

Details 2,6-Substituted chroman derivatives useful as beta-3... 2,6-Substituted chroman derivatives useful as beta-3...

2002-04-22

2003-12-09

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S282700, C514S337000

Reexamination Certificate

active

06660752

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel chroman compounds, pharmaceutical compositions containing such compounds, and methods of treating beta-3 adrenoreceptor-mediated conditions with such compositions.
BACKGROUND OF THE INVENTION
Adrenoreceptors, or adrenergic receptors, are sites on effector organs that are innervated by postganglionic adrenergic fibers of the sympathetic nervous system, and are classified as either alpha-adrenergic or beta-adrenergic receptors. Alpha-adrenergic receptors respond to norepinephrine and to such blocking agents as phenoxybenzamine and phentolamine, whereas beta-adrenergic receptors respond to epinephrine and to such blocking agents as propranolol.
Beta-adrenergic receptors are sub-classified as beta-1, beta-2, and beta-3 adrenoreceptors. Generally, beta-1 stimulation causes cardiostimulation, whereas beta-2 stimulation causes bronchodilation and vasodilation.
Beta-3 receptors are found on the cell surface of both white and brown adipocytes where their stimulation promotes both lipolysis and energy expenditure. Agonists of beta-3 adrenoreceptors are known to be useful in the treatment of hyperglycemia (diabetes) and obesity in mammals, as well as in the treatment of gastrointestinal disorders and neurogenetic inflammation (U.S. Pat. No. 5,561,142). Additionally, they are known to lower triglyceride and cholesterol levels and to raise high-density lipoprotein levels in mammals (U.S. Pat. No. 5,451,677). Accordingly, they are useful in the treatment of conditions such as hypertriglyceridemia, hypercholesterolemia, and in lowering high-density lipoprotein levels. They also may be useful in treating patients with Syndrome X, impaired fasting glucose, and/or impaired glucose tolerance, as well as in the treatment of atherosclerotic and cardiovascular diseases and related conditions.
Additionally, it is also believed that the compounds of this invention are effective in the treatment of ocular hypertension and glaucoma, and in the treatment of urinary disorders including pollakiuria and incontinence, as well as in the treatment of prostate disease and as topical anti-inflammatory agents.
It has now been found that certain novel chroman derivatives are effective as beta-3 agonists and are useful in the treatment of beta-3 adrenoreceptor-mediated conditions.
DESCRIPTION OF THE INVENTION
wherein
R is independently
hydroxy,
oxo,
halo,
cyano,
nitro,
C
1
-C
10
alkyl,
C
1
-C
10
haloalkyl,
CF
3
,
NR
1
R
1
,
SR
1
,
OR
1
,
SO
2
R
2
,
OCOR
2
,
NR
1
COR
2
,
COR
2
,
NR
1
SO
2
R,
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,
R
1
,
halo,
cyano,
NR
1
R
1
,
SR
1
,
CF
3
,
OR
1
,
C
3
-C
8
cycloalkyl,
NR
1
COR
2
,
COR
2
,
SO
2
R
2
,
OCOR
2
,
NR
1
SO
2
R
2
,
C
1
-C
10
alkyl, or
C
1
-C
10
alkoxy;
R
1
is
hydrogen,
(CH
2
)
d
—O—(CH
2
)
d
R
5
where each d is selected independently, or
C
1
-C
10
alkyl optionally substituted with 1 to 4 substituents each independently selected from
hydroxy,
halo,
CO
2
C
1
-C
4
-alkyl,
CO
2
H,
C
1
-C
10
alkoxy,
S(O)
b
C
1
-C
10
alkyl,
S(O)
b
-phenyl optionally substituted with halo, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, SO
2
—C
1
-C
4
alkyl, or CO
2
C
1
-C
4
alkyl; or
phenyl optionally substituted with CO
2
C
1
-C
4
-alkyl, CO
2
H, halo, or C
1
-C
10
alkyl; or
C
3
-C
8
cycloalkyl, phenyl, or naphthyl, each optionally substituted with 1 to 4 substituents each independently selected from halo, nitro, oxo, C
1
-C
10
alkyl, C
1
-C
10
alkoxy, C
1
-C
10
alkylthio, CO
2
C
1
-C
4
-alkyl, and CO
2
H, and
when two R
1
groups are attached to N as NR
1
R
1
, these R
1
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;
R
2
is
R
1
,
OR
1
,
NR
1
R
1
,
NHS(O)
b
phenyl optionally substituted with C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halo or nitro;
NHS(O)
b
naphthyl,
NHS(O)
b
C
1
-C
10
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 R
1
;
R
3
is hydrogen, C
1
-C
10
alkyl, or COR
2
;
R
4
is hydrogen, C
1
-C
10
alkyl, C
1
-C
10
alkyl-phenyl, or C
1
-C
10
alkyl-pyridyl;
R
5
is hydrogen or COOH;
R
6
is
hydrogen,
C
1
-C
10
alkyl optionally substituted with 1 to 4 substituents each independently selected from halo, phenyl, or phenyl-COR
2
, or
C
1
-C
10
alkyl-S(O)
b
C
1
-C
10
alkyl optionally substituted with COR
2
or C
3
-C
8
cycloalkyl;
Ar is
phenyl optionally fused to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from O, S, and N, said bicyclic moiety being optionally fused to a phenyl, or
a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, optionally fused to phenyl;
Y is
halo,
NO
2
,
R
6
,
SR
1
,
S(O)
b
-phenyl-CO
2
R
1
,
where, when the two R
4
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 R
4
attached to N and one R
4
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 R
4
group must be C
1
-C
10
alkyl-phenyl or C
1
-C
10
alkyl-pyridyl, or two R
4
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
COR
2
,
CONR
1
S(O)
2
R
9
,
COCH
2
SO
2
-thiazolyl optionally substituted with alkyl or amino,
halo,
NO
2
,
OR
1
,
R
1
,
SR
1
,
O—C
1
-C
6
-alkyl substituted by C
3
-C
6
-cycloalkyl,
O-phenyl optionally substituted by SO
2
CH
3
,
SO
2
NH
2
,
SO
2
NR
1
R
7
,
NR
1
R
1
,
NR
1
COC
1
-C
6
alkyl,
C
1
-C
10
COR
2
,
phenyl optionally substituted with halo, C
1
-C
4
alkyl, or C
1
-C
4
alkoxy,
tetrazolo;
R
7
is
phenyl or heteroaryl containing 3-6 C and 1-3 O, N, or S atoms, each optionally substituted by C
1
-C
4
alkyl, CN, NO
2
, CO—C
1
-C
4
alkyl, C
1
-C
4
alkoxy, or C
1
-C
4
haloalkyl,
CO—R
8
,
R
8
is
C
1
-C
6
alkyl optionally substituted with C
1
-C
4
alkoxy, N(CH
3
)
2
, or one or two CF
3
,
C
3
-C
6
-cycloalkyl,
phenyl optionally substituted with C
1
-C
4
alkoxy, halo, or C
1
-C
4
alkyl,
NH-phenyl optionally substituted with C
1
-C
4
alkyl, halo, C
1
-C
4
alkoxy, or C
1
-C
4
haloalkoxy,
NH-cyclohexyl;
R
9
is
C
3
-C
6
cycloalkyl,
thienyl optionally substituted with C
1
-C
4
alkyl or isoxazolyl,
pyridyl optionally substituted with —SO
2
—C
1
-C
4
alkyl,
pyrazolyl optionally substituted with halo or C
1
-C
4
alkyl,
isoxazolyl optionally substituted with C
1
-C
4
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.
The terms identified above have the following meaning throughout:
C
1
-C
10
alkyl means straight or branched chain alkyl groups having from one to about ten carbon atoms, which may be saturated, unsaturated, or partially saturated. Such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, as well as vinyl, allyl, propynyl, butenyl, butadienyl, isopropenyl, methyleneyl, ethylenyl, propenyl, ethynyl, and the like.
C
1
-C
10
haloalkyl means straight or branched chain alkyl groups having from about one to about ten carbon atoms where any C—C bond may be saturated or unsaturated, the alkyl groups being substituted

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