Selective &bgr;3 adrenergic agonists

Details Selective &bgr;3 adrenergic agonists Selective &bgr;3 adrenergic agonists

2000-04-17

2001-07-24

Lambkin, Deborah C. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S273700, C548S491000

Reexamination Certificate

active

06265581

ABSTRACT:

FIELD OF INVENTION
The present invention is in the field of medicine, particularly in the treatment of Type II diabetes and obesity. More specifically, the present invention relates to selective &bgr;
3
adrenergic receptor agonists useful in the treatment of Type II diabetes and obesity.
BACKGROUND OF THE INVENTION
The current preferred treatment for Type II, non-insulin dependent diabetes as well as obesity is diet and exercise, with a view toward weight reduction and improved insulin sensitivity. Patient compliance, however, is usually poor. The problem is compounded by the fact that there are currently no approved medications that adequately treat either Type II diabetes or obesity. The invention described herein is directed toward an effective and timely treatment for these serious diseases.
One therapeutic opportunity that has recently been recognized involves the relationship between adrenergic receptor stimulation and anti-hyperglycemic effects. Compounds that act as &bgr;
3
receptor agonists have been shown to exhibit a marked effect on lipolysis, thermogenesis and serum glucose levels in animal models of Type II (non-insulin dependent) diabetes.
The &bgr;
3
receptor, which is found in several types of human tissue including human fat tissue, has roughly 50% homology to the &bgr;
1
and &bgr;
2
receptor subtypes yet is considerably less abundant. The importance of the &bgr;
3
receptor is a relatively recent discovery since the amino-acid sequence of the human receptor was only elucidated in the late 1980's. A large number of publications have appeared in recent years reporting success in discovery of agents that stimulate the &bgr;
3
receptor. Despite these recent developments, there remains a need to develop a selective &bgr;
3
receptor agonist which has minimal agonist activity against the &bgr;
1
and &bgr;
2
receptors. In addition, indolylpropanolamines have been disclosed by Beedle et. al. U.S. Pat. No. 5,013,761.
The present invention provides compounds which are selective &bgr;
3
receptor agonists. As such, the compounds effectively lead to an increase in insulin sensitivity and are useful in treating Type II diabetes and other ailments implicated by the &bgr;
3
receptor, without cardiac or tremor-related side effects.
SUMMARY OF INVENTION
The present invention encompasses novel compounds described by Formula I below.
wherein:
X
1
is —OCH
2
—, —SCH
2
—, or a bond;
R
1
is a fused heterocycle of the formula:
R
2
and R
3
are independently H, C
1
-C
4
alkyl, or aryl;
R
4
is an optionally substituted heterocycle or a moiety selected from the group consisting of:
X
2
is a bond, or a 1 to 5 carbon straight or branched alkylene;
R
5
is H, or C
1
-C
4
alkyl;
R
6
is H, or C
1
-C
4
alkyl;
or R
5
and R
6
combine with the carbon to which each is attached to form a C
3
-C
6
cycloalkyl;
or R
6
combines with to X
2
and the carbon to which X
2
is attached to form a C
3
-C
8
cycloalkyl;
or R
6
combines with X
2
, the carbon to which X
2
is attached, and R
4
to form:
 provided that R
5
is H;
R
7
is H, halo, hydroxy, C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, aryl, CN, COOR
2
, CONHR
2
, NHCOR
2
, OR
2
, NHR
2
, SR
2
, SO
2
R
2
, SO
2
NHR
2
, or SOR
2
;
R
8
is independently H, halo or C
1
-C
4
alkyl;
R
9
is halo, CN, OR
10
, C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, CO
2
R
2
, CONR
11
R
12
, CONH(C
1
-C
4
alkyl or C
1
-C
4
alkoxy), SR
2
, CSNR
2
, CSNR
11
R
12
, SO
2
R
2
, SO
2
NR
11
R
12
, SOR
2
, NR
11
R
12
, optionally substituted aryl, optionally substituted heterocycle, or C
2
-C
4
alkenyl substituted with CN, CO
2
R
2
or CONR
11
R
12
;
R
10
is C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, (CH
2
)
n
C
3
-C
8
cycloalkyl, (CH
2
)
n
aryl, (CH
2
)
n
heterocycle, (CH
2
)
n
C
3
-C
8
optionally substituted cycloalkyl, (CH
2
)
n
optionally substituted aryl, (CH
2
)
n
optionally substituted heterocycle;
R
11
and R
12
are independently H, C
1
-C
4
alkyl, aryl, (CH
2
)
n
aryl, or combine with the nitrogen to which each is bound to form morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl;
A
1
and A
2
are independently O, S, NH, CH
2
, NCH
3
, or NCH
2
CH
3
;
m is 0 or 1;
n is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
The present invention also encompasses novel compounds described by Formula II below.
wherein:
R
1
is
X
1
is —OCH
2
—, —SCH
2
—, or a bond;
The bond between A
3
and A
4
is either a single or double bond;
A
3
and A
4
are independently carbon or nitrogen;
R
2
and R
3
are independently H, C
1
-C
4
alkyl, or aryl;
R
4
is an optionally substituted heterocycle or a moiety selected from the group consisting of:
X
2
is a bond, or a 1 to 5 carbon straight or branched alkylene;
R
5
is H, or C
1
-C
4
alkyl;
R
6
is H, or C
1
-C
4
alkyl;
or R
5
and R
6
combine with the carbon to which each is attached to form a C
3
-C
6
cycloalkyl;
or R
6
combines with to X
2
and the carbon to which X
2
is attached to form a C
3
-C
8
cycloalkyl;
or R
6
combines with X
2
, the carbon to which X
2
is attached, and R
4
to form:
 provided that R
5
is H;
R
7
is H, halo, hydroxy, C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, aryl, CN, COOR
2
, CONHR
2
, NHCOR
2
, OR
2
, NHR
2
, SR
2
, SO
2
R
2
, SO
2
NHR
2
, or SOR
2
;
R
8
is independently H, halo or C
1
-C
4
alkyl;
R
9
is halo, CN, OR
10
, C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, CO
2
R
2
, CONR
11
R
12
, CONH(C
1
-C
4
alkyl or C
1
-C
4
alkoxy), SR
2
, CSNR
2
, CSNR
11
R
12
, SO
2
R
2
, SO
2
NR
11
R
12
, SOR
2
, NR
11
R
12
, optionally substituted aryl, optionally substituted heterocycle, or C
2
-C
4
alkenyl substituted with CN, CO
2
R
2
or CONR
11
R
12
;
R
10
is C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, (CH
2
)
n
C
3
-C
8
cycloalkyl, (CH
2
)
n
aryl, (CH
2
)
n
heterocycle, (CH
2
)
n
C
3
-C
8
optionally substituted cycloalkyl, (CH
2
)
n
optionally substituted aryl, or (CH
2
)
n
optionally substituted heterocycle;
R
11
and R
12
are independently H, C
1
-C
4
alkyl, aryl, (CH
2
)
n
aryl or combine with the nitrogen to which each is bound to form morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl;
m is 0 or 1;
n is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
The present invention also provides for novel intermediates, useful in the preparation of compounds of Formulas I and II, described by Formula III below.
wherein:
A
5
is CH or N;
X
2
is a bond or a 1 to 5 carbon straight or branched alkylene.
R
5
is H, C
1
-C
4
alkyl;
R
6
is H, C
1
-C
4
alkyl;
or R
5
and R
6
combine with the carbon to which each is attached to form a C
3
-C
6
cycloalkyl;
or R
6
combines with X
2
and the carbon to which X
2
is attached to form a C
3
-C
8
cycloalkyl;
R
14
is C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, hydroxy, carboxy, tetrazolyl, acyl, COOR
2
, CONR
11
R
12
, CONH(C
1
-C
4
alkoxy), cyano, C
1
-C
4
alkoxy, C
1
-C
4
alkyl, phenyl, nitro, NR
11
R
12
, NHCO(C
1
-C
4
alkyl), NHCO(benzyl), NHCO(phenyl), SR
2
, S(C
1
-C
4
alkyl), OCO(C
1
-C
4
alkyl), SO
2
(NR
11
R
12
), SO
2
(C
1
-C
4
alkyl), or SO
2
(phenyl);
or pharmaceutically acceptable salts thereof.
The present invention also provides novel processes for making, as well as novel pharmaceutical formulations of, compounds of Formulas I and II.
The compounds of the present invention are selective &bgr;
3
receptor agonists and as such are useful for treating Type II diabetes and obesity, as well as useful for agonizing the &bgr;
3
receptor. Therefore, the present invention also provides for methods of treating Type II diabetes and obesity, as well as a method of agonizing the &bgr;
3
receptor.
In addition, the present invention provides the use of compounds of Formulas I and II for treating Type II diabetes and obesity as well the use of compounds of Formulas I and II for agonizing the &bgr;
3
receptor.
Another representation of the compounds of the present invention is given by Formula IV below.
wherein:
R
1
is a fused heterocycle of the formula:
R
2
is H, C
1
-C
4
alkyl, or aryl;
R
3
is H, C
1
-C
4
alkyl, aryl, or heterocycle;
R
4
is an optionally substituted heterocycle or a m

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