Selective &bgr;3 adrenergic agonists

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

1999-11-18

2003-09-09

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S236500

Reexamination Certificate

active

06617347

ABSTRACT:

FIELD OF THE 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. There are no currently 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 recently recognized therapeutic opportunity involves the relationship between adrenergic receptor stimulation and anti-hyperglycemic effects. Compounds that act as &bgr;
3
adrenergic receptor agonists have been shown to exhibit a marked effect on Lipolysis, thermogenesis, and serum glucose levels in animal models of Type II 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 both high intrinsic activity and minimal agonist activity against the &bgr;
1
and &bgr;
2
receptors.
SUMMARY OF INVENTION
The present invention provides a novel compound represented by Formula (I) below and methods of treating Type II diabetes, treating obesity, and stimulating the [3 receptor which comprise administering to a patient in need thereof a compound described by Formula I below.
wherein:
X
1
is —OCH
2
—, —SCH
2
—, or a bond;
R
1
is a heterocycle of the formula:
R
2
and R
3
are independently hydrogen, 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 hydrogen or C
1
-C
4
alkyl;
R
6
is hydrogen 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 X
2
and the carbon to which each is attached to form a (C
3
-C
8
cycloalkyl;
or R
6
combines with X
2
, R
4
, and the carbon to which each is attached to form:
provided that R
5
is hydrogen;
R
7
is hydrogen, hydroxy, cyano, oxo, CO
n
R
2
, CONHR
2
, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
haloalkyl, C
1
-C
4
optionally substituted alkyl, (CH
2
)
n
aryl, (CH
2
)
n
heterocycle, (CH
2
)
n
optionally substituted aryl, or (CH
2
)
n
optionally substituted heterocycle;
R
8
is independentLy hydrogen, 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
, CSNHR
2
, CSNR
11
R
12
, SO
2
R
2
, 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
alky:, 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 hydrogen, 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 piperaziny_;
R
13
is hydrogen, halo, aryl, or C
1
-C
4
alkyl;
m is 0 or 1;
n is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
The present invention also provides novel pharmaceutical formulations of the compounds of Formula I.
The present invention also provides a novel compound of Formula (I) wherein all variables except R
4
, R
6
and R
9
are as described above. R
4
additionally includes thiophene optionally substituted with R
9
; R
9
additionally includes NR
2
SO
2
R
2
and SO
2
NR
11
R
12
; and R
6
is: 1) hydrogen or C
1
-C
4
alkyl; 2) R
5
and R
6
combine with the carbon to which each is attached to form a C
3
-C
6
cycloalkyl; 3) R
6
combines with X
2
and the carbon to which each is attached to form a Z or Z—CH
2
, wherein Z is a C
3
-C
8
cycloalkyl attached to the nitrogen atom in Formula (I); or 4) R
6
combines with X
2
, R
4
, and the carbon to which each is attached to form:
provided that R
5
is hydroger.
Also included are methods of stimulating beta 3 receptors in a mammal in need thereof and methods of treating a mammal with Type II diabetes or obesity using a compound represented by Formula (I), modified as described in the previous paragraph. The method comprises administering a pharmaceutically effective amount of said compound.
The compounds of Formula I are selective &bgr;
3
receptor agonists and as such are useful for treating Type II diabetes and obesity, as well as useful for stimulating 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 stimulating the &bgr;
3
receptor.
DETAILED DESCRIPTION OF THE INVENTION
For the purposes of the present invention, as disclosed and claimed herein, the following terms, as used herein, are defined below. As they relate to the present invention, the terms below may not be interpreted, individually or collectively, to describe chemical structures that are unstable or impossible to construct.
The term “halo” represents fluorine, chlorine, bromine, or iodine.
The term “C
1
-C
4
alkyl” represents a cyclo, straight, or branched chain alkyl group having from one to four carbon atoms such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, and the like. A “haloalkyl” is one such alkyl substituted with one or more halo atoms, preferably one to three halo atoms. An example of a haloalkyl is trifluoromethyl. An “alkoxy” is a alkyl group covalently bonded by an —O— linkage.
The term “1 to 5 carbon straight or branched alkylene” represents a one to five carbon, straight or branched, alkylene moiety. A branched alkylene may have one or more points of branching. A 1 to 5 carbon straight or branched alkylene may optionally be unsaturated at one or more carbons. Thus, a 1 to 5 carbon straight or branched alkylene includes 1 to 5 carson alkylene, alkenylene and alkylidene moieties. Examples include but are not intended to be limited to methylene, ethylene, propylene, butylene, —CH(CH
3
)CH
2
—CH(C
2
H
5
)CH
2
—, —CH(CH
3
)CH(CH
3
—CH
2
C(CH
3
)
2
—, —CH
2
CH(CH
3
)CH
2
—, —C(CH
3
)
2
CH═, —CH═CHCH
2
—, —CH═CH—, —CH
2
CH
2
—C═CCH
2
—, and the like.
The “acyl” moiety, alone or in combination, is derived from an alkanoic acid containing from one to seven carbon atoms. The term “acyl” also includes moieties derived from an aryl carboxylic acid.
The term “aryl” represents an optionally substituted or unsubstituted phenyl or naphthyl. The term (CH
2
)naryl is preferably benzyl or phenyl.
The term “optionally substituted” as used herein means an optional substitution of one to three, preferably one or two groups independently selected from halo, 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, benzyl, 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
(C
1
-C
4
alkyl), or SO
2
(phenyl); provided that such substitution does not entirely destroy biological activity, as defined in this

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