Selective &bgr;3 adrenergic agonists

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

2000-05-12

2001-05-15

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...

C548S370100

Reexamination Certificate

active

06232337

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. 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 methods of treating Type II diabetes, treating obesity, and stimulating the &bgr;
3
receptor which comprise administering to a patient in need thereof a compound described by Formula I below.
where
n is 0 or 2;
m is 0 to 5;
r is 0 to 3;
A is
X
1
is
(1) —O—CH
2
—,
(2) —S—CH
2
—, or
(3) a bond;
R
1
is
(1) hydroxy,
(2) oxo,
(3) halogen,
(4) cyano,
(5) NR
8
R
8
,
(6) SR
8
,
(7) trifluoromethyl,
(8) C
1
-C
10
alkyl,
(9) OR
8
,
(10) SO
2
R
9
,
(11) OCOR
9
,
(12) NR
8
COR
9
,
(13) COR
9
,
(14) NR
8
SO
2
R
9
,
(15) NR
8
CO
2
R
8
, or
(16) C
1
-C
10
alkyl substituted by hydroxy, halogen, cyano, NR
8
R
8
, SR
8
, trifluoromethyl, OR
8
, C
3
-C
8
cycloalkyl, phenyl, NR
8
COR
9
, COR
9
, SO
2
R
9
, OCOR
9
, NR
8
SO
2
R
9
or NR
8
CO
2
R
8
;
R
2
and R
3
are independently
(1) hydrogen,
(2) C
1
-C
10
alkyl, or
(3) C
1
-C
10
alkyl with 1 to 4 substituents selected from hydroxy, C
1
-C
10
alkoxy, and halogen;
x is
(1) —CH
2
—,
(2) —CH
2
—CH
2
—,
(3) —CH═CH—, or
(4) —CH
2
O—;
R
4
and R
5
are independently
(1) hydrogen,
(2) C
1
-C
10
alkyl,
(3) halogen,
(4) NHR
8
,
(5) OR
8
,
(6) SO
2
R
9
, or
(7) NHSO
2
R
9
;
R
6
is
(1) hydrogen, or
(2) C
1
-C
10
alkyl;
R
7
is Z—(R
1a
)n;
R
1a
is
(1) R
1
, with the proviso that when A is phenyl, R
1a
is not C
1
-C
10
alkyl,
(2) C
3
-C
8
cycloalkyl,
(3) phenyl optionally substituted with up to 4 groups independently selected from R
8
, NR
8
R
8
, OR
8
, SR
8
, and halogen, or
(4) 5- or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, optionally substituted with up to four groups independently selected from oxo, R
8
, NR
8
R
8
, OR
8
, SR
8
, and halogen;
z is
(1) phenyl,
(2) naphthyl,
(3) a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen,
(4) a benzene ring fused to a C
3
-C
8
cycloalkyl ring,
(5) a benzene ring fused to a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen,
(6) a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen fused to a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, or
(7) a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen fused to a C
3
-C
8
cycloalkyl ring;
R
8
i s
(1) hydrogen,
(2) C
1
-C
10
alkyl,
(3) C
3
-C
8
cycloalkyl,
(4) Z optionally having 1 to 4 substituents selected from halogen, nitro, oxo, NR
10
OR
10
, C
1
-C
10
alkyl, C
1
-C
10
alkoxy, C
1
-C
10
alkylthio, and C
1
-C
10
alkyl having 1 to 4 substituents selected from hydroxy, halogen, CO
2
H, CO
2
-C
1
-C
10
alkyl, SO
2
—C
1
-C
10
alkyl, C
3
-C
8
cycloalkyl, C
1
-C
10
alkoxy, and Z optionally substituted by from 1 to 3 of halogen, C
1
-C
10
alkyl, or C
1
-C
10
alkoxy, or
(5) C
1
-C
10
alkyl having 1 to 4 substituents selected from hydroxy, halogen, CO
2
H, CO
2
—C
1
-C
10
alkyl, SO
2
—C
1
-C
10
alkyl, C
3
-C
8
cycloalkyl, C
1
-C
10
alkoxy, C
1
-C
10
alkyl, and Z optionally substituted by from 1 to 4 of halogen, C
1
-C
10
alkyl, or C
1
-C
10
alkoxy;
R
9
is
(1) R
8
, or
(2) NR
8
R
8
;
R
10
is
(1) C
1
-C
10
alkyl, or
(2) two R
10
groups together with the N to which they are attached formed a 5- or 6-membered ring optionally substituted with C
1
-C
10
alkyl; or a pharmaceutically acceptable salt thereof.
The present invention also provides novel pharmaceutical formulations of the compounds of Formula I.
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 alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration. Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
The alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
The term “halogen” is intended to include the halogen atoms fluorine, chlorine, bromine, and iodine.
Examples of 5 and 6-membered heterocycles and fused heterocycles of Z and R
1a
include pyridyl, quinolinyl, pyrimidinyl, pyrrolyl, thienyl, imidazolyl, thiazolyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl, tetrahydronaphthyl, dihydrobenzofuranyl, tetrahydroquinolinyl, furopyridine and thienopyridine.
The term “fleaving group” as used in the specification is understood by those skilled in the art. Generally, a leaving group is any group or atom that enhances the electrophilicity of the atom to which it is attached for displacement. Preferred leaving groups include but are not intended to be limited to p-nitrobenzene sulfonate, triflate, mesylate, tosylate, imidate, chloride, bromide, iodide, and the like.
The term “pharmaceutically effective amount”, as used herein, represents an amount of a compound of the invention that is capable of stimulating the &bgr;
3
receptor in mammals. The particular dose of the compound administered according to this invention will, of course, be determined by the particular circumstances surrounding the patient, including the compound administered, the route of administration, the

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