&bgr;3 adrenergic agonists

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

2002-12-13

2004-05-04

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S271100, C546S280400, C514S340000, C514S342000, C564S361000, C564S365000

Reexamination Certificate

active

06730792

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 &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.
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. Stimulation of the &bgr;
1
and &bgr;
2
receptors can cause adverse effects such as tachycardia, arrhythmia, or tremors. An agonist that is selective for the &bgr;
3
receptor over the &bgr;
1
and &bgr;
2
receptors is, therefore, more desirable for treating Type II diabetes or obesity relative to a non-selective agonist.
However, recent studies have suggested the presence of an atypical beta receptor associated with atrial tachycardia in rats (
Br. J. of Pharmacol.,
118:2085-2098, 1996). In other words, compounds that are not agonists of the &bgr;
1
and &bgr;
2
receptors can still modulate tachycardia through activation of a yet to be discovered &bgr;
4
or through some other unknown pathway.
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.
SUMMARY OF INVENTION
The present invention relates to a compound of formula I:
wherein:
A
1
, A
2
and A
3
are carbon or nitrogen provided that only one of A
1
, A
2
and A
3
can be nitrogen;
Het is an optionally substituted, optionally benzofused 5 or 6 membered heterocyclic ring;
R
1
, R
1a
and R
1b
are independently H, halo, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
4
haloalkyl, or SO
2
(C
1
-C
6
alkyl);
R
2
is H or C
1
-C
6
alkyl;
R
3
is H or C
1
-C
6
alkyl;
R
4
is H or C
1
-C
6
alkyl;
or R
3
and R
4
combine with the carbon to which both are attached to form a C
3
-C
6
cyclic ring;
or R
4
and X
1
combine with the carbon to which both are attached to form a C
3
-C
8
cyclic ring;
or R
4
combines with X
1
, the carbon to which both are attached, and the phenyl group to which X
1
is attached to form:
 wherein:
n and m are independently 0, 1, 2, or 3 provided that the sum of n+m is ≦4 and that R
3
is H;
X is OCH
2
, SCH
2
or a bond;
X
1
is a bond or a C
1
-C
5
divalent hydrocarbon moiety;
X
2
is O, S, NH, NHSO
2
, SO
2
NH, CH
2
or a bond; and
X
3
is optionally substituted phenyl or an optionally substituted 5 or 6 membered heterocyclic ring; or a pharmaceutical salt thereof.
The present invention also relates to processes for preparing, as well as novel pharmaceutical formulations containing, a compound of formula I. In another embodiment, the pharmaceutical formulations of the present invention may be adapted for use in treating Type II diabetes and obesity and for agonizing the &bgr;
3
receptor.
The present invention also relates to methods for treating Type II diabetes and obesity, as well as a method for agonizing the &bgr;
3
receptor employing a compound of formula I.
In addition, the present invention relates to a compound of formula I for use in treating Type II diabetes and obesity as well as a compound of formula I for use in agonizing the &bgr;
3
receptor. The present invention is further related to the use of a compound of formula I for the manufacture of a medicament for treating Type II diabetes and obesity as a well as for agonizing the &bgr;
3
receptor.
The present invention is also related to a compound of formula II:
which is useful as an intermediate to prepare a compound of formula I.
DETAILED DESCRIPTION
For the purposes of the present invention, as disclosed and claimed herein, the following terms are defined below.
The term “halo” represents fluoro, chloro, bromo, or iodo.
The terms “C
1
-C
6
alkyl” and “C
1
-C
4
alkyl” represent a straight, branched or cyclic hydrocarbon moiety having from one to six and one to four carbon atoms, respectively. C
1
-C
4
alkyl groups include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and cyclobutyl. A “C
1
-C
4
haloalkyl” group is a C
1
-C
4
alkyl moiety substituted with up to six halo atoms, preferably one to three halo atoms. An example of a haloalkyl group is trifluoromethyl. A “C
1
-C
6
alkoxy” group is a C
1
-C
6
alkyl moiety connected through an oxy linkage.
The term “divalent hydrocarbon moiety” refers to a straight or branched chain of carbon atoms that may optionally have one or more points of unsaturation. Thus, a hydrocarbon diradical according to the present invention includes 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
2
—, —CH═CHCH
2
—, —CH═CH—, —
C
═CCH
2
—, and the like.
The term “optionally substituted” as used herein means an optional substitution of one to three, preferably one or two groups independently selected from oxo, nitro, cyano, phenyl, benzyl, halo, C
1
-C
6
alkyl, C
1
-C
4
haloalkyl, COR
5
, NR
6
R
6
, NR
6
COR
5
, NR
6
SO
2
R
7
, OR
6
, OCOR
5
, OSO
2
R
7
, SR
6
, SOR
7
, SO
2
R
7
or SO
2
NR
6
R
6
; wherein
R
5
is H, C
1
-C
6
alkyl, phenyl, benzyl, C
1
-C
4
haloalkyl, NR
6a
R
6a
or OR
6a
;
R
6
and R
6a
are independently H, C
1
-C
6
alkyl or phenyl; or when two R
6
or R
6a
groups are attached to the same nitrogen atom, said R
6
or R
6a
groups, together with the nitrogen to which they are attached, may combine to form a piperidine, pyrrolidine, hexamethyleneimine or morpholine ring; and
R
7
is C
1
-C
6
alkyl or phenyl.
The term “heterocyclic ring” represents a stable, saturated, partially unsaturated, fully unsaturated or aromatic ring, said ring having from one to four heteroatoms that are independently selected from the group consisting of sulfur, oxygen, and nitrogen. The heterocycle may be attached at any point which affords a stable structure. Representative heterocyclic rings include 1,3-dioxolane, 4,5-dihydro-1H-imidazole, 4,5-dihydrooxazole, furan, imidazole, imidazolidine, isothiazole, isoxazole, morpholine, oxadiazole, oxazole, oxazolidinedione, oxazolidone, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrazole, thiadiazole, thiazole, thiophene and triazole. Representative “benzofused” heterocyclic rings include benzoxazole, benzimidazole, benzofuran, benzothiophene, benzothiazole, azaindole, and indole. Further specific examples of benzofused and non-benzofused heterocycles are described below in the Preparations and Examples sections.
The term “suitable solvent” refers to any solvent, or mixture of solvents, inert to the ongoing reaction that sufficiently solubilizes the reactants to afford a medium within which to effect the desired reaction.
The term “patient” includes human and non-human animals such as companion animals (dogs and cats and the like) and livestock animals. Livestock animals are animals raised for fo

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