Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-04-11
2004-11-30
Desai, Rita (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S409000, C514S410000, C546S016000, C546S268100, C548S408000, C548S411000
Reexamination Certificate
active
06825220
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 &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. For example, U.S. Pat. No. 5,786,356 discloses &bgr;
3
agonists of the formula:
wherein:
R
1
can be, among other things, a moiety of the formula:
A
1
and A
2
can be, among other things, NH, CH
2
, NCH
3
, or NCH
2
CH
3
; and
R
4
can be, among other things, a moiety of the formula:
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 and which displays a minimal propensity to cause atrial tachycardia.
SUMMARY OF THE INVENTION
The present invention relates to a compound of formula I:
wherein:
R
1
is H, CN, halo, C
1
-C
6
alkyl, C
1
-C
4
haloalkyl, CO
2
R
8
, CONHR
8
, NHCOR
8
, NHR
8
, OR
8
, SR
8
, SOR
8
, SO
2
R
8
or SO
2
NHR
8
;
R
1a
is H, halo or C
1
-C
6
alkyl;
R
2
is H, C
1
-C
6
alkyl or benzyl;
R
3
is C
1
-C
6
alkyl or benzyl;
or R
2
and R
3
combine with the carbon to which each are attached to form a C
3
-C
7
carbocyclic ring; provided that if R
3
is C
2
-C
6
alkyl or benzyl, then R
2
must be hydrogen;
R
4
is H or C
1
-C
6
alkyl;
R
5
and R
6
are independently H or C
1
-C
6
alkyl; or
R
5
and R
6
combine with the carbon to which each are attached to form a C
3
-C
6
carbocyclic ring;
or R
6
combines with X
1
, the carbon to which both are attached, and the phenyl group to which X
1
is attached to form a moiety selected from the group consisting of:
wherein:
m and n are independently 0, 1, 2, or 3 provided that the sum of n+q is ≦5 and that R
5
is H;
R
7
is hydrogen, optionally substituted phenyl or optionally substituted heterocycle;
R
8
is H or C
1
-C
6
alkyl;
X is OCH
2
, SCH
2
or a bond; and
X
1
is a bond or a C
1
-C
5
divalent hydrocarbon moiety; and
X
2
is O, S, NH, NHSO
2
, SO
2
NH, CH
2
or a bond; 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.
REFERENCES:
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XP002918140 ,1995, Cheng-I Lin Synthesis of 1,3-dihydro-3,3-dimethyl . . . .*
Lee, et al., J.Het.Chem., 32(1):1-11, 1995.
Mathvink, Bioorganic & Medicinal Chemistry Letters, 9(13):1869-1874, 1999.
Shuker, A J, et al;Tetrahedron Letters; 38(35):6149-6152, 1997.
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Jesudason Cynthia Darshini
Sall Daniel Jon
Stevens Freddie Craig
Werner John Arnold
Desai Rita
Eli Lilly and Company
Voy Gilbert T.
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