Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-10-11
2003-07-22
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S143000
Reexamination Certificate
active
06596734
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to compounds useful as &bgr;
3
-adrenoreceptor agonists.
BACKGROUND OF THE INVENTION
For many individuals, a tendency to experience weight problems and even obesity is often symptomatic of disease or disorders of the metabolism associated with serious and even life-threatening conditions. The decade of the 1990's witnessed dramatic increases in diabetes and obesity in the United States, and at the same time, Americans showed little improvement in eating habits or increasing their physical activity. In a study published in the Journal of the American Medical Association, the Center for Disease Control and Prevention (CDC) found a 61 percent increase in the percentage of Americans who are obese from 1991 to 2000 (12.0 percent to 19.8 percent), and a 49 percent increase in the percentage of Americans who have diabetes from 1990 to 2000 (4.9 percent to 7.3 percent). About nine percent of the national health care expenditures in the United States are directly related to obesity and physical inactivity. In 1997, the health care costs associated with diabetes were $98 billion.
A wide variety of approaches to the alleviation of obesity have ebbed and flowed though modem culture, ranging from a diverse collection of dietary strategies, to drugs, to surgical interventions, to hypnosis. All have met with indifferent success at best. A great deal of the difficulty in the art and practice of obesity and weight management has been a consequence of attention focused on the control of appetite, and reducing the amount of food intake. It has long been the belief of many that only by the control of caloric intake is it possible to regulate body weight and fat deposition and utilization. Since appetite is controlled and regulated in the brain, brain pharmacology and the alteration of brain chemistry has been a primary focus of weight regulation and control efforts. Only in very recent times has obesity been addressed in relation to the metabolic pathways of the body and their role and import in fat storage and usage in the body.
Recent research has elucidated some of the mechanisms of obesity and weight gain, and has revealed that much of the limitation of prior and current weight-loss techniques stems from the fact that they are biochemically, and particularly metabolically, unsound and incapable of stimulating, regulating and modulating metabolism of fats in adipose tissues. Increasing efforts have been directed to biochemical research into the mechanisms of fat deposition and metabolism.
Among the biochemical work of note has been the recent recognition of a role of &bgr;-adrenoreceptor activity in the metabolism of fats. It has been recognized that agonists for &bgr;-adrenoreceptors have, in some cases, produced marked weight loss in animals, particularly humans and other mammals. More recently, the loss of weight has been identified with the &bgr;-adrenoreceptor sub-type, &bgr;
3
-adrenoreceptor. It has been demonstrated that compounds that are significant &bgr;
3
-adrenoreceptor agonists produce marked weight loss in animals, particularly humans and other mammals, and that the loss is sustained with continuation of the administration of such compounds. These compounds provide potent regulation of fat metabolism. The compounds employed to date are also agonists for the &bgr;
1
-adrenoreceptor and the &bgr;
2
-adrenoreceptor sites. The lack of selectivity represents unwanted side effects of such compounds, and the compounds known as &bgr;
3
-adrenoreceptor agonists to-date are not suitable candidates for therapeutic usage because of undesirable side effects.
There is a need in the art for therapeutic agents that are highly potent and highly selective &bgr;
3
-adrenoreceptor agonists for effective stimulation, regulation and modulation of metabolism of fats in adipose tissues.
SUMMARY OF THE INVENTION
The present invention provides tetraisoquinoline compounds useful as &bgr;
3
-adrenoreceptor agonists. In a preferred embodiment, the compounds of the invention are highly specific &bgr;
3
-adrenoreceptor agonists that exhibit little or no affinity for the other &bgr;-adrenoreceptors.
In one aspect, the present invention provides compounds of the formula:
wherein:
each R
1
is —NHS(O)
m
R, wherein R is alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle;
each X is independently selected from the group consisting of halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxy, nitro, amino, and substituted amino;
R
2
is benzyl or benzyl substituted with one or more substituents selected from the group consisting of halo, CF
3
, hydroxy, nitro, alkoxy, substituted alkoxy, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, and substituted amino of formula —NHR′ or —R′R′, wherein each R′ is alkyl, substituted alkyl, —C(O)Y, —C(O)NHY, or —C(O)SY, wherein Y is alkyl or substituted alkyl;
R
3
is H or alkyl;
n is 0-3;
m is 1-2;
p is 1-4;
the sum of n and p is 1-4;
and pharmaceutically acceptable salts thereof.
In another aspect, the invention provides pharmaceutical compositions comprising at least one compound of Formula I and at least one pharmaceutically acceptable carrier. In a further aspect, the invention provides a method of treating obesity and related conditions that would benefit from stimulating, regulating and modulating metabolism of fats in adipose tissues, specifically by interaction with the &bgr;
3
-adrenoreceptor. The method involves administering a compound of Formula I, optionally with one or more pharmaceutically acceptable carriers, to an animal, preferably a human or other mammal.
DETAILED DESCRIPTION OF THE INVENTION
The present invention now will be described more fully hereinafter. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
I. Definitions
The following terms as used herein have the meanings indicated.
As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly dictates otherwise.
The term “alkyl” refers to hydrocarbon chains typically ranging from about 1 to about 12 carbon atoms in length, preferably 1 to about 6 atoms, and includes straight and branched chains. The hydrocarbon chains may be saturated or unsaturated.
“Cycloalkyl” refers to a saturated or unsaturated cyclic hydrocarbon chain, including bridged, fused, or spiro cyclic compounds, preferably comprising 3 to about 12 carbon atoms, more preferably 3 to about 8.
The term “substituted alkyl” or “substituted cycloalkyl” refers to an alkyl or cycloalkyl group substituted with one or more non-interfering substituents, such as, but not limited to, C3-C8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, and the like; acetylene; cyano; alkoxy, e.g., methoxy, ethoxy, and the like; lower alkanoyloxy, e.g., acetoxy; hydroxy; carboxyl; amino; lower alkylamino, e.g., methylamino; ketone; halo, e.g. chloro or bromo; phenyl; substituted phenyl, and the like.
“Alkoxy” refers to an —O—R group, wherein R is alkyl or substituted alkyl, preferably C1-C6 alkyl (e.g., methoxy or ethoxy).
“Aryl” means one or more aromatic rings, each of 5 or 6 core carbon atoms. Multiple aryl rings may be fused, as in naphthyl or unfused, as in biphenyl. Aryl rings may also be fused or unfused with one or more cyclic hydrocarbon, heteroaryl, or heterocyclic rings.
“Substituted aryl” is aryl having one or more non-interfering groups as substituents. For substitutions on a phenyl ring, the substituents may be in any orientation (i.e., ortho, meta or para).
“Heteroaryl” is an aryl g
Feller Dennis R.
Miller Duane D.
Alston & Bird LLP
Davis Zinna Northington
Molecular Design International Inc.
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