&bgr;3-adrenergic receptor agonist crystal forms, processes...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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Reexamination Certificate




The present invention provides the tosylate salt, the monohydrate of such salt, and pharmaceutical compositions comprising such salt, or such monohydrate, of the &bgr;
-adrenergic receptor agonist (R)-2-(2-(4-oxazol-4-yl-phenoxy)-ethylamino)-1-pyridin-3-yl-ethanol, which agonist is useful in treating, inter alia, hypoglycemia, and obesity, and for increasing the content of lean meat in edible animals.
Diabetes mellitus is characterized by metabolic defects in the production and utilization of carbohydrates which result in the failure to maintain appropriate blood sugar levels. The results of these defects include, inter alia, elevated blood glucose or hyperglycemia. Research in the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Current treatments include administration of exogenous insulin, oral administration of drugs, and dietary therapies.
Two major forms of diabetes mellitus are recognized. Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), is the result of an absolute deficiency of insulin, the hormone that regulates carbohydrate utilization. Type 2 diabetes, or non-insulin-dependent diabetes mellitus (NIDDM), often occurs with normal, or even elevated, levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most Type 2 diabetic patients are also obese.
The tosylate salt, the monohydrate of such salt, and the pharmaceutical compositions comprising such salt, or such monohydrate, of the present invention effectively lower blood glucose levels when administered orally to mammals with hyperglycemia or diabetes.
Obesity constitutes a major health risk that leads to mortality and incidence of Type 2 diabetes mellitus, hypertension, and dyslipidemia. In the United States, more than 50% of the adult population is overweight, and almost 25% of the population is considered to be obese. The incidence of obesity is increasing in the United States at a three-percent cumulative annual growth rate. While the vast majority of obesity occurs in the United States and Europe, the prevalence of obesity is also increasing in Japan. Furthermore, obesity is a devastating disease which can also wreak havoc on an individual's mental health and self-esteem, which can ultimately affect a person's ability to interact socially with others. Unfortunately, the precise etiology of obesity is complex and poorly understood, and societal stereotypes and presumptions regarding obesity only tend to exacerbate the psychological effects of the disease. Because of the impact of obesity on society in general, much effort has been expended in efforts to treat obesity, however, success in the long-term treatment and/or prevention thereof remains elusive.
The tosylate salt, the monohydrate of such salt, and the pharmaceutical compositions comprising such salt, or such monohydrate, of the present invention also reduce body weight or decrease weight gain when administered to a mammal. The ability of such salt, or such monohydrate, and such compositions to affect weight gain is due to activation of &bgr;
-adrenergic receptors which stimulate the metabolism of adipose tissue.
&bgr;-Adrenergic agents have been generally classified into &bgr;
, &bgr;
, and &bgr;
receptor-specific subtypes. Agonists of &bgr;-receptors generally promote the activation of adenyl cyclase. Activation of &bgr;
receptors involves an increase in heart rate while activation of &bgr;
receptors induces smooth muscle tissue relaxation which produces a drop in blood pressure and the onset of skeletal muscle tremors. Activation of &bgr;
receptors is known to stimulate lipolysis (e.g., the breakdown of adipose tissue triglycerides into glycerol and fatty acids) and metabolic rate (energy expenditure), thereby promoting the loss of fat mass. Accordingly, compounds that stimulate &bgr;
receptors are useful as anti-obesity agents, and can be further used to increase the content of lean meat in edible animals. In addition, compounds that are &bgr;
receptor agonists have hypoglycemic activity, however, the precise mechanism of this effect is presently unknown.
Until recently, &bgr;
-adrenergic receptors were thought to be found predominantly in adipose tissue, however, &bgr;
receptors are now known to be located in such diverse tissues as the intestine (J. Clin. Invest., 91, 344 (1993)), and the brain (Eur. J. Pharm., 219, 193 (1992)). Stimulation of &bgr;
receptors has also been demonstrated to induce relaxation of smooth muscle in the colon, trachea, and bronchi. See, for example, Life Sciences, 44, 1411 (1989), Br. J. Pharm., 112, 55 (1994), and Br. J. Pharmacol., 110, 1311 (1993). Furthermore, stimulation of &bgr;
receptors has also been found to induce relaxation of histamine-contracted guinea pig ileum. See, for example, J. Pharm. Exp. Ther., 260, 1, 192 (1992).
The &bgr;
receptor is also expressed in the human prostate (J. Clin. Invest., 91, 344 (1993)). Because stimulation of the &bgr;
receptor causes relaxation of smooth muscles that have been shown to express the &bgr;
receptor, i.e., intestinal smooth muscle, one of ordinary skill in the art would also predict relaxation of prostate smooth muscle. Therefore, &bgr;
agonists are useful in the treatment or prevention of prostate disease.
Commonly assigned U.S. Pat. No. 5,977,124 discloses certain &bgr;
-adrenergic receptor agonists having utility in the treatment of, inter alia, hypoglycemia and obesity.
U.S. Pat. No. 5,776,983 discloses certain catecholamines useful as &bgr;
U.S. Pat. No. 5,030,640 discloses certain &agr;-heterocylic ethanolamino alkyl indoles, which are useful as growth promoters, bronchodilators, anti-depressants, and anti-obesity agents.
U.S. Pat. No. 5,019,578 discloses certain &agr;-heterocyclic ethanolamines useful as growth promoters.
U.S. Pat. No. 4,478,849 discloses pharmaceutical compositions comprising certain ethanolamine derivatives and methods of using such compositions in the treatment of obesity and/or hyperglycemia.
U.S. Pat. No. 4,358,455 discloses certain heterocyclic compounds of the structural formula Het-CHOH—CH
—NH-aralkyl, which compounds as useful for treating glaucoma and cardiovascular disease.
European Patent Application Publication No. 0 516 349, published Dec. 2, 1992, discloses certain 2-hydroxyphenethyl amines which possess anti-obesity, hypoglycemic, and related utilities.
U.S. Pat. No. 5,153,210 discloses certain heterocyclic compounds of the formula R
which compounds are useful as anti-obesity and anti-hyperglycaemic agents.
PCT International Patent Application Publication No. WO 99/65877, published Dec. 23, 1999, discloses heterocyclic compounds having the structural formula
which compounds are useful for the treatment of disease susceptible to amelioration by the administration of an atypical &bgr;-adrenoceptor agonist.
Commonly assigned U.S. Provisional Application No. 60/242,274, filed Oct. 20, 2000, and incorporated herein by reference, discloses certain &bgr;
-adrenergic receptor agonists of structural Formula (I),
the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, including the aforementioned (R)-2-(2-(4-oxazol-4-yl-phenoxy)-ethylamino)-1-pyridin-3-yl-ethanol.
The present invention provides the tosylate salt of (R)-2-(2-(4-oxazol-4-yl-phenoxy)-ethylamino)-1-pyridin-3-yl-ethanol, the monohydrate of such salt; processes useful in the preparation of such salt and such monohydrate; pharmaceutical compositions comprising such salt, or such monohydrate; methods of treating &bgr;
-adrenergic receptor-mediated diseases, conditions, and disorders in a mammal using such salt, or such monohydrate, or such pharmaceutical compositions; and methods of increasing lean meat content in an edible animal using such salt, such monohydrate, or such pharmaceutical


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