US 2006O160834A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0160834 A1 Fong et al. (43) Pub. Date: Jul. 20, 2006 (54) COMBINATION THERAPY FOR THE Publication Classification TREATMENT OF HYPERTENSION (76) Inventors: Tung M. Fong, Somerset, NJ (US); (51) Int. Cl. Ngozi E. Erondu, Englishtown, NJ A6II 3/4747 (2006.01) (US); Douglas J. MacNeil, Westfield, A6II 3 L/353 (2006.01) NJ (US); James H. McIntyre, A6II 3/55 (2006.01) Piscataway, NJ (US); Leonardus H.T. (52) U.S. Cl. ........................... 514/278: 514/454: 514/635 Van Der Ploeg, Lansdale, PA (US) Correspondence Address: MERCK AND CO., INC (57) ABSTRACT PO BOX 2 OOO RAHWAY, NJ 07065-0907 (US) The present invention relates to compositions comprising an (21) Appl. No.: 10/559,111 anti-obesity agent and an anti-hypertensive agent useful for (22) PCT Filed: Jun. 2, 2004 the treatment of hypertension, hypertension associated with obesity, and hypertension-related disorders. The present (86). PCT No.: PCT/USO4/17090 invention further relates to methods of treating or preventing obesity, and obesity-related disorders, in a subject in need Related U.S. Application Data thereof by administering a composition of the present inven tion. The present invention further provides for pharmaceu (60) Provisional application No. 60/476,390, filed on Jun. tical compositions, medicaments, and kits useful in carrying 6, 2003. out these methods. US 2006/0160834 A1 Jul. 20, 2006 COMBINATION THERAPY FOR THE 0007 Metabolic syndrome, also known as syndrome X, TREATMENT OF HYPERTENSION is characterized by insulin resistance, along with abdominal obesity, hyperinsulinemia, high blood pressure, low HDL BACKGROUND OF THE INVENTION and high VLDL. Although the causal relationship between 0001. Hypertension, or high blood pressure, is a generally the various components of metabolic syndrome remains to symptomless condition characterized by abnormally high be confirmed, insulin resistance appears to play an important pressure in the arteries. Untreated high blood pressure role (Requen, G. M., et al., N. Eng. J. Med. 334:374-381 increases the risk of stroke, aneurysm, heart disease, heart (1996): Despres, J-P, et al., N. Engl. J. Med. 334:952-957 failure, heart attack, and kidney damage. Hypertension may (1996); Wajchenberg, B. L., et al., Diabetes/Metabolism also result in changes in the heart, such as enlargement of the Rev. 10:19-29 (1994)). Metabolic syndrome patients are at heart (cardiac hypertrophy and left ventricular hypertrophy) increased risk of developing the cardiovascular complica due to the increased work required to pump blood. For an tions listed above. otherwise healthy individual, high blood pressure is defined as a systolic pressure (pressure when the heart contracts) that 0008 High blood pressure is treated with a variety of averages 140 mm Hg or more, a diastolic pressure (pressure therapeutic agents including diuretics, adrenergic blockers, when the heart relaxes) that averages 90 mm Hg or more, or angiotensin converting enzyme (ACE) inhibitors, angio both. tensin II receptor antagonists, or angiotensin blockers, cal cium channel blockers or calcium channel antagonists, 0002 The pressure in arteries can be increased in various direct vasodilators, neutral endopeptidase inhibitors, and ways. For one, the heart can pump with more force, putting endothelin antagonists. Diuretics cause the reduction of out more fluid each second. Another possibility is that the water and Sodium, or block Sodium transport, resulting in a large arteries can lose their normal flexibility and become reduction in blood pressure. Adrenergic blockers consist of stiff, so that they can’t expand when the heart pumps blood a group of drugs, including alpha-blockers, beta-blockers, through them. Thus, the blood through each heartbeat is and the alpha/beta blocker, labetalol, that block the effects of forced through less space than normal, and the pressure the sympathetic nervous system, which responds to stress by increases. This occurs when arterial walls become thickened raising blood pressure. Angiotensin converting enzyme and stiff due to arteriosclerosis. Blood pressure is similarly (ACE) inhibitors lower blood pressure by dilating arteries by increased in vasoconstriction when the tiny arteries (arte blockin the effects of the angiotensin-renin-aldosterone sys rioles) are temporarily constricted as a result of stimulation tem. Angiotensin II receptor antagonists, or angiotensin by nerves or by hormones in the blood. A third way in which blockers, lower blood pressure by a mechanism similar to, the pressure in the arteries can be increased is for more fluid but more direct than, ACE inhibitors. Calcium channel to be added to the system. This happens when the kidneys blockers, or calcium channel antagonists, and direct vasodi malfunction and arent able to remove enough salt and water lators reduce blood pressure by causing blood vessel dila from the body. The volume of blood in the body increases, tion. Neutral endopeptidase inhibitors produce higher levels so the blood pressure increases. of atrial natiuretic peptide, which opens blood vessels. 0003 Cardiac hypertrophy, including left ventricular hypertrophy, is due to the response of the heart to chronic 0009 Obesity, a sedentary lifestyle, stress, and excessive pressure or volume overload. Left ventricular hypertrophy amounts of salt or alcohol can play a role in the development (LVH) is characterized by thickening of the left ventricular of high blood pressure in people who have an inherited wall, including increased left ventricular mass and increased sensitivity. Overweight people with high blood pressure are left ventricular wall thickness, and is defined as a left advised to reduce their weight to ideal levels. Changes in ventricular mass index exceeding 131 g/m of the body diet for those with diabetes, obesity, or high blood choles surface area in men, and 100 g/m in women (Savage et al., terol levels are also important for overall cardiovascular The Framingham Study, Circulation, 75 (1 Pt 2): 26-33 health. (1987). 0010 Obesity, which can be defined as a body weight 0004 Left ventricular hypertrophy is independently asso more than 20% above the ideal body weight, is a major ciated with increased incidence of cardiovascular disease, health concern in Western societies. It is estimated that about Such as congestive heart failure, ischaemic heart disease, 97 million adults in the United States are overweight or cardiovascular and all-cause mortality, Sudden death, and obese. Obesity is the result of a positive energy balance, as stroke. Regression of left ventricular hypertrophy has been a consequence of increased ratio of caloric intake to energy associated with a reduction in cardiovascular risk. It has also expenditure. The molecular factors regulating food intake been found that the incidence of morbid events in patients and body weight balance are incompletely understood. B. with progression of left Ventricular hypertrophy is greater Staels et al., J. Biol. Chem. 270(27), 15958 (1995): F. than in patients with regression of left ventricular hypertro Lonnguist et al., Nature Medicine 1 (9), 950 (1995). phy. Although the genetic and/or environmental factors leading 0005. Dyslipidemia and a serum cholesterol ester fatty to obesity are poorly understood, several genetic factors acid composition indicating a high dietary intake of Satu have been identified. rated and monounsaturated fats, as well as, obesity and 0011 Epidemiological studies have shown that increas hypertension, at age 50 have been shown to be predictive of ing degrees of overweight and obesity are important predic the prevalence of LVH at age 70 for men (Sundstroem, J. et tors of decreased life expectancy. Obesity causes or exac al., Circulation, February, 836-840 (2001). erbates many health problems, both independently and in 0006 Associations have also been found between left association with other diseases. The medical problems asso Ventricular hypertrophy and metabolic syndrome (Lind, L. et ciated with obesity, which can be serious and life-threaten al., J Hypertens. 13:433-38 (1995). ing, include type 2 diabetes mellitus, hypertension, elevated US 2006/0160834 A1 Jul. 20, 2006 plasma insulin concentrations, insulin resistance, dyslipi more than pharmacological anti-hypertensive treatment demias, hyperlipidemia, endometrial, breast, prostate, kid (MacMahon, S. W. et al., N Engl J Med., 314; 334-339 ney and colon cancer, osteoarthritis, respiratory complica (1986). tions, such as obstructive sleep apnea, gallstones, 0016. There is a continuing need for new methods of arterioscelerosis, heart disease, abnormal heart rhythms, and treating hypertension, hypertension associated with obesity, heart arrythmias (Kopelman, P. G., Nature 404, 635-643 and hypertension-related disorders, such as cardiac hyper (2000)). Obesity is also associated with metabolic syn trophy, left ventricular hypertrophy and metabolic syn drome, cardiac hypertrophy, in particular left ventricular drome. hypertrophy, premature death, and with a significant 0017. The present invention addresses these problems by increase in mortality and morbidity from stroke, myocardial providing a combination therapy comprising of at least one infarction, congestive heart failure, coronary heart disease, anti-obesity agent and at least one anti-hypertensive agent and Sudden death. for the treatment of obesity, hypertension, hypertension 0012 Abdominal obesity has been linked with a much associated