.\
`
`. '
`
`.. 'l(ll) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`IntemationaJ Bureau
`
`101111111101 ~ m110 111111111111111imrn11111111nm1m 1111111m111mm~0111111011
`
`(43) Intemational Publication Date
`6 January 2005 (06.01.2005)
`
`PCT
`
`(10) IntemationaJ Publication Number
`WO 2005/000217 A2
`
`(SI) International Patent CJasslficatlon7:
`
`A61K
`
`(21) Internatlonu.I AppUcallon Number:
`PCT/US2004/017120
`
`(22) International F1llng Date:
`
`2 June 2004 (02.06.2004)
`
`(25) F1llng Language:
`
`(26) Publlcatlon Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/476,387
`
`6 June 2003 (06.06.2003) US
`
`(71) Applicant (for all tksignated States ucept US): MERCK
`& CO., INC. [US/US); 126 East Lincoln Avenue, Rahway,
`NJ 07065-0907 (US).
`
`(72) Inventors; and
`(75) Inventors/AppHcanls(/orUSonly): ERONDU,Ngozi,E.
`[US/US]; 126 East Lincoln Avenue, Rahway, NJ 07065-
`0907 (US). FONG, Tung, M. [US/US]; 126 East Lincoln
`Avenue, Rahway, NJ 07065-0907 (US). MACNEIL, Dou(cid:173)
`gliw, J. [US/US); 126 East Lincoln Avenue, Rahway, NJ
`07065-0007 (US). VAN DER PLOEG, Leonardus, H. T.
`[NlJUS]; 126 East Lincoln Avenue, Rahway, NJ 07065-
`0907 (US).
`
`(74) Common Representative: MERCK & CO., INC.; 126
`East Lincoln Avenue, Rahway, NJ 07065-0907 (US).
`
`(81) Designated States (unless otherwise indicaJed. for every
`kind of national protection available): AB. AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY,BZ.:CA, CH, CN,
`CO, CR. CU, CZ. DE, DK, DM, DZ, EC, EE, F.G, .BS, FI;
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KB,
`KG, KP, KR, KZ, LC, LK, LR, LS, CT, LU. LV, MA, MD,
`MG, MK, MN, MW, MX, MZ, NA,Nl, NO,.N'Z, OM, PC},
`PH, PL, PT. RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
`TN, TR, TT, T'Z, UA, UG, US, UZ. VC, VN, YU, ZA, ZM,
`zw.
`
`(84) Designated States (unless otherwise indicaJed. for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, ICE, LS. MW. MZ. NA, SD, SL, SZ. TZ, UG, ZM,
`'ZW), Eurasian (AM, A'Z, BY, KG, KZ; MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DB. DK, EE, BS, FI,
`FR, GB, GR, HU, IE, IT, LU, MC, NL, PL. PT, RO, SB, Sl,
`SK, TR), OAPI (BF, BJ, CP. CG, Cl, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`.
`
`Published:
`-
`without intemntional search repon and: to be republished
`upon receipt oftluu repon
`
`For two-letter codes and or her abbreviations, refer to the ·Guid(cid:173)
`ance Notes on Codes and Abbreviations• appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazetre.
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`I '
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`r(cid:173)
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`,...-j
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`N =
`= ln (54) 11t!e: COMBINATION THERAPY FOR THE TREATMENT OF DYSLIPIDEMIA
`= = (57) Abstract: The present invention relates to compositions comprising an anti--0besity agent and an anti-dyslipidemic agent useful
`
`=~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~-
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`for the treatment of dyslipidemia, dyslipidemia associated with obesity and dyslipidemia-related disorders. The present invention
`N
`O further relates to methods of treating or preventing obesity, and obesity-related disorders, in a subject in need thereof by administering
`> 11 composition of the present invention. The present invention further provides for pharmaceutical compositions, medicaments, and
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`~ kits useful in carrying out these methods.
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`TITLE OF THE INVENTION
`COMBINATION THERAPY FOR THE TREATMENT OF DYSLIPIDEMIA
`
`BACKGROUND OF THE INVENTION
`Disorders of lipid metabolism, or dyslipidemias, include various conditions characterized by
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`abnormal concentrations of one or more lipids (i.e. cholesterol and triglycerides), and/or apolipoproteins
`(i.e., apolipoproteins A, B, C and B), and/or lipoproteins (i.e., the macromolecular corilpl~xes formed by
`the lipid and the apolipoprotein that allow lipids to circulate in blood, such as LDL, VLDL and IDL).
`Hyperlipidemia is associated with abnonnally high levels of lipids, LDL and VLDL cholesterol,: and/or
`triglycerides. Cholesterol is mostly carried in Low Density Lipoproteins (LDL), and this component is
`commonly known as the "bad" cholesterol because it has been shown that elevations in LDL-cholesterol
`correlate closely to the risk of coronary heart disea~. A smaller component of cholesterol is carried in
`the High Density Lipoproteins and is conunonly known as the "good" cholesterol. In fact, it is known
`that the primary function of HDL is to accept cholesterol deposited in the arterial wall and to transport it
`back to the liver for disposal through the intestine. Although it is desirable to lower elevated levels of
`LDL cholesterol, it is also desirable to increase levels of HDL cholesterol. Generally, it has been found
`that increased levels of HDL are associated with lower risk for coronary heart disease (CHD). See, for
`ex.ample, Gordon, et al., Am. J. Med., 62, 707-714 (1977); Stampfer, et al., N. England J. Med., 325, 373-
`381 (1991); and Kannel, et al., Ann. Internal Med., 90, 85-91 (1979). An example of an IIDL raising
`agent is nicotinic acid, a drug witl't limited utility because doses that achieve HDL raising are associated
`with undesirable effects, such as flushing.
`Dyslipidemias were originally classified by Fredrickson according to the combination of
`alterations mentioned above. The Fredrickson classification includes 6 phenotypes (i.e .• I, Ila, Ilb, m. IV
`and V) with the most common being the isolated hypercholesterolemia (or type Ila) which is usually
`accompained by elevated concentrations of total and LDL cholesterol. The initial treatment for
`
`hypercholesterolemia is often aimed at avoiding risk factors such as obesity, and at modifying the diet to
`one low in fat and cholesterol, coupled with appropriate physical exercise, followed by drug therapy
`when LDL-lowering goals are not met by diet and exercise alone.
`A second common form of dyslipidemia is the mixed or combined hyperlipidemia or type IIb and
`ill of the Fredrickson classification. This dyslipidemia is often prevalent in patients with type 2 diabetes,
`obesity and metabolic syndrome. In this dyslipidemia there are modest elevations of LDL-cholesterol,
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`.
`.
`. :
`accompanied by more pronounced elevations of small dense LDL-cholesterol partides, VLDL and/or
`IDL (i.e., triglyceride rich lipoproteins), and total triglycerides. In addition, concentrations of IIDL ,are
`often low.
`The risk of atherosclerosis and coronary artery or carotid artery disease. and therefore the risk of
`having a heart attack or stroke, increases as the total cholesterol level increases. Atherosclerosis refers to
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`a disease in which the wall of an artery becomes thicker and less elastic. In atherosclerosis,"fatty material
`
`accumulates under the inner lining of the arterial wall. Atherosclerosis can affect the arteries of the
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`brain, heart, kidneys, other vital organs, and the arms and legs. When atherosclerosis develops in the
`arteries that supply the brain (carotid arteries), a stroke may occur; when it develops in the arteries that
`supply the heart (coronary arteries). a heart attack may occur. Arteries affected with atherosclerosis lose
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`their elasticity, an as the atheromas (patchy thickening in the inner lining of the artery) grow, the arteries
`narrow. With time. the atheromas collect calcium deposits, may become brittle, and may rupture. Blood
`may then enter a ruptured atheroma, making it larger, so that it narrows the artery even more. A ruptured
`atheroma also may spill its fatty contents and trigger th~ formation of a blood clot (thrombus). The clot
`··
`10 may further narrow or even occlude the artery, or it may detach and float downstream where it causes an
`occlusion (embolism).
`Causes of high cholesterol levels include a diet high in saturated fats and cholesterol; cirrhosis,·
`poorly controlled diabetes, underactive thyroid gland, overactive pituitary gland, kidney failure!
`porphyria, and heredity. Causes of high triglyceride levels include excess calories in die't, severe
`uncontrolled diabetes, kidney failure, acute alcohol abuse, certain drugs, and heredity.
`Obesity is one of the factors contributing to high levels of certain lipids, such as VLDL and LDL,
`as a result, the initial treatment for overweight patients with high cholesterol or triglyceride levels i~ to
`lose weight. Levels of fatty material such as cholesterol and triglycerides may also be controlled with a
`variety of drugs. Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors block the
`synthesis of cholesterol and enhance the removal of low density lipoproteins from the blpodstream.
`HMG-CoA synthase inhibitors inhibit the biosynthesis of hydroxymethylglutaryl-coenz)'.me A from
`acetyl-coenzyme A. Lipoprotein synthesis inhibitors reduce the rate of very low density lipoprotein
`production. Bile acid sequestrants, or absorbers, bind bile acids in the intestine and enhance low density
`lipoprotein removal from the bloodstream. Renin angiotensin system inhibitors may als? decrease the
`formation of atherosclerotic plaques. Cholesterol absorption inhibitors inhibit intestinal choles~erol
`absorption by blocking the movement of cholesterol from the intestinal lumen into enterocytes of the
`small intestinal wall. Cholesteryl ester transfer protein (CETP) inhibitors inhibit the CETP mediated
`transport of various cholesteryl esters and triglycerides from HDL to LDL and VLDL. Other compounds
`reduce serum cholesterol levels primarily by mechanisms of action such as squalene synthetase
`inhibition, acyl coenzyme A - cholesterol acyl transferase (ACAT} inhibition, triglyceride synthesis
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`inhibition, MTP inhibition, bile acid sequestration, and transcription modulation, such as agonists or
`antagonists of nuclear hormones.
`Additionally, three sub-types of peroxisome proliferator activated receptor (PPAR} have been
`discovered and described; they are peroxisome proliferator activated receptor alpha (PPARa), .
`peroxisome proliferator activated receptor gamma (PPARy), and peroxisome proliferator ~tivated
`receptor delta (PPARS}. Fibric acid derivatives such as clofibrate, fenofibrate, benzafibrate, ciprofibrate,
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`beclofibrate and etofibrate, as well as gemfibrozil, each of which are PPARa ligands and/or activators,
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`..
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`produce a substantial reduction in plasma triglycerides as well as some increase in HDL.. The effects on
`LDL cholesterol are inconsistent and might depend upon the compound and/or the dyslipidemic
`phenotype. For these reasons, this class of compounds has been primarily used to treat
`hypertriglyceridemia (i.e, Fredrickson Type N and V) and/or mixed hyperlipidemia.
`It has been disclosed in W097/28149 that agonists of PPAR8 are useful in raising HDL plasma
`levels. W097127857, 97128115, 97128137 and 97127847 disclose compounds that are useful as
`antidiabetic, antiobesity, anti-atherosclerosis and antihyperlipidemic agents, and which may.exert their
`effect through activation of PPARs. PPARa agonists should improve the lipid profile and alleviate
`dyslipidemias by reducing elevated LDL levels and elevated triglyceride levels and/or increasing HDL
`levels.
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`Left ventricular hypertrophy (L VH), which is characterized by thickening of the left ventricular
`wall, is due to the response of the heart to chronic pressure or volume overload. Left ve~tricul~r
`hypertrophy is defined as a left ventricular mass i~dex exceeding 131 gtm2 of the body surface area in
`15 men, and 100 glm2 in women (Savage et al., The Framingham Study, Circulation, 75 (1 Pt 2): 26-33
`(1987).
`
`Left ventricular hypertrophy is independently associated with increased incidence of
`cardiovascular disease, such as congestive heart failure, ischaemic heart disease, cardiovascular an~ all(cid:173)
`cause mortality, sudden death, and stroke. Regression of left ventricular hypertrophy has been associated
`.
`.
`.
`20 with a reduction in cardiovascular risk. It has also been found that the incidence of morbid events in
`patients with progression of left ventricular hypertrophy is greater than in patients with regression of left
`ventricular hypertrophy.
`Dyslipidemia and a serum cholesterol ester fatty acid composition indicating a high dietary
`intake of saturated and monounsaturated fats, as well as, obesity and hypertension, at age 50 have ~n
`shown to be predictive of the prevalence of L VH at age 70 for men (Sundstroem, J. et al., Circulation,
`February , 836-840 (2001). The impact of obesity, dyslipidemia, and the evidence of high dietary intake
`of saturated fats on left vent.ricular hypertrophy was found to be independent of the history of ischemic
`heart disease, valvular disease, and the u~ of antihypertensive medication. Associations have also been
`found between left ventricular hypertrophy and metabolic syndrome (Lind, L. et al., J Hypertens. 13:433-
`38 (1995).
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`Metabolic syndrome, also known as syndrome X, is characterized by insulin res\stance, alo~g
`with abdominal obesity, hyperinsulinemia, high blood pressure, low HDL and high VLDL. Although the
`causal relationship between the various components of metabolic syndrome remains to be confirmed,
`insulin resistance appears to play an important role (Requen, G.M., et al., N. Eng. J. Med. 334:374-381
`(1996); Despres, J-P., et al., N. Engl. J. Med. 334:952-957 (1996); Wajchenberg, B. L .• et a)., Diabetes
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`/Metabolism Rev. 10:19-29 (1994)). Metabolic syndrome patients are at increased risk of developing the··
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`cardiovascular complications listed above.
`Obesity, which can be defined as a body weight more than 20% above the ideal ~ody weight, is a
`
`major health concern in Western societies. It is estimated that about 97 million adults in· the United:
`States are overweight or obese. Obesity is the result of a positive energy balance, as a consequence· of
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`increased ratio of caloric intake to energy expenditure. The molecular factors regulating fciod intake and
`body weight balance are incompletely understood. [B. Staels et al., J. Biol. Chem. 270(27), 15958
`( 1995); F. Lonnquist et al., Nature Medicine 1 (9). 950 ( 1995)]. Altho1;1gh the genetic andlor
`environmental factors leading to obesity are poorly understood, several genetic factors have _been
`identified.-
`Epidemiological studies have shown that increasing degrees of overweight and obesity are
`important predictors of decreased life expectancy. Obesity causes or exacerbates many health problems,
`both independently and in association with other diseases. The medical problems associated with
`obesity, which can be serious and life-threatening, include type 2 diabetes mellitus, hypertension,
`elevated plasma insulin concentrations, insulin resistance, dyslipidemias, hyperlipidemia, metabolic
`
`syndrome, endometrial, breast, prostate, kidney, and colon cancer, osteoarthritis, respiratory
`complications, such as obstructive sleep apnea, gallstones, arterioscelerosis, heart disease, abnormal
`
`heart rhythms, and heart arrythmias (Kopelman, P.G., Nature 404, 635-643 (2000)).
`Abdominal obesity has been linked with a much higher risk of coronary artery d~sease, and with ·
`three of its major risk factors: high blood pressure, diabetes that starts in adulthood, and hi~h levels of
`fats (lipids) in the blood. Losing weight dramatically reduces these risks. Abdominal obesity is further
`closely associated with glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and other diso~ers
`associated with metabolic syndrome (syndrome X), such as raised high blood pressure, decreased levels
`of high density lipoproteins (HDL) and increased levels of very low density lipoproteins.(VLDL)
`(Montague et al., Diabetes, 2000, 49: 883-888).
`Obesity is also associated with metabolic syndrome, cardiac hypertrophy, in particular left
`ventricular hypertrophy, premature death, and with a significant increase in mortality and morb~dity from
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`stroke, myocardial infarction, congestive heart failure, coronary heart disease, and sudde_n death ..
`Obesity and obesity-related disorders are often treated by encouraging patients to lose weight by
`reducing their food intake or by increasing their exercise level, thereby increasing their energy output. A
`sustained weight loss of 5% to 10% of body weight has been shown to improve the co-morbidit_ies
`associated with obesity and can lead 10 improvement of obesity-related disorders such as diabetes, lefl
`ventricular hypertrophy, osteoarthritis, and pulmonary and cardiac dysfunction.
`Weight loss drugs used for the treatment of obesity include orlistat (Davidson, M.H. et al. (1999)
`JAMA 281 :235-42), dexfenfluramine (Guy Grand, B. et al. (1989) Lancet 2: 1142-5), sibutramine (Bray,
`G. A. et al. (1999) Obes. Res. &:189-98) and phentennine (Douglas, A. et al. (1983) lnt . .J. Obes. 7:591-
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`5). However, the side effects of these drugs and anti-obesity agents may limit their use.
`Dexfenfluramine was withdrawn from the market because of suspected heart valvulopathy; orlistat is
`
`limited by gastrointestinal side effects; and the use of sibutramine is limited by its cardiovascular side
`
`effects, which have led to reports of deaths and its withdrawal from the market in Italy.:
`There is a continuing need for new methods of treating dyslipidemia, dyslipidemia associated
`with obesity and dyslipidemia-related disorders. There is currently no effective treatment for obesity,
`obesity related disorders, metabolic syndrome, cardiac hypenrophy and left ventricular hypenrophy.
`
`The present invention addresses this problem by providing a combination therapy comprising of •
`at least one anti-obesity agent and at least one anti-dyslipidemic agent for the treaunent of dysiipid.emia,-
`dyslipidemia associated with obesity, and dyslipidemia-related disorders. The combination of an anti-
`obesity agent and an anti-dyslipidemic agent, at their respective clinical doses, is expected to be more
`effective than treatment with either agent alone. Treatment with a combination of an anti-obesity agent
`and an anti-dyslipidemic agent at sub-clinical doses is expected to produce clinical efficacy with fewer
`side effects than treatment with either single agent at the monotherapy clinical dose. As a result,
`combination therapy is more likely to achieve the desired medical benefits without the trial and error
`involved in prescribing each agent individually during primary care.
`The present invention also provides a method for treating, controlling, or preventing obesity and
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`obesity-related disorders, such as cardiac hypenrophy and left ventricular hypertrophy.
`The present invention funher provides a method for synergistically treating, controlling, or:
`preventing metabolic syndrome comprised of administering the compositions of the present invention in
`combination with an anti-hypertensive agent and/or an anti-diabetic agent to a subject in, need there.of.
`Metabolic syndrome is a multi-factorial disease characterized by obesity, diabetes, hypertension and
`dyslipidemia. Due to the polygenic nature of the metabolic syndrome etiology, it is predicted that the
`combination therapies of the present invention will be more effective than currently avai.lable
`25 monotherapies in treating or reducing the risk of metabolic syndrome. Combinations of differe~t agents
`with different modes of action, e.g., a combination of an anti-obesity agent, an anti-dyslipidemic ag!!nl,
`an anti-diabetic agent, and an anti-hypertensive agent, will ·achieve a better outcome relative to
`monotherapies using agents with only one mode of action. Additionally, combination therapy is m~re
`likely to achieve the desired medical benefits without the trial and error of prescribing each agent alone
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`in primary care.
`
`SUMMARY OF THE INVENTION
`The present invention provides compositions comprising at least one anti-obesity agent and at
`least one anti-dyslipidemic agent useful in the treatment, control and/or prevention of dyslipidemia,
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`dyslipidemia associated with obesity, and dyslipidemia-related disorders, obesity and obesity-related
`dis.orders.
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`The present invention provides compositions comprising an anti-obesity agent seiected ·from the
`
`group consisting of: a 5Hr (serotonin) transporter inhibitor, a NE (norepinephrine) transporter inhibitor,
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`a CB-I (cannabinoind-1 receptor) antagonist/inverse agonist. a ghreJin antibody, a ghrelin antagonist, a
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`·
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`H3 (histamine HJ) antagonist/inverse agonist. a MCHIR (melanin concentrating hormone IR)
`antagonist, a MCH2R (melanin concentrating hormone 2R) agonist/antagonist, a NPY 1 "(neuropeptide Y
`YI) antagonist, a NPY2 (neuropeptide Y Y2) agonist, a NPY5 (neuropeptide Y Y5) antagonist. leptin. a
`leptin derivative, an opioid antagonist, an orexin antagonist, a BRS3 (bombesin receptor subty~ 3)
`agonist, a CCK-A (cholecystokinin-A) agonist, a CNTF (ciliary neurotrophic factor), a CNTF derivative;
`
`a GHS (growth honnone secretagogue receptor) agonist, 5Hr2c (serotonin receptor 2c) agonist. a Mc3r
`(melanocortin 3 receptor) agonist, a Mc4r (melanocortin 4 receptor) agonist, a monoamine reuptake ·
`inhibitor, a serotonin reuptake inhibitor, a GLP-1 (glucagon-like peptide 1) agonist, topiramate,
`
`phytophann compound 57, an ACC2 (acetyl-CoA carboxylase-2) inhibitor, a fJ3 (beta adrenergic receptor
`3) agonist, a DGATl (diacylglycerol acyltransferase I) inhibitor, a DGAT2 (diacylglycerol
`acyltransferase 2)inhibitor, a FAS (fatty acid synthase) inhibitor, a PDE (phosphodiesterase) inhibitor, a
`thyroid honnone p agonist, an UCP-1 (uncoupling protein 1), 2, or 3 activator, an acyl-estrogen, a
`glucocorticoid antagonist, an 111} HSD-1 (I I-beta hydroxy steroid dehydrogenase type J) inhibitor, a
`SCD-1 (stearoyl-CoA desaturase-1) inhibitor, a dipeptidyl peptidase N (DP-N) inhibitor, a lipase .
`inhibitor, a fatty acid transporter inhibitor, a dicarboxylate transporter inhibitor, a glucose transporter
`inhibitor, a phosphate transporter inhibitor, and phannaceuticaJly acceptable salts and esters thereof.
`The present invention provides compositions comprising an anti-dyslipidemic a~ent selected
`from the group consisting of:
`(1)
`a bile acid sequesterant,
`(2)
`a HMG-CoA reductase inhibitor,
`(3)
`a HMG-CoA synthase inhibitor,
`(4)
`a cholesterol absorption inhibitor,
`an acyl coenzyme A -cholesterol acyl transferase (ACA1) inhibitor,
`(5)
`a cholesteryl ester transfer protein (CETP) inhibitor,
`(6)
`a squalene synthetase inhibitor,
`an anti-oxidant,
`a PP AR a agonist,
`a FXR receptor modulator,
`
`(7)
`(8)
`(9)
`(IO)
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`( 11)
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`(12)
`(13)
`(14)
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`(JS)
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`a LXR receptor agonist,
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`a lipoprotein synthesis inhibitor,
`a renin angiotensin system inhibitor,
`a microsomal triglyceride transport inhibitor,
`a bile acid reabsorption inhibitor,
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`a PPARo agonist.
`(16)
`·a triglyceride synthesis inhibitor,
`( 17)
`a transcription modulator,
`(18)
`a squalene epoxidase inhibitor,
`(19)
`a low density lipoprotein (LDL) receptor inducer,
`(20)
`a platelet aggregation inhibitor,
`(21)
`a 5-LO or FLAP inhibitor,
`(22)
`a PPAR o partial agonist, and
`(23)
`niacin or a niacin receptor agonist,
`(24)
`and pharmaceutically acceptable salts and esters thereof.
`The compositions of the present invention are expected to be efficacious in the treatment of lipid
`disorders, such as dyslipidemia, hyperlipidemia, hypercholesterolemia, impaired fasting glucose,
`hyperinsulinemia, hyper-triglyceridemia. low levels of high density lipoprotein cholesterol, higli levels of
`plasma low density lipoprotein cholesterol, high levels of non- high density lipoprotein cholesterol and/or
`total cholesterol, high levels of plasma triglycerides. The compositions of the present invention are also
`expected to be efficacious for treating, preventing or reducing the risk of developing atherosclerosis, as
`well as for halting or slowing the progression of atherosclerotic disease once it has become clinically
`evident. The compositions of the present invention are also useful in the treatment, control and/or
`prevention of coronary artery or carotid artery disease, heart attack, and stroke.
`The compositions of the present invention are also useful in the treatment, control and/or
`prevention of obesity, overeating, binge eating, bulimia, elevated plasma insulin concentrations, insulin
`resistance, glucose tolerance intolerance, lipid disorders, low HDL levels, high LDL levels;
`hyperglycemia, neoplastic conditions, such as endometrial, breast, prostate, kidney, and colon cancer,
`osteoarthritis, obstructive sleep apnea, gallstones, abnonnal heart rhythms, heart arrythmias,
`atherosclerosis, myocardial infarction, congestive heart failure, sudden death, impaired fertility, ovarian
`hyperandrogenism, (polycystic ovary disease), craniopharyngioma, the Prader-Willi Syndrome,
`Frohlich's syndrome, GH-deficient subjects, normal variant short stature, Turner's syndrome. and other
`pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure
`as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia.
`Neuropeptide Y (NPY), via G protein-coupled NPY Y5 receptors (NPYS), is implicated in the
`development of cardiac hypertrophy, and left ventricular hypertrophy, during chronic stimulation of the
`sympathetic system by potentiating a-adrenergic signals. Recent studies have shown that agonism of the
`NPYS receptor in rodent cardiac myocytes may mediate hypertrophy (Bell, D. et al., J -Pharmacol-Exp(cid:173)
`Ther. 303: 581-91 (2002)).
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`NPY5 antagonists are expected to be beneficial in the treatment and /or prevention of cardiac
`hypertrophy. Furthermore, combination therapy with an anti-dyslipidemic agent and a NPY5 antagonist
`
`is beneficial for the treatment of cardiac hypertrophy. particularly left ventricular hypertrophy, associated
`
`with dyslipidemia and obesity. The combination of an anti-dyslipidemic agent and a NPY5 antagonist
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`will lower weight and treat, reduce or prevent cardiac hypertrophy leading to improved safety due to
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`reduced cardiac side effects and improved cardiac function in obese dyslipidemic patients. The
`combination of a NPY5 antagonist and an anti-dyslipidemic agent is expected to treat, reduce and/or
`prevent the cardiac hypertrophy, in particular the left ventricular hypertrophy, in a subject in need thereof
`with greater efficacy than either compound alone.
`The compositions of the present invention are further useful in the treatment, control and/or
`
`prevention of cardiac hypertrophy, particularly left ventricular hypertrophy.
`
`The compositions of the present invention are further useful in the treatment, control and/or
`prevention of metabolic syndrome.
`
`The present invention is also concerned with treatment of these conditions, and the use of the
`compositions of the present invention for manufacture of a medicament useful for treating these
`conditions.
`
`The invention is also concerned with pharmaceutical compositions comprising an anti-obesity
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`agent and an anti-dyslipidemic agent, as active ingredients.
`
`The present invention is also concerned with the use of an anti-obesity agent and an anti-
`dyslipidemic agent, for the manufacture of a medicament for the treatment of dyslipidemia, ~yslipidemia ·
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`associated with obesity, and dyslipidemia-related disorders. obesity, and obesity-related disorders, which
`comprises an effective amount of the anti-obesity agent and the anti-dyslipidemic agent, together or
`separately.
`
`The present invention is also concerned with a product containing an anti-obesity agent and an
`anti-dyslipidemic agent. as a combined preparation for simultaneous, separate or sequential use in
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`dyslipidemia, dyslipidemia associated with obesity, and dyslipidemia -related disorders. obesity. and
`obesity-related disorders.
`
`The present invention also relates to the treatment of dyslipidemia, dyslipidemia associated with
`
`obesity, dyslipidemia -related disorders, obesity. and obesity-related disorders with a combination of an
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`anti-obesity agent and an anti-dyslipidemic agent, which may be administered separately_.
`
`The invention also relates to combining separate pharmaceutical combinations into a kit form.
`
`DET All.ED DESCRIPTION OF TIIE INVENTION
`The present invention provides compositions comprising at least one anti-obesity agent and at
`least one anti-dyslipidemic agent useful in the treatment or prevention of dyslipidemia, dyslipidemia
`associated with obesity. dyslipidemia -related disorders. obesity and obesity-related disorders.
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`The methods and compositions of the present invention comprise an anti-obesity agent. The anti(cid:173)
`
`obesity agent useful in the compositions of the present invention may be any agent useful to decrease
`food intake known in the art. The anti-obesity agent may be peptidal or non-peptidal in nature, however,
`the use of a non-peptidal agent is preferred. For convenience, the use of an orally active anti-obesity
`agent is also preferred.
`In one embodiment of the present invention, the anti-obesity agent useful in the compositio.ns of .
`the present invention is selected from the group consisting of:
`a 5HT transporter inhibitor,
`(1)
`(2)
`a NE transporter inhibitor,
`(3)
`a CB-I antagonist/inverse agonist,
`(4)
`a ghrelin antibody,
`(5)
`a ghrelin antagonist.
`(6)
`a HJ antagonist/inverse agonist.
`a MCHlR antagonist.
`a MCH2R agoriist/antagonist,
`
`(7).
`
`(8)
`(9)
`(10)
`
`(11)
`(12)
`(13)
`(14)
`(15)
`(16)
`(17)
`
`a NPYl antagonist,
`
`a NPY2 agonist.
`a NPY5 antagonist,
`leptin,
`a leptin derivative,
`an opioid antagonist,
`an orexin antagonist,
`a BRS3 agonist,
`a CCK-A agonist,
`aCNTF,
`a CNTF derivative,
`a GHS agonist,
`
`(18)
`(19)
`(20)
`(21)
`
`(22)
`
`(23)
`
`5HT2c agonist,
`a Mc3r agonist,
`a Mc4r agonist,
`a monoamine reuptake inhibitor,
`(24).
`(25)
`a serotonin reuJ>take inhibitor,
`(26) GLP-1 agonist,
`(27) DP-IV inhibitor,
`(28)
`topiramate,
`(29)
`phytophann compound 57,
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`(30)
`(31)
`(32)
`(33)
`(34)
`(35)
`(36)
`(37)
`(38)
`(39)
`
`an ACC2 inhibitor,
`a Ji3 agonist,
`a DGATl inhibitor,
`a DGAT2 inhibitor,
`a FAS inhibitor,
`a PDE inhibitor,
`a thyroid honnone p agonist,
`an UCP-1, 2, or3 activator,
`an acyl-estrogen,
`a glucocorticoid antagonist,
`an up HSD-1 inhibitor,
`a SCD-1 inhibitor,
`a lipase inhibitor,
`a fatty acid transporter inhibitor,
`a dicarboxylate transporter inhibitor,
`a glucose transporter inhibitor, and
`a phosphate transporter inhibitor.
`(46)
`and pharmaceutically acceptable salts and esters thereof.
`In another embodiment of the present invention, the anti-obesity agent is selected from the group
`consisting of:
`
`(40)
`(41)
`(42)
`(43)
`
`(44)
`(45)
`
`(1)
`
`(2)
`
`(3)
`(4)
`(5)
`(6)
`(7)
`(8)
`(9)
`(10)
`
`(11)
`
`(12)
`(13)
`(14)
`(15)
`
`(16)
`
`a 5HT transporter inhibitor;
`a NE transporter inhibitor;
`a CB-1 antagonist/inverse agonist;
`a ghrelin antagonist;
`a H3 antagonist/inverse agonist;
`a MCHIR antagonist;
`a MCH2R agonist/antagonist;
`a NPY l antagonist;
`a NPY2 agonist;
`a NPY5 antagonist;
`· an opioid antagonist;
`an orexin antagonist;
`a BRS3 agonist;
`a CCK-A agonist;
`aCNTF;
`a CNTF derivative;
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`5
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`10
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`15
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`20
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`25
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`30
`
`(17)
`(18)
`(19)
`
`(20)
`(21)
`. (22)
`
`a GHS agonist;
`SHT2c agonist;
`a Mc3r agonist;
`a Mc4r agonist;
`a monoamine reuptake inhibitor;
`a serotonin reuptake inhibitor,
`(23) GL