1 (UL~ONAL!~PLI~TION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCf)
`
`(19) World Intellectual Property
`Organization
`In1emationa1 Bureau
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`•
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`lllllllllUllllDllllllHHRllilllllllDlllllllllll
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`(43) Intemalional Publication Date
`23 December 2004 (23.12.2004)
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`PCT
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`(10) International Publication Number
`WO 2004/110375 A2
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`(51) Intematlonal Patent Classlflcatlon7:
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`A61K
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`(74) Common Representative: MERCK & CO., INC.; 126
`East Lincoln Avenue, Rahway, NJ 07065-0907 (US).
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`(21) lnlemallonal Application Number:
`PCT/lJS2004/017291
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`(22) lnternallooal Flllng Date:
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`2 June 2004 (02.06.2004)
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`(25) Filing Language:
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`(26) PubUcatlon Language:
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`English
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`English
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`(30) Priority Data:
`60/476,388
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`6 June 2003 (06.06.2003) US
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`__ {71) Appllcants(for all designaJed Stales except US): MERCK
`-
`& CO.,INC. [US/US]; 126 East Lincoln Avenue, Rahway,
`
`(81) Designated States (unless otherwise lndicaJed, for every
`kind of national protection avaiJabte): AB, AO, AL, AM,
`AT, AU, AZ. BA, BB, BG.BR, BW,BY, BZ,CA, CH, CN,
`CO, CR, CU, CZ. DB, DK, DM, DZ, EC, EB, EO, ES, Fl,
`GB, GD, GB, GH, GM, HR, HU, ID, Il.., IN, IS, JP, KB,
`KO, KP, KR. KZ. LC, LK. LR, LS, LT; LU, LV, MA. MD,
`MO, MK, MN, MW, MX, MZ, NA, NI, NO, Nz, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SB, SG, SK, SL, SY, TJ, TM,
`TN, TR, TI, Tz, UA, UO, US, UZ. VC, VN, YU, ZA, ZM,
`zw.
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`{84) Designated States (unless otherwise indicaJed, for f!llt!ry
`kind of regional protection availabk): ARTPO (BW, GH,
`GM, KE, LS,· MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`EW"Opean {AT, BB. BO, CH, CY, CZ, DB, DK, EB, ES, Fl.
`FR. OB, GR, HU, IE. IT, LU, MC, NL. PL, PT, RO, SE. SI,
`SK. TR), OAPI (BF, BJ, CF, CG, GI. QM, GA, GN,.GQ,
`OW, ML. MR, NB, SN, TD, TG).
`.
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`Publlsbed:
`without international search repon and to be republished
`upon receipt of thal repon
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`For two-letter codes and other 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 P~ Gautte.
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`= NJ 07065-0907 (US). BANYU PHARMACEUI'ICAL
`=
`- (72) Inventors; and
`= (75) loventors/Appllcaots(forUSonly): ERONDU,Ng<W.E.
`= W07 {US). FONG, Tung, M. [USIUS]; 126 East Lincoln
`=
`=
`= Honcho, 2-Chome, Chuo-lcu, Tokyo 103-8416 (JP).
`_
`=
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`CO., LTD. [JP/JP]; 2-3, Nihombashi Honcho 2-Chome,
`Chuo-ku, Tokyo 103-8416 (JP).
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`[US/US]; 126 East Lincoln Avenue, Rahway, NJ 07065-
`
`Avenue, Rahway, NJ 07065-0907 (US). MACNEIL, Dou-
`glas, J. [US/US]; 126 East Lincoln Avenue, Rahway, NJ
`07065-0907 (US). VAN DER PLOEG, Leonardus, H. T.
`[NL/US]; 126 East Lincoln Avenue, Rahway, NJ 07065-
`0907 (US). KANATANI, AkJo [JP/JP]; 2-3, Nihombashi
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`M <
`'1') r(cid:173)
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`= c= (57) Abstract: The present invention relates to compositions comprising an anti-obesity agent and an anti-diabetic agent useful for
`M
`0 methods of treating or preventing obesity, and obesity-related disorders, in a subject in need thereof by administering a composition
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`~ ~~-~~~-~~~--~--~~~--~~~~~-~~---~~-~~~-~-~
`~ (54) TIUe: COMBINATION THERAPY FOR THE TREATMENT OF DIABETES
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`the treatment of diabetes, diabetes associated with obesity and diabetes-related disorders. 1lie present invention further relates to
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`:;;..... of the present invention. The present invention further provides for phannaceutical compositions, medicaments, and kits useful in
`~ carrying out these methods.
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`TITLE OF THE INVENTION
`COMBINATION THERAPY FOR THE TREATMENT OF DIABETES
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`BACKGROUND OFTHB INVENTION
`Diabetes is caused by multiple factors and is most simply characterized by elevated levels of
`plasma glucose (hyperglycemia) in the fasting state. There are two generally recognized forms of
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`diabetes: type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), in which patients product'. little
`or no insulin. the hormone which regulates glucose utilization, and type 2 diabetes, _or noninsulin(cid:173)
`dependent diabetes mellitus (NIDDM), wherein patients produce insulin and even exhibit
`hyperinsulinemia (plasma insulin levels that are the same or even elevated in comparison with non(cid:173)
`diabetic subjects), while at the same time demonstrating hyperglycemia. Type 1 diabetes is typically
`treated with exogenous insulin administered via injection. However, type 2 diabetics often develop
`"insulin resistance", such that the effect of insulin in stimulating glucose and lipid metabolism in the
`main insulin-sensitive tissues, namely, muscle, liver and adipose tissues; ·is d4oinished. Patients who are
`insulin resistant but not diabetic have elevated insulin levels that compensate for their insulin resistance,
`so that serum glucose levels are not elevated. In patients with NIDDM, the plasma insulin levels, even
`when they are elevated, are insufficient to overcome the pronounced insulin resistance, resulting in
`hyperglycemia.
`Insulin resistance is primarily due to a receptor binding defect that is not yet completely
`understood. Resistance to insulin results in insufficient activatian of glucose uptake, diminished
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`oxidation of glucose and storage of glycogen in muscle, inadequate insulin repress~on of lipoly~is in
`adipose tissue and inadequate glucose production and secretio~ by the liver.
`The persistent or uncontrolled hyperglycemia that occ1lrs in diabetics is associated with increased
`morbidity and premature mortality. Type 2 diabetics are at in!=reased risk of developing cardiovascular
`complications, e.g., atherosclerosis, coronary heart disease, stroke, peripheral vascular d_isease,
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`hypertension, nephropathy, neuropathy and retinopathy.
`Non-insulin dependent diabetes is also associated with cardiac hypertrophy, in P,articular left
`ventricular hypertrophy (Devereux, R. B., Circulation. 101:2271-2276 (2000)). Cardiac hyj>ertrophy,
`such as left ven~cular hypertrophy, is due to the response of the heart to chronic press~e or volume
`overload. Left ventricular hypertrophy (L VH) is characterized by thickening of the left ventricular wall.
`including increased left ventricular mass and increased left ventricular wall thickness, and is defined as a
`left ventricular mass index exceeding 131 glm2 of the body surface area in 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 and all(cid:173)
`cause mortality, sudden death, and stroke. Regression of left ventricular hypertrophy ~been associated
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`with a reduction in cardiovascular risk. It bas also been found that the incidence of morbid events in
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`patients with progression of left ventricular hypertrophy is greater than in patients with regression of left
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`ventricular hypertrophy.
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`Cmrent treatments for hypertrophy include non-pharmacological interventions, such as.weight
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`reduction. sodium restriction, and aerobic physical exercise can reduce left ventricular mass (Ghali, J.K.
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`et al., American Journal of Geriatric Cardiology, 6:38-49 (1997).
`Many patients who have insulin resistance but have not yet developed type 2 diabetes are also at
`a risk of developing metabolic syndrome, also referred to as syndrome x, insulin resistance syndrome, or
`plurimetabolic syndrome. The period of S to 10 years preceding the development ofimPafred glucose
`tolerance is associated with a number of hormonal imbalances, which give rise to an enlargement of
`visceral fat mass, hypertension, insulin resistance, and byperlipidemia (Bjornstop, P., Current Topics in
`Diabetes Research. eds. Belfore, F .• Bergman, R. N., and Molinath, G. M., Front Diabetes, Basel, Karger,
`12: 182-192 (1993)). Similarly, metabolic syndrome is cbaracterl7.ed by insulin resistance, along with
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`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., ~t 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.al., Piabetes
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`/Metabolism Rev. 10: 19-29 (1994)). Metabolic syndrome patients, whether or not they de.velop overt
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`diabetes mellitus, are at increased risk of developing the cardiovascular complications listed above.
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`20 Associations have also been found between left ventricular hypertrophy and metabolic syndrome (Lind,
`L. et al., 1 Hypertens. 13:433-38 (1995).
`Diabetes is treated with a variety of therapeutic agents including insulin sensitizers, such as
`PPARy agonists, such as glitazones; biguanides; protein tyrosine phospbatase-lB inhibitors; dipeptj.dyl
`peptidase N inhibitors; insulin; insulin mimetics; sulfonylureas; meglitinides; a-glucosid~ hydrolase
`inhibitors; and a-amylase inhibitors:
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`Increasing the plasma level of insulin by administration of sulfonylureas (e.g. t9lbutami~e and
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`glipizide) or meglitinides, which stimulate the pancreatic ~ells to secrete more insulin. and/or by
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`injection of insulin when sulfonylureas or meglitinides become ineffective, can result in insulin
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`· concentrations high enough to stimulate insulin-resistant tissues. However. dangerously low levels of
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`plasma glucose can result, and increasing insulin resistance due to the even higher plasma insulin levels
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`can occur. The biguanides increase insulin sensitivity resulting in some correction of hyperglycemia.
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`Metformin monotherapy is often used for treating type 2 diabetic patients who are also obese and/or
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`dyslipidemic. Lack of appropriate response to metformin is often followed by treatment with
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`sulfonylureas, tbiazolidinediones, insulin, or alpha glucosidase inhibitors. However, the two biguanides,
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`phenfonnin and metformin, can also induce lactic acidosis and nausea/diarrhea, respectively. Alpha
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`glucosidase inhibitors, such as acarbose, work by delaying absorption of glucose in the, intestine. Alpha-
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`amylase inhibitors inhibit the enzymatic degradation of starch or glycogen into maltose. which also
`reduces the amounts of bioavailable sugars.
`The glitazones, also known as thiazolidinediones (i.e. 5-benzylthiazolidine-2,4-diones), are a
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`more recently described class of compounds with potential for a novel mode of action in:alneJiorating
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`many symptoms of type 2 diabetes. These agents substantially increase insulin sensitivity in muscle,.
`liver and adipose tissue in several animal models of type 2 diabetes resulting in partial or complete
`correction of the elevated plasma levels of glucose without occurrence of hypoglycemia., The glitazones
`that are currently marketed are agonists of the peroxisome proliferator activated receptor; ~p AR) gamma ·
`subtype. PPAR-gamma agonism is generally believed to be responsible for the improv:ed iDsulin
`.
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`sensitization that is observed with the glitazones. Newer PPAR agonists that are being developed for
`treatment of Type 2 diabetes and/or dyslipidemia are agonists of one or more of the PPAR alpha. gamma
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`and delta subtypes.
`However, treatment of diabetes with PPAR y agonists bas been associated :with cardiac
`hypertrophy, or an increase in heart weight. Recent labeling revisions for Avandia® (rosiglitazone
`15 maleate}, a PPAR y agonist, indicate that patients may experience fluid accumulation and volume-related
`events such as edema and congestive heart failure. Caidiac hypertrophy related to PP AR y agonist .
`treatment is typically treated by withdrawing PP AR treatment.
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`Treatment of type 2 diabetes also typically includes physical exercise, weight control and dieting.
`While physical exercise and reductions in dietary intake of calories will dramatically improve the
`diabetic condition, compliance with this treatment is very poor because of well-entrenched sed~tary
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`lifestyles and excess food consumption, especially of foods containing high amounts of saturated faL
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`However, weight reduction and increased exercise are difficult for most people with diabetes.
`Abnormal glucose homeostasis is also associated both directly and indirectly :with obesity,.
`hypertension and alterations in lipid, lipoprotein and apolipoprotein metabolism. Obesity increases the
`likelihood of insulin resistance, and increases the likelihood that the resulting insulin resistance will
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`increase with increasing body weight. Therefore, therapeutic control of glucose homeostasis, lipid
`metabolism. obesity and hypertension are critically important in the clinical management and trea~nt
`of diabetes mellitus.
`Obesity, which can be defined as a body weight more than 20% above the ideal body weight, is a
`30 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 conseqn:ence o(
`increased ratio of caloric intake to energy expenditure. The molecular factors regulating food 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)]. Although the genetic and/or
`environmental factors leading to obesity are poorly understood, several genetic factors have been
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`identified.
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`Epidemiological studies have shown that increasing degrees of overweight and obesity are
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`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
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`obesity, which can be serious and life-threatening, include type 2 diabetes mellitus, hypertension,
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`elevated plasma insulin concentrations, insulin resistance, dyslipidemias, hyperlipidemia, endometrial,
`breast, prostate, kidney and.colon eancer, 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)). Obesity is also associated with metabolic ~yndro~.
`cardiac hypertrophy, in particular left ventricular hypertrophy, premature death. and with a significant
`increase in mortality and morbidity from stroke, myocardial infarction, congestive heart failure~ coronary·
`heart disease, and sudden death.
`Abdominal obesity has been linked with a much higher risk of coronary artery disease, and with
`three of its major risk factors: high blood pressure, diabetes that starts in adulthood, and. high l~vels 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 disorders
`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)
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`(Montague et al., Diabetes. 2000, 49: 883-888).
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`Obesity and obesity-related disorders, such as diabetes, are often treated by encouraging patients
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`to lose weight by reducing their food intake or by increasing their exercise level. thereby increasing their
`energy output. A sustained weight loss of So/o to 10% of body weight has been shown to lln.prove the co(cid:173)
`morbidities associated with obesity, such as diabetes, and can lead to improvement of obesity-related
`disorders such as diabetes1 left ventricular hypertrophy, osteoarthritis, and pulmonary and cardiac
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`dysfunction.
`Weight loss drugs used for the treatment of obesity include orlistat {Davidson, M.IL et ~· (1999)
`JAMA 281:235-42), dexfenfluramine {Guy Grand, B. et al. (1989) Lancet 2:1142-S), sibutramine {Bray,
`G. A. et al. {1999) Obes. Res. &:189-98) and phentermine {Douglas. A. et al. (1983) Int. J. Obes. 7:591-
`S). 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 gastromtestinal 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 diabetes, diabetes associated with
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`obesity, and diabetes-related disorders. There is also a need for new methods of treating and preventing
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`obesity and obesity related disorders, such as metabolic syndrome. There is currently no effective
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`treatment for metabolic syndrome.
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`The present invention addresses this problem by providing a combination therapy comprising of
`at least one anti-obesity agent and at least one enti-Oiabetic agent for the treatment of diabetes, diabetes
`associated with o~ity, end diabetes-related disorders. The combination of an anti-obesity ·agent and en·'·
`anti-Oiabetic agent, at their respective clinical doses, is expected to be more effective than tieatnient with
`either agent alone. Treatment with a combination of an anti-obesity agent and an anti-diabetic apt 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
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`achieve the desired medical benefits without the trial and error involved in prescribing each agent
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`individually during primary care.
`There is also a need for a method of treating diabetes with a PP AR y agonist without the cardiac
`hypertrophy side effect associated with PPAR y agonist monotberapy. The present invention provides a
`combination therapy comprising the administration of at least one NPY5 antagonist and at least one
`PPAR y agonist for the treatment of diabetes, while mitigating the left ventricular hypertrophy side effect
`associated with PP AR y agonist treatment
`The present invention further provides a method for synergistically treating and/or preventing
`metabolic syndrome comprised of administering the compositions of the present invention in
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`combination with an anti-hypertensive agent and/or an anti-dyslipidemic agent to a subject in need
`thereof. Metabolic syndrome is a multi-factorial disease characterized by obesity, diabe~s. 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 available
`monotherapies in treating or reducing the risk of metabolic syndrome. Combinations of diff~~t agents
`with different modes of action, eg., a combination of an anti-obesity agent, an anti-diabetic agent, and an
`anti-hypertensive agent, will achieve a better outcome relative to monotherapies using agents with only
`~e mode of action. Additionally. combination therapy is more likely to achieve the desired medical
`benefits without the trial and error of prescribing each agent alone in primary care.
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`SUMMARY OF THB INVENTION
`
`The present invention proVides compositions comprising at least one anti-obesi~ agent and at
`least one anti-diabetic agent useful in the treatment, control and/or prevention of diabetes, diabetes
`associated with obesity, and diabetes-related disorders.
`The present invention provides compositions comprising an anti-obesity agent selected from the
`group consisting of: a SHf (serotonin) transporter inhibitor, a NE (norepinephrine) transporter inhibitor,
`a CB-1 (cannabinoind-1 receptor) antagonist/inverse agonist, a ghrelin antibody, a ghrelin antagonist, a
`H3 (histamine H3) antagonistfmverse agonist, a MClilR (melanin concentrating hormone lR).
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`~tagonist, a MCH2R (melanin concentrating hormone 2R) agonist/anta~onist, a NPYl (neuropeptide Y
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`Yl) antagonist, a NPY2 (neuropeptide Y Y2) agonist, a NPYS (neuropeptide Y Y5) antagonist, leptin, a
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`leptin derivative, an opioid antagonist, an orexin antagonist, a BRS3 (bombesin receptor ·subtype 3)
`agonist, a CCK-A (cholecystokinin-A) agonist, a CNTF (ciliary nelll'Otrophic factor), a CNTF derivative. ..
`a OHS (growth hormone secretagogue receptor) agonist, 5lIT2c (serotonin receptor 2c) agonist, a Mc3r
`(melanocortin 3 receptor) agonist, a Mc4r (melanocortin 4 receptor) agonist, a monoamine reuptake
`inhibitor, a serotonin reuptake inhibitor, topiramate, phytopharm compound 57, an ACc2 (acet)'l-CoA
`carboxylase-2) inhibitor, a p3 (beta adrenergic receptor 3) agonist, a DGATl (diacylgly~l
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`acyltransferase 1) inhibitor, a DGAT2 (diacylglycerol acyltransferase 2) inhibitor, a FAS (fatty-_aci~
`synthase) inhibitor, a PDE (phosphodiesterase) inhibitor, a thyroid hormone p agonist, an UCP..:1
`:
`(uncoupling protein 1), 2, or 3 activator, an acyl-estrogen, a glucocorticoid antagonist, an up lisn:.1·
`(11-beta hydroxy steroid dehydrogenase type 1) inhibitor, a SCD-1 (stearoyl-CoA desa~l) inhibitor,
`a lipase inhibitor, a fatty acid transporter inhibitor, a dicarboxylate transporter inhibitor,·a glucose
`transporter inhibitor, a phosphate transporter inhibitor; and pharmaceutically acceptable salts and esters
`thereof.
`
`The present invention provides compositiens comprising an anti-diabetic agent selected from the
`group consisting of:
`(1)
`(2)
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`a sulfonylurea;
`a meglitinide;
`
`(3)
`(4)
`(5)
`(6)
`(7)
`(8)
`(9)
`(10)
`(11)
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`(12)
`(13)
`(14)
`(15)
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`(16)
`(17)
`( 18)
`(19)
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`an a-amylase inhibitor;
`an a-glucoside hydrolase inhibitor;
`a PPARy agonist;
`a PPAR aJy agonist;
`a biguanide;
`glucagon-like peptide 1 (GLP-1) agonist;
`a protein tyrosine phosphatase-lB (PTP-lB) inhibitor;
`a dipeptidyl peptidase IV (DP-IV) inhibitor;
`an insulin secreatagogue;
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`a fatty acid oxidation inhibitor;
`an A2 antagonist;
`a c-jun amino-terminal kinase inhibitor;
`insulin;
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`an insulin mimetic;
`a glycogen phosphorylase inhibitor;
`a VP AC2 receptor agonist; and
`a glucokinase activator;
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`and phannaceutically acceptable salts and esters thereof.
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`The compositions of the present invention are useful in the treatment. control and/or prevention
`of diabetes, in particular non-insulin dependent diabetes mellitus (NIDDM) in humans.
`The compositions of the present invention are further useful in the treatment. control and/or
`
`prevention of hyperlipidemia; dyslipidemia; obesity; abdominal obesity; hypercholesterolemia;
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`hypertrigyceridemia; atherosclerosis; coronary heart disease, stroke, hypertension, peripheral vascular
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`disease, va.Scular restenosis; nephropathy; neuropathy; inflammatory conditions, such as, but not limited
`to, irritable bo~el syndrome, inflammatory bowel disease, including Crobn' s disease and ulcerative.
`colitis; other inflammatory conditions; pancreatitis; neurodegenerative disease; retinopathy; neoplastic
`
`..
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`conditions, such as, but not limited to adipose cell tumors, adipose cell carcinomas, such as liposarcoma,
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`cancers, including gastric and bladder cancers; angiogenesis; Alzheimer's disease; psoriasis; and other
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`disorders where insulin resistance is a componenL
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`The compositions of the present invention are also useful in the treatment. control and/or
`prevention of overeating; bulimia; elevated plasma insulin concentrations; insulin resistance; glucose
`tolerance; lipid disorders; low HDL levels; high LDL levels; hyperglycemia; neoplastic conditions, such
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`as endometrial, breast. prostate, kidney and colon cancer; osteoarthritis; obstructive sleep apnea;
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`gallstones; abnormal heart rhythms; heart arrythmias; myocardial infarction; congestive heart failure;
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`sudden death; ovarian hyperandrogenism. (polycystic ovary disease); craniopharyngioma; the Prader(cid:173)
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`Willi Syndrome; Froblich's syndrome; OH-deficient subjects; normal variant short stature; Turner's
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`syndrome; and other pathological conditions showing reduced metabolic activity or a decrease in resting
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`energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphobl~tic
`leukemia
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`Neuropeptide Y (NPY), via G protein-coupled NPY YS receptors {NPY5), is implicated in the
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`development of cardiac hypertrophy, and left ventricular hypertrophy, during chronic stimulation of the
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`sympathetic system by potentiating a-adrenergic signals. Recent studies have shown that agonism of the
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`NPYS receptor in rodent cardiac myocytes may mediate hypertrophy (Bell, D. et al., J-Pharmacol-Bxp(cid:173)
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`Ther. 303: 581-91 (2002)).
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`NPYS antagonists are expected to be beneficial in the treatment and /or prevention of cardiac
`hypertrophy. Treatment with a combination of a NPY5 antagonist and a PP AR y (gamma) agonist is·
`expected to prevent the left ventricular hypertrophy associated with PP AR gamma agonist tieatmenL
`Furthermore, combination therapy with a PP AR gamma agonist and a NPYS antagonist is beneficial for
`the treatment of d~abetes, including diabetes associated with obesity, while miminizing cardiac,
`hypertrophy, including left ventricular hypertrophy. The combination of a PPAR gamma agonist and a
`NPY5 antagonist has the unexpected benefit of treating diabetes, while mitigating the cardiac
`hypertrophy side effect associated with PP AR gamma agonist monotherapy.
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`The compositions of the present invention are also useful in the treatment, control and/or
`prevention of diabetes while mitigating cardiac hypertrophy, including left ventricular hypertrophy. In
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`particular, the compositions of the present invention comprising a NPY YS antagonist and a PPAR y
`agonist are useful in the treatment. control and/or prevention of diabetes while mitigating the cardiac
`· hypertrophy side effect, in particular the left ventricular hypertrophy side effect, associated with with
`PP AR y agonist treatment
`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 treamig these '
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`conditions.
`Tlie invention is also concerned with pharmaceutical compositions comprising an anti-obesity
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`10
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`agent and an anti-dia~tic agent, as active ingredients.
`The present invention is also concerned with the use of an anti-obesity agent and an anti-diabetic
`agent, for the manufacture of a medicament for the treatment of diabetes, diabetes associated with
`obesity, and diabetes-related disorders, which comprises an effective amount of the anti-obesity agent
`and the anti-diabetic agent, together or separately.
`The present fuvention is also concerned with a product containing an anti-obesity agent and an
`anti-diabetic agent. as a combined preparation for simultaneous, separate or sequential ll:se in diabetes,
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`15
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`diabetes associated with obesity, and diabetes-related disorders.
`
`The present invention alro relates to the treatment of diabetes, diabetes associated with obesity,
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`20
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`an.d diabetes-related disorders, with a combination of an anti-obesity agent and an anti-diabetic agent.
`which may be administered separately.
`
`The invention also relates to combining separate pharmaceutical combinations into a kit form.
`
`DETAILED DESCRIPTION OF TIIE INVENTION
`The present invention provides compositions comprising at least one anti-obesity agent and at
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`least one anti-diabetic agent useful in the treatment or prevention of diabetes, diabetes associated with
`
`obesity, and diabetes-related disorders.
`
`The methods and compositions of the present invention comprise an anti-obesity agent The anf:i(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 compositions of
`the present invention is selected from the group consisting of:
`a SHT transporter inhibitor,
`(1)
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`10
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`20
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`(2)
`
`(22)
`
`(23)
`
`a NE transporter inhibitor,
`(3)
`a CB-1 antagonist/inverse agonist.
`(4)
`a ghrelin antibody,
`a ghrelin antagonist,
`(5)
`(6)
`a ID antagonist/inverse agonist.
`(7)
`a MCHlR antagonist.
`(8)
`a MCH2R agonist/antagonist.
`(9)
`a NPYl antagonist.
`a NPY2 agonist,
`(10)
`a NPY5 antagonist.
`(11)
`(12)
`leptin.
`a leptin derivative,
`(13)
`(14)
`an opioid antagonist.
`(15)
`an orexin antagonist,
`(16)
`a BRS3 agonist,
`(17)
`a CCK-A agonist,
`(18)
`aCNTF,
`(19)
`a CNTF derivative.
`(20). a GHS agonist,
`5HT2c agonist,
`(21)
`a Mc3r agonist,
`a Mc4r agonist,
`a monoamine reuptake inhibitor,
`a serotonin reuptake inhibitor,
`topiramate,
`pbytopharm compound 57,
`an ACCl inhibitor,
`a P3 agoilist,
`a DGATl inhibitor,
`a DOAT2 inhibitor,
`a FAS inhibitor,
`a PDE inhibitor,
`a thyroid hormone p agonist,
`an UCP-1, 2, or 3 activator,
`an acyl-estrogen,
`a glucocorticoid antagonist.
`
`(24)
`
`(25)
`(26)
`(27)
`(28)
`(29)
`(30)
`(31)
`(32)
`(33)
`(34)
`(35)
`(36)
`(37)
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`(38)
`
`(39)
`
`(40)
`
`(41)
`
`(42)
`
`(43)
`(44)
`
`an lljJ HSD-1 inhibitor,
`
`a SCJ)..1 inhibitor,
`
`a lipase inhibitor;
`
`a fatty acid transporter inlnlritor,
`
`a dicarboxylate transporter inhibitor,
`
`a glucose transporter inhibitor, and
`
`a phosphate transporter inhibitor;
`
`and pharmaceutically acceptable salts and esters thereof;
`provided that when the anti-pbesity agent is a Mc4r agonist, then the anti-diabetic agent is not seleCted
`from a sulfony lurea, an a-glucoside hydrolase inhibitor, a PP AR y agonist, a biguanide, a protein tyrosine
`phosphatase-ID inhibitor, insulin and an insulin mimetic.
`In another em~odiment of the present invention, the anti-obesity agent is selected from the group
`consisting of:
`
`(1)
`
`(2)
`(3)
`
`(4)
`
`(5)
`
`(6)
`
`{7)
`(8)
`
`(9)
`
`(10)
`(11)
`(12)
`
`(13)
`
`(14)
`
`(15)
`(16)
`
`(17)
`
`(18)
`
`(19)
`
`(20)
`
`(21)
`(22)
`
`a 5Hf transporter inhibitor;
`a NE transporter inhibitor;
`a CB-1 antagonist/inverse agonist;
`a ghrelin antagonist;
`a H3 antagonist/inverse agonist;
`a MCIUR antagonist;
`
`a MCH2R agonist/antagonist;
`a NPYl antagonist;
`a NPY2 agonist;
`a NPY5 antagonist;
`
`an opioid antagonist;
`
`an orexin antagonist;
`
`a BRS3 agonist;
`a CCK-A agonist;
`aCNTF;
`
`a CNTF derivative;
`
`a OHS agonist;
`
`5HI'2c agonist;
`
`a Mc3r agonist;
`
`a Mc4r agonist;
`
`a nionoamine reuptake inhibitor;
`
`a serotonin reuptake inhibitor;
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`topiramate;
`
`phytopbarm compound 57;
`an ACCl inht"bitor;
`a P3 agonist;
`a DOATl inhibitor;
`
`a DOAT2 inhibitor;
`a FAS inlu"bitor;
`a PDE inhibitor;
`a thyroid hormone p agonist;
`an UCP-1, 2, or 3 activator;
`an acyl-estrogen;
`a glucocorticoid antagonist;
`an llP HSD-1 inhibitor;
`a SCD-1 inhibitor;
`
`(23)
`
`(24)
`
`(2S)
`
`(26)
`
`(27)
`
`(28)
`(29)
`(30)
`(31)
`(32)
`(33)
`(34)
`(35)
`
`(36)
`(37)
`(38)
`(39)
`
`a lipase inhibitor;
`a fatty acid transporter inhibitor;
`a dicarboxylate transporter inhibitor; and
`a glucose transporter inln'bitor;
`(40)
`and pharmaceutically acceptable salts and esters thereof;