`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`•
`
`1111111111111 !llUlllllllrnHUlllllUllllUDU!llllllllH
`
`(43) International Publication Date
`23 December 2004 (23.12.2004)
`
`PCT
`
`(10) International Publication Number .
`WO 2004/110368 A2:
`
`(51) International Patent Classl6attlon7:
`
`A61K
`
`(74) Common Representative: MERCK & CO;, INC.; 126
`East Lincoln Avenue, Rahway, NJ 07065-0907 (US).
`
`(ll) lotemaUonal AppUcaUon Number:
`PCT/US2004/017090
`
`(ll) lntemaUonal Filing Date:
`
`2 June 2004 (02.06.2004)
`
`(25) FIUng Language:
`
`(26) PubUatlloo Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/476,390
`
`6 June 2003 (06.06.2003) US
`
`(71) Applicant (for all designated States except US): MERCK
`& CO., INC. fUS/US}; 126 East Lincoln Avenue, Rahway,
`NJ 07065-0907 (US).
`
`(72) Inventors; and
`(75) Invenlurs/AppUatols (for US only): FONG, Tung, M.
`
`(81) Designated States (unless otherwise iNlicated, 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, EG, HS, FI.
`GB, GD, GB, GH, GM, HR. HU, ID, ll., IN, IS, JP. KE,
`KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD.
`MG, MK, MN, MW, MX, MZ, NA, NT, NO,NZ, OM, PG,
`PH, PL, Pr, RO, RU, SC, SD, SE, SG, SK, SL, sY, TJ, TM,
`TN, TR, TI, Tz, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
`'ZW.
`
`(84) Designated Stales (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE. LS, MW, MZ. NA, SD, SL, SZ, T'Z. UG, ZM,
`'ZW), Eurasian (AM, AZ. BY, KG, KZ MD, RU, TJ, TM),
`European (AT, BB. BG, CH, CY. CZ, DE, DK. EE, HS, FI.
`FR. GB, GR, HU, IE, IT, LU, MC, NL, PL. Pr, RO, SE, SI,
`SK, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ,
`Gw, ML, MR, NB. SN, TD, TG).
`.
`
`PubUshed:
`-
`without international search ·~ort and lO ~ republished
`·
`upon receipt of that report
`
`For two-lener codes and other abbreviations, refer: to the. "Guid(cid:173)
`ance Noles on Codes and Abbreviations" appearing at ihe begin(cid:173)
`ning of each reglllar issue of rhe PCT Gazene.
`
`-
`-
`
`0007 (US). ERONDU. Ngozl, E [US/US]; 126 East Lin-
`coin Avenue, Rahway, NJ 07065-0907 (US). MACNEIL,
`Douglas, J. fUS/US]; 126 East Lincoln Avenue, Rahway,
`. NJ 07065-0907 (US). MCINTYRE, James, H. fUS/US];
`126 East Lincoln Avenue, Rahway, NJ 07065-0907 (US).
`~ VAN DER PLOEG, Leonardus, IL T. [Nl.AJS}; 126 East
`Lincoln Avenue, Rahway, NJ 07065-0907 (US).
`
`-
`
`=
`--
`= [US/US]; 126 Easl Lincoln Avenue, Rahway, NJ 07065-
`=
`=
`-------
`----
`
`00
`\C
`ff')
`0
`-"
`-" ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~-
`~ (54) TIUe: COMBINATION THERAPY FOR THE TREATMENT OF HYPl!RIENSION
`0
`0
`(57) Abstract: Tiie present invention relates to compositions comprising an anti-obesity agent and an anli-hypertensiw agent useful
`M for the treatment of hypenension, hypenension associated with obesity, and hypertension-related disorders. The present invention
`O further relates to methods of treating or preventing obesity, and obesity-related disorders, in a subject in need thereof by administering
`:> a composition of the present invention. The present invention fw1her provides for pharmaceuticaJ compositions, medicaments, and
`;iiil" kits useful in carrying out these methods.
`
`1 of 99
`
`PENN EX. 2243
`CFAD V. UPENN
`IPR2015-01836
`
`
`
`WO 2004/110368
`
`PCT/US2004/017090
`
`TITLE OF THE INVENTION
`COMBINATION THERAPY FOR THE TREATMENT OF HYPERTENSION
`
`BACKGROUND OF THE INVENTION
`
`5
`
`Hypertension, or high blood pressure, is a generally· symptomless condition cbaraeteriz.ed by
`
`abnormally high pressure in the arteries. Untreated high blood pressure increases the risk 'of stroke,
`aneurysm. heart disease, heart failure, heart attack, and kidney damage. Hypertension may also reSult in ,
`changes in the heart. such as enlargement of the heart (cardiac hypertrophy and left ventricular
`hypertrophy) due to the increased work required to pump blood. For an otherwise healthy indiVidual.
`high blood pressure is defined as a systolic pressure (pressure when the heart contracts) that averages 140
`nnn Hg or more, a diastolic pressure (pressure when the heart relaxes) that averages 90 mm Hg or more,
`
`or both.
`
`The pressure in arteries can be increased in various ways. For one, the heart c~ pump with
`more force, putting out more fluid each second. Another possibility is that the large arteries can lose
`their normal flexibility and become stiff, so that they can't expand when the heart pumps blood through ·
`
`them. .Thus, the blood through each heartbeat is forced through less space than normal, and the pressure
`
`increases. This occurs when arterial walls become thickened and stiff due to arteriosclerosis. Blood
`pressure is similarly increased in vasoconstriction - when the tiny arteries (arterioles) are temporarily
`consbicted as a result of stimulation by nerves or by hormones in the blood. A third way in which the
`pressure in the arteries can be increased is for more fluid to be added to the system. This happens when
`the kidneys malfunction and aren't able to remove enough salt and water from the body, The volwµe of
`blood in the body increases, so the blood pressure increases.
`Cardiac hypertrophy, including left venbicular hypertrophy, is due to the response of the heart to·
`chronic pressure or volume overload. Left ventricular hypertrophy (L VH) is characterized by thickening
`
`of the left venbicular wall, including increased left ventricular mass and increased left venbicular :Wall
`thickriess, and is defined as a left venbicular 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 q Pt.2): 26-33
`(1987).
`
`~ venbicular hypertrophy is independently associated with increased incidence of .
`
`cardiovascular disease, such as congestive heart failure, iscbaemic heart disease, cardiovascular and all(cid:173)
`cause mortality, sudden death, and stroke. Regression ofleft ventricular hypertrophy bas been associated
`with a ~uction in cardiovascular risk. It has also been found that the incidence of morbjd events in
`patients with progression of left venbicular 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 been
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`-1 -
`
`2 of 99
`
`PENN EX. 2243
`CFAD V. UPENN
`IPR2015-01836
`
`
`
`WO 2004/110368
`
`PCT/US2004/017090
`
`shown to be predictive of the prevalence of L VH at age 70 for men (Sundstroem. J. et al., Circulation, .
`
`February, 836-840 (2001).
`Associations have also been found between left ventricular hypertrophy and metabolic syndrome .
`(Lind, Let al., J Hypertens. 13:433-38 (1995).
`Metabolic syndrome. also known as syndrome X, is characteri7.ed by insuliii resistance, along
`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. 1. Med. 334:374-381
`(1996); Despres. 1-P., et al., N. Engl. I. Med 334:952-957 (1996); Wajchenberg, B. L, et al., Diabetes
`!Metabolism Rev. 10: 19-29 (1994)). :Metabolic syndrome patients are at increased ·risk cif developing the ·
`
`cardiovascular complications listed above.
`
`lllgh blood pressure is treated with a variety of therapeutic agents including diuretics, adrenergic
`
`blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin Il receptor antagonists, or
`
`angiotensin blockers, calcium channel blockers or calcium channel antagonists, direct vasodilators,
`.
`.
`neutral endopeptidase inhibitors, and endothelin antagonists. Diuretics cause the reduction of water and
`sodium, or block sodium transport, resulting in a reduction in blood pressure. Adrenergic blockers
`consist of a group of drugs, including alpha-blockers, beta-blockers, and the alpha/beta blocker, labetalol,
`
`5
`
`10
`
`15
`
`that block the effects of the sympathetic nervc:>us system, which responds to stress by raising blood
`pressure. An8iotensin converting enzyme (ACE) inhibitors lower blood pressure by dil~ting arteries by
`blockin the effects of the angiotensin-renin-aldosterone system. Angiotensin Il receptor antagonists, or
`
`20
`
`angiotensin blockers, lower blood pressure by a mechanism similar to, but more direct than, ACE
`
`inhibitors. Calcium channel blockers, or calcium channel antagonists, and direct vasodilators reduce
`
`blood pressure by causing blood vessel dilation. Neutral endopeptidase inhibitors produce higher levels
`
`of atrial natiuretic peptide, which opens blood vessels.
`
`25 ·
`
`Obesity, a seden~ lifestyle, stress, and excessive amounts of salt or alcohol can play a role in
`
`the development of high blood pressure in people who have an inherited sensitivity. Ov~rweigbt people
`
`with high blood pressure are advised to reduce their weight to ideal levels. Changes in diet for those with
`
`diabetes, obesity, or high blood cholesterol levels are also important for overall cardiovascular health.
`Obesity, which can be defined as a bOdy weight more than 209& 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 consequence of
`.
`.
`.
`.
`increased ratio of caloric intake to energy expenditure. The molecular factors regulating food iµtake and
`body weight balance are incompletely understood. [B. Staels et al., 1. Biol. Chem. 270(~7) • .15958 .
`(1995); F. Lonnquist et al., Nature Medicine 1(9). 950 (1995)]. Although the genetic and/or
`
`.
`
`'
`
`35
`
`environmental factors leading to obesity are poorly understood. several genetic factors have been
`identified.
`
`-2-
`
`3 of 99
`
`PENN EX. 2243
`CFAD V. UPENN
`IPR2015-01836
`
`
`
`WO 2004/110368
`
`PCT/US2004/017090
`
`Epidemiological studies have shown that increasing degrees of overweight and .oQe8ity ~
`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, endometrial,
`
`breast, prostate, kidney and colon cancer, osteoarthritis, respiratory complications; such a8 obstructive
`sleep apnea. gallstones, arterioscelerosis. heart disease, abnormal heart rhythms, and ~ arrythmlas
`(Kopelman. P.O., Nature 404, 635-643 (2000)). Obesity is also associated with metabolic syndrome~
`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 fac~ors: high blood pressure, diabetes that starts in adulthood. and high 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 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)
`
`(Montague et al., Diabetes, 2000, 49: 883-888).
`Obesity and obesity-related disorders are often treated by encouraging patients .to lose weight by
`reducing their food intalo( or by increasing their exercise level, thereby increasing their energy output. A
`sustained weight loss of S% to 10% of body weight has been shown to improve the co-mmbidities
`associated with obesity, such as diabetes, and can lead to improvement of obesity-related disorders such
`as metabolic syndrome, left ventricular hypertrophy, osteoarthritis. and pulmonary and cardiac
`dysfunction.
`Weight loss drugs used for the treatment of obesity include orlistat (Davidson, M.R et al. (1999)
`JAMA 281:23542), dexfenfluramine (Guy Grand, B. et al. (1989) Lancet 2:1142-5). sibutramine (Bray.
`0. A. et al. (1999) Obes. Res. &:189-98) and phentermine (Douglas. A. et al. (1983) Int. J. Obes. 7:591-
`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.
`Jn patients with hypertension. effective blood pressure control generally regarded as the most
`important intervention to reduce left ventricular hypertrophy. Blood pressure reduction and control in
`hypertensive patients is associated with a significant regression in left ventricular hypertrophy (Cesare,
`C. et al., Ital Heart J 3 (9):514-519 (2002). However, the variation in 24-hour blood pressure explains
`only 25-30% of the variation in left ventricular mass (Majahalme. S. et al., Am J Hypertens. 9:1110-1118
`
`S
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`-3-
`
`4 of 99
`
`PENN EX. 2243
`CFAD V. UPENN
`IPR2015-01836
`
`
`
`WO 2004/110368
`
`PCT/US2004/017090
`
`(1996). Non-pharmacological interventions, such as weight reduction, sodium restriction, and aerobic
`physical exercise can also reduce left ventricular mass (Ghali, J .K. et al., American Joumai of Geriatric
`Cardiology, 6:38-49 (1997). Weight reduction has also been shown to decrease left ventricular mass in
`overweight hypertensive patients even more than pharmacological anti-hypertensive treatment ·
`(MacMahon, S.W. et al., N Engl J Med., 314; 334-339 (1986).
`There is a continuing need for new methods of treating hypertension, hypertension associated
`with obesity, and hypertension-related disorders, such as cardiac hypertrophy, left ventricular
`hypertrophy and metabolic syndrome.
`The present invention addresses these problems by providing a combination therapy comprising
`of at least "one anti-obesity agent and at least one antj.-hypertensive agent for the treatment of obesity;
`. hypertension, hypertension associated with obesity, and hypertension -related disorders. The
`·combination of an anti-obesity agent and an anti-hypertensive 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-hypertensive 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.
`AB a result, combination therapy is more likely to ac~eve the desired medical benefits without the trial
`and error involved in prescribing each agent individually ·during primary care.
`The present invention further provides a method for synergistically treating and/or preven~g
`metabolic syndrome comprised of administering the compositions of the present invention in
`combination with an anti-diabetic agent and/or an anti-dyslipidemic agent to a subject in n~ thereof.
`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 predic~ that the
`combination therapies of the present invention will be more effective thaii currently available
`monotherapies in treating or reducing the risk of metabolic syndrome. Combinations of different agents
`with different modes of action, eg. a combination of an anti-obesity agent, an anti-hyperte~sive agent,
`with an anti-diabetic agent and/or an anti-dyslipidemic agent, will achieve a better outcQme relative to
`monotherapies using agents with only one mode of action. Additionally, combination the~py is more
`likely to achieve the desired medical benefits without the trial and error of prescribing each agent ajone
`in primary care.
`
`SUMMARY OF THE lNVENTION
`The present invention provides compositions comprising at least one anti-obesity agen~ and ~t
`least one anti-hypertensive agent useful in the treatment, control and/or prevention of hypertension,
`hypertension associated with obesity, and hypertension -related disorders. The present inveµtion further
`provides compositions comprising at least one anti-obesity agent and at least one anti-hypertensive agent
`useful in the treatment, control and/or prevention of obesity, and obesity-related disorders.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`-4-
`
`5 of 99
`
`PENN EX. 2243
`CFAD V. UPENN
`IPR2015-01836
`
`
`
`WO 2004/110368
`
`PCT/US2004/0J7090
`
`The present invention provides compositions comprising an anti-obesity agent selected. from the
`group consisting of: a 5lIT (serotonin) transporter inhibitor, a NE (norepinepbrine) ~r inhibitor,
`a CB-1 (cannabinoind-1 receptor) antagonist/inverse agonist, a ghrelin antibody, a ghrelin antagonist, a
`H3 (histamine H3) antagonistfmverse agonist, a MCfllR (melanin concentrating hormone IR)
`
`5
`
`antagonist, a MCH2R (melanin concentrating hormone 2R) agonist/antagonist. a NPYI (neuropeptide Y
`
`Yl) antagonist, a NPY2 (neuropeptide Y Y2) agonist, a NPYS (neuropeptide Y Y5) antagonist, leptin, a
`leptin derivative, an opioid antagonist, an orexio antagonist, a BRS3 (bombesin receptor subtype 3)
`agonist, a CCK-A (cbolecystokinin-A) agonist, a CNTF (ciliary neurotrophic factor), a~ derivative,
`a GHS (growth hormone secretagogue receptor) agonist, 5Hf2c (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 s7, an ACC2 (acetyl-CoA carbox.yfase-2) inhibitor, a f33 (beta adrenergic receptor
`3) agonist, a DGATl (diacylglycerol acyltransferase 1) inhibitor, a DGAT2 (diacylglycerol
`.
`acyltransferase 2)inhibitor, a FAS (fatty acid 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 1113 HSD-1 (I I-beta hydroxy steroid dehydrogenase type 1) inhibitor, a
`SCD-1 (stearoyl-CoA desaturase-1) inhibitor, a DPIV inhibitor, a lipase inhibitor, a f'tty acid ~orter.
`inhibitor, a dicarboxylate transporter inhibitor, a glucose transporter inhibitor, a phosphate transporter
`inhibitor; and pharmaceutically acceptable salts and esters thereof.
`The present invention. provides compositions comprising an anti-hypertensive agent selected
`from the group consisting of:
`(1)
`a diuretic,
`(2)
`a f3-adrenergic blocker,
`(3)
`a a.-adrenergic blocker,
`(4)
`an aldosterone inhibitor,
`
`(5)
`(6)
`(7)
`
`(8)
`(9)
`(10)
`
`an. alpha 1 blocker,
`calcium channel blocker,
`an angiotensin ci:>nverting enzyme inhibitor,
`a neutral endopeptidase inhibitor;
`an angiotensin II receptor antagonist,
`an endothelin antagonist,
`
`a vasodilator,
`(11)
`(12)
`an alpha 2a agonist, and
`an aJP adrenergic blocker,
`(13)
`and phannaceutically acceptable salts and esters thereof.
`
`-5-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`6 of 99
`
`PENN EX. 2243
`CFAD V. UPENN
`IPR2015-01836
`
`
`
`WO 2004/110368
`
`PCT/US2004/017090
`
`The compositions of the present invention are expected to be efficacious in the treatment, control
`and/or prevention of hypertension. The compositions are also expected to be useful for treating _and/or
`preventing heart disease, heart failure, heart attack. and kidney failure.
`Tbe compositions of the present invention are also useful in the treatment, control and/or
`
`5
`
`prevention of obesity, overeating; bulimia; elevated plasma insulin concentrations; insulin resistance;
`
`glucose intolerance; dyslipidemia; low lIDL levels; high LDL levels; hyperglycemia; metabolic
`
`syndrome; neoplastic conditions. such as endometrial, breast, prostate, kidney. and colon cancei;
`osteoarthritis; obstructive sleep apnea; gallstones; abnormal heart rhythms; heart arrythmias;
`osteoarthritis, atherosclerosis; myocardial infarction; congestive heart failure; sudden death; ovarian
`hyperandrogenism. (polycystic ovary disease); craniopharyngioma; the Prader-Willi Syndrome;
`· ·
`. Frohlich's syildrome; OH-deficient subjects; normal variant shOrt stature; Tmner's syndrome; and other
`· pathological cond.itions 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 YS receptors (NPY5), 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
`NPY5 receptor in rodent cardiac myocytes may mediate hypertrophy (Bell, D. et al., J-Pbarmacol-Bxp(cid:173)
`
`Ther. 303: 581-91 (2002)).
`NPY5 antagonists are expected to be beneficial in the treatment and /or prevention of cardiac
`hypertrophy. Furthermore, combination therapy with NPY5 antagonist and an anti-hyperte~ive agent is
`beneficial for the treatment of cardiac hypertrophy, ·particularly the left ventricular hypei;trophy,
`associated with hypertension and obesity. The combination of a NPY5 antagonist and an anti(cid:173)
`hypertensive agent will lower weight and treat, reduce or prevent cardiac hypertrophy_leading to
`improved safety, due to reduced cardiac side effects, and improved cardiac function in obese
`
`hypertensive patients. The combination of a NPY5 antagonist and an anti-hypertensive agent is expected
`to treat, reduce and/or prevent the cardiac hypertrophy, in particular the left ventricular hypertrophy,
`associated with hypertension and obesity, in a subject in need thereof with greater efficacy. than either
`compound alone.
`
`The compositions of the present invention are also useful in the treatment, control and/or
`prevention of cardiac hypertrophy, including left ventricular hypertrophy. In particular, the,compo~itions
`of the present invention comprising a NPY Y5 antagonist and an anti-hypertensive agent are expected to
`be useful in the treatment, control and/or prevention of cardiac hypertrophy, including left ventrfoular
`hypertrophy in a subject in need thereof.
`The compositions of the present invention are further useful in the treatment, control and/or
`prevention of metabolic syndrome.
`
`lO
`
`15
`
`20
`
`25
`
`30
`
`35
`
`-6-
`
`7 of 99
`
`PENN EX. 2243
`CFAD V. UPENN
`IPR2015-01836
`
`
`
`WO 2004/110368
`
`PCT/US2004/017090
`
`The present invention is also concerned with treatment of these conditions; and ihe Use of the
`coIDP.Ositions of the present invention for manufacture of a medicament useful for treating these
`conditions.
`
`The invention is also concerned.with phannaceutical compositions comprising an anti-obesity
`
`agent and an anti-hypertensive agent. as active ingredients.
`The present invention is also concerned with the use of an anti-obesity agent and an anti(cid:173)
`hypertensive agent, for the manufacture of a medicament for the treatment or prevention of hypertension.
`
`hypertension associated with obesity. and hypertension-related disorders. which comprises an effective
`amount of the anti-obesity agent and the anti-hypertensive agent. together or separately.· The p~~t
`invention is also concerned with the use of an anti:.Obesity agent and an anti-hypertensive agent. for the
`manufacture of a medicament for the treatment or prevention of obesity, and. obesity-related disorders,
`"which comprises an effective amount of the anti-obesity agent and the anti-hypertensive agent. together
`
`or separately.
`The present invention is also concerned with a product containing an anti-obesity agent and an
`anti-hypertensive agent. as a combined preparation for simultaneous, separate or sequential use in
`hypertension, hypertension associated with obesity. and hypertension -related disorders. The present
`invention is also concerned with a product containing an anti-obesity agent and an anti-bypertensiv~
`
`agent. as a combined preparation for simultaneous, separate or sequential use in obesity, and obesity(cid:173)
`related disorders.
`The present invention also relates to the treatment of obesity, hypertension, hypert~nsion
`associated with obesity, and hypertension -related disorders, with a combination of an anti-o~ty agent .
`and an anti-hypertensive agent, which may be administered separately. The present invention also relates
`
`to the treatment of obesity, and obesity-related disorders, with a combination of an anti-obesity agent and
`
`S
`
`10
`
`IS
`
`20
`
`an anti-hypertensive agent, which may be administered separately.
`
`2S
`
`The invention also relates to combining separate pharmaceutical combinations into a kit form.
`
`DETAILED DESCRIPTION OF THE lNVBNTION
`The present invention provides compositions comprising at least one anti-obesity agent~ at
`least one anti-hypertensive agent useful in the treatment or prevention of hypertension, hypertension
`
`30
`
`associated with obesity, and hypertension-related disorders. The present invention provides
`
`compositions comprising at least one anti-obesity agentand at least one anti-hypertensive agent useful in
`the treatment or prevention of obesity, and obesity-related disorders.
`
`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 decirease
`food intake known in the art. The anti-obesity agent may be peptidal or non-peptidal in nature, however,
`
`35
`
`-7-
`
`8 of 99
`
`PENN EX. 2243
`CFAD V. UPENN
`IPR2015-01836
`
`
`
`WO 2004/110368
`
`PCT/US2004/017090
`
`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:
`(1)
`a 5HT transporter inhibitor.
`a NB transporter inhibitor,
`(2)
`a CB-1 antagonist/inverse agonist.
`a ghrelin antibody,
`
`(3)
`(4)
`(5)
`(6)
`(7)
`(8)
`(9)
`(10)
`
`(11)
`(12)
`(13)
`
`(14)
`(IS)
`(16)
`(17)
`(18)
`{19)
`(20)
`(21)
`(22)
`(23)
`
`(24)
`
`(25)
`
`(26)
`
`(27)
`(28)
`
`(29)
`
`(30)
`(31)
`(32)
`
`a ghrelin antagonist.
`a ID antagonist/inverse agonist.
`a MCIUR antagonist.
`a MCH2R agonist/antagonist.
`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 OHS agonist.
`5lIT2c agonist,
`a Mc3r agonist.
`a Mc4r agonist,
`
`a monoamine reuptake inhibitor,
`a serotonin reuptake inhibitor,
`
`a GLP-1 agonist,
`topiramate,
`
`phytopharm compound 57,
`
`an ACC2 inhibitor.
`
`a ~3 agonist.
`a DGATl inhibitor,
`a DGAT2 inhibitor,
`
`-8-
`
`5
`
`10
`
`lS
`
`20
`
`25
`
`30
`
`35
`
`9 of 99
`
`PENN EX. 2243
`CFAD V. UPENN
`IPR2015-01836
`
`
`
`WO 2004/110368
`
`PCT/US2004/017090
`
`a FAS inln"bitor,
`
`a PDE inhibitor,
`a thyroid hormone p agonist,
`an UCP-1, 2, or 3 activator,
`an acyl-estrogen,
`
`a glucocorticoid antagonist,
`an 1113 HSD-1 inhibitor,
`a SCD-1 inhibitor,
`a DPIV inhibitor,
`a lipase inhibitor,
`
`(33)
`
`(34)
`
`(35)
`(36)
`
`(37)
`
`(38)
`(39)
`
`(40)
`(41)
`(42)
`(43)
`
`(44)
`(45)
`
`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:
`
`(1)
`(2)
`
`(3)
`(4)
`
`(5)
`
`(6)
`(7)
`(8)
`
`(9)
`(10)
`
`(11)
`
`(12)
`(13)
`(14)
`(15)
`
`(16)
`
`(17)
`
`(18)
`
`(19)
`
`a 5Hf transporter inhibitor;
`a NB transporter inhibitor;
`a CB-I antagonist/inverse agonist;
`a ghrelin antagonist;
`a ID antagonisifmverse agonist;
`a MOllR antagonist;
`a MCH2R agonist/antagonist;
`a ~YI antagonist;
`a NPYS antagonist;
`an.opioid antagonist;
`
`an orexin antagonist;
`a BRS3 agonist;
`a CCK-A agonist;
`. aCNTF;
`a CNTF derivative;
`a GHS agonist;
`5Hf2c agonist;
`a Mc3r agonist;
`a Mc4r agonist;
`
`-9-
`
`5
`
`IO
`
`I5
`
`20
`
`25
`
`30
`
`35
`
`10 of 99
`
`PENN EX. 2243
`CFAD V. UPENN
`IPR2015-01836
`
`
`
`WO 2004/110368
`
`PCTIUS2004/017090
`
`(27)
`
`(20)
`(21)
`(22)
`(23)
`(24)
`(25)
`(26)
`
`a monoamine reuptake inhibitor;
`a serotonin reuptake inhibitor;
`a GLP-1 agonist.
`topiramate;
`phytophann compound 57;
`an ACO. inhibitor;
`a P3 agonist;
`a DGATl inhibitor;
`a DGAT2 inhibitor;
`(28)
`(29)
`a FAS inhibitor;
`(30)
`a PDE Inhibitor;
`a thyroid hormone p agonist;
`(31)
`an UCP-1. 2. or 3 activator;
`(32)
`(33)
`an acyl~strogen;
`a glucocorticoid antagonist;
`(34)
`(35)
`an 11~ HSD-1 inhibitor;
`(36)
`a SCD-1 inhibitor;
`a DPIV inhibitor.
`(37)
`(38)
`a lipase inhibitor;
`(39)
`a fatty acid transporter inhibitor;
`a dicarboxylate transporter inhibitor; and
`(40)
`a glucose transporter inhibitor;
`(41)
`and pharmaceutically acceptable salts and esters thereof.
`In a class of this embodiment, the anti-obesity agent is a CB-1 antagonistrmverse agonist. and
`pharmaceutically acceptable salts or esters thereof. In a subclass of this class. the CB-1
`antagonist/inverse agonist is selected from rimonabant, and pharmaceutically acceptable salts or esters
`thereof.
`In another class of this embodiment. the anti-obesity agent is an opioid antagonist. and
`pharmaceutically acceptable salts or esters thereof. In a subclass of this ~lass. the opioid antagonist is
`selected from nalmefene, and pharmaceutically acceptable salts or esters thereof.
`In another class of this embodiment, the anti-obesity agent is a CNTF derivative, and
`pharmaceutically acceptable salts or esters thereof. In subclass of this class, the CNTF derivative is
`selected from axokine, and pharmaceutically acceptable salts or esters thereof.
`In another class of this embodiment. the anti-obesity agent is a monoamine reuptake inhibitor.
`and pharmaceutically acceptable salts or esters thereof. In a subclass of this class, the monoamine
`reuptake inhibitor is selected from sibutramine. and pharmaceutically acceptable salts and esters thereof.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`-10-
`
`11 of 99
`
`PENN EX. 2243
`CFAD V. UPENN
`IPR2015-01836
`
`
`
`WO 2004/110368
`
`PCT/US2004/017090
`
`In another class of this embodiment, the anti-obesity agent is an acyl-estrogen. and
`pharmaceutically acceptable salts or esters thereof. In a subclass of this class, the acyl~trogen. is
`selected from oleoyl-estrone, and pharmaceutically acceptable salts or esters thereof.
`In a class of this embodiment. the anti-obesity agent is a lipase inhibitor, and pharmaceutically
`acceptable salts or esters thereof. In a su9class of this embodiment. the lipase inhibitor is orlistat, .and the
`pharmaceutically acceptable salts thereof.
`In another class of this embodiment, the anti-obesity agent is a NPY2 agonist, and
`pharmaceutically acceptable salts or esters thereof. In a subclass of this class, the NPY2 agooist is
`selected from the group consisting of peptide YY (PYY), and PYY 3-36. and pbannaceutlcally
`acceptable salts thereof. In another subclass of this class. the NPY2 agonist is PYY 3-36. and :
`
`pharmaceutically acceptable salts thereof:
`In another class of this embodiment, the anti-obesity agent is a NPYS antagonist. and
`pharmaceutically acceptable salts or esters thereof.
`In a subclass of this class. the NPYS antagonists useful in the present invention are represented
`by the compounds of structural Formula I:
`
`S
`
`10
`
`15
`
`(I)
`
`and pharmaceutically acceptable salts and esters thereof. wherein
`Ar 1 is selected from the group consisting of:
`(1)
`aryl, and
`heteroaryl,
`(2)
`wherein the aryl and heteroaryl groups are unsubstituted or optionally substituted with a substituent
`selected from the group consisting of:
`halogen,
`(a)
`nitro,
`{b)
`
`(c)
`(d)
`
`(e)
`(Q
`
`(g)
`
`lower alkyl,
`halo(lower)alkyl,
`
`hydroxy(lower)alky