B6
`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll 111111111111111111111111111111111
`
`( 43) International Publication Date
`13 March 2008 (13.03.2008)
`
`(51) International Patent Classification:
`A61K 311397 (2006.01)
`A61P 9110 (2006.01)
`A61K 3117012 (2006.01)
`A61P 3100 (2006.01)
`A61P 3106 (2006.01)
`A61P 1116 (2006.01)
`
`PCT
`
`(10) International Publication Number
`WO 2008/030382 Al
`(81) Designated States (unless otheiwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH,
`CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG,
`ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL,
`IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK,
`LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW,
`MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL,
`PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY,
`TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA,
`ZM, ZW.
`
`(84) Designated States (unless otheiwise indicated, for every
`kind of regional protection available): ARIPO (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),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, MT, NL, PL,
`PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM,
`GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Declaration under Rule 4.17:
`as to the applicant's entitlement to claim the priority of the
`earlier application (Rule 4.17(iii))
`
`Published:
`with international search report
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`(21) International Application Number:
`PCT/US2007 /019065
`
`(22) International Filing Date: 29 August 2007 (29.08.2007)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/842,211
`
`5 September 2006 (05.09.2006) US
`
`(71) Applicant (for all desig1U1ted States except US): SCHER(cid:173)
`ING CORPORATION [US/US]; 2000 Galloping Hill
`Road, Kenilworth, New Jersey 07033 (US).
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): VELTRI, Enrico, P.
`[US/US]; 6 Toftrees Court, Princeton, New Jersey 08540
`(US).
`
`(74) Agents: RUSSELL, Mark W. et al.; Schering Cororation,
`2000 Galloping Hill Road, Patent Dept. K-6-1 1990, Ke(cid:173)
`nilworth, New Jersey 07033 (US).
`
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`g (54) Title: PHARMACEUTICAL COMBINATIONS FOR LIPID MANAGEMENT AND IN THE TREATMENT OF ATHERO(cid:173)
`
`QO ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
`
`f'l SCLEROSIS AND HEPATIC STEATOSIS
`~ (57) Abstract: A pharmaceutical combination comprising an effective amount of at least one cholesterol absorption inhibitor and
`
`~ at least one microsomal triglyceride transfer protein inhibitor (MTP).
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`PHARMACEUTICAL COMBINATIONS FOR LIPID MANAGEMENT AND IN THE
`
`TREATMENT OF ATHEROSCLEROSIS AND HEPATIC STEATOSIS
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`5
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`RELATED APPLICATIONS
`This application claims priority to provisional application USSN 60/842,211,
`filed on September 5, 2006, herein incorporated by reference.
`
`FIELD OF THE INVENTION
`The present invention relates to pharmaceutical combinations which are used in lipid
`10 management of a mammal, such as a human, and in the treatment of atherosclerosis
`and hepatic steatosis by administering an effective amount of the pharmaceutical
`combination. The pharmaceutical combinations comprise at least one cholesterol
`absorption inhibitor (CAI) and a microsomal triglyceride transfer protein (MTP)
`inhibitor.
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`BACKGROUND OF THE INVENTION
`Vascular disease is a term which broadly encompasses all disorders of blood
`vessels including small and large arteries and veins and blood flow. The most
`prevalent form of vascular disease is arteriosclerosis, a condition associated with the
`thickening and hardening of the arterial wall. Arteriosclerosis of the large vessels is
`referred to as atherosclerosis. Atherosclerosis is the predominant underlying factor in
`vascular disorders such as coronary artery disease, aortic aneurysm, arterial disease
`of the lower extremities and cerebrovascular disease.
`One major risk factor for arteriosclerosis is high serum cholesterol. A total
`cholesterol level in excess of 225-250 mg/di is associated with significant elevation of
`risk of vascular disease, particularly coronary heart disease.
`Chotesteryl esters are a major component of atherosclerotic lesions and the
`major storage form of cholesterol in arterial wall cells. Formation of cholesteryl esters
`is also a step in the intestinal absorption of dietary cholesterol. Thus, inhibition of
`
`cholesteryl ester formation and reduction of serum cholesterol can inhibit the
`progression of atherosclerotic lesion formation, decrease the accumulation of
`cholesteryl esters in the arterial wall, and block the intestinal absorption of dietary
`cholesterol.
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`The regulation of who•e-body cholesterol homeostasis in mammals and
`animals involves the regulation of dietary cholesterol and modulation of cholesterol
`biosynthesis, bile acid biosynthesis and the catabolism of the cholesterol-containing
`plasma lipoproteins. The liver is the major organ responsible for cholesterol
`biosynthesis and catabolism and, for this reason, it is a prime determinant of plasma
`cholesterol levels. The liver is the site of synthesis and secretion of very low density
`lipoproteins (VLDL) which are subsequently metabolized to low density tipoproteins
`(LDL) in the circulation. LDL are the predominant cholesterol-carrying lipoproteins in
`the plasma and an increase in their concentration is correlated with increased
`atherosclerosis. When intestinal cholesterol absorption is reduced, by whatever
`means, less cholesterol is delivered to the liver. The consequence of this action is
`decreased hepatic lipoprotein (VLDL) production and an increase in the hepatic
`clearance of plasma cholesterol, mostly as LDL. Thus, the net effect of inhibiting
`intestinal cholesterol absorption is a decrease in plasma cholesterol levels.
`U.S. Patents Nos. 5,846,966 and 5,661,145, respectively, disclose treatments
`for inhibiting atherosclerosis and reducing plasma cholesterol levels using such
`
`hydroxy-substituted azetidinone compounds or substituted 13-lactam compounds in
`combination with HMG-CoA reductase inhibitor compounds, which act by blocking
`hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase (the rate-limiting enzyme in
`hepatic cholesterol synthesis). HMG-CoA reductase inhibitors. e.g., statins such as
`lovastatin, simvastatin, and pravastatin, slow the progression of atherosclerotic lesions
`in the coronary and carotid arteries. Simvastatin and pravastatin have also been
`shown to reduce the risk of coronary heart disease events in patients with
`hypercholesterolemia and/or atherosclerotic coronary heart disease (CHO).
`Simvastatin is marketed worldwide, and sold in the U.S. under the tradename
`ZOCOR®. Methods for making it are described in U.S Patent Nos. 4,444,784;
`4,916,239; 4,820,850; among other patent and literature publications.
`U.S. Patent No. 5,698,527 discloses ergostanone derivatives substituted with
`disaccharides as cholesterol absorption inhibitors, employed alone or in combination
`with certain other cholesterol lowering agents, which are useful in the treatment of
`hypercholesterolemia and related disorders.
`Other vascular conditions frequently coexist with cholesterol levels associated
`with atherosclerosis. These may include hypertension, angina and/or arrhythmia.
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`The relevance of, for example, elevated blood pressure as a risk factor for
`atherosclerosis, cardiovascular and cerebrovascular disease in both men and women
`has been clarified in a large number of epidemiological studies.
`Clinical trials of blood pressure lowering using cardiovascular agents including,
`for example, calcium channel blockers, have shown beneficial effects in the treatment
`of early atherosclerotic lesions (see, e.g., Lichtien, P.R. et al. :Lancet, 335: 1109-1113
`(1990) and Waters, D. et al. Circulation 82: 1940-1953 (1990)). Scott (PCT patent
`Application No. WO 99/11260) describes combinations of an HMG CoA reductase
`inhibitor with an antihypertensive agent for the treatment of atherosclerosis and other
`symptoms of vascular disease risk. Additionally, Egon et al. (PCT Patent Application
`No. WO 96/40255) describe a combination therapy of antihypertensive agents
`including eplerenone and angiotensin II antagonist for treating cardiovascular disease.
`In vitro MTP catalyzes the transport of lipid molecules between phospholipid
`membranes. See, U.S. 6,472,414 B1. In vivo it has been reported that MTP mediates
`trigyceride absorption and chylomicron secretion from the intestine and VLDL
`secretion from the liver, by linking lipid molecules with apolipoprotein B (ApoB). (See,
`abstract of S. Williams & J.D. Best, Expert Opinion on Therapeutic Patents (April
`2003, vol.13, no. 4, pp. 470-488),www.expertopin.com/doi/abs/10.1517
`/13543776.13.4.479 ?cookieSet+1&journalCode). It follows that inhibition of MTP
`could reduce the level of all ApoB-contining proteins, including LDL. Drugs that inhibit
`MTP, therefore, potentially could be effective in reducing atherosclerotic vascular
`disease by lowering all levels of atherogenic lipoproteins. One commentator has
`suggested that while partial inhibition of MTP by an inhibitor could be useful when
`combined with other drugs that alter lipid metabolism, marked inhibition of MTO could
`cause significant adverse effects (Williams & Best).
`Substances that inhibit MTP are well known in the art. See US 2006/0166999
`A1 and US 6,472,414 B2, both herein incorportated by reference, which cites to EP
`705 831, EP 779 279, EP 779 276, EP 802 198 and EP 799 828, also incorporated by
`reference. Zaiss et al., Circulation, 100 (18 Suppl. I): 255 Abst. 13423 (1999) reports
`that implitiapide, a MTP inhibitor, prevents the formation of atherosclerotic plaques in
`mice.
`
`WO 2005/087234A1, incorporated by reference, discloses method and
`compositions for treating hyprlipidemia and/or hypercholesterolemia that comprise
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`administering to the subject and effective amount of an MTP inhibitor, wherein said
`administration comprises at least three step-wise, increasing dosages of the MTP
`inhibitor, the MTP inhibitor may be combined with a further lipid modifying compound,
`such as a HMG Co-A reductase inhibitor or ezetimibe.
`WO 00/38725 A 1, incorporated by reference, discloses cardiovascular
`therapeutic combinations including an ileal bile acid transport inhibitor or cholesteryl
`ester transport protein inhibitor in combination with a fibric acid derivative, nicotinic
`acid derivative, microsomal triglyceride transfer protein inhibitor, cholesterol
`absorption antagonist, phytosterol, stanol, antihypertensive agent or bile acid
`sequestrant.
`Despite recent improvements in the management of lipid levels in mammals,
`such as humans, as well as for the treatment for atherosclerosis, hyperlipidemia,
`lyperlipenia, hypertriglyceridemia, other vascular diseases and hepatic steatosis, there
`remains a need in the art for improved compositions and treatments these disease
`states.
`
`SUMMARY OF THE INVENTION
`The present invention provides for pharmaceutical combinations comprising at
`least one cholesterol absorption inhibitor, e.g., a sterol absorption inhibitor or a 5-a-
`stanol absorption inhibitor, and at least one microsomal triglyceride transfer protein
`inhibitor.
`The present invention also provides for a method for lipid management in a
`mammal in need thereof which comprises administering an effective amount of a
`pharmaceutical combination comprising at least one cholesterol absorption inhibitor,
`e.g., a sterol absorption inhibitor or a 5-a-stanol absorption inhibitor, and at least one
`microsomal triglyceride transfer protein inhibitor.
`An alternative embodiment of the present invention also provides for a method
`for the treatment, prevention or ameliorating the symptoms atherosclerosis in a
`mammal in need thereof by administering an effective amount of a composition
`comprising at least one cholesterol absorption inhibitor, e.g., a sterol absorption
`inhibitor, a 5-a-stanol absorption inhibitor, and at least one microsomal triglyceride
`transfer protein inhibitor.
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`Another embodiment of this invention provides for the mitigation, prevention or
`amelioration the symptoms or development of hepatic steatosis in a mammal in need
`thereof by administering at least one cholesterol absorption inhibitor, e.g., a sterol
`absorption inhibitor or a 5-a-stanol absorption inhibitor. and at least one microsomal
`triglyceride transfer protein inhibitor.
`Another embodiment of the present invention also provides for a method for
`lipid management in a mammal in need thereof which comprises administering an
`effective amount of a pharmaceutical combination comprising at least one cholesterol
`absorption inhibitor, e.g., a sterol absorption inhibitor or a 5-a-stanol absorption
`inhibitor, at least one microsomal triglyceride transfer protein inhibitor and at least one
`cholesterol lowering agent, e.g., a HMG-CoA reductase inhibitor.
`A further embodiment of the present invention provides for a method for the
`treatment, prevention or ameliorating the symptoms atherosclerosis in a mammal in
`need thereof by administering an effective amount of a composition comprising at
`least one cholesterol absorption inhibitor, e.g., a sterol absorption inhibitor, or a 5-a(cid:173)
`stanol absorption inhibitor, at least one microsomal triglyceride transfer protein
`inhibitor and at least one cholesterol lowering agent, e.g., a HMG-CoA reductase
`inhibitor.
`Another embodiment of this invention provides for the mitigation, prevention or
`amelioration the symptoms or development of hepatic steatosis in a mammal in need
`thereof by administering at least one cholesterol absorption inhibitor, e.g., a sterol
`absorption inhibitor or a 5-a-stanol absorption inhibitor, at least one microsomal
`triglyceride transfer protein inhibitor, and at least one cholesterol lowering agent, e.g.,
`a HMG-CoA reductase inhibitor.
`The present invention also relates to a kit for lipid management in a mammal or
`for the treatment, prevention or amelioration of the symptoms of atherosclerosis or
`hepatic steatosis which comprises at least one cholesterol absorption inhibitor and at
`least one microsomal triglyceride transfer protein inhibitor in separate form.
`
`DETAILED DESCRIPTION
`The terms used herein have their ordinary meaning and the meaning of such
`terms is independent at each occurrence thereof. That notwithstanding and except
`where stated otherwise, the following definitions apply throughout the specification
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`and claims: Chemical names, common names and chemical structures may be used
`interchangeably to describe that same structure. These definitions apply regardless of
`whether a term is used by itself or in combination with other terms, unless otherwise
`indicated. Hence, the definition of "alkyl" applies to "alkyl'' as well as the "alkyl" protion
`of "hydroxyalkyl", "haloalkyl", "alkoxy" etc.
`As used above, and throughout the specification, the following terms, unless
`otherwise indicated, shall be understood to have the following meanings:
`"Patient" includes both human and animals.
`"Mammal" means humans and other mammalian animals.
`"Alkyl• means an aliphatic hydrocarbon group which may be straight or
`branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred
`alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred
`alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means
`that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a
`linear alkyl chain. aLower alkyl" means a group having about 1 to about 6 carbon
`atoms in the chain which may be straight or branched. Non-limiting examples of
`suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n(cid:173)
`pentyl, heptyl, nonyl and decyl. R32-substituted alkyl groups include fluoromethyl,
`trifluoromethyl and cyclopropylmethyl .
`"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-
`carbon double bond and which may be straight or branched and comprising about 2 to
`about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about
`12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in
`the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl
`or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to
`about 6 carbon atoms in the chain which may be straight or branched. Non-limiting
`examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-
`2-enyl, n-pentenyl, octenyl and decenyl.
`"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-
`carbon triple bond and which may be straight or branched and comprising about 2 to
`about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about
`12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in
`the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl
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`or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to
`about 6 carbon atoms in the chain which may be straight or branched. Non-limiting
`examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl, 3-
`methylbutynyl, n-pentynyl, and decynyl.
`"Aryl" means an aromatic monocyclic or multicyclic ring system comprising
`about 6 to about 14 carbon atoms, preferably about 6 to about 1 O carbon atoms. The
`aryl group can be optionally substituted with one or more substituents , which may be
`the same or different, and are as defined herein or two substituents on adjacent
`'z;O
`yO
`
`· ~-c£ or _sJ' ... o). Non-limiting
`
`~J
`carbons can be linked together to form ~
`examples of suitable aryl groups include phenyl and naphthyl.
`"Heteroaryl" means an aromatic monocyclic or multicyclic ring system
`comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms,
`in which one to four of the ring atoms is an element other than carbon, for example
`nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain
`about 5 to r;1bout 6 ring atoms. The "heteroaryl'' can be optionally substituted by one or
`more substituents, which may be the same or different, and are as defined herein.
`The prefix aza, oxa or thia before the heteroaryl root name means that at least a
`nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen
`atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-
`limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl,
`pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl,
`pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,
`imidazo[1,2-a]pyridinyl, imidazo[2, 1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl,
`benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl,
`thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-
`triazinyl, benzothiazolyl and the like.
`"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising
`about 3 to about 1 O carbon atoms, preferably about 5 to about 10 carbon atoms.
`Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be
`optionally substituted with one or more substituents which may be the same or
`different, and are as defined above. Non-limiting examples of suitable monocyctic
`cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-
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`limiting examples of suitable multicyclic cycloalkyls include 1-decalin, norbornyl,
`adamantyl and the like. Further non-limiting examples of cycloalkyl include the
`following:
`
`and
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`.. Cycloalkylether" means a non-aromatic ring of 3 to 7 members comprising an
`oxygen atom and 2 to 7 carbon atoms. Ring carbon atoms can be substituted,
`provided that substituents adjacent to the ring oxygen do not include halo or
`substituents joined to the ring through an oxygen, nitrogen or sulfur atom.
`"Cycloalkenyl" means a non-aromatic mono or multicyclic ring system
`comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon
`atoms which contains at least one carbon-carbon double bond. The cycloalkenyl ring
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`can be optionally substituted with one or more substituents which may be the same or
`different, and are as defined above. Preferred cycloalkenyl rings contain about 5 to
`about 7 ring atoms. Non-limiting examples of suitable monocyclic cycloalkenyls
`include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. Non-limiting example
`of a suitable multicyclic cycloalkenyl is norbornylenyl.
`uHeterocyclenyl 0 (or "heterocycloalkeneyl") means a non-aromatic monocyclic
`or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about
`5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an
`element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in
`combination, and which contains at least one carbon-carbon double bond or carbon(cid:173)
`nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in
`the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.
`The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a
`nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The
`heterocyclenyl can be optionally substituted by one or more substituents. The nitrogen
`or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N(cid:173)
`oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic
`azaheterocyclenyl groups include 1,2,3,4- tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-
`dihydropyridyl, 1,2,3,6-tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidyl, 2-pyrrolinyl, 3-
`pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Non-limiting examples of suitable
`oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl,
`fluorodihydrofuranyl, and the like. Non-limiting example of a suitable multicyclic
`oxaheterocyclenyl group is 7-oxabicyclo[2.2. 1 ]heptenyl. Non-limiting examples of
`suitable monocyclic thiaheterocyclenyl rings include dihydrothiophenyl,
`dihydrothiopyranyl, and the like.
`"Halo" means fluoro, chloro, bromo, or iodo groups. Preferred are fluoro, chloro
`or bromo, and more preferred are fluoro and chloro.
`"Haloalkyl" means an alkyl as defined above wherein one or more hydrogen
`atoms on the alkyl is replaced by a halo group defined above.
`"Heterocyclylu (or heterocycloalkyl) means a non-aromatic saturated
`monocyclic or multicyclic ring system comprising about 3 to about 1 O ring atoms,
`preferably about 5 to about 10 ring atoms, in which 1-3, preferably 1 or 2 of the atoms
`in the ring system is an element other than carbon, for example nitrogen, oxygen or
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`sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms
`present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring
`atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at
`least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The
`heterocyclyl can be optionally substituted by one or more which may be the same or
`different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl
`can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non(cid:173)
`limiting examples of suitable monocyclic heterocyclyl rings include piperidyl,
`pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1 ,4-
`dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
`"Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as
`previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting
`examples of suitable aralkyl groups include benzyl, 2-phenethyl and
`naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
`"Arylcycloalkyl" means a group derived from a fused aryl and cycloalkyl as
`defined herein. Preferred arylcycloalkyls are those wherein aryl is phenyl and
`cycloalkyl consists of about 5 to about 6 ring atoms. The ary1cycloalkyl can be
`optionally substituted by one or more substituents. Non-limiting examples of suitable
`arylcycloalkyls include indanyl and 1,2,3,4-tetrahydronaphthyl and the like. The bond
`to the parent moiety is through a non-aromatic carbon atom.
`"Arylheterocycloalkyl'' means a group derived from a fused aryl and
`heterocycloalkyl as defined herein. Preferred arylcycloalkyls are those wherein aryl is
`phenyl and heterocycloalkyl consists of about 5 to about 6 ring atoms. The
`arylheterocycloalkyl can be optionally substituted by one or more substituents. Non-
`limiting examples of suitable arylheterocycloalkyls include
`
`s
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`The bond to the parent moiety is through a non-aromatic carbon atom.
`"Acyl" means an organic group in which the -OH of the carboxyl group is
`replaced by some other substituent. Suitable non-limiting examples include H-C(O)-,
`alkyl-C(O)-, alkenyl-C{O)-, alkynyl-C(O)-, aryl-C{O)- or cycloalkyl-C{O)- group in which
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`1s
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`the various groups are as previously described. The bond to the parent moiety is
`through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of
`suitable acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl
`and cyclohexanoyl.
`"Alkoxy" means an alkyl-0- group in which the alkyl group is as previously
`described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy,
`n-propoxy, isopropoxy, n-butoxy and heptoxy. The bond to the parent moiety is
`through the ether oxygen.
`"Alkyoxyalkyl" means a group derived from an alkoxy and alkyl as defined
`herein. The bond to the parent moiety is through the alkyl.
`"Arylalkenyl" means a group derived from an aryl and alkenyl as defined herein.
`Preferred arylalkenyls are those wherein aryl is phenyl and the alkenyl consists of
`about 3 to about 6 atoms. The arylatkenyl can be optionally substituted by one or
`more substituents. The bond to the parent moiety is through a non-aromatic carbon
`atom.
`
`"Arylalkynyl" means a group derived from a aryl and alkenyl as defined herein.
`Preferred arylalkynyls are those wherein aryl is phenyl and the alkynyl consists of
`about 3 to about 6 atoms. The arylalkynyl can be optionally substituted by one or more
`substituents. The bond to the parent moiety is through a non-aromatic carbon atom.
`The suffix "ene" on alkyl, aryl, hetercycloalkyl, etc. indicates a divalent moiety,
`e.g., -CH2CH2- is ethylene, and ~-0-~ is para-phenylene.
`The term "optionally substituted" means optional substitution with the specified
`groups, radicals or moieties, in available position or positions.
`Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or
`heteroarylalkyl moiety includes substitution on the ring portion and/or on the alkyl
`portion of the group.
`When a variable appears more than once in a group, or a variable appears
`more than once in the structure of a formula, the variables can be the same or
`different.
`With reference to the number of moieties (e.g., substituents, groups or rings) in
`a compound, unless otherwise defined, the phrases "one or more" and "at least one"
`mean that there can be as many moieties as chemically permitted, and the
`determination of the maximum number of such moieties is well within the knowledge
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`of those skilled in the art. With respect to the compositions and methods comprising
`the use of the phrase "at least one" in a phrase such as "at least one cholesterol
`absorption inhibitor" or "at least one microsomal triglyceride transfer protein inhibitor"
`means one to three cholesterol absorption inhibitors and independently one to three
`microsomal triglyceride protein inhibitors can be administered at the same time. with
`preference to one of each.
`As used herein, the term "composition" is intended to encompass a product
`comprising the specified ingredients in the specified amounts. as well as any product
`which results, directly or indirectly. from combination of the specified ingredients in the
`specified amounts.
`The wavy line l'\.J'\JV'V as a bond generally indicates a mixture of, or either of, the
`possible isomers, e.g., containing (R)- and (S)- stereochemistry. For example,
`~OH
`~OH o··'OH
`l. .. )
`means containing both l. .. )
`and
`N
`N
`N
`H
`H
`H
`Lines drawn into the ring systems, such as, for example:
`
`indicate that the indicated line (bond) may be attached to any of the substitutable ring
`carbon atoms.
`It is noted that the carbon atoms for formula I may be replaced with 1 to 3
`silicon atoms so long as all valency requirements are satisfied.
`It should also be noted that any heteroatom with unsatisfied valences in the text
`or structural formulae herein is assumed to have the hydrogen atom or atoms to
`satisfy the valences.
`Those skilled in the art will recognize that certain compounds in the structural
`formulae disclosed herein are tautomeric and all such tautomeric forms are
`contemplated herein as part of the present invention.
`As used herein, the term "cholesterol absorption inhibitor" means any agent
`capable of capable of inhibiting the absorption of one or more sterols, including but not
`limited to cholesterol, phytosterols (such as sitosterol, campesterol, stigmasterol and
`
`avenosterol), 5a.-stanols (such as cholestanol, 5a.-campestanol, 5a.-sitostanol), and/or
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`mixtures thereof, when administered in a therapeutically effective (sterol and/or Sa.-
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`stanol absorption inhibiting) amount to a mammal or human. Non-limiting examples of
`cholesterol absorption inhibitors include, for example, sterol absorption inhibitors, or 5-
`a-stanol absorption inhibitors. "Lipid lowering agents" lower the cholesterol level in a
`mammal, such as a human, by not interfering with the absortion of one or more sterols
`in the mammal. Non-limiting examples of compounds that act as lipid lowering agents
`include HMG-CoA reductase inhibitors, nicotinic acid and/or nicotinic acid receptor
`agonists, agonists or activators of peroxisome proliferators-activated receptors
`(PPAR) etc. "Microsomal triglyceride transfer protein inhibitors" are any agent that is
`capable of inhibiting MTP.