US 20070 155676A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0155676 A1 Burnett et al. (43) Pub. Date: Jul. 5, 2007

(54) SUBSTITUTED AZETIONONE (60) Provisional application No. 60/452,725, filed on Mar. COMPOUNDS, PROCESSES FOR 7, 2003. PREPARING THE SAME, FORMULATIONS AND USES THEREOF Publication Classification (75) Inventors: Duane A. Burnett, Bernardsville, NJ (51) Int. Cl. (US); John W. Clader, Cranford, NJ A61K 3 1/7052 (2006.01) (US) A6II 3 L/506 (2006.01) A61K 31/4709 (2006.01) Correspondence Address: A61K 31/4025 (2006.01) SCHERING-PLOUGH CORPORATION A61K 31/4439 (2006.01) PATENT DEPARTMENT (K-6-1, 1990) A 6LX 3L/397 (2006.01) 2000 GALLOPNG HILL ROAD C07D 405/14 (2006.01) KENILWORTH, NJ 07033-0530 (US) C07D 405/02 (2006.01) (52) U.S. Cl...... 514/23: 514/210.02:536/17.3; (73) Assignee: Schering Corporation, Kenilworth, NJ 54O72OO (21) Appl. No.: 11/708,449 (57) ABSTRACT Filed: Feb. 20, 2007 The present invention provides substituted azetidinone com (22) pounds, formulations and processes for preparing the same Related U.S. Application Data which can be useful for treating vascular conditions such as atherosclerosis or hypercholesterolemia, diabetes, obesity, (62) Division of application No. 10/792.346, filed on Mar. stroke, demyelination and lowering plasma levels of sterols 3, 2004, now Pat. No. 7,208,486. and/or stanols in a subject. US 2007/O 155676 A1 Jul. 5, 2007

SUBSTITUTED AZETIDINONE COMPOUNDS, 0006 U.S. Pat. Nos. 5,846,966 and 5,661,145, respec PROCESSES FOR PREPARING THE SAME, tively, disclose treatments for inhibiting atherosclerosis and FORMULATIONS AND USES THEREOF reducing plasma cholesterol levels using Such hydroxy Substituted aZetidinone compounds or Substituted B-lactam CROSS-REFERENCE TO RELATED compounds in combination with HMG CoA reductase APPLICATION inhibitor compounds, which act by blocking hydroxymeth 0001. This application claims the benefit of priority from ylglutaryl coenzyme A (HMG-CoA) reductase (the rate U.S. Provisional Patent Application Ser. No. 60/452,725, limiting enzyme in hepatic cholesterol synthesis). filed Mar. 7, 2003, incorporated herein by reference. 0007. Despite recent improvements in the treatment of vascular disease, there remains a need for improved com BACKGROUND OF THE INVENTION pounds, compositions and treatments for hyperlipidaemia, atherosclerosis and other vascular conditions that provide Field of the Invention more efficient delivery of treatment. 0002 The present invention relates to substituted azeti dinone compounds useful for treating vascular and lipidemic SUMMARY OF THE INVENTION conditions, and formulations and processes related thereto. 0008. In one embodiment, the present invention provides 0003 Atherosclerotic coronary heart disease (CHD) rep a compound represented by the structural formula (I): resents the major cause for death and vascular morbidity in the western world. Risk factors for atherosclerotic coronary heart disease include hypertension, diabetes mellitus, family (I) history, male gender, cigarette Smoke and high serum cho Q lesterol. A total cholesterol level in excess of 225-250 mg/dl is associated with significant elevation of risk of CHD. The newly revised NCEP ATP III low density lipoprotein (LDL p f 1 C) goal for patients with CHD or CHD risk equivalent is N X---Y--z, N <100 mg/dL (2.59 mmol/L), for individuals with two or %21 R2 R3 more risk factors is <130 mg/dL (3.37 mmol/L) and for Q5 N individuals with fewer than two risk factors is <160 mg/dL O N (4.14 mmol/L). 2HQ' 0004 The regulation of whole-body cholesterol homeo Stasis in mammals and animals involves the regulation of dietary cholesterol and modulation of cholesterol biosynthe or pharmaceutically acceptable isomers, salts, Solvates or sis, bile acid biosynthesis and the catabolism of the choles terol-containing plasma lipoproteins. The liver is the major esters of the compound of Formula (I), organ responsible for cholesterol biosynthesis and catabo wherein in Formula (I) above: lism and, for this reason, it is a prime determinant of plasma cholesterol levels. The liver is the site of synthesis and 0009 X, Y and Z can be the same or different and each secretion of very low density lipoproteins (VLDL) which are is independently selected from the group consisting of subsequently metabolized to low density lipoproteins (LDL) —CH2—, —CH(alkyl)- and —C(alkyl) ; in the circulation. LDL are the predominant cholesterol 0010 Q' and Q can be the same or different and each is carrying lipoproteins in the plasma and an increase in their independently selected from the group consisting of H, concentration is correlated with increased atherosclerosis. —(C-Cso alkylene)-G, OR, OC(O)R, When intestinal cholesterol absorption is reduced, by what OC(O)OR OC(O)NR'R'', and -L-M. ever means, less cholesterol is delivered to the liver. The 0011 Q is 1 to 5 substituents independently selected consequence of this action is decreased hepatic lipoprotein from the group consisting of alkyl, alkenyl, alkynyl, -(C- (VLDL) production and an increase in the hepatic clearance Coalkylene)-G, —(Co-Cio alkylene)-OR,-(Co-Cio alky of plasma cholesterol, mostly as LDL. Thus, the net effect of lene)-C(O)R. —(Co-Cio alkylene)-C(O)OR, —(Co-Co inhibiting intestinal cholesterol absorption is a decrease in alkylene)-OC(O)R. —(Co-Co alkylene)-OC(O)CR, plasma cholesterol levels and progression of atherosclerotic CH=CH-C(O)R, CH=CH-C(O)OR, C=C lesion formation. C(O)OR, C=C C(O)R, O (C-C alkylene)-OR, 0005 U.S. Pat. Nos. 5,767,115, 5,624,920, 5,668,990, -O-(C-Clo alkylene)-C(O)R. -O-(C-Clo alkylene)- 5,656,624 and 5,688.787, respectively, disclose hydroxy C(O)OR, CN, O (C-C alkylene)-C(O)NR'R'', Substituted aZetidinone compounds and Substituted B-lactam -O-(C-Co alkylene)-C(O)NRNR7C(O)OR, compounds useful for lowering cholesterol and/or in inhib -O-(C-Co alkylene)-C(O)(aryl)-N-N=N, iting the formation of cholesterol-containing lesions in —OC(O) (C-C alkylene)-C(O)OR, —(Co-Co alky mammalian arterial walls. U.S. Pat. No. 5,756,470, U.S. lene)-C(O)NR'R', —(Co-Co alkylene)-OC(O)NR'R''. Patent Application No. 2002/0137690, U.S. Patent Applica —NO. —(Co-Cio alkylene)-NR'R''. -O-(C-Clo alky tion No. 2002/0137689 and PCT Patent Application No. WO lene)-NRR7, NRC(O)R7, NRC(O)OR, 2002/066464 disclose sugar-substituted azetidinones and NRC(O)NR'R'', NRS(O) R, N(S(O),R), substituted aZetidinones useful for preventing or CHNOR, C(O)NR'R7, C(O)NRNRR7, S(O). treating atherosclerosis and reducing plasma cholesterol 2NR'R'', S(O).R. —O C(O)—(C-Clo alkylene)- levels. C(O)NR'R'', OC(O)–(C-C alkylene)-NRC(O)O-

US 2007/O 155676 A1 Jul. 5, 2007

p peptides in a Subject comprising a therapeutically effective -continued amount of the above compounds and a pharmaceutically (M9) acceptable carrier also are provided. 0038 Methods of treating or preventing a vascular con dition, diabetes, obesity, stroke, lowering a concentration of a sterol or stanol in plasma of a mammal, preventing demyelination or treating Alzheimer's disease and/or regu lating levels of amyloid p peptides in a Subject comprising the step of administering to a subject in need of Such treatment an effective amount of the above compounds of Formula (I) also are provided. 0039) Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” pharmaceutically acceptable salts of the moieties (M1) to (M9) and free acids of the moieties (M1) to (M9); DETAILED DESCRIPTION 0018) R, R can be the same or different and each is 0040. In its many embodiments, the present invention independently selected from the group consisting of hydro provides a novel class of compounds of Formula (I) above, gen, alkyl and aryl; processes for producing Such compounds, pharmaceutical 0019 R. R7 and R can be the same or different and each formulations or compositions comprising one or more of is independently selected from the group consisting of Such compounds, methods of preparing the same, and meth hydrogen, alkyl, aryl and arylalkyl, and ods of treatment, prevention, inhibition or amelioration of one or more conditions or diseases associated with vascular 0020 each R is independently alkyl, aryl or arylalkyl. conditions or other conditions such as are discussed in detail 0021 each R" is independentlyp y H or alkyl:y below. 0022) q is 0 or 1: 0041. The compounds of Formula (I) are capable of being metabolized in vivo to form a sterol and/or stanol absorption 0023 r is 0 or 1; inhibitor compound and a sterol biosynthesis inhibitor com 0024 m, n and pare independently selected from 0, 1, 2, pound. As used herein, “sterol absorption inhibitor” means 3 or 4, provided that at least one of q and r is 1, and the Sum a compound capable of inhibiting the absorption of one or of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when more sterols, including but not limited to cholesterol and p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5: phytosterols (such as sitosterol, campesterol, Stigmasterol and avenosterol) when administered in a therapeutically 0025) x1 is 1 to 10; effective (sterol absorption inhibiting) amount to a subject or 0026 x2 is 1 to 10; human. “Stanol absorption inhibitor” means a compound capable of inhibiting the absorption of one or more 0027 x3 is 1 to 10; 5C-stanols (such as cholestanol, 5C.-campestanol, 5C-sito 0028 x4 is 1 to 10; stanol) when administered in a therapeutically effective (stanol absorption inhibiting) amount to a subject or human. 0029 x5 is 1 to 10; The sterol or stanol absorption inhibitor can inhibit the 0030) x6 is 1 to 10; absorption of cholesterol from the intestinal lumen into enterocytes, leading to a decrease in the delivery of intestinal 0031 x7 is 1 to 10; sterol or stanol, respectively, to the liver. “Sterol biosynthe 0032) x8 is 1 to 10; sis inhibitor” means a compound, such as a 3-hydroxy-3- methylglutaryl coenzyme A (HMG CoA) reductase inhibi 0033 x9 is 1 to 10; tor, that blocks hydroxymethylglutaryl coenzyme A (HMG 0034 x 10 is 1 to 10; and CoA) reductase, which is the rate-limiting enzyme in hepatic cholesterol synthesis. 0035) x11 is 1 to 10; 0042. In an alternative embodiment, compounds of For 0036) with the proviso that at least one of Q', Q, Q, Q" mula (I) can have dual functionality, i.e., can exhibit sterol and Q is -L-M or the Sugar residue, disugar residue, trisugar and/or stanol absorption inhibiting properties and also block residue, tetrasugar residue, Sugar acid, amino Sugar, amino hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase. acid residue or oligopeptide residue of G is substituted with -L-M. 0043 Referring now to Formula (I), in one embodiment 0037 Pharmaceutical formulations or compositions for of the present invention, X, Y and Z are each —CH2—, the treatment or prevention of a vascular condition, diabetes, 0044) The sum of m, n, p, q and r is preferably 2, 3 or 4. obesity, stroke, lowering a concentration of a sterol or stanol more preferably 3. Also preferred are compounds of For in plasma of a mammal, preventing demyelination or treat mula (I) in which p, q and n are each Zero, r is 1 and m is ing Alzheimer's disease and/or regulating levels of amyloid 2 or 3. US 2007/O 155676 A1 Jul. 5, 2007

0045. In one embodiment, m, n and rare each Zero, q is (Sugar residues) 1. p is 2, and Z is —CH2—. Also preferred are compounds wherein m, n and r are each Zero, q is 1. p is 2, and Z is 0059) wherein R, R and R can be the same or different —CH2—, Q is —OR, wherein R is hydrogen and Q is and each is independently selected from the group consisting fluorine. of H. —OH, halo, NH, azido, alkoxyalkoxy or 0046 R and R are each preferably hydrogen. W R: 0047. In one embodiment, Q and Q can be -OR 0060 W is independently selected from the group con wherein R is hydrogen, or a group readily metabolizable to sisting of —NH COO)— —O C(O)— —O—C(O) a hydroxyl (such as —O(CO)R. O(CO)OR and N(R') NH C(O) N(R') and O C(S) –O(CO)NR'R', defined above). N(R') : 0048. In another embodiment Q is halo or -OR. 0061 R and R' can be the same or different and each 0049. In another embodiment, Q is -OR wherein R is is independently selected from the group consisting of H, H. alkyl, acetyl, aryl and arylalkyl, 0050. In yet another embodiment, Q is -L-M. 0062) R, R, R, R7, R and R can be the same or 0051). In another embodiment, Q is -L-M. different and each is independently selected from the group consisting of H, alkyl, acetyl, arylalkyl, —C(O)alkyl and 0052) In another embodiment, Q is -L-M. —C(O)aryl; 0053. In another embodiment, Q is -L-M. 0063) R' is independently selected from the group con 0054) In another embodiment, Q is -L-M. sisting of R*-substituted T, R-substituted-T-alkyl, R 0055. In another embodiment, Q is halo. substituted-alkenyl, R-substituted-alkyl, R*-substituted 0056. In another embodiment, Q, Q, Q, Q or Q is cycloalkyl and R-substituted-cycloalkylalkyl: independently —(Co-Co alkylene)-G. In another embodi 0064) R' is independently selected from the group con ment, Q', Q or Q is independently —(Co-Co alkylene)-G. sisting of H and alkyl; 0057. In another embodiment, Q" or Q is independently —(Co-Co alkylene)-G. 0065 T is independently selected from the group con sisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isox 0.058. In one embodiment, G is selected from the group azolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl, consisting of: pyrazolyl, imidazolyl and pyridyl; 0066) R' is 1 to 3 substituents which are each indepen Risa O OR4a R5aO ORa dently selected from the group consisting of H, halo, alkyl, —OH, phenoxy, —CF. - NO, alkoxy, methylenedioxy, OR3a OR3a oXo, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, —N(CH), —C(O) NHalkyl, —C(O) N(alkyl). —C(O)-alkyl, O O —C(O)-alkoxy and pyrrolidinylcarbonyl: or R is a cova C(O)OR2, CHOR6a lent bond and R', the nitrogen to which it is attached and OR7a R form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, O indolinyl or morpholinyl group, or a alkoxycarbonyl-Sub stituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, -HC -- OR5a, indolinyl or morpholinyl group. RO OR4a 0067. In another embodiment, G is selected from:

... iiiiOH, ... iiiiOH,

CO2H CH2OH O CHR OH OAc

iiiiOH, III OAc,

OH COCH3 US 2007/O 155676 A1 Jul. 5, 2007

C(O)—, CH=CH , C=C , N(alkyl)- -continued —N(alkylaryl)- or —NH , preferably —O—.

0069. The -(Co-Co alkylene)-G substituent is prefer PhCH2O OCH2Ph ably in the 4-position of the phenyl ring to which it is s attached. 'IIIOCH2Ph, 0070). In one embodiment, L is

wherein X1 is 1 to 5, preferably 3. 0071. In one embodiment, L is OCHPhs bOHPh

wherein X3 is 1 to 5, preferably 3. 0072. In one embodiment, M is - \ (M1)

O O HC s 2 NoH, o1 , YCH, or HC HC CH

CH3

pharmaceutically acceptable salts thereof. In another embodiment, M is

(M2)

O O

O O H H2CS CH, O1 C n c Y C NCH, H3C CH3 wherein Ac is acetyl and Ph is phenyl. 0068. In another embodiment, optionally one or more CH3 carbon atoms of the —(Co-Co alkylene)-radical of Q', Q, Q, Q and Q is independently replaced by —O , or pharmaceutically acceptable salts thereof. US 2007/O 155676 A1 Jul. 5, 2007

0073. In another embodiment, M 0076. In another embodiment, M can be selected from free acids obtained by ring opening of the lactone of M3 through M7 or M9, for example as shown below

(M3)

(M3A)

or pharmaceutically acceptable salts thereof. (M3B)

0074. In another embodiment, M is

(M4)

CH r (M4A) SOCH F or pharmaceutically acceptable salts thereof. 0075). In another embodiment, M is O O OH 1N1 c."N-N-2 c. 2- 2 N H H H N CH3, (M7) tic- N CH3 SOCH3 ^ -- (M4B) F

HC a 1 F YCH, o1 CH NCH O OH O H3C CH3 1 n-'n'-c. c. "na -E 21 N H H H OH N CH3, ic- N CH3 SOCH3 pharmaceutically acceptable salts thereof.

US 2007/O 155676 A1 Jul. 5, 2007

(II) O O O

OAc C Sr-rO O O

C

F O N CH, O1 r O H3C CH3

F CH3 15a

Another embodiment of the present invention is a compound of Formula (III)

(III)

OAc

15

Another embodiment of the present invention is a compound of Formula (IV)

(IV)

OAc

18 US 2007/O 155676 A1 Jul. 5, 2007 10

Another embodiment of the present invention is a compound of Formula (V)

(V) F

OAc s N O le H N O O

0078. When any of the compounds of Formulae (II-V) is metabolized, one of the compounds (sterol and/or stanol -continued (VIII) absorption inhibitor) which can be formed is represented by O OH Formula (VI) (ezetimibe) below: O O (VI) HC2 | E. NoH, o1 No1 Nchi, / M H3C H3C CH3

CH3

0080 Similarly, when the compound of Formula (III) is metabolized, compounds (sterol biosynthesis inhibitors) which can be formed include pravastatin and the free acid form of pravastatin. Likewise, when the compounds of Formulae (IV) or (V) are metabolized, compounds (sterol or pharmaceutically acceptable salts, esters or Solvates of the biosynthesis inhibitors) which can be formed include ator compound of Formula (VI). vastatin and the free acid form of atorvastatin. 0079 Alternatively or additionally, when the compound 0081. As used above, and throughout the specification, of Formula (II) is metabolized, compounds (sterol biosyn the following terms, unless otherwise indicated, shall be thesis inhibitor) which can be formed are represented by understood to have the following meanings: Formulae (VII) (free acid form of simvastatin) and (VIII) 0082 “Subject' includes both mammals and non-mam (simvastatin) below: malian animals. 0083 "Mammal includes humans and other mammalian animals. (VII) I0084) The above statements, wherein, for example, Q' H H O and Q are said to be independently selected from a group of 'n 1 NetNet, us -'s substituents, means that Q' and Q are independently oi? O V CH. selected, but also that where an Q" or Q variable occurs more than once in a molecule, those occurrences are inde HOS-CH: H3C H3C CH3 pendently selected (e.g., if Q' is —OR wherein R is I hydrogen, Q can be —OR wherein R is alkyl). Those skilled in the art will recognize that the size and nature of the CH substituent(s) will affect the number of substituents that can be present. US 2007/O 155676 A1 Jul. 5, 2007

0085. The term “optionally substituted” means optional groups are as previously described. Useful alkoxycarbony Substitution with the specified groups, radicals or moieties. lalkoxy groups can comprise 3 to about 12 carbon atoms, It should be noted that any atom with unsatisfied valences in preferably 3 to about 8 carbon atoms. A non-limiting the text, schemes, examples and tables herein is assumed to example of a Suitable alkoxycarbonylalkoxy group is have the hydrogen atom(s) to satisfy the Valences. CHCH O—C(O)—CH2—O—. The alkoxycarbonyla 0.086 The following definitions apply regardless of lkoxy is linked to an adjacent moiety through the ether whether a term is used by itself or in combination with other OXygen. terms, unless otherwise indicated. Therefore, the definition 0093 “Alkoxyiminoalkyl means an alkyl-O N=CH of “alkyl applies to “alkyl as well as the “alkyl portions alkylene-group in which the alkyl and alkylene groups are as of “hydroxyalkyl, "haloalkyl”, “alkoxy’, etc. previously described. Useful alkoxyiminoalkyl groups can 0087 As used herein, the term “alkyl means an aliphatic comprise 2 to about 12 carbon atoms, preferably 2 to about hydrocarbon group that can be straight or branched and 8 carbon atoms. The alkoxyiminoalkyl is linked to an comprises 1 to about 20 carbon atoms in the chain. Preferred adjacent moiety through the alkylene group. alkyl groups comprise 1 to about 12 carbon atoms in the 0094) “Alkyldioyl” means an ROC(O)-alkylene-C(O)– chain. More preferred alkyl groups comprise 1 to about 6 O— group in which R is alkyl or H and the alkylene group carbon atoms in the chain. "Branched' means that one or is as previously described. Useful alkyldioyl groups can more lower alkyl groups such as methyl, ethyl or propyl, are comprise 2 to about 12 carbon atoms, preferably 2 to about attached to a linear alkyl chain. “Lower alkyl means a 8 carbon atoms. Non-limiting examples of suitable alkyl group having about 1 to about 6 carbon atoms in a chain that dioyl groups include 1,3-propanediol. The alkyldioyl is may be straight or branched. The alkyl can be substituted by linked to an adjacent moiety through the ester oxygen. one or more substituents independently selected from the group consisting of halo, aryl, cycloalkyl, cyano, hydroxy, 0095 “Alkynyl' means an aliphatic hydrocarbon group alkoxy, alkylthio, amino, NH(alkyl). —NH(cycloalkyl). comprising at least one carbon-carbon triple bond and which N(alkyl), (which alkyls can be the same or different), may be straight or branched and comprising about 2 to about carboxy and —C(O)O-alkyl. Non-limiting examples of suit 15 carbon atoms in the chain. Preferred alkynyl groups have able alkyl groups include methyl, ethyl, n-propyl, isopropyl. about 2 to about 12 carbon atoms in the chain; and more n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, fluoromethyl, preferably about 2 to about 4 carbon atoms in the chain. trifluoromethyl and cyclopropylmethyl. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl 0088 “Alkenyl' means an aliphatic hydrocarbon group chain. “Lower alkynyl means about 2 to about 6 carbon (straight or branched carbon chain) comprising one or more atoms in the chain which may be straight or branched. double bonds in the chain and which can be conjugated or Non-limiting examples of Suitable alkynyl groups include unconjugated. Useful alkenyl groups can comprise 2 to ethynyl, propynyl, 2-butynyl, 3-methylbutynyl. n-pentynyl, about 15 carbonatoms in the chain, preferably 2 to about 12 and decynyl. The alkynyl group may be substituted by one carbon atoms in the chain, and more preferably 2 to about 6 or more substituents which may be the same or different, carbon atoms in the chain. “Lower alkenyl' means 2 to each substituent being independently selected from the about 6 carbon atoms in the chain that can be straight or group consisting of alkyl, aryl and cycloalkyl. branched. The alkenyl group can be substituted by one or more Substituents independently selected from the group 0.096 “Allyloxy' means HC-FCH-O-. The allyloxy consisting of halo, alkyl, aryl, cycloalkyl, cyano and alkoxy. is linked to an adjacent moiety through the ether oxygen. Non-limiting examples of Suitable alkenyl groups include ethenyl, propenyl. n-butenyl, 3-methylbut-enyl and n-pen 0097 "Aryl means an aromatic monocyclic or multicy tenyl. clic ring system comprising about 5 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl 0089. Where an alkyl or alkenyl chain joins two other group can be substituted with one or more “ring system variables and is therefore bivalent, the terms alkylene and substituents” which may be the same or different, and are as alkenylene, respectively, are used. defined herein. Non-limiting examples of suitable aryl 0090 “Alkoxy' means an alkyl-O group in which the groups include phenyl, naphthyl, indenyl, tetrahydronaph alkyl group is as previously described. Useful alkoxy groups thyl and indanyl. "Arylene' means a bivalent phenyl group, can comprise 1 to about 12 carbon atoms, preferably 1 to including ortho, meta and para-Substitution. about 6 carbon atoms. Non-limiting examples of Suitable 0098 “Aralkyl or “arylalkyl means an aryl-alkylene alkoxy groups include methoxy, ethoxy and isopropoxy. The group in which the aryl and alkylene are as previously alkyl group of the alkoxy is linked to an adjacent moiety described. Preferred aralkyls comprise a lower alkyl group. through the ether oxygen. Non-limiting examples of Suitable aralkyl groups include 0.091 “Alkoxyarylalkoxy' means an alkyl-O-aryl-alky benzyl, phenethyl and naphthlenylmethyl. The aralkyl is lene-O-group in which the alkyl, alkylene and aryl groups linked to an adjacent moiety through the alkylene group. are as previously described. Useful alkoxyarylalkoxy groups can comprise 7 to about 26 carbon atoms, preferably 7 to 0099 “Aryloxy' means an aryl-O group in which the about 12 carbon atoms. A non-limiting example of a Suitable aryl group is as previously described. Non-limiting alkoxyarylalkoxy group is methoxybenzyloxy. The examples of Suitable aryloxy groups include phenoxy and alkoxyarylalkoxy is linked to an adjacent moiety through the naphthoxy. The bond to the parent moiety is through the ether oxygen. ether oxygen. 0092 “Alkoxycarbonylalkoxy' means an alkyl-O 0.100 “Aralkoxy' or “arylalkyloxy' means an aralkyl C(O)-alkylene-O group in which the alkyl and alkylene O— group in which the aralkyl group is as previously US 2007/O 155676 A1 Jul. 5, 2007 described. Non-limiting examples of suitable aralkoxy pyrazolyl and isoxazolyl. Useful bicyclic groups are benzo groups include benzyloxy and 1- or 2-naphthalenemethoxy. fused ring systems derived from the heteroaryl groups The bond to the parent moiety is through the ether oxygen. named above, e.g., quinolyl, phthalazinyl, quinazolinyl, “Aralkoxycarbonyl' means an aralkoxy-C(O)— group in benzofuranyl, benzothienyl and indolyl. which the aralkoxy group is as previously described. 0107 “Heteroarylalkyl or “heteroaralkyl means a het 0101 “Aroyl means an aryl-C(O)—group in which the eroaryl-alkylene-group in which the heteroaryland alkyl are aryl group is as previously described. The bond to the parent as previously described. Preferred heteroaralkyls contain a moiety is through the carbonyl. Non-limiting examples of lower alkyl group. Non-limiting examples of Suitable het Suitable groups include benzoyl and 1- and 2-maphthoyl. eroaralkyl groups include pyridylmethyl 2-(furan-3-yl)ethyl 0102) “Aroyloxy' means an aroyl-O group in which and quinolin-3-ylmethyl. The bond to the parent moiety is the aroyl group is as previously described. The bond to the through the alkylene. “Heteroarylalkoxy' means a het parent moiety is through the ether oxygen. Non-limiting eroaryl-alkylene-O-group in which the heteroaryl and alky examples of Suitable groups include benzoyloxy and 1- and lene are as previously described. 2-naphthoyloxy. 0.108 “Heterocyclyl means a non-aromatic saturated 0103 “Cycloalkyl means a non-aromatic mono- or mul monocyclic or multicyclic ring system comprising about 3 to ticyclic ring system comprising about 3 to about 10 carbon about 10 ring atoms, preferably about 5 to about 10 ring atoms, preferably about 5 to about 10 carbon atoms. Pre atoms, in which one or more of the atoms in the ring system ferred cycloalkyl rings contain about 5 to about 7 ring atoms. is an element other than carbon, for example nitrogen, The cycloalkyl can be substituted with one or more “ring oxygen or Sulfur, alone or in combination. There are no system substituents’ which may be the same or different, adjacent oxygen and/or Sulfur atoms present in the ring and are as defined below. Non-limiting examples of suitable system. Preferred heterocyclyls contain about 5 to about 6 monocyclic cycloalkyls include cyclopropyl, cyclobutyl, ring atoms. The prefix aza, oxa or thia before the heterocy clyl root name means that at least a nitrogen, oxygen or cyclopentyl, cyclohexyl and the like. Non-limiting examples Sulfur atom respectively is present as a ring atom. The of suitable multicyclic cycloalkyls include 1-decalinyl, nor heterocyclyl can be optionally substituted by one or more bornyl, adamanty1 and the like. “Cycloalkylene' refers to a “ring system substituents’ which may be the same or corresponding bivalent ring, wherein the points of attach different, and are as defined herein. The nitrogen or sulfur ment to other groups include all positional isomers. atom of the heterocyclyl can be optionally oxidized to the 0104 “Dioxolanyl' means corresponding N-oxide, S-oxide or S.S.-dioxide. Non-limit ing examples of Suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxa nyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothi O). opyranyl, and the like. O 0109) “Heterocyclylalkyl means a heterocyclyl-alky lene-group in which the heterocyclyl and alkylene groups are as previously described. Preferred heterocyclylalkyls 0105) “Halo’ refers to fluorine, chlorine, bromine or contain a lower alkylene group. The bond to the parent iodine radicals. Preferred are fluoro, chloro or bromo, and moiety is through the alkylene. “Heterocyclylcarbonyl more preferred are fluoro and chloro. means a heterocyclyl-C(O)—group in which the heterocy clyl is as previously described. Preferred heterocyclylcar 0106 “Heteroaryl means a monocyclic or multicyclic bonyls contain a lower alkyl group. The bond to the parent aromatic ring system of about 5 to about 14 ring atoms, moiety is through the carbonyl. “Heterocyclylcarbonyla preferably about 5 to about 10 ring atoms, in which one or lkoxy' means a heterocyclyl-C(O)-alkoxy-group in which more of the atoms in the ring system is/are atoms other than the heterocyclyl and alkoxy are as previously described. carbon, for example nitrogen, oxygen or Sulfur. The het eroatom(s) interrupt a carbocyclic ring structure and have a 0.110) “Ring system substituent’ means a substituent sufficient number of delocalized pi electrons to provide attached to an aromatic or non-aromatic ring system that, for aromatic character, provided that the rings do not contain example, replaces an available hydrogen on the ring system. adjacent oxygen and/or Sulfur atoms. Preferred heteroaryls Ring system Substituents may be the same or different, each contain about 5 to about 6 ring atoms. The "heteroaryl can being independently selected from the group consisting of be optionally substituted by one or more “ring system aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, substituents” which may be the same or different, and are as alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, defined herein. The prefix aza, oxa or thia before the alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, heteroaryl root name means that at least a nitrogen, oxygen carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbo or Sulfur atom respectively, is present as a ring atom. A nyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkyl nitrogen atom of a heteroaryl can be oxidized to form the sulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio. corresponding N-oxide. All regioisomers are contemplated, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl. Examples of useful cycloalkenyl, heterocyclyl, heterocyclenyl, YYN . 6-membered heteroaryl groups include pyridyl, pyrimidinyl, YY-N-alkyl-, YYNC(O) and YYNSO, , wherein pyrazinyl, pyridazinyl and the like and the N-oxides thereof. Y, and Y, may be the same or different and are indepen Examples of useful 5-membered heteroaryl rings include dently selected from the group consisting of hydrogen, alkyl, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, aryl, and aralkyl. US 2007/O 155676 A1 Jul. 5, 2007

0111 "Sugar residue” means a moiety derived from an aldose or ketose that has 3 to 7 carbon atoms and may belong to the D or L series. Non-limiting examples of suitable aldoses from which the sugar residue can be formed include (CH2) Alk, glucose, mannose, galactose, ribose, erythrose and glycer \-N-Ak. aldehydes. A non-limiting example of a suitable ketose from Alks which the Sugar residue can be formed is fructose. 0112 “Disugar residue” means a moiety derived from a Sugar that can be hydrolyzed to two monosaccharide mol wherein n1 is 0 to 10 and Alk, Alk, and Alk, can be the ecules. Non-limiting examples of Suitable compounds from same or different and each is a straight or branched alkyl which the disugar residue can be formed include maltose, radical having 1 to 20 carbon atoms. lactose, cellobiose and Sucrose. 0.122 Compounds of the invention have at least one asymmetrical carbon atom and therefore all isomers, includ 0113 Examples of sugar residues and disugar residues ing enantiomers, stereoisomers, rotamers, tautomers and include those moieties G listed in detail above. racemates of the compounds of Formula (I) (where they 0114 Di-, tri- or tetrasaccharides are formed by acetal exist) are contemplated as being part of this invention. The like binding of two or more Sugars. The bonds may be in a invention includes d and 1 isomers in both pure form and in or 0 form. “Trisugar residue” means a moiety derived from admixture, including racemic mixtures. Isomers can be a Sugar that can be hydrolyzed to three monosaccharide prepared using conventional techniques, either by reacting molecules. "Tetrasugar residue” means a moiety derived optically pure or optically enriched starting materials or by from a Sugar that can be hydrolyzed to four monosaccharide separating isomers of a compound of the Formula I. Isomers molecules. may also include geometric isomers, e.g., when a double bond is present. Polymorphous forms of the compounds of 0115) If the sugar is substituted, the substitution is pref Formula (I), whether crystalline or amorphous, also are erably at the hydrogen atom of an OH group of the Sugar. contemplated as being part of this invention. 0116 “Sugar acid means an Sugar residue, such as can 0123 Those skilled in the art will appreciate that for be formed from glucuronic acid, galacturonic acid, gluconic some of the compounds of the Formula I, one isomer will acid, galactonic acid, mannonic acid, glucaric acid and show greater pharmacological activity than other isomers. galactaric acid. 0.124 Compounds of the invention with an amino group 0117 “Amino sugar means an amino-substituted sugar can form pharmaceutically acceptable salts with organic and residue Such as can be formed from glucosamine, galac inorganic acids. Examples of Suitable acids for salt forma tosamine, glucamine or 3-amino-1,2-propanediol. tion are hydrochloric, Sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, 0118 Suitable protective groups for the hydroxyl groups maleic, methanesulfonic and other and carboxylic of the Sugars include benzyl, acetyl, benzoyl, pivaloyl, trityl, acids well known to those in the art. The salt is prepared by tert-butyidimethylsilyl, benzilidene, cyclohexidene or iso contacting the free base form with a sufficient amount of the propylidene protective groups. desired acid to produce a salt. The free base form may be 0119) “Amino acid residue” means a moiety derived from regenerated by treating the salt with a suitable dilute aque an amino acid. The amino acid moiety can be prepared from ous base solution Such as dilute aqueous sodium bicarbon the D or L forms of the amino acid. Non-limiting examples ate. The free base form differs from its respective salt form of suitable amino acids from which the amino acid residue Somewhat in certain physical properties, such as solubility in can be prepared include alanine, arginine, asparagine, aspar polar solvents, but the salt is otherwise equivalent to its tic acid, cysteine, cystine, glutamic acid, glutamine, glycine, respective free base forms for purposes of the invention. histidine, hydroxylysine, hydroxyproline, isoleucine, leu 0.125 Certain compounds of the invention are acidic cine, lysine, methionine, phenylanine, proline, serine, threo (e.g., those compounds which possess a carboxyl group). nine, tryptophane, , Valine, 2-aminoadipic acid, These compounds form pharmaceutically acceptable salts 3-aminoadipic acid, beta-alanine, 2-aminobutyric acid, with inorganic and organic bases. Examples of Such salts are 4-aminobutyric acid, piperidino carboxylic acid, 6-aminoca the sodium, potassium, calcium, aluminum, gold and silver proic acid, 2-aminoheptanoic acid, 2-(2-thienyl)glycine, salts. Also included are salts formed with pharmaceutically penicillamine, N-ethylasparagine, 2-aminoisobutyric acid, acceptable amines Such as ammonia, alkyl amines, hydroxy 2-aminoisobutyric acid, 2-aminopimelic acid, 2,4-diami alkylamines, N-methylglucamine and the like. nobutyric acid, desmosine, 2.2-diaminopimelic acid, 2.3- diaminopropioninc acid, N-ethylglycine, 3-(2-thienyl)ala 0.126 Compounds of the invention with a carboxylic acid nine, sarcosine, N-methylisoleucine, 6-N-methyllysine, group can form pharmaceutically acceptable esters with an N-methylvaline, norvaline, norleucine, ornithine and N-me . Examples of suitable alcohols include methanol and thylglycine. ethanol. 0120 “Oligopeptide residue” means the residue of a 0.127 Prodrugs and solvates of the compounds of the peptide constructed of 2 to 9 of the amino acids mentioned invention are also contemplated herein. The term “prodrug’. above. as employed herein, denotes a compound that is a precursor which, upon administration to a Subject, under 0121) “Trialkylammonium alkyl radical” means the goes chemical conversion by metabolic or chemical pro group cesses to yield a compound of formula I or a salt and/or US 2007/O 155676 A1 Jul. 5, 2007

Solvate thereof (e.g., a prodrug on being brought to the Nos. 5,763,653, 4,323,648, 4,916,239, 5,763,646 or by physiological pH or through enzyme action is converted to routine separation methods from MEVACORR) lovastatin the desired drug form). A discussion of prodrugs is provided formulation which is commercially available from Merck & in T. Higuchi and V. Stella, Pro- as Novel Delivery Co. Inc. The compound for preparing M3, M3A or M3B can Systems (1987) Volume 14 of the A.C.S. Symposium Series, be prepared by methods such as are disclosed in U.S. Pat. and in Bioreversible Carriers in Drug Design, (1987) Nos. 5.273,995, 4,681,893, 5,969,156 or by routine separa Edward B. Roche, ed., American Pharmaceutical Associa tion methods from LIPITOR(R) atorvastatin formulation tion and Pergamon Press, both of which are incorporated which is commercially available from Pfizer. The compound herein by reference thereto. for preparing M4, M4A or M4B can be prepared by methods 012.8 “Solvate” means a physical association of a com such as are disclosed in U.S. Pat. No. 5,260,440 or by pound of this invention with one or more solvent molecules. routine separation methods from CRESTORR) rosuvastatin This physical association involves varying degrees of ionic formulation that is commercially available from AstraZen and covalent bonding, including hydrogen bonding. In cer eca. The compound for preparing M5, M5A or M5B can be tain instances the solvate will be capable of isolation, for prepared by methods such as are disclosed in U.S. Pat. Nos. example when one or more solvent molecules are incorpo 5,006,530 and 5,177,080. The compound for preparing M6, rated in the crystal lattice of the crystalline solid. “Solvate M6A or M6B can be prepared by methods such as are encompasses both solution-phase and isolatable solvates. disclosed in U.S. Pat. Nos. 5,872,130, 5,856,336, 5,011,930 Non-limiting examples of Suitable Solvates include ethano and 5,854.259. The compound for preparing M7, M7A, lates, methanolates, and the like. “Hydrate' is a solvate M7B or M8 can be prepared by methods such as are wherein the solvent molecule is H.O. disclosed in U.S. Pat. Nos. 4,346,227, 4,537,859, 4,410,629 or by routine separation methods from PRAVACHOLR) 0129 Generally, the azetidinone portion of the com pravastatin formulation which is commercially available pounds of Formula (I) can be prepared by a variety of from Bristol-Myers Squibb. The compound for preparing methods well known to those skilled in the art, for example M9, M9A or M9B can be prepared by methods such as are such as are disclosed in U.S. Pat. Nos. 5,631,365, 5,767,115, disclosed in U.S. Pat. Nos. 5,354,772 and 4,739,073 or by 5,846,966, 6,207,822, PCT Patent Application No. routine separation methods from LESCOLOR fluvastatin for 02/079174 and PCT Patent Application WO93/02048, each mulation that is commercially available from Novartis. of which is incorporated herein by reference, and in the Example below. Preferably the azetidinone is prepared from 0131). In general, the compounds of Formula (I) can be eZetimibe, such as can be prepared by routine separation prepared through the general routes described in Schemes 14 methods from ZETIAR eZetimibe formulation that is com below. mercially available from Schering-Plough Corporation. The benzylic hydroxyl of eZetimibe can be protected for example 0.132. The azetidinone portion of the molecule and -M by acetylation and deprotected after coupling to the by portion of the molecule can be linked by linker-L- as shown methods which would be evident to one skilled in the art. for example in Schemes 1-4 below. Non-limiting examples of Suitable compounds for preparing linker 0130. The statin compound for preparing the -M portion of the molecule can be prepared by a variety of methods, for example the stating compound for preparing M1 can be prepared by methods such as are disclosed in PCT WO 98/12188, U.S. Pat. Nos. 5,763,653, 5,763,646, 4,444,784, 4.582.915, 4,820,850, or by routine separation methods from ZOCORR simvastatin formulation which is commer cially available from Merck & Co. Inc. The compound for preparing M2 can be prepared by methods such as are include glutaric anhydride or Succinic anhydride, as shown disclosed in U.S. Pat. Nos. 4,231,938, 4.294,926, U.S. Pat. in Scheme 1 below.

OH O O O O OH OAc OAc r-r O O

Her NaH N N F O F O

12 13 US 2007/O 155676 A1 Jul. 5, 2007 15

-continued

O OH OAc Sr-r -- O O

N F O

F

13

OH O

O DCC C DMAP, DMAP-HCI -> Yo H.C CH CH

H3C

8

Simvastatin

O O O OAc Sr-r O O O O

C N CH, O1 ra, F O HC CH

F CH

15A

0.133 Generally, in Scheme 1, treatment of acetoxy- dicyclohexyl carbodiimide (DCC), in the presence of an protected eZetimibe 12 with glutaric anhydride in the pres- additive such as dimethylaminopyridine (DMAP) and dim ethylaminopyridine hydrochloride (DMAP-HCl) will form ence of a base such as sodium hydride will form the half compound 15A of the present invention. See Boden, E. P. et ester-half acid 13. Coupling of the free alcohol of a statin al., 50.J. Org. Chem. (1985) 2394-95. Other suitable esteri Such as simvastatin 8 using ester coupling reagents, such as fication reactions will be evident to those skilled in the art. US 2007/O 155676 A1 Jul. 5, 2007 16

Sc 2. G hesis: EZetimibe lin P

O Na" N~" HO s OAc C O O O OH DCC O DMAP DMAP-HC1 N -- HC C F 2 NoH, o 1 ra, HC CH

OH

14 13 Pravastatin

O O OAc r-r O O

N F O

F

15

0134 Generally, in Scheme 2, half ester-half acid 13 from 14 using ester coupling reagents as above in Scheme 1 to Scheme 1 can be coupled with the free alcohol of pravastatin form compound 15 of the present invention.

O O OH OH O HCI O N

C-X- F

16 17 Atorvastatin US 2007/O 155676 A1 Jul. 5, 2007 17

-continued

17 -- 13 DCC -- DMAP DMAP-HC1

F

O O

OAc r-r S. O O N O le H N O O

18

0135 Generally, in Scheme 3, treatment of a statin such as atorvastatin 16 with a mild acid such as HCl will generate the corresponding lactone 17. Coupling of the free alcohol of lactone 17 with half acid-half ester 13 using ester cou- O-(CH),-(O)C pling reagents as above in Scheme 1 forms compound 18 of the present invention. 0136. Non-limiting examples of Suitable compounds for include 4-bromobutyric acid trimethylsilylester or O-trim preparing linker ethylsilyl bromoacetate, as shown in Scheme 4 below.

OH

OAc 1. Cs2CO3

N in-- OSiMe3 2. H US 2007/0155676 A1 Jul. 5, 2007 18

-continued

N-- OH OAc C

F

19 DCC 19 H 17 DMAP DMAP-HCI F

OAc S. N O e H N O O

0137 Generally, in Scheme 4, treatment of acetoxy example atherosclerosis, hypercholesterolemia or sitoster protected ezetimibe 12 with a base such as cesium carbonate olemia), vascular inflammation, stroke, diabetes, obesity and a haloalkyl ester such as O-trimethylsilyl bromoacetate and/or to reduce the level of sterol(s) (such as cholesterol) or followed by mild acid hydrolysis of the trimethylsilyl ester stanol(s) in the plasma of a subject. As used herein, 'vas forms acid 19. Coupling of acid 19 with the free alcohol of cular comprises cardiovascular, cerebrovascular, peripheral a statin such as atorvastatin lactone 17 using ester coupling vascular and combinations thereof. The formulations or reagents as above in Scheme 1 forms compound 20 of the compositions, combinations and treatments of the present present invention. invention can be administered by any suitable means which produce contact of these compounds with the site of action 0138) The daily dose of the compound of Formula (I) can in the body, for example in the plasma, liver or small range from about 0.1 to about 1000 mg per day, preferably intestine of a mammal or human. about 0.25 to about 100 mg/day, and more preferably about 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 mg per day, given 0139 For administration of pharmaceutically acceptable in a single dose or 2-4 divided doses. The exact dose, salts of the above compounds, the weights indicated above however, is determined by the attending clinician and is refer to the weight of the acid equivalent or the base dependent on the potency of the compound administered, equivalent of the therapeutic compound derived from the the age, weight, condition and response of the patient. The salt. phrases “effective amount” and “therapeutically effective 0140). In one embodiment of the present invention, the amount’ mean that amount of a compound of Formula I, and compositions or therapeutic combinations can further com other pharmacological or therapeutic agents described prise one or more pharmacological or therapeutic agents or below, that will elicit a biological or medical response of a drugs such as lipid-lowering agents discussed below. As tissue, system, animal or mammal that is being sought by the used herein, “combination therapy’ or “therapeutic combi administrator (such as a researcher, doctor or veterinarian) nation” means the administration of two or more therapeutic which includes alleviation of the symptoms of the condition agents, such as a compound of Formula (I) and a lipid or disease being treated and the prevention, slowing or lowering or antihypertensive agent, to prevent or treat a halting of progression of one or more conditions, for condition as described above. Such administration includes example vascular conditions, such as hyperlipidaemia (for coadministration of these therapeutic agents in a substan US 2007/O 155676 A1 Jul. 5, 2007

tially simultaneous manner. Such as in a single tablet or which are available from Sankyo). Generally, a total daily capsule having a fixed ratio of active ingredients or in dosage of (s) can range from about 1 to multiple, separate capsules for each therapeutic agent. Also, about 50 grams per day, and preferably about 2 to about 16 Such administration includes use of each type of therapeutic grams per day in single or 2-4 divided doses. agent in a sequential manner. In either case, the treatment using the combination therapy will provide beneficial effects 0144. In an alternative embodiment, the compositions or in treating the condition. A potential advantage of the treatments of the present invention can further comprise one combination therapy disclosed herein may be a reduction in or more ileal bile acid transport (“IBAT) inhibitors (or the required amount of an individual therapeutic compound apical sodium co-dependent bile acid transport (ASBT) or the overall total amount of therapeutic compounds that inhibitors) coadministered with or in combination with the are effective in treating the condition. By using a combina compound of Formula (I) discussed above. The IBAT inhibi tion of therapeutic agents, the side effects of the individual tors can inhibit bile acid transport to reduce LDL cholesterol compounds can be reduced as compared to a monotherapy, levels. Non-limiting examples of suitable IBAT inhibitors which can improve patient compliance. Also, therapeutic include benzothiepines such as therapeutic compounds com agents can be selected to provide a broader range of com prising a 2.3.4.5-tetrahydro-1-benzothiepine 1,1-dioxide plimentary effects or complimentary modes of action. structure such as are disclosed in PCT Patent Application WO 00/38727 which is incorporated herein by reference. 0141 Non-limiting examples of additional cholesterol Generally, a total daily dosage of IBAT inhibitor(s) can biosynthesis inhibitors for use in the compositions, thera range from about 0.01 to about 1000 mg/day, and preferably peutic combinations and methods of the present invention about 0.1 to about 50 mg/day in single or 24 divided doses. include squalene synthase inhibitors, squalene epoxidase inhibitors and mixtures thereof. Non-limiting examples of 0145. In another alternative embodiment, the composi suitable HMG CoA synthetase inhibitors include L-659,699 tions or treatments of the present invention can further ((E.E)-11-3'R-(hydroxy-methyl)-4'-oxo-2R-oxetanyl-3,5, comprise nicotinic acid (niacin) and/or derivatives thereof 7R-trimethyl-2,4-undecadienoic acid); squalene synthesis coadministered with or in combination with the compound inhibitors, for example squalestatin 1; and squalene epoxi of Formula (I) discussed above. As used herein, “nicotinic dase inhibitors, for example, NB-598 ((E)-N-ethyl-N-(6.6- acid derivative” means a compound comprising a pyridine dimethyl-2-hepten-4-ynyl)-3-(3,3'-bithiophen-5-yl 3-carboxylate structure or a pyrazine-2-carboxylate struc )methoxybenzene-methanamine hydrochloride) and other ture, including acid forms, salts, esters, Zwitterions and sterol biosynthesis inhibitors such as DMP-565. Generally, tautomers, where available. Examples of nicotinic acid a total daily dosage of additional cholesterol biosynthesis derivatives include niceritrol, nicofuranose and acipimox inhibitor(s) can range from about 0.1 to about 160 mg per (5-methylpyrazine-2-carboxylic acid 4-oxide). Nicotinic day, and preferably about 0.2 to about 80 mg/day in single acid and its derivatives inhibit hepatic production of VLDL or 2-3 divided doses. and its metabolite LDL and increases HDL and apo A-1 levels. An example of a suitable nicotinic acid product is 0142. In another preferred embodiment, the composition NIASPANR) (niacin extended-release tablets) which are or treatment comprises the compound of Formula (I) in available from Kos. Generally, a total daily dosage of combination with one or more peroxisome proliferator nicotinic acid or a derivative thereof can range from about activated receptor(s) activator(s). In this embodiment, pref 500 to about 10,000 mg/day, preferably about 1000 to about erably the peroxisome proliferator-activated receptor acti 8000 mg/day, and more preferably about 3000 to about 6000 vator(s) is a fibric acid derivative such as gemfibrozil, mg/day in single or divided doses. clofibrate and/or fenofibrate. 0146 In another alternative embodiment, the composi 0143. In another alternative embodiment, the composi tions or treatments of the present invention can further tions, therapeutic combinations or methods of the present comprise one or more AcylCoA:Cholesterol O-acyltrans invention can further comprise one or more bile acid seques ferase (“ACAT) Inhibitors, which can reduce LDL and trants (insoluble anion exchange resins), coadministered VLDL levels, coadministered with or in combination with with or in combination with the compound of Formula (I) the compound of Formula (I) discussed above. ACAT is an discussed above. Bile acid sequestrants bind bile acids in the enzyme responsible for esterifying excess intracellular cho intestine, interrupting the enterohepatic circulation of bile lesterol and may reduce the synthesis of VLDL, which is a acids and causing an increase in the faecal excretion of product of cholesterol esterification, and overproduction of steroids. Bile acid sequestrants can lower intrahepatic cho apo B-100-containing lipoproteins. Non-limiting examples lesterol and promote the synthesis of apo B/E (LDL) recep of useful ACAT inhibitors include avasimibe, HL-004, lec tors that bind LDL from plasma to further reduce cholesterol imibide (DuP-128) and CL-277082 (N-(2,4-difluorophe levels in the . Non-limiting examples of suitable bile nyl)-N-4-(2,2-dimethylpropyl)phenylmethyl-N-hepty acid sequestrants include cholestyramine (a styrene-divinyl lurea). See P. Chang et al., “Current, New and Future benzene copolymer containing quaternary ammonium cat Treatments in Dyslipidaemia and Atherosclerosis'. Drugs ionic groups capable of binding bile acids, such as QUES 2000 July: 60(1): 55-93, which is incorporated by reference TRANR) or QUESTRAN LIGHTR) cholestyramine which herein. Generally, a total daily dosage of ACAT inhibitor(s) are available from Bristol-Myers Squibb), colestipol (a can range from about 0.1 to about 1000 mg/day in single or copolymer of diethylenetriamine and 1-chloro-2,3-ep 24 divided doses. oxypropane, such as COLESTID(R) tablets which are avail able from Pharmacia), and colesevelam hydrochloride (such 0.147. In another alternative embodiment, the composi as WelChol(R) Tablets (poly(allylamine hydrochloride) cross tions or treatments of the present invention can further linked with epichlorohydrin and alkylated with 1-bromode comprise one or more Cholesteryl Ester Transfer Protein cane and (6-bromohexyl)-trimethylammonium bromide) (“CETP) Inhibitors coadministered with or in combination US 2007/O 155676 A1 Jul. 5, 2007 20 with compound of Formula (I) discussed above. CETP is 0153. In another alternative embodiment, the composi responsible for the exchange or transfer of cholesteryl ester tions or treatments of the present invention can further carrying HDL and triglycerides in VLDL. Non-limiting comprise antioxidants, such as probucol, tocopherol, ascor examples of suitable CETP inhibitors are disclosed in PCT bic acid, B-carotene and selenium, or such as Patent Application No. WO 00/38721 and U.S. Pat. No. B or vitamin B2, coadministered with or in com 6,147,090, which are incorporated herein by reference. bination with the compound of Formula (I) discussed above. Pancreatic cholesteryl ester hydrolase (pCEH) inhibitors Generally, a total daily dosage of antioxidants or vitamins such as WAY-121898 also can be coadministered with or in can range from about 0.05 to about 10 grams per day in combination with the compound of Formula (I) discussed single or 2-4 divided doses. above. Generally, a total daily dosage of CETP inhibitor(s) can range from about 0.01 to about 1000 mg/day, and 0154) In another alternative embodiment, the composi preferably about 0.5 to about 20 mg/kg body weight/day in tions or treatments of the present invention can further single or divided doses. comprise monocyte and macrophage inhibitors such as polyunsaturated fatty acids (PUFA), 0148. In another alternative embodiment, the composi including throXine analogues such as CGS-26214 (a thyroX tions or treatments of the present invention can further ine compound with a fluorinated ring), gene therapy and use comprise probucol or derivatives thereof (such as AGI-1067 of recombinant proteins such as recombinant apo E. coad and other derivatives disclosed in U.S. Pat. Nos. 6,121,319 ministered with or in combination with the compound of and 6,147.250), which can reduce LDL levels, coadminis Formula (I) discussed above. Generally, a total daily dosage tered with or in combination with the compound of Formula of these agents can range from about 0.01 to about 1000 (I) discussed above. Generally, a total daily dosage of mg/day in single or 24 divided doses. probucol or derivatives thereof can range from about 10 to about 2000 mg/day, and preferably about 500 to about 1500 0.155 Also useful with the present invention are compo mg/day in single or 2-4 divided doses. sitions or therapeutic combinations that further comprise 0149. In another alternative embodiment, the composi hormone replacement agents and compositions. Useful hor tions or treatments of the present invention can further mone agents and compositions for hormone replacement comprise low-density lipoprotein (LDL) receptor activators, therapy of the present invention include androgens, estro coadministered with or in combination with the compound gens, progestins, their pharmaceutically acceptable salts and of Formula (I) discussed above. Non-limiting examples of derivatives thereof. Combinations of these agents and com suitable LDL-receptor activators include HOE-402, an imi positions are also useful. The dosage of androgen and dazolidinyl-pyrimidine derivative that directly stimulates estrogen combinations vary, desirably from about 1 mg to LDL receptor activity. See M. Huettinger et al., “Hypolipi about 4 mg androgen and from about 1 mg to about 3 mg demic activity of HOE-402 is Mediated by Stimulation of estrogen. the LDL Receptor Pathway”, Arterioscler. Thromb. 1993: 0156 The compositions, therapeutic combinations or 13:1005-12. Generally, a total daily dosage of LDL receptor methods of the present invention can further comprise one or activator(s) can range from about 1 to about 1000 mg/day in more obesity control . Useful obesity control single or 24 divided doses. medications include, but are not limited to, drugs that reduce 0150. In another alternative embodiment, the composi energy intake or Suppress appetite, drugs that increase tions or treatments of the present invention can further energy expenditure and nutrient-partitioning agents. Suit comprise fish oil, which contains Omega 3 fatty acids able obesity control medications include, but are not limited (3-PUFA), which can reduce VLDL and triglyceride levels, to, noradrenergic agents (such as diethylpropion, mazindol, coadministered with or in combination with the compound , , phendimetrazine, of Formula (I) discussed above. Generally, a total daily phendamine tartrate, , phendimetrazine dosage of fish oil or Omega 3 fatty acids can range from and tartrate); serotonergic agents (such as Sibutramine, fen about 1 to about 30 grams per day in single or 24 divided fluramine, dexfenfluramine, fluoxetine, fluvoxamine and doses. paroxtine); thermogenic agents (such as ephedrine, , 0151. In another alternative embodiment, the composi theophylline, and selective B3- ); alpha tions or treatments of the present invention can further blocking agents; kainite or AMPA receptor antagonists; comprise natural water soluble fibers, such as psyllium, leptin-lipolysis stimulated receptors; phosphodiesterase guar, oat and pectin, which can reduce cholesterol levels, enzyme inhibitors; compounds having nucleotide sequences coadministered with or in combination with the compound of the mahogany gene; fibroblast growth factor-10 polypep of Formula (I) discussed above. Generally, a total daily tides; monoamine oxidase inhibitors (such as befloxatone, dosage of natural water soluble fibers can range from about moclobemide, brofaromine, phenoxathine, esuprone, befol. 0.1 to about 10 grams per day in single or 24 divided doses. toloxatone, pirlindol, amiflamine, Sercloremine, bazi naprine, lazabemide, millacemide and caroXaZone); com 0152. In another alternative embodiment, the composi pounds for increasing lipid (such as evodiamine tions or treatments of the present invention can further compounds); and lipase inhibitors (such as orlistat). Gener comprise plant sterols, plant stanols and/or fatty acid esters ally, a total dosage of the above-described obesity control of plant stanols, such as sitostanol ester used in medications can range from 1 to 3,000 mg/day, desirably BENECOLR) margarine, which can reduce cholesterol lev from about 1 to 1,000 mg/day and more desirably from els, coadministered with or in combination with the com about 1 to 200 mg/day in single or 24 divided doses. pound of Formula (I) discussed above. Generally, a total daily dosage of plant sterols, plant stanols and/or fatty acid 0157 The compositions, therapeutic combinations or esters of plant stanols can range from about 0.5 to about 20 methods of the present invention can further comprise one or grams per day in single or 2-4 divided doses. more blood modifiers which are chemically different from US 2007/O 155676 A1 Jul. 5, 2007 the compounds of Formula (I) discussed above, for example, tolol, hydrochloride, hydrochloride, they contain one or more different atoms, have a different , bunolol hydrochloride, hydrochloride, arrangement of atoms or a different number of one or more hydrochloride, hydrochloride, ciclo atoms than the compounds of Formula (I) discussed above. prolol hydrochloride, dexpropranolol hydrochloride, diac Useful blood modifiers include but are not limited to anti etolol hydrochloride, dilevalol hydrochloride, esmolol coagulants (argatroban, bivalirudin, dalteparin Sodium, hydrochloride, hydrochloride, sulfate, desirudin, dicumarol, lyapolate Sodium, nafamo.stat mesy hydrochloride, levobetaxolol hydrochloride, late, phenprocoumon, tinzaparin Sodium, warfarin Sodium); hydrochloride, metalol hydrochloride, meto (anagrelide hydrochloride, bivalirudin, cil prolol, metoprolol tartrate, , sulfate, pen ostaZol, dalteparin Sodium, danaparoid sodium, daZOXiben butolol sulfate, , hydrochloride, so talol hydrochloride, efegatran Sulfate, enoxaparin Sodium, flure hydrochloride, timolol, timolol maleate, hydro tofen, ifetroban, ifetroban sodium, lamifiban, lotrafiban chloride, , bisoprolol, bisoprolol fumarate, nebiv hydrochloride, napsagatran, orbofiban acetate, roxifiban olol); adrenergic ; angiotensin converting enzyme acetate, sibrafiban, tinzaparin Sodium, trifenagrel, abcix (ACE) inhibitors (benazepril hydrochloride, benazeprilat, imab, Zolimomab aritox); fibrinogen receptor antagonists captopril, delapril hydrochloride, fosinopril sodium, liben (roxifiban acetate, fradafiban, orbofiban, lotrafiban hydro Zapril, moexipril hydrochloride, pentopril, perindopril, chloride, tirofiban, xemilofiban, monoclonal antibody 7E3, quinapril hydrochloride, quinaprilat, ramipril, spirapril sibrafiban); inhibitors (cilostazol, clopidogrel bisul hydrochloride, spiraprilat, teprotide, enalapril maleate, lisi fate, epoprostenol, epoprostenol sodium, ticlopidine hydro nopril, Zofenopril calcium, perindopril erbumine); antihy chloride, aspirin, ibuprofen, naproxen, Sulindae, idometha pertensive agents (althiazide, benzthiazide, captopril, cin, mefenamate, droxicam, diclofenac, Sulfinpyrazone, , chlorothiazide sodium, hydrochloride, piroXicam, dipyridamole); platelet aggregation inhibitors cyclothiazide, delapril hydrochloride, dilevalol hydrochlo (acadesine, beraprost, beraprost sodium, ciprostene calcium, ride, mesylate, fosinopril sodium, itazigrel, lifarizine, lotrafiban hydrochloride, orbofiban hydrochloride, , metoprolol Succinate, moexipril acetate, oxagrelate, fradafiban, orbofiban, tirofiban, hydrochloride, maleate, hydrochloride, Xemilofiban); hemorrheologic agents (pentoxifylline); lipo hydrochloride, hydrochloride, protein associated inhibitors; Factor VIIa inhibi primidolol, quinapril hydrochloride, quinaprilat, ramipril, tors (4H-31-benzoxazin-4-ones, 4H-3,1-benzoxazin-4- hydrochloride, candesartan, candesartan cilexetil, thiones, quinazolin-4-ones, quinazolin-4-thiones, telmisartan, amlodipine besylate, amlodipine maleate, benzothiazin-4-ones, imidazolyl-boronic acid-derived pep bevantolol hydrochloride), for example HYZAAR(R) or tide analogues TFPI-derived peptides, naphthalene-2-sul COZAARR) antihypertensive agents available from Merck fonic acid (1-3-(aminoiminomethyl)-benzyl)-2-oxo-pyrro & Co., Inc.; angiotensin II receptor antagonists (candesartan, lidin-3-(S)-yl)amide trifluoroacetate, dibenzofuran-2- irbesartan, losartan potassium, candesartan cilexetil, telmis sulfonic acid {1-3-(aminomethyl)-benzyl-5-oxo artan); anti-anginal agents (amlodipine besylate, amlodipine pyrrolidin-3-yl)-amide, tolulene-4-sulfonic acid 1-3- maleate, betaxolol hydrochloride, bevantolol hydrochloride, (aminoiminomethyl)-benzyl)-2-oxo-pyrrolidin-3-(S)-yl)- butoprozine hydrochloride, carvedilol, cinepaZet maleate, amide trifluoroacetate, 3,4-dihydro-1H-isoquinoline-2- metoprolol Succinate, molsidomine, monatepil maleate, sulfonic acid (1-3-(aminoiminomethyl)-benzyl)-2-oxo primidolol, ranolazine hydrochoride, tosifen, Verapamil pyrrolin-3-(S)-yl)-amide trifluoroacetate); Factor Xa hydrochloride); coronary vasodilators (fostedil, azaclorzine inhibitors (disubstituted pyrazolines, disubstituted triazo hydrochloride, chromonar hydrochloride, clonitrate, dilt lines, substituted n-(aminoiminomethyl)phenylpropyla iazem hydrochloride, dipyridamole, droprenilamine, eryth mides, substituted n-(aminomethyl)phenylpropylamides. rity1 tetranitrate, isosorbide dinitrate, isosorbide mononi tissue factor pathway inhibitor (TFPI), low molecular trate, lidoflazine, mioflazine hydrochloride, mixidine, weight heparins, heparinoids, benzimidazolines, benzox molsidomine, nicorandil, nifedipine, nisoldipine, nitroglyc aZolinones, benzopiperazinones, indanones, dibasic (amidi erine, hydrochloride, pentrinitrol, perhexiline noaryl) propanoic acid derivatives, amidinophenyl-pyrro maleate, prenylamine, propatyl nitrate, terodiline hydrochlo lidines, amidinophenyl-pyrrolines, amidinophenyl ride, tolamolol, Verapamil); (the combination prod isoxazolidines, amidinoindoles, amidinoazoles, bis uct of hydrochlorothiazide and spironolactone and the com arlysulfonylaminobenzamide derivatives, peptidic Factor bination product of hydrochlorothiazide and triamterene). Xa inhibitors). 0159. The compositions, therapeutic combinations or 0158. The compositions, therapeutic combinations or methods of the present invention can further comprise one or methods of the present invention can further comprise one or more antidiabetic medications for reducing blood glucose more cardiovascular agents which are chemically different levels in a human. Useful antidiabetic medications include, from the compounds of Formula (I) discussed above, for but are not limited to, drugs that reduce energy intake or example, they contain one or more different atoms, have a Suppress appetite, drugs that increase energy expenditure different arrangement of atoms or a different number of one and nutrient-partitioning agents. Suitable antidiabetic medi or more atoms than the compounds of Formula (I) discussed cations include, but are not limited to, Sulfonylurea (Such as above. Useful cardiovascular agents include but are not acetohexamide, chlorpropamide, gliamilide, gliclazide, limited to calcium channel blockers (clentiazem maleate, glimepiride, glipizide, glyburide, glibenclamide, tolaza amlodipine besylate, isradipine, nimodipine, felodipine, nil mide, and tolbutamide), meglitinide (such as repaglinide and vadipine, nifedipine, teludipine hydrochloride, diltiazem nateglinide), biguanide (such as metformin and buformin), hydrochloride, belfosdil, Verapamil hydrochloride, fostedil); alpha-glucosidase inhibitor (Such as acarbose, miglitol, cam adrenergic blockers ( hydrochloride, labetalol iglibose, and Voglibose), certain peptides (such as amlintide, hydrochloride, proroXan, hydrochloride, acebu pramlintide, exendin, and GLP-1 agonistic peptides), and US 2007/O 155676 A1 Jul. 5, 2007 22 orally administrable insulin or insulin composition for intes and additives include non-toxic compatible fillers, binders tinal delivery thereof. Generally, a total dosage of the Such as starch, disintegrants, buffers, preservatives, anti above-described antidiabetic medications can range from oxidants, lubricants, flavorings, thickeners, coloring agents, 0.1 to 1,000 mg/day in single or 2-4 divided doses. emulsifiers and the like. The amount of excipient or additive can range from about 0.1 to about 90 weight percent of the 0160 The compositions, therapeutic combinations or total weight of the treatment composition or therapeutic methods of the present invention can further comprise one or combination. One skilled in the art would understand that more treatments for Alzheimer's Disease which are chemi the amount of carrier(s), excipients and additives (if present) cally different from the compounds of Formula (I). Non limiting examples of Suitable treatments which can be useful can vary. in treating Alzheimer's Disease include administration of 0164. The treatment compositions of the present inven one or more of the following: cholinesterase inhibitors, tion can be administered in any conventional dosage form, muscarinic receptor agonists, M2 muscarinic receptor preferably an oral dosage form Such as a capsule, tablet, antagonists, release stimulators, powder, cachet, Suspension or solution. The formulations uptake stimulators, nicotinic receptor agonists, and pharmaceutical compositions can be prepared using anti-AB , Y-secretase inhibitors, B-secretase inhibi conventional pharmaceutically acceptable and conventional tors, amyloid aggregation inhibitors, amyloid precursor pro techniques. Several examples of preparation of dosage for tein antisense oligonucleotides, monoamine reuptake inhibi mulations are provided below. tors, human stem cells, gene therapy, nootropic agents, 0.165. The following formulation exemplifies a dosage AMPA receptor ligands, growth factors or growth factor form of this invention. In the formulation, the term "Active receptor agonists, anti-inflammatory agents, free radical Compound I designates a compound of Formula I Scavengers, antioxidants, Superoxide dismutase stimulators, described herein above. calcium channel blockers, apoptosis inhibitors, caspase inhibitors, monoamine oxidase inhibitors, estrogens and EXAMPLE estrogen receptor ligands, NMDA receptor antagonists, Jun N-terminal kinase (JNK) inhibitors, copper/zinc chelators, 0166) 5-HT1a receptor agonists, NGF stimulators, neuroprotective agents, H3 histamine receptor antagonists, calpain inhibi tors, poly ADP ribose polymerase inhibitors, prolylendopep tidase inhibitors, calcium modulators, corticortropin releas Tablets ing factor receptor antagonists, corticortropin releasing No. Ingredient mg tablet factor binding protein inhibitors, GABA modulators, 1 Active Compound I 2O GABA-A receptor antagonists, GABA-B receptor antago 2 Lactose monohydrate NF 55 nists, neuroimmunophilin ligands, sigma receptor ligands, 3 Microcrystalline cellulose NF 2O galanin receptor ligands, imidazoline/alpha adrenergic 4 Povidone (K29-32) USP 4 receptor antagonists, vasoactive intestinal peptide receptor 5 Croscarmellose sodium NF 8 agonists, benzodiazepine receptor inverse agonists, cannab 6 Sodium lauryl sulfate 2 inoid receptor agonists, thyrotropin releasing hormone 7 Magnesium stearate NF 1 receptor agonists, protein kinase C inhibitors, 5-HT3 recep Total 110 tor antagonists, prostaglandin receptor antagonists, topoi Somerase II inhibitors, steroid receptor ligand, nitric oxide modulators, RAGE inhibitors, dopamine receptor agonists, Method of Manufacture and combinations thereof. 0167 Mix Item No. 4 with purified water in suitable 0161 Mixtures of any of the pharmacological or thera mixer to form binder solution. Spray the binder solution and peutic agents described above can be used in the composi then water over Items 1, 2, 6 and a portion of Item 5 in a tions and therapeutic combinations of the present invention. fluidized bed processor to granulate the ingredients. Con tinue fluidization to dry the damp granules. Screen the dried 0162 The pharmaceutical treatment compositions (for granules and blend with Item No. 3 and the remainder of mulations or medicaments) and therapeutic combinations of Item 5. Add Item No. 7 and mix. Compress the mixture to the present invention can further comprise one or more appropriate size and weight on a suitable tablet machine. pharmaceutically acceptable carriers, one or more excipients and/or one or more additives. As used herein, the term 0.168. Since the present invention relates to treating con “composition' is intended to encompass a product compris ditions as discussed above, such as reducing the plasma ing the specified ingredients in the specified amounts, as sterol (especially cholesterol) concentrations or levels by well as any product which results, directly or indirectly, from treatment with a combination of active ingredients wherein combination of the specified ingredients in the specified the active ingredients may be administered separately, the invention also relates to combining separate pharmaceutical amountS. compositions in kit form. That is, a kit is contemplated 0163 Non-limiting examples of pharmaceutically wherein two separate units are combined: a pharmaceutical acceptable carriers include Solids and/or liquids such as composition comprising at least one compound of Formula ethanol, glycerol, water and the like. The amount of carrier (I) and a separate pharmaceutical composition comprising at in the treatment composition can range from about 5 to about least one other therapeutic agent as described above. The kit 99 weight percent of the total weight of the treatment will preferably include directions for the administration of composition or therapeutic combination. Non-limiting the separate components. The kit form is particularly advan examples of suitable pharmaceutically acceptable excipients tageous when the separate components must be administered US 2007/O 155676 A1 Jul. 5, 2007

in different dosage forms (e.g., oral and parenteral) or are same schedule. On Day 7 liver samples would be taken for administered at different dosage intervals. neutral lipid analyses. Samples of liver would be lipid extracted. Lipid extracts would be dried under nitrogen into 0169. The treatment compositions and therapeutic com HPLC sample vials, resuspended in hexane and injected binations of the present invention can inhibit the intestinal onto a Zorbax Sil (4.6x25 cm) silica column. Chromatog absorption of cholesterol in mammals, as shown in the raphy would be performed using an isocratic mobile phase Example below, and can be useful in the treatment and/or containing 98.8% hexane and 1.2% isopropanol at a flow prevention of conditions, for example vascular conditions, rate of 2 ml/min. Lipids can be detected by absorbance at Such as atherosclerosis, hypercholesterolemia and sitoster 206 nm and quantitated by computer integration (System olemia, stroke, obesity and lowering of plasma levels of Gold, Beckman) of elution profiles. Cholesterol concentra cholesterol in mammals, in particular in mammals. tions can be determined by the use of a response factor 0170 In another embodiment of the present invention, derived from a standard curve using known amounts of the compositions and therapeutic combinations of the cholesterol. Cholesteryl ester content of liver-derived present invention can inhibit sterol absorption or reduce samples can be derived from a standard curve constructed plasma concentration of at least one sterol selected from the using known amounts of cholesteryl oleate. Cholesteryl group consisting of phytosterols (such as sitosterol, campes oleate can be used as the standard since this is the major terol, Stigmasterol and avenosterol), 5C-stanols (such as cholesteryl ester species present in the liver and this specific cholestanol, 5C.-campestanol, 5C.-sitostanol), cholesterol cholesteryl ester has an extinction coefficient that approxi and mixtures thereof. The plasma concentration can be mates that of a weighted average for all the cholesteryl esters reduced by administering to a mammal in need of Such present in the liver. treatment an effective amount of at least one treatment 0.175. The reduction of hepatic cholesteryl ester accumu composition or therapeutic combination comprising a com lation is utilized as a marker for cholesterol absorption pound of Formula (I) described above. The reduction in inhibition. plasma concentration of sterols can range from about 1 to about 70 percent, and preferably about 10 to about 50 0176). It will be appreciated by those skilled in the art that percent. Methods of measuring serum total blood cholesterol changes could be made to the embodiments described above and total LDL cholesterol are well known to those skilled in without departing from the broad inventive concept thereof. the art and for example include those disclosed in PCT WO It is understood, therefore, that this invention is not limited 99/38498 at page 11, incorporated by reference herein. to the particular embodiments disclosed, but it is intended to Methods of determining levels of other sterols in serum are cover modifications that are within the spirit and scope of the disclosed in H. Gylling et al., "Serum Sterols During Stanol invention, as defined by the appended claims. Ester Feeding in a Mildly Hypercholesterolemic Popula tion”, J. Lipid Res. 40: 593-600 (1999), incorporated by 1. A compound represented by the structural formula (I): reference herein. 0171 Illustrating the invention are the following examples which, however, are not to be considered as (I) limiting the invention to their details. Unless otherwise Q indicated, all parts and percentages in the following examples, as well as throughout the specification, are by p f 1 weight. N X---Y--z, N EXAMPLE %21 R2 R3 Qs N 0172 Hypothetical In Vivo Evaluation O N 0173 The hypercholesterolemic Golden Syrian hamster 2HQ' can be used as the in vivo model to evaluate the oral potency and in vivo efficacy of cholesterol absorption inhibitors. Hamsters would be fed a cholesterol-containing diet for 7 or pharmaceutically acceptable isomers, salts, Solvates or days, which results in an increase in hepatic cholesteryl esters of the compound of Formula (I), wherein in Formula esters. A compound which blocks intestinal cholesterol (I) above: absorption would reduce the accumulation of hepatic cho X, Y and Z can be the same or different and each is lesteryl ester levels. independently selected from the group consisting of 0174 Male Golden Syrian hamsters (Charles River Labs, —CH2—, —CH(alkyl)- and —C(alkyl) ; Wilmington, Mass.) would be fed Wayne rodent chow until study onset. At study onset (Day 1) animals would be Q' and Q' can be the same or different and each is separated into groups (n=4-6/group) and fed chow Supple independently selected from the group consisting of H, mented with 0.5% by weight of cholesterol (Research Diets -G, —(C-Clso alkylene)-G, —OR. —OC(O)R. Inc., New Brunswick, N.J.). One group of hamsters would OC(O)OR, OC(O)NR'R'' and -L-M; receive a dosage of 3 mg/kg of body weight of any one of Q is 1 to 5 substituents independently selected from the the compounds of Formulae (II), (III), (IV) or (V) admin group consisting of alkyl, alkenyl, alkynyl, -G, —(C- istered once daily for 7 days, starting on Day 1 via oral Co alkylene)-G, —OR. —(C-Co alkylene)-OR', gavage in 0.2 ml corn oil. The control group of hamsters —C(O)R. —(C-C alkylene)-C(O)R. —C(O)CR, would receive placebo corn oil in the same amount on the —(C-C, alkylene)-C(O)OR, OC(O)R’, (C-C,

US 2007/O 155676 A1 Jul. 5, 2007 25

-continued -continued

CH

cro- -o-c-sco- * N N CNH -( ) s

(M4) O-C(O)-(CH2--O-(OC and

O-C(O)-(CH, -NHC(O)

wherein Me is methyl: M is selected from the group of moieties consisting of

(M1) (M5)

O O HC | 2 NoH, o1 , YCH, HC HC CH

CH3 (M2)

US 2007/O 155676 A1 Jul. 5, 2007 26

X1 is 1 to 10; -continued (M7) X2 is 1 to 10; x3 is 1 to 10; A. O X4 is 1 to 10;

O X5 is 1 to 10; O X6 is 1 to 10; and HC is 2 NCH, or1 n c Y YCH, X7 is 1 to 10; H.C. CH x8 is 1 to 10; X9 is 1 to 10; OH X10 is 1 to 10; and (M8) OH O X11 is 1 to 10;

O with the proviso that at least one of Q', Q, Q, Q and Q O is -L-M or the Sugar residue, disugar residue, trisugar HC | s residue, tetrasugar residue, Sugar acid, amino Sugar, or 2 NoH, or1 a c Y NCH, oligopeptide residue of G is substituted with -L-M, and wherein each of the above alkyl, alkenyl, alkynyl, alky H3C CH3 lene, alkoxyalkoxy, alkoxyalkoxyalkoxy alkoxycarbo nylalkoxy, alkoxyarylalkoxy, alkoxyiminoalkyl, alkyl dioyl, allyloxy, aryl, arylalkyl, aryloxy, arylalkoxy, aroyl, aroyloxy, aroylaroyloxy, arlalkoxycarbonyl, ben Zoylbenzoyloxy, heteroaryl, heteroarylalkyl, heteroary lalkoxy, dioxolanyl, heterocyclyl, heterocyclylalkyl, (M9) heterocyclylcarbonyl, or heterocyclylcarbonylalkoxy F groups, when present, is independently Substituted or unsubstituted. 2. The compound according to claim 1, wherein m, n and rare each Zero, q is 1. p is 2, and Z is —CH2—. 3. The compound according to claim 1, wherein m, n and rare each Zero, q is 1. p is 2, and Z is —CH2—, Q' is —OR, wherein R is hydrogen and Q is fluorine. 4. The compound according to claim 1, wherein RandR are each hydrogen. 5. The compound according to claim 1, wherein Q' and Q are each independently selected from the group consisting of OR, O(CO)R, O(CO)OR and O(CO)NR'R''. 6. The compound according to claim 1, wherein Q is halo pharmaceutically acceptable salts of the moieties (M1) to or OR. (M9) and free acids of the moieties (M1) to (M9); 7. The compound according to claim 1, wherein Q is R and R can be the same or different and each is -OR wherein R is H. independently selected from the group consisting of 8. The compound according to claim 1, wherein Q', Q, hydrogen, alkyl and aryl; Q, Q or Q is -L-M. R. R. and R can be the same or different and each is 9. The compound according to claim 1, wherein Q', Q, independently selected from the group consisting of Q, Q or Q is -G or —(C-Cso alkylene)-G. hydrogen, alkyl, aryl and arylalkyl, and 10. The compound according to claim 1, wherein G is each R is independently alkyl, aryl or arylalkyl. selected from the group consisting of: each R' is independently H or alkyl: q is 0 or 1; Risa O ORa Risa O OR4a r is 0 or 1: m, n and p are independently selected from 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the Sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the Sum of m, q and n is 1, 2, 3, 4 or 5: US 2007/O 155676 A1 Jul. 5, 2007 27

dioxy, Oxo, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -continued - N(CH), —C(O) NHalkyl, —C(O) N(alkyl). —C(O)-alkyl, —C(O)-alkoxy and pyrrolidinylcarbo nyl; or R is a covalent bond and R', the nitrogen to OR7a which it is attached and R form a pyrrolidinyl, pip O eridinyl, N-methyl-piperazinyl, indolinyl or morpholi nyl group, or a alkoxycarbonyl-Substituted pyrrolidi -HC OR5a, nyl, piperidinyl,- 0 N-methylpiperazinyl, indolinyl or morpholinyl group. RO OR4a 11. The compound according to claim 10, wherein G is selected from:

OR3b OH R4bO R

3 OR3a iiiOH, RaC) O O CHR and CO2H OH O CHR

... iiiiOH, III OAc, O OR5a -HC OH OCH2Ph ORa OR3a

wherein R, R and R can be the same or different and each is independently selected from the group consist ing of H. —OH, halo. —NH, azido, alkoxyalkoxy or W R; W is independently selected from the group consisting of -CH IIIOCH2Ph, NH-C(O) , O—C(O)—, O C(O) N(R) , NH C(O) N(R) and s - O C(S) N(R') : OCHPh OCHPh

OAc OAc OH OH R* and R' can be the same or different and each is independently selected from the group consisting of H, alkyl, acetyl, aryl and arylalkyl, iitiiOH, R, R, R, R7, R and R can be the same or different and each is independently selected from the group consisting of H, alkyl, acetyl, arylalkyl, —C(O)alkyl and —C(O)aryl; R" is independently selected from the group consisting of R-substituted T, R-substituted-T-alkyl, R*-substi tuted-alkenyl, R-substituted-alkyl, R-substituted cycloalkyl and R-substituted-cycloalkylalkyl: R" is independently selected from the group consisting of H and alkyl: T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl; R’ is 1 to 3 substituents which are each independently Selected from the group consisting of H, halo, alkyl, —OH, phenoxy, —CF, —NO, alkoxy, methylene US 2007/O 155676 A1 Jul. 5, 2007 28

15. The compound according to claim 1, wherein M is -continued

OAc (MI1)

O O and O O H NoH, o1 No1 NCH, / M H3C H3C CH3 F

CH

or pharmaceutically acceptable salts thereof. 16. The compound according to claim 1, wherein M is

(M2) wherein Ac is acetyl and Ph is phenyl. O C, 12. The compound according to claim 1, wherein option ally one or more carbon atoms of the —(C-C alkylene)- O O radical of Q', Q, Q, Q and Q is independently replaced H bv —O—. HC C C y - - - - 2 NoH, o 1 yo1 NCH, 13. The compound according to claim 1, wherein L is HC CH

CH3

O-C(O)-(CH), (O)C or pharmaceutically acceptable salts thereof. 17. The compound according to claim 1, wherein M is

(M3) 14. The compound according to claim 1, wherein L is O

CH3 O HC No. 1. O O N N |

or pharmaceutically acceptable salts thereof. US 2007/O 155676 A1 Jul. 5, 2007 29

18. The compound according to claim 1, wherein M is 19. The compound according to claim 1, wherein M is

(M7) (M4) A. O

O O HC It is 2 NCH, o 1 s NCH, H3C CH3

OH

or pharmaceutically acceptable salts thereof. 20. The compound according to claim 1, which is selected or pharmaceutically acceptable salts thereof. from the group consisting of

(II) O O O

OAc C Sr-rO O O

C

F N CH, O1 N^n, O H3C CH3

F CH3

15A

(III)

OAc C S^-r

15 US 2007/O 155676 A1 Jul. 5, 2007 30

-continued (IV)

S.

le H N O and O

18 (V) F

S N O le H N O O

21. A pharmaceutical composition for the treatment of lowering a concentration of cholesterol, phytosterol or atherosclerosis, hypercholesterolemia, Sitosterolemia, dia 5C-stanol in plasma of a mammal, treating demyelination or betes mellitus, obesity, stroke, lowering a concentration of treating Alzheimer's disease or regulating a level of an cholesterol, phytosterol or 5C.-stanol in plasma of a mam amyloid B peptide in a subject comprising the step of mal, treating demyelination or treating Alzheimer's disease administering to a subject in need of Such treatment an and/or regulating levels of amyloid 3 peptides in a subject comprising a therapeutically effective amount of a com effective amount of a compound of claim 1. pound of claim 1 in a pharmaceutically acceptable carrier. 24. A method of lowering cholesterol level in plasma of 22. A pharmaceutical composition comprising a choles a mammal in need of Such treatment comprising adminis terol-lowering effective amount of a compound of claim 1 in tering a pharmaceutically effective amount of the compound a pharmaceutically acceptable carrier. of claim 1. 23. A method of treating atherosclerosis, hypercholester olemia, Sitosterolemia, diabetes mellitus, obesity, stroke,