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), amino acid 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.