US 2003OO69221A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0069221A1 KOSOglou et al. (43) Pub. Date: Apr. 10, 2003 (54) COMBINATIONS OF STEROL ABSORPTION Related U.S. Application Data INHIBITOR(S) WITH CARDIOVASCULAR AGENT(S) FOR THE TREATMENT OF (60) Provisional application No. 60/323,842, filed on Sep. WASCULAR CONDITIONS 21, 2001. Provisional application No. 60/264,396, filed on Jan. 26, 2001. Provisional application No. (75) Inventors: Teddy Kosoglou, Jamison, PA (US); 60/264,600, filed on Jan. 26, 2001. Provisional appli Rudyard J. Ress, Flemington, NJ (US); cation No. 60/264,275, filed on Jan. 26, 2001. John T. Strony, Lebanon, NJ (US); Enrico P. Veltri, Princeton, NJ (US); Publication Classification William Hauer, Warren, NJ (US) (51) Int. Cl. ................................................ A61K 31/397 Correspondence Address: (52) U.S. Cl. ........................................................ 514/210.02 SCHERING-PLOUGH CORPORATION PATENT DEPARTMENT (K-6-1, 1990) (57) ABSTRACT 2000 GALLOPING HILL ROAD KENILWORTH, NJ 07033-0530 (US) The present invention provides compositions, therapeutic (73) Assignee: Schering Corporation combinations and methods including: (a) at least one Sterol absorption inhibitor and (b) at least one cardiovascular agent (21) Appl. No.: 10/057,339 different from the sterol absorption inhibitor, which can be useful for treating vascular conditions, obesity, diabetes and (22) Filed: Jan. 25, 2002 lowering plasma levels of Sterols. US 2003/0069221A1 Apr. 10, 2003 COMBINATIONS OF STEROL ABSORPTION ever means, less cholesterol is delivered to the liver. The INHIBITOR(S) WITH CARDIOVASCULAR consequence of this action is decreased hepatic lipoprotein AGENT(S) FOR THE TREATMENT OF WASCULAR (VLDL) production and an increase in the hepatic clearance CONDITIONS of plasma cholesterol, mostly as LDL. Thus, the net effect of inhibiting intestinal cholesterol absorption is a decrease in CROSS-REFERENCE TO RELATED plasma cholesterol levels. APPLICATIONS 0007 U.S. Pat. Nos. 5,767,115, 5,624,920, 5,668,990, 0001. This application claims the benefit of priority from 5,656,624 and 5,688,787, respectively, disclose hydroxy U.S. Provisional Patent Application Serial No. 60/323,842 Substituted azetidinone compounds and Substituted B-lactam filed Sep. 21, 2001, U.S. Provisional Patent Application compounds useful for lowering cholesterol and/or in inhib Serial No. 60/264,396 filed Jan. 26, 2001, U.S. Provisional iting the formation of cholesterol-containing lesions in Patent Application Serial No. 60/264,600 filed Jan. 26, 2001, mammalian arterial walls. U.S. Pat. Nos. 5,846,966 and and U.S. Provisional Patent Application Serial No. 60/264, 5,661,145, respectively, disclose hydroxy-Substituted azeti 275 filed Jan. 26, 2001, each incorporated herein by refer dinone compounds or Substituted B-lactam compounds in CCC. combination with HMG CoA reductase inhibitors for pre venting or treating atherosclerosis and reducing plasma FIELD OF THE INVENTION cholesterol levels. 0002 The present invention relates to methods, compo 0008 PCT Patent Application No. WO 00/38725 dis Sitions and therapeutic combinations comprising certain closes cardiovascular therapeutic combinations including an cardiovascular agents and Sterol absorption inhibitors for ileal bile acid transport inhibitor or cholesteryl ester trans treating atherOSclerosis, coronary artery disease and other port protein inhibitor in combination with a fibric acid derivative, nicotinic acid derivative, microSomal triglyceride vascular conditions in mammals. transfer protein inhibitor, cholesterol absorption antagonist, phytosterol, Stanol, antihypertensive agent or bile acid BACKGROUND OF THE INVENTION Sequestrant. 0.003 Vascular disease is a term that broadly encom 0009 U.S. Pat. No. 5,698,527 discloses ergostanone passes all disorders of blood vessels including Small and derivatives Substituted with disaccharides as cholesterol large arteries and veins and blood flow. The most prevalent absorption inhibitors, employed alone or in combination form of vascular disease is arterioSclerosis, a condition with certain other cholesterol lowering agents, which are associated with the thickening and hardening of the arterial useful in the treatment of hypercholesterolemia and related wall. Arteriosclerosis of the large vessels is referred to as disorders. atherosclerosis. Atherosclerosis is the predominant underly ing factor in vascular disorderS Such as coronary artery 0010. Other vascular conditions frequently coexist with disease, aortic aneurysm, arterial disease of the lower cholesterol levels associated with atherosclerosis. These extremities and cerebrovascular disease. may include hypertension, angina and/or arrhythmia. The relevance of, for example, elevated blood pressure as a risk 0004 One major risk factor for arteriosclerosis is high factor for atherosclerosis, cardiovascular and cerebrovascu Serum cholesterol. A total cholesterol level in excess of lar disease in both men and women has been clarified in a 225-250 mg/dl is associated with significant elevation of risk large number of epidemiological Studies. of vascular disease, particularly coronary heart disease. 0011 Clinical trials of blood pressure lowering using 0005 Cholesteryl esters are a major component of ath cardiovascular agents including, for example, calcium chan erosclerotic lesions and the major Storage form of choles nel blockers, have shown beneficial effects in the treatment terol in arterial wall cells. Formation of cholesteryl esters is of early atheroscleroticlesions (see, e.g., Lichtien, P. R. et al. also a step in the intestinal absorption of dietary cholesterol. :Lancet, 335: 1109-1113 (1990) and Waters, D. et al. Cir Thus, inhibition of cholesteryl ester formation and reduction culation 82: 1940-1953 (1990)). Scott (PCT patent Appli of Serum cholesterol can inhibit the progression of athero cation No. WO 99/11260) describes combinations of an Sclerotic lesion formation, decrease the accumulation of HMG CoA reductase inhibitor with an antihypertensive cholesteryl esters in the arterial wall, and block the intestinal agent for the treatment of atherosclerosis and other Symp absorption of dietary cholesterol. toms of vascular disease risk. Additionally, Egon et al. (PCT 0006 The regulation of whole-body cholesterol homeo Patent Application No. WO 96/40255) describe a combina Stasis in mammals and animals involves the regulation of tion therapy of antihypertensive agents including eplerenone dietary cholesterol and modulation of cholesterol biosynthe and angiotensin II antagonist for treating cardiovascular sis, bile acid biosynthesis and the catabolism of the choles disease. terol-containing plasma lipoproteins. The liver is the major 0012 Despite recent improvements in the treatment of organ responsible for cholesterol biosynthesis and catabo vascular disease, there remains a need in the art for lism and, for this reason, it is a prime determinant of plasma improved compositions and treatments for atherosclerosis, cholesterol levels. The liver is the site of synthesis and other vascular diseases and conditions associated with vas secretion of very low density lipoproteins (VLDL) which are cular diseases Such as hypertension, atherosclerosis, and Subsequently metabolized to low density lipoproteins (LDL) hyperlipidaemia. in the circulation. LDL are the predominant cholesterol carrying lipoproteins in the plasma and an increase in their SUMMARY OF THE INVENTION concentration is correlated with increased atherosclerosis. 0013 In one embodiment the present invention provides When intestinal cholesterol absorption is reduced, by what a composition comprising (a) at least one Sterol absorption US 2003/0069221A1 Apr. 10, 2003 inhibitor or pharmaceutically acceptable Salt or Solvate 0020 “Cardiovascular agents” which may used to treat thereof or prodrug of the at least one Sterol absorption the vascular conditions of the present invention, obesity or inhibitor or of the salt or solvate thereof; and (b) at least one diabetes and/or to reduce the level of Sterol(s) in the plasma, cardiovascular agent for treating a vascular condition, dia as used herein, are members of different classes, including betes, obesity and/or lowering a concentration of a Sterol in calcium channel blockers, angiotensin-converting enzyme plasma of a mammal which is different from the at least one (ACE) inhibitors, angiotensin-II receptor antagonists, sterol absorption inhibitor. diuretics, adrenergic blockers including beta-adrenergic 0.014. Therapeutic combinations also are provided com receptor blockers and alpha-adrenergic receptor blockers, prising: (a) a first amount of at least one sterol absorption adrenergic Stimulants, coronary vasodilators, antihyperten inhibitor or pharmaceutically acceptable Salt or Solvate Sive agents, diuretics, anti-anginal agents and combinations thereof or prodrug of the at least one Sterol absorption thereof. The phrase “cardiovascular agents' as used herein inhibitor or of the salt or solvate thereof; and (b) a second does not include HMGCoA reductase inhibitors. The car amount of at least one cardiovascular agent for treating a diovascular agents as defined above are chemically or Struc vascular condition in a mammal which is different from the turally different from the sterol absorption inhibitor(s) dis at least one sterol absorption inhibitor, wherein the first cussed below, for example, they contain one or more amount and the Second amount