US 2002O169134A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0169134A1 Davis (43) Pub. Date: Nov. 14, 2002 (54) USE OF SUBSTITUTED AZETIDINONE Related U.S. Application Data COMPOUNDS FOR THE TREATMENT OF STOSTEROLEMA (60) Provisional application No. 60/264,645, filed on Jan. 26, 2001. (75)75 Inventor: Harry R. Davis, Berkeley Heights, NJ Publication Classification (US) Correspondence Address: (51) Int. Cl." .................... A61K 31/397; A61K 31/7042 SCHERING-PLOUGH CORPORATION (52) U.S. Cl. ......................................... 514/23: 514/210.02 PATENT DEPARTMENT (K-6-1, 1990) (57) ABSTRACT 2000 GALLOPING HILL ROAD KENILWORTH, NJ 07033-0530 (US) The present invention is directed to the use of Sterol absorp tion inhibiting compounds, pharmaceutical compositions thereof, therapeutic combinations and their use in combina (73) Assignee: Schering Corporation tion with other lipid lowering agents to treat or prevent sitosterolemia and/or to lower the concentration of Sterol(s) (21) Appl. No.: 10/057,629 other than cholesterol in plasma or tissue of a mammal. Methods of treating or preventing vascular disease and (22) Filed: Jan. 25, 2002 coronary events also are provided. US 2002/0169134 A1 Nov. 14, 2002 USE OF SUBSTITUTEDAZETIDINONE absorption inhibitor, or prodrug of the at least one Sterol COMPOUNDS FOR THE TREATMENT OF absorption inhibitor or pharmaceutically acceptable Salt or STOSTEROLEMA Solvate of the least one Sterol absorption inhibitor, or mixture thereof. CROSS-REFERENCE TO RELATED APPLICATION 0008. In another embodiment, the present invention pro vides a method of treating or preventing Sitosterolemia, 0001) This application claims the benefit of U.S. Provi comprising administering to a mammal in need of Such sional Application Serial No. 60/264,645 filed Jan. 26, 2001. treatment: (1) an effective amount of at least one Sterol absorption inhibitor, or pharmaceutically acceptable Salt or FIELD OF THE INVENTION Solvate of the least one Sterol absorption inhibitor, or pro 0002 The present invention provides methods and phar drug of the least one Sterol absorption inhibitor or pharma maceutical compositions for treating or preventing Sitoster ceutically acceptable Salt or Solvate of the least one Sterol olemia by administering to a mammal in need of Such absorption, or mixture thereof, and (2) an effective amount treatment an effective amount of at least one treatment of at least one bile acid Sequestrant or other lipid lowering composition comprising at least one Sterol absorption inhibi agent. tor and optionally, an effective amount of at least one bile 0009. In another embodiment, the present invention pro acid Sequestrant or other lipid lowering agent. vides a method of treating or preventing Sitosterolemia comprising administering to a mammal in need of Such BACKGROUND OF THE INVENTION treatment: (1) an effective amount of at least one Sterol 0003. Sitosterolemia is a genetic lipid storage disorder absorption inhibitor, or pharmaceutically acceptable Salt or characterized by increased levels of Sitosterol and other Solvate of the least one Sterol absorption inhibitor, or pro plant Sterols in the plasma and other tissues due to increased drug of the least one Sterol absorption or pharmaceutically non-Selective intestinal absorption of Sterols and decreased acceptable Salt or Solvate of the least one Sterol absorption hepatic removal. Individuals having Sitosterolemia can inhibitor, or mixture thereof, and (2) at least one Sterol exhibit one or more of the following conditions: tendon and biosynthesis inhibitor. tuberous Xanthomas, arthritis, hemolytic episodes, acceler 0010. Other embodiments of the present invention ated atherosclerosis and myocardial infarctions, and can die include pharmaceutical compositions for the treatment or at an early age due to extensive coronary atherosclerosis. prevention of Sitosterolemia comprising an effective amount See Nguyen et al., “Regulation of cholesterol biosynthesis in of the compositions or combinations used in the methods Sitosterolemia: effects of lovastatin, cholestyramine, and described above in a pharmaceutically acceptable carrier. dietary sterol restriction”, Vol 32, Journal of Lipid Research, pp. 1941-1948, (1991), incorporated by reference herein. 0011) Another embodiment of the present invention is a method of reducing plasma or tissue concentration of at least 0004 Sitosterolemia can be treated with bile acid seques one non-cholesterol Sterol (Such as a phytosterol), 5C.-Stanol, trants (Such as cholestyramine, colesevelam hydrochloride or mixture thereof, comprising administering to a mammal and colestipol), however, these compounds have a tendency in need of Such treatment an effective amount of at least one to cause constipation in patients and therefore compliance treatment composition comprising an effective amount of at with this treatment is difficult. Bile acid sequestrants least one Sterol absorption inhibitor or at least one Stanol (insoluble anion exchange resins) bind bile acids in the absorption inhibitor, or pharmaceutically acceptable Salt or intestine, interrupting the enterohepatic circulation of bile Solvate of the least one sterol absorption inhibitor or the at acids and causing an increase in the fecal excretion of least one Stanol absorption inhibitor, or prodrug of the least Steroids. Use of bile acid Sequestrants is desirable because of one Sterol absorption inhibitor or the at least one Stanol their non-Systemic mode of action. Bile acid Sequestrants absorption inhibitor or pharmaceutically acceptable Salt or can lower intrahepatic cholesterol and promote the Synthesis of apo B/E (LDL) receptors which bind LDL from plasma Solvate of the least one sterol absorption inhibitor or the at to further reduce cholesterol levels in the blood. least one Stanol absorption inhibitor, or mixture thereof. 0012 Yet another embodiment of the present invention is 0005 Alternative treatments include ileal bypass Surgery a method of reducing plasma or tissue concentration of at and Selective low density lipoprotein plasmapheresis, which least one non-cholesterol Sterol, 5C.-Stanol, or mixture are physically undesirable for the patient. thereof, comprising administering to a Sitosterolemic mam 0006 An improved treatment for sitosterolemia is needed mal in need of Such treatment an effective amount of at least which can reduce the concentration of Sterols in plasma and one treatment composition comprising an effective amount tissues and inhibit associated debilitating physical effects. of at least one Sterol absorption inhibitor or at least one Also, treatments which reduce the plasma or tissue concen Stanol absorption inhibitor, or pharmaceutically acceptable tration of non-cholesterol Sterols Such as phytosterols and salt or Solvate of the least one sterol absorption inhibitor or 5C.-Stanols are needed. the at least one Stanol absorption inhibitor, or prodrug of the least one Sterol absorption inhibitor or the at least one Stanol SUMMARY OF THE INVENTION absorption inhibitor or pharmaceutically acceptable Salt or 0007. The present invention provides a method of treat Solvate of the least one sterol absorption inhibitor or the at ing or preventing Sitosterolemia, comprising administering least one Stanol absorption inhibitor, or mixture thereof. to a mammal in need of Such treatment an effective amount 0013 In another embodiment, the present invention pro of at least one Sterol absorption inhibitor, or pharmaceuti vides a method of treating vascular disease, arteriosclerosis cally acceptable Salt or Solvate of the least one Sterol and/or atherosclerosis, comprising administering to a mam US 2002/0169134 A1 Nov. 14, 2002 mal in need of Such treatment an effective amount of at least methods, compositions or combinations of this invention are one treatment composition comprising an effective amount represented by Formula (I): of at least one Sterol absorption inhibitor or at least one Stanol absorption inhibitor, or pharmaceutically acceptable salt or Solvate of the least one sterol absorption inhibitor or (I) the at least one Stanol absorption inhibitor, or prodrug of the R1 least one Sterol absorption inhibitor or the at least one Stanol Arl-A-Y --, Ari absorption inhibitor or pharmaceutically acceptable Salt or Solvate of the least one sterol absorption inhibitor or the at R2 least one Stanol absorption inhibitor, or mixture thereof to reduce plasma or tissue concentration of at least one non O NAr2 cholesterol Sterol, 5C.-Stanol or mixture thereof. 0.014. In another embodiment, the present invention pro vides a method of preventing or reducing risk of a cardio 0020 or isomers of the compounds of Formula (I), or vascular event comprising administering to a mammal an pharmaceutically acceptable Salts or Solvates of the com effective amount of at least one treatment composition pounds of Formula (I) or of the isomers of the compounds comprising an effective amount of at least one Sterol absorp of Formula (I), or prodrugs of the compounds of Formula (I) tion inhibitor or at least one Stanol absorption inhibitor, or or of the isomers, Salts or Solvates of the compounds of pharmaceutically acceptable Salt or Solvate of the least one Formula (I), wherein in Formula (I): Sterol absorption inhibitor or the at least one Stanol absorp 0021) Ar' is R-substituted aryl; tion inhibitor, or prodrug of the least one Sterol absorption inhibitor or the at least one stanol absorption inhibitor or 0022) Art is R-substituted aryl; pharmaceutically