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Patent Application Publication (10) Pub. No.: US 2009/0131395 A1 Antonelli Et Al

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Patent Application Publication (10) Pub. No.: US 2009/0131395 A1 Antonelli Et Al US 20090131395A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0131395 A1 Antonelli et al. (43) Pub. Date: May 21, 2009 (54) BIPHENYLAZETIDINONE CHOLESTEROL Publication Classification ABSORPTION INHIBITORS (51) Int. Cl. (75) Inventors: Stephen Antonelli, Lynn, MA A 6LX 3L/397 (2006.01) (US); Regina Lundrigan, C07D 205/08 (2006.01) Charlestown, MA (US); Eduardo J. A6IP 9/10 (2006.01) Martinez, St. Louis, MO (US); Wayne C. Schairer, Westboro, MA (52) U.S. Cl. .................................... 514/210.02:540/360 (US); John J. Talley, Somerville, MA (US); Timothy C. Barden, Salem, MA (US); Jing Jing Yang, (57) ABSTRACT Boxborough, MA (US); Daniel P. The invention relates to a chemical genus of 4-biphenyl-1- Zimmer, Somerville, MA (US) phenylaZetidin-2-ones useful in the treatment of hypercho Correspondence Address: lesterolemia and other disorders. The compounds have the HESLN ROTHENBERG EARLEY & MEST general formula I: PC S COLUMBIA. CIRCLE ALBANY, NY 12203 (US) (73) Assignee: MICROBIA, INC., Cambridge, MA (US) “O O (21) Appl. No.: 11/913,461 o R2 R4 X (22) PCT Filed: May 5, 2006 R \ / (86). PCT No.: PCT/USO6/17412 S371 (c)(1), (2), (4) Date: May 30, 2008 * / Related U.S. Application Data (60) Provisional application No. 60/677,976, filed on May Pharmaceutical compositions and methods for treating cho 5, 2005. lesterol- and lipid-associated diseases are also disclosed. US 2009/013 1395 A1 May 21, 2009 BPHENYLAZETIONONE CHOLESTEROL autoimmune disorders, (6) an agent used to treat demylena ABSORPTION INHIBITORS tion and its associated disorders, (7) an agent used to treat Alzheimer's disease, (8) a blood modifier, (9) a hormone FIELD OF THE INVENTION replacement agent/composition, (10) a chemotherapeutic 0001. The present invention relates to a chemical genus of agent, (11) a peptide which mitigates one or more symptoms 4-biphenyl-1-phenylaZetidin-2-ones, useful in the treatment of atherosclerosis, (12) an anti-cancer agent, (13) an agent of hypercholesterolemia and other disorders. used to treat bone loss and associated disorders, and (14) other agents. BACKGROUND OF THE INVENTION 0007. The compounds and pharmaceutical formulations 0002 1,4-Diphenylazetidin-2-ones and their utility for described herein can be used in methods for treating a con treating disorders of lipid metabolism are described in U.S. dition for which a cholesterol absorption inhibitor is indi Pat. No. 6,498,156, USRE37721, in U.S. published patent cated; preventing or treating a cholesterol related disease; applications 2004/0067913, 2004/0082561 and 2004/ inhibiting the absorption of or reducing plasma or tissue 0198700, in PCT applications WO02/50027, WO2004/ concentration of one or more sterols or stanols; preventing or 005247, WO2004/087655 and in European applications EP 1 treating sistoSerolemia; preventing or treating vascular dis 362855 and 1522541, the disclosures of which are incorpo eases/disorders and conditions, dyslipidemia, mixed dyslipi rated herein by reference. demia, hypo C-lipoproteinemia, LDL pattern B. LDL pattern 0003 4-Biaryl-1-phenylazetidin-2-ones and their utility A, primary dysbetalipoproteinemia (Frederickson Type III), for treating disorders of lipid metabolism are described in hyperlipidemia (including but not limited to hypercholester copending commonly owned U.S. patent application Ser. No. olemia, hypertriglyceridemia, Sitosterolemia), hypertension, 10/986,570 filed Nov. 10, 2004, the disclosure of which is angina pectoris, cardiac arrhythmias, congestive heart failure, incorporated herein by reference. and stroke; reducing the incidence of cardiovascular disease related events; preventing or treating vascular conditions and SUMMARY OF THE INVENTION associated thrombotic events; preventing or treating vascular inflammation; reducing blood plasma or serum concentra 0004. In a first aspect, the invention relates to compounds tions of C-reactive protein; preventing, treating, or ameliorat of formula I ing symptoms of Alzheimer's Disease (AD); regulating pro duction or levels of at least one amyloid f (AB) peptide: regulating the amount of ApoE isoform 4 in the bloodstream I and/or brain; preventing or treating cognitive related disor R'- e ders (including dementia); preventing or treating obesity; preventing or decreasing the incidence of Xanthomas; pre N-4 a venting or minimizing muscular degeneration and related N side effects associated with certain HMG-CoA reductase 2 inhibitors (statins); preventing or treating diabetes and asso R4 y-R ciated conditions; preventing or treating at least one autoim mune disorder, preventing or treating demyelination and { \ / associated disorders; preventing or treating cholesterol asso ciated tumors; inhibiting the expression of at least one mul tiple (“multi’)-drug resistance gene or protein in an animal cell; enhancing the effectiveness of a chemotherapeutic agent M in a Subject having cancer, reversing a multi-drug resistance / phenotype exhibited by an animal cell; modulating lipid raft structure; and preventing or treating osteopenia disorders wherein (bone loss disorders). The methods comprise administering a R" and Rare selected independently from the group consist therapeutically effective amount of a compound or pharma ing of hydrogen, halogen, —OH, and lower alkoxy; ceutical formulation described herein. R" is selected from the group consisting of hydrogen, -OH, 0008. The invention relates to an article of manufacture and a glucuronide; comprising a container, instructions, and a pharmaceutical R is selected from the group consisting of OH, -POH, formulation as described above. The instructions are for the —SOH, a Sugar, a polyol, a glucuronide and a Sugar carbam administration of the pharmaceutical formulation for a pur ate; and pose chosen from: treating a condition for which a cholesterol U is (C-C)-alkylene in which one or more —CH2— is absorption inhibitor is indicated; preventing or treating a cho replaced by a radical chosen from —S— —S(=O)—, lesterol related disease; inhibiting the absorption of or reduc SO. , —O—, —C(=O)—, —CH(glucuronide)-, and ing plasma or tissue concentration of one or more sterols or —CH(OH)—. stanols; preventing or treating sistoserolemia; preventing or 0005. The invention also includes pharmaceutically treating vascular diseases/disorders and conditions, dyslipi acceptable salts thereof, in any stereoisomeric form, or a demia, mixed dyslipidemia, hypo C-lipoproteinemia, LDL mixture of any such compounds in any ratio. pattern B. LDL pattern A, primary dysbetalipoproteinemia 0006. The compounds described herein can be included in (Frederickson Type III), hyperlipidemia (including but not pharmaceutical formulations comprising a pharmaceutically limited to hypercholesterolemia, hypertriglyceridemia, sito acceptable carrier and one or more of: (1) a dyslipidemic sterolemia), hypertension, angina pectoris, cardiac arrhyth agent, (2) an anti-diabetic agent, (3) an anti-hypertensive mias, congestive heart failure, and stroke; reducing the inci agent, (4) an anti-obesity agent, (5) an agent used to treat dence of cardiovascular disease-related events; preventing or US 2009/013 1395 A1 May 21, 2009 treating vascular conditions and associated thrombotic 0014 Examples of U linkages include, but are not limited events; preventing or treating vascular inflammation; reduc to the following: - SCH-CH(OH)–: S(=O)CHCH ing blood plasma or serum concentrations of C-reactive pro (OH)–: -SOCHCH(OH)–:-SCHC(=O)–: S(=O) tein; preventing, treating, or ameliorating symptoms of CHC(=O)–: -SOCHC(=O)–: —OCHCH(OH)–: Alzheimer's Disease (AD); regulating production or levels of –OCHC(=O)–: CH(OH)CHO : —C(=O) at least one amyloid B (AB) peptide; regulating the amount of CHO : -CH(OH)CHS : —C(=O)CHS : ApoE isoform 4 in the bloodstream and/or brain; preventing - CH-CH(OH)–: CHCHCH-CH(OH)–: —OCHCH or treating cognitive related disorders (including dementia); (=O)–: - SCHCH-CH(OH)–: - SCHCHC(=O)–: preventing or treating obesity; preventing or decreasing the - S(=O)CHCH-CH(OH)–: OCHCHCH(OH)–: incidence of Xanthomas; preventing or minimizing muscular - SOCHCH-CH(OH)–: —SOCHCHC(=O)–: degeneration and related side effects associated with certain -CH(OH)CHCH(OH)–: –OCHCH-CH(OH)–: HMG-CoA reductase inhibitors (statins); preventing or treat —SCH-CH(glucuronide)-; —S(=O)CH-CH(glucu ing diabetes and associated conditions; preventing or treating ronide)-; SOCHCH(glucuronide)-; —OCHCH(glucu at least one autoimmune disorder; preventing or treating ronide)-; —CH(glucuronide)CHO—: —CH(glucuronide) demyelination and associated disorders; preventing or treat CHS : —CH2CH(glucuronide)-; —CH2CH2CHCH ing cholesterol associated tumors; inhibiting the expression (glucuronide)-; —SCHCHCH(glucuronide)-; S(=O) of at least one multiple (“multi’)-drug resistance gene or CHCH-CH(glucuronide)-; —OCH2CH2CH(glucuronide)-; protein in an animal cell; enhancing the effectiveness of a —SOCHCHCH(glucuronide)-; —CH(glucuronide) chemotherapeutic agent in a Subject having cancer; reversing CHCH(glucuronide)-; and —OCH2CHCH(glucuronide)-. a multi-drug resistance phenotype exhibited by an animal Other variations for U would be obvious to those of ordinary cell; modulating lipid raft structure; treating or preventing a skill in the chemical arts. In addition, embodiments of Cs- and diseasee associated with lipid raft structure; and preventing or Co-alkylenes, in which one or more —CH2— is replaced treating osteopenia disorders (bone loss disorders). would be obvious to one of ordinary
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