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United States Patent (10) Patent No.: US 7,199,243 B2

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United States Patent (10) Patent No.: US 7,199,243 B2 US007 1992.43B2 (12) United States Patent (10) Patent No.: US 7,199,243 B2 Baglev et al. 45) Date of Patent: Apr. 3,9 2007 (54) PIPERIDINE COMPOUNDS USEFUL AS 6,376,494 B1 4/2002 Childers et al. ....... 514, 252.14 PPARACTIVATORS FOREIGN PATENT DOCUMENTS (75) Inventors: Scott W. Bagley, Mystic, CT (US); EP O548798 * 6, 1993 Thomas A. Brandt, North Stonington, JP O2.173426 g2002 CT (US); Robert W. Dugger, WO WO9210468 6, 1992 Stonington, CT (US); William A WO WO9219594 11, 1992 glon, s WO WO9307 141 4f1993 Hada, Waterford, CT (US); Cheryl M. WO WO 93.12086 6, 1993 Hayward, Old Lyme, CT (US); WO WO 96.02250 * 2, 1996 Zhengyu Liu, Carlsbad, CA (US) WO WO9602250 2, 1996 WO WO 9736579 10, 1997 (73) Assignees: Pfizer Inc., New York, NY (US); Pfizer WO WO9805331 2, 1998 Products Inc., Groton, CT (US) WO WO OO14066 3, 2000 WO WOOO234O7 4/2000 (*) Notice: Subject to any disclaimer, the term of this WO WO O1f90101 * 11, 2001 patent is extended or adjusted under 35 W W 93. H3. U.S.C. 154(b) by 340 days. WO WO O190101 11 2001 WO WO O228834 4/2002 (21) Appl. No.: 10/720,942 WO WO O23O896 4/2002 WO WO O2O64139 8, 2002 (22) Filed: Nov. 24, 2003 WO WO O2O64549 8, 2002 (65) Prior Publication Data OTHER PUBLICATIONS Palani et al., Journal of Medicinal Chemistry, 2005, 48, 4746.* US 2004/O157885 A1 Aug. 12, 2004 Heinone, T. Currect Atherosclerosis Reports, 2002, 4(1), Sum O O mary.* Related U.S. Application Data Thomas et al., Archives des Maladies du Coeur et des Vaisseaux, (60) Provisional application No. 60/429,506, filed on Nov. 1992, 85, Summary.* 26, 2002. Narayanaswamy et al., J. Vas. Intervent. Radiol., 11(1), 2000, s Summary. D* (51) Int. Cl Archives des Maladies du Coeur et des Vaisseaux, 1991, 84/11, we Summary.* CO7D 2II/08 (2006.01) Human and Ecological Risk Assessment, 1999, 84/11, Summary.* CO7D 2II/02 (2006.01) Patani et al., Chem. Rev., 1996, 96.3147-3176.* A6 IK 3/445 (2006.01) Komoto, T., et al., New Strong Fibrates with Piperidine Moiety, (52) U.S. Cl. ....................... 54.6/191; 546/184: 514/330 Chem. Pharm. Bull., vol. 48, No. 12, pp. 1878-1985 (2000). (58) Field of Classification Search 54.6/184 Eo * cited by examiner See application file for complete search history. Primary Examiner D. Margaret Seaman (74) Attorney,V, AgAgent, or Firm—Lisa A. Samuels; Charles W. (56) References Cited Ashbrook; Rosanne Goodman U.S. PATENT DOCUMENTS (57) ABSTRACT 3,801,581 A 4, 1974 Rossi et al. ............ 260,293.72 4,460,594. A * 7/1984 Markwell ................... 514,323 PPAR alpha activators, pharmaceutical compositions con 4476,311 A 10/1984 Shetty et al. ............... 548,531 taining such compounds and the use of Such compounds to 4,618,614 A * 10/1986 Hausberg et al. ........... 514,321 elevate certain plasma lipid levels, including high density 5,411,972 A 5/1995 Komoto et al. ............. 514,330 lipoprotein-cholesterol and to lower certain other plasma 5,420,305 A 5/1995 Ramig et al. ............... 549,292 lipid levels, such as LDL-cholesterol and triglycerides and 5,658,944 A 8/1997 Chapman, Jr. et al. ..... 514,748 accordingly to treat diseases which are exacerbated by low 5,994,356 A 11/1999 Pieper et al. ............... 514,252 levels of HDL cholesterol and/or high levels of LDL 6,153,758 A 1 1/2000 Sannicolo et al. .......... 548,111 cholesterol and triglycerides, such as atherosclerosis and 6,303,637 B1 10/2001 Bao et al. ................... 514,331 cardiovascular diseases, in mammals, including humans. 6,323,229 B1 1 1/2001 Howard ...................... 514,373 6,362.203 B1 3/2002 Mogi et al. ................. 514,327 12 Claims, No Drawings US 7,199,243 B2 1. 2 PPERDINE COMPOUNDS USEFUL AS in urine or blood. The administration of an excess dose of PPARACTIVATORS insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. CROSS-REFERENCE TO RELATED Treatment of non-insulin dependent diabetes mellitus (Type APPLICATION II diabetes, NIDDM) usually consists of a combination of diet, exercise, oral hypoglycemic agents, e.g., thiazolidene This application Ser. No. 10/720,942 claims the benefit of diones, and in more severe cases, insulin. However, the U.S. provisional application No. 60/429,506, filed Nov. 26, clinically available hypoglycemic agents can have side 2002. effects that limit their use. In the case of insulin dependent 10 diabetes mellitus (Type I), insulin is usually the primary BACKGROUND OF INVENTION course of therapy. U.S. Pat. No. 5,658,944, WO92/10468, WO97/36579, The present invention relates to peroxisome proliferator WO98/05331 and WO 00/23407 disclose agents for the activator receptor (PPAR) agonists, in particular, PPARC. treatment of atherosclerosis, obesity and diabetes. agonists, pharmaceutical compositions containing Such ago 15 T. Komoto et al., Chem. Pharm. Bull., 48 (12) 1978–1985 nists and the use of Such agonists to treat atherosclerosis, (2000), and JP14173426A disclose certain fibrate com hypercholesterolemia, hypertriglyceridemia, diabetes, obe pounds containing piperidine moieties. International Publi sity, osteoporosis and Syndrome X (also known as metabolic cation No. WO 93/12086 discloses arylamide derivatives syndrome) in mammals, including humans. useful for treating and preventing various thromboses, Atherosclerosis, a disease of the arteries, is recognized to embolisms, arterioscleroses, hypertensions and so forth. be the leading cause of death in the United States and International Publication No. WO 02/30896 discloses 2,2- Western Europe. The pathological sequence leading to ath diphenylbutanamide derivatives useful as peripherally act erosclerosis and occlusive heart disease is well known. The ing analgesic and neurogenic pain controller. U.S. Pat. No. earliest stage in this sequence is the formation of “fatty 5,411,972 discloses arylamide derivatives for treating hyper streaks' in the carotid, coronary and cerebral arteries and in 25 lipemia. U.S. Pat. No. 6,362.203 discloses 4-hydroxy-4- the aorta. These lesions are yellow in color due to the phenylpiperidine derivatives having peripheral analgesic presence of lipid deposits found principally within Smooth action. U.S. Pat. No. 5,994,356 discloses carboxylic acid muscle cells and in macrophages of the intima layer of the derivatives having aggregation-inhibiting activity. arteries and aorta. Further, it is postulated that most of the International Publication Nos. WO 02/064549 and cholesterol found within the fatty streaks, in turn, gives rise 30 02/064139 disclose certain compounds which are PPARC. to development of the “fibrous plaque,” which consists of activators. accumulated intimal smooth muscle cells laden with lipid U.S. Pat. No. 3,801,581 discloses certain C-phenyl-fatty and Surrounded by extra-cellular lipid, collagen, elastin and acids substituted by azacycloalkyl residues and their deriva proteoglycans. These cells plus matrix form a fibrous cap tives which are useful as anti-inflammatory and antiphlo that covers a deeper deposit of cell debris and more extra 35 gistic agents. International Publication No. WO 01/81310 cellular lipid. The lipid is primarily free and esterified discloses certain 1-aroyl-piperidinyl benzamidines which cholesterol. The fibrous plaque forms slowly, and is likely in inhibit Factor Xa or tryptase. time to become calcified and necrotic, advancing to the International Publication No. WO 01/90101 discloses “complicated lesion,” which accounts for the arterial occlu arylmethylamine derivatives for use as tryptase inhibitors. sion and tendency toward mural thrombosis and arterial 40 International Publication No. WO 01/85716 discloses nitro muscle spasm that characterize advanced atherosclerosis. substituted 2-piperidone compounds for the treatment of Epidemiological evidence has firmly established hyper cancer. International Publication No. WO 00/14066 dis lipidemia as a primary risk factor in causing cardiovascular closes 4.4-biarylpiperidine derivatives with opiod receptor disease (CVD) due to atherosclerosis. In recent years, lead activity. U.S. Pat. No. 6,153,755 discloses a process for ers of the medical profession have placed renewed emphasis 45 preparing piperidine compounds and intermediates there on lowering plasma cholesterol levels, and low density fore. lipoprotein cholesterol in particular, as an essential step in International Publication No. WO 96/02250A1 discloses prevention of CVD. The upper limits of “normal are now haloperidol analogs and their uses. International Publication known to be significantly lower than heretofore appreciated. No. WO 02/28834 discloses processes for the preparation of As a result, large segments of Western populations are now 50 aryl-piperidine carbinols and intermediates thereof. realized to be at particularly high risk. Additional indepen U.S. Pat. No. 6,376,494 discloses cycloalkyl-substituted dent risk factors include glucose intolerance, left ventricular aryl-piperazines, piperidines and tetrahydropyridines as hypertrophy, hypertension, and being of the male sex. Car serotonergic agents, which may be useful for the treatment diovascular disease is especially prevalent among diabetic of anxiety, depression, cognitive deficits and prostate cancer. Subjects, at least in part because of the existence of multiple 55 U.S. Pat. No. 6,303,637 discloses heterocyclic potassium independent risk factors in this population. Successful treat channel inhibitors to treat autoimmune disorders, cardiac ment of hyperlipidemia in the general population, and in arrhythmias and the like. U.S. Pat. No. 6.323,229 discloses diabetic subjects in particular, is therefore of exceptional N-acyl and N-aroyl aralkylamides useful in treating or medical importance. preventing migraine, depression and other disorders for In spite of the early discovery of insulin and its subse 60 which a 5-HT agonist or antagonist is indicated. U.S. Pat. quent widespread use in the treatment of diabetes, and the No. 6,153,758 discloses heteroarylic-arylic diphosphines as later discovery of and use of Sulfonylureas, biguanides and chiral catalysts for Stereocontrolled reactions.
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