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[R-(R*R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl-3-- phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof |
| RE40667 |
[R-(R*R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl-3-- phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof
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| Patent Drawings: | |
| Inventor: |
Roth |
| Date Issued: |
March 17, 2009 |
| Application: |
11/653,830 |
| Filed: |
January 16, 2007 |
| Inventors: |
Roth; Bruce (San Jose, CA)
|
| Assignee: |
Warner-Lambert Company LLC (New York, NY) |
| Primary Examiner: |
McKane; Joseph K. |
| Assistant Examiner: |
Kosack; Joseph R |
| Attorney Or Agent: |
Connolly, Bove Lodge & Hutz LLP |
| U.S. Class: |
514/422; 514/423; 548/517; 548/537 |
| Field Of Search: |
514/422; 514/423; 548/517; 548/537 |
| International Class: |
A61K 31/40; A61K 31/35; C07D 207/327 |
| U.S Patent Documents: |
|
| Foreign Patent Documents: |
601981; 621874; 1161380; 1268768; 1304080; 1330441; 2021546; 2465565; 01 171 588; 171588; 0 024 348; 0 114 027; 0 171 588; 0 211 416; 0 221 025; 0 232 997; 0 247 633; 0 251 625; 0 259 086; 0 319 856; 0 330 172; 89103078.5; 0 409 281; 1197/87; 890391; 2240/1982; 10572/1983; 62-289577; 72652/1988; 1987-5372; WO 84/02131; PT84975; WO 88/07582; WO 89/07598; PT89774; WO 90/00553; WO 97 03959; WO 99/47138 |
| Other References: |
Hall and Roush, J. Org. Chem., 47: 4611-4621 (1982). cited by other.
Roush and Gillis, J. Org. Chem., 47: 4825-4829 (1982). cited by other.
Sit et al, J. Med. Chem., 33:2982 (1990). cited by other.
Amin et al., J. Pharmacology 46:13 (1993). cited by other.
Underberg et al., J. Pharm. Biomed Anal. 8(8-12): 681-683 (1990). cited by other.
Stinson, Chemical and Engineering News, 70(39): 46-79 (1992). cited by other.
Stinson, Chemical and Engineering News, 71(39): 38-64 (1993). cited by other.
Burlinson, Tablets and Tabletting, William Heinemann medical Books Ltd. : London, 1968. cited by other.
Casy, A.F. Stereochemistry and Biological Activity. Medicinal Chemistry, Wiley: New York, 1970. cited by other.
Rawlins, Bentley's Textbook of Pharmaceutics, 8.sup.th Ed., Bailliere Tindall: London, 1977. cited by other.
Seeman, P. Drug Receptors. Kalant H. et al. eds., Principles of Medical Pharmacology, 4.sup.thEdition, University of Toronto Press: Toronto, 1985. cited by other.
Lachman et al., Proformulation, The Theory and Practice of Industrial Pharmacy, 3.sup.rd Edition, Lea & Febiger: Philadelphia, 1986. cited by other.
Lieberman et al., eds. Pharmaceutical Dosage Forms Tablets, 2.sup.nd Edition (vol. 1), Marcel Dekker: New York, 1989. cited by other.
Gennaro, Remington's Pharmaceutical Sciences, 18.sup.th Ed., Mack Printing Company: Easton, Pennsylvania, 1990. cited by other.
Banker, Rhodes, eds., Modern Pharmaceutics, 3.sup.rd Edition, Marcel Dekker, Inc.: New York, 1996. cited by other.
Kibbe, A.H., ed., Handbook of Pharmaceutical Excipients, 3.sup.rd Ed., Pharmaceutical Press: London, 2000. cited by other.
The Merck Index, 10.sup.th Edition (1983), entry 5949: N-Methylglucamine, pp. 870-871. cited by other.
The Merck Index, 12.sup.th Edition (1996), entry 897: Atorvastatin, p. 146. cited by other.
Transcript of evidence given by Dr. Scallen in US trial of Prizer, Inc., et al. v Ranbaxy Laboratories Limited wt. al., Court file No. 03-209-JJF, on Dec. 3, 2004. cited by other.
Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances, Feb. 1987. cited by other.
Stein et al., The Lovastatin-Niacin Trial: Effects on Lipoproteins. Arteriosclerosis and Thrombosis 11: 1458a (1991). cited by other.
Dujovne et al., The Lovastatin-Niacin Trial: Adverse Events. Arteriosclerosis and Thrombosis 11: 1458a (1991). cited by other.
Frost, P.H. et al., Lipid Metabolism. In PA Fitzgerald, Ed., Handbook of Clinical Endocrinology, 2.sup.nd Edition, Appleton and Lange, 1991. cited by other.
Frost, P.H. et al., Lovastatin-Niacin Comparative Trial. JACC 19, 374A, 1992. cited by other.
Lovastatin Study Groups I through IV. Lovastatin 5-year safety and efficacy study. Arch. Intren. Med. 153: 1079-1087 (1993). cited by other.
Illingworth, D.R. et al., Comparative effects of lovastatin and niacin in primary hypercholesterolemia: A prospective trial. Arch. Intern. Med. 154: 1586-1595 (1994). cited by other.
Stein, E.A. et al., Efficacy and tolerability of low-dose simvastatin and niacin, alone and in combination, in patients with combined hyperlipidemia: a prospective trial. J. Cardiovasc. Pharmacol. Therapeut. 1: 107-116 (1996). cited by other.
Frost, P.H. et al., Rationale for use of non-high-density lipoprotein cholestrol rather than low-density lipoprotein cholesterol as a tool for lipoprotein cholestrol screening and assessment of risk and therapy, Am. J. Cardiol. 81: 26B-31B (1998).cited by other.
Havel, R.J. et al., The role of non-high-density lipoprotein cholesterol in evaluation and treatment of lipid disorders. J. Clin. Endocrinology and Metabolism 85: 2105-2108 (2000). cited by other.
The Cholestrol Myth, Atlantic Monthly, Sep. 1989. cited by other.
National Cholesterol Education Program Guideline III (2004 Update). cited by other.
Results of the National Cholesterol Education (NCEP) Program Evaluation Project Utilizing Novel E-Technology (NEPTUNE) II Survey and Implications for Treatment under Recent NCEP Writing Group Recommendations. cited by other.
Chapter 1--Selling to Everyone High Cholesterol. In Moynihan R. and Cassels A., Selling Sickness, Avalon Publishing Group: 2005, pp. 1-21. cited by other.
Letter dated Dec. 2, 2005 from Taylor Wessing to L. Caswell attaching expert reports of Dr. Newton dated May 27, 2005 and Jun. 17, 2005 that were filed in Ranbaxy (UK) v. Warner-Lambert Company, HC-04C 02167, and said reports. cited by other.
Trial transcripts taken on Jul. 18 to 22, 2005 and Jul. 25, 2005 in Ranbaxy (UK) Limited v. Warner-Lambert Company, HC-04C 02167. cited by other.
Warner-Lambert Company Notices of Application court files T-507-05, T-1128-05. cited by other.
English translation of Austrian decisions invalidating Austrian Patent No. 207 ,896. cited by other.
Lipitor advertising placed in the Canadian Medical Association Journal, from 1997 to 2005. cited by other.
Consenus Conference. Lowering Blood Cholesterol to Prevent Heart Disease. JAMA 253: 1080-2086 (1985). cited by other.
Report on the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. The Expert Panel. Arch. Intern. Med. 148: 36-69 (1988). cited by other.
Canadian Consenus Conference on Cholestrol. Final Report, Canadian Consenus Conference on the Prevention of Heart and Vascular Disease by Altering Serum Cholesterol and Serum Lipoprotein Factors. CMAJ 139: 111-63 (1988). cited by other.
Frolich et al., Rationale for and Outline of the Recommendations of the Working Group of Hypercholesterolemia and Other Dyslipidemias: Interim Report. Can. J. Cardiol. 14 (supp. A): 17A-21A (1998). cited by other.
Fodor et al., for the Working Group on Hypercholesterolemia and Other Dyslipidemias: Recommendations for the Management and Treatment of Dyslipidemia. CMAJ 162 (10): 1441-1447 (2000). cited by other.
Fodor et al., Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: 2003 update. CMAJ 168(9): 921-924 (2003). cited by other.
NHLBI News Release May 15, 2001, http://www.nhlbi.nih.gov/new/press/01-05-15.htm. cited by other.
Manuel et al., The 2003 Canadian Recommendations for Dyslipidemia Management: Revisions are Needed. CMAJ 172: 1027-1032 (2005). cited by other.
Documents compiled by the World Health Organization's Department of Essential Drugs & Medicines Policy published as http://www.drugpromo.info/read-reviews.asp?id=4 and http://www.drugpromo.info/read-reviews.asp?id=5. cited by other.
Wazana, A., JAMA 283(3): (373-380 (2000). cited by other.
Brophy et al., Statin wars following coronary revascularization--Evidence based clinical practice? Can. J. Cardiol. 22(1): 54-58 (2006). cited by other.
Havel et al., A multicenter study of mevinolin (lovastatin) in treatment of heterozygous familial hypercholestolemia. Annals Int. Med. 107: 609 (1987). cited by other.
Lovastatin Study Group III. A multicenter comparison of lovastatin and cholestyramine in the therapy of severe primary hypercholesterolemia. JAMA 260: 359 (1988). cited by other.
Defendants' Trial Exhibit 3323, "Data Provided to Patent Office in '995 Specification and Data from Experiment 107," from Pfizer, Inc et al. v. Ranbaxy Laboratories Limited et al., US District Court, District of Deleware, 03-209-JJF. cited by other.
Defendants' Trial Exhibit 3325 from Pfizer, Inc. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF. cited by other.
Defendants' Trial Exhibit 3325A from Pflizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF. cited by other.
Dietschy 1, CSI IC.sub.50 values, from Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF. cited by other.
Dietschy 2, COR IC.sub.50 values, from Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF. cited by other.
Dietschy 3, IC.sub.50 values (nM) for head-to-head CSI and COR screens, from Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF. cited by other.
Dietschy 4, AICS data, from Pfizer, Inc et al. v. Ranbaxy Laboratories Limited. et al., US District Court, District of Delaware, 03-209-JJF. cited by other.
Defendants' Trial Exhibit 319 from Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US. District Court, District of Delaware, 03-209-JJF. cited by other.
Defendants' Trial Exhibit 321 from Pfizer, Inc et al, v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF. cited by other.
Roth et al., Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus. J.Med. Chem. 34(1): 357-366 (Jan. 1991). cited by other.
Warner-Lambert Pharmaceutical Research Report No. RR-740-02620, Acute Inhibition of Cholesterol Synthesis in the Rat by the Calcium Salts (Racemic and Chiral) of CI-971, dated May 31, 1989, identified as DTX 11 in Pfizer, Inc et al. v. RanbaxyLaboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF. cited by other.
Warner-Lambert/Parke-Davis memo to Oberkfell and Pieroni from Newton and Roth re: PD 134298-38A Product Profile A for HMG-Co-A Reductase Inhibitor, Jun. 1, 1989, identified as DTX 142 in Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., USDistrict Court, District of Delaware, 03-209-JJF. cited by other.
Warner-Lambert/Parke-Davis Pharmaceutical Research Report RR-740-01682, CSI (Cholesterol Synthesis Inhibitors): A Rapid Screen for Inhibitors of Cholesterol Synthesis in Crude Microsomal Preparations from Rat Liver, dated May 3, 1985, identified asDTX 271 in Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF. cited by other.
Parke-Davis Memo re: Lead Compound Pharmacological Profile for CI-981 (PD 134298-38A) to Mr. H.F. Oberkfell and Mr. J. Peroni from Newton and Roth, dated Sep. 28, 1989, identified as DTX 4 in Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, etal., US District Court, District of Delaware, 03-209-JJF. cited by other.
Chemist's Binder of Biological Data, identified as DTX 552, in Pfizer, Inc et al., v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF. cited by other.
CI-981 IND submitted to the FDA, identified as DTX 326 in Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF. cited by other.
Sit et al., Synthesis, Biological Profile, and Quantitative Structure Activity Relationship of a Series of Novel 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors. J. Med. Chem.33: 2982-2999 (1990). cited by other.
Alberts Am.J.Cardiology vol. 62, 10J-15J (1988). cited by other.
Alberts Proc Natl Acad Sci USA Jul. 1980;777(7):3957-61. cited by other.
Ariens et al. Cholinergic and Anticholinergic Drugs: Do they act on common receptors?, Ann NY Acad Sci, vol. 144, pp. 842-868 (1967). cited by other.
Ariens Stereochemistry and Biological Activity of Drugs, 11-53, 89-102, 161-185 (1983). cited by other.
Ariens Stereochemistry, a Basis for Sophisticated Nonsense in Pharmacokinetics and Clinical Pharmacology, Eur. J. Clin. Pharmacol., vol. 26, pp. 663-668 (1984). cited by other.
Ariens, E.J. "Implications of the Neglect of Stereochemistry in Pharmacokinetics and Clinical Pharmacology", Drug Intelligence and Clinical Pharmacy, (Oct. 1987), vol. 21, 827-829. cited by other.
Ariens, E.J., "Stereochemistry in the Analysis of Drug-Action. Part II", Medicinal Research Reviews, (1987), vol. 7, No. 3, 367-387. cited by other.
Ariens, E.J., "Stereochemistry: A Source of Problems in Medicinal Chemistry", Medicinal Research Reviews, (1986), vol. 6, No. 4, 451-466. cited by other.
Ariens, Chirality in bioactive agents and its pitfalls, TIPS, Elsevier Science Publishers B.V., Amsterdam, pp. 200-205 (1986). cited by other.
Audebert Direct Resolution of Enantiomers in Column Liquid Chromatography, J. Liquid Chromatography, vol. 2, No. 8, 1063-1095 (1979). cited by other.
Banitt, E.H. et al., "Resolution of Flecainide Acetate, N-(2-Piperidylmethyl)-2,5-bi5(2,2,2,-trifluoroethoxy)benzamide Acetate, and Antiarrhythmic Properties of the Enantiomers", J. Med. Chem. (1986),29:299-302. cited by other.
Berge et al. Pharmaceutical Salts, J. Pharm. Sci., vol. 66(1):1-19 (1977). cited by other.
Braun, M et al., Tetrahedron Lett., 25, 5031-5034 (1984). cited by other.
Brown, A.G. et al., "Crystal and Molecular Structure of Compactin, a New Antifungal Metabolite from Penicillium brevicompactum", J. Chem. Soc. Perkin I, (1976) 1165-1170. cited by other.
Burger Medicinal Chemistry, Chapter 7, pp. 81-107 (1970). cited by other.
Carey et al. "Advanced Organic Chemistry", 2nd Ed., Chapter 2 and p. 75 (1984). cited by other.
Stinson Chemical and Engineering News, 70, Sep. 28, 46 (1992). cited by other.
Stinson Chemical and Engineering News, 71, Sep. 27, 38 (1993). cited by other.
Collet et al. Optical Resolution by Direct Crystallization of Enantiomer Mixtures, Chemical Reviews, vol. 80, No. 3, 215-230 (1980). cited by other.
Conant et al. The Chemistry of Organic Compounds, A Year's Course in Organic Chemistry, 4.sup.th ed. Macmillan, New York, 1954, p. 234. cited by other.
Cook Enantioselective Drug Analysis, Pharmacy International, vol. 6, No. 12, pp. 302-305 (1985). cited by other.
Decamp Chirality, 1989, 1:2-6. cited by other.
Demerson et al. Resolution of Etodolac and Antiinflammatory and Prostaglandin Synthetase inhibiting Properties of the Enantiomers, J. Med. Chem., vol. 26, No. 12, 1778-1780 (1983). cited by other.
Dotsevi, C. et al., "Chromatographic Optical Resolution through Chiral Complexation of Amino Ester Salts by a Host Covalently Bound to Silica Gel", J. Am. Chem. Soc., (1975), 97:1259-1261. cited by other.
Dugan, R.E. et al., "Factors Affecting the Diurnal Variation in the Level of .beta.-Hydroxy-.beta.-Methylglutaryl Coenzyme A Reductase and Cholestrol-Synthesizing Activity in Rat Liver", Archiv. Biochem. Biophys., (1972), 152:21-27. cited by other.
Eliel et al., Stereochemistry of Organic Compounds, Wiley, New York, 1994, pp. 329-331, and remainder of Section 7-3. cited by other.
Eliel et al., Section 3-1--Compounds with One Asymmetric Carbon Atom, Stereochemistry of Carbon Compounds, McGraw-Hill Book Company, Inc. (1962). cited by other.
Eliel et al., Section 4-4--Resolution of Racemic Modifications, Stereochemistry of Carbon Compounds, McGraw-Hill Book Company, Inc. pp. 47-74 (1962). cited by other.
Endo, J Med Chem., 28: 401-405 (1985). cited by other.
Endo, A. et al., "Biochemical Aspect of HMG CoA Reductase Inhibitors", Adv. in Enzyme Regulation, Proceedings of the 28 Symposium on Regulation of Enzyme Activity and Synthesis in Normal and Neoplastic Tissues held at Indiana University School ofMedicine, Indianapolis, Indiana, (Oct. 2 and 3, 1988), vol. 28, pp. 53-64. cited by other.
Endo, A. et al., "Inhibition of Cholesterol Synthesis in vitro and in vivo by ML-236A and ML-236B, Competitive Inhibitors of 3-Hydroxy-3-methylglutaryl- Coenzyme A Reductase", Eur. J. Biochem., (1977), 77:31-36. cited by other.
Endo, A., "Chemistry, Biochemistry, and Pharmacology of HMG-CoA Reductase Inhibitors," Klin. Wochenschr, (1988) 66:421-427. cited by other.
Falck, J.R. et al., "Total Synthesis of (+)-Dihydromevinolin", Tetrahedron Letters, (1984), vol. 25, No. 33, pp. 3563-3566. cited by other.
Fessenden et al. Section 4.10--Resolution of a Racemic Mixture, Organic Chemistry, 2.sup.nd Ed., Willard Grant Press, Boston (1982). cited by other.
Fieser et al. Organic Chemistry, D. C. Heath, Boston, 2nd ed., 1950, pp. 267-274. cited by other.
Fogassy, E. et al., "Pseudosymmetry and Chiral Discrimination in Optical Resolution via Diasteroisomeric Salt Formation. The Crystal Structures of (R)- and (S)-N-Methylamphetamine Bitartrates (RMERTA and SMERTA)", J. Chem. Soc. Perkin Trans. II,(1986) 1881-1886. cited by other.
Gekkan-Yakuji, vol. 29, No. 10, pp. 23-26 ( with English translation). cited by other.
Goldman, M. et al., "Resolution of Chiral Olefinic Hydrocarbons and Sulfoxides by High-Performance Liquid Chromatography via Diasteromeric Platinum Complexes", J. Am. Chem. Soc.; (1982) 104:1093-1095. cited by other.
Gould, P.L., "Salt Section for Basic Drugs", Int. J. Pharmaceutics, (1986), 33.201-217. cited by other.
Greene Chapter 6--Preformulation, in Modem Pharmaceutics, Banker and Rhodes, Marcel Dekker Inc., New York. cited by other.
Grieco, P.A. et al., "Convergent, Enantiospecific Total Synthesis of the Hypocholesterolemic Agent (+)- Compactin", J. Am. Chem. Soc., (1986) 108:5908-5919. cited by other.
Grieco, P.A. et al., "Total Synthesis of the Hypocholesterolemic Agent (+)- Compactin", J. Am.Chem. Soc., (1983), 105:1403-1404. cited by other.
Grundy, S.M., "HMG-CoA Reductase Inhibitors for Treatment of Hypercholesterolemia", N.E. J. Med., (Jul. 7, 1988), vol. 319, No. 1, pp. 24-33. cited by other.
Guindon, Y. et al., "Preparation of ethyl 5(S),6-epoxy- 3(R)-(methoxymethoxy)hexanoate: A key chiral intermediate for mevinolin and compactin", Tetrahedron Letters, (1985), vol. 26, No. 9, pp. 1185-1188. cited by other.
Heathcock et al. J. Med. Chem. 1987, 30, 1858-1873. cited by other.
Heathcock et al. J. Med. Chem. 1989, 32, 197-202. cited by other.
Helmchen et al, Agnew Chem. Int. Edn. 1979. 18, pp. 63-65. cited by other.
Hirama M. et al., "Chiral Total Synthesis of Compactin", J. Am. Chem. Soc., (1982), 104:4251-4253. cited by other.
Hirama, M. et al., "Total Synthesis of (+)-Monacolin K (Mevinolin)", Tetrahedron Letters, (1983), vol. 24, No. 17, pp. 1811-1812. cited by other.
Hoeg, J.M. et al., "3.-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors in the Treatment of Hypercholesterolemia", JAMA, (Dec. 25, 1987), vol. 258, No. 24, p. 3532-3536. cited by other.
Hoffman et al, J. Med. Chem., 29: 159-169 (Feb. 1986). cited by other.
Hoffman W.F. et al., "3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 4. Side Chain Ester Derivatives of Mevinolin", J. Med. Chem. (1986) 29:849-852. cited by other.
Hsu, C-T, et al., "Total Synthesis of the Hypocholesterolemic Agent Compactin", J. Am. Chem.Soc., (1983), 105:593-601. cited by other.
Hubbard et al. Chiral Pharmacology and its Consequences for Therapeutic Monitoring, Clin. Biochem., vol. 19, pp. 107-112 (1986). cited by other.
Jackson et al. Characterization and Antifertility Activity in Rats of S(+) a-Chlorohydrin Chem.-Biol Interactions, vol. 17, No. 1, 117-120 (1977). cited by other.
Jacques et al Enantiomers, Racemates, and Resolutions, John Wiley & Sons, Toronto (1981)(See C-56-59 for mention of specific sections). cited by other.
Jacques et al. Types of Crystalline Racemates, Enantiomers, Racemates, and Resolutions, c.1, 3-23 (1981). cited by other.
Jacques et al. Formation and Seperation of Diastereomers, Enantiomers, Racemates, and Resolutions, c.5, 251-281 (1981). cited by other.
Jacques et al Section 5.1.2--Resolution of Bases, Enantiomers, Racemates, and Resolutions, John Wiley & Sons, Toronto (1981). cited by other.
Jacques et al. Experimental Aspects and Art of Resolutions, Enantiomers, Racemates, and Resolutions, c.7, 378-434 (1981). cited by other.
Johnson et al. Tetrahedron Letters, vol. 29, No. 31, pp. 3757-3760, 1988. cited by other.
Kalant et al Chapter 9--Drug Receptors, Principles of Medical Pharmacology, 4th ed., University of Toronto Press, Toronto (1985). cited by other.
Kalant et al Chapter 10--Specificity of Drug Action, Principles of Medical Pharmacology, 4th ed., University of Toronto Press, Toronto (1985). cited by other.
Kaneko et al. Eur. J. Biochem., 87:313-321 (1978). cited by other.
Kathawala, E.G., "Exciting Developments in the Area of HMG-CoA Reductase Inhibitors", Trends in Medicinal Chemistry '88: Proceedings of the Xth International Symposium on Medicinal Chemistry, Budapest, Aug. 15-19, 1988, (disclosed at the conferencein Aug. 1988), pp. 709-728 (textbook received at CISTI on Jun. 23, 1989). cited by other.
Kemp et al. Organic Chemistry, Worth, New York, 1980, pp. 172 and 173. cited by other.
Kim, Y.H. et al., Chiral Differentiation by the P-(+)- Hexahelicene-7,7'-dicarboxylic Acid Disodium Salt. Resolution of N-2,4-Dinitrophenyl-.alpha.-amino-acid Esters by High Performance Liquid Chromatography, J. Chem. Soc., Chem. Commun., (1982), p.1336-1337. cited by other.
Krause et al. Atherosclerosis, 117:237 (1995). cited by other.
Lee, TIPS, 8:442-446 (1987). cited by other.
Lee, T-J, "An expeditious chiral route to analogs of mevinolin and compactin", Tetrahedron Letters, (1985), vol. 26, No. 41, pp. 4995-4996. cited by other.
Lee, T-J, et al., "Structural Modification of Mevinolin", J. Org. Chem., (1982), 47:4750-4757. cited by other.
Lehmann et al. Stereoselectivity and Affinity in Molecular Pharmacology, Jucker, E.(ed), Progress in Drug Research, vol. 20, Birkhauser, Basel Stuttgard, pp. 101-142. cited by other.
Lehmann Stereoselective Molecular Recognition in Biology. Cuatrecasas, P., Greaves M.F. (eds), Receptors and Recognition, vol. 5, Series A, Chapman and Hall, London, pp. 1-77 (1978). cited by other.
Lim et al. Enantiomeric resolution of di-threo-methylphenidate, U.S.P. (Ritalin.RTM.), by high- performance liquid chromatography, J. Chromatology, vol. 328, 378-386 (1985). cited by other.
Liu et al. Effect of Enantiomeric Purity on Solubility Determination of Dexclamol Hydrochloride, J. Pharm. Sci., vol. 67, pp. 636-638 (1978). cited by other.
Lynch et al., Tetrahedron Letters, 28: 1385-1388 (1987). cited by other.
Majewski et al. Tetrahedron Letters, vol. 25, No. 20 pp. 2101-2104 1984. cited by other.
Mantell, G., "Lipid Lowering Drugs in Atherosclerosis--The HMG-CoA Reductase Inhibitors", Clin. and Exper. Hyper.-Theory and Practice, (Jan. 1, 1989), vol. 11, Issue 5-6, 927-941. cited by other.
March Methods of Resolution, in Advanced Organic Chemistry--Reactions, Mechanisms and Structure, 2nd Ed., McGraw Hill, New York 1977, pp. 108-111. cited by other.
Martindale, The Extra Pharmacopoeia (ed. Reynolds 28th ed. 1982), p. 44. cited by other.
McBlain et al. Facile Route to the Resolution of the Enantiomers of 1-Chloro-2-[2,2,2,-trichloro-1-(4-chlorophenyl)ethyl]benzene (o.p'-DDT), J. Ag. Food Chem., vol. 25, No. 1, 59-63 (1977). cited by other.
Meyers, A.I., et al., "Separation of Diastereomers Using a Low Cost Preparative Medium-Pressure Liquid Chromatograph", J. Org. Chem., (1979), vol. 44, No. 13, p. 2247-2249. cited by other.
Morrison et al Section 7.9--Reactions of chiral molecules with optically active reagents. Resolution, Organic Chemistry, 3rd Ed., Allyn and Bacon, Inc., Boston (1973). cited by other.
Nakamura et al. Biochemistry, 24:1364-1376 (1985). cited by other.
Narasaka et al. Tetrahedron, 40, 223-2238 (1984). cited by other.
Pirkle, W.H. et al., "Broad Spectrum Methods for the Resolution of Optical Isomers. A Discussion of the Reasons Underlying the Chromatographic Separability of Some Diasteromeric Carbamates", J. Org. Chem,1977), vol. 42, No. 11, pp. 1839-1844. citedby other.
Portoghese Relationships between Stereostructure and Pharmacological Activities, Elliott, H.W., Cutting, W.C., Dreisbach, R.H. (eds), Annual Review of Pharmacology, vol. 10, Annual Reviews Inc., Palo Alto, CA, pp. 51-76 (1970). cited by other.
Prasad, K. et al., "Asymmetric synthesis of (3R-trans)- and (3S-cis)-hydroxy-5-pentanolides", Tetrahedron Letters, (1984), vol. 25, No. 32, pp. 3391-3394. cited by other.
Prugh et al., Tetrahedron Letters 23: 281-284 (1982). cited by other.
Ravin Chapter 75--Preformulation, Remington's Pharmaceutical Sciences, 16th Ed., Philadelphia College of Pharmacy and Science (1980). cited by other.
Repta et al. Utilization of an Enantiomer as a Solution to a Pharmaceutical Problem: Application to Solubilization of I,2-Di(4-piperazine-2,6-dione)Propane, J. Pharm. Sci., vol. 65, pp. 238-242. cited by other.
Robinson Absolute configurations of(-+-)-and (-)-1- amino 3-chloropropan-2-ol hydrochlorides, Chemistry and Industry, No. 15, p. 652 (1976). cited by other.
Rosen, T. et al., "Tetrahedron Report Nu. 208--The Synthesis of Mevinic Acids", Tetrahedron, (1986), vol. 42, No. 18, pp. 4909-4951. cited by other.
Roth et al. Tetrahedron Letters, vol. 29, No. 11, pp. 1255-1258 (1988). cited by other.
Roth, Progress In Med. Chem., 40, 1-22 (2002). cited by other.
Saigo, K. et al., "Optical Resolution of 2-Amino-1,2-diphenylethanol by Preferential Crystallization and Its Utilization in Fractional Crystallization and Enantioselective Reduction of Prochiral Ketones", Bull. Chem. Soc. Jpn., (1982) 55:1568-1573.cited by other.
Schneider, C.S. et al., "Dopamine Autoreceptor Agonists: Resolution and Pharmacological Activity of 2,6-Diaminotetrahydrobenzothiazole and an Aminothiazole Analogue of Apomorphine", J. Med. Chem., (1987), 30:494-498. cited by other.
Serizawa, N. et al., "Microbial Hydroxylation of ML-236B (Compactin) and Monacolin K (MG-530B)", J. Antibotics, (May 1983), 36:604-607. cited by other.
Shaw, CDER FDA Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances (1987). cited by other.
Slater, E.E. et al., "Mechanism of Action and Biological Profile of HMG CoA Reductase Inhibitors, A New Therapeutic Alternative", Drugs, (1988) 36 (Suppl. 3):72-82. cited by other.
Sletzinger, M. et al., "A Diasterospecific, Non-Racemic Synthesis of a Novel .beta.-Hydroxy-.delta.Lactone HMG-CoA reductase Inhibitor", Tetrahedron Letters, (1985), vol. 26, No. 25, pp. 2951-2954. cited by other.
Stokker et al., J. Med. Chem 28:347-358 (1985). cited by other.
Stokker et al. J. Med. Chem. 1986, 29, 170-181. cited by other.
Stokker et al. J. Org. Chem, 1986, 51, 4931-4934. cited by other.
Stokker, G.E. et al., "3-Hydroxy-3-methylglutaryl- coenzyme A Reductase Inhibitors. 5. 6-(Fluoren-9-yl)- and 6-(fluoren-9-ylidenyl)-3,5-dihydroxyhexanoic acids and their lactone derivatives", J. Med. Chem., (May 1986), 29(5):852-855. cited by other.
Streitwieser et al., Introduction to Organic Chemistry, Macmillan, New York, 3rd ed. 1985, p. 695. cited by other.
Streitwieser Jr., A., "Stereoisomerism", Introduction to Organic Chemistry, Macmillan, New York, 3rd ed. 1985 Chapter 7, pp. 113-139. cited by other.
Takano et al. Synthesis, Jul. 1989, vol. 7, p. 539-541. cited by other.
The Merck Index, 10th Ed., (1983), entry 5949. N-Methylglucamine, p. 870-871. cited by other.
The Merck Index, 12th Ed., (1996), entry 897. Atorvastatin, p. 146. cited by other.
Tobert, J.A., "New developments in lipid-lowering therapy: the role of inhibitors of hydroxymethylglutarylcoenzyme A reductase", Circulation, (1987), 76, No. 3, 534-538. cited by other.
Viret et al. Simple Optical Resolution of Terleucine, Tetrahedron Letters, vol. 27, No. 48, pp. 5865-5868 (1986). cited by other.
Vollhardt Section 5-7--Resolution: The Separation of Enantiomers, in Organic Chemistry, W.H. Freeman and Company, New York (1987). cited by other.
Vriesema, B.K. et al., "Resolution of 2-amino-5-thiomethyl pentanoic acid (homomethionine) with aminopeptidase from pseudomonas putidaor chiral phosphoric acids", Tetrahedron Letters, (1986), vol. 26, No. 18, p. 2045-2048. cited by other.
Walking, D. et al., "Decision Analysis in Drug Product Development", Drug & Cosmetic Industry, (1973) 112(3):39-41. cited by other.
Weissbuch, I. et al., "Design of Polymeric Inhibitors for the Control of Crystal Polymorphism. Induced Enantiomeric Resolution of Racemic Histidine by Crystallization at 25.degree. C.", J. Am. Chem. Soc., (1987) 109:1869-1871. cited by other.
Wells Pharmaceutical Preformulation: The Physicochemical Properties of Drug Substances--Chapter 2 (1988). cited by other.
Whilen Topics in Stereochemistry, 6, 107-1776 (1971). cited by other.
Wilen et al. Tetrahedron, 33, 2725-2736 (1977). cited by other.
Willaims, K.M., "Chirality: Pharmacokinetics and Pharmacodynamics in 3 Dimensions", Clinical and Experimental Pharmacology and Physiology, (Jun. 1989), vol. 16, No. 6, pp. 465-470. cited by other.
Witiak et al. Pharmaceuticals, Optically Active, Encyclopedia of Chemical Technology, 3ed, vol. 17, 311-345 (1982). cited by other.
Wong, C-H. et al., "Mutual Resolution of (.+-.)-ephedrine and Z-DL-Amino Acid Induced by Seeding Chiral Salt", Tetrahedron Letters No. 40, (1978), p. 3813-3816. cited by other.
Yang, Y-L, et al., "Mevinic Acids and Analogues: Preparation of a Key Chiral Intermediate", Tetrahedron Letters, (1982), vol. 23, No. 42, pp. 4305-4308. cited by other.
Yoshino et al. Diabetes Research and Clinical Practice 2 (1986) 179-181. cited by other.
Pfizer Inc, et al. v. Ranbaxy Pharmaceuticals Limited, et al., 457 F 3d 1284 (Fed. Cir. 2006) (Exhibit 1 to Preliminary Amendment). cited by other.
Pfizer Inc, et al. v. Ranbaxy Pharmaceuticals Limited, et al., 405 F. Supp. 2d 495 (D. Del. 2005) (Exhibit 2 Preliminary Amendment). cited by other.
"Pfizer's Proposed Findings of Fact", CA No. 03-209-JJF (Exhibit 3 to Preliminary Amendment). cited by other.
"Pfizer's Proposed Supplemental Findings of Fact", CA No. 03-209-JJF (Exhibit 4 to Preliminary Amendment). cited by other.
"Pfizer's Proposed Conclusions of Law", CA No. 03-209-JJF (Exhibit 5 to Preliminary Amendment). cited by other.
"Pfizer's Proposed Supplemental Conclusions of Law", CA No. 03-209-JJF (Exhibit 6 to Preliminary Amendment). cited by other.
"Opening Proposed Findings of Fact and Conclusions of Law of Defendants Ranbaxy Laboratories Limited and Ranbaxy Pharmaceuticals Inc.", CA No. 03-209-JJF (Exhibit 7 to Preliminary Amendment). cited by other.
"Petition for Panel Rehearing and Petition for Rehearing En Banc by Defendants-Appellants Ranbaxy Laboratories Limited and Ranbaxy Pharmaceuticals Inc." No. 2006-1179 (Exhibit 8 to Preliminary Amendment). cited by other.
"Plaintiff-Appellee's Response to Petition for Rehearing En Banc", No. 2006-1179 (Exhibit 9 to Preliminary Amendment). cited by other.
"Order" denying Request for Panel Rehearing and Rehearing En Banc (Exhibit 10 to Preliminary Amendment). cited by other.
"Pfizer's Post-Trial Opening Brief", CA No. 03-209-JJF (Exhibit 11 to Preliminary Amendment). cited by other.
"Opening Post-Trial Brief of Defendants Ranbaxy Laboratories Limited and Ranbaxy Pharmaceuticals Inc.", CA No. 03-209-JJF (Exhibit 12 to Preliminary Amendment). cited by other.
"Pfizer's Corrected Post-Trial Reply Brief", CA No. 03-209-JJF (Exhibit 13 to Preliminary Amendment). cited by other.
"Defendant Ranbaxy Laboratories Limited and Ranbaxy Pharmaceuticals Inc.'s Opposition Post-Trial Brief", CA No. 03-209-JJF (Exhibit 14 to Preliminary Amendment). cited by other.
Summaries of Non-United States Proceedings Involving Counterparts to U.S. Patent No. 5,273,995, including: i) List of Countries (3 sheets); ii) Table of Foreign Lawsuits (5 sheets); and iii) Lipitor Canada Enantiomer Cases Document Schedules (28sheets) (Exhibit 15 to Preliminary Amendment). cited by other.
"Brief of Defendants-Appellants Ranbaxy Laboratories Limited and Ranbaxy Pharmaceuticals, Inc." No. 06-1179 (Exhibit 16 to Preliminary Amendment). cited by other.
"Brief of Plaintiffs-Appellees, Pfizer Inc." No. 06-1179 (Exhibit 17 to Preliminary Amendment). cited by other.
"Reply Brief of Defendants-Appellants Ranbaxy Laboratories Limited and Ranbaxy Pharmaceuticals, Inc." No. 06-1179 (Exhibit 18 to Preliminary Amendment). cited by other.
Sanofi-Synthelabo et al. v. Apotex, Inc. et al., No. 06-1613 (Fed. Cir. Dec. 8, 2006) (Exhibit 20 to Preliminary Amendment). cited by other.
US 5,273,995 prosecution history, marked as Defendant's Trial Exhibit 139 in CA No. 023-209 (D. Del.) and comprising pages stamped RA0147320-RA014884 (Exhibit 22 to Preliminary Amendment). cited by other.
CA 1,330,441 file history which includes Canadian Patent Application No. 590,367 as filed Feb. 7, 1989. cited by other.
CA 2,021,546 file history. cited by other.
European Patent Application 87 107 847.3 file history. cited by other.
European Patent Application 90 113 986.5 Claims (part of EP 0409281 file history C152). cited by other.
European Patent Application 90 113 986.5 Claims as granted (part of EP 0409281 file history C152). cited by other.
European Patent Application 90 113 986.5 (Jan. 25, 2000 Communication) (part of EP 0409281 file history C152). cited by other.
European Patent Application 90 113 986.5 Refusal (Sep. 5, 1998) (part of EP 0409281 file history C152). cited by other.
European Patent Application 90 113 986.5 file history. cited by other.
EP 0409281 file history. cited by other.
US 4,618,893 file history. cited by other.
US 5,003,080 file history. cited by other.
CTT Collaborators, "Efficacy and Safety of Cholesterol-Lowering Treatment: Prospective Meta-Analysis of Data from 90 056 Participants in 14 Randomised Trials of Statins", The Lancet, 2005, Vol. 366, pp. 1267-1278. cited by other.
Pfizer Inc.v. Ranbaxy Labs. Ltd., 405 F. Supp. 2d 495 (D. Del. 2005). cited by other.
Pfizer Inc. v. Ranbaxy Labs. Ltd. , 457 F.3d 1284 (Fed. Cir. 2006). cited by other.
Berge, Stephen M. et al., "Pharmaceutical Salts," Journal of Pharm. Science, vol. 66, No. 1 (Jan. 1, 1977). cited by other.
"Guidelines For Submitting Supporting Documentation in Drug Applications For The Manufacture of Drug Substances," Center for Drug Evaluation and Research, Food and Drug Administration, Department of Health and Human Services, Feb. 1987. cited byother.
Ranbaxy Australia Pty. Ltd. v. Warner-Lambert Co. LLC, decision by The Federal Court of Australia (Dec. 20, 2006). cited by other.
Pfizer Canada Inc. v. The Minister of Health and Ranbaxy Labs. Ltd., 2007 FC 91 (Jan. 25, 2007). cited by other.
Letter of Aug. 19, 1998 from US PTO to Francis J. Tinney regarding patent extension for Lipitor. cited by other.
Letter of Nov. 7, 2005 from William Curatolo of Pfizer Global Research & Development and Stephen R. Bym of SSCI, Inc. to the Division of Dockets Management, food and Drug Administration, entitled Citizen Petition. cited by other.
NOC listings for rosuvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, simvastatin, cerivastatin. cited by other.
Ranbaxy Reply in Support of Petition for Certiorari (Exhibit 25 to Supplemental Communication). cited by other.
Supreme Court decision denying Certiorari (Exhibit 26 to Supplemental Communication). cited by other.
Ranbaxy's Apr. 12, 2007 ANDA Notice Letter (Exhibit 27 to Supplemental Communication). cited by other.
Pfizer Complaint (138 Delaware Action) (Exhibit 28 to Supplemental Communication). cited by other.
Ranbaxy Amended Answer and Counterclaims (138 Delaware Action) (Exhibit 29 to Supplemental Communication). cited by other.
Pfizer Reply to Ranbaxy's Amended Answer (138 Delaware Action) (Exhibit 30 to Supplemental Communication). cited by other.
Pfizer Briefs in Support of Motions to Dismiss (138 Delaware Action) (Exhibit 31 to Supplemental Communication). cited by other.
Ranbaxy Responses to Motions to Dismiss (138 Delaware Action) (Exhibit 32 to Supplemental Communication). cited by other.
Teva ANDA Notice Letter (Exhibit 33 to Supplemental Communication). cited by other.
KSR decision (Exhibit 34 to Supplemental Communication). cited by other.
Commissioner's Memorandum re: KSR decision (Exhibit 35 to Supplemental Communication). cited by other.
Pfizer v. Apotex decision (Exhibit 36 to Supplemental Communication). cited by other.
Order Denying Rehearing, and Dissents,in Pfizer v. Apotex decision (Exhibit 37 to Supplenental Communication). cited by other.
Danish decision, Engllish translation (Exhibit 38 to Supplemental Communication). cited by other.
Australian decision, Ranbaxy Australia v. Warner-Lambert Co. LLC (Exhibit 39 to Supplemental Communication). cited by other.
Canada decision, Docket T-507-05, dated Jan. 25, 2007 (Exhibit 40 to Supplemental Communication). cited by other.
Pfizer Canada v. Canada (Minister of Health), 2006 F.C. 1471 (Exhibit 41 to Supplemental Communication). cited by other.
EPO Technical Opinion (Exhibit 42 to Supplemental Communication). cited by other.
Pfizer Complaint (Exhibit 43 to Supplemental Communication). cited by other.
Wanner, C., et al., "Atorvastatin in Patients with Type 2 Diabetes Mellitus Undergoing Hemodialysis", The New England Journal of Medicine, 2005, vol. 353, No. 3, pp. 238-248. cited by other.
Patti, G., et al., "Randomized Trial of Atorvastatin for Reduction of Postoperative Atrail Fibrillation in Patients Undergoing Cardiac Surgery. Results of the ARMYDA-3 (Atorvastatin for Reduction of Myocardial Dysrhythmia After Cardiac Surgery",Circulation, 2006, vol. 114, pp. 1455-1461. cited by other.
"Management of Dyslipidemia in Adults with Diabetes", Diabetes Care, 2003, vol. 26, Supp. 1, pp. S83-S86. cited by other.
"Summary of Revisions for the Clinical Practice Recommendations", Diabetes Care, 2005, vol. 28, Supp. 1, p. S3. cited by other.
"Standards of Medical Care in Diabetes-2008", Diabetes Care, 2008, vol. 31, Supp. 1, pp. S12-S54. cited by other.
Smith, S. C., et al., "AHA. ACC Guidelines for Secondary Prevention for Patients with Coronary and Other Atherosclerotic Vascular Disease: 2006 Update", J. Am. Coll. Cardiol., 2006, vol. 47, No. 10, pp. 2130-2139. cited by other.
Koren, M. J., et al., "Clinical Outcomes in Managed-Care Patients with Coronary Heart Disease Treated Aggressively in Lipid-Lowering Disease Management Clinics", Journal of the American College of Cardiology, 2004, vol. 44, No. 9, pp. 1772-1779.cited by other.
Patti, G., et al., "Atorvastatin Pretreatment Improves Outcomes in Patients with Acute Coronary Syndromes Undergoing Early Percutaneous Coronary Intervention", Journal of the American College of Cardiology, 2007, vol. 49, No. 12, pp. 1272-1278.cited by other.
van Wissen, S., et al., "Long-Term Safety and Efficacy of High-Dose Atorvastatin Treatment in Patients with Familial Hypercholesterolemia", The American Journal of Cardiology, 2005, vol. 95, pp. 264-266. cited by other.
Sever, P. S., et al., "The Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm: Extended Observations 2 Years After Trial Closure", European Heart Journal, 2007, pp. 1-10. cited by other.
Raal, F. J., et al., "A Single-Centre Retrospective Observational Study to Evaluate the Change in Total Cholesterol and LDL Cholesterol in Hyperlipidaemic Patients Switched from Atorvastattin to Simvastatin", Cardiovascular Journal of South Africa,2004, vol. 15, No. 3, pp. 118-123. cited by other.
Knopp, R. H., et al., "Efficacy and Safety of Atorvastatin in the Prevention of Cardiovascular End Points in Subjects with Type 2 Diabetes", Diabetes Care, 2006, vol. 29, No. 7, pp. 1478-1485. cited by other.
McKenney, J. M., et al., "Use of a Treatment Algorithm to Achieve NCEP ATP III Goals with Atorvastatin", J. Cardiovasc Pharmacol. 2005, vol. 46, No. 5, pp. 594-599. cited by other.
Gresser, U., et al., "Atorvastatin: Gold Standard for Prophylaxis of Myocardial Ischemia and Stroke", European Journal of Medical Research, 2004, vol. 9, pp. 1-17. cited by other.
Bone, H. G., "Effects of Atorvastatin on Bone in Postmenopausal Women with Dyslipidemia: A Double-Blind, Placebo-Controlled, Dose-Ranging Trial", The Journal of Clinical Endocrinology & Metabolism, 2007, vol. 92, No. 12, pp. 4671-4677. cited byother.
Colhoun, H. M., et al., "Primary Prevention of Cardiovascular Disease with Atorvastatin in Type 2 Diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): Multicentre Randomised Placebo-Controlled Trial", The Lancet, 2004, vol. 364, pp.685-696. cited by other.
CTT Collaborators, "Efficacy of Cholesterol-Lowering Therapy in 18,686 People with Diabetes in 14 Randomised Trials of Statins: A Meta-Analysis", The Lancet, 2008, vol. 371, pp. 117-125. cited by other.
Pedersen, T. R., et al., "High-Dose Atorvastatin vs Usual-Dose Simvastatin for Secondary Prevention After Myocardial Infarction", JAMA-Express, 2005, vol. 294, No. 19, pp. 2437-2445. cited by other.
Law, M. R., et al., "Quantifying Effect of Statins on Low Density Lipoprotein Cholesterol, Ischaemic Heart Disease, and Stroke: Systematic Review and Meta-Analysis", BMJ, 2003, vol. 326, pp. 1-7. cited by other.
McCrindle, B. W., et al., "Efficacy and Safety of Atorvastatin in Children and Adolescents with Familial Hypercholesterolemia or Severe Hyperlipidemia: A Multicenter, Randomized, Placebo-Controlled Trial", The Journal of Pediatrics, 2003, vol. 142,pp. 74-80. cited by other.
Jones, P. H., et al., "Comparison of the Efficacy and Safety of Atorvastatin Iniitated at Different Starting Doses in Patients with Dyslipidemia", American Heart Journal, 2005, vol. 149, pp. 111e1-111e8. cited by other.
Ncep, "Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report", National Institutes of Health, 2002, pp. I-1 through Ref.-49. cited by other.
Larosa, J. C., et al., "Intensive Lipid Lowering Atorvastatin in Patients with Stable Coronary Disease", The New England Journal of Medicine, 2005, vol. 352, pp. 1-11. cited by other.
"KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease", American Journal of Kidney Diseases, 2007, vol. 49, No. 2, Suppl. 2, pp. S1-S179. cited by other.
Cannon, C. P., et al., "Comparison of Intensive and Moderate Lipid Lowering with Statins After Acute Coronary Syndromes", The New England Journal of Medicine, 2004, vol. 350, No. 15, pp. 1-10. cited by other.
Deedwania, P., et al., "Effects of Intensive Versus Moderate Lipid-Lowering Therapy on Myocardial Ischemia in Older Patients with Coronary Heart Disease: Results of the Study Assessing Goals in the Elderly (SAGE)", Circulation, 2007, vol. 155, pp.700-707. cited by other.
Adams, R. J., et al., "Update to the AHA/ASA Recommendation for the Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack", Stroke, 2008, vol. 39, pp. 1-6. cited by other.
Sparcl Investigators, "High-Dose Atorvastatin After Stroke or Transient Ischemic Attack", The New England Journal of Medicine, 2006, vol. 355, No. 6, pp. 1-11. cited by other.
McCarey, D. W., et al., "Trial of Atorvastatin in Rheumatoid Arthritis (TARA): Double-Blind, Randomised-Placebo-Controlled Trial", The Lancet, 2004, vol. 363, pp. 2015-2021. cited by other.
LaRosa, J. C., et al., "Safety and Efficacy of Atorvastatin -Induced very Low-Density Lipoprotein Cholesterol Levels in Patients with Coronary Heart Disease (A Post Hoc Analysis of the Treating to New Targets [TNT]Study", Am J Cardiol, 2007, vol.100, pp. 747-752. cited by other.
Shepherd, J., et al., "Effect of Intensive Lipid Lowering with Atorvastatin on Renal Function in Patients with Coronary Heart Disease: The Treating to New Targets (TNT) Study", Clin J Am Soc Nephrol. ePress, 2007, vol. 2, pp. 1131-1139. cited byother.
Waters, D. D., et al., "Effects of High-Dose Atorvastatin on Cerebrovascular Events in Patients with Stable Coronary Disease in the TNT (Treating to New Targets) Study", Journal of the American College of Cardiology, 2006, vol. 48, No. 9, pp.1973-1799. cited by other.
Khush, K. K., et al., "Effect of High-Dose Atorvastatin on Hospitalizations for Heart Failure", Circulation, 2007, vol. 115, pp. 576-583. cited by other.
Phillips, B., et al., "Switching Statins: The Impact on Patient Outcomes", The British Journal of Cardiology, 2007, vol. 14, pp. 280-285. cited by other.
Ford, I., et al., "Long-Term Follow-Up of the West of Scotland Coronary Prevention Study", The New England Journal of Medicine, 2007, vol. 357, No. 15, pp. 1477-1486. cited by other.
Decision of the Federal Court of Australia, dated May 28, 2008. cited by other.
Notice of Intent to Issue Ex Parte Reexamination Certificate, dated Apr. 29, 2008, in Reexamination of US. Pat No. 4,681,893. cited by other.
Consent Judgement and Order of the Court, dated May 15, 2008, in Pfizer Inc. et al. v. Cobalt Pharmaceuticals. cited by other.
Foody et al, Clinical Therapeutics 30: 195 (2008). cited by other.
Transcript of Testimony of Dr. James Bowman from Delaware Lipitor trial, given Dec. 12, 2004. cited by other.
Tobert, J.A. et al, "Cholesterol-lowering Effect of Mevinolin, an Inhibitor of 3- hydroxyl-3-methylglutaryl-Coenzyme A Reductase, in Healthy Volunteers", J. Clin. Invest. 69:913 (1982). cited by other.
"Petition for a Writ of Certiorari," Ranbaxy Laboratories Limited et al. v. Pfizer Inc. et al., No. 06-1179, Jan. 22, 2007. (Exhibit 23 to Supplemental Communication). cited by other.
Pfizer Opposition to Ranbaxy Petition for Certiorari, Feb. 26, 2007. (Exhibit 24 to Supplemental Communication). cited by other.
Complaint, Civil Action No. 07-790, United States District Court for the District of Deleware, Dec. 6, 2007 (without exhibits). cited by other.
Complaint, Civil Action No. 1:07-cv-12257, United States District Court for the District of Massachusetts, Dec. 7, 2007 (without exhibits). cited by other.
English Language version of DK 171588 B1 (Feb. 10, 1997). cited by other.
Exhibit 60--Opinion of Delaware District Court--Ranbaxy Caduet.RTM. Case (Nov. 29, 2007). cited by other.
J. W. Hubbard et al.; Clinical Biochemistry, vol. 19, pp. 107-112 (Apr. 1986). cited by other.
Exhibit 15C--Updates and Corrections to Previous Exhibits 15, 15A and 15B. cited by other.
German Decision, Oct. 29, 2007 (English translation). cited by other.
Cobalt Pharmaceuticals, Paragraph IV Certification, Oct. 24, 2007. cited by other.
Mar. 20, 2008 Decision of Federal Court of Appeal(Canada) in Proceedings Between (Pfizer Canada Inc. and Warner-Lambert Company, LLC) and (The Minister of Health and Ranbaxy Laboratories Limited); Case Caption: A-79-07 (Citation: 2008 FCA 108).cited by other.
English Language translation of ruling by The Court of Appeal of the Hague (Feb. 28, 2008). cited by other.
Joint Stipulation; Civil Action No. 07-360 (JJF) (filed Jan. 28, 2008, so ordered Jan. 30, 2008). cited by other.
Joint Stipulation; Civil Action No. 07-360 (JJF) (filed Mar. 10, 2008, so ordered Mar. 11, 2008). cited by other.
Response to Non-Final Office Action in Reexamination of '893 Patent (Control No. 90/008,727) dated Mar. 7, 2008. cited by other.
Third Information Disclosure Statement in Reexamination of '893 Patent (Control No. 90/008,727) dated Mar. 7, 2008. cited by other.
Answer, Affirmative Defenses and Counterclaims of Defendant Cobalt Pharmaceuticals, Inc.; C.A. No. 07-790-JJF (Jan. 25, 2008). cited by other.
Reply to Counterclaims; C.A. No. 07-790-JJF (Feb. 22, 2008). cited by other.
Certified English language translation of Apr. 7, 2008 Decision of Provincial Court of Barcelona (Spain); Appeal from Commercial Court decision; Parties--Krn Pharma, S.L.; Laboratorios Cinfa, S.A. et al. and Warner-Lambert Company et al.; Judgement184/2007-2. cited by other.
Second ANDA Notice Letter from Teva Pharmaceuticals USA, Inc. to Pfizer, Inc and Warner-Lambert Company (Mar. 12, 2008). cited by other.
Stipulated Amended Order of Final Judgement in Civil Action No. 07-138 (JJF) (Dec. 13, 2007). cited by other.
First Office Action in Reexamination of '893 Patent (Control No. 90/008,727) dated Jan. 10, 2008. cited by other.
Jan. 4, 2008 Decision of Canadian Court in Proceedings Between (Pfizer Canada Inc. and Warner-Lambert Company, LLC) and (The Minister of Health and Apotex Inc.); Case Caption: T-16-06. cited by other.
"Examination Guidelines for Determining Obviousness Under 35 U.S.C. .sctn. 103 in View of Supreme Court Decision in KSR International Co. v. Teleflex Inc. , " 72 Fed. Reg. 57526 (Oct. 10, 2007). cited by other.
Aventis Pharma Deutschland GmbH v. Lupin Pharmaceutical , Inc. , 799 F. 3d 1293 (Fed. Cir. Sep. 11, 2007). cited by other.
Aventis Pharma Deutschland Gmbh. v. Lupin Pharmaceuticals, Inc. , 2006 U.S. Dist. Lexis 48246 (E.D.Va. 2006). cited by other.
Alberts et al., PNAS USA 77:3957 (1980). cited by other.
Illingworth and Bacon, Am. J. Cardiol. 30:33G (1987). cited by other.
"Consent Order and Stipulated Injunction" in C.A. No. 07-cv-138-JJF ("Caduet.RTM. case") dated Jun. 20, 2008. cited by other. |
|
| Abstract: |
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-((1-methylethyl)- -3-phenyl-4-[(phenylamino)-carbonyl)]-1H-pyrrole-1-heptanoic acid or (2R-trans)-5-(4-fluoro-phenyl)-2-(1-methylethyl-N,4-diphenyl-1-[2-(tetrah- ydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide; and pharmaceutically acceptable salts thereof. |
| Claim: |
I claim:
.[.1. [R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methyl- ethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid or(2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrah- ydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide; or pharmaceutically acceptable salts thereof..].
.[.2. A compound of claim 1 which is [R-(R*R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)-- 3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid..].
.[.3. A compound of claim 1 which is (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrah- ydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide..].
.[.4. The monosodium salt of the compound of claim 2..].
.[.5. The monopotassium salt of the compound of claim 2..].
6. The hemicalcium salt of .[.the compound of claim 2.]. .Iadd.[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methyl- ethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid.Iaddend..
.[.7. The N-methylglucamine salt of the compound of claim 2..].
.[.8. The hemimagnesium salt of the compound of claim 2..].
.[.9. The hemizinc salt of the compound of claim 2..].
.[.10. The 1-deoxy-1-(methylamino)-D-glucitol mixture with the compound of claim 2..].
.[.11. A pharmaceutical composition for treating hypercholesterolemia comprising a hypocholesterolemic effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier..].
.[.12. A method of inhibiting cholesterol synthesis in a human suffering from hypercholesterolemia comprising administering a compound of claim 1 in unit dosage form..].
.Iadd.13. A pharmaceutical composition for treating hypercholesterolemia comprising a hypocholesterolemic effective amount of the hemicalcium salt of [R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methyleth-yl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid and a pharmaceutically acceptable carrier..Iaddend.
.Iadd.14. A method of inhibiting cholesterol synthesis in a human suffering from hypercholesterolemia comprising administering to said human the hemicalcium salt of [R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)--3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid in unit dosage form..Iaddend. |
| Description: |
BACKGROUND OF THE INVENTION
Trans-(.+-.)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-tetrah- ydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamides are among compounds of U.S. Pat. No. 4,681,893 having usefulness as inhibitors of cholesterolbiosynthesis. The compounds therein broadly include 4- hydroxypyran-2-ones and the corresponding ring-opened acids derived therefrom.
It is now unexpectedly found that the enantiomer having the R form of the ring-opened acid of trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-tetrahydro-4- -hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide; that is[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)- -3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, provides surprising inhibition of the biosynthesis of cholesterol.
It is known that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) exists as the 3R-stereoisomer. Additionally, as shown in the study of a series of 5-substituted 3,5-dihydroxypentanoic acids by Stokker et al., in"3-Hydroxy-3-methylglutaryl-Coenzyme A Reductase Inhibitors. 1. Structural Modification of 5-Substituted 3,5-Dihydroxypentanoic acids and Their Lactone Derivatives," J. Med. Chem. 1985, 28, 347-358, essentially all of the biological activity residedin the trans diastereomer of (E)-6-[2-(2,4-dichlorophenyl)ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyr- anone having a positive rotation. Further, the absolute configuration for the .beta.-hydroxy-.delta.-lactone moiety common to mevlnolin of theformula (1a) ##STR00001## apparently is required for inhibition of HMG-CoA reductase. This is reported by Lynch et al. in "Synthesis of an HMB-CoA Reductase Inhibitor; A diastereoselective Aldol Approach in Tetrahedron Letters, Vol. 28, No. 13, pp. 1385-1388 (1987) as the 4R, 6R configuration.
However, an ordinarily skilled artisan may not predict the unexpected and surprising inhibition of cholesterol biosynthesis of the present invention in view of these disclosures.
SUMMARY OF THE INVENTION
Accordingly the present invention provides for compounds consisting of [R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-((1-methylethyl- )-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid (compound of formula I),pharmaceutically acceptable salts thereof and (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrah- ydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide (the lactone form of the heptanoic acid or compound of formulaII).
The present invention also relates to a pharmaceutical composition, useful as a hypocholesterolemic agent, comprising a hypocholesterolemic effective amount of [R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)--3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, its pharmaceutically acceptable salts of (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl-N,4-diphenyl-1-[2-(tetrahy- dro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide acid;and a pharmaceutically acceptable carrier. Further, the present invention is also a method of treating mammals, including humans, suffering from hypercholesterolemia by administering to such mammal a dosage form of the pharmaceutical compositiondescribed above.
DETAILED DESCRIPTION OF THE INVENTION
The pharmaceutically acceptable salts of the invention are those generally derived by dissolving the free acid or the lactose; preferably the lactone, in aqueous or aqueous alcohol solvent or other suitable solvents with an appropriate base andisolating the salt by evaporating the solution or by reacting the free acid or lactone; preferably the lactone and base in an organic solvent in which the salt separates directly or can be obtained by concentration of the solution.
In practice, use of the salt form amounts to use of the acid or lactone form. Appropriate pharmaceutically acceptable salts within the scope of the invention are those derived from bases such as sodium hydroxide, potassium hydroxide, lithiumhydroxide, calcium hydroxide, 1-deoxy-2-(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide, aluminum hydroxide, ferrous or ferric hydroxide, ammonium hydroxide or organic amines such as N-methylglucamine, choline, arginine and the like. Preferably, the lithium, calcium, magnesium, aluminum and ferrous or ferric salts are prepared from the sodium or potassium salt by adding the appropriate reagent to a solution of the sodium or potassium salt, i.e., addition of calcium chloride to asolution of the sodium or potassium salt of the compound of the formula I will give the calcium salt thereof.
The free acid can be prepared by hydrolysis of the lactone form of formula II or by passing the salt through the cationic exchange resin (H+resin) and evaporating the water.
The most preferred embodiment of the present invention is [R-(R*R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)-- 3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, hemicalcium salt.
Generally, the compounds I and II of the present invention may be prepared by the processes described in U.S. Pat. No. 4,681,893 which is incorporated by reference therefor, or (2) synthesizing the desired chiral form beginning from startingmaterials which are known or readily prepared using processes analogous to those which are known.
Specifically, resolution of the racemate may be accomplished as shown in Scheme I (where Ph is phenyl) as follows: ##STR00002## ##STR00003##
The "trans racemate" of Scheme 1 means a mixture of the following: ##STR00004## ##STR00005##
Generally, conditions for Scheme 2 are as shown in the Examples 1-5 hereinafter.
One of ordinary skill in the art would recognize variations in the Schemes 1 and 2 which are appropriate for the preparation of the compounds of the present invention.
The compounds according to present invention and especially according to the compound of the formula I inhibit the biosynthesis of cholesterol as found in the CSI screen that is disclosed in U.S. Pat. No. 4,681,893 which is now alsoincorporated by reference therefor. The CSI data of the compound I, its enantiomer the compound II and the racemate of these two compounds are as follows:
TABLE-US-00001 IC.sub.50 Compound (micromoles/liter) [R--(R*R*)] isomer 0.0044 [S--(R*R*)] isomer 0.44 Racemate 0.045
Accordingly, the present invention is the pharmaceutical composition prepared from the compound of the formula I or II or pharmaceutically acceptable salts thereof.
These compositions are prepared as described in U.S. Pat. No. 4,681,893 which is, therefore, again incorporated by reference here.
Likewise, the present invention is a method of use as hypolipidemic or hypocholesterolemic agents. The compounds of the present invention utilized in the pharmaceutical method of this invention are administered to the patient at dosage levels offrom 10 to 500 mg per day which for a normal human adult of approximately 70 kg is a dosage of from 0.14 to 7.1 mg/kg of body weight per day. The dosages may be preferably from 0.5 to 1.0 mg/kg per day.
The dosage is preferably administered as a unit dosage form. The unit dosage form for oral or parenteral use may be varied or adjusted from 10 to 500 mg, preferably from 20 to 100 mg according to the particular application and the potency of theactive ingredient. The compositions can, if desired, also contain other active therapeutic agents. Determinations of optimum dosages for a particular situation is within the skill of the art.
The compounds of the formula I and II and their pharmaceutically acceptable salts are in general equivalent for the activity of the utility as described herein.
The following examples illustrate particular methods for preparing compounds in accordance with this invention. These examples are thus not to be read as limiting the scope of the invention.
EXAMPLE 1
285 ml 2.2M n-butyl lithium (in Hexane) is added dropwise to 92 ml diisopropylamine in 300 ml THF at 50.degree.-60.degree. C. in a 1000 ml 1 neck flask via dropping funnel and under nitrogen. The well stirred yellow solution is allowed to warmto about -20.degree. C. Then it is cannulated into a suspension of 99 g S(+)-2-acetoxy-1,1,2-triphenylethanol in 500 ml absolute THF, kept in a 2L-3 neck flask at -70.degree. C. When addition is complete, the reaction mixture is allowed to warm to-10.degree. C. over a period of two hours. Meanwhile, a suspension of 0.63 mol MgBr.sub.2 is prepared by dropping 564 ml (0.63 mol) of bromine into a suspension of 15.3 g of magnesium (0.63 mol) in 500 ml THF plus in 3 L flask equipped with refluxcondenser, and overhead stirrer. When this is completed, the MgBr.sub.2 suspension is cooled to -78.degree. C. and the enolate solution (dark brown) is cannulated into the suspension within 30 minutes. Stirring is continued for 60 minutes at-78.degree. C. 150 g 5-(4-fluorophenyl)-2-(1-methylethyl)-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrr- ole-3-carboxamide in 800 ml THF absolute was added dropwise over 30 minutes; then stirred for 90 minutes at -78.degree. C., then quenched with 200 ml AcOHat -78.degree. C. This is removed to a cool bath, 500 ml of H.sub.2O is added and the mixture concentrated in vacuo at 40.degree.-50.degree. C. 500 ml of 1:1 EtOAc/Heptane is added to the yellowish slurry and filtered. The filtrate is washedextensively with 0.5N HCl, then several times with H.sub.2O and finally with EtOAc/Heptane (3:1) that was cooled with dry ice to -20.degree. C. The light brown crystalline product (Example 1A) is dried in vacuum oven at 40.degree. C. The yield is 194g.
The product 1A is recrystallized from EtOAc at -10.degree. C. to yield 100 g to yield product 1B and then recrystallized from acetone/pentane to yield 90 g to yield product 1C. The mother liquor is combined from the wash of the crude materialand recrystallized from EtOAc/Hexane. 33 g of 1B shows the following: HPLC: 97.4:2.17 of the R,S to S,S isomers. 28.5 g of 1C shows the following: HPLC:95.7:3.7. The combined 1B and 1C is recrystallized from CHCl.sub.3 MeOH 10:1; providing a product1F having a yield of 48.7 g of white crystal.
The mother liquor of the first aqueous wash is crystallized (EtOAc/Heptane) to yield product 1D of 21.4 g; HPLC: 71.56:25.52.
The mother liquor of 1B and 1C is combined and recrystallized from CHCl.sub.3/MeOH/Heptane to yield 55.7 g white crystals of product 1G.
1D is recrystallized from CHCl.sub.3/MeOH to yield the product 1H.
All mother liquor is combined, concentrated then the residue is dissolved in hot CHCl.sub.3/MeOH 10:1; put on a silica gel column; and eluted with EtOAc/Hexane 40:60. The material crystallized out on the column and the silica gel is extractedwith CHCl.sub.3/MeOH and concentrated. Recrystallization of the residue from CHCl.sub.3/Heptane 3:1 yields 33.7 g of product 1I.
The mother liquor of 1I is recrystallized to yield 18.7 g of product 1K.
The mother liquor of 1K is crystallized to yield 6.3 g of product 1L.
1I, 1K and 1L is combined and recrystallized from CHCl.sub.3/Heptane to yield 48 g.
The combined mother liquor of 1I, 1K, and 1L is concentrated to yield 31 g of 1M.
The product 1F provides the following data.
TABLE-US-00002 Anal: 1F m.p. 229-230.degree. C. Calc. Found C: 77.84 77.14 H: 6.02 6.45 N: 3.56 3.13
These data are consistent with the formula ##STR00006##
EXAMPLE 2
162 g (0.206M) of the combined products 1F, 1G, 1H and 1L of Example 1 are suspended in 800 ml Methanol/THF (5:3). Cooled to 0.degree. C. and added to 11.7 g sodium methoxide. The mixture is stirred until everything is dissolved, then put inthe freezer overnight. The reaction mixture is allowed to warm to room temperature, quenched with 15 ml HOAc, then concentrated in vacuo at 40.degree. C. to obtain expected product as follows: ##STR00007##
This product is added to 500 ml H.sub.2O and extracted twice with EtOAc (300 ml). The combined extracts are washed with saturated NaHCO.sub.3, brine, dried over anhydrous magnesium sulfate, filtered and the solvent evaporated. The residue ischromatographed on silica gel in EtOAc/Heptane (1:4) as eluent to yield 109 g colorless oil which is recrystallized from Et.sub.2O/Heptane to yield:
73.9 g first crop; white crystals
8.2 g second crop; white crystals.
The crystals provide the following data:
m.p. 125.degree.-126.degree. C., .alpha..sub.D.sup.20=4.23.degree. (1.17M, CH.sub.3OH)
TABLE-US-00003 Calc. Found C: 72.76 72.51 H: 6.30 6.23 N: 5.30 5.06
These data are consistent with the formula ##STR00008##
EXAMPLE 3
77 ml of diisopropylamine is dissolved in 250 ml THF in a 2000 ml three-neck flask equipped with thermometer and dropping funnel. The reaction mixture is kept under nitrogen. The mixture is cooled to -42.degree. C. and added to 200 ml 2.2M ofn-butyl lithium (in Hexane) dropwise over 20 minutes and stirred for 20 minutes before adding dropwise 62 ml of t-butylacetate, dissolved in 200 ml THF (over about 30 minutes). This mixture is stirred 30 minutes at -40.degree. C., then 140 ml 2.2M ofn-butyl lithium is added over 20 minutes. When addition is complete, 81 g of the product of Example 2 in 500 ml absolute THF is added as quickly as possible without allowing the temperature to rise above -40.degree. C. Stirring is continued for fourhours at -70.degree. C. The reaction mixture is then quenched with 69 ml glacial acetic acid and allowed to warm to room temperature. The mixture is concentrated in vacuo and the residue is taken up in EtOAc, washed with water extensively, thensaturated NH.sub.4Cl, NaHCO.sub.3 (saturated), and finally with brine. The organic layer is dried over anhydrous MgSO.sub.4, filtered and the solvent evaporated. The NMR of the reaction is consistent with starting material plus product in about equalamounts plus some material on the baseline of the TLC. The material of the baseline of the TLC is separated from starting material and the product is extracted by acid/base extraction. The organic phase is dried and concentrated in vacuo to yield 73 g.The NMR and TLC are consistent with the formula ##STR00009##
EXAMPLE 4
73 g crude product of Example 3 is dissolved in 500 ml absolute THF and 120 ml triethyl borane is added, followed by 0.7 t-butylcarboxylic acid. The mixture is stirred under a dry atmosphere for 10 minutes, cooled to -78.degree. C. and 70 mlmethanol is added and followed by 4.5 g sodium borohydride. The mixture is again stirred at -78.degree. C. for six hours. Then poured slowly into a 4:1:1 mixture of ice/30% H.sub.2O.sub.2/H.sub.2O. This mixture is stirred overnight then allowed towarm to room temperature.
CHCl.sub.3 (400 ml) is added and the mixture is partitioned. The water layer is extracted again with CHCl.sub.3. The organic extracts are combined and washed extensively with H.sub.2O until no peroxide could be found. The organic layer isdried over MgSO.sub.4, filtered and the solvent is evaporated.
The residue is treated by flash chromatography on silica gel, i.e. EtOAc/Hexane 1:3 to yield 51 g.
The product is dissolved in THF/MeOH and added to 100 ml in NaOH, then stirred for four hours at room temperature. The solution is concentrated at room temperature to remove organic solvent, added to 100 ml H.sub.2O, and extracted with Et.sub.2Otwice. The aqueous layer is acidified with 1N HCl and extracted with EtOAc three times. The combined organic layers are washed with H.sub.2O. The organic layer is dried with anhydrous MgSO.sub.4, filtered, and the solvent evaporated. The residue istaken up in 2 liters of toluene and heated to reflux using a Dean-Stark trap for 10 minutes.
The reaction mixture is allowed to cool to room temperature overnight. Reflux is repeated for 10 minutes and cooled for 24 hours.
The procedure above is repeated. The reaction is left at room temperature for the next 10 days, then concentrated to yield 51 g of colorless foam.
This product is dissolved in minimum CHCl.sub.3 and chromatographed on silica gel eluting with EtOAc/Heptane (50:50) to yield 23 g in pure material.
Chromatography on silica gel in CHCl.sub.3/2-propanol (98.5:1.5) yields 13.2 g.
TABLE-US-00004 Calc. C: 73.31 H: 6.15 N: 5.18
EXAMPLE 5
Preparation of 2R-trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-tetrahydr- o-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H/-pyrrole-3-carboxamide
The product of Example 4 is recrystallized from EtOAc/Hexane. Fraction 1 yields 8.20 g of 4A. The another liquor yields 4.60 g of 4B, HPLC of 4B shows 100% of the product to be the [R-(R*R*)] isomer. 4A is recrystallized to yield 4.81 g of 4C. 4B is chromatographed on silica gel in CHCl.sub.3/2-propanol to yield 4.18 g colorless foam of 4D showing .alpha..sub.D.sup.23+24.53.degree. (0.53% in CHCl.sub.3). 4C is recrystallized and the mother liquor of 4C is to yield 2.0 g.HPLC which indicates100% of the R-trans isomer 2R-trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-tetrahydr- o-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.
EXAMPLE 6
Preparation of diastereomeric .alpha.-methylbenzylamides
A solution of the racemate, trans-(.+-.)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-tetra- hydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, (30 g, 55.5 ml) in (R)-(+)-.alpha.-methylbenzylamine (575 ml, 4.45 mol,98% Aldrich) is stirred overnight at room temperature.
The resulting solution is then diluted with ether (2 l) and then washed exhaustively with 2M HCl (4.times.500 ml), water (2.times.500 ml) and brine (2.times.500 ml). The organic extract is then dried over MgSO.sub.4, filtered and concentrated invacuo to yield 28.2 g of the diastereomeric .alpha.-methylbenzylamides as a white solid; m.p. 174.0.degree.-177.degree.. The .alpha.-methylbenzylamides are separated by dissolving 1.5 g of the mixture in 1.5 ml of 98:1.9:0.1CHCl.sub.3:CH.sub.3OH:NH.sub.4OH (1000 mg/ml) and injecting onto a preparative HPLC column (silica gel, 300 mm.times.41.4 mm I.D.) by gastight syringe and eluting with the above solvent mixture. Fractions are collected by UV monitor. Diastereomer 1elutes at 41 minutes. Diastereomer 2 elutes at 49 minutes. Center cut fractions are collected. This procedure is repeated three times and the like fractions are combined and concentrated. Examination of each by analytical HPLC indicates thatdiastereomer 1 is 99.84% pure and diastereomer 2 is 96.53% pure. Each isomer is taken on separately to following Examples.
EXAMPLE 7
Preparation of 2R-trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahyd- ro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide
To an ethanolic solution (50M) of diastereomer 1 of Example 6, [3R-[3R*(R*),5R*]]-2-(4-fluorophenyl)-[.beta.],[.delta.]-dihydroxy-5-(1-m- ethylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-N-(1-phenylethyl-1H-pyrrole- -1-heptanamide, (hydroxy centersare both R) (1 g, 1.5 mmol) is added 1N NaOH (3.0 ml, 3 mmol). The resulting solution is heated to reflux for 48 hours.
The solution is cooled to room temperature and concentrated in vacuo. The residue is resuspended in water and carefully acidified with 6N HCl. The resulting acidic solution is extracted with ethyl acetate. The organic extract is washed withwater, brine, dried over MgSO.sub.4, filtered and concentrated in vacuo. This residue is redissolved in toluene (100 ml) and heated to reflux with azeotropic removal of water for three hours. This is cooled to room temperature and concentrated in vacuoto yield 1.2 g of a yellow semi-solid. Flash chromatography on silica gel eluting with 40% EtOAc/Hexane gives 0.42 g of a white solid which still contains impurities. This is rechromatographed to give 0.1 g of essentially pure R,R, enantiomer,2R-trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-tetrahydr- o-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, as a white foam. HPLC shows this material to be 94.6% chemically pure [.alpha.].sub.D.sup.23:0.51% inCHCl.sub.3=25.5.degree.. The peak at room temperature=53.46 minutes is tentatively assigned to an unknown diastereomer resulting from the 2% (S)-(-)-.alpha.-methylbenzylamine present in the Aldrich .alpha.-methylbenzylamine.
EXAMPLE 8
Preparation of 2S-trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahyd- ro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide-(S,S enantiomer of the compound prepared in Example 5
Carrying out the procedure described in Example 7 on diastereomer 2 afforded 0.6 g of a foamy solid which was flash chromatographed on silica gel. Elution with 50% EtOAc/Hexane gave 0.46 g of essentially pure S,S, enantiomer2S-trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahyd- ro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, as a white foam. HPLC showed this material to be 97.83% chemically pure. [.alpha.].sub.D.sup.23=0.51% inCHCl.sub.3=-24.8%.
EXAMPLE 9
Hydrolysis of chemical lactone of formula II
To a room temperature, solution of the lactone in THF is added a solution of sodium hydroxide in water. The mixture is stirred for two hours HPLC:99.6% (product); 0.34 to (starting lactone). The mixture is diluted with 3 L water, extracted withethyl acetate (2.times.1 L) and acidified to pH.times.4 by addition of 37 ml of 5N hydrochloric acid. The aqueous layer is extracted with 2.times.1.5 L portions of ethyl acetate. The combined ethyl acetate extracts are washed with 2.times.1 L of water,brine and dried, gave after filtration the ethyl acetate solution of the required face-acid. This solution is used directly in the fraction of the N-methylglucamine salt.
The ethyl acetate extracts from the brine-water were concentrated to give 15.5 g of an off-white solid.
EXAMPLE 10
Calcium Salt from Sodium Salt and/or Lactone
Dissolve one mole lactone (540.6 g) in 5 L of MeOH; after dissolution add 1 L H.sub.2O. While stirring, add one equivalent NaOH and follow by HPLC until 2% or less lactone and methyl ester of the diolacid remains (cannot use an excess of NaOH,because Ca(OH).sub.2 will form an addition of CaCl.sub.2). Charge NaOH as caustic (51.3 ml, 98 eq.) or as pellets (39.1 g, 0.98 eq.).
The above procedure is shown as follows: ##STR00010##
Upon completion of hydrolysis, add 10 L H.sub.2O, then wash at least two times with a 1:1 mixture of EtOAc/Hexane. Each wash should contain 10 L each of EtOAc/Hexane. If sodium salt is pure, add 15 L of MeOH. If it is impure and/or containscolor, add 100 g of G-60 charcoal, stir for two hours and filter over supercel. Wash with 15 L MeOH. Perform a wt/vol % on the reaction mixture, by HPLC, to determine the exact amount of salt in solution.
Dissolve 1 eq. or slight excess CaCl.sub.2.2H.sub.2O (73.5 g) in 20 L H.sub.2O. Heat both reaction mixture and CaCl.sub.2 solution to 60.degree. C. Add CaCl.sub.2 solution slowly, with high agitation. After completion addition, cool slowly to15.degree. C. and filter. Wash filter cake with 5 L H.sub.2O. Dry at 50.degree. C. in vacuum oven.
Can be recrystallized by dissolving in 4 L of EtOAc (50.degree. C.) filtering over supercel, washing with 1 L EtOAc, then charging 3 L of hexane to the 50.degree. C. rxn solution.
The above procedure is shown as follows: ##STR00011##
EXAMPLE 11
Treatment of Ethyl Acetate Solution of Free-acid of the Formula I with N-methylglucamine
To a solution of the free-acid of the formula I (0.106M) in ethyl acetate (3 L) is added a solution of N-methylglucamine (20.3 g, 0.106 m) in (1:1) water-acetone (120 ml, 120 ml) with vigorous stirring at room temperature. Stirring is continuedfor 16 hours and the hazy solution concentrated in vacuo to .about.250 mp. Toluene (1 L) is added and the mixture concentrated to a white solid .about.100 g. The solid is dissolved in 1670 ml acetone and filtered into a three-neck flask equipped with amechanical stirrer and thermostat controlled thermometer. The flask and filter is washed with 115 ml (1:1) water-acetone and the clear solution is cooled slowly. This provided a precipitate which is re-dissolved by heating back to 65.degree. C.Addition of a further 20 ml of water followed by the washing gives a crystalline product which was isolated by filtration. The solids are washed with 1200 ml CH.sub.3Cl and vacuum dried at 255.degree. to give a white solid. Analysis of this materialindicates that it contains 4% amine as well as 0.4% residual acetone and 0.67% water. Analytical results are noted as follows:
Melting point: 105.degree.-155.degree. C. (decomposition) Analysis Expected: C=63.73; H-6.95; N=5.57; F2=9.53. Analysis Found: C=62.10; H-6.89; N-5.34; F2. C=61.92; H-7.02; N=5.38; F2. H.sub.2O=0.47% (KF) HPLC: MeOH, H.sub.2O, THF (40; 550;250) Econosil: C18, 5 .mu., 25 CM 256 nm: 1.0 ml/min. 6-81 min.: 98.76% Opt. Ret.: [.alpha.]b=-10.33.degree. (c=1.00, MeOH) Residual Solvents: CH.sub.2CH=0.26% Titrations: HClO.sub.4 (0.1N)=203.8% Bu.sub.4NOH (0.1N)=98.5%
Other salts prepared in a manner analogous to those processes appropriately selected from Examples 10 and 11 above may be the potassium salt, hemimagnesium salt, hemizinc salt or the 1-deoxy-2-(methylamino)-D-glucitol complex of the compound offormula I.
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