USOO63651.86B1 (12) United States Patent (10) Patent No.: US 6,365,186 B1 Huval et al. (45) Date of Patent: *Apr. 2, 2002 (54) COMBINATION THERAPY FOR TREATING EP 326386 8/1989 HYPERCHOLESTEROLEMIA EP 329 124 8/1989 EP 36932.3 5/1990 (75) Inventors: Chad Cori Huval, Somerville; Stephen EP O 375 350 A2 6/1990 Randall Holmes-Farley, Arlington; EP 380392 B1 8/1990 John S. Petersen, Acton; Pradeep K. E. 3. B1 3.1991/1991 Dhal, Westford, all of MA (US) EP 464.845 B1 1/1992 EP O 580 O78 A1 1/1994 (73) ASSignee: GelTex Pharmaceuticals, Inc., EP O 580 O79 A1 1/1994 Waltham, MA (US) EP O 665 245 A1 8/1995 GB 86O303 2/1961 (*) Notice: Subject to any disclaimer, the term of this GB 2 O90 605 A 7/1982 patent is extended or adjusted under 35 GB 227.0312 3/1994 U.S.C. 154(b) by 0 days. GB 2329 334 3/1999 JP 56-51992 5/1981 This patent is Subject to a terminal dis- E. 3.E. claimer. WO WO 90/OO897 2/1990 WO WO 98/291.07 7/1998 (21) Appl. No.: 09/311,103 WO WO 98/40375 9/1998 (22) Filed: May 13, 1999 OTHER PUBLICATIONS Related U.S. Application Data McCarthy, P.A., “New Approaches to Atherosclerosis: An Overview,” Medicinal Research Reviews, 13(2):139-159 (63) Continuation-in-part of application No. 08/964,536, filed on (1993). Nov. 5, 1997, now Pat. No. 6,083,497. Heming, A.E. and Flanagan, T.L., “Considerations in the (51) Int. Cl." ........................ A61K 9/10; A61K 31/787; Selection of Cation Exchange Resins for Therapeutic Use,” A61P 9/10 In Annals of the New York Academy of Sciences, 57:239-251 (52) U.S. Cl. ........................................ 424/486; 514/824 (1954). (58) Field of Search ................................. 424/400, 486, Harada, Susumu and Kunio Arai, “The Cyclo-copolymer 424/78.35, 78.14, 78.15; 514/824 ization of Diallyl Compounds and Sulfur Dioxide, II. Dial lyldimethylammonium Chloride and Sulfur Dioxide,” Die (56) References Cited Makromolekulare Chemie 107:64-77 (1967). U.S. PATENT DOCUMENTS (List continued on next page.) 2.926,161 A 2/1960 Butler et al. ............... 260/89.7 3.262,850 A 7/1966 Jones et al. ................... 167/65 Primary Examiner Edward J. Webman 3.288,770 A 11/1966 Butler .......... ... 260/88.3 (74) Attorney, Agent, or Firm-Hamilton, Brook, Smith & 3,369,025 A 2/1968 Bolhofer et al. .. ... 260/295 Reynolds, P.C. 3,494.957 A 2/1970 Nakanishi et al. .......... 260/473 3,607.909 A 9/1971 Boulogne et al. ....... 260/477 R (57) ABSTRACT 3,674,836 A 7/1972 Creger ................... 260/473 G 3,700,623 A 10/1972 Keim .................... 260/80.3 R The invention relates to methods for treating hypercholes 3,716,583 A 2/1973 Nakamura et al. .......... 260/520 terolemia and atherosclerosis, and reducing Serum choles 3,723,446 A 3/1973 Scherm et al. ........ 260/295.5 R terol in a mammal. The methods of the invention comprise 3,781,328 A 12/1973 Witte et al. ............. 260/471 R administering to a mammal a first amount of a bile acid 3,833,531 A 9/1974 Keim ........ ... 260/29.6 CM Sequestrant compound which is an unsubstituted polydial 3,840,504. A 10/1974 Keim .................... 260/79.3 A lylamine polymer and a Second amount of a cholesterol 3,948,973 A 4/1976 Phillips ..... ... 260/473 lowering agent. The first and Second amounts together 3.966,694 A 6/1976 Espy et al. ... ... 526/11.2 3,971,798. A 7/1976 Humbert et al. ............ 2600s comprise a therapeutically effective amount. (List continued on next page.) The invention further relates to pharmaceutical composi tions useful for the treatment of hypercholesterolemia and FOREIGN PATENT DOCUMENTS atherOSclerosis, and for reducing Serum cholesterol. The CA 2007641 8/1990 pharmaceutical compositions comprise a combination of a CA 20164.67 12/1990 first amount of an unsubstituted polydiallylamine polymer DE 2038835 2/1971 compound and a Second amount of a cholesterol-lowering DE 214907O 4/1973 agent. The first and Second amounts comprise a therapeuti DE 2250327 4/1973 cally effective amount. The pharmaceutical compositions of DE 312.2499 12/1981 the present invention may optionally contain a pharmaceu EP 22478 B1 1/1981 tically acceptable carrier. EP 33538 B1 8/1981 EP 244364 11/1987 EP 245003 11/1987 EP 321090 6/1989 30 Claims, No Drawings US 6,365,186 B1 Page 2 U.S. PATENT DOCUMENTS Falck, J.R. and Yang, Y-L., “Total Synthesis of (+)-Dihy 3,983,140 A 9/1976 Endo et al. .............. 260/343.5 dromevinolin.” Tetrahedron Lett., 25(33), 3563-66 (1984). 3,984,413 A 10/1976 Metz et al. ................. 260/254 Beck, G., et al., “Synthesis and Biological Activity of New 3.990,958 A 11/1976 Sasse ........ ... 204/159.22 4,049,813 A 9/1977 Nadelson .................... 424/263 HMG-CoA Reductase Inhibitors. 1. Lactones of Pyridine 4,058,552 A 11/1977 Mieville ...................... 560/52 and Pyrimidine-Substituted 3,5-Dihydroxy-6-heptenoic 4,121.986 A 10/1978 Battaerd ................ 204/159.22 (-heptanoic) Acids,” J. Med. Chem., 33(1), 52-60 (1990). 4,230,626 A 10/1980 Chorvat ................... 260/397.2 4231938 A 11/1980 Monaghan et al. ...... 260/343.5 Jendralla, H., et al., “Synthesis and Biological Activity of 4,298.715 A 11/1981 Van Eenam ......... ... 525/340 New HMG-CoA Reductase Inhibitors. 3. Lactones of 4,346.227 A 8/1982 Terahara et al. .. ... 560/119 6-Phenoxy-3,5-dihydroxyhexanoic Acids,” J. Med. Chem., 4,444,784. A 4/1984 Hoffman et al. ............ 424/279 34(10) 2962–83 (1991). 4,450,171 A 5/1984 Hoffman et al. ............ 424/279 4,452.957 A 6/1984 Neigel ......................... 526/71 Chiang, Y-C.P., et al., “Total Synthesis of L-659,699, a 4.483,999 A 11/1984 Thiele et al. ................. 560/57 Novel Inhibitor of Cholesterol Biosynthesis,” J. Org. Chem., 4,739,073. A 4/1988 Kathawala .... ... 548/406 4,759,923 A 7/1988 Buntin et al. .. ... 424/440 54(24), 5708–12 (1989). 4,812,540 A 3/1989 Kageno et al. ... 526/218.1 Ogawa, H., et al., "Pannorin, A New 4.937,259 A 6/1990 Lee .................. ... 514/460 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase 5,134,155 A 7/1992 Connolly et al. ... 514/403 5,200,482 A 4f1993 Gartner ............ ... 526/295 Inhibitor Produced by Chrysosporium pannorum,” J. Anti 5,273.995 A 12/1993 Roth ................ ... 514/422 biot., 44(7), 762–7 (1991). 5,274,155 A 12/1993 Thottathi et al. ... 556/405 Carte, B.K., et al., “Rawsonol, An Inhibitor of HMG-CoA 5,316,765 A 5/1994 Folkers et al. .... ... 424/94.1 5,428,112 A 6/1995 Ahlers et al. ..... ... 525/326.7 Reductase from the Tropical Green Alga Avrain villea Raw 5,430,110 A 7/1995 Ahlers et al. ..... ... 525/328.2 Soni,” Phytochemistry, 28(11), 2917–19 (1989). 5,462,730 A 10/1995 McTaggart et al. ...... 424/78.35 5,607,669 A 3/1997 Mandeville, III Baumann, K.L., et al., “The Convergent Synthesis of et al. ....................... 424/78.12 CI-981, an Optically Active, Highly Potent, Tissue selective 5,618,530 A 4/1997 Mandeville, III Inhibitor of HMG-CoA Reductase.” Tetrahedron Lett., et al. ....................... 424/78.12 33(17), 2283–4 (1992). 5,624.963 A 4/1997 Mandeville, III et al. ... 514/789 5,679,717 A 10/1997 Mandeville, III et al. ... 514/742 Larsen, S.D., et al., “Design and Synthesis of Seco-oxys 5,693,675 A 12/1997 Mandeville, III et al. ... 514/742 terol Analogs S Potential Inhibitors of 5,703,188 A 12/1997 Mandeville, III et al. ... 526/290 3-Hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) 6,083,497 A * 7/2000 Huval et al. Reductase Gene Transcription,” J. Med. Chem., 37(15), OTHER PUBLICATIONS 2343–51 (1994). Negi, Youji et al., “Cyclopolymerization of Diallylamine Kumar, N., et al., “Separation of Derivatives in Dimethyl Sulfoxide,” Journal of Polymer 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibi Science: Part A-1, 5:1951–1965 (1967). tor drug Substance diastereomers, and their analogues on Kuron, G.W. et al., “The Bile Acid Binding and Hypocho B-cyclodextrin Stationary phase,” J. Chromatrogr: A, lesterolemic Action of Two Water-soluble Polymers,” Ath 678(2): 259-63 (1994). erosclerosis 37:353–360 (1980). Stokker, G.E., “Synthesis of L-669,262, a Potent HMG Hodgkin, J.H. et al., “Use of 'C-NMR in the Study of CoA Reductase Inhibitor,” J. Org. Chem., 59(20), 5983-6 Reactions on Crosslinked Resins,” Journal of Polymer Sci (1994). ence 19(5):1239–1249 (1981). United States Serial No. 08/777,408, filed on Dec. 30, 1996, Kramer, W., et al., “Bile Acid Derived HMG-CoA Reduc “Poly(diallylamine)-Based Bile Acid Sequestrant” by tase Inhibitors,” Biochimica et Biophysica Acta, 1227(3), Stephen Randall Holmes-Farley, Pradeep K. Dhal and John 137-54 (1994). S. PeterSen. Huang, Y. and Hall, I.H., “Hypolipidemic Effects of C, B, Takano, S., et al., “Enantioconvergent Synthesis of a Prom and Y-Alkylaminophenone Analogs in Rodents, Eur: J. ising HMG Co-A Reductase Inhibitor NK-104 from Both Enantiomers of Epichlorohydrin.” Tetrahedron ASSymetry, Med. Chem., 31(4), 281–90 (1996). 4(2), 201–4 (1993). Huang, Y. and Hall, I.H., “Hypolipidemic Activity of Sood, A., et al., “Boron analogues of amino acids VI.