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United States Patent (10) Patent N0.: US 6,951,860 B2 Mehanna Et A1

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United States Patent (10) Patent N0.: US 6,951,860 B2 Mehanna Et A1 US006951860B2 (12) United States Patent (10) Patent N0.: US 6,951,860 B2 Mehanna et a1. (45) Date of Patent: Oct. 4, 2005 (54) CALCIUM CHANNEL BLOCKERS 5,132,106 A 7/1992 Tuloup et a1. ......... .. 514/223.5 5,134,139 A 7/1992 Kawai et a1. 514/211.07 Inventors: (Us); JinyungSI Mehanna, T_ Kim, Sudbury, Boston, MA 5,144,029 A 9/1992 AdamsWard et 618.1. a1. ............... .. 540/610 (Us) 5,198,433 A 3/1993 Palfreyman et a1. 514/217.11 5,276,026 A 1/1994 Barrrsh et a1. ....... .. 514/212.02 (73> Assignees Messeeheseees Cellege ef Phesmeey, 2:531:33 2 511333 81315152111111: 1:: iii/552:5 Bostons MA (Us) 5,360,809 A 11/1994 Axelsson 618.1. 514/338 _ _ _ _ _ 5,387,592 A 2/1995 Bradbury et a1. ......... .. 514/312 (*) Notlcel sublectto any dlsclalmer?heterm Ofthls 5,496,815 A 3/1996 OZeki et a1. .... .. 514/2242 patent is eXtended or adjusted under 35 5,514,693 A 5/1996 COZZl et a1. .... .. 514/341 U.S.C. 154(1)) by 183 days. 5,607,939 A 3/1997 Kato et a1. ................ .. 514/278 5,623,051 A 4/1997 Catterall et a1. .......... .. 530/324 (21) Appl. NO.Z 09/998,623 OTHER PUBLICATIONS (22) Flled: Oct‘ 31’ 2001 Gialdi et al., Abstract to CA 56:4664g.* (65) Prior Publication Data McMurry, John, Editor of Second Edition, Organic Chem istry, 1984, pp. 742—746.* Us 200301156551“ Aug- 22, 2002 Protiva, et al. of CZ 105,590 of CA59:10010f, Nov. 15, 1962* Related US‘ Application Data Goodman & Gilman’s The Pharmacological Basis of Thera _ _ _ _ _ peutics, 9th Edition, pp. 767—774, 1996* (62) 113913175I2IIQ£fPZFP§ZatgO24€IZ§S 8/ 982’953’ ?led on Dec‘ 2’ Gialdi, et al., Chemical Abstracts, Mar. 8, 1962, 4664g, vol. ’ ' ' ’ ’ ' 56, No. 5, The American Chemical Society. (51) Int. Cl.7 .......................................... .. A61K 31/4965 Fujita, M_ et 311, “Synthesis and Ca2+ Antagonistic Activity (52) US. Cl. .......................... .. 514/252.12; 514/252.13; of 2—[2—[(Aminoalkyl)oXy]—5—methoXyphenyl]—3, 514/255.03; 514/255.04; 514/613; 514/617; 4—dihydro—4—methyl—3—oXo—2H—1,4—benZo—thiaZines”, J. 514/618; 514/310; 514/255.4 Med. Chem, 1990, pp. 1898—1905, vol. 33, American (58) Field of Search ..................... .. 514/252.12, 252.13, Chemical Society 514/255_03, 255,04, 613, 617, 618, 619 Yamamoto, K, et al., “Novel Calcium Antagonists. Synthesis and Structure—Activity Relationship Studies of BenZothia (56) References Cited zoline Derivatives”, J. Med. Chem, 1988, pp. 919—930, vol. 31, American Chemical Society. U.S. PATENT DOCUMENTS Jilek, J .; et al., “Preparation of neW antimicrobial (phenylth 4,550,116 A 10/1985 SO10 618.1. .. 514/327 io)benZylamines”, Chemical Abstracts Accession No. 4,593,033 A 6/1986 Hartman et a1. 514/290 19921612134 (Abstract only). 4,596,805 A 6/1986 Jiang ............... .. .. 514/264.1 Jilek, J ., et al., “Potential antidepressasnts: 2—(methyoXy— 4,640,930 A 2/1987 Mohacsi et a1. 514/431 and hydroXyphenylthio)benZylamines as selective inhibitors 4,654,353 A 3/1987 Alker 618.1. 514/334 of 5—hydroXytryptamine re—uptake in the brain”, Chemical 4,742,069 A 5/1988 Jaunin et a1. 514/356 Abstracts Accession No. 19901458496 (Abstract only). 4,758,669 A 7/1988 Johnson et a1. 541/263 4,791,117 A 12/1988 Press . .. 514/300 * cited by examiner 4,829,076 A 5/1989 SZilagyi et a1. 514/356 4,847,273 A 7/1989 Jaunin et a1. ............. .. 514/347 Primary Examiner—DWayne Jones 4,918,073 A 4/1990 Riiger et a1. ......... .. 514/252.12 (74) Attorney, Agent, or Firm—Wolf, Green?eld & Sacks, 4,918,074 A 4/1990 Tsuda et a1. 514/252.12 PC 4,959,359 A 9/1990 Mohacsi et a1. ..... .. 514/211.03 4,988,713 A 1/1991 Frigerio et a1. ........... .. 514/356 (57) ABSTRACT 4,992,432 A 2/1991 Mohacsi et a1. ..... .. 514/211.03 4,994,612 A 2/1991 Jaunin et a1. ............... .. 564/88 The invention involves the identi?cation of a family of 5,017,586 A 5/1991 Schlager ................... .. 514/318 compounds Which block calcium channels. The compounds 5,025,010 A 6/1991 Oekonomopulos can be formulated in pharmaceutical carriers and adminis et a1. ..................... .. 514/224.2 tered to subjects. The compounds are useful for treating 5,034,395 A 7/1991 Tamada et a1. .. 514/277 disorders associated With calcium channel activity, such as, 5,036,098 A 7/1991 Kimura et a1. ............ .. 514/438 cardiovascular diseases, for example hypertension, conges 5,039,674 A 8/1991 Fujikura et a1. 514/217.04 tive heart failure, arrhythmia and angina. 5,070,088 A 12/1991 AtWal .......... .. 514/212.08 5,071,844 A 12/1991 Alker et a1. 514/211.11 5,106,845 A 4/1992 Carr et a1. ................ .. 514/218 4 Claims, 4 Drawing Sheets U.S. Patent 0a. 4,2005 Sheet 2 0f 4 US 6,951,860 B2 FIG. 2 10 -0— COMP #1 5.. ()~ _5~ CHARGE IN 10_ MAP (mmHgI ' _15_ -20_ -25 '30 I I l I I I T I 10 30 B0 100 130 180 270 500 DOSE IN MEG/KG FIG. 3 10 -O- COMP 2 5- +DILT. '30 I I I I I I I I 10 30 B0 100 130 180 270 500 DOSE IN HCG/KG U.S. Patent 0a. 4,2005 Sheet 3 0f 4 US 6,951,860 B2 FIG. 4 ‘30 I I I I I I I I 10 30 B0 100 130 180 270 500 DOSE IN HUG/KG FIG. 5 -0- COMP 4 5- + DILT. '30 I I I I I I I I 10 30 B0 100 130 180 270 500 DOSE IN MEG/KB U.S. Patent 0a. 4,2005 Sheet 4 0f 4 US 6,951,860 B2 FIG. 5 -o- COMP s s- n + 0m. “30 I I I If T I I I 10 30 60 100 130 180 270 500 DOSE IN MCGIKG FIG. 7 US 6,951,860 B2 1 2 CALCIUM CHANNEL BLOCKERS “4” and “5” forming an amide function With N,N dimethylaminoethyl substitution at the amide nitrogen. Sci RELATED APPLICATIONS entists at central research laboratory at Osaka, Japan, syn thesiZed a series of potent calcium channel blockers in This application is a divisional of Ser. No. 08/982,953, Which the seven membered ring of diltiaZem Was replaced ?led on Dec. 2, 1997, Which is now US. Pat. No. 6,541,479. With 6- and 5- membered fused-ring systems. These tWo neW FIELD OF THE INVENTION classes of calcium channel blockers, the benZothiaZine and benZothiaZole respectively (Yamamoto, K., J. Med. Chem., This invention relates to a class of aromatic compounds v.31, p. 919—930 (1988); Fujita, M.,J. Med. Chem., v. 33, p. Which are blockers of calcium channels. The invention also 10 1898—1905 (1990)) demonstrated potent calcium channel relates to pharmaceutical compositions, methods of blocking blocking activity. Some of these compounds even demon calcium channels, kits and methods of treatment using the strated more tissue selectivity toWard calcium channels in class of compounds described herein, as Well as intermediate blood vessels. compounds useful in the preparation of the compounds. 15 SUMMARY OF THE INVENTION BACKGROUND OF THE INVENTION A neW family of calcium channel blockers, Which are Calcium channel blockers are a chemically diverse class de?ned by the structures set forth beloW, have been identi of compounds having important therapeutic value in the ?ed according to the invention. The members of the neW control of a variety of diseases including several cardiovas family of compounds constitute a neW class of calcium cular disorders, such as hypertension, angina, and cardiac channel blockers Which is not encompassed by any of the arrhythmias (Fleckenstein, Cir. Res. v. 52, (suppl. 1), three knoWn classes of calcium channel blockers, the p.13—16 (1983); Fleckenstein, Experimental Facts and dihydropyridines, the phenyl alkyl amines, or the benZothi Therapeutic Prospects, John Wiley, NeW York (1983); aZepines. Of the three knoWn classes the compounds of the McCall, D., Curr Pract Cara'i0l, v. 10, p. 1—11 (1985)). invention are most structurally similar to the benZothiaZ Calcium channel blockers are a heterogenous group of epine class of calcium channel blockers, Which have the drugs that prevent or sloW the entry of calcium into cells by folloWing structural formula. regulating cellular calcium channels. (Remington, The Sci ence and Practice of Pharmacy, Nineteenth Edition, Mack Publishing Company, Eaton, Pa., p.963 (1995)). The regu lation of calcium entry into the cells of the cardiovascular system is of paramount importance to the proper functioning of this system. Cardiac and vascular smooth muscle cells have calcium channels Within the cell membrane. Calcium in?ux through these channels initiates a process of electro mechanical coupling Which ultimately leads to muscle con traction. The ability to regulate the entry of calcium into cardiac and vascular smooth muscle cells is a poWerful therapeutic approach in the treatment of angina and hyper tension respectively. LikeWise, blocking calcium in?ux into cardiac tissues and conduction systems provides a useful Prior to the instant invention it Was believed that the fused approach to control certain types of arrhythmia. ring structure of the benZothiaZepines Was essential for the Calcium channel blockers are also believed to be useful in calcium channel blocking activity of these compounds. the treatment of other disorders in Which the regulation of Applicants, hoWever, have surprisingly discovered that com calcium plays a role in normal hemostasis.
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