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(12) United States Patent (10) Patent No.: US 6,844,355 B2 Somberg Et Al

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(12) United States Patent (10) Patent No.: US 6,844,355 B2 Somberg Et Al USOO684.4355B2 (12) United States Patent (10) Patent No.: US 6,844,355 B2 Somberg et al. (45) Date of Patent: Jan. 18, 2005 (54) OPTICALLY ACTIVE ISOMERS OF QUININE Catterall, (1992) Physiol. Rev. 72(supp):S15-S48. AND QUINDINE AND THEIR RESPECTIVE Chan et al., (1991) J. Chromatogr. 571:291-297. BIOLOGICALACTION Chen et al., (1998) Nature 392:293–296. (75) Inventors: John C. Somberg, Lake Forest, IL Coplen et al., (1991) Circulation 84:527. (US); Vasant Ranade, Libertyville, IL Drabowicz et al., (1984) “Chemical Abstracts” Phosphorus (US) Sulfur 16:2676–270 (XP002165239). Engler et al., (1985) Helv. Chim. Acta. 68:789–800. (73) Assignee: Academic Pharmaceuticals, Inc., Lake Ficker et al., (1998) Circ. Res. 82:386–395. Bluff, IL (US) Gellens et al., (1992) Proc. Natl. Acad. Sci. 89:554–558. (*) Notice: Subject to any disclaimer, the term of this Gutzwiller et al., (1973) “Chemical Abstracts” Helv. Chim. patent is extended or adjusted under 35 Acta. 79:1494–1503 (XP002165238). U.S.C. 154(b) by 0 days. Hartmann et al. (1994) Circ. Res. 75:114-122. Karle I.L. et al., (1981) Proc. Natl. Acad. Sci. 78:5938–5941. (21) Appl. No.: 10/168,919 Karle, J.M. (1997) Antimicrob. Agents Chemother. (22) PCT Filed: Dec. 22, 2000 41:791-794. Kiehn et al. (1996) Circulation 94:2572–2579. (86) PCT No.: PCT/US00/352.13 Krafte et al., (1994) Europ. J. Pharma. 266:245-254. S371 (c)(1), Li et al. (1996) Circ. Res. 78:689-696. (2), (4) Date: Oct. 30, 2002 Sanguinetti et al., (1990) J. Gen. Physiol.96:195-215. (87) PCT Pub. No.: WO01/46.188 Sanguinetti et al., (1995) Cell 81:299-307. Sanguinetti et al., (1996) Nature 384:80–83. PCT Pub. Date:Jun. 28, 2001 Spector et al., (1996) J. Gen. Phsyiol. 107:611-619. (65) Prior Publication Data Synders et al., (1991) Mol. Pharmacol. 41:322–330. Trudeau et al., (1995) Science 269:92–95. US 2003/0212098 A1 Nov. 13, 2003 Van Neuten et al. (1978) Life Sci. 28:453-458. Related U.S. Application Data Wang et al., (1995) Hum. Mol. Genet. 4:1603–1607. (60) Provisional application No. 60/171952, filed on Dec. 23, Willius, et al. (1942) Proc. Staff Meet. Mayo Clin. 1999. 17:294-296. (51) Int. Cl." ..................... A61K 31/437; CO7D 453/04 International Search Report for International Application (52) U.S. Cl. ....................... 514305; 54.6/134; 546/1.12; PCT/US OO/352.13. 514/299 Primary Examiner-Charanjit S. Aulakh (58) Field of Search ................................. 514/305, 299; (74) Attorney, Agent, or Firm McDonnell Boehnen 546/134, 112 Hulbert & Berghoff LLP (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS The present invention provides methods for purifying, iden 3,907.806 A 9/1975 Guenter et al. tifying and using optically active isomers of quinine and 3,929,795. A 12/1975 Walter et al. quinidine as well as compositions comprising Such optically active isomers. Such optically active isomers having desired FOREIGN PATENT DOCUMENTS actions on cardiac Sodium and potassium channel function EP OOOO 3O2 1/1979 substantially separable from undesirable effects on GI motil ity can be useful for more effective therapy of cardiac OTHER PUBLICATIONS arrhythmias. Also disclosed are methods for assaying the Barhaninet al., (1996) Nature 384(6604):78–80. levels of Such isomers present in the biological fluids. Bennet et al., (1995) Nature 376:683–685. Busch et al., (1994) Eur J. Pharmacol. 264:33–37. 20 Claims, 10 Drawing Sheets U.S. Patent Jan. 18, 2005 Sheet 1 of 10 US 6,844,355 B2 OCH3 Compound C t -- Fig. 1 U.S. Patent Jan. 18, 2005 Sheet 2 of 10 US 6,844,355 B2 Compound R R R R 2a - H ...inIII. H 2b H 2C ..svil H 2d - H 2e -as ball H 2f - H 2g aw H U.S. Patent Jan. 18, 2005 Sheet 4 of 10 US 6,844,355 B2 U.S. Patent Jan. 18, 2005 Sheet 5 of 10 US 6,844,355 B2 00:4 ogDÅ 0,0 U.S. Patent Jan. 18, 2005 Sheet 6 of 10 US 6,844,355 B2 .O. 0.3 G.6 (). ot obon too othb o'o 4 or 2 Fig. 6 U.S. Patent Jan. 18, 2005 Sheet 7 of 10 US 6,844,355 B2 to-1 o s o O O O Os O' O O Fig. 7 U.S. Patent Jan. 18, 2005 Sheet 8 of 10 US 6,844,355 B2 100 IM Anioradone U.S. Patent Jan. 18, 2005 Sheet 9 of 10 US 6,844,355 B2 Control 107 M | Fig. 9 A U.S. Patent Jan. 18, 2005 Sheet 10 of 10 US 6,844,355 B2 ES Quinidine kill Quinine Fig. 9 B US 6,844,355 B2 1 2 OPTICALLY ACTIVE ISOMERS OF QUININE However, its prolongation of the QT interval due to APD AND QUINDINE AND THEIR RESPECTIVE (action potential duration) prolongation is not well under BIOLOGICALACTION stood. Subsequently, quinidine is found to Show a significant effect in blocking the potassium repolarizing current, thus possessing type III Vaughn Williams (classification) effect. This application claims the benefit of U.S. Provisional More recently the prolongation of APD has been found to be Application Ser. No. 60/171952, filed Dec. 23, 1999, which both an anti-arrhythmic action, as well as being the basis for is incorporated herein by reference in its entirety. the development of a rapid Ventricular tachycardia with BACKGROUND OF THE INVENTION unique morphology called Torsade de Pointes Ventricular tachycardia. Additionally, two potassium channels have 1. Field of the Invention been reported to be critically involved in human repolariza The present invention relates generally to the resolving of tion; one being IK, the rapid rectifier and the Second being Stereoisomers of quinidine and quinine. More particularly, IK, a slower ion channel in the human myocardium. While the invention relates to the identification of the biological the anti-arrhythmic action of many agents on Supraventricu activity of the different Stereoisomers of quinidine and 15 lar arrhythmia and Ventricular arrhythmias are moderated quinine. via inhibition of Sodium channel (ex procainamide) the 2. Description of the Related Art effect on the potassium channels (IK, and IK) may be an Quinidine is the most prescribed anti-arrhythmic agent in important anti-arrhythmic action. However, Strong IK, the United States. However, the clinical utility of quinidine blocking action often leads to pro-arrhythmia of the TorSade is limited by the adverse effect of diarrhea. In addition, de Pointes variety. Thus, a chiral isolate that has less IK, quinidine causes arrhythmias, especially the torSade de action, but retains Sodium channel inhibition may offer pointes variety that results from a long QT interval. The considerably leSS pro-arrhythmia. Additionally, an agent Significant proarrhythmia (worsening of Ventricular causing leSS contractile augmentation of the GI Smooth arrhythmias) associated with quinidine are possibly due to muscle may also be a significant advantage, Since So many its combined effect on both the Sodium depolarizing current 25 patients discontinue quinidine due to the diarrhea. Contrac and the potassium repolarizing current. tile augmentation may not be the only mechanism of qui The first medicinal remedy for the treatment of cardiac nidine induced diarrhea. A Secretory action of quinidine may arrhythmias is derived from the bark of the cinchona tree, also be an important contributor to the agents diarrheal indigenous to South America, where South American Indi effects. ans long-used cinchona as medication. Europeans brought Quinidine has a duplicate drug in nature, quinine, the well the remedy back from their New World explorations. Jean known anti-malarial agent. Quinine is the chemical mirror Baptiste Senac, a French physician, is the first to describe the image of quinidine, similar to the differences of the right use of cinchona extract for cardiac irregularities (Willius, F from the left hand-identical but can't overlap, a structural A, et al., Proc. Staff Meet. Mayo Clin, 1942, 17, 294–296). characteristic in chemistry known as chirality. This results in Subsequently, a ship's captain with the medical condition 35 quinidine and quinine being Stereoisomers of each other. auricular (atrial) fibrillation is seen by one of the leading Quinine not only causes constipation, rather than diarrhea, European cardiologists, Professor Wenckebach, who had no but it affects cardiac ion channels a lot less than quinidine. treatment for the condition (Wenckebach, K F. Die unregel These differences come about because of the mirror image massige Herztatigkeit und ihre klinische bedeutung. W. relationships of the molecule at one chiral center. Thus, Engelmann, Leipzig, 1914). The ship's captain showed 40 because two different stereoisomers exist that have different Wenckebach how the bark of the cinchona could control the configurations, they cannot fit into receptors the same way. cardiac irregularity. Following this, Wenckebach popular Since it is assumed that the anti-arrhythmic action, QT ized the use of the cinchona extract for arrhythmia therapy. prolongation, and diarrhea occur as a result of the molecules The principal active anti-arrhythmic ingredient of cinchona, acting at Specific receptor Sites Such as ion channels, it quinidine, is identified in 1918 by the American chemist, 45 would be anticipated that they have differed effects at Frey (Frey, W. et al., Wien. Klin. Wschr, 1918, 55,849-853). differention channels. In fact, Stereoisomeric Segregation of While quinidine is still actively prescribed in the United drug effects is a well established pharmacological Strategy to States, its use is severely limited by a number of problems. determine if a drug acts at a receptor Site. Thus, if one The drug prolongs the QT interval on the electrocardiogram, Stereoisomer is active and the other is not, this is taken to in a very heterogeneous way, creating a predisposition 50 mean that the molecule acts at a specific binding site.
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