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(12) United States Patent (10) Patent No.: US 8,110,569 B2 Putman Et Al

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(12) United States Patent (10) Patent No.: US 8,110,569 B2 Putman Et Al US008110569B2 (12) United States Patent (10) Patent No.: US 8,110,569 B2 Putman et al. (45) Date of Patent: Feb. 7, 2012 (54) ENANTIOMERICALLY PURES-ETIFOXINE, Blanco, et al., Synthesis of Chiral Sulfinic Acids: Sodium(1S-exo)- PHARMACEUTICAL COMPOSITIONS 2-Bornanesulfinate, Synthesis 7:584-86 (00/00/1989). THEREOF AND METHODS OF THEIR USE Corisco, et al., Evaluation of the Psychotropic Effect of Etifoxine Through Pursuit Rotor Performance and GSR, Psychopharmacologia (Berl.) 45:301-03 (00/00/1976). (75) Inventors: David Putman, Irvine, CA (US); Derk Csomos, et al., Synthesis and Transformations of Hogenkamp, Carlsbad, CA (US); 2-(phenylhydroxymethyl)cyclohexylamines, Tetrahedron, Olivier Dasse, Foothill Ranch, CA (US); 57(15):3175-83 (00/00/2001). Edward R. Whittemore, Costa Mesa, Dale, et al., Nuclear Magnetic Resonance Enantiomer Reagents. CA (US); Mark S. Jensen, Wake Forest, Configurational Correlations via Nuclear Magnetic Resonance Chemical Shifts of Diastereomeric Mandelate, O-Methylmandelate, NC (US) and O-Methoxy-O-trifluoromethylphenylacetate, MTPA) Esters, J. (73) Assignee: The Regents of the University of Am. Chem. Soc. 95(2): 512-19 (Jan. 24, 1973. Dosa, et al., Catalytic Asymmetric Addition of ZnPh to Ketones: California, Oakland, CA (US) Enantioselective Formation of Quaternary Stereocenters, J. Am. Chem. Soc. 120(2):445-46 (Jan. 1, 1998). (*) Notice: Subject to any disclaimer, the term of this Forrat, et al., Chiral Tertiary Alcohols from a trans-1-arenesulfonyl patent is extended or adjusted under 35 amino-2-isobomeolsulfonylaminocyclohexane-catalyzed Addition U.S.C. 154(b) by 195 days. of Organizincs to Ketones, Tetrahedron: Asymmetry 16:3341-44 (0.0/ 00/2005). (21) Appl. No.: 11/726.289 Garcia, et al., Highly Enantioselective Catalytic Phenylation of Ketones with a Constrained Geometry Titanium Catalyst, Org. Let (22) Filed: Mar 20, 2007 ters 5(20) 3641-44 (00/00/2003), Including Supporting Information, pp. S1-S31. (65) Prior Publication Data Hamon, et al. The Modulatory Effects of the Anxiolytic Etifoxine of GABA Receptors are Mediated by the B Subunit, Neuropharmacol US 2008/OO38331 A1 Feb. 14, 2008 ogy, 45:293-03 (00/00/2003). Hoeve, et al., The Design of Resolving Agents. Chiral Cyclic Phos Related U.S. Application Data phoric Acides, J. Org. Chem. 50(23):4508-14 (00/00/1985). Hole, et al., The Tail-Flick and Formalin Tests in Rodents: Changes in (60) Provisional application No. 60/784,513, filed on Mar. Skin Temperature as a Confounding Factor, Pain 53:247-54 (00/00/ 20, 2006. 1993). Hubner, et al., Uber die Umsetzung von Hydroxysteroiden mit (51) Int. Cl. Carbodiimiden, J. fur Praktische Chemie. (Leibzig) 311(4) 630-34 CO7D 265/18 (2006.01) (00/00/1969). A6 IK3I/536 (2006.01) Matsugi, et al., A Novel Separation Technique of Diastereomeric (52) U.S. Cl. ....................................... 514/230.5:544/90 Esters of Pyridylethanols by Extraction: Formal Total Synthesis of PNU-142721, HIV-1 Reverse Transcriptase Inhibitor, Tetrahedron (58) Field of Classification Search .................... 544/90; 60(14):3311-17 (00/00/2004). 514/230.5 Pierce, et al., Practical Asymmetric Synthesis of Efavirenz (DMP See application file for complete search history. 266), and HIV-1 Reverse Transcriptase Inhibitor, J. Org. Chem. 63(23):8536-43 (00/00/1998). (56) References Cited Prieto, et al., Highly Enantioselective Arylation of Ketones, Tetrahe dron: Asymmetry, 14:1955-57 (00/00/2003). U.S. PATENT DOCUMENTS Ravi, et al., Thermal Fries Rearrangement of Anilides, Indian J. 3,725,404 A * 4, 1973 Kuch et al. ...................... 544/90 Chem. 30B(4):443-45 (04/00/1991). 6,638,528 B1 10/2003 Kanios Saito, et al., Synthesis of Alkyl-3--thioglucopyranosides, a Series of 2007/0021415 A1 1/2007 Le Guernet al. New Nonionic Detergents, Chem. Pharm. Bull.33(2):503-08 (00/00/ 2007/0167446 A1 7/2007 Verleye et al. 1985). FOREIGN PATENT DOCUMENTS (Continued) DE 3439055 A1 4f1986 EP 1273 301 A2 1, 2003 EP 1745786 1, 2007 Primary Examiner — Kahsay T Habte OTHER PUBLICATIONS (74) Attorney, Agent, or Firm — Cooley LLP Hamon et al. Neuropharmacology 45 (2003), 293-303.* Corsico et al. Psychopharmacologia (Berl.) 45, 301-303 (1976).* (57) ABSTRACT Vippagunta et al., “Crystalline Solids' Advanced Drug Delivery Reviews, vol. 48, pp. 3-26 (2001).* Enantiomerically pure S-etifoxine and pharmaceutically Aladro, et al., Enantioselective Synthesis of o-Hydroyacids Through Oxidation of Terminal Alkenes with AD-mix, TEMPO, Tetrahedron acceptable salts, Solvates, hydrates or prodrugs thereof are Letters 41(17):3209-13 (00/00/2000). provided. Also provided are pharmaceutical compositions Baldwin, et al., The Synthesis of 4-arylsulfanyl-substituted Kainoid comprising the compounds and methods of treating disorders Analogues from trans-4-hydroxy--proline.Tetrahedron associated with central nervous system using the compounds 57(37):7991-97 (00/00/2001). and pharmaceutical compositions. Blanco, et al., Chiral Sulfinic Acids: Synthesis of Sodium (IS, 2S, 5R)-2-Isopropyl-5-methylcyclohexanesufinate by a Novel Route, Tetrahedron 51(3):935-40 (00/00/1995). 47 Claims, 10 Drawing Sheets US 8,110,569 B2 Page 2 OTHER PUBLICATIONS Ligands for Catalytic Asymmetric Wacker-Type Cyclization, J. Org. Chem. 64(5):1620-25 (00/00/001999), Including Supporting Infor Sanki, et al., Synthesis of Anomerically PureVinyl Sulfone-Modified mation, pp. 1-10. Pent-2-Enofuranosides and Hex-2-Enopyranosides: A Group of Whittemore, et al., Pharmacology of the Human Y-Aminobutyric Highly Reactive Michael Acceptors for Acessing Carbohydrate Acid Receptor O4 Subunit Expressed in Xenopus laevis Oocytes, Mole. Pharm. 50: 1364-75 (00/00/1996). Based Synthons, Tetrahedron 59(36):7203-14 (00/00/2003). Yoder, The Replacement of Secondary Hydroxyl Groups by Sulfonic Schaus, et al., Highly Selective Hydrolytic Kinetic Resolution of Acid Substitutents, Iowa State College, ChemSec. of Iowa Agr. Exp. Terminal Epoxides Catalyzed by Chiral (salen)Co' Complexes. Station, 200Paper No. J 2751): 1317-21, (10/00/1955). Practical Synthesis of Enantioenriched Terminal Epoxides and 1,2- Tsang et al., Curr Pharm Des. 2004; 10(9): 1035-44. Diols, J. Am. Chem. Soc. 124(7): 1307-15 (00/00/2000), Including Dawson et al., CNS Spectr. 2005:10(1): 21-7. Supporting Information, pp. S1-S23. Lydiard R.D. J Clin Psychiatry. 2003, 64 Suppl 3:21-7. Su, et al., Fries-Type Rearrangement of Acylanilides in theYtterbium Anthony Krantis, News Physiol. Sci. 15, 2000. Triflate, J. Chem. Res. 9:611-13 (00/00/2004). European Patent Application 07753576 Office Action mailed Nov. UoZumi, Cationic Palladium Boxax Complexes for Catalytic Asym 29, 2010. metric Wacker-Type Cyclization, J. Org. Chem. 63(15):5071-75 (0.0/ European Patent Application07753576 Office Action mailed Feb. 11, 00/1998), Including Supporting Information, pp. i-ix. 2011. UoZumi, et al., Design and Preparation of 3.3'-Disubstituted 2,2'- Bis(oxazolyl)-1. 1'-Binaphthyls (Boxax):New Chiral Bis(oxazoline) * cited by examiner U.S. Patent Feb. 7, 2012 Sheet 1 of 10 US 8,110,569 B2 so so st Sn 8/6 Se 198 g s 3 S 3 S. S U.S. Patent Feb. 7, 2012 Sheet 2 of 10 US 8,110,569 B2 mAU 1000 800 600 400 200 O 2 4. 6 8 10 12 14 FG.2A mAU 5. 1200 AREA 30353.1 1000 800 600 400 200 AREA 56.842 O 2 4. 6 8 10 12 14 FIG.2B U.S. Patent Feb. 7, 2012 Sheet 3 of 10 US 8,110,569 B2 0.10 : g 0.08 0.06 a. 0.04 0.02 0.00 Ha-a-1N 2.00 4.00 6.00 8.00 10.00 12.00 14.00 MINUTES FIG.3A 150.00 100.00 e 50.00 0.00 -50.00 -100.00 -150.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 MINUTES FG.3B U.S. Patent Feb. 7, 2012 Sheet 4 of 10 US 8,110,569 B2 g 300 - A - GABA-122 (n=4) LL7, 200 -V-GABA 112 (n=3) 5 100 S O -100-th -t-t-t-t-t- - 10.0 -7 -6 -5 -4 (ETIFOXINE PEAK 1' (LOGM) FG.4A 3 300 -V-GABA 122 (n=3) 5 -V-GABA 112 (n=4) 2 200 S. 100 S 0 SSR -100 ------ -10.0 -7 -6 5 -4 ETIFOXINE PEAK 2 (LOGM) FG4B U.S. Patent US 8,110,569 B2 U.S. Patent Feb. 7, 2012 US 8,110,569 B2 (u/bu) ONOO U.S. Patent Feb. 7, 2012 Sheet 10 of 10 US 8,110,569 B2 FIG.8 US 8,110,569 B2 1. 2 ENANTIOMERICALLY PURE S-ETIFOXINE, and compositions are useful in methods for treating, prevent PHARMACEUTICAL COMPOSITIONS ing, ameliorating or managing symptoms of diseases or dis THEREOF AND METHODS OF THEIR USE orders associated with cardiovascular disorders such as hypertension, and gut motility disorders such as irritable This application claims priority to U.S. provisional appli bowel syndrome. The methods provided herein comprise cation Ser. No. 60/784,513, filed Mar. 20, 2006, entitled administering to a subject in need thereofan effective amount "Enantiomerically Pure (-)-Etifoxine, Pharmaceutical Com of enantiomerically pure (-)-etifoxine, or a salt, Solvate, positions Thereof And Methods Of Their Use'. The disclo hydrate or prodrug thereof substantially free of the other sure of the above referenced application is incorporated by enantiomer. reference herein in its entirety. 10 In particular embodiments, enantiomerically pure (-)-eti foxine is useful for the treatment or prevention of anxiety with FIELD OF THE INVENTION little or no sedating side effects. In further particular embodi ments, enantiomerically pure (-)-etifoxine is useful for the Provided herein are S-etifoxine and pharmaceutically treatment or prevention of pain, e.g. neuropathic pain, with acceptable salts, Solvates, hydrates and prodrugs thereof, 15 little or no sedating side effects.
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