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WO 2007/109289 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 27 September 2007 (27.09.2007) WO 2007/109289 Al (51) International Patent Classification: (74) Agents: INSOGNA, Anthony, M. et al; Jones Day, 222 C07D 265/14 (2006.01) A61P 25/00 (2006.01) East 41st Street, New York, NY 10017-6702 (US). A61K 31/535 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/US2007/006959 AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY,BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, (22) International Filing Date: 20 March 2007 (20.03.2007) FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, (25) Filing Language: English LS, LT, LU, LY,MA, MD, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, (26) Publication Language: English RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (30) Priority Data: 60/784,513 20 March 2006 (20.03.2006) US (84) Designated States (unless otherwise indicated, for every (71) Applicant (for all designated States except US): XYTIS kind of regional protection available): ARIPO (BW, GH, INC. [US/US]; 101 Theory Suite 100, Irvine, CA 92617 GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (US). ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (72) Inventors; and FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PL, (75) Inventors/Applicants (for US only): PUTMAN, David, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, G. [US/US]; 26 Silveroak, Irvine, CA 92620 (US). GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). HOGENKAMP, Derk, J. [US/US]; 4510 Park Drive, Carlsbad, CA 92008 (US). DASSE, Olivier, A. [FR/US]; Published: 24 Carillon Place, Foothill Ranch, CA 92610 (US). — with international search report WHITTEMORE, Edward, R. [US/US]; 337 Magnolia St., Costa Mesa, CA 92627 (US). JENSEN, Mark, S. For two-letter codes and other abbreviations, refer to the "G uid [US/US]; 2709 Blue Ravine Rd., Wake Forest, NC 27587 ance Notes on Codes and Abbreviations" appearing at the beg in (US). ning of each regular issue of the PCT Gazette. (54) Title: ENANTIOMERICALLY PURE S-ETIFOXINE, PHARMACEUTICAL COMPOSITIONS THEREOF AND METH ODS OF THEIR USE (57) Abstract: Enantiomerically pure S-etifoxine and pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof are provided. Also provided are pharmaceutical compositions comprising the compounds and methods of treating disorders associated with central nervous system using the compounds and pharmaceutical compositions. ENANTIOMERICALLY PURE S-ETIFOXINE, PHARMACEUTICAL COMPOSITIONS THEREOF AND METHODS OF THEIR USE [00011 This application claims priority to U.S. provisional application Serial No. 60/784,513, filed March 20, 2006, entitled "Enantiomerically Pure (-)-Etifoxine, Pharmaceutical Compositions Thereof And Methods Of Their Use". The disclosure of the above referenced application is incorporated by reference herein in its entirety. FIELD OF THE INVENTION [0002] Provided herein are S-etifoxine and pharmaceutically acceptable salts, solvates, hydrates and prodrugs thereof, compositions comprising the same and methods of using the compounds and compositions. BACKGROUND OF THE INVENTION [0003] Etifoxine is chemically named as [6-chloro-2-(ethylamino)-4-methyl-4- phenyl-4H-3.,l-benzoxazine]. A hydrochloride salt of etifoxine, Stresam, is sold in France for the treatment of anxiety. Etifoxine was originally disclosed in U.S. Patent No. 3,725,404. Although etifoxine is chiral, as far as the inventors are aware, there is no disclosure of its resolution or asymmetric synthesis. Etifoxine has a depressive effect on the central nervous system and is an anticonvulsant. It is also known to have tranquillizing effects, narcosis-prolonging effects and analgesic properties. See, e.g., Corisco etal, Psychopharmacologia (Bed.) 45, 301-303, 1976. [0004] Etifoxine hydrochloride has been extensively studied and reportedly can be used in the treatment of a variety of disorders. For example, European Patent No. EP1273301, German Patent No. DE3439055 and U.S. Patent Nos. 3,725,404 and 6,638,528 disclose uses of etifoxine as an anticonvulsant, a tranquilizer and an anxiolytic drug. It has been reported to act as a modulator of GABA receptor complex activity. See, Hamon et al, 2003, Neuropharmacology, 45, 293-303. [0005] There remains a need for methods of using the same for treating anxiety and other conditions. SUMMARY OF THE INVENTION [0006] Provided herein are pure (-)-etifoxine and salts, solvates, hydrates and prodrugs thereof. Also provided are compositions comprising pure (-)-etifoxine or a salt, solvate, hydrate or prodrug thereof and a pharmaceutical carrier, excipient or diluent. [0007] The compounds and compositions are useful, for example, in methods for treating, preventing, ameliorating or managing symptoms of diseases or disorders amenable to treatment, prevention, amelioration or management with racemic etifoxine. In certain embodiments, provided herein are methods for treating, preventing, ameliorating or managing symptoms of diseases or disorders including, but not limited to conditions associated with anxiety, convulsions, disorders of the central nervous system and mental disorders. Disorders of the central nervous system include but are not limited to multiple sclerosis, muscle relaxation in spinal spasticity, cerebral palsy, trigeminal neuralgia, migraine, Alzheimer's disease, pain, drug withdrawal symptoms and convulsive disorders, such as epilepsy. Mental disorders include, but are not limited to, anxiety disorders; mood disorders; sleep disorders; delirium, dementia and amnestic and other cognitive disorders; attention deficit and disruptive behavior disorders; and substance related disorders. In certain embodiments, the compounds and compositions are useful in methods for treating, preventing, ameliorating or managing symptoms of diseases or disorders associated with cardiovascular disorders such as hypertension, and gut motility disorders such as irritable bowel syndrome. The methods provided herein comprise administering to a subject in need thereof an effective amount of enantiomerically pure (-)-etifoxine, or a salt, solvate, hydrate or prodrug thereof substantially free of the other enantiomer. [0008] In particular embodiments, enantiomerically pure (-)-etifoxine is useful for the treatment or prevention of anxiety with little or no sedating side effects. In further particular embodiments, enantiomerically pure (-)-etifoxine is useful for the treatment or prevention of pain, e.g. neuropathic pain, with little or no sedating side effects. [0009] The absolute configuration of (+)-etifoxine was determined to be R by X- ray crystallographic analysis as described in the examples below. (-)-Etifoxine was assigned to be the corresponding S enantiomer. BRIEF DESCRIPTION OF DRAWINGS [0010] FIG. 1 provides an HPLC trace illustrating resolution of the two enantiomers of etifoxine by chiral HPLC - the two peaks in the trace, peak 1and peak 2, correspond to pure enantiomers of etifoxine; [0011] FIG. 2A provides an HPLC trace of the enantiomer corresponding to isolated peak 1; [0012] FIG. 2B provides an HPLC trace of the enantiomer corresponding to isolated peak 2; [0013] FIG. 3A provides an HPLC trace of etifoxine enantiomers; [0014] FIG. 3B provides an optical rotation trace of R-etifoxine and S-etifoxine; [0015] FIG. 4A provides GABA subunit selectivity of R-etifoxine using a 2- electrode clamp technique; [0016] FIG. 4B provides GABA subunit selectivity of S-etifoxine using a 2- electrode clamp technique; [0017] FIG. 5 illustrates the effect of S-etifoxine on late phase licking in the mouse formalin test; [0018] FIG. 6A provides representative chromatogram of a plasma sample extracted 30 minutes following a 30 mg/kg/po dose of S-etifoxine; [0019] FIG. 6B provides representative chromatogram of racemic etifoxine spiked into plasma at 100 ng/mL; and [0020] FIGS. 7A and 7B provide plots of plasma concentration of S-etifoxine over time. [0021] FIG. 8 provides X-crystal structure of the adduct of R-etifoxine obtained in Example 4. DETAILED DESCRIPTION OF THE INVENTION Definitions [0022] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. [0023] As used herein pure S-etifoxine is substantially free from R-etifoxine (i.e., in enantiomeric excess). In other words, the "S" form of etifoxine is substantially free from the "R" form of the compound and is, thus, in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more
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