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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date PCT 12 March 2009 (12.03.2009) WO 2009/033054 Al (51) International Patent Classification: (74) Agents: WORRALL, Timothy A. et al.; 370 Seventeenth C07C 309/15 (2006.01) A61K 31/661 (2006.01) Street, Suite 4700, Denver, Colorado 80202 (US). C07F 9/09 (2006.01) A61P 25/00 (2006.01) A61K 31/255 (2006.01) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (21) International Application Number: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, PCT/US2008/075444 CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, (22) International Filing Date: IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, 5 September 2008 (05.09.2008) LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, (25) Filing Language: English RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (26) Publication Language: English ZW (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 60/970,924 7 September 2007 (07.09.2007) US GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, 61/061,059 12 June 2008 (12.06.2008) US ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (71) Applicant (for all designated States except US): XENO- FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,MC, MT, NL, PORT, INC. [US/US]; 3410 Central Expressway, Santa NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, Clara, California 95051 (US). CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventors; and Declarations under Rule 4.17: (75) Inventors/Applicants (for US only): JANDELEIT, — as to the identity of the inventor (Rule 4.17(i)) Bernd [DE/US]; 219 OTCeefe Street, Menlo Park, Cal — as to applicant's entitlement to applyfor and be granted a ifornia 94025 (US). LI, Yunxiao [CN/US]; 180 Elm patent (Rule 4.17(U)) Court, No. 812, Sunnyvale, California 94046 (US). — as to the applicant's entitlement to claim the priority of the GALLOP, Mark A. [NZ/US]; 3410 Central Express earlier application (Rule 4.17(Ui)) Way, Santa Clara, California 95051 (US). ZERANGUE, Noa [US/US]; 2323 Coronet Drive, Belmont, California Published: 94002 (US). VIRSIK, Peter A. [US/US]; 131 Escanyo — with international search report Way, Portola Valley, California 94028 (US). FISCHER, — before the expiration of the time limit for amending the Wolf-Nicolas [DE/US]; 871 West Knickerbocker Drive, claims and to be republished in the event of receipt of Sunnyvale, California 94087 (US). amendments (54) Title: COMPLEX PANTOIC ACID ESTER NEOPENTYL SULFONYL ESTER CYCLIZATION RELEASE PRODRUGS OF ACAMPROSATE, COMPOSITIONS THEREOF, AND METHODS OF USE (57) Abstract: Pantoic acid ester neopentyl sulfonyl ester prodrugs of acamprosate of formula (I), pharmaceutical compositions comprising such prodrugs, and methods of using such prodrugs and compositions thereof for treating diseases are disclosed. In particular, acamprosate prodrugs exhibiting enhanced oral bioavailability and methods of using acamprosate prodrugs to treat neu rodegenerative disorders, psychotic disorders, mood disorders, anxiety disorders, somatoform disorders, movement disorders, sub stance abuse disorders, binge eating disorders, cortical spreading depression related disorders, tinnitus, sleeping disorders, multiple sclerosis and pain are disclosed. PCT PATENT APPLICATION FOR COMPLEX PANTOIC ACID ESTER NEOPENTYL SULFONYL ESTER CYCLIZATION RELEASE PRODRUGS OF ACAMPROSATE, COMPOSITIONS THEREOF, AND METHODS OF USE BY BERND JANDELEIT, YUNXIAO LI, MARK A. GALLOP, NOA ZERANGUE, PETER A. VIRSIK AND WOLF-NICOLAS FISCHER COMPLEX PANTOIC ACID ESTER NEOPENTYL SULFONYL ESTER CYCLIZATION RELEASE PRODRUGS OF ACAMPROSATE, COMPOSITIONS THEREOF, AND METHODS OF USE [001] This application claims priorty to U.S. Provisional Application Serial Nos. 60/970,924 filed September 7, 2007, and 61/061,059 filed June 12, 2008, each of which is incorporated by reference in its entirety. FIELD [002] Disclosed herein are pantoic acid ester neopentyl sulfonyl ester prodrugs of acamprosate that exhibit enhanced oral bioavailability, pharmaceutical compositions comprising such prodrugs, and methods of using such prodrugs and compositions thereof for treating diseases. In particular, acamprosate prodrugs exhibiting enhanced oral bioavailability and methods of using acamprosate prodrugs to treat neurodegenerative disorders, psychotic disorders, mood disorders, anxiety disorders, somatoform disorders, movement disorders, substance abuse disorders, binge eating disorder, cortical spreading depression related disorders, sleeping disorders, tinnitus, multiple sclerosis, and pain. BACKGROUND [003] Prodrugs are derivatized forms of drugs that following administration are converted or metabolized to an active form of the drug in vivo. Prodrugs are used to modify one or more aspects of the pharmacokinetics of a drug in a manner that enhances the therapeutic efficacy of a drug. For example, prodrugs are often used to enhance the oral bioavailability of a drug. To be therapeutically effective, drugs exhibiting poor oral bioavailability may require frequent dosing, large administered doses, or may need to be administered by other than oral routes, such as intravenously. In particular, many drugs with sulfonic acid groups exhibit poor oral bioavailability. [004] Intramolecular cyclization prodrug strategies have been used to modify the pharmacokinetics of drugs (Bundgaard in "A Textbook of Drug Design and Development," Krogsgaard-Larsen and Bundgaard Eds., Harwood Academic, Philadelphia, 1991, pp. 113-192; Bungaard and Nielsen, US 5,073,641; Santos et al, Bioorganic & Medicinal Chemistry Letters, 2005, 15, 1595-1598; Papot et al., Curr Med Chem - Anti-Cancer Agents, 2002, 2, 155-185; and Shan et al, JPharm Sciences 1997, 86(7), 765-767). Intramolecular cyclization release prodrug strategies have been applied to drugs containing sulfonic acid functional groups. Prodrugs comprising a substituted neopentyl sulfonate ester derivative in which the neopentyl group is removed in vivo by unmasking a nucleophilic heteroatom bonded to a substituted neopentyl moiety followed by intramolecular cyclization to generate the parent drug in the sulfonic acid or sulfonic acid salt form have been described (Roberts and Patch, US 5,596,095; and Roberts et al., Tetrahedron Lett 1997, 38(3), 355-358). In such prodrugs the nucleophilic heteroatom can be nitrogen or oxygen and the nitrogen or oxygen nucleophile can be masked with any amine or alcohol protecting group, respectively, capable of being deprotected in vivo. Roberts and Patch also disclose that the masked nucleophilic group can be a carboxylic ester, e.g., -OCOR where R can be aryl, substituted aryl, heteroaryl, C - alkyl, arylalkyl, or heteroarylalkyl. However, Roberts and Patch do not provide biological or pharmacological data to indicate which if any of the substituted neopentyl sulfonate esters release the prodrug in vivo and would therefore be useful for enhancing the oral bioavailability of the corresponding drug. [005] 3-(Acetylamino)propylsulfonic acid (also refered to as iV- acetylhomotaurine), acamprosate, is a derivative of homotaurine, a naturally occurring structural analog of γ- aminobutyric acid (GABA) that appears to affect multiple receptors in the central nervous system (CNS). As an antiglutamatergic agent, acamprosate is believed to exert a neuropharmacological effect as an antagonist of N-τnethyl-D-aspartate (NMDA) receptors. The mechanism of action is believed to include blocking of the Ca2+ channel to slow Ca2+ influx and reduce the expression of c-fos, leading to changes in messenger RNA transcription and the concomitant modification to the subunit composition of NMDA receptors in selected brain regions (Zornoza et al, CNS Drug Reviews, 2003, 9(4), 359-374; and Rammes et al, Neuropharmacology 2001, 40, 749-760). In addition, acamprosate may block GABA B receptors (Daost, et al, Pharmacol Biochem Behav. 1992, 41, 669-74; and Johnson et al., Psychopharmacology 2000, 149, 327-344). Similar mechanisms are believed to be associated with the activity of other glutamate modulators such as riluzole, JV- acetylcysteine, β-lactams, amantadine, lamictal, memantine, neramexane, remacemide, ifenprodil, and dextromethorphan. [006] Other diseases or disorders known to be associated with modulation of NMDA activity and for which modulators of NMDA receptor activity are clinically useful include psychotic disorders such as schizophrenia and schizoaffective disorder; mood disorders such as anxiety disorders including posttraumatic stress disorder and obsessive-compulsive disorder, depression, mania, bipolar disorder; and somatoform disorders such as somatization disorder, conversion disorder, hypochondriasis, and body dysmorphic disorder; movement disorders such as Tourette's syndrome, focal dystonia, Huntington's disease, Parkinson's disease, Syndeham's chorea, systemic lupus erythematosus, drug-induced movement disorders, tardive dyskinesia, blepharospasm, tic disorder, and spasticity; substance abuse disorders such as alcohol abuse disorders, narcotic abuse disorders, and nicotine abuse
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