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(12) United States Patent (10) Patent No.: US 8,735,376 B2 Muhammad Et Al

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(12) United States Patent (10) Patent No.: US 8,735,376 B2 Muhammad Et Al US008735376B2 (12) United States Patent (10) Patent No.: US 8,735,376 B2 Muhammad et al. (45) Date of Patent: May 27, 2014 (54) CARBONATE PRODRUGS AND METHODS 2004/0058946 A1 3/2004 Buchwald et al. OF USING THE SAME 2004/O186081 A1 9, 2004 Slusher et al. 2005.0020576 A1 1/2005 Zhang et al. 2005, 0026850 A1 2/2005 Robinson et al. (75) Inventors: Naweed Muhammad, Fremont, CA 2005/0026879 A1 2/2005 Robinson et al. (US); Keith R. Bley, Mountain View, 2005, 0080260 A1 4/2005 Mills et al. CA (US) 2005, 01476.68 A1 7/2005 Bertelsen et al. 2006.0089383 A1 4/2006 Le Bourdonnec et al. Assignee: 2006, O116422 A1 6/2006 De Groot et al. (73) Acorda Therapeutics, Inc., Ardsley, NY 2007/0042999 A1 2/2007 West et al. (US) 2008/0318905 A1 12/2008 Muhammad et al. 2011/0212926 A1 9/2011 Muhammad et al. (*) Notice: Subject to any disclaimer, the term of this 2011/0263545 A1 10, 2011 Muhammad et al. patent is extended or adjusted under 35 U.S.C. 154(b) by 328 days. FOREIGN PATENT DOCUMENTS Appl. No.: 12/993,089 WO WO-0008033 A1 2, 2000 (21) WO WO-O 1/52852 A1 T 2001 WO WO-2005, O77394 A1 8, 2005 (22) PCT Fled: May 20, 2009 WO WO-2006/O14282 A2 2, 2006 WO WO-2009/143295 A1 11, 2009 (86) PCT NO PCT/US2O09/044746 WO WO-2009/143297 A1 11, 2009 S371 (c)(1), WO WO-2009/143299 A1 11, 2009 (2), (4) Date: Apr. 21, 2011 OTHER PUBLICATIONS PCT Pub. No.: WO2O09/143297 Berenblum, I. et al. (1959). "Skin-Initiating Action and Lung (87) Carcinogenesis by Derivatives of Urethane (Ethyl Carbamate)) and PCT Pub. Date: Nov. 26, 2009 Related Compounds.” Biochemical Pharmacology 2:168-176. Extended European Search Report mailed on Mar. 27, 2012, for EP (65) Prior Publication Data Patent Application No. 09751525.8, filed on May 20, 2009, 7 pages. Kazlauskas, R.J. etal. (1985). "Synthesis of Methoxycarbonyl Phos US 2011 FO212927 A1 Sep. 1, 2011 phate, a New Reagent Having High Phosphoryl Donor Potential for Use in ATP Cofactor Regeneration.” J. Org. Chem. 50(7): 1069-1076. FDA Anesthetic and Life Support Drugs Advisory Committee (May Related U.S. Application Data 7, 2008). “AQUAVANCR) (Fospropofol Disodium) Injection.” Web (60) Provisional application No. 61/054,765, filed on May Slide Presentation, 150 pages. 20, 2008. Hadzimichalis, N.M. et al. (Dec. 2007, e-pub. Oct. 5, 2007). "Acetaminophen-Mediated Cardioprotection via Inhibition of the Int. C. Mitochrondrial Permeability Transition Pore-Induced Apoptotic (51) Pathway.” Am. J. Physiol. Heart Circ. Physiol. 293:H3348-H3355. A6 IK3I/664 (2006.01) International Search Report mailed on Jul. 7, 2009, for PCT Patent C07F 9/06 (2006.01) Application No. PCT/US09/44746, filed on May 20, 2009, 1 page. (52) U.S. C. International Search Report mailed on Jul. 16, 2009, for PCT Patent USPC ........................................... 514/119,558/179 Application No. PCT/US09/44743, filed on May 20, 2009, 1 page. (58) Field of Classification Search Krise, J.P. et al. (Aug. 12, 1999, e-pub. Jul. 17, 1999). “Novel Prodrug USPC ........................................... 514/119; 558/179 Approach for Tertiary Amines: Synthesis and Preliminary Evaluation See application file for complete search history. of N-Phosphonooxymethyl Prodrugs,” Journal of Medicinal Chem istry 42(16):3094-3100. Lee, T. etal. (Oct. 2, 2006). “Solubility, Polymorphism, Crystallinity, (56) References Cited and Crystal Habit of Acetaminophen and Ibuprofen by Initial Solvent Screening.” Pharmaceutical Technology, located at <http://license. U.S. PATENT DOCUMENTS icopyright.net/user/viewFreeUse...act?fuid=MTI5NDIOMzY%3D>. 4.322,410 3/1982 Stjepanovic et al. last visited on May 26, 2011, 16 pages. 5,001,115 3, 1991 Sloan 5,073,641 12/1991 Bundgaard et al. (Continued) 5,272,171 12/1993 Ueda et al. 5,498,729 3, 1996 Domb Primary Examiner — Kristin Vajda 5,939.405 8/1999 Starrett, Jr. et al. (74) Attorney, Agent, or Firm — Morrison & Foerster LLP 5,985,856 11/1999 Stella et al. 6,043,285 3, 2000 Pinza et al. 6,140,310 10, 2000 Glazier (57) ABSTRACT 6,204.257 3, 2001 Stella et al. The present invention provides carbonate prodrugs which 6,214,811 4/2001 Glazier et al. comprise a carbonic phosphoric anhydride prodrug moiety 6,362,172 3, 2002 Ueda et al. 6.451,776 9, 2002 Stella et al. attached to the hydroxyl or carboxyl group of a parent drug 6,713,089 3, 2004 Bertelsen et al. moiety. The prodrugs may provide improved physicochemi 6,825.204 11/2004 Liu cal properties over the parent drug. Also provided are meth 6,872,838 3/2005 Stella et al. ods of treating a disease or condition that is responsive to the 6,916,825 7/2005 Senn-Bilfinger et al. 7,230,005 6, 2007 Shafer et al. parent drug using the carbonate prodrugs, as well as kits and 7,244,718 7/2007 Stella et al. unit dosages. 2002/0090398 7/2002 Dunn et al. 2003/0022876 1/2003 Ashton et al. 11 Claims, 3 Drawing Sheets US 8,735,376 B2 Page 2 (56) References Cited U.S. Appl. No. 12/993,091, internationally filed on May 20, 2009, for Muhammad et al. OTHER PUBLICATIONS Written Opinion of the International Searching Authority mailed on Jul. 7, 2009, for PCT Patent Application No. PCT/US09/44746, filed Maharaj. H. etal. (2006, e-pub. Jul. 20, 2006). "Acetylsalicylic Acid on May 20, 2009, 5 pages. and Acetaminophen Protect Against Oxidative Neurotoxicity.” Meta Written Opinion of the International Searching Authority mailed on bolic Brain Disease 21(2-3): 189-199. Jul. 16, 2009, for PCT Patent Application No. PCT/US09/44743, Moller, P.L. et al. (2005). “Intravenous Acetaminophen filed on May 20, 2009, 5 pages. (Paracetamol): Comparable Analgesic Efficacy, but Better Local Baliga, S.S. (May 2009). "Acetaminophen Confers Neuroprotection Safety than Its Prodrug, Propacetamol, for the Postoperative Pain During Early Cerebral Ischemia-Reperfusion.” A Dissertation sub After Third Molar Surgery.” Anesth. Analg. 101:90-96. mitted to the Graduate School-New Brunswick Rutgers, The State University of New Jersey and The Graduate School of Biomedical Moller, P.L. et al. (2005, e-pub. Mar. 24, 2005). “Onset of Sciences University of Medicine and Dentistry and Dentistry of New Acetaminophen Analgesia: Comparison of Oral and Intravenous Jersey, 125 pages. Routes After Third Molar Surgery.” British Journal of Anaesthesia Mayo Clinic (updated Jul. 13, 2013). “Myocardial Ischemia Preven 94(5):642-648. tion.” located at http://www.mayoclinic.com/health/myocardial Poste, G. et al. (1976). “Lipid Vesicles as Carriers for Introducing ischemia/DSO 1179/DSECTION=prevention, last visited on Oct. 29, Biologically Active Materials into Cells.” Chapter 4 in Methods in 2013, 2 pages. Cell Biology, Prescott, D.M. ed., Academic Press, Inc.: New York, Wikipedia (last modified Aug. 21, 2013). “Ischemia,” located at NY, XIV:33-71. http://en.wikipedia.org/wiki/Ischemia, last visited on Sep. 11, 2013, Roberts II, L.J. et al. (2001). "Analgesic-Antipyretic and Antiinflam four pages. matory Agents and Drugs Employed in the Treatment of Gout.” Wikipedia (last modified on Sep. 8, 2013). “Paracetamol.” located at Chapter 27 in Goodman & Gillman's The Pharmacalogical Basis of http://en.wikipedia.org/wiki/Paracetamol, last visited on Sep. 11, Therapeutics, 10' Edition, McGraw Hill, Medical Publishing Divi 2013, 19 pages. sion: New York, NY. pp. 687-731. Laird, B. et al. (May 2008, e-pub. Apr. 23, 2008). “Management of U.S. Appl. No. 12/993,088, internationally filed on May 20, 2009, for Cancer Pain: Basic Principles and Neuropathic Cancer Pain.” Euro Muhammad et al. pean Journal of Cancer 44(8): 1078-1082. U.S. Patent May 27, 2014 Sheet 1 of 3 US 8,735,376 B2 O O 10 20 30 40 50 60 Time (min) FIGURE 1 U.S. Patent May 27, 2014 Sheet 2 of 3 US 8,735,376 B2 250 - C t 200 - als --- T ------- C (----- -------, --- --- 3 1, 150 - S o, N2 100 C . 50 - CD aC O O 10 2O 30 40 50 60 Time (Min) FIGURE 2 U.S. Patent May 27, 2014 Sheet 3 of 3 US 8,735,376 B2 m st 4 Acetaminophen 5. A: c Compound (IV) 12U . 3 8. 1A \ 9 . C 4EO .A E s - - - f's- g re--- areer--- SO 8O 3. 8. Time (minutes post-dose) FIGURE 3 US 8,735,376 B2 1. 2 CARBONATE PRODRUGS AND METHODS (SporanoXR), Voriconazole (VfendR) and Zisprasidone (Ge OF USING THE SAME odon(R) are examples of Successful applications of this tech nique. However, this application generally requires a large CROSS REFERENCE TO RELATED excess of cyclodextrin relative to the amount of drug being APPLICATIONS solubilized and may not impart the desired increase in solu bility to the entire drug sample (for instance, a dosage of 10 This application is submitted under 35 U.S.C. S371 as a mg itraconazole, 200 mg of Voriconazole, or 20 mg of U.S. national stage application of International Application Zisprasidone requires 400 mg, 3200 mg. or 294 mg of cyclo No. PCT/US2009/044746, entitled “Carbonate Prodrugs and dextrin, respectively). Methods of Using The Same” and filed on May 20, 2009, 10 While the importance of discovering new drugs cannot be which claims priority benefit of U.S. Provisional Application overstated, the ability to improve the physicochemical prop No. 61/054,765, entitled “Carbonate Prodrugs and Methods erties of existing drugs has it bounties. Therefore, there is still of Using The Same" filed May 20, 2008, the content of which a clear and unmet need for improved drugs, such as prodrugs is hereby incorporated by reference in its entirety as if it was of existing drugs.
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