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5994392 Tion of Application No. 67375.734 Eb3-1685, PEN. T USOO5994392A United States Patent (19) 11 Patent Number: 5,994,392 Shashoua (45) Date of Patent: Nov.30, 1999 54 ANTIPSYCHOTIC PRODRUGS COMPRISING 5,120,760 6/1992 Horrobin ................................. 514/458 AN ANTIPSYCHOTICAGENT COUPLED TO 5,141,958 8/1992 Crozier-Willi et al. ................ 514/558 AN UNSATURATED FATTY ACID 5,216,023 6/1993 Literati et al. .......................... 514/538 5,246,726 9/1993 Horrobin et al. ....................... 424/646 5,516,800 5/1996 Horrobin et al. ....................... 514/560 75 Inventor: Victor E. Shashoua, Brookline, Mass. 5,580,556 12/1996 Horrobin ................................ 424/85.4 73 Assignee: Neuromedica, Inc., Conshohocken, Pa. FOREIGN PATENT DOCUMENTS 30009 6/1981 European Pat. Off.. 21 Appl. No.: 08/462,820 009 1694 10/1983 European Pat. Off.. 22 Filed: Jun. 5, 1995 09 1694 10/1983 European Pat. Off.. 91694 10/1983 European Pat. Off.. Related U.S. Application Data 59-025327 2/1984 Japan. 1153629 6/1989 Japan. 63 Continuation of application No. 08/080,675, Jun. 21, 1993, 1203331 8/1989 Japan. abandoned, which is a continuation of application No. 07/952,191, Sep. 28, 1992, abandoned, which is a continu- (List continued on next page.) ation of application No. 07/577,329, Sep. 4, 1990, aban doned, which is a continuation-in-part of application No. OTHER PUBLICATIONS 07/535,812,tion of application Jun. 11, No. 1990, 67,375.734 abandoned, Eb3-1685, which is a continu-PEN. T. Higuchi et al. 66 Prodrugs as Noye Drug Delivery Sys 4,933,324, which is a continuation-in-part of application No. tems”, American Chem. Society, ACS Symposium Series, 07/160,667, Feb. 26, 1988, Pat. No. 4939,174. vol. 14, pp. 14–15 (1975). (51) Int. Cl." ..................................................... A61K 31/38 (List continued on next page.) 52 U.S. Cl. .......................... 514/437; 514/432; 514/546; 514/549, 514/552; 514/678; 514/688; 554/85; Primary Examiner-Gary Geist 554/101; 554/223; 554/224;554/229; 549/1; ASSistant Examiner Deborah D. Carr 549/23; 549/26; 568/303; 568/308; 568/335 Attorney, Agent, or Firm Wolf, Greenfield & Sacks, P.C. 58 Field of Search .............................. 554/78, 223, 224, 57 ABSTRACT 554/85, 101, 229; 564/204, 207; 560/144, 163; 514/2, 17, 284, 400, 415, 849, 627, The invention involves the formation of a prodrug from a 432, 437, 566,549, 554, 678, 688; 548/342, fatty acid carrier and a neuroactive drug. The prodrug is 504, 507; 568/303, 308,355; 549/1, 23, stable in the environment of both the stomach and the 26 bloodstream and may be delivered by ingestion. The prodrug passes readily through the blood brain barrier. Once in the 56) References Cited central nervous System, the prodrug is hydrolyzed into the fatty acid carrier and the drug to release the drug. In a U.S. PATENT DOCUMENTS preferred embodiment, the carrier is 4, 7, 10, 13, 16, 19 4,346,085 8/1982 Growdon et al..... ... 424/199 docosahexa-enoic acid and the drug is dopamine. Both are 4,351,831 9/1982 Growdon et al. ......................... 514/78 normal components of the central nervous System. The 4.550,109 10/1985 Folkers et al. ... ... 514/249 covalent bond between the drug and the carrier preferably is 4,554.272 11/1985 Bock et al. ...... ... 514/219 an amide bond, which bond may Survive the conditions in 2. 1. Ele al. ......................... s'. the Stomach. Thus, the prodrug may be ingested and will not 4,933,3242 - a? a 6/1990 Shashouaang et al................................... .... 514/17 be tly,teletely into the carrier molecule and drug 4,939,174 7/1990 Shashoua ......... s14540 molecule in Ine Slomacn. 4,968,672 11/1990 Jacobson et al. ......................... 514/46 5,116,624 5/1992 Horrobin ................................. 424/702 44 Claims, 2 Drawing Sheets A 5t A? J///WY 47 S 30 S &S 20 ar f (7 W A. A A5 ASA / / / 4) 5,994,392 Page 2 FOREIGN PATENT DOCUMENTS Oshima, M., et al., “Effects of Docosahexaenoic Acid 1287022 11/1989 Japan. (DHA) on Intestinal Polyp Development in APC Delta 716 6016548 1/1994 Japan. Knockout Mice', Carcinogenesis, (1995), 8027010 1/1996 Japan. 16(11):2605–2607. (Abstract). 8163991 6/1996 Japan. Deutsch, H.F., et al., “Cytotoxic Effects of Daunomycin 9025231 1/1997 Japan. -Fatty Acid Complexes on Rat Hepatoma', Cancer Res, 96.03433 10/1996 South Africa. (1983), 43(6):2668–2672. (Abstract). PCT8500520 2/1985 WIPO. PCT8900757 2/1989 WIPO. Karmali, R.A., et al., “Effect of Omega-3 Fatty Acids on WO 94.12530 6/1994 WIPO. Growth of a Rat Mammary Tumor, J Natl Cancer Inst (1984), 73(2):457-461. (Abstract). OTHER PUBLICATIONS Tinsley, I.J., et al., “Influence of Dietary Fatty Acids on the S. Iwakami et al., “Inhibition of Arachidonate 5-Lipoxyge Incidence of Mammary Tumors in the CH3H Mouse”, nase by Phenolic Compounds”, Chem. Pharm. Bull. (Japan), Cancer Res, (1998), 41(4): 1460–1465. (Abstract). 34(9), 3960–3963, 1986. Anel, A., et al., “Increased Cytotoxicity of Polyunsaturated Y. Makino et al., Chemical Abstracts, vol. 106, No. 12, Fatty Acids on Human Tumoral B and T-Cell Lines Com issued 23 Mar. 23, 1987, “Pharmaceuticals Permeable to pared with Normal Lymphocytes", Leukemia, (1992), Blood-Brain Barrier", p. 363, Abstract No. 90177x, Japan 6(7):680-688. (Abstract). Kokai Tokyo Koho, JP61,204,136, dated Sep. 10, 1986. Jenski, L.J., et al., “Docosahexaenoic Acid-Induced Alter G. Dhopeshwarker, Chemical Abstracts, vol. 76, No. 16, ation of Thy-1 and CD8 Expression on Murine Spleno issued Apr. 17, 1972, “Fatty Acid Transport Into the Brain', cytes”, Biochim Biophys Acta, (1995), 1236(1):39-50. p. 276, Abstract No. 97365c, Biochim Biophys. Acta 1972, 255(2)572-9. (Abstract). R. Spector, Chemical Abstracts, vol. 108, No. 11, issued de Antueno, R.J., et al., “In Vitro Effect of Eicosapentaenoic Mar. 14, 1988, “Fatty Acid Transport Through the Blood and Docosahexaenoic Acids on Prostaglandin E2 Synthesis rain Barrier', p. 435, Abstract No. 92100q, J. Neurochem. in a Human Lung Carcinoma’, Biochem Int., (1989), 1988, 50(2), 639–43. 19(3):489–496. (Abstract). I. Yamatsu et al., Chemical Abstracts, vol. 100, No. 19, Kinsella, J.E., et al., “Effects of Polyunsaturated Fatty Acids issued May 7, 1984, “Polyprenyl Carboxylic Acid Amides”, on the Efficacy of ANtineoplastic Agents Toward L5178Y p. 555, Abstract No. 156839Z, EP91,694 dated Oct. 19, Lyphoma Cells”, Biochem Pharmacol, (1993), 1983. 45(9): 1881-1887. (Abstract). V.E. Shashoua, et al., “Y-Aminobutyric Acid Esters. 1. Syn Ehringer, W., et al., “A Comparison of the Effects of thesis ... ', Journal of Medicinal Chemistry, vol. 27, No. 5, Linolenic (18:3 Omega 3) and Docosahexaenoic (22:6 pp. 659-664 (1984). Omega 3) Acids on Phospholipid Bilayers”, Chem Phys J.N. Jacob, et al., “Y-Aminobutyric Acid Esters.2.Synthesis Lipids, (1990), 54(2):79-88. (Abstract). Brain Uptake ... ', J. of Medicinal Chemistry, vol.28, No.1, pp. 106–110 (1985). Guffy, M.M., et al., “Effect of Cellular Fatty Acid Alteration G.W. Hesse et al., “Inhibitory Effect of on Adriamycin Sensitivity in Cultured L1210 Murine Leu Cholesteryly-Aminobutyrate” Neurolpharmacology, vol. kemia Cells”, Cancer Res, (1984), 44(5):1863–1866. 24, No. 2, pp. 139–146, (1985). (Abstract). G. Bourat et al., “Long Chain Esters of Pipotiazine as Madhavi, N., et al., “Effect of N-6 and N-3 Fatty Acids on Long-Acting Psychotropic Pro-Drugs”, pp. 105-114, the Survival of Vincristine Sensitive and Resistant Human (1976) Med. Chem. Proc. Int. Symp. 5th. Cervical Carcinoma Cells in Vitro", Cancer Lett, (1994), K.A. Jacobson et al., “Adenosine analogs with covalently 84(1):31-41. (Abstract). attached lipids . , FEBS Letters, vol.225, Nos.1.2 pp. Kinsella, J.E., et al., “Effects of Polyunsaturated Fatty Acids 97–102 (Dec. 1987). on the Efficacy of Antineoplastic Agents Toward L5178Y A. Garzon-Aburbeh et al., “A Lymphotropic Prodrug of Lymphoma Cells”, Biochem Pharmacol, (1993.) L-Dopa:Synthesis” J. Med. Chem. 29: 687-691 (1986). 45(9): 1881-1887. (Abstract). U.K. Mazumdar & D.C. Dey, “Preparation and Evaluation Begin, M.E., et al., “Differential Killing of Human Carci of Ethambutol Derivatives”, Indian J. Pharm. Sci. 47(6): noma Cells Supplemented with N-3 and N-6 Polyunsatu 179–180 (1984). L.M. Gunne et al., “Oral Dyskinesia in Rats Following Brain rated Fatty Acids”, J Natl Cancer Inst, (1986), Lesions and Neuroleptic Drug Administration”, Psychop 77(5):1053-1062. (Abstract). harmacology 77:134–9 1982. Falconer, J.S., et al., “Effect of Eicosapentaenoic Acid and R.J. Baldessarini et al., “Dopamine and the Pathophysiology Other Fatty Acids on the Growth in Vitro of Human Pan of Dyskinesis. ", Ann. Rev. Neurosci. 3: 23-41 (1980). creatic Cancer Cell Lines”, Br J Cancer, (1994.) J.P. Lohr et al., “Neuroleptic-Induced Movement Disorders 69(5):826-832. (Abstract). ... ", Psychiatry, vol. 3, (1989). Plumb, J.A., et al., “Effect of Polyunsaturated Fatty Acids on Jacobson, K. et al., Adenosine analogs with covalently the Drug Sensitivity of Human Tumour Cell Lines Resistant attached lipids have enhanced potency at A1-adenosine to Either Cisplatin or Doxorubicin', Br J Cancer, (1993), receptors, FEBS Letters 225:97-102, Dec. 1987. 67(4):728-733. (Abstract). Anel, B., et al. “Cytotoxicity of Chlorambucil and Chloram de Smidt, P.C., et al., “Characteristics of ASSociation of bucil-Fatty Acid Conjugates Against Normal Human Oleoyl Derivatives of 5-Fluorodeoxy-Uridine and Methotr Peripheral Blood Lymphocytes”, Biochem Pharmacol, exate with Low-Density Lipoproteins (LDL)”, Pharm Res, (1990),40(6): 1193–1200. (Abstract). (1992), 9(4):565-569.
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