US008314077B2

(12) United States Patent (10) Patent No.: US 8,314,077 B2 Webb et al. (45) Date of Patent: *Nov. 20, 2012

(54) FATTY ACID-PHARMACEUTICAL AGENT (56) References Cited CONUGATES U.S. PATENT DOCUMENTS (75) Inventors: Nigel L. Webb, Bryn Mawr, PA (US); 3,539,573 A 11/1970 Schmutz Matthews O. Bradley, Laytonsville, 4,088.646 A * 5/1978 Ishida et al...... 544,313 4,097,597 A 6, 1978 Horrom et al. MD (US); Charles S. Swindell, Merion, 4,185,095 A 1/1980 Young PA (US); Victor E. Shashoua, 4,287.184 A 9/1981 Young Brookline, MA (US) 4,346,085 A 8, 1982 Growdon et al. 4,351,831 A 9, 1982 Growden et al. 4,407,744 A 10/1983 Young (73) Assignee: Luitpold Pharmaceuticals, Inc., 4.550,109 A 10, 1985 Folkers et al. Shirley, NY (US) 4,554,272 A 11/1985 Bocket al. 4,558,049 A 12/1985 Bernardi et al. 4,636,494. A 1/1987 Growdon et al. (*) Notice: Subject to any disclaimer, the term of this 4,684,646 A 8/1987 Chang et al. patent is extended or adjusted under 35 4,692,441 A 9, 1987 Alexander et al. U.S.C. 154(b) by 0 days. 4,704,393 A 1 1/1987 Wakabayashi et al. 4,729,989 A 3, 1988 Alexander This patent is Subject to a terminal dis 4,788,063 A 11/1988 Fisher et al. claimer. (Continued) (21) Appl. No.: 10/455.250 FOREIGN PATENT DOCUMENTS DE 2602175 7, 1976 (22) Filed: Jun. 5, 2003 (Continued) (65) Prior Publication Data OTHER PUBLICATIONS US 2004/0106589 A1 Jun. 3, 2004 Hardman, J. G., Editor-in-Chief of Goodman & Gilman's The Phar macological Basis of Therapeutics, Ninth Edition, pp. 1225-1233 and Related U.S. Application Data 1243-1252, 1996.* (Continued) (63) Continuation of application No. 09/730,450, filed on Dec. 5, 2000, now Pat. No. 6,576,636, which is a Primary Examiner — Phyllis G. Spivack continuation of application No. 08/651,428, filed on (74) Attorney, Agent, or Firm — Wolf, Greenfield & Sacks, May 22, 1996, now abandoned. P.C. (57) ABSTRACT (51) Int. C. The invention provides conjugates offatty acids and pharma A6 IK3I/7068 (2006.01) ceutical agents useful in treating noncentral nervous system (52) U.S. Cl...... S14/49 conditions. Methods for selectively targeting pharmaceutical (58) Field of Classification Search ...... None agents to desired tissues are provided. See application file for complete search history. 6 Claims, 14 Drawing Sheets

5 O

-5 OO

- OO -9 -8 -7 -6 -5 -4 LOG-10 OF SAMPLE CONCENTRATION (MOLAR) CCRF-CEM-O- SR. ----- RPM-8226--e- - - K-562- - -a - - HL-60 (TB)-(- - MOLT-4 D . . . . US 8,314,077 B2 Page 2

U.S. PATENT DOCUMENTS 6,043,230 A 3/2000 Arimilli et al. 4.814,470 A 3, 1989 Colin et all 6,069,249 A 5/2000 Arimilli et al. 4,857,653 A 8/1989 Colin et al. 88s. A 358 SAeneal 4,868,161 A 9/1989 Roberts 6.107,499 A 82000 Shashoua 4.902,505 A 2/1990 Pardridge et al. 6.136,796 A 10/2000 Kozak 4,933,324. A 6/1990 Shashoua 6,153,653 A 2000 Shashoua 4,939,174. A 7/1990 Shashoua 6.166,089 A 32000 Kozak 4,943,579 A 7, 1990 Vishnuvajala et al. 6.97,764 B1 3/2001 Bradley 4,968,672 A 11, 1990 Jacobson et al. 6,225.444 B1 5, 2001 Shashoua 5,059,699 A 10/1991 Kingston et al. 6,225.460 Bi 52001 Bischofberger etal 5,068.224. A 1 1/1991 Frvklund et al. 4- 4 - Derger et al. 5.2556 A 5, 1992 ME Camine 6,245,811 B1 6/2001 Horrobin et al. 5,112,863 A 5/1992 Hashimoto et al. 3. R $398: S. 5,116,624. A 5/1992 Horrobin et al. 6.28376 B 82001 Whittaker et al. 5, 120,760 A 6/1992 Horrobin 6.291,690 B1 9/2001 Mayhew et al. 5,141,958 A 8, 1992 Crozier-Willi et al. 6,384,019- w B1 5, 2002 Mvhynren ettal al. 5,169,762. A 12/1992 Grey et al. 6,407,075 B1 6/2002 Scott et al. 5,169,764 A 12/1992 Shooter et al. 6407135 B1 6/2002 Lai etal 5,194,654. A 3/1993 Hostetler et al. 6,448,392 B1 9/2002 Hostetler et al 5,214,062 A 5, 1993 Market al. I w 5,216.023. A 6/1993 Literatietal 6,576,636 B2 * 6/2003 Webb et al...... 514,263.38 4 kW - c. 6,602,902 B2 * 8/2003 Shashoua et al. ... 514,449 5,216,142 A 6, 1993 Horribinet al. T.235.583 B1 6, 2007 Webb etal 5,223,2635,246,726 A 9,6/1993 1993 HostetlerHorrobin et al. 7.816,398wkw B2: 10/2010 SwindeletalWindell et al...... 514,449 5,250,722 A 10/1993 Bombardelli et al. 2001/0006962 Al 72001 Myhren et al. 5,276,020 A 1/1994 Horribin et al. 2003/0065023 Al 42003 Swindellet al. 5,284.876 A 2, 1994 Shashoua 2012/0148595 A1 6, 2012 Swindell et al. 5,308,832 A 5/1994 Garleb et al. 5,314,991 A 5, 1994 Oka et al. FOREIGN PATENT DOCUMENTS 5,336,684. A 8/1994 Murray et al. DE 4224.737 2, 1994 5,352.596 A 10/1994 Cheung et al. EP 0 030 009 A1 6, 1981 5,356,928 A 10/1994 Murray et al. EP 0 091 694 A1 10, 1983 5.362,831 A 1 1/1994 Mongelli et al. EP O 311 100 A2 4, 1989 5,411,947 A 5/1995 Hostetler et al. EP O 350 287 10, 1990 5,420,276 A 5/1995 Norbeck EP O 599 576 A1 1/1994 5,447.936 A 9/1995 Hausheer et al. EP O 615 752 A2 9, 1994 5,453.520 A 9/1995 Bombardelli et al. EP O 693 498 A1 1, 1996 5,453.521. A 9/1995 Gaullier et al. FR 2698 269 A 8, 1997 5,459.256 A 10/1995 Marquez et al. JP T5-9469 1, 1975 5,466,841. A 1 1/1995 Horrobin et al. JP T5-427/1983 4f1983 5,468,754. A 1 1/1995 Hausheer et al. JP 59025327 A 2, 1984 5,473,055 A 12/1995 Mongelli et al. JP 59-2041.75 11, 1984 5,476,954. A 12/1995 Bourzat et al. JP 61204136 11, 1984 5,484.809 A 1/1996 Hostetler et al. JP 1153629. A 6, 1989 5,484.876 A 1/1996 Kawakami JP 1203331 A 8, 1989 5,494,999 A 2, 1996 Hale et al. JP 1287022. A 11, 1989 5,496,714. A 3/1996 Comb et al. JP 6O16548 A 1, 1994 5,504,102 A 4/1996 Agharkar et al. JP 6O72868 3, 1994 5,516,800 A 5/1996 Horrobin JP TO82146 3, 1995 5,532,372 A 7/1996 Saji et al. JP 8027010 A 1/1996 5,532,374. A 7/1996 Lee et al. JP 8151334 6, 1996 5.534499 A 7/1996 Ansell JP 8163991. A 6, 1996 5,545,719 A 8/1996 Shashoua JP 8245378 A 9, 1996 5,580,556 A 12/1996 Horrobin JP 9025231. A 1/1997 5,580,899 A 12/1996 Mayhew et al. JP 9030963 2, 1997 5,597.719 A 1/1997 Freed et al. WO WO 85,00520 2, 1985 5,603,959 A 2/1997 Horrobin et al. WO WO 89.02733 4f1989 5,604,198. A 2, 1997 Poduslo et al. WO WO 89,07938 9, 1989 5,604,216 A 2, 1997 Horrobin WO WO 90/OO555 1, 1990 5,646,180 A 7/1997 Chaturvedi WO WO92, 16554 10, 1992 5,654.290 A 8/1997 Bayon et al. WO WO92/2O362 11, 1992 5,716,614 A 2, 1998 Katz et al. WO WO93/OO910 1, 1993 5,750,572 A 5/1998 Bruzzese WO WO93, 11668 6, 1993 5,795,909 A 8/1998 Shashoua et al. WO WO94,07880 4f1994 5,814,456 A 9, 1998 O’Rand et al. WO WO94/11547 5, 1994 5,824,701 A 10/1998 Greenwald et al. WO WO 94.12530 6, 1994 5,827,819 A 10/1998 Yatvin et al. WO WO94f13654 6, 1994 5,919,815. A 7/1999 Bradley et al. WO WO94/20089 A1 9, 1994 5,922,695 A 7/1999 Arimilliet al. WO WO94,22887 10, 1994 5,925,669 A 7/1999 Katz et al. WO WO94,24107 10, 1994 5,955.459 A 9/1999 Bradley et al. WO WO95/O1969 1, 1995 5,977,061 A 1 1/1999 Holy et al. WO WO95/13270 5, 1995 5,977,089 A 1 1/1999 Arimilliet al. WO WO95/13271 5, 1995 5,977,174. A 1 1/1999 Bradley et al. WO WO95/33736 12/1995 5,985,854. A 1 1/1999 Kozak WO WO 96.01259 1, 1996 5,994,392 A 1 1/1999 Shashoua WO WO96,04001 2, 1996 6,005,004 A 12/1999 Katz et al. WO WO96, 12696 5, 1996 6,024,977 A 2/2000 Yatvin et al. WO WO96,22303 T 1996 US 8,314,077 B2 Page 3

WO WO96,27380 9, 1996 7-Phosphonooxymethyl Ether, a Potential Prodrug of Paclitaxel.” J. WO WO96,34855 11, 1996 of Labelled Compounds and Radiopharmaceuticals, vol. XXXIX. WO WO96,34858 11, 1996 No. 2. WO WO 97.33173 A 9, 1997 WO WO97/.44026 11, 1997 D’Orlando, et al., “Citicoline (CDP-Choline): Mechanisms of Action WO WO97/.44063 11, 1997 and Effects in Ischemic Brain Injury.” Neurol. Res. 17, 1995, pp. WO WO 97/44336 11, 1997 281-284. WO WO98,096.21 4f1998 Ehringer, W., et al., “A Comparison of the Effects of Linolenic (18:3 WO WO98, 17325 4f1998 Omega 3) and Docosahexaenoic (22:6 Omega 3) Acids on WO WO 98.21223 5, 1998 Phospholipid Bilayers.” Chem Phys Lipids, 54, 1990, pp. 79-88. WO WO 98.32718 7, 1998 WO WO99.02733 A1 1, 1999 Falconer, J.S., et al., “Effect of Eicosapentaenoic Acid and Other WO WO99,2662O 6, 1999 Fatty Acids on the Growth InVitro of Human Pancreatic Cancer Cell WO WO99/44600 9, 1999 Lines.” Br: J. Cancer, 69, 1994, pp. 826-832. WO WO 99.52887 10, 1999 Ferrari et al., “9-Cis-6,6'-Diapo-Gamma, Gamma-Carotenedioic WO WOOO/O1417 1, 2000 Acid Derivatives and Pharmaceutical Compositions Containing WO WOOO,53231 9, 2000 Them.” p. 710. Abs. 20423w, Chem. Abs. 95(23), Dec. 7, WO WOOOf 678O2 11, 2000 1981, EP30,009 Jun. 10, 1981. WO WOO1,62085 A1 8, 2001 WO WO O2/087586 A1 11, 2002 Funauchi, M. et al., “Effects of liposteroid on the hemophagocytic ZA 96.03433 A 10, 1996 syndrome in Systemic lupus erythematosus.” Lupus, 12, 2003, pp. 483-485. OTHER PUBLICATIONS Garzon-Aburbeh, et al., “A Lymphotropic Product of L-Dopa: Synthesis,” J. Med. Chem. 29, 1986, pp. 687-691. Zelvyte et al., Anticancer Research (May-Jun. 2003), 23(3B), pp. Georget al., “The Medicinal Chemistry of Taxol.” in “Taxol Science 2267-2273 (Abstract).* and Applications' ed. Matthew Suffness. Boca Raton: CRC Press, Aihara, M. et al., “Effects of liposteroid on skin lesions in autoim Inc., 1995, pp. 317-375. mune MRLlprlpr mice.” Journal of Dermatological Science, 16, Greenwald et al., “Highly Water Soluble Taxol Derivatives: 7-Poly 1997, pp. 45-51. ethylene Glycol Carbamates and Carbonates.” J. Org. Chem. 60, Anel, A., et al., “Increased Cytotoxicity of Polyunsaturated Fatty 1995, pp. 331-336. Acidson Human Tumoral Band T-Cell Lines Compared with Normal Lymphocytes.” Leukemia, 6(7), 1992, pp. 680-688. Guffy, M.M., et al., “Effect of Cellular Fatty Acid Alteration on Anel, B., et al. "Cytotoxicity of Chlorambucil and Chlorambucil Adriamycin Sensitivity in Cultured L1210 Murine Leukemia Cells.” Fatty Acid Conjugates Against Human Lymphomas and Normal Cancer Res, 44, 1984, pp. 1863-1866. Human Peripheral Blood Lymphocytes.” Biochem Pharmacol, 40(6), Gunne, et al., “Oral Dyskinesia in Rats Following Brain Lesions and 1990, pp. 1193-1200. Neuroleptic Drug Administration.” Psychopharmacology 77, 1982, Ansari et al., “Fatty acid conjugates of xenobiotics. Toxicol. Lett. pp. 134-139. 75, 1995, pp. 1-17. Halmos et al., “Fatty acid conjugates of 2'-deoxy-5-fluorouridine as Baldessarini, et al., “Dopamine and Pathophysiology of prodrugs for the selective delivery of 5-fluorouracil to tumor cells.” Dyskinesis . . . .” Ann. Rev. Neurosci., 3, 1980, pp. 23-41. Biochem. Pharmacol. 44(1), 1992, pp. 149-155. Begin, M.E., et al., “Differential Killing of Human Carcinoma Cells Hazard Database, "Chemical Tertogens, Carcinogens, Mutagens: Supplemented with N-3 and N-6 Polyunsaturated Fatty Acids,” JNatl Dexamethasone palmitate.” http://www.evol.nw.ru/labs/lab38/ Cancer Inst, 77(5), 1986, pp. 1053-1062. (Abstract). spirov/hazard? dexamethasone palmitate.html, printed from website Bourat, et al., “Long Chain Esters of Pipotiazine as Long-Acting on Aug. 31, 2004. Psychotropic Pro-Drug.” Med. Chem. Proc. Int. Symp. 5", 1976, pp. Hesse et al., “Inhibitory Effect of Cholesteryl-Y-Aminobutyrate.” 105-114. Neurolpharmacology, vol. 24. No. 2, 1985, pp. 139-146. Burns, C.P., et al., “Effect of Docosahexaenoic Acid on Rate of Hesse, et al., "Uptake in brain neurophysiological activity of two Differentiation of H1-60 Human Leukemia, Cancer Res., 49, 1989, lipid esters of gamma-aminobutyric acid.” Neuropharmacol. 27:6. pp. 3252-3258. 1988, pp. 637-640. Carboni et al., “Synthesis of a Photoaffinity Analog of Taxol as an Higuchi et al., (Editors), “Prodrugs as Novel Drug Delivery Sys Approach to Identify the Taxol Binding Site on Microtubules,” Jour tems.” ACS Symposium Series, vol. 14, ACS, Washington, 1975, pp. nal of Medicinal Chem. (Sep. 8, 1992). 14-15. Chajes, V., et al., “Influence of N-3 Fatty Acids on the Growth of Hong et al., “Nucleoside-ether lipid conjugates as biotransformed Human Breast Cancer Cells in Vitro: Relationship to Peroxides and prodrugs of antitumor and antiviral nucleosides.” J. Lipid Mediators Vitamin-E.” Breast Cancer Res Treat, 34, 1995, pp. 199-212. Cell Signalling, 10, 1994, pp. 159-161. Chen et al., “Taxol Structure-Activity Relationships: Synthesis and Hoshi, K. et al., “Double-Blind Study with Liposteroid in Rheuma Biological Evaluation of Taxol Analogs Modified at C-7. Bioorganic toid Arthritis.” Drugs Exptl. Clin. Res., XI(9), 1985, pp. 621-626. & Medicinal Chemistry Letters, vol. 4. No. 18, 1994, pp. 2223-2228. Iwakami, et al., “Inhibition of Arochidonate 5-Lipoxygenase by Phe de Antueno, R.J., et al., “In Vitro Effect of Eicosapentaenoic and nolic Compounds.” Chem. Pharm. Bull. (Japan), 34(9), 1986, pp. Docosahexaenoic Acids on Prostaglandin E2 Synthesis in a Human 3960-3963. Lung Carcinoma.” Biochem Int, 19(3), 1989, pp. 489-496. (Abstract). Jacob, et al., “Y-Aminobutyric Acid Esters. 1. Synthesis. . . .” Journal de Groot et al., “Synthesis and Biological Evaluation of 2'-Carbam of Medicinal Chemistry, vol. 28, No. 1, 1985, pp. 106-110. ate-Linked and 2'-Carbonate-Linked Prodrugs of Paclitaxel: Selec Jacob, et al., “Y-Aminobutyric Acid Esters.3. Synthesis, brain uptake tive Activation by the Tumor-Associated Protease Plasmin.” J. Med. and pharmacological properties of C-18 Glyceryl lipid esters of Chem., vol.43, 2000, pp. 3093-3102. BAGA with varying degree ofunsaturation.”.J. Med Chem. 30, 1987. de Smidt, P.C., et al., “Characteristics of Association of Oleoyl pp. 1573-1576. Derivatives of 5-Fluorodeoxy-Uridine and Methotrexate with Low Jacob, et al., “Synthesis, brain uptake and pharmacological proper Density Lipoproteins (Ldl).” Pharm Res, 9(4), 1992, pp. 565-569. ties of a glyceryl lipid containing GABA and the GABA-T inhibitor, Deutsch, H.F., et al., “Cytotoxic Effects of Daunomycin-Fatty Acid gamma-vinyl-GABA. J. Med. Chem. 33, 1990, pp. 733-736. Complexes on Rat Hepatoma Cells.” Cancer Res, 43, 1983, pp. Jacobson, K., et al., “Adenosine analogs with covalently attached 2668-2672. lipids have enhanced potency at A 1-adenosine receptors.” FEBS Dhopeshwarker, G., “Fatty Acid Transport through the Blood-Brain Letters 225:1.2, 1987, pp. 97-102. Barrier.” Biochim Biophy's. Acta, 255, pp. 572-579. Jenski, L.J., et al., “Docosahexaenoic Acid-Induced Alteration of Dischino et al., “Synthesis of the Monosodium Salt of Carbon-14 Thy-1 and Cd8 Expression on Murine Splenocytes.” Biochim Labeled Paclitaxel (TaxolR) 2'-Ethyl Carbonate Biophy's Acta, 1236(1), 1995, pp. 39-50. US 8,314,077 B2 Page 4

Jenski, L.J., et al., “Omega 3 Fatty Acids Increase Spontaneous Yamatsu et al., “Polyprenyl Carboxylic Acid Amides.” Chemical Release of Cytosolic Components from Tumor Cells.” Lipids, 26(5), Abstracts, vol. 100, No. 19 issued May 7, 1984, p. 555, Abstract No. 1991, pp. 353-358. 156839Z, EP91, 694, dated Oct. 19, 1983. Jenski, L.J., et al., “Omega-3 Fatty Acid-Containing Liposomes in Yokoyama, K. et al., “Development of a Corticosteroid Incorporated Cancer Therapy.” ProcSoc Exp Biol Med. 210(3), 1995, pp. 227-233. in Lipid Microspheres (Liposteroid).” Drugs Exptl. Clin. Res., XI(9), Karmali, R.A., et al., “Effect of Omega-3 Fatty Acids on Growth of a 1985, pp. 611-620. Rat Mammary Tumor,” JNatl Cancer Inst, 73(2), 1984, pp. 457-461. Zerouga, M., et al., “Phospholipid Class as a Determinant in (Abstract). Docosahexaenoic Acid's Effect on Tumor CellViability.” Anticancer Karmali, R., “N-3 Fatty Acids: Biochemical Actions in Cancer.” J. Res, 16, 1996, pp. 2863-2868. (Abstract). Nutr Sci. Vitaminol. (Tokyo), 1992, pp. 148-152. (Abstract). Zijlstra, J.G., et al., “Influence of Docosahexaenoic Acid in Vitro on Kinsella, J.E. et al., “Effects of Polyunsaturated Fatty Acids on the Intracellular Adriamycin Concentration in Lymphocytes and Human Efficacy of Antineoplastic Agents Toward L5178y Lymphoma Adriamycin-Sensitive and Resistant Small-Cell Lung Cancer Cell Cells.” Biochem Pharmacol, 45(9), 1993, pp. 1881-1887. (Abstract). Lines, and on Cytotoxicity in the Tumor Cell Lines.” IntJ Cancer, 40, Lohr, et al., “Neuroleptic-Induced Movement Disorders . . . .” Psy 1987, pp. 850-856. chiatry, vol. 3, 1989, pp. 1-16. “Cytosar-U cytarabine for injection, USP” Product insert, Feb. 2002. Madhavi, N., et al., “Effect of N-6 and N-3 Fatty Acids on the Bolwell et al., Leukemia 5:253-60 (May 1988) Abstract. Survival of Vincristine Sensitive and Resistant Human Cervical Car Braam et al., “Rain-, Wind-, and Touch-Induced Expression of cinoma Cells in Vitro'. Cancer Lett, 84, 1994, pp. 31-41. Calmodulin and Calmodulin-Related Genes in Arabidopsis', Cell, Makino, et al., “Pharmaceuticals Permeable to Blood-Brain Barrier.” 60 357-364 (1990). Chemical Abstracts, vol. 106, No. 12, (90.177x) issued Mar. 23, 1987. Bridges. et al., “N'-(2,2-Diphenylethyl)adenosine, a Novel Marder, S.R., “Management of Schizophrenia.” J. Clin. Psychiatry Adenosine Receptor Agonist with Antipsychotic-like Activity'. J. (supp3), 57, 1996, pp. 9-13. Med. Chem. 30: 1709-1711 (1987). Mazumdar, et al., “Preparation and Evaluation of EthambutolDeriva Devita Jr. et al., Cancer Principles & Practice of Oncology, 5' Ed. pp. tives.” Indian J. Pharm. Sci. 47(6), 1985, pp. 179-180. 443-444. Minami, M., et al., “Effects of Low-Dose Eicosapentaenoic Acid, Ertel et al., “Type III (D-Agatoxins: A Family of Probes for Similar Docosahexaenoic Acid and Dietary Fat on the Incidence, Growth and Binding Sites on L- and N-Type Calcium Channels'. Biochemistry, Cell Kinetics of Mammary Carcinomas in Rats.” Oncology, 53(5), 33:5098-5108 (1994). 1996, pp. 398-405. Guénard et al., “Effects of the Hydrophobicity of Taxoids on their Mizushima, Y. et al., “Tissue distribution and anti-inflammatory Interaction with Tubulin'. Bioorganic & Medicinal Chemistry vol. 8, activity of corticosteroids incorporated in lipid emulsion.” (2000) pp. 145-156. Nishio, et al., “Novel Water-Soluble Derivatives of Docosahexaenoic Haas et al., Onkology:53-57 (Feb. 1980). Acid Increase Diacyl-Glycerol Production Mediated by Ho et al., “Pharmacology of 5'-Esters of 1-3-D- Phosphatidylcholine-Specific Phospholipase C.” Proc. Soc. Exp. Arabinofuranosylcytosine.” Cancer Research 37 (Jun. 1977), pp. Biol. Med. 203(2), 1993, pp. 200-208. 1640-1643. Oshima, M., et al., “Effects of Docosahexaenoic Acid (Dha) on Ho et al., “Pharmacologic Studies of Cyclocytidine and Intestinal Polyp Development in Apc Delta 716 Knockout Mice.” Arabinosylcytosine in Dogs.” Drug Metabolism and Disposition 3(4) Carcinogenesis, 16(11), 1995, pp. 2605-2607. (1975), pp. 309-313. Pascale, A.W., et al., “Omega-3 fatty acid modification of membrane Kataoka et al., “Effect and Mode of Action of N'-Behenoyl-f-D- structure and function. Alteration by docosahexaenoic acid of tumor Arabinofuranosylcytosine.” Recent Results in Cancer Research 70 cell sensitivity to immune cytolysis.” Nutr Cancer, 19(2), 1993, pp. (1980), pp. 147-151. 147-157. Kretsinger et al., “The EF-Hand, Homologs and Analogs”, Novel Plumb, J.A., et al., “Effect of Polyunsaturated Fatty Acids on the Calcium-Binding Proteins, 17-37 (1991). Drug Sensitivity of Human Tumour Cell Lines Resistant to Either Konigstorfer et al., “Biosynthesis of Ependymins from Goldfish Cisplatin or Doxorubicin.” Br.J Cancer, 67, 1993, pp. 728-733. Brain”, J. Biol. Chem., vol. 264 (23): 13689-13692 (1989). Pouillart, “Role ofbutyric acid and its derivatives in the treatment of Konigstorfer et al., “Molecular Characterization of an Ependymin colorectal cancer and hemoglobinopathies.” Life Sci., 63(20), 1998, Precursor from Goldfish Brain”. J. Neurochem, 52:310-312 (1989). pp. 1739-1760. Leonard et al., “Identification and Characterization of mRNAs Regu Rose, W.C., “Preclinical Antitumor Activity of Taxanes', in “Taxol lated by Nerve Growth Factor in PC12 Cells'. Molecular and Cellu Science and Applications' ed. Matthew Suffness, Boca Raton: CRC lar Biology, 7(9):3156-67 (1987). Press, Inc., 1995, pp. 317-375. Marsden et al., “H NMR Studies of Synthetic Peptide Analogues of Schabitz, et al., “The effects of Prolonged Treatment with Citicoline Calcium-Bining Site III of Rabbit Skeletal Troponin C: Effect of the in Temporary Experimental Focal Ischemia.” J. Neurol. Sci., 138(1- Lanthanum Affinity of the Interchange of Aspartic Acid and 2), 1996, pp. 21-25. (Abstract). Asparagine Residues at the Metal Ion Coordinating Positions'. Bio Seki, J. et al., “A nanometer lipid emulsion, lipid nano-sphere chemistry, 27:4198-4206 (1988). (LNSR), as a parenteral drug carrier for passive drug targeting.” Meier et al., “Molecular cloning of bovine and chick nerve growth International Journal of Pharmaceutics, 273, 2004, pp. 75-83. (NGF) . . . . The EMBO.J. vol. 5, 7: 1489-1493 (1986). Shashoua, et al., “Y-Aminobutyric Acid Esters. 1. Synthesis....”.J. of Nicolaou et al., “Design synthesis and biological activity of Med. Chem., vol. 27, 1984, pp. 659-664. protaxols', Nature 364:464-466 (Jul 1993). Specter, R., “Fatty Acid Transport Through the Blood-Brain Bar Rentsch, et al., “Pharmacokinetics of N'-Octadecyl-1-?3-D- rier”. J. of Neurochem, 50:2, 1988, pp. 639-643. Arabinofuranosylcytosine in Plasma and Whole Blood after Intrave Swindell, et al., “Characterization of the Taxol Structure-Activity nous and Oral Administration to Mice,” J. Pharm. Pharmacol. 49 Profile for the Locus of the A-Ring Side Chain'. Bioorganic & (1997), pp. 1076-1081. Medicinal Chem. Litrs, vol. 4, No. 12, 1994, pp. 1531-1536. Rocco et al., “Models of Fibronectin'. The EMBO Journal, 6: 2343 Tessier, C., et al., “Docosahexaenoic Acid Is a Potent Inhibitor of Rat 2349 (1987). Uterine Stromal Cell Proliferation.” Biochem Biophy's Res Commun, Scott et al., “Isolation and nucleotide sequence of cDNA 207(3), 1995, pp. 1015-1021. encoding ... ', Nature 302,538-540 (1983). Tinsley, I.J., et al., “Influence of Dietary Fatty Acids on the Incidence Shashoua, “Ependymin, a Brain Extracellular Glycoprotein, and of Mammary Tumors in the C3h Mouse.” Cancer Res, 41, 1981, pp. CNS Plasticity,” reprinted from Activity-Driven CNS Changes in 1460-1465. Learning and Development, vol. 627 of the Annals of the New York Ueda et al., “Synthesis and Antitumor Evaluation of Academy of Sciences, Aug. 5, 1991). 2'-Oxycarbonylpaclitaxels (Paclitaxel-2'-Carbonates).” Bioorganic Shashoua, “The Role of Brain Extracellular Proteins . . . . Cellular & Medicinal Chemistry Letters, vol. 4. No. 15, 1994, pp. 1861-1864. and Mol. Neurobiol. 5 (1/2): 183-207 (1985). US 8,314,077 B2 Page 5

Shashoua et al., “Evidence for the In Vivo Polymerization of PCT/US98/24421—Neuromedica, Inc.—Search Report Mar, 9. Ependymin: Brain Extracellular Glycoprotein', Brain Research, 1999. 522, 181-190 (1990). PCT/US98/24490 Neuromedica, Inc.–Search Report Feb. 26, Shashoua, “The role of ependymin in the development of long lasting 1999. PCT/US99/01786 Neuromedica, Inc.–Search Report Jul. 6, synaptic charges”.J. Physiol. Paris, 83:232-239 (1988-1989). 1999. Shea et al., “Effect of Retinoic Acid on Growth and Morphological PCT/US00/06160 Protarga, Inc. Search Report–Apr. 5, 2001. Differentiation of Mouse NB2a Neuroblastoma Cells in Culture', PCT/US00/12752 Protarga, Inc. Search Report–Oct. 31, 2000. Developmental Brain Research, 21:307-314 (1985). Nilsson et al., “First-in-human study of a novel nucleoside analogue, Suphioglu et al., “Molecular Cloning and Immunological Character CP-4126, in patients with advanced solid tumors”, Journal of Clini ization of Cynd 7. A Novel Calcium-Binding Allergin from Bermuda cal Oncology, ASCO annual meeting proceedings (post-meeting edi Grass Pollen, FEBS Letters, 402:167-172 (1997). tion) vol. 27:15S 2577 (2009). Terasawa, et al., “Neurocalcin' a novel calcium binding protein from Bergman, A. M. et al., Antiproliferative activity and mechanism of bovine brain J. Biol. Chem. 267:27 (1992), pp. 19596-19599. action offatty acid derivatives of gemcitabine in leukemia and solid Yamamoto et al., “The Survival of Rat Cerebral Cortical Neurons in tumor cell lines and in human xenografis (Nucleosides, Nucleotides the Presence of Trophic APP Peptides' J. Neurobiol. 25, 585-594 & Nucleic Acids) vol. 23, Nos. 8 & 9, (2004): 1329-1333. (1994). Hendlisz, A. et al., Phase I study of oral CP-4 126, a gemcitabine Yokokawa et al., “The Synthesis of Rat Cerebral Cortical Neurons in analog, in patients with advanced solid tumors (J Clin Oncol 28, the Presence of EF-Hand Type Calcium-Binding Peptides' Chem. 2010 (suppl; abstre 13078). Lett, 1627-1630 (1989). Immordino. M. L. et al., Preparation, characterization, cytotoxicity Yoshida, et al., “N'-Behenoyl-1-?3-D- and pharmacokinetics of liposomes containing lipophilic Arabinofuranosylcytosine(BH-AC) Pharmacokinetics' Cancer and gemcitabineprodrugs (J of Controlled Release) 100 (2004): 331-346. Chemical Treatment (Cancer and Chemotherapy) 14(6) (1987), Part Nilsson, A. et al., First-in-human study of a novel nucleoside ana I, pp. 1820-1824 Japanese Language with English Summary. logue, CP-4 126, inpatients with advanced solid tumors (JClin Oncol Young et al., “Differentiation of PC12 cells in response to a cAMP 27, 2009 No. 15S (May 20 Supplement), 2009: 2577. analogue is accompanied by Sustained activation of mitogen-acti A Study of CP-4 126 in Patients With Advanced Pancreatic Cancer, vated protein kinase Comparison with the effects of insulin, growth Clavis Pharma ASA, Clinical Trials Identifier NCT00913 198 (Sep.3, factors and phorbol esters, FEBS Letters, 338:212-216 (1994). 2010). International Search Report for PCT/US02/09389, mailed: Feb. 10, No Author Listed). Drug metabolism. Burger's Medicinal Chemis 2004. try and Drug Delivery. 5' Edition. vol. I: Principles and Practice. Ed. International Search Report for PCT/US02/09471, mailed: Jan. 22, Wolff. John Wiley & Sons. 1995: pp. 171-174. 2004. No Author Listed). Fatty amines. Ullmann's Encyclopedia of Indus International Search Report for PCT/US00/06160, mailed: Apr. 5, trial Chemistry. Eds. Gerhartz et al. VCH Verlagsgesellschaft, 2001. Weinheim. 1985; 5' Edition: vol. A 2; p. 18. PCT/GB97/02362 Scotia Holdings, PLC Search Report Feb. Brockmann et al., Fatty acids. Ullmann's Encyclopedia of Industrial 1, 1999. Chemistry. Eds. Gerhartz et al. VCHVerlagsgesellschaft, Weinheim. PCT/GB99/00563 Scotia Holdings, PLC Search Report Aug. 1987; 5' Edition: vol. A 10; pp. 245-255. 19, 1999. Guillonneau et al., Synthesis of 9-O-substituted derivatives of PCT/US89/00757–Shashoua Search Report Jun. 14, 1989. 9-hydroxy-5, 6-dimethyl-6H-pyrido4.3-bcarbazole-1-carboxylic PCT/US91/03346–Shashoua Search Report Sep. 6, 1991. acid (2-(dimethylamino)ethyl)amide and their 10- and 11-methyl PCT/US97/08792 Neuromedica, Inc.—Search Report—Aug. 28. analogues with improved antitumor activity. J Med Chem. Jun. 17. 1998. 1999;42(12): 2191-203. PCT/US97/08866 Neuromedica, Inc. Search Report–Sep. 3, Riemenschneider, Carboxylic acids, aliphatic. Ullmann's Encyclo 1997. pedia of Industrial Chemistry. Eds. Gerhartz et al. VCH PCT/US97/08867 Neuromedica, Inc. Search Report Jan. 9, Verlagsgesellschaft, Weinheim. 1986; 5' Edition: vol. A 5; pp. 235 1997. 248. PCT/US98/24412 Neuromedica, Inc.—Search Report—Feb. 22. 1999. * cited by examiner U.S. Patent Nov. 20, 2012 Sheet 1 of 14 US 8,314,077 B2

- s O 1. CD l O LII CD CC - I O Ll O - 1 OO -9 -8 .7 -6 -5 -4 LOGO OF SAMPLE CONCENTRATION (MOLAR) CCRF-CEM-o- SR. --0--- RPM-8226- -o- - - K-562- - -a - - HL-60 (TB)-Q- - MOLT-4 D Fig. 1

1 OO NON-SMALL CELL UNG CANCER

5 O

-5 OO

- 1 OO 9 -8 -7 -6 -5 -4 LOGo OF SAMPLE CONCENTRATION (MOLAR) A549/ATCC-O- EKVX --O-- NC-H.322M--- a--- NC-H226--O-- NC-H23---0-- HOP-92...... NC-H522--O - - HOP-62---Fig. 2 a-- NCI-H460------U.S. Patent Nov. 20, 2012 Sheet 2 of 14 US 8,314,077 B2

1OO

5 O

-5 OO

- 1 OO -9 -8 -7 -6 -5 -4 LOGO OF SAMPLE CONCENTRATION (MOLAR) COLO 205-O- HCT-1 16-- (- - HCT-15- - -a-- KM12- - O -- SW-620---4--- HT29.....O. Fig. 3

1 OO CNS CANCER

5 O

-5 OO

-1 O O 9 -8 -7 -6 -5 -4 LOGO OF SAMPLE CONCENTRATION (MOLAR) SF-268-O- SF-295 --K)-- SF-539 - - - A - - - SNB-75 -- O - - U251 - " -0- - - SNB-19...... Fig. 4 U.S. Patent Nov. 20, 2012 Sheet 3 of 14 US 8,314,077 B2

1 OO

5 O

-5 OO

- 1 O O -9 -8 -7 -6 -5 -4 LOGO OF SAMPLE CONCENTRATION (MOLAR) LOX MV -o- UACC-257--4--- SK-MEL-2... . . 0- - - SK-MEL-5 - - O - M14 --- a-- MALME-3M--C)-- UACC-62- - - A - Fig. 5

1OO OVARAN CANCER

O

LOGo OF SAMPLE CONCENTRATION (MOLAR) IGROW 1 -O- OWCAR-3- - - - OVCAR-4- A- - OCVAR-8 - - O - SK-OV-3 - - -0.- OVCAR-5'-O- Fig. 6 U.S. Patent Nov. 20, 2012 Sheet 4 of 14 US 8,314,077 B2

1 OO

O

LOGo OF SAMPLE CONCENTRATION (MOLAR) 786-O-O- A498 - - C - - ACHN- - - A - - - CAK-1...... RXF 393-- o- - TK-10-- 0---. UO-31 - A-. Fig. 7

1 OO PROSTRATE CANCER

O

- 1 O o 9 8 7 6 - 5 4 LOGO OF SAMPLE CONCENTRATION (MOLAR) PC-3-O- Fig. 8 U.S. Patent Nov. 20, 2012 Sheet 5 of 14 US 8,314,077 B2

1 OO L H

3O1 so CD 1 O LIJ CD CC H 2. O Y L Cl - 1 OO -9 -8 -7 -6 -5 -4 LOGO OF SAMPLE CONCENTRATION (MOLAR) MCF7 -O- MDA-N---0-- HS 578 ...O.... MDA-MB-435--O-- MDA-MB-231/ -- A - - T-47D----...- MCF 7/ADR-RE--Q- Fig.BT-549-...-A-...- 9 1 OO LEUKEMA -N--

5 O

-5 OO

- 1 OO -9 -8 -7 -6 -5 -4 LOGo OF SAMPLE CONCENTRATION (MOLAR) CCRF-CEM-o- SR. --0--- RPM-8226- -o- - - K-562 - - -a -- HL-60 (TB) -g- -Fig. MOLT-4 10 o U.S. Patent Nov. 20, 2012 Sheet 6 of 14 US 8,314,077 B2

1 OO

5 O

-5 OO

- 1 O O -9 -8 -7 -6 -5 -4 LOGo OF SAMPLE CONCENTRATION (MOLAR) A549/ATCC-O- EKVX --O-- NC-H.322M- - - -A- - - NC-H226-- O - - NC-H23---0-- HOP-92-...... NC-H522- -o- - HOP-62----Fig. 11 NC-H460------

1 OO

5 O

O

LOGO OF SAMPLE CONCENTRATION (MOLAR) COLO 205-O- HCT-116- - (- - HCT-15---a-- KM12- - O --Fig. SW-620---0--- 12 HT29...... U.S. Patent Nov. 20, 2012 Sheet 7 of 14 US 8,314,077 B2

1 OO

5 O

-5 OO

- 1 OO -9 -8 -7 -6 -5 -4 LOGo OF SAMPLE CONCENTRATION (MOLAR) SF-268-O- SF-295 - -3- - SF-539 - - - A SNB-75 -- O -- U251 - '-0- " - SNB-19. . . . . O. . . . . Fig. 13

- 1 OO 9 -8 -7 -6 -5 -4 LOG-10 OF SAMPLE CONCENTRATION (MOLAR) LOX MV -o- UACC-257- -0- - SK-MEL-2.....O..... SK-MEL-5 - - O - - M14 - - -A-- MALME-3M--Q-- UACC-62 - - - A - Fig. 14 U.S. Patent Nov. 20, 2012 Sheet 8 of 14 US 8,314,077 B2

OWARIAN CANCER 1 OO

5 O

-5 OO

-1 O O 9 -8 -7 -6 -5 -4 LOGO OF SAMPLE CONCENTRATION (MOLAR) GROV1 -O- OVCAR-3--O-- OVCAR-4--A- - OCWAR-8 - - a-- SK-OV-3-...-0.- : OWCAR-5"O'" Fig. 15

RENAL CANCER

O

-9 -8 -7 -6 -5 -4 LOGo OF SAMPLE CONCENTRATION (MOLAR) 786-O-O-I - A498--K) - ACHN- - - A --- CAK-1: ... O. . . . . RXF393-- o- - TK-10--0-- UO-31 - A - Fig. 16 U.S. Patent Nov. 20, 2012 Sheet 9 of 14 US 8,314,077 B2

PROSTRATE CANCER 1 OO eR

O

- 1 OO -9 -8 -7 -6 -5 -4 LOGo OF SAMPLE CONCENTRATION (MOLAR) PC-3-o- Fig. 17

- S O 1. CD Ll O ld (D H 2 L O (Y l n - 1 OO -9 -8 -7 -6 -5 -4 LOGO OF SAMPLE CONCENTRATION (MOLAR) MCF 7 -O- MDA-N- -0 - - HS 578T...... MDA-MB-435- - - - MDA-MB-231/ -- A - - T-47D--...- MCF 7/ADR-RE--&- BT-549-...-a-...- Fig. 18 U.S. Patent Nov. 20, 2012 Sheet 10 of 14 US 8,314,077 B2

LEUKEMA

C - s O 1. CD L1 O CD

1 OO NON-SMALL CELL LUNG CANCER C

TC H S O 1. CD l O L

H9 2. l O Y n

1 O -9 -8 - -6 LOGo OF SAMPLE CONCENTRATION (MOLAR) A549/ATCC-O- NC-H322M-...-8.-. NCI-H226 ...... O...... NC-H23-- O - HOP-62 --- a--- NC-H522 - - - EKVX-- C -. NC-H460 --- A.-- Fig. 20 U.S. Patent Nov. 20, 2012 Sheet 11 of 14 US 8,314,077 B2

COLON CANCER

T - S. O CY CD 1 O CD - 2. O -50 C1 l - 1 OO - 10 -9 -8 -7 -6 LOGo OF SAMPLE CONCENTRATION (MOLAR) COLO 205-O- KM12-...---- HCT-15 ...... HT29--O-- HCT-1 16---- a--- HCC-2995- - (s-- SW-620-a-Fig. 21 CNS CANCER

1 OO T - - - - - A.

H s O 1. CD L O L CD CC - 2. O I Cl

1 O -9 -8 -7 -6 LOGo OF SAMPLE CONCENTRATION (MOLAR) SF-268-O- SF-295 - -g- - SF-539 - - - A - - - SNB-75 -- O -- U251 - '-0 - SNB-19...... Fig. 22 U.S. Patent Nov. 20, 2012 Sheet 12 of 14 US 8,314,077 B2

MELANOMA

-5 O

-1 O O -1 O -9 -8 -7 -6 LOGO OF SAMPLE CONCENTRATION (MOLAR) LOX IMVI -o- SK-MEL-5 -, --, - SK-MEL-2..... O. . . . . SK-MEL-28 - - O - - M14 --- a-- UACC-62 -...--...- MALME-3M--Q-- UACC-257-...-a - Fig. 23

OVARAN CANCER

o g - -7 - LOGO OF SAMPLE CONCENTRATION (MOLAR) GROW1 -O- OVCAR-3--O-- OVCAR-4--a- - OCWAR-8 - - O - SK-OV-3-...-0.- . OVCAR-5'-O- Fig. 24 U.S. Patent Nov. 20, 2012 Sheet 13 of 14 US 8,314,077 B2

RENAL CANCER

H s O CD 1 O L CD H I O (Y

- 1 OO - 1 O -9 -8 -7 -6 LOGO OF SAMPLE CONCENTRATION (MOLAR) 786-O-O- . A498--K) - ACHN- - - A - - - CAK-1: ...... RXF 393 - - O - - SN 12C -- 0- - - TK-1 O - - A -- UO31-...- ... Fig. 25 PROSTRATE CANCER

-5 OO

- 1 O O -1 O -9 -8 -7 -6 LOGo OF SAMPLE CONCENTRATION (MOLAR) PC-3-O- DU-145- -()-- Fig. 26 U.S. Patent Nov. 20, 2012 Sheet 14 of 14 US 8,314,077 B2

BREAST CANCER

C - s O 1. CD I O 1 CD < H 2. O Y ?h

- 1 O - - -7 -6 LOGo OF SAMPLE CONCENTRATION (MOLAR) MCF 7 -O- MDA-N-, -0 - - HS 578 ... O.... MDA-MB-435- - - - MDA-MB-231/ -- A - - T-47D-...- MCF 7/ADR-RE--Q-- BT-549-...-A-...- Fig. 27 US 8,314,077 B2 1. 2 FATTY ACID-PHARMACEUTICAL AGENT Taxol has the following formula: CONUGATES

AcO O CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 09/730,450, filed Dec. 5, 2000, which is a continuation of 10 application Ser. No. 08/651,428, filed May 22, 1996, now HO abandoned, both hereby incorporated by reference. PhCO

BACKGROUND OF THE INVENTION Taxanes have the basic three ring structure (A, B and C), 15 substituted or unsubstituted. Improving drug selectivity for target tissue is an estab Taxol’s carbons are numbered conventionally as follows: lished goal in the medical arts. In general, it is desirable to

deliver a drug selectively to its target, so that dosage and, consequently, side effects can be reduced. This is particularly the case for toxic agents such as anti-cancer agents because achieving therapeutic doses effective for treating the cancer is often limited by the toxic side effects of the anti-cancer agent on normal, healthy tissue. The problems relating to lack of drug selectivity can be exemplified by Taxol.R. 25 Taxol.R (paclitaxel) was first isolated in 1971 from the bark of Taxus brevifolia and was approved in 1992 by the US Food and Drug Administration for treatment of metastatic ovarian Based upon the taxanes tested to date, as many questions cancer and later for breast cancer. Its mechanism of action is have been raised as have been answered, and general rules 30 have not been fashioned easily in predicting selectivity, activ believed to involve promoting formation and hyperstabiliza ity and Solubility. Firstly, no rules have emerged regarding tion of microtubules, thereby preventing the disassembly of selectivity. Those taxanes that are strongly active appear to microtubules necessary for completion of cell division. It also have activity as broad as Taxol's activity, and no headway has been reported that Taxol induces expression of cytokines, appears to have been made in terms of developing a more affects the activity of kinases and blocks processes essential selective Taxol analog. for metastasis, in as yet uncharacterized mechanisms of Some information about activity has emerged. Numerous action. substitutions have been made at C7, C9, C10, C19, R1 and combinations thereof while retaining significant, but usually Taxol has attracted unusually strong scientific attention, reduced, activity. Substitutions at C2, C4 and 2'OH, however, not only because of its unique antiproliferative mechanism of are generally not tolerated. These conclusions are only gen action, but also because it is active against nearly all cancers 40 eralities, for example, because some substitutions at C9-C10 against which it has been tested and because it has been (cyclic derivatives) are not tolerated and Some Substitutions at C2 (meta substitutions on the phenyl) are tolerated. Likewise, discovered to be an analog of numerous closely related com the C13 side chain and, in particular, the 2'OH are required, pounds occurring naturally. These compounds, taxanes, are although the minimum structural requirements of the side now recognized as a new class of anticancer compounds. 45 chain have not been determined for therapeutic efficacy. Taxol's strength against cancers of diverse tissue origin Attempts to improve Taxol's solubility have not resulted in also represents a significant drawback. An ideal anticancer Successful clinical products. One approach has been to manu agent has tissue specificity, thereby reducing side-effects on facture prodrugs of Taxol, which prodrugs undergo in vivo normal (dividing) cells. Taxol analogs with tissue specificity transformation into Taxol and some other product. Attempts therefore are desired. Another drawback of Taxol is its 50 were made to esterify the C7 hydroxy and 2 hydroxy groups, with the hope that the bond would be stable in solution (to extreme insolubility. Taxol can be administered effectively in permit preferred administration modes—i.V. over at least 24 a solvent including cremophor, which combination can pro hours) but would cleave readily in vivo. The groups tested Voke severe hypersensitive immune responses. As a result of were all hydrophilic and included amines, short carboxylic these drawbacks, and also as a result of the potential for 55 acids (using e.g. Succinic anhydride and glutaric anhydride), modifying Taxol at numerous sites as demonstrated by other Sulfonic acids, amino acids and phosphates. Generally, activ naturally-occurring taxanes with anticancer activity, a search ity was reduced although some Success was obtained with for more selective taxanes was launched. certain derivatives. Again, no particular pattern emerged per To date, more than 200 taxanes have been synthesized (or mitting one to predict reliably which groups could be substi isolated) and tested in vitro or in vivo for anticancer activity. 60 tuted on Taxol to yield a therapeutically useful product, The results, however, have been so disappointing that the although it was suggested that the 2'OH derivatives may National Cancer Institute (NCI) generally no longer is inter cleave more easily than the C7 OH derivatives. ested in testing Taxol analogs. In general with Taxol analogs, Several other factors add to the problem of predicting the Solubility problems remain, and/or potency is sharply which Taxol analogs will be effective. Multiple mechanisms reduced, and/or selectivity is not improved, and/or the ratio of 65 of action have been proposed in the literature, and a change in the median toxic dose to the median effective dose (“thera one position may have no effect on activity on one such peutic index') is unacceptably reduced. mechanism but may eliminate activity on another mecha US 8,314,077 B2 3 4 nism. In addition, changes that favorably influence activity 30 carbon atoms. In one instance, enhanced receptor binding may unfavorably influence bioavailability. For example, activity was observed (foranadenosine receptoragonist), and Taxol affects microtubule formation inside a cell, but a it was postulated that the pendant lipid molecule interacted change in structure that increases intracellular activity may with the phospholipid membrane to act as a distill anchor for adversely affect the ability of Taxol to gain entry into a cell. 5 the receptor ligand in the membrane micro environment of the Taxol also is known to bind to proteins, and the effect on receptor. This increase in potency, however, was not observed activity that results from a change in Taxol's binding to pro when the same lipid derivatives of adenosine receptor antago tein (in terms of conformation, cellular absorption and Solu nists were used, and generalizations thus were not made bility) is unknown. possible by those studies. It has been reported that Taxol does not get into the brain, 10 apparently excluded by the bloodbrainbarrier. It is not known SUMMARY OF THE INVENTION why this is so, as Taxol is lipophilic, gets into cells and might be expected to cross the blood brain barrier. The present invention involves the unexpected finding that Among the most promising of the two hundred analogs conjugates of pharmaceutical agents and a highly lipophilic 15 group, a C8-C26, naturally ocurring, unbranched carbon tested is Taxotere (docetaxel), because of its slightly chain, have a different selectivity relative to the unconjugated increased activity and solubility. Oddly, however, Taxotere pharmaceutical agents. differs from Taxolat sites which typically do not have a strong In one embodiment, the conjugates render the activity of influence on activity, and one would not predict the improve these conjugates selective, in general, for colon tissue, breast ments in Taxotere from these differences, even in hindsight. tissue and central nervous system tissue (“targeted tissues’). Taxotere has the following formula: The conjugates, also unexpectedly, restrict the activity of these conjugates to cell types within these tissue categories relative to that of the unconjugated pharmaceutical agents. The conjugates, further unexpectedly, can reduce sharply the 25 activity of these conjugates relative to that of the unconju gated pharmaceutical agents in most cell lines of tissue types other than colon, breast, and central nervous system, thereby reducing potential side effects of the conjugates versus those of the unconjugated pharmaceutical agents. The therapeutic 30 index of the conjugates is improved, versus that of the uncon jugated pharmaceutical agents. According to one aspect of the invention, a method is Ph provided for targeting a therapeutic agent to a noncentral nervous system tissue to treat a noncentral nervous system Fatty acids previously have been conjugated with drugs to 35 condition. A conjugate of a C8-C22, unbranched, naturally help the drugs as conjugates cross the blood brain barrier. occurring fatty acid and a pharmaceutical agent is adminis DHA (docosahexaenoic acid) is a 22 carbon naturally-occur tered to a subject in need of such treatment. In certain embodi ring, unbranched fatty acid that previously has been shown to ments, the tissue is breast tissue, gastrointestinal tissue and be unusually effective, when conjugated to a drug, in crossing ovarian tissue and the condition calls for treatment of breast the blood brain barrier. DHA is attached via the acid group to 40 tissue, gastrointestinal tissue or ovarian tissue, respectively. hydrophilic drugs and renders these drugs more hydrophobic In other embodiments, the tissue can be tissue of the Blood (lipophilic). DHA is an important constituent of the brain and and Blood Forming system: including platelets, blood vessel recently has been approved as an additive to infantformula. It wall, and bone marrow; Cardiovascular system: including is present in the milk of lactating women. The mechanism of heart and vascular system; Digestive and excretory system: action by which DHA helps drugs conjugated to it cross the 45 including alimentary tract, biliary tract, kidney, liver, pan blood brain barrier is unknown. creas and urinary tract; Endocrine system: including adrenal Another example of the conjugation offatty acids to a drug gland, kidney, ovary, pituitary gland, renal gland, salivary is the attachment of pipotiazine to Stearic acid, palmitic acid, gland, sebaceous gland, testis, thymus gland and thyroid enanthic acid, undecylenic acid or 2.2-dimethyl-palmitic gland; Musclar system: including muscles that move the acid. Pipotiazine is a drug that acts within the central nervous 50 body. Reproductive System: including breast, ovary, penis system. The purpose of conjugating pipotiazine to the fatty and uterus; Respiratory system: including bronchus, lung and acids was to create an oily solution of the drug as a liquid trachea: Skeletal system: including bones and joints; Tissue, implant for slow release of the drug when injected intramus fiber, and integumentary system: including adipose tissue, cularly. The release of the drug appeared to depend on the cartilage, connective tissue, cuticle, dermis, epidermis, epi particular fatty acid selected, and the drug was tested for its 55 thelium, fascia, hair follicle, ligament, bone marrow, melanin, activity in the central nervous system. melanocyte, mucous membrane, skin, soft tissue, synovial Lipidic molecules, including the fatty acids, also have been capsule and tendon. conjugated with drugs to render the conjugates more lipo Unbranched, naturally occurring fatty acids embraced by philic than the drug. In general, increased lipophilicity has the invention include C8:0 (caprylic acid), C10:0 (capric been Suggested as a mechanism for enhancing intestinal 60 acid), C12:0 (lauric acid), C14:0 (myristic acid), C16:0 uptake of drugs into the lymphatic system, thereby enhancing (palmitic acid), C16:1 (palmitoleic acid), C16:2, C18:0 the entry of the conjugate into the brain and also thereby (stearic acid), C18:1 (oleic acid), C18:1-7 (vaccenic), C18: avoiding first-pass metabolism of the conjugate in the liver. 2-6 (linoleic acid), C18:3-3 (C-linolenic acid), C18:3-5 (eleo The type of lipidic molecules employed have included phos stearic), C18:3-6 (6-linolenic acid), C18:4-3, C20:1 (gondoic pholipids, non-naturally occurring branched and unbranched 65 acid), C20:2-6, C20:3–6 (dihomo-y-linolenic acid), C20:4-3, fatty acids, and naturally occurring branched and unbranched C20:4-6 (arachidonic acid), C20:5-3 (eicosapentaenoic acid), fatty acids ranging from as few as 4 carbonatoms to more than C22:1 (docosenoic acid), C22:4-6 (docosatetraenoic acid), US 8,314,077 B2 5 6 C22:5-6 (docosapentaenoic acid), C22:5-3 (docosapen receptor antagonist; Steroid; stimulant; suppressant; Symp taenoic), C22:6-3 (docosahexacnoic acid) and C24:1-9 (ner tomatic multiple Sclerosis; synergist; thyroid hormone; thy Vonic). Highly preferred unbranched, naturally occurring roid inhibitor, thyromimetic; tranquilizer; amyotrophic lat fatty acids are those with between 14 and 22 carbon atoms. eral Sclerosis agent; cerebral ischemia agent, Paget’s disease The most preferred fatty acid is docosahexaenoic acid. agent; unstable angina agent; uricoSuric; vasoconstrictor; It is preferred that the conjugate be of a single fatty acid vasodilator, Vulnerary; wound healing agent; Xanthine oxi molecule and the covalent attachment be directly to the phar dase inhibitor. maceutical agent (i.e., free of a linker molecule between the In one particularly preferred embodiment of the invention, active pharmaceutical agent and the fatty acid. the drug is an anti-cancer agent. Examples of anti-cancer The pharmaceutical agent may be any pharmacological 10 agents are described in greater detail in the specification. compound or diagnostic agent, as desired. The pharmaceuti Included are the taxanes, (e.g., Taxol and Taxotere). Conju cal agent, however, is not an adenosine receptor agonist or gates of C8-C22, unbranched, naturally occurring fatty acids antagonist. The pharmaceutical agent, of course, has an activ and taxoids also are embraced by the invention. ity outside of the central nervous system. C8-C26 fatty acids previously have been conjugated to Examples of catagories of pharmaceutical agents include: 15 drugs that are active in the central nervous system. The inven adrenergic agent, adrenocortical steroid; adrenocortical Sup tion thus also contemplates the use of C8-C22, unbranched, pressant; alcohol deterrent; aldosterone antagonist; amino naturally occurring fatty acids in the manufacture of a medi acid; ammonia detoxicant; anabolic; analeptic; analgesic; cament for treating a noncentral nervous system condition. androgen; anesthesia, adjunct to; anesthetic; anorectic; The invention further contemplates compositions of matter antagonist; anterior pituitary Suppressant; anthelmintic; anti that are conjugates of C8-C22, unbranched, naturally occur acne agent; anti-adrenergic; anti-allergic; anti-amebic; anti ring fatty acids and noncentral nervous system active phar androgen; anti-anemic; anti-anginal; anti-anxiety; anti-ar maceutical agents. thritic; anti-asthmatic; anti-atherosclerotic; antibacterial; A noncentral nervous system active pharmaceutical agent anticholelithic; anticholelithogenic; anticholinergic; antico is one that has no function or use in the central nervous agulant; anticoccidal; anticonvulsant; antidepressant; 25 system. Its only therapeutic use is outside of the central ner antidiabetic; antidiarrheal; antidiuretic; antidote; anti-emetic; Vous system. Examples of Such pharmaceutical agents anti-epileptic; anti-estrogen; antifibrinolytic; antifungal; include, but are not limited to: Blood glucose regulators. Such antiglaucoma agent; antihemophilic; antihemorrhagic; anti as tolaZamide, tolbutamide, chlorpropamide, acetohexamide, histamine; antihyperlipidemia; antihyperlipoproteinemic; and, glipizide; HMGcoA reductase inhibitors, such as Lov antihypertensive; antihypotensive; anti-infective; anti-infec 30 astatin (Mevacor), Simvastatin (Zocor), Pravastatin (Prava tive, topical; anti-inflammatory; antikeratinizing agent; anti chol), and, Fluvstatin (Lescol); Muscosal Protectives, such as malarial; antimicrobial; antimigraine; antimitotic; antimy Misoprostol (Cytotec); Gastrointestinal Motality affectors, cotic, antinauseant, antineoplastic, antineutropenic, such as Cisapride (Propulsid), Metoclopramide (Reglan), antiobessional agent; antiparasitic; antiparkinsonian; anti and, Hyoscyamine (Levsin); Antidiarrheals. Such as Diphe peristaltic, antipneumocystic; antiproliferative; antiprostatic 35 noxylate hydrochloride (Lomotil), Metronidazole (Flagyl), hypertrophy; antiprotozoal; antipruritic; antipsychotic; anti Methylprednisolone (Medrol), and, Sulfasalazine (AZulfi rheumatic; antischistosomal; antiseborrheic; antisecretory; dine); and Hormones for treating, inter alia, ovarian condi antispasmodic; antithrombotic; antitussive; anti-ulcerative; tions, such as Progesterone, Norgestrel, Norethynodrel, anti-urolithic; antiviral; appetite Suppressant; benign pros Norethindrone, Levonorgestrel, Ethyndiol, Mestranol, tatic hyperplasia therapy agent, blood glucose regulator, bone 40 Estrone, Equilin, 17alpha dihydroequilin, equilenin, 17alpha resorption inhibitor; bronchodilator; carbonic anhydrase dihydroequilenin, 17 alpha esradiol, 27 bea estradiol, Leu inhibitor, cardiac depressant; cardioprotectant; cardiotonic; prolide (Lupron), Testolactone, Climiphene, urofollitropin, cardiovascular agent; choleretic; cholinergic; cholinergic bromocriptine, gonadorelin, danazol, dehydroepiandroster agonist, cholinesterase deactivator, coccidiostat; cognition one, androstenedione, dihydrotestosterone, Relaxin, follicu adjuvant; cognition enhancer, depressant; diagnostic aid; 45 lostatin, Follicle regulatory protein, Gonadocrinins, Oocyte diuretic; dopaminergic agent: ectoparasiticide; emetic; maturation inhibitor and, Insulin growth factor. Other com enzyme inhibitor, estrogen; fibrinolytic; fluorescent agent; pounds are detailed below. free oxygen radical scavenger; gastrointestinal motility effec The methods of the invention are useful for treating a tor; glucocorticoid; gonad-stimulating principle; hair growth variety of medical conditions including conditions involving stimulant; hemostatic; histamine H2 receptor antagonists; 50 abnormal mammalian-cell proliferation. They further are hormone; hypocholesterolemic; hypoglycemic; hypolipi useful in treating diabetes and its complications, excess acid demic; hypotensive; imaging agent; immunizing agent; secretion, cardiovascular conditions involving cholesterol immunomodulator; immunoregulator; immunostimulant; (e.g., hyperlipidemia and hypercholesterolemia), diarrhea, immunosuppressant; impotence therapy adjunct, inhibitor; ovarian diseases (e.g. endometriosis, ovarian cysts, etc.) and keratolytic: LHRH agonist; liver disorder treatment; luteol 55 as contraceptive agents. Other conditions treatable according ysin; memory adjuvant; mental performance enhancer; mood to the invention will be apparent to those skilled in the art regulator, mucolytic; mucosal protective agent, mydriatic; based upon the disclosure and lists of compounds provided. nasal decongestant; neuromuscular blocking agent; neuro The methods and/or products of the invention also are protective; NMDA antagonist; non-hormonal sterol deriva useful in treating conditions specific to noncentral nervous tive; oxytocic; plasminogen activator; platelet activating fac 60 system tissue. Such conditions can be specific to any of the tor antagonist, platelet aggregation inhibitor, post-stroke and tissues described above, including breast, gastrointestinal and post-head trauma treatment; potentiator, progestin; prostag ovarian tissue. landing prostate growth inhibitor, prothyrotropin; psychotro pic; pulmonary Surface; radioactive agent; regulator, relax BRIEF DESCRIPTION OF THE DRAWINGS ant; repartitioning agent, Scabicide, Sclerosing agent; 65 sedative; sedative-hypnotic; selective adenosine A1 antago FIG. 1 is a graph plotting concentration of conjugate 1 nist, serotonin antagonist; serotonin inhibitor, serotonin Versus percent growth of leukemia cells. US 8,314,077 B2 7 8 FIG. 2 is a graph plotting concentration of conjugate 1 FIG. 27 is a graph plotting concentration of Taxol versus Versus percent growth of non-Small cell lung cancer cells. percent growth of breast cancer cells. FIG. 3 is a graph plotting concentration of conjugate 1 Versus percent growth of colon cancer cells. DETAILED DESCRIPTION OF THE INVENTION FIG. 4 is a graph plotting concentration of conjugate 1 versus percent growth of CNS cancer cells. cis-docosahexaenoic acid (DHA) is a naturally occurring FIG. 5 is a graph plotting concentration of conjugate 1 fatty acid. It is an unbranched chain fatty acid with six double Versus percent growth of melanoma cells. bonds, all cis. Its structure is as follows: FIG. 6 is a graph plotting concentration of conjugate 1 Versus percent growth of ovarian cancer cells. 10 FIG. 7 is a graph plotting concentration of conjugate 1 OH Versus percent growth of renal cancer cells. FIG. 8 is a graph plotting concentration of conjugate 1 O Versus percent growth of prostate cancer cells. FIG. 9 is a graph plotting concentration of conjugate 1 15 DHA can be isolated, for example, from fish oil or can be Versus percent growth of breast cancer cells. chemically synthesized. These methods, however, can gener FIG. 10 is a graph plotting concentration of conjugate 2 ate trans isomers, which are difficult and expensive to sepa Versus percent growth of leukemia cells. rate and which may present safety problems in humans. The FIG. 11 is a graph plotting concentration of conjugate 2 preferred method of production is biological synthesis to Versus percent growth of non-Small cell lung cancer cells. FIG. 12 is a graph plotting concentration of conjugate 2 produce the all cis isomer. The preferred source of DHA is Versus percent growth of colon cancer cells. from Martek Biosciences Corporation of Columbia, Md. FIG. 13 is a graph plotting concentration of conjugate 2 Martek has a patented system for manufacturing DHA using versus percent growth of CNS cancer cells. microalgae which synthesize only a single isomer of DHA. FIG. 14 is a graph plotting concentration of conjugate 2 25 the all cis isomer. Martek’s patents include U.S. Pat. Nos. Versus percent growth of melanoma cells. 5,374,657, 5,492,938, 5,407,957 and 5,397,591. FIG. 15 is a graph plotting concentration of conjugate 2 DHA also is present in the milk of lactating women, and Versus percent growth of ovarian cancer cells. Martek’s licensee has obtained approval in Europe of DHA as FIG. 16 is a graph plotting concentration of conjugate 2 a nutritional Supplement for infant formula. Versus percent growth of renal cancer cells. 30 It is known that DHA can be unstable in the presence of FIG. 17 is a graph plotting concentration of conjugate 2 oxygen. To stablizie DHA and its conjugates it is important to versus percent growth of prostate cancer cells. add anti-oxidants to the material after it is synthesized. One FIG. 18 is a graph plotting concentration of conjugate 2 method of stablization is to make-up the newly synthesized Versus percent growth of breast cancer cells. material in the following solution: 100g neat DHA-taxol plus FIG. 19 is a graph plotting concentration of Taxol versus 35 100 g of vehicle (100 ml propylene glycol, 70 mg alph percent growth of leukemia cells. tocopherol, 5 mg dialaurylthiodipropionic acid, 50 mgascor FIG. 20 is a graph plotting concentration of Taxol versus bic acid) prepared and held under argon in amber, sealed vials percent growth of non-Small cell lung cancer cells. and stored at four degrees centigrade. The following anti FIG. 21 is a graph plotting concentration of Taxol versus oxidants may also be employed: ascorbic acid, ascorbyl percent growth of colon cancer cells. 40 palmitate, dilauryl ascorbate, hydroquinone, butyated FIG. 22 is a graph plotting concentration of Taxol versus hydroxyanisole, sodium metabisulfite, t-B carotene and X-to percent growth of CNS cancer cells. copherol. A heavy metal chelator Such as ethylenediamiine FIG. 23 is a graph plotting concentration of Taxol versus tetra-acetic acid (EDTA) may also be used. percent growth of melanoma cells. Paclitaxel was first isolated from the bark of Taxus brevi FIG. 24 is a graph plotting concentration of Taxol versus 45 folia (Wani et al., J. Am. Chem. Soc., 93, 2325, 1971). Its percent growth of ovarian cancer cells. isolation and synthesis have been reported extensively in the FIG. 25 is a graph plotting concentration of Taxol versus literature. Applicants obtained paclitaxel from a commercial percent growth of renal cancer-cells. source, Hauser Laboratories, of Boulder, Colo. FIG. 26 is a graph plotting concentration of Taxol versus percent growth of prostate cancer cells. Example 1

TAXOL N

conjugate 1 US 8,314,077 B2 9 10 A solution of Taxol (41 umol) in methylene chloride (2.5 of intermediate A (52 umol) in methylene chloride (3 mL) mL) under argon was mixed with 4-dimethylaminopyridine was mixed at ambient temperature under argon with 4-dim (41 mol), dicyclohexylcarbodiimide (82 umol), and DHA ethylaminopyridine (52 umol), dicyclohexylcarbodiimide (41 umol) and the reaction mixture was stirred at ambient (104 umol), and DHA (52 umol). The reaction mixture was temperature for two hours. Following dilution with ether, the stirred for ten hours, diluted with ether, passed through celite, reaction mixture was washed with 5% hydrochloric acid, water, Saturated aqueous sodium chloride, dried, and concen and concentrated. Chromatography of the residue produced trated. Radial chromatography of the residue produced 45 mg 65.9 mg of intermediate B. A solution of intermediate B (51 (94%) of crystalline Taxol-DHA conjugate 1. umol) in acetonitrile (2 mL) at 0°C. under argon was mixed 10 with 49% aqueous HF (0.2 mL) and the reaction mixture was Example 2 stirred for one hour. After dilution with ether, the reaction

AcO O OH

TAXOL

conjugate 2

The production of analog 2 involves several steps including mixture was washed with water, Saturated aqueous sodium a number of protection-acylation-deprotection steps. A solu chloride, dried, and concentrated. Radial chromatography of tion of Taxol (59 umol) in methylene chloride (2.5 mL) was the residue produced 44.6 mg (75%) of Taxol-DHA conju mixed at ambient temperature under argon with imidazole 60 gate 2. (147 umol) and triethylsilyl chloride (147 umol). The reaction Example 3 mixture was stirred for thirty minutes, diluted with additional methylene chloride, washed with water, Saturated aqueous Conjugates 1 and 2 were sent to the United States National Sodium chloride, dried, and concentrated. Chromatography 65 Cancer Institute (NCI) for screening in the NCI's anticancer of the residue produced 50 mg (88%) of intermediate A plus screening program. The conjugates were provided in ethanol 5 mg of the 2, 7-di(triethylsilyl) ether derivative. A solution (approximately 40 mg analog/2 ml ethanol). The conjugates US 8,314,077 B2 11 12 were sealed in vials under argon to avoid exposure of the at Zero in the graphs), Taxol was more effective against non conjugates to oxygenbecause the conjugates were believed to small cell lung cancer line H522 than against H460 (by about be sensitive to oxygen. Instructions were provided to store at 3 logs), whereas conjugates 1 and 2 were slightly more effec 4° C. and to open the vials only when ready for immediate tive against H460 than H522. As another example, Taxol was experimental use. Instructions also were provided to use the 5 least effective at TGI against CNSU251, whereas conjugate 1 ethanol Solutions containing the conjugates directly or to was most effective against CNSU251 and conjugates 2 was dissolve the analogs further in DMSO (dimethylsulfoxide) at also very effective against CNSU251 (relative to other CNS appropriate concentrations, with Vortexing if necessary for cell lines). As a further example, Taxol was equivalent in adequate dispersal. activity toward MDA-N and MDA-MB-435 breast cancer The activities of conjugates 1 and 2 were tested against 57 10 cell lines at all concentrations tested, whereas conjugates 1 cancer cell lines. The results are presented in FIGS. 1-9 for and 2 were more effective against MDA-N than MDA-MB conjugate 1, FIGS. 10-18 for conjugate 2 and FIGS. 19-27 for 435 at all concentrations tested. Taxol. To understand the data, reference is made to the guides To further illustrate the differences in the activity of con provided by the NCI, excerpted as follows: jugates 1 and 2 versus that of Taxol, the NCI subjected the The Calculated Measurement of Effect: Percentage 15 data to a statistical analysis designed by the NCI to reflect Growth (PG) differences in the pattern of activity of anticancer agents. The measured effect of the compound on a cell line is Conjugate 1 and conjugate 2 were determined to be statisti currently calculated according to one or the other of the cally different in their pattern of activity versus Taxol in this following two expressions: unique measurement by the NCI. If (Mean OD-Meanifex OD)20,izeid then It also is to be noted that, in general, conjugates 1 and 2 PG=100x (Mean OD-Mean OD), were one thousand to ten thousand times less potent than (Mean OD-Mean Od) Taxol for many cell lines tested. This reduction in activity is important, especially since conjugates 1 and 2 maintained If (Mean OD-Meanies OD)<0,izeid then strong activity against Some cell lines. Conjugates 1 and 2 will PG=100x (Mean OD-Mean Od), 25 Mean Od be sufficiently active against certain cell lines, but will have, zees on average, a Substantially and disproportionately lower Where: activity against other cell lines, reducing potential side Mean OD, The average of optical density measurements effects. For example, the TGI for Taxol against CNS SF-539 of SRB-derived color just before exposure of cells to the is -6.95, and the TGI for conjugate 1 against this cell line is test compound. 30 -5.13 and for conjugate 2 is -5.53. (In other words, the Mean OD, The average of optical density measurements activity of the conjugates was reduced versus that of Taxol by of SRB-derived color after 48 hours exposure of cells to the less than 2 logs). The GI50 for Taxol against CNS SF 539 is test compound. -7.52, whereas the GI50s for conjugates 1 and 2 are -6.22 and Mean OD, The average of optical density measurements -5.56, respectively (again less than 2 logs difference). In of SRB-derived color after 48 hours with no exposure of 35 contrast, Taxol has a G150 for cell line CNSSF 268 of less cells to the test compound. than -10.0, whereas conjugates 1 and 2 have GI50s for Experimental data was collected against each cell CNSSF 268 of 5.36 and 5.28, respectively. This represents a line. . . . . Each concentration is expressed as the logo (molar reduction of activity in the conjugates vs. that of Taxol by at orug/ml).... The response parameters GI50, TGI, and LC50 least about 5 logs activity. On average, the G150 for Taxol are interpolated values representing the concentrations at 40 across all cell lines tested is at least -9.19. (It is probably which the PG is +50, 0, and -50, respectively. Sometimes much higher since concentrations less than -10 were not these response parameters cannot be obtained by interpola tested, and if Taxol was active at -10.0, -10 (instead of the tion. If, for instance, all of the PGs in a given row exceed +50, actual lower value) was used in calculating the average of then none of the three parameters can be obtained by inter -9.19. There were 27 instances when this occurred.) The polation. In such a case, the value given for each response 45 average GI50s for conjugates 1 and 2, on the other hand, were parameter is the highest concentration tested. This practice is 5.49 and 5.22, respectively. Therefore, the average difference extended similarly to the other possible situations where a in activity for Taxol vs. the conjugates is at least between 3 response parameter cannot be obtained by interpolation. and 4 logs. Thus, the sharp reduction in the activity of the Dose-Response Curves: conjugates against many cell lines vs. a lesser reduction for The dose-response curve page of the data package is cre 50 other cell lines is expected to reduce the potential side effects ated by plotting the PGs against the logo of the correspond of the conjugates versus those of Taxol at effective doses. ing concentration for every cell line. The cell line curves are Cancers other than CNS, breast and colon cancer can be grouped by subpanel. Horizontal lines are provided at the PG treated. For example, there was activity against non-Small cell values of +50, 0, and -50. The concentrations corresponding lung cancer cells, melanoma cells and ovarian cancer cells. to points where the curves cross these lines are the GI50, TGI 55 However, the activity was relatively reduced and was and LC50, respectively. extremely specific, limiting the utility of the conjugates for Several important distinctions are apparent from the data. treating generally such cancers. In any event, cancer patients Most important, the patterns of anticancer actively for conju could be evaluated to determine if a conjugate is strongly gates 1 and 2 differ from that of Taxol. In one sense, conju active against the patient’s cancer prior to selecting the con gates 1 and 2 are effective anticancer agents against a more 60 jugate as the anti-cancer agent of choice for that patient. restricted set of cancer cell lines. For example, conjugates 1 The foregoing experiments establish that DHA analogs and 2 were not very effective against any of the six leukemia have altered specificity versus that of Taxol for cancer cell cancer cell lines tested, whereas Taxol was somewhat effec lines. Because of this altered specificity, it also is clear that the tive against all four leukemia cell lines against which Taxol conjugates themselves are gaining access into the target cells was tested. (See FIGS. 1, 10 and 19.) 65 (as opposed to simply releasing Taxol into the environment The relative activity against members within a class of outside of the cell). Thus, the DHA moiety appears to selec cancers also was altered. For example, at TGI (horizontal line tively target certain cell types as opposed to others. The ability US 8,314,077 B2 13 14 of the conjugates to gain entry into the targeted cells was unknown prior to the invention, and the ability of the DHA moiety to selectively target certain cell types was unexpected. The same is true of DHA-Taxotere covalent conjugates, examples of which are presented below. Taxotere’s synthesis is has been reported extensively in the literature. One example is Kanazawa, A. et al., J. Organic Chem. 1994, Vol. 59, pp. 1238-1240. Example 4

TAXOTERE

DHA? dicyclohexylcarbodiimide 4-dimethylaminopyridine

conjugate 3

30 A solution of Taxotere in methylene chloride under argonis mixed with 4-dimethylaminopyridine, dicyclohexylcarbodi imide, and DHA. The reaction mixture is stirred at ambient temperature. Radial chromatography of the residue is per formed to produce Taxotere-DHA conjugate 3. 35 Example 5

triethylsilyl chloride TAXOTERE He imidazole HO 9 OSi(CH2CH3)3 X--O -Nulls III IIH DHA? dicyclohexylcarbodiimide Ph outs O 4-dimethylaminopyridine (CHCH.);Sió

aqueous HF X, H O ---

(CHCH.);Sió US 8,314,077 B2 15 16 -continued

o o o o o o O

X1,O . Ph

conjugate 4

A solution of Taxotere in dimethylformamide is mixed at concentrated. Radial chromatography of the residue is per ambient temperature under argon with imidazole and trieth formed to produce intermediate D. A solution of intermediate ylsilyl chloride. The reaction mixture is stirred at ambient D in acctonitrile at 0°C. under argon is mixed with 49% temperature, diluted with methylene chloride, washed with aqueous HF and the reaction mixture is stirred at the same water, Saturated acqueous sodium chloride, dried, and con temperature. After dilution with ether, the reaction mixture is centrated. Radial chromatography of the residue is performed washed with water, Saturated aqueous sodium chloride, dried, to produce intermediate C. A solution of intermediate C in 25 and concentrated Radial chromatography of the residue is methylene chloride is mixed at ambient temperature under argon with 4 dimethylaminopyridine, dicyclohexylcarbodi performed to produce Taxotere-DHA conjugate 4. imide, and DHA. The reaction mixture is stirred at ambient temperature, diluted with ether, passed through celite, and Example 6

tert-butyldimethylsilyl chloride TAXOTERE imidazole

1 equivalent DHA -- dicyclohexylcarbodiimide 4-dimethylaminopyridine tert-C4Ho(CH3)2Si HO

E

O aqueous HF X He

Ph US 8,314,077 B2 17 -continued

conjugate 4

A solution of Taxotere in dimethylformamide is mixed at the residue is performed to produce intermediate F. (Interme ambient temperature under argon with imidazole and tert diate H also is obtained and used in Example 8 below.) A butylydimethylsilyl chloride. The reaction mixture is stirred solution of intermediate F in acetonitrile at 0°C. under argon at ambient temperature, diluted with methylene chloride, is mixed with aqueous HF and the reaction mixture is stirred washed with water, Saturated aqueous Sodium chloride, dried, and concentrated. Radial chromatography of the residue is at the same temperature. After dilution with ether, the reaction performed to produce intermediate E. A solution of interme mixture is washed with water, Saturated aqueous sodium diate Ein methylene chloride is mixed at ambient temperature 5 chloride, dried, and concentrated Radial chromatography of under argon with 4-dimethylaminopyridine, dicyclohexyl the residue is performed to produce Taxotere-DHA conjugate carbodiimide, and 1 equivalent of DHA. The reaction mixture 4. is stirred at ambient temperature, diluted with ether, passed through celite, and concentrated. Radial chromatography of Example 7

tert-butyldimethylsilyl chloride TAXOTERE imidazole

DHA? dicyclohexylcarbodiimide -- 4-dimethylaminopyridine tert-C4Ho(CH3)2Si HO 1. O Ph E

A A A O O

Xu-- O aqueous HF Her US 8,314,077 B2 19 20 -continued o o o o o o O O X--O a Ph

conjugate 5

A solution of Taxotere in dimethylformamide is mixed at 15 celite, and concentrated. Radial chromatography of the resi ambient temperature under argon with imidazole and tert due is performed to produce intermediate G. A solution of butylydimethylsilyl chloride. The reaction mixture is stirred intermediate G in acetonitrile at 0°C. under argon is mixed at ambient temperature, diluted with methylene chloride, with aqueous HF and the reaction mixture is stirred at the washed with water, Saturated aqueous Sodium chloride, dried, and concentrated. Radial chromatography of the residue is same temperature. After dilution with ether, the reaction mix performed to produce intermediate E. A solution of interme ture is washed with water, Saturated aqueous sodium chloride, diate Ein methylene chloride is mixed at ambient temperature dried, and concentrated. Radial chromatography of the resi under argon with 4-dimethylaminopyridine, dicyclohexyl due is performed to produce Taxotere-DHA conjugate 5. carbodiimide, and DHA. The reaction mixture is stirred at ambient temperature, diluted with ether, passed through Example 8

tert-butyldimethylsilyl chloride TAXOTERE imidazole

HO

X H O 1 equivalent DHA --- Ph -Nulls Out E i dicyclohexylcarbodiimide tert-C4H)(CH3)2Sió HO 1. 4-dimethylaminopyridine O Ph E

O

HO O O o Xu-- O aqueous HF Ph E Ol' N-O -- tert-CH3(CH3)2Sió HO CP 5A US 8,314,077 B2 21 22 -continued

conjugate 6

A solution of taxotere in dimethylformamide is mixed at Adrenocortical steroid: Ciprocinonide; Desoxycorticos ambient temperature under argon with imidazole and tert terone Acetate; Desoxycorticosterone Pivalate; Dexametha butylydimethylsilyl chloride. The reaction mixture is stirred sone Acetate: Fludrocortisone Acetate: Flumoxonide; Hydro at ambient temperature, diluted with methylene chloride, cortisone Hemisuccinate; Methylprednisolone washed with water, Saturated aqueous Sodium chloride, dried, Hemisuccinate; Naflocort; Procinonide; Timobesone and concentrated. Radial chromatography of the residue is Acetate; Tipredane. performed to produce intermediate E. A solution of interme 25 Adrenocortical Suppressant: Aminoglutethimide; Trilos diate Ein methylene chloride is mixed at ambient temperature tane. under argon with 4-dimethylaminopyridine, dicyclohexyl Alcohol deterrent: Disulfiram. carbodiimide, and 1 equivalent of DHA. The reaction mixture Aldosterone antagonist: Canrenoate Potassium, Can is stirred at ambient temperature, diluted with ether, passed renone; Dicirenone; Mexrenoate Potassium; Prorenoate through celite, and concentrated. Radial chromatography of 30 Potassium; Spironolactone. the residue is performed to produce intermediate H (and Amino acid: Alanine; Aspartic Acid; Cysteine Hydrochlo intermediate F which was used above on Example 6. A solu ride: Cystine: Histidine: Isoleucine; Leucine; Lysine: Lysine tion of intermediate H in acetonitrite at 0°C. under argon is Acetate; Lysine Hydrochloride; Methionine; Phenylalanine: mixed with aqueous HF and the reaction mixture is stirred at Proline; Serine; Threonine; Tryptophan; Tyrosine; Valine. the same temperature. After dilution with ether, the reaction 35 Ammonia detoxicant: Arginine: Arginine Glutamate; Argi mixture is washed with water, Saturated aqueous sodium nine Hydrochloride. chloride, dried, and concentrated. Radial chromatography of Anabolic: Bolandiol Dipropionate; Bolasterone; Bold the residue is performed to produce Taxotere-DHA conjugate enone Undecylenate; Bolenol; Bolmantalate: Ethylestrenol; 6. Methenolone Acetate; Methenolone Enanthate; Mibolerone; DHA and other naturally occurring, unbranched fatty acids 40 Nandrolone Cyclotate; Norbolethone; Pizotyline; Quin may be conjugated to virtually any drug compound or diag bolone; Stenbolone Acetate; Tibolone; Zeranol. nostic agent and used according to the methods of the present Analeptic: Modafinil. invention so long as the pharmaceutical agent has a use out Analgesic: Acetaminophen; Alfentanil Hydrochloride; side of the central nervous system. Pharmaceutical agents Aminobenzoate Potassium; Aminobenzoate Sodium; Ani include the following categories and specific examples. It is 45 doxime; Anileridine: Anileridine Hydrochloride; Anilopam not intended that the category be limited by the specific Hydrochloride; Anirolac, Antipyrine; Aspirin; Benoxapro examples. Those of ordinary skill in the art will be able to fen; Benzydamine Hydrochloride; Biciifadine Hydrochlo identify readily those pharmaceutical agents that have utility ride; Brifentanil Hydrochloride; Bromadoline Maleate; Bro outside of the central nervous system. Those of ordinary skill mfenac Sodium: Buprenorphine Hydrochloride; Butacetin: in the art will recognize also numerous other compounds that 50 Butixirate; Butorphanol; Butorphanol Tartrate; Carbam fall within the categories and that are useful according to the azepine; Carbaspirin Calcium; Carbiphene Hydrochloride: invention. Carfentanil Citrate: Ciprefadol Succinate; Ciramadol; Cira Adrenergic: Adrenalone; Amidephrine Mesylate; Apra madol Hydrochloride; Clonixeril; Clonixin; Codeine; clonidine Hydrochloride: Brimonidine Tartrate; Dapiprazole Codeine Phosphate: Codeine Sulfate; Conorphone Hydro Hydrochloride; Deterenol Hydrochloride; Dipivefrin; 55 chloride: Cyclazocine; Dexoxadrol Hydrochloride; Dex Dopamine Hydrochloride: Ephedrine Sulfate: Epinephrine; pemedolac; Dezocine; Diflunisal; Dihydrocodeine Bitartrate; Epinephrine Bitartrate: Epinephryl Borate; Esproduin Dimefadane; Dipyrone; Doxpicomine Hydrochloride; Drin Hydrochloride; Etafedrine Hydrochloride; Hydroxyamphet idene: Enadoline Hydrochloride: Epirizole; Ergotamine Tar amine Hydrobromide: Levonordefrin; Mephentermine Sul trate; Ethoxazene Hydrochloride; Etofenarnate; Eugenol; fate; Metaraminol Bitaritrate; Metizoline Hydrochloride: 60 Fenoprofen; Fenoprofen Calcium; Fentanyl Citrate; Floc Naphazoline Hydrochloride; Norepinephrine Bitartrate; Oxi tafenine: Flufenisal; Flunixin: Flumixin Meglumine: Flupir dopamine: Oxymetazoline Hydrochloride; Phenylephrine tine Maleate; FluproduaZone: Fluradoline Hydrochloride; Hydrochloride; Phenylpropanolamine Hydrochloride; Phe Flurbiprofen; Hydromorphone Hydrochloride; Ibufenac: nylpropanolamine Polistirex: Prenalterol Hydrochloride; Indoprofen; Ketazocine; Ketorfanol: Ketorolac Propylhexedrine; Pseudoephedrine Hydrochloride; Tetrahy 65 Tromethamine: Letimide Hydrochloride; Levomethadyl drozoline Hydrochloride; Tramazoline Hydrochloride: Acetate; Levomethadyl Acetate Hydrochloride; Levonantra Xylometazoline Hydrochloride. dol Hydrochloride; Levorphanol Tartrate; Lofemizole US 8,314,077 B2 23 24 Hydrochloride; Lofentanil Oxalate; Lorcinadol; Lornoxi cinate; Mazindol; Mefenorex Hydrochloride; Phenrmetra cam: Magnesium Salicylate; Mefenamic Acid; Menabitan Zine Hydrochloride: Phentermine; Sibutramine Hydrochloride; Meperidine Hydrochloride; Meptazinol Hydrochloride. Hydrochloride; Methadone Hydrochloride; Methadyl Antagonist: Atipamezole; Atosiban; Bosentan, Cimeti Acetate; Methopholine; Methotrimeprazine; Metkephamid dine, Cimetidine Hydrochloride; Clentiazem Maleate; Acetate; Mimbane Hydrochloride; Mirfentanil Hydrochlo Detirelix Acetate; Devazepide; Donetidine: Etintidine ride; MolinaZone: Morphine Sulfate; Moxazocine; Nabitan Hydrochloride; Famotidine: Fenmetozole Hydrochloride: Hydrochloride; Nalbuphine Hydrochloride; Nalmexone Flumazenil; Icatibant Acetate: Icotidine; Isradipine; Metia Hydrochloride: Namoxyrate; Nantradol Hydrochloride: mide: Nadide; Nalmefene; Nalmexone Hydrochloride; Naproxen; Naproxen Sodium; Naproxol; Nefopam Hydro 10 chloride; Nexeridine Hydrochloride; Noracymethadol Naloxone Hydrochloride; Naltrexone; Nilvadipine; Oxilor Hydrochloride; Ocfentanil Hydrochloride; Octazamide: phan: Oxmetidine Hydrochloride; Oxmetidine Mesylate: Olvanil; Oxetorone Fumarate: Oxycodone; Oxycodone Quadazocine Mesylate; Ranitidine: Ranitidine Bismuth Cit Hydrochloride: Oxycodone Terephthalate: Oxymorphone rate; Ranitidine Hydrochloride; Sufotidine; Teludipine Hydrochloride; Pemedolac, Pentamorphone; Pentazocine; 15 Hydrochloride; Tiapamil Hydrochloride; Tiotidine: Pentazocine Hydrochloride: Pentazocine Lactate; Vapiprost Hydrochloride; Zaltidine Hydrochloride. Phenazopyridine Hydrochloride; Phenyramidol Hydrochlo Anterior pituitary activator: Epimestrol. ride; Picenadol Hydrochloride; Pinadoline; Pirfenidone; Anterior pituitary Suppressant: DanaZol. Piroxicam Olamine; Pravadoline Maleate; Prodilidine Anthelmintic: Albendazole; Anthelmycin; Bromoxanide; Hydrochloride; Profadol Hydrochloride; Propiram Fuma Bunamidine Hydrochloride: Butonate; Cambendazole; Car rate; Propoxyphene Hydrochloride; Propoxyphene Napsy bantel Lauryl Sulfate; Clioxanide; Closantel: Cyclobenda late: Proxazole; Proxazole Citrate; Proxorphan Tartrate; Pyr Zole; Dichlorvos; Diethylcarbamazine Citrate; Dribendazole; roliphene Hydrochloride; Remifentanil Hydrochloride; Dymanthine Hydrochloride; Etibendazole: Fenbendazole; Salcolex: Salethamide Maleate; Salicylamide; Salicylate Furodazole: Hexylresorcinol; Mebendazole; Morantel Tar Meglumine; Salsalate: Sodium Salicylate: Spiradoline Mesy 25 trate; Niclosamide: Nitramisole Hydrochloride; Nitrodan; late; Sufentanil; Sufentanil Citrate; Talmetacin; Talniflumate; Oxantel Pamoate; Oxfendazole; Oxibendazole; Parbenda Talosalate: Tazadolene Succinate; Tebufelone; Tetrydamine: Zole; Piperamide Maleate; Piperazine; Piperazine Citrate; Tifurac Sodium; Tilidine Hydrochloride; Tiopinac; Tonazo Piperazine Edetate Calcium; Proclonol; Pyrantel Pamoate: cine Mesylate: Tramadol Hydrochloride; Trefentanil Hydro Pyrantel Tartrate; Pyrvinium Pamoate; Rafoxanide; Stilba chloride; Trolamine: Veradoline Hydrochloride; Verilopam 30 Zium Iodide; Tetramisole Hydrochloride; Thiabendazole; Hydrochloride; Volazocine: Xorphanol Mesylate: Xylazine Ticarbodine; Tioxidazole; Triclofenol Piperazine; Vincofos: Hydrochloride; Zenazocine Mesylate: Zomepirac Sodium; Zilantel. Zucapsaicin. Anti-acne: Adapalene; Erythromycin Salnacedin; Inocote Androgen: Fluoxymesterone; Mesterolone; Methyltest rone Acetate. osterone; Nandrolone Decanoate; Nandrolone Phenpropi 35 Anti-adrenergic: Acebutolol; Alprenolol Hydrochloride; onate; Nisterime Acetate; Oxandrolone: Oxymetholone: Atenolol; Bretylium Tosylate: Bunolol Hydrochloride; Car Silandrone; Stanozolol; Testosterone; Testosterone Cypi teolol Hydrochloride: Celiprolol Hydrochloride; Cetamolol onate; Testosterone Enanthate; Testosterone Ketolaurate; Hydrochloride: Cicloprolol Hydrochloride; Dexpropranolol Testosterone Phenylacetate; Testosterone Propionate; Tres Hydrochloride; Diacetolol Hydrochloride; Dihydroergota tolone Acetate. 40 mine Mesylate; Dilevalol Hydrochloride; Esmolol Hydro Anesthesia, adjunct to: Sodium Oxybate. chloride; Exaprolol Hydrochloride: Fenspiride Hydrochlo Anesthetic: Aliflurane; Benoximate Hydrochloride; Ben ride; Flestolol Sulfate; Labetalol Hydrochloride; Zocaine; Biphenamine Hydrochloride; Bupivacaine Hydro Levobetaxolol Hydrochloride; Levobunolol Hydrochloride: chloride; Butamben; Butamben Picrate; Chloroprocaine Metalol Hydrochloride; Metoprolol; Metoprolol Tartrate; Hydrochloride; Cocaine; Cocaine Hydrochloride; Cyclopro 45 Nadolol; Pamatolol Sulfate; Penbutolol Sulfate; Phentola pane; Desflurane; Dexivacaine; Diamocaine Cyclamate; mine Mesylate; Practolol; Propranolol Hydrochloride; Dibucaine; Dibucaine Hydrochloride; Dyclonine Hydrochlo Proroxan Hydrochloride; Solypertine Tartrate; Sotalol ride; Enflurane; Ether; Ethyl Chloride: Etidocaine; Etoxadrol Hydrochloride; Timolol; Timolol Maleate; Tiprenolol Hydrochloride; Euprocin Hydrochloride: Fluroxene; Hal Hydrochloride; Tolamolol; Zolertine Hydrochloride. othane; Isobutamben; Isoflurane; Ketamine Hydrochloride: 50 Anti-allergic: Amlexanox; Astemizole, AZelastine Hydro Levoxadrol Hydrochloride; Lidocaine; Lidocaine Hydro chloride; EclaZolast; Minocromil Nedocromil; Nedocromil chloride; Mepivacaine Hydrochloride; Methohexital Calcium; Nedocromil Sodium; Nivinedone Sodium; Sodium; Methoxyflurane: Midazolam Hydrochloride: Mida Pemirolast Potassium; Pentigetide: Pirquinozol; Poisonoak Zolam Maleate; Minaxolone; Nitrous Oxide; Norflurane; Extract; Probicromil Calcium; Proxicromil: Repirinast: Tet Octodrine; Oxethazaine; Phencyclidine Hydrochloride: 55 razolast Meglumine; Thiazinamium Chloride; Tiacrilast; Tia Pramoxine Hydrochloride; Prilocalne Hydrochloride: crilast Sodium; Tiprinast Meglumine; Tixanox. Procaine Hydrochloride; Propanidid; Proparacaine Hydro Anti-amebic: Berythromycin; Bialamicol Hydrochloride; chloride; Propofol; Propoxycaine Hydrochloride; Pyr Chloroquine; Chloroquine Hydrochloride; Chloroquine rocaine; Pisocaine; Rodocaine; Roflurane; Salicyl Alcohol: Phosphate: Clamoxyquin Hydrochloride; Clioquinol; Emet Sevoflurane; Teflurane; Tetracaine; Tetracaine Hydrochlo 60 ine Hydrochloride; Iodoquinol; Paromomycin Sulfate; Quin ride; Thiamylal; Thiamylal Sodium; Thiopental Sodium; famide: Symetine Hydrochloride; Teclozan; Tetracycline: Tiletamine Hydrochloride; Zolamine Hydrochloride. Tetracycline Hydrochloride. Anorectic compounds including dexfenfluramine. Anti-androgen: Benorterone; Cioteronel, Cyproterone Anorexic: Aminorex: Amphecloral; Chlorphentermine Acetate; Delmadinone Acetate; Oxendolone; Topterone: Hydrochloride; Clominorex; Clortermine Hydrochloride: 65 Zanoterone. Diethylpropion Hydrochloride: Fenfluramine Hydrochlo Anti-anemic: Epoetin Alfa: Epoetin Beta; Ferrous Sulfate, ride; Fenisorex: Fludorex: Fluminorex; Levamfetamine Suc Dried; Leucovorin Calcium. US 8,314,077 B2 25 26 Anti-anginal: Amlodipine Besylate; Amlodipine Maleate; Sodium; Cyclacillin: Cycloserine; Dalfopristin; Dapsone; Betaxolol Hydrochloride; Bevantolol Hydrochloride; Buto Daptomycin; Demeclocycline; Demeclocycline Hydrochlo prozine Hydrochloride; Carvedilol; Cinepazet Maleate; ride; Demecycline; Denofungin: Diaveridine; Dicloxacillin; Metoprolol Succinate; Molsidomine; Monatepil Maleate; Dicloxacillin Sodium; Dihydrostreptomycin Sulfate; Dipy Primidolol; Ranolazine Hydrochloride; Tosifen: Verapamil rithione; Dirithromycin; Doxycycline; Doxycycline Cal Hydrochloride. cium; Doxycycline Fosfatex: Doxycycline Hyclate; Droxa Anti-anxiety agent: Adatanserin Hydrochloride; Alpidem; cin Sodium: Enoxacin; Epicillin: Epitetracycline Binospirone Mesylate: Bretazenil; Glemanserin; Ipsapirone Hydrochloride; Erythromycin; Erythromycin Acistrate; Hydrochloride; Mirisetron Maleate; Ocinaplon; Ondansetron Erythromycin Estolate; Erythromycin Ethylsuccinate; Eryth Hydrochloride; Panadiplon; Pancopride; Pazinaclone: 10 romycin Gluceptate; Erythromycin Lactobionate; Erythro Serazapine Hydrochloride; Tandospirone Citrate; mycin Propionate; Erythromycin Stearate; Ethambutol Zalospirone Hydrochloride. Hydrochloride; Ethionamide; Fleroxacin; Floxacillin: Flu Anti-arthritic: Lodelaben. dalanine; Flumequine; Fosfomycin; Fosfomycin Anti-asthmatic: Ablukast, Ablukast Sodium; Azelastine Tromethamine; Fumoxicillin; Furazolium Chloride; Furazo Hydrochloride: Bunaprolast; Cinalukast; Cromitrile Sodium; 15 lium Tartrate; Fusidate Sodium; Fusidic Acid, Gentamicin Cromolyn Sodium: Enofelast; Isamoxole; Ketotifen Fuma Sulfate: Gloximonam; Gramicidin; Haloprogin: Hetacillin; rate; Levcromakalim; Lodoxamide Ethyl, Lodoxamide Hetacillin Potassium: Hexedine: Ibafloxacin: Imipenem; Iso Tromethamine; Montelukast Sodium; Ontazolast: Oxarba conazole; Isepamicin; Isoniazid; Josamycin; Kanamycin Sul Zole: Oxatomide: Piriprost; Piriprost Potassium; Pirolate: fate; Kitasamycin; Levofuraltadone; Levopropylcillin Potas Pobilukast Edamine; Quazolast; Repirinast; Ritolukast; sium; Lexithromycin; Lincomycin; Lincomycin Sulukast; Tetrazolast Meglumine; Tiaramide Hydrochloride: Hydrochloride; Lomefloxacin; Lomefloxacin Hydrochlo Tibenelast Sodium; Tomelukast; Tranilast; Verlukast; Ver ride; Lomefloxacin Mesylate: Loracarbef: Mafenide; Meclo ofylline; Zarirlukast. cycline; Meclocycline Sulfosalicylate; Megalomicin Potas Anti-atherosclerotic: Mifobate; Timefuronc. sium Phosphate; Mequidox: Meropenem; Methacycline: Antibacterial: Acedapsone; Acetosulfone Sodium; Alame 25 Methacycline Hydrochloride; Methenamine; Methenamine cin; Alexidine: Amdinocillin; Amdinocillin Pivoxil; Amicy Hippurate; Methenamine Mandelate; Methicillin Sodium; cline; Amifloxacin; Amifloxacin Mesylate; Amikacin; Ami Metioprim; Metronidazole Hydrochloride; Metronidazole kacin Sulfate; Aminosalicylic acid; Aminosalicylate Sodium; Phosphate: Mezlocillin: Mezlocillin Sodium; Minocycline: Amoxicillin; Amphomycin; Ampicillin; Ampicillin Sodium; Minocycline Hydrochloride; Mirincamycin Hydrochloride: Apalcillin Sodium; Apramycin; Aspartocin, Astromicin Sul 30 Monensin; Monensin Sodium; Nafcillin Sodium; Nalidixate fate: Avilamycin; AVoparcin; Azithromycin; AZlocillin; Sodium; Nalidixic Acid; Natamycin; Nebramycin; Neomy AZlocillin Sodium: Bacampicillin Hydrochloride: Bacitra cin Palmitate; Neomycin Sulfate; Neomycin Undecylenate: cin; Bacitracin Methylene Disalicylate; Bacitracin Zinc; Netilmicin Sulfate; Neutramycin; Nifuradene; Nifurald Bambermycins; Benzoylpas Calcium; Berythromycin; eZone; Nifuratel; Nifuratrone; Nifurdazil; Nifurimide: Betamicin Sulfate; Biapenem; Biniramycin; Biphenamine 35 Nifurpirinol; Nifurcquinazol; Nifirthiazole; Nitrocycline; Hydrochloride; Bispyrithione Magsulfex; Butikacin: Nitrofurantoin: Nitromide: Norfloxacin; Novobiocin Butirosin Sulfate; Capreomycin Sulfate; Carbadox; Carbeni Sodium; Ofloxacin; Ormetoprim: Oxacillin Sodium; Oxi cillin Disodium; Carbenicillin Indanyl Sodium; Carbenicillin monam. Oximonam Sodium; Oxolinic Acid: Oxytetracy Phenyl Sodium; Carbenicillin Potassium; Carumonam cline: Oxytetracycline Calcium; Oxytetracycline Hydrochlo Sodium; Cefaclor; Cefadroxil, Cefamandole; Cefamandole 40 ride; Paldimycin; Parachlorophenol; Paulomycin; Nafate; Cefamandole Sodium; Cefaparole; Cefatrizine; Pefloxacin: Pefloxacin Mesylate; Penamecillin: Penicillin G Cefazaflur Sodium; Cefazolin; Cefazolin Sodium; Cefbu BenZathine; Penicillin G Potassium; Penicillin G Procaine; peraZone; Cefdinir, Cefepime: Cefepime Hydrochloride; Penicillin G Sodium; Penicillin V: Penicillin V BenZathine; Cefetecol; Cefixime; Cefinenoxime Hydrochloride; Cefin Penicillin V Hydrabamine; Penicillin V Potassium; Pentizi etazole; Cefinetazole Sodium; Cefonicid Monosodium; 45 done Sodium; Phenyl Aminosalicylate; Piperacillin Sodium; Cefonicid Sodium; CefoperaZone Sodium; Ceforanide; Pirbenicillin Sodium; Piridicillin Sodium; Pirlimycin Hydro Cefotaxime Sodium; Cefotetan: Cefotetan Disodium; Cefo chloride; Pivampicillin Hydrochloride; Pivampicillin Pamo tiam Hydrochloride; Cefoxitin: Cefoxitin Sodium; Ce?pimi ate; Pivampicillin Probenate; Polymyxin B Sulfate; Porfiro Zole; Ce?pimizole Sodium; Ce?piramide: Ce?piramide mycin; Propikacin; Pyrazinamide: Pyrithione Zinc; Sodium; Ce?pirome Sulfate; Cefpodoxime Proxetil: Cef 50 Quindecamine Acetate; Quinupristin, Racephenicol; prozil; Cefroxadine; Cefsulodin Sodium; Ceftazidime: Cef Ramoplanin; Ranimycin; Relomycin; Repromicin; Rifabu tibuten; Ceftizoxime Sodium; Ceftriaxone Sodium; tin; Rifametane; Rifamexil; Rifamide: Rifampin; Rifapen Cefuroxime; Cefuroxime Axetil: Cefuroxime Pivoxetil: tine; Rifaximin; Rolitetracycline: Rolitetracycline Nitrate: Cefuroxime Sodium; Cephacetrile Sodium; Cephalexin; Rosaramicin; Rosaramicin Butyrate; Rosaramicin Propi Cephalexin Hydrochloride; Cephaloglycin; Cephaloridine: 55 onate; Rosaramicin Sodium Phosphate; Rosaramicin Stear Cephalothin Sodium; Cephapirin Sodium; Cephradine; Ceto ate; Rosoxacin; Roxarsone; Roxithromycin; Sancycline; cycline Hydrochloride; Cetophenicol; Chloramphenicol; Sanfetrinem Sodium; Sarmoxicillin; Sarpicillin; Scopafun Chloramphenicol Palmitate; Chloramphenicol Pantothenate gin, Sisomicin; Sisomicin Sulfate; Sparfloxacin; Spectino Complex: Chloramphenicol Sodium Succinate; Chlorhexi mycin Hydrochloride: Spiramycin; Stallimycin Hydrochlo dine Phosphanilate; Chloroxylenol; Chlortetracycline Bisul 60 ride; Steffimycin; Streptomycin Sulfate; Streptonicozid: fate; Chlortetracycline Hydrochloride; Cinoxacin: Ciprof Sulfabenz, Sulfabenzamide; Sulfacetamide; Sulfacetamide loxacin: Ciprofloxacin Hydrochloride: Cirolemycin; Sodium; Sulfacytine; Sulfadiazine: Sulfadiazine Sodium; Clarithromycin; Clinafloxacin Hydrochloride; Clindamycin; Sulfadoxine; Sulfalene; Sulfamerazine; Sulfameter, Sul Clindamycin Hydrochloride; Clindamycin Palmitate Hydro famethazine; Sulfamethizole; Sulfamethoxazole; Sulfa chloride; Clindamycin Phosphate; Clofazimine; Cloxacillin 65 monomethoxine; Sulfamoxole; Sulfanilate Zinc, Sulfanitran; Benzathine; Cloxacillin Sodium; Cloxyquin; Colistimethate Sulfasalazine; Sulfasomizole; Sulfathiazole; Sulfazamet; Sodium; Colistin Sulfate; Coumermycin; Coumermycin Sulfisoxazole; Sulfisoxazole Acetyl; Sulfisoxazole Diola US 8,314,077 B2 27 28 mine; Sulfomyxin; Sulopenem; Sultamicillin; Suncillin Fumarate; Cyclindole: Cypenamine Hydrochloride; Cyproli Sodium; Talampicillin Hydrochloride; Teicoplanin; Tema dol Hydrochloride: Cyproximide; Daledalin Tosylate: floxacin Hydrochloride; Temocillin; Tetracycline; Tetracy Dapoxetine Hydrochloride; Dazadrol Maleate; Dazepinil cline Hydrochloride Tetracycline Phosphate Complex: Hydrochloride; Desipramine Hydrochloride; Dexamisole; Tetroxoprim; Thiamphenicol; Thiphencillin Potassium; 5 Deximafen; Dibenzepin Hydrochloride; Dioxadrol Hydro Ticarcillin Cresyl Sodium; Ticarcillin Disodium; Ticarcillin chloride; Dothiepin Hydrochloride; Doxepin Hydrochloride: Monosodium; Ticlatone; Tiodonium Chloride; Tobramycin; Duloxetine Hydrochloride; Eclanamine Maleate; Encyprate; Tobramycin Sulfate; Tosufloxacin; Trimethoprim; Trimetho Etoperidone Hydrochloride; Fantridone Hydrochloride: Fen prim Sulfate; Trisulfapyrimidines; Troleandomycin; Tros metozole Hydrochloride: Fenmetramide: Fezolamine Fuma pectomycin Sulfate; Tyrothricin; Vancomycin; Vancomycin 10 rate: Fluotracen Hydrochloride: Fluoxetine: Fluoxetine Hydrochloride; Virginiamycin; Zorbamycin. Hydrochloride: Fluparoxan Hydrochloride; Garnfexine: Anticholelithic: Monoctanoin. Guanoxyfen Sulfate: Imafen Hydrochloride: Imiloxan Anticholelithogenic: Chenodiol; Ursodiol. Hydrochloride; Irnipramine Hydrochloride; Indeloxazine Anticholinergic: Alverinc Citrate; Anisotropine Methyl Hydrochloride; Intriptyline Hydrochloride; Iprindole: Iso bromide: Atropine; Atropine Oxide Hydrochloride; Atropine 15 carboxazid; Ketipramine Fumarate; Lofepramine Hydro Sulfate; Belladonna; Benapryzine Hydrochloride; Benzetim chloride; Lortalamine: Maprotiline: Maprotiline Hydrochlo ide Hydrochloride; Benzilonium Bromide: Biperiden; ride; Melitracen Hydrochloride; Milacemide Hydrochloride; Biperiden Hydrochloride; Biperiden Lactate; Clidinium Bro Minaprine Hydrochloride; Mirtazapine: Moclobemide: mide: Cyclopentolate Hydrochloride; Dexetimide: Dicyclo Modaline Sulfate; Napactadine Hydrochloride; Napamezole mine Hydrochloride; Dihexyverine Hydrochloride; Domazo Hydrochloride: Nefazodone Hydrochloride; Nisoxetine: line Fumarate; Elantrine; Elucaine; Ethybenztropine; Nitrafudam Hydrochloride; Nomifensine Maleate; Nortrip Eucatropine Hydrochloride: Glycopyrrolate: Heteronium tyline Hydrochloride; Octriptyline Phosphate; Opipramol Bromide: Homatropine Hydrobromide; Homatropine Meth Hydrochloride: Oxaprotiline Hydrochloride: Oxypertine: ylbromide: Hyoscyamine: Hyoscyamine Hydrobromide: Paroxetine; Phenelzine Sulfate: Pirandamine Hydrochloride: Hyoscyamine Sulfate; Isopropamide Iodide; Mepenzolate 25 Pizotyline: Pridefine Hydrochloride; Prolintane Hydrochlo Bromide: Methylatropine Nitrate; Metoquizine; Oxybutynin ride; Protriptyline Hydrochloride: Quipazine Maleate; Roli Chloride; Parapenzolate Bromide: Pentapiperium Methylsul cyprine; Seproxetine Hydrochloride: Sertraline Hydrochlo fate; Phencarbamide: Poldine Methylsulfate; Proalurnide; ride; Sibutramine Hydrochloride; Sulpiride: Suritozole; Propantheline Bromide: Propenzolate Hydrochloride; Sco Tametraline Hydrochloride; Tampramine Fumarate; Tan polamine Hydrobromide: Tematropium Methylsulfate; 30 damine Hydrochloride; Thiazesim Hydrochloride; Thozali Tiquinamide Hydrochloride; Tofenacin Hydrochloride: none; Tomoxetine Hydrochloride; Trazodone Hydrochloride; Toquizine: Triampyzine Sulfate; Trihexyphenidyl Hydro Trebenzomine Hydrochloride; Trimipramine; Trimipramine chloride; Tropicamide. Maleate; Venlafaxine Hydrochloride; Viloxazine Hydrochlo Anticoagulant: Ancrod; Anticoagulant Citrate Dextrose ride; Zimeldine Hydrochloride; Zometapine. Solution; Anticoagulant Citrate Phosphate Dextrose Adenine 35 Antidiabetic: Acetohexamide; Buformin; Butoxamine Solution; Anticoagulant Citrate Phosphate Dextrose Solu Hydrochloride; Camiglibose; Chlorpropamide; Ciglitazone: tion; Anticoagulant Heparin Solution; Anticoagulant Sodium Englitazone Sodium: Etoformin Hydrochloride; Gliamilide; Citrate Solution; Ardeparin Sodium; Bivalirudin; Bromindi Glibornuride; Glicetanile Sodium; Gliflumide; Glipizide: one; Dalteparin Sodium; Desirudin; Dicumarol; Heparin Cal Glucagon; Glyburide; Glyhexamide: Glymidine Sodium; cium; Heparin Sodium; Lyapolate Sodium; Nafamostat 40 Glyoctamide; Glyparamide; Insulin; Insulin, Dalanated; Mesylate; Phenprocoumon; Tinzaparin Sodium; Warfarin Insulin Human; Insulin Human, Isophane; Insulin Human Sodium. Zinc, Insulin Human Zinc, Extended; Insulin, Isophane; Insu Anticoccidal: Maduramicin. lin Lispro: Insulin, Neutral; Insulin Zinc; Insulin Zinc, Anticonvulsant: Albutoin: Ameltolide; Atolide; Buramate; Extended; Insulin Zinc, Prompt; Linogliride; Linogliride Carbamazepine; Cinromide; Citenamide; Clonazepam, 45 Fumarate; Metformin; Methyl Palmoxirate; Palmoxirate Cyheptamide: Dezinamide: Dimethadione; Divalproex Sodium; Pioglitazone Hydrochloride; Pirogliride Tartrate; Sodium: Eterobarb; Ethosuximide; Ethotoin: Flurazepam Proinsulin Human; Seglitide Acetate; Tolazamide; Tolbuta Hydrochloride: Fluzinamide; Fosphenyloin Sodium; Gabap mide; Tolpyrramide; TroglitaZone; Zopolrestat. entin; Ilepcimide; Lamotrigine; Magnesium Sulfate; Mephe Antidiarrheal: Rolgamidine, Diphenoxylate hydrochloride nyloin; Mephobarbital; Methetoin: MethSuximide: Milace 50 (Lomotil), Metronidazole (Flagyl), Methylprednisolone mide Hydrochloride; Nabazenil; Nafimidone Hydrochloride; (Medrol), Sulfasalazine (AZulfidine). Nitrazepam; Phenacemide; Phenobarbital; Phenobarbital Antidiuretic: Argipressin Tannate; Desmopressin Acetate; Sodium; Phensuximide; Phenyloin; Phenyloin Sodium; Lypressin. Primidone; Progabide; Ralitoline: Remacemide Hydrochlo Antidote: Dimercaprol; Edrophonium Chloride; Fomepi ride; Ropizine; Sabeluzole; Stiripentol; Sulthiame: Thiopen 55 Zole; Leucovorin Calcium; Levoleucovorin Calcium; Meth tal Sodium; Tiletamine Hydrochloride; Topiramate; Tri ylene Blue: Protamine Sulfate. methadione; Valproate Sodium; Valproic Acid; Vigabatrin; Antidyskinetic: Selegiline Hydrochloride. Zoniclezole Hydrochloride; Zonisamide. Anti-emetic: Alosetron Hydrochloride: Batanopride Antidepressant: Adatanserin Hydrochloride; Adinazolam; Hydrochloride: Bemesetron; Benzquinamide: Chlorprom Adinazolam Mesylate; Alaproclate; Aletamine Hydrochlo 60 azine; Chlorpromazine Hydrochloride; Clebopride: Cycliz ride; Amedalin Hydrochloride; Amitriptyline Hydrochloride; ine Hydrochloride; Dimenhydrinate; Diphenidol; Diphenidol Amoxapine: Aptazapine Maleate; AZaloxan Fumarate; Hydrochloride; Diphenidol Pamoate; Dolasetron Mesylate: Azepindole: Azipramine Hydrochloride; Bipenamol Hydro Domperidone; Dronabinol; Fludorex: Flumeridone: chloride; Bupropion Hydrochloride; Butacetin; Butriptyline Galdansetron Hydrochloride; Granisetron; Granisetron Hydrochloride; Caroxazone; Cartazolate: Ciclazindol; 65 Hydrochloride: Lurosetron Mesylate; Meclizine Hydrochlo Cidoxepin Hydrochloride: Cilobamine Mesylate; Clodazon ride; Metoclopramide Hydrochloride; Metopimazine; Hydrochloride; Clomipramine Hydrochloride; Cotinine Ondansetron Hydrochloride; Pancopride; Prochlorperazine: US 8,314,077 B2 29 30 Prochlorperazine Edisylate: Prochlorperazine Maleate; Antihypertensive: Alflizosin Hydrochloride; Alipamide: Promethazine Hydrochloride; Thiethylperazine. Thiethylp Althiazide; Amiquinsin Hydrochloride; Amlodipine Besy erazine Malate: Thiethylperazine Maleate; Trimethobenza late: Amlodipine Maleate; Anaritide Acetate; Atiprosin Male mide Hydrochloride; Zacopride Hydrochloride. ate; Belfosdil; Bemitradine; Bendacalol Mesylate; Bendrof Anti-epileptic: Felbamate; Loreclezole; Tolgabide. lumethiazide; Benzthiazide. Betaxolol Hydrochloride: Anti-estrogen: Clometherone; Delmadinone Acetate; Bethanidine Sulfate; Bevantolol Hydrochloride; Biclodil Nafoxidine Hydrochloride: Nitromifene Citrate; Raloxifene Hydrochloride; Bisoprolol; Bisoprolol Fumarate; Bucindolol Hydrochloride; Tamoxifen Citrate; Toremifene Citrate; Tri Hydrochloride; Bupicomide: Buthiazide; Candoxatril; Can oxifene Mesylate. doxatrilat; Captopril; Carvedilol; Ceronapril; Chlorothiazide 10 Sodium: Cicletanine: Cilazapril; Clonidine; Clonidine Antifibrinolytic: Nafamostat Mesylate. Hydrochloride; Clopamide: Cyclopenthiazide: Cyclothiaz Antifungal: Acrisorcin; Ambruticin; Amphotericin B; AZa ide: Darodipine; Debrisoquin Sulfate; Delapril Hydrochlo conazole; AZaserine; Basifungin: Bifonazole; Biphenamine ride; Diapamide; Diazoxide; Dilevalol Hydrochloride; Dilt Hydrochloride; Bispyrithione Magsulfex; Butoconazole iazem Malate; Ditekiren: Doxazosin Mesylate: Ecadotril; Nitrate; Calcium Undecylenate; Candicidin; Carbol-Fuchsin; 15 Enalapril Maleate; Enalaprilat; Enalkiren: Endralazine Chlordantoin: Ciclopirox: Ciclopirox Olamine: Cilofungin: Mesylate: Epithiazide: Eprosartan; Eprosartan Mesylate: Cisconazole; Clotrimazole; Cuprimyxin, Denofungin; Dipy Fenoldopam Mesylate: Flavodilol Maleate; Flordipine; rithione; Doconazole; Econazole; Econazole Nitrate; Enil Flosequinan; Fosinopril Sodium; Fosinoprilat; Guanabenz; conazole; Ethonam Nitrate: Fenticonazole Nitrate: Filipin; Guanabenz, Acetate; Guanacline Sulfate; Guanadrel Sulfate; Fluconazole: Flucytosine; Fungimycin; Griseofulvin; Hamy Guancydine; Guanethidine Monosulfate; Guanethidine Sul cin; Isoconazole; Itraconazole; Kalafungin; Ketoconazole; fate; Guanfacine Hydrochloride; Guanisoquin Sulfate; Gua Lomofungin; Lydimycin; Mepartricin; Miconazole; Micona noclor Sulfate; Guanoctine Hydrochloride; Guanoxabenz; Zole Nitrate; Monensin; Monensin Sodium; Naftifine Hydro Guanoxan Sulfate; Guanoxyfen Sulfate; Hydralazine Hydro chloride; Neomycin Undecylenate; Nifuratel; Nifurmerone: chloride; Hydralazine Polistirex; Hydroflumethiazide; Inda Nitralamine Hydrochloride; Nystatin; Octanoic Acid; 25 crinone; Indapamide; Indolapril Hydrochloride; Indoramin; Orconazole Nitrate; Oxiconazole Nitrate; Oxifungin Hydro Indoramin Hydrochloride; Indorenate Hydrochloride: Laci chloride; Parconazole Hydrochloride; Partricin; Potassium dipine; Leniquinsin; Levcromakalim; Lisinopril; Lofexidine Iodide: Proclonol; Pyrithione Zinc: Pyrrolnitrin; Rutanycin; Hydrochloride; Losartan Potassium; Losulazine Hydrochlo Sanguinarium Chloride; Saperconazole; Scopafungin: Sele ride; Mebutamate; Mecamylamine Hydrochloride; Medrox nium Sulfide: Sinefungin; Sulconazole Nitrate; Terbinafine; 30 alol; Medroxalol Hydrochloride; Methalthiazide; Methy Terconazole; Thiram; Ticlatone; Tioconazole; Tolciclate: clothiazide; Methyldopa; Methyldopate Hydrochloride: Tolindate; Tolnaftate; Triacetin: Triafungin: Undecylenic Metipranolol; Metolazone: Metoprolol Fumarate; Meto Acid; Viridofulvin; Zinc Undecylenate; Zinoconazole prolol Succinate; Metyrosine; Minoxidil; Monatepil Male Hydrochloride. ate; Muzolimine; Nebivolol; Nitrendipine; Oformine: Par Antiglaucoma agent: AlprenoXime Hydrochloride; Col 35 gyline Hydrochloride; Pazoxide: Pelanserin Hydrochloride: forsin; Dapiprazole Hydrochloride; Dipivefrin Hydrochlo Perindopril Erbumine; Phenoxybenzamine Hydrochloride: ride; Naboctate Hydrochloride; Pilocarpine: Pimabine. Pinacidil: Pivopril; Polythiazide; Prazosin Hydrochloride: Antihemophilic: Antihemophilic Factor. Primidolol; Prizidilol Hydrochloride: Quinapril Hydrochlo Antihemorrhagic: Poliglusam. ride; Quinaprilat; Quinazosin Hydrochloride: Quinelorane Antihistaminic: Acrivastine; Antazoline Phosphate: 40 Hydrochloride: Quinpirole Hydrochloride: Quinuclium Bro Astemizole; AZatadine Maleate; Barmastine; Bromodiphen mide: Ramipril; Rauwolfia Serpentina; Reserpine; Saprisar hydramine Hydrochloride; Brompheniramine Maleate; tan Potassium; Saralasin Acetate: Sodium Nitroprusside; Sul Carbinoxamine Maleate; Cetirizine Hydrochloride; Chlor finalol Hydrochloride: Tasosartan; Teludipine pheniramine Maleate; Chlorpheniramine Polistirex: Cin Hydrochloride; Temocapril Hydrochloride; Terazosin narizine; Clemastine; Clemastine Fumarate; Closiramine 45 Hydrochloride; Terlakiren; Tiamenidine; Tiamenidine Aceturate; Cycliramine Maleate, Cyclizine; Cyproheptadine Hydrochloride; Ticrynafen; Tinabinol; TiodaZosin; Tipen Hydrochloride; Dexbrompheniramine Maleate; Dexchlor tosin Hydrochloride; Trichlormethiazide; Trimazosin Hydro pheniramine Maleate; Dimethindene Maleate; Diphenhy chloride; Trimethaphan Camsylate; Trimoxamine Hydro dramine Citrate; Diphenhydramine Hydrochloride; Doras chloride; Tripamide; Xipamide; Zankiren Hydrochloride: tine Hydrochloride; Doxylamine Succinate; Ebastine; 50 Zofenoprilat Arginine. Levocabastine Hydrochloride; Loratadine: Mianserin Hydro Antihypotensive: Ciclafrine Hydrochloride; Midodrine chloride: Noberastine; Orphenadrine Citrate; Pyrabrom: Hydrochloride. Pyrilamine Maleate: Pyroxamine Maleate; Rocastine Hydro Anti-infective: Difloxacin Hydrochloride. Lauryl Iso chloride; Rotoxamine; Tazifylline Hydrochloride: Temelas quinolinium Bromide; Moxalactam Disodium; Omidazole; tine; Terfenadine; Tripelennamine Citrate; Tripelennamine 55 Pentisomicin; Sarafloxacin Hydrochloride; Protease inhibi Hydrochloride; Triprolidine Hydrochloride; Zolamine tors of HIV and other retroviruses: Integrase Inhibitors of Hydrochloride HIV and other retroviruses; Cefaclor (Ceclor); Acyclovir Antihyperlipidemic: Cholestyramine Resin; Clofibrate; (Zovirax); Norfloxacin (Noroxin); Cefoxitin (Mefoxin); Colestipol Hydrochloride: Crilvastatin; Dalvastatin: Dex Cefuroxime axetil (Ceftin): Ciprofloxacin (Cipro). trothyroxine Sodium; Fluvastatin Sodium; Gemfibrozil; Lec 60 Anti-infective, topical: Alcohol; Aminacrine Hydrochlo imibide; Lovastatin; Niacin; Pravastatin Sodium; Probucol; ride; Benzethonium Chloride; Bithionolate Sodium; Bro Simvastatin: Tiqueside; Xenbucin. mchlorenone; Carbamide Peroxide; Cetalkonium Chloride; Antihyperlipoproteinemic: Acifran; Beloxamide: Bezafi Cetylpyridinium Chloride: Chlorhexidine Hydrochloride: brate; Boxidine; Butoxamine Hydrochloride; Cetaben Clioquinol; Domiphen Bromide: Fenticlor: Fludazonium Sodium: Ciprofibrate; Gemcadiol; Halofenate: Lifibrate; 65 Chloride; Fuchsin, Basic; Furazolidone; Gentian Violet; Meglutol; Nafenopin: Pimetime Hydrochloride: Theofibrate; Halduinols: Hexachlorophene: Hydrogen Peroxide: Ich Tilbric Acid; Treloxinate. thammol: Imidecyl Iodine: Iodine: Isopropyl Alcohol US 8,314,077 B2 31 32 Mafenide Acetate; Meralein Sodium; Mercufenol Chloride; Antinauseant: Buclizine Hydrochloride; Cyclizine Lac Mercury, Ammoniated; Methylbenzethonium Chloride: tate; Naboctate Hydrochloride Nitrofurazone: Nitromersol; Octenidine Hydrochloride; Antineoplastic: Acivicin, Aclarubicin; Acodazole Hydro Oxychlorosene: Oxychlorosene Sodium; Parachlorophenol, chloride; Acronine; Adozelesin; Aldesleukin; Altretamine; Camphorated; Potassium Permanganate; Povidone-Iodine: Ambomycin; Ametantrone Acetate; Aminoglutethimide; Sepazonium Chloride: Silver Nitrate; Sulfadiazine, Silver; Amsacrine; AnastroZole; Anthramycin; Asparaginase; Symclosene: Thimerfonate Sodium; Thimerosal: Troclosene Asperlin; AZacitidine; AZetepa, Azotomycin; Batimastat; Potassium. Benzodepa; Bicalutamide: Bisantrene Hydrochloride; Bisna Anti-inflammatory: Alclofenac; Alclometasone Dipropi fide Dimesylate; Bizelesin; Bleomycin Sulfate; Brequinar onate; Algestone Acetonide; Alpha Amylase; Amcinafal; 10 Sodium; Bropirimine; Busulfan; Cactinomycin; Calusterone: Amcinafide: Amfenac Sodium; Amiprilose Hydrochloride; Caracemide: Carbetimer; Carboplatin: Carmustine; Carubi Anakinra, Anirolac, AnitraZafen; ApaZone; BalsalaZide cin Hydrochloride; Carzelesin; Cedefingol: Chlorambucil; Disodium; Bendazac. Benoxaprofen; Benzydamine Hydro Cirolemycin; Cisplatin: Cladribine: Crisinatol Mesylate: chloride; Bromelains; Broperamole; Budesonide; Carprofen; Cyclophosphamide; Cytarabine; Dacarbazine; Dactinomy Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate: 15 cin; Daunorubicin Hydrochloride; Decitabine; Dexormapl Clobetasone Butyrate; Clopirac; Cloticasone Propionate: atin, DeZaguanine; DeZaguanine Mesylate; Diaziquone; Cormethasone Acetate; Cortodoxone; Deflazacort; Des Docetaxel; Doxorubicin; Doxorubicin Hydrochloride: onide; DeSoximetasone; Dexamethasone Dipropionate; Droloxifene; Droloxifene Citrate; Dromostanolone Propi Diclofenac Potassium; Diclofenac Sodium; Diflorasone onate; Duazomycin; Edatrexate. Eflornithine Hydrochloride: Diacetate; Diflumidone Sodium; Diflunisal; Difluprednate: Elsamitrucin; Enloplatin: Enpromate: Epipropidine: Epirubi Diftalone; Dimethyl Sulfoxide; Drocinonide; Endrysone: cin Hydrochloride; Erbulozole; Esorubicin Hydrochloride: Enlimomab: Enolicam Sodium; Epirizole; Etodolac.; Etofe Estramustine; Estramustine Phosphate Sodium; Etanidazole; namate; Felbinac; Fenamole: Fenbufen, Fenclofenac; Fen Ethiodized Oil I 131; Etoposide; Etoposide Phosphate; Eto clorac; Fendosal: Fenpipalone: Fentiazac.; Flazalone: Fluaza prine: Fadrozole Hydrochloride; Fazarabine: Fenretinide; cort; Flufenamic Acid, Flumizole; Flunisolide Acetate; 25 Floxuridine: Fludarabine Phosphate: Fluorouracil; Flurocit Flunixin: Flunixin Meglumine: Fluocortin Butyl; Fluo abine; Fosquidone; Fostriecin Sodium; Gemcitabine; Gem rometholone Acetate; FluguaZone: Flurbiprofen; Fluretofen; citabine Hydrochloride; Gold Au 198: Hydroxyurea; Idaru Fluticasone Propionate; Furaprofen; Furobufen; Halcinon bicin Hydrochloride; Ifosfamide; Ilmofosine; Interferon ide; Halobetasol Propionate; Halopredone Acetate; Ibufenac: Alfa-2a: Interferon Alfa-2b: Interferon Alfa-n1; Interferon Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol: 30 Alfa-n3; Interferon Beta-I a: Interferon Gamma-Ib; I propl Ilonidap; Indomethacin; Indomethacin Sodium; Indoprofen; atin; Irinotecan Hydrochloride; Lanreotide Acetate; Letro Indoxole: Intrazole; Isoflupredone Acetate; Isoxepac: Isoxi Zole; Leuprolide Acetate; Liarozole Hydrochloride; Lometr cam; Ketoprofen; Lofemizole Hydrochloride; Lomoxicam; exol Sodium; Lomustine; Losoxantrone Hydrochloride: Loteprednol Etabonate; Meclofenamate Sodium; Meclofe Masoprocol; Maytansine: Mechlorethamine Hydrochloride: namic Acid; Meclorisone Dibutyrate; Mefenamic Acid; 35 Megestrol Acetate; Melengestrol Acetate; Melphalan; Mesalamine: MeseclaZone; Methylprednisolone Suleptan Menogaril; Mercaptopurine; Methotrexate; Methotrexate ate; Morniflumate; Nabumetone; Naproxen; Naproxen Sodium; Metoprine; Meturedepa; Mitindomide; Mitocarcin; Sodium; Naproxol; Nimazone; Olsalazine Sodium; Orgot Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; ein; Orpanoxin: Oxaprozin: Oxyphenbutazone; Paranyline Mitotane; Mitoxantrone Hydrochloride: Mycophenolic Acid: Hydrochloride; Pentosan Polysulfate Sodium; Phenbutazone 40 Nocodazole; Nogalamycin; Ormaplatin: Oxisuran: Pacli Sodium Glycerate; Pirfenidone: Piroxicam; Piroxicam Cin taxel; Pegaspargase; Peliomycin; Pentamustine; Peplomycin namate; Piroxicarn Olamine: Pirprofen; Prednazate; Prife Sulfate; Perfosfamide; Pipobroman; Piposulfan; PiroX lone: Prodolic Acid; ProquaZone: Proxazole; Proxazole Cit antrone Hydrochloride; Plicamycin; Plomestane: Porfimer rate; Rimexolone; Romazarit; Salcolex; Salnacedin; Sodium; Porfiromycin; Prednimustine: Procarbazine Hydro Salsalate: Sanguinarium Chloride; Seclazone: Sermetacin; 45 chloride; Puromycin; Puromycin Hydrochloride; Pyrazofu Sudoxicam; Sulindac: Suprofen; Talmetacin; Talniflumate; rin; Riboprine; Rogletimide: Safingol: Safingol Hydrochlo Talosalate: Tebufelone; Tenidap: Tenidap Sodium; Tenoxi ride; Semustine; SimtraZene: Sparfosate Sodium; cam; Tesicam, Tesimide; Tetrydamine; Tiopinac Tixocortol Sparsomycin; Spirogermanium Hydrochloride; Spiromus Pivalate: Tolimetin; Tolimetin Sodium; Triclonide; Triflumi tine; Spiroplatin: Streptonigrin: Streptozocin; Strontium date; Zidometacin: Zomepirac Sodium. 50 Chloride Sr89; Sulofenur; Talisomycin; Taxane:Taxoid; Tec Antikeratinizing agent: Doretinel; Linarotene; Pelretin. ogalan Sodium; Tegafur; Teloxantrone Hydrochloride: Antimalarial: Acedapsone; Amodiaquine Hydrochloride; Temoporfin; Teniposide; Teroxirone; Testolactone: Thiami Amquinate; Arteflene; Chloroquine; Chloroquine Hydro prine; Thioguanine: Thiotepa; Tiazofurin; Tirapazamine; chloride; Chloroquine Phosphate: Cycloguanil Pamoate: Topotecan Hydrochloride; Toremifene Citrate; Trestolone Enpiroline Phosphate: Halofantrine Hydrochloride: 55 Acetate; Triciribine Phosphate; Trimetrexate; Trimetrexate Hydroxychloroquine Sulfate; Mefloquine Hydrochloride: Glucuronate; Triptorelin; Tubulozole Hydrochloride; Uracil Menoctone; Mirincamycin Hydrochloride: Primaquine Mustard; Uredepa; Vapreotide: Verteporfin; Vinblastine Sul Phosphate: Pyrimethamine; Quinine Sulfate; Tebuquine. fate; Vincristine Sulfate; Vindesine; Vindesine Sulfate; Vine Antimicrobial: Aztreonam; Chlorhexidine Gluconate: Imi pidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; durea; Lycetamine; Nibroxane: PiraZmonam Sodium; Propi 60 Vinorelbine Tartrate; Vinrosidine Sulfate; Vinzolidine Sul onic Acid; Pyrithione Sodium; Sanguinarium Chloride; Tige fate; Vorozole; Zeniplatin: Zinostatin: Zorubicin Hydrochlo monam Dicholine. ride. Antimigraine: Dolasetron Mesylate: Naratriptan Hydro Other anti-neoplastic compounds include: 20-epi-1,25 chloride: Sergolexole Maleate; Sumatriptan Succinate: dihydroxyvitamin D3:5-ethynyluracil; abiraterone; aclarubi Zatosetron Maleate. 65 cin; acylfulvene; adecypenol; adoZelesin; aldesleukin; ALL Antimitotic: Podofilox. TKantagonists; altretamine; ambamustine; amidox; amifos Antimycotic: Amorolfine. tine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; US 8,314,077 B2 33 34 anastroZole; andrographolide, angiogenesis inhibitors; my caperoxide B; mycobacterial cell wall extract; myriapor antagonist D; antagonist G. antarelix; anti-dorsalizing mor one; N-acetyldinaline; N-substituted benzamides; nafarelin; phogenetic protein-1, antiandrogen, prostatic carcinoma; nagrestip; naloxone-pentazocine; napavin; naphterpin, nar antiestrogen; antineoplaston; antisense oligonucleotides; tograstim; nedaplatin: nemorubicin; neridronic acid; neutral aphidicolin glycinate; apoptosis gene modulators; apoptosis endopeptidase; nilutamide; nisarmycin; nitric oxide modula regulators; apurinic acid; ara-CDP-DL-PTBA; arginine tors; nitroxide antioxidant; nitrullyn; O6-benzylguanine; oct deaminase; asulacrine; atamestane; atrimustine; axinastatin reotide; okicenone; oligonucleotides; onapristone; 1; axinastatin 2; axinastatin 3; aZasetron; azatoxin; azaty ondansetron; ondansetron; oracin; oral cytokine inducer, rosine; baccatin III derivatives; balanol; batimastat; BCR/ ormaplatin: osaterone; oxaliplatin, oxaunomycin; paclitaxel ABL antagonists; benzochlorins; benzoylstaurosporine; beta 10 analogues; paclitaxel derivatives; palauamine; palmitoyl lactam derivatives; beta-alethine; betaclamycin B; betulinic rhizoxin; pamidronic acid; panaxytriol; panomifene; para acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinyl bactin; paZelliptine; pegaspargase; peldesine; pentosan spernine; bisnafide; bistratene A: bizelesin; breflate; bropir polysulfate sodium; pentostatin: pentrozole; perflubron; per imine; budotitane; buthionine Sulfoximine; calcipotriol: fosfamide; perillyl alcohol; phenazinomycin; phenylacetate; calphostin C; camptothecin derivatives; canarypox IL-2; 15 phosphatase inhibitors; picibanil; pilocarpine hydrochloride; capecitabine; carboxamide-amino-triazole; carboxyamidot pirarubicin; piritrexim; placetin A; placetin B; plasminogen riazole; CaRest M3; CARN 700; cartilage derived inhibitor; activator inhibitor, platinum complex; platinum compounds; carzelesin; casein kinase inhibitors (ICOS); castanospermine; platinum-triamine complex; porfimer Sodium; porfiromycin; cecropin B; cetrorelix; chlorins; chloroquinoxaline Sulfona propyl bis-acridone; prostaglandin J2, proteasome inhibitors; mide; cicaprost; cis-porphyrin, cladribine; clomifene ana protein A-based immune modulator, protein kinase C inhibi logues; clotrimazole; collismycin A; collismycin B, combre tor, protein kinase C inhibitors, microalgal; protein tyrosine tastatin A4, combretastatin analogue; conagenin: phosphatase inhibitors; purine nucleoside phosphorylase crambescidin 816; crisinatol; cryptophycin 8: cryptophycin A inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemo derivatives; curacin A; cyclopentanthraquinones; cyclo globin polyoxyethylene conjugate; raf antagonists; raltitr platam, cypemycin; cytarabine ocfosfate; cytolytic factor, 25 exed; ramosetron; ras farnesyl protein transferase inhibitors; cytostatin: dacliximab; decitabine; dehydrodidemnin B; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated: deslorelin; dexifosfamide; dexraZOxane; dexVerapamil; rhenium Re 186 etidronate; rhizoxin: ribozymes: RII retina diaziquone; didemnin B; didox; diethylnorspermine; dihy mide; rogletimide; rohitukine; romurtide; roquinimex: dro-5-azacytidine, dihydrotaxol. 9-; dioxamycin; diphenyl rubiginone B1; ruboxyl; safingol: Saintopin; SarCNU; sarco spiromustine; docosanol; dolasetron: doxifluridine; drolox 30 phytol A; SargramoStim; Sdi 1 mimetics; Semustine; senes ifene; dronabinol; duocarmycin SA; ebselen; ecomustine; cence derived inhibitor 1; sense oligonucleotides; signal edelfosine; edrecolomab; efornithine; elemene; emitefur; transduction inhibitors; signal transduction modulators: epirubicin, epristeride; estramustine analogue; estrogen ago single chain antigen binding protein; sizofiran; Sobuzoxane: nists; estrogen antagonists; etanidazole; etoposide phos Sodium borocaptate; sodium phenylacetate; Solverol; phate; exemestane; fadrozole; faZarabine; fenretinide; 35 Somatomedin binding protein; Sonermin; Sparfosic acid; spi filgrastim; finasteride; flavopiridol; flezelastine; fluasterone: camycin D; spiromustine; splenopentin; spongistatin 1: fludarabine; fluorodaunorunicin hydrochloride; forfenimex: squalamine; stem cell inhibitor; stem-cell division inhibitors; formestane; fostriecin, fotemustine; gadolinium texaphyrin, stipiamide; stromelysin inhibitors; sulfinosine; Superactive gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; vasoactive intestinal peptide antagonist; Suradista; Suramin; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; 40 Swainsonine; synthetic glycosaminoglycans; tallimustine; hexamethylene bisacetamide; hypericin; ibandronic acid; tamoxifen methiodide; tauromustine; tazarotene; tecogalan idarubicin; idoxifene; idramantone, ilmofosine; illomastat; Sodium, tegafur, tellurapyrylium; telomerase inhibitors; imidazoacridones; imiquimod; immunostimulant peptides; temoporfin, temozolomide; teniposide; tetrachlorodecaox insulin-like growth factor-1 receptor inhibitor; interferon ide; tetrazomine; thaliblastine; thalidomide; thiocoraline; agonists; interferons; interleukins; iobenguane; iododoxoru 45 thrombopoietin; thrombopoietin mimetic; thymalfasin; thy bicin; ipomeanol, 4-, irinotecan; iroplact; irsogladine; mopoietin receptoragonist; thymotrinan; thyroid stimulating isobengaZole; isohomohalicondrin B; itasetron, jasplakino hormone; tin ethyl etiopurpurin; tirapazamine; titanocene lide; kahalalide F. lamellarin-N triacetate; lanreotide; leina dichloride; topotecan; top sentin; toremifene; totipotent stem mycin; lenograstim; lentinan Sulfate; leptolstatin; letrozole; cell factor; translation inhibitors; tretinoin; triacetyluridine: leukemia inhibiting factor; leukocyte alpha interferQn; leu 50 triciribine; trimetrexate; triptorelin; tropisetron; turosteride; prolide--estrogen-progesterone; leuprorelin; levamisole; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors: ube liarozole; linear polyamine analogue; lipophilic disaccharide nimex: urogenital sinus-derived growth inhibitory factor; peptide; lipophilic platinum compounds; lissoclinamide 7: urokinase receptor antagonists; vapreotide; variolin B; vector lobaplatin, lombricine; lometrexol; lonidamine; losox system, erythrocyte gene therapy; Velaresol; Veramine; Ver antrone; lovastatin; loxoribine; lurtotecan; lutetium texaphy 55 dins; verteporfin; vinorelbine; vinxaltine; vitaxin; Vorozole; rin; lysofylline; lytic peptides; maitansine; mannostatin A; Zanoterone; Zeniplatin: Zilascorb; Zinostatin stimalamer. marimastat; masoprocol; maspin; matrilysin inhibitors; Anti-cancer Supplementary Potentiating Agents: Tricyclic matrix metalloproteinase inhibitors; menogaril; merbarone; anti-depressant drugs (e.g., imipramine, desipramine, amit meterelin; methioninase; metoclopramide: MIF inhibitor; ryptyline, clomipramine, trimipramine, doxepin, nortrip mifepristone; miltefosine; mirimostim; mismatched double 60 tyline, protriptyline, amoxapine and maprotiline); non-tricy Stranded RNA, mitoguaZone; mitolactol; mitomycin ana clic anti-depressant drugs (e.g., Sertraline, traZodone and logues; mitonafide; mitotoxin fibroblast growth factor-sa citalopram); Ca" antagonists (e.g., Verapamil, nifedipine, porin; mitoxantrone; mofarotene; molgramostim; mono nitrendipine and caroverine); Calmodulin inhibitors (e.g., clonal antibody, human chorionic gonadotrophin; prenylamine, trifluoroperazine and clomipramine); Amphot monophosphoryl lipid A+myobacterium cell wall sk; mopi 65 ericin B; Triparanol analogues (e.g., tamoxifen); antiarrhyth damol, multiple drug resistance gene inhibitor, multiple mic drugs (e.g., quinidine); antihypertensive drugs (e.g., tumor Suppressor 1-based therapy; mustard anticancer agent; reserpine); Thiol depleters (e.g., buthionine and Sulfoximine) US 8,314,077 B2 35 36 and Multiple Drug Resistance reducing agents such as Trifluperidol; Triflupromazine; Triflupromazine Hydrochlo Cremaphor EL. The compounds of the invention also can be ride; Ziprasidone Hydrochloride. administered with cytokines such as granulocyte colony Antirheumatic: Auranofin, Aurothioglucose: Bindarit; stimulating factor. Lobenzarit Sodium; Phenylbutazone; Pirazolac: Prinomide Antineutropenic: Filgrastim; Lenograstim; Molgra Tromethamine; Seprilose. mostim; Regramostim; Sargramostim. Antischistosomal: Becanthone Hydrochloride; Hycan Antiobsessional agent: Fluvoxamine Maleate. thone; Lucanthone Hydrochloride; Niridazole; Oxarn Antiparasitic: Abamectin; ClorSulon; Ivennectin. niquine; Pararosaniline Pamoate; Teroxalene Hydrochloride. Antiparkinsonian: Benztropine Mesylate; Biperiden; Antiseborrheic: Chloroxime; Piroctone; Piroctone Ola Biperiden Hydrochloride; Biperiden Lactate; Carmantadine: 10 mine; Resorcinol Monoacetate. Ciladopa Hydrochloride; Dopamantine; Ethopropazine Antisecretory: Arbaprostil; Deprostil: Fenoctimine Sul fate; Octreotide; Octreotide Acetate; Omeprazole Sodium; Hydrochloride: Lazabemide; Levodopa; Lometraline Hydro Rioprostil; Trimoprostil. chloride; Mofegiline Hydrochloride: Naxagolide Hydrochlo Antispasmodic: Stilonium Iodide; Tizanidine Hydrochlo ride; Pareptide Sulfate; Procyclidine Hydrochloride; 15 ride. Quinelorane Hydrochloride; Ropinirole Hydrochloride: Sel Antithrombotic: Anagrelide Hydrochloride; Bivalirudin; egiline Hydrochloride; Tolcapone: Trihexyphenidyl Hydro Dalteparin Sodium; Danaparoid Sodium; Dazoxiben Hydro chloride. chloride: Efegatran Sulfate; Enoxaparin Sodium: Ifetroban: Antiperistaltic: Difenoximide Hydrochloride; Difenoxin; Ifetroban Sodium; Tinzaparin Sodium; Trifenagrel. Diphenoxylate Hydrochloride; Fluperamide: Lidamidine Antitussive: Benzonatate; Butamirate Citrate; Chlophedi Hydrochloride; Loperamide Hydrochloride: Malethamer; anol Hydrochloride: Codeine Polistirex: Codoxime; Dex Nufenoxole; Paregoric. tromethorphan: Dextromethorphan Hydrobromide: Dex Antipneumocystic: Atovaquone. tromethorphan Polistirex: Ethyl Dibunate; Guaiapate: Antiproliferative agent: Piritrexim Isethionate. Hydrocodone Bitartrate; Hydrocodone Polistirex; Levopro Antiprostatic hypertrophy: Sitogluside. 25 poxyphene Napsylate: Noscapine; Pemerid Nitrate; Antiprotozoal: Amodiaquine; AZanidazole; Bamidazole; Pipazethate: Suxemerid Sulfate. Camidazole; Chlortetracycline Bisulfate; Chlortetracycline Anti-ulcerative: Aceglutamide Aluminum; Cadexomer Hydrochloride: Flubendazole: Flunidazole; Halofuginone Iodine; Cetraxate Hydrochloride; Enisoprost: Isotiquimide: Hydrobromide: Imidocarb Hydrochloride; Ipronidazole; Lansoprazole; Lavoltidine Succinate; Misoprostol; Nizati Metronidazole; Misonidazole; Moxinidazole; Nitarsone; Par 30 dine; Nolinium Bromide: Pantoprazole; Pifamine: Piren tricin; Puromycin; Puromycin Hydrochloride; Ronidazole; Zepine Hydrochloride; Rabeprazole Sodium; Remiprostol; Sulnidazole; Tinidazole. Roxatidine Acetate Hydrochloride: Sucralfate: Sucrosofate Antipruritic: Cyproheptadine Hydrochloride Methdila Potassium; Tolimidone. zine; Methdilazine Hydrochloride; Trimeprazine Tartrate. Anti-urolithic: Cysteamine: Cysteamine Hydrochloride; Antipsoriatic: Acitretin: Anthralin; Azaribine; Calcipot 35 Tricitrates riene; Cycloheximide: Enazadrem Phosphate; Etretinate; Antiviral: Acemannan; Acyclovir, Acyclovir Sodium; LiaroZole Fumarate; Lonapalene; Tepoxalin. Adefovir; Alovudine; Alvircept Sudotox: Amantadine Antipsychotic: Acetophenazine Maleate; Alentemol Hydrochloride; Aranotin: Arildone: Atevirdine Mesylate: Hydrobromide: Alpertine; Azaperone: Batelapine Maleate; Avridine; Cidofovir, Cipamfylline; Cytarabine Hydrochlo Benperidol; BenZindopyrine Hydrochloride; Brofoxine; Bro 40 ride; Delavirdine Mesylate: Desciclovir; Didanosine; Disox mperidol; Bromperidol Decanoate: Butaclamol Hydrochlo aril: Edoxudine; Enviradene; Enviroxime; Famciclovir, ride; Butaperazine; Butaperazine Maleate; Carphenazine Famotine Hydrochloride; Fiacitabine; Fialuridine; Fosari Maleate; Carvotroline Hydrochloride; Chlorpromazine: late; Foscamet Sodium; Fosfonet Sodium; Ganciclovir, Gan Chlorpromazine Hydrochloride; Chlorprothixene; Cin ciclovir Sodium; Idoxuridine; Kethoxal; Lamivudine; Lobu perene; Cintriamide: Clomacran Phosphate: Clopenthixol; 45 cavir; Memotine Hydrochloride; Methisazone; Nevirapine; Clopimozide; Clopipazan Mesylate; Cloroperone Hydro Penciclovir; Pirodavir, Ribavirin; Rimantadine Hydrochlo chloride; Clothiapine; Clothixamide Maleate; Clozapine; ride; Saquinavir Mesylate: Somantadine Hydrochloride; Cyclophenazine Hydrochloride; Droperidol; Etazolate Sorivudine: Statolon; Stavudine; Tilorone Hydrochloride: Hydrochloride: Fenimide: Flucindole: Flumezapine; Trifluridine; Valacyclovir Hydrochloride: Vidarabine; Fluphenazine Decanoate: Fluphenazine Enanthate: 50 Vidarabine Phosphate; Vidarabine Sodium Phosphate: Fluphenazine Hydrochloride: Fluspiperone: Fluspirilene: Viroxime; Zalcitabine; Zidovudine; Zinviroxime. Flutroline; Gevotroline Hydrochloride; Halopemide: Halo Appetite suppressant: Dexfenfluramine Hydrochloride; peridol; Haloperidol Decanoate; Iloperidone: Imidoline Phendimetrazine Tartrate; Phentermine Hydrochloride. Hydrochloride; Lenperone; Mazapertine Succinate: Benign prostatic hyperplasia therapy agent: Tamsulosin Mesoridazine; Mesoridazine Besylate; Metiapine; Milenper 55 Hydrochloride. one; Milipertine: Molindone Hydrochloride; Naranol Hydro Blood glucose regulators: Human insulin; Glucagon; chloride: Neflumozide Hydrochloride; Ocaperidone; Olanza Tolazamide; Tolbutamide; Chloropropamide: Acetohexam pine; Oxiperomide; Penfluridol; Pentiapine Maleate; ide and Glipizide. Perphenazine: Pimozide; Pinoxepin Hydrochloride; Pipam Bone resorption inhibitor: Alendronate Sodium: Etidr perone; Piperacetazine; Pipotiazine Palmitate; Piquindone 60 onate Disodium; Pamidronate Disodium. Hydrochloride; Prochlorperazine Edisylate: Prochlorpera Bronchodilator: Albuterol; Albuterol Sulfate; AZanator zine Maleate; Promazine Hydrochloride; Remoxipride: Maleate; Bamifylline Hydrochloride; Bitolterol Mesylate: Remoxipride Hydrochloride; Rimcazole Hydrochloride: Butaprost; Carbuterol Hydrochloride; Clorprenaline Hydro Seperidol Hydrochloride: Sertindole: Setoperone; Spiper chloride; Colterol Mesylate; Doxaprost; Doxofylline: one. Thioridazine: Thioridazine Hydrochloride; Thiothixene; 65 Dyphylline; Enprofylline; Ephedrine; Ephedrine Hydrochlo Thiothixene Hydrochloride; Tioperidone Hydrochloride: ride; Fenoterol: Fenprinast Hydrochloride; Guaithylline; Tiospirone Hydrochloride; Trifluoperazine Hydrochloride: Hexoprenaline Sulfate; Hoquizil Hydrochloride; Ipratropium US 8,314,077 B2 37 38 Bromide: Isoetharine: Isoetharine Hydrochloride: Isoet Depressant: Omeprazole. harine Mesylate: Isoproterenol Hydrochloride: Isoproterenol Diagnostic aid: Aminohippurate Sodium; Anazolene Sulfate; Metaproterenol Polistirex: Metaproterenol Sulfate; Sodium; Arclofenin; Arginine; Bentiromide: Benzylpenicil Nisbuterol Mesylate Oxtriphylline: Picumeterol Fumarate; loyl Polylysine; Butedronate Tetrasodium: Butilfenin; Coc Piquizil Hydrochloride: Pirbuterol Acetate; Pirbuterol cidioidin; Corticorelin Ovine Triflutate; Corticotropin, Hydrochloride; Procaterol Hydrochloride; Pseudoephedrine Repository; Corticotropin Zinc Hydroxide; Diatrizoate Sulfate; QuaZodine; Quinterenol Sulfate; Racepinephrine; Meglumine; Diatrizoate Sodium; Diatrizoic Acid; Diphtheria Racepinephrine Hydrochloride; Reproterol Hydrochloride: Toxin for Schick Test: Disofenin; Edrophonium Chloride: Rimiterol Hydrobromide: Salmeterol: Salmeterol Xinafoate: Ethiodized Oil: Etifenin; Exametazime; Ferristenc; Feru Soterenol Hydrochloride; Sulfonterol Hydrochloride: Sulox 10 moxides; Ferumoxsil; Fluorescein; Fluorescein Sodium; ifen Oxalate; Terbutaline Sulfate; Theophylline: Xanoxate Gadobenate Dimeglumine; Gadoteridol: Gadodiamide: Sodium; Zindotrine; Zinterol Hydrochloride. Gadopentetate Dimegiumine; Gadoversetamide; Histoplas Carbonic anhydrase inhibitor: Acetazolamide: Acetazola min: Impromidine Hydrochloride; Indigotindisulfonate mide Sodium; Dichlorphenamide; Dorzolamide Hydrochlo Sodium; Indocyanine Green: Iobenguane Sulfate I 123; ride; Methazolamide: Sezolamide Hydrochloride. 15 Iobenzamic Acid, Iocarmate Meglumine; Iocarmic Acid, Ioc Cardiac depressant: Acecainide Hydrochloride: Acetyl etamic Acid, Iodamide: Iodamide Megilumine; Iodipamide choline Chloride; Actisomide; Adenosine; Amiodarone; Meglumine; Iodixanol; Iodoxamate Meglumine: Iodoxamic Aprindine: Aprindine Hydrochloride; Artilide Fumarate; Acid, Ioglicic Acid, Ioglucol, Ioglucomide: Ioglycamic Acid; Azimilide Dihydrochloride; Bidisomide; Bucainide Maleate; Iogulamide: Iohexol; Iomeprol; Iopamidol; Iopanoic Acid; Bucromarone; Butoprozine Hydrochloride: Capobenate Iopentol, Iophendylate; profenin, Iopronic Acid, Ioprocemic Sodium; Capobenic Acid; Cifenline; Cifernline Succinate; Acid, Iopydol; Iopy done; Iosefamic Acid, Ioseric Acid, IoSu Clofilium Phosphate: Disobutamide; Disopyramide: Disopy lamide Meglumine: Iosumetic Acid; Iotasul; Iotetric Acid: ramide Phosphate; Dofetilide; Drobuline; Edifolone Acetate; Iothalamate Meglumine; Iothalamate Sodium; Iothalamic Emilium Tosylate: Encainide Hydrochloride; Flecainide Acid; Iotrolan; Iotroxic Acid: Ioversol; Ioxaglate Meglu Acetate; Ibutilide Fumarate; Indecainide Hydrochloride; Ipa 25 mine; IoXagiate Sodium; Ioxaglic Acid, Ioxilan, Ioxotrizoic Zilide Fumarate; Lorajmine Hydrochloride; Lorcainide Acid; Ipodate Calcium; Ipodate Sodium; Isosulfan Blue; Hydrochloride; Meobentine Sulfate; Mexiletine Hydrochlo Leukocyte Typing Serum; Lidofenin; Mebrofenin: Meglu ride; Modecainide; Moricizine; Oxiramide: Pirmenol Hydro mine; Metrizamide; Metrizoate Sodium; Metyrapone: chloride; Pirolazamide; Pranolium Chloride; Procainamide Metyrapone Tartrate; Mumps Skin Test Antigen; Pentetic Hydrochloride; Propafenone Hydrochloride; Pyrinoline: 30 Acid; Propyliodone; Quinaldine Blue: Schick Test Control; Quindonium Bromide: Quinidine Gluconate; Quinidine Sul Sermorelin Acetate: Sodium Iodide 1123; Sprodiamide: fate; Recainam Hydrochloride: Recainam Tosylate: Risotil Stannous Pyrophosphate: Stannous Sulfur Colloid; Succi ide Hydrochloride; Ropitoin Hydrochloride: Sematilide mer; Teriparatide Acetate; Tetrofosmin. Tolbutamide Hydrochloride; Suricainide Maleate: Tocainide; Tocainide Sodium; Tuberculin; Tyropanoate Sodium; Xylose. Hydrochloride; Transcainide. 35 Diuretic: Ambuphylline; Ambuside; Amiloride Hydro Cardioprotectant: Dexrazoxane: Draflazine. chloride; Azolimine; AZosemide; Brocrinat: Bumetanide; Cardiotonic: Actodigin; Amrinone; Bemoradan; Butopam Chlorothiazide; Chlorthalidone; Clazolimine; Clorexolone; ine; Carbazeran; Carsatirin Succinate; Deslanoside; Digitalis; Ethacrynate Sodium: Ethacrynic Acid; Etozolin; Fen Digitoxin; Digoxin; Dobutamine; Dobutamine Hydrochlo quizone; Furosemide; Hydrochlorothiazide: Isosorbide: ride; Dobutamine Lactobionate; Dobutamine Tartrate; Enoxi 40 Mannitol; Mefruside; Ozolinone; Piretanide; Spiroxasone: mone: ImaZodan Hydrochloride; Indolidan; Isomazole Torsemide; Triamterene; Triflocin, Urea. Hydrochloride; Levdobutamine Lactobionate; Lixazinone Dopaminergic agent: Ibopamine. Sulfate; Medorinone; Milrinone: Pelrinone Hydrochloride: Ectoparasiticide: Nifluridide; Permethrin. Pimobendan; Piroximone; Prinoxodan; Proscillaridin; Emetic: Apomorphine Hydrochloride. Quazinone; Tazolol Hydrochloride: Vesnarinone. 45 Enzyme inhibitor: Acetohydroxamic Acid. Alrestatin Cardiovascular agent: Dopexamine; Dopexamine Hydro Sodium; Aprotinin; Benazepril Hydrochloride; Benazeprilat; chloride. Benurestat; Bromocriptine; Bromocriptine Mesylate: Cilas Choleretic: Dehydrocholic Acid: Fencibutirol; Hymec tatin Sodium; Flurofamide; Lergotrile; Lergotrile Mesylate: romone; Piprozolin; Sincalide; Tocamphyl. Levcycloserine: Libenzapril; Pentopril; Pepstatin: Perin Cholinergic: Aceclidine: Bethanechol Chloride; Carba 50 dopril; Polignate Sodium; Sodium Amylosulfate; Sorbinil; chol; Demecarium Bromide: Dexpanthenol; Echothiophate Spirapril Hydrochloride: Spiraprilat; Taleranol; Teprotide; Iodide: Isoflurophate; Methacholine Chloride; Neostigmine Tolfamide; Zofenopril Calcium. Bromide; Neostigmine Methylsulfate; Physostigmine; Phys Estrogen: Chlorotrianisene; Dienestrol; Diethylstilbestrol; ostigmine Salicylate: Physostigmine Sulfate; Pilocarpine; Diethylstilbestrol Diphosphate; Equilin; Estradiol; Estradiol Pilocarpine Hydrochloride; Pilocarpine Nitrate; Pyridostig 55 Cypionate; Estradiol Enanthate; Estradiol Undecylate; Estra mine Bromide. diol Valerate; EstraZinol Hydrobromide; Estriol; Estrofurate; Cholinergic agonist: Xanomeline; Xanomeline Tartrate. Estrogens, Conjugated; Estrogens, Esterified; Estrone; Cholinesterase Deactivator: Obidoxime Chloride; Prali Estropipate; Ethinyl Estradiol: Fenestrel; Mestranol: doxime Chloride; Pralidoxime Iodide; Pralidoxime Mesy Nylestriol: Quinestrol. late. 60 Fibrinolytic: Anistreplase; Bisobrin Lactate; Brinolase. Coccidiostat: Arprinocid; Narasin; Semduramicin; Sem Free oxygen radical scavenger: Pegorgotein. duramicin Sodium. Gastrointestinal Motility agents: Cisapride (Propulsid); Cognition adjuvant: Ergoloid Mesylates; Piracetam; Metoclopramide (Reglan); Hyoscyamine (Levsin). Pramiracetam Hydrochloride; Pramiracetam Sulfate:Tacrine Glucocorticoid: Amcinonide; Beclomethasone Dipropi Hydrochloride. 65 onate; Betamethasone; Betamethasone Acetate. Betametha Cognition enhancer: Besipirdine Hydrochloride: Linopir sone Benzoate: Betamethasone Dipropionate; Betametha dine: Sibopirdine. sone Sodium Phosphate; Betamethasone Valerate; US 8,314,077 B2 39 40 Carbenoxolone Sodium; Clocortolone Acetate; Clocortolone Polysaccharide Vaccine Group C; Mumps Virus Vaccine Pivalate; Cloprednol; Corticotropin; Corticotropin, Reposi Live: Pertussis Immune Globulin; Pertussis Vaccine; Pertus tory; Corticotropin Zinc Hydroxide: Cortisone Acetate; Cor sis Vaccine Adsorbed; Plague Vaccine; Poliovirus Vaccine tivaZol; Descinolone Acetonide; Dexamethasone; Dexam Inactivated; Poliovirus Vaccine Live Oral; Rabies Immuune ethasone Sodium Phosphate; Diflucortolone; Diflucortolone Globulin; Rabies Vaccine; Rh(D) Immune Globulin; Pivalate: Flucloronide; Flumethasone: Flumethasone Piv RubellaVirus Vaccine Live: Smallpox Vaccine; Tetanus Anti alate: Flunisolide; Fluocinolone Acetonide; Fluocinonide; toxin; Tetanus Immune Globulin; Tetanus Toxoid: Tetanus Fluocortolone: Fluocortolone Caproate: Fluorometholone: Toxoid Adsorbed; Typhoid Vaccine; Yellow Fever vaccine; Fluperolone Acetate: Fluprednisolone: Fluprednisolone Val Vaccinia Immune Globulin; Varicella-Zoster Immune Globu erate: Flurandrenolide; Formocortal: Hydrocortisone: 10 lin. Hydrocortisone Acetate; Hydrocortisone Buteprate; Hydro Immunomodulator: Dimepranol Acedoben; Imiquimod; cortisone Butyrate; Hydrocortisone Sodium Phosphate: Interferon Beta-1b: Lisofylline: Mycophenolate Mofetil: Hydrocortisone Sodium Succinate; Hydrocortisone Valerate; Prezatide Copper Acetate. Medrysone; Methylprednisolone; Methylprednisolone Immunoregulator: Azarole: Fanctizole Mesylate; Frenti Acetate; Methylprednisolone Sodium Phosphate; Methyl 15 Zole: Oxamisole Hydrochloride: Ristianol Phosphate; Thy prednisolone Sodium Succinate; Nivazol; Paramethasone mopentin; Tilomisole. Acetate; Prednicarbate; Prednisolone; Prednisolone Acetate; Immunostimulant: Loxoribine; Teceleukin. Prednisolone Hemisuccinate; Prednisolone Sodium Phos Immunosuppressant: Azathioprine; Azathioprine Sodium; phate; Prednisolone Sodium Succinate; Prednisolone Tebu CyclospCrine; Daltroban; Gusperimus Trihydrochloride: tate; Prednisone: Prednival; Ticabesone Propionate; Tral Sirolimus; Tacrolimus. onide; Triamcinolone; Triamcinolone Acetonide; Impotence therapy adjunct: Delequamine Hydrochloride. Triamcinolone Acetonide Sodium; Triamcinolone Diacetate; Inhibitor: Acarbose; Atorvastatin Calcium; Benserazide; Triamcinolone Hexacetonide. Brocresine; Carbidopa; Clavulanate Potassium; Dazmegrel; Gonad-stimulating principle: Buserelin Acetate; Clomi Docebenone: Epoprostenol; Epoprostenol Sodium; Epris phene Citrate; Ganirelix Acetate; Gonadorelin Acetate; 25 teride; Finasteride: Flurbiprofen Sodium; Furegrelate Gonadorelin Hydrochloride; Gonadotropin, Chorionic; Sodium; Lufironil; Miglitol; Orlistat; Pimagedine Hydro Menotropins. chloride; Pirmagrel: Ponalrestat; Ridogrel; Sulbactam Ben Hair growth stimulant: Minoxidil. Zathine; Sulbactam Pivoxil Sulbactam Sodium; Suronacrine Hemostatic: Aminocaproic Acid: Oxamarin Hydrochlo Maleate; Tazobactam; Tazobactam Sodium; Ticlopidine ride; Sulmarin; Thrombin; Tranexamic Acid. 30 Hydrochloride; Tirilazad NIesylate; Tolrestat; Velnacrine Histamine H2 receptor antagonists: Ranitidine (Zantac); Maleate; Zifrosilone; Zileuton. Famotidine (Pepcid); Cimetidine (Tagamet); Nizatidine Keratolytic: Alcloxa; Aldioxa: Benzoyl Peroxide: Diben (Axid). Zothiophene; Etarotene; Isotretinoin; Motretinide; Picotrin Hormone: Diethylstilbestrol; Progesterone; 17 hydroxy Diolamine: Resorcinol: Resorcinol Monoacetate; Salicylic progesterone; Medroxyprogesterone; Norgestrel; Nor 35 Acid, Sumarotene; Tazarotene; Tetroquinone; Tretinoin. ethynodrel; Estradiol; Megestrol (Megace); Norethindrone: LHRH agonist: Deslorelin: Goserelin; Histrelin; Lutrelin Levonorgestrel; Ethyndiol: Ethinyl estradiol; Mestranol: Acetate; Nafarelin Acetate. Estrone; Equilin; 17 alpha dihydroequilin; equilenin; 17 Liver disorder treatment: Ialotilate. alpha dihydroequilenin; 17 alpha estradiol; 17 beta estradiol; Luteolysin: Fenprostalene. Leuprolide (lupron); Glucagon; Testolactone; Clomiphene; 40 Memory adjuvant: Dimoxamine Hydrochloride: Ribami Han memopausal gonadotropins; Human chorionic gonadot nol. ropin: Urofollitropin; Bromocriptine; Gonadorelin; Luteiniz Mental performance enhancer: Aniracetam. ing hormone releasing hormone and analogs; Gonadotropins; Mood regulator: Fengabine. Danazol; Testosterone; Dehydroepiandrosterone; Andros Mucolytic: Acetylcysteine; Carbocysteine; Domiodol. tenedione; Dihydroestosterone: Relaxin: Oxytocin; Vaso 45 Mucosal Protective agents: Misoprostol (Cytotec). pressin; Folliculostatin: Follicle regulatory protein; Gona Mydriatic: Berefrine. doctrinins; Oocyte maturation inhibitor; Insulin growth Nasal decongestant: Nemazoline Hydrochloride; Pseu factor, Follicle Stimulating Hormone; Luteinizing hormone; doephedrine Polistirex. Tamoxifen; Corticorelin Ovine Triflutate; Cosyntropin: Neuroleptic: Duoperone Fumarate; Risperidone. Metogest; Pituitary, Posterior; Seractide Acetate; Somalapor; 50 Neuromuscular blocking agent: Atracurium Besylate: Somatrem: Somatropin; Somenopor: Somidobove. Cisatracurium Besylate; Doxacurium Chloride; Gallamine Hypocholesterolemic: Lifibrol. Triethiodide; Metocurine Iodide; Mivacurium Chloride; Pan Hypoglycemic: DarglitaZone Sodium: Glimepiride. curonium Bromide; Pipecuronium Bromide: Rocuronium Hypolipidemic: AzalanstatDihydrochloride; Colestolone; Bromide: Succinylcholine Chloride; Tubocurarine Chloride: Surfomer; Xenalipin. 55 Vecuronium Bromide. Hypotensive: Viprostol. Neuroprotective: Dizocilpine Maleate. HMGCoA reductase inhibitors: Lovastatin (Mevacor); NMDA antagonist: Selfotel. Simvastatin (Zocor); Pravastatin (Pravachol); Fluvasatin (Le Non-hormonal sterol derivative: Pregnenolone Succinate. Scol). Oxytocic: Carboprost; Carboprost Methyl: Carboprost Immunizing agent: Antirabies Serum; Antivenin (Latro 60 Tromethamine; Dinoprost: Dinoprost Tromethamine; Dino dectus mactans); Antivenin (Micrurus Fulvius); Antivenin prostone; Ergonovine Maleate; Meteneprost; Methylergono (Crotalidae) Polyvalent; BCG Vaccine. Botulism Antitoxin; vine Maleate; Oxytocin; Sparteine Sulfate. Cholera Vaccine; Diphtheria Antitoxin; Diphtheria Toxoid; Plasminogen activator: Alteplase; Urokinase. Diphtheria Toxoid Adsorbed; Globulin, Immune: Hepatitis B Platelet activating factor antagonist: Lexipafant. Immune Globulin; Hepatitis B Virus Vaccine Inactivated: 65 Platelet aggregation inhibitor: Acadesine; Beraprost; Bera Influenza Virus Vaccine; Measles Virus Vaccine Live: Men prost Sodium, Ciprostene Calcium; ItaZigrel; Lifarizine; ingococcal Polysaccharide Vaccine Group A; Meningococcal Oxagrelate. US 8,314,077 B2 41 42 Post-stroke and post-head trauma treatment: Citicoline Sclerosing agent: Ethanolamine Oleate; Morrhuate Sodium. Sodium; Tribenoside. Potentiator: Pentostatin; Talopram Hydrochloride. Sedative: Propiomazine. Progestin: Algestone Acetophenide; Amadinone Acetate: Sedative-hypnotic: Allobarbital; Alonimid; Alprazolam: Anagestone Acetate; Chlormadinone Acetate; Cingestol; 5 Amobarbital Sodium; Bentazepam; Brotizolam: Butabar Clogestone Acetate; Clomegestone Acetate; Desogestrel; bital; Butabarbital Sodium: Butalbital; Capuride; Carboclo Dimethisterone; Dydrogesterone; Ethynerone; Ethynodiol ral; Chloral Betaine; Chloral Hydrate; Chlordiazepoxide Diacetate; Etonogestrel; Flurogestone Acetate; Gestaclone; Hydrochloride; Cloperidone Hydrochloride; Clorethate: Gestodene; Gestonorone Caproate: Gestrinone; Haloproges Cyprazepam; Dexciamol Hydrochloride; Diazepam; Dichlo terone; Hydroxyprogesterone Caproate; Levonorgestrel; 10 ralphenazone; Estazolam: Ethchlorvynol; Etomidate: Fenobam; Flunitrazepam; Fosazepam; Glutethimide: Lynestrenol; Medrogestone; Medroxyprogesterone Acetate; Halazepam, Lorimetazepam, Mecloqualone; Meprobamate; Methynodiol Diacetate; Norethindrone; Norethindrone Acetate; Norethynodrel; Norgestimate; Norgestomet; Norg Methaqualone; Midaflur; Paraldehyde; Pentobarbital; Pento estrel; Oxogestone Phenpropionate; Progesterone; barbital Sodium; Perlapine; Prazepam; Quazepam; 15 Reclazepam; Roletamide: Secobarbital; Secobarbital Quingestanol Acetate; Quingestrone; Tigestol. Sodium; Suproclone; Thalidomide: Tracazolate: Trepipam Prostaglandin: Cloprostenol Sodium; Fluprostenol Maleate; Triazolam; Tricetamide; Triclofos Sodium; Trime Sodium; Gemeprost; Prostalene; Sulprostone. tozine: Uldazepam; Zaleplon; Zolazepam Hydrochloride; Prostate growth inhibitor: Pentomone. Zolpidem Tartrate. Prothyrotropin: Protirelin. Selective adenosine A1 antagonist: Apaxifylline. Psychotropic: Minaprine. Serotonin antagonist: Altanserin Tartrate; Amesergide; Pulmonary surface: Beractant; Colfosceril Palmitate. Ketanserin; Ritanserin. Radioactive agent: Fibrinogen I 125: Fludeoxyglucose F Serotonin inhibitor: Cinanserin Hydrochloride: Fenclo 18; Fluorodopa F 18; Insulin I 125; Insulin I 131; Iobenguane nine; Fonazine Mesylate; Xylamidine Tosylate. I 123: Iodipamide Sodium I 131; Iodoantipyrine I 131; Iodo 25 Serotonin receptor antagonist: Tropanserin Hydrochlo cholesterol I 131; Iodohippurate Sodium I 123: Iodohippurate ride. Sodium I 125 Iodohippurate Sodiun I 131; Iodopyracet I 125; Steroid: Dexamethasone Acefurate; Mometasone Furoate. Iodopyracet I 131; Iofetamine Hydrochloride I 123: Iomethin Stimulant: Amfonelic Acid; Amphetamine Sulfate; Ampy I 125; Iomethin I 131; Iothalamate Sodium I 125; Iothalamate zine Sulfate; Arbutamine Hydrochloride; Azabon; Caffeine: Sodium I 131; Iotyrosine 1131; Liothyronine I 125; Liothy 30 Ceruletide; Ceruletide Diethylamine: Cisapride; Dazopride ronine I 131 Merisoprol Acetate Hg 197; Merisoprol Acetate Fumarate; Dextroamphetamine; Dextroamphetamine Sul Hg 203: Merisoprol Hg 197: Selenomethionine Se75; Tech fate; Difluanine Hydrochloride: Dimefline Hydrochloride: netium Tc 99m Antimony Trisulfide Colloid; Technetium Tc Doxapram Hydrochloride; Etryptamine Acetate; Ethamivan: 99m Bicisate; Technetium Tc 99m Disofenin; Technetium Tc Fenethylline Hydrochloride: Flubanilate Hydrochloride: 99m Etidronate; Technetium Tc 99m Exametazime; Techne 35 Flurothyl; Histamine Phosphate: Indriline Hydrochloride: tium Tc 99m Furifosmin; Technetium Tc 99m Gluceptate; Mefexamide; Methamphetamine Hydrochloride; Meth Technetium Tc 99m Lidofenin Technetium Tc 99m Mebro ylphenidate Hydrochloride; Pemoline: Pyrovalerone Hydro fenin; Technetium Tc 99m Medronate; Technetium Tc 99m chloride; Xamoterol: Xamoterol Fumarate. Medronate Disodium; Technetium Tc 99m Mertiatide; Tech Suppressant: Amflutizole; Colchicine: Tazofelone. Symp netium Tc 99m Oxidronate; Technetium Tc 99m Pentetate; 40 tomatic multiple Sclerosis: Fampridine. Technetium Tc 99m Pentetate Calcium Trisodium; Techne Synergist: Proadifen Hydrochloride. tium Tc 99m Sestamibi; Technetium Tc 99m Siboroxime; Thyroid hormone: Levothyroxine Sodium; Liothyronine Technetium Tc 99m Succimer: Technetium Tc 99m Sulfur Sodium; Liotrix. Colloid; Technetium Tc 99m Teboroxime; Technetium Tc Thyroid inhibitor: Methimazole; Propylthiouracil. 99m Tetrofosmin; Technetium Tc 99m Tiatide; Thyroxine 1 45 Thyromimetic: Thyromedan Hydrochloride. 125; Thyroxine 1 131; Tolpovidone 1 31; Triolein 1125; Tranquilizer: Bromazepam; Buspirone Hydrochloride: Triolein 1131. Chlordiazepoxide: Clazolam; Clobazam; Clorazepate Dipo Regulator: Calcifediol; Calcitonin; Calcitriol: Clodronic tassium; CloraZepate Monopotassium; DemoXepam, Acid; Dihydrotachysterol: Etidronic Acid: Oxidronic Acid; Dexmedetomidine: Enciprazine Hydrochloride; Gepirone Piridironate Sodium; Risedronate Sodium; Secalciferol. 50 Hydrochloride; Hydroxyphenamate; Hydroxyzine Hydro Relaxant: Adiphenine Hydrochloride; Alcuronium Chlo chloride; Hydroxy Zine Pamoate; Ketazolam; Lorazepam, ride; Aminophylline: Azumolene Sodium; Baclofen; Ben LorZafone; Loxapine; Loxapine Succinate; Medazepam Zoctamine Hydrochloride: Carisoprodol; Chlorphenesin Car Hydrochloride; Nabilone; Nisobamate: Oxazepam; Pent bamate; ChlorZoxazone; Cinflumide: Cinnamedrine; abamate; Pirenperone; Ripazepam, Rolipram; Sulazepam, Clodanolene; Cyclobenzaprine Hydrochloride; Dantrolene: 55 Taciamine Hydrochloride; Temazepam; Triflubazam; Dantrolene Sodium; Fenalamide: Fenyripol Hydrochloride: Tybamate; Valnoctamide. Fetoxylate Hydrochloride: Flavoxate Hydrochloride; Fle Amyotrophic lateral Sclerosis agents: Riluzole. tazepam; Flumetramide: Flurazepam Hydrochloride; Cerebral ischemia agents: Dextrorphan Hydrochloride. Hexafluorenium Bromide: Isomylamine Hydrochloride; Lor Paget’s disease agents: Tiludronate Disodium. bamate; Mebeverine Hydrochloride; Mesuprine Hydrochlo 60 Unstable angina agents: Tirofiban Hydrochloride. ride; Metaxalone; Methocarbamol; Methixene Hydrochlo Uricosuric: BenZbromarone; Irtemazole; Probenecid; ride; Nafomine Malate; NeleZaprine Maleate; Papaverine Sulfinpyrazone. Hydrochloride; Pipoxolan Hydrochloride; Quinctolate: Rito Vasoconstrictor: Angiotensin Amide: Felypressin; Methy drine: Ritodrine Hydrochloride; Rolodine: Theophylline sergide; Methysergide Maleate. Sodium Glycinate; Thiphenamil Hydrochloride; Xilobam. 65 Vasodilator: Alprostadil; AZaclorzine Hydrochloride; Bar Repartitioning agent: Cimaterol. nethan Sulfate: Bepridil Hydrochloride; Buterizine; Cetiedil Scabicide: Amitraz: Crotamiton. Citrate; Chromonar Hydrochloride; Clonitrate; Diltiazem US 8,314,077 B2 43 44 Hydrochloride; Dipyridamole; Droprenilamine; Erythrityl Sartan; candesartan cilexetil, candoXatril; candoXatrilat; Tetranitrate; Felodipine: Flunarizine Hydrochloride; Foste capecitabine; capromab; capsaicin; captopril; carbazomycin dil: Hexobendine; Inositol Niacinate; Iproxamine Hydro C; carbetocin, carbovir, carboxamide-amino-triazole; car chloride; Isosorbide Dinitrate; Isosorbide Mononitrate; Isox boxyamidotriazole; carboxymethylated beta-1,3-glucan, car suprine Hydrochloride; Lidoflazine; Mefenidil; Mefenidil peritide; carteolol; carumonam, carvedilol; carvotroline; car Fumarate; Mibefradil Dihydrochloride; Mioflazine Hydro Zelesin; castanospermine; cebaracetam; cecropin B; chloride: Mixidine; Nafronyl Oxalate: Nicardipine Hydro cefcapene pivoxil, cefdaloxime pentexil tosilate, cefdinir, chloride; Nicergoline; Nicorandil; Nicotinyl Alcohol; Nife cefditoren pivoxil, cefepime; cefetamet; cefetamet pivoxil; dipine; Nimodipine; Nisoldipine; Oxfenicine; Oxprenolol cefixime; cefluprenam, cefinetazole; cefiminox, cefodizime; Hydrochloride; Pentaerythritol Tetranitrate; Pentoxifylline: 10 cefoselis, cefotetan, cefotiam, cefotiam hexetil, cefoZopran; Pentrinitrol; Perhexiline Maleate; Pindolol; Pirsidomine; cefpimizole; ce?piramide; ce?pirome; cefpodoxime proxetil: Prenylamine: Propatyl Nitrate; Suloctidil; Terodiline Hydro cefprozil; cefsulodin; cefteram; ceftibuten; cefiriaxone: chloride; Tipropidil Hydrochloride; Tolazoline Hydrochlo cefuroxime axetil, celastrol; celikalim, celiprolol; cepacidine ride; Xanthinol Niacinate. A; cericlamine; cerivastatin: ceronapril; certoparin Sodium; Vulnerary: Allantoin. 15 cetiedil; cetirizine; chloroorienticin A; chloroorienticin B; Wound healing agent: ErSofernin. chloroquinoxaline Sulfonamide, cibenzoline; cicaprost; Xanthine oxidase inhibitor: Allopurinol; Oxypurinol ciclesonide; cicletanine: cicloprolol, cidofovir, cilansetron; Other pharmaceutical agents include: 1-decpyrrolidinone; cilaZapril; cilnidipine; cilobradine; cilostazol; cimetropium 1-dodecpyrrolidinone; 16-alpha fluoroestradiol; 16-epi bromide; cinitapride; cinolazepam, cioteronel; ciprofibrate; estriol: 16alpha-gitoxin; 17alpha estradiol; 17beta estradiol; ciprofloxacin; ciprostene, cis-porphyrin, cisapride; cisatracu 1alpha-hydroxyvitamin D2; 2'-nor-cGMP; 20-epi-1.25 dihy rium besilate, cistinexine; citalopram; citicoline; citreamicin droxyvitamin D3; 22-oxacalcitriol: 2CVV: 3-isobutyl alpha; cladribine; clarithromycin; clausenamide; clebopride; GABA; 6-FUDCA: 7-methoxytacrine; abamectin; abano clinafloxacin; clobaZam; clobetaSone butyrate; clodronic quil; abecarnil; abiraterone; acadesine; acamprosate; acar acid; clomethiazole; clopidogrel; clotrimazole; colestimide; bose; aceclofenac; acemannan; acetomepregenol; acetyl-L- 25 colfosceril palmitate; collismycin A; collismycin B; combre carnitine; acetylcysteine, N-; acetylmethadol; acifran; tastatin A4, complestatin; conagenin, contignasterol; contor acipimox; acitemate; acitretin; aclarubicin; aclatonium; trostatin: cosalane; costatolide; cotinine; coumermycin A1, napadisilate; aconiazide; acrivastinet; adafenoxate; ada cucumariosid; curacin A; curdlan Sulfate; curiosin; cycla palene; adatanserin; adecypenol; adefovir dipivoxil, adelm Zosin; cyclic HPMPC; cyclobenzaprine; cyclobut A: cyclobut idrol; ademetionine; adinazolam; adiposin; adoZelesin; 30 G; cyclocapron; cycloplatam, cyclosin; cyclothialidine; adrafinil; alacepril; aladapcin; alaptide; albendazole, albola cyclothiazomycin; cypemycin; cyproterone; cytarabine brin; aldecalmycin; aldesleukin; alendronic acid; alentemol; ocfosfate; cytochalasin B; dacliximab; dactimicin; daidzein; alfacalcidol; alfuzosin; alglucerase; allinastine; alosetron; daidzin, dalfopristin; dalteparin Sodium; danaparoid; daph alpha idoSone; alprostadil; altretamine; altromycin B; amba nodorin A; dapiprazole; dapitant; darifenacin; darlucin A; mustine; amelometasone; ameSergide; amezinium metilsul 35 darsidomine; ddUTP, decitabine; deferiprone; deflazacort; fate; amfebutamone; amidox; amifloxacin; amifostine; amio dehydrodidemnin B; dehydroepiandrosterone; delapril; darone; amisulpride; amlexanox; amlodipine; amlodipine; deleduanine; delfaprazine; delmopinol; delphinidin; deoxy ampiroXicam, amrinone; amrubicin; amsacrine; amylin; pyridinoline; deprodone; depsidomycin; deramciclane; der amythiamicin; anagrelide; anakinra; ananain; anaritide; anas matan Sulfate; desflurane; desirudin; deslorelin; desmo trozole; andrographolide; anordrin; apadoline; apafant; 40 pressin; desogestrel; desoxoamiodarone; detajmium apaxifylline; aphidicolinglycinate; apraclonidine: aprosulate bitartrate; dexifosfamide; dexketoprofen; dexloxiglumide: Sodium; aptiganel; apurinic acid; aranidipine; arbekacin; dexmedetomidine; dexpemedolac, dexraZoxane; dexSotalol; arbidol; arbutamine; ardeparin Sodium; arecatannin B1; arga dextrin 2-sulphate; dexVerapamil, dezinamide; dezocine; troban; aripiprazol; arotinolol; asimadoline; aspalatone; diaziquone; diclofenac digolil; diclofenac potassium; dicra asperfuran; aspoxicillin; astemizole; asulacrine; atamestane; 45 nin; didemnin B; didox; dienogest; diethylhomospermine; atenolol. S-: atevirdine; atosiban; atovaquone; atpenin B; atri diethylnorspermine; dihydrexidine; dihydro-5-azacytidine: mustine; atrinositol; aureobasidin A. azadirachtine; aza dimethyl prostaglandin A1, dimethylhomospermine; setron; azatyrosine; azelaic acid; azelastine; azelnidipine; dimiracetam; dioxamycin; diphency prone; diphenyl spiro azimilide, azithromycin; aZosemide; aztreonam, baccatin III; mustine; diprafenone; dipropylnorspermine; dirithromycin; bacoside A: bacoside B; bactobolamine; balazipone: balhi 50 discodermolide; disulfiram; ditekiren; docarpamine; mycin; balofloxacin; balsalazide; bambuterol; baohuoside 1: docosanol, 1-, dolfetilide; dolasetron; domitroban; dopexam barnidipine; basifungin; batebulast; batimastat; beauvericin; ine; dorzolamide; doSmalfate; dotarizine, doxacurium chlo becaplermin; becliconazole; befloxatone; belfosdil; bellena ride: doxazosin: doxifluridine: doxofylline; draculin; drafla mine; benflumetol; benidipine; benzisoxazole; benzochlor zine; droloxifene; dronabinol; drosperidone; drotaverine ins; benzoidazoxan; benzoylstaurosporine; benztropine; 55 acephyllinate; droxicam; ebiratide; ebrotidine; ebselen; bepridil; beractant; beraprost; berlafenone; bertosamil: ecabapide; ecabet, ecadotril, ecdlisteron; echicetin; echista besipirdine; beta-alethine; betaclamycin B; betamipron; tin; ecomustine; ecteinascidin 722; ecteinascidin 729; ectein betaxolol; betulinic acid; bevantolol; bicalutamide: bife ascidin 743; edaravone; edelfosine; edobacomab: edrecolo melane; bimakalim, bimithil; binospirone; bioxalomycin mab; efegatran; eflornithine; efonidipine; egualen, elcatonin; alpha2; biriperone; bis-benzimidazole A: bis-benzimidazole 60 eletriptan; elgodipine; eliprodil, eltenac; emakalim, emedas B; bisantrene; bisaramil: bisaziridinylspermine; bisnafide: tine; emiglitate; emitefur; emoctakin; enadoline hydrochlo bisoprolol; bistramide D; bistramide K: bistratene A: boldine: ride; enalapril; enazadrem, englitaZone; enlimomab; enoxa bopindolol; brefeldin; breflate: brimonidine; bromfenac; bro cin; enoxaparin Sodium; enoXimone; entacapone; mperidol; bropirimine; bucindolol; budesonide; budipine; enterostatin: epoprostenol; epoxymexrenone; epristeride; budotitane; bunaprolast; bunaZosin; butenafine; buthionine 65 eprosartan; eptastigmine; erdosteine; ersentilide; erSofermin; Sulfoximine; butiXocort propionate; cadexomer iodine, cal erythritol; esuprone; etanidazole; etanterol; ethacizin; ethi anolide A, calcipotriol, calphostin C; camonagrel; cande nylestradiol; etizolam: etodolac, etoposide phosphate; etra US 8,314,077 B2 45 46 bamine; eveminomicin; examorelin; exemestane; fadrozole; monophosphate; methylprednisolone aceponate; methyl faerieflungin; famciclovir, fampiridine; fantofarone; faro prednisolone Suleptanate; metipamide; metoclopramide; penem; fasidotril; fasudil; fazarabine; fedotozine; felbarnate; metoprolol, S-; metrifonate; mibefradil; michellamine B: fenofibrate; fenoldopam; fenretinide; fenspiride; fenticona microcolin A; midodrine; mifepristone; miglitol; millace Zole; fepradinol; ferpifosate sodium; ferristene; ferrixan; mide; milameline; mildronate; milnacipran; milrinone; ferumoxsil; fexofenadine; flavopiridol; flecainide; fle miltefosine; minaprine; miokamycin, mipragoside; mirfenta robuterol; fleroxacin; flesinoxan; flezelastine; flobufen, flo nil; mirimoStim, mirtazapine; misoprostol; mitoguaZone; moxef florfenicol; florifenine; flosatidil; fluasterone; flu mitolactol, mitonafide; mitoxantrone; mivacurium chloride; conazole; fludarabine; flumazenil; flumecinol; flumequine; mivaZerol; mixanpril; mizolastine, mizoribine; moclobe flunarizine; fluocalcitriol: fluorodaunorunicin hydrochloride: 10 mide; modafinil; moexipril; mofarotene; mofeZolac, molgra fluoxetine, R-; fluoxetine, S-; fluparoxan; flupirtine; flurbi mostim; mometasone; montirelin; mopidamol; moracizine; profen axetil: flurithromycin; fluticasone propionate; flutri mosapramine; mosapride; motilide; moxiraprine; moXoni mazole; fluvastatin; fluvoxamine; forasartan; forfenimex: dine; nadifloxacin; nadroparin calcium; nafadotride; nafamo formestane; formoterol; formoterol, R.R-; fosfomycin; stat; nafarelin; naftopidil; naglivan; nagrestip; nalmefene; trometamol; fosinopril; fosphenytoin; fostriecin, fotemus 15 naphterpin, napsagatran; naratriptan; nartograstim; nasaru tine, gabapentin; gadobenic acid, gadobutrol; gadodiamide; plase; nateplase; niperotidine: niravoline; nisamycin; nisin; gadodiamide-EOB-DTPA; gadolinium texaphyrin; gadoteric nisoldipine, nitaZoxamide: nitecapone; nitrendipine; nitren acid; gadoteridol; gadoversetamide; galantamine; dipine, S-: nitrofurantoin monohydrate; nitrullyn; nizatidine; galdansetron; gallopamil; galocitabine; gamolenic acid; ofloxacin, okicenone: olanzapine, olopatadine; olprinone; ganirelix; gepirone; gestrinone; girisopam; glaspimod; glau olsalazine; omeprazole; onapristone; ondansetron; cocalyxin A; glutapyrone; glycopine; glycopril; granisetron; ondansetron, R-; ontaZolast; oracin; otenZepad: Oxaliplatin: grepafloxacin; halichondrin B; halofantrine; halomon; halo oxamisole; Oxandrolone; oxaprozin, oxaunomycin; oXcarba predone; hatomamicin; hatomarubigin A; hatomarubigin B; Zepine; oxiconazole; oxiracetam; oxodipine; oZagrel, palaua hatomarubigin C; hatomarubigin D; ibogaine; ibopamine; mine; palinavir, palmitoylrhizoxin; pamaqueside; pam ibudilast, illimaquinone, ilmofosine; illomastat; illoperidone; 25 icogrel, pamidronic acid; panamesine; panaxytriol: iloprost; imidapril; imidazenil; indinavir; indolidan: panipenem; panipenum; pannorin; panomifene; pantethine; indometacin famesil; indometacin; tropine ester, indoramin; pantoprazole; parabactin; parnaparin Sodium; paroxetine; inocoterone; inogatran; inolimomab; interferon alfa, inter parthenolide; paZelliptine; paZufloxacin; pefloxacin: pegas feron alfa-2a: interferon alfa-2b; interferon alfa-N1; inter pargase; peldesine; pemedolac, pemirolast; penciclovir, pen feron alfa-n3; interferon beta; interferon beta-1a1; interferon 30 tafuside; pentamidine; pentamorphone; pentigetide; pen beta-1b; interferon gamma-1a; interferon gamma-1b; inter tosan; pentostatin: pentroZole; perflubron; perfosfamide; feron omega; interferon, consensus; interleukin-1; interleu pergolide; perindoprilat; perospirone: phenaridine: phenazi kin-1 alpha; interleukin-1 beta; interleukin-10; interleukin nomycin; phenserine; phensuccinal; phentolamine mesilate; 11; interleukin-12; interleukin-12; interleukin-15; phenylacetate; phenylalanylketoconazole;picenadol; piciba interleukin-2; interleukin-3; interleukin-4; interleukin-5; 35 nil; picroliv; picumeterol; pidotimod; pilocarpine hydrochlo interleukin-7: interleukin-8; iobenguane; iobitridol; iodoam ride; pilsicainide; pimagedine; pimilprost; pimobendan; iloride; iododoxorubicin; iofratol; iomeprol; iopentol; iopro pinacidil; pinocebrin; pioglitaZone; pipecuronium bromide; mide; iopyrol; iotriside; ioversol; ioxilan; ipazilide; IpdR; pirarubicin; piretanide; pirfenidone; piritrexim; pirlindole; ipenoxazone; ipidacrine; ipomeanol, 4-, ipriflavone; ipsa pirmagrel; pirmenol; pirodavir, pirodomast, piroxicam cin pirone; irbesartan; irinotecan; irloxacin; irsogladine; irtem 40 namate; propagermanium; propentofylline; propionylcar azole; isalsteine; isbogrel, isepamicin; isobengaZole; isoflox nitine, L- propiram; propiram-paracetamol; propiverine; ythepin; isohomohalicondrin B; isopropyl unoprostone; propyl bis-acridone; prostaglandin J2, prostratin; protegrin: isradipine; itameline; itasetron; itopride; itraconazole, keto protoSufloxacin; prulifloxacin; pyrazoloacridine; quazepam, profen, R-, ketoprofen, S-; ketorolac, lacidipine; lactitol; lac quetiapine; quiflapon; quinagolide; quinapril; quinfamide: tivicin; laennec; lafutidine; lamellarin-N triacetate; lami 45 quinupristin; raloxifene; raltitrexed; ramatroban; ramipril; fiban; lamivudine; lamotrigine; lanoconazole; lanperisone; ramosetron; ranelic acid; ranitidine bismuth citrate; ranola lanreotide; lansoprazole; latanoprost; lateritin; laurocapram; Zine; recainam; regavirumab, relaxin; repirinast; resinfera lazabemide; lemefloxacin; lemildipine; leminoprazole; toxin; reticulon; reviparin sodium; revizinone; ricasetron; lenercept; lenograstim; lentinan Sulfate; leptin; leptolstatin: ridogrel; rifabutin: rifapentine; rifaximin: rilopirox, riluzole; lercanidipine; lerisetron; lesopitron; letraZuril; letrozole; leu 50 rimantadine, rimexolone; rimoprogin, riodipine; ripisartan; comyzin; leuprorelin; levcromakalim; levetiracetam; levobe risedronic acid; rispenzepine; risperidone; ritanserin; riti taxolol; levobunolol; levobupivacaine; levocabastine; levo penem; ritipenem acoxil; ritolukast, ritonavir, rizatriptan carnitine; levodropropizine; levofloxacin; levomoprolol; benzoate; rohitukine; rokitamycin; ropinirole; ropivacaine; levonorgestrel; levormeloxifene; levosimendan; levo roquinimex: roXatidine, roXindole; roXithromycin; rubigi Sulpiride; linotroban; linsidomine; lintitript; lintopride; lio 55 none B1; ruboxyl, rufloxacin; rupatidine, ruzadolane; Safin thyronine sodium; lirexapride; lisinopril; lobaplatin; lobu gol; Safironil; Saintopin; salbutamol, R-; Salmeterol; salme cavir, Iodoxamide; lombricine; lomefloxacin, lomerizine; terol, R-salnacedin; Sameridine; Sampatrilat; Sanfetrinem; lometrexol; lonazolac, lonidamine; loracarbef loratadine; Saprisartan; sapropterin; saquinavir, SarCNU; sarcophytol A lorglumide; lornoxicam, losartan; losigamone; losoxantrone; Sargramostim; Sarpogrelate; Saruplase; Saterinone; satigrel; loteprednol; loviride; loxoribine; lubeluzole; lurtotecan; 60 Satumomab pendetide; selegiline; selenium thiosemicarba luteinizing hormone; lutetium; luZindole; lydicamycin; Zone; sematilide; semduramicin; Semotiadil; Semustine; ser lysofylline; lysostaphin, magainin 2 amide; magnolol; mal morelin; Sertaconazole; sertindole; Sertraline; setiptiline; lotochromene; mallotojaponin; malotilate; mangafodipir, Sevirumab; sevoflurane; seZolamide; silipide; silteplase; sim manidipine; maniwamycin A; mannostatin A; manumycin E: endan; simvastatin; sinitrodil; sinnabidol; sipatrigine; siroli manumycin F; mapinastine; marimastat; Martek 8708; Mar 65 mus; sizofiran; Somatomedin B; somatomedin C; Somatrem: tek 92211; masoprocol; maspin; massetolide; meterelin; Somatropin; Sonermin; Sotalol; staurosporine; stavudine; methoxatone; methylhistamine, R-alpha; methylinosine stepronin; stipiamide; stiripentol; Stobadine. Succibun; US 8,314,077 B2 47 48 Sucralfate; Sulfasalazine; sulfinosine; Sulfoxamine; tive, topical; anti-inflammatory; antikeratinizing agent; anti Sulopenem; Sultamicillin; Sultopride; Sulukast, Sumatriptan; malarial; antimicrobial; antimitotic; antimycotic, antine Symakalim, tandospirone; tapgen; taprostene; tasosartan; oplastic, antineutropenic, antiparasitic; antiperistaltic, taZanolast, tazarotene; teicoplanin; telenzepine; tellurapyry antipneumocystic; antiproliferative; antiprostatic hypertro lium; telmesteine; telmisartan; temocapril; temoporfin, temo- 5 phy; antiprotozoal; antipruritic; antipsoriatic; antirheumatic; Zolomide; tenidap; teniposide; tenosal; tenoxicam; tepirin antischistosomal; antiseborrheic; antisecretory; antispas dole; tepoxalin, teraZosin; terbinafine; terfenadine; modic; antithrombotic; antitussive; anti-ulcerative: anti terflavoxate; terguride; teriakiren; terlipressin; terodiline; ter urolithic; antiviral; appetite Suppressant; benign prostatic tatolol; testosterone buciclate; tetrachlorodecaoxide; tetra hyperplasia therapy agent, bone resorption inhibitor; bron Zomine; thaliblastine; thalidomide; thiocoraline; thiofedrine; 10 chodilator, carbonic anhydrase inhibitor, cardiac depressant; thiomarinol; thioperamide; thyroid stimulating hormone; cardioprotectant; cardiotonic; cardiovascular agent; choler tiagabine; tianeptine; tiapafant; tibolone; ticlopidine; tienox etic; cholinergic; cholinergic agonist; cholinesterase deacti olol; tilisolol; tilnoprofenarbamel; tiludronic acid; tinzaparin vator, coccidiostat; diagnostic aid; diuretic; ectoparasiticide; Sodium, tiotropium bromide; tipredane; tiqueside; tirandaly enzyme inhibitor, estrogen; fibrinolytic; free oxygen radical digin; tirapazamine; tirilazad; tirofiban; tiropramide; topsen- 15 Scavenger, glucocorticoid; gonad-stimulating principle; hair tin, torasemide; toremifene; to Sufloxacin; trafermin; tran dollapril; traXanox; tretinoin, tretinoin tocoferil; growth stimulant; hemostatic; hormone; hypocholester triacetyluridine; tricaprilin; trichohyalin; trichosanthin, olemic; hypoglycemic; hypolipidemic; hypotensive; immu alpha; triciribine; trientine: triflavin; trimegestone; triptore nizing agent; immunomodulator; immunoregulator, immu lin; troglitaZone; trombodipine; tropisetron; trospectomycin; 20 nostimulant; immunosuppressant; impotence therapy trovafloxacin; troVirdine; tucaresol; tulobuterol; tylogenin: adjunct; inhibitor, keratolytic: LHRH agonist; liver disorder urapidil; uridine triphosphate; Valaciclovir, Valproate magne treatment; luteolysin; mucolytic; mydriatic; nasal deconges sium; Valproate semisodium; Valsartan; vamicamide; vana tant; neuromuscular blocking agent; non-hormonal sterol deine; vaminolol; vapreotide; variolin B; velaresol; venlafax derivative; oxytocic; plasminogen activator; platelet activat ine; Veramine; Verapamil, (S); Verdins; Veroxan; verteporfin; 25 ing factor antagonist, platelet aggregation inhibitor, potentia Vesnarinone; Vexibinol; vigabatrin; vinburnine citrate; Vin tor, progestin; prostaglandin; prostate growth inhibitor, pro burnine resinate: Vinconate; Vinorelbine; Vinpocetine; Vinpo thyrotropin; pulmonary Surface; radioactive agent; regulator; cetine citrate; Vintoperol; vinxaltine; Voriconazole; Vorozole; relaxant, repartitioning agent; Scabicide; sclerosing agent; VOXergolide; Xemilofiban, Ximoprofen; yangambin: Zab selective adenosine A1 antagonist; Steroid; Suppressant; icipril; Zacopride; Zacopride, R-; Zafirlukast; Zalcitabine; 30 symptomatic multiple Sclerosis; synergist; thyroid hormone; Zaleplon; Zalospirone; Zaltoprofen, Zanamivir, Zankiren, Zan thyroid inhibitor; thyromimetic: amyotrophic lateral sclero oterone; Zatebradine; Zatosetron: Zenarestat; Zeniplatin: sis agents; Paget’s disease agents; unstable angina agents; Zifrosilone; Zilascorb; Zileuton; Zinostatin stimalamer, uricoSuric; vasoconstrictor; vasodilator, Vulnerary; wound Ziprasidone; Zoledronic acid; Zolmitriptan; Zolpidem; Zonisa healing agent; Xanthine oxidase inhibitor. mide; Zopiclone; Zopiclone, S-; Zopolrestat; Zotepine. 35 As used herein, a taxane is a molecule that possesses the The invention also embraces novel compositions of matter following tricyclic carbon-atom connectivity network, which that are covalent conjugates of unbranched, naturally occur may incorporate carbon-carbon multiple bonds, and which ring fatty acids and pharmaceutical agents that are noncentral through the involvement of carbon-atom-noncarbon-atom nervous system active agents. Noncentral nervous system bonds may include Substituents, functional groups, and addi active agents have no function or use within the central ner- 40 tional rings. vous system. Their only use is outside of the central nervous system. Such agents include all drugs within certain of the foregoing categories and only some drugs within other of the foregoing categories. For example, the entire catagory of blood glucose regulators have no use or function within the 45 central nervous system. In contrast, certainanti-cancer agents are useful in the central nervous system whereas others are not. For example, central nervous system cancers are not hormone dependent, and, therefore, an anti-cancer agent Such as Tamoxifen which treats certain hormone dependent can- 50 cers is not useful in the central nervous system. Those skilled A taxoid is a molecule structurally related to a taxane in in the art will be able to identify readily those catagories which the above taxane carbon-atom connectivity network is and/or members of a catagory which are noncentral nervous altered, for example, by cleavage of one or more of the car system active agents. Among the foregoing compounds, the bocyclic rings, by deletion or addition of carbon Substituents, following catagories and/or members of the following cat- 55 by connection of carbon atoms normally not bonded to each agories are noncentral nervous system active agents: adreno other, by disconnection of carbon atoms normally bonded to cortical steroid; adrenocortical Suppressant, aldosterone each other, or by Some other reorganization of or adjustment antagonist; amino acid; anabolic; androgen; antagonist; to the taxane carbon-atom connectivity network, but in which anthelmintic; anti-acne agent; anti-adrenergic; anti-allergic; one or more structural features characteristic of the taxane anti-amebic; anti-androgen; anti-anemic; anti-anginal; anti- 60 carbon-atom connectivity network are conserved. arthritic; anti-asthmatic; anti-atherosclerotic; antibacterial; The compounds useful in the invention may be delivered in anticholelithic; anticholelithogenic; anticholinergic; antico the form of anti-cancer cocktails. An anti-cancer cocktail is a agulant; anticoccidal; antidiabetic; antidiarrheal; antidi mixture of any one of the compounds useful with this inven uretic; antidote; anti-estrogen; antifibrinolytic; antifungal; tion with another anti-cancer agent Such as an anti-cancer antiglaucomaagent; antihemophilic; antihemorrhagic; anti- 65 drug, a cytokine, and/or Supplementary potentiating agent(s). histamine; antihyperlipidemia; antihyperlipoproteinemic; The use of cocktails in the treatment of cancer is routine. In antihypertensive; antihypotensive; anti-infective; anti-infec this embodiment, a common administration vehicle (e.g., pill, US 8,314,077 B2 49 50 tablet, implant, injectable solution, etc.) would contain both acid find use in the preparation of injectables. Carrier formu the conjugate useful in this invention and the anti-cancer drug lations suitable for oral, Subcutaneous, intravenous, intramus and/or supplementary potentiating agent. cular, etc. can be found in Remington's Pharmaceutical Sci The compounds of the invention, when used in cocktails, ences, Mack Publishing Company, Easton, Pa. are administered in therapeutically effective amounts. A A subject as used herein means humans, primates, horses, therapeutically effective amount will be determined by the cows, pigs, sheep, goats, dogs, cats and rodents. parameters discussed below; but, in any event, is that amount The conjugates of the invention are administered in effec which establishes a level of the drug(s) in the area of the tumor tive amounts. An effective amount means that amount neces which is effective in inhibiting the tumor growth. sary to delay the onset of inhibit the progression of halt When administered, the formulations of the invention are 10 altogether the onset or progression of or diagnose the particu applied in pharmaceutically acceptable amounts and in phar lar condition being treated. In general, an effective amount for maceutically acceptable compositions. Such preparations treating cancer will be that amount necessary to inhibit mam may routinely contain salts, buffering agents, preservatives, malian cancer cell proliferation in-situ. When administered to compatible carriers, and optionally other therapeutic ingredi a Subject, effective amounts will depend, of course, on the ents. When used in medicine the salts should be pharmaceu 15 particular condition being treated; the severity of the condi tically acceptable, but non-pharmaceutically acceptable salts tion; individual patient parameters including age, physical may conveniently be used to prepare pharmaceutically condition, size and weight; concurrent treatment; frequency acceptable salts thereof and are not excluded from the scope of treatment; and the mode of administration. These factors of the invention. Such pharmacologically and pharmaceuti are well known to those of ordinary skill in the art and can be cally acceptable salts include, but are not limited to, those addressed with no more than routine experimentation. It is prepared from the following acids: hydrochloric, hydrobro preferred generally that a maximum dose be used, that is, the mic, Sulphuric, nitric, phosphoric, maleic, acetic, Salicylic, highest safe dose according to Sound medical judgment. p-toluene Sulfonic, tartaric, citric, methane Sulfonic, formic, Dosage may be adjusted appropriately to achieve desired malonic, Succinic, naphthalene-2-sulfonic, and benzene Sul drug levels, locally or systemically. Generally, daily oral fonic. Also, pharmaceutically acceptable salts can be pre 25 doses of active compounds will be from about 0.01 mg/kg per pared as alkaline metal oralkaline earth salts, such as Sodium, day to 1000 mg/kg per day. It is expected that IV doses in the potassium or calcium salts. range of about 1 to 1000 mg/m per day will be effective. In Suitable buffering agents include: acetic acid and a salt the event that the response in a Subject is insufficient at Such (1-2% W/V): citric acid and a salt (1-3% W/V); boric acid and doses, even higher doses (or effective higher doses by a dif a salt (0.5-2.5% W/V); and phosphoric acid and a salt (0.8-2% 30 ferent, more localized delivery route) may be employed to the W/V). extent that patient tolerance permits. Continuous IV dosing Suitable preservatives include benzalkonium chloride over, for example 24 hours or multiple doses per day are (0.003-0.03% W/V); chlorobutanol (0.3-0.9% W/V); para contemplated to achieve appropriate systemic levels of com bens (0.01-0.25% W/V) and thimerosal (0.004-0.02% W/V). pounds. The active compounds of the present invention may be a 35 A variety of administration routes are available. The par pharmaceutical composition having a therapeutically effec ticular mode selected will depend of course, upon the particu tive amount of a conjugate of the invention optionally lar drug selected, the severity of the disease state being treated included in a pharmaceutically-acceptable carrier. The term and the dosage required for therapeutic efficacy. The methods “pharmaceutically-acceptable carrier as used herein means of this invention, generally speaking, may be practiced using one or more compatible solid or liquid filler, dilutants or 40 any mode of administration that is medically acceptable, encapsulating Substances which are suitable for administra meaning any mode that produces effective levels of the active tion to a human or other animal. The term “carrier denotes an compounds without causing clinically unacceptable adverse organic or inorganic ingredient, natural or synthetic, with effects. Such modes of administration include oral, rectal, which the active ingredient is combined to facilitate the appli Sublingual, topical, nasal, transdermal, intradermal or cation. The components of the pharmaceutical compositions 45 parenteral routes. The term “parenteral' includes subcutane are capable of being commingled with the molecules of the ous, intravenous, intramuscular, or infusion. Intravenous present invention, and with each other, in a manner Such that routes are preferred. there is no interaction which would substantially impair the The compositions may conveniently be presented in unit desired pharmaceutical efficacy. dosage form and may be prepared by any of the methods well Compositions Suitable for parenteral administration con 50 known in the art of pharmacy. All methods include the step of Veniently comprise a sterile preparation of the conjugates of bringing the conjugates of the invention into association with the invention. This preparation may be formulated according a carrier which constitutes one or more accessory ingredients. to known methods. Formulations for taxanes can be found in In general, the compositions are prepared by uniformly and Chapter 9 of Taxol. Science and Applications, CRC Press, intimately bringing the compounds into association with a Inc., 2000 Corporate Boulevard, N.W., Boca Raton, Fla. 55 liquid carrier, a finely divided solid carrier, or both, and then, 33431. In general, Taxol has been formulated as a 6 ma/ml if necessary, shaping the product. cremophor EL (polyoxyethylated castor oil)/ethanol mixture, Compositions Suitable for oral administration may be pre which is diluted to final volume with normal saline or 5% sented as discrete units such as capsules, cachets, tablets, or dextrose. A 15 mg/ml solution of taxotere has been formu lozenges, each containing a predetermined amount of the lated in polysorbate 80 (polyoxyethylene sorbitanmo 60 active compound. Other compositions include Suspensions in nooleate)/ethanol mixture, diluted with 5% dextrose. aqueous liquors or non-aqueous liquids such as a syrup, an The sterile preparation thus may be a sterile solution or elixir, or an emulsion. Suspension in a non-toxic parenterally-acceptable diluent or Other delivery systems can include time-release, delayed solvent. In addition, sterile, fixed oils are conventionally release or Sustained release delivery systems. Such systems employed as a solvent or Suspending medium. For this pur 65 can a void repeated administrations of the active compounds pose any bland fixed oil may be employed including synthetic of the invention, increasing convenience to the Subject and the mono or di-glycerides. In addition, fatty acids such as oleic physician. Many types of release delivery systems are avail US 8,314,077 B2 51 52 able and known to those of ordinary skill in the art. They administering to a subject in need of Such treatment a include polymer based systems such as polylactic and polyg covalent conjugate of a C8-26, unbranched, naturally lycolic acid, polyanhydrides and polycaprolactone; nonpoly occurring fatty acid and gemcitabine effective for treat mer systems that are lipids including sterols such as choles ing said condition. terol, cholesterol esters and fatty acids or neutral fats such as 5 2. The method of claim 1, wherein the tissue is gastrointes mono-, diand triglycerides; hydrogel release systems; Silastic tinal tissue and wherein the Subject has a condition calling for systems; peptide based systems; wax coatings, compressed treatment of gastrointestinal tissue with the pharmaceutical tablets using conventional binders and excipients, partially agent. fused implants and the like. In addition, a pump-based hard 3. The method of claim 1, wherein the fatty acid is selected ware delivery system can be used, some of which are adapted 10 from the group consisting of C8:0 (caprylic acid), C10:0 for implantation. (capric acid), C12:0 (lauric acid), C14:0 (myristic acid), A long-term Sustained release implant also may be used. C16:0 (palmitic acid), C16:1 (palmitoleic acid), C16:2. "Long-term' release, as used herein, means that the implantis C18:0 (stearic acid), C18:1 (oleic acid), C18:1-7 (vaccenic), constructed and arranged to deliver therapeutic levels of the C18:2-6 (linoleic acid), C18:3-3 (O-linolenic acid), C18:3-5 active ingredient for at least 30 days, and preferably 60 days. 15 (eleostearic), C18:3-6 (8-linolenic acid), C18:4-3, C20:1 Long-term Sustained release implants are well knownto those (gondoic acid), C20:2-6, C20:3–6 (dihomo-y-linolenic acid), of ordinary skill in the art and include some of the release C20:4-3, C20:4-6 (arachidonic acid), C20:5-3 (eicosapen systems described above. Such implants can be particularly taenoic acid), C22:1 (docosenoic acid), C22:4-6 (docosatet useful in treating solid tumors by placing the implant near or raenoic acid), C22:5-6 (docosapentaenoic acid), C22:5-3 directly within the tumor, thereby affecting localized, high (docosapentaenoic), C22:6-3 (docosahexaenoic acid) and doses of the compounds of the invention. C24: 1-9 (nervonic). The conjugates of the invention also are useful, in general, 4. The method of claim 1, wherein the fatty acid is selected for treating mammalian cell proliferative disorders other than from the group consisting of C14:0 (myristic acid), C16:0 cancer, including psoriasis, actinic keratosis, etc. They fur (palmitic acid), C16:1 (palmitoleic acid), C16:2, C18:0 ther are useful in treating diabetes and its complications, 25 (stearic acid), C18:1 (oleic acid), C18:1-7 (vaccenic), C18: excess acid secretion, cardiovascular conditions involving 2-6 (linoleic acid), C18:3-3 (C-linolenic acid), C18:3-5 (eleo cholesterol (e.g., hyperlipidemia and hypercholesterolemia), stearic), C18:3-6(8-linolenic acid), C18:4-3, C20:1 (gondoic diarrhea, ovarian diseases (e.g. endometriosis, ovarian cysts, acid), C20:2-6, C20:3–6 (dihomo-y-linolenic acid), C20:4-3, etc.) and as contraceptive agents. C20:4-6 (arachidonic acid), C20:5-3 (eicosapentaenoic acid), Those skilled in the art will be able to recognize with no 30 C22:1 (docosenoic acid), C22:4-6 (docosatetraenoic acid), more than routine experimentation numerous equivalents to C22:5-6 (docosapentaenoic acid), C22:5-3 (docosapen the specific products and processes described above. Such taenoic), and C22:6-3 (docosahexaenoic acid). equivalents are intended to be included within the scope of the 5. The method of claim 1, wherein the fatty acid is C18:1. appended claims. 6. The method of claim 1, wherein the abnormal mamma We claim as follows: 35 lian-cell proliferation condition is cancer. 1. A method for targeting gemcitabine to a noncentral nervous system tissue to treat an abnormal mammalian-cell proliferation condition comprising: