USOO6576636B2

12) United States Patent 10) Patent No.: US 6,576,6369 9 B2 Webb et al. (45) Date of Patent: Jun. 10, 2003

(54) METHOD OF TREATING A LIVER 5,141,958 A 8/1992 Crozier-Willi et al...... 514/558 DSORDER WITH FATTY ACID-ANTIVIRAL 5,194,654 A 3/1993 Hostetler et al...... 558/152 AGENT CONJUGATES 5,214,062 A 5/1993 Mark et al...... 514/369 5,216,023 A 6/1993 Literati-Nagy et al...... 514/538 (75) Inventors: Nigel L. Webb, Bryn Mawr, PA (US); 5223.2635216,142 A 3:6/1993 E.I.".Horribin et al...... 3.514/SO Matthews O. Bradley, Laytonsville, 5,246,726. A 9/1993 Horrobin et al...... 424/646 MD (US); Charles S. Swindell, 5,250,722. A 10/1993 Bombardelli et al...... 560/104 Merion, PA (US); Victor E. Shashoua, 5,276,020 A 1/1994 Horribin et al...... 514/45 Brookline, MA (US) 5,278.324 A 1/1994 Kingston et al. 5,284.876 A 2/1994 Shashoua et al...... 514/549 (73) Assignee: Protarga, Inc., King of Prussia, PA 5,308,832 A 5/1994 Garleb et al...... 514/2 (US) 5,336,684 A 8/1994 Murray et al...... 514/449 5,356,928 A 10/1994 Murray et al...... 514/449 (*) Notice: Subject to any disclaimer, the term of this 5,362.831. A 11/1994 Mongelli et al...... 526/304 palet is tended or adjusted under 35 ER SE NE, s,s, U.S.C. 154(b) by 42 days. 5,453.520 A 9/1995 Bombardelli et al...... 549/510 21 Ap1. No.: 09/730,450 5,453.521 A 9/1995 Gaullier et al...... 549/541 (21) p . No.: 09/730, (List continued on next page.) (22) Filed: Dec. 5, 2000 FOREIGN PATENT DOCUMENTS (65) Prior Publication Data EP O O30 009 A1 6/1981 US 2001/0002404 A1 May 31, 2001 E. s 3. A2 i. Related U.S. Application Data E. s 5. A. 3.E. (63) Continuation of application No. 08/651,428, filed on May F. g O g A. SE; 22, 1996, now abandoned. JP 75-427/1983 4/1983 (51) Int. Cl." ...... A61K 31/52; A61K 31/70; JP 5902S327 A 2/1984 A61K 31/66; A61K 31/415; A61K 31/13; JP 59-2041.75 11/1984 (52) U.S. Cl...... 514261; 514/43,A61K31/135 514/45; E...... A "...SES 514/49; 514/50, 514/120; 514/262; 514/395; 1287022 A 11/1989 514/418; 514/651; 514/659; 514/662; 514/54 (58) Field of Search ...... 514/261, 262, (List continued on next page.) 514/662, 49, 50, 395, 120, 418, 43, 659, OTHER PUBLICATIONS 54, 651, 45 Anel, A., et al., “Increased Cytotoxicity Of Polyunsaturated 56 Ref Cited Fatty Acids On Human Tumoral B And And T-Cell Lines (56) CS Compared With Normal Lymphocytes", Leukemia, (1992), U.S. PATENT DOCUMENTS 6(7):680-688. Anel, B., et al., “Cytotoxicity Of Chlorambucil And 3,539,573 A 11/1970 Schmutz ------260/268 Chlorambucil-Fatty Acid Conjugates Against Human Lym 4,088.646 A 5/1978 Ishida et al...... 544/313 phomas And Normal Human Peripheral Blood Lympho E. A CE.81: E.".wer s al ------:E. cytes”,Baldessarini, Biochem et Pharmacol,al. Dopamine (1990),40(6): and Pathophysiology 1193–1200. of 4,554.272 A 11/1985 Bocket al...... si4,219 Ryskinesis: "Ann Rev. Neurosci, 3231 (1989). 4,558,049 A 12/1985 Bernardi et al...... 514/234 Begin, M.E., et al., “Differential Killing Of Human Carci 4,636,494 A 1/1987 Growdon et al...... 514/78 noma Cells Supplemented With N-3 And N-6 Polyunsatu 4,684,646 A 8/1987 Chang et al...... 514/221 rated Fatty Acids”, J Natl Cancer Inst, (1986), 4,692,441 A 9/1987 Alexander et al...... 514/194 77(5):1053-1062. (Abstract). 4,704,393 A 11/1987 Wakabayashi et al...... 514/274 Bourat, et al., “Long Chain Esters of Pipotiazine as Long AS A i Alder, ------5. Acting Psychotropic Pro-Drug, Med. Chem. Proc. Int. 4,814,4702 a-Y-2 A 3/1989 ColinSC etC al.a .... - - - E. Symp. 5th (1976) pp. 105 114. 4,857,653 A 8/1989 Colin et al...... 549/511 (List continued on next page.) 4.902,505 A 2/1990 Pardridge et al. . ... 424/85.7 Primary Examiner William R. A. Jarvis 4,939,174.4,933,324 A 7/19906/1990 Shashoua...... Shashoua ...... Is..., 514/17 (74) Attorney, Agent, or Firm . Wolf,. . . Greenfield & Sacks, 4,943,579 A 7/1990 Vishnuvajala et al... 514,283 C, 4.968,672 A 11/1990 Jacobson et al...... 514/46 (57) ABSTRACT 5,059,699 A 10/1991 Kingston et al. 5,112,596 A 5/1992 Malfroy-Camine ...... 424/2 The invention provides conjugates of fatty acids and anti 5,112,863 A 5/1992 Hashimoto et al...... 514/534 Viral agents useful in treating liver disorders. 5,116,624 A 5/1992 Horrobin et al...... 424/702 5,120,760 A 6/1992 Horrobin ...... 514/458 5 Claims, 14 Drawing Sheets US 6,576,636 B2 Page 2

U.S. PATENT DOCUMENTS WO WO95/13271 5/1995 WO WO95/33736 12/1995 5,459.256 A 10/1995 Marquez et al. WO WO 96/O1259 1/1996 5,466.841 A 11/1995 Horrobin et al...... 554/79 WO WO 96/04001 2/1996 5,468,754 A 11/1995 Hausheer et al...... 514/283 WO WO 96/12696 5/1996 5,473,055 A 12/1995 Mongelli et al...... 530/329 WO WO 96/22303 7/1996 5,476.954. A 12/1995 Bourzat et al...... 549/510 WO WO 96/27380 9/1996 5,484.809 A 1/1996 Hostetler et al...... 514/449 WO WO 96/34855 11/1996 5,504,102 A 4/1996 Agharkar et al. . ... 514/449 WO WO 96/34858 11/1996 5,516,800 A 5/1996 Horrobin ...... 514/560 WO WO 97/44026 11/1997 5.532,374. A 7/1996 Lee et al...... 546/167 WO WO 97/44063 11/1997 5,534,499 A 7/1996 Ansell WO WO 97/44336 11/1997 5,545,719 A 8/1996 Shashoua ...... 530/345 WO WO 98/17325 4/1998 5,580,556 A 12/1996 Horribin ...... 424/85.4 WO WO 98/21223 5/1998 5,580,899 A 12/1996 Mayhew et al...... 514/449 WO WO 98/32718 7/1998 5,604.216 A 2/1997 Horrobin ...... 514/182 WO WO 99/52887 10/1999 5,646,180 A 7/1997 Chaturvedi 514/471 ZA 96.03433 A 10/1996 5,654,290 A 8/1997 Bayon et al...... 514/77 5,716,614 A 2/1998 Katz et al...... 424/94.3 OTHER PUBLICATIONS 5,750,572 A 5/1998 Bruzzese ...... 514/560

5,795,909 A 8/1998 Shashoua et all ... 514/449 Burns, C.P., et al., “Effect Of On 5,827,819 A 10/1998 Yatvin et al...... 514/2 Rate Of Differentiation Of Hl-60 Human Leukemia, Can 5,919,815 A 7/1999 Bradley et al...... 514/449 cer Res, (1989), 49:3252–3258. 5,922,695 A 7/1999 Arimilli et al. Carboni et al., “Synthesis of a Photoaffinity Analog of Taxol 5,925,669 A 7/1999 Katz et al...... 514/449 as an Approach to Identify the Taxol Binding Site on 5,955.459 A 9/1999 Bradley et al...... 514/220 Microtubules”,Journal of Medicinal Chem. (Sep. 8, 1992). 5,977,061 A 11/1999 Holyet al. Chajes, V., et al., “Influence Of N-3 Fatty Acids. On The 5,977,0895,977,174. A 11/1999 ArimiiBradley et al...... s4S4 Growth of Human Breast Cancer Cells. In Vitro.f--- . Relation 5,985,854 A 11/1999 Kozak ship To Peroxides And Vitamin-E, Breast Cancer Res 5,994,392 A 11/1999 Shashoua...... 514,437 Treat, (1995), 34:199–212. 6,005,004 A 12/1999 Katz et al...... 514/549 de Antueno, R.J., et al., “In Vitro Effect Of Eicosapentaenoic 6,024,977 A 2/2000 Yatvin et al...... 424/450 And Docosahexaenoic Acids. On Prostaglandin E2 Synthesis 6,043,230 A 3/2000 Arimilli et al. In A Human Lung Carcinoma", Biochem Int, (1989), 6,069.249 A 5/2000 Arimilli et al. 19(3):489–496. (Abstract). 6,077,837 A 6/2000 Kozak de Smidt, P.C., et al., “Characteristics Of ASSociation Of 6,080,877 A 6/2000 Swindell et al...... 549/510 Oleoyl Derivatives Of 5-Fluorodeoxy-Uridine And Meth 6,136,796.6,107,499 A 10/20008/2000 ShashouaKozak ...... 554/78 otrexate With Low-Density Lipoproteins (Ldl)”,ss Pharm 6,166,089 A 12/2000 Kozak Res, (1992), 9(4):565-569. 6,225,460 B1 5/2001 Bischofberger et al. Deutsch, H.F., et al., “Cytotoxic Effects Of Daunomycin 6.245,811 B1 6/2001 Horrobin et al. Fatty Acid Complexes On Rat Hepatoma”, CELLS, Cancer 6.252,060 B1 6/2001 Hostetler Res, (1983), 43:2668–2672. 6,281,376 B1 8/2001 Whittaker et al. Dhopeshwarker, G., “Fatty Acid Transport Through the 6,291,690 B1 9/2001 Mayhew et al. Blood-Brain Barrier.”, Biochim Biophys. Acta 255:572-579 2001/OOO6962 A1 7/2001 Myhren et al. (1985). D’Orlando, et al., “Citicoline (CDP-Choline): Mechanisms FOREIGN PATENT DOCUMENTS of Action and Effects in Ischemic Brain Injury”, Neurol. Res. JP 6O16548 A 1/1994 (1995) 17:281–284. JP 6O72868 3/1994 Ehringer, W., et al., “A Comparison Of The Effects Of JP 70821.46 3/1995 Linolenic ( 18:3 Omega 3) And Docosahexaenoic (22:6 JP 8O27010 A 1/1996 Omega 3) Acids. On Phospholipid Bilayers”, Chem Phys JP 8151334 6/1996 Lipids, (1990), 54.79-88. JP 8163991 6/1996 Falconer, J.S., et al., Effect Of Eicosapentaenoic Acid And JP 9025231 A 1/1997 JP 9030963 2/1997 Other Fatty Acids. On The Growth. In Vitro Of Human WO Pancreatic Cancer Cell Lines, Br. J. Cancer, (1994.) WO 85/OO520 2/1985 69:826-832. WO WO 89/02733 4/1989 WO WO 89/07938 9/1989 Ferrari et al., “9-Cis-6,6'-Diapo-Gamma, Gamma-Caro WO WO 90/00555 1/1990 tenedioic Acid Derivatives And Pharmaceutical Composi WO WO 92/20362 11/1992 tions Containing Them', p. 710. Abs. 20423W, Chem. Abs. WO WO 93/00910 1/1993 95(23), 12/7/81, EP30,009 06/10/81 06/10/81 (1981). WO WO 93/11668 6/1993 Garzon-Aburbeh, et al., “A Lymphotropic Product of WO WO 94/07880 4/1994 L-Dopa: Synthesis” J. Med. Chem. 29: 687-691 (1986). WO WO 94/11547 5/1994 WO WO 94/12530 6/1994 Georget al., “The Medicinal Chemistry of Taxol”, in “Taxol WO WO 94/13654 6/1994 Science And Applications' ed. Matthew Suffness. Boca WO WO 94/22887 10/1994 Raton: CRC Press, Inc., 1995, pp. 317-375. WO WO 94/24107 10/1994 Guffy, M.M., et al., “Effect Of Cellular Fatty Acid Alteration WO WO95/O1969 1/1995 On Adriamycin Sensitivity In Cultured L1210 Murine Leu WO WO95/13270 5/1995 kemia Cells”, Cancer Res, (1984), 44:1863–1866. US 6,576,636 B2 Page 3

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Dischino et al., “Synthesis of the Monosodium Salt of Hong et al., "Nucleoside-ether lipid conjugates as biotrans Carbon-14 Labeled Paclitaxel (Taxol?F) 2-Ethyl Carbonate formed prodrugs of antitumor and antiviral nucleosides,” J. 7-Phosphonooxymethyl Ether, a Potential Prodrug of Pacli Lipid Mediators Cell Signalling (1994), 10, 159–161. taxel, J. of Labelled Compounds and Radiopharmaceuti cals, vol. XXXIX, No. 2, 1996. Pouillart “Role of butyric acid and its derivatives in the Greenwald, et al., “Hightly Water Soluble Taxol Deriva treatment of colorectal cancer and hemoglobinopathies,” tives: 7-Polyethylene Glycol Carbamates and Carbonates”, Life Sci. (1998), 63(20), 1739–1760. J. Org. Chem. 1995, 60, pp. 331-336. Halmos et al., “Fatty acid conjugates of Ueda, et al., “Synthesis and Antitumor Evaluation of 2'-deoxy-5-fluorouridine as prodrugs for the selective 2'-Oxycarbonylpaclitaxels (Paclitaxel-2'-Carbonates)”, delivery of 5-fluorouracil to tumor cells,” Biochem. Phar Bioorganic & Medicinal Chemistry Letters, vol. 4, No. 15, macol. (1992), 44(1), 149-155. pp. 1861–1864, 1994. U.S. Patent Jun. 10, 2003 Sheet 1 of 14 US 6,576,636 B2

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H s O n1 CD l O L

H9 Z O Y n

1 O -9 -8 -7 -6 LOGO OF SAMPLE CONCENTRATION (MOLAR) SF-268-O- SF-295 --K)-- SF-539 - - - A- - - SNB-75 -- O - - U251 - 0 SNB-19. . . . o. . . . . Fig. 22 U.S. Patent Jun. 10, 2003 Sheet 12 of 14 US 6,576,636 B2

MELANOMA

1 O -9 -8 -7 -6 LOG-10 OF SAMPLE CONCENTRATION (MOLAR) LOX IMV -o- SK-MEL-5 -, -0--- SK-MEL-2..... -0..... SK-MEL-28 - - O - - M14 --- a-- UACC-62 -...--...- MALME-3M--O-- UACC-257- - A - Fig. 23

OVARAN CANCER

10 -9 -8 -7 -6 LOG10 OF SAMPLE CONCENTRATION (MOLAR) GROV1 -O- OVCAR-3--O-- OVCAR-4--a- - OCVAR-8 - - O - SK-OV-3-...-0.-Fig. 24 OVCAR-5"O'" U.S. Patent Jun. 10, 2003 Sheet 13 of 14 US 6,576,636 B2

RENAL CANCER

H s O 1. CD O L CD CC H Z O -50 Y I ? - 1 OO - 10 -9 -8 -7 -6 LOGO OF SAMPLE CONCENTRATION (MOLAR) 786-O-O- A498--K) - ACHN---a- - - CAK-1: ....O..... RXF 393 - - O - - SN 12C -- 0- - TK-10--- A.- : Ud)31-...- ... 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. -O-- 26 U.S. Patent Jun. 10, 2003 Sheet 14 of 14 US 6,576,636 B2

BREAST CANCER

H S O 1. CD - O L

9H Z O Y ?

-10 -9 - a -7 -6 LOG10 OF SAMPLE CONCENTRATION (MOLAR) MCF 7-O- MDA-N---0--- HS 578T...... MDA-MB-435--O-- MDA-MB-231/ -- A- - T-47D--...- MCF 7/ADR-RE--C)-- BT-549-...-A-...- Fig. 27 US 6,576,636 B2 1 2 METHOD OF TREATING ALIVER Taxanes have the basic three ring structure (A, B and C), DSORDER WITH FATTY ACID-ANTIVIRAL Substituted or unsubstituted. AGENT CONJUGATES Taxol's carbons are numbered conventionally as follows:

This application is a continuation of Ser. No. 08/651,428, filed May 22, 1996, now abandoned. BACKGROUND OF THE INVENTION Improving drug Selectivity for target tissue is an estab 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 particu larly 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 Based upon the taxanes tested to date, as many questions anti-cancer agent on normal, healthy tissue. The problems 15 have been raised as have been answered, and general rules relating to lack of drug Selectivity can be exemplified by have not been fashioned easily in predicting Selectivity, TaxolcE). activity and Solubility. Firstly, no rules have emerged regard Taxol.E) (paclitaxel) was first isolated in 1971 from the ing Selectivity. Those taxanes that are strongly active appear bark of Taxus brevifolia and was approved in 1992 by the US to have activity as broad as Taxol's activity, and no headway Food and Drug Administration for treatment of metastatic appears to have been made in terms of developing a more ovarian cancer and later for breast cancer. Its mechanism of Selective Taxol analog. action is believed to involve promoting formation and Some information about activity has emerged. Numerous hyperStabilization of microtubules, thereby preventing the substitutions have been made at C7, C9, C10, C19, R and disassembly of microtubules necessary for completion of combinations thereof while retaining Significant, but usually cell division. It also has been reported that Taxol induces expression of cytokines, affects the activity of kinases and 25 reduced, activity. Substitutions at C2, C4 and 2'OH, blockS processes essential for metastasis, in as yet unchar however, are generally not tolerated. These conclusions are acterized mechanisms of action. only generalities, for example, because Some Substitutions at Taxol has attracted unusually Strong Scientific attention, C9-C10 (cyclic derivatives) are not tolerated and some not only because of its unique antiproliferative mechanism Substitutions at C2 (meta Substitutions on the phenyl) are of action, but also because it is active against nearly all tolerated. Likewise, the C13 Side chain and, in particular, the cancers against which it has been tested and because it has 2OH are required, although the minimum Structural require been discovered to be an analog of numerous closely related ments of the side chain have not been determined for compounds occurring naturally. These compounds, taxanes, therapeutic efficacy. are now recognized as a new class of anticancer compounds. Attempts to improve Taxol's solubility have not resulted Taxol's Strength against cancers of diverse tissue origin 35 in Successful clinical products. One approach has been to also represents a Significant drawback. An ideal anticancer manufacture prodrugs of Taxol, which prodrugs undergo in agent has tissue specificity, thereby reducing Side-effects on Vivo transformation into Taxol and Some other product. normal (dividing) cells. Taxol analogs with tissue specificity Attempts were made to esterify the C7 hydroxy and 2 therefore are desired. Another drawback of Taxol is its hydroxy groups, with the hope that the bond would be stable extreme insolubility. Taxol can be administered effectively 40 in Solution (to permit preferred administration modes-i.V. in a Solvent including cremophor, which combination can over at least 24 hours) but would cleave readily in vivo. The provoke Severe hyperSensitive immune responses. AS a groupS tested were all hydrophilic and included amines, result of these drawbacks, and also as a result of the potential Short carboxylic acids (using e.g. Succinic anhydride and for modifying Taxol at numerous Sites as demonstrated by glutaric anhydride), Sulfonic acids, amino acids and phos other naturally-occurring taxanes with anticancer activity, a 45 phates. Generally, activity was reduced although Some Suc Search for more Selective taxanes was launched. ceSS was obtained with certain derivatives. Again, no par To date, more than 200 taxanes have been synthesized (or ticular pattern emerged permitting one to predict reliably isolated) and tested in vitro or in Vivo for anticancer activity. which groups could be substituted on Taxol to yield a The results, however, have been So disappointing that the therapeutically useful product, although it was Suggested National Cancer Institute (NCI) generally no longer is interested in testing Taxol analogs. In general with Taxol 50 that the 2' OH derivatives may cleave more easily than the analogs, the Solubility problems remain, and/or potency is C7 OH derivatives. Sharply reduced, and/or Selectivity is not improved, and/or Several other factors add to the problem of predicting the ratio of the median toxic dose to the median effective which Taxol analogs will be effective. Multiple mechanisms dose (“therapeutic index') is unacceptably reduced. of action have been proposed in the literature, and a change Taxol has the following formula: 55 in one position may have no effect on activity on one Such mechanism but may eliminate activity on another mecha

nism. In addition, changes that favorably influence activity AcO O OH may unfavorably influence bioavailability. For example, O Taxol affects microtubule formation inside a cell, but a 60 change in Structure that increases intracellular activity may R1 Ph us NH O II IIH adversely affect the ability of Taxol to gain entry into a cell. Taxol also is known to bind to proteins, and the effect on -Nulls3. S S EN D O activity that results from a change in Taxol's binding to 2 O HO s OAc protein (in terms of conformation, cellular absorption and OH PhCO 65 solubility) is unknown. It has been reported that Taxol does not get into the brain, apparently excluded by the blood brain barrier. It is not US 6,576,636 B2 3 4 known why this is So, as Taxol is lipophilic, gets into cells SUMMARY OF THE INVENTION and might be expected to cross the blood brain barrier. The present invention involves the unexpected finding Among the most promising of the two hundred analogs that conjugates of pharmaceutical agents and a highly lipo tested is Taxotere (docetaxel), because of its slightly philic group, a C8-C26, naturally ocurring, unbranched increased activity and solubility. Oddly, however, Taxotere carbon chain, have a different selectivity relative to the differs from Taxol at sites which typically do not have a unconjugated pharmaceutical agents. Strong influence on activity, and one would not predict the In one embodiment, the conjugates render the activity of improvements in Taxotere from these differences, even in these conjugates Selective, in general, for colon tissue, breast 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 activity of these conjugates relative to that of the unconju 15 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 index of the conjugates is improved, verSuS that of the unconjugated pharmaceutical agents. According to one aspect of the invention, a method is 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 condition. A conjugate of a C8-C22, unbranched, naturally help the drugs as conjugates cross the blood brain barrier. 25 occurring fatty acid and a pharmaceutical agent is adminis DHA (docosahexaenoic acid) is a 22 carbon naturally tered to a Subject in need of Such treatment. In certain occurring, unbranched fatty acid that previously has been embodiments, the tissue is breast tissue, gastrointestinal shown to be unusually effective, when conjugated to a drug, tissue and ovarian tissue and the condition calls for treat in crossing the blood brain barrier. DHA is attached via the ment of breast tissue, gastrointestinal tissue or ovarian acid group to hydrophilic drugs and renders these drugs tissue, respectively. In other embodiments, the tissue can be more hydrophobic (lipophilic). DHA is an important con tissue of the Blood and Blood Forming system: including Stituent of the brain and recently has been approved as an platelets, blood vessel wall, and bone marrow, Cardiovas additive to infant formula. It is present in the milk of cular System: including heart and vascular system; Digestive lactating women. The mechanism of action by which DHA and excretory System: including alimentary tract, biliary helps drugs conjugated to it croSS the blood brain barrier is 35 tract, kidney, liver, pancreas and urinary tract; Endocrine unknown. System: including adrenal gland, kidney, ovary, pituitary Another example of the conjugation of fatty acids to a gland, renal gland, Salivary gland, Sebaceous gland, testis, drug is the attachment of pipotiazine to Stearic acid, palmitic thymus gland and thyroid gland; Muscular System: includ acid, enanthic acid, undecylenic acid or 2,2-dimethyl ing muscles that move the body. Reproductive System: palmitic acid. Pipotiazine is a drug that acts within the 40 including breast, ovary, penis and uterus, Respiratory Sys central nervous System. The purpose of conjugating pipo tem: including bronchus, lung and trachea, Skeletal System: tiazine to the fatty acids was to create an oily Solution of the including bones and joints, Tissue, fiber, and integumentary drug as a liquid implant for slow release of the drug when System: including adipose tissue, cartilage, connective injected intramuscularly. The release of the drug appeared to tissue, cuticle, dermis, epidermis, epithelium, fascia, hair depend on the particular fatty acid Selected, and the drug was 45 follicle, ligament, bone marrow, melanin, melanocyte, tested for its activity in the central nervous System. mucous membrane, skin, Soft tissue, Synovial capsule and Lipidic molecules, including the fatty acids, also have tendon. been conjugated with drugs to render the conjugates more Unbranched, naturally occurring fatty acids embraced by lipophilic than the drug. In general, increased lipophilicity the invention include C8:0 (caprylic acid), C10:0 (capric has been Suggested as a mechanism for enhancing intestinal 50 acid), C12:0 (lauric acid), C14:0 (myristic acid), C16:0 uptake of drugs into the lymphatic System, thereby enhanc (palmitic acid), C16:1 (palmitoleic acid), C16:2, C18:0 ing the entry of the conjugate into the brain and also thereby (stearic acid), C18:1 (oleic acid), C18:1-7 (vaccenic), avoiding first-pass metabolism of the conjugate in the liver. C18:2-6 (linoleic acid), C18:3-3 (O-linolenic acid), The type of lipidic molecules employed have included C18:3-5 (eleostearic), C18:3–6 (8-linolenic acid), C18:4-3, phospholipids, non-naturally occurring branched and 55 C20:1 (gondoic acid), C20:2-6, C20:3–6 (dihomo-y- unbranched fatty acids, and naturally occurring branched linolenic acid), C20:4-3, C20:4-6 (arachidonic acid), and unbranched fatty acids ranging from as few as 4 carbon C20:5-3 (eicosapentaenoic acid), C22:1 (docoSenoic acid), atoms to more than 30 carbon atoms. In one instance, C22:4-6 (do cosate tra e no ic acid), C22:5-6 enhanced receptor binding activity was observed (for an (docosapentaenoic acid), C22:5-3 (docosapentaenoic), adenosine receptor agonist), and it was postulated that the 60 C22:6-3 (docosahexaenoic acid) and C24:1-9 (nervonic). pendant lipid molecule interacted with the phospholipid Highly preferred unbranched, naturally occurring fatty acids membrane to act as a distill anchor for the receptor ligand in are those with between 14 and 22 carbon atoms. The most the membrane micro environment of the receptor. This preferred fatty acid is docosahexaenoic acid. increase in potency, however, was not observed when the It is preferred that the conjugate be of a single fatty acid Same lipid derivatives of adenosine receptor antagonists 65 molecule and the covalent attachment be directly to the were used, and generalizations thus were not made possible pharmaceutical agent (i.e., free of a linker molecule between by those studies. the active pharmaceutical agent and the fatty acid. US 6,576,636 B2 S 6 The pharmaceutical agent may be any pharmacological anti-cancer agents are described in greater detail in the compound or diagnostic agent, as desired. The pharmaceu Specification. Included are the taxanes, (e.g., Taxol and tical agent, however, is not an adenosine receptor agonist or Taxotere). Conjugates of C8-C22, unbranched, naturally antagonist. The pharmaceutical agent, of course, has an occurring fatty acids and taxoids also are embraced by the activity outside of the central nervous System. invention. Examples of catagories of pharmaceutical agents include: C8-C26 fatty acids previously have been conjugated to adrenergic agent, adrenocortical ; adrenocortical Sup preSSant; alcohol deterrent, aldosterone antagonist, amino drugs that are active in the central nervous System. The acid; ammonia detoxicant; anabolic; analeptic, analgesic, invention thus also contemplates the use of C8-C22, androgen; anesthesia, adjunct to; anesthetic, anorectic, unbranched, naturally occurring fatty acids in the manufac antagonist, anterior pituitary SuppreSSant; anthelmintic, anti ture of a medicament for treating a noncentral nervous agent, anti-adrenergic, anti-allergic, anti-amebic, anti System condition. The invention further contemplates com androgen; anti-anemic; anti-anginal; anti-anxiety; anti positions of matter that are conjugates of C8-C22, arthritic, anti-asthmatic, anti-atherOSclerotic, antibacterial; unbranched, naturally occurring fatty acids and noncentral anticholelithic, anticholelithogenic, anticholinergic, antico nervous System active pharmaceutical agents. agulant; anticoccidal; anticonvulsant; antidepressant; 15 A noncentral nervous System active pharmaceutical agent antidiabetic, antidiarrheal; antidiuretic, antidote, anti is one that has no function or use in the central nervous emetic, anti-epileptic, anti-estrogen; antifibrinolytic, anti System. Its only therapeutic use is outside of the central fungal, antiglaucoma agent; antihemophilic; antihemor nervous System. Examples of Such pharmaceutical agents rhagic; antihist a mine; antihyper lipidemia; include, but are not limited to: Blood glucose regulators, antihyperlipoproteinemic, antihypertensive; antihypoten Such as tola Zamide, tolbutamide, chlorpropamide, Sive, anti-infective; anti-infective, topical; anti acetohexamide, and, glipizide, HMGco A reductase inflammatory; antikeratinizing agent, antimalarial; antimi inhibitors, such as Lovastatin (Mevacor), Simvastatin crobial; antimigraine; antimitotic; antimycotic, (Zocor), Pravastatin (Pravachol), and, Fluvstatin (Lescol); antinauseant, antineoplastic, antineutropenic, antiobessional Muscosal Protectives, such as Misoprostol (Cytotec); Gas agent, antiparasitic, antiparkinsonian; antiperistaltic, antip 25 trointestinal Motality affectors, Such as Cisapride neumocystic, antiproliferative; antiprostatic hypertrophy; (Propulsid), Metoclopramide (Reglan), and, Hyoscyamine antiprotozoal; antipruritic, antipsychotic, antirheumatic; (Levsin); Antidiarrheals, Such as Diphenoxylate hydrochlo antischistosomal; antiseborrheic, antisecretory; antispas ride (Lomotil), Metronidazole (Flagyl), modic, antithrombotic, antituSSive, anti-ulcerative; anti (Medrol), and, Sulfasalazine (AZulfidine); and Hormones urolithic, antiviral; appetite SuppreSSant; benign prostatic for treating, inter alia, ovarian conditions, Such as hyperplasia therapy agent, blood glucose regulator, bone , Norgestrel, Norethynodrel, Norethindrone, resorption inhibitor, bronchodilator; carbonic anhydrase Levonorgestrel, Ethyndiol, Mestranol, Estrone, Equilin, 17 inhibitor, cardiac depressant, cardioprotectant; cardiotonic; alpha dihydroeduilin, equilenin, 17 alpha dihydroeguilenin, cardiovascular agent; choleretic, cholinergic, cholinergic 17 alpha esradiol, 27 bea estradiol, Leuprolide (Lupron), agonist, cholinesterase deactivator, coccidioStat; cognition 35 Testolactone, Climiphene, urofollitropin, bromocriptine, adjuvant; cognition enhancer, depressant, diagnostic aid; gonadore lin, dana Zol, dehydroepiandro Sterone, diuretic, dopaminergic agent, ectoparasiticide, emetic; andro Stenedione, dihydrote Stosterone, Relaxin, enzyme inhibitor; estrogen; fibrinolytic, fluorescent agent; folliculostatin, Follicle regulatory protein, Gonadocrinins, free oxygen radical Scavenger, gastrointestinal motility Oocyte maturation inhibitor and, Insulin growth factor. effector; ; gonad-stimulating principle; hair 40 growth Stimulant; hemostatic; histamine H2 receptor Other compounds are detailed below. antagonists, hormone, hypocholesterolemic, hypoglycemic, The methods of the invention are useful for treating a hypolipidemic, hypotensive; imaging agent, immunizing variety of medical conditions including conditions involving agent; immunomodulator; immunoregulator; immunostimu abnormal mammalian-cell proliferation. They further are lant; immunosuppressant, impotence therapy adjunct; 45 useful in treating diabetes and its complications, excess acid inhibitor, keratolytic; LHRH agonist; liver disorder treat Secretion, cardiovascular conditions involving cholesterol ment; luteolysin; memory adjuvant; mental performance (e.g., hyperlipidemia and hypercholesterolemia), diarrhea, enhancer, mood regulator, mucolytic, mucosal protective ovarian diseases (e.g. endometriosis, ovarian cysts, etc.) and agent, mydriatic, nasal decongestant; neuromuscular block as contraceptive agents. Other conditions treatable accord ing agent; neuroprotective; NMDA antagonist; non 50 ing to the invention will be apparent to those skilled in the hormonal Sterol derivative, Oxytocic, plasminogen activator; art based upon the disclosure and lists of compounds pro platelet activating factor antagonist, platelet aggregation vided. inhibitor, post-Stroke and post-head trauma treatment; The methods and/or products of the invention also are potentiator, progestin, prostaglandin; prostate growth inhibi useful in treating conditions Specific to noncentral nervous tor, prothyrotropin; psychotropic, pulmonary Surface; radio 55 System tissue. Such conditions can be specific to any of the active agent, regulator, relaxant, repartitioning agent, Scabi tissues described above, including breast, gastrointestinal cide, Sclerosing agent, Sedative, Sedative-hypnotic, Selective and ovarian tissue. adenosine Al antagonist; Serotonin antagonist; Serotonin BRIEF DESCRIPTION OF THE DRAWINGS inhibitor, Serotonin receptor antagonist; Steroid; Stimulant; SuppreSSant; Symptomatic multiple Sclerosis, Synergist; thy 60 FIG. 1 is a graph plotting concentration of conjugate 1 roid hormone; thyroid inhibitor; thyromimetic; tranquilizer; Versus percent growth of leukemia cells. amyotrophic lateral Sclerosis agent; cerebral ischemia agent; FIG. 2 is a graph plotting concentration of conjugate 1 Paget's disease agent; unstable angina agent, uricoSuric; Versus percent growth of non-Small cell lung cancer cells. vasoconstrictor; vasodilator; Vulnerary, wound healing FIG. 3 is a graph plotting concentration of conjugate 1 agent; Xanthine oxidase inhibitor. 65 Versus percent growth of colon cancer cells. In one particularly preferred embodiment of the FIG. 4 is a graph plotting concentration of conjugate 1 invention, the drug is an anti-cancer agent. Examples of versus percent growth of CNS cancer cells. US 6,576,636 B2 7 8 FIG. 5 is a graph plotting concentration of conjugate 1 DETAILED DESCRIPTION OF THE Versus percent growth of melanoma cells. INVENTION FIG. 6 is a graph plotting concentration of conjugate 1 Versus percent growth of ovarian cancer cells. cis-docosahexaenoic acid (DHA) is a naturally occurring FIG. 7 is a graph plotting concentration of conjugate 1 5 fatty acid. It is an unbranched chain fatty acid with Six Versus percent growth of renal cancer cells. double bonds, all cis. Its structure is as follows: FIG. 8 is a graph plotting concentration of conjugate 1 OH Versus percent growth of prostate cancer cells. FIG. 9 is a graph plotting concentration of conjugate 1 Versus percent growth of breast cancer cells. FIG. 10 is a graph plotting concentration of conjugate 2 Versus percent growth of leukemia cells. DHA can be isolated, for example, from fish oil or can be FIG. 11 is a graph plotting concentration of conjugate 2 chemically Synthesized. These methods, however, can gen erate trans isomers, which are difficult and expensive to versus percent growth of non-Small cell lung cancer cells. 15 Separate and which may present Safety problems in humans. FIG. 12 is a graph plotting concentration of conjugate 2 The preferred method of production is biological Synthesis Versus percent growth of colon cancer cells. to produce the all cis isomer. The preferred source of DHA FIG. 13 is a graph plotting concentration of conjugate 2 is from Martek Biosciences Corporation of Columbia, Md. versus percent growth of CNS cancer cells. 2O Martek has a patented System for manufacturing DHA using FIG. 14 is a graph plotting concentration of conjugate 2 microalgae which Synthesize only a single isomer of DHA, Versus percent growth of melanoma cells. the all cis isomer. Martek’s patents include U.S. Pat. Nos. FIG. 15 is a graph plotting concentration of conjugate 2 5,374,657, 5,492,938, 5.407,957 and 5,397,591. Versus percent growth of ovarian cancer cells. DHA also is present in the milk of lactating women, and FIG. 16 is a graph plotting concentration of conjugate 2 25 Martek’s licensee has obtained approval in Europe of DHA Versus percent growth of renal cancer cells. as a nutritional Supplement for infant formula. FIG. 17 is a graph plotting concentration of conjugate 2 It is known that DHA can be unstable in the presence of Versus percent growth of prostate cancer cells. oxygen. To Stablizie DHA and its conjugates it is important FIG. 18 is a graph plotting concentration of conjugate 2 to add anti-oxidants to the material after it is Synthesized. Versus percent growth of breast cancer cells. 3O One method of Stablization is to make-up the newly Syn FIG. 19 is a graph plotting concentration of Taxol versus thesized material in the following solution: 100 g neat percent growth of leukemia cells. DHA-taxol plus 100 g of vehicle (100 ml propylene glycol, FIG. 20 is a graph plotting concentration of Taxol versus 70 mg alph-tocopherol, 5 mg dialaurylthiodipropionic acid, percent growth of non-Small cell lung cancer cells. 35 50 mg ascorbic acid) prepared and held under argon in amber, Sealed Vials and Stored at four degrees centigrade. FIG. 21 is a graph plotting concentration of Taxol verSuS The following anti-oxidants may also be employed: ascorbic percent growth of colon cancer cells. acid, ascorbyl palmitate, dilauryl ascorbate, hydroquinone, FIG. 22 is a graph plotting concentration of Taxol verSuS butyated hydroxyanisole, Sodium meta bisulfite, t-B caro percent growth of CNS cancer cells. 40 tene and X-tocopherol. A heavy metal chelator Such as FIG. 23 is a graph plotting concentration of Taxol verSuS ethylenediamine tetra-acetic acid (EDTA) may also be used. percent growth of melanoma cells. Paclitaxel was first isolated from the bark of Taxus FIG. 24 is a graph plotting concentration of Taxol verSuS brevifolia (Wani et al., J. Am. Chem. Soc., 93, 2325, 1971). percent growth of ovarian cancer cells. Its isolation and Synthesis have been reported extensively in FIG. 25 is a graph plotting concentration of Taxol versus 45 the literature. Applicants obtained paclitaxel from a com percent growth of renal cancer cells. mercial 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

P h N H O

Ph

Os conjugate 1

65 FIG. 27 is a graph plotting concentration of Taxol verSuS A solution of Taxol (41 umol) in methylene chloride (2.5 percent growth of breast cancer cells. mL) under argon was mixed with 4-dimethylaminopyridine US 6,576,636 B2 9 10 (41 umol), dicyclohexylcarbodiimide (82 umol), and DHA passed through celite, and concentrated. Chromatography of (41 umol) and the reaction mixture was stirred at ambient the residue produced 65.9 mg of intermediate B. A solution temperature for two hours. Following dilution with ether, the of intermediate B (51 umol) in acetonitrile (2 mL) at 0° C. reaction mixture was washed with 5% hydrochloric acid, under argon was mixed with 49% aqueous HF (0.2 mL) and water, Saturated acqueous Sodium chloride, dried, and con the reaction mixture was stirred for one hour. After dilution centrated. Radial chromatography of the residue produced with ether, the reaction mixture was washed with water, 45 mg (94%) of crystalline Taxol-DHA conjugate 1. Saturated aqueous Sodium chloride, dried, and concentrated. Radial chromatography of the residue produced 44.6 mg EXAMPLE 2 (75%) of Taxol-DHA conjugate 2.

O - NH TAXOL He- E Ph E ÖstEt,

conjugate 2

The production of analog 2 involves Several Steps includ EXAMPLE 3 ing a number of protection-acylation-deprotection Steps. A Conjugates 1 and 2 were Sent to the United States solution of Taxol (59 umol) in methylene chloride (2.5 mL) National Cancer Institute (NCI) for screening in the NCI's was mixed at ambient temperature under argon with imida 55 anticancer Screening program. The conjugates were pro zole (147 umol) and triethylsilyl chloride (147 umol). The vided in ethanol (approximately 40 mg analog/2 ml ethanol). The conjugates were Sealed in Vials under argon to avoid reaction mixture was stirred for thirty minutes, diluted with exposure of the conjugates to oxygen because the conjugates additional methylene chloride, washed with water, Saturated were believed to be Sensitive to oxygen. Instructions were aqueous Sodium chloride, dried, and concentrated. Chroma 60 provided to store at 4 C. and to open the vials only when tography of the residue produced 50 mg (88%) of interme ready for immediate experimental use. Instructions also diate A plus 5 mg of the 2, 7-di(triethylsilyl) ether deriva were provided to use the ethanol Solutions containing the tive. A solution of intermediate A (52 umol) in methylene conjugates directly or to dissolve the analogs further in chloride (3 mL) was mixed at ambient temperature under DMSO (dimethylsulfoxide) at appropriate concentrations, argon with 4-dimethylaminopyridine (52 umol), dicyclo 65 with Vortexing if necessary for adequate dispersal. hexylcarbodiimide (104 umol), and DHA (52 umol). The The activities of conjugates 1 and 2 were tested against 57 reaction mixture was Stirred for ten hours, diluted with ether, cancer cell lines. The results are presented in FIGS. 1-9 for US 6,576,636 B2 11 12 conjugate 1, FIGS. 10–18 for conjugate 2 and FIGS. 19–27 To further illustrate the differences in the activity of for Taxol. To understand the data, reference is made to the conjugates 1 and 2 versus that of Taxol, the NCI subjected guides provided by the NCI, excerpted as follows: the data to a statistical analysis designed by the NCI to The Calculated Measurement of Effect: Percentage Growth reflect differences in the pattern of activity of anticancer (PG) agents. Conjugate 1 and conjugate 2 were determined to be The measured effect of the compound on a cell line is statistically different in their pattern of activity versus Taxol currently calculated according to one or the other of the following two expressions: in this unique measurement by the NCI. If (Mean OD-Mean OD -e)20, then It also is to be noted that, in general, conjugates 1 and 2 PG=100x(Mean OD -Mean OD)/(Mean OD were one thousand to ten thousand times less potent than Mean Od) Taxol for many cell lines tested. This reduction in activity is If (Mean OD-Mean OD cer)<0. then important, especially Since conjugates 1 and 2 maintained PG=100x(Mean OD -Mean Ode)/Mean Od Strong activity against Some cell lines. Conjugates 1 and 2 Where: will be Sufficiently active against certain cell lines, but will Mean OD=The average of optical density measurements 15 have, on average, a Substantially and disproportionately of SRB-derived color just before exposure of cells to the test lower activity against other cell lines, reducing potential side compound. effects. For example, the TGI for Taxol against CNS SF-539 Mean OD=The average of optical density measurements is -6.95, and the TGI for conjugate 1 against this cell line is of SRB-derived color after 48 hours exposure of cells to the -5.13 and for conjugate 2 is -5.53. (In other words, the test compound. activity of the conjugates was reduced versus that of Taxol Mean OD=The average of optical density measurements by less than 2 logs). The GI50 for Taxol against CNS SF 539 of SRB-derived color after 48 hours with no exposure of is -7.52, whereas the GI50s for conjugates 1 and 2 are -6.22 cells to the test compound. and -5.56, respectively (again less than 2 logs difference). In Experimental data was collected against each cell line. . . . contrast, Taxol has a GI50 for cell line CNSSF 268 of less Each concentration is expressed as the logo (molar or 25 than -10.0, whereas conjugates 1 and 2 have GI50s for ug/ml). . . . The response parameters GI50, TGI, and LC50 CNSSF 268 of 5.36 and 5.28, respectively. This represents are interpolated values representing the concentrations at a reduction of activity in the conjugates VS. that of Taxol by which the PG is +50, 0, and -50, respectively. Sometimes at least about 5 logs activity. On average, the GI50 for Taxol these response parameters cannot be obtained by interpola across all cell lines tested is at least -9.19. (It is probably tion. If, for instance, all of the PGS in a given row exceed much higher Since concentrations less than -10 were not +50, then none of the three parameters can be obtained by tested, and if Taxol was active at -10.0, -10 (instead of the interpolation. In Such a case, the value given for each actual lower value) was used in calculating the average of response parameter is the highest concentration tested. . . . -9.19. There were 27 instances when this occurred.) The This practice is extended similarly to the other possible average GI50s for conjugates 1 and 2, on the other hand, Situations where a response parameter cannot be obtained by 35 were 5.49 and 5.22, respectively. Therefore, the average interpolation. difference in activity for Taxol VS. the conjugates is at least Dose-Response Curves: between 3 and 4 logs. Thus, the Sharp reduction in the The dose-response curve page of the data package is activity of the conjugates against many cell lines VS. a lesser created by plotting the PGS against the logo of the corre reduction for other cell lines is expected to reduce the sponding concentration for every cell line. The cell line 40 potential Side effects of the conjugates versus those of Taxol curves are grouped by Subpanel. Horizontal lines are pro at effective doses. vided at the PG values of +50, 0, and -50. The concentra tions corresponding to points where the curves croSS these Cancers other than CNS, breast and colon cancer can be lines are the GI50, TGI and LC50, respectively. treated. For example, there was activity against non-Small Several important distinctions are apparent from the data. 45 cell lung cancer cells, melanoma cells and ovarian cancer Most important, the patterns of anticancer actively for cells. However, the activity was relatively reduced and was conjugates 1 and 2 differ from that of Taxol. In one Sense, extremely specific, limiting the utility of the conjugates for conjugates 1 and 2 are effective anticancer agents against a treating generally Such cancers. In any event, cancer patients more restricted Set of cancer cell lines. For example, con could be evaluated to determine if a conjugate is Strongly jugates 1 and 2 were not very effective against any of the Six 50 active against the patient's cancer prior to Selecting the leukemia cancer cell lines tested, whereas Taxol was Some conjugate as the anti-cancer agent of choice for that patient. what effective against all four leukemia cell lines against The foregoing experiments establish that DHA analogs which Taxol was tested. (See FIGS. 1, 10 and 19.) have altered Specificity verSuS that of Taxol for cancer cell The relative activity against members within a class of lines. Because of this altered specificity, it also is clear that cancers also was altered. For example, at TGI (horizontal 55 the conjugates themselves are gaining access into the target line at Zero in the graphs), Taxol was more effective against cells (as opposed to simply releasing Taxol into the envi non-small cell lung cancer line H522 than against H460 (by ronment outside of the cell). Thus, the DHA moiety appears about 3 logs), whereas conjugates 1 and 2 were slightly more to Selectively target certain cell types as opposed to others. effective against H460 than H522. As another example, The ability of the conjugates to gain entry into the targeted Taxol was least effective at TGI against CNSU251, whereas 60 cells was unknown prior to the invention, and the ability of conjugate 1 was most effective against CNSU251 and con the DHA moiety to Selectively target certain cell types was jugates 2 was also very effective against CNSU251(relative unexpected. to other CNS cell lines). As a further example, Taxol was The same is true of DHA-Taxotere covalent conjugates, equivalent in activity toward MDA-N and MDA-MB-435 examples of which are presented below. Taxotere’s Synthesis breast cancer cell lines at all concentrations tested, whereas 65 has been reported extensively in the literature. One example conjugates 1 and 2 were more effective against MDA-N than is Kanazawa, A. et al., J. Organic Chem. 1994, Vol. 59, pp. MDA-MB-435 at all concentrations tested. 1238-1240. US 6,576,636 B2 13 14 EXAMPLE 4

TAXOTERE

DHA?dicyclohexylcarbodiimide 4-dimethylaminopyridine

O conjugate 3

A Solution of Taxotere in methylene chloride under argon the residue is performed to produce Taxotere-DHA conju is mixed with 4-dimethylamin opyridine, gate 3. dicyclohexylcarbodiimide, and DHA. The reaction mixture is Stirred at ambient temperature. Radial chromatography of EXAMPLE 5

HO 9 OSi(CH2CH3)3

TAXOTERE triethylsilyl chloride NH III IIH DHA?dicyclohexylcarbodiimide --- E He imidazole 1N1a w O 4-dimethylamonipyridine Ph O HO O OAc C (CH-CH2)SiO 1. O Ph

o o o o o o O

O 9 OSi(CH2CH) O

X- NHE III IIH Heaqueous HF 1\-1No f O HO O ÖAc D (CH-CH2)SiO 1. O Ph

o o o o o o O

X O - s H

conjugate 4 H US 6,576,636 B2 15 16 A solution of Taxotere in dimethylformamide is mixed at A solution of Taxotere in dimethylformamide is mixed at ambient temperature under argon with imidazole and trieth ambient temperature under argon with imidazole and tert ylsilyl chloride. The reaction mixture is stirred at ambient butylydimethylsilyl chloride. The reaction mixture is stirred temperature, diluted with methylene chloride, washed with at ambient temperature, diluted with methylene chloride, water, Saturated acqueous Sodium chloride, dried, and con washed with water, Saturated acqueous Sodium chloride, centrated. Radial chromatography of the residue is per dried, and concentrated. Radial chromatography of the resi formed to produce intermediate C. A Solution of intermedi due is performed to produce intermediate E. A Solution of ate C in methylene chloride is mixed at ambient temperature intermediate E in methylene chloride is mixed at ambient under argon with 4 dimethylaminopy ridine, temperature under argon with 4-dimethylaminopyridine, dicyclohexylcarbodiimide, and DHA. The reaction mixture dicyclohexylcarbodiimide, and 1 equivalent of DHA. The is stirred at ambient temperature, diluted with ether, passed through celite, and concentrated. Radial chromatography of reaction mixture is Stirred at ambient temperature, diluted the residue is performed to produce intermediate D. A with ether, passed through celite, and concentrated. Radial Solution of intermediate D in acctonitrile at 0° C. under chromatography of the residue is performed to produce argon is mixed with 49% acqueous HF and the reaction 15 intermediate F. (Intermediate H also is obtained and used in mixture is stirred at the same temperature. After dilution Example 8 below.) A solution of intermediate F in acetoni with ether, the reaction mixture is washed with water, trile at 0°C. under argon is mixed with aqueous HF and the Saturated acqueous Sodium chloride, dried, and concentrated reaction mixture is stirred at the same temperature. After Radial chromatography of the residue is performed to pro dilution with ether, the reaction mixture is washed with duce Taxotere-DHA conjugate 4. water, Saturated aqueous Sodium chloride, dried, and con centrated Radial chromatography of the residue is performed EXAMPLE 6 to produce Taxotere-DHA conjugate 4.

HO O

tert-butyldiethylsilyl chloride H 1 equivalent DHA TAXOTERE --- He imidazole dicyclohexylcarbodiimide 1S-1Ns 4-dimethylaminopyridine HO 6 ÖAc E tert-C4Ho(CH3)2SiO O Ph

aqueous HF

conjugate 4 US 6,576,636 B2 17 18 EXAMPLE 7

HO O OH

tert-butyldiethylsilyl chloride IIIH DHA/dicyclohexylcarbodiimide TAXOTERE - - He imidazole 1N1\os s O 4-dimethylaminopyridine tert-CH0(CH3)2SiO E

o o o o o o O O

O aqueous HF --- ,

conjugate 5

A solution of Taxotere in dimethylformamide is mixed at through celite, and concentrated. Radial chromatography of ambient temperature under argon with imidazole and tert the residue is performed to produce intermediate G. A butylydimethylsilyl chloride. The reaction mixture is stirred Solution of intermediate G in acetonitrile at 0° C. under at ambient temperature, diluted with methylene chloride, 45 argon is mixed with aqueous HF and the reaction mixture is washed with water, Saturated aqueous Sodium chloride, Stirred at the same temperature. After dilution with ether, the dried, and concentrated. Radial chromatography of the resi reaction mixture is washed with water, Saturated aqueous due is performed to produce intermediate E. A Solution of Sodium chloride, dried, and concentrated. Radial chroma intermediate E in methylene chloride is mixed at ambient tography of the residue is performed to produce Taxotere temperature under argon with 4-dimethylaminopyridine, 50 DHA conjugate 5. dicyclohexylcarbodiimide, and DHA. The reaction mixture is stirred at ambient temperature, diluted with ether, passed EXAMPLE 8

OH

tert-butyldimethylsilyl chloride H O I I IIH 1 equivalent DHA X --- TAXOTERE - C imidazole O dicyclohexylcarbodiimide 4-dimethylaminopyridine Ph --- tert-CH0(CH3)2SiO US 6,576,636 B2 19 20 -continued

aqueous HF -es

Ph conjugate 6

A Solution of taxotere in dimethylformamide is mixed at Epinephrine Bitaritrate; Epinephryl Borate; Esproquin ambient temperature under argon with imidazole and tert Hydrochloride; Etafedrine Hydrochloride; Hydroxyamphet butylydimethylsilyl chloride. The reaction mixture is stirred amine Hydrobromide; Levonordefrin; Mephentermine Sul at ambient temperature, diluted with methylene chloride, fate; Metaraminol Bitartrate; Metizoline Hydrochloride; washed with water, Saturated aqueous Sodium chloride, Naphazoline Hydrochloride; Norepinephrine Bitartrate; dried, and concentrated. Radial chromatography of the resi Oxidopamine; Oxymetazoline Hydrochloride; Phenyleph due is performed to produce intermediate E. A Solution of 35 rine Hydrochloride; Phenylpropanolamine Hydrochloride; intermediate E in methylene chloride is mixed at ambient Phenylpropanolamine Polistirex, Prenalterol Hydrochloride; temperature under argon with 4-dimethylaminopyridine, Propylhexedrine; Pseudoephedrine Hydrochloride; Tetrahy dicyclohexylcarbodiimide, and 1 equivalent of DHA. The drozoline Hydrochloride; Tramazoline Hydrochloride; reaction mixture is Stirred at ambient temperature, diluted 40 Xylometazoline Hydrochloride. with ether, passed through celite, and concentrated. Radial Adrenocortical Steroid: , DeSoxycorticos chromatography of the residue is performed to produce terone Acetate, DeSoxycorticosterone Pivalate, Dexametha intermediate H (and intermediate F which was used above Some Acetate, Acetate, ; on Example 6. A Solution of intermediate H in acetonitrite at Hemisuccinate; Methylprednisolone O C. under argon is mixed with aqueous HF and the reaction 45 Hemisuccinate; ; ; Timobesone mixture is stirred at the same temperature. After dilution Acetate, . with ether, the reaction mixture is washed with water, Adrenocortical Suppressant: Aminoglutethimide; Trilos Saturated aqueous Sodium chloride, dried, and concentrated. tane. Radial chromatography of the residue is performed to pro duce Taxotere-DHA conjugate 6. Alcohol deterrent: Disulfiram. 50 Aldosterone antagonist: Canrenoate Potassium, Can DHA and other naturally occurring, unbranched fatty renone; Dicirenone; Mexrenoate Potassium; Prorenoate acids may be conjugated to virtually any drug compound or Potassium, . diagnostic agent and used according to the methods of the Amino acid: Alanine, Aspartic Acid, Cysteine Hydrochlo present invention So long as the pharmaceutical agent has a ride, Cystine, Histidine; Isoleucine; Leucine, Lysine; Lysine use outside of the central nervous System. Pharmaceutical 55 agents include the following categories and Specific Acetate; Lysine Hydrochloride; Methionine; Phenylalanine; examples. It is not intended that the category be limited by Proline; Serine; Threonine; Tryptophan; Tyrosine; Valine. the specific examples. Those of ordinary skill in the art will Ammonia detoxicant: Arginine: Arginine Glutamate; be able to identify readily those pharmaceutical agents that Arginine Hydrochloride. have utility outside of the central nervous system. Those of 60 Anabolic: Bolandiol Dipropionate; Bolasterone; Bold ordinary skill in the art will recognize also numerous other enone Undecylenate; Bolenol; Bolmantalate; Ethylestrenol; compounds that fall within the categories and that are useful Methenolone Acetate; Methenolone Enanthate; Mibolerone; according to the invention. Nandrolone Cyclotate; Norbolethone; Pizotyline; Quin Adrenergic: Adrenalone, Amidephrine MeSylate; Apra bolone; Stenbolone Acetate; ; Zeranol. clonidine Hydrochloride; Brimonidine Tartrate; Dapiprazole 65 Analeptic: Modafinil. Hydrochloride; Deterenol Hydrochloride; Diplivefrin; Analgesic: Acetaminophen; Alfentanil Hydrochloride; Dopamine Hydrochloride; Ephedrine Sulfate; Epinephrine; Aminobenzoate Potassium; Aminobenzoate Sodium; Ani US 6,576,636 B2 21 22 doXime, Anileridine, Anileridine Hydrochloride; Anilopam Hydrochloride; Cocaine; Cocaine Hydrochloride; Cyclopro Hydrochloride; Anirolac, Antipyrine, ; Benoxapro pane, Desflurane, Dexivacaine; Diamocaine Cyclamate; fen; Benzydamine Hydrochloride; Biciifadine Hydrochlo Dibucaine; Dibucaine Hydrochloride; Dyclonine Hydro ride; Brifentanil Hydrochloride; Bromadoline Maleate; Bro chloride; Enflurane; Ether; Ethyl Chloride; Etidocaine; mfenac Sodium; Buprenorphine Hydrochloride; Butacetin; Etoxadrol Hydrochloride; Euprocin Hydrochloride; FluroX Butixirate; Butorphanol; Butorphanol Tartrate; Carbam ene; Halothane; Isobutamben; Isoflurane; Ketamine Hydro aZepine, Carbaspirin Calcium; Carbiphene Hydrochloride; chloride; Levoxadrol Hydrochloride; Lidocaine; Lidocaine Carfentanil Citrate; Ciprefadol Succinate; Ciramadol; Cira Hydrochloride; Mepivacaine Hydrochloride; Methohexital madol Hydrochloride; Clonixeril; Clonixin; Codeine; Sodium; Methoxyflurane; Midazolam Hydrochloride; Mida Codeine Phosphate; Codeine Sulfate; Conorphone Hydro Zolam Maleate; Minaxolone; Nitrous Oxide; Norflurane; chloride; Cyclazocine; Dexoxadrol Hydrochloride; Dex Octodrine; Oxethazaine; Phencyclidine Hydrochloride; pemedolac, Dezocine; Diflunisal; Dihydrocodeine Bitar Pramoxine Hydrochloride; Prilocaine Hydrochloride; trate; Dimefadane; Dipyrone; Doxpicomine Hydrochloride; Procaine Hydrochloride; Propanidid; Proparacaine Hydro Drinidene; Enadoline Hydrochloride; Epirizole; Ergotamine chloride; Propofol; Propoxycaine Hydrochloride; Pyr Tartrate; Ethoxazene Hydrochloride; Etofenamate; Eugenol; 15 rocaine, Risocaine, Rodocaine, Roflurane, Salicyl Alcohol, Fenoprofen; Fenoprofen Calcium; Fentanyl Citrate; Floc Sevoflurane; Teflurane; Tetracaine; Tetracaine Hydrochlo tafenine; Flufenisal; Flunixin; Flunixin Meglumine; Flupir ride; Thiamylal; Thiamylal Sodium; Thiopental Sodium; tine Maleate; FluproduaZone; Fluradoline Hydrochloride; Tiletamine Hydrochloride; Zolamine Hydrochloride. Flurbiprofen; Hydromorphone Hydrochloride; Ibufenac; Indoprofen; Keta Zo cine; Ketorfanol; Ketorolac Anorectic compounds including dexfenfluramine. Tromethamine; Letimide Hydrochloride; Levomethadyl Anorexic: Aminorex, Amphecloral; Chlorphentermine Acetate; Levomethadyl Acetate Hydrochloride; Levonant Hydrochloride; Clominorex; Clortermine Hydrochloride; radol Hydrochloride; Levorphanol Tartrate; Lofemizole Diethylpropion Hydrochloride; Fenfluramine Hydrochlo Hydrochloride; Lofentanil Oxalate; Lorcinadol; Lornoxi ride; Fenisorex, Fludorex, Fluminorex, Levamfetamine Suc cam; Magnesium Salicylate; Mefenamic Acid, Menabitan cinate; Mazindol; Mefenorex Hydrochloride; Phenmetra Hydrochloride; Meperidine Hydrochloride; Meptazinol 25 Zine Hydrochloride; Phentermine; Sibu tramine Hydrochloride; Methadone Hydrochloride; Methadyl Hydrochloride. Acetate; Methopholine; Methotrimeprazine; Metkephamid Antagonist: Atipamezole, Atosiban; Bosentan, Cimeti Acetate; Mimbane Hydrochloride; Mirfentanil Hydrochlo dine, Cimetidine Hydrochloride; Clentiazem Maleate; ride; Molinazone; Morphine Sulfate; Moxazocine; Nabitan Detirelix Acetate; Devazepide; Donetidine; Etintidine Hydrochloride; Nalbuphine Hydrochloride; Nalmexone Hydrochloride; Famotidine, Fenmetozole Hydrochloride; Hydrochloride; Namoxyrate; Nantradol Hydrochloride; Flumazenil; Icatibant Acetate, Icotidine, Isradipine; Metia Naproxen; Naproxen Sodium; Naproxol; Nefopam Hydro mide; Nadide; Nalmefene; Nalmexone Hydrochloride; chloride; Nexeridine Hydrochloride; Noracy methadol Naloxone Hydrochloride; Naltrexone; Nilvadipine; Oxilor phan; Oxmetidine Hydrochloride; Oxmetidine Mesylate; Hydrochloride; Ocfentanil Hydrochloride; Octazamide; 35 Olvanil; Oxetorone Fumarate; Oxycodone; Oxycodone Quadazocine Mesylate; Ranitidine; Ranitidine Bismuth Cit Hydrochloride; Oxycodone Terephthalate; Oxymorphone rate; Ranitidine Hydrochloride; Sufotidine; Teludipine Hydrochloride; Pemedolac, Pentamorphone; Pentazocine; Hydrochloride; Tiapamil Hydrochloride; Tiotidine; Pentazocine Hydrochloride; Pentazocine Lactate; Vapi.prost Hydrochloride; Zaltidine Hydrochloride. Phenazopyridine Hydrochloride; Phenyramidol Hydrochlo 40 Anterior pituitary activator: Epimestrol. ride; Picenadol Hydrochloride; Pinadoline; Pirfenidone; Anterior pituitary Suppressant: . 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; 45 zole; Dichlorvos, Diethylcarbamazine Citrate; Dribenda Pyrroliphene Hydrochloride; Remifentanil Hydrochloride; zole; Dymanthine Hydrochloride; Etibendazole; Salcolex; Salethamide Maleate; Salicylamide; Salicylate Fenbendazole; Furodazole, Hexylresorcinol; Mebendazole; Meglumine; Salsalate; Sodium Salicylate; Spiradoline Morantel Tartrate; Niclosamide; Nitramisole Hydrochloride; Mesylate; Sufentanil; Sufentanil Citrate; Talmetacin; Talni Nitrodan; Oxantel Pamoate, Oxfendazole; Oxibendazole; flumate; Talosalate; Tazadolene Succinate; Tebufelone; 50 Parbendazole; Piperamide Maleate; Piperazine; Piperazine Tetrydamine; Tifurac Sodium; Tilidine Hydrochloride; Citrate; Piperazine Edetate Calcium; Proclonol; Pyrantel Tiopinac; Tonazocine Mesylate; Tramadol Hydrochloride; Pamoate; Pyrantel Tartrate; Pyrvinium Pamoate; Rafox Trefentanil Hydrochloride; Trolamine; Veradoline Hydro anide; Stilbazium Iodide; Tetramisole Hydrochloride; Thia chloride; Verilopam Hydrochloride; Volazocine; Xorphanol bendazole; Ticarbodine; Tioxidazole; Triclofenol Pipera Mesylate; Xylazine Hydrochloride; Zenazocine Mesylate; 55 Zine; Vincofos, Zilantel. Zomepirac Sodium, Zucapsaicin. Anti-acne: ; Salnacedin; Inoco Androgen: ; Mesterolone; Methyltest terone Acetate. osterone; Nandrolone Decanoate; Nandrolone Phenpropi Anti-adrenergic: Acebutolol, Alprenolol Hydrochloride; onate, Nisterime Acetate; Oxandrolone, Oxymetholone; Atenolol, Bretylium Tosylate; Bunolol Hydrochloride; Car Silandrone; Stanozolol; Testosterone; Testosterone Cypi 60 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. mine Mesylate; Dilevalol Hydrochloride; Esmolol Hydro Anesthesia, adjunct to: Sodium Oxybate. chloride; Exaprolol Hydrochloride; Fenspiride Hydrochlo Anesthetic: Aliflurane; Benoxinate Hydrochloride; Ben 65 ride; Flestolol Sulfate; Labe talol Hydrochloride; Zocaine; Biphenamine Hydrochloride; Bupivacaine Hydro Levobetaxolol Hydrochloride; Levobunolol Hydrochloride; chloride; Butamben; Butamben Pierate; Chloroprocaine Metalol Hydrochloride; Metoprolol; Metoprolol Tartrate; US 6,576,636 B2 23 24 Nadolol, Pamatolol Sulfate; Penbutolol Sulfate; Phentola Sodium; Cefbuperazone; Cefdinir, Cefepime; Cefepime mine Mesylate; Practolol; Propranolol Hydrochloride; Hydrochloride; Cefetecol; Cefixime; Cefnmenoxime Hydro Proroxan Hydrochloride; Solypertine Tartrate; Sotalol chloride; Cefinetazole; Cefinetazole Sodium; Cefonicid Hydrochloride; Timolol; Timolol Maleate; Tiprenolol Monosodium; Cefonicid Sodium; Cefoperazone Sodium; Hydrochloride; Tolamolol; Zolertine Hydrochloride. Ceforanide; Cefotaxime Sodium; Cefotetan; Cefotetan Anti-allergic: Amlexanox, AStemizole, AZelastine Hydro Disodium; Cefotiam Hydrochloride; Cefoxitin; Cefoxitin chloride; Eclazolast; Minocromil; Nedocromil; Nedocromil Sodium; Ce?pimizole; Ce?pimizole Sodium; Ce?piramide; Calcium; Nedocromil Sodium; Nivine done Sodium; Ce?piramide Sodium; Ce?pirome Sulfate; Cefpodoxime Pemirolast Potassium; Pentigetide; Pirquinozol; Poisonoak Proxetil, Cefprozil; Cefroxadine; Cefsulodin Sodium; Extract; Probicromil Calcium; ProXicromil, Repirinast; Tet Ceftazidime; Ceftibuten; Ceftizoxime Sodium; Ceftriaxone razolast Meglumine; Thiazinamium Chloride; Tiacrilast; Sodium; Cefuroxime; Cefuroxime Axetil, Cefuroxime Piv Tiacrilast Sodium; Tiprinast Meglumine; Tixanox. oxetil, Cefuroxime Sodium; Cephacetrile Sodium; Cephal Anti-amebic: Berythromycin; Bialamicol Hydrochloride; exin; Cephalexin Hydrochloride; Cephaloglycin; Cephalo Chloroquine; Chloroquine Hydrochloride; Chloroquine ridine; Cephalothin Sodium; Cephapirin Sodium; Phosphate; Clamoxyquin Hydrochloride; Clioquinol; Emet 15 Cephradine; Cetocycline Hydrochloride; Cetophenicol; ine Hydrochloride; Iodoquinol; Paromomycin Sulfate; Chloramphenicol; Chloramphenicol Palmitate; Chloram phenicol Pantothenate Complex; Chloramphenicol Sodium Quinfamide; Symetine Hydrochloride; Teclozan; Tetracy Succinate; Chlorhexidine Phosphanilate; Chloroxylenol; cline; Hydrochloride. Chlortetracycline Bisulfate; Chlortetracycline Hydrochlo Anti-androgen: Benorterone, Cioteronel, ride; Cinoxacin; Ciprofloxacin; Ciprofloxacin Hydrochlo Acetate; , Oxendolone; Topterone; ride; Cirolemycin; Clarithromycin; Clinafloxacin Hydro Zanoterone. chloride; ; Clindamycin Hydrochloride; Anti-anemic: Epoetin Alfa; Epoetin Beta; Ferrous Sulfate, Clindamycin Palmitate Hydrochloride; Clindamycin Phos Dried; Leucovorin Calcium. phate; Clofazimine; Cloxacillin Benzathine; Cloxacillin Anti-anginal: Amlodipine BeSylate, Amlodipine Maleate; 25 Sodium; Cloxyquin; Colistimethate Sodium; Colistin Sul Betaxolol Hydrochloride; Bevantolol Hydrochloride; Buto fate, Coumermycin; Coumermycin Sodium; Cyclacillin; prozine Hydrochloride; Carvedilol; Cinepazet Maleate; CycloSerine; Dalfopristin; ; Daptomycin; Demeclo Metoprolol Succinate; Molsidomine; Monatepil Maleate; cycline, Demeclocycline Hydrochloride; Demecycline; Primidolol; Ranolazine Hydrochloride; Tosifen; Verapamil Denofingin; Diaveridine; Dicloxacillin; Dicloxacillin Hydrochloride. Sodium; Dihydrostreptomycin Sulfate; Dipyrithione; Anti-anxiety agent: Adatanserin Hydrochloride; Alpidem; Dirithromycin; Doxycycline; Doxycycline Calcium; Doxy BinoSpirone MeSylate, BretaZenil; Glemanserin; Ipsapirone cycline Fosfatex; Doxycycline Hyclate; Droxacin Sodium; Hydrochloride; Mirisetron Male ate, Ocinaplon, Enoxacin; Epicillin; Epitetracycline Hydrochloride; Eryth Ondansetron Hydrochloride; Panadiplon; Pancopride; Pazi romycin; Erythromycin Acistrate; Erythromycin Estolate; naclone, Serazapine Hydrochloride, TandoSpirone Citrate; 35 Erythromycin EthylSuccinate; Erythromycin Gluceptate; Zalospirone Hydrochloride. Erythromycin Lactobionate; Erythromycin Propionate; Anti-arthritic: Lodelaben. Erythromycin Stearate; Ethambutol Hydrochloride; Ethionamide; Fleroxacin; Floxacillin; Fludalanine; Flume Anti-asthmatic: Ablukast, Ablukast Sodium, AZelastine quine; Fosfomycin; Fosfomycin Tromethamine; Fumoxicil Hydrochloride; Bunaprolast; Cinalukast; Cromitrile 40 lin; Furazolium Chloride; Furazolium Tartrate; Fusidate Sodium; Cromolyn Sodium; Enofelast; Isamoxole; Keto Sodium; Fusidic Acid, Gentamicin Sulfate; Gloximonam; tifen Fumarate; Levcromakalim; Lodoxamide Ethyl, Gramicidin; Haloprogin; Hetacillin; Hetacillin Potassium; Lodoxamide Tromethamine; Montelukast Sodium, Ontazo Hexedine, Ibafloxacin; Imipenem; ISOconazole, Isepamicin; last; Oxarbazole; Oxatomide; Piriprost; Piriprost Potassium; Isoniazid; Josamycin, Kanamycin Sulfate; Kitasamycin; Pirolate; Pobilukast Edamine; Quazolast; Repirinast; 45 Levofuraltadone; Levopropylcillin Potassium; Lexithromy Ritolukast; Sulukast; Tetrazolast Meglumine; Tiaramide cin; Lincomycin; Lincomycin Hydrochloride, Lomefloxa Hydrochloride; Tibenelast Sodium; Tomelukast; Tranilast; cin; Lomefloxacin Hydrochloride; Lomefloxacin Mesylate; Verlukast; Verofylline; Zarirlukast. Loracarbef, Mafenide; Meclocycline; Meclocycline Sul Anti-atherosclerotic: Mifobate; Timefuronc. fosalicylate; Megalomicin Potassium Phosphate; Mequidox; Antibacterial: AcedapSone; AcetoSulfone Sodium; Ala 50 Meropenem; Methacycline; Methacycline Hydrochloride; mecin; Alexidine, Amdinocillin; Amdinocillin Pivoxil, Ami Methenamine; Methenamine Hippurate; Methenamine cycline; Amifloxacin; Amifloxacin MeSylate; Amikacin; Mandelate; Methicillin Sodium; Metioprim; Metronidazole Amikacin Sulfate; AminoSalicylic acid; AminoSalicylate Hydrochloride; Metronidazole Phosphate; Mezlocillin; Sodium; Amoxicillin; Amphomycin; Ampicillin; Ampicillin Mezlocillin Sodium; ; Minocycline Hydrochlo Sodium; Apalcillin Sodium; Apramycin; ASpartocin, Astro 55 ride; Mirincamycin Hydrochloride; Monensin; Monensin micin Sulfate, Avilamycin; AVoparcin, Azithromycin; Sodium; Nafcillin Sodium; Nalidixate Sodium; Nalidixic Azlocillin; Azlocillin Sodium; Bacampicillin Hydrochlo Acid; Natamycin; Nebramycin; Neomycin Palmitate; Neo ride; Bacitracin; Bacitracin Methylene Disalicylate; Baci mycin Sulfate; Neomycin Undecylenate; Netilmicin Sulfate; tracin Zinc, Bambermycins, Benzoylpas Calcium, Beryth Neutramycin; Nifuradene; Nifuraldezone; Nifuratel; Nifu romycin; Betamicin Sulfate; Biapenem; Biniramycin; 60 ratrone; Nifurd azil; Nifurimide; Nifurpirinol; Biphenamine Hydrochloride; Bispyrithione Magsulfex; Nifurcquinazol; Nifurthiazole; Nitrocycline; Nitrofurantoin; Butikacin; Butirosin Sulfate; Capreomycin Sulfate; Carba Nitromide; Norfloxacin; Novobiocin Sodium; Ofloxacin; dox; Carbenicillin Disodium; Carbenicillin Indanyl Sodium; Ormetoprim; Oxacillin Sodium; Oximonam; Oximonam Carbenicillin Phenyl Sodium; Carbenicillin Potassium; Sodium; Oxolinic Acid; Oxytetracycline; Oxytetracycline Carumonam Sodium; Cefaclor, Cefadroxil, Cefamandole; 65 Calcium; Oxytetracycline Hydrochloride; Paldimycin; Cefamandole Nafate; Cefamandole Sodium; Cefaparole; Parachlorophenol; Paulomycin; Pefloxacin; Pefloxacin Cefatrizine; Cefazaflur Sodium; Cefazolin; Cefazolin Mesylate; Penamecillin; Penicillin G BenZathine; Penicillin US 6,576,636 B2 25 26 G Potassium; Penicillin G Procaine; Penicillin G Sodium; Anticoccidal: Maduramicin. Penicillin V; Penicillin V BenZathine; Penicillin V Hydrab Anticonvulsant: Albutoin; Ameltolide; Atollide; Bura amine: Penicillin V Potassium; Pentizidone Sodium; Phenyl mate; Carbamazepine, Cinromide, Citenamide, Clon Aminosalicylate; Piperacillin Sodium; Pirbenicillin Sodium; azepam, Cyheptamide, Dezinamide; Dimethadione; Dival Piridicillin Sodium; Pirlimycin Hydrochloride; Pivampicil proex Sodium; Eterobarb; Ethosuximide; Ethotoin; lin Hydrochloride; Pivampicillin Pamoate; Pivampicillin Flurazepam Hydrochloride; Fluzinamide; Fosphenytoin Probenate; Polymyxin B Sulfate; Porfiromycin; Propikacin; Sodium; Gabapentin, Ilepcimide, Lamotrigine; Magnesium PyraZinamide, Pyrithione Zinc, Quindecamine Acetate; Sulfate; Mephenytoin; Mephobarbital; Methetoin; MethSux Quinupristin, Racephenicol; Ramoplanin; Ranimycin; Relo imide: Milacemide Hydrochloride; Nabazenil; Nafimidone mycin; Repromicin; Rifabutin; Rifametane; Rifamexil; Hydrochloride; Nitrazepain; Phenacemide; Phenobarbital; Rifamide; Rifampin; Rifapentine; Rifaximin; Rolitetracy Phenobarbital Sodium; Phensuximide; Phenytoin; Pheny cline, Rolitetracycline Nitrate: Rosaramicin; Rosaramicin toin Sodium; Primidone; Progabide; Ralitoline; Remace Butyrate; Rosaramicin Propionate; Rosaramicin Sodium mide Hydrochloride; Ropizine; Sabeluzole; Stiripentol; Phosphate, Rosaramicin Stearate; ROSoxacin; RoxarSone; Roxithromycin; Sancycline; Sanfeltrinem Sodium; Sarmox Sulthiame; Thiopental Sodium; Tiletamine Hydrochloride; icillin, Sarpicillin; Scopafingin; Sisomicin; Sisomicin Sul 15 Topiramate; Trimethadione: Valproate Sodium; Valproic fate, Spariloxacin; Spectinomycin Hydrochloride; Spiramy Acid; Vigabatrin; Zoniclezole Hydrochloride; Zonisamide. cin; Stallimycin Hydrochloride; Steffimycin; Streptomycin Antidepressant: Adatanserin Hydrochloride: Adinazolam; Sulfate; Streptonicozid; Sulfabenz, Sulfabenzamide; Sulfac Adinazolam MeSylate; Alaproclate; Aletamine Hydrochlo etamide; Sodium; Sulfacytine; Sulfadiazine; ride; Amedalin Hydrochloride; Amitriptyline Hydrochlo Sulfadiazine Sodium; Sulfadoxine, Sulfalene; Sulfamera ride, Amoxapine, Aptazapine Maleate, AZaloxan Fumarate; Zine; Sulfameter; Sulfamethazine; Sulfamethizole; Sul Azepindole; Azipramine Hydrochloride; Bipenamol Hydro famethoxazole; Sulfamonomethoxine, Sulfamoxole; Sulfa chloride; Bupropion Hydrochloride; Butacetin; Butriptyline nilate Zinc, Sulfanitran; SulfaSalazine, SulfaSomizole; Hydrochloride; CaroXaZone; CartaZolate, CiclaZindol; Sulfathiazole; Sulfazamet, Sulfisoxazole; Sulfisoxazole Cidoxepin Hydrochloride; Cilobamine Mesylate; Clodazon Acetyl; Sulfisoxazole Diolamine; Sulfomyxin; Sulopenem; 25 Hydrochloride; Clomipramine Hydrochloride; Cotinine Sultamicillin; Suncillin Sodium; Talampicillin Hydrochlo Fumarate; Cyclindole; Cypenamine Hydrochloride; Cypro ride; Teicoplanin; Temafloxacin Hydrochloride; Temocillin; lidol Hydrochloride; Cyproximide; Daledalin Tosylate; Tetracycline; Tetracycline Hydrochloride; Tetracycline Dapoxetine Hydrochloride; Dazadrol Maleate; Dazepinil Phosphate Complex; Tetroxoprim; Thiamphenicol; Hydrochloride; Desipramine Hydrochloride; Dexamisole; Thiphencillin Potassium; Ticarcillin Cresyl Sodium; Ticar Deximafen; Dibenzepin Hydrochloride; Dioxadrol Hydro cillin Disodium; Ticarcillin Monosodium; Ticlatone; Tiodo chloride; Dothiepin Hydrochloride; Doxepin Hydrochlo nium Chloride; Tobramycin; Tobramycin Sulfate; Tosu ride; Duloxetine Hydrochloride; Eclanamine Maleate; floxacin; Trimethoprim; Trimethoprim Sulfate; Encyprate; Etoperidone Hydrochloride; Fantridone Hydro TriSulfapyrimidines, Troleandomycin; Trospectomycin Sul chloride; Fenmetozole Hydrochloride; Fenmetramide; fate; Tyrothricin: Vancomycin; Vancomycin Hydrochloride; 35 Fezolamine Fumarate; Fluotracen Hydrochloride; Fluoxet Virginiamycin; Zorbamycin. ine; Fluoxetine Hydrochloride; Fluparoxan Hydrochloride; Anticholelithic: Monoctanoin. Gamfexine; Guanoxyfen Sulfate; Imafen Hydrochloride; Anticholelithogenic: Chenodiol; Ursodiol. Imiloxan Hydrochloride; Imipramine Hydrochloride; Inde Anticholinergic: Alverinc Citrate; Anisotropine Methyl loxazine Hydrochloride; Intriptyline Hydrochloride; Iprin bromide; Atropine; Atropine Oxide Hydrochloride; Atropine 40 dole; Isocarboxazid; Ketipramine Fumarate, Lofepramine Sulfate; Belladonna; Benapry Zine Hydrochloride; Ben Hydrochloride; Lortalamine; Maprotiline; Maprotiline Zetimide Hydrochloride; Benzilonium Bromide; Biperiden; Hydrochloride; Melitracen Hydrochloride; Milacemide Biperiden Hydrochloride; Biperiden Lactate; Clidinium Hydrochloride: Minaprine Hydrochloride; Mirtazapine; Bromide; Cyclopentolate Hydrochloride; Dexetimide; Dicy Moclobemide; Modaline Sulfate; Napacitadine Hydrochlo clomine Hydrochloride; Dihexyverine Hydrochloride: 45 ride; Napamezole Hydrochloride; Nefazodone Hydrochlo Domazoline Fumarate; Elantrine; Elucaine; Ethybenz ride; Nisoxetine; Nitrafudam Hydrochloride; Nomifensine tropine; Eucatropine Hydrochloride: Glycopyrrolate; Het Maleate; Nortriptyline Hydrochloride; Octriptyline Phos eronium Bromide; Homatropine Hydrobromide; Homatro phate; Opipramol Hydrochloride; Oxaprotiline Hydrochlo pine Methylbromide; Hyoscyamine; Hyoscyamine ride; Oxypertine; Paroxetine; Phenelzine Sulfate; Piran Hydrobromide; Hyoscyamine Sulfate; Isopropamide Iodide; 50 damine Hydrochloride; Pizotyline; Pridefine Hydrochloride; Mepenzolate Bromide; Methylatropine Nitrate; Meto Prolintane Hydrochloride; Protriptyline Hydrochloride; quizine; Oxybutynin Chloride; Parapenzolate Bromide; Pen Quipazine Maleate; Rolicyprine; Seproxetine Hydrochlo tapiperium Methylsulfate; Phencarbamide; Poldine Methyl ride; Sertraline Hydrochloride; Sibutramine Hydrochloride; sulfate; Proglumide; Propantheline Bromide; Propenzolate Sulpiride; Suritozole; Tametraline Hydrochloride; Tam Hydrochloride; Scopolamine Hydrobromide; Tematropium 55 pramine Fumarate; Tandamine Hydrochloride; Thiazesim Methylsulfate; Tiquinamide Hydrochloride; Tofenacin Hydrochloride; Thozalinone; Tomoxetine Hydrochloride; Hydrochloride; Toquizine; Triampyzine Sulfate; Trihex Trazodone Hydrochloride; Trebenzomine Hydrochloride; yphenidyl Hydrochloride; Tropicamide. Trimipramine; Trimipramine Maleate; Venlafaxine Hydro Anticoagulant: Ancrod; Anticoagulant Citrate Dextrose chloride; Viloxazine Hydrochloride; Zimeldine Hydrochlo Solution; Anticoagulant Citrate Phosphate Dextrose 60 ride, Zometapine. Adenine Solution; Anticoagulant Citrate Phosphate Dex Antidiabetic: Acetohexamide; Buformin; Butoxamine trose Solution; Anticoagulant Heparin Solution; Anticoagul Hydrochloride, Camiglibose, Chlorpropamide, CiglitaZone; lant Sodium Citrate Solution; Ardeparin Sodium; Bivaliru Englitazone Sodium; Etoformin Hydrochloride; Gliamilide; din; Bromindione; Dalteparin Sodium; Desirudin; Glibomuride; Glicetanile Sodium; Gliflumide; Glipizide; Dicumarol; Heparin Calcium; Heparin Sodium; Lyapolate 65 Glucagon; Glyburide; Glyhexamide; Glymidine Sodium; Sodium; Nafamostat Mesylate; Phenprocoumon; Tinzaparin Glyoctamide, Glyparamide; Insulin; Insulin, Dalanated; Sodium; Warfarin Sodium. Insulin Human; Insulin Human, Isophane; Insulin Human US 6,576,636 B2 27 28 Zinc, Insulin Human Zinc, Extended; Insulin, Isophane; hydramine Hvdrochloride; Brompheniramine Maleate; Insulin Lispro, Insulin, Neutral; Insulin Zinc, Insulin Zinc, Carbinoxamine Maleate; Cetirizine Hydrochloride; Chlor Extended; Insulin Zinc, Prompt; Linogliride; Linogliride pheniramine Maleate; Chlorpheniramine Polistirex, Cin Fumarate; Metformin; Methyl Palmoxirate; Palmoxirate narizine; Clemastine; Clemastine Fumarate; Closiramine Sodium; Pioglitazone Hydrochloride; Pirogliride Tartrate; Aceturate; Cycliramine Maleate; Cyclizine, Cyproheptadine Proinsulin Human; Seglitide Acetate; Tolazamide; Tolbuta Hydrochloride; Dexbrompheniramine Maleate; Dexchlor mide; Tolpyrramide; TroglitaZone, Zopolrestat. pheniramine Maleate; Dimethindene Maleate; Diphenhy Antidiarrheal: Rolgamidine, Diphenoxylate hydrochlo dramine Citrate; Diphenhydramine Hydrochloride; Doras ride (Lomotil), Metronidazole (Flagyl), Methylprednisolone tine Hydrochloride; Doxylamine Succinate; Ebastine; (Medrol), Sulfasalazine (AZulfidine). Levocabastine Hydrochloride; Loratadine; Mianserin Antidiuretic: Argipressin Tannate; DeSmopressin Acetate; Hydrochloride; Nobe rastine; Orphenadrine Citrate; Lypressin. Pyrabrom; Pyrilamine Maleate; Pyroxamine Maleate; Antidote: Dimercaprol; Edrophonium Chloride; Fomepi Rocastine Hydrochloride; Rotoxamine; Tazifylline Hydro zole; Leucovorin Calcium; Levoleucovorin Calcium; Meth chloride; Temelastine; Terfenadine; Tripelennamine Citrate; ylene Blue; Protamine Sulfate. 15 Tripelennamine Hydrochloride; Triprolidine Hydrochloride; Antidyskinetic: Selegiline Hydrochloride. Zolamine Hydrochloride. Anti-emetic: Alosetron Hydrochloride; Batanopride Antihyperlipidemic: Cholestyramine Resin; Clofibrate; Hydrochloride; Bemesetron; Benzquinamide; Chlorprom Colestipol Hydrochloride; Crilvastatin; Dalvastatin; Dex azine; Chlorpromazine Hydrochloride; Clebopride; Cycliz trothyroxine Sodium; Fluvastatin Sodium; Gemfibrozil; ine Hydrochloride; Dimenhydrinate; Diphenidol; Dipheni Lecimibide; Lovastatin; Niacin; Pravastatin Sodium; Probu dol Hydrochloride; Diphenidol Pamoate; Dolasetron col; Simvastatin; Tiqueside; Xenbucin. Mesylate; Domperidone; Dronabinol; Fludorex; Flumeri Antihyperlipoproteinemic: Acifran; Beloxamide, BeZafi done; Galdansetron Hydrochloride; Granisetron; Granis brate; Boxidine; Butoxamine Hydrochloride; Cetaben etron Hydrochloride; Lurosetron Mesylate; Meclizine Sodium; Ciprofibrate; Gemcadiol; Halofenate; Lifibrate; Hydrochloride; Metoclopramide Hydrochloride; Metopi 25 Meglutol; Nafenopin; Pimetine Hydrochloride; Theofibrate; mazine; Ondansetron Hydrochloride; Pancopride; Prochlo Tibric Acid, Treloxinate. rperazine; Prochlorperazine Edisylate; Prochlorperazine Antihypertensive: Alfuzosin Hydrochloride; Alipamide; Maleate; Promethazine Hydrochloride; Thiethylperazine; Althiazide; Amiquinsin Hydrochloride; Amlodipine Besy Thiethylperazine Malate; Thiethylperazine Maleate; Tri late, Amlodipine Maleate; Anaritide Acetate; AtiproSin methobenzamide Hydrochloride; Zacopride Hydrochloride. Maleate; Belfosdil; Bemitradine; Bendacalol Mesylate; Anti-epileptic: Felbamate; LorecleZole, Tolgabide. Bendroflumethiazide; Benzthiazide, Betaxolol Hydrochlo Anti-estrogen: Clometherone; Delmadinone Acetate; ride; Bethanidine Sulfate; Bevantolol Hydrochloride; Nafoxidine Hydrochloride; Nitromifene Citrate; Raloxifene Biclodil Hydrochloride; Bisoprolol, Bisoprolol Fumarate; Hydrochloride; Tamoxifen Citrate; Toremifene Citrate; Tri Bucindolol Hydrochloride; Bupicomide; Buthiazide: Can oxifene Mesylate. 35 doXatril; Candoxatrilat, Captopril; Carvedilol, Ceronapril; Chlorothiazide Sodium; Cicletanine; CilaZapril; Clonidine; Antifibrinolytic: Nafamostat Mesylate. Clonidine Hydrochloride; Clopamide; Cyclopenthiazide; Antifungal: Acrisorcin; Ambruticin; Amphotericin B; Cyclothiazide; Darodipine; Debrisoquin Sulfate; Delapril AZaconazole, AZaserine; Basifungin; Bifonazole; Biphe namine Hydrochloride; Bispyrithione Magsulfex; Buto Hydrochloride; Diapamide; Diazoxide; Dilevalol Hydro 40 chloride; Diltiazem Malate; Ditekiren; Doxazosin Mesylate; conazole Nitrate, Calcium Undecylenate; Candicidin; Ecadotril, Enalapril Maleate; Enalaprilat, Enalkiren; Carbol-Fuchsin; Chlordantoin; Ciclopirox, Ciclopirox Ola Endralazine MeSylate; Epithiazide, EproSartan; EproSartan mine, Cillofungin; Cisconazole; Clotrimazole; Cuprimyxin; Mesylate; Fenoldopam Mesylate; Flavodilol Maleate; Flo Denofungin; Dipyrithione; Doconazole; Econazole; Econa rdipine, FloSequinan; Fosinopril Sodium; Fosinoprilat, Gua Zole Nitrate; Enilconazole; Ethonam Nitrate; Fenticonazole 45 nabenz, Guanabenz. Acetate; Guanacline Sulfate; Guanadrel Nitrate; Filipin; Fluconazole; Flucytosine; Fungimycin; Sulfate; Guancydine; Guanethidine Monosulfate; Guanethi Griseofulvin; Hamycin; ISOconazole, Itraconazole; Kalafun dine Sulfate; Guanfacine Hydrochloride; Guanisoquin Sul gin; , Lomofungin; Lydimycin; Mepartricin; fate; Guanoclor Sulfate; Guanoctine Hydrochloride; Guan ; Miconazole Nitrate; Monensin; Monensin oXabenz, Guanoxan Sulfate; Guanoxy fen Sulfate; Sodium; Naftifine Hydrochloride; Neomycin Undecylenate; 50 Hydralazine Hydrochloride; Hydralazine Polistirex; Nifuratel; Nifurmerone; Nitralamine Hydrochloride; Nysta Hydroflumethiazide, Indacrinone; Indapamide; Indolapril tin; Octanoic Acid, Orconazole Nitrate; Oxiconazole Hydrochloride; Indoramin; Indoramin Hydrochloride; Nitrate; Oxifungin Hydrochloride; Parconazole Hydrochlo Indorenate Hydrochloride; Lacidipine; Leniquinsin, Levcro ride; Partricin; Potassium Iodide; Proclonol; Pyrithione Zinc, Pyrrolnitrin; Rutamycin; Sanguinarium Chloride; makalim; Lisinopril, Lofexidine Hydrochloride; LOSartan 55 Potassium; Losulazine Hydrochloride; Mebutamate; Saperconazole: Scopafungin; Selenium Sulfide, Sinefingin; Mecamylamine Hydrochloride; Medroxalol; Medroxalol Sulconazole Nitrate; Terbinafine; Terconazole; Thiram; Hydrochloride; Methalthiazide; Methyclothiazide; Methyl Ticlatone; Tioconazole; Tolciclate; Tolindate; Tolnaftate; dopa; Methyldopate Hydrochloride; Metipranolol; Metola Triacetin; Triafungin; Undecylenic Acid; Viridofulvin; Zinc Undecylenate; Zinoconazole Hydrochloride. Zone; Metoprolol Fumarate; Metoprolol Succinate; Mety 60 rosine; Minoxidil; Monatepil Maleate; Muzolimine; Antiglaucoma agent: AlprenoXime Hydrochloride; Col Nebivolol; Nitrendipine; Ofornine; Pargyline Hydrochlo forsin; Dapiprazole Hydrochloride; Dipivefrin Hydrochlo ride; Pazoxide; Pelanserin Hydrochloride; Perindopril Erbu ride; Naboctate Hydrochloride; Pilocarpine; Pimabine. mine; Phenoxybenzamine Hydrochloride; Pinacidil; Pivo Antihemophilic: Antihemophilic Factor. pril; Polythiazide; Prazosin Hydrochloride; Primidolol; Antihemorrhagic: Poliglusam. 65 Prizidilol Hydrochloride; Quinapril Hydrochloride; Quinap Antihistaminic: Acrivastine; Antazoline Phosphate, rilat; Quinazosin Hydrochloride; Quinelorane Hydrochlo Astemizole, AZatadine Maleate; Barmastine, Bromodiphen ride; Quinpirole Hydrochloride: Quinuclium Bromide; US 6,576,636 B2 29 30 Ramipril; Rauwolfia Serpentina; Reserpine, Saprisartan Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pir Potassium; Saralasin Acetate; Sodium Nitroprusside; Sulfi fenidone; PiroXicam, Piroxicam Cinnamate; Piroxicam Ola malol Hydrochloride; Tasosartan; Teludipine Hydrochloride; mine; Pirprofen; ; Prifelone; Prodolic Acid; Pro Temocapril Hydrochloride; Terazosin Hydrochloride; Terla quaZone; Proxazole; Proxazole Citrate; ; kiren; Tiamenidine; Tiamenidine Hydrochloride; Tic Romazarit; Salcolex, Salnacedin, Salsalate, Sanguinarium rynafen; Tinabinol; Tiodazosin; Tipentosin Hydrochloride; Chloride; SeclaZone, Sermetacin; Sudoxicam, Sulindac, Trichlormethiazide; Trimazosin Hydrochloride; Tri Suprofen; Talmetacin; Talniflumate; Talosalate; Tebufelone; methaphan Camsylate; Trimoxamine Hydrochloride; Tripa Tenidap; Tenidap Sodium, Tenoxicam, TeSicarn; Tesimide; mide; Xipamide; Zankiren Hydrochloride; Zofenoprilat Tetrydamine; Tiopinac; Pivalate; Tolimetin; Tol Arginine. metin Sodium; ; Triflumidate; Zidometacin; Antihypotensive: Ciclafrine Hydrochloride-Midodrine Zomepirac Sodium. Hydrochloride. Antikeratinizing agent: Doretinel; Linaroteine, Pelretin. Anti-infective: Difloxacin Hydrochloride; Lauryl Iso Antimalarial: AcedapSone; Amodiaquine Hydrochloride; quinolinium Bromide; Moxalactam Disodium; Ornidazole; Amguinate, Arteflene; Chloroquine; Chloroquine Hydro Pentisomicin; Sarafloxacin Hydrochloride; Protease inhibi 15 chloride; Chloroquine Phosphate, Cycloguanil Pamoate; tors of HIV and other retroviruses; Integrase Inhibitors of Empiroline Phosphate; Halofantrine Hydrochloride; HIV and other retroviruses; Cefaclor (Ceclor); Acyclovir Hydroxychloroquine Sulfate; Mefloquine Hydrochloride; (Zovirax); Norfloxacin (Noroxin); Cefoxitin (Mefoxin); Menoctone; Mirincamycin Hydrochloride; Primacquine Cefuroxime axetil (Ceftin); Ciprofloxacin (Cipro). Phosphate; Pyrimethamine; Quinine Sulfate; Tebuduine. Anti-infective, topical: Alcohol, Aminacrine Hydrochlo ride; Benzethonium Chloride: Bithionolate Sodium; Bro Antimicrobial: Aztreonam, Chlorhexidine Gluconate; mchlorenone; Carbamide Peroxide; Cetalkonium Chloride; Imidurea; Lycetamine; Nibroxane; Pirazmonam Sodium; Cetylpyridinium Chloride: Chlorhexidine Hydrochloride; Propionic Acid; Pyrithione Sodium; Sanguinarium Chloride; Clioquinol; Domiphen Bromide; Fenticlor; Fludazonium Tigemonam Dicholine. Chloride; Fuchsin. Basic; Furazolidone; Gentian Violet, 25 Antimigraine: Dolasetron Mesylate; Naratriptan Hydro Halquinols; Hexachlorophene: Hydrogen Peroxide; Ich chloride, SergoleXole Maleate, Sumatriptan Succinate; thammol, Imidecyl Iodine, Iodine; Isopropyl Alcohol, Zatosetron Maleate. Mafenide Acetate; Meralein Sodium; Mercufenol Chloride; Antimitotic: Podofilox. Mercury, Ammoniated; Methylbenzethonium Chloride; Antimycotic: Amorolfine. Nitrofurazone; Nitromersol; Octenidine Hydrochloride; Antinauseant: Buclizine Hydrochloride; Cyclizine Lac Oxychlorosene; Oxychlorosene Sodium; Parachlorophenol, tate; Naboctate Hydrochloride. Camphorated; Potassium Permanganate; Povidone-Iodine; Antineoplastic: Acivicin, Aclarubicin; Acodazole Hydro Sepazonium Chloride; Silver Nitrate; Sulfadiazine, Silver; chloride, Acronine; Adozelesin; Aldesleukin; Altretamine; Symclosene; Thimerfonate Sodium; Thimerosal: Troclosene Ambomycin; Ametantrone Acetate; Aminoglutethimide; Potassium. 35 AmSacrine; Anastrozole; Anthramycin; Asparaginase; Anti-inflammatory: Alclofenac; Dipropi ASperlin, AZacitidine, AZetepa, AZOtomycin; Batimastat; onate, AlgeStone Acetonide; Alpha Amylase, ; Benzodepa; ; Bisantrene Hydrochloride; ; Amfenac Sodium; Amiprilose Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate; Bre Anakinra, Anirolac, AnitraZafen; ApaZone; BalsalaZide quinar Sodium; Bropirimine; BuSulfan; Cactinomycin; Disodium; Bendazac, Benoxaprofen; Benzydamine Hydro 40 Calusterone; Caracemide, Carbetimer; Carboplatin; Car chloride; Bromelains, Broperamole; , Carpro mustine; Carubicin Hydrochloride; Carzelesin; Cedefingol; fen; Cicloprofen; Cintazone; Cliprofen; Propi Chlorambucil; Cirolemycin; Cisplatin; Cladribine; Crisnatol onate; Butyrate; Clopirac, MeSylate; Cyclophosphamide, Cytarabine; Dacarbazine; Propionate; Cormethasone Acetate; Cortodoxone, Deflaza Dactinomycin; Daunorubicin Hydrochloride; Decitabine; cort, , ; Dipropi 45 DeXormaplatin, DeZaguanine, DeZaguanine MeSylate; onate; Diclofenac Potassium; Diclofenac Sodium; Diflo Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydro rasone Diacetate; Diflumidone Sodium; Diflunisal; chloride; Droloxifene; Droloxifene Citrate; Dromostanolone ; Diftalone; Dimethyl Sulfoxide; ; Propionate; Duazomycin; Edatrexate, Eflomithine Hydro Endrysone; Enlimomab, Enolicam Sodium; Epirizole; Etod chloride; Elsamitrucin; Enloplatin, Enpromate; Epipropi olac, Etofenamate; Felbinac, Fenamole, Fenbufen, Fen 50 dine; Epirubicin Hydrochloride; Erbulozole; Esorubicin clofenac, Fenclorac, Fendosal, Fenpipalone, Fentiazac, Hydrochloride; Estramustine; Estramustine Phosphate Flazalone; , Flufenamic Acid, Flumizole; Sodium; Etanidazole; Ethiodized Oil I 131; Etoposide; Eto Acetate; Flumixin; Flunixin Meglumine; Fluo poside Phosphate; Etoprine; Fadrozole Hydrochloride; Faz cortin Butyl; Acetate; FluguaZone; Flurbi arabine; ; Floxuridine; Fludarabine Phosphate; profen; Fluretofen; Propionate; Furaprofen; 55 Fluorouracil; Flurocitabine; Fosquidone; Fostriecin Sodium; Furobufen; ; Halobetasol Propionate; Halopre Gemcitabine; Gemcitabine Hydrochloride; Gold Au 198; done Acetate, Ibufenac, ; Ibuprofen Aluminum; Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; Ilmo Ibuprofen Piconol; Ilonidap; Indomethacin; Indomethacin fosine; Interferon Alfa-2a, Interferon Alfa-2b; Interferon Sodium; Indoprofen; Indoxole; Intrazole; Alfa-n1; Interferon Alfa-n3; Interferon Beta-I a; Interferon Acetate; ISOXepac, ISOXicam, Ketoprofen, Lofemizole 60 Gamma-Ib, I proplatin; Irinotecan Hydrochloride; Lan Hydrochloride; Lornoxicam, Lote prednol Etabonate; reotide Acetate; Letrozole; Leuprolide Acetate; Meclofenamate Sodium; Meclofenamic Acid, Hydrochloride; Lometrexol Sodium; Lomustine; Losox Dibutyrate; Mefenamic Acid; Mesalamine; Meseclazone; antrone Hydrochloride; Masoprocol; Maytansine; Mechlo Methylprednisolone Suleptanate; Morniflumate; Nabume rethamine Hydrochloride; ; Melengestrol tone; Naproxen; Naproxen Sodium; Naproxol; Nimazone; 65 Acetate; Melphalan; Menogaril; Mercaptopurine; Methotr Olsalazine Sodium; Orgotein; Orpanoxin; Oxaprozin, exate; Methotrexate Sodium; Metoprine; Meturedepa; Mit Oxyphenbutazone; Paranyline Hydrochloride; Pentosan indomide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; US 6,576,636 B2 31 32 Mitomycin; Mitosper; Mitotane; Mitoxantrone Hydrochlo tine, gadolinium teXaphyrin, gallium nitrate; galocitabine; ride; Mycophenolic Acid, Nocodazole; Nogalamycin; ganirelix; gelatinase inhibitors, gemcitabine; glutathione Ormaplatin; OXisuran; Paclitaxel, Pegaspargase, Peliomy inhibitors, hepSulfam; heregulin; hexamethylene bisaceta cin; Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipo mide; hypericin; ibandronic acid; idarubicin; idoxifene, broman; Piposulfan; Piroxantrone Hydrochloride; Plicamy idramantone, ilmofoSine, illomastat; imidazoacridones, imi cin; Plomestane; Porfimer Sodium; Porfiromycin; quimod, immunostimulant peptides; insulin-like growth ; Procarbazine Hydrochloride; Puromycin; factor-1 receptor inhibitor; interferon agonists, interferons, Puromycin Hydrochloride; Pyrazofurin; Riboprine; interleukins, iobenguane; iododoxorubicin; ipomeanol, 4-, Rogletimide; Safingol; Safingol Hydrochloride; Semustine; irinotecan; iroplact, irSogladine, isobengaZole, isohomohali SimtraZene, Sparfosate Sodium; SparSomycin; Spirogerma condrin B; itasetron, jasplakinolide; kahalalide F; nium Hydrochloride; Spiromustine; Spiroplatin; Streptoni lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; grin; Streptozocin; Strontium Chloride Sr 89; Sulofenur; lentinan Sulfate; leptolstatin; letrozole; leukemia inhibiting Talisomycin; Taxane, Taxoid; Tecogalan Sodium, Tegafur, factor; leukocyte alpha interferon; leuprolide--estrogen Teloxantrone Hydrochloride; Temoporfin; Teniposide; progesterone; leuprorelin; levamisole; liarozole; linear Teroxirone; Testolactone; Thiamiprine; Thioguanine; 15 polyamine analogue, lipophilic disaccharide peptide; lipo Thiotepa; Tiazofurin, Tirapazamine; Topotecan Hydrochlo philic platinum compounds, lisSoclinamide 7; lobaplatin; ride; Toremifene Citrate; Trestolone Acetate; Triciribine lombricine, lometrexol; lonidamine; loSOXantrone; lovasta Phosphate; Trimetrexate; Trimetrexate Glucuronate; Trip tin, loxoribine; lurtotecan; lutetium teXaphyrin, lySofylline; torelin; Tubulozole Hydrochloride; Uracil Mustard; Ure lytic peptides, maitansine; mannostatin A, marimastat; depa; Vapreotide; Verteporfin; Vinblastine Sulfate; Vincris masoprocol; maspin; matrilysin inhibitors, matrix metallo tine Sulfate; Vindesine; Vindesine Sulfate; Vinepidine proteinase inhibitors, menogaril; merbarone; meterelin; Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorel methioninase; metoclopramide; MIF inhibitor; mifepris bine Tartrate; Vinrosidine Sulfate; Vinzolidine Sulfate; tone, miltefosine, mirimoStim, mismatched double Stranded Vorozole; Zeniplatin; Zinostatin; Zorubicin Hydrochloride. RNA, mitoguaZone, mitolactol, mitomycin analogues, Other anti-neoplastic compounds include: 20-epi-1,25 25 mitonafide; mitotoxin fibroblast growth factor-Saporin; dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclaru mitoxantrone; mofaroteine; molgramoStim; monoclonal bicin; acylfulvene, adecypenol; adoZelesin; aldesleukin; antibody, human chorionic gonadotrophin, monophosphoryl ALL-TK antagonists, altretamine; ambamustine, amidox; lipid A +myobacterium cell wall Sk, mopidamol, multiple amifostine; aminolevulinic acid; amrubicin; amsacrine; drug resistance gene inhibitor, multiple tumor Suppressor anagrelide, anastrozole; andrographolide, angiogenesis 1-based therapy; mustard anticancer agent; my caperoxide B; inhibitors, antagonist D; antagonist G, antarelix; anti mycobacterial cell wall eXtract; myriaporo ne; dorsalizing morphogenetic protein-1, antiandrogen, proS N-acetyldinaline; N-substituted benzamides; nafarelin; tatic carcinoma, antieStrogen; antineoplaston, antisense oli nagreStip; naloxone +pentazocine, napavin, naphterpin, nar gonucleotides, aphidicolin glycinate, apoptosis gene tograstim; nedaplatin; nemorubicin; neridronic acid; neutral modulators, apoptosis regulators, apurinic acid, ara-CDP 35 endopeptidase; nilutamide, nisamycin; nitric oxide modula DL-PTBA, arginine deaminase, asulacrine; atameStane; atri tors, nitroxide antioxidant; nitrullyn; O6-benzylguanine; mustine; axinastatin 1; axinastatin 2; axinastatin 3; aza octreotide, okice none, oligonucleotides; ; Setron; azatoxin; aZatyrosine; baccatin III derivatives, Ondansetron; ondansetron; oracin, oral cytokine inducer, balanol; batimastat; BCR/ABL antagonists; benzochlorins; ormaplatin; OSaterone, Oxaliplatin, oxaunomycin; paclitaxel benzoylstauroSporine; beta lactam derivatives, beta 40 analogues, paclitaxel derivatives, palauamine; palmitoyl alethine; betaclamycin B; betulinic acid; bFGF inhibitor; rhizoxin; pamidronic acid; panaxytriol, panomifene, para bicalutamide, bisantrene, bisaZiridinylspermine; bisnafide; bactin; paZelliptine, pegaspargase; peldesine; pentosan bistratene A, bizelesin, breflate, bropirimine; budotitane; polysulfate Sodium; pentostatin; pentrozole; perflubron; per buthionine Sulfoximine, calcipotriol, calphostin C; camp fosfamide; perillyl alcohol; phenazinomycin; phenylacetate; tothecin derivatives; canarypox IL-2, capecitabine; 45 phosphatase inhibitors, picibanil; pilocarpine hydrochloride; carboxamide-amino-triazole; carboxyamidotriazole, CaRest pirarubicin; piritrexim; placetin A; placetin B; plasminogen M3; CARN 700; cartilage derived inhibitor; carzelesin; activator inhibitor; platinum complex, platinum compounds, casein kinase inhibitors (ICOS), castanospermine; cecropin platinum-triamine complex, porfimer Sodium; porfiromycin; B; cetrorelix; chlorins, chloroquinoxaline Sulfonamide, cica propyl bis-acridone; prostaglandin J2, proteasome inhibi prost, cis-porphyrin, cladribine; clomifene analogues, clot 50 tors, protein A-based immune modulator, protein kinase C rimazole; collismycin A, collismycin B; combretastatin A4, inhibitor; protein kinase C inhibitors, microalgal; protein combretastatin analogue; conagenin, crambescidin 816; cri tyrosine phosphatase inhibitors, purine nucleoside phospho Snatol; cryptophycin 8; cryptophycin A derivatives, curacin rylase inhibitors, purpurins, pyrazoloacridine, pyridoxylated A., cyclopentanthraquinones, cycloplatam, cypemycin; cyt hemoglobin polyoxyethylene conjugate, raf antagonists, arabine ocfosfate, cytolytic factor; cytostatin, dacliximab, 55 raltitrexed; ramosetron; ras farnesyl protein transferase decitabine; dehydrodidemnin B; deslorelin; dexifosfamide; inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine deXraZoxane, deXVerapamil, diaziquone; didemnin B; didox; demethylated; rhenium Re 186 etidronate; rhizoxin; diethylnorSpermine, dihydro-5-azacytidine, dihydrotaxol, ribozymes, RII retinamide, rogle timide, rohitukine; 9-, dioxamycin; diphenyl Spiromustine, docosanol; dolas romurtide, roquinimex, rubiginone B1, ruboxyl, Safingol; etron, doxifluridine, droloxifene, dronabinol; duocarmycin 60 Saintopin; SarCNU; Sarcophytol A, SargramoStim; Sdi 1. SA, ebSelen; ecomustine, edelfosine; edrecolomab, eflorni mimetics, Semustine, Senescence derived inhibitor 1; Sense thine; elemene; emitefur, epirubicin, epristeride; estramus oligonucleotides, Signal transduction inhibitors, Signal trans tine analogue; estrogen agonists, estrogen antagonists; duction modulators, Single chain antigen binding protein; etanidazole, etoposide phosphate; exemestane, fadrozole; sizofiran; Sobuzoxane, Sodium borocaptate, Sodium pheny fazarabine; fenretinide; filgrastim; finasteride, flavopiridol; 65 lacetate, Solverol, Somatomedin binding protein; Sonermin; fleZelastine; fluiasterone; fludarabine; fluorodaunorunicin Sparfosic acid; Spicamycin D; Spiromustine; Splenopentin; hydrochloride; forfenimex, formeStane; fostriecin, fotemus Spongistatin 1; Squalamine; Stem cell inhibitor, Stem-cell US 6,576,636 B2 33 34 division inhibitors; stipiamide; stromelysin inhibitors; sulfi Antipsychotic: Acetophenazine Maleate; Alentemol nosine; Superactive vasoactive intestinal peptide antagonist; Hydrobromide, Alpertine, AZaperone; Batelapine Maleate; Suradista; Suramin; Swainsonine, Synthetic glycosaminogly Benperidol; BenZindopyrine Hydrochloride; Brofoxine; cans, tallimustine, tamoxifen methiodide, tauromustine; taZ Bromperidol; Bromperidol Decanoate; Butaclamol Hydro arotene, tecogalan Sodium, tegafur, tellurapyrylium; telom chloride; Butaperazine; Butaperazine Maleate; Carphena erase inhibitors, temoporfin, temozolomide; teniposide; zine Maleate; Carvotroline Hydrochloride; Chlorpromazine; tetrachlorodecaoxide, tetraZomine; thaliblastine; thalido Chlorpromazine Hydrochloride; Chlorprothixene; Cin mide; thiocoraline; thrombopoietin; thrombopoietin perene: Cintriamide; Clomacran Phosphate, Clopenthixol; mimetic; thymalfasin; thymopoietin receptor agonist, thy Clopimozide; Clopipazan Mesylate; Cloroperone Hydro motrinan; thyroid Stimulating hormone, tin ethyl etiopurpu rin; tirapazamine, titanocene dichloride; topotecan; topsen 1O chloride; Clothiapine; Clothixamide Maleate; Clozapine; tin, toremifene; totipotent Stem cell factor; translation Cyclophenazine Hydrochloride; Droperidol; Etazolate inhibitors, , triacetyluridine, triciribine, trimetrex Hydrochloride; Fenimide; Flucindole; Flumezapine; ate, triptorelin; tropisetron; turosteride, tyrosine kinase Fluphenazine Decanoate, Flu phena Zine Enant hate; inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogeni Fluphenazine Hydrochloride; Fluspiperone; Fluspirilene; tal Sinus-derived growth inhibitory factor; urokinase recep 15 Flutroline; Gevotroline Hydrochloride; Halopemide; Halo tor antagonists, vapreotide; variolin B; Vector System, eryth peridol, Haloperidol Decanoate, Iloperidone, Imidoline rocyte gene therapy, VelareSol, Veramine, Verdins, Hydrochloride; Lenperone; MaZapertine Succinate; verteporfin, Vinorelbine; VinXaltine, Vitaxin; Vorozole; Zan Mesoridazine; Mesoridazine Besylate; Metiapine; Milenper oterone; Zeniplatin, Zilascorb, Zinostatin stimalamer. one; Milipertine; Molindone Hydrochloride; Naranol Anti-cancer Supplementary Potentiating Agents: Tricy Hydrochloride; Neflumozide Hydrochloride; Ocaperidone; clic anti-depressant drugs (e.g., imipramine, desipramine, Olanzapine; Oxiperomide; Penfluridol; Pentiapine Maleate; amitryptyline, clomipramine, trimipramine, doxepin, Perphenazine; Pimozide; Pinoxepin Hydrochloride; Pipam nortriptyline, protriptyline, amoxapine and maprotiline); perone, Piperacetazine, Pipotiazine Palmitate; Piquindone non-tricyclic anti-depressant drugs (e.g., Sertraline, traz Hydrochloride; Prochlorperazine Edisylate; Prochlorpera odone and citalopram); Ca' antagonists (e.g., Verapamil, 25 zine Maleate; Promazine Hydrochloride; Remoxipride; nifedipine, nitrendipine and caroverine); Calmodulin inhibi Remoxipride Hydrochloride; Rimcazole Hydrochloride; tors (e.g., prenylamine, trifluoropera Zine and Seperidol Hydrochloride; Sertindole; Setoperone; Spiper clomipramine); Amphotericin B; Triparanol analogues (e.g., one; Thioridazine; Thioridazine Hydrochloride; Thiothix tamoxifen); antiarrhythmic drugs (e.g., quinidine); antihy ene; Thiothixene Hydrochloride; Tioperidone Hydrochlo pertensive drugs (e.g., reserpine); Thiol depleters (e.g., ride; Tiospirone Hydrochloride; Trifluoperazine buthionine and Sulfoximine) and Multiple Drug Resistance Hydrochloride; Trifluperidol; Triflu promazine; Triflupro reducing agents Such as Cremaphor EL. The compounds of mazine Hydrochloride; Ziprasidone Hydrochloride. the invention also can be administered with cytokines Such Antirheumatic: Auranofin, Aurothioglucose, Bindarit; as granulocyte colony Stimulating factor. Lobenzarit Sodium; Phenylbutazone; Pirazolac, Prinomide Antineutropenic: Filgrastim; Lenograstim; Molgra 35 moStim; RegramoStim; SargramoStim. Tromethamine; Seprilose. Antischistosomal: Becanthone Hydrochloride; Hycan Antiobsessional agent: Fluvoxamine Maleate. thone; Lucanthone Hydrochloride; Niridazole; Oxam Antiparasitic: Abamectin; ClorSulon; Ivermectin. niquine; Pararosaniline Pamoate; Teroxalene Hydrochlo Antiparkinsonian: Benztropine MeSylate, Biperiden; ride. Biperiden Hydrochloride; Biperiden Lactate; Carmantadine; 40 Ciladopa Hydrochloride; Dopamantine; Ethopropazine Antiseborrheic: Chloroxime; Piroctone; Piroctone Ola Hydrochloride; LaZabemide; Levodopa, Lometraline mine; Resorcinol Monoacetate. Hydrochloride; Mofegiline Hydrochloride; Naxagolide Antisecretory: Arbaprostil; Deprostil; Fenoctimine Sul Hydrochloride; Pareptide Sulfate; Procyclidine Hydrochlo fate; Octreotide; Octreotide Acetate; Omeprazole Sodium; ride; Quinelorane Hydrochloride; Ropinirole Hydrochlo 45 Rioprostil; Trimoprostil. ride; Selegiline Hydrochloride; Tolcapone; Trihexyphenidyl Hydrochloride. Antispasmodic: Stilonium Iodide; Tizanidine Hydrochlo Antiperistaltic: Difenoximide Hydrochloride; Difenoxin; ride. Diphenoxylate Hydrochloride; Fluperamide; Lidamidine Antithrombotic: Anagrelide Hydrochloride; Bivalirudin; Hydrochloride; Loperamide Hydrochloride; Malethamer; 50 Dalteparin Sodium; Danaparoid Sodium; Dazoxiben Hydro Nufenoxole; Paregoric. chloride; Efegatran Sulfate; Enoxaparin Sodium; Ifetroban; Antipneumocystic: Atovaquone. Ifetroban Sodium; Tinzaparin Sodium; Trifenagrel. Antiproliferative agent: Piritrexim Isethionate. Antitussive: Benzonatate; Butamirate Citrate; Chlophedi Antiprostatic hypertrophy: SitogluSide. 55 anol Hydrochloride; Codeine Polistirex, Codoxime; Dex Antiprotozoal: Amodiaquine, AZanidazole; Bamnidazole; tromethorphan; Dextromethorphan Hydrobromide; Dex Carnidazole; Chlortetracycline Bisulfate; Chlortetracycline tromethorphan Polistirex, Ethyl Dibunate; Guaiapate; Hydrochloride; Flubendazole; Flunidazole; Halofuginone Hydrocodone Bitartrate; Hydrocodone Polistirex; Levopro Hydrobromide; Imidocarb Hydrochloride; Ipronidazole; poxyphene Napsylate; Noscapine; Pemerid Nitrate; Metronidazole; Misonidazole; Moxinidazole; NitarSone; Par 60 Pipazethate; Suxemerid Sulfate. tricin; Puromycin; Puromycin Hydrochloride; Ronidazole; Anti-ulcerative: Aceglutamide Aluminum; CadeXomer Sulnidazole; Tinidazole. Iodine; Cetraxate Hydrochloride; Enisoprost, Isotiquimide; Antipruritic: Cyproheptadine Hydrochloride: Methdila Lansoprazole, LaVoltidine Succinate, Misoprostol; Nizati zine; Methdilazine Hydrochloride; Trimeprazine Tartrate. dine; Nolinium Bromide; Pantoprazole; Pifamine; Piren Antipsoriatic: ; Anthralin, AZaribine, Calcipot 65 Zepine Hydrochloride; Rabeprazole Sodium; Remiprostol; riene; Cycloheximide, EnaZadrem Phosphate; ; Roxatidine Acetate Hydrochloride; Sucralfate; Sucrosofate Liarozole Fumarate, Lonapalene; Tepoxalin. Potassium; Tolimidone. US 6,576,636 B2 35 36 Anti-urolithic: Cysteamine; Cysteamine Hydrochloride; Quinidine Sulfate; Recainam Hydrochloride; Recainam Tricitrates. Tosylate; Risotilide Hydrochloride; Ropitoin Hydrochlo Antiviral: Acemannan, Acyclovir, Acyclovir Sodium; ride; Sematilide Hydrochloride; Suricainide Maleate; Adefovir; Alovudine; Alvircept Sudotox; Amantadine Tocainide; Tocainide Hydrochloride; Transcainide. Hydrochloride; Aranotin; Arildone; Atevirdine Mesylate; Cardioprotectant: DeXraZOxane, Draflazine. Avridine, Cidofovir; Cipamfylline; Cytarabine Hydrochlo Cardiotonic: Actodigin; Amrinone; Bemoradan; Buto ride; Delavirdine Mesylate; Desciclovir; Didanosine; Dis pamine; CarbaZeran; CarSatrin Succinate, Deslanoside; oxaril; Edoxudine, Enviradene; EnviroXime; Famciclovir, Digitalis, Digitoxin; Digoxin; Dobutamine; Dobutamine Famotine Hydrochloride; Fiacitabine; Fialuridine; Fosari Hydrochloride; Dobutamine Lactobionate; Dobutamine Tar late; Foscamet Sodium; Fosfonet Sodium; Ganciclovir, trate, Enoximone, ImaZOdan Hydrochloride; Indolidan; Iso Ganciclovir Sodium; Idoxuridine; Kethoxal; Lamivudine; mazole Hydrochloride; Levdobutamine Lactobionate; Lix Lobucavir; Memotine Hydrochloride; Methisazone; Nevi azinone Sulfate; Medorinone; Milrinone; Pelrinone rapine; Penciclovir; Pirodavir; Ribavirin; Rimantadine Hydrochloride; Pimobendan; Piroximone; Prinoxodan; Hydrochloride; Saquinavir Mesylate; Somantadine Hydro Proscillaridin; Quazinone; Tazolol Hydrochloride; chloride; Sorivudine; Statolon; Stavudine; Tilorone Hydro 15 Vesnarinone. chloride; Trifluridine; Valacyclovir Hydrochloride; Vidara Cardiovascular agent: Dopexamine; Dopexamine Hydro bine; Vidarabine Phosphate; Vidarabine Sodium Phosphate; chloride. Viroxime; Zalcitabine; Zidovudine; ZinviroXime. Appetite Suppressant: Dexfenfluramine Hydrochloride; Choleretic: Dehydrocholic Acid, Fencibutirol; Hymec Phendimetrazine Tartrate; Phentermine Hydrochloride. romone, Piprozolin; Sincalide, Tocamphyl. Cholinergic: Aceclidine; Bethanechol Chloride; Caiba Benign prostatic hyperplasia therapy agent: Tamsulosin chol; Demecarium Bromide; Dexpanthenol; Echothiophate Hydrochloride. Iodide; Isoflurophate; Methacholine Chloride; Neostigmine Blood glucose regulators: Human insulin; Glucagon; Bromide; Neostigmine Methylsulfate; Physostigmine; Phy TolaZamide, Tolbutamide; Chloropropamide, Acetohexam 25 SoStigmine Salicylate; PhySoStigmine Sulfate; Pilocarpine; ide and Glipizide. Pilocarpine Hydrochloride; Pilocarpine Nitrate; Pyridostig Bone resorption inhibitor: Alendronate Sodium; Etidr mine Bromide. onate Disodium; Pamidronate Disodium. Cholinergic agonist: Xanomeline, Xanomeline Tartrate. Bronchodilator: Albuterol; Albuterol Sulfate; AZanator Maleate; Bamifylline Hydrochloride; Bitolterol Mesylate; Cholinesterase Deactivator: Obidoxime Chloride; Prali Butaprost; Carbuterol Hydrochloride; Clorprenaline Hydro doxime Chloride; Pralidoxime Iodide; Pralidoxime Mesy chloride; Colterol Mesylate; Doxaprost; Doxofylline; late. Dyphylline; Enprofylline; Ephedrine; Ephedrine Hydro CoccidioStat: Arprinocid; Narasin; Semduramicin; Sem chloride; Fenoterol; Fenprinast Hydrochloride; Guaithyl duramicin Sodium. line; Hexoprenaline Sulfate; Hoquizil Hydrochloride; Ipra 35 Cognition adjuvant: Ergoloid MeSylates, Piracetam; tropium Bromide; Isoetharine; Isoetharine Hydrochloride; Pramiracetam Hydrochloride; Pramiracetam Sulfate; Isoetharine Mesylate; Isoproterenol Hydrochloride; Isopro Tacrine Hydrochloride. terenol Sulfate; Metaproterenol Polistirex; Metaproterenol Cognition enhancer: Besipirdine Hydrochloride; Linopir Sulfate; Nisbuterol Mesylate; Oxtriphylline; Picumeterol dine, Sibopirdine. Fumarate; Piquizil Hydrochloride; Pirbuterol Acetate; Pir 40 Depressant: Omeprazole. buterol Hydrochloride; Procaterol Hydrochloride; Pseu Diagnostic aid: Aminohippurate Sodium; Anazolene doephedrine Sulfate; QuaZodine; Quinterenol Sulfate; Sodium; Arclofenin, Arginine; Bentiromide; Benzylpenicil Racepinephrine, Racepinephrine Hydrochloride; Reproterol loyl Polylysine; Butedronate Tetrasodium; Butilfenin; Coc Hydrochloride; Rimiterol Hydrobromide; Salmeterol; Sal cidioidin; Corticorelin Ovine Triflutate Corticotropin, meterol Xinafoate; Soterenol Hydrochloride; Sulfonterol 45 Repository; Corticotropin Zinc Hydroxide; Diatrizoate Hydrochloride; Suloxifen Oxalate; Terbutaline Sulfate; Meglumine; Diatrizoate Sodium; Diatrizoic Acid; Diphthe Theophylline; Xanoxate Sodium; Zindotrine; Zinterol ria Toxin for Schick Test; Disofenin; Edrophonium Chlo Hydrochloride. ride; Ethiodized Oil, Etifenin; Exametazime, Ferristenc; Carbonic anhydrase inhibitor: Acetazolamide, Acetazola Ferumoxides; Ferumoxsil; Fluorescein, Fluorescein mide Sodium; Dichlorphenamide; Dorzolamide Hydrochlo 50 Sodium; Gadobenate Dimeglumine; Gadoteridol; Gadodia ride; Methazolamide; Sezolamide Hydrochloride. mide, Gadopentetate Dimeglumine, Gadoversetamide, His Cardiac depressant: Acecainide Hydrochloride, Acetyl toplasmin, Impromidine Hydrochloride; Indigotindisul choline Chloride; Actisomide, Adenosine, Amiodarone; fonate Sodium; Indocyanine Green; lobenguane Sulfate I Aprindine; Aprindine Hydrochloride; Artilide Fumarate; 123; lobenzamic Acid, Iocarmate Meglumine; locarmic Azimilide Dihydrochloride; Bidisomide; Bucainide Male 55 Acid, locetamic Acid, lodamide, lodamide Megilumine, lodi ate, Bucromarone; Butoprozine Hydrochloride, Capobenate pamide Meglumine; lodixanol; lodoxamate Meglumine; Sodium; Capobenic Acid; Cifenline; Cifenline Succinate; lodoxamic Acid, loglicic Acid, loglucol, loglucomide; logly Clofilium Phosphate; Disobutamide; Disopyramide; Dis camic Acid, logulamide; lohexol, lomeprol; lopamidol; opyramide Phosphate; Dofetilide; Drobuline; Edifolone lopanoic Acid, Iopentol; lophendylate; I profenin, Iopronic Acetate; Emilium Tosylate; Encainide Hydrochloride; 60 Acid; loprocemic Acid; lopydol; Iopy done; losefamic Acid; Flecainide Acetate; Ibutilide Fumarate; Indecainide Hydro IoSeric Acid, loSulamide Meglumine; loSumetic Acid; Iota chloride; Ipazilide Fumarate; Lorajmine Hydrochloride; Sul; Iotetric Acid; Iothalamate Meglumine; lothalamate Lorcainide Hydrochloride; Meobentine Sulfate; Mexiletine Sodium; lothalamic Acid; Iotrolan; lotroXic Acid, loverSol; Hydrochloride; Modecainide; Moricizine; Oxiramide; Pir loxaglate Meglumine, Ioxagiate Sodium, Ioxaglic Acid; menol Hydrochloride; Pirolazamide; Pranolium Chloride; 65 Ioxilan, Ioxotrizoic Acid, Ipodate Calcium, Ipodate Sodium; Procainamide Hydrochloride; Propafenone Hydrochloride; ISOSulfan Blue; Leukocyte Typing Serum; Lidofenin, Pyrinoline; Quindonium Bromide; Quinidine Gluconate; Mebrofenin; Meglumine; Metrizamide; Metrizoate Sodium; US 6,576,636 B2 37 38 ; Metyrapone Tartrate; Mumps Skin Test Anti Hair growth stimulant: Minoxidil. gen; Pentetic Acid; Propyliodone; Quinaldine Blue; Schick Hemostatic: Aminocaproic Acid, OXamarin Hydrochlo Test Control; Sermorelin Acetate; Sodium Iodide I 123; ride; Sulmarin; Thrombin; Tranexamic Acid. Sprodiamide; Stannous Pyrophosphate; Stannous Histamine H2 receptor antagonists: Ranitidine (Zantac); Colloid; Succimer; Teriparatide Acetate; Tetrofosmin; Tolb Famotidine (Pepcid); Cimetidine (Tagamet); Nizatidine utamide Sodium; Tuberculin; Tyropanoate Sodium; Xylose. (Axid). Diuretic: Ambuphylline; Ambuside; Amiloride Hydro Hormone: Diethylstilbestrol; Progesterone; 17 hydroxy chloride, AZolimine, AZOSemide, Brocrinat, Bumetanide; progesterone; Medroxyprogesterone, Norgestrel; Nor Chlorothiazide; Chlorthalidone; Clazolimine; Clorexolone; ethynodrel; Estradiol; Megestrol (Megace); Norethindrone; Ethacrynate Sodium; Ethacrynic Acid; Etozolin; Fen Levonorgestrel; Ethyndiol; Ethinyl estradiol; Mestranol; quizone; Furosemide; Hydrochlorothiazide, ISOSorbide; Estrone, Equilin; 17 alpha dihydroequilin; equilenin; 17 Mannitol; Mefruside; Ozolinone; Piretanide; Spiroxasone; alpha dihydroequilenin; 17 alpha estradiol; 17 beta estradiol; Torsemide; Triamterene; Triflocin, Urea. Leuprolide (lupron); Glucagon; Testolactone; Clomiphene; Dopaminergic agent: Ibopamine. Han memopausal gonadotropins, Human chorionic gona Ectoparasiticide: Nifluridide; Permethrin. 15 dotropin; Urofollitropin; Bromocriptine; Gonadorelin; Emetic: Apomorphine Hydrochloride. Luteinizing hormone releasing hormone and analogs, Gona Enzyme inhibitor: Acetohydroxamic Acid, Alrestatin dotropins; Danazol; Testosterone, Dehydroepiandrosterone; Sodium; Aprotinin; Benazepril Hydrochloride; Benazepri Androstenedione, Dihydroestosterone, Relaxin, Oxytocin, lat; Benurestat; Bromocriptine; Bromocriptine Mesylate; Vasopressin; Folliculostatin; Follicle regulatory protein; Cilastatin Sodium; Flurofamide, Lergotrile, Lergotrile Gonadoctrinins, Oocyte maturation inhibitor; Insulin growth Mesylate; Levcycloserine; Libenzapril; Pentopril; Pepstatin; factor, Follicle Stimulating Hormone, Luteinizing hormone; Perindopril; Polignate Sodium; Sodium Amylosulfate; Sor Tamoxifen.; Corticorelin Ovine Triflutate; Cosyntropin; binil; Spirapril Hydrochloride; Spiraprilat; Taleranol; Tepro Metogest; Pituitary, Posterior; Seractide Acetate; Somal tide; Tolfamide; Zofenopril Calcium. 25 apor, Somatrem; Somatropin; Somenopor, Somidobove. Estrogen: Chlorotrianisene; Dienestrol; Diethylstil Hypocholesterolemic: Lifibrol. bestrol; Diethylstilbestrol Diphosphate; Equilin; Estradiol; Hypoglycemic: DarglitaZone Sodium: Glimepiride. Estradiol Cypionate; Estradiol Enanthate; Estradiol Unde cylate; Estradiol Valerate; EstraZinol Hydrobromide; Estriol; Hypolipidemic: AzalanstatDihydrochloride; Colestolone; Estrofurate; Estrogens, Conjugated; Estrogens, Esterified; Surfomer; Xenalipin. Estrone; Estropipate; Ethinyl Estradiol; Fenestrel; Mestra Hypotensive: Viprostol. nol; Nylestriol; Quinestrol. HMGCoA reductase inhibitors: Lovastatin (Mevacor); Fibrinolytic: Anistreplase; Bisobrin Lactate; Brinolase. Simvastatin (Zocor); Pravastatin (Pravachol); Fluvasatin Free oxygen radical Scavenger: Pegorgotein. (Lescol). Gastrointestinal Motility agents: Cisapride (Propulsid); 35 Immunizing agent: Antirabies Serumn; Antivenin Metoclopramide (Reglan), Hyoscyamine (Levsin). (Latrodectus mactans); Antivenin (Micrurus Fulvius); Anti Glucocorticoid: , Beclomethasone Dipropi venin (Crotalidae) Polyvalent; BCG Vaccine; Botulism onate, ; , Betametha Antitoxin; Cholera Vaccine; Diphtheria Antitoxin; Diphthe Sone Benzoate, Betamethasone Dipropionate, Betametha ria Toxoid; Diphtheria Toxoid Adsorbed; Globulin, Immune; sone Sodium Phosphate; ; 40 Hepatitis B Immune Globulin; Hepatitis B Virus Vaccine Sodium; Acetate; Clocor Inactivated; Influenza Virus Vaccine; Measles Virus Vaccine tolone Pivalate; ; Corticotropin; Corticotropin, Live, Meningococcal Polysaccharide Vaccine Group A; Repository; Corticotropin Zinc Hydroxide; Meningococcal Polysaccharide Vaccine Group C; Mumps Acetate; , Acetonide; Dexametha Virus Vaccine Live; Pertussis Immune Globulin; Pertussis Sone; Dexamethasone Sodium Phosphate; ; 45 Vaccine; Pertussis Vaccine Adsorbed; Plague Vaccine; Diflucortolone Pivalate; Flucloronide; Flumethasone; Flu Poliovirus Vaccine Inactivated; Poliovirus Vaccine Live Pivalate; Flunisolide; Acetonide; Oral; Rabies Immune Globulin; Rabies Vaccine; Rho(D) ; ; Fluocortolone Caproate; Fluo Immune Globulin; Rubella Virus Vaccine Live; Smallpox rometholone; Acetate; ; Flu Vaccine; Tetanus Antitoxin; Tetanus Immune Globulin; Valerate; Flurandrenolide; ; 50 Tetanus Toxoid; Tetanus Toxoid Adsorbed; Typhoid Vac Hydrocortisone; ; Hydrocortisone cine; Yellow Fever vaccine; Vaccinia Immune Globulin; Butep rate; ; Hydrocortisone Varicella-Zoster Immune Globulin. Sodium Phosphate; Hydrocortisone Sodium Succinate; Immunomodulator: Dimepranol Acedoben; Imiquimod; ; ; Methylprednisolone; Interferon Beta-lb., Lisofylline; Mycophenolate Mofetil, Methylprednisolone Acetate; Methylprednisolone Sodium 55 Prczatide Copper Acetate. Phosphate; Methylprednisolone Sodium Succinate; Nivazol; Immunoregulator: AZarole, Fanetizole MeSylate; Frenti Acetate; ; Prednisolone; Pred zole; Oxamisole Hydrochloride; Ristianol Phosphate; Thy nisolone Acetate, Prednisolone Hemisuccinate, Predniso mopentin; Tilomisole. lone Sodium Phosphate; Prednisolone Sodium Succinate; Immunostimulant: Loxoribine; Teceleukin. ; ; Prednival; 60 Propionate; ; ; Triamcinolone Immunosuppressant: AZathioprine, AZathioprine Sodium; Acetonide; Sodium; Triamcino Cyclosporine; Daltroban; Gusperimus Trihydrochloride; lone Diacetate; Triamcinolone Hexacetonide. Sirolimus; Tacrolimus. Gonad-stimulating principle: Buserelin Acetate; Clomi Impotence therapy adjunct: Delequamine Hydrochloride. phene Citrate; Ganirelix Acetate; Gonadorelin Acetate; 65 Inhibitor: Acarbose; Atorvastatin Calcium; Benserazide; Gonadorelin Hydrochloride; Gonadotropin, Chorionic; Brocresine; Carbidopa; Clavulanate Potassium; DaZmegrel, Menotropins. Docebenone; Epoprostenol; Epoprostenol Sodium; Epris US 6,576,636 B2 39 40 teride; Finasteride; Flurbiprofen Sodium; Furegrelate Psychotropic: Minaprine. Sodium; Lufironil; Miglitol; Orlistat; Pimagedine Hydro Pulmonary surface: Beractant; Colfosceril Palmitate. chloride; Pirmagrel: Ponalrestat; Ridogrel; Sulbactam Ben Zathine; Sulbactam Pivoxil, Sulbactam Sodium; Suronacrine Radioactive agent: Fibrinogen 1125; Fludeoxyglucose F Maleate; Tazobactam; Tazobactam Sodium; Ticlopidine 5 18; Fluorodopa F 18; Insulin I 125; Insulin I 131; Ioben Hydrochloride; Tirilazad Mesylate; Tolrestat; Velnacrine guane I 123; Iodiparinide Sodium I 131; lodoantipyrine I 131; Iodocholesterol I 131; Iodohippurate Sodium I 123; Maleate; Zifrosilone; Zileuton. Iodohippurate Sodium I 125; Iodohippurate Sodium I 131; Keratolytic: Alcloxa; Aldioxa; ; Diben Iodopyracet I 125; Iodop-racet I 131; Iofetamine Hydro Zothiophene; Etarotene; ; ; Picotrin chloride I 123, Iomethin I 125; Iomethin I 131; Iothalamate Diolamine; Resorcinol; Resorcinol Monoacetate; Salicylic Sodium I 125; Iothalamate Sodium I 131; Iotyrosine I 131; Acid, Sumaroteine, Tazaroteine, Tetroquinone; Tretinoin. Liothyronine I 125; Liothyronine I 131. Merisoprol Acetate LHRH agonist: Deslorelin: Goserelin; Histrelin; Lutrelin Hg 197; Merisoprol Acetate Hg 203; Merisoprol Hg 197; Acetate, Nafarelin Acetate. Selenomethionine Se 75; Technetium Tc 99m Antimony Liver disorder treatment: Malotilate. 15 Trisulfide Colloid; Technetium Tc 99m Bicisate; Technetium Luteolysin: FenproStalene. Tc 99m Disofenin; Technetium Tc 99m Etidronate; Techne Memory adjuvant: Dimoxamine Hydrochloride; Ribami tium Tc 99m Exametazime; Technetium Tc 99m Furifosmin, nol. Technetium Tc 99m Gluceptate; Technetium Tc 99m Lid ofenin; Technetium Tc 99m Mebrofenin; Technetium Tc Mental performance enhancer: Aniracetam. 99m Medronate; Technetium Tc 99m Medronate Disodium; Mood regulator: Fengabine. Technetium Tc 99m Mertiatide; Technetium Tc 99m Oxidr Mucolytic: Acetylcysteine: Carbocysteine; Domiodol. onate; Technetium Tc 99m Pentetate; Technetium Tc 99m Mucosal Protective agents: Misoprostol (Cytotec). Pentetate Calcium Trisodium; Technetium Tc 99m Sesta Mydriatic: Berefrine. mibi; Technetium Tc 99m Siboroxime; Technetium Tc 99m 25 Succimer; Technetium Tc 99m Sulfur Colloid; Technetium Nasal decongestant: Nemazoline Hydrochloride; Pseu Tc 99m Teboroxime; Technetium Tc 99m Tetrofosmin; doephedrine Polistirex. Technetium Tc 99m Tiatide; Thyroxine I 125; Thyroxine I Neuroleptic: Duoperone Fumarate; Risperidone. 131; Tolpovidone I 131; Triolein I 125; Triolein 1131. Neuromuscular blocking agent: Atracurium BeSylate; Regulator: Calcifediol; Calcitonin; Calcitriol; Clodronic Cisatracurium Besylate; Doxacurium Chloride; Gallamine Acid; Dihydrotachysterol, Etidronic Acid; Oxidronic Acid; Triethiodide; Metocurine Iodide, Mivacurium Chloride; Piridironate Sodium; Risedronate Sodium; Secalciferol. Pancuronium Bromide; Pipecuronium Bromide; Rocuro nium Bromide; Succinylcholine Chloride; Tubocurarine Relaxant: Adiphenine Hydrochloride; Alcuronium Chlo ride; Aminophylline; AZumolene Sodium; Baclofen; Ben Chloride; Vecuronium Bromide. Zoctamine Hydrochloride; Carisoprodol; Chlorphenesin Neuroprotective: Dizocilpine Maleate. 35 Carbamate; ChlorZOXaZone; Cinflumide, Cinnamedrine; NMDA antagonist: Selfotel. Clodanolene; Cyclobenzaprine Hydrochloride; Dantrolene; Non-hormonal sterol derivative: Succinate. Dantrolene Sodium; Fenalamide; Fenyripol Hydrochloride; Oxytocic: Carboprost; Carboprost Methyl; Carboprost Fetoxylate Hydrochloride; Flavoxate Hydrochloride; Fle Tromethamine; Dinoprost; Dinoprost Tromethamine; Dino tazepam, Flumetramide, Flurazepam Hydrochloride; prostone; Ergonovine Maleate; Meteneprost, Methylergono 40 Hexafluorenium Bromide; Isomylamine Hydrochloride; vine Maleate; Oxytocin; Sparteine Sulfate. Lorbamate; Mebeverine Hydrochloride; Mesuprine Hydro Plasminogen activator: Alteplase, Urokinase. chloride; Metaxalone; Methocarbamol; Methixene Hydro chloride; Nafomine Malate; NeleZaprine Maleate; Papaver Platelet activating factor antagonist: Lexipafant. ine Hydrochloride; Pipoxolan Hydrochloride; Quinctolate; Platelet aggregation inhibitor: Acadesine; Beraprost; 45 Ritodrine; Ritodrine Hydrochloride; Rolodine; Theophylline Beraprost Sodium, Ciprostene Calcium; ItaZigrel, Lifariz Sodium Glycinate; Thiphenamil Hydrochloride; Xilobam. ine, OXagrelate. Repartitioning agent: Cimaterol. Post-Stroke and post-head trauma treatment: Citicoline Sodium. Scabicide: Amitraz, Crotamiton. Potentiator: Pentostatin; Talopram Hydrochloride. 50 Sclerosing agent: Ethanolamine Oleate; Morrhuate Progestin: AlgeStone Acetophenide; Amadinone Acetate: Sodium; Tribenoside. Anagestone Acetate; ; Cingestol; Sedative: Propiomazine. ClogeStone Acetate; Clomegestone Acetate; ; Dimethisterone; Dydrogesterone; Ethynerone; Ethynodiol Sedative-hypnotic: Allobarbital; Alonimid; Alprazolam; 55 Amobarbital Sodium; Bentazepam; Brotizolam; Butabar Diacetate; ; Flurogestone Acetate; Gestaclone; bital; Butabarbital Sodium; Butalbital; Capuride; Carboclo , Gestonorone Caproate; GeStrinone, Haloproges ral; Chloral Betaine; Chloral Hydrate; Chlordiazepoxide terone; Hydroxyprogesterone Caproate; Levonorgestrel; Hydrochloride; Cloperidone Hydrochloride; Clore thate; LyneStrenol; ; Medroxyprogesterone Acetate; Cyprazepam, Dexclamol Hydrochloride; Diazepam, Methynodiol Diacetate; Norethindrone; Norethindrone 60 Dichloralphenazone; Estazolam; Ethchlorvynol; Etomidate; Acetate, Norethynodrel; Norgestimate, , Norg Fenobam; Flunitrazepam, FoSazepam, Glute thimide; eStrel; OXogestone Phen propionate; Progesterone; Halazepam, Lormetazepam, Mecloqualone; Meprobamate; Quingestanol Acetate; ; Tigestol. Methaqualone; Midaflur; Paraldehyde; Pentobarbital; Pen Prostaglandin: Cloprostenol Sodium; Fluprostenol tobarbital Sodium; Perlapine, Prazepam, Quazepam, Sodium; Gemeprost; Prostalene; Sulprostone. 65 Reclazepam; Roletamide; Secobarbital; Secobarbital Prostate growth inhibitor: Pentomone. Sodium; Suproclone; Thalidomide; Tracazolate; Trepipam Prothyrotropin: Protirelin. Maleate; Triazolam; Tricetamide; Triclofos Sodium; Trime US 6,576,636 B2 41 42 toZine, Uldazepam, Zaleplon; Zolazepam Hydrochloride; Terodiline Hydrochloride; Tipropidil Hydrochloride; Tola Zolpidem Tartrate. Zoline Hydrochloride; Xanthinol Niacinate. Selective adenosine A1 antagonist: Apaxifylline. Vulnerary: Allantoin. Wound healing agent: ErSofermin. Serotonin antagonist: Altanserin Tartrate; AmeSergide, Xanthine oxidase inhibitor: Allopurinol; Oxypurinol Ketanserin; Ritanserin. Other pharrnaceutical agents include: 1-decpyrrolidinone; Serotonin inhibitor: Cinanserin Hydrochloride; Fenclo 1-dodecpyrrollidinone; 16-alpha fluoroe Stradiol; nine; Fonazine Mesylate; Xylamidine Tosylate. 16-; 16alpha-gitoxin; 17alpha estradiol, 17beta Serotonin receptor antagonist: Tropanserin Hydrochlo estradiol; 1alpha-hydroxyvitamin D2; 2'-nor-cGMP; 20-epi ride. 1.25 dihydroxyvitamin D3; 22-oxacalcitriol; 2CVV; 3-isobutyl GABA; 6-FUDCA, 7-methoxytacrine; abamec Steroid: ; Furoate. tin, abanoquil; abecamil; abiraterone; acadesine; acampro Stimulant: Amfonelic Acid; Amphetamine Sulfate; Sate; acarbose, aceclofenac; acemannan; acetomepregenol; Ampyzine Sulfate; Arbutamine Hydrochloride; Azabon; acetyl-L-camitine; acetylcysteine, N-; acetylmethadol; aci Caffeine; Ceruletide; Ceruletide Diethylamine; Cisapride; 15 fran; acipimox; acitemate; acitretin, aclarubicin, aclatonium; DaZopride Fumarate; Dextroamphetamine, Dextroamphet napadisilate; aconiazide, acrivastinet; adafenoxate, ada amine Sulfate; Difluanine Hydrochloride; Dimefline Hydro palene; adatanserin; adecypenol; adefovir dipivoxil, adelm chloride; Doxapram Hydrochloride; Etryptamine Acetate; idrol, ademetionine, adinazolam, adiposin; adoZelesin; Etharnivan; Fenethylline Hydrochloride; Flubanilate Hydro adrafinil; alacepril; aladapcin; alaptide; albendazole, albo chloride; Flurothyl; Histamine Phosphate; Indriline Hydro labrin; aldecalmycin; aldesleukin; alendronic acid; alente chloride; Mefexamide; Methamphetamine Hydrochloride; mol; alfacalcidol; alfuzosin; alglucerase, alinastine, aloS Methylphenidate Hydrochloride; Pemoline; Pyrovalerone etron; alpha idoSone; alproStadil; altretamine; altromycin B; Hydrochloride; Xamoterol; Xamoterol Fumarate. ambamustine, ; ameSergide, ameZinium metilsulfate; amfebutamone, amidox, amifloxacin; amifoS Suppressant: Amflutizole; Colchicine: TaZofelone. tine, amiodarone; amisulpride; amlexanoX, amlodipine; Symptomatic multiple Sclerosis: Fampridine. 25 amlodipine, ampiroXicam, amrinone; amrubicin; amsacrine; Synergist: Proadifen Hydrochloride. amylin; amythiamicin; anagrelide; anakinra, ananain; anaritide; anastrozole; andrographolide; anordrin; apado Thyroid hormone: Levothyroxine Sodium; Liothyronine line; apafant; apaxifylline, aphidicolin glycinate, apracloni Sodium; Liotrix. dine, aproSulate Sodium; aptiganel; apurinic acid, aranid Thyroid inhibitor: Methimazole; Propylthiouracil. ipine; arbekacin; arbidol; arbutamine, ardeparin Sodium; Thyromimetic: Thyromedan Hydrochloride. arecatannin B1; argatroban; aripiprazol; arotinolol, asima Tranquilizer: Bromazepam; Buspirone Hydrochloride; doline; aspalatone; asperfuran; aspoxicillin, astemizole; asu lacrine; atameStane, atenolol, S-; ateVirdine, atoSiban, atova Chlordiazepoxide; Clazolam; Clobazam; Clorazepate Dipo quone; atpenin B; atrimustine; atrinositol; aureobasidin A, tassium, CloraZepate Monopotassium; Demoxepam, azadirachtine, azasetron; azatyrosine; ; azelas Dexmedetomidine; Enciprazine Hydrochloride; Gepirone 35 tine; azelnidipine, azimilide, azithromycin; azoSemide; Hydrochloride; Hydroxyphenamate; Hydroxyzine Hydro aztreonam, baccatin III; bacoside A, bacoside B; bactobo chloride; Hydroxy Zine Pamoate; Ketazolam; Lorazepam, lamine; balaZipone, balhimycin; balofloxacin, balsalazide, LorZafone, Loxapine, Loxapine Succinate; Medazepam bambuterol, baohuoSide 1, barnidipine, basifungin; batebu Hydrochloride; Nabilone; Nisobamate; Oxazepam; Pent last, batimaStat; beauvericin; becaplermin; becliconazole; abamate; Pirenperone, Ripazepam, Rolipram; Sulazepam, 40 befloxatone; belfosdil; bellenamine; benflumetol; benid Taciamine Hydrochloride; Temazepam; Triflubazam; ipine; benzisoxazole; benzochlorins; benzoidaZOXan; ben Tybamate; Valnoctamide. ZoylstauroSporine; benztropine, bepridil, beractant; bera Amyotrophic lateral Sclerosis agents: Riluzole. prost, berlafenone; bertosamil, besipirdine, beta-alethine; betaclamycin B; betamipron; betaxolol, betulinic acid; Cerebral ischemia agents: Dextrorphan Hydrochloride. 45 bevantolol; bicalutamide; bifemelane; bimakalim, bimithil, Paget's disease agents: Tiluldronate Disodium. binoSpirone; bioxalomycin alpha2, biriperone; bis Unstable angina agents: Tirofiban Hydrochloride. benzimidazole A, bis-benzimidazole B; bisantrene; bisa Uricosuric: Benzbromarone; Irtemazole; Probenecid; ramil; bisaziridinylspermine; bisnafide; bisoprolol, bistra Sulfinpyrazone. mide D; bistramide K; bistratene A, boldine; bopindolol; 50 brefeldin; breflate; brimonidine; bromfenac; bromperidol; Vasoconstrictor: Angiotensin Amide, Felypressin, Methy bropirimine; bucindolol, budeSonide; budipine; budotitane; Sergide, MethySergide Maleate. bunaprolast; bunaZoSin; butenafine; buthionine Sulfoximine; Vasodilator: Alprostadil; AZaclorzine Hydrochloride; propionate; cadeXomer iodine, calanolide A, cal Bamethan Sulfate; Bepridil Hydrochloride; Buterizine; cipotriol, callphostin C, camonagrel, candesartan; cande Cetiedil Citrate; Chromonar Hydrochloride; Clonitrate; Dil 55 Sartan cileXetil, candoXatril; candoXatrilat, capecitabine; tiazem Hydrochloride; Dipyridamole; Droprenilamine; capromab, capsaicin; captopril; carbazomycin C; carbeto Erythrityl Tetranitrate; Felodipine; Flunarizine Hydrochlo cin; carbovir, carboxamide-amino-triazole; carboxyamidot ride; Fostedil; Hexobendine; Inositol Niacinate; Iproxamine riazole; carboxymethylated beta-1,3-glucan, carperitide; Hydrochloride; Isosorbide Dinitrate; Isosorbide Mononi carteolol, carumonam, carvedilol; carvotroline, carZelesin; trate; IsoxSuprine Hydrochloride; Lidoflazine; Mefenidil; 60 castanospermine, cebaracetam; cecropin B; cefcapene piv Mefenidil Fumarate; Mibefradil Dihydrochloride; Miofla oxil, cefdaloxime penteXil tosilate, cefdinir, cefditoren piv zine Hydrochloride; Mixidine; Nafronyl Oxalate; Nicar oxil, cefepime, cefetamet, cefetamet pivoxil, cefixime, cef dipine Hydrochloride; Nicergoline; Nicorandil; Nicotinyl luprenam, cefimetazole, cefminox, cefodizime, cefoSelis, Alcohol; Nifedipine; Nimodipine; Nisoldipine; Oxfenicine; cefotetan, cefotiam, cefotiam heXetil, cefoZopran, cefpimi Oxprenolol Hydrochloride; Pentaerythritol Tetranitrate; 65 Zole, cefpiramide, cefpirome, cefpodoxime proxetil, cef Pentoxifylline; Pentrinitrol; Perhexiline Maleate; Pindolol; prozil, cefSulodin, cefteram, ceftibuten, ceftriaxone, Pirsidomine; Prenylamine; Propatyl Nitrate; Suloctidil; cefuroxime axetil, celastrol; celikalim, celiprolol, cepaci US 6,576,636 B2 43 44 dine A, cericlamine; cerivastatin; ceronapril; certoparin ine; forasartan; forfenimex, formeStane; formoterol; Sodium, cetiedil; cetirizine, chloroorienticin A, chloroorien formoterol, R.R-; fosfomycin; trometamol; fosinopril; fos ticin B; chloroquinoxaline Sulfonamide, cibenzoline, cica phenytoin; fostriecin, fotemustine, gabapentin, gadobenic prost, , cicletanine, cicloprolol, cidofovir, acid; gadobutrol; gadodiamide; gadodiamide-EOB-DTPA; cilansetron; cilaZapril; cilnidipine; cilobradine, ciloStaZol; gadolinium teXaphyrin, gadoteric acid, gadoteridol; cimetropium bromide, cinitapride, cinolazepam, cioteronel; gadoverSetamide, galantamine; galdansetron; gallopamil, ciprofibrate, ciprofloxacin; ciprostene, cis-porphyrin, galocitabine, gamolenic acid, ganirelix; gepirone, cisapride, cisatracurium besilate, cistinexine, citalopram; gestrinone; girisopam; glaspimod, glaucocalyxin A; citicoline, citreamicin alpha; cladribine; clarithromycin; glutapyrone; glycopine, glycopril; granisetron; grepafloxa clausenamide; clebopride; clinafloxacin; clobaZam; clobeta cin; halichondrin B; halofantrine; halomon; ; Sone butyrate; clodronic acid; clomethiazole; clopidogrel; hatomamicin; hatomarubigin A; hatomarubigin B; clotrimazole; colestimide; colfoSceril palmitate; collismycin hatomarubigin C, hatomarubigin D, ibogaine, ibopamine; A, collismycin B; combretastatin A4, complestatin; conage ibudilast, illimaquinone, ilmofoSine, illomastat, illoperidone; nin; contignasterol, contortrostatin; coSalane, costatolide; iloprost, imidapril, imidazenil; indinavir; indolidan; cotinine; coumermycin Al; cucumariosid; curacin A; curdlan 15 indometacin farnesil; indometacin; tropine ester; indoramin; sulfate; curiosin; cyclazosin; cyclic HPMPC; cyclobenza inocoterone; inogatran; inolimomab, interferon alfa, inter prine, cyclobut A, cyclobut G., cyclocapron; cycloplatam, feron alfa-2a, interferon alfa-2b; interferon alfa-N 1; inter cyclosin; cyclothialidine, cyclothiazomycin; cypemycin; feron alfa-n3; interferon beta; interferon beta-1al; interferon cyproterone; cytarabine ocfosfate; cytochalasin B, daclix beta-1b, interferon gamma-1a; interferon gamma-1b; inter imab, dactimicin; daidzein, daidzin; dalfopristin; dalteparin feron omega; interferon, consensus, interleukin-1, Sodium; danaparoid; daphnodorin A; dapiprazole, dapitant; interleukin-1 alpha; interleukin-1 beta; interleukin-10; darifenacin; darlucin A; darsidomine; ddUTP, decitabine; interleukin-11; interleukin-12, interleukin-12, interleukin deferiprone; , dehydrodidemnin B, dehydroepi 15; interleukin-2, interleukin-3; interleukin-4, interleukin-5; androsterone, delapril, deleguamine; delfaprazine, delmopi interleukin-7; interleukin-8; iobenguane; iobitridol; iodoam nol; delphinidin; deoxypyridinoline, ; depSido 25 iloride; iododoxorubicin; iofratol; iomeprol; iopentol, iopro mycin; deramciclane, dermatan Sulfate; desflurane; mide; iopyrol; iotriside; ioVerSol, ioxilan; ipazilide, IpdR; desirudin; deslorelin; desmopressin; desogestrel; desoxoa ipenoxazone; ipidacrine; ipomeanol, 4-, ipriflavone, ipsa miodarone, detajmium bit artrate; dexifosfamide; dexketo pirone, irbesartan; irinotecan; irloxacin; irSogladine, irtem profen; dexloxiglumide, dexmedetomidine, dexpemedolac, azole; isalsteine, isbogrel, isepamicin; isobengaZole, isof deXraZoxane, deXSotalol, dextrin 2-Sulphate, deXVerapamil; loxythepin; isohomohalicondrin B; isopropyl unoprostone; deZinamide, dezocine; diaziquone; diclofenac digolil; isradipine; itameline; itasetron; itopride, itraconazole; diclofenac potassium, dicranin; didemnin B, didox; ketoprofen, R-, ketoprofen, S-, ketorolac, lacidipine; lacti dienogest; diethylhomospermine; diethylnorspermine; dihy tol; lactivicin; laennec, lafutidine, lamellarin-N triacetate; drexidine, dihydro-5-azacytidine, dimethyl prostaglandin lamifiban, lamivudine, lamotrigine; lanoconazole; lan A1; dimethylhomospermine; dimiracetam; dioxamycin; 35 perisone; lanreotide; lanSoprazole; latanoprost; lateritin; lau diphencyprone, diphenyl Spiromustine, diprafenone; dipro rocapram; lazabemide, lemefloxacin; lemildipine, lemino pylnorspermine, dirithromycin; discodermolide; disulfiram; prazole; lenercept; lenograstim; lentinan Sulfate; leptin; ditekiren; docarpamine, docosanol, 1-, dolfetilide; dolas leptolstatin; lercanidipine; lerisetron; lesopitron; letraZuril; etron; domitroban; dopexamine; dorZolamide; doSmalfale; letrozole; leucomyzin; leuprorelin; levcromakalim, levelti dotarizine, doxacurium chloride, doxazosin, doxifluridine, 40 racetam; levobetaxolol, levobunolol, levobupivacaine; levo doxofylline; draculin; draflazine; droloxifene, dronabinol; cabastine, levocarnitine; levodropropizine; levofloxacin; drosperidone; drotaverine acephyllinate; droxicam, ebi levomoprolol, levonorgestrel; levormeloxifene, levosimen ratide, elbrotidine, ebSelen, ecabapide, ecabet, ecadotril; dan; levOSulpiride; linotroban; linsidomine; lintitript; linto ecdlisteron; echicetin; echistatin; ecomustine, ecteinascidin pride; liothyronine Sodium; lirexapride; lisinopril; lobapl 722; ecteinascidin 729; ecteinascidin 743; edaravone, edel 45 atin; lobucavir, lodoxamide, lombricine, lomefloxacin; fosine, edobacomab, edrecolomab, efegatran; eflomithine; lomerizine, lometrexol; lonazolac, lonidamine; loracarbef; efonidipine, egualen, elcatonin; eletriptan; elgodipine; elip loratadine, lorglumide, lomoxicam, losartan; losigamone; rodil, eltenac, emakalim, emedastine, emiglitate; emitefur, loSOXantrone, ; loviride; loxoribine, lubeluzole; emoctakin; enadoline hydrochloride; enalapril; enaZadrem, lurtotecan; luteinizing hormone; lutetium; luZindole, lydica englitaZone, enlimomab, enoxacin; enoxaparin Sodium; 50 mycin; lySofylline; lysostaphin, magainin 2 amide, mag enoximone, entacapone, enterostatin, epoprostenol; nolol, mallotochromene; mallotojaponin; malotilate; man epoxymeXrenone, epristeride, eprosartan; eptastigmine; gafodipir; manidipine, maniwamycin A, mannostatin A, erdosteine; erSentilide, erSofermin; erythritol; eSuprone; manumycin E, manumycin F; mapinastine, marimastat; etanidazole; etanterol, ethacizin; ethinylestradiol, etizolam; Martek 8708; Martek 92211; masoprocol; maspin; masse etodolac, etoposide phosphate, etrabamine; everninomicin; 55 tolide, meterelin; methoxatone, methylhistamine, R-alpha; examorelin; exemestane, fadrozole, faerieflungin; famciclo methylinosine monophosphate, methylprednisolone ace Vir; fampridine, fantofarone, faropenem; fasidotril; fasudil; ponate, methylprednisolone Suleptanate; metipamide; meto fazarabine; fedotoZine, felbamate, fenofibrate; fenoldopam; clopramide, metoprolol, S-, metrifonate; mibefradil; mich fenretinide, fenspiride, fenticonazole; fepradinol, ferpifoS ellamine B, microcolin A, midodrine; ; ate Sodium; ferristene; ferriXan; ferumoxSil; feXofenadine, 60 miglitol; millacemide, milameline, mildronate; milnacipran; flavopiridol, flecainide, flerobuterol, fleroxacin; flesinoxan; milrinone; miltefosine; minaprine, miokamycin, miprago flezelastine; flobufen, flomoxef; florfenicol; florifenine; flo Side, mirfentanil; mirimoStim, mirtazapine, misoprostol; Satidil; fluiasterone; fluconazole; fludarabine; flumazenil; flu mitoguaZone, mitolactol, mitonafide, mitoxantrone, miva mecinol; flumequine; flunarizine; fluocalcitriol, fluo curium chloride; mivaZerol; mixanpril; mizolastine, mizor rodaunorunicin hydrochloride; fluoxetine, R-; fluoxetine, S-; 65 ibine; moclobemide; modafinil; moexipril; mofaroteine; fluparoXan; flupirtine; flurbiprofen axetil, flurithromycin; mofeZolac, molgramoStim; mometasone; montirelin, mopi ; flutrimazole; fluvastatin; fluvoxam damol, moracizine; mosapramine; mosapride; motilide; US 6,576,636 B2 45 46 moxiraprine; moxonidine; nadifloxacin; nadroparin cal lating hormone, tiagabine; tianeptine; tiapafant; tibolone; cium; nafadotride, nafamoStat; nafarelin, naftopidil, nagli ticlopidine, tienoXolol, tilisolol, tilnoprofen arbamel, Van, nagreStip; nailmefene, naphterpin, napsagatran; tiludronic acid; tinzaparin Sodium, tiotropium bromide; naratriptan; nartograstim; nasaruplase; nateplase, niperoti tipredane; tiqueside; tirandaly digin; tirapazamine; tirilazad; dine, niravoline, nisamycin; nisin; nisoldipine, nitaZOX tirofiban; tiropramide; topSentin; torasemide, toremifene, anide, nitecapone, nitrendipine, nitrendipine, S-, nitrofuran toSufloxacin; trafermin; trandolapril; traXanox, tretinoin, tre to in monohydrate, nitrullyn; nizatidine, ofloxacin; tinoin tocoferil, triacetyluridine, tricaprilin; trichohyalin; okicenone, olanzapine, olopatadine, olprinone; Olsalazine; trichoSanthin, alpha; triciribine, trientine: triflavin; trimege omeprazole; Onapristone, ondansetron; ondansetron, R-; Stone; triptorelin; troglitaZone; trombodipine; tropisetron; ontaZolast, oracin; otenZepad, oxaliplatin, oxamisole, OXan trospectomycin; trovafloxacin; troVirdine, tucaresol; drolone, Oxaprozin, oxaunomycin; oxcarbazepine; oxicona tulobuterol; tylogenin, urapidil; uridine triphosphate; Valaci Zole, OXiracetam; OXOdipine; OZagrel, palauamine, palinavir, clovir, Valproate magnesium; Valproate Semisodium; Valsar palmitoylrhizoxin; pamaqueside, pamicogrel, pamidronic tan; vamicamide, Vanadeine, Vaninolol, Vapreotide; variolin acid; panamesine; panaxytriol, panipenem; panipenum; pan B; velareSol, Venlafaxine, Veramine; Verapamil, (S); Verdins, norin; panomifene, pantethine, pantoprazole, parabactin; 15 Veroxan, Verteporfin; Vesnarinone, Vexibinol; vigabatrin; pamaparin Sodium, paroxetine, parthenolide, paZelliptine; Vinbumine citrate; Vinbumine resinate: Vinconate; Vinorel paZufloxacin, pefloxacin; pegaspargase; peldesine, pemed bine, Vinpocetine, Vinpocetine citrate; Vintoperol, VinXal olac, pemirolast, penciclovir, pentafuside; pentamidine, tine; Voriconazole, Vorozole, VOXergolide; Xemilofiban; pentamorphone; pentigetide; pentosan, pentostatin; pentro Ximoprofen; yangamblin, Zabicipril; Zacopride; Zacopride, Zole; perflubron; perfosfamide; pergolide; perindoprilat; R-; Zafirlukast; Zalcitabine; Zaleplon; ZaloSpirone; Zaltopro peroSpirone; phenaridine, phenazinomycin; phenserine; fen, Zanamivir, Zankiren, Zanoterone; Zatebradine, phensuccinal; phentolamine mesilate; phenylacetate; pheny Zatosetron; Zenarestat; Zeniplatin, Zifrosilone; Zilascorb, lalanylketoconazole, picenadol, picibanil, picroliv, picume Zileuton; Zinostatin stimalamer, Ziprasidone; Zoledronic terol, pidotimod; pilocarpine hydrochloride, pilsicainide; acid; Zolmitriptan; Zolpidem; Zonisamide, Zopiclone; pimagedine, pimilprost, pimobendan; pinacidil; pinocebrin; 25 Zopiclone, S-, Zopolrestat; Zotepine. pioglitaZone; pipecuronium bromide, pirarubicin; piret The invention also embraces novel compositions of mat anide, pirfenidone, piritrexim; pirlindole, pirmagrel, pirme ter that are covalent conjugates of unbranched, naturally nol; pirodavir, pirodomast, piroXicam cinnamate; propager occurring fatty acids and pharmaceutical agents that are manium; propentofylline, propionylcarnitine, L-, propiram; noncentral nervous System active agents. Noncentral ner propiram + paracetamol, propiverine, propyl bis-acridone; Vous System active agents have no function or use within the prostaglandin J2, prostratin, protegrin, protoSufloxacin; pru central nervous System. Their only use is outside of the lifloxacin; pyrazoloacridine, quazepam; quetiapine, qui central nervous System. Such agents include all drugs within flapon; quinagolide, quinapril, quinfamide, quinupristin, certain of the foregoing categories and only Some drugs raloxifene, raltitrexed; ramatroban; ramipril; ramosetron; within other of the foregoing catagories. For example, the ranelic acid, ranitidine bismuth citrate, ranolazine; 35 entire catagory of blood glucose regulators have no use or recainam; regaVirumab, relaxin, repirinast, resinferatoxin; function within the central nervous System. In contrast, reticulon; reviparin Sodium; revizinone; ricasetron; ridogrel; certain anti-cancer agents are useful in the central nervous rifabutin, rifapentine, rifaximin, rilopiroX, riluzole, riman System whereas others are not. For example, central nervous tadine, rimeXolone, rimoprogin, riodipine; ripisartan; System cancers are not hormone dependent, and, therefore, risedronic acid; rispenzepine, risperidone; ritanserin; riti 40 an anti-cancer agent Such as Tamoxifen which treats certain penem; ritipenem acoxil, ritolukast, ritonavir, rizatriptan hormone dependent cancers is not useful in the central benzoate, rohitukine, rokitamycin; ropinirole; ropivacaine; nervous system. Those skilled in the art will be able to roquinimex, roXatidine, roXindole; roXithromycin; rubigi identify readily those catagories and/or members of a cat none B1, ruboxyl, rufloxacin, rupatidine, ruzadolane, Saf agory which are noncentral nervous System active agents. ingol, Safironil; Saintopin; Salbutamol, R-; Salmeterol; 45 Among the foregoing compounds, the following catagories Salmeterol, R-Salnacedin, Sameridine, Sampatrilat, San and/or members of the following catagories are noncentral fetrinem; Saprisartan; Sapropterin; Saquinavir, SarCNU; Sar nervous System active agents: adrenocortical Steroid; cophytol A SargramoStim; Sarpogrelate, Sarup lase; adrenocortical SuppreSSant; aldosterone antagonist, amino Saterinone; Satigrel, Satumomab pendetide, Selegiline, Sele acid; anabolic; androgen; antagonist; anthelmintic, anti-acne nium thiosemicarbazone, Sematilide, Semduramicin; Semo 50 agent, anti-adrenergic, anti-allergic, anti-amebic, anti tiadil; Semustine, Sermorelin; Sertaconazole, Sertindole, Ser androgen; anti-anemic, anti-anginal; anti-arthritic, anti traline, Setiptiline, Sevirumab, Sevoflurane; SeZolamide, asthmatic, anti-atherOSclerotic, antibacterial; anticholelithic, Silipide, Silteplase, Simendan; Simvastatin; Sinitrodil, Sinna anticholelithogenic, anticholinergic, anticoagulant; anticoc bidol; Silpatrigine, Sirolimus, sizofiran; Somatomedin B; cidal; antidiabetic, antidiarrheal; antidiuretic, antidote, anti Somatomedin C; Somatrem, Somatropin; Sonermin; Sotalol; 55 estrogen; antifibrinolytic, antifungal; antiglaucomaagent; Staurosporine; Stavudine, Stepronin; Stipiamide, Stiripentol; antihemophilic, antihemorrhagic, antihistamine; antihyper Stobadine, Succibun; Sucralfate, SulfaSalazine, Sulfinosine; lipidemia; antihyperlipoproteinemic, antihypertensive; anti Sulfoxamine, Sulopenem; Sultamicillin; Sultopride, Sulukast, hypotensive; anti-infective; anti-infective, topical; anti Sumatriptan; Symakalim, tandoSpirone, tapgen; taprostene; inflammatory; antikeratinizing agent; antimalarial; tasOSartan; taZanolast, tazaroteine, teicoplanin, telenzepine; 60 antimicrobial; antimitotic; antimycotic, antineoplastic, tellurapyrylium, telmesteine; telmisartan; temocapril; antineutropenic, antiparasitic, antiperistaltic, antipneu temoporfin, temozolomide; tenidap; teniposide; tenosal; mocystic, antiproliferative, antiprostatic hypertrophy; anti tenoxicam, tepirindole; tepoxalin, teraZosin; terbinafme, ter protozoal; antipruritic, antipsoriatic, antirheumatic; antis fenadine, terflavoxate, terguride; terlakiren, terlipressin; chistoSomal; antiseborrheic, antisecretory; antispasmodic, terodiline; tertatolol, testosterone buciclate, tetrachlorode 65 antithrombotic, antituSSive, anti-ulcerative, anti-urolithic, caoxide, tetraZomine; thaliblastine; thalidomide; thiocora antiviral; appetite Suppressant, benign prostatic hyperplasia line; thiofedrine; thiomarinol; thioperamide; thyroid Stimu therapy agent, bone resorption inhibitor, bronchodilator; US 6,576,636 B2 47 48 carbonic anhydrase inhibitor; cardiac depressant, cardiopro When administered, the formulations of the invention are tectant, cardiotonic, cardiovascular agent, choleretic, cho applied in pharmaceutically acceptable amounts and in linergic, cholinergic agonist, cholinesterase deactivator; pharmaceutically acceptable compositions. Such prepara coccidiostat; diagnostic aid; diuretic, ectoparasiticide; tions may routinely contain Salts, buffering agents, enzyme inhibitor; estrogen; fibrinolytic, free oxygen radical preservatives, compatible carriers, and optionally other Scavenger, glucocorticoid; gonad-stimulating principle; hair therapeutic ingredients. When used in medicine the Salts growth Stimulant, hemostatic, hormone, hypocholester should be pharmaceutically acceptable, but non olemic, hypoglycernic, hypolipidemic, hypotensive; immu pharmaceutically acceptable Salts may conveniently be used nizing agent; immunomodulator; immunoregulator; immu nostimulant; immunosuppressant; impotence therapy to prepare pharmaceutically acceptable Salts thereof and are adjunct; inhibitor; keratolytic; LHRH agonist; liver disorder not excluded from the Scope of the invention. Such phar treatment, luteolysin; mucolytic, mydriatic, nasal deconges macologically and pharmaceutically acceptable Salts tant; neuromuscular blocking agent; non-hormonal Sterol include, but are not limited to, those prepared from the derivative; oxytocic, plasminogen activator, platelet activat following acids: hydrochloric, hydrobromic, Sulphuric, ing factor antagonist, platelet aggregation inhibitor, poten nitric, phosphoric, maleic, acetic, Salicylic, p-toluene tiator, progestin, prostaglandin, prostate growth inhibitor; 15 Sulfonic, tartaric, citric, methane Sulfonic, formic, malonic, prothyrotropin, pulmonary Surface; radioactive agent; regu Succinic, naphthalene-2-Sulfonic, and benzene Sulfonic. lator, relaxant, repartitioning agent; Scabicide, Sclerosing Also, pharmaceutically acceptable Salts can be prepared as agent, Selective adenosine A1 antagonist; Steroid; Suppres alkaline metal or alkaline earth Salts, Such as Sodium, Sant; Symptomatic multiple Sclerosis, Synergist; thyroid hor potassium or calcium Salts. mone, thyroid inhibitor; thyromimetic; amyotrophic lateral Suitable buffering agents include: acetic acid and a Salt Sclerosis agents, Paget’s disease agents, unstable angina (1-2% W/V); citric acid and a salt (1–3% W/V); boric acid agents, uricoSuric; vasoconstrictor; vasodilator, Vulnerary; and a salt (0.5-2.5% W/V); and phosphoric acid and a salt wound healing agent; Xanthine oxidase inhibitor. (0.8–2% W/V). AS used herein, a taxane is a molecule that possesses the Suitable preservatives include benzalkonium chloride following tricyclic carbon-atom connectivity network, 25 which may incorporate carbon-carbon multiple bonds, and (0.003–0.03% W/V); chlorobutanol (0.3–0.9% W/V); para which through the involvement of carbon-atom-noncarbon bens (0.01-0.25% W/V) and thimerosal (0.004–0.02% atom bonds may include Substituents, functional groups, and W/V). additional rings. The active compounds of the present invention may be a pharmaceutical composition having a therapeutically effec tive amount of a conjugate of the invention optionally included in a pharmaceutically-acceptable carrier. The term “pharmaceutically-acceptable carrier as used herein means one or more compatible Solid or liquid filler, dilutants or 35 encapsulating Substances which are Suitable for administra tion to a human or other animal. The term “carrier' denotes an organic or inorganic ingredient, natural or Synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compo A taxoid is a molecule Structurally related to a taxane in Sitions are capable of being commingled with the molecules which the above taxane carbon-atom connectivity network is 40 of the present invention, and with each other, in a manner altered, for example, by cleavage of one or more of the such that there is no interaction which would substantially carbocyclic rings, by deletion or addition of carbon impair the desired pharmaceutical efficacy. Substituents, by connection of carbon atoms normally not bonded to each other, by disconnection of carbon atoms Compositions Suitable for parenteral administration con normally bonded to each other, or by Some other reorgani 45 Veniently comprise a sterile preparation of the conjugates of Zation of or adjustment to the taxane carbon-atom connec the invention. This preparation may be formulated according tivity network, but in which one or more Structural features to known methods. Formulations for taxanes can be found in characteristic of the taxane carbon-atom connectivity net Chapter 9 of Taxol. Science and Applications, CRC Press, work are conserved. Inc., 2000 Corporate Boulevard, N.W., Boca Raton, Fla. The compounds useful in the invention may be delivered 50 33431. In general, Taxol has been formulated as a 6 mg/ml in the form of anti-cancer cocktails. An anti-cancer cocktail cremophor EL (polyoxyethylated castor oil)/ethanol is a mixture of any one of the compounds useful with this mixture, which is diluted to final volume with normal Saline invention with another anti-cancer agent Such as an anti or 5% dextrose. A 15 mg/ml solution of taxotere has been cancer drug, a cytokine, and/or Supplementary potentiating formulated in polysorbate 80 (polyoxyethylene agent(s). The use of cocktails in the treatment of cancer is 55 sorbitanmonooleate)/ethanol mixture, diluted with 5% dex routine. In this embodiment, a common administration trOSe. vehicle (e.g., pill, tablet, implant, injectable Solution, etc.) The Sterile preparation thus may be a sterile Solution or would contain both the conjugate useful in this invention Suspension in a non-toxic parenterally-acceptable diluent or and the anti-cancer drug and/or Supplementary potentiating Solvent. In addition, Sterile, fixed oils are conventionally agent. 60 employed as a Solvent or Suspending medium. For this The compounds of the invention, when used in cocktails, purpose any bland fixed oil may be employed including are administered in therapeutically effective amounts. A Synthetic mono or di-glycerides. In addition, fatty acids Such therapeutically effective amount will be determined by the as oleic acid find use in the preparation of injectables. parameters discussed below; but, in any event, is that Carrier formulations Suitable for oral, Subcutaneous, amount which establishes a level of the drug(s) in the area 65 intravenous, intramuscular, etc. can be found in Remington's of the tumor which is effective in inhibiting the tumor Pharmaceutical Sciences, Mack Publishing Company, growth. Easton, Pa. US 6,576,636 B2 49 SO A Subject as used herein means humans, primates, horses, polyglycolic acid, polyanhydrides and polycaprolactone; cows, pigs, sheep, goats, dogs, cats and rodents. nonpolymer Systems that are lipids including Sterols Such as The conjugates of the invention are administered in cholesterol, cholesterol esters and fatty acids or neutral fats effective amounts. An effective amount means that amount Such as mono-, di and triglycerides, hydrogel release Sys necessary to delay the onset of, inhibit the progression of, tems, Silastic Systems, peptide based Systems, wax coatings, halt altogether the onset or progression of or diagnose the compressed tablets using conventional binders and particular condition being treated. In general, an effective excipients, partially fused implants and the like. In addition, amount for treating cancer will be that amount necessary to a pump-based hardware delivery System can be used, Some inhibit mammalian cancer cell proliferation in-situ. When of which are adapted for implantation. administered to a Subject, effective amounts will depend, of A long-term Sustained release implant also may be used. course, on the particular condition being treated; the Severity "Long-term' release, as used herein, means that the implant of the condition; individual patient parameters including is constructed and arranged to deliver therapeutic levels of age, physical condition, Size and weight; concurrent treat the active ingredient for at least 30 days, and preferably 60 ment, frequency of treatment; and the mode of administra days. Long-term Sustained release implants are well known tion. These factors are well known to those of ordinary skill 15 to those of ordinary skill in the art and include some of the in the art and can be addressed with no more than routine release Systems described above. Such implants can be experimentation. It is preferred generally that a maximum particularly useful in treating Solid tumors by placing the dose be used, that is, the highest Safe dose according to implant near or directly within the tumor, thereby affecting Sound medical judgment. localized, high-doses of the compounds of the invention. Dosage may be adjusted appropriately to achieve desired The conjugates of the invention also are useful, in general, drug levels, locally or Systemically. Generally, daily oral for treating mammalian cell proliferative disorders other doses of active compounds will be from about 0.01 mg/kg than cancer, including psoriasis, actinic keratosis, etc. They per day to 1000 mg/kg per day. It is expected that IV doses further are useful in treating diabetes and its complications, in the range of about 1 to 1000 mg/m per day will be exceSS acid Secretion, cardiovascular conditions involving effective. In the event that the response in a Subject is 25 cholesterol (e.g., hyperlipidemia and hypercholesterolemia), insufficient at Such doses, even higher doses (or effective diarrhea, ovarian diseases (e.g. endometriosis, ovarian cysts, higher doses by a different, more localized delivery route) etc.) and as contraceptive agents. may be employed to the extent that patient tolerance permits. Those skilled in the art will be able to recognize with no Continuous IV dosing over, for example 24 hours or mul more than routine experimentation numerous equivalents to tiple doses per day are contemplated to achieve appropriate the Specific products and processes described above. Such Systemic levels of compounds. equivalents are intended to be included within the Scope of the appended claims. A variety of administration routes are available. The We claim as follows: particular mode Selected will depend of course, upon the 1. A method for targeting a pharmaceutical agent to liver particular drug Selected, the Severity of the disease State 35 tissue to treat a liver disorder, comprising: administering to being treated and the dosage required for therapeutic effi a Subject in need of Such treatment a covalent conjugate of cacy. The methods of this invention, generally speaking, a C8-26, unbranched, naturally occurring fatty acid and an may be practiced using any mode of administration that is antiviral agent in an amount effective for treating Said medically acceptable, meaning any mode that produces disorder provided that the drug is not an adenosine receptor effective levels of the active compounds without causing 40 agonist or antagonist. clinically unacceptable adverse effects. Such modes of 2. The method of claim 1, wherein the antiviral agent is administration include oral, rectal, Sublingual, topical, nasal, Selected from the group consisting of Acemannan, transdermal, intradermal or parenteral routes. The term Acyclovir, Acyclovir Sodium, Adefovir, Alovudine, Alvir "parenteral' includes Subcutaneous, in travenous, cept Sudotox, Amantadine Hydrochloride, Aranotin, intramuscular, or infusion. Intravenous routes are preferred. 45 Arildone, Atevirdine Mesylate, Avridine, Cidofovir, The compositions may conveniently be presented in unit Cipamfylline, Cytarabine Hydrochloride, Delavirdine dosage form and may be prepared by any of the methods Mesylate, Desciclovir, Didanosine, Disoxaril, Edoxudine, well known in the art of pharmacy. All methods include the Enviradene, EnviroXime, Famciclovir, Famotine Step of bringing the conjugates of the invention into asso Hydrochloride, Fiacitabine, Fialuridine, Fosarilate, Fosca ciation with a carrier which constitutes one or more acces 50 met Sodium, Fosfonet Sodium, Ganciclovir, Ganciclovir Sory ingredients. In general, the compositions are prepared Sodium, Idoxuridine, Kethoxal, Lamivudine, Lobucavir, by uniformly and intimately bringing the compounds into Memotine Hydrochloride, Me thisazone, Nevirapine, asSociation with a liquid carrier, a finely divided Solid Penciclovir, Pirodavir, Ribavirin, Rimantadine carrier, or both, and then, if necessary, Shaping the product. Hydrochloride, Saquinavir Mesylate, Somantadine Compositions Suitable for oral administration may be 55 Hydrochloride, Sorivudine, Statolon, Stavudine, Tilorone presented as discrete units Such as capsules, cachets, tablets, Hydrochloride, Trifluridine, Valacyclovir Hydrochloride, or lozenges, each containing a predetermined amount of the Vidarabine, Vidarabine Phosphate, Vidarabine Sodium active compound. Other compositions include Suspensions Phosphate, Viroxime, Zalcitabine, Zidovudine, and Zin in aqueous liquors or non-aqueous liquids Such as a Syrup, ViroXime. an elixir, or an emulsion. 60 3. The method of claim 1, wherein the fatty acid is Other delivery Systems can include time-release, delayed Selected from the group consisting of C8:0 (caprylic acid), release or Sustained release delivery Systems. Such Systems C10:0 (capric acid), C12:0 (lauric acid), C14:0 (myristic can avoid repeated administrations of the active compounds acid), C16:0 (palmitic acid), C16:1 (palmitoleic acid), of the invention, increasing convenience to the Subject and C16:2, C18:0 (stearic acid), C18:1 (oleic acid), C18:1-7 the physician. Many types of release delivery Systems are 65 (vaccenic), C18:2-6 (linoleic acid), C18:3-3 (O-linolenic available and known to those of ordinary skill in the art. acid), C18:3-5 (eleostearic), C18:3–6 (8-linolenic acid), They include polymer based Systems. Such as polylactic and C18:4-3, C20:1 (gondoic acid), C20:2-6, C20:3–6 (dihomo US 6,576,636 B2 S1 52 y-linolenic acid), C20:4-3, C20:4-6 (arachidonic acid), C20:1 (gondoic acid), C20:2-6, C20:3–6 (dihomo-y- C20:5-3 (eicosapentaenoic acid), C22:1 (docoSenoic acid), linolenic acid), C20:4-3, C20:4-6 (arachidonic acid), C22:4-6 (doco sate tra enoic acid), C22:5-6 C20:5-3 (eicosapentaenoic acid), C22:1 (docoSenoic acid), (docosapentaenoic acid), C22:5-3 (docosapentaenoic), C22:4- 6 (do cosate tra e no ic acid), C22:5-6 C22:6-3 (docosahexaenoic acid) and C24:1–9 (nervonic). (docosapentaenoic acid), C22:5-3 (docosapentaenoic), and 4. The method of claim 1, wherein the fatty acid is Selected from the group consisting of C14:0 (myristic acid), C22:6-3 (docosahexaenoic acid). C16:0 (palmitic acid), C16:1 (palmitoleic acid), C16:2, 5. The method of claim 1, wherein the antiviral agent is C18:0 (stearic acid), C18:1 (oleic acid), C18:1-7 (vaccenic), adefovir. C18:2-6 (linoleic acid), C18:3-3 (O-linolenic acid), C18:3-5 (eleostearic), C18:3–6 (8-linolenic acid), C18:4-3,