US 2004O106589A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0106589 A1 Webb et al. (43) Pub. Date: Jun. 3, 2004

(54) FATTY ACID-PHARMACEUTICAL AGENT (22) Filed: Jun. 5, 2003 CONJUGATES Related U.S. Application Data (75) Inventors: Nigel L. Webb, Bryn Mawr, PA (US); Matthews O. Bradley, Laytonsville, (63) Continuation of application No. 09/730,450, filed on MD (US); Charles S. Swindell, Dec. 5, 2000, now Pat. No. 6,576,636, which is a Merion, PA (US); Victor E. Shashoua, continuation of application No. 08/651,428, filed on Brookline, MA (US) May 22, 1996, now abandoned. Correspondence Address: Publication Classification Edward R. Gates Wolf, Greenfield & Sacks, P.C. (51) Int. Cl...... A61K 31156; A61K 31/22 600 Atlantic Avenue (52) U.S. Cl...... 514/182; 514/549 Boston, MA 02210 (US) (57) ABSTRACT (73) Assignee: Protarga Pharmaceuticals, Inc., King The invention provides conjugates of fatty acids and phar of Prussia, PA maceutical agents useful in treating noncentral nervous System conditions. Methods for Selectively targeting phar (21) Appl. No.: 10/455,250 maceutical agents to desired tissues are provided. Patent Application Publication Jun. 3, 2004 Sheet 1 of 14 US 2004/0106589 A1

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MELANOMA 1 OO relaas - i.

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NON-SMALL CEL UNG CANCER 1 OO Sea

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LEUKEMA

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COLON CANCER

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MEANOMA

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RENAL CANCER

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FATTY ACID-PHARMACEUTICAL AGENT 0006 Taxol has the following formula: CONJUGATES

AcO O OH BACKGROUND OF THE INVENTION R 0001 Improving drug selectivity for target tissue is an "YNH O established goal in the medical arts. In general, it is desirable to deliver a drug Selectively to its target, So that dosage and, -Nulls III IIH consequently, Side effects can be reduced. This is particu Pir Y. So i Nlo larly the case for toxic agents Such as anti-cancer agents OH HO s 5Ac because achieving therapeutic doses effective for treating the PhCO2 cancer is often limited by the toxic side effects of the anti-cancer agent on normal, healthy tissue. The problems 0007 Taxanes have the basic three ring structure (A, B relating to lack of drug Selectivity can be exemplified by and C), Substituted or unsubstituted. TaxolcE). 0008 Taxol's carbons are numbered conventionally as follows: 0002 Taxole (paclitaxel) was first isolated in 1971 from the bark of Taxus brevifolia and was approved in 1992 by the

US Food and Drug Administration for treatment of meta Static Ovarian cancer and later for breast cancer. Its mecha nism of action is believed to involve promoting formation and hyperStabilization of microtubules, thereby preventing the disassembly of microtubules necessary for completion of cell division. It also has been reported that Taxol induces expression of cytokines, affects the activity of kinases and blockS processes essential for metastasis, in as yet unchar acterized mechanisms of action. 0.003 Taxol has attracted unusually strong scientific 0009 Based upon the taxanes tested to date, as many attention, not only because of its unique antiproliferative questions have been raised as have been answered, and general rules have not been fashioned easily in predicting mechanism of action, but also because it is active against selectivity, activity and solubility. Firstly, no rules have nearly all cancers against which it has been tested and emerged regarding Selectivity. Those taxanes that are because it has been discovered to be an analog of numerous Strongly active appear to have activity as broad as Taxol's closely related compounds occurring naturally. These com activity, and no headway appears to have been made in terms pounds, taxanes, are now recognized as a new class of of developing a more Selective Taxol analog. anticancer compounds. 0010 Some information about activity has emerged. 0004 Taxol's strength against cancers of diverse tissue Numerous Substitutions have been made at C7, C9, C10, origin also represents a significant drawback. An ideal C19, R1 and combinations thereof while retaining signifi anticancer agent has tissue Specificity, thereby reducing cant, but usually reduced, activity. Substitutions at C2, C4 and 2'OH, however, are generally not tolerated. These con Side-effects on normal (dividing) cells. Taxol analogs with clusions are only generalities, for example, because Some tissue specificity therefore are desired. Another drawback of substitutions at C9-C10 (cyclic derivatives) are not tolerated Taxol is its extreme insolubility. Taxol can be administered and Some Substitutions at C2 (meta Substitutions on the effectively in a Solvent including cremophor, which combi phenyl) are tolerated. Likewise, the C13 side chain and, in nation can provoke Severe hyperSensitive immune particular, the 2'OH are required., although the minimum responses. As a result of these drawbacks, and also as a Structural requirements of the Side chain have not been result of the potential for modifying Taxol at numerous Sites determined for therapeutic efficacy. as demonstrated by other naturally-occurring taxanes with 0011 Attempts to improve Taxol's solubility have not anticancer activity, a Search for more Selective taxanes was resulted in Successful clinical products. One approach has launched. been to manufacture prodrugs of Taxol, which prodrugs undergo in Vivo transformation into Taxol and Some other 0005 To date, more than 200 taxanes have been synthe product. Attempts were made to esterify the C7 hydroxy and sized (or isolated) and tested in vitro or in Vivo for anticancer 2' hydroxy groups, with the hope that the bond would be activity. The results, however, have been So disappointing Stable in Solution (to permit preferred administration that the National Cancer Institute (NCI) generally no longer modes-i.V. over at least 24 hours) but would cleave readily is interested in testing Taxol analogs. In general with Taxol in Vivo. The groups tested were all hydrophilic and included analogs, the Solubility problems remain, and/or potency is amines, short carboxylic acids (using e.g. Succinic anhydride Sharply reduced, and/or Selectivity is not improved, and/or and glutaric anhydride), Sulfonic acids, amino acids and the ratio of the median toxic dose to the median effective phosphates. Generally, activity was reduced although Some dose (“therapeutic index') is unacceptably reduced. Success was obtained with certain derivatives. Again, no US 2004/0106589 A1 Jun. 3, 2004 particular pattern emerged permitting one to predict reliably central nervous System. The purpose of conjugating pipo which groups could be substituted on Taxol to yield a tiazine to the fatty acids was to create an oily Solution of the therapeutically useful product, although it was Suggested drug as a liquid implant for slow release of the drug when that the 2'OH derivatives may cleave more easily than the C7 injected intramuscularly. The release of the drug appeared to OH derivatives. depend on the particular fatty acid Selected, and the drug was 0012 Several other factors add to the problem of pre tested for its activity in the central nervous System. dicting which Taxol analogs will be effective. Multiple 0018 Lipidic molecules, including the fatty acids, also mechanisms of action have been proposed in the literature, have been conjugated with drugs to render the conjugates and a change in one position may have no effect on activity more lipophilic than the drug. In general, increased lipophi on one Such mechanism but may eliminate activity on licity has been Suggested as a mechanism for enhancing another mechanism. In addition, changes that favorably intestinal uptake of drugs into the lymphatic System, thereby influence activity may unfavorably influence bioavailability. enhancing the entry of the conjugate into the brain and also For example, Taxol affects microtubule formation inside a thereby avoiding first-pass metabolism of the conjugate in cell, but a change in Structure that increases intracellular the liver. The type of lipidic molecules employed have activity may adversely affect the ability of Taxol to gain included phospholipids, non-naturally occurring branched entry into a cell. Taxol also is known to bind to proteins, and and unbranched fatty acids, and naturally occurring the effect on activity that results from a change in Taxol's branched and unbranched fatty acids ranging from as few as binding to protein (in terms of conformation, cellular 4 carbon atoms to more than 30 carbon atoms. In one absorption and Solubility) is unknown. instance, enhanced receptor binding activity was observed 0013. It has been reported that Taxol does not get into the (for an adenosine receptor agonist), and it was postulated brain, apparently excluded by the blood brain barrier. It is that the pendant lipid molecule interacted with the phospho not known why this is So, as Taxol is lipophilic, gets into lipid membrane to act as a distill anchor for the receptor cells and might be expected to cross the blood brain barrier. ligand in the membrane micro environment of the receptor. This increase in potency, however, was not observed when 0.014) Among the most promising of the two hundred the same lipid derivatives of adenosine receptor antagonists analogs tested is Taxotere (docetaxel), because of its slightly were used, and generalizations thus were not made possible increased activity and solubility. Oddly, however, Taxotere by those studies. differs from Taxol at sites which typically do not have a Strong influence on activity, and one would not predict the SUMMARY OF THE INVENTION improvements in Taxotere from these differences, even in hindsight. 0019. The present invention involves the unexpected finding that conjugates of pharmaceutical agents and a 0.015 Taxotere has the following formula: highly lipophilic group, a C8-C26, naturally ocurring, unbranched carbon chain, have a different Selectivity rela

tive to the unconjugated pharmaceutical agents. 0020. In one embodiment, the conjugates render the activity of these conjugates Selective, in general, for colon tissue, breast tissue and central nervous System tissue ("tar geted tissues’). The conjugates, also unexpectedly, restrict the activity of these conjugates to cell types within these tissue categories relative to that of the unconjugated phar maceutical agents. The conjugates, further unexpectedly, can reduce Sharply the activity of these conjugates relative to that of the unconjugated pharmaceutical agents in most cell lines of tissue types other than colon, breast, and central nervous System, thereby reducing potential Side effects of 0016 Fatty acids previously have been conjugated with the conjugates versus those of the unconjugated pharmaceu drugs to help the drugs as conjugates croSS the blood brain tical agents. The therapeutic index of the conjugates is barrier. DHA (docosahexaenoic acid) is a 22 carbon natu improved, verSuS that of the unconjugated pharmaceutical rally-occurring, unbranched fatty acid that previously has agents. been shown to be unusually effective, when conjugated to a drug, in crossing the bloodbrain barrier. DHA is attached via 0021 According to one aspect of the invention, a method the acid group to hydrophilic drugs and renders these drugs is provided for targeting a therapeutic agent to a noncentral nervous System tissue to treat a noncentral nervous System more hydrophobic (lipophilic). DHA is an important con condition. A conjugate of a C8-C22, unbranched, naturally Stituent of the brain and recently has been approved as an occurring fatty acid and a pharmaceutical agent is adminis additive to infant formula. It is present in the milk of tered to a Subject in need of Such treatment. In certain lactating women. The mechanism of action by which DHA embodiments, the tissue is breast tissue, gastrointestinal helps drugs conjugated to it croSS the blood brain barrier is tissue and ovarian tissue and the condition calls for treat unknown. ment of breast tissue, gastrointestinal tissue or ovarian 0.017. Another example of the conjugation of fatty acids tissue, respectively. In other embodiments, the tissue can be to a drug is the attachment of pipotiazine to Stearic acid, tissue of the Blood and Blood Forming system: including palmitic acid, enanthic acid, undecylenic acid or 2,2-dim platelets, blood vessel wall, and bone marrow, Cardiovas ethyl-palmitic acid. Pipotiazine is a drug that acts within the cular System: including heart and vascular System; Digestive US 2004/0106589 A1 Jun. 3, 2004 and excretory System: including alimentary tract, biliary chodilator; carbonic anhydrase inhibitor, cardiac depressant; tract, kidney, liver, pancreas and urinary tract; Endocrine cardioprotectant; cardiotonic, cardiovascular agent, choler System: including adrenal gland, kidney, ovary, pituitary etic, cholinergic, cholinergic agonist, cholinesterase deacti gland, renal gland, Salivary gland, Sebaceous gland, testis, Vator, coccidiostat; cognition adjuvant; cognition enhancer, thymus gland and thyroid gland; Musclar System: including depressant, diagnostic aid; diuretic, dopaminergic agent; muscles that move the body. Reproductive System: includ ectoparasiticide, emetic, enzyme inhibitor; estrogen; fibrin olytic, fluorescent agent, free oxygen radical Scavenger; ing breast, ovary, penis and uterus, Respiratory System: gastrointestinal motility effector; glucocorticoid, gonad including bronchus, lung and trachea, Skeletal System: Stimulating principle; hair growth Stimulant; hemostatic; including bones and joints, Tissue, fiber, and integumentary histamine H2 receptor antagonists, hormone, hypocholes System: including adipose tissue, cartilage, connective tis terolemic, hypoglycemic, hypolipidemic, hypotensive; Sue, cuticle, dermis, epidermis, epithelium, fascia, hair fol imaging agent, immunizing agent, immunomodulator; licle, ligament, bone marrow, melanin, melanocyte, mucous immunoregulator; immunostimulant; immunosuppressant; membrane, skin, Soft tissue, Synovial capsule and tendon. impotence therapy adjunct; inhibitor, keratolytic; LHRH agonist, liver disorder treatment, luteolysin; memory adju 0022. Unbranched, naturally occurring fatty acids vant; mental performance enhancer, mood regulator, muco embraced by the invention include C8:0 (caprylic acid), lytic, mucosal protective agent, mydriatic, nasal deconges C10:0 (capric acid), C12:0 (lauric acid), C14:0 (myristic tant; neuromuscular blocking agent; neuroprotective; acid), C16:0 (palmitic acid), C16:1 (palmitoleic acid), NMDA antagonist; non-hormonal sterol derivative; oxyto C16:2, C18:0 (stearic acid), C18:1 (oleic acid), C18:1-7 cic, plasminogen activator, platelet activating factor antago (vaccenic), C18:2-6 (linoleic acid), C18:3-3 (O-linolenic nist, platelet aggregation inhibitor, post-Stroke and post acid), C18:3-5 (eleostearic), C18:3-6 (6-linolenic acid), head trauma treatment; potentiator, progestin; C18:4-3, C20:1 (gondoic acid), C20:2-6, C20:3–6 (dihomo prostaglandin; prostate growth inhibitor, prothyrotropin; y-linolenic acid), C20:4-3, C20:4-6 (arachidonic acid), psychotropic, pulmonary Surface; radioactive agent; regula C20:5-3 (eicosapentaenoic acid), C22:1 (docoSenoic acid), tor, relaxant, repartitioning agent, Scabicide, Sclerosing C22:4-6 (docosatetraenoic acid), C22:5-6 (docosapen agent, Sedative, Sedative-hypnotic, Selective adenosine A1 taenoic acid), C22:5-3 (docosapentaenoic), C22:6-3 antagonist, Serotonin antagonist, Serotonin inhibitor, Sero (docosahexacnoic acid) and C24:1-9 (nervonic). Highly tonin receptor antagonist; Steroid; Stimulant; Suppressant; preferred unbranched, naturally occurring fatty acids are Symptomatic multiple Sclerosis, Synergist; thyroid hormone; those with between 14 and 22 carbon atoms. The most thyroid inhibitor; thyromimetic, tranquilizer; amyotrophic preferred fatty acid is docosahexaenoic acid. lateral Sclerosis agent; cerebral ischemia agent, Paget's 0023. It is preferred that the conjugate be of a single fatty disease agent, unstable angina agent, uricOSuric; vasocon acid molecule and the covalent attachment be directly to the Strictor; vasodilator, Vulnerary, wound healing agent; Xan pharmaceutical agent (i.e., free of a linker molecule between thine oxidase inhibitor. the active pharmaceutical agent and the fatty acid. 0026. In one particularly preferred embodiment of the 0024. The pharmaceutical agent may be any pharmaco invention, the drug is an anti-cancer agent. Examples of logical compound or diagnostic agent, as desired. The phar anti-cancer agents are described in greater detail in the maceutical agent, however, is not an adenosine receptor Specification. Included are the taxanes, (e.g., Taxol and agonist or antagonist. The pharmaceutical agent, of course, Taxotere). Conjugates of C8-C22, unbranched, naturally has an activity outside of the central nervous System. occurring fatty acids and taxoids also are embraced by the 0.025 Examples of catagories of pharmaceutical agents invention. include: adrenergic agent, adrenocortical Steroid; adrenocor 0027 C8-C26 fatty acids previously have been conju tical Suppressant, alcohol deterrent; aldosterone antagonist; gated to drugs that are active in the central nervous System. amino acid, ammonia detoxicant; anabolic; analeptic, anal The invention thus also contemplates the use of C8-C22, gesic, androgen; anesthesia, adjunct to; anesthetic; anorec unbranched, naturally occurring fatty acids in the manufac tic, antagonist; anterior pituitary Suppressant, anthelmintic, ture of a medicament for treating a noncentral nervous anti-acne agent, anti-adrenergic, anti-allergic, anti-amebic; System condition. The invention further contemplates com anti-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, antidiabetic, antidiarrheal; antidiuretic, antidote, anti 0028. A noncentral nervous system active pharmaceutical emetic, anti-epileptic, anti-estrogen; antifibrinolytic, anti agent is one that has no function or use in the central nervous fungal; antiglaucoma agent; antihemophilic, antihemor System. Its only therapeutic use is outside of the central rhagic; antihistamine; antihyperlipidemia; nervous System. Examples of Such pharmaceutical agents antihyperlipoproteinemic, antihypertensive, antihypoten include, but are not limited to: Blood glucose regulators, Sive, anti-infective, anti-infective, topical; anti-inflamma Such as tolaZamide, tolbutamide, chlorpropamide, aceto tory; antikeratinizing agent, antimalarial, antimicrobial; hexamide, and, glipizide, HMGcoA reductase inhibitors, antimigraine; antimitotic, antimycotic, antinauSeant, antine such as Lovastatin (Mevacor), Simvastatin (Zocor), Pravas oplastic, antineutropenic, antiobessional agent; antiparasitic, tatin (Pravachol), and, Fluvstatin (Lescol); Muscosal Pro antiparkinsonian; antiperistaltic, antipneumocystic, antipro tectives, Such as Misoprostol (Cytotec); Gastrointestinal liferative, antiprostatic hypertrophy; antiprotozoal; antipru Motality affectors, such as Cisapride (Propulsid), Metoclo ritic, antipsychotic, antirheumatic, antischistoSomal; antise pramide (Reglan), and, Hyoscyamine (Levsin); Antidiarrhe borrheic, antisecretory; antispasmodic, antithrombotic, als, such as Diphenoxylate hydrochloride (Lomotil), Met antituSSive, anti-ulcerative, anti-urolithic, antiviral; appetite ronidazole (Flagyl), Methylprednisolone (Medrol), and, SuppreSSant; benign prostatic hyperplasia therapy agent; SulfaSalazine (AZulfidine); and Hormones for treating, inter blood glucose regulator, bone resorption inhibitor; bron alia, Ovarian conditions, Such as Progesterone, Norgestrel, US 2004/0106589 A1 Jun. 3, 2004

Norethynodrel, Norethindrone, Levonorgestrel, Ethyndiol, 0044 FIG. 14 is a graph plotting concentration of con Mestranol, Estrone, Equilin, 17 alpha dihydroequilin, jugate 2 versus percent growth of melanoma cells. equilenin, 17 alpha dihydroequilenin, 17 alpha esradiol, 27 bea estradiol, Leuprolide (Lupron), Testolactone, Climi 004.5 FIG. 15 is a graph plotting concentration of con phene, urofollitropin, bromocriptine, gonadorelin, danazol, jugate 2 versus percent growth of ovarian cancer cells. dehydroepiandrosterone, androstenedione, dihydrotestoster 0046 FIG. 16 is a graph plotting concentration of con one, Relaxin, folliculoStatin, Follicle regulatory protein, jugate 2 versus percent growth of renal cancer cells. Gonadocrinins, Oocyte maturation inhibitor and, Insulin 0047 FIG. 17 is a graph plotting concentration of con growth factor. Other compounds are detailed below. jugate 2 versus percent growth of prostate cancer cells. 0029. The methods of the invention are useful for treating a variety of medical conditions including conditions involv 0048 FIG. 18 is a graph plotting concentration of con ing abnormal mammalian-cell proliferation. They further are jugate 2 versus percent growth of breast cancer cells. useful in treating diabetes and its complications, excess acid 0049 FIG. 19 is a graph plotting concentration of Taxol Secretion, cardiovascular conditions involving cholesterol Versus percent growth of leukemia cells. (e.g., hyperlipidemia and hypercholesterolemia), diarrhea, ovarian diseases (e.g. endometriosis, ovarian cysts, etc.) and 0050 FIG. 20 is a graph plotting concentration of Taxol as contraceptive agents. Other conditions treatable accord Versus percent growth of non-Small cell lung cancer cells. ing to the invention will be apparent to those skilled in the 0051 FIG. 21 is a graph plotting concentration of Taxol art based upon the disclosure and lists of compounds pro Versus percent growth of colon cancer cells. vided. 0052 FIG. 22 is a graph plotting concentration of Taxol 0030 The methods and/or products of the invention also versus percent growth of CNS cancer cells. are useful in treating conditions Specific to noncentral ner Vous System tissue. Such conditions can be specific to any of 0053 FIG. 23 is a graph plotting concentration of Taxol the tissues described above, including breast, gastrointesti Versus percent growth of melanoma cells. nal and Ovarian tissue. 0054 FIG. 24 is a graph plotting concentration of Taxol Versus percent growth of ovarian cancer cells. BRIEF DESCRIPTION OF THE DRAWINGS 0055 FIG. 25 is a graph plotting concentration of Taxol 0.031 FIG. 1 is a graph plotting concentration of conju Versus percent growth of renal cancer-cells. gate 1 verSuS percent growth of leukemia cells. 0056 FIG. 26 is a graph plotting concentration of Taxol 0.032 FIG. 2 is a graph plotting concentration of conju Versus percent growth of prostate cancer cells. gate 1 versus percent growth of non-Small cell lung cancer 0057 FIG. 27 is a graph plotting concentration of Taxol cells. Versus percent growth of breast cancer cells. 0.033 FIG. 3 is a graph plotting concentration of conju gate 1 verSuS percent growth of colon cancer cells. DETAILED DESCRIPTION OF THE 0034 FIG. 4 is a graph plotting concentration of conju INVENTION gate 1 verSuS percent growth of CNS cancer cells. 0.058 cis-docosahexaenoic acid (DHA) is a naturally 0.035 FIG. 5 is a graph plotting concentration of conju occurring fatty acid. It is an unbranched chain fatty acid with gate 1 verSuS percent growth of melanoma cells. six double bonds, all cis. Its structure is as follows:

o o o o o OH

0.036 FIG. 6 is a graph plotting concentration of conju gate 1 verSuS percent growth of Ovarian cancer cells. 0059) DHA can be isolated, for example, from fish oil or 0037 FIG. 7 is a graph plotting concentration of conju can be chemically Synthesized. These methods, however, gate 1 verSuS percent growth of renal cancer cells. can generate trans isomers, which are difficult and expensive 0.038 FIG. 8 is a graph plotting concentration of conju to Separate and which may present Safety problems in gate 1 verSuS percent growth of prostate cancer cells. humans. The preferred method of production is biological 0.039 FIG. 9 is a graph plotting concentration of conju Synthesis to produce the all cis isomer. The preferred Source gate 1 verSuS percent growth of breast cancer cells. of DHA is from Martek Biosciences Corporation of Colum 0040 FIG. 10 is a graph plotting concentration of con bia, Md. Martek has a patented System for manufacturing jugate 2 versus percent growth of leukemia cells. DHA using microalgae which Synthesize only a single 0041 FIG. 11 is a graph plotting concentration of con isomer of DHA, the all cis isomer. Martek’s patents include jugate 2 verSuS percent growth of non-Small cell lung cancer U.S. Pat. Nos. 5,374,657, 5,492,938, 5,407,957 and 5,397, cells. 591. 0.042 FIG. 12 is a graph plotting concentration of con 0060 DHA also is present in the milk of lactating jugate 2 versus percent growth of colon cancer cells. Women, and Martek’s licensee has obtained approval in 0.043 FIG. 13 is a graph plotting concentration of con Europe of DHA as a nutritional supplement for infant jugate 2 versus percent growth of CNS cancer cells. formula. US 2004/0106589 A1 Jun. 3, 2004

0061. It is known that DHA can be unstable in the presence of oxygen. To Stablizie DHA and its conjugates it is important to add anti-oxidants to the material after it is Synthesized. One method of Stablization is to make-up the newly synthesized material in the following solution: 100 g neat DHA-taxol plus 100 g of vehicle (100 ml propylene glycol, 70 mg alph-tocopherol, 5 mg dialaurylthiodipropi onic acid, 50 mg ascorbic acid) prepared and held under argon in amber, Sealed Vials and Stored at four degrees centigrade. The following anti-oxidants may also be employed: ascorbic acid, ascorbyl palmitate, dilauryl ascor bate, hydroquinone, butyated hydroxyanisole, Sodium meta bisulfite, t-B caroteine and X-tocopherol. A heavy metal chelator Such as ethylenediamiine tetra-acetic acid (EDTA) may also be used. 0.062 Paclitaxel was first isolated from the bark of Taxus brevifolia (Wani et al., J. Am. Chem. Soc., 93, 2325, 1971). Its isolation and Synthesis have been reported extensively in the literature. Applicants obtained paclitaxel from a com mercial Source, Hauser Laboratories, of Boulder, Colo. Example 1 0063)

TAXOL

conjugate 1 0064. A solution of Taxol (41 umol) in methylene chlo ride (2.5 mL) under argon was mixed with 4-dimethylami nopyridine (41 umol), dicyclohexylcarbodiimide (82 umol), and DHA (41 umol) and the reaction mixture was stirred at ambient temperature for two hours. Following dilution with ether, the reaction mixture was washed with 5% hydrochlo ric acid, water, Saturated acqueous Sodium chloride, dried, and concentrated. Radial chromatography of the residue produced 45 mg (94%) of crystalline Taxol-DHA conjugate 1.

EXAMPLE 2 0065

AcO

TAXOL -e- US 2004/0106589 A1 Jun. 3, 2004

-continued

AcO O O

conjugate 2

0.066 The production of analog 2 involves several steps provided to store at 4 C. and to open the vials only when including a number of protection-acylation-deprotection ready for immediate experimental use. Instructions also steps. A solution of Taxol (59 umol) in methylene chloride were provided to use the ethanol Solutions containing the (2.5 mL) was mixed at ambient temperature under argon conjugates directly or to dissolve the analogs further in with imidazole (147 umol) and triethylsilyl chloride (147 DMSO (dimethylsulfoxide) at appropriate concentrations, almol). The reaction mixture was stirred for thirty minutes, with Vortexing if necessary for adequate dispersal. diluted with additional methylene chloride, washed with 0068 The activities of conjugates 1 and 2 were tested water, Saturated acqueous Sodium chloride, dried, and con against 57 cancer cell lines. The results are presented in centrated. Chromatography of the residue produced 50 mg FIGS. 1-9 for conjugate 1, FIGS. 10-18 for conjugate 2 and (88%) of intermediate A plus 5 mg of the 2, 7-di(triethyl FIGS. 19-27 for Taxol. To understand the data, reference is silyl) ether derivative. A solution of intermediate A (52 made to the guides provided by the NCI, excerpted as umol) in methylene chloride (3 mL) was mixed at ambient follows: temperature under argon with 4-dimethylaminopyridine (52 0069. The Calculated Measurement of Effect: Percentage umol), dicyclohexylcarbodiimide (104 umol), and DHA (52 Growth (PG) almol). The reaction mixture was stirred for ten hours, 0070 The measured effect of the compound on a cell line diluted with ether, passed through celite, and concentrated. is currently calculated according to one or the other of the Chromatography of the residue produced 65.9 mg of inter following two expressions: mediate B. A solution of intermediate B (51 umol) in acetonitrile (2 mL) at 0°C. under argon was mixed with 49% 0.071) If (Mean OD-Mean OD tzero)20, then

aqueous HF (0.2 mL) and the reaction mixture was stirred PG=100x(Mean OD-Meantest OD tzeic )/(Mean OD for one hour. After dilution with ether, the reaction mixture Mean Odzero) was washed with water, Saturated aqueous Sodium chloride, 0072) If (Mean OD-Meantest OD)<0, then dried, and concentrated. Radial chromatography of the resi PG=100x(Mean ODes-Mean Ode)/Mean Odeo due produced 44.6 mg (75%) of Taxol-DHA conjugate 2. 0073) Where: 0074) Mean OD=The average of optical density EXAMPLE 3 measurements of SRB-derived color just before expo 0067 Conjugates 1 and 2 were sent to the United States Sure of cells to the test compound. National Cancer Institute (NCI) for screening in the NCI's 0075 Mean OD=The average of optical density anticancer Screening program. The conjugates were pro measurements of SRB-derived color after 48 hours vided in ethanol (approximately 40 mg analog/2 ml ethanol). exposure of cells to the test compound. The conjugates were Sealed in Vials under argon to avoid 0076 Mean OD= The average of optical density exposure of the conjugates to oxygen because the conjugates measurements of SRB-derived color after 48 hours were believed to be Sensitive to oxygen. Instructions were with no exposure of cells to the test compound. US 2004/0106589 A1 Jun. 3, 2004

0.077 Experimental data was collected against each cell maintained Strong activity against Some cell lines. Conju line. . . . Each concentration is expressed as the logo (molar gates 1 and 2 will be Sufficiently active against certain cell or ug/ml). . . . The response parameters GI50, TGI, and lines, but will have, on average, a Substantially and dispro LC50 are interpolated values representing the concentra portionately lower activity against other cell lines, reducing tions at which the PG is +50, 0, and -50, respectively. potential side effects. For example, the TGI for Taxol against Sometimes these response parameters cannot be obtained by interpolation. If, for instance, all of the PGS in a given row CNS SF-539 is -6.95, and the TGI for conjugate 1 against exceed +50, then none of the three parameters can be this cell line is -5.13 and for conjugate 2 is -5.53. (In other obtained by interpolation. In Such a case, the value given for words, the activity of the conjugates was reduced verSuS that each response parameter is the highest concentration tested. of Taxol by less than 2 logs). The GI50 for Taxol against This practice is extended similarly to the other possible CNS SF 539 is -7.52, whereas the GI50s for conjugates 1 Situations where a response parameter cannot be obtained by and 2 are -6.22 and -5.56, respectively (again less than 2 interpolation. logs difference). In contrast, Taxol has a G150 for cell line 0078 Dose-Response Curves: CNSSF 268 of less than -10.0, whereas conjugates 1 and 2 have GI50s for CNSSF 268 of 5.36 and 5.28, respectively. 0079 The dose-response curve page of the data package This represents a reduction of activity in the conjugates VS. is created by plotting the PGS against the logo of the that of Taxol by at least about 5 logs activity. On average, corresponding concentration for every cell line. The cell line curves are grouped by Subpanel. Horizontal lines are pro the G150 for Taxol across all cell lines tested is at least vided at the PG values of +50, 0, and -50. The concentra -9.19. (It is probably much higher since concentrations less tions corresponding to points where the curves croSS these than -10 were not tested, and if Taxol was active at -10.0, lines are the GI50, TGI and LC50, respectively. -10 (instead of the actual lower value) was used in calcu lating the average of -9.19. There were 27 instances when 0080) Several important distinctions are apparent from the data. Most important, the patterns of anticancer actively this occurred.) The average GI50s for conjugates 1 and 2, on for conjugates 1 and 2 differ from that of Taxol. In one Sense, the other hand, were 5.49 and 5.22, respectively. Therefore, conjugates 1 and 2 are effective anticancer agents against a the average difference in activity for Taxol vs. the conjugates more restricted Set of cancer cell lines. For example, con is at least between 3 and 4 logs. Thus, the Sharp reduction in jugates 1 and 2 were not very effective against any of the six the activity of the conjugates against many cell lines VS. a leukemia cancer cell lines tested, whereas Taxol was Some lesser reduction for other cell lines is expected to reduce the what effective against all four leukemia cell lines against potential Side effects of the conjugates versus those of Taxol which Taxol was tested. (See FIGS. 1, 10 and 19.) at effective doses. 0081. The relative activity against members within a 0084 Cancers other than CNS, breast and colon cancer class of cancers also was altered. For example, at TGI can be treated. For example, there was activity against (horizontal line at Zero in the graphs), Taxol was more non-Small cell lung cancer cells, melanoma cells and ovarian effective against non-Small cell lung cancer line H522 than cancer cells. However, the activity was relatively reduced against H460 (by about 3 logs), whereas conjugates 1 and 2 and was extremely specific, limiting the utility of the con were slightly more effective against H460 than H522. As jugates for treating generally Such cancers. In any event, another example, Taxol was least effective at TGI against cancer patients could be evaluated to determine if a conju CNSU251, whereas conjugate 1 was most effective against gate is Strongly active against the patient's cancer prior to CNSU251 and conjugates 2 was also very effective against Selecting the conjugate as the anti-cancer agent of choice for CNSU251 (relative to other CNS cell lines). As a further that patient. example, Taxol was equivalent in activity toward MDA-N and MDA-MB-435 breast cancer cell lines at all concentra 0085. The foregoing experiments establish that DHA tions tested, whereas conjugates 1 and 2 were more effective analogs have altered specificity versus that of Taxol for against MDA-N than MDA-MB-435 at all concentrations cancer cell lines. Because of this altered specificity, it also is tested. clear that the conjugates themselves are gaining acceSS into the target cells (as opposed to simply releasing Taxol into the 0082 To further illustrate the differences in the activity of environment outside of the cell). Thus, the DHA moiety conjugates 1 and 2 versus that of Taxol, the NCI subjected appears to Selectively target certain cell types as opposed to the data to a statistical analysis designed by the NCI to others. The ability of the conjugates to gain entry into the reflect differences in the pattern of activity of anticancer targeted cells was unknown prior to the invention, and the agents. Conjugate 1 and conjugate 2 were determined to be ability of the DHA moiety to selectively target certain cell statistically different in their pattern of activity versus Taxol types was unexpected. in this unique measurement by the NCI. 0086 The same is true of DHA-Taxotere covalent con 0.083. It also is to be noted that, in general, conjugates 1 jugates, examples of which are presented below. Taxotere's and 2 were one thousand to ten thousand times leSS potent Synthesis has been reported extensively in the literature. One than Taxol for many cell lines tested. This reduction in example is Kanazawa, A. et al., J. Organic Chem. 1994, Vol. activity is important, especially Since conjugates 1 and 2 59, pp. 1238-1240. US 2004/0106589 A1 Jun. 3, 2004

EXAMPLE 4 0087

TAXOTERE

DHA?dicyclohexylcarbodiimide 4-dimethylaminopyridine

A.C

conjugate 3

0088 A Solution of Taxotere in methylene chloride under argon is mixed with 4-dimethylaminopyridine, dicyclohexy lcarbodiimide, and DHA. The reaction mixture is stirred at ambient temperature. Radial chromatography of the residue is performed to produce Taxotere-DHA conjugate 3. EXAMPLE 5 0089) triethylsilyl chloride TAXOTERE --- imidazole

HO 9 OSi(CH2CH) O X- H O III IIH DHA?dicyclohexylcarbodiimide ------4-dimethylaminopyridine

CHCH)SiO3 23

aqueous HF Hess US 2004/0106589 A1 Jun. 3, 2004

-continued

O A.C

O1. Ph conjugate 4

0090. A solution of Taxotere in dimethylformamide is the residue is performed to produce intermediate D. A mixed at ambient temperature under argon with imidazole Solution of intermediate D in acctonitrile at 0° C. under and triethylsilyl chloride. The reaction mixture is stirred at argon is mixed with 49% acqueous HF and the reaction ambient temperature, diluted with methylene chloride, mixture is stirred at the same temperature. After dilution washed with water, Saturated acqueous Sodium chloride, with ether, the reaction mixture is washed with water, dried, and concentrated. Radial chromatography of the resi Saturated acqueous Sodium chloride, dried, and concentrated due is performed to produce intermediate C. A Solution of Radial chromatography of the residue is performed to pro intermediate C in methylene chloride is mixed at ambient duce Taxotere-DHA conjugate 4. temperature under argon with 4 dimethylaminopyridine, dicyclohexylcarbodiimide, and DHA. The reaction mixture EXAMPLE 6 is stirred at ambient temperature, diluted with ether, passed through celite, and concentrated. Radial chromatography of O091)

tert-butyldimethylsilyl chloride TAXOTERE He imidazole HO O OH

X - O H. O. s 1 equivalent DHA Her ---- dicyclohexylcarbodiimide 4-dimethylaminopyridine tert-CH(CH3)2SiO A.

aqueous HF Xu H O Her -N-Ol tert-CH(CH3)2SiO HO US 2004/0106589 A1 Jun. 3, 2004 10

-continued

A.C

conjugate 4

0092. A solution of Taxotere in dimethylformamide is Radial chromatography of the residue is performed to pro mixed at ambient temperature under argon with imidazole duce intermediate F. (Intermediate H also is obtained and and tert-butyly dimethylsilyl chloride. The reaction mixture used in Example 8 below.) A solution of intermediate F in is stirred at ambient temperature, diluted with methylene acetonitrile at 0° C. under argon is mixed with aqueous HF chloride, washed with water, Saturated acqueous Sodium and the reaction mixture is stirred at the same temperature. chloride, dried, and concentrated. Radial chromatography of After dilution with ether, the reaction mixture is washed with the residue is performed to produce intermediate E. A water, Saturated aqueous Sodium chloride, dried, and con solution of intermediate E in methylene chloride is mixed at centrated Radial chromatography of the residue is performed ambient temperature under argon with 4-dimethylaminopy to produce Taxotere-DHA conjugate 4. ridine, dicyclohexylcarbodiimide, and 1 equivalent of DHA. The reaction mixture is stirred at ambient temperature, EXAMPLE 7 diluted with ether, passed through celite, and concentrated. O093)

tert-butyldimethylsilyl chloride TAXOTERE Hess imidazole

DHA?dicyclohexylcarbodiimide He 4-dimethylaminopyridine tert-CH0(CH3)2SiO

aqueous HF He US 2004/0106589 A1 Jun. 3, 2004

-continued

conjugate 5

0094. A solution of Taxotere in dimethylformamide is raphy of the residue is performed to produce intermediate G. mixed at ambient temperature under argon with imidazole A solution of intermediate G in acetonitrile at 0° C. under and tert-butyly dimethylsilyl chloride. The reaction mixture argon is mixed with aqueous HF and the reaction mixture is is stirred at ambient temperature, diluted with methylene Stirred at the same temperature. After dilution with ether, the chloride, washed with water, Saturated acqueous Sodium reaction mixture is washed with water, Saturated aqueous chloride, dried, and concentrated. Radial chromatography of Sodium chloride, dried, and concentrated. Radial chroma the residue is performed to produce intermediate E. A tography of the residue is performed to produce Taxotere solution of intermediate E in methylene chloride is mixed at DHA conjugate 5. ambient temperature under argon with 4-dimethylaminopy ridine, dicyclohexylcarbodiimide, and DHA. The reaction EXAMPLE 8 mixture is stirred at ambient temperature, diluted with ether, passed through celite, and concentrated. Radial chromatog O095

tert-butyldimethylsilyl chloride TAXOTERE Her imidazole

1 equivalent DHA He dicyclohexylcarbodiimide 4-dimethylaminopyridine

HO O O o Xu- NH Q aqueous HF -N- -- tert-C, Ho(CH3)2SiO US 2004/0106589 A1 Jun. 3, 2004 12

-continued

conjugate 6

0.096] A solution of taxotere in dimethylformamide is rine Bitartrate; Oxidopamine; Oxymetazoline Hydrochlo mixed at ambient temperature under argon with imidazole ride; Phenylephrine Hydrochloride; Phenylpropanolamine and tert-butyly dimethylsilyl chloride. The reaction mixture Hydrochloride; Phenylpropanolamine Polistirex, Prenalterol is stirred at ambient temperature, diluted with methylene Hydrochloride; Propylhexedrine; Pseudoephedrine Hydro chloride, washed with water, Saturated acqueous Sodium chloride; Tetrahydrozoline Hydrochloride; Tramazoline chloride, dried, and concentrated. Radial chromatography of Hydrochloride; Xylometazoline Hydrochloride. the residue is performed to produce intermediate E. A 0099 Adrenocortical steroid: Ciprocinonide; Desoxycor solution of intermediate E in methylene chloride is mixed at ticosterone Acetate; DeSoxycorticosterone Pivalate; Dexam ambient temperature under argon with 4-dimethylaminopy ethasone Acetate, Fludrocortisone Acetate, Flumoxonide; ridine, dicyclohexylcarbodiimide, and 1 equivalent of DHA. Hydrocortisone Hemisuccinate; Methylprednisolone The reaction mixture is stirred at ambient temperature, Hemisuccinate; Naflocort; Procinonide; Timobesone diluted with ether, passed through celite, and concentrated. Acetate; Tipredane. Radial chromatography of the residue is performed to pro 0100 Adrenocortical suppressant: Aminoglutethimide; duce intermediate H (and intermediate F which was used TriloStane. above on Example 6. A solution of intermediate H in acetonitrite at 0° C. under argon is mixed with aqueous HF 0101 Alcohol deterrent: Disulfiram. and the reaction mixture is stirred at the same temperature. 0102 Aldosterone antagonist: Canrenoate Potassium; After dilution with ether, the reaction mixture is washed with Canrenone; Dicirenone; Mexrenoate Potassium; Prorenoate water, Saturated acqueous Sodium chloride, dried, and con Potassium, Spironolactone. centrated. Radial chromatography of the residue is per formed to produce Taxotere-DHA conjugate 6. 0103) Amino acid: Alanine; Aspartic Acid; Cysteine Hydrochloride; Cystine; Histidine; Isoleucine; Leucine; 0097 DHA and other naturally occurring, unbranched Lysine; Lysine Acetate; Lysine Hydrochloride; Methionine; fatty acids may be conjugated to virtually any drug com Phenylalanine; Proline; Serine; Threonine; Tryptophan; pound or diagnostic agent and used according to the meth Tyrosine; Valine. ods of the present invention So long as the pharmaceutical 0.104) Ammonia detoxicant: Arginine: Arginine agent has a use outside of the central nervous System. Glutamate, Arginine Hydrochloride. Pharmaceutical agents include the following categories and Specific examples. It is not intended that the category be 0105 Anabolic: Bolandiol Dipropionate; Bolasterone; limited by the specific examples. Those of ordinary skill in Boldenone Undecylenate; Bolenol; Bolmantalate; Ethyl the art will be able to identify readily those pharmaceutical estrenol; Methenolone Acetate; Methenolone Enanthate; agents that have utility outside of the central nervous System. Mibolerone; Nandrolone Cyclotate; Norbolethone; Pizoty Those of ordinary skill in the art will recognize also numer line; Quinbolone; Stenbolone Acetate; Tibolone; Zeranol. ous other compounds that fall within the categories and that 0106 Analeptic: Modafinil. are useful according to the invention. 0107 Analgesic: Acetaminophen; Alfentanil Hydrochlo 0.098 Adrenergic: Adrenalone; Amidephrine Mesylate; ride; Aminobenzoate Potassium; Aminobenzoate Sodium; Apraclonidine Hydrochloride; Brimonidine Tartrate; Anidoxime; Anileridine; Anileridine Hydrochloride; Anilo Dapiprazole Hydrochloride; Deterenol Hydrochloride; pam Hydrochloride; Anirolac, Antipyrine, Aspirin; Benox Dipivefrin; Dopamine Hydrochloride; Ephedrine Sulfate; aprofen; Benzydamine Hydrochloride; Biciifadine Hydro Epinephrine; Epinephrine Bitartrate; Epinephryl Borate; chloride; Brifentanil Hydrochloride; Bromadoline Maleate; Esprocquin Hydrochloride; Etafedrine Hydrochloride; Bromfenac Sodium; Buprenorphine Hydrochloride; Butace Hydroxyamphetamine Hydrobromide; Levonordefrin; tin; Butixirate; Butorphanol; Butorphanol Tartrate; Carbam Mephentermine Sulfate; Metaraminol Bitartrate; Metizoline aZepine, Carbaspirin Calcium; Carbiphene Hydrochloride; Hydrochloride; Naphazoline Hydrochloride; Norepineph Carfentanil Citrate; Ciprefadol Succinate; Ciramadol; Cira US 2004/0106589 A1 Jun. 3, 2004

madol Hydrochloride; Clonixeril; Clonixin; Codeine; docaine; Etoxadrol Hydrochloride; Euprocin Hydrochlo Codeine Phosphate; Codeine Sulfate; Conorphone Hydro ride; Fluroxene; Halothane; Isobutamben; Isoflurane; chloride; Cyclazocine; Dexoxadrol Hydrochloride; Dex Ketamine Hydrochloride; Levoxadrol Hydrochloride; pemedolac, Dezocine; Diflunisal; Dihydrocodeine Bitar Lidocaine; Lidocaine Hydrochloride; Mepivacaine Hydro trate; Dimefadane; Dipyrone; Doxpicomine Hydrochloride; chloride; Methohexital Sodium; Methoxyflurane; Mida Drinidene; Enadoline Hydrochloride; Epirizole; Ergotamine Zolam Hydrochloride; Midazolam Maleate; Minaxolone; Tartrate; Ethoxazene Hydrochloride; Etofenarnate; Eugenol; Nitrous Oxide; Norflurane; Octodrine; Oxethazaine; Phen Fenoprofen; Fenoprofen Calcium; Fentanyl Citrate; Floc cyclidine Hydrochloride; Pramoxine Hydrochloride; Prilo tafenine; Flufenisal; Flunixin; Flunixin Meglumine; Flupir calne Hydrochloride; Procaine Hydrochloride; Propanidid; tine Maleate; FluproduaZone; Fluradoline Hydrochloride; Proparacaine Hydrochloride; Propofol; Propoxycaine Flurbiprofen; Hydromorphone Hydrochloride; Ibufenac; Hydrochloride; Pyrrocaine; Pisocaine; Rodocaine; Roflu Indoprofen; Ketazocine, Ketorfanol; Ketorolac rane; Salicyl Alcohol; Sevoflurane; Teflurane; Tetracaine; Tromethamine; Letimide Hydrochloride; Levomethadyl Tetracaine Hydrochloride; Thiamylal; Thiamylal Sodium; Acetate; Levomethadyl Acetate Hydrochloride; Levonant Thiopental Sodium; Tiletamine Hydrochloride; Zolamine radol Hydrochloride; Levorphanol Tartrate; Lofemizole Hydrochloride. Hydrochloride; Lofentanil Oxalate; Lorcinadol; Lornoxi cam; Magnesium Salicylate; Mefenamic Acid, Menabitan 0111 Anorectic compounds including dexfenfluramine. Hydrochloride; Meperidine Hydrochloride; Meptazinol 0112 Anorexic: Aminorex; Amphecloral; Chlorphenter Hydrochloride; Methadone Hydrochloride; Methadyl mine Hydrochloride; Clominorex; Clortermine Hydrochlo Acetate; Methopholine; Methotrimeprazine; Metkephamid ride; Diethylpropion Hydrochloride; Fenfluramine Hydro Acetate; Mimbane Hydrochloride; Mirfentanil Hydrochlo chloride; Fenisorex, Fludorex, Fluminorex, Levamfetamine ride; Molinazone; Morphine Sulfate; Moxazocine; Nabitan Succinate; Mazindol; Mefenorex Hydrochloride; Phenrme Hydrochloride; Nalbuphine Hydrochloride; Nalmexone trazine Hydrochloride; Phentermine; Sibutramine Hydro Hydrochloride; Namoxyrate; Nantradol Hydrochloride; chloride. Naproxen; Naproxen Sodium; Naproxol; Nefopam Hydro chloride; Nexeridine Hydrochloride; Noracymethadol 0113 Antagonist: Atipamezole; Atosiban; Bosentan; Hydrochloride; Ocfentanil Hydrochloride; Octazamide; Cimetidine, Cimetidine Hydrochloride; Clentiazem Male Olvanil; Oxetorone Fumarate; Oxycodone; Oxycodone ate; Detirelix Acetate; Devazepide; Donetidine; Etintidine Hydrochloride; Oxycodone Terephthalate; Oxymorphone Hydrochloride; Famotidine, Fenmetozole Hydrochloride; Hydrochloride; Pemedolac, Pentamorphone; Pentazocine; Flumazenil; Icatibant Acetate, Icotidine, Isradipine; Metia Pentazocine Hydrochloride; Pentazocine Lactate; mide, Nadide, Nalmefene; Nalmexone Hydrochloride; Phenazopyridine Hydrochloride; Phenyramidol Hydrochlo Naloxone Hydrochloride; Naltrexone; Nilvadipine; Oxilor ride; Picenadol Hydrochloride; Pinadoline; Pirfenidone; phan; Oxmetidine Hydrochloride; Oxmetidine Mesylate; Piroxicam Olamine; Pravadoline Maleate; Prodilidine Quadazocine Mesylate; Ranitidine; Ranitidine Bismuth Cit Hydrochloride; Profadol Hydrochloride; Propiram Fuma rate; Ranitidine Hydrochloride; Sufotidine; Teludipine rate; Propoxyphene Hydrochloride; Propoxyphene Napsy Hydrochloride; Tiapamil Hydrochloride; Tiotidine; late; Proxazole; Proxazole Citrate; Proxorphan Tartrate; Vapi.prost Hydrochloride; Zaltidine Hydrochloride. Pyrroliphene Hydrochloride; Remifentanil Hydrochloride; 0114 Anterior pituitary activator: Epimestrol. Salcolex; Salethamide Maleate; Salicylamide; Salicylate Meglumine; Salsalate; Sodium Salicylate; Spiradoline 0115) Anterior pituitary suppressant: Danazol. Mesylate; Sufentanil; Sufentanil Citrate; Talmetacin; Talni 0116. Anthelmintic: Albendazole; Anthelmycin; Bro flumate; Talosalate; Tazadolene Succinate; Tebufelone; moxanide; Bunamidine Hydrochloride; Butonate; Cam Tetrydamine; Tifurac Sodium; Tilidine Hydrochloride; bendazole; Carbantel Lauryl Sulfate; Clioxanide; Closantel; Tiopinac; Tonazocine Mesylate; Tramadol Hydrochloride; Cyclobendazole; Dichlorvos; Diethylcarbamazine Citrate; Trefentanil Hydrochloride; Trolamine; Veradoline Hydro Dribendazole; Dymanthine Hydrochloride; Etibendazole; chloride; Verilopam Hydrochloride; Volazocine; Xorphanol Fenbendazole; Furodazole, Hexylresorcinol; Mebendazole; Mesylate; Xylazine Hydrochloride; Zenazocine Mesylate; Morantel Tartrate; Niclosamide; Nitramisole Hydrochloride; Zomepirac Sodium, Zucapsaicin. Nitrodan; Oxantel Pamoate, Oxfendazole; Oxibendazole; 0108 Androgen: Fluoxymesterone; Mesterolone; Meth Parbendazole; Piperamide Maleate; Piperazine; Piperazine yltestosterone; Nandrolone Decanoate; Nandrolone Phen Citrate; Piperazine Edetate Calcium; Proclonol; Pyrantel propionate; Nisterime Acetate; Oxandrolone; Pamoate; Pyrantel Tartrate; Pyrvinium Pamoate; Rafox Oxymetholone; Silandrone; Stanozolol; Testosterone; Test anide; Stilbazium Iodide; Tetramisole Hydrochloride; Thia osterone Cypionate; Testosterone Enanthate, Testosterone bendazole; Ticarbodine; Tioxidazole; Triclofenol Pipera Ketolaurate; Testosterone Phenylacetate; Testosterone Pro Zine; Vincofos, Zilantel. pionate; Trestolone Acetate. 0117 Anti-acne: Adapalene; Erythromycin Salnacedin; 0109 Anesthesia, adjunct to: Sodium Oxybate. Inocoterone Acetate. 0110 Anesthetic: Aliflurane; Benoximate Hydrochloride; 0118 Anti-adrenergic: Acebutolol; Alprenolol Hydro Benzocaine; Biphenamine Hydrochloride; Bupivacaine chloride; Atenolol; Bretylium Tosylate; Bunolol Hydrochlo Hydrochloride; Butamben; Butamben Picrate; Chlorop ride; Carteolol Hydrochloride; Celiprolol Hydrochloride; rocaine Hydrochloride; Cocaine; Cocaine Hydrochloride; Cetamolol Hydrochloride; Cicloprolol Hydrochloride; Dex Cyclopropane, Desflurane, Dexivacaine; Diamocaine propranolol Hydrochloride; Diacetolol Hydrochloride; Cyclamate; Dibucaine; Dibucaine Hydrochloride; Dyclo Dihydroergotamine Mesylate; Dilevalol Hydrochloride; nine Hydrochloride; Enflurane; Ether; Ethyl Chloride; Eti Esmolol Hydrochloride; Exaprolol Hydrochloride; Fen US 2004/0106589 A1 Jun. 3, 2004 spiride Hydrochloride; Flestolol Sulfate; Labetalol Hydro ride; Bacitracin; Bacitracin Methylene Disalicylate; Baci chloride; Levobetaxolol Hydrochloride; Levobunolol tracin Zinc, Bambermycins, Benzoylpas Calcium, Beryth Hydrochloride; Metalol Hydrochloride; Metoprolol; Meto romycin; Betamicin Sulfate; Biapenem; Biniramycin; prolol Tartrate; Nadolol; Pamatolol Sulfate; Penbutolol Sul Biphenamine Hydrochloride; Bispyrithione Magsulfex; fate; Phentolamine Mesylate; Practolol; Propranolol Hydro Butikacin; Butirosin Sulfate; Capreomycin Sulfate; Carba chloride; Proroxan Hydrochloride; Solypertine Tartrate; dox; Carbenicillin Disodium; Carbenicillin Indanyl Sodium; Sotalol Hydrochloride; Timolol; Timolol Maleate; Tipre Carbenicillin Phenyl Sodium; Carbenicillin Potassium; nolol Hydrochloride; Tolamolol; Zolertine Hydrochloride. Carumonam Sodium; Cefaclor, Cefadroxil, Cefamandole; 0119) Anti-allergic: Amlexanox; Astemizole; Azelastine Cefamandole Nafate; Cefamandole Sodium; Cefaparole; Hydrochloride; Eclazolast; Minocromil Nedocromil; Cefatrizine; Cefazaflur Sodium; Cefazolin; Cefazolin Nedocromil Calcium; Nedocromil Sodium; Nivinmedone Sodium; Cefbuperazone; Cefdinir, Cefepime; Cefepime Sodium; Pemirolast Potassium; Pentigetide; Pirquinozol; Hydrochloride; Cefetecol; Cefixime; Cefinenoxime Hydro Poisonoak Extract; Probicromil Calcium; ProXicromil, chloride; Cefinetazole; Cefinetazole Sodium; Cefonicid Repirinast; Tetrazolast Meglumine; Thiazinamium Chlo Monosodium; Cefonicid Sodium; Cefoperazone Sodium; ride; Tiacrilast; Tiacrilast Sodium; Tiprinast Meglumine; Ceforanide; Cefotaxime Sodium; Cefotetan; Cefotetan Tixanox. Disodium; Cefotiam Hydrochloride; Cefoxitin; Cefoxitin 0120 Anti-amebic: Berythromycin; Bialamicol Hydro Sodium; Ce?pimizole; Ce?pimizole Sodium; Ce?piramide; chloride; Chloroquine; Chloroquine Hydrochloride; Chloro Ce?piramide Sodium; Ce?pirome Sulfate; Cefpodoxime quine Phosphate; Clamoxyquin Hydrochloride, Clioquinol, Proxetil, Cefprozil; Cefroxadine; Cefsulodin Sodium; Emetine Hydrochloride; Iodoquinol; Paromomycin Sulfate; Ceftazidime; Ceftibuten; Ceftizoxime Sodium; Ceftriaxone Sodium; Cefuroxime; Cefuroxime Axetil, Cefuroxime Piv Quinfamide; Symetine Hydrochloride; Teclozan; Tetracy oxetil, Cefuroxime Sodium; Cephacetrile Sodium; Cephal cline; Tetracycline Hydrochloride. exin; Cephalexin Hydrochloride; Cephaloglycin; Cephalo 0121 Anti-androgen: Benorterone; Cioteronel; Cyproter ridine; Cephalothin Sodium; Cephapirin Sodium; one Acetate; Delmadinone Acetate, Oxendolone; Topterone; Cephradine; Cetocycline Hydrochloride; Cetophenicol; Zanoterone. Chloramphenicol; Chloramphenicol Palmitate; Chloram phenicol Pantothenate Complex; Chloramphenicol Sodium 0122) Anti-anemic: Epoetin Alfa; Epoetin Beta; Ferrous Succinate; Chlorhexidine Phosphanilate; Chloroxylenol; Sulfate, Dried; Leucovorin Calcium. Chlortetracycline Bisulfate; Chlortetracycline Hydrochlo 0123 Anti-anginal: Amlodipine Besylate; Amlodipine ride; Cinoxacin; Ciprofloxacin; Ciprofloxacin Hydrochlo Maleate; Betaxolol Hydrochloride; Bevantolol Hydrochlo ride; Cirolemycin; Clarithromycin; Clinafloxacin Hydro ride; Butoprozine Hydrochloride; Carvedilol; Cinepazet chloride; Clindamycin; Clindamycin Hydrochloride; Maleate; Metoprolol Succinate; Molsidomine; Monatepil Clindamycin Palmitate Hydrochloride; Clindamycin Phos Maleate; Primidolol; Ranolazine Hydrochloride; Tosifen; phate; Clofazimine; Cloxacillin Benzathine; Cloxacillin Verapamil Hydrochloride. Sodium; Cloxyquin; Colistimethate Sodium; Colistin Sul fate; Coumermycin, Coumermycin Sodium; Cyclacillin; 0.124. Anti-anxiety agent: Adatanserin Hydrochloride; CycloSerine; Dalfopristin; DapSone; Daptomycin; Demeclo Alpidem; BinoSpirone MeSylate; Bretazenil; GlemanSerin; cycline; Demeclocycline Hydrochloride; Demecycline; Ipsapirone Hydrochloride; Mirisetron Maleate; Ocinaplon; Denofungin; Diaveridine; Dicloxacillin; Dicloxacillin Ondansetron Hydrochloride; Panadiplon; Pancopride; Pazi Sodium; Dihydrostreptomycin Sulfate; Dipyrithione; naclone, Serazapine Hydrochloride, TandoSpirone Citrate; Dirithromycin; Doxycycline; Doxycycline Calcium; Doxy Zalospirone Hydrochloride. cycline Fosfatex; Doxycycline Hyclate; Droxacin Sodium; Enoxacin; Epicillin; Epitetracycline Hydrochloride; Eryth 0.125 Anti-arthritic: Lodelaben. romycin; Erythromycin Acistrate; Erythromycin Estolate; 0.126 Anti-asthmatic: Ablukast; Ablukast Sodium; Erythromycin EthylSuccinate; Erythromycin Gluceptate; Azelastine Hydrochloride; Bunaprolast; Cinalukast; Cromi Erythromycin Lactobionate; Erythromycin Propionate; trile Sodium; Cromolyn Sodium; Enofelast; Isamoxole; Erythromycin Stearate; Ethambutol Hydrochloride; Ketotifen Fumarate; Levcromakalim; Lodoxamide Ethyl; Ethionamide; Fleroxacin; Floxacillin; Fludalanine; Flume Lodoxamide Tromethamine; Montelukast Sodium, Ontazo quine; Fosfomycin; Fosfomycin Tromethamine; Fumoxicil last; Oxarbazole; Oxatomide; Piriprost; Piriprost Potassium; lin; Furazolium Chloride; Furazolium Tartrate; Fusidate Pirolate; Pobilukast Edamine; Quazolast; Repirinast; Sodium; Fusidic Acid, Gentamicin Sulfate; Gloximonam; Ritolukast; Sulukast; Tetrazolast Meglumine; Tiaramide Gramicidin; Haloprogin; Hetacillin; Hetacillin Potassium; Hydrochloride; Tibenelast Sodium; Tomelukast; Tranilast; Hexedine, Ibafloxacin; Imipenem; ISOconazole, Isepamicin; Verlukast; Verofylline; Zarirlukast. Isoniazid; Josamycin; Kanamycin Sulfate; Kitasamycin; Levofuraltadone; Levopropylcillin Potassium; Lexithromy 0127. Anti-atherosclerotic: Mifobate; Timefuronc. cin; Lincomycin; Lincomycin Hydrochloride, Lomefloxa 0128 Antibacterial: Acedapsone; Acetosulfone Sodium; cin; Lomefloxacin Hydrochloride; Lomefloxacin Mesylate; Alamecin; Alexidine, Amdinocillin; Amdinocillin Pivoxil, Loracarbef, Mafenide; Meclocycline; Meclocycline Sul Amicycline; Amifloxacin; Amifloxacin MeSylate; Amika fosalicylate; Megalomicin Potassium Phosphate; Mequidox; cin; Amikacin Sulfate; AminoSalicylic acid; Aminosalicylate Meropenem; Methacycline; Methacycline Hydrochloride; Sodium; Amoxicillin; Amphomycin; Ampicillin; Ampicillin Methenamine; Methenamine Hippurate; Methenamine Sodium; Apalcillin Sodium; Apramycin; ASpartocin, Astro Mandelate; Methicillin Sodium; Metioprim; Metronidazole micin Sulfate; AVillamycin; AVoparcin, Azithromycin; Hydrochloride; Metronidazole Phosphate; Mezlocillin; Azlocillin; Azlocillin Sodium; Bacampicillin Hydrochlo Mezlocillin Sodium; Minocycline; Minocycline Hydrochlo US 2004/0106589 A1 Jun. 3, 2004 ride; Mirincamycin Hydrochloride; Monensin; Monensin Hydrobromide; Hyoscyamine Sulfate; Isopropamide Iodide; Sodium; Nafcillin Sodium; Nalidixate Sodium; Nalidixic Mepenzolate Bromide; Methylatropine Nitrate; Meto Acid; Natamycin; Nebramycin; Neomycin Palmitate; Neo quizine; Oxybutynin Chloride; Parapenzolate Bromide; Pen mycin Sulfate; Neomycin Undecylenate; Netilmicin Sulfate; tapiperium Methylsulfate; Phencarbamide; Poldine Methyl Neutramycin; Nifuradene; Nifuraldezone; Nifuratel; Nifu sulfate; Proalurnide; Propantheline Bromide; Propenzolate ratrone, Nifurdazil; Nifurimide; Nifurpirinol; Hydrochloride; Scopolamine Hydrobromide; Tematropium Nifurcquinazol; Nifirthiazole; Nitrocycline; Nitrofurantoin; Methylsulfate; Tiquinamide Hydrochloride; Tofenacin Nitromide; Norfloxacin; Novobiocin Sodium; Ofloxacin; Hydrochloride; Toquizine; Triampyzine Sulfate; Trihex Ormetoprim; Oxacillin Sodium; Oximonam; Oximonam yphenidyl Hydrochloride; Tropicamide. Sodium; Oxolinic Acid; Oxytetracycline; Oxytetracycline Calcium; Oxytetracycline Hydrochloride; Paldimycin; 0132) Anticoagulant: Ancrod; Anticoagulant Citrate Dex Parachlorophenol; Paulomycin; Pefloxacin: Pefloxacin trose Solution; Anticoagulant Citrate Phosphate Dextrose Mesylate; Penamecillin; Penicillin G BenZathine; Penicillin Adenine Solution; Anticoagulant Citrate Phosphate Dex G Potassium; Penicillin G Procaine; Penicillin G Sodium; trose Solution; Anticoagulant Heparin Solution; Anticoagul Penicillin V; Penicillin V BenZathine; Penicillin V Hydrab lant Sodium Citrate Solution; Ardeparin Sodium; Bivaliru amine; Penicillin V Potassium; Pentizidone Sodium; Phenyl din; Bromindione; Dalteparin Sodium; Desirudin; Aminosalicylate; Piperacillin Sodium; Pirbenicillin Sodium; Dicumarol; Heparin Calcium; Heparin Sodium; Lyapolate Piridicillin Sodium; Pirlimycin Hydrochloride; Pivampicil Sodium; Nafamostat Mesylate; Phenprocoumon; Tinzaparin lin Hydrochloride; Pivampicillin Pamoate; Pivampicillin Sodium; Warfarin Sodium. Probenate; Polymyxin B Sulfate; Porfiromycin; Propikacin; PyraZinamide, Pyrithione Zinc, Quindecamine Acetate; 0.133 Anticoccidal: Maduramicin. Quinupristin, Racephenicol; Ramoplanin; Ranimycin; Relo 0134) Anticonvulsant: Albutoin; Ameltolide; Atolide; mycin; Repromicin; Rifabutin; Rifametane; Rifamexil; Buramate; Carbamazepine, Cinromide, Citenamide, Clon Rifamide; Rifampin; Rifapentine; Rifaximin; Rolitetracy azepam, Cyheptamide, Dezinamide; Dimethadione; Dival cline, Rolitetracycline Nitrate: Rosaramicin; Rosaramicin proex Sodium; Eterobarb; Ethosuximide; Ethotoin; Flu Butyrate; Rosaramicin Propionate; Rosaramicin Sodium razepam Hydrochloride; Fluzinamide; Fosphenyloin Phosphate, Rosaramicin Stearate; ROSoxacin; RoxarSone; Sodium; Gabapentin, Ilepcimide, Lamotrigine; Magnesium Roxithromycin; Sancycline; Sanfeltrinem Sodium; Sarmox Sulfate; Mephenyloin; Mephobarbital; Methetoin; MethSux icillin, Sarpicillin; Scopafungin, Sisomicin; Sisomicin Sul imide: Milacemide Hydrochloride; Nabazenil; Nafimidone fate, Sparfloxacin; Spectinomycin Hydrochloride; Spiramy Hydrochloride; Nitrazepam; Phenacemide; Phenobarbital; cin; Stallimycin Hydrochloride; Steffimycin; Streptomycin Phenobarbital Sodium; Phensuximide; Phenyloin; Pheny Sulfate; Streptonicozid; Sulfabenz, Sulfabenzamide; Sulfac loin Sodium; Primidone; Progabide; Ralitoline; Remace etamide; Sulfacetamide Sodium; Sulfacytine; Sulfadiazine; mide Hydrochloride; Ropizine; Sabeluzole; Stiripentol; Sulfadiazine Sodium; Sulfadoxine, Sulfalene; Sulfamera Sulthiame; Thiopental Sodium; Tiletamine Hydrochloride; Zine, Sulfameter, Sulfamethazine, Sulfamethizole; Sul Topiramate; Trimethadione; Valproate Sodium; Valproic famethoxazole; Sulfamonomethoxine, Sulfamoxole; Sulfa Acid; Vigabatrin; Zoniclezole Hydrochloride; Zonisamide. nilate Zinc, Sulfanitran; SulfaSalazine, SulfaSomizole; Sulfathiazole; Sulfazamet, Sulfisoxazole; Sulfisoxazole 0.135 Antidepressant: Adatanserin Hydrochloride; Adi Acetyl; Sulfisoxazole Diolamine; Sulfomyxin; Sulopenem; nazolam, Adinazolam MeSylate; Alaproclate; Aletamine Sultamicillin; Suncillin Sodium; Talampicillin Hydrochlo Hydrochloride; Amedalin Hydrochloride; Amitriptyline ride; Teicoplanin; Temafloxacin Hydrochloride; Temocillin; Hydrochloride, Amoxapine, Aptazapine Maleate, AZaloxan Tetracycline; Tetracycline Hydrochloride Tetracycline Phos Fumarate, AZepindole, AZipramine Hydrochloride; Bipen phate Complex; Tetroxoprim; Thiamphenicol; Thiphencillin amol Hydrochloride; Bupropion Hydrochloride; Butacetin; Potassium; Ticarcillin Cresyl Sodium; Ticarcillin Disodium; Butriptyline Hydrochloride; Caroxazone; Cartazolate; Ticarcillin Monosodium; Ticlatone; Tiodonium Chloride; Ciclazindol; Cidoxepin Hydrochloride; Cilobamine Mesy Tobramycin; Tobramycin Sulfate; Tosufloxacin; Trimetho late; Clodazon Hydrochloride; Clomipramine Hydrochlo prim; Trimethoprim Sulfate; Trisulfapyrimidines; Trolean ride; Cotinine Fumarate; Cyclindole; Cypenamine Hydro domycin; Trospectomycin Sulfate; Tyrothricin; Vancomy chloride; Cyprolidol Hydrochloride; Cyproximide; cin; Vancomycin Hydrochloride; Virginiamycin; Daledalin Tosylate; Dapoxetine Hydrochloride; Dazadrol Zorbamycin. Maleate; Dazepinil Hydrochloride; Desipramine Hydro chloride; Dexamisole; Deximafen; Dibenzepin Hydrochlo 0129. Anticholelithic: Monoctanoin. ride; Dioxadrol Hydrochloride; Dothiepin Hydrochloride; Doxepin Hydrochloride; Duloxetine Hydrochloride; Eclan 0130 Anticholelithogenic: Chenodiol; Ursodiol. amine Maleate; Encyprate; Etoperidone Hydrochloride; 0131) Anticholinergic: Alverinc Citrate; Anisotropine Fantridone Hydrochloride; Fenmetozole Hydrochloride; Methylbromide; Atropine; Atropine Oxide Hydrochloride; Fenmetramide; Fezolamine Fumarate; Fluotracen Hydro Atropine Sulfate; Belladonna; Benapryzine Hydrochloride; chloride; Fluoxetine; Fluoxetine Hydrochloride; Fluparoxan Benzetimide Hydrochloride; Benzilonium Bromide; Hydrochloride; Garnfexine; Guanoxyfen Sulfate; Imafen Biperiden; Biperiden Hydrochloride; Biperiden Lactate; Cli Hydrochloride; Imiloxan Hydrochloride; Irnipramine dinium Bromide; Cyclopentolate Hydrochloride; Dexetim Hydrochloride; Indeloxazine Hydrochloride; Intriptyline ide; Dicyclomine Hydrochloride; Dihexyverine Hydrochlo Hydrochloride; Iprindole; Isocarboxazid; Ketipramine ride; Domazoline Fumarate; Elantrine; Elucaine; Fumarate, Lofepramine Hydrochloride; Lortalamine; Ethybenztropine; Eucatropine Hydrochloride: Glycopyrro Maprotiline; Maprotiline Hydrochloride; Melitracen Hydro late; Heteronium Bromide; Homatropine Hydrobromide; chloride; Milacemide Hydrochloride; Minaprine Hydro Homatropine Methylbromide; Hyoscyamine; Hyoscyamine chloride; Mirtazapine; Moclobemide; Modaline Sulfate; US 2004/0106589 A1 Jun. 3, 2004

Napacitadine Hydrochloride; Napamezole Hydrochloride; 0144 Antifibrinolytic: Nafamostat Mesylate. Nefazodone Hydrochloride; Nisoxetine; Nitrafudam Hydro 0145 Antifungal: Acrisorcin; Ambruticin; Amphotericin chloride; Nomifensine Maleate; Nortriptyline Hydrochlo B; AZaconazole, AZaSerine; Basifungin; Bifonazole, Biphe ride; Octriptyline Phosphate; Opipramol Hydrochloride; namine Hydrochloride; Bispyrithione Magsulfex; Buto Oxaprotiline Hydrochloride; Oxypertine; Paroxetine; conazole Nitrate, Calcium Undecylenate, Candicidin; Car Phenelzine Sulfate; Pirandamine Hydrochloride; Pizotyline; bol-Fuchsin; Chlordantoin; Ciclopirox, Ciclopirox Olamine; Pridefine Hydrochloride; Prolintane Hydrochloride; Protrip Cillofungin; Cisconazole; Clotrimazole; Cuprimyxin; Deno tyline Hydrochloride; Quipazine Maleate; Rolicyprine; fungin; Dipyrithione; Doconazole; Econazole; Econazole Seproxetine Hydrochloride; Sertraline Hydrochloride; Nitrate; Enilconazole; Ethonam Nitrate; Fenticonazole Sibutramine Hydrochloride; Sulpiride; Suritozole; Tametra Nitrate; Filipin; Fluconazole; Flucytosine; Fungimycin; line Hydrochloride; Tampramine Fumarate; Tandamine Griseofulvin; Hamycin; ISOconazole, Itraconazole, Kalafun Hydrochloride; Thiazesim Hydrochloride; Thozalinone; gin; Ketoconazole, Lomofungin; Lydimycin; Mepartricin; Tomoxetine Hydrochloride; Trazodone Hydrochloride; Miconazole; Miconazole Nitrate; Monensin; Monensin Trebenzomine Hydrochloride; Trimipramine; Trimipramine Sodium; Naftifine Hydrochloride; Neomycin Undecylenate; Maleate; Venlafaxine Hydrochloride; Viloxazine Hydro Nifuratel; Nifurmerone; Nitralamine Hydrochloride; Nysta tin; Octanoic Acid, Orconazole Nitrate; Oxiconazole chloride; Zimeldine Hydrochloride; Zometapine. Nitrate; Oxifungin Hydrochloride; Parconazole Hydrochlo 0.136 Antidiabetic: Acetohexamide; Buformin; Butox ride; Partricin; Potassium Iodide; Proclonol; Pyrithione amine Hydrochloride; Camiglibose, Chlorpropamide; Cigli Zinc, Pyrrolnitrin; Rutanycin; Sanguinarium Chloride; tazone; Englitazone Sodium; Etoformin Hydrochloride; Saperconazole, Scopafungin; Selenium Sulfide, Sinefungin; Gliamilide; Glibornuride; Glicetanile Sodium; Gliflumide; Sulconazole Nitrate; Terbinafine; Terconazole; Thiram; Glipizide, Glucagon; Glyburide; Glyhexamide; Glymidine Ticlatone; Tioconazole; Tolciclate; Tolindate; Tolnaftate; Sodium; Glyoctamide, Glyparamide; Insulin; Insulin, Triacetin; Triafungin; Undecylenic Acid; Viridofulvin; Zinc Dalanated; Insulin Human; Insulin Human, Isophane; Insu Undecylenate; Zinoconazole Hydrochloride. lin Human Zinc, Insulin Human Zinc, Extended; Insulin, 0146 Antiglaucoma agent: Alprenoxime Hydrochloride; Isophane; Insulin Lispro, Insulin, Neutral; Insulin Zinc, Colforsin; Dapiprazole Hydrochloride; Dipivefrin Hydro Insulin Zinc, Extended; Insulin Zinc, Prompt; Linogliride; chloride; Naboctate Hydrochloride; Pilocarpine; Pimabine. Linogliride Fumarate; Metformin; Methyl Palmoxirate; Pal 0147 Antihemophilic: Antihemophilic Factor. moxirate Sodium; Pioglitazone Hydrochloride; Pirogliride Tartrate; Proinsulin Human; Seglitide Acetate; Tolazamide; 0148 Antihemorrhagic: Poliglusam. Tolbutamide; Tolpyrramide; TroglitaZone, Zopolrestat. 0149 Antihistaminic: Acrivastine; Antazoline Phos phate, Astemizole, AZatadine Maleate, Barmastine, Bromo 0.137 Antidiarrheal: Rolgamidine, Diphenoxylate hydro diphenhydramine Hydrochloride; Brompheniramine Male chloride (Lomotil), Metronidazole (Flagyl), Methylpred ate; Carbinoxamine Maleate; Cetirizine Hydrochloride; nisolone (Medrol), Sulfasalazine (AZulfidine). Chlorpheniramine Maleate; Chlorpheniramine Polistirex; Cinnarizine; Clemastine; Clemastine Fumarate; Closiramine 0138 Antidiuretic: Argipressin Tannate; Desmopressin Aceturate; Cycliramine Maleate, Cyclizine, Cyproheptadine Acetate, Lypressin. Hydrochloride; Dexbrompheniramine Maleate; Dexchlor 0139 Antidote: Dimercaprol; Edrophonium Chloride; pheniramine Maleate; Dimethindene Maleate; Diphenhy Fomepizole; LeucoVorin Calcium; Levoleucovorin Cal dramine Citrate; Diphenhydramine Hydrochloride; Doras cium; Methylene Blue; Protamine Sulfate. tine Hydrochloride; Doxylamine Succinate; Ebastine; Levocabastine Hydrochloride; Loratadine; Mianserin 0140 Antidyskinetic: Selegiline Hydrochloride. Hydrochloride; Noberastine; Orphenadrine Citrate; 0141 Anti-emetic: Alosetron Hydrochloride; Batano Pyrabrom; Pyrilamine Maleate; Pyroxamine Maleate; pride Hydrochloride; Bemesetron; Benzquinamide; Chlor Rocastine Hydrochloride; Rotoxamine; Tazifylline Hydro promazine; Chlorpromazine Hydrochloride; Clebopride; chloride: Temelastine; Terfenadine; Tripelennamine Citrate; Cyclizine Hydrochloride; Dimenhydrinate; Diphenidol; Tripelennamine Hydrochloride; Triprolidine Hydrochloride; Diphenidol Hydrochloride; Diphenidol Pamoate; Dolas Zolamine Hydrochloride etron Mesylate; Domperidone; Dronabinol; Fludorex; Flu 0150 Antihyperlipidemic: Cholestyramine Resin; Clofi meridone, Galdansetron Hydrochloride; Granisetron; Gran brate; Colestipol Hydrochloride; Crilvastatin; Dalvastatin; isetron Hydrochloride; Lurosetron Mesylate; Meclizine Dextrothyroxine Sodium; Fluvastatin Sodium; Gemfibrozil; Hydrochloride; Metoclopramide Hydrochloride; Metopi Lecimibide; Lovastatin; Niacin; Pravastatin Sodium; Probu mazine; Ondansetron Hydrochloride; Pancopride; Prochlo col; Simvastatin; Tiqueside; Xenbucin. rperazine, Prochlorperazine Edisylate; Prochlorperazine 0151. Antihyperlipoproteinemic: Acifran; Beloxamide; Maleate; Promethazine Hydrochloride; Thiethylperazine; Bezafibrate; Boxidine; Butoxamine Hydrochloride; Cetaben Thiethylperazine Malate; Thiethylperazine Maleate; Tri Sodium; Ciprofibrate; Gemcadiol; Halofenate; Lifibrate; methobenzamide Hydrochloride; Zacopride Hydrochloride. Meglutol; Nafenopin; Pimetine Hydrochloride; Theofibrate; 0142 Anti-epileptic: Felbamate; Loreclezole; Tolgabide. Tibric Acid, Treloxinate. 0152 Antihypertensive: Alflizosin Hydrochloride; Alipa 0143 Anti-estrogen: Clometherone; Delmadinone mide; Althiazide, Amiquinsin Hydrochloride, Amlodipine Acetate; Nafoxidine Hydrochloride; Nitromifene Citrate; BeSylate; Amlodipine Maleate; Anaritide Acetate; AtiproSin Raloxifene Hydrochloride; Tamoxifen Citrate; Toremifene Maleate; Belfosdil; Bemitradine; Bendacalol Mesylate; Citrate; Trioxifene Mesylate. Bendroflumethiazide; Benzthiazide, Betaxolol Hydrochlo US 2004/0106589 A1 Jun. 3, 2004

ride; Bethanidine Sulfate; Bevantolol Hydrochloride; Alcohol Mafenide Acetate; Meralein Sodium; Mercufenol Biclodil Hydrochloride; Bisoprolol; Bisoprolol Fumarate; Chloride; Mercury, Ammoniated; Methylbenzethonium Bucindolol Hydrochloride; Bupicomide; Buthiazide, Can Chloride; Nitrofurazone; Nitromersol; Octenidine Hydro doXatril; CandoXatrilat, Captopril; Carvedilol, Ceronapril; chloride; Oxychlorosene; Oxychlorosene Sodium; Parachlo Chlorothiazide Sodium; Cicletanine; CilaZapril; Clonidine; rophenol, Camphorated; Potassium Permanganate; Povi Clonidine Hydrochloride; Clopamide; Cyclopenthiazide; done-Iodine; Sepazonium Chloride; Silver Nitrate; Cyclothiazide; Darodipine; Debrisoquin Sulfate; Delapril Sulfadiazine, Silver; Symclosene; Thimerfonate Sodium; Hydrochloride; Diapamide; Diazoxide; Dilevalol Hydro Thimerosal: Troclosene Potassium. chloride; Diltiazem Malate; Ditekiren; Doxazosin Mesylate; Ecadotril, Enalapril Maleate, Enalaprilat, Enalkiren; 0156 Anti-inflammatory: Alclofenac; Alclometasone Endralazine MeSylate, Epithiazide, EproSartan; Eprosartan Dipropionate, AlgeStone Acetonide; Alpha Amylase; Mesylate; Fenoldopam Mesylate; Flavodilol Maleate; Flo Amcinafal, Amcinafide, Amfenac Sodium; Amiprilose rdipine, FloSequinan; Fosinopril Sodium; Fosinoprilat, Gua Hydrochloride; Anakinra, Anirolac, AnitraZafen; ApaZone; nabenz, Guanabenz. Acetate; Guanacline Sulfate; Guanadrel Balsalazide Disodium; Bendazac, Benoxaprofen; Benzy Sulfate; Guancydine; Guanethidine Monosulfate; Guanethi damine Hydrochloride; Bromelains; Broperamole; Budes dine Sulfate; Guanfacine Hydrochloride; Guanisoquin Sul onide; Carprofen, Cicloprofen; CintaZone; Cliprofen; Clo fate; Guanoclor Sulfate; Guanoctine Hydrochloride; Guan betasol Propionate; Clobetasone Butyrate; Clopirac, oXabenz, Guanoxan Sulfate; Guanoxyfen Sulfate; CloticasOne Propionate; Cormethasone Acetate; Cortodox Hydralazine Hydrochloride; Hydralazine Polistirex; one; Deflazacort, DeSonide; DeSoximetasone; Dexametha Hydroflumethiazide, Indacrinone; Indapamide; Indolapril Sone Dipropionate, Diclofenac Potassium; Diclofenac Hydrochloride; Indoramin; Indoramin Hydrochloride; Sodium; Diflorasone Diacetate; Diflumidone Sodium; Indorenate Hydrochloride, Lacidipine; Leniquinsin; Levcro Diflunisal; Difluprednate; Diftalone; Dimethyl Sulfoxide; makalim; Lisinopril, Lofexidine Hydrochloride; LOSartan Drocinonide; Endrysone; Enlimomab, Enolicam Sodium; Potassium; Losulazine Hydrochloride; Mebutamate; Epirizole; Etodolac, Etofenamate; Felbinac; Fenamole; Fen Mecamylamine Hydrochloride; Medroxalol; Medroxalol bufen, Fenclofenac, Fenclorac, Fendosal, Fenpipalone, Fen Hydrochloride; Methalthiazide; Methyclothiazide; Methyl tiazac, Flazalone, Fluazacort, Flufenamic Acid, Flumizole; dopa; Methyldopate Hydrochloride; Metipranolol; Metola Flunisolide Acetate; Flumixin; Flunixin Meglumine; Fluo Zone; Metoprolol Fumarate; Metoprolol Succinate; Mety cortin Butyl; Fluorometholone Acetate; FluguaZone; Flurbi rosine; Minoxidil; Monatepil Maleate; Muzolimine; profen; Fluretofen; Fluticasone Propionate; Furaprofen; Nebivolol; Nitrendipine; Oformine; Pargyline Hydrochlo Furobufen; Halcinonide; Halobetasol Propionate; Halopre ride; Pazoxide; Pelanserin Hydrochloride; Perindopril Erbu done Acetate, Ibufenac, Ibuprofen; Ibuprofen Aluminum; mine; Phenoxybenzamine Hydrochloride; Pinacidil; Pivo Ibuprofen Piconol; Ilonidap; Indomethacin; Indomethacin pril; Polythiazide; Prazosin Hydrochloride; Primidolol; Sodium; Indoprofen; Indoxole; Intrazole; Isoflupredone Prizidilol Hydrochloride; Quinapril Hydrochloride; Quinap Acetate; ISOXepac, ISOXicam, Ketoprofen, Lofemizole rilat; Quinazosin Hydrochloride; Quinelorane Hydrochlo Hydrochloride, Lomoxicam, Loteprednol Etabonate; ride; Quinpirole Hydrochloride; Quinuclium Bromide; Meclofenamate Sodium; Meclofenamic Acid, Meclorisone Ramipril; Rauwolfia Serpentina; Reserpine, Saprisartan Dibutyrate; Mefenamic Acid; Mesalamine; Meseclazone; Potassium; Saralasin Acetate; Sodium Nitroprusside; Sulfi Methylprednisolone Suleptanate; Morniflumate; Nabume malol Hydrochloride; Tasosartan; Teludipine Hydrochloride; tone; Naproxen; Naproxen Sodium; Naproxol; Nimazone; Temocapril Hydrochloride; Terazosin Hydrochloride; Terla Olsalazine Sodium; Orgotein; Orpanoxin; Oxaprozin, kiren; Tiamenidine; Tiamenidine Hydrochloride; Tic Oxyphenbutazone; Paranyline Hydrochloride; Pentosan rynafen; Tinabinol; Tiodazosin; Tipentosin Hydrochloride; Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pir Trichlormethiazide; Trimazosin Hydrochloride; Tri fenidone; PiroXicam, Piroxicam Cinnamate; PiroXicarn Ola methaphan Camsylate; Trimoxamine Hydrochloride; Tripa mine; Pirprofen; Prednazate; Prifelone; Prodolic Acid; Pro mide; Xipamide; Zankiren Hydrochloride; Zofenoprilat quaZone; Proxazole; Proxazole Citrate; RimeXolone; Arginine. Romazarit; Salcolex, Salnacedin, Salsalate, Sanguinarium Chloride; SeclaZone, Sermetacin; Sudoxicam, Sulindac, 0153 Antihypotensive: Ciclafrine Hydrochloride; Mido Suprofen; Talmetacin; Talniflumate; Talosalate; Tebufelone; drine Hydrochloride. Tenidap; Tenidap Sodium, Tenoxicam, TeSicam, Tesimide; 0154 Anti-infective: Difloxacin Hydrochloride. Lauryl Tetrydamine; Tiopinac Tixocortol Pivalate; Tolimetin; Tol Isoquinolinium Bromide; Moxalactam Disodium; Omida metin Sodium; Triclonide; Triflumidate; Zidometacin; zole; Pentisomicin; Sarafloxacin Hydrochloride; Protease Zomepirac Sodium. inhibitors of HIV and other retroviruses; Integrase Inhibitors O157 Antikeratinizing agent: Doretinel; Linarotene; Pel of HIV and other retroviruses; Cefaclor (Ceclor); Acyclovir retin. (Zovirax); Norfloxacin (Noroxin); Cefoxitin (Mefoxin); Cefuroxime axetil (Ceftin); Ciprofloxacin (Cipro). 0158 Antimalarial: Acedapsone; Amodiaquine Hydro chloride; Amquinate; Arteflene; Chloroquine; Chloroquine O155 Anti-infective, topical: Alcohol; Aminacrine Hydrochloride; Chloroquine Phosphate; Cycloguanil Pamo Hydrochloride; Benzethonium Chloride; Bithionolate ate, Enpiroline Phosphate; Halofantrine Hydrochloride; Sodium; Bromchlorenone; Carbamide Peroxide; Cetalko Hydroxychloroquine Sulfate; Mefloquine Hydrochloride; nium Chloride; Cetylpyridinium Chloride: Chlorhexidine Menoctone; Mirincamycin Hydrochloride; Primacquine Hydrochloride; Clioquinol; Domiphen Bromide; Fenticlor; Phosphate; Pyrimethamine; Quinine Sulfate; Tebuduine. Fludazonium Chloride; Fuchsin, Basic; Furazolidone; Gen tian Violet; Halquinols; Hexachlorophene: Hydrogen Per 0159 Antimicrobial: Aztreonam; Chlorhexidine Glucon oxide, Ichthammol, Imidecyl Iodine, Iodine, Isopropyl ate, Imidurea; Lycetamine, Nibroxane, PiraZmonam US 2004/0106589 A1 Jun. 3, 2004

Sodium; Propionic Acid; Pyrithione Sodium; Sanguinarium Triciribine Phosphate; Trimetrexate; Trimetrexate Glucur Chloride; Tigemonam Dicholine. onate; Triptorelin; Tubulozole Hydrochloride; Uracil Mus tard; Uredepa; Vapreotide; Verteporfin; Vinblastine Sulfate; 0160 Antimigraine: Dolasetron Mesylate; Naratriptan Vincristine Sulfate; Vindesine; Vindesine Sulfate; Vinepi Hydrochloride; Sergolexole Maleate; Sumatriptan Succi dine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; nate, Zatosetron Maleate. Vinorelbine Tartrate; Vinrosidine Sulfate; Vinzolidine Sul 0161) Antimitotic: Podofilox. fate; Vorozole; Zeniplatin; Zinostatin; Zorubicin Hydrochlo 0162 Antimycotic: Amorolfine. ride. 0.165 Other anti-neoplastic compounds include: 20-epi 0163 Antinauseant: Buclizine Hydrochloride; Cyclizine 1.25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; Lactate; Naboctate Hydrochloride aclarubicin; acylfulvene, adecypenol; adoZelesin; aldesleu 0164 Antineoplastic: Acivicin; Aclarubicin; Acodazole kin; ALL-TK antagonists, altretamine; ambamuStine; ami Hydrochloride, Acronine, Adozelesin; Aldesleukin; Altre doX, amifostine; aminolevulinic acid; amrubicin; amsacrine; tamine; Ambomycin; Ametantrone Acetate; Aminoglute anagrelide; anastroZole; andrographolide, angiogenesis thimide, AmSacrine; Anastrozole, Anthramycin; Asparagi inhibitors, antagonist D; antagonist G, antarelix; anti-dor nase; ASperlin, AZacitidine, AZetepa, AZotomycin; Salizing morphogenetic protein-1, antiandrogen, prostatic Batimastat; Benzodepa; Bicalutamide; Bisantrene Hydro carcinoma, antiestrogen; antineoplaston; antisense oligo chloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sul nucleotides, aphidicolin glycinate, apoptosis gene modula fate, Brequinar Sodium; Bropirimine; BuSulfan; Cactinomy tors, apoptosis regulators, apurinic acid, ara-CDP-DL cin, Calusterone; Caracemide, Carbetimer; Carboplatin; PTBA, arginine deaminase, asulacrine, atameStane; Carmustine; Carubicin Hydrochloride; Carzelesin; Cedefin atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; aza gol; Chlorambucil; Cirolemycin; Cisplatin; Cladribine; Cri Setron; azatoxin; azatyrosine, baccatin III derivatives, bal Snatol MeSylate; Cyclophosphamide, Cytarabine; Dacarba anol; batimastat, BCR/ABL antagonists, benzochlorins, zine; Dactinomycin; Daunorubicin Hydrochloride; benzoylstauroSporine; beta lactam derivatives, beta Decitabine, Dexormaplatin, DeZaguanine, DeZaguanine alethine; betaclamycin B; betulinic acid; bFGF inhibitor; Mesylate; Diaziquone; Docetaxel; Doxorubicin; Doxorubi bicalutamide, bisantrene; bisaziridinylspermine; bisnafide; cin Hydrochloride; Droloxifene; Droloxifene Citrate; Dro bistratene A, bizelesin; breflate; bropirimine; budotitane; moStanolone Propionate, DuaZomycin; Edatrexate, Eflorni buthionine Sulfoximine, calcipotriol, calphostin C; camp thine Hydrochloride; Elsamitrucin; Enloplatin, Enpromate; tothecin derivatives, canarypox IL-2, capecitabine, carboxa Epipropidine; Epirubicin Hydrochloride; Erbulozole; ESO mide-amino-triazole; carboxyamidotriazole; CaRest M3; rubicin Hydrochloride; Estramustine; Estramustine Phos CARN 700; cartilage derived inhibitor; carzelesin; casein phate Sodium; Etanidazole; Ethiodized Oil I 131; Etoposide; kinase inhibitors (ICOS), castanospernine; cecropin B; Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; cetrorelix; chlorins, chloroquinoxaline Sulfonamide, cica Fazarabine, Fenretinide; Floxuridine, Fludarabine Phos prost, cis-porphyrin, cladribine; clomifene analogues, clot phate, Fluorouracil; Flurocitabine; FoSquidone; Fostriecin rimazole; collismycin A, collismycin B, combretastatin A4, Sodium; Gemcitabine; Gemcitabine Hydrochloride; Gold combretastatin analogue, conagenin, crambescidin 816; cri Au 198; Hydroxyurea; Idarubicin Hydrochloride; Ifosfa Snatol; cryptophycin 8; cryptophycin A derivatives, curacin mide; Ilmofosine; Interferon Alfa-2a, Interferon Alfa-2b; A., cyclopentanthraquinones, cycloplatam, cypemycin; cyt Interferon Alfa-n1; Interferon Alfa-n3; Interferon Beta-I a, arabine ocfoSfate; cytolytic factor; cytostatin, dacliximab, Interferon Gamma-Ib, Iproplatin; Irinotecan Hydrochloride; decitabine; dehydrodidemnin B; deslorelin; dexifosfamide; Lanreotide Acetate; Letrozole; Leuprolide Acetate; Liaro deXraZOxane, deXVerapamil, diaziquone; didemnin B; didox; Zole Hydrochloride; Lometrexol Sodium; Lomustine; diethylnorspermine, dihydro-5-aZacytidine, dihydrotaXol, Losoxantrone Hydrochloride; Masoprocol; Maytansine; 9-, dioxamycin; diphenyl Spiromustine, docosanol; dolas Mechlorethamine Hydrochloride; Megestrol Acetate; etron, doxifluridine, droloxifene, dronabinol; duocarmycin Melengestrol Acetate; Melphalan, Menogaril; Mercaptopu SA, ebSelen; ecomustine, edelfosine; edrecolomab, eflorni rine; Methotrexate; Methotrexate Sodium; Metoprine; thine; elemene; emitefur, epirubicin, epristeride, estramus Meturedepa; Mitindomide; Mitocarcin; Mitocromin; tine analogue, estrogen agonists, estrogen antagonists; Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; etanidazole, etoposide phosphate; exemestane, fadrozole; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocoda fazarabine; fenretinide; filgrastim; finasteride, flavopiridol; Zole; Nogalamycin; Ormaplatin; OXisuran; Paclitaxel, fleZelastine, fluiasterone, fludarabine; fluorodaunorunicin Pegaspargase, Peliomycin; Pentamustine, Peplomycin Sul hydrochloride; forfenimex, formeStane; fostriecin, fotemus fate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone tine, gadolinium teXaphyrin, gallium nitrate; galocitabine; Hydrochloride; Plicamycin; Plomestane; Porfimer Sodium; ganirelix; gelatinase inhibitors, gemcitabine; glutathione Porfiromycin; Prednimustine; Procarbazine Hydrochloride; inhibitors, hepSulfam; heregulin; hexamethylene bisaceta Puromycin; Puromycin Hydrochloride; Pyrazofurin; Ribo mide; hypericin; ibandronic acid; idarubicin; idoxifene, prine, Rogletimide, Safingol, Safingol Hydrochloride; idramantone, ilmofoSine, illomastat; imidazoacridones, imi Semustine; SimtraZene, Sparfosate Sodium, SparSomycin; quimod, immunostimulant peptides; insulin-like growth fac Spirogermanium Hydrochloride, Spiromustine, Spiroplatin; tor-1 receptor inhibitor; interferon agonists, interferons, Streptonigrin; Streptozocin; Strontium Chloride Sr 89; interleukins, iobenguane; iododoxorubicin; ipomeanol, 4-, Sulofenur; Talisomycin; Taxane, Taxoid; Tecogalan irinotecan; iroplact, irSogladine, isobengaZole, isohomohali Sodium; Tegafur, Teloxantrone Hydrochloride; Temoporfin; condrin B; itasetron, jasplakinolide; kahalalide F, lamel TenipoSide; Teroxirone; Testolactone; Thiamiprine; larin-N triacetate, lanreotide; leinamycin; lenograstim; len Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; Topote tinan Sulfate; leptolstatin; letrozole; leukemia inhibiting can Hydrochloride; Toremifene Citrate; Trestolone Acetate; factor; leukocyte alpha interferQn; leuprolide--estrogen US 2004/0106589 A1 Jun. 3, 2004 progesterone; leuprorelin; levamisole; liarozole; linear rin; tirapazamine, titanocene dichloride; topotecan; topSen polyamine analogue, lipophilic disaccharide peptide, lip tin, toremifene, totipotent Stem cell factor; translation ophilic platinum compounds, lisSoclinamide 7; lobaplatin; inhibitors, tretinoin, triacetyluridine, triciribine, trimetrex lombricine, lometrexol; lonidamine; loSOXantrone; lovasta ate, triptorelin; tropisetron; turosteride; tyrosine kinase tin, loxoribine; lurtotecan; lutetium teXaphyrin, lySofylline; inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogeni lytic peptides, maitansine; mannostatin A, marimastat; tal Sinus-derived growth inhibitory factor; urokinase recep masoprocol; maspin; matrilysin inhibitors, matrix metallo tor antagonists, vapreotide; variolin B; vector System, eryth proteinase inhibitors, menogaril; merbarone; meterelin; rocyte gene therapy; VelareSol, Veramine; Verdins, methioninase; metoclopramide; MIF inhibitor; mifepris verteporfin, Vinorelbine; VinXaltine, Vitaxin; Vorozole; Zan tone; miltefosine, mirimoStim, mismatched double Stranded oterone; Zeniplatin, Zilascorb, Zinostatin stimalamer. RNA, mitoguaZone, mitolactol, mitomycin analogues, 0166 Anti-cancer Supplementary Potentiating Agents: mitonafide, mitotoxin fibroblast growth factor-Saporin; Tricyclic anti-depressant drugs (e.g., imipramine, mitoxantrone; mofaroteine; molgramoStim; monoclonal anti desipramine, amitryptyline, clomipramine, trimipramine, body, human chorionic gonadotrophin, monophosphoryl doxepin, nortriptyline, protriptyline, amoxapine and mapro lipid A+myobacterium cell wall Sk, mopidamol, multiple tiline); non-tricyclic anti-depressant drugs (e.g., Sertraline, drug resistance gene inhibitor, multiple tumor Suppressor trazodone and citalopram); Ca" antagonists (e.g., Vera 1-based therapy; mustard anticancer agent; my caperoxide B; pamil, nifedipine, nitrendipine and caroverine); Calmodulin mycobacterial cell wall extract; myriaporone, N-acetyldina inhibitors (e.g., prenylamine, trifluoroperazine and clomi line, N-Substituted benzamides, nafarelin, nagreStip; nalox pramine); Amphotericin B; Triparanol analogues (e.g., one-pentazocine, napavin, naphterpin, nartograstim; neda tamoxifen); antiarrhythmic drugs (e.g., quinidine); antihy platin, nemorubicin; neridronic acid; neutral endopeptidase; pertensive drugs (e.g., reserpine); Thiol depleters (e.g., nilutamide, nisarmycin; nitric oxide modulators, nitroxide buthionine and sulfoximine) and Multiple Drug Resistance antioxidant, nitrullyn, O6-benzylguanine; Octreotide, oki reducing agents Such as Cremaphor EL. The compounds of cenone, oligonucleotides; Onapristone; ondansetron; the invention also can be administered with cytokines Such Ondansetron; oracin, oral cytokine inducer; Ormaplatin; as granulocyte colony Stimulating factor. OSaterone, Oxaliplatin; OXaunomycin, paclitaxel analogues, paclitaxel derivatives, palauamine, palmitoylrhizoxin; pam 0.167 Antineutropenic: Filgrastim; Lenograstim; Mol idronic acid, panaxytriol; panomifene, parabactin; paZellip gramoStim; RegramoStim; SargramoStim. tine, pegaspargase; peldesine; pentosan polysulfate Sodium; 0168 Antiobsessional agent: Fluvoxamine Maleate. pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase 0169. Antiparasitic: Abamectin; Clorsulon; Ivennectin. inhibitors, picibanil; pilocarpine hydrochloride, pirarubicin; 0170 Antiparkinsonian: Benztropine Mesylate; piritrexim; placetin A; placetin B; plasminogen activator Biperiden; Biperiden Hydrochloride; Biperiden Lactate; inhibitor, platinum complex, platinum compounds, plati Carmantadine, Ciladopa Hydrochloride; Dopamantine; num-triamine complex, porfimer Sodium; porfiromycin; pro Ethopropazine Hydrochloride; LaZabemide; Levodopa, pyl bis-acridone; prostaglandin J2, proteasome inhibitors, Lometraline Hydrochloride; Mofegiline Hydrochloride; protein A-based immune modulator, protein kinase C inhibi Naxagolide Hydrochloride; Pareptide Sulfate; Procyclidine tor, protein kinase C inhibitors, microalgal; protein tyrosine Hydrochloride; Quinelorane Hydrochloride; Ropinirole phosphatase inhibitors, purine nucleoside phosphorylase Hydrochloride; Selegiline Hydrochloride; Tolcapone; Tri inhibitors, purpurins, pyrazoloacridine, pyridoxylated hexyphenidyl Hydrochloride. hemoglobin polyoxyethylene conjugate, raf antagonists, raltitrexed; ramosetron; ras farnesyl protein transferase 0171 Antiperistaltic: Difenoximide Hydrochloride; inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine Difenoxin; Diphenoxylate Hydrochloride; Fluperamide; demethylated; rhenium Re 186 etidronate; rhizoxin; Lidamidine Hydrochloride; Loperamide Hydrochloride; ribozymes, RII retinamide, rogletimide; rohitukine; Malethamer; Nufenoxole; Paregoric. romurtide, roquinimex, rubiginone B1, rubOXyl; Safingol; 0172 Antipneumocystic: Atovaquone. Saintopin; SarCNU; Sarcophytol A, SargramoStim; Sidi 1. mimetics, Semustine, Senescence derived inhibitor 1; Sense 0173 Antiproliferative agent: Piritrexim Isethionate. oligonucleotides, Signal transduction inhibitors, Signal trans 0.174 Antiprostatic hypertrophy: Sitogluside. duction modulators, Single chain antigen binding protein; sizofiran; Sobu ZOxane, Sodium borocaptate, Sodium pheny 0.175 Antiprotozoal: Amodiacquine; Azanidazole; Bami lacetate, Solverol, Somatomedin binding protein; Sonermin; dazole; Camidazole; Chlortetracycline Bisulfate; Chlortet Sparfosic acid; Spicamycin D; Spiromustine; Splenopentin; racycline Hydrochloride: Flubendazole; Flunidazole; Spongistatin 1; Squalamine; Stem cell inhibitor, Stem-cell Halofuginone Hydrobromide; Imidocarb Hydrochloride; division inhibitors; stipiamide; stromelysin inhibitors; sulfi Ipronidazole; Metronidazole; Misonidazole; Moxinidazole; nosine; Superactive vasoactive intestinal peptide antagonist; NitarSone; Partricin; Puromycin; Puromycin Hydrochloride; Suradista; Suramin; Swainsonine, Synthetic glycosaminogly Ronidazole; Sulnidazole; Tinidazole. cans, tallimustine, tamoxifen methiodide, tauromustine; taZ arotene, tecogalan Sodium, tegafur, tellurapyrylium; telom 0176 Antipruritic: Cyproheptadine Hydrochloride Meth erase inhibitors, temoporfin, temozolomide; teniposide; dilazine; Methdilazine Hydrochloride; Trimeprazine Tar tetrachlorodecaoxide, tetraZomine; thaliblastine; thalido trate. mide; thiocoraline; thrombopoietin; thrombopoietin 0177 Antipsoriatic: Acitretin; Anthralin; Azaribine; Cal mimetic; thymalfasin; thymopoietin receptor agonist, thy cipotriene; Cycloheximide, EnaZadrem Phosphate, Etreti motrinan; thyroid Stimulating hormone, tin ethyl etiopurpu nate, Liarozole Fumarate, Lonapalene, Tepoxalin. US 2004/0106589 A1 Jun. 3, 2004 20

0.178 Antipsychotic: Acetophenazine Maleate; Alente tiquimide, Lansoprazole, LaVoltidine Succinate, MisoproS mol Hydrobromide; Alpertine; Azaperone; Batelapine Male tol; Nizatidine; Nolinium Bromide; Pantoprazole; Pifamine; ate; Benperidol; BenZindopyrine Hydrochloride; Brofoxine; Pirenzepine Hydrochloride; Rabeprazole Sodium; Remi Bromperidol; Bromperidol Decanoate; Butaclamol Hydro prostol; Roxatidine Acetate Hydrochloride; Sucralfate; chloride; Butaperazine; Butaperazine Maleate; Carphena Sucrosofate Potassium; Tolimidone. zine Maleate; Carvotroline Hydrochloride; Chlorpromazine; Chlorpromazine Hydrochloride; Chlorprothixene; Cin 0187 Anti-urolithic: Cysteamine; Cysteamine Hydro perene, Cintriamide, Clomacran Phosphate, Clopenthixol; chloride; Tricitrates Clopimozide; Clopipazan Mesylate; Cloroperone Hydro 0188 Antiviral: Acemannan; Acyclovir; Acyclovir chloride; Clothiapine; Clothixamide Maleate; Clozapine; Sodium; Adefovir; Alovudine; Alvircept Sudotox; Amanta Cyclophenazine Hydrochloride; Droperidol; Etazolate dine Hydrochloride; Aranotin; Arildone; Atevirdine Mesy Hydrochloride; Fenimide; Flucindole; Flumezapine; late; Avridine, Cidofovir; Cipamfylline; Cytarabine Hydro Fluphenazine Decanoate, Fluphenazine Enanthate; chloride; Delavirdine Mesylate; Desciclovir; Didanosine; Fluphenazine Hydrochloride; Fluspiperone; Fluspirilene; Disoxaril; Edoxudine; Enviradene; Enviroxime; Famciclo Flutroline; Gevotroline Hydrochloride; Halopemide; Halo vir; Famotine Hydrochloride; Fiacitabine; Fialuridine; Fosa peridol; Haloperidol Decanoate, Iloperidone, Imidoline rilate; Foscamet Sodium; Fosfonet Sodium; Ganciclovir, Hydrochloride; Lenperone, Mazapertine Succinate; Ganciclovir Sodium; Idoxuridine; Kethoxal; Lamivudine; Mesoridazine; Mesoridazine Besylate; Metiapine; Milenper Lobucavir; Memotine Hydrochloride; Methisazone; Nevi one; Milipertine; Molindone Hydrochloride; Naranol rapine; Penciclovir; Pirodavir; Ribavirin; Rimantadine Hydrochloride; Neflumozide Hydrochloride; Ocaperidone; Hydrochloride; Saquinavir Mesylate; Somantadine Hydro Olanzapine; Oxiperomide; Penfluridol; Pentiapine Maleate; chloride; Sorivudine; Statolon; Stavudine; Tilorone Hydro Perphenazine; Pimozide; Pinoxepin Hydrochloride; Pipam chloride; Trifluridine; Valacyclovir Hydrochloride; Vidara perone, Piperacetazine, Pipotiazine Palmitate; Piquindone bine; Vidarabine Phosphate; Vidarabine Sodium Phosphate; Hydrochloride; Prochlorperazine Edisylate; Prochlorpera Viroxime; Zalcitabine; Zidovudine; ZinviroXime. zine Maleate; Promazine Hydrochloride; Remoxipride; Remoxipride Hydrochloride; Rimcazole Hydrochloride; 0189 Appetite suppressant: Dexfenfluramine Hydro Seperidol Hydrochloride; Sertindole; Setoperone; Spiper chloride; Phendimetrazine Tartrate; Phentermine Hydro one; Thioridazine; Thioridazine Hydrochloride; Thiothix chloride. ene; Thiothixene Hydrochloride; Tioperidone Hydrochlo 0.190 Benign prostatic hyperplasia therapy agent: Tam ride; TioSpirone Hydrochloride; Trifluoperazine Sulosin Hydrochloride. Hydrochloride; Trifluperidol; Triflu promazine; Triflupro 0191 Blood glucose regulators: Human insulin; Gluca mazine Hydrochloride; Ziprasidone Hydrochloride. gon; TolaZamide, Tolbutamide, Chloropropamide; Aceto 0179 Antirheumatic: Auranofin; Aurothioglucose; Bin hexamide and Glipizide. darit; Lobenzarit Sodium; Phenylbutazone; Pirazolac, Pri 0.192 Bone resorption inhibitor: Alendronate Sodium; nomide Tromethamine; Seprilose. Etidronate Disodium; Pamidronate Disodium. 0180 Antischistosomal: Becanthone Hydrochloride; 0193 Bronchodilator: Albuterol; Albuterol Sulfate; Aza Hycanthone; Lucanthone Hydrochloride; Niridazole; nator Maleate; Bamifylline Hydrochloride; Bitolterol Mesy Oxarnniquine; Pararosaniline Pamoate; Teroxalene Hydro late; Butaprost; Carbuterol Hydrochloride; Clorprenaline chloride. Hydrochloride; Colterol Mesylate; Doxaprost; Doxofylline; 0181 Antiseborrheic: Chloroxime; Piroctone; Piroctone Dyphylline; Enprofylline; Ephedrine; Ephedrine Hydro Olamine; Resorcinol Monoacetate. chloride; Fenoterol; Fenprinast Hydrochloride; Guaithyl line; Hexoprenaline Sulfate; Hoquizil Hydrochloride; Ipra 0182 Antisecretory: Arbaprostil; Deprostil; Fenoctimine tropium Bromide; Isoetharine; Isoetharine Hydrochloride; Sulfate; Octreotide; Octreotide Acetate; Omeprazole Isoetharine Mesylate; Isoproterenol Hydrochloride; Isopro Sodium; Rioprostil; Trimoprostil. terenol Sulfate; Metaproterenol Polistirex, Metaproterenol 0183 Antispasmodic: Stilonium Iodide; Tizanidine Sulfate; Nisbuterol Mesylate Oxtriphylline; Picumeterol Hydrochloride. Fumarate; Piquizil Hydrochloride; Pirbuterol Acetate; Pir buterol Hydrochloride; Procaterol Hydrochloride; Pseu 0184 Antithrombotic: Anagrelide Hydrochloride; Biva doephedrine Sulfate; QuaZodine; Quinterenol Sulfate; lirudin; Dalteparin Sodium; Danaparoid Sodium; Dazoxiben Racepinephrine, Racepinephrine Hydrochloride; Reproterol Hydrochloride; Efegatran Sulfate; Enoxaparin Sodium; Hydrochloride; Rimiterol Hydrobromide; Salmeterol; Sal Ifetroban; Ifetroban Sodium; Tinzaparin Sodium; meterol Xinafoate; Soterenol Hydrochloride; Sulfonterol Trifenagrel. Hydrochloride; Suloxifen Oxalate; Terbutaline Sulfate; 0185 Antitussive: Benzonatate; Butamirate Citrate; Theophylline; Xanoxate Sodium; Zindotrine; Zinterol Chlophedianol Hydrochloride; Codeine Polistirex; Hydrochloride. Codoxime; Dextromethorphan; Dextromethorphan Hydro 0194 Carbonic anhydrase inhibitor: Acetazolamide; bromide; Dextromethorphan Polistirex, Ethyl Dibunate; Acetazolamide Sodium; Dichlorphenamide; Dorzolamide Guaiapate; Hydrocodone Bitartrate; Hydrocodone Polis Hydrochloride; Methazolamide; Sezolamide Hydrochloride. tireX; Levopropoxyphene Napsylate, NoScapine, Pemerid 0.195 Cardiac depressant: Acecainide Hydrochloride; Nitrate; Pipazethate; Suxemerid Sulfate. Acetylcholine Chloride; Actisomide, Adenosine; Amio 0186 Anti-ulcerative: Aceglutamide Aluminum; Cadex darone; Aprindine, Aprindine Hydrochloride; Artilide omer Iodine; Cetraxate Hydrochloride; Enisoprost; Iso Fumarate; Azimilide Dihydrochloride; Bidisomide; Bucain US 2004/0106589 A1 Jun. 3, 2004

ide Maleate; Bucromarone; Butoprozine Hydrochloride; phonium Chloride; Ethiodized Oil, Etifenin; Exametazime; Capobenate Sodium; Capobenic Acid; Cifenline; Cifernline Ferristenc; Ferumoxides; FerumoxSil; Fluorescein; Fluores Succinate; Clofilium Phosphate; Disobutamide; Disopyra cein Sodium, Gadobenate Dimeglumine, Gadoteridol; mide; Disopyramide Phosphate; Dofetilide; Drobuline; Edi Gadodiamide, Gadopentetate Dimeglumine, Gadoverseta folone Acetate; Emilium Tosylate; Encainide Hydrochlo mide; Histoplasmin, Impromidine Hydrochloride, Indig ride; Flecainide Acetate; Ibutilide Fumarate; Indecainide otindisulfonate Sodium; Indocyanine Green, Iobenguane Hydrochloride; Ipazilide Fumarate; Lorajmine Hydrochlo Sulfate I 123; Iobenzamic Acid; Iocarmate Meglumine; ride; Lorcainide Hydrochloride; Meobentine Sulfate; Mexi Iocarmic Acid, Iocetamic Acid, Iodamide, Iodamide letine Hydrochloride; Modecainide; Moricizine; Oxiramide; Megilumine, Iodipamide Meglumine, Iodixanol, Iodoxamate Pirmenol Hydrochloride; Pirolazamide; Pranolium Chlo Meglumine, Iodoxamic Acid, Ioglicic Acid, Ioglucol, Ioglu ride; Procainamide Hydrochloride; Propafenone Hydrochlo comide, Ioglycamic Acid, Iogulamide, Iohexol; Iomeprol; ride; Pyrinoline; Quindonium Bromide; Quinidine Glucon Iopamidol, Iopanoic Acid, Iopentol; Iophendylate; I profe ate; Quinidine Sulfate; Recainam Hydrochloride; Recainam nin, Iopronic Acid, Ioprocemic Acid, Iopydol, Iopy done; Tosylate; Risotilide Hydrochloride; Ropitoin Hydrochlo Iosefamic Acid, IoSeric Acid, IoSulamide Meglumine, IoSu ride; Sematilide Hydrochloride; Suricainide Maleate; metic Acid; Iotasul; Iotetric Acid; Iothalamate Meglumine; Tocainide; Tocainide Hydrochloride; Transcainide. Iothalamate Sodium; Iothalamic Acid; Iotrolan; Iotroxic Acid, IoverSol; Ioxaglate Meglumine, Ioxagiate Sodium; 0196) Cardioprotectant: Dexrazoxane; Draflazine. Ioxaglic Acid, Ioxilan, Ioxotrizoic Acid, Ipodate Calcium; 0.197 Cardiotonic: Actodigin; Amrinone; Bemoradan; Ipodate Sodium; ISOSulfan Blue; Leukocyte Typing Serum; Butopamine; Carbazeran; CarSatrin Succinate, Deslanoside; Lidofenin; Mebrofenin; Meglumine; Metrizamide; Metri Digitalis, Digitoxin; Digoxin; Dobutamine; Dobutamine Zoate Sodium; Metyrapone; Metyrapone Tartrate; Mumps Hydrochloride; Dobutamine Lactobionate; Dobutamine Tar Skin Test Antigen; Pentetic Acid; Propyliodone; Quinaldine trate; Enoximone, ImaZodan Hydrochloride; Indolidan; Iso Blue, Schick Test Control; Sermorelin Acetate; Sodium mazole Hydrochloride; Levdobutamine Lactobionate; Lix Iodide 1123; Sprodiamide; Stannous Pyrophosphate; Stan azinone Sulfate; Medorinone; Milrinone; Pelrinone nous Sulfur Colloid; Succimer; Teriparatide Acetate; Tetro Hydrochloride; Pimobendan; Piroximone; Prinoxodan; fosmin; Tolbutamide Sodium; Tuberculin; Tyropanoate Proscillaridin; Quazinone; Tazolol Hydrochloride; Sodium; Xylose. Vesnarinone. 0208 Diuretic: Ambuphylline; Ambuside; Amiloride 0198 Cardiovascular agent: Dopexamine; Dopexamine Hydrochloride; Azolimine; Azosemide; Brocrinat; Bumet Hydrochloride. anide; Chlorothiazide, Chlorthalidone; Clazolimine; Clor eXolone; Ethacrynate Sodium; Ethacrynic Acid, EtoZolin; 0199 Choleretic: Dehydrocholic Acid; Fencibutirol; Fenguizone; Furosemide; Hydrochlorothiazide; Isosorbide; Hymecromone; Piprozolin; Sincalide; Tocamphyl. Mannitol; Mefruside; Ozolinone; Piretanide; Spiroxasone; 0200 Cholinergic: Aceclidine; Bethanechol Chloride; Torsemide; Triamterene; Triflocin, Urea. Carbachol; Demecarium Bromide; Dexpanthenol; Dopaminergic agent: Ibopamine. Echothiophate Iodide; Isoflurophate; Methacholine Chlo 0209) ride; Neostigmine Bromide; Neostigmine Methylsulfate; 0210) Ectoparasiticide: Nifluridide; Permethrin. PhySoStigmine, PhySoStigmine Salicylate; PhySOStigmine Sulfate; Pilocarpine; Pilocarpine Hydrochloride; Pilocarpine 0211 Emetic: Apomorphine Hydrochloride. Nitrate; Pyridostigmine Bromide. 0212 Enzyme inhibitor: Acetohydroxamic Acid; Alresta tin Sodium; Aprotinin; Benazepril Hydrochloride; Benazep 0201 Cholinergic agonist: Xanomeline; Xanomeline Tar rilat; Benurestat; Bromocriptine; Bromocriptine Mesylate; trate. Cilastatin Sodium; Flurofamide, Lergotrile; Lergotrile 0202 Cholinesterase Deactivator: Obidoxime Chloride; Mesylate; Levcycloserine; Libenzapril; Pentopril; Pepstatin; Pralidoxime Chloride; Pralidoxime Iodide, Pralidoxime Perindopril; Polignate Sodium; Sodium Amylosulfate; Sor Mesylate. binil; Spirapril Hydrochloride; Spiraprilat; Taleranol; Tepro tide; Tolfamide; Zofenopril Calcium. 0203 Coccidiostat: Arprinocid; Narasin; Semduramicin; Semduramicin Sodium. 0213 Estrogen: Chlorotrianisene; Dienestrol; Diethyl stilbestrol; Diethylstilbestrol Diphosphate; Equilin; Estra 0204 Cognition adjuvant: Ergoloid Mesylates; Pirac diol; Estradiol Cypionate; Estradiol Enanthate; Estradiol etam; Pramiracetam Hydrochloride; Pramiracetam Sulfate; Undecylate; Estradiol Valerate; EstraZinol Hydrobromide; Tacrine Hydrochloride. Estriol, Estrofurate; Estrogens, Conjugated; Estrogens, 0205 Cognition enhancer: Besipirdine Hydrochloride; Esterified; Estrone; Estropipate; Ethinyl Estradiol; Fenes Linopirdine; Sibopirdine. trel; Mestranol; Nylestriol; Quinestrol. 0206. Depressant: Omeprazole. 0214. Fibrinolytic: Anistreplase; Bisobrin Lactate; Brino lase. 0207 Diagnostic aid: Aminohippurate Sodium; Ana Zolene Sodium; Arclofenin, Arginine, Bentiromide, Benzyl 0215 Free oxygen radical Scavenger: Pegorgotein. penicilloyl Polylysine; Butedronate Tetrasodium; Butilfe 0216 Gastrointestinal Motility agents: Cisapride (Pro nin; Coccidioidin; Corticorelin Ovine Triflutate; Corticotropin, Repository; Corticotropin Zinc Hydroxide; pulsid); Metoclopramide (Reglan), Hyoscyamine (Levsin). Diatrizoate Meglumine; Diatrizoate Sodium; Diatrizoic 0217 Glucocorticoid: Amcinonide; Beclomethasone Acid; Diphtheria Toxin for Schick Test; Disofenin; Edro Dipropionate, Betamethasone; Betamethasone Acetate; US 2004/0106589 A1 Jun. 3, 2004 22

Betamethasone Benzoate, Betamethasone Dipropionate; 0226 Hypotensive: Viprostol. Betamethasone Sodium Phosphate; Betamethasone Valer ate, CarbenoXolone Sodium, Clocortolone Acetate; Clocor 0227 HMGCoA reductase inhibitors: Lovastatin (Meva tolone Pivalate; Cloprednol; Corticotropin; Corticotropin, cor); Simvastatin (Zocor); Pravastatin (Pravachol); Fluva Repository; Corticotropin Zinc Hydroxide; Cortisone Satin (Lescol). Acetate; CortivaZol, Descinolone Acetonide; Dexametha 0228 Immunizing agent: Antirabies Serum; Antivenin Sone; Dexamethasone Sodium Phosphate; Diflucortolone; (Latrodectus mactans); Antivenin (Micrurus Fulvius); Anti venin (Crotalidae) Polyvalent; BCG Vaccine; Botulism Diflucortolone Pivalate; Flucloronide; Flumethasone; Flu Antitoxin; Cholera Vaccine; Diphtheria Antitoxin; Diphthe methasone Pivalate; Flunisolide; Fluocinolone Acetonide; ria Toxoid; Diphtheria Toxoid Adsorbed; Globulin, Immune; Fluocinonide; Fluocortolone; Fluocortolone Caproate; Fluo Hepatitis B Immune Globulin; Hepatitis B Virus Vaccine rometholone; Fluperolone Acetate; Fluprednisolone; Flu Inactivated; Influenza Virus Vaccine; Measles Virus Vaccine prednisolone Valerate; Flurandrenolide; Formocortal; Live, Meningococcal Polysaccharide Vaccine Group A; Hydrocortisone; Hydrocortisone Acetate; Hydrocortisone Meningococcal Polysaccharide Vaccine Group C; Mumps Buteprate; Hydrocortisone Butyrate; Hydrocortisone Virus Vaccine Live; Pertussis Immune Globulin; Pertussis Sodium Phosphate; Hydrocortisone Sodium Succinate; Vaccine; Pertussis Vaccine Adsorbed; Plague Vaccine; Hydrocortisone Valerate; Medrysone; Methylprednisolone; Poliovirus Vaccine Inactivated; Poliovirus Vaccine Live Methylprednisolone Acetate; Methylprednisolone Sodium Oral; Rabies Immuune Globulin; Rabies Vaccine, Rh(D) Phosphate; Methylprednisolone Sodium Succinate; Nivazol; Immune Globulin; Rubella Virus Vaccine Live; Smallpox Paramethasone Acetate; Prednicarbate; Prednisolone; Pred Vaccine; Tetanus Antitoxin; Tetanus Immune Globulin; nisolone Acetate, Prednisolone Hemisuccinate, Predniso Tetanus Toxoid; Tetanus Toxoid Adsorbed; Typhoid Vac lone Sodium Phosphate; Prednisolone Sodium Succinate; cine; Yellow Fever vaccine; Vaccinia Immune Globulin; Prednisolone Tebutate; Prednisone; Prednival; Ticabesone Varicella-Zoster Immune Globulin. Propionate; Tralonide; Triamcinolone; Triamcinolone 0229 Immunomodulator: Dimepranol Acedoben; Imi Acetonide; Triamcinolone Acetonide Sodium; Triamcino quimod; Interferon Beta-1b; Lisofylline; Mycophenolate lone Diacetate; Triamcinolone Hexacetonide. Mofetil, Prczatide Copper Acetate. 0218. Gonad-stimulating principle: Buserelin Acetate; 0230 Immunoregulator: Azarole; Fanctizole Mesylate; Clomiphene Citrate; Ganirelix Acetate; Gonadorelin Frentizole; Oxamisole Hydrochloride; Ristianol Phosphate; Acetate; Gonadorelin Hydrochloride; Gonadotropin, Chori Thymopentin; Tilomisole. onic, Menotropins. 0231) Immunostimulant: Loxoribine; Teceleukin. 0219 Hair growth stimulant: Minoxidil. 0232 Immunosuppressant: Azathioprine; Azathioprine 0220 Hemostatic: Aminocaproic Acid; Oxamarin Sodium; CyclospCrine; Daltroban; Gusperimus Trihydro Hydrochloride; Sulmarin; Thrombin; Tranexamic Acid. chloride; Sirolimus; Tacrolimus. 0221) Histamine H2 receptor antagonists: Ranitidine 0233 Impotence therapy adjunct: Deleguamine Hydro (Zantac); Famotidine (Pepcid); Cimetidine (Tagamet); Niza chloride. tidine (Axid). 0234. Inhibitor: Acarbose, Atorvastatin Calcium; Benser 0222 Hormone: Diethylstilbestrol; Progesterone; 17 azide, Brocresine; Carbidopa; Clavulanate Potassium; hydroxy progesterone; Medroxyprogesterone, Norgestrel; DaZmegrel, Docebenone; Epoprostenol; Epoprostenol Norethynodrel; Estradiol; Megestrol (Megace); Norethin Sodium; Epristeride; Finasteride; Flurbiprofen Sodium; drone; Levonorgestrel; Ethyndiol; Ethinyl estradiol; Mestra Furegrelate Sodium; Lufironil; Miglitol; Orlistat; Pimage nol; Estrone, Equilin; 17 alpha dihydroeguilin; equilenin; 17 dine Hydrochloride; Pirmagrel: Ponalrestat; Ridogrel; Sul alpha dihydroequilenin; 17 alpha estradiol, 17beta estradiol; bactam BenZathine; Sulbactam Pivoxil Sulbactam Sodium; Leuprolide (lupron); Glucagon; Testolactone; Clomiphene; Suronacrine Maleate; Tazobactam, Tazobactam Sodium; Han memopausal gonadotropins, Human chorionic gona Ticlopidine Hydrochloride; Tirilazad NIesylate; Tolrestat; dotropin; Urofolitropin; Bromocriptine; Gonadorelin; Velnacrine Maleate; Zifrosilone; Zileuton. Luteinizing hormone releasing hormone and analogs, Gona 0235 Keratolytic: Alcloxa; Aldioxa; Benzoyl Peroxide; dotropins; Danazol; Testosterone, Dehydroepiandrosterone; Dibenzothiophene; Etarotene; Isotretinoin; Motretinide; Androstenedione, Dihydroestosterone; Relaxin, Oxytocin, Picotrin Diolamine; Resorcinol; Resorcinol Monoacetate; Vasopressin; Folliculostatin; Follicle regulatory protein; Salicylic Acid, Sumarotene, Tazarotene, Tetroquinone; Tre Gonadoctrinins, Oocyte maturation inhibitor; Insulin growth tinoin. factor, Follicle Stimulating Hormone, Luteinizing hormone; Tamoxifen; Corticorelin Ovine Triflutate; Cosyntropin; 0236 LHRH agonist: Deslorelin: Goserelin; Histrelin; Metogest; Pituitary, Posterior; Seractide Acetate; Somal Lutrelin Acetate, Nafarelin Acetate. apor, Somatrem; Somatropin; Somenopor, Somidobove. 0237 Liver disorder treatment: Ialotilate. 0223 Hypocholesterolemic: Lifibrol. 0238 Luteolysin: Fenprostalene. 0224 Hypoglycemic: Darglitazone Sodium: Glime 0239 Memory adjuvant: Dimoxamine Hydrochloride; piride. Ribaminol. 0225 Hypolipidemic: Azalanstat Dihydrochloride; 0240 Mental performance enhancer: Aniracetam. Colestolone; Surfomer; Xenalipin. 0241 Mood regulator: Fengabine. US 2004/0106589 A1 Jun. 3, 2004

0242 Mucolytic: Acetylcysteine; Carbocysteine; Domi Iodopyracet I 125; Iodopyracet I 131; Iofetamine Hydro odol. chloride I 123, Iomethin I 125; Iomethin I 131; Iothalamate Sodium I 125; Iothalamate Sodium I 131; Iotyrosine 1131; 0243 Mucosal Protective agents: Misoprostol (Cytotec). Liothyronine I 125; Liothyronine I 131 Merisoprol Acetate 0244 Mydriatic: Berefrine. Hg 197; Merisoprol Acetate Hg 203; Merisoprol Hg 197; Selenomethionine Se 75; Technetium Tc 99m Antimony 0245 Nasal decongestant: Nemazoline Hydrochloride; Trisulfide Colloid; Technetium Tc 99m Bicisate; Technetium Pseudoephedrine Polistirex. Tc 99m Disofenin; Technetium Tc 99m Etidronate; Techne 0246 Neuroleptic: Duoperone Fumarate; Risperidone. tium Tc 99m Exametazime; Technetium Tc 99m Furifosmin, Technetium Tc 99m Gluceptate; Technetium Tc 99m Lid 0247 Neuromuscular blocking agent: Atracurium Besy ofenin Technetium Tc 99m Mebrofenin; Technetium Tc 99m late; Cisatracurium Besylate; Doxacurium Chloride; Gal Medronate; Technetium Tc 99m Medronate Disodium; lamine Triethiodide; Metocurine Iodide, Mivacurium Chlo Technetium Tc 99m Mertiatide; Technetium Tc 99m Oxidr ride; Pancuronium Bromide; Pipecuronium Bromide; onate; Technetium Tc 99m Pentetate; Technetium Tc 99m Rocuronium Bromide; Succinylcholine Chloride; Tub Pentetate Calcium Trisodium; Technetium Tc 99m Sesta ocurarine Chloride; Vecuronium Bromide. mibi; Technetium Tc 99m Siboroxime; Technetium Tc 99m 0248 Neuroprotective: Dizocilpine Maleate. Succimer; Technetium Tc 99m Sulfur Colloid; Technetium Tc 99m Teboroxime; Technetium Tc 99m Tetrofosmin; 0249 NMDA antagonist: Selfotel. Technetium Tc 99m Tiatide; Thyroxine 1 125; Thyroxine 1 0250) Non-hormonal sterol derivative: Pregnenolone 13 1; Tolpovidone 131; Triolein 1125; Triolein 1131. Succinate. 0264 Regulator: Calcifediol; Calcitonin; Calcitriol; Clo 0251 Oxytocic: Carboprost; Carboprost Methyl; Carbo dronic Acid; Dihydrotachysterol, Etidronic Acid; Oxidronic prost Tromethamine, Dinoprost, Dinoprost Tromethamine; Acid, Piridironate Sodium; Risedronate Sodium; Secalcif Dinoprostone; Ergonovine Maleate; Meteneprost; Methyl erol. ergonovine Maleate; Oxytocin, Sparteine Sulfate. 0265 Relaxant: Adiphenine Hydrochloride; Alcuronium 0252) Plasminogen activator: Alteplase; Urokinase. Chloride; Aminophylline; Azumolene Sodium; Baclofen; 0253 Platelet activating factor antagonist: Lexipafant. Benzoctamine Hydrochloride; Carisoprodol; Chlorphenesin Carbamate; ChlorZOXaZone, Cinflumide, Cinnamedrine; 0254 Platelet aggregation inhibitor: Acadesine; Bera Clodanolene; Cyclobenzaprine Hydrochloride; Dantrolene; prost; Beraprost Sodium, Ciprostene Calcium; ItaZigrel, Dantrolene Sodium; Fenalamide; Fenyripol Hydrochloride; Lifarizine; OXagrelate. Fetoxylate Hydrochloride; Flavoxate Hydrochloride; Fle 0255 Post-stroke and post-head trauma treatment: Citi tazepam, Flumetramide, Flurazepam Hydrochloride; coline Sodium. Hexafluorenium Bromide; Isomylamine Hydrochloride; Lorbamate; Mebeverine Hydrochloride; Mesuprine Hydro 0256 Potentiator: Pentostatin; Talopram Hydrochloride. chloride; Metaxalone; Methocarbamol; Methixene Hydro 0257 Progestin: Algestone Acetophenide; Amadinone chloride; Nafomine Malate; NeleZaprine Maleate; Papaver Acetate: AnageStone Acetate; Chlormadinone Acetate; ine Hydrochloride; Pipoxolan Hydrochloride; Quinctolate; CingeStol; Clogestone Acetate; Clomegestone Acetate; Ritodrine; Ritodrine Hydrochloride; Rolodine; Theophylline DeSogeStrel; Dimethisterone; Dydrogesterone; Ethynerone; Sodium Glycinate; Thiphenamil Hydrochloride; Xilobam. Ethynodiol Diacetate; EtonogeStrel; Flurogestone Acetate; 0266 Repartitioning agent: Cimaterol. Gestaclone, Gestodene, Gestonorone Caproate; Gestrinone; Haloprogesterone; Hydroxyprogesterone Caproate; 0267 Scabicide: Amitraz, Crotamiton. Levonorgestrel; Lynestrenol; Medrogestone; MedroX yprogesterone Acetate; Methynodiol Diacetate, Norethin 0268 Sclerosing agent: Ethanolamine Oleate; Morrhuate drone; Norethindrone Acetate; Norethynodrel; Norgesti Sodium; Tribenoside. mate, Norgestomet; Norgestrel; Oxogestone Phenpropionate; Progesterone, Quingestanol Acetate; 0269 Sedative: Propiomazine. Quingestrone; TigeStol. 0270 Sedative-hypnotic: Allobarbital; Alonimid; Alpra 0258 Prostaglandin: Cloprostenol Sodium; Fluprostenol Zolam; Amobarbital Sodium; Bentazepam; Brotizolam; But Sodium; Gemeprost; Prostalene; Sulprostone. abarbital; Butabarbital Sodium; Butalbital; Capuride; Car bocloral; Chloral Betaine; Chloral Hydrate; 0259 Prostate growth inhibitor: Pentomone. Chlordiazepoxide Hydrochloride; Cloperidone Hydrochlo ride; Clorethate; Cyprazepam; Dexciamol Hydrochloride; 0260 Prothyrotropin: Protirelin. Diazepam, DichloralphenaZone; Estazolam, EthchlorVynol; 0261) Psychotropic: Minaprine. Etomidate, Fenobam; Flunitrazepam, FoSazepam, Glute thimide, Halazepam, Lormetazepam, Mecloqualone; Mep 0262 Pulmonary surface: Beractant; Colfosceril Palmi robamate; Methaqualone; Midaflur; Paraldehyde; Pentobar tate. bital; Pentobarbital Sodium; Perlapine; Prazepam; 0263 Radioactive agent: Fibrinogen I 125; Fludeoxyglu Quazepam, Reclazepam, Roletamide, Secobarbital; Seco cose F 18; Fluorodopa F 18; Insulin I 125; Insulin I 131; barbital Sodium; Suproclone; Thalidomide; Tracazolate; Iobenguane I 123; Iodipamide Sodium I 131; Iodoantipyrine Trepipam Maleate; Triazolam; Tricetamide; Triclofos I 131; Iodocholesterol I 131; Iodohippurate Sodium I 123; Sodium; Trimetozine, Uldazepam, Zaleplon; Zolazepam Iodohippurate Sodium I 125 Iodohippurate Sodiun I 131; Hydrochloride; Zolpidem Tartrate. US 2004/0106589 A1 Jun. 3, 2004 24

0271 Selective adenosine A1 antagonist: Apaxifylline. Mefenidil Fumarate; Mibefradil Dihydrochloride; Miofla zine Hydrochloride; Mixidine; Nafronyl Oxalate; Nicar 0272 Serotonin antagonist: Altanserin Tartrate; Ameser dipine Hydrochloride; Nicergoline; Nicorandil; Nicotinyl gide, Ketanserin; Ritanserin. Alcohol; Nifedipine; Nimodipine; Nisoldipine; Oxfenicine; 0273 Serotonin inhibitor: Cinanserin Hydrochloride; Oxprenolol Hydrochloride; Pentaerythritol Tetranitrate; Fenclonine; Fonazine Mesylate; Xylamidine Tosylate. Pentoxifylline; Pentrinitrol; Perhexiline Maleate; Pindolol; Pirsidomine; Prenylamine; Propatyl Nitrate; Suloctidil; 0274 Serotonin receptor antagonist: Tropanserin Hydro Terodiline Hydrochloride; Tipropidil Hydrochloride; Tola chloride. Zoline Hydrochloride; Xanthinol Niacinate. 0275 Steroid: Dexamethasone Acefurate; Mometasone Furoate. 0290 Vulnerary: Allantoin. 0276 Stimulant: Amfonelic Acid; Amphetamine Sulfate; 0291 Wound healing agent: Ersofernin. Ampyzine Sulfate; Arbutamine Hydrochloride; Azabon; Caffeine; Ceruletide; Ceruletide Diethylamine; Cisapride; 0292 Xanthine oxidase inhibitor: Allopurinol; Oxypu DaZopride Fumarate; Dextroamphetamine, Dextroamphet rinol amine Sulfate; Difluanine Hydrochloride; Dimefline Hydro 0293. Other pharmaceutical agents include: 1-decpyrro chloride; Doxapram Hydrochloride; Etryptamine Acetate; lidinone, 1-dodecpyrrolidinone; 16-alpha fluoroestradiol; Ethamivan; Fenethylline Hydrochloride; Flubanilate Hydro 16-epieStriol; 16alpha-gitoxin; 17alpha estradiol, 17beta chloride; Flurothyl; Histamine Phosphate; Indriline Hydro estradiol; 1alpha-hydroxyvitamin D2; 2'-nor-cGMP; 20-epi chloride; Mefexamide; Methamphetamine Hydrochloride; 1.25 dihydroxyvitamin D3; 22-oxacalcitriol; 2CVV; Methylphenidate Hydrochloride; Pemoline; Pyrovalerone 3-isobutyl GABA; 6-FUDCA, 7-methoxytacrine; abamec Hydrochloride; Xamoterol; Xamoterol Fumarate. tin, abanoquil, abecarnil; abiraterone; acadesine; acampro 0277 Suppressant: Amflutizole; Colchicine: Tazofelone. Sate; acarbose, aceclofenac; acemannan; acetomepregenol; Symptomatic multiple Sclerosis: Fampridine. acetyl-L-carnitine; acetylcysteine, N-; acetylmethadol; aci fran; acipimox; acitemate; acitretin, aclarubicin, aclatonium; 0278 Synergist: Proadifen Hydrochloride. napadisilate; aconiazide, acrivastinet; adafenoxate, ada palene; adatanserin; adecypenol; adefovir dipivoxil, adelm 0279 Thyroid hormone: Levothyroxine Sodium; Liothy idrol; ademetionine; adinazolam, adiposin; adoZelesin; ronine Sodium; Liotrix. adrafinil; alacepril; aladapcin; alaptide; albendazole, albo 0280 Thyroid inhibitor: Methimazole; Propylthiouracil. labrin; aldecalmycin; aldesleukin; alendronic acid; alente mol; alfacalcidol; alfuzosin; alglucerase, alinastine, aloS 0281) Thyromimetic: Thyromedan Hydrochloride. etron; alpha idoSone; alproStadil; altretamine; altromycin B; 0282 Tranquilizer: Bromazepam; Buspirone Hydrochlo ambamustine, amelometasone; ameSergide, ameZinium ride; Chlordiazepoxide, Clazolam, Clobazam, CloraZepate metilsulfate; amfebutamone, amidox, amifloxacin; amifoS Dipotassium, CloraZepate Monopotassium, Demoxepam, tine; amiodarone, amisulpride; amlexanoX, amlodipine; Dexmedetomidine; Enciprazine Hydrochloride; Gepirone amlodipine, ampiroXicam, amrinone; amrubicin; amsacrine; Hydrochloride; Hydroxyphenamate; Hydroxyzine Hydro amylin; amythiamicin; anagrelide; anakinra, ananain; chloride; Hydroxy Zine Pamoate; Ketazolam; Lorazepam, anaritide; anastrozole; andrographolide; anordrin; apado LorZafone, Loxapine, Loxapine Succinate; Medazepam line; apafant; apaxifylline, aphidicolin glycinate, apracloni Hydrochloride; Nabilone; Nisobamate; Oxazepam; Pent dine, aproSulate Sodium; aptiganel; apurinic acid, aranid abamate; Pirenperone, Ripazepam, Rolipram; Sulazepam, ipine; arbekacin; arbidol; arbutamine, ardeparin Sodium; Taciamine Hydrochloride; Temazepam; Triflubazam; arecatannin B1; argatroban; aripiprazol; arotinolol, asima Tybamate; Valnoctamide. doline; aspalatone; asperfuran; aspoxicillin, astemizole; asu lacrine; atameStane, atenolol, S-; ateVirdine, atoSiban, atova 0283 Amyotrophic lateral sclerosis agents: Riluzole. quone; atpenin B; atrimustine; atrinositol; aureobasidin A, 0284 Cerebral ischemia agents: Dextrorphan Hydrochlo azadirachtine, azasetron; azatyrosine; azelaic acid; azelas ride. tine; azelnidipine, azimilide, azithromycin; azoSemide; aztreonam, baccatin III; bacoside A, bacoside B; bactobo 0285 Paget’s disease agents: Tiluldronate Disodium. lamine; balaZipone, balhimycin; balofloxacin, balsalazide, 0286 Unstable angina agents: Tirofiban Hydrochloride. bambuterol, baohuoSide 1, barnidipine, basifungin; batebu last, batimaStat; beauvericin; becaplermin; becliconazole; 0287 Uricosuric: Benzbromarone; Irtemazole; befloxatone; belfosdil; bellenamine; benflumetol; benid Probenecid; Sulfinpyrazone. ipine; benzisoxazole; benzochlorins; benzoidaZOXan; ben ZoylstauroSporine; benztropine, bepridil, beractant; bera 0288 Vasoconstrictor: Angiotensin Amide; Felypressin; prost, berlafenone; bertosamil, besipirdine, beta-alethine; Methysergide; Methysergide Maleate. betaclamycin B; betamipron; betaxolol, betulinic acid; 0289 Vasodilator: Alprostadil; AZaclorzine Hydrochlo bevantolol; bicalutamide; bifemelane; bimakalim, bimithil, ride; Barnethan Sulfate; Bepridil Hydrochloride; Buterizine; binoSpirone; bioxalomycin alpha2, biriperone, bis-benzimi Cetiedil Citrate; Chromonar Hydrochloride; Clonitrate; Dil dazole A, bis-benzimidazole B, bisantrene; bisaramil, tiazem Hydrochloride; Dipyridamole; Droprenilamine; bisaziridinylspermine; bisnafide; bisoprolol; bistramide D; Erythrityl Tetranitrate; Felodipine; Flunarizine Hydrochlo bistramide K; bistratene A, boldine; bopindolol; brefeldin; ride; Fostedil; Hexobendine; Inositol Niacinate; Iproxamine breflate; brimonidine; bromfenac; bromperidol; bropir Hydrochloride; Isosorbide Dinitrate; Isosorbide Mononi imine; bucindolol; budesonide; budipine; budotitane; trate; IsoxSuprine Hydrochloride; Lidoflazine; Mefenidil; bunaprolast; bunaZoSin; butenafine; buthionine Sulfoximine; US 2004/0106589 A1 Jun. 3, 2004

butiXocort propionate; cadeXomer iodine, calanolide A, cal englitaZone, enlimomab, enoxacin; enoxaparin Sodium; cipotriol, calphostin C, camonagrel, candesartan; cande enoXimone, entacapone, enterostatin; epoprostenol; Sartan cileXetil, candoxatril; candoxatrilat, capecitabine; epoxymeXrenone, epristeride, eproSartan; eptastigmine; capromab, capsaicin; captopril; carbazomycin C; carbeto erdosteine, erSentilide, erSofermin; erythritol; eSuprone; cin; carbovir, carboxamide-amino-triazole, carboxyamidot etanidazole; etanterol, ethacizin; ethinylestradiol, etizolam; riazole; carboxymethylated beta-1,3-glucan, carperitide; etodolac, etoposide phosphate, etrabamine; eveninomicin; carteolol, carumonam, carvedilol; carvotroline, carZelesin; examorelin; exemestane, fadrozole; faerieflungin; famciclo castanospermine, cebaracetam; cecropin B; cefcapene piv Vir; fampridine, fantofarone, faropenem; fasidotril; fasudil; oxil, cefdaloxime penteXil tosilate, cefdinir, cefditoren piv fazarabine; fedotozine; felbarnate, fenofibrate; fenoldopam; oxil, cefepime, cefetamet, cefetamet pivoxil, cefixime, cef fenretinide; fenspiride, fenticonazole; fepradinol, ferpifoS luprenam, cefinetazole, cefminox, cefodizime, cefoSelis, ate Sodium; ferristene; ferrixan, ferumoxSil; feXofenadine, cefotetan, cefotiam, cefotiam heXetil, cefoZopran, cefpimi flavopiridol, flecainide, flerobuterol, fleroxacin; flesinoxan; Zole, cefpiramide, cefpirome, cefpodoxime proxetil, cef flezelastine; flobufen, flomoxef; florfenicol; florifenine; flo prozil, cefSulodin, cefteram, ceftibuten, cefiriaxone; Satidil; fluiasterone; fluconazole; fludarabine; flumazenil; flu cefuroxime axetil, celastrol; celikalim, celiprolol, cepaci mecinol; flumequine; flunarizine; fluocalcitriol, fluo dine A, cericlamine; cerivastatin; ceronapril; certoparin rodaunorunicin hydrochloride; fluoxetine, R-; fluoxetine, S-; Sodium, cetiedil; cetirizine, chloroorienticin A, chloroorien fluparoXan; flupirtine; flurbiprofen axetil, flurithromycin; ticin B; chloroquinoxaline Sulfonamide, cibenzoline, cica fluticasone propionate; flutrimazole; fluvastatin, fluvoxam prost, cicleSonide, cicletanine, cicloprolol, cidofovir, ine; forasartan; forfenimex, formeStane, formoterol; formot cilansetron; cilaZapril; cilnidipine; cilobradine, ciloStaZol; erol, R,R-; fosfomycin; trometamol, fosinopril; foSpheny cimetropium bromide, cinitapride, cinolazepam, cioteronel; toin; fostriecin, fotemustine, gabapentin, gadobenic acid; ciprofibrate; ciprofloxacin; ciprostene, cis-porphyrin, gadobutrol; gadodiamide; gadodiamide-EOB-DTPA; gado cisapride, cisatracurium besilate, cistinexine, citalopram; linium teXaphyrin, gadoteric acid, gadoteridol, gadoverseta citicoline, citreamicin alpha; cladribine; clarithromycin; mide, galantamine; galdansetron; gallopamil, galocitabine; clausenamide; clebopride; clinafloxacin; clobaZam; clobeta gamolenic acid, ganirelix, gepirone; geStrinone; girisopam, Sone butyrate; clodronic acid; clomethiazole; clopidogrel; glaspimod, glaucocalyxin A, glutapyrone, glycopine; gly clotrimazole; colestimide; colfoSceril palmitate; collismycin copril; granisetron; grepafloxacin; halichondrin B; halofan A, collismycin B; combretastatin A4, complestatin; conage trine; halomon; halopredone; hatomamicin; hatomarubigin nin; contignasterol, contortrostatin; coSalane, costatolide; A, hatomarubigin B; hatomarubigin C, hatomarubigin D; cotinine; coumermycin A1, cucumariosid; curacin A; curd ibogaine, ibopamine, ibudilast, illimaquinone, ilmofoSine; lan sulfate; curiosin; cyclazosin; cyclic HPMPC; cycloben ilomastat, illoperidone, iloprost, imidapril, imidazenil; indi Zaprine, cyclobut A, cyclobut G., cyclocapron; cycloplatam, navir; indolidan; indometacin fameSil; indometacin; tropine cyclosin; cyclothialidine, cyclothiazomycin; cypemycin; ester; indoramin; inocoterone, inogatran; inolimomab, inter cyproterone; cytarabine ocfosfate; cytochalasin B, daclix feron alfa, interferon alfa-2a, interferon alfa-2b; interferon imab, dactimicin; daidzein, daidzin; dalfopristin; dalteparin alfa-N1; interferon alfa-n3; interferon beta; interferon beta Sodium; danaparoid; daphnodorin A; dapiprazole, dapitant; 1a1; interferon beta-1b; interferon gamma-1a; interferon darifenacin; darlucin A; darsidomine; ddUTP, decitabine; gamma-1b; interferon omega; interferon, consensus, inter deferiprone; deflazacort, dehydrodidemnin B, dehydroepi leukin-1, interleukin-1 alpha; interleukin-1beta; interleukin androsterone, delapril, deleguamine; delfaprazine, delmopi 10, interleukin-11; interleukin-12, interleukin-12, interleu nol; delphinidin; deoxypyridinoline, deprodone; depSido kin-15; interleukin-2, interleukin-3, interleukin-4, mycin; deramciclane, dermatan Sulfate, desflurane; interleukin-5, interleukin-7; interleukin-8; iobenguane; desirudin; deslorelin; desmopressin; desogestrel; desoxoa iobitridol; iodoamiloride; iododoxorubicin; iofratol; iome miodarone, detajmium bit artrate; dexifosfamide; dexketo prol; iopentol, iopromide; iopyrol; iotriside; ioVerSol, ioX profen; dexloxiglumide, dexmedetomidine, dexpemedolac, ilan; ipazilide, IpdR; ipenoxazone, ipidacrine, ipomeanol, deXraZoxane, deXSotalol, dextrin 2-Sulphate, deXVerapamil; 4-, ipriflavone, ipsapirone, irbesartan; irinotecan, irloxacin; dezinamide, dezocine, diaziquone, diclofenac digolil; irSogladine, irtemazole; isalsteine, isbogrel, isepamicin; diclofenac potassium, dicranin; didemnin B; didox; isobengaZole, isofloxythepin; isohomohalicondrin B; iso dienogest; diethylhomospermine; diethylnorspermine, dihy propyl unoprostone, isradipine; itameline; itasetron; ito drexidine, dihydro-5-azacytidine, dimethyl prostaglandin pride; itraconazole, ketoprofen, R-, ketoprofen, S-, ketoro A1; dimethylhomospermine, dimiracetam; dioxamycin; lac, lacidipine, lactitol; lactivicin; laennec, lafutidine, diphencyprone, diphenyl Spiromustine, diprafenone; dipro lamellarin-N triacetate; lamifiban, lamivudine, lamotrigine; pylnorspermine, dirithromycin; discodermolide; disulfiram; lanoconazole, lanperisone; lanreotide; lanSoprazole; latano ditekiren; docarpamine, docosanol, 1-, dolfetilide; dolas prost; lateritin; laurocapram; lazabemide; lemefloxacin; etron; domitroban; dopexamine; dorZolamide; doSmalfate; lemildipine, leminoprazole; lenercept; lenograstim; lentinan dotarizine, doxacurium chloride, doxazosin, doxifluridine, Sulfate, leptin; leptolstatin; lercanidipine, lerisetron; leso doxofylline; draculin; draflazine; droloxifene, dronabinol; pitron; letraZuril; letrozole; leucomyzin; leuprorelin; levcro drosperidone, drotaverine acephyllinate, droxicam, ebi makalim, levetiracetam; leVobetaxolol, levobunolol, ratide, elbrotidine, ebSelen, ecabapide, ecabet, ecadotril; levobupivacaine; levocabastine, leVocarnitine; levodro ecdlisteron; echicetin; echistatin; ecomustine, ecteinascidin propizine; levofloxacin; levomoprolol, levonorgestrel; 722; ecteinascidin 729; ecteinascidin 743; edaravone, edel levormeloxifene, levosimendan; levoSulpiride; linotroban; fosine, edobacomab, edrecolomab, efegatran; eflornithine; linsidomine; lintitript; lintopride; liothyronine Sodium; lir efonidipine, egualen, elcatonin; eletriptan; elgodipine; elip exapride; lisinopril; lobaplatin; lobucavir, Iodoxamide, lom rodil, eltenac, emakalim, emedastine, emiglitate; emitefur, bricine, lomefloxacin, lomerizine, lometrexol; lonazolac, emoctakin; enadoline hydrochloride; enalapril; enaZadrem, lonidamine, loracarbef, loratadine, lorglumide, lornoxicam, US 2004/0106589 A1 Jun. 3, 2004 26

losartan; losigamone, loSOXantrone; loteprednol; loviride; ingol, Safironil; Saintopin; Salbutamol, R-; Salmeterol, Sal loxoribine; lubeluzole; lurtotecan; luteinizing hormone; meterol, R-Salnacedin, Sameridine, Sampatrilat, Sanfetrinem; lutetium, luZindole, lydicamycin; lySofylline; lysostaphin, Saprisartan; Sapropterin; Saquinavir, SarCNU; Sarcophytol A magainin 2 amide; magnolol, mallotochromene; malloto SargramoStim; Sarpogrelate, Saruplase, Saterinone; Satigrel, japonin; malotilate; mangafodipir; manidipine; maniwamy Satumomab pendetide; Selegiline, Selenium thiosemicarba cin A, mannostatin A, manumycin E, manumycin F; mapi Zone, Sematilide, Semduramicin; Semotiadil, Semustine, Ser nastine; marimastat; Martek 8708; Martek 92211; morelin; Sertaconazole, Sertindole, Sertraline, Setiptiline; masoprocol; maspin; massetolide, meterelin; methoxatone; Sevirumab, Sevoflurane, SeZolamide, Silipide, Silteplase; methylhistamine, R-alpha; methylinosine monophosphate; Simendan; Simvastatin; Sinitrodil; Sinnabidol; Silpatrigine; methylprednisolone aceponate, methylprednisolone Sulep Sirolimus, sizofiran; Somatomedin B, Somatomedin C, tanate, metipamide; metoclopramide, metoprolol, S-; met Somatrem; Somatropin; Sonermin; Sotalol, StauroSporine; rifonate; mibefradil; michellamine B; microcolin A, mido Stavudine, Stepronin; Stipiamide, Stiripentol; Stobadine, Suc drine; mifepristone, miglitol; millacemide; milameline; cibun; Sucralfate, SulfaSalazine, Sulfinosine, Sulfoxamine; mildronate, milnacipran; milrinone; miltefosine; minaprine; Sulopenem; Sultamicillin; Sultopride, Sulukast, Sumatriptan; miokamycin, mipragoside; mirfentanil; mirimoStim, mir Symakalim, tandoSpirone; tapgen; taprostene; tasOSartan; tazapine; misoprostol, mitoguaZone, mitolactol, mitonafide; taZanolast, tazarotene; teicoplanin; telenzepine, tellurapyry mitoxantrone; mivacurium chloride; mivaZerol, mixanpril; lium; telmesteine; telmisartan; temocapril; temoporfin; mizolastine, mizoribine; moclobemide; modafinil; moex temozolomide; tenidap; tenipoSide; tenoSal; tenoxicam, ipril; mofaroteine; mofeZolac, molgramoStim; mometasone; tepirindole; tepoxalin; teraZoSin; terbinafine; terfenadine, montirelin; mopidamol; moracizine; mosapramine; terflavoxate, terguride; teriakiren, terlipressin, terodiline; moSapride; motilide; moxiraprine; moxonidine; nadifloxa tertatolol, testosterone buciclate, tetrachlorodecaoxide, tet cin; nadroparin calcium, nafadotride, nafamoStat; nafarelin; raZomine; thaliblastine; thalidomide; thiocoraline; naftopidil, naglivan, nagreStip; nalmefene, naphterpin, nap thiofedrine; thiomarinol; thioperamide, thyroid Stimulating Sagatran; naratriptan, nartograstim; nasaruplase, nateplase; hormone; tiagabine; tianeptine, tiapafant; tibolone, ticlopi niperotidine, niravoline, nisamycin; nisin; nisoldipine, nita dine, tienoXolol, tilisolol, tilnoprofen arbamel, tiludronic ZOXamide, nitecapone, nitrendipine, nitrendipine, S-, nitro acid; tinzaparin Sodium, tiotropium bromide; tipredane; furantoin monohydrate, nitrullyn; nizatidine, ofloxacin, oki tiqueside; tirandalydigin; tirapazamine; tirilazad; tirofiban; cenone; Olanzapine, olopatadine, olprinone; Olsalazine; tiropramide; topSentin; toraSemide, toremifene, toSufloxa omeprazole; Onapristone, ondansetron, Ondansetron, R-; cin; trafermin; trandolapril; traXanox, tretinoin, tretinoin OntaZolast, oracin; otenZepad; Oxaliplatin, oxamisole, OXan tocoferil; triacetyluridine; tricaprilin; trichohyalin; tricho drolone, Oxaprozin, oxaunomycin; oxcarbazepine; oxicona Santhin, alpha; triciribine; trientine: triflavin; trimegestone; Zole, OXiracetam; OXOdipine; OZagrel, palauamine, palinavir, triptorelin; troglitaZone; trombodipine; tropisetron; troSpec palmitoylrhizoxin; pamaqueside, pamicogrel, pamidronic tomycin; trovafloxacin; troVirdine; tucareSol, tulobuterol; acid; panamesine; panaxytriol, panipenem; panipenum; pan tylogenin, urapidil, uridine triphosphate, Valaciclovir, Val norin; panomifene, pantethine, pantoprazole, parabactin; proate magnesium; Valproate Semisodium; Valsartan; vami parnaparin Sodium, paroxetine, parthenolide, paZelliptine; camide, Vanadeine, Vaminolol, Vapreotide; variolin B; paZufloxacin, pefloxacin; pegaspargase; peldesine, pemed VelareSol, Venlafaxine, Veramine; Verapamil, (S); Verdins, olac, pemirolast, penciclovir, pentafuside; pentamidine, Veroxan, Verteporfin; Vesnarinone, Vexibinol; vigabatrin; pentamorphone; pentigetide; pentosan, pentostatin; pentro Vinburnine citrate; Vinburnine resinate: Vinconate; Vinorel Zole, perflubron; perfosfamide; pergolide, perindoprilat; bine, Vinpocetine, Vinpocetine citrate; Vintoperol, VinXal peroSpirone; phenaridine, phenazinomycin; phenserine; tine; Voriconazole; Vorozole, VOXergolide, Xemilofiban; phensuccinal; phentolamine mesilate; phenylacetate; pheny Ximoprofen; yangamblin, Zabicipril; Zacopride; Zacopride, lalanylketoconazole, picenadol, picibanil, picroliv, picume R-; Zafirlukast; Zalcitabine; Zaleplon; ZaloSpirone; Zaltopro terol, pidotimod; pilocarpine hydrochloride, pilsicainide; fen, Zanamivir; Zankiren, Zanoterone; Zatebradine, pimagedine, pimilprost, pimobendan; pinacidil; pinocebrin; Zatosetron; Zenarestat; Zeniplatin, Zifrosilone; Zilascorb, pioglitaZone; pipecuronium bromide, pirarubicin; piret Zileuton; Zinostatin stimalamer, Ziprasidone; Zoledronic anide, pirfenidone, piritrexim; pirlindole, pirmagrel, pirme acid; Zolmitriptan; Zolpidem; Zonisamide, Zopiclone, Zopi nol; pirodavir, pirodomast, piroXicam cinnamate; propager clone, S-, Zopolrestat; Zotepine. manium; propentofylline, propionylcarnitine, L-, propiram; propiram-paracetamol, propiverine; propyl bis-acridone; 0294 The invention also embraces novel compositions of prostaglandin J2, prostratin, protegrin, protoSufloxacin; pru matter that are covalent conjugates of unbranched, naturally lifloxacin; pyrazoloacridine, quazepam, quetiapine, qui occurring fatty acids and pharmaceutical agents that are flapon; quinagolide, quinapril, quinfamide, quinupristin, noncentral nervous System active agents. Noncentral ner raloxifene, raltitrexed; ramatroban; ramipril; ramosetron; Vous System active agents have no function or use within the ranelic acid; ranitidine bismuth citrate; ranolazine; central nervous System. Their only use is outside of the recainam; regaVirumab, relaxin, repirinast, resinferatoxin; central nervous System. Such agents include all drugs within reticulon; reviparin Sodium; revizinone; ricasetron; ridogrel; certain of the foregoing categories and only Some drugs rifabutin, rifapentine, rifaximin, rilopiroX, riluzole, riman tadine, rimeXolone, rimoprogin, riodipine, ripisartan; within other of the foregoing categories. For example, the risedronic acid; rispenzepine, risperidone; ritanserin; riti entire catagory of blood glucose regulators have no use or penem; ritipenem acoxil, ritolukast, ritonavir, rizatriptan function within the central nervous System. In contrast, benzoate, rohitukine, rokitamycin; ropinirole; ropivacaine; certain anti-cancer agents are useful in the central nervous roquinimex, roXatidine, roXindole; roXithromycin; rubigi System whereas others are not. For example, central nervous none B1, ruboxyl, rufloxacin, rupatidine, ruzadolane, Saf System cancers are not hormone dependent, and, therefore, US 2004/0106589 A1 Jun. 3, 2004 27 an anti-cancer agent Such as Tamoxifen which treats certain

hormone dependent cancers is not useful in the central nervous system. Those skilled in the art will be able to identify readily those catagories and/or members of a cat agory which are noncentral nervous System active agents. Among the foregoing compounds, the following catagories and/or members of the following catagories are noncentral nervous System active agents: adrenocortical Steroid; adrenocortical SuppreSSant; aldosterone antagonist, amino acid; anabolic, androgen; antagonist; anthelmintic, anti-acne agent, anti-adrenergic, anti-allergic, anti-amebic, anti-an 0296. A taxoid is a molecule structurally related to a drogen; anti-anemic, anti-anginal; anti-arthritic, anti-asth taxane in which the above taxane carbon-atom connectivity matic, anti-atherOSclerotic, antibacterial; anticholelithic, network is altered, for example, by cleavage of one or more anticholelithogenic, anticholinergic, anticoagulant; anticoc of the carbocyclic rings, by deletion or addition of carbon cidal; antidiabetic, antidiarrheal; antidiuretic, antidote, anti Substituents, by connection of carbon atoms normally not estrogen; antifibrinolytic, antifungal; antiglaucomaagent; bonded to each other, by disconnection of carbon atoms antihemophilic; antihemorrhagic, antihistamine; antihyper normally bonded to each other, or by Some other reorgani lipidemia; antihyperlipoproteinemic, antihypertensive; anti Zation of or adjustment to the taxane carbon-atom connec hypotensive, anti-infective, anti-infective, topical; anti-in tivity network, but in which one or more Structural features flammatory; antikeratinizing agent, antimalarial; characteristic of the taxane carbon-atom connectivity net antimicrobial; antimitotic, antimycotic, antineoplastic, work are conserved. antineutropenic, antiparasitic, antiperistaltic, antipneu 0297. The compounds useful in the invention may be mocystic, antiproliferative, antiprostatic hypertrophy; anti delivered in the form of anti-cancer cocktails. An anti-cancer protozoal; antipruritic, antipsoriatic, antirheumatic; antis cocktail is a mixture of any one of the compounds useful chistoSomal; antiseborrheic, antisecretory; antispasmodic, with this invention with another anti-cancer agent Such as an antithrombotic, antituSSive, anti-ulcerative: anti-urolithic, anti-cancer drug, a cytokine, and/or Supplementary potenti antiviral; appetite Suppressant, benign prostatic hyperplasia ating agent(s). The use of cocktails in the treatment of cancer therapy agent, bone resorption inhibitor, bronchodilator; is routine. In this embodiment, a common administration carbonic anhydrase inhibitor; cardiac depressant, cardiopro vehicle (e.g., pill, tablet, implant, injectable Solution, etc.) tectant, cardiotonic, cardiovascular agent, choleretic, cho would contain both the conjugate useful in this invention linergic, cholinergic agonist, cholinesterase deactivator; and the anti-cancer drug and/or Supplementary potentiating coccidioStat; diagnostic aid; diuretic, ectoparasiticide; agent. enzyme inhibitor; estrogen; fibrinolytic, free oxygen radical Scavenger, glucocorticoid; gonad-stimulating principle; hair 0298 The compounds of the invention, when used in growth Stimulant; hemostatic, hormone, hypocholester cocktails, are administered in therapeutically effective olemic, hypoglycemic, hypolipidemic, hypotensive; immu amounts. A therapeutically effective amount will be deter nizing agent; immunomodulator; immunoregulator; immu mined by the parameters discussed below; but, in any event, nostimulant; immunosuppreSSant; impotence therapy is that amount which establishes a level of the drug(s) in the adjunct; inhibitor; keratolytic; LHRH agonist; liver disorder area of the tumor which is effective in inhibiting the tumor treatment, luteolysin; mucolytic, mydriatic, nasal deconges growth. tant; neuromuscular blocking agent; non-hormonal Sterol derivative; oxytocic, plasminogen activator, platelet activat 0299 When administered, the formulations of the inven ing factor antagonist, platelet aggregation inhibitor, poten tion are applied in pharmaceutically acceptable amounts and tiator, progestin, prostaglandin, prostate growth inhibitor; in pharmaceutically acceptable compositions. Such prepa prothyrotropin, pulmonary Surface; radioactive agent; regu rations may routinely contain Salts, buffering agents, pre lator, relaxant, repartitioning agent; Scabicide, Sclerosing Servatives, compatible carriers, and optionally other thera agent, Selective adenosine A1 antagonist; Steroid; Suppres peutic ingredients. When used in medicine the Salts should Sant; Symptomatic multiple Sclerosis, Synergist; thyroid hor be pharmaceutically acceptable, but non-pharmaceutically mone, thyroid inhibitor; thyromimetic; amyotrophic lateral acceptable Salts may conveniently be used to prepare phar maceutically acceptable Salts thereof and are not excluded Sclerosis agents, Paget’s disease agents, unstable angina from the Scope of the invention. Such pharmacologically agents, uricoSuric; vasoconstrictor; vasodilator, Vulnerary; and pharmaceutically acceptable Salts include, but are not wound healing agent; Xanthine oxidase inhibitor. limited to, those prepared from the following acids: hydro 0295 AS used herein, a taxane is a molecule that pos chloric, hydrobromic, Sulphuric, nitric, phosphoric, maleic, SeSSes the following tricyclic carbon-atom connectivity net acetic, Salicylic, p-toluene Sulfonic, tartaric, citric, methane work, which may incorporate carbon-carbon multiple bonds, Sulfonic, formic, malonic, Succinic, naphthalene-2-Sulfonic, and which through the involvement of carbon-atom-noncar and benzene Sulfonic. Also, pharmaceutically acceptable bon-atom bonds may include Substituents, functional Salts can be prepared as alkaline metal or alkaline earth Salts, groups, and additional rings. Such as Sodium, potassium or calcium Salts. US 2004/0106589 A1 Jun. 3, 2004 28

0300 Suitable buffering agents include: acetic acid and a tion. These factors are well known to those of ordinary skill salt (1-2% W/V); citric acid and a salt (1-3% W/V); boric in the art and can be addressed with no more than routine acid and a salt (0.5-2.5% W/V); and phosphoric acid and a experimentation. It is preferred generally that a maximum salt (0.8-2% W/V). dose be used, that is, the highest Safe dose according to 0301 Suitable preservatives include benzalkonium chlo Sound medical judgment. ride (0.003-0.03% W/V); chlorobutanol (0.3-0.9% W/V); 0307 Dosage may be adjusted appropriately to achieve parabens (0.01-0.25% W/V) and thimerosal (0.004-0.02% desired drug levels, locally or Systemically. Generally, daily oral doses of active compounds will be from about 0.01 W/V). mg/kg per day to 1000 mg/kg per day. It is expected that IV 0302) The active compounds of the present invention doses in the range of about 1 to 1000 mg/m per day will be may be a pharmaceutical composition having a therapeuti effective. In the event that the response in a Subject is cally effective amount of a conjugate of the invention insufficient at Such doses, even higher doses (or effective optionally included in a pharmaceutically-acceptable carrier. higher doses by a different, more localized delivery route) The term "pharmaceutically-acceptable carrier' as used may be employed to the extent that patient tolerance permits. herein means one or more compatible Solid or liquid filler, Continuous IV dosing over, for example 24 hours or mul dilutants or encapsulating Substances which are Suitable for tiple doses per day are contemplated to achieve appropriate administration to a human or other animal. The term "car Systemic levels of compounds. rier denotes an organic or inorganic ingredient, natural or 0308) A variety of administration routes are available. Synthetic, with which the active ingredient is combined to The particular mode Selected will depend of course, upon the facilitate the application. The components of the pharma particular drug Selected, the Severity of the disease State ceutical compositions are capable of being commingled with being treated and the dosage required for therapeutic effi the molecules of the present invention, and with each other, cacy. The methods of this invention, generally speaking, in a manner Such that there is no interaction which would may be practiced using any mode of administration that is Substantially impair the desired pharmaceutical efficacy. medically acceptable, meaning any mode that produces 0303 Compositions suitable for parenteral administra effective levels of the active compounds without causing tion conveniently comprise a Sterile preparation of the clinically unacceptable adverse effects. Such modes of conjugates of the invention. This preparation may be for administration include oral, rectal, Sublingual, topical, nasal, mulated according to known methods. Formulations for transdermal, intradermal or parenteral routes. The term taxanes can be found in Chapter 9 of Taxol. Science and "parenteral' includes Subcutaneous, intravenous, intramus Applications, CRC Press, Inc., 2000 Corporate Boulevard, cular, or infusion. Intravenous routes are preferred. N.W., Boca Raton, Fla. 33431. In general, Taxol has been 0309 The compositions may conveniently be presented formulated as a 6 ma/ml cremophor EL (polyoxyethylated in unit dosage form and may be prepared by any of the castor oil)/ethanol mixture, which is diluted to final volume methods well known in the art of pharmacy. All methods with normal saline or 5% dextrose. A 15 mg/ml solution of include the Step of bringing the conjugates of the invention taxotere has been formulated in polysorbate 80 (polyoxy into association with a carrier which constitutes one or more ethylene sorbitanmonooleate)/ethanol mixture, diluted with accessory ingredients. In general, the compositions are pre 5% dextrose. pared by uniformly and intimately bringing the compounds 0304. The sterile preparation thus may be a sterile solu into association with a liquid carrier, a finely divided Solid tion or Suspension in a non-toxic parenterally-acceptable carrier, or both, and then, if necessary, Shaping the product. diluent or Solvent. In addition, Sterile, fixed oils are conven 0310 Compositions suitable for oral administration may tionally employed as a Solvent or Suspending medium. For be presented as discrete units Such as capsules, cachets, this purpose any bland fixed oil may be employed including tablets, or lozenges, each containing a predetermined Synthetic mono or di-glycerides. In addition, fatty acids Such amount of the active compound. Other compositions include as oleic acid find use in the preparation of injectables. Suspensions in aqueous liquors or non-aqueous liquids Such Carrier formulations Suitable for oral, Subcutaneous, intra as a Syrup, an elixir, or an emulsion. venous, intramuscular, etc. can be found in Remington's 0311. Other delivery systems can include time-release, Pharmaceutical Sciences, Mack Publishing Company, Eas delayed release or Sustained release delivery Systems. Such ton, Pa. Systems can a void repeated administrations of the active compounds of the invention, increasing convenience to the 0305) A subject as used herein means humans, primates, Subject and the physician. Many types of release delivery horses, cows, pigs, sheep, goats, dogs, cats and rodents. Systems are available and known to those of ordinary skill in 0306 The conjugates of the invention are administered in the art. They include polymer based Systems Such as poly effective amounts. An effective amount means that amount lactic and polyglycolic acid, polyanhydrides and polycapro necessary to delay the onset of, inhibit the progression of, lactone; nonpolymer Systems that are lipids including Sterols halt altogether the onset or progression of or diagnose the Such as cholesterol, cholesterol esters and fatty acids or particular condition being treated. In general, an effective neutral fats Such as mono-, di and triglycerides, hydrogel amount for treating cancer will be that amount necessary to release Systems, Silastic Systems, peptide based Systems, inhibit mammalian cancer cell proliferation in-situ. When wax coatings, compressed tablets using conventional bind administered to a Subject, effective amounts will depend, of erS and excipients, partially fused implants and the like. In course, on the particular condition being treated; the Severity addition, a pump-based hardware delivery System can be of the condition; individual patient parameters including used, Some of which are adapted for implantation. age, physical condition, Size and weight; concurrent treat 0312 Along-term Sustained release implant also may be ment, frequency of treatment; and the mode of administra used. "Long-term' release, as used herein, means that the US 2004/0106589 A1 Jun. 3, 2004 29 implant is constructed and arranged to deliver therapeutic C20:5-3 (eicosapentaenoic acid), C22:1 (docoSenoic acid), levels of the active ingredient for at least 30 days, and C22:4-6 (docosatetraenoic acid), C22:5-6 (docosapen preferably 60 days. Long-term Sustained release implants taenoic acid), C22:5-3 (docosapentaenoic), C22:6-3 are well known to those of ordinary skill in the art and (docosahexaenoic acid) and C24:1-9 (nervonic). include Some of the release Systems described above. Such 8. The method of claim 1, wherein the fatty acid is implants can be particularly useful in treating Solid tumors Selected from the group consisting of C14:0 (myristic acid), by placing the implant near or directly within the tumor, C16:0 (palmitic acid), C16:1 (palmitoleic acid), C16:2, thereby affecting localized, high-doses of the compounds of C18:0 (stearic acid), C18:1 (oleic acid), C18:1-7 (vaccenic), the invention. C18:2-6 (linoleic acid), C18:3-3 O-linolenic acid), C18:3-5 (eleostearic), C18:3-6 (6-linolenic acid), C18:4-3, C20:1 0313 The conjugates of the invention also are useful, in (gondoic acid), C20:2-6, C20:3–6 (dihomo-y-linolenic acid), general, for treating mammalian cell proliferative disorders C20:4-3, C20:4-6 (arachidonic acid), C20:5-3 (eicosapen other than cancer, including psoriasis, actinic keratosis, etc. taenoic acid), C22:1 (docoSenoic acid), C22:4-6 (docosatet They further are useful in treating diabetes and its compli raenoic acid), C22:5-6 (docosapentaenoic acid), C22:5-3 cations, excess acid Secretion, cardiovascular conditions (docosapentaenoic), and C22:6-3 (docosahexaenoic acid). involving cholesterol (e.g., hyperlipidemia and hypercho 9. A pharmaceutical preparation comprising: lesterolemia), diarrhea, ovarian diseases (e.g. endometriosis, ovarian cysts, etc.) and as contraceptive agents. a covalent conjugate of a C8-C26 uunbranched, naturally 0314. Those skilled in the art will be able to recognize occurring fatty acid and a noncentral nervous System with no more than routine experimentation numerous active agent, and equivalents to the Specific products and processes described a pharmaceutically acceptable carrier. above. Such equivalents are intended to be included within 10. The pharmaceutical preparation of claim 9, wherein the Scope of the appended claims. the fatty acid is Selected from the group consisting of C8:0 (caprylic acid), C10:0 (capric acid), C12:0 (lauric acid), We claim as follows: C14:0 (myristic acid), C16:0 (palmitic acid), C16:1 (palmi 1. A method for targeting a pharmaceutical agent to a toleic acid), C16:2, C18:0 (stearic acid), C18:1 (oleic acid), noncentral nervous System tissue to treat a noncentral ner C18:1-7 (vaccenic), C18:2-6 (linoleic acid), C18:3-3 (B-li Vous System condition comprising: nolenic acid), C18:3-5 (eleostearic), C18:3-6 (6-linolenic administering to a Subject in need of Such treatment a acid), C18:4-3, C20:1 (gondoic acid), C20:2-6, C20:3-6 covalent conjugate of a C8-26, unbranched, naturally (dihomo-y-linolenic acid), C20:4-3, C20:4-6 (arachidonic occurring fatty acid and a pharmaceutical agent effec acid), C20:5-3 (eicosapentaenoic acid), C22:1 (docosenoic tive for treating Said condition provided that the drug is acid), C22:4-6 (docosatetraenoic acid), C22:5-6 (docosap not an adenosine receptor agonist or antagonist. entaenoic acid), C22:5-3 (docosapentaenoic), C22:6-3 2. The method of claim 1, wherein the tissue is breast (docosahexaenoic acid) and C24:1-9 (nervonic). tissue and wherein the Subject has a condition calling for 11. The pharmaceutical preparation of claim 9, wherein treatment of breast tissue with the pharmaceutical agent. the fatty acid is Selected from the group consisting of C14:0 3. The method of claim 1, wherein the tissue is gas (myristic acid), C16:0 (palmitic acid), C16:1 (palmitoleic trointestinal tissue and wherein the Subject has a condition acid), C16:2, C18:0 (stearic acid), C18:1 (oleic acid), calling for treatment of gastrointestinal tissue with the C18:1-7 (vaccenic), C18:2-6 Oinoleic acid), C18:3-3 (C-li pharmaceutical agent. nolenic acid), C18:3-5 (eleostearic), C18:3-6 (6-linolenic 4. The method of claim 1, wherein the tissue is ovarian acid), C18:4-3, C20:1 (gondoic acid), C20:2-6, C20:3-6 tissue and wherein the Subject has a condition calling for (dihomo-y-linolenic acid), C20:4-3. C20:4-6 (arachidonic treatment of ovarian tissue with the pharmaceutical agent. acid), C20:5-3 (eicosapentaenoic acid), C22:1 (docoSenoic 5. The method of claim 1, wherein the pharmaceutical acid), C22:4-6 (docosatetraenoic acid), C22:5-6 (docosap agent is a noncentral nervous System active agent that is entaenoic acid), C22:5-3 (docosapentaenoic), and C22:6-3 nonactive within the central nervous System. (docosahexaenoic acid). 6. The method of claim 1, wherein the drug is an anti 12. The pharmaceutical agent of claims 9-11, wherein the cancer agent. noncentral nervous System active agent is active on a tissue 7. The method of claim 1, wherein the fatty acid is Selected from the group consisting of: Selected from the group consisting of C8:0 (caprylic acid), Blood and Blood Forming tissue; Cardiovascular system C10:0 (capric acid), C12:0 (lauric acid), C14:0 (myristic tissue; Digestive and excretory System tissue, Endo acid), C16:0 (palmitic acid), C16:1 (palmitoleic acid), crine System tissue; Musclar System tissue; Reproduc C16:2, C18:0 (stearic acid), C18:1 (oleic acid), C18:1-7 tive System tissue; Respiratory System tissue, Skeletal (vaccenic), C18:2-6 (linoleic acid), C18:3-3 (O-linolenic System tissue, and Fiber and integumentary System acid), C18:3-5 (eleostearic), C18:3-6(6-linolenic acid), tissue. C18:4-3, C20:1 (gondoic acid), C20:2-6, C20:3–6 (dihomo y-linolenic acid), C20:4-3, C20:4-6 (arachidonic acid),