WO1997044063A2 - Dha-pharmaceutical agent conjugates - Google Patents

Dha-pharmaceutical agent conjugates Download PDF

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Publication number
WO1997044063A2
WO1997044063A2 PCT/US1997/008867 US9708867W WO9744063A2 WO 1997044063 A2 WO1997044063 A2 WO 1997044063A2 US 9708867 W US9708867 W US 9708867W WO 9744063 A2 WO9744063 A2 WO 9744063A2
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WIPO (PCT)
Prior art keywords
hydrochloride
sodium
tissue
conjugate
acid
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PCT/US1997/008867
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French (fr)
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WO1997044063A3 (en
Inventor
Matthews O. Bradley
Victor E. Shashoua
Nigel L. Webb
Charles S. Swindell
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Neuromedica, Inc.
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Application filed by Neuromedica, Inc. filed Critical Neuromedica, Inc.
Priority to DE69730217T priority Critical patent/DE69730217T2/en
Priority to AT97926723T priority patent/ATE273025T1/en
Priority to EP97926723A priority patent/EP0909183B1/en
Priority to AU31425/97A priority patent/AU725759B2/en
Priority to JP54281197A priority patent/JP4402173B2/en
Priority to CA002255614A priority patent/CA2255614C/en
Publication of WO1997044063A2 publication Critical patent/WO1997044063A2/en
Publication of WO1997044063A3 publication Critical patent/WO1997044063A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Taxol® (paclitaxel) was first isolated in 1971 from the bark of Taxus brevifolia and was approved in 1992 by the US Food and Drug Administration for treatment of metastatic ovarian cancer and later for breast cancer.
  • Taxol induces expression of cytokines, affects the activity of kinases and blocks processes essential for metastasis, in as yet uncharacterized mechanisms of action.
  • Taxol has attracted unusually strong scientific attention, not only because of its unique antiproliferative mechanism of action, but also because it is active against nearly ail cancers against which it has been tested and because it has been discovered to be an analog of numerous closely related compounds occurring naturally. These compounds, taxanes. are now recognized as a new class of anticancer compounds.
  • Taxol's strength against cancers of diverse tissue origin also represents a significant drawback.
  • ⁇ n ideal anticancer agent has tissue specificity, thereby reducing side-effects on normal (dividing) cells. Taxol analogs with tissue specificity therefore arc desired.
  • Another drawback of Taxol is its extreme insolubility. Taxol can be administered effectively in a solvent including cremophor, which combination can provoke severe hypersensitive immune responses. As a result of these drawbacks, and also as a result of the potential for modifying Taxol at numerous sites as demonstrated by other naturally-occurring taxanes with anticancer activity, a search for more selective taxanes was launched.
  • Taxol analogs In general with Taxol analogs, the solubility problems remain, and/or potency is sharply reduced, and/or selectivity is not improved, and/or the ratio of the median toxic dose to the median effective dose ("therapeutic index") is unacceptably reduced.
  • Taxol has the following formula:
  • Taxanes have the basic three ring structure (A, B and C), substituted or unsubstituted. Taxol's carbons are numbered conventionally as follows:
  • Taxol's solubility Attempts to improve Taxol's solubility have not resulted in successful clinical products.
  • One approach has been to manufaclurc prodrugs of Taxol, which prodrugs undergo in vivo transformation into Taxol and some other product. Attempts were made to esterify the C7 hydroxy and 2' hydroxy groups, with the hope that the bond would be stable in solution (to permit preferred administration modes -i.v. over at least 24 hours) but would cleave readily in vivo.
  • the groups tested were all hydrophilic and included amines, short carboxylic acids (using e.g. succinic anhydride and glutaric - j - anhydride), sulfonic acids, amino acids and phosphates.
  • Taxol affects microtubule formation inside a cell, but a change in structure that increases intracellular activity may adversely affect the ability of Taxol to gain entry into a cell. Taxol also is known to bind to proteins, and the effect on activity that results from a change in Taxol ' s binding to protein (in terms of conformation, cellular absorption and solubility) is unknown. It has been reported that Taxol does not get into the brain, apparently excluded by the blood brain barrier. It is not known why this is so, as Taxol is lipophilic, gets into cells and might be expected to cross the blood brain barrier.
  • Taxotere (docetaxcl), because of its slightly increased activity and solubility. Oddly, however, Taxotere differs from Taxol at sites which typically do not have a strong influence on activity, and one would not predict the improvements in Taxotere from these differences, even in hindsight. Taxotere has the following formula:
  • DHA docosahexaenoic acid
  • DHA is a 22 carbon naturally-occurring, unbranched fatly acid that previously has been attached to drugs to help deliver them across the blood brain barrier. DHA is attached via the acid group to hydrophilic drugs and renders these drugs more hydrophobic
  • DHA lipophilic
  • the present invention involves the unexpected finding that conjugates of pharmaceutical agents and a highly lipophilic group, a C22 unbranched carbon chain, have a different selectivity relative to the unconjugated pharmaceutical agents.
  • the conjugates in general, render the activity of these compounds selective for colon tissue, breast tissue and central nervous system tissue ("targeted tissues").
  • the conjugates also unexpectedly, restrict the activity of these compounds to cell types witiiin these tissue categories relative to that of the unconjugated pharmaceutical agents.
  • the conjugates further unexpectedly, reduce sharply the activity of these compounds 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 the conjugates versus those of the unconjugated pharmaceutical agents.
  • the therapeutic index of the conjugates may be improved, versus that of the unconjugated pharmaceutical agents.
  • a method for targeting a pharmaceutical agent to a noncentral nervous system tissue to treat a noncentral nervous system condition is provided.
  • a covalent conjugate of m-docosahexacnoic acid and a pharmaceutical agent effective for treating said condition is administered to a subject in need of such treatment.
  • the conjugate consists only of c «-docosahexaenoic acid and the pharmaceutical agent, wherein the c ⁇ -docosahexaenoic acid is conjugated directly to the pharmaceutical agent, free of linker, for example via the carboxylic acid group of the c/.v-docosahcxaenoic acid and a reactive group such as a free amino or hydroxyl group of the pharmaceutical agent.
  • the tissue is breast tissue, gastrointestinal tissue and ovarian tissue and the condition calls for treatment of breast tissue, gastrointestinal tissue or ovarian tissue, respectively.
  • the conjugates of the invention can be isolated conjugates.
  • An isolated conjugate is one which is separated from other different docosahexaenoic acid-pharmaceutical agent conjugates.
  • the pharmaceutical agent may be any pharmacological compound or diagnostic agent, as desired.
  • the pharmaceutical agent of course, has an activity outside of the central nervous system.
  • catagorics of pharmaceutical agents include: adrcncrgic agent; adrcnocortical steroid; adrenocortical suppressant; alcohol deterrent; aldosterone antagonist; amino acid; ammonia detoxicant; anabolic; analcplic; analgesic; androgen; anesthesia, adjunct to; anesthetic; anorcctic; antagonist; anterior pituitary suppressant; anthelmintic; anti-acne agent; anti-adrenergic; anti-allergic; anti-amebic; anti-androgen; anti-anemic; anti-anginal; anti-anxiety; anti-arthritic; anti-asthmatic; anti-atherosclerotic; antibacterial; anticholelithic; anticholelithogenic; anticholinergic; anticoagulant; anticocci
  • the pharmaceutical agent is a non anti-cancer agent.
  • the pharmaceutical agent is an anti-cancer agent.
  • anti-cancer agents are described in greater detail in the specification. Included specifically are the taxanes (e.g., Taxol and Taxotere). Conjugates of c ⁇ -docosahexaenoic acid and taxoids also are embraced by the invention.
  • C/.v-docosahexaenoic acid previously has been conjugated to drugs that are active in the central nervous system.
  • the present invention contemplates the use of c ⁇ -docosahexaenoic acid in the manufacture of a medicament for treating a noncentral nervous system condition.
  • the invention further contemplates compositions of matter that are covalent conjugates of cw-docosahexaenoic acid and noncentral nervous system active pharmaceutical agents.
  • a noncentral nervous system active pharmaceutical agent is one that has no function or use in the central nervous system. Its only therapeutic use is outside of the central nervous system.
  • Blood glucose regulators such as tolazamide, tolbutamide, chlorpropamide, acetohexamide, and, glipizide
  • HMGcoA reductase inhibitors such as Lovastatin (Mevacor), Simvastatin (Zocor), Pravastatin (Pravachol), and, Fluvstatin (Lescol)
  • Muscosal Protectives such as Misoprostol (Cytotec)
  • Gastrointestinal motility affectors such as Cisapride (Propulsid), Metoclopramide (Reglan), and, Hyoscyamine (Lcvsin);
  • Antidiarrheals such as Diphenoxylatc hydrochloride (Lomotil), Metronidazole (Flagyl), Mcthylprednisolonc (Medrol), and, Sulfasalazinc (Azulfidine); and Hormones for treating, inter alia,
  • Ethyndiol, Mestranol, Estronc, Equilin, 17 alpha dihydroequilin, equilenin, 17 alpha dihydroequilenin, 17 alpha esradiol, 27 bea estradiol, Lcuprolidc (Lupron), Testolactone, Climiphcnc, urofollitropin, bromocriptinc, gonadorclin, danazol, dehydroepiandrosteronc, androstencdione, dihydrotestosterone, Relaxin, folliculostatin, Follicle regulatory protein, Gonadocrinins, Oocyte maturation inhibitor, and, Insulin growth factor. Other compounds arc detailed below.
  • the methods and/or products of the invention are useful for treating a variety of medical conditions including conditions involving abnormal mammalian-cell proliferation. They further are useful in treating diabetes and its complications, excess acid secretion, cardiovascular conditions involving cholesterol (e.g., hyperlipidcmia and hypcrcholcsterolcmia), diarrhea, ovarian diseases (e.g. endometriosis. ovarian cysts, etc.) and as contraceptive agents.
  • Other conditions treatable according to the invention will be apparent to those skilled in the art based upon the disclosure and lists of compounds provided.
  • Noncentral nervous system tissue includes tissue of the: Blood and Blood Forming system: including platelets, blood vessel wall, and bone marrow; Cardiovascular system: including heart and vascular system; Digestive and excretory system: including alimentary tract, biliary tract, kidney, liver, pancreas and urinary tract; Endocrine system: including adrenal gland, kidney, ovary, pituitary gland, renal gland, salivaiy giand, sebaceous gland, testis, thymus gland and thyroid gland; Musclar system: including muscles that move the body.
  • Blood and Blood Forming system including platelets, blood vessel wall, and bone marrow
  • Cardiovascular system including heart and vascular system
  • Digestive and excretory system including alimentary tract, biliary tract, kidney, liver, pancreas and urinary tract
  • Endocrine system including adrenal gland, kidney, ovary, pituitary gland, renal gland, salivaiy giand, sebaceous gland, testis, thymus gland and thyroid gland
  • Musclar system
  • Reproductive System including breast, ovary, penis and uterus;
  • Respiratory system including bronchus, lung and trachea;
  • Skeletal system including bones and joints: Tissue, fiber, and integumentary system: including adipose tissue, cartilage, connective tissue, cuticle, dermis, epidermis, epithelium, fascia, hair follicle, ligament, bone marrow.
  • Figure 1 is a graph plotting concentration of conjugate 1 versus percent growth of leukemia cells.
  • Figure 2 is a graph plotting concentration of conjugate 1 versus percent growth of non-small cell lung cancer cells.
  • Figure 3 is a graph plotting concentration of conjugate 1 versus percent growth of colon cancer cells.
  • Figure 4 is a graph plotting concentration of conjugate 1 versus percent growth of CNS cancer cells.
  • Figure 5 is a graph plotting concentration of conjugate 1 versus percent growth of melanoma cells.
  • Figure 6 is a graph plotting concentration of conjugate 1 versus percent growth of ovarian cancer cells.
  • Figure 7 is a graph plotting concentration of conjugate 1 versus percent growth of renal cancer cells.
  • Figure 8 is a graph plotting concentration of conjugate 1 versus percent growth of prostate cancer cells.
  • Figure 9 is a graph plotting concentration of conjugate I versus percent growth of breast cancer cells.
  • Figure 10 is a graph plotting concentration of conjugate 2 versus percent growth of leukemia cells.
  • Figure 1 1 is a graph plotting concentration of conjugate 2 versus percent growth of non-small cell lung cancer cells.
  • Figure 12 is a graph plotting concentration of conjugate 2 versus percent growth of colon cancer cells.
  • Figure 13 is a graph plotting concentration of conjugate 2 versus percent growth of CNS cancer cells.
  • Figure 14 is a graph plotting concentration of conjugate 2 versus percent growth of melanoma cells.
  • Figure 15 is a graph plotting concentration of conjugate 2 versus percent growth of ovarian cancer cells.
  • Figure 16 is a graph plotting concentration of conjugate 2 versus percent growth of renal cancer cells.
  • Figure 17 is a graph plotting concentration of conjugate 2 versus percent growth of prostate cancer cells.
  • Figure 1 8 is a graph plotting concentration of conjugate 2 versus percent growth of breast cancer cells.
  • Figure 19 is a graph plotting concentration of Taxol versus percent growth of leukemia ceils.
  • Figure 20 is a graph plotting concentration of Taxol versus percent growth of non-small cell lung cancer cells.
  • Figure 21 is a graph plotting concentration of Taxol versus percent growth of colon camccr cells.
  • Figure 22 is a graph plotting concentration of Taxol versus percent growth of CNS cancer cells.
  • Figure 23 is a graph plotting concentration of Taxoi versus percent growth of melanoma cells.
  • Figure 24 is a graph plotting concentration of Taxol versus percent growth of ovarian cancer cells.
  • Figure 25 is a graph plotting concentration of Taxol versus percent growth of renal cancer cells.
  • Figure 26 is a graph plotting concentration of Taxol versus percent growth of prostate cancer cells.
  • Figure 27 is a graph plotting concentration of Taxol versus percent growth of breast cancer cells.
  • DHA Cw-docosahexaenoic acid
  • DHA can be isolated, for example, from fish oil or can be chemically synthesized. These methods, however, can generate trans isomers, which are difficult and expensive to separate and which may present safety problems in humans.
  • the preferred method of production is biological synthesis to produce the all cis isomer.
  • the preferred source of DHA is from Martek Biosciences Corporation of Columbia, Maryland. Martek has a patented system for manufacturing DHA using microalgae which synthesize only a single isomer of DHA, the all cis isomer. Martek's patents include U.S. Pat. Nos. 5,374,657, 5,492:938, 5.407,957 and 5,397.591 .
  • DHA also is present in the milk of lactating women, and Martek's licensee has obtained approval in Europe of DMA as a nutritional supplement for infant formula.
  • 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:
  • Paclitaxel was first isolated from the bark of Taxus brevil ' olia (Wani el al., J. Am. Chem. Soc.. 93, 2325, 1971 ). Its isolation and synthesis have been reported extensively in the literature. Applicants obtained paclitaxel from a commercial source, Hauscr Laboratories, of Boulder, Colorado.
  • analog 2 involves several steps including a number of protection-acylation-deprotection steps.
  • a solution of Taxol (59 ⁇ mol) in methylene chloride (2.5mL) was mixed at ambient temperature under argon with imidazole (147 ⁇ mol) and triethylsilyl chloride (147 ⁇ mol).
  • the reaction mixture was stirred for thirty minutes, diluted with additional methylene chloride, washed with water, saturated aqueous sodium chloride, dried, and concentrated. Chromatography of the residue produced 50mg (88%) of intermediate A plus 5mg of the 2', 7-di(triethylsilyl) ether derivative.
  • Conjugates 1 and 2 were sent to the United States National Cancer Institute (NCI) for screening in the NCI's anticancer screening program.
  • the conjugates were provided in ethanol (approximately 40mg analog/2ml ethanol).
  • the conjugates were scaled in vials under argon to avoid exposure of the conjugates to oxygen because the conjugates were believed to be sensitive to oxygen.
  • Instructions were provided to store at 4°C and to open the vials only when ready for immediate experimental use. Instructions also were provided to use the ethanol solutions containing the conjugates dircctiy or to dissolve the analogs further in DMSO (dimethylsulfoxide) at appropriate concentrations, with vortexing if necessary for adequate dispersal.
  • DMSO dimethylsulfoxide
  • Mean OO Ucw The average of optical density measurements of SRB-derived color just before exposure of cells to the test compound.
  • Mean OD lcst The average of optical density measurements of SRB-derived color after 48 hours exposure of cells to the lest compound.
  • Mean OD c , r The average of optical density measurements of SRB-derived color after 48 hours with no exposure of cells to the test compound.
  • the response parameters GI50, TGI, and LC50 are interpolated values representing the concentrations at which the PG is +50, 0, and -50, respectively. Sometimes these response parameters cannot be obtained by interpolation. If, for instance, all of the PGs in a given row exceed +50, then none of the three parameters can be obtained by interpolation. In such a case, the value given for each response parameter is the highest concentration tested. ... This practice is extended similarly to the other possible situations where a response parameter cannot be obtained by interpolation. Dose-Responsc Curves:
  • the dose-response curve page of the data package is created by plotting the PGs against the log, 0 of the corresponding concentration for every cell line.
  • the cell line curves are grouped by subpanel. Horizontal lines are provided at the PG values of +50, 0, and -50.
  • the concentrations corresponding to points where the curves cross these lines are the GI50, TGI and LC50, respectively.
  • conjugates 1 and 2 are effective anticancer agents against a more restricted set of cancer cell lines.
  • conjugates 1 and 2 were not very effective against any of the six leukemia cancer cell lines tested, whereas Taxol was somewhat effective against all four leukemia celi lines against which Taxol was tested. (See Figs. 1 , 10 and 19.)
  • Taxol was more effective against non-small cell lung cancer line H522 than against H460 (by about 3 logs), whereas conjugates 1 and 2 were slightly more effective against H460 than H522.
  • Taxol was least effective at TGI against CNSU251, whereas conjugate 1 was most effective against CNSU251 and conjugates 2 was also very effective against CNSU251 (relative to other CNS cell lines).
  • Taxol was equivalent in activity toward 'MDA-N and MDA-MB-435 breast cancer cell lines at all concentrations tested, whereas conjugates 1 and 2 were more effective against MDA-N than MDA-MB-435 at all concentrations tested.
  • conjugates I and 2 were determined to, be statistically different in their pattern of activity versus Taxol in this unique measurement by the NCI.
  • conjugates 1 and 2 were one thousand to ten thousand times less potent than Taxol for many cell lines tested. This reduction in activity is important, especially since conjugates 1 and 2 maintained strong activity against some cell lines. Conjugates 1 and 2 will be sufficiently active against certain cell lines, but will have, on average, a substantially and disproportionately lower activity against other cell lines, reducing potential side effects.
  • the TGI for Taxol against CNS SF-539 is -6.95. and the TGI for conjugate 1 against this cell line is -5.13 and for conjugate 2 is -5.53.
  • the GI50 for Taxol against CNS SF 539 is -7.52, whereas the GI50s for conjugates 1 and 2 are -6.22 and -5.56, respectively (again less than 2 logs difference).
  • Taxol has a GI50 for cell line CNSSF 268 of less than -10.0, whereas conjugates 1 and 2 have GI50s for CNSSF 268 of 5.36 and 5.28, respectively.
  • Cancers other than CNS, breast and colon cancer can be treated.
  • cancer patients could be evaluated to determine if a conjugate is strongly active against the patient's cancer prior to selecting the conjugate as the anti-cancer agent of choice for that patient.
  • Taxotere's synthesis has been reported extensively in the literature.
  • One example is Kanazawa. A. ct al., J. Organic Chem. 1994, Vol. 59, pp. 1238-1240.
  • Example 4 is Kanazawa. A. ct al., J. Organic Chem. 1994, Vol. 59, pp. 1238-1240.
  • i ⁇ gatc 3 A solution of Taxotere in methylene chloride under argon is mixed with 4-d ⁇ methylam ⁇ nopyrid ⁇ ne, dicyclohexylcarbodiimide. and DII ⁇ . The reaction mixture is stirred at ambient temperature. Radial chromatography of the residue is performed to produce Taxotere-DHA con
  • a solution of Taxotere in dimethyl formamide is mixed at ambient temperature under argon with imidazole and triethylsilyl chloride.
  • the reaction mixture is stirred at ambient temperature, diluted with methylene chloride, washed with water, saturated acqueous sodium chloride, dried, and concentrated. Radial chromatography of the residue is performed to produce intermediate C.
  • a solution of Taxotere in dimethylformamide is mixed at ambient temperature under argon with imidazole and / ⁇ ?/7-butylydimethylsilyl chloride.
  • the reaction mixture is stirred at ambient temperature, diluted with methylene chloride, washed with water, saturated aqueous sodium chloride, dried, and concentrated.
  • Radial chromatography of the residue is performed to produce intermediate E.
  • a solution of intermediate E in methylene chloride is mixed at ambient temperature under argon with 4-dimethylaminopyridine, dicyclohexylcarbodiimide, and 1 equivalent of DHA.
  • the reaction mixture is stirred at ambient temperature, diluted with ether, passed through celite, and concentrated.
  • intermediate F Radial chromatography of the residue is performed to produce intermediate F (Intermediate H also is obtained and used in Example 8 below.)
  • a solution of intermediate F in acetonitrile at 0°C under argon is mixed with aqueous HF and the reaction mixture is stirred at the same temperature. After dilution with ether, the reaction mixture is washed with water, saturated aqueous sodium chloride, dried, and concentrated Radial chromatography of the residue is performed to produce Taxotere-DHA conjugate 4.
  • a solution of Taxotere in dimethylformamide is mixed at ambient temperature under argon with imidazole and /m-butylydimethylsilyl chloride.
  • the reaction mixture is stirred at ambient temperature, diluted with methylene chloride, washed with water, saturated aqueous sodium chloride, dried, and concentrated.
  • Radial chromatography of the residue is performed to produce intermediate E.
  • a solution of intermediate E in methylene chloride is mixed at ambient temperature under argon with 4-dimethylaminopyridine, dicyclohexylcarbodiimide, and DHA.
  • the reaction mixture is stirred at ambient temperature, diluted with ether, passed through celite, and concentrated. Radial chromatography of the residue is performed to produce intermediate G.
  • conjugate 6 ⁇ solution of taxotere in dimcthylformamide is mixed at ambient temperature under argon with imidazole and (cr/-butylydimethylsilyl chloride.
  • the reaction mixture is stirred at ambient temperature, diluted with methylene chloride, washed with water, saturated aqueous sodium chloride, dried, and concentrated.
  • Radial chromatography of the residue is performed to produce intermediate E.
  • a solution of intermediate E in methylene chloride is mixed at ambient temperature under argon with 4-dimethylaminopyridine, dicyclohexylcarbodiimide. and 1 equivalent of DHA.
  • the reaction mixture is stirred at ambient temperature, diluted with ether, passed through celile, and concentrated.
  • DHA may be conjugated to virtually any drug compound or diagnostic agent and used according to the methods of the present invention so long as the pharmaceutical agent has a use outside of the central nervous system.
  • Pharmaceutical agents include the following categories and specific examples. It is not intended that the category be limited by the specific examples. Those of ordinary skill in the art will be able to identify readily those pharmaceutical agents that have utility outside of the central nervous system. Those of ordinary skill in the art will recognize also numerous other compounds that fall within the categories and that are useful according to the invention.
  • Adrcncrgic ⁇ drenalonc; ⁇ midephrine Mesylate; Apraclonidinc Hydrochloride; Brimonidine
  • Adrenocortical steroid Ciprocinonide; Desoxycorticosterone Acetate; Desoxycorticosterone Pivalate; Dexamethasone Acetate; Fludrocortisone Acetate; Fiumoxonide; Hydrocortisone Hemi suecinate; Methylprednisolone Hemisuccinate; Naflocort; Procinonide; Timobesone Acetate; Tipredanc.
  • Adrenocortical suppressant Aminoglutethimide; Trilostane.
  • Aldosterone antagonist Canrenoate Potassium; Canrenone; Dicirenone; Mexrenoate Potassium; Prorenoate Potassium; Spironolactone.
  • Amino acid Alanine; Aspartic Acid; Cysteine Hydrochloride; Cystine; Histidine; Isoleucine; Leucine; Lysine; Lysine Acetate; Lysine Hydrochloride; Methionine; Phenylalanine; Proline; Serine; Threonine: Tryptophan; Tyrosine; Valine.
  • Arginine Arginine Glutamate; ⁇ rginine Hydrochloride.
  • Analgesic Acetaminophen; ⁇ lfentanil Hydrochloride; Aminobenzoatc Potassium; Aminobenzoatc Sodium; Anidoxime; Anileridine; Anileridine Hydrochloride; Anilopam Hydrochloride; Anirolac; ⁇ ntipyrinc; Aspirin; Benoxaprofen; Benzydamine Hydrochloride; Bicifadine Hydrochloride; Brifentanil Hydrochloride; Bromadoline Maleate; Bromfenac Sodium; Buprenorphine Hydrochloride; Butacctin; Butixiratc; Butorphanol; Butorphanol Tartrate; Carbamazcpinc; Carbaspirin Calcium; Carbiphcne Hydrochloride; Carfentanil Citrate; Ciprcfadol Suecinate; Ciramadol; Ciramadol Hydrochloride; Clonixcril; Clonixin
  • Ketazocine Ketorfanol
  • Ketorolac Tromethamine Letimide Hydrochloride
  • Levomethadyl Acetate
  • Lofemizolc Hydrochloride Lofentanil Oxalate; Lorcinadol; Lornoxicam: Magnesium Salicylate;
  • Mefenamic Acid Menabitan Hydrochloride; Meperidine Hydrochloride; Meptazinol Hydrochloride; Methadone Hydrochloride; Methadyl Acetate; Methopholine; Methotrimeprazine; Metkephamid
  • Oxycodone Terephthalate Oxymorphone Hydrochloride; Pemedolac; Pentamorphone; Pentazocine;
  • Pentazocine Hydrochloride Pentazocine Lactate; Phenazopyridine Hydrochloride; Phcnyramidol
  • Sufentanil Sufentanil Citrate; Talmetacin ; Talniflumate ; Talosalate ; Tazadoiene Suecinate;
  • Tebufclone Tetrydaminc ; Tifurac Sodium; Tilidinc I Iydrochloridc; Tiopinac; Tonazocine Mesylate; Tramadol Hydrochloride; Trefentanil Hydrochloride; Trolamine: VeradoHne
  • ⁇ ndrogcn Fluoxymestcronc; Mestcrolonc; Methyltcstostcronc; Nandrolone Dccanoatc; Nandrolone Phenpropionate; Nisterime Acetate; Oxandrolonc; Oxymetholonc; Silandrone; Stanozolol; Testosterone; Testosterone Cypionatc; Testosterone Enanthatc; Testosterone Kctolauratc; ' Testosterone Phenylacetate; Testosterone Propionatc; Trestolone Acetate. Anesthesia, adjunct to: Sodium Oxybate.
  • Bupivacaine Hydrochloride Butamben; Butamben Picrate; Chloroprocaine Hydrochloride; Cocaine; Cocaine Hydrochloride; Cyclopropane; Desflurane; Dexivacainc; Diamocaine Cyclamate;
  • Etidocaine Etoxadrol Hydrochloride
  • Euprocin Hydrochloride Fluroxene; Halothane; Isobutamben;
  • Anorectic compounds including dexfenfiuramine.
  • Anorexic Aminorex; Amphecloral; Chlorphentcrmine Hydrochloride; Clominorex; Clortermine Hydrochloride; Diethylpropion Hydrochloride; Fcnfluraminc Hydrochloride; Fenisorex; Fludorcx; Fluminorcx; Levamfetaminc Suecinate; Mazindol; Mcfcnorcx Hydrochloride; Phenmctrazine Hydrochloride: Phcntcrminc; Sibulramine Hydrochloride.
  • Antagonist ⁇ tipamczole; ⁇ tosiban; Boscntan; Cimctidinc; Cimetidinc I Iydrochloridc; Clcntiazcm Maleate; Detirelix Acetate; Dcvazepidc; Donetidine; Etintidine Hydrochloride ; Famotidine;
  • Fenmetozole Hydrochloride Flumazenil; Icatibant Acetate; lcotidine; Isradipine; Metiamidc;
  • Oxiloiphan Oxmctidine I Iydrochloridc ; Oxmclidinc Mesylate ; Quadazocinc Mesylate; Ranilidinc;
  • Ranitidine Bismuth Citrate Ranilidinc Hydrochloride ; Sufotidinc; Tcludipine Hydrochloride; Tiapamil Hydrochloride; Tiotidine; Vapiprost Hydrochloride; Zaltidine Hydrochloride.
  • Anterior pituitary activator Epimcstrol.
  • Anterior pituitary suppressant Danazol.
  • Anthelmintic Albendazole; Anthelmycin; Bromoxanide; Bunamidine Hydrochloride; Butonate;
  • Cambendazole Carbantel Lauryl Sulfate; Clioxanide; Closantel; Cyclobendazole; Dichlorvos; Diethylcarbamazine Citrate; Dribendazole; Dymanthine Hydrochloride; Etibendazole;
  • Nitramisole Hydrochloride Nitrodan; Oxantel Pamoate; Oxfendazolc; Oxibendazole; Parbendazole;
  • ⁇ nti-acnc Adapalene; Erythromycin Salnacedin; Inocotcrone Acetate.
  • Anti-adrenergic ⁇ cebutolol; Alprenolol Hydrochloride; Atenolol; Bretylium Tosyiate; Bunolol Hydrochloride; Carteolol Hydrochloride; Celiprolol Hydrochloride; Cetamolol Hydrochloride;
  • Cicloprolol Hydrochloride Dexpropranolol Hydrochloride; Diacetolol Hydrochloride;
  • Levobetaxolol Hydrochloride Levobunolol Hydrochloride; Mctalol Hydrochloride; Metoprolol; Metoprolol Tartrate; Nadolol; Pamatolol Sulfate; Pcnbutolol Sulfate; Phentolamine Mesylate;
  • Anti-allergic ⁇ mlexanox; ⁇ stemizole; ⁇ zclastinc Hydrochloride; Eclazolast ; Minocrorrul ;
  • Anti-amcbic Berythromycin ; Bialamicol Hydrochloride; Chloroquinc; Chloroquinc Hydrochloride;
  • Chloroquinc Phosphate Clamoxyquin Hydrochloride; Clioquinol ; Emetine I Iydrochloridc; Iodoquinol; Paromomycin Sulfate; Quinfamide; Symetme Hydrochloride; Teclozan; Tctracycline; Tetracycline Hydrochloride.
  • ⁇ nti-androgen Benorterone; Cioteroncl; Cyproterone Acetate; Delmadinone Acetate ; Oxendolone; Topterone; Zanoterone.
  • Epoetin Alfa Epoetin Beta ; Ferrous Sulfate, Dried; Leucovorin Calcium.
  • Anti-anginal Amlodipinc Besylate; Amlodipine Maleate; Betaxolol Hydrochloride ; Bevantolol Hydrochloride ; Butoprozine Hydrochloride; Carvedilol ; Cinepazet Maleate; Metoprolol Suecinate ; Molsidominc ; Monatepil Maleate; Primidolol ; Ranolazine Hydrochloride; Tosifen; Verapamil Hydrochloride.
  • Anti-anxiety agent ⁇ datanserin Hydrochloride: Alpidem: Binospirone Mesylate; Bretazenil; Glemanserin; Ipsapironc Hydrochloride; Miriselron Maleate; Ocinaplon; Ondansetron Hydrochloride ; Panadiplon; Pancopridc ; Pazinaclonc; Serazapinc Hydrochloride; Tandospironc Citrate; Zalospirone Hydrochloride.
  • Anti-arthritic Lodelaben .
  • Anti-asthmatic Ablukast; ⁇ blukast Sodium; Azelastine Hydrochloride : Bunaprolast; Cinalukast;
  • Lodoxamide Ethyl Lodoxamide Tromethaminc; Montclukast Sodium; Ontazolast; Oxarbazole;
  • Oxatomidc Piriprost; Piriprost Potassium; Pirolatc; Pobilukast Edamine; Quazolast ; Repirinast;
  • Anti-athcrosclcrotic Mifobate; Timcfuronc.
  • Antibacterial Acedapsonc; ⁇ cctosulfonc Sodium; Alamecin; Alexidine; ⁇ mdinocillin; Amdinocillin Pivoxil; Amicyclinc; ⁇ mifloxacin; Amifloxacin Mesylate; Amikacin; Amikacin Sulfate;
  • Methylene Disalicylate Bacitracin Zinc; Bambermycins; Benzoylpas Calcium; Berythromycin ;
  • Cefaclor Cefadroxil
  • Cefamandolc Cefamandolc Nafatc
  • Ccfamandole Sodium Cefaparole
  • Cefatrizine Cefazaflur Sodium; Cefazolin; Cefazolin Sodium; Cefbuperazonc; Cefdinir; Cefepime;
  • Cefepime Hydrochloride Cefetecol; Cefixime; Cefmenoxime Hydrochloride; Cefmetazole;
  • Cefoxitin Cefoxitin Sodium; Cefpimizole; Cefpimizole Sodium; Cefpiramide; Cefpiramide Sodium;
  • Cefpirome Sulfate Cefpodoxime Proxetil; Cefprozil; Cefroxadine; Cefsulodin Sodium; Ceftazidime;
  • Ceftibutcn Ceftizoxime Sodium
  • Cefuroximc Cefuroxime ⁇ xetil
  • Pantothenatc Complex Chloramphenicol Sodium Suecinate; Chlorhexidine Phosphanilate;
  • Chl ⁇ roxylenol Chlortetracycline Bisulfate; Chlortetracycline Hydrochloride; Cinoxacin;
  • Ciprofloxacin Ciprofloxacin Hydrochloride; Cirolemycin ; Clarithromycin; Clinafloxacin Hydrochloride; Clindamycin; Clindamycin Hydrochloride; Clindamycin Palmitate Hydrochloride;
  • Colistimethatc Sodium Colistin Sulfate; Coumermycin; Coumermycin Sodium; Cyclacillin;
  • Cycioserine Dalfopristin; Dapsonc ; Daptomycin; Dcmeclocyclinc; Demeclocycline Hydrochloride;
  • Erythromycin Gluceptatc Erythromycin Lactobionate; Erythromycin Propionate; Erythromycin
  • Ilaloprogin Hctacillin; Hetacillin Potassium; Ilcxedinc; lbafloxacin; Imipencm; Isoconazolc; Isepamicin; Isoniazid; Josamycin; Kanamycin Sulfate; Kitasamycin; Levofuraltadone;
  • Lomefloxacin Lomefloxacin Hydrochloride; Lomefloxacin Mesylate; Loracarbef; Mafenide;
  • Meclocycline Meclocycline Sulfosalicylate; Megalomicin Potassium Phosphate; Mequidox; Meropcnem; Methacycline; Methacycline Hydrochloride; Methenamine; Methenamine Hippurate;
  • Nifuratcl Nifuratrone; Nifurdazil; Nifurimide; Nifurpirinol; Nifurquinazol; Nifurthiazole;
  • Pivampicillin Hydrochloride Pivampicillin Pamoate; Pivampicillin Probenate; Polymyxin B Sulfate; Porfiromycin ; Propikacin; Pyrazinamide; Pyrithione Zinc; Quindecamine Acetate; Quinupristin;
  • Rifamide Rifampin; Rifapcnline; Rifaximin; Rolitetracyclinc; Rolitetracyclinc Nitrate;
  • Rosaramicin Stearate Rosoxacin; Roxarsone; Roxithromycin; Sancycline; Sanfetrinem Sodium; Samioxicillin; Sarpicillin; Scopafungin ; Sisomicin; Sisomicin Sulfate; Sparfioxacin; Spectinomycin
  • Sulfadiazine Sulfadiazinc Sodium; Sulfadoxine; Sulfalcne; Sulfamcrazinc; Sulfamctcr;
  • Anticholelithic Monoctanoin.
  • Anticholinergic Alverinc Citrate; Anisotropine Methylbromide; ⁇ tropine; Atropine Oxide
  • Toquizinc Triampyzinc Sulfate; Trihexyphenidyl Hydrochloride; Tropicamide.
  • Anticoagulant ⁇ ncrod; Anticoagulant Citrate Dextrose Solution ; Anticoagulant Citrate Phosphate Dextrose Adenine Solution; Anticoagulant Citrate Phosphate Dextrose Solution; Anticoagulant Ilcparin Solution; Anticoagulant Sodium Citrate Solution; ⁇ rdeparin Sodium; Bivalirudin ; Bromindionc; Dalteparin Sodium ; Dcsirudin; Dicumarol; I lcparin Calcium; Ileparin Sodium; Lyapolatc Sodium; Nafamostat Mesylate ; Phcnprocoumon; Tinzaparin Sodium ; Warfarin Sodium. ⁇ nticoccidal: Maduramicin.
  • ⁇ nticonvulsant Albutoin; ⁇ mcltolidc; ⁇ tolidc; Buramalc; Carbamazcpinc ; Cinromidc; Citenamide; P T U 7/08867
  • Antidepressant Adatanserin Hydrochloride; Adinazolam ; ⁇ dinazolam Mesylate; ⁇ laproclate;
  • Hydrochloride Bupropion Hydrochloride; Butacetin; Butriptyline Hydrochloride; Caroxazone; Cartazolate; Ciclazindol; Cidoxepin Hydrochloride; Cilobamine Mesylate; Clodazon Hydrochloride;
  • Cyprolidol Hydrochloride Cyproximide ; Daledalin Tosylatc; Dapoxctine Hydrochloride; Dazadrol
  • Imipramine Hydrochloride Indeloxazine Hydrochloride; Intriptyline Hydrochloride; Iprindole; Isocarboxazid; Ketipramine Fumarate; Lofepramine Hydrochloride; Lortalamine; Maprotiline;
  • Nomifensine Maleate Nortriptyline Hydrochloride; Octriptyline Phosphate; Opipramol Hydrochloride; Oxaprotiline Hydrochloride; Oxypertine; Paroxetine; Phenelzine Sulfate;
  • Pirandamine Hydrochloride Pizotyline ;
  • Pridefine Hydrochloride Prolintane Hydrochloride;
  • Protriptylinc Hydrochloride Quipazine Maleate ; Rolicyprine; Seproxetine Hydrochloride; Sertraline Hydrochloride; Sibutramine Hydrochloride ; Sulpiride; Suritozole; Tametralinc Hydrochloride; Tampramine Fumarate; Tandamine Hydrochloride: Thiazesim Hydrochloride; Thozalinone; Tomoxetine Hydrochloride; Trazodone Hydrochloride; Trebenzomine Hydrochloride; Trimipramine; Trimipramine Maleate; Venlafaxinc Hydrochloride; Viloxazine Hydrochloride; Zimeldine Hydrochloride; Zometapine.
  • Antidiabetic ⁇ cetohexamide; Buformin; Butoxamine Hydrochloride ; Camiglibose;
  • Glibornuride Glicetanile Sodium; Gliflumide; Glipizide; Glucagon; Glyburide; Glyhexamide; Glymidine Sodium; Glyoctamide; Glyparamide; Insulin; Insulin, Dalanated; Insulin Human; Insulin
  • Pirogliride Tartrate; Proinsulin Human; Seglitide Acetate; Tolazamide; Tolbutamide; Tolpyrramide; Troglitazone; Zopolrestat.
  • Antidiarrheal Rolgamidine, Diphenoxylate hydrochloride (Lomotil), Metronidazole (Flagyl), Methylprednisolone (Medrol), Sulfasalazine (Azulfidine).
  • Antidiuretic ⁇ rgipressin Tannate; Desrnopressin Acetate; Lypressin .
  • Antidote Dimercaprol; Edrophonium Chloride; Fomepizolc; Lcucovorin Calcium ; Levolcucovorin Calcium; Methylene Blue ; Protamine Sulfate.
  • Anti-emetic Alosetron Hydrochloride; Batanopride Hydrochloride; Bemesetron; Benzquinamide; Chlorpromazine ; Chlorpromazine Hydrochloride ; Clebopride; Cyclizine Hydrochloride; Dimenhydrinate; Diphenidol; Diphenidol Hydrochloride; Diphenidol Pamoate; Dolasetron Mesylate ; Domperidone; Dronabinol; Fludorex; Flumeridone; Galdansetron Hydrochloride; Granisetron; Granisetron I Iydrochloridc; Lurosetron Mesylate; Mcclizine Hydrochloride; Metoclopramidc Hydrochloride; Metopimazine; Ondansetron Hydrochloride ; Pancopride; Prochlorperazine; Prochlorpcrazine Edisylate; Prochlorperazine Maleate ; Promethazinc Hydrochloride ; Thiethy
  • Anti-epileptic Felbamate; Loreclezole; Tolgabide.
  • Anti-estrogen Clometherone; Delmadinone Acetate ; Nafoxidine Hydrochloride; Nitromifcne Citrate; Raloxifene Hydrochloride; Tamoxifen Citrate; Toremifene Citrate ; Trioxifene Mesylate.
  • Antifibrinolytic Nafamostat Mesylate .
  • Antifungal Acrisorcin; Ambruticin; Amphotericin B; Azaconazole; Azaserine; Basifungin;
  • Cilofungin Cisconazole; Clotrimazole; Cuprimyxin: Denofungin ; Dipyrithione; Doconazole; Econazole; Econazolc Nitrate; Enilconazole; Ethonam Nitrate; Fenticonazole Nitrate; Filipin;
  • Fluconazole Flucytosine; Fungimycin; Griseofulvin; Hamycin; Isoconazole ; Itraconazole;
  • Nitralamine Hydrochloride Nystatin; Octanoic Acid; Orconazole Nitrate; Oxieonazolc Nitrate; Oxifungin Hydrochloride; ParConazole Hydrochloride; Partricin ; Potassium Iodide ;
  • Proclonol Pyrithione Zinc ; Pyrrolnitrin; Rutamycin; Sanguinarium Chloride ; Saperconazole;
  • Scopafungin Selenium Sulfide ; Sincfungin; Sulconazolc Nitrate; Terbinafinc; Tcrconazole;
  • Ticlatone Tioconazole; Tolciclate; Tolindate; Tolnaftate; Triacetin; Triafungin;
  • Antiglaucoma agent ⁇ lprcnoxime Hydrochloride ; Colforsin; Dapiprazole Hydrochloride ; Dipivefrin Hydrochloride ; Naboctate Hydrochloride ; Pilocarpine; Pirnabine.
  • Antihemophilic Antihemophilic Factor.
  • Antihemorrhagic Poliglusam.
  • Antihistaminic ⁇ crivastine; ⁇ ntazoline Phosphate; Astemizole ; Azatadine Maleate; Barmastine;
  • Cetirizine Hydrochloride Chlorpheniramine Maleate; Chlorpheniramine Polistirex; Cinnarizine;
  • ⁇ ntihyperlipidemic Cholestyramine Resin ; Clofibrate; Colestipol Hydrochloride; Crilvastatin;
  • Niacin Niacin ; Pravastatin Sodium; Probucol; Simvastatin; Tiquesidc; Xenbucin.
  • Antihyperlipoproteinemic Acontinentn; Beloxamide; Bezafibratc; Boxidine; Butoxamine Hydrochloride; Cetaben Sodium; Ciprofibrate; Gemcadiol; Halofenate ; Lifibrate; Meglutol; Nafenopin; Pimetine Hydrochloride; Theofibratc; Tibric ⁇ cid; Treloxinate.
  • ⁇ ntihypcrtensive Alfuzosin Hydrochloride; Alipamide ; Althiazide; Amiquinsin Hydrochloride; ⁇ mlodipine Besylatc ; Amlodipinc Maleate ; Anaritide Acetate ; Atiprosin Maleate; Belfosdil; Bemitradine; Bendacalol Mesylate; Bendroflumcthiazidc ; Benzthiazide ; Betaxolol Hydrochloride ; Bethanidinc Sulfate; Bevantolol Hydrochloride ; Biclodil Hydrochloride; Bisoprolol; Bisoprolol Fumarate; Bucindolol Hydrochloride; Bupicomide; Buthiazide: Candoxatril; Candoxatrilat; Captopril ; Carvedilol ; Ceronapril; Chlorothiazide Sodium ; Cicl
  • Ciclafrinc Hydrochloride Midodrine Hydrochloride.
  • Anti-infective Difloxacin Hydrochloride ; Lauryl lsoquinolinium Bromide; Moxalactam Disodium; Ornidazole; Pentisomicin; Sarafloxacin Hydrochloride; Protease inhibitors of HIV and other retroviruscs; Intcgrase Inhibitors of HIV and other rctroviruscs; Cefaclor (Ccclor); Acyclovir (Zovirax); Norfloxacin (Noroxin); Cefoxitin (Mefoxin); Cefuroxime axetil (Ceftin); Ciprofloxacin (Cipro).
  • Anti-infective, topical Alcohol; Aminacrine Hydrochloride; Benzethonium Chloride : Bithionolate Sodium; Bromchlorenone; Carbamide Peroxide; Cetalkonium Chloride; Cetylpyridinium Chloride : Chlorhcxidinc Hydrochloride; Clioquinol ; Domiphen Bromide; Fenticlor; Fludazonium Chloride; Fuchsin, Basic; Furazolidone ; Gentian Violet; Halquinols; Hexachlorophene: Hydrogen Peroxide; Ichthammol: Imidecyl Iodine; Iodine; Isopropyl Alcohol; Mafenide Acetate; Meralein Sodium; Mercufcnol Chloride; Mercury, Ammoniated; Methylbenzethonium Chloride; Nitrofurazone; Nitromersol; Octenidine Hydrochloride; Oxychlorosene; Oxychlorosene Sodium
  • Anti-inflammatory Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; Alpha Amyiase;
  • Enlimomab Enolicam Sodium ; Epirizole ; Etodolac; Etofenamatc ; Felbinac; Fenamole; Fenbufen; Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone; Fluazacoit; Flufenamic Acid;
  • Halcinonide Halobetasol Propionate; Halopredone Acetate; Ibufenac ; Ibuprofen; Ibuprofen
  • Ibuprofen Piconol Inode
  • Indomethacin Indomethacin Sodium
  • Indoprofen Indoxole
  • Intrazole Isoflupredone Acetate
  • Isoxepac Isoxicam
  • Ketoprofen Lofemizole
  • Proxazole Proxazole Citrate ; Rimexolone; Romazarit ; Salcolcx ; Salnacedin; Salsalate ;
  • Talniflumate Talosalate ; Tebufelone ; Tenidap; Tenidap Sodium; Tenoxicam; Tesicam; Tcsimide; Tetrydamine ; Tiopinac; Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide; Triflumidatc;
  • Zidometacin Zidometacin; Zomepirac Sodium .
  • Anlikeratinizing agent Doretinel; Linarotene; Pelretin.
  • ⁇ nlimalarial ⁇ ccdapsonc ; ⁇ modiaquinc Hydrochloride ; ⁇ mquinalc; ⁇ rtcflcnc; Chloroquinc ;
  • Chloroquine Hydrochloride Chloroquine Phosphate ; Cycloguanil Pamoate; Enpiroline Phosphate; Halofantrine Hydrochloride ; Hydroxychioroquine Sulfate ; Mefloquine Hydrochloride; Menoctone;
  • Mirincamycin Hydrochloride Primaquine Phosphate; Pyrimethamine; Quinine Sulfate; Tcbuquine.
  • Antimicrobial Aztreonam; Chlorhexidine Gluconate; Imidurea; Lycetamine; Nibroxane; Pirazmonam Sodium; Propionic Acid ; Pyrithionc Sodium; Sanguinarium Chloride ; Tigemonam Dicholine.
  • Antimigraine Dolasetron Mesylate ; Naratriptan Hydrochloride; Sergolexole Maleate; Sumatriptan Suecinate; Zatosetron Maleate.
  • Antimitotic Podofilox.
  • Antimycotic Amorolfine.
  • Antinauscant Buclizine Hydrochloride ; Cyclizine Lactate; Naboctate Hydrochloride .
  • Antineoplastic ⁇ civicin; ⁇ clarubicin; ⁇ codazolc Hydrochloride; ⁇ cronine; ⁇ dozelesin;
  • Anastrozole Anthramycin; Asparaginase; Asperlin ; Azacitidine; Azetepa; Azotomycin; Batimastat;
  • Benzodepa Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Bropirimine ; Busulfan; Cactinomycin; Calusteronc; Caracemiide;
  • Carbetimer Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin; Cedefingol;
  • Cytarabine dacarbazine; Dactinomycin; Daunorubicin Hydrochloride; Decitabine; Dexormaplatin;
  • Edatrexate Eflomithine Hydrochloride ; Elsamitrucin; Enloplatin; Enpromate; Epipropidine;
  • Fadrozole Hydrochloride Fazarabinc; Fenretinide; Floxuridine ; Fludarabine Phosphate;
  • Fluorouracil Fluorouracil; Flurocitabine; Fosquidonc; Fostriecin Sodium; Gemcitabine; Gemcitabine
  • Mitosper Mitosper; Mitotane; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin;
  • Temoporlin Teniposide; Teroxirone; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; Topotecan Hydrochloride; Toremifene Citrate; Trestolone Acetate; Triciribine
  • Vindesine Sulfate Vinepidine Sulfate; Vinglycinate Sulfate; Vinleursine Sulfate; Vinorelbine
  • anti-neoplastic compounds include: 20-epi-l ,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelidc; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing mo ⁇ hogenetic protein- 1 ; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTB
  • IL-2 capecitabine
  • carboxamide-amino-triazole carboxyamidotriazole
  • CaRest M3 CARN 700
  • cartilage derived inhibitor carzelesin
  • casein kinase inhibitors ICOS
  • castanospermine cecropin
  • thymopoietin receptor agonist thymotrinan
  • thyroid stimulating hormone tin ethyl etiopurpurin
  • tirapazamine titanocene dichloride
  • titanocene dichloride topotecan
  • topsentin toremifene
  • totipotent stem cell factor translation inhibitors; tretinoin; triacetyluridine: triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubcnimex; urogenitai sinus- derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbinc; vinxaltinc; vitaxin; vorozo
  • Tricyclic anti-depressant drugs e.g., imipramine, desipramine, amitryptyiine, clomipramine, trimipramine, doxepin, nortriptyline, protriptyline, amoxapine and maprotiline
  • non-tricyclic anti-depressant drugs e.g., sertralinc, trazodone and citalopram
  • Ca +* antagonists e.g., verapamil, nifedipine, nitrendipine and carovcrine
  • Calmodulin inhibitors e.g., prenylamine, trifluoroperazine and clomipramine
  • Amphotericin B Triparanol analogues (e.g., tamoxifen); antiarrhythmic drugs (e.g., quinidinc); antihypertensive drugs (e.g., reserpine); Thiol depleters (e.g., buthionine and sulfoximine) and Multiple Drug Resistance reducing agents such as Cremaphor EL.
  • the compounds of the invention also can be administered with cytokines such as granulocyte colony stimulating factor.
  • ⁇ ntineutropenic Filgrastim; Lcnograstim; Molgramostim; Regramostim; Sargramostim.
  • ⁇ ntiobscssional agent Fluvoxamine Maleate.
  • Antiparasitic Abamcctin; Clorsulon; lvermcclin.
  • Bcnztropinc Mesylate Biperiden; Biperiden Hydrochloride; Biperiden Lactate; Carmantadine; Ciladopa Hydrochloride; Dopamantine; Ethopropazine Hydrochloride; Lazabemide; Levodopa; Lomctraline Hydrochloride; Mofcgiline Hydrochloride; Naxagolide Hydrochloride; Pareptide Sulfate; Procyclidine Hydrochloride; Quinclorane Hydrochloride; Ropinirole Hydrochloride; Selcgilinc Hydrochloride; Tolcaponc; Trihexyphcnidyl I Iydrochloridc
  • Antiperistaltic Difenoximide Hydrochloride; Difenoxin; Diphenoxylate Hydrochloride; Fluperamide; Lidamidine Hydrochloride; Loperamidc Hydrochloride; Malethamcr; Nufcnoxolc; Paregoric. Antipncumocystic: Atovaquone.
  • Antiproliferative agent Piritrexim Isethionate.
  • Antiprostatic hypertrophy Sitogluside.
  • Antiprotozoal Amodiaquine; Azanidazole; Bamnidazole; Camidazole; Chlortetracycline Bisulfate ; Chlortetracycline Hydrochloride; Flubendazole; Flunidazole; Halofuginone Hydrobromide; Imidocarb Hydrochloride; Ipronidazole; Metronidazole; Misonidazole; Moxnidazoie; Nitarsone; Partricin; Puromycin; Puromycin Hydrochloride; Ronidazolc; Sulnidazole; Tinidazole.
  • ⁇ ntipruritic Cyproheptadine Hydrochloride ; Methdilazine; Methdilazine Hydrochloride; Trimeprazine Tartrate.
  • Antipsoriatic Acitretin; Anthralin; Azaribine; Calcipotriene; Cycloheximide; Enazadrem Phosphate; Etretinatc; Liarozole Fumarate; Lonapalenc; Tepoxalin.
  • Antipsychotic Acetophenazine Maleate; Alentemol Hydrobromide; Alpertine; Azaperone;
  • Carphenazine Maleate Carvotroline Hydrochloride; Chlo ⁇ romazine; Chlo ⁇ romazine
  • Fluphenazine Hydrochloride Fluspiperonc; Fluspirilene; Flutrolinc; Gevotroline Hydrochloride;
  • Halopemidc Haloperidol; Haloperidol Decanoate; Iloperidonc; Imidoline Hydrochloride;
  • Pinoxcpin Hydrochloride Pipampcronc; Piperacctazinc; Pipotiazinc Palmitate; Piquindone
  • Antirheumatic Auranofin; Aurothioglucose; Bindarit; Lobenzarit Sodium; Phenylbutazone; Pirazolac; Prinomide Tromethamine; Seprilose.
  • Antischistosomal Becanthone Hydrochloride; Hycanthone; Lucanthone Hydrochloride; Niridazole; Oxamniquine; Pararosanilinc Pamoate; Teroxalene Hydrochloride.
  • Antiseborrheic Chloroxine; Piroctonc; Piroctone Olamine; Resorcinol Monoacetate.
  • ⁇ ntisecretory Arbaprostil; Deprostil; Fenoctimine Sulfate; Octreotide: Octreotide Acetate; Omeprazole Sodium; Rioprostil; Trimoprostil.
  • Antispasmodic Stilonium Iodide; Tizanidine Hydrochloride.
  • Antithrombotic ⁇ nagrelidc Hydrochloride; Bivalirudin ; Daltcparin Sodium ; Danaparoid Sodium; Dazoxibcn Hydrochloride; Efegatran Sulfate; Enoxaparin Sodium; Ifetroban; Ifetroban Sodium; Tinzaparin Sodium ; Trifcnagrel.
  • Antitussive Benzonatatc; Butamirate Citrate; Chlophcdianol Hydrochloride; Codeine Polistirex; Codoximc; Dextromethorphan; Dcxtromethorphan Hydrobromide; Dextrometho ⁇ han Polistirex; Ethyl Dibunatc; Guaiapate; Hydrocodonc Bitartratc; Hydrocodonc Polistirex; Levopropoxyphene Napsylate; Noscapine; Pemerid Nitrate; Pipazcthatc; Suxemcrid Sulfate.
  • Anti-ulcerative Accglutamide Aluminum; Cadcxomer Iodine ; Cctraxate Hydrochloride; Enisoprost; Isotiquimide; Lansoprazolc; Lavoltidine Suecinate; Misoprostol; Nizatidine; Nolinium Bromide ; Pantoprazole; Pifarninc; Pirenzcpinc Hydrochloride; Rabcprazole Sodium ; Remiprostol; Roxalidinc Acetate Hvdrochloride; Sucralfatc; Sucrosofate Potassium; Tolimidone.
  • Anti-urolithic Cystcamine; Cysteamine Hydrochloride; Tricitrates .
  • Antiviral Accmannan; Acyclovir; Acyciovir Sodium; Adefovir; Alovudinc; Alvircept Sudotox; Amantadine Hydrochloride; Aranotin; Arildone; Atevirdine Mesylate; ⁇ vridinc; Cidofovir; Cipamfylline; Cytarabine Hydrochloride; Delavirdine Mesylate; Desciclovir; Didanosine; Disoxaril; Edoxudine; Enviradene; Enviroximc; Famciclovir; Famotine Hydrochloride; Fiacitabine; Fialuridine; Fosarilate; Foscarnet Sodium; Fosfonet Sodium; Ganciclovir; Ganciclovir Sodium; Idoxuridine; Kethoxal; Lamivudine; Lobucavir; Memotine Hydrochloride; Methisazone; Nevirapine; Penciclovir; Pirodavir; Rib
  • Benign prostatic hyperplasia therapy agent Tamsulosin Hydrochloride.
  • Blood glucose regulators Human insulin; Glucagon; Tolazamide; Tolbutamide; Chloropropamidc; ⁇ cctohcxamide and Glipizidc.
  • Bone rcsorption inhibitor Alcndronate Sodium; Etidronatc Disodium; Pamidronatc Disodium.
  • Bronchodilator ⁇ lbutcrol; ⁇ lbutcrol Sulfate; ⁇ zanator Maleate; Bamifyllinc Hydrochloride; Bitolierol Mesylate; Butaprost; Carbuterol Hydrochloride; Clo ⁇ renaline Hydrochloride; Colt ⁇ rol
  • Fenoterol Fcnprinast Hydrochloride
  • Guaithylline Hexoprenaline Sulfate
  • Hoquizil Hydrochloride Hoquizil Hydrochloride
  • Pirbuterol Hydrochloride Procatcrol Hydrochloride; Pscudocphedrinc Sulfate; Quazodinc ;
  • Carbonic anhydrasc inhibitor Acetazolamide; ⁇ cctazolamide Sodium; Dichlo ⁇ henamide; Dorzolamidc Hydrochloride; Methazolamide; Sezolamide Hydrochloride.
  • Cardiac depressant Acecainide Hydrochloride; Acetylcholine Chloride; Actisomide; Adenosine;
  • Capobenic Acid Cifenline; Cifcnline Suecinate; Clofilium Phosphate; Disobutamide: Disopyramide;
  • Cardioprotectant Dexrazoxane; Drafiazine.
  • Cardiotonic ⁇ ctodigin; ⁇ mrinonc; Bcmoradan; Bulopaminc; Carbazcran; Carsatrin Suecinate; Deslanoside; Digitalis; Digitoxin; Digoxin; Dobutaminc; Dobutamine Hydrochloride; Dobutamine Lactobionatc; Dobutaminc Tartrate; Enoximonc; Imazodan Hydrochloride; Indolidan; Isomazjole Hydrochloride; Lcvdobutamine Lactobionatc; Lixazinone Sulfate; Mcdorinone; Milrinone; Pelrinone Hydrochloride: Pimobcndan; Piroximonc; Prinoxodan; Proscillaridin; Quazinonc; Tazolol Hydrochloride; Vcsnarinone.
  • Cardiovascular agent Dopcxamine; Dopexamine Hydrochloride.
  • Choleretic Dehydrocholic Acid; Fencibutirol: Hymecromone; Piprozolin; Sincalide; Tocamphyl. Cholinergic: Aceclidine; Bethanechol Chloride; Carbachol; Demecarium Bromide; Dexpanthenol; Echothiophate Iodide; Isoflurophate; Methacholine Chloride; Neostigmine Bromide; Neostigmine Methylsulfatc; Physostigminc; Physostigmine Salicylate; Physostigmine Sulfate; Piloca ⁇ ine ; Pilocarpine Hydrochloride; Piloca ⁇ ine Nitrate; Pyridostigmine Bromide.
  • Cholinergic agonist Xanomeline; Xanomeline Tartrate.
  • Cholinesterase Deactivator Obidoxime Chloride; Pralidoxime Chloride; Pralidoximc Iodide; Pralidoxime Mesylate.
  • Coccidiostat A ⁇ rinocid; Narasin ; Semduramicin; Semduramicin Sodium.
  • Cognition adjuvant Ergoloid Mesylates; Piracetam; Pramiracctam Hydrochloride; Pramiracctam Sulfate; Tacrine Hydrochloride.
  • Cognition enhancer Besipirdine Hydrochloride; Linopirdine; Sibopirdine .
  • Diagnostic aid Aminohippurate Sodium;'Anazolene Sodium; ⁇ rclofenin; Arginine ; Bentiromide; Benzylpenicilloyl Polylysine; Butedronatc Tetrasodium; Butilfenin; Coccidioidin; Corticorelin Ovine Triflutate ; Corticotropin.
  • Diuretic Ambuphylline ; ⁇ mbuside; Amiloride Hydrochloride; Azolimine; Azosemide; Brocrinat; Bumctanide; Chlorothiazide; Chlorthalidone; Clazoliminc; Clorexolone; Ethacrynate Sodium; Ethacrynic ⁇ cid; Etozolin; Fenquizone; Furosemide; Hydrochlorothiazide; Isosorbidc; Mannitol ; Mefruside; Ozolinone; Pirctanidc; Spiroxasone; Torsemidc; Triamterene; Triflocin; Urea.
  • Dopaminergic agent Ibopaminc.
  • Emetic Apomorphine Hydrochloride.
  • Enzyme inhibitor Acetohydroxamic Acid; Alrestatin Sodium; Aprotinin; Benazepril Hydrochloride;
  • Bcnazcprilat Bcnurcstat; Bromocripiinc; Bromocriptine Mesylate; Cilastatin Sodium; Flurofamide;
  • Teprotide Tolfamide; Zofcnopril Calcium.
  • Estrogen Chlorotrianisenc; Dienestrol; Diethylslilbestrol; Dielhylslilbestrol Diphosphate; Equidin;
  • Estradiol Estradiol Cypionate; Estradiol Enanthatc; Estradiol Undecylate; Estradiol Valerate;
  • Estrazinol Hydrobromide Estriol; Estrofurate; Estrogens, Conjugated; Estrogens, Esterified;
  • Fibrinolytic ⁇ nistreplasc; Bisobrin Lactate; Brinolasc.
  • Free oxygen radical scavenger Pcgorgotein.
  • Gastrointcstinal Motility agents Cisapride (Propulsid); Metoclopramidc (Reglan); Hyoscyamine (Levsin).
  • Glucocorticoid ⁇ mcinonide; Beclomethasone Dipropionate; Betamethasone; Betamethasone Acetate; Betamethasone Benzoate; Betamethasone Dipropionate; Betamethasone Sodium Phosphate; Betamethasone Valerate; Carbenoxolone Sodium; Clocortolone Acetate; Clocortolone Pivalate; Cloprednol: Corticotropin; Corticotropin, Repository; Corticotropin Zinc Hydroxide; Cortisone Acetate; Cortivazol; Descinolone Acetonide; Dexamethasone; Dexamethasone Sodium Phosphate; Diflucortolone; Diflucortolone Pivalate; Flucloronide; Flumethasone; Flumethasone Pivalate; Flunisolide; Fluocinolone Acetonide; Fluocinonide; Fluocortolone; Fluocortolone Caproate; Fluorometholone;
  • Gonad-stimulating principle Buserelin Acetate; Clomiphcne Citrate; Ganirelix Acetate: Gonadorelin Acetate; Gonadorelin Hydrochloride; Gonadotropin. Chorionic; Menotropins.
  • Hair growth stimulant Minoxidil .
  • Hemostatic ⁇ minocaproic Acid; Oxamarin Hydrochloride; Sulmarin; Thrombin; Trancxamic Acid.
  • Histamine 112 receptor antagonists Ranilidinc (Zantac); Famotidinc (Pcpcid); Cimetidinc (Tagamct); Nizatidinc ( ⁇ xid).
  • Hormone Dielhylslilbestrol; Progesterone; 17 hydroxy progesterone; Mcdroxyprogcstcronc; Norgcstrcl; Norcthynodrcl; Estradiol; Mcgcstrol (Mcgacc); Norclhindronc; Levonorgcstrcl; Ethyndiol; Ethinyl estradiol; Mestranol; Estrone; Equilin; 17 alpha dihydrocquilin; equiienin; 17 alpha dihydroequilenin; 17 alpha estradiol; 17 beta estradiol; Leuprolide (lupron); Glucagon; Testolactone; Clomiphene; Han memopausal gonadotropins; Human chorionic gonadotropin; Urofollitropin; Bromocriptine; Gonadorelin; Luteinizing hormone releasing hormone and analogs; Gonadotropins; Danazol; Testoster
  • HMGCoA reductase inhibitors Lovastatin (Mevacor); Simvastatin (Zocor); Pravastatin (Pravachol); Fluvasatin (Lescol).
  • Immunizing agent Antirabies Serum; Antivenin (Latrodectus mactans); Antivenin (Micrums Fulvius); Antivenin (Crotalidac) Polyvalent; BCG Vaccine; Botulism Antitoxin; Cholera Vaccine; Diphtheria Antitoxin; Diphtheria Toxoid; Diphtheria Toxoid Adsorbed; Globulin, Immune; Hepatitis B Immune Globulin; Hepatitis B Vims Vaccine Inactivated; Influenza Vims Vaccine; Measles Vims Vaccine Live; Meningococcal Polysaccharide Vaccine Group ⁇ ; Meningococcal Polysaccharide Vaccine Group C; Mumps Virus Vaccine Live; Pertussis Immune Globulin; Pertussis Vaccine; Pertussis Vaccine Adsorbed; Plague Vaccine; Poliovirus Vaccine Inactivated; Poliovirus Vaccine
  • Immunoreguiator Azarole; Fanetizole Mesylate; Frentizole; Oxamisole Hydrochloride; Ristianol Phosphate; Thymopentin; Tilomisole.
  • Immunostimulant Loxoribine ; Teceleukin.
  • Immunosuppressant Azathioprine; Azathioprine Sodium; Cyclosporine; Daltroban; Gusperimus
  • Trihydrochloride Trihydrochloride; Sirolimus; Tacrolimus.
  • Impotence therapy adjunct Delequamine Hydrochloride.
  • Inhibitor Acarbose; Atorvastatin Calcium; Benserazide ; Brocresine; Carbidopa; Clavulanate Potassium; Dazmegrel; Doccbenonc; Epoprostenol; Epoprostenol Sodium; Epristeridc; Finastcridc; Flurbiprofen Sodium; Furcgrclate Sodium; Lufironil; Miglitol; Orlistat; Pimagcdinc Hydrochloride; Pirmagrel; Ponalrestat; Ridogrel; Sulbactam Benzathine ; Sulbactam Pivoxil ; Sulbactam Sodium ; Suronacrine Maleate; Tazobactam; Tazobactam Sodium; Ticlopidine Hydrochloride; Tirilazad Mesylate; Tolrestat; Velnacrine Maleate; Zifrosilone; Zileuton.
  • Keratolytic Alcloxa ; Aldioxa ; Benzoyl Peroxide; Dibenzothiophene; Etarotene; Isotretinoin; Motretinide; Picotrin Diolaminc; Resorcinol; Resorcinol Monoacetatc ; Salicylic Acid; Sumarotcne; Tazarotene; Tetroquinone; Trctinoin.
  • LHRH agonist Deslorclin; Goserelin; I listrclin; Lutrclin Acetate; Nafarelin Acetate.
  • liver disorder treatment Malotilate.
  • Memory adjuvant Dimoxamine Hydrochloride; Ribaminol.
  • Mucolytic Acetylcysteine; Carbocysteine; Domiodol.
  • Mucosal Protective agents Misoprostol (Cytotec).
  • Nasal decongestant Nemazoline Hydrochloride; Pseudoephedrine Polistirex.
  • Neuroleptic Duoperone Fumarate; Risperidone.
  • Neuromuscular blocking agent Atracurium Besylate; Cisatracurium Besylate; Doxacurium Chloride; Gallamine Triethiodide; Metocurine Iodide; Mivacurium Chloride; Pancuronium Bromide; Pipecuronium Bromide; Rocuronium Bromide; Succinylcholine Chloride; Tubocurarine Chloride; Vecuronium Bromide.
  • Neuroprotectivc Dizocilpine Maleate.
  • NMDA antagonist Sclfotel.
  • Non-hormonal sterol derivative Prcgncnolonc Suecinate.
  • Oxytocic Carboprost; Carboprost Methyl; Carboprost Tromethamine; Dinoprost ; Dinoprost Tromethamine ; Dinoprostonc ; Ergonovine Maleate; Meteneprost ; Methylergonovine Maleate; Oxytocin; Spartcine Sulfate.
  • Plasminogen activator ⁇ llcplasc; Urokinasc.
  • Platelet activating factor antagonist Lcxipafant.
  • Platelet aggregation inhibitor ⁇ cadesinc; Bcraprost; Bcraprost Sodium; Ciprostcnc Calcium; llazigrcl; l.ifarizine; Oxagrclatc.
  • Post-stroke and post-head trauma treatment Citicoline Sodium.
  • Potcntiator Pentostatin; Talopram Hydrochloride.
  • Progestin Algestone Acetophenide; Amadinone Acetate; ⁇ nagestone Acetate; Chlormadinone Acetate; Cingeslol; Clogestone Acetate; Clomegestone Acetate; Desogestrel; Dimcthisterone; Dydrogesterone; Ethynerone; Ethynodiol Diacetate; Etonogestrel; Flurogestonc Acetate; Gestaclone; Gestodene; Gestonorone Caproate: Gcstrinonc; Haloprogcsterone; Hydroxyprogesteronc Caproate; Levonorgestrel; Lynestrenol; Medrogestone; Medroxyprogesterone Acetate; Methynodiol Diacetate; Norethindrone; Norethindrone Acetate; Norethynodrel; Norgestimate; Norgestomet; Norgestrel; Oxogestone Phenpropionate; Progesterone; Quingestanol A
  • Prostaglandin Cloprostcnol Sodium; Fluprostenol Sodium; Gemcprost; Prostalene; Sulprostone.
  • Prostate growth inhibitor Pentomone.
  • Prothyrotropin Protirelin.
  • Pulmonary surface Beractant; Colfosccril Palmitate.
  • Radioactive agent Fibrinogen 1 125 ; Fludcoxyglucosc F 18 ; Fluorodopa F 18 ; Insulin I 125;
  • Liothyroninc 1 131 Merisoprol Acetate Mg 197; Mcrisoprol ⁇ cctalc I Ig 203; Mcrisoprol Hg 197 ;
  • Cinflumide Cinnamedrine; Clodanolene; Cyclobenzaprine Hydrochloride; Dantrolene; Dantrolene
  • Repartitioning agent Cimateroi.
  • Scabicide Amitraz; Crotamiton.
  • Sclerosing agent Ethanolamine Olcate; Morrhuate Sodium; Tribcnoside.
  • Sedative-hypnotic AUobarbital; ⁇ lonimid; Alprazolam; ⁇ mobarbital Sodium; Bentazepam; Brolizolam; Bulabarbital; Butabarbital Sodium; Bulalbital; Capuride; Carbocloral; Chloral Bclainc;
  • Chloral Hydrate Chlordiazepoxidc Hydrochloride; Clopcridone Hydrochloride; Clorcthatc;
  • Cyprazcpam Dexclamol Hydrochloride; Diazepam; Dichloralphenazonc; Estazolam; Ethchlorvynol; Etomidate; Fenobam; Flunitrazepam: Fosazepam; Glutethimide; Halazepam; Lormetazepam; Mecloqualone; Meprobamatc; Methaqualone; Midaflur: Paraldehyde; Pentobarbital; Pentobarbital Sodium; Perlapine; Prazepam; Quazepam; Rcclazepam; Roletamide; Secobarbital; Secobarbital Sodium; Suproclone; Thalidomide; Tracazolate; Trepipam Maleate; Triazolam; Tricetamide; Triclofos Sodium; Trimetozine; Uldazepam; Zaleplon; Zolazepam Hydrochloride; Zolpidem Tartrate.
  • Selective adcnosine Al antagonist Apaxifylline.
  • Serotonin antagonist ⁇ ltanserin Tartrate; Amesergide; Ketanserin; Ritanserin.
  • Serotonin inhibitor Cinanserin Hydrochloride; Fencionine; Fonazine Mesylate; Xylamidine
  • Serotonin receptor antagonist Tropanserin Hydrochloride.
  • Steroid Dexamethasone Acefuratc; Momctasone Furoate.
  • Stimulant Amfonelic Acid; Amphetamine Sulfate; ⁇ mpyzine Sulfate; ⁇ rbulamine Hydrochloride; Azabon; Caffeine; Cerulctide; Ceruletide Diethylamine; Cisapride; Dazopride Fumarate; Dcxtroamphctaminc: Dextroamphctamine Sulfate; Difluaninc Hydrochloride; Dimefiinc Hydrochloride; Doxapram Hydrochloride; Etryptamine Acetate; Ethamivan; Fcncthylline Hydrochloride; Flubanilatc Hydrochloride; Flurolhyl; Histamine Phosphate; Indrilinc Hydrochloride; Mefexamide; Methamphetamine Hydrochloride; Mcthylphenidate Hydrochloride; Pemoiinc; Pyrovaleronc Hydrochloride; Xamotcrol; X
  • Suppressant ⁇ mfiutizolc; Colchicinc; Tazofclonc.
  • Fampridinc Symptomatic multiple sclerosis
  • Synergist Proadifcn Hydrochloride.
  • Thyroid hormone Levothyroxine Sodium; Liothyronine Sodium; Liotrix.
  • Thyroid inhibitor Methimazole; Propylthiouracil.
  • Thyromimetic Thyromedan Hydrochloride.
  • Tranquilizer Bromazepam; Buspirone Hydrochloride; Chlordiazepoxide; Ciazolam; Clobazam; Clorazepate Dipotassium; Clorazepate Monopotassium; Demoxepam; Dexmedetomidine; Enciprazine Hydrochloride; Gepirone Hydrochloride; Hydroxyphenamate; Hydroxyzine Hydrochloride; Hydroxyzine Pamoate; Ketazolam; Lorazepam; Lorzafone; Loxapine; Loxapinc Suecinate; Medazepam Hydrochloride; Nabilone; Nisobamate ; Oxazepam; Pentabamate; Pirenperone; Ripazepam; Rolipram; Sulazepam; Taciamine Hydrochloride; Temazepam; Triflubazam; Tybamate; Valnoctamide.
  • Amyotrophic lateral sclerosis agents Riluzole.
  • Cerebral ischemia agents Dextrorphan Hydrochloride.
  • Uricosuric Benzbromarone; Irtemazole; Probenecid; Sulfinpyrazone.
  • Vasoconstrictor ⁇ ngiotensin Amide; Fclypressin; Methysergide; Methyscrgide Maleate.
  • Vasodilator ⁇ lprostadil; Azaclorzinc Hydrochloride; Bamcthan Sulfate; Bepridil Hydrochloride; Buterizine; Cetiedil Citrate; Chromonar Hydrochloride; Clonitratc; Diltiazem Hydrochloride; Dipyridamolc; Droprcnilamine; Erythrityl Tctranitrate; Fclodipinc; Flunarizine Hydrochloride; Fosledil; I lcxobendine; Inosilol Niacinatc; Iproxaminc Hydrochloride; Isosorbide Dinilrate; Isosorbide Mononitralc; Isoxsuprinc Hydrochloride; Lidofiazinc; Mcfcnidil; Mcfcnidil Fumarate; Mibcfradil Dihydrochloride; Miofiazinc Hydrochloride; Mixidinc; Nafronyl Oxalat
  • Wound healing agent Ersofermin.
  • Xanthine oxidase inhibitor Allopurinol; Oxypurinol
  • Other pharmaceutical agents include: 1-decpyrrolidinone; 1-dodecpyrrolidinone; 16-alpha fluoroestradiol; 16-epiestriol; l ⁇ alpha-gitoxin; 17alpha estradiol; I 7beta estradiol; lalpha- hydroxyvitamin D2; 2'-nor-cGMP; 20-epi-l,25 dihydroxyvitamin D3; 22-oxacalcitriol; 2CVV; 3- isobutyl G ⁇ BA; 6-FUDC ⁇ ; 7-mcthoxytacrine; abamcctin; abanoquil; abecarnil; abiratcrone; acadcsine; acamprosate; acarbose; aceclofenac; acemannan; acetomcpregcnol; acetyl-L-carnitine; acetylcysteine, N-; acetylmethadol
  • balofloxacin balsalazidc; bambuterol; baohuosidc 1 ; barnidipine; basifungin; batebulast; batimastat; bcauvericin; becaplermin; becliconazolc; bcfloxatone; belfosdil; bellenamine; benflumetol; benidipinc; benzisoxazolc; benzochlorins; benzoidazoxan; bcnzoylstaurosporine; benztropine; bcpridil; beractant; beraprost; berlafenone; bertosamil; besipirdine; beta-alethine; betaclamycin B; betamipron; betaxolol; betulinic acid; bevantoiol; bicalutamide; bifemelane; bimakalim; bimithil; binospirone; bioxal
  • Noncentral nervous system active agents have no function or use within the central nervous system. Their only use is outside of the central nervous system. Such agents include all drugs within certain of the foregoing categories and only some drugs within other of the foregoing catagorics. For example, the entire calagoiy of blood glucose regulators have no use or lunction within the central nervous system. In contrast, certain anti-cancer agents are useful in the central nervous system whereas others arc not. For example, central nervous system cancers arc not hormone dependent, and, therefore, 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 catagory which are noncentral nervous system active agents.
  • the following catagories and/or members of the following catagorics are noncentral nervous system active agents: adrenocortical steroid; adrenocortical suppressant; aldosterone antagonist; amino acid; anabolic; androgen; antagonist; anthelmintic; anti-acne agent; anti-adrcnergic; anti-allergic; anti-amebic; anti-androgen; anti-anemic; anti-anginal; anti-arthritic; anti-asthmatic; anti-alherosclcrotic; antibacterial; anticholelithic; anticholelithogenic; anticholinergic; anticoagulant; anticoccidal; antidiabetic; antidiarrheal; antidiuretic; antidote; anti-estrogen; antifibrinolytic; antifungal; antiglaucoma agent; antihemophilic; antihemorrhagic; antihistamine; antihyperlipid
  • a taxane is a molecule that possesses the following tricyclic carbon-atom connectivity network, which may inco ⁇ orate carbon-carbon multiple bonds, and which through the involvement of carbon-atom-noncarbon-atom bonds may include substituents, functional groups, and additional rings.
  • a laxoid is a molecule structurally related to a taxane in which the above taxane carbon-atom connectivity network is altered, for example, by cleavage of one or more of the carbocyclic rings, by deletion or addition of carbon substituents, by connection of carbon atoms normally not bonded to each other, by disconnection of carbon atoms normally bonded to each other, or by some other reorganization of or adjustment to the taxane carbon-atom connectivity network, but in which one or more structural features characteristic of the taxane carbon-atom connectivity network are conserved.
  • the compounds useful in the invention may be delivered in the fo ⁇ n of anti-cancer cocktails.
  • An anti-cancer cocktail is a mixture of any one of the compounds useful with this invention with another anti-cancer agent such as an anti-cancer drug, a cytokine, and/or supplementary potentiating agcnt(s).
  • Another anti-cancer agent such as an anti-cancer drug, a cytokine, and/or supplementary potentiating agcnt(s).
  • a common administration vehicle e.g., pill, tablet, implant, injectable solution, etc.
  • a therapeutically effective amount will be determined by the parameters discussed below; but, in any event, is that amount which establishes a level of the drug(s) in the area of the tumor which is effective in inhibiting the tumor growth.
  • the formulations of the invention When administered, the formulations of the invention arc applied in pharmaceutically acceptable amounts and in pharmaceutically acceptable compositions. Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic ingredients. When used in medicine the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used lo prepare pharmaceutically acceptable salts thereof and arc not excluded from the scope of the invention.
  • Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic.
  • salts can be 5 prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts.
  • Suitable buffering agents include: acetic acid and a salt (1 -2% W/V); citric acid and a salt (1-3% W/V); boric acid and a salt (0.5-2.5% W/V); and phosphoric acid and a salt (0.8-2% W/V).
  • Suitable preservatives include benzalkonium chloride (0.003-0.03% W/V); chlorobutanol (0.3-0.9% W/V); parabens (0.01-0.25% W/V) and thimerosal (0.004-0.02% W/V).
  • the active compounds of the present invention may be a pharmaceutical composition having a therapeutically effective amount of a conjugate of the invention optionally included in a pharmaceutically-acceptable carrier.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler, dilutants or encapsulating substances which are suitable for administration to a human or other animal.
  • carrier denotes an organic or
  • compositions 15 inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
  • the components of the pharmaceutical compositions are capable of being commingled with the molecules of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.
  • compositions suitable for parenteral administration conveniently comprise a sterile 0 preparation of the conjugates of the invention.
  • This preparation may be formulated according to known methods.
  • Formulations for taxanes can be found in Chapter 9 of Taxol: Science and Applications. CRC Press, Inc., 2000 Co ⁇ orate Boulevard. N. W., Boca Raton. FL 33431.
  • Taxol has been formulated as a 6 mg/ml cremophor EL (polyoxycthylated castor oil)/ethanol mixture, which is diluted to final volume with normal saline or 5% dextrose.
  • a 15mg/ml solution 5 of taxotere has been formulated in polysorbate 80 (polyoxyethylene sorbitanmonooieatej/ethanol mixture, diluted with 5% dextrose.
  • the sterile preparation thus may be a sterile solution or suspension in a non-toxic parenterally-acceptable diluent or solvent.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be any bland fixed oil.
  • fatty acids such as oleic acid find use in the preparation of injcctablcs.
  • Carrier formulations suitable for oral, subcutaneous, intravenous, intramuscular, etc. can be found in Remington's Pharmaceutical Sciences. Mack Publishing Company. Easton. PA.
  • a subject as used herein means humans, primates, horses, cows, pigs, sheep, goats, dogs, cats and rodents.
  • the conjugates of the invention are administered in effective amounts.
  • An effective amount means that amount necessary to delay the onset of, inhibit the progression of, halt altogether the onset or progression of or diagnose the particular condition being treated.
  • an effective amount for treating cancer will be that amount necessary to inhibit mammalian cancer cell proliferation in-situ.
  • effective amounts will depend, of course, on the particular condition being treated; the severity of the condition; individual patient parameters including age, physical condition, size and weight; concurrent treatment; frequency of treatment; and the mode of administration. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to sound medical judgment.
  • Dosage may be adjusted appropriately to achieve desired drug levels, locally or systemically.
  • daily oral doses of active compounds will be from about 0.01 mg/kg per day to 1000 mg/kg per day. It is expected that IV doses in the range of about 1 to 1000 mg/m : per day will be effective. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Continuous IV dosing over, for example 24 hours or multiple doses per day are contemplated to achieve appropriate systemic levels of compounds.
  • a variety of administration routes arc available. The particular mode selected will depend of course, upon the particular drug selected, the severity of ihe disease state being treated and the dosage required for therapeutic efficacy.
  • the methods of this invention may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects.
  • modes of administration include oral, rectal, sublingual, topical, nasal, transdermal or parenteral routes.
  • parenteral includes subcutaneous, intravenous, intramuscular, or infusion. Intravenous routes are preferred.
  • compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the slcp of bringing the conjugates of the invention into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid earner, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • compositions suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active compound.
  • Other compositions include suspensions in aqueous liquors or non-aqueous liquids such as a syrup, an elixir, or an emulsion.
  • Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the active compounds of the invention, increasing convenience to the subject and the physician.
  • Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer based systems such as polylactic and polyglycolic acid, polyanhydrides and polycaprolactone; nonpolymer systems that are lipids including sterois such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-, di and triglycerides; hydrogel release systems; silastic systems; peptide based systems; wax coatings, compressed tablets using conventional binders and excipients, partially fused implants and the like.
  • a pump-based hardware delivery system can be used, some of which are adapted for implantation.
  • a long-term sustained release implant also may be used.
  • Long-term release as used herein, means that the implant is constmctcd and arranged to deliver therapeutic levels of the active ingredient for at least 30 days, and preferably 60 days.
  • Long-term sustained release implants are well known to those of ordinary skill in the art and include some of the release systems described above. Such implants can be particularly useful in treating solid tumors by placing the implant near or directly within the tumor, thereby affecting iocalized, high-doses of the compounds of the invention.
  • the conjugates of the invention also are useful, in general, for treating mammalian cell proliferative disorders other than cancer, including psoriasis, actinic kcratosis, etc. They further are useful in treating diabetes and its complications, excess acid secretion, cardiovascular conditions involving cholesterol (e.g., hyperlipidemia and hypercholcsterolcmia), diarrhea, ovarian diseases
  • cndomclriosis e.g. cndomclriosis, ovarian cysts, etc.
  • contraceptive agents e.g. cndomclriosis, ovarian cysts, etc.

Abstract

The invention provides conjugates of cis-docosahexaenoic acid and pharmaceutical agents useful in treating noncentral nervous system conditions. Methods for selectively targeting pharmaceutical agents to desired tissues are provided.

Description

DHA-PHARMACEUTICAL AGENT CONJUGATES
Background of the Invention
Improving drug selectivity for target tissue is an established goal in the medical arts. In general, it is desirable to deliver a drug selectively to its target, so that dosage and, consequently, side effects can be reduced. This is particularly the case for toxic agents such as anti-cancer agents because achieving therapeutic doses effective for treating the cancer is often limited by the toxic side effects of the anti-cancer agent on normal, healthy tissue. The problems relating to lack of drug selectivity can be exemplified by Taxol®. Taxol® (paclitaxel) was first isolated in 1971 from the bark of Taxus brevifolia and was approved in 1992 by the US Food and Drug Administration for treatment of metastatic ovarian cancer and later for breast cancer. Its mechanism of action is believed lo involve promoting formation and hypcrstabilization 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 uncharacterized mechanisms of action.
Taxol has attracted unusually strong scientific attention, not only because of its unique antiproliferative mechanism of action, but also because it is active against nearly ail cancers against which it has been tested and because it has been discovered to be an analog of numerous closely related compounds occurring naturally. These compounds, taxanes. are now recognized as a new class of anticancer compounds.
Taxol's strength against cancers of diverse tissue origin also represents a significant drawback. Λn ideal anticancer agent has tissue specificity, thereby reducing side-effects on normal (dividing) cells. Taxol analogs with tissue specificity therefore arc desired. Another drawback of Taxol is its extreme insolubility. Taxol can be administered effectively in a solvent including cremophor, which combination can provoke severe hypersensitive immune responses. As a result of these drawbacks, and also as a result of the potential for modifying Taxol at numerous sites as demonstrated by other naturally-occurring taxanes with anticancer activity, a search for more selective taxanes was launched. To date, more than 200 taxanes have been synthesized (or isolated) and tested in vitro or in vivo for anticancer activity. The results, however, have been so disappointing that the National Cancer Institute (NCI) generally no longer is interested in testing Taxol analogs. In general with Taxol analogs, the solubility problems remain, and/or potency is sharply reduced, and/or selectivity is not improved, and/or the ratio of the median toxic dose to the median effective dose ("therapeutic index") is unacceptably reduced.
Taxol has the following formula:
Figure imgf000004_0001
Taxanes have the basic three ring structure (A, B and C), substituted or unsubstituted. Taxol's carbons are numbered conventionally as follows:
Figure imgf000004_0002
Based upon the taxanes tested to date, as many questions have been raised as have been answered, and general rules have not been fashioned easily in predicting selectivity, activity and solubility. Firstly, no rules have emerged regarding selectivity. Those taxanes that are strongly active appear to have activity as broad as Taxol's activity, and no headway appears to have been made in terms of developing a more selective Taxol analog. Some information about activity "has emerged. Numerous substitutions have been made at
C7, C9, C IO, C 19, R, and combinations thereof while retaining significant, but usually reduced, activity. Substitutions at C2, C4 and 2'OI 1, however, are generally not tolerated. These conclusions arc only generalities, for example, because some substitutions at C9-C10 (cyclic derivatives) arc not tolerated and some substitutions at C2 (mcta substitutions on the phenyl) arc tolerated. Likewise, the C 13 side chain and, in particular, the 2'OH arc required, although the minimum structwral requirements of Ihc side chain have not been determined for therapeutic efficacy.
Attempts to improve Taxol's solubility have not resulted in successful clinical products. One approach has been to manufaclurc prodrugs of Taxol, which prodrugs undergo in vivo transformation into Taxol and some other product. Attempts were made to esterify the C7 hydroxy and 2' hydroxy groups, with the hope that the bond would be stable in solution (to permit preferred administration modes -i.v. over at least 24 hours) but would cleave readily in vivo. The groups tested were all hydrophilic and included amines, short carboxylic acids (using e.g. succinic anhydride and glutaric - j - anhydride), sulfonic acids, amino acids and phosphates. Generally, activity was reduced although some success was obtained with certain derivatives. Again, no particular pattern emerged permitting one to predict reliably which groups could be substituted on Taxol to yield a therapeutically useful product, although it was suggested that the 2' OH derivatives may cleave more easily than the C7 OH derivatives.
Several other factors add to the problem of predicting which Taxol analogs will be effective. Multiple mechanisms of action have been proposed in the literature, and a change in one position may have no effect on activity on one such mechanism but may eliminate activity on another mechanism. In addition, changes that favorably influence activity may unfavorably influence bioavailability. For example, Taxol affects microtubule formation inside a cell, but a change in structure that increases intracellular activity may adversely affect the ability of Taxol to gain entry into a cell. Taxol also is known to bind to proteins, and the effect on activity that results from a change in Taxol's binding to protein (in terms of conformation, cellular absorption and solubility) is unknown. It has been reported that Taxol does not get into the brain, apparently excluded by the blood brain barrier. It is not known why this is so, as Taxol is lipophilic, gets into cells and might be expected to cross the blood brain barrier.
Among the most promising of the two hundred analogs tested is Taxotere (docetaxcl), because of its slightly increased activity and solubility. Oddly, however, Taxotere differs from Taxol at sites which typically do not have a strong influence on activity, and one would not predict the improvements in Taxotere from these differences, even in hindsight. Taxotere has the following formula:
Figure imgf000005_0001
DHA (docosahexaenoic acid) is a 22 carbon naturally-occurring, unbranched fatly acid that previously has been attached to drugs to help deliver them across the blood brain barrier. DHA is attached via the acid group to hydrophilic drugs and renders these drugs more hydrophobic
(lipophilic). DHA is an important constituent of the brain and recently has been approved in Europe as an additive to infant formula. It is present in the milk of lactating women. The mechanism of action by which DHA helps drugs conjugated to it cross the blood brain barrier is unknown.
Summary of the Invention The present invention involves the unexpected finding that conjugates of pharmaceutical agents and a highly lipophilic group, a C22 unbranched carbon chain, have a different selectivity relative to the unconjugated pharmaceutical agents. The conjugates, in general, render the activity of these compounds selective for colon tissue, breast tissue and central nervous system tissue ("targeted tissues"). The conjugates, also unexpectedly, restrict the activity of these compounds to cell types witiiin these tissue categories relative to that of the unconjugated pharmaceutical agents. The conjugates, further unexpectedly, reduce sharply the activity of these compounds 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 the conjugates versus those of the unconjugated pharmaceutical agents. The therapeutic index of the conjugates may be improved, versus that of the unconjugated pharmaceutical agents.
According to one aspect of the invention, a method is provided for targeting a pharmaceutical agent to a noncentral nervous system tissue to treat a noncentral nervous system condition. A covalent conjugate of m-docosahexacnoic acid and a pharmaceutical agent effective for treating said condition is administered to a subject in need of such treatment. Preferably, the conjugate consists only of c«-docosahexaenoic acid and the pharmaceutical agent, wherein the cώ-docosahexaenoic acid is conjugated directly to the pharmaceutical agent, free of linker, for example via the carboxylic acid group of the c/.v-docosahcxaenoic acid and a reactive group such as a free amino or hydroxyl group of the pharmaceutical agent. In preferred embodiments, the tissue is breast tissue, gastrointestinal tissue and ovarian tissue and the condition calls for treatment of breast tissue, gastrointestinal tissue or ovarian tissue, respectively.
The conjugates of the invention can be isolated conjugates. An isolated conjugate is one which is separated from other different docosahexaenoic acid-pharmaceutical agent conjugates.
The pharmaceutical agent may be any pharmacological compound or diagnostic agent, as desired. The pharmaceutical agent, of course, has an activity outside of the central nervous system. Examples of catagorics of pharmaceutical agents include: adrcncrgic agent; adrcnocortical steroid; adrenocortical suppressant; alcohol deterrent; aldosterone antagonist; amino acid; ammonia detoxicant; anabolic; analcplic; analgesic; androgen; anesthesia, adjunct to; anesthetic; anorcctic; antagonist; anterior pituitary suppressant; anthelmintic; anti-acne agent; anti-adrenergic; anti-allergic; anti-amebic; anti-androgen; anti-anemic; anti-anginal; anti-anxiety; anti-arthritic; anti-asthmatic; anti-atherosclerotic; antibacterial; anticholelithic; anticholelithogenic; anticholinergic; anticoagulant; anticoccidal; anticonvulsant; antidepressant; antidiabetic; antidiarrheal; antidiuretic; antidote; anti-emetic; anti-epileptic; anti-estrogen; antifibrinolytic; antifungal; antiglaucoma agent; antihemophilic; antihemorrhagic; antihistamine; antihyperlipidemia; antihyperlipoproteinemic; antihypertensive; antihypotensive; anti-infective; anti-infective, topical; anti-inflammatory; antikeratinizing agent; antimalarial; antimicrobial; antimigraine; antimitotic; antimycotic, antinauseant, antineopiastic, antineutropenic, antiobessional agent; antiparasitic; antiparkinsonian; antiperistaltic, antipneumocystic; anfiproliferative; antiprostatic hypertrophy; antiprotozoal; antipruritic; antipsychotic; antirheumatic; antischistosomal; antiseborrheic; antisecretory; antispasmodic; antithrombotic; antitussivc: anti-ulcerativc; anti-uroiithic; antiviral; appetite suppressant; benign prostatic hyperplasia therapy agent; blood glucose regulator; bone resorption inhibitor; bronchodilator; carbonic anhydrase inhibitor; cardiac depressant; cardioprotectant; cardiotonic; cardiovascular agent; cholcretic; cholinergic; cholinergic agonist; cholinesterase deactivator; coccidiostat; cognition adjuvant; cognition enhancer; depressant; diagnostic aid; diuretic; dopaminergic agent; cctoparasiticidc; emetic; enzyme inhibitor; estrogen; fibrinolytic; fluorescent agent; free oxygen radical scavenger; gastrointestinal motilily effector; glucocorticoid; gonad-stimulating principle; hair growth stimulant; hemostatic; histaminc H2 receptor antagonists; hormone; hypocholestcroiemic; hypoglycemic; hypolipidemic; hypotcnsivc; imaging agent; immunizing agent; immunomodulator; immunorcgulator; immunostimulant; immunosuppressant; impotence therapy adjunct; inhibitor; keralolytic; LNRJ I agonist; liver disorder treatment; luteolysin; memory adjuvant; mental performance enhancer; mood regulator; mucolytic; mucosal protective agent; mydriatic; nasal dccongestant; neuromuscular blocking agent; neuroprotectivc; NMDA antagonist; non-hormonal sterol derivative; oxytocic; plasminogen activator; platelet activating factor antagonist; platelet aggregation inhibitor; post-stroke and post-head trauma treatment; potentiator; progestin; prostaglandin; prostate growth inhibitor; prothyrotropin; psychotropic; pulmonary surface; radioactive agent; regulator; relaxant; repartitioning agent; scabicidc; sclcrosing agent; sedative; sedative-hypnotic; selective adcnosinc Al antagonist; serotonin antagonist; serotonin inhibitor; serotonin receptor antagonist; steroid; stimulant; suppressant; symptomatic multiple sclerosis; synergist; thyroid hormone; thyroid inhibitor; thyromimctic; tranquilizcr; treatment of amyotrophic lateral sclerosis; treatment of cerebral ischemia; treatment of Paget's disease; treatment of unstable angina; uricosuric: vasoconstrictor; vasodilator; vulnerary; wound healing agent; xanthine oxidase inhibitor.
In important embodiments of the invention, the pharmaceutical agent is a non anti-cancer agent. In another embodiment of the invention, the pharmaceutical agent is an anti-cancer agent. Examples of anti-cancer agents are described in greater detail in the specification. Included specifically are the taxanes (e.g., Taxol and Taxotere). Conjugates of cώ-docosahexaenoic acid and taxoids also are embraced by the invention.
C/.v-docosahexaenoic acid previously has been conjugated to drugs that are active in the central nervous system. The present invention contemplates the use of cώ-docosahexaenoic acid in the manufacture of a medicament for treating a noncentral nervous system condition. The invention further contemplates compositions of matter that are covalent conjugates of cw-docosahexaenoic acid and noncentral nervous system active pharmaceutical agents. A noncentral nervous system active pharmaceutical agent is one that has no function or use in the central nervous system. Its only therapeutic use is outside of the central nervous system. Examples of such agents include, but are not limited to: Blood glucose regulators, such as tolazamide, tolbutamide, chlorpropamide, acetohexamide, and, glipizide; HMGcoA reductase inhibitors, such as Lovastatin (Mevacor), Simvastatin (Zocor), Pravastatin (Pravachol), and, Fluvstatin (Lescol); Muscosal Protectives, such as Misoprostol (Cytotec); Gastrointestinal motility affectors, such as Cisapride (Propulsid), Metoclopramide (Reglan), and, Hyoscyamine (Lcvsin); Antidiarrheals, such as Diphenoxylatc hydrochloride (Lomotil), Metronidazole (Flagyl), Mcthylprednisolonc (Medrol), and, Sulfasalazinc (Azulfidine); and Hormones for treating, inter alia, ovarian conditions, such as Progesterone, Norgeslrel, Norethynodrel, Norcthindrone, Levonorgcstrel. Ethyndiol, Mestranol, Estronc, Equilin, 17 alpha dihydroequilin, equilenin, 17 alpha dihydroequilenin, 17 alpha esradiol, 27 bea estradiol, Lcuprolidc (Lupron), Testolactone, Climiphcnc, urofollitropin, bromocriptinc, gonadorclin, danazol, dehydroepiandrosteronc, androstencdione, dihydrotestosterone, Relaxin, folliculostatin, Follicle regulatory protein, Gonadocrinins, Oocyte maturation inhibitor, and, Insulin growth factor. Other compounds arc detailed below.
The methods and/or products of the invention are useful for treating a variety of medical conditions including conditions involving abnormal mammalian-cell proliferation. They further are useful in treating diabetes and its complications, excess acid secretion, cardiovascular conditions involving cholesterol (e.g., hyperlipidcmia and hypcrcholcsterolcmia), diarrhea, ovarian diseases (e.g. endometriosis. ovarian cysts, etc.) and as contraceptive agents. Other conditions treatable according to the invention will be apparent to those skilled in the art based upon the disclosure and lists of compounds provided.
The methods and/or products of the invention also are useful in treating conditions specific to noncentral nervous system tissue. Such conditions can be specific to breast tissue, gastrointestinal tissue and ovarian tissue. The tissue also may be other noncentral nervous system tissues. Noncentral nervous system tissue includes tissue of the: Blood and Blood Forming system: including platelets, blood vessel wall, and bone marrow; Cardiovascular system: including heart and vascular system; Digestive and excretory system: including alimentary tract, biliary tract, kidney, liver, pancreas and urinary tract; Endocrine system: including adrenal gland, kidney, ovary, pituitary gland, renal gland, salivaiy giand, sebaceous gland, testis, thymus gland and thyroid gland; Musclar system: including muscles that move the body. Reproductive System: including breast, ovary, penis and uterus; Respiratory system: including bronchus, lung and trachea; Skeletal system: including bones and joints: Tissue, fiber, and integumentary system: including adipose tissue, cartilage, connective tissue, cuticle, dermis, epidermis, epithelium, fascia, hair follicle, ligament, bone marrow. melanin, melanocyte, mucous membrane, skin, soft tissue, synovial capsule and tendon.
Brief Description of the Drawings
Figure 1 is a graph plotting concentration of conjugate 1 versus percent growth of leukemia cells. Figure 2 is a graph plotting concentration of conjugate 1 versus percent growth of non-small cell lung cancer cells.
Figure 3 is a graph plotting concentration of conjugate 1 versus percent growth of colon cancer cells.
Figure 4 is a graph plotting concentration of conjugate 1 versus percent growth of CNS cancer cells.
Figure 5 is a graph plotting concentration of conjugate 1 versus percent growth of melanoma cells.
Figure 6 is a graph plotting concentration of conjugate 1 versus percent growth of ovarian cancer cells. Figure 7 is a graph plotting concentration of conjugate 1 versus percent growth of renal cancer cells.
Figure 8 is a graph plotting concentration of conjugate 1 versus percent growth of prostate cancer cells.
Figure 9 is a graph plotting concentration of conjugate I versus percent growth of breast cancer cells.
Figure 10 is a graph plotting concentration of conjugate 2 versus percent growth of leukemia cells.
Figure 1 1 is a graph plotting concentration of conjugate 2 versus percent growth of non-small cell lung cancer cells.
Figure 12 is a graph plotting concentration of conjugate 2 versus percent growth of colon cancer cells. Figure 13 is a graph plotting concentration of conjugate 2 versus percent growth of CNS cancer cells.
Figure 14 is a graph plotting concentration of conjugate 2 versus percent growth of melanoma cells.
Figure 15 is a graph plotting concentration of conjugate 2 versus percent growth of ovarian cancer cells.
Figure 16 is a graph plotting concentration of conjugate 2 versus percent growth of renal cancer cells.
Figure 17 is a graph plotting concentration of conjugate 2 versus percent growth of prostate cancer cells. Figure 1 8 is a graph plotting concentration of conjugate 2 versus percent growth of breast cancer cells.
Figure 19 is a graph plotting concentration of Taxol versus percent growth of leukemia ceils.
Figure 20 is a graph plotting concentration of Taxol versus percent growth of non-small cell lung cancer cells. Figure 21 is a graph plotting concentration of Taxol versus percent growth of colon camccr cells.
Figure 22 is a graph plotting concentration of Taxol versus percent growth of CNS cancer cells.
Figure 23 is a graph plotting concentration of Taxoi versus percent growth of melanoma cells.
Figure 24 is a graph plotting concentration of Taxol versus percent growth of ovarian cancer cells. Figure 25 is a graph plotting concentration of Taxol versus percent growth of renal cancer cells.
Figure 26 is a graph plotting concentration of Taxol versus percent growth of prostate cancer cells. Figure 27 is a graph plotting concentration of Taxol versus percent growth of breast cancer cells.
Detailed Description of the Invention
Cw-docosahexaenoic acid (DHA) is a naturally occurring fatty acid. It is an unbranched chain fatty acid with six double bonds, all cis. Its structure is as follows:
Figure imgf000011_0001
DHA can be isolated, for example, from fish oil or can be chemically synthesized. These methods, however, can generate trans isomers, which are difficult and expensive to separate and which may present safety problems in humans. The preferred method of production is biological synthesis to produce the all cis isomer. The preferred source of DHA is from Martek Biosciences Corporation of Columbia, Maryland. Martek has a patented system for manufacturing DHA using microalgae which synthesize only a single isomer of DHA, the all cis isomer. Martek's patents include U.S. Pat. Nos. 5,374,657, 5,492:938, 5.407,957 and 5,397.591 .
DHA also is present in the milk of lactating women, and Martek's licensee has obtained approval in Europe of DMA as a nutritional supplement for infant formula.
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 DI IA-laxol plus 100 g of vehicle (100ml propylene glycol, 70 mg alph-locophcrol. 5 mg dialaurylthiodipropionic acid, 50 mg ascorbic acid) prepared and held under argon in amber, sealed vials and stored al four degrees centigrade. The following anti-oxidants may also be employed: ascorbic acid, ascorbyl palmitate, dilauryl ascorbatc, hydroquinone. butyated hydroxyanisolc, sodium mela bisulfite,
Figure imgf000011_0002
carotene and rx-tocophcrol. A heavy metal chelator such as clhylcnediamine tctra-acetic acid (EDTA) may also be used.
Paclitaxel was first isolated from the bark of Taxus brevil'olia (Wani el al., J. Am. Chem. Soc.. 93, 2325, 1971 ). Its isolation and synthesis have been reported extensively in the literature. Applicants obtained paclitaxel from a commercial source, Hauscr Laboratories, of Boulder, Colorado.
Example 1
TAXOL
Figure imgf000012_0001
conjugate 1
A solution of Taxol (41 μmol) in methylene chloride (2.5mL) under argon was mixed with 4-dimethylaminopyridine (41 μmol), dicyclohexylcarbodiimide (82μmol), and DHA (41 μmol) and the reaction mixture was stirred at ambient temperature for two hours. Following dilution with ether, the reaction mixture was washed with 5% hydrochloric acid, water, saturated aqueous sodium chloride, dried, and concentrated. Radial chromatography of the residue produced 45mg (94%) of crystalline Taxol-DHA conjugate 1.
Example 2
Figure imgf000012_0002
The production of analog 2 involves several steps including a number of protection-acylation-deprotection steps. A solution of Taxol (59μmol) in methylene chloride (2.5mL) was mixed at ambient temperature under argon with imidazole (147μmol) and triethylsilyl chloride (147μmol). The reaction mixture was stirred for thirty minutes, diluted with additional methylene chloride, washed with water, saturated aqueous sodium chloride, dried, and concentrated. Chromatography of the residue produced 50mg (88%) of intermediate A plus 5mg of the 2', 7-di(triethylsilyl) ether derivative. A solution of intermediate A (52μmoI) in methylene chloride (3mL) was mixed at ambient temperature under argon with 4-dimethylaminopyridine (52μmol), dicyclohexylcarbodiimide (104μmol), and DHA (52μmol). The reaction mixture was stirred for ten hours, diluted with ether, passed through celite, and concentrated. Chromatography of the residue produced 65.9mg of intermediate B. A solution of intermediate B (51 μmol) in acetonitrile (2mL) at 0°C under argon was mixed with 49% aqueous HF (0.2mL) and the reaction mixture was stirred for one hour. After dilution with ether, the reaction mixture was washed with water, saturated aqueous sodium chloride, dried, and concentrated. Radial chromatography of the residue produced 44.6mg (75%) of Taxol-DHA conjugate 2.
Example 3
Conjugates 1 and 2 were sent to the United States National Cancer Institute (NCI) for screening in the NCI's anticancer screening program. The conjugates were provided in ethanol (approximately 40mg analog/2ml ethanol). The conjugates were scaled in vials under argon to avoid exposure of the conjugates to oxygen because the conjugates were believed to be sensitive to oxygen. Instructions were provided to store at 4°C and to open the vials only when ready for immediate experimental use. Instructions also were provided to use the ethanol solutions containing the conjugates dircctiy or to dissolve the analogs further in DMSO (dimethylsulfoxide) at appropriate concentrations, with vortexing if necessary for adequate dispersal.
The activities of conjugates 1 and 2 were tested against 57 cancer cell lines. The results arc presented in Figs. 1 -9 for conjugate 1 , Figs. 10-18 for conjugate 2 and Figs 19-27 for Taxol. To understand the data, reference is made to the guides provided by the NCI, excerpted as follows: The Calculated Measurement of Effect: Percentage Growth CPGI
The measured effect of the compound on a cell line is currently calculated according to one or the other of the following two expressions:
If (Mean ODlcsI -Mean ODlmo) > 0, then
PG = 100 x (Mean ODlcs[ -Mean ODliCro)/(Mean ODctr, -Mean Od^J
If (Mean ODtcst -Mean ODtt(.ro) < 0, then
PG = 100 x (Mean ODlcM -Mean Odlzero)/Mean Odlzcro
Where:
Mean OOUcw = The average of optical density measurements of SRB-derived color just before exposure of cells to the test compound.
Mean ODlcst = The average of optical density measurements of SRB-derived color after 48 hours exposure of cells to the lest compound.
Mean ODc,r| = The average of optical density measurements of SRB-derived color after 48 hours with no exposure of cells to the test compound.
Experimental data was collected against each cell line. ... Each concentration is expressed as the log,0 (molar or μg/ml). ... The response parameters GI50, TGI, and LC50 are interpolated values representing the concentrations at which the PG is +50, 0, and -50, respectively. Sometimes these response parameters cannot be obtained by interpolation. If, for instance, all of the PGs in a given row exceed +50, then none of the three parameters can be obtained by interpolation. In such a case, the value given for each response parameter is the highest concentration tested. ... This practice is extended similarly to the other possible situations where a response parameter cannot be obtained by interpolation. Dose-Responsc Curves:
The dose-response curve page of the data package is created by plotting the PGs against the log,0 of the corresponding concentration for every cell line. The cell line curves are grouped by subpanel. Horizontal lines are provided at the PG values of +50, 0, and -50. The concentrations corresponding to points where the curves cross these lines are the GI50, TGI and LC50, respectively.
Several important distinctions are apparent from the data. Most important, the patterns of anticancer actively for conjugates 1 and 2 differ from that of Taxol. In one sense, conjugates 1 and 2 are effective anticancer agents against a more restricted set of cancer cell lines. For example, conjugates 1 and 2 were not very effective against any of the six leukemia cancer cell lines tested, whereas Taxol was somewhat effective against all four leukemia celi lines against which Taxol was tested. (See Figs. 1 , 10 and 19.)
The relative activity against members within a class of cancers also was altered. For example, at TGI (horizontal line at zero in the graphs), Taxol was more effective against non-small cell lung cancer line H522 than against H460 (by about 3 logs), whereas conjugates 1 and 2 were slightly more effective against H460 than H522. As another example, Taxol was least effective at TGI against CNSU251, whereas conjugate 1 was most effective against CNSU251 and conjugates 2 was also very effective against CNSU251 (relative to other CNS cell lines). As a further example, Taxol was equivalent in activity toward 'MDA-N and MDA-MB-435 breast cancer cell lines at all concentrations tested, whereas conjugates 1 and 2 were more effective against MDA-N than MDA-MB-435 at all concentrations tested.
To further illustrate the differences in the activity of conjugates I and 2 versus that of Taxol, the NCI subjected the data to a statistical analysis designed by the NCI to reflect differences in the pattern of activity of anticancer agents. Conjugate 1 and conjugate 2 were determined to, be statistically different in their pattern of activity versus Taxol in this unique measurement by the NCI.
It also is to be noted that, in general, conjugates 1 and 2 were one thousand to ten thousand times less potent than Taxol for many cell lines tested. This reduction in activity is important, especially since conjugates 1 and 2 maintained strong activity against some cell lines. Conjugates 1 and 2 will be sufficiently active against certain cell lines, but will have, on average, a substantially and disproportionately lower activity against other cell lines, reducing potential side effects. For 7 0886
- 14 - exampje. the TGI for Taxol against CNS SF-539 is -6.95. and the TGI for conjugate 1 against this cell line is -5.13 and for conjugate 2 is -5.53. (In other words, the activity of the conjugates was reduced versus that of Taxol by less than 2 logs). The GI50 for Taxol against CNS SF 539 is -7.52, whereas the GI50s for conjugates 1 and 2 are -6.22 and -5.56, respectively (again less than 2 logs difference). In contrast, Taxol has a GI50 for cell line CNSSF 268 of less than -10.0, whereas conjugates 1 and 2 have GI50s for CNSSF 268 of 5.36 and 5.28, respectively. This represents a reduction of activity in the conjugates vs. that of Taxol by at least about 5 logs activity! On average, the GI50 for Taxol across all cell lines tested is at least -9.19. (It is probably much higher since concentrations less than -10 were not tested, and if Taxol was active at -10.0, -10 (instead of the actual lower value) was used in calculating the average of -9.19. There were 27 instances when this occurred.) The average GI50s for conjugates 1 and 2 , on the other hand, were 5.49 and 5.22, respectively. Therefore, the average difference in activity for Taxol vs. the conjugates is al least between 3 and 4 logs. Thus, the sharp reduction in the activity of the conjugates against many cell lines vs. a lesser reduction for other cell lines is expected to reduce the potential side effects of the conjugates versus those of Taxol at effective doses.
Cancers other than CNS, breast and colon cancer can be treated. For example, there was activity against non-small cell lung cancer cells, melanoma cells and ovarian cancer cells. However, the activity was relatively reduced and was extremely specific, limiting the utility of the conjugates for treating generally such cancers. In any event, cancer patients could be evaluated to determine if a conjugate is strongly active against the patient's cancer prior to selecting the conjugate as the anti-cancer agent of choice for that patient.
The foregoing experiments establish that DHA analogs have altered specificity versus that of Taxol for cancer cell lines. Because of this altered specificity, it also is clear that the conjugates themselves are gaining access into the target cells (as opposed to simply releasing Taxol into the environment outside of the cell). Thus, the DHA moiety appears to selectively target certain cell types as opposed lo others. The ability of the conjugates to gain entry into the cells was unknown prior to the invention, and the ability of the DHA moiety to selectively target certain cell types was unexpected.
The same is true of DHA-Taxotere covalent conjugates, examples of which are presented below. Taxotere's synthesis has been reported extensively in the literature. One example is Kanazawa. A. ct al., J. Organic Chem. 1994, Vol. 59, pp. 1238-1240. Example 4
TAXOTERE
Figure imgf000017_0001
conjugate 3
A solution of Taxotere in methylene chloride under argon is mixed with 4-dιmethylamιnopyridιne, dicyclohexylcarbodiimide. and DIIΛ. The reaction mixture is stirred at ambient temperature. Radial chromatography of the residue is performed to produce Taxotere-DHA con|iιgatc 3.
Example 5
TAXOTERE
DHA / dicyclohexylcarbodiimi 4 -dimethylaminopyπdine
aqueous HF
Figure imgf000017_0002
A solution of Taxotere in dimethyl formamide is mixed at ambient temperature under argon with imidazole and triethylsilyl chloride. The reaction mixture is stirred at ambient temperature, diluted with methylene chloride, washed with water, saturated acqueous sodium chloride, dried, and concentrated. Radial chromatography of the residue is performed to produce intermediate C. A
5 solution of intermediate C in methylene chloride is mixed at ambient temperature under argon with 4 dimethylaminopyridine. dicyclohexylcarbodiimide, and DHA. The reaction mixture is stirred at ambient temperature, diluted with ether, passed through celite, and concentrated. Radial chromatography of the residue is performed to produce intermediate D. A solution of intermediate D in acetonitrile at 0°C under argon is mixed with 49% aqueous HF and the reaction mixture is
I o stirred at the same temperature. After dilution with ether, the reaction mixture is washed with water, saturated aqueous sodium chloride, dried, and concentrated Radial chromatography of the residue is performed to produce Taxotere-DHA conjugate 4.
Figure imgf000018_0001
1 equivalen! DHA dicyclohexylcarbodiimide 4-dimethylaminopyridine
25
Figure imgf000018_0002
Figure imgf000018_0003
A solution of Taxotere in dimethylformamide is mixed at ambient temperature under argon with imidazole and /<?/7-butylydimethylsilyl chloride. The reaction mixture is stirred at ambient temperature, diluted with methylene chloride, washed with water, saturated aqueous sodium chloride, dried, and concentrated. Radial chromatography of the residue is performed to produce intermediate E. A solution of intermediate E in methylene chloride is mixed at ambient temperature under argon with 4-dimethylaminopyridine, dicyclohexylcarbodiimide, and 1 equivalent of DHA. The reaction mixture is stirred at ambient temperature, diluted with ether, passed through celite, and concentrated. Radial chromatography of the residue is performed to produce intermediate F (Intermediate H also is obtained and used in Example 8 below.) A solution of intermediate F in acetonitrile at 0°C under argon is mixed with aqueous HF and the reaction mixture is stirred at the same temperature. After dilution with ether, the reaction mixture is washed with water, saturated aqueous sodium chloride, dried, and concentrated Radial chromatography of the residue is performed to produce Taxotere-DHA conjugate 4.
Example 7
/ert-6u!yldιmethylsιlyl chloride
TAXOTERE imidazole tert
Figure imgf000019_0001
Figure imgf000019_0002
A solution of Taxotere in dimethylformamide is mixed at ambient temperature under argon with imidazole and /m-butylydimethylsilyl chloride. The reaction mixture is stirred at ambient temperature, diluted with methylene chloride, washed with water, saturated aqueous sodium chloride, dried, and concentrated. Radial chromatography of the residue is performed to produce intermediate E. A solution of intermediate E in methylene chloride is mixed at ambient temperature under argon with 4-dimethylaminopyridine, dicyclohexylcarbodiimide, and DHA. The reaction mixture is stirred at ambient temperature, diluted with ether, passed through celite, and concentrated. Radial chromatography of the residue is performed to produce intermediate G. A solution of intermediate G in acetonitrile at 0°C under argon is mixed with aqueous HF and the reaction mixture is stirred at the same temperature. After dilution with ether, the reaction mixture is washed with water, saturated aqueous sodium chloride, dried, and concentrated. Radial chromatography of the residue is performed to produce Taxotere-DHA conjugate 5.
Example 8
1 equivalent OHA dicyclohexylcarbodiimide 4-dimethylaminopyridine
aqueous HF
Figure imgf000020_0001
conjugate 6 Λ solution of taxotere in dimcthylformamide is mixed at ambient temperature under argon with imidazole and (cr/-butylydimethylsilyl chloride. The reaction mixture is stirred at ambient temperature, diluted with methylene chloride, washed with water, saturated aqueous sodium chloride, dried, and concentrated. Radial chromatography of the residue is performed to produce intermediate E. A solution of intermediate E in methylene chloride is mixed at ambient temperature under argon with 4-dimethylaminopyridine, dicyclohexylcarbodiimide. and 1 equivalent of DHA. The reaction mixture is stirred at ambient temperature, diluted with ether, passed through celile, and concentrated. Radial chromatography of the residue is performed to produce intermediate H (and intermediate F which was used above on Example 6. A solution of intermediate H in acetonitrile at 0°C under argon is mixed with aqueous HF and the reaction mixture is stirred at the same temperature. After dilution with ether, the reaction mixture is washed with water, saturated aqueous sodium chloride, dried, and concentrated. Radial chromatography of the residue is performed to produce Taxotere-DHA conjugate 6.
DHA may be conjugated to virtually any drug compound or diagnostic agent and used according to the methods of the present invention so long as the pharmaceutical agent has a use outside of the central nervous system. Pharmaceutical agents include the following categories and specific examples. It is not intended that the category be limited by the specific examples. Those of ordinary skill in the art will be able to identify readily those pharmaceutical agents that have utility outside of the central nervous system. Those of ordinary skill in the art will recognize also numerous other compounds that fall within the categories and that are useful according to the invention.
Adrcncrgic: Λdrenalonc; Λmidephrine Mesylate; Apraclonidinc Hydrochloride; Brimonidine
Tartrate; Dapiprazole Hydrochloride; Deterenol Hydrochloride; Dipivefrin; Dopamine Hydrochloride; Ephedrinc Sulfate; Epincphrinc; Epincphrine Bitartratc; Epincphryl Borπtc;
Esproquin Hydrochloride; Etafedrinc Hydrochloride; Hydroxyamphetamine Hydrobromidc;
Levonordefrin; Mephcnterminc Sulfate; Mctaraminol Bitartratc; Metizoline Hydrochloride;
Naphazoline Hydrochloride; Norepinephrine Bitartratc; Oxidopamine; Oxymetazoline
Hydrochloride; Phenylcphrine Hydrochloride; Phenylpropanolamine I Iydrochloridc; Phenylpropanolamine Polistircx; Prcnallerol Hydrochloride; Propylhexedrinc; Pscudocphcdrinc
Hydrochloride; Tctrahydrozolinc Hydrochloride; Tramazolinc Hydrochloride; Xylomctazolinc
I Iydrochloridc. Adrenocortical steroid: Ciprocinonide; Desoxycorticosterone Acetate; Desoxycorticosterone Pivalate; Dexamethasone Acetate; Fludrocortisone Acetate; Fiumoxonide; Hydrocortisone Hemi suecinate; Methylprednisolone Hemisuccinate; Naflocort; Procinonide; Timobesone Acetate; Tipredanc.
Adrenocortical suppressant: Aminoglutethimide; Trilostane.
Alcohol deterrent: Disulfiram.
Aldosterone antagonist: Canrenoate Potassium; Canrenone; Dicirenone; Mexrenoate Potassium; Prorenoate Potassium; Spironolactone.
Amino acid: Alanine; Aspartic Acid; Cysteine Hydrochloride; Cystine; Histidine; Isoleucine; Leucine; Lysine; Lysine Acetate; Lysine Hydrochloride; Methionine; Phenylalanine; Proline; Serine; Threonine: Tryptophan; Tyrosine; Valine.
Ammonia detoxicant: Arginine: Arginine Glutamate; Λrginine Hydrochloride.
Anabolic: Bolandiol Dipropionate; Bolasteronc; Boldcnone Undecylenate; Bolenol; Bolmantalate; Ethyleslrcnol; Methcnolone Acetate; Mcthcnolone Enanthalc; Mibolerone; Nandroionc Cyclolatc; Norbolethonc; Pizotyline; Quinbolonc; Stcnbolonc Acetate; Tibolone; Zeranol.
Analeplic: Modalinil.
Analgesic: Acetaminophen; Λlfentanil Hydrochloride; Aminobenzoatc Potassium; Aminobenzoatc Sodium; Anidoxime; Anileridine; Anileridine Hydrochloride; Anilopam Hydrochloride; Anirolac; Λntipyrinc; Aspirin; Benoxaprofen; Benzydamine Hydrochloride; Bicifadine Hydrochloride; Brifentanil Hydrochloride; Bromadoline Maleate; Bromfenac Sodium; Buprenorphine Hydrochloride; Butacctin; Butixiratc; Butorphanol; Butorphanol Tartrate; Carbamazcpinc; Carbaspirin Calcium; Carbiphcne Hydrochloride; Carfentanil Citrate; Ciprcfadol Suecinate; Ciramadol; Ciramadol Hydrochloride; Clonixcril; Clonixin; Codeine ; Codeine Phosphate; Codeine Sulfate: Conorphone Hydrochloride; Cyclazocinc; Dexoxadrol 1 Iydrochloridc; Dexpemedolac; Dezocinc; Diflunisal: Dihydrocodeinc Bitartratc; Dimefadanc; Dipyrone; Doxpicominc
Hydrochloride; Drinidene; Enadoline Hydrochloride; Epirizole; Ergotamine Tartrate; Ethoxazene
Hydrochloride; Etofenamate; Eugenol; Fcnoprofen; Fenoprofcn Calcium; Fentanyl Citrate;
Floctafenine; Flufenisal; Flunixin; Flunixin Megluminc; Flupirtine Maleate; Fluproquazone; Fluradoline Hydrochloride; Flurbiprofen ; Hydromorphone Hydrochloride; Ibufenac; Indoprofen;
Ketazocine; Ketorfanol; Ketorolac Tromethamine; Letimide Hydrochloride; Levomethadyl Acetate;
Levomethadyl Acetate Hydrochloride; Levonantradol Hydrochloride; Levorphanol Tartrate;
Lofemizolc Hydrochloride; Lofentanil Oxalate; Lorcinadol; Lornoxicam: Magnesium Salicylate;
Mefenamic Acid; Menabitan Hydrochloride; Meperidine Hydrochloride; Meptazinol Hydrochloride; Methadone Hydrochloride; Methadyl Acetate; Methopholine; Methotrimeprazine; Metkephamid
Acetate; Mimbane Hydrochloride; Mirfcntanil Hydrochloride; Molinazonc; Morphine Sulfate;
Moxazocine; Nabitan Hydrochloride; Nalbuphine Hydrochloride; Nalmcxone Hydrochloride ;
Namoxyrate; Nantradol Hydrochloride; Naproxcn ; Naproxen Sodium ; Naproxol; Nefopam
Hydrochloride; Nexeridine Hydrochloride; Noracymethadol Hydrochloride; Ocfentanil Hydrochloride; Octazamide; Olvanil; Oxetorone Fumarate; Oxycodone; Oxycodone Hydrochloride;
Oxycodone Terephthalate; Oxymorphone Hydrochloride; Pemedolac; Pentamorphone; Pentazocine;
Pentazocine Hydrochloride; Pentazocine Lactate; Phenazopyridine Hydrochloride; Phcnyramidol
Hydrochloride; Picenadol Hydrochloride; Pinadoline; Pirfenidone; Piroxicam Olamine; Pravadoline
Maleate; Prodilidine Hydrochloride; Profadol Hydrochloride; Propiram Fumarate; Propoxyphene Hydrochloride; Propoxyphene Napsylate; Proxazolc ; Proxazole Citrate ; Proxorphan Tartrate;
Pyrroliphcne HydiOchloridc; Rcmifcntanil Hydrochloride; Salcolcx ; Salcthamide Maleate;
Salieylamidc; Salicylate Mcgiuminc; Salsalatc ; Sodium Salicylate; Spiradolinc Mesylate;
Sufentanil; Sufentanil Citrate; Talmetacin ; Talniflumate ; Talosalate ; Tazadoiene Suecinate;
Tebufclone ; Tetrydaminc ; Tifurac Sodium; Tilidinc I Iydrochloridc; Tiopinac; Tonazocine Mesylate; Tramadol Hydrochloride; Trefentanil Hydrochloride; Trolamine: VeradoHne
Hydrochloride; Verilopam Hydrochloride; Volazocinc; Xorphanol Mesylate; Xylazine
Hydrochloride; Zcnazocinc Mesylate; Zomcpirac Sodium ; Zucapsaicin.
Λndrogcn: Fluoxymestcronc; Mestcrolonc; Methyltcstostcronc; Nandrolone Dccanoatc; Nandrolone Phenpropionate; Nisterime Acetate; Oxandrolonc; Oxymetholonc; Silandrone; Stanozolol; Testosterone; Testosterone Cypionatc; Testosterone Enanthatc; Testosterone Kctolauratc; 'Testosterone Phenylacetate; Testosterone Propionatc; Trestolone Acetate. Anesthesia, adjunct to: Sodium Oxybate.
Anesthetic: Aliflurane; Benoxinate Hydrochloride; Benzocaine; Biphenamine Hydrochloride ;
Bupivacaine Hydrochloride; Butamben; Butamben Picrate; Chloroprocaine Hydrochloride; Cocaine; Cocaine Hydrochloride; Cyclopropane; Desflurane; Dexivacainc; Diamocaine Cyclamate;
Dibucaine; Dibucaine Hydrochloride; Dyclonine Hydrochloride; Enflurane; Ether; Ethyl Chloride;
Etidocaine; Etoxadrol Hydrochloride; Euprocin Hydrochloride; Fluroxene; Halothane; Isobutamben;
Isoflurane; Ketamine Hydrochloride; Levoxadrol Hydrochloride ; Lidocaine; Lidocaine
Hydrochloride; Mepivacaine Hydrochloride; Methohexital Sodium; Methoxyflurane; Midazolam Hydrochloride; Midazolam Maleate; Minaxolonc; Nitrous Oxide; Norflurane; Octodrine;
Oxethazaine; Phencyclidine Hydrochloride; Pramoxine Hydrochloride; Prilocaine Hydrochloride;
Procaine Hydrochloride; Propanidid; Proparacaine Hydrochloride; Propofol; Propoxycaine
Hydrochloride; Pyrrocaine; Risocaine; Rodocaine; Roflurane; Salicyl Alcohol; Sevoflurane;
Teflurane; Tctracaine; Tctracaine Hydrochloride; Thiamylal; Thiamylal Sodium; Thiopental Sodium ; Tiletamine Hydrochloride; Zolamine Hydrochloride.
Anorectic compounds including dexfenfiuramine.
Anorexic: Aminorex; Amphecloral; Chlorphentcrmine Hydrochloride; Clominorex; Clortermine Hydrochloride; Diethylpropion Hydrochloride; Fcnfluraminc Hydrochloride; Fenisorex; Fludorcx; Fluminorcx; Levamfetaminc Suecinate; Mazindol; Mcfcnorcx Hydrochloride; Phenmctrazine Hydrochloride: Phcntcrminc; Sibulramine Hydrochloride.
Antagonist: Λtipamczole; Λtosiban; Boscntan; Cimctidinc; Cimetidinc I Iydrochloridc; Clcntiazcm Maleate; Detirelix Acetate; Dcvazepidc; Donetidine; Etintidine Hydrochloride ; Famotidine;
Fenmetozole Hydrochloride ; Flumazenil; Icatibant Acetate; lcotidine; Isradipine; Metiamidc;
Nadide; Nalmefene; Nalmexone Hydrochloride ; Naloxone Hydrochloride; Naltrexone; Nilvadipine;
Oxiloiphan; Oxmctidine I Iydrochloridc ; Oxmclidinc Mesylate ; Quadazocinc Mesylate; Ranilidinc;
Ranitidine Bismuth Citrate ; Ranilidinc Hydrochloride ; Sufotidinc; Tcludipine Hydrochloride; Tiapamil Hydrochloride; Tiotidine; Vapiprost Hydrochloride; Zaltidine Hydrochloride.
Anterior pituitary activator: Epimcstrol. Anterior pituitary suppressant: Danazol.
Anthelmintic: Albendazole; Anthelmycin; Bromoxanide; Bunamidine Hydrochloride; Butonate;
Cambendazole; Carbantel Lauryl Sulfate; Clioxanide; Closantel; Cyclobendazole; Dichlorvos; Diethylcarbamazine Citrate; Dribendazole; Dymanthine Hydrochloride; Etibendazole;
Fenbendazolc; Furodazole; Hexylresorcinol; Mebendazole; Morantel Tartrate; Niclosamide;
Nitramisole Hydrochloride; Nitrodan; Oxantel Pamoate; Oxfendazolc; Oxibendazole; Parbendazole;
Piperamide Maleate; Piperazine; Piperazine Citrate; Piperazine Edetate Calcium; Proclonol; Pyrantel
Pamoate; Pyrantel Tartrate; Pyrvinium Pamoate; Rafoxanide; Stilbazium Iodide; Tetramisole Hydrochloride; Thiabendazole; Ticarbodine; Tioxidazole; Triclofenol Piperazine; Vincofos; Zilantel.
Λnti-acnc: Adapalene; Erythromycin Salnacedin; Inocotcrone Acetate.
Anti-adrenergic: Λcebutolol; Alprenolol Hydrochloride; Atenolol; Bretylium Tosyiate; Bunolol Hydrochloride; Carteolol Hydrochloride; Celiprolol Hydrochloride; Cetamolol Hydrochloride;
Cicloprolol Hydrochloride; Dexpropranolol Hydrochloride; Diacetolol Hydrochloride;
Dihydrocrgotaminc Mesylate; Dilcvalol Hydrochloride; Esmolol Hydrochloride; Exaprolol
Hydrochloride; Fenspiride Hydrochloride; Flestolol Sulfate; Labetalol Hydrochloride ;
Levobetaxolol Hydrochloride; Levobunolol Hydrochloride; Mctalol Hydrochloride; Metoprolol; Metoprolol Tartrate; Nadolol; Pamatolol Sulfate; Pcnbutolol Sulfate; Phentolamine Mesylate;
Practolol; Propranolol I Iydrochloridc; Proroxan Hydrochloride; Soiypcrtinc Tartrate; Sotalol
Hydrochloride; Timolol; Timolol Maleate; Tiprcnolol 1 Iydrochloridc; Tolamolol; Zolcrtine
Hydrochloride.
Anti-allergic: Λmlexanox; Λstemizole; Λzclastinc Hydrochloride; Eclazolast ; Minocrorrul ;
Nedocromil ; Ncdocromil Calcium ; Ncdocromil Sodium ; Nivimedonc Sodium; Pemirolast
Potassium ; Pcntigetidc; Pirquinozol; Poisonoak Extract; Probicromil Calcium; Proxicromil;
Repirinast ; Tetrazolast Meglumine; Thiazinamium Chloride; Tiacrilast; Tiacrilast Sodium; Tiprinast
Meglumine; Tixanox.
Anti-amcbic : Berythromycin ; Bialamicol Hydrochloride; Chloroquinc; Chloroquinc Hydrochloride;
Chloroquinc Phosphate ; Clamoxyquin Hydrochloride; Clioquinol ; Emetine I Iydrochloridc; Iodoquinol; Paromomycin Sulfate; Quinfamide; Symetme Hydrochloride; Teclozan; Tctracycline; Tetracycline Hydrochloride.
Λnti-androgen: Benorterone; Cioteroncl; Cyproterone Acetate; Delmadinone Acetate ; Oxendolone; Topterone; Zanoterone.
Anti-anemic: Epoetin Alfa; Epoetin Beta ; Ferrous Sulfate, Dried; Leucovorin Calcium.
Anti-anginal: Amlodipinc Besylate; Amlodipine Maleate; Betaxolol Hydrochloride ; Bevantolol Hydrochloride ; Butoprozine Hydrochloride; Carvedilol ; Cinepazet Maleate; Metoprolol Suecinate ; Molsidominc ; Monatepil Maleate; Primidolol ; Ranolazine Hydrochloride; Tosifen; Verapamil Hydrochloride.
Anti-anxiety agent: Λdatanserin Hydrochloride: Alpidem: Binospirone Mesylate; Bretazenil; Glemanserin; Ipsapironc Hydrochloride; Miriselron Maleate; Ocinaplon; Ondansetron Hydrochloride ; Panadiplon; Pancopridc ; Pazinaclonc; Serazapinc Hydrochloride; Tandospironc Citrate; Zalospirone Hydrochloride. Anti-arthritic: Lodelaben .
Anti-asthmatic: Ablukast; Λblukast Sodium; Azelastine Hydrochloride : Bunaprolast; Cinalukast;
Cromitrilc Sodium; Cromolyn Sodium; Enofelast; Isamoxoic; Kclotifcn Fumarate; Levcromakalim;
Lodoxamide Ethyl ; Lodoxamide Tromethaminc; Montclukast Sodium; Ontazolast; Oxarbazole;
Oxatomidc; Piriprost; Piriprost Potassium; Pirolatc; Pobilukast Edamine; Quazolast ; Repirinast;
Ritolukast; Sulukast; Tctrazolast Meglumine ; Tiaramide Hydrochloride; Tibenelast Sodium; Tomclukast; Tranilast; Verlukasl; Vcrofyllinc ; Zarirlukasl.
Anti-athcrosclcrotic: Mifobate; Timcfuronc.
Antibacterial: Acedapsonc; Λcctosulfonc Sodium; Alamecin; Alexidine; Λmdinocillin; Amdinocillin Pivoxil; Amicyclinc; Λmifloxacin; Amifloxacin Mesylate; Amikacin; Amikacin Sulfate;
Λminosalicyiic acid; Λminosalicylatc sodium; Λmoxicillin: Λmphomycin; Λmpicillin; Λmpicillin
Sodium; Apalcillin Sodium; Apramycin; Aspartocin; Astromicin Sulfate; Avilamycin; Λvoparcin; Azithromycin; Λzlocillin; Azlocillin Sodium; Bacampicillin Hydrochloride; Bacitracin; Bacitracin
Methylene Disalicylate; Bacitracin Zinc; Bambermycins; Benzoylpas Calcium; Berythromycin ;
Betamicin Sulfate; Biapenem; Biniramycin; Biphenamine Hydrochloride ; Bispyrithione Magsulfex;
Butikacin; Butirosin Sulfate; Capreomycin Sulfate; Carbadox; Carbenicillin Disodium; Carbenicillin Indanyl Sodium; Carbenicillin Phenyl Sodium; Carbenicillin Potassium; Carumonam Sodium;
Cefaclor; Ccfadroxil; Cefamandolc; Cefamandolc Nafatc; Ccfamandole Sodium; Cefaparole;
Cefatrizine; Cefazaflur Sodium; Cefazolin; Cefazolin Sodium; Cefbuperazonc; Cefdinir; Cefepime;
Cefepime Hydrochloride; Cefetecol; Cefixime; Cefmenoxime Hydrochloride; Cefmetazole;
Cefmetazole Sodium; Cefonicid Monosodium; Cefonicid Sodium; Ccfoperazone Sodium; Ceforanide; Cefotaxime Sodium; Cefotetan; Cefotetan Disodium; Cefotiam Hydrochloride;
Cefoxitin; Cefoxitin Sodium; Cefpimizole; Cefpimizole Sodium; Cefpiramide; Cefpiramide Sodium;
Cefpirome Sulfate; Cefpodoxime Proxetil; Cefprozil; Cefroxadine; Cefsulodin Sodium; Ceftazidime;
Ceftibutcn; Ccftizoxime Sodium; Ceftriaxone Sodium; Cefuroximc: Cefuroxime Λxetil; Cefuroxime
Pivoxetil; Cefuroxime Sodium; Cephacetrile Sodium; Cephalcxin; Ccphalexin Hydrochloride; Ccphaloglycin; Cephaloridinc; Ccphalothin Sodium; Ccphapirin Sodium; Cephradine; Cetocyclinc
Hydrochloride; Cetophenicol; Chloramphenicol; Chloramphenicol Palmitate; Chloramphenicol
Pantothenatc Complex ; Chloramphenicol Sodium Suecinate; Chlorhexidine Phosphanilate;
Chlόroxylenol; Chlortetracycline Bisulfate; Chlortetracycline Hydrochloride; Cinoxacin;
Ciprofloxacin; Ciprofloxacin Hydrochloride; Cirolemycin ; Clarithromycin; Clinafloxacin Hydrochloride; Clindamycin; Clindamycin Hydrochloride; Clindamycin Palmitate Hydrochloride;
Clindamycin Phosphate; Clofazimine ; Cloxacillin Bcnzathinc; Cloxacillin Sodium; Cloxyquin;
Colistimethatc Sodium; Colistin Sulfate; Coumermycin; Coumermycin Sodium; Cyclacillin;
Cycioserine; Dalfopristin; Dapsonc ; Daptomycin; Dcmeclocyclinc; Demeclocycline Hydrochloride;
Demccycline; Denofungin ; Diaveridine; Dicloxacillin; Dicloxacillin Sodium; Dihydrostrcptomycin Sulfate; Dipyrithione; Dirithromycin; Doxycycline; Doxycycline Calcium ; Doxycycline Fosfalex;
Doxycycline Hyclate; Droxacin Sodium; Enoxacin; Epicillin; Epitetracycline Hydrochloride;
Erythromycin; Erythromycin Λcistrate; Erylhromycin Estolatc; Erythromycin Elhylsuccinate;
Erythromycin Gluceptatc: Erythromycin Lactobionate; Erythromycin Propionate; Erythromycin
Stearate; Ethambutol Hydrochloride; Ethionamidc; Fleroxacin; Floxacillin; Fludalaninc; Flumequinc; Fosfomycin; Fosfomycin Tromethamine; Fumoxicillin; Furazolium Chloride;
Furazolium Tartrate; Fusidatc Sodium: Fusidic Acid; Gcntamicin Sulfate; Gloximonam; Gramicidin;
Ilaloprogin; Hctacillin; Hetacillin Potassium; Ilcxedinc; lbafloxacin; Imipencm; Isoconazolc; Isepamicin; Isoniazid; Josamycin; Kanamycin Sulfate; Kitasamycin; Levofuraltadone;
Levopropylcillin Potassium; Lcxithromycin; Lincomycin; Lincomycin Hydrochloride;
Lomefloxacin; Lomefloxacin Hydrochloride; Lomefloxacin Mesylate; Loracarbef; Mafenide;
Meclocycline; Meclocycline Sulfosalicylate; Megalomicin Potassium Phosphate; Mequidox; Meropcnem; Methacycline; Methacycline Hydrochloride; Methenamine; Methenamine Hippurate;
Methcnamine Mandelate; Methicillin Sodium; Metioprim; Metronidazolc Hydrochloride;
Metronidazole Phosphate; Mezlocillin; Mezlocillin Sodium; Minocycline; Minocycline
Hydrochloride; Mirincamycin Hydrochloride ; Monensin ; Monensin Sodium ; Nafcillin Sodium;
Nalidixate Sodium; Nalidixic Acid; Natamycin; Ncbramycin; Neomycin Palmitate; Neomycin Sulfate; Neomycin Undecylenatc ; Netilmicin Sulfate; Neutramycin; Nifuradene; Nifuraldezone;
Nifuratcl ; Nifuratrone; Nifurdazil; Nifurimide; Nifurpirinol; Nifurquinazol; Nifurthiazole;
Nitrocycline; Nitrofurantoin; Nitromide; Norfloxacin; Novobiocin Sodium; Ofloxacin; Ormetoprim;
Oxacillin Sodium; Oximonam; Oximonam Sodium; Oxolinic Acid; Oxytetracycline;
Oxytetracycline Calcium; Oxytetracycline Hydrochloride; Paldimycin; Parachlorophenol; Paulomycin; Pefloxacin; Pefloxacin Mesylate; Penamecillin; Penicillin G Benzathine; Penicillin G
Potassium; Penicillin G Procaine; Penicillin G Sodium; Penicillin V; Penicillin V Benzathine;
Penicillin V Hydrabamine; Penicillin V Potassium; Pentizidone Sodium; Phenyl Aminosalicylate;
Piperacillin Sodium; Pirbenicillin Sodium; Piridicillin Sodium; Pirlimycin Hydrochloride;
Pivampicillin Hydrochloride; Pivampicillin Pamoate; Pivampicillin Probenate; Polymyxin B Sulfate; Porfiromycin ; Propikacin; Pyrazinamide; Pyrithione Zinc; Quindecamine Acetate; Quinupristin;
Racephenicol; Ramoplanin; Ranimycin; Rciomycin; Repromicin; Rifabutin; Rifametane; Rifamexil;
Rifamide; Rifampin; Rifapcnline; Rifaximin; Rolitetracyclinc; Rolitetracyclinc Nitrate;
Rosaramicin; Rosaramicin Butyrale; Rosaramicin Propionate; Rosaramicin Sodium Phosphate;
Rosaramicin Stearate; Rosoxacin; Roxarsone; Roxithromycin; Sancycline; Sanfetrinem Sodium; Samioxicillin; Sarpicillin; Scopafungin ; Sisomicin; Sisomicin Sulfate; Sparfioxacin; Spectinomycin
Hydrochloride; Spiramycin; Stallimycin Hydrochloride; Steffimycin; Streptomycin Sulfate;
Streptonicozid; Sulfabenz ; Sulfabenzamide; Sulfacetamide; Sulfacetamidc Sodium; Sulfacytine;
Sulfadiazine; Sulfadiazinc Sodium; Sulfadoxine; Sulfalcne; Sulfamcrazinc; Sulfamctcr;
Sulfamethazine; Sulfamcthizolc; Sulfamcthoxazole; Sulfamonomethoxinc; Sulfamoxolc; Sulfanilate Zinc; Sulfanitran ; Sulfasalazinc; Sulfasomizole; Sulfathiazole; Sulfazamet; Sulfisoxazolc;
Sulfisoxazole Acetyl; Sulfisoxazolc Diolamine; Sulfomyxin; Sulopencm; Sultamicillin; Suncillin
Sodium; Talampicillin Hydrochloride; Teicoplanin; Tcmafloxacin Hydrochloride; Tcmocillin; Tetracycline; Tetracycline Hydrochloride ; Tetracyclinc Phosphate Complex; Tctroxoprim; Thiamphenicol; Thiphencillin Potassium; Ticarcillin Cresyl Sodium; Ticarcillin Disodium; Ticarcillin Monosodium; Ticlatone; Tiodonium Chloride; Tobramycin; Tobramycin Sulfate; Tosufloxacin; Trimethoprim; Trimethoprim Sulfate: Trisulfapyrimidines; Troleandomycin; Trospectomycin Sulfate; Tyrothricin; Vancomycin; Vancomycin Hydrochloride; Virginiamycin; Zorbamycin.
Anticholelithic: Monoctanoin.
Anticholelithogenic: Chenodiol; Ursodiol.
Anticholinergic: Alverinc Citrate; Anisotropine Methylbromide; Λtropine; Atropine Oxide
Hydrochloride; Atropine Sulfate; Belladonna; Benapryzine Hydrochloride; Benzetimide
Hydrochloride; Benzilonium Bromide; Biperidcn ; Biperiden Hydrochloride; Biperiden Lactate ; Clidinium Bromide; Cyclopentolate Hydrochloride; Dexetimide; Dicyclomine Hydrochloride;
Dihexyvcrinc Hydrochloride; Domazoline Fumarate; Elantrinc; Elucaine; Ethybcnztropinc;
Eucatropine Hydrochloride; Glycopyrrolate; Heteronium Bromide; Homatropine Hydrobromide;
Homatropine Methylbromide; I lyoscyaminc; Hyoscyamine Hydrobromide; Hyoscyamine Sulfate;
Isopropamidc Iodide; Mepenzolate Bromide; Methylatropine Nitrate; Metoquizine; Oxybutynin Chloride; Parapenzolate Bromide; Pentapiperium Methylsulfatc; Phencarbamidc; Poldinc
Methylsulfatc; Proglumidc; Propanthcline Bromide; Propenzolatc I Iydrochloridc; Scopolaminc
Hydrobromide: Tcmatropium Methylsulfatc; Tiquinamidc I Iydrochloridc; Tofcnacin Hydrochloride;
Toquizinc; Triampyzinc Sulfate; Trihexyphenidyl Hydrochloride; Tropicamide.
Anticoagulant: Λncrod; Anticoagulant Citrate Dextrose Solution ; Anticoagulant Citrate Phosphate Dextrose Adenine Solution; Anticoagulant Citrate Phosphate Dextrose Solution; Anticoagulant Ilcparin Solution; Anticoagulant Sodium Citrate Solution; Λrdeparin Sodium; Bivalirudin ; Bromindionc; Dalteparin Sodium ; Dcsirudin; Dicumarol; I lcparin Calcium; Ileparin Sodium; Lyapolatc Sodium; Nafamostat Mesylate ; Phcnprocoumon; Tinzaparin Sodium ; Warfarin Sodium. Λnticoccidal: Maduramicin.
Λnticonvulsant: Albutoin; Λmcltolidc; Λtolidc; Buramalc; Carbamazcpinc ; Cinromidc; Citenamide; P T U 7/08867
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Clonazcpam; Cyheptamide; Dezinamide; Dimcthadione; Divalproex Sodium; Eterobarb; Ethosuximide; Ethotoin; Flurazepam Hydrochloride ; Fluzinamide; Fosphenytoin Sodium; Gabapentin; Ilepcimide; Lamotrigine; Magnesium Sulfate ; Mephenytoin; Mephobarbital ; Methetoin; Methsuximide; Milaccmide Hydrochloride ; Nabazenil; Nafimidone Hydrochloride; Nitrazepam ; Phenacemide; Phenobarbital ; Phenobarbital Sodium ; Phensuximide; Phenytoin; Phenytoin Sodium; Primidone; Progabide; Ralitoline; Remacemide Hydrochloride; Ropizinc; Sabeluzole ; Stiripentol; Sulthiame; Thiopental Sodium ; Tiletamine Hydrochloride ; Topiramate; Trimcthadione; Valproate Sodium; Valproic Acid; Vigabatrin; Zoniclezole Hydrochloride; Zonisamide.
Antidepressant: Adatanserin Hydrochloride; Adinazolam ; Λdinazolam Mesylate; Λlaproclate;
Λletamine Hydrochloride; Amedalin Hydrochloride; Amitriptyline Hydrochloride; Amoxapine;
Aptazapine Maleate; Λzaioxan Fumarate; Azepindole; Λzipramine Hydrochloride; Bipenamol
Hydrochloride; Bupropion Hydrochloride; Butacetin; Butriptyline Hydrochloride; Caroxazone; Cartazolate; Ciclazindol; Cidoxepin Hydrochloride; Cilobamine Mesylate; Clodazon Hydrochloride;
Clomipramine Hydrochloride; Cotinine Fumarate; Cyclindole; Cypenamine Hydrochloride;
Cyprolidol Hydrochloride; Cyproximide ; Daledalin Tosylatc; Dapoxctine Hydrochloride; Dazadrol
Maleate; Dazepinil Hydrochloride; Desipramine Hydrochloride; Dexamisole; Deximafen;
Dibenzepin Hydrochloride; Dioxadrol Hydrochloride; Dothiepin Hydrochloride; Doxepin Hydrochloride; Duloxetine Hydrochloride; Eclanamine Maleate; Encypratc; Etoperidone
Hydrochloride; Fantridonc Hydrochloride; Fenmetozole Hydrochloride ; Fenmetramide; Fezolaminc
Fumarate; Fluotracen Hydrochloride ; Fluoxetine; Fluoxetine I Iydrochloridc; Fluparoxan
Hydrochloride; Gamfexine; Guanoxyfen Sulfate ; Imafen Hydrochloride; Imiloxan Hydrochloride;
Imipramine Hydrochloride; Indeloxazine Hydrochloride; Intriptyline Hydrochloride; Iprindole; Isocarboxazid; Ketipramine Fumarate; Lofepramine Hydrochloride; Lortalamine; Maprotiline;
Maprotiline Hydrochloride; Melitraccn Hydrochloride; Milaccmide 1 Iydrochloridc; Minaprine
Hydrochloride; Mirtazapine; Moclobemide; Modaline Sulfate; Napactadine Hydrochloride;
Napamezole Hydrochloride; Nefazodonc Hydrochloride; Nisoxetine; Nitrafudam Hydrochloride;
Nomifensine Maleate; Nortriptyline Hydrochloride; Octriptyline Phosphate; Opipramol Hydrochloride; Oxaprotiline Hydrochloride; Oxypertine; Paroxetine; Phenelzine Sulfate;
Pirandamine Hydrochloride; Pizotyline ; Pridefine Hydrochloride; Prolintane Hydrochloride;
Protriptylinc Hydrochloride; Quipazine Maleate ; Rolicyprine; Seproxetine Hydrochloride; Sertraline Hydrochloride; Sibutramine Hydrochloride ; Sulpiride; Suritozole; Tametralinc Hydrochloride; Tampramine Fumarate; Tandamine Hydrochloride: Thiazesim Hydrochloride; Thozalinone; Tomoxetine Hydrochloride; Trazodone Hydrochloride; Trebenzomine Hydrochloride; Trimipramine; Trimipramine Maleate; Venlafaxinc Hydrochloride; Viloxazine Hydrochloride; Zimeldine Hydrochloride; Zometapine.
Antidiabetic: Λcetohexamide; Buformin; Butoxamine Hydrochloride ; Camiglibose;
Chlorpropamide; Ciglitazone; Englitazone Sodium; Etoformin Hydrochloride; Gliamilidc;
Glibornuride; Glicetanile Sodium; Gliflumide; Glipizide; Glucagon; Glyburide; Glyhexamide; Glymidine Sodium; Glyoctamide; Glyparamide; Insulin; Insulin, Dalanated; Insulin Human; Insulin
Human, Isophane; Insulin Human Zinc; Insulin Human Zinc, Extended; Insulin, Isophanc; Insulin
Lispro; Insulin. Neutral; Insulin Zinc; Insulin Zinc, Extended; Insulin Zinc, Prompt; Linogliride;
Linogliride Fumarate; Metformin; Methyl Palmoxirate; Palmoxiratc Sodium; Pioglitazone
Hydrochloride; Pirogliride Tartrate; Proinsulin Human; Seglitide Acetate; Tolazamide; Tolbutamide; Tolpyrramide; Troglitazone; Zopolrestat.
Antidiarrheal: Rolgamidine, Diphenoxylate hydrochloride (Lomotil), Metronidazole (Flagyl), Methylprednisolone (Medrol), Sulfasalazine (Azulfidine).
Antidiuretic: Λrgipressin Tannate; Desrnopressin Acetate; Lypressin .
Antidote: Dimercaprol; Edrophonium Chloride; Fomepizolc; Lcucovorin Calcium ; Levolcucovorin Calcium; Methylene Blue ; Protamine Sulfate.
Antidyskinetic: Selegiline Hydrochloride
Anti-emetic: Alosetron Hydrochloride; Batanopride Hydrochloride; Bemesetron; Benzquinamide; Chlorpromazine ; Chlorpromazine Hydrochloride ; Clebopride; Cyclizine Hydrochloride; Dimenhydrinate; Diphenidol; Diphenidol Hydrochloride; Diphenidol Pamoate; Dolasetron Mesylate ; Domperidone; Dronabinol; Fludorex; Flumeridone; Galdansetron Hydrochloride; Granisetron; Granisetron I Iydrochloridc; Lurosetron Mesylate; Mcclizine Hydrochloride; Metoclopramidc Hydrochloride; Metopimazine; Ondansetron Hydrochloride ; Pancopride; Prochlorperazine; Prochlorpcrazine Edisylate; Prochlorperazine Maleate ; Promethazinc Hydrochloride ; Thiethylperazine; Thiethylperazine Malate; Thiethylpcrazine Maleate; Trimethobenzamide Hydrochloride; Zacopride Hydrochloride.
Anti-epileptic: Felbamate; Loreclezole; Tolgabide.
Anti-estrogen: Clometherone; Delmadinone Acetate ; Nafoxidine Hydrochloride; Nitromifcne Citrate; Raloxifene Hydrochloride; Tamoxifen Citrate; Toremifene Citrate ; Trioxifene Mesylate.
Antifibrinolytic: Nafamostat Mesylate .
Antifungal: Acrisorcin; Ambruticin; Amphotericin B; Azaconazole; Azaserine; Basifungin;
Bifonazole; Biphenamine Hydrochloride ; Bispyrithione Magsulfex ; Butoconazole Nitrate; Calcium
Undecylenatc; Candicidin; Carbol-Fuchsin; Chlordantoin; Ciclopirox; Ciclopirox Olamine;
Cilofungin; Cisconazole; Clotrimazole; Cuprimyxin: Denofungin ; Dipyrithione; Doconazole; Econazole; Econazolc Nitrate; Enilconazole; Ethonam Nitrate; Fenticonazole Nitrate; Filipin;
Fluconazole; Flucytosine; Fungimycin; Griseofulvin; Hamycin; Isoconazole ; Itraconazole;
Kalafungin; Ketoconazole; Lomofungin; Lydimycin; Mepartricin ; Miconazole; Miconazole Nitrate;
Monensin ; Monensin Sodium ; Naftifine Hydrochloride; Neomycin Undecylenate ; Nifuratel ;
Nifuimerone; Nitralamine Hydrochloride: Nystatin; Octanoic Acid; Orconazole Nitrate; Oxieonazolc Nitrate; Oxifungin Hydrochloride; ParConazole Hydrochloride; Partricin ; Potassium Iodide ;
Proclonol ; Pyrithione Zinc ; Pyrrolnitrin; Rutamycin; Sanguinarium Chloride ; Saperconazole;
Scopafungin ; Selenium Sulfide ; Sincfungin; Sulconazolc Nitrate; Terbinafinc; Tcrconazole;
Thiram; Ticlatone ; Tioconazole; Tolciclate; Tolindate; Tolnaftate; Triacetin; Triafungin;
Undecylcnic Acid; Viridofulvin; Zinc Undecylenate; Zinoconazole Hydrochloride.
Antiglaucoma agent : Λlprcnoxime Hydrochloride ; Colforsin; Dapiprazole Hydrochloride ; Dipivefrin Hydrochloride ; Naboctate Hydrochloride ; Pilocarpine; Pirnabine.
Antihemophilic: Antihemophilic Factor.
Antihemorrhagic: Poliglusam. Antihistaminic: Λcrivastine; Λntazoline Phosphate; Astemizole ; Azatadine Maleate; Barmastine;
Bromodiphenhydramine Hydrochloride; Brompheniramine Maleate; Carbinoxaminc Maleate;
Cetirizine Hydrochloride; Chlorpheniramine Maleate; Chlorpheniramine Polistirex; Cinnarizine;
Clemastine; Clemastine Fumarate; Closiramine Aceturate; Cycliramine Maleate; Cyclizine; Cyprohcptadine Hydrochloride ; Dcxbrompheniramine Maleate; Dexchlorpheniramine Maleate;
Dimethindenc Maleate; Diphenhydramine Citrate; Diphenhydramine Hydrochloride; Dorastine
Hydrochloride; Doxylamine Suecinate; Ebastine; Levocabastine Hydrochloride; Loratadine;
Mianserin Hydrochloride ; Noberastine; Orphenadrine Citrate ; Pyrabrom; Pyrilamine Maleate;
Pyroxamine Maleate; Rocastine Hydrochloride; Rotoxaminc; Tazifyllinc Hydrochloride; Temclastine; Terfenadine; Tripelennamine Citrate; Tripelennamine Hydrochloride; Triprolidine
Hydrochloride; Zolamine Hydrochloride .
Λntihyperlipidemic: Cholestyramine Resin ; Clofibrate; Colestipol Hydrochloride; Crilvastatin;
Dalvastatin; Dextrothyroxine Sodium; Fluvastatin Sodium ; Gemfibrozil; Lecimibide; Lovastatin;
Niacin ; Pravastatin Sodium; Probucol; Simvastatin; Tiquesidc; Xenbucin.
Antihyperlipoproteinemic: Acifran; Beloxamide; Bezafibratc; Boxidine; Butoxamine Hydrochloride; Cetaben Sodium; Ciprofibrate; Gemcadiol; Halofenate ; Lifibrate; Meglutol; Nafenopin; Pimetine Hydrochloride; Theofibratc; Tibric Λcid; Treloxinate.
Λntihypcrtensive: Alfuzosin Hydrochloride; Alipamide ; Althiazide; Amiquinsin Hydrochloride; Λmlodipine Besylatc ; Amlodipinc Maleate ; Anaritide Acetate ; Atiprosin Maleate; Belfosdil; Bemitradine; Bendacalol Mesylate; Bendroflumcthiazidc ; Benzthiazide ; Betaxolol Hydrochloride ; Bethanidinc Sulfate; Bevantolol Hydrochloride ; Biclodil Hydrochloride; Bisoprolol; Bisoprolol Fumarate; Bucindolol Hydrochloride; Bupicomide; Buthiazide: Candoxatril; Candoxatrilat; Captopril ; Carvedilol ; Ceronapril; Chlorothiazide Sodium ; Ciclctanine; Cilazapril; Clonidμie; Clonidine Hydrochloride; Clopamide ; Cyclopenthiazidc; Cyclothiazide ; Darodipine ; Debrisoquin Sulfate; Delapril Hydrochloride; Diapamide ; Diazoxide; Dilevalol Hydrochloride ; Diltiazem Malate; Ditekiren; Doxazosin Mesylate; Ecadotril; Enalapril Maleate: Enalaprilat; Enalkiren; Endralazinc Mesylate; Epithiazidc ; Eprosartan; Eprosartan Mesylate; Fenoidopam Mesylate ; Flavodilol Maleate; Flordipine; Flosequinan; Fosinopril Sodium ; Fosinoprilat; Guanabenz; Guanabenz Acetate; Guanaclinc Sulfate; Guanadrcl Sulfate; Guancydinc; Guanethidine Monosulfatc; Guanethidine Sulfate; Guanfacinc Hydrochloride; Guanisoquin Sulfate; Guanoclor Sulfate; Guanoctine Hydrochloride; Guanoxabenz; Guanoxan Sulfate; Guanoxyfcn Sulfate ; Hydralazine Hydrochloride; Hydralazine Polistirex; Hydroflumethiazide ; Indacrinone ; Indapamide ; Indolapril Hydrochloride; Indoramin; Indoramin Hydrochloride; Indorcnate Hydrochloride; Lacidipinc; Leniquinsin; Levcromakalim ; Lisinopril; Lofexidine Hydrochloride; Losartan Potassium; Losulazine Hydrochloride; Mcbutamatc; Mecamylamine Hydrochloride; Medroxalol; Medroxalol Hydrochloride; Methalthiazide ; Methyclothiazide ; Methyldopa; Methyldopate Hydrochloride; Metipranolol; Metolazone ; Metoprolol Fumarate: Metoprolol Suecinate ; Metyrosine; Minoxidil ; Monatepil Maleate ; Muzolimine ; Nebivolol; Nitrendipine; Ofornine; Pargyline Hydrochloride; Pazoxide; Pelanserin Hydrochloride ; Pcrindopril Erbumine; Phenoxybenzamine Hydrochloride; Pinacidil; Pivopril; Polythiazide ; Prazosin Hydrochloride; Primidolol ; Prizidilol Hydrochloride; Quinapril Hydrochloride ; Quinaprilat ; Quinazosin Hydrochloride; Quinelorane Hydrochloride ; Quinpirole Hydrochloride: Quinuclium Bromide; Ramipril ; Rauwolfia Serpentina; Reserpine; Saprisartan Potassium: Saralasin Acetate; Sodium Nitroprusside; Sulfinalol Hydrochloride; Tasosartan; Teludipine Hydrochloride ; Temocapril Hydrochloride; Terazosin Hydrochloride; Terlakiren; Tiamenidine; Tiamenidine Hydrochloride; Ticrynafen ; Tinabinol; Tiodazosin; Tipentosin Hydrochloride; Trichlormethiazidc ; Trimazosin Hydrochloride; Trimethaphan Camsylate; Trimoxamine Hydrochloride; Tripamide; Xipamide ; Zankircn I Iydrochloridc: Zofenoprilat Arginine.
Antihypotensive: Ciclafrinc Hydrochloride; Midodrine Hydrochloride.
Anti-infective: Difloxacin Hydrochloride ; Lauryl lsoquinolinium Bromide; Moxalactam Disodium; Ornidazole; Pentisomicin; Sarafloxacin Hydrochloride; Protease inhibitors of HIV and other retroviruscs; Intcgrase Inhibitors of HIV and other rctroviruscs; Cefaclor (Ccclor); Acyclovir (Zovirax); Norfloxacin (Noroxin); Cefoxitin (Mefoxin); Cefuroxime axetil (Ceftin); Ciprofloxacin (Cipro).
Anti-infective, topical: Alcohol; Aminacrine Hydrochloride; Benzethonium Chloride : Bithionolate Sodium; Bromchlorenone; Carbamide Peroxide; Cetalkonium Chloride; Cetylpyridinium Chloride : Chlorhcxidinc Hydrochloride; Clioquinol ; Domiphen Bromide; Fenticlor; Fludazonium Chloride; Fuchsin, Basic; Furazolidone ; Gentian Violet; Halquinols; Hexachlorophene: Hydrogen Peroxide; Ichthammol: Imidecyl Iodine; Iodine; Isopropyl Alcohol; Mafenide Acetate; Meralein Sodium; Mercufcnol Chloride; Mercury, Ammoniated; Methylbenzethonium Chloride; Nitrofurazone; Nitromersol; Octenidine Hydrochloride; Oxychlorosene; Oxychlorosene Sodium; Parachlorophenol, Camphorated; Potassium Permanganate; Povidone-Iodine; Sepazonium Chloride; Silver Nitrate; Sulfadiazine, Silver; Symclosene; Thimerfonate Sodium; Thimerosal : Troclosene Potassium.
Anti-inflammatory: Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; Alpha Amyiase;
Amcinafal; Amcinafide; Amfenac Sodium; Amiprilosc Hydrochloride; Anakinra; Anirolac ;
Anitrazafen; Apazonc; Balsalazide Disodium; Bendazac; Benoxaprofen ; Benzydamine
Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate;
Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone; Dexamethasone
Dipropionate; Diclofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate; Diflumidone
Sodium; Diflunisal ; Difluprednatc; Diftalone; Dimethyl Sulfoxide; Drocinonide; Endrysone;
Enlimomab ; Enolicam Sodium ; Epirizole ; Etodolac; Etofenamatc ; Felbinac; Fenamole; Fenbufen; Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone; Fluazacoit; Flufenamic Acid;
Flumizole; Flunisolide Acetate; Flunixin ; Flunixin Meglumine ; Fluocortin Butyl; Fluoromctholone
Acetate; Fluquazonc; Flurbiprofen ; Fluretofen; Fluticasonc Propionate; Furaprofen; Furobufcn;
Halcinonide; Halobetasol Propionate; Halopredone Acetate; Ibufenac ; Ibuprofen; Ibuprofen
Aluminum; Ibuprofen Piconol; Ilonidap; Indomethacin; Indomethacin Sodium; Indoprofen ; Indoxole ; Intrazole; Isoflupredone Acetate; Isoxepac; Isoxicam; Ketoprofen; Lofemizole
Hydrochloride ; Lornoxicam ; Loteprednol Etabonate; Mcclofenamate Sodium; Meclofenamic Acid;
Meclorisone Dibutyrate; Mefenamic Acid ; Mesalaminc; Meseclazone; Methylprednisolone
Suleptanate; Morniflumate; Nabumetone; Naproxen ; Naproxen Sodium ; Naproxol ; Nimazone;
Olsalazine Sodium; Orgotein ; Orpanoxin; Oxaprozin; Oxyphenbutazone; Paranyline Hydrochloride; Pentosan Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pirfenidone ; Piroxicam; Piroxiqam
Cinnamate; Piroxicam Olamine; Pirprofen; Prednazate; Prifelone; Prodolic Acid; Proquazone;
Proxazole; Proxazole Citrate ; Rimexolone; Romazarit ; Salcolcx ; Salnacedin; Salsalate ;
Sanguinarium Chloride ; Seclazone ; Sermetacin; Sudoxicam; Sulindac; Suprofen; Talmetacin;
Talniflumate ; Talosalate ; Tebufelone ; Tenidap; Tenidap Sodium; Tenoxicam; Tesicam; Tcsimide; Tetrydamine ; Tiopinac; Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide; Triflumidatc;
Zidometacin; Zomepirac Sodium . Anlikeratinizing agent: Doretinel; Linarotene; Pelretin.
Λnlimalarial : Λccdapsonc ; Λmodiaquinc Hydrochloride ; Λmquinalc; Λrtcflcnc; Chloroquinc ;
Chloroquine Hydrochloride ; Chloroquine Phosphate ; Cycloguanil Pamoate; Enpiroline Phosphate; Halofantrine Hydrochloride ; Hydroxychioroquine Sulfate ; Mefloquine Hydrochloride; Menoctone;
Mirincamycin Hydrochloride ; Primaquine Phosphate; Pyrimethamine; Quinine Sulfate; Tcbuquine.
Antimicrobial: Aztreonam; Chlorhexidine Gluconate; Imidurea; Lycetamine; Nibroxane; Pirazmonam Sodium; Propionic Acid ; Pyrithionc Sodium; Sanguinarium Chloride ; Tigemonam Dicholine.
Antimigraine: Dolasetron Mesylate ; Naratriptan Hydrochloride; Sergolexole Maleate; Sumatriptan Suecinate; Zatosetron Maleate.
Antimitotic: Podofilox.
Antimycotic: Amorolfine.
Antinauscant : Buclizine Hydrochloride ; Cyclizine Lactate; Naboctate Hydrochloride .
Antineoplastic: Λcivicin; Λclarubicin; Λcodazolc Hydrochloride; Λcronine; Λdozelesin;
Aldesleukin ; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide ; Amsacrine;
Anastrozole; Anthramycin; Asparaginase; Asperlin ; Azacitidine; Azetepa; Azotomycin; Batimastat;
Benzodepa; Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Bropirimine ; Busulfan; Cactinomycin; Calusteronc; Caracemiide;
Carbetimer; Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin; Cedefingol;
Chlorambucil; Cirolemycin ; Cisplatin; Cladribine; Crisnatol Mesylate; Cyclophosphamide ;
Cytarabine ; Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride; Decitabine; Dexormaplatin;
Dezaguanine; Dezaguanine Mesylate; Diaziquone; Docctaxel; Doxorubicin; Doxorubicin Hydrochloride; Droloxifene; Droloxifene Citrate; Dromostanolone Propionate; Duazomycin;
Edatrexate; Eflomithine Hydrochloride ; Elsamitrucin; Enloplatin; Enpromate; Epipropidine;
Epirubicin Hydrochloride; Erbulozole; Esonibicin Hydrochloride; Estramustine; Estramustine Phosphate Sodium; Etanidazole; Ethiodized Oil I 131 ; Etoposide; Etoposide Phosphate; Etoprine;
Fadrozole Hydrochloride; Fazarabinc; Fenretinide; Floxuridine ; Fludarabine Phosphate;
Fluorouracil; Flurocitabine; Fosquidonc; Fostriecin Sodium; Gemcitabine; Gemcitabine
Hydrochloride; Gold Au 198 ; Hydroxyurea; Idarubicin Hydrochloride; Ifosfamidc; Ilmofosine; Interferon Alfa-2a ; Interferon Alfa-2b ; Interferon Alfa-nl ; Interferon Alfa-n3; Interferon Beta-I a
; Interferon Gamma-I b; Iproplatin; Irinotecan Hydrochloride ; Lanreotide Acetate; Letrozole;
Leuprolidc Acetate ; Liarozole Hydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone
Hydrochloride; Masoprocol; Maytansine; Mechlorethamine Hydrochloride; Megestrol Acetate;
Melengestrol Acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate Sodium; Metoprine; Meturedepa; MiUndomide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin;
Mitosper; Mitotane; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin;
Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate;
Perfosfamide; Pipobroman; Piposulfan; Piroxantrone Hydrochloride; Plicamycin; Plomestane;
Porfimer Sodium; Porfiromycin ; Prednimustine; Procarbazine Hydrochloride; Puromycin ; Puromycin Hydrochloride; Pyrazofurin; Riboprine: Rogletimide; Safingol ; Safingol Hydrochloride
; Semustine; Simtrazene; Sparfosatc Sodium; Sparsomycin; Spirogermanium Hydrochloride;
Spiromustine; Spiroplatin; Slreptonigrin; Streptozocin; Strontium Chloride Sr 89; Sulofenur;
Talisomycin; Taxane; Taxoid; Tecogalan Sodium; Tegafur; Teloxantrone Hydrochloride;
Temoporlin; Teniposide; Teroxirone; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; Topotecan Hydrochloride; Toremifene Citrate; Trestolone Acetate; Triciribine
Phosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin; Tubulozole Hydrochloride; Uracil
Mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine;
Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine
Tartrate; Vinrosidine Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin; Zorubicin Hydrochloride.
Other anti-neoplastic compounds include: 20-epi-l ,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelidc; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing moφhogenetic protein- 1 ; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTB A; arginine deaminase; asulacrinc; atamestanc; atrimustine; axinastatin 1 ; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betuiinic acid; bFGF inhibitor; bicaiutamide; bisantrenc; bisaziridinylspcrmine; bisnafidc; bistratene Λ; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox
IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin
B; cetrorelix; chlorins; chloroquinoxalinc sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin: dacliximab: decitabine; dehydrodidemnin B; deslorelin; dcxifosfamidc; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazolc; etoposide phosphate; exemestanc; fadrozole; fazarabine; fcnretinidc; filgrastim; finasteridc; flavopiridol; flezelastinc; fluasterone: fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine: glutathione inhibitors; hepsulfam: heregulin; hcxamcthylcnc bisacctamidc; hypericin; ibandronic acid; idarubicin; idoxifenc; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunoslimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; irinotecan; iroplact; irsogladine; isobengazolc; isohomohalicondrin B; itasetron; jasplakinolide: kahalalide F; lamellafin-
N triacetate; lanreotidc; lcinamycin; lcnograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; lcuprolidc + estrogen + progesterone; leuprorelin; levamisole; liarozoie; linear polyaminc analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lomctrexol; lonidaminc; losoxantrone; lovastatin; ioxoribinc; lurtotecan; lutctium texaphyrin; lysofyllinc; lytic peptides; maitansine; mannostatin A; marimastat: masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; mcnogaril: mcrbarone; metcrelin; methioninasc; metoclopramidc; MIF inhibitor; mifepristone; miltefosinc; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryi lipid A + myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone + pentazocine; napavin; naphteφin; nartograstim; nedaplatin: nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06-benzylguaninc; octreotide; okicenonc; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid: panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesinc; pcntosan poiysulfate sodium; pentostatin; pentrozole; perflubron: perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocaφine hydrochloride; piranibicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; propyl bis- acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylasc inhibitors; puφurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors: ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronatc; rhizoxin; ribozymcs; RII rctinamidc; rogletimide; rohitukinc; romurtidc; roquinimex: rubiginone B 1 ; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; scmustinc; senescence derived inhibitor 1 ; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptatc; sodium phenylacetate; solvcrol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1 ; squalaminc; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodidc; tauromustine; tazarotene; tecogalan sodium; tegafur; tcllurapyrylium; tclomcrasc inhibitors; tcmoporfin; temozolomide; teniposidc; tetrachlorodecaoxide; tctrazominc; thaliblastine: thaiidomidc; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; 7 867
- 38 - thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene dichloride; topotecan; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine: triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubcnimex; urogenitai sinus- derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbinc; vinxaltinc; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer.
Anti-cancer Supplementary Potentiating Agents: Tricyclic anti-depressant drugs (e.g., imipramine, desipramine, amitryptyiine, clomipramine, trimipramine, doxepin, nortriptyline, protriptyline, amoxapine and maprotiline); non-tricyclic anti-depressant drugs (e.g., sertralinc, trazodone and citalopram); Ca+* antagonists (e.g., verapamil, nifedipine, nitrendipine and carovcrine); Calmodulin inhibitors (e.g., prenylamine, trifluoroperazine and clomipramine);
Amphotericin B; Triparanol analogues (e.g., tamoxifen); antiarrhythmic drugs (e.g., quinidinc); antihypertensive drugs (e.g., reserpine); Thiol depleters (e.g., buthionine and sulfoximine) and Multiple Drug Resistance reducing agents such as Cremaphor EL. The compounds of the invention also can be administered with cytokines such as granulocyte colony stimulating factor.
Λntineutropenic: Filgrastim; Lcnograstim; Molgramostim; Regramostim; Sargramostim.
Λntiobscssional agent: Fluvoxamine Maleate.
Antiparasitic: Abamcctin; Clorsulon; lvermcclin.
Antiparkinsonian: Bcnztropinc Mesylate; Biperiden; Biperiden Hydrochloride; Biperiden Lactate; Carmantadine; Ciladopa Hydrochloride; Dopamantine; Ethopropazine Hydrochloride; Lazabemide; Levodopa; Lomctraline Hydrochloride; Mofcgiline Hydrochloride; Naxagolide Hydrochloride; Pareptide Sulfate; Procyclidine Hydrochloride; Quinclorane Hydrochloride; Ropinirole Hydrochloride; Selcgilinc Hydrochloride; Tolcaponc; Trihexyphcnidyl I Iydrochloridc
Antiperistaltic: Difenoximide Hydrochloride; Difenoxin; Diphenoxylate Hydrochloride; Fluperamide; Lidamidine Hydrochloride; Loperamidc Hydrochloride; Malethamcr; Nufcnoxolc; Paregoric. Antipncumocystic: Atovaquone.
Antiproliferative agent: Piritrexim Isethionate.
Antiprostatic hypertrophy: Sitogluside.
Antiprotozoal: Amodiaquine; Azanidazole; Bamnidazole; Camidazole; Chlortetracycline Bisulfate ; Chlortetracycline Hydrochloride; Flubendazole; Flunidazole; Halofuginone Hydrobromide; Imidocarb Hydrochloride; Ipronidazole; Metronidazole; Misonidazole; Moxnidazoie; Nitarsone; Partricin; Puromycin; Puromycin Hydrochloride; Ronidazolc; Sulnidazole; Tinidazole.
Λntipruritic: Cyproheptadine Hydrochloride ; Methdilazine; Methdilazine Hydrochloride; Trimeprazine Tartrate.
Antipsoriatic: Acitretin; Anthralin; Azaribine; Calcipotriene; Cycloheximide; Enazadrem Phosphate; Etretinatc; Liarozole Fumarate; Lonapalenc; Tepoxalin.
Antipsychotic: Acetophenazine Maleate; Alentemol Hydrobromide; Alpertine; Azaperone;
Batelapine Maleate; Benperidol; Benzindopyrine Hydrochloride; Brofoxine; Bromperidol; Bromperidol Decanoate; Butaclamol 'Hydrochloride; Butapcrazine; Butapcrazine Maleate:
Carphenazine Maleate; Carvotroline Hydrochloride; Chloφromazine; Chloφromazine
Hydrochloride; Chlorprothixcnc; Cinpercne; Cintriamidc; Clomacran Phosphate; Clopenthixol;
Clopimozide; Clopipazan Mesylate; Cloroperone Hydrochloride; Clothiapine; Clothixamide
Maleate; Clozapine; Cyclophenazine Hydrochloride; Droperidol; Etazolate Hydrochloride; Fenimide; Flucindole; Flumezapine; Fluphenazine Decanoate; Fluphenazine Enanthate;
Fluphenazine Hydrochloride; Fluspiperonc; Fluspirilene; Flutrolinc; Gevotroline Hydrochloride;
Halopemidc; Haloperidol; Haloperidol Decanoate; Iloperidonc; Imidoline Hydrochloride;
Lenperone; Mazapertine Suecinate; Mesoridazinc; Mesoridazine Bcsylate; Mctiapinc; Milenperone;
Milipertine; Molindone Hydrochloride; Naranol Hydrochloride; Ncfiumozide Hydrochloride; Ocapcridonc; Olanzapine; Oxiperomide; Penfiuridol; Pcntiapine Maleate; Pcrphenazinc; Pimozidc;
Pinoxcpin Hydrochloride; Pipampcronc; Piperacctazinc; Pipotiazinc Palmitate; Piquindone
I Iydrochloridc; Prochlorperazine Edisylalc; Prochlorperazine Maleate; Promazine Hydrochloride; Remoxipride; Remoxipridc Hydrochloride; Rimcazole Hydrochloride; Seperidol Hydrochloride; Sertindole ; Setoperonc; Spiperonc; Thioridazine ; Thioridazine Hydrochloride; Thiothixene; Thiothixene Hydrochloride; Tioperidone Hydrochloride; Tiospirone Hydrochloride; Trifluoperazine Hydrochloride; Trifluperidol; Triflupromazine; Triflupromazine Hydrochloride; Ziprasidone Hydrochloride.
Antirheumatic: Auranofin; Aurothioglucose; Bindarit; Lobenzarit Sodium; Phenylbutazone; Pirazolac; Prinomide Tromethamine; Seprilose.
Antischistosomal: Becanthone Hydrochloride; Hycanthone; Lucanthone Hydrochloride; Niridazole; Oxamniquine; Pararosanilinc Pamoate; Teroxalene Hydrochloride.
Antiseborrheic: Chloroxine; Piroctonc; Piroctone Olamine; Resorcinol Monoacetate.
Λntisecretory: Arbaprostil; Deprostil; Fenoctimine Sulfate; Octreotide: Octreotide Acetate; Omeprazole Sodium; Rioprostil; Trimoprostil.
Antispasmodic: Stilonium Iodide; Tizanidine Hydrochloride.
Antithrombotic: Λnagrelidc Hydrochloride; Bivalirudin ; Daltcparin Sodium ; Danaparoid Sodium; Dazoxibcn Hydrochloride; Efegatran Sulfate; Enoxaparin Sodium; Ifetroban; Ifetroban Sodium; Tinzaparin Sodium ; Trifcnagrel.
Antitussive: Benzonatatc; Butamirate Citrate; Chlophcdianol Hydrochloride; Codeine Polistirex; Codoximc; Dextromethorphan; Dcxtromethorphan Hydrobromide; Dextromethoφhan Polistirex; Ethyl Dibunatc; Guaiapate; Hydrocodonc Bitartratc; Hydrocodonc Polistirex; Levopropoxyphene Napsylate; Noscapine; Pemerid Nitrate; Pipazcthatc; Suxemcrid Sulfate.
Anti-ulcerative: Accglutamide Aluminum; Cadcxomer Iodine ; Cctraxate Hydrochloride; Enisoprost; Isotiquimide; Lansoprazolc; Lavoltidine Suecinate; Misoprostol; Nizatidine; Nolinium Bromide ; Pantoprazole; Pifarninc; Pirenzcpinc Hydrochloride; Rabcprazole Sodium ; Remiprostol; Roxalidinc Acetate Hvdrochloride; Sucralfatc; Sucrosofate Potassium; Tolimidone. Anti-urolithic: Cystcamine; Cysteamine Hydrochloride; Tricitrates .
Antiviral: Accmannan; Acyclovir; Acyciovir Sodium; Adefovir; Alovudinc; Alvircept Sudotox; Amantadine Hydrochloride; Aranotin; Arildone; Atevirdine Mesylate; Λvridinc; Cidofovir; Cipamfylline; Cytarabine Hydrochloride; Delavirdine Mesylate; Desciclovir; Didanosine; Disoxaril; Edoxudine; Enviradene; Enviroximc; Famciclovir; Famotine Hydrochloride; Fiacitabine; Fialuridine; Fosarilate; Foscarnet Sodium; Fosfonet Sodium; Ganciclovir; Ganciclovir Sodium; Idoxuridine; Kethoxal; Lamivudine; Lobucavir; Memotine Hydrochloride; Methisazone; Nevirapine; Penciclovir; Pirodavir; Ribavirin; Rimantadine Hydrochloride; Saquinavir Mesylate; Somantadine Hydrochloride; Sorivudinc; Statolon; Stavudine; Tilorone Hydrochloride; Trifluridinc; Valacyclovir Hydrochloride; Vidarabine; Vidarabine Phosphate; Vidarabine Sodium Phosphate; Viroxime; Zalcitabine; Zidovudinc; Zinviroxime.
Appetite suppressant: Dexfenfluramine Hydrochloride; Phendimetrazine Tartrate; Phentermine I Iydrochloridc.
Benign prostatic hyperplasia therapy agent: Tamsulosin Hydrochloride.
Blood glucose regulators: Human insulin; Glucagon; Tolazamide; Tolbutamide; Chloropropamidc; Λcctohcxamide and Glipizidc.
Bone rcsorption inhibitor: Alcndronate Sodium; Etidronatc Disodium; Pamidronatc Disodium.
Bronchodilator: Λlbutcrol; Λlbutcrol Sulfate; Λzanator Maleate; Bamifyllinc Hydrochloride; Bitolierol Mesylate; Butaprost; Carbuterol Hydrochloride; Cloφrenaline Hydrochloride; Coltβrol
Mesylate; Doxaprost; Doxofylline; Dyphyllinc; Enprofylline; Ephedrine; Ephedrine Hydrochloride;
Fenoterol; Fcnprinast Hydrochloride; Guaithylline; Hexoprenaline Sulfate ; Hoquizil Hydrochloride;
Ipratropium Bromide; Isoetharine; Isoetharine Hydrochloride; Isoctharine Mesylate; Isoproterenol
Hydrochloride; Isoproterenol Sulfate; Metaproterenol Polistirex; Mctaprotcrcnol Sulfate; Nisbuterol Mesylate; Oxtriphyllinc; Picumcterol Fumarate; Piquizil Hydrochloride; Pirbuterol Acetate;
Pirbuterol Hydrochloride; Procatcrol Hydrochloride; Pscudocphedrinc Sulfate; Quazodinc ;
Quinlcrcnol Sulfate; Raccpincphrinc; Raccpincphrinc Hydrochloride; Reprolcrol Hydrochloride; Rimiterol Hydrobromide; Salmeterol; Salmeterol Xinafoate; Soterenol Hydrochloride; Sulfonterol Hydrochloride; Suloxifen Oxalatc; Terbutaline Sulfate; Theophylline; Xanoxatc Sodium; Zindotrine; Zinterol Hydrochloride.
Carbonic anhydrasc inhibitor: Acetazolamide; Λcctazolamide Sodium; Dichloφhenamide; Dorzolamidc Hydrochloride; Methazolamide; Sezolamide Hydrochloride.
Cardiac depressant: Acecainide Hydrochloride; Acetylcholine Chloride; Actisomide; Adenosine;
Amiodarone; Aprindine; Aprindine Hydrochloride; Artilide Fumarate; Λzimilide Dihydrochloride; Bidisomide; Bucainide Maleate; Bucromarone; Butoprozine Hydrochloride ; Capobenate Sodium;
Capobenic Acid; Cifenline; Cifcnline Suecinate; Clofilium Phosphate; Disobutamide: Disopyramide;
Disopyramide Phosphate; Dofetilide; Drobuline; Edifolone Acetate; Emilium Tosylatc; Encainidc
Hydrochloride; Flccainide Acetate; Ibutilide Fumarate; Indecainide Hydrochloride; Ipazilide
Fumarate; Lorajmine Hydrochloride; Lorcainide Hydrochloride; Meobentine Sulfate; Mexiletine Hydrochloride; Modecainide; Moricizine; Oxiramide; Pirmenol Hydrochloride; Pirolazamide;
Pranolium Chloride; Procainamide Hydrochloride; Propafenonc Hydrochloride; Pyrinoline;
Quindonium Bromide; Quinidine Gluconate; Quinidine Sulfate; Recainam Hydrochloride; Recainam
Tosylate; Risotilide Hydrochloride; Ropitoin Hydrochloride; Sematilide Hydrochloride; Suricainide
Maleate; Tocainidc; Tocainidc Hydrochloride; Transcainidc.
Cardioprotectant: Dexrazoxane; Drafiazine.
Cardiotonic: Λctodigin; Λmrinonc; Bcmoradan; Bulopaminc; Carbazcran; Carsatrin Suecinate; Deslanoside; Digitalis; Digitoxin; Digoxin; Dobutaminc; Dobutamine Hydrochloride; Dobutamine Lactobionatc; Dobutaminc Tartrate; Enoximonc; Imazodan Hydrochloride; Indolidan; Isomazjole Hydrochloride; Lcvdobutamine Lactobionatc; Lixazinone Sulfate; Mcdorinone; Milrinone; Pelrinone Hydrochloride: Pimobcndan; Piroximonc; Prinoxodan; Proscillaridin; Quazinonc; Tazolol Hydrochloride; Vcsnarinone.
Cardiovascular agent: Dopcxamine; Dopexamine Hydrochloride.
Choleretic: Dehydrocholic Acid; Fencibutirol: Hymecromone; Piprozolin; Sincalide; Tocamphyl. Cholinergic: Aceclidine; Bethanechol Chloride; Carbachol; Demecarium Bromide; Dexpanthenol; Echothiophate Iodide; Isoflurophate; Methacholine Chloride; Neostigmine Bromide; Neostigmine Methylsulfatc; Physostigminc; Physostigmine Salicylate; Physostigmine Sulfate; Pilocaφine ; Pilocarpine Hydrochloride; Pilocaφine Nitrate; Pyridostigmine Bromide.
Cholinergic agonist: Xanomeline; Xanomeline Tartrate.
Cholinesterase Deactivator: Obidoxime Chloride; Pralidoxime Chloride; Pralidoximc Iodide; Pralidoxime Mesylate.
Coccidiostat: Aφrinocid; Narasin ; Semduramicin; Semduramicin Sodium.
Cognition adjuvant: Ergoloid Mesylates; Piracetam; Pramiracctam Hydrochloride; Pramiracctam Sulfate; Tacrine Hydrochloride.
Cognition enhancer: Besipirdine Hydrochloride; Linopirdine; Sibopirdine .
Depressant: Omeprazolc.
Diagnostic aid: Aminohippurate Sodium;'Anazolene Sodium; Λrclofenin; Arginine ; Bentiromide; Benzylpenicilloyl Polylysine; Butedronatc Tetrasodium; Butilfenin; Coccidioidin; Corticorelin Ovine Triflutate ; Corticotropin. Repository ; Corticotropin Zinc Hydroxide; Diatrizoate Meglumine; Diatrizoate Sodium; Diatrizoic Acid; Diphtheria Toxin for Schick Test; Disofenin; Edrophonium Chloride; Ethiodized Oil; Etifenin; Exametazime; Ferristenc; Ferumoxides; Ferumoxsil; Fluorescein; Fluorescein Sodium; Gadobenate Dimcgiumine; Gadoteridol; Gadodiamide; Gadopcntetøte Dimegiumine; Gadovcrsetamide; Histoplasmin; Impromidine Hydrochloride; Indigotindisulfonate Sodium; Indocyanine Green ; Iobcnguane Sulfate I 123; Iobenzamic Acid; Iocarmatc Meglumine; Iocarmic Acid; Iocctamic Acid; Iodamide; Iodamidc Megiuminc; lodipamidc Meglumine; Iodixanol; Iodoxamale Megiuminc; Iodoxamic Acid; Ioglicic Acid; Ioglucol; loglucomidc; Ioglycamic Acid; logulamidc; lohcxol; lomcprol; lopamidol; lopanoic Acid; lopentol; lophendylale; Iprofcnin; Iopronic Acid; loprocemic Acid; lopydol; lopydonc; losefamic Acid; loscric Acid; Iosulamidc Meglumine; losumetic Acid; lotasul: lotctric Acid; lothalamatc Meglumine: lothalamate Sodium; Iothalamic Acid; Iotrolan; lotroxic Acid; Ioversol; loxaglate Meglumine; Ioxagiate Sodium; Ioxaglic Acid; Ioxilan; loxotrizoic Acid; Ipodate Calcium; Ipodate Sodium; Isosulfan Blue; Leukocyte Typing Serum; Lidofenin; Mebrofenin; Meglumine; Metrizamide; Metrizoate Sodium; Metyrapone; Metyrapone Tartrate; Mumps Skin Test Antigen; Pentetic Acid; Propyliodone; Quinaldine Blue; Schick Test Control; Sermorelin Acetate ; Sodium Iodide 1 123; Sprodiamide; Stannous Pyrophosphate; Stannous Sulfur Colloid; Succimer; Teriparatide Acetate; Tetrofosmin; Tolbutamide Sodium; Tuberculin; Tyropanoate Sodium; Xylose.
Diuretic: Ambuphylline ; Λmbuside; Amiloride Hydrochloride; Azolimine; Azosemide; Brocrinat; Bumctanide; Chlorothiazide; Chlorthalidone; Clazoliminc; Clorexolone; Ethacrynate Sodium; Ethacrynic Λcid; Etozolin; Fenquizone; Furosemide; Hydrochlorothiazide; Isosorbidc; Mannitol ; Mefruside; Ozolinone; Pirctanidc; Spiroxasone; Torsemidc; Triamterene; Triflocin; Urea.
Dopaminergic agent: Ibopaminc.
Ectoparasiticide: Niflurididc; Permethrin.
Emetic: Apomorphine Hydrochloride.
Enzyme inhibitor: Acetohydroxamic Acid; Alrestatin Sodium; Aprotinin; Benazepril Hydrochloride;
Bcnazcprilat; Bcnurcstat; Bromocripiinc; Bromocriptine Mesylate; Cilastatin Sodium; Flurofamide;
Lergotrile; Lergotrile Mesylate; Lcvcycloserine; Libenzapril; Pentopril; Pepstatin; Perindopril;
Polignatc Sodium; Sodium Λmylosulfate: Sorbinil; Spirapril Hydrochloride; Spiraprilat; Taleranol;
Teprotide; Tolfamide; Zofcnopril Calcium. Estrogen: Chlorotrianisenc; Dienestrol; Diethylslilbestrol; Dielhylslilbestrol Diphosphate; Equidin;
Estradiol; Estradiol Cypionate; Estradiol Enanthatc; Estradiol Undecylate; Estradiol Valerate;
Estrazinol Hydrobromide; Estriol; Estrofurate; Estrogens, Conjugated; Estrogens, Esterified;
Estrone; Estropipate; Ethinyl Estradiol; Fenestrel; Mestranol; Nylestriol; Quinestrol.
Fibrinolytic: Λnistreplasc; Bisobrin Lactate; Brinolasc.
Free oxygen radical scavenger: Pcgorgotein. Gastrointcstinal Motility agents: Cisapride (Propulsid); Metoclopramidc (Reglan); Hyoscyamine (Levsin).
Glucocorticoid: Λmcinonide; Beclomethasone Dipropionate; Betamethasone; Betamethasone Acetate; Betamethasone Benzoate; Betamethasone Dipropionate; Betamethasone Sodium Phosphate; Betamethasone Valerate; Carbenoxolone Sodium; Clocortolone Acetate; Clocortolone Pivalate; Cloprednol: Corticotropin; Corticotropin, Repository; Corticotropin Zinc Hydroxide; Cortisone Acetate; Cortivazol; Descinolone Acetonide; Dexamethasone; Dexamethasone Sodium Phosphate; Diflucortolone; Diflucortolone Pivalate; Flucloronide; Flumethasone; Flumethasone Pivalate; Flunisolide; Fluocinolone Acetonide; Fluocinonide; Fluocortolone; Fluocortolone Caproate; Fluorometholone; Fluperolone Acetate; Fluprednisolone; Fluprednisolone Valerate; Flurandrenolide; Formocortal; Hydrocortisonc: Hydrocortisone Acetate: Hydrocortisone Buteprate; Hydrocortisonc Butyrate; Hydrocortisone Sodium Phosphate; Hydrocortisone Sodium Suecinate; Hydrocortisone Valerate; Medrysone; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Sodium Phosphate; Methylprednisolone Sodium Suecinate; Nivazol; Paramcthasonc Acetate; Prednicarbate; Prednisolonc; Prcdnisoione Acetate; Prcdnisolonc Hcmisuccinate: Prednisolone Sodium Phosphate; Prednisolonc Sodium Suecinate; Prcdnisolonc Tcbutate: Prednisonc; Prednival; Ticabesonc Propionate; Tralonidc; Triamcinolonc; Triamcinolonc Acetonide; Triamcinolone Acetonide Sodium; Triamcinolonc Diacetate; Triamcinolone Hcxacetonide.
Gonad-stimulating principle: Buserelin Acetate; Clomiphcne Citrate; Ganirelix Acetate: Gonadorelin Acetate; Gonadorelin Hydrochloride; Gonadotropin. Chorionic; Menotropins.
Hair growth stimulant: Minoxidil .
Hemostatic: Λminocaproic Acid; Oxamarin Hydrochloride; Sulmarin; Thrombin; Trancxamic Acid.
Histamine 112 receptor antagonists: Ranilidinc (Zantac); Famotidinc (Pcpcid); Cimetidinc (Tagamct); Nizatidinc (Λxid).
Hormone: Dielhylslilbestrol; Progesterone; 17 hydroxy progesterone; Mcdroxyprogcstcronc; Norgcstrcl; Norcthynodrcl; Estradiol; Mcgcstrol (Mcgacc); Norclhindronc; Levonorgcstrcl; Ethyndiol; Ethinyl estradiol; Mestranol; Estrone; Equilin; 17 alpha dihydrocquilin; equiienin; 17 alpha dihydroequilenin; 17 alpha estradiol; 17 beta estradiol; Leuprolide (lupron); Glucagon; Testolactone; Clomiphene; Han memopausal gonadotropins; Human chorionic gonadotropin; Urofollitropin; Bromocriptine; Gonadorelin; Luteinizing hormone releasing hormone and analogs; Gonadotropins; Danazol; Testosterone; Dehydroepiandrosterone; Androstcnedionc; Dihydroestosterone; Relaxin; Oxytocin; Vasopressin; Folliculostatin; Follicle regulatory protein; Gonadoctrinins; Oocyte maturation inhibitor; Insulin growth factor; Follicle Stimulating Hormone; Luteinizing hormone; Tamoxifen.; Corticorelin Ovine Triflutate; Cosyntropin; Metogest; Pituitary, Posterior; Seractide Acetate; Somalapor; Somatrem; Somatropin; Somenopor; Somidobove.
Hypocholesterolemic: Lifibrol.
Hypoglycemic: Darglitazone Sodium: Glimepiride.
Hypolipidemic: Azalanstat Dihydrochloride; Colestolone; Surfomer; Xenalipin.
Hypotcnsivc: Viprostol.
HMGCoA reductase inhibitors: Lovastatin (Mevacor); Simvastatin (Zocor); Pravastatin (Pravachol); Fluvasatin (Lescol).
Immunizing agent: Antirabies Serum; Antivenin (Latrodectus mactans); Antivenin (Micrums Fulvius); Antivenin (Crotalidac) Polyvalent; BCG Vaccine; Botulism Antitoxin; Cholera Vaccine; Diphtheria Antitoxin; Diphtheria Toxoid; Diphtheria Toxoid Adsorbed; Globulin, Immune; Hepatitis B Immune Globulin; Hepatitis B Vims Vaccine Inactivated; Influenza Vims Vaccine; Measles Vims Vaccine Live; Meningococcal Polysaccharide Vaccine Group Λ; Meningococcal Polysaccharide Vaccine Group C; Mumps Virus Vaccine Live; Pertussis Immune Globulin; Pertussis Vaccine; Pertussis Vaccine Adsorbed; Plague Vaccine; Poliovirus Vaccine Inactivated; Poliovirus Vaccine Live Oral; Rabies Immune Globulin; Rabies Vaccine; Rh(,(D) Immune Globulin; Rubella Virus Vaccine Live; Smallpox Vaccine; Tetanus Antitoxin; Tetanus Immune Globulin; Tetanus Toxoid; Tetanus Toxoid Adsorbed; Typhoid Vaccine; Yellow Fever vaccine; Vaccinia Immune Globulin; Varicella-Zoster Immune Globulin. Immunomodulator: Dimepranol Λcedoben; Imiquimod; Interferon Beta- l b; Lisofylline; Mycophenolate Mofetil; Prczatide Copper Acetate.
Immunoreguiator: Azarole; Fanetizole Mesylate; Frentizole; Oxamisole Hydrochloride; Ristianol Phosphate; Thymopentin; Tilomisole.
Immunostimulant: Loxoribine ; Teceleukin.
Immunosuppressant: Azathioprine; Azathioprine Sodium; Cyclosporine; Daltroban; Gusperimus
Trihydrochloride; Sirolimus; Tacrolimus.
Impotence therapy adjunct: Delequamine Hydrochloride.
Inhibitor: Acarbose; Atorvastatin Calcium; Benserazide ; Brocresine; Carbidopa; Clavulanate Potassium; Dazmegrel; Doccbenonc; Epoprostenol; Epoprostenol Sodium; Epristeridc; Finastcridc; Flurbiprofen Sodium; Furcgrclate Sodium; Lufironil; Miglitol; Orlistat; Pimagcdinc Hydrochloride; Pirmagrel; Ponalrestat; Ridogrel; Sulbactam Benzathine ; Sulbactam Pivoxil ; Sulbactam Sodium ; Suronacrine Maleate; Tazobactam; Tazobactam Sodium; Ticlopidine Hydrochloride; Tirilazad Mesylate; Tolrestat; Velnacrine Maleate; Zifrosilone; Zileuton.
Keratolytic: Alcloxa ; Aldioxa ; Benzoyl Peroxide; Dibenzothiophene; Etarotene; Isotretinoin; Motretinide; Picotrin Diolaminc; Resorcinol; Resorcinol Monoacetatc ; Salicylic Acid; Sumarotcne; Tazarotene; Tetroquinone; Trctinoin.
LHRH agonist: Deslorclin; Goserelin; I listrclin; Lutrclin Acetate; Nafarelin Acetate.
Liver disorder treatment: Malotilate.
Luteolysin: Fenprostalcnc.
Memory adjuvant: Dimoxamine Hydrochloride; Ribaminol.
Mental performance enhancer: Aniracetam. Mood regulator: Fengabine.
Mucolytic: Acetylcysteine; Carbocysteine; Domiodol.
Mucosal Protective agents: Misoprostol (Cytotec).
Mydriatic: Berefrine.
Nasal decongestant: Nemazoline Hydrochloride; Pseudoephedrine Polistirex.
Neuroleptic: Duoperone Fumarate; Risperidone.
Neuromuscular blocking agent: Atracurium Besylate; Cisatracurium Besylate; Doxacurium Chloride; Gallamine Triethiodide; Metocurine Iodide; Mivacurium Chloride; Pancuronium Bromide; Pipecuronium Bromide; Rocuronium Bromide; Succinylcholine Chloride; Tubocurarine Chloride; Vecuronium Bromide.
Neuroprotectivc: Dizocilpine Maleate.
NMDA antagonist: Sclfotel.
Non-hormonal sterol derivative: Prcgncnolonc Suecinate.
Oxytocic: Carboprost; Carboprost Methyl; Carboprost Tromethamine; Dinoprost ; Dinoprost Tromethamine ; Dinoprostonc ; Ergonovine Maleate; Meteneprost ; Methylergonovine Maleate; Oxytocin; Spartcine Sulfate.
Plasminogen activator: Λllcplasc; Urokinasc.
Platelet activating factor antagonist: Lcxipafant.
Platelet aggregation inhibitor: Λcadesinc; Bcraprost; Bcraprost Sodium; Ciprostcnc Calcium; llazigrcl; l.ifarizine; Oxagrclatc. Post-stroke and post-head trauma treatment: Citicoline Sodium.
Potcntiator: Pentostatin; Talopram Hydrochloride.
Progestin: Algestone Acetophenide; Amadinone Acetate; Λnagestone Acetate; Chlormadinone Acetate; Cingeslol; Clogestone Acetate; Clomegestone Acetate; Desogestrel; Dimcthisterone; Dydrogesterone; Ethynerone; Ethynodiol Diacetate; Etonogestrel; Flurogestonc Acetate; Gestaclone; Gestodene; Gestonorone Caproate: Gcstrinonc; Haloprogcsterone; Hydroxyprogesteronc Caproate; Levonorgestrel; Lynestrenol; Medrogestone; Medroxyprogesterone Acetate; Methynodiol Diacetate; Norethindrone; Norethindrone Acetate; Norethynodrel; Norgestimate; Norgestomet; Norgestrel; Oxogestone Phenpropionate; Progesterone; Quingestanol Acetate; Quingestrone; Tigestol.
Prostaglandin: Cloprostcnol Sodium; Fluprostenol Sodium; Gemcprost; Prostalene; Sulprostone.
Prostate growth inhibitor: Pentomone.
Prothyrotropin: Protirelin.
Psychotropic: Minaprine.
Pulmonary surface: Beractant; Colfosccril Palmitate.
Radioactive agent: Fibrinogen 1 125 ; Fludcoxyglucosc F 18 ; Fluorodopa F 18 ; Insulin I 125;
Insulin I 131 ; Iobenguane I 123; Iodipamide Sodium 1 131 ; Iodoantipyrinc 1 131 ; Iodocholesterol 1 131 ; lodohippurate Sodium I 123 ; lodohippurate Sodium I 125 ; lodohippurate Sodium 1 131 ; lodopyracct I 125 ; Iodopyracci 1 131 ; lofetaminc HydiOchloridc I 123 ; lomethin I 125 ; lomethin
1 131 ; lothalamatc Sodium I 125 ; lothalamatc Sodium I 131 ; Iolyrosinc 1 131 ; Liothyroninc 1 125;
Liothyroninc 1 131 ; Merisoprol Acetate Mg 197; Mcrisoprol Λcctalc I Ig 203; Mcrisoprol Hg 197 ;
Sclcnomcthioninc Sc 75 ; Technctium Tc 99m Antimony Trisullidc Colloid; Technctium Tc 99m Bicisatc ; Technctium Tc 99m Disofenin ; Teehnetium Tc 99m Etidronatc ; Technctium Tc 99m
Exametazimc ; Technctium 'Tc 99m Furifosmin ; 'Technctium 'Tc 99m Gluccptatc ; Technctium Tc
99m Lidofcnin ; Teehnetium 'Tc 99m Mebrofenin ; Technctium Tc 99m Medronate ; Teehnetium Tc 99m Medronate Disodium; Teehnetium Tc 99m Mertiatide ; Teehnetium Tc 99m Oxidronate ; Teehnetium Tc 99m Pentetate; Teehnetium Tc 99m Pentetate Calcium Trisodium; Teehnetium Tc 99m Sestamibi ; Teehnetium Tc 99m Siboroxime ; Teehnetium Tc 99m Succimer ; Teehnetium Tc 99m Sulfur Colloid ; Teehnetium Tc 99m Teboroxime ; Teehnetium Tc 99m Tctrofosmin ; Teehnetium Tc 99m Tiatidc; Thyroxine 1 125; Thyroxine 1 131 ; Tolpovidone 1 131 ; Triolein 1 125; Triolein 1 131.
Regulator: Calcifediol; Calcitonin; Calcitriol; Clodronic Acid; Dihydrotachysterol; Etidronic Acid; Oxidronic Acid; Piridronate Sodium; Risedronate Sodium; Secalciferol.
Relaxant: Adiphenine Hydrochloride; Alcuronium Chloride; Aminophylline; Azumolene Sodium;
Baclofen; Benzoctamine Hydrochloride; Carisoprodol; Chlorphenesin Carbamate; Chlorzoxazone;
Cinflumide; Cinnamedrine; Clodanolene; Cyclobenzaprine Hydrochloride; Dantrolene; Dantrolene
Sodium; Fenalamide; Fenyripol Hydrochloride; Fetoxylate Hydrochloride; Flavoxate Hydrochloride; Fletazepam; Flumetramide; Flurazepam Hydrochloride; Hexafluorenium Bromide; Isomylamine
Hydrochloride; Lorbamatc; Mebcverinc Hydrochloride; Mesuprine Hydrochloride ; Metaxalone;
Methocarbamol; Methixenc Hydrochloride; Nafomine Malate; Nelezaprine Maleate; Papaverine
Hydrochloride: Pipoxolan Hydrochloride; Quinctolatc; Ritodrine; Ritodrine Hydrochloride;
Rolodine; Theophylline Sodium Glycinate; Thiphenamil Hydrochloride; Xilobam.
Repartitioning agent: Cimateroi.
Scabicide: Amitraz; Crotamiton.
Sclerosing agent: Ethanolamine Olcate; Morrhuate Sodium; Tribcnoside.
Sedative: Propiomazine.
Sedative-hypnotic: AUobarbital; Λlonimid; Alprazolam; Λmobarbital Sodium; Bentazepam; Brolizolam; Bulabarbital; Butabarbital Sodium; Bulalbital; Capuride; Carbocloral; Chloral Bclainc;
Chloral Hydrate; Chlordiazepoxidc Hydrochloride; Clopcridone Hydrochloride; Clorcthatc;
Cyprazcpam; Dexclamol Hydrochloride; Diazepam; Dichloralphenazonc; Estazolam; Ethchlorvynol; Etomidate; Fenobam; Flunitrazepam: Fosazepam; Glutethimide; Halazepam; Lormetazepam; Mecloqualone; Meprobamatc; Methaqualone; Midaflur: Paraldehyde; Pentobarbital; Pentobarbital Sodium; Perlapine; Prazepam; Quazepam; Rcclazepam; Roletamide; Secobarbital; Secobarbital Sodium; Suproclone; Thalidomide; Tracazolate; Trepipam Maleate; Triazolam; Tricetamide; Triclofos Sodium; Trimetozine; Uldazepam; Zaleplon; Zolazepam Hydrochloride; Zolpidem Tartrate.
Selective adcnosine Al antagonist: Apaxifylline.
Serotonin antagonist: Λltanserin Tartrate; Amesergide; Ketanserin; Ritanserin.
Serotonin inhibitor: Cinanserin Hydrochloride; Fencionine; Fonazine Mesylate; Xylamidine
Tosylatc.
Serotonin receptor antagonist: Tropanserin Hydrochloride.
Steroid: Dexamethasone Acefuratc; Momctasone Furoate.
Stimulant: Amfonelic Acid; Amphetamine Sulfate; Λmpyzine Sulfate; Λrbulamine Hydrochloride; Azabon; Caffeine; Cerulctide; Ceruletide Diethylamine; Cisapride; Dazopride Fumarate; Dcxtroamphctaminc: Dextroamphctamine Sulfate; Difluaninc Hydrochloride; Dimefiinc Hydrochloride; Doxapram Hydrochloride; Etryptamine Acetate; Ethamivan; Fcncthylline Hydrochloride; Flubanilatc Hydrochloride; Flurolhyl; Histamine Phosphate; Indrilinc Hydrochloride; Mefexamide; Methamphetamine Hydrochloride; Mcthylphenidate Hydrochloride; Pemoiinc; Pyrovaleronc Hydrochloride; Xamotcrol; Xamoterol Fumarate.
Suppressant: Λmfiutizolc; Colchicinc; Tazofclonc.
Symptomatic multiple sclerosis: Fampridinc.
Synergist: Proadifcn Hydrochloride. Thyroid hormone: Levothyroxine Sodium; Liothyronine Sodium; Liotrix.
Thyroid inhibitor: Methimazole; Propylthiouracil.
Thyromimetic: Thyromedan Hydrochloride.
Tranquilizer: Bromazepam; Buspirone Hydrochloride; Chlordiazepoxide; Ciazolam; Clobazam; Clorazepate Dipotassium; Clorazepate Monopotassium; Demoxepam; Dexmedetomidine; Enciprazine Hydrochloride; Gepirone Hydrochloride; Hydroxyphenamate; Hydroxyzine Hydrochloride; Hydroxyzine Pamoate; Ketazolam; Lorazepam; Lorzafone; Loxapine; Loxapinc Suecinate; Medazepam Hydrochloride; Nabilone; Nisobamate ; Oxazepam; Pentabamate; Pirenperone; Ripazepam; Rolipram; Sulazepam; Taciamine Hydrochloride; Temazepam; Triflubazam; Tybamate; Valnoctamide.
Amyotrophic lateral sclerosis agents: Riluzole.
Cerebral ischemia agents: Dextrorphan Hydrochloride.
Paget's disease agents: Tiludronate Disodium.
Unstable angina agents: Tirofiban I Iydrochloridc
Uricosuric: Benzbromarone; Irtemazole; Probenecid; Sulfinpyrazone.
Vasoconstrictor : Λngiotensin Amide; Fclypressin; Methysergide; Methyscrgide Maleate.
Vasodilator: Λlprostadil; Azaclorzinc Hydrochloride; Bamcthan Sulfate; Bepridil Hydrochloride; Buterizine; Cetiedil Citrate; Chromonar Hydrochloride; Clonitratc; Diltiazem Hydrochloride; Dipyridamolc; Droprcnilamine; Erythrityl Tctranitrate; Fclodipinc; Flunarizine Hydrochloride; Fosledil; I lcxobendine; Inosilol Niacinatc; Iproxaminc Hydrochloride; Isosorbide Dinilrate; Isosorbide Mononitralc; Isoxsuprinc Hydrochloride; Lidofiazinc; Mcfcnidil; Mcfcnidil Fumarate; Mibcfradil Dihydrochloride; Miofiazinc Hydrochloride; Mixidinc; Nafronyl Oxalatc; Nicardipine Hydrochloride; Nicergoiine: Nicorandil; Nicotinyl Alcohol; Nifcdipine; Nimodipine; Nisoldipine; Oxfenicine; Oxprenolol Hydrochloride; Pentaerythritol Tetranitratc; Pentoxifylline; Pentrinitrol; Perhexiline Maleate; Pindolol; Pirsidominc; Prenylamine; Propatyl Nitrate; Suloctidil: Terodiline Hydrochloride; Tipropidil Hydrochloride; Tolazoline Hydrochloride; Xanthinol Niacinate. Vulnerary: Allantoin.
Wound healing agent: Ersofermin.
Xanthine oxidase inhibitor: Allopurinol; Oxypurinol
Other pharmaceutical agents include: 1-decpyrrolidinone; 1-dodecpyrrolidinone; 16-alpha fluoroestradiol; 16-epiestriol; lόalpha-gitoxin; 17alpha estradiol; I 7beta estradiol; lalpha- hydroxyvitamin D2; 2'-nor-cGMP; 20-epi-l,25 dihydroxyvitamin D3; 22-oxacalcitriol; 2CVV; 3- isobutyl GΛBA; 6-FUDCΛ; 7-mcthoxytacrine; abamcctin; abanoquil; abecarnil; abiratcrone; acadcsine; acamprosate; acarbose; aceclofenac; acemannan; acetomcpregcnol; acetyl-L-carnitine; acetylcysteine, N-; acetylmethadol; acifran; acipimox; acitematc; acitretin; aclarubicin; aclatonium; napadisilate; aconiazide; acrivastinet; adafenoxate; adapalene; adatanserin; adecypenol; adefovir dipivoxil; adelmidrol; ademetionine; adinazolam; adiposin; adozelesin; adrafinil; alacepril; aladapcin; alaptide; albendazole; albolabrin; aldecalmycin; aldeslcukin; alendronic acid; alentemol; alfacalcidol; alfuzosin; alglucerase; alinastinc; alosetron; alpha idosone; alprosladil: altretamine; altromycin B; ambamustine; amelometasone; amesergide; amezinium metilsulfate; amfebutamone; amidox: amifloxacin; amifostiπe; amiodaronc: amisulpridc; amlexanox; amlodipinc; amlodipine; ampiroxicam; amrinone; amrubicin; amsacrine; amylin; amythiamicin; anagrelide: anakinra; ananain; anaritide; anastrozolc; andrographolidc; anordrin; apadolinc; apafant; apaxifyllinc; aphidicolin glycinate; apraclonidine; aprosulate sodium; aptiganel; apurinic acid; aranidipime; arbckacin; arbidol; arbutaminc; ardeparin sodium; arccatannin Bl ; argatroban; aripiprazol; arotinolol; asimadolinc; aspalatone; aspcrfuran; aspoxicillin; astcmizolc; asulacrinc; atamcstane; atenolol, S-; atcvirdine; atosiban; alovaquone; atpenin B; atrimustinc: atrinositol; aurcobasidin A; azadirachtine; azasetron; azatyrosinc; azelaic acid; azelastine; azelnidipinc; azimilidc; azitliromycin; azo.semide; aztreonam; baccatin III; bacoside Λ; bacosidc B; bactobolamine; balazipone; balhimycin;. balofloxacin; balsalazidc; bambuterol; baohuosidc 1 ; barnidipine; basifungin; batebulast; batimastat; bcauvericin; becaplermin; becliconazolc; bcfloxatone; belfosdil; bellenamine; benflumetol; benidipinc; benzisoxazolc; benzochlorins; benzoidazoxan; bcnzoylstaurosporine; benztropine; bcpridil; beractant; beraprost; berlafenone; bertosamil; besipirdine; beta-alethine; betaclamycin B; betamipron; betaxolol; betulinic acid; bevantoiol; bicalutamide; bifemelane; bimakalim; bimithil; binospirone; bioxalomycin alpha2; biriperone; bis- benzimidazole A; bis-benzimidazole B; bisantrene; bisaramil; bisaziridinylspermine; bisnafide; bisoprolol; bistramidc D; bistramide K; bistratene A; boldine; bopindolol; brefeldin; breflate; brimonidine; bromfenac; bromperidol; bropirimine; bucindolol; budesonide; budipine; budotitane; bunaprolast; bunazosin; butenafine; buthionine sulfoximine; butixocort propionate; cadexomer iodine; calanolide A; calcipotriol; calphostin C; camonagrel; candesartan; candesartan cilexetil; candoxatril; candoxatrilat; capccitabine; capromab; capsaicin; captopril; carbazomycin C; carbetocin; carbovir; carboxamide-amino-triazole; carboxyamidotriazole; carboxymethylatcd beta-
1,3-glucan; caφeritide; carteolol; carumonam; carvedilol: carvotroline; carzelesin; castanospermine: cebaracetam; cecropin B; cefcapene pivoxil; cefdaloxime pentexil tosilate; ccfdinir; cefditoren pivoxil; cefepime; cefetamct; ccfetamet pivoxil; cefixime; cefluprenam; cefmetazole; cefminox; ccfodizimc; ccfoselis; cefotetan; cefotiam; cefotiam hexetil; cefozopran; cefpimizole; cefpiramide; cefpirome; cefpodoxime proxctil; cefprozil; cefsulodin; ccfteram; ceftibuten; ceftriaxone; cefuroxime axetil; celastrol; cclikalim; celiprolol; cepacidine Λ; ccriclaminc; cerivastatin; ceronapril; certoparin sodium; cctiedil; cetirizine; chlorooricnticin A; chloroorienticin B; chloroquinoxaline sulfonamide; cibenzoline; cicaprost; ciclesonidc; cicletanine; cicloprolol; cidofovir; cilansetron; cilazapril; cilnldipine; cilobradinc; cilostazol; cimetropium bromide; cinitapridc; cinolazcpam; ciotcroncl; ciprolibratc; ciprofloxacin; ciproslenc; cis-porphyrin; cisapride; cisatracurium besilate; cistinexinc; citalopram; citicoline; citreamicin alpha; cladribinc; clarithromycin; clauscnamide; clebopride; clinafloxacin; clobazam; clobetasone butyrate; clodronic acid; clomethiazole; clopidogrel; clotrimazole; colestimide; colfosceril palmitate; collismycin A; collismycin B; combretastatin A4; complcstatin; conagenin; contignastcrol; contortrostajin; cosalane; costatolide; cotinine; coumermycin A 1 ; cucumariosid; curacin A; curdlan sulfate; curiosin; cyclazosin; cyclic I IPMPC; cyclobcnzaprinc; cyclobut A; cyciobut G; cyclocapron; cycloplatam; cyclosin; cyclothialidine; cyclothiazomycin; cypemycin; cyproterone; cytarabine ocfosfate; cytochalasin B; dacliximab; dactimicin; daidzein; daidzin; dalfopristin; daltcparin sodium; danaparoid; daphnodorin A; dapiprazole; dapitant; darifenacin; darlucin A; darsidomine; ddUTP; decitabine; dcfcripronc; dcflazacorl; dehydrodidemnin B; dchydrocpiandrostcronc; dclapril; dclequaminc: dclfaprazinc; delmopinol; delphinidin; deoxypyridinolinc: dcprodone; dcpsidomycin; deramciclanc; dermatan sulfate; desflurane; desimdin; deslorelin; desmoprcssin; desogestrel; desoxoamiodarone; detajmium bitartratc; dexifosfamidc; dexketoprofen; dexloxiglumide; dexmedetomidinc; dexpemedolac; dexrazoxane; dexsotalol; dextrin 2-sulphate; dexverapamil; dezinamide; dezocine; diaziquone; diclofenac digolil; diclofenac potassium; dicranin; didemnin B; didox; dienogest; diethylhomospermine; diethylnorspcrminc; dihydrexidinc; dihydro-5-azacytidinc; dimethyl prostaglandin Al ; dimethylhomospermine; dimiracetam; dioxamycin; diphency prone; diphenyl spiromustine; diprafenone; dipropylnorspermine; dirithromycin; discodermolide; disulfiram; ditekiren; docaφamine; docosanol, 1-; dofetilide; dolasetron; domitroban; dopexamine; dorzolamide; dosmalfatc; dotarizine; doxacurium chloride; doxazosin; doxifluridine; doxofylline; draculin; drafiazine; droloxifene; dronabinol; drosperidone; drotaverine acephyllinate; droxicam; ebiratide; ebrotidinc; ebselen; ecabapide; ecabet; ecadotrii; ecdisteron; echicetin; echistatin; ecomustine; ecteinascidin 722; ecteinascidin 729; ecteinascidin 743; edaravone; edelfosine; edobacomab; edrecolomab; efegatran; eflomithine; efonidipine; egualen; elcatonin; eletriptan; elgodipine; eliprodil; eltenac; emakalim; emedastine; emiglitate; emitefur; emoctakin; enadoline hydrochloride; enalapril; enazadrem; cnglitazone; cnlimomab; enoxacin; cnoxaparin sodium; enoximone; entacapone; enterostatin; epoprostenol; epoxymexrenone; epristeride; eprosartan; eptastigminc; erdosteine; ersentilide; ersofermin; erythritol; csuprone; etanidazole; ctanterol; ethacizin; ethinylestradiol; etizolam; etodolac; etoposide phosphate; etrabamine; everninomicin; cxamorelin; cxemcstanc; fadrozole; faeriefungin; famciclovir; fampridinc; fantofaronc; faropcnem; fasidotril; fasudil; fazarabine; fedotozine; felbamate; fcnofibratc; fenoldopam; fcnretinide; fcnspiride; fenticonazole; fepradinol; fcrpifosate sodium; fcrristcne; ferrixan; ferumoxsil; fexofenadine; flavopiridol; flccainide; ficrobuterol; fieroxacin; ficsinoxan; flezelastine; flobufcn; fiomoxcf; florfenicol; florifenine; flosatidil; fluasterone; fluconazolc; fludarabine; flumazenil; flumecinol; flumequinc; flunarizinc; fluocalcitrioi; fluorodaunorunicin hydrochloride; fluoxetine, R-; fluoxetine, S-; fluparoxan; flupirtine; flurbiprofen axetil; flurilhromycin; fluticasone propionate; flutrimazolc; fluvastatin; fluvoxaminc; forasartan; forfenimex; formestane; formotcrol; formolcrol,
R,R-; fosfomycin; trometamol; fosinopril; fosphcnytoin; fostriecin; fotemustine; gabapentin; gadobenic acid; gadobutrol; gadodiamide; gadodiamidc-EOB-DTPA; gadolinium texaphyrin; gadoteric acid; gadoteridol; gadovcrsctamidc; galantaminc; galdansctron; gallopamil; galocitabine; gamolenic acid; ganirelix; gepirone; gestrinonc; girisopam; glaspimod; glaucocalyxin A; glutapyrone; glycopine; glycopril; granisetron; grepafloxacin; halichondrin B; halofantrine; halomon; halopredonc; hatomamicin; hatomarubigin A; hatomarubigin B; hatomarubigin C; hatomambigin D; ibogaine; ibopaminc; ibudilast; illimaquinone; ilmofosine; ilomastat; ilopcridone; iloprost; imidapril; imidazenil; indinavir; indolidan; indometacin famesil; indometacin; tropine ester; indoramin; inocotcronc; inogatran; inolimomab; interferon alia; interferon alfa-2a; interferon alfa-2b; interferon alfa-Nl ; interferon alfa-n3; interferon beta; interferon beta-lal; interferon beta-lb interferon gamma- 1 a; interferon gamma- 1 b; interferon omega; interferon, consensus; interleukin- 1 interleukin-1 alpha; interleukin- 1 beta; interleukin- 10; interleukin-1 1 ; interleukin- 12; interleukin- 12 interleukin- 15; interleukin-2; intcrleukin-3; interleukin-4; interleukin-5; interleukin-7; interleukin-8 iobenguane; iobitridol; iodoamiloride; iododoxorubicin; iofratol; iomeprol; iopentol; iopromide iopyrol; iotriside; ioversoi; ioxilan; ipazilide; IpdR; ipcnoxazone; ipidacrine; ipomeanol, 4- ipriflavone; ipsapirone; irbesartan; irinotecan; irioxacin; irsogladine; irtemazole; isalsteine; isbogrel isepamicin; isobengazole; isofloxythepin; isohomohalicondrin B; isopropyl unoprostone; isradipine itameline; itasetron; itopride; itraconazole; ketoprofen, R-; ketoprofen, S-; ketorolac; lacidipine lactitol; lactivicin; laennec; lafutidine; lamellarin-N triacetate; lamifiban; lamivudine; lamotrigine lanoconazole; lanperisone; lanreotide; lansoprazolc; latanoprost; lateritin; laurocapram; lazabemide lemefloxacin; lemildipine; leminoprazolc; lenercept; lenograstim; lentinan sulfate; leptin leptolstatin; lercanidipinc; lcrisetron; lesopitron; lctrazurii; letrozole; leucomyzin; leuprorelin levcromakalim; levetiracetam; lcvobetaxolol; levobunolol; levobupivacaine; levocabastine levocarnitinc; lcvodropropizinc; levofloxacin; lcvomoprolol; lcvonorgcstrel; levormeloxifcnc levosimendan; levosulpiride; linotroban; linsidomine; lintitript; lintopride; liothyronine sodium lircxapridc; lisinopril; lobaplatin; lobucavir; lodoxamide; lombricine; lomefloxacin; lomcrizine lometrcxol; lonazolac; lonidaminc; loracarbcf; loratadine; iorglumide; lornoxicam; losartan losigamonc; Iosoxantronc; loteprednol; loviridc; Ioxoribinc; lubcluzole: lurtotecan; luteinizing hormone; lutetium; luzindole; lydicamycin; lysofylline; lysostaphin; magainin 2 amide; magnolol; mallotochromene; mallotojaponin; malotilatc; mangafodipir; manidipinc; maniwamycin A; mannostatin A; manumycin E; manumycin F; mapinastine; marimastat; Martek 8708; Martek 9221 1 ; masoprocol; maspin; massetolide; meterelin; mcthoxatonc; methylhistamine, R-alpha; methylinosine monophosphate; methylprednisolone accponate; methylprednisolone suleptanate; metipamide; metoclopramidc; metoprolol, S-; metrifonatc; mibefradil; michellamine B: microcolin A; midodrine; mifepristone; miglitol; milaccmide; milamelinc; mildronatc; milnacipran; milrinone; miltcfosinc; minaprinc; miokamycin; mipragosidc; mirfcntanil; mirimoslim; mirtazapinc; misoprostol; mitoguazonc: mitolactol; mitonafide; mitoxantronc; mivacurium chloride; mivazerol; mixanpril; mizolastine; mizoribinc; moclobemide; modafinil; moexipril; mofarotcne; mofezolac; molgramostim; mometasonc; montirelin; mopidamol; moracizine; mosapramine; mosapride motilide; moxiraprine; moxonidine; nadifloxacin; nadroparin calcium; nafadotride; nafamostat nafarelin; naftopidil; naglivan; nagrestip; nalmefene; naphteφin; napsagatran; naratriptan nartograstim; nasaruplase; nateplase; nipcrotidine; niravolinc; nisamycin; nisin; nisoldipine nitazoxanide; nitecapone; nitrendipine; nitrendipine. S-; nitrofurantoin monohydrate; nitrullyn nizatidine; ofloxacin; okiccnoπe; olanzapine; olopatadinc; olprinone; olsalazine; omeprazole onapristone; ondansetron; ondansetron, R-; ontazolast; oracin; otenzepad; oxaliplatin; oxamisolc oxandrolone; oxaprozin; oxaunomycin; oxcarbazepine; oxieonazolc; oxiracetam; oxodipine; ozagrel palauamine; palinavir; palmitoylrhizoxin; pamaqueside; pamicogrel; pamidronic acid; panamesine panaxytriol; panipenem; panipcnum; pannorin; panomifene; pantethine; pantoprazole; parabactin parnaparin sodium; paroxetinc; parthenolidc; pazelliptinc; pazufloxacin; pefloxacin; pegaspargase peldesine; pemedolac; pemirolast; penciclovir; pentafuside; pentamidine; pentamoφhone pentigetide; pentosan; pentostatin; pentrozolc; perflubron; perfosfamidc; pergolide; perindoprilat perospironc; phenaridine; phenazinomycin; phenserine; phensuccinal; phentolamine mesilate phenylacetate; phenylalanyl ketoconazole; picenadol; picibanil; picroliv; picumeterol; pidotimod pilocaφine hydrochloride; pilsicainide; pimagedine; pimilprost; pimobendan; pinacidil; pinocebrin pioglitazone; pipecuronium bromide; piranibicin; piretanide; pirfenidone; piritrexim; pirlindole pirmagrel; pirmenol; pirodavir; pirodomast; piroxicam cinnamate: propagermanium; propentofylline propionylcarnitine, L-; propiram; propiram + paracetamol; propivcrine; propyl bis-acridonc proslaglandin J2; prostratin; protcgrin; protosufioxacin; prulifioxacin; pyrazoloacridine; quazcpam quctiapine; quiflapon; quinagolide; qumapril; quinfamidc; quinupristin; raloxifenc; raltitrexed ramatroban; ramipril; ramosetron; raneiic acid; ranitidine bismuth citrate; ranolazine; recainam regavirumab; relaxin; repirinast; rcsinfcratoxin; rcticulon; rcviparin sodium; rcvizinonc; ricasctron ridogrel; rifabutin; rifapcntine; rifaximin; rilopirox; riluzole; rimantadinc; rimexolone; rimoprogin riodipinc; ripisartan; riscdronic acid; rispcnzcpinc; rispcridonc; ritanscrin; rilipcncm; ritipcrvem acoxil; ritoiukast; ritonavir; rizatriptan bcnzoate; rohitukinc; rokitamycin; ropinirole; ropivacaine; roquinimcx; roxatidinc; roxindolc; roxithromycin; rubiginonc B l ; ruboxyl; rufioxacin; rupatidine; ruzadoiane; safingol; safironil; saintopin; salbutamol, R-; salmeterol; salmeterol, R-salnacedin; sameridinc; sampatrilat: sanfclrincm; saprisartan; saproptcπn; saquinavir; SarCNU; sarcophytol A sargramostim; sarpogrclate; samplasc; saterinone; satigrel; satumomab pendctidc; selegiline; selenium thiosemicarbazone; scmatilidc; semduramicin; semotiadil; semustine; sermorelin; scrtaconazolc: scrtindolc; scrtraline; setiptiline; sevirumab; scvofiuranc; sezolamide; silipide; silteplase; simendan; simvastatin; sinitrodil; sinnabidol; sipatrigine; sirolimus; sizofiran; somatomedin B; somatomedin C; somatrem; somatropin; sonermin; sotalol; staurosporine; stavudine; stepronin; stipiamide; stiripentol; stobadinc; succibun; sucralfate; sulfasalazine; sulfinosine; sulfoxamine; sulopenem; sultamicillin; sultopride: sulukast; sumatriptan: symakalim; tandospironc; tapgen; taprostene; tasosartan; tazanolast; tazarotene; teicoplanin; telenzepine; tcllurapyrylium; tclmesteine; telmisartan; temocapril; temoporfin; temozolomidc; tenidap; teniposide; tenosal; tenoxicam; tcpirindole; tepoxalin; terazosin; terbinafine; terfenadine; terflavoxate; terguride; terlakiren; terlipressin; terodiline; tcrtatolol; testosterone buciclate; tetrachlorodecaoxide; tetrazomine; thaliblastine; thalidomidc; thiocoraline; thiofedrine: thiomarinol; thioperamidc; thyroid stimulating hormone; tiagabinc; tianeptine; tiapafant; tibolone; ticlopidine; tienoxolol; tilisolol; tilnoprofen arbamel; tiludronic acid; tinzaparin sodium; tiotropium bromide; tipredane; tiqueside; tirandalydigin; tirapazamine; tirilazad; tirofiban; tiropramide; topsentin; torasemide; toremifene: tosufloxacin; trafermin; trandolapril; traxanox; tretinoin; tretinoin tocoferii; triacetyluridine; tricaprilin; trichohyalin; trichosanthin, alpha; triciribine; trientine; triflavin; trimegestone; triptorelin; troglitazone; trombodipine; tropisetron; trospectomycin; trovafloxacin; trovirdinc; tucaresol; tulobutcrol; tylogcnin; urapidil; uridinc triphosphatc; valaciclovir; valproate magnesium; valproate semisodium; valsartan; vamicamide; vanadeinc; vaninolol; vapreotide; variolin B; vclaresol; vcnlafaxine; veramine; verapamil, (S); verdins; veroxan; vcrteporfin; vcsnarinonc; vexibinol; vigabatrin; vinburnine citrate; vinburnine resinate; vinconate; vinorelbine; vinpocctine; vinpocctinc citrate; vintopcrol; vinxaltinc; voriconazolc; vorozole; voxergolidc; xemilofiban; ximoprofen; yangambin; zabiciprii; zacopride; zacopridc, R-; zafirlukast: zalcitabine; zaleplon; zalospirone; zaltoprofen; zanamivir; zankiren; zanoteronc; zatebradine; zatosetron; zcnarcstat; zeniplatin; zifrosilone; zilascorb; zileuton; zinostatin stimalamcr; ziprasidonc; zolcdronic acid; zolmitriptan; zolpidem; zonisamide; zopiclone; zopiclonc, S-; zopolrestat; zotepine. The invention also embraces novel compositions of matter that are covalent conjugates of
DHA and pharmaceutical agents that are noncentral nervous system active agents. Noncentral nervous system active agents have no function or use within the central nervous system. Their only use is outside of the central nervous system. Such agents include all drugs within certain of the foregoing categories and only some drugs within other of the foregoing catagorics. For example, the entire calagoiy of blood glucose regulators have no use or lunction within the central nervous system. In contrast, certain anti-cancer agents are useful in the central nervous system whereas others arc not. For example, central nervous system cancers arc not hormone dependent, and, therefore, 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 catagory which are noncentral nervous system active agents.
Among the foregoing compounds, the following catagories and/or members of the following catagorics are noncentral nervous system active agents: adrenocortical steroid; adrenocortical suppressant; aldosterone antagonist; amino acid; anabolic; androgen; antagonist; anthelmintic; anti-acne agent; anti-adrcnergic; anti-allergic; anti-amebic; anti-androgen; anti-anemic; anti-anginal; anti-arthritic; anti-asthmatic; anti-alherosclcrotic; antibacterial; anticholelithic; anticholelithogenic; anticholinergic; anticoagulant; anticoccidal; antidiabetic; antidiarrheal; antidiuretic; antidote; anti-estrogen; antifibrinolytic; antifungal; antiglaucoma agent; antihemophilic; antihemorrhagic; antihistamine; antihyperlipidemia; antihyperlipoproteinemic; antihypertensive; antihypotensive; anti-infective: anti-infective, topical; anti-inflammatory; antikeratinizing agent; antimalarial; antimicrobial; antimitotic; antimycotic, antineoplastic, antineutropenic, antiparasitic; antiperistaltic, antipneumocystic; anfiproliferative; antiprostatic hypertrophy; antiprotozoal; antipmritic; antipsoriatic; antirheumatic; antischistosomal; antiseborrheic; antisecretory; antispasmodic; antithrombotic: antitussive; anti-ulcerative; anti-urolithic; antiviral; appetite suppressant; benign prostatic hypeφlasia therapy agent; bone resoφtion inhibitor; bronchodilator; carbonic anhydrase inhibitor; cardiac depressant; cardioprotectant; cardiotonic; cardiovascular agent; cholcretic; cholinergic; cholinergic agonist; cholinesterase deactivator; coccidiostat; diagnostic aid; diuretic; cctoparasiticide; enzyme inhibitor; estrogen; fibrinolytic; free oxygen radical scavenger; glucocorticoid; gonad-stimulating principle; hair growth stimulant; hemostatic; hormone; hypocholcstcrolemic; hypoglyccmic; hypolipidemic; hypotensive; immunizing agent; immunomodulator; immunoregulator; immunostimulant; immunosuppressant; impotence therapy adjunct; inhibitor; keratolytic; LHR11 agonist; liver disorder treatment; lutcolysin; mucolytic; mydriatic; nasal dccongcstant; ncuromuscular blocking agent; non-hormonal sterol derivative; oxytocic; plasminogen activator; platelet activating factor antagonist; platelet aggregation inhibitor; potcntiator; progestin; proslaglandin; prostate growth inhibitor; prothyrotropin; pulmonary surface; radioactive agent; regulator; relaxant; repartitioning agent; scabicidc; sclerosing agent; selective adenosinc Al antagonist; steroid; suppressant; symptomatic multiple sclerosis; synergist; thyroid hormone; thyroid inhibitor; thyromimetic: amyotrophic lateral sclerosis agents: Paget's disease agents; unstable angina agents; uricosuric; vasoconstrictor; vasodilator; vulnerary; wound healing agent: xanthine oxidase inhibitor. As used herein, a taxane is a molecule that possesses the following tricyclic carbon-atom connectivity network, which may incoφorate carbon-carbon multiple bonds, and which through the involvement of carbon-atom-noncarbon-atom bonds may include substituents, functional groups, and additional rings.
Figure imgf000062_0001
A laxoid is a molecule structurally related to a taxane in which the above taxane carbon-atom connectivity network is altered, for example, by cleavage of one or more of the carbocyclic rings, by deletion or addition of carbon substituents, by connection of carbon atoms normally not bonded to each other, by disconnection of carbon atoms normally bonded to each other, or by some other reorganization of or adjustment to the taxane carbon-atom connectivity network, but in which one or more structural features characteristic of the taxane carbon-atom connectivity network are conserved.
The compounds useful in the invention may be delivered in the foπn of anti-cancer cocktails. An anti-cancer cocktail is a mixture of any one of the compounds useful with this invention with another anti-cancer agent such as an anti-cancer drug, a cytokine, and/or supplementary potentiating agcnt(s). The use of cocktails in the treatment of cancer is routine. In this embodiment, a common administration vehicle (e.g., pill, tablet, implant, injectable solution, etc.) would contain both the conjugate useful in this invention and the anti-cancer drug and/or supplementary potentiating agent.
The compounds of the invention, when used in cocktails, are administered in therapeutically effective amounts. A therapeutically effective amount will be determined by the parameters discussed below; but, in any event, is that amount which establishes a level of the drug(s) in the area of the tumor which is effective in inhibiting the tumor growth.
When administered, the formulations of the invention arc applied in pharmaceutically acceptable amounts and in pharmaceutically acceptable compositions. Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic ingredients. When used in medicine the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used lo prepare pharmaceutically acceptable salts thereof and arc not excluded from the scope of the invention. Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic. sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulfonic, tartaric, citric, methane sulfonic, formic, malonic, succinic, naphthalene-2-sulfonic, and benzene sulfonic. Also, pharmaceutically acceptable salts can be 5 prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts.
Suitable buffering agents include: acetic acid and a salt (1 -2% W/V); citric acid and a salt (1-3% W/V); boric acid and a salt (0.5-2.5% W/V); and phosphoric acid and a salt (0.8-2% W/V). Suitable preservatives include benzalkonium chloride (0.003-0.03% W/V); chlorobutanol (0.3-0.9% W/V); parabens (0.01-0.25% W/V) and thimerosal (0.004-0.02% W/V). l o The active compounds of the present invention may be a pharmaceutical composition having a therapeutically effective amount of a conjugate of the invention optionally included in a pharmaceutically-acceptable carrier. The term "pharmaceutically-acceptable carrier" as used herein means one or more compatible solid or liquid filler, dilutants or encapsulating substances which are suitable for administration to a human or other animal. The term "carrier" denotes an organic or
15 inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions are capable of being commingled with the molecules of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.
Compositions suitable for parenteral administration conveniently comprise a sterile 0 preparation of the conjugates of the invention. This preparation may be formulated according to known methods. Formulations for taxanes can be found in Chapter 9 of Taxol: Science and Applications. CRC Press, Inc., 2000 Coφorate Boulevard. N. W., Boca Raton. FL 33431. In general, Taxol has been formulated as a 6 mg/ml cremophor EL (polyoxycthylated castor oil)/ethanol mixture, which is diluted to final volume with normal saline or 5% dextrose. A 15mg/ml solution 5 of taxotere has been formulated in polysorbate 80 (polyoxyethylene sorbitanmonooieatej/ethanol mixture, diluted with 5% dextrose.
The sterile preparation thus may be a sterile solution or suspension in a non-toxic parenterally-acceptable diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be
30 employed including synthetic mono ordi-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injcctablcs. Carrier formulations suitable for oral, subcutaneous, intravenous, intramuscular, etc. can be found in Remington's Pharmaceutical Sciences. Mack Publishing Company. Easton. PA.
A subject as used herein means humans, primates, horses, cows, pigs, sheep, goats, dogs, cats and rodents.
The conjugates of the invention are administered in effective amounts. An effective amount means that amount necessary to delay the onset of, inhibit the progression of, halt altogether the onset or progression of or diagnose the particular condition being treated. In general, an effective amount for treating cancer will be that amount necessary to inhibit mammalian cancer cell proliferation in-situ. When administered to a subject, effective amounts will depend, of course, on the particular condition being treated; the severity of the condition; individual patient parameters including age, physical condition, size and weight; concurrent treatment; frequency of treatment; and the mode of administration. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to sound medical judgment.
Dosage may be adjusted appropriately to achieve desired drug levels, locally or systemically. Generally, daily oral doses of active compounds will be from about 0.01 mg/kg per day to 1000 mg/kg per day. It is expected that IV doses in the range of about 1 to 1000 mg/m: per day will be effective. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Continuous IV dosing over, for example 24 hours or multiple doses per day are contemplated to achieve appropriate systemic levels of compounds.
A variety of administration routes arc available. The particular mode selected will depend of course, upon the particular drug selected, the severity of ihe disease state being treated and the dosage required for therapeutic efficacy. The methods of this invention, generally speaking, may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects. Such modes of administration include oral, rectal, sublingual, topical, nasal, transdermal or parenteral routes. The term "parenteral" includes subcutaneous, intravenous, intramuscular, or infusion. Intravenous routes are preferred.
The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the slcp of bringing the conjugates of the invention into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid earner, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
Compositions suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active compound. Other compositions include suspensions in aqueous liquors or non-aqueous liquids such as a syrup, an elixir, or an emulsion.
Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the active compounds of the invention, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer based systems such as polylactic and polyglycolic acid, polyanhydrides and polycaprolactone; nonpolymer systems that are lipids including sterois such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-, di and triglycerides; hydrogel release systems; silastic systems; peptide based systems; wax coatings, compressed tablets using conventional binders and excipients, partially fused implants and the like. In addition, a pump-based hardware delivery system can be used, some of which are adapted for implantation.
A long-term sustained release implant also may be used. "Long-term" release, as used herein, means that the implant is constmctcd and arranged to deliver therapeutic levels of the active ingredient for at least 30 days, and preferably 60 days. Long-term sustained release implants are well known to those of ordinary skill in the art and include some of the release systems described above. Such implants can be particularly useful in treating solid tumors by placing the implant near or directly within the tumor, thereby affecting iocalized, high-doses of the compounds of the invention.
The conjugates of the invention also are useful, in general, for treating mammalian cell proliferative disorders other than cancer, including psoriasis, actinic kcratosis, etc. They further are useful in treating diabetes and its complications, excess acid secretion, cardiovascular conditions involving cholesterol (e.g., hyperlipidemia and hypercholcsterolcmia), diarrhea, ovarian diseases
(e.g. cndomclriosis, ovarian cysts, etc.) and as contraceptive agents.
Those skilled in the art will be able to recognize with no more than routine experimentation numerous equivalents to the specific products and processes described above. Such equivalents arc intended to be included within the scope of the appended claims.

Claims

P- 64 -CLAIMS
1. A method for targeting a pharmaceutical agent to a noncentral nervous system tissue to treat a noncentral nervous system condition comprising: administering to a subject in need of such treatment a covalent conjugate of d.T-docosahexaenoic acid and a pharmaceutical agent effective for treating said condition.
2. The method of claim 1 , wherein the c/.v-docosahcxacnoic acid is conjugated directly to the pharmaceutical agent.
3. The method of claim 2, wherein the tissue is breast tissue and wherein the subject has a condition calling for treatment of breast tissue with the pharmaceutical agent.
4. The method of claim 2, wherein the tissue is gastrointestinal tissue and wherein the subject has a condition calling for treatment of gastrointestinal tissue with the pharmaceutical agent.
5. The method of claim 2, wherein the tissue is ovarian tissue and wherein the subject has a condition calling for treatment of ovarian tissue with the pharmaceutical agent.
6. The method of claim 2, wherein' the pharmaceutical agent is a noncentral nervous system active agent that is nonactivc within the central nervous system.
7. The method of claim 2, wherein the drug is an anli-canccr agent.
8. The method of claim 7, wherein the drug is Taxol.
9. The method of claim 8, wherein the conjugate is
Figure imgf000066_0001
10. The method of claim 8, wherein the conjugate is
Figure imgf000067_0001
1 1. The method of claim 7, wherein the dmg is Taxotere.
12. The method of claim 1 1 , wherein the conjugate is
Figure imgf000067_0002
13. The method of claim 1 1 , wherein the conjugate is
Figure imgf000067_0003
14. The method of claim 1 1, wherein the conjugate is
15. The method of claim 1 1 , wherein the conjugate is
Figure imgf000068_0002
16. The method of claim 1 , 2, 3, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14 or 15, wherein the condition is breast cancer.
17. The method of claim 1 , 2, 3, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14 or 15. wherein the condition is colon cancer.
18. The method of claim 1. 2, 3, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14 or 15. wherein the condition is ovarian cancer.
19. A pharmaceutical preparation comprising: a covalent conjugate of c/s-docosahexaenoic acid and a noncentral nervous system active agent, and a pharmaceutically acceptable carrier.
20. The pharmaceutical preparation of claim 19, wherein the cύ-docosahexaenoic acid is conjugated directly to the active agent.
21. The pharmaceutical preparation as claimed in claim 20, wherein the noncentral nervous system active agent is active on a tissue selected from the group consisting of:
Blood and Blood Forming tissue; Cardiovascular system tissue; Digestive and excretory system tissue; Endocrine system tissue; Musclar system tissue; Reproductive System tissue; Respiratory system tissue; Skeletal system tissue; and Fiber and integumentary system tissue.
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