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US 2002001 0208A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0010208A1 Shashoua et al. (43) Pub. Date: Jan. 24, 2002

(54) DHA-PHARMACEUTICAL AGENT Related U.S. Application Data CONJUGATES OF (63) Continuation of application No. 09/135,291, filed on (76) Inventors: Victor Shashoua, Brookline, MA (US); Aug. 17, 1998, now abandoned, which is a continu Charles Swindell, Merion, PA (US); ation of application No. 08/651,312, filed on May 22, Nigel Webb, Bryn Mawr, PA (US); 1996, now Pat. No. 5,795,909. Matthews Bradley, Layton, PA (US) Publication Classification Correspondence Address: Edward R. Gates, Esq. (51) Int. Cl." ...... A61K 31/337 Wolf, Greenfield & Sacks, P.C. (52) U.S. Cl...... 514/449 600 Atlantic Avenue Boston, MA 02210 (US) (57) ABSTRACT The invention provides conjugates of cis-docosahexaenoic (21) Appl. No.: 09/846,838 acid and pharmaceutical agents useful in treating noncentral nervous System conditions. Methods for Selectively target 22) Filled: Mayy 1, 2001 ingg pharmaceuticalp agents9. to desired tissues are pprovided. Patent Application Publication Jan. 24, 2002 Sheet 1 of 14 US 2002/0010208A1

1 OO

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MELANOMA 1 OO

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1 OO PROSTRATE CANCER O

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LOGo OF SAMPLE CONCENTRATION (MOLAR) PC-3-O- Fig. 8 Patent Application Publication Jan. 24, 2002 Sheet 5 of 14 US 2002/0010208A1

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OVARAN CANCER 1 OO Cys's S.

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1 OO PROSTRATE CANCER --

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EUKEMA

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COLON CANCER

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MELANOMA

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LOGO OF SAMPLE CONCENTRATION (MOLAR) IGROV1 -o- OVCAR-3--O--OVCAR-4--a-- OCVAR-8 - - - - SK-OV-3-...-0.-Fig. 24 : OWCAR-5"O" Patent Application Publication Jan. 24, 2002 Sheet 13 of 14 US 2002/0010208A1

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o -9 -8 -7 -6 LOGo OF SAMPLE CONCENTRATION (MOLAR) PC-3-O- DU-145-Fig. -O-- 26 Patent Application Publication Jan. 24, 2002 Sheet 14 of 14 US 2002/0010208A1

BREAS CANCER

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2. O 1. l - O g - -7 -6 LOG10 OF SAMPLE CONCENTRATION (MOLAR) MCF 7 -O- MDA-N---4--. - HS 578T. O.... MDA-MB-435- -e- - MDA-MB-231/ -- a-- -47D---a-...- MCF 71ADR-RE--&- B-549-...-A-...- Fig. 27 US 2002/0010208A1 Jan. 24, 2002

DHA-PHARMACEUTICAL AGENT CONJUGATES 0006 Taxol has the following formula: OF TAXANES

BACKGROUND OF THE INVENTION AcO O OH 0001 Improving selectivity for target tissue is an established goal in the medical arts. In general, it is desirable H O to deliver a drug Selectively to its target, So that dosage and, X. consequently, Side effects can be reduced. This is particu Y Yo Y Y Ph 3 2 O i larly the case for toxic agents Such as anti-cancer agents HO because achieving therapeutic doses effective for treating the H PhCO2 A.C 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 0007 Taxanes have the basic three ring structure (A. B TaxolcE). and C), Substituted or unsubstituted. 0002 Taxole () was first isolated in 1971 from 0008 Taxol's are numbered conventionally as the bark of Taxus brevifolia and was approved in 1992 by the follows: US Food and Drug Administration for treatment of meta Static Ovarian cancer and later for breast cancer. Its mecha nism of action is believed to involve promoting formation and hyperStabilization of , thereby preventing the disassembly of microtubules necessary for completion of cell division. It also has been reported that Taxol induces expression of cytokines, affects the activity of kinases and blockS processes essential for metastasis, in as yet unchar acterized mechanisms of action. 0.003 Taxol has attracted unusually strong scientific attention, not only because of its unique antiproliferative mechanism of action, but also because it is active against nearly all against which it has been tested and 0009 Based upon the taxanes tested to date, as many because it has been discovered to be an analog of numerous questions have been raised as have been answered, and closely related compounds occurring naturally. These com general rules have not been fashioned easily in predicting pounds, taxanes, are now recognized as a new class of selectivity, activity and solubility. Firstly, no rules have anticancer compounds. emerged regarding Selectivity. Those taxanes that are Strongly active appear to have activity as broad as Taxol's 0004 Taxol's strength against cancers of diverse tissue activity, and no headway appears to have been made in terms origin also represents a significant drawback. An ideal of developing a more Selective Taxol analog. anticancer agent has tissue Specificity, thereby reducing 0010 Some information about activity has emerged. Side-effects on normal (dividing) cells. Taxol analogs with Numerous Substitutions have been made at C7, C9, C10, tissue specificity therefore are desired. Another drawback of C19, R and combinations thereof while retaining signifi Taxol is its extreme insolubility. Taxol can be administered cant, but usually reduced, activity. Substitutions at C2, C4 effectively in a Solvent including cremophor, which combi and 2'OH, however, are generally not tolerated. These con clusions are only generalities, for example, because Some nation can provoke Severe hyperSensitive immune substitutions at C9-C10 (cyclic derivatives) are not tolerated responses. As a result of these drawbacks, and also as a and Some Substitutions at C2 (meta Substitutions on the result of the potential for modifying Taxol at numerous Sites phenyl) are tolerated. Likewise, the C13 side chain and, in as demonstrated by other naturally-occurring taxanes with particular, the 2'OH are required, although the minimum anticancer activity, a Search for more Selective taxanes was Structural requirements of the Side chain have not been launched. determined for therapeutic efficacy. 0011 Attempts to improve Taxol's solubility have not 0005 To date, more than 200 taxanes have been synthe resulted in Successful clinical products. One approach has sized (or isolated) and tested in vitro or in Vivo for anticancer been to manufacture of Taxol, which prodrugs activity. The results, however, have been So disappointing undergo in Vivo transformation into Taxol and Some other that the National Cancer Institute (NCI) generally no longer product. Attempts were made to esterify the C7 hydroxy and is interested in testing Taxol analogs. In general with Taxol 2' hydroxy groups, with the hope that the bond would be analogs, the Solubility problems remain, and/or is Stable in Solution (to permit preferred administration Sharply reduced, and/or Selectivity is not improved, and/or modes-i.V. over at least 24 hours) but would cleave readily the ratio of the median toxic dose to the median effective in Vivo. The groups tested were all hydrophilic and included dose (“therapeutic index') is unacceptably reduced. amines, short carboxylic acids (using e.g. Succinic anhydride and glutaric anhydride), Sulfonic acids, amino acids and . Generally, activity was reduced although Some Success was obtained with certain derivatives. Again, no US 2002/0010208A1 Jan. 24, 2002 particular pattern emerged permitting one to predict reliably tissues”). The conjugates, also unexpectedly, restrict the which groups could be substituted on Taxol to yield a activity of these compounds to cell types within these tissue therapeutically useful product, although it was Suggested categories relative to that otthe unconjugated pharmaceuti that the 2' OH derivatives may cleave more easily than the cal agents. The conjugates, further unexpectedly, reduce C7 OH derivatives. Sharply the activity of these compounds relative to that of the unconjugated pharmaceutical agents in most cell lines of 0012 Several other factors add to the problem of pre tissue types other than colon, breast, and central nervous dicting which Taxol analogs will be effective. Multiple System, thereby reducing potential Side effects of the con mechanisms of action have been proposed in the literature, jugates versus those of the unconjugated pharmaceutical and a change in one position may have no effect on activity agents. The therapeutic index of the conjugates may be on one Such mechanism but may eliminate activity on improved, verSuS that of the unconjugated pharmaceutical another mechanism. In addition, changes that favorably agents. influence activity may unfavorably influence . For example, Taxol affects formation inside a 0018. According to one aspect of the invention, a method cell, but a change in Structure that increases intracellular is provided for targeting a pharmaceutical agent to a non activity may adversely affect the ability of Taxol to gain central nervous System tissue to treat a noncentral nervous entry into a cell. Taxol also is known to bind to proteins, and System condition. A covalent conjugate of cis-docosahex the effect on activity that results from a change in Taxol's anoic acid and a pharmaceutical agent effective for treating binding to protein (in terms of conformation, cellular Said condition is administered to a Subject in need of Such absorption and Solubility) is unknown. treatment. In preferred embodiments, the tissue is breast tissue, gastrointestinal tissue and Ovarian tissue and the 0013. It has been reported that Taxol does not get into the condition calls for treatment of breast tissue, gastrointestinal , apparently excluded by the blood brain barrier. It is tissue or ovarian tissue, respectively. not known why this is So, as Taxol is lipophilic, gets into cells and might be expected to cross the blood brain barrier. 0019. The pharmaceutical agent may be any pharmaco 0.014) Among the most promising of the two hundred logical compound or diagnostic agent, as desired. The phar analogs tested is Taxotere (), because of its slightly maceutical agent, of course, has an activity outside of the increased activity and solubility. Oddly, however, Taxotere central nervous System. differs from Taxol at sites which typically do not have a 0020 Examples of catagories of pharmaceutical agents Strong influence on activity, and one would not predict the include: agent, adrenocortical ; adrenocor improvements in Taxotere from these differences, even in tical Suppressant, deterrent; antagonist; hindsight. ; ammonia detoxicant; anabolic; analeptic, anal gesic, ; , adjunct to; ; anorec 0.015 Taxotere has the following formula: tic, antagonist; anterior pituitary SuppreSSant; anthelmintic, anti- agent, anti-adrenergic, anti-allergic, anti-amebic;

anti-androgen; anti-anemic, anti-anginal; anti-anxiety; anti arthritic, anti-asthmatic, anti-atherOSclerotic, antibacterial; anticholelithic, anti-hole lithogenic, , antico agulant; anticoccidal; ; ; antidiabetic, antidiarrheal; antidiuretic, antidote, anti emetic, anti-epileptic, anti-; antifibrinolytic, anti fungal; antiglaucoma agent; antihemophilic, antihemor rhagic, ; antihyperlipidemia; antihyperlipoproteinemic, antihypertensive, antihypoten Sive, anti-infective, anti-infective, topical; anti-inflamma tory; antikeratinizing agent, antimalarial; antimicrobial; antimigraine; antirlitotic, antimycotic, antinauseant, antine oplastic, antineutropenic, antiobessional agent; antiparasitic, 0016 DHA (docosahexaenoic acid) is a 22 natu antiparkinsonian, antiperistaltic, antipneumocystic, antipro rally-occurring, unbranched fatty acid that previously has liferative; antiproStatic hypertrophy; antiprotozoal; antipru been attached to to help deliver them acroSS the blood ritic, , antirheumatic, antischistoSomal; antise brain barrier. DHA is attached via the acid group to hydro borrheic, antisecretory; , antithrombotic, philic drugs and renders these drugs more hydrophobic antituSSive; anti-ulcerative; anti-urolithic, antiviral; appetite (lipophilic). DHA is an important constituent of the brain SuppreSSant; benign prostatic hyperplasia therapy agent; and recently has been approved in as an additive to blood regulator, resorption inhibitor; bron infant formula. It is present in the milk of lactating women. chodilator; carbonic anhydrase inhibitor, cardiac ; The mechanism of action by which DHA helps drugs cardioprotectant; cardiotonic, cardiovascular agent, choler conjugated to it croSS the blood brain barrier is unknown. etic, , cholinergic , deacti Vator, coccidiostat; cognition adjuvant; cognition enhancer, SUMMARY OF THE INVENTION depressant, diagnostic aid; , doparninergic agent; ectoparasiticide, emetic, inhibitor; estrogen; fibrin 0.017. The present invention involves the unexpected olytic, fluorescent agent, free oxygen radical Scavenger; finding that conjugates of pharmaceutical agents and a gastrointestinal motility effector; , gonad highly lipaphilic group, a C22 unbranched carbon chain, Stimulating principle; hair growth ; hemostatic; have a different Selectivity relative to the unconjugated H2 antagonists, , hypocholes pharmaceutical agents. The conjugates, in general, render terolemic, hypoglycemic, hypolipidemic, hypotensive; the activity of these compounds Selective for colon tissue, imaging agent, immunizing agent, immunomodulator; breast tissue and central nervous System tissue ("targeted immunoregulator, imnuunostimulant; immunosuppressant; US 2002/0010208A1 Jan. 24, 2002

impotence therapy adjunct; inhibitor, keratolytic; LNRH tions involving (e.g., hyperlipidemia and hyper agonist, liver disorder treatment, luteolysin; memory adju cholesterolemia), diarrhea, ovarian diseases (e.g. vant; mental performance enhancer, mood regulator, muco endometriosis, ovarian cysts, etc.) and as contraceptive lytic, mucosal protective agent, mydriatic, nasal deconges agents. Other conditions treatable according to the invention tant; neuromuscular blocking agent; neuroprotective; will be apparent to those skilled in the art based upon the NMDA antagonist; non-hormonal sterol derivative; oxyto disclosure and lists of compounds provided. cic, plasminogen activator, platelet activating factor antago 0024. The methods and/or products of the invention also nist, platelet aggregation inhibitor, post-Stroke and post are useful in treating conditions Specific to noncentral ner head trauma treatment; potentiator, progestin; Vous System tissue. Such conditions can be specific to breast ; growth inhibitor, prothyrotropin; tissue, gastrointestinal tissue and Ovarian tissue. The tissue psychotropic, pulmonary Surface; radioactive agent; regula also may be other noncentral nervous System tissues. Non tor, relaxant, repartitioning agent, Scabicide, Sclerosing central nervous System tissue includes tissue of the: Blood agent, , Sedative-, Selective Al and Blood Forming System: including platelets, blood vessel antagonist, antagonist, Serotonin inhibitor, Sero wall, and bone marrow, Cardiovascular System: including tonin ; Steroid; Stimulant; SuppreSSant; heart and vascular System; Digestive and excretory System: Symptomatic multiple Sclerosis, Synergist; hormone; including alimentary tract, biliary tract, kidney, liver, pan thyroid inhibitor; thyromimetic; tranquilizer; treatment of creas and urinary tract; : including adrenal amyotrophic lateral Sclerosis, treatment of cerebral gland, kidney, ovary, , renal gland, Salivary ischemia; treatment of Paget’s disease; treatment of unstable gland, Sebaceous gland, testis, thymus gland and thyroid angina; uricoSuric; vasoconstrictor; vasodilator; Vulnerary; gland; Musclar System: including muscles that move the wound healing agent; oxidase inhibitor. body. Reproductive System: including breast, ovary, penis 0021. In one particularly preferred embodiment of the and uterus, Respiratory System: including bronchus, lung invention, the phannaceutical agent is an anti-cancer agent. and trachea, Skeletal System: including and joints; Examples of anti-cancer agents are described in greater TiSSue, fiber, and integumentary System: including adipose detail in the Specification. Included specifically are the tissue, cartilage, connective tissue, cuticle, dermis, epider taxanes (e.g., Taxol and Taxotere). Conjugates of cis mis, epithelium, fascia, hair follicle, ligament, bone marrow, docosahexanoic acid and taxoids also are embraced by the melanin, melanocyte, mucous membrane, skin, Soft tissue, invention. Synovial capsule and tendon. 0022. Cis-docosahexanoic acid previously has been con BRIEF DESCRIPTION OF THE DRAWINGS jugated to drugs that are active in the central nervous System. The present invention contemplates the use of cis-docosa 0.025 FIG. 1 is a graph plotting concentration of conju hexanoic acid in the manufacture of a medicarnent for gate 1 verSuS percent growth of leukemia cells. treating a noncentral nervous System condition. The inven 0026 FIG. 2 is a graph plotting concentration of conju tion further contemplates compositions of matter that are gate 1 versus percent growth of non-Small cell lung cancer covalent conjugates of cis-docosahexanoic acid and noncen tral nervous System active pharmaceutical agents. A non cells. central nervous System active pharmaceutical agent is one 0027 FIG. 3 is a graph plotting concentration of conju that has no function or use in the central nervous System. Its gate 1 verSuS percent growth of colon cancer cells. only therapeutic use is outside of the central nervous System. Examples of Such agents include, but are not limited to: 0028 FIG. 4 is a graph plotting concentration of conju Blood glucose regulators, Such as , , gate 1 verSuS percent growth of CNS cancer cells. , , and, , HMGcoA 0029 FIG. 5 is a graph plotting concentration of conju reductase inhibitors, Such as (Mevacor), Simv gate 1 verSuS percent growth of melanoma cells. astatin (Zocor), (Pravachol), and, Fluvstatin (Lescol); Muscosal Protectives, such as (Cyto 0030 FIG. 6 is a graph plotting concentration of conju tec); Gastrointestinal motility affectors, Such as gate 1 verSuS percent growth of Ovarian cancer cells. (Propulsid), (Reglan), and, 0031 FIG. 7 is a graph plotting concentration of conju (Levsin); Antidiarrheals, Such as hydrochlo gate 1 verSuS percent growth of renal cancer cells. ride (Lomotil), (Flagyl), (Medrol), and, (AZulfidine); and 0032 FIG. 8 is a graph plotting concentration of conju for treating, inter alia, ovarian conditions, Such as Progest gate 1 verSuS percent growth of cells. erone, , Norethynodrel, Norethindrone, 0033 FIG. 9 is a graph plotting concentration of conju , Ethyndiol, , , , 17 gate 1 verSuS percent growth of breast cancer cells. alpha dihydroequilin, , 17 alpha dihydroequilenin, 17 alpha esradiol, 27 bea , Leuprolide (Lupron), 0034 FIG. 10 is a graph plotting concentration of con , Climiphene, urofollitropin, , jugate 2 versus percent growth of leukemia cells. gonadorelin, , , androstene 0035 FIG. 11 is a graph plotting concentration of con dione, , , folliculoStatin, Follicle jugate 2 verSuS percent growth of non-Small cell lung cancer regulatory protein, Gonadocrinins, Oocyte maturation cells. inhibitor, and, growth factor. Other compounds are 0036 FIG. 12 is a graph plotting concentration of con detailed below. jugate 2 versus percent growth of colon cancer cells. 0023 The methods and/or products of the invention are useful for treating a variety of medical conditions including 0037 FIG. 13 is a graph plotting concentration of con conditions involving abnormal mammalian-cell prolifera jugate 2 versus percent growth of CNS cancer cells. tion. They further are useful in treating diabetes and its 0038 FIG. 14 is a graph plotting concentration of con complications, exceSS acid Secretion, cardiovascular condi jugate 2 versus percent growth of melanoma cells. US 2002/0010208A1 Jan. 24, 2002

0.039 FIG. 15 is a graph plotting concentration of con jugate 2 versus percent growth of ovarian cancer cells. 0040 FIG. 16 is a graph plotting concentration of con jugate 2 versus percent growth of renal cancer cells. 0041 FIG. 17 is a graph plotting concentration of con jugate 2 versus percent growth of prostate cancer cells. 0.042 FIG. 18 is a graph plotting concentration of con 0053 DHA can be isolated, for example, from fish oil or can be chemically Synthesized. These methods, however, jugate 2 versus percent growth of breast cancer cells. can generate trans isomers, which are difficult and expensive to Separate and which may present Safety problems in 0.043 FIG. 19 is a graph plotting concentration of Taxol humans. The preferred method of production is biological Versus percent growth of leukemia cells. Synthesis to produce the all cis isomer. The preferred Source of DHA is from Martek Biosciences Corporation of Colum 0044 FIG. 20 is a graph plotting concentration of Taxol bia, Md. Martek has a patented System for manufacturing Versus percent growth of non-Small cell lung cancer cells. DHA using microalgae which Synthesize only a single isomer of DHA, the all cis isomer. Martek’s patents include 004.5 FIG. 21 is a graph plotting concentration of Taxol U.S. Pat. Nos. 5,374,657, 5,492,938, 5,407,957 and 5,397, Versus percent growth of colon cancer cells. 591. 0054 DHA also is present in the milk of lactating 0.046 FIG. 22 is a graph plotting concentration of Taxol Women, and Martek’s licensee has obtained approval in versus percent growth of CNS cancer cells. Europe of DHA as a nutritional supplement for infant formula. 0047 FIG. 23 is a graph plotting concentration of Taxol 0055. It is known that DHA can be unstable in the Versus percent growth of melanoma cells. presence of oxygen. To Stablizie DHA and its conjugates it is important to add anti-oxidants to the material after it is 0.048 FIG. 24 is a graph plotting concentration of Taxol Synthesized. One method of Stablization is to make-up the Versus percent growth of ovarian cancer cells. newly synthesized material in the following solution: 100 g neat DHA-taxol plus 100 g of vehicle (IOOml propylene 0049 FIG. 25 is a graph plotting concentration of Taxol glycol, 70 mg alph-tocopherol, 5 mg dialaurylthiodipropi Versus percent growth of renal cancer cells. onic acid, 50 mg ascorbic acid) prepared and held under argon in amber, Sealed Vials and Stored at four degrees 0050 FIG. 26 is a graph plotting concentration of Taxol centigrade. The following anti-oxidants may also be Versus percent growth of prostate cancel cells. employed: ascorbic acid, ascorbyl palmitate, dilauryl ascor bate, hydroquinone, butyated hydroxyanisole, meta 0051 FIG. 27 is a graph plotting concentration of Taxol bisulfite, t-B caroteine and X-tocopherol. A heavy metal Versus percent growth of breast cancer cells. chelator Such as ethylenediamine tetra- (EDTA) may also be used. DETAILED DESCRIPTION OF THE 0056 Paclitaxel was first isolated from the bark of Taxus INVENTION brevifolia (Wani et al., J. Am. Chem. Soc., 93, 2325, 1971). Its isolation and Synthesis have been reported extensively in 0.052 cis-docosahexaenoic acid (DHA) is a naturally the literature. Applicants obtained paclitaxel from a com occurring fatty acid. It is an unbranched chain fatty acid with mercial Source, Hauser Laboratories, of Boulder, Colo. six double bonds, all cis. Its structure is as follows: EXAMPLE 1.

TAXOL

conjugate 1 US 2002/0010208A1 Jan. 24, 2002

0.058 A Solution of Taxol (41 umol) in methylene chlo 0059. The production of analog 2 involves several steps ride (2.5 mL) under argon was mixed with 4-dimethylami including a number of protection-acylation-deprotection nopyridine (41 umol), dicyclohexylcarbodiimide (82/tmol), steps. A solution of Taxol (59 umol) in methylene chloride and DHA (41 umol) and the reaction mixture was stirred at (2.5 mL) was mixed at ambient temperature under argon ambient temperature for two hours. Following dilution with with (147 umol) and triethylsilyl chloride (147 ether, the reaction mixture was washed with 5% hydrochlo almol). The reaction mixture was stirred for thirty minutes, ric acid, water, Saturated acqueous Sodium chloride, dried, diluted with additional methylene chloride, washed with and concentrated. Radial chromatography of the residue water, Saturated aqueous Sodium chloride, dried, and con produced 45 mg (94%) of crystalline Taxol-DHA conjugate centrated. Chromatography of the residue produced 50 mg 1. (88%) of intermediate A plus 5 mg of the 2, 7-di(triethyl

TAXOL He

conjugate 2 US 2002/0010208A1 Jan. 24, 2002

silyl) ether derivative. A solution of intermediate A (52 umol) in methylene chloride (3 mL) was mixed at ambient -continued temperature under argon with 4-dimethylaminopyridine (52 Mean ODI = The average of optical density measurements of SRB umol), dicyclohexylcarbodiimide (104 umol), and DHA (52 derived color after 48 hours with no exposure of cells to almol). The reaction mixture was stirred for ten hours, the test compound. diluted with ether, passed through celite, and concentrated. Chromatography of the residue produced 65.9 mg of inter 0067 Experimental data was collected against each cell mediate B. A solution of intermediate B (51 umol) in line. . . . Each concentration is expressed as the logo (molar acetonitrile (2 mL) at 0°C. under argon was mixed with 49% or /g/ml).... The response parameters GI50, TGI, and LC50 aqueous HF (0.2 mL) and the reaction mixture was stirred are interpolated values representing the concentrations at for one hour. After dilution with ether, the reaction mixture which the PG is +50, 0, and -50, respectively. Sometimes was washed with water, Saturated aqueous Sodium chloride, these response parameters cannot be obtained by interpola dried, and concentrated. Radial chromatography of the resi tion. If, for instance, all of the PGS in a given row exceed due produced 44.6 mg (75%) of Taxol-DHA conjugate 2. +50, then none of the three parameters can be obtained by interpolation. In Such a case, the value given for each EXAMPLE 3 response parameter is the highest concentration tested. . . . 0060 Conjugates 1 and 2 were sent to the United States This practice is extended similarly to the other possible National Cancer Institute (NCI) for screening in the NCI's Situations where a response parameter cannot be obtained by anticancer Screening program. The conjugates were pro interpolation. vided in (approximately 40 mg analog/2 ml ethanol). 0068 Dose-Response Curves: The conjugates were Sealed in Vials under argon to avoid 0069. The dose-response curve page of the data package exposure of the conjugates to oxygen because the conjugates is created by plotting the PGS against the logo of the were believed to be Sensitive to oxygen. Instructions were corresponding concentration for every cell line. The cell line provided to store at 4 C. and to open the vials only when curves are grouped by Subpanel. Horizontal lines are pro ready for immediate experimental use. Instructions also were provided to use the ethanol Solutions containing the vided at the PG values of +50, 0, and -50. The concentra conjugates directly or to dissolve the analogs further in tions corresponding to points where the curves croSS these DMSO (dimethylsulfoxide) at appropriate concentrations, lines are the GI50, TGI and LC50, respectively. with Vortexing if necessary for adequate dispersal. 0070. Several important distinctions are apparent from the data. Most important, the patterns of anticancer actively 0061 The activities of conjugates 1 and 2 were tested for conjugates 1 and 2 differ from that of Taxol. In one Sense, against 57 cancer cell lines. The results are presented in conjugates 1 and 2 are effective anticancer agents against a FIGS. 1-9 for conjugate 1, FIGS. 10-18 for conjugate 2 and more restricted Set of cancer cell lines. For example, con FIGS. 19-27 for Taxol. To understand the data, reference is jugates 1 and 2 were not very effective against any of the Six made to the guides provided by the NCI, excerpted as leukemia cancer cell lines tested, whereas Taxol was Some follows: what effective against all four leukemia cell lines against 0062) The Calculated Measurement of Effect: Percentage which Taxol was tested. (See FIGS. 1, 10 and 19.) Growth (PG) 0071. The relative activity against members within a class of cancers also was altered. For example, at TGI 0.063. The measured effect of the compound on a cell line (horizontal line at Zero in the graphs), Taxol was more is currently calculated according to one or the other of the effective against non-Small cell lung cancer line H522 than following two expressions: against H460 (by about 3 logs), whereas conjugates 1 and 2 0064. If (Mean OD-Mean OD)20, then were slightly more effective against H460 than H522. As another example, Taxol was least effective at TGI against PG=100x(Mean ODes-Mean OD)/(Mean ODI Mean Odzero) CNSU251, whereas conjugate 1 was most effective against CNSU251 and conjugates 2 was also very effective against 0065. If (Mean OD-Mean OD)<0, then CNSU251(relative to other CNS cell lines). As a further PG=100x(Mean ODes Mean Oder)/Mean Odeo example, Taxol was equivalent in activity toward MDA-N and MDA-MB-435 breast cancer cell lines at all concentra 0066. Where: tions tested, whereas conjugates 1 and 2 were more effective against MDA-N than MDA-MB-435 at all concentrations tested. Mean ODze = The average of optical density measurements of SRB-derived color just before exposure of cells to 0072) To further illustrate the differences in the activity of the test compound. conjugates 1 and 2 versus that of Taxol, the NCI subjected Mean ODes = The average of optical density measurements of SRB derived color after 48 hours exposure of cells to the test the data to a statistical analysis designed by the NCI to compound. reflect differences in the pattern of activity of anticancer agents. Conjugate 1 and conjugate 2 were determined to be US 2002/0010208A1 Jan. 24, 2002

statistically different in their pattern of activity versus Taxol lines VS. a lesser reduction for other cell lines is expected to in this unique measurement by the NCI. reduce the potential Side effects of the conjugates verSuS 0073. It also is to be noted that, in general, conjugates 1 those of Taxol at effective doses. and 2 were one thousand to ten thousand times leSS potent 0074 Cancers other than CNS, breast and colon cancer than Taxol for many cell lines tested. This reduction in can be treated. For example, there was activity against activity is important, especially Since conjugates 1 and 2 non-Small cell lung cancer cells, melanoma cells and ovarian maintained Strong activity against Some cell lines. Conju cancer cells. However, the activity was relatively reduced gates 1 and 2 will be Sufficiently active against certain cell and was extremely specific, limiting the utility of the con lines, but will have, on average, a Substantially and dispro jugates for treating generally Such cancers. In any event, portionately lower activity against other cell lines, reducing cancer patients could be evaluated to determine if a conju potential side effects. For example, the TGI for Taxol against gate is Strongly active against the patient's cancer prior to CNS SF-539 is -6.95, and the TGI for conjugate 1 against Selecting the conjugate as the anti-cancer agent of choice for this cell line is -5.13 and for conjugate 2 is -5.53. (In other that patient. words, the activity of the conjugates was reduced verSuS that 0075. The foregoing experiments establish that DHA of Taxol by less than 2 logs). The GI50 for Taxol against analogs have altered specificity versus that of Taxol for CNS SF 539 is -7.52, whereas the GI50s for conjugates 1 cancer cell lines. Because of this altered specificity, it also is and 2 are -6.22 and -5.56, respectively (again less than 2 clear that the conjugates themselves are gaining acceSS into logs difference). In contrast, Taxol has a G150 for cell line the target cells (as opposed to simply releasing Taxol into the CNSSF 268 of less than -10.0, whereas conjugates 1 and 2 environment outside of the cell). Thus, the DHA moiety have GISOs for CNSSF 268 of 5.36 and 5.28, respectively. appears to Selectively target certain cell types as opposed to This represents a reduction of activity in the conjugates VS. others. The ability of the conjugates to gain entry into the that of Taxol by at least about 5 logs activity. On average, cells was unknown prior to the invention, and the ability of the G150 for Taxol across all cell lines tested is at least the DHA moiety to Selectively target certain cell types was -9.19. (It is probably much higher since concentrations less unexpected. than -10 were not tested, and if Taxol was active at -10.0, -10 (instead of the actual lower value) was used in calcu 0076. The same is true of DHA-Taxotere covalent con lating the average of -9.19. There were 27 instances when jugates, examples of which are presented below. Taxotere's this occurred.) The average GI50s for conjugates 1 and 2, Synthesis has been reported extensively in the literature. One on the other hand, were 5.49 and 5.22, respectively. There example is Kanazawa, A. et al., J. Organic Chem. 1994, Vol. fore, the average difference in activity for Taxol vs. the 59, pp. 1238-1240. conjugates is at least between 3 and 4 logs. Thus, the Sharp reduction in the activity of the conjugates against many cell EXAMPLE 4

TAXOTERE

DHA?dicyclohexylcarbodiimide 4-dimethylaminopyridine

X,

Ph

O conjugate 3 US 2002/0010208A1 Jan. 24, 2002

0078 A Solution of Taxotere in methylene chloride under intermediate C in methylene chloride is mixed at ambient argon is mixed with 4-dimethylaminopyridine, dicy clo temperature under argon with 4 dimethylaminopyridine, hexylcarbodiimide, and DHA. The reaction mixture is dicyclohexylcarbodiimide, and DHA. The reaction mixture Stirred at ambient temperature. Radial chromatography of the residue is performed to produce Taxotere-DHA conju is stirred at ambient temperature, diluted with ether, passed gate 3. through celite, and concentrated. Radial chromatography of the residue is performed to produce intermediate D. A EXAMPLE 5 Solution of intermediate D in acctonitrile at 0° C. under

triethylsilyl chloride TAXOTERE He imidazole HO O

X NH O III IIH DHA?dicyclohexylcarbodiimide Ph--- E E O Her4-dimethylaminopyridine (CH3CH2)SiO HO O ÖAc

C O1. Ph

O

l aqueous HF X. NH O - D E Ph

CHCH-)-Si63 23

X.ul H

Ph

conjugate 4

0080 A solution of Taxotere in dimethylformamide is argon is mixed with 49% acqueous HF and the reaction mixed at ambient temperature under argon with imidazole and triethylsilyl chloride. The reaction mixture is stirred at mixture is stirred at the same temperature. After dilution ambient temperature, diluted with methylene chloride, with ether, the reaction mixture is washed with water, washed with water, Saturated acqueous sodium chloride, Saturated acqueous Sodium chloride, dried, and concentrated dried, and concentrated. Radial chromatography of the resi Radial chromatography of the residue is performed to pro due is performed to produce intermediate C. A Solution of duce Taxotere-DHA conjugate 4. US 2002/0010208A1 Jan. 24, 2002

EXAMPLE 6

tert-butyldimethylsilyl chloride TAXOTERE He imidazole

1 equivalent DHA dicyclohexylcarbodiimide 4-dimethylaminopyridine

E 1.

aqueous HF XuO H O Her

Ph O tert-CH0(CH3)2SiO HO

X,

Ph

H conjugate 4

0082) A solution of Taxotere in dimethylformamide is ture, diluted with ether, passed through celite, and concen mixed at ambient temperature under argon with imidazole trated. Radial chromatography of the residue is performed to and tert-butyly dimethylsilyl chloride. The reaction mixture produce intermediate F. (Intermediate H also is obtained and is stirred at ambient temperature, diluted with methylene used in Example 8 below) A solution of intermediate F in chloride, washed with water, Saturated acqueous Sodium acetonitrile at 0° C. under argon is mixed with aqueous HF chloride, dried, and concentrated. Radial chromatography of the residue is performed to produce intermediate E. A and the reaction mixture is stirred at the same temperature. solution of intermediate E in methylene chloride is mixed at After dilution with ether, the reaction mixture is washed with ambient temperature under argon with 4-dimethylamni water, Saturated aqueous Sodium chloride. dried. and con nopyridine, dicyclohexylcarbodiimide, and 1 equivalent of centrated Radial chromatographiy of the residue is per DHA. The reaction mixture is stirred at ambient tempera formed to produce Taxotere-DHA conjugate 4. US 2002/0010208A1 Jan. 24, 2002 10

EXAMPLE 7

tert-butyldimethylsilyl chloride TAXOTERE imidazole

HO O

X-l H O DHA?dicyclohexylcarbodiimide He w s 4-dimethylaminopyridine Ph Y Y Y Y O

E O

o o o o o O

O NH Q

Ph

0084. A solution of Taxotere in dimethylformamide is mixture is stirred at ambient temperature, diluted with ether, mixed at ambient temperature under argon with imidazole passed through celite, and concentrated. Radial chromatog and tert-butyly dimethylsilyl chloride. The reaction mixture raphy of the residue is performed to produce intermediate G. is stirred at ambient temperature, diluted with methylene A solution of intermediate G in acetonitrile at 0° C. under chloride, washed with water. Saturated acqueous Sodium argon is mixed with aqueous HF and the reaction mixture is chloride, dried, and concentrated. Radial chromatography of Stirred at the same temperature. After dilution with ether, the the residue is performed to produce intermediate E. A reaction mixture is washed with water, Saturated aqueous solution of intermediate E in methylene chloride is mixed at Sodium chloride, dried, and concentrated. Radial chroma ambient temperature under argon with 4-dimethylaminopy tography of the residue is performed to produce Taxotere ridine, dicyclohexylcarbodiimide, and DHA. The reaction DHA conjugate 5. US 2002/0010208A1 Jan. 24, 2002

EXAMPLE 8

tert-butyldimethylsilyl chloride TAXOTERE imidazole

1 equivalent DHA dicyclohexylcarbodiimide 4-dimethylaminopyridine

E

HO 9 O

aqueous HF He

ter 4 C 3 Si HO

X

Ph lul H conjugate 6

0.086 A solution of taxotere in dimethylformamide is and the reaction mixture is stirred at the same temperature. mixed at ambient temperature under argon with imidazole After dilution with ether, the reaction mixture is washed with and tert-butyly dimethylsilyl chloride. The reaction mixture water, Saturated aqueous Sodium chloride, dried, and con is stinted at ambient temperature, diluted with methylene centrated. Radial chromatography of the residue is per chloride, washed with water, Saturated acqueous Sodium formed to produce Taxotere-DHA conjugate 6. chloride, dried, and concentrated. Radial chromatography of the residue is performed to produce intermediate E. A 0087 DHA may be conjugated to virtually any drug solution of intermediate E in methylene chloride is mixed at compound or diagnostic agent and used according to the ambient temperature under argon with 4-dimethylaminopy methods of the present invention So long as the pharmaceu ridine, diyclohexylcarbodiimide, and 1 equivalent of DHA. tical agent has a use outside of the central nervous System. The reaction mixture is stirred at ambient temperature, Pharmaceutical agents include the following categories and diluted with ether, passed through celite, and concentrated. Specific examples. It is not intended that the category be Radial chromatography of the residue is performed to pro limited by the specific examples. Those of ordinary skill in duce intermediate H (and intermediate F which was used the art will be able to identify readily those pharmaceutical above on Example 6. A solution of intermediate H in agents that have utility outside of the central nervous System. acetonitrite at 0° C. under argon is mixed with aqueous HF Those of ordinary skill in the art will recognize also numer US 2002/0010208A1 Jan. 24, 2002 ous other compounds that fall within the categories and that ; Fenoprofen ; Citrate; Floc are useful according to the invention. tafenine; Flufenisal; Flunixin; Flunixin Meglumine; Flupir tine Maleate; FluproduaZone; Fluradoline Hydrochloride; 0088 Adrenergic: ; Mesylate; ; Hydrochloride; Ibufenac; Hydrochloride; Tartrate; Indoprofen; , ; Hydrochloride; Hydrochloride; Tromethamine; Letimide Hydrochloride; Levomethadyl Dipivefrin; Doparnine Hydrochloride; Sulfate; ; Levomethadyl Acetate Hydrochloride; Levonant Epinephrine; Epinephrine Bitartrate; Epinephryl Borate; radol Hydrochloride; Tartrate; Lofemizole Esprbquin Hydrochloride; Hydrochloride; Hydrochloride; Oxalate; Lorcinadol; Lornoxi Hydroxyamphetamine Hydrobromide; Levonordefrin; cam; Mlagnesium Salicylate; ; Sulfate; Bitartrate; Metizoline Hydrochloride; Meperidine Hydrochloride; Hydrochloride; Hydrochloride; Norepineph Hydrochloride; Hydrochloride; Methadyl rine Bitartrate; ; Hydrochlo Acetate; Methopholine; Methotrimeprazine; Metkephamid ride; Hydrochloride; Acetate; Mimbane Hydrochloride; Hydrochlo Hydrochloride; Phenylpropanolamine Polistirex, ride; Molinazone; Sulfate; ; Hydrochloride; ; Hydro Hydrochloride; Hydrochloride; chloride; Tetrahydrozoline Hydrochloride; Trarnazoline Hydrochloride; Namoxyrate; Nantradol Hydrochloride; Hydrochloride; Hydrochloride. ; Naproxen Sodium; Naproxol; Hydro 0089 Adrenocortical steroid: ; Desoxycor chloride; Hydrochloride; ticosterone Acetate; DeSoxycorticosterone Pivalate; Dexam Hydrochloride; Hydrochloride; Octazamide; ethasone Acetate, Acetate, ; Olvanil; Fumarate; ; Oxycodone Hemisuccinate; Metbylprednisolone Hydrochloride; Oxycodone Terephthalate; Hemisuccinate; ; ; Hydrochloride; Pemedolac, ; ; Acetate, . Pentazocine Hydrochloride; Pentazocine Lactate, Hydrochloride; Phenyramidol Hydrochlo 0090 Adrenocortical suppressant: ; ride; Hydrochloride; Pinadoline; Pirfenidone; . Olamine; Maleate; 0091 Alcohol deterrent: . Hydrochloride; Hydrochloride; Fuma rate; Propoxyphene Hydrochloride; Propoxyphene Napsy 0092 Aldosterone antagonist: Canrenoate Potassium; late; ; Proxazole Citrate; Tartrate; ; ; ; Prorenoate Pyrroliphene Hydrochloride; Hydrochloride; Potassium, . Salcolex; Salethamide Maleate; ; Salicylate 0.093 Amino acid: ; ; Meglumine; ; Sodium Salicylate; Hydrochloride; Cystine; ; Isoleucine; ; Mesylate; . Sufentanil Citrate; Talmetacin; Talni ; Lysine Acetate; Lysine Hydrochloride, ; flumate; Talosalate; Tazadolene Succinate; Tebufelone; ; ; ; ; ; Tetrydamine; Tifurac Sodium; Hydrochloride; ; Valine. Tiopinac; Mesylate; Trarnadol Hydrochloride; Hydrochloride; Trolamine; Veradoline Hydro 0094) Ammonia detoxicant: Arginine: Arginine chloride; Verilopam Hydrochloride; ; Glutamate, Arginine Hydrochloride. Mesylate; Hydrochloride; Mesylate; 0.095 Anabolic: Dipropionate; ; Sodium, Zucapsaicin. Undecylenate; ; ; Ethyl 0098 Androgen: ; ; Meth estrenol; Methenolone Acetate; Methenolone Enanthate; yltestosterone; Decanoate; Nandrolone Phen ; Nandrolone Cyclotate; Norbolethone; Pizoty propionate; Acetate; ; line; ; Acetate; ; . ; ; ; ; Test osterone Cypionate, , Testosterone 0096 Analeptic: . Ketolaurate; Testosterone Phenylacetate; Testosterone Pro 0097 : Acetaminophen; Hydrochlo pionate; Acetate. ride; Aminobenzoate Potassium; Aminobenzoate Sodium; Anidoxime; ; Anileridine Hydrochloride; Anilo 0099 Anesthesia, adjunct to: . pam Hydrochloride; Anirolac, Antipyrine, ; Benox 0100 Anesthetic: ; Benoximate Hydrochloride; aprofen; Hydrochloride; Biciifadine Hydro ; Biphenamine Hydrochloride; chloride; Hydrochloride; Maleate; Hydrochloride; ; Butamben Picrate; Chlorop Sodium; Hydrochloride; Butace rocaine Hydrochloride; ; Cocaine Hydrochloride; tin; Butixirate; ; Butorphanol Tartrate; Carbam , , Dexivacaine, Diarnocaine aZepine, Carbaspirin Calcium; Carbiphene Hydrochloride; Cyclamate; Dibucaine; Dibucaine Hydrochloride; Dyclo Citrate; Succinate; Cirarnadol; Cira nine Hydrochloride; ; Ether; Ethyl Chloride; Eti madol Hydrochloride; Clonixeril; Clonixin; ; docaine; Hydrochloride; Euprocin Hydrochlo Codeine ; Codeine Sulfate; Conorphone Hydro ride; ; ; Isobutamben; ; chloride; ; Hydrochloride; Dex Hydrochloride; Levoxadrol Hydrochloride; pemedolac, ; ; Bitar ; Lidocaine Hydrochloride; Hydro trate; Dimefadane; Dipyrone; Hydrochloride; chloride; Sodium; ; Mida Drinidene; Hydrochloride; Epirizole; Zolam Hydrochloride; Maleate; ; Tartrate; Ethoxazene Hydrochloride; Etofenamate; Eugenbl; ; Norflurane; ; Oxethazaine; Phen US 2002/0010208A1 Jan. 24, 2002 cyclidine Hydrochloride; Pramnoxine Hydrochloride; Hydrochloride; ; Timolol Maleate; Tipre Hydrochloride; Hydrochloride; Pro nolol Hydrochloride; Tolarnolol; Hydrochloride. panidid; Proparacaine Hydrochloride; ; Pro 0109 Anti-allergic: ; ; poxycaine Hydrochloride, Pyrrocaine, ; Hydrochloride; Eclazolast; Minocromil; Nedocromil; Rodocaine; ; Salicyl Alcohol; ; Teflu Nedocromil Calcium; Nedocromil Sodium; Nivinmedone rane; ; Tetracaine Hydrochloride; ; Sodium; Pemirolast Potassium; Pentigetide; Pirquinozol; Thiamylal Sodium; Thiopental Sodium; Tiletarnine Hydro Poisonoak Extract; Probicromil Calcium; ProXicromil, chloride; Hydrochloride. Repirinast; Tetrazolast Meglumine; Thiazinamium Chlo 0101 compounds including . ride; Tiacrilast; Tiacrilast Sodium; Tiprinast Meglumine; Tixanox. 0102) Anorexic: -Amphecloral; Chlorphenter mine Hydrochloride; ; Hydrochlo 0110 Anti-amebic: Berythromycin; Bialamicol Hydro ride; Diethylpropion Hydrochloride; Hydro chloride; ; Chloroquine Hydrochloride; Chloro chloride; , , , Levamfetamine quine Phosphate; Clamoxyquin Hydrochloride, , Succinate; ; Hydrochloride; Phenme Emetine Hydrochloride; Iodoquinol; Sulfate; trazine Hydrochloride; ; Hydro Quinfamide; Symetine Hydrochloride; Teclozan; Tetracy chloride. cline; Hydrochloride. 0111 Anti-androgen: ; ; Cyproter 0103) Antagonist: ; Atosiban; ; one Acetate; Acetate, ; ; , Cimetidine Hydrochloride; Male . ate; Detirelix Acetate; ; Donetidine; Etintidine Hydrochloride; , Hydrochloride; 0112 Anti-anemic: Epoetin Alfa; Epoetin Beta; Ferrous ; Acetate, Icotidine, , Metiaa Sulfate, Dried; Leucovorin Calcium. mide; Nadide; ; Nalmexone Hydrochloride; 0113 Anti-anginal: Besylate; Amlodipine Hydrochloride; ; ; Oxilor Maleate; Hydrochloride; Hydrochlo phan; Hydrochloride; Oxmetidine Mesylate; ride; Butoprozine Hydrochloride; ; Cinepazet Mesylate; ; Ranitidine Bismuth Cit Maleate; Succinate; ; rate; Ranitidine Hydrochloride; ; Teludipine Maleate; ; Hydrochloride; Tosifen; Hydrochloride; Tiapamil Hydrochloride; Tiotidine; Hydrochloride. Vapi.prost Hydrochloride; Zaltidine Hydrochloride. 0114 Anti-anxiety agent: Hydrochloride; 0104 Anterior pituitary activator: . ; MeSylate; ; ; Hydrochloride; Mirisetron Maleate; ; 0105 Anterior pituitary suppressant: Danazol. Hydrochloride; ; Pancopride; Pazi 0106 Anthelmintic: Albendazole; Anthelmycin; Bro naclone, Hydrochloride; Citrate; moxanide; Bunamidine Hydrochloride; Butonate; Cam Hydrochloride. Anti-arthritic: Lodelaben. bendazole; Carbantel Lauryl Sulfate; Clioxanide; Closantel; 0115) Anti-asthmatic: Ablukast; Ablukast Sodium; Cyclobendazole; Dichlorvos; Citrate; AZelastine Hydrochloride; Bunaprolast; Cinalukast, Dribendazole; Dymanthine Hydrochloride; Etibendazole; Cromnitrile Sodium; Cromolyn Sodium; Enofelast; Isamox ; Furodazole, Hexylresorcinol; Mebendazole; ole; Fumarate; Levcromakalim; Lodoxamide Tartrate; Niclosamide; Nitramisole Hydrochloride; Ethyl; Lodoxamide Tromethamine; Montelukast Sodium; Nitrodan; Oxantel Pamoate, Oxfendazole; Oxibendazole; Ontazolast; Oxarbazole; ; Piriprost; Piriprost Parbendazole; Piperamide Maleate; ; Piperazine Potassium; ; Pobilukast Edamine; Quazolast; Repi Citrate; Piperazine Edetate Calcium; Proclonol; rinast; Ritolukast, Sulukast, TetraZolast Meglumine; Tiara Pamoate; Pyrantel Tartrate; Pyrvinium Pamoate; Rafox mide Hydrochloride; Tibenelast Sodium; Tomelukast; Tra anide; Stilbazium Iodide; Tetramisole Hydrochloride; Thia nilast; Verlukast; Verofylline; Zarirlukast. bendazole; Ticarbodine; Tioxidazole; Triclofenol Pipera Zine; Vincofos, Zilantel. 0116. Anti-atherosclerotic: Mifobate; Timefuronc. 0107 Anti-acne: Adapalene; Salnacedin; 0117 Antibacterial: Acedapsone; Acetosulfone Sodium; Acetate. Alamecin; Alexidine, Amdinocillin; Amdinocillin Pivoxil, Amicycline; Amifloxacin; Amifloxacin MeSylate; Amika 0108 Anti-adrenergic: ; Hydro cin; Amikacin Sulfate; AminoSalicylic acid; chloride; , Tosylate; Bunolol Hydrochlo Sodium; ; Amphomycin; Ampicillin; Ampicillin ride; Hydrochloride; Hydrochloride; Sodium; Apalcillin Sodium; Apramycin; ASpartocin, Astro Hydrochloride; Hydrochloride; Dex micin Sulfate; AVillamycin; AVoparcin, Azithromycin; Hydrochloride; Hydrochloride; Azlocillin; Azlocillin Sodium; Bacampicillin Hydrochlo Mesylate; Dilevalol Hydrochloride; ride; Bacitracin; Bacitracin Methylene Disalicylate; Baci Esmolol Hydrochloride; Hydrochloride; Fen tracin , Bambermycins, Benzoylpas Calcium, Beryth spiride Hydrochloride; Sulfate; Hydro romycin; Betamicin Sulfate; Biapenem; Biniramycin; chloride; Hydrochloride; Biphenamine Hydrochloride; Bispyrithione Magsulfex; Hydrochloride; Metalol Hydrochloride; Metoprolol; Meto Butikacin; Butirosin Sulfate; Capreomycin Sulfate; Carba prolol Tartrate; ; Sulfate; Sul ; Carbenicillin Disodium; Carbenicillin Indanyl Sodium; fate; Mesylate; ; Propranolol Hydro Carbenicillin Phenyl Sodium; Carbenicillin Potassium; chloride; Proroxan Hydrochloride; Solypertine Tartrate; Carumonam Sodium; Cefaclor, Cefadroxil, Cefamandole; US 2002/0010208A1 Jan. 24, 2002

Cefamandole Nafate; Cefamandole Sodium; Cefaparole; Ormetoprim; Oxacillin Sodium; Oximonam; Oximonam Cefatrizine; Cefazaflur Sodium; Cefazolin; Cefazolin Sodium; ; ; Oxytetracycline Sodium; Cefbuperazone; Cefdinir; Cefepime; Cefepime Calcium; Oxytetracycline Hydrochloride; Paldimycin; Hydrochloride; Cefetecol; Cefixime; Cefnmenoxime Hydro Parachlorophenol; Paulomycin; Pefloxacin; Pefloxacin chloride; Cefnmetazole; Cefnmnetazole Sodium; Cefonicid Mesylate; Penamecillin; G BenZathine; Penicillin Monosodium; Cefonicid Sodium; Cefoperazone Sodium; G Potassium; Penicillin G Procaine; Penicillin G Sodium; Ceforanide; Cefotaxime Sodium; Cefotetan; Cefotetan Penicillin V; Penicillin V BenZathine; Penicillin V Hydrab Disodium; Cefotiam Hydrochloride; Cefoxitin; Cefoxitin amine; Penicillin V Potassium; Pentizidone Sodium; Phenyl Sodium; Ce?pimizole; Ce?pimizole Sodium; Ce?piramide; Aminosalicylate; Piperacillin Sodium; Pirbenicillin Sodium; Ce?piramide Sodium; Ce?pirome Sulfate; Cefpodoxime Piridicillin Sodium; Pirlimycin Hydrochloride; Pivampicil Proxetil, Cefprozil; Cefroxadine; Cefsulodin Sodium; lin Hydrochloride; Pivampicillin Pamoate; Pivampicillin Ceftazidime; Ceftibuten; Ceftizoxime Sodium; Ceftriaxone Probenate; Sulfate; Porfiromycin; Propikacin; Sodium; Cefuiroxime; Cefuroxime Axetil, Cefuroxime Piv PyraZinamide, Pyrithione Zinc, Quindecamine Acetate; oxetil, Cefuroxime Sodium; Cephacetrile Sodium; Cephal Quinupristin, Racephenicol; Ramoplanin; Ranimycin; Relo exin; Cephalexin Hydrochloride; Cephaloglycin; Cephalo mycin; Repromicin; Rifabutin; Rifametane; Rifamexil; ridine; Cephalothin Sodium; Cephapirin Sodium; Rifamide; Rifampin; Rifapentine; ; Rolitetracy Cephradine; Cetocycline Hydrochloride; Cetophenicol; cline, Rolitetracycline Nitrate; Rosaramicin; Rosaramicin ; Chloramphenicol Palmitate; Chloram Butyrate; Rosaramicin Propionate; Rosaramicin Sodium phenicol Pantothenate Complex; Chloramphenicol Sodiun Phosphate, Rosaramicin Stearate; ROSoxacin; RoxarSone; Succinate; Phosphanilate; ; ; Sancycline; Sanfeltrinem Sodium; Sarmox Bisulfate; Chlortetracycline Hydrochlo icillin, Sarpicillin; Scopafungin; Sisomicin; Sisomicin Sul ride; Cinoxacin; ; Ciprofloxacin Hydrochlo fate, Sparfloxacin; Spectinomycin Hydrochloride; Spiramy ride; Cirolemycin; ; Clinafloxacin Hydro cin; Stallimycin Hydrochloride; Steffimycin; chloride; ; Clindamycin Hydrochloride; Sulfate; Streptonicozid; Sulfabenz, Sulfabenzamide; Sulfac Clindamycin Palmitate Hydrochloride; Clindamycin Phos etamide; Sulfacetamide Sodium; Sulfacytine; Sulfadiazine; phate; Clofazimine; Cloxacillin BenZathine; Cloxacillin Sulfadiazine Sodium; Sulfadoxine, Sulfalene; Sulfamera Sodium; Cloxyquin; Colistimethate Sodium; Sul Zine, Sulfameter, Sulfamethazine, Sulfamethizole; Sul fate, Coumermycin; Coumermycin Sodium; Cyclacillin; famethoxazole; Sulfamonomethoxine, Sulfamoxole, Sulfa ; Dalfopristin; DapSone; Daptomycin; Demeclo nilate Zinc, Sulfanitran; SulfaSalazine, SulfaSomizole; cycline; Hydrochloride; Demecycline; Sulfathiazole; Sulfazamet; Sulfisoxazole; Sulfisoxazole Denofuingin; Diaveridine; ; Dicloxacillin Acetyl; Sulfisoxazole Diolamine; Sulfomyxin; Sulopenem; Sodium; Dihydrostreptomycin Sulfate; Dipyrithione; Sultamicillin; Suncillin Sodium; Talampicillin Hydrochlo Dirithromycin; ; Doxycycline Calcium; Doxy ride; Teicoplanin; Temafloxacin Hydrochloride; Temocillin; cycline Fosfatex; Doxycycline Hyclate; Droxacin Sodium; Tetracycline; Tetracycline Hydrochloride Tetracycline Phos Enoxacin; Epicillin; Epitetracycline Hydrochloride; Eryth phate Complex; Tetroxoprim; ; Thiphencillin romycin; Erythromycin Acistrate; Erythromycin Estolate; Potassium; Ticarcillin Cresyl Sodium; Ticarcillin Disodium; Erythromycin EthylSuccinate; Erythromycin Gluceptate; Ticarcillin Monosodium; Ticlatone; Tiodonium Chloride; Erythromycin Lactobionate; Erythromycin Propionate; Tobramycin; Tobramycin Sulfate; Tosufloxacin; Trimetho Erythromycin Stearate; Ethambutol Hydrochloride; prim; Trimethoprim Sulfate; Trisulfapyrimidines; Trolean Ethionamide; Fleroxacin; Floxacillin; Fludalanine; Flume domycin; Trospectomycin Sulfate; Tyrothricin; Vancomy quine; Fosfomycin; Fosfomycin Tromethamine; Fumoxicil cin; Hydrochloride; Virginiamycin; lin; Furazolium Chloride; Furazolium Tartrate; Fusidate Zorbamycin. Sodium; Fusidic Acid, Gentamicin Sulfate; Gloximonam; Gramicidin; ; ; Hetacillin Potassium; 0118 Anticholelithic: Monoctanoin. Hexedine, Ibafloxacin; ; , Iseparnicin; 0119) Anticholelithogenic: Chenodiol; Ursodiol. ; Josamycin; Kanamycin Sulfate; Kitasamycin; Levofuraltadone; Levopropylcillin Potassium; Lexithromy 0120 Anticholinergic: Alverinc Citrate; Anisotropine cin; Lincomycin; Lincomycin Hydrochloride; Lomefloxa Methylbromide; ; Atropine Oxide Hydrochloride; cin; Lomefloxacin Hydrochloride; Lomefloxacin Mesylate; Atropine Sulfate; Belladonna; Benapryzine Hydrochloride; Loracarbef, Mafenide; Meclocycline; Meclocycline Sul Benzetimide Hydrochloride; Benzilonium ; fosalicylate; Megalomicin Potassium Phosphate; Mequidox; ; Biperiden Hydrochloride; Biperiden Lactate; Cli Meropenem; Methacycline; Methacycline Hydrochloride; dinium Bromide; Hydrochloride; Dexetim Methenamine; Methenamine Hippurate; Methenamine ide; Dicyclomine Hydrochloride; Hydrochlo Mandelate; Methicillin Sodium; Metioprim; Metronidazole ride; Domazoline Fumarate; Elantrine; Elucaine; Hydrochloride; Metronidazole Phosphate; Mezlocillin; Ethybenztropine; Eucatropine Hydrochloride; Glycopyrro Mezlocillin Sodium; ; Minocycline Hydrochlo late; Heteronium Bromide; Hydrobromide; ride; Mirincamycin Hydrochloride; Monensin; Monensin Homatropine Methylbromide; Hyoscyamine; Hyoscyamine Sodiumr, Sodium; Nalidixate Sodium; Nalidixic Hydrobromide; Hyoscyamine Sulfate; Iodide; Acid; Natamnycin; Nebramycin; Palmitate; Neo Bromide; Nitrate; Meto mycin Sulfate; Neomycin Undecylenate; Netilmicin Sulfate; quizine; Chloride; Parapenzolate Bromide; Pen Neutramycin; Nifuradene; Nifuraldezone; ; Nifu tapiperium Methylsulfate; Phencarbamide; Methyl ratrone, Nifurdazil; Nifurimide; Nifurpirinol; sulfate; ; ; Propenzolate Nifurcquinazol; Nifurthiazole; Nitrocycline; Nitrofirantoin; Hydrochloride; Hydrobromide; Tematropium Nitromide; Norfloxacin; Novobiocin Sodium; ; Methylsulfate; Tiquinamide Hydrochloride; US 2002/0010208A1 Jan. 24, 2002

Hydrochloride; Toquizine; Triampyzine Sulfate; Trihex tyline Hydrochloride; Maleate; Rolicyprine; yphenidyl Hydrochloride; Tropicamnide. Hydrochloride; Hydrochloride; Sibutramine Hydrochloride; ; ; Tametra 0121 Anticoagulant: Ancrod; Anticoagulant Citrate Dex line Hydrochloride; Fumarate; trose Solution; Anticoagulant Citrate Phosphate Dextrose Hydrochloride; Thiazesim Hydrochloride; ; Solution; Anticoagulant Citrate Phosphale Dex Tomoxetine Hydrochloride; Hydrochloride; trose Solution; Anticoagulant Heparin Solution; Anticoagul Trebenzomine Hydrochloride; ; Trimipramine lant Sodium Citrate Solution; Ardeparin Sodium; Bivaliru Maleate; Hydrochloride; Hydro din; Bromindione; Dalteparin Sodium; Desirudin; chloride; Zimeldine Hydrochloride; . Dicumarol; Heparin Calcium; Heparin Sodium; Lyapolate Sodium; Nafamostat Mesylate; Phenprocoumon; Tinzaparin 0.125 Antidiabetic: Acetohexamide; Buformin; Butox Sodium; Warfarin Sodium. amine Hydrochloride; Camiglibose, Chlorpropamide; Cigli tazone; Englitazone Sodium; Etoformin Hydrochloride; 0122) Anticoccidal: Maduramicin. Gliamilide; Glibomuride; Glicetanile Sodium; Gliflumide; 0123 Anticonvulsant: Albutoin; Ameltolide; Atolide; Glipizide, ; Glyburide; Glyhexamide; Glymidine Buramate; , Cinromide, Citenamide, Clon Sodium; Glyoctamide, Glyparamide; Insulin; Insulin, azepam, Cyheptamide, DeZinamide; Dimethadione; Dival Dalanated; Insulin Human; Insulin Human, Isophane; Insu proex Sodium; ; ; ; Flu lin Human Zinc, Insulin Human Zinc, Extended; Insulin, razepam Hydrochloride; Fluzinamide; Isophane; , Insulin, Neutral; Insulin Zinc, Sodium; , Ilepcimide, ; Insulin Zinc, Extended; Insulin Zinc, Prompt; Linogliride; Sulfate; ; Mephobarbital; Methetoin; MethSux Linogliride Fumarate; ; Methyl Palmoxirate; Pal imide; Hydrochloride; Nabazenil; Nafimidone moxirate Sodium; Pioglitazone Hydrochloride; Pirogliride Hydrochloride; ; ; ; Tartrate; Proinsulin Human; Seglitide Acetate; Tolazamide; Phenobarbital Sodiumr; ; ; Pheny Tolbutamide; Tolpyrramide; ; Zopolrestat. toin Sodium; ; ; Ralitoline; Remace 0.126 Antidiarrheal: Rolgamidine, Diphenoxylate hydro mide Hydrochloride; Ropizine; ; ; chloride (Lomotil), Metronidazole (Flagyl), Methylpred Sulthiame; Thiopental Sodiumr; Hydrochloride; nisolone (Medrol), Sulfasalazine (AZulfidine). ; ; Sodium; Valproic Acid; Vigabatrin; Zoniclezole Hydrochloride; . 0127. Antidiuretic: Argipressin Tannate; Desmopressin Acetate, Lypressin. 0.124 Antidepressant: Adatanserin Hydrochloride; Adi naZolarn, MeSylate, ; Aletamine 0128 Antidote: ; Edrophonium Chloride; Hydrochloride; Hydrochloride; Fomepizole; LeucoVorin Calcium; LevoleucoVorin Cal Hydrochloride, , Maleate, AZaloxan cium; ; Protamine Sulfate. Fumarate, , Hydrochloride; Bipen 0129. Antidyskinetic: Hydrochloride. amol Hydrochloride; Hydrochloride; Butacetin; Hydrochloride; ; ; 0.130 Anti-emetic: Hydrochloride; Batano ; Hydrochloride; Mesy pride Hydrochloride; ; ; Chlor late; Clodazon Hydrochloride; Clornipramine Hydrochlo ; Hydrochloride; ; ride; Fumarate; Cyclindole; Hydro Hydrochloride; ; Diphenidol; chloride; Cyprolidol Hydrochloride; Cyproximide; Diphenidol Hydrochloride; Diphenidol Pamoate; Dolas Tosylate; Hydrochloride; Dazadrol etron Mesylate; ; ; Fludorex; Flurn Maleate; Dazepinil Hydrochloride; Desiprarnine Hydro eridone; Galdansetron Hydrochloride; ; Granis chloride; Dexamisole; Deximafen; Hydrochlo etron Hydrochloride; Lurosetron Mesylate; ride; Dioxadrol Hydrochloride; Dothiepin Hydrochloride; Hydrochloride; Metoclopramide Hydrochloride; Metopi Hydrochloride; Hydrochloride; Eclan mazine; Ondansetron Hydrochloride; Pancopride; Prochlo amine Maleate; Encyprate; Hydrochloride; rperazine, Edisylate; Prochlorperazine Fantridone Hydrochloride; Fehnmetozole Hydrochloride; Maleate; Hydrochloride; ; ; Fumarate; Hydro Thiethylperazine Malate; Thiethylperazine Maleate; Tri chloride; ; Fluoxetine Hydrochloride; methobenzamide Hydrochloride; Hydrochloride. Hydrochloride; Gamfexine; Guanoxyfen Sulfate; Imafen 0131) Anti-epileptic: ; ; . Hydrochloride; Hydrochloride; Hydrochloride; Hydrochloride; 0132) Anti-estrogen: Clometherone; Delmadinone Hydrochloride; ; ; Ketipramine Acetate; Hydrochloride; Citrate; Fumarate, Hydrochloride; ; Hydrochloride; Citrate; ; Maprotiline Hydrochloride; Hydro Citrate; Mesylate. chloride; Milacemide Hydrochloride; Hydro 0133) Antifibrinolytic: Nafarnostat Mesylate. chloride; ; ; Modaline Sulfate; Napacitadine Hydrochloride; Napamezole Hydrochloride; 0134) : Acrisorcin; Ambruticin; Amphotericin Hydrochloride; ; Nitrafudam Hydro B; AZaconazole, AZaSerine; Basifungin; Bifonazole, Biphe chloride; Maleate; Hydrochlo namine Hydrochloride; Bispyrithione Magsulfex; Buto ride; Phosphate; Hydrochloride; conazole Nitrate, Calcium Undecylenate, ; Car Hydrochloride; ; ; bol-Fuchsin; ; , Ciclopirox Olamine; Sulfate; Hydrochloride; Pizotyline; Cilofingin; Cisconazole; ; Cuprimyxin, Deno Hydrochloride; Hydrochloride; Protrip fungin; Dipyrithione; Doconazole; ; Econazole US 2002/0010208A1 Jan. 24, 2002

Nitrate; Enilconazole; Ethonam Nitrate; Hydrochloride; Diapamide; ; Dilevalol Hydro Nitrate; Filipin; Fluconazole; Flucytosine; Fungimycin; chloride; Malate; Ditekiren; Mesylate; ; Hamycin; ISOconazole, ; Kalafun , Enalapril Maleate, Enalaprilat, Enalkiren; gin; , Lomofungin; Lydimycin; ; Endralazine MeSylate; Epithiazide, EproSartan; EproSartaln ; Miconazole Nitrate; Monensin; Monensin Mesylate; Mesylate; Flavodilol Maleate; Flo Sodium; Naftifme Hydrochloride; Neomycin Undecylenate; rdipine, ; Fosinopril Sodium; Fosinoprilat, Gua Nifuratel; Nifurmerone; Nitralairine Hydrochloride; Nysta nabenz, . Acetate; Guanacline Sulfate; tin; Octanoic Acid, Orconazole Nitrate; Sulfate; Guancydine; Monosulfate; Guanethi Nitrate; Oxifingin Hydrochloride; Parconazole Hydrochlo dine Sulfate; Hydrochloride; Guanisoquin Sul ride; Partricin; ; Proclonol; Pyrithione fate; Sulfate; Guanoctine Hydrochloride; Guan Zinc, Pyrrolnitrin; Rutamycin; Sanguinarium Chloride; oXabenz, Sulfate; Guanoxyfen Sulfate; Saperconazole, Scopafungin; Sulfide, Sineflingin; Hydrochloride; Hydralazine Polistirex; Sulconazole Nitrate; Terbinafine; ; Thiram; , ; ; Indolapril Ticlatone; ; Tolciclate; Tolindate; ; Hydrochloride; ; Indoramin Hydrochloride; Triacetin; Triafungin; Undecylenic Acid; Viridofulvin; Zinc Hydrochloride; ; Leniquinsin, Levcro Undecylenate; Zinoconazole Hydrochloride. makalim; Lisinopril, Hydrochloride; LOSartan 0135 Antiglaucoma agent: Alprenoxime Hydrochloride; Potassium; Losulazine Hydrochloride; Mebutarnate; ; Dapiprazole Hydrochloride; Dipivefrin Hydro Hydrochloride; ; Medroxalol chloride; Hydrochloride; ; Pirnabine. Hydrochloride; Methalthiazide; ; Methyl dopa; Methyldopate Hydrochloride; ; Metola 0.136 Antihemophilic: Antihemophilic Factor. Zone; Metoprolol Fumarate; Metoprolol Succinate; Mety 0.137 Antihemorrhagic: Poliglusam. rosine; ; Monatepil Maleate; ; 0138 Antihistaminic: ; Phos ; ; Ofornine; Hydrochlo phate, Astemizole, Maleate; Barmastine, Bromo ride; Pazoxide; Hydrochloride; Perindopril Erbu Hydrochloride; Male mine; Hydrochloride; ; Pivo ate; Maleate; Hydrochloride; pril; ; Hydrochloride; Primidolol; Chlorpheniramine Maleate; Chlorpheniramine Polistirex; Prizidilol Hydrochloride; Quinapril Hydrochloride; Quinap ; ; Clemastine Fumarate; Closirar rilat; Hydrochloride; Hydrochlo nine Aceturate; Cycliramine Maleate; Cyclizine, Cyprohep ride; Hydrochloride; Quinuclium Bromide; tadine Hydrochloride; Dexbrompheniramnine Maleate; Ramipril; Rauwolfia Serpentina; , Saprisartan Maleate; Dimethindene Maleate; Potassium; Saralasin Acetate; Sodium Nitroprusside; Sulfi Diphenhydramine Citrate; Diphenhydramine Hydrochlo malol Hydrochloride; Tasosartan; Teludipine Hydrochloride; ride; Dorastine Hydrochloride; Doxylaine Succinate; Ebas Temocapril Hydrochloride; Hydrochloride; Terla tine; Hydrochloride; ; kiren; ; Tiamenidine Hydrochloride; Tic Hydrochloride; Noberastine; Citrate; rynafen; ; ; Tipentosin Hydrochloride; Pyrabrom; Pyrilamine Maleate; Pyroxamine Maleate; ; Hydrochloride; Tri Rocastine Hydrochloride; Rotoxamine; Tazifylline Hydro methaphan Camsylate; Trimoxamine Hydrochloride; Tripa chloride; Temelastine; Telfenadine; Citrate; mide; ; Zankiren Hydrochloride; Zofenoprilat Tripelennamine Hydrochloride; Hydrochloride; Arginine. Zolamine Hydrochloride. 0.142 Antihypotensive: Hydrochloride; Mido 0139 Antihyperlipidemic: Cholestyramine Resin; Clofi drine Hydrochloride. brate; Hydrochloride; Crilvastatin; Dalvastatin; 0.143 Anti-infective: Difloxacin Hydrochloride; Lauryl Sodium; Sodium; ; Isoquinolinium Bromide; Moxalactam Disodium; Ornida Lecimibide; Lovastatin; ; Pravastatin Sodium; Probu zole; Pentisomicin; Sarafloxacin Hydrochloride; Protease col; ; Tiqueside; Xenbucin. inhibitors of HIV and other retroviruses; Integrase Inhibitors 0140 Antihyperlipoproteinemic: Acifran; Beloxamide; of HIV and other retroviruses; Cefaclor (Ceclor); Acyclovir ; Boxidine; Butoxamine Hydrochloride; Cetaben (Zovirax), Norfloxacin (Noroxin); Cefoxitin (Mefoxin); Sodium; ; Gemcadiol; Halofenate; Lifibrate; Cefuroxime axetil (Ceftin); Ciprofloxacin (Cipro). ; ; Pimetine Hydrochloride; Theofibrate; 0144 Anti-infective, topical: Alcohol; Aminacrine Tibric Acid, Treloxinate. Hydrochloride; : Bithionolate 0141 Antihypertensive: Hydrochloride; Alipa Sodium; Bromchlorenone; Carbamide Peroxide; Cetalko mide; Althiazide, Amiquinsin Hydrochloride, Amlodipine nium Chloride; Cetylpyridiniurn Chloride: Chlorhexidine BeSylate; Amlodipine Maleate; Anaritide Acetate; Hydrochloride; Clioquinol, ; Fenticlor; Maleate; Belfosdil; Bemitradine; Bendacalol Mesylate; Fludazonium Chloride; Fuchsin, Basic; ; Gen ; Benzthiazide, Betaxolol Hydrochlo tian Violet; Halquinols; : Per ride; Sulfate; Bevantolol Hydrochloride; oxide; Ichtharmol, Imidecyl , Iodine, Isopropyl Alco Biclodil Hydrochloride; ; Bisoprolol Fumarate; hol; Mafenide Acetate; Meralein Sodium; Mercufenol Hydrochloride; ; Buthiazide: Can Chloride; , Ammoniated; Methylbenzethonium doXatril; CandoXatrilat, Captopril; Carvedilol, Ceronapril; Chloride; ; ; Octenidine Hydro Sodium; ; CilaZapril; ; chloride; Oxychlorosene; Oxychlorosene Sodium; Parachlo Clonidine Hydrochloride; ; ; rophenol, Camphorated; ; Povi ; ; Debrisoquin Sulfate; Delapril done-Iodine; Sepazonium Chloride; Nitrate; US 2002/0010208A1 Jan. 24, 2002

Sulfadiazine, Silver; Symclosene; Thimerfonate Sodium; 0150 Antimitotic: Podofilox. Thimerosal: Troclosene Potassiun. 0151. Antimycotic: Amorolfine. 0145 Anti-inflammatory: Alclofenac; Dipropionate; Acetonide; Alpha Amylase; 0152 Antinauseant: Hydrochloride; Cyclizine , , Amfenac Sodium; Amiprilose Lactate; Naboctate Hydrochloride. Hydrochloride; Anakinra, Anirolac, AnitraZafen; ApaZone; Disodium; Bendazac, ; Benzy 0153 Antineoplastic: Acivicin; ; Acodazole damine Hydrochloride; Bromelains; Broperamole; Budes Hydrochloride, Acronine, Adozelesin; Aldesleukin; Altre onide, Carprofen, Cicloprofen; CintaZone, Cliprofen; Clo tamine; Ambomycin; Ametantrone Acetate; Aminoglute betasol Propionate; Butyrate; Clopirac, thimide, ; , Anthramycin; Asparagi Propionate; Cormethasone Acetate; Cortodox nase; ASperlin, , AZetepa, AZOtomycin; one; , , ; -Dexametha Batimastat; Benzodepa; ; Bisantrene Hydro Sone Dipropionate, Potassium; Diclofenac chloride; Bisnafide Dimesylate; Bizelesin; Sul Sodium; Diacetate; -Diflumidone Sodium; fate; Brequinar Sodium; Bropirimine; ; Cactinomy Diflunisal; ; Diftalone; ; cin, ; Caracemide, Carbetimer; ; ; Endrysone; Enlimomab Enolicam Sodium; ; Carubicin Hydrochloride; Carzelesin; Cedefin Epirizole; , Etofenamate; Felbinac; Fenamole; Fen gol; Chlorarnbucil; Cirolemycin; ; ; Cri bufen, Fenclofenac, Fenclorac, Fendosal, Fenpipalone, Fen Snatol MeSylate; , ; Dacarba tiazac, Flazalone, , , Flumizole; zine; ; Hydrochloride; Acetate; Flumixin; Flunixin Meglumine; Fluo ; DeXormaplatin, DeZaguanine, DeZaguanine cortin Butyl; Acetate; FluguaZone; Flurbi Mesylate; Diaziquone; Docetaxel; ; Doxorubi profen; Fluretofen; Propionate; Furaprofen; cin Hydrochloride; ; Droloxifene Citrate; Dro Furobufen; ; Halobetasol Propionate; Halopre moStanolone Propionate, DuaZomycin; Edatrexate, Eflo done Acetate, Ibufenac, ; Ibuprofen Aluminum; mithine Hydrochloride; ; Enloplatin; Ibuprofen Piconol; Ilonidap; Indomethacin; Indomethacin Enpromate; Epipropidine; Hydrochloride; Erbu Sodiumn; Indoprofen; Indoxole; Intrazole; lozole; Esorubicin Hydrochloride; ; Estramus Acetate; ISOXepac, , Ketoprofel, Lofemizole tine Phosphate Sodium; Etanidazole; Ethiodized Oil I 131; Hydrochloride, , Etabonate; ; Etoposide Phosphate; Etoprine; Meclofenamate Sodium; , Hydrochloride; Fazarabine; Fenretinide; , Flu Dibutyrate; Mefenamic Acid; Mesalamine; Meseclazone; darabine Phosphate, ; Flurocitabine; Fosqui Methylprednisolone Suleptanate; Morniflumate; Nabume done; Fostriecin Sodium; ; Gemcitabine Hydro tone; Naproxen; Naproxen Sodium; Naproxol; Nimazone; chloride; Au 198; Hydroxyurea; Sodium; Orgotein; Orpanoxin; , Hydrochloride; ; Ilmofosine; Interferon Alfa-2a; Oxyphenbutazone; Paranyline Hydrochloride; Pentosan Interferon Alfa-2b Interferon Alfa-n1; Interferon Alfa-n3; Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pir Interferon Beta-1a; Interferon Gamma-1b; I proplatin; Irino fenidone; PiroXicarn; Piroxicam Cinnamate; Piroxicam Ola tecan Hydrochloride; Lanreotide Acetate; ; Leu mine; Pirprofen; ; Prifelone; Prodolic Acid; Pro prolide Acetate, Liarozole Hydrochloride, Lometrexol quaZone; Proxazole; Proxazole Citrate; ; Sodium; ; Hydrochloride; Maso Romazarit; Salcolex, Salnacedin, Salsalate, Sanguinarium procol; Maytansine; Mechlorethamine Hydrochloride; Chloride; SeclaZone, Sermetacin; Sudoxicam, , Acetate; Acetate; ; ; Talmetacin; Talniflumate; Talosalate; Tebufelone; Menogaril; ; ; Methotrexate Tenidap; Tenidap Sodium, , TeSicam, Tesimide; Sodium; Metoprine; Meturedepa; Mitindomide; Mitocarcin; Tetrydamine; Tiopinac; Pivalate; ; Tol Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; metin Sodium; ; Triflumidate; Zidometacin; ; Hydrochloride; Mycophenolic Zomepirac Sodium. Acid, ; Nogalamycin; Ormaplatin, Oxisuran; Paclitaxel, , Peliomycin; Pentamustine, Peplo 0146 Antikeratinizing agent: Doretinel; Linarotene; Pel mycin Sulfate; Perfosfamide; ; Piposulfan; retin. Piroxantrone Hydrochloride; ; ; Por fimer Sodium; Porfiromycin; ; 0147 Antimalarial: Acedapsone; Hydro Hydrochloride; ; Puromycin Hydrochloride; chloride; Amquinate; Arteflene; Chloroquine; Chloroquine Pyrazofurin; Riboprine; Rogletimide; Safingol; Safingol Hydrochloride; Chloroquine Phosphate; Cycloguanil Pamo Hydrochloride; ; SimtraZene; Sparfosate Sodium; ate, Enpiroline Phosphate; Halofantrine Hydrochloride; SparSomycin; Spirogermanium Hydrochloride; Spiromus Sulfate; Hydrochloride; tine, Spiroplatin; Streptonigrin, Streptozocin, Menoctone; Mirincamycin Hydrochloride; Primaquine Chloride Sr 89; Sulofenur; Talisomycin; ; Taxoid; Phosphate; Pyrimethamine; Sulfate; Tebuduine. Tecogalan Sodium; , Teloxantrone Hydrochloride; 0148 Antimicrobial: Aztreonam; Chliorhexidine Glu ; ; Teroxirone; Testolactone; Thiami conate, Imidurea; Lycetamine, Nibroxane, PiraZmonam prine; Thioguanine; ; TiaZofuirin; Tirapazamine; Sodium; Propionic Acid; Pyrithione Sodium; Sanguinarium Hydrochloride; Toremifene Citrate; Trestolone Chloride; Tigemonam Dicholine. Acetate; Triciribine Phosphate; Trimetrexate; Trinmetrexate Glucuronate; Triptorelin; Tubulozole Hydrochloride; 0149 Antimigraine: Mesylate; Mustard; Uredepa; Vapreotide; ; Sul Hydrochloride; Maleate; Succi fate; Sulfate; Vindesline; Vindesline Sulfate; Vine nate, Maleate. pidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; US 2002/0010208A1 Jan. 24, 2002

Vinorelbine Tartrate; Vinrosidine Sulfate; Vinzolidine Sul lytic , maitansine; mannostatin A, marimastat; fate; Vorozole; Zeniplatin; Zinostatin; Hydrochlo masoprocol; maspin; ratrilysin inhibitors, matrix metallo ride. proteinase inhibitors, menogaril; merbarone; meterelin; 0154) Other anti-neoplastic compounds include: 20-epi methioninase; metoclopramide; MIF inhibitor; mifepris 1.25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; tone, miltefosine, mirimoStim, mismatched double Stranded aclarubicin; acylfulvene, adecypenol; adoZelesin; aldesleu RNA, , mitolactol, mitomycin analogues, kin; ALL-TKantagonists, altretanine; ambamustine, anidox; mitonafide; mitotoxin fibroblast growth factor-Saporin; amifostine; ; ; ainsacrine; mitoxantrone; mofarotene; molgramoStim; monoclonal anti ; anastroZole; andrographolide, angiogenesis body, human chorionic gonadotrophin, monophosphoryl inhibitors, antagonist D; antagonist G, antarelix; anti-dor A+myobacterium cell wall Sk, mopidamol, multiple Salizing morphogenetic protein-i, , prostatic drug resistance gene inhibitor, multiple tumor Suppressor carcinoma, ; antineoplaston; antisense oligo 1-based therapy; mustard anticancer agent; my caperoxide B; , aphidicolin glycinate, apoptosis gene modula mycobacterial cell wall extract; myriaporone, N-acetyldina tors, apoptosis regulators, apurinic acid, ara-CDP-DL line, N-Substituted , nafarelin, nagreStip; nalox PTBA, arginine deaminase, asulacrine, ; one-pentazocine, napavin, naphterpin, nartograstim; neda ; axinastatin 1; axinastatin 2; axinastatin 3; aza platin, nemorubicin; neridronic acid; neutral endopeptidase; Setron; azatoxin; azatyrosine, baccatin III derivatives, bal , nisamycin, modulators, nitroxide , batimastat, BCR/ABL antagonists, benzochlorins, antioxidant, nitrullyn, O6-benzylguanine; , oki benzoylstauroSporine; beta lactam derivatives, beta cenone, oligonucleotides; ; ondansetron; alethine; betaclamycin B; ; bFGF inhibitor; Ondansetron; oracin, oral cytokine inducer; Ormaplatin; bicalutamide, bisantrene, bisaZiridinylspermine; bisnafide; , , oxaunomycin; paclitaxel analogues, bistratene A, bizelesin; breflate; bropirirnine; budotitane; paclitaxel derivatives, palauamine, palmitoylrhizoxin; pam buthionine Sulfoximine, calcipotriol, calphostin C; camp idronic acid, panaxytriol; , parabactin; paZellip tothecin derivatives, canarypox IL-2, , carboxa tine, pegaspargase; peldesine, Sodium; mide-amino-triazole; ; CaRest M3; ; pentrozole; ; perfosfamide, perillyl CARN 700; cartilage derived inhibitor; carzelesin; casein alcohol; phenazinomycin; phenylacetate; phosphatase kinase inhibitors (ICOS), castanospermine; cecropin B; inhibitors, picibanil; pilocarpine hydrochloride, ; ; chlorins, chloroquinoxaline , cica piritrexim; placetin A; placetin B; plasminogen activator prost, cis-porphyrin, cladribine; analogues, clot inhibitor; platinum complex, platinum compounds, plati rimazole; collismycin A; collismycin B; combretastatin A4, num-triamine complex, ; porfiromycin; pro combretastatin analogue; conagenin, crambescidin 816; cri pyl bis-acridone; prostaglandin J2, proteasome inhibitors, Snatol; cryptophycin 8; cryptophycin A derivatives, curacin protein A-based immune modulator, protein kinase C inhibi A., cyclopentanthraquinones, cycloplatam, cypemycin; cyt tor, protein kinase C inhibitors, microalgal; protein tyrosine arabine ocfosfate, cytolytic factor; cytostatin, dacliximab, phosphatase inhibitors, phosphorylase decitabine; dehydrodidemnin B; deslorelin; dexifosfamide; inhibitors, purpurins, pyrazoloacridine, pyridoxylated deXraZoxane, deXVerapamil, diaziquone; didemnin B; didox; hemoglobin polyoxyethylene conjugate, raf antagonists, diethylnorspermine, dihydro-5-aZacytidine, dihydrotaxol, ; ; ras farnesyl protein transferase 9-, dioxamycin; diphenyl Spiromustine, docosanol; dolas inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine etron, , droloxifene, dronabinol; duocarmycin demethylated; rhenium Re 186 etidronate; rhizoxin; SA, ebSelen; ecomustine, edelfosine; edrecolomab, eflorni ribozymes, RII retinamide, rogletimide, rohitukine; thine; elemene; emitefur, epirubicin, ; estramus romurtide, roquinimex, rubiginone B 1; ruboxyl, Safingol; tine analogue; estrogen , estrogen antagonists; Saintopin; SarCN-U; Sarcophytol A, SargramoStim; Sidi 1. etanidazole, etoposide phosphate; , fadrozole; mimetics, Semustine, Senescence derived inhibitor 1; Sense fazarabine; fenretinide; filgrastim; , flavopiridol; oligonucleotides, Signal transduction inhibitors, Signal trans fleZelastine, fluiasterone, ; fluorodaunorunicin duction modulators, Single chain antigen binding protein; hydrochloride; forfenimex, ; fostriecin, fotemus sizofiran; Sobuzoxane, Sodium borocaptate, Sodium pheny tine, teXaphyrin, gallium nitrate, galocitabine; lacetate, Solverol, binding protein; Sonermin; ganirelix; gelatinase inhibitors, gemcitabine, Sparfosic acid; Spicamycin D; Spiromustine; Splenopentin; inhibitors, hepSulfam; heregulin; hexamethylene bisaceta Spongistatin 1; Squalamine; Stem cell inhibitor, Stem-cell mide; ; ibandronic acid; idarubicin; , division inhibitors; stipiamide; stromelysin inhibitors; sulfi idramantone, ilrnofoSine, illomastat, imidazoacridones, imi nosine; Superactive vasoactive intestinal antagonist; quimod, immunostimulant peptides; insulin-like growth fac Suradista; ; Swainsonine, Synthetic glycosaminogly tor-1 receptor inhibitor; interferon agonists, interferons, cans, tallimustine, tarnoxifen methiodide, tauromustine; taZ interleukins, iobenguane; iododoxorubicin; ipomeanol, 4-, arotene, tecogalan Sodium, tegafur, tellurapyrylium; telom ; iroplact, irSogladine, isobengaZole, isohomohali erase inhibitors, temoporfin, ; teniposide; condrin B; itasetron, jasplakinolide, kahalalide F, lamel tetrachlorodecaoxide, tetraZomine; thaliblastine; thalido larin-N triacetate, lanreotide; leinamycin; lenograstim; len mide; thiocoraline; thrombopoietin; thrombopoietin tinan Sulfate, leptolstatin; letrozole; leukemia inhibiting mimetic; thymalfasin; receptor agonist, thy factor; leukocyte alpha interferon; leuprolide--estrogen motrinan; thyroid Stimulating hormone, tin ethyl etiopurpu ; ; ; liarozole; linear rin; tirapazamine, titanocene dichloride; topotecan; topSen polyamine analogue, lipophilic disaccharide peptide; lipo tin, toremifene, totipotent Stem cell factor; translation philic platinum compounds, lisSoclinamide 7; lobaplatin; inhibitors, , triacetyluridine, triciribine, trimetrex lombricine, lometrexol; ; loSOXantrone; lovasta ate, triptorelin; ; ; tyrosine kinase tin, loxoribine; ; lutetium teXaphyrin, lySofylline; inhibitors; tyrphostins; UBC inhibitors; ; urogeni US 2002/0010208A1 Jan. 24, 2002 tal Sinus-derived growth inhibitory factor; urokinase recep zine Maleate; Carvotroline Hydrochloride; Chlorpromazine; tor antagonists, vapreotide; variolin B; Vector System, eryth Chlorpromazine Hydrochloride; ; Cin rocyte gene therapy; VelareSol, Veramine, Verdins, perene, Cintriamide; Clomacran Phosphate, ; verteporfm; , VinXaltine, Vitaxin; Vorozole; Zan ; Clopipazan Mesylate; Cloroperone Hydro oterone; Zeniplatin, Zilascorb, Zinostatin stimalamer. chloride; Clothiapine; Clothixamide Maleate; ; Cvclophenazine Hydrochloride; ; O155 Anti-cancer Supplementary Potentiating Agents: Hydrochloride; Fenimide; ; ; anti-depressant drugs (e.g., imipramine, Decanoate, Fluphenazine Enanthate; , amitryptyline, clornipramine, triripranine, Fluphenazine Hydrochloride; Fluspiperone; Fluspirlene; doxepin, nortriptyline, , amoxapine and mapro Flutroline; Hydrochloride; Halopemide; Halo tiline); non-tricyclic anti-depressant drugs (e.g., Sertraline, peridol; Decanoate, , Imidoline trazodone and ); Ca" antagonists (e.g., Verapar Hydrochloride; , Succinate; nil, , nitrendipine and ); Calmodulin ; Mesoridazine Besylate; ; Milenper inhibitors (e.g., , trifluoroperazine and clomi one; Milipertine; Hydrochloride; pramine); ; analogues (e.g., Hydrochloride; Neflumozide Hydrochloride; ; tamoxifen); antiarrhythmic drugs (e.g., ); antihy ; Oxiperomide; ; Pentiapine Maleate; pertensive drugs (e.g., reserpine); Thiol depleters (e.g., ; ; Hydrochloride; Pipam buthionine and Sulfoximine) and Multiple Drug Resistance perone, , Palmnitate, reducing agents Such as Cremaphor EL. The compounds of Hydrochloride; Prochlorperazine Edisylate; Prochlorpera the invention also can be administered with cytokines Such zine Maleate; Promazine Hydrochloride; ; as granulocyte colony Stimulating factor. Remoxipride Hydrochloride; Hydrochloride; 0156 Antineutropenic: Filgrastim; Lenograstim; Mol Seperidol Hydrochloride; ; ; Spiper gramoStim; RegramoStim; SargramoStim. one; ; Thioridazine Hydrochloride; Thiothix ene; Thiothixene Hydrochloride; Tioperidone Hydrochlo O157 Antiobsessional agent: Maleate. ride; Hydrochloride; 0158 Antiparasitic: Abamecttin; Clorsulon; . Hydrochloride; ; Triflu promazine; Triflupro 0159 Antiparkinsonian: Benztropine Mesylate; mazine Hydrochloride; Hydrochloride. Biperiden; Biperiden Hydrochloride; Biperiden Lactate; 0168 Antirheumatic: ; ; Bin Carmantadine, Hydrochloride; Dopamantine; darit; Lobenzarit Sodium; Phenylbutazone; Pirazolac, Pri Ethopropazine Hydrochloride; Lazabemnide; Levodopa; nomide Tromethamine; Seprilose. Lometraline Hydrochloride; Hydrochloride; Naxagolide Hydrochloride; Pareptide Sulfate; 0169. Antischistosomal: Becanthone Hydrochloride; Hydrochloride; Quinelorane Hydrochloride; Hycanthone; Hydrochloride; Niridazole; Hydrochloride; Selegiline Hydrochloride; ; Tri Oxamniquine; Pararosaniline Parnoate; Teroxalene Hydro hexyphenidyl Hydrochloride. chloride. 0160 Antiperistaltic: Difenoximide Hydrochloride; 0170 Antiseborrheic: ; Piroctone; Piroctone ; Diphenoxylate Hydrochloride; Fluperamide; Olamine; Resorcinol Monoacetate. Lidamidine Hydrochloride; Hydrochloride; 0171 Antisecretory: Arbaprostil; Deprostil; Fenoctimine Maletharner; Nufenoxole; . Sulfate; Octreotide, Octreotide Acetate; 0.161 Antipneumocystic: Atovaquone. Sodium; Rioprostil; Trimoprostil. 0162 Antiproliferative agent: Piritrexim Isethionate. 0172 Antispasmodic: Stilonium Iodide; Hydrochloride. 0163 Antiprostatic hypertrophy: Sitogluside. 0173 Antithrombotic: Anagrelide Hydrochloride; Biva 0164 Antiprotozoal: Amodiaquine; ; Bam lirudin; Dalteparin Sodium; Danaparoid Sodium; Dazoxiben nidazole; Carnidazole; Chlortetracycline Bisulfate; Chlo Hydrochloride; Efegatran Sulfate; Enoxaparin Sodium; rtetracycline Hydrochloride; Flubendazole; Flunidazole; Ifetroban; Ifetroban Sodium; Tinzaparin Sodium; Halofuginone Hydrobromide; Imidocarb Hydrochloride; Trifenagrel. Ipronidazole; Metronidazole; Misonidazole; Moxinidazole; NitarSone; Partricin; Puromycin; Puromycin Hydrochloride; 0.174 Antitussive: ; Butarnirate Citrate; Ronidazole; Sulnidazole; Tinidazole. Chlophedianol Hydrochloride; Codeine Polistirex; ; ; Dextromethorphan Hydro 0.165 Antipruritic: Hydrochloride; bromide; Dextromethorphan Polistirex, Ethyl ; ; Methdilazine Hydrochloride; Trimeprazine Guaiapate; Bitartrate; Hydrocodone Polis Tartrate. tireX; Napsylate, , Pemerid 0166 Antipsoriatic: Acitrelin; Anthralin; Azaribine; Cal Nitrate; Pipazethate; Suxemerid Sulfate. cipotriene; Cycloheximide, EnaZadrem Phosphate, Etreti 0.175 Anti-ulcerative: Aluminum; Cadex nate, Liarozole Fumarate, Lonapalene, Tepoxalin. omer Iodine; Hydrochloride; Enisoprost; Iso 0167 Antipsychotic: Maleate; Alente tiquimide, , Succinate, MisoproS mol Hydrobromide; Alpertine; ; Male tol; ; Nolinium Bromide; ; Pifarnine; ate; ; BenZindopyrine Hydrochloride; Brofbxine; Hydrochloride; Sodium; Remi ; Bromperidol Decanoate; Hydro prostol; Hydrochloride; ; chloride; ; Butaperazine Maleate; Carphena Sucrosofate Potassium; . US 2002/0010208A1 Jan. 24, 2002 20

0176 Anti-urolithic: ; Cysteamine Hydro Hydrochloride; Ipazilide Fumarate; Lorajrmine Hydrochlo chloride; Tricitrates. ride; Lorcainide Hydrochloride; Meobentine Sulfate; Mexi 0177 Antiviral: Acemannan; Acyclovir; Acyclovir letine Hydrochloride; Modecainide; Moricizine; Oxiramide; Sodium; Adefovir; Alovudine; Alvircept Sudotox; Amanta Pirmenol Hydrochloride; Pirolazamide; Pranolium Chlo dine Hydrochloride; Aranotin; Arildone; Mesy ride; Hydrochloride; Hydrochlo late; Avridine, Cidofovir; Cipamfylline; Cytarabine Hydro ride; Pyrinoline; Quindonium Bromide; Quinidine Glucon chloride; Mesylate; Desciclovir; Didanosine; ate; Quinidine Sulfate; Recainam Hydrochloride; Recainam Disoxaril; Edoxudine; Enviradene; Enviroxime; Famciclo Tosylate; Risotilide Hydrochloride; Ropitoin Hydrochlo vir; Famotine Hydrochloride; Fiacitabine; Fialuridine; Fosa ride; Sematilide Hydrochloride; Suricainide Maleate; rilate; Foscarnet Sodium; Fosfonet Sodium; Ganciclovir, ; Tocainide Hydrochloride; Transcainide. Ganciclovir Sodium; Idoxuridine; Kethoxal; Lamivudine; 0.184 Cardioprotectant: Dexrazoxane; Draflazine. Lobucavir; Memotine Hydrochloride; Methisazone; Nevi rapine; Penciclovir; Pirodavir; Ribavirin; 0185. Cardiotonic: Actodigin; Anrinone; Bemoradan; Hydrochloride; Saquinavir Mesylate; Somantadine Hydro Butopamine; CarbaZeran; CarSatrin Succinate; Deslanoside; chloride; Sorivudine; Statolon; Stavudine; Tilorone Hydro Digitalis, ; Digoxin; ; Dobutamine chloride; Trifluridine; Valacyclovir Hydrochloride; Vidara Hydrochloride; Dobutamine Lactobionate; Dobutamine Tar bine; Vidarabine Phosphate; Vidarabine Sodium Phosphate; trate, , ImaZOdan Hydrochloride; Indolidan; Iso Viroxime; Zalcitabine; Zidovudine; ZinviroXime. mazole Hydrochloride; Levdobutamine Lactobionate; Lix azinone Sulfate; Medorinone; ; Pelrinone 0.178 Appetite suppressant: Dexfenflurarnine Hydro Hydrochloride; ; Piroximone; Prinoxodan; chloride; Tartrate; Phentermine Hydro Proscillaridin; Quazinione; Hydrochloride; chloride. . 0179 Benign prostatic hyperplasia therapy agent: Tam 0186 Cardiovascular agent: ; Dopexamine Sulosin Hydrochloride. Hydrochloride. 0180 Blood glucose regulators: Human insulin; Gluca 0187 Choleretic: Dehydrocholic Acid; Fencibutirol; gon; TolaZamide, Tolbutamide, Chloropropamide; Aceto Hymecromone; Piprozolin; ; Tocamphyl. hexamide and Glipizide. Bone resorption inhibitor: Alendr onate Sodium; Etidronate Disodium; Pamidronate 0188 Cholinergic: ; Chloride; Disodium. ; Demecarium Bromide; Dexpanthenol; Echothiophate Iodide; Isoflurophate; Chlo 0181 Bronchodilator: Albuterol; Albuterol Sulfate; Aza ride; Neostigmine Bromide; Neostigmine Methylsulfate; nator Maleate; Hydrochloride; Mesy PhySoStigmine, PhySoStigmine Salicylate; PhySOStigmine late; Butaprost; Hydrochloride; Clorprenaline Sulfate; Pilocarpine; Pilocarpine Hydrochloride; Pilocarpine Hydrochloride; Mesylate; Doxaprost; Doxofylline; Nitrate; Pyridostignine Bromide. Dyphylline; ; Ephedrine; Ephedrine Hydro chloride; ; Fenprinast Hydrochloride; Guaithyl 0189 Cholinergic agonist: ; Xanomeline Tar line; Sulfate; Hoquizil Hydrochloride; Ipra trate. tropium Bromide; Isoetharine; Isoetharine Hydrochloride; 0190. Cholinesterase Deactivator: Obidoxime Chloride; Isoetharine Mesylate; Isoproterenol Hydrochloride; Isopro Pralidoxime Chloride; Pralidoxime Iodide, Pralidoxime terenol Sulfate; Metaproterenol Polistirex; Metaproterenol Mesylate. Sulfate; Nisbuterol Mesylate; Oxtriphylline; Picumeterol Fumarate; Piquizil Hydrochloride; Acetate; Pir 0191 Coccidiostat: Arprinocid; Narasin; Semduramicin; buterol Hydrochloride; Hydrochloride; Pseu Semduramicin Sodium. doephedrine Sulfate; QuaZodine; Quinterenol Sulfate; 0.192 Cognition adjuvant: Mesylates; Pirac Racepinephrine, Racepinephrine Hydrochloride; etam; Hydrochloride; Pramiracetam Sulfate; Hydrochloride; Hydrobromide; ; Sal Hydrochloride. meterol Xinafoate; Soterenol Hydrochloride; Sulfonterol Hydrochloride; Suloxifen Oxalate; Sulfate; 0193 Cognition enhancer: Besipirdine Hydrochloride; ; Xanoxate Sodium; Zindotrine; ; Sibopirdine. Hydrochloride. 0194 Depressant: Omeprazole. 0182 Carbonic anhydrase inhibitor: ; 0.195 Diagnostic aid: Aminohippurate Sodium; Ana Acetazolamide Sodiurn, Dichlorphenamide; Dorzolamide Zolene Sodium; Arclofenin; Arginine, Bentiromide; Benzyl Hydrochloride; Methazolamide; Sezolamide Hydrochloride. penicilloyl Polylysine; Butedronate Tetrasodium; Butilfe 0183 Cardiac depressant: Acecainide Hydrochloride; nin; Coccidioidin; Ovine Triflutate; Chloride; Actisomide, Adenosine, Amio Corticotropin, Repository; Corticotropin Zinc Hydroxide; darone; , Aprindine Hydrochloride; Artilide Meglumine; Diatrizoate Sodium; Diatrizoic Fumarate; Dihydrochloride; Bidisomide; Bucain Acid; Diphtheria Toxin for Schick Test; Disofenin; Edro ide Maleate; Bucromarone; Butoprozine Hydrochloride; phonium Chloride; Ethiodized Oil, Etifenin; Exametazime; Capobenate Sodium; Capobenic Acid; Cifenline; Cifenline Ferristenc; Ferumoxides; FerumoxSil; Fluorescein; Fluores Succinate; Clofilium Phosphate; Disobutamide; Disopyra cein Sodium, Gadobenate Dimeglumine, ; mide; Phosphate; ; Drobuline; Edi , Gadopentetate Dimeglumnine, Gadoverseta folone Acetate; Emilium Tosylate; Hydrochlo mide; Histoplasmin, Hydrochloride, Indig ride; Acetate; Fumarate; Indecainide otindisulfonate Sodium; Indocyanine Green, Iobenguane US 2002/0010208A1 Jan. 24, 2002

Sulfate I 123; ; Iocarminate Meglumine; Sone; Sodium Phosphate; ; Iocammic Acid, , , Iodamide Diflucortolone Pivalate; Flucloronide; Flumethasone; Flu Megilumine, Iodipamide Meglumine, , Iodoxamate Pivalate; Flunisolide; Acetonide; Meglumine, , Ioglicic Acid, Ioglucol, Ioglu ; ; Fluocortolone Caproate; Fluo comide, Ioglycamic Acid, Iogulamide, ; ; rometholone; Acetate; ; Flu Ioparnidol; , ; Iophendylate; I profe Valerate; Flurandrenolide; ; nin, Iopronic Acid, Ioprocemic Acid, , Iopy done; Hydrocortisone; ; Hydrocortisone Iosefamic Acid, IoSeric Acid, IoSulamide Meglumine, IoSul Buteprate; ; Hydrocortisone metic Acid; Iotasul; Iotetric Acid; Iothalarnate Meglumine; Sodium Phosphate; Hydrocortisone Sodium Succinate; Iothalamate Sodium; Iothalamic Acid; ; Iotroxic ; ; Methylprednisolone; Acid, , Ioxaglate Meglumine, Ioxagiate Sodium; Methylprednisolone Acetate; Methylprednisolorre Sodium , , loxotrizoic Acid, Ipodate Calcium; Phosphate; Methylprednisolone Sodium Succinate; Nivazol; ; ISOSulfan Blue; Leukocyte Typing Serum; Paramnethasone Acetate; ; Prednisolone; Lidofenin; Mebrofenin; Meglumine; ; Metri ; Prednisolone Hemisuccinate; Pred Zoate Sodium; ; Metyrapone Tartrate; Mumps nisolone Sodium Phosphate; Prednisolone Sodium Succi Skin Test Antigen; Pentetic Acid; ; Quinaldine nate; ; ; Prednival; Ticabe Blue, Schick Test Control; Acetate; Sodium Sone Propionate, ; ; Triarncinolone Iodide I 123; Sprodiamide; Stannous Pyrophosphate; Stan Acetonide; Triarncinolone Acetonide Sodium; Triamcino nous Sulfuir Colloid; Succimer; Acetate; Tetro lone Diacetate; Triarncinolone Hexacetonide. fosmin; Tolbutamide Sodium; Tuberculin; Tyropanoate 0206 Gonad-stimulating principle: Buserelin Acetate; Sodium; Xylose. Clomiphene Citrate; Ganirelix Acetate; Gonadorelin 0196) Diuretic: Ambuphylline; Ambuside; Acetate; Gonadorelin Hydrochloride; , Chori Hydrochloride; Azolimine; ; Brocrinat; Bumet onic, Menotropins. anide; Chlorothiazide, Chlorthalidone; Clazolimine; Clor eXolone; Ethacrynate Sodium; Ethacrynic Acid, ; 0207 Hair growth stimulant: Minoxidil. ; ; ; Isosorbide; 0208 Hemostatic: Aminocaproic Acid; Oxarnarin ; ; ; ; ; Hydrochloride; Sulmarin; Thrombin; Tranexamic Acid. Torsemide; ; Triflocin, . 0209 antagonists: Ranitidine 0197) agent: . (Zantac); Famotidine (Pepcid); Cimetidine (Tagamet); Niza 0198) Ectoparasiticide: Nifuridide; . tidine (Axid). 0210 Hormone: ; Progesterone; 17 0.199) Emetic: Hydrochloride. hydroxy progesterone; , Norgestrel; 0200 : ; Alresta Norethynodrel; Estradiol; Megestrol (Megace); Norethin tin Sodium; Aprotinin; Benazepril Hydrochloride; Benazep drone; Levonorgestrel; Ethyndiol, Ethinyl estradiol; Mestra rilat; Benurestat; Bromocriptine; Bromocriptine Mesylate; nol, Estrone, Equilin; 17 alpha dihydroeguilin; equilenin; 17 Cilastatin Sodium; Flurofamide; ; Lergotrile alpha dihydroequilenin; 17 alpha estradiol; 17 beta estradiol; Mesylate; Levcycloserine; Libenzapril; Pentopril; Pepstatin; Leuprolide (lupron); Glucagon; Testolactone; Clomiphene; Perindopril; Polignate Sodium; Sodium Amylosulfate; Sor Han memopausal , Human chorionic gona binil; Spirapril Hydrochloride; Spiraprilat; ; Tepro dotropin; Urofolitropin; Bromocriptine; Gonadorelin; tide; Tolfamide; Zofenopril Calcium. Luteinizing hormone releasing hormone and analogs, Gona dotropins; Danazol; Testosterone, Dehydroepiandrosterone; 0201 Estrogen: ; ; Diethyl , Dihydroestosterone, Relaxin, Oxytocin, ; Diethylstilbestrol Diphosphate; Equilin; Estra Vasopressin; Folliculostatin; Follicle regulatory protein; diol; ; Estradiol Enanthate; Estradiol Gonadoctrinins, Oocyte maturation inhibitor; Insulin growth Undecylate; ; Hydrobromide; factor, Follicle Stimulating Hormone, Luteinizing hormone; , ; , Conjugated; Estrogens, Tamoxifen.; Corticorelin Ovine Triffutate; Cosyntropin; Esterified; Estrone; ; Ethinyl Estradiol; Fenes ; Pituitary, Posterior; Seractide Acetate; Somal trel; Mestranol; Nylestriol; . apor, Somatrem; Somatropin; Somenopor, Somidobove. 0202 Fibrinolytic: Anistreplase; Bisobrin Lactate; Brino 0211 Hypocholesterolemic: Lifibrol. lase. 0212 Hypoglycemic: Darglitazone Sodium: Glime 0203 Free oxygen radical scavenger: Pegorgotein. piride. 0204 Gastrointestinal Motility agents: Cisapride (Pro 0213 Hypolipidemic: Azalanstat Dihydrochloride; pulsid); Metoclopramide (Reglan), Hyoscyamine (Levsin). Colestolone; Surfomer; Xenalipin. 0205 Glucocorticoid: ; Beclomethasone 0214) Hypotensive: Viprostol. Dipropionate, ; ; , Betamethasone Dipropionate; 0215 HMGCoA reductase inhibitors: Lovastatin (Meva Betamethasone Sodium Phosphate; Betamethasone Valer cor); Simvastatin (Zocor); Pravastatin (Pravachol); Fluva ate, Sodium, Acetate; Clocor Satin (Lescol). tolone Pivalate; ; Corticotropin; Corticotropin, 0216. Immunizing agent: Antirabies Serum; Antivenin Repository; Corticotropin Zinc Hydroxide; (Latrodectus mactans); Antivenin (Micnirus Fulvius); Anti Acetate; , Acetonide; Dexametha venin (Crotalidae) Polyvalent; BCG Vaccine; Botulism US 2002/0010208A1 Jan. 24, 2002 22

Antitoxin; Cholera Vaccine; Diphtheria Antitoxin; Diphthe 0234 Neuroleptic: Duoperone Fumarate; . ria Toxoid; Diphtheria Toxoid Adsorbed; Globulin, Immune; Hepatitis B Immune Globulin; Hepatitis B Virus Vaccine 0235 Neuromuscular blocking agent: Atracurium Besy Inactivated; Influenza Virus Vaccine; Measles Virus Vaccine late; Cisatracurium Besylate; ; Gal Live, Meningococcal Polysaccharide Vaccine Group A; lamine Triethiodide; Iodide, Mivacurium Chlo Meningococcal Polysaccharide Vaccine Group C; Mumps ride; ; ; Virus Vaccine Live; Pertussis Immune Globulin; Pertussis ; Succinylcholine Chloride; Tub Vaccine; Pertussis Vaccine Adsorbed; Plague Vaccine; ocurarine Chloride; . Poliovirus Vaccine Inactivated; Poliovirus Vaccine Live 0236 Neuroprotective: Maleate. Oral; Rabies Immune Globulin; Rabies Vaccine, Rh(D) Immune Globulin; Rubella Virus Vaccine Live; Smallpox 0237 NMDA antagonist: . Vaccine; Tetanus Antitoxin; Tetanus Immune Globulin; 0238) Non-hormonal steroll derivative: Tetanus Toxoid; Tetanus Toxoid Adsorbed; Typhoid Vac Succinate. cine; Yellow Fever vaccine; Vaccinia Immune Globulin; 0239). Oxytocic: Carboprost; Carboprost Methyl; Carbo Varicella-Zoster Immune Globulin. prost Tromethamine, Dinoprost, Dinoprost Tromethamine; 0217. Immunomodulator: Dimepranol Acedoben; Imi Dinoprostone; Ergonovine Maleate; Meteneprost; Methyl quimod; Interferon Beta-1b; Lisofylline; Mycophenolate ergonovine Maleate; Oxytocin, Sulfate. Mofetil, Prczatide Copper Acetate. 0240 Plasminogen activator: Alteplase; Urokinase. 0218 Immunoregulator: Azarole; Mesylate; Frentizole; Oxamisole Hydrochloride; Ristianol Phosphate; 0241 Platelet activating factor antagonist: Lexipafant. Thymopentin; Tilomisole. 0242 Platelet aggregation inhibitor: Acadesine; Bera prost; Beraprost Sodium, Ciprostene Calcium; ItaZigrel, 0219) Immunostimulant: Loxoribine; Teceleukin. Lifarizine, OXagrelate. 0220 Immunosuppressant: ; Azathioprine Sodium; Cyclosporine; Daltroban; Gusperimus Trihydro 0243 Post-stroke and post-head trauma treatment: Citi chloride; ; . coline Sodium. 0221) Impotence therapy adjunct: Deleguamine Hydro 0244 Potentiator: Pentostatin; Hydrochloride. chloride. 0245 Progestin: ; Acetate; Acetate; Chlorrnadinone Acetate; 0222 Inhibitor: Acarbose, Calcium; Benser ; Acetate; Acetate; azide, Brocresine; ; Clavulanate Potassium; ; ; ; ; DaZmegrel, Docebenone; Epoprostenol; Epoprostenol Ethynodiol Diacetate; ; Flurogestone Acetate; Sodium; Epristeride; Finasteride; Flurbiprofen Sodium; , , ; ; Furegrelate Sodium; Lufironil; Miglitol; ; Pimage ; Hydroxyprogesterone Caproate; dine Hydrochloride; Pirmagrel; Ponalrestat; Ridogrel; Sul Levonorgestrel; ; ; MedroX bactam BenZathine; Sulbactarn Pivoxil, Sulbactam Sodium; yprogesterone Acetate; Methynodiol Diacetate, Norethin Suronacrine Maleate; Tazobactam, Tazobactam Sodium; drone; Norethindrone Acetate; Norethynodrel; Norgesti Hydrochloride; Mesylate; Tolrestat; mate, ; Norgestrel; Velnacrine Maleate; Zifrosilone; Zileuton. Phenpropionate; Progesterone, Acetate; 0223 Keratolytic: Alcloxa; Aldioxa; Benzoyl Peroxide; ; . Dibenzothiophene; Etarotene; Isotretinoin; Motretinide; 0246 Prostaglandin: Cloprostenol Sodium; Fluprostenol Picotrin Diolamine; Resorcinol; Resorcinol Monoacetate; , Sumarotene, Tazarotene, Tetroquinone; Tre Sodium; Gemeprost; Prostalene; Sulprostone. tinoin. 0247 Prostate growth inhibitor: . 0224 LHRH agonist: Deslorelin; ; Histrelin; 0248 Prothyrotropin: Protirelin. Lutrelin Acetate, Nafarelin Acetate. 0249 Psychotropic: Minaprine. 0225 Liver disorder treatment: Malotilate. 0250 Pulmonary surface: Beractant; Colfosceril Palmi 0226 Luteolysin: Fenprostalene. tate. 0227 Memory adjuvant: Dimoxamine Hydrochloride; 0251 Radioactive agent: Fibrinogen 1125; Fludeoxyglu Ribaminol. cose F 18; Fluorodopa F 18; Insulin I 125; Insulin I 131; lobenguane I 123; lodipamide Sodium I 131; lodoantipyrine 0228 Mental performance enhancer: . I 131; Iodocholesterol I 131 Iodohippurate Sodium I 123; 0229 Mood regulator: . Iodohippurate Sodium I 125; Iodohippurate Sodium I 131; 0230. Mucolytic: ; Carbocysteine; Dormi Iodopyracet I 125; Iodopyracet I 131; Hydro odol. chloride I 123, Iomethin I 125; Iomethin I 131; lothalamate Sodium I 125; Iotalamate Sodium I 131; Iotyrosine 1131; 0231) Mucosal Protective agents: Misoprostol (Cytotec). I 125; Liothyronine I 131; Merisoprol Acetate Hg 197; Merisoprol Acetate Hg 203; Merisoprol Hg 197; 0232) Mydriatic: . Selenomethionine Se 75; Technetium Tc 99m Antimony 0233 Nasal decongestant: Nemazoline Hydrochloride; Trisulfide Colloid; Technetium Tc 99m Bicisate; Technetium Pseudoephedrine Polistirex. Tc 99m Disofenin; Technetium Tc 99m Etidronate; Techne US 2002/0010208A1 Jan. 24, 2002

tium Tc 99m Exametazime; Technetium Tc 99m Furifosmin, 0263 Steroid: Dexamethasone Acefuirate; Technetium Tc 99m Gluceptate; Technetium Tc 99m Lid Furoate. ofenin; Technetium Tc 99m Mebrofenin; Technetium Tc 0264. Stimulant: ; Sulfate; 99m Medronate; Technetium Tc 99m Medronate Disodium; AmpyZine Sulfate; Hydrochloride; Azabon; Technetium Tc 99m Mertiatide; Technetium Tc 99m Oxidr ; ; Ceruletide Diethylamine; Cisapride; onate; Technetium Tc 99m Pentetate; Technetium Tc 99m Fumarate; ; Dextroamnphet Pentetate Calcium Trisodium; Technetium Tc 99m Sesta amine Sulfate; Difluanine Hydrochloride; Dimefline Hydro mibi; Technetium Tc 99m Siboroxime; Technetium Tc 99m chloride; Doxapram Hydrochloride; Etryptamine Acetate; Succimer; Technetium Tc 99m Colloid; Technetium Ethamivan; Hydrochloride; Flubanilate Hydro Tc 99m Teboroxime; Technetium Tc 99m Tetrofosmin; chloride; ; Histamine Phosphate; Indriline Hydro Technetium Tc 99m Tiatide; Thyroxine 1 125; Thyroxine 1 chloride; ; Hydrochloride; 131; Tolpovidone 1131; Triolein 1125; Triolein 1131. Hydrochloride; ; 0252) Regulator: Calcifediol; ; Calcitriol; Clo Hydrochloride; ; Xamoterol Fumarate. dronic Acid; Dihydrotachysterol, Etidronic Acid; Oxidronic Acid, Piridironate Sodium; Risedronate Sodium; Secalcif 0265 Suppressant: Amflutizole; ; Tazofelone. erol. 0266 Symptomatic multiple sclerosis: Fampridine. 0253) Relaxant: Adiphenine Hydrochloride; Alcuronium 0267 Synergist: Hydrochloride. Chloride; ; Azumolene Sodium; ; Hydrochloride; ; Chlorphenesin 0268 Thyroid hormone: Sodium; Liothy ; , Cinflumide, ; ronine Sodium; . Clodanolene; Hydrochloride; ; 0269) Thyroid inhibitor: Methimazole; . Dantrolene Sodium; Fenalamide; Fenyripol Hydrochloride; Fetoxylate Hydrochloride; Hydrochloride; Fle 0270. Thyromimetic: Thyromedan Hydrochloride. tazeparn; Flumetramide, Hydrochloride; 0271 Tranquilizer: ; Hydrochlo Hexafluorenium Bromide; Isomylamine Hydrochloride; ride; , , , ; Hydrochloride; Mesuprine Hydro Dipotassium, CloraZepate Monopotassium; D.emoxepam, chloride; ; ; Methixene Hydro ; Hydrochloride; chloride; Nafomine Malate; NeleZaprine Maleate; Papaver Hydrochloride; Hydroxyphenarnate; Hydro ine Hydrochloride; Pipoxolan Hydrochloride; Quinctolate; chloride; Hydroxy Zine Pamoate; ; , ; Ritodrine Hydrochloride; Rolodine; Theophylline LorZafone, , Loxapine Succinate; Medazeparn Sodium Glycinate; Thiphenamil Hydrochloride; Xilobam. Hydrochloride; ; ; Oxazeparn; Pent abamate; , RipaZeparn; Rolipram; Sulazeparn; 0254 Repartitioning agent: . Taciamine Hydrochloride; ; Triflubazarn; 0255 Scabicide: , Crotamiton. ; . 0256 Sclerosing agent: Ethanolamine Oleate; Morrhuate 0272 Amyotrophic lateral Sclerosis agents: . Sodium; Tribenoside. 0273) Cerebral ischemia agents: Hydrochlo 0257 Sedative: . ride. 0258 Sedative-hypnotic: ; Alonimid; Alpra 0274) Paget's disease agents: Tiluldronate Disodium. Zolam; Sodium; ; ; But abarbital; Sodium; ; Capuride; Car 0275 Unstable angina agents: Tirofiban Hydrochloride. bocloral; Betaine; ; 0276 Uricosuric: ; Irtemazole; Chlordiazepoxide Hydrochloride; Cloperidone Hydrochlo Probenecid; Sulfinpyrazone. ride; Clorethate; ; Dexclamol Hydrochloride; , ; , ; 0277 Vasoconstrictor: Angiotensin Amide; Felypressin; , Fenobarn; , , Glute ; Methysergide Maleate. thimide, , Lornetazepam, ; Mep 0278 Vasodilator: Alprostadil; AZaclorzine Hydrochlo robamate; ; ; ; Pentobar ride; Barnethan Sulfate; Hydrochloride; Buterizine; bital; Sodium; ; ; Cetiedil Citrate; Chromonar Hydrochloride; Clonitrate; Dil , , Roletamide, ; Seco tiazem Hydrochloride; ; Droprenillarnine; Sodium; ; ; ; Erythrityl Tetranitrate; ; Hydrochlo Trepiparn Maleate; ; Tricetamide; ride; ; ; Niacinate; Iproxarnine Sodium; , , ; Hydrochloride; ; Isosorbide Mononi Hydrochloride; Tartrate. trate; Hydrochloride; ; Mefenidil; Mefenidil Fumarate; Dihydrochloride; Miofla 0259 Selective adenosine Al antagonist: Apaxifylline. zine Hydrochloride; Mixidine; Nafronyl Oxalate; Nicar 0260 Serotonin antagonist: Tartrate; Ameser dipine Hydrochloride; ; ; Nicotinyl gide, ; . Alcohol; Nifedipine; ; ; Oxfenicine; Hydrochloride; Pentaerythritol Tetranitrate; 0261 Serotonin inhibitor: Hydrochloride; ; Pentrinitrol; Perhexiline Maleate; ; ; Fonazine Mesylate; Tosylate. Pirsidomine; Prenylamine; Propatyl Nitrate; Suloctidil; 0262 Serotonin receptor antagonist: Hydro Hydrochloride; Tipropidil Hydrochloride; Tola chloride. Zoline Hydrochloride; Xanthinol Niacinate. US 2002/0010208A1 Jan. 24, 2002 24

0279 Vulnerary: Allantoin. luprenam, cefimetazole, cefrninox, cefodizime, cefoSelis, cefotetan, cefotiam, cefotiam heXetil, cefoZopran, cefpimi 0280 Wound healing agent: Ersofermin. Zole, cefpiramide, cefpirome, cefpodoxime proxetil, cef 0281 Xanthine oxidase inhibitor: ; Oxypu prozil, cefSulodin, cefteram, ceftibuten, ceftriaxone; rinol cefuroxime axetil, celastrol; celikalim, celiprolol, cepaci 0282. Other pharmaceutical agents include: 1-decpyrro dine A, ; ; ceronapril; certoparin lidinone, 1-dodecpyrrolidinone; 16-alpha fluoroestradiol; Sodium, cetiedil; cetirizine, chloroorienticin A, chloroorien 16-; 16alpha-gitoxin; 17alpha estradiol, 17beta ticin B; chloroquinoxaline Sulfonamide, cibenzoline, cica estradiol; lalpha-hydroxyvitamin D2; 2'-nor-cGMP; 20-epi prost, , cicletanine, cicloprolol, cidofovir, 1.25 dihydroxyvitarnin D3; 22-oxacalcitriol; 2CVV; ; cilaZapril; ; cilobradine, ; 3-isobutyl GABA; 6-FUDCA, 7-methoxytacrine; abamec , , , cioteronel; tin, ; ; abiraterone; acadesine; acampro ciprofibrate, ciprofloxacin; ciprostene, cis-porphyrin, Sate; acarbose, aceclofenac; acemannan; acetomepregenol; cisapride, , cistinexine, citaloprarn, acetyl-L-, acetylcysteine, N-; ; aci , citreamicin alpha; cladribine; clarithromycin; fran; ; acitemate; acitretin, aclarubicin, aclatonium; clausenamide; clebopride; clinafloxacin; clobaZam; clobeta napadisilate; aconiazide, acrivastinet; , ada Sone butyrate, clodronic acid; ; , palene; adatanserin; adecypenol; adefovir dipivoxil, adelm clotrimazole; colestimide; colfoSceril palmitate, collismycin idrol; ademetionine; adinazolam, adiposin; adoZelesin; A, collismycin B; combretastatin A4, complestatin; conage ; alacepril; aladapcin; alaptide; albendazole, albo nin; contignasterol, contortroStatin; coSalane; costatolide; labrin; aldecalmycin; aldesleukin; alendronic acid; alente cotinine; coumerrnycin A1, cucumariosid; curacin A; curd mol; alfacalcidol; alfuZoSin; alglucerase, alinastine, aloS lan sulfate; curiosin; cyclazosin; cyclic HPMPC; cycloben etron; alpha idoSone; alproStadil; ; altromycin B; Zaprine, cyclobut A, cyclobut G., cyclocapron; cycloplatam, ambamustine; ; , ameZinium cyclosin; cyclothialidine, cyclothiazomycin; cypemycin; metilsulfate; amfebutamone, amidox, amifloxacin; amifoS ; cytarabine ocfosfate; cytochalasin B, daclix tine, , ; amlexanoX, amlodipine; imab, dactimicin; ; ; dalfopristin; dalteparin amlodipine, ampiroXicam, anrinone, arnrubicin; amsacrine; Sodium; danaparoid; daphnodorin A; dapiprazole, dapitant; ; amythiamicin; anagrelide, anakinra, ananain; ; darlucin A; darsidomine; ddUTP, decitabine; anaritide; anastrozole; andrographolide, ; apado deferiprone, deflazacort, dehydrodiderniin B, dehydroepi line, apafant; apaxifylline, aphidicolin glycinate, apracloni , delapril; deleguamine, delfaprazine, delmopi dine, aproSulate Sodium, , apurinic acid, aranid nol; delphinidin; deoxypyridinoline; ; depSido ipine; arbekacin; arbidol; arbutamine, ardeparin Sodium; mycin; derarnciclane; dermatan Sulfate, desflurane; arecatannin B1; argatroban; aripiprazol; , asima desirudin; deslorelin; desmopressin; desogestrel; desoxoa doline; aspalatone; asperfiran; aspoxicillin; astemizole, asu miodarone; detajmium bitartrate; dexifosfamide, deXketo lacrine; atameStane, atenolol, S-; ate Virdine, atosiban; atova profen; dexloxiglumide, dexmedetomidine, deXpemedolac, quone; atpenin B; atrimustine; atrinositol; aureobasidin A, deXraZOxane, deXSotalol, dextrin 2-Sulphate, deXVerapamil, azadirachtine, ; azatyrosine; ; azelas dezinamide, dezocine, diaziquone, diclofenac digolil; tine; , azimilide, azithromycin; azoSemide; diclofenac potassium; dicranin; didernin B; didox; aztreonam, baccatin III; bacoside A, bacoside B; bactobo ; diethylhomospermine; diethylnorspermine, dihy lamine; balaZipone, balhimycin; balofloxacin; balsalazide, drexidine, dihydro-5-azacytidine, dimethyl prostaglandin , baohuoSide 1, , basifimgin; batebu A1; dimethylhomospermine, dimiracetam; dioxamycin; last, batimastat, beauvericin; ; becliconazole; diphency prone, diphenyl Spiromustine, ; dipro ; belfosdil; bellenamine; benflumetol; benid pylnorSpernine, dirithromycin; discodermolide; disulfiram; ipine; ; benzochlorins; benzoidaZOXan; ben ditekiren; docarpamine, docosanol, 1-, dolfetilide; dolas ZoylstauroSporine; benztropine, bepridil, beractant; bera etron; domitroban; dopexamine, dorZolamide; doSmalfate; prost, berlafenone; bertosamil; besipirdine, beta-alethine; , doxacurium chloride, doxazosin, doxifluridine, betaclamycin B; betarnipron; betaxolol, betulinic acid; doxofylline, draculin; draflazine; droloxifene, dronabinol, bevantolol; bicalutamide; ; , bimithil, drosperidone, acephyllinate, droxicam, ebi binoSpirone; bioxalomycin alpha2, biriperone, bis-benzimi ratide, elbrotidine, ebSelen, ecabapide, ecabet, ecadotril; dazole A, bis-benzimidazole B, bisantrene; bisaramil; ecdlisteron; echicetin; echistatin; ecomustine, ecteinascidin bisaziridinylspermine; bisnafide; bisoprolol; bistramide D; 722; ecteinascidin 729; ecteinascidin 743; edaravone, edel bistramide K; bistratene A, boldine; ; brefeldin; fosine, edobacomab, edrecolomab, efegatran; eflornithine; breflate; brimonidine; bromfenac; bromperidol; bropir , egualen, elcatonin; ; elgodipine, elip imine; bucindolol; ; ; budotitane; rodil, eltenac, emlkalim, , emiglitate, emitefur; bunaprolast; ; butenafine; buthionine Sulfoximine; emoctakin; enadoline hydrochloride; enalapril; enaZadrem, propionate; cadeXomer iodine, calanolide A, cal englitaZone, enlimomab, enoxacin; enoxaparin Sodium; cipotriol, calphostin C, camonagrel, candesartan; cande enoXimone, , enterostatin; epoprostenol; Sartan cileXetil, ; candoxatrilat, capecitabine; epoxymeXrenone, epristeride, eproSartan; eptastigmine; capromab, ; captopril; carbazomycin C; carbeto , , erSofermin; erythiritol; ; cin; carbovir, carboxamide-amino-triazole, carboxyamidot etanidazole; etanterol, ethacizin; , ; riazole; carboxymethylated beta-1,3-glucan, carperitide; etodolac, etoposide phosphate, etrabamine; everninomicin; carteolol, carumonarn; carvedilol, carvotroline; carZelesin; examorelin; exemestane, fadrozole; faerieflungin; famnci castanospermine, cebaracetam; cecropin B; cefcapene piv clovir, fampridine, , faropenem; fasidotril; oxil, cefdaloxime penteXil tosilate, cefdinir, cefditoren piv , faZarabine, ; felbamate; ; oxil, cefepime, cefetamet, cefetamet pivoxil, cefixime, cef fenoldopam, fenretinide; ; fenticonazole; fepradi US 2002/0010208A1 Jan. 24, 2002

nol; ferpifoSate Sodium; ferristene; ferrixan; ferumoxSil; prednisolone Suleptanate; metipamide; metoclopramide; ; flavopiridol; flecainide; flerobuterol; fleroxa metoprolol, S-; metrifonate; mibefradil; michellamine B; cin; ; flezelastine; flobufen, flomoxef; florfenicol; microcolin A, ; , miglitol; millace florifenine; floSatidil; fluiasterone; fluconazole; fludarabine; mide; ; mildronate, ; milrinone; flumazenil; flumecinol, flumequine; flunarizine; fluocal miltefosine, minaprine, miokamycin, mipragoside; mirfen citriol; fluorodaunorunicin hydrochloride; fluoxetine, R-; tanil; mirimoStim, mirtazapine; misoprostol, mitoguaZone; fluoxetine, S-; fluparoXan; ; flurbiprofen axetil, mitolactol, mitonafide; mitoxantrone; ; flurithromycin; ; ; fluvas , mixanpril, , mizoribine, moclobe tatin; fluvoxamine; forasartan; forfenimex, formeStane; fon mide; modafmil, moexipril; mofarotene; mofeZolac, mol noterol; forrnoterol, R,R-; fosfomycin; trometamol, foSino gramoStim; mometasone; montirelin; mopidamol, mora pril; fosphenytoin, fostriecin, , gabapentin; cizine, ; ; motilide; moxiraprine; , , gadodiamide, gadodiamide ; nadifloxacin; nadroparin calcium; ; EOB-DTPA; gadolinium teXaphyrin, , gadot nafamoStat; nafarelin, , naglivan, nagreStip; eridol, ; ; galdansetron; gallo nalmefene, naphterpin, napSagatran; naratriptan; nar pamil, galocitabine, gamolenic acid, ganirelix, gepirone; tograstim; nasaruplase; nateplase, , ; gestrinone; girisopam; glaspimod, glaucocalyxin A, nisanycin; nisin; nisoldipine, nitaZOXanide, ; glutapyrone; glycopine, glycopril; granisetron; grepafloxa nitrendipine, nitrendipine, S-, nitrofurantoin monohydrate; cin; halichondrin B; halofantrine; halomon; ; nitrullyn; nizatidine, ofloxacin, okicenone, olanzapine, olo hatomamicin; hatomarubigin A; batomarubigin B; patadine, olprinone; Olsalazine, omeprazole, onapristone; hatomarubigin C, hatomarubigin D, , ibopamine; Ondansetron; ondansetron, R-, OntaZolast, oracin; otenZe ibudilast, illimaquinone, ilmofoSine, illomastat, illoperidone; pad; Oxaliplatin, oxamisole, Oxandrolone, Oxaprozin, iloprost, imidapril, ; ; indolidan; oXaunomycin; ; oxiconazole, ; farnesil; indometacin; tropine ester; indoramin; ; OZagrel, palauamine; palinavir, palmitoyl inocoterone; inogatran; inolimomab, interferon alfa, inter rhizoxin; pamaqueside, parnicogrel, pamidronic acid; panar feron alfa-2a, interferon alfa-2b; interferon alfa-N 1; inter nesine; panaxytriol, panipenem, panipenum; pannorin; feron alfa-n3; interferon beta; interferon beta-1a1; interferon panomifene, pantethine, pantoprazole, parabactin; pama beta-1b, interferon gamma-1a; interferon gamma-1b; inter parin Sodium; paroxetine, , paZelliptine, paZu feron omega; interferon, consensus, interleukin-1, interleu floxacin; pefloxacin, pegaspargase; peldesline, pemedolac, kin-1 alpha; interleukin- beta; interleukin-10; interleukin-l pemirolast, penciclovir, pentafuside, , pentam 1, interleukin-12, interleukin-12, interleukin-15; interleu orphone, pentigetide; pentosan, pentostatin; pentroZole; per kin-2, interleukin-3, interleukin-4, interleukin-5, interleu flubron; perfosfamide, ; perindoprilat, ; kin-7; interleukin-8; iobenguane; ; iodoarniloride; , phenazinomycin; phenserine; phensuccinal; iododoxorubicin; iofratol; iomeprol; iopentol; ; phentolamine mesilate; phenylacetate; phenylalanyl keto iopyrol; iotriside; ioVerSol; ioxilan; ipazilide, IpdR; ipenOX conazole, picenadol, picibanil; picroliv, picumeterol, pidoti aZone, ipidacrine; ipomeanol, 4-, ipriflavone, ipsapirone; mod; pilocarpine hydrochloride; ; , irbesartan; irinotecan, irloxacin; irSogladine, irtemazole; pimilprost; pimobendan; pinacidil; pinocebrin; pioglitaZone; isalsteine, isbogrel, isepamicin; isobengaZole, isoflox pipecuronium bromide, pirarubicin; piretanide, pirfenidone; ythepin, isohomohalicondrin B; isopropyl unoprostone, isra piritrexim; , pirmagrel, pirmenol; pirodavir, piro dipine; itameline; itasetron; ; itraconazole, ketopro domast, piroXicairn cinnamate; propagernanium; pro fen, R-, , S-, ketorolac, lacidipine, lactitol; pentofylline; propionylcarnitine, L-, propiram; propiram-- lactivicin; laennec, , lamelfarin-N triacetate; lami ; ; propyl bis-acridone; fiban, lamivudine, lamotrigine; lanoconazole; ; prostaglandin J2, prostratin, protegrin, protoSufloxacin; pru lanreotide; lanSoprazole; latanoprost; lateritin; laurocapram; lifloxacin; pyrazoloacridine, quazepam, , qui , lemefloxacin; lemildipine, leminoprazole; flapon; , quinapril, quinfamide, quinupristin, lenercept; lenograstim; lentinan Sulfate, ; leptolstatin; raloxifene, raltitrexed; ramatroban; rainipril, ramosetron; , ; ; letraZuril; letrozole; ranelic acid; ranitidine bismuth citrate; ranolazine; leucomyzin; leuprorelin; levcromakalim, ; recainam; regaVirumab, relaxin, repirinast, resinferatoxin; levobetaxolol, levobunolol, ; levocabastine; reticulon; reviparin Sodium; revizinone; ; ridogrel, levocarnitine, ; ; levo rifabutin, rifapentine, rifaximin, rilopiroX, riluzole, riman , levonorgestrel; ; ; tadine, rimeXolone, rimoprogin, , ripisartan; , linotroban; ; lintitript; lintopride; risedronic acid; rispenzepine, risperidone; ritanserin; riti liothyronine Sodium; lirexapride; lisinopril; lobaplatin; lobu penem; ritipenem acoxil, ritolukast, , cavir, lodoxamide, lombricine, lomefloxacin, ; benzoate, rohitukine, rokitamycin; ropinirole; ; lometrexol; lonazolac, lonidamine, loracarbef, loratadine, roquinimex, roXatidine, ; roXithromycin; rubigi , lomoxicam, losartan; losigamone; loSOXantrone; none B1, ruboxyl, rufloxacin, rupatidine, ruzadolane, Saf loteprednol; loviride, loxoribine; ; lurtotecan; ingol, Safironil; Saintopin; , R-; Salmeterol, Sal luteinizing hormone; lutetium; luZindole; lydicamycin; meterol, R-Salnacedin; Sarneridine, Sampatrilat; ly Sofylline; lysostaphin, magainin 2 amide, ; mal Sanfeltrineem, Saprisartan; Sapropterin; Saquinavir, SarCNU; lotochromene; mallotojaponin; malotilate; ; Sarcophytol A Sargrarnostim; , Saruplase; , maniwamycin A, mannostatin A, manumycin Saterinone; Satigrel, Satumomab pendetide, Selegiline, Sele E; manumycin F; mapinastine; marimastat; Martek 8708; nium thiosemicarbazone, Sematilide, Semduramicin; Semo Martek 92211; masoprocol; maspin; massetolide, meterelin; tiadil; Semustine, Sermorelin; Sertaconazole, Sertindole, Ser methoxatone, methylhistamine, R-alpha; methylinosine traline, , Sevirumab, Sevoflurane, SeZolamide; monophosphate; methylprednisolone aceponate; methyl Silipide, Silteplase, Simendan; Simvastatin; Sinitrodil, Sinna US 2002/0010208A1 Jan. 24, 2002 26 bidol; Silpatrigine; Sirolimus, sizofiran, Somatomedin B; asthmatic, anti-atherOSclerotic, antibacterial; anticholelithic, Somatomedin C; Somatrem, Somatropin; Sonermin; Sotalol; anticholelithogenic, anticholinergic, anticoagulant; anticoc Staurosporine; Stavudine, ; Stipiamide, Stiripentol; cidal; antidiabetic, antidiarrheal; antidiuretic, antidote, anti Stobadine, Succibun; Sucralfate, SulfaSalazine, Sulfmosine; estrogen; antifibrinolytic, antifungal; antiglaucoma agent; Sulfoxamine, Sulopenem; Sultamicillin; , Sulukast, antihemophilic, antihemorrhagic, antihistamine; antihyper Sumatriptan; Symakalim, tandoSpirone, tapgen; taprostene; lipidemia; antihyperlipoproteinemic, antihypertensive; anti tasOSartan; taZanolast, tazaroteine, teicoplanin, ; hypotensive, anti-infective, anti-infective, topical; anti-in tellurapyrylium, telmesteine, ; temocapril; flammatory; antikeratinizing agent, antimalarial; temoporfm, temozolomide; tenidap; tenipoSide; tenosal; antimicrobial; antimitotic, antimycotic, antineoplastic, tenoxicam, tepirindole; tepoxalin, teraZosin, terbinafine, ter antineutropenic, antiparasitic, antiperistaltic, antipneu fenadine, terflavoxate, ; terlakiren, terlipressin; mocystic, antiproliferative, antiprostatic hypertrophy; anti terodiline; , , tetrachlorode protozoal; antipruritic, antipsoriatic, antirheumatic; antis caoxide, tetraZomine; thaliblastine; thalidomide; thiocora chistoSomal; antiseborrheic, antisecretory; antispasmodic, line; thiofedrine; thiomarinol; ; thyroid Stimu antithrombotic, antituSSive, anti-ulcerative, anti-urolithic, lating hormone, ; ; tiapafant; tibolone; antiviral; appetite Suppressant, benign prostatic hyperplasia ticlopidine, ; , tilnoprofen arbamel, therapy agent, bone resorption inhibitor, bronchodilator; tiludronic acid; tinzaparin Sodium, ; carbonic anhydrase inhibitor; cardiac depressant, cardiopro tipredane; tiqueside; tirandalydigin; tirapazamine; tirilazad; tectant, cardiotonic, cardiovascular agent, choleretic, cho tirofiban; , topSentin; , toremifene, linergic, cholinergic agonist, cholinesterase deactivator; toSufloxacin; trafermin; trandolapril; traXanox, tretinoin, tre coccidioStat; diagnostic aid; diuretic, ectoparasiticide; tinoin tocoferil, triacetyluridine, tricaprilin; trichohyalin; enzyme inhibitor; estrogen; fibrinolytic, free oxygen radical trichoSanthin, alpha; triciribine, trientine; triflavin; trimege Scavenger, glucocorticoid; gonad-stimulating principle; hair Stone; triptorelin; troglitaZone; trombodipine; tropisetron; growth Stimulant, hemostatic, hormone, hypocholester trospectomycin; trovafloxacin; troVirdine, tucareSol; olemic, hypoglycemic, hypolipidemic, hypotensive; immu ; tylogenin, , triphosphate; Valaci nizing agent; immunomodulator; immunoregulator, immu clovir, Valproate magnesium; Valproate Semisodium; Valsar nostimulant; immunosuppressant, impotence therapy tan; vamicamide, Vanadeine, Vaninolol, Vapreotide; variolin adjunct; inhibitor; keratolytic; LHRH agonist; liver disorder B; velareSol, Venlafaxine, Veramine; Verapamil, (S); Verdins, treatment, luteolysin; mucolytic, mydriatic, nasal deconges Veroxan; verteporfin; Vesnarinone, Vexibinol; vigabatrin; tant; neuromuscular blocking agent; non-hormonal Sterol citrate; Vinburnine resinate; Vinconate; Vinorel derivative; oxytocic, plasminogen activator; platelet activat bine; Vinpocetine, Vinpocetine citrate; Vintoperol, Vinxal ing factor antagonist, platelet aggregation inhibitor, poten tine, Voriconazole, Vorozole, VOXergolide, Xemilofiban; tiator; progestin, prostaglandin, prostate growth inhibitor; Ximoprofen; yangamblin, Zabicipril; Zacopride; Zacopride, prothyrotropin; pulmonary Surface; radioactive agent, regu R-; ; Zalcitabine; Zaleplon; ZaloSpirone; Zaltopro lator, relaxant, repartitioning agent; Scabicide, Sclerosing fen, Zanamivir; Zankiren, Zanoterone; Zatebradine, agent, Selective adenosine Al antagonist; Steroid; Suppres Zatosetron; Zenarestat; Zeniplatin, Zifrosilone; Zilascorb, Sant; Symptomatic multiple Sclerosis, Synergist; thyroid hor Zileuton; Zinostatin stimalamer, Ziprasidone; Zoledronic mone: thyroid inhibitor; thyromimetic; amyotrophic lateral acid; ; Zolpidem; Zonisamide, Zopiclonre, Zopi Sclerosis agents, Paget’s disease agents, unstable angina clone, S-, Zopolrestat; . agents, uricoSuric; vasoconstrictor; vasodilator, Vulnerary; 0283 The invention also embraces novel compositions of wound healing agent; Xanthine oxidase inhibitor. matter that are covalent conjugates of DHA and pharma 0284. As used herein, a taxane is a molecule that pos ceutical agents that are noncentral nervous System active SeSSes the following tricyclic carbon-atom connectivity net agents. Noncentral nervous System active agents have no work, which may incorporate carbon-carbon multiple bonds, function or use within the central nervous System. Their only and which through the involvement of carbon-atom-noncar use is outside of the central nervous System. Such agents bon-atom bonds may include Substituents, functional include all drugs within certain of the foregoing categories groups, and additional rings. and only Some drugs within other of the foregoing catago ries. For example, the entire catagory of blood glucose regulators have no use or function within the central nervous System. In contrast, certain anti-cancer agents are useful in the central nervous System whereas others are not. For example, central nervous System cancers are not hormone dependent, and, therefore, an anti-cancer agent Such as Tamoxifen which treats certain hormone dependent 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 follow 0285) A taxoid is a molecule structurally related to a ing catagories and/or members of the following catagories taxane in which the above taxane carbon-atom connectivity are noncentral nervous System active agents: adrenocortical network is altered. for example, by cleavage of one or more Steroid; adrenocortical SuppreSSant; aldosterone antagonist; of the carbocyclic rings, by deletion or addition of carbon amino acid; anabolic, androgen; antagonist; anthelmintic, Substituents, by connection of carbon atoms normally not anti-acne agent, anti-adrenergic, anti-allergic, anti-amebic; bonded to each other, by disconnection of carbon atoms anti-androgen; anti-anemic, anti-anginal; anti-arthritic, anti normally bonded to each other, or by Some other reorgani US 2002/0010208A1 Jan. 24, 2002 27

Zation of or adjustment to the taxane carbon-atom connec in a manner Such that there is no interaction which would tivity network, but in which one or more Structural features Substantially impair the desired pharmaceutical efficacy. characteristic of the taxane carbon-atom connectivity net 0292 Compositions suitable for parenteral administra work are conserved. tion conveniently comprise a Sterile preparation of the 0286 The compounds useful in the invention may be conjugates of the invention. This preparation may be for delivered in the form of anti-cancer cocktails. An anti-cancer mulated according to known methods. Formulations for cocktail is a mixture of any one of the compounds useful taxanes can be found in Chapter 9 of Taxol. Science and with this invention with another anti-cancer aoent Such as an Applications, CRC Press, Inc., 2000 Corporate Boulevard, anti-cancer drug, a cytokine, and/or Supplementary potenti N.W., Boca Raton, Fla. 33431. In general, Taxol has been ating agent(s). The use of cocktails in the treatment of cancer formulated as a 6 mg/ml cremophor EL (polyoxyethylated is routine. In this embodiment, a common administration castor oil)/ethanol mixture, which is diluted to final volume vehicle (e.g., pill, tablet, implant, injectable Solution, etc.) with normal saline or 5% dextrose. A 15 mg/ml solution of would contain both the conjugate useful in this invention taxotere has been formulated in polysorbate 80 (polyoxy and the anti-cancer drug and/or Supplementary potentiating sorbitanrnonooleate)/ethanol mixture, diluted with agent. 5% dextrose. 0287. The compounds of the invention, when used in 0293. The sterile preparation thus may be a sterile solu cocktails, are administered in therapeutically effective tion or Suspension in a non-toxic parenterally-acceptable amounts. A therapeutically effective amount will be deter diluent or Solvent. In addition, Sterile, fixed oils are conven mined by the parameters discussed below; but, in any event, tionally employed as a Solvent or Suspending medium. For is that amount which establishes a level of the drug(s) in the this purpose any bland fixed oil may be employed including area of the tumor which is effective in inhibiting the tumor Synthetic mono or di-glycerides. In addition, fatty acids Such growth. as oleic acid find use in the preparation of injectables. 0288 When administered, the formulations of the inven Carrier formulations Suitable for oral, Subcutaneous, intra tion are applied in pharmaceutically acceptable amounts and venous, intramuscular, etc. can be found in Remington's in pharmaceutically acceptable compositions. Such prepa Pharmaceutical Sciences, Mack Publishing Company, Eas rations may routinely contain Salts, buffering agents, pre ton, Pa. Servatives, compatible carriers, and optionally other thera 0294. A Subject as used herein means humans, primates, peutic ingredients. When used in the Salts should horses, cows, pigs, sheep, goats, dogs, cats and rodents. be pharmaceutically acceptable, but non-pharmaceutically acceptable Salts may conveniently be used to prepare phar 0295) The conjugates of the invention are administered in maceutically acceptable Salts thereof and are not excluded effective amounts. An effective amount means that amount from the Scope of the invention. Such pharmacologically necessary to delay the onset of, inhibit the progression of, and pharmaceutically acceptable Salts include, but are not halt altogether the onset or progression of or diagnose the limited to, those prepared from the following acids: hydro particular condition being treated. In general, an effective chloric, hydrobromic, Sulphuric, nitric, phosphoric, maleic, amount for treating cancer will be that amount necessary to inhibit mammalian cancer cell proliferation in-situ. When acetic, Salicylic, p- Sulfonic, tartaric, citric, methane administered to a Subject, effective amounts will depend, of Sulfonic, formic, malonic, Succinic, naphthalene-2-Sulfonic, course, on the particular condition being treated; the Severity and Sulfonic. Also, pharmaceutically acceptable of the condition; individual patient parameters including Salts can be prepared as alkaline metal or alkaline earth Salts, age, physical condition, Size and weight; concurrent treat Such as Sodium, potassium or calcium Salts. ment; frequency of treatment; and the mode of administra 0289 Suitable buffering agents include: acetic acid and a tion. These factors are well known to those of ordinary skill salt (1-2% W/V); and a salt (1-3% W/V); boric in the art and can be addressed with no more than routine acid and a salt (0.5-2.5% W/N); and phosphoric acid and a experimentation. It is preferred generally that a maximum salt (0.8-2% W/V). dose be used, that is, the highest Safe dose according to 0290 Suitable preservatives include benzalkonium chlo Sound medical judgment. ride (0.003-0.03% W/V); (0.3-0.9% W/V); 0296 Dosage may be adjusted appropriately to achieve (0.01-0.25% W/V) and thimerosal (0.004-0.02% desired drug levels, locally or Systemically. Generally, daily W/V). 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 0291. The active compounds of the present invention doses in the range of about 1 to 1000 mg/m per day will be may be a pharmaceutical composition having a therapeuti effective. In the event that the response in a Subject is cally effective amount of a conjugate of the invention insufficient at Such doses, even higher doses (or effective optionally included in a pharmaceutically-acceptable carrier. higher doses by a different, more localized delivery route) The term "pharmaceutically-acceptable carrier' as used may be employed to the extent that patient tolerance permits. herein means one or more compatible Solid or liquid filler, Continuous IV dosing over, for example 24 hours or mul dilutants or encapsulating Substances which are Suitable for tiple doses per day are contemplated to achieve appropriate administration to a human or other animal. The term "car rier denotes an organic or inorganic ingredient, natural or Systemic levels of compounds. Synthetic, with which the active ingredient is combined to 0297. A variety of administration routes are available. facilitate the application. The components of the pharma The particular mode Selected will depend of course, upon the ceutical compositions are capable of being commingled with particular drug Selected, the Severity of the disease State the molecules of the present invention, and with each other, being treated and the dosage required for therapeutic effi US 2002/0010208A1 Jan. 24, 2002 28 cacy. The methods of this invention, generally speaking, are well known to those of ordinary skill in the art and may be practiced using any mode of administration that is include Some of the release Systems described above. Such medically acceptable, meaning any mode that produces implants can be particularly useful in treating Solid tumors effective levels of the active compounds without causing by placing the implant near or directly within the tumor, clinically unacceptable adverse effects. Such modes of thereby affecting localized, high-doses of the compounds of administration include oral, rectal, Sublingual, topical, nasal, the invention. transderminal or parenteral routes. The term "parenteral' 0302) The conjugates of the invention also are useful, in includes Subcutaneous, intravenous, intramuscular, or infu general, for treating mammalian cell proliferative disorders Sion. Intravenous routes are preferred. other than cancer, including psoriasis, actinic keratosis, etc. 0298 The compositions may conveniently be presented They further are useful in treating diabetes and its compli in unit dosage form and may be prepared by any of the cations, excess acid Secretion, cardiovascular conditions methods well known in the art of pharmacy. All methods involving cholesterol (e.g., hyperlipidemia and hypercho include the Step of bringing the conjugates of the invention lesterolemia), diarrhea, ovarian diseases (e.g. endometriosis, into association with a carrier which constitutes one or more ovarian cysts, etc.) and as contraceptive agents. accessory ingredients. In general, the compositions are pre 0303 Those skilled in the art will be able to recognize pared by uniformly and intimately bringing the compounds with no more than routine experimentation numerous into association with a liquid carrier, a fmely divided Solid equivalents to the Specific products and processes described carrier, or both, and then, if necessary, Shaping the product. above. Such equivalents are intended to be included within 0299 Compositions suitable for oral administration may the Scope of the appended claims. be presented as discrete units Such as capsules, cachets, tablets, or lozenges, each containing a predetermined We claim as follows: amount of the active compound. Other compositions include 1. A method for targeting a pharmaceutical agent to a Suspensions in aqueous liquors or non-aqueous liquids Such noncentral nervous System tissue to treat a noncentral ner as a Syrup, an elixir, or an emulsion. Vous System condition comprising: 0300 Other delivery systems can include time-release, administering to a Subject in need of Such treatment a delayed release or Sustained release delivery Systems. Such covalent conjugate of cis-docosahexanoic acid and a Systems can avoid repeated administrations of the active pharmaceutical agent effective for treating Said condi compounds of the invention, increasing convenience to the tion. Subject and the physician. Many types of release delivery 2. The method of claim 1, wherein the tissue is breast Systems are available and known to those of ordinary skill in tissue and wherein the Subject has a condition calling for the art. They include polymer based Systems Such as poly treatment of breast tissue with the pharmaceutical agent. lactic and polyglycolic acid, polyanhydrides and polycapro 3. The method of claim 1, wherein the tissue is gas lactone; nonpolymer Systems that are including Sterols trointestinal tissue and wherein the Subject has a condition Such as cholesterol, cholesterol esters and fatty acids or calling for treatment of gastrointestinal tissue with the neutral fats Such as mono-, di and triglycerides, hydrogel pharmaceutical agent. release Systems, Silastic Systems, peptide based Systems, 4. The method of claim 1, wherein the tissue is ovarian wax coatings, compressed tablets using conventional bind tissue and wherein the Subject has a condition calling for erS and excipients, partially fuised implants and the like. In treatment of ovarian tissue with the pharmaceutical agent. addition, a pump-based hardware delivery System can be 5. The method of claim 1, wherein the pharmaceutical used, Some of which are adapted for implantation. agent is a noncentral nervous System active agent that is 0301 Along-term sustained release implant also may be nonactive within the central nervous System. used. "Long-term' release, as used herein, means that the 6. The method of claim 1, wherein the drug is an anti implant is constructed and arranged to deliver therapeutic cancer agent. levels of the active ingredient for at least 30 days, and 7. The method of claim 6, wherein the drug is Taxol. preferably 60 days. Long-term Sustained release implants 8. The method of claim 7, wherein the conjugate is

Ph

o O US 2002/0010208A1 Jan. 24, 2002 29

9. The method of claim 7, wherein the conjugate is

AcO 9 O

10. The method of claim 6. wherein the drug is Taxotere. 11. The method of claim 10, wherein the conjugate is

Ph

12. The method of claim 10, wherein the conjugate is

US 2002/0010208A1 Jan. 24, 2002 30

13. The method of claim 10, wherein the conjugate is

15. The method of claim 1, 2, 5, 6, 7, 8, 9, 10, 1, 12, 13 19. The pharmaceutical preparation as claimed in claim or 14, wherein the condition is breast cancer. 19, wherein the noncentral nervous System active agent is 16. The method of claim 1, 2, 5, 6, 7, 8, 9, 10, 11, 12, 13 active on a tissue Selected from the group consisting of: or 14, wherein the condition is colon cancer. Blood and Blood Forming tissue; Cardiovascular system 17. The method of claim 1, 2, 5, 6, 7, 8, 9, 10, 11, 12, 13 tissue; Digestive and excretory System tissue, Endo or 14, wherein the condition is ovarian cancer. crine System tissue; Musclar System tissue; Reproduc 18. A pharmaceutical preparation comprising: tive System tissue; Respiratory System tissue, Skeletal a covalent conjugate of cis-docosahexanoic acid and a System tissue, and Fiber and integumentary System noncentral nervous System active agent, and tissue. a pharmaceutically acceptable carrier. k . . . .