US 2002O177609A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0177609 A1 Swindell et al. (43) Pub. Date: Nov. 28, 2002

(54) FATTY ALCOHOL DRUG CONJUGATES Related U.S. Application Data (60) Provisional application No. 60/278,457, filed on Mar. (76) Inventors: Charles S. Swindell, Merion, PA (US); 23, 2001. Glenn J. Fegley, Eagleville, PA (US) Publication Classification Correspondence Address: (51) Int. Cl." ...... A61K 31/4453; A61K 31/40; Edward R. Gates, Esq. A61K 31/15 Chantal Morgan D'Apuzzo (52) U.S. Cl...... 514/329; 514/426; 514/640; Wolf, Greenfield & Sacks, P.C. 546/244; 548/558; 564/256 600 Atlantic Ave Boston, MA 02210 (US) (57) ABSTRACT The invention provides conjugates of fatty alcohols and (21)21) AppAppl. No.: 10/107,537/107, p harmaceutical agents9. useful in treating9. cancer, Viruses, psychiatric disorders. Compositions, pharmaceutical prepa rations, and methods of preparation of the fatty alcohols 22) Filled: Mar. 25, 2002 p harmaceutical agent9. coniugatesJug are pprovided. US 2002/0177609 A1 Nov. 28, 2002

FATTY ALCOHOL DRUG CONJUGATES was observed (for an adenosine receptor agonist), and it was postulated that the pendant lipid molecule interacted with RELATED APPLICATION the phospholipid membrane to act as a distal anchor for the 0001. This application claims priority under 35 U.S.C. S receptor ligand in the membrane micro environment of the 119 (e) from U.S. provisional patent application Serial No. receptor. This increase in potency, however, was not 60/278,457, filed on Mar. 23, 2001, entitled Fatty Alcohol observed when the same lipid derivatives of adenosine Drug Conjugates. The contents of the provisional applica receptor antagonists were used, and generalizations thus tion are expressly incorporated herein by reference. were not made possible by those Studies. 0007 Of key importance in the treatment of cancer, FIELD OF THE INVENTION Viruses, and psychiatric illness is the Selectivity and target 0002 The invention relates to conjugates of fatty alco ing of drugs to tissues. The increased targeting reduces the hols and pharmaceutical agents Such as anticancer, antiviral, amount of pharmaceutical agents needed, and the frequency and antipsychotic agents useful, for example, in treating of administration of the pharmaceutical agents, both features cancer, Viruses, and psychiatric disorders, and compositions especially important in treatments that involve administra and formulations thereof. Methods for making and using the tion of pharmaceutical agents that may be toxic to Surround conjugates also are provided. ing tissues and may cause side effects. Because of the critical importance of effective treatments for cancer, Viral diseases BACKGROUND OF THE INVENTION and psychiatric disorders and the difficulty in Selectively 0.003 Improving drug selectivity for target tissue is an targeting the affected tissues, there is presently a need for established goal in the medical arts. In general, it is desirable effective methods to target tissues with powerful drugs, to deliver a drug Selectively to its target, So that dosage and, while also reducing the Side effects and difficult administra consequently, Side effects can be reduced. This is particu tion regimens. larly the case for toxic agents Such as anticancer agents because achieving therapeutic doses effective for treating the 0008 Fatty alcohols are lipidic molecules terminating in cancer is often limited by the toxic side effects of the an alcohol group (unlike fatty acids, which, of course, anticancer agent on normal, healthy tissue. terminate in a carboxylic acid group). Unlike fatty acids, fatty alcohols are not a prevalent tissue component of 0004 Extensive research has been done on the use of mammals. They typically are prepared Synthetically using fatty acids as agents that improve Selectivity of drugs for fatty acids as a starting material. their target tissues. Fatty acids previously have been conju gated with drugs to help the drugs as conjugates croSS the blood brain barrier. DHA (docosahexaenoic acid) is a 22 SUMMARY OF THE INVENTION carbon naturally-occurring, unbranched fatty acid that pre 0009. The invention relates to the surprising discovery viously has been shown to be unusually effective, when that fatty alcohols can be conjugated to pharmaceutical conjugated to a drug, in crossing the blood brain barrier. agents for treatment of a variety of disorders, including but DHA is attached via the acid group to hydrophilic drugs and not limited to cancer, Viral infections, and psychiatric dis renders these drugs more hydrophobic (lipophilic). The eases. The benefits of these pharmaceutical-fatty alcohol mechanism of action by which DHA helps drugs conjugated conjugates include one or more of the following: targeting of to it cross the blood brain barrier is unknown. the drug to the tissue of interest; favorably affecting the 0005 Another example of the conjugation of fatty acids volume of distribution of the drug in the tissue of interest; to a drug is the attachment of pipotiazine to Stearic acid, reducing toxicity of the drug, reducing Side effects of the palmitic acid, enanthic acid, undecylenic acid or 2,2-dim drug, reducing clearance of the drug, reducing the necessary ethyl-palmitic acid. Pipotiazine is a drug that acts within the Volume and/or frequency of administration of the drug, or central nervous System. The purpose of conjugating pipo increasing the amount of drug that a Subject can tolerate by tiazine to the fatty acids was to create an oily Solution of the favorably affecting volume of distribution, tissue distribu drug as a liquid implant for slow release of the drug when tion, and/or release kinetics of active drug from an inactive injected intramuscularly. The release of the drug appeared to conjugate in certain embodiments. Another Surprising aspect depend on the particular fatty acid Selected, and the drug was of the fatty alcohol-pharmaceutical agent conjugates is that tested for its activity in the central nervous System. once the fatty alcohols are Separated from conjugation to the 0006 Lipidic molecules, including fatty acids, also have pharmaceutical agents in Vivo, the fatty alcohols can be been conjugated with drugs to render the conjugates more readily converted into naturally occurring fatty acids. lipophilic than the unconjugated drugs. In general, increased lipophilicity has been Suggested as a mechanism for enhanc 0010) Any and all of these aforementioned characteristics ing intestinal uptake of drugs into the lymphatic System, of the fatty alcohol-pharmaceutical agent conjugates may thereby enhancing the entry of the conjugate into the brain benefit Subjects in need of treatment for diseaseS Such as and also thereby avoiding first-pass metabolism of the cancer, psychiatric disorders, and viral diseases and may conjugate in the liver. The type of lipidic molecules allow altered dosages of drugs to be administered leSS employed have included phospholipids, non-naturally frequently, with better results and fewer side effects. occurring branched and unbranched fatty acids, and natu rally occurring branched and unbranched fatty acids ranging 0011. According to one aspect of the invention, compo from as few as 4 carbon atoms to more than 30 carbon Sitions of matter are provided. The composition, or com atoms. In one instance, enhanced receptor binding activity pound, has a pharmaceutical agent (i.e., drugs) conjugated to US 2002/0177609 A1 Nov. 28, 2002 a fatty group of a fatty alcohol via a carbonate linkage and guanidine linkages are provided. These compounds are of has the following formula: the formula: lsO RO OX

0012 wherein R is a C-C fatty group of a fatty alcohol ROH and X is a pharmaceutical agent moiety of a pharma 0020 wherein R is a C-C fatty group of a fatty alcohol ceutical agent XOH. ROH and X is a pharmaceutical agent moiety of a pharma 0013. According to another aspect of the invention, phar ceutical agent XNH (or XOH). maceutical agents conjugated to fatty alcohols via phosphate 0021 According to still another aspect of the invention, linkers are provided. The compounds have the formula: pharmaceutical agents linked to fatty alcohols via thiono carbamate linkages are provided. These compounds are of the formula:

RO-P-ZX S OR ls XHN OR 0014) wherein R is a C-C fatty group of a fatty alcohol ROH, X is a pharmaceutical agent moiety of a pharmaceu tical agent XZH, wherein Z is O, a primary amino group, or 0022 wherein R is a C-C fatty group of a fatty alcohol a Secondary amino group, and R' is Selcted from H, an ion, ROH and X is a pharmaceutical agent moiety of a pharma or a protecting group. ceutical agent XNH. 0.015 According to another aspect of the invention, phar 0023. According to still another aspect of the invention, maceutical agents conjugates linked via a carbamate linkage pharmaceutical agents linked to fatty alcohols via phospho to fatty alcohols are provided. These compounds have the nate linkages are provided. These compounds are of the formula: formula:

11-OR or

0024 wherein R is a C-C fatty group of a fatty alcohol 0016 wherein R is a C-C fatty group of a fatty alcohol ROH and X is a pharmaceutical agent moiety of a pharma ROH, X is a pharmaceutical agent moiety of a pharmaceu ceutical agent XCHPOH, XCHRPOH, or tical agent XOH, and R" is Selected from H, an alkyl group, XCR'R"POH, wherein RandR" are independently selected an alkenyl group, an alkynyl group, an aryl group, and the from alkyl, alkenyl, aryl, alkyl-Substituted heteroatom, alk like. enyl-Substituted heteroatom, or aryl-Substituted heteroatom, and the like. 0.017. According to another aspect of the invention, phar maceutical agents conjugated to fatty alcohol via ester 0025. According to still another aspect of the invention, linkages are provided. These compounds have the following pharmaceutical agents linked to fatty alcohols via Oxime formula: linkages are provided. These compounds are of the formula:

O

RO us X l O

0.018 wherein R is a C-C fatty group of a fatty alcohol ROH and X is a pharmaceutical agent moiety of a pharma 0026 which are (E) and (Z) isomers wherein R is a C-C fatty group of a fatty alcohol ROH and X is a ceutical agent XCO)OH. pharmaceutical agent moiety of a pharmaceutical agent 0.019 According to yet another aspect of the invention, bearing a ketone or aldehyde finctionality, i.e., XC(O)H or pharmaceutical agents conjugated to fatty alcohols via XC(O)R’ wherein R' is alkyl, alkenyl, aryl, and the like. US 2002/0177609 A1 Nov. 28, 2002

0.027 According to yet another aspect of the invention, acid, docOSapentaenoic acid, docosahexaenoic acid, and pharmaceutical agents conjugated to fatty alcohols via nervonic acid. These fatty acids encompass all of the various isourea linkages are provided. These compounds are of the possible isomers, including (E) and (Z) Stereochemistry formula: about the double bonds as well as placement of the double bonds. For example, as used herein, linolenic acid encom passes Y-linolenic acid, dihomo-Y-linolenic acid, as well as NH O-linolenic acid which differ by the placement of the double bonds in the carbon chain but have the Same molecular Y RO lsN formula (and molecular weight). H 0034. In some embodiments, the fatty alcohol moiety has a carbon Structure the same as a fatty acid Selected from the 0028 wherein R is a C-C fatty group of a fatty alcohol group consisting of octanoic (caprylic); nonanoic (pelar ROH and X is a pharmaceutical agent moiety of a pharma gonic); decanoic (capric); undecanoic (hendecanoic), dode canoic (lauric); tridecanoic, tetradecanoic (myristic); penta ceutical agent XNH2. decanoic, hexadecanoic (pamitic); heptadecanoic 0029. According to yet another aspect of the invention, (margaric); octadecanoic (stearic); 12-hydroxy Stearic; pharmaceutical agents conjugated to fatty alcohols are pro nonadecanoic, eicosanoic (arachidic); heneicosanoic, vided. These compounds are of the formula: docosanoic (behemic); tricosanoic, and tetracosanoic (ligno ceric). 0035) In these and other embodiments, the fatty alcohol moiety has a carbon Structure the same as a fatty acid RO n ls 1. X N N Selected from the group consisting of: 10-undecenoic (hen H H decenoic); 11-dodecenoic, 12-tridecenoic, 9-tetradecenoic (myristoleic); 9-trans-tetradecenoic (myristelaidic); 10-pen tadecenoic, 10-trans-pentadecenoic, 9-hexadecenoic (palmi 0030 wherein R is a C-C fatty group of a fatty alcohol toleic); 8-trans-hexadecenoic (palmitelaidic); 10-heptade ROH and X is a pharmaceutical agent moiety of a pharma cenoic, 10-trans-heptadecenoic, 6-octadecenoic ceutical agent XNH. (petroselinic), 6-trans-octadecenoic (petroselaidic); 8-octa decenoic (oleic); 9-11-octadecenoic (vaccenic); 11-trans 0031. In certain embodiments, the fatty alcohol moiety octadecenoic (transvaccenic); 9-cis-12 hydroxy-octade has a carbon Structure that is the Same as the carbon Structure cenoic (ricinoleic); 9-trans-12-hydroxy-octadecenois of a naturally occurring fatty alcohol or acid. In Some (ricinelaidic); 7-nonadecenoic, 7-trans-nonadecenoic, embodiments, the fatty alcohol moiety has a carbon Struc 10-nonadecenoic, 10-trans-nonadecenoic, 10-13-nonadeca ture which is the same as the carbon Structure of fatty acids dienoic, 10-13-trans-nona-decadienoic, 8-12-octadecadi which occur naturally in humans. Preferably, the fatty alco enoic (linoleic); 9-trans-12-trans octadecadienoic (lino hol moiety has a carbon Structure which is the same as a elaidic); octadecadienoic (conjugaged); 9-12-15 C2-C26, and even more preferably a C-C2, fatty acid octadecatrienoic (linolenic), 6-9-12-octadecatrienoic occurring naturally in humans. (gamma linolenic); 11-trans-eicosenoic, 8-eicosenoic, 0032. In other embodiments, the fatty alcohol moiety has 11-eicoSenoic, 5-eicoSenoic, 11-14-eicosadienoic, 8-11-14 eicosatrienoic (homogamma linolenic); 11-14-17-eicosa a carbon Structure that is the same as an unnatural fatty trienoic, 5-8-11-14-eicosatetraenoic (arachidonic), 5-8-11 alcohol or acid. In Some embodiments, the fatty alcohol 14-17-eicosapentaenoic, 10-13-16-19-docosapentaenoic, moiety has an even number of carbon atoms. In other arachidonic, 13-docoSenoic (erucic), 13-transdocoSenoic embodiments, the fatty alcohol moiety has an odd number of (brassidic); 13-16-docosadienoic; 13-16-19-docosatrienoic; carbon atoms. In Some embodiments, the carbon Structure is 7-10-13-16-docosatetraenoic, 4-7-10-13-16-19-docosa Saturated and in other embodiments, the carbon Structure is hexaenoic (DHA); 12-heneicoSenoic, 12-15-heneicosadi unsaturated (olefinic). Preferably, the carbon structure is enoic, 14-tricoSenoic, and 15-tetracosenoic (nervonic). unsaturated, that is, has at least one double bond. 0036) One skilled in the art will recognize that fatty 0033. In some embodiments, the fatty alcohol moiety has alcohols may be converted to O-fatty alcohol hydroxy a carbon Structure that is the same as any of the following lamines before conjugation to pharmaceutical agents. They fatty acids: caprylic acid, capric acid, undecylenic acid, may be linked via analogous linkages to the linkages of fatty lauric acid, myristic acid, palmitic acid, palmitoleic acid, alcohols, including thionocarbamate linkages, carbamate Stearic acid, oleic acid, vaccenic acid, linoleic acid, linolenic linkages, guanidine linkages, amide linkages, thiourea link acid, eleoStearic acid, gondoic acid, arachidonic acid, ages, phosphoramide linkages, phosphonamide linkages, eicosapentaenoic acid, docoSenoic acid, docOSatetraenoic and the like, as exemplified below:

lsO -o US 2002/0177609 A1 Nov. 28, 2002

-continued rts O -os-N o X O

S rsrso S

1 o

NH

0037 wherein X is a pharmaceutical agent moiety of a anti-urolithic, antiviral; appetite SuppreSSant; benign proS pharmaceutical agent XOH, XNH, etc. tatic hyperplasia therapy agent, blood glucose regulator; 0.038. Many pharmaceutical agents are useful in the bone resorption inhibitor, bronchodilator, carbonic anhy present invention. AS those skilled in the art will recognize, drase inhibitor; cardiac depressant, cardioprotectant; cardio any pharmaceutical agent having a group to which a fatty tonic, cardiovascular agent, choleretic, cholinergic, cholin alcohol may be conjugated (either directly or via a linkage ergic agonist, cholinesterase deactivator, coccidiostat; as described) is useful in the present invention. Such phar cognition adjuvant, cognition enhancer, depressant, diag maceutical agents contain groupS Such as -OH, -NH2, nostic aid; diuretic, dopaminergic agent; ectoparasiticide; -NHR", -COH, -SH, -POH and the like (wherein emetic, enzyme inhibitor; estrogen; fibrinolytic, fluorescent R" denotes a group Such as alkyl, aryl, alkenyl, alkynyl, agent, free oxygen radical Scavenger; gastrointestinal motil etc.). Many pharmaceutical agents, such as flavopiridol, ity effector; glucocorticoid; gonad-stimulating principle; contain more than one group to which fatty alcohols may be hair growth Stimulant; hemostatic; histamine H2 receptor conjugated. AS those skilled in the art will recognize, it is antagonists, hormone, hypocholesterolemic, hypoglycemic, possible to choose which group of the pharmaceutical agent hypolipidemic, hypotensive; imaging agent, immunizing the fatty alcohol will be conjugated to by using, for example, agent; immunomodulator; immunoregulator; immunostimu well know protection and deprotection Strategies. Generally, lant; immunosuppreSSant; impotence therapy adjunct; conjugation of just one fatty alcohol moiety to one pharma inhibitor; keratolytic; LNRH agonist; liver disorder treat ceutical agent is preferable, although one skilled in the art ment; luteolysin; memory adjuvant; mental performance will recognize that conjugation of more than one fatty enhancer, mood regulator, mucolytic, mucosal protective alcohol to one pharmaceutical agent is possible. agent, mydriatic, nasal decongestant; neuromuscular block ing agent; neuroprotective; NMDA antagonist; non-hor 0039. In certain embodiments, the pharmaceutical agent monal Sterol derivative; oxytocic, plasminogen activator; may be Selected from an adrenergic agent, adrenocortical platelet activating factor antagonist, platelet aggregation Steroid; adrenocortical Suppressant, alcohol deterrent, aldos inhibitor, post-Stroke and post-head trauma treatment; terone antagonist; amino acid; ammonia detoxicant; ana potentiator, progestin, prostaglandin; prostate growth inhibi bolic; analeptic, analgesic; androgen; anesthesia; anesthetic; tor, prothyrotropin; psychotropic, pulmonary Surface; radio anorectic, antagonist, anterior pituitary SuppreSSant; anthel active agent, regulator, relaxant, repartitioning agent, Scabi mintic, anti-acne agent, anti-adrenergic, anti-allergic, anti cide, Sclerosing agent, Sedative, Sedative-hypnotic, Selective amebic, anti-androgen; anti-anemic, anti-anginal; anti-anxi adenosine Al antagonist; Serotonin antagonist; Serotonin ety; anti-arthritic, anti-asthmatic; anti-atherOSclerotic, inhibitor; Serotonin receptor antagonist; Steroid; Stimulant; antibacterial; anticholelithic, anticholelithogenic, anticho SuppreSSant; Symptomatic multiple Sclerosis, Synergist; thy linergic, anticoagulant; anticoccidal; anticonvulsant, antide roid hormone; thyroid inhibitor; thyromimetic; tranquilizer; preSSant; antidiabetic, antidiarrheal; antidiuretic, antidote; agent for treatment of amyotrophic lateral Sclerosis, agent anti-emetic, anti-epileptic, anti-estrogen; antifibrinolytic, for treatment of cerebral ischemia, agent for treatment of antifingal; antiglaucoma agent, antihemophilic; antihemor Paget's disease, agent for treatment of unstable angina; rhagic, antihistamine; antihyperlipideric, antihyperlipopro uricoSuric; vasoconstrictor; vasodilator, Vulnerary, wound teinemic, antihypertensive, antihypotensive, anti-infective; anti-infective, topical; anti-inflammatory; antikeratinizing healing agent; and Xanthine oxidase inhibitor. agent; antimalarial; antimicrobial; antimigraine; antimitotic, 0040. In certain important embodiments, the pharmaceu antimycotic, antinauseant, antineoplastic, antineutropenic, tical agent is an anticancer agent. Important anticancer antiobessional agent, antiparasitic, antiparkinsonian; anti agents include: Acivicin, Aclarubicin; Acodazole Hydro peristaltic, antipneumocystic, antiproliferative, antiprostatic chloride; Acronine, Adozelesin; Adriamycin; Aldesleukin; hypertrophy; antiprotozoal; antipruritic, antipsychotic, anti Alitretinoin, Allopurinol Sodium; Altretamine; Ambomycin; rheumatic, antischistosomal; antiseborrheic, antisecretory; Ametantrone Acetate; Aminoglutethimide, Amsacrine; antispasmodic, antithrombotic, antituSSive, anti-ulcerative; Anastrozole; Annonaceous Acetogenins, Anthramycin; US 2002/0177609 A1 Nov. 28, 2002

ASimicin; Asparaginase; ASperlin, AZacitidine, AZetepa, atin; Zinostatin; Zorubicin Hydrochloride; 2-Chlorodeoxy AZotomycin; Batimastat; BenZOdepa; Bexaroteine, Bicaluta adenosine; 2-Deoxyformycin, 9-aminocamptothecin, ralti mide; Bisantrene Hydrochloride; Bisnafide Dimesylate; trexed; N-propargyl-5,8-dideaZafolic acid; 2-chloro-2'- Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Bropir arabino-fluoro-2'-deoxyadenosine, 2-chloro-2'- imine, Bullatacin; BuSulfan, Cabergoline; Cactinomycin; deoxyadenosine; anisomycin; trichostatin A; hPRL-G129R; Calusterone; Caracemide, Carbetimer; Carboplatin; Car CEP-751; linomide; sulfur mustard; nitrogen mustard mustine; Carubicin Hydrochloride; Carzelesin; Cedefingol; (mechlor ethamine); cyclophosphamide; melphalan; chlorambucil; ifosfamide; busulfan; N-methyl-N-ni Celecoxib; Chlorambucil; Cirolemycin; Cisplatin; Cladrib trosourea (MNU);N,N'-Bis(2-chloroethyl)-N-nitrosourea ine; Crisnatol MeSylate; Cyclophosphamide, Cytarabine; (BCNU); N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea Dacarbazine; DACA (N-2-(Dimethyl-amino) ethylacri (CCNU); N-(2-chloroethyl)-N'-(trans-4-methylcyclohexyl dine-4-carboxamide); Dactinomycin; Daunorubicin Hydro N-nitrosourea (MeCCNU); N-(2-chloroethyl)-N'-(diethyl chloride; Daunomycin; Decitabine; Denileukin Diftitox; )ethylphosphonate-N-nitroSourea (fotemustine); Streptozo DeXormaplatin, DeZaguanine, DeZaguanine MeSylate; tocin; diacarbazine (DTIC); mitozolomide; temozolomide; Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydro thiotepa, mitomycin C, AZQ; adoZelesin; Cisplatin; Carbo chloride; Droloxifene; Droloxifene Citrate; Dromostanolone platin; Ormaplatin; Oxaliplatin; C1-973; DWA 2114R, Propionate; Duazomycin; Edatrexate, Eflornithine Hydro JM216; JM335; Bis (platinum); tomudex; azacitidine; cyt chloride; Elsamitrucin; Enloplatin, Enpromate; Epipropi arabine, gemcitabine, 6-Mercaptopurine; 6-Thioguanine; dine; Epirubicin Hydrochloride; Erbulozole; Esorubicin Hypoxanthine; tenipoSide, 9-amino camptothecin, Topote Hydrochloride; Estramustine; Estramustine Phosphate can; CPT-11; Doxorubicin; Daunomycin; Epirubicin; daru Sodium; Etanidazole; Ethiodized Oil I 131; Etoposide; Eto bicin; mitoxantrone; losoxantrone; Dactinomycin (Actino poside Phosphate; Etoprine; Fadrozole Hydrochloride; Faz mycin D); amsacrine, pyrazoloacridine, all-trans retinol, arabine; Fenretinide; Floxuridine; Fludarabine Phosphate; 14-hydroxy-retro-retinol; all-trans retinoic acid; N-(4-Hy Fluorouracil; 5-FdUMP, Flurocitabine; Fosquidone; Fos droxyphenyl) retinamide; 13-cis retinoic acid; 3-Methyl triecin Sodium; FK-317; FK-973; FR-66979; FR-900482; TTNEB; 9-cis retinoic acid; fludarabine and (2-F-ara-AMP); Gemcitabine; Gemcitabine Hydrochloride; Gemtuzumab 2-chlorodeoxyadenosine (2-Cda). OZogamicin; Gold Au 198; Goserelin Acetate; Guanacone; Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; Ilmo 0041. Other anti-neoplastic compounds include 20-epi-1, fosine; Interferon Alfa-2a, Interferon Alfa-2b; Interferon 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; acla Alfa-n1; Interferon Alfa-n3; Interferon Beta-I a; Interferon rubicin; acylfulvene, adecypenol; adoZelesin; aldesleukin; Gamma-Ib, I proplatin; Irinotecan Hydrochloride; Lan ALL-TK antagonists, altretamine; ambamustine; amidox; reotide Acetate; Letrozole; Leuprolide Acetate; Liarozole amifostine; aminolevulinic acid; amrubicin; amsacrine; Hydrochloride; Lometrexol Sodium; Lomustine; LoSox anagrelide; anastroZole; andrographolide, angiogenesis antrone Hydrochloride; Masoprocol; Maytansine; Mechlo inhibitors, antagonist D; antagonist G, antarelix; anti-dor rethamine Hydrochloride; Megestrol Acetate; Melengestrol Salizing morphogenetic protein-1, antiandrogen, prostatic Acetate; Melphalan; Menogaril; Mercaptopurine; Methotr carcinoma, antiestrogen; antineoplaston; antisense oligo exate; Methotrexate Sodium; Methoxsalen; Metoprine; nucleotides, aphidicolin glycinate, apoptosis gene modula Meturedepa; Mitindomide; Mitocarcin; Mitocromin; tors, apoptosis regulators, apurinic acid, ara-CDP-DL Mitogillin; Mitomalcin; Mitomycin; Mytomycin C; Mito PTBA, arginine deaminase, asulacrine, atameStane; sper; Mitotane; Mitoxantrone Hydrochloride; Mycophenolic atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; aza Acid, Nocodazole; Nogalamycin; Oprelvekin; Ormaplatin; Setron; azatoxin; azatyrosine, baccatin III derivatives, bal Oxisuran, Paclitaxel, Pamidronate Disodium; Pegaspargase; anol; batimastat, BCR/ABL antagonists, benzochlorins, Peliomycin; Pentamustine; Peplomycin Sulfate; Perfosfa benzoylstauroSporine; beta lactam derivatives, beta mide; Pipobroman; Piposulfan; Piroxantrone Hydrochlo alethine; betaclamycin B; betulinic acid; bFGF inhibitor; ride; Plicamycin; Plomestane; Porfimer Sodium; Porfiromy bicalutamide, bisantrene, bisaZiridinylspermine; bisnafide; cin; Prednimustine; Procarbazine Hydrochloride; bistratene A, bizelesin, breflate, bleomycin A, bleomycin Puromycin; Puromycin Hydrochloride; Pyrazofurin; Ribo B, bropirimine; budotitane; buthionine Sulfoximine; calci prine, Rituximab, Rogletimide, Rolliniastatin; Safingol, Saf potriol, calphostin C; camptothecin derivatives (e.g., 10-hy ingol Hydrochloride, Samarium/Lexidronam, Semustine; droxy-camptothecin); canarypox IL-2, capecitabine; car SimtraZene, Sparfosate Sodium; SparSomycin; Spirogerma boxamide-amino-triazole; carboxyamidotriazole, CaRest nium Hydrochloride, Spiromustine, Spiroplatin; Squamo M3; CARN 700; cartilage derived inhibitor; carzelesin; cin; Squamotacin; Streptonigrin, Streptozocin, Strontium casein kinase inhibitors (ICOS), castanospermine; cecropin Chloride Sr 89; Sulofenur; Talisomycin; Taxane; Taxoid; B; cetrorelix; chlorins, chloroquinoxaline Sulfonamide, cica Tecogalan Sodium; Tegafur, Teloxantrone Hydrochloride; prost, cis-porphyrin, cladribine; clomifene analogues, clot Temoporfin; Teniposide; Teroxirone; Testolactone; Thiami rimazole; collismycin A, collismycin B; combretastatin A4, prine; Thioguanine; Thiotepa; Thymitaq, Tiazofurin, Tira combretastatin analogue, conagenin, crambescidin 816; cri pazamine; Tomudex; TOP-53; Topotecan Hydrochloride; Snatol; cryptophycin 8; cryptophycin A derivatives, curacin Toremifene Citrate; Trastuzumab; Trestolone Acetate; A., cyclopentanthraquinones, cycloplatam, cypemycin; cyt Triciribine Phosphate; Trimetrexate; Trimetrexate Glucur arabine ocfoSfate; cytolytic factor; cytostatin, dacliximab, onate; Triptorelin; Tubulozole Hydrochloride; Uracil Mus decitabine; dehydrodidemnin B; 2'deoxycoformycin (DCF); tard; Uredepa; Valrubicin; Vapreotide; Verteporfin; Vinblas deslorelin; dexifosfamide; deXraZOxane, deXVerapamil, tine; Vinblastine Sulfate; Vincristine; Vincristine Sulfate; diaziquone, didemnin B; didox; diethylnorSpernine, dihy Vindesine; Vindesine Sulfate; Vinepidine Sulfate; Vinglyci dro-5-azacytidine, dihydrotaXol, 9-, dioxamycin; diphenyl nate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; Spiromustine, discodermolide; docosanol; dolasetron, doxi Vinrosidine Sulfate; Vinzolidine Sulfate; Vorozole; Zenipl fluridine, droloxifene, dronabinol; duocarmycin SA; US 2002/0177609 A1 Nov. 28, 2002

ebSelen, ecomustine, edelfosine, edrecolomab, eflornithine; inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine elemene; emitefur; epirubicin; epothilones (AR=H.B., demethylated; rhenium Re 186 etidronate; rhizoxin; R=Me); epithilones, epristeride; estramustine analogue; ribozymes, RII retinamide, rogletimide, rohitukine; estrogen agonists; estrogen antagonists; etanidazole; etopo romurtide, roquinimex, rubiginone B1, ruboxyl, Safingol; Side, etoposide 4'-phosphate (etopofos); exemestane; fadro Saintopin; SarCNU; Sarcophytol A, SargramoStim; Sdi 1. Zole; faZarabine; fenretinide; filgrastim; fmasteride, fla mimetics, Semustine, Senescence derived inhibitor 1; Sense vopiridol; fleZelastine, fluiasterone, fludarabine; oligonucleotides, Signal transduction inhibitors, Signal trans fluorodaunorunicin hydrochloride; forfenimex, formeStane; duction modulators, Single chain antigen binding protein; fostriecin, fotemustine, gadolinium teXaphyrin, gallium sizofiran; Sobuzoxane, Sodium borocaptate, Sodium pheny lacetate, Solverol, Somatomedin binding protein; Sonermin; nitrate; galocitabine; ganirelix; gelatinase inhibitors, gem Sparfosic acid; Spicamycin D; Spiromustine; Splenopentin; citabine; glutathione inhibitors, hepSulfam; heregulin; heX Spongistatin 1; Squalamine; Stem cell inhibitor, Stem-cell amethylene bisacetamide; homoharringtonine (HHT); division inhibitors; stipiamide; stromelysin inhibitors; sulfi hypericin; ibandronic acid; idarubicin; idoxifene, idraman nosine; Superactive vasoactive intestinal peptide antagonist; tone, ilmofoSine, illomastat, imidazoacridones, imiquimod; Suradista; Suramin; Swainsonine, Synthetic glycosaminogly inmnunostimulant peptides; insulin-like growth factor-1 cans, tallimustine, tamoxifen methiodide, tauromustine, taZ receptor inhibitor; interferon agonists, interferons, interleu arotene, tecogalan Sodium, tegafur, tellurapyrylium; telom kins, iobenguane; iododoxorubicin; ipomeanol, 4-, irinote erase inhibitors, temoporfin, temozolomide; teniposide; can; iroplact, irSogladine, isobengaZole, isohomohalicon tetrachlorodecaoxide, tetraZomine; thaliblastine; thalido drin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N mide; thiocoraline; thrombopoietin; thrombopoietin triacetate; lanreotide; leinamycin; lenograstim; lentinan Sul mimetic; thymalfasin; thymopoietin receptor agonist, thy fate, leptolstatin; letrozole; leukemia inhibiting factor; leu motrinan; thyroid Stimulating hormone, tin ethyl etiopurpu kocyte alpha interferon; leuprolide +estrogen +progester rin; tirapazamine, titanocene dichloride; topotecan; topSen one; leuprorelin; levamisole; liarozole; linear polyamine tin, toremifene, totipotent Stem cell factor; translation analogue, lipophilic disaccharide peptide; lipophilic plati inhibitors, tretinoin, triacetyluridine, triciribine, trimetrex num compounds, lisSoclinamide 7; lobaplatin, lombricine; ate, triptorelin; tropisetron; turosteride; tyrosine kinase lometrexol; lonidamine; loSOXantrone; lovastatin; loxorib inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogeni ine; lurtotecan; lutetium teXaphyrin, lySofylline, lytic pep tal Sinus-derived growth inhibitory factor; urokinase recep tides, maitansine, mannostatin A, marimastat; masoprocol; tor antagonists, vapreotide; variolin B; vector System, eryth maspin; matrilysin inhibitors, matrix metalloproteinase rocyte gene therapy; VelareSol, Veramine; Verdins, inhibitors, menogaril; merbarone, meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; verteporfin; Vinorelbine; Vinxaltine; Vitaxin; Vorozole; Zan mirimostim; mismatched double stranded RNA, mithracin; oterone; Zeniplatin, Zilascorb, and Zinostatin stimalamer. mitoguaZone, mitolactol, mitomycin analogues, mitonafide; 0042. Other anticancer agents include antiproliferative mitotoxin fibroblast growth factor-Saporin, mitoxantrone; agents (e.g., piritrexim isothionate), antiprostatic hypertro mofarotene; molgramoStim; monoclonal antibody, human phy agent (e.g., Sitogluside), benign prostatic hyperplasia chorionic gonadotrophin, monophosphoryl lipid A+myo therapy agents (e.g., tamsulosin hydrochloride), prostate bacterium cell wall Sk, mopidamol, multiple drug resistance growth inhibitor agents (e.g., pentomone), and radioactive gene inhibitor, multiple tumor SuppreSSor 1-based therapy; agents: fibrinogen I 125; fludeoxyglucose F 18; fluorodopa mustard anticancer agent; my caperoxide B; mycobacterial F 18; insulin I 125; insulin I 131; iobenguane I 123; cell wall extract; myriaporone, N-acetyldinaline, N-Substi iodipamide sodium I 131; iodoantipyrine I 131; iodocholes tuted benzamides, nafarelin, nagreStip; naloxone +pentaZO terol I 131; iodohippurate sodium I 123; iodohippurate cine, napavin, naphterpin, nartograstim; nedaplatin, nemo Sodium I 125; iodohippurate sodium I 131; iodopyracet I rubicin; neridronic acid; neutral endopeptidase, nilutamide; 125; iodopyracet I 131; iofetamine hydrochloride I 123; nisamycin; nitric oxide modulators, nitroxide antioxidant; iomethin 1125; iomethin I 131; iothalamate Sodium I 125; nitrullyn;O6-benzylguanine; Octreotide, okicenone, oligo iothalamate sodium I 131; iotyrosine I 131; liothyronine I nucleotides, onapristone; ondansetron, Ondansetron; oracin; 125; liothyronine I 131; merisoprol acetate Hg 197; mer oral cytokine inducer; Ormaplatin, OSaterone, Oxaliplatin; isoprol acetate Hg 203; merisoprol Hg 197; selenomethion oXaunomycin; paclitaxel analogues, paclitaxel derivatives, ine Se 75; technetium Tc 99m antimony trisulfide colloid; palauamine; palmitoylrhizoxin; pamidronic acid; panax technetium Tc 99m bicisate; technetium Tc 99m disofenin; ytriol, panomifene, parabactin; paZelliptine, pegaspargase; technetium Tc 99m etidronate; technetium Tc 99m exam peldesline, pentosan polysulfate Sodium; pentostatin; pentro etazime, technetium Tc 99m furifosmin, technetium Tc 99m Zole, perflubron; perfosfamide, perillyl alcohol; phenazino gluceptate; technetium Tc 99m lidofenin; technetium Tc mycin; phenylacetate; phosphatase inhibitors, picibanil; 99mmebrofenin; technetium Tc 99m medronate; technetium pilocarpine hydrochloride, pirarubicin; piritrexim; placetin Tc 99m medronate disodium; technetium Tc 99mmertiatide; A, placetin B;plasminogen activator inhibitor, platinum technetium Tc 99m oxidronate; technetium Tc 99m pen complex, platinum compounds, platinum-triamine complex; tetate, technetium Tc 99m pentetate calcium trisodium; podophyllotoxin; porfimer Sodium; porfiromycin; propyl technetium Tc 99m Sestamibi; technetium Tc 99m bis-acridone; prostaglandin J2, proteasome inhibitors, pro Siboroxime; technetium Tc 99m Succimer, technetium Tc tein A-based immune modulator; protein kinase C inhibitor; 99m Sulfur colloid; technetium Tc 99m teboroxime; techne protein kinase C inhibitors, microalgal; protein tyrosine tium Tc 99m tetrofosmin, technetium Tc 99m tiatide; thy phosphatase inhibitors, purine nucleoside phosphorylase roxine I 125; thyroxine I 131; tolpovidone I 131; triolein I inhibitors, purpurins, pyrazoloacridine, pyridoxylated 125; and triolein I 131. hemoglobin polyoxyethylene conjugate, raf antagonists, 0043 Another category of anticancer agents useful as raltitrexed; ramosetron; ras farnesyl protein transferase pharmaceutical agents in the present invention include anti US 2002/0177609 A1 Nov. 28, 2002

cancer Supplementary potentiating agents. Anticancer abine; Fialuridine; Fosarilate; Foscamet Sodium; Fosfonet Supplementary potentiating agents include tricyclic anti Sodium; Ganciclovir, Ganciclovir Sodium; Idoxuridine; depressant drugs (e.g., imipramine, desipramine, amitryp Indinavir, Kethoxal; Lamivudine; Lobucavir; Memotine tyline, clomipramine, trimipramine, doxepin, nortriptyline, Hydrochloride; Methisazone; Nelfinavir, Nevirapine; Pen protriptyline, amoxapine and maprotiline); non-tricyclic ciclovir; Pirodavir; Ribavirin; Rimantadine Hydrochloride; anti-depressant drugs (e.g., Sertraline, trazodone and citalo Ritonavir; Saquinavir Mesylate; Somantadine Hydrochlo pram); Ca++antagonists (e.g., Verapamil, nifedipine, nitren ride; Sorivudine; Statolon; Stavudine; Tilorone Hydrochlo dipine and caroverine); calmodulin inhibitors (e.g., preny lamine, trifluoroperazine and clomipramine); amphotericin ride; Trifluridine; Valacyclovir Hydrochloride; Vidarabine; B; triparanol analogues (e.g., tamoxifen); antiarrhythmic Vidarabine Phosphate; Vidarabine Sodium Phosphate; drugs (e.g., quinidine); antihypertensive drugs (e.g., reser ViroXime, Zalcitabine, Zidovudine; ZinviroXime, integrase pine); thiol depleters (e.g., buthionine and Sulfoximine) and inhibitors, TMC-125 and TMC-114. Adefovir, cidofovir, multiple drug resistance reducing agents Such as Cremaphor BRL 47923, and BRL 44385 are particularly important EL. pharmaceutical agents. 0044 One particularly preferred class of anticancer 0047 Particularly preferred pharmaceutical agents useful agents for use in the present invention are taxanes. Among in the present invention include: annonaceous acetogenins, the taxanes, paclitaxel and docetaxel are preferred. Another asimicin; rolliniastatin, guanacone, Squarnocin, bullatacin; preferred anticancer agent for use in the present invention is squamotacin; taxanes; methotrexate FR-900482; FK-973; 3, flavopirodol. Other important anticancer agents are annona FR-66979; FK-317; 5-FU; FUJDR; FdUMP; Hydroxyurca; ceous acetogenins and SN-38. meta-pac, irinotecan; SN-38; 7-hydroxyStauroSporine; 10-OH campto; topotecan; adriamycin; cis-Pt; carbo-Pt; 0.045 Another category of pharmaceutical agents for use bleomycin; mitomycin C, mithramycin; capecitabine, cyt in the present invention is antipsychotic agents. Antipsy arabine; 2-Cl-2'deoxyadenosine; fludarabine-PO, mitox chotic agents include lorazepam, chlordiazepoxide; cloraZe antrone, mitoZolomide, pentostatin; and tomudeX. pate, diazepam, alprazolam; hydroxy Zine, buSpirone; ven lafaxine, mephobarbital; meprobamate; doxepin; 0048. Other particularly preferred pharmaceutical agents perphenazine, hydroxy Zine pamoate; Venlafaxine, mirtaza for use in the present invention include: gemcitabine, doc pine; nefazodone; bupropion; phenelZine; tranylcypromine; etaxel, paclitaxel, Vincristine, vinblastine, Vinorelbine, citalopram; paraXefine, Sertraline, amitrptyline, protrip SN-38, BRL 47923, BRL 44385, cidofivor, anhydrovinblas tyline, divalproex, clonazepam, clozapine, haloperidol; lox tine, flavopiridol, purvalanol A, purvalanol B, aminopurv apine, molindone; thiothixene; pimnozide, risperidone; que alanol, roscovitine, etoposide, 7-ethyl-10-hydroxycamptoth fiapine; thiothixen; Olanzapine; quetiapine; ecin, 10-hydroxycamptothecin, doxorubicin, mitomycin C, prochlorperazine; mesoridazin; trifluoperazine, chlorprom mithracin, epothilone B, epothilone D, camptothecin, dis azine; perphenazine; and fluvoxamine. Most preferred antip codermolide, adefovir (PMEA), TMC-125, and TMC-114, Sychotics include: clozapine, Venlafaxine, risperidone; que Valganciclovir, fomivirSen, Zanamivir, Oseltamivir, rimanti fiapine; thiothixen; and olanzapine. dine; adefovir dipivoxil; tenofovir; tenofovir disoproxil;vi ramidine, 3-deaZaneplanocin A, neplanocin A; Saquanivir; 0046) Another category of pharmaceutical agents useful maribavir, N-methanocarbathymidine, fuSaric acid, Syngua in the present invention is antiviral agents. Antiviral agents nol; glycyrrhyzic acid; fludaribine; entecavir; MIV-210. include nucleoside analogs, nonnucleoside reverse tran Scriptase inhibitors, protease inhibitors, integrase inhibitors, 0049. One skilled in the art will readily recognize those including the following: Acemannan, Acyclovir, Acyclovir pharmaceutical agents are Suitable for conjugation with fatty Sodium; Adefovir; Alovudine; Alvircept Sudotox; Amanta alcohols with no more than routine skill. For example, one dine Hydrochloride; Aranotin; Arildone; Atevirdine Mesy skilled in the art will recognize that flavopiridol does not late; Avridine; BRL 47923; BRL 44385; Cidofovir; Cipam contain a carboxylic acid moiety and as a result, an ester fylline; Cytarabine Hydrochloride; Delavirdine Mesylate; conjugation is not conveniently Synthesized. Preferred phar Desciclovir, Didanosine; Disoxaril; Edoxudine; Enviradene; maceutical agents are shown in Table 1, along with preferred Enviroxime; Famciclovir; Famotine Hydrochloride; Fiacit linkages.

TABLE 1.

FATTY ALCOHOL PHARMACEUTICAL AGENT CONUGATES Carbonate Phosphate Carbamate Ester Guanidine Phosphonate Oxime Isourea Thionocarbamate Thionocarbonate Paclitaxel X X Docetaxel X Gemcitabine X X X Vincristine X X X Vinblastine X X X X Camptothecin X CPT-11 X SN-38 X Mitomycin C X X Doxorubicin X X X X Adefovir X X X US 2002/0177609 A1 Nov. 28, 2002

TABLE 1-continued

FATTY ALCOHOL PHARMACEUTICAL AGENT CONUGATES Carbonate Phosphate Carbamate Ester Guanidine Phosphonate Oxime Isourea Thionocarbamate Thionocarbonate BRL 47923 X BRL 44385 Roscovotine Purvalanol A Puvalanol B Flavopiridol Cidofovir Ribavirin *Derived from either fatty alcohol or O-fatty alkyl hydroxylamine. 0050 Although the above examples are preferred, they leaving groups include N-hydroxySuccinimidyl, N-hydrox are not limiting. Other conjugates may be Synthesized phthalimidyl, imidazoylpara-nitrophenyl, ortho-nitrophe according to the invention. nyl, azido, hydroxybenzotriazolyl, chloro, fluoro, N-hy 0051. According to another aspect of the invention, com droxymaleimidyl, pentafluorophenyl, 2,4,5-trichlorophenyl, positions of matter are provided. The compositions are 2,4,6-trichlorophenyl, 1-hydroxypiperidinyl, pentacholor useful as intermediates to fatty alcohol pharmaceutical agent phenyl, 3,4,5-trimethoxyphenyl, hydroxypyridinyl, 4-dim conjugates and are of the following formula: ethylaminopyridinyl, 1-triazolopyridinyl, pyrazolyl, 3,5- dimethylpyrazolyl, and 1H-1,2,3-triazaolo-4,5-b] pyridinyl. These leaving groups may optionally be Substi O tuted with electron withdrawing groups or electron donating groups. Other leaving groups are groups include, but are not RO us T limited to:

0.052 wherein R is a C-C fatty group of a fatty alcohol ROH and T is a leaving group. O 0.053 According to another aspect of the invention, com pounds useful as intermediates to the pharmaceutical agent fatty alcohol conjugates of the formula: O -

RO-P-T OR es OY H O 0054) are provided wherein R is a C-C group of a fatty alcohol ROH, R' is selcted from H, an ion, or a protecting group and T is a leaving group. n 0.055 According to yet another aspect of the invention, compounds which are useful as intermediates in the Synthe sis of pharmaceutical agent fatty alcohol conjugates are provided. These compounds are of the formula: X, ~~~~. Chris 0056 wherein R is a C-C group of a fatty alcohol ROH, T is a leaving group, and BOC is a tert-butoxy group. 0057. In certain embodiments, the leaving group T is OH, ~r a halogen, or another leaving group. Particularly important US 2002/0177609 A1 Nov. 28, 2002

0062. In another aspect of the invention, pharmaceutical -continued preparations comprising a compound of the formula:

RO-P-ZX

OR

0063 wherein R is a C-C fatty group of a fatty alcohol ROH, X is a pharmaceutical agent moiety of a pharmaceu tical agent XZH, wherein Z is O, a primary amino group, or a Secondary amino group, and R' is Selcted from H, an ion, or a protecting group, and a pharmaceutically acceptable carrier are provided. 0064. According to still another aspect of the invention, pharmaceutical preparations comprising a compound of the formula:

0065 wherein R is a C-C fatty group of a fatty alcohol ROH and X is a pharmaceutical agent moiety of a pharma ceutical agent HNR"X, wherein R" is selected from H, an alkyl group, an alkenyl group, an alkynyl group, or an aryl group and a pharmaceutically acceptable carrier are pro vided. 0066 According to yet another aspect of the invention, pharmaceutical preparations comprising a compound of the formula: 0.058. The fatty alcohols and fatty alcohol moieties of important and preferred embodiments are as described O above, as if Specifically restated herein. us RO X 0059 Those of skill in the art will appreciate that various modifications to the Synthetic methods described are poS sible, and included in the invention. Such modifications 0067 wherein R is a C-C fatty group of a fatty alcohol include, for example, polymer Supported, or Solid phase, ROH and X is a pharmaceutical agent moiety of a pharma chemistry. ceutical agent XCOO)OH and a pharmaceutically acceptable carrier are provided. 0060 According to another aspect of the invention, phar 0068 According to still another aspect of the invention, maceutical preparations of all of the compositions described pharmaceutical preparations comprising a compound of the herein are provided. In one embodiment, the pharmaceutical formula: preparation comprises a compound of the formula: lsO RO OX

0061 wherein R is a C-C fatty group of a fatty alcohol 0069 wherein R is a C-C fatty group of a fatty alcohol ROH, and X is a pharmaceutical agent moiety of the ROH and X is a pharmaceutical agent moiety of a pharma pharmaceutical agent XOH, and a pharmaceutically accept ceutical agent XOH and a pharmaceutically acceptable able carrier. carrier are provided. US 2002/0177609 A1 Nov. 28, 2002

0070 According to another aspect of the invention, phar 0078. According to still another aspect of the invention, maceutical preparations comprising a compound of the pharmaceutical preparations comprising a compound of the formula: formula:

S

ls RO n ls Y X XHN OR N N H H 0071 wherein R is a C-C fatty group of a fatty alcohol ROH and X is a pharmaceutical agent moiety of a pharma 0079 wherein R is a C-C fatty group of a fatty alcohol ceutical agent XOH and a pharmaceutically acceptable ROH and X is a pharmaceutical agent moiety of a pharma carrier are provided. ceutical agent XNH2 and a pharmaceutically acceptable 0.072 According to another aspect of the invention, phar carrier are provided. maceutical preparations comprising a compound of the formula: 0080. The fatty alcohols and fatty alcohol moieties of important and preferred embodiments are as described above, as if Specifically restated herein. '' OR p OR 0081 Certain embodiments of the pharmaceutical agent 1n-1 O 1n-1 categories are as listed above, and particularly important | categories are anticancer agents, antipsychotic agents and O O antiviral agents. Important Such agents and preferred embodiments are as described above, as if Specifically 0.073 and a pharmaceutically acceptable carrier are pro restated herein. Vided wherein R is a C-C fatty group of a fatty alcohol ROH and X is a pharmaceutical agent moiety of a pharma 0082) According to another aspect of the invention, meth ceutical agent XCHPOH, XCHRPOH, or ods for treating disorders are provided. In one aspect, XCR'R"POH, wherein RandR" are independently selected methods of treating disorders comprising administering to a from alkyl, alkenyl, aryl, alkyl-substituted heteroatom, alk Subject in need of Such treatment a pharmaceutical prepa enyl-Substituted heteroatom, or aryl-Substituted heteroatom, ration comprising a compound of the formula: and the like. 0.074 According to another aspect of the invention, phar O maceutical preparations comprising a compound of the formula: ls RO OX

0083) and a pharmaceutically acceptable carrier are pro Vided wherein R is a C-C fatty group of a fatty alcohol ROH, and X is a pharmaceutical agent moiety of the pharmaceutical agent XOH. 0075 XOH and a pharmaceutically acceptable carrier are 0084. In another aspect of the invention, methods for provided wherein R is a C-C fatty group of a fatty alcohol treating disorders comprising administering to a Subject in ROH and X is a pharmaceutical agent moiety of a pharma need of Such treatment a pharmaceutical preparation com ceutical agent bearing a ketone or aldehyde functionality, prising a compound of the formula: i.e., XC(O)H or XCO)R’ wherein R' is alkyl, alkenyl, aryl, and the like. 0.076 According to another aspect of the invention, phar maceutical preparations comprising a compound of the RO-P-ZX formula: OR

NH 0085 and a pharmaceutically acceptable carrier are pro us Y Vided wherein R is a C-C fatty group of a fatty alcohol RO N H ROH, X is a pharmaceutical agent moiety of a pharmaceu tical agent XZH, wherein Z is O, a primary amino group, or a Secondary amino group, and R' is Selcted from H, an ion, 0.077 wherein R is a C-C fatty group of a fatty alcohol or a protecting group. ROH and X is a pharmaceutical agent moiety of a pharma ceutical agent XNH2 and a pharmaceutically acceptable 0086. In another aspect of the invention, methods of carrier are provided. treating disorders comprising administering to a Subject in US 2002/0177609 A1 Nov. 28, 2002 need of Such treatment a pharmaceutical preparation com 0093 and a pharmaceutically acceptable carrier are pro prising a compound of the formula: vided wherein R is a C-C fatty group of a fatty alcohol ROH and X is a pharmaceutical agent moiety of a pharma ceutical agent XOH. 0094. In another aspect of the invention, methods of treating disorders comprising administering to a Subject in need of Such treatment a pharmaceutical preparation com prising a compound of the formula:

0.087 and a pharmaceutically acceptable carrier are pro OR Vided wherein R is a C-C fatty group of a fatty alcohol X P O 1n-1 ROH and X is a pharmaceutical agent moiety of a pharma ceutical agent XOH, and R" is Selected from an alkyl group, O O an alkenyl group, an alkynyl group, or an aryl group. 0088. In another aspect of the invention, methods of 0095 and a pharmaceutically acceptable carrier are pro treating disorders comprising administering to a Subject in Vided wherein R is a C-C fatty group of a fatty alcohol need of Such treatment a pharmaceutical preparation com ROH and X is a pharmaceutical agent moiety of a pharma prising a compound of the: ceutical agent XCHPOH, XCHRPOH, or XCR'R"POH, wherein RandR" are independently selected O from alkyl, alkenyl, aryl, alkyl-Substituted heteroatom, alk enyl-Substituted heteroatom, or aryl-Substituted heteroatom, us and the like. RO X 0096. In another aspect of the invention, methods of treating disorders comprising administering to a Subject in 0089 and a pharmaceutically acceptable carrier are pro need of Such treatment a pharmaceutical preparation com vided wherein R is a C-C fatty group of a fatty alcohol prising a compound of the formula: ROH and X is a pharmaceutical agent moiety of a pharma ceutical agent XCO)OH. 0090. In another aspect of the invention, methods of treating disorders comprising administering to a Subject in need of Such treatment a pharmaceutical preparation com prising a compound of the formula: 0097 and a pharmaceutically acceptable carrier are pro vided wherein R is a C-C fatty group of a fatty alcohol ROH and X is a pharmaceutical agent moiety of a pharma ceutical agent bearing a ketone or aldehyde functionality, HN ls N1 X H i.e., XC(O)H or XCO)R’ wherein R' is alkyl, alkenyl, aryl, and the like. R 0098. In another aspect of the invention, methods of treating disorders comprising administering to a Subject in 0.091 and a pharmaceutically acceptable carrier are pro need of Such treatment a pharmaceutical preparation com Vided wherein R is a C-C fatty group of a fatty alcohol prising a compound of the formula: ROH and X is a pharmaceutical agent moiety of a pharma ceutical agent XNH2. NH 0092. In another aspect of the invention, methods of Y treating disorders comprising administering to a Subject in RO ls N need of Such treatment a pharmaceutical preparation com H prising a compound of the formula: 0099 and a pharmaceutically acceptable carrier are pro Vided wherein R is a C-C fatty group of a fatty alcohol S ROH and X is a pharmaceutical agent moiety of a pharma ls ceutical agent XNH2. XHN OR 0100. In still another aspect of the invention, methods of treating disorders comprising administering to a Subject in US 2002/0177609 A1 Nov. 28, 2002

need of Such treatment a pharmaceutical preparation com phosphate linkage is provided. The method comprises react prising a compound of the formula: ing an intermediate of the formula:

RO n ls Y X RO-P-T N N H H OR

0101 and a pharmaceutically acceptable carrier are pro 0.108 with a pharmaceutical agent XZH for a time suf Vided wherein R is a C-C fatty group of a fatty alcohol ficient to form the compound wherein R is a C-C fatty ROH and X is a pharmaceutical agent moiety of a pharma group of a fatty alcohol ROH, X is a pharmaceutical agent ceutical agent XNH2. moiety of the pharmaceutical agent XZH, wherein Z is O, a 0102) The fatty alcohols and fatty alcohol moieties of primary amino group, or a Secondary amino group, and R' is important and preferred embodiments are as described Selcted from H, an ion, a protecting group or a Second above, as if Specifically restated herein. pharmaceutical agent. 0103) Certain embodiments of the pharmaceutical agent 0109) Alternatively, the pharmaceutical agent fatty alco categories are as listed above, and particularly important hol conjugates may be Synthesized by first derivatizing the categories are anticancer agents, antipsychotic agents and pharmaceutical agent at a carboxylic acid group with a antiviral agents. Important Such agents and preferred phosphate linkage-leaving group moiety and then coupling embodiments are as described above, as if Specifically to a fatty alcohol. Although both methods may be accom restated herein. plished using techniques known to those of skill in the art, exemplary Synthetic methods are also provided in the 0104. In certain embodiments, the disorder is a mamma Examples. lian cell proliferative disorder, a mammalian Viral disorder, or mammalian psychiatric disorder. 0110. According to yet another embodiment of the inven tion, methods of making pharmaceutical agents conjugated 0105. According to another aspect of the invention, meth to a fatty alcohols via carbamate linkages are provided. The ods of Synthesizing fatty alcohol pharmaceutical agent con method compriseS reacting an intermediate of the formula jugate compounds are provided. Generally, the methods ROC(O)T with a pharmaceutical agent of the formula involve derivatizing a fatty alcohol with an appropriate HNR"X for a time sufficient to form the compound wherein linkage and leaving group to form an intermediate and R is a C-C fatty group of a fatty alcohol ROH, X is a reacting the intermediate with a pharmaceutical agent to pharmaceutical agent moiety of the pharmaceutical agent of form the conjugate compound. Alternatively, the pharma the fonnula HNR"X, R" is a H, an alkyl group, an aryl group, ceutical agent may be derivatized with an appropriate link etc. and T is a leaving group. age and leaving group and reacted with a fatty alcohol to form the conjugate compound. Generally, it is preferred to 0111. According to still another embodiment of the couple the fatty alcohol with a linkage and leaving group invention, methods of making pharmaceutical agents con before conjugating the fatty alcohol with the pharmaceutical jugated to fatty alcohols via guanidine linkages are pro agent. AS will be clear to those skilled in the art, other vided. The method comprises reacting a fatty alcohol ROH reactive groups of the pharmaceutical agent besides the Site with a guanylation agent Such as 1,3-bis(tert-butoxy carbo to be conjugated may have to be protected, which can be nyl)-2-methyl-2-thiopseudourea or 1,3-bis(tert-butoxy car accomplished by routine methods known in the art, as bonyl-1H-pyrazole-1-carboxamidine and reacting the result described in, for example, Greene T. W., et al., In “Protective ing product with a pharmaceutical agent of the formula Groups in Organic Synthesis', 3rd Ed., John Wiley & Sons, XOH for a time sufficient to form the compound wherein R Inc., New York, N.Y.; 1999, hereby included by reference. is a C-C fatty group of the fatty alcohol, and X is a Nonetheless, Several representative Synthetic methods are pharmaceutical agent moiety of the pharmaceutical agent of shown in the Examples. the formula XOH. 0106. In one embodiment, methods of synthesizing a 0112 According to yet another aspect of the invention, pharmaceutical agent conjugated to a fatty alcohol via methods of making fatty alcohols conjugated to pharmaceu carbonate linkages and ester linkages are provided. The tical agents via isourea linkages are provided. The method method compriseS reacting an intermediate of the formula comprises adding an azido group to a fatty alcohol, reducing ROC(O)T with a pharmaceutical agent of the formula XOH the azido group to an amino group, reacting the amino group for a time Sufficient to form the conjugate wherein R is a with the 4-nitrophenyl chloroformate, and coupling the C-C2s fatty group of a fatty alcohol ROH, X is a pharma product to a pharmaceutical agent XNH for a time Sufficient ceutical agent moiety of the pharmaceutical agent of the to form the conjugate. formula XOH or XCO)OH, and T is a leaving group. As 0113. According to still another aspect of the invention, will be apparent to those of skill in the art, a pharmaceutical methods of making fatty alcohols conjugated to pharmaceu agent XOH would result in a conjugate via a carbonate tical agents via thionocarbamate linkages are provided. The linkage and a pharmaceutical agent XCO(O)H would result method comprises treating a fatty alcohol with thiophosgene in a conjugate Via an ester linkage. (or a similar reagent Such as di-2-pyridylthionocarbonate or 0107. In another embodiment, a method of synthesizing di-N-hydroxysuccinimidyl thionocarbonate) fatty alkyl a pharmaceutical agent conjugated to a fatty alcohol via a chlorothionoformate (or fatty alkyl 2-pyridyl thionocarbon US 2002/0177609 A1 Nov. 28, 2002

ate or fatty alkyl N-hydroxSuccinimidyl thionocarbonate). 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, Treatment of any one of these activated intermediates fur 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350 or nishes the corresponding thionocarbamate conjugates, link 1400 mg/meter of body surface area (BSA). In one embodi ing a pharmaceutical agent to a a fatty alcohol. ment, the amount is administered to the Subject over a period 0114. According to still another aspect of the invention, of 24 hours or less, 6 hours or less, 3 hours or less, or 2 hours methods of making fatty alcohols conjugated to pharmaceu or less. In Some embodiments, the fatty alcohol has a C-C, tical agents via phosphonate linkages are provided. The fatty alcohol carbon Structure. In important embodiments, method comprises treating a pharmaceutical agent possess the fatty alcohol has the carbon Structure of a C-C, ing a phosphonate group with either thionyl chloride or unbranched, naturally occurring fatty acid. In certain par oxalyl chloride to give the corresponding phosphonic ticularly preferred embodiments, the fatty alcohol has the dichloride intermediate. Treatment of this intermediate with Same carbon Structure as linoleic acid, palmitic acid, arachi either one or two equivalents of a fatty alcohol, furnishes the donic acid, eicosapentaenoic acid, docosahexaenoic acid, monophosphonate conjugate and bisphosphonate conjugate, 2-octanoate, 2-hexanoate, CH-hexanoate, CH-butanoate, respectively. or oleic acid. In preferred embodiments, the taxane is paclitaxel. In important embodiments, when the taxane is 0115 According to still another aspect of the invention, paclitaxel, the fatty alcohol is conjugated at the 2' OH methods of making fatty alcohols conjugated to pharmaceu position of paclitaxel. tical agents via Oxime linkages are provided. The method 0119). In any of the foregoing embodiments, the maxi comprises converting a fatty alcohol to an O-fatty alkyl mum tolerated dose can be determined according to proce hydoxylamine, then condensing the O-fatty alkyl hydoxy dures known to those of ordinary skill in the art. The lamine with a ketone or aldehyde moiety of a pharmaceu Maximum Tolerated Doses of many compounds are already tical agent to funnish the (E) or (Z) oxime conjugate. known. Some for known anticancer agents are listed below. 0116. According to another aspect of the invention, a 0120 According to another aspect of the invention, a fatty alcohol-anticancer compound conjugate in Some composition of matter is provided. The composition com embodiments is believed to be confined, unexpectedly, to the prises a crystal of a conjugate of a polyunsaturated fatty plasma Space of a Subject receiving Such treatment, and that alcohol and a drug. In preferred embodiments, the fatty the conjugate has, Surprisingly, (i) a Smaller volume of alcohol has a carbon Structure of a C-C or C-C fatty distribution as compared to the unconjugated anticancer acid. In Some embodiments the fatty alcohol has the carbon compound alone (in many instances ~100 fold less), and (ii) Structure of a naturally-occurring, unbranched fatty acid. In a Smaller clearance as compared to the unconjugated anti certain embodiments, the fatty alcohol has the same carbon cancer compound alone (in many instances 100 fold less). Structure as the carbon Structure of linoleic acid, palmitic Moreover, it is believed that the fatty alcohol-anticancer acid, arachidonic acid, elcosapentaenoic acid, docosa compound conjugate may be present at a higher concentra hexaenoic acid, 2-octanoate, 2-hexanoate, CH-hexanoate, tion in tumor cells as compared to the unconjugated anti CH-butanoate, or oleic acid. cancer compound. 0121. In any of the foregoing embodiments, the drug can 0117 Thus, a fatty alcohol-anticancer compound conju be among those listed below. The drug must contain a Site gate composition for administration to a Subject is provided. (reactive group) amenable for conjugation to a fatty alcohol The composition includes at least one fatty alcohol-antican or to a fatty alcohol derivative as described herein. Chemists cer compound conjugate in a container for administration to of ordinary skill in the art can make Such determinations. a Subject. The amount of the fatty alcohol-anticancer com The anticancer compound can be a taxane. In certain pound in the container is at least about 10% greater than the embodiments, the taxane is paclitaxel. hi important embodi maximum tolerated dose (MTD) for the unconjugated at ments, when the taxane is paclitaxel, the fatty alcohol is least one anticancer compound (based on the weight of the conjugated at the 2' OH position of paclitaxel. anticancer compound in the conjugate versus the weight of 0.122 The invention in another aspect provides compo the anticancer compound itself, or calculated on a molar Sitions and formulations for administration to a Subject, basis of the conjugate versus the unconjugated anticancer preferably a human Subject, containing amounts of a fatty compound). Preferably the amount of the fatty alcohol alcohol-anticancer compound conjugate which exceeds the anticancer compound in the container is at least about 20% maximum tolerated dose for the unconjugated anticancer greater than the MITD, 30% greater than the MTD, 40% compound. The fatty alcohol-anticancer compound conju greater than the MTD, 50% greater than the MTD, 75% gate preferably is in a container for administration to a greater than the MTD, a 100% greater than the MTD, 200% subject. Preferably the container is a container for intrave greater than the MTD, 300% greater than the MTD, or 400% nous administration, Such as an IV bag. greater than the MTD for the unconjugated at least one 0123 The amount of the fatty alcohol-anticancer com anticancer compound. In certain preferred embodiments, the pound in the container is at least about 10% greater than the container is a container for intravenous administration. In MTD for the unconjugated compound. Preferably the other embodiments, the anticancer compound is a taxane, amount of the fatty alcohol-anticancer compound in the preferably paclitaxel or docetaxel. In important embodi container is at least about 20%, 30%, 40%, 50%, 75%, ments, the conjugate is not encapsulated in a liposome. 100%, 200%, 300% or 400% greater than the MTD for the 0118 According to yet another aspect of the invention, a unconjugated at least one anticancer compound. The anti method for treating a Subject having an abnormal mamma cancer compound is preferably a taxane, particularly pacli lian proliferative disorder is provided. The method involves taxel or docetaxel. administering to the Subject a fatty alcohol-taxane conjugate 0.124. Although the conjugate may be encapsulated in a in an amount of the conjugate which is at least 250,275,300, liposome, it is preferred that the conjugate is not encapsu US 2002/0177609 A1 Nov. 28, 2002 lated by a lipoSome in Some embodiments. The preferred and octadecanol (18:0-OH). Fatty alcohols also can be Subjects for the method are humans. Synthesized, typically from fatty acids, natural or Synthetic. Thus, fatty alcohols can have the same carbon Structure of 0.125 The conjugated anticancer compounds described naturally occurring polyunsaturated fatty acids but have a herein are less toxic and more effective than the correspond terminal alcohol group instead of the terminal acid group of ing unconjugated anticancer compounds. Therefore the fatty the fatty acids (i.e., are the alcohol form of polyunsaturated alcohol-anticancer compound conjugates can be adminis fatty acids). In Some embodiments, the fatty alcohol pref tered in amounts which are equally toxic but more effective, erably has the Same carbon Structure as a C-C, or in doses which are equally effective and less toxic than the unbranched, naturally occurring fatty acid. In other embodi corresponding unconjugated anticancer compounds. In gen ments, the fatty alcohol preferably has the same carbon eral, conjugation of fatty alcohol to anticancer compounds Structure as the carbon structure of a C-C and permits an increase in the maximum tolerated dose relative unbranched naturally occurring fatty acids. In other words, to unconjugated anticancer compounds. the fatty alcohol may have 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 carbon atoms. DETAILED DESCRIPTION OF THE INVENTION 0131 Alternatively, the fatty alcohol may have a carbon Structure which is the same as that of an unnatural fatty acid. 0.126 The invention described herein relates to the prepa The carbon Structure may have an even or odd amount of ration of fatty alcohol-pharmaceutical agent conjugates and carbons, (E) or (Z) stereochemistry about each double bond, methods of using the conjugates in the treatment of disease. and encompasses isomers of naturally occurring fatty moi The conjugates may be a direct conjugate between the fatty eties of naturally occurring fatty acids, formed by, for alcohol and the pharmaceutical agent, Such as by an ester example, differing placement of the double bonds through bond, or via a linkage Such as a carbonate phosphate, out the carbon chain. It will be obvious to those of skill in carbamate, guanidine, thionocarbamate, isourea, or urea the art that various isomers of the fatty alcohols and fatty linkage. In certain embodiments the conjugate breaks apart acids described are included. For example, there are Several in Vivo into components that are naturally occurring or that isomers of linoleic acid, which differ in the placement of the are readily metabolized into molecules that are naturally double bonds. occurring. This is a particularly desirable aspect of the invention. 0132 Carbon structures of fatty alcohols useful in the present invention include carbon Structures of the following 0127. The invention provides compositions of matter. fatty acids: octanoic (caprylic); nonanoic (pelargonic); The invention also provides intermediates formed in the decanoic (capric); undecanoic (hendecanoic); dodecanoic process of making the compositions of matter. The invention (lauric); tridecanoic, tetradecanoic (myristic); pentade also provides Substantially pure crystals of a conjugate of a canoic, hexadecanoic (pamitic); heptadecanoic (margaric); fatty alcohol and a pharmaceutical agent. The invention also octadecanoic (Stearic); 12-hydroxy Stearic; nonadecanoic, encompasses methods of preparing and conjugating the fatty eicosanoic (arachidic); heneicosanoic, docosanoic alcohols and pharmaceutical agents. Examples of processes (behenic); tricosanoic, tetracosanoic (lignoceric). of making compositions of matter, and the intermediates in the process, which are not intended to be limiting is, for 0133) Other carbon structures of fatty alcohols useful in example, the Synthesis of etopophos fatty alcohol phosphate the present invention include carbon Structures of the fol ester (in the Examples). Several Synthetic processes are lowing fatty acids: 10-undecenoic (hendecenoic), 11-dode described herein, although one of skill in the art will cenoic, 12-tridecenoic, 9-tetradecenoic (myristoleic); recognize that there may be other possible Synthetic meth 9-trans-tetradecenoic (myristelaidic); 10-pentadecenoic, ods. 10-trans-pentadecenoic, 9-hexadecenoic (palmitoleic); 8-trans-hexadecenoic (pahnitelaidic); 10-heptadecenoic, 0128. In the preparation of the compositions, fatty alco 10-trans-heptadecenoic, 6-octadecenoic (petroselinic); hols may be reacted with pharmaceutical agents to produce 6-trans-octadecenoic (petroselaidic); 8-octadecenoic (oleic); conjugates. AS used herein, "reacting a fatty alcohol (or a 9-11-octadecenoic (vaccenic); 11-trans-octadecenoic (trans fatty alcohol intermediate) with a pharmaceutical agent vaccenic); 9-cis-12hydroxy-octadecenoic (ricinoleic); means the fatty alcohol and the pharmaceutical agent are 9-trans-12-hydroxy-octadecenois (ricinelaidic); 7-nonade contacted under appropriate conditions for a time Sufficient cenoic, 7-trans-nonadecenoic, 10-nonadecenoic, 10-trans to result in the covalent conjugation of the pharmaceutical nonadecenoic, 10-13-nonadecadienoic, 10-13-trans-nona agent and the fatty alcohol (or the fatty alcohol intermedi decadienoic, 8-12-octadecadienoic (linoleic); 9-trans-12 ate). Such conditions encompass standard chemistry meth trans octadecadienoic (linoelaidic); octadecadienoic ods, which may be determined by one of skill in the art. (conjugaged); 9-12-15-octadecatrienoic (linolenic), 6-9-12 0129. In the preparation of the compositions, certain of octadecatrienoic (gamma linolenic); 11-trans-eicosenoic, the reactants may have leaving groups. AS used herein, the 8-eicoSenoic, 11-eicoSenoic, 5-eicoSenoic, 11-14-eicOSadi term “leaving group” means a chemical moiety which is enoic, 8-11-14-eicosatrienoic (homogamma linolenic); removed in the course of the reaction and does not form part 11-14-17-eicosatrienoic, 5-8-11-14-eicosatetraenoic of the conjugate. Leaving groups are well known in the art. (arachidonic); 5-8-11-14-17-eicosapentaenoic, 7-10-13-16 Thus, one of ordinary skill can Select an appropriate leaving 19-docosapentaenoic, arachidonic, 13-docoSenoic (erucic); 13-transdocoSenoic (brassidic); 13-16-docOSadienoic, group with no more than routine skill. 13-16-19-docosatrienoic, 7-10-13-16-docosatetraenoic, 4-7- 0130 Fatty alcohols are lipidic molecules that naturally 10-13-16-19-docosahexaenoic (DHA); 12-heneicosenoic; occur in plants, and limited types have also been identified 12-15-heneicosadienoic, 14-tricoSenoic, 15-tetracoSenoic in cultured human cells, including hexadecanol (C16-0-OH) (nervonic). US 2002/0177609 A1 Nov. 28, 2002

0134. In certain important embodiments, the carbon System tissue and noncentral nervous System tissue. Such Structure of fatty alcohol can be the same as the carbon conditions can be specific to breast tissue, gastrointestinal Structure of linoleic acid, palmitic acid, arachidonic acid, tissue and Ovarian tissue. The tissue also may be other eicosapentaenoic acid, docosahexaenoic acid, 2-octanoate, noncentral nervous System tissues. Noncentral nervous Sys 2-hexanoate, CH-hexanoate, CH-butanoate, or oleic acid. tem tissue includes tissues of the blood and blood forming In particularly preferred embodiments, the fatty alcohol has System: including platelets, blood vessel wall, and bone the same carbon Structure as: linoleic acid, palmitic acid, marrow, cardiovascular System: including heart and Vascu arachidonic acid, eicosapentaenoic acid, or docosahexaenoic lar System; digestive and excretory System: including ali acid. mentary tract, biliary tract, kidney, liver, pancreas and urinary tract; endocrine System: including adrenal gland, 0135) Some fatty alcohols are naturally occurring and kidney, ovary, pituitary gland, renal gland, Salivary gland, may therefore be obtained from natural sources. Other fatty Sebaceous gland, testis, thymus gland and thyroid gland; alcohols can be made by converting fatty acids to fatty muscular System: including muscles that move the body; alcohols using Standard methods, which are well known to reproductive System: including breast, ovary, penis and those of ordinary skill in the art. For example, fatty alcohols uterus, respiratory System: including bronchus, lung and can be Synthesized from fatty acids by forming the corre trachea, Skeletal System: including bones and joints, tissue, sponding fatty acid methyl ester and then reducing the ester fiber, and integumentary System: including adipose tissue, with NaBH, LiAlH, or another reducing agent. cartilage, connective tissue, cuticle, dermis, epidermis, epi 0.136 The methods and/or products of the invention are thelium, fascia, hair follicle, ligament, bone marrow, mela useful for treating a variety of medical conditions. The nin, melanocyte, mucous membrane, Skin, Soft tissue, Syn conditions will be apparent from the list of drugs below. ovial capsule and tendon. Among the conditions are abnormal mammalian-cell prolif 0.139. A pharmaceutical agent, according to this aspect of eration, psychosis, infectious disease, cardiovascular condi the invention can be any drug that can form a conjugate with tions, Stroke, Alzheimer's disease, and dementia. One a fatty alcohol or a fatty alcohol intermediate according to important embodiment is conditions involving abnormal the invention. Preferably, the drug has free groups reactive mammalian cell proliferation. The methods and/or products with a free alcohol of the fatty alcohol or the reactive group of the invention may be useful for treating cancers including, of one of the intermediates of the invention. More prefer but not limited to, biliary tract cancer, bladder cancer, brain ably, the drug has a free -OH (hydroxyl group), -NH cancer including glioblastomas and medulloblastomas, (primary amino group), -NHR' (secondary amino group breast cancer; cervical cancer, choriocarcinoma, colon can wherein R' is alkyl, aryl, etc.), -SH (thio group) or -COH cer, endometrial cancer, esophageal cancer, gastric cancer, (carboxylic acid) group. hematological neoplasms including acute lymphocytic and myelogenous leukemia; multiple myeloma; AIDS-associ 0140. A pharmaceutical agent moiety, according to the ated leukemias and adult T-cell leukemia lymphoma; invention, is a pharmaceutical agent that has lost a hydrogen, intraepithelial neoplasms including Bowen's disease and in the case of, for example, an -OH, -NH, -NHR', or Paget's disease; liver cancer; lung cancer, lymphomas -COH group. including Hodgkin's disease and lymphocytic lymphomas, 0141 AS used herein, pharmaceutical agents may be neuroblastomas, oral cancer including Squamous cell carci Selected from, but are not limited to, the following agents: noma, ovarian cancer including those arising from epithelial adrenergic agent, adrenocortical Steroid; adrenocortical Sup cells, Stromal cells, germ cells and mesenchymal cells, preSSant; alcohol deterrent, aldosterone antagonist, amino pancreatic cancer, prostate cancer, rectal cancer, Sarcomas acid; ammonia detoxicant; anabolic; analeptic, analgesic, including leiomyosarcoma, rhabdomyosarcoma, liposar androgen; anesthesia; anesthetic; anorectic; antagonist, ante coma, fibrosarcoma, and Osteosarcoma; Skin cancer includ rior pituitary Suppressant, anthelmintic, anti-acne agent; ing melanoma, Kaposi's Sarcoma, basocellular cancer, and anti-adrenergic, anti-allergic, anti-amebic, anti-androgen; Squamous cell cancer, testicular cancer including germinal anti-anemic, anti-anginal; anti-anxiety; anti-arthritic, anti tumors Such as Seminoma, non-Seminoma (teratomas, cho asthmatic, anti-atherOSclerotic, antibacterial; anticholelithic, riocarcinomas), Stromal tumors, and germ cell tumors; thy anticholelithogenic, anticholinergic, anticoagulant; anticoc roid cancer including thyroid adenocarcinoma and medullar cidal; anticonvulsant, antidepressant, antidiabetic, antidiar carcinoma, and renal cancer including adenocarcinoma and rheal; antidiuretic, antidote, anti-emetic, anti-epileptic, anti Wilms tumor. estrogen; antifibrinolytic, antifingal; antiglaucoma agent; 0.137 The products and/or methods of the invention are antihemophilic, antihemorrhagic, antihistamine; antihyper useful, in general, for treating mammalian cell proliferative lipidemia; antihyperlipoproteinemic, antihypertensive; anti disorders other than cancer including psoriasis, actinic kera hypotensive, anti-infective, anti-infective, topical; anti-in tosis, etc. They further are useful in treating diabetes and its flammatory; antikeratinizing agent, antimalarial; complications, exceSS acid Secretion, cardiovascular condi antimicrobial; antimigraine; antimitotic, antimycotic, antin tions involving cholesterol (e.g., hyperlipidemia and hyper auSeant, antineoplastic, antineutropenic, antiobessional cholesterolemia), diarrhea, ovarian diseases (e.g. agent, antiparasitic, antiparkinsonian; antiperistaltic, antip endometriosis, ovarian cysts, etc.) and as contraceptive neumocystic, antiproliferative; antiprostatic hypertrophy; agents. Other conditions treatable according to the invention antiprotozoal; antipruritic, antipsychotic, antirheumatic; will be apparent to those skilled in the art based upon the antischistosomal; antiseborrheic, antisecretory; antispas disclosure and lists of compounds provided. modic, antithrombotic, antituSSive; anti-ulcerative; anti urolithic, antiviral; appetite SuppreSSant; benign prostatic 0.138. The methods and/or products of the invention also hyperplasia therapy agent, blood glucose regulator, bone are useful in treating conditions Specific to central nervous resorption inhibitor; bronchodilator, carbonic anhydrase US 2002/0177609 A1 Nov. 28, 2002

inhibitor; cardiac depressant, cardioprotectant; cardiotonic; Sepazonium Chloride; Silver Nitrate; Sulfadiazine, Silver; cardiovascular agent; choleretic, cholinergic, cholinergic Symclosene; Thimerfonate Sodium; Thimerosal; Troclosene agonist, cholinesterase deactivator, coccidioStat; cognition Potassium. adjuvant; cognition enhancer, depressant, diagnostic aid; 0144 Antibacterials include, but are not limited to, diuretic, dopaminergic agent, ectoparasiticide, emetic; AcedapSone; AcetoSulfone Sodium; Alamecin, Alexidine, enzyme inhibitor; estrogen; fibrinolytic, fluorescent agent; Amdinocillin; Amdinocillin Pivoxil; Amicycline; Amifloxa free oxygen radical Scavenger, gastrointestinal motility cin; Amifloxacin MeSylate; Arnikacin; Amikacin Sulfate; effector; glucocorticoid; gonad-stimulating principle; hair AminoSalicylic acid; AminoSalicylate Sodium; Amoxicillin; growth Stimulant; hemoStatic; histamine H2 receptor Amphomycin; Ampicillin; Ampicillin Sodium; Apalcillin antagonists, hormone, hypocholesterolemic, hypoglycemic, Sodium; Apramycin; ASpartocin, Astromicin Sulfate; AVila hypolipidemic, hypotensive; imaging agent, immunizing mycin; AVoparcin, Azithromycin, AZlocillin, AZlocillin agent; immunomodulator; immunoregulator; immunostimu Sodium; Bacampicillin Hydrochloride; Bacitracin; Bacitra lant; immunosuppreSSant; impotence therapy adjunct; cin Methylene Disalicylate; Bacitracin Zinc, Bambermy inhibitor, keratolytic; LNRH agonist; liver disorder treat cins; Benzoylpas Calcium; Berythromycin; Betamicin Sul ment; luteolysin; memory adjuvant; mental performance fate; Biapenem; Biniramycin; Biphenamine Hydrochloride; enhancer, mood regulator, mucolytic, mucosal protective Bispyrithione Magsulfex; Butikacin; Butirosin Sulfate; agent, mydriatic, nasal decongestant; neuromuscular block Capreomycin Sulfate; Carbadox; Carbenicillin Disodium; ing agent; neuroprotective; NMDA antagonist; non-horm Carbenicillin Indanyl Sodium; Carbenicillin Phenyl nonal Sterol derivative; oxytocic, plasminogen activator; Sodium; Carbenicillin Potassium; Carumonam Sodium; platelet activating factor antagonist, platelet aggregation Cefaclor; Cefadroxil, Cefamandole; Cefamandole Nafate; inhibitor, post-Stroke and post-head trauma treatment; Cefamandole Sodium; Cefaparole; Cefatrizine; Cefazaflur potentiator, progestin, prostaglandin; prostate growth inhibi Sodium; Cefazolin; Cefazolin Sodium; CefbuperaZone; Cef tor, prothyrotropin; psychotropic, pulmonary Surface; radio dinir; Cefepime; Cefepime Hydrochloride; Cefetecol; active agent, regulator, relaxant, repartitioning agent, Scabi Cefixime; Cefinenoxime Hydrochloride; Cefinetazole; cide, Sclerosing agent, Sedative, Sedative-hypnotic, Selective Cefinetazole Sodium; Cefonicid Monosodium; Cefonicid adenosine Al antagonist; Serotonin antagonist; Serotonin Sodium; Cefoperazone Sodium; Ceforanide; Cefotaxime inhibitor, Serotonin receptor antagonist; Steroid; Stimulant; Sodium; Cefotetan; Cefotetan Disodium; Cefotiam Hydro SuppreSSant; agent for treatment of Symptomatic multiple chloride; Cefoxitin; Cefoxitin Sodium; Ce?pimizole; Cefpi Sclerosis, Synergist; thyroid hormone; thyroid inhibitor; thy mizole Sodium; Ce?piramide; Ce?piramide Sodium; Cef romimetic, tranquilizer, agent for treatment of amyotrophic pirome Sulfate; Cefpodoxime Proxetil, Cefprozil; lateral Sclerosis, agent for treatment of cerebral ischemia; Cefroxadine; CefSulodin Sodium; Ceftazidime; Ceftibuten; agent for treatment of Paget's disease, agent for treatment of Ceftizoxime Sodium; Ceftriaxone Sodium; Cefuroxime; unstable angina; uricoSuric; vasoconstrictor; vasodilator; Cefuroxime Axetil, Cefuroxime Pivoxetil, Cefuroxime Vulnerary; Wound healing agent; and Xanthine oxidase Sodium; Cephacetrile Sodium; Cephalexin; Cephalexin inhibitor. Hydrochloride; Cephaloglycin; Cephaloridine; Cephalothin 0.142 Lists of compounds in each of these categories can Sodium; Cephapirin Sodium; Cephradine; Cetocycline be found in U.S. Pat. No. 5,795,909, the disclosure of which Hydrochloride; Cetophenicol; Chloramphenicol; Chloram is incorporated herein by reference. Among preferred groups phenicol Palmitate; Chloramphenicol Pantothenate Com of drugs are anticancer agents, antiinfectives including and plex; Chloramphenicol Sodium Succinate; Chlorhexidine antibacterials and antivirals, and neurological agents includ Phosphanilate; Chloroxylenol; Chlortetracycline Bisulfate; ing antipsychotics. Anticancer agents, antivirals, antipsy Chlortetracycline Hydrochloride; Cinoxacin; Ciprofloxacin; chotics, and preferred anticancer agents, preferred antivirals, Ciprofloxacin Hydrochloride; Cirolemycin; Clarithromycin; and preferred antipsychotics are as described below. Clinafloxacin Hydrochloride; Clindamycin; Clindamycin Hydrochloride; Clindamycin Palmitate Hydrochloride; 0143 Antiinfectives include, but are not limited to, Clindamycin Phosphate; Clofazimine; Cloxacillin Benza Difloxacin Hydrochloride; Lauryl Isoquinolinium Bromide; thine; Cloxacillin Sodium; Cloxyquin; Colistimethate Moxalactam Disodium; Ornidazole; Pentisomicin; Sara Sodium; Colistin Sulfate; Coumermycin; Coumermycin floxacin Hydrochloride; Protease inhibitors of HIV and Sodium; Cyclacillin; CycloSerine; Dalfopristin; DapSone; other retroviruses; Integrase inhibitors of HIV and other Daptomycin; Demeclocycline, Demeclocycline Hydrochlo retroviruses; Cefaclor (Ceclor); Acyclovir (Zovirax); Nor ride; Demecycline; Denoflingin; Diaveridine; Dicloxacillin; floxacin (Noroxin); Cefoxitin (Mefoxin); Cefuroxime axetil Dicloxacillin Sodium; Dihydrostreptomycin Sulfate; Dipy (Ceftin); Ciprofloxacin (Cipro); Aminacrine Hydrochloride; rithione; Dirithromycin; Doxycycline; Doxycycline Cal Benzethonium Chloride; Bithionolate Sodium; Bromchlo cium; Doxycycline Fosfatex; Doxycycline Hyclate; Droxa renone; Carbamide Peroxide; Cetalkonium Chloride; cin Sodium, Enoxacin; Epicillin; Epitetracycline Cetylpyridinium Chloride: Chlorhexidine Hydrochloride; Hydrochloride; Erythromycin; Erythromycin Acistrate; Clioquinol; Domiphen Bromide; Fenticlor; Fludazonium Erythromycin Estolate; Erythromycin Ethylsuccinate; Chloride; Fuchsin, Basic; Furazolidone; Gentian Violet, Erythromycin Gluceptate; Erythromycin Lactobionate; Halquinols; Hexachlorophene: Hydrogen Peroxide; Ich Erythromycin Propionate; Erythromycin Stearate; Etham thammol, Imidecyl Iodine, Iodine; Isopropyl Alcohol; butol Hydrochloride; Ethionamide; Fleroxacin; Floxacillin; Mafenide Acetate; Meralein Sodium; Mercufenol Chloride; Fludalanine; Flumequine; Fosfomycin; Fosfomycin Mercury, Ammoniated; Methylbenzethonium Chloride; Tromethamine; Fumoxicillin; Furazolium Chloride; Furazo Nitrofurazone; Nitromersol; Octenidine Hydrochloride; lium Tartrate; Fusidate Sodium; Fusidic Acid, Gentamicin Oxychlorosene; Oxychlorosene Sodium; Parachlorophenol, Sulfate; Gloximonam, Gramicidin; Haloprogin, Hetacillin; Camphorated; Potassium Permanganate; PoVidone-lodine, Hetacillin Potassium; Hexedine; Tbafloxacin; Inipenem; US 2002/0177609 A1 Nov. 28, 2002

ISOconazole, Isepamicin; Isoniazid; Josamycin; Kanamycin pounds useful in the invention may be delivered in the form Sulfate; Kitasamycin; Levofuraltadone; Levopropylcillin of anticancer cocktails. An anticancer cocktail is a mixture Potassium; Lexithromycin; Lincomycin; Lincomycin of any one of the compounds useful with this invention with Hydrochloride; Lomefloxacin; Lomefloxacin Hydrochlo another anticancer agent Such as an anticancer drug, a ride; Lomefloxacin Mesylate; Loracarbef, Mafenide; Meclo cytokine, and/or Supplementary potentiating agent(s). The cycline; Meclocycline Sulfosalicylate; Megalomicin Potas use of cocktails in the treatment of cancer is routine. In this sium Phosphate; Mequidox; Meropenem; Methacycline; embodiment, a common administration vehicle (e.g., pill, Methacycline Hydrochloride; Methenamine; Methenamine tablet, implant, injectable Solution, etc.) would contain both Hippurate; Methenamine Mandelate; Methicillin Sodium; the fatty alcohol-anticancer pharmaceutical conjugate useful Metioprim; Metronidazole Hydrochloride; Metronidazole in this invention and/or Supplementary potentiating agent. Phosphate; Mezlocillin; Meziocillin Sodium; Minocycline; Minocycline Hydrochloride; Mirincamycin Hydrochloride; 0146 Anticancer agents include, but are not limited to, Monensin; Monensin Sodium; Nafcillin Sodium; Nalidixate Antineoplastic agents Such as: Acivicin, Aclarubicin; Sodium; Nalidixic Acid; Natamycin; Nebramycin; Neomy Acodazole Hydrochloride, Acronine, Adozelesin, Adriamy cin Palmitate; Neomycin Sulfate; Neomycin Undecylenate; cin; Aldesleukin; Alitretinoin, Allopurinol Sodium; Altre Netilmicin Sulfate; Neutramycin; Nifuradene; Nifurald tamine; Ambomycin; Ametantrone Acetate; Aminoglute eZone; Nifuratel; Nifuratrone, Nifurdazil; Nifurimide; thimide; AmSacrine; Anastrozole; Annonaceous Nifirpirinol; Nifurcquinazol; Nifurthiazole; Nitrocycline; Acetogenins, Anthramycin; ASimicin; Asparaginase, Asper Nitrofurantoin; Nitromide; Norfloxacin; Novobiocin lin, AZacitidine, AZetepa, AZOtomycin; Batimastat; Ben Sodium; Ofloxacin; Ormetoprim; Oxacillin Sodium; Oxi ZOdepa; Bexaroteine, Bicalutamide, Bisantrene Hydrochlo monam, OXimonam Sodium; OXolinic Acid, Oxytetracy ride; Bisnafide Dimnesylate; Bizelesin; Bleomycin Sulfate; cline; Oxytetracycline Calcium; Oxytetracycline Hydro Brequinar Sodium; Bropirimine; Bullatacin; Busulfan; Cab chloride; Paldimycin; Parachlorophenol; Paulomycin; ergoline; Cactinomycin; Calusterone; Caracemide, Carbe Pefloxacin; Pefloxacin Mesylate; Penamecillin; Penicillin G timer; Carboplatin; Carmustine; Carubicin Hydrochloride; Benzathine; Penicillin G Potassium; Penicillin G Procaine; Carzelesin; Cedefingol; Celecoxib; Chlorambucil; Cirole Penicillin G Sodium; Penicillin V; Penicillin V BenZathine; mycin; Cisplatin; Cladribine; Crisnatol Mesylate; Cyclo Penicillin V Hydrabamine; Penicillin V Potassium; Pentizi phosphamide; Cytarabine; Dacarbazine; DACA(N-2-(Pim done Sodium; Phenyl Aminosalicylate; Piperacillin Sodium; ethyl-amino)ethylacridine-4-carboxamide); Dactinomycin; Pirbenicillin Sodium; Piridicillin Sodium; Pirlimycin Daunorubicin Hydrochloride; Daunomycin; Decitabine; Hydrochloride; Pivampicillin Hydrochloride; Pivampicillin Denileukin Diftitox; DeXormaplatin, DeZaguanine, DeZa Pamoate; Pivampicillin Probenate; Polymyxin B Sulfate; guanine MeSylate; Diaziquone; Docetaxel; Doxorubicin; Porfiromycin; Propikacin; Pyrazinamide; Pyrithione Zinc; Doxorubicin Hydrochloride; Droloxifene; Droloxifene Cit Quindecamine Acetate; Quinupristin, Racephenicol; rate; DromoStanolone Propionate; DuaZomycin; Edatrexate, Ramoplanin; Ranimycin; Relomycin; Repromicin; Rifabu Eflornithine Hydrochloride; Elsamitrucin; Enloplatin; tin; Rifametane; Rifamexil; Rifamide; Rifampin; Rifapen Enpromate; Epipropidine; Epirubicin Hydrochloride; Erbu tine; Rifaximin; Rolitetracycline; Rolitetracycline Nitrate; lozole; Esorubicin Hydrochloride; Estramustine; Estramus Rosaramicin; Rosaramicin Butyrate; Rosaramicin Propi tine Phosphate Sodium; Etanidazole; Ethiodized Oil I 131; onate, Rosaramicin Sodium Phosphate, Rosaramicin Stear Etoposide; Etoposide Phosphate; Etoprine; Fadrozole ate, ROSoxacin; RoxarSone; Roxithromycin; Sancycline; Hydrochloride; Fazarabine; Fenretinide; Floxuridine, Flu Sanfetrinem Sodium; Sarmoxicillin; Sarpicillin; Scopafun darabine Phosphate; Fluorouracil; 5-FdUMP, Flurocitabine; gin, Sisomicin; Sisomicin Sulfate, Sparfloxacin; Spectino Fosquidone; Fostriecin Sodium; FK-317; FK-973; mycin Hydrochloride; Spiramycin; Stallimycin Hydrochlo FR-66979; FR-900482; Gemcitabine; Gemcitabine Hydro ride; Steffimycin; Streptomycin Sulfate; Streptonicozid; chloride; Gemtuzumab OZogamicin; Gold Au 198; Goser Sulfabenz, Sulfabenzamide, Sulfacetamide; Sulfacetamide elin Acetate; Guanacone, Hydroxyurea, Idarubicin Hydro Sodium; Sulfacytine; Sulfadiazine; Sulfadiazine Sodium; chloride; Ifosfamide; Ilmofosine; Interferon Alfa-2a, Sulfadoxine, Sulfalene; Sulfamerazine; Sulfameter; Sul Interferon Alfa-2b; Interferon Alfa-n1; Interferon Alfa-n3; famethazine; Sulfamethizole; Sulfamethoxazole; Sulfa Interferon Beta-I a; Interferon Gamma-Ib, Iproplatin; Irino monomethoxine, Sulfamoxole; Sulfanilate Zinc, Sulfanit tecan Hydrochloride; Lanreotide Acetate; Letrozole; Leu ran, SulfaSalazine; Sulfasomizole; Sulfathiazole; prolide Acetate, Liarozole Hydrochloride, Lometrexol Sulfazamet; Sulfisoxazole; Sulfisoxazole Acetyl; Sulfisox Sodium; Lomustine; Losoxantrone Hydrochloride; Maso azole Diolamine; Sulfomyxin; Sulopenem; Sultamicillin; procol; Maytansine; Mechlorethamine Hydrochloride; Suncillin Sodium; Talampicillin Hydrochloride; Teicopla Megestrol Acetate; Melengestrol Acetate; Melphalan; nin; Temafloxacin Hydrochloride; Temocillin; Tetracycline; Menogaril; Mercaptopurine; Methotrexate; Methotrexate Tetracycline Hydrochloride; Tetracycline Phosphate Com Sodium; Methoxsalen; Metoprine; Meturedepa; Mitindo plex; Tetroxoprim; Thiamphenicol; Thiphencillin Potas mide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; sium; Ticarcillin Cresyl Sodium; Ticarcillin Disodium; Mitomycin; Mytomycin C; Mitosper; Mitotane; Mitox Ticarcillin Monosodium; Ticlatone; Tiodonium Chloride; antrone Hydrochloride; Mycophenolic Acid; Nocodazole; Tobramycin; Tobramycin Sulfate; Tosufloxacin; Trimetho Nogalamycin; Oprelvekin; Ormaplatin; Oxisuran; Pacli prim; Trimethoprim Sulfate; Trisulfapyrimidines; Trolean taxel, Pamidronate Disodium; Pegaspargase, Peliomycin; domycin; Trospectomycin Sulfate; Tyrothricin; Vancomy Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobro cin; Vancomycin Hydrochloride, Virginiamycin; and man; Piposulfan; Piroxantrone Hydrochloride; Plicamycin; Zorbamycin. Plomestane; Porfimer Sodium; Porfiromycin; Prednimus tine; Procarbazine Hydrochloride; Puromycin; Puromycin 0145 The invention encompasses the preparation and use Hydrochloride; Pyrazofurin; Riboprine; Rituximab, of fatty alcohol-anticancer pharmaceutical agents. The com Rogletimide; Rolliniastatin; Safingol; Safingol Hydrochlo US 2002/0177609 A1 Nov. 28, 2002

ride, Samarium/Lexidronam, Semustine, 7-hydroxyStauro droxy-camptothecin); canarypox IL-2, capecitabine; car Sporine, SimtraZene, Sparfosate Sodium, SparSomycin; boxamide-amino-triazole; carboxyamidotriazole, CaRest Spirogermanium Hydrochloride, Spiromustine, Spiroplatin; M3; CARN 700; cartilage derived inhibitor; carzelesin; Squamocin, Squamotacin; Streptonigrin, Streptozocin, casein kinase inhibitors (ICOS), castanospermine; cecropin Strontium Chloride Sr 89; Sulofenur; Talisomycin; Taxane; B; cetrorelix; chlorins, chloroquinoxaline Sulfonamide, cica Taxoid; Tecogalan Sodium; Tegafur; Teloxantrone Hydro prost, cis-porphyrin, cladribine; clomifene analogues, clot chloride; Temoporfin, TenipoSide; Teroxirone, TeStolactone; rimazole; collismycin A, collismycin B; combretastatin A4, Thiamiprine; Thioguanine; Thiotepa; Thymitaq, Tiazofurin; combretastatin analogue, conagenin, crambescidin 816; cri Tirapazamine; Tomudex; TOP-53; Topotecan Hydrochlo Snatol; cryptophycin 8; cryptophycin A derivatives, curacin ride; Toremifene Citrate; Trastuzumab; Trestolone Acetate; A., cyclopentanthraquinones, cycloplatam, cypemycin; cyt Triciribine Phosphate; Trimetrexate; Trimetrexate Glucur onate; Triptorelin; Tubulozole Hydrochloride; Uracil Mus arabine ocfoSfate; cytolytic factor; cytostatin, dacliximab, tard; Uredepa; Valrubicin; Vapreotide; Verteporfin; Vinblas decitabine; dehydrodidemnin B; 2'deoxycoformycin (DCF); tine; Vinblastine Sulfate; Vincristine; Vincristine Sulfate; deslorelin; dexifosfamide; deXraZOxane, deXVerapamil, Vindesine; Vindesine Sulfate; Vinepidine Sulfate; Vinglyci diaziquone, didemnin B, didox; diethylnorSpermine, dihy nate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; dro-5-azacytidine, dihydrotaXol, 9-, dioxamycin; diphenyl Vinrosidine Sulfate; Vinzolidine Sulfate; Vorozole; Zenipl Spiromustine, discodermolide; docosanol; dolasetron, doxi atin; Zinostatin; Zorubicin Hydrochloride; 2-Chlorodeoxy fluridine, droloxifene, dronabinol; duocarmycin SA; adenosine; 2-Deoxyformycin, 9-aminocamptothecin, ralti ebSelen; ecomustine, edelfosine, edrecolomab, eflornithine; trexed; N-propargyl-5,8-dideaZafolic acid; 2-chloro-2'- elemene; emitefur; epirubicin; epothilones (A, R=H, B, arabino-fluoro-2'-deoxyadenosine; 2-chloro-2'- R=Me); epithilones, epristeride; estramustine analogue; deoxyadenosine; anisomycin; trichostatin A; hPRL-G129R; estrogen agonists; estrogen antagonists; etanidazole; etopo CEP-751; linomide; Sulfur mustard; nitrogen mustard Side, etoposide 4'-phosphate (etopofos); exemestane; fadro (mechlor ethamine); cyclophosphamide; melphalan; Zole; faZarabine; fenretinide; filgrastim; finasteride; fla chlorambucil; ifosfamide; busulfan; N-methyl-N-ni vopiridol; fleZelastine; fluiasterone, fludarabine; trosourea (MNU), N, N'-Bis(2-chloroethyl)-N-nitrosourea fluorodaunorunicin hydrochloride; forfenimex, formeStane; (BCNU); N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea fostriecin, fotemustine, gadolinium teXaphyrin, gallium (CCNU); N-(2-chloroethyl)-N'-(trans-4-methylcyclohexyl nitrate; galocitabine; ganirelix, gelatinase inhibitors, gem N-nitrosourea (MeCCNU); N-(2-chloroethyl)-N'-(diethyl citabine, glutathione inhibitors, hepSulfam; heregulin; heX )ethylphosphonate-N-nitroSourea (fotemustine); Streptozo amethylene bisacetamide; homoharringtonine (HHT); tocin; diacarbazine (DTIC); mitozolomide; temozolomide; hypericin; ibandronic acid; idarubicin; idoxifene; idraman thiotepa, mitomycin C, AZQ; adoZelesin; Cisplatin; Carbo tone; ihnofosine, illomastat, imidazoacridones, imiquimod; platin; Ormaplatin; Oxaliplatin; C1-973; DWA 2114R, immunostimulant peptides; insulin-like growth factor-1 JM216; JM335; Bis (platinum); tomudex; azacitidine; cyt receptor inhibitor; interferon agonists, interferons, interleu arabine, gemcitabine, 6-Mercaptopurine; 6-Thioguanine; kins, iobenguane; iododoxorubicin; ipomeanol, 4-, irinote Hypoxanthine; tenipoSide, 9-amino camptothecin, Topote can; iroplact, irSogladine, isobengaZole; isohomohalicon can; CPT-11; Doxorubicin; Daunomycin; Epirubicin; daru drin B; itasetron; jasplakinolide; kahalalide F, lamellarin-N bicin; mitoxantrone; losoxantrone; Dactinomycin (Actino triacetate; lanreotide; leinamycin; lenograstim; lentinan Sul mycin D); amsacrine, pyrazoloacridine, all-trans retinol; fate; leptolstatin; letrozole; leukemia inhibiting factor; leu 14-hydroxy-retro-retinol; all-trans retinoic acid; N-(4-Hy kocyte alpha interferon; leuprolide-estrogen-progesterone; droxyphenyl) retinamide; 13-cis retinoic acid; 3-Methyl leuprorelin; levamisole, liarozole, linear polyamine ana TTNEB; 9-cis retinoic acid; fludarabine (2-F-ara-AMP); and logue, lipophilic disaccharide peptide, lipophilic platinum 2-chlorodeoxyadenosine (2-Cda). compounds, lisSoclinamide 7; lobaplatin, lombricine, lom etrexol; lonidamine; loSOXantrone; lovastatin; loxoribine; 0.147. Other anti-neoplastic compounds include, but are lurtotecan; lutetium texaphyrin, lySofylline; lytic peptides, not limited to, 20-epi-1,25 dihydroxyvitamin D3; 5-ethyny maitansine; mannostatin A, marimaStat; masoprocol; luracil; abiraterone, aclarubicin; acylfulvene, adecypenol; maspin; matrilysin inhibitors, matrix metalloproteinase adoZelesin; aldesleukin; ALL-TK antagonists, altretamine; inhibitors, menogaril; merbarone; meterelin; methioninase; ambamustine; amidox, amifostine; aminolevulinic acid; metoclopramide; MIF inhibitor; mifepristone; miltefosine; amrubicin; amsacrine; anagrelide; anastrozole, androgra mirimostim; mismatched double stranded RNA, mithracin; pholide, angiogenesis inhibitors, antagonist D; antagonist G; mitoguaZone, mitolactol, mitomycin analogues, mitonafide; antarelix; anti-dorsalizing morphogenetic protein-i, antian mitotoxin fibroblast growth factor-Saporin, mitoxantrone; drogen, prostatic carcinoma; antiestrogen; antineoplaston; mofaroteine; molgramoStim; monoclonal antibody, human antisense oligonucleotides, aphidicolin glycinate, apoptosis chorionic gonadotrophin, monophosphoryl lipid A+myo gene modulators, apoptosis regulators, apurinic acid, ara bacterium cell wall Sk, mopidamol, multiple drug resistance CDP-DL-PTBA, arginine deaminase; asulacrine; atames gene inhibitor, multiple tumor SuppreSSor 1-based therapy; tane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; mustard anticancer agent; mycaperoxide B; mycobacterial aZasetron; azatoxin; azatyrosine; baccatin III derivatives, cell wall extract; myriaporone, N-acetyldinaline, N-Substi balanol; batimastat; BCR/ABL antagonists; benzochlorins; tuted benzamides, nafarelin, nagreStip; naloxone-pentazo benzoylstauroSporine; beta lactam derivatives, beta cine, napavin; naphterpin, nartograstim; nedaplatin, nemo alethine; betaclamycin B; betulinic acid; bFGF inhibitor; rubicin; neridronic acid; neutral endopeptidase, nilutamide; bicalutamide, bisantrene, bisaZiridinylspermine; bisnafide; nisamycin; nitric oxide modulators, nitroxide antioxidant; bistratene A, bizelesin, breflate, bleomycin A, bleomycin nitrullyn; O6-benzylguanine; Octreotide, okicenone, oligo B, bropirimine; budotitane, buthionine Sulfoximine, calci nucleotides; Onapristone; Ondansetron, Ondansetron, oracin; potriol, calphostin C; camptothecin derivatives (e.g., 10-hy oral cytokine inducer; Ormaplatin, OSaterone; Oxaliplatin; US 2002/0177609 A1 Nov. 28, 2002 oXaunomycin; paclitaxel analogues, paclitaxel derivatives, Hg 197; Merisoprol Acetate Hg 203; Merisoprol Hg 197; palauamine; palmnitoylrhizoxin; pamidronic acid; panax Selenomethionine Se 75; Technetium Tc 99m Antimony ytriol, panomifene, parabactin; paZelliptine, pegaspargase; peldesline, pentosan polysulfate Sodium; pentostatin; pentro Trisulfide Colloid; Technetium Tc 99m Bicisate; Technetium Zole, perflubron; perfosfamide, perillyl alcohol; phenazino Tc 99m Disofenin; Technetium Tc 99m Etidronate; Techne mycin; phenylacetate; phosphatase inhibitors, picibanil; tium Tc 99m Exametazime; Technetium Tc 99m Furifosmin, pilocarpine hydrochloride, pirarubicin; piritrexim; placetin Technetium Tc 99m Gluceptate; Technetium Tc 99m Lid A, placetin B; plasminogen activator inhibitor, platinum ofenin; Technetium Tc 99m Mebrofenin; Technetium Tc complex, platinum compounds, platinum-triamine complex; 99m Medronate; Technetium Tc 99m Medronate Disodium; podophyllotoxin; porfimer Sodium; porfiromycin; propyl Technetium Tc 99m Mertiatide; Technetium Tc 99m Oxidr bis-acridone; prostaglandin J2, proteasome inhibitors, pro tein A-based immune modulator; protein kinase C inhibitor; onate; Technetium Tc 99m Pentetate; Technetium Tc 99m protein kinase C inhibitors, microalgal; protein tyrosine Pentetate Calcium Trisodium; Technetium Tc 99m Sesta phosphatase inhibitors, purine nucleoside phosphorylase mibi; Technetium Tc 99m Siboroxime; Technetium Tc 99m inhibitors, purpurins, pyrazoloacridine, pyridoxylated Succimer; Technetium Tc 99m Sulfur Colloid; Technetium hemoglobin polyoxyethylene conjugate, raf antagonists, Tc 99m Teboroxime; Technetium Tc 99m Tetrofosmin; raltitrexed; ramosetron; ras fameSyl protein transferase Technetium Tc 99m Tiatide; Thyroxine I 125; Thyroxine I inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine 131; Tolpovidone I 131; Triolein I 125; and Triolein I 131. demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes, RII retinamide, rogletimide; rohitukine; 0149 Anticancer Supplementary Potentiating Agents romurtide, roquinimex, rubiginone B1, rubOXyl; Safingol; Saintopin; SarCNU; Sarcophytol A, SargramoStim; Sidi 1. also may be conjugated to fatty alcohol moieties. Such mimetics, Semustine, Senescence derived inhibitor 1; Sense agents include, but are not limited to, Tricyclic anti-depres oligonucleotides, Signal transduction inhibitors, Signal trans Sant drugs (e.g., imipramine, desipramine, amitryptyline, duction modulators, Single chain antigen binding protein; clomipramine, trimipramine, doxepin, nortriptyline, protrip sizofiran; Sobu ZOxane, Sodium borocaptate, Sodium pheny tyline, amoxapine and maprotiline); non-tricyclic anti-de lacetate, Solverol, Somatomedin binding protein; Sonermin; pressant drugs (e.g., Sertraline, trazodone and citalopram); Sparfosic acid; Spicamycin D; Spiromustine; Splenopentin; Ca++antagonists (e.g., Verapamil, nifedipine, nitrendipine Spongistatin 1; Squalamine; Stem cell inhibitor, Stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfi and caroverine); Calmodulin inhibitors (e.g., prenylamine, nosine; Superactive vasoactive intestinal peptide antagonist; trifluoroperazine and clomipramine); Amphotericin B; Tri Suradista; Suramin; Swainsonine, Synthetic glycosaminogly paranol analogues (e.g., tamoxifen); antiarrhythmic drugs cans, tallimustine, tamoxifen methiodide, tauromustine; taZ (e.g., quinidine); antihypertensive drugs (e.g., reserpine); arotene, tecogalan Sodium, tegafur, tellurapyrylium; telom Thiol depleters (e.g., buthionine and sulfoximine) and Mul erase inhibitors, temoporfin, temozolomide; teniposide; tiple Drug Resistance reducing agents Such as Cremaphor tetrachlorodecaoxide, tetraZomine; thaliblastine; thalido mide; thiocoraline; thrombopoietin; thrombopoietin EL. The compounds of the invention also can be adminis mimetic; thymalfasin; thymopoietin receptor agonist, thy tered with cytokines Such as granulocyte colony Stimulating motrinan; thyroid Stimulating hormone, tin ethyl etiopurpu factor. rin; tirapazamine, titanocene dichloride; topotecan; topsen tin, toremifene, totipotent Stem cell factor; translation 0150 Preferred anticancer agents (some with their MTDs inhibitors, tretinoin, triacetyluridine, triciribine, trimetrex shown in parentheses) include, but are not limited to, ate, triptorelin; tropisetron; turosteride; tyrosine kinase annonaceous acetogenins; asimicin; rolliniastatin; guana inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogeni cone, Squamocin, bullatacin; Squamotacin; taxanes, pacli tal Sinus-derived growth inhibitory factor; urokinase recep taxel (225 mg/ml); gemcitabine (1000 mg/mi); methotrex tor antagonists, vapreotide; variolin B; Vector System, eryth ate (15 gm/m i.v.+leuco.<500 mg/m i.v. w/o leuco); rocyte gene therapy; VelareSol, Veramine, Verdins, FR-900482; FK-973; 3, FR-66979; FK-317; 5-FU (500 verteporfin, Vinorelbine; VinXaltine, Vitaxin; Vorozole; Zan mg/ml/dayx5 days); FUDR (100 mg/kgx5 in mice, 0.6 oterone; Zeniplatin, Zilascorb, and Zinostatin stimalamer. mg/kg/day in human i.a.); FdUMP; Hydroxyurca (35 mg/kg/d in man); Docetaxel (60-100 mg/m); discoder 0.148. Other anticancer agents include, but are not limited mollide; epothilones; Vincristine (1.4 mg/m); vinblastine to, antiproliferative agents (e.g., Piritrexim Isothionate), (escalating: 3.3-11.1 mg/m, or rarely to 18.5 mg/m); antiprostatic hypertrophy agents (e.g., Sitogluside), benign vinorelbine (30 mg/m/wk); meta-pac; irinotecan (50-150 prostatic hyperplasia therapy agents: (e.g., Tamsulosin mg/ml, 1x/wk depending on patient response); SN-38 (-100 Hydrochloride), Prostate growth inhibitors (e.g., Pento times more potent than Irinotecan); 10-OH campto; topote mone) and radioactive agents: Fibrinogen 1125; Fludeoxy can (1.5 mg/m/day in humans, 1x iv. LD10 mice=75 glucose F 18; Fluorodopa F 18; Insulin I 125; Insulin I 131; mg/m); etoposide (100 mg/m in man); adriamycin; fla lobenguane 1123; lodipamide Sodium I 131; lodoantipyrine vopiridol; Cis-Pt (100mg/m in man); carbo-Pt (360 mg/m I 131; Iodocholesterol I 131; lodohippurate Sodium I 123; in man); bleomycin (20 mg/ml); mitomycin C (20 mg/ml); lodohippurate Sodium I 125; lodohippurate Sodium 1131; mithramycin (30 ug/kg); capecitabine (2.5 g/m orally); lodopyracet I 125; lodopyracet I 131; lofetamine Hydro cytarabine (100 mg/m/day); 2-Cl-2'deoxyadenosine; Flu chloride I 123, lomethin I 125; lomethin I 131; lothalamate darabine-PO (25 mg/m°/day, x5 days); mitoxantrone (12 Sodium I 125; lothalamate Sodium t 131; Iotyrosine I 131; 14 mg/ml); mitozolomide (>400 mg/ml); Pentostatin; and Liothyronine I 125; Liothyronine I 131; Merisoprol Acetate Tomudex. US 2002/0177609 A1 Nov. 28, 2002 20

0151 Taxanes are particularly preferred pharmaceutical nostic methods for proliferative disease and the clinical agents. AS used herein, a taxane is a molecule that possesses delineation of proliferative diseases are well-known to those the following tricyclic (A, B, and C) carbon-atom connec of skill in the medical arts. tivity network: 0158 An effective amount means that amount necessary to delay the onset of, inhibit the progression of, halt alto gether the onset or progression of or diagnose the particular condition being treated. For example, an effective amount for treating cancer will be that amount necessary to inhibit altogether, delay, or slow mammalian cancer cell prolifera tion in situ. 0159. When administered to a subject, effective amounts will depend, of course, on the particular condition being treated; the Severity of the condition; individual patient parameters including age, physical condition, Size and weight; concurrent treatment; frequency of treatment; and 0152 shown with optional methyl groups and may incor the mode of administration. These factors are well known to porate carbon-carbon multiple bonds, Substituents, finctional those of ordinary skill in the art and can be addressed with groups, and additional rings. Taxanes are conventially num no more than routine experimentation. It is preferred gen bered as shown above. erally that a maximum dose be used, that is, the highest Safe 0153. A taxoid is a molecule structurally related to a dose according to Sound medical judgment. taxane in which the above taxane carbon-atom connectivity 0160 The maximum tolerated dose (MTD) for any thera network is altered, for example, by cleavage of one or more peutic compound is identified as part of its clinical evalua of the carbocyclic rings, by deletion or addition of carbon tion. For example, phase I trials can include a determination Substituents, by connection of carbon atoms normally not of the maximum tolerated dose, dose limiting toxicities bonded to each other, by disconnection of carbon atoms (DLT) and pharmacokinetics of a test compound. “Maxi normally bonded to each other, or by Some other reorgani mum tolerated dose,” as used herein, refers to the largest Zation of or adjustment to the taxane carbon-atom connec dose of a pharmaceutical agent that an adult patient can take tivity network, but in which one or more Structural features with Safety to treat a particular disease or condition. Thus, characteristic of the taxane carbon-atom connectivity net the MTD for any Food and Drug Administration (FDA) work are conserved. approved therapeutic compound is known to those of ordi 0154 Paclitaxel and docetaxel are both taxanes and are nary skill in the art as a matter of the public record. The preferred anticancer pharmaceutical agents in the invention. MTD for any particular therapeutic compound may vary Another preferred pharmaceutical agent useful in the present according to its formulation (e.g., injectable formulation, invention includes flavopiridol, which is not a taxane anti implantable bioerodible polymer formulation, oral formula cancer pharmaceutical agent. tion), route of delivery (e.g., intravenous, oral, intratumoral), manner of delivery (e.g., infusion, bolus injection), dosing O155 As used herein, “annonaceous acetogenin' schedule (e.g., hourly, daily, weekly) and the like. The MTD includes inhibitors of the enzyme NADH:ubiquinone oxi frequently is defined as the highest dose level at which 50% doreductase, including, but not limited to: asimicin (CAS of Subjects administered with the drug develop a dose Reg. No. 102989-24-2), rolliniastatin asimicin (CAS Reg. limiting toxicity. The doses for anti-neoplastic pharmaceu No. 157966-79-5), guanacone (CAS Reg. No. 212616-61 tical agents found in the Physicians Desk Reference (PDR) 0), squamocin asimicin (CAS Reg. No. 120298-30-8), bul are defined as the MTD for those agents. The MTD is further latacin asimicin (CAS Reg. No. 123123-32-0), and squamo defined to include only doses for drugs (including anti tacin asimicin (CAS Reg. No. 174158-66-8). neoplastics) used as single agents and without additional 0156 AS used herein the mitomycins are a family of cellular, genetic, pharmaceutical, or other agents added to compounds that are highly potent DNA croSS-linking agents, alter the MTD. Other definitions which are clinically rel and include, but are not limited to: mytomycin C, FR-66979, evant and generally accepted will be known to one of FR-900482, FK-973, and FK-317. ordinary skill in the art. 0.161 Measurement of maximum tolerated dose may be O157 The conjugates of the invention are administered in expressed as weight of drug per weight of Subject, weight of effective amounts to a Subject in need of treatment with the drug per body surface area, etc. The MTD of anticancer pharmaceutical agents. Such Subjects and Such amounts can compounds is frequently expressed as weight per Square be determined by those of ordinary skill in the art. For example, a Subject in need of antiproliferative treatment meters (mg/m) of body surface area. For example, the MTD includes Subjects diagnosed with a mammalian proliferative for paclitaxel infusion in humans is 225 mg/m . The most disorder (e.g. cancer) or being Suspected of having, devel often used clinical tolerated dose is 175 mg/m. MTD also oping or Suspected of developing a mammalian proliferative may be expressed as a dose relative to a time component, disorder. Methods for identifying subject suspected of hav Such as weight of drug per body Surface area per day. ing proliferative disease may include physical examination, 0162 For therapeutics which have not yet been subjected biopsy, Subject's family medical history, Subject's medical to human clinical trials, or Subjected to any determination of history, or a number of imaging technologies Such as mam the MTD in humans (e.g., experimental or highly toxic mography, magnetic resonance imaging, magnetic reso compounds), one of skill in the art can estimate the MTD by nance spectroScopy, or positron emission tomography. Diag using animal models. Calculation of MTD in animals may US 2002/0177609 A1 Nov. 28, 2002 be based on a number of physiological parameters, Such as progression of or halt altogether the onset or progression of death, particular toxicities, drug induced weight loSS, etc. the viral infection. In particular embodiments, the infection Using death as an endpoint, the MTD may be the dose given is a retroviral infection, and most particularly an HIV test animals in which each member of the test group Sur infection. In general, an effective amount will be that amount vived. Using toxicity as an endpoint, the MTD may be the necessary to inhibit the Symptoms or physiological (e.g., dose at which moderate but not severe toxicity is observed. immunological or viral) characteristics of the viral infection, Using weight loss as an endpoint, the MTD may be the dose any of which otherwise would have occurred in a Subject above which a certain percent change in body weight is experiencing a viral infection absent the treatment of the induced. Other methods for determining MTDs using animal invention. Several parameters may be used to assess reduc models and various endpoints are known to one of ordinary tion of viral infection, including inhibited viral replication, skill in the art. Correlation of animal MTDs to human MTDs a lessened decrease of CD4+ T cell counts, a stabilization of for a therapeutic compound is an accepted practice in the CD4+ T cell count or even an increased CD4+ T cell count, pharmaceutical arts. and/or an inhibited increase of viral load or even a decreased Viral load, for example, as compared to pretreatment patient 0163 For example, it has been determined that a conju parameters, untreated patients or, in the case of treatment gate of DHA and paclitaxel (TaxoprexinTM) has a maximum with cocktails, patients having a viral infection treated with tolerated dose in animals (mice, rats and dogs) which is antiviral agents alone (i.e. without the conjugate of the about 4-5 times greater (by weight) than paclitaxel alone or invention). These parameters can be monitored using stan about 3-4 times greater (by molarity) than paclitaxel alone. dard diagnostic procedures including ELISA, polymerase 0164. In one aspect of the invention the Subjects have a chain reaction (PCR and RT-PCR), and flow cytometry. need for treatment with an antiviral agent. One of ordinary 0167. In one aspect of the invention, subjects having a skill in the art is familiar with a variety of antiviral agents psychosis are treated. One of ordinary skill in the art is which are used in the medical arts to treat Viral infections. familiar with a variety of antipsychotic agents which are Another category of pharmaceutical agents useful in the used in the medical arts to treat psychoses Such as Schizo present invention is antiviral agents. Antiviral agents phrenia. Antipsychotic agents include, but are not limited to, include, but are not limited to, nucleoside analogs, non Acetophenazine Maleate; Alentemol Hydrobromide; Alper nucleoside reverse transcriptase inhibitors, protease inhibi tine, AZaperone; Batelapine Maleate; Benperidol; BenZin tors, integrase inhibitors, including, for example, the fol dopyrine Hydrochloride; Brofoxine; Bromperidol; Bromp lowing: Acemannan, Acyclovir, Acyclovir Sodium; eridol Decanoate; Butaclamol Hydrochloride; Butaperazine; Adefovir; Alovudine; Alvircept Sudotox; Amantadine Butaperazine Maleate; Carphenazine Maleate; Carvotroline Hydrochloride; Aranotin; Arildone; Atevirdine Mesylate; Hydrochloride; Chlorpromazine; Chlorpromazine Hydro Avridine; BRL 47923; BRL 44385; Cidofovir; Cipamfyl chloride; Chlorprothixene; Cinperene; Cintriamide; Clo line; Cytarabine Hydrochloride; Delavirdine Mesylate; macran Phosphate; Clopenthixol; Clopimozide, Clopipazan Desciclovir, Didanosine; Disoxaril; Edoxudine; Enviradene; Mesylate; Cloroperone Hydrochloride; Clothiapine; Enviroxime; Famciclovir; Famotine Hydrochloride; Fiacit Clothixamide Maleate; Clozapine; Cyclophenazine Hydro abine; Fialuridine; Fosarilate; Foscarnet Sodium; Fosfonet chloride; Droperidol; Etazolate Hydrochloride; Fenimide; Sodium; Ganciclovir, Ganciclovir Sodium; Idoxuridine; Flucindole, FlumeZapine, Fluphenazine Decanoate; Indinavir, Kethoxal; Lamivudine; Lobucavir; Memotine Fluphenazine Enanthate; Fluphenazine Hydrochloride; Hydrochloride; Methisazone; Nelfinavir, Nevirapine; Pen Fluspiperone; Fluspirilene; Flutroline; Gevotroline Hydro ciclovir; Pirodavir; Ribavirin; Rimantadine Hydrochloride; chloride; Halopemide; Haloperidol; Haloperidol Decanoate; Ritonavir; Saquinavir Mesylate; Somantadine Hydrochlo Iloperidone; Imidoline Hydrochloride; Lenperone; Mazap ride; Sorivudine; Statolon; Stavudine; Tilorone Hydrochlo ertine Succinate; Mesoridazine; Mesoridazine Besylate; ride; Trifluridine; Valacyclovir Hydrochloride; Vidarabine; Metiapine; Milenperone; Milipertine; Molindone Hydro Vidarabine Phosphate; Vidarabine Sodium Phosphate; chloride; Naranol Hydrochloride; Neflumozide Hydrochlo ViroXime, Zalcitabine, Zidovudine; ZinviroXime, integrase ride; Ocaperidone; Olanzapine; Oxiperomide; Penfluridol; inhibitors, TMC-125, and TMC-114, valganciclovir; Pentiapine Maleate; Perphenazine; Pimozide; Pinoxepin fomivirSen, Zanamivir, Oseltamivir, rimantidine, adefovir Hydrochloride; Pipamperone; Piperacetazine; Pipotiazine dipivoxil; tenofovir; tenofovir disoproxil; viramidine; 3-dea Palmitate; Piquindone Hydrochloride; Prochlorperazine Zaneplanocin A, neplanocin A; Saquanivir; maribavir, Edisylate; Prochlorperazine Maleate; Promazine Hydro N-methanocarbathymidine, fuSaric acid, Synguanol, glycyr chloride; Quetiapine; Remoxipride; Remoxipride Hydro rhyzic acid; fludaribine; entecavir; MIV-210. Adefovir, cido fovir, BRL47923, and BRL 44385 are particularly important chloride; Risperidone; Rimcazole Hydrochloride; Seperidol pharmaceutical agents. Hydrochloride; Sertindol; Setoperone; Spiperone; Thior idazine; Thioridazine Hydrochloride; Thiothixene; Thio 0.165. The invention thus is used in connection with thixene Hydrochloride; Tioperidone Hydrochloride; treating Subjects having, Suspected of having, developing or Tiospirone Hydrochloride; Trifluoperazine Hydrochloride; Suspected of developing a viral infection, including, for Trifluperidol; Triflupromazine; Triflupromazine Hydrochlo example, a retroviral infection such as HIV. A preferred ride; and Ziprasidone Hydrochloride. antiviral agent useful in the present invention is adefovir. 0168 Preferred antipsychotics include, but are not lim Adefovir, 9-(2-phosphonomethyoxylethyl) adenine ited to, Lorazepam, chlordiazepoxide; clorazepate; diaz (PMEA) is a nucleotide analog that has been shown to be epam, alprazolam; hydroxy Zine, buSpirone, Venlafaxine, useful for, among other uses, as a reverse transcriptase mephobarbital; meprobamate, doxepin; perphenazine; inhibitor. hydroxy Zine pamoate; Venlafaxine, mirtazapine; nefaz 0166 An effective amount in the case of a virus means odone; bupropion; phenelZine; tranylcypromine, citalopram; that amount necessary to delay the onset of, inhibit the paraXefine; Sertraline, amitriptyline; protriptyline, dival US 2002/0177609 A1 Nov. 28, 2002 22 proex, clonazepam, clozapine, haloperidol; loxapine, molin 0173 Suitable surfactants for use with the present inven done; thiothixene; pimozide, risperidone; quefiapine; thio tion include nonionic agents, Such as long-chain fatty acids thixen; olanzapine, quetiapine, prochlorperazine; and their water-insoluble derivatives. These include fatty meSoridazin; trifluoperazine, chlorpromazine, perphena alcohols Such as lauryl cetyl and Stearyl alcohol, glyceryl Zine, and fluvoxamine. Most preferred antipsychotics esterS Such as the naturally occurring mono-, di- and trig include: clozapine, Venlafaxine, risperidone, quefiapine; lycerides, and fatty acid esters of fatty alcohols, Such as thiothixen; and Olanzapine. propylene glycol, polyethylene glycol, Sorbitan, Sucrose and 0169. An effective amount in the case of psychosis means cholesterol. Also useful are compounds that are those that that amount alone or with multiple doses, necessary to delay have polyoxyethylene groups added through an ether link the onset of, inhibit completely or lessen the progression of age with an alcohol group. Compounds that are particularly or halt altogether the onset or progression of the psychotic useful in the present invention include the polyoxyethylene condition Such as Schizophrenia. In general, an effective Sorbitan fatty acid esters and polyoxyethylene glycerol and amount will be that amount necessary to inhibit either Steroidal esters. Particularly preferred Surfactants are Cre negative or positive Symptoms of the psychotic condition, mophore(R EL and Cremophor(R) EL-P, which are polyoxy and preferably both negative and positive Symptoms of the ethylated castor oil Surfactants. psychotic condition Such as Schizophrenia. The inhibition of 0.174. It is contemplated that other surfactants may be the negative and/or positive Symptoms of Schizophrenia can used to solubilize the compositions described herein. For be monitored by Standard psychiatric evaluation of the example, it is contemplated that polySorbate 80, polySorbate Subject Over time. In addition, other physiological methods 20, Sodium laurate, Sodium oleate, and Sorbitan monooleate for monitoring the changes in brain function which accom may be useful in certain embodiments of the present inven pany Symptoms of Schizophrenia also can be employed to tion. Anionic Surfactants may also be useful in the practice monitor the inhibition of the symptoms. For example, the of the present invention. Examples of these include, but are State of advancement of Schizophrenia can be assessed using not limited to, Sodium cholate, Sodium lauryl Sulfate, Sodium magnetic resonance imaging (MRI) (See, e.g., DeLisi et al., deoxycholate, Sodium laurate, Sodium oleate, and potassium (Psychiatry Res. 74(3):129-140, 1997) or positron emission laurate. tomography (PET) (see, e.g., Sabri et al., Lancet 349:1735 1739, 1997; Andreasen et al., Lancet 349:1730-1734, 1997). 0.175. In certain embodiments, dehydrated ethanol is used When administered to a subject, effective amounts will as a Solvent for the compositions described herein. In other depend, of course, on the particular condition being treated; embodiments, glycols Such as propylene glycol or polyeth the Severity of the condition; individual patient parameters ylene glycol are within the Scope of the invention. Simple including age, physical condition, Size and weight; concur complex polyols may also be Suitable Solvents. Moreover, rent treatment, frequency of treatment; and the mode of the use of non-dehydrated alcohols may also be Suitable administration. These factors are well known to those of within the Scope of the present invention. It is recognized ordinary skill in the art and can be addressed with no more that the determination of a Solvent and its proper concen than routine experimentation. It is preferred generally that a tration to fully Solubilize the conjugate, Such as the fatty alcohol-anticancer, fatty alcohol-antiviral, and fatty alcohol maximum dose be used, that is, the highest Safe dose antipsychotic compositions is within the Scope of a skilled according to Sound medical judgment. artisan, and would not require undue experimentation. 0170 In general, dosage may be adjusted appropriately to achieve desired drug levels, locally or Systemically. Gener 0176 When administered, the formulations of the inven ally, daily oral doses of conjugates will be from about 0.01 tion are applied in pharmaceutically acceptable composi mg/kg per day to 1000 mg/kg per day, preferably 0.01 mg/kg tions. Such preparations may routinely contain Salts, buff per day to 10 mg/kg per day. It is expected that IV doses in ering agents, preservatives, compatible carriers, and the same range will be effective. In the event that the optionally other therapeutic ingredients. When used in medi response in a Subject is insufficient at Such doses, even cine the Salts should be pharmaceutically acceptable, but higher doses (or effective higher doses by a different, more non-pharmaceutically acceptable Salts may conveniently be localized delivery route) may be employed to the extent that used to prepare pharmaceutically acceptable Salts thereof patient tolerance permits. Continuous IV dosing over, for and are not excluded from the Scope of the invention. Such example 24 hours or multiple doses per day also are con pharmacologically and pharmaceutically acceptable Salts templated to achieve appropriate Systemic levels of com include, but are not limited to, those prepared from the pounds. following acids: hydrochloric, hydrobromic, Sulphuric, nitric, phosphoric, maleic, acetic, Salicylic, p-toluene Sul 0171 Pharmaceutical preparations and compositions fonic, tartaric, citric, methane Sulfonic, formic, malonic, herein which contain anticancer, antiviral or antipsychotic Succinic, naphthalene-2-Sulfonic, and benzene Sulfonic. compounds optionally can contain additional anticancer, Also, pharmaceutically acceptable Salts can be prepared as antiviral or antipsychotic compounds respectively (i.e. cock alkaline metal or alkaline earth Salts, Such as Sodium, tails). The foregoing preparations, formulations and compo potassium or calcium Salts. Sitions may be encapsulated by liposomes, according to Standard procedures for preparation of liposomes, but pref 0177 Suitable buffering agents include: acetic acid and a erably are not. salt (1-2% W/V); citric acid and a salt (1-3% W/V); and 0172 The compositions also can contain other compo phosphoric acid and a salt (0.8-2% W/V). nents useful in formulating pharmaceutical preparations for 0.178 Suitable preservatives include benzalkonium chlo administration to humans, including Surfactants, Solvents, ride (0.003-0.03% W/V); chlorobutanol (0.3-0.9% W/V); preservatives, diluents, and the like, all of which are stan parabens (0.01-0.25% W/V) and thimerosal (0.004-0.02% dard in the pharmaceutical arts. W/V). US 2002/0177609 A1 Nov. 28, 2002

0179 The active compounds of the present invention 0185. Compositions suitable for oral administration may may be a pharmaceutical composition having a therapeuti be presented as discrete units Such as capsules, cachets, cally effective amount of a conjugate of the invention tablets, or lozenges, each containing a predetermined optionally included in a pharmaceutically-acceptable carrier. amount of the active compound. Other compositions include The term "pharmaceutically-acceptable carrier' as used Suspensions in aqueous liquors or non-aqueous liquids Such herein means one or more compatible Solid or liquid filler, as a Syrup, an elixir, or an emulsion. dilutants or encapsulating Substances which are Suitable for 0186. Other delivery systems can include time-release, administration to a human or other animal. The term "car delayed release or Sustained release delivery Systems. Such rier denotes an organic or inorganic ingredient, natural or Systems can avoid repeated administrations of the active Synthetic, with which the active ingredient is combined to compounds of the invention, increasing convenience to the facilitate the application. The components of the pharma Subject and the physician. Many types of release delivery ceutical compositions are capable of being commingled with Systems are available and known to those of ordinary skill in the molecules of the present invention, and with each other, the art. They include polymer based Systems Such as poly in a manner Such that there is no interaction which would lactic and polyglycolic acid, polyanhydrides and polycapro Substantially impair the desired pharmaceutical efficacy. lactone; nonpolymer Systems that are lipids including Sterols 0180 Compositions suitable for parenteral administra Such as cholesterol, cholesterol esters and fatty acids or tion conveniently comprise a Sterile preparation of the neutral fats Such as mono-, di- and triglycerides, hydrogel conjugates of the invention. This preparation may be for release Systems, Silastic Systems, peptide based Systems, mulated according to known methods. Formulations for wax coatings, compressed tablets using conventional bind taxanes can be found in Chapter 9 of Taxol. Science and erS and excipients, partially fused implants and the like. In Applications, CRC Press, Inc., 2000 Corporate Boulevard, addition, a pump-based hardware delivery System can be N.W., Boca Raton, Fla. 33431. In general, Taxol has been used, Some of which are adapted for implantation. formulated as a 6 mg/ml cremophor EL (polyoxyethylated castor oil)/ethanol mixture, which is diluted to final volume 0187. A long-term sustained release implant also may be with normal saline or 5% dextrose. A 15 mg/ml solution of used. "Long-term' release, as used herein, means that the taxotere has been formulated in polysorbate 80 (polyoxy implant is constructed and arranged to deliver therapeutic ethylene sorbitaumonooleate)/ethanol mixture, diluted with levels of the active ingredient for at least 30 days, and 5% dextrose. preferably 60 days. Long-term Sustained release implants are well known to those of ordinary skill in the art and 0181. The sterile preparation thus may be a sterile solu tion or Suspension in a non-toxic parenterally-acceptable include Some of the release Systems described above. diluent or Solvent. In addition, Sterile, fixed oils are conven 0188 Those skilled in the art will be able to recognize tionally employed as a Solvent or Suspending medium. For with no more than routine experimentation numerous this purpose any bland fixed oil may be employed including equivalents to the Specific products and processes described Synthetic mono or di-glycerides. In addition, fatty acids Such above. Such equivalents are intended to be included within as oleic acid fmd use in the preparation of injectables. the Scope of the appended claims. Carrier formulations Suitable for oral, Subcutaneous, intra 0189 The following examples are provided to guide venous, intramuscular, etc. can be found in Remington's those skilled in the art. Various changes and modifications Pharmaceutical Sciences, Mack Publishing Company, Eas may be made, as will be evident to those skilled in the art, ton, Pa. and are within the Scope of the invention. Linoleyl alcohol, 0182 A Subject, as used herein, means humans, primates, other fatty alcohols, and fatty acids were obtained from horses, cows, pigs, sheep, goats, dogs, cats, and rodents. Nu-Chek Prep, Inc. (Elysian, Minn.). The reagents and 0183) A variety of administration routes are available. Solvents used are readily available, for example, from Ald The particular mode Selected will depend of course, upon the rich Chemical Co., Inc (Milwaukee, Wis.), EM Sciences particular drug Selected, the Severity of the disease State (Cincinnati, Ohio), and VWR Scientific (Bridgeport, N.J.). being treated and the dosage required for therapeutic effi cacy. The methods of this invention, generally speaking, EXAMPLES may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces Example 1 effective levels of the active compounds without causing clinically unacceptable adverse effects. Such modes of Synthesis of Linoleyl Para-nitrophenyl Carbonate administration include oral, rectal, Sublingual, topical, nasal, 0190. To a vigorously stirring room temperature solution transdermal or parenteral routes. The term "parenteral' containing linoleyl alcohol (1.07 g., 4.05 mmol, 1.0 equiv), includes Subcutaneous, intravenous, intramuscular, or infu CHCl (15 ML), and EtN (845.9 uL, 6.07 mmol, 1.5 Sion. Intravenous and oral routes are preferred. equiv) under an argon atmosphere, was added dropwise a 0184 The compositions may conveniently be presented Solution containing para-nitrophenyl chloroformate (815.6 in unit dosage form and may be prepared by any of the mg, 4.05 mmol, 1.0 equiv) and CHCl (5 mL). After one methods well known in the art of pharmacy. All methods hour, the reaction appeared to be complete, as monitored by include the Step of bringing the conjugates of the invention thin layer chromatography. To insure completeness, approxi into association with a carrier which constitutes one or more mately 50 mg ofpara-nitrophenyl chloroformate was added, accessory ingredients. In general, the compositions are pre and the reaction allowed to stir an additional 0.5 hr. At this pared by uniformly and intimately bringing the compounds time, the reaction was concentrated to approximately /2 into association with a liquid carrier, a finely divided Solid volume, and the Supernatant was decanted directly to carrier, or both, and then, if necessary, Shaping the product. two (2) Biotage 3.0 gram Silica gel Samplets (Biotage, Inc., US 2002/0177609 A1 Nov. 28, 2002 24

Charlottesville, Va.). The carbonate product was purified on the Biotage Quad 4 Purification System using two 25M 40 gram Silica cartridges, eluting with 1:9 EtOAC/heXanes. The product carbonate was isolated as a clear faint yellow viscous liquid (1.47 gram; 84.2% yield). The reaction is shown schematically below: O Cl

O ON OH EtN, CHCl2 linoleyl alcohol 84% NO2 1s,O C linoleyl para-nitrophenyl carbonate Example 2 noleyl carbonate paclitaxel was purified on the Biotage Quad 4 Purification System using a 25M 40 gram silica Synthesis of 2'-Linoleyl Carbonate Paclitaxel cartridges, eluting the first 20 fractions using 1:3 EtOAC/ 0191) To a vigorously stirring room temperature solution hexanes, and the final 20 fractions using 1:1 EtOAC/hexanes. containing paclitaxel (500 mg, 0.59 mmol, 1.0 equiv), Yield: 651.5 mg (97.1%); clear glassy white solid. CHCl (3 mL), and 4-dimethylaminopyridine (78.7 mg, 0.64 mmol, 1.1 equiv) under an argon atmosphere, was 0.192 Optionally, 2'-linoleyl carbonate paclitaxel may be added dropwise a Solution containing linoleyl, para-nitro recrystallized from ethanol at a concentration of approxi phenyl carbonate (as prepared in Example 1) (303.2 mg, mately 150 mg/mL. The pure compound (pure by flash Silica 0.70 mmol, 1.2 equiv) and CHCl (2.0 mL). After stirring chromatography) dissolves at this concentration with the aid 80 minutes, the reaction was shown to be complete by thin of Sonication, Vortexing, and/or gentle heating (50° C.), and layer chromatography. At this time, the reaction Solution was Slowly crystallizes upon cooling. The reaction is shown added directly to a Biotage 3.0 gram Silica Samplet. 2'-Ii schematically below:

ON

DMAP, CH2Cl2 97%

P232 Paclitaxel, 2'-linoleyl carbonate (LOC-Pac) C66H33NO16 MW = 1146.38 0193 The following compounds are synthesized using analogous methods: US 2002/0177609 A1 Nov. 28, 2002 25

US 2002/0177609 A1 Nov. 28, 2002 26

Example 3 Syntesis of a Fatty Alcohol-adefovir Conjugate Via a Carbamate Linkage 0194 Adefovir (PMEA) is conjugated to a fatty alcohol using the following procedure:

Z. r O NS ROC(O)T f \ / N

rO Ca o o TMSBr, CHCl2 n O

rO

Ca o A A o N O

0195 wherein Z is methyl or ethyl and ROC(O)T is:

NO2 1s,O O O

O O

o N. M. o. O ulo1 O. US 2002/0177609 A1 Nov. 28, 2002 27

Example 4 Synthesis of a Fatty Alcohol-Vincristine Conjugate Via an Ester Linkage 0196) Vincristine is conjugated to a fatty alcohol at position 23 using the following procedure:

1) ROH He2) Ac2O, pyridine

0.197 Vinblastine is conjugated to fatty alcohols using the Same procedure. US 2002/0177609 A1 Nov. 28, 2002 28

Example 5 Synthesis of a Fatty Alcohol-Vincristine Conjugate Via a Carbonate Linkage 0198 Vincristine is conjugated to a fatty alcohol at position 4 using the following procedure:

0199 wherein ROC(O)OT is as described above. Vin blastine is conjugated to fatty alcohols using the same procedure. US 2002/0177609 A1 Nov. 28, 2002 29

Example 6 Synthesis of an O-Fatty Alkyl Hydroxylamine 0200 Fatty alcohols were derivatized to O-fatty alkyl hydroxylamine a using the following procedure:

1n 11 Y1\11n 11a. MsCl OH Hepyridine, CH2Cl2

OMS

N-OH

OMs —O - O

o o o1 N O O

o o O1 N NHNH2Lv1.2

O o o o1 NH2

0201 wherein MsCl is methanesulfonyl chloride. Example 7 Synthesis of an O-Fatty Alkyl Hydroxylamine Conjugated to a Phannaceutical Agent 0202) The fatty alcohol is first derivatized to a hydroxy lamine as in Example 6 and then conjugated to a pharma ceutical agent (XOH) using the following procedure: s" o o o1 NH2 ON O O EtN, CHCl2 lo o1 r O NO2 H o O <'' HeXOH O NO orslo O

0203 wherein EtN is triethylamine. US 2002/0177609 A1 Nov. 28, 2002 30

Example 8 Synthesis of an O-Fatty Alkyl Hydroxylamine Conjugated to a Pharmaceutical Agent 0204. The fatty alcohol is first derivatized to a hydroxy lamine as in Example 6 and then conjugated to a pharma ceutical agent (XNH) using the following procedure: s" O o o -NH2 ON O EtN, CHCl2

lo o1 r O NO

lo o1 r XNH2 O NO

o1 r Yx O

Example 9 Synthesis of a Fatty Alcohol Pharmaceutical Agent Conjugate Via a Guanidine Linkage 0205 The fatty alcohol is conjugated to a pharmaceutical agent (XNH) using the following procedure:

BOC YN ls o OH BOCNH T PPh3, DEAD (or PS-DEAD), THF, 25° C. s

BOC n

BOC n ls 1) XNH2 N T ------N-N--~~ 2) TFA or HC US 2002/0177609 A1 Nov. 28, 2002

0206 wherein 0210 wherein 1. ^ cy 1. ^ cy

0207 and PPha is triphenyl phosphine, DEAD is diethyl 0211 and PPh3 is triphenyl phosphine, DEAD is dietlyl aZodicarboxylate, PS-DEAD is polystyrene-supported aZodicarboxylate, PS-DEAD is polystyrene-supported diethyl azodicarboxylate, THF is a tetrahydrofiran solvent, diethylazodicarboxylate, THF is a tetrahydrofuiran solvent, TFA is trifluoroacetic acid and HCl is hydrochloric acid. TFA is trifluoroacetic acid and HCl is hydrochloric acid. Example 9 Example 11 Synthesis of an O-Fatty Alkyl Hydroxylamine Conjugated to a Pharmaceutical Agent Examples of Etoposide Conjugates 0208. The O-fatty alkyl hydroxylamine (prepared as 0212. The following etoposide-fatty alcohol conjugates described above) is conjugated to a pharmaceutical agent were prepared using analogous methods to those described (XOH) using the following procedure: above and in the Specification:

BOCN N

ls HeXOH BOCNH PPhs, DEAD (or PS-DEAD), THF, 25° C. BOC n N Oa BOC ls 1) o o NH2 n 2) TFA or HCI

X NH

HN ls N1 O o o H X N Example 10 Synthesis of a Fatty Alcohol Pharmaceutical Agent Conjugate Via a Guanidine Linkage 0209 The fatty alcohol is conjugated to a pharmaceutical agent (XNH) using the following procedure:

BOC n OH ls PPh3, DEAD (or PS-DEAD), THF, 25° C.

BOC n

BOC n ls 1) XNH2 --~ N-N--~~N T - 2) TFA or HCI - NH

HN ls N Y X ~-N-N--~~ H US 2002/0177609 A1 Nov. 28, 2002 32

H3CO OCH

Etoposide, 4'-linoleyl carbamate (C18)

H3CO OCH

Etoposide, 4'-docosahexaenyl carbonate US 2002/0177609 A1 Nov. 28, 2002 33

-continued

H3CO 4 OCH3

Etoposide, 4"-linoleyl carbonate

Example 12 Examples of Clozapine Coniugates 0213 The following clozapine-fatty alcohol conjugates are prepared using analogous methods to those described above and in the Specification:

N NE C 1s.N

NS C

N

1'N,le o A o US 2002/0177609 A1 Nov. 28, 2002 34

-continued

N NS C esN (i.

N C

N

1. NH Example 13 Examples of Gemcitabine Conjugates 0214. The following gemcitabine-fatty alcohol conju gates are prepared using analogous methods to those described above and in the Specification:

US 2002/0177609 A1 Nov. 28, 2002 35

Example 14 Examples of Flavopiridol Conjugates 0215. The following flavopiridol-fatty alcohol conjugates are prepared using analogous methods to those described above and in the Specification:

0216) Similarly, conjugates are prepared with fatty alco hols conjugated at the 5 position and at the 3 position of flavopiridol. US 2002/0177609 A1 Nov. 28, 2002 36

Example 15 Examples of RoScovitine Conjugates 0217. The following roscovitine-fatty alcohol conjugates are prepared using analogous methods to those described above and in the Specification:

Sl-N O O ul-I-2

Roscovitine, 3'-linoleyl carbonate

Roscovitine, 3'-linoleyl carbamate (C18) 0218. Similarly, conjugates are prepared with fatty alco hols either conjugated to the 1" guanidinium amine nitrogen or the C6 benzyl amine nitrogen in after protecting the primary hydroxyl group of roScovitine. Example 16 Examples of Mytomycin Conjugates 0219. The following roscovitine-fatty alcohol conjugates were prepared using analogous methods to those described above and in the Specification:

O

y-l

Mitomycin C, Linoleyl carbamate US 2002/0177609 A1 Nov. 28, 2002 37

-continued

Mitomycin C, Docosahexaenyl carbamate

Example 17 Examples of Purvalanol Coniugates 0220. The following purvalanol B-fatty alcohol conju gates were prepared using analogous methods to those described above and in the Specification:

Cl HOC o o . .

Purvalanol B, linoleyl carbonate - c. CI. O) " )- Purvalanol B, linoleyl ester

0221 Conjugation at the carboxylic acid moiety of Pur Valanol A requires protection of the free hydroxyl group, which may be routinely accomplished by those of skill in the art. One skilled in the art will also appreciate that fatty alcohols may also be conjugated to an amino group of purvalanol A as well as that analogous fatty alcohol conju gates may be formed with purvalanol B. US 2002/0177609 A1 Nov. 28, 2002 38

Example 18 Synthesis of Etopophos Fatty Alcohol Conjugates 0222. The following etopophos-fatty alcohol phosphate conjugates are prepared using two different methodologies, as shown below:

On 1 NG-Pr)2 P 9.------s imidazole, CH2Cl2 N(i-Pr)2

imidazole, CHCl2

MeO OMe

2) TFA, CHCl2

MeO OMe US 2002/0177609 A1 Nov. 28, 2002 39

-continued

Etopophos Fatty Alcohol Phosphate Ester

imidazole, CH2Cl2

MeO OMe

OH

imidazole, CHCl2

MeO OMe US 2002/0177609 A1 Nov. 28, 2002 40

-continued

1) t-BuOOH, CHCl2 2) TEACH.C.

MeO OMe

MeO OMe

Etopophos Fatty Alcohol Phosphate Ester

Example 19 -continued Synthesis of a Fatty Alcohol-SN-38 Conjugate Via a Carbonate Linkage SN-38 is Conjugated to a Fatty Alcohol at Position 20 Using the Following Procedure: 0223)

Et3SiCl, imidazole, DMF 1) ROC(O)T Base 2)He TBAF US 2002/0177609 A1 Nov. 28, 2002 41

0224 wherein EtSiCl is chlorotriethylsilane, DMF is -continued dimethylformamide, the base is N,N-diisopropylethylamine or 4-dimethylaminopyridine, and TBAF is tetra-n-butylam monium fluoride. Example 20

Examples of SN-38 Conjugates

0225. The following SN-38-fatty alcohol conjugates are prepared using analogous methods to those described above and in the Specification:

o A o N O N O 2 N \ / O

OH O

- r s N O N S 2 N \ / O

OH O

o o lo US 2002/0177609 A1 Nov. 28, 2002 42

Example 21 Synthesis of a Fatty Alcohol-adefovir Conjugate Via a Phosphonate Linkage Adefovir is Conjugated to a Fatty Alcohol Using the Following Procedure: 0226

p. OH 1n-1 O 1) SOCl2 (neat)

O 1N1-S-1a1a1 Y1 Y1-N-1 |-O r1S-1| NS N 5 O S 7 N PMEA, bis-linoleyl phosphonate ester

NH2

O 1S-1i. o o | N O

(S\N Z N PMEA, linoleyl phosphonate ester

NH2

0227. As one skilled in the art will recognize, one equiva lent of linoleyl alcohol will generally form a conjugate with one fatty alcohol moiety and two equivalents of linoleyl alcohol will generally form a conjugate with two fatty alcohol moieties. Example 22 Synthesis of a Fatty Alcohol Pharmaceutical Agent Conjugate Via an Oxime Linkage 0228. The fatty alcohol is converted to an O-fatty alkyl hydroxylamine and then conjugated to a pharmaceutical agent via an OXime linkage using the following procedure: US 2002/0177609 A1 Nov. 28, 2002 43 US 2002/0177609 A1 Nov. 28, 2002 44

What is claimed is: 6. The compound of claim 5 wherein the pharmaceutical 1. A compound of the formula: agent is an anticancer drug. 7. The compound of claim 5 wherein the pharmaceutical O agent is an antiviral drug. 8. The compound of claim 5 wherein the pharmaceutical RO lsOX agent is an antipsychotic drug. 9. The compound of claim 5 wherein the pharmaceutical wherein r is a C-C fatty group of a fatty alcohol ROH and agent is paclitaxel. X is a pharmaceutical agent moiety of a pharmaceutical 10. The compound according to claim 9 wherein the agent XOH. compound is: 2. The compound of claim 1, wherein the fatty alcohol ROH has a carbon structure that is the same as a carbon Structure of a fatty acid occurring naturally in humans.

3. The compound of claim 1, wherein the fatty alcohol ROH has a carbon structure that is the same as a carbon Structure of a C-C fatty acid occurring naturally in humans. 4. The compound of claim 1, wherein the fatty alcohol ROH has a carbon structure that is the same as a carbon Structure of a C-C fatty acid occurring naturally in humans. 5. The compound of claim 1, wherein the fatty alcohol ROH has a carbon structure that is the same as a carbon Structure of a fatty acid Selected from myristic acid, palmitic acid, palmitoleic acid, Stearic acid, oleic acid, Vaccenic acid, linoleic acid, linolenic acid, arachidonic acid, eicosapen taenoic acid, docOSenoic acid, docOSatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, and nervonic 11. The compound according to claim 9 wherein the acid. compound is Selected from the group consisting of

US 2002/0177609 A1 Nov. 28, 2002

12. The compound of claim 5 wherein the pharmaceutical 16. The compound of claim 14, wherein the fatty alcohol agent is flavopiridol. ROH has a carbon structure that is the same as a carbon 13. The compound according to claim 12 wherein the Structure of a C-C fatty acid occurring naturally in compound is Selected from the group consisting of humans.

O OH

C O O 1s,O OH

Me O O 1s,

C

O OH

OH

N Me , and O OH

C

O O

N

Me

14. A compound of the formula: 17. The compound of claim 14, wherein the fatty alcohol ROH has a carbon structure that is the same as a carbon Structure of a C-C fatty acid occurring naturally in humans. RO-P-ZX 18. The compound of claim 14, wherein the fatty alcohol ROH has a carbon structure that is the same as a carbon OR Structure of a fatty acid Selected from myristic acid, palmitic acid, palmitoleic acid, Stearic acid, oleic acid, Vaccenic acid, linoleic acid, linolenic acid, arachidonic acid, eicosapen wherein R is a C-C fatty group of a fatty alcohol ROH, X taenoic acid, docoSenoic acid, docOSatetraenoic acid, is a pharmaceutical agent moiety of a pharmaceutical agent docosapentaenoic acid, docosahexaenoic acid, and nervonic XZH, wherein ZiSO, a primary amino group, or a Secondary acid. amino group, and R' is H, an ion, or a protecting group. 19. The compound of claim 14, wherein R' is selected 15. The compound of claim 14, wherein the fatty alcohol from the group consisting of H, Na', K", Li", and NH". ROH has a carbon structure that is the same as a carbon 20. The compound of claim 18 wherein the pharmaceu Structure of a fatty acid occurring naturally in humans. tical agent is an anticancer drug. US 2002/0177609 A1 Nov. 28, 2002 46

21. The compound of claim 18 wherein the pharmaceu 36. The compound of claim 34, wherein the fatty alcohol tical agent is an antiviral drug. ROH has a carbon structure that is the same as a carbon 22. The compound of claim 18 wherein the pharmaceu Structure of a C-C fatty acid occurring naturally in tical agent is an antipsychotic drug. humans. 37. The compound of claim 34, wherein the fatty alcohol 23. The compound of claim 18 wherein the pharmaceu ROH has a carbon structure that is the same as a carbon tical agent is paclitaxel. Structure of a C-C fatty acid occurring naturally in 24. The compound of claim 18 wherein the pharmaceu humans. tical agent is flavopiridol. 38. The compound of claim 34, wherein the fatty alcohol 25. The compound of claim 18 wherein the pharmaceu ROH has a carbon structure that is the same as a carbon tical agent is adefovir. Structure of a fatty acid Selected from myristic acid, palmitic 26. A compound of the formula: acid, palmitoleic acid, Stearic acid, oleic acid, Vaccenic acid, linoleic acid, linolenic acid, arachidonic acid, eicosapen taenoic acid, docoSenoic acid, docOSatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, and nervonic acid. 39. The compound of claim 38 wherein the pharmaceu tical agent is an anticancer drug. 40. The compound of claim 38 wherein the pharmaceu tical agent is an antiviral drug. 41. The compound of claim 38 wherein the pharmaceu wherein R is a C-C fatty group of a fatty alcohol ROH and tical agent is an antipsychotic drug. X is a pharmaceutical agent moiety of a pharmaceutical 42. The compound of claim 38 wherein the pharmaceu agent HNR"X, wherein R" is H, an alkyl group, an alkenyl tical agent is adefovir. group, an alkynyl group, or an aryl group. 43. A compound of the formula: 27. The compound of claim 26, wherein the fatty alcohol ROH has a carbon structure that is the same as a carbon Structure of a C-C fatty acid occurring naturally in humans. 28. The compound of claim 26, wherein the fatty alcohol HN ls N1-x ROH has a carbon structure that is the same as a carbon H Structure of a C-C fatty acid occurring naturally in R humans. 29. The compound of claim 26, wherein the fatty alcohol wherein R is a C-C fatty group of a fatty alcohol ROH and ROH has a carbon structure that is the same as a carbon X is a pharmaceutical agent moiety of a pharmaceutical Structure of a fatty acid Selected from myristic acid, palmitic agent XNH. acid, palmitoleic acid, Stearic acid, oleic acid, Vaccenic acid, 44. The compound of claim 43, wherein the fatty alcohol linoleic acid, linolenic acid, arachidonic acid, eicosapen ROH has a carbon structure that is the same as a carbon taenoic acid, docoSenoic acid, docOSatetraenoic acid, Structure of a fatty acid occurring naturally in humans. docosapentaenoic acid, docosahexaenoic acid, and nervonic acid. 45. The compound of claim 43, wherein the fatty alcohol ROH has a carbon structure that is the same as a carbon 30. The compound of claim 29 wherein the pharmaceu Structure of a C-C fatty acid occurring naturally in tical agent is an anticancer drug. humans. 31. The compound of claim 29 wherein the pharmaceu 46. The compound of claim 43, wherein the fatty alcohol tical agent is an antiviral drug. ROH has a carbon structure that is the same as a carbon 32. The compound of claim 29 wherein the pharmaceu Structure of a C-C fatty acid occurring naturally in tical agent is an antipsychotic drug. humans. 33. The compound of claim 29 wherein the pharmaceu 47. The compound of claim 43, wherein the fatty alcohol tical agent is adefovir. ROH has a carbon structure that is the same as a carbon 34. A compound of the formula: Structure of a fatty acid Selected from myristic acid, palmitic acid, palmitoleic acid, Stearic acid, oleic acid, Vaccenic acid, linoleic acid, linolenic acid, arachidonic acid, eicosapen O taenoic acid, docoSenoic acid, docOSatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, and nervonic us acid. RO X 48. The compound of claim 47 wherein the pharmaceu tical agent is an anticancer drug. wherein R is a C-C fatty group of a fatty alcohol ROH and 49. The compound of claim 47 wherein the pharmaceu X is a pharmaceutical agent moiety of a pharmaceutical tical agent is an antiviral drug. agent XCO)OH. 50. The compound of claim 47 wherein the pharmaceu 35. The compound of claim 34, wherein the fatty alcohol tical agent is an antipsychotic drug. ROH has a carbon structure that is the same as a carbon 51. The compound of claim 47 wherein the pharmaceu Structure of a fatty acid occurring naturally in humans. tical agent is paclitaxel. US 2002/0177609 A1 Nov. 28, 2002 47

52. The compound of claim 47 wherein the pharmaceu acid, palmitoleic acid, Stearic acid, oleic acid, Vaccenic acid, tical agent is flavopiridol. linoleic acid, linolenic acid, arachidonic acid, eicosapen 53. The compound of claim 47 wherein the pharmaceu taenoic acid, docoSenoic acid, docOSatetraenoic acid, tical agent is adefovir. docosapentaenoic acid, docosahexaenoic acid, and nervonic 54. A compound of the formula: acid. 60. The compound of claim 59 wherein Y is tert-butoxy carbonyl. O 61. The compound of claim 59 wherein R' is H or Na". 62. The compound of claim 59 wherein T is -SCH or ls pyrazole. RO T 63. A pharmaceutical preparation comprising a compound wherein R is a C-C fatty group of a fatty alcohol ROH and of the formula T is a leaving group. 55. The compound of claim 54, wherein the fatty alcohol O ROH has a carbon structure that is the same as a carbon Structure of a fatty acid Selected from myristic acid, palmitic ls acid, palmitoleic acid, Stearic acid, oleic acid, Vaccenic acid, RO OX linoleic acid, linolenic acid, arachidonic acid, eicosapen taenoic acid, docoSenoic acid, docOSatetraenoic acid, wherein R is a C-C fatty group of a fatty alcohol ROH, docosapentaenoic acid, docosahexaenoic acid, and nervonic and X is a pharmaceutical agent moiety of the pharmaceu acid. tical agent XOH, and a pharmaceutically acceptable carrier. 56. The compound of claim 55, wherein T is paranitro 64. The pharmaceutical preparation of claim 63, wherein phenol, N-hydroxySuccinimide, or benzotriazole. the fatty alcohol ROH has a carbon structure that is the same 58. A compound of the formula: as a carbon Structure of a fatty acid from myristic acid, palmitic acid, palmitoleic acid, Stearic acid, oleic acid, vaccenic acid, linoleic acid, linolenic acid, arachidonic acid, NY eicosapentaenoic acid, docoSenoic acid, docOSatetraenoic acid, docOSapentaenoic acid, docosahexaenoic acid, and YN ls T nervonic acid. 65. The pharmaceutical preparation of claim 64 wherein R the pharmaceutical agent is an anticancer drug, an antiviral drug, or an antipsychotic drug. wherein R is a C-C group of a fatty alcohol ROH, R' is 66. The pharmaceutical preparation of claim 64 wherein H, an ion, a protecting group, or a pharmaceutical agent, Y the pharmaceutical agent is paclitaxel, flavopiridol, or ade is a protecting group, and T is a leaving group. fovir. 59. The compound of claim 58, wherein the fatty alcohol 67. A pharmaceutical preparation according to claim 66 ROH has a carbon structure that is the same as a carbon wherein the compound is Selected from the group consisting Structure of a fatty acid Selected from myristic acid, palmitic of:

US 2002/0177609 A1 Nov. 28, 2002 48

-continued

us , and

US 2002/0177609 A1 Nov. 28, 2002 49

68. A pharmaceutical preparation comprising a compound of the formula: usO RO X RO-P-ZX wherein R is a C-C fatty group of a fatty alcohol ROH and OR X is a pharmaceutical agent moiety of a pharmaceutical agent XCOO)OH and a pharmaceutically acceptable carrier. wherein R is a C-C fatty group of a fatty alcohol ROH, X 78. The pharmaceutical preparation of claim 77, wherein is a pharmaceutical agent moiety of a pharmaceutical agent the fatty alcohol ROH has a carbon structure that is the same as a carbon Structure of a fatty acid Selected from myristic XZH, wherein ZiSO, a primary amino group, or a Secondary acid, palmitic acid, palmitoleic acid, Stearic acid, oleic acid, amino group, and R' is H, an ion, or a protecting group, and vaccenic acid, linoleic acid, linolenic acid, arachidonic acid, a pharmaceutically acceptable carrier. eicosapentaenoic acid, docoSenoic acid, docOSatetraenoic 69. The pharmaceutical preparation of claim 68, wherein acid, docOSapentaenoic acid, docosahexaenoic acid, and the fatty alcohol ROH has a carbon structure that is the same nervonic acid. as a carbon Structure of a fatty acid Selected from myristic 79. The pharmaceutical preparation of claim 78 wherein acid, palmitic acid, palmitoleic acid, Stearic acid, oleic acid, the pharmaceutical agent is an anticancer drug, an antiviral vaccenic acid, linoleic acid, linolenic acid, arachidonic acid, drug, or an antipsychotic drug. eicosapentaenoic acid, docoSenoic acid, docOSatetraenoic 80. A pharmaceutical preparation comprising a compound acid, docosapentaenoic acid, docosahexaenoic acid, and of the formula: nervonic acid. 70. The pharmaceutical preparation of claim 69, wherein R" is H or Na. 71. The pharmaceutical preparation of claim 69 wherein the pharmaceutical agent is an anticancer drug, an antiviral drug, or an antipsychotic drug. 72. The pharmaceutical preparation of claim 69 wherein the pharmaceutical agent is paclitaxel, flavopiridol, or ade wherein R is a C-C fatty group of a fatty alcohol ROH and fovir. X is a pharmaceutical agent moiety of a pharmaceutical 73. A pharmaceutical preparation comprising a compound agent XNH and a pharmaceutically acceptable carrier. of the formula: 81. The pharmaceutical preparation of claim 83, wherein the fatty alcohol ROH has a carbon structure that is the same as a carbon Structure of a fatty acid Selected from myristic acid, palmitic acid, palmitoleic acid, Stearic acid, oleic acid, vaccenic acid, linoleic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid, docoSenoic acid, docOSatetraenoic acid, docOSapentaenoic acid, docosahexaenoic acid, and nervonic acid. 82. The pharmaceutical preparation of claim 81 wherein wherein R is a C-C fatty group of a fatty alcohol ROH and the pharmaceutical agent is an anticancer drug, an antiviral X is a pharmaceutical agent moiety of a pharmaceutical drug, or an antipsychotic drug. agent HNR"X, wherein R" is H, an alkyl group, or an aryl 83. A method of making a compound of the formula: group and a pharmaceutically acceptable carrier.

74. The pharmaceutical preparation of claim 73, wherein O the fatty alcohol ROH has a carbon structure that is the same as a carbon Structure of a fatty acid Selected from myristic ls acid, palmitic acid, palmitoleic acid, Stearic acid, oleic acid, RO OX vaccenic acid, linoleic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid, docoSenoic acid, docOSatetraenoic comprising reacting an intermediate of the formula acid, docosapentaenoic acid, docosahexaenoic acid, and ROC(O)T with a pharmaceutical agent of the formula XOH nervonic acid. for a time sufficient to form the compound wherein R is a 75. The pharmaceutical preparation of claim 73 wherein C-C2s fatty group of a fatty alcohol ROH, and X is a the pharmaceutical agent is an anticancer drug, an antiviral pharmaceutical agent moiety of the pharmaceutical agent of drug, or an antipsychotic drug. the formula XOH. 84. The method of claim 83, wherein the fatty alcohol 76. The pharmaceutical preparation of claim 73 wherein ROH has a carbon structure that is the same as a carbon the pharmaceutical agent is adefovir. Structure of a fatty acid Selected from myristic acid, palmitic 77. A pharmaceutical preparation comprising a compound acid, palmitoleic acid, Stearic acid, oleic acid, Vaccenic acid, of the formula: linoleic acid, linolenic acid, arachidonic acid, eicosapen US 2002/0177609 A1 Nov. 28, 2002 50 taenoic acid, docoSenoic acid, docOSatetraenoic acid, linoleic acid, linolenic acid, arachidonic acid, eicosapen docosapentaenoic acid, docosahexaenoic acid, and nervonic taenoic acid, docoSenoic acid, docOSatetraenoic acid, acid. docosapentaenoic acid, docosahexaenoic acid, and nervonic 85. The method of claim 84 wherein the pharmaceutical acid. agent is an anticancer drug, an antiviral drug, or an antip 93. The method of claim 92 wherein the pharmaceutical Sychotic drug. agent is an anticancer drug, an antiviral drug, or an antip 86. The method of claim 84 wherein the pharmaceutical Sychotic drug. agent is paclitaxel or flavopiridol. 94. The method of claim 92 wherein the pharmaceutical 87. A method of making a compound of the formula: agent is paclitaxel, flavopiridol, or adefovir. 95. A method of making a compound of the formula:

O O RO-P-ZX OR us RO X comprising reacting an intermediate of the formula: comprising: derivatizing a pharmaceutical agent of the formula O XC(O)OH with a leaving group to form an intermedi ate, and RO-P-T reacting the intermediate with a fatty alcohol of the OR formula ROH for a time Sufficient to form the com pound wherein R is a C-C fatty group of the fatty with a pharmaceutical agent XZH for a time Sufficient to alcohol, and X is a pharmaceutical agent moiety of the form the compound wherein R is a C-C fatty group of a pharmaceutical agent of the formula XC(O)OH. fatty alcohol ROH, X is a pharmaceutical agent moiety of 96. The method of claim 95, wherein the fatty alcohol the pharmaceutical agent XZH, wherein Z is O, a primary ROH has a carbon structure that is the same as a carbon amino group, or a Secondary amino group, and R' is H, an Structure of a fatty acid Selected from myristic acid, palmitic ion, a protecting group or a Second pharmaceutical agent. acid, palmitoleic acid, Stearic acid, oleic acid, Vaccenic acid, 88. The method of claim 87, wherein the fatty alcohol linoleic acid, linolenic acid, arachidonic acid, eicosapen ROH has a carbon structure that is the same as a carbon taenoic acid, docoSenoic acid, docOSatetraenoic acid, Structure of a fatty acid Selected from myristic acid, palmitic docosapentaenoic acid, docosahexaenoic acid, and nervonic acid, palmitoleic acid, Stearic acid, oleic acid, Vaccenic acid, acid. linoleic acid, linolenic acid, arachidonic acid, eicosapen 97. The method of claim 96 wherein the pharmaceutical taenoic acid, docoSenoic acid, docOSatetraenoic acid, agent is an anticancer drug, an antiviral drug, or an antip docosapentaenoic acid, docosahexaenoic acid, and nervonic Sychotic drug. acid. 98. A method of treating a disorder comprising adminis 89. The method of claim 88 wherein the pharmaceutical tering to a Subject in need of Such treatment a pharmaceu agent is an anticancer drug, an antiviral drug, or an antip tical preparation comprising a compound of the formula: Sychotic drug. 90. The method of claim 88 wherein the pharmaceutical agent is paclitaxel, flavopiridol, or adefovir. O 91. A method of making a compound of the formula: us RO OX

and a pharmaceutically acceptable carrier wherein R is a C-C fatty group of a fatty alcohol ROH, and X is a pharmaceutical agent moiety of the pharmaceutical agent XOH. 99. The method of claim 98, wherein the fatty alcohol ROH has a carbon structure that is the same as a carbon comprising reacting an intermediate of the formula Structure of a fatty acid Selected from myristic acid, palmitic ROC(O)T with a pharmaceutical agent of the formula acid, palmitoleic acid, Stearic acid, oleic acid, Vaccenic acid, HNR"X for a time sufficient to form the compound wherein linoleic acid, linolenic acid, arachidonic acid, eicosapen R is a C-C fatty group of a fatty alcohol ROH, X is a taenoic acid, docoSenoic acid, docOSatetraenoic acid, pharmaceutical agent moiety of the pharmaceutical agent of docosapentaenoic acid, docosahexaenoic acid, and nervonic the formula HNR"X, R" is a H, an alkyl group, or an aryl acid. grOup. 100. The method of claim 99 wherein the pharmaceutical 92. The method of claim 91, wherein the fatty alcohol agent is an anticancer drug, an antiviral drug, or an antip ROH has a carbon structure that is the same as a carbon Sychotic drug. Structure of a fatty acid Selected from myristic acid, palmitic 101. The method of claim 99 wherein the pharmaceutical acid, palmitoleic acid, Stearic acid, oleic acid, Vaccenic acid, agent is paclitaxel or flavopiridol. US 2002/0177609 A1 Nov. 28, 2002 51

102. The method of claim 99 wherein the disorder is a mammalian cell proliferation disorder. 103. The method of claim 102 wherein the pharmaceutical agent is paclitaxel. 104. The method of claim 102 wherein the compound is:

AcO

105. The method of claim 102 wherein the compound is Selected from the group consisting of:

and

106. The method of claim 102 wherein the pharmaceutical agent is flavopiridol. 107. The method of claim 102 wherein the compound is Selected from the group consisting of:

US 2002/0177609 A1 Nov. 28, 2002 52

-continued O

O 1s, , and

Cl

O OH

OH

N

Me O OH

Cl or oy O O O

N

Me

108. The method of claim 99 wherein the disorder is a 114. The method of claim 113 wherein the pharmaceutical mammalian psychiatric disorder. agent is paclitaxel. 109. A method of treating a disorder comprising admin 115. The method of claim 113 wherein the pharmaceutical istering to a Subject in need of Such treatment a pharmaceu agent is flavopiridol. tical preparation comprising a compound of the formula: 116. The method of claim 110 wherein the disorder is a mammalian Viral disorder. O 117. The method of claim 110 wherein the disorder is a

RO-P-ZX mammalian psychiatric disorder. 118. A method of treating a disorder comprising admin OR istering to a Subject in need of Such treatment a pharmaceu tical composition comprising a compound of the formula: and a pharmaceutically acceptable carrier wherein R is a C-C fatty group of a fatty alcohol ROH, X is a pharma ceutical agent moiety of a pharmaceutical agent XZH, wherein Z is O, a primary amino group, or a Secondary amino group, and R' is H, an ion, or a protecting group. 110. The method of claim 109, wherein the fatty alcohol ROH has a carbon structure that is the same as a carbon Structure of a fatty acid Selected from myristic acid, palmitic acid, palmitoleic acid, Stearic acid, oleic acid, Vaccenic acid, and a pharmaceutically acceptable carrier wherein R is a linoleic acid, linolenic acid, arachidonic acid, eicosapen C-C fatty group of a fatty alcohol ROH and X is a taenoic acid, docoSenoic acid, docOSatetraenoic acid, pharmaceutical agent moiety of a pharmaceutical agent docosapentaenoic acid, docosahexaenoic acid, and nervonic HNR"X, wherein R" is H, an alkyl group, or an aryl group. acid. 119. The method of claim 118, wherein the fatty alcohol 111. The method of claim 110 wherein the pharmaceutical ROH has a carbon structure that is the same as a carbon agent is an anticancer drug, an antiviral drug, or an antip Structure of a fatty acid Selected from myristic acid, palmitic Sychotic drug. acid, palmitoleic acid, Stearic acid, oleic acid, Vaccenic acid, 112. The method of claim 110 wherein the pharmaceutical linoleic acid, linolenic acid, arachidonic acid, eicosapen agent is paclitaxel, flavopiridol, or adefovir. taenoic acid, docoSenoic acid, docOSatetraenoic acid, 113. The method of claim 110 wherein the disorder is a docosapentaenoic acid, docosahexaenoic acid, and nervonic mammalian cell proliferation disorder. acid. US 2002/0177609 A1 Nov. 28, 2002

120. The method of claim 119 wherein the pharmaceutical 130. The method of claim 126 wherein the disorder is a agent is an anticancer drug, an antiviral drug, or an antip mammalian psychiatric disorder. Sychotic drug. 131. A method of treating a disorder comprising admin 121. The method of claim 119 wherein the disorder is a istering to a Subject in need of Such treatment a pharmaceu mammalian cell proliferation disorder. tical composition comprising a compound of the formula: 122. The method of claim 119 wherein the disorder is a mammalian Viral disorder. 123. The method of claim 122 wherein the pharmaceutical agent is adefovir. 124. The method of claim 119 wherein the disorder is a mammalian psychiatric disorder. 125. A method of treating a disorder comprising admin istering to a Subject in need of Such treatment a pharmaceu tical composition comprising a compound of the formula: and a pharmaceutically acceptable carrier wherein R is a C-C fatty group of a fatty alcohol ROH and X is a pharmaceutical agent moiety of a pharmaceutical agent O XNH, and a pharmaceutically acceptable carrier. us 132. The method of claim 131, wherein the fatty alcohol RO X ROH has a carbon structure that is the same as a carbon Structure of a fatty acid Selected from myristic acid, palmitic and a pharmaceutically acceptable carrier wherein R is a acid, palmitoleic acid, Stearic acid, oleic acid, Vaccenic acid, C-C fatty group of a fatty alcohol ROH and X is a linoleic acid, linolenic acid, arachidonic acid, eicosapen pharmaceutical agent moiety of a pharmaceutical agent taenoic acid, docoSenoic acid, docOSatetraenoic acid, XC(O)OH and a pharmaceutically acceptable carrier. docosapentaenoic acid, docosahexaenoic acid, and nervonic 126. The method of claim 125, wherein the fatty alcohol acid. ROH has a carbon structure that is the same as a carbon 133. The method of claim 132 wherein the pharmaceutical Structure of a fatty acid Selected from myristic acid, palmitic agent is an anticancer drug, an antiviral drug, or an antip acid, pahmitoleic acid, Stearic acid, oleic acid, vaccenic acid, Sychotic drug. linoleic acid, linolenic acid, arachidonic acid, eicosapen 134. The method of claim 132 wherein the pharmaceutical taenoic acid, docoSenoic acid, docosatetraenoic acid, agent is adefovir. docosapentaenoic acid, docosahexaenoic acid, and nervonic 135. The method of claim 132 wherein the disorder is a acid. 127. The method of claim 126 wherein the pharmaceutical mammalian cell proliferation disorder. agent is an anticancer drug, an antiviral drug, or an antip 136. The method of claim 132 wherein the disorder is a Sychotic drug. mammalian Viral disorder. 128. The method of claim 126 wherein the disorder is a 137. The method of claim 132 wherein the disorder is a mammalian cell proliferation disorder. mammalian psychiatric disorder. 129. The method of claim 126 wherein the disorder is a mammalian Viral disorder.