Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D277/24—Radicals substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
  • C07D493/04—Ortho-condensed systems

Definitions

• the present invention relates to a stereospecific process for the preparation of epothilone derivatives and intermediates therefor.
• Epothilones are macrolide compounds which find utility in the pharmaceutical field.
• Epothilones A and B having the structures:
• TAXOL ® cytotoxic activity against rapidly proliferating cells, such as, tumor cells or other hyperproliferative cellular disease, see Angew. Chem. Int. Ed. Engl, Vol. 35, No.13/14, 1567-1569 (1996).
• Epothilones A and B have been synthesized and have been used to treat a variety of cancers and other abnormal proliferative diseases. Such analogs are disclosed in Hofle et al., Angew. Chem. Int. Ed. Engl., 35, No.13/14 (1996); WO93/10121 published May 27, 1993 and WO97/19086 published May 29, 1997; and Nicolaou et al, Angew Chem. Int. Ed. Engl., Vol. 36, No. 19, 2097-2103 (1997); and Su et al, Angew Chem. Int. Ed. Engl., Vol. 36, No. 19, 2093-2096 (1997).
• the present invention is a process for preparing stereospecific aziridinyl epothilones and the intermediates derived therein.
• the invention is directed to a process for preparing compounds of structure VI
• R,, R 2 , R 3 , R 4 , R 5 are selected from the group H or alkyl and when R, and R 2 are alkyl can be joined to form a cycloalkyl;
• R t is selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, or heterocyclo;
• R 7 is selected from the group consisting of alkyl, substituted alkyl, aryl, or substituted aryl;
• P is selected from the group H, alkyl, substituted alkyl, alkanoyl, substituted alkanoyl, aroyl, substituted aroyl, trialkylsilyl, aryl dialkylsilyl, diaryl alkylsilyl, triarylsilyl; which comprises: (a) reacting a compound of structure I
• R 1-6 and P are defined as above with at least one metal halide salt to form structure II;
• alkyl refers to optionally substituted, straight or branched chain saturated hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms.
• lower alkyl refers to optionally substituted alkyl groups of 1 to 4 carbon atoms.
• substituted alkyl refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkyl
• aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be optionally substituted.
• substituted aryl refers to an aryl group substituted by, for example, one to four substituents such as alkyl; substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido, aryloxy and the like.
• substituents such as alkyl; substituted alkyl, halo
• the substituent may be further substituted by halo, hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.
• aralkyl refers to an aryl group bonded directly through an alkyl group, such as benzyl.
• substituted alkene and “substituted alkenyl” refer to a moiety having a carbon to carbon double bond, which can be part of a ring system, with at least one substituent being a lower alkyl or substituted lower alkyl. Other substituents are as defined for substituted alkyl.
• cycloalkyl refers to a optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C 3 -C 7 carbocyclic ring.
• exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl.
• substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
• heterocycle refers to an optionally substituted, unsaturated, partially saturated, or fully saturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring.
• Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized.
• the heterocyclic group may be attached at any heteroatom or carbon atom.
• Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl,
• bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,l-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl,
• substituents include one or more alkyl groups as described above or one or more groups described above as alkyl substituents. Also included are smaller heterocyclos, such as, epoxides and aziridines.
• alkanoyl refers to -C(O)-alkyl.
• substituted alkanoyl refers to -C(O)-substituted alkyl.
• aroyl refers to -C(O)-aryl.
• substituted aroyl refers to -C(O)-substituted aryl.
• trimkylsilyl refers to -Si(alkyl) 3 .
• aryl dialkylsilyl refers to -Si(alkyl) 2 (aryl).
• diaryl alkylsilyl refers to -Si(aryl) 2 (alkyl).
• heteroatoms shall include oxygen, sulfur and nitrogen.
• halogen refers to fluorine, chlorine, bromine and iodine.
• the compounds of formula VI may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine and tributylamine, with pyridine and amino acids such as arginine, lysine and the like.
• alkali metals such as sodium, potassium and lithium
• alkaline earth metals such as calcium and magnesium
• organic bases such as dicyclohexylamine and tributylamine, with pyridine and amino acids such as arginine, lysine and the like.
• Such salts can be obtained, for example, by exchanging the carboxylic acid protons, if they contain a carboxylic acid, from compounds of formula VI with the desired ion in a medium in which the salt precipitates or in an aqueous medium followed by evaporation.
• Other salts can be formed as known to
• the compounds of formula VI form salts with a variety of organic and inorganic acids.
• Such salts include those formed with hydrogen chloride, hydrogen bromide, methanesulfonic acid, hydroxyethanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid and various others (e.g. nitrates, phosphates, borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates and the like).
• Such salts are formed by reacting a compound of formula I through IV in an equivalent amount of the acid in a medium in which the salt precipitates or in an aqueous medium followed by evaporation.
• inner salts can be formed and are included within the term salts as used herein.
• prodrugs and solvates of the compounds of formula VI are also contemplated herein.
• the term prodrug denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula I through IV, or a salt and/or solvate thereof.
• compounds of formula I through IV may form a carboxylate ester moiety.
• the carboxylate esters are conveniently formed by esterifying any of the carboxylic acid functionalities found on the disclosed ring structure(s).
• Solvates of the compounds of formula I through IV are preferably hydrates.
• prodrugs are well known in the art.
• prodrug delivery derivatives see: a) Design of Prodrugs, H. Bundgaard (editor), Elsevier (1985); b) Methods in Enzymology, K. Widder et al. (editors), Academic Press,
• the compounds of the invention are microtubule-stabilizing agents. They are thus useful in the treatment of a variety of cancers and other proliferative diseases including, but not limited to, the following; carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin; including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burketts lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia; - tumors of mesenchymal origin, including fibrosarcoma and rhabdomyoscar
• Compounds of the invention will also inhibit angiogenesis, thereby affecting the growth of tumors and providing treatment of tumors and tumor-related disorders.
• Such anti-angiogenesis properties of the compounds of formula VI will also be useful in the treatment of other conditions responsive to anti-angiogenesis agents including, but not limited to, certain forms of blindness related to retinal vascularization, arthritis, especially inflammatory arthritis, multiple sclerosis, restinosis and psoriasis.
• Compounds of the invention will induce or inhibit apoptosis, a physiological cell death process critical for normal development and homeostasis. Alterations of apoptotic pathways contribute to the pathogenesis of a variety of human diseases.
• Compounds of formula VI as modulators of apoptosis, will be useful in the treatment of a variety of human diseases with aberrations in apoptosis including, but not limited to, cancer and precancerous lesions, immune response related diseases, viral infections, degenerative diseases of the musculoskeletal system and kidney disease.
• diseases including, but not limited to, cancer and precancerous lesions, immune response related diseases, viral infections, degenerative diseases of the musculoskeletal system and kidney disease.
• compounds of the invention may also be used to treat conditions other than cancer or other proliferative diseases.
• Such conditions include, but are not limited to viral infections such as herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus; autoimmune diseases such as systemic lupus erythematosus, immune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel diseases and autoimmune diabetes mellitus; neurodegenerative disorders such as Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; AIDS; myelodysplastic syndromes; aplastic anemia; ischemic injury associated myocardial infarctions; stroke and reperfusion injury; restenosis; arrhythmia; atherosclerosis; toxin-induced or alcohol induced liver diseases; hematological diseases such as chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system such as osteopo
• the present invention thus provides a method of treating a subject, preferably mammals and especially humans, in need of treatment for any of the aforementioned conditions, especially cancer or other proliferative diseases, comprising the step of administering to a subject in need thereof of at least one compound of formula I and II in an amount effective therefor.
• Other therapeutic agents such as those described below may be employed with the inventive compounds in the present method.
• such other therapeutic agent(s) may be administered prior to, simultaneously with or following the administration of the compound(s) of the present invention.
• the effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for a human of from about 0.05 to 200 mg/kg/day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day.
• the compounds are administered in a dosage of less than 100 mg/kg/day, in a single dose or in 2 to 4 divided doses.
• the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.
• Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats and the like, subject to the aforementioned disorders.
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising at least one of the compounds of formula VI capable of treating cancer or other proliferative diseases in an amount effective therefor, and a pharmaceutically acceptable vehicle or diluent.
• the compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation or called for by accepted pharmaceutical practice.
• the compounds of formula VI may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents.
• the present compounds may, for example, be administered in a form suitable for immediate release or extended release.
• Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.
• the present compounds may also be administered liposomally.
• the active substance can be utilized in a composition such as a tablet, capsule, solution or suspension containing about 5 to about 500 mg per unit dosage of a compount or mixture of compounds of formula VI or in a topical form (0.01 to 5% by weight compound of formulaVI, one to five treatments per day). They may be compounded in a conventional manner with a physiologically acceptable vehicle or carrier, excipient, binder, preservative, stabilizer, flavor, etc., or with a topical carrier.
• the compounds of formula VI can also be formulated in compositions such as sterile solutions or suspensions for parenteral administration.
• compositions such as sterile solutions or suspensions for parenteral administration.
• About 0.1 to 500 mg of a compound of formula VI may be compounded with a physiologically acceptable vehicle, carrier, excipient, binder preservative, stabilizer, etc., in a unit dosage form as called for by accepted pharmaceutical practice.
• the amount of active sustance in these compositions or preparations is preferably such that a suitable dosage in the range indicated is obtained.
• compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art.
• Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used.
• Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and or cyclodextrins.
• fast dissolving diluents such as mannitol, lactose, sucrose and or cyclodextrins.
• high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG).
• Such formulations may also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g. Gantrez), and agents to control release such as polyacrylic copolymer (e.g. Carbopol 934).
• compositions for nasal aerosol or inhalation administration include solutions in saline which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
• exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parentally acceptable diluents or solvents, such as cremophor, mannitol, 1,3- butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
• compositions for rectal administration include suppositories which may contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperature, but liquify and/or dissolve in the rectal cavity to release the drug.
• a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperature, but liquify and/or dissolve in the rectal cavity to release the drug.
• exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
• the compounds of the invention may be administered topically to treat plaques associated with psoriasis and as such may be formulated as a cream or ointment.
• the compounds of the invention may be administered either alone or in combination with other anti-cancer and cytotoxic agents and treatments useful in the treatment of cancer or other proliferative diseases.
• anti-cancer and cytotoxic drug combinations wherein the second drug chosen acts in a different manner or different phase of the cell cycle, e.g. S phase, than the present compounds of formula I and II which exert their effects at the G 2 -M phase.
• Example classes of anti-cancer and cytotoxic agents include, but are not limited to: alkylating agents, such as nitorgen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes; antimetabolites, such as folate antagonists, purine analogues, and pyrimidine analogues; antibiotics, such as anthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes, such as L-asparaginase; farnesyl-protein transferase inhibitors; hormonal agents, such as glucocorticoids, estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone anatagonists, octreotide acetate; microtubule-disruptor agents, such as ecteinascidins or their analogs and derivatives; micro
• anti-cancer and cytotoxic agents include, but are not limited to, mechlorethamine hydrochlordie, cyclophosphamide, chlorambucil, melphalan, ifosfamide, busulfan, carmustin, lomustine, semustine, sfreptozocin, thiotepa, dacarbazine, methotrexate, thioguanine, mercaptopurine, fludarabine, pentastatin, cladribin, cytarabine, fluorouracil, doxorubicin hydrochloride, daunorubicin, idarubicin, bleomycin sulfate, mitomycin C, actinomycin D, safracins, saframycins, quinocarcins, discodermolides, vincristine, vinblastine, vinorelbine tartrate, etoposide, teniposide,
• Preferred members of these classes include, but are not limited to paclitaxel, cisplatin, carboplatin, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, mitomycin C, ecteinascidin 743, porfiromycin, 5- fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, and leurosine.
• anti-cancer and other cytotoxic agents include the following: epothilone derivatives as found in German Patent No. 4138042.8; WO 97/19086, WO 98/22461, WO 98/25929, WO 98/38192, WO 99/01124, WO 99/02224, WO 99/02514, WO 99/03848, WO 99/07692, WO99/27890, and WO 99/28324; WO 99/43653, WO 99/54330, WO 99/54318, WO 99/54319, WO 99/65913, WO 99/67252, WO 99/67253, and WO 00/00485; cyclin dependent kinase inhibitors as found in WO 99/24416; and prenyl-protein transferase inhibitors as found in WO 97/30992 and WO 98/54966.
• the combinations of the present invention may also be formulated or co- administered with other therapeutic agents that are selected for their particular usefulness in administering therapies associates with the aforementioned conditions.
• the compounds of the invention may be formulated with agents to prevent nausea, hypersensitivity, and gastric irritation, such as antiemetics, and H, and H 2 antihistaminics.
• hydroxyl groups of formula I, where P, is hydrogen, R,. 5 are methyl and R ⁇ s is 2-methyl-4-thiazolyl can be optionally protected, for example, with triethylsilyl ethers, using methods known in the art.
• Other hydroxyl-protecting groups which are known in the art, and defined above as P catalyst can also be used (see T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, 1991).
• a compound of formula II, where X is a halogen can be prepared from a compound of formula I by treatment with a metal halide salt, such as cesium halides, lithium halides, magnesium halides, and zinc halides, and including but not limited to, lithium bromide, magnesium bromide, zinc bromide, and zinc chloride. More preferably, the metal halide salt is magnesium bromide.
• a compound of formula III can be prepared from a compound of formula II by treatment with an azide salt such as lithium azide, sodium azide, tetraalkylammonium azide, or trialkylsilyl azide. Preferably the azide salt is sodium azide.
• a compound of formula IV, where R 7 is alkyl, substituted alkyl, aryl or substituted aryl, can be prepared from a compound of formula III by a Mitsunobu reaction (see O. Mitsunobu and M. Yamada, Bull. Chem. Soc. Japan 40: 2380 (1967)) using triphenylphosphine, an azodicarboxylate, and a carboxylic acid such as 4-nitrobenzoic acid (see D. L. Hughes, Organic Reactions, Volume 42, Edited by L. Paquette et al., John Wiley & Sons, Inc., New York, 1992; and S.F. Martin and J.A. Dodge, Tetrahedron Letters, 3017 (1991)).
• a compound of formula V can be prepared from one of formula IV by hydrolysis or ammoniolysis of the ester group using, for example, a solution of ammonia in methanol.
• Other methods of ester cleavage such as sodium hydroxide, potassium cyanide in methanol, and potassium carbonate in methanol, are well known in the art (see T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, 1991, pp. 87-104).
• a compound of formula V, where P, is a hydroxyl-protecting group can be deprotected using trifluoroacetic acid in dichloromethane, or other methods known in the art, such as hydrogen fluoride in acetonitrile, tetra-n-butylammonium fluoride, or acetic acid in THF/water.
• Hydroxyl-protecting groups may be alkanoyl, substituted alkanoyl, aroyl, substituted aroyl, trialkylsilyl, aryl dialkysilyl, diaryl alkylsilyl, or triarylsilyl.
• the hydroxyl-protecting group is trialkylsilyl, more preferably the protecting group is triethylsilyl.
• P is a protecting group other than triethylsilyl
• deprotection methods known in the art can be used (see T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, 1991, pp.10- 142).
• Reduction of the azido group and subsequent cyclization of a compound of formula V with a reducing agent, such as a triaryl- or trialkylphosphine provides a compound of formula VI, where R,. 5 are methyl and R ⁇ ; is 2-methyl-4- thiazolyl.
• a compound of formula V, where P, is an hydroxyl-protecting group and R 8 is alkyl, substituted alkyl, aryl, or substituted aryl can be converted to an alkyl-, a substituted alkyl-, an aryl-, or a substituted arylsulfonate ester VII by treatment with an alkyl-, a substituted alkyl-, an aryl-, or a substituted arylsulfonyl chloride.
• Reduction of the azido group and subsequent cyclization of a compound of formula VII using a reducing agent such as a triaryl- or trialkylphosphine provides a compound of the invention such as formula VI (where R,.
• azide reducing agents are well known in the art including, but not limited to, hydrogen, Lindlar's catalyst (Pd, CaCO 3 /Pb), tri-n-butyltin hydride, stannous chloride, hydrogen sulfide, and 1,3-propanedithiol.
• a compound of formula III where P, is a hydroxyl-protecting group can be converted to a compound of formula VIII where X is a halogen by treatment with, for example, triphenylphosphine and a carbon tetrahalide.
• X is a halogen
• Alternative reagents for the conversion of a hydroxyl group to a halogen are well known in the art, such as thionyl chloride or phosphorous tribromide (see R.C. Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, pp. 352-359).
• Reduction of the azido group and subsequent cyclization of a compound of formula VIII using a reducing agent such as a triaryl- or trialkylphosphine provides a compound of the invention such as VI (where R,. 5 are methyl and R e is 2-methyl-4- thiazolyl).
• a reducing agent such as a triaryl- or trialkylphosphine
• Other azide reducing agents are well known in the art including, but not limited to, hydrogen, Lindlar's catalyst (Pd, CaCO 3 /Pb), tri-n-butyltin hydride, stannous chloride, hydrogen sulfide, and 1,3-propanedithiol.
• Et 3 SiCl 25 ml, 149 mmol was added to Epothilone A (10.39 g, 21 mmol), NN-diisopropylethylamine (55 mL, 315 mmol), and imidazole (7.15 g, 105 mmol) in DMF (75 mL) at 25 °C.
• the reaction mixture was heated at 55°C for 6.5 hours and concentrated in vacuo.
• the residue was then diluted with CH 2 C1 2 (100 mL) and the organic extracts were washed with ⁇ aHCO 3 (30 mL), dried over Na 2 SO 4 and concentrated in vacuo.

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