Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
  • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention concerns the novel antitumor compound, 7-O-methoxymethyl paclitaxel, pharmaceutical compositions thereof, and its use as an antitumor agent.
• Taxol® (paclitaxel) is a natural product extracted from the bark of Pacific yew trees, Taxus brevifolia. It has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis. It has been recently approved for the treatment of ovarian cancer; and studies involving breast, colon, and lung cancers have shown promising results. The results of paclitaxel clinical studies are reviewed in Rowinsky and
• Taxotere® a semi-synthetic analog of paclitaxel named Taxotere® has also been found to have good antitumor activity in animal models. Taxotere® is also currently undergoing clinical trials in Europe and the United States. The structures of paclitaxel and Taxotere® are shown below along with the conventional numbering system of taxane molecules; such numbering system is also employed in this application.
• the present invention relates to the novel compound 7-0- methoxymethyl paclitaxel, having the formula (I):
• Ph is phenyl
• Ac is acetyl
• Bz is -C(0)Ph.
• mice Balb/c x DBA/2 F ⁇ hybrid mice were implanted intraperitoneally, as described by William Rose in Evaluation of Madison 109 Lung
• Carcinoma as a Model for Screening Antitumor Drugs, Cancer Treatment Reports. 65, No. 3-4 (1981), with 0.5 mL of a 2% (w/v) brei of M109 lung carcinoma.
• mice were treated with compound (I) under study by receiving intraperitoneal injections of various doses on days 5 and 8 post-tumor implant. Mice were followed daily for survival until approximately 75 -90 days post-tumor implant. One group of mice per experiment remained untreated and served as the control group. Median survival times of compound-treated (T) mice were compared to the median survival time of the control (C) mice. The ratio of the two values for each compound-treated group of mice was multiplied by 100 and expressed as a percentage (i.e. % T/C). Any % T/C value > 125 is considered significant antitumor activity.
• Compound (I) exhibited a % T/C value of 192 at a dose of 50 mg / kg / injection.
• the compound of formula (I) of the instant invention is an effective tumor inhibiting agent, and thus is useful in human and /or veterinary medicine.
• another aspect of the instant invention concerns a method for inhibiting human and /or other mammalian tumors which comprises administering to a tumor bearing host an antitumor effective amount of a compound of formula (I).
• the compound of formula (I) of the present invention may be used in a manner similar to that of paclitaxel; therefore, an oncologist skilled in the art of cancer treatment will be able to ascertain, without undue experimentation, an appropriate treatment protocol for administering a compound of the present invention.
• the dosage, mode and schedule of administration for the compound of this invention is not particularly restricted.
• the compound of the present invention may be administered via any suitable route of administration, preferably parenterally; the dosage may be, for example, in the range of about 1 to about 100 mg/kg of body weight, or about 20 to about 500 mg/m ⁇ .
• the actual dose used will vary according to the particular composition formulated, the route of administration, and the particular site, host and type of tumor being treated. Many factors that modify the action of the drug will be taken into account in determining the dosage including age, weight, sex, diet and the physical condition of the patient.
• the present invention also provides pharmaceutical compositions (formulations) containing an antitumor effective amount of the compound of formula (I) in combination with one or more pharmaceutically acceptable carriers, excipients, diluents or adjuvants.
• pharmaceutically acceptable carriers examples include, for example, United States Patents Nos. 4,960,790 and 4,814,470, and such examples may be followed to formulate the compound of this invention.
• the compound of the present invention may be formulated in the form of tablets, pills, powder mixtures, capsules, injectables, solutions, suppositories, emulsions, dispersions, food premix, and in other suitable forms.
• sterile solid compositions for example, freeze dried and, if desired, combined with other pharmaceutically acceptable excipients.
• Such solid compositions can be reconstituted with sterile water, physiological saline, or a mixture of water and an organic solvent, such as propylene glycol, ethanol, and the like, or some other sterile injectable medium immediately before use for parenteral administration.
• Typical of pharmaceutically acceptable carriers are, for example, manitol, urea, dextrans, lactose, potato and maize starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, ethyl cellulose, poly(vinylpyrrolidone), calcium carbonate, ethyl oleate, isopropyl myristate, benzyl benzoate, sodium carbonate, gelatin, potassium carbonate, silicic acid.
• the pharmaceutical preparation may also contain nontoxic auxiliary substances such as emulsifying, preserving, wetting agents, and the like as for example, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene monostearate, glyceryl tripalmitate, dioctyl sodium sulfosuccinate, and the like.
• auxiliary substances such as emulsifying, preserving, wetting agents, and the like as for example, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene monostearate, glyceryl tripalmitate, dioctyl sodium sulfosuccinate, and the like.
• NMR nuclear magnetic resonance
• TMS tetramethylsilane
• the compound of formula (I) can be prepared from paclitaxel according to the following process scheme and procedure.
• TES triethylsilyl
• TRC1 means triethylsilylchloride

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Epoxy Compounds (AREA)

Applications Claiming Priority (3)

Publications (2)

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• 1997
  • 1997-05-08 EP EP97926480A patent/EP0906095A1/en not_active Ceased
  • 1997-05-08 AU AU31240/97A patent/AU706955B2/en not_active Ceased
  • 1997-05-08 JP JP09541052A patent/JP2000510148A/ja active Pending
  • 1997-05-08 WO PCT/US1997/008079 patent/WO1997042948A1/en not_active Application Discontinuation
  • 1997-05-08 CA CA002253443A patent/CA2253443A1/en not_active Abandoned

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