WO1997042948A1 - 7-o-methoxymethyl paclitaxel - Google Patents
7-o-methoxymethyl paclitaxel Download PDFInfo
- Publication number
- WO1997042948A1 WO1997042948A1 PCT/US1997/008079 US9708079W WO9742948A1 WO 1997042948 A1 WO1997042948 A1 WO 1997042948A1 US 9708079 W US9708079 W US 9708079W WO 9742948 A1 WO9742948 A1 WO 9742948A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- paclitaxel
- compound
- methoxymethyl
- ethyl acetate
- mmol
- Prior art date
Links
- 229930012538 Paclitaxel Natural products 0.000 title claims abstract description 20
- 229960001592 paclitaxel Drugs 0.000 title claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 230000000259 anti-tumor effect Effects 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 230000004614 tumor growth Effects 0.000 claims 2
- 241000124008 Mammalia Species 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 10
- 206010028980 Neoplasm Diseases 0.000 description 9
- -1 acetyl Taxotere Chemical group 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
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- 239000000203 mixture Substances 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229940063683 taxotere Drugs 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
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- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
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- 230000003595 spectral effect Effects 0.000 description 3
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- 241000202349 Taxus brevifolia Species 0.000 description 2
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- 238000010171 animal model Methods 0.000 description 2
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- UBJAHGAUPNGZFF-XOVTVWCYSA-N bms-184476 Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC(C)=O)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)C=3C=CC=CC=3)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OCSC)C(=O)C1=CC=CC=C1 UBJAHGAUPNGZFF-XOVTVWCYSA-N 0.000 description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 2
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- 238000002474 experimental method Methods 0.000 description 2
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
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- 239000000546 pharmaceutical excipient Substances 0.000 description 2
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- PVNIQBQSYATKKL-UHFFFAOYSA-N tripalmitin Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCC PVNIQBQSYATKKL-UHFFFAOYSA-N 0.000 description 2
- ICLYJLBTOGPLMC-KVVVOXFISA-N (z)-octadec-9-enoate;tris(2-hydroxyethyl)azanium Chemical compound OCCN(CCO)CCO.CCCCCCCC\C=C/CCCCCCCC(O)=O ICLYJLBTOGPLMC-KVVVOXFISA-N 0.000 description 1
- CDOUZKKFHVEKRI-UHFFFAOYSA-N 3-bromo-n-[(prop-2-enoylamino)methyl]propanamide Chemical compound BrCCC(=O)NCNC(=O)C=C CDOUZKKFHVEKRI-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
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- 201000009030 Carcinoma Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 238000011765 DBA/2 mouse Methods 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
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- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
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- 229920001249 ethyl cellulose Polymers 0.000 description 1
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- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
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- 239000007928 intraperitoneal injection Substances 0.000 description 1
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- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
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- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
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- 229920001515 polyalkylene glycol Polymers 0.000 description 1
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- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940117013 triethanolamine oleate Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (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)
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP97926480A EP0906095A1 (en) | 1996-05-16 | 1997-05-08 | 7-o-methoxymethyl paclitaxel |
| CA002253443A CA2253443A1 (en) | 1996-05-16 | 1997-05-08 | 7-o-methoxymethyl paclitaxel |
| AU31240/97A AU706955B2 (en) | 1996-05-16 | 1997-05-08 | 7-O-methoxymethyl paclitaxel |
| JP09541052A JP2000510148A (ja) | 1996-05-16 | 1997-05-08 | ７―ｏ―メトキシメチルパクリタキセル |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1791996P | 1996-05-16 | 1996-05-16 | |
| US60/017,919 | 1996-05-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1997042948A1 true WO1997042948A1 (en) | 1997-11-20 |
Family
ID=21785279
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1997/008079 WO1997042948A1 (en) | 1996-05-16 | 1997-05-08 | 7-o-methoxymethyl paclitaxel |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0906095A1 (enrdf_load_stackoverflow) |
| JP (1) | JP2000510148A (enrdf_load_stackoverflow) |
| AU (1) | AU706955B2 (enrdf_load_stackoverflow) |
| CA (1) | CA2253443A1 (enrdf_load_stackoverflow) |
| WO (1) | WO1997042948A1 (enrdf_load_stackoverflow) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4960790A (en) * | 1989-03-09 | 1990-10-02 | University Of Kansas | Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof |
| US5646176A (en) * | 1992-12-24 | 1997-07-08 | Bristol-Myers Squibb Company | Phosphonooxymethyl ethers of taxane derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2191224A1 (en) * | 1994-06-28 | 1996-01-11 | Pharmacia & Upjohn Company | 7-ether-taxol analogs, antineoplastic use and pharmaceutical compositions containing them |
-
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 WO PCT/US1997/008079 patent/WO1997042948A1/en not_active Application Discontinuation
- 1997-05-08 JP JP09541052A patent/JP2000510148A/ja active Pending
- 1997-05-08 CA CA002253443A patent/CA2253443A1/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4960790A (en) * | 1989-03-09 | 1990-10-02 | University Of Kansas | Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof |
| US5646176A (en) * | 1992-12-24 | 1997-07-08 | Bristol-Myers Squibb Company | Phosphonooxymethyl ethers of taxane derivatives |
Non-Patent Citations (1)
| Title |
|---|
| HANDBOOK OF PHARMACOLOGY, October 1975, Vol. 28, DIGENIS et al., "Drug Latentiation", pages 86-112. * |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2000510148A (ja) | 2000-08-08 |
| AU706955B2 (en) | 1999-07-01 |
| EP0906095A4 (enrdf_load_stackoverflow) | 1999-05-12 |
| AU3124097A (en) | 1997-12-05 |
| CA2253443A1 (en) | 1997-11-20 |
| EP0906095A1 (en) | 1999-04-07 |
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