WO1994020485A1 - Process for the preparation of 9-desoxotaxanes - Google Patents
Process for the preparation of 9-desoxotaxanes Download PDFInfo
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- WO1994020485A1 WO1994020485A1 PCT/US1994/002382 US9402382W WO9420485A1 WO 1994020485 A1 WO1994020485 A1 WO 1994020485A1 US 9402382 W US9402382 W US 9402382W WO 9420485 A1 WO9420485 A1 WO 9420485A1
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- Prior art keywords
- hydroxy
- hydrogen
- alkenyl
- aryl
- alkynyl
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- 0 CC1(C)C([C@@](*)C([C@](C)([C@](*)C[C@@]2OC3)[C@]([C@]4O5)[C@@]23O)=O)=C(C)[C@@](*)C[C@]14OC5=O Chemical compound CC1(C)C([C@@](*)C([C@](C)([C@](*)C[C@@]2OC3)[C@]([C@]4O5)[C@@]23O)=O)=C(C)[C@@](*)C[C@]14OC5=O 0.000 description 3
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to a process for the preparation of taxol, baccatin III and 10-desacetyl- baccatin III derivatives or other taxanes having new C9 functional groups.
- Taxol is a natural product extracted from the bark of yew trees. 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
- Taxotere has an activity significantly greater than taxol.
- the present invention is directed to a process for the preparation of analogs or derivatives of taxol, baccatin III, 10-desacetyl baccatin III or other taxanes in which the C9 keto substituent is reduced to the corresponding hydroxy group.
- the C9 hydroxy substituent may thereafter be selectively replaced by another functional group and/or other
- R 1 is hydrogen, hydroxy, protected hydroxy or together with R 14 forms a carbonate
- R 2 is hydrogen, hydroxy, -OCOR 31 , or together with R 2a forms an oxo;
- R 2a is hydrogen or together with R 2 forms an oxo
- R 4 is hydrogen, together with R 4a forms an oxo, oxirane or methylene, or together with R 5a and the carbon atoms to which they are attached form an oxetane ring;
- R 4a is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano, hydroxy, -OCOR 30 , or together with R 4 forms an oxo, oxirane or methylene;
- R 5 is hydrogen or together with R 5a forms an oxo
- R 5a is hydrogen, hydroxy, protected hydroxy, acyloxy, together with R 5 forms an oxo, or together with R 4 and the carbon atoms to which they are attached form an oxetane ring;
- R 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R 6a forms an oxo;
- R 6a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R 6 forms an oxo;
- R 7 is hydrogen or together with R 7a forms an oxo
- R 7a is hydrogen, halogen, protected hydroxy, -OR 28 , or together with R 7 forms an oxo;
- R 9 is hydrogen;
- R 9a is hydrogen, hydroxy, protected hydroxy, or acyloxy
- R 10 is hydrogen or together with R 10a forms an oxo
- R 10a is hydrogen, -OCOR 29 , hydroxy or protected hydroxy, or together with R 10 forms an oxo;
- R 13 is hydroxy, protected hydroxy or
- R 14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R 1 forms a carbonate;
- R 14a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl
- R 28 is hydrogen, acyl, or hydroxy protecting group
- R 29 , R 30 and R 31 are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl;
- X 1 is -OX 6 , -SX 7 , or -NX 8 X 9 ;
- X 2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
- X 3 and X 4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
- X 5 is -COX 10 , -COOX 10 , -COSX 10 , -CONX 8 X 10 , or -SO 2 X 11 ;
- X 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxy protecting group
- X 7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group
- X 8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl;
- X 9 is an amino protecting group
- X 10 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl alkynyl, aryl or heteroaryl;
- X 11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, -OX 10 , or -NX 8 X 14 ;
- X 14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl.
- the present invention is additionally directed to a derivative of baccatin III or 10-desacetyl baccatin III having the following formula which is a key inter- mediate in the synthesis of a new series of tetracyclic taxanes
- R 2 , R 4a , R 7a , R 10a and R 14 are as previously defined and R 13 is hydroxy or protected hydroxy.
- TES means triethylsilyl
- TMS trimethylsilyl
- TPAP means tetrapropylammonium perruthenate
- DMAP means p-dimethylamino pyridine
- DMF means dimethyl- formamide
- LDA lithium diisopropylamide
- LAH means lithium aluminum hydride
- Red-Al means sodium bis (2-methoxyethoxy) aluminum hydride
- 10-DAB means 10- desacetylbaccatin III
- protected hydroxy means -OR wherein R is a hydroxy protecting group
- sulfhydryl protecting group includes, but is not limited to, hemithioacetals such as 1-ethoxyethyl and methoxymethyl, thioesters, or thiocarbonates
- amine protecting group includes, but is not limited to, carbamates, for example, 2,2,2-trichloroethylcarbamate or tertbutylc
- alkyl carbonates having from one to six carbon atoms and substituted with one or more halogen atoms such as 2,2,2-trichloroethoxymethyl and 2,2,2-trichloroethyl; alkenyl carbonates having from two to six carbon atoms such as vinyl and allyl; cycloalkyl carbonates have from three to six carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and phenyl or benzyl carbonates optionally substituted on the ring with one or more C ⁇ alkoxy, or nitro.
- Other hydroxyl, sulfhydryl and amine protecting groups may be found in "Protective Groups in Organic Synthesis" by T. W. Greene, John Wiley and Sons, 1981.
- alkyl groups described herein, either alone or with the various substituents defined hereinabove are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, aryl, hexyl, and the like .
- alkenyl groups described herein, either alone or with the various substituents defined herein- above are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, iso- butenyl, aryl, hexenyl, and the like.
- alkynyl groups described herein, either alone or with the various substituents defined herein- above are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, aryl, hexynyl, and the like.
- aryl moieties described herein either alone or with various substituents, contain from 6 to 15 carbon atoms and include phenyl.
- Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc. Phenyl is the more preferred aryl.
- heteroaryl moieties described herein either alone or with various substituents, contain from 5 to 15 atoms and include, furyl, thienyl, pyridyl and the like. Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc.
- the acyloxy groups described herein contain alkyl, alkenyl, alkynyl, aryl or heteroaryl groups.
- moieties described herein may be alkyl, alkenyl,
- alkynyl, aryl, heteroaryl and/or may contain nitrogen, oxygen, sulfur, halogens and include, for example, lower alkoxy such as methoxy, ethoxy, butoxy, halogen such as chloro or fluoro, nitro, amino, and keto.
- the C9 keto substituent of a taxane having a C9 keto and a C7 hydroxy substuent may be selectively reduced to yield the corresponding C9 ⁇ - hydroxy derivative.
- the reducing agent is preferably a an aluminum hydride or a borohydride such as triacetoxyborohydride, more preferably a tetraalkylborohydride or tetraalkylaluminumhydride, and most preferably, tetra- butylammoniumborohydride (Bu 4 NBH 4 ).
- the C13 hydroxy group of 7- protected-9 ⁇ -hydroxy derivative 6 may be protected with trimethylsilyl or other protecting group which can be selectively removed relative to the C7 hydroxy protecting group as illustrated in Reaction Scheme 2, to enable further selective manipulation of the various
- derivative 11 can be provided by oxidation of 10- desacetyl derivative 8. Thereafter, the C13 hydroxy protecting group can be selectively removed followed by attachment of a side chain as described above to yield 9- acetoxy-10-oxo-taxol or other 9 -acetoxy-10-oxotetracylic taxanes having a C13 side chain.
- the C9 acetate group can be selectively removed by reduction of 10-oxo derivative 11 with a reducing agent such as samarium diiodide to yield 9-desoxo-10-oxo derivative 12 from which the C13 hydroxy protecting group can be selectively removed followed by attachment of a side chain as described above to yield 9-desoxo-10-oxo-taxol or other 9-desoxo-10-oxotetracylic taxanes having a C13 side chain.
- a reducing agent such as samarium diiodide
- Reaction Scheme 4 illustrates a reaction in which 10-DAB is reduced to yield pentaol 13.
- the C7 and C10 hydroxyl groups of pentaol 13 can then be selectively protected with the triethylsilyl or another protecting group to produce triol 14 to which a C13 side chain can be attached as described above or, alternatively, after further modification of the tetracylic substituents.
- Taxanes having C9 and/or C10 acyloxy substituents other than acetate can be prepared using 10- DAB as a starting material as illustrated in Reaction Scheme 5.
- Reaction of 10-DAB with triethylsilyl chloride in pyridine yields 7-protected 10-DAB 15.
- the C10 hydroxy substituent of 7-protected 10-DAB 15 may then be readily acylated with any standard acylating agent to yield derivative 16 having a new C10 acyloxy substituent.
- derivative 16 yields 9 ⁇ -hydroxy derivative 17 to which a C13 side chain may be attached.
- the C10 and C9 groups can be caused to migrate as set forth in Reaction Scheme 2, above.
- 9-desoxo tetracyclic taxanes having alternative C2 and/or C4 esters can be prepared using baccatin III and 10-DAB as starting materials.
- the C2 and/or C4 esters of baccatin III and 10-DAB can be selectively reduced to the corresponding alcohol(s) using reducing agents such as LAH or Red-Al, and new esters can
- the C2 and/or C4 alcohols may be converted to new C2 and/or C4 esters through formation of the corresponding alkoxide by treatment of the alcohol with a suitable base such as LDA followed by an acylating agent such as an acid chloride.
- triol 18 Deprotonation of triol 18 with LDA followed by introduction of an acid chloride selectively gives the C4 ester.
- an acid chloride for example, when acetyl chloride was used, triol 18 was converted to 1,2 diol 4 as set forth in Reaction Scheme 7.
- Triol 18 can also readily be converted to the 1,2 carbonate 19.
- Acetylation of carbonate 19 under vigorous standard conditions provides carbonate 21 as described in Reaction Scheme 8; addition of alkyllithiums or Grignard reagents to carbonate 19 provides the C2 ester having a free hydroxyl group at C4 as set forth in Reaction Scheme 6.
- C4 substituents can be provided by reacting carbonate 19 with an acid chloride and a tertiary amine to yield carbonate 22 which is then reacted with alkyllithiums or Grignard reagents to provide 10-DAB derivatives having new substituents at C2.
- baccatin III may be used as a starting material and reacted as shown in Reaction Scheme 10. After being protected at C7 and C13, baccatin III is reduced with LAH to produce 1,2,4,10 tetraol 24. Tetraol 24 is converted to carbonate 25 using Cl 2 CO and pyridine, and carbonate 25 is acylated at C10 with an acid chloride and pyridine to produce carbonate 26 (as shown) or with acetic anhydride and pyridine (not shown). Acetylation of carbonate 26 under vigorous standard conditions provides carbonate 27 which is then reacted with alkyl lithiums to provide the baccatin III derivatives having new substituents at C2 and C10.
- 10-desacetoxy derivatives of baccatin III and 10-desoxy derivatives of 10-DAB may be prepared by reacting baccatin III or 10-DAB (or their derivatives) with samarium diiodide. Reaction between the tetracyclic taxane having a C10 leaving group and samarium diiodide may be carried out at 0°C in a solvent such as tetrahydrofuran.
- the samarium diiodide selectively abstracts the C10 leaving group; C13 side chains and other substituents on the tetracyclic nucleus remain undisturbed.
- C9 keto substituent may be reduced to provide the corresponding 9-desoxo-9 ⁇ - hydroxy-10-desacetyoxy or 10-desoxy derivatives as otherwise described herein.
- C7 dihydro and other C7 substituted taxanes can be prepared as set forth in Reaction Schemes 11, 12 and 12a.
- Baccatin III may be converted into 7-fluoro baccatin III by treatment with FAR at room temperature in THF solution.
- Other baccatin derivatives with a free C7 hydroxyl group behave similarly.
- 7-chloro baccatin III can be prepared by treatment of baccatin III with methane sulfonyl chloride and triethylamine in methylene chloride solution containing an excess of triethylamine hydro- chloride.
- Taxanes having C7 acyloxy substituents can be prepared as set forth in Reaction Scheme 12a, 7,13- protected 10-oxo-derivative 11 is converted to its corresponding C13 alkoxide by selectively removing the C13 protecting group and replacing it with a metal such as lithium. The alkoxide is then reacted with a ⁇ -lactam or other side chain precursor. Subsequent hydrolysis of the C7 protecting groups causes a migration of the C7 hydroxy substituent to C10, migration of the C10 oxo substituent to C9, and migration of the C9 acyloxy substituent to C7.
- an appropriate side chain can be attached to the C13 oxygen of these substances.
- 10-Deacetyl-9 ⁇ -hydroxy-9-deoxo baccatin (III) A mixture of 10-deacetyl baccatin (III) (300 mg, 0.55 mmol) and n-Bu 4 NBH 4 (709 mg, 2.76 mmol) in 50 mL of CH 2 Cl 2 was stirred for 12 h at room temperature. The resulting mixture was diluted with ethyl acetate, and quenched by stirring with aqueous NaHCO 3 solution for 20 min. The organic layer was washed with aqueous NaHCO 3 and brine, dried over Na 2 SO 4 , and concentrated to give a residue which was purified by flash chromatography. Elution with ethyl acetate- methanol ( 50:1) afforded 256 mg (85%) of
- the solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added.
- the mixture was partitioned between saturated aqueous NaHCO 3 and 60/40 ethyl acetate/hexane.
- Taxanes 67-3, 70-2, 70-3, 70-4, 75-1, 74-4, and 74-3 of Examples 11-17 were evaluated in in vitro
- cytotoxicity activity against human colon carcinoma cells HCT-116 Cytotoxicity was assessed in HCT116 human colon carcinoma cells by XTT (2,3-bis(2-methoxy-4-nitro-5- sulfophenyl)-5-[(phenyl-amino)carbonyl]-2H-tetrazolium hydroxide) assay (Scudiero et al, "Evaluation of a soluble tetrazolium/ formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines", Cancer Res. 48:4827-4833, 1988). Cells were plated at 4000 cells/well in 96 well microtiter plates and 24 hours later drugs were added and serial diluted.
- the cells were incubated at 37°C for 72 hours at which time the tetrazolium dye, XTT, was added.
- a dehydrogenase enzyme in live cells reduces the XTT to a form that absorbs light at 450 nm which can be quantitated spectrophotometrically. The greater the absorbance the greater the number of live cells.
- the results are expressed as an IC 50 which is the drug concentration required to inhibit cell proliferation (i.e. absorbance at 450 nm) to 50% of that of untreated control cells.
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Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP94911465A EP0687260B1 (en) | 1993-03-05 | 1994-03-04 | Process for the preparation of 9-desoxotaxanes |
CA002157114A CA2157114C (en) | 1993-03-05 | 1994-03-04 | Process for the preparation of 9-desoxotaxanes |
US08/522,307 US6066747A (en) | 1993-03-05 | 1994-03-04 | Process for the preparation of 9-desoxotaxanes |
DE69432140T DE69432140T2 (de) | 1993-03-05 | 1994-03-04 | Verfahren zur Herstellung von 9-Desoxotaxanen |
DK94911465T DK0687260T3 (da) | 1993-03-05 | 1994-03-04 | Fremgangsmåde til fremstillingen af 9-desoxotaxaner |
AU63971/94A AU689770B2 (en) | 1993-03-05 | 1994-03-04 | Process for the preparation of 9-desoxotaxanes |
AT94911465T ATE232854T1 (de) | 1993-03-05 | 1994-03-04 | Verfahren zur herstellung von 9-desoxotaxanen |
JP52020494A JP3892481B2 (ja) | 1993-03-05 | 1994-03-04 | 9−デスオキソタキサンの製法 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/026,978 US5990325A (en) | 1993-03-05 | 1993-03-05 | Process for the preparation of 9-desoxotaxol, 9-desoxobaccatin III and analogs thereof |
US08/026,978 | 1993-03-05 | ||
US9508793A | 1993-07-20 | 1993-07-20 | |
US08/095,087 | 1993-07-20 |
Related Parent Applications (3)
Application Number | Title | Priority Date | Filing Date |
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US08/026,978 Continuation-In-Part US5990325A (en) | 1991-09-23 | 1993-03-05 | Process for the preparation of 9-desoxotaxol, 9-desoxobaccatin III and analogs thereof |
US08/034,247 Continuation-In-Part US5430160A (en) | 1991-09-23 | 1993-03-22 | Preparation of substituted isoserine esters using β-lactams and metal or ammonium alkoxides |
US9508793A Continuation-In-Part | 1991-09-23 | 1993-07-20 |
Related Child Applications (3)
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US08522307 A-371-Of-International | 1994-03-04 | ||
US08/522,307 A-371-Of-International US6066747A (en) | 1993-03-05 | 1994-03-04 | Process for the preparation of 9-desoxotaxanes |
US09/566,970 Continuation US6495704B1 (en) | 1991-09-23 | 2000-05-09 | 9-desoxotaxanes and process for the preparation of 9-desoxotaxanes |
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WO1994020485A1 true WO1994020485A1 (en) | 1994-09-15 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/US1994/002382 WO1994020485A1 (en) | 1993-03-05 | 1994-03-04 | Process for the preparation of 9-desoxotaxanes |
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US (1) | US6066747A (es) |
EP (1) | EP0687260B1 (es) |
JP (2) | JP3892481B2 (es) |
AT (1) | ATE232854T1 (es) |
AU (1) | AU689770B2 (es) |
CA (1) | CA2157114C (es) |
DE (1) | DE69432140T2 (es) |
DK (1) | DK0687260T3 (es) |
ES (1) | ES2193154T3 (es) |
PT (1) | PT687260E (es) |
WO (1) | WO1994020485A1 (es) |
Cited By (17)
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US5589502A (en) * | 1994-11-17 | 1996-12-31 | Tanabe Seiyaku Co., Ltd. | Baccatin derivatives and processes for preparing the same |
US5635531A (en) * | 1996-07-08 | 1997-06-03 | Bristol-Myers Squibb Company | 3'-aminocarbonyloxy paclitaxels |
US5677470A (en) * | 1994-06-28 | 1997-10-14 | Tanabe Seiyaku Co., Ltd. | Baccatin derivatives and processes for preparing the same |
US5773464A (en) * | 1996-09-30 | 1998-06-30 | Bristol-Myers Squibb Company | C-10 epoxy taxanes |
EP0856512A2 (en) * | 1997-01-24 | 1998-08-05 | Virginia Tech Intellectual Properties, Inc. | 1-deoxy paclitaxels, method of preparation and pharmaceutical use |
US5902822A (en) * | 1997-02-28 | 1999-05-11 | Bristol-Myers Squibb Company | 7-methylthiooxomethyl and 7-methylthiodioxomethyl paclitaxels |
US5912264A (en) * | 1997-03-03 | 1999-06-15 | Bristol-Myers Squibb Company | 6-halo-or nitrate-substituted paclitaxels |
EP0927175A1 (en) * | 1996-05-06 | 1999-07-07 | Florida State University | 1-deoxy baccatin iii, 1-deoxy taxol and 1-deoxy taxol analogs and method for the preparation thereof |
US5977386A (en) * | 1996-12-24 | 1999-11-02 | Bristol-Myers Squibb Company | 6-thio-substituted paclitaxels |
US6017935A (en) * | 1997-04-24 | 2000-01-25 | Bristol-Myers Squibb Company | 7-sulfur substituted paclitaxels |
US6369244B1 (en) | 1991-09-23 | 2002-04-09 | Florida State University | C13 amido substituted taxane derivatives and pharmaceutical compositions containing them |
EP1664033A2 (en) * | 2003-09-25 | 2006-06-07 | Tapestry Pharmaceuticals, Inc. | 9,10-alpha,alpha-oh-taxane analogs and methods for production the reof |
EP1810968A2 (en) * | 2003-09-25 | 2007-07-25 | Tapestry Pharmaceuticals, Inc. | 9, 10-a, a-OH-texane analogs and methods for production thereof |
US8273789B2 (en) | 2007-03-28 | 2012-09-25 | Tapestry Pharmaceuticals, Inc. | Biologically active taxane analogs and methods of treatment by oral administration |
US8409574B2 (en) | 2007-02-28 | 2013-04-02 | James D. McChesney | Taxane analogs for the treatment of brain cancer |
US11786504B2 (en) | 2006-09-28 | 2023-10-17 | Tapestry Pharmaceuticals, Inc. | Taxane analogs for the treatment of brain cancer |
US11873308B2 (en) | 2006-11-06 | 2024-01-16 | Tapestry Pharmaceuticals, Inc. | Biologically active taxane analogs and methods of treatment by oral administration |
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US6794523B2 (en) | 1991-09-23 | 2004-09-21 | Florida State University | Taxanes having t-butoxycarbonyl substituted side-chains and pharmaceutical compositions containing them |
US6495704B1 (en) * | 1991-09-23 | 2002-12-17 | Florida State University | 9-desoxotaxanes and process for the preparation of 9-desoxotaxanes |
US6710191B2 (en) | 1993-03-05 | 2004-03-23 | Florida State University | 9β-hydroxytetracyclic taxanes |
JP4502338B2 (ja) * | 1999-09-17 | 2010-07-14 | 株式会社横浜国際バイオ研究所 | タキソイド化合物の製造法 |
CA2385528C (en) | 1999-10-01 | 2013-12-10 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
US7847111B2 (en) * | 2006-06-19 | 2010-12-07 | Canada Inc. | Semi-synthetic route for the preparation of paclitaxel, docetaxel, and 10-deacetylbaccatin III from 9-dihydro-13-acetylbaccatin III |
CA2723654A1 (en) * | 2008-05-07 | 2009-11-12 | Ivax Research, Llc | Processes for preparation of taxanes and intermediates thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4921974A (en) * | 1988-09-29 | 1990-05-01 | Merck & Co., Inc. | Intermediates and processes in the preparation of 5-oxygenated HMG-COA reductase inhibitors |
Family Cites Families (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1256444A (en) * | 1986-04-30 | 1989-06-27 | Kazunori Kan | Process for preparing 4-acetoxy-3- hydroxyethylazetidin-2-one derivatives |
FR2601675B1 (fr) * | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | Derives du taxol, leur preparation et les compositions pharmaceutiques qui les contiennent |
FR2601676B1 (fr) * | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | Procede de preparation du taxol et du desacetyl-10 taxol |
US4876399A (en) * | 1987-11-02 | 1989-10-24 | Research Corporation Technologies, Inc. | Taxols, their preparation and intermediates thereof |
US4942184A (en) * | 1988-03-07 | 1990-07-17 | The United States Of America As Represented By The Department Of Health And Human Services | Water soluble, antineoplastic derivatives of taxol |
FR2629818B1 (fr) * | 1988-04-06 | 1990-11-16 | Centre Nat Rech Scient | Procede de preparation du taxol |
FR2629819B1 (fr) * | 1988-04-06 | 1990-11-16 | Rhone Poulenc Sante | Procede de preparation de derives de la baccatine iii et de la desacetyl-10 baccatine iii |
US4960790A (en) * | 1989-03-09 | 1990-10-02 | University Of Kansas | Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof |
US5175315A (en) * | 1989-05-31 | 1992-12-29 | Florida State University | Method for preparation of taxol using β-lactam |
MY110249A (en) * | 1989-05-31 | 1998-03-31 | Univ Florida State | Method for preparation of taxol using beta lactam |
US5015744A (en) * | 1989-11-14 | 1991-05-14 | Florida State University | Method for preparation of taxol using an oxazinone |
US5136060A (en) * | 1989-11-14 | 1992-08-04 | Florida State University | Method for preparation of taxol using an oxazinone |
US5059699A (en) * | 1990-08-28 | 1991-10-22 | Virginia Tech Intellectual Properties, Inc. | Water soluble derivatives of taxol |
MX9102128A (es) * | 1990-11-23 | 1992-07-08 | Rhone Poulenc Rorer Sa | Derivados de taxano,procedimiento para su preparacion y composicion farmaceutica que los contiene |
FR2679230B1 (fr) * | 1991-07-16 | 1993-11-19 | Rhone Poulenc Rorer Sa | Nouveaux derives d'analogues du taxol, leur preparation et les compositions qui les contiennent. |
US5430160A (en) * | 1991-09-23 | 1995-07-04 | Florida State University | Preparation of substituted isoserine esters using β-lactams and metal or ammonium alkoxides |
US5250683A (en) * | 1991-09-23 | 1993-10-05 | Florida State University | Certain substituted taxanes and pharmaceutical compositions containing them |
US5338872A (en) * | 1993-01-15 | 1994-08-16 | Florida State University | Process for the preparation of 10-desacetoxybaccatin III and 10-desacetoxytaxol and derivatives thereof |
US5274124A (en) * | 1991-09-23 | 1993-12-28 | Florida State University | Metal alkoxides |
US5283253A (en) * | 1991-09-23 | 1994-02-01 | Florida State University | Furyl or thienyl carbonyl substituted taxanes and pharmaceutical compositions containing them |
US5243045A (en) * | 1991-09-23 | 1993-09-07 | Florida State University | Certain alkoxy substituted taxanes and pharmaceutical compositions containing them |
US5350866A (en) * | 1991-09-23 | 1994-09-27 | Bristol-Myers Squibb Company | 10-desacetoxytaxol derivatives |
US5227400A (en) * | 1991-09-23 | 1993-07-13 | Florida State University | Furyl and thienyl substituted taxanes and pharmaceutical compositions containing them |
US5489601A (en) * | 1991-09-23 | 1996-02-06 | Florida State University | Taxanes having a pyridyl substituted side-chain and pharmaceutical compositions containing them |
US5284865A (en) * | 1991-09-23 | 1994-02-08 | Holton Robert A | Cyclohexyl substituted taxanes and pharmaceutical compositions containing them |
US5399726A (en) * | 1993-01-29 | 1995-03-21 | Florida State University | Process for the preparation of baccatin III analogs bearing new C2 and C4 functional groups |
US5229526A (en) * | 1991-09-23 | 1993-07-20 | Florida State University | Metal alkoxides |
IT1254517B (it) * | 1992-03-06 | 1995-09-25 | Indena Spa | 14-beta idrossi-10-deacetil-baccatina iii, suoi derivati, loro prepazione ed impiego terapeutico |
US5254703A (en) * | 1992-04-06 | 1993-10-19 | Florida State University | Semi-synthesis of taxane derivatives using metal alkoxides and oxazinones |
US5440056A (en) * | 1992-04-17 | 1995-08-08 | Abbott Laboratories | 9-deoxotaxane compounds |
DK0639186T3 (da) * | 1992-04-17 | 1999-12-13 | Abbott Lab | Taxolderivater |
FR2697019B1 (fr) * | 1992-10-15 | 1994-11-25 | Rhone Poulenc Rorer Sa | Nouveaux dérivés du taxane, leur préparation et les compositions pharmaceutiques qui les contiennent. |
US5405972A (en) * | 1993-07-20 | 1995-04-11 | Florida State University | Synthetic process for the preparation of taxol and other tricyclic and tetracyclic taxanes |
-
1994
- 1994-03-04 DK DK94911465T patent/DK0687260T3/da active
- 1994-03-04 JP JP52020494A patent/JP3892481B2/ja not_active Expired - Fee Related
- 1994-03-04 US US08/522,307 patent/US6066747A/en not_active Expired - Lifetime
- 1994-03-04 ES ES94911465T patent/ES2193154T3/es not_active Expired - Lifetime
- 1994-03-04 WO PCT/US1994/002382 patent/WO1994020485A1/en active IP Right Grant
- 1994-03-04 PT PT94911465T patent/PT687260E/pt unknown
- 1994-03-04 AT AT94911465T patent/ATE232854T1/de not_active IP Right Cessation
- 1994-03-04 AU AU63971/94A patent/AU689770B2/en not_active Ceased
- 1994-03-04 CA CA002157114A patent/CA2157114C/en not_active Expired - Fee Related
- 1994-03-04 EP EP94911465A patent/EP0687260B1/en not_active Expired - Lifetime
- 1994-03-04 DE DE69432140T patent/DE69432140T2/de not_active Expired - Fee Related
-
2003
- 2003-07-09 JP JP2003272410A patent/JP4101131B2/ja not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4921974A (en) * | 1988-09-29 | 1990-05-01 | Merck & Co., Inc. | Intermediates and processes in the preparation of 5-oxygenated HMG-COA reductase inhibitors |
Cited By (39)
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US6730782B2 (en) | 1991-09-23 | 2004-05-04 | Florida State University | Carbamoyl substituted β-lactams |
US6369244B1 (en) | 1991-09-23 | 2002-04-09 | Florida State University | C13 amido substituted taxane derivatives and pharmaceutical compositions containing them |
US5677470A (en) * | 1994-06-28 | 1997-10-14 | Tanabe Seiyaku Co., Ltd. | Baccatin derivatives and processes for preparing the same |
US5589502A (en) * | 1994-11-17 | 1996-12-31 | Tanabe Seiyaku Co., Ltd. | Baccatin derivatives and processes for preparing the same |
US5608073A (en) * | 1994-11-17 | 1997-03-04 | Tanabe Seiyaku Co., Ltd. | Baccatin derivatives and processes for preparing the same |
EP0927175A1 (en) * | 1996-05-06 | 1999-07-07 | Florida State University | 1-deoxy baccatin iii, 1-deoxy taxol and 1-deoxy taxol analogs and method for the preparation thereof |
EP0927175A4 (en) * | 1996-05-06 | 2002-05-22 | Univ Florida State | 1-DEOXYBACCATIN III, 1-DEOXYTAXOL AND 1-DEOXYTAXOL ANALOG AND METHOD FOR THE PRODUCTION THEREOF |
US5635531A (en) * | 1996-07-08 | 1997-06-03 | Bristol-Myers Squibb Company | 3'-aminocarbonyloxy paclitaxels |
US5773464A (en) * | 1996-09-30 | 1998-06-30 | Bristol-Myers Squibb Company | C-10 epoxy taxanes |
US5977386A (en) * | 1996-12-24 | 1999-11-02 | Bristol-Myers Squibb Company | 6-thio-substituted paclitaxels |
EP0856512A3 (en) * | 1997-01-24 | 1998-12-09 | Virginia Tech Intellectual Properties, Inc. | 1-deoxy paclitaxels, method of preparation and pharmaceutical use |
EP0856512A2 (en) * | 1997-01-24 | 1998-08-05 | Virginia Tech Intellectual Properties, Inc. | 1-deoxy paclitaxels, method of preparation and pharmaceutical use |
US5902822A (en) * | 1997-02-28 | 1999-05-11 | Bristol-Myers Squibb Company | 7-methylthiooxomethyl and 7-methylthiodioxomethyl paclitaxels |
US5912264A (en) * | 1997-03-03 | 1999-06-15 | Bristol-Myers Squibb Company | 6-halo-or nitrate-substituted paclitaxels |
US6017935A (en) * | 1997-04-24 | 2000-01-25 | Bristol-Myers Squibb Company | 7-sulfur substituted paclitaxels |
EP1785416A3 (en) * | 2003-09-25 | 2007-05-30 | Tapestry Pharmaceuticals, Inc. | 9, 10-alpha, alpha-OH-Taxane Analogs and methods for production thereof |
US9402824B2 (en) | 2003-09-25 | 2016-08-02 | Tapestry Pharmaceuticals, Inc. | 9,10-α, α-OH-taxane analogs and methods for production thereof |
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US11147793B2 (en) | 2006-09-28 | 2021-10-19 | Tapestry Pharmaceuticals, Inc. | Taxane analogs for the treatment of brain cancer |
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US10143677B2 (en) | 2007-02-28 | 2018-12-04 | Tapestry Pharmaceuticals, Inc. | Taxane analogs for the treatment of brain cancer |
US8409574B2 (en) | 2007-02-28 | 2013-04-02 | James D. McChesney | Taxane analogs for the treatment of brain cancer |
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Also Published As
Publication number | Publication date |
---|---|
JP4101131B2 (ja) | 2008-06-18 |
DK0687260T3 (da) | 2003-06-10 |
EP0687260A1 (en) | 1995-12-20 |
EP0687260B1 (en) | 2003-02-19 |
EP0687260A4 (en) | 1995-11-06 |
ATE232854T1 (de) | 2003-03-15 |
JP3892481B2 (ja) | 2007-03-14 |
US6066747A (en) | 2000-05-23 |
AU689770B2 (en) | 1998-04-09 |
ES2193154T3 (es) | 2003-11-01 |
JP2004002456A (ja) | 2004-01-08 |
JPH08507526A (ja) | 1996-08-13 |
DE69432140T2 (de) | 2003-07-31 |
CA2157114C (en) | 2003-12-16 |
PT687260E (pt) | 2003-07-31 |
AU6397194A (en) | 1994-09-26 |
DE69432140D1 (de) | 2003-03-27 |
CA2157114A1 (en) | 1994-09-15 |
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