CN1048982C - 用金属烷氧化物和β-内酰胺半合成紫杉烷衍生物的方法 - Google Patents

用金属烷氧化物和β-内酰胺半合成紫杉烷衍生物的方法 Download PDF

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Publication number: CN1048982C
Authority: CN; China
Prior art keywords: acyloxy; aryl; hydrogen; alkyl; heteroaryl
Prior art date: 1991-09-23
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired - Fee Related

Application number

CN92112286A

Other languages

English (en)

Chinese (zh)

Other versions

CN1075315A (zh

Inventor

R·A·霍尔顿

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Florida State University

Original Assignee

Florida State University

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1991-09-23

Filing date

1992-09-23

Publication date

2000-02-02

1992-09-23 Application filed by Florida State University filed Critical Florida State University

1993-08-18 Publication of CN1075315A publication Critical patent/CN1075315A/zh

2000-02-02 Application granted granted Critical

2000-02-02 Publication of CN1048982C publication Critical patent/CN1048982C/zh

2007-09-23 Anticipated expiration legal-status Critical

Status Expired - Fee Related legal-status Critical Current

Links

238000000034 method Methods 0.000 title claims abstract description 39
150000004703 alkoxides Chemical class 0.000 title claims abstract description 38
229910052751 metal Inorganic materials 0.000 title claims abstract description 38
239000002184 metal Substances 0.000 title claims abstract description 38
150000003952 β-lactams Chemical class 0.000 title claims abstract description 38
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 title claims abstract description 17
238000006243 chemical reaction Methods 0.000 claims abstract description 21
-1 ethoxyl methyl Chemical group 0.000 claims description 84
239000001257 hydrogen Substances 0.000 claims description 45
229910052739 hydrogen Inorganic materials 0.000 claims description 45
125000003118 aryl group Chemical group 0.000 claims description 40
125000000217 alkyl group Chemical group 0.000 claims description 36
OVMSOCFBDVBLFW-VHLOTGQHSA-N 5beta,20-epoxy-1,7beta,13alpha-trihydroxy-9-oxotax-11-ene-2alpha,4alpha,10beta-triyl 4,10-diacetate 2-benzoate Chemical compound O([C@@H]1[C@@]2(C[C@H](O)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)O)C(=O)C1=CC=CC=C1 OVMSOCFBDVBLFW-VHLOTGQHSA-N 0.000 claims description 33
125000003342 alkenyl group Chemical group 0.000 claims description 29
125000000304 alkynyl group Chemical group 0.000 claims description 27
125000004423 acyloxy group Chemical group 0.000 claims description 23
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 23
125000001072 heteroaryl group Chemical group 0.000 claims description 23
239000001301 oxygen Substances 0.000 claims description 23
229910052760 oxygen Inorganic materials 0.000 claims description 23
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
125000002252 acyl group Chemical group 0.000 claims description 8
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
125000003545 alkoxy group Chemical group 0.000 claims description 6
230000008569 process Effects 0.000 claims description 6
230000000903 blocking effect Effects 0.000 claims description 5
229910052744 lithium Inorganic materials 0.000 claims description 5
125000006239 protecting group Chemical group 0.000 claims description 5
125000003368 amide group Chemical group 0.000 claims description 3
125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 3
229910052749 magnesium Inorganic materials 0.000 claims description 3
229910052700 potassium Inorganic materials 0.000 claims description 3
229910000077 silane Inorganic materials 0.000 claims description 3
238000006884 silylation reaction Methods 0.000 claims description 3
229910052708 sodium Inorganic materials 0.000 claims description 3
229910052719 titanium Inorganic materials 0.000 claims description 3
125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 2
CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 claims description 2
ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 claims description 2
150000002431 hydrogen Chemical class 0.000 claims 11
125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims 2
125000004104 aryloxy group Chemical group 0.000 claims 1
125000005553 heteroaryloxy group Chemical group 0.000 claims 1
QCIWZIYBBNEPKB-UHFFFAOYSA-N tert-butyl(dimethyl)silane Chemical compound C[SiH](C)C(C)(C)C QCIWZIYBBNEPKB-UHFFFAOYSA-N 0.000 claims 1
229960001592 paclitaxel Drugs 0.000 abstract description 86
229930012538 Paclitaxel Natural products 0.000 abstract description 85
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 abstract description 67
229940123237 Taxane Drugs 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 159
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WSDQIHATCCOMLH-UHFFFAOYSA-N phenyl n-(3,5-dichlorophenyl)carbamate Chemical compound ClC1=CC(Cl)=CC(NC(=O)OC=2C=CC=CC=2)=C1 WSDQIHATCCOMLH-UHFFFAOYSA-N 0.000 description 32
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 30
238000002360 preparation method Methods 0.000 description 27
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UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 20
238000001953 recrystallisation Methods 0.000 description 19
238000003756 stirring Methods 0.000 description 19
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 17
239000012044 organic layer Substances 0.000 description 16
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125000004435 hydrogen atom Chemical class [H]* 0.000 description 15
229910052757 nitrogen Inorganic materials 0.000 description 14
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
239000000741 silica gel Substances 0.000 description 13
229910002027 silica gel Inorganic materials 0.000 description 13
238000005160 1H NMR spectroscopy Methods 0.000 description 12
125000004432 carbon atom Chemical group C* 0.000 description 12
238000003381 deacetylation reaction Methods 0.000 description 12
SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 12
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230000008859 change Effects 0.000 description 9
239000002243 precursor Substances 0.000 description 9
239000002904 solvent Substances 0.000 description 9
229940063683 taxotere Drugs 0.000 description 9
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 8
239000002253 acid Substances 0.000 description 7
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238000013459 approach Methods 0.000 description 5
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XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
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230000015572 biosynthetic process Effects 0.000 description 4
150000001721 carbon Chemical group 0.000 description 4
230000000694 effects Effects 0.000 description 4
FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 4
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239000000047 product Substances 0.000 description 4
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SKJSIVQEPKBFTJ-HUWILPJBSA-N taxusin Chemical compound C1[C@@H](C2(C)C)C[C@H](OC(C)=O)C(C)=C2[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@]2(C)CC[C@H](OC(=O)C)C(=C)[C@@H]12 SKJSIVQEPKBFTJ-HUWILPJBSA-N 0.000 description 4
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
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ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
239000003513 alkali Substances 0.000 description 3
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150000003936 benzamides Chemical class 0.000 description 3
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ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
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150000001299 aldehydes Chemical class 0.000 description 1
239000000956 alloy Substances 0.000 description 1
229910045601 alloy Inorganic materials 0.000 description 1
238000005576 amination reaction Methods 0.000 description 1
DVARTQFDIMZBAA-UHFFFAOYSA-O ammonium nitrate Chemical class [NH4+].[O-][N+]([O-])=O DVARTQFDIMZBAA-UHFFFAOYSA-O 0.000 description 1
230000000259 anti-tumor effect Effects 0.000 description 1
PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
229910052794 bromium Inorganic materials 0.000 description 1
201000011510 cancer Diseases 0.000 description 1
150000001722 carbon compounds Chemical class 0.000 description 1
230000003197 catalytic effect Effects 0.000 description 1
239000003153 chemical reaction reagent Substances 0.000 description 1
238000002512 chemotherapy Methods 0.000 description 1
KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 1
238000009833 condensation Methods 0.000 description 1
230000005494 condensation Effects 0.000 description 1
239000012043 crude product Substances 0.000 description 1
239000003814 drug Substances 0.000 description 1
230000032050 esterification Effects 0.000 description 1
238000005886 esterification reaction Methods 0.000 description 1
MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 1
OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 1
FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 1
229910052731 fluorine Inorganic materials 0.000 description 1
125000002541 furyl group Chemical group 0.000 description 1
229930195733 hydrocarbon Natural products 0.000 description 1
150000002430 hydrocarbons Chemical class 0.000 description 1
230000005764 inhibitory process Effects 0.000 description 1
KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
229910052747 lanthanoid Inorganic materials 0.000 description 1
150000002602 lanthanoids Chemical class 0.000 description 1
208000032839 leukemia Diseases 0.000 description 1
AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
238000004519 manufacturing process Methods 0.000 description 1
238000013507 mapping Methods 0.000 description 1
CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 1
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
125000001624 naphthyl group Chemical group 0.000 description 1
150000002896 organic halogen compounds Chemical class 0.000 description 1
150000002900 organolithium compounds Chemical class 0.000 description 1
150000002901 organomagnesium compounds Chemical class 0.000 description 1
230000003647 oxidation Effects 0.000 description 1
238000007254 oxidation reaction Methods 0.000 description 1
125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
238000012545 processing Methods 0.000 description 1
QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
239000000376 reactant Substances 0.000 description 1
239000011541 reaction mixture Substances 0.000 description 1
238000007363 ring formation reaction Methods 0.000 description 1
238000000926 separation method Methods 0.000 description 1
229910052710 silicon Inorganic materials 0.000 description 1
239000010703 silicon Substances 0.000 description 1
241000894007 species Species 0.000 description 1
238000004611 spectroscopical analysis Methods 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
125000001424 substituent group Chemical group 0.000 description 1
YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
238000010189 synthetic method Methods 0.000 description 1
150000003505 terpenes Chemical class 0.000 description 1
235000007586 terpenes Nutrition 0.000 description 1
125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
150000003512 tertiary amines Chemical class 0.000 description 1
150000007970 thio esters Chemical class 0.000 description 1
150000003555 thioacetals Chemical class 0.000 description 1
230000009466 transformation Effects 0.000 description 1
229940070710 valerate Drugs 0.000 description 1
NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1

Classifications

- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Epoxy Compounds (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

CN92112286A 1991-09-23 1992-09-23 用金属烷氧化物和β-内酰胺半合成紫杉烷衍生物的方法 Expired - Fee Related CN1048982C (zh)

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date
US76380591A	1991-09-23	1991-09-23
US763,805		1991-09-23
US86384992A	1992-04-06	1992-04-06
US863,849		1992-04-06

Publications (2)

Publication Number	Publication Date
CN1075315A CN1075315A (zh)	1993-08-18
CN1048982C true CN1048982C (zh)	2000-02-02

Family

ID=51348512

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CN92112286A Expired - Fee Related CN1048982C (zh)	1991-09-23	1992-09-23	用金属烷氧化物和β-内酰胺半合成紫杉烷衍生物的方法

Country Status (7)

Country	Link
CN (1)	CN1048982C (de)
IL (1)	IL103191A (de)
MX (1)	MX9205369A (de)
MY (1)	MY109876A (de)
NZ (1)	NZ244459A (de)
PT (1)	PT100883B (de)
TW (1)	TW229204B (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CN1393438B (zh) *	2001-06-21	2010-11-03	中国医学科学院药物研究所	紫杉烷衍生物及其制法和用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
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

1992
- 1992-09-16 IL IL10319192A patent/IL103191A/en not_active IP Right Cessation
- 1992-09-21 MY MYPI92001682A patent/MY109876A/en unknown
- 1992-09-21 PT PT100883A patent/PT100883B/pt active IP Right Grant
- 1992-09-22 MX MX9205369A patent/MX9205369A/es unknown
- 1992-09-23 CN CN92112286A patent/CN1048982C/zh not_active Expired - Fee Related
- 1992-09-23 NZ NZ244459A patent/NZ244459A/xx not_active IP Right Cessation
- 1992-10-21 TW TW081108377A patent/TW229204B/zh active

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
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

Also Published As

Publication number	Publication date
TW229204B (de)	1994-09-01
PT100883A (pt)	1994-02-28
IL103191A (en)	2001-07-24
NZ244459A (en)	1995-01-27
PT100883B (pt)	1999-07-30
MY109876A (en)	1997-09-30
MX9205369A (es)	1993-03-01
CN1075315A (zh)	1993-08-18
IL103191A0 (en)	1993-02-21

Legal Events

Date	Code	Title	Description
1993-08-18	C06	Publication
1993-08-18	PB01	Publication
1995-01-11	C10	Entry into substantive examination
1995-01-11	SE01	Entry into force of request for substantive examination
2000-02-02	C14	Grant of patent or utility model
2000-02-02	GR01	Patent grant
2002-06-12	C15	Extension of patent right duration from 15 to 20 years for appl. with date before 31.12.1992 and still valid on 11.12.2001 (patent law change 1993)
2002-06-12	OR01	Other related matters
2010-12-01	C17	Cessation of patent right
2010-12-01	CF01	Termination of patent right due to non-payment of annual fee	Granted publication date: 20000202 Termination date: 20091023

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