CN1192016C - 4－(脱二甲氨基)四环素的制备方法 - Google Patents

4－(脱二甲氨基)四环素的制备方法 Download PDF

Info

Publication number: CN1192016C
Authority: CN; China
Prior art keywords: tetracyclines; acetate; sodium; dedimethylamino; aqueous solution
Prior art date: 1998-05-26
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

CNB991051548A

Other languages

English (en)

Chinese (zh)

Other versions

CN1236775A (zh

Inventor

W·赫吉

J·加林多

P·桑托斯

L·加瓦霍

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.)

Hovione Inter AG

Original Assignee

Hovione Inter AG

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.)

1998-05-26

Filing date

1999-04-21

Publication date

2005-03-09

1999-04-21 Application filed by Hovione Inter AG filed Critical Hovione Inter AG

1999-12-01 Publication of CN1236775A publication Critical patent/CN1236775A/zh

2005-03-09 Application granted granted Critical

2005-03-09 Publication of CN1192016C publication Critical patent/CN1192016C/zh

2019-04-21 Anticipated expiration legal-status Critical

Status Expired - Fee Related legal-status Critical Current

Links

239000004098 Tetracycline Substances 0.000 title claims abstract description 22
238000000034 method Methods 0.000 title claims abstract description 21
238000002360 preparation method Methods 0.000 title claims abstract description 10
229940040944 tetracyclines Drugs 0.000 title abstract 4
235000019364 tetracycline Nutrition 0.000 claims abstract description 19
239000007864 aqueous solution Substances 0.000 claims abstract description 9
230000002378 acidificating effect Effects 0.000 claims abstract description 4
-1 tetracycline compounds Chemical class 0.000 claims description 19
229960002180 tetracycline Drugs 0.000 claims description 18
229930101283 tetracycline Natural products 0.000 claims description 18
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 13
239000000243 solution Substances 0.000 claims description 11
WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 8
BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 8
239000000203 mixture Substances 0.000 claims description 7
VLDBEZDOSUKOBS-UHFFFAOYSA-O 2-(3-hydroxyphenyl)ethyl-trimethylazanium Chemical compound C[N+](C)(C)CCC1=CC=CC(O)=C1 VLDBEZDOSUKOBS-UHFFFAOYSA-O 0.000 claims description 6
NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 6
QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 claims description 4
229910052753 mercury Inorganic materials 0.000 claims description 4
229910052697 platinum Inorganic materials 0.000 claims description 4
IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 4
JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 4
229910001220 stainless steel Inorganic materials 0.000 claims description 4
239000010935 stainless steel Substances 0.000 claims description 4
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
FPFWEULFOPRXCH-UHFFFAOYSA-L [Cl-].[Na+].[I-].[Na+] Chemical compound [Cl-].[Na+].[I-].[Na+] FPFWEULFOPRXCH-UHFFFAOYSA-L 0.000 claims description 2
229910052799 carbon Inorganic materials 0.000 claims description 2
235000007715 potassium iodide Nutrition 0.000 claims description 2
229960004839 potassium iodide Drugs 0.000 claims description 2
150000003839 salts Chemical class 0.000 claims description 2
239000001632 sodium acetate Substances 0.000 claims description 2
235000017281 sodium acetate Nutrition 0.000 claims description 2
238000006722 reduction reaction Methods 0.000 claims 4
CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims 2
150000003863 ammonium salts Chemical class 0.000 claims 1
239000001569 carbon dioxide Substances 0.000 claims 1
229910002092 carbon dioxide Inorganic materials 0.000 claims 1
238000006243 chemical reaction Methods 0.000 abstract description 12
230000002829 reductive effect Effects 0.000 abstract description 12
150000001875 compounds Chemical class 0.000 abstract description 9
238000000605 extraction Methods 0.000 abstract description 5
239000003960 organic solvent Substances 0.000 abstract description 5
150000003522 tetracyclines Chemical class 0.000 abstract description 3
230000001225 therapeutic effect Effects 0.000 abstract description 3
238000005868 electrolysis reaction Methods 0.000 abstract 1
239000003792 electrolyte Substances 0.000 abstract 1
239000012022 methylating agents‎ Substances 0.000 abstract 1
GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 abstract 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 description 14
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 12
229910052725 zinc Inorganic materials 0.000 description 12
239000011701 zinc Substances 0.000 description 12
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
238000004128 high performance liquid chromatography Methods 0.000 description 10
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
239000012074 organic phase Substances 0.000 description 6
238000001035 drying Methods 0.000 description 5
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
229910052757 nitrogen Inorganic materials 0.000 description 5
239000011541 reaction mixture Substances 0.000 description 5
239000007787 solid Substances 0.000 description 5
239000003153 chemical reaction reagent Substances 0.000 description 4
238000004821 distillation Methods 0.000 description 4
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
230000002152 alkylating effect Effects 0.000 description 3
239000000047 product Substances 0.000 description 3
239000002904 solvent Substances 0.000 description 3
238000011282 treatment Methods 0.000 description 3
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
102000005741 Metalloproteases Human genes 0.000 description 2
108010006035 Metalloproteases Proteins 0.000 description 2
238000007872 degassing Methods 0.000 description 2
ZOMNIUBKTOKEHS-UHFFFAOYSA-L dimercury dichloride Chemical compound Cl[Hg][Hg]Cl ZOMNIUBKTOKEHS-UHFFFAOYSA-L 0.000 description 2
239000007789 gas Substances 0.000 description 2
125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 2
238000001556 precipitation Methods 0.000 description 2
238000010025 steaming Methods 0.000 description 2
238000003756 stirring Methods 0.000 description 2
239000000725 suspension Substances 0.000 description 2
238000010189 synthetic method Methods 0.000 description 2
125000005208 trialkylammonium group Chemical group 0.000 description 2
238000001291 vacuum drying Methods 0.000 description 2
238000009834 vaporization Methods 0.000 description 2
230000008016 vaporization Effects 0.000 description 2
SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 1
CRTGSPPMTACQBL-UHFFFAOYSA-N 2,3-dihydroxycyclopent-2-en-1-one Chemical compound OC1=C(O)C(=O)CC1 CRTGSPPMTACQBL-UHFFFAOYSA-N 0.000 description 1
HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 description 1
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
102000004190 Enzymes Human genes 0.000 description 1
108090000790 Enzymes Proteins 0.000 description 1
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
206010061218 Inflammation Diseases 0.000 description 1
208000029578 Muscle disease Diseases 0.000 description 1
241001597008 Nomeidae Species 0.000 description 1
208000010641 Tooth disease Diseases 0.000 description 1
208000025865 Ulcer Diseases 0.000 description 1
239000002253 acid Substances 0.000 description 1
239000000654 additive Substances 0.000 description 1
230000000996 additive effect Effects 0.000 description 1
230000029936 alkylation Effects 0.000 description 1
238000005804 alkylation reaction Methods 0.000 description 1
230000000845 anti-microbial effect Effects 0.000 description 1
239000008346 aqueous phase Substances 0.000 description 1
229910052786 argon Inorganic materials 0.000 description 1
206010003246 arthritis Diseases 0.000 description 1
229940075397 calomel Drugs 0.000 description 1
239000003638 chemical reducing agent Substances 0.000 description 1
239000003795 chemical substances by application Substances 0.000 description 1
238000004140 cleaning Methods 0.000 description 1
238000002425 crystallisation Methods 0.000 description 1
230000008025 crystallization Effects 0.000 description 1
206010012601 diabetes mellitus Diseases 0.000 description 1
229960003722 doxycycline Drugs 0.000 description 1
239000003814 drug Substances 0.000 description 1
230000000694 effects Effects 0.000 description 1
238000003379 elimination reaction Methods 0.000 description 1
238000001704 evaporation Methods 0.000 description 1
230000008020 evaporation Effects 0.000 description 1
238000001914 filtration Methods 0.000 description 1
239000012467 final product Substances 0.000 description 1
208000024693 gingival disease Diseases 0.000 description 1
239000011521 glass Substances 0.000 description 1
XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
238000007654 immersion Methods 0.000 description 1
230000004054 inflammatory process Effects 0.000 description 1
239000003112 inhibitor Substances 0.000 description 1
238000004519 manufacturing process Methods 0.000 description 1
239000000463 material Substances 0.000 description 1
229910052751 metal Inorganic materials 0.000 description 1
239000002184 metal Substances 0.000 description 1
230000001035 methylating effect Effects 0.000 description 1
125000004433 nitrogen atom Chemical group N* 0.000 description 1
239000001103 potassium chloride Substances 0.000 description 1
235000011164 potassium chloride Nutrition 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
238000011321 prophylaxis Methods 0.000 description 1
239000012266 salt solution Substances 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
239000011734 sodium Substances 0.000 description 1
238000000638 solvent extraction Methods 0.000 description 1
230000009466 transformation Effects 0.000 description 1
231100000397 ulcer Toxicity 0.000 description 1
238000005406 washing Methods 0.000 description 1
239000002699 waste material Substances 0.000 description 1
150000003751 zinc Chemical class 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
- C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings
- C07C2603/44—Naphthacenes; Hydrogenated naphthacenes
- C07C2603/46—1,4,4a,5,5a,6,11,12a- Octahydronaphthacenes, e.g. tetracyclines

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Chemical Kinetics & Catalysis (AREA)
Health & Medical Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Animal Behavior & Ethology (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Engineering & Computer Science (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Electrolytic Production Of Non-Metals, Compounds, Apparatuses Therefor (AREA)

CNB991051548A 1998-05-26 1999-04-21 4－(脱二甲氨基)四环素的制备方法 Expired - Fee Related CN1192016C (zh)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
PT102.160		1998-05-26
PT102160A PT102160B (pt)	1998-05-26	1998-05-26	Processo para a preparacao de 4-(des-dimetilamino)-tetraciclinas

Publications (2)

Publication Number	Publication Date
CN1236775A CN1236775A (zh)	1999-12-01
CN1192016C true CN1192016C (zh)	2005-03-09

Family

ID=20085765

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CNB991051548A Expired - Fee Related CN1192016C (zh)	1998-05-26	1999-04-21	4－(脱二甲氨基)四环素的制备方法

Country Status (17)

Country	Link
US (1)	US6143161A (2)
EP (1)	EP0962552B1 (2)
JP (1)	JP2000034264A (2)
KR (1)	KR19990087905A (2)
CN (1)	CN1192016C (2)
AT (1)	ATE213788T1 (2)
AU (1)	AU746608B2 (2)
CA (1)	CA2272598C (2)
DE (1)	DE69900927T2 (2)
ES (1)	ES2173706T3 (2)
HU (1)	HUP9900761A3 (2)
IL (1)	IL129244A (2)
IN (1)	IN192877B (2)
NO (1)	NO325059B1 (2)
NZ (1)	NZ334940A (2)
PT (1)	PT102160B (2)
ZA (1)	ZA992484B (2)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
SI1753713T1 (sl)	2004-05-21	2017-01-31	President And Fellows Of Harvard College	Sinteza tetraciklinov in njihovih analogov
WO2007117639A2 (en) *	2006-04-07	2007-10-18	The President And Fellows Of Harvard College	Synthesis of tetracyclines and analogues thereof
EP2487160B1 (en) *	2006-10-11	2016-02-03	President and Fellows of Harvard College	Synthesis of Enone Intermediate
WO2010126607A2 (en)	2009-04-30	2010-11-04	President And Fellows Of Harvard College	Synthesis of tetracyclines and intermediates thereto
PT108978B (pt)	2015-11-24	2020-03-09	Hovione Farm S A	Sais de tetraciclinas

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
GB1349043A (en) *	1971-04-05	1974-03-27	Pliva Pharm & Chem Works	Process for the preparation of 6-demethyl-6-deoxy-6-methylene tetracyclines
US5308839A (en) *	1989-12-04	1994-05-03	The Research Foundation Of State University Of New York	Composition comprising non-steroidal anti-inflammatory agent tenidap and effectively non-antibacterial tetracycline
JP3016587B2 (ja) *	1989-12-04	2000-03-06	ザ・リサーチ・ファンデーション・オブ・ステート・ユニバーシティ・オブ・ニューヨーク	非ステロイド抗炎症剤及びテトラサイクリンの配合
US5223248A (en) *	1991-02-11	1993-06-29	The Research Foundation Of State University Of New York	Non-antibacterial tetracycline compositions possessing antiplaque properties
CA2094874C (en) *	1992-04-27	2003-02-11	Thomas F. Mcnamara	Non-antibacterial tetracycline compositons possessing antiplaque properties
JPH069523A (ja) *	1992-06-18	1994-01-18	Kuraray Co Ltd	４−デジメチルアミノテトラサイクリンの精製法
DK0599397T3 (da) *	1992-11-17	1996-09-16	Univ New York State Res Found	Tetracycliner, herunder non-mikrobielle, kemisk-modificerede tetracycliner, inhiberer overdreven collagentværbinding ved diabetes
US5552297A (en) *	1993-12-21	1996-09-03	Abbott Laboratories	Lead detection method and reggents utilizing aminolevulinic acid dehydratase and tertiary phosphines
US5789395A (en) *	1996-08-30	1998-08-04	The Research Foundation Of State University Of New York	Method of using tetracycline compounds for inhibition of endogenous nitric oxide production

1998
- 1998-05-26 PT PT102160A patent/PT102160B/pt not_active IP Right Cessation
1999
- 1999-03-25 HU HU9900761A patent/HUP9900761A3/hu unknown
- 1999-03-26 AU AU22444/99A patent/AU746608B2/en not_active Ceased
- 1999-03-30 NZ NZ334940A patent/NZ334940A/xx unknown
- 1999-03-30 IL IL12924499A patent/IL129244A/xx not_active IP Right Cessation
- 1999-03-31 ZA ZA9902484A patent/ZA992484B/xx unknown
- 1999-04-01 AT AT99302600T patent/ATE213788T1/de active
- 1999-04-01 EP EP99302600A patent/EP0962552B1/en not_active Expired - Lifetime
- 1999-04-01 DE DE69900927T patent/DE69900927T2/de not_active Expired - Lifetime
- 1999-04-01 ES ES99302600T patent/ES2173706T3/es not_active Expired - Lifetime
- 1999-04-09 IN IN555DE1999 patent/IN192877B/en unknown
- 1999-04-09 KR KR1019990012481A patent/KR19990087905A/ko not_active Ceased
- 1999-04-13 JP JP11105105A patent/JP2000034264A/ja active Pending
- 1999-04-21 CN CNB991051548A patent/CN1192016C/zh not_active Expired - Fee Related
- 1999-04-29 NO NO19992072A patent/NO325059B1/no not_active IP Right Cessation
- 1999-05-21 CA CA002272598A patent/CA2272598C/en not_active Expired - Fee Related
- 1999-05-24 US US09/317,396 patent/US6143161A/en not_active Expired - Fee Related

Also Published As

Publication number	Publication date
JP2000034264A (ja)	2000-02-02
IL129244A0 (en)	2000-02-17
EP0962552B1 (en)	2002-02-27
HUP9900761A3 (en)	2000-06-28
NO992072L (no)	1999-11-29
NO325059B1 (no)	2008-01-21
PT102160A (pt)	1999-11-30
HUP9900761A2 (hu)	1999-12-28
NO992072D0 (no)	1999-04-29
HU9900761D0 (en)	1999-05-28
DE69900927D1 (de)	2002-04-04
PT102160B (pt)	2001-04-30
ZA992484B (en)	1999-10-05
ATE213788T1 (de)	2002-03-15
AU746608B2 (en)	2002-05-02
CA2272598C (en)	2008-01-22
CN1236775A (zh)	1999-12-01
EP0962552A1 (en)	1999-12-08
IN192877B (2)	2004-05-29
CA2272598A1 (en)	1999-11-26
ES2173706T3 (es)	2002-10-16
DE69900927T2 (de)	2002-08-29
IL129244A (en)	2003-01-12
AU2244499A (en)	1999-12-02
KR19990087905A (ko)	1999-12-27
US6143161A (en)	2000-11-07
NZ334940A (en)	2000-05-26

Legal Events

Date	Code	Title	Description
1999-12-01	C06	Publication
1999-12-01	PB01	Publication
2001-06-06	C10	Entry into substantive examination
2001-06-06	SE01	Entry into force of request for substantive examination
2005-03-09	C14	Grant of patent or utility model
2005-03-09	GR01	Patent grant
2013-06-12	C17	Cessation of patent right
2013-06-12	CF01	Termination of patent right due to non-payment of annual fee	Granted publication date: 20050309 Termination date: 20120421

Publication	Publication Date	Title
CN1926102B (zh)	2011-01-05	N-保护的4-酮脯氨酸衍生物的制备方法
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