BG62738B1 - Метод за получаване на 1-(2'-дезокси-2',2'-дифлуор-d- рибофуранозил)-4-аминопиримидин-2-он хидрохлорид - Google Patents

Метод за получаване на 1-(2'-дезокси-2',2'-дифлуор-d- рибофуранозил)-4-аминопиримидин-2-он хидрохлорид Download PDF

Info

Publication number: BG62738B1
Authority: BG; Bulgaria
Prior art keywords: difluoro; deoxy; ribofuranosyl; methanol; aminopyrimidin
Prior art date: 1994-12-13

Application number

BG101591A

Other languages

Bulgarian (bg)

English (en)

Other versions

BG101591A (en

Inventor

Richard Berglund

Original Assignee

Eli Lilly And Company

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.)

1994-12-13

Filing date

1997-06-10

Publication date

2000-06-30

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=23397211&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=BG62738(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

1997-06-10 Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company

1998-03-31 Publication of BG101591A publication Critical patent/BG101591A/xx

2000-06-30 Publication of BG62738B1 publication Critical patent/BG62738B1/bg

Links

238000004519 manufacturing process Methods 0.000 title abstract description 3
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 78
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 34
SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims abstract description 15
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 13
150000003973 alkyl amines Chemical class 0.000 claims abstract description 12
229960005144 gemcitabine hydrochloride Drugs 0.000 claims abstract description 12
239000007787 solid Substances 0.000 claims abstract description 9
239000012296 anti-solvent Substances 0.000 claims abstract description 7
230000003197 catalytic effect Effects 0.000 claims abstract description 4
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 45
238000000034 method Methods 0.000 claims description 20
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 9
238000002360 preparation method Methods 0.000 claims description 7
239000002904 solvent Substances 0.000 claims description 7
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
-1 benzoyl-O-ribofuranosyl Chemical group 0.000 claims description 6
229940104302 cytosine Drugs 0.000 claims description 4
ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
238000011065 in-situ storage Methods 0.000 claims description 2
101100065885 Caenorhabditis elegans sec-15 gene Proteins 0.000 claims 1
125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 1
QFDBXPKKSDSURA-UHFFFAOYSA-N oxolane;propan-1-ol Chemical compound CCCO.C1CCOC1 QFDBXPKKSDSURA-UHFFFAOYSA-N 0.000 claims 1
125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims 1
239000000203 mixture Substances 0.000 description 21
239000000047 product Substances 0.000 description 14
238000004128 high performance liquid chromatography Methods 0.000 description 9
238000006243 chemical reaction Methods 0.000 description 8
HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 7
239000011541 reaction mixture Substances 0.000 description 7
238000003756 stirring Methods 0.000 description 7
239000003153 chemical reaction reagent Substances 0.000 description 6
QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 6
239000000126 substance Substances 0.000 description 6
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
239000000706 filtrate Substances 0.000 description 4
239000002244 precipitate Substances 0.000 description 4
WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
239000002253 acid Substances 0.000 description 3
230000015572 biosynthetic process Effects 0.000 description 3
239000006227 byproduct Substances 0.000 description 3
150000001875 compounds Chemical class 0.000 description 3
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
239000012065 filter cake Substances 0.000 description 3
229940095102 methyl benzoate Drugs 0.000 description 3
125000006239 protecting group Chemical group 0.000 description 3
238000003797 solvolysis reaction Methods 0.000 description 3
239000007858 starting material Substances 0.000 description 3
HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
238000010511 deprotection reaction Methods 0.000 description 2
JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 2
229960005277 gemcitabine Drugs 0.000 description 2
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
229910000041 hydrogen chloride Inorganic materials 0.000 description 2
239000000543 intermediate Substances 0.000 description 2
230000000269 nucleophilic effect Effects 0.000 description 2
150000003839 salts Chemical class 0.000 description 2
GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
238000005406 washing Methods 0.000 description 2
QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
239000005711 Benzoic acid Substances 0.000 description 1
OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
206010061902 Pancreatic neoplasm Diseases 0.000 description 1
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
230000002411 adverse Effects 0.000 description 1
125000000217 alkyl group Chemical group 0.000 description 1
150000001412 amines Chemical class 0.000 description 1
235000019270 ammonium chloride Nutrition 0.000 description 1
230000000840 anti-viral effect Effects 0.000 description 1
235000010233 benzoic acid Nutrition 0.000 description 1
230000000903 blocking effect Effects 0.000 description 1
201000011510 cancer Diseases 0.000 description 1
238000005119 centrifugation Methods 0.000 description 1
239000003795 chemical substances by application Substances 0.000 description 1
238000001816 cooling Methods 0.000 description 1
238000002425 crystallisation Methods 0.000 description 1
230000008025 crystallization Effects 0.000 description 1
238000010908 decantation Methods 0.000 description 1
229940043279 diisopropylamine Drugs 0.000 description 1
WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
238000001035 drying Methods 0.000 description 1
239000003480 eluent Substances 0.000 description 1
238000001914 filtration Methods 0.000 description 1
230000007062 hydrolysis Effects 0.000 description 1
238000006460 hydrolysis reaction Methods 0.000 description 1
239000012535 impurity Substances 0.000 description 1
230000003993 interaction Effects 0.000 description 1
238000002955 isolation Methods 0.000 description 1
JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
230000014759 maintenance of location Effects 0.000 description 1
208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
239000000463 material Substances 0.000 description 1
150000002825 nitriles Chemical class 0.000 description 1
239000012038 nucleophile Substances 0.000 description 1
230000000174 oncolytic effect Effects 0.000 description 1
239000003960 organic solvent Substances 0.000 description 1
201000002528 pancreatic cancer Diseases 0.000 description 1
208000008443 pancreatic carcinoma Diseases 0.000 description 1
230000000704 physical effect Effects 0.000 description 1
230000001376 precipitating effect Effects 0.000 description 1
BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
239000003380 propellant Substances 0.000 description 1
230000001681 protective effect Effects 0.000 description 1
239000003586 protic polar solvent Substances 0.000 description 1
238000010992 reflux Methods 0.000 description 1
239000012453 solvate Substances 0.000 description 1
238000003786 synthesis reaction Methods 0.000 description 1
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- 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

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Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Engineering & Computer Science (AREA)
Biochemistry (AREA)
Biotechnology (AREA)
General Health & Medical Sciences (AREA)
Genetics & Genomics (AREA)
Molecular Biology (AREA)
Saccharide Compounds (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

BG101591A 1994-12-13 1997-06-10 Метод за получаване на 1-(2'-дезокси-2',2'-дифлуор-d- рибофуранозил)-4-аминопиримидин-2-он хидрохлорид BG62738B1 (bg)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US08/355,372 US5637688A (en)	1994-12-13	1994-12-13	Process for preparing 1-(2'-deoxy-2'-difluoro-d-ribofuranosyl)-4-aminopyrimidin-2-one hydrochloride
PCT/US1995/014864 WO1996018637A1 (en)	1994-12-13	1995-11-14	Process for preparing 1-(2'-deoxy-2',2'-difluoro-d-ribofuranosyl-4-aminopyrimidin-2-one) hydrochloride

Publications (2)

Publication Number	Publication Date
BG101591A BG101591A (en)	1998-03-31
BG62738B1 true BG62738B1 (bg)	2000-06-30

Family

ID=23397211

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
BG101591A BG62738B1 (bg)	1994-12-13	1997-06-10	Метод за получаване на 1-(2'-дезокси-2',2'-дифлуор-d- рибофуранозил)-4-аминопиримидин-2-он хидрохлорид

Country Status (31)

Country	Link
US (2)	US5637688A (de)
EP (1)	EP0719788B1 (de)
JP (1)	JPH10510806A (de)
KR (1)	KR100424991B1 (de)
CN (1)	CN1047177C (de)
AR (1)	AR001041A1 (de)
AT (1)	ATE179986T1 (de)
AU (1)	AU689674B2 (de)
BG (1)	BG62738B1 (de)
BR (1)	BR9509979A (de)
CO (1)	CO4520286A1 (de)
CZ (1)	CZ290941B6 (de)
DE (1)	DE69509624T2 (de)
DK (1)	DK0719788T3 (de)
ES (1)	ES2130542T3 (de)
GR (1)	GR3030265T3 (de)
HU (1)	HU219021B (de)
IL (1)	IL115852A (de)
MY (1)	MY112488A (de)
NO (1)	NO306783B1 (de)
NZ (1)	NZ296476A (de)
PE (1)	PE49296A1 (de)
PL (1)	PL181732B1 (de)
RO (1)	RO117327B1 (de)
RU (1)	RU2154648C2 (de)
SI (1)	SI0719788T1 (de)
TW (1)	TW379226B (de)
UA (1)	UA48152C2 (de)
WO (1)	WO1996018637A1 (de)
YU (1)	YU49314B (de)
ZA (1)	ZA959320B (de)

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JP2009513623A (ja)	2005-10-28	2009-04-02	アーチファーマラブズリミテッド	塩酸ジェムシタビンの改良された製造方法
KR101259637B1 (ko) *	2005-12-14	2013-04-30	주식회사종근당	1-(2´-데옥시-2´,2´-디플루오로-디-리보푸라노실)-4-아미노피리미딘-2-온또는 그의 염산염의 제조방법
RU2345087C2 (ru) *	2006-02-06	2009-01-27	Др. Редди`С Лабораторис Лтд.	Способ получения и очистки гемцитабина гидрохлорида
US8912321B2 (en) *	2006-10-10	2014-12-16	Gilead Pharmasset Llc	Preparation of nucleosides ribofuranosyl pyrimidines
US20090069354A1 (en) *	2007-09-12	2009-03-12	Protia, Llc	Deuterium-enriched gemcitabine
JO2778B1 (en)	2007-10-16	2014-03-15	ايساي انك	Certain Compounds, Compositions and Methods
TWI415858B (zh) *	2007-11-06	2013-11-21	Pharmaessentia Corp	β－核苷之新穎合成技術
IT1393062B1 (it) *	2008-10-23	2012-04-11	Prime Europ Therapeuticals	Procedimento per la preparazione di gemcitabina cloridrato
US8609631B2 (en)	2009-04-06	2013-12-17	Eisai Inc.	Compositions and methods for treating cancer
AU2010234562B2 (en) *	2009-04-06	2016-05-12	Taiho Pharmaceutical Co., Ltd.	Combination of cytidine-based antineoplastic drugs with cytidine deaminase inhibitor and use thereof in the treatment of cancer
JP5687687B2 (ja) *	2009-04-06	2015-03-18	大塚製薬株式会社	癌を治療するための（２’−デオキシ−リボフラノシル）−１，３，４，７−テトラヒドロ−（１，３）ジアゼピン−２−オン誘導体
UY32546A (es) *	2009-04-06	2010-10-29	Eisai Inc	Composiciones y metodos para tratar cancer
CN101525361B (zh) *	2009-04-21	2010-11-17	济南圣鲁金药物技术开发有限公司	基于吉西他滨结构的前药及其合成方法及应用
EP2431376B2 (de) *	2009-05-15	2024-02-07	Delta-Fly Pharma, Inc.	Neuer stabiler kristall aus 1-(2'-cyan-2'-desoxy-beta-d-arabinofuranosyl)cytosin-monohydrochlorid
CN101628927B (zh) *	2009-08-07	2012-10-10	卡硼瑞（北京）科技有限公司	以1,3,5-三-O-苯甲酰基-α-D-呋喃核糖为原料立体选择性制备β-二氟胞苷盐酸盐的方法
CN102453064B (zh) *	2011-06-30	2014-07-09	江苏豪森药业股份有限公司	制备吉西他滨盐酸盐的方法
CN102659884B (zh) *	2012-04-23	2014-07-02	南京臣功制药股份有限公司	盐酸吉西他滨的提纯方法
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US5223608A (en) *	1987-08-28	1993-06-29	Eli Lilly And Company	Process for and intermediates of 2',2'-difluoronucleosides
JPH0673086A (ja) *	1992-06-22	1994-03-15	Eli Lilly & Co	立体選択的な陰イオングリコシル化法
AU4134793A (en) *	1992-06-22	1993-12-23	Eli Lilly And Company	2'-deoxy-2',2'-difluoro(2,6,8-substituted) purine nucleosides having anti-viral and anti-cancer activity and intermediates
UA41261C2 (uk) *	1992-06-22	2001-09-17	Елі Ліллі Енд Компані	Спосіб одержання збагачених бета-аномером нуклеозидів
KR100252451B1 (ko) *	1992-09-01	2000-04-15	피터 지. 스트링거	뉴클레오사이드의아노머화방법
US5637688A (en) *	1994-12-13	1997-06-10	Eli Lilly And Company	Process for preparing 1-(2'-deoxy-2'-difluoro-d-ribofuranosyl)-4-aminopyrimidin-2-one hydrochloride

1994
- 1994-12-13 US US08/355,372 patent/US5637688A/en not_active Expired - Lifetime
1995
- 1995-11-01 AR AR33407495A patent/AR001041A1/es unknown
- 1995-11-02 PE PE1995283631A patent/PE49296A1/es not_active IP Right Cessation
- 1995-11-02 IL IL11585295A patent/IL115852A/xx not_active IP Right Cessation
- 1995-11-03 ZA ZA959320A patent/ZA959320B/xx unknown
- 1995-11-09 SI SI9530272T patent/SI0719788T1/xx unknown
- 1995-11-09 DK DK95308030T patent/DK0719788T3/da active
- 1995-11-09 ES ES95308030T patent/ES2130542T3/es not_active Expired - Lifetime
- 1995-11-09 EP EP95308030A patent/EP0719788B1/de not_active Expired - Lifetime
- 1995-11-09 AT AT95308030T patent/ATE179986T1/de active
- 1995-11-09 DE DE69509624T patent/DE69509624T2/de not_active Expired - Lifetime
- 1995-11-10 CO CO95053319A patent/CO4520286A1/es unknown
- 1995-11-13 YU YU70895A patent/YU49314B/sh unknown
- 1995-11-14 CZ CZ19971798A patent/CZ290941B6/cs not_active IP Right Cessation
- 1995-11-14 BR BR9509979A patent/BR9509979A/pt not_active Application Discontinuation
- 1995-11-14 WO PCT/US1995/014864 patent/WO1996018637A1/en not_active Ceased
- 1995-11-14 RU RU97111801/04A patent/RU2154648C2/ru not_active IP Right Cessation
- 1995-11-14 TW TW084112041A patent/TW379226B/zh not_active IP Right Cessation
- 1995-11-14 CN CN95196792A patent/CN1047177C/zh not_active Expired - Fee Related
- 1995-11-14 UA UA97062781A patent/UA48152C2/uk unknown
- 1995-11-14 JP JP8518835A patent/JPH10510806A/ja active Pending
- 1995-11-14 RO RO97-01060A patent/RO117327B1/ro unknown
- 1995-11-14 PL PL95321046A patent/PL181732B1/pl unknown
- 1995-11-14 NZ NZ296476A patent/NZ296476A/xx not_active IP Right Cessation
- 1995-11-14 AU AU41101/96A patent/AU689674B2/en not_active Ceased
- 1995-11-14 KR KR1019970703880A patent/KR100424991B1/ko not_active Expired - Fee Related
- 1995-11-14 HU HU9800673A patent/HU219021B/hu not_active IP Right Cessation
- 1995-11-16 MY MYPI95003490A patent/MY112488A/en unknown
1997
- 1997-04-11 US US08/837,071 patent/US5808048A/en not_active Expired - Lifetime
- 1997-06-10 BG BG101591A patent/BG62738B1/bg unknown
- 1997-06-11 NO NO972679A patent/NO306783B1/no not_active IP Right Cessation
1999
- 1999-05-19 GR GR990401358T patent/GR3030265T3/el unknown

Also Published As

Publication number	Publication date
DE69509624D1 (de)	1999-06-17
IL115852A0 (en)	1996-01-31
HUT77929A (hu)	1998-11-30
GR3030265T3 (en)	1999-08-31
MX9704322A (es)	1997-09-30
UA48152C2 (uk)	2002-08-15
IL115852A (en)	1999-09-22
YU49314B (sh)	2005-06-10
US5808048A (en)	1998-09-15
EP0719788A3 (de)	1996-09-25
CZ179897A3 (en)	1997-09-17
ES2130542T3 (es)	1999-07-01
WO1996018637A1 (en)	1996-06-20
NZ296476A (en)	1998-12-23
NO306783B1 (no)	1999-12-20
KR100424991B1 (ko)	2004-05-20
TW379226B (en)	2000-01-11
NO972679D0 (no)	1997-06-11
EP0719788B1 (de)	1999-05-12
RU2154648C2 (ru)	2000-08-20
HU219021B (hu)	2001-01-29
PL321046A1 (en)	1997-11-24
DE69509624T2 (de)	1999-10-07
NO972679L (no)	1997-06-11
AU689674B2 (en)	1998-04-02
PE49296A1 (es)	1996-11-21
DK0719788T3 (da)	1999-11-01
US5637688A (en)	1997-06-10
AU4110196A (en)	1996-07-03
BR9509979A (pt)	1998-06-09
AR001041A1 (es)	1997-09-24
ZA959320B (en)	1997-05-05
MY112488A (en)	2001-06-30
BG101591A (en)	1998-03-31
ATE179986T1 (de)	1999-05-15
CO4520286A1 (es)	1997-10-15
CZ290941B6 (cs)	2002-11-13
EP0719788A2 (de)	1996-07-03
SI0719788T1 (en)	1999-10-31
YU70895A (sh)	1998-09-18
RO117327B1 (ro)	2002-01-30
PL181732B1 (en)	2001-09-28
JPH10510806A (ja)	1998-10-20
CN1047177C (zh)	1999-12-08
CN1169728A (zh)	1998-01-07

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