NO313383B1 - Pyrazinforbindelse, anvendelse og fremstilling derav samt farmasöytisk blanding - Google Patents

Pyrazinforbindelse, anvendelse og fremstilling derav samt farmasöytisk blanding Download PDF

Info

Publication number: NO313383B1
Authority: NO; Norway
Prior art keywords: compound; formula; pyrazine; trichlorophenyl; compounds
Prior art date: 1997-03-01

Application number

NO19994213A

Other languages

English (en)

Norwegian (no)

Other versions

NO994213L (no

NO994213D0 (no

Inventor

Brian Cox

Malcolm Stuart Nobbs

Gita Punjabhai Shah

Dean David Edney

Michael Simon Loft

Original Assignee

Glaxo Group Ltd

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.)

1997-03-01

Filing date

1999-08-31

Publication date

2002-09-23

1997-03-01 Priority claimed from GBGB9704275.8A external-priority patent/GB9704275D0/en

1997-04-23 Priority claimed from GBGB9708183.0A external-priority patent/GB9708183D0/en

1999-08-31 Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd

1999-08-31 Publication of NO994213D0 publication Critical patent/NO994213D0/no

1999-10-29 Publication of NO994213L publication Critical patent/NO994213L/no

2002-09-23 Publication of NO313383B1 publication Critical patent/NO313383B1/no

Links

KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Natural products C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 title claims description 75
PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 title claims description 38
-1 Pyrazine compound Chemical class 0.000 title claims description 7
238000002360 preparation method Methods 0.000 title claims description 6
239000008194 pharmaceutical composition Substances 0.000 title 1
150000001875 compounds Chemical class 0.000 claims description 140
239000000203 mixture Substances 0.000 claims description 69
238000006243 chemical reaction Methods 0.000 claims description 23
238000000034 method Methods 0.000 claims description 16
238000011282 treatment Methods 0.000 claims description 15
229910052757 nitrogen Inorganic materials 0.000 claims description 14
229910052739 hydrogen Inorganic materials 0.000 claims description 13
239000001257 hydrogen Substances 0.000 claims description 12
150000003839 salts Chemical class 0.000 claims description 12
208000002193 Pain Diseases 0.000 claims description 11
208000020925 Bipolar disease Diseases 0.000 claims description 10
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
125000000217 alkyl group Chemical group 0.000 claims description 10
206010015037 epilepsy Diseases 0.000 claims description 9
125000005843 halogen group Chemical group 0.000 claims description 9
239000003795 chemical substances by application Substances 0.000 claims description 8
230000003405 preventing effect Effects 0.000 claims description 6
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208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
206010012335 Dependence Diseases 0.000 claims description 4
238000007796 conventional method Methods 0.000 claims description 4
ZHXTWWCDMUWMDI-UHFFFAOYSA-N dihydroxyboron Chemical compound O[B]O ZHXTWWCDMUWMDI-UHFFFAOYSA-N 0.000 claims description 4
230000004770 neurodegeneration Effects 0.000 claims description 4
230000003647 oxidation Effects 0.000 claims description 4
238000007254 oxidation reaction Methods 0.000 claims description 4
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
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201000010099 disease Diseases 0.000 claims description 3
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125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
125000001624 naphthyl group Chemical group 0.000 claims description 2
125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
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HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms

NO19994213A 1997-03-01 1999-08-31 Pyrazinforbindelse, anvendelse og fremstilling derav samt farmasöytisk blanding NO313383B1 (no)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
GBGB9704275.8A GB9704275D0 (en)	1997-03-01	1997-03-01	Pharmacologically active compound
GBGB9708183.0A GB9708183D0 (en)	1997-04-23	1997-04-23	Pharmacologically active compound
PCT/EP1998/001077 WO1998038174A1 (en)	1997-03-01	1998-02-26	Pyrazine compounds

Publications (3)

Publication Number	Publication Date
NO994213D0 NO994213D0 (no)	1999-08-31
NO994213L NO994213L (no)	1999-10-29
NO313383B1 true NO313383B1 (no)	2002-09-23

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ID=26311097

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
NO19994213A NO313383B1 (no)	1997-03-01	1999-08-31	Pyrazinforbindelse, anvendelse og fremstilling derav samt farmasöytisk blanding

Country Status (46)

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US (2)	US6255307B1 (es)
EP (1)	EP0966448B1 (es)
JP (1)	JP3369189B2 (es)
KR (1)	KR100544263B1 (es)
CN (1)	CN1105111C (es)
AP (1)	AP9901632A0 (es)
AR (1)	AR011174A1 (es)
AT (1)	ATE251143T1 (es)
AU (1)	AU732915B2 (es)
BG (1)	BG103723A (es)
BR (1)	BR9807814B1 (es)
CA (1)	CA2282585C (es)
CO (1)	CO4950513A1 (es)
CZ (1)	CZ295618B6 (es)
DE (1)	DE69818643T2 (es)
DK (1)	DK0966448T3 (es)
EA (1)	EA002102B1 (es)
EE (1)	EE9900376A (es)
ES (1)	ES2205469T3 (es)
GE (1)	GEP20012555B (es)
GT (1)	GT199800046A (es)
HK (1)	HK1023116A1 (es)
HN (2)	HN1998000036A (es)
HR (1)	HRP980107A2 (es)
HU (1)	HU225852B1 (es)
ID (1)	ID22850A (es)
IL (1)	IL131293A (es)
IS (1)	IS5163A (es)
JO (1)	JO2035B1 (es)
MA (1)	MA26473A1 (es)
MY (1)	MY118612A (es)
NO (1)	NO313383B1 (es)
NZ (1)	NZ337121A (es)
OA (1)	OA11151A (es)
PA (1)	PA8448201A1 (es)
PE (1)	PE58299A1 (es)
PL (1)	PL192864B1 (es)
PT (1)	PT966448E (es)
SI (1)	SI0966448T1 (es)
SK (1)	SK117399A3 (es)
SV (1)	SV1998000029A (es)
TR (1)	TR199902082T2 (es)
TW (1)	TW513416B (es)
UY (1)	UY24911A1 (es)
WO (1)	WO1998038174A1 (es)
YU (1)	YU40799A (es)

Families Citing this family (39)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US6420354B1 (en)	1998-06-08	2002-07-16	Advanced Medicine, Inc.	Sodium channel drugs and uses
GB9818881D0 (en)	1998-08-28	1998-10-21	Glaxo Group Ltd	Compounds
GB9907965D0 (en) *	1999-04-09	1999-06-02	Glaxo Group Ltd	Medical use
US6479498B1 (en)	1999-06-04	2002-11-12	Theravance, Inc.	Sodium channel drugs and uses
WO2001060806A2 (en) *	2000-02-16	2001-08-23	Neurogen Corporation	Substituted arylpyrazines
EP1500653A1 (en) *	2000-02-16	2005-01-26	Neurogen Corporation	Substituted arylpyrazines
GB0010971D0 (en) *	2000-05-05	2000-06-28	Glaxo Group Ltd	Process
GB0016040D0 (en) *	2000-06-29	2000-08-23	Glaxo Group Ltd	Novel process for preparing crystalline particles
SE0102439D0 (sv) *	2001-07-05	2001-07-05	Astrazeneca Ab	New compounds
SE0102438D0 (sv) *	2001-07-05	2001-07-05	Astrazeneca Ab	New compounds
EP1446387B1 (en) *	2001-11-21	2009-11-04	Pharmacia & Upjohn Company LLC	Substituted aryl 1,4-pyrazine derivatives
US6992087B2 (en)	2001-11-21	2006-01-31	Pfizer Inc	Substituted aryl 1,4-pyrazine derivatives
EP1458386B1 (en) *	2001-12-27	2007-04-18	Ortho-McNeil Pharmaceutical, Inc.	Aroyl pyrrole heteroeryl and methanols useful for treating a central nervous system disorder
JP2005533014A (ja)	2002-04-26	2005-11-04	ファルマシア・アンド・アップジョン・カンパニー・エルエルシー	置換ピラジン誘導体
CA2496197A1 (en)	2002-08-20	2004-03-04	Neurogen Corporation	5-substituted-2-arylpyrazines as modulators of crf receptors
SE0203754D0 (sv) *	2002-12-17	2002-12-17	Astrazeneca Ab	New compounds
SE0203753D0 (sv) *	2002-12-17	2002-12-17	Astrazeneca Ab	New compounds
CA2514574A1 (en)	2003-01-30	2004-08-12	Dynogen Pharmaceuticals, Inc.	Use of sodium channel modulators for treating gastrointestinal tract disorders
TW200510373A (en) *	2003-07-14	2005-03-16	Neurogen Corp	Substituted quinolin-4-ylamine analogues
CA2595855C (en)	2005-01-25	2017-07-04	Synta Pharmaceuticals Corp.	Pyrazine compounds for inflammation and immune-related uses
MX2007009923A (es) *	2005-02-15	2008-03-04	Jazz Pharmaceuticals	Forma farmaceutica y metodo para liberacion sostenida de un compuesto de pirazina sustituido.
NL2000284C2 (nl) *	2005-11-04	2007-09-28	Pfizer Ltd	Pyrazine-derivaten.
WO2007083239A1 (en) *	2006-01-23	2007-07-26	Pfizer Limited	Pyridine derivatives as sodium channel modulators
CA2685952C (en) *	2007-05-03	2012-03-13	Pfizer Limited	N- [6-amino-5- (phenyl) pyrazin-2-yl] -isoxazole-4-carboxamide derivatives and related compounds as nav1.8 channel modulators for the treatment of pain
GB0800741D0 (en)	2008-01-16	2008-02-20	Univ Greenwich	Cyclic triazo and diazo sodium channel blockers
GB201111712D0 (en)	2011-07-08	2011-08-24	Gosforth Ct Holdings Pty Ltd	Pharmaceutical compositions
FR3001151B1 (fr)	2013-01-21	2016-04-08	Pf Medicament	Association d'un bloqueur de courant sodique lent et d'un inhibiteur du courant if sinusal et les compositions pharmarceutiques la contenant
JO3517B1 (ar) *	2014-01-17	2020-07-05	Novartis Ag	ان-ازاسبيرو الكان حلقي كبديل مركبات اريل-ان مغايرة وتركيبات لتثبيط نشاط shp2
EA036446B1 (ru)	2016-06-14	2020-11-11	Новартис Аг	Соединения и композиции для подавления активности shp2
US11602512B1 (en)	2016-07-22	2023-03-14	Flamel Ireland Limited	Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11602513B1 (en)	2016-07-22	2023-03-14	Flamel Ireland Limited	Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11504347B1 (en)	2016-07-22	2022-11-22	Flamel Ireland Limited	Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
UY37341A (es)	2016-07-22	2017-11-30	Flamel Ireland Ltd	Formulaciones de gamma-hidroxibutirato de liberación modificada con farmacocinética mejorada
CN108101857B (zh) *	2016-11-24	2021-09-03	韶远科技（上海)有限公司	制取2-氨基-3-溴-6-氯吡嗪的可放大工艺
CN107011273A (zh) *	2017-05-04	2017-08-04	无锡捷化医药科技有限公司	一种合成6‑碘‑3‑(2,3‑二氯苯基)吡嗪‑2‑胺的方法
CA3127871A1 (en)	2019-03-01	2020-09-10	Flamel Ireland Limited	Gamma-hydroxybutyrate compositions having improved pharmacokinetics in the fed state
US11779557B1 (en)	2022-02-07	2023-10-10	Flamel Ireland Limited	Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11583510B1 (en)	2022-02-07	2023-02-21	Flamel Ireland Limited	Methods of administering gamma hydroxybutyrate formulations after a high-fat meal
CN115611700A (zh) *	2022-10-11	2023-01-17	辽宁东大光明化工科技有限责任公司	一种1-溴-2,5-二氯-3-氟苯的制备方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4402958A (en) *	1981-11-19	1983-09-06	American Cyanamid Company	Novel (substituted phenyl)-1,2,4-triazolo (4,3-A)pyrazines and novel 2-hydrazino-(substituted phenyl)pyrazine intermediates
DE3873812D1 (de)	1987-04-07	1992-09-24	Ciba Geigy Ag	3h-1,2,3-triazolo(4,5-d)pyrimidine.
JPH08238778A (ja) *	1995-03-07	1996-09-17	Brother Ind Ltd	インク噴射装置の電極形成方法

1998
- 1998-02-23 MA MA24973A patent/MA26473A1/fr unknown
- 1998-02-24 PE PE1998000134A patent/PE58299A1/es not_active Application Discontinuation
- 1998-02-26 EA EA199900687A patent/EA002102B1/ru not_active IP Right Cessation
- 1998-02-26 EE EEP199900376A patent/EE9900376A/xx unknown
- 1998-02-26 ES ES98913592T patent/ES2205469T3/es not_active Expired - Lifetime
- 1998-02-26 AU AU68237/98A patent/AU732915B2/en not_active Ceased
- 1998-02-26 US US09/380,062 patent/US6255307B1/en not_active Expired - Fee Related
- 1998-02-26 JP JP53731098A patent/JP3369189B2/ja not_active Expired - Fee Related
- 1998-02-26 NZ NZ337121A patent/NZ337121A/xx not_active IP Right Cessation
- 1998-02-26 SI SI9830578T patent/SI0966448T1/xx unknown
- 1998-02-26 HU HU0001802A patent/HU225852B1/hu not_active IP Right Cessation
- 1998-02-26 GT GT199800046A patent/GT199800046A/es unknown
- 1998-02-26 MY MYPI98000852A patent/MY118612A/en unknown
- 1998-02-26 PL PL335441A patent/PL192864B1/pl unknown
- 1998-02-26 BR BRPI9807814-3A patent/BR9807814B1/pt not_active IP Right Cessation
- 1998-02-26 WO PCT/EP1998/001077 patent/WO1998038174A1/en active IP Right Grant
- 1998-02-26 EP EP98913592A patent/EP0966448B1/en not_active Expired - Lifetime
- 1998-02-26 JO JO19982035A patent/JO2035B1/en active
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- 1998-02-26 IL IL13129398A patent/IL131293A/xx not_active IP Right Cessation
- 1998-02-26 AT AT98913592T patent/ATE251143T1/de active
- 1998-02-26 CN CN98804593A patent/CN1105111C/zh not_active Expired - Fee Related
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- 1998-02-26 YU YU40799A patent/YU40799A/sh unknown
- 1998-02-26 CO CO98010500A patent/CO4950513A1/es unknown
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- 1998-02-26 KR KR1019997007937A patent/KR100544263B1/ko not_active IP Right Cessation
- 1998-02-26 CZ CZ19993111A patent/CZ295618B6/cs not_active IP Right Cessation
- 1998-02-26 ID IDW990951A patent/ID22850A/id unknown
- 1998-02-26 DE DE69818643T patent/DE69818643T2/de not_active Expired - Lifetime
- 1998-02-26 DK DK98913592T patent/DK0966448T3/da active
- 1998-02-26 AP AP9901632A patent/AP9901632A0/xx unknown
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- 1998-02-27 AR ARP980100906A patent/AR011174A1/es active IP Right Grant
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- 1998-02-27 HR HR9708183.0A patent/HRP980107A2/hr not_active Application Discontinuation
- 1998-03-03 TW TW087103079A patent/TW513416B/zh not_active IP Right Cessation
1999
- 1999-02-11 HN HN1999000019A patent/HN1999000019A/es unknown
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2000
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2001
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Also Published As

Publication number	Publication date
EE9900376A (et)	2000-04-17
HUP0001802A2 (hu)	2001-05-28
AP9901632A0 (en)	1999-09-30
MY118612A (en)	2004-12-31
HU225852B1 (en)	2007-11-28
IS5163A (is)	1999-08-24
ATE251143T1 (de)	2003-10-15
US6599905B2 (en)	2003-07-29
HUP0001802A3 (en)	2001-07-30
TR199902082T2 (xx)	2000-04-21
CN1105111C (zh)	2003-04-09
EP0966448A1 (en)	1999-12-29
AU6823798A (en)	1998-09-18
HN1998000036A (es)	1999-08-23
MA26473A1 (fr)	2004-12-20
EA002102B1 (ru)	2001-12-24
EA199900687A1 (ru)	2000-04-24
BG103723A (bg)	2001-05-31
AU732915B2 (en)	2001-05-03
SV1998000029A (es)	1998-12-11
CZ311199A3 (cs)	2000-02-16
CO4950513A1 (es)	2000-09-01
CN1253551A (zh)	2000-05-17
JP3369189B2 (ja)	2003-01-20
KR20000075859A (ko)	2000-12-26
PL192864B1 (pl)	2006-12-29
US20020169172A1 (en)	2002-11-14
PL335441A1 (en)	2000-04-25
CA2282585A1 (en)	1998-09-03
SK117399A3 (en)	2000-06-12
US6255307B1 (en)	2001-07-03
DE69818643T2 (de)	2004-10-07
JO2035B1 (en)	1999-05-15
DE69818643D1 (de)	2003-11-06
GEP20012555B (en)	2001-10-25
IL131293A0 (en)	2001-01-28
UY24911A1 (es)	2000-12-29
ES2205469T3 (es)	2004-05-01
AR011174A1 (es)	2000-08-02
EP0966448B1 (en)	2003-10-01
PA8448201A1 (es)	2000-05-24
TW513416B (en)	2002-12-11
IL131293A (en)	2003-07-31
WO1998038174A1 (en)	1998-09-03
HRP980107A2 (en)	1998-12-31
HK1023116A1 (en)	2000-09-01
OA11151A (en)	2003-04-22
DK0966448T3 (da)	2004-02-02
SI0966448T1 (en)	2004-04-30
JP2000511203A (ja)	2000-08-29
YU40799A (sh)	2001-09-28
BR9807814B1 (pt)	2009-01-13
CA2282585C (en)	2006-06-06
PT966448E (pt)	2004-02-27
NZ337121A (en)	2001-03-30
HN1999000019A (es)	1999-08-23
GT199800046A (es)	1999-08-20
BR9807814A (pt)	2000-02-22
KR100544263B1 (ko)	2006-01-23
NO994213L (no)	1999-10-29
CZ295618B6 (cs)	2005-09-14
NO994213D0 (no)	1999-08-31
ID22850A (id)	1999-12-09
PE58299A1 (es)	1999-06-23

Legal Events

Date	Code	Title	Description
2013-09-30	MM1K	Lapsed by not paying the annual fees

Publication	Publication Date	Title
NO313383B1 (no)	2002-09-23	Pyrazinforbindelse, anvendelse og fremstilling derav samt farmasöytisk blanding
CN102329325B (zh)	2013-11-27	吡咯并嘧啶酮类dpp-iv抑制剂
CA2853008A1 (en)	2013-05-10	Pharmaceutical compounds
CN107438604B (zh)	2021-12-03	新吡啶化合物
US6503909B1 (en)	2003-01-07	Pyrazine compounds
CN103626825A (zh)	2014-03-12	靶向肝脏的糖原磷酸化酶抑制剂胆酸类衍生物、其制备方法及医药用途
EP0874849B1 (en)	2001-09-19	2,7-substituted octahydro-pyrrolo 1,2-a]pyrazine derivatives
US5728709A (en)	1998-03-17	Alkyl and aralkyl-substituted pyrrolocarbazole derivatives that stimulate platelet production
CA2220808C (en)	2002-09-10	Substituted pyridines
US6008361A (en)	1999-12-28	Substituted pyridines
JPH07242670A (ja)	1995-09-19	ピロロ［３，２−ｅ］ピラゾロ［１，５−ａ］ピリミジン誘導体及びこれを含有する循環器系疾患治療剤
EP3634409B1 (en)	2021-04-07	Orexin receptor antagonists
JP2002308773A (ja)	2002-10-23	ピラジン化合物
JPH0222257A (ja)	1990-01-25	Ｎ―シクロアルキルアミノエチルベンズアミド誘導体、その製造方法及び医薬用途
MXPA99007910A (es)	2000-04-24	Compuestos de pirazina
KR20050019935A (ko)	2005-03-03	피라진 화합물을 포함하는 제약 조성물
MXPA01001983A (es)	2002-03-05	Compuestos de pirazina