JP2001517623A - トロンビン阻害薬 - Google Patents

トロンビン阻害薬

Info

Publication number: JP2001517623A
Authority: JP; Japan
Prior art keywords: mammal; alkyl; administering; preventing; treating
Prior art date: 1997-09-23
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 Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Withdrawn

Application number

JP2000512538A

Other languages

English (en)

Japanese (ja)

Inventor

コバーン，クレイグ

バツカ，ジヨージフ・ピー

ウイリアムズ，ピーター・デイ

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.)

Merck and Co Inc

Original Assignee

Merck and Co Inc

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.)

1997-09-23

Filing date

1998-09-18

Publication date

2001-10-09

1998-04-15 Priority claimed from GBGB9807941.1A external-priority patent/GB9807941D0/en

1998-09-18 Application filed by Merck and Co Inc filed Critical Merck and Co Inc

2001-10-09 Publication of JP2001517623A publication Critical patent/JP2001517623A/ja

Status Withdrawn legal-status Critical Current

Links

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235000010413 sodium alginate Nutrition 0.000 description 1
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WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
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NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
238000010532 solid phase synthesis reaction Methods 0.000 description 1
239000000600 sorbitol Substances 0.000 description 1
235000010356 sorbitol Nutrition 0.000 description 1
239000007858 starting material Substances 0.000 description 1
238000003860 storage Methods 0.000 description 1
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238000007920 subcutaneous administration Methods 0.000 description 1
239000006203 subcutaneous dosage form Substances 0.000 description 1
125000001424 substituent group Chemical group 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
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BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
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210000001519 tissue Anatomy 0.000 description 1
OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
230000000699 topical effect Effects 0.000 description 1
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LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
230000001810 trypsinlike Effects 0.000 description 1
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125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
229960005080 warfarin Drugs 0.000 description 1
PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
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239000000230 xanthan gum Substances 0.000 description 1
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229930195724 β-lactose Natural products 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- 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
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Life Sciences & Earth Sciences (AREA)
General Health & Medical Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Medicinal Chemistry (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
Chemical Kinetics & Catalysis (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Pharmacology & Pharmacy (AREA)
Animal Behavior & Ethology (AREA)
General Chemical & Material Sciences (AREA)
Heart & Thoracic Surgery (AREA)
Cardiology (AREA)
Biochemistry (AREA)
Vascular Medicine (AREA)
Biophysics (AREA)
Urology & Nephrology (AREA)
Genetics & Genomics (AREA)
Molecular Biology (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Diabetes (AREA)
Hematology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

JP2000512538A 1997-09-23 1998-09-18 トロンビン阻害薬 Withdrawn JP2001517623A (ja)

Applications Claiming Priority (5)

Application Number	Priority Date	Filing Date	Title
US5980197P	1997-09-23	1997-09-23
GBGB9807941.1A GB9807941D0 (en)	1998-04-15	1998-04-15	Thrombin inhibitors
GB9807941.1		1998-04-15
GB60/059,801		1998-04-15
PCT/US1998/019471 WO1999015169A1 (en)	1997-09-23	1998-09-18	Thrombin inhibitors

Publications (1)

Publication Number	Publication Date
JP2001517623A true JP2001517623A (ja)	2001-10-09

Family

ID=26313472

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
JP2000512538A Withdrawn JP2001517623A (ja)	1997-09-23	1998-09-18	トロンビン阻害薬

Country Status (5)

Country	Link
EP (1)	EP1017383A4 (de)
JP (1)	JP2001517623A (de)
AU (1)	AU740447B2 (de)
CA (1)	CA2301614A1 (de)
WO (1)	WO1999015169A1 (de)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US6239132B1 (en)	1999-04-23	2001-05-29	Merck & Co., Inc.	Thrombin inhibitors
WO2000074682A1 (en) *	1999-06-04	2000-12-14	Merck & Co., Inc.	Thrombin inhibitors
FR2795072B1 (fr) *	1999-06-15	2001-07-27	Adir	Nouveaux derives bicycliques d'amino-pyrazinones, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
GB0507577D0 (en)	2005-04-14	2005-05-18	Novartis Ag	Organic compounds
CN118290402A (zh)	2018-03-08	2024-07-05	因赛特公司	作为PI3K-γ抑制剂的氨基吡嗪二醇化合物
WO2020010003A1 (en)	2018-07-02	2020-01-09	Incyte Corporation	AMINOPYRAZINE DERIVATIVES AS PI3K-γ INHIBITORS

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
TW263498B (de) *	1993-11-10	1995-11-21	Takeda Pharm Industry Co Ltd
EP0802916A1 (de) *	1994-12-22	1997-10-29	Biochem Pharma Inc	Niedermolekulare bizyklische thrombin-inhibitoren

1998
- 1998-09-18 EP EP98947119A patent/EP1017383A4/de not_active Withdrawn
- 1998-09-18 CA CA002301614A patent/CA2301614A1/en not_active Abandoned
- 1998-09-18 JP JP2000512538A patent/JP2001517623A/ja not_active Withdrawn
- 1998-09-18 AU AU93973/98A patent/AU740447B2/en not_active Ceased
- 1998-09-18 WO PCT/US1998/019471 patent/WO1999015169A1/en not_active Application Discontinuation

Also Published As

Publication number	Publication date
WO1999015169A1 (en)	1999-04-01
AU9397398A (en)	1999-04-12
AU740447B2 (en)	2001-11-01
EP1017383A4 (de)	2001-11-28
CA2301614A1 (en)	1999-04-01
EP1017383A1 (de)	2000-07-12

Publication	Publication Date	Title
JP2002516326A (ja)	2002-06-04	イミダゾピリジン系トロンビン阻害薬
US6376499B1 (en)	2002-04-23	Thrombin inhibitors
AU753479B2 (en)	2002-10-17	Pyrazinone thrombin inhibitors
JP2001514227A (ja)	2001-09-11	ピラジノン系トロンビン阻害薬
JP2000508334A (ja)	2000-07-04	ピラジノン系トロンビン阻害薬
JP2001502691A (ja)	2001-02-27	トロンビン阻害剤
JP2002525370A (ja)	2002-08-13	トロンビン阻害剤
JP2010150275A (ja)	2010-07-08	ピラジノントロンビン阻害剤
JP2003514905A (ja)	2003-04-22	ピラジノン系トロンビン阻害薬
JP2001517623A (ja)	2001-10-09	トロンビン阻害薬
AU762908B2 (en)	2003-07-10	Thrombin inhibitors
US6528503B2 (en)	2003-03-04	Thrombin inhibitors
US6087373A (en)	2000-07-11	Thrombin inhibitors
JP2001524522A (ja)	2001-12-04	トロンビン阻害剤
US6350745B1 (en)	2002-02-26	Thrombin inhibitors
JP2001518466A (ja)	2001-10-16	トロンビン阻害薬
US6133297A (en)	2000-10-17	Thrombin inhibitors

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