TWI633091B - 作為因子ｘｉａ抑制劑之經取代四氫異喹啉化合物 - Google Patents

作為因子ｘｉａ抑制劑之經取代四氫異喹啉化合物 Download PDF

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TWI633091B
TWI633091B TW106107254A TW106107254A TWI633091B TW I633091 B TWI633091 B TW I633091B TW 106107254 A TW106107254 A TW 106107254A TW 106107254 A TW106107254 A TW 106107254A TW I633091 B TWI633091 B TW I633091B
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alkyl
mmol
group
thrombosis
compound
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TW106107254A
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TW201722918A (zh
Inventor
Michael J. Orwat
麥克Ｊ 歐華
Donald J. P. Pinto
唐諾Ｊ Ｐ 皮托
Leon M. Ii Smith
黎爾Ｍ 二世 史密斯
Shefali SRIVASTAVA
斯菲利 斯里瓦斯塔瓦
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Bristol-Myers Squibb Company
必治妥美雅史谷比公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Hematology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
TW106107254A 2011-10-14 2012-10-12 作為因子ｘｉａ抑制劑之經取代四氫異喹啉化合物 TWI633091B (zh)

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US201161547292P 2011-10-14 2011-10-14
US61/547,292 2011-10-14

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TWI633091B true TWI633091B (zh) 2018-08-21

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Families Citing this family (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011100401A1 (en) 2010-02-11 2011-08-18 Bristol-Myers Squibb Company Macrocycles as factor xia inhibitors
TW201311689A (zh) 2011-08-05 2013-03-16 必治妥美雅史谷比公司 作為因子ｘｉａ抑制劑之新穎巨環化合物
TW201319068A (zh) 2011-08-05 2013-05-16 必治妥美雅史谷比公司 作為ｘｉａ因子抑制劑之環狀ｐ１接合劑
DK2766346T3 (en) 2011-10-14 2017-07-03 Bristol Myers Squibb Co SUBSTITUTED TETRAHYDROISOQUINOL COMPOUNDS AS FACTOR XIA INHIBITORS
ES2699226T3 (es) 2011-10-14 2019-02-08 Bristol Myers Squibb Co Compuestos de tetrahidroisoquinolina sustituidos como inhibidores del factor XIa
EP2766347B1 (en) 2011-10-14 2016-05-04 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor xia inhibitors
JP6220786B2 (ja) 2012-07-19 2017-10-25 大日本住友製薬株式会社 １−（シクロアルキルカルボニル）プロリン誘導体
EP2882734B1 (en) 2012-08-03 2016-10-12 Bristol-Myers Squibb Company Dihydropyridone as factor xia inhibitors
SI2880026T1 (sl) 2012-08-03 2017-04-26 Bristol-Myers Squibb Company Dihidropiridon p1 kot faktor xia inhibitorjev
ES2668318T3 (es) * 2012-10-12 2018-05-17 Bristol-Myers Squibb Company Formas cristalinas de inhibidor del factor XIa
EP2906552B1 (en) 2012-10-12 2017-11-22 Bristol-Myers Squibb Company Guanidine substituted tetrahydroisoquinoline compounds as factor xia inhibitors
WO2014059214A1 (en) * 2012-10-12 2014-04-17 Bristol-Myers Squibb Company Guanidine and amine substituted tetrahydroisoquinoline compounds as factor xia inhibitors
JP6479763B2 (ja) 2013-03-25 2019-03-06 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ 第ｘｉａ因子阻害剤としての置換アゾール含有のテトラヒドロイソキノリン
MX362902B (es) * 2013-06-05 2019-02-22 Shanghai Lumosa Therapeutics Co Ltd Compuestos novedosos con actividades triples de trombólisis, anti-trombótica y depuración de radicales y síntesis, nano-estructura y uso de los mismos.
NO2760821T3 (enExample) 2014-01-31 2018-03-10
ES2784841T3 (es) 2014-01-31 2020-10-01 Bristol Myers Squibb Co Macrociclos con grupos aromáticos P2' como inhibidores del factor XIa
KR101927114B1 (ko) 2014-02-07 2018-12-10 엑시테라 파마슈티컬스 인코퍼레이티드 치료 화합물 및 조성물
EP3104702B1 (en) 2014-02-11 2022-08-10 Merck Sharp & Dohme LLC Factor xia inhibitors
US9944643B2 (en) 2014-02-11 2018-04-17 Merck Sharp & Dohme Corp. Factor XIa inhibitors
EP3131897B8 (en) 2014-04-16 2022-08-03 Merck Sharp & Dohme LLC Factor ixa inhibitors
US9808445B2 (en) 2014-04-16 2017-11-07 Merck Sharp & Dohme Corp. Factor IXa inhibitors
US10093683B2 (en) 2014-04-22 2018-10-09 Merck Sharp & Dohme Corp. Factor XIa inhibitors
US9868727B2 (en) 2014-07-28 2018-01-16 Merck Sharp & Dohme Corp. Factor XIa inhibitors
JP6526796B2 (ja) 2014-09-04 2019-06-05 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Ｆｘｉａ阻害剤であるジアミドマクロ環
US9453018B2 (en) 2014-10-01 2016-09-27 Bristol-Myers Squibb Company Pyrimidinones as factor XIa inhibitors
WO2016205482A1 (en) 2015-06-19 2016-12-22 Bristol-Myers Squibb Company Diamide macrocycles as factor xia inhibitors
CN107849026B (zh) 2015-07-29 2021-01-01 百时美施贵宝公司 携带烷基或环烷基p2′部分的因子xia大环抑制剂
CN107922393A (zh) 2015-07-29 2018-04-17 百时美施贵宝公司 携带非芳族p2,基团的因子xia新大环
MA43128A (fr) 2015-10-29 2018-09-05 Merck Sharp & Dohme Inhibiteurs du facteur xia
EP3371162B1 (en) 2015-10-29 2022-01-26 Merck Sharp & Dohme Corp. Macrocyclic spirocarbamate derivatives as factor xia inhibitors, pharmaceutically acceptable compositions and their use
CN107540659A (zh) * 2016-06-29 2018-01-05 四川科伦博泰生物医药股份有限公司 四氢异喹啉类化合物、其制备方法、药物组合物及其用途
US10143681B2 (en) 2016-08-22 2018-12-04 Merck Sharp & Dohme Corp. Factor XIa inhibitors
RU2742771C2 (ru) 2016-08-31 2021-02-10 Цзянсу Хэнжуй Медицин Ко., Лтд. Производное оксопиколинамида, способ его получения и его фармацевтическое применение
CN109721539B (zh) * 2017-10-27 2021-07-09 天津药物研究院有限公司 吡唑酰胺类衍生物及其制备方法和用途
CN109867660A (zh) * 2017-12-01 2019-06-11 四川科伦博泰生物医药股份有限公司 含季铵离子的四氢异喹啉酰胺化合物及其药物用途
WO2019144811A1 (zh) * 2018-01-26 2019-08-01 四川科伦博泰生物医药股份有限公司 四氢异喹啉类衍生物及其制备方法和用途
WO2019156929A1 (en) 2018-02-07 2019-08-15 eXIthera Pharmaceuticals Inc. Therapeutic compounds and compositions
JP7458984B2 (ja) * 2018-03-28 2024-04-01 四川科倫博泰生物医薬股▲フン▼有限公司 テトラヒドロイソキノリン系誘導体、その製造方法及び用途
WO2019218899A1 (zh) * 2018-05-17 2019-11-21 四川科伦博泰生物医药股份有限公司 含聚乙二醇醚的四氢异喹啉酰胺化合物及其药物用途
KR20210028232A (ko) 2018-07-02 2021-03-11 지앙수 헨그루이 메디슨 컴퍼니 리미티드 옥시피리딘 아미드 유도체의 결정 형태 및 이를 위한 제조 방법
KR20210084581A (ko) * 2018-10-30 2021-07-07 엑시테라 파마슈티컬스 인코퍼레이티드 치료 화합물 및 조성물
WO2020092592A1 (en) * 2018-10-30 2020-05-07 Exithera Pharmaceuticals, Inc. Therapeutic compounds and compositions
CN114206854B (zh) 2019-09-27 2023-02-24 深圳信立泰药业股份有限公司 FXIa抑制剂及其制备方法和医药用途
WO2021136390A1 (zh) * 2019-12-31 2021-07-08 上海京新生物医药有限公司 凝血因子XIa抑制剂
JP2023534704A (ja) * 2020-07-22 2023-08-10 ヤンセン ファーマシューティカ エヌ．ベー． 第ｘｉａ因子阻害剤として有用な化合物
TW202506125A (zh) * 2023-04-19 2025-02-16 美商必治妥美雅史谷比公司 米爾維仙(milvexian)於治療及預防患有心血管或腦血管疾病之患者之血栓病況的用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003041641A2 (en) * 2001-11-09 2003-05-22 Bristol-Myers Squibb Company Tetrahydroisoquinoline analogs as modulators of chemokine receptor activity
WO2005014533A2 (en) * 2003-08-08 2005-02-17 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions, and methods of use

Family Cites Families (74)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1525186A (fr) 1967-03-29 1968-05-17 Roussel Uclaf Nouvelles pénicillines et procédé de préparation
DE3065190D1 (en) 1979-11-05 1983-11-10 Beecham Group Plc Enzyme derivatives, and their preparation
DE4034829A1 (de) 1990-11-02 1992-05-07 Merck Patent Gmbh Cyclopeptide
JP3190431B2 (ja) 1991-07-01 2001-07-23 三菱化学株式会社 ケトン誘導体
GB9206757D0 (en) 1992-03-27 1992-05-13 Ferring Bv Novel peptide receptor ligands
US5624936A (en) 1995-03-29 1997-04-29 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1996034010A2 (en) 1995-03-29 1996-10-31 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US5869682A (en) 1996-04-03 1999-02-09 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
JP2000507597A (ja) 1996-04-03 2000-06-20 メルク エンド カンパニー インコーポレーテッド ファルネシルタンパク質トランスフェラーゼ阻害剤
PE121699A1 (es) 1997-02-18 1999-12-08 Boehringer Ingelheim Pharma Heterociclos biciclicos disustituidos como inhibidores de la trombina
ZA985247B (en) 1997-06-19 1999-12-17 Du Pont Merck Pharma Guanidine mimics as factor Xa inhibitors.
TW557297B (en) 1997-09-26 2003-10-11 Abbott Lab Rapamycin analogs having immunomodulatory activity, and pharmaceutical compositions containing same
JP4594520B2 (ja) 1998-03-19 2010-12-08 バーテックス ファーマシューティカルズ インコーポレイテッド カスパーゼのインヒビター
HUP0102514A3 (en) 1998-05-26 2002-03-28 Warner Lambert Co Pyrido-pyrimidin and pyrimido-pyrimidin derivatives as inhibitors of cellular proliferation and pharmaceutical compositions thereof
US6307049B1 (en) 1998-09-30 2001-10-23 The Procter & Gamble Co. Heterocyclic 2-substituted ketoamides
EP1016663A1 (en) 1999-01-02 2000-07-05 Aventis Pharma Deutschland GmbH Novel malonic acid derivatives, processes for their preparation, their use and pharmaceutical compositions containing them (inhibition of factor Xa activity)
AU3043100A (en) 1999-01-02 2000-07-24 Aventis Pharma Deutschland Gmbh Novel malonic acid derivatives, processes for their preparation, their use and pharmaceutical compositions containing them (inhibition of factor xa activity)
EP1169338B1 (de) 1999-04-09 2004-11-03 Abbott GmbH & Co. KG Niedermolekulare inhibitoren von komplementproteasen
AU5413600A (en) 1999-06-14 2001-01-02 Eli Lilly And Company Compounds
DE19962924A1 (de) 1999-12-24 2001-07-05 Bayer Ag Substituierte Oxazolidinone und ihre Verwendung
EP1125925A1 (en) 2000-02-15 2001-08-22 Applied Research Systems ARS Holding N.V. Amine derivatives for the treatment of apoptosis
ATE310728T1 (de) 2000-05-11 2005-12-15 Bristol Myers Squibb Co Tetrahydroisochinolin-analoga als wachstumshormon-sekretagoga
SV2003000617A (es) 2000-08-31 2003-01-13 Lilly Co Eli Inhibidores de la proteasa peptidomimetica ref. x-14912m
AR035216A1 (es) 2000-12-01 2004-05-05 Astrazeneca Ab Derivados de acido mandelico ,derivados farmaceuticamente aceptables, uso de estos derivados para la fabricacion de medicamentos, metodos de tratamiento ,procesos para la preparacion de estos derivados, y compuestos intermediarios
WO2003011222A2 (en) 2001-07-27 2003-02-13 Merck & Co., Inc. Thrombin inhibitors
IL160693A0 (en) 2001-09-21 2004-08-31 Bristol Myers Squibb Co Lactam-containing compounds and derivatives thereof as factor xa inhibitors
US20040180855A1 (en) 2003-02-19 2004-09-16 Schumacher William A. Methods of treating thrombosis with reduced risk of increased bleeding times
US7138412B2 (en) 2003-03-11 2006-11-21 Bristol-Myers Squibb Company Tetrahydroquinoline derivatives useful as serine protease inhibitors
US7129264B2 (en) 2003-04-16 2006-10-31 Bristol-Myers Squibb Company Biarylmethyl indolines and indoles as antithromboembolic agents
US7417063B2 (en) 2004-04-13 2008-08-26 Bristol-Myers Squibb Company Bicyclic heterocycles useful as serine protease inhibitors
US7453002B2 (en) 2004-06-15 2008-11-18 Bristol-Myers Squibb Company Five-membered heterocycles useful as serine protease inhibitors
US7429604B2 (en) 2004-06-15 2008-09-30 Bristol Myers Squibb Company Six-membered heterocycles useful as serine protease inhibitors
US20100190688A1 (en) 2004-07-12 2010-07-29 Bin Chao Tetrapeptide analogs
US7459564B2 (en) 2005-01-13 2008-12-02 Bristol-Myers Squibb Company Substituted biaryl compounds as factor XIa inhibitors
US20060183771A1 (en) 2005-02-17 2006-08-17 Seiffert Dietmar A Novel combination of selective factor VIIa and/or factor XIa inhibitors and selective plasma kallikrein inhibitors
ES2622488T3 (es) 2005-06-17 2017-07-06 Basf Se Procedimiento de producción de reforzadores del blanqueador
US20070112012A1 (en) 2005-11-11 2007-05-17 Markus Boehringer Carbocyclic fused cyclic amines
AU2006325746A1 (en) 2005-12-14 2007-06-21 Bristol-Myers Squibb Company Six-membered heterocycles useful as serine protease inhibitors
BRPI0620010A2 (pt) 2005-12-14 2011-11-22 Bristol-Myers Squibb Company compostos ánalogos de arilpropionamida, arilacrilamida, arilpropinamida, ou arilmetiluréia, processo para sua preparação, composição farmacêutica e uso dos mesmos
US8466295B2 (en) 2005-12-14 2013-06-18 Bristol-Myers Squibb Company Thiophene derivatives as factor XIa inhibitors
PE20071132A1 (es) 2005-12-23 2007-12-14 Bristol Myers Squibb Co Compuestos macrociclicos como inhibidores del factor viia
KR20090079191A (ko) 2006-08-23 2009-07-21 밸리언트 파마슈티컬즈 인터내셔널 칼륨 채널 조절제로서 ４-(ｎ-아자사이클로알킬) 아닐리드의 유도체
ES2546815T3 (es) 2006-12-15 2015-09-28 Bristol-Myers Squibb Company Análogos de arilpropilamida, arilacrilamida, arilpropinamida o arilmetilurea como inhibidores del factor XIa
PE20081775A1 (es) 2006-12-20 2008-12-18 Bristol Myers Squibb Co Compuestos macrociclicos como inhibidores del factor viia
CN101784516B (zh) 2007-06-13 2014-07-02 百时美施贵宝公司 作为凝血因子抑制剂的二肽类似物
ES2380648T3 (es) 2008-03-13 2012-05-17 Bristol-Myers Squibb Company Derivados de piridazina como inhibidores del factor XIA
US8624040B2 (en) 2009-06-22 2014-01-07 Millennium Pharmaceuticals, Inc. Substituted hydroxamic acids and uses thereof
WO2011002520A2 (en) 2009-07-02 2011-01-06 Angion Biomedica Corp. Small molecule inhibitors of parp activity
AR077695A1 (es) 2009-08-04 2011-09-14 Schering Corp Derivados de pirimidina como inhibidores del factor ixa
WO2011100401A1 (en) 2010-02-11 2011-08-18 Bristol-Myers Squibb Company Macrocycles as factor xia inhibitors
WO2013009527A2 (en) 2011-07-08 2013-01-17 Merck Sharp & Dohme Corp. Factor ixa inhibitors
TW201311689A (zh) 2011-08-05 2013-03-16 必治妥美雅史谷比公司 作為因子ｘｉａ抑制劑之新穎巨環化合物
TW201319068A (zh) 2011-08-05 2013-05-16 必治妥美雅史谷比公司 作為ｘｉａ因子抑制劑之環狀ｐ１接合劑
EP2766347B1 (en) 2011-10-14 2016-05-04 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor xia inhibitors
DK2766346T3 (en) 2011-10-14 2017-07-03 Bristol Myers Squibb Co SUBSTITUTED TETRAHYDROISOQUINOL COMPOUNDS AS FACTOR XIA INHIBITORS
ES2699226T3 (es) 2011-10-14 2019-02-08 Bristol Myers Squibb Co Compuestos de tetrahidroisoquinolina sustituidos como inhibidores del factor XIa
IN2014CN04676A (enExample) 2011-12-21 2015-09-18 Ono Pharmaceutical Co
EP2807157A1 (en) 2012-01-27 2014-12-03 Novartis AG 5-membered heteroarylcarboxamide derivatives as plasma kallikrein inhibitors
EP2807156A1 (en) 2012-01-27 2014-12-03 Novartis AG Aminopyridine derivatives as plasma kallikrein inhibitors
JP2015083542A (ja) 2012-02-08 2015-04-30 大日本住友製薬株式会社 ３位置換プロリン誘導体
JP6348900B2 (ja) 2012-05-10 2018-06-27 バイエル ファーマ アクチエンゲゼルシャフト 凝固因子ｘｉおよび／またはその活性化形態である因子ｘｉａに結合しうる抗体ならびにその用途
GB201209138D0 (en) 2012-05-24 2012-07-04 Ono Pharmaceutical Co Compounds
JP6220786B2 (ja) 2012-07-19 2017-10-25 大日本住友製薬株式会社 １−（シクロアルキルカルボニル）プロリン誘導体
EP2882734B1 (en) 2012-08-03 2016-10-12 Bristol-Myers Squibb Company Dihydropyridone as factor xia inhibitors
SI2880026T1 (sl) 2012-08-03 2017-04-26 Bristol-Myers Squibb Company Dihidropiridon p1 kot faktor xia inhibitorjev
EP2906552B1 (en) 2012-10-12 2017-11-22 Bristol-Myers Squibb Company Guanidine substituted tetrahydroisoquinoline compounds as factor xia inhibitors
ES2668318T3 (es) 2012-10-12 2018-05-17 Bristol-Myers Squibb Company Formas cristalinas de inhibidor del factor XIa
WO2014059214A1 (en) 2012-10-12 2014-04-17 Bristol-Myers Squibb Company Guanidine and amine substituted tetrahydroisoquinoline compounds as factor xia inhibitors
WO2014120346A1 (en) 2012-12-19 2014-08-07 Merck Sharp & Dohme Corp. Factor ixa inhibitors
GB201300304D0 (en) 2013-01-08 2013-02-20 Kalvista Pharmaceuticals Ltd Benzylamine derivatives
GB2510407A (en) 2013-02-04 2014-08-06 Kalvista Pharmaceuticals Ltd Aqueous suspensions of kallikrein inhibitors for parenteral administration
JP6479763B2 (ja) 2013-03-25 2019-03-06 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ 第ｘｉａ因子阻害剤としての置換アゾール含有のテトラヒドロイソキノリン
ES2784841T3 (es) 2014-01-31 2020-10-01 Bristol Myers Squibb Co Macrociclos con grupos aromáticos P2' como inhibidores del factor XIa
NO2760821T3 (enExample) 2014-01-31 2018-03-10

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003041641A2 (en) * 2001-11-09 2003-05-22 Bristol-Myers Squibb Company Tetrahydroisoquinoline analogs as modulators of chemokine receptor activity
WO2005014533A2 (en) * 2003-08-08 2005-02-17 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions, and methods of use

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