OA12323A - Protease inhibitors. - Google Patents
Protease inhibitors. Download PDFInfo
- Publication number
- OA12323A OA12323A OA1200200295A OA1200200295A OA12323A OA 12323 A OA12323 A OA 12323A OA 1200200295 A OA1200200295 A OA 1200200295A OA 1200200295 A OA1200200295 A OA 1200200295A OA 12323 A OA12323 A OA 12323A
- Authority
- OA
- OAPI
- Prior art keywords
- methyl
- azepan
- pyridine
- amide
- butyl
- Prior art date
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- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 title abstract description 9
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- 238000000034 method Methods 0.000 claims abstract description 85
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
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Classifications
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- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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- C07C271/12—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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- C07C271/14—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
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- C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
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- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings 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
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C07D491/00—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
- 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
- C07D491/04—Ortho-condensed systems
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- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Families Citing this family (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020128476A1 (en) * | 1996-08-08 | 2002-09-12 | Smithkline Beecham Corporation | Inhibitors of cysteine protease |
US20030144175A1 (en) | 1998-12-23 | 2003-07-31 | Smithkline Beecham Corporation | Protease inhibitors |
US6596715B1 (en) | 1999-11-10 | 2003-07-22 | Smithkline Beecham Corporation | Protease inhibitors |
AU1474801A (en) | 1999-11-10 | 2001-06-06 | Smithkline Beecham Corporation | Protease inhibitors |
US6583137B1 (en) | 1999-11-10 | 2003-06-24 | Smithkline Beecham Corporation | Protease inhibitors |
US7071184B2 (en) * | 2000-03-21 | 2006-07-04 | Smithkline Beecham Corporation | Protease inhibitors |
CO5280093A1 (es) * | 2000-04-18 | 2003-05-30 | Smithkline Beecham Corp | Metodos de tratamiento |
CO5280088A1 (es) * | 2000-04-18 | 2003-05-30 | Smithkline Beecham Corp | Inhibidores de proteasa |
AU2001286983A1 (en) * | 2000-09-01 | 2002-03-13 | Smith Kline Beecham Corporation | Method of treatment |
PL366232A1 (en) * | 2000-11-22 | 2005-01-24 | Smithkline Beecham Corporation | Protease inhibitors |
WO2003045909A2 (en) * | 2001-11-21 | 2003-06-05 | Smithkline Beecham Corporation | Methods and intermediates for the synthesis of azepines |
AU2003263738A1 (en) * | 2002-05-22 | 2003-12-02 | Smithkline Beecham Corporation | Protease inhibitors |
AU2003273697A1 (en) * | 2002-10-08 | 2004-05-04 | Merck Frosst Canada Ltd | 4-amino-azepan-3-one compounds as cathepsin k inhibitors useful in the treatment of osteoporosis |
US20040192674A1 (en) * | 2003-02-14 | 2004-09-30 | Marquis Robert W. | Cathepsin L inhibitors |
JP2007520491A (ja) * | 2004-01-23 | 2007-07-26 | スミスクライン・ビーチャム・コーポレイション | ベンゾフラン−2−カルボン酸{(s)−3−メチル−1−[(4s,7r)−7−メチル−3−オキソ−1−(ピリジン−2−スルホニル)−アゼパン−4−イルカルバモイル]−ブチル}−アミドの製造方法 |
KR100603014B1 (ko) * | 2004-07-21 | 2006-07-24 | 황호연 | 라벨용 포장필름의 제조방법, 상기 제조방법으로 제조된라벨용 포장필름 및 상기 포장필름의 사용방법 |
JP5067968B2 (ja) * | 2004-10-07 | 2012-11-07 | ビテ ファーマシューティカルズ, インコーポレイテッド | ジアミノアルカンアスパラギン酸プロテアーゼ阻害剤 |
PE20070171A1 (es) * | 2005-06-30 | 2007-03-08 | Boehringer Ingelheim Int | GLICINAMIDAS SUSTITUIDAS CON EFECTO ANTITROMBOTICO E INHIBIDOR DEL FACTOR Xa |
TWI411607B (zh) * | 2005-11-14 | 2013-10-11 | Vitae Pharmaceuticals Inc | 天門冬胺酸蛋白酶抑制劑 |
CL2007002689A1 (es) | 2006-09-18 | 2008-04-18 | Vitae Pharmaceuticals Inc | Compuestos derivados de piperidin-1-carboxamida, inhibidores de la renina; compuestos intermediarios; composicion farmaceutica; y uso en el tratamiento de enfermedades tales como hipertension, insuficiencia cardiaca, fibrosis cardiaca, entre otras. |
JPWO2008149971A1 (ja) | 2007-06-08 | 2010-08-26 | 日本ケミファ株式会社 | 脳動脈瘤の治療または予防薬 |
US20100317697A1 (en) * | 2007-06-20 | 2010-12-16 | Baldwin John J | Renin Inhibitors |
EP2170815A2 (en) * | 2007-06-20 | 2010-04-07 | Vitae Pharmaceuticals, Inc. | Renin inhibitors |
JPWO2009054454A1 (ja) | 2007-10-24 | 2011-03-03 | 国立大学法人 東京医科歯科大学 | カテプシン阻害剤を有効成分として含有するToll様受容体のシグナル伝達の調整剤 |
WO2009087379A2 (en) | 2008-01-09 | 2009-07-16 | Amura Therapeutics Limited | Tetrahydrofuro (3, 2 -b) pyrrol- 3 -one derivatives as inhibitors of cysteine proteinases |
US20110160300A1 (en) * | 2008-06-20 | 2011-06-30 | Marlys Hammond | Renin Inhibitors and Methods of Use Thereof |
MX2010014557A (es) * | 2008-06-26 | 2011-02-15 | Vitae Pharmaceuticals Inc | Sales de 2-((r)-(3-clorofenil)((r)-1-((s)-2-(metilamino)-3-((r)-te trahidro-2h-piran-3-il)propilcarbamoil)piperidin-3-il)metoxi)etil carbamato de metilo. |
AR077692A1 (es) * | 2009-08-06 | 2011-09-14 | Vitae Pharmaceuticals Inc | Sales de 2-((r)-(3-clorofenil) ((r)-1-((s) -2-(metilamino)-3-((r)-tetrahidro-2h-piran-3-il) propilcarbamoil) piperidin -3-il) metoxi) etilcarbamato de metilo |
SG194842A1 (en) | 2011-05-16 | 2013-12-30 | Bayer Ip Gmbh | Use of cathepsin k inhibition for the treatment and/or prophylaxis of pulmonary hypertension and/or heart failure |
CN103275070A (zh) * | 2013-05-10 | 2013-09-04 | 郑彪 | 调节单核细胞增殖的四环化合物及其应用 |
EP3009425B1 (en) * | 2013-06-14 | 2018-06-06 | Seikagaku Corporation | Alpha-oxoacylaminocaprolactam |
JP6336973B2 (ja) * | 2013-06-14 | 2018-06-06 | 生化学工業株式会社 | α−オキソアシルアミノカプロラクタム誘導体 |
AU2017326466B2 (en) | 2016-09-16 | 2021-11-11 | Lighthouse Pharmaceuticals, Inc. | Ketone inhibitors of lysine gingipain |
EP4125919A1 (en) * | 2020-03-26 | 2023-02-08 | GlaxoSmithKline Intellectual Property Development Limited | Cathepsin inhibitors for preventing or treating viral infections |
Family Cites Families (95)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4038247A (en) | 1970-05-19 | 1977-07-26 | Ciba-Geigy Corporation | Stabilizing polyolefins with diacyl dihydrazides |
US5142056A (en) | 1989-05-23 | 1992-08-25 | Abbott Laboratories | Retroviral protease inhibiting compounds |
US5057525A (en) | 1981-10-01 | 1991-10-15 | Janssen Pharmaceutica N.V. | Novel N-(3-hydroxy-4-piperidinyl) benzamide derivatives |
IT1195287B (it) | 1981-11-05 | 1988-10-12 | Ausonia Farma Srl | Derivato tiazolico,procedimento per la sua preparazione e relative composizioni farmaceutiche |
US4518528A (en) | 1983-05-19 | 1985-05-21 | Rasnick David W | α Amino fluoro ketones |
US4749792A (en) | 1984-09-26 | 1988-06-07 | E. R. Squibb & Sons, Inc. | Diamino ketones and alcohols as analgesic agents |
US4638101A (en) | 1985-01-02 | 1987-01-20 | General Electric Company | Compositions |
US4638010A (en) * | 1985-02-28 | 1987-01-20 | E. R. Squibb & Sons, Inc. | Ester substituted aminoalkanoylureido amino and imino acid and ester compounds |
JP2570686B2 (ja) | 1985-12-23 | 1997-01-08 | 日産化学工業株式会社 | ピラゾ−ル誘導体 |
DE3600288A1 (de) | 1986-01-08 | 1987-07-16 | Bayer Ag | Verwendung von amiden zur verbesserung der kulturpflanzen-vertraeglichkeit von herbizid wirksamen sulfonylharnstoff-derivaten |
ZA871860B (en) | 1986-03-14 | 1988-10-26 | Syntex Inc | Transglutaminase inhibitors |
US5374637A (en) | 1989-03-22 | 1994-12-20 | Janssen Pharmaceutica N.V. | N-(3-hydroxy-4-piperidinyl)(dihydrobenzofuran, dihydro-2H-benzopyran or dihydrobenzodioxin)carboxamide derivatives |
US4994471A (en) | 1989-05-12 | 1991-02-19 | Boc, Inc. | N-aryl-N-(1-substituted-3-alkoxy-4-piperidinyl)amides and pharmaceutical compositions and methods employing such compounds |
UA41251C2 (uk) | 1990-01-04 | 2001-09-17 | Пфайзер, Інк. | Гідровані азотвмісні гетероциклічні сполуки, похідні піперидину, фармацевтична композиція та спосіб пригнічення активності речовини р в організмі |
GB9019558D0 (en) | 1990-09-07 | 1990-10-24 | Szelke Michael | Enzyme inhibitors |
EP0504938A3 (en) | 1991-03-22 | 1993-04-14 | Suntory Limited | Prophylactic and therapeutic agent for bone diseases comprising di- or tripeptide derivative as active ingredient |
JP3190431B2 (ja) | 1991-07-01 | 2001-07-23 | 三菱化学株式会社 | ケトン誘導体 |
JPH05140063A (ja) | 1991-11-19 | 1993-06-08 | Suntory Ltd | ジペプチド誘導体及びそれを有効成分とする骨疾患の予防及び治療剤 |
US5216168A (en) | 1992-04-01 | 1993-06-01 | G. D. Searle & Co. | 2- and 3- amino and azido derivatives of 1,5-iminosugars |
US5206251A (en) | 1992-04-01 | 1993-04-27 | G. D. Searle & Co. | 2- and 3- amino and azido derivatives of 1,5-iminosugars |
AU4544993A (en) | 1992-06-24 | 1994-01-24 | Cortex Pharmaceuticals, Inc. | Use of calpain inhibitors in the inhibition and treatment of medical conditions associated with increased calpain activity |
US5374623A (en) | 1992-08-20 | 1994-12-20 | Prototek, Inc. | Cysteine protease inhibitors effective for in vivo use |
DK0603769T3 (da) | 1992-12-25 | 1999-06-14 | Mitsubishi Chem Corp | Alfa-aminoketonderivater |
CA2111930A1 (en) | 1992-12-25 | 1994-06-26 | Ryoichi Ando | Aminoketone derivatives |
JPH06199850A (ja) | 1992-12-28 | 1994-07-19 | Tanabe Seiyaku Co Ltd | インドール含有ペプチド及びその製法 |
JP2848232B2 (ja) | 1993-02-19 | 1999-01-20 | 武田薬品工業株式会社 | アルデヒド誘導体 |
EP1645629A1 (en) | 1993-04-06 | 2006-04-12 | Forsyth Dental Infirmary For Children | Human osteoclast-specific and related genes |
CA2122227A1 (en) | 1993-04-29 | 1994-10-30 | Roland E. Dolle | Peptide analogs as irreversible interleukin-1.beta. protease inhibitors |
AU7714594A (en) | 1993-08-13 | 1995-03-14 | Merck & Co., Inc. | Substituted ketone derivatives as inhibitors of interleukin-1beta converting enzyme |
US5501969A (en) | 1994-03-08 | 1996-03-26 | Human Genome Sciences, Inc. | Human osteoclast-derived cathepsin |
ATE181333T1 (de) | 1994-04-13 | 1999-07-15 | Takeda Chemical Industries Ltd | Azirdin-derivate, deren herstellung und verwendung |
US5585387A (en) | 1994-10-07 | 1996-12-17 | Torcan Chemical Ltd. | Prepration of cisapride |
US6544767B1 (en) | 1994-10-27 | 2003-04-08 | Axys Pharmaceuticals, Inc. | Cathespin O2 protease |
US5734977A (en) * | 1994-11-10 | 1998-03-31 | Telefonaktiebolaget Lm Ericsson | Fraud detection in radio communications network |
TW438591B (en) | 1995-06-07 | 2001-06-07 | Arris Pharm Corp | Reversible cysteine protease inhibitors |
PL328877A1 (en) | 1995-10-30 | 1999-03-01 | Smithkline Beecham Corp | Method of inhibiting cathepsin k |
JP2000500742A (ja) | 1995-10-30 | 2000-01-25 | スミスクライン・ビーチャム・コーポレイション | プロテアーゼ阻害剤 |
US6083947A (en) * | 1996-01-29 | 2000-07-04 | The Regents Of The University Of California | Method for treating sexual dysfunctions |
US5902882A (en) | 1996-04-17 | 1999-05-11 | Hoffmann-La Roche Inc. | Assymetric synthesis of azepines |
WO1997049668A1 (en) | 1996-06-13 | 1997-12-31 | Smithkline Beecham Corporation | Inhibitiors of cysteine protease |
WO1997047642A1 (en) | 1996-06-14 | 1997-12-18 | Smithkline Beecham Corporation | Cathepsin k gene |
US5861298A (en) | 1996-06-17 | 1999-01-19 | Smithkline Beecham Corporation | Cathepsin K gene |
DZ2285A1 (fr) | 1996-08-08 | 2002-12-25 | Smithkline Beecham Corp | Inhibiteurs de protéase de la cystéine. |
US5830850A (en) | 1996-08-28 | 1998-11-03 | Mount Sinai School Of Medicine Of The City Of New York | Methods for the treatment of bone resorption disorders, including osteoporosis |
EP0923535A4 (en) | 1996-08-28 | 2001-01-10 | Smithkline Beecham Corp | CYSTEINE PROTEASE INHIBITORS |
DE69717647T2 (de) | 1996-09-19 | 2003-09-25 | Aventis Pharmaceuticals Inc., Bridgewater | 3-mercaptoacetylamino-1,5-substituierte-2-oxo-azepan derivate und deren verwendung als inhibitoren von matrix-metalloproteinasen |
US5948669A (en) | 1997-02-26 | 1999-09-07 | Smithkline Beecham Corporation | Rat cathepsin K polynucleotide and polypeptide sequence |
AR012374A1 (es) | 1997-04-15 | 2000-10-18 | Smithkline Beecham Corp | Inhibidores de proteasas, composiones farmaceuticas y usos para la preparacion de medicamentos. |
JP2002501502A (ja) | 1997-04-25 | 2002-01-15 | スミスクライン・ビーチャム・コーポレイション | プロテアーゼ阻害物質 |
MA26487A1 (fr) | 1997-04-29 | 2004-12-20 | Smithkline Beecham Corp | Heterocyclecetohydrazides inhibiteurs de proteases, procede pour leur preparation et compositions pharmaceutiques les contenant . |
US6566373B2 (en) | 1997-05-06 | 2003-05-20 | Smithkline Beecham Corporation | Protease inhibitors |
IL132630A0 (en) | 1997-05-08 | 2001-03-19 | Smithkline Beecham Corp | Protease inhibitors |
KR20010012316A (ko) | 1997-05-08 | 2001-02-15 | 스튜어트 알. 수터, 스티븐 베네티아너, 피터 존 기딩스 | 프로테아제 억제제 |
MA26540A1 (fr) | 1997-09-04 | 2004-12-20 | Smithkline Beecham Corp | Composes nouveaux inhibiteurs de proteases et compositions pharmaceutiques les contenant. |
MA26618A1 (fr) | 1998-04-09 | 2004-12-20 | Smithkline Beecham Corp | Composes et compositions pharmaceutiques pour le traitement du paludisme |
JP2002515428A (ja) | 1998-05-21 | 2002-05-28 | スミスクライン・ビーチャム・コーポレイション | プロテアーゼ阻害剤 |
DZ2796A1 (fr) | 1998-05-21 | 2003-12-01 | Smithkline Beecham Corp | Composés à fonction bis-aminométhyl-carbonyle nouveaux, procédé pour leur préparation et compositions pharmaceutiques les contenant. |
DZ2815A1 (fr) | 1998-06-12 | 2003-12-01 | Smithkline Beecham Corp | Inhibiteurs de protéase. |
AR018915A1 (es) | 1998-06-24 | 2001-12-12 | Smithkline Beecham Corp | Inhibidores de proteasas diacilhidrazinicos, composicion farmaceutica que la comprenden, usos de los mismos para la manufactura de un medicamento, unprocedimiento de fabricacion de dichos compuestos |
JP2003527819A (ja) | 1998-08-14 | 2003-09-24 | スミスクライン・ビーチャム・コーポレイション | カテプシンkの阻害方法 |
CO5150165A1 (es) | 1998-11-13 | 2002-04-29 | Smithkline Beecham Plc | Inhibidores de proteasa: tipo catepsina k |
CO5180541A1 (es) | 1998-12-23 | 2002-07-30 | Smithkline Beechman Corp | Inhibidores de proteasa del tipo de 1,3-diaminocetonas con anillo de 8-14 miembros |
US20030044399A1 (en) | 1998-12-23 | 2003-03-06 | Smithkline Beecham Corporation | Method of treatment |
TR200101869T2 (tr) * | 1998-12-23 | 2002-01-21 | Smithkline Beecham Corporation | Proteaz İnhibitörleri. |
JP2002536437A (ja) | 1999-02-09 | 2002-10-29 | ブリストル−マイヤーズ スクイブ カンパニー | FXaのラクタム抑制剤および方法 |
DZ3083A1 (fr) | 1999-02-19 | 2004-06-02 | Smithkline Beecham Corp | Composés nouveaux inhibiteurs de protéases, procédé pour leur préparation et compositions pharmaceutiques les conentant. |
UY26026A1 (es) | 1999-03-16 | 2000-10-31 | Smithkline Beecham Corportion | Inhibidores de proteasas |
UY26088A1 (es) | 1999-03-31 | 2000-10-31 | Smithkline Beecham Corp | Inhibidores de proteasas |
MXPA02000888A (es) | 1999-07-28 | 2002-07-30 | Aventis Pharm Prod Inc | Compuestos de oxoazaheterociclilos substituidos. |
EP1231921A4 (en) | 1999-11-10 | 2004-06-23 | Smithkline Beecham Corp | PROTEASE INHIBITORS |
JP2003513927A (ja) | 1999-11-10 | 2003-04-15 | スミスクライン・ビーチャム・コーポレイション | プロテア−ゼ阻害剤 |
AU1474701A (en) | 1999-11-10 | 2001-06-06 | Smithkline Beecham Corporation | Protease inhibitors |
WO2001034153A1 (en) | 1999-11-10 | 2001-05-17 | Smithkline Beecham Corporation | Protease inhibitors |
EP1233771A4 (en) | 1999-11-10 | 2003-05-14 | Smithkline Beecham Corp | PROTEASE INHIBITORS |
JP2003513928A (ja) | 1999-11-10 | 2003-04-15 | スミスクライン・ビーチャム・コーポレイション | プロテアーゼ阻害剤 |
US6596715B1 (en) | 1999-11-10 | 2003-07-22 | Smithkline Beecham Corporation | Protease inhibitors |
JP2003513922A (ja) | 1999-11-10 | 2003-04-15 | スミスクライン・ビーチャム・コーポレイション | プロテアーゼ阻害剤 |
US6583137B1 (en) | 1999-11-10 | 2003-06-24 | Smithkline Beecham Corporation | Protease inhibitors |
JP2003513925A (ja) | 1999-11-10 | 2003-04-15 | スミスクライン・ビーチャム・コーポレイション | プロテア−ゼ阻害剤 |
AU1474801A (en) * | 1999-11-10 | 2001-06-06 | Smithkline Beecham Corporation | Protease inhibitors |
WO2001034565A2 (en) | 1999-11-10 | 2001-05-17 | Smithkline Beecham Corporation | Protease inhibitors |
DE10004572A1 (de) * | 2000-02-02 | 2001-08-09 | Boehringer Ingelheim Pharma | Neue positive allosterische AMPA-Rezeptor Modulatoren (PAARM), Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel |
US7071184B2 (en) * | 2000-03-21 | 2006-07-04 | Smithkline Beecham Corporation | Protease inhibitors |
US20030114437A1 (en) | 2002-10-17 | 2003-06-19 | Cummings Maxwell D. | Protease inhibitors |
AU2001286983A1 (en) | 2000-09-01 | 2002-03-13 | Smith Kline Beecham Corporation | Method of treatment |
PL366232A1 (en) | 2000-11-22 | 2005-01-24 | Smithkline Beecham Corporation | Protease inhibitors |
US20040034013A1 (en) | 2001-04-17 | 2004-02-19 | Cummings Maxwell D | Methods of treatment |
EP1401453A4 (en) | 2001-05-17 | 2005-04-06 | Smithkline Beecham Corp | PROTEASE INHIBITORS |
WO2003026770A1 (en) | 2001-09-24 | 2003-04-03 | Smithkline Beecham Corporation | Method for removing metal from the products of olefin metathesis reactions |
WO2003045909A2 (en) | 2001-11-21 | 2003-06-05 | Smithkline Beecham Corporation | Methods and intermediates for the synthesis of azepines |
EP1532115A4 (en) | 2002-05-22 | 2006-01-11 | Smithkline Beecham Corp | INHIBITORS OF PROTEASE |
US20050256105A1 (en) | 2002-05-22 | 2005-11-17 | Jeong Jae U | Protease inhibitors |
AU2003263738A1 (en) | 2002-05-22 | 2003-12-02 | Smithkline Beecham Corporation | Protease inhibitors |
EP1511492A2 (en) | 2002-05-22 | 2005-03-09 | Smithkline Beecham Corporation | Protease inhibitors |
US7366462B2 (en) | 2003-10-24 | 2008-04-29 | Qualcomm Incorporated | Method and apparatus for seamlessly switching reception between multimedia streams in a wireless communication system |
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2001
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- 2001-03-07 EA EA200201001A patent/EA005893B1/ru unknown
- 2001-03-07 CZ CZ20023168A patent/CZ20023168A3/cs unknown
- 2001-03-07 PL PL01357727A patent/PL357727A1/xx not_active Application Discontinuation
- 2001-03-07 MX MXPA02009305A patent/MXPA02009305A/es active IP Right Grant
- 2001-03-07 AU AU4344101A patent/AU4344101A/xx active Pending
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- 2001-03-07 IL IL15096401A patent/IL150964A0/xx unknown
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- 2001-03-07 OA OA1200200295A patent/OA12323A/en unknown
- 2001-03-07 AP APAP/P/2002/002593A patent/AP1540A/en active
- 2001-03-07 CA CA002404206A patent/CA2404206A1/en not_active Abandoned
- 2001-03-07 NZ NZ520588A patent/NZ520588A/en unknown
- 2001-03-07 SK SK1363-2002A patent/SK13632002A3/sk unknown
- 2001-03-07 KR KR1020027012366A patent/KR20020082896A/ko active IP Right Grant
- 2001-03-07 EP EP01916412A patent/EP1307203A4/en not_active Withdrawn
- 2001-03-07 BR BR0109356-8A patent/BR0109356A/pt not_active IP Right Cessation
- 2001-03-07 WO PCT/US2001/007094 patent/WO2001070232A1/en active IP Right Grant
- 2001-03-07 DZ DZ013318A patent/DZ3318A1/fr active
- 2001-03-07 JP JP2001568430A patent/JP2003527429A/ja active Pending
- 2001-03-07 HU HU0300068A patent/HUP0300068A2/hu unknown
- 2001-03-19 UY UY26625A patent/UY26625A1/es not_active Application Discontinuation
- 2001-03-21 PE PE2001000259A patent/PE20011233A1/es not_active Application Discontinuation
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2002
- 2002-07-29 BG BG106962A patent/BG106962A/bg unknown
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2006
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Also Published As
Publication number | Publication date |
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AR032877A1 (es) | 2003-12-03 |
US20060194787A1 (en) | 2006-08-31 |
KR20020082896A (ko) | 2002-10-31 |
JP2003527429A (ja) | 2003-09-16 |
AP1540A (en) | 2006-01-11 |
AU4344101A (en) | 2001-10-03 |
AP2002002593A0 (en) | 2002-09-30 |
EA005893B1 (ru) | 2005-06-30 |
BG106962A (bg) | 2003-03-31 |
US7563784B2 (en) | 2009-07-21 |
DZ3318A1 (fr) | 2001-09-27 |
NO20024528D0 (no) | 2002-09-20 |
UY26625A1 (es) | 2001-09-28 |
EP1307203A1 (en) | 2003-05-07 |
BR0109356A (pt) | 2003-06-03 |
US20040044201A1 (en) | 2004-03-04 |
CZ20023168A3 (cs) | 2003-02-12 |
US7071184B2 (en) | 2006-07-04 |
IL150964A0 (en) | 2003-02-12 |
CN1416346A (zh) | 2003-05-07 |
WO2001070232A1 (en) | 2001-09-27 |
EA200201001A1 (ru) | 2003-02-27 |
NZ520588A (en) | 2004-06-25 |
NO20024528L (no) | 2002-11-19 |
PE20011233A1 (es) | 2002-02-07 |
MXPA02009305A (es) | 2003-03-12 |
MY141596A (en) | 2010-05-31 |
SK13632002A3 (sk) | 2003-02-04 |
EP1307203A4 (en) | 2005-08-17 |
CA2404206A1 (en) | 2001-09-27 |
HUP0300068A2 (en) | 2003-05-28 |
AU2001243441B2 (en) | 2004-11-25 |
PL357727A1 (en) | 2004-07-26 |
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