ES2153809T1 - Inhibicion de la cinasa de raf por uso de difenil-ureas sustituidas simetrica y asimetricamente. - Google Patents
Inhibicion de la cinasa de raf por uso de difenil-ureas sustituidas simetrica y asimetricamente.Info
- Publication number
- ES2153809T1 ES2153809T1 ES98963809T ES98963809T ES2153809T1 ES 2153809 T1 ES2153809 T1 ES 2153809T1 ES 98963809 T ES98963809 T ES 98963809T ES 98963809 T ES98963809 T ES 98963809T ES 2153809 T1 ES2153809 T1 ES 2153809T1
- Authority
- ES
- Spain
- Prior art keywords
- optionally substituted
- alkyl
- halogen
- alkoxy
- until reaching
- Prior art date
- 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.)
- Granted
Links
- 230000005764 inhibitory process Effects 0.000 title 1
- 229910052736 halogen Inorganic materials 0.000 abstract 13
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 10
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 abstract 8
- 125000005843 halogen group Chemical group 0.000 abstract 8
- 125000001072 heteroaryl group Chemical group 0.000 abstract 6
- 125000003118 aryl group Chemical group 0.000 abstract 5
- 150000002367 halogens Chemical class 0.000 abstract 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 3
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 abstract 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 abstract 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical group C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 abstract 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical group N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 abstract 2
- 125000003710 aryl alkyl group Chemical group 0.000 abstract 2
- 125000004429 atom Chemical group 0.000 abstract 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical group C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 abstract 2
- 125000001589 carboacyl group Chemical group 0.000 abstract 2
- 125000004076 pyridyl group Chemical group 0.000 abstract 2
- 101100440696 Caenorhabditis elegans cor-1 gene Proteins 0.000 abstract 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Chemical group C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 abstract 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 abstract 1
- 125000003545 alkoxy group Chemical group 0.000 abstract 1
- 125000002877 alkyl aryl group Chemical group 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical group O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 abstract 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 abstract 1
- 125000001624 naphthyl group Chemical group 0.000 abstract 1
- LYKMMUBOEFYJQG-UHFFFAOYSA-N piperoxan Chemical group C1OC2=CC=CC=C2OC1CN1CCCCC1 LYKMMUBOEFYJQG-UHFFFAOYSA-N 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C275/36—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with at least one of the oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. N-aryloxyphenylureas
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/32—Sulfur atoms
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- C07D277/62—Benzothiazoles
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- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
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- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Quinoline Compounds (AREA)
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Abstract
Un compuesto de fórmula I: **fórmula I** en la que A es **fórmula II** R3, R4, R5 y R6 son, cada uno independientemente, H, halógeno, NO2, alquilo C1-10, opcionalmente sustituido con halógeno hasta llegar a perhaloalquilo, alcoxi C1-10, opcionalmente sustituido con halógeno hasta llegar a perhaloalcoxi, arilo C6-12, opcionalmente sustituido con alquilo C1-10 ó alcoxi C1-10, ó heteroarilo C5-12, opcionalmente sustituido con alquilo C1-10 ó alcoxi C1-10, y uno de los R3-R6 puede ser -X-Y; o dos R3-R 6 adyacentes pueden ser en común un anillo de arilo o heteroarilo con 5-12 átomos, opcionalmente sustituido con alquilo C1-10, alcoxi C1-10, cicloaquilo C3-10, alquenilo C2-10, alcanoílo C1-10, arilo C6-12, heteroarilo C5-12; arilalquilo C6-12, alquilarilo C6-12, halógeno; NR1 R1 ; -NO2; -CF3; -COOR1 ; -NHCOR 1 ; -CN; -CONR1 R1 ; -SO2R2 ; -SOR2 ; -SR2 ; en que R1 es H o alquilo C1-10 y R2 es alquilo C1-10, opcionalmente sustituido con halógeno hasta llegar a perhalo, estando el -S(O2)- opcionalmente incorporado en el anillo de arilo o heteroarilo; R4'',R5'' y R6'' son independientemente H, halógeno, alquilo C1-C10, opcionalmente sustituido con halógeno hasta llegar a perhaloalquilo, **fórmula III** alcoxi C1-C10 opcionalmente sustituido con halógeno hasta llegar a perhaloalcoxi o -X-Y, y uno cualquiera de los R4'', R5'' ó R6'' es -X-Y, o dos radicales adyacentes de R4 0, R 5 0 y R 6 0 en común son un anillo heteroarilo con 5-12 átomos, opcionalmente sustituido con alquilo C1-10, alcoxiC1-10, cicloalquilo C3-10, alquenilo C2-10, alcanoílo C1-10, arilo C6-12, heteroarilo C5-12 o arilalquilo C6-12; R6 0 es adicionalmente -NHCOR 1 , -NR 1 COR 1 ó NO2; R1 es alquilo C1-10 opcionalmente sustituido con halógeno hasta llegar a perhalo; R3 0 es H, halógeno, alquilo C1-C10, opcionalmente sustituido con halógeno hasta llegar a perhaloalquilo, alcoxi C1-C10, opcionalmente sustituido con halógeno hasta llegar a perhaloalcoxi; X es-CH2-, -S-, -N(CH3)-, -NHC(O)-, -CH2-S-, -S-CH2-, -C(O)- o -O-; y X es adicionalmente un enlace simple cuando Y es piridilo; e Y es fenilo, piridilo, naftilo, piridona, pirazina, pirimidina, benzodioxano, benzopiridina o benzotiazol, cada uno opcionalmente sustituido con alquilo C1-10, alcoxi C1-10, halógeno, OH, -SCH3, NO2 o, cuando Y es fenilo, con **fórmula IV** o una de sus sales farmacéuticamente aceptables, con la condición de que si X es -O- o -S-, R3'' y R6'' son H, e Y es fenilo sin sustituir con OH, entonces R6 ha de ser alcoxi.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US996344 | 1992-12-23 | ||
| US99634497A | 1997-12-22 | 1997-12-22 |
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| Publication Number | Publication Date |
|---|---|
| ES2153809T1 true ES2153809T1 (es) | 2001-03-16 |
| ES2153809T3 ES2153809T3 (es) | 2005-07-16 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES98963809T Expired - Lifetime ES2153809T3 (es) | 1997-12-22 | 1998-12-22 | Inhibicion de la cinasa raf por uso de difnil-ureas sustituidas simetrica y asimetricamente. |
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| EP (2) | EP1049664B1 (es) |
| JP (1) | JP4607318B2 (es) |
| KR (1) | KR100704977B1 (es) |
| CN (1) | CN1213022C (es) |
| AT (1) | ATE291011T1 (es) |
| AU (1) | AU763024B2 (es) |
| BG (1) | BG64594B1 (es) |
| BR (1) | BR9814375A (es) |
| CA (1) | CA2315646C (es) |
| CU (1) | CU23393A3 (es) |
| CZ (1) | CZ301102B6 (es) |
| DE (2) | DE1049664T1 (es) |
| ES (1) | ES2153809T3 (es) |
| GR (1) | GR20010300006T1 (es) |
| HU (1) | HU227711B1 (es) |
| ID (1) | ID26956A (es) |
| IL (2) | IL136690A0 (es) |
| MX (1) | MXPA00006231A (es) |
| NO (1) | NO329181B1 (es) |
| NZ (1) | NZ505843A (es) |
| PL (1) | PL195808B1 (es) |
| RU (1) | RU2247109C9 (es) |
| SK (1) | SK286564B6 (es) |
| TR (2) | TR200100874T2 (es) |
| WO (1) | WO1999032436A1 (es) |
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| US9638690B2 (en) | 2014-11-07 | 2017-05-02 | The University Of British Columbia | Compounds and compositions for use as alkylating agent sensors and methods of use thereof |
| SG11201706630UA (en) | 2015-02-25 | 2017-09-28 | Eisai R&D Man Co Ltd | Method for suppressing bitterness of quinoline derivative |
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| CN104817493A (zh) * | 2015-03-11 | 2015-08-05 | 西安交通大学 | 一种芳杂环酰胺取代的二芳基脲化合物及其制备方法和应用 |
| CN104744350A (zh) * | 2015-03-11 | 2015-07-01 | 西安交通大学 | 一种吡啶取代的二芳基脲化合物及其制备方法和应用 |
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| BR112017027227B1 (pt) | 2015-06-16 | 2023-12-12 | Eisai R&D Management Co., Ltd | Agente anti-câncer |
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| CN107922375B (zh) * | 2015-07-30 | 2020-05-22 | 正大天晴药业集团股份有限公司 | 靶向idh2突变的抗肿瘤化合物及其使用方法 |
| JP6553726B2 (ja) | 2015-08-20 | 2019-07-31 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 腫瘍治療剤 |
| US12303505B2 (en) | 2017-02-08 | 2025-05-20 | Eisai R&D Management Co., Ltd. | Tumor-treating pharmaceutical composition |
| BR112019023064A2 (pt) | 2017-05-16 | 2020-06-09 | Eisai R&D Man Co Ltd | tratamento de carcinoma hepatocelular |
| CN108997209B (zh) * | 2018-06-11 | 2020-08-04 | 山东罗欣药业集团恒欣药业有限公司 | 一种瑞戈非尼的制备方法 |
| MA52954A (fr) * | 2018-06-21 | 2021-04-28 | Cellestia Biotech Ag | Procédé pour la fabrication d'aminoéthers de diaryle et sels de chlorhydrate d'aminoéthers de diaryle |
| CN110128299B (zh) * | 2019-05-13 | 2020-11-10 | 浙江大学 | 一种二苯基脲类抗肿瘤小分子抑制剂及其制备方法 |
| CN113121484A (zh) | 2019-12-31 | 2021-07-16 | 复星弘创(苏州)医药科技有限公司 | 一种制备3-位被酰胺基烷基取代的香豆素类化合物的方法及其产物和相关中间体 |
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| US2140495A (en) * | 1932-03-26 | 1938-12-20 | Ici Ltd | Bis (2, 3-hydroxy-naphthoyl-maminophenyl) urea |
| US3284433A (en) * | 1963-07-17 | 1966-11-08 | Merck & Co Inc | 4-phenoxy-carbanilides |
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| JP2717481B2 (ja) * | 1992-08-25 | 1998-02-18 | 富士写真フイルム株式会社 | ハロゲン化銀カラー写真感光材料 |
| US5470882A (en) * | 1994-06-02 | 1995-11-28 | Smithkline Beecham Corp. | Anti-inflammatory compounds |
| EP0809492A4 (en) * | 1995-02-17 | 2007-01-24 | Smithkline Beecham Corp | IL-8 RECEPTOR ANTAGONISTS |
| US5773459A (en) * | 1995-06-07 | 1998-06-30 | Sugen, Inc. | Urea- and thiourea-type compounds |
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| US6011029A (en) * | 1996-02-26 | 2000-01-04 | Bristol-Myers Squibb Company | Inhibitors of farnesyl protein transferase |
| CN1118462C (zh) * | 1997-04-22 | 2003-08-20 | 神经研究公司 | 取代的苯基衍生物、其制备方法以及用途 |
| US6093742A (en) * | 1997-06-27 | 2000-07-25 | Vertex Pharmaceuticals, Inc. | Inhibitors of p38 |
| HUP0101704A3 (en) * | 1997-12-22 | 2002-12-28 | Bayer Corp Pittsburgh | Kinease substituted heterocyclic ureas with raf inhibition activity and pharmaceutical compositions containing them |
| WO1999032463A1 (en) * | 1997-12-22 | 1999-07-01 | Bayer Corporation | INHIBITION OF p38 KINASE USING SYMMETRICAL AND UNSYMMETRICAL DIPHENYL UREAS |
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1998
- 1998-12-22 EP EP98963809A patent/EP1049664B1/en not_active Expired - Lifetime
- 1998-12-22 KR KR1020007007015A patent/KR100704977B1/ko not_active Expired - Fee Related
- 1998-12-22 ID IDW20001415A patent/ID26956A/id unknown
- 1998-12-22 HU HU0004437A patent/HU227711B1/hu not_active IP Right Cessation
- 1998-12-22 EP EP03026051A patent/EP1449834A3/en not_active Withdrawn
- 1998-12-22 NZ NZ505843A patent/NZ505843A/xx not_active IP Right Cessation
- 1998-12-22 AT AT98963809T patent/ATE291011T1/de not_active IP Right Cessation
- 1998-12-22 JP JP2000525373A patent/JP4607318B2/ja not_active Expired - Fee Related
- 1998-12-22 DE DE1049664T patent/DE1049664T1/de active Pending
- 1998-12-22 ES ES98963809T patent/ES2153809T3/es not_active Expired - Lifetime
- 1998-12-22 PL PL98342078A patent/PL195808B1/pl not_active IP Right Cessation
- 1998-12-22 TR TR2001/00874T patent/TR200100874T2/xx unknown
- 1998-12-22 CN CNB98812503XA patent/CN1213022C/zh not_active Expired - Fee Related
- 1998-12-22 CA CA2315646A patent/CA2315646C/en not_active Expired - Fee Related
- 1998-12-22 WO PCT/US1998/026081 patent/WO1999032436A1/en not_active Ceased
- 1998-12-22 AU AU19054/99A patent/AU763024B2/en not_active Ceased
- 1998-12-22 TR TR2000/02616T patent/TR200002616T2/xx unknown
- 1998-12-22 BR BR9814375-1A patent/BR9814375A/pt not_active IP Right Cessation
- 1998-12-22 RU RU2000120165/04A patent/RU2247109C9/ru not_active IP Right Cessation
- 1998-12-22 CZ CZ20002351A patent/CZ301102B6/cs not_active IP Right Cessation
- 1998-12-22 MX MXPA00006231A patent/MXPA00006231A/es not_active IP Right Cessation
- 1998-12-22 DE DE69829412T patent/DE69829412T2/de not_active Expired - Lifetime
- 1998-12-22 SK SK961-2000A patent/SK286564B6/sk not_active IP Right Cessation
- 1998-12-22 IL IL13669098A patent/IL136690A0/xx active IP Right Grant
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2000
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- 2000-06-21 NO NO20003230A patent/NO329181B1/no not_active IP Right Cessation
- 2000-06-22 CU CU20000153A patent/CU23393A3/es not_active IP Right Cessation
- 2000-07-12 BG BG104599A patent/BG64594B1/bg unknown
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2001
- 2001-02-28 GR GR20010300006T patent/GR20010300006T1/el unknown
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