ES2153337T3 - Inhibidores de la quinasa raf. - Google Patents
Inhibidores de la quinasa raf. Download PDFInfo
- Publication number
- ES2153337T3 ES2153337T3 ES98923601T ES98923601T ES2153337T3 ES 2153337 T3 ES2153337 T3 ES 2153337T3 ES 98923601 T ES98923601 T ES 98923601T ES 98923601 T ES98923601 T ES 98923601T ES 2153337 T3 ES2153337 T3 ES 2153337T3
- Authority
- ES
- Spain
- Prior art keywords
- baselineskip
- mmol
- methyl
- thiophene
- carboxylic
- 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.)
- Expired - Lifetime
Links
- 239000003112 inhibitor Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 21
- 230000001404 mediated effect Effects 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims description 8
- 108091000080 Phosphotransferase Proteins 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 102000020233 phosphotransferase Human genes 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- 230000010261 cell growth Effects 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 55
- 108010077182 raf Kinases Proteins 0.000 abstract description 15
- 102000009929 raf Kinases Human genes 0.000 abstract description 15
- 150000003672 ureas Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- -1 by example Substances 0.000 description 63
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 54
- 239000002253 acid Substances 0.000 description 46
- 239000000243 solution Substances 0.000 description 41
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 150000004702 methyl esters Chemical class 0.000 description 30
- 239000000203 mixture Substances 0.000 description 30
- 239000007787 solid Substances 0.000 description 19
- 238000005481 NMR spectroscopy Methods 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 238000003818 flash chromatography Methods 0.000 description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- LTEUXHSAYOSFGQ-UHFFFAOYSA-N 5-(trifluoromethyl)-1,3,4-thiadiazol-2-amine Chemical compound NC1=NN=C(C(F)(F)F)S1 LTEUXHSAYOSFGQ-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 239000000047 product Substances 0.000 description 12
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 102000016914 ras Proteins Human genes 0.000 description 7
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
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- 239000000546 pharmaceutical excipient Substances 0.000 description 6
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- 239000003765 sweetening agent Substances 0.000 description 6
- IFLKEBSJTZGCJG-UHFFFAOYSA-N 3-methylthiophene-2-carboxylic acid Chemical compound CC=1C=CSC=1C(O)=O IFLKEBSJTZGCJG-UHFFFAOYSA-N 0.000 description 5
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- MGYGFNQQGAQEON-UHFFFAOYSA-N 4-tolyl isocyanate Chemical compound CC1=CC=C(N=C=O)C=C1 MGYGFNQQGAQEON-UHFFFAOYSA-N 0.000 description 4
- IDJHZGAZTMKNNP-UHFFFAOYSA-N 5-tert-butyl-3-[(4-methylphenyl)carbamoylamino]thiophene-2-carboxylic acid Chemical compound C1=CC(C)=CC=C1NC(=O)NC1=C(C(O)=O)SC(C(C)(C)C)=C1 IDJHZGAZTMKNNP-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
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- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 4
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 4
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- 239000011734 sodium Substances 0.000 description 4
- 150000004992 toluidines Chemical class 0.000 description 4
- LTNUSYNQZJZUSY-UHFFFAOYSA-N 3,3-dimethylbutanal Chemical compound CC(C)(C)CC=O LTNUSYNQZJZUSY-UHFFFAOYSA-N 0.000 description 3
- QENGPZGAWFQWCZ-UHFFFAOYSA-N 3-Methylthiophene Chemical compound CC=1C=CSC=1 QENGPZGAWFQWCZ-UHFFFAOYSA-N 0.000 description 3
- GUNJHLAUFYAHFN-UHFFFAOYSA-N 5-(bromomethyl)-3-[(4-methylphenyl)carbamoylamino]thiophene-2-carboxylic acid Chemical compound C1=CC(C)=CC=C1NC(=O)NC1=C(C(O)=O)SC(CBr)=C1 GUNJHLAUFYAHFN-UHFFFAOYSA-N 0.000 description 3
- VREBZCCBSCIQPP-UHFFFAOYSA-N 5-tert-butyl-2-[(4-methylphenyl)carbamoylamino]thiophene-3-carboxylic acid Chemical compound C1=CC(C)=CC=C1NC(=O)NC1=C(C(O)=O)C=C(C(C)(C)C)S1 VREBZCCBSCIQPP-UHFFFAOYSA-N 0.000 description 3
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D409/02—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or 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
- C07D307/68—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
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US12642097P | 1997-05-23 | 1997-05-23 | |
| US86302197A | 1997-05-23 | 1997-05-23 | |
| US863021 | 1997-05-23 | ||
| PCT/US1998/010376 WO1998052559A1 (en) | 1997-05-23 | 1998-05-21 | Raf kinase inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| ES2153337T1 ES2153337T1 (es) | 2001-03-01 |
| ES2153337T3 true ES2153337T3 (es) | 2008-11-01 |
Family
ID=26824631
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES98923601T Expired - Lifetime ES2153337T3 (es) | 1997-05-23 | 1998-05-21 | Inhibidores de la quinasa raf. |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0986382B1 (enExample) |
| JP (1) | JP2002500650A (enExample) |
| AT (1) | ATE399007T1 (enExample) |
| AU (1) | AU7585598A (enExample) |
| CA (1) | CA2291065C (enExample) |
| DE (2) | DE986382T1 (enExample) |
| DK (1) | DK0986382T3 (enExample) |
| ES (1) | ES2153337T3 (enExample) |
| GR (1) | GR20010300033T1 (enExample) |
| WO (1) | WO1998052559A1 (enExample) |
Families Citing this family (67)
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| US7329670B1 (en) | 1997-12-22 | 2008-02-12 | Bayer Pharmaceuticals Corporation | Inhibition of RAF kinase using aryl and heteroaryl substituted heterocyclic ureas |
| PL341356A1 (en) * | 1997-12-22 | 2001-04-09 | Bayer Ag | Raf kinase inhibition employing aryl- and heteroaryl-substituted heterocyclic ureas |
| US7517880B2 (en) | 1997-12-22 | 2009-04-14 | Bayer Pharmaceuticals Corporation | Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas |
| AU2003204708B2 (en) * | 1997-12-22 | 2006-05-25 | Bayer Healthcare Llc | Inhibition of Raf Kinase using Substituted Heterocyclic Ureas |
| NZ505844A (en) * | 1997-12-22 | 2003-10-31 | Bayer Ag | Inhibition of raf kinase using substituted heterocyclic ureas |
| US8124630B2 (en) | 1999-01-13 | 2012-02-28 | Bayer Healthcare Llc | ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
| SI1140840T1 (sl) * | 1999-01-13 | 2006-06-30 | Bayer Pharmaceuticals Corp | Omega-karboksiarilno substituirane difenil secnine kot inhibitorji raf kinaze |
| ATE538794T1 (de) | 1999-01-13 | 2012-01-15 | Bayer Healthcare Llc | Gamma carboxyarylsubstituierte diphenylharnstoffverbindungen als p38 kinasehemmer |
| WO2000042012A1 (en) | 1999-01-13 | 2000-07-20 | Bayer Corporation | φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS |
| US7351834B1 (en) | 1999-01-13 | 2008-04-01 | Bayer Pharmaceuticals Corporation | ω-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
| SK287419B6 (sk) * | 1999-01-13 | 2010-09-07 | Bayer Corporation | Použitie difenylových močovín substituovaných omega-karboxyarylovou skupinou ako inhibítorov rafkinázy |
| UA73492C2 (en) | 1999-01-19 | 2005-08-15 | Aromatic heterocyclic compounds as antiinflammatory agents | |
| WO2000050425A1 (en) | 1999-02-22 | 2000-08-31 | Boehringer Ingelheim Pharmaceuticals, Inc. | Polycyclo heterocyclic derivatives as antiinflammatory agents |
| CA2360740A1 (en) | 1999-03-02 | 2000-09-08 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as reversible inhibitors of cathepsin s |
| ATE309237T1 (de) | 1999-03-12 | 2005-11-15 | Boehringer Ingelheim Pharma | Aromatische heterozyklische verbindungen als antientzündungwirkstoffe |
| IL144897A0 (en) | 1999-03-12 | 2002-06-30 | Boehringer Ingelheim Pharma | Compounds useful as anti-inflammatory agents |
| HN2000000051A (es) * | 1999-05-19 | 2001-02-02 | Pfizer Prod Inc | Derivados heterociclicos utiles como agentes anticancerosos |
| US6573409B1 (en) | 1999-07-02 | 2003-06-03 | The Nutrasweet Company | Process for the preparation of 3,3-dimethylbutanal |
| ATE312823T1 (de) | 1999-07-09 | 2005-12-15 | Boehringer Ingelheim Pharma | Verfahren zur herstellung heteroarylsubstituierter ureaverbindungen |
| US6420364B1 (en) | 1999-09-13 | 2002-07-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compound useful as reversible inhibitors of cysteine proteases |
| US6525046B1 (en) | 2000-01-18 | 2003-02-25 | Boehringer Ingelheim Pharmaceuticals, Inc. | Aromatic heterocyclic compounds as antiinflammatory agents |
| US6608052B2 (en) | 2000-02-16 | 2003-08-19 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as anti-inflammatory agents |
| US6414013B1 (en) | 2000-06-19 | 2002-07-02 | Pharmacia & Upjohn S.P.A. | Thiophene compounds, process for preparing the same, and pharmaceutical compositions containing the same background of the invention |
| DE10050492A1 (de) * | 2000-10-11 | 2002-04-25 | Morphochem Ag | Verfahren zur Herstellung von 5-Oxo-2,5-dihydro-furan-2-carbonsäureamiden und 6-Oxo-3,6-dihydro-2H-pyran-2-carbonsäureamiden |
| EP1341771A2 (en) | 2000-11-29 | 2003-09-10 | Glaxo Group Limited | Benzimidazole derivatives useful as tie-2 and/or vegfr-2 inhibitors |
| US7235576B1 (en) | 2001-01-12 | 2007-06-26 | Bayer Pharmaceuticals Corporation | Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
| US7371763B2 (en) | 2001-04-20 | 2008-05-13 | Bayer Pharmaceuticals Corporation | Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas |
| JP2004530690A (ja) | 2001-05-16 | 2004-10-07 | ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド | 抗炎症性薬剤として有用なジアリールウレア誘導体 |
| JP2004531571A (ja) | 2001-05-25 | 2004-10-14 | ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド | サイトカイン生産のインヒビターとしてのカルバメート及びオキサミド化合物 |
| PL395097A1 (pl) * | 2001-06-11 | 2011-10-10 | Vertex Pharmaceuticals (Canada) Incorporated | Sposób wytwarzania związku o wzorze A stanowiącego pochodną tiofenu |
| EP1709965A3 (en) * | 2001-07-11 | 2006-12-27 | Boehringer Ingelheim Pharmaceuticals, Inc. | Methods of treating cytokine mediate diseases |
| ES2400070T3 (es) * | 2001-12-03 | 2013-04-05 | Bayer Healthcare Llc | Compuestos de aril-urea en combinación con otros agentes citostáticos o citotóxicos para tratamiento de cánceres humanos |
| MXPA04007832A (es) | 2002-02-11 | 2005-09-08 | Bayer Pharmaceuticals Corp | Aril-ureas con actividad inhibitoria de angiogenesis. |
| ATE529406T1 (de) | 2002-02-11 | 2011-11-15 | Bayer Healthcare Llc | Aryl-harnstoffe als kinase inhibitoren |
| WO2003072569A1 (en) | 2002-02-25 | 2003-09-04 | Boehringer Ingelheim Pharmaceuticals, Inc. | 1,4-disubstituted benzofused cycloalkyl urea compounds useful in treating cytokine mediated diseases |
| DE60310730T2 (de) | 2002-07-09 | 2007-05-16 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmazeutische zusammensetzungen aus anticholinergica und p38 kinase hemmern zur behandlung von erkrankungen der atemwege |
| EP1615878B1 (en) | 2003-01-14 | 2012-04-04 | Cytokinetics, Inc. | Compounds, compositions and methods of treatment for heart failure |
| CA2526285A1 (en) | 2003-05-15 | 2004-12-23 | Arqule, Inc. | Inhibitors of p38 and methods of using the same |
| EP1636585B2 (en) | 2003-05-20 | 2012-06-13 | Bayer HealthCare LLC | Diaryl ureas with kinase inhibiting activity |
| HRP20060073B1 (hr) | 2003-07-23 | 2014-03-14 | Bayer Healthcare Llc | Fluoro supstituirana omega-karboksiaril difenil urea za lijeäśenje i prevenciju bolesti i stanja |
| BRPI0413585A (pt) * | 2003-08-15 | 2006-10-17 | Astrazeneca Ab | composto ou sal farmaceuticamente aceitável ou um precursor hidrolisável in vivo deste, uso de um composto ou um sal deste farmaceuticamente aceitável, métodos para o tratamento de cáncer, e de infecções associadas com cáncer, composição farmacêutica, e, processo para preparação e uso de um composto ou um sal farmacêuticamente aceitável ou um precursor hidrolisável in vivo |
| TW200530236A (en) | 2004-02-23 | 2005-09-16 | Chugai Pharmaceutical Co Ltd | Heteroaryl phenylurea |
| CN101010315A (zh) | 2004-04-30 | 2007-08-01 | 拜耳制药公司 | 用于治疗癌症的取代的吡唑基脲衍生物 |
| WO2006009726A2 (en) | 2004-06-17 | 2006-01-26 | Cytokinetics, Inc. | Substituted urea derivatives for treating cardiac diseases |
| US7829560B2 (en) | 2004-07-08 | 2010-11-09 | Arqule, Inc. | 1,4-disubstituted naphthalenes as inhibitors of P38 MAP kinase |
| US20060035893A1 (en) | 2004-08-07 | 2006-02-16 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders |
| US8178672B2 (en) | 2004-10-19 | 2012-05-15 | Arqule, Inc. | Synthesis of imidazooxazole and imidazothiazole inhibitors of p38 MAP kinase |
| JP2008523071A (ja) | 2004-12-07 | 2008-07-03 | ルーカス ファーマシューティカルズ， インコーポレイテッド | Ｍａｐキナーゼの尿素インヒビター |
| JP2008523072A (ja) | 2004-12-07 | 2008-07-03 | ルーカス ファーマシューティカルズ， インコーポレイテッド | タンパク質キナーゼの阻害剤 |
| GB0428082D0 (en) | 2004-12-22 | 2005-01-26 | Welcome Trust The Ltd | Therapeutic compounds |
| PE20060777A1 (es) | 2004-12-24 | 2006-10-06 | Boehringer Ingelheim Int | Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas |
| CN104688697A (zh) | 2005-03-07 | 2015-06-10 | 拜尔健康护理有限责任公司 | 用于治疗癌症的包含ω-羧芳基取代的二苯基脲的药物组合物 |
| EP2546246A3 (en) | 2005-05-13 | 2013-04-24 | Virochem Pharma Inc. | Compounds and methods for the treatment or prevention of flavivirus infections |
| US7538223B2 (en) | 2005-08-04 | 2009-05-26 | Cytokinetics, Inc. | Compounds, compositions and methods |
| JP5072595B2 (ja) | 2005-08-05 | 2012-11-14 | 中外製薬株式会社 | マルチキナーゼ阻害剤 |
| US7825120B2 (en) | 2005-12-15 | 2010-11-02 | Cytokinetics, Inc. | Certain substituted ((piperazin-1-ylmethyl)benzyl)ureas |
| TW200808321A (en) | 2005-12-15 | 2008-02-16 | Cytokinetics Inc | Certain chemical entities, compositions and methods |
| WO2007078815A2 (en) | 2005-12-16 | 2007-07-12 | Cytokinetics, Inc. | Certain chemical entities, compositions, and methods |
| EP1962852B1 (en) | 2005-12-19 | 2017-01-25 | Cytokinetics, Inc. | Compounds, compositions and methods |
| EP1992344A1 (en) | 2007-05-18 | 2008-11-19 | Institut Curie | P38 alpha as a therapeutic target in pathologies linked to FGFR3 mutation |
| CN102627657B (zh) * | 2012-03-09 | 2015-01-07 | 苏州施亚生物科技有限公司 | 3-(4-甲氧基-苄基)-1h-嘧啶-2,4-二酮衍生物的合成方法 |
| WO2015041534A1 (en) | 2013-09-20 | 2015-03-26 | Stichting Het Nederlands Kanker Instituut | P90rsk in combination with raf/erk/mek |
| EP3046557A1 (en) | 2013-09-20 | 2016-07-27 | Stichting Het Nederlands Kanker Instituut | Rock in combination with mapk-pathway |
| US20170027940A1 (en) | 2014-04-10 | 2017-02-02 | Stichting Het Nederlands Kanker Instituut | Method for treating cancer |
| CN106470974B (zh) | 2014-04-17 | 2019-07-16 | 韩国巴斯德研究所 | 用于治疗病毒感染的化合物 |
| WO2015178770A1 (en) | 2014-05-19 | 2015-11-26 | Stichting Het Nederlands Kanker Instituut | Compositions for cancer treatment |
| HUE053286T2 (hu) * | 2016-10-26 | 2021-06-28 | Ishihara Sangyo Kaisha | Eljárás 3-metil-2-tiofénkarbonsav elõállítására |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61268678A (ja) * | 1985-05-17 | 1986-11-28 | バイエル・アクチエンゲゼルシヤフト | 生産増進剤 |
| US5597719A (en) * | 1994-07-14 | 1997-01-28 | Onyx Pharmaceuticals, Inc. | Interaction of RAF-1 and 14-3-3 proteins |
| US5773459A (en) * | 1995-06-07 | 1998-06-30 | Sugen, Inc. | Urea- and thiourea-type compounds |
| DE1019040T1 (de) * | 1997-05-23 | 2001-02-08 | Bayer Corp., West Haven | Hemmung von p38 kinase aktivität durch arylharnstoff |
-
1998
- 1998-05-21 EP EP98923601A patent/EP0986382B1/en not_active Expired - Lifetime
- 1998-05-21 CA CA2291065A patent/CA2291065C/en not_active Expired - Fee Related
- 1998-05-21 WO PCT/US1998/010376 patent/WO1998052559A1/en not_active Ceased
- 1998-05-21 AU AU75855/98A patent/AU7585598A/en not_active Abandoned
- 1998-05-21 ES ES98923601T patent/ES2153337T3/es not_active Expired - Lifetime
- 1998-05-21 AT AT98923601T patent/ATE399007T1/de not_active IP Right Cessation
- 1998-05-21 DK DK98923601T patent/DK0986382T3/da active
- 1998-05-21 JP JP55061898A patent/JP2002500650A/ja active Pending
- 1998-05-21 DE DE0986382T patent/DE986382T1/de active Pending
- 1998-05-21 DE DE69839639T patent/DE69839639D1/de not_active Expired - Lifetime
-
2001
- 2001-06-29 GR GR20010300033T patent/GR20010300033T1/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE986382T1 (de) | 2001-01-25 |
| CA2291065C (en) | 2010-02-09 |
| ES2153337T1 (es) | 2001-03-01 |
| GR20010300033T1 (en) | 2001-06-29 |
| AU7585598A (en) | 1998-12-11 |
| EP0986382A1 (en) | 2000-03-22 |
| CA2291065A1 (en) | 1998-11-26 |
| DK0986382T3 (da) | 2008-10-20 |
| DE69839639D1 (en) | 2008-08-07 |
| EP0986382B1 (en) | 2008-06-25 |
| JP2002500650A (ja) | 2002-01-08 |
| ATE399007T1 (de) | 2008-07-15 |
| EP0986382A4 (en) | 2001-04-11 |
| WO1998052559A1 (en) | 1998-11-26 |
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