DE69724789T2 - Bicyclische heteroaromatic verbindungen als protein tyrosin kinase inhibitoren - Google Patents
Bicyclische heteroaromatic verbindungen als protein tyrosin kinase inhibitoren Download PDFInfo
- Publication number
- DE69724789T2 DE69724789T2 DE69724789T DE69724789T DE69724789T2 DE 69724789 T2 DE69724789 T2 DE 69724789T2 DE 69724789 T DE69724789 T DE 69724789T DE 69724789 T DE69724789 T DE 69724789T DE 69724789 T2 DE69724789 T2 DE 69724789T2
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- Germany
- Prior art keywords
- methyl
- group
- pyrido
- benzyl
- indazol
- 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.)
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- 102000004169 proteins and genes Human genes 0.000 title claims description 6
- 108090000623 proteins and genes Proteins 0.000 title claims description 6
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Chemical compound OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 title claims description 4
- 150000002390 heteroarenes Chemical class 0.000 title description 2
- 229940043355 kinase inhibitor Drugs 0.000 title 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 title 1
- -1 methylenedioxy Chemical group 0.000 claims description 298
- 150000001875 compounds Chemical class 0.000 claims description 196
- 238000000034 method Methods 0.000 claims description 77
- 125000000217 alkyl group Chemical group 0.000 claims description 58
- 239000003153 chemical reaction reagent Substances 0.000 claims description 48
- 229910052757 nitrogen Inorganic materials 0.000 claims description 46
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 41
- 150000003839 salts Chemical class 0.000 claims description 39
- 239000012453 solvate Substances 0.000 claims description 30
- 125000005843 halogen group Chemical group 0.000 claims description 27
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 25
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 25
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 24
- 230000000694 effects Effects 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 230000008569 process Effects 0.000 claims description 22
- 238000011282 treatment Methods 0.000 claims description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 238000006467 substitution reaction Methods 0.000 claims description 19
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 18
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- QNDFCSITSCMNGP-UHFFFAOYSA-N n-(1-benzylindazol-5-yl)-6-chloropyrido[3,4-d]pyrimidin-4-amine Chemical compound N1=CN=C2C=NC(Cl)=CC2=C1NC(C=C1C=N2)=CC=C1N2CC1=CC=CC=C1 QNDFCSITSCMNGP-UHFFFAOYSA-N 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 17
- 206010028980 Neoplasm Diseases 0.000 claims description 16
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 16
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 15
- 150000001412 amines Chemical class 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 125000003282 alkyl amino group Chemical group 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 125000001041 indolyl group Chemical group 0.000 claims description 13
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 13
- 125000004175 fluorobenzyl group Chemical group 0.000 claims description 12
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
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- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 10
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- 125000003545 alkoxy group Chemical group 0.000 claims description 9
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 8
- 150000003852 triazoles Chemical class 0.000 claims description 8
- DYYZXRCFCVDSKD-UHFFFAOYSA-N N6,N6-dimethyl-N4-[1-(phenylmethyl)-5-indazolyl]pyrido[3,4-d]pyrimidine-4,6-diamine Chemical compound N1=CN=C2C=NC(N(C)C)=CC2=C1NC(C=C1C=N2)=CC=C1N2CC1=CC=CC=C1 DYYZXRCFCVDSKD-UHFFFAOYSA-N 0.000 claims description 7
- 201000004681 Psoriasis Diseases 0.000 claims description 7
- 201000011510 cancer Diseases 0.000 claims description 7
- 125000001589 carboacyl group Chemical group 0.000 claims description 7
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- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
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- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 5
- BMIOWXJYLRLVHA-UHFFFAOYSA-N 4-n-(1-benzylindazol-5-yl)-6-n-methylpyrido[3,4-d]pyrimidine-4,6-diamine Chemical compound N1=CN=C2C=NC(NC)=CC2=C1NC(C=C1C=N2)=CC=C1N2CC1=CC=CC=C1 BMIOWXJYLRLVHA-UHFFFAOYSA-N 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 150000004702 methyl esters Chemical class 0.000 claims description 5
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 claims description 5
- 229910052727 yttrium Inorganic materials 0.000 claims description 5
- JFXFEXXASOCJBR-UHFFFAOYSA-N 4-n-(1-benzylindazol-5-yl)-6-n-ethyl-6-n-methylpyrido[3,4-d]pyrimidine-4,6-diamine Chemical compound N1=CN=C2C=NC(N(C)CC)=CC2=C1NC(C=C1C=N2)=CC=C1N2CC1=CC=CC=C1 JFXFEXXASOCJBR-UHFFFAOYSA-N 0.000 claims description 4
- HKNPEKHQRROZPD-UHFFFAOYSA-N 4-n-[1-[(3-fluorophenyl)methyl]indazol-5-yl]-6-n,6-n-dimethylpyrido[3,4-d]pyrimidine-4,6-diamine Chemical compound N1=CN=C2C=NC(N(C)C)=CC2=C1NC(C=C1C=N2)=CC=C1N2CC1=CC=CC(F)=C1 HKNPEKHQRROZPD-UHFFFAOYSA-N 0.000 claims description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 4
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 4
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 125000005879 dioxolanyl group Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 4
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- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 3
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 3
- MAAXBKQABSWUKL-UHFFFAOYSA-N 2-[4-[4-[(1-benzylindazol-5-yl)amino]pyrido[3,4-d]pyrimidin-6-yl]piperazin-1-yl]-n-propan-2-ylacetamide Chemical compound C1CN(CC(=O)NC(C)C)CCN1C(N=CC1=NC=N2)=CC1=C2NC1=CC=C(N(CC=2C=CC=CC=2)N=C2)C2=C1 MAAXBKQABSWUKL-UHFFFAOYSA-N 0.000 claims description 3
- XKGUJMPYDBMSDA-UHFFFAOYSA-N 4-n-(1-benzyl-3-methylindazol-5-yl)-6-n,6-n-dimethylpyrido[3,4-d]pyrimidine-4,6-diamine Chemical compound N1=CN=C2C=NC(N(C)C)=CC2=C1NC(C=C1C(C)=N2)=CC=C1N2CC1=CC=CC=C1 XKGUJMPYDBMSDA-UHFFFAOYSA-N 0.000 claims description 3
- YZZIGXZRNAEFCP-UHFFFAOYSA-N 4-n-(1-benzylindol-5-yl)-6-n,6-n-dimethylpyrido[3,4-d]pyrimidine-4,6-diamine Chemical compound N1=CN=C2C=NC(N(C)C)=CC2=C1NC(C=C1C=C2)=CC=C1N2CC1=CC=CC=C1 YZZIGXZRNAEFCP-UHFFFAOYSA-N 0.000 claims description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9614763 | 1996-07-13 | ||
| GBGB9614763.2A GB9614763D0 (en) | 1996-07-13 | 1996-07-13 | Heterocyclic compounds |
| GB9625492 | 1996-12-07 | ||
| GBGB9625492.5A GB9625492D0 (en) | 1996-12-07 | 1996-12-07 | Heterocyclic compounds |
| PCT/EP1997/003674 WO1998002438A1 (en) | 1996-07-13 | 1997-07-11 | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69724789D1 DE69724789D1 (de) | 2003-10-16 |
| DE69724789T2 true DE69724789T2 (de) | 2004-07-01 |
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| Application Number | Title | Priority Date | Filing Date |
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| DE69724789T Expired - Fee Related DE69724789T2 (de) | 1996-07-13 | 1997-07-11 | Bicyclische heteroaromatic verbindungen als protein tyrosin kinase inhibitoren |
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| EA (1) | EA199900022A1 (show.php) |
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| US5679683A (en) * | 1994-01-25 | 1997-10-21 | Warner-Lambert Company | Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family |
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| GB9510757D0 (en) | 1994-09-19 | 1995-07-19 | Wellcome Found | Therapeuticaly active compounds |
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-
1997
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- 1997-07-11 PE PE1997000611A patent/PE91198A1/es not_active Application Discontinuation
- 1997-07-11 AP APAP/P/1999/001434A patent/AP9901434A0/en unknown
- 1997-07-11 EP EP97930518A patent/EP0912570B1/en not_active Expired - Lifetime
- 1997-07-11 PL PL97331221A patent/PL331221A1/xx unknown
- 1997-07-11 AR ARP970103102A patent/AR007856A1/es unknown
- 1997-07-11 BR BR9710359A patent/BR9710359A/pt not_active Application Discontinuation
- 1997-07-11 CA CA002260061A patent/CA2260061A1/en not_active Abandoned
- 1997-07-11 WO PCT/EP1997/003674 patent/WO1998002438A1/en not_active Ceased
- 1997-07-11 US US09/214,270 patent/US6174889B1/en not_active Expired - Fee Related
- 1997-07-11 ID IDP972412A patent/ID19403A/id unknown
- 1997-07-11 AT AT97930518T patent/ATE249458T1/de not_active IP Right Cessation
- 1997-07-11 JP JP10505598A patent/JP2000514445A/ja not_active Ceased
- 1997-07-11 AU AU34439/97A patent/AU3443997A/en not_active Abandoned
- 1997-07-11 EP EP02080417A patent/EP1304110A3/en not_active Withdrawn
- 1997-07-11 IL IL12779697A patent/IL127796A0/xx unknown
- 1997-07-11 CN CN97197876A patent/CN1230187A/zh active Pending
- 1997-07-11 ES ES97930518T patent/ES2206729T3/es not_active Expired - Lifetime
- 1997-07-11 EA EA199900022A patent/EA199900022A1/ru unknown
- 1997-07-11 CZ CZ9989A patent/CZ8999A3/cs unknown
- 1997-07-11 YU YU1099A patent/YU1099A/sr unknown
- 1997-07-11 TR TR1999/00049T patent/TR199900049T2/xx unknown
- 1997-07-11 DE DE69724789T patent/DE69724789T2/de not_active Expired - Fee Related
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1998
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-
1999
- 1999-01-12 NO NO990124A patent/NO990124L/no not_active Application Discontinuation
- 1999-01-13 KR KR1019997000298A patent/KR20000023812A/ko not_active Withdrawn
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2000
- 2000-06-30 US US09/608,971 patent/US6723726B1/en not_active Expired - Fee Related
Also Published As
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|---|---|
| WO1998002438A1 (en) | 1998-01-22 |
| ES2206729T3 (es) | 2004-05-16 |
| EP1304110A3 (en) | 2003-12-17 |
| PL331221A1 (en) | 1999-07-05 |
| IL127796A0 (en) | 1999-10-28 |
| CN1230187A (zh) | 1999-09-29 |
| DE69724789D1 (de) | 2003-10-16 |
| EP0912570A1 (en) | 1999-05-06 |
| PE91198A1 (es) | 1999-01-15 |
| BR9710359A (pt) | 1999-08-17 |
| HRP970371A2 (en) | 1998-08-31 |
| US6174889B1 (en) | 2001-01-16 |
| YU1099A (en) | 1999-11-22 |
| US6723726B1 (en) | 2004-04-20 |
| CZ8999A3 (cs) | 1999-06-16 |
| NO990124D0 (no) | 1999-01-12 |
| JP2000514445A (ja) | 2000-10-31 |
| EP1304110A2 (en) | 2003-04-23 |
| AU3443997A (en) | 1998-02-09 |
| IS4939A (is) | 1998-12-31 |
| AP9901434A0 (en) | 1999-03-31 |
| EA199900022A1 (ru) | 1999-08-26 |
| NO990124L (no) | 1999-03-11 |
| ID19403A (id) | 1998-07-09 |
| AR007856A1 (es) | 1999-11-24 |
| ATE249458T1 (de) | 2003-09-15 |
| KR20000023812A (ko) | 2000-04-25 |
| EP0912570B1 (en) | 2003-09-10 |
| CA2260061A1 (en) | 1998-01-22 |
| TR199900049T2 (xx) | 1999-04-21 |
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