Patent EA-005032-B1 (EA)
Title: Pyrrole substituted 2-indolinone (variants), pharmaceutical composition (variants), method for modulation of catalytic activity method for treating and preventing a protein kinase related disorders in an organism
Inventor: TANG PENG CHO
IPC: A61P17/06
Filed: 1999-05-28
Abstract: 1. A pyrrole substituted 2-indolinone having the chemical structure: wherein: R<1>, R<2> and R<7> are hydrogen; R<3>, R<4>, R<5> and R<6> are independently selected from the group consisting of hydrogen, hydroxy, halogen, unsubstituted C1-C4 alkyl, substituted with carbonic acid, unsubstituted C1-C4 alkoxy, a group of carbonic acid, unsubstituted aryl, aryl, substituted with at least one group of unsubstituted C1-C4 alkyloxy, and morpholino R<8> is unsubstituted C1-C4 alkyl; R<9> is -(CH2)(CH2)C(O)OH and R<10> is unsubstituted C1-C4 alkyl; 2. 3-[2,4-dimethyl-5-(2-oxo-1,2-dihydroindole-3-ylidenemethyl)-1H-pyrrol-3-yl]-propionic acid of the formula 3. A pharmaceutical composition, comprising a compound of claim 1, salt or prodrug thereof and a physiologically acceptable carrier or excipient. 4. A method for the modulation of the catalytic activity of a protein kinase comprising contacting said protein kinase with a compound, salt or prodrug of claim 1. 5. The method of claim 13 wherein said protein kinase is selected from the group consisting of a receptor tyrosine kinase, a non-receptor tyrosine kinase and a serinethreonine kinase. 6. A pharmaceutical composition, comprising: a compound, salt or prodrug of claim 2; and, a physiologically acceptable carrier or excipient. 7. A method for treating or preventing a protein kinase related disorder in an organism comprising administering a therapeutically effective amount of a compound, salt or prodrug of claim 1 or 2 to said organism. 8. The method of claim 7 comprising administering therapeutically effective amount of 3-[2, 4-Dimethyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrol-3-yl]-propionic acid to said organism. 9. The method of claim 7 wherein said protein kinase related disorder is selected from the group consisting of a receptor tyrosine kinase related disorder, a non-receptor tyrosine kinase related disorder and a serine-threonine kinase related disorder. 10. The method of claim 7 wherein said protein kinase related disorder is selected from the group consisting of an EGFR related disorder, a PDGFR related disorder, an IGFR related disorder and a flk related disorder. 11. The method of claim 7 wherein said protein kinase related disorder is a cancer selected from the group consisting of squamous cell carcinoma, astrocytoma, Kapos's sarcoma, glioblastoma, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, glioma, colorectal cancer, genitourinary cancer and gastrointestinal cancer. 12. The method of claim 7 wherein said protein kinase related disorder is selected from the group consisting of diabetes, an autoimmune disorder, a hyperproliferation disorder, restenosis, fibrosis, psoriasis, osteoarthritis, rheumatoid arthritis, angiogenesis, an inflammatory disorder, an immunological disorder and a cardiovascular disorder. 13. The method of claim 16 wherein said organism is a human. 14. A compound from the group consisting of: 3-[5-(5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid, 3-[2,4-Dimethyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrol-3-yl]-propionic acid, 3-[5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid, 3-[5-(5-Iodo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid, 3-[2,4-Dimethyl-5-(4-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrol-3-yl]-propionic acid, 3-[2,4-Dimethyl-5-(5-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrol-3-yl]-propionic acid, 3-[5-(6-Hydroxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrol-3-yl]-propionic acid, 3-[5-(6-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrol-3-yl]-propionic acid, 3-{5-[6-(3-Methoxy-phenyl)-2-oxo-1,2-dihydroindol-3ylindenementhyl]-2,4-dimethyl-1H-pyrrol-3-yl}-propionic acid, 3-{5-[6-(3-Ethoxy-phenyl)-2-oxo-1,2-dihydroindol-3ylindenementhyl]-2,4-dimethyl-1H-pyrrol-3-yl}-propionic acid, 3-[2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrol-3-yl]-propionic acid, 3-{5-[6-(4-Methoxy-phenyl)-2-oxo-1,2-dihydroindol-3ylindenementhyl]-2,4-dimethyl-1H-pyrrol-3-yl}-propionic acid, 3-{5-[6-(2-Methoxy-phenyl)-2-oxo-1,2-dihydroindol-3ylindenementhyl]-2,4-dimethyl-1H-pyrrol-3-yl}-propionic acid, 3-[2,4-Dimethyl-5-(6-morpholin-4-yl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrol-3-yl]-propionic acid, 3-[5-Chloro-4-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrol-3-yl]-propionic acid.