Synthesis and in vitro EGFR (ErbB1) tyrosine kinase inhibitory activity of 4-N-substituted 6-aryl-7H-pyrrolo[2,3-d]pyrimidine-4-amines

European Journal of Medicinal Chemistry

Volumn 46, Issue 12, 2011, Pages 6002-6014

  Kaspersen, Svein Jacob ^a   Sørum, Christopher ^a,b   Willassen, Veronica ^a   Fuglseth, Erik ^a   Kjøbli, Eli ^a   Bjørkøy, Geir ^a   Sundby, Eirik ^a   Hoff, Brd Helge ^a  

^a NORWEGIAN UNIVERSITY OF SCIENCE AND TECHNOLOGY   (Norway)

^b Weifa AS   (Norway)

Author keywords

4 Chloropyrolopyrimidines; Cancer; ErbB1; Pyrroles; Pyrrolopyrimidine; Tyrosine kinase

Indexed keywords

4 [4 (BENZYLAMINO) 7H PYRROLO[2,3 D]PYRIMIDIN 6 YL]PHENOL HYDROBROMIDE; 4 [4 [(1 PHENYLETHYL)AMINO] 7H PYRROLO[2,3 D]PYRIMIDIN 6 YL]PHENOL HYDROBROMIDE; 4 [4 [(1 PHENYLPROPYL)AMINO] 7H PYRROLO[2,3 D]PYRIMIDIN 6 YL]PHENOL HYDROBROMIDE; 4 [4 [(2 FLUOROBENZYL)AMINO] 7H PYRROLO[2,3 D]PYRIMIDIN 6 YL]PHENOL HYDROBROMIDE; 4 [4 [(3 FLUOROBENZYL)AMINO] 7H PYRROLO[2,3 D]PYRIMIDIN 6 YL]PHENOL HYDROBROMIDE; 4 [4 [(4 FLUOROBENZYL)AMINO] 7H PYRROLO[2,3 D]PYRIMIDIN 6 YL]PHENOL HYDROBROMIDE; 4 [4 [[1 (2 FLUOROPHENYL)ETHYL]AMINO] 7H PYRROLO[2,3 D]PYRIMIDIN 6 YL]PHENOL HYDROBROMIDE; 4 [4 [[1 (2 TOLYL)ETHYL]AMINO] 7H PYRROLO[2,3 D]PYRIMIDIN 6 YL]PHENOL HYDROBROMIDE; 4 [4 [[1 (3 FLUORPHENYL)ETHYL]AMINO] 7H PYRROLO[2,3 D]PYRIMIDIN 6 YL]PHENOL HYDROBROMIDE; 4 [4 [[1 (4 BROMOPHENYL)ETHYL]AMINO] 7H PYRROLO[2,3 D]PYRIMIDIN 6 YL]PHENOL HYDROBROMIDE; 4 [4 [[1 (4 FLUOROPHENYL)ETHYL]AMINO] 7H PYRROLO[2,3 D]PYRIMIDIN 6 YL]BENZONITRILE; 4 [4 [[1 (4 TOLYL)ETHYL]AMINO] 7H PYRROLO[2,3 D]PYRIMIDIN 6 YL]PHENOL HYDROBROMIDE; 4 [4 [[1 [4 (TRIFLUOROMETHYL)PHENYL]ETHYL]AMINO] 7H PYRROLO[2,3 D]PYRIMIDIN 6 YL]PHENOL HYDROBROMIDE; 6 (4 BROMOPHENYL) N (1 PHENYLETHYL) 7H PYRROLO[2,3 D]PYRIMIDIN 4 AMINE; 6 (4 BROMOPHENYL) N [1 (4 FLUOROPHENYL)ETHYL] 7H PYRROLO[2,3 D]PYRIMIDIN 4 AMINE; 6 (4 FLUOROPHENYL) N (1 PHENYLETHYL) 7H PYRROLO[2,3 D]PYRIMIDIN 4 AMINE; 6 (4 FLUOROPHENYL) N [1 (4 FLUOROPHENYL)ETHYL] 7H PYRROLO[2,3 D]PYRIMIDIN 4 AMINE; 6 (4 METHOXYPHENYL) N (1 PHENYLPROPYL) 7H PYRROLO[2,3 D]PYRIMIDIN 4 AMINE; 6 (4 METHOXYPHENYL) N [1 (NAPHTHALEN 1 YL)ETHYL] 7H PYRROLO[2,3 D]PYRIMIDIN 4 AMINE; 6 PHENYL N (1 PHENYLETHYL) 7H PYRROLO[2,3 D]PYRIMIDIN 4 AMINE; [4 [[1 (1 TOLYL)ETHYL]AMINO] 7H PYRROLO[2,3 D]PYRIMIDIN 6 YL]PHENOL HYDROBROMIDE; BENZYL DERIVATIVE; EPIDERMAL GROWTH FACTOR RECEPTOR; N [1 (4 FLUOROPHENYL)ETHYL] 6 PHENYL 7H PYRROLO[2,3 D]PYRIMIDIN 4 AMINE; N BENZYL 6 (4 METHOXYPHENYL) 7H PYRROLO[2,3 D]PYRIMIDIN 4 AMINE; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE KINASE INHIBITOR; PYRROLE DERIVATIVE; PYRROLOPYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

AEROBIC METABOLISM; AMINATION; ARTICLE; ATOM; CATALYSIS; CELL MEMBRANE; CHEMICAL STRUCTURE; CONCENTRATION RESPONSE; CONFOCAL MICROSCOPY; CONTROLLED STUDY; DEMETHYLATION; DRUG MECHANISM; DRUG POTENCY; ENDOCYTOSIS; ENZYME ACTIVITY; ENZYME INHIBITION; HELA CELL; HUMAN; HUMAN CELL; IC 50; IMMUNOHISTOCHEMISTRY; IN VITRO STUDY; INTERNALIZATION; REACTION TIME; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION; THERMAL EXPOSURE;

ANTINEOPLASTIC AGENTS; HELA CELLS; HUMANS; MODELS, MOLECULAR; NEOPLASMS; PROTEIN KINASE INHIBITORS; PYRIMIDINES; PYRROLES; RECEPTOR, EPIDERMAL GROWTH FACTOR; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 80955151786     PISSN: 02235234     EISSN: 17683254     Source Type: Journal    
DOI: 10.1016/j.ejmech.2011.10.012     Document Type: Article

References (52)

1. D. Mukherji, and J. Spicer Second-generation epidermal growth factor tyrosine kinase inhibitors in non-small cell lung cancer Expert Opin. Invest. Drugs 18 2009 293 301
2. P.S. Sharma, R. Sharma, and T. Tyagi Receptor tyrosine kinase inhibitors as potent weapons in war against cancers Curr. Pharm. Des. 15 2009 758 776
3. R. Bose, and X. Zhang The ErbB kinase domain: structural perspectives into kinase activation and inhibition Exp. Cell Res. 315 2009 649 658
4. V.L. Keedy, and A.B. Sandler Inhibition of angiogenesis in the treatment of non-small cell lung cancer Cancer Sci. 98 2007 1825 1830 (Pubitemid 350002185)
5. M.W. Pedersen, and H.S. Poulsen Epidermal growth factor receptor in cancer therapy Sci. Med. (Narberth, PA, U. S.) 8 2002 206 217
6. B.R. Voldborg, L. Damstrup, M. Spang-Thomsen, and H.S. Poulsen Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials Ann. Oncol. 8 1997 1197 1206 (Pubitemid 28164074)
7. P. Traxler Tyrosine kinases as targets in cancer therapy - successes and failures Expert Opin. Ther. Targets 7 2003 215 234 (Pubitemid 36512022)
8. I.H. Madshus, and E. Stang Internalization and intracellular sorting of the EGF receptor: a model for understanding the mechanisms of receptor trafficking J. Cell Sci. 122 2009 3433 3439
9. P. Traxler, G. Bold, W.K.-D. Brill, J. Frei, Pyrrolopyrimidines and Processes for the Preparation Thereof WO 9702266, 1996.
10. G. Caravatti New 7H-Pyrrolo[2,3-d]Pyrimidines Inhibiting ErbB and VEGF Receptor Tyrosine Kinases 2004 Abstracts, 36th Central Regional Meeting of the American Chemical Society, Indianapolis, IN, United States
11. M. Croyle, N. Akeno, J.A. Knauf, D. Fabbro, X. Chen, J.E. Baumgartner, H.A. Lane, and J.A. Fagin RET/PTC-induced cell growth is mediated in part by epidermal growth factor receptor (EGFR) activation: evidence for molecular and Functional Interactions between RET and EGFR Cancer Res. 68 2008 4183 4191
12. P. Traxler, P.R. Allegrini, R. Brandt, J. Brueggen, R. Cozens, D. Fabbro, K. Grosios, H.A. Lane, P. McSheehy, J. Mestan, T. Meyer, C. Tang, M. Wartmann, J. Wood, and G. Caravatti AEE788: a dual family epidermal growth factor Receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity Cancer Res. 64 2004 4931 4941 (Pubitemid 38924540)
13. Y.W. Park, M.N. Younes, S.A. Jasser, O.G. Yigitbasi, G. Zhou, C.D. Bucana, B.N. Bekele, and J.N. Myers AEE788, a dual tyrosine kinase receptor inhibitor, induces endothelial cell apoptosis in human cutaneous squamous cell carcinoma xenografts in nude mice Clin. Cancer Res. 11 2005 1963 1973 (Pubitemid 40471862)
14. T. Schneider-Merck, and M. Trepel Lapatinib, recent results Cancer Res. 184 2010 45 59
15. P. Traxler, G. Bold, E. Buchdunger, G. Caravatti, P. Furet, P. Manley, T. O'Reilly, J. Wood, and J. Zimmermann Tyrosine kinase inhibitors: from rational design to clinical trials Med. Res. Rev. 21 2001 499 512 (Pubitemid 32959239)
16. R. Hoekstra, H. Dumez, A.L.M. Eskens Ferry, G.A. van der, S.T. Planting Andre, H.G. de, K.C. Sizer, C. Ravera, S. Vaidyanathan, C. Bucana, I.J. Fidler, A.T. van Oosterom, and J. Verweij. Phase I and pharmacologic study of PKI166, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies Clin. Cancer Res. 11 2005 6908 6915 (Pubitemid 41428748)
17. T. Takada, H.M. Weiss, O. Kretz, G. Gross, and Y. Sugiyama Hepatic transport of PKI166, an epidermal growth factor receptor kinase inhibitor of the pyrrolo-pyrimidine class, and its main metabolite, ACU154 Drug Metab. Dispos 32 2004 1272 1278 (Pubitemid 39410912)
18. K. Mensa-Wilmot, Tyrosine Kinase Inhibitors as Anti-kinetolastid and Anti-Apicomplexan Protozoal Agents WO 2008066755, 2007.
19. M. Parsons, J.A. Ledbetter, G.L. Schieven, Inhibitors of Tyrosine Phosphorylation in Protozoa as Drugs EP 507256, 1992.
20. F.J. Gamo, L.M. Sanz, J. Vidal, C. de Cozar, E. Alvarez, J.L. Lavandera, D.E. Vanderwall, D.V.S. Green, V. Kumar, S. Hasan, J.R. Brown, C.E. Peishoff, L.R. Cardon, and J.F. Garcia-Bustos Thousands of chemical starting points for antimalarial lead identification Nature 465 2010 305 310
21. N. Tapinos, M. Ohnishi, and A. Rambukkana ErbB2 receptor tyrosine kinase signaling mediates early demyelination induced by leprosy bacilli Nat. Med. 12 2006 961 966 (Pubitemid 44175150)
22. J.M. Franklin Robin, and C. Zhao Tyrosine kinases: maiming myelin in leprosy Nat. Med. 12 2006 889 890 (Pubitemid 44175138)
23. D.J. Collins A synthesis, and certain properties, of ethyl 2-amino-5-nitronicotinate J. Chem. Soc. 1963 1337 1339
24. T. Kobayashi, T. Inoue, Z. Kita, H. Yoshiya, S. Nishino, K. Oizumi, and T. Kimura Novel 2-amino-1,4-dihydropyridine calcium antagonists. I. Synthesis and antihypertensive effects of 2-amino-1,4-dihydropyridine derivatives having nitroxyalkoxycarbonyl groups at 3- and/or 5-position Chem. Pharm. Bull. 43 1995 788 796
25. E. Toja, A. DePaoli, G. Tuan, and J. Kettenring Synthesis of 2-amino-3-(ethoxycarbonyl)pyrroles Synthesis 1987 272 274
26. V. Pittala, G. Romeo, L. Salerno, M.A. Siracusa, M. Modica, L. Materia, I. Mereghetti, A. Cagnotto, T. Mennini, G. Marucci, P. Angeli, and F. Russo 3-Arylpiperazinylethyl-1H-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione derivatives as novel, high-affinity and selective alpha 1-adrenoceptor ligands Bioorg. Med. Chem. Lett. 16 2006 150 153 (Pubitemid 41630624)
27. X. Cai, C. Qian, S. Gould, Fused Bicyclic Pyrimidines as PTK Inhibitors Containing a Zinc Binding Moiety WO 2008033745, 2007.
28. P. Traxler, P. Furet, W.K.D. Brill, Pyrrolopyrimidinderivate mit antiproliferativer wirkung EP 682027, 1995.
29. B.P. Fors, P. Krattiger, E. Strieter, and S.L. Buchwald Water-mediated catalyst preactivation: an efficient protocol for C-N Cross-coupling reactions Org. Lett. 10 2008 3505 3508
30. K.W. Anderson, T. Ikawa, R.E. Tundel, and S.L. Buchwald The selective reaction of aryl halides with KOH: synthesis of phenols, aromatic ethers, and benzofurans J. Am. Chem. Soc. 128 2006 10694 10695 (Pubitemid 44277754)
31. D.S. Surry, and S.L. Buchwald Dialkylbiaryl phosphines in Pd-catalyzed amination: a user's guide Chem. Sci. 2 2011 27 50
32. E. Paliakov, and L. Strekowski Boron tribromide mediated debenzylation of benzylamino and benzyloxy groups Tetrahedron Lett. 45 2004 4093 4095 (Pubitemid 38581820)
33. G. Caravatti, J. Bruggen, E. Buchdunger, R. Cozens, P. Furet, N. Lydon, T. O'Reilly, and P. Traxler Pyrrolo[2,3-d]pyrimidine and pyrazolo[3,4-d] pyrimidine derivatives as selective inhibitors of the EGF receptor tyrosine kinase ACS Symposium Series 796 2001 231 244
34. R.A. Wolfe, R. Wu, and G.H. Sato Epidermal growth factor-induced down-regulation of receptor does not occur in HeLa cells grown in defined medium Proc. Natl. Acad. Sci. U. S. A. 77 1980 2735 2739 (Pubitemid 10057910)
35. B.K. Park, N.R. Kitteringham, and P.M. O'Neill Metabolism of fluorine-containing drugs Annu. Rev. Pharmacol. Toxicol. 41 2001 443 470 (Pubitemid 32385895)
36. H. Böhm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K. Muller, U. Obst-Sander, and M. Stahl Fluorine in medicinal chemistry ChemBioChem 5 2004 637 643 (Pubitemid 39257085)
37. Y.J. Wu, C.D. Davis, S. Dworetzky, W.C. Fitzpatrick, D. Harden, H. He, R.J. Knox, A.E. Newton, T. Philip, C. Polson, D.V. Sivarao, L.Q. Sun, S. Tertyshnikova, D. Weaver, S. Yeola, M. Zoeckler, and M.W. Sinz Fluorine substitution can block CYP3A4 metabolism-dependent inhibition: identification of (S)-N-[1-(4-Fluoro-3-morpholin-4-ylphenyl)ethyl]-3-(4-fluorophenyl)acrylamide as an orally bioavailable KCNQ2 opener devoid of CYP3A4 metabolism-dependent inhibition J. Med. Chem. 46 2003 3778 3781 (Pubitemid 37034130)
38. C.H. Yun, T.J. Boggon, Y. Li, M.S. Woo, H. Greulich, M. Meyerson, and M.J. Eck Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity Cancer Cell 11 2007 217 227 (Pubitemid 46349842)
39. 6 Magn. Reson. Chem. 48 2010 244 248
40. A.J. Trott, and O. Olson AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading J. Comput. Chem. 31 2010 455 461
41. M.F. Sanner Python: a programming language for software integration and development J. Mol. Graphics Modell. 17 1999 57 61 (Pubitemid 30029318)
42. B.A. Pollok, B.D. Hamman, S.M. Rodems, L.R. Makings, Optical Probes and Assays WO 2000066766, 2000.
43. C. Soerum, N. Simic, E. Sundby, and B.H. Hoff Magn. Reson. Chem. 48 2010 244 248
44. M.T. Cocco, C. Congiu, A. Maccioni, A. Plumitallo, M.L. Schivo, and G. Palmieri Synthesis and biological activity of some pyrrole derivatives. I Farmaco, Ed. Sci. 43 1988 103 112
45. R.M. Grotzfeld, H.K. Patel, S.A. Mehta, Z.V. Milanov, A.G. Lai, D.J. Lockhart, Pyrrolopyrimidine Derivatives and Analogs and Their Use in the Treatment and Prevention of Diseases US 2005153989, 2005.
46. G. Bold, H.G. Capraro, G. Caravatti, P. Traxler, Preparation of 7H-pyrrolo[2,3-d]pyrimidines as Protein Tyrosine Kinase Inhibitors US 2004248911, 2004.
47. G. Bold, P.W. Manley, A. Martin-Kohler, U. Sequin, Oxazolo-and Fuoropyrimidines Asn Their Use in Medicaments Against Tumors WO 2002092603, 2002.
48. B. Miriyala, S. Bhattacharyya, and J.S. Williamson Chemoselective reductive alkylation of ammonia with carbonyl compounds: synthesis of primary and symmetrical secondary amines Tetrahedron 60 2004 1463 1471 (Pubitemid 38147775)
49. G. Jones Synthesis of some dimethyl- and ethylisoquinolines J. Chem. Soc. 1960 1918 1923
50. G. Hou, F. Gosselin, W. Li, J.C. McWilliams, Y. Sun, M. Weisel, P.D. O'Shea, C. y. Chen, I.W. Davies, and X. Zhang Enantioselective hydrogenation of N-H imines J. Am. Chem. Soc. 131 2009 9882 9883
51. X. Cai, C. Qian, S. Gould, H. Zhai, Multi-functional Small Molecules as Anti-proliferative Agents WO 2008033747, 2007.
52. D.J. Resta, K.C. Sizer, P. Traxler, Use of Organic Compounds US 20030139430, 2003.