Phenylamino-pyrimidine (PAP) - Derivatives: A new class of potent and highly selective PDGF-Receptor autophosphorylation inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 11, 1996, Pages 1221-1226

  Zimmermann, Jürg ^a   Buchdunger, Elisabeth ^a   Mett, Helmut ^a   Meyer, Thomas ^a   Lydon, Nicholas B ^a   Traxler, Peter ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ANILINE DERIVATIVE; PLATELET DERIVED GROWTH FACTOR; PLATELET DERIVED GROWTH FACTOR RECEPTOR; PROTEIN SERINE THREONINE KINASE; PROTEIN TYROSINE KINASE; PYRIMIDINE DERIVATIVE;

ARTICLE; ATHEROSCLEROSIS; AUTOPHOSPHORYLATION; CANCER; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SYNTHESIS; FIBROSIS; RECEPTOR AFFINITY;

EID: 0029951570     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/0960-894X(96)00197-7     Document Type: Article

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27. 33 (119.8 g, 0.68 mol) in isopropanol (700 ml) was added 3-nitro-phenyl-guanidine nitrate (165.4 g, 0.68 mol), suspended in isopropanol (300 ml). Following the addition of sodium hydroxide (30.0 g, 0.75 mol), the reaction mixture is stirred for 8 hours at reflux. After cooling to room temperature, the suspension is filtrated and the product washed with isopropanol (200 ml). The residue is suspended in water (300 ml), stirred at rt for 30 min, filtrated and washed with ethanol and ether to give 82.4 g ( 41.3%) of N-(3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidinamine as a solid. A suspension thereof (17.0 g, 0.058 mol) and palladium ( 5% on charcoal, 1.7 g) in tetrahydrofurane (1700 ml) was stirred under a hydrogen athmosphere (1 bar) for 21 h at rt. Filtration, evaporation and crystallisation (methylenchloride) gave N-(3-amino-phenyl)-4-(3-pyridyl)-2-pyrimidinamine (9.3 g, 60.9 %). A solution of this amine (9.3 g, 35.3 mMol) and benzoylchloride (7.57 g, 53.9 mmol) in pyridine (300 ml) was stirred at rt for 23 h. Evaporation and crystallisation (dimethylformamide, water) gave 2.37 g ( 18.3 %) of 1 as a yellowish solid.
28. Inhibition of PDGF-stimulated total cellular tyrosine phosphorylation in BALB / c 3T3 cells was measured using a microtiter ELISA assay according to Trinks, U.; Buchdunger, E.; Furet, P.; Kump, W.; Mett, H.; Meyer, T.; Mueller, M.; Regenass, U.; Rihs, G.; Lydon, N. ; Traxler, P. J. Med. Chem. 1994, 37, 1015-1027. Purification of protein kinases and in vitro enzyme tests are described in Andrejauskas-Buchdunger, E. ; Regenass, U. Cancer Res. 1992, 52, 5353-5358.
29. Inhibition of PDGF-stimulated total cellular tyrosine phosphorylation in BALB / c 3T3 cells was measured using a microtiter ELISA assay according to Trinks, U.; Buchdunger, E.; Furet, P.; Kump, W.; Mett, H.; Meyer, T.; Mueller, M.; Regenass, U.; Rihs, G.; Lydon, N. ; Traxler, P. J. Med. Chem. 1994, 37, 1015-1027. Purification of protein kinases and in vitro enzyme tests are described in Andrejauskas-Buchdunger, E. ; Regenass, U. Cancer Res. 1992, 52, 5353-5358.
30. Kinetic analysis of a very similar PAP-derivative shows an ATP-competitive inhibition of PKC (manuscript Archiv der Pharmazie, in preparation).
31. X-ray analysis of compound 4 shows the conformation depicted in the scheme.
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