The synthesis and SAR of new 4-(N-alkyl-N-phenyl)amino-6,7-dimethoxyquinazolines and 4-(N-alkyl-N-phenyl)amino-pyrazolo[3,4-d]pyrimidines, inhibitors of CSF-1R tyrosine kinase activity

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 4, 1997, Pages 421-424

  Myers, Michael R ^a   Setzer, Natalie N ^a   Spada, Alfred P ^a   Persons, Paul E ^a   Ly, Cuong Q ^a   Maguire, Martin P ^a   Zulli, Allison L ^a   Cheney, Daniel L ^a   Zilberstein, Asher ^a   Johnson, Susan E ^a   Franks, Carol F ^a   Mitchell, Karen J ^a  

^a SANOFI   (France)

Author keywords

[No Author keywords available]

Indexed keywords

COLONY STIMULATING FACTOR RECEPTOR; ISOENZYME; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE KINASE INHIBITOR; PYRAZOLO[3,4 D]PYRIMIDINE DERIVATIVE; QUINAZOLINE DERIVATIVE; RPR 1085185A; UNCLASSIFIED DRUG;

ANIMAL TISSUE; ARTICLE; CELL STRAIN 3T3; CONTROLLED STUDY; DRUG SYNTHESIS; ENZYME INHIBITION; ENZYME SPECIFICITY; IN VITRO STUDY; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; STRUCTURE ACTIVITY RELATION;

EID: 0031576836     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)00035-8     Document Type: Article

References (14)

1. 1. Partially disclosed in Myers, M. R.; Spada, A. P.; Maguire, M. P.; Persons, P. E.; Zilberstein, A., Hsu, C.-Y.; Johnson, S., WO PCT 95/15758, publ. June 15, 1995.
2. 2. Sherr, C. J. Trends in Genetics 1991, 398. Sherr, C. J.; Borzillo, G. V.; Kato, J. -Y.; Shurtleff, S. A.; Downing, J. R.; Roussel, M. F. Seminars in Hematology 1991, 143. Vairo, G.; Hamilton, J. A. Immunology Today 1991, 362. Roth, P.; Stanley, E. R. Current Topics in Microbiology and Immunology 1992, 141.
3. Sherr, C. J. Trends in Genetics 1991, 398. Sherr, C. J.; Borzillo, G. V.; Kato, J. -Y.; Shurtleff, S. A.; Downing, J. R.; Roussel, M. F. Seminars in Hematology 1991, 143. Vairo, G.; Hamilton, J. A. Immunology Today 1991, 362. Roth, P.; Stanley, E. R. Current Topics in Microbiology and Immunology 1992, 141.
4. Sherr, C. J. Trends in Genetics 1991, 398. Sherr, C. J.; Borzillo, G. V.; Kato, J. -Y.; Shurtleff, S. A.; Downing, J. R.; Roussel, M. F. Seminars in Hematology 1991, 143. Vairo, G.; Hamilton, J. A. Immunology Today 1991, 362. Roth, P.; Stanley, E. R. Current Topics in Microbiology and Immunology 1992, 141.
5. Sherr, C. J. Trends in Genetics 1991, 398. Sherr, C. J.; Borzillo, G. V.; Kato, J. -Y.; Shurtleff, S. A.; Downing, J. R.; Roussel, M. F. Seminars in Hematology 1991, 143. Vairo, G.; Hamilton, J. A. Immunology Today 1991, 362. Roth, P.; Stanley, E. R. Current Topics in Microbiology and Immunology 1992, 141.
6. 3. See accompanying article in this journal and references 5 and 10 therein for more information regarding inhibitor N-1 interactions with the catalytic domain of other tyrosine kinases.
7. 50s were determined from a minimum of two separate determinations.
8. 5. A recent independent report describes the discovery of substituted 4-(2,3-dihydro-N-indolyl)-quinazolines including compound 4; Arnold, L. D., WO PCT 95/23141 publ. Aug. 31, 1995.
9. 6. Ab initio equilibrium geometries were obtained at the HF-6-31G** level for the eclipsed and extended conformations for 2 and 4. Single point energies were then calculated at the same level using a self-consistent reaction field model paramaterized for 1,2-dichloroethane. The results indicate a 1.9 kcal preference of 2 for the eclipsed conformation. Calculations were performed using the PS-GVB program, v2.3 (Ringnalda, M. N.; Langlois, J.-M.; Murphy, R. B.; Greeley, B. H.; Cortic, C.; Russo, T. V., Marten, B.; Donnelly Jr., R. E.; Pollard, T. W.; Cao, Y.; Muller, R. P.; Mainz, D. T.; Wright, J. R.; Miller, G. H.; Goddard III, W. A.; Freisner, R. A. Schrodinger, Inc. 1996).
10. 7 . Ife, R. J.: Brown, T. H.; Blurton, P.; Keeling, D. J.; Leach, C. A.; Meeson, M. L.; Parsons, M. E.; Theobald, C. J. J. Med. Chem. 1995, 38, 2763.
11. 1H NMR, MS, and CHN analysis.
12. 3 For some examples, reaction with the N-alkylaniline required longer reaction times (EtOH, reflux, up to 2 h). Difficult examples (such as 4 and 9) required heating the chloroquinazoline with excess N-alkylaniline neat at approx. 110 °C. In some cases the compounds were isolated as the free base via concentration of the reaction mixture followed by aqueous work-up and recrystallization (EtOH and/or EtOAc).
13. 10. The EGF-R activity of compound 13 has been reported previously in Rewcastle, G. W.; Denny, W. A.; Bridges, A. J.; Zhou, H.; Cody, D. R.; McMichael, A.; Fry, D. W. J. Med. Chem. 1995, 38, 3482-3487.
14. 11. Maguire, M.; Sheets, K. R.; McVety, K.; Spada, A. P.; Zilberstein, A. J. Med. Chem. 1994, 37, 2129.