Design and SAR of thienopyrimidine and thienopyridine inhibitors of

VEGFR-2 kinase activity

Michael J. Munchhof , , Jean S. Beebe, Jeffery M. Casavant, Beth A. Cooper, Jonathan L. Doty, R.
Carla Higdon, Stephen M. Hillerman, Catherine I. Soderstrom, Elisabeth A. Knauth, Matthew A. Marx,
Ann Marie K. Rossi, Susan B. Sobolov and Jianmin Sun

Pfizer Global Research and Development, Groton Laboratories MS8220-2405, Eastern

Point Road, Groton, CT 06340, USA

Received 19 August 2003;

revised 14 October 2003;
accepted 15 October 2003. ;
Available online 27 November 2003.

Abstract

Novel classes of thienopyrimidines and thienopyridines have been identified as potent

inhibitors of VEGFR-2 kinase. The synthesis and SAR of these compounds is presented,
along with successful efforts to diminish EGFR activity present in the lead series.

Graphical Abstract

Novel thienopyrimidines and thienopyridines have been identified as potent inhibitors of

VEGFR-2 kinase activity. The synthesis and SAR of these compounds is presented,
highlighting our successful effort to diminish the EGFR kinase activity in the lead series.
Synthesis of Substituted Thienopyrimidine-4-ones
Alexandre Ivachtchenko,*† Sergiy Kovalenko,‡ Olena V. Tkachenko,‡ and Oleksiy
Parkhomenko‡
Chemical Diversity Labs, Inc., 11558 Sorrento Valley Road, Suite 5, San Diego,
California 92121, and Institute of Combinatorial Organic Chemistry, Kharkiv, Ukraine
J. Comb. Chem., 2004, 6 (4), pp 573–583
DOI: 10.1021/cc049946l
Publication Date (Web): May 19, 2004
Copyright © 2004 American Chemical Society

Abstract

The parallel solution-phase synthesis of more than 3000 substituted thienopyrimidin-4-

ones has been accomplished. Key reactions include assembly of the 2-thioxopyrimidin-4-
one ring by condensation of isomeric aminothiophenecarboxylates or their appropriate
reactive derivatives (isothiocyanates or dithiocarbamates) with the corresponding
isothiocyanates or amines. The libraries from libraries were then obtained in good yields
and purities using solution-phase alkylation and acylation methodologies. Simple manual
techniques for parallel reactions using special CombiSyn synthesizers were coupled with
easy purification procedures (crystallization from the reaction mixtures) to give high-
purity final products. The scope and limitations of the developed approach are discussed.
Bioorg Med Chem Lett. 1999 Mar 22;9(6):797-802.

Cytotoxic effects of NSL-1406, a new thienopyrimidine

derivative, on leukocytes and osteoclasts.
Katada J, Iijima K, Muramatsu M, Takami M, Yasuda E, Hayashi M, Hattori M, Hayashi
Y.

Life Science Research Center, Advanced Technology Research Laboratories, Nippon

Steel Corporation, Kawasaki, Japan.

Abstract

We synthesized a series of thienopyrimidine derivatives and examined their cytotoxic

effects on several cell lines. One of the derivatives, NSL-1406, was shown to exert potent
cytotoxic effects on leukemia cell line including P388 cells and J774 cells. It was also
inhibitory on mouse osteoclasts and suppressed the in vitro bone resorption by osteoclasts
at nanomolar concentrations.

Synthesis, cytostatic and anti-HIV evaluations of the new unsaturated

acyclic C-5 pyrimidine nucleoside analogues

Tatjana Gazivodaa, Silvana Raić-Malića, Vedran Krištafora, Damjan Makucb, Janez

Plavecb, Siniša Bratulićc, Sandra Kraljević-Pavelićc, Krešimir Pavelićc, Lieve
Naesensd, Graciela Andreid, Robert Snoeckd, Jan Balzarinid and Mladen Mintasa, ,

a
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology,
University of Zagreb, Marulićev trg 19, HR-10000 Zagreb, Croatia
b
Slovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, POB 660, SL-
1001 Ljubljana, Slovenia
c
Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, POB 1016,
HR-10001 Zagreb, Croatia
d
Rega Institute for Medical Research, Katholieke Universiteit Leuven,
Minderbroedersstraat 10, B-3000 Leuven, Belgium

Received 8 January 2008;

revised 20 March 2008;
accepted 28 March 2008.
Available online 1 April 2008.
Abstract

A series of the novel C-5 alkynyl pyrimidine nucleoside analogues (1–14) in which the
sugar moiety was replaced by the conformationally restricted Z- and E-2-butenyl spacer
between the phthalimido and pyrimidine ring were synthesized by using Sonogashira
cross-coupling reaction. Cytostatic activity evaluation of the novel compounds showed
that E-isomers exhibited, in general, better cytostatic activities than the corresponding Z-
isomers. E-isomer 14 exhibited the best cytostatic effect against all evaluated malignant
cell lines, particularly against hepatocellular carcinoma (Hep G2, IC50 = 4.3 μM).
However, this compound was also cytotoxic to human normal fibroblasts (WI 38). Its Z-
isomer 7 showed highly specific antiproliferative activity against Hep G2 (IC50 = 18 μM)
and no cytotoxicity to WI 38. Moreover, compounds 3, 4 and 14 expressed some
marginal inhibitory activity against HIV-1 and HIV-2.

Graphical abstract

Keywords: Unsaturated acyclic pyrimidine nucleoside analogues; Z- and E-isomers;

Cytostatic evaluations; Anti-HIV activity