Dihydropyrrolo[1,2-b]pyrazoles:

Synthesis of new derivatives and their biological evaluation

Lukáš Tenora^1,3, Juraj Galeta^1,3, Vladimír Kryštof^2, Radim Nencka^3 Pavel Majer^3, Andrej
Jančařík^3 and Milan Potáček^1


^1Department of Chemistry, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech
Republic ^2Laboratory of Growth Regulators, Palacký University, Šlechtitelů 11, 783 71 Olomouc,
Czech Republic

^3Institute of Organic Chemistry and Biochemistry AS CR v.v.i., Flemingovo nám. 2, 166 10, Praha 6,
Czech Republic

175258@mail.muni.cz, potacek@chemi.muni.cz

      During the last two decades, compounds with dihydropyrrolo[1,2-b]pyrazole (DPP) core showed
promising biological activity. Sawyer published series of papers dealing with this field of organic
chemistry.^[1-5] These DPP derivatives are inhibitors of transforming growth factor b type I (also
known as ALK5) of kinase receptor domain. TGF-b plays an important role in many pathological states
including inflammation, fibrosis, cancer, asthma and cardiovascular diseases.^[6-11]

      In my talk I will present our recent work aimed at synthesis of some analogues of these
compounds with DPP core bearing 2-pyridyl, 2-(6-methylpyridyl), 2-(6-ethylpyridyl), 4-pyridyl,
4-quinolinyl, 2-cyanophenyl or 2-cyano-3-methylphenyl moiety at position 2. Homoallenyl aldehyde
(with H, alkyl or amine substitution at position 3), synthesized according to our improved
procedure,^[12] is a key intermediate for the creation of DPP core. Various palladium catalyzed
coupling reactions (Suzuki, Sonogashira, Heck, direct arylation and C-H activation) are shown in
the following schemes. Conditions for substitution of position 4 were discovered and they will be
discuss as well. Based on some docking studies a series of compounds were selected for biological
screening. In few cases, these tests shown a selective activity as inhibitors of ALK5 kinase (the
best compound around 100 nM) and for some other derivatives lower activity in inhibition of CDK2/E
was also observed. Biological testing of some recently prepared compounds is ongoing and it will be
also discuss in my talk.


Scheme 1.


References:


[1]    J. S. Sawyer et al. Bioorg. Med. Chem. Lett. 14 (2004) 3581-3584.

[2]    H.-Y. Li et al. Bioorg. Med. Chem. Lett. 14, (2004) 3585-3588.

[3]    H.-Y. Li et al. J. Med. Chem. 49, (2006) 2138-2142.

[4]    H.-Y. Li et al. Tetrahedron 63, (2007) 11763-11770.

[5]    H.-Y. Li et al. J. Med. Chem. 51 (2008) 2302-2306.

[6]    Nakamura, T. et al. Kidney Int. 41, (1992) 1213-1221.

[7]    Derynck, R. et al. Nature Genet. 29, (2001) 117-129.

[8]    Ray, S. et al. J. Gastroent. Hepatol. 18, (2003) 393-403.

[9]    McCaffrey, T. A. Cytokine Growth Factor Rev. 11, (2000) 103-114.

[10]  Chamberlain, J. Cardiovasc. Drug Rev. 19, (2001) 329-344.

[11]  Duvernelle, C. Pul. Pharmacol. Ther. 16, (2003) 181-196.

[12]  Zachová, H. et al. Eur. J. Org. Chem. 12, (2005) 2548-2557.