Pyrrolo[3,4-c]- and thieno- [3,4-c]isoquinolines — new heterocyclic hits for the drag design of oncolytic compounds

1Bogdan, NM
2Bogza, SL
Pendiukh, VV
Stepanova, DS
1Sujkov, SYu.
1Institute of Organic Chemistry of the NAS of Ukraine, Kyiv
2L. M. Litvinenko Institute of Physical-Organic and Coal Chemistry of the NAS of Ukraine, Kyiv
Dopov. Nac. akad. nauk Ukr. 2020, 7:62-71
https://doi.org/10.15407/dopovidi2020.07.062
Section: Chemistry
Language: Ukrainian
Abstract: 

The synthesis and cyclization reactions of 3-amino-4-arylpyrroles and 3-amino-4-arylthiophenes with aromatic and heterocyclic aldehydes under the conditions of the Pictet—Spengler reaction are investigated. The course of the reaction of 2-formyl-2-(3,4-dimethoxyphenyl)-acetonitrile with aminomalonic ester was analyzed and the effect of the reaction conditions on the output of intermediate enamine was studied by NMR to inves tigate its E/Z isomerism in solution. A simple method for the preparation of methyl 1H-3-amino-4-(3,4-dimethoxyphenyl)- pyrrole carboxylate was developed. Optimization of the cyclization reaction of 3-amino-4- arylpyrrole with benzaldehydes in the Pictet—Spengler conditions was carried out. The dependence of the output of the cyclization products of aminopyrroles on the substrate — catalyst ratio is shown. The pyrrolo [3,4-c] isoquinoline derivatives were obtained. A preparative method for the synthesis of diethyl 2-{[(E, Z)-2-cyano-2- (3,4-dimethoxyphenyl)ethen-1-yl]oxy}-propanedioate was developed, and the possibilities of its cyclization to 3-amino-4-(3,4-dimethoxyphenyl)-furan were investigated. The interaction of methyl 3-amino-4-(3,4-dimetho xyphenyl)-2-carboxylate with functionalized benzaldehydes and heterocyclic aldehydes was studied. Thieno[3,4-c]iso quinoline derivatives with functionalized aryl and heterocyclic substituents in the position 5 were synthesized with good yields. When interacting with ninghydrin, the spiroderivative thieno[3,4-c] isoquinoline — 1,3-dihydro-4′ H-spiroinden-2,5′ - thieno[3,4-c]isoquinoline-1,3-dione was obtained. Synthesized compounds and their derivatives can be promising as building blocks for the molecular design of new biologically active substances.

Keywords: 3-aminopyrrole, 3-aminothiophene, cyclization, isoquinoline, Pictet—Spengler reaction
References: 

1. Bogza, S. L., Kobrakov, K. I., Malienko, A. A., Perepichka, I. F., Sujkov, S. Yu., Bryce, M. R., Lyubchik, S. B., Batsanov, A. S. & Bogdan, N. M. (2005). A versatile synthesis of pyrasolo[3,4-c] isoquinoline derivatives by reaction of 4-aryl-5-amino-pyrazoles with aryl/heteroaryl aldehydes: the effect of heterocycle on the reaction pathways. Org. Biomol. Chem., 3, No. 5, pp. 932-940. https://doi.org/10.1039/B417002D
2. Drug Data Report. (2007). Oncolytic drugs. № 29. 644 p.
3. Pat. 7872014 US, IPC C07D471/02, A61K31/4745, A61K, A61K31/437, C07D471/04, A61P29/00. Anaplastic lymphoma kinase modulators and methods of use. Anand, N. K., Blazey, C. M., Bowles, O. J., Bussenius, J., Costanzo, S., Curtis, J. K., Dubenko, L., Kennedy, A. R., Khoury, R. G., Kim, A. I., Manalo, J. L., Peto, C. J., Rice, K. D. & Tsang, T. H., Publ. 18.01.2011.
4. Kondratov, R. V., Komarov, P. G., Becker, Y., Ewenson, A. & Gudkov, A. V. (2001). Small molecules that dramatically alter multidrug resistance phenotype by modulating the substrate specificity of P-glycoprotein. Proc. Natl. Acad. Sci. USA., 98, Iss. 24, pp. 14078-14083. https://doi.org/10.1073/pnas.241314798
5. Rochais, C., Lisowski, V., Dallemagne, P. & Rault, S. (2004). First synthesis of methyl 3-amino-4-(het)aryl- 1H-pyrrole-2-carboxylates as useful scaffolds in medicinal chemistry. Tetrahedron, 60, No. 10, pp. 2267-2270. https://doi.org/10.1016/j.tet.2004.01.019
6. Lisowski, V., Léonce, S., Kraus-Berthier, L., Sopková-de Oliveira Santos, Ja., Pierré, A., Atassi, G., Caignard, D., Renard, P. & Rault, S. (2004). Design, synthesis, and evaluation of novel thienopyrrolizinones as antitubulin agents. J. Med. Chem., 47, No. 6, pp. 1448-1464. https://doi.org/10.1021/jm030961z
7. Gupton, J. T., Crawford, E., Mahoney, M., Clark, E., Curry, W., Lane, A., Shimozono, A., Moore-Stoll, V., Elofson, K., Juekun, W., Newton, M., Yeudall, S., Jaekle, E., Kanters, R. & Sikorski, Ja. (2018). Application of vinylogous carbamates and vinylogous aminonitriles to the regiospecific synthesis of uniquely functionalized pyrroles and quinolones. Tetrahedron, 74, Iss. 52, pp. 7408-7420. https://doi.org/10.1016/j.tet.2018.10.078
8. Lauria, A., Diana, P., Barraja, P., Montalbano, A., Cirrincione, G., Dattolo, G. & Almerico, A. (2002). New tricyclic systems of biological interest. Annelated 1,2,3-triazolo[1,5-a]pyrimidines through domino reaction of 3-azidopyrroles and methylene active nitriles. Tetrahedron, 58, Iss. 48, pp. 9723-9727. https://doi.org/10.1016/S0040-4020(02)01245-0
9. Pittalà, V., Siracusa, M., Modica, M., Salerno, L., Pedretti, A., Vistoli, G., Cagnotto, A., Mennini, T. & Romeo G. (2011). Synthesis and molecular modeling of 1H-pyrrolopyrimidine-2,4-dione derivatives as ligands for the α1-adrenoceptors. Bioorg. Med. Chem., 19, Iss. 17, pp. 5260-5276. https://doi.org/10.1016/j.bmc.2011.06.043
10. Elliott, A. J., Montgomery, J. A. & Walsh, D. A. (1996). A short, facile synthesis of 2-amino-1,5-dihydro-4Hpyrrolo[3,2-d]-pyrimidin-4-one (9-deazaguanine). Tetrahedron Lett., 37, Iss. 25, pp. 4339-4340. https://doi.org/10.1016/0040-4039(96)00840-4
11. Kamath, V. P., Juarez-Brambila, J. J., Morris, C. B., Winslow, C. D. & Morris, P. E., Jr. (2009). Development of a practical synthesis of a purine nucleoside phosphorylase inhibitor: BCX-4208. Org. Process Res. Dev., 13, No. 5, pp. 928-932. https://doi.org/10.1021/op9001142
12. Lisowski, V., Vu, D. N., Feng, X. & Rault S. (2002). Synthesis of new ethyl 3-amino-4-arylfuran-2-carboxylates. Synthesis, No. 6, pp. 753-756. https://doi.org/10.1002/chin.200237110
13. Jourdan, F., Laduree, D. & Robba, M. (1994). Synthesis of thieno[3,2-d]pyrimidine-2,4-diones cyclic and acyclic nucleosides as potential anti HIV agents. J. Heterocycl. Chem., 31, No. 2, pp. 305-312. https://doi.org/10.1002/jhet.5570310208