The synthesis, transformations and biological activity of thieno[2,3-d]pyrimidine derivatives with the carboxylic groups as the substituents in the pyrimidine ring

Authors

  • O. D. Vlasova National University of Pharmacy of the Ministry of Health of Ukraine, Ukraine
  • S. V. Vlasov National University of Pharmacy of the Ministry of Health of Ukraine, Ukraine
  • V. I. Kabachnyy National University of Pharmacy of the Ministry of Health of Ukraine, Ukraine https://orcid.org/0000-0001-8620-2225
  • V. S. Vlasov National University of Pharmacy of the Ministry of Health of Ukraine, Ukraine

DOI:

https://doi.org/10.24959/ophcj.20.209835

Keywords:

thiophene, pyrimidine, carboxylic acid

Abstract

Aim. To reveal the prospects of the search of novel medicinal substances based on the studies of the derivatives of thieno[2,3-d]pyrimidine with the carboxylic groups as the substituents in the pyrimidine ring using the analysis of the published literature data.

Results and discussion. The study has shown a wider range of the pharmacological activity of thieno[2,3-d]pyrimidine-2-carboxylic acid derivatives compared to thieno[2,3-d]pyrimidine-4-carboxylic acids, as well as their availability, despite the fact that the number of preparative methods for the synthesis of these substances is rather limited. The most popular method is cyclization of 2-aminothiophene-3-carboxylic acids with ethyl cyanoformate. On the other hand, thieno[2,3-d]pyrimidine-4-carboxylic acid derivatives are presented in even fewer studies and are poorly studied; many of them are difficult to be synthesized and practically are not found in the pharmacological patent literature.

Conclusions. The literature data analysis has revealed the small number of efficient synthetic methods suitable for preparation of thieno[2,3-d]pyrimidines with the carboxylic groups as the substituents in the pyrimidine ring, as well as their low availability for the pharmacological studies. It is also noteworthy that the derivatives of thieno[2,3-d]pyrimidine-4-carboxylic acids are even less studied than the related compounds of thieno[2,3-d]pyrimidine-2-carboxylic acid series, and therefore, more attention should be paid to them as the objects for experimental chemistry and pharmacology.

Received: 12.08.2020
Revised: 23.09.2020
Accepted: 08.10.2020

Supporting Agencies

  • The work has been performed as a part of scientific works of National University of Pharmacy on the topic «Organic synthesis and analysis of BAS
  • development of dugs based on substances of synthetic nature» (№01144000943
  • 2019-2024 years)

Downloads

Download data is not yet available.

References

  1. Hafez, H.; Al-Duaij, O.; El-Gazzar, A. Design, Synthesis and Pharmacological Evaluation of New Nonsteroidal Anti-Inflammatory Derived from 3-Aminobenzothieno[2,3-d]pyrimidines. International Journal of Organic Chemistry 2013, 3 (2), 110–118. https://doi.org/10.4236/ijoc.2013.32012.
  2. Vlasov, S. V.; Chernykh, V. P. Synthesis, antiinflammatory and antimicrobial activity of 6-(1H-benzimidazol-2-yl)-5-methyl-4-(alkylthio)thieno[2,3-d]pyrimidines. News of Pharmacy 2016, 3, 9–16. https://doi.org/10.24959/nphj.16.2112.
  3. Vlasov, S. V.; Chernykh, V. P. Synthesis and antimicrobial activity of 3-benzyl-5-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-сarboxylic acid amides. ScienceRise: Pharmaceutical Science 2016, 1 (1), 4–9. https://doi.org/10.15587/2519-4852.2016.72700.
  4. Vlasov, S. V.; Chernykh, V. P.; Osolodchenko, T. P. Synthesis and the antimicrobial activity of ethyl 3-alkyl-2-(alkylthio)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate derivatives. News of Pharmacy 2015, 3, 3–8. https://doi.org/10.24959/nphj.15.2070.
  5. Verma, A. K.; Martin, A.; Kant, R.; Kumari, R.; Sharma, B. B.; Gupta V. K. Synthesis, Characterization, Antimicrobial and Anti-Inflammatory activities of novel N-(Sugar Pyranosyl) Thienopyrimidine 4-Amine derivatives. Journal of Pharmacy Research 2014, 8 (11), 1677–1681.
  6. Vlasov, S. V.; Kovalenko, S. M.; Chernykh, V. P. Antimicrobial activity of ethyl 4-[2-arylidenohydrazino]-5-methylthieno[2,3-d]pyrimidine-6-carboxylates. Pharmaceutical review 2014, 4, 8–12. https://doi.org/10.11603/2312-0967.2014.4.3441.
  7. Vlasov, S. V.; Kovalenko, S. M.; Chernykh, V. P.; Krolenko, K. Yu. Synthesis of 5-methyl-4-thio-6-(1,3,4-oxadiazol-2-yl)thieno[2,3-d]pyrimidines and their antimicrobial activity study. J. Chem. Pharm. Res. 2014, 6 (6), 22–27.
  8. Vlasov, S. V.; Kovalenko, S. M.; Fedosov, A. I.; Chernykh, V. P. The synthesis of novel 3-substituted 1-alkyl-5-methyl-6-(3-aryl-1,2,4-oxadiazole-5-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones and their antimicrobial activity. Journal of Organic and Pharmaceutical Chemistry 2011, 9 (3), 51–55.
  9. Vlasov, S. V.; Zaremba, O. V.; Kovalenko, S. M.; Fedosov, A. I.; Chernykh, V. P. Synthesis of 5-methylthieno[2,3-d]pyrimidin-4(3H)-one derivatives modified in position 6 with 1,2,4- and 1,3,4-oxadiazole and their biological activity. Journal of Organic and Pharmaceutical Chemistry 2011, 9 (4), 24–30.
  10. Brookings, D. C.; Ford, D. J.; Ghawalkar, A. R.; Herman, J.; Huang, Q.; Kulisa, C. L.; Louat, T.; Neuss, J. C.; Reuberson, J. T.; Vanderhoydonck, B. Therapeutically Active Fused Pyrimidine Derivatives. U.S. Patent 2014309222, Oct 16, 2014.
  11. Michaelides, M. R.; McClellan, W. J.; Frey, R. R.; Curtin, M. L.; Steinman, D. H.; Dai, Y.; Holms, J. H. Inhibitors of protein kinases. U.S. Patent 2007135387, June 14, 2007.
  12. McClellan, W. J.; Dai, Y.; Abad-Zapatero, C.; Albert, D. H.; Bouska, J. J.; Glaser, K. B.; Magoc, T. J.; Marcotte, P. A.; Osterling, D. J.; Stewart, K. D.; Davidsen, S. K.; Michaelides, M. R. Discovery of potent and selective thienopyrimidine inhibitors of Aurora kinases. Bioorg. Med. Chem. Lett. 2011, 21 (18), 5620–5624. https://doi.org/10.1016/j.bmcl.2011.06.041.
  13. Cox, J. M.; Marsden, J. H. E.; Burrell, R. A.; Elmore, N.; Shephard, M. C. Thienopyrimidines. German patent DE 2654090, June 23, 1977.
  14. Ota, C.; Kumata, S.; Kawaguchi, S. Novel herbicides, usage thereof, novel thienopyrimidine derivatives, intermediates of the same, and process for production thereof. European patent EP1544202, June 22, 2005.
  15. Shishoo, C. J.; Devani, M. B.; Bhadti, V. S.; Jain, K. S.; Ananthan, S. Reaction of nitriles under acidic conditions. Part VI. Synthesis of condensed 4-chloro- and 4-aminopyrimidines from ortho-aminonitriles. J. Heterocycl. Chem. 1990, 27 (2), 119–126. https://doi.org/10.1002/jhet.5570270201.
  16. Levy, D. E.; Smyth, M. S.; Scarborough, R. M. Piperazine and homopiperazine compounds. U.S. Patent 2003153556, Aug 14, 2003.
  17. Lee, C. S.; Lee, T. H.; Yoon, S. K.; Choi, J. S.; Jang, Y. J.; Kim, S. W.; Chang, H. K.; Park, M. J.; Kim, T. H.; Ahn, Y. H.; Park, H. D.; Park, H. J.; Lim, D. C.; Lee, J. Y.; Lee, S. H.; Park, W. S.; Oh, Y. S. Fused heterocyclic compound. U.S. Patent 2011166121, July 07, 2011.
  18. Umeda, N.; Takada, M.; Ikeyama, S.; Ichikawa, K. Thienopyrimidine compounds and their salts and process for preparation of both. European patent EP1329454, July 23, 2003.
  19. Yamada, H.; Umeda, N.; Uchida, S.; Shiinoki, Y.; Horikoshi, H.; Mochizuki, N. Thienopyrimidine compounds and salts thereof and process for the preparation of the same. U.S. Patent 6,482,948, Nov 19, 2002.
  20. Jang, M.-Y.; Jonghe, S. D.; Belle, K. V.; Louat, T.; Waer, M.; Herdewijn, P. Synthesis, immunosuppressive activity and structure–activity relationship study of a new series of 4-N-piperazinyl-thieno[2,3-d]pyrimidine analogues. Bioorg. Med. Chem. Lett. 2010, 20 (3), 844–847. https://doi.org/10.1016/j.bmcl.2009.12.098.
  21. Louat, T. A. M.; Herman, J. F.; Lin, Y.; Waer, M. J. A.; Vanderhoydonck, B.; Jang, M.-Y.; Gao, L.-J.; De Jonghe, S.; Herdewijn, P. Thiazolopyrimidine modulators as immunosuppressive agents. U.S. Patent 2012046278, Feb 23, 2012.
  22. Herman, J. F.; Louat, T. A. M. Anti-cancer activity of novel bicyclic heterocycles. U.S. Patent 2014088088, Mar 27, 2014.
  23. Dang, Q.; Carruli, E.; Tian, F.; Dang, F. W.; Gibson, T.; Li, W.; Bai, H.; Chung, M.; Hecker, S. J. A tandem decarboxylation and inverse electron-demand Diels–Alder reaction of amino-thiophenecarboxylic acids with 1,3,5-triazines. Tetrahedron Lett. 2009, 50 (24), 2874–2876. https://doi.org/10.1016/j.tetlet.2009.03.180.
  24. Ried, W.; Beller, G. Reaktionen von Chlorpyrimidinen, I Synthese von Thieno[2,3-d]pyrimidinen und Pyrrolo[2,3-d]pyrimidinen. Liebigs Ann. Chem. 1988, 1988 (7), 633–642. https://doi.org/10.1002/jlac.198819880704.
  25. Ono, N.; Hironaga, H.; Ono, K.; Kaneko, S.; Murashima, T.; Ueda, T.; Tsukamura, C.; Ogawa, T. A new synthesis of pyrroles and porphyrins fused with aromatic rings. J. Chem. Soc., Perkin Trans. 1 1996, 5, 417–423. https://doi.org/10.1039/P19960000417.
  26. Murashima, T.; Fujita, K.-i.; Ono, K.; Ogawa, T.; Uno, H.; Ono, N. A new facet of the reaction of nitro heteroaromatic compounds with ethyl isocyanoacetate. J. Chem. Soc., Perkin Trans. 1 1996, 12, 1403–1407. https://doi.org/10.1039/P19960001403.
  27. Goto T.; Kondo Y.; Takuwa T.; Honjo E.; Hamaguchi W.; Hoshii H.; Shiraishi N. Sulfur-containing bicyclic compound. U.S. Patent 2015111876, Apr 23, 2015.
  28. Vlasova, O. D.; Krolenko, K. Y.; Nechayev, M. A.; Shynkarenko, P. E.; Kabachnyy, V. I.; Vlasov, S. V. Efficient method for the synthesis of novel substituted thieno[2,3-d]pyrimidine-4-carboxylic acids, their derivatization, and antimicrobial activity. Chem. Heterocycl. Comp. 2019, 55 (2), 184–188. https://doi.org/10.1007/s10593-019-02437-1.

Downloads

Published

2020-12-01

How to Cite

(1)
Vlasova, O. D.; Vlasov, S. V.; Kabachnyy, V. I.; Vlasov, V. S. The Synthesis, Transformations and Biological Activity of thieno[2,3-d]pyrimidine Derivatives With the Carboxylic Groups As the Substituents in the Pyrimidine Ring. J. Org. Pharm. Chem. 2020, 18, 4-13.

Issue

Vol. 18 No. 4(72) (2020)

Section

Original Researches

License

Copyright (c) 2020 National University of Pharmacy

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors publishing their works in the Journal of Organic and Pharmaceutical Chemistry agree with the following terms:

1. Authors retain copyright and grant the journal the right of the first publication of the work under Creative Commons Attribution License allowing everyone to distribute and re-use the published material if proper citation of the original publication is given.

2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal’s published version of the work (e.g., post it to an institutional repository or publish it in a book) providing proper citation of the original publication.

3. Authors are permitted and encouraged to post their work online (e.g. in institutional repositories or on authors’ personal websites) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (see The Effect of Open Access).