The study of the neurotropic activity of the pyrrolopyrimidin-4-ones rearrangement products under the action of phosphorus oxychloride

Authors

  • Ekaterina V. Zaliznaya Ukrainian State University of Chemical Technology, Ukraine
  • Svetlana A. Varenichenko Ukrainian State University of Chemical Technology, Ukraine https://orcid.org/0000-0001-7240-3456
  • Oleg K. Farat Ukrainian State University of Chemical Technology, Ukraine https://orcid.org/0000-0002-3603-2720
  • Victor I. Markov Ukrainian State University of Chemical Technology, Ukraine

DOI:

https://doi.org/10.24959/ophcj.20.193867

Keywords:

rearrangement, pyrrolopyrimidin-4-ones, aminohydroacridines, neurotropic activity, Tacrine

Abstract

Aim. To synthesize the annelated 4-aminopyridines and study the biological activity of one of products.

Results and discussion. In the laboratory of the Research Institute of Biomedical Problems of the Dnipropetrovsk Medical Academy the studies of the effect of 2,3,3-trimethyl-2,3,5,6,7,8-hexahydro-1H-pyrrolo[3,4-b]quinolin-9-amine on the neuroactivity in the “open field” model have been conducted. According to the results of the experiment it has been found that in two hours after the administration of the oil solution of the compound the indices of the motor activity of mice are significantly reduced.

Experimental part. 2,3,3-Trimethyl-2,3,5,6,7,8-hexahydro-1H-pyrrolo[3,4-b]quinolin-9-amine and 2,3,6,7,7-pentamethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-amine were obtained by the rearrangement of the corresponding pyrrolopyrimidin-4-ones under the action of the excess of phosphorus oxychloride in toluene. The initial pyrrolopyrimidin-4-ones were synthesized by the condensation of 4-amino-1,2,2-trimethyl-2,5-dihydro-1H-pyrrole-3-carbonitrile with ketones. The structure of all compounds obtained was confirmed by 1H NMR-spectroscopy, mass spectrometry and elemental analysis.

Conclusions. The neurotropic activity has been detected for the oil solution of 2,3,3-trimethyl-2,3,5,6,7,8-hexahydro-1H-pyrrolo[3,4-b]quinolin-9-amine on the “open field” model. It has been found that the aqueous solution of this compound does not exhibit the neurotropic activity regardless of the administered dose. Taking into account the presence of the neurotropic activity further research in this field is a promising way to search novel bioactive molecules among 4-aminopyridine derivatives, which are structural analogs of the drug Tacrine.

 

Received: 26.12.2019
Revised: 20.01.2020
Accepted: 27.02.2020

Supporting Agency

  • The budget theme of the Ministry of Education and Science of Ukraine No. 0115U003159

Downloads

Download data is not yet available.

References

  1. Keri, R. S.; Quintanova, C.; Marques, S. M.; Esteves, A. R.; Cardoso, S. M.; Santos, M. A. Design, synthesis and neuroprotective evaluation of novel tacrine–benzothiazole hybrids as multi-targeted compounds against Alzheimer’s disease. Bioorg. Med. Chem. 2013, 21 (15), 4559-4569. https://doi.org/10.1016/j.bmc.2013.05.028.
  3. Савельєва, О. В.; Шумова, Г. С.; Владимирова, І. М. Аналіз фармацевтичного ринку ноотропних засобів в Україні. ScienceRise 2015, 11 (4), 30-36. https://doi.org/10.15587/2313-8416.2015.54873.
  5. Chao, X.; He, X.; Yang, Y.; Zhou, X.; Jin, M.; Liu, S.; Cheng, Z.; Liu, P.; Wang, Y.; Yu, J.; Tan, Y.; Huang, Y.; Qin, J.; Rapposelli, S.; Pi, R. Design, synthesis and pharmacological evaluation of novel tacrine–caffeic acid hybrids as multi-targeted compounds against Alzheimer’s disease. Bioorg. Med. Chem. Lett. 2012, 22 (20), 6498-6502. https://doi.org/10.1016/j.bmcl.2012.08.036.
  7. Hebda, M.; Bajda, M.; Więckowska, A.; Szałaj, N.; Pasieka, A.; Panek, D.; Godyń, J.; Wichur, T.; Knez, D.; Gobec, S.; Malawska, B. Synthesis, Molecular Modelling and Biological Evaluation of Novel Heterodimeric, Multiple Ligands Targeting Cholinesterases and Amyloid Beta. Molecules 2016, 21 (4), 410-434. https://doi.org/10.3390/molecules21040410.
  9. Boulebd, H.; Ismaili, L.; Bartolini, M.; Bouraiou, A.; Andrisano, V.; Martin, H.; Bonet, A.; Moraleda, I.; Iriepa, I.; Chioua, M.; Belfaitah, A.; Marco-Contelles, J. Imidazopyranotacrines as Non-Hepatotoxic, Selective Acetylcholinesterase Inhibitors, and Antioxidant Agents for Alzheimer’s Disease Therapy. Molecules 2016, 21 (4), 400-416. https://doi.org/10.3390/molecules21040400.
  11. Markov, V. I.; Farat, O. K.; Varenichenko, S. A.; Velikaya, E. V. Rearrangement of 5’,6’,7’,8’-tetrahydro-1’H-spiro(cyclohexane-1,2’-quinazolin)-4’(3’H)-one during the Vilsmeier reaction. Mendeleev Commun. 2012, 22 (2), 101-102. https://doi.org/10.1016/j.mencom.2012.03.017.
  13. Zaliznaya, E. V.; Farat, O. K.; Gorobets, N. Y.; Markov, V. I.; Zubatyuk, R. I.; Mazepa, A. V.; Vashchenko, E. V. Reactions of octahydroacridine-4-carbonitrile (carboxamide) with electrophilic reagents. Chem. Heterocycl. Comp. 2015, 51 (4), 327-333. https://doi.org/10.1007/s10593-015-1703-8.
  15. Zaliznaya, E. V.; Farat, O. K.; Varenichenko, S. A.; Mazepa, A. V.; Markov, V. I. Functionalization of tetra- and octahydroacridine derivatives through Michael addition. Tetrahedron Lett. 2016, 57 (31), 3485-3487. https://doi.org/10.1016/j.tetlet.2016.06.096.
  17. Zalizna, E. V.; Polishuk, T. P.; Varenichenko, S. A.; Farat, O. K.; Markov, V. I. The interreaction of 4,5-diformyl-2,3,6,7,8,10-hexahydroacridine-8a(1h)-carbonitrile with n-nucleophiles. Journal of Organic and Pharmaceutical Chemistry 2016, 14 (3), 38-42. https://doi.org/10.24959/ophcj.16.888.
  19. Zaliznaya, E. V.; Smetanin, N. V.; Varenichenko, S. A.; Mazepa, A. V.; Farat, O. K.; Markov, V. I. Synthesis of new hexahydro-5H-indolo[3,2-c]acridines and indolylbutanoic acids by Fischer cyclization of arylhydrazones. Chem. Heterocycl. Comp. 2018, 54 (2), 138-145. https://doi.org/10.1007/s10593-018-2245-7.
  21. Dimroth, K.; Aurich, H. G. Zur Cyanmethylierung schwach basischer Amine. Chem. Ber. 1965, 98 (12), 3902-3906. https://doi.org/10.1002/cber.19650981217.
  23. Schramm, S.; Schmitz, E.; Gründemann, E. Einfache Darstellung von 4-Oxo-tetrahydropyrimidinen. Journal für Praktische Chemie 1984, 326 (2), 279-286. https://doi.org/10.1002/prac.19843260213.
  25. Cavalla, J. F. 899. 3-Amino-4-cyano-3-pyrrolines: their hydrolysis to 3-pyrrolidones and their reaction with hydrogen sulphide. Journal of the Chemical Society (Resumed) 1962, (0), 4664-4672. https://doi.org/10.1039/JR9620004664.
  27. Cavalla, J. F. 3-amino-4-cyano-3-pyrrolines: Their conversion to pyrrolo[3,4-d]pyrimidines. Tetrahedron Lett. 1964, 5 (39), 2807-2808. https://doi.org/10.1016/S0040-4039(00)70425-4.
  29. Cavalla, J. F.; Willis, J. A. D. Substituted pyrrolo[3,4-d]pyrimidines: their preparation from 3-amino-4-cyano-3-pyrrolines. Journal of the Chemical Society C: Organic 1967, (0), 693-697. https://doi.org/10.1039/J39670000693.
  31. Pretsch, E.; Bühlmann, P.; Badertscher, M. Structure Determination of Organic Compounds. 4th ed.;Springer-VerlagBerlinHeidelberg:Berlin, 2009; p 433.
  33. Varenichenko, S. A.; Farat, O. K.; Markov, V. I. Reactivity of Substituted 2-Spiropyrimidin-4-Ones Under Vilsmeier–Haack Conditions. Chem. Heterocycl. Comp. 2015, 50 (11), 1602-1607. https://doi.org/10.1007/s10593-014-1626-9.
  35. Zigeuner, G.; Gübitz, G. Über das Tetrahydrospiro[cyclohexan-1,2'(1'H)-chinazolin]-4'(3'H)-on. Monatsh Chem 1970, 101 (5), 1547-1558. https://doi.org/10.1007/BF00911421.
  37. Upadysheva, A. V.; Grigor’eva, N. D.; Ryabokobylko, Y. S.; Znamenskaya, A. P. Recyclization of 2,2-disubstituted 4(3H)-oxo- and 4-chloro-1,2-dihydropyrimidines to 4-aminopyridine derivatives. Chem. Heterocycl. Comp. 1983, 19 (1), 95-100. https://doi.org/10.1007/BF00512825.
  39. Bischoff, C.; Herma, H. Eine einfache Synthese des Cyclohexanon-2-carbonsäure-amids sowie dessen Reaktionen. Journal für Praktische Chemie 1976, 318 (5), 773-778. https://doi.org/10.1002/prac.19763180508.
  41. Upadysheva, A. V.; Grigor’eva, N. D.; Znamenskaya, A. P. Intramolecular rearrangement of two-ring 2,2-disubstituted 4-oxo-1,2,3,4-tetrahydropyrimidines under the influence of polyphosphoric acid. Chem. Heterocycl. Comp. 1977, 13 (11), 1240-1243. https://doi.org/10.1007/BF00475956.
  43. Andreani, A.; Leoni, A.; Locatelli, A.; Morigi, R.; Rambaldi, M.; Pietra, C.; Villetti, G. 4-Aminopyridine derivatives with antiamnesic activity. Eur. J. Med. Chem. 2000, 35 (1), 77-82. https://doi.org/10.1016/S0223-5234(00)00103-3.

Downloads

Published

2020-03-05

How to Cite

(1)
Zaliznaya, E. V.; Varenichenko, S. A.; Farat, O. K.; Markov, V. I. The Study of the Neurotropic Activity of the Pyrrolopyrimidin-4-Ones Rearrangement Products under the Action of Phosphorus Oxychloride. J. Org. Pharm. Chem. 2020, 18, 39-44.

Issue

Vol. 18 No. 1(69) (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).