The synthesis and analgesic properties of N-(benzyl)-2-hydroxy-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamides

I. V. Ukrainets, T. V. Alexeeva, O. O. Davydenko, V. V. Grinenko

Abstract


Continuing the search for new analgesics among derivatives of azahetarylcaboxylic acids by the reaction of ethyl 2-hydroxy-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate and benzylamines in boiling ethanol the corresponding group of N-(benzyl)-2-hydroxy-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamides has been synthesized. The structure of the compounds obtained has been confirmed by the data of elemental analysis and NMR 1H spectroscopy. It is noted that the signals of aromatic protons of pyrido-pyrimidine nuclei are shifted downfield and generally for a typical AMX spin system. At the same time, the signals of aromatic protons of benzilamide fragments on the contrary are shifted upfield in all cases and focused on very narrow segments of the spectra, thereby undergoing strong distortion. According to the results of the primary pharmacological screening it has been found that using the standard model of “acetic acid writhings” all N-(benzyl)-2-hydroxy-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamides without exception have analgesic properties to a greater or lesser  degree. Practically the same regularities of the benzylamide fragment structure –biological effect relationship as in the case of 4-hydroxyquinolin-2-ones analogues have been found. Based on it the conclusion about bioisosterism of 4-hydroxyquinolin-2-one and 2-hydroxy-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine nuclei has been made.


Keywords


amidation; tricarbonylmethane heterocyclic derivatives; 2-hydroxy-4-oxo-4H-pyrido[1,2-a] pyrimidine-3-carboxamides; synthesis; bioisosteric replacements; analgesic activity

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References


Kesmati M., Torabi M. Basic and Clinical Neuroscience, 2014, Vol. 5, No.1, pp.80-87.

Ondachi P. W., Castro A. H., Bartkowiak J. M., Luetje C. W., Damaj M. I., Mascarella S. W., Navarro H. A., Carroll F. I. Journal of Medicinal Chemistry, 2014, Vol. 57, No.3, pp.836-848. DOI: 10.1021/jm401602p.

Dulu T. D., Kanui T. I., Towett P. K., Maloiy G. M., Abelson K. S. In Vivo, 2014, Vol. 28, No.1, pp.39-48.

Tao P. L., Law P. Y., Loh H. H. International Union of Biochemistry and Molecular Biology Life, 2010, Vol. 62, No.2, pp.103-111. DOI: 10.1002/iub.292.

Zor F., Ozturk S., Bilgin F., Isik S., Cosar A. Burns: Journal of the International Society for Burn Injuries, 2010, Vol. 36, No.4, pp.501-505. DOI: 10.1016/j. burns.2009.08.007.

Keri R. S., Patil M. R., Patil S. A., Budagumpi S. European Journal of Medicinal Chemistry, 2015, Vol. 89, pp.207-251. DOI: 10.1016/j.ejmech.2014.10.059.

Ukrainets I. V., Gorokhova O. V., Nidal Amin Jaradat, Petrushova L. A., Mospanova E. V., Savchenkova L. V., Kuz’min V. E., Lyahovsky A. V. 4-Hydroxyquinolin- 2-ones and their Close Structural Analogues as a New Source of Highly Effective Pain-killers. In book: Pain and Treatment, Racz G. B. and Noe C. E. (Ed.), Rijeka: InTech, 2014, pp.21-73.

Ukrainets I. V., Gorokhova O. V., Andreeva K. V. Russian Journal of Organic Chemistry, 2013, Vol. 49, No.6, pp.867-871. DOI:10.1134/S1070428013060122.

Ukrainets I. V., Mospanova E. V., Jaradat N. A., Bevz O. V., Turov A. V. Chemistry of Heterocyclic Compounds, 2012, Vol. 48, No.9, pp.1347-1356. DOI:10.1007/s10593-012-1143-1147.

Ukrainets I. V., Gorokhova O. V., Andreeva K. V., Davidenko A. A. Zhurnal Organichnoi ta Farmatsevtichnoi Khimii – Journal of Organic and Pharmaceutical Chemistry, 2014, Vol. 12, No.1(45), pp.51-55. 1

Dhiman R., Sharma S., Singh G., Nepali K., Singh Bedi P. M. Archiv der Pharmazie (Weinheim). 2013, Vol. 346, No.1, pp.7-16. DOI: 10.1002/ardp.201200296.

Chatzopoulou M., Bonovolias I. D., Nicolaou I., Demopoulos V. J., Vizirianakis I. S. Tsiftsoglou A. S. European Journal of Medicinal Chemistry, 2012, Vol. 50, pp.75-80. DOI: 10.1016/j.ejmech.2012.01.041.

Pegklidou K., Koukoulitsa C., Nicolaou I., Demopoulos V. J. Bioorganic & Medicinal Chemistry, 2010, Vol. 18. No.6, pp.2107-2114. DOI: 10.1016/j. bmc.2010.02.010.

Vijayan R. S., Bera I., Prabu M., Saha S., Ghoshal N. Journal of chemical information and modeling, 2009, Vol. 49, No.11, pp.2498-2511. DOI: 10.1021/ ci900309s.

Tosco P., Lolli M. L. Journal of molecular modeling, 2008, Vol. 14, No.4, pp.279-291. DOI: 10.1007/s00894-008-0269-0.

Ukrainets I. V., Tugaibei I. A., Bereznyakova N. L., Kravchenko V. N., Turov A. V. Chemistry of Heterocyclic Compounds, 2008, Vol. 44, No.5, pp.565-575. DOI: 10.1007/s10593-008-0076-7.

Vogel H. G. Drug Discovery and Evaluation: Pharmacological Assays. Berlin, Springer; 2008, pp.1030-1032.

Sigidin Ya. A., Shvarts G. Ya., Arzamastsev A. P., Liberman S. S. Lekarstvennaya terapiya vospalitel’nogo protsessa (Drug Therapy of the Anti-inflammatory Process). Moscow, Meditsina; 1988, pp.60-63.

Sernov L. N., Gatsura V. V. Elementy experimentalnoi pharmakologii (Elements of Experimental Pharmacology). Moscow, Nauka, 2000, pp.308-316.

Mospanova Ye. V., Ukrainets I. V., Bevz O. V., Savchenkova L. V., Yankovich S. I. Zhurnal Organichnoi ta Farmatsevtichnoi Khimii – Journal of Organic and Pharmaceutical Chemistry, 2012, Vol. 10, No.2(38), pp.50-53.

Ukrainets I. V., Bereznyakova N. L., Petyunin G. P., Tugaibei I. A., Rybakov V. B., Chernyshev V. V., Turov A. V. Chemistry of Heterocyclic Compounds, 2007, Vol. 43, No.6, pp.729-739. DOI: 10.1007/s10593-007-0119-5.


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DOI: https://doi.org/10.24959/ophcj.15.850

Abbreviated key title: Ž. org. farm. hìm.

ISSN 2518-1548 (Online), ISSN 2308-8303 (Print)