DOI: https://doi.org/10.24959/ophcj.19.965

The synthesis and biological assessment of [[1,2,4]triazolo[4,3-a]pyridine-3-yl]acetamides with an 1,2,4-oxadiazol cycle in positions 6, 7 and 8

V. R. Karpina, S. S. Kovalenko, S. M. Kovalenko, O. V. Zaremba, O. V. Silin, T. Langer

Abstract


Fused heterocyclic 1,2,4-triazoles have provided much attention due to variety of their interesting biological properties.

Aim. To develop the method for the synthesis of novel 2-[(1,2,4-oxadiazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-yl]acetamides and conduct the biological assessment of the compounds synthesized.

Results and discussion. A diverse set of acetamides newly synthesized consists of 32 analogs bearing an 1,2,4-oxadiazole cycle in positions 6, 7 and 8. A convenient scheme of the synthesis starts from commercially available 2-chloropyridine-3-, 2-chloropyridine-4-, 2-chloropyridine-5-carboxylic acids with amidoximes to form the corresponding 2-chloro-[3-R1-1,2,4-oxadiazol-5-yl]pyridines, then follows the reaction of  hydrazinolysis with an excess of hydrazine hydrate. The process continues via the ester formation with the pyridine ring closure, then the amide formations of the end products are obtained by hydrolysis into acetic acid.

Experimental part. A series of new 2-[6-(1,2,4-oxadiazol-5-yl)-, 2-[7-(1,2,4-oxadiazol-5-yl)-, 2-[8-(1,2,4-oxadiazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-yl]acetamides were obtained in good yields, and their structures were proven by the method of 1H NMR spectroscopy. The prognosis and study of their pharmacological activity were also conducted.

Conclusions. The synthetic approach of obtaining the representatives of 2-[(1,2,4-oxadiazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-yl]acetamides previously unknown can be used as an applicable method for the synthesis of diverse functionalized [1,2,4]triazolo[4,3-a]pyridine derivatives.


Keywords


triazolopyridine; (1,2,4-oxadiazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridine; 1,2,4-oxadiazole

Full Text:

PDF

References


Sadana, A. K., Mirza, Y., Aneja, K. R., & Prakash, O. (2003). Hypervalent iodine mediated synthesis of 1–aryl/hetryl–1,2,4–triazolo[4,3–a] pyridines and 1–aryl/hetryl 5–methyl–1,2,4–triazolo[4,3–a]quinolines as antibacterial agents. European Journal of Medicinal Chemistry, 38 (5), 533–536. https://doi.org/10.1016/s0223-5234(03)00061-8

Prakash, O., Hussain, K., Aneja, D. K., Sharma, C., & Aneja, K. R. (2011). A facile iodine(III)–mediated synthesis of 3–(3–aryl–1–phenyl–1H–pyrazol–4–yl)–[1,2,4]triazolo[4,3–a]pyridines via oxidation of 2–((3–aryl–1–phenyl–1H–pyrazol–4–yl)methylene)–1–(pyridin–2–yl)hydrazines and their antimicrobial evaluations. Organic and Medicinal Chemistry Letters, 1 (1), 1.https://doi.org/10.1186/2191-2858-1-1

Lawson, E. C., Hoekstra, W. J., Addo, M. F., Andrade–Gordon, P., Damiano, B. P., Kauffman, J. A., … Maryanoff, B. E. (2001). 1,2,4–Triazolo[3,4–a]pyridine as a novel, constrained template for fibrinogen receptor (GPIIb/IIIa) antagonists. Bioorganic & Medicinal Chemistry Letters, 11 (19), 2619–2622. https://doi.org/10.1016/s0960-894x(01)00529-7

Chao C., Haibing D., Haibing G., Feng H., Lei J., Fang L., Yuan M., Huixin W., Yao–Chang X., Hongping Y., Ji Y. Z. (2013). 6–substituted 3–(quinolin–6–yl–thio)–[1,2,4]triazolo[4,3–a]pyradines as tyrosine kinase. Patent WO 2013038362 A1. 21.03.2013.

Alcaraz L., Panchal T.A., Jennings A.S.R., Cridland A., Hurley C. (2014). Derivatives of [1,2,4]triazolo[4,3–a]pyridine as p38–MAP kinase inhibitors. Patent WO2014194956 A1. 11.12.2014.

Jerome, K. D., Rucker, P. V., Xing, L., Shieh, H. S., Baldus, J. E., Selness, S. R., … McClure, K. F. (2010). Continued exploration of the triazolopyridine scaffold as a platform for p38 MAP kinase inhibition. Bioorganic & Medicinal Chemistry Letters, 20 (2), 469–473. https://doi.org/10.1016/j.bmcl.2009.11.114

Kalgutkar, A. S., Hatch, H. L., Kosea, F., Nguyen, H. T., Choo, E. F., McClure, K. F., … Letavic, M. A. (2006). Preclinical pharmacokinetics and metabolism of 6–(4–(2,5–difluorophenyl)oxazol–5–yl)–3–isopropyl–[1,2,4]–triazolo[4,3–a]pyridine, a novel and selective p38α inhibitor: identification of an active metabolite in preclinical species and human liver microsomes. Biopharmaceutics & Drug Disposition, 27 (8), 371–386. https://doi.org/10.1002/bdd.520

Liu, X.–H., Xu, X.–Y., Tan, C.–X., Weng, J.–Q., Xin, J.–H., & Chen, J. (2014). Synthesis, crystal structure, herbicidal activities and 3D–QSAR study of some novel 1,2,4–triazolo[4,3–a]pyridine derivatives. Pest Management Science, 71 (2), 292–301. https://doi.org/10.1002/ps.3804

Guan, L.–P., Zhang, R.–P., Sun, Y., Chang, Y., & Sui, X. (2012). Synthesis and Studies on the Anticonvulsant Activity of 5–alkoxy–[1,2,4]triazolo[4,3–a]pyridine Derivatives. Arzneimittelforschung, 62 (08), 372–377. https://doi.org/10.1055/s-0032-1314821

Cid–Núñez J. M., Trabanco–Suárez A. A., Lavreysen H., Ceusters M. (2015). 1,2,4–triazolo[4,3–a]pyridine compounds and their use as positive allosteric modulators of mGluR2 receptors. Patent WO2015032790 A1. 12.03.2015.

Lavreysen, H., Langlois, X., Donck, L. V., Nuñez, J. M. C., Pype, S., Lütjens, R., & Megens, A. (2015). Preclinical evaluation of the antipsychotic potential of the mGlu2–positive allosteric modulator JNJ–40411813. Pharmacology Research & Perspectives, 3 (2), e00097. https://doi.org/10.1002/prp2.97

Nandini, R. P., Deepnandan, S. D. (2010). Studies of Antipsychotic drugs as potential schizophrenia agents. J. Chem. Pharm. Res., 2 (1), 458–472.

Padalkar, V. S., Patil, V. S., Phatangare, K. R., Umape, P. G., & Sekar, N. (2011). Efficient Synthesis of 3–Substituted 1,2,4–Triazolo[4,3–a]pyridine by [Bis(Trifluroacetoxy)iodo]benzene–Catalyzed Oxidative Intramolecular Cyclization of Heterocyclic Hydrazones. Synthetic Communications, 41 (6), 925–938. https://doi.org/10.1080/00397911003707162

Katritzky, A. R., Rees, C. W., Scriven, E. F. V. (1996). The Structure, Reactions, Synthesis, and Uses of Heterocyclic Compounds. Pergamon: Oxford, New York, 8, 367–388.

Wang, Y., Sarris, K., Sauer, R. D., Djuric, S. W. (2007). Simple oxidation of pyrimidinylhydrazones to triazolopyrimidines and their inhibition of Shiga toxin trafficking. Tetrahedron Lett., 48, 2237–2240.

Bourgeois, P., Cantegril, R., Chěne, A., Gelin, J., Mortier, J., & Moyroud, J. (1993). An Improved Synthesis of 3–Substituted 1,2,4–Triazolo[4,3–a]pyridines and 1,2,4–Triazolo[4,3–b]pyridazines. Synthetic Communications, 23 (22), 3195–3199. https://doi.org/10.1080/00397919308011179

Crljenak, S., Tabakovic, I., Jeremic, D., Gaon, I., Enzell, C. R., & Inoue, K. (1983). Electrochemical Synthesis of Heterocyclic Compounds. XV. Anodic Synthesis of s–Triazolo[4,3–a]pyridine Derivatives. Acta Chemica Scandinavica, 37b, 527–535. https://doi.org/10.3891/acta.chem.scand.37b-0527


GOST Style Citations


1. Hypervalent iodine mediated synthesis of 1–aryl/hetryl–1,2,4–triazolo[4,3–a]pyridines and 1–aryl/hetryl 5–methyl–1,2,4–triazolo[4,3–a]quinolines as antibacterial agents / A. Sadana, Y. Mirza, K. Aneja et al. // Eur. J. Med. Chem. – 2003. – Vol. 38. – P. 533–536. https://doi.org/10.1016/s0223-5234(03)00061-8

 

2. A facile iodine(III)–mediated synthesis of 3–(3–aryl–1–phenyl–1H–pyrazol–4–yl)–[1,2,4]triazolo[4,3–a]pyridines via oxidation of 2–((3–aryl–1–phenyl–1H–pyrazol–4–yl)methylene)–1–(pyridin–2–yl)hydrazines and their antimicrobial evaluations / O. Prakash, K. Hussain, K. Deepak et al. // Org. Med. Chem. Lett. – 2011. – Vol. 1, Issue 1. – P. 1. https://doi.org/10.1186/2191-2858-1-1

 

3. 1,2,4–triazolo[3,4–a]pyridine as a novel, constrained template for fibrinogen receptor (GPIIb/IIIa) antagonists / E. C. Lawson, W. J. Hoekstra, M. F. Addo et al. // Bioorg. Med. Chem. Lett. – 2001. – Vol. 11. – P. 2619. https://doi.org/10.1016/s0960-894x(01)00529-7

 

4. 6–Substituted 3–(quinolin–6–yl–thio)–[1,2,4]triazolo[4,3–a]pyradines as tyrosine kinase. Pat. WO 2013038362 (A1) / C. Chao, D. Haibing, G. Haibing et al. – declared : 13.09.2012 ; published : 21.03.2013.

 

5. Derivatives of [1,2,4]triazolo[4,3–a]pyridine as p38–MAP kinase inhibitors. Patent WO2014194956 (A1) / L. Alcaraz, T. A. Panchal, A. S. R. Jennings et al. – declared : 06.06.2013 ; published : 11.12.2014.

 

6. Continued exploration of the triazolopyridine scaffold as a platform for p38 MAP kinase inhibition / K. D. Jerome, P. V. Rucker, L. Xing et al. // Bioorg. & Med. Chem. Lett. – 2010. – Vol. 20, Issue 2. – P. 469–473. https://doi.org/10.1016/j.bmcl.2009.11.114

 

7. Preclinical pharmacokinetics and metabolism of 6–(4–(2,5–difluorophenyl)oxazol–5–yl)–3–isopropyl–[1,2,4]–triazolo[4,3–a]pyridine, a novel and selective p38alpha inhibitor : identification of an active metabolite in preclinical species and human liver microsomes / A. S. Kalgutkar, H. L. Hatch, F. Kosea et al. // Biopharm. Drug Dispos. – 2006. – Vol. 27. – P. 371. https://doi.org/10.1002/bdd.520

 

8. Synthesis, crystal structure, herbicidal activities and 3D-QSAR study of some novel 1,2,4–triazolo[4,3–a]pyridine derivatives / X. H. Liu, X. Y. Xu, C. X. Tan et al. // Pest Manag. Sci. – 2015. – Vol. 71, Issue 2. – P. 292–301. https://doi.org/10.1002/ps.3804

 

9. Synthesis and studies on the anticonvulsant activity of 5–alkoxy–[1,2,4]triazolo[4,3–a]pyridine derivatives / L. P. Guan, R. P. Zhang, Y. Sun et al. // Arzneimittelforschung. – 2012. – Vol. 62, Issue 8. – P. 372–377. https://doi.org/10.1055/s-0032-1314821

 

10. 1,2,4–Triazolo[4,3–a]pyridine compounds and their use as positive allosteric modulators of mGluR2 receptors. Pat. WO2015032790 (A1) / J. M. Cid–Núñez, A. A. Trabanco-Suárez, H. Lavreysen et al. – declared : 03.09.2014 ; published : 12.03.2015.

 

11. Preclinical evaluation of the antipsychotic potential of the mGlu2–positive allosteric modulator JNJ–40411813 / H. Lavreysen, X. Langlois, L. V. Donck et al. // Pharmacol. Res. Perspect. – 2015. – Vol. 3, Issue 2. – P. e00097. https://doi.org/10.1002/prp2.97

 

12. Nandini, R. P. Studies of Antipsychotic drugs as potential schizophrenia agents / R. P. Nandini, S. D. Deepnandan // J. Chem. Pharm. Res. – 2010. – Vol. 2, Issue 1. – P. 458–472.

 

13. Vikas, S. Padalkar. Efficient Synthesis of 3–Substituted 1,2,4–Triazolo[4,3–a]pyridine by [Bis(Trifluroacetoxy)iodo]benzene-Catalyzed Oxidative Intramolecular Cyclization of Heterocyclic Hydrazones / S. Padalkar Vikas, S. Patil Vikas, R. Kiran // Synthetic Communications. – 2011. – Vol. 41, Issue 6. – P. 925–938. https://doi.org/10.1080/00397911003707162

 

14. Katritzky, A. R. The Structure, Reactions, Synthesis, and Uses of Heterocyclic Compounds / A. R. Katritzky, C. W. Rees, E. F. V. Scriven // Pergamon. – 1996. – Vol. 8, Chapter 13. – P. 367–388.

 

15. Wang, Y. Simple oxidation of pyrimidinylhydrazones to triazolopyrimidines and their inhibition of Shiga toxin trafficking / Y. Wang, K. Sarris, R. D. Sauer // Tetrahedron Lett. – 2007. – Vol. 48. – P. 2237–2240

 

16. Bourgeois, P. An Improved Synthesis of 3–Substituted 1,2,4–Triazolo[4,3–a]pyridines and 1,2,4–Triazolo[4,3–b]pyridazines / P. Bourgeois, R. Cantegril, A. Chene // J. Synth. Comm. – 1993. – Vol. 23, P. 3195–3199. https://doi.org/10.1080/00397919308011179

 

17. Crljenak, S. Electrochemical Synthesis of Heterocyclic Compounds. XV. Anodic Synthesis of s–Triazolo[4,3–a]pyridine Derivatives / S. Crljenak, I. Tabakovic, D. Jeremic // Acta Chem. Scand. – 1983. – Vol. 37b, P. 527–535. https://doi.org/10.3891/acta.chem.scand.37b-0527





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

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

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