[(N-Aryl)piperazinil]bythylpyrimidine derivatives with neurotropic and actoprotective properties

S. A. Andronati, S. G. Soboleva, A. V. Zamkova, T. L. Karasyova, I. M. Rakipov, D. I. Tsymbal


In this study the potential ligands of 5-HT1A receptors – arylpiperazines containing the residues of tetrahydropyrimidine as terminal fragments, compounds (1-6) and dihydropyrimidine – (7) have been synthesized. The structures of compounds 1-7 have been confi rmed by IR-spectroscopy, mass spectrometry and 1H-NMR-spectroscopy. Substances 2, 3, 4 and 7 inhibit the specifi c binding of the radioligand [3H]8-OH-DPAT with 5-HT1A receptors; it has been found that they have a pronounced affi nity for these receptors. In the confl ict situation test compounds of 1-5 and 7 showed anxiolytic properties, whereas phenylpiperazinil- and о-tolylpiperazinilbutyl-4-methyl-5-izopropyl-1,2,3,-6-tetrahydropyrimidine-2-thio-6-ones (1 and 2) exceeded the known drug buspirone by the level of the anxiolytic activity. The absence of this activity in compound 6 is probably due to the differences of substituents at N1 atom of the pyrimidine nucleus of compound 6 and other compounds of this series. It has been shown that on the model of hyperthermia all of these compounds in the dose range of 0.04-0.1 mg/kg possessed a high actoprotective activity increased the rat capacity work by 1.4-2.5 times compared to the control. The most active compound 3 in the ED50 dose of 0.04 mg/kg increased the duration of swimming in rats by 2.2 times (122%) compared to bemithylum. Some of the compounds (15 mg/kg) showed antihypoxic activity on the models of hemic (compounds 2-4, 7) and normobaric hypoxia (compounds 1, 2, 6) and exceeded bemithylym (33.5 mg/kg) by their activity. The compounds synthesized are low toxic with the LD50 value of 150-250 mg/kg.


arylpiperazine; pyrimidines; affi nity; 5-HT1A receptors; neurotropic and actoprotective properties


Peroutka S. J. Pharmacol. Rev., 1991, Vol. 43, No.4, pp.579-586.

New J. S. Med. Res. Rev, 1990, Vol. 10(3), pp.283-326.

Casnalosi, Schweizer E., Case W. G, Rickels K. J. Clin. Psycopharmacol., 1987, Vol. 7, No.1, pp.31-33.

Glennon R. A., Naiman N. A., Pierson M. E. et al. Drug Dev. Res., 1989, Vol. 16, pp.335-343.

Forster E. A., Cliffe I. A., Bill D. J. et al. Eur. J. Pharmacol., 1995, Vol. 281, No.1, pp.81-88.

Cliffe I. A., Brightwell C. I., Fletcher A. et al. J. Med. Chem., 1993, Vol. 36, pp.1509-1510.

Bermawy M. E., Raghupathi R., Ingher S. P. J. Med. Res., 1992, Vol. 2, pp.88-95.

Grychowska K., Masurier N., Verdiй H., Satała G., Bojarski A. J., Martinez J., Pawłowski M., Subra G., Zajdel P. Chemical Biology & Drug Design, 2015, Vol. 86, issue 4, pp.697-703. Doi: 10.1111/cbdd.12539

Chilmonczyk Zd., Szelejewska-Wozniakowska A., Cybulski J. et al. Arch. Pharm. Pharm. Med. Chem., 1997, Vol. 330, pp.146-160.

Andronati S. A., Makan S. Yu., Kolodeev G. E., Berezhnoy D. S. Khimiko-farmatsevticheskij zhurnal – Chemical-pharmaceutical journal, 2003, Vol. 35, No.11, pp.11-14.

Karaseva T. L., Golturenko A. V., Makan S. Yu. et al. Voprosy bioilogicheskoy, medicynskoy i farmatsevticheskoy khimii – Issues of medical and phar- maceutical chemistry, 2005, No.3, pp.25-27.

Bogatsky A. V., Andronati S. A., Litvinova L. A. et al. Pat. 1263 Ukraine, Opubl.: 30.12.93; O™icialny bulleten. “Promyslova vlasnist” – Of™icial bulletin “Industrial property”, 1993, No.3.

Soboleva S. G., Gerasimenko I. F., Kravchuk L. G. et al. Doklady NAN Ukrainy, Reports NAN of Ukraine, 1992, Vol. 327, No.3, pp.349-353.

Soboleva S. G., Andronati S. A., Karaseva T. L. et al. Doklady NAN Ukrainy, Reports NAN of Ukraine, 2013, No.2, pp.119-124.

Aspelund H. Acta Acad. Aboens., Math et Phys., 1958, Vol. 21, No.10, p.20.

Baker B. R., Robert E. Schaub, Joseph R. Joseph et al. J. Org. Chem., 1953, Vol. 18, pp.133-137.

Bellami А. Infrakrasnye spetry slozhnyh molekul – (Infrared spectra of complex molecules), Moskow: Mir, 1963.

Lakin G. F. Biomertriya (Biomertrics), High. sch., Moskow 1990. with program “Microsoft Excel” for Windows-2000.

Gatsyra V. V. Metody pervichnogo farmakologicheskogo issledovaniyabiologicheski aktivnyh vechestv (Methods primary pharmacological studies of biologically active substances), Мoskow, 1974, pp.27-28.

Strebneva V. М., Davydova V. N., Hasina E. I. et al. Abstracts of Papers. Х1 Rosijskij nacionalnyj kongress “Chelovek i lekarstvo” (XI Russian national congress “Man and Medicine”), Мoskow, 2004, pp.831-832.

Lukianchuk V. D., Savchenkova L. V., Nemyatyh О. D. et al. Poshuk i eksperimentalnoe vyvchennya protygipoksychnyh zasobiv (Search and experimental study of potential antihypoxic compounds), Guidelines Kyiv, 2002, p.28.

Korablev M. V., Lukienko P. I. Protivogipoksicheskie sredstva (Antihypoxic agents), Minsk: Belarus, 1976, p.189.

Karaev А. L., Kozlova G. S., Smirnova T. N. et al. Eksperimentalnaya i kinicheskaya farmakologiya Experimental and clinical pharmacology, 2005, Vol. 68, No.6, pp.9-11.

Pitkevich E. S., Lozinskiy М. О., Lyzikov А. N. et al. Bemitil (bemitylum) – antigipoksant, actoprotector: farmacologicheskoe primenenie v medicine (Bemithyl (bemithylum) – antihypoxant, actoprotector: pharmacological effects and clinical applications in medicine): Inform. Bul., Кyiv, 2001, p.44.

Vinogradov V. М., Krivoruchko B. I. Psihofarmacologiya i biologicheskaya narcologiya – Psychopharmacology and Biological Narcology, 2001, Vol. 1, No.1, pp.27-37

GOST Style Citations

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

Abbreviated key title: J. Org. Pharm. Chem.

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