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Synthesis and analgesic activity of aliphatic ketones-derived chiral hexahydro-2H-chromenes

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Abstract

New hexahydro-2H-chromenes were synthesized by reactions of monoterpenoid (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol with aliphatic ketones in the presence of montmorillonite clay H+-K10. The compounds formed and isolated as a pair of diastereoisomers were evaluated for their analgesic activity in vivo. It was found that the analgesic activity of (4aR,8R,8aR)-4,7-dimethyl-3,4,4a,5,8,8a-hexahydrospiro[chromene-2,1ʹ-cyclohexane]-4,8-diol 8b significantly exceeds (two orders of magnitude higher) the activity of diclofenac sodium in the acetic acid-induced writhing test. It has low acute toxicity and is very promising for further development.

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Scheme 1
Scheme 2

References

  1. Baishya G, Sarmah B, Hazarika N (2013) An environmentally benign synthesis of octahydro-2H-chromen-4-ols via modified montmorillonite K10 catalyzed Prins cyclization reaction. Synlett 24:1137–1141. https://doi.org/10.1055/s-0032-1316915

  2. Dragomanova S, Tancheva L, Georgieva M (2018) A review: biological activity of myrtenal and some myrtenal-containing medicinal plant essential oils. Scr Sci Pharm 5:22–33. https://doi.org/10.14748/ssp.v5i2.5614

  3. Eddy NB, Leimbach D (1953) Synthetic analgesics. II. Dithienylbutenyl- and dithienylbutylamines. J Pharm Exp Ther 107:385–393

  4. EPA (2002) Health effects test guideline 870.1100: Acute oral toxicity, U.S. EPA document 712-C-02-190. U.S. EPA, Office of Prevention, Pesticides and Toxic Substances

  5. Hamann LG, Meyer HJ, Ruppar DA, Marschke KB, Lopez FJ, Allegretto EA, Karanewsky DS (2005) Structure–activity relationships and sub-type selectivity in an oxabicyclic estrogen receptor α/β agonist scaffold. Bioorg Med Chem Lett 15:1463–1466. https://doi.org/10.1016/j.bmcl.2004.12.077

  6. Il’ina IV, Korchagina DV, Morozova EA, Tolstikova TG, Volcho KP, Salakhutdinov NF (2019) Synthesis and analgesic activity of octahydro-2H-chromenols-derivatives of aliphatic ketones. Russ Chem Bull 68:1061–1066. https://doi.org/10.1007/s11172-019-2520-5

  7. Il’ina I, Mikhalchenko O, Pavlova A, Korchagina D, Tolstikova T, Volcho K, Salakhutdinov N, Pokushalov E (2014) Highly potent analgesic activity of monoterpene-derived (2S,4aR,8R,8aR)-2-aryl-4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diols. Med Chem Res 23:5063–5073. https://doi.org/10.1007/s00044-014-1071-4

  8. Il’ina I, Pavlova A, Korchagina D, Ardashov O, Tolstikova T, Volcho K, Salakhutdinov N (2017) Synthesis and analgesic activity of monoterpenoid-derived alkyl-substituted chiral hexahydro-2H-chromenes. Med Chem Res 26:1415–1426. https://doi.org/10.1007/s00044-017-1847-4

  9. Il’ina IV, Volcho KP, Mikhalchenko OS, Korchagina D, Salakhutdinov NF (2011) Reactions of verbenol epoxide with aromatic aldehydes containing hydroxy or methoxy groups in the presence of montmorillonite clay. Helv Chim Acta 94:502–513. https://doi.org/10.1002/hlca.201000269

  10. Il’ina I, Volcho K, Korchagina D, Barkhash V, Salakhutdinov N (2007) Reactions of allyl alcohols of the pinane series and of their epoxides in the presence of montmorillonite clay. Helv Chim Acta 90:353–368. https://doi.org/10.1002/hlca.200790042

  11. Ilyina IV, Zarubaev VV, Lavrentieva IN, Shtro AA, Esaulkova IL, Korchagina DV, Borisevich SS, Volcho KP, Salakhutdinov NF (2018) Highly potent activity of isopulegol-derived substituted octahydro-2H-chromen-4-ols against influenza A and B viruse. Bioorg Med Chem Lett 28:2061–2067. https://doi.org/10.1016/j.bmcl.2018.04.057

  12. Khvostov MV, Borisov SA, Tolstikova TG, Dushkin AV, Tsyrenova BD, Chistyachenko YS, Polyakov NE, Dultseva GG, Onischuk AA, An’kov SV (2017) Supramolecular complex of Ibuprofen with larch polysaccharide arabinogalactan: studies on bioavailability and pharmacokinetics. Eur J Drug Metab Pharmacokinet 42:431–440. https://doi.org/10.1007/s13318-016-0357-y

  13. Kurbakova S, Il’ina I, Pavlova A, Korchagina D, Yarovaya O, Tolstikova T, Volcho K, Salakhutdinov N (2014) Synthesis and analgesic activity of monoterpenoid-derived 2-aryl-4,4,7-trimethyl-4a,5,8,8a-tetrahydro-4H-benzo[d][1,3]dioxin-8-ols. Med Chem Res 23:1709–1717. https://doi.org/10.1007/s00044-013-0772-4

  14. Le Bars D, Gozariu M, Cadden SW (2002) Animal models of nociception. Pharm Rev 53:597–652

  15. Li-Zhulanov NS, Zakharenko AL, Chepanova AA, Patel J, Zafar A, Volcho KP, Salakhutdinov NF, Reynisson J, Leung IKH, Lavrik OI (2018) A novel class of tyrosyl-DNA phosphodiesterase 1 inhibitors that contains the octahydro-2H-chromen-4-ol scaffold. Molecules 23:2468. https://doi.org/10.3390/molecules23102468

  16. Li-Zhulanov NS, Il’ina IV, Chicca A, Schenker P, Patrusheva OS, Nazimova EV, Korchagina DV, Krasavin M, Volcho KP, Salakhutdinov NF (2019) Effect of chiral polyhydrochromenes on cannabinoid system. Med Chem Res 28:450–464. https://doi.org/10.1007/s00044-019-02294-9

  17. Melnikova I (2010) Pain market. Nat Rev Drug Disco 9:589–590. https://doi.org/10.1038/nrd3226

  18. Mikhalchenko O, Il’ina I, Pavlova A, Morozova E, Korchagina D, Tolstikova T, Pokushalov E, Volcho K, Salakhutdinov N (2013) Synthesis and analgesic activity of new heterocyclic compounds derived from monoterpenoids. Med Chem Res 22:3026–3034. https://doi.org/10.1007/s00044-012-0310-9

  19. Mikhalchenko OS, Korchagina DV, Volcho KP, Salakhutdinov NF (2014) Formation of the compounds with an epoxychromene framework: role of the methoxy groups. Helv Chim Acta 97:1406–1421. https://doi.org/10.1002/hlca.201300461

  20. Mikhalchenko OS, Volcho KP, Salakhutdinov NF (2013) Synthesis of heterocyclic compounds by interaction of aldehydes with monoterpenoids. In: Torrioni L, Pescasseroli E (eds) New developments in aldehydes research. Nova Science Publishers, New York, NY, p 49–80

  21. Mironov AN (2013) Guidelines for preclinical studies of drugs. Grif and K, Moscow

  22. Moore ND (2009) In search of an ideal analgesic for common acute pain. Acute Pain 11:129–137. https://doi.org/10.1016/j.acpain.2009.09.003

  23. Patrusheva OS, Volcho KP, Salakhutdinov NF (2018) Synthesis of oxygen-containing heterocyclic compounds based on monoterpenoids. Russ Chem Rev 87:771–796. https://doi.org/10.1070/RCR4810

  24. Pavlova A, Mikhalchenko O, Rogachev A, Il’ina I, Korchagina D, Gatilov Yu, Tolstikova T, Volcho K, Salakhutdinov N (2015) Synthesis and analgesic activity of stereoisomers of 2-(3(4)-hydroxy-4(3)-methoxyphenyl)-4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diols. Med Chem Res 24:3821–3830. https://doi.org/10.1007/s00044-015-1426-5

  25. Pavlova AV, Nazimova EV, Mikhal’chenko OS, Il’ina IV, Korchagina DV, Ardashov OV, Morozova EA, Tolstikova TG, Volcho KP, Salakhutdinov NF (2016) Synthesis and analgesic activity of 4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromen-4,8-diols containing thiophene substituents. Chem Nat Compd 52:813–820. https://doi.org/10.1007/s10600-016-1785-2

  26. Pavlova A, Patrusheva O, Il’ina I, Volcho K, Tolstikova T, Salakhutdinov N (2017) The decisive role of mutual arrangement of hydroxy and methoxy groups in (3(4)-hydroxy-4(3)-methoxyphenyl)-4,7-dimethyl-3,4,4a,5,8,8ahexahydro-2H-chromene-4,8-diols in their biological activity. Lett Drug Des Disco 14:508–514. https://doi.org/10.2174/1570180813666161102142642

  27. Pershin GN (1971) Methods of experimental chemotherapy: practical guidance, 2nd edn. Medicina, Moscow

  28. Ponomarev K, Pavlova A, Suslov E, Ardashov O, Korchagina D, Nefedov A, Tolstikova T, Volcho K, Salakhutdinov N (2015) Synthesis and analgesic activity of new compounds combining azaadamantane and monoterpene moieties. Med Chem Res 24:4146–4156. https://doi.org/10.1007/s00044-015-1464-z

  29. Salakhutdinov NF, Volcho KP, Yarovaya OI (2017) Monoterpenes as a renewable source of biologically active compounds. Pure Appl Chem 89:1105–1117. https://doi.org/10.1515/pac-2017-0109

  30. Sidorenko AYu, Il’ina IV, Kravtsova AV, Aho A, Ardashov OV, Li-Zhulanov NS, Volcho KP, Salakhutdinov NF, Murzin DYu, Agabekov VE (2018a) Preparation of chiral isobenzofurans from 3-carene in the presence of modified clays. Mol Catal 459:38–45. https://doi.org/10.1016/j.mcat.2018.07.025

  31. Sidorenko AYu, Kravtsova AV, Wärna J, Aho A, Heinmaa I, Il’ina IV, Ardashov OV, Volcho KP, Salakhutdinov NF, Murzin DYu, Agabekov VE (2018b) Preparation of octahydro-2H-chromen-4-ol with analgesic activity from isopulegol and thiophene-2-carbaldehyde in the presence of acid-modified clays. Mol Catal 453:139–148. https://doi.org/10.1016/j.mcat.2018.05.007

  32. Slater Sh, Lasonkar PB, Haider S, Alqahtani MJ, Chittiboyina AG, Khan IA (2018) One-step, stereoselective synthesis of octahydrochromanes via the Prins reaction and their cannabinoid activities. Tetrahedron Lett 59:807–810. https://doi.org/10.1016/j.tetlet.2018.01.040

  33. Syubaev RD, Mashkovskii MD, Shvarts GY, Pokryshkin VI (1986) Comparative pharmacological activity of modern nonsteroidal antiinflammatory preparations. Pharm Chem J 20:17–22. https://doi.org/10.1007/BF00766871

  34. Szychowski J, Truchon J-F, Bennani YL (2014) Natural products in medicine: transformational outcome of synthetic chemistry. J Med Chem 57:9292–9308. https://doi.org/10.1021/jm500941m

  35. Tolstikova TG, Pavlova AV, Morozova EA, Khomenko TM, Volcho KP, Salakhutdinov NF (2012) The analgesic activity of 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepine-6-amine and its hydrochloride. Lett Drug Des Disco 9:513–516. https://doi.org/10.2174/157018012800389296

  36. Williams CM, Mander LN (2001) Chromatography with silver nitrate. Tetrahedron 57:425–447. https://doi.org/10.1016/S0040-4020(00)00927-3

  37. Woodcock J (2009) A difficult balance—pain management, drug safety, and the FDA. N Engl J Med 361:2105–2107. https://doi.org/10.1056/NEJMp0908913

  38. Yunes RA, Filho VC, Ferreira J, Calixto JB (2005) Pain relief with oral cannabinoids in familial Mediterranean fever. Stud Nat Prod Chem 30:191–212. https://doi.org/10.1111/j.1365-2044.1997.139-az0132.x

  39. Zheng Ya, Tice CM, Singh SB (2014) The use of spirocyclic scaffolds in drug discovery. Bioorg Med Chem Lett 24:3673–3682. https://doi.org/10.1016/j.bmcl.2014.06.081

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Acknowledgements

Authors would like to acknowledge the Multi-Access Chemical Research Center SB RAS for spectral and analytical measurements.

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Correspondence to Konstantin Volcho.

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Il’ina, I., Morozova, E., Pavlova, A. et al. Synthesis and analgesic activity of aliphatic ketones-derived chiral hexahydro-2H-chromenes. Med Chem Res (2020). https://doi.org/10.1007/s00044-020-02518-3

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Keywords

  • Terpene
  • Chromene
  • Heterocyclic compounds
  • Analgesic activity
  • Acetic acid-induced writhing test
  • Hot plate test