Analgesic Properties of New Pyrrolidinomorphinane Derivatives: Revealing Potential Pathways

Abstract

The pyrrolidinomorphinane derivatives have been found to be active in the writhing tests in mice with the analgesic effect being antagonized by naloxone. This suggests that analgesia is mediated by the opioid system. The compounds also displayed anti-inflammatory activity in formalin and histamine edema experimental models and the data may be evidence for anti-inflammatory activity involvement in the inhibition of pain reaction.

Keywords

Pyrrolidinomorphinane derivatives analgesic naloxone anti-inflammatory activity

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Compound VI: Yield 91%, mp 245–246oC (from ethanol). 1H NMR (CDCl₃, 500 MHz) 5: 1.93 (2H, m, H₂-15), 2.41 (3H, s, CH₃-N), 2.43 (1H, dd, J = 18.7, 6.6 Hz, H₁-10), 2.48 (1H, ddd, J = 12.4, 4.0, 2.2, H₁-16), 2.55 (1H, ddd, J = 12.6, 12.1, 1.5 Hz, H₁-16), 3.15 (1H, d, J = 8.1 Hz, H-8), 3.23 (1H, dd, J_10-10 = 18.7 Hz, H₁-10β), 3.68 (3H, s, CH₃0-C⁶), 3.79 (3H, s, CH₃0-C³), 3.98 (1H, d, J = 6.6 Hz, H-9), 4.36 (1H, d, J = 8.1 Hz, H-7), 4.66 (1H, d, J = 1.5 Hz, H-5β), 5.42 (1H, d, J = 8.7 Hz, H-19), 5.82 (1H, dd, J = 8.7, 1.4 Hz, H-18), 6.55 (1H, d, J = 8.1 Hz, H-1), 6.63 (1H, d, J = 8.1 Hz, H-2), 7.04 (2H, d, J = 8.7 Hz, H-2″ and 6″), 7.49 (2H, d, J = 8.7 Hz, H-3″ and 5″). Calcd for C₂₉H₂₇N₂O₅Br: 562.11037. Found: 562.10925. Compound VIII: Yield 88%, mp 248-250oC (from ethanol). 1H NMR (CDCl₃) δ: 1.87 (1H, ddd, J = 13.2, 4.2, 1.5 Hz, H₁-15), 2.15 (1H, ddd, J = 13.2, 12.1, 2.6 Hz, H₁-15), 2.41 (3H, s, CH₃-N), 2.43 (2H, m, H₁-10 and H₁-16), 2.55 (1H, ddd, J = 12.7, 12.1, 1.5 Hz, H₁-16), 2.89 (2H, m, H₁-2′ and H-8), 3.13 (2H, m, H₁2′, H₁-5′), 3.26 (1H, d, J = 19.1 Hz, H₁-10), 3.32 (1H, ddd, J = 9.6, 9.6, 7.5, 1.6 Hz, H-7), 3.42 (1H, m, H₁-5′), 3.58 (3H, s, CH₃0-C⁶), 3.81 (3H, s, CH₃0-C³), 3.86 (1H, d, J = 6.2 Hz, H-9), 4.63 (1H, ddd, J = 1.6, 1.4, 1.3 Hz, H-5), 5.33 (1H, dd, J = 8.8, 1.3 Hz, H-19), 5.78 (1H, dd, J = 8.8, 1.4 Hz, H-18), 6.42 (1H, d, J = 8.1 Hz, H-1), 6.53 (1H, d, J = 8.1 Hz, H-2), 6.58 (1H, d, J = 8.6 Hz, H-2″), 6.62 (1H, d, J = 8.4 Hz, H-6″), 7.25, 7.26 (each 1H, d, J = 8.6, 8.4 Hz, H-3″ and H-5^″). Calcd. for C₂₉H₃₁BrN₂O₃: 534.15184. Found: 534.15224. Compound I: Yield 72%, mp 218-220oC (from ethanol). ¹H NMR (CDCl₃) 5: 1.89 - 2.08 (2H, m, H₂-15), 2.43 (2H, m, H₁-10 and H₁-16), 2.45 c (3H, s, CH₃N), 2.58 (1H, ddd, J =12.4, 12.1, 2.7 Hz, H₁-16), 2.98 (1H, d, J = 8.1 Hz, H-8), 3.24 (1H, d, J = 18.3 Hz, H₁-10), 3.95 (1H, d, J = 5.8 Hz, H-9), 4.34 (1H, d, J = 8.1 Hz, H-7), 4.52 (1H, d, J 1.5 Hz, H-5), 5.42 (1H, d, J = 8.7 Hz, H-19), 5.85 (1H, dd, J 8.7, 1.5 Hz, H-18), 6.51 (1H, d, J = 8.2 Hz, H-1), 6.64 (1H, d, J = 8.2 Hz, H-2), 7.10 (2H, m, H^2′,6″), 7.40 (3H, m, H^{3″,4″,5″}). Compound II: Yield 96%, mp 219-220oC (from ethyl acetate). ¹H NMR (CDCl₃) δ: 1.79 (1H, ddd, J = 13.5, 5.3, 2.5 Hz, H₁-15), 1.98 (1H, ddd, J = 13.5, 12.1, 6.2 Hz, H₁-15), 2.49 (2H, m, H₁-10 and H₁-16), 2.42 (3H, s, CH₃-N), 2.53 (1H, ddd, J = 12.3, 12.1, 2.5 Hz, H₁-16), 3.07 (1H, d, J = 8.1 Hz, H-8), 3.20 (1H, d, J = 18.6 Hz, H₁-10), 3.93 (1H, d, J = 5.8 Hz, H-9), 4.38 (1H, d, J = 8.1 Hz, H-7), 4.49 (1H, d, J = 1.5 Hz, H-5), 5.33 (1H, d, J = 8.7 Hz, H-19), 5.77 (1H, dd, J = 8.7 и 1.5 Hz, H-18), 6.45 (1H, d, J = 8.2 Hz, H-1), 6.60 (1H, d, J = 8.2), 7.00 (2H, d, J = 8.6 Hz, H-2″ and H-6″), 7.46 (2H, d, J = 8.6 Hz, H-3″ and H-5″). Calcd. for C₂₇H₂₃BrN₂O₅: 534.0791. Found: 534.0790.

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