Combining rimonabant and fentanyl in a single entity: preparation and pharmacological results

Abstract

Based on numerous pharmacological studies that have revealed an interaction between cannabinoid and opioid systems at the molecular, neurochemical, and behavioral levels, a new series of hybrid molecules has been prepared by coupling the molecular features of two wellknown drugs, ie, rimonabant and fentanyl. The new compounds have been tested for their affinity and functionality regarding CB₁ and CB₂ cannabinoid and μ opioid receptors. In [³⁵S]-GTPγS (guanosine 5′-O-[gamma-thio]triphosphate) binding assays from the post-mortem human frontal cortex, they proved to be CB₁ cannabinoid antagonists and μ opioid antagonists. Interestingly, in vivo, the new compounds exhibited a significant dual antagonist action on the endocannabinoid and opioid systems.

Keywords:

• fentanyl
• rimonabant
• cannabinoid
• opioid
• behavioral assays

Supplementary material

Synthesis procedures and characterization of new compounds

General

Melting points were determined with a Reichert Jung Thermovar apparatus (Reichert Optische Werke, Vienna, Austria). Mass spectra (MS) were recorded using electrospray positive mode. Elemental analysis was performed on a Heraeus CHN-O rapid analyzer (Foss Heraeus GmbH, Hanau, Germany). Analyses indicated by symbols of the elements or functions were within ±0.4% of theoretical values. Analytical high-performance liquid chromatography (HPLC) was run on a Waters 6000 with a Delta Pak C 18.5 μm (Waters, Cerdanyola del Vallès, Spain), 300 Å, 3.9×150 mm column, using CH₃CN/H₂O 95/5 (0.05% trifluoroacetic acid [TFA]) as eluent; flow rate 1 mL per minute; 254 nm. Nuclear magnetic resonance (NMR, ¹H, ¹³C) spectra were recorded on Varian 300 (Agilent, Barcelona, Spain) and 400 unity spectrometers. All chemical shifts are reported in ppm. s: singlet; t: triplet; m: multiplet; brt: broad triplet; dp: double quadruplet; brm: broad multiplet; p: pentuplet; q: quadruplet; brd: broad doublet; brs: broad signal.

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-(N-(1-phenethylpiperidin-4yl)propionamido)propyl)-1H-pyrazole-3-carboxamide (4a)

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride (2) (60 mg, 0.15 mmol), TEA (triethylamine) (26 μL, 0.19 mmol) and N-(3-aminopropyl)-N-(1-phenethylpiperidin-4-yl)propionamide (3a) (82 mg, 0.11 mmol), affording 4a as a yellow oil (44%): 1H NMR (399.93 MHz, CDCl₃) δ7.43–7.04 (m, 12H), 4.46 (m, 1H), 3.43 (m, 2H), 3.37 (t, 2H, J=7.1 Hz), 3.28 (m, 2H), 3.1 (m, 2H), 2.77 (m, 2H), 2.59 (m, 2H), 2.35 (s, 3H), 2.32 (m, 2H), 2.05 (m, 2H), 1.84 (m, 2H), 1.69 (m, 2H), 1.10 (t, 3H, J=7.3 Hz); ¹³C NMR (99.98 MHz, CDCl₃) δ 173.7, 162.8, 145.2, 142.8, 140.1, 136.0, 135.7, 134.9, 132.9, 130.8, 130.6, 130.2, 128.9, 128.8, 128.6, 128.4, 127.8, 126.1, 117.5, 60.3, 55.3, 53.2, 51.5, 41.1, 39.4, 36.9, 33.8, 30.1, 26.9, 26.8, 9.7, 9.6, 9.4; MS (ES⁺) (electrospray) m/z (%): 680 (100) [M+H]⁺; HPLC 99% purity; anal. (elemental analysis) C36H40Cl3N5O2.H2O (C, H, N, O).

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-(N-(1-phenethylpiperidin-4-yl)propionamido)butyl)-1H-pyrazole-3-carboxamide (4b)

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride (2) (60 mg, 0.15 mmol), TEA (26 μL, 0.19 mmol) and N-(4-aminobutyl)-N-(1-phenethylpiperidin-4-yl)propionamide (3b) (63 mg, 0.19 mmol), affording 4b as a yellowish solid (99%): melting point 80°C–82°C; ¹H NMR (399.93 MHz, CDCl₃) δ 7.42–7.05 (m, 12H), 4.51 (m, 1H), 3.43 (m, 2H), 3.23 (m, 2H), 2.89 (m, 2H), 2.78 (m, 2H), 2.61 (m, 2H), 2.37 (s, 3H), 2.32 (m, 2H), 2.10 (m, 2H), 1.92 (m, 2H), 1.64 (m, 2H), 1.12 (t, 3H, J=73 Hz); ¹³C NMR (99.98 MHz, CDCl₃) δ 173.9, 162.7, 145.0, 143.0, 139.9, 135.9, 135.8, 134.9, 132.9, 130.7, 130.5, 130.2, 129.1, 128.8, 128.8, 128.4, 126.1, 117.6, 60.2, 55.1, 53.1, 43.12, 38.2, 33.6, 30.6, 28.7, 27.3, 26.8, 9.7, 9.4; MS (ES⁺) m/z (%): 696 (100) [M+H]⁺; HPLC 99% purity; anal. C37H42Cl3N5O2.1.5H2O (C, H, N, O).

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(5-(N-(1-phenethyl piperidin-4-yl)propionamido)pentyl)-1H-pyrazole-3-carboxamide (4c)

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride (2) (49 mg, 0.12 mmol), TEA (21 μL, 0.15 mmol) and N-(5-aminopentyl)-N-(1-phenethylpiperidin-4-yl)propionamide (3c) (52 mg, 0.15 mmol), affording 4c as a yellow solid (73%): ¹H NMR (399.93 MHz, CDCl₃) (mixture of rotamers) δ 7.40–6.92 (m, 12H), 5.80 (m, 0.4H), 4.55 (m, 0.3H), 3.83 (m, 0.6H), 3.70 (m, 0.7H), 3.44 (m, 2H), 3.10 (m, 2H), 2.74 (m, 2H), 2.56 (m, 2H), 2.35 (s, 3H), 2.30 (m, 2H), 2.07 (m, 2H), 1.80 (m, 2H), 1.65–1.30 (m, 8H), 1.12 (m, 3H); ¹³C NMR (99.98 MHz, CDCl₃) δ 173.8, 173.0, 162.7, 144.9, 138.8, 136.0, 134.9, 133.0, 130.8, 130.6, 130.5, 130.3, 128.9, 128.6, 128.4, 127.9, 126.1, 117.7, 60.4, 55.3, 53.3, 53.0, 43.3, 42.6, 38.7, 33.6, 30.7, 31.3, 29.5, 29.2, 9.8, 9.6, 9.4; MS (ES⁺) m/z (%): 710 (100) [M+H]⁺; HPLC 99% purity; anal. C38H44Cl3N5O2 (C, H, N, O).

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(6-(N-(1-phenethy lpiperidin-4-yl)propionamido)hexyl)-1H-pyrazole-3-carboxamide (4d)

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride (2) (60 mg, 0.15 mmol), TEA (26 μL, 0.19 mmol) and N-(6-aminohexyl)-N-(1-phenethylpiperidin-4-yl)propionamide (3d) (68 mg, 0.19 mmol), affording 4d as a white solid (54%): melting point 69°C–71°C; ¹H NMR (399.93 MHz, CDCl₃) (mixture of rotamers) δ 7.43–6.92 (m, 12H), 4.46 (m, 0.6H), 3.55 (m, 0.4H), 3.41 (m, 2H), 3.20–3.04 (m, 4H), 2.79 (m, 2H), 2.59 (m, 2H), 2.37 (s, 3H), 2.32 (m, 2H), 2.06 (brt, 2H, J=11.7 Hz), 1.86 (dq, 2H, J=3.4 and 12.2 Hz), 1.68 (brm, 2H), 1.60, 1.54, 1.39 and 1.31 (m, 8H), 1.14 (m, 3H); ¹³C NMR (99.98 MHz, CDCl₃) δ 173.7, 162.7, 145.0, 143.1, 140.1, 136.0, 135.8, 134.9, 133.0, 130.8, 130.6, 130.5, 130.3, 128.9, 128.6, 128.4, 127.9, 126.1, 117.7, 60.4, 54.5, 53.2, 51.4, 43.4, 42.0, 38.8, 33.9, 30.9, 31.6, 30.0, 29.8, 26.9, 26.7, 26.6, 9.8, 9.7, 9.4; MS (ES⁺) m/z (%): 724 (100) [M+H]⁺; HPLC 99% purity; anal. C39H46Cl3N5O2 (C, H, N, O).

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(7-(N-(1-phenethylpiperidin-4yl)propionamido)heptyl)-1H-pyrazole-3-carboxamide (4e)

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride (2) (60 mg, 0.15 mmol), TEA (26 μL, 0.19 mmol) and N-(7-aminoheptyl)-N-(1-phenethylpiperidin-4-yl)propionamide (3e) (41 mg, 0.11 mmol), affording 4e as an orange oil (55%): ¹H NMR (399.93 MHz, CDCl₃) (mixture of rotamers) δ7.41–6.91 (m, 12H), 4.45 (m, 0.7H), 3.53 (m, 0.3H), 3.39 (p, 2H, J=7.0 Hz), 3.17 (t, 2H, J=8.0 Hz), 3.10 (m, 2H), 2.79 (m, 2H), 2.60 (m, 2H), 2.36 (s, 3H), 2.30 (m, 2H), 2.05 (brt, 2H, J=11.7 Hz), 1.84 (q, 2H, J=11.3 Hz), 1.67 (brd 2H, J=10.7 Hz), 1.58, 1.51, 1.35, 1.26 (m, 10H), 1.30 (m, 3H); ¹³C NMR (99.98 MHz, CDCl₃) δ 173.7, 172.9, 162.6, 145.0, 143.0, 140.1, 135.9, 135.8, 134.8, 132.9, 130.8, 130.5, 130.3, 117.6, 60.4, 55.2, 53.1, 51.2, 43.4, 38.9, 38.8, 33.8, 29.6, 27.0, 26.9, 9.8, 9.6, 9.4, 42.1, 31.6, 30.8, 28.9, 27.1; MS (ES⁺) m/z (%): 738 (100); [M+H]⁺; HPLC 99% purity; anal. C40H48Cl3N5O2.0.5H2O (C, H, N, O).

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(8-(N-(1-phenethylpiperidin-4-yl)propionamido)octyl)-1H-pyrazole-3-carboxamide (4f)

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride (2) (60 mg, 0.15 mmol), TEA (26 μL, 0.19 mmol) and N-(8-aminooctyl)-N-(1-phenethylpiperidin-4-yl)propionamide (3f) (40 mg, 0.10 mmol), affording 4f as an orange solid (87%): melting point 59°C–60°C; ¹H NMR (399.93 MHz, CDCl₃) (mixture of rotamers) δ 7.40–6.93 (m, 12H), 4.45 (m, 0.8H), 3.45 (m, 0.2H), 3.38 (m, 2H), 3.12 (m, 2H), 3.04 (m, 2H), 2.79 (m, 2H), 2.61 (m, 2H), 2.35 (s, 3H), 2.31 (m, 2H), 2.02 (m, 2H), 1.87 (m, 2H), 1.68 (m, 2H), 1.56–1.28 (m, 12H), 1.13 (m, 3H); ¹³C NMR (99.98 MHz, CDCl₃) δ 173.8, 172.9, 162.6, 145.1, 144.8, 140.5, 136.0, 134.9, 133.0, 130.8, 130.5, 130.3, 128.9, 128.6, 128.4, 127.9, 126.1, 117.7, 60.4, 53.3, 53.2, 43.5, 39.0, 33.9, 31.7, 30.9, 29.3, 29.2, 27.2, 29.7, 26.9, 26.7, 9.8, 9.6, 9.4; MS (ES⁺) m/z (%): 750 (100) [M+H]⁺; HPLC 98% purity; anal. C41H50Cl3N5O2.H2O (C, H, N, O).

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(9-(N-(1-phenethylpiperidin-4-yl)propionamido)nonyl)-1H-pyrazole-3-carboxamide (4g)

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride (2) (60 mg, 0.15 mmol), TEA (26 μL, 0.19 mmol) and N-(9-aminononyl)-N-(1-phenethylpiperidin-4-yl)propionamide (3g) (30 mg, 0.07 mmol) affording 4g as a yellow oil (85%): ¹H NMR (399.93 MHz, CDCl₃) (mixture of rotamers) δ 7.73–6.92 (m, 12H), 4.45 (m, 0.7H), 3.53 (m, 0.3H), 3.39, 3.10 (m, 2H), 3.07 (m, 2H), 2.80 (m, 2H), 2.57 (m, 2H), 2.35 (s, 3H), 2.30 (m, 2H), 2.08 (m, 2H), 1.84 (q, 2H, J=12.2 Hz), 1.67 (m, 2H), 1.58, 1.49 and 1.26 (m, 14H), 1.13 (m, 3H); ¹³C NMR (99.98 MHz, CDCl₃) δ 173.7, 172.9, 162.6, 145.1, 143.1, 135.9, 134.8, 132.9, 130.8, 130.6, 130.5, 130.3, 128.9, 128.6, 128.4, 127.8, 127.2, 60.4, 55.3, 53.2, 51.4, 43.5, 39.0, 33.8, 31.6, 30.9, 30.0, 29.5, 29.2, 27.3, 27.2, 26.7, 26.9, 9.8, 9.6, 9.4; MS (ES⁺) m/z (%): 764 (100) [M+H]⁺; HPLC 98% purity; anal. C42H52Cl3N5O2.1.25H2O (C, H, N, O).

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(12-(N-(1-phenethylpiperidin-4-yl)propionamido)dodecyl)-1H-pyrazole-3-carboxamide (4h)

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride (2) (60 mg, 0.15 mmol), TEA (26 μL, 0.19 mmol) and N-(12-aminododecyl)-N-(1-phenethylpiperidin-4-yl)propionamide (3h) (78 mg, 0.19 mmol), affording 4h as an orange oil (99%): ¹H NMR (399.93 MHz, CDCl₃) δ 7.40–6.91 (m, 12H), 4.41 (m, 1H), 3.36 (q, 2H, J=7.5 Hz), 3.14–2.96 (m, 4H), 2.78 (m, 2H), 2.58 (m, 2H), 2.30 (m, 3H), 2.23 (m, 2H), 1.97 (m, 2H), 1.80 (m, 2H), 1.62 (m, 2H), 1.55–1.19 (m, 20H), 1.08 (m, 3H); ¹³C NMR (99.98 MHz, CDCl₃) δ 174.2, 173.3, 163.0, 145.5, 143.4, 136.4, 136.3, 135.3, 133.4, 131.2, 130.9, 130.7, 129.3, 129.1, 128.9, 128.3, 127.8, 126.5, 118.1, 60.9, 55.7, 53.8, 53.7, 53.5, 44.1, 42.7, 39.5, 34.26, 31.4, 30.2, 29.9, 29.8, 29.7, 27.8, 27.7, 27.4, 27.2; MS (ES⁺) m/z (%): 808 (100) [M+H]⁺; HPLC 98% purity; anal. C45H58Cl3N5O2.H2O (C, H, N, O).

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-(N-(1-phenethylpiperidin-4-yl)propionamido)phenyl)-1H-pyrazole-3-carboxamide (4i)

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride (2) (60 mg, 0.15 mmol), TEA (15 μL, 0.11 mmol) and N-(3-aminophenyl)-N-(1-phenethyl-piperidin-4-yl)propionamide (3i) (35 mg, 0.09 mmol), affording 4i as a yellow solid (48%): melting point 105°C–108°C; ¹H NMR (399.93 MHz, CDCl₃) δ 7.53–6.73 (m, 16H), 4.58 (m, 1H), 2.91 (brs, 2H, J=10.5 Hz), 2.61 (m, 2H), 2.43 (m, 2H), 2.33 (s, 3H), 2.07 (brt, 2H, J=11.5 Hz), 1.91 (m, 2H), 1.75 (brt, 2H, J=14.0 Hz), 1.39 (m, 2H), 0.94 (t, 3H, J=7.5 Hz); ¹³C NMR (99.98 MHz, CDCl₃) δ 173.4, 160.5, 144.5, 143.6, 139.5, 138.9, 136.2, 135.7, 135.1, 133.0, 132.9, 130.8, 130.5, 130.4, 129.6, 129.0, 128.6, 128.3, 127.9, 126.8, 126.0, 125.8, 121.4, 119.2, 118.3, 60.4, 53.1, 52.2, 33.8, 30.6, 28.5, 9.6, 9.5; MS (ES⁺) m/z (%): 716 (100) [M+H]⁺; HPLC 99% purity; anal. C39H38Cl3N5O2.3H2O (C, H, N, O).

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-(N-(1-phenethylpiperidin-4yl)propionamido)benzyl)-1H-pyrazole-3-carboxamide (4j)

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride (2) (60 mg, 0.15 mmol), TEA (26 μL, 0.19 mmol) and N-(3-(aminomethyl)benzyl)-N-(1-phenethylpiperidin-4-yl)propionamide (3j) (60 mg, 0.15 mmol), affording 4j as a yellow solid (60%): melting point 83°C–85°C; ¹H NMR (399.93 MHz, CDCl₃) (mixture of rotamers) δ 7.40–7.06 (m, 16H), 4.60 (m, 4H), 4.51 (m, 1H), 3.67 (m, 1H), 3.00 (m, 2H), 2.74 (m, 2H), 2.55 (m, 2H), 2.48 (q, 0.5H, J=7.3 Hz), 2.40 (s, 3H), 2.23 (q, 1.5H, J=7.3 Hz), 2.11 (m, 2H), 1.79 (m, 2H), 1.65 (m, 2H), 1.20 (t, 1H, J=7.3 Hz), 1.07 (t, 2H, J=7.3 Hz); ¹³C NMR (99.98 MHz, CDCl₃) δ 174.7, 173.9, 162.6, 144.7, 143.1, 140.1, 139.1, 138.3, 136.0, 135.9, 134.9, 132.9, 130.8, 130.5, 130.3, 129.0, 128.9, 128.6, 128.4, 127.9, 127.2, 126.5, 126.1, 124.8, 124.5, 117.9, 60.3, 53.0, 51.5, 50.7, 46.3; MS (ES⁺) m/z (%): 742 (100) [M+H]⁺; HPLC 99% purity; anal. C41H42N5O2.0.5H2O (C, H, N, O).

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-[(4-N-(1-phenethylpiperidin-4-yl)propionamido)cyclohexyl]methyl)cyclo-hexyl-1H-pyrazole-3-carboxamide (4k)

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride (2) (49 mg, 0.12 mmol), TEA (21 μL, 0.15 mmol) and N-(4-((4-aminocyclohexyl)methyl) cyclohexyl)-N-(1-phenethylpiperidin-4-yl)propionamide (3k) (70 mg, 0.15 mmol), affording 4k as a yellow solid (73%): ¹H NMR (399.93 MHz, CDCl₃) δ 7.36–6.69 (m, 12H), 4.12 (m, 1H), 3.84 (m,1H), 3.47 (m, 1H), 3.05 (m, 2H), 2.57 (m, 2H), 2.53 (m, 2H), 2.31 (s, 3H), 2.27 (m, 2H), 2.02 (m, 2H), 1.86 (m, 2H), 1.63 (m, 2H), 1.99–1.31 (m, 20H), 1.19 (m, 3H); ¹³C NMR (99.98 MHz, CDCl₃) δ 172.8, 161.9, 145.2, 142.9, 140.0, 136.0, 135.9, 134.8, 132.9, 130.8, 130.6, 130.3, 128.8, 128.6, 128.4, 127.8, 126.1, 117.7, 60.5, 56.0, 53.3, 48.5, 45.5, 37.5, 34.4, 33.1, 32.1, 32.0, 29.6, 29.3, 33.8, 28.6, 24.5, 9.6, 9.4; MS (ES⁺) m/z (%): 816 (100) [M+H]⁺; HPLC 99% purity; anal. C46H56Cl3N5O2.2H2O (C, H, N, O).

Acknowledgments

This work was supported by grants from the Spanish Ministry of Economy and Competitivity (SAF2012-40075, SAF2009-12422, SAF2010-20521, SAF2011-26818), Red de Trastornos Adictivos (RETICS RD06/001), the Madrid Government (CANNAB-CM, S2010/BMD-2308), the University of the Basque Country (UFI 11/35), the Basque Government (IT-199-07, SAIOTEK S-PE10UN14), and the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM. AME is the recipient of a predoctoral fellowship from the Basque Government. PM is the recipient of a fellowship (JAE-Pre-2010-01119) from Junta para la Ampliación de Estudios, cofinanced by the European Social Fund. The authors thank Laura Hernández-Folgado for her help in preparation of the manuscript.

Disclosure

The authors report no conflicts of interest in this work.