Oligomer-opioid agonist conjugates
A technology of compounds and compositions, applied in the field of oligomer-opioid agonist conjugates, capable of solving problems such as death, first-pass metabolism, opioid agonist abuse, etc.
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Embodiment 1
[0304] Preparation of oligomer-nalbuphine conjugate - "Method A"
[0305] PEG-nalbuphine was prepared using the first method. The method employed in this example is schematically shown below.
[0306]
[0307] Desalination of nalbuphine hydrochloride dihydrate:
[0308] Nalbuphine hydrochloride dihydrate (600 mg from Sigma) was dissolved in water (100 mL). Add saturated K 2 CO 3 aqueous solution, then adjust the pH to 9.3 with 1N HCl solution and saturate with NaCl. The solution was extracted with dichloromethane (5 x 25 mL). The combined organic solutions were washed with brine (100 mL), washed with Na 2 SO 4 Dried, concentrated to dryness and dried under high vacuum to yield nalbuphine (483.4 mg, 97% recovery). in CDCl 3 pass in 1 H-NMR confirmed the product.
[0309] Synthesis of 3-O-mPEG 3 - Nalbuphine (2) (n=3):
[0310]
[0311] Nalbuphine (28.5 mg, 0.08 mmol) was dissolved in a mixture of acetone (2 mL) and toluene (1.5 mL). Potassium carbonate (21 m...
Embodiment 2
[0327] Preparation of oligomer-nalbuphine conjugate - "Method B"
[0328] The second method was used to prepare PEG-nalbuphine. The method employed in this example is schematically shown below.
[0329]
[0330]
[0331] Synthesis of 3-O-MEM-nalbuphine (3):
[0332]
[0333] Dissolve nalbuphine (321.9 mg, 0.9 mmol) in acetone / toluene (19 mL / 8 mL). Potassium carbonate (338 mg, 2.45 mmol) was then added followed by MEMCl (160 μL, 1.41 mmol). The resulting mixture was stirred at room temperature for 21 hours, and MeOH (0.3 mL) was added to quench the reaction. The reaction mixture was concentrated to dryness under reduced pressure. The residue was mixed with water (5 mL) and brine (15 mL), extracted with dichloromethane (3 x 15 mL). The combined organic solutions were washed with brine, washed with Na 2 SO 4 Dry and concentrate. The residue was separated by Biotage automated flash column chromatography using 2-10% MeOH in dichloromethane to give the product 3-O-M...
Embodiment 3
[0377] Preparation of oligomer-nalbuphine conjugate - "Method C"
[0378] The third method was used to prepare PEG-nalbuphine. The method employed in this example is schematically shown below.
[0379]
[0380] Synthesis of TrO-PEG 5 -OH(7)(n=5):
[0381] PEG 5 -Di-OH(6) (n=5) (5.88 g, 24.19 mmol) was dissolved in toluene (30 mL), and concentrated under reduced pressure to remove toluene. The residue was dried under high vacuum. Anhydrous DMF (40 mL) was added followed by DMAP (0.91 g, 7.29 mmol) and TrCl (trityl chloride) (1.66 g, 5.84 mmol). The resulting mixture was heated at 50 °C for 22 hours. The reaction was concentrated to remove solvent (high vacuum, 50 °C). The residue was mixed with water and extracted with EtOAc (3 x 25 mL). The combined organic solutions were washed with brine, washed with Na 2 CO 3 Dry and concentrate. The residue was purified by flash column chromatography on silica gel to give the product 1.29g in 46% yield. in CDCl 3 pass in ...
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