Compositions and methods for enhancing analgesic potency of covalently bound compounds, attenuating its adverse side effects, and preventing their abuse
A technology of covalent bonding and composition, applied in the field of compositions and methods for improving the analgesic effect of covalently bonded compounds, reducing their side effects and preventing their abuse
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Embodiment 1
[0201] Example 1. Leu-hydrocodone
[0202] Reagent MW weight mmol Molar equivalent 1. Hydrocodone 299 1.00g 3.34 1.0 1. LiN(TMS) 2 , in THF 1M 10.5ml 10.5 3.15 1. THF - 25ml - - 2. Boc-Leu-OSu 328 3.28g 10.0 3.0
[0203] Addition of LiN(TMS) to hydrocodone in THF via syringe 2 of THF solution. The solution was stirred at room temperature for 5 minutes, then Boc-Leu-OSu was added. The resulting reaction mixture was stirred at room temperature for 18 hours. The reaction was neutralized to pH 7 with 6M HCl. Solvent was removed. The crude product was dissolved in CHCl 3 (100ml), washed with saturated sodium bicarbonate (3 x 100ml), dried over magnesium sulfate, filtered and the solvent removed. Solid collected as yellow powder (1.98 g, 95% yield): 1 H NMR (DMSO-d 6 )δ 0.86(dd, 6H), 1.31(s, 9H), 1.46(s, 2H), 1.55(m, 2H), 1.69(m, 1H), 1.87(dt, 1H), 2.07(dt, 2H) , 2.29(s, 3H), 2.43(m, 2H), 2.93(d, 1H), 3.11(s, 1H), 3...
Embodiment 2
[0206] Example 2. Example of a conjugate containing two different amino acids: Ala-Pro-Hydrocodone
[0207] Reagent MW weight mmol Molar equivalent Pro-Hydrocodone 468 0.25g 0.53 1.0 Boc-Leu-OSu 286 0.33g 1.2 2.26 NMM 101 0.50ml 5.38 10.2 DMF - 10ml - -
[0208] To a solution of Pro-hydrocodone in DMF was added NMM followed by Boc-Ala-OSu. The solution was stirred at room temperature for 18 hours. Solvent was removed. The crude product was purified by preparative HPLC (Phenomenex Luna C18, 30×250 mm, 5 μM, 100 ; gradient elution: 100 water / 00.1% TFA-MeCN → 0 / 100; 30ml / min.). Solid collected as light yellow powder (0.307 g, 85% yield): 1 H NMR (DMSO-d 6 )δ 1.16(d, 3H), 1.35(s, 9H), 1.51(m, 2H), 1.86-2.10(m, 6H), 2.50(m, 1H), 2.54(m, 1H), 2.69(m, 1H), 2.88(s, 3H), 3.02(dd, 1H), 3.26(d, 1H), 3.55(m, 1H), 3.67(m, 1H), 3.72(s, 3H), 3.80(s, 1H ), 4.25(m, 1H), 4.43(d, 1H), 5.01(s, 1H), 5.59(d, 1H), 6.75(d, 1H), 6.88(d,...
Embodiment 3
[0210] Example 3. Example of a conjugate containing two identical amino acids: Glu-Glu-Hydrocodone
[0211] Glu-Glu-hydrocodone was prepared according to the similar method of Example 2, but the amino acid raw material was Boc-Glu(OtBu)-OSu, and the conjugate raw material was Glu-hydrocodone.
[0212] tripeptide hydrocodone conjugate
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