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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

Inactive Publication Date: 2009-05-20
SHIRE PLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Morphine has been found to be different from other agonists such as methadone and fentanyl in that it binds to receptors and triggers a cellular response resulting in analgesia, but it does not induce endocytosis like other agonists

Method used

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  • Compositions and methods for enhancing analgesic potency of covalently bound compounds, attenuating its adverse side effects, and preventing their abuse
  • Compositions and methods for enhancing analgesic potency of covalently bound compounds, attenuating its adverse side effects, and preventing their abuse
  • Compositions and methods for enhancing analgesic potency of covalently bound compounds, attenuating its adverse side effects, and preventing their abuse

Examples

Experimental program
Comparison scheme
Effect test

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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Abstract

The invention generally relates to compositions and methods with covalently bound compounds, such as controlled substances covalently attached to a chemical moiety, and opioid antagonists or covalently bound opioid antagonists to enhance analgesic potency and / or attenuate one or more adverse effects of covalently bound compounds, including adverse side effect(s) in humans such as nausea, vomiting, dizziness, headache, sedation (somnolence), physical dependence or pruritis. This invention relates to compositions and methods for selectively enhancing the analgesic potency of a covalently bound compound and simultaneously attenuating anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and / or tolerance effects associated with the administration of a covalently bound compound. The methods of the invention comprise administering to a subject an analgesic or sub-analgesic amount of a covalently bound compound and an amount of excitatory opioid receptor antagonist such as naltrexone or nalmefene effective to enhance the analgesic potency of a covalently bound compound and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and / or tolerance effects of covalently bound compound. The invention also relates to the addition of covalently-bound opioid antagonists to the compositions containing covalently bound compounds such that if the compositions are subjected to manipulation by illicit chemists, the opioid antagonist is released effectively reducing or eliminating the euphoric effect of the covalently bound compounds.

Description

[0001] Cross-References to Related Applications [0002] Pursuant to 35 U.S.C. §119(e), this application claims the benefit of U.S. Provisional Application No. 60 / 796,352, filed May 1, 2006; Benefit of U.S. Provisional Application 60 / 849,776; Claimed under 35 U.S.C. §119(e) Benefit of U.S. Provisional Application 60 / 849,775 filed October 6, 2006; Claimed under 35 U.S.C. §119(e) Benefit of U.S. Provisional Application 60 / 849,774, filed October 6, 2006; claim under 35 U.S.C. § 119(e) benefit of U.S. Provisional Application 60 / 791,892, filed April 1, 2006, each in its entirety The contents are incorporated herein by reference. Background technique [0003] Severe pain can be relieved by the administration of morphine or other dual-acting opioid agonists due to the fact that they mediate analgesic effects through their activation of inhibitory opioid receptors on nociceptive neurons ( See North, Trends Neurosci., Vol. 9, pp. 114-117 (1986) and Crain and Shen, Trends Pharmacol. S...

Claims

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Application Information

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IPC IPC(8): A61K31/485A61K9/20
Inventor R·J·柯克S·克里希南J·S·芒克里夫
Owner SHIRE PLC
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