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Compositions and methods for enhancing opioid receptor binding by opioid hexadienoic acid esters and optionally substituted hexadienoic acid esters

A technology of hexadienoate and methyl hexanoate, applied in the field of opioid-derived compositions, can solve the problem that naloxone cannot flow through the BBB quickly, and achieve the effect of lasting neutralization/awake effect

Pending Publication Date: 2022-07-29
KAPPA PHARMA LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0026] IA. Elkiweri et al. Competing substrates named p-glycoprotein and organic anion transporter differentially reduce blood organ transport of fentanyl and loperamide: drug in Sprague-Dawley rats Kinetics and Pharmacodynamics" (published online in 2009 in https: / / www.ncbi.nlm.nih.gov / pubmed / 19095843 ) described that naloxone and fentanyl share a cellular influx transporter, which is saturated due to high concentrations of fentanyl in plasma, so that naloxone does not flow through rapidly regardless of dose BBB

Method used

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  • Compositions and methods for enhancing opioid receptor binding by opioid hexadienoic acid esters and optionally substituted hexadienoic acid esters
  • Compositions and methods for enhancing opioid receptor binding by opioid hexadienoic acid esters and optionally substituted hexadienoic acid esters
  • Compositions and methods for enhancing opioid receptor binding by opioid hexadienoic acid esters and optionally substituted hexadienoic acid esters

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0082] (E)-3-(cyclobutanemethyl)-9-((3,7-dimethyloctane-2,6-diethylenetriamine-1-yl)oxy)-1,2, 3,4,5,6,7,7a-Octahydro-4aH-4,12-methylbenzofuro[3,2-e]isoquinoline-4a,7-diol, nalbuphine-aroma Leaf base, (NB-20). To a suspension of nalbuphine hydrochloride (400 mg, 1.0 mmol) in acetone (20 mL) and toluene (20 mL) was added potassium bicarbonate (280 mg, 2.0 mmol) at room temperature. Geranyl bromide (320 mg, 1.5 mmol) was added. The reaction mixture was stirred under reflux conditions for 4 hours and at room temperature overnight. The reaction mixture was evaporated and the residue was purified by column chromatography (silica gel, EtOAc / heptane / methanol, 1:1:0.10). After evaporation of selected fractions, a colorless oil formed in 45% yield and 91% purity by HPLC. by NMR 1 H to confirm the structure.

[0083] 3-(Cyclobutanemethyl)-9-(((2E,6E)-3,7,11-trimethyldodecyl-2,6,10-triethylenetetramin-1-yl) oxy)-1,2,3,4,5,6,7,7a-octahydro-4aH-4,12-methylbenzofuro[3,2-e]isoquinoline...

example 2

[0103] Example 2 - Stability in simulated gastrointestinal fluid (sGIF).

[0104] The stability evaluation of NB-33 in simulated gastrointestinal fluid (sGIF) is as follows, and Table 1 summarizes the data of each compound.

[0105] sGIF is 0.5% pepsin (Alfa Aesar, pepsin, porcine stomach) in 0.1 N HCl in water. Each derivative (50 mg) was mixed with sGIF (50 mL) and incubated on a shaker at a temperature of 37°C. The hydrolysis and release of nalbuphine was monitored by HPLC at T=0 hours, 0.5 hours, 1 hour, 2 hours and 4 hours. The acceptance criterion is that no less than 80% of the derivatives are still intact after 4 hours.

example 3-

[0106] Example 3- Stability in human plasma.

[0107] The stability of NB-56 in human plasma was assessed as follows, and Table 1 summarizes the data for each compound.

[0108] NB-56 (1.0 mg) was dissolved in 10 mL of plasma (pooled normal human plasma, sodium citrate, Innovative Research Corporation) while stirring at a temperature of 20°C for 10 minutes. The solution was incubated at 37°C. Take 1 mL of solution for each sample. MeCN (0.05 mL) was added to the sample solution. Shake for 1 minute and then centrifuge (15 minutes, 14.000 r / m). The supernatant was filtered off and extracted with EtOAc (2 x 20 mL). Use MgSO 4 The combined extracts were dried and concentrated in vacuo. The residue was dissolved in methanol (20 μl). The solution was used for HPLC injection.

[0109] The hydrolysis and release of nalbuphine was monitored by HPLC at T=0 hours, 0.5 hours, 1 hour, 2 hours and 4 hours. The acceptance criterion is that no less than 20% of the derivatives are h...

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Abstract

The present invention relates to opioid-derived compositions and antagonists thereof for use in the field of opioid receptor modulation related therapies. The invention discloses a 3-hexadienoic acid ester modifier of an opioid drug. The 3-hexadienoic acid ester modifier is used for improving the combination of the opioid drug and an opioid receptor during oral administration. A 3-hexadienoate modifier of nalbuphine or a pharmaceutically acceptable salt thereof is formulated for improving the quality of pain management during intravenous, intranasal, transdermal, sublingual, rectal, local, intramuscular, subcutaneous or inhalation administration. The 3-hexadienoic acid ester modifier of the opioid antagonist is prepared and is used for improving the inhibition effect on an opioid receptor during oral administration. Also formulated is a 3-hexadienoic acid ester modifier of naloxone or a pharmaceutically acceptable salt thereof for use in improving sobering quality during intravenous, intranasal, transdermal, sublingual, rectum, local, intramuscular, subcutaneous or inhalation administration.

Description

[0001] This application is a PCT application to non-provisional US Patent Application No. 16 / 540,058, filed on August 14, 2019, and claims a patent filed on August 11, 2019 entitled "By Opioid Hexadienoic Acid Esters and Optionally Substituted Hexadienoic Acids" U.S. Patent Act Priority 119 of prior U.S. Provisional Patent No. 62 / 885,311 to Compositions and Methods for Ester-Enhanced Opioid Receptor Binding. technical field [0002] The present invention relates to opioid-derived compositions for use in therapeutic areas related to opioid receptor modulation. Background technique [0003] Nalbuphine (Nubain), as an analgesic for moderate to severe pain, was launched in 1979 and has been effectively used in clinical practice so far. It is mainly used in combination with anesthetics for preoperative and postoperative analgesia, and for acute and chronic pain management during childbirth. More recently, its use has expanded to the treatment of movement disorders, skin disorder...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P25/36C07C229/38C07D221/28
CPCA61P25/36C07D221/28C07C219/22C07D489/08C07D489/02C07D221/26A61P17/00A61P25/14
Inventor G·尼科诺夫L·伊萨库兰M·V·沃隆科夫
Owner KAPPA PHARMA LLC
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