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Opioid ketal compounds and uses thereof

a technology of opioid ketal and ketal compounds, which is applied in the field of new opioid ketal compounds, can solve the problems of abuse and diversion, and the use of opioid compounds has been reported to have a number of potential side effects, and achieve the effects of treating, preventing pain, and preventing pain

Inactive Publication Date: 2016-08-25
NORDBOTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to new compounds, pharmaceutical compositions, and methods of treating pain. Specifically, the invention is about new compounds of Formula I, Formula II, and Formula III, as well as pharmaceutical compositions containing them. These compounds can be used to treat, ameliorate, or prevent pain in mammals. The invention also includes methods of preparing these compounds and the use of them in making medications for pain treatment. The technical effects of the invention include providing new compounds with improved pain treatment efficacy and safety.

Problems solved by technology

The use of opioid compounds has been reported to have a number of potential side effects, including abuse and diversion.

Method used

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  • Opioid ketal compounds and uses thereof
  • Opioid ketal compounds and uses thereof
  • Opioid ketal compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation examples

Example 1

[0220]

[0221]Preparation of a compound of Formula IV (oxycodone 2,4-pentanediol ketal): Oxycodone free base (2.91 g), p-toluenesulfonic acid monohydrate (2.17 g) and 2,4-pentanediol (5.40 g, mixture of isomers) were stirred in toluene (250 mL) and heated under reflux with a Dean Stark water trap attached. After 3½ hours, the mixture was cooled, treated with triethylamine (5 mL), and washed with water (2×50 mL). The toluene solution was concentrated under reduced pressure to a clear resin that solidified on standing to afford a white solid (Formula I) (3.87 g). FIG. 7 provides the 1H NMR (d6-DMSO) spectrum of the compound of Formula IV (oxycodone 2,4-pentanediol ketal).

[0222]Using the procedure detailed herein, isomers IVC and IVD were prepared by reacting oxycodone with 2S,4S-pentanediol and 2R,4R-pentanediol, respectively. In addition, using the procedure detailed herein, a mixture of isomers IVA and IVB was prepared by reacting oxycodone with meso-2,4-pentanediol.

example 2

[0223]

[0224]Preparation of compound of Formula V (oxycodone 1,3-butanediol ketal): Oxycodone free base (1.58 g), p-toluenesulfonic acid (1.19 g) and 1,3-butanediol (5.73 g, mixture of isomers) were stirred in toluene (125 mL) and heated under reflux with a Dean Stark water trap attached. After 5 hours the mixture was cooled and washed with saturated sodium bicarbonate solution (2×50 mL), then with water (50 ml). The solution was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to a colorless resin that solidified on standing to afford a white solid (2.12 g). FIG. 8 provides the 1H NMR (d6-DMSO) spectrum of the compound of Formula V (oxycodone 1,3-butanediol ketal).

[0225]Using the general scheme shown above, the following compounds were prepared and characterized. Characterization was carried out using an LC / MS system. The LC / MS utilized a Phenomenex Luna C18 column and a gradient elution with the first solvent of 90% 2.8 mM ammonium formate in water, 1...

example 3

[0227]A mixture of isomers of oxycodone 2,4-pentanediol ketal along with unreacted oxycodone at a concentration of 2 mg / ml was subjected to hydrolysis in USP Simulated Gastric Fluid (SGF) (0.2% NaCl and 0.32% pepsin in 0.084 N HCl) at 37° C., with analysis of the hydrolyzed oxycodone conducted by LC / MS. Results from the hydrolysis are shown in Table 1a and illustrated in FIG. 1.

[0228]As a comparison, a mixture of isomers of oxycodone 2,4-pentanediol ketal along with unreacted oxycodone was dissolved in 0.1 N HCl at a concentration of 2 mg / ml and heated to 37° C. The course of the hydrolysis was monitored by LC / MS. Results from the hydrolysis are shown in Table 1b and illustrated in FIG. 1.

TABLE 1aSimulated Gastric FluidKetalKetalKetalKetalHoursOxycodone ABCD07.326.610.338.417.30.5819.925.79.832.811.71.2535.325.310.425.23.824324.29.7211.635123.710.214.20.85458.722.79.19.40

TABLE 1b0.1N HClKetalKetalKetalKetalHoursOxycodone ABCD011.424.710.735.817.30.58325.525.910.629.28.61.1673325.610...

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Abstract

This invention relates to opioid ketal compounds of Formula (I), Formula (II), or Formula (III): or a pharmaceutically acceptable salts thereof, wherein R1 is H or CH3, R2 is H or OH, n is 0, 1, 2 or 3, R3 and R4 are independently H or optionally substituted C1-C4 alkyl, or when n is 0, then R3 and R4 and the carbon atoms to which they are attached together form six, or seven membered ring, which is optionally mono or disubstituted by C1-C4 alkyl. The invention also relates to oxycodone ketal compounds of Formula (IV) or (V): or a pharmaceutically acceptable salts thereof. The invention also relates to the use of such compounds for the treatment, prevention, or amelioration of pain.

Description

BACKGROUND OF THE INVENTION[0001]1. Field of the Invention[0002]This invention is in the field of medicinal chemistry. In particular, the invention relates to novel opioid ketal compounds.[0003]2. Related Art[0004]The primary location of pain control is in the central nervous system (CNS). The three primary classes of opioid receptors, μ (mu), κ (kappa), and δ (delta), are distributed throughout the CNS and the periphery (Foss, J. F., The American Journal of Surgery 182 (Suppl. to November 2001):19S-26S (2001)). The principal receptor involved in pain management is the μ opioid receptor (Foss, J. F., ibid).[0005]Opioids, also known as opioid agonists, are a group of compounds that bind to the above mentioned opioid receptors, and exhibit opium or morphine-like properties. The opioids are widely administered for a variety of medical indications but primarily they are employed as moderate to strong analgesics. Examples of opioid compounds include, but are not limited to, morphine, oxy...

Claims

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Application Information

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IPC IPC(8): C07D489/08
CPCC07D489/09C07D489/08C07D491/20C07D489/02A61P25/04A61P43/00A61K9/0053A61K31/485A61K45/06
Inventor KUPPER, ROBERT J.GLOWAKY, RAYMOND C.
Owner NORDBOTICS INC
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