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Novel morphine derivatives

A drug and compound technology, applied in the field of new morphine derivatives, can solve problems such as addiction

Inactive Publication Date: 2009-09-02
NEORPHYS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, like morphine, it may cause symptoms of addiction

Method used

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  • Novel morphine derivatives
  • Novel morphine derivatives
  • Novel morphine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] Example 1: Synthesis of C6G-Cya

[0095] In the reactor, 2 molar equivalents of cysteamine were dissolved in anhydrous dimethylformamide (DMF) at a concentration of 138 g / l. After dissolving in dry DMF, 1 molar equivalent of commercially available codeine-6-glucuronide·TFA was added at a concentration of 47 g / l.

[0096] 4 molar equivalents of diisopropylethylamine (DIEA) were added and the reactor was placed in an ice bath (0°C). 1.2 molar equivalents of benzotriazol-1-yl-oxy-tri-pyrrolidinylphosphonium hexafluorophosphate (PyBOP) pre-dissolved in DMF at a concentration of 225 g / l was added dropwise to the reaction mixture, It was then stirred at room temperature for 3 hours.

[0097] The disulfide bridges were then reduced by adding 2.5 molar equivalents of tris(2-carboxyethyl)phosphine (TCEP) at a concentration of 214 g / l, predissolved in water / TFA 0.1%. After 2 hours of reaction, the product was purified by preparative HPLC.

[0098] 10.3 mg C6G-cya was obtain...

Embodiment 2

[0099] Example 2: Synthesis of M3Et-6G-cya

[0100] Synthesis of M3ET-6G:

[0101] In the reactor, 1 molar equivalent of morphine-6-glucuronide 2H 2 O(M6G) was poured and dissolved in water at a concentration of 100 g / l. 5 equivalents of cesium carbonate were added and the mixture was stirred at room temperature for 5 minutes.

[0102] An equal volume of dichloromethane with water was added to the mixture. 5 equivalents of bromoethane and 2 equivalents of tetrabutylammonium bisulfate (TBAHS) were added successively. Stirring was continued for 72 hours at room temperature. The product was purified by preparative HPLC.

[0103] Nuclear Overhauser effect (NOE) experiments by proton nuclear magnetic resonance (NMR) indicated that the morphine derivative carried an ethyl group on the oxygen atom at the 3-position. In fact, the control radiation of the ethyl group affects the signal of the phenolic aromatic protons.

[0104] Obtained 45.8 mg of M3Et-6G: [M+H] + =490-M TFA...

Embodiment 3

[0109] Example 3: Synthesis of M3Et-6G-cya-cya-M3Et-6G

[0110] In the reactor, 1 molar equivalent of cysteamine·dihydrochloride was dissolved in DMF at a concentration of 86 g / l. 2 molar equivalents of M3Et-6G-cya pre-dissolved in DMF at a concentration of 97 g / l were added. Then 5 molar equivalents of pure DIEA were introduced and the mixture was cooled to 0°C in an ice bath. 2.4 molar equivalents of PyBOP dissolved in DMF at a concentration of 22.9 g / l were added dropwise. Stirring was continued for 3 hours at room temperature. The product was then purified by preparative HPLC.

[0111] Obtained 40.5 mg of M3Et-6G-cya-cya-M3Et-6G dimer: [M+H]+ =1096-M TFA =1322 - Purity: 95% - Yield = 81%.

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Abstract

The present invention relates to novel morphine-6-glucuronide derivatives, to pharmaceutical compositions containing them and to uses thereof. Said derivatives have the following structures, where the group Pcntite (A), except substituents X, is called MR36G-NR1 R2-S-, R1 = saturated or unsaturated, straight- or branched-chain C1-C10 alkyl, the alkyl chain being optionally interrupted by one or more heteroatoms selected from O, S and N, R2 = H, saturated or unsaturated, straight- or branched-chain C1-C5 alkyl, or an aryl, heteroaryl or (C1-C5) alkylaryl group, R3 = Y(C=Z)R or YR, Y and Z independently = O or S, R = saturated or unsaturated, straight- or branched-chain C1-C6 alkyl with the proviso that R3 is not -O-CH3, X = H, an -S-R4-W group, or a MR,6G-NR I R2-S- group, with R4 = saturated or unsaturated, straight- or branched-chain C1 -C8 alkyl which can include amide, ester or ether bonds and W is either a d-receptor antagonist, or a K-receptor antagonist and a pharmaceutically acceptable salt thereof.

Description

technical field [0001] The present invention relates to novel morphine derivatives, pharmaceutical compositions containing said novel morphine derivatives, and their use for the treatment of pain and sexual dysfunction. Background technique [0002] Morphine is currently the drug of choice for the treatment of acute pain, regardless of the intensity of the pain. This opioid is used in about 80% of cases of acute pain after surgery. Despite its high efficiency, the use of morphine implies a variety of side effects, specific to opioids, such as respiratory depression, nausea, vomiting, inhibition of intestinal transit, addiction and tolerance (Minoru Nariata et al., 2001, Pharmacol et Ther, 89, 1-15). [0003] There are three main classes of opioid receptors: mu, kappa, and delta, all belonging to the family of G protein-coupled receptors. Western blot analysis, FRET (fluorescence resonance energy transfer) and BRET (bioluminescence resonance energy transfer) have highlight...

Claims

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Application Information

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IPC IPC(8): C07H17/00A61K31/7048A61K31/706
CPCC07H17/00A61P15/00A61P15/08A61P25/00A61P25/04A61P25/06A61P29/00C07D403/08C07D403/02A61K31/7048A61K31/706
Inventor 卡里纳·拉尔布雷罗格·拉哈娜塞德里克·卡斯泰
Owner NEORPHYS
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