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Novel morphine derivatives

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

Inactive Publication Date: 2012-08-22
NEORPHYS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0096] Example 1: Synthesis of C6G-Cya

[0097] In the reactor, 2 molar equivalents of cysteamine were dissolved in anhydrous dimethylformamide (DMF) at a concentration of 138 g / l. After dissolution in dry DMF, 1 molar equivalent of commercially available codeine-6-glucuronide·TFA was added at a concentration of 47 g / l.

[0098] 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-oxyl-tris-pyrrolidinylphosphonium hexafluorophosphate (PyBOP) dissolved in DMF at a concentration of 225 g / l in advance was added dropwise to the reaction mixture, It was then stirred at room temperature for 3 hours.

[0099] The disulfide bridges were then reduced by adding 2.5 molar equivalents of tris(2-carboxyethyl)phosphine (TCEP) predissolved in water / TFA 0.1% at a concentration of 214 g / l. After 2 hours of reaction, the product was purified by preparative HPLC.

[0100] 10.3 mg of C6G-cy...

Embodiment 2

[0101] Example 2: Synthesis of M3Et-6G-cya

[0102] Synthesis of M3ET-6G:

[0103] In the reactor, 1 molar equivalent of morphine-6-glucuronide·2H 2 O(M6G) was poured and dissolved in water to a concentration of 100g / l. 5 equivalents of cesium carbonate were added, and the mixture was stirred at room temperature for 5 minutes.

[0104] An equal volume of dichloromethane to water was added to the mixture. 5 equivalents of ethyl bromide and 2 equivalents of tetrabutylammonium hydrogensulfate (TBAHS) were added continuously. Stirring was continued at room temperature for 72 hours. The product was purified by preparative HPLC.

[0105] Nuclear Overhouse effect (NOE) experiments by proton nuclear magnetic resonance (NMR) indicated that the oxygen atom at position 3 of the morphine derivative bears an ethyl group. In fact, the controlled irradiation of the ethyl group affects the signal of the phenolic aromatic proton.

[0106] Obtained 45.8 mg of M3Et-6G: [M+H] + =490-M ...

Embodiment 3

[0111] Example 3: Synthesis of M3Et-6G-cya-cya-M3Et-6G

[0112]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, previously 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 at room temperature for 3 hours. The product was then purified by preparative HPLC.

[0113] 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. 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 mogroup 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 indepre 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 = saturatendently = 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 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 treating 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 said pain. This opioid is used in about 80% of cases of acute pain after surgery. Despite its high efficacy, the use of morphine implies multiple 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 highlighted monomers a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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