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Eastern poppy base compound and its medical use

A technology of oripavine and compound, applied in the field of oripavine compound, can solve the problems of low analgesic efficacy, necessity of injection, low oral bioavailability and the like

Inactive Publication Date: 2011-08-31
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the analgesic efficacy of buprenorphine is not high, only 40%; and the oral bioavailability is not high, it must be injected or sublingually

Method used

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  • Eastern poppy base compound and its medical use
  • Eastern poppy base compound and its medical use
  • Eastern poppy base compound and its medical use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Example 1. Preparation of 7α-[1-hydroxyl-1-methyl-3-(thiophen-3-yl)-propyl]-6,14-ethylene bridge tetrahydrooripavine (Ia-1)

[0075] 1.1 Preparation of 7α-vinyl-6,14-ethylene bridged tetrahydrothebaine (compound of formula III)

[0076] Put 100g of thebaine (compound of formula II) and 180ml of methyl ketene into the reaction flask, heat and reflux for 1 hour, distill off the remaining methyl ketene under reduced pressure, add 120ml of methanol, heat to dissolve, cool, and filter the solid. Washed twice with methanol and dried to obtain 112 g of the title compound (compound of formula III), melting point 118-120°C.

[0077] 1.2 Preparation of 7α-acetyl-6,14-ethyl bridged tetrahydrothebaine (compound of formula IV)

[0078] 40g of the compound of formula III obtained in Example 1.1, 8g of 10% palladium carbon and 400ml of absolute ethanol are placed in a hydrogenation kettle, and 40-50kg / cm2 of hydrogen gas is passed into it. 2 , carried out hydrogenation at 50-60°C fo...

Embodiment 2

[0085] Example 2. N-allyl-7α-[1-hydroxyl-1-methyl-3-(thiophen-3-yl)-propyl]-6,14-endoethylene bridged tetrahydronoropapium Preparation of Base (Ia-2)

[0086] 2.1 Preparation of N-cyano-7α-[1-hydroxy-1-methyl-3-(thiophen-3-yl)-propyl]-6,14-ethyl-tetrahydronorthebaine

[0087] Take 17.5 g of cyanogen bromide and dissolve it in 125 ml of chloroform, add 50.0 g of a solution of the compound of formula V dissolved in 275 ml of chloroform, reflux for 12 hours, evaporate the solvent after the reaction is completed, and treat with a small amount of absolute ethanol to obtain 48.0 g of white powder with a melting point of 198 -200°C. Elemental analysis (C 29 h 36 N 2 o 4 S): Calculated: C 68.75%, H 6.76%, N 5.53%; Found: C 68.84%, H 6.60%, N 5.49%.

[0088] 2.2 Preparation of 7α-[1-hydroxy-1-methyl-3-(thiophen-3-yl)-propyl]-6,14-endoethylenetetrahydronoripavine hydrochloride

[0089] Take 4g of the compound prepared in Example 2.1, 10g of potassium hydroxide and 50g of diethyle...

Embodiment 3

[0094] Example 3. N-Cyclopropylmethyl-7α-[1-Hydroxy-1-methyl-3-(thiophen-3-yl)-propyl]-6,14-endoethylene-bridged tetrahydronordong Preparation of Papaverine (Ia-3)

[0095] According to the method of Example 2.3, cyclopropylmethyl bromide was used instead of allyl bromide to obtain the title compound with a melting point of 178-180°C. 1 H-NMR (δppm): 9.05 (s, 1H); 7.42-7.04 (m, 3H); 6.71-6.53 (dd, 2H); 4.54 (s, 1H); 4.32 (s, 1H); 3H); 1.44(s, 3H).

[0096] According to the method of Example 1.5, the hydrochloride Ia-3·HCl of the above title compound was prepared. The melting point is 276-278°C. Elemental analysis (C 31 h 39 NO 4 S.HCl.1 / 2H 2 O): calculated: C 65.72%, H 7.24%, N 2.47%; found: C 65.35%, H 7.20%, N 2.32%.

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Abstract

The invention comprises an oripavine compound, wherein the definition of R1-R3 as the claim, and also comprises the medicinal composition, production and pharmaceutical use of the oripavine compound. The oripavine compound can be used to prepare analgesic and withdrawal medicines.

Description

Technical field: [0001] The present invention relates to oripavine compounds, their preparation method, pharmaceutical composition containing them, and the use of said compounds for preparing analgesics or opioid addiction withdrawal drugs. Background technique: [0002] Analgesics are one of the most commonly used drugs clinically, but strong analgesics such as morphine, pethidine, etc. have a strong potential to induce dependence, and long-term use can easily cause addiction and tolerance; although non-narcotic analgesics There is no dependence potential, but the analgesic effect is weak, which is not enough to relieve severe pain in patients with cancer, trauma and surgery. [0003] For example, British Patent 1136214 discloses the following compounds: [0004] [0005] in, [0006] R 1 is alkyl, phenyl or phenylalkyl; R 2 is cyclopropylmethyl or allyl; R 3 Is hydrogen or methyl; these compounds have potent central analgesic activity or morphine antagonist activit...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D489/12A61K31/4748A61P25/04A61P25/36
Inventor 仲伯华宫泽辉王竞艳俞刚刘春河吴波史卫国张振清谢剑炜
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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