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Morphinan derivatives the quaternary ammonium salts thereof substituted in position 14, method for production and use thereof

A compound, C1-C6 technology, applied in the field of morphinan derivatives and their 14-substituted quaternary ammonium salts, preparation and their use, can solve the problems of weak effects

Inactive Publication Date: 2008-02-13
阿尔卡森制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The previously described quaternization of 14-hydroxymorphinan-6-ones (such as norhydromorphone or naloxone) resulted in rather weak effects (see M.A.lorio et al; Eur.J.Med.Chem.- Chim. Ther. 1984, 19, 301-303)

Method used

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  • Morphinan derivatives the quaternary ammonium salts thereof substituted in position 14, method for production and use thereof
  • Morphinan derivatives the quaternary ammonium salts thereof substituted in position 14, method for production and use thereof
  • Morphinan derivatives the quaternary ammonium salts thereof substituted in position 14, method for production and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0170] Synthesis of 17-allyl-4,5α-epoxy-3-methoxy-14β-(3-phenylpropyloxy)morphinan-6-one hydrochloride (compound 1·HCl)

[0171]

[0172] Under stirring, N 2 Protection, 0°C (bath temperature), NaH (0.97g, 40.4mmol) (obtained from 1.62g of 60% NaH oil dispersion washed with petroleum ether) was added to 14-hydroxycodeinone (Iijima et al.J .Med.Chem.1978,21,pg.398) (3.00g, 9.6mmol) in 100ml of anhydrous N,N-dimethylformamide solution, after 20 minutes, add cinnamyl bromide (2.28g, 11.6mmol ), the mixture was stirred at 0° C. (bath temperature) for an additional 30 minutes and for a further 4.5 hours with cooling removed. Ice cubes were added to terminate the reaction until no more hydrogen gas was evolved, finally bringing the water volume to 100 ml. The precipitated product was extracted with dichloromethane (3×100ml), the organic phases were combined, washed with 250ml of saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed under r...

Embodiment 2

[0177] Synthesis of 17-cyclobutylmethyl-4,5α-epoxy-3-methoxy-14β-(3-phenylpropoxy)morphinan-6-one hydrochloride (compound 2·HCl)

[0178]

[0179] Compound 2

[0180] 4,5α-epoxy-3-methoxy-14β-(3-phenylpropoxy)morphinan-6-one hydrochloride (500mg, 1.19mmol), potassium carbonate (1.00g, 7.24mmol) and Cyclobutylmethyl bromide (0.6ml, 5.43mmol) was dissolved in anhydrous N,N-dimethylformamide (7ml), and stirred at 80°C (bath temperature) for 24 hours under the protection of nitrogen in the absence of moisture, and the inorganic residue, and washed three times with dichloromethane, each 20ml. The filtrate was evaporated under reduced pressure, the oily residue was dissolved in 100ml of dichloromethane, washed with water (3×100ml) and saturated sodium chloride (4×100ml), dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue (520mg brown oil) was purified by column chromatography (silica gel: CH 2 Cl 2 / MeOH / conc.NH 4 OH=250:2:0.5), the oily distill...

Embodiment 3

[0182] Synthesis of 17-cyclopropylmethyl-4,5α-epoxy-3-methoxy-14β-(3-phenylpropoxy)morphinan-6-one hydrochloride (compound 3·HCl)

[0183]

[0184] Compound 3

[0185] 4,5α-epoxy-3-methoxy-14β-(3-phenylpropoxy)morphinan-6-one hydrochloride (1.5g, 3.57mmol), potassium carbonate (3.00g, 21.7mmol) and cyclopropylmethyl bromide (1.0ml, 6.62mmol) in anhydrous N,N-dimethylformamide (10ml), in the absence of moisture, under the protection of nitrogen, stirred at 80°C (bath temperature) for 4 hours, The inorganic residue was filtered off and washed three times with 10 mL of dichloromethane. The filtrate was evaporated under reduced pressure, the oily residue was dissolved in 50ml of dichloromethane, washed with water (3×50ml) and saturated sodium chloride (4×50ml), dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue (1.42g yellow oil) was purified by column chromatography (silica gel: CH 2 Cl 2 / MeOH / conc.NH 4 OH=250:2:0.5), the oily distillation r...

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Abstract

The invention relates to a class of morphinan compounds and the quaternary ammonium salts thereof, substituted in position 14, which may be used as highly-active analgesics or also as opioid antagonists. The invention further relates to the pharmaceutically-acceptable salts and easily-produced derivatives thereof, a process for production thereof and use thereof in the production of pharmaceutical specialities.

Description

technical field [0001] The content of the present invention includes a class of morphinan compounds and derivatives substituted at 14-position quaternary ammonium salt, wherein the derivatives substituted with 14-position quaternary ammonium salt can be used as highly active analgesic and opioid antagonist. The present invention also includes pharmaceutically acceptable salts and readily produced derivatives, their preparation and the use of these medicinal properties. Background technique [0002] The presence of opioid receptors that mediate analgesic effects as central nervous system (CNS) receptors has been clearly demonstrated, and these receptors are subdivided into three subtypes, μ, κ, and δ. Activation of these receptors by opioid agonists results in analgesic effects. The activation of μ receptors has the highest analgesic activity, however, some N-methylmorphinan derivatives (morphine, oxymorphone, hydromorphone, etc.) body partial agonists, they are also effect...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D489/08C07D489/02C07D489/04A61K31/485A61P25/04A61P25/20C07D489/00
CPCC07D489/08C07D489/00A61P1/00A61P1/10A61P19/02A61P25/00A61P25/04A61P25/20A61P25/32A61P25/36A61P29/00A61P3/04A61P39/02
Inventor 赫欧姆特·史密德哈默玛瑞阿纳施柏塔约翰内斯·舒茨伊丽莎白格莱勒珐尔阔舒尔勒柏提纳赛勒库尔特施图伯格
Owner 阿尔卡森制药有限公司