7 alpha-substituted phenyl-6 alpha, alpha-endo-ethylidene(ethenylidene)-tetrahydrochysene paramorphine derivant or its salt, preparation method and application thereof

A technology of tetrahydrothebaine and derivatives, applied in the field of pharmacy, can solve problems such as failure to achieve success and limited bioavailability, and achieve the effect of reducing side effects

Inactive Publication Date: 2011-06-08
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to limited bioavailability and side effects such as anxiety and hallucinations, clinical trials were ultimately unsuccessful (Pande AC et al., Clin Neuropharmacol, 1996, vol 19, 451-6)

Method used

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  • 7 alpha-substituted phenyl-6 alpha, alpha-endo-ethylidene(ethenylidene)-tetrahydrochysene paramorphine derivant or its salt, preparation method and application thereof
  • 7 alpha-substituted phenyl-6 alpha, alpha-endo-ethylidene(ethenylidene)-tetrahydrochysene paramorphine derivant or its salt, preparation method and application thereof
  • 7 alpha-substituted phenyl-6 alpha, alpha-endo-ethylidene(ethenylidene)-tetrahydrochysene paramorphine derivant or its salt, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1 prepares R in I formula with method 5 = H, NO 2 Compounds and their salts

[0036] Preparation of 7α-(4'-nitro-phenyl)-6α,14α-endo-vinylidene-tetrahydrothebaine and its hydrochloride

[0037] Add 2g (6.42mmol) of thebaine, 2.5g (0.0168mol 6) of m-nitrostyrene and 10mL of xylene into a 25mL three-necked flask equipped with magnetic stirring, reflux condenser and thermometer. The reaction was refluxed for 24 hours, concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography, eluting with ethyl acetate / petroleum ether. 2.12 g of 7α-p-nitrophenylthebaine was obtained as light yellow foam, m.p.99-102°C, yield 71.7%. The free base was dissolved in absolute ethanol, and HCl / ether solution was added dropwise to adjust the pH to 4-5. After filtration and drying, the hydrochloride was obtained as white powder, m.p.216-218°C.

[0038] IR(KBr)υ3441, 2928, 1518, 1346, 1108, 796, 696cm -1 . 1 H NMR (CDCl 3 )δ8.09 (dd, 2H, J 1...

Embodiment 2

[0039] Embodiment 2 prepares R in I formula with method 1 =R 2 =R 3 =CH 3 , R 4 =-CH=CH-,R 5 =o-NH 2 Compound hydrochloride (LQ002C) and R 1 =R 2 =R 3 =CH 3 , R 4 =-CH=CH-,R 5 = m-NH 2 Compound Hydrochloride (LQ003C)

[0040] Preparation of 7α-(4'-amino-phenyl)-6α,14α-endo-vinylidene-tetrahydrothebaine and its hydrochloride (LQ004C)

[0041] Add 1g (2.17mmol) 7α-(4'-nitro-phenyl)-6α,14α-endo-ethenylidene (en)yl- Tetrahydrothebaine, 60mL absolute ethanol, keep warm at 60°C. Add 1.5 mL (25.9 mmol) of 85% hydrazine hydrate dropwise, add 1 part of Raney Ni (catalytic amount), filter while hot to remove excess Raney Ni, and concentrate the filtrate to dryness to obtain 1.00 g of white foam. Methanol was recrystallized to obtain 0.73 g of off-white needle crystals, yield 77.7%, m.p.200.0-202.2°C. After dissolving the free base in absolute ethanol, add HCl / ether solution dropwise to adjust the pH to 4-5, filter and vacuum-dry to obtain its hydrochloride, white powder,...

Embodiment 3

[0042] Example 3 Preparation of 7α-(2'-guanidino-phenyl)-6α, 14α-endo-ethenide(en)yl-tetrahydrothebaine bistrifluoroacetate and 7α-(3'- Guanidino-phenyl)-6α,14α-endo-ethenylidene-tetrahydrothebaine trifluoroacetate

[0043] Preparation of 7α-(2'-guanidino-phenyl)-6α,14α-endo-vinylidene-tetrahydrothebaine bis-trifluoroacetate

[0044] Add 100mg (0.232mmol) of 7α-(4'-amino-phenyl)-6α,14α-endo-ethhenylidene-tetrahydropyrrole to a 25mL three-necked flask with magnetic stirring, air condenser and addition funnel Baine, 90mg (0.31mmol) Boc-protected methylthiourea, 50mg (0.184mmol) HgCl 2 , 5 mL DMF and 80 uL triethylamine. Reaction 2d at room temperature. Add 10% (g / g) Na to the filtrate 2 CO 3 Mix 30mL of the solution and 50mL of ethyl acetate, shake well, let stand for liquid separation, and discard the aqueous phase. Wash the organic phase with distilled water, add a sufficient amount of anhydrous Na after the organic phase is combined 2 SO 4 dry. Filter and concentrate...

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Abstract

The invention belongs to the pharmaceutical field, and relates to a derivative of 7-Alpha-substituted phenyl-tetrahydrothebaine shown in formula (I) and the pharmaceutically-accepted salts thereof. The derivative shown in formula (I) is prepared by the following steps: reacting with substituted styrene reagent via thebaine, and then subjecting to the related conversion. According to the results of the animal experiment, the compound has analgesic activity, wherein 7-Alpha-(4'-amino-phenyl)-6-Alpha, 14-Alpha-endo-vinylidene-tetrahydrothebaine hydrochloride (LQ004C) has an activity to the isolated tissue, which is similar to butophanol tartrate, and is a typical Kappa excitant; and the compound exhibits remarkable analgesic activity in the mice acetic acid writhing method and the mice heat radiation tail-flick method, and can be further prepared into low-addiction analgetics.

Description

technical field [0001] The invention belongs to the field of pharmacy and relates to condensed ring morphine derivatives and their salts, in particular to 7α-substituted phenyl-6α, 14α-endo-ethenyl-tetrahydrothebaine with general formula (I) Derivatives, salts and preparation methods thereof, and related to the use of such derivatives in treatment, especially in the treatment of pain. Background technique [0002] Pain is a common clinical symptom, and the market demand for analgesics is huge. In clinical treatment, opioid analgesics are widely used for moderate to severe pain, especially postoperative pain and pain in patients with advanced cancer. Although the analgesic effect of this type of drug is reliable, and it is still irreplaceable so far, there are serious adverse reactions such as respiratory depression and addiction, and long-term use will cause patient tolerance to the drug and hyperalgesia. Moreover, many opioids belong to the category of narcotic drug contr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D489/12A61K31/485A61P25/04
Inventor 李炜祁红仇缀百陈红专曾一斌杨杰
Owner FUDAN UNIV
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