Fused ring morphines derivative, and preparation method therefor and application thereof

A derivative, cycloalkyl technology, applied in the field of fused-ring morphine derivatives, can solve the problems of restlessness, restricted development, dose-dependent hallucinations, etc.

Active Publication Date: 2016-02-03
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But on the other hand, κ receptor agonists can cause side effects such as hallucinations and restlessn

Method used

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  • Fused ring morphines derivative, and preparation method therefor and application thereof
  • Fused ring morphines derivative, and preparation method therefor and application thereof
  • Fused ring morphines derivative, and preparation method therefor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1 same method can prepare IV formula compound

[0029] Preparation of 7α-(4'-nitro-phenyl)-6α,14α-endo-vinyl-tetrahydrothebaine

[0030] Add 2g (6.42mmol) of thebaine, 2.5g (0.0168mol) of p-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.

[0031] IR(KBr)υ3441,2928,1518,1346,1108,796,696cm -1 . 1 HNMR (CDCl 3 )δ8.09(dd,2H,J 1 =2.35Hz,J 2 =8.61Hz), 7.36(dd,2H,J 1 =2.35Hz,J 2 =11.35Hz),6.66(d,1...

Embodiment 2

[0032] R in the I formula can be prepared with the same method in embodiment 2 2 =C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 5 -C 7 Cycloalkenyl, C 3 -C 6 Cycloalkyl C 1 -C 6 Alkyl, C 5 -C 7 Cycloalkenyl C 1 -C 6 Alkyl, aryl, heterocyclic aryl, aryl C 1 -C 6 Alkyl, or heterocyclic aryl C 1 -C 6 Alkyl compounds and their salts

[0033] Preparation of N-cyclopropylmethyl-7α-p-nitrophenyl-6α,14α-endo-vinyl-tetrahydrothebaine hydrochloride

[0034] Add 3.4g (12.6mmol) of 7α-p-nitrophenyl-6α,14α-endo-vinyl-tetrahydrothebaine and 90ml of acetonitrile into a 250mL single-necked flask under nitrogen protection, and then add diisopropyl azodicarboxylate 7.88ml (37.8mmol), reflux reaction for 4h, stop the reaction, spin the reaction solution to dryness, add 1N HCl90ml, reflux for 4h, after the reaction is over, a large amount of solid precipitates, filter, wash the filter cake with ethyl acetate, and dry to obtain a light yellow soli...

Embodiment 3

[0036] Embodiment 3 can prepare R in I formula with method 4 is-CH 2 -CH 2 -, R 5 = Derivatives of H

[0037] Preparation of N-cyclopropylmethyl-7α-p-aminophenyl-4α,14α-endo-ethylene-tetrahydrothebaine

[0038] Add 2.63g (5.25mmol) of the compound N-cyclopropylmethyl-7α-p-nitrophenyl-4α,14α-endo-vinyl-tetrahydrothebaine, 60ml of ethanol and 5% palladium carbon in a pressure bottle 0.67g (0.315mmol), feed hydrogen, 65psi, heat at 50oC for 48h, stop the reaction, filter the reaction solution to remove palladium carbon, spin the filtrate to obtain 2.1g of white foamy solid, yield: 84.6%, melting point: 94-95oC . [MS][M+H] + :473.3.IRυ700.60,731.20,807.81,902.82,881.35,957.90,939.68,1008.38,1055.10,1092.31,1162.70,1204.44,1262.50,1328.78,1440.09,1515.67,1500.13,1623.06,2834.01,2929.68,3048.58,3360.32,3457.49cm -1 . 1 HNMR (600MHz, CDCl 3 )δ7.12(d, J=8.3Hz, 2H), 6.72(d, J=8.1Hz, 1H), 6.65(d, J=8.3Hz, 2H), 6.58(d, J=8.1Hz, 1H) ,5.29(s,2H),4.60(s,1H),3.87(s,3H),3.21(t,J=12....

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Abstract

The invention belongs to the field of pharmacy, and relates to a fused ring morphines derivative, and a preparation method therefor and application thereof. The invention particularly relates to 7 alpha-(4'-substituted amino-phenyl)-6 alpha, 14 alpha-endo-ethylidene (alkenyl)-tetrahydrothebaine series derivatives of a general formula (I) and pharmaceutically acceptable salts. The derivatives of the general formula (I) are prepared by reaction of thebaine and substituted styrenes reagents and a series of conversion, and 7 alpha-(4'-benzamido-phenyl)-6 alpha, 14 alpha-endo-ethylidene (alkenyl)-tetrahydrothebaine is a typical high-selectivity k ligand, and can be used for preparing drugs for stopping pain, resisting depression, resisting opiate addiction, relieving itching and the like. The formula is as shown in the specification.

Description

technical field [0001] The invention belongs to the field of pharmacy and relates to condensed ring morphine derivatives. It specifically relates to 7α-(4'-substituted amino-phenyl)-6α,14α-endo-ethenide(en)yl-tetrahydrothebaine derivatives of general formula (I) and their preparation methods, and to these derivatives The use of drugs in the field of opioid receptor therapy. Background technique [0002] Studies have shown that pain is the body's response to harmful stimuli and can protect itself from harm. As early as the 1950s, studies have found that activating opioid receptors can produce analgesic effects. After more than 40 years of exploration and hard work, in the 1990s, various subtypes of opioid receptors were cloned one after another, thus, the understanding of opioid receptors entered a new stage. Currently known, opioid receptors are composed of four subtypes, namely μ, δ, κ and ORL1 (orphan opioid receptor). [0003] Studies have shown that morphine and typi...

Claims

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Application Information

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IPC IPC(8): C07D489/12A61K31/485A61P25/04A61P1/00A61P25/24A61P25/02
Inventor 李炜邵黎明张木美刘景根徐学军
Owner FUDAN UNIV
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