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Tetrahydronorepinebaine derivative and preparation method and application thereof

A technology of methaba and its derivatives, which is applied in the field of opioid receptor therapy, and can solve problems such as analgesia and sedation addiction

Active Publication Date: 2021-04-16
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Central analgesics such as morphine and pethidine are all of the type of μ agonists, and most of them have side effects such as analgesia, sedation, respiratory depression and addiction

Method used

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  • Tetrahydronorepinebaine derivative and preparation method and application thereof
  • Tetrahydronorepinebaine derivative and preparation method and application thereof
  • Tetrahydronorepinebaine derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] The preparation of N-desmethylthebaine hydrochloride (1):

[0067]

[0068] 10.0g of thebaine (32.12mmol, 1.0eq) was added to a 250mL single-necked flask, 100mL of acetonitrile and 7.6mL of diisopropyl azodicarboxylate (38.54mmol, 1.2eq) were added, and the reaction was refluxed for 6h. Stop the reaction, spin off the solvent under reduced pressure, add 100mL of methanol to dissolve, add 11.1g of pyridine hydrochloride (96.36mmol, 3.0eq) to the solution, stir at room temperature for 6h, after the reaction is over, a large amount of solids are precipitated, filter, and wash with ethyl acetate The filter cake was washed and dried to obtain 4.5 g of intermediate 1 as a white solid, with a yield of 46.6% and a melting point of 260.3°C. ESI-MS (M+H)+: 298.2.

Embodiment 2

[0070] The preparation of N-cyclopropylmethyl northebaine (2):

[0071]

[0072]Add compound N-desmethylthebaine hydrochloride 3.5g (10.5mmol), DMF30mL and sodium carbonate 3.3g (31.5mmol) in the 50mL single-necked flask under the protection of nitrogen, add bromocyclopropylmethane 1.3ml (13.6 mmol), the temperature was raised to 110°C for 2.5h, and the reaction was stopped. The reaction solution was extracted three times with EA, washed with saturated brine, dried overnight, and spin-dried on silica gel column chromatography (PE:EA=1:1) to obtain 2 as light yellow 2.6 g of oil, yield: 70.0%. 1 H NMR (400MHz, CDCl 3 )δ6.68(d, J=8.2Hz, 1H), 6.61(d, J=8.1Hz, 1H), 5.60(d, J=6.4Hz, 1H), 5.06(d, J=6.4Hz, 1H) ,3.98(d,J=6.9Hz,1H),3.86(s,3H),3.61(s,3H),3.31(d,J=17.7Hz,1H),3.01–2.80(m,2H),2.75( dd,J=18.0,6.7Hz,1H),2.53(d,J=6.1Hz,2H),2.22(td,J=12.5,5.3Hz,1H),1.75(d,J=11.9Hz,1H), 0.96(s,1H),0.58(d,J=6.9Hz,2H),0.19(d,J=3.9Hz,2H); ESI-MS(M+H) + :352.2.

Embodiment 3

[0074] Preparation of N-cyclopropylmethyl-7α-(3'-nitro)phenyl-6α,14α-indovinylidene-tetrahydronorthebaine (3):

[0075]

[0076] Add N-cyclopropylmethylnorthebaine (2.0 g, 5.69 mmol), 2-nitrostyrene (1.5 mL, 11.2 mmol) and no Water o-xylene (20 mL). Refluxed for 30 hours, concentrated to dryness under reduced pressure, silica gel column chromatography (PE:EA=10:1) obtained A-1 as light yellow foamy solid 1.3g, yield 45.7%, melting point: 190.0-191.4°C. 1 H NMR (400MHz, CDCl 3 )δ8.13–8.03(m,2H),7.56(d,J=6.0Hz,1H),7.40(t,J=7.8Hz,1H),7.28–7.24(m,1H),6.65(d,J =7.9Hz,1H),6.56(d,J=8.0Hz,1H),5.95(d,J=8.4Hz,1H),5.77–5.67(m,1H),4.75(s,1H),3.84(d ,J=2.3Hz,3H),3.60(s,1H),3.46(t,J=10.6Hz,1H),3.38(d,J=2.5Hz,3H),3.15(d,J=18.8Hz,2H ),2.74(s,1H),2.43(dd,J=33.4,21.1Hz,4H),2.19–2.06(m,1H),1.96(d,J=12.5Hz,1H),1.36(d,J= 13.6Hz, 1H), 0.81(s, 1H), 0.52(d, J=8.9Hz, 2H), 0.14(s, 2H), 0.01(dd, J=4.5, 1.9Hz, 1H); ESI-MS( M+H) + :501.5.

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Abstract

The invention relates to a preparation method of a compound with a general formula (I) or pharmaceutically acceptable salts thereof, and relates to an application of the derivatives in the field of opioid receptor treatment, and an application of the derivatives in preparation of medicines for treating pain, depression, opioid addiction and pruritus. The treatment of pains comprise treatment or relief of pains, chronic pains, neuropathic pains and cancer pains during an operation; the pruritus comprises intractable pruritus accompanied by serious diseases such as uremia, diabetic nephropathy, chronic liver diseases and malignant tumors. Formula (I) as shown in the specification,.

Description

technical field [0001] The present invention relates to the preparation method of the compound with general formula (I) or its pharmaceutically acceptable salts, and relates to the use of these derivatives in the field of opioid receptor therapy. Background technique [0002] Opioid receptors are mainly divided into three receptor subtypes: μ, δ, and κ. Central analgesic drugs such as morphine and pethidine used clinically belong to the type of μ agonists, and most of them have side effects such as analgesia, sedation, respiratory depression and addiction. δ receptors are widely distributed in the central nervous system, it has a regulatory effect on μ receptors, and participates in the formation of tolerance dependence. κ receptors are widely expressed in the brain, and activating κ receptors can antagonize the agonistic effect of μ receptors, block drug addiction, anxiety, diuresis, hallucinations and other effects. It has been reported in the literature that κ ligand ha...

Claims

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Application Information

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IPC IPC(8): C07D491/08A61P29/00A61P25/04A61P13/12A61P3/10A61P1/16A61P35/00A61P17/04
Inventor 邵黎明刘景根李炜王瑜珺何倩魏园园
Owner FUDAN UNIV
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