Multi-hydrogen isoquinoline derivative as well as preparation method and medical application thereof

A technology of hydroisoquinoline and derivatives, which is applied in the field of polyhydroisoquinoline derivatives and its preparation, can solve the problems of long cycle, high cost, low success rate, etc., and achieve small side effects, good drug properties, and safety high effect

Inactive Publication Date: 2020-12-04
江阴迈康升华医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the actual process of new drug development, especially in the field of central nervous system, the success rate of this method is quite low, and the cost is very high and the cycle is very long

Method used

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  • Multi-hydrogen isoquinoline derivative as well as preparation method and medical application thereof
  • Multi-hydrogen isoquinoline derivative as well as preparation method and medical application thereof
  • Multi-hydrogen isoquinoline derivative as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1 (6-methylpyridin-3-yl) (4a-(pyridin-2-yl)-3,4,4a,5,10,10a-hexahydrobenzo[g]isoquinoline-2( Synthesis of 1H)-yl)methanone:

[0063]

[0064] 1.1 3-oxo-4-(pyridin-2-yl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl)4-ethyl ester:

[0065] Under nitrogen atmosphere, 1-(tert-butyl) 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (5 g, 18.4 mmol) was dissolved in 100 mL THF, the system was cooled to -78 °C, and 37 mL LHMDS ( 1M) THF solution, stirred for 30min, added 2-fluoropyridine (3.58g, 36.8mmol), continued to react overnight, TLC followed the reaction, after the reaction, added water to the system, and extracted with ethyl acetate (30mL×3 ), the combined organic phases were concentrated and purified by column chromatography to obtain 2.5g yellow viscous product. Yield: 39%. LC-MS (ESI+): m / z 349 (M+1).

[0066] 1.2 tert-butyl 3-oxo-4-(pyridin-2-yl)piperidine-1-carboxylate:

[0067] Under nitrogen atmosphere, 3-oxo-4-(pyridin-2-yl)piperidine-1,4-dicarboxylic...

Embodiment 2

[0076] Example 2 4a-(pyridin-2-yl)-2-(pyridin-3-ylmethyl)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]isoquine Synthesis of morphine:

[0077]

[0078] Dissolve 4a-(pyridin-2-yl)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]isoquinoline (40 mg, 0.15 mmol) in 2 mL of DCM, add Nicotinic aldehyde (32.5mg, 0.3mmol), NaBH(OAc) 3 (128.5mg, 0.6mmol) and 0.1mLEt 3 N, stirred at room temperature for 7h, followed the reaction by TLC. After the reaction, 1mL of water was added to the system, and extracted with DCM / MeOH (15 / 1) (2mL×3), the organic phases were combined, washed with saturated brine, Na 2 SO 4 It was dried, concentrated by filtration, and purified by column chromatography to obtain 50 mg of yellow oil, which was converted into citrate to obtain 63 mg. Yield: 90%. LC-MS(ESI+):m / z 356 (M+1); 1H NMR(300MHz,MeOD):δ8.43-8.34(m,3H),7.76-7.74(m,3H),7.36-7.29(m,2H), 7.24-7.20(m,1H),7.17-7.12( m,1H),7.05-7.00(m,1H),6.90-6.87(m,1H),3.52(m,2H), 3.41-3.23(m,2H),2.68-2.57(m,2H),2.41- 2.35(m,...

Embodiment 3

[0079] Example 3 2-((6-methylpyridin-3-yl)methyl)-4a-(pyridin-2-yl)-1,2,3,4,4a,5,10,10a-octahydrobenzene And [g] the synthesis of isoquinoline:

[0080]

[0081] 4a-(Pyridin-2-yl)-1,2,3,4,4a,5,10,10a-Octahydrobenzo[g]isoquinoline (40 mg, 0.15 mmol) was dissolved in 2 mL DCM and added to 6 -Methylnicotinaldehyde (36.7mg, 0.3mmol), NaBH(OAc) 3 (128.5mg, 0.6mmol) and 0.1mLEt 3 N, stirred at room temperature for 7h, followed the reaction by TLC. After the reaction, 1mL of water was added to the system, and extracted with DCM / MeOH (15 / 1) (2mL×3), the organic phases were combined, washed with saturated brine, Na 2 SO 4 It was dried, concentrated by filtration, and purified by column chromatography to obtain 47.1 mg of yellow oil, which was converted into citrate to obtain 62.2 mg. Yield: 81%. LC-MS(ESI+):m / z 370(M+1); 1 H NMR (300MHz, MeOD): δ8.77(br s, 1H), 8.28(s, 1H), 7.78(t, J=7.8Hz, 1H), 7.67(d, J=8.1Hz, 1H), 7.68 -7.32(m,4H),7.26(d,J=6.9Hz,1H),7.16(t,J=7.5Hz,1H),7.02...

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Abstract

The invention relates to a multi-hydrogen isoquinoline derivative as well as a preparation method and medical application thereof, the multi-hydrogen isoquinoline derivative is a compound as shown ina formula (I) or cis/trans isomers, enantiomers, diastereoisomers, racemates, solvates, hydrates or pharmaceutically acceptable salts thereof, and Z, R1, R2, G, n, W and Y are defined in the specification. The novel molecular polyhydroisoquinoline derivative is novel in structure, higher in safety, small in side effect and better in patent medicine property, has the analgesic activity equal to oreven higher than that of morphine, is simple in synthesis operation, provides a feasible method for realizing large-scale preparation in a laboratory, can be used for preparing medicines for preventing, treating and improving pain, and has wide application prospects. The pain such as acute pain, chronic pain such as inflammatory pain and peripheral mediated neuropathic pain, preferably migraine, is treated, the effect is remarkable, and the derivative is worthy of popularization.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a polyhydroisoquinoline derivative, a preparation method and medical application thereof. Background technique [0002] Pain is divided into acute pain and chronic pain. The drugs for acute pain are mainly opioids, and the drugs for chronic pain are mainly non-steroidal anti-inflammatory drugs (NSAIDs). These two types of drugs have relatively large side effects, so the development of More efficient analgesic drugs with lower side effects have always been the focus of research in the field of analgesia. [0003] The opioid system consists of three endogenous peptide families (enkephalins, dynorphins, and β-endorphins, respectively) and three homologous receptor families (mu opioid receptors (MOR), delta opioid receptors, Opioid receptors (DOR) and kappa opioid receptors (KOR), Filizola and Devi, 2013; Cox et al.) and nociceptive receptors (NOP) (Lord and Waterfield, 1977; Mar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D401/06C07D413/14A61P29/00A61P25/04A61P25/06
CPCC07D401/14C07D401/06C07D413/14A61P29/00A61P25/04A61P25/06
Inventor 钟华李百志孙桂优姜兰草
Owner 江阴迈康升华医药科技有限公司
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