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1,2,3,4-Tetrahydroisoquinoline derivatives, preparation methods and applications thereof

A technology of tetrahydroisoquinoline and its derivatives, applied in its preparation, 1, can solve problems such as cognitive changes, drug resistance, dependence, and side effects

Active Publication Date: 2020-07-10
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These drugs are effective in the treatment of nociceptive pain, but have limited treatment for neuropathic pain and are associated with serious side effects, including cognitive changes, sedation, nausea, and development of tolerance and dependence

Method used

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  • 1,2,3,4-Tetrahydroisoquinoline derivatives, preparation methods and applications thereof
  • 1,2,3,4-Tetrahydroisoquinoline derivatives, preparation methods and applications thereof
  • 1,2,3,4-Tetrahydroisoquinoline derivatives, preparation methods and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0116] Preparation of intermediates

[0117] 1. Intermediate 1: Preparation of ethyl 3-(2-(benzyloxy)-3-methoxyphenyl)-2-((diphenylmethylene)amino)propionate

[0118]

[0119] At room temperature, to 2-(benzyloxy)-1-(chloromethyl)-3-methoxybenzene (6.8g, 25.88mmol) in acetonitrile (60mL) was added potassium iodide (5.59g, 33.65mmol) , Cesium carbonate (16.87g, 51.76mmol), ethyl 2-((diphenylmethylene)amino) acetate (6.92g, 25.88mmol), then under nitrogen protection, stir overnight in an oil bath at 50°C . After cooling, the organic solvent was removed by rotary evaporation under reduced pressure, ethyl acetate and water layer were added, the ethyl acetate phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography (eluent: petroleum ether / Ethyl acetate=10:1) to obtain ethyl 3-(2-(benzyloxy)-3-methoxyphenyl)-2-((benzylidene)amino)propionate (8.9g, 70%).

[0120] MS m / z(ESI): 494.6[M+H] + .

[0121] 2. Intermediate 2: Prepar...

Embodiment 1

[0130] Example 1: 5-(Benzyloxy)-6-methoxy-2-(1-phenylcyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-3- Preparation of carboxylic acid

[0131]

[0132] Step 1: Preparation of 1-phenylcyclohexane-1-carbonyl chloride

[0133]

[0134] At room temperature, oxalyl chloride (248 mg, 1.96 mmol) and DMF (0.2 mL) were added to a solution of 1-phenylcyclohexane-1-carboxylic acid (200 mg, 0.98 mmol) in dichloromethane (5 mL), and the reaction was at room temperature After stirring for 2 hours, the solvent was removed under reduced pressure to obtain crude 1-phenylcyclohexane-1-carbonyl chloride (230 mg), which was directly used in the next reaction.

[0135] The second step: Ethyl 5-(benzyloxy)-6-methoxy-2-(1-phenylcyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline- Preparation of 3-carboxylate

[0136]

[0137] At room temperature, add ethyl 5-(benzyloxy)-6-methoxy-1 to a solution of 1-phenylcyclohexane-1-carbonyl chloride (100mg, 0.45mmol) in dichloromethane (5mL) , 2,3,4-Tetra...

Embodiment 2

[0143] Example 2: 5-(Benzyloxy)-6-methoxy-2-(1-phenylcyclopropane-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxy Acid preparation

[0144]

[0145] Preparation method of 5-(benzyloxy)-6-methoxy-2-(1-phenylcyclopropane-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Refer to Example 1. MS m / z(ESI): 458.2[M+H] + ;

[0146] 1 H NMR(400MHz, CDCl 3 )δ7.41-7.28(m,6H), 7.23-7.13(m,4H), 6.88-6.69(m,1H), 6.68-6.44(m,1H), 5.11-4.82(m,3H), 4.66 4.13 (m, 2H), 3.84 (s, 3H), 3.40-2.75 (m, 2H), 1.54-1.19 (m, 4H).

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PUM

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Abstract

Provided is a 1,2,3,4-tetrahydroisoquinoline derivative having a structure of formula (I), its preparation method and application. The compound of formula (I) can be used for the development of primary neuropathy, secondary neuropathy, peripheral neuropathy, neuropathy caused by mechanical nerve injury or biochemical nerve injury, painful diabetic neuropathy (PDN) or related neurological disease drugs, with broadly application foreground.

Description

Technical field [0001] The invention belongs to the field of drug development, and specifically relates to 1,2,3,4-tetrahydroisoquinoline derivatives, preparation methods and applications thereof. Background technique [0002] Neuropathic pain is a chronic pain disease caused by primary damage or dysfunction of the nervous system. A variety of different injuries, such as trauma, nerve damage, or infection, can cause neuropathic pain. The most common types of neuropathic pain include diabetic neuralgia (DNP), post-herpetic neuralgia (PHN and AIDS-related neuropathic pain. In contrast to secondary (injury pain), neuropathic pain may be in trauma A few days or even months after the occurrence, it is often chronic pain, which is characterized by hyperalgesia, sensory hypersensitivity to stimulation, allodynia and spontaneous burning pain. The current treatments for neuropathic pain mainly include anticonvulsants, Antidepressants, narcotic analgesics and local anesthetics. Standard t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/26A61K31/4375A61P25/02
CPCC07D217/26C07D405/12A61K31/4375
Inventor 孙广俊马建斌谭松良高鹏李成海包如迪
Owner SHANGHAI HANSOH BIOMEDICAL