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1,2,3,4-Tetrahydroisoquinoline derivatives, and preparation method and application thereof

A technology of tetrahydroisoquinoline and its derivatives, which is applied in the direction of drug combination, pharmaceutical formula, medical preparations containing active ingredients, etc., and can solve the problems of drug resistance and dependence, cognitive changes, side effects, etc.

Active Publication Date: 2017-03-08
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, and preparation method and application thereof
  • 1,2,3,4-Tetrahydroisoquinoline derivatives, and preparation method and application thereof
  • 1,2,3,4-Tetrahydroisoquinoline derivatives, and preparation method and application 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] To a solution of 2-(benzyloxy)-1-(chloromethyl)-3-methoxybenzene (6.8 g, 25.88 mmol) in acetonitrile (60 mL) was added potassium iodide (5.59 g, 33.65 mmol) at room temperature , cesium carbonate (16.87g, 51.76mmol), ethyl 2-((diphenylmethylene)amino)acetate (6.92g, 25.88mmol), then stirred overnight in a 50°C oil bath under nitrogen protection . After cooling, the organic solvent was removed by rotary evaporation under reduced pressure, ethyl acetate and a water layer were added, the ethyl acetate phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated for column chromatography (eluent: petroleum ether / ethyl acetate=10:1) to give ethyl 3-(2-(benzyloxy)-3-methoxyphenyl)-2-((diphenylmethylene)amino)propionate (8.9g, 70%).

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

Embodiment 1

[0130] Example 1: 5-(benzyloxy)-6-methoxy-2-(1-phenylcyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-3- Preparation of Carboxylic Acids

[0131]

[0132] The first step: the preparation of 1-phenylcyclohexane-1-carbonyl acid 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 carried out at room temperature. After stirring for 2 hours under reduced pressure, the solvent was removed under reduced pressure to obtain crude 1-phenylcyclohexane-1-carbonyl acid chloride (230 mg), which was directly used in the next reaction.

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

[0136]

[0137] To a solution of 1-phenylcyclohexane-1-carbonyl acid chloride (100 mg, 0.45 mmol) in dichloromethane (5...

Embodiment 2

[0143] Example 2: 5-(benzyloxy)-6-methoxy-2-(1-phenylcyclopropane-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxy Preparation of acid

[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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Abstract

The invention discloses 1,2,3,4-tetrahydroisoquinoline derivatives, and a preparation method and application thereof. The invention particularly relates to 1,2,3,4-tetrahydroisoquinoline derivatives having the structure of formula (I) shown in the specification, and a preparation method and application thereof, wherein substituents in the formula (I) are as defined in the specification. Such series of compounds are active for treating, preventing or relieving neuropathy or neuropathic pain, are applicable to the development of drugs for treating primary neuropathy, secondary neuropathy, peripheral neuropathy, neuropathy due to mechanical nerve injury or biochemical nerve injury, painful diabetic neuropathy (PDN) or related neuropathic diseases, and have a promising application prospect.

Description

technical field [0001] The invention belongs to the field of drug development, and specifically relates to 1,2,3,4-tetrahydroisoquinoline derivatives, a preparation method and application thereof. Background technique [0002] Neuropathic pain is a chronic pain disease caused by primary damage or dysfunction of the nervous system. Many different injuries, such as trauma, nerve injury or infection, can cause neuropathic pain. The most common types of neuropathic pain include diabetic neuralgia (DNP), postherpetic neuralgia (PHN), and AIDS-related neuropathic pain. As opposed to secondary (injury pain), neuropathic pain may Days or even months after onset, often chronic pain characterized by hyperalgesia, sensory hypersensitivity to stimuli, allodynia, and spontaneous causalgia.Current treatments for neuropathic pain mainly include anticonvulsants, Antidepressants, narcotic analgesics, and local anesthetics. Standard treatments include Pfizer's anticonvulsant Lyrica (pregabal...

Claims

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Application Information

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IPC IPC(8): C07D217/26C07D405/12A61K31/472A61K31/4725A61P25/00A61P25/02A61P3/10
CPCC07D217/26C07D405/12A61K31/4375
Inventor 孙广俊马建斌谭松良高鹏李成海喻红平包如迪徐耀昌
Owner SHANGHAI HANSOH BIOMEDICAL
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