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2-(2,2-diarylethyl)-cyclamine derivative or salt, and synthesis and application and composition thereof

A technology of derivatives and cyclic amines, applied in the field of 2--cyclic amine derivatives and its preparation, to achieve the effect of enhancing antagonistic activity

Active Publication Date: 2019-10-25
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is no report on the antagonistic activity of similar diaryl cyclic amine derivatives on M receptors.

Method used

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  • 2-(2,2-diarylethyl)-cyclamine derivative or salt, and synthesis and application and composition thereof
  • 2-(2,2-diarylethyl)-cyclamine derivative or salt, and synthesis and application and composition thereof
  • 2-(2,2-diarylethyl)-cyclamine derivative or salt, and synthesis and application and composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0239] 2-(2,2-Diphenylethyl)-N-methylpiperidine (II-1)

[0240] synthetic route:

[0241]

[0242] 1.1 Synthesis of 2-(2,2-distyryl)-N-methylpiperidine

[0243] Weigh 2-bromo-1,1-diphenylethylene (2.59g, 10mmol) and dissolve it in 60ml N-methylpiperidine, add MnCl 2 (126 mg, 1 mmol), stirred at room temperature. Slowly add 40ml of dimethyl zinc in n-hexane solution (1.0M, 40mmol), heat to 50-100°C (usually 70°C), stir the reaction, monitor the reaction by TLC, after the reaction is complete. The reaction was quenched with 20-100ml saturated sodium hydroxide solution, the mixture was extracted with dichloromethane (3x 100ml), the organic phases were combined, dried with anhydrous sodium sulfate, and after the solvent was removed by rotary evaporation, the resulting residue was subjected to silica column chromatography After separation and purification, 1.9 g of a light brown oily product can be obtained (69% yield). 1 HNMR (400MHz, CDCl 3 ), δ: 7.43-7.34(m, 3H), 7.31-7.24...

Embodiment 2

[0247] 2-[2-(2-Hydroxy-phenyl)-phenethyl]-N-methylpiperidine (II-2, and its chiral monomers II-2a-1 and II-2a-2), 2 -[2-(2-Hydroxy-phenyl)-phenethyl]-N,N-dimethylpiperidinium bromide (I-2a-Br, and its chiral monomers I-2a-1-Br and I-2a-2-Br) and 2-[2-(2-hydroxy-phenyl)-phenethyl]-N,N-dimethylpiperidinium iodide (I-2a-I)

[0248] synthetic route:

[0249]

[0250] 2.1 Synthesis of (2-methoxymethoxy-phenyl)(phenyl)-methanone

[0251] Dissolve (2-hydroxy-phenyl)(phenyl)-methanone (1.98g, 10mmol) in dichloromethane (50ml), add diisopropylethylamine (30mmol), stir at room temperature, add methyl chloride methyl ether (20 mmol). Heated to reflux for 12 hours, monitored by TLC, after the reaction was completed. The reaction solution was cooled to room temperature, the solvent was removed by rotary evaporation, and purified by silica column chromatography to obtain 2.2 g of a brown oily product of (2-methoxymethoxy-phenyl) (phenyl)-methanone (yield 91 %). 1 H NMR (400MHz, CDC...

Embodiment 3

[0270] 2-[2,2-bis(2-hydroxy-phenyl)-ethyl]-N-methylpiperidine (II-3 racemate, and its chiral monomer II-3-1, II-3 -2), 2-[2,2-bis(2-hydroxy-phenyl)-ethyl]-N,N-dimethylpiperidinium bromide (I-3-Br, and its chiral monomer I -3-1-Br, I-3-2-Br) and 2-[2,2-bis(2-hydroxy-phenyl)-ethyl]-N,N-dimethylpiperidinium iodide (I -3-I, and its chiral monomer I-3-1-I, I-3-2-I)

[0271] synthetic route:

[0272]

[0273] 3.1 Synthesis of bis(2-methoxymethoxy-phenyl)-methanone

[0274] According to the steps described in 2.1 of Example 2, bis(2-hydroxy-phenyl)-methanone is used as raw material, and the amount of DIEA and chloromethyl methyl ether is doubled, and bis(2-methoxymethyl ether) can be prepared Oxy-phenyl)-methanone as brown oily product, 92% yield. 1 HNMR (400MHz, CDCl 3 ), δ: 7.54-7.52 (m, 2H), 7.43-7.39 (m, 2H), 7.12-7.04 (m, 4H), 4.98 (s, 4H), 3.26 (s, 6H).

[0275] 3.2 Synthesis of 3,3-bis(2-methoxymethoxy-phenyl)-methyl acrylate

[0276] According to the steps described...

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PUM

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Abstract

The invention provides 2-(2,2-diarylethyl)-cyclamine derivative or salt, and synthesis and application and a composition thereof. Biological activity testing shows that the 2-(2,2-diarylethyl)-cyclamine derivative has great M receptor antagonistic activity, and can serve as pharmaceutical active ingredients to be used for treating muscarinic receptor mediated or regulated diseases comprising asthma, chronic obstructive pulmonary disease (COPD), overactive bladder (OAB), bronchospasm accompanied with COPD, visceral spasm, irritable bowel syndrome, Parkinson's disease, depression or anxiety, schizophrenia and related mental illness, and the like.

Description

technical field [0001] The invention relates to the field of pharmaceutical components for treating or preventing diseases related to M receptor antagonism, in particular to a 2-(2,2-diarylethyl)-cyclic amine derivative and a preparation method thereof. Background technique [0002] Muscarinic acetylcholine receptors (M receptors) are widely distributed in smooth muscle, myocardium, central and peripheral nerve tissues and various glands, and are divided into five subtypes (M1-M5). Studies have shown that the occurrence and disease process of many major diseases, such as COPD, asthma, OAB, Parkinson's syndrome, etc., are closely related to the dysfunction of different subtypes of M receptors. Therefore, the study of M receptor antagonists has become one of the hot spots in pharmaceutical research. [0003] 3,3-Diarylpropylamine derivatives are widely studied drug intermediates with M-receptor antagonism, and can be used to treat various neurological disorders related to M-r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/14C07D211/22C07D207/08C07D409/06A61P11/06A61P11/00A61P13/00A61P13/10A61P1/00A61P25/16A61P25/24A61P25/22A61P25/18A61P11/02A61P37/08
CPCC07D211/14C07D211/22C07D207/08C07D409/06A61P11/06A61P11/00A61P13/00A61P13/10A61P1/00A61P25/16A61P25/24A61P25/22A61P25/18A61P11/02A61P37/08A61K31/4535A61K31/445A61K31/40C07D307/52
Inventor 梁鑫淼赵耀鹏刘艳芳王纪霞王长健王志伟杜娜娜张秀莉郭志谋王超然
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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