2-(2,2-diarylvinyl)-quaternary ammonium salt type cyclic amine derivative and preparation method thereof

A technology of diarylethene and quaternary ammonium salt, which is applied in the directions of active ingredients of heterocyclic compounds, drug combinations, pharmaceutical formulations, etc. Problems such as few cyclic amine derivatives

Pending Publication Date: 2020-04-10
TAIZHOU GUOKEHUAWU BIOMEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, there are few reports on diaryl vinyl cyclic amine derivatives, and there are few studies on their biological target activity
GB765853 reported several tertiary amine type (2,2-diphenylvinyl)-piperidine derivative

Method used

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  • 2-(2,2-diarylvinyl)-quaternary ammonium salt type cyclic amine derivative and preparation method thereof
  • 2-(2,2-diarylvinyl)-quaternary ammonium salt type cyclic amine derivative and preparation method thereof
  • 2-(2,2-diarylvinyl)-quaternary ammonium salt type cyclic amine derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0140] Synthesis of 2-[(E)-2-(2-hydroxy-phenyl)-2-phenyl-vinyl-]-N,N-dimethylpiperidinium bromide (I-1)

[0141] According to the steps described in the synthetic method Scheme 1, 2-[(E)-2-(2-hydroxyl-phenyl)-2-phenyl-vinyl-]-N-methylpiperidine is reacted with methyl bromide to prepare The target product I-1 was obtained as a white solid with a yield of 98%. MS(m / z): 308.2[M+H] + . 1 H NMR (400MHz, CD 3 OD), δ: 7.46-7.43(m, 2H), 7.41-7.39(m, 1H), 7.22-7.20(m, 2H), 7.15-7.11(m, 1H), 6.89(d, J=7.6Hz, 1H),6.83(d,J=6.8Hz,1H),6.77-6.73(m,1H),6.07(d,J=9.6Hz,1H),3,64-3.62(m,1H),3.50-3.46 (m,1H),2.97-2.94(m,1H),2.87(s,3H),2,80(s,3H),2.21-2.18(m,1H),1.93-1.90(m,2H),1.84 -1.77(m,2H),1.58-1.55(m,1H).

Embodiment 2

[0143] 2-[2,2-bis(2-hydroxy-phenyl)-vinyl-]-N,N-dimethylpiperidinium bromide (I-2 and its chiral monomer I-2-1, I -2-2) Synthesis

[0144] According to the steps described in the synthetic method Scheme 1, the target product I-2 can be obtained by reacting 2-[2,2-bis(2-hydroxy-phenyl)-vinyl]-N-methylpiperidine with methyl bromide, Yield 95%. MS(m / z): 324.2[M+H] + . 1 H NMR (400MHz, CD 3 OD), δ: 7.33(d, J=4Hz, 1H), 7.18-7.14(m, 1H), 7.12-7.09(m, 1H), 6.97-6.92(m, 2H), 6.85-6.80(m, 2H ),6.78-6.73(m,1H),4.52(q,J=10.4Hz,1H),2.99(d,J=13.2Hz,1H),2.74(b,1H),2.54(b,1H),2.43 (s, 3H), 2.39 (s, 3H), 2.17-2.08 (m, 2H), 1.76-1.60 (m, 2H), 1.50-1.42 (m, 2H), 1.41-1.31 (m, 2H).

[0145] A pair of enantiomeric monomers of 2-[2,2-bis(2-hydroxy-phenyl)-vinyl]-N-methylpiperidine are respectively reacted with methyl bromide to obtain the target product Sexual monomer compound I-2-1 or I-2-2.

[0146] Through HPLC chiral analysis, the retention times of I-2-1 and I-2-2 are: 14.4min and 20....

Embodiment 3

[0148] 2-[(E)-2-(2-Hydroxy-5-methyl-phenyl)-2-phenyl-vinyl-]-N,N-dimethylpiperidinium bromide / iodide (I- 3-Br, I-3-I, and their chiral monomers) synthesis:

[0149] According to the steps described in the synthetic method Scheme 1, 2-[(E)-2-(2-hydroxyl-5-methyl-phenyl)-2-phenyl-vinyl-]-N-methylpiperidine and The white solid target product I-3-Br or I-3-I can be obtained by reacting methyl bromide or methyl iodide with a yield of 99%. MS(m / z): 322.2[M+H] + . 1 H NMR (400MHz, CD 3 OD), δ: 7.36-7.32 (m, 5H), 7.11-7.09 (m, 1H), 6.87-6.85 (m, 1H), 6.81-6.80 (m, 1H), 6.08 (d, J=9.6Hz, 1H),3.80-3.72(m,1H),3.53-3.46(m,1H),3.33-3.22(m,1H),3.14(s,3H),2.94(s,3H),2.27(s,3H) ,2.15-2.05(m,2H),2.0-1.86(m,2H),1.85-1.75(m,1H),1.55-1.43(m,1H).

[0150] A pair of enantiomeric monomers of 2-[(E)-2-(2-hydroxy-5-methyl-phenyl)-2-phenyl-vinyl-]-N-methylpiperidine Respectively react with methyl bromide to obtain the target chiral monomer compound I-3-Br-1 or I-3-Br-2.

[0151] Through HPLC ch...

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Abstract

The invention provides a quaternary ammonium salt type 2-(2,2-diarylvinyl)cyclic amine derivative and a preparation method thereof, wherein the aryl substituent of the quaternary ammonium salt type 2-(2,2-diarylvinyl)cyclic amine derivative has hydroxyl or a hydroxyl derivative group at the ortho-positions of vinyl. The biological activity test results show that the compound has good muscarinic receptor antagonism activity, and can be used as an active pharmaceutical ingredient in treatment of diseases related to muscarinic receptor antagonism.

Description

technical field [0001] The present invention is used in the field of pharmaceutical components for treating or preventing anticholinergic-related diseases, and relates to a novel structure of quaternary ammonium salt-type cyclic amine derivatives, especially 2-(2,2-diarylethenyl)- Quaternary ammonium salt type cyclic amine derivative and its preparation method. Background technique [0002] Organic amine derivatives containing diaryl vinyl groups are an important class of intermediates in drug synthesis, and they also have various pharmacological activities. Brit. J. Pharmacol. 1951, 6, 560-571 reported that a series of tertiary amine type diaryl allylamine compounds (as shown in structure III) have obvious antihistamine, antispasmodic and anesthetic activities. ActaPharmacol.et toxicol.1951, 7, 51-64 found a compound 1,1-diphenyl-3-dimethylamino-butene with a similar structure, which has anticholinergic effect and exhibits obvious antispasmodic activity , also has mild an...

Claims

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Application Information

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IPC IPC(8): C07D211/22C07D207/08C07D409/06A61P11/06A61P37/08A61P11/00A61P1/00A61P25/18A61P25/22A61P25/24A61K31/445A61K31/4535A61K31/40
CPCC07D211/22C07D207/08C07D409/06A61P11/06A61P37/08A61P11/00A61P1/00A61P25/18A61P25/22A61P25/24
Inventor 梁鑫淼赵耀鹏王长健王纪霞刘艳芳宋聪王志伟
Owner TAIZHOU GUOKEHUAWU BIOMEDICAL TECH CO LTD
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