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Novel use of amine compounds

A compound and application technology, applied in the field of medicinal chemistry, can solve problems such as unclear domain functions

Pending Publication Date: 2018-03-27
SHANGHAI LEADO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A 2-helical calcium-binding motif domain is present at the N-terminus of TRPA1, but the domain's role is unclear
At present, there are few domestic studies, but foreign pharmaceutical companies have developed a series of pyrimidinedione TRPA1 inhibitors, and the TRPA1 channel has also become a research hotspot for new analgesics

Method used

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  • Novel use of amine compounds
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preparation example Construction

[0142] The present invention provides the preparation methods of compounds 1 and 2, and the specific synthesis strategies are as follows:

[0143]

[0144] In the formula, n, R 1 , R 2 and x 1 The definition is the same as above.

[0145] 1) Dissolve 3-fluorocatechol, dibromo compounds with different chain lengths and potassium carbonate in N,N-dimethylformamide, and heat to react. After the reaction, water was added to the reaction system, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to obtain intermediate II.

[0146] 2) Dissolving intermediate II, chiral amine compound and potassium tert-butoxide in dimethyl sulfoxide, and reacting at 120-150° C. for 10-20 hours. After the reaction, water was added to the reaction system, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate,...

Embodiment 1

[0160] 4-Fluorobenzo[1,3]dioxolane (Intermediate II-1)

[0161]

[0162] Dissolve 4 g of 3-fluorocatechol, 3.36 ml of methylene bromide and 6.5 g of potassium carbonate in 30 ml of N,N-dimethylformamide, and react at 110°C for 2 hours. After the reaction, water was added to the reaction system, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography (petroleum ether) to obtain the title compound (intermediate II-1), 3.5 grams of light yellow oil, yield 80%.

[0163] 1 H NMR (400MHz, CDCl 3 ) δ 6.81–6.73 (m, 1H), 6.66 (ddt, J=8.6, 7.4, 1.1 Hz, 2H), 6.01 (s, 2H).

Embodiment 2

[0165] 5-Fluoro-2,3-dihydrobenzo[b][1,4]dioxane (Intermediate II-2)

[0166]

[0167] 2 g of 3-fluorocatechol, 1.51 ml of 1,2-dibromoethane and 6.6 g of potassium carbonate were dissolved in 30 ml of N,N-dimethylformamide, and reacted at 50°C for 12 hours. After the reaction, water was added to the reaction system, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography (petroleum ether) to obtain the title compound (intermediate II-2), 1.6 g of light yellow oil, yield 66%.

[0168] 1 H NMR (400MHz, CDCl 3 ) δ 7.04 (d, J = 5.9Hz, 2H), 7.00–6.94 (m, 1H), 2.72 (d, J = 5.7Hz, 4H), 1.77 (dt, J = 6.6, 3.4Hz, 4H).

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Abstract

The invention provides a preparation method and novel use of amine compounds. Specifically, the invention provides compounds shown in the formula A or their optical isomers, racemes, solvates or pharmaceutically acceptable salts and a medical use thereof. The above compounds can be used for preparation of a pharmaceutical composition or a preparation. The pharmaceutical composition or preparationis used for (a) inhibiting a transient receptor potential channel protein TRPA1 and (b) treating diseases associated with the transient receptor potential channel protein, wherein each group is defined in the specification.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, more specifically to the preparation of amine compounds and their application in inhibiting the transient receptor potential channel protein TRPA1. Background technique [0002] Transient receptor potential (TRP) is a protein superfamily composed of important cation channels existing on the cell membrane. It was first discovered by Minke et al. when studying the visual transmission system of Drosophila. Subsequent studies have discovered a series of TRP family channel members. According to the sequence homology of about 30 TRP channels found in mammals, they are divided into six subfamilies, namely TRPC, TRPV, TRPM, TRPML, TRPA and TRPP. Both the C-terminal and N-terminal of the TRP channel are located in the cell membrane, and contain six transmembrane domains of S1-S6. The ligand-binding reaction sites on domains S1-S4 may be gated pores, but the S4 domain lacks positively charged amino aci...

Claims

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Application Information

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IPC IPC(8): C07D409/12A61K31/381A61K31/5377A61K31/496A61K31/397A61K31/4025A61K31/4525A61P29/00A61P11/00A61P11/06A61P1/00A61P13/02A61P1/04A61P17/04
CPCC07D409/12
Inventor 王友鑫曲振林张玲玲
Owner SHANGHAI LEADO PHARMATECH CO LTD
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