Benzoheterocycle compound and preparation method as well as medical application thereof

A compound and application technology, applied in the field of medicinal chemistry, to achieve the effects of simple operation and post-treatment, mild reaction conditions, and abundant raw materials

Active Publication Date: 2012-08-08
CHINA PHARM UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The second-generation antihistamines developed after the 1980s, including terfenadine and loratadine, are effective against H 1 High receptor selectivity, no side effects of central sedation, but in the clinical application process, terfenadine and astemizole have been withdrawn from the market due to the serious side effect of inducing arrhythmia, which also prompts people to continue to develop a new generation of anti-inflammatory drugs. histamine drugs

Method used

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  • Benzoheterocycle compound and preparation method as well as medical application thereof
  • Benzoheterocycle compound and preparation method as well as medical application thereof
  • Benzoheterocycle compound and preparation method as well as medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] 1-(4-Chlorobenzyl)-2-(4-piperidine)benzimidazole (CPUYW01)

[0045]

[0046] (1) Preparation of N-(4-chlorobenzyl)-o-phenylenediamine

[0047] O-phenylenediamine (1.1g, 10mmol), p-chlorobenzyl chloride (1.6g, 10mmol), K 2 CO 3 3g was put into the reaction flask in turn, 10mL of DMF was added, heated to 40°C and stirred for 3h. After the reaction was completed, the reaction solution was cooled to room temperature and poured into water, extracted twice with dichloromethane (2×20mL), washed 4 times with water, and anhydrous Na 2 SO 4 Drying and separation by column chromatography (PE:EA=8:1) gave 2.1 g of a brown solid, yield 91%, m.p.74-76°C.

[0048] (2) Preparation of N-Boc-4-piperidinecarboxylic acid

[0049] Dissolve piperidine-4-carboxylic acid (1.3g, 10mmol) in (v:v=1:2) tetrahydrofuran and 1N NaOH mixed solution 15mL, add Boc 2 O (2.4g, 11mmol), after reacting at room temperature for 2h, the liquid was separated, and the pH value was adjusted to 5-6 with 1...

Embodiment 2

[0053] 1-(4-fluorobenzyl)-2-(4-piperidine)benzimidazole (CPUYW02)

[0054]

[0055] (1) Preparation of N-(4-fluorobenzyl)-o-phenylenediamine

[0056] Prepared according to step 1 in Example 1, substituting p-fluorobenzyl bromide for p-chlorobenzyl chloride, to obtain 1.8 g of brown solid, yield 82%, m.p.78-80°C.

[0057] (2) Preparation of title compound

[0058] Prepared according to step 3 of Example 1, the target compound was obtained as a yellow solid 1.1 g, yield 32%, m.p.186-187°C. 1 H NMR (CDCl 3 , 300MHz, δppm) 1.81-2.05(m, 5H, -NH), 2.67-2.76 (dt, 2H, J=12.6Hz, J=2.7Hz, ), 2.90-3.00 (m, 1H, ), 3.21-3.25 (d, 2H, J=12.6Hz, ), 5.34(s, 2H, ), 6.99-7.02(d, 4H, J=6.3Hz, Ar-H), 7.19-7.29(m, 3H, Ar-H), 7.79-7.81(d, 1H, J=7.8Hz, Ar-H) HRMS calcd for C 19 h 20 N 3 F[M+H] + : 310.1714; found: 310.1718IR(KBr): 3382, 2935, 1652, 822

Embodiment 3

[0060] 1-(4-Chlorobenzyl)-2-(4-piperidine)benzimidazole (CPUYW03)

[0061]

[0062] (1) Ethyl N-Boc-4-piperidine ethanoate

[0063] N-Boc-4-piperidone (4.9g, 24.4mmol), triethyl phosphoroacetate (7.1g, 31.7mmol), anhydrous K 2 CO 3 (10g, 73.3mmol) was placed in 130mL of anhydrous DMF, heated to 70°C under N2 conditions, kept for 22 hours, removed the oil bath, cooled the reaction solution to 30°C, poured it into a large amount of water, a large amount of solids precipitated, pumped Filter, wash the filter cake twice with water, and dry to obtain 6.7 g of white solid, yield 97%, m.p.82-83°C.

[0064] (2) N-Boc-4-piperidine ethyl acetate

[0065] Dissolve ethyl N-Boc-4-piperidine ethanoate (2.7g, 10mmol) in ethanol and heat to 30°C, add Pd / C (270mg, 10%), ammonium formate (1.6g, 25mmol) aqueous solution. N 2 Heated to 40°C under protection. After 3.5 h, TLC monitored that the reaction was complete. Concentrate the reaction solution to a small volume, add n-hexane and ...

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Abstract

The invention relates to the field of pharmaceutical chemistry, in particular to a benzoheterocycle compound and a preparation method, a pharmaceutical preparation comprising same as well as medical application thereof. Pharmacological experiments prove that the compound has a strong antagonistic effect on H1 receptors; and a part of compounds have certain antagonistic activity to the PAF (Platelet Activating Factor) receptors. The type of compounds and the medical preparations thereof can be used for preparing medicaments for treating a series of diseases caused by allergy, such as allergic asthma, allergic rhinitis, allergic pharyngitis, urticaria or eczema.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of benzoheterocyclic compounds, a preparation method thereof, pharmaceutical preparations and medical applications thereof. Background technique [0002] Allergic diseases are major diseases affecting human health. Within 15 years, the number of people suffering from allergic diseases will account for 1 / 2 of the world's population. The World Health Organization (WHO) listed this type of disease as "the disease that should be studied and prevented in the 21st century". The 8th is designated as the first "World Allergy Day (World Allergy Day)". [0003] antihistamines H 1 Receptor antagonists are the main drugs for the clinical treatment of allergic diseases, and they are divided into four categories according to their structural characteristics. Drugs discovered before the 1980s are called first-generation antihistamines, including diphenhydramine and chlorpheniramin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/06C07D401/04C07D401/12C07D209/24A61K31/454A61K31/496A61P37/08
Inventor 汪小涧尤启冬孙丽席眉扬黄婧婕付继华尹大力
Owner CHINA PHARM UNIV
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