Compound with dual antagonistic activity of histamine receptor and application

A compound and drug technology, applied in the field of medicinal chemistry, can solve the problems of weak anti-inflammatory effect and decreased body resistance, and achieve the effects of enhanced anti-inflammatory activity, significant anti-inflammatory effect, and good medicinal prospects

Active Publication Date: 2018-12-28
HEFEI IND PHARMA INST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, although antihistamines commonly used in clinical practice such as desloratadine and rupatadine have good anti-allergic effects, their anti-inflammat

Method used

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  • Compound with dual antagonistic activity of histamine receptor and application
  • Compound with dual antagonistic activity of histamine receptor and application
  • Compound with dual antagonistic activity of histamine receptor and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] 8-Chloro-6,11-dihydro-11-(1-(6-methylpyrazin-2-yl)methyl)piperidin-4-ylidene)-5H-benzo[5,6]ring Synthesis of Hepta[1,2-b]pyridine (LP-1)

[0045] Synthesis of step 1 intermediate 2-(chloromethyl)-6-methylpyrazine

[0046]

[0047] SM (500mg, 4.62mmol), NCS (617mg, 4.53mmol) and carbon tetrachloride (13mL) were sequentially added to a 50mL single-necked bottle, and heated to reflux under nitrogen protection. BPO (22mg, 0.077mmol) was added to the above reaction solution, and the reaction was refluxed for 3h. NCS (62mg, 0.45mmol) was added to the above reaction solution, refluxed for 2h and then transferred to room temperature for overnight reaction. After the reaction was monitored by TLC (PE:EA=4:1), water (10 mL) was added to the reaction solution, extracted with dichloromethane (10 mL×3), and the organic layers were combined. Wash with saturated sodium chloride solution (5 mL×3), and collect the organic phase. Dry over anhydrous magnesium sulfate, filter with s...

Embodiment 2

[0052] 8-Chloro-6,11-dihydro-11-(1-((3,5,6-trimethylpyrazin-2-yl)methyl)piperidin-4-ylidene)-5H-benzo Synthesis of [5,6]cyclohepta[1,2-b]pyridine (LP-2)

[0053] With reference to the method of Example 1, 2,6 dimethylpyrazine was replaced by 2,3,5,6-tetramethylpyrazine, and the compound 8-chloro-6,11-dihydro-11-(1 -((3,5,6-trimethylpyrazin-2-yl)methyl)piperidin-4-ylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (LP-2) (103 mg, 51.5% yield), pale yellow solid. 1 H NMR 400MHz (CDCl 3 )δ9.01(s,1H),8.82(s,1H),8.41(dd,J=1.6Hz,J=4.8Hz,1H),7.45(dd,J=1.6Hz,J=7.6Hz,1H) ,7.13(d,J=7.6Hz,2H),3.80(s,2H),3.33-3.42(m,2H),2.76-2.88(m,4H),2.53-2.60(m,10H),2.79-2.51 (m,5H)

Embodiment 3

[0055] 8-Chloro-6,11-dihydro-11-(1-(6-trifluoromethylpyrazin-2-yl)methyl)piperidin-4-ylidene)-5H-benzo[5,6 Synthesis of ]cyclohepta[1,2-b]pyridine (LP-3)

[0056] With reference to the method of Example 1, 2,6 dimethylpyrazine was replaced by 6-trifluoromethylpyrazine, and the compound 8-chloro-6,11-dihydro-11-(1-(6-tri Fluoromethylpyrazin-2-yl)methyl)piperidin-4-ylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (LP-3) (36mg, 40.9 % yield), white solid. 1 H NMR 400MHz (CDCl 3 )δ9.02(s,1H),8.83(s,1H),8.40(dd,J=1.6Hz,J=4.8Hz,1H),7.45(dd,J=1.6Hz,J=7.6Hz,1H) ,7.13-7.16(m,3H),7.07-7.10(m,1H),3.80(s,2H),3.33-3.42(m,2H),2.76-2.88(m,4H),2.53-2.60(m, 1H),2.79-2.51(m,5H)

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Abstract

The invention relates to the field of pharmaceutical chemistry and in particular relates to a class of compounds (I) with dual antagonistic activity of histamine H1 and H4 receptors. Pharmacodynamic experiments prove that the compounds disclosed by the invention have dual antagonistic effects of the histamine H1 and H4 receptors. The compounds disclosed by the invention have obvious anti-allergicactivity, can further inhibit inflammatory factor release and achieve anti-inflammatory actions.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of 1 、H 4 Compounds with dual receptor antagonist activity and pharmaceutical uses. Background technique [0002] Allergic reactions are usually caused by tissue damage or dysfunction after the body is stimulated by allergens (antigenic substances), causing mast cells to release different inflammatory mediators such as histamine, prostaglandins and leukotrienes, resulting in an inflammatory response. At present, antihistamines and anti-inflammatory hormone drugs are mainly used for clinical treatment of such diseases. where antihistamines are H 1 Receptor antagonist-based, H 1 Receptor antagonists can compete with H 1 Receptor binding, blocking histamine and H 1 receptors, and then inhibit histamine to exert biological effects and play an anti-allergic effect [Zolaly MA.Histamine H 1 Antagonists and clinical characteristics of febrile seizures[J].Int J Gen Med.20...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61K31/497A61P37/08A61P29/00
CPCA61P29/00A61P37/08C07D401/14
Inventor 何广卫许勤龙储昭兴李家明莫佳佳李丰刘为中赵炎林高峰
Owner HEFEI IND PHARMA INST
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