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Compound, preparation method and application thereof in preparation of medicine for preventing/curing autoimmune diseases

An autoimmune and compound technology, applied in the field of medicine, can solve problems affecting the quality of life of patients, joint destruction, deformity, etc.

Inactive Publication Date: 2018-05-18
田甜
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

If not treated properly, often results in joint destruction and deformity and affects the patient's quality of life

Method used

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  • Compound, preparation method and application thereof in preparation of medicine for preventing/curing autoimmune diseases
  • Compound, preparation method and application thereof in preparation of medicine for preventing/curing autoimmune diseases
  • Compound, preparation method and application thereof in preparation of medicine for preventing/curing autoimmune diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: Synthesis of 2,4-dichloro-6-(cyclohexyloxy)-3-methylpyridine

[0033]

[0034] To a solution of sodium hydride NaH (4.51 g, 0.188 mmol, 60 wt % in mineral oil) in THF (200 mL) was added cyclohexanol (15.6 mL, 0.15 mol) dropwise at 0 °C. After stirring at 0°C for 30 minutes, a THF (40 mL) solution of 2,4,6-trichloro-3-methylpyridine (Compound 1) (26.52 g, 0.135 mol) was added dropwise via syringe. The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction was cooled to 0°C, and saturated aqueous ammonium chloride solution was slowly added to quench the reaction. The reaction mixture was allowed to warm to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. P...

Embodiment 2

[0035] Example 2: Synthesis of 7-(4-chloro-6-(cyclohexyloxy)-3-methylpyridin-2-yl)-2-oxa-7-azaspiro[3.5]nonane

[0036]

[0037] A 2L three-necked flask equipped with a mechanical stirrer, a thermometer and a dropping funnel was charged with ethanol (375mL), water (375mL) and 2-oxa-7-azaspiro[3.5]nonane (19.08g, 0.15 mol), the resulting solution was cooled (with an ice-salt bath) to about 0°C, and a solution of compound 2 (33.37g, 0.128mol) in ethyl acetate (47.5mL) was added dropwise within about 20 minutes, keeping the temperature low at 10°C. The dropping funnel was rinsed twice with ethyl acetate (20 mL), and the rinses were transferred to the reaction mixture. The reaction was checked by TLC to determine when the reaction was complete. After the reaction, ice water (375 mL) was added and stirred for 30 minutes to complete the precipitation. The white solid was filtered off, washed 6 times with water (225 mL for each wash), and dried under vacuum at 40-50 °C until a ...

Embodiment 3

[0038] Example 3: Synthesis of 7-(6-(cyclohexyloxy)-4-hydrazino-3-methylpyridin-2-yl)-2-oxa-7-azaspiro[3.5]nonane

[0039]

[0040] Under nitrogen purging, the suspension of compound 3 (41.95g, 0.120mol) synthesized in Example 2 and hydrazine monohydrate (7.51g, 0.15mol) in dioxane (255mL) was boiled and refluxed for 6 Hour. Ice water (400 mL) was added to the reaction mixture and left overnight. The resulting precipitate was filtered off, washed 3 times with water (260 mL each), and dried under vacuum at 40-50 °C until constant weight to give 7-(6-(cyclohexyloxy)-4-hydrazino-3-methanol ylpyridin-2-yl)-2-oxa-7-azaspiro[3.5]nonane (compound 4), 27.77g, yield 66.8%. 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.08-1.29(m, 5H),1.58-1.69(m, 3H), 1.84(t, 4H), 1.88-1.98(m, 4H),2.31(s, 1H), 2.40(s, 3H) ,3.71(t, 4H), 4.17(m, 1H), 4.72(s, 4H), 5.21(s, 1H). 13 C-NMR (125 MHz, CDCl 3 )δ: 11.50, 24.60, 25.92, 28.55, 30.44, 38.75, 45.85, 76.82, 81.26, 85.95, 109.94, 147.44, 161.81, 164.78. LC-M...

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Abstract

The invention discloses a compound of formula (I) as shown in the description, wherein R is selected from formulas in the description. The compound of formula (I) can inhibit the generation of IL-12 in vitro and has an inhibiting effect on HaCat cell proliferation, and the compound has excellent activity in SD rat collagen induced rheumatoid arthritis models. The compound of formula (I) can be used for deeper development of the preparation of candidate medicine for preventing / curing autoimmune diseases.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a compound, a preparation method and its application in the preparation of drugs for preventing / treating autoimmune diseases. Background technique [0002] Autoimmune diseases are a class of diseases caused by the body's immune response to self-antigens, resulting in damage to its own tissues. At present, the research on IL-12 family at home and abroad mainly focuses on autoimmune diseases, such as multiple sclerosis (multiple sclerosis, MS), inflammatory bowel disease (inflammatory bowel disease, IBD), rheumatoid arthritis (Rheumatoid Arthritis, RA ), psoriasis, etc. [0003] Rheumatoid arthritis is an autoimmune disease mainly characterized by chronic inflammation of the synovium of the joints, which can cause joint swelling and pain, and then lead to cartilage destruction, joint deformity, and eventually disability of varying degrees. If not treated properly, it often results in joint ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/107A61K31/444A61P37/02A61P25/00A61P29/00A61P19/02A61P17/06A61P1/00
CPCC07D491/107
Inventor 田甜陆超王灵玺
Owner 田甜
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