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Triazole compound, synthesis method and application thereof

A compound, triazole technology, applied in the field of biomedicine, can solve problems such as adverse reactions, long-term use of high-dose selective COX2 inhibitors, and side effects are not recommended

Active Publication Date: 2018-12-04
EAST CHINA NORMAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, because COX enzymes are in the upstream of prostaglandin synthesis, they non-specifically affect the biosynthesis of various prostaglandins and involve many normal physiological regulation functions. Therefore, long-term use of NSAIDs will cause gastrointestinal, kidney, liver and cardiovascular diseases. Adverse reactions
Side effects in some cardiovascular patients, especially those with a history of atherosclerotic heart disease, long-term use of high doses of selective COX2 inhibitors is not currently recommended

Method used

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  • Triazole compound, synthesis method and application thereof
  • Triazole compound, synthesis method and application thereof
  • Triazole compound, synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0116] Example 1-1, Compound (S)-4-(1-(1-(4-(trifluoromethyl)benzyl)-4-methyl-1hydrogen-1,2,3-triazole-5 - Preparation of formamido) ethyl) benzoic acid (YJ001)

[0117]

[0118] Take 4-trifluoromethylbenzyl bromide (717mg, 3mmol) in anhydrous dimethyl sulfoxide (4ml), add sodium azide (215mg, 3.3mmol), and stir at room temperature for 24h. After the reaction was completed, it was extracted with ethyl acetate, and the crude product 4-trifluoromethylbenzyl azide (556 mg, 92%) was obtained after conventional treatment.

[0119] Dissolve 4-trifluoromethylbenzyl azide (556mg, 2.77mmol) in anhydrous toluene (5ml), add ethyl 2-butynoate (224mg, 2mmol), react at 120°C for 12h and cool to room temperature. Most of the solvent was removed under reduced pressure, and after conventional treatment, it was passed through a silica gel column to obtain the intermediate 1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazole-4-methyl-5- Ethyl formate (210 mg, 35%).

[0120] Dissolve ethyl 1-(4...

Embodiment 1-37

[0128] Example 1-37, Compound (S)-4-(1-(1-(4-(trifluoromethyl)benzyl)-4-(4-fluorophenyl)-1hydrogen-1,2,3 - Preparation of triazole-5-carboxamido) ethyl) benzoic acid (YJ037)

[0129]

[0130]Take 4-trifluoromethylbenzyl bromide (23.9g, 100mmol) in anhydrous dimethyl sulfoxide (30ml), add sodium azide (7.15g, 110mmol), and stir at room temperature for 24h. After the reaction was completed, it was extracted with ethyl acetate, and the crude product 4-trifluoromethylbenzyl azide (18.492 g, 92%) was obtained after conventional treatment.

[0131] Dissolve ethyl propiolate (9.8g, 100mmol) in acetone (30ml), add silver nitrate (1.7g, 10mmol), and react with N-bromosuccinimide (19.58g, 110mmol) at room temperature for 12h , most of the solvent was removed under reduced pressure, and after routine treatment, it was passed through a silica gel column to obtain ethyl bromopropiolate (17.6 g, 99%).

[0132] Dissolve 4-trifluoromethylbenzyl azide (18.492g, 92mmol) in anhydrous toluen...

Embodiment 1-45

[0141] Example 1-45, compound (S)-4-(1-(5-(trifluoromethyl)-1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-tri Preparation of azole-4-carboxamido)ethyl)benzoic acid (YJ045)

[0142]

[0143] Take 4-trifluoromethylbenzyl bromide (717mg, 3mmol) in anhydrous dimethyl sulfoxide (4ml), add sodium azide (215mg, 3.3mmol), and stir at room temperature for 24h. After the reaction was completed, it was extracted with ethyl acetate, and the crude product 4-trifluoromethylbenzyl azide (556 mg, 92%) was obtained after conventional treatment.

[0144] Dissolve 4-trifluoromethylbenzyl azide (556mg, 2.77mmol) in anhydrous toluene (5ml), add 4,4,4-trifluoro-2-butyne ethyl ester (332mg, 2mmol), in After reacting at 120°C for 12h, it was cooled to room temperature. Most of the solvent was removed under reduced pressure, and the silica gel column was passed after conventional treatment to obtain the intermediate ethyl 5-(trifluoromethyl)-1-(4-(trifluoromethyl)benzyl)-1H-1,2,3 - Ethyl triazole-4-car...

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Abstract

The invention discloses a triazole compound as shown in a formula I and a formula II, and a pharmaceutical derivative and a hydrate of the triazole compound, a composition containing the triazole compound and a preparation method thereof. The invention also discloses a use of the triazole compound serving as a prostaglandin EP4 receptor antagonist for preventing and treating prostaglandin PGE2 mediated diseases, including malignant tumors, autoimmune diseases, inflammation, pains or osteoarthritis.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to a class of triazole compounds and their synthesis method and application. The triazole compounds of the present invention are used as prostaglandin receptor EP4 antagonists for preventing and treating diseases mediated by prostaglandin PGE2. Including malignancy, autoimmune disease, inflammation, pain, etc. Background technique [0002] Gene mutations, epigenetic changes, chronic inflammation, poor diet and lifestyle are all key factors that induce cancer. Among them, high-fat diet can lead to the occurrence of various malignant tumors such as colorectal cancer, pancreatic cancer, breast cancer and prostate cancer. It is a biologically active lipid formed by the metabolism of arachidonic acid (AA) in animal fat through related metabolic pathways mediated by human cyclooxygenase (Cyclooxygenase, COX) and lipoxygenase (Lipoxygenase, LOX), Eicosanoids such as prostaglandins (PGs) and leuk...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/04C07D409/04C07D405/04C07D405/06A61K31/4192A61P37/04A61P37/06A61P37/08A61P29/00A61P19/08A61P35/00A61P35/02
CPCC07D249/04C07D405/04C07D405/06C07D409/04
Inventor 章涵堃卢伟强刘明耀杨俊杰于薇薇胡龙龙张昕沛刘文娟林仙花
Owner EAST CHINA NORMAL UNIV
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