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Triazole naphthoquinone connected aromatic (heterocyclic) ring derivative

A technology of triazole naphthalene and its derivatives, which is applied in the field of chemical medicine and can solve the problems of limited anti-tumor activity and large side effects of bone marrow suppression

Active Publication Date: 2018-08-31
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, small molecule inhibitors for DHODH include buquinar (Brequinar), which has certain anti-tumor activity. Phase I clinical trials for the treatment of tumors were carried out in 1986, 1988 and 1990 respectively, but its anti-tumor activity is limited. Moreover, side effects such as bone marrow suppression are relatively large, and it has not been clinically approved for the treatment of malignant tumors.

Method used

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  • Triazole naphthoquinone connected aromatic (heterocyclic) ring derivative
  • Triazole naphthoquinone connected aromatic (heterocyclic) ring derivative
  • Triazole naphthoquinone connected aromatic (heterocyclic) ring derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1, Preparation of 3-methoxy-[1,1'-biphenyl]-4-amino (intermediate 1a)

[0030]

[0031] 4-bromoaniline 1g (5.81mmol) and m-methoxyphenylboronic acid 883mg (5.81mmol.1eq) potassium carbonate (4.82g 34.88mmol 6eq) [1,1'-bis (diphenylphosphino) ferrocene ] Palladium dichloride (425.35mg 581mmol6eq) was placed in a 100ml two-neck bottle, injected with 30ml (dioxane: water = 3:1) under nitrogen protection, and reacted at 80 for 3.5h. After the reaction is monitored by TLC, post-processing vacuum distillation to the remaining about 10ml, the solution is poured into a separatory funnel, extracted 2-3 times with dichloromethane, dried with anhydrous Na2SO4, filtered, vacuum distilled and spin-dried to obtain black oily droplets , separated and purified by silica gel column chromatography with petroleum ether:ethyl acetate=6:1 to obtain about 720 mg of light yellow oily liquid with a yield of 62%.

[0032] 1 H-NMR (400MHz, CDCl 3 ):8.02–7.94(m,4H),7.46(t,J=7.9Hz,1H...

Embodiment 2

[0033] Example 2, Preparation of 3-trifluoromethoxy-[1,1'-biphenyl]-4-amino (intermediate 1b)

[0034]

[0035] 4-Bromoaniline 1g (5.81mmol) and m-trifluoromethoxyphenylboronic acid 1200mg (5.81mmol.1eq) potassium carbonate (4.82g 34.88mmol 6eq) [1,1'-bis (diphenylphosphino) di Ferrocene]palladium dichloride (425.35mg 581mmol6eq) was placed in a 100ml two-neck flask, injected with 30ml (dioxane:water=3:1) under nitrogen protection, and reacted at 80°C for 3.5h. After the reaction is monitored by TLC, post-processing vacuum distillation to the remaining about 10ml, the solution is poured into a separatory funnel, extracted 2-3 times with dichloromethane, dried with anhydrous Na2SO4, filtered, vacuum distilled and spin-dried to obtain black oily droplets , separated and purified by silica gel column chromatography with petroleum ether:ethyl acetate=6:1 to obtain about 780 mg of light yellow oily liquid with a yield of 53%.

[0036] 1 H-NMR (400MHz, CDCl 3 ):8.02–7.94(m,4H)...

Embodiment 3、3

[0037] Example 3, Preparation of 3.5-difluoro-(3-trifluoromethoxy-[1,1'-biphenyl])-4-amino (intermediate 1c)

[0038]

[0039]4-Bromo-3.5-difluoro-aniline 1g (4.81mmol) and m-trifluoromethoxyphenylboronic acid 990mg (4.81mmol.1eq) potassium carbonate (4.82g 24.88mmol 6eq) [1,1'-bis(di Phenylphosphino)ferrocene]palladium dichloride (425.35mg 481mmol 6eq) was placed in a 100ml two-necked flask, injected with 30ml (dioxane: water = 3:1) under nitrogen protection, and reacted at 80°C for 3.5h. After the completion of the reaction monitored by TLC, post-processing vacuum distillation to the remaining about 10ml, the solution was poured into a separatory funnel, extracted 2-3 times with dichloromethane, dried with anhydrous Na2SO4, filtered, vacuum distilled and spin-dried to obtain black oily droplets , separated and purified by silica gel column chromatography with petroleum ether:ethyl acetate=6:1 to obtain about 680 mg of light yellow oily liquid with a yield of 49%.

[0040...

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Abstract

The invention belongs to the field of chemical medicine, particularly relates to a micromolecule capable of resisting malignant tumor, acute leukemia and arthritis, multiple sclerosis and immunological rejection and a preparation and application of the micromolecule, and aims to solve the technical problems that at present the clinic lacks the dihydrolactate dehydrogenase inhibitor micromolecule market drug for resisting colorectal cancer and the toxic and side effects of compounds of existing other pharmacological models are large. In order to solve the technical problems, the invention provides a triazole naphthoquinone connected aromatic (heterocyclic) ring derivative, the derivative is mainly that triazole is connected with different aromatic (heterocyclic) rings, the compound has theadvantages that the malignant tumor resistance activity is high, the toxic and side effects are low and clinic drug resistance can be overcome and has a great value on the development of malignant tumor treatment drugs.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and in particular relates to triazole naphthoquinone biaryl (hetero)cyclic derivatives and their preparation methods and uses. Background technique [0002] Small-molecule targeted anti-tumor drugs have clear curative effects and high safety, and can achieve precise treatment for cancer patients, so they have become a hot spot and trend in cancer drug research and development in recent years. [0003] Dihydroorotate dehydrogenase (dihydroorotate dehydrogenase, DHODH) exists in the inner membrane of human mitochondria, and is an iron-containing flavin-dependent enzyme. It catalyzes the fourth step reaction in the de novo synthesis pathway of pyrimidine nucleotides in nucleic acid in vivo, and is the rate-limiting enzyme for pyrimidine nucleotide synthesis. Pyrimidine nucleotides are necessary for the synthesis of DNA, RNA, glycoproteins, and phospholipids in organisms. Therefore, the synthes...

Claims

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Application Information

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IPC IPC(8): C07D249/22C07D401/10C07D403/10C07D405/10A61K31/4192A61K31/4439A61K31/506A61P35/00A61P35/02A61P19/02A61P29/00A61P37/06
CPCC07D249/22C07D401/10C07D403/10C07D405/10
Inventor 赵瀛兰罗有福魏于全
Owner SICHUAN UNIV
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