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Thiazole derivative acting as DHODH inhibitor and its application

A compound, C1-C6 technology, applied in the field of medicinal chemistry and pharmacotherapeutics, can solve the problems of mucositis side effects, narrow therapeutic window, and restrictions on wide application

Inactive Publication Date: 2013-04-24
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Brequinar is used for anti-tumor and host immune response caused by organ transplantation, but the therapeutic window of Brequinar is narrow, and when administered orally in combination with cisplatin or cyclosporin A, it is easy to cause side effects of thrombocytopenia and mucositis, which limits its clinical application Wide application in

Method used

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  • Thiazole derivative acting as DHODH inhibitor and its application
  • Thiazole derivative acting as DHODH inhibitor and its application
  • Thiazole derivative acting as DHODH inhibitor and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Embodiment 1: the synthetic general method of compound 1-18:

[0063]

[0064] Dissolve ethyl chloroacetoacetate (9.52g, 57.84mmol) in 100mL ethanol, add thioacetamide (4.8g, 63.9mmol) under stirring condition, raise the temperature to reflux temperature, stir and reflux for 2h, and wait for the reaction to be completed. The solvent was removed from the reaction solution under reduced pressure to obtain 9.80 g of an orange-pink solid with a yield of 91.1%, which was directly used in the next reaction.

[0065] Weigh LiOH·H 2 O (1.25g, 29.7mmol) was dissolved in 50mL of water, and the ester (2.5g, 13.5mmol) synthesized by one-step reaction was added under stirring conditions, and the temperature was raised to 90°C. As the reaction progressed, the solid gradually dissolved, and the reaction was stopped after 1h. The pH of the reaction solution was adjusted to neutral to slightly acidic with dilute hydrochloric acid, and a large amount of solids precipitated out. After...

Embodiment 2

[0140] Embodiment 2: the synthetic general method of compound 19-45:

[0141] Synthesis of Thiourea

[0142]

[0143] Dissolve arylamine (8mmol, 1eq) in 24mL of acetone, add the weighed triethylenediamine (24mmol, 3eq) under stirring conditions, then add 20mL of carbon disulfide dropwise, a large amount of solid appears, continue to stir at room temperature for 24h, filter the reaction with suction solution, the filter cake was washed with petroleum ether, and after drying, the filter cake was dissolved in 50 mL of chloroform, and BTC (2.7 mmol, 0.33 eq) was weighed and dissolved in 30 mL of chloroform, added dropwise to the reaction solution within 1 h, and stirred at room temperature. solution overnight. After the reaction, the reaction solution was suction filtered, the filter cake was washed with dichloromethane, the obtained filtrate was directly added to silica gel and spin-dried, and then dry-loaded (PE eluted).

[0144] Dissolve NCS in a small amount of dichlorome...

Embodiment 3

[0240] Embodiment 3: the synthesis general method of compound 46-63:

[0241]

[0242] Compound 46-63

[0243] Synthesis method: Dissolve 1 mmol of substituted phenylthiourea and 1 mmol of 2-chloroacetylacetone (ethyl 2-chloroacetoacetate) in 20 mL of methanol, reflux overnight, spin dry methanol, add a small amount of dilute potassium carbonate aqueous solution to neutralize, and saturate It was washed with brine, extracted with ethyl acetate, and the organic layer was concentrated and dried to obtain the product by column chromatography.

[0244] Target compound spectral data

[0245] 2-(4-Methyl-3-chloroanilino)-4-methyl-5-acetylthiazole

[0246]

[0247] 1 H NMR (400MHz, DMSO) δ (ppm): 7.79(d, J=2.0Hz, 1H), 7.48-7.38(m, 1H), 7.30(d, J=8.0Hz, 1H), 2.55(s, 3H ), 2.42(s, 3H), 2.27(s, 3H).

[0248] HRMS (ESI) calcd for C 13 h 13 ClN 2 OS(M+H + )281.0515, found 281.0515;

[0249] 2-(3,4-Methylanilino)-4-methyl-5-acetylthiazole

[0250]

[0251] 1 H NMR (400...

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PUM

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Abstract

The invention relates to a thiazole derivative which is shown as general formula I and acts as a DHODH (dihydroorotate dehydrogenase) inhibitor, and its application. The compound provided in the invention can be used for treatment or prevention of various DHODH-mediated diseases, including but not limited to rheumatoid arthritis, tumors, organ transplantation rejection, psoriasis and other autoimmune diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and pharmacotherapeutics, and specifically relates to thiazole derivatives as DHODH inhibitors and applications thereof. Background technique [0002] Dihydroorotate dehydrogenase (Dihydroorotate dehydrogenase, DHODH) is an enzyme that catalyzes the dehydrogenation of dihydroorotate to convert it into orotate. This process belongs to the fourth step reaction of pyrimidine de novo synthesis pathway, so DHODH is the key enzyme of nucleic acid pyrimidine synthesis. Inhibition of DHODH can block the synthesis of nascent pyrimidines, resulting in obstacles to DNA and RNA synthesis. For most organisms, pyrimidine bases can be obtained through de novo synthesis and salvage pathways, but rapidly differentiating human cells, such as activated T-lymphocytes, B-lymphocytes, and tumor cells, require de novo synthesis of pyrimidine ways to meet their growth needs. This makes DHODH inhibitors useful as ant...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56C07D277/42C07D277/46C07D417/12A61K31/4164A61K31/4168A61K31/4178A61K31/4436A61P13/12A61P19/02A61P29/00A61P35/00A61P37/02
CPCC07D277/42C07D277/46C07D277/56C07D417/06C07D417/12A61P13/12A61P17/06A61P19/02A61P29/00A61P35/00A61P37/00A61P37/02A61P37/06
Inventor 赵振江韩乐许鸣豪高瑞黄瑾刁妍妍曹贤文崔坤强李洪林徐玉芳
Owner EAST CHINA UNIV OF SCI & TECH
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