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Dihydroorotate dehydrogenase inhibitors

A compound and application technology, applied in the field of dihydroorotate dehydrogenase inhibitors, can solve problems such as hyperplasia

Inactive Publication Date: 2018-10-02
INST OF MITOCHONDRIA SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, in terms of candidiasis, DHOD inhibitors show proliferation inhibition, indispensable

Method used

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Examples

Experimental program
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manufacture example

[0126] The compounds used in the present invention will be specifically described below by way of examples. Furthermore, these compounds do not limit the scope of the present invention.

[0127] 1. Derivatives 215-15-COOEt, 215-15-COOIPr, 215-13-COOH

[0128] [hua 1]

[0129]

[0130] 12-(3-Chloro-5-formyl-2,6-dihydroxy-4-tolyl)dodecane Ethyl acetate

[0131] (215-15-COOEt).

[0132] CHCl in acetic anhydride (12.5 ml, 132 mmol) 3 (16 ml) solution, 30% aqueous hydrogen peroxide (10 ml, 98 mmol) was added at 0°C, and the mixture was stirred at the same temperature for 1 hour. Next, maleic anhydride (10.0 g, 102 mmol) was added as it was kept, and the mixture was stirred for 2 hours while gradually returning to room temperature. The heat generation of the reaction solution was confirmed, and cyclododecanone (compound 1, 2.52 g, 13.8 mmol) was added as a single unit, and the mixture was stirred at 35° C. for 16 hours. After returning the reaction solution to room temp...

Embodiment 1

[0685] [Example 1] Determination of DHOD inhibitor

[0686] DHOD inhibitor activity was measured at concentrations of 200 nM and 1000 nM using the compounds of the present invention.

[0687] Add 190 μl of assay buffer (100 mM HEPES pH8.0, 150 mM NaCl, 5% glycerol, 0.05% Triton X-100, 200 μM dihydroorotic acid, 120 μM DCIP, 11 μM decaubiquinone) and 5 μl of each inhibitor’s DMSO solution, and add 8 μg / ml of human DHOD solution 5μl, start the enzymatic reaction (end concentration 0.2μg / ml (4nM) of human DHOD), measure the reduction of DCIP at 600nm for 20 minutes, according to the change of the absorbance value at 600nm after 0 minutes and 20 minutes, The value when only the DMSO solution was added was controlled by the End Point Assay(), and the inhibition rate of human DHOD at the concentration of 200 nM and 1000 nM of each compound was measured. In addition, the concentration (nM) that inhibits 50% of the activity of human DHOD was defined as IC50 (50% inhibitory concentra...

Embodiment 2

[0690] [Example 2] Anticancer effect

[0691] Conventional anticancer agents directly act on the process of cell division, but have low specificity to tumor cells and strong damage to normal cells, so serious side effects appear, which is a serious problem. Later, molecular targeted drugs appeared, targeting molecules related to tumor cell proliferation, infiltration, and metastasis to inhibit the deterioration of tumor cells, not only inhibiting tumor cells, but also inhibiting tumor metastasis.

[0692] Therefore, screening was carried out by a cancer cell proliferation inhibition test using a panel of 39 human cancer cell lines (JFCR39) and Cancer Cell Informatics (cancer cell informatics) using information analysis (Kong D., T. Yamori; Bioorganic & Med. Chem., 20, 1947-51, 2012). The concentration (μM) that inhibits the growth of human cancer cells by 50% is referred to as GI50 (50% inhibitory concentration).

[0693] The results are shown in Table 2.

[0694] Inhibitor...

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Abstract

The invention provides a novel dihydroorotate dehydrogenase inhibitor, which can be applied to various diseases. The active ingredients include formula (I) (in the formula, X represents a halogen atom, R1 represents a hydrogen atom, R2 represents an alkyl group with 1 to 7 carbons, R3 represents -CHO, R4 represents -CH2-CH=C(CH3) A compound represented by -R0 (where R0 represents an alkyl group with 1 to 12 carbons that may have substituents on the terminal carbon and / or non-terminal carbon, etc.)), its optical isomers, and the compounds and The pharmaceutically acceptable salt of the optical isomer has a good inhibitory effect on dihydroorotate dehydrogenase, and can be used as an immunosuppressant, rheumatoid therapeutic agent, anticancer agent, rejection treatment drug, and antiviral drug , anti-H.pylori (Helicobacter pylori) drugs and diabetes treatment drugs, etc.

Description

technical field [0001] The present invention relates to a dihydroorotate dehydrogenase (hereinafter abbreviated as "DHOD") inhibitor, which uses a dihydroxybenzene derivative having an alkyl side chain and containing a halogen as an active ingredient. Furthermore, the present invention relates to immunosuppressive agents, rheumatoid agents, anticancer agents, rejection agents, diabetes agents, Antiviral drugs and anti-Helicobacter pylori (Helicobacter pylori) (hereinafter, "Helicobacter pylori" is described as "H. pylori") drugs. Background technique [0002] The earliest report of human DHOD inhibitor was in 1985, NSC368390 (later renamed Brequinar (buquinar)) at 20-40mg / kg / day, inhibited more than 90% of human MX-1 breast cancer, The proliferation of LX-1 lung cancer, BL / STX-1 gastric cancer, and CX-1 colon carcinomas can also be seen in HCT-15clone A (clone A) and DLD-2 tumors, among which DLD -2 Inhibition of proliferation of colorectal cancer is as high as 98% (non-pa...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/11A61K9/08A61K31/121A61K31/216A61K31/222A61K31/336A61K31/341A61K31/351A61K31/357A61K47/10A61P1/04A61P3/10A61P29/00A61P31/04A61P31/12A61P35/00A61P37/06A61P43/00C07C47/56C07C47/565C07C47/575C07C49/258C07C69/14C07C69/24C07C69/738C07D303/14C07D307/20C07D309/12
CPCA61K9/0019A61K9/1623A61K9/2018A61K9/2027A61K9/2054A61K9/2059A61K9/4866A61K47/02A61K47/12A61K47/34C07C47/56C07C47/565C07C47/575C07C49/258C07C69/63C07C69/738C07D303/14C07D303/32C07D307/20C07D309/12A61K31/11A61K31/121A61K31/216A61K31/222A61K31/336A61K31/341A61K31/351A61K31/357A61P1/04A61P3/10A61P29/00A61P31/04A61P31/12A61P35/00A61P37/06A61P43/00C07C49/248C07C49/255
Inventor 北洁稻冈健丹尼尔斋本博之山本雅一
Owner INST OF MITOCHONDRIA SCI INC
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