Dihydroorotic acid dehydrogenase inhibitor

A technology of dihydroorotic acid and dehydrogenase, which is applied in anti-inflammatory agents, pill delivery, antiviral agents, etc., and can solve problems such as hyperplasia

Inactive Publication Date: 2015-04-29
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 inhibi

Method used

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Examples

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manufacture example

[0126] The following examples illustrate the compounds used in the present invention in detail. Again, these compounds do not limit the scope of the present invention.

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

[0128] [chemical 1]

[0129]

[0130] Ethyl 12-(3-chloro-5-formyl-2,6-dihydroxy-4-methylphenyl)dodecanate (215-15-COOEt).

[0131] CHCl in acetic anhydride (12.5ml, 132mmol) 3 (16ml) solution, 30% aqueous hydrogen peroxide (10ml, 98mmol) was added at 0°C, and stirred at the same temperature for 1 hour. Next, maleic anhydride (10.0 g, 102 mmol) was added while maintaining its individuality, and the mixture was stirred for 2 hours while gradually returning to room temperature. After confirming that the reaction solution was exothermic, cyclododecanone (compound 1, 2.52 g, 13.8 mmol) was added while maintaining its individuality, and stirred at 35° C. for 16 hours. After returning the reaction solution to room temperature, it was further...

Embodiment 1

[0686] [Example 1] DHOD inhibitor assay

[0687] Using the compounds of the present invention, the DHOD inhibitor activity was determined at concentrations of 200 nM and 1000 nM.

[0688] Add 190 μl of Assay Buffer (100 mM HEPES pH8.0, 150 mM NaCl, 5% Glycerol, 0.05% Triton X-100, 200 μM dihydroorotate, 120 μM DCIP, 11 μM Decylubiquinone) and 5 μl of DMSO solution of each inhibitor, and add 5 μl of 8 μg / ml human DHOD solution , start the enzyme reaction (human DHOD with an end concentration of 0.2μg / ml (4nM)), measure the reduction of DCIP at 600nm for 20 minutes, and control it with End Point Assay () according to the change of the absorbance value at 600nm after 0 minutes and 20 minutes The value when only DMSO solution was added, and the human DHOD inhibition rate of each compound at concentrations of 200 nM and 1000 nM were determined. Also, the concentration (nM) that inhibits 50% of the activity of human DHOD was defined as IC50 (50% inhibitory concentration). The resu...

Embodiment 2

[0691] [Example 2] Anticancer effect

[0692] Conventional anticancer agents act directly 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. Afterwards, molecular targeted drugs appeared, targeting molecules related to tumor cell proliferation, invasion, and metastasis to inhibit tumor cell deterioration, not only inhibit tumor cells, but also inhibit tumor metastasis.

[0693] Therefore, screening was carried out by using a cancer cell growth inhibition test using a panel of 39 kinds of human cancer cell lines (JFCR39) and using Cancer Cell Informatics (Kong D., T. . Yamori; Bioorganic & Med. Chem., 20, 1947-51, 2012). The concentration (μM) that inhibits the growth of human cancer cells by 50% was defined as GI50 (50% inhibitory concentration).

[0694] The results are shown in Table 2.

[0695] Inhibitory effect on various human cancer cells.

[0696] [Ta...

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Abstract

The present invention provides a novel dihydroorotic acid dehydrogenase inhibitor which is applicable to various diseases. When used as an active ingredient, a compound represented by formula (I): (wherein X represents a halogen atom, R 1 represents a hydrogen atom, R 2 represents an alkyl group containing 1 to 7 carbon atoms, R 3 represents -CHO, and R 4 represents -CH 2 -CH=C(CH 3 )-R 0 (wherein R 0 represents an alkyl group containing 1 to 12 carbon atoms which may have a substituent on the terminal carbon and/or on a non-terminal carbon, etc.)), an optical isomer thereof or a pharmaceutically acceptable salt thereof has a high inhibitory effect on dihydroorotic acid dehydrogenase and can be used as an immunosuppressive agent, a therapeutic agent for rheumatism, an anticancer agent, a therapeutic agent for graft rejection, an antiviral agent, an anti- H . pylori agent, a therapeutic agent for diabetes or the like.

Description

technical field [0001] The present invention relates to a dihydroorotic acid dehydrogenase (dihydroorotic acid dehydrogenase; hereinafter referred to as "DHOD") inhibitor, which uses dihydroxybenzene derivatives having alkyl side chains and containing halogen as active ingredients. Also, the present invention relates to immunosuppressants, rheumatoid therapeutic agents, anticancer agents, rejection reaction therapeutic agents, diabetes therapeutic agents, Antiviral drugs and anti-Helicobacter pylori (Helicobacter pylori) (hereinafter, "Helicobacter pylori" will be referred to as "H. pylori") drugs. Background technique [0002] The earliest report of human DHOD inhibitors was in 1985. NSC368390 (later changed to Brequinar (buquinar)) at 20-40mg / kg / day inhibited more than 90% of human MX-1 breast cancer in nude mice, The hyperplasia of LX-1 lung cancer, BL / STX-1 gastric cancer, and CX-1 colon carcinomas can also be seen in HCT-15clone A (colon A) and DLD-2 tumors (tumors), a...

Claims

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Application Information

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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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