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Aromatic hydrocarbon receptor modulator

A technology of aromatic hydrocarbon receptors and modulators, applied in the field of compounds and their pharmaceutically acceptable salts, can solve the problems of cancer discovery and treatment

Active Publication Date: 2018-07-03
ARIAGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although remarkable advances have been made in the medical treatment of some cancers, with targeted drugs and immunotherapy greatly improving patient survival rates, the overall 5-year survival rate for all cancer patients has only improved over the past 20 years 10% per month
Moreover, cancer discovery and treatment are extremely difficult due to drug resistance or uncontrolled metastasis and rapid growth of malignant tumors

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110] Example 1 Compound 1-1 and Compound 1-2

[0111]

[0112] Synthesis of Intermediate 1a

[0113] To a suspension of Boc-L-valine (0.8g, 3.68mmol) in dichloromethane and water (12mL / 12mL), add sodium bicarbonate (1.546g, 18.411mmol) and tetrabutyl Ammonium bromide (0.237g, 0.736mmol) was cooled to below 0°C, and chloromethyl chlorosulfonate (0.91g, 5.52mmol) was slowly added dropwise to the reaction solution, and stirred overnight. The reaction solution was extracted twice with dichloromethane, the organic phase was washed once with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography (PE / EA=20 / 1 ) was purified to obtain oily intermediate 1a (0.97g, yield 99%).

[0114] Synthesis of compound 1-1

[0115] Sodium hydride (0.165 g, 4.139 mmol) was added in batches to a solution of raw material S1 (1 g, 3.763 mmol) in dimethylformamide (DM...

Embodiment 2

[0118] Example 2 Compound 2-1 and Compound 2-2

[0119]

[0120] Synthesis of Intermediate 2a

[0121] The method was the same as the synthesis of intermediate 1a, and oily intermediate 2a (2.3 g, yield 95%) was prepared from Boc-L-tert-leucine (2 g, 8.647 mmol).

[0122] Synthesis of Compound 2-1

[0123] The method was the same as the synthesis of compound 1-1, and compound 2-1 (1.4 g, yield 74%) was prepared from intermediate 2a (1 g, 3.6 mmol). 1 H NMR (400MHz, CDCl 3 ): δ9.24(s, 1H), 8.50~8.52(m, 1H), 8.46(s, 1H), 7.57~7.60(m, 1H), 7.39~7.43(m, 1H), 6.42(d, J =11.2Hz, 1H), 6.17(d, J=11.2Hz, 1H), 5.05(d, J=9.2Hz, 1H), 4.10(d, J=8.4Hz, 1H), 4.04(s, 3H), 1.42(s, 9H), 0.83(s, 9H). MS (ESI) m / z: 530[M+1] + .

[0124] Synthesis of compound 2-2

[0125] The method was the same as the synthesis of compound 1-2. Compound 2-2 (0.85 g, yield 70%) was prepared from compound 2-1 (1.4 g, 2.6 mmol). 1 H NMR (400MHz, CDCl 3 ): δ9.24(s, 1H), 8.94(s, 1H), 8.36(d, J=7.2Hz, 1H),...

Embodiment 3

[0126] Example 3 Compound 3

[0127]

[0128] Synthesis of intermediate 3a

[0129] Weigh methyl glycolate (3g, 33.3mmol), add dichloromethane (50mL) and paraformaldehyde (1.3g, 43.3mmol), lower the temperature to below -20°C, and continue to introduce the current hydrogen chloride gas to keep- React at 20°C for 30 minutes, remove hydrogen chloride gas, add anhydrous magnesium sulfate and anhydrous sodium sulfate, continue to keep warm for 1 hour, room temperature overnight. The solid was removed by filtration, the mother liquor was concentrated to dryness at room temperature and then purified by silica gel column chromatography to obtain intermediate 3a (1.2 g, yield 26%).

[0130] Synthesis of compound 3

[0131] The method was the same as the synthesis of compound 1-1. Compound 3 (280 mg, yield 74%) was prepared as light yellow solid from starting material S1 (286 mg, 1 mmol) and intermediate 3a (500 mg, 3.6 mmol). 1 H NMR (400MHz, CDCl 3 ): δ9.19(s, 1H), 8.55~8.56(m...

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Abstract

The invention discloses an aromatic hydrocarbon receptor modulator shown in a formula (I) and a pharmaceutically acceptable salt thereof. The formula (I) is described in the specification, wherein R'is H, CN, CH2(OH)RO, CmH2m+1, CnH2n-1, CnH2n-3 or two groups (described in the specification), and two Ra groups are independently H or jointly form =O or =N-W3-R1; A is a C6-C10 aromatic ring unsubstituted or with 1-3 R substituted, a C2-C10 heteroaromatic ring mixed with 1-5 heteroatoms selected from N, O and S or a quaternary to heptatomic nonaromatic heterocyclic ring which is mixed with 1-3 heteroatoms selected from N, O and S and contains C=N; Q is R, or a C6-C10 aromatic ring unsubstituted or with 1-3 R substituted, or a C2-C10 heteroaromatic ring mixed with 1-5 heteroatoms selected from N, O and S; and R is RC connected with C or RN connected with N. The compound shown in a formula (I) can regulate AhR activity and can be used for inhibiting cancer cell growth as well as migrationand invasion of tumor cells.

Description

technical field [0001] The invention belongs to the technical field of antitumor compounds, and relates to a class of compounds capable of regulating the activity of aromatic hydrocarbon receptors (AhR) and pharmaceutically acceptable salts thereof. Background technique [0002] Due to changes in the environment and lifestyle, the incidence of cancer is increasing day by day, coupled with its high mortality rate, which seriously threatens human health. Although remarkable advances have been made in the medical treatment of some cancers, with targeted drugs and immunotherapy greatly improving patient survival rates, the overall 5-year survival rate for all cancer patients has only improved over the past 20 years 10% per month. Moreover, cancer discovery and treatment are extremely difficult due to drug resistance or uncontrolled metastasis and rapid growth of malignant tumors. [0003] Aryl hydrocarbon receptors (AhR, Aryl hydrocarbon receptor) are a class of intracellular ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/06C07D413/06C07D409/06C07D403/06C07H19/044C07D209/12C07D401/06C07D417/10C07D417/14A61K31/4245A61K31/4178A61K31/4439A61K31/404A61K31/506A61K31/7056A61K31/4025A61K31/427A61K31/433A61P35/00
CPCC07D209/12C07D401/06C07D403/06C07D409/06C07D413/06C07D417/06C07D417/10C07D417/14C07H19/044A61P35/00A61K31/4025A61K31/404A61K31/4178A61K31/4245A61K31/427A61K31/433A61K31/4439A61K31/506A61K31/7056C07D419/14A61K31/497A61P35/04A61K31/4196A61K31/437A61K31/5377
Inventor 杨录青李国栋张所明
Owner ARIAGEN INC
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