3-aryl quinoline compound as well as preparation method and medical application thereof

Abstract

The invention relates to the field of medicinal chemistry, and specifically relates to a 3-aryl quinoline compound with a general formula I. The compound can serve as a selective estrogen receptor modulator for curing or preventing various medical adaptation diseases related to post-menopause syndromes, and is particularly applicable for curing ER-(+) type breast cancer. Besides, the compound can also be used for preparing angiogenesis inhibitor medicine.

Description

technical field

[0001] The invention relates to the field of medicinal chemistry, in particular to a class of 3-aryl quinoline compounds. The compounds can be used as selective estrogen receptor modulators to treat or prevent various medical indications related to postmenopausal syndrome, and are especially suitable for treating ER-(+) breast cancer. At the same time, the compounds can also be used in the preparation of drugs as angiogenesis inhibitors. Background technique

[0002] Tumors are diseases characterized by the uncontrolled proliferation and spread of abnormal cells. The 2014 "Global Cancer Facts and Figures" report by the American Cancer Society shows that in 2012, there were 14 million new cancer cases and 8.2 million deaths worldwide, of which 3.07 million new cancer patients were added in China and about 2.2 million people died. Accounting for 21.9% and 26.8% of the global total, respectively. The report predicts that global cancer cases will show a rapid ...

Examples

specific Embodiment approach

[0047] The specific embodiment (described embodiment is only used to illustrate the present invention, is not used to limit the present invention)

[0048] The preparation of some compounds is carried out as follows:

[0049] 1 H-NMR nuclear magnetic resonance was determined by Bruker AV300 (300MHz) nuclear magnetic resonance instrument (TMS was the internal standard), and mass spectrometry was determined by Shimadzu GC / MS-QP2010 mass spectrometer (EI-MS), Agilent1100LC-MSD-Trap / SL type mass spectrometer (ESI-MS) measurement.

[0050] The silica gel used for column chromatography is 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel (Qingdao Ocean Chemical Factory), and the eluent is petroleum ether-ethyl acetate system or chloroform-methanol system. Thin-layer chromatography (TLC) uses a GF254 thin-layer chromatography plate (Yantai Jiangyou Silica Gel Development Co., Ltd.); the TLC development system is a petroleum ether-ethyl acetate system or a chloroform-methanol sy...

Embodiment 1

[0052] Preparation of N-(3-methoxyphenyl)-2-(4-methoxyphenyl)acetamide (3)

[0053] Dissolve p-methoxyphenylacetic acid 2 (5 g, 30.1 mmol), EDCI (5.78 g, 30.1 mmol), HOBt (4.06 g, 30.1 mmol) in 100 mL CH 2 Cl 2 , stirred at 0°C for 1 hour. Then 3-methoxyaniline (1) (3.7 g, 30.1 mmol) was added to the mixture and stirred at room temperature for 10 hours. The reaction solution was washed with saturated sodium chloride solution. The organic layer was evaporated under reduced pressure to give 3 (7.8 g, 96%) as a white solid. MS (ESI, m / z): 272.1 [M+H] +

Embodiment 2

[0055] Preparation of 2-chloro-7-methoxy-3-(4-methoxyphenyl)quinoline (4)

[0056] DMF (3 mL, 38.7 mmol) was added dropwise to POCl under ice bath 3 (12 mL, 129 mmol) and stirred for 30 minutes. Compound 3 (7 g, 25.8 mmol) was added into the mixture and stirred until dissolved, then heated to 100° C. for 4 hours. The mixture was then poured into ice water and extracted with ethyl acetate. The organic layer was evaporated under reduced pressure. Purified by column chromatography to obtain yellow solid 4 (5 g, 65%). MS (ESI, m / z): 301 [M+H] +

technical field

[0001] The invention relates to the field of medicinal chemistry, in particular to a class of 3-aryl quinoline compounds. The compounds can be used as selective estrogen receptor modulators to treat or prevent various medical indications related to postmenopausal syndrome, and are especially suitable for treating ER-(+) breast cancer. At the same time, the compounds can also be used in the preparation of drugs as angiogenesis inhibitors. Background technique

[0002] Tumors are diseases characterized by the uncontrolled proliferation and spread of abnormal cells. The 2014 "Global Cancer Facts and Figures" report by the American Cancer Society shows that in 2012, there were 14 million new cancer cases and 8.2 million deaths worldwide, of which 3.07 million new cancer patients were added in China and about 2.2 million people died. Accounting for 21.9% and 26.8% of the global total, respectively. The report predicts that global cancer cases will show a rapid ...

Examples

specific Embodiment approach

[0047] The specific embodiment (described embodiment is only used to illustrate the present invention, is not used to limit the present invention)

[0048] The preparation of some compounds is carried out as follows:

[0049] 1 H-NMR nuclear magnetic resonance was determined by Bruker AV300 (300MHz) nuclear magnetic resonance instrument (TMS was the internal standard), and mass spectrometry was determined by Shimadzu GC / MS-QP2010 mass spectrometer (EI-MS), Agilent1100LC-MSD-Trap / SL type mass spectrometer (ESI-MS) measurement.

[0050] The silica gel used for column chromatography is 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel (Qingdao Ocean Chemical Factory), and the eluent is petroleum ether-ethyl acetate system or chloroform-methanol system. Thin-layer chromatography (TLC) uses a GF254 thin-layer chromatography plate (Yantai Jiangyou Silica Gel Development Co., Ltd.); the TLC development system is a petroleum ether-ethyl acetate system or a chloroform-methanol sy...

Embodiment 1

[0052] Preparation of N-(3-methoxyphenyl)-2-(4-methoxyphenyl)acetamide (3)

[0053] Dissolve p-methoxyphenylacetic acid 2 (5 g, 30.1 mmol), EDCI (5.78 g, 30.1 mmol), HOBt (4.06 g, 30.1 mmol) in 100 mL CH 2 Cl 2 , stirred at 0°C for 1 hour. Then 3-methoxyaniline (1) (3.7 g, 30.1 mmol) was added to the mixture and stirred at room temperature for 10 hours. The reaction solution was washed with saturated sodium chloride solution. The organic layer was evaporated under reduced pressure to give 3 (7.8 g, 96%) as a white solid. MS (ESI, m / z): 272.1 [M+H] +

Embodiment 2

[0055] Preparation of 2-chloro-7-methoxy-3-(4-methoxyphenyl)quinoline (4)

[0056] DMF (3 mL, 38.7 mmol) was added dropwise to POCl under ice bath 3 (12 mL, 129 mmol) and stirred for 30 minutes. Compound 3 (7 g, 25.8 mmol) was added into the mixture and stirred until dissolved, then heated to 100° C. for 4 hours. The mixture was then poured into ice water and extracted with ethyl acetate. The organic layer was evaporated under reduced pressure. Purified by column chromatography to obtain yellow solid 4 (5 g, 65%). MS (ESI, m / z): 301 [M+H] +

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