Substituted beta-carboline compound and preparation method thereof

A compound, carboline technology, applied in the fields of organic chemistry, drug combination, anti-tumor drugs, etc., can solve the problems of multi-drug resistance, easy mutation, and fast growth of tumor cells.

Inactive Publication Date: 2013-06-05
上海药明康德新药开发有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because tumors have the ability to metastasize in the early stage, tumor cells grow rapidly and easily mutate, resulting in multi-drug resistance, leading to the failure of chemotherapy, so it is still necessary to research and develop new anti-tumor drugs to meet the needs of clinical treatment

Method used

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  • Substituted beta-carboline compound and preparation method thereof
  • Substituted beta-carboline compound and preparation method thereof
  • Substituted beta-carboline compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] .

[0063] 1) Synthetic compound 9

[0064] In a 1L round bottom flask, dissolve L-tryptophan methyl ester hydrochloride (100 g, 0.45 mol) in 500 mL of acetonitrile and 50 mL of methanol, add acetaldehyde (40 g, 0.9 mol), and react at 80 °C Under stirring for 16 h, the solution was spin-dried under vacuum to obtain the crude product 9 (109 g, 88% yield). ESI-MS: 244.7 [M+H] + .

[0065] 2) Synthetic compound 10

[0066] In a 500 mL round bottom flask, the compound 9 (86 g, 0.35 mol) was dissolved in 100 mL DMF, and potassium permanganate (113 g, 0.70 mol) was added at 0°C, and the reaction was stirred at 30°C for 3 h. After the raw materials were consumed, the solid was removed by filtration. After the solution was evaporated to dryness, the compound was obtained 10 (66 g, 78% yield). ESI-MS: 240.9 [M+H] + , 1 H NMR (CD 3 OD, 400 MHz) d 8.60 (s, 1H), 8.12-8.09 (m, 1H), 7.55-7.53 (m, 2H), 7.28-7.24 (m, 1H), 3.972 (s, 3H), 2.77 (s, 3H).

[0067] 3...

Embodiment 2

[0072] .

[0073] 1) Synthetic compounds 12

[0074] Compound in 250 mL round bottom flask 10 (6 g, 25 mmol) was dissolved in 100 mL tetrahydrofuran, 60% sodium hydrogen (2.4 g, 100 mmol) was added at 0°C, stirred for 1 h, and methyl iodide (7.1 g, 50 mmol) was added, and the reaction solution was heated at room temperature After stirring overnight, neutralize with concentrated hydrochloric acid, obtain a yellow precipitate after filtration, and obtain a yellow powder compound after drying the precipitate 12 (5.6 g, 93% yield).

[0075] 2) Synthetic compounds 2

[0076] In a 10 mL reaction vial, compound 12 (70 mg) was dissolved in THF (2 mL), added 1 equivalent of 1,1`-carbonyldiimidazole (CDI) and stirred for 1 h, then added 1 equivalent of piperazine, and the reaction solution was stirred at room temperature for 16 h. Preparative high performance liquid phase purification to obtain the compound 2 (50 mg, 56% yield). ESI-MS: 308.4 [M + H] + ; 1 H NMR (DM...

Embodiment 3

[0078] .

[0079] 1) Synthetic compounds 13

[0080] Compound in 250 mL round bottom flask 10 (5 g, 20.8 mmol) was dissolved in 100 mL of tetrahydrofuran, 60% sodium hydrogen (2 g, 83 mmol) was added at 0°C, and after stirring for 1 h, n-butyl bromide (4.25 g, 31.2 mmol) was added, and the reaction solution was After stirring overnight at room temperature, neutralize with concentrated hydrochloric acid, obtain a yellow precipitate after filtration, and obtain a light yellow powder compound after drying the precipitate 13 (5.5 g, 95% yield). ESI-MS: 282.9 [M+H] + , 1 H NMR (DMSO-d6, 400 MHz) d 8.96 (s, 1H), 8.48 (d, J=8 Hz, 1H), 8.85 (d, J=8 Hz, 1H), 7.71 (t, J=8Hz, 1H), 7.39 (t, J=8Hz, 1H), 4.66 (t, J=8Hz, 2H), 3.150 (s, 3H), 1.77-1.73 (m, 2H), 1.40-1.34 (m, 2H), 0.90(t, J= 7.2 Hz, 3H) .

[0081] 2) Synthetic compounds 3

[0082] In a 10 mL reaction vial, compound 13(70 mg) was dissolved in THF (2 mL), and 1.2 equivalents of N-methylpiperazine, 2 equival...

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Abstract

The invention relates to a substituted beta-carboline compound and a preparation method thereof, and mainly solves the technical problem that substituted derivatives of beta-carboline compounds are few. The beta-carboline compounds have a general formula (I and II). The substituted beta-carboline compound passes pharmacodynamic antineoplastic activity tests and presents good antineoplastic activity, and is expected to be used for preparation of novel antineoplastic drugs.

Description

technical field [0001] The invention relates to a substituted β-carboline compound and a preparation method thereof. Background technique [0002] Malignant tumors are major diseases that threaten human health. According to incomplete statistics, there are about 20 million new cases in the world every year; in my country, there are about 1.6-2 million new cases and 1.3 million deaths each year. With the advent of population aging, the prevalence rate is increasing year by year. The treatment of tumor has been paid close attention to all over the world. Because tumors have the ability to metastasize in the early stage, tumor cells grow rapidly and easily mutate, resulting in multi-drug resistance, leading to the failure of chemotherapy. Therefore, it is still necessary to research and develop new anti-tumor drugs to meet the needs of clinical treatment. [0003] Topoisomerase (Topo) is an essential enzyme for DNA replication, which catalyzes the transient separation of sing...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D519/00A61P35/00
Inventor 肖志勇刘中乾雷灿王静陈泽斌韩国辉肖贻崧贺海鹰陈曙辉
Owner 上海药明康德新药开发有限公司
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