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1,3,6,9-substitution beta-carboline compound and preparation method thereof

A compound and carboline technology, applied in the field of 1,3,6,9-substituted β-carboline compounds and their preparation, can solve the problems of fast growth of tumor cells, failure of chemotherapy, multidrug resistance, etc.

Active Publication Date: 2013-06-05
SHANGHAI STA PHARMA R&D CO LTD
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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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  • 1,3,6,9-substitution beta-carboline compound and preparation method thereof
  • 1,3,6,9-substitution beta-carboline compound and preparation method thereof
  • 1,3,6,9-substitution beta-carboline compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] .

[0072] 1) Synthetic compound 9

[0073] In a 1L round bottom flask, tryptamine (32.0 g, 0.2 mol) was dissolved in 450 mL of acetonitrile, ethyl glyoxylate (43.5 g, 427.2 mmol) was added, the reaction was stirred at 80°C for 10 h, and the solution was spin-dried under vacuum After the crude product was obtained, the compound was obtained by silica gel column chromatography 9 (7.8 g, 16.3% yield).

[0074] 2) Synthetic compound 10

[0075] In a 250 mL round bottom flask, compound 9 (7.8 g, 32.5 mmol) and NaOH (2.6 g, 64 mmol) were dissolved in 40 mL ethanol and 80 mL water, the reaction was heated to reflux for 1 h, the ethanol was evaporated under reduced pressure, neutralized with concentrated hydrochloric acid until the pH value was 5, and cooled , filtered the precipitate to obtain the compound 10 (2.9 g, 42% yield). ESI-MS: 213.0 [M+H] + ; 1 H NMR (DMSO-d 6, 400 MHz ,): δ 11.89 (s, 1H), 8.54-8.50 (m, 2H), 8.39 (d, J = 8.0 Hz,1H), 7.89 (d...

Embodiment 2

[0079] .

[0080] 1) Synthetic compound 11

[0081] Add 5-methyl-indoleethylamine hydrochloride (300 g, 142.5 mmol) in 450 mL of acetonitrile in a 1L round bottom flask, add ethyl glyoxylate (43.5 g, 427.2 mmol) and ice to the solution Acetic acid (80 mL), the reaction was stirred at 40 °C for 10 h, the solution was spin-dried in vacuo, dissolved in DCM, and the residual acid was neutralized with saturated sodium bicarbonate solution, the organic layer was dried with anhydrous sodium sulfate, and the solvent was concentrated to dryness After obtaining the compound 11 It was directly used in the next reaction without purification.

[0082] 2) Synthetic compound 12

[0083] Compound in 500 mL round bottom flask 11 (34.5 g, 133.8 mmol) was dissolved in 240 mL of dichloroethane, sulfur powder (21 g, 656.1 mmol) was added, the reaction was stirred at 85°C for 10 h, the insoluble precipitate was removed by filtration, and a light yellow solid was obtained after...

Embodiment 3

[0089] .

[0090] 1) Synthetic compound 14

[0091] Compound in 100 mL round bottom flask 12 (4.5 g, 17.7 mmol) was dissolved in 60 mL of tetrahydrofuran, 60% sodium hydrogen (2.1 g, 53.1 mmol) was added at 0°C, and after stirring for 1 h, methyl iodide (5 g, 35.4 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 14 (3.9 g, 90.5% yield). ESI-MS: 240.8 [M+H] + , 1 H NMR (CD 3 OD, 400 MHz) d 8.52 (d, J = 8.0 Hz, 1H), 8.23 ​​(d, J = 8.1 Hz, 1H), 8.14 (s, 1H), 7.66 (s, 2H), 4.21 (s, 3H), 2.56 (s, 3H).

[0092] 2) Synthetic compound 3

[0093] In a 10 mL reaction vial, compound 12 (70 mg) was dissolved in THF (2 mL), and 1.2 equivalents of benzylamine, 2 equivalents of triethylamine, 1.2 equivalents of EDCI and 1.5 equivalents of HOBT were ad...

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Abstract

The invention relates to 1,3,6,9-substitution beta-carboline compound and a preparation method thereof and mainly solves the technical problem that substitution derivate of existing beta-carboline compound is small. A structural general formula of the compound is shown as (I and II). Pharmacodynamic antineoplastic activity tests show that the compound is good in antineoplastic activity and can be applied to preparing novel antineoplastic medicine.

Description

technical field [0001] The invention relates to 1,3,6,9-substituted β-carboline compounds 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 enzyme necessary for DNA replication, which catalyzes the transient separation ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P35/00
CPCY02P20/55
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 SHANGHAI STA PHARMA R&D CO LTD
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