High morpholine compound, preparation method, pharmaceutical composition and application

A high morpholine and compound technology, applied in the field of medicine, can solve the problems of serious toxic and side effects, low inhibitory activity, lack of specificity of anti-tumor drugs, etc., and achieve the effect of good marketization prospects.

Pending Publication Date: 2022-03-08
TIANJIN MEDICAL UNIV
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Problems solved by technology

[0005] In view of this, in order to solve the defects of existing antitumor drugs such as lack of specificity, serious toxic and side effects, and low inhibitory activity, the present invention proposes a homomorpholine compound, and provides its preparation method, pharmaceutical composition, and Application in the preparation of antineoplastic drugs; the homomorpholine compound is effective on cancer cells, especially human prostate cancer cell line PC3, human breast cancer cell line MCF-7, human glioma cell U87 and human laryngeal squamous Cell cancer cell line SNU1076 has obvious proliferation inhibitory effect, blocks the cell cycle in the G1 phase, and effectively inhibits the phosphorylation level of key proteins in the PI3K / AKT / mTOR pathway at the molecular level, and has the potential to be a new type of anti-tumor drug Potential, with good market prospects

Method used

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  • High morpholine compound, preparation method, pharmaceutical composition and application
  • High morpholine compound, preparation method, pharmaceutical composition and application
  • High morpholine compound, preparation method, pharmaceutical composition and application

Examples

Experimental program
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Effect test

Embodiment 1

[0101] 4-(4-(2-Methyl-1H-benzo[d]imidazol-1-yl)-6-morpholinyl-1,3,5-triazin-2-yl)-1,4-homo Preparation of morpholine:

[0102] 2-Methyl-1H-benzimidazole (0.30g, 2.28mmol), 4-(4,6-dichloro-1,3,5-triazin-2-yl)-1,4-homomorpholine (0.54g, 2.28mmol), potassium carbonate (1.26g, 9.12mmol) was dissolved in DMF (9mL). After addition, stir at room temperature. TLC, add 5mL of water to the reaction solution, filter the precipitate, wash with DMF, dry to obtain 0.05g (yield 6.4%) 4-(4-chloro-6-(2-methyl-1H-benzo[d] imidazol-1-yl)-1,3,5-triazin-2-yl)morpholine;

[0103] Take 4-(4-chloro-6-(2-methyl-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)morpholine (0.03g, 0.08 mmol) in homomorpholine (0.30g, 2.97mmol), added, heated to reflux for reaction, cooled, diluted with water, TLC, filtered with suction to obtain 0.02g (yield 64.0%) 4-(4-(2-methyl -1H-benzo[d]imidazol-1-yl)-6-morpholinyl-1,3,5-triazin-2-yl)-1,4-homomorpholine.

[0104] The target product that makes is detected, and its ...

Embodiment 2

[0108] 2-(Difluoromethyl)-4-methoxy-1-(4-morpholinyl-6-(1,4-homomorpholinyl-4-yl)-1,3,5-triazine- Preparation of 2-yl)-1H-benzo[d]imidazol-6-amine:

[0109] 2-Methoxy-4-nitroaniline (20g, 120mmol), glacial acetic acid (60mL), stirred in an ice bath, slowly added concentrated sulfuric acid (100mL) dropwise, controlled temperature 0-10°C in an ice bath, and Mixed acid (70% nitric acid (7.8mL, 120mmol) and concentrated sulfuric acid (4.6mL, 80mmol)) was added dropwise to the system, and after the drop was completed, the reaction was continued at 0-10°C with stirring for 15min, and the temperature was raised to room temperature to continue the reaction, monitored by TLC. After completion, the system was poured into ice water, stirred for 20 minutes, filtered with suction, washed with water, and dried. 4,6-Dinitroaniline.

[0110] Dissolve 2-methoxy-4,6-dinitroaniline (8g, 37.5mmol) in triethylamine (24mL) and acetonitrile (20mL), then add 10% Pd / C (0.37g), and cool to 15°C, add...

Embodiment 3

[0120] 2-(Difluoromethyl)-4-methoxy-1-(4-((3-morpholinyl)amino)-6-(1,4-homomorpholinyl-4-yl)-1 , Preparation of 3,5-triazin-2-yl)-1H-benzo[d]imidazol-6-amine:

[0121] Dissolve anhydrous sodium carbonate (0.53g, 5mmol) in water (6mL), stir to dissolve, add cyanuric chloride (0.92g, 5mmol) at 0°C, stir evenly, and homomorpholine (0.51g, 5mmol) of water (1.25mL) solution was slowly dripped into the above system, the dropwise addition was completed, the temperature was controlled at 0-5°C, and the reaction was carried out for 4h. After suction filtration and washing with water, 0.008g (yield 0.65%) of 4- (4,6-dichloro-1,3,5-triazin-2-yl)-1,4-homomorpholine;

[0122] Replace 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine with 4-(4,6-dichloro-1,3,5-triazin-2-yl )-1,4-homomorpholine, homomorpholine is replaced by N-(3-aminopropyl) morpholine, and all the other required raw materials, reagents and preparation methods are the same as in Example 2, and obtain the product 2 of yield 51...

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Abstract

The invention provides a high morpholine compound, a preparation method, a pharmaceutical composition and application. The general formula of the high morpholine compound or pharmaceutically acceptable salt thereof is shown as (I). The high morpholine compound provided by the invention has an obvious proliferation inhibition effect on cancer cells, especially a human prostate cancer cell line PC3, a human breast cancer cell line MCF-7, a human glioma cell U87, a human laryngeal squamous cell carcinoma cell line SNU1076 and the like, and blocks the cell cycle at the G1 phase; the phosphorylation level of key protein in a PI3K / AKT / mTOR pathway is effectively inhibited on the molecular level, and the compound has the potential of being prepared into a novel anti-tumor drug and has a good market prospect.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a homomorpholine compound, a preparation method, a pharmaceutical composition and an application. Background technique [0002] Malignant tumors are known as the "number one killer" and "incurable disease" of human beings, and they pose a great threat to the physical and mental health of all human beings. At present, the number of cancer patients is increasing year by year, and the mortality rate caused by cancer remains high, ranking second among the ten major diseases. 20% of the world's new cancer patients are in China, and 24% of cancer deaths are in China. Against this backdrop, the antineoplastic drug market is developing rapidly. [0003] Traditional anti-tumor drugs are mainly cytotoxic drugs. Because their anti-tumor mechanism is to kill cells, they also have a killing effect on normal cells, resulting in severe side effects such as bone marrow suppression...

Claims

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Application Information

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IPC IPC(8): C07D413/14A61P35/00A61K31/553
CPCC07D413/14A61P35/00
Inventor 孔德新贾闻青张少璐程先超王营营
Owner TIANJIN MEDICAL UNIV
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