7-methoxy-1h-indole compound, preparation method, pharmaceutical composition and application

A compound, methoxy technology, applied in the field of 7-methoxy-1H-indole compounds, can solve the problems of low oral bioavailability of peptide compounds, limited clinical application, etc., and achieve great application value and side effects. Small, high-yield effects

Active Publication Date: 2022-05-03
北京华氏信华科生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Moreover, the oral bioavailability of peptide compounds is low, which limits their clinical application

Method used

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  • 7-methoxy-1h-indole compound, preparation method, pharmaceutical composition and application
  • 7-methoxy-1h-indole compound, preparation method, pharmaceutical composition and application
  • 7-methoxy-1h-indole compound, preparation method, pharmaceutical composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Compounds as shown in Formula 1: 1-(4-(4-(cyclopropyl(2,6-difluorophenyl)amino)-6-(2-fluoro-4-methoxyphenyl)-7 -methoxy-1H-indol-2-yl)-3-fluorophenyl)-3-methoxyurea; its synthetic reaction formula is as follows:

[0059]

[0060] The first step: compound 1a (113.7g, 300.0mmol), compound 1b (50.7g, 300.0mmol), Pd(dppf)Cl 2 (11.0g, 15.0mmol), potassium carbonate (92.9g, 720mmol) were dissolved in DMF (800mL), heated to 100°C for 10 hours, and the reaction was monitored by TLC. After the reaction was completed, water (500mL) was added to quench the reaction. Ethyl ester (500 mL×2) was extracted, the organic layers were combined, dried, concentrated, and separated by column chromatography to obtain 106.4 g of a light yellow solid (compound 1c), with a yield of 75.8%. Wherein, the structural formula of compound 1a is shown in formula 1a, and other compounds can be deduced in the same way.

[0061] The second step: compound 1c (106.0g, 226.4mmol), compound 1d (38.5g, 226...

Embodiment 2

[0068] Compound shown in formula 2: 1-(4-(4-((2-chloro-6-fluorophenyl) (cyclopropyl) amino)-6-(2-fluoro-4-methoxyphenyl )-7-methoxy-1H-indol-2-yl)-3-fluorophenyl)-3-methoxyurea; its synthetic reaction formula is as follows:

[0069]

[0070] The first step: compound 1a (37.9g, 100.0mmol), compound 2a (18.5g, 100.0mmol), Pd(dppf)Cl 2 (3.7g, 5.0mmol), potassium carbonate (20.7g, 150.0mmol) were dissolved in DMF (200mL), and the temperature was raised to 100° C. for 10 hours, and the reaction was monitored by TLC. After the reaction was completed, water (200mL) was added to quench the reaction. Extracted with ethyl acetate (200 mL×2), combined the organic layers, dried, concentrated, and separated by column chromatography to obtain 36.4 g of a light yellow solid (compound 2b), with a yield of 75.2%.

[0071] The second step: compound 2b (35.0g, 72.3mmol), compound 1d (12.3g, 72.3mmol), Pd(PPh 3 ) 4 (4.2g, 3.6mmol), cesium carbonate (35.1g, 108.5mmol) were dissolved in dioxa...

Embodiment 3

[0078]Compounds as shown in formula 3: 1-(4-(4-(cyclopropyl(2-fluoro-6-methoxyphenyl) amino)-6-(2-fluoro-4-methoxyphenyl )-7-methoxy-1H-indol-2-yl)-3-fluorophenyl)-3-methoxyurea; its synthetic reaction formula is as follows:

[0079]

[0080] The first step: compound 1a (37.9g, 100.0mmol), compound 3a (18.1g, 100.0mmol), Pd(dppf)Cl 2 (3.7g, 5.0mmol), potassium carbonate (20.7g, 150.0mmol) were dissolved in DMF (200mL), and the temperature was raised to 100° C. for 10 hours, and the reaction was monitored by TLC. After the reaction was completed, water (200mL) was added to quench the reaction. Extracted with ethyl acetate (200 mL×2), combined the organic layers, dried the organic layers, concentrated, and separated by column chromatography to obtain 34.5 g of a light yellow solid (compound 3b), with a yield of 71.9%.

[0081] The second step: compound 3b (24.0g, 50.0mmol), compound 1d (8.5g, 50.0mmol), Pd(PPh 3 ) 4 (2.9g, 2.5mmol), cesium carbonate (32.4g, 100.0mmol) were...

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Abstract

The invention relates to 7-methoxy-1H-indole compounds, a preparation method, a pharmaceutical composition and application, and belongs to the technical field of chemical medicine. The 7-methoxyl-1H-indole compound has a structure as shown in formula I: wherein, R 1 Represents a substituted or unsubstituted phenyl or aromatic heterocyclic group, R 2 Represents a substituted or unsubstituted phenyl or aromatic heterocyclic group, R 1 and R 2 Can be the same or different. The 7-methoxyl-1H-indole compounds, pharmaceutically acceptable salts, and pharmaceutical compositions containing these compounds as active ingredients are used as GnRH antagonists for the treatment of sex hormone-related diseases, with less side effects; Patients in need of such treatment or prevention are given therapeutically effective doses of one or more 7-methoxy-1H-indole compounds described in the present invention to achieve the purpose of treatment. The synthesis method of the 7-methoxyl-1H-indole compound has few by-products and high yield.

Description

technical field [0001] The invention relates to 7-methoxy-1H-indole compounds, a preparation method, a pharmaceutical composition and application, and belongs to the technical field of chemical medicine. Background technique [0002] Gonadotropin-releasing hormone (GnRH) is a decapeptide released from the hypothalamus, also known as luteinizing hormone-releasing hormone, known as a hormone that controls the secretion of sex hormones at the top, and GnRH acts on the pituitary gland to stimulate luteinizing hormone Biosynthesis and release of hormone (LH) and follicle-stimulating hormone (FSH). Among them, LH is responsible for regulating the production of gonadal steroids in both sexes and regulating late ovarian follicle development and ovulation in female mammals. FSH regulates sperm formation in men and follicle development in women. Drugs that specifically regulate GnRH receptors can control the secretion of lower LH, FSH and sex hormones, so it is expected to be used a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04C07D209/14A61K31/4439A61K31/404A61P35/00A61P15/00
CPCC07D401/04C07D209/14A61P35/00A61P15/00
Inventor 王永广牛永涛孙学涛苏小庭戴信敏
Owner 北京华氏信华科生物科技有限公司
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