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A compound containing a seven-membered lactam ring and its application

A technology of lactam rings and compounds, applied in the field of medicine, can solve the problems of high local recurrence and radiation resistance

Active Publication Date: 2021-09-10
上海康邦德生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although radiotherapy has made great progress in the field of tumor treatment, high local recurrence and radiation resistance will still occur after radiotherapy.

Method used

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  • A compound containing a seven-membered lactam ring and its application
  • A compound containing a seven-membered lactam ring and its application
  • A compound containing a seven-membered lactam ring and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] The preparation of 3-chloro-1-phenylallyl-6,7-dihydro-1H-azepine-2(5H)-one, the synthetic route is as follows:

[0049]

[0050] Weigh 62 mg of cinnamic acid 1 and dissolve in anhydrous dichloromethane (2 mL), add oxalyl chloride (0.18 mL) and a catalytic amount of DMF. After stirring at room temperature for 2 hours, the solvent was evaporated under reduced pressure to obtain compound 2, which was directly used in the next step.

[0051] The compound 3-chloro-6,7-dihydro-1H-azepine-2(5H)-one (3,68mg) was dissolved in anhydrous tetrahydrofuran (5mL), cooled to -78°C and slowly added n-butyl Lithium tetrahydrofuran solution (2.5M, 0.2mL), continued the reaction for 15 minutes, and then added dropwise the anhydrous tetrahydrofuran solution of compound 2 obtained in one step. Slowly rise to room temperature and react for 30 minutes, quenched, extracted with dichloromethane, dried, and evaporated under reduced pressure to obtain a crude product, which was separated by chro...

Embodiment 2

[0053] (E)-N-(4-(3-(6-Chloro-7-oxo-2,3,4,7-tetrahydro-1H-azaheptacycline-1-yl)-3-oxopropene- 1-base) the preparation of phenyl) acrylamide, synthetic route is as follows:

[0054]

[0055] Weigh 62 mg of compound 4 and dissolve in anhydrous dichloromethane (2 mL), add oxalyl chloride (0.18 mL) and a catalytic amount of DMF. After stirring at room temperature for 2 hours, the solvent was evaporated under reduced pressure to obtain compound 5, which was directly used in the next step.

[0056] The compound 3-chloro-6,7-dihydro-1H-azepine-2(5H)-one (3,68mg) was dissolved in anhydrous tetrahydrofuran (5mL), cooled to -78°C and slowly added n-butyl Lithium tetrahydrofuran solution (2.5M, 0.2mL), continued to react for 15 minutes, and then added dropwise the anhydrous tetrahydrofuran solution of compound 5 obtained in one step. Slowly rise to room temperature and react for 30 minutes, quenched, extracted with dichloromethane, dried, evaporated the solvent under reduced pressure...

Embodiment 3

[0060] (E)-2-Chloro-N-(4-(3-(6-Chloro-7-oxo-2,3,4,7-tetrahydro-1H-azaheptane-1-yl)-3- Preparation of oxypropen-1-yl) phenyl) acetamide:

[0061]

[0062] Dissolve Intermediate 7 (57 mg) in dichloromethane (10 mL), add 18 μL of triethylamine, react at 0°C for 10 minutes, slowly add 35 μL of chloroacetyl chloride, react at 0°C for 4 hours, extract with dichloromethane, wash with water , separated by chromatographic column to obtain compound I-3, light yellow solid, yield, 68%. 1 H NMR (300MHz, CDCl 3 )δ: 1.98-2.04 (m, 2H, J=6.3Hz, CH 2 ), 2.34-2.41 (q, 2H, J=7.0Hz, CH 2 ),3.97-4.02(t,2H,J=6.4Hz,NCH 2 ), 5.78-5.82 (d, 1H, J = 10.5Hz, = CH), 6.21-6.30 (dd, 1H, J 1 =10.0Hz,J 2 =10.1Hz, =CH), 6.43-6.49(d,1H,J=17.0Hz,=CH),6.76-6.81(t,1H,J=7.8Hz,=CH),7.39-7.44(d,2H, J=15.5Hz, Ar-H), 7.53-7.56(d, 2H, J=8.6Hz, Ar-H), 7.60-7.64(d, 2H, J=8.7Hz, Ar-H), 7.74-7.79( d,1H,J=15.5Hz,=CH); 13 C NMR (75MHz, CDCl 3 )δ: 23.82, 26.04, 41.45, 118.99, 119.97, 128.61, 129.60, 130.99, 131.05...

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Abstract

The invention discloses a compound containing a seven-membered lactam ring, its cis-trans isomers or a pharmaceutically acceptable salt thereof, the structure of which is shown in general formula (I): wherein: R 1 selected from hydrogen, halogen; R 2 , R 3 , R 4 each independently selected from the following groups: hydrogen, R 5 , R 6 each independently selected from the following groups: hydrogen, lower alkyl or R 5 with R 6 Linked to form a five-membered ring or a six-membered ring, when forming a five-membered ring or a six-membered ring, R 5 , R 6 each independently selected from hydrogen, CH, CH 2 , O, S or NR 7 ; 7 selected from hydrogen, hydroxy, lower alkyl, cycloalkyl, aryl. The compound containing the seven-membered lactam ring of the present invention has antitumor activity and can improve the radiotherapy sensitivity of tumor cells, and they can be used to prepare antitumor drugs or radiotherapy sensitization drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a compound containing a seven-membered lactam ring and its application in preparing antitumor drugs and radiosensitizing drugs. Background technique [0002] Malignant tumor is a common and frequently-occurring disease, and has become one of the major diseases that seriously threaten human life and health. Tumor treatment includes surgical treatment, chemotherapy, radiotherapy, etc. With the development of CT imaging technology, computer technology and radiotherapy equipment, radiotherapy has attracted more and more attention, and has been widely used in the treatment of tumors, especially head and neck tumors, Prostate cancer, esophageal cancer, colon cancer, lung cancer, pancreatic cancer, etc. The current mainstream radiotherapy techniques include stereotactic radiotherapy and stereotactic radiosurgery. Although radiotherapy has made great progress in the field of tumor treat...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D223/10A61K31/55A61P35/00A61P35/02A61P31/10A61P25/00A61P7/02
CPCA61P7/02A61P25/00A61P31/10A61P35/00A61P35/02C07D223/10
Inventor 庄友华王娟
Owner 上海康邦德生物医药有限公司
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