Compound containing heptatomic lactam ring and application of compound

A technology of lactam ring and compound, applied in the field of medicine, can solve the problems of high local recurrence and radiation resistance, and achieve the effect of improving the sensitivity of radiotherapy

Active Publication Date: 2018-12-07
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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  • Compound containing heptatomic lactam ring and application of compound
  • Compound containing heptatomic lactam ring and application of compound
  • Compound containing heptatomic lactam ring and application of compound

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 heptatomic lactam ring and a cis-trans-isomer or pharmaceutical salt of the compound. The structure of the compound is represented by a general formula(I) (shown in the description), wherein R1 is selected from hydrogen and halogen; R2, R3 and R4 are respectively selected from the following groups: hydrogen, formula, formula, formula or formula (shown in the description); R5 and R6 are respectively selected from the following groups: hydrogen, low level alkyl or are linked to form a five-member ring or a hexatomic ring and are respectively selected from hydrogen, CH, CH2, O, S or NR7 when being linked to form a five-member ring or a hexatomic ring; R7 is selected from hydrogen, hydroxy, low level alkyl, naphthenic base and aryl. The compoundcontaining the heptatomic lactam ring has antitumor activity, is capable of improving the radiotherapy sensitivity of tumor cells and can be used for preparing 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 Applications(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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