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Benzodiazepine derivatives, preparation method and application thereof

A technology of benzodiazepine and derivatives, applied in the field of chemical synthesis of drugs, to achieve mild reaction conditions, good medicinal potential, and reduce side effects

Active Publication Date: 2021-01-29
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Benzodiazepinones were first used for psychotropic drugs in 1960, and later, due to their good pharmacokinetic properties and non-toxicity, they were used to treat other diseases, such as HIV, vascular diseases and arteriosclerosis, HCV, RNAi ( RNAinterference), leukemia, etc.; there is no relevant report about its ability to inhibit tumor growth

Method used

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  • Benzodiazepine derivatives, preparation method and application thereof
  • Benzodiazepine derivatives, preparation method and application thereof
  • Benzodiazepine derivatives, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Compound 1: 3-methyl-11-(5-(4-nitrophenyl)furan-2-yl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b , E][1,4]diazepin-1-one

[0051] Use raw material A as (raw material A1), raw material B is (raw material B1), raw material C is (raw material C1).

[0052] The synthetic route is as follows:

[0053]

[0054] The specific synthesis method is:

[0055] In a 250ml round bottom flask, add o-phenylenediamine (1.0g, 9.25mol), 5-methyl-1,3-cyclohexanedione (1.4g, 11.10mmol), p-toluenesulfonic acid (100mg), solvent Using anhydrous toluene, reflux for 12h. TLC detection, after the reaction, concentrated under reduced pressure, added 100ml of ethyl acetate (EA): ethanol (EtOH) = 9: 1 mixed solvent, continued to reflux for 1h, cooled and stood, and directly filtered to obtain a yellow solid, namely Intermediate I1, yield 92%. No further purification is required, and the next reaction can be carried out directly.

[0056]Add intermediate I1 (200mg, 0.925mmol), 5-(4-nitropheny...

Embodiment 2

[0060] Compound 2: 7-methyl-11-phenyl 2,3,4,5,10,11 hexahydro-1H-dibenzo[b,E][1,4]diazepin-1-one

[0061] Use raw material A as (raw material A1), raw material B is (raw material B1), raw material C is (Raw material C2).

[0062] The synthetic route is as follows:

[0063]

[0064] The specific preparation method is similar to the preparation method of compound 1, and will not be repeated here.

[0065] The yield of compound 2 was 75%.

[0066] That 1 H NMR data are as follows:

[0067] 1 H NMR (400MHz, DMSO-d 6 )δ8.76(d,J=17.7Hz,1H),7.15–7.03(m,4H),6.99(dd,J=8.8,4.7Hz,1H),6.94–6.84(m,1H),6.64–6.48 (m,3H),6.24(d,J=5.3Hz,1H),5.69(dd,J=33.0,3.6Hz,1H),4.09(s,1H),2.78–2.62(m,1H),2.43( dd,J=16.3,11.0Hz,1H),2.35–1.88(m,4H),1.05(dd,J=6.2,2.1Hz,3H).ESI-MS m / z 304.16[M+H] + .

Embodiment 3

[0069] Compound 3: (4-(methylsulfonyl)phenyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine- 1-keto

[0070] Use raw material A as (raw material A1), raw material B is (raw material B1), raw material C is (Raw material C3).

[0071] The synthetic route is as follows:

[0072]

[0073] The specific preparation method is similar to the preparation method of compound 1, and will not be repeated here.

[0074] The yield of compound 3 was 76%.

[0075] That 1 H NMR data are as follows:

[0076] 1 H NMR (400MHz, DMSO-d 6 )δ8.83(d,J=11.8Hz,1H),7.67(dd,J=8.4,4.3Hz,2H),7.32(dd,J=8.2,5.3Hz,2H),6.47–6.18(m,3H ),5.79–5.69(m,1H),3.11(s,3H),2.71(dd,J=19.5,13.0Hz,2H),2.32–2.16(m,2H),2.07(d,J=4.8Hz, 1H), 2.03(s,2H), 1.99–1.88(m,2H).ESI-MS m / z 382.14[M+H] + .

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Abstract

The present invention belongs to the field of chemical medicine, and specifically relates to a benzodiazepine derivative, the general formula of which is as follows: In some embodiments of the compound, it is proved that the compound can have a better stimulatory effect on the Hippo pathway, thereby It has an inhibitory effect on the proliferation of tumor cells, has good medicinal potential, and provides a new potential choice for clinical medication; at the same time, the preparation method of the new compound provided by the invention is simple, the reaction conditions are mild, and it is easy to operate and control , low energy consumption, high yield, low cost, suitable for industrial production, the prepared compound has high biological activity, strong selectivity to tumor cells, remarkable drug-like properties, and has broad market prospects.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis of medicines, in particular to benzodiazepine derivatives and their preparation methods and applications. Background technique [0002] The Hippo pathway was discovered in Drosophila more than 20 years ago, and it plays an important role in tissue regeneration and repair and tumor therapy. Inhibition of the Hippo pathway contributes to tissue repair and organ regeneration during injury; while the activation of the Hippo pathway can control cell proliferation and thus achieve the effect of controlling tumors. [0003] In normal cells, the Hippo pathway is in a state of dynamic balance. When the pathway is inhibited, cell proliferation is promoted and cell apoptosis is inhibited; when excessive proliferation occurs, the Hippo pathway changes from inhibition to activation, inhibiting cell proliferation, thereby maintaining the vitality of organs and tissues. A proper size state. When the...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D243/38C07D405/04C07D403/04A61K31/551C07D243/10A61P35/00A61P35/02
Inventor 杨胜勇李琳丽
Owner SICHUAN UNIV