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Benzodiazepine derivative and preparation and application methods thereof

A technology of benzodiazepine and derivatives, which is applied in the field of chemical synthesis of drugs, and achieves the effects of high yield, simple preparation method and low cost

Active Publication Date: 2019-05-10
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 derivative and preparation and application methods thereof
  • Benzodiazepine derivative and preparation and application methods thereof
  • Benzodiazepine derivative and preparation and application methods thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] 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

[0050] Use raw material A as (raw material A1), raw material B is (raw material B1), raw material C is (raw material C1).

[0051] The synthetic route is as follows:

[0052]

[0053] The specific synthesis method is:

[0054] 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, 92% yield. No further purification is required, and the next reaction can be carried out directly.

[0055] Add intermediate I1 (200mg, 0.925mmol), 5-(4-nitrophen...

Embodiment 2

[0059] Compound 2: 7-methyl-11-phenyl 2,3,4,5,10,11 hexahydro-1H-dibenzo[b,E][1,4]diazepin-1-one

[0060] Use raw material A as (raw material A1), raw material B is (raw material B1), raw material C is (Raw material C2).

[0061] The synthetic route is as follows:

[0062]

[0063] The specific preparation method is similar to the preparation method of compound 1, and will not be repeated here.

[0064] The yield of compound 2 was 75%.

[0065] That 1 H NMR data are as follows:

[0066] 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

[0068] Compound 3: (4-(methylsulfonyl)phenyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine- 1-keto

[0069] Use raw material A as (raw material A1), raw material B is (raw material B1), raw material C is (Raw material C3).

[0070] The synthetic route is as follows:

[0071]

[0072] The specific preparation method is similar to the preparation method of compound 1, and will not be repeated here.

[0073] The yield of compound 3 was 76%.

[0074] That 1 H NMR data are as follows:

[0075] 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 invention belongs to the field of chemical medicines and particularly relates to a benzodiazepine derivative. The formula of the benzodiazepine derivative is shown as followings. Embodiments of the compound proves that the compound can achieve good agonistic effects on Hippo pathways and inhibiting effects on proliferation of tumor cells and accordingly have good medicinal potential and provide a new potential choice for clinical medication; meanwhile, the preparation method of the benzodiazepine derivative is simple and convenient, mild in reaction conditions, convenient to operate and control, low in energy consumption, high in yield, low in cost and applicable industrial production; the prepared benzodiazepine derivative is high in bioactivity and selectivity to tumor cells and significant in drug-likeness and has a broad market prospect.

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