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Chiral diaryl-beta-lactam compound, preparation method and pharmaceutical application thereof

A technology of lactams and compounds, applied in medicines, the field of novel chiral diaryl-β-lactam compounds, can solve the problems of prolonging the survival period of patients, toxic and side effects, etc.

Active Publication Date: 2021-04-09
FUDAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] According to the latest research, great progress has been made in the research on tubulin aggregation inhibitors, especially the structural modification of Combretastatin A-4. 4P) and BNC105 phosphate disodium salt (BNC105P) have entered phase III and phase II clinical trials, respectively, for the treatment of various solid tumors (J.Med.Chem.2016,59,8685-8711); but this Some drugs still have certain toxic and side effects, and there are also deficiencies in prolonging the survival of patients. Up to now, no drug has been approved for marketing.

Method used

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  • Chiral diaryl-beta-lactam compound, preparation method and pharmaceutical application thereof
  • Chiral diaryl-beta-lactam compound, preparation method and pharmaceutical application thereof
  • Chiral diaryl-beta-lactam compound, preparation method and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1 (3S,4R)-1-(3,4,5-trimethoxyphenyl)-3-aminomethyl-4-(3-hydroxyl-4-methoxyphenyl)azetidine Synthesis of alkan-2-ones (1)

[0045] Referring to the literature (J.Med.Chem.2016,59,10329-10334) method, the present invention synthesizes the target compound 1 according to the following route:

[0046]

[0047] Reagents and conditions: (a) Pd 2 (dba) 3 (1%),(R,R,R)-Ph-SKP(2.5%),K 2 CO 3 (aq.), CH 2 Cl 2 ,25℃, 3h; (b)Sn[N(TMS) 2 ] 2 , toluene, reflux, 3h; (c) TBAF, THF, 0℃, 1h; (d) i) BnCl, K 2 CO 3 , MeCN, reflux, 12h; ii) B 2 (pin) 2 (1.3equiv), CuCl(5%), MeOH(1.5equiv), PPh 3 (15%),t-BuOLi(10%),THF,25℃,12h; iii)NaBO 3 4H 2 O,H 2 O, THF, 25℃, 2 h; (e) Isoindoline-1,3-dione, DIAD, PPh 3 , THF, 25℃, 3h; (f) N 2 h 4 .H 2 O, EtOH, reflux, 4h; (g) Pd / C, H 2 , EtOH, 25°C, 12h.

[0048] 1.1(S)-2-[1-(3-tert-butyldimethylsilyloxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenylamino)methyl ] Synthesis of ethyl acrylate (1c)

[0049] Into a 50 mL Schlenk tu...

Embodiment 2

[0062] The synthesis of embodiment 2 compound 2,3,4,5,6,7,8 and 9

[0063]

[0064] The specific operation is as follows: In a 25mL eggplant-shaped bottle, weigh the raw material for 1h (20mg, 0.04mmol), dissolve it in 1.5mL of dichloromethane, add acid chloride (0.21mmol) and triethylamine (25μL, 0.21mmol), and stir at room temperature , TLC spot plate detection reaction progress. After the reaction was complete, water was added, extracted three times with dichloromethane, the combined organic phases were washed once with saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration by rotary evaporation, 10% Pd / C (3 mg) and ethanol (1 mL) were added, and the reaction was carried out at room temperature under normal pressure hydrogen for 12 hours. Remove Pd / C by filtration, evaporate to dryness, and separate and purify with silica gel (300-400 mesh) column chromatography.

[0065] 2.1(3S,4R)-1-(3,4,5-trimethoxyphenyl)-4-(3-hydroxy-4-methoxy...

Embodiment 3

[0089] Example 3 (3S,4R)-1-(3,4,5-trimethoxyphenyl)-4-(3-hydroxyl-4-methoxyphenyl)-3-phthalimide Synthesis of Methylazetidin-2-one (10)

[0090]

[0091] In a 25mL eggplant-shaped flask, 1g (20mg, 0.032mmol), Pd / C (3mg) and ethanol (1mL) were added. Reacted at room temperature under normal pressure with hydrogen for 12 hours, filtered to remove the catalyst, and separated by column chromatography (developer: PE / EA 2:1) to obtain 14 mg of yellow solid (10) with a yield of 83%. mp 88-90℃. 1 HNMR (400MHz, CDCl 3 ):δ7.87-7.85(m,2H),7.74-7.72(m,2H),6.84(s,1H),6.79(d,J=8.2Hz,1H),6.73(d,J=8.2Hz, 1H), 6.52(s, 2H), 5.66(s, 1H), 4.97(s, 1H), 4.27(dd, J=14.2, 4.8Hz, 1H), 4.11(dd, J=13.8, 9.8Hz, 1H ),3.82(s,3H),3.75(s,3H),3.70(s,6H),3.44-3.41(m,1H). 13 C NMR (150MHz, CDCl 3): δ167.4, 163.1, 152.8, 146.2, 145.6, 133.9, 133.6, 132.9, 131.2, 129.6, 122.9, 117.1, 111.3, 110.4, 94.3, 60.3, 59.5, 58.4, 55.4, 55.3, 35.9.ESI z):519.1(M+H + ).ESI-HRMS(m / z):calcd for C 28 h 27 N 2 o ...

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Abstract

The invention belongs to the field of synthetic pharmacochemistry in new drug research and development, and relates to a novel chiral diaryl-beta-lactam compound with antitumor activity and a general formula structure shown as the specification and application of the novel chiral diaryl-beta-lactam compound in antitumor drug research and development. The invention further discloses application of the compound, a pharmaceutical salt thereof and a compound medicine thereof in preparation of medicines for preventing or treating tumor-related diseases. The compound or the pharmaceutically acceptable salt thereof provided by the invention can effectively inhibit the growth of nude mouse transplanted tumors in vitro and in vivo by inhibiting a regulation and control mechanism of inhibiting tumor cell proliferation by inhibiting tubulin aggregation, and can be used for preparing medicines for preventing or treating tumor-related diseases; wherein the tumor-related diseases comprise benign and malignant tumors and other diseases caused by the tumors.

Description

technical field [0001] The invention belongs to the field of new drug R&D and synthetic medicinal chemistry, and relates to a novel chiral diaryl-β-lactam compound with antitumor activity, a preparation method, antitumor activity in vivo and in vitro, and the compound and its acceptable pharmaceutical salt or The application of the compound drug with it as one of the components in the preparation of drugs for the prevention and treatment of tumor-related diseases. Background technique [0002] According to data records, in September 2018, the World Health Organization published the "Global Cancer Statistics 2018" report online in the US "CA: A Cancer Journal for Clinicians", reporting that the incidence of cancer in the world is becoming more and more severe, and the number of new cases in 2018 is as high as 18.1 million, and 9.6 million deaths during the same period. Due to factors such as population aging, smoking, and unhealthy diet, it is predicted that by 2030, there w...

Claims

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Application Information

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IPC IPC(8): C07D205/08C07D403/06A61K31/397A61K31/4035A61P35/00
CPCC07D205/08C07D403/06A61P35/00C07B2200/07Y02P20/55
Inventor 王洋唐海荣程嘉怡梁玉茹丁奎岭
Owner FUDAN UNIV