Phthalazine derivative, preparation method and applications thereof

A derivative, phthalazine technology, applied in the field of phthalazine derivatives and its preparation, can solve the problems of complex pharmacokinetics, adverse reactions, drug interactions, inability to completely kill tumor cells, and easy drug resistance

Active Publication Date: 2020-02-28
HEFEI UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, single-target antitumor drugs often cannot completely kill tumor cells, and are prone to drug resistance after a period of time. Therefore, the emergence of "cocktail therapy" has solved the problem of drug resistance to a certain extent, but At the same time, it also brings the disadvantages of combination therapy that cannot be ignored.
For example, complex pharmacokinetic properties, unpredictable adverse reactions, highly prone to drug interactions, etc.

Method used

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  • Phthalazine derivative, preparation method and applications thereof
  • Phthalazine derivative, preparation method and applications thereof
  • Phthalazine derivative, preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] N-(4-((2-aminophenyl)carbamoyl)benzyl)-2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl) Preparation of benzamide (compound 1):

[0043]

[0044] Step 1: Synthesis of 4-(aminomethyl) methyl benzoate

[0045] Dissolve 1 g of 4-(aminomethyl)benzoic acid (0.0066 mol) in 20 ml of methanol, and stir for 5 mins under ice-cooling. Slowly add 0.71ml of thionyl chloride dropwise, after the drop is complete, stir in an ice bath for 10mins, then raise the temperature to 60°C, and stir at reflux overnight. After the completion of the reaction as monitored by TLC, the methanol was evaporated under reduced pressure to obtain 0.98 g of a white solid after drying, with a yield of 90.5%, and the product was directly used in Step 2.

[0046]Step 2: Synthesis of methyl 4-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamido)methyl)benzoate

[0047] 0.5g 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (0.0017mol), 0.35g1-(3-dimethylaminopropyl )-3-Et...

Embodiment 2

[0053] N-((4-((2-aminophenyl)carbamoyl)cyclohexyl)methyl)-2-fluoro-5-((4-oxo-3,4-dihydro-phthalazine-1- base) methyl) benzamide (compound 2)

[0054]

[0055] According to the preparation method of compound 1, tranexamic acid was used instead of 4-(aminomethyl)benzoic acid, and the rest of the operations were the same. The product is a white solid. m.p.243℃-246℃. 1 H NMR (600MHz, DMSO-d 6 )δ (ppm): 12.56 (s, 1H), 8.98 (s, 1H), 8.27–8.17 (m, 2H), 7.96 (d, J = 8.0Hz, 1H), 7.87 (t, J = 7.6Hz, 1H), 7.81(t, J=7.5Hz, 1H), 7.51(d, J=5.3Hz, 1H), 7.42(s, 1H), 7.20–7.11(m, 2H), 6.86(t, J=7.6 Hz, 1H), 6.69(d, J=7.8Hz, 1H), 6.51(t, J=7.5Hz, 1H), 4.75(s, 2H), 4.31(s, 2H), 3.09(t, J=6.1 Hz, 2H), 2.30(t, J=12.0Hz, 1H), 1.86(d, J=12.1Hz, 2H), 1.79(d, J=11.8Hz, 2H), 1.49(s, 1H), 1.44– 1.33(m,2H),0.97(q,J=11.7Hz,2H).HRMS(ESI-TOF):m / z 528.2435[M+H] + ;calcd for C 30 h 31 FN 5 o 3 + [M+H] + 528.2405.

Embodiment 3

[0057] N-(6-((2-aminophenyl)amino)-6-oxohexyl)-2-fluoro-5-((4-oxo-3,4-dihydro-phthalazin-1-yl) Methyl) benzamide (compound 3)

[0058]

[0059] According to the preparation method of compound 1, 4-(aminomethyl)benzoic acid was replaced with 6-aminocaproic acid, and other operations were the same. The product is brown-yellow solid. m.p.104℃-106℃. 1 H NMR (600MHz, DMSO-d 6 )δ (ppm): 12.61 (s, 1H), 9.11 (s, 1H), 8.35–8.18 (m, 2H), 7.95 (d, J = 8.0Hz, 1H), 7.87 (t, J = 7.2Hz, 1H), 7.81(t, J=7.3Hz, 1H), 7.51(t, J=10.9Hz, 1H), 7.42(s, 1H), 7.14(dt, J=35.8, 18.7Hz, 2H), 6.85( t,J=7.4Hz,1H),6.68(d,J=7.7Hz,1H),6.49(t,J=7.0Hz,1H),4.30(s,2H),3.20(d,J=5.5Hz, 2H), 2.29(t, J=7.0Hz, 2H), 1.58(d, J=6.8Hz, 2H), 1.50(s, 2H), 1.32(s, 2H).HRMS(ESI-TOF): m / z 502.2269[M+H] + ;calcd for C 28 h 29 FN 5 o 3 + [M+H] + 502.2249.

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Abstract

The invention discloses a phthalazine derivative, a preparation method and applications thereof, and belongs to the field of medicinal chemistry, wherein the phthalazine derivative prepared by the invention is a good PARP and HDAC double-target inhibitor. According to the invention, by using a design method based on a medicine splicing principle, the basic functional groups of a marketed medicineolaparib (PARP inhibitor) are reserved while a functional group structure capable of acting with HDAC protein is introduced into the tail part, so the designed brand-new compound can simultaneously inhibit PARP and HDAC, the advantages of the two inhibitors can be simultaneously provided, the combined effect of the two inhibitors can be completely provided, the low-toxicity and high-efficiency targeting antitumor inhibitor can be obtained, the application of the phthalazine derivative in the development of drugs for preventing and/or treating PARP and HDAC related diseases is developed, and the phthalazine derivative has great application value.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a phthalazine derivative and a preparation method and application thereof. Background technique [0002] Tumor is a serious disease that directly threatens human life. In my country, the incidence of cancer is second only to cardiovascular and cerebrovascular diseases, and it is a disease with a very high incidence. Moreover, the morbidity and mortality of cancer are still increasing every year. Tumor treatment is a worldwide problem. Traditional cytotoxic antitumor drugs lack definite targets, and thus often produce severe side effects. In recent years, the research and development of global anti-tumor drugs has shifted from traditional cytotoxic drugs to the development of new anti-tumor drugs with clear targets, high efficiency and low toxicity. Among them, the development of new targeted anti-tumor drugs based on epigenetics has become an important direction of anti-tumo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D237/32A61P35/00
CPCC07D237/32A61P35/00C07B2200/07Y02P20/55
Inventor 廖晨钟田永彬谢周令吕笑
Owner HEFEI UNIV OF TECH
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