2-p-nitrostyryl-4-substituted aminoquinazoline derivatives and their preparation methods and applications

An aminoquinazoline and nitrostyryl technology, which is applied in the field of 2-p-nitrostyryl-4-substituted aminoquinazoline derivatives and their preparation, can solve the problems of inability to exhibit antitumor activity and the like, and achieve normal Low cytotoxicity, strong antitumor activity, and high safety

Active Publication Date: 2022-02-08
GUANGXI NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] There are many derivatives of 2-p-nitrostyryl-4-substituted aminoquinazoles, each of which exhibits different biological activities, but the derivatives of the above-mentioned 2-p-nitrostyryl-4-substituted aminoquinazoles cannot Directly interact with DNA, and cannot show its anti-tumor activity by acting on DNA

Method used

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  • 2-p-nitrostyryl-4-substituted aminoquinazoline derivatives and their preparation methods and applications
  • 2-p-nitrostyryl-4-substituted aminoquinazoline derivatives and their preparation methods and applications
  • 2-p-nitrostyryl-4-substituted aminoquinazoline derivatives and their preparation methods and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Embodiment 1: preparation compound 2a

[0028] 1) Add anthranilamide in acetic anhydride, the addition of anthranilamide in every milliliter of acetic anhydride is 1.2mmol, fully stir and react at room temperature for 1 hour (TLC monitors the reaction, developer: V 乙酸乙酯 :V 石油醚 =1:2), precipitate solid, obtain reaction mixture; 2) add water in reaction mixture, and suction filtration, get filter residue; Wash filter residue with saturated sodium bicarbonate solution, water and ethyl acetate successively, then wash The good filter residue was dried to obtain the compound 2a, which was a white solid with a yield of 87%.

[0029] m.p.172~174℃; 1 H NMR (400MHz, CD 3 OD)δ: 8.35(d, J=8.3Hz, 1H), 7.72(dd, J=7.9, 1.4Hz, 1H), 7.49~7.43(m, 1H), 7.15~7.11(m, 1H), 2.15( s,3H).(the resonance ofO-H was not observed in CD 3 OD).

[0030] The structural formula of the prepared compound 2a is:

Embodiment 2

[0031] Embodiment 2: preparation compound 2b

[0032] The compound 2-amino-5-chlorobenzamide was used to replace anthranilamide, and the synthesis method was the same as in Example 1 to obtain the compound 2b with a yield of 99%.

[0033] 6-Chloro-2-methylquinazolin-4-ol(2b).White solid, yield 99%, m.p.191~193℃. 1 H NMR (400MHz, CDCl 3 )δ:10.96(s,1H),8.61(d,J=8.9Hz,1H),7.73~7.34(m,1H),2.20(s,3H).(the resonance of O-H was not observed in CDCl 3 ).

[0034] The structural formula of the prepared compound 2b is:

Embodiment 3

[0035] Embodiment 3: preparation compound 3a

[0036] 1) Add compound 2a, p-nitrobenzaldehyde and acetic acid successively in the reaction vessel, the addition of compound 2a in every milliliter of acetic acid is 0.9mmol, the addition of p-nitrobenzaldehyde is 1.2mmol, the reaction vessel is placed in oil In bathing pot, under nitrogen protection, heating and stirring under reflux reaction 12h (TLC monitors reaction, developer: V乙酸乙酯 :V 石油醚 =1:2), cooling; 2) suction filtration, take the filter residue, wash and dry to obtain compound 3a, compound 3a is a light yellow solid, and the yield is 60%.

[0037] m.p.315~317℃. 1 H NMR (400MHz, DMSO-d 6 )δ: 12.44(s, 1H), 8.30(d, J=8.6 Hz, 2H), 8.13(d, J=8.0Hz, 1H), 8.04(d, J=16.2Hz, 1H), 7.93(d, J=8.6Hz, 2H),7.86~7.82(m,1H),7.71(d,J=8.0Hz,1H),7.54~7.50(m,1H),7.20(d,J=16.2Hz,1H).

[0038] The structural formula of the prepared compound 3a is:

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Abstract

The 2-p-nitrostyryl-4-substituted aminoquinazoline derivatives of the present invention and their preparation method and application utilize a simple method to synthesize 2-p-nitrostyryl-4-substituted aminoquinazoline derivatives, The yield is high, the production cost is low, and the obtained 2-p-nitrostyryl-4-substituted aminoquinazoline derivatives can directly interact with DNA, and show strong anti-tumor activity by acting on DNA. In the test of ‑803 gastric cancer xenograft tumor model, the in vivo antitumor effect of 2‑p-nitrostyryl‑4‑substituted aminoquinazoline derivatives is comparable to that of epirubicin, the first drug currently used in clinical treatment of gastric cancer. Moreover, the toxicity is very small, and it has almost no effect on the body weight of the treated mice, so it has high medical value.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to 2-p-nitrostyryl-4-substituted aminoquinazoline derivatives and their preparation methods and applications. Background technique [0002] DNA is a very important target of drug molecules. Compounds that can interact with DNA have important applications in the development of new anti-tumor drugs and the design of DNA probes, especially in the development of anti-tumor drugs. At present, many drug molecules that produce good anti-tumor effects by acting on DNA, such as doxorubicin, epirubicin, mitoxantrone and other anti-tumor drugs are very commonly used anti-tumor drugs in clinic. 2-p-nitrostyryl-4-substituted aminoquinazole is believed to restore the active conformation of mutant p53, thereby restoring the transcriptional function of mutant p53, and has a wide range of biological activities. 2-p-nitrostyryl-4-substituted amino Based on the structure of quinazole, after structu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94A61P35/00
CPCA61P35/00C07D239/94
Inventor 苏桂发韦辛未潘成学袁静梅
Owner GUANGXI NORMAL UNIV
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