Quinnazolidone derivative, preparation method for same and application thereof

Abstract

The invention discloses a quinnazolidone derivative, a preparation method for the same and application thereof. As shown in the following constitutional formula of the quinnazolidone derivative, R1 refers to F, Cl, Br or I, R2 refers to NH(CH2)nNR5, NR5 or NH(CH2)nAr, R3 refers to Ar, R4 refers to NHCO(CH2)nNR5 or CONH(CH2)nNR5, Ar stands for various aromatic nucleuses, n is equal to 1, 2, 3, 4, or 5, and R5 refers to C1-6 alkyl, C3-6 naphthenic base, piperidyl, morpholinyl, piperazine or oxazoline. The quinnazolidone derivative has quite high inhibitory action on protooncogene DNA (deoxyribose nucleic acid) such as telomeric DNA, c-kit and the like, and has remarkable inhibitory action on various cancer cell strains, is small in toxicity to normal cells, and has a wide application space for preparation of anti-cancer drugs.

Description

technical field

[0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to quinazolones derivatives and their preparation methods and applications. Background technique

[0002] Cancer is a major disease that threatens human health and life safety. According to statistics, there are about 4 million new cancer patients in the world every year. The research and development of anticancer drugs has always been a hot spot for chemists and pharmacologists. Finding anticancer drugs with high efficiency, high selectivity and less toxic side effects is one of the important directions of drug research and development. Designing and synthesizing anticancer drugs with DNA as the target, especially designing and synthesizing small molecule inhibitors for the special advanced structure of proto-oncogene DNA such as telomere DNA and c-kit, which have important physiological significance, is an important aspect for the development of new antica...

Examples

Embodiment 1

[0041] Embodiment 1: the synthesis of compound F-J11

[0042] Dissolve 0.1 mol of dry 4-nitro-2-aminobenzoic acid in 50 ml of acetic anhydride, and reflux at 130° C. for 2 hours. The reaction was cooled to room temperature and filtered with suction to obtain a white solid. The crude product was recrystallized from ethyl acetate to obtain white solid powder F-J11.

[0043] Yield: 61%; 1 H NMR (400MHz, CDCl 3 )δ7.89 (dd, J=9.2, 8.3Hz, 1H), 7.28 (dd, J=10.3, 6.9Hz, 1H), 2.40(s, 3H). LC-MS m / z: 198 [M+H ] + .

[0044]

[0045] Compound F-J11

Embodiment 2

[0046] Embodiment 2: the synthesis of compound F-J21

[0047]Dissolve 6 g of dry F-J11 (0.03 mol) in 19.5 g of aniline, stir at room temperature for 30 minutes, let stand, and filter with suction to obtain a white solid. The white solid was dissolved in 2% NaOH aqueous solution, and after 15 minutes, the clarified solution precipitated a solid, which was filtered by suction to obtain white solid powder F-J21.

[0048] Yield: 62%; 1 H NMR (400MHz, DMSO) δ8.05-7.98(m, 1H), 7.77(dd, J=11.4, 7.3Hz, 1H), 7.55(dq, J=14.2, 7.1Hz, 3H), 7.46(d, J=7.1Hz, 2H), 2.12(s, 3H).LC-MS m / z: 273[M+H] + .

[0049]

[0050] Compound F-J21

Embodiment 3

[0051] Embodiment 3: the synthesis of compound F-J31

[0052] Dissolve 5.7g of dry F-J21 (21mmol) and 10.5g of N-methylpiperazine (0.105mol) in 10ml of DMF, add a catalytic amount of sodium carbonate, react at 140°C for 2 hours, and remove by rotary evaporation under reduced pressure part of DMF, then pour the solution into 20ml of water, filter with suction to obtain a white solid, wash with water several times, and dry to obtain white solid F-J31.

[0053] Yield: 94%; 1 H NMR (400MHz, CDCl 3 )δ7.81(d, J=12.9Hz, 1H), 7.54(dt, J=14.0, 7.0Hz, 3H), 7.25(d, J=7.0Hz, 2H), 7.11(d, J=7.8Hz, 1H), 3.37-3.28(m, 4H), 2.71-2.60(m, 4H), 2.39(s, 3H), 2.21(s, 3H).LC-MS m / z: 353[M+H] + .

[0054]

[0055] Compound F-J31

technical field

[0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to quinazolones derivatives and their preparation methods and applications. Background technique

[0002] Cancer is a major disease that threatens human health and life safety. According to statistics, there are about 4 million new cancer patients in the world every year. The research and development of anticancer drugs has always been a hot spot for chemists and pharmacologists. Finding anticancer drugs with high efficiency, high selectivity and less toxic side effects is one of the important directions of drug research and development. Designing and synthesizing anticancer drugs with DNA as the target, especially designing and synthesizing small molecule inhibitors for the special advanced structure of proto-oncogene DNA such as telomere DNA and c-kit, which have important physiological significance, is an important aspect for the development of new antica...

Examples

Embodiment 1

[0041] Embodiment 1: the synthesis of compound F-J11

[0042] Dissolve 0.1 mol of dry 4-nitro-2-aminobenzoic acid in 50 ml of acetic anhydride, and reflux at 130° C. for 2 hours. The reaction was cooled to room temperature and filtered with suction to obtain a white solid. The crude product was recrystallized from ethyl acetate to obtain white solid powder F-J11.

[0043] Yield: 61%; 1 H NMR (400MHz, CDCl 3 )δ7.89 (dd, J=9.2, 8.3Hz, 1H), 7.28 (dd, J=10.3, 6.9Hz, 1H), 2.40(s, 3H). LC-MS m / z: 198 [M+H ] + .

[0044]

[0045] Compound F-J11

Embodiment 2

[0046] Embodiment 2: the synthesis of compound F-J21

[0047]Dissolve 6 g of dry F-J11 (0.03 mol) in 19.5 g of aniline, stir at room temperature for 30 minutes, let stand, and filter with suction to obtain a white solid. The white solid was dissolved in 2% NaOH aqueous solution, and after 15 minutes, the clarified solution precipitated a solid, which was filtered by suction to obtain white solid powder F-J21.

[0048] Yield: 62%; 1 H NMR (400MHz, DMSO) δ8.05-7.98(m, 1H), 7.77(dd, J=11.4, 7.3Hz, 1H), 7.55(dq, J=14.2, 7.1Hz, 3H), 7.46(d, J=7.1Hz, 2H), 2.12(s, 3H).LC-MS m / z: 273[M+H] + .

[0049]

[0050] Compound F-J21

Embodiment 3

[0051] Embodiment 3: the synthesis of compound F-J31

[0052] Dissolve 5.7g of dry F-J21 (21mmol) and 10.5g of N-methylpiperazine (0.105mol) in 10ml of DMF, add a catalytic amount of sodium carbonate, react at 140°C for 2 hours, and remove by rotary evaporation under reduced pressure part of DMF, then pour the solution into 20ml of water, filter with suction to obtain a white solid, wash with water several times, and dry to obtain white solid F-J31.

[0053] Yield: 94%; 1 H NMR (400MHz, CDCl 3 )δ7.81(d, J=12.9Hz, 1H), 7.54(dt, J=14.0, 7.0Hz, 3H), 7.25(d, J=7.0Hz, 2H), 7.11(d, J=7.8Hz, 1H), 3.37-3.28(m, 4H), 2.71-2.60(m, 4H), 2.39(s, 3H), 2.21(s, 3H).LC-MS m / z: 353[M+H] + .

[0054]

[0055] Compound F-J31

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