Dihydro pyrrolidone derivative and application of same in preparing antitumor drugs

Abstract

The invention provides a dihydro pyrrolidone derivation and an application of the same in preparing antitumor drugs. The structural formula of the dihydro pyrrolidone derivative is as indicated in theformula I, wherein R<1> refers to an aromatic base, alkyl or heterocyclic radical; R<2> refers to alkoxy, amino or secondary amino; R<3> refers to amino, secondary amino, alkoxy, aryloxy, alkyl sulphanyl, aromatic sulfur or nitrogenous heterocyclic radical. The provided compound has remarkable inhibitory effect on tumor cells especially growth of human breast cancel cells, human colon cancer cells, human cervical cancer cells and human lung cancer cells, high characteristics of antitumor activity in vitro and broad spectrum antitumor are represented, and the dihydro pyrrolidone derivation canbe applied to prevention and treatment of multiple tumor diseases of breast cancer, colon cancer, cervical cancer, lung cancer and the like in a manner of being individually or combined with other drugs. The preparation process of the compound is simple and easy to implement, reaction conditions are moderate, raw materials for reaction are easy to obtain, industrialization is easy to realize, andwide application value is achieved.

Description

technical field

[0001] The present invention relates to a class of dihydropyrrolone derivatives with multiple antitumor activities and their application in the preparation of various tumor suppressor drugs. Background technique

[0002] Cancer is becoming the "second killer" after cardiovascular disease, which seriously endangers human health (CA-Cancer JClin. 2016, 66(1): 7-30), and it is also one of the main diseases causing human death. According to statistics, the incidence and mortality of cancer in my country are generally on the rise, among which lung cancer, breast cancer, and colorectal cancer are at the forefront. At present, the means of clinical cancer treatment include surgical resection, radiation therapy, chemical drug therapy, immunotherapy and gene therapy which have emerged in recent years. Chemotherapy is a method of systemic treatment, and it is the first choice for tumors that have spread and metastasized. However, the existing anticancer drugs are sti...

Examples

Embodiment 1

[0057] 2,5-Dihydro-1-(3-trifluoromethylphenyl)2-(3-methoxy-4-hydroxyphenyl)-4-(3-trifluoromethylphenylamino)-5-oxo- 1 H-Methyl 4-(3-(trifluoromethyl)phenylamino)-1-(3-(trifluoromethyl)phenyl)-2,5-dihydro-2-(4-hydroxy-3-methoxyphenyl) -5-oxo-1 H -pyrrole-3-carboxylate Compound 1) 54% yield, yellow solid, mp: 121–122 ºC; IR(KBr) ν max = 3783, 3354, 2923, 2851, 2309, 1701, 1640, 1451, 1330, 1273, 1167, 1124, 1028, 881, 785, 688, 532; 1 H NMR (400 MHz, CDCl 3 ) δ =8.28 (s, 1H), 7.80(s, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.53–7.35 (m, 6H), 6.83 (s, 2H), 6.66 (s,1H), 5.83 (s, 1H), 5.61 (s, 1H), 3.83 (s, 3H) , 3.63 (s, 3H) ppm; 13 C NMR (101MHz, CDCl 3 ) δ =164.4, 163.7, 146.7, 145.7, 141.1, 138.9, 136.9, 131.2, 130.9,129.4, 129.0, 127.1, 126.0, 125.6, 122.2, 121.3, 121.1, 119.3, 119.2, 119.2,119.2, 114.5, 111.4, 109.2, 63.0 , 55.9, 51.4 ppm; HR-ESI-MS for C 27 h 20 f 6 N 2 o 5 ([M+H] + ) Calcd: 567.1340; Found: 567.1340.

Embodiment 2

[0059] 2,5-Dihydro-1-phenyl-2-(3-methoxy-4-hydroxyphenyl)-4-phenylamino-5-oxo-1 H - Ethyl pyrrole-3-carboxylate

[0060] (ethyl 2,5-dihydro-2-(4-hydroxy-3-methoxyphenyl)-5-oxo-1-phenyl-4-(phenyl-amino)-1 H -

[0061] pyrrole-3-carboxylate compound 2) 58% yield, yellow solid, mp: 107– 108 ºC;IR (KBr) ν max = 3294, 2929, 1693, 1599, 1507, 1375, 1231, 1122, 1032, 758,692, 506; 1 H NMR (400 MHz, CDCl 3 ) δ = 8.19 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H),7.40 –7.05 (m, 8H), 6.84 (m, 2H), 6.65 (s, 1H), 5.79 (s, 1H), 5.56 (s, 1H),4.05 (dt, J = 6.7, 4.5 Hz, 2H), 3.81 (s, 3H), 1.06 (t, J = 7.1 Hz, 3H) ppm; 13 C NMR (101 MHz, CDCl 3 ) δ = 164.4, 164.0, 146.5, 145.4, 141.6, 138.7, 136.5,128.8, 128.4, 125.7, 124.5, 122.5, 121.6, 114.1, 109.1,63.2, 55.9, 53.8, 13.8 PPM; HR- ESI-MS for C 26 h 24 N 2 o 5 ([M+H] + ) Calcd: 445.1758; Found: 445.1755.

Embodiment 3

[0063] 2,5-Dihydro-1-phenyl-2-(3-methoxy-4-hydroxyphenyl)-4-phenylamino-5-oxo-1 H -Methyl 2,5-dihydro-2-(4-hydroxy-3-methoxyphenyl)-5-oxo-1-phenyl-4-(phenyl-amino)-1 H -

[0064] pyrrole-3-carboxylate compound 3) 54% yield, yellow solid, mp: 183– 184 ºC; 1 H NMR (400 MHz, CDCl 3 ) δ = 8.16 (s, 1H), 7.47 (d, J = 7.9 Hz, 2H), 7.40– 7.06(m, 8H), 6.83 (m, 2H), 6.65 (s, 1H), 5.78 (s, 1H), 5.56 (s, 1H), 3.81 (s, 3H) , 3.58 (s, 3H) ppm; 13 C NMR (101 MHz, CDCl 3 ) δ = 164.7, 164.0, 146.6, 145.4, 141.8, 138.6, 136.5, 128.8, 128.4, 128.3, 125.8, 124.7, 122.9, 122.8, 121.3, 114.2, 109.4, 109.2, 5.5 pm

technical field

[0001] The present invention relates to a class of dihydropyrrolone derivatives with multiple antitumor activities and their application in the preparation of various tumor suppressor drugs. Background technique

[0002] Cancer is becoming the "second killer" after cardiovascular disease, which seriously endangers human health (CA-Cancer JClin. 2016, 66(1): 7-30), and it is also one of the main diseases causing human death. According to statistics, the incidence and mortality of cancer in my country are generally on the rise, among which lung cancer, breast cancer, and colorectal cancer are at the forefront. At present, the means of clinical cancer treatment include surgical resection, radiation therapy, chemical drug therapy, immunotherapy and gene therapy which have emerged in recent years. Chemotherapy is a method of systemic treatment, and it is the first choice for tumors that have spread and metastasized. However, the existing anticancer drugs are sti...

Examples

Embodiment 1

[0057] 2,5-Dihydro-1-(3-trifluoromethylphenyl)2-(3-methoxy-4-hydroxyphenyl)-4-(3-trifluoromethylphenylamino)-5-oxo- 1 H-Methyl 4-(3-(trifluoromethyl)phenylamino)-1-(3-(trifluoromethyl)phenyl)-2,5-dihydro-2-(4-hydroxy-3-methoxyphenyl) -5-oxo-1 H -pyrrole-3-carboxylate Compound 1) 54% yield, yellow solid, mp: 121–122 ºC; IR(KBr) ν max = 3783, 3354, 2923, 2851, 2309, 1701, 1640, 1451, 1330, 1273, 1167, 1124, 1028, 881, 785, 688, 532; 1 H NMR (400 MHz, CDCl 3 ) δ =8.28 (s, 1H), 7.80(s, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.53–7.35 (m, 6H), 6.83 (s, 2H), 6.66 (s,1H), 5.83 (s, 1H), 5.61 (s, 1H), 3.83 (s, 3H) , 3.63 (s, 3H) ppm; 13 C NMR (101MHz, CDCl 3 ) δ =164.4, 163.7, 146.7, 145.7, 141.1, 138.9, 136.9, 131.2, 130.9,129.4, 129.0, 127.1, 126.0, 125.6, 122.2, 121.3, 121.1, 119.3, 119.2, 119.2,119.2, 114.5, 111.4, 109.2, 63.0 , 55.9, 51.4 ppm; HR-ESI-MS for C 27 h 20 f 6 N 2 o 5 ([M+H] + ) Calcd: 567.1340; Found: 567.1340.

Embodiment 2

[0059] 2,5-Dihydro-1-phenyl-2-(3-methoxy-4-hydroxyphenyl)-4-phenylamino-5-oxo-1 H - Ethyl pyrrole-3-carboxylate

[0060] (ethyl 2,5-dihydro-2-(4-hydroxy-3-methoxyphenyl)-5-oxo-1-phenyl-4-(phenyl-amino)-1 H -

[0061] pyrrole-3-carboxylate compound 2) 58% yield, yellow solid, mp: 107– 108 ºC;IR (KBr) ν max = 3294, 2929, 1693, 1599, 1507, 1375, 1231, 1122, 1032, 758,692, 506; 1 H NMR (400 MHz, CDCl 3 ) δ = 8.19 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H),7.40 –7.05 (m, 8H), 6.84 (m, 2H), 6.65 (s, 1H), 5.79 (s, 1H), 5.56 (s, 1H),4.05 (dt, J = 6.7, 4.5 Hz, 2H), 3.81 (s, 3H), 1.06 (t, J = 7.1 Hz, 3H) ppm; 13 C NMR (101 MHz, CDCl 3 ) δ = 164.4, 164.0, 146.5, 145.4, 141.6, 138.7, 136.5,128.8, 128.4, 125.7, 124.5, 122.5, 121.6, 114.1, 109.1,63.2, 55.9, 53.8, 13.8 PPM; HR- ESI-MS for C 26 h 24 N 2 o 5 ([M+H] + ) Calcd: 445.1758; Found: 445.1755.

Embodiment 3

[0063] 2,5-Dihydro-1-phenyl-2-(3-methoxy-4-hydroxyphenyl)-4-phenylamino-5-oxo-1 H -Methyl 2,5-dihydro-2-(4-hydroxy-3-methoxyphenyl)-5-oxo-1-phenyl-4-(phenyl-amino)-1 H -

[0064] pyrrole-3-carboxylate compound 3) 54% yield, yellow solid, mp: 183– 184 ºC; 1 H NMR (400 MHz, CDCl 3 ) δ = 8.16 (s, 1H), 7.47 (d, J = 7.9 Hz, 2H), 7.40– 7.06(m, 8H), 6.83 (m, 2H), 6.65 (s, 1H), 5.78 (s, 1H), 5.56 (s, 1H), 3.81 (s, 3H) , 3.58 (s, 3H) ppm; 13 C NMR (101 MHz, CDCl 3 ) δ = 164.7, 164.0, 146.6, 145.4, 141.8, 138.6, 136.5, 128.8, 128.4, 128.3, 125.8, 124.7, 122.9, 122.8, 121.3, 114.2, 109.4, 109.2, 5.5 pm

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