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Oxadiazole thioether derivative as well as preparation method and application thereof

A technology of oxadiazole sulfide and derivatives, which is applied in the field of oxadiazole sulfide derivatives and their preparation, can solve the problems of low anticancer activity, difficult synthesis, unfavorable medicines and the like, and achieves good inhibitory activity and post-processing. Convenience and high affinity

Active Publication Date: 2021-10-19
HEFEI UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] PD176252 has defects such as low anticancer activity and high toxicity, which is not conducive to drug production, and the synthesis is difficult and the yield is low

Method used

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  • Oxadiazole thioether derivative as well as preparation method and application thereof
  • Oxadiazole thioether derivative as well as preparation method and application thereof
  • Oxadiazole thioether derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] (S)-N-(2-(1H-indol-3-yl)-1-(5-propylmercapto-1,3,4-oxadiazol-2-yl)ethyl)-2-(4 Preparation of -(trifluoromethyl)phenyl)acetamide (compound 1)

[0026]

[0027] Step 1: Synthesis of (2-(4-(trifluoromethyl)phenyl)acetamido)-L-tryptophan methyl ester

[0028] Add 1.02g 4-(trifluoromethyl)phenylacetic acid (0.005mol), 1.53g tryptophan methyl ester hydrochloride (0.006mol), 1.26g triethylamine (0.012mol) to a 100mL single-necked flask, and then add Dry dichloromethane 50mL, stir at room temperature for 30min, then add 1.25g 1-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (0.0065mol) and 0.09g 1- Hydroxybenzotriazole (0.00065mol), stirred at room temperature for 24h. After the TLC monitoring reaction finishes, first wash twice with 5% (w / v) dilute hydrochloric acid, then wash twice with water, evaporate dichloromethane under reduced pressure, obtain 1.87g light yellow oily liquid intermediate 1 after drying, yield was 92.6%. 1 H NMR (600MHz, DMSO-d6) δ10.91(...

Embodiment 2

[0037] (S)-N-(2-(1H-indol-3-yl)-1-(5-butylmercapto-1,3,4-oxadiazol-2-yl)ethyl)-2-(4 Preparation of -(trifluoromethyl)phenyl)acetamide (compound 2)

[0038]

[0039] According to the preparation method of compound 1, 1-chlorobutane was used to replace 2-chloropropane, and other operations were the same. The product is a yellow solid powder with a yield of 67.7%. NMR: δ10.91(s,1H),9.02(d,J=7.9Hz,1H),7.59(d,J=8.1Hz,2H),7.49(d,J=7.9Hz,1H),7.33-7.31 (m,3H),7.14(d,J=1.9Hz,1H),7.06(t,J=7.6Hz,1H),6.96(dd,J=10.9,3.8Hz,1H),5.32(td,J= 15.2,7.6Hz,1H),3.56(s,2H),3.31(m,2H),3.13(t,J=7.2Hz,2H),1.67-1.56(m,2H),1.36-1.34(m,2H ),0.87(t,J=7.4Hz,3H). 13 C NMR (151MHz, DMSO-d 6 )δ169.49, 167.38, 163.76, 140.82, 136.19, 129.88, 127.22(q, J=31.7Hz), 127.14, 125.05(q, J=3.7Hz), 124.42(q, J=272.2Hz), 124.12, 121.12, 118.62 ,118.06,111.57,108.93,46.46,41.63,31.74,31.02,29.16,21.08,13.43. Chemical formula: C 25 h 25 f 3 N 4 o 2 S,TOF-HRMS:m / z 503.1723[M+H] + (calcd. 503.1725).

Embodiment 3

[0041] (S)-N-(2-(1H-indol-3-yl)-1-(5-pentylmercapto-1,3,4-oxadiazol-2-yl)ethyl)-2-(4 Preparation of -(trifluoromethyl)phenyl)acetamide (compound 3)

[0042]

[0043] According to the preparation method of compound 1, 2-chloropropane was replaced with 1-chloropentane, and the rest of the operations were the same. The product is a brown solid powder with a yield of 64.2%. NMR: 1 H NMR (600MHz, DMSO-d 6 )δ10.90(s, 1H), 9.02(d, J=7.9Hz, 1H), 7.58(d, J=8.1Hz, 2H), 7.48(d, J=7.9Hz, 1H), 7.33-7.31( m, 3H), 7.14(d, J=2.3Hz, 1H), 7.06(t, J=7.6Hz, 1H), 6.96(dd, J=10.9, 3.8Hz, 1H), 5.31(td, J=15.2 ,7.8Hz,1H),3.56(s,2H),3.28-3.25(m,2H),3.12(t,J=7.3Hz,2H),1.64(td,J=14.6,7.3Hz,2H),1.33 -1.22(m,4H),0.85(t,J=7.1Hz,3H). 13 C NMR (151MHz, DMSO-d 6 )δ169.45, 167.35, 163.72, 140.78, 136.16, 129.84, 127.22(q, J=31.7Hz), 127.10, 125.01(q, J=3.8Hz), 124.42(q, J=272.2Hz), 124.09, 121.07, 118.57 ,118.02,111.53,108.92,46.44,41.60,31.99,30.00,28.62,28.22,21.59,13.85. Chemical formula: C 26 h...

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Abstract

The invention discloses an oxadiazole thioether derivative as well as a preparation method and application thereof, and relates to the technical field of medicinal chemistry. The oxadiazole thioether derivative with a novel structure is designed and successfully synthesized, and research shows that the compounds have high affinity with GRPR and belong to good GRPR inhibitors; moreover, compared with PD176252, the compounds have better inhibitory activity on human gastric cancer cells HGC-27, human prostate cancer cells PC-3 and human non-small cell lung cancer cells A549; and meanwhile, the synthetic route for preparing the compound is simple, the reaction condition is mild, post-treatment is convenient, and industrial production is easy.

Description

Technical field: [0001] The invention relates to the technical field of medicinal chemistry, in particular to an oxadiazole thioether derivative and a preparation method and application thereof. Background technique: [0002] Cancer is still the second leading killer of human beings! The morbidity and mortality of various types of cancer are still increasing year by year. Traditional chemotherapy drugs have obvious toxic and side effects due to the lack of clear targets. Therefore, the development of low-toxicity and broad-spectrum anticancer drugs with clear targets has become a research hotspot in the field of medicine. [0003] Biomedical research has proved that gastrin-releasing pepeide receptor (GRPR), as a tumor autogrowth factor receptor and morphological differentiation factor receptor, is overexpressed in various tumor tissues (Journal of Nuclear Medicine, 2020, 61,792-798), such as hormone-independent prostate cancer, breast cancer, non-small cell lung cancer, g...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/06A61P35/00
CPCC07D413/06A61P35/00
Inventor 王淮朱雨婷姚日生邓胜松
Owner HEFEI UNIV OF TECH