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A kind of benzimidazolo[2,1-b]thiazole compound and its application

A technology of benzimidazole and thiazole, which is applied in the field of medicine, can solve the problems of high toxicity and side effects and inconspicuous curative effect, and achieve the effects of good inhibitory activity, extended dosing time interval, and excellent metabolic stability

Active Publication Date: 2021-08-24
JIANGNAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] The occurrence and development of malignant tumors is a complex process. Traditional therapeutic drugs are mainly divided into alkylating agents, antimetabolite drugs, natural products and antibiotics. The disadvantages of these types of drugs are that their curative effect is not obvious and their side effects are large

Method used

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  • A kind of benzimidazolo[2,1-b]thiazole compound and its application
  • A kind of benzimidazolo[2,1-b]thiazole compound and its application
  • A kind of benzimidazolo[2,1-b]thiazole compound and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0165] Example 1 1-(5-methylisoxazol-3-yl)-3-[4-(7-(2-morpholinyl)ethoxy]benzo[d]imidazo[2,1- b] Thiazol-2-yl)phenyl)urea (compound 1)

[0166]

[0167] Intermediate 5a (79.1mg, 0.20mmol), 6b (48.1mg, 0.22mmol), 4-dimethylaminopyridine (DMAP, 1.5mg, 0.01mmol) were successively added to chloroform (2mL), and added under stirring Triethylamine (TEA, 3.0 mg, 0.03 mmol) was refluxed for 20 h. After the reaction was completed, it was cooled to 0° C., and a white solid precipitated out, and the mixture was stirred for 2 h. Suction filtration, the filter cake was washed with cold chloroform, and dried to give white solid 1 (84.0 mg, 80.8%) MS-ESI (m / z): 519.3 [M+H] + . 1 HNMR (300MHz, DMSO-d 6 )δ9.69(s,1H),9.34(s,1H),8.66(s,1H),7.95(d,J=8.9Hz,1H),7.80(d,J=9.6Hz,3H),7.55( d,J=8.2Hz, 2H), 7.26(d,J=8.9Hz,1H), 6.59(s,1H), 4.47(s,2H), 3.87(s,4H), 2.40(s,3H).

Embodiment 2

[0168] Example 2 1-(3-(tert-butyl)isoxazol-5-yl)-3-(4-(7-(2-morpholinoethoxy)benzo[d]imidazo[2, 1-b]thiazol-2-yl)phenyl)urea (compound 2)

[0169]

[0170] Compound 2 was synthesized with reference to compound 1, and the moles of raw materials were the same, the difference was that intermediate 6b was replaced by intermediate 6c. 60.8 mg of white solid was obtained with a yield of 54.2%. MS-ESI(m / z):561.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.93(s,1H),8.61(s,1H),8.15–8.08(m,1H),7.86(d,J=8.8Hz,1H),7.78(d,J=8.3Hz,2H), 7.68(d,J=2.4Hz,1H),7.53(d,J=8.4Hz,2H),7.16(dd,J=8.9,2.5Hz,1H),6.08(s,1H),4.16(t,J =5.7Hz, 2H), 3.59(t, J=4.6Hz, 4H), 2.97(s, 2H), 2.73(t, J=5.7Hz, 2H), 1.27(s, 9H).

Embodiment 2A

[0171] Example 2A 1-(3-(tert-butyl)isoxazol-5-yl)-3-(4-(7-(2-morpholinoethoxy)benzo[d]imidazo[2, 1-b] thiazol-2-yl) phenyl) urea hydrochloride (compound 2A)

[0172]

[0173] Example 2 (56.1 mg) was dissolved in acetonitrile (1 mL), and 1 mol / L HCl (1.5 mL) was slowly added under stirring. After stirring for a while, the solvent was removed by lyophilization to obtain pale yellow solid Example 2A (58.5 mg). 1 H NMR (400MHz,D 2 O)δ9.16(s,1H),8.71(s,1H),8.27–8.20(m,1H),7.79(d,J=8.8Hz,1H),7.84(d,J=8.3Hz,2H) ,7.78(d,J=2.4Hz,1H),7.65(d,J=7.6Hz,2H),7.26(dd,J=7.7,2.5Hz,1H),6.20(s,1H),4.31(t, J=5.4Hz, 2H), 3.69(t, J=4.4Hz, 4H), 2.97(s, 2H), 2.79(t, J=5.4Hz, 2H), 1.31(s, 9H).

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Abstract

The invention discloses a benzimidazolo[2,1-b]thiazole compound and an application thereof, belonging to the technical field of medicine. The benzimidazolo[2,1-b]thiazole analogs synthesized in the present invention have an inhibitory activity of more than 90% on FLT3, wherein the compounds (compounds 2, 4, 6, 8 and 10) have an inhibitory activity on FLT3-ITD kinase IC 50 lower values, especially for compound 2, whose IC 50 value is only 5.60nM, therefore, the compound of the present invention can be used as the inhibitor of FLT3, or be used for preparing medicine, and said medicine can affect the enzymatic activity of one or more tyrosine kinases and interfere with the enzyme activity produced by said Kinase-transduced signals to regulate or inhibit diseases associated with abnormal cell proliferation hold great promise.

Description

technical field [0001] The invention relates to a benzimidazolo[2,1-b]thiazole compound and its application, belonging to the technical field of medicine. Background technique [0002] The occurrence and development of malignant tumors is a complex process. Traditional therapeutic drugs are mainly divided into alkylating agents, antimetabolite drugs, natural products, and antibiotics. Small molecule kinase inhibitors are currently an area of ​​interest as potential cancer therapies. Protein kinases are catalysts that play key roles in nearly every aspect of cell biology and biochemistry. These enzymes generate signaling modules that regulate cell cycle progression, proliferation, programmed cell death (apoptosis), cytoskeletal function, motility, differentiation, development, transcription and translation. The roles of protein kinases are numerous, and their careful regulation is critical because aberrant activity can lead to cancer, cardiovascular disease, inflammation, a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D513/04A61K31/5377A61K31/429A61K45/06A61P35/00A61P35/02A23L33/10
CPCA23V2002/00A23L33/10A61P35/00A61P35/02C07D513/04A23V2200/308
Inventor 唐春雷赵宽涛张晴张立勋范为正
Owner JIANGNAN UNIV
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