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FAK targeting compounds, markers thereof, and preparation methods and applications thereof

A technology of compounds and precursor compounds, applied in the field of compounds, can solve the problem that the tumor suppressing activity needs to be improved, etc.

Active Publication Date: 2020-06-05
BEIJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, the tumor suppressive activity of these existing small molecule inhibitors of FAK needs to be improved.

Method used

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  • FAK targeting compounds, markers thereof, and preparation methods and applications thereof
  • FAK targeting compounds, markers thereof, and preparation methods and applications thereof
  • FAK targeting compounds, markers thereof, and preparation methods and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0143] Embodiment 1. The organic synthesis of compound 27aa

[0144] The DMF (300mL) solution of compound 2 (20g, 183.4mmol) was cooled to 0°C under an ice bath, sodium hydride (8.8g, 220mmol, 60% in mineral oil, 1.2 equiv) was added in batches, stirred at 0°C for 1h, 2-Chloro-3-nitropyridine (compound 1) (20 g, 126.5 mmol, 0.7 equiv) was added, slowly raised to room temperature, and stirring continued for 5 h. After the reaction, DMF was poured into 1L of water, and then extracted with ethyl acetate (300 mL*3 times). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1 to 3 / 1) to obtain compound 3 (22.2g, brown-yellow solid , yield 75.9%); The structure of compound 3 is characterized as follows:

[0145] 1 H NMR (400MHz, CDCl 3 ,δppm):8.67(dd,J=1.6Hz,4.7Hz,1H),8.26-8.23(m,1H),7.47-7.44(m,1H),3.42(s,3H),3.07(s,3H) .

...

Embodiment 2

[0168] Embodiment 2. The organic synthesis of compound 27ab

[0169] Compound 4 was obtained by referring to the method of Example 1, and 5-bromo-2,4-dichloropyrimidine was used instead of 2,4,5-trichloropyrimidine to react with compound 4 to obtain compound 6b having a structure similar to compound 6a;

[0170] Compound 12 was obtained by referring to the method of Example 1, and compound 6b was used instead of compound 6a to react with compound 12 to obtain compound 27ab (0.51 g, light green solid, yield 33.1%) having a structure similar to compound 27aa. The structure of compound 27ab is characterized as follows:

[0171] 1 H NMR (400MHz, CDCl 3 ,δppm):8.80(d,J=6.3Hz,1H),8.35(s,1H),8.19-8.17(m,2H),7.94(d,J=5.8Hz,1H),7.29-7.27(m, 1H), 7.19(s, 1H), 6.53(d, J=1.6Hz, 1H), 6.47(dd, J=1.6Hz, 5.8Hz, 1H), 3.85(s, 3H), 3.69(t, J= 3.4Hz, 2H), 3.29(s, 3H), 3.20(t, J=3.1Hz, 4H), 3.05(s, 3H), 2.75(t, J=2.8Hz, 4H), 2.66(t, J= 3.4Hz, 2H).

[0172] 13 C NMR (400MHz, CDCl 3 ,δppm):1...

Embodiment 3

[0174] Embodiment 3. The organic synthesis of compound 27ac

[0175] Compound 4 was prepared by referring to the method of Example 1, and 5-fluoro-2,4-dichloropyrimidine was used instead of 2,4,5-trichloropyrimidine to react with compound 4 to obtain compound 6c having a structure similar to compound 6a.

[0176] Referring to the method of Example 2, compound 6c was used instead of compound 6b to react with compound 12 to obtain compound 27ca (0.98 g, yellow solid, yield 59.6%) which was similar in structure to compound 27ab. The structure of compound 27ac is characterized as follows:

[0177] 1 H NMR (400MHz, CDCl 3 ,δppm):8.85(d,J=8.2Hz,1H),8.19(dd,J=1.2Hz,4.4Hz,1H),8.00-7.96(m,3H),7.32-7.29(m,1H),7.19 (s,1H),6.54(d,J=2.2Hz,1H),6.50(dd,J=2.0Hz,8.7Hz,1H),3.86(s,3H),3.75(t,J=4.8Hz,2H ),3.28(s,3H),3.23(s,4H),3.04(s,3H),2.82(s,4H),2.72(s,2H).

[0178] 13 C NMR (400MHz, CDCl 3 ,δppm):155.35,149.20,146.75,143.76,142.29,142.00,141.16,140.97,132.96,130.34,123.76,122.44,120.18...

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Abstract

The present invention provides FAK targeting compounds. The structure of the FAK targeting compounds is represented by a formula (I), R1 is -F, -Cl, -Br, -CH3 or -OCH3; R2, R3 and R5 are respectivelymethoxyl or -H; and R4 / R6 is -H, -CH2CH2OH or -CH2CH2F. The invention also provides compounds for radio-labeling the FAK targeting compounds. The FAK targeting compounds have an excellent in-vitro FAKkinase activity inhibition effect; and the radioactive markers have ideal biological distribution in the body of a mouse bearing S180 tumor. The invention also provides a preparation method of the compounds and the radioactive markers, and an application of the compounds and the radioactive markers in the preparation of tumor drugs.

Description

technical field [0001] The present invention relates to the field of compounds, in particular to a class of compounds targeting FAK (Focal Adhesion Kinase) and its F-18 marker, as well as their preparation methods and applications. Background technique [0002] Focal Adhesion Kinase (Focal Adhesion Kinase, FAK) is a non-receptor tyrosine kinase, which plays a vital role in the occurrence, development and metastasis of tumors. FAK is highly or overexpressed in most types of tumor cells, therefore, FAK is a potential target for tumor diagnosis and treatment. [0003] It is also necessary to develop radiopharmaceuticals with high specificity and sensitivity for tumors. Over the past three decades, a number of radiopharmaceuticals have been designed and developed to image and identify the unique biochemical properties of tumor tissue. The high expression of FAK in tumors can also be used as early diagnosis, treatment and prognosis evaluation of tumors at the level of radiophar...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D239/48A61K51/04A61P35/00A61K101/02
CPCA61K51/0459A61P35/00C07B2200/05C07D239/48C07D401/12
Inventor 张华北齐月恒
Owner BEIJING NORMAL UNIVERSITY
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