A class of compounds targeting FAK, labels, and preparation methods and applications of compounds and labels

A compound and targeted technology, applied in the field of compounds

Inactive Publication Date: 2017-06-30
BEIJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The present invention designs and synthesizes novel 5-chloro-1,3-pyrimidines and 1,3,5-triazine tumor growth inhibitors targeting FAK; in addition, as far as we know, until now, in In terms of research on small-molecule drugs targeting FAK, people have

Method used

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  • A class of compounds targeting FAK, labels, and preparation methods and applications of compounds and labels
  • A class of compounds targeting FAK, labels, and preparation methods and applications of compounds and labels
  • A class of compounds targeting FAK, labels, and preparation methods and applications of compounds and labels

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] Example 1. [ 19 F] TM-2, [ 18 F]Organic synthesis of the labeled precursor IM2-2, IM3-2 and IM4-2 of TM-2

[0096] The synthetic route is as follows:

[0097]

[0098]

[0099] Specific steps:

[0100] Synthesis of II-01

[0101] Add 2-amino-N-methylbenzamide (1.53g, 10mmol), potassium carbonate (2.07g, 15mmol), DMF (15mL) in sequence to a 100mL reaction flask, and add 2,4,5-trichloropyrimidine under stirring (1.85 g, 10 mmol). The reaction solution was stirred at 75° C. for 5 h, the reaction solution was poured into water, solids were precipitated, and the filter cake was collected by suction filtration. The filter cake was slurried with 50% acetonitrile-water, and after drying, 2 g of light yellow solid II-01 was obtained, with a yield of 67%; 1 H NMR (500MHz, DMSO-d 6 ,δppm):12.18(s,1H),8.84(s,1H),8.52(d,J=10.5Hz,1H),8.46(s,1H),7.79(d,J=10.0Hz,1H),7.59 (t,J=10.0Hz,1H),7.21(t,J=9.5Hz,1H),2.81(s,3H).

[0102] Synthesis of II-02

[0103]In the reaction f...

Embodiment 2

[0121] Example 2. [ 19 F] TM-1, [ 18 F] Organic Synthesis of Labeled Precursor IM2-1, IM3-1 and IM4-1 of TM-1

[0122] The synthetic route is as follows:

[0123]

[0124] Specific steps:

[0125] [ 19 F] Synthesis of TM-1

[0126] In the 100mL reaction bottle, add the [ 19 F] TM-2 (200mg, 1eq), MeOH (10mL), 38% formaldehyde aqueous solution (0.5mL), slowly add NaBH in batches under stirring in an ice bath 4 (78mg, 5eq). After the addition, continue to stir in ice bath for 0.5h. Add water, extract with ethyl acetate, dry the organic layer, concentrate and purify by column chromatography (DCM / MeOH=10 / 1) to obtain the target compound as a yellow solid [ 19 F] TM-1 (135mg, Yield: 66%); 1 H NMR (500MHz, DMSO-d 6 ,δppm):11.57(s,1H),8.70(d,J=5.0Hz,1H),8.61(d,J=10.0Hz,1H),8.07(s,1H),8.02(s,1H),7.67 (d, J=15.0Hz, 1H), 7.35(d, J=10.0Hz, 1H), 7.27(t, J=9.5Hz, 1H), 7.05(t, J=5.0Hz, 1H), 6.25(s ,1H),6.14-6.16(m,1H),4.71(t,J=5.0Hz,1H),4.59(t,J=5.0Hz,1H),4.27(t,J=5.0Hz,1H),4....

Embodiment 3

[0133] Example 3. [ 19 F] TM-3, [ 18 F] Organic Synthesis of Labeled Precursor IM2-3 of TM-3, Organic Synthesis of IM3-3 and IM4-3

[0134] The synthetic route is as follows:

[0135]

[0136] Specific steps:

[0137] Preparation of compound 2

[0138] Add 1 (5g, 1eq), acetonitrile (30mL), and 3-(dimethylamino)pyrrolidine (5.4g, 1.5eq) to a 100mL reaction flask in sequence, and reflux at 85°C for 5h. After the reaction is complete as monitored by TLC, concentrate directly to remove The solvent was acetonitrile, and the residue was purified by column chromatography (PE / ethyl acetate=2 / 1) to obtain the target compound 2 (6.3 g, Yield: 79%) as a yellow solid; 1 H NMR (500MHz, DMSO-d 6 ,δppm):12.11(brs,1H),7.88(d,J=12.0Hz,1H),6.33(dd,J=12.0Hz,2.5Hz,1H),6.05-6.07(m,1H),3.53-3.65 (m,2H),3.25-3.37(m,1H),3.16(t,J=10.5Hz,1H),2.76-2.83(m,1H),2.25(s,6H),2.14-2.17(m,1H ),1.77-1.84(m,1H).

[0139] Preparation of compound 3

[0140] Add 2 (6g, 1eq), DMF (15mL), 2-bromoethanol (5...

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Abstract

The present invention provides a class of compounds targeting FAK, wherein the structure is represented by the following formula (I), X is an N atom or a Cl-substituted C atom, R1 is -OH, -O-CH2-CH2-OH or -O-CH2-CH2-F, and R2 is methylamino or dimethylamino. The present invention further provides a class of radioactively labeled compounds targeting FAK. According to the present invention, the compounds have excellent in vitro FAK kinase activity inhibition effects, and the radioactive labels have ideal biodistribution in rice bearing S180 tumor. The present invention further provides preparation methods of the compounds and the radioactive labels, and applications in preparation of antitumor drugs. The formula (I) is defined in the specification.

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] Tumor is one of the major diseases that endanger human health and life, and the early diagnosis and individualized treatment of tumor have become an important focus of radiopharmaceutical research. Focal Adhesion Kinase (FAK) is involved in many aspects of tumorigenesis and development, and participates in various biological behaviors such as tumor cell adhesion, invasion, migration, proliferation and apoptosis. FAK is overexpressed in almost all tumor cells, so the expression level of FAK can be used as an indicator for early diagnosis, treatment and prognosis evaluation of tumors, and is an important target for tumor diagnosis and treatment. [0003] People have developed a variety of small molecule FAK inhibitors,...

Claims

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Application Information

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IPC IPC(8): C07D403/12A61K31/506A61K31/53A61P35/00A61K51/04A61K101/02
CPCY02P20/55C07D403/12A61K51/0459A61K51/0461
Inventor 张华北方煜王大伟齐月恒刘建萍高航
Owner BEIJING NORMAL UNIVERSITY
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