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Insulin-like growth factor-1 receptor tyrosine kinase inhibitor and uses thereof

A use, halogen technology, applied in the field of medicinal chemistry, can solve problems such as poor BBB permeability

Active Publication Date: 2020-01-10
PHARMABLOCK SCIENCES (NANJING) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although PPP has good IGF-1R inhibitory activity and low toxicity, it is found in the study that its BBB permeability is not good, and it is difficult to play a role in brain gliomas, such as astrocytoma

Method used

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  • Insulin-like growth factor-1 receptor tyrosine kinase inhibitor and uses thereof
  • Insulin-like growth factor-1 receptor tyrosine kinase inhibitor and uses thereof
  • Insulin-like growth factor-1 receptor tyrosine kinase inhibitor and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Compound 1: Rel-(5R,5aS,8aR,9R)-2,2-difluoro-9-hydroxy-5-(3,4,5-trimethoxyphenyl)-5, 8,8a,9-Tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one

[0064]

[0065] Synthesis of Intermediate 1.1: 4-vinyldihydrofuran-2(3H)-one

[0066]

[0067] 2-Butene-1,4-diol (206.4 g, 2.34 mol, 1.0 e.q.) was dissolved in triethyl orthoacetate (546.7 g, 3.4 mol, 1.4 e.q.) with stirring, and catalytic hydroquinone (54.00 g , 0.49mol, 0.2e.q.), and the resulting mixture was heated to 120°C. The ethanol formed in situ is continuously distilled off until no more ethanol is produced. The temperature was raised to 150 °C and the reaction mixture was stirred for an additional 48 hours. Intermediate 1.1 was collected by vacuum distillation (70-75°C, 2-3 mmHg) as a colorless oil (170.0 g, yield 65%). 1 HNMR (400MHz, CDCl 3 )δ (ppm) 2.36 (dd, J = 17.4Hz, 8.7Hz, 1H), 2.69 (dd, J = 17.7Hz, 8.4Hz, 1H), 3.19-3.29 (m, 1H), 4.01-4.14 (m, 1H), 4.43-4.47(m, 1H), 5.17-5.23(m, 2H)...

Embodiment 2

[0087] Compound 2: Rel-(5R,5aR,8aS,9R)-2,2-difluoro-8-oxo-9-(3,4,5-trimethoxyphenyl)-5, 5a,6,8,8a,9-Hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl Acetate

[0088]

[0089] Compound 1 (1.15 g, 2.55 mmol, 1.0 e.q.) was dissolved in DCM (30 mL) with stirring, Et 3 N (770mg, 7.6mmol, 3.0e.q.), 4-dimethylaminopyridine (310mg, 2.55mmol, 1.0e.q.), acetyl chloride (400mg, 5.1mmol, 2.0e.q.) was added at ice-water bath temperature, and the resulting mixture was Stir at ambient temperature for 12 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride, and the aqueous phase was extracted with additional DCM. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The obtained crude product was recrystallized from PE / EtOAc to afford compound 2 (810 mg, 65% yield) as a white solid. 1 HNMR (400MHz, CDCl3) δ (ppm) 7.02 (s, 1H), 6.76 (s, 1H), 6.41 (s, 2H), 5.81 (d, J = 6.3Hz, 1H), 4.48-4.34 (m, ...

Embodiment 3

[0091] Compound 3: Rel-(5R,5aS,8aR,9S)-2,2,9-trifluoro-5-(3,4,5-trimethoxyphenyl)-5,8,8a, 9-Tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one

[0092]

[0093] Compound 1 (700 mg, 1.60 mmol, 1.0 e.q.) was dissolved in DCM (20 mL) with stirring, diethylaminosulfur trifluoride (520 mg, 3.20 mmol, 2.0 e.q.) was added dropwise, and the resulting mixture was stirred at room temperature 12 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and stirred for an additional 30 minutes. The organic phase was separated and the aqueous phase was extracted with additional DCM. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography (200-300 mesh silica gel, DCM / MeOH=100 / 1-50 / 1) gave compound 3 (130 mg, 18% yield) as a white solid. 1 HNMR (400MHz, CDCl 3 )δ(ppm)7.27(s,1H),6.66(s,1H),6.44(s,2H),5.49-5.34(m,1H),4.60-4.47(m,2H),4.20(d,J= 5.0Hz, 1H), 3...

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Abstract

The invention discloses a class of compounds capable of being used as an insulin-like growth factor-1 receptor tyrosine kinase inhibitor, and a preparation method thereof, a pharmaceutical compositioncontaining the compound, and applications of the pharmaceutical composition in prevention or treatment of tumors, especially brain glioma.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an insulin-like growth factor-1 receptor tyrosine kinase inhibitor and its application. Background technique [0002] Insulin-like growth factor-1 receptor (IGF-1R) is a member of the tyrosine protein kinase family, its signaling pathway is closely related to tumorigenesis, and plays an important role in the proliferation of malignant cells, resistance to apoptosis and transformation . [0003] Cyclolignan podophyllotoxin (Podophyllotoxin) is a natural product extracted from the plant Podophyllum of the Berberaceae, which can bind to β-tubulin to cause the inhibition of microtubule aggregation and the pause of mitosis, but its toxic side effects hinder Its development in the field of anticancer drugs. [0004] Patent document WO2002102804A shows that the stereoisomer Picropodophyllin (PPP) with a cis structure on the lactone ring of podophyllotoxin has good IGF-1R inhibitory ...

Claims

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Application Information

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IPC IPC(8): C07D493/04A61K31/36A61P35/00
CPCC07D493/04A61P35/00
Inventor 李进
Owner PHARMABLOCK SCIENCES (NANJING) INC
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