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Novel small molecule inhibitor of insulin-like growth factor-1 receptor and application of novel small molecule inhibitor

A technology of small molecule inhibitors and growth factors, applied in medical preparations containing active ingredients, organic active ingredients, organic chemistry, etc., can solve problems such as poor effect and difficulty penetrating the blood-brain barrier, and achieve long half-life, Effect of good blood-brain barrier permeability

Inactive Publication Date: 2020-12-25
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although picropodophyllotoxin has high specificity and few side effects, our research in mice shows that it metabolizes quickly in the body and does not easily pass through the blood-brain barrier, which may be an important reason for its poor effect in human clinical trials

Method used

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  • Novel small molecule inhibitor of insulin-like growth factor-1 receptor and application of novel small molecule inhibitor
  • Novel small molecule inhibitor of insulin-like growth factor-1 receptor and application of novel small molecule inhibitor
  • Novel small molecule inhibitor of insulin-like growth factor-1 receptor and application of novel small molecule inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1, relative-(5R,5aS,8aR,9R)-2,2-difluoro-9-hydroxyl-5-(3,4,5-trimethoxyphenyl)-5,8,8a,9 -Tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]-dioxan-6(5aH)-one (compound 1)

[0047]

[0048] Step 1), synthesis of 4-vinyldihydrofuran-2(3H)-one (intermediate 1.1):

[0049] To a mixture of 2-butene-1,4-diol (206.4g, 2.34mol, 1.0eq) and triethylorthoacetate (546.7g, 3.4mol, 1.4eq) was added catalytic hydroquinone (54.00g , 0.49mol, 0.2eq), the mixture was heated to 120°C. Ethanol was continued to be distilled off until no more ethanol was produced, the reaction temperature was raised to 150°C and the reaction mixture was stirred for 48 hours. Intermediate 1.1 was collected by vacuum distillation (70-75 °C, 2-3 mmHg) as a colorless oil (170.0 g, 65% yield). 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), 5.75-5.84(m, 1H).

[0050] Step 2), re...

Embodiment 2

[0062] Example 2, relative-(5R,5aS,8aR,9R)-2,2-difluoro-8-oxa-9-(3,4,5-trimethoxyphenyl)-5,5a,6, 8,8a,9-Hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]-dioxan-5-yl acetate (compound 2)

[0063]

[0064] Compound 1 (1.15g, 2.55mmol, 1.0eq) and dichloromethane (30ml) were continuously stirred and mixed, and Et 3 N (770mg, 7.6mmol, 3.0eq) and DMAP (310mg, 2.55mmol, 1.0eq), then AcCl (400mg, 5.1mmol, 2.0eq) was added under ice bath, and the mixture was stirred at ambient temperature for 12 hours. LiAl(OtBu) was added dropwise 3 (200ml, 197mmol, 2.0eq), then gradually heated to ambient temperature overnight. React with saturated NH 4 Quenched with Cl, the aqueous phase was further extracted with dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The residue was recrystallized from petroleum ether / ethyl acetate to obtain compound 2 (810 mg, yield 65%) as a white solid. 1 HNMR (400MHz, CDCl 3 )δ(ppm)7.02(s,1H),...

Embodiment 3

[0065] Example 3, relative-(5R,5aS,8aR,9R)-2,2,9-trifluoro-5-(3,4,5-trimethoxyphenyl)-5,8,8a,9-tetrahydrofuran And[3',4':6,7]naphtho[2,3-d][1,3]-dioxan-6(5aH)-one (Compound 3)

[0066]

[0067] Compound 1 (700mg, 1.60mmol, 1.0eq) and dichloromethane (20ml) were continuously stirred and mixed, diethylaminosulfur trifluoride (520mg, 3.20mmol, 2.0eq) was added dropwise, and the mixture was stirred at ambient temperature for 12 Hour. React with saturated NaHCO 3 Quenched and stirring was continued for 30 minutes. After separation of the organic phase, the aqueous phase was further extracted with dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (200-300 silica gel, dichloromethane:methanol=100 / 1-50 / 1) to obtain compound 3 (130 mg, yield 18%) 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(d,J=50.8Hz,1H...

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Abstract

The invention provides a novel small-molecule inhibitor of an insulin-like growth factor 1 receptor and application of the novel small-molecule inhibitor. The novel small-molecule inhibitor is a derivative of picropodophyllotoxin; fluorine atoms are used for replacing hydrogen atoms at two positions of the left side of picropodophyllotoxin, so that the capacity of molecules penetrating through a blood-brain barrier is improved; meanwhile, deuterium atoms are used for replacing hydrogen atoms, so that the half-life period of the molecules in an organism can be effectively prolonged. The small-molecule inhibitor can be used for preparing drugs for preventing and treating cancers. Compared with picropodophyllotoxin in the clinical test stage at present, the small-molecule inhibitor has higherblood-brain barrier permeability and longer in-vivo half-life while maintaining the action mechanism and biochemical characteristics of picropodophyllotoxin. When used alone, the small-molecule inhibitor can effectively inhibit proliferation and brain metastasis of various tumors, and can be synergistically combined with other anti-cancer drugs, so that proliferation of tumor cells is efficientlyinhibited, and the lifetime is remarkably prolonged.

Description

technical field [0001] The present invention relates to a new compound and a novel substituted picropodophyllotoxin derivative for inhibiting insulin-like growth factor-1 receptor IGF-1R for treating IGF-1R-dependent diseases, especially cancer. Background technique [0002] The occurrence of primary nervous system malignant tumors is increasing year by year. Glioma refers to brain tumors derived from glial cells, including astrocytic tumors, oligodendroglial tumors and ependymal tumors (Muir CS, Storm et al. al., Cancer Surv,19-20:369-392,1994; Louis DN et al., Acta Neuropathol,131:803-820,2016), is the most common type of primary tumor. Chemotherapy represented by temozolomide is the current gold standard for the treatment of high-grade glioma, but it can only prolong the survival of patients very limitedly. Targeted drug therapy with better efficacy has not been successful in glioma so far, because most targeted drugs cannot penetrate the blood-brain barrier. It has bee...

Claims

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Application Information

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IPC IPC(8): C07D493/04A61K31/365A61P35/00
CPCC07D493/04A61P35/00
Inventor 王英杰康博
Owner ZHEJIANG UNIV
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