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5-substituted difluoro piperidine compound capable of penetrating blood brain barrier

A compound and drug technology, applied in the field of hydrates and their polymorphs, 5-substituted difluoropiperidine derivatives, and its salts, can solve problems such as limited therapeutic effects, reduce drug resistance, and improve tablet intake compliance Sexuality, good pharmacokinetics and high biological activity

Active Publication Date: 2019-10-22
WEISHANG (SHANGHAI) BIO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the existence of the blood-brain barrier (BBB), no drug targeting VEGFR2 is effective for glioma. Radiation therapy, chemotherapy and surgery are still the main means of treatment, but the therapeutic effect is limited

Method used

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  • 5-substituted difluoro piperidine compound capable of penetrating blood brain barrier
  • 5-substituted difluoro piperidine compound capable of penetrating blood brain barrier
  • 5-substituted difluoro piperidine compound capable of penetrating blood brain barrier

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0310] The synthesis of intermediate 2,6-difluoro-4-deuteromethoxybenzonitrile A2, the synthetic route is as follows:

[0311]

[0312] Step: Add deuterated methanol (698 mg, 19.34 mmol), azodicarbonyldipiperidine (4.88 g, 19.34 mmol) and tributylphosphine (3.91 g, 19.34 mmol). The reaction mixture was stirred at 65 °C for 3 hours and cooled to room temperature. The reaction mixture was filtered, concentrated, and purified by silica gel column (n-hexane / ethyl acetate=20:1) to obtain product A2 (500 mg, 45% yield) as a pale yellow solid. LC-MS: (ESI) m / z=173 (M+H) + .

[0313] Synthesis of intermediate 2,6-difluoro-4-ethoxybenzonitrile A3, the synthetic route is as follows:

[0314]

[0315] To a solution of A1 (7.0 g, 45.2 mmol) in N,N-dimethylformamide (100 mL) was added iodoethane (14 g, 90.3 mmol) and potassium carbonate (12.46 g, 90.3 mmol). The reaction mixture was stirred at 60 °C for 2 hours and cooled to room temperature. After the reaction mixture was conc...

Embodiment 2

[0334] Synthesis of compounds 1, 17 and 33: ((R / S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-4-((4-fluoro- Synthesis of 2-methyl-1H-indol-5-yl)oxy)-7-methoxyquinazoline (1) and separation into enantiomerically pure (R)- 5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy )-7-methoxyquinazoline 1(17) and (S)-5-((3,3-difluoro-1-methylpiperidin-4 base)oxy)-4-((4- Fluoro-2-methyl-1H-indol-5-yl)oxy)-7-methoxyquinazoline 1(33), the synthetic route is as follows:

[0335]

[0336] Step 1: Add 4-fluoro-2-methyl-1H-indol-5-ol (15 mg, 0.091 mmol) and cesium carbonate (30 mg , 0.091 mmol) was stirred at 70°C for 1 hour under nitrogen protection, cooled to room temperature, added water (20 mL), and extracted with ethyl acetate (20 mL, 3 times). The organic phase was dried over sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column (dichloromethane / methanol=300:1 to 100:1) to give the product 1 as a whit...

Embodiment 3

[0339]Synthesis of compounds 4, 20 and 36: (R / S)-N-(5-chlorobenzo[d][1,3]dioxol-4-yl)-5-((3,3 -Synthesis of -difluoro-1-methylpiperidin-4-yl)oxy)-7-methoxyquinazolin-4-amine (4) and separation into enantiomerically pure (R)-N-(5-chlorobenzo[d][1,3]dioxol-4-yl)-5-((3,3-difluoro-1-methylpiperidine -4-yl)oxy)-7-methoxyquinazolin-4-amine (20) and (S)-N-(5-chlorobenzo[d][1,3]dioxolane En-4-yl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-7-methoxyquinazolin-4-amine (36), synthesized The route is as follows:

[0340]

[0341] Step 1: A mixture of A7 (223 mg, 0.568 mmol) and 5-chlorobenzo[d][1,3]dioxol-4-amine (217 mg, 1.137 mmol) in acetic acid (20 mL) , stirred at 80°C for 16 hours under nitrogen protection. After cooling, it was treated with saturated sodium bicarbonate solution to pH = 8 and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column (dichloromethane / m...

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Abstract

The invention discloses a 5-substituted difluoro piperidine compound capable of penetrating blood brain barrier, wherein the compound has a structural formula represented by a formula (I). According to the present invention, the 5-substituted difluoro piperidine compound, the derivative and the pharmaceutical salt thereof can unexpectedly penetrate blood brain barrier, can have the pharmaceuticalproperties of protein kinase inhibitors, can particularly treat vascular endothelial growth factor receptor 2 or SRC kinase family (FYN)-mediated medical conditions, can further be used for treating or preventing abnormal protein kinase activity related disorders such as cancer, cancer brain metastasis, primary brain cancers such as glioma, malignant glioma, cancer meningeal metastasis, Alzheimer's disease, neurological diseases and the like.

Description

technical field [0001] The present invention relates to novel 5-substituted difluoropiperidine derivatives, salts, hydrates and polymorphs thereof; in particular to a 5-substituted difluoropiperidine compound capable of crossing the blood-brain barrier. Background technique [0002] Biological signal transduction refers to the sending of stimulating or inhibiting signals into cells, and through a series of signal transmissions, biological responses occur in cells. Many signaling pathways and their biological responses have been studied extensively. Distinct defects in signaling pathways have been found to be responsible for many diseases, including various forms of cancer, metabolic disorders, inflammatory diseases, vascular and neuronal diseases. These defects tend to occur at the genetic level, such as overexpression of DNA, insertions, deletions or translocations, or overexpression of proteins, which in some cancers allow cells to proliferate uncontrollably. [0003] Si...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D405/14C07D401/12A61K31/517A61P35/00A61P25/28
CPCC07D401/14C07D405/14C07D401/12A61P35/00A61P25/28A61P25/18
Inventor 钟卫
Owner WEISHANG (SHANGHAI) BIO PHARMA CO LTD
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