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Substituted quinazoline compound capable of crossing blood-brain barrier

A compound, the technology of deuterated alkyl, applied in the field of substituted quinazoline compounds, can solve the problems of limited therapeutic effect, etc., to reduce drug resistance, improve tablet intake compliance, good pharmacokinetics and high biological activity Effect

Active Publication Date: 2018-05-25
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), these currently approved drugs cannot achieve effective intracranial doses for the treatment and / or prevention of central nervous system metastases of lung cancer, such as brain metastases, meningeal metastases
About 40-50% of lung cancer patients develop central nervous system metastases. For symptomatic brain metastases, radiotherapy and surgery are still the main means of treatment, but the therapeutic effect is limited

Method used

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  • Substituted quinazoline compound capable of crossing blood-brain barrier
  • Substituted quinazoline compound capable of crossing blood-brain barrier
  • Substituted quinazoline compound capable of crossing blood-brain barrier

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0245] Synthesis of intermediate 5-fluoro-4-methoxy-2-nitrobenzonitrile A6 and 1-bromo-5-fluoro-4-(deuteromethoxy)-2-nitrobenzene C1, the synthetic route is as follows :

[0246] Step 1: To a solution of A1 (2.0 g, 10.5 mmol) and triethylamine (1.3 g, 12.6 mmol) in dichloromethane (10 mL) was added dropwise ethyl chloroformate in dichloromethane (3 mL) at 0 °C Ester (1.4 g, 12.6 mmol) solution. The reaction mixture was stirred at 0 °C for 1 h and allowed to reach room temperature. The reaction mixture was then washed twice with water. The organic layer was dried over magnesium sulfate and evaporated in vacuo to afford product A2 (2.7 g, 100% yield) as a colorless oil.

[0247]Step 2: To a solution of A2 (2.7 g, 10.3 mmol) in concentrated sulfuric acid (4.6 mL) was added dropwise fuming nitric acid (0.73 mL, 15.5 mmol) at 10°C. After 1 hour, the reaction mixture was poured into ice / water and extracted twice with ethyl acetate. The combined organic layers were washed with...

Embodiment 2

[0268] Synthesis of compounds 7, 23 and 25: (R / S)-nitrogen-(3-chloro-2,4-difluorophenyl)-6-{[3,3-difluoro-1-(oxetane Synthesis of alkane-3-yl)piperidin-4-yl]oxyl group}-7-methoxyquinazolin-4-amine (7) and separation into enantiomerically pure ( R)-nitrogen-(3-chloro-2,4-difluorophenyl)-6-{[3,3-difluoro-1-(oxetane-3-yl)piperidin-4-yl ]oxy}-7-methoxyquinazolin-4-amine (23) and (S)-nitrogen-(3-chloro-2,4-difluorophenyl)-6-{[3,3- Difluoro-1-(oxetane-3-yl)piperidin-4-yl]oxy}-7-methoxyquinazolin-4-amine (25), the synthetic route is as follows:

[0269]

[0270] Step 1: A mixture of A9 (90 mg, 0.21 mmol) and 3-chloro-2-,4-difluoroaniline (38 mg, 0.23 mmol) in acetic acid (2 mL) was stirred at 120° C. for 3 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 stirred in hydrochloric ...

Embodiment 3

[0274] Synthesis of Compounds 2, 12 and 14: (R / S)-6-{[3,3-Difluoro-1-(oxetan-3-yl)piperidin-4-yl]oxyl}- Synthesis of nitrogen-(3-ethynyl-2-fluorophenyl)-7-methoxyquinazolin-4-amine 2 and separation into enantiomerically pure (R)-6 by HPLC chiral separation column -{[3,3-Difluoro-1-(oxetane-3-yl)piperidin-4-yl]oxy}-nitrogen-(3-ethynyl-2-fluorophenyl)-7 -Methoxyquinazolin-4-amine (12) and (S)-6-{[3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl] Oxygen)-nitrogen-(3-ethynyl-2-fluorophenyl)-7-methoxyquinazolin-4-amine (14), the synthetic route is as follows:

[0275]

[0276] Step 1: A mixture of A9 (210 mg, 0.48 mmol) and 2-fluoro-3-((trimethylsilyl)ethynyl)aniline (199 mg, 0.96 mmol) in acetic acid (4.2 mL) at 80 °C Stir under nitrogen for 16 hours. 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 obtain a residue, which was purified...

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Abstract

The present invention discloses a substituted quinazoline compound capable of crossing blood-brain barrier, wherein the structure formula of the compound is represented by a formula (I) defined in thespecification. According to the present invention, the substituted quinazoline compound, the derivative and the pharmaceutical salt thereof can unexpectedly cross blood-brain barrier, have the characteristics of drugs used as protein kinase inhibitors, are especially used for medical conditions mediated by the activation mutation forms of epidermal growth factor receptor, and can be used for treating or preventing disorders associated with abnormal protein kinase activity, wherein the disorders comprise cancers, cancer brain metastasis, cancer meningeal metastases, nerve center diseases and the like.

Description

technical field [0001] The present invention relates to novel quinazoline derivatives, their salts, hydrates and their polymorphs; in particular to a substituted quinazoline 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, which tend to occur at the genetic level, such as DNA insertions, deletions or translocations, allow cells to proliferate uncontrollably in some cancers. [0003] Signal transduction is often mediated by certain proteins called kinases. Ki...

Claims

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Application Information

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IPC IPC(8): C07D405/14C07D401/12A61K31/517A61P35/00A61P25/28
CPCC07D401/12C07D405/14C07B2200/07A61P25/28A61P35/00A61P35/04
Inventor 钟卫
Owner WEISHANG (SHANGHAI) BIO PHARMA CO LTD
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