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Pyrrolidine[3,4-d]pyrimidine derivative and preparation method and application thereof

An alkyl and compound technology, applied in the field of pyrrolidine [3], can solve the problems of complex pathogenesis of cancer and difficult treatment.

Active Publication Date: 2012-07-18
SHANGHAI ALLIST PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although with the continuous development of medical technology, cancer treatment methods based on surgery, radiotherapy and chemotherapy have made great progress, but due to the complex mechanism of cancer pathogenesis, the treatment is extremely difficult, so it is necessary to look for small molecules with high efficiency and low toxicity. Anticancer drugs have always been one of the difficulties and hot spots in the field of cancer treatment

Method used

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  • Pyrrolidine[3,4-d]pyrimidine derivative and preparation method and application thereof
  • Pyrrolidine[3,4-d]pyrimidine derivative and preparation method and application thereof
  • Pyrrolidine[3,4-d]pyrimidine derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Example 11-(4-(5-cyclopropyl-1H-pyrazole-3-amino)-6-(4-fluorobenzoyl)-6,7-dihydro-5H-pyrrole[3,4- d] Synthesis of pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide

[0094]

[0095] The title compound was prepared by the following steps.

[0096]1) Synthesis of compound (b):

[0097]

[0098] Dissolve 300g of ethyl glycine hydrochloride in 450ml of water under ice-cooling, add 457ml of 4.7M NaOH (aq), then add 227ml of ethyl acrylate, and stir overnight at room temperature. After the reaction was detected by TLC, the reaction solution was extracted with DCM, and the organic phase was washed with anhydrous Na 2 SO 4 After drying, filtering and rotary evaporation, 513.1 g of the crude yellow oily liquid compound (b) was obtained.

[0099] 2) Synthesis of compound (c):

[0100]

[0101] With 513.1g compound (b), 392g benzyl chloride, 432gK 2 CO 3 , 3.78gNaI dissolved in 1LEtOH, N 2 Under protection, reflux overnight. After the reaction was...

Embodiment 2

[0134] Example 21-(6-acetyl-4-(5-cyclopropyl-1H-pyrazole-3-amino)-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidine-2- Synthesis of -N-(6-fluoro-pyridin-3-yl)pyrrolidine-2-carboxamide

[0135]

[0136] Referring to the synthesis method of compound (j) in Example 1, acetyl chloride was used to replace p-fluorobenzoyl chloride in the reactant prepared from the intermediate, and compound 2 was obtained according to the synthesis steps of the compound in Example 1.

[0137] 1H-NMR (CDCl 3 , 400MHz):

[0138] δ8.34-8.37(m, 1H), 8.13-8.17(m, 1H), 7.17-7.20(m, 1H), 6.23(s, 1H), 4.58-4.69(m, 4H), 3.72-3.78(m , 2H), 3.56-3.64(m, 1H), 2.28-2.33(m, 1H), 2.15(s, 3H), 1.90-2.04(m, 3H), 1.74-1.78(m, 1H), 0.81-0.92 (m, 2H), 0.75-0.79 (m, 1H), 0.65-0.73 (m, 1H);

[0139] ESI (+) m / z: 492

Embodiment 3

[0140] Example 34-(5-cyclopropyl-1H-pyrazole-3-amino)-2-(2-(6-fluoropyridin-3-yl-carbamoyl)pyrrol-1-yl)-5H-pyrrole Synthesis of [3,4-d]pyrimidine-6(7H)-tert-butyl carboxylate

[0141]

[0142] Referring to the synthesis method of compound (j) in Example 1, tert-butyl chloroformate was used to replace p-fluorobenzoyl chloride in the reactant prepared from the intermediate, and compound 3 was obtained according to the synthesis steps of the compound in Example 1.

[0143] 1 H-NMR (CDCl 3 , 400MHz):

[0144]δ8.30-8.34(m, 1H), 8.15-8.17(m, 1H), 7.15-7.20(m, 1H), 6.24(s, 1H), 4.52-4.70(m, 4H), 3.68-3.78(m , 2H), 3.52-3.60(m, 1H), 2.24-2.33(m, 1H), 1.93-2.04(m, 3H), 1.75-1.80(m, 1H), 1.34(s, 9H), 0.81-0.92 (m, 2H), 0.75-0.79 (m, 1H), 0.65-0.73 (m, 1H);

[0145] ESI(+) m / z: 550

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Abstract

The invention discloses a pyrrolidine[3,4-d]pyrimidine derivative and a preparation method and an application thereof. The pyrrolidine[3,4-d]pyrimidine derivative is an inhibitor of a type I insulin-like growth factor receptor (IGF-1R), and has a good IGF-1R inhibiting function and a good cancer cell proliferation inhibiting function, so that the pyrrolidine[3,4-d]pyrimidine derivative can be taken as a therapeutic agent for treating tumors and relevant diseases.

Description

technical field [0001] The invention relates to a pyrrolidine[3,4-d]pyrimidine derivative that inhibits the activity of type I insulin-like growth factor receptor (IGF-1R) and a preparation method thereof, and such Use of derivatives in the treatment of cancer and related diseases. Background technique [0002] Cancer is one of the most serious diseases threatening human life and health. Among various diseases, the mortality rate of malignant tumors ranks second, second only to cardiovascular and cerebrovascular diseases. Although with the continuous development of medical technology, cancer treatment methods based on surgery, radiotherapy and chemotherapy have made great progress, but due to the complex mechanism of cancer pathogenesis, the treatment is extremely difficult, so it is necessary to look for small molecules with high efficiency and low toxicity. Anticancer drugs have always been one of the difficulties and hot spots in the field of cancer treatment today. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P35/00
Inventor 罗会兵郭建辉
Owner SHANGHAI ALLIST PHARM CO LTD
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