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(1H-pyrazolo[3,4-d]pyrimidine)-4-amino derivative and application of same as IDO inhibitor to drug preparation

A pharmaceutical and alkyl technology, applied in the field of 1H-pyrazole[3,4-d]pyrimidine)-4-amino derivatives, can solve the problems of reducing tryptophan concentration, stagnation of synthesis, inhibiting killing effect, etc. Excellent inhibitory effect

Active Publication Date: 2017-07-28
XIHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Under normal circumstances, IDO is expressed at a low level in the body, but most tumor cells will form a high expression of IDO, which converts L-tryptophan into N-formylkynurenine, reducing the color of the cell microenvironment. The concentration of tryptophan makes the synthesis of tryptophan-dependent T cells stagnate in the G1 phase, and the proliferation of T cells is inhibited, thereby inhibiting the killing effect of the body's immune system on tumor tissue

Method used

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  • (1H-pyrazolo[3,4-d]pyrimidine)-4-amino derivative and application of same as IDO inhibitor to drug preparation
  • (1H-pyrazolo[3,4-d]pyrimidine)-4-amino derivative and application of same as IDO inhibitor to drug preparation
  • (1H-pyrazolo[3,4-d]pyrimidine)-4-amino derivative and application of same as IDO inhibitor to drug preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1 Synthesis of intermediate 6-methyl-1H-pyrazol[3,4-d]pyrimidin-4(7H)-one (8b) of the present invention

[0042] The synthetic route is as follows:

[0043]

[0044] Compound (7) (CAS: 5334-31-6, 1.0 g, 7.94 mmol) was added into a mixed solution of glacial acetic acid (6 mL) and polyphosphoric acid (6 mL), and reacted at 120° C. for 7 hours. The reaction solution was cooled to room temperature, poured into 70 mL of water, adjusted to pH 5 with 50% NaOH aqueous solution, a white solid precipitated, filtered, and the filter cake was washed with a large amount of water. Suspend the filter cake in methanol, stir for 10 minutes, filter, and wash the filter cake with 50 mL of ethyl acetate. The filter cake was vacuum-dried under reduced pressure to obtain 887.5 mg of white solid, with a yield of 76%.

Embodiment 2

[0045] Embodiment 2 Preparation of Compound 1a of the present invention

[0046] The synthetic route is as follows:

[0047]

[0048] 8a(CAS:315-30-0) can be purchased directly.

[0049] 1. Synthesis of Compound 9a

[0050] Compound 8a (0.5g, 3.68mmol) was added dropwise into thionyl chloride (15ml) and DMF (1.5mL) under the protection of argon. After the dropwise addition, the temperature was raised to 80° C. for reflux reaction for 2 hours. The reaction solution was cooled to room temperature, slowly poured into 150 mL of vigorously stirred ice water, extracted three times with 100 mL of ethyl acetate, combined the organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and spin-dried to obtain 367 mg of yellow powder 9a, yield 64 %.

[0051] 2. Synthesis of compound 1a

[0052] Compound 9a (0.32mmol) and compound 10a (40.6mg, 0.27mmol) were dissolved in DMF (1.5mL), triethylamine (66.8μL, 0.484mmol) was added, and reacted at 80°C for 4 ho...

Embodiment 3

[0054] Embodiment 3 The preparation of compound 1b of the present invention

[0055]

[0056] Compound 1b was synthesized according to a similar method in Example 2, except that compound 9b was used instead of compound 9a to obtain yellow solid 1b with a yield of 41%.

[0057] 4-((1H-pyrazol[3,4-d]pyrimidin-4-amino)methyl)benzoic acid (1b). 1 H-NMR (400MHz, d 6 -DMSO,ppm):δ14.50(s,1H,br,COOH),13.41(s,1H,pyrazole NH),8.79(m,1H,amino),8.23(s,1H,pyrimidine CH),8.17( s,1H,pyrazole CH),7.91(d,2H,J=7.6Hz,Ar-H2 and Ar-H6),7.46(d,2H,J=7.6Hz,Ar-H3 and Ar-H5),4.82( d,2H,J=5.2Hz,benzyl-CH 2 ).ESI-MS:270.09[M+H].

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Abstract

The invention discloses a (1H-pyrazolo[3,4-d]pyrimidine)-4-amino derivative and a preparation method thereof, and application of the derivative as an IDO inhibitor. The derivative provided by the invention can be used for preventing and / or treating a plurality of diseases, such as Alzheimer's disease, cataract, infections related to cellular immune activation, autoimmune diseases, AIDS, cancers, depression or metabolic disorder of tryptophan.

Description

technical field [0001] The present invention relates to 1H-pyrazol[3,4-d]pyrimidine)-4-amino derivatives, and also relates to their preparation methods and their use as IDO inhibitors. Background technique [0002] Indoleamine 2,3-dioxygenase (Indoleamine 2,3-dioxygenase, IDO) catalyzes the epoxidation and cleavage of indole in indoleamine molecules such as tryptophan, making it catabolized by the kynuric acid pathway. fast enzyme. [0003] IDO plays an important role in tumor immune immunity and tumorigenesis. Under normal circumstances, IDO is expressed at a low level in the body, but most tumor cells will form a high expression of IDO, which converts L-tryptophan into N-formylkynurenine, reducing the color of the cell microenvironment. The concentration of tryptophan makes the synthesis of tryptophan-dependent T cells stagnate in the G1 phase, and the proliferation of T cells is inhibited, thereby inhibiting the killing effect of the body's immune system on tumor tissue...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P25/28A61P37/02A61P31/18A61P35/00A61P25/24A61P27/12A61P31/00
Inventor 钱珊王周玉李国菠杨羚羚张曼王伟何彦颖何涛
Owner XIHUA UNIV