1, 2, 3-triazolopyrimidine compound and preparation method and application thereof

A compound, C1-C4 technology, applied in the direction of organic chemistry, drug combination, pharmaceutical formulation, etc., can solve the problem of lack of similar compounds and so on

A compound, C1-C4 technology, applied in the direction of organic chemistry, drug combination, pharmaceutical formulation, etc., can solve the problem of lack of similar compounds and so on

CN113549080AActive Publication Date: 2021-10-26INST OF RADIATION MEDICINE CHINESE ACADEMY OF MEDICAL SCI +1
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  • 1, 2, 3-triazolopyrimidine compound and preparation method and application thereof
  • 1, 2, 3-triazolopyrimidine compound and preparation method and application thereof
  • 1, 2, 3-triazolopyrimidine compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1 3-(3,5-dichloro-4-(4-chlorobenzoyl)benzyl)-3,6-dihydro-7H-[1,2,3]triazolo[4,5 -d] pyrimidin-7-one (B)

[0047]

[0048] Under nitrogen protection, carboxyamidotriazole (640 mg, 1.51 mmol), p-toluenesulfonic acid monohydrate (143.34 mg, 0.76 mmol) and trimethyl orthoformate (1602.4 mg, 15.1 mmol) were added into THF. The reaction solution was stirred at 90°C for 6 hours. Stop the reaction, cool to room temperature, add 5 mL of ethyl acetate, wash with water three times, dry the ethyl acetate layer with anhydrous sodium sulfate, filter, evaporate to dryness under reduced pressure, and the residue is separated by column chromatography (eluent petroleum ether: ethyl acetate 1:1), a white solid (0.498g, 76.2%) was obtained. 1 H NMR (400MHz, DMSO-d 6 ) δ 12.74 (s, 1H), 8.32 (s, 1H), 7.76 (s, 2H), 7.67 (s, 2H), 7.63 (s, 2H), 5.89 (s, 2H).

Embodiment 2

[0049] Example 2 (4-chlorophenyl) (2,6-dichloro-4-((7-(propylamino)-3H-[1,2,3]triazolyl[4,5-d]pyrimidine- 3-yl)methyl)phenyl)methanone (C1)

[0050]

[0051] Under nitrogen protection, 3-(3,5-dichloro-4-(4-chlorobenzoyl)benzyl)-3,6-dihydro-7H-[1,2,3]triazolo[ 4,5-d]pyrimidin-7-one (200mg, 0.46mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (265.5mg, 0.60mmol) and phenylhexafluorophosphate Triazol-1-oxytris(dimethylamino)phosphorus (106.6 mg, 0.70 mmol) was added to acetonitrile. The reaction was stirred at room temperature for 12 hours. The reaction was stopped, and acetonitrile was distilled off under reduced pressure. Add 5 mL of ethyl acetate, wash with water three times, dry the ethyl acetate layer with anhydrous sodium sulfate, filter, evaporate to dryness under reduced pressure, and separate the residue by column chromatography (eluent petroleum ether: ethyl acetate 2:1) , to obtain a white solid (0.160 g, 73.1%). 1 HNMR (400MHz, DMSO-d 6 )δ9.11(t, J=5.8Hz, 1H), 8.43(...

Embodiment 3

[0052] The synthesis of embodiment 3 compounds

[0053] With reference to the method of embodiment 2, prepare following formula compound:

[0054]

[0055] (4-Chlorophenyl)(2,6-dichloro-4-((7-(isopropylamino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)methyl)phenyl)methanone . NMR data: 1 H NMR (400MHz, DMSO-d 6 )δ8.96(d, J=8.0Hz, 1H), 8.43(s, 1H), 7.77(d, J=8.6Hz, 2H), 7.65(d, J=7.9Hz, 4H), 5.90(s, 2H), 4.53 (dt, 1H), 1.28 (dd, J=19.1, 6.5Hz, 6H).

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Abstract

The invention discloses a compound and a preparation method thereof, wherein the compound is shown as a formula I and can inhibit secretion of inflammasome nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) and interleukin-1beta (IL-1beta). ELISA experiments show that the compound can significantly inhibit the activity of NLRP3 and reduce the expression of NLRP3 downstream inflammatory factors IL-1beta. The compound shown in the formula I is expected to become a novel anti-inflammatory drug and an autoimmune disease treatment drug.

Description

technical field [0001] The invention belongs to the field of medical technology, and relates to a preparation method and application of a class of 1,2,3-triazolopyrimidine small molecule compounds, in particular to a novel nucleotide binding oligomerization inhibitor capable of inhibiting inflammasomes Small-molecule drugs for domain-like receptor protein 3 (NLRP3) and interleukin-1β (IL-1β), methods for preparing the compound, and the compound as an inflammasome nucleotide-binding oligomerization domain-like receptor Application of body protein inhibitor or interleukin-1β inhibitor drug in preparation of anti-inflammatory drug and autoimmune disease drug. Background technique [0002] The following background introduction related to the present invention is used to help the understanding of the present invention, but should not be considered as the prior art of the present invention. All cited publications are incorporated by reference in full. [0003] It is well known t...

Claims

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Application Information

Patent Timeline
26 Oct 2021
Publication
CN113549080A
IPC
C07D487/04; A61P35/00; A61P37/00; A61P29/00; A61K31/519
CPC
C07D487/04; A61P35/00; A61P37/00; A61P29/00; Y02A50/30
Inventors
李祎亮; 朱蕾