Application of IRAK4 inhibitor in treatment of ALI/ARDS
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A technology of inhibitors and uses, applied in the field of medical use, can solve problems such as no IRAK4 inhibitors yet
Pending Publication Date: 2021-10-22
SHANGHAI LEADINGTAC PHARM CO LTD
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CA-4948, BAY-1834845, BAY-1830839, BMS-986126, and PF-06650833 are several IRAK4 inhibitors currently in the clinical development stage, which inhibit IRAK4-mediated downstream signaling pathways by inhibiting IRAK4 kinase activity. The activity of inflammato
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Embodiment 1
[1365] Example 1.N-[2-(3-hydroxyl-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoro Preparation of methyl) pyridine-2-amide (146) (synthesized with reference to the preparation method of Example 11 of patent CN107406416)
[1366]
[1367] Step 1: Preparation of methyl 5-nitro-1H-indazole-6carboxylate (Int-2)
[1368]
[1369] In a three-necked flask, dissolve 4.60g (26.1mmol) of 1H-indazole-6-carboxylic acid methyl ester in 120ml of sulfuric acid (96%), and cool to minus 15°C. Cooled nitrating acid (10 ml 96% sulfuric acid in 5 ml 65% nitric acid) was added dropwise. After the dropwise addition, the reaction solution continued to stir for 1 h (internal temperature -13° C.). The reaction solution was added to ice, the precipitate was filtered out with suction, washed with water, and dried in a drying oven at 50°C at low temperature. 5.10 g of the target compound was obtained.
[1370] MS(ESI): m / z=222.1[M+H] + .
[1371] Step 2: Preparation of 5-...
Embodiment 2
[1387] Example 2. (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-( Preparation of 2-methylpyridin-4-yl)oxazole-4-carboxamide (41)
[1388]
[1389] Step 1: Preparation of 6-chloro-2-nitropyridin-3-ol (Int-7)
[1390]
[1391] 11 g (85.27 mmol) of 6-chloropyridin-3-ol was dissolved in 50 ml of sulfuric acid and cooled to 0°C in an ice-salt bath, and 10 ml of nitric acid (65%) solution was slowly added dropwise while maintaining the reaction temperature below 10°C. After the dropwise addition, continue to stir and react for 3 hours, then pour into 400ml of ice water, stir for 30 minutes, filter, wash the filter cake with water three times, collect and dry the filter cake to obtain 10.43 g of the target compound.
[1392] MS(ESI): m / z=175.1[M-H] + .
[1393] Step 2: Preparation of 2-amino-6-chloropyridin-3-ol (Int-8)
[1394]
[1395] Dissolve 10.43g (0.06mol) of 6-chloro-2-nitropyridin-3-ol in 100ml of ethanol, then add 33.6g (0.6mol) ...
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Abstract
The invention belongs to the field of medicines, and particularly relates to a novel application of an IRAK4 small-molecule inhibitor in preparation of medicines for treating or preventing acute lung injury or acute respiratory distress syndrome and related diseases thereof. Experiments prove that the IRAK4 small-molecule inhibitor can obviously reduce the generation of inflammatory factors and prevent infiltration of eosinophilic granulocytes, neutrophil granulocytes and lymphocytes, has good prevention and treatment effects on LPS-induced acute lung injury or acute respiratory distress syndrome, and can be used for preparing medicines for preventing and treating acute lung injury or acute respiratory distress syndrome. The IRAK4 inhibitor is expected to become a new generation of medicine for treating acute lung injury and acute respiratory distress syndrome.
Description
technical field [0001] The invention belongs to the field of medical application, and specifically the invention relates to the application of an IRAK4 inhibitor in the preparation of medicines for preventing or treating ALI / ARDS diseases and related diseases. Background technique [0002] Acute lung injury (ALI) / acute respiratory distress syndrome (ARDS) is an acute progressive hypoxic respiratory failure caused by various pathogenic factors in and out of the lungs other than cardiogenic. ALI / ARDS has the same pathophysiological changes and is two stages of the same disease. ALI represents the early and relatively mild stage of the disease, while ARDS represents the later stage of the more severe disease. Multiple risk factors can induce ALI / ARDS, mainly divided into pulmonary factors (direct factors): such as severe lung infection, aspiration of gastric contents, lung contusion, inhalation of toxic gases, drowning, oxygen toxicity, etc., and extrapulmonary factors (Indire...
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