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Heterocyclic ring-containing compound, application thereof and composition containing heterocyclic ring-containing compound

A compound and pharmaceutical technology, which can be applied in the direction of active ingredients of heterocyclic compounds, drug combinations, and medical preparations containing active ingredients, and can solve problems such as single structure.

Pending Publication Date: 2020-10-30
GENEROS BIOPHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem to be solved by the present invention is the defect that the structure of the existing STAT5 inhibitors is relatively single. Therefore, the present invention provides a compound containing a heterocycle, its application and a composition containing it. The structure of this type of compound is Novel, with better STAT5 inhibitory activity

Method used

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  • Heterocyclic ring-containing compound, application thereof and composition containing heterocyclic ring-containing compound
  • Heterocyclic ring-containing compound, application thereof and composition containing heterocyclic ring-containing compound
  • Heterocyclic ring-containing compound, application thereof and composition containing heterocyclic ring-containing compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1211] Example 1.3-(1-propionylpiperidin-4-yl)benzo[d]oxazol-2(3H)-one (P1)

[1212]

[1213] Step 1.1. Synthesis of tert-butyl 4-(2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-1-carboxylate

[1214]

[1215] CH 2 Cl 2 (300 mL) the solution was stirred and NaBH(OAc) was added 3 (32.4g, 151mmol), and stirred at room temperature for 14h, added CH 2 Cl 2 (1000mL) and saturated NaHCO 3 (1500mL) was diluted and the layers were separated. use CH 2 Cl 2 (2*500ml) extract the aqueous layer, wash the combined organic layer with brine, Na 2 SO 4 Dry and remove solvent under reduced pressure. CH 2 Cl 2 (300mL) was diluted, carbonyldiimidazole (18g, 110mmol) was added, stirred for 16h, washed with CH 2 Cl 2 (1L) and 1N HCl (1L), and the layers were separated. use CH 2 Cl 2 (2*500ml) extract the aqueous layer, wash the combined organic layer with brine, Na 2 SO 4 Dry and remove the solvent under reduced pressure. Purification by silica gel column chromatography (PE:EA=1...

Embodiment 2

[1222] Example 2.3-(1-(3,3,3-trifluoropropionyl)piperidin-4-yl)benzo[d]oxazol-2(3H)-one (P2)

[1223]

[1224] Step 2.1. 3-(1-(3,3,3-trifluoropropionyl)piperidin-4-yl)benzo[d]oxazol-2(3H)-one (P2)

[1225]

[1226] To DCM (15ml) was added 3-(piperidin-4-yl)benzo[d]oxazol-2(3H)-one (1.5g, 6.88mmol) and K 2 CO 3 (1.99g, 13.8mmol), 3,3,3-trifluoropropyl chloride (1.05g, 11.4mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 4 hours, the reaction mixture was filtered, and the filtrate was concentrated. The product was purified by silica gel column chromatography (PE:EA:DCM=1:1:1) to obtain the desired white solid (1.75 g, yield 77%). 1 H NMR (400MHz, CDCl 3 ):δ7.23(dd,J=5.2,1.2Hz,1H),7.21-7.12(m,2H),7.04(dd,J=8.0,1.2Hz,1H),4.94-4.89(m,1H), 4.44-4.37(m,1H),4.01-3.97(m,1H),3.38-3.27(m,3H),2.78-2.70(m,1H),2.37-2.23(m,2H),2.04-1.98(m ,2H).MS(ESI)m / z 329.1[M+H] + .

Embodiment 3

[1227] Example 3.3-(1-(2-(pyridin-4-yl)acetyl)piperidin-4-yl)benzo[d]oxazol-2(3H)-one (P3)

[1228]

[1229] Step 3.1. Synthesis of 3-(1-(2-(pyridin-4-yl)acetyl)piperidin-4-yl)benzo[d]oxazol-2(3H)-one (P3)

[1230]

[1231] In 3-(piperidin-4-yl)benzo[d]oxazol-2(3H)-one (1.5g, 6.88mmol) and K 2 CO 3 (2.8g, 20.6mmol) in DCM (20ml), 2-(pyridin-4-yl)acetyl chloride hydrochloride (2.0g, 10.3mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 4 hours, the reaction mixture was filtered, and the filtrate was concentrated. Using high performance liquid chromatography (20-95% CH 3 CN aqueous solution) to obtain a white solid (1.07 g, yield 46%). 1 H NMR (400MHz, DMSO-d 6 ): δ8.51(d, J=6.0Hz, 2H), 7.35-7.29(m, 4H), 7.23-7.19(m, 1H), 7.15-7.11(m, 1H), 4.57(d, J=13.2 Hz, 1H), 4.43-4.35(m, 1H), 4.09(d, J=14.4Hz, 1H), 3.85(s, 2H), 3.23-3.16(m, 1H), 2.76-2.69(m, 1H) ,2.09-1.98(m,2H),1.86-1.81(m,2H).MS(ESI)m / z 338.0[M+H] + .

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Abstract

The invention discloses a heterocyclic ring-containing compound, application thereof and a composition containing the heterocyclic ring-containing compound. The present invention provides a compound represented by a formula XII or a pharmaceutically acceptable salt thereof. The compound is novel in structure and has relatively good STAT5 inhibitory activity.

Description

technical field [0001] The present invention relates to a compound containing heterocycle, its application and composition containing it. Background technique [0002] Rheumatoid arthritis is a chronic systemic autoimmune disease characterized by joint synovial inflammation. Its incidence is about 1% of the total adults. Its main manifestations are symmetrical multiple recurrent arthritis, and the small joints of the hands and feet are most likely to be involved. Early or acute onset joints are mostly red, swollen, hot, painful and movement disorder; late stage can lead to joint destruction, stiffness, deformity and loss of function, as well as osteoporosis and skeletal muscle atrophy. Throughout the course of the disease, it may be accompanied by fever, anemia, weight loss, vasculitis, subcutaneous nodules and other lesions, and may also involve multiple organs throughout the body. It is a disease with a high disability rate and significantly increases the patient's morta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/04C07D413/14C07D471/04C07D401/14C07D401/04C07D403/04C07D491/048C07D495/04C07D487/04C07D471/10C07D211/58C07D211/44C07D235/26C07D471/06C07D417/04C07D209/46A61K31/454A61K31/4545A61K31/4375A61K31/4184A61K31/5377A61K31/438A61K31/445A61K31/5513A61K31/55A61K31/4035A61K31/4725A61K31/4709A61K31/498A61P19/02
CPCC07D413/04C07D413/14C07D471/04C07D401/14C07D401/04C07D403/04C07D491/048C07D495/04C07D487/04C07D471/10C07D211/58C07D211/44C07D235/26C07D471/06C07D417/04C07D209/46A61P19/02
Inventor 傅新元卢涔宾刘新宇陆费成晨周轶
Owner GENEROS BIOPHARMA LTD
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