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Proteolysis targeting chimera, and pharmaceutical composition and application thereof

A technology of proteolysis and proteolysis, which is applied in the field of proteolysis-targeted chimera and its pharmaceutical composition, can solve the problems of low treatment efficiency, limited reports, and large dosage, achieve good treatment effect and reduce the level of positive cells Effect

Active Publication Date: 2021-10-22
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The first generation of FLT3-ITD inhibitors, such as Dovitinib, has been used in many clinical studies. However, the evaluation of clinical studies found that Dovitinib has the defects of high dosage and low treatment efficiency.
Although the treatment efficiency of the second-generation FLT3-ITD inhibitors such as Quizartinib has been significantly improved, drug resistance problems have emerged
However, there are very limited reports on GPCR degradation (e.g., FLT3)

Method used

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  • Proteolysis targeting chimera, and pharmaceutical composition and application thereof
  • Proteolysis targeting chimera, and pharmaceutical composition and application thereof
  • Proteolysis targeting chimera, and pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1: the synthesis of compound 1 and 2

[0026] The synthetic route of compound 1 (n=4), 2 (n=5) and 14 (n=6) is as follows:

[0027]

[0028] The specific preparation steps of intermediate 4 in the technical route are: dissolving 5-fluoro-2-nitroaniline (4.68g, 30.0mmol) in dry 1-methyl-2-pyrrolidone (NMP, 150mL), and then Triethylamine (10.4 mL, 75.0 mmol) and 1-tert-butoxycarbonylpiperazine (6.15 g, 33.0 mmol) were added, and the mixture was heated to 110° C. for 15 h. The reaction solution was cooled to room temperature, poured into 150 mL of water, and a yellow precipitate appeared. Filter through a glass funnel under reduced pressure, and wash the filter cake twice with ether. The filter cake was collected and dried under vacuum to give compound 4 as a yellow solid (7.93 g, 82%).

[0029] Intermediate 4 was detected, and the detection data was: M.p.244.2-245.1℃; IR(KBr):3468,3335,2974,1676,1656,1618,1566,1474,1424,1370,1246,1222,1170,1120 ,1038cm ...

Embodiment 2

[0045] Example 2: Synthesis of Compound 19a-i

[0046] The synthetic route of compound 19a-i is as follows:

[0047]

[0048] The specific preparation steps of intermediate 18a in the technical route are: add intermediate 15 (273mg, 1.00mmol) to dry tetrahydrofuran (5mL), then add 3-bromopropionyl chloride A2a (514mg, 3.00mmol) to the above mixture in the liquid. The mixture was heated to reflux for 6h. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. Then add saturated NaHCO 3 (50 mL), and extracted with dichloromethane (50 mL). The organic phase was collected and washed with Na 2 SO 4 dry. Filter and concentrate under reduced pressure to obtain the crude product, which is purified by silica gel column chromatography (CH 2 Cl 2 :CH 3 OH=60:1), finally obtained white solid compound 18a (290 mg, 71%).

[0049] Intermediate 15 was detected, and the detection data was: M.p.180.6-181.7℃; IR(KBr):3354,3208,3100,1767,169...

Embodiment 3

[0071] Example 3: Synthesis of Compounds 24a-c

[0072] The synthetic route of compound 24a-c is as follows:

[0073]

[0074] The preparation method of intermediate 21 in the technical route is the same as that of 11, and the obtained intermediate 21 is a purple-gray solid with a yield of 79%. Detect it, and its detection data is: M.p.>300℃; IR(KBr):3177,1725,1702,740cm -1 . 1 HNMR (400MHz, CDCl 3 )δ11.13(s, 1H), 8.27(d, J=7.9Hz, 1H), 7.92(d, J=7.3Hz, 1H), 7.58(t, J=7.6Hz, 1H), 5.16(dd, J=12.7,5.4Hz,1H),2.89(ddd,J=18.1,13.9,5.4Hz,1H),2.69–2.52(m,2H),2.18–1.90(m,1H). 13 C NMR (100MHz, CDCl 3 )δ172.7, 169.7, 166.0, 165.3, 145.4, 135.6, 133.2, 131.8, 123.2, 90.3, 49.1, 30.9, 21.8. HRMS (ESI) calculated for C 13 h 10 IN 2 o 4 + [M+H] + :384.9680, found 384.9682.

[0075] The specific preparation steps of intermediate 23a in the technical route are: adding CH to intermediate 8 (574mg, 1.20mmol) 2 Cl 2 (6mL), TFA (4mL), stirred at room temperature for 2h. The mixt...

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Abstract

The invention discloses a proteolysis targeting chimera. The proteolysis targeting chimera can effectively induce FLT3-ITD degradation in FLT3-ITD positive cells MOM-13 and MV-4-11 in a dose-dependent mode and a time-dependent mode. In-vivo researches show that the proteolysis targeting chimera can significantly reduce the CD45+ positive cell level in mice with acute myelogenous leukemia, and shows a good treatment effect on acute myelogenous leukemia.

Description

technical field [0001] The invention belongs to the field of chemical medicines, and in particular relates to a proteolysis-targeting chimera and its pharmaceutical composition and application. Background technique [0002] FLT3 mutation is the most common gene mutation in AML patients. This mutation can cause autophosphorylation and dimerization of FLT3 without ligand participation, systemically activate the FLT3 signaling pathway, promote cell proliferation and differentiation, and lead to the occurrence of AML. and development. FLT3-internal tandem duplication (ITD) is the main type of FLT3 mutation, accounting for about 25% of all AML, while the incidence of point mutations in the activation loop (FLT3-TKD) is lower, only 7-10%. Compared with patients without FLT3-ITD mutations, patients with FLT3-ITD mutations tend to have poor prognosis, increased risk of recurrence, and shorter overall survival (OS), so FLT3-ITD has become an important target for the treatment of AML...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/496A61P35/02A61P35/00
CPCC07D401/14A61P35/02A61P35/00
Inventor 杨光李辰黄袆磊
Owner NANKAI UNIV
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