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A class of mtor/hdac dual inhibitors and their applications

A dual inhibitor and dosage form technology, applied in the field of mTOR/HDAC dual inhibitor composition, can solve problems such as inability to terminate

Active Publication Date: 2021-06-11
ANHUI UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Existing anti-IPF drugs can only delay the disease process, but cannot stop or reverse the fibrosis process, so it is urgent to develop anti-IPF drugs with new mechanisms of action

Method used

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  • A class of mtor/hdac dual inhibitors and their applications
  • A class of mtor/hdac dual inhibitors and their applications
  • A class of mtor/hdac dual inhibitors and their applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Synthesis of 5-(4-amino-3-(2-aminopyrimidine-5-)-1H-pyrazolo[3,4-d]pyrimidine-1)-N-hydroxypentanamide (compound 3).

[0060] (1) Synthesis of ethyl 5-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidine-1-)valerate (intermediate 24):

[0061] Add 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.5g), ethyl 5-bromovalerate (1.3g), anhydrous potassium carbonate (1.1 g) and anhydrous DMF (20 mL), stirred at 60°C for 12 hours. Add an appropriate amount of water to the system, let it stand, and filter with suction to obtain a crude product, which is 1.7 g of an off-white solid through silica gel column chromatography.

[0062] (2) Synthesis of ethyl 5-(4-amino-3-(2-aminopyrimidine-5-)-1H-pyrazolo[3,4-d]pyrimidine-1-)pentanoate (compound 25):

[0063] Add intermediate 24 (400mg), 2-aminopyrimidine-5-boronic acid pinacol ester (250mg), Pd(PPh 3 ) 4 (119mg), saturated NaHCO 3 solution (2mL), DME (8mL), H 2 O (2 mL), the system was fully replaced with nitrogen, and stirred and reacted...

Embodiment 2

[0067] Synthesis of 5-(4-amino-3-(6-aminopyridine-3-)-1H-pyrazolo[3,4-d]pyrimidine-1)-N-hydroxypentanamide (Compound 1).

[0068] Compound 1 was prepared with reference to Example 1, only in step (2), 2-aminopyrimidine-5-boronic acid pinacol ester was replaced by 2-aminopyridine-5-boronic acid pinacol ester, and then the same method was used for hydroxylamine hydrolysis An off-white solid was obtained.

[0069] The result of high resolution mass spectrometry is: ESI-HRMS: 343.1639[M+H] + .

Embodiment 3

[0071]Synthesis of 7-(4-amino-3-(6-aminopyridine-3-)-1H-pyrazolo[3,4-d]pyrimidine-1)-N-hydroxyheptanamide (compound 2).

[0072] Compound 2 was prepared with reference to Example 1, and only in step (1) was 5-bromopentanoic acid ethyl ester replaced with 7-bromoheptanoic acid ethyl ester, and in step (2) 2-aminopyrimidine-5-boronic acid pina The alcohol ester was replaced by 2-aminopyridine-5-boronic acid pinacol ester, and then the off-white solid was obtained by hydroxylaminolysis using the same method.

[0073] 1 H NMR (400MHz, DMSO-d 6 ):δ8.22(s,1H),8.18(d,2.0Hz,1H),7.64(dd,2.0Hz,8.8Hz,1H),6.80(brs,2H),6.58(d,8.8Hz,1H) ,6.24(s,2H),4.29(t,6.8Hz,2H),1.92(t,7.6Hz,2H),1.84-1.75(m,2H),1.51-1.40(m,2H),1.26-1.24( m,4H); ESI-HRMS: 371.1949[M+H] + .

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Abstract

The invention discloses a class of mTOR / HDAC dual inhibitors and applications thereof. The dual inhibitors have dual inhibitory effects on mTOR and HDAC, have better curative effect than mTOR inhibitors, and can be used to prepare anti-tumor and anti-idiopathic pulmonary fibrotic drugs.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a class of mTOR / HDAC dual inhibitors and applications thereof, and also relates to mTOR / HDAC dual inhibitor compositions and applications thereof. Background technique [0002] The overactivation of PI3K / Akt / mTOR (PAM) signaling pathway caused by PIK3CA mutation and abnormal tumor suppressor gene PTEN is one of the most common carcinogenic factors. mTOR is a key signaling molecule of this pathway, which exists in protein complexes mTORC1 and mTORC2, and abnormal activation of mTOR can be seen in many malignant tumors. The marketing of the first-generation mTOR inhibitors Temsirolimus and Everolimus has fully confirmed the application value of mTOR as a therapeutic target for malignant tumors. However, the above two drugs can only inhibit mTORC1, so their anti-tumor spectrum is narrow; in addition, they can activate the S6K / IRS1 / PI3K negative feedback pathway, resul...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61P35/00A61P35/02A61P11/00A61K31/519
CPCA61P11/00A61P35/00A61P35/02C07D487/04
Inventor 马晓东彭成军张明明李传润陶强强王虎传胡孟奇董宁
Owner ANHUI UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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