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Phenyl triazole MLL1-WDR5 protein-protein interaction inhibitor

A phenyl, C1-C4 technology, applied in the field of medicinal chemistry, can solve problems such as abnormal Hox gene expression

Pending Publication Date: 2018-10-30
CHINA PHARM UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The complex makes the expression of the Hox gene regulated by MLL1 abnormal through Pol II, which in turn causes a series of serious consequences and induces the occurrence of MLL leukemia

Method used

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  • Phenyl triazole MLL1-WDR5 protein-protein interaction inhibitor
  • Phenyl triazole MLL1-WDR5 protein-protein interaction inhibitor
  • Phenyl triazole MLL1-WDR5 protein-protein interaction inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058]

[0059] 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1, Methyl 2,3-triazole-4-carboxylate (1)

[0060] Preparation of 4-(4-methylpiperazin-1-yl)-3-nitroaniline (IIb):

[0061] Compound 4-fluoro-3-nitroaniline (II) (6 g, 38.4 mmol) was dissolved in 50 mL of acetonitrile, N-methylpiperazine (5.8 g, 6.3 mL, 57.6 mmol) and N,N-diiso Propylethylamine (9.5mL, 57.6mmol) was then heated to reflux for 12h. After spin-dried, the crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain a reddish-brown solid (8.9 g, 97.8%). 1 H NMR (300MHz, DMSO-d 6 )δ7.06(d, J=8.6Hz, 1H), 6.76(s, 1H), 6.69(d, J=8.5Hz, 1H), 5.34(s, 2H), 2.70(t, J=4.4Hz, 4H),2.27(br s,4H),2.09(s,3H).m / z(EI-MS):259.1[M+Na] + .

[0062] Preparation of 1-(4-azido-2-nitrophenyl)-4-methylpiperazine (Ia):

[0063] Compound 4-(4-methylpiperazin-1-yl)-3-nitroaniline (IIb) (4.0g, 17.0mmol) was dissolved in 100m...

Embodiment 2

[0071]

[0072] 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1, Preparation of 2,3-triazole-4-carboxylic acid (2):

[0073] Compound 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H- Methyl 1,2,3-triazole-4-carboxylate (1) (2.3g, 4.6mmol) was dissolved in THF, lithium hydroxide solution (1M, 15mL) was added, stirred at room temperature for 8h, then spin-dried to remove THF, Then it was acidified with 2M hydrochloric acid to give a white solid (1.7g, 80.4%). 1 HNMR (300 MHz, DMSO-d 6 )δ9.52-9.45(m,2H),8.69(s,1H),7.73(dd,J=8.7,2.7Hz,1H),7.46(d,J=8.6Hz,1H),6.92(d,J =9.2Hz,1H),5.53(s,2H),3.92(s,3H),3.00-2.90(m,4H),2.50(br s,4H), 2.28(d,J=2.6Hz,3H), 2.24(s,3H).(EI-MS):488.9[M+H] + .

Embodiment 3

[0075]

[0076] 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-N,N- Preparation of dimethyl-1H-1,2,3 triazole-4-carboxamide (3):

[0077] Compound 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H- 1,2,3-triazole-4-carboxylic acid (2) (0.18g, 0.36mmol) was dissolved in 10mL of DMF, added BOP (0.32g, 0.72mmol), triethylamine (0.10mL, 0.72mmol) and After dimethylaminohydrochloride (58.7mg, 0.72mmol), stir at room temperature for 4h. Then the reaction solution was diluted by adding 50 mL of ethyl acetate, washed with saturated sodium chloride solution to remove DMF, took the organic phase and dried it over anhydrous sodium sulfate, and spin-dried the organic solvent to obtain the crude product, which was separated and purified by silica gel column chromatography (dichloromethane:methanol=50 : 1) to obtain off-white solid. Yield 78.4%. 1 H NMR (300MHz, DMSO-d 6 )δ9.59(s,1H),9.18(s,1H),8.63(d,J=2.5H...

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Abstract

The invention relates to the field of medicinal chemistry, in particularly to a phenyl triazole MLL1-WDR5 protein-protein interaction inhibitor (I) and a preparation method thereof. Pharmacodynamic tests prove that a compound provided by the invention has strong MLL1-WDR5 protein-protein interaction inhibiting activity.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of phenylbitriazole MLL1-WDR5 protein-protein interaction inhibitors, its preparation and medical application. Background technique [0002] Histone methylation plays a key role in many biological processes and is a major research topic in the field of epigenetic regulation. Histone H3K4 methyltransferase MLL1 gene translocation rearrangement can lead to mixed lineage leukemia (MLL1, acute myeloid leukemia and acute lymphoblastic leukemia). About 10% of leukemia patients have rearrangements of the MLL1 gene. After the MLL1 gene is rearranged, it fuses with other chaperone genes to form a fusion gene, expressing a carcinogenic MLL fusion protein. The fusion protein can interact with RNA polymerase II (RNA polymerase II, Pol II)-related elongation factors to form a super elongation complex (super elongation complex, SEC). The complex makes the expression of the Hox gen...

Claims

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Application Information

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IPC IPC(8): C07D249/06C07D401/12C07D405/12C07D403/10A61P35/02A61K31/496A61K31/5377A61K31/551
CPCA61P35/02C07D249/06C07D401/12C07D403/10C07D405/12A61K31/496A61K31/5377A61K31/551
Inventor 尤启冬郭小可李冬冬陈维琳王志慧
Owner CHINA PHARM UNIV
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