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JNK inhibitor as well as pharmaceutical composition and application thereof

A compound and solvate technology, applied in the field of compounds that can inhibit the activity of JNK, can solve problems such as the complexity of liver fibrosis reversal process

Pending Publication Date: 2021-03-30
WUHAN LL SCI & TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the reversal process of liver fibrosis is very complicated, and many signaling pathways such as the known MAPK / EKR signaling pathway, MAPK signaling pathways such as SAPK / JNK and MEK5, and non-MAPK signaling pathways such as PI3K / Akt and Notch all play an important role in it. effect
[0006] Currently, there are no marketed drugs that inhibit the JNK pathway for the treatment of many conditions including fibrosis

Method used

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  • JNK inhibitor as well as pharmaceutical composition and application thereof
  • JNK inhibitor as well as pharmaceutical composition and application thereof
  • JNK inhibitor as well as pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0381] Embodiment 1: the preparation of compound (T001A) and (T001)

[0382]

[0383] 1.1 Preparation of compound (T001-2)

[0384] To a solution of 5-bromo-2,4-dichloropyrimidine (4g, 17.4mmol) in acetonitrile (40ml) was added sodium methylthiolate (2.4g, 34.8mmol) at room temperature. After the addition was complete, stir overnight at room temperature. Water was added and extracted with ethyl acetate. The organic phase was collected, dried and concentrated under reduced pressure, and then purified by silica gel column chromatography (EA / PE=1 / 50) to obtain 3.48 g of white solid, with a yield of 82.8%.

[0385] 1 H NMR (400MHz, CDCl 3 ): δ=8.31(s, 1H), 2.59(s, 3H).

[0386] 1.2 Preparation of compound (T001-3)

[0387] Compound T001-2 (3.48 g, 14.54 mmol), dioxane (10 ml) and tert-butylamine (6.38 g, 87.2 mmol) were added to the sealed tube. After the addition was completed, the tube was sealed and reacted at 100°C for 72 hours. The completion of the reaction was mo...

Embodiment 2

[0399] Embodiment 2: the preparation of compound (T002)

[0400] Hydroxylamine hydrochloride (114 mg, 1.65 mmol) and triethylamine (166 mg, 1.65 mmol) were added to a solution of compound T001A (100 mg, 0.33 mmol) in ethanol (2 ml) at room temperature. After heating to 80°C for 2 hours, it was cooled to room temperature, concentrated under reduced pressure, purified by preparative high performance liquid chromatography (ammonium bicarbonate method), and freeze-dried to obtain 100 mg of white solid with a yield of 90%.

[0401] 1 H NMR (400MHz, DMSO-d 6 ):δ=9.48(s,1H),8.43-8.34(m,1H),8.09(s,1H),6.17(s,1H),5.72(s,1H),4.57-4.56(m,1H), 3.90-3.87(m,1H),2.98-2.96(m,1H),2.17-2.14(m,1H),1.95-1.92(m,1H),1.69-1.65(m,1H),1.36(s,9H ), 1.23-0.98 (m, 4H), 0.94 (d, J=6Hz, 3H); Rt=3.214min, [M+H]+=337.2.

Embodiment 3

[0402] Embodiment 3: the preparation of compound (T003)

[0403]

[0404] To a solution of compound T002 (50 mg, 0.148 mmol) in methanol (3 ml) was added 2 drops of acetic acid, 2 drops of acetic anhydride and wet palladium on carbon (about 10 mg) at room temperature. After the addition was completed, the mixture was replaced with nitrogen and then with hydrogen, and stirred overnight at room temperature. After concentration under reduced pressure, it was purified by preparative high-performance liquid chromatography (ammonium bicarbonate method), and after freeze-drying, 17.1 mg of a yellow solid was obtained, with a yield of 35.8%.

[0405] 1 H NMR (400MHz, DMSO-d 6 ):δ=10.62-10.60(br,1H),6.17(s,1H),6.57-6.28(brs,1H),6.24-6.07(brs,1H),6.04-5.96(brs,2H),4.55-4.54 (m,1H),3.87-3.84(m,1H),2.98-2.93(m,1H),2.15-2.12(m,1H),1.92-1.90(m,1H),1.67-1.63(m,1H) , 1.36(s, 9H), 1.20-0.97(m, 4H), 0.93(d, J=6.4Hz, 3H); Rt=2.846min, [M+H]+=321.2.

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Abstract

The invention provides a compound represented by a formula (I), racemates, stereoisomers, tautomers, isotope markers, solvates, polymorphic substances, nitrogen oxides, or pharmaceutically acceptablesalts thereof, and application as a JNK inhibitor. The invention also provides a preparation method of the compound shown in the formula (I), a pharmaceutical composition containing the compound shownin the formula (I), and application of the compound shown in the formula (I) to preparation of a medicine, and the medicine is used for treating diseases which can be treated by inhibiting the activity of JNK.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a compound capable of inhibiting JNK activity, its pharmaceutical composition and application. Background technique [0002] Mitogen-activated protein kinases (mitogen-activated protein kinases, MAPK) is one of the important pathways in the eukaryotic signal transmission network. The MAPK chain consists of three classes of protein kinases MAP3K-MAP2K-MAPK, which transmit upstream signals to downstream response molecules through sequential phosphorylation. In mammals, there are three major MAPK signal transduction pathways: ERK (extracellular signal-regulated kinase) 1 / 2, JNK (c-Jun N-terminal kinase) and p38 signal pathway, among which ERK1 / 2 signal transduction pathway Regulating cell growth and differentiation, JNK and p38MAPK signal transduction pathways play an important role in stress responses such as inflammation and apoptosis. JNK is an important member of the MAPK family, which...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48C07D403/12C07D401/04C07D401/12C07D405/12C07D403/04C07D403/06C07D239/47C07D213/85C07D213/82C07D239/50A61K31/505A61K31/506A61K31/5377A61K31/455A61P19/02A61P19/00A61P11/06A61P11/00A61P11/02A61P1/00A61P1/04A61P1/16A61P1/18A61P9/10A61P13/12A61P17/06A61P3/10A61P3/04A61P9/00A61P37/06A61P43/00A61P41/00A61P17/02A61P17/08A61P25/08A61P25/28A61P25/16A61P31/04A61P31/12A61P35/00A61P35/02A61P37/00
CPCC07D239/48C07D403/12C07D401/04C07D401/12C07D405/12C07D403/04C07D403/06C07D239/47C07D213/85C07D213/82C07D239/50A61K31/505A61K31/506A61K31/5377A61K31/455A61P19/02A61P19/00A61P11/06A61P11/00A61P11/02A61P1/00A61P1/04A61P1/16A61P1/18A61P9/10A61P13/12A61P17/06A61P3/10A61P3/04A61P9/00A61P37/06A61P43/00A61P41/00A61P17/02A61P17/08A61P25/08A61P25/28A61P25/16A61P31/04A61P31/12A61P35/00A61P35/02A61P37/00C07D239/38A61P3/00
Inventor 李金平娄军陈永凯郭晓丹张轶涵曾弦钱丽娜王朝东
Owner WUHAN LL SCI & TECH DEV
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