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Tricyclic compound as plasma kallikrein inhibitor and application thereof

A compound and solvate technology, applied in the field of tricyclic compounds, can solve problems such as poor physical and chemical properties, affecting drug bioavailability, and poor selectivity of related enzyme serine proteases, etc., to achieve high selectivity, novel structure, and good activity.

Active Publication Date: 2021-06-22
CHENGDU KANGHONG PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the benzamidine or guanidine group in the structure constitutes the pharmacophore of BCX4161, its poor physical and chemical properties may affect the bioavailability of the drug, so it needs to be administered in a larger dose
In addition, existing plasma kallikrein inhibitors also suffer from poor selectivity to related enzymes such as KLK1, thrombin and other serine proteases
No small molecule plasma kallikrein inhibitors have been approved to date

Method used

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  • Tricyclic compound as plasma kallikrein inhibitor and application thereof
  • Tricyclic compound as plasma kallikrein inhibitor and application thereof
  • Tricyclic compound as plasma kallikrein inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-8-((5-methyl-1H-pyrazol-1-yl)methyl)-10,11 -Dihydro-5H-benzo[e]imidazo[1,2-a][1,4]diazepine - Preparation of 2-formamide (compound 1)

[0088]

[0089] Step a): Preparation of ethyl 2-amino-2-(hydroxyimino)acetate

[0090] Water (110 mL) was slowly added to ethyl cyanoformate (30.0 g, 0.303 mol), hydroxylamine hydrochloride (31.6 g, 0.455 mol) and sodium carbonate (80.3 g, 0.758 mol) in ethanol (200 mL) mixture, and the addition was completed , the reaction solution was stirred at 20°C for 10 h. After the reaction, the solvent was evaporated under reduced pressure, the residue was extracted with ethyl acetate (200 mL×3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain 2-Amino-2-(hydroxyimino) ethyl acetate, yield 65.0%, 1 H NMR (400MHz, DMSO-d 6 )δ10.66-9.12(m,1H),8.24(s,2H),5.79-5.31(m,2H),4.07-3.97(m,2H),1.18...

Embodiment 2

[0122] 8-((1H-pyrazol-1-yl)methyl)-N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-10,11-dihydro-5H -Benzo[e]imidazo[1,2-a][1,4]diazepine - Preparation of 2-formamide (compound 2)

[0123]

[0124] Step a): Preparation of methyl 4-((1H-pyrazol-1-yl)methyl)-2-nitrobenzoate

[0125] 4-Bromomethyl-2-nitro-benzoic acid methyl ester (10.0 g, 36.487 mmol), 1H-pyrazole (2.48 g, 36.487 mmol), potassium carbonate (10.08 g, 72.974 mmol) and acetonitrile (50 mL) Add it into a reaction flask, stir and react at 50°C for 12 h under the protection of nitrogen, evaporate the solvent under reduced pressure after the reaction, dilute the residue with water (100 mL), extract with ethyl acetate (100 mL×2), combine the organic layers, and saturated sodium chloride Washed with aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The obtained crude product was purified by silica gel column chromatography (elue...

Embodiment 3

[0143] N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-8-((4-methyl-1H-pyrazol-1-yl)methyl)-10,11 -Dihydro-5H-benzo[e]imidazo[1,2-a][1,4]diazepine - Preparation of 2-formamide (compound 3)

[0144]

[0145] The operation process is the same as in Example 2, except that the starting material 1H-pyrazole in step a is replaced by 4-methyl-1H-pyrazole to obtain N-((6-amino-2,4-lutidine-3 -yl)methyl)-8-((4-methyl-1H-pyrazol-1-yl)methyl)-10,11-dihydro-5H-benzo[e]imidazol[1,2-a ][1,4]diazepine -2-formamide, 1 H NMR (400MHz, DMSO-d 6 )δ8.18(brs,1H),7.70(s,1H),7.45-7.44(m,3H),7.26(s,1H),6.96(d,J=7.6Hz,1H),6.60(s,1H ),6.41-6.38(m,2H),5.30(s,2H),5.04(s,2H),4.40(s,2H),4.28(d,J=6.0Hz,2H),2.51(s,3H) ,2.37(s,3H),1.97(s,3H); ESI-MS(m / z): 457.1[M+H] + .

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Abstract

The invention provides a tricyclic plasma kallikrein inhibitor compound which is novel in structure, good in activity and high in selectivity. The tricyclic plasma kallikrein inhibitor compound can be widely applied to prevention or treatment of diseases related to plasma kallikrein activity.

Description

technical field [0001] The present invention relates to a tricyclic compound with selective inhibitory activity on plasma kallikrein and its application. Background technique [0002] Plasma kallikrein (PK) is a member of the serine protease family and was first discovered in mammalian plasma. It is encoded by a single gene (KLKB1) located on chromosome 4q35. It is mainly synthesized in the liver and exists in the blood circulation in a large amount in the form of plasma prokallikrein (PPK). PPK further cleaves its internal Arg- IIe bond activates conversion to PK (Yousef, G.M. et al. An overview of the kallikrein gene families in humans and other species: Emerging candidate tumor markers. Clin. Biochem. 2003, 36, 443-452). PK is a key enzyme of kallikrein-kinin system (KKS), which can act on high-molecular-weight kininogen (KH), thereby activating it to release small-molecule bradykinin (BK), and then acting on bradykinin Peptide receptors are involved in biological proce...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/551A61P35/00A61P29/00A61P27/02A61P3/10A61P9/14A61P1/18A61P9/00A61P13/12A61P25/18A61P25/00A61P19/02A61P9/02A61P11/00A61P7/04A61P1/00
CPCC07D487/04A61P35/00A61P29/00A61P27/02A61P3/10A61P9/14A61P1/18A61P9/00A61P13/12A61P25/18A61P25/00A61P19/02A61P9/02A61P11/00A61P7/04A61P1/00A61K31/551A61P7/00C07D413/12C07D403/02
Inventor 强晓明万剑飞刘婷吴红丽柯潇
Owner CHENGDU KANGHONG PHARMA GRP
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