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Tetracyclic compound as plasma kallikrein inhibitor and application thereof

A compound and solvate technology, applied in the field of tetracyclic compounds, can solve the problems of poor physical and chemical properties of compounds, poor oral bioavailability, poor selectivity of related enzymes serine protease, etc., and achieves high selectivity, novel structure and good activity. Effect

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

[0004] However, the currently reported peptide and small molecule plasma kallikrein inhibitors have many limitations.
For example, icaratide has been reported to have the risk of causing allergic reactions
However, most of the reported small molecule plasma kallikrein inhibitors have highly polar and ionizable guanidino or amidino functional groups, which are considered difficult to penetrate biomembranes and lead to very poor oral bioavailability (Tamie , J. et al. ASP-634: an oral drug candidate for diabetic macular edema. ARVO Annual Meeting Abstract, 2012, 53, 2240)
Biocryst has developed an oral plasma kallikrein inhibitor BCX4161 (Collis, P. et al., BCX4161, an oral kallikrein inhibitor: safety and pharmacokinetic results of a Phase 1 study in healthy volunteers. J. Allergy Clin. Immunol 2014, 133, Volume 133, Issue 2, Supplement, 2014, AB39), the pharmacophore benzamidinyl group in its structure may lead to poor physical and chemical properties of the compound and thus affect the bioavailability of the drug, so it needs to be administered in a larger dose. The dosage reaches 400mg each time, and it takes three times a day
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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  • Tetracyclic compound as plasma kallikrein inhibitor and application thereof
  • Tetracyclic compound as plasma kallikrein inhibitor and application thereof
  • Tetracyclic compound as plasma kallikrein inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-12,13-dihydro-7H-imidazol[1,2-a]naphthalene[1,2-e] [1,4]diazepine - Preparation of 10-carboxamide

[0075]

[0076] Step a): Preparation of ethyl 2-amino-2-(hydroxyimino)acetate

[0077] 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),5.79-5.31(m,2H),4.07-3.97(m,2H),1.18-1.13(m,3H); ESI-MS(m / z):133.2[ M+H] + .

[...

Embodiment 2

[0094] N-(4-(aminomethyl)benzyl)-12,13-dihydro-7H-imidazo[1,2-a]naphthalene[1,2-e][1,4]diazepine - Preparation of 10-carboxamide

[0095]

[0096] Step a): (4-((12,13-Dihydro-7H-imidazol[1,2-a]naphthalene[1,2-e][1,4]diazepine Preparation of -10-carboxamide)methyl)benzyl)carbamate tert-butyl ester

[0097] 12,13-dihydro-7H-imidazol[1,2-a]naphthalene[1,2-e][1,4]diazepine -10-Formic acid (100mg, 0.358mmol), (4-(aminomethyl)benzyl) tert-butyl carbamate (127mg, 0.537mmol), HBTU (204mg, 0.537mmol), triethylamine (80mg, 0.573mmol ) and DMF (3mL) were added to the reaction flask, and stirred at room temperature for 5h. After the reaction, the reaction solution was diluted with water, extracted with ethyl acetate (20mL×3), and the organic layers were combined, followed by water (10mL×2) and saturated chlorine Wash with sodium chloride aqueous solution (10mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a light yell...

Embodiment 3

[0101] N-((1-aminoisoquinolin-6-yl)methyl)-12,13-dihydro-7H-imidazol[1,2-a]naphthalene[1,2-e][1,4]di Aza - Preparation of 10-carboxamide

[0102]

[0103] The operation process is the same as in Example 1, except that 5-(aminomethyl)-4,6-dimethylpyridine-2-diamine dihydrochloride in step i is treated with 6-(aminomethyl)isoquinoline- 1-amine substitution, N-((1-aminoisoquinolin-6-yl)methyl)-12,13-dihydro-7H-imidazol[1,2-a]naphthalene[1,2-e] [1,4]diazepine -10-Formamide; ESI-MS(m / z): 435.2[M+H] + .

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Abstract

The invention provides a tetracyclic plasma kallikrein inhibitor compound which is novel in structure, good in activity and high in selectivity, and 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 tetracyclic 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. Encoded by a single gene (KLKB1) located on chromosome 4q35, it is mainly synthesized in the liver and abundantly present in the blood circulation in the form of plasma prokallikrein (PPK), which is further cleaved from its intrinsic Arg by coagulation factor XIIa -IIe key activation converted to PK. 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 processes such as coagulation, fibrinolysis, complement activation, and inflammation. [0003] In recent years, with the in-depth research ...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P27/02A61P3/10A61P9/00A61P1/18A61P25/00A61P13/12A61P1/00A61P29/00A61P7/10A61P31/00A61P9/02A61P35/00A61P11/00A61P7/02A61P7/04A61K31/551
CPCC07D487/04A61P27/02A61P3/10A61P9/00A61P1/18A61P25/00A61P13/12A61P1/00A61P29/00A61P7/10A61P31/00A61P9/02A61P35/00A61P11/00A61P7/02A61P7/04
Inventor 吴红丽柯潇强晓明刘婷
Owner CHENGDU KANGHONG PHARMA GRP
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