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Pyrimidinones as factor xia inhibitors

A technology selected from compounds, applied in medical preparations containing active ingredients, extracellular fluid diseases, drug combinations, etc., can solve problems such as limiting oral availability and intestinal permeability

Active Publication Date: 2017-05-31
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These functional groups are known to limit intestinal permeability and thus oral availability

Method used

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  • Pyrimidinones as factor xia inhibitors
  • Pyrimidinones as factor xia inhibitors
  • Pyrimidinones as factor xia inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0087] In another embodiment, the present invention provides a composition comprising at least one compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

[0088] In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvent thereof compounds.

[0089] In another embodiment, the present invention provides a pharmaceutical composition comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable Accepted salts or solvates.

[0090] In another embodiment, the present invention provides methods for preparing compounds of the present invention.

[0091] In another embodiment, the present inventio...

Embodiment 1

[0456] Example 1. (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo -1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 2,6 ] Preparation of octadecadecan-1(18),2(6),4,14,16-penten-8-one trifluoroacetate

[0457]

[0458] 1A. Preparation of 1-(difluoromethyl)-4-nitro-1H-pyrazole

[0459] Will Cs 2 CO 3 (14.41 g, 44.2 mmol) was suspended in a solution of 4-nitro-1H-pyrazole (5.00 g, 44.2 mmol) and DMF (40 mL). After heating to 120°C for 5 min, solid sodium 2-chloro-2,2-difluoroacetate (13.48 g, 88 mmol) was added in 10 equal portions over 20 min. After an additional 10 min of heating, the reaction was complete. The mixture was added to a separatory funnel containing 100 mL of water and washed with Et 2 O (2 x 50 mL) was extracted. The combined organic layers were concentrated. Purification by normal phase chromatography eluting with a hexane / EtOAc gradient gave 1-(difluoromethyl)-4-nitro-1H-pyrazole (6.99 ...

Embodiment 2

[0474] Example 2. (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo -1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 2,6 ] Octadecyl-1(18),2,5,14,16-penten-8-one trifluoroacetate

[0475]

[0476] 2A. Preparation of 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0477] To a solution of 4-nitro-1H-pyrazole (5.0 g, 44.2 mmol) in THF (100 mL) was added N-cyclohexyl-N-methylcyclohexylamine (0.948 mL, 4.43 mmol) at 0 °C, Then SEM-Cl (12.55 mL, 70.7 mmol) was added dropwise. The reaction mixture was then gradually warmed to room temperature and stirred overnight at room temperature. The reaction mixture was then concentrated before purification by using normal phase chromatography to give 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.4 g, 21% yield). 1 H NMR (500MHz, CDCl 3 )δ8.31(s,1H),8.10(s,1H),5.46(s,2H),3.67-3.55(m,2H),0.99-0.90(m,2H),0.05-0.03(m,9H) .

[0478] 2B. (S)-(1-(4-(4-n...

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Abstract

The present invention provides compounds of Formula (I) or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and / or inflammatory disorders using the same.

Description

technical field [0001] The present invention generally relates to novel macrocyclic compounds and analogs thereof, which are inhibitors of Factor XIa and / or plasma kallikrein; compositions containing them; and methods of using them, for example for the treatment or For the prevention of thromboembolic disorders, or for the treatment of retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema. Background technique [0002] Although anticoagulants such as warfarin are available Heparin, low molecular weight heparin (LMWH), and synthetic pentasaccharides) and antiplatelet agents (such as aspirin and clopidogrel ), but thromboembolic disease remains the leading cause of death in developed countries. The oral anticoagulant warfarin inhibits posttranslational mutations in coagulation factors VII, IX, X, and prothrombin and has been shown to be effective against venous and arterial thrombosis. However, its use is limited due to its narrow t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/18A61K31/517A61P7/02
CPCA61P11/00A61P13/12A61P43/00A61P7/00A61P7/02A61P7/06A61P9/00A61P9/04A61P9/06A61P9/10C07D471/18C07D403/10C07D213/61C07D239/34A61K31/4162A61K31/506
Inventor A·K·迪尔格J·R·考特I·德卢卡方天安杨武王裕丰K·B·帕比斯蒂W·R·艾温朱晔恒R·R·韦克斯勒D·J·P·平托M·J·奥瓦特L·M·史密斯二世
Owner BRISTOL MYERS SQUIBB CO
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