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Factor xiia inhibitors

A kind of atomic, selected technology, applied in the field of producing the compound of the present invention, can solve the problem of not being suitable for long-term anticoagulation and the like

Pending Publication Date: 2021-01-01
UNIV OF LEEDS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, if the infestin-4 or antibody approach is successful, they will need to be administered intravenously, making them less suitable for long-term anticoagulation

Method used

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Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0316] For some steps of the preparation methods of the compounds of the present invention it may be necessary to protect potentially reactive functions which are not reacted and thus cleavage of the protecting group. In this case, any compatible protecting group can be used. In particular, protection and deprotection methods such as those described by T.W. GREENE (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981) or P.J. Kocienski (Protecting groups, GeorgThieme Verlag, 1994) can be used. All of the above reactions used in the previous methods and the preparation of novel starting materials are conventional and references to literature precedents and examples and preparations relating thereto, appropriate reagents and reaction conditions for their performance or preparation and separation of desired The procedures for the production are well known to those skilled in the art.

[0317] Additionally, the compounds of the invention, as well as int...

Embodiment and

[0332] Example and Synthesis

[0333] 1H-NMR: Spectra were acquired on a Bruker DRX 400MHz or Jeol ECS 400MHz spectrometer. Spectra were measured at 294K (unless otherwise noted) and referenced to TMS (0.0 ppm), DMSO-d6 (2.50 ppm), CDCl3 (7.26 ppm), and chemical shifts are reported in parts per million (ppm) ( δ-value). Reports coupling constants (J) in hertz (Hz) and expresses spectral splitting patterns as singlet (s), doublet (d), triplet (t), quartet (q), multiplet, or more Overlap signal (m), broad signal (br); solvents are provided in parentheses.

[0334] abbreviation

[0335] The following abbreviations are used in the examples and other descriptive sections.

[0336] ABCN: azobicyclohexanenitrile; Boc: tert-butoxycarbonyl; Cbz: benzyloxycarbonyl; DavePhos: 2-dicyclohexylphosphine-2'-(N,N-dimethylamino)biphenyl; dba: three (dibenzylideneacetone); DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DCE: 1,2-dichloroethane; DCM: dichloromethane; DIAD: Diisopropyl azodicarboxy...

Embodiment

[0659] Example Procedure X: Synthesis of (R)-4-(1-methyl-1H-pyrazol-4-yl)-tetrahydropyrrole-1,2-dicarboxylic acid 1-tert-butyl ester

[0660]

[0661] Step 1: Triflate of (R)-4-trifluoromethanesulfonyloxy-2,5-dihydro-pyrrole-1,2-dicarboxylate 1-tert-butyl 2-methyl ester form

[0662]

[0663] at -78°C, in N 2 Under atmosphere, lithium bis(trimethylsilyl)amide (1 M solution in THF, 44.0 mmol, 44.0 mL) was added dropwise to (R)-4-oxo-tetrahydropyrrole-1 over 20 minutes, In a stirred solution of 1-tert-butyl 2-dicarboxylate 2-methyl ester (40.0 mmol, 9.72 g) in anhydrous THF (50 mL). The resulting solution was stirred at -78°C for 1 hour, then a solution of N-phenyl-bis(trifluoromethanesulfonamide) (44.0 mmol, 15.7 g) in anhydrous THF (40 mL) was added dropwise over 20 minutes. The resulting solution was stirred at -78°C for 2 hours, then allowed to warm to room temperature over 2 hours. Saturated aqueous ammonium chloride (100 mL) was added to the reaction mixture, fol...

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Abstract

The invention relates to compounds of formula (I) and methods of treatment by using the compounds. The invention also relates to processes and methods for producing the compounds of the invention. Thecompounds of the invention are modulators of Factor XII (e.g. Factor XIIa). In particular, the compounds are inhibitors of Factor XIIa and may be useful as anticoagulants.

Description

technical field [0001] The present invention relates to compounds and methods of treatment (or prevention) using the compounds. The invention also relates to processes and methods for producing the compounds of the invention. Compounds of the invention are modulators of Factor XII (eg, Factor XIIa). In particular, the compounds are inhibitors of Factor XIIa and they can be used as anticoagulants. Background technique [0002] Cardiovascular disease is the leading cause of death in developed countries, affecting millions of people worldwide every year. The disease is usually caused by atherosclerosis of the arterial wall, which develops over several years and is characterized by inflammation of the endothelium, subendothelial lipid deposits, macrophage infiltration and plaque appearance. During the acute phase of the disease, atherosclerotic plaques become unstable and rupture, triggering thrombus formation. The occurrence of thrombi (blood clots), which occlude blood ves...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/40A61P7/02
CPCA61K31/40A61K31/4439A61K31/4192A61K31/416A61K31/437A61K31/5386A61K31/4025A61K31/4725A61K31/496A61K31/4355A61K31/4995A61P7/02A61K31/454A61K31/506C07D207/16C07D401/06C07D401/14C07D403/12C07D403/14C07D405/14C07D409/14C07D471/04
Inventor 海伦·菲莉帕普理查德·福斯特科林·菲什威克夏洛特·雷维尔伊恩·尤尔罗格·泰勒阿兰·内勒菲利浦·斯潘塞·法伦斯图尔特·克罗斯比安娜·霍普金斯露西·朱丽叶·格特佐扬阿利斯泰尔·詹姆斯·麦克奈尔马克·理查德·斯图尔特纳塔莉·路易丝·温菲尔德
Owner UNIV OF LEEDS
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