Five-membered heterocycles useful as serine protease inhibitors.

A compound, solvate technology, applied in the field of treatment of thrombotic or inflammatory diseases

Inactive Publication Date: 2007-07-25
BRISTOL MYERS SQUIBB CO
View PDF10 Cites 7 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This contrasts with other clotting factor gene-targeted trials

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Five-membered heterocycles useful as serine protease inhibitors.
  • Five-membered heterocycles useful as serine protease inhibitors.
  • Five-membered heterocycles useful as serine protease inhibitors.

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0541] The preparation of prodrugs is well known in the art and is described, for example, in Medicinal Chemistry: Principles and Practice, ed. F.D. King, The Royal Society of Chemistry, Cambridge, UK, 1994, which is hereby incorporated by reference in its entirety.

[0542] Also provided herein are radiolabeled compounds of the invention wherein one or more of said atoms is replaced by a radioactive isotope of that atom (e.g., C is replaced by 13 C or 14 C substitution; isotopes of hydrogen include tritium and deuterium). These compounds have many potential applications, eg, as standards and reagents for determining the ability of potential drugs to bind target proteins or receptors, or to image compounds of the invention bound to biological receptors in vivo or in vitro.

[0543] The compound of the invention is preferably isolated and purified after its preparation to obtain a composition containing 98% or more, preferably 99%, by weight of the compound of the invention ("...

Embodiment 1

[0676] (S)-4-carbamimidoyl-N-(2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethyl)benzamide, bis(trifluoroacetic acid) salt

[0677] Step A: (S)-tert-butyl 2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethylcarbamate:

[0678] To the EtOH / H of L-N-(Boc)-phenylalanine (750mg, 3.77mmol) 2 Add Cs to O (1:1, 7.4ml) solution 2 CO 3 (650 mg, 1.89 mmol). The reaction was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the resulting salt was suspended in DMF (4.7ml). 2-Bromoacetophenone (1.0 g, 3.77 mmol) was added in one portion and the reaction was stirred at room temperature for 1.5 hours. The reaction was filtered to remove CsBr. The solid was washed with DMF. The combined washings and filtrate were concentrated in vacuo to give a yellow solid (650mg). The crude intermediate was placed in a flask fitted with a Dean-Stark trap and dissolved in xylene (10ml). Add NH to the flask 4 OAc (2.64 g, 30 mmol), and the reaction was heated to reflux for 3 hours. The r...

Embodiment 2

[0685] (S)-4-(aminomethyl)-N-(2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethyl)cyclohexanecarboxamide, di-trifluoroacetic acid salt.

[0686] Step A: (S)-(4-((2-Phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethyl)carbamoyl)cyclohexyl)methylcarbamate tert-butyl ester : The product (75mg, 0.15mmol) and N-(Boc)-p-aminomethylcyclohexanecarboxylic acid (tranexamic acid) (75mg, 0.29mmol) in the embodiment 1 step B were dissolved in pyridine (1.7ml) . BOP reagent (152 mg, 0.344 mmol) was added and the reaction was stirred at room temperature for 12 hours. The reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and washed with Na 2 SO 4 Dry, filter and distill in vacuo. The crude product was used in the next step without further purification. MS 503.2(M+H) + .

[0687] Alternatively, the product from step B of Example 1 was coupled with 1.0 equivalents of N-Boc-p-aminomethylcyclohexanecarboxylic acid, 1.2 equivalents of HOAt, 5.0 equi...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The present invention provides a method for treating a thrombotic or an inflammatory disorder administering to a patient in need thereof a therapeutically effective amount of at least one compound of Formula (I) or Formula (V): (I) or a stereoisomer or pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, L, Z, R<3>, R<4>, R<6>, R<11>, X<1>, X<2>, and X<3> are as defined herein. The compounds of Formula (I) are useful as selective inhibitors of serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and/or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors. This invention also provides compounds within the scope of Formula I and relates to pharmaceutical compositions comprising these compounds.

Description

technical field [0001] The present invention provides a method of treating thrombotic or inflammatory diseases, the method comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of formula (I) or formula (V): [0002] [0003] Or its stereoisomer or pharmaceutically acceptable salt or solvate form, wherein variable A, L, Z, R 3 , R 4 , R 6 , R 11 、X 1 、X 2 and x 3 as defined herein. The compounds of formula (I) are useful as selective inhibitors of serine proteases such as thrombin, Factor Xa, Factor XIa, Factor IXa, Factor Vila and / or plasma kallikrein in the coagulation cascade and / or in the contact activation system. The invention particularly relates to compounds which are selective inhibitors of factor XIa or dual inhibitors of fXIa and plasma kallikrein. The invention also relates to pharmaceutical compositions comprising these compounds and methods of using them. Background technique [0004] Facto...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/00A61P7/02A61K31/4164A61K31/00
Inventor J·J·汉格兰德M·L·荃J·M·斯马尔赫尔G·S·比萨基J·R·科尔特T·J·弗里恩斯Z·孙K·A·罗西C·L·卡瓦拉罗
Owner BRISTOL MYERS SQUIBB CO
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap