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Diamide macrocycles that are FXIA inhibitors

一种化合物、杂环的技术，应用在作为FXIA抑制剂的二胺大环化合物领域，能够解决限制肠渗透、限制可口服性能等问题

Active Publication Date: 2017-08-18
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is well known that such functions may limit intestinal permeability and thus oral performance

Method used

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  • Diamide macrocycles that are FXIA inhibitors
  • Diamide macrocycles that are FXIA inhibitors
  • Diamide macrocycles that are FXIA inhibitors

Examples

Experimental program
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preparation example Construction

[0191] The preparation of prodrugs is known in the art and described in, for example, King, F.D., ed., Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., Ed., The Practice of Medicinal Chemistry, Academic Press, San Diego, CA (1999) .

[0192] The present invention is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 c.

[0193] Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those describ...

Embodiment 1

[0465] (±)-N-[8-({2-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]ethyl}carbamoyl)-2 , 10-dioxo-1,2,3,4,5,6,7,8,9,10-decahydro-1,9-benzodiazepine-13-yl] Methyl carbamate

[0466]

[0467] 1A. (±) 2-Aminopent-4-enoic acid methyl ester HCl salt: To a suspension of 2-aminopent-4-enoic acid (1.9 g, 16.50 mmol) in MeOH (50 mL) at 0 °C Thionyl chloride (2.168 mL, 29.7 mmol) was added dropwise. After the addition, the cooling bath was removed and the reaction was stirred overnight at room temperature. Solvent was removed to afford a white solid.

[0468] 1 H NMR (400MHz, CD 3 OD)δ5.79(dd, J=10.1, 7.5Hz, 1H), 5.42-5.11(m, 2H), 3.84(s, 3H), 2.90-2.35(m, 2H).

[0469] 1B. (±) 2-(2-amino-4-nitrobenzamido)methyl pent-4-enoate: 2-amino-4-nitrobenzoic acid (2.199g, 12.08mmol ) in DMF (24ml) was added 1A (2g, 12.08mmol), HOBT (0.925g, 6.04mmol), DIEA (6.33ml, 36.2mmol) and EDC (2.55g, 13.28mmol). The reaction was stirred at room temperature under Ar for 16 hours. The reaction mixt...

Embodiment 2

[0479] Example 2 (Enantiomer 1) and Example 3 (Enantiomer 2)

[0480] N-[8-({2-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]ethyl}carbamoyl)-2,10-di Methyl oxo-1,2,3,4,5,6,7,8,9,10-decahydro-1,9-benzodiazepinedodeca-13-yl]carbamate (enantiomer 1) and

[0481] N-[8-({2-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]ethyl}carbamoyl)-2,10-di Methyl oxo-1,2,3,4,5,6,7,8,9,10-decahydro-1,9-benzodiazepinedodeca-13-yl]carbamate (enantiomer 2)

[0482]

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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. The invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and / or inflammatory disorders using the same.

Description

[0001] Cross References to Related Applications [0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 045,589, filed September 4, 2014, which is incorporated herein in its entirety. technical field [0003] The present invention relates generally to novel macrocyclic compounds and analogs thereof as inhibitors of Factor XIa and / or plasma kallikrein, compositions containing them, and their use, for example, for the treatment or prevention of thromboembolic ) disorders, or methods for treating retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema. Background technique [0004] Despite anticoagulants such as warfarin Heparin, low molecular weight heparin (LMWH) and synthetic pentasaccharides and antiplatelet agents such as aspirin and clopidogrel available, but thromboembolic disease remains the leading cause of death in developed countries. The oral anticoagulant warfarin inh...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07D401/06C07D401/12C07D403/06C07D409/12A61K31/4523A61K31/41A61K31/4025A61K31/4709A61K31/395A61P7/02
CPCC07D401/06C07D401/12C07D403/06C07D403/12C07D409/12A61P11/00A61P13/12A61P7/02A61P9/10
Inventor 史俊W·R·尤因L·尼尔森胡子伦陈丽芬
Owner BRISTOL MYERS SQUIBB CO
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