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Macrocyclic factor VIIa inhibitors useful as anticoagulants

A technology of atoms and medicinal salts, applied in the field of macrocyclic coagulation factor VIIa inhibitors that can be used as anticoagulant drugs, can solve the problems of limited use, slow therapeutic effect, narrow therapeutic index, etc.

Inactive Publication Date: 2009-12-23
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its use is limited because of its narrow therapeutic index, slow onset of therapeutic action, various dietary and drug interactions, and the need for monitoring and dose adjustments

Method used

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  • Macrocyclic factor VIIa inhibitors useful as anticoagulants
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  • Macrocyclic factor VIIa inhibitors useful as anticoagulants

Examples

Experimental program
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preparation example Construction

[0274] The preparation of prodrugs is well known in the art and described for example in Medicinal Chemistry: Principles and Practice, ed. F.D. King, The Royal Society of Chemistry, Cambridge, UK, 1994 .

[0275]The application also provides isotopically labeled compounds of the present invention, that is, wherein one or more of the atoms is replaced by the isotope of the atom (for example, C is replaced by 13 C or 14 C instead; and isotopes of hydrogen include tritium and deuterium). Such compounds have a variety of potential uses, for example, as standards or reagents in determining the ability of a potential pharmaceutical compound to bind a target protein or receptor, or for in vivo or in vitro testing of compounds of the invention that bind to biological receptors. for imaging.

[0276] The compounds of the invention are preferably isolated and purified after their preparation to obtain a composition ("substantially pure") comprising equal to or greater than 98%, prefer...

Embodiment 1

[0631] Example 1: (R)-7-ethanesulfonyl-2-(3-oxo-2,3-dihydro-1H-isoindol-5-ylamino)-4,11-diaza-tri ring [14.2.2.1 6，10 ] Hexa-1(19), 6, 8, 10(21), 16(20), 17-hexaene-3, 12-dione

[0632]

[0633] Add ethanethiol (2.8 mL, 38 mmol) to 2-fluoro-5-nitrobenzonitrile (5.00 g, 30.1 mmol) and triethylamine (9.3 mL, 67 mmol) in DMF (100 mL ) in the solution. The reaction mixture was stirred for 1 hour, then poured into water (500 mL). The formed precipitate was isolated by filtration, dissolved in DCM, washed with water and brine, dried (MgSO 4 ), and concentrated under reduced pressure. The residue (6.14 g) was dissolved in DCM (100 mL), cooled to 0 °C and treated with mCPBA (16.0 g, 71 mmol) in one portion. The reaction mixture was stirred at room temperature overnight, then extracted with sodium bicarbonate solution (sat.), sodium bisulfite solution (10%) and brine. Dry the organic layer (MgSO 4 ), and concentrated under reduced pressure to afford 1A (5.6 g, 80%) as a pale ...

Embodiment 2

[0644] Example 2: (R)-7-ethanesulfonyl-2-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-ylamino)-4,11-diazepine - tricyclic [14.2.2.1 6，10 ] Hexa-1(19), 6, 8, 10(21), 16(20), 17-hexaene-3, 12-dione

[0645]

[0646] Using a procedure similar to that used to prepare 1E, 1D (500 mg, 0.99 mmol) and intermediate 1 (161 mg, 0.99 mmol) were reacted with glyoxylic acid monohydrate (91 mg, 0.99 mmol) to afford 2A (643 mg, 0.812 mmol, 96% yield) as a yellow foam. MS(ESI)m / z679.5(M+H) + .

[0647] Example 2

[0648] Using a procedure similar to that used to prepare Example 1, 2A (640 mg, 0.943 mmol) was deprotected with TFA and cyclized with BOP to afford the racemic macrocycle (150 mg, 28.4% yield), which It is a yellow solid. The racemate was separated into Peak 1 (28 mg, 0.050 mmol) and Example 2 (25 mg, 0.045 mmol) using the following conditions: Chiralcel OD-H (2.0 cm x 25 cm, 5 microns, Chiral Technologies, Inc.), 50% MeOH / EtOH (1:1) / 50% heptane, 20 mL / min flow rate, and UV det...

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Abstract

The present invention relates generally to novel macrocycles of Formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein the variables A, B, C, D, L, M, W, Z1, Z2, Z3, Z4, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are as defined herein. These compounds are selective inhibitors of factor VIIa which can be used as medicaments.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application No. 60 / 870,864, filed December 20, 2006, and US Provisional Application No. 60 / 984,460, filed November 1, 2007, each of which is hereby incorporated by reference. technical field [0003] The present invention provides novel macrocycles and analogs thereof which are selective inhibitors of the serine protease factor VIIa. The invention also relates to pharmaceutical compositions comprising these compounds and methods of using these compounds. Background technique [0004] Thromboembolic disease remains a leading cause of death in developed countries despite the effectiveness of anticoagulant and antiplatelet agents, such as warfarin ( warfarin) Heparin, low molecular weight heparin (LMWH), and synthetic pentosan, and such antiplatelet agents as aspirin and clopidogrel The oral anticoagulant warfarin inhibits post-translational maturation of coagulation...

Claims

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Application Information

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IPC IPC(8): C07D255/04A61K31/395C07D271/12A61P7/02
Inventor 尼古拉斯·R·沃茨埃尔登·S·普里斯特利丹尼尔·L·切尼彼得·W·格伦兹张晓军弗拉迪米尔·拉德齐亚塔布兰登·帕克赫斯特卢西亚诺·米勒
Owner BRISTOL MYERS SQUIBB CO
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