Process for preparing chiral bicycloprolinates as intermediates for the preparation of peptidomimetic protease inhibitors

摘要

The present invention relates to peptidomimetic compounds according to formula 1 useful as protease inhibitors (1), particularly as serine protease inhibitors and more particularly as hepatitis C NS3 protease inhibitors; intermediates thereto; their preparation including novel steroselective process to intermediates. The invention is also directed to pharmaceutical compositions and to methods for using the compounds for inhibiting HCV protease or treating a patient suffering from an HCV infection or physiological condition related to the infection. Also provided are pharmaceutical combinations comprising, in addition to one or more HCV serine protease inhibitors, one or more interferons exhibiting anti-HCV activity and/or one or more compounds having anti-HCV activity and a pharmaceutically acceptable carrier, and methods for treating or preventing a HCV infection in a patient using the compositions. The present invention is also directed to a kit or pharmaceutical pack for treating or preventing HCV infection in a patient.
a pharmaceutically acceptable salt or prodrug thereof, or a solvate of such a compound, its salt or its prodrug, wherein:
R 0 is a bond or difluoromethylene;
R 1 is hydrogen, optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group;
R 2 and R 9 are each independently optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group;
R 3 , R 5 and R 7 are each independently an optionally substituted (1,1- or 1,2-) cycloalkylene, an optionally substituted (1,1- or 1,2-)heterocyclylene, methylene or ethylene, each substituted with one substituent selected from the group consisting -of an optionally substituted aliphatic group, an optionally substituted cyclic group or an optionally substituted aromatic group, and wherein the methylene or ethylene is further optionally substituted with an aliphatic group substituent;
R 4 , R 6 , R 8 and R 10 are each independently is hydrogen or optionally substituted aliphatic group;
is a substituted monocyclic azaheterocyclyl wherein the unsaturatation is in the ring distal to the ring bearing the R 9 -L-(N(R 8 )-R 7 -C(O)-) n N(R 6 )-R 5 -C(O)-N moiety and to which the -C(O)-N(R 4 )-R 3 -C(O)C(O)NR 2 R 1 moiety is attached;
L is -C(O)-, -OC(O)-, -NR 10 C(O)-, -S(O) 2 -, or -NR 10 S(O) 2 -; and
n is 0 or 1;