Combinatorial synthesis of libraries of macrocyclic compounds useful in drug discovery

摘要

A library of macrocyclic compounds of the formula (I);where part (A) is a; bivalent radical, a —(CH2)y— bivalent radical or a covalent bond;where part (B) is a; bivalent radical, a —(CH2)z— bivalent radical, or a covalent bond;where part (C) is a; bivalent radical, a —(CH2)t— bivalent radical, or a covalent bond; andwhere part (T) is a —Y-L-Z— radical wherein Y is CH2 or CO, Z is NH or O and L is a bivalent radical. These compounds are useful for carrying out screening assays or as intermediates for the synthesis of other compounds of pharmaceutical interest. A process for the preparation of these compounds in a combinatorial manner, is also disclosed.

主权项

1. A macrocyclic compound of formula I:and pharmaceutically acceptable salts thereof, wherein A1 is where the nitrogen is bonded to T and the carbonyl is bonded to A2; x is 0, 1 or 2; R1 is selected from the group consisting of: wherein (P) indicates the point of attachment to CH; W1 to W16 are each independently hydrogen or a protecting group used for orthogonal protection in peptide synthesis; and X is selected from the group consisting of: A2 is selected from the group consisting of prolinyl, 4-hydroxyprolinyl, 4-tert-butoxyprolinyl; and where the nitrogen is bonded to the carbonyl of Al and the carbonyl is bonded to A3; wherein y is 0, 1 or 2; R2 is selected from the group consisting of: wherein (P) indicates the point of attachment to CH; and W1 to W16 are each independently hydrogen or a protecting group used for orthogonal protection in peptide synthesis; A3 is selected from the group consisting of prolinyl, 4-hydroxyprolinyl, 4-tert-butoxyprolinyl; and where the nitrogen is bonded to the carbonyl of A2 and the carbonyl is bonded to T; wherein z is 0, 1 or 2; R3 is selected from the group consisting of: wherein (P) indicates the point of attachment to CH; and W1 to W16 are each independently hydrogen or a protecting group used for orthogonal protection in peptide synthesis; and (T) is selected from the group consisting of: wherein (A3) indicates the site of a covalent bond to A3 of formula I and (A1) indicates the site of a covalent bond to A1 of formula I.