Combinatorial synthesis of libraries of macrocyclic compounds useful in drug discovery
View Patent ↗A library of macrocyclic compounds of the formula (I) where part (A) is a bivalent radical, a —(CH 2 ) y — bivalent radical or a covalent bond; where part (B) is a bivalent radical, a —(CH 2 ) z — bivalent radical, or a covalent bond; where part (C) is a bivalent radical, a —(CH 2 ) t — bivalent radical, or a covalent bond; and where part (T) is a —Y-L-Z- radical wherein Y is CH 2 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.
1. A macrocyclic compound of formula I:
and pharmaceutically acceptable salts thereof, wherein A 1 is
where the nitrogen is bonded to T and the carbonyl is bonded to A 2 ;
X is 0, 1 or 2;
R 1 is selected from the group consisting of:
wherein (P) indicates the point of attachment to CH;
W 1 to W 16 are each independently hydrogen or a protecting group used for orthogonal protection in peptide synthesis; and
X is selected from the group consisting of:
A 2 is selected from the group consisting of prolinyl, 4-hydroxyprolinyl, 4-tert-butoxyprolinyl; and
where the nitrogen is bonded to the carbonyl of A 1 and the carbonyl is bonded to A 3 ; wherein
y is 0, 1 or 2;
R 2 is selected from the group consisting of:
wherein (P) indicates the point of attachment to CH; and
W 1 to W 16 are each independently hydrogen or a protecting group used for orthogonal protection in peptide synthesis;
A 3 is selected from the group consisting of prolinyl, 4-hydroxyprolinyl, 4-tert-butoxyprolinyl; and
where the nitrogen is bonded to the carbonyl of A 2 and the carbonyl is bonded to T; wherein
z is 0, 1 or 2;
R 3 is selected from the group consisting of:
wherein (P) indicates the point of attachment to CH; and
W 1 to W 16 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 (A 3 ) indicates the site of a covalent bond to A 3 of formula I and (A 1 ) indicates the site of a covalent bond to A 1 of formula I;
M is selected from the group consisting of —O—, —S—, —NH—, and —N(CH 3 )—;
R 10 and R 11 are independently —H or —CH 3 ; and
n1, n2, n3, n4, n5, n6 and n7 are independently 1 or 2;
with the proviso that compounds wherein R 1 is —(CH 2 ) 3 —NW 3 —C(═NW 2 )—NHW 1 , R 2 is —H and R 3 is —CH 2 CO 2 W 5 are excluded.
2. The macrocyclic compound of claim 1 , wherein T is selected from the group consisting of:
wherein (A 3 ) indicates the site of a covalent bond to A 3 of formula I and (A 1 ) indicates the site of a covalent bond to A 1 of formula I.