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US 11,596,635 B2Granted
Pharmaceutical compositions comprising macrolide diastereomers, methods of their synthesis and therapeutic uses
AssigneeRegeneron Pharmaceuticals, Inc.
InventorsThomas Nittoli, Nareshkumar F. Jain, Thomas Patrick Markotan
Life of this patent
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Abstract
The disclosure relates to compositions comprising diastereomer of a macrolide exhibiting improved therapeutic profile in the context of inhibiting cell proliferation compared to the corresponding compositions comprising mixture of diastereomers. The disclosure further provides drug-ligand conjugates formed using diastereomer of the macrolide. The disclosure also provides novel method of preparation of diastereomer of the macrolide and their therapeutic uses.
Claims12
A diastereomer of Formula I
- wherein the diastereomer is characterized by a 1H NMR characterized by delta shifts of (300 MHz, CDCl3) δ 6.85 (d, 1H, J=4 Hz), 6.72 (m, 1H), 6.65 (d, 1H, J=4 Hz), 6.44 (dd, 1H, J=15 Hz, 11 Hz), 6.25 (s, 1H), 5.67 (dd, 1H, J=16 Hz, 9 Hz), 5.41 (m, 1H), 4.79 (d, 1H, J=11 Hz), 4.30 (t, 1H, J=11 Hz), 3.72 (m, 2H), 3.51 (d, 1H, J=9 Hz), 3.37 (m, 4H), 3.27 (m, 1H), 3.23 (s, 3H), 3.16-2.99 (m, 4H), 2.85 (m, 7H), 2.62 (m, 3H), 2.39 (ddd, 1H, J=19 Hz, 12 Hz, 4 Hz), 2.18 (br m, 2H), 1.77 (br m, 3H), 1.66 (s, 3H), 1.60-1.47 (m, 4H), 1.31 (m, 6H), 1.05 (m, 2H), and 0.82 (s, 3H);
- and
- wherein the diastereomer characterized by the delta shifts is present in a diastereomeric excess of more than 90%, and wherein the diastereomeric excess is based on a composition comprising a mixture of at least two diastereomers having different stereochemical configurations at the chiral carbon that is bound to the sulfur atom of Formula I.
A compound of Formula I
- wherein the compound is characterized by a 1H NMR characterized by delta shifts of (300 MHz, CDCl3) δ 6.85 (d, 1H, J=4 Hz), 6.72 (m, 1H), 6.65 (d, 1H, J=4 Hz), 6.44 (dd, 1H, J=15 Hz, 11 Hz), 6.25 (s, 1H), 5.67 (dd, 1H, J=16 Hz, 9 Hz), 5.41 (m, 1H), 4.79 (d, 1H, J=11 Hz), 4.30 (t, 1H, J=11 Hz), 3.72 (m, 2H), 3.51 (d, 1H, J=9 Hz), 3.37 (m, 4H), 3.27 (m, 1H), 3.23 (s, 3H), 3.16-2.99 (m, 4H), 2.85 (m, 7H), 2.62 (m, 3H), 2.39 (ddd, 1H, J=19 Hz, 12 Hz, 4 Hz), 2.18 (br m, 2H), 1.77 (br m, 3H), 1.66 (s, 3H), 1.60-1.47 (m, 4H), 1.31 (m, 6H), 1.05 (m, 2H), and 0.82 (s, 3H);
- and
- wherein the compound characterized by the delta shifts is present in a diastereomeric excess of more than 90%, and wherein the diastereomeric excess is based on a composition comprising a mixture of at least two diastereomers having different stereochemical configurations at the chiral carbon that is bound to the sulfur atom of Formula I;
- prepared by a process comprising the steps of
- (a) contacting
- (i) a compound of Formula III
- wherein R1 and R2 are hydrogen;
- and
- n is one;
- (ii) a compound of Formula IV
- wherein Y1 is
- (iii) silica gel;
- (iv) a diluent comprising an organic solvent and water;
- and
- (b) isolating the compound of Formula I.
12 more elements
An antibody-drug conjugate prepared by contacting a compound of Formula I
- wherein the compound is characterized by a 1H NMR characterized by delta shifts of (300 MHz, CDCl3) δ 6.85 (d, 1H, J=4 Hz), 6.72 (m, 1H), 6.65 (d, 1H, J=4 Hz), 6.44 (dd, 1H, J=15 Hz, 11 Hz), 6.25 (s, 1H), 5.67 (dd, 1H, J=16 Hz, 9 Hz), 5.41 (m, 1H), 4.79 (d, 1H, J=11 Hz), 4.30 (t, 1H, J=11 Hz), 3.72 (m, 2H), 3.51 (d, 1H, J=9 Hz), 3.37 (m, 4H), 3.27 (m, 1H), 3.23 (s, 3H), 3.16-2.99 (m, 4H), 2.85 (m, 7H), 2.62 (m, 3H), 2.39 (ddd, 1H, J=19 Hz, 12 Hz, 4 Hz), 2.18 (br m, 2H), 1.77 (br m, 3H), 1.66 (s, 3H), 1.60-1.47 (m, 4H), 1.31 (m, 6H), 1.05 (m, 2H), and 0.82 (s, 3H);
- and
- wherein the compound characterized by the delta shifts is present in a diastereomeric excess of more than 90%, and wherein the diastereomeric excess is based on a composition comprising a mixture of at least two diastereomers having different stereochemical configurations at the chiral carbon that is bound to the sulfur atom of Formula I;
- with an antibody or antigen-binding fragment thereof,
- wherein the compound of Formula I is prepared by a process comprising the steps of
- (a) contacting
- (i) a compound of Formula III
- wherein R1 and R2 are hydrogen;
- and
- n is one;
- (ii) a compound of Formula IV
- wherein Y1 is
- (iii) silica gel;
- (iv) a diluent comprising an organic solvent and water;
- and
- (b) isolating the antibody-drug conjugate of Formula I.
13 more elements
A process for preparing a compound of Formula I
- wherein the compound of Formula I is characterized by a 1H NMR characterized by delta shifts of (300 MHz, CDCl3) δ 6.85 (d, 1H, J=4 Hz), 6.72 (m, 1H), 6.65 (d, 1H, J=4 Hz), 6.44 (dd, 1H, J=15 Hz, 11 Hz), 6.25 (s, 1H), 5.67 (dd, 1H, J=16 Hz, 9 Hz), 5.41 (m, 1H), 4.79 (d, 1H, J=11 Hz), 4.30 (t, 1H, J=11 Hz), 3.72 (m, 2H), 3.51 (d, 1H, J=9 Hz), 3.37 (m, 4H), 3.27 (m, 1H), 3.23 (s, 3H), 3.16-2.99 (m, 4H), 2.85 (m, 7H), 2.62 (m, 3H), 2.39 (ddd, 1H, J=19 Hz, 12 Hz, 4 Hz), 2.18 (br m, 2H), 1.77 (br m, 3H), 1.66 (s, 3H), 1.60-1.47 (m, 4H), 1.31 (m, 6H), 1.05 (m, 2H), and 0.82 (s, 3H);
- and
- wherein the compound characterized by the delta shifts is present in a diastereomeric excess of more than 90%, and wherein the diastereomeric excess is based on a composition comprising a mixture of at least two diastereomers having different stereochemical configurations at the chiral carbon that is bound to the sulfur atom of Formula I;
- the process comprising the steps of
- (a) contacting
- a compound of Formula III
- wherein R1 and R2 are hydrogen;
- and
- n is one;
- (ii) a compound of Formula IV
- wherein Y1 is
- (iii) silica gel;
- (iv) a diluent comprising an organic solvent and water;
- and
- (b) isolating the compound of Formula (I).
12 more elements
Dependencies are inferred from the claim text.