Pharmaceutical compositions comprising macrolide diastereomers, methods of their synthesis and therapeutic uses
AssigneeRegeneron Pharmaceuticals, Inc.
InventorsThomas NITTOLI, Nareshkumar F. JAIN, Thomas Patrick MARKOTAN
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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.
Claims30
A composition comprising a plurality of drug molecules of formula I:
- wherein:
- X is
- Y is Y1 or Y2 further wherein
- Y1 is
- or H;
- Y2 is —Cl, —Br, —I, or
- Z is H or SO3H;
- R1 and R2 are independently selected from H or alkyl;
- n is an integer from 0 to 50;
- and wherein the drug molecules present in the composition comprises a mixture of at least two diastereomers, a first diastereomer and a second diastereomer, further wherein said first diastereomer and second diastereomer are otherwise identical, except that said first and second diastereomers have different stereochemical configuration at a chiral carbon represented by (*) in formula X, wherein said chiral carbon atom is a carbon atom that is bound to a sulfur atom, and said first or second diastereomer is present in a diastereomeric excess of greater than 50%.
A composition comprising a plurality of ligand-drug conjugates of Formula II:
- wherein:
- A is
- W is selected from S, O, or NR3;
- L is a ligand;
- further wherein:
- L is capable of binding to a cell or cell population;
- R1, R2 and R3 are each independently selected from H or alkyl;
- n is an integer from 0 to 10;
- p is an integer from 1 to 10;
- and wherein the ligand-drug conjugates are present in the composition in a diastereomeric excess of greater than 50%.
A method for preparing composition comprising a plurality of drug molecules of formula I:
- wherein:
- X is
- Y is Y1 or Y2 further wherein
- Y1 is
- or H;
- Y2 is —Cl, —Br, —I, or
- R1 and R2 are independently selected from H or alkyl;
- n is an integer from 0 to 50;
- and wherein the drug molecules present in the composition comprises a mixture of at least two diastereomers, a first diastereomer and a second diastereomer, further wherein said first diastereomer and second diastereomer are otherwise identical, except that said first and second diastereomers have different stereochemical configuration at a chiral carbon represented by (*) in formula X, wherein said chiral carbon atom is a carbon atom that is bound to a sulfur atom, and said first or second diastereomer is present in a diastereomeric excess of greater than 50%,
- the method comprising:
- (a) providing a mixture comprising
- (i) a starting material which has a formula III:
- (ii) a compound of formula IV:
- Y1 is
- or H;
- Y2 is —Cl, —Br, —I, or
- Z is H or SO3H;
- R1 and R2 are independently selected from H or alkyl;
- and
- each n is an integer from 0 to 50;
- (iii) an organic solvent,
- (iv) water, and
- (v) a solid substrate;
- (b) allowing the mixture of step (a) to react until some of the starting material is converted to the compound of formula I;
- and
- (c) removing crude compound of formula I from the mixture of step (b).
A composition comprising a plurality of drug molecules of formula I:
- wherein:
- X is
- Y is
- or H;
- R1 and R2 are each independently selected from H or alkyl;
- n is an integer from 0 to 10;
- and
- wherein the drug molecules are present in the composition in an diastereomeric excess of greater than 50% and show greater anti-proliferative activity than a corresponding composition comprising drug molecules of formula I that are not present in a diastereomeric excess of greater than 50%.
A compound of formula (i):
- wherein the compound is stereomerically pure.
A compound of formula (ii):
- wherein the compound is stereomerically pure.
Dependencies are inferred from the claim text.