Pharmaceutical compositions comprising macrolide diastereomers, methods of their synthesis and therapeutic uses

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.

What is claimed is: 
     
         1 . A composition comprising a plurality of drug molecules of formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         X is 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         Y is Y 1  or Y 2  further wherein 
         Y 1  is 
       
       
         
           
           
               
               
           
         
         
           or H; 
         
         Y 2  is —Cl, —Br, —I, or 
       
       
         
           
           
               
               
           
         
         Z is H or SO 3 H; 
         R 1  and R 2  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%. 
       
     
     
         2 . The composition of  claim 1 , wherein n is 1, and R 1  and R 2  are each independently hydrogen. 
     
     
         3 . The composition of  claim 1 , wherein the drug molecules are present in the composition in a diastereomeric excess of at least 95%. 
     
     
         4 . The composition of  claim 1 , wherein formula I is represented by: 
       
         
           
           
               
               
           
         
       
       or mixtures thereof in a diastereomeric excess of greater than 50%. 
     
     
         5 . A composition comprising a plurality of ligand-drug conjugates of Formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         A is 
       
       
         
           
           
               
               
           
         
         W is selected from S, O, or NR 3 ; 
         L is a ligand; 
         further wherein: 
         L is capable of binding to a cell or cell population; 
         R 1 , R 2  and R 3  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%. 
       
     
     
         6 . The composition of  claim 5 , wherein the ligand is an antibody or an antigen-binding fragment thereof, W is NH, and R 1 , R 2  are each independently selected from H. 
     
     
         7 . The composition of  claim 6 , wherein the antibody or antigen-binding fragment thereof specifically binds a tumor-associated antigen. 
     
     
         8 . The composition of  claim 7 , wherein the ligand-drug conjugates are present in the composition in a diastereomeric excess of more than 95%. 
     
     
         9 . The composition of  claim 7 , wherein the tumor-associated antigen is selected from the group consisting of AFP, ALK, BAGE proteins, β-catenin, brc-abl, BRCA1, BORIS, CA9, carbonic anhydrase IX, caspase-8, CD40, CDK4, CEA, CTLA4, CLEC12A, cyclin-B1, CYP1B1, EGFR, EGFRvIII, ErbB2/Her2, ErbB3, ErbB4, ETV6-AML, EphA2, Fra-1, FOLR1, GAGE proteins (e.g., GAGE-1, -2), GD2, GD3, GloboH, glypican-3, GM3, gp100, Her2, HLA/B-raf, HLA/k-ras, HLA/MAGE-A3, hTERT, LMP2, MAGE proteins (e.g., MAGE-1, -2, -3, -4, -6, and -12), MART-1, mesothelin, ML-IAP, Muc1, Muc16 (CA-125), MUM1, NA17, NY-BR1, NY-BR62, NY-BR85, NY-ESO1, OX40, p15, p53, PAP, PAX3, PAX5, PCTA-1, PLAC1, PRLR, PRAME, PSMA (FOLH1), RAGE proteins, Ras, RGS5, Rho, SART-1, SART-3, Steap-1, Steap-2, survivin, TAG-72, TGF-β, TMPRSS2, Tn, TRP-1, TRP-2, tyrosinase, and uroplakin-3. 
     
     
         10 . A method for preparing composition comprising a plurality of drug molecules of formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         X is 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         Y is Y 1  or Y 2  further wherein 
         Y 1  is 
       
       
         
           
           
               
               
           
         
         
           or H; 
         
         Y 2  is —Cl, —Br, —I, or 
       
       
         
           
           
               
               
           
         
         R 1  and R 2  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: 
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         Y 1  is 
       
       
         
           
           
               
               
           
         
         
           or H; 
         
         Y 2  is —Cl, —Br, —I, or 
       
       
         
           
           
               
               
           
         
         Z is H or SO 3 H; 
         R 1  and R 2  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). 
       
     
     
         11 . The method of  claim 10 , further comprising (d) purifying the compound of formula I obtained in step (c). 
     
     
         12 . The method of  claim 10 , wherein the solid substrate is selected from the group consisting of silica gel, celite, alumina, a zeolite, and crushed molecular sieves. 
     
     
         13 . The method of  claim 10 , wherein n is 1, and R 1  and R 2  are each independently hydrogen. 
     
     
         14 . The method of  claim 10 , wherein the organic solvent comprises a polar aprotic solvent. 
     
     
         15 . The method of  claim 14 , wherein the polar aprotic solvent comprises acetonitrile. 
     
     
         16 . The method of  claim 10 , wherein the organic solvent and the water are present in ratio from about 1:1 to about 4:1 or from about 1:1 to about 10:1. 
     
     
         17 . The method of  claim 10 , wherein the molar ratio of the starting material having formula III and the compound of formula IV is from about 1:1 to about 1:3. 
     
     
         18 . The method of  claim 10 , further comprising combining the compound of formula I with an antibody or antigen-binding fragment thereof to make an antibody-drug conjugate. 
     
     
         19 . The method of  claim 18 , wherein the compound of formula I is attached to the antibody or antigen-binding fragment via an S, O, or NR 3 . 
     
     
         20 . The method of  claim 10 , wherein the formula I is represented by the following structure: 
       
         
           
           
               
               
           
         
       
       in a diastereomeric excess of greater than 50%. 
     
     
         21 . The composition of  claim 1  or  5 , wherein the drug molecules or the ligand-drug conjugates are contained within the composition in a therapeutically effective amount, and further comprising a pharmaceutically acceptable diluent, carrier or excipient. 
     
     
         22 . The composition of  claim 21 , further comprising a therapeutically effective amount of a second chemotherapeutic agent. 
     
     
         23 . A method of treating a disease sensitive to treatment with said method, said method comprising parenterally administering to a patient in need thereof a therapeutically effective dose of the composition of  claim 1  or  5 . 
     
     
         24 . The method of  claim 23 , wherein said disease is selected from tumor, autoimmune disease, and inflammatory disease. 
     
     
         25 . A composition comprising a plurality of drug molecules of formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         X is 
       
       
         
           
           
               
               
           
         
         Y is 
       
       
         
           
           
               
               
           
         
         
           or H; 
         
         R 1  and R 2  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%. 
       
     
     
         26 . The composition of  claim 1 , wherein one of the at least two diastereomers is a compound of formula (i) 
       
         
           
           
               
               
           
         
       
     
     
         27 . The composition of  claim 1 , wherein one of the at least two diastereomers is a compound of formula (ii) 
       
         
           
           
               
               
           
         
       
     
     
         28 . The composition of  claim 1 , wherein one of the at least two diastereomers is characterized by a  1 H NMR spectra of  FIG. 1 . 
     
     
         29 . A compound of formula (i): 
       
         
           
           
               
               
           
         
       
       wherein the compound is stereomerically pure. 
     
     
         30 . A compound of formula (ii): 
       
         
           
           
               
               
           
         
       
       wherein the compound is stereomerically pure.