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

Patent metadata

Field	Value
Publication number	US-2016354482-A1
Application number	US-201414913965-A
Country	US
Kind code	A1
Filing date	Aug 26, 2014
Priority date	Aug 26, 2013
Publication date	Dec 8, 2016
Grant date	—

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.

First claim

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 1

Assignees

• Regeneron Pharma

Inventors

• Nittoli Thomas
• Jain Nareshkumar F
• Markotan Thomas Patrick

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D498/18

  Bridged systems · CPC title