Meropenem derivatives and uses thereof

Patent metadata

Field	Value
Publication number	US-9725451-B2
Application number	US-201414777018-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Aug 8, 2017
Grant date	Aug 8, 2017

Abstract

The present invention provides novel derivative of β-lactam antibiotics, such as meropenem. The inventive compounds include compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. Also provided are particles (e.g., nanoparticles) and pharmaceutical compositions thereof that are mucus penetrating. The inventive particles and pharmaceutical compositions may be useful in delivering an inventive compound to the respiratory tract of a subject. The invention further provides methods of using and kits including the inventive compounds, particles thereof, and/or pharmaceutical compositions thereof for treating and/or preventing a pulmonary disease (e.g., a respiratory tract infection).

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof;
wherein:
------ is a single bond or null;
is a single or double bond;
R A is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R B is —C(═O)—N(Me) 2 , —CH 2 —NH—S(═O) 2 —NH 2 ,

 =NH, or

R C is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R F is hydrogen or methyl; and
provided that when R A is an unsubstituted C 4 aliphatic, then R C is an unsubstituted C 6 -C 12 aliphatic, a substituted aliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

2. The compound of claim 1 , wherein R A is substituted or unsubstituted, 6- to 14-membered aryl.

3. The compound of claim 1 , wherein R A is substituted phenyl.

4. The compound of claim 1 , wherein R A is unsubstituted phenyl.

5. The compound of claim 1 , wherein R C is substituted or unsubstituted, 6- to 14-membered aryl.

6. The compound of claim 1 , wherein R C is substituted phenyl.

7. The compound of claim 1 , wherein R C is unsubstituted phenyl.

8. The compound of claim 1 , wherein the compound is of Formula (I-A):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

9. A compound of Formula (I-A-1):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

10. The compound of claim 1 , wherein the compound is of Formula (I-B):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

11. The compound of claim 1 , wherein the compound is of Formula (I-C):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

12. The compound of claim 1 , wherein the compound is of Formula (I-D):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

13. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, and optionally a pharmaceutically acceptable excipient.

14. A pharmaceutical composition comprising:
a plurality of particles comprising:
a core comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, and
a coating of a surface altering agent surrounding the core,
wherein the surface altering agent is a triblock copolymer of the structure:
(hydrophilic block)-(hydrophobic block)-(hydrophilic block),

wherein the surface altering agent is present on the outer surface of the core at a density of at least 0.01 surface altering agent per nm 2 ; and

optionally a pharmaceutically acceptable excipient.

15. A pharmaceutical composition comprising:
a plurality of particles comprising:
a core comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, and
a coating of a surface altering agent surrounding the core,
wherein the surface altering agent is a synthetic polymer having pendant hydroxyl groups on the backbone of the polymer, the polymer having a molecular weight of at least about 1 kDa and less than or equal to about 1000 kDa, and wherein the polymer is at least about 30% hydrolyzed and less than about 95% hydrolyzed,
wherein the surface altering agent is present on the outer surface of the core at a density of at least 0.01 surface altering agent per nm 2 ; and

optionally a pharmaceutically acceptable excipient.

16. The pharmaceutical composition of claim 14 , wherein the average size of the core ranges from about 50 nm to about 1 μm.

17. The pharmaceutical composition of claim 14 , wherein the average size of the coated particle ranges from about 50 nm to about 1 μm.

18. The pharmaceutical composition of claim 14 , wherein the average smallest cross-sectional dimension of the plurality of coated particles ranges from about 50 nm to about 1 μm.

19. The pharmaceutical composition of claim 14 , wherein the polydispersity index of the cores and/or coated particles is less than about 0.2, less than about 0.15, less than about 0.1, or less than about 0.05.

20. The pharmaceutical composition of claim 14 , wherein the compound, or the pharmaceutically acceptable salt thereof, constitutes at least about 50 wt %, at least about 60 wt %, at least about 70 wt %, at least about 80 wt %, at least about 90 wt %, at least about 95 wt %, or at least about 99 wt % of the core.

21. The pharmaceutical composition of claim 14 , wherein the aqueous solubility of the compound, or the pharmaceutically acceptable salt thereof, is less than 1 mg/mL, less than 0.1 mg/mL, or less than 0.01 mg/mL at 25° C.

22. The pharmaceutical composition of claim 14 , wherein the surface altering agent is present in the pharmaceutical composition in an amount of between about 0.05 wt % and about 5 wt % of the pharmaceutical composition.

23. The pharmaceutical composition of claim 14 , wherein the surface altering agent is covalently attached to the core.

24. The pharmaceutical composition of claim 14 , wherein the surface altering agent is non-covalently adsorbed to the core.

25. The pharmaceutical composition of claim 14 , wherein the surface altering agent is present on the outer surface of the core at a density of at least about 0.01, at least about 0.03, at least about 0.1, at least about 0.3, at least about 1, at least about 3, at least about 10, or at least about 30 surface altering agents per nm 2 .

26. The pharmaceutical composition of claim 15 , wherein the polymer comprises pendant hydroxyl groups on the backbone of the triblock copolymer.

27. The pharmaceutical composition of claim 14 , wherein at least one hydrophilic block of the triblock copolymer comprises poly(ethylene glycol).

Assignees

• Kala Pharmaceuticals Inc

Inventors

• Ong Winston Zapanta
• Nowak Pawel Wojciech
• Kim Jinsoo
• Enlow Elizabeth M
• Bourassa James
• Cu Yen
• Popov Alexey
• Chen Hongming

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D477/20 Primary

  Sulfur atoms · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K9/5015

  Organic compounds, e.g. fats, sugars · CPC title