Methods and compositions for inhibiting clostridium difficile spore germination and outgrowth

Patent metadata

Field	Value
Publication number	US-9340569-B2
Application number	US-200913126687-A
Country	US
Kind code	B2
Filing date	Nov 2, 2009
Priority date	Nov 3, 2008
Publication date	May 17, 2016
Grant date	May 17, 2016

Abstract

Certain bile acids, including novel bile acids, and derivatives thereof can be used to inhibit the germination of C. difficile spores and/or the growth of C. difficile cells. The methods and compositions of the invention are useful for preventing and treating C. difficile -associated diseases, including but not limited to C. difficile colitis.

First claim

What is claimed is:

1. A method of treating Clostridium difficile -associated disease in a mammalian subject, comprising administering to a mammalian subject having C. difficile -associated disease an effective amount of a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:
the compound is an inhibitor of C. difficile spore germination;
R 1 is selected from the group consisting of —CO 2 H and −CO 2 (R 2 );
each R 2 is independently a straight or branched chain C1-C10 alkyl; and
each of R 4 and R 5 is independently selected from the group consisting of —OH and —OC(═O)(C1-C10 alkyl), to inhibit growth of C. difficile in the subject, thereby treating the C. difficile -associated disease, wherein the C. difficile -associated disease is selected from the group consisting of C. difficile colitis and pseudomembranous colitis.

2. The method of claim 1 , wherein the compound of Formula I is chenodeoxycholate or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 , wherein the compound of Formula I is ursodeoxycholate or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 , wherein the mammalian subject is a human.

5. The method of claim 1 , wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl; and
both R 4 and R 5 are —OH.

6. The method of claim 1 , wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl;
R 4 is —OH; and
R 5 is —OC(═O)(C1-C10 alkyl).

7. The method of claim 1 , wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl;
R 4 is —OH; and
R 5 is —OC(═O)(CH 3 ).

8. The method of claim 1 , wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl;
both R 4 and R 5 are —OC(═O)(C1-C10 alkyl).

9. The method of claim 1 , wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl;
both R 4 and R 5 are —OC(═O)(CH 3 ).

10. A method of reducing risk of developing Clostridium difficile -associated disease in a mammalian subject receiving antibiotic therapy, comprising administering to a mammalian subject receiving antibiotic therapy and at risk of developing C. difficile -associated disease an effective amount of a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:
the compound is an inhibitor of C. difficile spore germination;
R 1 is selected from the group consisting of —CO 2 H and —CO 2 (R 2 );
each R 2 is independently a straight or branched chain C1-C10 alkyl; and
each of R 4 and R 5 is independently selected from the group consisting of —OH and —OC(═O)(C1-C10 alkyl), to inhibit germination of C. difficile spores in the subject, thereby reducing the risk of developing Clostridium difficile -associated disease in the subject, wherein the C. difficile -associated disease is selected from the group consisting of C. difficile colitis and pseudomembranous colitis.

11. The method of claim 10 , wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl; and
both R 4 and R 5 are —OH.

12. The method of claim 10 , wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl;
R 4 is —OH; and
R 5 is —OC(═O)(C1-C10 alkyl).

13. The method of claim 10 , wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl;
R 4 is —OH; and
R 5 is —OC(═O)(CH 3 ).

14. The method of claim 10 wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl;
both R 4 and R 5 are —OC(═O)(C1-C10 alkyl).

15. The method of claim 10 , wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl;
both R 4 and R 5 are —OC(═O)(CH 3 ).

16. The method of claim 10 , wherein the mammalian subject is a human.

Assignees

• Sorg Joseph
• Sonenshein Abraham L
• Univ Tufts

Inventors

• Sorg Joseph
• Sonenshein Abraham L

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K31/575 Primary

  substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol · CPC title

• A61K31/545

  Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula: [IMAGE cpc-sch-A61K-0953.gif] , e.g. cephalosporins, {cefaclor, or cephalexine} · CPC title

• A61K45/06

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