Cysteamine prodrugs

Patent metadata

Field	Value
Publication number	US-11357750-B2
Application number	US-201816480773-A
Country	US
Kind code	B2
Filing date	Jan 25, 2018
Priority date	Jan 25, 2017
Publication date	Jun 14, 2022
Grant date	Jun 14, 2022

Abstract

Described herein are prodrugs of cysteamine and pharmaceutically acceptable salts, solvates, and esters thereof. Also described herein are pharmaceutical compositions comprising prodrugs of cysteamine, or pharmaceutically acceptable salts, solvates, and esters thereof, and methods of treatment comprising administering prodrugs of cysteamine, or pharmaceutically acceptable salts, solvates, and esters thereof.

First claim

The invention claimed is:

1. A compound according to formula (I),
X(—R) n    (I)

or a pharmaceutically acceptable salt, solvate, or ester thereof,

wherein:
X is a pharmaceutically acceptable moiety;
R comprises a moiety which releases cysteamine after administration to a subject;
X(R) n is: (a) derived from a carbohydrate, a sugar alcohol, or polymeric alcohol, wherein at least one —OH group of the carbohydrate, the sugar alcohol, or the polymeric alcohol is replaced by R; or (b) derived from glycerol, wherein at least one —OH group of glycerol is replaced by R; and
n is a number from 1 to 100.

2. The compound of claim 1 , wherein X(R) n is derived from a carbohydrate, a sugar alcohol, or polymeric alcohol, wherein at least one —OH group of the carbohydrate, the sugar alcohol, or the polymeric alcohol is replaced by R.

3. The compound of claim 1 , wherein X(R) n is derived from polymeric alcohol, wherein at least one —OH group of the polymeric alcohol is replaced by R.

4. The compound of claim 1 , wherein X(R) n is derived from glycerol, wherein at least one —OH group of glycerol is replaced by R.

5. The compound of claim 2 , wherein the carbohydrate is selected from the group consisting of a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, cellulose, a modified cellulosic, and starch.

6. The compound of claim 1 , wherein R comprises cysteamine, or a substituted form thereof, which is linked to X through a linking group which can be cleaved in vivo, thereby releasing cysteamine, or the substituted form thereof.

7. The compound of claim 6 , wherein the substituted form of cysteamine has the following structure:

wherein R 1 is

and
each R 2 is independently H or an alkyl.

8. The compound of claim 6 , wherein the substituted form of cysteamine has the following structure:

wherein R 1 is

and
each R 2 is independently H or an alkyl.

9. The compound of claim 6 , wherein the linking group forms a thiocarbonate or thioester which is hydrolyzed enzymatically in vivo, thereby releasing cysteamine, or the substituted form thereof.

10. The compound of claim 1 , having a structure according to formula (IIA), (IIB), or (IIE)

or a pharmaceutically acceptable salt, solvate, or ester thereof,
wherein:
each R 1 is independently H or

and
each R 2 is independently H or an alkyl.

11. The compound of claim 1 , having a structure according to formula (IIA)

or a pharmaceutically acceptable salt, solvate, or ester thereof,
wherein:
each R 1 is independently H or

and
each R 2 is independently H or an alkyl.

12. The compound of claim 6 , wherein the linking group forms a sulfoxide which is reduced and cleaved enzymatically in vivo, thereby releasing cysteamine or the substituted form thereof.

13. The compound of claim 12 , having a structure according to formula (IIC)

or a pharmaceutically acceptable salt, solvate, or ester thereof,
wherein:
each R 1 is independently H or

 and
each R 2 is independently H or an alkyl.

14. The compound of claim 6 , wherein the linking group forms a disulfide bond which is reduced in vivo, thereby releasing cysteamine.

15. The compound of claim 14 , having a structure according to formula (IID)

or a pharmaceutically acceptable salt, solvate, or ester thereof,
wherein:
each R 1 is independently H or

 and
each R 2 is independently H or an alkyl.

16. The compound of claim 1 , having a structure according to formula (III)

wherein:
each R 4 is independently H,

and at least one R is

each R 1 is independently H or

and each R 2 is independently H or alkyl.

17. The compound of claim 16 , wherein each R 4 is

each R 1 is independently H or

and each R 2 is independently H or alkyl.

18. The compound of claim 11 , having the following structure:

19. A pharmaceutical composition comprising a compound of claim 1 .

20. The pharmaceutical composition according to claim 19 , further comprising a corticosteroid.

Assignees

• Childrens Hospital Med Ct

Inventors

• Perrett Stephen

Classifications

• C07C323/60

  with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms · CPC title

• A61K31/573

  substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone · CPC title

• C07C329/06 Primary

  having sulfur atoms of thiocarbonic groups bound to acyclic carbon atoms · CPC title

• A61K31/25 Primary

  with polyoxyalkylated alcohols, e.g. esters of polyethylene glycol · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title