Carbon monoxide-releasing molecules for therapeutic applications and methods for the preparation and use thereof

Patent metadata

Field	Value
Publication number	US-10751344-B2
Application number	US-201916423094-A
Country	US
Kind code	B2
Filing date	May 27, 2019
Priority date	Jun 9, 2014
Publication date	Aug 25, 2020
Grant date	Aug 25, 2020

Abstract

Carbon monoxide-releasing organic molecules are described herein. The molecules can be synthesized prior to administration (e.g., ex vivo) or formed in vivo. In those embodiments where the molecules are formed in vivo, reactants are administered under physiological conditions and undergo a cycloaddition reaction to form a product which releases carbon monoxide. In applying such reactions for therapeutic applications in vivo, the cycloaddition and CO release typically occur only under near-physiological or physiological conditions. For example, in some embodiments, the cycloaddition reaction and/or release of carbon monoxide occur at a temperature of about 37° C. and pH of about 7.4. Pharmaceutical compositions and methods for release carbon monoxide are also described.

First claim

What is claimed is:

1. A compound according to Formula IX:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are phenyl, each of which is optionally substituted with one or more R 11 moieties, or R 1 and R 2 are phenyl and are taken together to form a fused tricyclic moiety which is optionally substituted with one or more R 11 moieties, wherein
R 3 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
each R 4 and R 5 is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, a protecting moiety R P , a linking moiety R L , a targeting moiety R T , and a solubility-enhancing moiety R S ;
R 6 is independently selected from the group consisting of substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, a protecting moiety R P , a linking moiety R L , a targeting moiety R T , and a solubility-enhancing moiety R S ;
each R 11 is independently selected from the group consisting of halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N(R a ) 2 , —SR a , —S(O)R a , —S(O) 2 R a , —OS(O)OR a , —OS(O) 2 OR a , —OP(OR a ) 2 , —OP(O)HOR a , —OP(OR a ) 2 , —OP(O)(R a ) 2 , —P(O)(OR a ) 2 , —ONO, —ONO 2 , —NO 2 , —(C═O)R 5 , —(C═O)OR 6 , —(C═O)NR 7 R 8 , a linking moiety R L , a targeting moiety R T , and a solubility-enhancing moiety R S ;
R a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, and heteroaryl;
each R 7 , R 8 , R 9 , and R 10 is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
X is NR 14 wherein R 14 is hydrogen or alkyl, which is optionally substituted with halogen, haloalkyl, haloalkoxy, —OR′, or —NR′R″,
R′ and R″ are independently selected from the group consisting of hydrogen and unsubstituted alkyl; or
R′ and R″, when attached to the same nitrogen atom, are combined with the nitrogen to which they are attached to form heterocycloalkyl or heteroaryl;
each R 15 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
or, alternatively two OR′ are taken together to form an oxo moiety; and subscript n is 1, 2 or 3.

2. The compound of claim 1 , wherein R 4 and R 5 are hydrogen.

3. The compound of claim 2 , wherein subscript n is 1 or 2.

4. The compound of claim 1 , wherein X is NR 14 and R 14 is selected from the group consisting of hydrogen, alkyl, and heteroalkyl.

5. The compound of claim 4 , wherein R 4 and R 5 are hydrogen.

6. The compound of claim 5 , wherein subscript n is 1 or 2.

7. A method for generating carbon monoxide in vivo or ex vivo, the method comprising:
allowing a precursor molecule according to claim 1 to react to form an organic molecule that releases carbon monoxide under physiological conditions.

8. The method of claim 7 , wherein the carbon monoxide is released in an amount effective for the treatment of inflammation, cardiovascular disease, cancer, sepsis, or a combination thereof.

9. The method of claim 8 , wherein R 4 and R 5 are hydrogen.

10. The method of claim 9 , wherein subscript n is 1 or 2.

11. The method of claim 8 , wherein X is NR 14 and R 14 is selected from the group consisting of hydrogen, alkyl, and heteroalkyl.

12. The method of claim 11 , wherein R 4 and R 5 are hydrogen.

13. The method of claim 12 , wherein subscript n is 1 or 2.

14. A method for treating inflammation, cardiovascular disease, cancer, sepsis, or a combination thereof, the method comprising administering an effective amount of a compound according to claim 1 to a subject in need thereof.

15. The method of claim 14 , wherein R 4 and R 5 are hydrogen.

16. The method of claim 15 , wherein subscript n is 1 or 2.

17. The method of claim 14 , wherein X is NR 14 and R 14 is selected from the group consisting of hydrogen, alkyl, and heteroalkyl.

18. The method of claim 17 , wherein R 4 and R 5 are hydrogen.

19. The method of claim 18 , wherein subscript n is 1 or 2.

20. The method of claim 14 , wherein the compound is administered parenterally.

Assignees

• Univ Georgia State Res Found

Inventors

• Wang Binghe
• Wang Danzhu
• Ji Xingyue
• Draganov Alexander
• Dai Chaofeng
• Damera Krishna
• Merlin Didier
• Viennois Emilie
• Zheng Yueqin

Classifications

• C07B37/12

  Diels-Alder reactions · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K31/216

  of acids having aromatic rings, e.g. benactizyne, clofibrate · CPC title

• A61K31/122 Primary

  having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin · CPC title

• A61K31/015

  carbocyclic · CPC title