Enzyme-triggered carbon monoxide releasing molecules

Patent metadata

Field	Value
Publication number	US-11377435-B2
Application number	US-201916712639-A
Country	US
Kind code	B2
Filing date	Dec 12, 2019
Priority date	Jun 12, 2017
Publication date	Jul 5, 2022
Grant date	Jul 5, 2022

Abstract

The present invention generally relates to carbon monoxide releasing compounds and compositions, and their use as carbon monoxide prodrugs. The compounds disclosed herein contain a cyclopentadienone moiety, a non-reactive dienophile, and an enzyme-cleavable tethering moiety connecting the cyclopentadienone moiety to the non-reactive dienophile. Cleavage of the enzyme-cleavable tethering moiety results in conversion of the non-reactive dienophile to a reactive dienophile.

First claim

What is claimed is:

1. A compound having a structure according to Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
the moiety —X—Y— is selected from the group consisting of —O—C(O)— and —C(O)—O—;
Z is selected from the group consisting of —O— and —S—;
R 1 is selected from the group consisting of —C(O)R 1a , H, C 1-8 alkyl, C 3-8 cycloalkyl, and C 6-10 aryl;
R 1a is selected from the group consisting of —NR 1b R 1c , C 1-8 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 3- to 8-membered heterocyclyl, 5- to 12-membered heteroaryl, —OR 1b , and a solubilizing moiety;
R 1b and R 1c are independently selected from H, C 1-8 alkyl, C 3-8 cycloalkyl, and a solubilizing moiety;
R 2 and R 3 are taken together to form a fused tricyclic moiety, or
R 2 and R 3 are independently C 6-10 aryl;
R 4 , R 5 , and R 6 are independently selected from the group consisting of H and C 1-6 alkyl;
R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are optionally and independently substituted with one or more R 7 ;
each R 7 is independently selected from the group consisting of C 1-4 alkyl, halogen, —CN, —OR a , —C(O)R b , —C(O)OR a , —OC(O)R b , —N(R a ) 2 , —NR a C(O)R b , —C(O)N(R a ) 2 , —S(O)R b , —S(O) 2 R b , —S(O) 2 OR a , —S(O) 2 N(R a ) 2 , and —NR a S(O) 2 R b ;
each R a is independently selected from the group consisting of H and C 1-4 alkyl;
each R b is C 1-4 alkyl; and
subscript t is 0, 1, 2, or 3.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the moiety —X—Y— is —O—C(O)—.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are taken together to form a fused tricyclic moiety.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having a structure according to Formula Ia:

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, having a structure according to Formula Ib:

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1a is selected from the group consisting of 3- to 8-membered heterocyclyl and —NR 1b R 1c ;
R 1b is selected from H and C 1-8 alkyl; and
R 1c is selected from H, C 1-8 alkyl, and a solubilizing moiety.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein the solubilizing moiety is selected from the group consisting of an oligo(ethylene glycol), a poly(ethylene glycol), and a monosaccharide.

8. The compound of claim 1 , which is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

9. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

10. A method for delivering carbon monoxide to a subject in need thereof, the method comprising administering to the subject a compound having a structure according to Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
the moiety —X—Y— is selected from the group consisting of —O—C(O)— and —C(O)—O—;
Z is selected from the group consisting of —O— and —S—;
R 1 is selected from the group consisting of —C(O)R 1a , H, C 1-8 alkyl, C 3-8 cycloalkyl, and C 6-10 aryl;
R 1a is selected from the group consisting of —NR 1b R 1c , C 1-8 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 3- to 8-membered heterocyclyl, 5- to 12-membered heteroaryl, —OR 1b , and a solubilizing moiety;
R 1b and R 1c are independently selected from H, C 1-8 alkyl, C 3-8 cycloalkyl, and a solubilizing moiety;
R 2 and R 3 are taken together to form a fused tricyclic moiety, or
R 2 and R 3 are independently C 6-10 aryl;
R 4 , R 5 , and R 6 are independently selected from the group consisting of H and C 1-6 alkyl;
R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are optionally and independently substituted with one or more R 7 ;
each R 7 is independently selected from the group consisting of C 1-4 alkyl, halogen, —CN, —OR a , —C(O)R b , —C(O)OR a , —OC(O)R b , —N(R a ) 2 , —NR a C(O)R b , —C(O)N(R a ) 2 , —S(O)R b , —S(O) 2 R b , —S(O) 2 OR a , —S(O) 2 N(R a ) 2 , and —NR a S(O) 2 R b ;
each R a is independently selected from the group consisting of H and C 1-4 alkyl;
each R b is C 1-4 alkyl; and
subscript t is 0, 1, 2, or 3.

11. A method for treating a disease or condition, the method comprising administering to a subject having said disease or condition an effective amount of a compound having a structure according to Formula I:

or a pharmaceutically acceptable salt thereof,
wherein the disease or condition is selected from the group consisting of a cardiovascular condition, an ophthalmic condition, a neurological condition, a urological condition, diabetes, inflammation, bacterial infection, hypertension, hypothermia, asthma, gastric injury, irritable bowel syndrome, kidney dysfunction, sepsis, ischemia, respiratory distress syndrome, autoimmune disorders, thrombosis, cancer, wounds, and rejection in organ transplantation;
and wherein:
the moiety —X—Y— is selected from the group consisting of —O—C(O)— and —C(O)—O—;
Z is selected from the group consisting of —O— and —S—;
R 1 is selected from the group consisting of —C(O)R 1a , H, C 1-8 alkyl, C 3-8 cycloalkyl, and C 6-10 and;
R 1a is selected from the group consisting of —NR 1b R 1c , C 1-8 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 3- to 8-membered heterocyclyl, 5- to 12-membered heteroaryl, —OR 1b , and a solubilizing moiety;
R 1b and R 1c are independently selected from H, C 1-8 alkyl, C 3-8 cycloalkyl, and a solubilizing moiety;
R 2 and R 3 are taken together to form a fused tricyclic moiety, or
R 2 and R 3 are independently C 6-10 aryl;
R 4 , R 5 , and R 6 are independently selected from the group consisting of H and C 1-6 alkyl;
R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are optionally and independently substituted with one or more R 7 ;
each R 7 is independently selected from the group consisting of C 1-4 alkyl, halogen, —CN, —OR a , —C(O)R b , —C(O)OR a , —OC(O)R b , —N(R a ) 2 , —NR a C(O)R b , —C(O)N(R a ) 2 , —S(O)R b , —S(O) 2 R b , —S(O) 2 OR a , —S(O) 2 N(R a ) 2 , and —NR a S(O) 2 R b ;
each R a is independently selected from the group consisting of H and C 1-4 alkyl;
each R b is C 1-4 alkyl; and
subscript t is 0, 1, 2, or 3.

12. The method of claim 11 , wherein the disease or condition is selected from the group consisting of inflammation, cancer, rejection in organ transplantation, bacterial infection, and thrombosis.

Assignees

• Univ Georgia State Res Found

Inventors

• Wang Binghe
• Ji Xingyue

Classifications

• C07D321/10 Primary

  condensed with carbocyclic rings or ring systems · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D265/30

  not condensed with other rings · CPC title

• A61K31/42

  Oxazoles · CPC title

• A61P29/00 Primary

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