Carbon monoxide-releasing molecules for therapeutic applications and methods of making and using thereof

Patent metadata

Field	Value
Publication number	US-10300069-B2
Application number	US-201515317705-A
Country	US
Kind code	B2
Filing date	Jun 9, 2015
Priority date	Jun 9, 2014
Publication date	May 28, 2019
Grant date	May 28, 2019

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

The invention claimed is:

1. A method for generating carbon monoxide in vivo or ex vivo, the method comprising:
combining a first unsaturated molecule and a second unsaturated molecule and allowing the unsaturated molecules to react to form an organic molecule that releases an effective amount of carbon monoxide under physiological conditions; or
allowing a precursor molecule having a first site of unsaturation and a second site of unsaturation to react to form an organic molecule that releases an effective amount of carbon monoxide under physiological conditions.

2. The method of claim 1 , wherein the first unsaturated molecule is a diene having a structure according to Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
each R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of hydrogen, 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(O)(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 ;
or, alternatively, R 1 and R 2 are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and are taken together to form a fused tricyclic moiety which is optionally substituted with one or more R 9 moieties, wherein each R 9 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(O)(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 ;
each R 5 , R 6 , R 7 , and R 8 is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and
R a is selected from the group consisting of H, alkyl, aryl, cycloalkyl, and heteroaryl.

3. The method of claim 1 , wherein the second unsaturated molecule is a dienophile having a structure according to Formula V:

or a pharmaceutically acceptable salt thereof, wherein:
each R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 is independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted 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(O)(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 ;
each R 5′ , R 6′ , R 7′ , and R 8′ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
R 14 or R 15 is optionally taken together with R 16 or R 17 to form fused cycloalkyl, fused heterocyclyl, fused aryl, or fused heteroaryl, each of which is optionally substituted with R 9′ ;
R 18 or R 19 is optionally taken together with R 20 or R 21 to form fused cycloalkyl, fused heterocyclyl, fused aryl, or fused heteroaryl, each of which is optionally substituted with R 9′ ;
each R 9′ 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(O)(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 ;
Y is selected from the group consisting of CR 22a R 22b , S, O, and NR a ;
X is selected from the group consisting of CR 23a R 23b , S, O, and NR a ;
wherein each R 22a , R 22b , R 23a , and R 23b is defined as for R 5′ ;
wherein R 22a or R 22b is optionally taken together with R 23a or R 23b to form a cyclic moiety optionally substituted with R 9′ ;
R a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl; and
subscript t is 0 or 1.

4. The method of claim 1 , wherein the precursor molecule has a structure according to Formula IX:

or a pharmaceutically acceptable salt thereof, wherein:
each R 4 , R 5 , and R 6 is independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted 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(O)(OR a ) 2 , —OP(O)(R a ) 2 , —P(O)(OR a ) 2 , —ONO, —ONO 2 , —NO 2 , —(C═O)R 7 , —(C═O)OR 8 , —(C═O)NR 9 R 10 , a protecting moiety R P , a linking moiety R L , a targeting moiety R T , and a solubility-enhancing moiety R S ;
R 3 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
R 1 and R 2 are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,
or, alternatively, R 1 and R 2 are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and are taken together to form a fused tricyclic moiety which is optionally substituted with one or more R 11 moieties, wherein
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(O)(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 CR 12 R 13 , S, O, or NR 14 , wherein each R 12 and R 13 is defined as for R 1 , and R 14 is defined as for R 7 ;
each R 15 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
or, alternatively two OR 15 are taken together to form an oxo moiety; and
subscript n is 1, 2 or 3.

5. The method of claim 1 , wherein the precursor molecule has a structure according to Formula XIV:

or a pharmaceutically acceptable salt there

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

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P29/00

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