Bifunctional agents possessing antioxidant and antiarrhythmic activity

• US 20040259763A1
• Filed: 01/09/2003
• Published: 12/23/2004
• Est. Priority Date: 07/12/2000
• Status: Active Grant

• Current Assignee: Uni-pharma Kleon Tsetis Pharmaceutical Laboratories S.A.
• Original Assignee: Uni-pharma Kleon Tsetis Pharmaceutical Laboratories S.A.
• Inventors: Makriyannis, Alexandros, Calogeropoulou, Theodora, Koufaki, Maria
• Granted Patent: US 7,115,657 B2
• Time in Patent Office: Days
• US Class Current: 514/1
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: C07D 311/66 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 311/72 3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols

Abstract

The present invention relates to novel bifunctional agents possessing antioxidant and antiarrhytmic activity, methods for the synthesis of the same and their applications in treating ischemia-reperfusion injury, as well as a variety of disorders related to free radicals and/or arrhythmias. These bifunctional drugs should prefrentially segregate in the membrane and produce their antiarrhytmic effects while, at the same time, help in protecting the membrane lipids by scavenging free radicals. The present invention comprises compounds represented by Formula (I), wherein R₁, R₂, R₃, R₄, R₅ are further defined.

Claims

1. A compound of Formula I

2. A compound according to claim 1 wherein

X═

CH₂ n=1

R₁=Me, R₂=Alkyl

R₃=CONHCH₂CH₂N Et₂

R₄, R₅=Me

3. A compound according to claim 1 wherein

X═

CH₂ n=1

R₁=Me, R₂=Alkyl

R₃=NHCOCH₂N Et₂

R₄, R₅=Me

4. A compound according to claim 1 wherein

X═

CH₂NHCOCH₂N Et₂ n=1

R₁=Me, R₂=Alkyl

R₃, R₄, R₅=Me

5. A compound according to claim 2 wherein the compound is selected from one of the following:

N-(3,4dihydro-6-hydroxy-2,2,7,8-tetramethyl-2H-1-benzopyran-5-carbonyl)-N′

N′

-diethyl ethylenediamine

N-(3,4-dihydro-2-hexyl-6-hydroxy-2,7,8-trimethyl-2H-1-benzopyran-5-carbonyl)-N,N′

-diethyl ethylenediamine

N-(3,4-dihydro-2dodecyl-6-hydroxy-2,7,8-trimethyl-2H-1-benzopyran-5-carbonyl)-N,N′

diethyl ethylenediamine

6. A compound according to claim 3 wherein the compound is selected from one of the following:

N-(3,4-dihydro-6-hydroxy-2,2,7,8-tetramethyl-2H-1-benzopyran-5-yl)-(diethylamino) acetamide

N-(3,4-dihydro-6-hydroxy-2-hexyl-2,7,8-trimethyl-2H-1-benzopyran-5-yl)-(diethylamino) acetamide

7. A compound according to claim 4 wherein the compound is selected from one of the following:

N-(3,4-dihydro-6-hydroxy-2,2,5,7,8-pentamethyl-2H-1-benzopyran4-yl)(diethylamino) acetamide

N-(3,4-dihydro-6-hydroxy-2-hexyl-2,5,7,8-tetramethyl-2H-1-benzopyran-4-yl) (diethylamino) acetamide

8. Compounds of Formula I combine the key features responsible for the activity of class I or III antiarrhythmics with nuclei possessing antioxidant properties and are effective in reducing reperfusion arrhythmias.

9. Pharmaceutical formulations containing compounds of Formula I and their acceptable salts.