Substituted porphyrins

• US 6,479,477 B1
• Filed: 04/23/1999
• Issued: 11/12/2002
• Est. Priority Date: 04/24/1998
• Status: Expired due to Term

• Current Assignee: Aeolus Sciences Incorporated, Duke University, Goodnow Capital, L.L.C.
• Original Assignee: Aeolus Pharmaceuticals, Inc., Duke University
• Inventors: Pechulis, Anthony D. Jr., Day, Brian J., Trova, Michael P., Crapo, James D., Gauuan, Polivina Jolicia F.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US09/296,615
• Time in Patent Office: 1,299 Days
• Field of Search: 540/145, 514/183, 514/410
• US Class Current: 514/183
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings

Abstract

The present invention relates, in general, to a method of modulating physiological and pathological processes and, in particular, to a method of modulating cellular levels of oxidants and thereby processes in which such oxidants are a participant. The invention also relates to compounds and compositions suitable for use in such methods. Compounds of the invention include those of Formula I.

Claims

1. A compound of Formula I or Formula II;

or pharmaceutically acceptable salt thereof, wherein

R₁ and R₃ are independently;

—

CO₂C_1-4 alkyl;

or

—

CO₂(CH₂)_nCX₃, wherein X is halogen and n=1 to 3;

R₂ is;

—

H

—

C_1-4alkyl

—

COOH

—

CO₂C_1-4 alkyl,

—

CO₂(CH₂)_nCX₃, wherein X is halogen and n=1 to 3,

—

CON(CH₃)₂, or

—

CX₃, wherein X is halogen; and

R₄ is;

—

H,

—

C_1-4 alkyl

—

COOH,

—

CO₂C_1-4 alkyl,

—

CO₂(CH₂)_nCX₃, wherein X is halogen and n=1 to 3,

—

CON(CH₃)₂, or

—

CX₃, wherein X is halogen, and

each A is, independently, hydrogen or halogen,

wherein when said compound is of Formula II, M is a metal selected from the group consisting of manganese, iron, copper, cobalt, nickel and zinc and Z⁻

is a counterion.

2. The compound according to claim 1 wherein R₁ and R₃ are, independently, —

CO₂C_1-4alkyl or —

CO₂CH₂CX₃, R₂ is —

H, —

CO₂C_1-3alkyl, —

CO₂CH₂CX₃, —

CON(CH₃)₂ or CX₃ and R₄ is —

H, —

COOH, —

CO₂C_1-3alkyl, —

CON(CH₃)₂ or —

CX₃.

3. The compound according to claim 2 wherein R₁ and R₃ are, independently, —

CO₂C_1-3alkyl, R₂ is —

CO₂C_1-3alkyl, —

CON(CH₃)₂ or —

CX₃, and R₄ is —

H, —

COOH, —

CO₂C_1-3alkyl, —

CON(CH₃)₂ or —

CX₃.

4. The compound according to claim 3 wherein R₁ or R₃ is —

CO₂CH₃, —

CO₂CH₂CH₃, or —

CON(CH₃)₂, R₂ is —

CO₂CH₃, —

CO₂CH₂CH₃, or CX₃, and R₄ is —

H, —

COOH, —

CO₂CH₃, —

CO₂CH₂CH₃ or CX₃.

5. The compound according to claim 3 wherein R₁, R₂ and R₃ are, independently, —

CO₂CH₃ or —

CO₂CH₂CH₃, and R₄ is —

H, —

COOH, —

CO₂CH₃ or —

CO₂CH₂CH₃ or —

CO₂CH₂₂CH₃.

6. The compound according to claim 5 wherein R₁, R₂, R₃ and R₄ are, independently, —

CO₂CH₃ or —

CO₂CH₂Cl₃.

7. The compound according to claim 1 wherein at least one A is a halogen.

8. The compound according to claim 1 wherein each A is hydrogen.

9. The compound according to claim 1 wherein said compound is of Formula II and M is manganese.

10. The compound according to claim 1 wherein said compound is of Formula II, M is manganese, R₁, R₂, R₃ and R₄ are, independently, —

CO₂CH₃ or —

CO₂CH₂CH₃, and each A is a hydrogen.

11. A method of protecting a cell from oxidant-induced toxicity comprising contacting said cell with a protective amount of a compound of Formula I or Formula II:

or pharmaceutically acceptable salt thereof, wherein

R₁ and R₃ are, independently;

—

CO₂C_1-4 alkyl;

or

—

CO₂(CH₂)_nCX₃, wherein X is halogen and n=1to 3;

R₂ is;

—

H

—

C_1-4alkyl

—

COOH

—

CO₂C_1-4alkyl,

—

CO₂(CH₂)_nCX₃, wherein X is halogen and n=1 to 3,

—

CON(CH₃)₂, or

—

CX₃, wherein X is halogen; and

R₄ is;

—

H,

—

C_1-4alkyl

—

COOH,

—

CO₂C_1-4alkyl,

—

CO₂(CH₂)_nCX₃, wherein X is halogen and n=1 to 3,

—

CON(CH₃)₂, or

—

CX₃, wherein X is halogen, and

each A is, independently, hydrogen or halogen,

wherein when said compound is of Formula II, M is a metal selected from the group consisting of manganese, iron, copper, cobalt, nickel and zinc and Z⁻

is a counterion.

12. The method according to claims 11 wherein said compound is of Formula II and M is manganese.

13. The method according to claim 11 wherein said cell is a mammalian cell.

23. The method according to any one of claims 11, 14, 16 and 18 wherein each A is hydrogen.

14. A method of treating a patient suffering from a condition that results from or that is exacerbated by oxidant-induced toxicity comprising administering to said patient an effective amount of a compound of Formula I or Formula II:

or pharmaceutically acceptable salt thereof, wherein

R₁ and R₃ are, independently;

—

CO₂C_1-4 alkyl;

or

—

CO₂(CH₂)_nCX₃, wherein X is halogen and n=1 to 3;

R₂ is;

—

H

—

C_1-4alkyl

—

COOH

—

CO₂C_1-4 alkyl,

—

CO₂(CH₂)_nCX₃, wherein X is halogen and n=1 to 3,

—

CON(CH₃)₂, or

—

CX₃, wherein X is halogen; and

R₄ is;

—

H,

—

C_1-4 alkyl

—

COOH,

—

CO₂C_1-4 alkyl,

—

CO₂(CH₂)_nCX₃, wherein X is halogen and n=1 to 3,

—

CON(CH₃)₂, or

—

CX₃, wherein X is halogen, and

each A is, independently, hydrogen or halogen,

wherein when said compound is of Formula II, M is a metal selected from the group consisting of manganese, iron, copper, cobalt, nickel and zinc and Z⁻

is a counterion.

15. The method according to claim 14 wherein said compound is of Formula II and M is manganese.

16. A method of treating a pathological condition of a patient that results from a degradation product of NO, comprising administering to said patient an effective amount of a compound of Formula I or Formula II

or pharmaceutically acceptable salt thereof, wherein

R₁ and R₃ are, independently;

—

CO₂C_1-4 alkyl;

or

—

CO₂(CH₂)_nCX₃, wherein X is halogen and n=1 to 3;

R₂ is;

—

H

—

C_1-4 alkyl

—

COOH

—

CO₂C_1-4 alkyl,

—

CO₂(CH₂)_nCX₃, wherein X is halogen and n=1 to 3,

—

CON(CH₃)₂, or

—

CX₃, wherein X is halogen; and

R₄ is;

—

H,

—

C_1-4alkyl

—

COOH,

—

CO₂C_1-4 alkyl,

—

CO₂(CH₂)_nCX₃, wherein X is halogen and n=1 to 3,

—

CON(CH₃))₂, or

—

CX₃, wherein X is halogen, and

each A is, independently, hydrogen or halogen,

wherein when said compound is of Formula II, M is a metal selected from the group consisting of manganese, iron, copper, cobalt, nickel and zinc and Z⁻

is a counterion.

17. The method according to claim 16 wherein said compound is of Formula II and M is manganese.

18. A method of treating a patient for an inflammatory disease comprising administering to said patient an effective amount of a compound of Formula I or Formula II:

or pharmaceutically acceptable salt thereof, wherein

R₁ and R₃ are, independently;

—

CO₂C_1-4 alkyl;

or

—

CO₂(CH₂)_nCX₃, wherein X is halogen and n=1 to 3;

R₂ is,

—

H

—

C_1-4alkyl

—

COOH

—

CO₂C_1-4 alkyl,

—

CO₂(CH₂)_nCX₃, wherein X is halogen and n=1 to 3,

—

CON(CH₃)₂, or

—

CX₃, wherein X is halogen, and

R₄ is;

—

H,

—

C_1-4alkyl

—

COOH,

—

CO₂C_1-4 alkyl,

—

CO₂(CH₂)_nCX₃, wherein X is halogen and n=1 to 3,

—

CON(CH₃)₂, or

—

CX₃, wherein X is halogen, and

each A is, independently, hydrogen or halogen,

wherein when said compound is of Formula II, M is a metal selected from the group consisting of manganese, iron, copper, cobalt, nickel and zinc and Z⁻

is a counterion.

19. The method according to claim 18 wherein said compound is of Formula II and M is manganese.

20. The method according to claim 18 wherein said inflammatory disease is an inflammatory lung disease.

21. The method according to claim 20 wherein said inflammatory lung disease is bronchopulmonary disease.

22. The method according to claim 20 wherein said inflammatory lung disease is asthma.