Manganese or iron complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide

• US 6,525,041 B1
• Filed: 03/14/1996
• Issued: 02/25/2003
• Est. Priority Date: 06/06/1995
• Status: Expired due to Term

• Current Assignee: Pharmacia Corporation (Pfizer Inc.)
• Original Assignee: Pharmacia Corporation (Pfizer Inc.)
• Inventors: Neumann, William L., Riley, Dennis P., Lennon, Patrick J., Henke, Susan L., Weiss, Randy H., Aston, Karl W.
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US08/596,887
• Time in Patent Office: 2,539 Days
• Field of Search: 514/184, 514/185, 540/465
• US Class Current: 514/184
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 259/00 Heterocyclic compounds containing rings having more than four nitrogen atoms as the only ring hetero atoms
• CPC Class Codes: C07F 13/005 Compounds without a metal-carbon linkage
• CPC Class Codes: C07F 15/025 without a metal-carbon linkage
• CPC Class Codes: C07F 9/6524 having four or more nitrogen atoms as the only ring hetero atoms
• CPC Class Codes: Y10S 977/904 for medical, immunological, body treatment, or diagnosis
• CPC Class Codes: Y10S 977/915 Therapeutic or pharmaceutical composition

Abstract

Low molecular weight mimics of superoxide dismutase (SOD) represented by the formula:

wherein R, R′, R₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, and R′₉, M, X, Y, Z and n are as defined herein, useful as therapeutic agents for inflammatory disease states and disorders, ischemic/reperfusion injury, stroke, atherosclerosis, and all other conditions of oxidant-induced tissue damage or injury.

Claims

1. A compound which is a complex represented by the formula:

wherein at least one pair of “

R”

groups on adjacent carbon atoms of the macrocycle selected from the group consisting of R₉ or R′

₉ and R or R′

, R₁ or R′

₁ and R₂ or R′

₂, R₃ or R′

₃ and R₄ or R′

₄, R₅ or R′

₅ and R₆ or R′

₆, and R₇ or R′

₇ and R₈ or R′

₈ are substituted alkyl substituted alkenyl, substituted alkynyl, substituted cycloalkyl or substituted cycloalkenyl radicals wherein the substituents are independently selected from the group consisting of —

OR₁₀, —

NR₁₀R₁₁, —

COR₁₀, —

CO₂R₁₀, —

CONR₁₀R₁₁, —

O—

(—

(CH₂)_a—

O)_b—

R₁₀, —

SR₁₀, —

SOR₁₀, —

SO₂R₁₀, —

SO₂NR₁₀R₁₁, —

N(OR₁₀)(R₁₁), —

P(O)(OR₁₀)(OR₁₁), —

P(O)(OR₁₀)(R₁₁) and —

OP(O)(OR₁₀)(OR₁₁);

or

at least one pair of “

R”

groups on adjacent carbon atoms of the macrocycle selected from the group consisting of R₉ or R′

₉ and R or R′

, R₁ or R′

₁ and R₂ or R′

₂, R₃ or R′

₃ and R₄ or R′

₄, R₅ or R′

₅ and R₆ or R′

₆, and R₇ or R′

₇ and R₈ or R′

₈ are independently selected wherein one “

R”

group of the pair is an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl radical and the other “

R”

group on the adjacent carbon atom of the macrocycle is a substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl or substituted cycloalkenyl radical wherein the substituents are independently selected from the group consisting of —

OR₁₀, —

NR₁₀R₁₁, —

COR₁₀, —

CO₂R₁₀, —

CONR₁₀R₁₁, —

O—

(—

(CH₂)_a—

O)_b—

R₁₀, —

SR₁₀, —

SOR₁₀, —

SO₂R₁₀, —

SO₂NR₁₀R₁₁, —

N(OR₁₀)(R₁₁), —

P(O)(OR₁₀)(OR₁₁), —

P(O)(OR₁₀)(R₁₁) and —

OP(O)(OR₁₀)(OR₁₁);

wherein R₁₀ and R₁₁ are independently selected from the group consisting of hydrogen and alkyl groups, and a and b are integers independently selected from 1 to 6; and

wherein the remaining “

R”

groups are hydrogen or, optionally, are independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals and radicals attached to the α

-carbon of α

-amino acids;

or

R₁ or R′

₁ and R₂ or R′

₂, R₃ or R′

₃ and R₄ or R′

₄, R₅ or R′

₅ and R₆ or R′

₆, R₇ or R′

₇ and R₈ or R′

₈ and R₉ or R′

₉ and R or R′

together with the carbon atoms to which they are attached independently form a saturated, partially saturated or unsaturated cyclic having 3 to 20 carbon atoms;

or

R or R′ and

R₁ or R′

₁, R₂ or R′

₂ and R₃ or R′

₃, R₄ or R′

₄ and R₅ or R′

₅, R₆ or R′

₆ and R₇ or R′

₇, and R₈ or R′

₈ and R₉ or R′

₉ together with the carbon atoms to which they are attached independently form a nitrogen containing heterocycle having 2 to 20 carbon atoms provided that when the nitrogen containing heterocycle is an aromatic heterocycle which does not contain a hydrogen attached to the nitrogen, the hydrogen attached to the nitrogen in said formula, which nitrogen is also in the macrocycle and the R groups attached to the same carbon atoms of the macrocycle are absent;

wherein M is Mn; and

wherein X, Y and Z are ligands independently selected from the group consisting of halide, oxo, aqua, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloaryl amino, amine oxides, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl sulfenic acid, aryl sulfenic acid, alkyl sulfinic acid, aryl sulfinic acid, alkyl thiol carboxylic acid, aryl thiol carboxylic acid, alkyl thiol thiocarboxylic acid, aryl thiol thiocarboxylic acid, alkyl carboxylic acid, aryl carboxylic acid, urea, alkyl urea, aryl urea, alkyl aryl urea, thiourea, alkyl thiourea, aryl thiourea, alkyl aryl thiourea, sulfate, sulfite, bisulfate, bisulfite, thiosulfate, thiosulfite, hydrosulfite, alkyl phosphonic acid, aryl phosphonic acid, alkyl phosphinic acid, aryl phosphinic acid, alkyl phosphinous acid, aryl phosphinous acid, phosphate, thiophosphate, phosphite, pyrophosphite, triphosphate, hydrogen phosphate, dihydrogen phosphate, alkyl guanidino, aryl guanidino, alkyl aryl guanidino, alkyl carbamate, aryl carbamate, alkyl aryl carbamate, alkyl thiocarbamate, aryl thiocarbamate, alkylaryl thiocarbamate, alkyl dithiocarbamate, aryl dithiocarbamate, alkylaryl dithiocarbamate, bicarbonate, carbonate, perchlorate, chlorate, chlorite, hypochlorite, perbromate, bromate, bromite, hypobromite, tetrahalomanganate, tetrafluoroborate, hexafluoroantimonate, hypophosphite, iodate, periodate, metaborate, tetraaryl borate, tetra alkyl borate, tartrate, salicylate, succinate, citrate, ascorbate, saccharinate, amino acid, hydroxamic acid, thiotosylate, and anions of ion exchange resins, or the corresponding anions thereof, or X, Y and Z are independently attached to one or more of the “

R”

groups and n is 0 or 1.

2. The compound of claim 1, wherein at least one pair of “

R”

groups on adjacent carbon atoms of the macrocycle selected from the group consisting of R₉ or R′

₉ and R or R′

, R₁ or R′

₁ and R₂ or R′

₂, R₃ or R′

₃ and R₄ or R′

₄, R₅ or R′

₅ and R₆ or R′

₆, and R₇ or R′

₇ and R₈ or R′

₈ are substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl or substituted cycloalkenyl radicals wherein the substituents are independently selected from the group consisting of —

OR₁₀, —

NR₁₀R₁₁, —

COR₁₀, —

CO₂R₁₀, —

CONR₁₀R₁₁, —

O—

(—

(CH₂)_a—

O)_b—

R₁₀, —

SR₁₀, —

SOR₁₀, —

SO₂R₁₀, —

SO₂NR₁₀R₁₁, —

N(OR₁₀)(R₁₁), —

P(O)(OR₁₀)(OR₁₁), —

P(O)(OR₁₀)(R₁₁) and —

OP(O)(OR₁₀)(OR₁₁); and

wherein the remaining “

R”

groups are hydrogen or, optionally, are independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals and radicals attached to the α

-carbon of α

-amino acids;

or

R₁ or R′

₁ and R₂ or R′

₂, R₃ or R′

₃ and R₄ or R′

₄, R₅ or R′

₅ and R₆ or R′

₆, R₇ or R′

₇ and R₈ or R′

₈, and R₉ or R′

₉ and R or R′

together with the carbon atoms to which they are attached independently form a saturated, partially saturated or unsaturated cyclic having 3 to 20 carbon atoms;

or

R or R′ and

R₁ or R′

₁, R₂ or R′

₂ and R₃ or R′

₃, R₄ or R′

₄ and R₅ or R′

₅, R₆ or R′

₆ and R₇ or R′

₇ and R₈ or R′

₈, and R₉ or R′

₉ together with the carbon atoms to which they are attached with the carbon atoms to which they are attached independently form a nitrogen containing heterocycle having 2 to 20 carbon atoms provided that when the nitrogen containing heterocycle is an aromatic heterocycle which does not contain a hydrogen attached to the nitrogen, the hydrogen attached to the nitrogen in said formula, which nitrogen is also in the macrocycle and the R groups attached to the same carbon atoms of the macrocycle are absent.

3. The compound of claim 2, wherein R₁₀ and R₁₁ are hydrogen.

4. The compound of claim 2, wherein said substituents are independently selected from the group consisting of —

OR₁₀ and —

NR₁₀R₁₁.

5. The compound of claim 4, wherein the “

R”

groups of the at least one pair of “

R”

groups on adjacent carbon atoms of the macrocycle are substituted alkyl groups.

6. The compound of claim 2, wherein the “

R”

groups of the at least one pair of “

R”

groups on adjacent carbon atoms of the macrocycle are substituted alkyl groups.

7. The compound of claim 6, wherein said substituents on the at least one pair of “

R”

groups on adjacent carbon atoms of the macrocycle are independently —

OR₁₀.

8. The compound of claim 7, wherein the complex is:

9. The compound of claim 1, wherein at least one pair of “

R”

groups on adjacent carbon atoms of the macrocycle selected from the group consisting of R₉ or R′

₉ and R or R′

, R₁ or R′

₁ and R₂ or R′

₂, R₃ or R′

₃ and R₄ or R′

₄, R₅ or R′

₅ and R₆ or R′

₆, and R₇ or R′

₇ and R₈ or R′

₈, are independently selected wherein one “

R”

group of the pair is an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl radical and the other “

R”

group on the adjacent carbon atom of the macrocycle is a substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl or substituted cycloalkenyl radical wherein the substituents are independently selected from the group consisting of —

OR₁₀, —

NR₁₀R₁₁, —

COR₁₀, —

CO₂R₁₀, —

CONR₁₀R₁₁, —

O—

(—

(CH₂)_a—

O)_b—

R₁₀, —

SR₁₀, —

SOR₁₀, —

SO₂R₁₀, —

SO₂NR₁₀R₁₁, —

N(OR₁₀)(R₁₁), —

P(O)(OR₁₀)(OR₁₁), —

P(O)(OR₁₀)(R₁₁) and —

OP(O)(OR₁₀)(OR₁₁); and

wherein the remaining “

R”

groups are hydrogen or, optionally, are independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals and radicals attached to the α

-carbon of α

-amino acids;

or

R₁ or R′

₁ and R₂ or R′

₂, R₃ or R′

₃ and R₄ or R′

₄, R₅ or R′

₅ and R₆ or R′

₆, R₇ or R′

₇ and R₈ or R′

₈, and R₉ or R′

₉ and R or R′

together with the carbon atoms to which they are attached independently form a saturated, partially saturated or unsaturated cyclic having 3 to 20 carbon atoms;

or

R or R′ and

R₁ or R′

₁, R₂ or R′

₂ and R₃ or R′

₃, R₄ or R′

₄ and R₅ or R′

₅, R₆ or R′

₆ and R₇ or R′

₇, and R₈ or R′

₈, and R₉ or R′

₉ together with the carbon atoms to which they are attached independently form a nitrogen containing heterocycle having 2 to 20 carbon atoms provided that when the nitrogen containing heterocycle is an aromatic heterocycle which does not contain a hydrogen attached to the nitrogen, the hydrogen attached to the nitrogen in said formula, which nitrogen is also in the macrocycle and the R groups attached to the same carbon atoms of the macrocycle are absent.

10. The compound of claim 9, wherein R₁₀ and R₁₁ are hydrogen.

11. The compound of claim 9, wherein said substituents are independently selected from the group consisting of —

OR₁₀ and —

NR₁₀R₁₁.

12. The compound of claim 11, wherein one “

R”

group of the at least one pair of “

R”

groups on adjacent carbon atoms of the macrocycle is an alkyl group and the other “

R”

group on the adjacent carbon atom of the macrocycle is a substituted alkyl group.

13. The compound of claim 9, wherein one “

R”

group of the at least one pair of “

R”

groups on adjacent carbon atoms of the macrocycle is an alkyl group and the other “

R”

group on the adjacent carbon atom of the macrocycle is a substituted alkyl group.

14. The compound of claim 13, wherein said substituent on the carbon atom of the at least one pair of “

R”

groups on adjacent carbon atoms of the macrocycle which is a substituted group is —

OR₁₀.

15. The compound of claim 1, wherein X, Y and Z are independently selected from the group consisting of halide, alkyl sulfonic acid, aryl sulfonic acid, alkyl sulfenic acid, aryl sulfenic acid, alkyl sulfinic acid, aryl sulfinic acid, alkyl thiol carboxylic acid, aryl thiol carboxylic acid, alkyl thiol thiocarboxylic acid, aryl thiol thiocarboxylic acid, alkyl carboxylic acid, aryl carboxylic acid, alkyl phosphonic acid, aryl phosphonic acid, alkyl phosphinic acid, aryl phosphinic acid, alkyl phosphinous acid, aryl phosphinous acid, amino acid, hydroxamic acid, nitrate and bicarbonate anions.

16. A pharmaceutical composition in unit dosage form useful for dismutating superoxide comprising:

(a) a therapeutically or prophylactically effective amount of a complex of claim 1; and

(b) a nontoxic, pharmaceutically acceptable carrier, adjuvant or vehicle.

17. A method of treating a disease or disorder which is mediated, at least in part, by superoxide comprising administering to a subject in need of such treatment, a therapeutically, prophylactically, or resuscitative effective amount of a complex of claim 1.

18. The method of claim 17, wherein said disease or disorder is selected from the group consisting of ischemic reperfusion injury, surgically-induced ischemia, inflammatory bowel disease, rheumatoid arthritis, atherosclerosis, thrombosis, platelet aggregation, oxidant-induced tissue injuries and damage, osteoarthritis, psoriasis, organ transplant rejections, radiation-induced injury, stroke, acute pancreatitis, insulin-dependent diabetes mellitus, adult and infantile respiratory distress, metastasis and carcinogenesis.

19. The method of claim 18, wherein said disease or disorder is selected from the group consisting of ischemic reperfusion injury, stroke, atherosclerosis and inflammatory bowel disease.

20. The method of claim 19, wherein said complex is represented by the formula:

21. A method of using a complex of claim 1, comprising formulating said complex into a pharmaceutical composition and administering said composition to a subject in need of treatment of a disease or disorder which is mediated at least in part by superoxide or oxygen radicals derived therefrom.