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

• US 6,084,093 A
• Filed: 05/16/1995
• Issued: 07/04/2000
• Est. Priority Date: 07/19/1991
• Status: Expired due to Fees

• Current Assignee: Pharmacia Corporation (Pfizer Inc.)
• Original Assignee: GD Searle LLC (Pfizer Inc.)
• Inventors: Neuman, William L., Modak, Anil S., Riley, Dennis P., Lennon, Patrick J., Weiss, Randy H., Aston, Karl W.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Sripada, Pavanaram K.
• Application Number:
  US08/442,147
• Time in Patent Office: 1,876 Days
• Field of Search: 540/465, 514/161
• US Class Current: 540/465
• 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: Y10S 977/915 Therapeutic or pharmaceutical composition

Abstract

The present invention is directed to low molecular weight mimics of superoxide dismutase (SOD) represented by the formula: ##STR1## 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 and X, Y, Z and n are as defined herein, useful as therapeutic agents for inflammatory disease states and disorders, ischemic/reperfusion injury, stroke, atherosclerosis, hypertension and all other conditions of oxidant-induced tissue damage or injury.

Claims

1. A compound represented by the formula:

##STR7## 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 independently are selected from the group consisting of hydrogen and 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 ring structure 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, 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;

R and R'"'"', R₁ and R'"'"'₁, R₂ and R'"'"'₂, R₃ and R'"'"'₃, R₄ and R'"'"'₄, R₅ and R'"'"'₅, R₆ and R'"'"'₆, R₇ and R'"'"'₇, R₈ and R'"'"'₈, and R₉ and R'"'"'₉, together with the carbon atom to which they are attached independently form a saturated, partially saturated, or unsaturated ring structure having 3 to 20 carbon atoms;

or one of 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 together with a different one of 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 which is attached to a different carbon atom in the macrocyclic ligand may be bound to form a strap represented by the formula

space="preserve" listing-type="equation">(CH.sub.2).sub.x M(CH.sub.2).sub.w L(CH.sub.2).sub.z J(CH.sub.2).sub.y

wherein w, x, y and z independently are integers from 0 to 10, and M, L and J are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, alkaryl, alkheteroaryl, aza, amide, ammonium, thia, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphino, phosphonium, keto, ester, carbamate, urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza and combinations thereof; and

combination thereof;

wherein at least one "R" group is not hydrogen or if one "R" group is methyl, at least one other "R" group is not hydrogen.

2. Compound of claim 1 represented by the formula:

##STR8## wherein R is selected from the group consisting of alkyl having 2 to 22 carbon atoms, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl radicals.

3. Compound of claim 1 wherein at least one of 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 form a saturated, partially saturated or unsaturated ring structure having 3 to 20 carbon atoms, or at least one of 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 form a nitrogen containing heterocycle having 2 to 20 carbon atoms;

and all of the remaining "R" groups are independently selected from hydrogen or alkyl groups.

4. Compound of claim 3 wherein at least one of 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 is a cyclohexano group, and all of the remaining "R" groups are hydrogen.

5. Compound of claim 4 represented by the formula:

##STR9##

6. Compound of claim 4 represented by the formula:

7. Compound of claim 1 wherein at least one of the "R" groups is selected from the group consisting of alkyl, cycloalkylalkyl and aralkyl radicals and the remaining "R" groups are selected from the group consisting of hydrogen, a saturated, partially saturated or unsaturated ring structure having 3 to 20 carbon atoms, and a nitrogen containing heterocycle having 2 to 20 carbon atoms.

8. Compound of claim 7 wherein at least two of the "R" groups are selected from the group consisting of alkyl, cycloalkylalkyl and aralkyl radicals and the remaining "R" groups are selected from the group consisting of hydrogen, a saturated, partially saturated or unsaturated cyclic having 3 to 20 carbon atoms, and a nitrogen containing heterocycle having 2 to 20 carbon atoms.

9. Compound of claim 8 represented by the formula: