Substituted pyridino pentaazamacrocyle complexes having superoxide dismutase activity

• US 6,214,817 B1
• Filed: 09/16/1999
• Issued: 04/10/2001
• Est. Priority Date: 06/20/1997
• Status: Expired due to Term

• Current Assignee: Pfizer Inc.
• Original Assignee: Monsanto Company (Bayer AG)
• Inventors: Neumann, William L., Riley, Dennis P., Salvemini, Daniela, Grapperhaus, Margaret Lanahan, Kusturin, Carrie L., Lennon, Patrick, Fobian, Yvette M., Sikorski, James A., Henke, Susan L., Aston, Karl W.
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): Sripada, Pavanaram K
• Application Number:
  US09/398,120
• Time in Patent Office: 572 Days
• Field of Search: 540/473, 540/474, 514/183, 514/184, 514/186
• US Class Current: 514/186
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 39/00 General protective or antinoxious agents
• 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: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 : Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 471/06 : Peri-condensed systems
• CPC Class Codes: C07D 471/08 : Bridged systems
• CPC Class Codes: C07F 13/005 : Compounds without a metal-carbon linkage
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention relates to compounds which are effective as catalysts for dismutating superoxide and, more particularly, the manganese or iron complexes of substituted, unsaturated heterocyclic pentaazacyclopentadecane ligands which catalytically dismutate superoxide.

Claims

1. A catalyst for the dismutation of superoxide having the following formula:

wherein a nitrogen of the macrocycle and the two adjacent carbon atoms to which it is attached independently form a substituted, unsaturated, nitrogen-containing heterocycle W having 2 to 20 carbon atoms, which may be an aromatic heterocycle, in which case the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and the R groups attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent;

and wherein R, R₁, 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 represent hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals;

and, optionally, one or more of 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, or R₈ or R′

₈ and R₉ or R′

₉ together with the carbon atoms to which they are attached independently form a substituted or unsubstituted nitrogen containing heterocycle having 2 to 20 carbon atoms, which may be an aromatic heterocycle, in which case the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and the R groups attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent;

and, optionally, one or more of 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 cyclic or heterocyclic having 3 to 20 carbon atoms;

and, optionally, one of R, R₁, 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′

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

2. The catalyst of claim 1, being further described by the formula:

wherein U and V are saturated cyclic structures containing between 3 and 20 carbon atoms and form a cycloalkyl ring with the carbon atoms of the macrocycle to which they are attached.

3. The catalyst of claim 2, wherein U and V are saturated cyclic structures containing between 4 and 10 carbon atoms and form a cycloalkyl ring with the carbon atoms of the macrocycle to which they are attached.

4. The catalyst of claim 2, wherein U and V are trans-cyclohexanyl fused rings.

5. The catalyst of claim 2, wherein W is a substituted pyridino moiety.

6. The catalyst of claim 2, wherein U and V are trans-cyclohexanyl fused rings and W is a substituted pyridino moiety.

7. The catalyst of claim 2, wherein W is a substituted pyridino moiety with one to three substituents selected from the group consisting of cyclohexyl and benzyloxy.

8. The catalyst of claim 2, wherein W is a substituted pyridino moiety with one to three substituents selected from the group consisting of alkyl (2-thioacetic acid) esters and aryl (2-thioacetic acid) esters.

9. The catalyst of claim 2, wherein W is a substituted pyridino moiety with one to three substituents selected from the group consisting of hydroxyl alkyl thio, methoxyarylthio, and alkoxycarbonylarylthio.

10. The catalyst of claim 1, wherein the catalyst is selected from the group consisting of Compounds 1, 3, 4, 7, 10, 13, 15, 14, 16, 25, 28, 31, and 42.

21. A pharmaceutical composition comprising the catalyst of claim 1 and a pharmaceutically acceptable carrier.

22. The pharmaceutical composition of claim 21 wherein the composition is formulated for topical application.

23. The pharmaceutical composition of claim 21 wherein the composition is formulated for parenteral administration.

24. A pharmaceutical composition comprising the catalyst of claim 2 and a pharmaceutically acceptable carrier.

25. The pharmaceutical composition of claim 24 wherein the composition is formulated for topical application.

26. The pharmaceutical composition of claim 24 wherein the composition is formulated for parenteral administration.

27. A method for dismutating superoxide anions comprising adding a compound of claim 1 to an aqueous environment containing superoxide anions.

28. A method of preventing or treating a disease or disorder in which superoxide anions are implicated, comprising administering to a subject in need of such prevention or treatment, a therapeutically, prophylactically, pathologically, or resuscitative effective amount of at least one compound of claim 1.

29. The method of claim 28 wherein said disease or disorder is selected from the group consisting of reperfusion injury to the ischemic myocardium, general inflammation, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, hypertension, psoriasis, organ transplant rejections, organ preservation, radiation-induced injury, platelet aggregation, stroke, autoimmune diseases, refractory hypotension, adult respiratory distress, carcinogenesis, severe chronic pain, reversal of opioid tolerance, hyperalgesia, and sepsis.

30. The method of claim 28 wherein said disease or disorder is selected from the group consisting of ischemic reperfusion injury, inflammation, hyperalgesia, sepsis, refractory hypotension, stroke, reversal of opioid tolerance, and hypertension.

31. A method of synthesizing a compound of claim 1 having the formula:

wherein W is an aromatic nitrogen containing heterocycle consisting of six atoms in the heterocyclic ring and substituted opposite the nitrogen which is a member of the macrocycle with a nucleophile, and wherein R, R₁, 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 are as defined in claim 1, while maintaining the chelated complex of the transition metal ion and the ligand, the method comprising;

a) providing a compound of the formula;

 

wherein W is a an aromatic nitrogen containing heterocycle consisting of six atoms in the heterocyclic ring and substituted opposite the nitrogen which is a member of the macrocycle with a halide;

b) adding a nucleophile to the compound in a); and

c) stirring the reaction mixture until the completion of the reaction.

11. A macrocyclic organic ligand with the following formula:

wherein a nitrogen of the macrocycle and the two adjacent carbon atoms to which it is attached independently form a substituted, unsaturated, nitrogen-containing heterocycle W having 2 to 20 carbon atoms, which may be an aromatic heterocycle, in which case the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and the R groups attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent;

and wherein R, R₁, 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 represent hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals;

and, optionally, one or more of 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, or R₈ or R′

₈ and R₉ or R′

₉ together with the carbon atoms to which they are attached independently form a substituted or unsubstituted nitrogen containing heterocycle having 2 to 20 carbon atoms, which may be an aromatic heterocycle, in which case the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and the R groups attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent;

and, optionally, one or more of 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 cyclic or heterocyclic having 3 to 20 carbon atoms;

and, optionally, one of R, R₁, 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′

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

12. The ligand of claim 11, being further described by the formula:

wherein U and V are saturated cyclic structures containing between 3 and 20 carbon atoms and form a cycloalkyl ring with the carbon atoms of the macrocycle to which they are attached.

13. The ligand of claim 12, wherein U and V are saturated cyclic structures containing between 4 and 10 carbon atoms and form a cycloalkyl ring with the carbon atoms of the macrocycle to which they are attached.

14. The ligand of claim 12, wherein U and V are trans-cyclohexanyl fused rings.

15. The ligand of claim 12, wherein W is a substituted pyridino moiety.

16. The ligand of claim 12, wherein U and V are trans-cyclohexanyl fused rings and W is a substituted pyridino moiety.

17. The ligand of claim 12, wherein W is a substituted pyridino moiety with at least one substituent selected from the group consisting of cyclohexyl and benzyloxy.

18. The ligand of claim 12, wherein W is a substituted pyridino moiety with at least one substituent selected from the group consisting of alkyl (2-thioacetic acid) esters and aryl (2-thioacetic acid) esters.

19. The ligand of claim 12, wherein W is a substituted pyridino moiety with at least one substituent selected from the group consisting of hydroxyl alkyl thio, methoxyarylthio, and alkoxycarbonylarylthio.

20. The ligand of claim 11, wherein the ligand is selected from the group consisting of the precursor ligands of Compounds 1, 3, 4, 7, 10, 13, 15, 14, 16, 25, 28, 31, and 42.