Oxidant scavengers

• US 5,994,339 A
• Filed: 06/07/1995
• Issued: 11/30/1999
• Est. Priority Date: 10/15/1993
• Status: Expired due to Term

• Current Assignee: Aeolus Sciences Incorporated, Duke University, Goodnow Capital, L.L.C., The University Of Alabama At Birmingham Research Foundation
• Original Assignee: Duke University, The University Of Alabama At Birmingham Research Foundation
• Inventors: Day, Brian J., Fridovich, Irwin, Crapo, James D., Freeman, Bruce A., Folz, Rodney J., Oury, Tim
• Primary Examiner(s): Wax, Robert A.
• Assistant Examiner(s): Saidha, Tekchand
• Application Number:
  US08/476,866
• Time in Patent Office: 1,637 Days
• Field of Search: 435/85.1, 435/94.4, 435/189, 435/240.2, 435/320.1, 435/252.3, 435/254, 536/23.2, 536/27, 424/94.4, 514/185, 540/145, 252/399, 252/400.23
• US Class Current: 514/185
• CPC Class Codes: A01K 2207/15 Humanized animals
• CPC Class Codes: A01K 2217/00 Genetically modified animals
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/03 Animal model, e.g. for test or diseases
• CPC Class Codes: A01K 2267/0368 Animal model for inflammation
• CPC Class Codes: A01K 67/0278 Knock-in vertebrates, e.g. humanised vertebrates
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/546 Porphyrines; Porphyrine with an expanded ring system, e.g. texaphyrine
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07K 14/8121 Serpins
• CPC Class Codes: C12N 15/8509 for producing genetically modified animals, e.g. transgenic
• CPC Class Codes: C12N 9/0089 acting on superoxide as acceptor (1.15)

Abstract

The present invention relates, in general, to a method of modulating physiological and pathological processes and, in particular, to a method of modulating intra- and extracellular 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.

Claims

1. A method of treating an inflammatory condition in a patient in need of such treatment comprising administering to said patient an effective amount of a mimetic of superoxide dismutase (SOD) or extracellular SOD (EC-SOD) comprising a porphyrin moiety, under conditions such that said treatment is effected, wherein the mimetic is of the formula:

##STR23## or a pharmaceutically acceptable salt thereof, wherein;

R₁ is a bond ##STR24## wherein X is a halogen and Y is an alkyl group and wherein ##STR25## indicates bonding to R₂ at any position and ##STR26## indicates bonding to R₂ and the substituent at any position; and

R₂ is a bond ##STR27## wherein Y'"'"' is hydrogen or an alkyl group and wherein n is 1 to 8; and

R₃ is --Y", --OH, --NH₂, --N⁺ (Y")₃, --COOH, --COO^-, --SO₃ H, --SO₃^-, --CH₂ --PO₃ H₂ or --CH₂ --PO₃ H^-, wherein Y" is an alkyl group, optionally complexed with a metal selected from the group consisting of manganese, copper and iron.

3. The method according to claim 1 wherein said inflammatory condition is an inflammation of the lungs of said patient.

5. The method according to claim 1 wherein --R₁ --R--R₃ is ##STR33##

7. The method according to claim 5 wherein said inflammatory condition is an inflammation of the lungs of said patient.

9. The method according to claim 1 wherein a GAG binding moiety is attached to said mimetic.

10. The method according to claim 9 wherein said GAG binding moiety corresponds to the C-terminal end of EC-SOD, or portion thereof, having heparin binding affinity.

11. The method according to claim 9 wherein said GAG binding moiety comprises a repeat of positively charged amino acids.

2. A method of treating a disorder resulting from aberrant smooth muscle function in a patient in need of such treatment comprising administering to said patient an effective amount of a mimetic of SOD or EC-SOD comprising a porphyrin moiety, under conditions such that said treatment is effected, wherein the mimetic is of the formula:

##STR28## or a phamraceutically acceptable salt thereof, wherein;

R₁ is a bond, ##STR29## wherein X is a halogen and Y is an alkyl group and wherein ##STR30## indicates bonding to R₂ at any position and ##STR31## indicates bonding to R₂ and the substituent at any position; and

R₂ is a bond, ##STR32## wherein Y'"'"' is hydrogen or an alkyl group and wherein n is 1 to 8; and

R₃ is --Y", --OH, --NH₂, --N⁺ (Y")₃, --COOH, --COO^-, --SO₃ H, --SC₃^-, --CH₂ --PO₃ H₂ or --CH₂ --PO₃ H^-, wherein Y" is an alkyl group, optionally complexed with a metal selected from the group consisting of maganese copper and iron.

4. The method according to claim 2 wherein said aberrant smooth muscle function is in the lung airways or vasculature of said patient.

6. The method according to claim 2 wherein --R₁ --R₂ --R₃ is:

8. The method according to claim 6 wherein said aberrant smooth muscle function is in the lung airways or vasculature of said patient.

12. The method according to claim 2 wherein a GAG binding moiety is attached to said mimetic.

13. The method according to claim 12 wherein said GAG binding moiety corresponds to the C-terminal end of EC-SOD, or portion thereof, having heparin binding affinity.

14. The method according to claim 12 wherein said GAG binding moiety comprises a repeat of positively charged amino acids.