Substituted porphyrins

• US 20040058902A1
• Filed: 06/09/2003
• Published: 03/25/2004
• Est. Priority Date: 06/07/2002
• Status: Active Grant

• Current Assignee: Duke University, Nokia Corporation
• Original Assignee: Duke University
• Inventors: Fridovich, Irwin, Batinic-Haberle, Ines, Spasojevic, Ivan
• Granted Patent: US 7,485,721 B2
• Time in Patent Office: Days
• US Class Current: 514/185
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings

Abstract

A series of ortho isomers of meso tetrakis N-alkylpyridylporphyrins (alkyl being methyl, ethyl, n-propyl, n-butyl, n-hexyl, and n-octyl) and their Mn(III) complexes were synthesized and characterized by elemental analysis, uv/vis spectroscopy, electrospray ionization mass spectrometry and electrochemistry. An increase in the number of carbon atoms in the alkyl chains from 1 to 8 is accompanied by an increase in: (a) lipophilicity measured by the chromatographic retention factor, R_f; (b) metal-entered redox potential, E_1/2 from +220 to +367 mV vs NHE, and (c) proton dissociation constant, pK_a2 from 10.9 to 13.2. A linear correlation was found between E_1/2 and R_f of the Mn(III) porphyrins and between the pK_a2 and R_f of the metal-free compounds. As the porphyrins become increasingly more lipophilic, the decrease in hydration disfavors the separation of charges, while enhancing the electron-withdrawing effect of the positively charged pyridyl nitrogen atoms. Consequently, the E_1/2 increases linearly with the increase in pK_a2, a trend in porphyrin basicity opposite from the one we previously reported for other water-soluble Mn(III) porphyrins. All of these Mn(III) porphyrins are potent catalysts for superoxide dismutation (disproportionation). Despite the favorable increase of E_1/2 with the increase in chain length, the catalytic rate constant decreases from methyl (log k_cat=7.79) to n-butyl, and then increases such that the n-octyl is as potent an SOD mimic as are the methyl and ethyl compounds. The observed behavior originates from an interplay of hydration and steric effects that modulate electronic effects.

Claims

1. A compound of formula

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

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

4. The compound according to claim 1 wherein said compound is of Formula I or III.

5. The compound according to claim 4 wherein said compound is of Formula I and M is manganese.

6. A method of protecting cells from oxidant-induced toxicity comprising contacting said cells with a protective amount of the compound of claim 1 under conditions such that the protection is effected.

7. The method according to claim 6 wherein said cells are mammalian cells.

8. A method of treating a pathological condition of a patient resulting from oxidant-induced toxicity comprising administering to said patient an effective amount of the compound of claim 1 under conditions such that the treatment is effected.

9. A method of treating a pathological condition of a patient resulting from degradation of NO′

, comprising administering to said patient an effective amount of the compound of claim 1 under conditions such that the treatment is effected.

10. A method of treating a patient for inflammatory lung disease comprising administering to said patient an effective amount of the compound of claim 1 under conditions such that the treatment is effected.