Non-genotoxic metalloporphyrins as synthetic catalytic scavengers of reactive oxygen species

• US 6,403,788 B1
• Filed: 07/11/2000
• Issued: 06/11/2002
• Est. Priority Date: 07/11/2000
• Status: Expired due to Fees

• Current Assignee: Eukarion, Inc.
• Original Assignee: Eukarion, Inc.
• Inventors: Cosledan, Frédéric, Meunier, Bernard
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): Habte, Kahsay
• Application Number:
  US09/613,891
• Time in Patent Office: 700 Days
• Field of Search: 540/145, 514/185, 514/81
• US Class Current: 540/145
• 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

This invention relates to compounds which are non-genotoxic metalloporphyrins. These compounds are synthetic catalytic scavengers of reactive oxygen chemical species. The invention also relates to pharmaceutical compositions comprising these compounds and to methods of use of these compounds for preventing or arresting free radical associated diseases or conditions.

Claims

1. A compound of Structural Formula I:

or a complex thereof with a first row transition metal ion, wherein

R₁, R₂, R₃ and R₄ are the same or different and are each a group of the formula

 

wherein L is a linker of 2 to 12 atoms in length, wherein said atoms are carbon atoms optionally interspersed with from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur;

X is nitrogen or phosphorus;

R₁₃, R₁₄ and R₁₅ are each, independently, hydrogen, alkyl or arylalkyl; and

Y—

is a monovalent anion;

R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂ are each independently selected from the group consisting of hydrogen, alkyl and halo; and

each R₁₆ independently represents one or more substituents independently selected from the group consisting of hydrogen, hydroxy, halo and alkyl.

2. The compound of claim 1 wherein R₁, R₂, R₃ and R₄ are the same.

3. The compound of claim 1 wherein R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and R₁₂ are each hydrogen.

4. The compound of claim 1 wherein L is selected from the group consisting of linear or branched C₂-C₁₂ alkylene and linear or branched alkylene interspersed at one or more positions with a heteroatom selected from the group consisting of oxygen, nitrogen and sulphur.

5. The compound of claim 2 wherein R₁₃, R₁₄ and R₁₅ are each independently selected from the group consisting of hydrogen and linear and branched C₁-C₂₀ alkyl.

6. The compound of claim 4 wherein R₁₃, R₁₄ and R₁₅ are each independently hydrogen or methyl or ethyl.

7. The compound of claim 5 wherein R₁₃ and R₁₄ are each independently, methyl or ethyl and R₁₅ is hydrogen.

8. The compound of claim 3 wherein L is a linear C₂-C₆ alkylene group.

9. The compound of claim 7 wherein L is an ethylene group.

10. The compound of claim 2 wherein R₁₆ represents hydrogen.

11. The compound of claim 2 wherein R₁, R₂, R₃ and R₄ are each connected to the 3 position of the phenyl ring and R₁₆ represents methyl groups at the 2, 4 and 6 positions of the phenyl ring.

12. The compound of claim 2 wherein:

R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂ are each hydrogen;

R₁₆ represents hydrogen;

R₁, R₂, R₃ and R₄ are connected to the 3 or 4 position of the phenyl ring;

L is an ethylene group; and

R₁₃, R₁₄ and R₁₅ are each, independently, hydrogen, methyl or ethyl.

39. A method of reducing oxyradical- or reactive oxygen-induced damage to cells comprising introducing a compound of claim 1 to said cells wherein said introducing results in a decrease in the amount of free oxygen radical or nonradical reactive oxygen species in said cells when compared to not introducing said compound, wherein said decrease in the amount of free oxygen radical or nonradical reactive oxygen species reduces oxyradical- or reactive oxygen-induced damage to said cells.

13. A compound selected from the group of ligands consisting of:

meso-tetrakis[4-(N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenyl]porphyrinato;

meso-tetrakis[4-(N-(2-(N,N-dimethylammonio)ethyl)aminosulfonyl)phenyl]porphyrinato A⁴⁻

;

meso-tetrakis[4-(N-(2-(N,N,N-trimethylammonio)ethyl)aminosulfonyl)phenyl]porphyrinato A⁴⁻

;

meso-tetrakis[4-(N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)phenyl]porphyrinato;

meso-tetrakis[4-(N-(2-(N,N-diethylammonio)ethyl)aminosulfonyl)phenyl]porphyrinato A⁴⁻

;

meso-tetrakis[4-(N-(2-(N,N,N-triethylammonio)ethyl)aminosulfonyl)phenyl]porphyrinato A⁴⁻

;

meso-tetrakis[4-(N-(2-(N,N,N-ethyldimethylammonio)ethyl)aminosulfonyl)phenyl]porphyrinato A⁴⁻

;

meso-tetrakis[4-(N-(2-(N,N,N-diethylmethylammonio)ethyl)aminosulfonyl)phenyl]porphyrinato A⁴⁻

;

meso-tetrakis[3-(N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato;

meso-tetrakis[3-(N-(2-(N,N-dimethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato A⁴⁻

;

meso-tetrakis[3-(N-(2-(N,N-diethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato A⁴⁻

;

meso-tetrakis[3-(N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato;

meso-tetrakis[3-(N-(2-(N,N,N-triethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato A⁴⁻

;

meso-tetrakis[3-(N-(2-(N,N,N-trimethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato A⁴⁻

;

meso-tetrakis[3-(N-(2-(N,N-ethyldimethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato A⁴⁻

;

meso-tetrakis[3-(N-(2-(N,N,N-diethylmethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato A⁴⁻

;

meso-tetrakis[4-(N-(2-(N,N-ethylmethylamino)ethyl)aminosulfonyl)phenyl]porphyrinato;

meso-tetrakis[4-(N-(2-(N,N-ethylmethylammonio)ethyl)aminosulfonyl)phenyl]porphyrinato A⁴⁻

;

meso-tetrakis[3-(N-(2-(N,N-ethylmethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato A⁴⁻

; and

meso-tetrakis[3-(N-(2-(N,N-ethylmethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato A⁴⁻

;

meso-tetrakis[4-(N-(2-(N,N-dimethylphosphonio)ethyl)aminosulfonyl)phenyl]porphyrinato;

meso-tetrakis[4-(N-(2-(N,N-diethylphosphonio)ethyl)aminosulfonyl)phenyl]porphyrinato;

meso-tetrakis[3-(N-(2-(N,N-dimethylphosphonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato;

meso-tetrakis[3-(N-(2-(N,N-diethylphosphonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato A⁴⁻

;

meso-tetrakis[3-(N-(2-(N,N-diethylphosphonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato; and

meso-tetrakis[4-(N-(2-(N,N-ethylmethylphosphonio)ethyl)aminosulfonyl)phenyl]porphyrinato;

or a complex thereof with a first row transition metal ion;

wherein A⁴⁻

represents from 1 to 4 anions having a total electronic charge of 4⁻

.

14. The compound of claim 13 wherein said compound is a complex with a transition metal ion selected from the group consisting of manganese, iron, cobalt, copper and zinc.

15. The compound of claim 14 wherein the transition metal ion is Mn(III) or Fe(III) and the transition metal ion is bonded to an additional anionic ligand.

16. The compound of claim 15 wherein the additional anionic ligand is selected from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl and ZCOO⁻

, wherein Z is an alkyl, aryl or arylalkyl group.

17. The compound of claim 16 wherein the additional anionic ligand is hydroxyl, chloro or acetato.

18. A pharmaceutical formulation comprising one or more pharmaceutically acceptable carriers, diluents or excipients and a therapeutically effective amount of at least one compound represented by Structural Formula I:

or a complex thereof with a first row transition metal ion, wherein

R₁, R₂, R₃ and R₄ are the same or different and are each a group of the formula

 

wherein L is a linker of 2 to 12 atoms in length, wherein said atoms are carbon atoms optionally interspersed with from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur;

X is nitrogen or phosphorus;

R₁₃, R₁₄ and R₁₅ are each, independently, hydrogen, alkyl or arylalkyl; and

Y—

is a monovalent anion;

R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂ are each independently selected from the group consisting of hydrogen, alkyl and halo; and

each R₁₆ independently represents one or more substituents independently selected from the group consisting of hydrogen, hydroxy, halo and alkyl.

19. A pharmaceutical formulation of claim 18 wherein the compound is selected from the group consisting of meso-tetrakis[4-(N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)phenyl]porphyrinato manganese(III) pentachloride, meso-tetrakis[4-(N-(2-(N,N-diethylammonio)ethyl)aminosulfonyl)phenyl]porphyrinato diaqua-iron (III) pentachloride, meso-tetrakis[3-(N-(2-(N,N-diethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato diaqua-manganese(III) pentachloride, meso-tetrakis[3-(N-(2-(N,N-diethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato diaqua-iron (III) pentachloride, meso-tetrakis[4-(N-(2-N,N,N-diethylmethylammonio)ethyl)aminosulfonyl)phenyl]porphyrinato diaqua-manganese(III) pentaacetate, meso-tetrakis[3-(N-(2-(N,N,N-diethylmethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato diaqua-manganese(III) pentaacetate, and meso-tetrakis[3-(N-2-(N,N,N,-diethylmethylammonio)ethyl)aminosulfonyl)2,4,6-trimethylphenyl]porphyrinato diaqua-iron (III) pentaacetate.

20. A pharmaceutical formulation of claim 18 wherein the compound is non-genotoxic.

21. A method of treating, preventing or arresting a free radical associated disease or condition comprising administering to a mammal in need of a therapeutically effective amount of a compound, represented by Structural Formula I:

or a complex thereof with a first row transition metal ion, wherein

R₁, R₂, R₃ and R₄ are the same or different and are each a group of the formula

 

wherein L is a linker of 2 to 12 atoms in length, wherein said atoms are carbon atoms optionally interspersed with from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;

X is nitrogen or phosphorus;

R₁₃, R₁₄ and R₁₅ are each, independently, hydrogen, alkyl or arylalkyl; and

Y—

is a monovalent anion;

R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂ are each independently selected from the group consisting of hydrogen, alkyl and halo; and

each R₁₆ independently represents one or more substituents independently selected from the group consisting of hydrogen, hydroxy, halo and alkyl;

wherein said administering of the compound alleviates or prevents free radical associated disease or conditions.

22. A method of claim 21 wherein the compound is selected from the group consisting of:

Structural Formula II, Structural Formula III, Structural Formula IV, Structural Formula V, Structural Formula VI, Structural Formula VII and Structural Formula VIII.

23. A method of claim 21 wherein the compound is non-genotoxic.

24. A method of claim 21, wherein the free radical associated disease or condition is damage resulting from a stroke, Alzheimer'"'"'s disease, dementia, Parkinson'"'"'s disease, Lou Gehrig disease, motor neuron disorders, Huntington'"'"'s disease, cancer, multiple sclerosis, systemic lupus erythematosus, scleroderma, eczema, dermatitis, delayed type hypersensitivity, psoriasis, gingivitis, adult respiratory distress syndrome, septic shock, multiple organ failure, inflammatory diseases, asthma, allergic rhinitis, pneumonia, emphysema, chronic bronchitis, AIDS, inflammatory bowel disease, gastric ulcers, pancreatitis, transplantation rejection, atherosclerosis, hypertension, congestive heart failure, myocardial ischemic disorders, angioplasty, endocarditis, retinopathy of prematurity, cataract formation, uveitis, rheumatoid arthritis, oxygen toxicity, herpes simplex infection, burns, osteoarthritis and aging.

25. A compound represented by the following Structural Formula II:

26. A compound represented by the following Structural Formula III:

27. A compound represented by the following Structural Formula IV:

28. A compound represented by the following Structural Formula V:

29. A compound represented by the following Structural Formula VI:

30. A compound represented by the following Structural Formula VII:

31. A compound represented by the following Structural Formula VIII:

32. A method of preparing the compound, meso-tetrakis[4-(N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)phenyl]porphyrinato manganese (III) pentachloride, represented by Structural Formula II, comprising:

(a) reacting meso-tetraphenyl porphyrin, Structural Formula i, with chlorosulfonic acid and subsequently N,N-diethylenediamine thereby forming first intermediate, Structural Formula ii, meso-tetrakis[4-(N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)phenyl]porphyrin;

(b) reacting first intermediate, Structural Formula ii, with Mn(OAc)₂ in the presence of a hindered base, thereby forming second intermediate, Structural Formula iii, meso-tetrakis[4-(N-(2-(N,N-diethylamino))aminosulfonyl)phenyl]porphyrinato hydroxo-manganese (III); and

(c) reacting second intermediate, Structural Formula iii, meso-tetrakis[4-(N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)phenyl]porphyrinato hydroxo-manganese (III) with hydrochloric acid thereby forming Structural Formula II, meso-tetrakis[4-(N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)phenyl]porphyrinato diaqua-manganese (III) pentachloride,

33. A method of preparing compound, meso-tetrakis[4-(N-(2-(N,N-diethylammonio)ethyl)aminosulfonyl)phenyl]porphyrinato diaqua-iron(III) pentachloride, represented by Structural Formula III, comprising:

(a) reacting meso-tetraphenyl porphyrin, Structural Formula i with chlorosulfonic acid and subsequently N,N-diethylenediamine thereby forming first intermediate, Structural Formula ii, meso-tetrakis[4-(N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)phenyl]porphyrin;

(b) reacting first intermediate, Structural Formula ii, with FeCl₂ in the presence of a hindered base, thereby forming second intermediate, Structural Formula iv, -oxo-[meso-tetrakis[4−

(N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)phenyl]porphyrinato iron(III); and

(c) reacting second intermediate, Structural Formula iv, μ

-oxo-[meso-tetrakis[4-(N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)phenyl]porphyrinato iron(III) with hydrochloric acid, thereby forming Structural Formula III, meso-tetrakis[3-(N-(2-(N,N-diethylammonio)ethyl)aminosulfonyl)phenyl]porphyrinato diaqua-iron(III) pentachloride,

34. A Method of preparing compound meso-tetrakis[3-(N-(2-(N,N-diethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato diaqua-manganese (III) pentachloride represented by Structural Formula IV comprising:

(a) reacting meso-tetrakis(2,4,6-trimethylphenyl)porphyrin, Structural Formula v with chlorosulfonic acid and subsequently N,N-diethylenediamine thereby forming first intermediate, Structural Formula vi, meso-tetrakis[3,(N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrin;

(b) reacting first intermediate, Structural Formula vi, with Mn(OAc)₂ in the presence of hindered base thereby forming second intermediate, Structural Formula vii, meso-tetrakis[3,(N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato hydroxo-manganese (III); and

(c) reacting second intermediate, Structural Formula vii, with hydrochloric acid thereby forming Structural Formula IV, meso-tetrakis[3-(N-(2-(N,N-diethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato diaqua-manganese (III) pentachloride,

35. A method of preparing compound meso-tetrakis[3-(N-(2-(N,N-diethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato diaqua-iron(III) pentachloride represented by Structural Formula V comprising:

(a) reacting meso-tetrakis(2,4,6-trimethylphenyl)porphyrin, Structural Formula v, with chlorosulfonic acid and subsequently N,N-diethylenediamine thereby forming first intermediate, Structural Formula vi, meso-tetrakis[3,(N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrin;

(b) reacting first intermediate, Structural Formula vi, with ferrous chloride in the presence of a hindered base thereby forming second intermediate, Structural Formula viii, meso-tetrakis[3-N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato hydroxo-iron (III); and

(c) reacting second intermediate, Structural Formula viii, with hydrochloric acid thereby forming Structural Formula V, meso-tetrakis[3-(N-(2-(N,N-diethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato diaqua-iron (III) pentachloride,

36. A method of preparing compound, meso-tetrakis[4-(N-(2-(N,N,N-diethylmethylammonio)ethyl)aminosulfonyl)phenyl]porphyrinato diaqua-manganese (III) pentaacetate, represented by Structural Formula VI, comprising:

(a) reacting meso-tetraphenyl porphyrin, Structural Formula i, with chlorosulfonic acid and subsequently N,N-diethylenediamine thereby forming first intermediate, Structural Formula ii, meso-tetrakis[4-(N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)phenyl]porphyrin;

(b) reacting first intermediate, Structural Formula ii, with Mn(OAc)₂ in the presence of hindered base, thereby forming second intermediate, Structural Formula iii, meso-tetrakis[4-(N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)phenyl]porphyrinato hydroxo-manganese (III);

(c) reacting second intermediate, Structural Formula iii, with methyl iodide thereby forming third intermediate, meso-tetrakis[4-(N-(2-(N,N,N,-diethylmethylammonio)ethyl)aminosulfonyl)phenyl]porphyrinato diaqua-manganese (III) pentaiodide, structural formula ix; and

(d) reacting Structural Formula ix with AGI-X8 acetate form resin to exchange the counter ion from iodide to acetate thereby forming Structural Formula VI, meso-tetrakis[4-(N-(2-(N,N,N-diethylmethylammonio)ethyl)aminosulfonyl)phenyl]porphyrinato diaqua-manganese (III) pentaacetate,

37. A method of preparing compound, meso-tetrakis[3-(N-(2-(N,N,N-diethylmethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato diaqua-manganese (III) pentaacetate, represented by Structural Formula VII comprising:

(a) reacting meso-tetrakis (2,4,6-trimethylphenyl)porphyrin, Structural Formula v, with chlorosulfonic acid and subsequently N,N-diethylenediamine, thereby forming first intermediate, Structural Formula vi, meso-tetrakis[3,(N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrin;

(b) reacting first intermediate, Structural Formula vi, with Mn(OAc)₂ in the presence of a hindered base, thereby forming second intermediate, Structural Formula vii, meso-tetrakis[3,(N-(²-(N,N-diethylamino)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrin hydroxo-manganese (III);

(c) reacting second intermediate, Structural Formula vii, with methyl iodide thereby forming third intermediate, Structural Formula x, meso-tetrakis[3-(N-(2-(N,N,N,-diethylmethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato diaqua-manganese (III) pentaiodide; and

(d) reacting third intermediate, Structural Formula x, with AGI-X8 acetate form resin to exchange the counter ion from iodide to acetate thereby forming meso-tetrakis[3-(N-(2-(N,N,N-diethylmethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato manganese (III) pentaacetate represented by Structural Formula VII,

38. A method of preparing compound, meso-tetrakis[3-(N-(2-(N,N,N,-diethylmethylammonio)ethyl)aminosulfonyl)2,4,6-trimethylphenyl]porphyrinato diaqua-iron (III) pentaacetate. Structural Formula VIII comprising;

(a) reacting meso-tetrakis(2,4,6-trimethylphenyl)porphyrin, Structural Formula v, with chlorosulfonic acid and subsequently N,N-diethylenediamine thereby forming first intermediate, Structural Formula vi, meso-tetrakis[3, (N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrin;

(b) reacting first intermediate, Structural formula vi, with ferrous chloride in the presence of a hindered base thereby forming second intermediate, Structural Formula viii, meso-tetrakis[3-(N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)2,4,6-trimethylphenyl]porphyrinato hydroxo-iron (III);

(c) reacting Structural Formula viii, meso-tetrakis[3-(N-(2-(N,N-diethylamino)ethyl)aminosulfonyl)2,4,6-trimethylphenyl]porphyrinato hydroxo-iron(III) with methyl iodide to form Structural Formula xi meso-tetrakis[3-(N-(2-(N,N,N-diethylmethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato diaqua-iron (III) pentaiodide; and

(d) reacting Structural Formula xi, meso-tetrakis[3-(N-(2-(N,N,N-diethylmethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato diaqua-iron (III) pentaiodide, with AGI-X8 acetate form resin to exchange the counter ion from iodide to acetate thereby forming Structural Formula VIII, meso-tetrakis[3-(N-(2-(N,N,N,-diethylmethylammonio)ethyl)aminosulfonyl)-2,4,6-trimethylphenyl]porphyrinato diaqua-iron (III) pentaacetate,