METHODS OF MAKING SUBSTITUTED PORPHYRIN PHARMACEUTICAL COMPOUNDS AND COMPOSITIONS

• US 20190330220A1
• Filed: 12/19/2017
• Published: 10/31/2019
• Est. Priority Date: 12/20/2016
• Status: Active Application

• Current Assignee: Biomimetix Jv, LLC, Duke University
• Original Assignee: Biomimetix Jv, LLC, Duke University
• Inventors: Batinic-Haberle, Ines, Tovmasyan, Artak, Dzolic, Zrinka Rajic, Spasojevic, Ivan, Lee, Christopher Allen
• Application Number:
  US16/468,911
• Publication Number:
  US 20190330220A1
• Time in Patent Office: Days
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07F 13/005 Compounds without a metal-carbon linkage

Abstract

Described herein are methods and intermediates useful for making substituted porphyrins, including Mn(III) orthoN-butoxyethylpyridylporphyrin, and compositions comprising the same. In some embodiments, a method of the present invention provides a composition having a certain percentage or yield (e.g., at least 80%, 85%, 90%, or 95% by weight) of a compound of the present invention.

Claims

1. A method of making a compound of Formula 001:

2. The method of claim 1, wherein said monitoring step is carried out with a pH sensor or detector contacting said mixed solution during said oxygenating step.

3. The method of claim 1 or 2, wherein said periodically adjusting step is carried out by adding a base to said mixed solution when said monitored pH is less than 7.6 or 7.8, and/or adding an acid to said mixed solution when said monitored pH is greater than 8.2 or 8.4.

4. The method of claim 1 to 3, wherein said step of providing said compound of Formula 001-2 is carried out by providing a composition of pyridyl porphyrins,

said composition comprising said compound of Formula 001-2 in a combination with other different pyridyl porphyrins,

wherein at least 80, 85, 90, or 95 percent by weight of all pyridyl porphyrins in said composition is said compound of Formula 001-2.

5. The method of claim 1 to 4, wherein at least 80, 85, 90, or 95 percent by weight of all manganese pyridyl-porphyrins produced from said compound of Formula 001-2, or said composition comprising said compound of Formula 001-2, is said compound of Formula 001.

6. The method of claim 4 or claim 5 dependent on claim 4, wherein not more than 20, 15, 10 or 5 percent by weight of all manganese pyridyl-porphyrins produced from said method consist of compounds of Formulas (iii), (iv), (v), (vi), (vii) and (viii):

7. A method of making a compound of Formula 001-2

8. The method of claim 7, wherein said combining step (b) is carried out with a 2-butoxyethyl p-toluenesulfonate composition comprising less than 1 weight percent (relative to said 2-butoxyethyl p-toluenesulfonate) of tetrahydrofuran (THF).

9. The method of claim 7 or 8, wherein said tri-n-octylamine is included in an amount in a range of about 5 to about 25 molar excess over H₂T-2-PyP.

10. A pharmaceutical composition comprising metallated pyridyl-porphyrins in a pharmaceutically acceptable carrier, wherein at least 80, 85, 90 or 95 percent by weight of all of said metallated pyridyl-porphyrins in said composition is a compound of Formula 001:

11. The composition of claim 10, wherein X is selected from the group consisting of Cl, PF₆ tosylate, mesylate, and besylate.

12. The composition of claim 10 or 11, wherein said carrier is an aqueous carrier.

13. The composition of claim 10 to 12, wherein said composition comprises, excluding the weight of said carrier, less than 1, 1.3 or 2 percent by weight free manganese.

14. The composition of claims 10 to 13, wherein not more than 20, 15, 10 or 5 percent by weight of all metallated pyridyl-porphyrins in said composition consist of compounds of Formulas (iii), (iv), (v), (vi), (vii) and (viii):

15. The composition of claim 10 to 14 for use in treating inflammatory lung disease, neurodegenerative disease, radiation injury, cancer, diabetes, cardiac conditions, or sickle cell disease.

16. A method of making a compound of Formula 002:

17. The method of claim 16, wherein said monitoring step is carried out with a pH sensor or detector contacting said mixed solution during said oxygenating step.

18. The method of claim 16 or 17, wherein said periodically adjusting step is carried out by adding a base to said mixed solution when said monitored pH is less than 7.6 or 7.8, and/or adding an acid to said mixed solution when said monitored pH is greater than 8.2 or 8.4.

19. The method of claim 16 to 18, wherein said step of providing said compound of Formula 002-2 is carried out by providing a composition of pyridyl porphyrins,

said composition comprising said compound of Formula 002-2 in a combination with other different pyridyl porphyrins,

wherein at least 80, 85, 90, or 95 percent by weight of all pyridyl porphyrins in said composition is said compound of Formula 002-2.

20. The method of claim 16 to 19, wherein at least 80, 85, 90, or 95 percent by weight of all manganese pyridyl-porphyrins produced from said compound of Formula 002-2, or said composition comprising said compound of Formula 002-2, is said compound of Formula 002.

21. The method of claim 19 or claim 20 dependent on claim 19, wherein not more than 20, 15, 10 or 5 percent by weight of all manganese pyridyl-porphyrins produced from said method consist of compounds of Formulas (iiia), (iva), (va), (via), (viia) and (viiia):

22. A method of making a compound of Formula 002-2

23. The method of claim 22, wherein said combining step (b) is carried out with a 2-alkoxyethyl p-toluenesulfonate composition comprising less than 1 weight percent (relative to said 2-alkoxyethyl p-toluenesulfonate) of tetrahydrofuran (THF).

24. The method of claim 22 or 23, wherein said tri-n-octylamine is included in an amount in a range of about 5 to about 25 molar excess over H₂T-2-PyP.

25. A pharmaceutical composition comprising metallated pyridyl-porphyrins in a pharmaceutically acceptable carrier, wherein at least 80, 85, 90 or 95 percent by weight of all of said metallated pyridyl-porphyrins in said composition is a compound of Formula 002:

26. The composition of claim 25, wherein X is selected from the group consisting of Cl, PF₆ tosylate, mesylate, and besylate.

27. The composition of claim 25, wherein R in a compound of Formula 002 is a C4 alkyl, a C5 alkyl or a C6 alkyl.

28. The composition of claim 25 to 27, wherein said carrier is an aqueous carrier.

29. The composition of claim 25 to 28, wherein said composition comprises, excluding the weight of said carrier, less than 1, 1.3 or 2 percent by weight free manganese.

30. The composition of claims 25 to 29, wherein not more than 20, 15, 10 or 5 percent by weight of all metallated pyridyl-porphyrins in said composition consist of compounds of Formulas (iiia), (iva), (va), (via), (viia) and (viia):

31. The composition of claim 25 to 30 for use in treating inflammatory lung disease, neurodegenerative disease, radiation injury, cancer, diabetes, cardiac conditions, or sickle cell disease.