Biologically active methylene blue derivatives

• US 7,371,744 B2
• Filed: 11/26/2003
• Issued: 05/13/2008
• Est. Priority Date: 05/30/2001
• Status: Expired due to Fees

• Current Assignee: Photopharmica Limited
• Original Assignee: Photopharmica Limited
• Inventors: O'Grady, Cassandra C., Mellish, Kirste J., Brown, Stanley B., Vernon, David I., Griffiths, John
• Primary Examiner(s): Marschel; Ardin H.
• Assistant Examiner(s): Royds; Leslie A
• Application Number:
  US10/723,420
• Publication Number:
  US 20040147508A1
• Time in Patent Office: 1,630 Days
• Field of Search: 514/224.8
• US Class Current: 514/224.8
• CPC Class Codes: A61K 41/0057 Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
• CPC Class Codes: A61K 49/003 Thiazine dyes
• CPC Class Codes: A61K 8/4986 with sulfur as the only hetero atom
• CPC Class Codes: A61L 2/0029 Radiation
• CPC Class Codes: A61L 2/0082 using chemical substances
• CPC Class Codes: A61L 2/08 Radiation
• CPC Class Codes: A61L 2/232 layered or coated
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 17/10 Anti-acne agents
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/02 Local antiseptics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• 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: A61Q 11/00 : Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
• CPC Class Codes: C07D 279/18 : [b, e]-condensed with two six-membered rings

Abstract

A phenothiazinium compound of Formula (I):

wherein:

• A and B each independently is

in which R′ and R″ each independently is a linear, branched or cyclic hydrocarbon group, or R′ and R″ together with the N atom to which they are attached form an optionally substituted 5-, 6- or 7-membered ring;

• and where X^P− is a counteranion and P is 1, 2 or 3;
• except for the compounds in which A and B are both either —N(CH₃)₂ or
• —N(CH₂CH₃)₂ for use in a treatment that requires removal, deactivation or killing of unwanted tissues or cells.

Claims

1. A method of treatment of a fungal infection due to Candida albicans, Gram negative bacterial infection due to E. coli or P. aeruginosa, or Gram positive bacterial infection due to S. aureus or methicillin resistant S. aureus, the method comprising administering to a subject having an area infected with Candida albicans, E. coli, P. aeruginosa, S. aureus or methicillin resistant S. aureus, by systemic administration or by local application to said infected area, a therapeutically effective amount of a compound selected from the group consisting of:

[3,7-(tetra-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3,7-(tetra-n-butylamino)-phenothiazin-5-ium]_P X^P−

,

[3,7-(tetra-n-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3,7-(tetra-iso-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-butylamino)-7-(N,N-di-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-hexylamino)-7-(N,N-di-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(2-ethylpiperidino)-7-(N,N-di-n-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(2-methylpyrrolidino)-7-(N,N-di-n-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3,7-(N,N-tetra-iso-butylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-butylamino)-7-(N,N-di-iso-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-diethylamino)-7-(N,N-di-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-pentylamino)-7-(N,N-di-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-butylamino)-7-(N,N-di-n-pentylamino)-phenothiazin-5-ium]_P X^P−

, and

[3-((N-ethyl-N-cyclohexyl) amino)-7((-N-ethyl)-N-cyclohexyl) amino-phenothiazin-5-ium]_P X^P−

,

wherein X^P−

is a counteranion and P is 1, 2 or 3,

and exposing said infected area to light to render active said compound and

thereby effecting said treatment of said fungal infection, said Gram negative bacterial infection or said Gram positive bacterial infection.

2. The method according to claim 1 wherein said compound is [3,7-(tetra-n-butylamino)-phenothiazin-5-ium]_P X^P−

.

3. The method according to claim 1 wherein said method comprises administering to said subject, by local application to said infected area, said therapeutically effective amount of said compound of Formula (I).

4. The method according to claim 1 wherein said method is a method of treating said Gram negative bacterial infection or said Gram positive bacterial infection.

5. The method according to claim 4 wherein said method is a method of treating said Gram positive bacterial infection due to methicillin resistant S. aureus.

6. The method according to claim 1 wherein said fungal infection, Gram negative bacterial infection or Gram positive bacterial infection is present at a bum wound, ulcer or surgical wound.

7. The method according to claim 1 wherein said fungal infection, Gram negative bacterial infection or Gram positive bacterial infection is present on the gums of said subject.

11. The method according to any one of claims 1, 8, 9 and 10 wherein the counteranion represented by X^P−

is selected from the group consisting of F⁻

, Br⁻

, Cl⁻

, I⁻

, NO₃⁻

, SCN⁻

, Cl₃⁻

, ClO₄⁻

, IO₃⁻

, BF₄⁻

, HSO₄⁻

, H₂PO₄⁻

, CH₃SO₄⁻

, N₃⁻

, SO₄²⁻

, HPO₄²⁻

, PO₄³⁻

, acetate, lactate, citrate, tartrate, glycolate, glycerate, glutamate, β

-hydroxyglutamate, glucouronate, gluconate, malate and aspartate.

12. The method according to claim 11 wherein the counteranion represented by X^P−

is a halide.

13. The method according to any one of claims 1, 8, 9 and 10 wherein said compound [3,7-(tetra-n-butylamino)-phenothiazin-5-ium]_P X^P−

, [3,7-(tetra-n-pentylamino)-phenothiazin-5-ium]_P X^P−

or [3-((N-ethyl-N-cyclohexyl) amino)-7((-N-ethyl)-N-cyclohexyl) amino-phenothiazin-5-ium]_P X^P−

.

8. A method of killing or deactivating any Candida albicans, E. coli, P. aeruginosa, S. aureus or methicillin resistant S. aureus present on a surface or in a fluid comprising:

contacting or applying a compound selected from the group consisting of;

[3,7-(tetra-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3,7-(tetra-n-butylamino)-phenothiazin-5-ium]_P X^P−

,

[3,7-(tetra-n-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3,7-(tetra-iso-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-butylamino)-7-(N,N-di-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-hexylamino)-7-(N,N-di-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(2-ethylpiperidino)-7-(N,N-di-n-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(2-methylpyrrolidino)-7-(N,N-di-n-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3,7-(N,N-tetra-iso-butylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-butylamino)-7-(N,N-di-iso-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-diethylamino)-7-(N,N-di-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-pentylamino)-7-(N,N-di-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-butylamino)-7-(N,N-di-n-pentylamino)-phenothiazin-5-ium]_P X^P−

, and

[3-((N-ethyl-N-cyclohexyl) amino)-7((-N-ethyl)-N-cyclohexyl) amino-phenothiazin-5-ium]_P X^P−

,

wherein X^P−

is a counteranion and P is 1, 2 or 3,

to said surface or fluid; and

exposing said surface or fluid to which said compound has been applied or contacted to light to activate said compound and thereby kill or deactivate said Candida albicans, E. coli, P. aeruginosa, S. aureus or methicillin resistant S. aureus.

9. A method for killing or deactivating any Candida albicans, E. coli, P. aeruginosa, S. aureus or methicillin resistant S. aureus present in a fluid comprising contacting the fluid with a composite formed between:

a compound selected from the group consisting of;

[3,7-(tetra-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3,7-(tetra-n-butylamino)-phenothiazin-5-ium]_P X^P−

,

[3,7-(tetra-n-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3,7-(tetra-iso-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-butylamino)-7-(N,N-di-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-hexylamino)-7-(N,N-di-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(2-ethylpiperidino)-7-(N,N-di-n-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(2-methylpyrrolidino)-7-(N,N-di-n-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3,7-(N,N-tetra-iso-butylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-butylamino)-7-(N,N-di-iso-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-diethylamino)-7-(N,N-di-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-pentylamino)-7-(N,N-di-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-butylamino)-7-(N,N-di-n-pentylamino)-phenothiazin-5-ium]_P X^P−

, and

[3-((N-ethyl-N-cyclohexyl) amino)-7((-N-ethyl)-N-cyclohexyl) amino-phenothiazin-5-ium]_P X^P−

,

wherein X^P−

is a counteranion and P is 1, 2 or 3,

and a polymer and exposing said fluid to which said composite has been contacted to light to activate said composite and thereby kill or deactivate said Candida albicans, E. coli, P. aeruginosa, S. aureus or methicillin resistant S. aureus.

10. A method of treating a skin disease selected from the group consisting of psoriasis, acne, vitiligo and eczema comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of:

[3,7-(tetra-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3,7-(tetra-n-butylamino)-phenothiazin-5-ium]_P X^P−

,

[3,7-(tetra-n-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3,7-(tetra-iso-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-butylamino)-7-(N,N-di-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-hexylamino)-7-(N,N-di-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(2-ethylpiperidino)-7-(N,N-di-n-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(2-methylpyrrolidino)-7-(N,N-di-n-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3,7-(N,N-tetra-iso-butylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-butylamino)-7-(N,N-di-iso-pentylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-diethylamino)-7-(N,N-di-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-pentylamino)-7-(N,N-di-n-propylamino)-phenothiazin-5-ium]_P X^P−

,

[3-(N,N-di-n-butylamino)-7-(N,N-di-n-pentylamino)-phenothiazin-5-ium]_P X^P−

, and

[3-((N-ethyl-N-cyclohexyl) amino)-7((-N-ethyl)-N-cyclohexyl) amino-phenothiazin-5-ium]_P X^P−

,

wherein X^P−

is a counteranion and P is 1, 2 or 3,

and exposing an area of skin of said subject affected by said skin disease to light to render active said compound and

thereby effecting said treatment of said skin disease.