Biologically active methylene blue derivatives

• US 20080261960A1
• Filed: 04/04/2008
• Published: 10/23/2008
• Est. Priority Date: 05/30/2001
• Status: Active Grant

• Current Assignee: Stanley Beames Brown, Stephen John Lyon
• Original Assignee: Photopharmica Limited
• Inventors: Vernon, David Ian, Brown, Stanley Beames, Mellish, Kirste Joanne, O'Grady, Cassandra Claire, Griffiths, John, Roberts, David John Howard, Tunstall, Richard George
• Granted Patent: US 7,915,254 B2
• Time in Patent Office: Days
• US Class Current: 514/226.2
• 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

The present invention relates to 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.

The invention also relates to compositions comprising the compounds of Formula I, to selected compounds of Formula I, use of the compounds of Formula I as medicaments and as a PDT agent or a photodiagnostic agent, a conjugate or composite formed between a compound of Formula I and a polymer; and to a method for sterilising fluids in which the fluid is passed over the conjugate or composite whilst it is illuminated.

The compounds are biologically active photosensitisers which are strongly photocytotoxic and have application in the areas of photodynamic therapy (PDT), as well as for the diagnosis and detection of medical conditions and related uses in photochemical internalisation, in the production of cancer vaccines, in the treatment and prevention of microbial infections and in photodisinfection or photosterilisation.

Claims

1-42. -42. (canceled)

43. A method of inducing a photocytoxic effect, comprising applying to an area to be treated an effective amount of a compound of formula

53. A method according to any of claims 43 to 51, wherein said method is against quiescent/stationary bacteria.

54. A method according to any of claims 43 to 51, wherein said method is used against bacteria.

57. A method as claimed in any of claims 43 to 51 or 55, wherein in said compound R¹, R², R³, and R⁴ are the same and are selected from n-propyl, n-butyl, n-pentyl and n-hexyl.

59. A method as claimed in any of claims 43 to 49 or 55, wherein R¹, R², R³ and R⁴ each represent n-pentyl.

62. A method as claimed in any of claims 43 to 49 or 55, wherein R¹, R², R³ and R⁴ each represent n-butyl.

65. A method according to any of claims 43 to 49, wherein X^P−

is selected from F⁻

, Br⁻

, Cl⁻

, I⁻

, NO₃⁻

, SCN⁻

, ClO₃⁻

, ClO₄⁻

, IO₃⁻

, BF₄⁻

, HSO₄⁻

, H₂PO₄⁻

, CH₃SO₄⁻

, N₃⁻

, SO₄²⁻

, HPO₄²⁻

, PO₄³⁻

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

-hydroxyglutamate, glucouronate, gluconate, malate and aspartate.

66. A method according to any of claims 43 to 49 or 55, wherein —

NR¹R² and —

NR³R⁴ each independently is linear or branched —

C_nH_2nY wherein n is 1-10 and Y is H, F, Cl, Br, I, —

OH, —

OCH₃, —

OC₂H₅, —

OC₃H₇, —

CN, —

OCOCH₃ or phenyl, or R¹, R², R³ and R⁴ are independently cyclohexyl.

67. A method according to any of claims 43 to 49 or 51, wherein the sum of the carbon atoms in alkyl side chains represented by R¹, R², R³ and R⁴ is from 14 to 40.

68. A method according to claim 66, wherein the sum of the carbon atoms is from 18 to 30.

69. A method according to any of claims 43 to 49, 51 or 55, wherein said compound is provided in a composition which contains pharmaceutically acceptable carriers, excipients or adjuvants.

70. A method according to any of claims 43 to 49, 51 or 55 wherein said compound is provided in a composition which includes liposomes, nano-particles, colloidal suspensions, micelles, micro-emulsions, vesicles or nano-spheres.

71. A method according to any of claims 43 to 49, 51 or 55 wherein said compound is provided in a composition, which includes a delivery vehicle or excipient selected from alcohols, dimethyl sulphoxide, water, saline, solubilisers, isotonising agents, pH regulators, dyes, gelling agents, thickeners, buffers and combinations thereof.

72. A method according to claim 69, wherein the concentration of said compound is in the range 0.0005 to 20%.

73. A method according to any of claims 43 to 46, which comprises:

treating ulcers, nail infections, parasitic infections, stomach infections, malaria, leprosy, bacterial and fungal spore inactivation, treatment of prions and viral infections, for ear, nose and throat infections, tuberculosis, sexually transmitted diseases, herpes, for treatment of Candida localised infections.

75. A method according to any of claims 43 to 51, wherein said compound is part of a composite or conjugate.

44. A method of photodynamic therapy which comprises applying to an area to be treated an effective amount of a compound of formula

45. A method of treatment of microbial infections, the method comprising systemic administration or applying to an area to be treated, a therapeutically effective amount of a compound of formula

55. A method of treatment according to claim 45, wherein said infection is 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. aeruginose, S. aureus or methicillin resistant S. aureus, by systemic administration or by local application to said affected area, a therapeutically effective amount of a compound of Formula (I).

46. A method of prevention of microbial infections, the method comprising systemic administration or applying to an area to be treated, a therapeutically effective amount of a compound of formula

47. A method of sterilising a surface or a fluid comprising contacting or applying a compound of formula

74. A method according to claim 47 or claim 50, for sterilising surgical implants and stents, bandages, dressings, IV lines and catheters.

48. A method of treatment or prevention of microbial infection at any stage in a wound, surgical incision or burn wound, comprising applying to an area to be treated a composition comprising a therapeutically effective amount of a compound of formula

49. A method of treatment of microbial infections, burn wounds and other lesions and of dental bacterial disease, the method comprising applying to the area to be treated a therapeutically effective amount of a compound of formula

56. A method according to claim 49, wherein in said compound R¹, R², R³, R⁴ each independently is linear or branched —

C_nH_2nY wherein n is 1-6, Y is H and where X<sup>−

P</sup> represents Cl⁻

, Br⁻

, I⁻

, F⁻

, NO₃⁻

, HSO₄⁻

, CH₃CO₂⁻

or a dianion namely SO₄²⁻

or H₂PO₄².

50. A method of sterilising a surface or a fluid comprising applying a compound of formula

58. A method as claimed in claim 50 or claim 56, wherein in said compound R¹, R²R³ and R⁴ are the same and are selected from n-propyl, n-butyl, n-pentyl and n-hexyl.

60. A method as claimed in claim 50 or claim 56, wherein R¹, R², R³ and R⁴ each represent n-pentyl.

61. A method as claimed in claim 50 or claim 56, wherein R¹, R², R³ and R⁴ each represent n-pentyl and X^P−

represents

Cl⁻

, Br⁻

, I⁻

, F⁻

, NO₃⁻

, HSO₄⁻

, CH₃CO₂⁻

or a dianion namely SO₄²⁻

or H₂PO₄²⁻

.

63. A method as claimed in claim 50 or claim 56, wherein R¹, R², R³ and R⁴ each represent n-butyl.

64. A method as claimed in claim 50 or claim 56, wherein R¹, R², R³ and K each represent n-butyl and X^P−

represents

Cl⁻

, Br⁻

, I⁻

, F⁻

, NO₃⁻

, HSO₄⁻

, CH₃CO₂⁻

or a dianion namely SO₄²⁻

or H₂PO₄²⁻

.

51. 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 of the formula