Esters of 5-aminolevulinic acid and their use as photosensitizing compounds in photochemotherapy

• US 7,287,646 B2
• Filed: 10/14/2004
• Issued: 10/30/2007
• Est. Priority Date: 03/10/1995
• Status: Expired due to Fees

• Current Assignee: Photocure ASA
• Original Assignee: Photocure ASA
• Inventors: Klaveness, Jo, Braenden, Jon Erik, Godal, Aslak, Moan, Johan, Steen, Harald, Peng, Qian, Warloe, Trond, Bjorseth, Alf, Nilsen, Nils, Gierskcky, Karl E
• Primary Examiner(s): Zucker; Paul A.
• Application Number:
  US10/966,408
• Publication Number:
  US 20050107471A1
• Time in Patent Office: 1,111 Days
• Field of Search: None
• US Class Current: 206/569
• CPC Class Codes: A61K 41/0061 5-aminolevulinic acid-based PDT: 5-ALA-PDT involving porphyrins or precursors of protoporphyrins generated in vivo from 5-ALA
• CPC Class Codes: A61K 49/0021 the fluorescent group being a small organic molecule
• CPC Class Codes: A61K 49/0052 Small organic molecules oligomers, polymers, dendrimers A61K49/0054
• CPC Class Codes: C07C 229/22 the carbon skeleton being further substituted by oxygen atoms

Abstract

The present invention relates to compounds being esters of 5-aminolevulinic acids or pharmaceutically acceptable salts thereof, including compounds of formula (I) R₂²N—CH₂COCH₂—CH₂CO—OR¹ (wherein R¹ may represent alkyl optionally substituted by hydroxy, alkoxy, acyloxy, alkoxycarbonyloxy, amino, aryl, oxo or fluoro groups and optionally interrupted by oxygen, nitrogen, sulphur or phosphorus atoms; and R² represents a hydrogen atom or a group R¹, and both R² groups may be the identical or different), and their use in diagnosis and photochemotherapy of disorders or abnormalities of external or internal surfaces of the body, and products and kits for performing the invention.

Claims

1. A compound selected from the group consisting of 3,3-dimethyl-1-butyl 5-amino-4-oxopentanoate, 2-methoxyethyl 5-amino-4-oxopentanoate, 3,6-dioxa-1-octyl 5-amino-4-oxopentanoate, 3,6,9-trioxa-decyl 5-amino-4-oxopentanoate, 4-isopropylbenzyl 5-aminolevulinate, 3-methylbenzyl 5-aminolevulinate, 2-methylbenzyl 5-aminolevulinate, and 4-[t-butyl]benzyl 5-aminolevulinate, and pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein the compound is 3,3-dimethyl-1-butyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound is 2-methoxyethyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein the compound is 3,6-dioxa-1-octyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein the compound is 3,6,9-trioxa-decyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein the compound is 4-isopropylbenzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, wherein the compound is 3-methylbenzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1, wherein the compound is 2-methylbenzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1, wherein the compound is 4-[t-butyl]benzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical carrier or excipient.

11. The pharmaceutical composition of claim 10, wherein the compound is 3,3-dimethyl-1-butyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition of claim 10, wherein the compound is 2-methoxyethyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition of claim 10, wherein the compound is 3,6-dioxa-1-octyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition of claim 10, wherein the compound is 3,6,9-trioxa-decyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition of claim 10, wherein the compound is 4-isopropylbenzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition of claim 10, wherein the compound is 3-methylbenzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition of claim 10, wherein the compound is 2-methylbenzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition of claim 10, wherein the compound is 4-[t-butyl]benzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

19. A product comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, at least one surface-penetration assisting agent, and optionally one or more chelating agents as a combined preparation for simultaneous, separate or sequential use in treating disorders or abnormalities of external or internal surfaces of the body which are responsive to photochemotherapy.

20. The product of claim 19, wherein the compound is 3,3-dimethyl-1-butyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

21. The product of claim 19, wherein the compound is 2-methoxyethyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

22. The product of claim 19, wherein the compound is 3,6-dioxa-1-octyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

23. The product of claim 19, wherein the compound is 3,6,9-trioxa-decyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

24. The product of claim 19, wherein the compound is 4-isopropylbenzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

25. The product of claim 19, wherein the compound is 3-methylbenzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

26. The product of claim 19, wherein the compound is 2-methylbenzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

27. The product of claim 19, wherein the compound is 4-[t-butyl]benzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

28. A kit for use in photochemotherapy of disorders or abnormalities of external or internal surfaces of the body comprising:

a) a first container containing a compound of claim 1, or a pharmaceutically acceptable salt thereof,

b) a second container containing at least one surface penetration assisting agent; and

optionally

c) one or more chelating agents contained either within said first container or in a third container.

29. The kit of claim 28, wherein the compound is 3,3-dimethyl-1-butyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

30. The kit of claim 28, wherein the compound is 2-methoxyethyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

31. The kit of claim 28, wherein the compound is 3,6-dioxa-1-octyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

32. The kit of claim 28, wherein the compound is 3,6,9-trioxa-decyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

33. The kit of claim 28, wherein the compound is 4-isopropylbenzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

34. The kit of claim 28, wherein the compound is 3-methylbenzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

35. The kit of claim 28, wherein the compound is 2-methylbenzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

36. The kit of claim 28, wherein the compound is 4-[t-butyl]benzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

37. A method of diagnosis or photochemotherapeutic treatment of disorders or abnormalities of external or internal surfaces of the body, comprising:

a) administering to said external or internal surfaces, a composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof,

b) exposing said external or internal surfaces to light.

38. The method of claim 37 wherein the light is in the wavelength region 300–

800 nm.

39. The method of claim 37 or 38, wherein the composition further comprises at least one surface-penetration assisting agent and optionally one or more chelating agents.

40. The method of claim 37, wherein the compound is 3,3-dimethyl-1-butyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

41. The method of claim 40 wherein the light is in the wavelength region 300–

800nm.

42. The method of claim 40 or 41, wherein the composition further comprises at least one surface-penetration assisting agent and optionally one or more chelating agents.

43. The method of claim 37, wherein the compound is 2-methoxyethyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

44. The method of claim 43, wherein the light is in the wavelength region 300–

800 nm.

45. The method of claim 43 or 44, wherein the composition further comprises at least one surface-penetration assisting agent and optionally one or more chelating agents.

46. The method of claim 37, wherein the compound is 3,6-dioxa-1-octyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

47. The method of claim 46, wherein the light is in the wavelength region 300–

800 nm.

48. The method of claim 46 or 47, wherein the composition further comprises at least one surface-penetration assisting agent and optionally one or more chelating agents.

49. The method of claim 37, wherein the compound is 3,6,9-trioxa-decyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

50. The method of claim 49, wherein the light is in the wavelength region 300–

800 nm.

51. The method of claim 49 or 50, wherein the composition further comprises at least one surface-penetration assisting agent and optionally one or more chelating agents.

52. The method of claim 37, wherein the compound is 4-isopropylbenzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

53. The method of claim 52 wherein the light is in the wavelength region 300–

800 nm.

54. The method of claim 52 or 53, wherein the composition further comprises at least one surface-penetration assisting agent and optionally one or more chelating agents.

55. The method of claim 37, wherein the compound is 3-methylbenzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

56. The method of claim 55 wherein the light is in the wavelength region 300–

800 nm.

57. The method of claim 55 or 56, wherein the composition further comprises at least one surface-penetration assisting agent and optionally one or more chelating agents.

58. The method of claim 37, wherein the compound is 2-methylbenzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

59. The method of claim 58, wherein the light is in the wavelength region 300–

800 nm.

60. The method of claim 58 or 59, wherein the composition further comprises at least one surface-penetration assisting agent and optionally one or more chelating agents.

61. The method of claim 37, wherein the compound is 4-[t-butyl]benzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

62. The method of claim 61 wherein the light is in the wavelength region 300–

800 nm.

63. The method of claim 61 or 62, wherein the composition further comprises at least one surface-penetration assisting agent and optionally one or more chelating agents.

64. A method of in vitro diagnosis, of abnormalities or disorders by assaying a sample of body fluid or tissue of a patient, said method comprising at least the following steps:

i) admixing said body fluid or tissue with a compound of claim 1, or a pharmaceutically acceptable salt thereof,

ii) exposing said mixture to light,

iii) ascertaining the level of fluorescence, and

iv) comparing the level of fluorescence to control levels.

65. The method of claim 64, wherein the compound is 3,3-dimethyl-1-butyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

66. The method of claim 64, wherein the compound is 2-methoxyethyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

67. The method of claim 64, wherein the compound is 3,6-dioxa-1-octyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

68. The method of claim 64, wherein the compound is 3,6,9-trioxa-decyl 5-amino-4-oxopentanoate, or a pharmaceutically acceptable salt thereof.

69. The method of claim 64, wherein the compound is 4-isopropylbenzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

70. The method of claim 64, wherein the compound is 3-methylbenzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

71. The method of claim 64, wherein the compound is 2-methylbenzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.

72. The method of claim 64, wherein the compound is 4-[t-butyl]benzyl 5-aminolevulinate, or a pharmaceutically acceptable salt thereof.