3,7-DIAMINO-10H-PHENOTHIAZINE SALTS AND THEIR USE

• US 20090054419A1
• Filed: 03/28/2007
• Published: 02/26/2009
• Est. Priority Date: 03/29/2006
• Status: Active Grant

• Current Assignee: Wista Laboratories Ltd.
• Original Assignee: Wista Laboratories Ltd.
• Inventors: Harrington, Charles Robert, Horsley, David, Rickard, Janet Elizabeth, Wischik, Claude Michel, Sinclair, James Peter, Storey, John Mervyn David, Baddeley, Thomas Craven, Marshall, Colin
• Granted Patent: US 7,888,350 B2
• Time in Patent Office: Days
• US Class Current: 514/226.200
• CPC Class Codes: A61K 31/5415 ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 279/20 : with hydrogen atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 279/22 : with carbon atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C09B 21/00 : Thiazine dyes
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

This invention pertains generally to the field of phenothiazine compounds, and more particularly to certain stably reduced phenothiazine compounds, specifically, certain 3,7 diamino-10H-phenothiazine (DAPTZ) compounds of the following formula wherein: each of R¹ and R⁹ is independently selected from: —H; C_1-4alkyl; C_2-4alkenyl; and halogenated C_1-4alkyl; each of R^3NA and R^3NB is independently selected from: —H; C_1-4alkyl; C_2-4alkenyl; and halogenated C_1-4alkyl; each of R^7NA and R^7NB is independently selected from: —H; C_1-4alkyl; C_2-4alkenyl; and halogenated C_1-4alkyl; each of HX¹ and HX² is independently a protic acid; and pharmaceutically acceptable salts, solvates, and hydrates thereof. These compounds are useful as drugs, for example, in the treatment of tauopathies, such as Alzheimer'"'"'s disease, and also as prodrugs for the corresponding oxidized thioninium drugs (for example, methythioninium chloride, MTC).

Claims

1. A compound selected from compounds of the following formula and pharmaceutically acceptable salts, solvates, and hydrates thereof:

2. A compound according to claim 1, wherein each of R¹ and R⁹ is independently —

H, -Me, -Et, or —

CF₃.

3. A compound according to claim 1, wherein each of R¹ and R⁹ is independently —

H, -Me, or -Et.

4. A compound according to claim 1, wherein R¹ and R⁹ are the same.

5. A compound according to claim 1, wherein each of R¹ and R⁹ is independently —

H.

6. A compound according to claim 1, wherein each of R^3NA and R^3NB is independently -Me, -Et, -nPr, -nBu, —

CH₂—

CH═

CH₂, or —

CF₃.

7. A compound according to claim 1, wherein R^3NA and R^3NB are the same.

8. A compound according to claim 1, wherein each of R^7NA and R^7NB is independently -Me, -Et, -nPr, -nBu, —

CH₂—

CH═

CH₂, or —

CF₃.

9. A compound according to claim 1, wherein R^7NA and R^7NB are the same.

10. A compound according to claim 1, with the proviso that:

at least one of R^3NA and R^3NB and R^7NA and R^7NB is other than -Et.

11. A compound according to claim 1, with the proviso that:

if;

each of R¹ and R⁹ is —

H;

then;

R^3NA and R^3NB and R^7NA and R^7NB are not each -Et.

12. A compound according to claim 1, wherein each of the groups —

N(R^3NA)(R^3NB) and —

N(R^7NA)(R^7NB) is independently selected from;

—

NMe₂, —

NEt₂, —

N(nPr)₂, —

N(Bu)₂, —

NMeEt, —

NMe(nPr), and —

N(CH₂CH═

CH₂)₂.

13. A compound according to claim 1, wherein the groups —

N(R^3NA)(R^3NB) and —

N(R^7NA)(R^7NB) are the same, and are selected from;

—

NMe₂ and —

NEt₂.

14. A compound according to claim 1, wherein the groups —

N(R^3NA)(R^3NB) and —

N(R^7NA)(R^7NB) are the same.

15. A compound according to claim 1, with the proviso that:

each of the groups —

N(R^3NA)(R^3NB) and —

N(R^7NA)(R^7NB) is other than —

NEt₂.

16. A compound according to claim 1, wherein the groups —

N(R^3NA)(R^3NB) and —

N(R⁷NA)(R^7NB) are the same, and are selected from;

—

NMe₂, —

N(nPr)₂, —

N(Bu)₂, —

NMeEt, —

NMe(nPr), and —

N(CH₂CH═

CH₂)₂.

17. A compound according to claim 1, wherein each of the groups —

N(R^3NA)(R^3NB) and —

N(R^7NA)(R^7NB) is;

—

NMe₂.

18. A compound according to claim 1, wherein each of HX¹ and HX² is independently a monoprotic acid.

19. A compound according to claim 1, wherein each of HX¹ and HX² is independently a hydrohalide acid.

20. A compound according to claim 1, wherein each of HX¹ and HX² is independently selected from HCl, HBr, and HI.

21. A compound according to claim 1, wherein HX¹ and HX² are each HCl.

22. A compound according to claim 1, wherein HX¹ and HX² are each HBr.

24. A compound according to claim 1, selected from compounds of the following formula, and pharmaceutically acceptable salts, solvates, and hydrates thereof:

25. A compound according to claim 1, selected from compounds of the following formula, and pharmaceutically acceptable salts, solvates, and hydrates thereof:

27. A compound according to claim 1, in substantially purified form.

28. A compound according to claim 1, wherein one or more of the carbon atoms of the compound is ¹¹C.

30. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier or diluent.

31. A method of preparing a pharmaceutical composition comprising admixing a compound according to claim 1, and a pharmaceutically acceptable carrier or diluent.

50. A method of treatment or prophylaxis of a disease of protein aggregation in a subject comprising administering to said subject a prophylactically or therapeutically effective amount of a compound according to claim 1.

51. A method of treatment or prophylaxis of a tauopathy in a subject comprising administering to said subject a prophylactically or therapeutically effective amount of a compound according to claim 1.

52. A method of treatment or prophylaxis of a neurodegenerative tauopathy in a subject comprising administering to said subject a prophylactically or therapeutically effective amount of a compound according to claim 1.

53. A method of treatment or prophylaxis of Alzheimer'"'"'s disease in a subject comprising administering to said subject a prophylactically or therapeutically effective amount of a compound according to claim 1.

54. A method of treatment or prophylaxis of skin cancer or melanoma in a subject comprising administering to said subject a prophylactically or therapeutically effective amount of a compound according to claim 1.

55. A method of treatment or prophylaxis of a viral, bacterial or protozoal disease condition in a subject comprising administering to said subject a prophylactically or therapeutically effective amount of a compound according to claim 1.

56. A method of treatment or prophylaxis of Hepatitis C, HIV, or West Nile Virus (WNV) in a subject comprising administering to said subject a prophylactically or therapeutically effective amount of a compound according to claim 1.

57. A method of treatment or prophylaxis of malaria in a subject comprising administering to said subject a prophylactically or therapeutically effective amount of a compound according to claim 1.

58. A method of reversing and/or inhibiting the aggregation of a protein comprising contacting the protein with an effective amount of a compound according to claim 1.

59. A method of reversing and/or inhibiting the aggregation of a protein in the brain of a mammal, which aggregation is associated with a disease state, the method comprising the step of administering to said mammal in need of said treatment, a prophylactically or therapeutically effective amount of a compound according to claim 1.

60. A method of inactivating a pathogen in a sample, comprising the steps of introducing a compound according to claim 1 into the sample, and then exposing the sample to light.

23. (canceled)

26. (canceled)

29. (canceled)

32-49. -49. (canceled)

61. A pharmaceutical composition comprising a compound of the following formula:

62. A method of treatment of a neurodegenerative tauopathy in a subject comprising administering to said subject a therapeutically effective amount of a composition according to claim 61.

63. A method of treatment of Alzheimer'"'"'s disease in a subject comprising administering to said subject a therapeutically effective amount of a composition according to claim 61.

64. A pharmaceutical composition comprising a compound of the following formula:

65. A method of treatment of a neurodegenerative tauopathy in a subject comprising administering to said subject a therapeutically effective amount of a composition according to claim 64.

66. A method of treatment of Alzheimer'"'"'s disease in a subject comprising administering to said subject a therapeutically effective amount of a composition according to claim 64.