3, 7-diamino-10H-phenothiazine salts and their use

Patent metadata

Field	Value
Publication number	US-12324810-B2
Application number	US-202418595985-A
Country	US
Kind code	B2
Filing date	Mar 5, 2024
Priority date	Mar 29, 2006
Publication date	Jun 10, 2025
Grant date	Jun 10, 2025

Abstract

Described are methods of preparing reduced 3,7-diamino-10H-phenothiazine (DAPTZ) compounds of formula:

wherein: R 1 and R 9 are independently selected from: —H; C 1-4 alkyl; C 2-4 alkenyl; and halogenated C 1-4 alkyl; each of R 3NA and R 3NB is independently selected from: —H; C 1-4 alkyl; C 2-4 alkenyl; and halogenated C 1-4 alkyl; each of R 7NA and R 7NB is independently selected from: —H; C 1-4 alkyl; C 2-4 alkenyl; and halogenated C 1-4 alkyl; each of HX 1 and HX 2 is independently a protic acid; and pharmaceutically acceptable salts, solvates, and hydrates thereof. These methods are particularly useful for producing stable reduced forms, and with high purity. The stability and purity are especially relevant for pharmaceutical compositions for the treatment of disease. The compounds are useful for treatment of e.g. tauopathies, such as Alzheimer's disease, and also as prodrugs for the corresponding oxidized thioninium drugs.

First claim

What is claimed is:

1. A method of treatment of fronto-temporal dementia in a subject in need thereof,
the method comprising administering to the subject a therapeutically effective amount of a bis protic acid salt compound of the following formula:

wherein:
each of R 1 and R 9 is independently selected from the group consisting of: —H, C 1-4 alkyl, C 2-4 alkenyl, and halogenated C 1-4 alkyl;
each of R 3NA and R 3NB is independently selected from the group consisting of: —H, C 1-4 alkyl, C 2-4 alkenyl, and halogenated C 1-4 alkyl;
each of R 7NA and R 7NB is independently selected from the group consisting of: —H, C 1-4 alkyl, C 2-4 alkenyl, and halogenated C 1-4 alkyl; and
each of HX 1 and HX 2 is independently a protic acid, wherein if any of HX 1 or HX 2 is a hydrohalic acid, then each is independently selected from the group consisting of HCl and HBr.

2. The method according to claim 1 , wherein each of R 1 and R 9 is independently —H, -Me, -Et, or —CF 3 .

3. The method according to claim 1 , wherein each of R 1 and R 9 is independently —H, -Me, or -Et.

4. The method according to claim 1 , wherein R 1 and R 9 are the same.

5. The method according to claim 1 , wherein each of R 1 and R 9 is independently —H.

6. The method according to claim 1 , wherein each of R 3NA and R 3NB is independently -Me, -Et, -nPr, -nBu, —CH 2 —CH═CH 2 , or —CF 3 .

7. The method according to claim 1 , wherein R 3NA and R 3NB are the same.

8. The method according to claim 1 , wherein each of R 7NA and R 7NB is independently -Me, -Et, -nPr, -nBu, —CH 2 —CH═CH 2 , or —CF 3 .

9. The method according to claim 1 , wherein R 7NA and R 7NB are the same.

10. The method 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. The method according to claim 1 , with the proviso that:
if: each of R 1 and R 9 is —H;
then: R 3NA and R 3NB and R 7NA and R 7NB are not each -Et.

12. The method according to claim 1 , wherein each of the groups —N(R 3NA )(R 3NB ) and —N(R 7NA )(R 7NB ) is independently selected from the group consisting of: -NMe 2 , -NEt 2 , —N(nPr) 2 , —N(Bu) 2 , —NMeEt, —NMe(nPr), and —N(CH 2 CH═CH 2 ) 2 .

13. The method 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 the group consisting of: —NMe 2 and —NEt 2 .

14. The method according to claim 1 , wherein the groups —N(R 3NA )(R 3NB ) and —N(R 7NA )(R 7NB ) are the same.

15. The method 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 —NEt 2 .

16. The method 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 the group consisting of: —NMe 2 , —N(nPr) 2 , —N(Bu) 2 , —NMeEt, —NMe(nPr), and —N(CH 2 CH═CH 2 ) 2 .

17. The method according to claim 1 , wherein each of the groups —N(R 3NA )(R 3NB ) and —N(R 7NA )(R 7NB ) is: —NMe 2 .

18. The method according to claim 1 , wherein each of HX 1 and HX 2 is independently a monoprotic acid.

19. The method according to claim 1 , wherein each of HX 1 and HX 2 is independently a hydrohalide acid.

20. The method according to claim 1 , wherein each of HX 1 and HX 2 is independently an organic acid.

21. The method according to claim 1 , wherein the compound is administered as a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or diluent.

22. The method according to claim 21 , wherein the pharmaceutical composition is a dosage unit which comprises 20 to 300 mg of the compound.

23. The method according to claim 22 , wherein the pharmaceutical composition is a dosage unit which comprises about 30 mg of the compound.

24. The method according to claim 22 , wherein the dosage unit is a tablet or capsule.

25. The method according to claim 1 , wherein the administering is oral.

Assignees

• Wista Lab Ltd

Inventors

• Wischik Claude Michel
• Rickard Janet Elizabeth
• Harrington Charles Robert
• Horsley David
• Storey John Mervyn David
• Marshall Colin
• Sinclair James Peter
• Baddeley Thomas Craven

Classifications

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C09B21/00

  Thiazine dyes · CPC title

• C07D279/20 Primary

  with hydrogen atoms directly attached to the ring nitrogen atom · CPC title

• C07D279/22

  with carbon atoms directly attached to the ring nitrogen atom · CPC title

• A61K31/5415 Primary

  ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam · CPC title