3,6-disubstituted xanthylium salts

Patent metadata

Field	Value
Publication number	US-9549933-B2
Application number	US-201414181234-A
Country	US
Kind code	B2
Filing date	Feb 14, 2014
Priority date	Dec 10, 2008
Publication date	Jan 24, 2017
Grant date	Jan 24, 2017

Abstract

Described are a compound of formula (II) or (III):

The compounds are effective in the treatment of disease, including a tauopathy condition or a disease of tau protein aggregation.

First claim

What is claimed is:

1. A method of treatment of a tauopathy condition or a disease of tau protein aggregation comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (II):

wherein:
X − is a counter ion;
Y is selected from O, NH, and S
wherein
when Y is O, Z is N or C—R 5 ; and
when Y is NH, Z is N; and
when Y is S, Z is C—R 5 ;

—R 1 , and —R 2 are each independently C 1-6 alkyl,

or R 1 and R 2 , together with the nitrogen atom to which they are bound, form a saturated C 3-7 heterocycle;
—R 3 and —R 4 are each independently C 1-6 alkyl,

or R 3 and R 4 , together with the nitrogen atom to which they are bound, form a saturated C 3-7 heterocycle;
—R 5 is independently —H, or C 1-6 alkyl, which is unsubstituted or substituted with one or more substituents —R 5A , or phenyl, which is unsubstituted or substituted with one or more substituents —R 5A ;
each —R 5A is independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH, —OR 6 , —SH, —SR 6 , —CN, —NO 2 , —NH 2 , —NHR 6 , —NR 6 2 , —NHC(═O)R 6 , —NR 6 C(═O)R 6 , —C(═O)OR 6 , —OC(═O)R 6 , —C(═O)NH 2 , —C(═O)NHR 6 , and —C(═O)NR 6 2 , —C(═O)R 6 , —S(═O)R 6 , —S(═O) 2 R 6 , and —S(═O) 2 OH;
each —R 6 is independently C 1-4 alkyl, phenyl, or benzyl;
—R 7 and —R 8 are each independently selected from the group consisting of: —H, C 1-4 alkyl, C 2-4 alkenyl, and halogenated C 1-4 alkyl; and
additionally, when Z is C—R 5 and R 5 is phenyl, —R 7 and —R 8 are each independently selected from the group consisting of: —H, C 1-4 alkyl, C 2-4 alkenyl, halogenated C 1-4 alkyl; and a bridging group, W, which is bonded to said R 5 ;
W is O, NR 17 , S, or C(R 17 ) 2 wherein each R 17 is independently selected from the group consisting of: —H, C 1-4 alkyl, and R 5A ;
with the proviso that the compound is not 3,6-bis-dimethylamino xanthylium chloride (DMAXC); and
wherein the dosage of the compound that is administered is from 1 μg to 10 mg per kg of body weight of said patient.

2. A method according to claim 1 , wherein X − is selected from the group consisting of: NO 3 − , ClO 4 − , F − , Cl − , Br − , I − , ZnCl 3 − , FeCl 4 − and PF 6 − .

3. A method according to claim 1 , wherein —R 5 is independently —H, or C 1-6 alkyl, which is unsubstituted or substituted with —R 5A .

4. A method according to claim 1 , wherein —R 5 is C 1-4 alkyl, which is unsubstituted or substituted with one or more substituents —R 5A .

5. A method according to claim 4 , wherein each —R 5A is independently selected from the group consisting of —F, —Cl, —Br, and —I.

6. A method according to claim 4 , wherein —R 5 is —CF 3 .

7. A method according to claim 4 , wherein —R 5 is -Et.

8. A method according to claim 1 , wherein —R 5 is phenyl, which is substituted with one or more substituents —R 5A .

9. A method according to claim 8 , wherein each —R 5A is independently selected from NH 2 and NO 2 .

10. A method according to claim 1 , wherein the compound is a compound of formula (II) wherein —R 1 , —R 2 , —R 3 and —R 4 are each independently C 1-6 alkyl.

11. A method according to claim 10 , wherein —R 7 and —R 8 are each independently selected from: —H, C 1-4 alkyl, C 2-4 alkenyl, and halogenated C 1-4 alkyl.

12. A method according to claim 1 , wherein the compound is of formula (IIa):

13. A method according to claim 12 , wherein at least one of —R 1 and —R 2 , and one of —R 3 and —R 4 is -Et.

14. A method according to claim 12 , wherein —R 1 , —R 2 , —R 3 and —R 4 are each -Et.

15. A method according to claim 12 , wherein R 1 and R 2 , together with the nitrogen atom to which they are bound, form a saturated C 3-7 heterocycle and R 3 and R 3 , together with the nitrogen atom to which they are bound, independently form a saturated C 3-7 heterocycle
wherein each of said saturated C 3-7 heterocycles is independently selected from: morpholine, piperidine, and pyrrolidine.

16. A method according to claim 1 wherein the compound is selected from the group consisting of:

Com-

pound
Structure and Name

E

F

G

I

I• HNO 3

J

AB

AC

AD

AF

AG

Assignees

• Wista Lab Ltd

Inventors

• Clunas Scott
• Storey John Mervyn David
• Rickard Janet Elizabeth
• Horsley David
• Harrington Charles Robert
• Wischik Claude Michel

Classifications

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/28

  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 title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C09B11/28

  Pyronines {; Xanthon, thioxanthon, selenoxanthan, telluroxanthon dyes} · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title