Heterocyclic compounds and their use for the treatment of neurodegenerative tauopathies

Patent metadata

Field	Value
Publication number	US-9649317-B2
Application number	US-201314429101-A
Country	US
Kind code	B2
Filing date	Sep 19, 2013
Priority date	Sep 19, 2012
Publication date	May 16, 2017
Grant date	May 16, 2017

Abstract

The present invention is directed to triazolopyrimidine, phenylpyrimidine, pyridopyridazine, and pyridotriazine compounds which are microtubule-stabilizing compounds and their use in the treatment of neurodegenerative disorders, in particular, tauopathies, such as for example, Alzheimer's disease, frontotemporal lobar degeneration, Pick's disease, progressive supranuclear palsy (PSP), and corticobasal degeneration. In addition, the compounds of the invention may be useful for other diseases where tau pathology is a comorbidity or where microtubule function is compromised, for example, schizophrenia, Parkinson's disease (PD), PD with dementia, Lewy body disease with dementia, and amyotrophic lateral sclerosis.

First claim

What is claimed:

1. A method of treating a neurodegenerative disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of formula II:

wherein
R 1 is H, Cl, F, or Br;
R 2 is C 1-6 alkyl or substituted C 1-6 alkyl;
R 3 is H; or R 2 and R 3 , together with the N atom to which they are attached, form a heterocycloC 3-6 alkyl;
R 4 is H, Cl, F, or Br;
R 5 is H, Cl, F, or Br;
R 6 is F, Cl, Br, —N 3 , —OC 1-6 alkyl, —OC 1-6 alkyleneOH, —OC 1-6 alkylene-halo,
—OC 1-6 alkyleneNR 7 R 8 , —OC 1-6 substituted-alkyleneNR 7 R 8 , or
—OC 3-6 cycloalkyleneNR 7 R 8 , wherein R 7 and R 8 are each independently H,
C 1-6 alkyl, substituted C 1-6 alkyl, —C(O)C 1-6 alkyl, or aryl; or R 7 and R 8 together form a heterocyclic ring;

or a stereochemical isomer thereof;
or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein R 1 is Cl.

3. The method of claim 1 , wherein R 2 is C 1-6 alkyl.

4. The method of claim 3 , wherein R 2 is methyl, ethyl, propyl, or isopropyl.

5. The method of claim 1 , wherein R 2 is substituted C 1-6 alkyl.

6. The method of claim 5 , wherein R 2 is —CH(CH 3 )(CF 3 ).

7. The method of claim 5 , wherein R 2 is —CH 2 (CF 3 ).

8. The method of claim 1 , wherein R 3 is H.

9. The method of claim 1 , wherein R 4 is F.

10. The method of claim 1 , wherein R 5 is F.

11. The method of claim 1 , wherein R 3 , R 4 , and R 5 are each F.

12. The method of claim 1 , wherein R 6 is F.

13. The method of claim 1 , wherein R 6 is —OC 1-6 alkyleneNR 7 R 8 .

14. The method of claim 13 , wherein R 6 is —O—CH 2 CH 2 CH 2 —N(CH 3 ) 2 or —O—CH 2 CH 2 CH 2 —NH(CH 3 ).

15. The method of claim 1 , wherein R 6 is OC 1-6 cycloalkyleneNR 7 R 8 .

16. The method of claim 15 , wherein R 6 is

17. The method of claim 1 , wherein R 6 is —OC 1-6 alkyl.

18. The method of claim 1 , wherein R 6 is —OC 1-6 alkyleneOH.

19. The method of claim 1 , wherein R 6 is —OC 1-6 alkylene-halo.

20. The method of claim 1 , wherein R 6 is —OC 1-6 substituted-alkyleneNR 7 R 8 .

21. The method of claim 20 , wherein R 7 is H.

22. The method of claim 20 , wherein R 8 is C 1-6 alkyl.

23. The method of claim 20 , wherein R 8 is substituted C 1-6 alkyl.

24. The method of claim 23 , wherein the alkyl is substituted with CF 3 .

25. The method of claim 20 , wherein R 8 is —C(O)C 1-6 alkyl.

26. The method of claim 20 , wherein R 8 is aryl.

27. The method of claim 1 , wherein the compound of formula II is

R 1
R 2
R 3
R 4
R 5
R 6

Cl
H
H
F
F
F

Cl
—CH(CH 3 )CF 3 (S)
H
F
F
F

Cl
—CH(CH 3 )CF 3 (R)
H
F
F
F

Cl
—CH(CH 3 )CF 3 (S,R)
H
F
F
F

Cl
—CH(CH 3 )CF 3 (S)
H
F
F
—OCH 2 CH 2 CH 2 NHCH 3

Cl
—CH(CH 3 )CF 3 (R)
H
F
F
—OCH 2 CH 2 CH 2 NHCH 3

Cl
—CH(CH 3 )CF 3 (S,R)
H
F
F
—OCH 2 CH 2 CH 2 NHCH 3

Cl
H
H
F
F
—OCH 2 CH 2 CH 2 NHCH 3

Cl
—CH(CH 3 )CF 3 (S)
H
F
F
—OCH 2 CH 2 CH 2 N(CH 3 ) 2

Cl
—CH(CH 3 )CF 3 (R)
H
F
F
—OCH 2 CH 2 CH 2 N(CH 3 ) 2

Cl
—CH(CH 3 )CF 3 (S,R)
H
F
F
—OCH 2 CH 2 CH 2 N(CH 3 ) 2

Cl
—CH(CH 3 )CF 3 (S)
H
F
F

Cl
—CH(CH 3 )CF 3 (R)
H
F
F

Cl
—CH(CH 3 )CF 3 (S,R)
H
F
F

Cl
—CH(CH 3 )CF 3 (S)
H
F
F

Cl
—CH(CH 3 )CF 3 (S)
H
F
F

Assignees

• Univ Pennsylvania

Inventors

• Ballatore Carlo
• Brunden Kurt R
• Hoye Adam T
• Lee Virginia M Y
• Smith Amos B
• Trojanowski John Q

Classifications

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/5377 Primary

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/50

  Pyridazines; Hydrogenated pyridazines · CPC title

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/506 Primary

  not condensed and containing further heterocyclic rings · CPC title