Benzylideneguanidine derivatives and therapeutic use for the treatment of protein misfolding diseases

Patent metadata

Field	Value
Publication number	US-10100020-B2
Application number	US-201715467613-A
Country	US
Kind code	B2
Filing date	Mar 23, 2017
Priority date	Jan 10, 2013
Publication date	Oct 16, 2018
Grant date	Oct 16, 2018

Abstract

The present invention relates to a compound of formula (I), or a tautomer and/or a pharmaceutically acceptable salt thereof, wherein: R 1 is alkyl, Cl, F or Br; R 2 is H or F; R 3 is selected from H and alkyl; R 4 is selected from H and C(O)R 6 ; R 5 is H; or R 4 and R 5 are linked to form a heterocyclic group which is optionally substituted with one or more R 10 groups; R 6 is selected from R 7 , OR 7 and NR 8 R 9 ; R 7 , R 8 and R 9 are each independently selected from alkyl, cycloalkyl, aralkyl, cycloalkenyl, heterocyclyl and aryl, each of which is optionally substituted with one or more R 10 groups; each R 10 is independently selected from halogen, OH, CN, NO 2 , COO-alkyl, aralkyl, SO 2 -alkyl, SO 2 -aryl, COOH, CO-alkyl, CO-aryl, NH 2 , NH-alkyl, N(alkyl) 2 , CF 3 , alkyl and alkoxy; X and Z are each independently CR 11 , and Y is selected from CR 11 and N; and R 11 is H or F; for use in treating a disorder associated with protein misfolding stress and in particular associated with accumulation of misfolded proteins.

First claim

The invention claimed is:

1. A method for treating a retinal disorder in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof,

or a tautomeric form thereof wherein,
R 1 is alkyl, Cl, F or Br;
R 2 is H or F;
R 3 is selected from H and alkyl;
R 4 is selected from H and C(O)R 6 ;
R 5 is H;
or R 4 and R 5 are linked to form a heterocyclic group which is optionally substituted with one or more R 10 groups;
R 6 is selected from R 7 , OR 7 and NR 8 R 9 ;
R 7 , R 8 and R 9 are each independently selected from alkyl, cycloalkyl, aralkyl, cycloalkenyl, heterocyclyl and aryl, each of which is optionally substituted with one or more R 10 groups;
each R 10 is independently selected from halogen, OH, NO 2 , CN, COO-alkyl, aralkyl, SO 2 -alkyl, SO 2 -aryl, COOH, CO-alkyl, CO-aryl, NH 2 , NH-alkyl, N(alkyl) 2 , CF 3 , alkyl and alkoxy;
X and Z are each independently CR 11 , and Y is selected from CR 11 and N; and
R 11 is H or F.

2. The method according to claim 1 wherein R 1 is Cl, Br, Me, H or F, and R 4 and R 5 are linked to form a heterocyclic group optionally substituted with one or more R 10 groups.

3. The method according to claim 1 wherein R 2 is H.

4. The method according to claim 1 Y is CR 11 .

5. The method according to claim 1 wherein Y is N.

6. The method according to claim 1 wherein R 3 and R 4 are both H.

7. The method according to claim 1 wherein R 3 is H and R 4 is C(O)R 6 .

8. The method according to claim 1 wherein R 6 is Me or OMe.

9. The method according to claim 1 wherein said compound is of formula (Ia), or a pharmaceutically acceptable salt thereof,

or a tautomeric form thereof, wherein R 1 , R 2 , R 3 and R 10 are as defined in claim 1 .

10. The method according to claim 1 wherein said compound is selected from the following:

or a tautomeric form thereof or a pharmaceutically acceptable salt thereof.

11. The method according to claim 10 wherein said compound is Example 1, Example 16, or a pharmaceutically acceptable salt thereof.

12. The method according to claim 10 wherein said compound is Example 15 or a pharmaceutically acceptable salt thereof.

13. The method according to claim 1 wherein the retinal disorder is associated with PPP1R15A-PP1.

14. The method according to claim 1 wherein the retinal disorder is chosen from retinitis pigmentosa, retinal ciliopathies, macular degeneration, retinopathy of prematurity, light-induced retinal degeneration, retinal detachment and diabetic retinopathy.

15. The method according to claim 14 wherein the retinal ciliopathies is Bardet-Biedl Syndrome (BBS).

16. A method of treating a retinal disorder in a human subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of formula (II),

or a pharmaceutically acceptable salt thereof, or a tautomeric form thereof wherein,
R 1 alkyl, Cl, F or Br;
R 2 is H or F;
R 3 is selected from H and alkyl;
R 4 is selected from H and C(O)R 6 ;
R 5 is H;
or R 4 and R 5 are linked to form a heterocyclic group which is optionally substituted with one or more R 10 groups;
R 6 is selected from R 7 , OR 7 and NR 8 R 9 ;
R 7 , R 8 and R 9 are each independently selected from alkyl, cycloalkyl, aralkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl, each of which is optionally substituted with one or more R 10 groups;
each R 10 is independently selected from halogen, OH, CN, NO 2 , COO-alkyl, aralkyl, SO 2 -alkyl, SO 2 -aryl, COOH, CO-alkyl, CO-aryl, NH 2 , NH-alkyl, N(alkyl) 2 , CF 3 , alkyl and alkoxy;
X and Z are each independently CR 11 , and Y is N; and
R 11 is H or F.

17. A method of treating a retinal disorder in a human subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of formula (III),

or a pharmaceutically acceptable salt thereof, or a tautomeric form thereof wherein,
R 1 is alkyl, Cl, F or Br;
R 2 is H or F;
R 3 is selected from H and alkyl;
R 4 is C(O)R 6 ;
R 5 is H;
or R 4 and R 5 are linked to form a heterocyclic group which is optionally substituted with one or more R 10 groups;
R 6 is selected from R 7 , OR 7 and NR 8 R 9 ;
R 7 , R 8 and R 9 are each independently selected from alkyl, cycloalkyl, aralkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl, each of which is optionally substituted with one or more R 10 groups;
each R 10 is independently selected from halogen, OH, CN, NO 2 , COO-alkyl, aralkyl, SO 2 -alkyl, SO 2 -aryl, COOH, CO-alkyl, CO-aryl, NH 2 , NH-alkyl, N(alkyl) 2 , CF 3 , alkyl and alkoxy;
X and Z are each independently CR 11 , and Y is selected from CR 11 and N; and
R 11 is H or F.

18. A method according to claim 17 wherein the compound is of formula (IIIa),

19. A method of treating a retinal disorder in a human subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of formula (IV),

or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein,
R 1 is alkyl or Br;
R 2 is H;
R 3 is selected from H and alkyl;
R 4 is selected from H and C(O)R 6 ;
R 5 is H;
or R 4 and R 5 are linked to form a heterocyclic group which is optionally substituted with one or more R 10 groups; R 6 is selected from OR 7 and NR 8 R 9 ;
R 7 , R 8 and R 9 are each independently selected from alkyl, cycloalkyl, aralkyl, cycloalkenyl, heterocyclyl and aryl, each of which is optionally substituted with one or more R 10 groups;
each R 10 is independently selected from halogen, OH, CN, NO 2 , COO-alkyl, aralkyl, SO 2 -alkyl, SO 2 -aryl, COOH, CO-alkyl, CO-aryl, NH 2 , NH-alkyl, N(alkyl) 2 , CF 3 , alkyl and alkoxy;
X and Z are each CH and Y is CR 11 ;
R 11 is H or F.

20. The method according to claim 1 comprising also administering to the subject one or more other active agents.

Assignees

• Medical Res Council
• Inflectis Bioscience
• Res & Innovation Uk

Inventors

• Guedat Philippe
• Bertolotti Anne

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · 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

• A61P25/16

  Anti-Parkinson drugs · CPC title