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

Patent metadata

Field	Value
Publication number	US-9682943-B2
Application number	US-201414760350-A
Country	US
Kind code	B2
Filing date	Jan 10, 2014
Priority date	Jan 10, 2013
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

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

What is claimed is:

1. A method for treating Charcot Marie Tooth neuropathy or severe Dejerine-sottas syndrome in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof,

or a tautomer 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;
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;
R 11 is H or F.

2. The method according to claim 1 wherein R 1 is Cl, Br, Me, H or F.

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

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

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

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

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

7. The method according to claim 1 wherein the compound is

or a tautomer thereof,
or a pharmaceutically acceptable salt of one of the foregoing.

8. The method according to claim 7 wherein the compound is

or a tautomer thereof,
or a pharmaceutically acceptable salt thereof.

9. A method of treating Charcot Marie Tooth neuropathy or severe Dejerine-sottas syndrome in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound of formula (II), or a pharmaceutically acceptable salt thereof,

or a tautomer 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;
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.

10. A method of treating Charcot Marie Tooth neuropathy or severe Dejerine-sottas syndrome in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound of formula (III), or a pharmaceutically acceptable salt thereof,

or a tautomer 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;
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.

11. A method of treating Charcot Marie Tooth neuropathy or severe Dejerine-sottas syndrome in a subject in need thereof, said method comprising administering to said 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;
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.

12. A method of treating Charcot Marie Tooth neuropathy or severe Dejerine-sottas syndrome in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound selected from the following, and pharmaceutically acceptable salts thereof,

or a tautomer thereof.

13. The method according to claim 1 wherein R 1 is Cl.

Assignees

• Medical Res Council
• Inflectis Bioscience

Inventors

• Guedat Philippe
• Bertolotti Anne

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P27/02

  Ophthalmic agents · CPC title