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

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.