1, 4, 8-triazaphenanthrene derivatives for the treatment of neurodegenerative disorders

1. A compound of following formula (I):

or a pharmaceutically acceptable salt and/or solvate thereof, a stereoisomer, or a mixture of stereoisomers in any proportions,

wherein:

is a single or double bond,

X 1 is:

NR 1a when is a single bond, and

N when is a double bond,

X 2 is:

CR 2a R 2b when is a single bond, and

CR 2c when is a double bond,

R 1 is a hydrogen or a (C 1 -C 6 )alkyl group,

R 2 is an aryl or heteroaryl group, optionally substituted by one or more groups selected from a halogen atom, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, aryl, N 3 , NO 2 , OH, NH 2 , and —NH—((C 1 -C 6 )alkyl),

R 1a and R 2c are each independently a hydrogen atom or a (C 1 -C 6 )alkyl group, and

R 2a and R 2b are each independently a (C 1 -C 6 )alkyl group.

2. The compound according to claim 1 , being a compound of following formula (Ia):

or a pharmaceutically acceptable salt and/or solvate thereof, a stereoisomer, or a mixture of stereoisomers in any proportions,

wherein R 1 and R 2 are as defined in claim 1 .

3. The compound according to claim 1 , wherein R 2 is an aryl group optionally substituted by one or more groups selected from a halogen atom, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, OH and aryl.

4. The compound according to claim 1 , wherein R 2 is a phenyl, naphthyl, pyridyl, quinoxalyl or quinolyl group, optionally substituted by one or more groups selected from a halogen atom, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, aryl, N 3 , NO 2 , OH, NH 2 , and —NH—((C 1 -C 6 )alkyl).

5. The compound according to claim 4 , wherein R 2 is a phenyl group, optionally substituted by one or more groups selected a halogen atom, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, OH and aryl.

6. The compound according to claim 4 , wherein R 2 is a phenyl group, optionally substituted by one or more groups selected (C 1 -C 6 )alkoxy and OH.

7. The compound according to claim 1 , selected from the following compounds:

and the pharmaceutically acceptable salts and/or solvates thereof.

8. A method for neurotrophy or neuroprotection comprising administering to a patient in need thereof an effective amount of a compound of following formula (I):

or a pharmaceutically acceptable salt and/or solvate thereof, a stereoisomer, or a mixture of stereoisomers in any proportions,

wherein:

is a single or double bond,

X 1 is:

NR 1a when is a single bond, and

N when is a double bond,

X 2 is:

CR 2a R 2b when is a single bond, and

CR 2c when is a double bond,

R 1 and R 2 are each independently a hydrogen atom; a halogen atom; a linear or branched, saturated or unsaturated hydrocarbon chain having from 1 to 10 carbon atoms; an optionally substituted aryl; or an optionally substituted heteroaryl,

R 1a and R 2c are each independently a hydrogen atom or a (C 1 -C 6 )alkyl group, and

R 2a and R 2b are each independently a (C 1 -C 6 )alkyl group.

9. A method for treating a neurodegenerative disease selected from Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis, comprising administering to a patient in need thereof an effective amount of a compound of following formula (I):

or a pharmaceutically acceptable salt and/or solvate thereof, a stereoisomer, or a mixture of stereoisomers in any proportions,

wherein:

is a single or double bond,

X 1 is:

NR 1a when is a single bond, and

N when is a double bond,

X 2 is:

CR 2a R 2b when is a single bond, and

CR 2c when is a double bond,

R 1 and R 2 are each independently a hydrogen atom; a halogen atom; a linear or branched, saturated or unsaturated hydrocarbon chain having from 1 to 10 carbon atoms; an optionally substituted aryl; or an optionally substituted heteroaryl,

R 1a and R 2c are each independently a hydrogen atom or a (C 1 -C 6 )alkyl group, and

R 2a and R 2b are each independently a (C 1 -C 6 )alkyl group.

10. The method according to claim 9 , wherein the neurodegenerative disease is Parkinson's disease.

11. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 1 .

12. A process for preparing a compound of following formula (I):

or a pharmaceutically acceptable salt and/or solvate thereof, a stereoisomer, or a mixture of stereoisomers in any proportions,

wherein:

is a single or double bond,

X 1 is:

NR 1a when is a single bond, and

N when is a double bond,

X 2 is:

CR 2a R 2b when is a single bond, and

CR 2c when is a double bond,

R 1 and R 2 are each independently a hydrogen atom; a halogen atom; a linear or branched, saturated or unsaturated hydrocarbon chain having from 1 to 10 carbon atoms; an optionally substituted aryl; or an optionally substituted heteroaryl,

R 1a and R 2c are each independently a hydrogen atom or a (C 1 -C 6 )alkyl group, and

R 2a and R 2b are each independently a (C 1 -C 6 )alkyl group,

comprising the following successive steps:

(a1) coupling between an amino-quinoxaline of following formula (II):

wherein R 1 and R 2 are as defined above,

with a propargyl halide of formula CH≡C—CHR 2c Hal or CH═C—CR 2a R 2b Hal wherein:

R 2a and R 2b are each independently a (C 1 -C 6 )alkyl group,

R 2c is a hydrogen atom or a (C 1 -C 6 )alkyl group, and

Hal is a halogen atom,

to give a compound of following formula (IIIa) or (IIIb):

wherein R 1 , R 2 , R 2a , R 2b and R 2c are as defined above,

(b1) cycloisomerization of the compound of formula (IIIa) or (IIIb) obtained in the preceding step and aromatization when is a double bond to give a compound of formula (I), and

(c1) optionally salification and/or solvation of the compound of formula (I) obtained in the preceding step to give a pharmaceutically acceptable salt and/or solvate of the compound of formula (I).

13. The process according to claim 12 , wherein Hal is Cl, Br or I.

14. A process for preparing a compound of following formula (I):

or a pharmaceutically acceptable salt and/or solvate thereof, a stereoisomer, or a mixture of stereoisomers in any proportions,

wherein:

is a single or double bond,

X 1 is:

NR 1a when is a single bond, and

N when is a double bond,

X 2 is:

CR 2a R 2b when is a single bond, and

CR 2c when is a double bond,

R 1 and R 2 are each independently a hydrogen atom; a halogen atom; a linear or branched, saturated or unsaturated hydrocarbon chain having from 1 to 10 carbon atoms; an optionally substituted aryl; or an optionally substituted heteroaryl, and

wherein at least one of R 1 and R 2 is a linear or branched, saturated or unsaturated hydrocarbon chain having from 1 to 10 carbon atoms; an optionally substituted aryl; or an optionally substituted heteroaryl,

R 1a and R 2c are each independently a hydrogen atom or a (C 1 -C 6 )alkyl group, and

R 2a and R 2b are each independently a (C 1 -C 6 )alkyl group,

comprising the following successive steps:

(a2) coupling of a compound of formula (I) as defined above wherein at least one of R 1 and R 2 is a halogen atom,

with a boronic acid derivative of formula R 3 —B(R 4 ) 2 or R 3 —BF 3 − K + wherein R 3 is a linear or branched, saturated or unsaturated hydrocarbon chain having from 1 to 10 carbon atoms; an optionally substituted aryl; or an optionally substituted heteroaryl, and R 4 is a (C 1 -C 6 )alkyl, OH or (C 1 -C 6 )alkoxy group,

or with a zinc derivative of formula R 3 —Zn-Hal wherein R 3 is as defined above and Hal is a halogen atom,

or with a stannane derivative of formula R 3 -SnA 1 A 2 A 3 wherein R 3 is as defined above and A 1 , A 2 and A 3 , which can be identical or different, are each a (C 1 -C 6 )alkyl group,

or with a magnesium derivative of formula R 3 —Mg-Hal wherein R 3 and Hal are as defined above,

or with a silicon derivative of formula R 3 —SiMe 2 OH, R 3 —SiF 3 or R 3 —Si(OA 1 )(OA 2 )(OA 3 ) wherein R 3 , A 1 , A 2 and A 3 are as defined above,

or with an alkyne of formula R′—C≡CH wherein R′ is a protecting group or a linear or branched, saturated or unsaturated hydrocarbon chain having from 1 to 8 carbon atoms,

(b2) when step (a2) was performed with an alkyne of formula R′—C≡CH wherein R′ is a protecting group, deprotection of the protecting group of the alkyne function, and

(c2) optionally salification and/or solvation of the compound of formula (I) obtained in the preceding step to give a pharmaceutically acceptable salt and/or solvate of the compound of formula (I).

15. The process according to claim 14 , wherein at least one of R 1 and R 2 is Cl, Br or I and Hal is Cl, Br or I.