Selective organic cation transporters inhibitors for the treatment of depressive disorders

1. A compound of Formula (I)

or a pharmaceutically acceptable tautomer, salt or solvate thereof, wherein:

represents a single bond linking R C to the double bond either with a (Z)- or (E)-stereochemistry;

X represents halo, acetate, trifluoroacetate or triflate;

R A and R B are independently selected from alkyl;

R C represents hydrogen or alkoxy;

R 2 and R 3 are independently selected from hydrogen, hydroxyl, alkoxy, halo, haloalkyl, haloalkyloxy, amino, alkylamino, aminoalkyl, alkyloxycarbonyl and COOH;

R 1 , R 4 , R 1′ , R 2′ , R 3′ , R 4′ , R 5′ and R 6′ are hydrogen;

wherein at least one of R 2 , R 3 is other than hydrogen.

2. The compound according to claim 1 , of Formula (Ia) or (Ib)

or a pharmaceutically acceptable tautomer, salt or solvate thereof, wherein X, R A , R B , R C , R 1 , R 2 , R 3 , R 4 , R 1′ , R 2′ , R 3′ , R 4′ , R 5′ and R 6′ are as defined in claim 1 .

3. The compound according to claim 1 , of Formula (I-1)

or a pharmaceutically acceptable tautomer, salt or solvate thereof, wherein , X, R A , R B , R C and R 2 are as defined in claim 1 .

4. The compound according to claim 1 , of Formula (Ia-1) or (Ib-1):

or a pharmaceutically acceptable tautomer, salt or solvate thereof, wherein X, R A , R B , R C and R 2 are as defined in claim 1 .

5. The compound according to claim 1 , selected from the group consisting of:

(Z)-1-isopropyl-4-((1-isopropyl-6-methoxy-3,4-dihydroquinolin-2(1H)-ylidene)methyl)quinolin-1-ium iodide;

(Z)-1-isopropyl-4-((1-isopropyl-6-methoxy-3,4-dihydroquinolin-2(1H)-ylidene)(methoxy)methyl)quinolin-1-ium iodide;

and a pharmaceutically acceptable tautomer, salt or solvate thereof.

6. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable tautomer, salt or solvate thereof, and at least one pharmaceutically acceptable carrier.

7. Medicament comprising a compound according to claim 1 , or a pharmaceutically acceptable tautomer, salt or solvate thereof.

8. A method for the treatment of depressive disorders and anxiety disorders comprising administering a compound according to claim 1 or a pharmaceutically acceptable tautomer, salt or solvate thereof to a patient.

9. A method for inhibiting organic cation transporters (OCTs) comprising administering a compound according to claim 1 or a pharmaceutically acceptable tautomer, salt or solvate thereof.

10. Process for manufacturing a compound of Formula (I) according to claim 1 or a pharmaceutically acceptable tautomer, salt or solvate thereof, characterized in that it comprises the regioselective reduction of intermediate of Formula (II)

wherein , X, R A , R B , R C , R 1 , R 2 , R 3 , R 4 , R 1′ , R 2′ , R 3′ , R 4′ , R 5′ and R 6′ are as defined in claim 1 ;

in presence of sodium dithionite (Na 2 S 2 O 4 ).

11. The process according to claim 10 , comprising a preliminary step of synthesis of intermediate of Formula (II) comprising the coupling between intermediate of Formula (III) and intermediate of Formula (IV), in presence of a base:

wherein R A , R B , R 1 , R 2 , R 3 , R 4 , R 1′ , R 2′ , R 3′ , R 4′ , R 5′ and R 6′ are as defined in claim 1 ; and

Y A is —CH 2 R C , wherein R C is as defined in Formula (I); and Y B is hydrogen or a leaving group selected from halo, acetate, tosylate, mesylate and sulfate; Y B is halo; more;

or

Y A is hydrogen or a leaving group selected from halo, acetate, tosylate, mesylate and sulfate; and Y B is —CH 2 R C , wherein R C is as defined in Formula (I).

12. A pharmaceutical composition comprising a compound according to claim 2 , or a pharmaceutically acceptable tautomer, salt or solvate thereof, and at least one pharmaceutically acceptable carrier.