Inhibitors of PDE6Delta for use in the prevention and/or treatment of epilepsy and/or neurodegenerative disorders

A method for treating epilepsy in a subject suffering from epilepsy comprising, administering to said subject in need thereof, a therapeutically effective amount of an inhibitor of PDE6δ, wherein said inhibitor of PDE6δ is a compound of formula (AA1);

• wherein the compound of formula (AA1) has the following structure:
• wherein, each dotted line individually represents an optional double bond, wherein maximally two dotted lines selected from the five dotted lines are a double bond;
• E1 is independently selected from CR1 and N;
• E2 is independently selected from NR2 and O;
• E3 is independently selected from CR3 and N;
• Ra is hydrogen and Rb is hydrogen;
• or Ra and Rb are taken together to form a substituted or unsubstituted 4, 5, 6, 7 or 8 membered ring containing one N atom;
• Q is independently selected from NRb—C(O);
• C(O);
• and C(O) NH;
• each R1, R3, R4, R5 and R6 is independently selected from hydrogen;
• halogen;
• —OH;
• —OR10;
• —SH;
• —SR10;
• —S(O)R11;
• —S(O)2R11;
• —SO2NR12R13;
• trifluoromethyl;
• trifluoromethoxy;
• nitro;
• —NHC(O)R10;
• NHS(O)2R10;
• —NHC(O)NR12R13;
• —NR10C(O)R10;
• —NR10S(O)2R10;
• —NR10C(O)NR12R13;
• —NR12R13;
• -cyano;
• —COOH;
• —COOR10;
• —C(O)NR12R13;
• —C(O)R11;
• alkyl;
• alkenyl;
• alkynyl;
• aryl;
• heterocycle;
• arylalkylene;
• arylalkenylene;
• arylalkynylene;
• heterocycle-alkylene;
• heterocycle-alkenylene;
• and heterocycle-alkynylene;
• wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, optionally includes one or more heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, said heteroatoms being selected from the atoms O, S and N;
• wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene can be unsubstituted or substituted with Z;
• wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
• R2 is selected from hydrogen;
• alkyl;
• alkenyl;
• and alkynyl;
• n is selected from 0;
• 1 and 2;
• L is independently selected from being not present;
• —O—;
• —NH—;
• —NR10—;
• C1-6alkylene;
• C1-6alkenylene;
• and C1-6alkynylene;
• wherein each of said C1-6alkylene, C1-6alkenylene or C1-6alkynylene optionally includes one or more heteroatoms, said heteroatoms being selected from the heteroatoms consisting of O, S and N, and wherein each of said C1-6alkylene, C1-6alkenylene or C1-6alkynylene, is unsubstituted or substituted;
• wherein a carbon atom or heteroatom of said C1-6alkylene, C1-6alkenylene or C1-6alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S—O or S(O)2;
• B represents a cyclic structure selected from cycloalkyl;
• cycloalkenyl;
• cycloalkynyl;
• aryl;
• and heterocycle;
• m is selected from 0;
• 1;
• 2;
• 3;
• 4 and 5;
• R8 is independently selected from hydrogen;
• halogen;
• alkyl;
• alkenyl;
• alkynyl;
• —OH;
• —OR10;
• —SH;
• —SR10;
• —S(O)R11;
• —S(O)2R11;
• —SO2NR12R13;
• trifluoromethyl;
• trifluoromethoxy;
• nitro;
• —NHC(O)R10;
• —NHS(O)2R10;
• —NHC(O)NR12R13;
• —NR10C(O)R10;
• —NR10S(O)2R10;
• —NR10C(O)NR12R13;
• —NR12R13;
• -cyano;
• —COOH;
• —COOR10;
• —C(O)NR12R13;
• and —C(O)R11;
• wherein said alkyl, alkenyl and alkynyl optionally includes one or more heteroatoms, said heteroatoms being selected from the atoms O, S and N;
• wherein said alkyl, alkenyl and alkynyl can be unsubstituted or substituted with Z;
• wherein a carbon atom or heteroatom of said alkyl, alkenyl and alkynyl, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
• each Z is independently selected from halogen;
• —OH;
• —OR10;
• —SH;
• —SR10;
• —S(O)R11;
• —S(O)2R11;
• —SO2NR12R13;
• trifluoromethyl;
• trifluoromethoxy;
• nitro;
• —NHC(O)R10;
• NHS(O)2R10;
• —NHC(O)NR12R13;
• —NR10C(O)R10;
• —NR10S(O)2R10;
• —NR10C(O)NR12R13;
• —NR12R13;
• -cyano;
• —COOH;
• —COOR10;
• —C(O)NR12R13;
• and —C(O)R11;
• each Z1 is independently selected from hydrogen;
• alkyl;
• and Z;
• each R10 is independently selected from alkyl;
• alkenyl;
• alkynyl;
• aryl;
• heterocycle;
• arylalkylene;
• arylalkenylene;
• arylalkynylene;
• heterocycle-alkylene;
• heterocycle-alkenylene and heterocycle-alkynylene;
• wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene optionally include one or more heteroatoms in the alkyl (ene), alkenyl (ene) or alkynyl (ene) moiety, said heteroatom selected from O, S and N;
• wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
• each R101 is independently selected from hydrogen and R10;
• each R11 is independently selected from hydroxyl;
• alkyl;
• alkenyl;
• alkynyl;
• aryl;
• heterocycle;
• arylalkylene;
• arylalkenylene;
• arylalkynylene;
• heterocycle-alkylene;
• heterocycle-alkenylene and heterocycle-alkynylene;
• wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene optionally include one or more heteroatoms in the alkyl (ene), alkenyl (ene) and alkynyl (ene) moiety, said heteroatom selected from O, S and N;
• wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
• each R12 and R13 is independently selected from hydrogen;
• alkyl;
• alkenyl;
• alkynyl;
• aryl;
• heterocycle;
• arylalkylene;
• arylalkenylene;
• arylalkynylene;
• heterocycle-alkylene;
• heterocycle-alkenylene and heterocycle-alkynylene;
• wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene optionally include one or more heteroatoms in the alkyl (ene), alkenyl (ene) or alkynyl (ene) moiety, said heteroatom selected from O, S and N;
• wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
• wherein R12 and R13 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted
• and each of X, Y, T, W and V is independently selected from —CZ1H—;
• —CZ1—;
• —C—;
• —N—;
• NR101;
• —O—;
• —S—;
• or —CO—;
• and form with the dotted lines one of the cycles having one of the structural formula (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (IXa), (Xa), (XIa), (XIIa), (XIIIa), (XIVa), (XVa), (XVIa), (XVIIa), (XVIIIa), (XIXa), (XXa), (XXIa), (XXIIa), (XXIIIa) or (XXIVa)
• wherein the left side of the formula (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (IXa), (Xa), (XIa), (XIIa), (XIIIa), (XIVa), (XVa), (XVIa), (XVIIa), (XVIIIa), (XIXa), (XXa), (XXIa), (XXIIa), (XXIIIa), (XXIVa) is attached to Q and the right side thereof is attached to L;
• and
• enantiomers, tautomers, solvates, hydrates, salts or prodrugs thereof.