Certain arylaliphatic and heteroaryl-aliphatic piperazinyl pyrazines and their use in the treatment of serotonin-related diseases

A compound of the general formula (I):

• wherein
• Ar is aryl or heteroaryl which may be independently substituted in one or more positions by C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-acyl, C1-6-alkylsulphonyl, cyano, nitro, hydroxy, C2-6-alkenyl, C2-6-alkynyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, halogen, —N(R2)(R3), aryl, alkoxy, arylthio, aryl-C1-4-alkyl, aryl-C2-4-alkenyl, aryl-C2-4-alkynyl, heterocyclyl, heterocyclyloxy, heterocyclylthio or heterocyclyl-C1-4-alkyl, wherein any aryl and heterocyclyl residues as substituents or part of substituents on aryl or heteroaryl in turn may be substituted in one or more positions independently of each other by halogen, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-acyl, C1-6-alkylsulphonyl, nitro, trifluoromethyl, trifluoromethylthio, cyano, hydroxy, amino, C1-6-alkylamino, di(C1-6-alkyl)amino or C1-6-acylamino;
• A is (i) —O—, —S—, —SO2— or —NH—;
• (ii) a C1-4-alkyl-substituted nitrogen atom, or (iii) a C1-8-alkylene chain or a heteroalkylene chain having 2 to 8 chain atoms, which optionally contains one or more unsaturations, wherein C1-8-alkylene and heteroalkylene may be independently substituted in one or more positions by C1-4-alkyl or oxo, and wherein two juxtaposed or spaced chain atoms in C1-8-alkylene or heteroalkylene optionally are joined through an alkylene bridge having 1 to 5 chain carbon atoms or a heteroalkylene bridge having 2 to 5 chain atoms, or two spaced chain atoms in C1-8-alkylene or heteroalkylene optionally are joined through a bridging bond, to form a saturated or partially or fully unsaturated carbocyclic or heterocyclic ring having 3 to 8 ring members;
• B is —C(R4)(R5)—, —OC(R4)(R5)—, —N(R6)C(R4)(R5)—, —N(R6)—, —O—, —S— or —SO2—;
• R is C3-8-cycloalkyl, aryl or heteroaryl, each of which may be substituted in one or more positions independently of each other by C1-6-alkyl, C1-6-alkoxy, fluoro-C1-6-alkoxy, 2,2,2-trifluoroethoxy, C3-5-alkynyloxy, C3-5-alkenyloxy, dimethylamino-C1-6-alkoxy, methylamino-C1-6-alkoxy, C1-6-alkylthio, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethylthio, difluoromethoxy, difluoromethylthio, trifluoromethoxy, trifluoromethylthio, halogen, hydroxy, nitro, cyano, trifluoromethylsulphonyloxy, C1-6-alkylsulphonamido, C2-6-alkenyl, C2-6-alkynyl, C1-6-acyl, C1-6-alkylcarbonyl-C1-6-alkyl, C1-6-alkylsulphonyl, C1-6-alkylsulphonyloxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkoxycarbonyl, C1-6-alkoxycarbonyl-C1-6-alkyl, C1-6-acyloxy-C1-6-alkyl, hydroxy-C1-6-alkyl, hydroxy-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkylthio, hydroxy-C1-6-alkylthio, heteroaryl-C1-6-alkylthio, aryl-C1-6-alkylthio, C1-6-alkoxy-C1-6-alkylamino, N—(C1-6-alkoxy-C1-6-alkyl)-N-methylamino, C3-6-cycloalkyl-C1-6-alkoxy, aryl-C1-6-alkoxy, heterocyclyl-C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyloxy, aryl, aryloxy, arylthio, arylsulphonyl, aryl-C1-6-acyl, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylsulphonyl, heterocyclylamino, heterocyclyl-C-1-6-acyl, —N(R2)(R3), —CON(R7)(R8) or, when R is optionally substituted C3-8-cycloalkyl, oxo, wherein any cycloalkyl, aryl and heterocyclyl residues as substituents on C3-8-cycloalkyl, aryl or heteroaryl or as part of substituents on C3-8-cycloalkyl, aryl or heteroaryl in turn may be substituted in one or more positions independently of each other by C1-4-alkyl, C1-4-alkoxy, methanesulphonamido, C1-4-alkylthio, C1-4-alkylsulphonyl, C1-4-acyl, heterocyclyl, heterocyclyloxy, heterocyclylthio, aryloxy, arylthio, fluoromethyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, halogen, hydroxy, nitro, cyano, N(R2)(R3) or, for C3-8-cycloalkyl and partially or fully saturated heterocyclyl, oxo or hydroxy;
• R1 is (i) a saturated or unsaturated azacyclic or aminoazacyclic ring, or a saturated diazacyclic or aminodiazacyclic ring, which has 4 to 7 ring members, or a saturated aminoazabicyclic, azabicyclic or diazabicyclic ring which has 7 to 10 ring members, which mono- or bicyclic rings may be mono- or disubstituted in one or more positions independently of each other by, preferably bound to a carbon atom, C1-4-alkyl, C1-6-alkoxy, fluoromethyl, trifluoromethyl, difluoromethyl, oxo, hydroxymethyl or methoxymethyl or —N(R6)2, or, preferably bound to a ring nitrogen atom, hydroxy, 2-hydroxyethyl or 2-cyanoethyl, or, bound to a ring nitrogen atom, C1-6-acyl, C1-4-alkoxycarbonyl or tetrahydropyran-2-yl, and wherein a saturated azacyclic ring may contain a further heteroatom selected from oxygen and sulphur;
• or (ii) a group —[C(R4)(R5)]xN(R2a)(R3a);
• R2 and R3 independently of each other are hydrogen, C1-6-alkyl, C1-6-acyl, —CON(R7)(R8), aryl, heterocyclyl, aryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-acyl or heterocyclyl-C1-6-acyl, wherein any aryl and heterocyclyl residues in turn may be substituted in one or more positions independently of each other by halogen, C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, C1-4-alkylsulphonyl, methanesulphonamido, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio or —N(R2)(R3);
• or R2 and R3 together with the nitrogen atom to which they are bound form a saturated heterocyclic ring having 4-7 ring members and optionally containing a further heteroatom, which ring may be substituted by C1-6-alkyl, C1-6-alkoxy, oxo or hydroxy;
• R2a and R3a independently of each other are hydrogen, methyl or ethyl, or R2a and R3a together with the nitrogen atom to which they are bound form a pyrrolidine, piperazine or morpholine ring;
• R4 and R5 independently of each other, and independently on each substituted carbon atom, are hydrogen or C1-6-alkyl;
• R6 is hydrogen or C1-6-alkyl;
• R7 and R8 independently of each other are hydrogen, C1-6-alkyl, aryl, heteroaryl, aryl-C1-4-alkyl or heteroaryl-C1-4-alkyl, wherein aryl and heteroaryl residues in turn may be substituted in one or more positions independently of each other by halogen, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkylsulphonyl, methanesulphonamido, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio or —N(R2)(R3);
• or R7 and R8 together with the nitrogen atom to which they are bound form a saturated heterocyclic ring having 4-7 ring members and optionally containing a further heteroatom;
• n is 0 or 1;
• and
• x is 2, 3 or 4;
• with the proviso that (i) when —A—R is phenoxy or phenylthio, then Ar is other than quinoxalinyl or pyridyl, and (ii) when A is ethenylene, then Ar is other than quinoxalinyl;
• and pharmaceutically acceptable salts, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof.