| 主权项 |
1. A combination of a PPAR-α agonist or a prodrug thereof and a DGAT inhibitor, wherein the DGAT inhibitor has the following formulaor a stereochemically isomeric form thereof, wherein
A represents CH or N; the dotted line represents an optional bond in case A represents a carbon atom; X represents —C(═O)—; —O—C(═O)—; —C(═O)—C(═O)—; —NRx—C(═O)—; —Z1—C(═O)—; —Z1—NRx—C(═O)—; —C(═O)—Z1—; —NRx—C(═O)—Z1—; —S(═O)p-; —C(═S)—; —NRx—C(═S)—; —Z1—C(═S)—; —Z1—NR—C(═S)—; —C(═S)—Z1—; or —NRx—C(═S)—Z1—; Z1 represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6allcynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6allcynediyl may optionally be substituted with hydroxyl or amino; and wherein two hydrogen atoms attached to the same carbon atom in C1-6alkanediyl may optionally be replaced by C1-6alkanediyl; Y represents NRx—C(═O)—Z2—; —NRx—C(═O)—Z2NRy—; —NRx—C(═O)—Z2—NRy—C(═O)—; —NRx—C(═O)—Z2—NRy—C(═O)—O—; —NRx—C(═O)—Z2—O—; —NRx—C(═O)—Z2—O—C(═O)—; —NRx—C(═O)—Z2—C(═O)—; —NRx—C(═O)—Z2—C(═O)—O—; —NRx —C(═O)—O—Z2—C(═O)—; —NRx—C(═O)—O—Z2—C(═O)—O—; —NRx—C(═O)—O—Z2—O—C(═O)—; —NRx—C(═O)—Z2—C(═O)—NRy—; —NRx—C(═O)—Z2—NRy—C(═O)—NRy—; —C(═O)—Z2—; —C(═O)—Z2—O—; —C(═O)—NRx—Z2—; —C(═O)—NRx—Z2—O—; —C(═O)—NRx—Z2—C(═O)—O—; —C(═O)—NRx—Z2—O—C(═O)—; —C(═O)—NRx—O—Z2—; —C(═O)—NRx—Z2—NRy—; —C(═O)—NRx—Z2—NRy—C(═O)—; or —C(═O)—NRx—Z2—NRy—C(═O)—O—; Z2 represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with C1-4alkyloxy, C1-4alkylthio, hydroxyl, cyano or aryl; and wherein two hydrogen atoms attached to the same carbon atom in the definition of Z2 may optionally be replaced by C1-6alkanediyl; Rx represents hydrogen or C1-4alkyl; Ry represents hydrogen; C1-4alkyl optionally substituted with C3-6cycloalkyl or aryl or Het; C2-4alkenyl; or —S(═O)p-aryl; R1 represents C1-12alkyl optionally substituted with cyano, C1-4alkyloxy, C1-4alkyl-oxyC1-4alkyloxy, C3-6cycloalkyl or aryl; C2-6alkenyl; C2-6alkynyl; C3-6cycloalkyl; adamantanyl; aryl1; aryl1C1-6alkyl; Het1; or Het1C1-6alkyl; provided that when Y represents —NRx—C(═O)—Z2—; —NRx—C(═O)—Z2—NRy; —NRx—C(═O)—Z2—C(═O)—NRy—; —C(═O)—Z2—; —NRx—C(═O)—Z2—NRy—C(═O)—NRy—; —C(═O)—NRx—Z2—; —C(═O)—NRx—O—Z2—; or —C(═O)—NRx—Z2—NRy—; then R1 may also represent hydrogen; R2 represents hydrogen, C1-12alkyl, C2-6alkenyl or R3; R3 represents C3-6cycloalkyl, phenyl, naphthalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said C3-6cycloalkyl, phenyl, naphthalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or 6-membered aromatic heterocycle containing 1 or 2 N atoms may optionally be substituted with at least one substituent, each substituent independently selected from the group consisting of hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with hydroxy; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono-or di(C1-4alkyl)amino; C1-4alkylcarbonylamino; —S(═O)p—C1-4alkyl; R5R4N—C(═O)—; R5R4N—C1-6alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; and Het-O—; R4 represents hydrogen; C1-4alkyl optionally substituted with hydroxyl or C1-4alkyloxy; R7R6N—C1-4alkyl; C1-4alkyloxy; Het; Het-C1-4alkyl; aryl; or R7R6N—C(═O)—C1-4alkyl; R5 represents hydrogen or C1-4alkyl; R6 represents hydrogen; C1-4alkyl; or C1-4alkylcarbonyl; R7 represents hydrogen or C1-4alkyl; or R6 and R7 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms each independently selected from the group consisting of O, S, S(═O)p and N; and which heterocycle may optionally be substituted with C1-4alkyl; R8 represents hydrogen; halo; C1-4alkyl; or C1-4alkyl substituted with hydroxyl; aryl represents phenyl or phenyl substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono-or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono-or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono-or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl; aryl1 represents phenyl, naphthalenyl or fluorenyl; each of said phenyl, naphthalenyl or fluorenyl optionally substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono-or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono-or di(C1-6alkyl)amino; R5R4N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—;—S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; and Het-O—; Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; said monocyclic heterocycle or said bi-or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono-or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono-or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono-or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl; Het1 represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; said monocyclic heterocycle or said bi-or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono-or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono-or di(C1-6alkyl)amino; R5R4N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; and Het-O—; p represents 1 or 2; provided that if X represents —O—C(═O)—, then R2 represents R3; a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. |
