Novel CB 1 receptor inverse agonists

A pharmaceutical compositions comprising a compound of formula (I)

• 327
• wherein
• X is C or N;
• R1 is hydrogen or lower alkyl;
• R2 is lower alkyl or —(CH2)n—R2a;
• R2, is cycloalkyl, optionally mono-, di-, tri- or tetra-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, fluorinated lower alkyl or fluorinated lower alkoxy;
• a 5-or 6-membered monovalent saturated heterocyclic ring containing one to three heteroatoms independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, amino, lower alkylamino, cycloalkyl, oxo, fluorinated lower alkyl or fluorinated lower alkoxy;
• a 5- or 6-membered monovalent heteroaromatic ring containing one to four heteroatoms independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, amino, lower alkylamino or cycloalkyl;
• or phenyl, which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, lower alkylamino, halogenated lower alkyl, halogenated lower alkoxy or nitro;
• R3 is cycloalkyl, optionally mono-, di-, tri- or tetra-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, fluorinated lower alkyl or fluorinated lower alkoxy;
• or phenyl, which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, lower alkylamino, halogenated lower alkyl, halogenated lower alkoxy or nitro;
• R4 is a 5- or 6-membered monovalent heteroaromatic ring containing one to three heteroatoms independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, amino, lower alkylamino;
• naphthyl, which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, lower alkylamino, halogenated lower alkyl, halogenated lower alkoxy or nitro;
• or phenyl which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, nitro, halogenated lower alkyl, halogenated lower alkoxy, cyano, lower alkylsulfonyl or —NR7R8;
• or two adjacent substituents of the said phenyl residue together are —O—(CH2)p—O— or —(CH2)2—C(O)NH—;
• R5 and R6 are each independently hydrogen, lower alkyl, halogen or fluorinated methyl;
• R7 and R8 are each independently hydrogen or lower alkyl;
• or R7 and R8 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or aromatic heterocyclic ring optionally containing one or two further heteroatoms independently selected from nitrogen, oxygen and sulfur, said saturated or aromatic heterocyclic ring being optionally substituted by hydroxy, lower alkyl, lower alkoxy, halogen, amino or lower alkylamino;
• m is 1 or 2;
• n is 0 or 1;
• p is 1, 2 or 3;
• or a pharmaceutically acceptable salt thereof;
• and
• a pharmaceutically acceptable carrier and/or adjuvant.

A method for the treatment and/or prophylaxis of a disease associated with the modulation of the CB1 receptors which method comprises administering, to a patient in need thereof, a therapeutically effective amount of a compound of formula (I)

• 328
• wherein
• X is C or N;
• R1 is hydrogen or lower alkyl;
• R2 is lower alkyl or —(CH2)n—R2a;
• R2a is cycloalkyl, optionally mono-, di-, tri- or tetra-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, fluorinated lower alkyl or fluorinated lower alkoxy;
• a 5-or 6-membered monovalent saturated heterocyclic ring containing one to three heteroatoms independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, amino, lower alkylamino, cycloalkyl, oxo, fluorinated lower alkyl or fluorinated lower alkoxy;
• a 5- or 6-membered monovalent heteroaromatic ring containing one to four heteroatoms independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, amino, lower alkylamino or cycloalkyl;
• or phenyl, which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, lower alkylamino, halogenated lower alkyl, halogenated lower alkoxy or nitro;
• R3 is cycloalkyl, optionally mono-, di-, tri- or tetra-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, fluorinated lower alkyl or fluorinated lower alkoxy;
• or phenyl, which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, lower alkylamino, halogenated lower alkyl, halogenated lower alkoxy or nitro;
• R4 is a 5- or 6-membered monovalent heteroaromatic ring containing one to three heteroatoms independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, amino, lower alkylamino;
• naphthyl, which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, lower alkylamino, halogenated lower alkyl, halogenated lower alkoxy or nitro;
• or phenyl which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, nitro, halogenated lower alkyl, halogenated lower alkoxy, cyano, lower alkylsulfonyl or —NR7R8;
• or two adjacent substituents of the said phenyl residue together are —O—(CH2)p—O— or —(CH2)2—C(O)NH—;
• R5 and R6 are each independently hydrogen, lower alkyl, halogen or fluorinated methyl;
• R7 and R8 are each independently hydrogen or lower alkyl;
• or R7 and R8 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or aromatic heterocyclic ring optionally containing one or two further heteroatoms independently selected from nitrogen, oxygen and sulfur, said saturated or aromatic heterocyclic ring being optionally substituted by hydroxy, lower alkyl, lower alkoxy, halogen, amino or lower alkylamino;
• m is 1 or 2;
• n is 0 or 1;
• p is 1, 2 or 3;
• or a pharmaceutically acceptable salt thereof.