Phenylindole derivatives as 5-HT2A receptor ligands

A compound having formula I, or a pharmaceutically acceptable salt thereof:

• wherein
• A and B independently represent hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-6 alkyl or C1-6 alkoxy;
• X represents hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy or phenyl;
• Y represents phenyl;
• R1 represents hydrogen or C1-6 alkyl;
• R2 represents hydrogen, methyl, ethyl, 2-methoxyethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl or n-pentyl;
• and
• R3 represents C1-6 alkyl, C2-6 alkenyl, C3-9 cycloalkyl, aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents;
• or
• R2 and R3 taken together with the intervening nitrogen atom represent a group of formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l) or (m):
• in which the broken line represents an optional chemical bond;
• Z represents oxygen, sulphur, N—R6 or CR7R8;
• R4 represents hydrogen, C1-6 alkyl, C1-6 alkoxy(C1-6)alkyl, C3-7 heterocycloalkyl(C1-6)alkyl or aryloxy;
• R5 represents hydrogen, C1-6 alkyl or C1-6 alkoxy(C1-6)alkyl;
• R6 represents hydrogen, —COR9 or —CO2R9;
• or C1-6 alkyl, C2-6 alkenyl, C3-9 cycloalkyl, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, C3-7 heterocycloalkyl(C1-6)alkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
• R7 represents hydrogen, hydrocarbon, a heterocyclic group, —COR9 or —CO2R9;
• R8 represents hydrogen, phenyl or acetoxy;
• and
• R9 represents C1-6 alkyl.

A pharmaceutical composition comprising a therapeutically effective amount of a compound having formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, further comprising a second anti-schizophrenic medicament, or a pharmaceutically acceptable salt thereof:

• wherein
• A and B independently represent hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-6 alkyl or C1-6 alkoxy;
• X and Y independently represent hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy or phenyl;
• R1 represents hydrogen or C1- 6 alkyl;
• R2 represents hydrogen, methyl, ethyl, 2-methoxyethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl or n-pentyl;
• and
• R3 represents C1-6 alkyl, C2-6 alkenyl, C3-9 cycloalkyl, aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents, with the proviso that the heterocycloalkyl(C1-6)alkyl and heteroaryl(C1-6)alkyl groups do not include the heterocycle and heteroaryl groups selected from pyridine N-oxide, pyridine, 2-hydroxypyridine, indole, benzimidazole, quinoline, pyrimidine, imidazole, naphthyridine, and tetrahydronaphthyridine;
• or
• R2 and R3 taken together with the intervening nitrogen atom represent a group of formula (a), (b), (c), (d), (e), (f), (g), (h), (i), G), (k), (l) or (m):
• in which the broken line represents an optional chemical bond;
• Z represents oxygen, sulphur, N—R6 or CR7R8;
• R4 represents hydrogen, C1-6 alkyl, C1-6 alkoxy(C1-6)alkyl, C3-7 heterocycloalkyl(C1-6)alkyl or aryloxy,
• R5 represents hydrogen, C1-6 alkyl or C1-6 alkoxy(C1-6)alkyl;
• R6 represents hydrogen, —COR9 or —CO2R9;
• or C1-6 alkyl, C2-6 alkenyl, C3-9 cycloalkyl, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, C3-7 heterocycloalkyl](C1-6)alkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
• R7 represents hydrogen, hydrocarbon, a heterocyclic group, —COR9 or —CO2R9;
• R8 represents hydrogen, phenyl or acetoxy;
• and
• R9 represents C1-6 alkyl;
• with the proviso that:
• (i) when A and B independently represent hydrogen, halogen, cyano, nitro, alkyl or alkoxy, and X and Y independently represent hydrogen, halogen, alkyl or alkoxy, then R3 does not represent alkyl, and R2 and R3 taken together with the intervening nitrogen atom do not represent piperidin-1-yl or morpholin-4-yl;
• and
• (ii) when A, B, X, Y and R1 each represents hydrogen, then R2 and R3 taken together with the intervening nitrogen atom do not represent piperidin-1-yl, morpholin-4-yl, pyrrolidin-1-yl, 2-methylpiperidin-1-yl or homopiperidin-1-yl.

A method for the treatment of clinical conditions for which a selective antagonist of 5-HT2A receptors is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound having formula I, or a pharmaceutically acceptable salt thereof:

• wherein
• A and B independently represent hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-6 alkyl or C1-6 alkoxy;
• X and Y independently represent hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy or phenyl;
• R1 represents hydrogen or C1-6 alkyl;
• R2 represents hydrogen, methyl, ethyl, 2-methoxyethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl or n-pentyl;
• and
• R3 represents C1-6 alkyl, C2-6 alkenyl, C3-9 cycloalkyl, aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents, with the proviso that the heterocycloalkyl(C1-6)alkyl and heteroaryl(C1-6)alkyl groups do not include the heterocycle and heteroaryl groups selected from pyridine N-oxide, pyridine, 2-hydroxypyridine, indole, benzimidazole, quinoline, pyrimidine, imidazole, naphthyridine, and tetrahydronaphthyridine;
• or
• R2 and R3 taken together with the intervening nitrogen atom represent a group of formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l) or (m):
• in which the broken line represents an optional chemical bond;
• Z represents oxygen, sulphur, N—R6 or CR7R8;
• R4 represents hydrogen, C1-6 alkyl, C1-6 alkoxy(C1-6)alkyl, C3-7 heterocycloalkyl(C1-6)alkyl or aryloxy;
• R5 represents hydrogen, C1-6 alkyl or C1-6 alkoxy(C1-6)alkyl;
• R6 represents hydrogen, —COR9 or —CO2R9;
• or C1-6 alkyl, C2-6 alkenyl, C3-9 cycloalkyl, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, C3-7 heterocycloalkyl(C1-6)alkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
• R7 represents hydrogen, hydrocarbon, a heterocyclic group, —COR9 or —CO2R9;
• R8 represents hydrogen, phenyl or acetoxy;
• and
• R9 represents C1-6 alkyl;
• with the proviso that:
• (i) when A and B independently represent hydrogen, halogen, cyano, nitro, alkyl or alkoxy, and X and Y independently represent hydrogen, halogen, alkyl or alkoxy, than R3 does not represent alkyl, and R2 and R3 taken together with the intervening nitrogen atom do not represent piperidin-1-yl or morpholin-4yl;
• and
• (ii) when A, B, X, Y and R1 each represents hydrogen, then R2 and R3 taken together with the intervening nitrogen atom do not represent piperidin-1-yl, morpholin-4-yl, pyrrolidin-1-yl, 2-methylpiperidin-1-yl or homopiperidin-1-yl.