Phenylindole derivatives as 5-HT2A receptor ligands
First Claim
Patent Images
1. A compound having formula I, or a pharmaceutically acceptable salt thereof;
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whereinA represents hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-6 alkyl or C1-6 alkoxy;
B represents trifluoromethyl or trifluoromethoxy,;
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;
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.
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Accused Products
Abstract
A class of tryptamine analogues bearing an optionally substituted phenyl nucleus at the 2-position are selective antagonists of the human 5-HT2A receptor and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of adverse neurological conditions, including psychotic disorders such as schizophrenia.
49 Citations
14 Claims
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1. A compound having formula I, or a pharmaceutically acceptable salt thereof;
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wherein A represents hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-6 alkyl or C1-6 alkoxy;
B represents trifluoromethyl or trifluoromethoxy,;
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;
orR2 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. - View Dependent Claims (2, 4, 5, 8, 9, 12, 13)
wherein R2 and R3 are as defined in claim 1.
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4. A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in claim 1 in association with a pharmaceutically acceptable carrier.
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5. A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in claim 2 in association with a pharmaceutically acceptable carrier.
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8. A pharmaceutical composition as claimed in claim 4, further comprising a second anti-schizophrenic medicament.
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9. A composition as claimed in claim 5 further comprising a second anti-schizophrenic medicament.
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12. 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 as claimed in claim 1.
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13. 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 as claimed in claim 2.
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3. A compound having formula I, or a pharmaceutically acceptable salt thereof:
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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;
orR2 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. - View Dependent Claims (6, 10, 14)
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7. 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:
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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;
orR2 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.
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11. 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:
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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;
orR2 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.
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Specification