N-((phenyl, benzodioxinyl or N-heteroarylpiperazinyl)alkyl)-N-(N-heteroaryl)substituted carboxamides
First Claim
1. A compound of the formula ##STR13## or a pharmaceutically acceptable acid addition salt thereof, wherein A is an alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more lower alkyl groups;
- Z is oxygen or sulphur;
R is hydrogen or lower alkyl;
R1 is aryl, tetrahydronaphthyl, heteroaryl, wherein aryl is phenyl or naphthyl each of which may be optionally substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, halogen, haloloweralkyl, nitro, nitrile, aminocarbonyl, loweralkoxycarbonyl, amino, loweralkylamino, or di-loweralkylamino, and heteroaryl is a monocyclic aromatic heterocyclic ring having 5 ring members and having as heteroatoms one or two N atoms or one N atom and one O or S atom, or a monocyclic aromatic heterocyclic ring having 6 ring members and having as heteroatoms one or two N atoms, or a bicyclic aromatic heterocyclic ring system having one such 5 or 6 membered monocyclic aromatic heterocyclic ring fused to a benzene ring, wherein such heteroaryl or tetrahydronaphthyl ring may be optionally substituted as for aryl,or R1 is a bicyclic oxygen-containing aryl radical of the formula ##STR14## wherein the heterocyclic oxygen-containing ring has 5 to 7 ring members, said heterocyclic ring being non-aromatic and optionally having one further hetero ring member selected from --O--, --S--, --SO2 or NR7, wherein R7 is hydrogen or lower alkyl and wherein R8 and R9 represent hydrogen or one or more substituents independently selected from lower alkyl, halogen, hydroxy, loweralkoxy, hydroxyloweralkyl, loweralkoxyloweralkyl, loweralkanoyloxy(loweralkyl), loweralkylcarbonyl, loweralkylcarbonyl(loweralkyl), amino, loweralkylamino or di-loweralkylamino,or R1 is an bicyclic oxygen-containing aryl radical of the formula ##STR15## wherein R8 and R9 are as defined above;
R2 is a monocyclic aromatic heterocyclic ring having 6 members and having as heteroatoms one or two N atoms or a bicyclic aromatic heterocyclic ring system having one such 6 membered monocyclic aromatic heterocyclic ring fused to a benzene ring, which may be optionally substituted as for aryl, provided that, said bicyclic heterocyclic radical is connected to the amino nitrogen of formula I via such heterocyclic ring; and
R3 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(loweralkyl), aryl, aryl(loweralkyl), a group of formula --NR4 R5, or a group of formula OR6, in which R4 is hydrogen, lower alkyl, aryl or aryl(loweralkyl) and R5 is hydrogen, lower alkyl, --CO(loweralkyl), aryl, --COaryl, aryl(loweralkyl), cycloalkyl or cycloalkyl(loweralkyl), or R4 and R5 together with the nitrogen atom to which they are both attached represent azetidino, pyrrolidino, piperidino, hexahydroazepino, morpholino or piperazino which may be optionally substituted by lower alkyl, aryl or aryl(loweralkyl), and R6 is lower alkyl, cycloalkyl, cycloalkyl(loweralkyl), aryl, or aryl(loweralkyl),wherein aryl is as defined for R1 and cycloalkyl or cycloalkenyl is a mono-, bi-, tri-, or tetracyclic hydrocarbon group of 3 to 12 carbon atoms.
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Abstract
Piperazine derivatives of formula I ##STR1## and their pharmaceutically acceptable acid addition salts are 5-HT1A binding agents, particularly 5-HT1A antagonists and may be used, for example, as anxiolytics. In the formula A is C2-4 alkylene chain optionally substituted by lower alkyl, Z is oxygen or sulphur, R is hydrogen or lower alkyl, R1 is a mono or bicyclic aryl or heteroaryl radical, R2 is a mono or bicyclic heteroaryl radical and R3 is hydrogen or a specified radical such as lower alkyl, cycloalkyl, aryl, heteroaryl or optionally substituted amino.
91 Citations
43 Claims
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1. A compound of the formula ##STR13## or a pharmaceutically acceptable acid addition salt thereof, wherein A is an alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more lower alkyl groups;
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Z is oxygen or sulphur; R is hydrogen or lower alkyl; R1 is aryl, tetrahydronaphthyl, heteroaryl, wherein aryl is phenyl or naphthyl each of which may be optionally substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, halogen, haloloweralkyl, nitro, nitrile, aminocarbonyl, loweralkoxycarbonyl, amino, loweralkylamino, or di-loweralkylamino, and heteroaryl is a monocyclic aromatic heterocyclic ring having 5 ring members and having as heteroatoms one or two N atoms or one N atom and one O or S atom, or a monocyclic aromatic heterocyclic ring having 6 ring members and having as heteroatoms one or two N atoms, or a bicyclic aromatic heterocyclic ring system having one such 5 or 6 membered monocyclic aromatic heterocyclic ring fused to a benzene ring, wherein such heteroaryl or tetrahydronaphthyl ring may be optionally substituted as for aryl, or R1 is a bicyclic oxygen-containing aryl radical of the formula ##STR14## wherein the heterocyclic oxygen-containing ring has 5 to 7 ring members, said heterocyclic ring being non-aromatic and optionally having one further hetero ring member selected from --O--, --S--, --SO2 or NR7, wherein R7 is hydrogen or lower alkyl and wherein R8 and R9 represent hydrogen or one or more substituents independently selected from lower alkyl, halogen, hydroxy, loweralkoxy, hydroxyloweralkyl, loweralkoxyloweralkyl, loweralkanoyloxy(loweralkyl), loweralkylcarbonyl, loweralkylcarbonyl(loweralkyl), amino, loweralkylamino or di-loweralkylamino, or R1 is an bicyclic oxygen-containing aryl radical of the formula ##STR15## wherein R8 and R9 are as defined above;
R2 is a monocyclic aromatic heterocyclic ring having 6 members and having as heteroatoms one or two N atoms or a bicyclic aromatic heterocyclic ring system having one such 6 membered monocyclic aromatic heterocyclic ring fused to a benzene ring, which may be optionally substituted as for aryl, provided that, said bicyclic heterocyclic radical is connected to the amino nitrogen of formula I via such heterocyclic ring; andR3 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(loweralkyl), aryl, aryl(loweralkyl), a group of formula --NR4 R5, or a group of formula OR6, in which R4 is hydrogen, lower alkyl, aryl or aryl(loweralkyl) and R5 is hydrogen, lower alkyl, --CO(loweralkyl), aryl, --COaryl, aryl(loweralkyl), cycloalkyl or cycloalkyl(loweralkyl), or R4 and R5 together with the nitrogen atom to which they are both attached represent azetidino, pyrrolidino, piperidino, hexahydroazepino, morpholino or piperazino which may be optionally substituted by lower alkyl, aryl or aryl(loweralkyl), and R6 is lower alkyl, cycloalkyl, cycloalkyl(loweralkyl), aryl, or aryl(loweralkyl), wherein aryl is as defined for R1 and cycloalkyl or cycloalkenyl is a mono-, bi-, tri-, or tetracyclic hydrocarbon group of 3 to 12 carbon atoms. - View Dependent Claims (2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 43)
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5. A compound as claimed in claim l in which R2 is pyridyl-2-yl, quinolin-2-yl or thiazol-2-yl.
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39. A compound of the formula ##STR16## or a pharmaceutically acceptable acid addition salt thereof, wherein A is an alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more lower alkyl groups;
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Z is oxygen or sulphur, R is hydrogen or lower alkyl; R1 is aryl, tetrahydronaphthyl, heteroaxyl, wherein aryl, is phenyl or naphthyl each of which may be optionally substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, halogen, haloloweralkyl, nitro, nitrile aminocarbonyl, loweralkoxycarbonyl, amino, loweralkylamino, or di-loweralkylamino, and heteroaryl is a monocyclic aromatic heterocyclic ring having 5 ring members and having as heteroatoms one or two N atoms or one N atom and one O or S atom, or a monocyclic aromatic heterocyclic ring having 6 ring members and having as heteroatoms one or two N atoms, or a bicyclic aromatic heterocyclic ring system having one such 5 or 6 membered monocyclic aromatic heterocyclic ring fused to a benzene ring, R2 is a monocyclic aromatic heterocyclic ring having 6 ring members and having as heteroatoms one or two N atoms or a bicyclic aromatic heterocyclic ring system having one such 6 membered monocyclic aromatic heterocyclic ring fused to a benzene ring, which may be optionally substituted as for aryl provided that, said bicyclic heterocyclic radical is connected to the amino nitrogen of formula I via such heterocyclic ring; R3 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(loweralkyl), aryl, aryl(loweralkyl), a group of formula --NR4 R5, or a group of formula OR6, in which R4 is hydrogen, lower alkyl, aryl or aryl(loweralkyl) and R5 is hydrogen, lower alkyl, --CO(loweralkyl), aryl, --COaryl, aryl(loweralkyl), cycloalkyl or cycloalkyl(loweralkyl), or R4 and R5 together with the nitrogen atom to which they are both attached represent azetidino pyrrolidino, piperidino, hexahydroazepino, morpholino or piperazino which may be optionally substituted by lower alkyl, aryl or aryl(loweralkyl), and R6 is lower alkyl cycloalkyl, cycloalkyl(loweralkyl), aryl or aryl(loweralkyl), wherein aryl is as defined for R1 and cycloalkyl or cycloalkenyl is a mono-, bi-, tri-, or tetracyclic hydrocarbon group of 3 to 12 carbon atoms.
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40. A compound of the formula ##STR17## or a pharmaceutically acceptable acid addition salt thereof, wherein A is an alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more lower alkyl groups;
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Z is oxygen or sulphur; R is hydrogen or lower alkyl; R1 is a bicyclic oxygen-containing aryl radical of the formula ##STR18## wherein the heterocyclic oxygen-containing ring has 5 to 7 ring members, said heterocyclic ring being non-aromatic and optionally having one further hetero ring member selected from --O--, --S--, --SO2 or NR7, R2 is a monocyclic aromatic heterocyclic ring having 6 ring members and having as heteroatoms one or two N atoms or a bicyclic aromatic heterocyclic ring system having one such 6 membered monocyclic aromatic heterocyclic ring fused to a benzene ring, which may be optionally substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, halogen, haloloweralkyl, nitro, nitrite, aminocarbonyl, loweralkoxycarbonyl, amino, loweralkylamino, or di-loweralkylamino, provided that, said bicyclic heterocyclic radical is connected to the amino nitrogen of formula I via such heterocyclic ring; R3 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(loweralkyl), aryl, aryl(loweralkyl), a group of formula --NR4 R5, or a group of formula OR6, in which R4 is hydrogen, lower alkyl, aryl or aryl(loweralkyl) R5 is hydrogen, lower alkyl, --CO(loweralkyl), aryl, --COaryl, aryl(loweralkyl), cycloalkyl or cycloalkyl(loweralkyl), or R4 and R5 together with the nitrogen atom to which they are both attached represent azetidino, pyrrolidino, piperidino, hexahydroazepino, morpholino or piperazino which may be optionally substituted by lower alkyl, aryl or aryl(loweralkyl), R6 is lower alkyl cycloalkyl, cycloalkyl(loweralkyl), aryl, or aryl(loweralkyl), wherein aryl is as defined for R1 and cycloalkyl or cycloalkenyl is a mono-, bi-, tri-, or tetracyclic hydrocarbon group of3 to 12 carbon atoms; R7 is hydrogen or lower alkyl; and R8 and R9 represent hydrogen or one or more substituents independently selected from lower alkyl, halogen, hydroxy, loweralkoxy, hydroxyloweralkyl, loweralkoxyloweralkyl, loweralkanoyloxy(loweralkyl), loweralkylcarbonyl, loweralkylcarbonyl(loweralkyl), amino, loweralkylamino or di-loweralkylamino.
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41. A compound of the formula ##STR19## or a pharmaceutically acceptable acid addition salt thereof, wherein A is an alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more lower alkyl groups;
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Z is oxygen or sulphur; R is hydrogen or lower alkyl; R1 is a bicyclic oxygen-containing aryl radical of the formula ##STR20## R2 is a monocyclic aromatic heterocyclic ring having 6 ring members and having as heteroatoms one or two N atoms or a bicyclic aromatic heterocyclic ring system having one such 6 membered monocyclic aromatic heterocyclic ring fused to a benzene ring, which may be optionally substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, halogen, haloloweralkyl, nitro, nitrile, aminocarbonyl, loweralkoxycarbonyl, amino, loweralkylamino, or di-loweralkylamino, provided that, said bicyclic heterocyclic radical is connected to the amino nitrogen of formula I via such heterocyclic ring; R3 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(loweralkyl), aryl, aryl(loweralkyl), a group of formula --NR4 R5, or a group of formula OR6, in which R4 is hydrogen, lower alkyl, aryl or aryl(loweralkyl) and R5 is hydrogen, lower alkyl, --CO(loweralkyl), aryl, --COaryl, aryl(loweralkyl), cycloalkyl or cycloalkyl(loweralkyl), or R4 and R5 together with the nitrogen atom to which they are both attached represent azetidino, pyrrolidino, piperidino, hexahydroazepino, morpholino or piperazino which may be optionally substituted by lower alkyl, aryl or aryl(loweralkyl); R6 is lower alkyl, cycloalkyl, cycloalkyl(loweralkyl), aryl, or aryl(loweralkyl), wherein aryl is as defined for R1 and cycloalkyl or cycloalkenyl is a mono-, bi-, tri-, or tetracyclic hydrocarbon group of 3 to 12 carbon atoms; and R8 and R9 represent hydrogen or one or more substituents independently selected from lower alkyl, halogen, hydroxy, loweralkoxy, hydroxyloweralkyl, loweralkoxyloweralkyl, loweralkanoyloxy(loweralkyl), loweralkylcarbonyl, loweralkylcarbonyl(loweralkyl), amino, loweralkylamino or di-loweralkylamino.
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42. A compound of the formula ##STR21## or a pharmaceutically acceptable acid addition salt thereof, wherein A is an alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more lower alkyl groups,
Z is oxygen or sulphur; -
R is hydrogen or lower alkyl; R1 is a bicyclic oxygen-containing aryl radical selected from the group consisting of;
##STR22## R2 is a monocyclic aromatic heterocyclic ring having 6 ring members and having as heteroatoms one or two N atoms or a bicyclic aromatic heterocyclic ring system having one such 6 membered monocyclic aromatic heterocyclic ring fused to a benzene ring, which may be optionally substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, halogen, haloloweralkyl, nitro, nitrile, aminocarbonyl, loweralkoxycarbonyl, amino, loweralkylamino, or di-loweralkylamino, provided that, said bicyclic heterocyclic radical is connected to the amino nitrogen of formula I via such heterocyclic ring;R3 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(loweralkyl), aryl, aryl(loweralkyl), a group of formula --NR4 R5, or a group of formula OR6, in which R4 is hydrogen, lower alkyl, aryl or aryl(loweralkyl) R5 is hydrogen, lower alkyl, --CO(loweralkyl), aryl, --COaryl, aryl(loweralkyl), cycloalkyl or cycloalkyl(loweralkyl), or R4 and R5 together with the nitrogen atom to which they are both attached represent azetidino, pyrrolidino, piperidino, hexahydroazepino, morpholino or piperazino which may be optionally substituted by lower alkyl, aryl or aryl(loweralkyl), R6 is lower alkyl, cycloalkyl, cycloalkyl(loweralkyl), aryl, or aryl(loweralkyl), wherein aryl is as defined for R1 and cycloalkyl or cycloalkenyl is a mono-, bi-, tri-, or tetracyclic hydrocarbon group of 3 to 12 carbon atoms; and R8 and R9 represent hydrogen or one or more substituents independently selected from lower alkyl, halogen, hydroxy, loweralkoxy, hydroxyloweralkyl, loweralkoxyloweralkyl, loweralkanoyloxy(loweralkyl), loweralkylcarbonyl, loweralkylcarbonyl(loweralkyl), amino, loweralkylamino or di-loweralkylamino.
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Specification