Piperazine derivatives as 5-HT antagonists

Details Piperazine derivatives as 5-HT antagonists Piperazine derivatives as 5-HT antagonists

1995-05-24

1997-04-22

McKane, Joseph

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

544295, 544296, 544360, 544363, 544364, 544392, 514254, 514255, A61K 31405, C07D40304

Patent

active

056229518

DESCRIPTION:

BRIEF SUMMARY
This application is A371 PCT/GB93/02661 filed Dec. 24, 1995.
This invention relates to piperazine derivatives, to processes for their preparation, to their use and to pharmaceutical compositions containing them. The novel compounds act on the central nervous system by binding to 5-HT receptors (as more fully explained below) and hence can be used as medicaments for treating humans and other mammals.
The novel compounds of the invention are those of the general formula ##STR2## and the pharmaceutically acceptable acid addition salts thereof. In formula (I) or heteroaryl radicals, groups or a spirocycloalkyl group and
The term "lower" as used herein means that the radical referred to contains 1 to 6 carbon atoms. Preferably such radicals contain 1 to 4 carbon atoms. Examples of "lower alkyl" radicals are methyl, ethyl, propyl, isopropyl, butyl, tert.-butyl, pentyl and isopentyl.
When R and/or R.sup.3 represents two same or different lower alkyl groups the two groups may be on the same or different carbon atoms. When R.sup.3 represents a spirocycloalkyl group the cyclic alkane ring (i.e. the R.sup.3 group together with the carbon atom to which it is attached) can contain, for example, from 3 to 7 carbon atoms.
When used herein "aryl" means an aromatic radical having 6 to 12 carbon atoms (eg phenyl or naphthyl) which optionally may be substituted by one or more substituents. Preferred substituents are lower alkyl, lower alkoxy (eg methoxy, ethoxy, propoxy, butoxy), halogen, halo(lower)alkyl (eg trifluoromethyl), nitro, nitrile, amido, (lower)alkoxycarbonyl, amino, (lower)alkylamino, di(lower)alkylamino, thio(lower)alkyl or phenyl substituents. Two substituents on the aromatic ring may be connected together to form another ring system. For example R.sup.1 may be a bicyclic oxygen-containing radical of the formula ##STR3## wherein the heterocyclic ring containing the oxygen atom contains a total of 5 to 7 ring members, said heterocyclic ring being saturated or unsaturated and optionally containing one or more hetero ring members (eg O, N or S) in addition to the oxygen atom illustrated and the bicyclic oxygen radical being optionally substituted by one or more substituents such as the substituents mentioned above in connection with "aryl". A preferred example of such a bicyclic oxygen radical is an optionally substituted radical of the formula ##STR4## Preferably R.sup.1 is a phenyl radical containing a substituent in the ortho position. A particularly preferred example of R.sup.1 is o-(lower)alkoxyphenyl eg o-methoxyphenyl.
Preferably R.sup.2 is phenyl, a substituted phenyl radical (for example alkyl-phenyl) pyridyl or alkyl substituted pyridyl.
The term "heteroaryl" refers to an aromatic radical containing one or more hetero atoms (eg oxygen, nitrogen, sulphur), which may be optionally substituted by one or more substituents and which is linked to the rest of the molecule via a carbon ring atom. Examples of suitable substituents for "heteroaryl" are given above in connection with "aryl" radicals. The heteroaryl radical may, for example, contain up to 11 ring atoms. Preferably the heteroaryl radical is a monocyclic radical containing 5 to 7 ring atoms or a bicyclic radical containing 8 to 11 ring atoms. Preferably the hetero ring contains a nitrogen hetero atom with or without one or more further hetero atoms. When R.sup.1 is a heteroaryl group it is preferably an optionally substituted pyrimidyl, quinolinyl, isoquinolinyl, or indolyl radical. When R.sup.2 is a heteroaryl group it is preferably pyridyl (eg 2- or 3-pyridyl optionally substituted by one or more lower alkyl and/or lower alkoxy groups), indolyl or oxadiazole optionally substituted by lower alkyl.
Preferred compounds have the following substituents either independently or in combination: (particularly 3,5-dimethylpyridin-2-yl)
The compounds of the invention can exist in various stereochemical forms. The compounds of the invention may be a mixture of cis and trans isomers or as separate cis and trans isomers. For example, when n and m are both 2 the

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