Piperazine derivatives as 5-HT.sub.1A ligands

Details Piperazine derivatives as 5-HT.sub.1A ligands Piperazine derivatives as 5-HT.sub.1A ligands

1995-05-24

1997-12-02

Bernhardt, Emily

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514254, 544295, 544360, 544363, 544364, A61K 31495, A61K 31505, C07D40106, C07D40114

Patent

active

056936427

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB 94/00539 filed Mar. 17, 1994.
This invention relates to piperazine derivatives, to processes for their preparation, to their use and to pharmaceutical compositions containing them. The novel compounds act upon the central nervous system by binding to 5-HT receptors (as more fully explained below) and hence can be used as medicaments for treating human 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 more lower alkyl groups and cycloalkyl) --S--, --SO-- or --SO.sub.2- or X can also be --(CH.sub.2).sub.n -- (where n is 0, 1 or 2) when R.sup.3 is cycloalkyl.
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. A cycloalkyl group preferably contains 3 to 7 carbon atoms. Examples of the cycloalkyl group R.sup.3 include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
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 trifuoromethyl), nitro, nitrile, amido, (lower)alkoxycarbonyl, amino, (lower)alkylamino or di(lower)alkylamino 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.
The term "heteroaryl" refers to an aromatic radical containing one or more hetero ring atoms (eg oxygen, nitrogen, sulphur) and which may be optionally substituted by one or more substituents. Examples of suitable substituents are given above in connection with "aryl" radicals. The heteroaryl radical may, for example, contain up to 10 ring atoms. Preferably the heteroaryl radical is a monocyclic radical containing 5 to 7 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.
Preferred compounds have the following substituents either independently or in combination: or bicyclic heteroaryl (eg indolyl)
The compounds of the invention may be prepared by methods known in the art from known starting materials or starting materials that may be prepared by conventional methods.
One method of preparing the compounds of the invention comprises alkylating a piperazine derivative of formula ##STR5## with an alkylating agent providing the group ##STR6##
The alkylating agent may be, for example, a compound of formula ##STR7## where R.sup.2, R.sup.3, R.sup.4, X and A are as defined above and Z is a leaving group such as halogen or an alkyl- or aryl-sulphonyloxy group.
The compounds of formula (I) in which X is --CHOH--, --S-- or --CH.sub.2 -- may also be prepared by reduction of an amide of formula ##STR8## where R, R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as defined above and X is --CH

REFERENCES:
patent: 5346896 (1994-09-01), Ward et al.
H. Morren et al., Industrie Chimique Belge, 1963, 28, 123-134.

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