Piperazine derivatives

Details Piperazine derivatives Piperazine derivatives

1995-05-24

1997-05-06

McKane, Joseph

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514210, 514252, 514254, 540481, 540598, 540599, 544362, 544363, 544371, 544373, A61K 3155, C07D48712

Patent

active

056271778

DESCRIPTION:

BRIEF SUMMARY
This application is a National phase filing under 37 USC .sctn. 371 of PCT/GB93/02660 filed Dec. 24, 1993.
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.
GB 2230781-A and GB 2230780-A disclose some piperazine derivatives which exhibit 5-HT.sub.1A receptor affinity.
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, the group consisting of optionally substituted indolyl, isoindolyl, quinolinyl, isoquinolinyl, indazolyl and benzotriazolyl, 3 to 12 carbon atoms, cycloalkyl(lower)alkyl, aryl or aryl(lower)alkyl both attached represent a saturated heterocyclic ring which may contain a further hetero atom (eg an azetidino, pyrrolidino, piperidino, hexahydroazepino, heptamethyleneimino, morpholino or piperazino ring which may be optionally substituted by lower alkyl, aryl or aryl(lower)alkyl).
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 alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and isopentyl. When R.sup.3 is an alkyl radical a particularly preferred radical is a tertiary alkyl radical such as tert-butyl. Examples of cycloalkyl groups of 3 to 12 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl groups also include bicyclic, tricyclic and tetracyclic groups eg adamantyl.
When used herein "aryl" means an aromatic radical having 6 to 12 carbon atoms (e.g. phenyl or naphthyl) which optionally may be substituted by one or more substituents commonly used in medicinal chemistry, eg substituents such as lower alkyl, lower alkoxy, lower alkylthio, halogen, trifluoromethyl, nitro, carbalkoxy, carboxamido, cyano, amino, (lower)alkylamino and di(lower)alkylamino.
Examples of aryl(lower)alkyl include, for example, benzyl in which the phenyl group may be substituted as defined above.
The bicyclic nitrogen containing heteroaromatic radical Z may be unsubstituted or substituted by, for example, one or more same or different substituents selected from lower alkyl, halogen, halo(lower)alkyl (eg trifluoromethyl), nitro, nitrile, oxo, hydroxy, (lower)alkoxy, hydroxy(lower)alkyl, (lower)-alkoxy(lower)alkyl, lower alkanoyloxy(lower)alkyl, lower alkylcarbonyl, (lower)alkylcarbonyl(lower)alkyl, carboxamido, (lower)alkoxy carbonyl, amino, (lower)alkylamino or di(lower)alkylamino. A particularly preferred substituent is (lower)alkoxycarbonyl e.g. --CO.O.CH.sub.3.
Where Z is an optionally substituted indolyl or indazolyl radical, the radical is preferably linked via position 4 or 7 (most preferably via position 4) to the nitrogen atom of the piperazine ring. When Z is an optionally substituted quinolinyl or isoquinolinyl radical, the radical is preferably linked via position 5 or 8 (most preferably via position 5) to the nitrogen atom of the piperazine ring.
Examples of preferred compounds are cycloalkyl hexahydroazepino ring indol-4-yl optionally substituted by, for example methoxycarbonyl in, for example the 2-position
The compounds of the invention may be prepared by methods known in the art from known starting or starting materials that may be prepared by conventional methods. One method comprises alkylation of a piperazine compound of formula ##STR3## (where Z and R are as defined above) with an alkylating agent providing the group
The alkylating agent may be, for example a compound of formula leaving group such as halogen or an alkyl- or aryl-sulphonyloxy group. Alternatively the alkylating agent may be an unsaturated compound of formula of formula (V) is reacted with the piperazine of formu

REFERENCES:
patent: 5169845 (1992-12-01), Cliffe et al.
patent: 5382583 (1995-01-01), Cliffe et al.
M. El-Bermawy et al., Medicinal Chemistry Research 2:88-95 (1992).

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