Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-10-29
1999-12-28
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
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Patent
active
060082194
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel amino-substituted bicyclic derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, as modulators of D.sub.3 receptors, in particular as antipsychotic agents.
European Patent Application No. 26848, describes a class of 2-amino-5-hydroxy-1,2,3,4-tetrahydronaphthalenes which are said to be inhibitors of prolactin secretion and to be useful in the treatment of circulatory disorders and Parkinsonism.
European Patent Application No. 270947 describes compounds of the formula: ##STR2## wherein R.sup.1 is hydrogen or alkyl; R.sup.2 is inter alia alkyl; R.sup.3 is inter alia a group --(CH.sub.2).sub.a R.sup.4 wherein a is from 1 to 10 and R.sup.4 may be --NR.sup.11 R.sup.12. The meanings of R.sup.11 and R.sup.12 may be selected from inter alia hydrogen and COR.sup.13 and R.sup.13 may be inter alia aryl having 6-12 carbon atoms, e.g. phenyl, naphthyl or biphenyl. These compounds are said to have affinity for cerebral receptors of the 5-HT.sub.1 type and to be useful in the treatment of a variety of conditions including anxiety, depression, cognitive deficits and migraine.
We have now found a class of amino-tetralin derivatives which have affinity for dopamine receptors, in particular the D.sub.3 receptor, and thus potential in the treatment of conditions wherein modulation of the D.sub.3 receptor is beneficial, eg as antipsychotic agents.
In a first aspect the present invention provides compounds of formula (I): ##STR3## wherein X represents a single bond, O, S or CR.sup.9 R.sup.10 where R.sup.9 and R.sup.10 each independently represent a hydrogen atom or a C.sub.1-4 alkyl group; selected from: a hydrogen or halogen atom, a hydroxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, C.sub.1-4 alkoxyC.sub.1-4 alkyl, C.sub.3-6 cycloalkylC.sub.1-4 alkoxy, C.sub.1-4 alkanoyl, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkylsulphonyl, C.sub.1-4 alkylsulphonyloxy, C.sub.1-4 alkylsulphonylC.sub.1-4 alkyl, arylsulphonyl, arylsulphonyloxy or arylsulphonylC.sub.1-4 alkyl group or a group R.sup.11 OCO(CH2).sub.p, R.sup.11 R.sup.12 NCO(CH2).sub.p or R.sup.11 R.sup.12 NSO.sub.2 (CH.sub.2).sub.p where each of R.sup.11 R.sup.12 independently represents a hydrogen atom or a C.sub.1-4 alkyl group and p represents zero or an integer from 1 to 4; hydrogen atom or a C.sub.1-4 alkyl group; or arylC.sub.1-4 alkyl group; ##STR4## wherein Ar represents an optionally substituted 5- or 6-membered aromatic heterocyclic ring or a group of structure (d): ##STR5## R.sup.13 represents a hydrogen or halogen atom, or a hydroxy, cyano, nitro, H.sub.2 NCO, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkanoyl or C.sub.1-4 alkylsulphonyl group or an optionally substituted 5- or 6-membered heterocyclic ring; from: a hydrogen or halogen atom, or a hydroxy, cyano, nitro, H.sub.2 NCO, C.sub.1-4 alkyl, C.sub.1-4 alkoxy C.sub.1-4 alkanoyl or C.sub.1-4 alkylsulphonyl, group;
In the compounds of formula (I) above an alkyl or alkenyl group or moiety may be straight or branched. Alkyl groups which may be employed include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and any branched isomers thereof such as isopropyl, t-butyl, sec-pentyl, and the like. Alkenyl groups may similarly be straight or branched. Further the double bond may be at any appropriate position in the alkenyl chain.
When one or more of R.sup.1a, R.sup.1b and R.sup.1c represents an arylsulphonyl, arylsulphonyloxy or arylsulphonylC.sub.1-4 alkyl group, the aryl moiety may be selected from phenyl, naphthyl, and tetrahydronaphthyl; preferably the aryl moiety is phenyl.
A halogen atom present in the compounds of formula (I) may be fluorine, chlorine, bromine or iodine.
R.sup.1a, R.sup.1b and R.sup.1c preferably each independently represent a hydrogen or halogen (eg fluorine, chlorine or bromine) atom, or a hydroxy, cyano, trifluoromethoxy, trifluoromethanesulfonyloxy, C.sub.1-4 alkoxy (eg methoxy), C.sub.3-6 cycloalkylC.sub.1-4
REFERENCES:
patent: 4410519 (1983-10-01), Seiler et al.
patent: 4880802 (1989-11-01), Schohe et al.
patent: 5118704 (1992-06-01), Minaskanian et al.
Boyfield et al., "A Novel Series of 2-Aminotetralins with High Affinity and Selectivity for the Dopamine D3 Receptor," Bioorganic & Medicinal Chemistry Letters, vol. 7, No. 15, pp. 1995-1998, 1997.
Johnson Christopher Norbert
Stemp Geoffrey
Ford John M.
Kessinger Ann M.
Kinzig Charles M.
SmithKline Beech p.l.c.
Stein-Fernandez Nora
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