Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-12-14
2000-06-27
Huang, Evelyn Mei
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5142298, 514291, 514411, 544101, 546 89, 546101, 548427, 548430, A61K 31473, A61K 31404, C07D22110, C07D20960, C07D26536
Patent
active
060807520
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of PCT/EP97/02985, Jun. 6, 1997.
The present invention relates to novel tricyclic amine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, as modulators of dopamine D.sub.3 receptors, in particular as antipsychotic agents.
We have now found a class of tricyclic amine 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, e.g. as antipsychotic agents.
In a first aspect the present invention provides compounds of formula (I): ##STR3## wherein R.sup.1 represents a group of formula (A) or (B): ##STR4## R.sup.2 represents a hydrogen atom or a C.sub.1-4 alkyl group; R.sup.3 represents a substituent selected from: a hydrogen or halogen atom, a hydroxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, arylC.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, a group R.sup.3' OCO(CH.sub.2).sub.p, R.sup.3' R.sup.4 NCO(CH.sub.2).sub.p or R.sup.3' R.sup.4 NSO.sub.2 (CH.sub.2).sub.p where each of R.sup.3' and R.sup.4 independently represents a hydrogen atom or a C.sub.1-4 alkyl group and p represents zero or an integer from 1 to 4, or a group Ar.sup.2 --Z, wherein Ar.sup.2 represents an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered aromatic heterocyclic ring and Z represents a bond, O, S, or CH.sub.2 ; phenyl ring or an optionally substituted 5- or 6-membered aromatic heterocyclic ring; and --(CH.sub.2).sub.m Y.sup.1 (CH.sub.2).sub.n --, wherein y.sup.1 represents O, S, SO.sub.2, or CO and m and n each represent zero or 1 such that the sum of m+n is zero or 1;
In the compounds of formula (I) above an alkyl 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.
When R.sup.3 represents an arylC.sub.1-4 alkoxy, arylsulphonyl, arylsulphonyloxy or arylsulphonylC.sub.1-4 alkyl group, the aryl moiety may be selected from an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered heterocyclic ring.
A halogen atom present in the compounds of formula (I) may be fluorine, chlorine, bromine or iodine.
When q is 2, the substituents R.sup.3 may be the same or different. Preferably q represents 1.
When Ar, Ar.sup.1 or Ar.sup.2 represents an optionally substituted phenyl group this may carry one or more substituents selected from: a hydrogen or halogen atom, or a hydroxy, cyano, nitro, C.sub.1-4 alkyl, C.sub.1-4 alkoxy C.sub.1-4 alkanoyl or C.sub.1-4 alkylsulphonyl group.
An optionally substituted 5- or 6-membered heterocyclic aromatic ring, as defined for either of the groups Ar, Ar.sup.1 or Ar.sup.2 may contain from 1 to 4 heteroatoms selected from O, N or S. When the ring contains 2-4 heteroatoms, one is preferably selected from O, N and S and the remaining heteroatoms are preferably N. Examples of 5 and 6-membered heterocyclic groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl and pyrazolyl. The heterocyclic ring may be optionally substituted by one or more substituents selected from: a hydrogen or halogen atom, or a hydroxy, cyano, nitro, C.sub.1-4 alkyl, C.sub.1-4 alkoxy C.sub.1-4 alkanoyl or C.sub.1-4 alkylsulphonyl group.
It will be appreciated that for use in medicine the salts of formula (I) should be physiologically acceptable. Suitable physiologically acceptable salts will be apparent to those skilled in the art and include for e
REFERENCES:
patent: 5318966 (1994-06-01), Bruderer
Sonesson, et al., Substituted (s)-Phenylpiperidines and Rigid Congeners as Preferential Dopamine Autoreceptor Antagonists: Synthesis and Structure-Activity Relationships, J Med. Chem., vol. 37, pp. 2734-2753 (1994).
Lin, et al, Centrally Acting Serotonergic and Dopaminergic agents. 1. Synthesis and Structure-Activity Relationships of 2,3,3a, 4,5,9b-Hexahydro-1H-benz[e]indole Derivatives, J. Med. Chem. vol. 36, pp. 1053-1068 (1993).
Jeffrey Phillip
Johnson Christopher Norbert
Smith Stephen Allan
Stemp Geoffrey
Huang Evelyn Mei
King William T.
Kinzig Charles M.
Simon Soma G.
SmithKline Beecham Plc
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