Phenylpyrrole derivatives and their use as antipsychotic agents

Details Phenylpyrrole derivatives and their use as antipsychotic agents Phenylpyrrole derivatives and their use as antipsychotic agents

1995-09-28

1997-11-18

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514299, 514306, 514413, 540593, 546112, 546138, 548453, C07D47104, C07D45502, A61K 31435

Patent

active

056887906

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP94/00992 filed on Mar. 29, 1994.
The present invention relates to novel phenylpyrrole derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, in particular as and psychotic agents.
European Patent Application No. 241053, describes compounds of the formula: ##STR3## wherein A is an unsaturated 5-membered heterocyclic ring, such as 2,5-pyrrolyl, or 3,5- or 1,4- pyrazolyl; X is a nitrogen or carbon atom; R.sub.1, R.sub.2, R.sub.3 are each hydrogen or alkyl; R.sub.4 is aryl, heteroaryl, arylcarbonyl or heteroaryl-carbonyl; R is selected from a variety of substituents and n is 0-4. The compounds are said to have antipsychotic properties.
European Patent Application No. 259930 describes compounds of the formula: ##STR4## wherein A is an unsaturated 5-membered heterocyclic ring, such as 2,5-pyrrolyl, 1,4-pyrazolyl or 2,5-furyl; R is hydrogen, alkyl or optionally substituted phenyl; R.sup.1 is alkyl, alkenyl or forms a ring with the phenyl group; R.sup.2 is hydrogen, hydroxy or alkoxy; R.sup.3 is selected from a variety of substituents and n is 0-3. These compounds are also said to have antipsychotic properties.
We have now found a novel class of 2-phenylpyrroles which exhibit dopamine antagonist activity and thus have potential as antipsychotic agents.
In a first aspect the present invention provides compounds of formula (I): ##STR5## wherein R.sup.1 represents C.sub.1-4 alkyl; and hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxyC.sub.1-4 alkyl, C.sub.1-4 alkylsulphonyl, trifluoromethylsulphonyl; optionally substituted arylsulphonyl, optionally substituted heteroarylsulphonyl, optionally substituted aralkylsulphonyl, optionally substituted heteroaralkylsulphonyl, nitro, cyano, amino, mono- or di-alkylamino, trifluoromethyl, trifluoromethoxy, hydroxyl, hydroxyC.sub.1-4 alkyl, C.sub.1-4 alkylthio, C.sub.1-4 alkanoyl, C.sub.1-4 alkoxycarbonyl, aminosulphonyl, or mono- or diC.sub.1-4 alkylaminosulphonyl; or (wherein m is 2 to 4 and p is zero or 1) which chain may be optionally substituted by one or two C.sub.1-4 alkyl groups; ##STR6## wherein each of n and m independently represent an integer from 1 to 3; and salts thereof.
In the compounds of formula (I) 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.
A halogen atom present in the compounds of formula (I) may be a fluorine, chlorine, bromine or iodine atom.
When R.sup.1 and R.sup.2 together form a group --(CH.sub.2).sub.m Op wherein p is 1 it will be appreciated that the oxygen atom is attached to the phenyl ring at the R.sup.2 position: ##STR7##
When the (CH.sub.2).sub.m moiety is substituted by two C.sub.1-4 alkyl groups these are preferably substituted on the same carbon atom e.g. a gem-dimethyl substituent.
Representative aryl groups or moieties present in any of the substituents R.sup.2, R.sup.3, R.sup.4 and R.sup.5 in compounds of formula (I) include phenyl, naphthyl, and tetrahydronaphthyl. Suitable examples of heteroaryl groups include both 5 and 6-membered heterocycles containing one or more oxygen, sulphur or nitrogen atoms, such as furyl, thienyl, pyrryl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazyl, pyrimidyl and pyrazyl. Suitable substituents for said aryl and heteroaryl groups include halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxyC.sub.1-4 alkyl, nitro, cyano, amino, mono- or diC.sub.1-4 alkylamino, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyC.sub.1-4 alkyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl.
R.sup.1 preferably represents methyl or ethyl, or together with R.sup.2 forms a C.sub.2-3 alkylene chain.
Preferably at least one of R.sup.2 to R.sup.5 is hydrogen, and the other substituents are selected from halogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, phenylsulphonyl, C.sub.1-3 alkylsulphonyl, C

REFERENCES:
patent: 5330990 (1994-07-01), Hansen
patent: 5523299 (1996-06-01), Stemp et al.
J Med Chem vol. 35, No. 13, 1992, pp. 2355-2363; I. Peterson et al; `Conformational analysis of dopamine D-2 receptor antagonists of the benzamide series in relation to a recently proposed D-2 receptor-interaction model`.

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