Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-01-29
1997-06-10
McKane, Joseph K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514427, 548517, 548525, A61K 3140, C07D207323
Patent
active
056376090
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP94/02412 filed on Jul. 30, 1994, published as WO95/04039 Feb. 9, 1995.
The present invention relates to novel phenylpyrrole derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, in particular as antipsychotic agents.
European Patent Application No. 241053, describes compounds of the formula: ##STR2## 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: ##STR3## 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 have high affinity for dopamine D.sub.3 receptors and thus have potential as antipsychotic agents.
In a first aspect the present invention provides compounds of formula (I): ##STR4## 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, hydroxy, hydroxyalkyl, C.sub.1-4 alkylthio, C.sub.1-4 alkanoyl, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkanoyl, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkanoyl, C.sub.1-4 alkoxycarbonyl, or --SO.sub.2 NR.sup.11 R.sup.12 wherein R.sup.11 and R.sup.12 each independently represent hydrogen, C.sub.1-4 alkyl or C.sub.1-4 alkoxyC.sub.1-4 alkyl, or NR.sup.11 R.sup.12 forms a 3- to 8- membered fully saturated heterocyclic ring, a 5- to 8-membered partially saturated heterocyclic ring, or a 5- to 8-membered fully saturated heterocyclic ring which contains in addition to the nitrogen atom an oxygen or sulphur atom; or O.sub.p ; substituted by one or two C.sub.1-4 alkyl groups; and Y represents a group of formula: ##STR5## wherein R.sup.6 represents C.sub.1-6 alkyl, C.sub.3-6 alkenyl or C.sub.3-6 cycloalkylC.sub.1-4 alkyl; hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxyC.sub.1-4 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyalkyl, C.sub.1-4 alkanoyl, C.sub.1-4 alkoxycarbonyl, amino or mono- or dialkylamino;
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.
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, pyrrolyl, 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, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyalkyl, C.sub.1-4 alkanoyl, C.sub.1-4 alkoxycarbonyl, amino and mono- or -dialkylamino.
When R.sup.1 and R.sup.2 together form a group --(CH.sub.2).sub
REFERENCES:
patent: 5523299 (1996-06-01), Stemp et al.
CA 122: 81113b 5-(2-alkoxyphenyl)pyrroles . . . agents. Stemp et al., p. 1065.
J. Med. Chem., vol. 30, 1987, pp. 2099-2104, Van Wijngaarden et al `2-Phenylpyrroles as conformationally restricted benzamide analogues`.
J. Med. Chem., vol. 31, 1988, pp. 1934-1940, Van Wijngaarden et al `2-Phenylpyrroles as conformationally restricted benzamide analogues`.
J. Med. Chem., vol. 35, pp. 2355-2363, I. Pettersson 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`.
Johnson Christopher N.
Stemp Geoffrey
King William T.
Lentz Edward T.
McKane Joseph K.
SmithKline Beecham Plc
Stein-Fernandez Nora
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