Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-11-27
1997-12-30
McKane, Joseph
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514323, 546 15, 546201, A61K 31445, C07D40114
Patent
active
057030871
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/DK94/00407 filed Oct. 28, 1994.
FIELD OF INVENTION
The present invention is concerned with a class of novel phenylindole compounds related to the atypical neuroleptic sertindole 2-imidazolidinone), however being substituted in the 4- and/or 5-position of the imidazolidinone ring. Said compounds or a salt or prodrug thereof are useful as antipsychotics, antidepressants, antihypertensives and/or in the treatment of extrapyramidal side effects induced by antipsychotic drugs and negative symptoms of schizophrenia.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 4,710,500 corresponding to EP 200,322 B discloses in general optionally 5-substituted 1-aryl-3-(4-piperidyl)-, 1-aryl-3-(1-piperazinyl)- or 1-aryl-3-(1,2,3,6-tetrahydro-4-pyridyl)indole derivatives having hydrogen or alkyl, alkenyl or certain heterocycle-lower alkyl substituents at the nitrogen atom in the piperidyl, piperazinyl or tetrahydropyridyl group.
Most of the compounds were shown to be potent and long-lasting centrally acting dopamine antagonists in vivo, and accordingly to be useful in the treatment of psychoses, and all the compounds were proven to be strong centrally acting 5-HT.sub.2 receptor antagonists in vivo indicating effects in the treatment of depression, extrapyramidal side effects induced by antipsychotic drugs and negative symptoms of schizophrenia. The antipsychotic activity of one compound, i.e. the atypical neuroleptic compound sertindole (recommended INN name), -imidazolidinone, is described in U.S. Pat. No. 5,112,838 corresponding to EP 392,959A.
In our International Patent Application Publ. No. WO 92/00070 a subclass of the 3-(4-piperidyl) compounds, including sertindole, were found to show anxiolytic activity. Furthermore, said 3-(4-piperidyl) compounds have been reported to be useful in the treatment of hypertension, drug abuse and cognitive disorders (International Patent Publications Nos. WO 92/15301, WO 92/15302 and WO 92/15303).
Metabolism studies have shown that a major circulating metabolite of the antipsychotic compound sertindole exists in humans. It is believed that prevention of the formation of said major metabolite might be advantageous.
Accordingly, the object of the invention is to provide novel drugs having a similar pharmacological profile to that of sertindole, in which drugs, however, the formation of said metabolite is either delayed or prevented.
SUMMARY OF THE INVENTION
It has now been found that said major circulating metabolite of sertindole is the compound ,3-dihydroimidazol-2-one which is structurally identical to sertindole except for the double bond in the 1,3-dihydroimidazol-2-one ring. Furthermore, a class of novel phenylindole compounds related to sertindole, wherein the metabolic transformation of the imidazolidinone ring to a 1,3-dihydroimidazol-2-one ring is delayed or blocked, have been found to show a similar pharmacological profile to that of sertindole.
Accordingly, the present invention relates to novel compounds having general Formula I ##STR2## wherein R.sup.1 -R.sup.4 are independently selected from the group consisting of hydrogen, deuterium, halogen, C.sub.1-6 alkyl, cycloalkyl, cycloalkyl-C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, aryl, hydroxy, C.sub.1-6 alkoxy, cycloalkyloxy, cycloalkyl-C.sub.1-6 alkyloxy, aryl-C.sub.1-6 alkyloxy, aryloxy, C.sub.1-6 alkylthio, cycloalkylthio, cycloalky-C.sub.1-6 alkylthio, aryl-C.sub.1-6 alkylthio and arylthio, with the proviso that all 4 substituents cannot be hydrogen; or constitutes an oxo group or a thioxo group and, if only one oxo or thioxo group is present, the other two substituents are selected from the above group defined for R.sup.1 -R.sup.4, with the proviso that they may not both be hydrogen; or together to form a 3-8 membered spiro ring optionally containing one oxygen or sulfur atom in the ring;
In another aspect the invention relates to a method for the preparation of the novel compounds of Formula I.
In yet another aspect the invention relates to a pharmaceutical composition comprising a novel co
REFERENCES:
patent: 4710500 (1987-12-01), Perregaard
patent: 5112838 (1992-05-01), Perregaard et al.
Andersen Kim
B.o slashed.ges.o slashed. Klaus Peter
Bopp Barbara
Moltzen Ejner Knud
Mulford Darcy
H. Lundbeck A/S
McKane Joseph
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