2-(piperidinylmethyl)-4-phenyl-2,3-dihydro-4H-1,4-benzoxazines u

Details 2-(piperidinylmethyl)-4-phenyl-2,3-dihydro-4H-1,4-benzoxazines u 2-(piperidinylmethyl)-4-phenyl-2,3-dihydro-4H-1,4-benzoxazines u

1989-10-11

1992-01-28

Daus, Donald G.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

544 6, 544 51, 544 70, 544105, C07D26536, C07D27916, A61K 31535, A61K 3154

Patent

active

050844547

DESCRIPTION:

BRIEF SUMMARY
DESCRIPTION

The present invention relates to substituted 4-aryl derivatives of 2,3-dihydro-4H-1,4-benzoxazine and 2,3-dihydro-4H-1,4-benzothiazine, to a process for their preparation, to pharmaceutical compositions containing them, and to their use in the preparation of pharmaceutical compositions having anti-psychotic activity.
Most of the classical drugs, up to now used in therapy for the management of psychotic disorders, act mainly on the dopaminergic pathways as dopamine antagonists. This pharmacological activity is closely associated with their antischizophrenic effects, in particular against symptoms, such as hallucinations and delusions. However the dopamine antagonists now available in therapy are meagrely effective against other symptoms of schizophrenia, such as apathy and withdrawn social behaviour, and unfortunately are associated with extrapyramidal side effects. Therefore in therapy remains a strong need of drugs active in treating also these latter aspects of the psychotic syndrome, and having no, or negligible, neurological side effects.
The invention provides compounds having the following general formula (I) ##STR2## wherein X represents --O-- or --S--; C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, amino, nitro or trihalo-C.sub.1 -C.sub.6 alkyl; alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl or phenyl-C.sub.1 -C.sub.6 alkyl; or R.sub.2 and R.sub.3, taken together with the nitrogen atom to which they are linked, form an unsubstituted or substituted, 6-membered, saturated, heteromonocyclic ring optionally containing a further heteroatom chosen from oxygen, sulphur and nitrogen; amino or trihalo-C.sub.1 -C.sub.6 alkyl; and the pharmaceutically acceptable salts thereof.
The invention also includes within its scope all the possible isomers, stereoisomers and optical isomers and their mixtures, and the metabolites and the metabolic precursors or bio-precursors of the compounds of formula (I).
A halogen atom is e.g. chlorine, bromine or fluorine, preferably it is fluorine.
The alkyl, alkenyl, alkynyl and alkoxy groups may be branched or straight chain groups. A C.sub.1 -C.sub.6 alkyl group is preferably a C.sub.1 -C.sub.4 alkyl group, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec. butyl or tert. butyl, more preferably it is methyl or ethyl. A C.sub.2 -C.sub.6 alkenyl group is preferably a C.sub.2 -C.sub.4 alkenyl group, in particular allyl. A C.sub.2 -C.sub.6 alkynyl group is preferably a C.sub.2 -C.sub.4 alkynyl group, in particular propargyl.
A phenyl-C.sub.1 -C.sub.6 alkyl group is preferably a phenyl-C.sub.1 -C.sub.4 alkyl, in particular benzyl or phenethyl.
A C.sub.1 -C.sub.6 alkoxy group is preferably a C.sub.1 -C.sub.4 alkoxy group, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert.butoxy, more preferably it is methoxy or ethoxy.
A trihalo-C.sub.1 -C.sub.6 alkyl group is preferably a trihalo-C.sub.1 -C.sub.4 alkyl group, e.g. trichloro-C.sub.1 -C.sub.4 alkyl or trifluoro-C.sub.1 -C.sub.4 alkyl, more preferably it is trifluoromethyl.
When R.sub.2 and R.sub.3, taken together with the nitrogen atom to which they are linked, form an heteromonocyclic ring as defined above, it may be for example a ring chosen from the group including piperidine, piperazine, morpholine or thiomorpholine, which may be unsubstituted or substituted at one or two carbon atoms by one or two substituents independently chosen from the group including:
a) hydroxy and C.sub.1 -C.sub.6 alkyl;
b) phenyl unsubstituted or substituted by one to three substituents independently chosen from hydroxy, halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy and trifluoro-methyl;
c) 2-keto-1-benzoimidazolinyl; and
d) 1-phenyl-4-keto-5-imidazolidinyl, so as to provide e.g. a 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one condensed ring system, i.e. ##STR3## in which the phenyl ring is unsubstituted or substituted by one to three substituents chosen independently from hydroxy, halogen, C.sub.1 -C.sub.6 alkyl and trifluoromethyl, and the nitrogen atom at the 1-position of the imidazolidine ring may be unsubsti

REFERENCES:
patent: 3058980 (1962-10-01), Berg
Drug Evaluations, 6th Edition, American Medical Association, Chicago, Ill., (1986), pp. 111-113.

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