Alkylaminobenzothiazole and -benzoxazole derivatives

Details Alkylaminobenzothiazole and -benzoxazole derivatives Alkylaminobenzothiazole and -benzoxazole derivatives

1998-11-09

2000-08-15

Bernhardt, Emily

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

544368, 424 111, 424 137, 435 71, A61K 31496, C07D41312, C07D41712

Patent

active

061037257

DESCRIPTION:

BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Stage application under 35 U.S.C. .sctn. 371 of PCT/EP97/02505 filed May 2, 1997, which claims priority from EP 96.201.282.9, filed May 10, 1996.
The present invention concerns alkylaminobenzothiazoles and -benzoxazoles; it further relates to processes for their preparation, compositions comprising them, as well as their use as a medicine. The compounds of the present invention exhibit specific dopamine D.sub.4 receptor antagonism and may particularly be useful as antipsychotics, especially in the treatment and/or prevention of psychotic disorders such as schizophrenia. In addition, the present invention concerns compounds of formula (I) containing a radioactive isotope; a process of marking dopamine D.sub.4 receptor sites; and a process for imaging an organ.
It is generally accepted knowledge that dopamine receptors are important for many biochemical functions in the animal body. For example, altered functions of these receptors not only participate in the genesis of psychosis, but also of anxiety, emesis, motoric functions, addiction, sleep, feeding, learning, memory, sexual behaviour, regulation of immunological responses and blood pressure. Since dopamine receptors control a great number of pharmacological events, some of which are thus far unknown, there is a possibility that compounds which exhibit a specific binding affinity for the D.sub.4 receptor may exert a wide range of therapeutic effects in humans.
EP-A-0,335,586, published on Oct. 4, 1989, describes 2-[4-(diarylmethyl)-1-piperazinyl)alkylamino]benzothiazoles and -benzoxazoles having antihistaminic and antiallergic activity.
The alkylaminobenzothiazoles and -benzoxazoles of the present invention surprisingly show a high degree of dopamine D.sub.4 receptor binding affinity. Moreover, the present compounds have a selective affinity for the dopamine D.sub.4 receptor over other dopamine receptors in the human body. The subject compounds also show variable affinity for other receptors such as, for example, serotonin receptors, histamine receptors, adrenergic receptors, cholinergic receptors and the .sigma.-binding site.
The present invention concerns compounds having the formula ##STR2## the N-oxide forms, the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, wherein phenylcarbonyl; nitro, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, haloC.sub.1-6 alkyl, aminosulfonyl, mono- or di(C.sub.1-4 alkyl)-aminosulfonyl; or of formula --CH.dbd.CH--CH.dbd.CH--.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C.sub.1-4 alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C.sub.1-6 alkyl is meant to include C.sub.1-4 alkyl and the higher homologues thereof having 5 or 6 carbon atoms such as, for example pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; haloC.sub.1-6 alkyl is defined as polyhalosubstituted C.sub.1-6 alkyl, in particular C.sub.1-6 alkyl substituted with 1 to 6 halogen atoms, more in particular difluoro- or trifluoromethyl.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. Said salts can be obtained by treating the base form of the compounds of formula (I) with appropriate acids such as inorganic acids, for example, hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like acids; or organic acids, such as, for example, acetic, hydroxy-acetic, propanoic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
The term addition salt as used hereinabove also

REFERENCES:
patent: 5164397 (1992-11-01), Pascal et al.
patent: 5731438 (1998-03-01), Cook et al.
Van Toc et al, Nature, vol. 350, p. 610-614 (1991).
TenBrink et al., J.Med.Chem., vol. 39, p.2435-2437, 1996.
Chimioca Therapeutica, vol. VIII, No. 6, Nov. 1973, Paris, FR. pp. 655-658 "Bases de Manich Derivees d' Amino-2 Benzothiazoles:etude des Activites Analagestiques et Antiinflammatoire".

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