Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-04-25
1998-06-30
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540546, 540547, C07D49804, C07D51304, A61K 3155
Patent
active
057734330
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is the national stage of application No. PCT/EP 95/04197, filed on Oct. 25, 1995, which application claims priority from EP 94.203.177.4, filed on Nov. 2, 1994.
This invention concerns substituted tetracyclic oxazepine and thiazepine derivatives having antipsychotic, cardiovascular and gastrokinetic activity and their preparations; it further relates to compositions comprising them, as well as their use as a medicine.
Compounds of similar structure are described in U.S. Pat. No. 4,039,558 which discloses pyrrolidinodibenzo-azepine, -oxazepine, -thiazepine and -diazepine derivatives, having antihistamine, sedative and antidepressant properties. EP-A-0,421,823 describes similar dibenzopyrazino- or benzo-pyrido-pyrazino-azepine derivatives having anti-allergic and anti-asthmatic activities. The present compounds differ therefrom by the presence of an isoxazolidine ring, and by their pharmacological properties.
This invention concerns compounds of formula ##STR2## the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, and also the N-oxide forms thereof, wherein: R.sup.1 and R.sup.2 each independently are hydrogen; C.sub.1-6 alkyl; C.sub.1-6 alkylcarbonyl; trihalomethylcarbonyl; C.sub.1-6 alkyl substituted with hydroxy, C.sub.1-6 alkyloxy, carboxyl, C.sub.1-6 alkylcarbonyloxy, C.sub.1-6 alkyloxycarbonyl or aryl; or R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached may form a morpholinyl ring or a radical of formula: ##STR3## wherein: R.sup.13, R.sup.14, R.sup.15 and R.sup.16 each independently are hydrogen, halo, trifluoromethyl, or C.sub.1-6 alkyl; or C.sub.1-6 alkyl; or alkanediyl; trihalomethylcarbonyl; substituted with hydroxy, C.sub.1-6 alkyloxy, carboxyl, C.sub.1-6 alkylcarbonyloxy, C.sub.1-6 alkyloxycarbonyl or aryl; each independently are hydrogen, halo, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, amino, mono- or di(C.sub.1-6 alkyl)amino, C.sub.1-6 alkylcarbonylamino, aminosulfonyl, mono- or di(C.sub.1-6 alkyl)-aminosulfonyl, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkyloxycarbonyl; from halo, hydroxy, C.sub.1-6 alkyl and trifluoromethyl.
In the foregoing definitions C.sub.1-6 alkyl defines straight and branch chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl; C.sub.4-5 alkanediyl defines bivalent straight and branch chained saturated hydrocarbon radicals having from 4 to 5 carbon atoms such as, for example, 1,4-butanediyl, 1,5-pentanediyl; halo is generic to fluoro, chloro, bromo and iodo.
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, hydroxyacetic, propanoic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluene-sulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
The compounds of formula (I) containing acidic protons may also be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and
REFERENCES:
patent: 4039558 (1977-08-01), van der Burg et al.
Obara et al., Chemical Abstracts, vol. 126 No. 4, p. 584, (abstract for WO 9633983). Jan. 27, 1997.
Andrés-Gil José Ignacio
Fernandez-Gadea Francisco Javier
Meert Theo Frans
Sipido Victor Karel
Bernhardt Emily
Ciambrone Coletti Ellen
Janssen Pharmaceutica N.V.
Kessinger Ann M.
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