Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-06-09
1997-11-04
Bond, Robert T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540523, A61K 3155, C07D22316
Patent
active
056839979
DESCRIPTION:
BRIEF SUMMARY
This application is the United States National phase of International Application Ser. No. PCT/EP93/03425, filed 6 Dec. 1993.
The invention relates to substituted 3-amino-1-arylalkylbenzazepin-2-ones of the general formula ##STR2## wherein Ar is aryl; aryl-lower alkoxy-lower alkyl, aryl-lower alkyl or C.sub.3 -C.sub.7 cycloalkyl-lower alkyl; SO.sub.3 H.sub.2 ; lower alkoxycarbonyl; lower alkoxy-lower alkoxycarbonyl; aryl-lower alkoxycarbonyl; aryloxycarbonyl; carbamoyl; carbamoyl that (i) is monosubstituted by hydroxy, lower alkanesulfonyl, halo-lower alkanesulfonyl or by arylsulfonyl, (ii) is monosubstituted or disubstituted, the substituents being independent of one another, by lower alkyl, lower alkenyl, lower alkynyl or by phenyl-lower alkyl or (iii) is disubstituted by lower alkylene or by lower alkylene-X.sub.1 -lower alkylene, X.sub.1 being O, S or NH; selected from the group consisting of: lower alkyl, aryl-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, aryl-lower alkoxy, C.sub.3 -C.sub.7 -cycloalkyl, C.sub.3 -C.sub.7 cycloalkyl-lower alkyl, nitro, halogen, trifluoromethyl, amino and amino that is monosubstituted or disubstituted, the substituents being independent of one another, by lower alkyl, aryl-lower alkyl or by aryl, or disubstituted by lower alkylene or by lower alkyleneoxy-lower alkylene; thereof as well as to pharmaceutical compositions that comprise compounds of formula (I) or pharmaceutically acceptable salts thereof.
Lactams of the benzazepin-2-one type are described, for example, in U.S. Pat. No. 4,477,464. Those compounds have an acyl-alkyl radical at the 1-N atom of the heterocycle and may be used as ACE inhibitors in the treatment of cardiovascular disorders.
Benzo-fused lactams of the type of compounds of formula I described above are disclosed in U.S. Pat. No. 4,692,522. In the compounds specified therein, the 1-N-atom has a substituent that is in turn substituted by an acyl radical, while the N-atom bonded at the 3-position of the heterocycle in such a constellation may be both N-acylated and N-alkylated. Also specified are those compounds that are substituted at the 1-N-atom of the heterocycle by a non-acylated radical, the amino group bonded at the 3-position of the heterocycle being N-acylated only. Compounds of that substance class may be used as cholecystokinin antagonists.
In contrast, the compounds of the present invention, in which the 1-N-atom of the benzazepinone ring has a non-acylated hydrocarbon radical and in which the amino group bonded in the 3-position of the ring is N-alkylated, have a different spectrum of activity. AT.sub.2 ! of angiotensin(II) which differ in respect of their different affinities for synthetic angiotensin-II analogues.
AT.sub.2 -receptors can be identified in various body tissues. Such receptors are described in the relevant literature as being expressed, for example, in neuron tumour cells, in transformed neural cells, in various regions of the central nervous system, in the heart and the arteries, in female reproductive organs, such as the uterus and the ovaries, in the adrenal glands and the pancreas and also in healing skin.
Surprisingly, the compounds of the present invention exhibit selective binding to the angiotensin-II-AT.sub.2 -receptor in the model described by Whitebread et al., Biochem. Biophys. Res. Comm. 1989; 163, 184-191. Those binding properties of the compounds according to the invention were detected below a concentration of 50 .mu.mol/l. Accordingly, the compounds according to the invention may be used especially in the prophylactic or therapeutic treatment of symptoms that are caused by AT.sub.2 -receptors.
It has been demonstrated that an AT.sub.2 -receptor stimulation al., Biochem. Biophys. Res. Commun. 1992, 183, 206-211: Botari et al., Front. Neuroendocrinol. 1993, 44, 207-213; Brechler et al., Regul. Peptide 1993, 44, 207-213; Kambayashi et al., J. Biol. Chem. 1993, 268, 24543-24546! Biochem. Biophys. Res. Commun. 1992, 183, 206-211; Botari et al., Front. Neuroendocrinol. 1993, 44,
Buhlmayer Peter
Furet Pascal
Bond Robert T.
Ciba-Geigy Corporation
Mathias Marla J.
Nowak Henry P.
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