Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-07-12
1997-03-11
Bond, Robert T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540491, A61K 3155, C07D51304
Patent
active
056101538
DESCRIPTION:
BRIEF SUMMARY
The invention relates to substituted 3-amino-1-arylalkyl-benzazepin-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; 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-Z.sub.1 -lower alkylene, Z.sub.1 being O, S or NH; 5-tetrazolyl; PO.sub.2 H.sub.2 ; PO.sub.3 H.sub.2 or SO.sub.3 H.sub.2 ; unsubstituted or mono- or poly-substituted by substituents 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.
There are described in the literature two receptor sub-types [AT.sub.1 and 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 cell line PC12W and in AT.sub.2 -receptor transfected COS cells [Botari et 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, 207-213; Brechler et al., Regul. Peptide 1993, 44, 207-213: Summers et al., Am. J. Physiol. 1991, 260, 679-687; Summers et al., Proc. Natl. Acad. Sci. USA 1991, 88, 7567-7571] and et al., FEBS 1992, 309, 161-164].
In addition, the AT.sub.2 -receptor is involved in cell growth and cell proliferation, since it is especially expressed in high density during foetal development [Grady et al., J. Clin. Invest. 1991, 88 921-933].
As a result of the ability of AT.sub.2 -ligands to inhibit the proliferation of vascular endothelial cells, and since endothelial cell proliferation is the cause of angiogenesis, which is in turn a prerequisite for tumour growth and the development of metastases, the compounds according to the invention may be used in the treatment of cancer and those disorders generally associated with benign and malignant proliferation.
AT.sub.2 -receptors also bring about the modulation of phosphotyrosine phosphatase activity (PTPase activity), which is associated with growth-inhibiting and antiproliferative effects. AT.sub.2 -rece
REFERENCES:
patent: 4477464 (1984-10-01), Slade et al.
Buhlmayer Peter
Furet Pascal
Bond Robert T.
Ciba-Geigy Corporation
Ferraro Gregory D.
Mathias Marla J.
Nowak Henry P.
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