Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1998-07-16
2000-05-23
Kumar, Shailendra
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514307, 514311, 514357, 514538, 514626, 514649, 546139, 546176, 546329, 560 39, 564165, 564168, 564198, 564337, A61K 31165, C07C23305
Patent
active
060666722
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to amino compounds useful as medicines, and in particular it relates to amino compounds useful as therapeutical drugs for various diseases in which angiotensin IV participates.
BACKGROUND ART
In the renin-angiotensin system, peptides relating to coronary vessels and electrolyte homeostasis are produced by the enzymatic peptide-degradation cascade. In the cascade, angiotensinogen is first converted by renin into physiologically inert angiotensin I, angiotensin II, angiotensin III and finally into angiotensin IV which is a hexapeptide, successively. Angiotensin IV receptor is known to be distributed at high concentration in various organs such as brain (in particular, hippocampus), adrenal gland, heart, kidney, smooth muscle cells and endothelial cells. It is also reported that angiotensin IV relates to various physiological functions such as acceleration of renal blood flow (Swanson et al., Regulatory Peptides, 1992, 40, 409), cerebral vasodilation (Haberl et al., Circ. Res., 1991, 68, 1621), inhibition of cell proliferation (Barker and Aceto, Am. J. Physio., 1990, 259, H610) and hypermnesia (Miller-Wing, et al., J. Pharmacol. Exp. Thr., 1993, 266, 1718).
On the other hand, some peptide compounds are reported to act on angiotensin IV receptor agonistically (Sardinia, et al., Peptides, 1993, 14, 949; ibid., 1994, 8, 1399). However, these peptides should be composed of at least 5 amino acids to express high activities and have some problems in safety and the like. The amino compounds of the present invention have not been known.
DISCLOSURE OF THE INVENTION
As a result of extensive researches in order to provide amino compounds which agonistically act on the angiotensin IV receptor at low concentration, the present inventors have found that specific amino compounds agonistically act on the angiotensin IV receptor strongly, and thereby the present invention has been accomplished.
The present invention relates to an amino compound represented by the following Formula (1): ##STR2## wherein X is CH.sub.2 NH or CONH, Y is CH.sub.2 NH or CONH with the proviso that X and Y are not CONH at the same time; Z is; CH.dbd.C(R.sup.4)R.sup.5, CH.sub.2 CH(R.sup.4)R.sup.5 or an alkoxycarbonyl group, R.sup.1 is a hydrogen atom; a lower alkyl group, a cycloalkyl group, a cycloalkyl-substituted alkyl group, an aralkyl group or an aryl group, each group of which is substituted or unsubstituted, R.sup.2 and R.sup.3 are each independently a lower alkyl group or an aralkyl group, each group of which is substituted or unsubstituted, and R.sup.4 and R.sup.5 are each independently a hydrogen atom; an alkyl group, an aralkyl group, an aryl group or a heteroaryl group, each group of which is substituted or unsubstituted; or a pharmaceutically acceptable salt thereof. Additionally, the present invention provides a medicine or angiotensin IV receptor agonist, comprising the amino compound of Formula (1) or the pharmaceutically acceptable salt thereof as an effective component.
In the present specification, the definitions used in the general formulae have the following means, unless otherwise noted.
The alkoxycarbonyl group is preferably a C.sub.2 -C.sub.10 alkoxycarbonyl group, specific examples of which are a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an allyloxycarbonyl group and a benzyloxycarbonyl group.
The lower alkyl group refers to a straight or branched C.sub.1 -C.sub.6 alkyl group, and specific examples of the alkyl group which is unsubstituted are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 1,2-dimethylpropyl group, a hexyl group, an isohexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,
REFERENCES:
patent: 5439919 (1995-08-01), Miyachi et al.
Krebs, et al., Characterization of the binding properties and physiological action of divalinal-angiotensin IV, a putative AT4 receptor Antagonist', Regul. Pept., 67 (28) (1996) p. 123130.
Sardinia, et al., "AT4 receptor binding relationship; N-terminal-modified angiontensin IV analogues", Peptides (Tarrytown, N.Y.)15(8) (1994), pp. 1399-1406.
Bernier, et al., "Characterization of a binding site for angiotensin IV on bovine aortic endothelial cells", Eur. J. Pharmacol., Mol. Pharmacol., Sect., 291(2) (1995) pp. 191-200.
Bernier, et al., "A specific binding site recognizing a fragment of angiotensin II in bovine adrenal cortex membranes"., Eur. J. Pharmacol., 271(1) (1994) pp. 55-63.
Hall, et al., "Identification and characterization of a novel angiotensin binding site in cultured vascular smooth muscle cells that is specific for the hexapeptide (3-8) fragment of angiotensin II angiotensin IV", Regul. Pept., 44(2) (1993) pp. 225-232.
Swanson, et al., "Discovewry of a distinct binding site for angiotensin II (3-8), a putative angiotensin IV receptor", Regul. Pept., 40(3) (1992) pp. 409-419.
WO, 94/00492, A1, Jan. 6, 1994.
Haberl, et al., "Angiotensin Degradation Products Mediate Endothelium-Dependent Dilation of Rabbit Brain Arterioles", Circ. Res., 68(6) (1991) pp. 1621-1627.
Baker, et al., "Angiontensin II stimulation of protein synthesis and cell growth in chick heart cells", Am. J. Physical. 259 (1990) H610-H618.
Miller-Wing, et al., "Central angiotensin IV Binding sites: Distribution and specificity in Guinea Pig Brain", J. Phamracol. Exp. Thr. 266(3) (1993) pp. 1718-1726.
Goda Kenichi
Kobori Takeo
Ota Tomomi
Sugimoto Kikuo
Tomisawa Kazuyuki
Kumar Shailendra
Sagami Chemical Research Center
Taisho Pharmaceutical Co. Ltd.
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