Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-03-28
1997-11-25
Higel, Floyd D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514255, 514314, 514341, 514389, 544139, 544370, 546152, 5462741, 5483111, 5483175, 5483185, 5483191, A61K 31415, A61K 31495, C07D23380, C07D23386
Patent
active
056913354
DESCRIPTION:
BRIEF SUMMARY
This application is A 371 PCT/JP 95/01485 filed Jul. 26, 1995.
TECHNICAL FIELD
The present invention relates to an imidazolidine derivative, a chymase inhibitor comprising the same as an active ingredient and a medicine comprising the same as an active ingredient, such as a prophylactic and therapeutic agent for a disease of the cardiac or circulatory system, which is caused by the abnormal acceleration of production of angiotensin II.
BACKGROUND ART
A renin-angiotensin system is one of mechanisms by which the blood pressure of a living body is controlled. Angiotensin I (hereinafter abbreviated as "Ang I") is excised from angiotensinogen biosynthesized in vivo by a renal enzyme renin, and two amino acid residues of its C-terminal are liberated to form angiotensin II (hereinafter abbreviated as "Ang II"). It is considered that this Ang II constricts a peripheral vessel and stimulates a sympathetic nerve, thereby exhibiting a hypertensive effect. Accordingly, Ang II is an important substance for maintaining the blood pressure. It is however considered that the abnormal acceleration of its production may result in an attack of hypertension or heart failure. From such a point of view, attention is paid to the relation between an enzyme converts Ang I to Ang II, and diseases of the heart or circulatory organs, including hypertension, and various ACE inhibitors have been developed as anti-hypertensive and anti-cardiodysfunctional agents.
Recently, it has also been revealed that Ang II has an action of facilitating cell growth in addition to the actions of constricting the peripheral vessel and stimulating the sympathetic nerve. For example, Naftilan et al. have used cultured cells of a rat vascular smooth muscle to show that Ang II plays an important part in the growth of a vascular have revealed that Ang II serves as a growth factor for myocardial cells, interstitial cells, angioendothelial cells and vascular smooth muscle cells and so deeply affects the progress of intravascular stenosis attendant on sclerotic vascular lesions, vascular restenosis after the operation of percutaneous transluminal coronary angioplasty (hereinafter abbreviated as "PTCA"), arteriosclerosis, peripheral circulatory failure, diabetic and nondiabetic nephropathy, and a morbid state called the remodeling of ventricular structure after myocardial infarction.
On the basis of these findings, it has been variously attempted to prevent and treat these diseases by suppressing the cell growth-facilitating action of Ang II with an ACE inhibitor. For example, in Europe, the prophylactic effect of an ACE inhibitor, cilazapril on the vascular restenosis after the operation of PTCA has been evaluated by random multifacility collaboration using a placebo as a control. In this clinical study, however, no statistically significant difference has been recognized between cilazapril and the placebo, and so it has been unable to be confirmed that cilazapril has an efficacy in the prevention of 1, pp. 100-110 (1992)!.
The result of this clinical study suggests that an Ang II producing pathway in which no ACE participates exists in the human. In fact, Okunishi et al. have identified another enzyme than ACE, which converts Ang I to Ang II, 277 (1984), and Biochem. Biophys. Res. Commun., Vol. 149, pp. 1186 (1987)!. This enzyme is an enzyme belonging to the serine protease and referred to as chymase, and converts Ang I to Ang II with better efficiency and higher selectivity than ACE. The enzymatic activity of this enzyme is inhibited by chymostatin, but not inhibited by any ACE inhibitor. Namely, it is considered that in the human, two pathways of an ACE pathway inhibited by ACE inhibitors and a chymase pathway not inhibited by any ACE inhibitor exist as pathways in which Ang II is produced, and so in the clinical study described above, a clinical effect could not be sufficiently achieved even when the ACE pathway was blocked by the ACE inhibitor because the chymase pathway has still functioned.
On the other hand, Urata et al. have purified chymase from
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Identification of a Highly Specific Chymase as the Major Angiotensin II-forming Enzyme in the Human Heart, Urata et al, J. Biol. Chem., vol. 265, No. 36, pp. 22348-22357 (1990). (This reference is discussed at p. 4, lines 6-7 of the specification.).
Wellinga et al., J. Agr. Food. Chem., 21(3), 1973, 348-54.
Viski et al., Acta Chim. Hung., 112(3), 1983, 323-34.
Fukami Harukazu
Hiroshi Shibata
Kakutani Saki
Masayuki Saitoh
Niwata Shinjiro
Higel Floyd D.
Suntory Limited
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