Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-05-28
1998-09-29
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514259, 544123, 544284, 544285, A61K 31495, A61K 31505, C07D23972, C07D40302
Patent
active
058146318
DESCRIPTION:
BRIEF SUMMARY
This application claims benefit of priority under 35 U.S.C. .sctn.371 from PCT/JP96/02830, filed Sep. 27, 1996.
TECHNICAL FIELD
The present invention relates to a pharmaceutical composition, a medicament for the prevention or treatment of cardiac and circulatory system diseases derived from the abnormal exacerbation of angiotensin II production, and a chymase inhibitor, containing a quinazoline derivative as an effective ingredient, and a novel quinazoline derivative useful as a chymase inhibitor and said pharmaceutical compositions.
BACKGROUND ART
A renin-angiotensin system is one of mechanisms by which the blood pressure of a living body is controlled. Angiotensin I (hereinafter referred to as Ang I) is excised from angiotensinogen biosynthesized in vivo by a renal enzyme renin, and two amino acid residues of C-terminal are cleaved to form angiotensin II (hereinafter referred to as Ang II). It is considered that this Ang II constricts a peripheral blood vessels 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 this perspective, attention is paid to the relation between the enzymes referred to as ACES)! and diseases of the heart or circulatory organs, including hypertension and various ACE inhibitors have been developed as anti-hypertensive and anti-cardiodysfunctional agents.
Further, recently, it has been revealed that Ang II has, in addition to its actions in constriction of the peripheral blood vessel and stimulation of sympathetic nerves, an action of facilitating cell growth. For example, Naftilan et al. have used cultured cells of a rat vascular smooth muscle to show that Ang II plays an important role in the growth of a vascular smooth muscle cells (see Hypertension, vol. 13, pp. 706-711, 1989). These facts 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 non-diabetic nephropathy, and a morbid state called the remodeling of the ventricle structure after myocardial infarction.
Based on this finding, various attempts have been made to prevent or 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 the ACE inhibitor cilazapril on 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, therefore the effectiveness of cilazapril in prevention of vascular restenosis after the operation of PTCA could not be confirmed (see Circulation, vol. 86, no. 1, pp. 100-110, 1992).
The results of the above clinical study suggests that 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 in canine, simian, and human arterial tissue (see J. Hypertension, vol. 2, p. 277, 1984 and Biochem. Biophys. Res. Commun., vol. 149, p. 1186, 1987). This enzyme is an enzyme referred to as chymase and belongs to the family of serine proteases. It 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 is not inhibited by any ACE inhibitor. Namely, it is considered that in humans, two pathways of the ACE pathway inhibited by an ACE inhibitor and the chymase pathway not inhibited by an A
REFERENCES:
patent: 4684654 (1987-08-01), Wright, Jr. et al.
patent: 4854965 (1989-08-01), Bracha et al.
J. Garcia Tercero, et al., "N-Arilsulfonil Ditiocarbamatos de Metilo Como Intermedios en la Sintesis de Heterociclos. Preparacion de Los Sistemas Isomeros 2-Arilsulfonilamino-3-1, 4H-Benzoxazin-4-Onas Y S-Arilsulfonyl-2-4 (1H, 3H)-Quinazolindionas", Anales de Quimica, Ser. C, (1987), 83(2), pp. 247-250.
Hideki Okunishi et al., "Ensho," Japanese Journal of Inflammation, vol. 14, pp. 193-197 (1994).
Does the New Angiotensin Converting Enzyme Inhibitor Cilazapril Prevent Restenosis After Percutaneous Transluminal Coronary Angioplasty? Circulation, vol. 86, No. 1, pp. 100-110 (1992).
Hidenori Urata et al., "Identification of a Highly Specific Chymase As the Major Angiotensin II-Forming Enzyme in the Human Heart," Journal Of Biological Chemistry, vol. 265, pp. 22348-22356 (1990).
Allen Naftilan et al., "Angiotensin II Induces c-fos Expression in Smooth Muscle Via Transcriptional Control," Hypertension, vol. 13, pp. 706-711 (1989).
Hideki Okunishi et al., "Different Distribution of Two Types of Angiotensin II-Generating Enzymes in the Aortic Wall," Biochemical Biophysical Research Communications, vol. 149, pp. 1186-1192 (1987).
Hideki Okunishi et al., "Evidence for A Putatively New Angiotensin II-Generating Enzyme in the Vascular Wall," Journal of Hypertension, vol. 2, pp. 277-284 (1984).
Helv. Chim. Acta, vol. 9, pp. 980-991 (1926), H. Rupe.
Fukami Harukazu
Ito Akiko
Kakutani Saki
Kiso Yoshinobu
Niwata Shinjiro
Grumbling Matthew V.
Suntory Limited
LandOfFree
Quinazoline derivatives and applications thereof does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Quinazoline derivatives and applications thereof, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Quinazoline derivatives and applications thereof will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-686513