Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-01-21
2001-06-26
Rotman, Alan L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S238000, C544S333000, C544S346000
Reexamination Certificate
active
06251905
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel tricyclic compound, which is useful as a medicine having an excellent activity of inhibiting platelet-derived growth factor (PDGF), antihypertensive activity, ameliorating activity of renal diseases and lowering the cholesterol level, a process for producing the compound, and a pharmaceutical composition containing the compound.
BACKGROUND ART
With the progressive increase of aged population in recent years, various ischemic diseases in cerebral and cardiac vessels have been also increasing. As the therapeutic agents of these diseases, calcium channel blockers or angiotensin converting enzymes (ACE) inhibitors have been widely used in the clinical field and have served to decrease cerebrovascular disturbances due to hypertension. However, the mortality from ischemic heart diseases has not yet been decreased. For improving them, it has been considered that lowering blood pressure is not sufficient but improving lipid metabolism is necessary. And, the degree of antihypertensive action is important; namely, it has been considered that, the agents which keep the elasticity of blood vessels are more preferable even if their antihypertensive action is milder than the agents which lower blood pressure markedly. For keeping the elasticity of blood vessels, it is necessary to positively improve vascular hypertrophy or fibrosis. As the diseases causing vascular hypertrophy, there are mentioned, for example, hypertension, diabetes, glomerulosclerosis (chronic renal failure) and arteriosclerosis. Precutaneous transliminal coronary angioplasty (PTCA) is generally carried out in the case of coronary artery obstruction caused by platelet aggregation and accumulation. In this case, however, there is often observed that endothelium is injured to cause proliferation of vascular smooth muscle toward the inside of vessels and to lead to restoerosis.
As one of the common phenomena observed in these diseases mentioned above, the enhanced expression of platelet-derived growth factor (PDGF) or PDGF receptors (mRNA) has been reported.
More specifically stating; 1) In spontaneously hypertensive rats (SHR) and renal hypertensive animals, expression of PDGF or PDGF receptors is enhanced, or the tyrosine kinase activity associated with PDGF receptors is enhanced (R. Sarzani et al., Hypertension, 18, III 93/1991; P. Pauletto et al., 15th International Meeting of Hypertension, Melbourne, Abstract 1197/1994; M. D. Sauro and B. Thomas, Life Sci., 53, PL371/1993). 2) In the essential hypertensive patients with diabetes, it has been observed that blood concentration of PDGF in blood is higher than normal subjects. (P. Bolli et al., 15th International Meeting of Hypertension, Melbourne, Abstract 767/1994). 3) In human atherosclerotic plaques, expression of PDGF mRNA is enhanced (T. Barrett and P. Benditt, Proc. Natl. Acad. Sci. USA, 85, 2810/1988; J. N. Wilcox et al., J. Clin. Invest., 82, 1134/1988), in the vascular smooth muscle cells of diabetic rats with arteriosclerosis, expression of PDGF receptors is enhanced (T. Kanzaki, Y. Saitoh, Gendai Iryo (Modern Therapeutics), 23, 2614/1991). 4) In the blood vessels of balloon injured animals and humans after PTCA, the expression of PDGF or PDGF receptor is enhanced (M. W. Majesky et al., J. Cell Biol., 111, 2149/1990; M. Ueda et al., Circulation, 86 (Suppl.), 1/1992). 5) In renal mesangial cells of 5/6 nephrectomized rats, a model of focal glomerulosclerosis, expression of PDGF is enhanced (J. Floege et al., Kidney Int., 41, 297/1992). 6) In mesangium proliferative nephritis (IgA nephropathy) and a model of nephritis in rats, enhancement of PDGF in mesangial cells is observed (R. J. Johnson et al., J. Am. Soc. Nephrol., 4, 119/1993; H. E. Abboud et al., Kidney Int., 43, 252/1993). It is demonstrated that PDGF proliferates vascular smooth muscle cells or renal glomerular mesangial cells in vitro experiments (R. Ross et al., Cell, 46, 155/1986); J. Floege et al., Clin. Exp. Immunol., 86, 334/1991) and in vivo experiments (A. Jawien et al., J. Clin. Invest., 89, 507/1992; Y. Isaka et al., J. Clin. Invest., 92 2597/1993; J. Floege et al., J. Clin. Invest., 92, 2952/1993). It is also reported that the action of cytokine TGF-&bgr; (transforming growth factor &bgr;) is via the action of PDGF expressed by TGF-&bgr; (E. G. Battegay et al., Cell, 63, 515/1990). Furthermore, recently there have been a number of reports that hypertensive vascular hypertrophy and cardiac hypertrophy due to congestive heart failure are suppressed by administration of ACE inhibitors or angiotensin antagonistic agent. It is considered that, also in the angiotensin-mediated vascular hypertrophy and cardiac hypertrophy, PDGF plays a role (A. J. Naftilan et al., J. Clin. Invest., 83, 1419/1989; G. H. Gibbons et al., J. Clin. Invest., 90, 456/1992). Besides, it has been known that, in respect of the proliferation of vascular smooth muscle cells or renal mesangial cells, LDL-cholesterol and PDGF mutually cooperate to enhance the proliferation, which has been considered as one of factors causing arteriosclerosis. Therefore, drugs capable of specifically inhibiting the action of PDGF are expected to be useful therapeutic agents of various circulatory disturbances including arteriosclerosis.
On the other hand, as the tricyclic compounds, the following compounds are disclosed in the following literature references, namely, (1) J. Heterocycl. Chem., 1972, 9 (1), p.85, (2) J. Heterocycl. Chem., 1976, 13 (5), p.1029-1031, (3) J. Mol. Struct., Perkin Trans.1, 1978, 49 (2), p415-420, (4) J. Pharm. Soc. Jpn., 1978, 98 (5) p.631-635, (5) J. Crystallogr. Spectrosc. Res., 1989, 19 (1), p.159-166, (6) Bull. Pol. Acad. Sci., Chem., 1989, 37 (7-8), p.313-316, and (7) J. Chem. Soc., Perkin Trans. 1, 1987, (5), p.1159-1163. However, no reports concerning the therapeutic uses of these compounds has been found yet.
Structural Formula
Symbol
R
1
= H or CH
3
X = O or H
2
R
1
= H or CH
3
R
2
= H or CH
3
R
1
= SCH
3
R
2
= H or CH
3
DISCLOSURE OF INVENTION
Circumstances being such as above, the development of novel and safely administrable therapeutic agents has been desired, which inhibit the action of PDGF.
The present inventors have made extensive and intensive studies, and succeeded in synthesizing, for the first time, a compound of the formula: (I′)(hereinafter called the compound (I′))
wherein ring A is a nitrogen-containing heterocyclic ring, having two nitrogen atoms as the hetero-atoms, which is optionally substituted with oxo or thioxo; ring Q may optionally be substituted;
Y is an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted mercapto group, excluding methyl group as Y; and
R
1
is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group, or a salt thereof, whose characteristic feature of the chemical structure lies in the tricyclic condensed heterocyclic ring of the formula:
and the substituent on ring A, as the representative of the tricyclic condensed heterocyclic ring wherein the three kinds of rings of the pyridine ring Q, the imidazole ring and the heterocyclic ring A containing nitrogen-atom are condensed, comprising nitrogen-atom at the head of bridge in the condensed ring, especially a compound of the formula (I) (hereinafter called the compound (I)):
wherein ring A, ring Q and R
1
are as defined above;
B is an optionally substituted divalent hydrocarbon;
X is a bond, an oxygen atom or a sulfur atom;
R
2
is a hydrogen atom or an optionally substituted hydrocarbon group or, R
2
and B may form a ring together with the adjacent nitrogen atom; and
R
3
is an electron-withdrawing group, or a salt thereof, whose characteristic feature of the chemical structure lies in the tricyclic condensed heterocyclic ring of the formula:
as mentioned above and the side-chain having an electron-withdrawing group at the terminal nitrogen, and found that the compound (I′) or (I) produced th
Kawamoto Tetsuji
Shibouta Yumiko
Takatani Muneo
Tomimatsu Kiminori
Rotman Alan L.
Takeda Chemical Industries Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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