Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-10-27
2002-06-25
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06410535
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to pharmaceutical compositions for preventing and/or treating diseases having vascular dysfunction associated with insulin resistance, comprising as an active ingredient a compound of the formula (I):
wherein R
1
and R
2
each represents a hydrogen atom or taken together with each other represent a single bond, while R
3
represents —CH(OH)CH(OH)CH
3
, —CH(OCOCH
3
)CH(OCOCH
3
)CH
3
, —CH
3
, —CH
2
OH or a phenyl group when R
1
and R
2
each represents a hydrogen atom, or —COCH(OH)CH
3
when R
1
and R
2
together represents a single bond, or a pharmaceutically acceptable salt thereof.
Insulin resistance is a pathologic state observed in patients with type II diabetes and typically characterized by a lack of lowering of blood glucose level even under a high insulin state. Recently, a pathologic state characterized by a complication of abnormal glucose tolerance, obesity, hypertension and hyperlipidemia in one individual was reported and named insulin resistance syndrome, syndrome X or offal fat syndrome. Large-scale epidemiological studies showed that these pathologic states are basically associated with insulin resistance and may be a hazardous factor in various arteriosclerotic diseases. Consequently, it is clinically important to explain and prevent these states.
We have clinically examined the role of insulin resistance in vascular endothelial dysfunction and an advanced state thereof, such as arteriosclerotic process as well as various arteriosclerotic diseases. We first found that marked hyperinsulinemia independent from other hazardous factors, i.e. insulin resistance also occurs in diseases other than diabetes such as non-diabetic coronary vasoconstrictive angina (Shinozaki, K. et al., Circulation 1995, 92: 1749-1757). We also showed the presence of marked insulin resistance in effort angina or cases having significant constrictive lesion In cerebral angiography (Shinozaki, K. et al., Diabetes Care 1996, 19: 1-7; Shinozaki, K. et al., Stroke 1996, 27:37-43). Furthermore, we also showed the presence of insulin resistance and initial arteriosclerosis in vivo (Shinozaki, K. et al., Arterioscler. Thromb. Vasc. Biol., 1997, 17: 3302-3310).
Vascular endothelium has been known to play an important role in vascular tonus or thrombopoiesis, and in 1980, the presence of endothelium-derived relaxing factor (EDRF) was first reported. The entity of EDRF was proved to be nitric oxide (NO) in 1987. NO is a gaseous radical and has been shown to readily pass through cell membranes and exert a wide variety of effects such as circulation control, neurotransmission, inhibition of platelet aggregation, antibacterial or anticancer effect. NO not only controls metabolism by reacting with heme enzyme or SH enzyme groups, but also has physiological functions and pathological activity by crosstalking with active oxygen species such as superoxide (O
2
−
), SH compounds, ascorbic acid or the like. However, its in vivo molecular entity is still unknown in many respects because all of these molecules are unstable.
NO having a wide variety of effects as described above is produced when L-arginine is oxidized from N
G
-hydroxyl-L-arginine into L-citrulline and the reaction is catalyzed by an enzyme called NO synthase (NOS). NOS widely occurs in the vascular endothelium, nervous system, kidney, platelets, cardiac muscles, smooth muscles, etc. and the gene therefor has already been cloned and structurally analyzed. As a result, the gene for NOS was found to contain a binding site for (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (hereinafter referred to as “BH4”) included in compounds of the formula (I) as active ingredients of the present invention, in addition to those for coenzymes such as calmodulin (CaM), flavin, NADPH. Moreover, BH4 has been suggested to actually be involved in control of the function of NOS.
We examined the in vivo influence of a high insulin state on superoxide production and endothelium-dependent vasorelaxing ability, on the hypothesis that vascular tonus abnormality and vascular endothelial cell disorder might be caused by increased production of active oxygen species in insulin resistant state. The result showed that some mechanism hinders activation of NOS in insulin resistant state while NOS is activated in the vascular endothelium to maintain the vasorelaxing ability in an exogenous high insulin state induced by externally administering insulin. This suggests that the presence of superoxide may be excessive on vascular walls due to a decrease of NO resulting in an acceleration of arteriosclerosis and enhancement of vasoconstriction in insulin resistant states (Shinozaki, K., Kashiwagi, A. et al. : Superoxide anion impairs endothelium-dependent vascular relaxation in insulin resistant rat aortas. Jap. J. Pharmacology 75 (1997) suppl. 1, p. 11).
Thus, the relationship between insulin resistant states and endothelial dysfunction has been posited. Various studies have been made on drugs for improving vascular dysfunction caused by insulin resistance to prevent or treat various diseases associated therewith and thiazolidine dione derivatives were mentioned as candidates therefor (Law, R. E. et al., Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia, J. Clin. Invest. 98: 1897, 1996). However, no definite conclusion has yet been reached.
Recent investigations of various vascular diseases at a molecular level have led to a therapeutic strategy directed to blood vessels such as endothelial cells. And it is considered that one of the most promising therapies is to treat blood vessels with an agent which controls production of the entity of EDRF, i.e. NO, or an agent which has an antioxidant action (Gibbons, G. H., Dzau, V. J., Science. Vol. 272, 689-693, 1996). For example, antioxidant agents such as vitamins E or probucol are expected to resist oxidative stress in coronary arteriorestenosis known to be caused by the metabolite having an oxidant action following percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG) (Tardif, J. C. et al.: N. Eng. J. Med. 1997, 337: 365-372), and nitrate agents such as nitroglycerin preparations are used as exogenous NO donors for therapy of angina. However, no drug or therapy that satisfies this therapeutic strategy has yet been established.
The purpose of therapy is to prevent complications of the vascular system caused by insulin resistance so that patients may enjoy a prolonged and higher quality of life. This requires lifelong management by long-term pharmacotherapy. In spite of various studies on therapeutic agents for insulin resistance as described above, no drug exists at present that is completely satisfactory in terms of side effects, safety during long- term use and improvement in QOL (quality of life). Thus, the development of therapeutic agents satisfying truly desirable conditions is in great demand.
The compounds of the formula (I) as active ingredients in pharmaceutical compositions of the present invention are known compounds for use in pharmaceutical compositions against malignant hyperphenylalaninemia, depression, Parkinson's disease, etc. For example, see Japanese Patent Public Disclosure (KOKAI) Nos. 25323/84, 76086/84, 277618/86 and 267781/88.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a safe pharmaceutical composition for diseases having vascular dysfunction associated with insulin resistance without side effects, which prevents the progress of conditions, prevents the progress of complications and improves the quality of life of patients.
We, the inventors, hypothesized about therapy for diseases having vascular dysfunction associated with insulin resistance that endothelial dysfunction caused by insulin resistant state might be improved by controlling both of increased production of active oxygen species and decreased production of NO to normalize each of them. As a result of careful studies to improve endothelium-dependent vasorelaxation, we unexpected
Kashiwagi Atsunori
Kikkawa Ryuichi
Nishio Yoshihiko
Okamura Tomio
Shinozaki Kazuya
Henley III Raymond
Manelli Denison & Selter PLLC
Suntory Limited
White, Jr. Paul E.
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