Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-11-21
1995-11-07
Higel, Floyd D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514401, 5483541, A61K 31415, C07D23306
Patent
active
054648572
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to novel 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide derivatives, their use as highly safe therapeutic agents for maintaining blood pressure having an imidazoline derivative as the active ingredient and intended for maintaining blood pressure of man for treatment of shock by means of removing excess nitric oxide (hereinafter referred to as "NO") which is the very substance constituting endothelium-derived relaxing factor (hereinafter referred to as "EDRF"), which causes relaxation of the vascular smooth muscles.
DESCRIPTION OF THE PRIOR ART
In the past it was well known that the vascular endothelial cells secrete a substance contributing to relaxation of the vascular smooth muscles, i.e. EDRF. (Ref. Nature, Vol. 288, 373-376, 1980). After a while it was substantiated that NO produced from L-arginine is the very substance which constitutes EDRF. (Ref. Nature, Vol. 327, 524-526, 1987; and Proc. Natl. Acad. Sco., USA, Vol. 84, 9265-9269, 1987).
There exist as NO-synthesizing enzymes (NO synthase) produced by the endothelial cells the following two kinds of enzymes: (1) the endogenous type which is always present in the vascular endothelium (Ref. Pharm. Rev., Vol. 43, 109-142, 1991; The Lancet, Vol. ii, 997-1000, 1989) and (2) the type which is derived from endotoxin or cytokines such as tumor necrosis factor (TNF)(Ref. Pharm. Rev., Vol. 43, 109-142, 1991). While the former type (1) is thought to contribute to physiological adjustment of the vascular resistance, the abrupt progress of the synthesis of NO due to the latter type (2) is considered to cause the decline in the vascular resistance and the accompanying fall in blood pressure, presumably causing shock. Most of the patients having syndrome do not respond to a vasopressor such as norepinephrine and dopamine and fail to recover.
Various therapies have been studied to cope with such shock as described above caused by endotoxin or cytokines. One of those therapeutic approaches was intended to treat laboratory animals in endotoxin shock or patients in septic shock, using L-arginine analogue which is an NO synthase inhibitor. (Ref. The Lancet, Vol. 338, 1555-1557, 1991, and the Lancet, Vol. 338, 1557-1558, 1991). Since the increasing production of EDRF (namely, NO) is the conclusive and universal phenomenon which occurs with the fall in blood pressure of the patient in endotoxin shock, the effort to decrease the amount of NO is an excellent therapeutic approach to treat endotoxin shock or similar cases. Such a therapeutic agent capable of neutralizing the action of NO by itself is to advantageous in consideration of the complexity involved in the therapy to neutralize the action of endotoxin or individual cytokine.
Nevertheless, there have been presented reports to the effect that caution must be taken in determining the dosage to be administered, since the effect of this NO synthase inhibitor to maintain blood pressure when administered for treatment of shock strongly depends on the dosage such that if it is too little, its efficacy is totally lost, and, conversely, if the dosage is excessive, the patient is led to an extremely dangerous condition as is induced by violent rise and fall in the blood pressure (Ref. The Lancet, Vol. 338, 1555-1557, 1991; The Lancet, Vol. 338, 1557-1558, 1991. In view of the significance of the aforementioned reports, there still remain unresolved problems associated with safety of the NO synthase inhibitor. Moreover, since the NO synthase inhibitor is an L-arginine derivative, there is a possibility that this inhibitor adversely affects L-arginine-dependent protein synthesizing systems other than the NO synthase as well as metabolic systems such as the (Krebs-Henseleit) urea cycle. In this sense, use of such inhibitor is feared that the administration of this NO synthase inhibitor can be accompanied by some side effects. In particular, it will conceivably give rise to many unknown questions if the inhibitor is administered in a copious amount over an extensive
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Caneschi et al., Inorg. Chem., vol. 30, pp. 3936-3941 (1991).
Osiecki et al, J. Amer. Chem. Soc., vol. 90, No. 4, pp. 1078-1079 (1968).
Shemomura et al., J. Chem. Soc. Perkins Trans, II, pp. 795-798 (1988).
Akaike Takaaki
Maeda Hiroshi
Miyamoto Yoichi
Higel Floyd D.
Hiroshi Maeda
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