Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1996-08-21
1999-02-09
Ambrose, Michael G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
558 5, A61K 3121
Patent
active
058695265
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to amino acid derivatives, more particularly to .delta.-(S-methylisothioureido)-L-norvaline which has a nitric oxide synthase (NOS) inhibiting action and which inhibits the formation of nitric oxide (NO) so as to prove effective against the pathology of cerebrovascular diseases in the manifestation of which excess NO or NO metabolites are speculated to play an important role. The invention also relates to preventives and therapeutics of such cerebrovascular diseases that comprise the .delta.-(S-methylisothioureido)-L-norvaline or pharmaceutically acceptable salts thereof as an effective ingredient.
BACKGROUND ART
Recent studies have revealed that NO, which is at least one of the endothelium-derived relaxing factors (EDRF) (Nature, 327, 524-526, 1987; Nature, 333, 664-666, 1988), not only has a vasodilation effect and a platelet aggregation and adhesion inhibiting effect but also plays an important role in the maintenance of biological functions as an intra-/inter-cellular signaling molecule. (Trends Pharmacol. 10, 428-431, 1989; Trends Neurosci. 14, 29-39, 1987; Trends Biochem. 16, 81-83, 1991; Trends Neurosci. 13, 1-6, 1992; Trends Pharmacol. 12, 130-131, 1991; Trends Pharmacol. 12, 87-88, 1991; Trends Pharmacol. 12, 125-128, 1991).
It has also been established that NO is produced not only from endothelial cells but also from other cells such as neurons, glial cells and macrophages and at least three distinct clones encoding independent NOS enzymes have been isolated (Nature, 351, 714-718, 1991; Proc. Natl. Acad. Sci. USA, 89, 11141-11145, 1992; Proc. Natl. Acad. Sci. USA, 89, 6348-6352, 1992; FEBS Lett., 307, 287-293, 1992; J. Clin. Inv., 90, 2092-2096, 1992; Science, 256, 225-228, 1992; J. Biol. Chem., 267, 6370-6374, 1992; Proc. Natl. Acad. Sci. USA, 90, 11419-11423, 1993; Biochem., 32, 11600-11605, 1993; Proc. Natl. Acad. Sci. USA, 90, 3491-3495, 1993; FEBS Lett., 316, 175-180, 1993; Biochem. Biophys. Res. Commun., 191, 89-94, 1993; Proc. Natl. Acad. Sci. USA, 89, 6711-6715, 1992; Biochem. Biophys. Res. Commun., 191, 767-774, 1993; Proc. Natl. Acad. Sci. USA, 90, 9730-9734, 1993).
It is also interesting to note that the pathophysiological role of NO has been unravelled at an accelerated rate (Pharmacol. Rev., 43, 109-142, 1991; Neurol. Prog., 32, 197-311, 1992; FASEB J., 6, 3051-3064, 1992).
Among the NOS inhibitors, N.sup.G -nitro-L-arginine (L-NNA) has been found to be capable of ameliorating ischemic cerebral infarction and edema (Eur. J. Pharmacol. 204, 339-340, 1991; Neurosci. Lett., 147, 159-162, 1992). This finding opened a road to the application of a substance having a NOS inhibiting activity to a therapeutic of cerebrovascular diseases.
In the brain region where the blood flow is interrupted, cytotoxic edema occurs first, followed by vasogenic edema. Brain edema is developed several hours after the occurrence of cerebral ischemia and its progress continues for about one week from the onset in clinical settings. Thereafter, the brain edema decreases gradually and, depending on the focal range of infarction, the edema persists as an infarcted area from one to three months. Since the brain is covered with the rigid skull, cerebral edema causes an increase in the brain volume. If the cerebral edema exceeds a certain limit, there occurs an abrupt increase in the tissue pressure and the intracranical pressure, often inducing fatal hernia and eventually aggravating the encephalopathy to determine the scope of the subsequent infarcted area (J. Neurosurg. 77, 169-184, 1992). Thus, the treatment of cerebral edema which is critical to the patient's life and the prognosis of his disease is clinically a very important objective. The three primary methods currently used to treat cerebral edema are hyperpnea, the drainage of cerebrospinal fluid and the use of hypertonic solutions, steroids or the like; however, in almost all cases, these methods provide only temporary ameliorative effect and there is not much promise for the therapeutic efficacy to be finally achi
REFERENCES:
patent: 5364881 (1994-11-01), Griffith et al.
Makino Toshihiko
Nagafuji Toshiaki
Ambrose Michael G.
Chugai Seiyaku Kabushiki Kaisha
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