Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1997-02-11
2000-09-26
Barts, Samuel
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
558 4, 558 5, A61K 31215
Patent
active
061243515
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to amino acid derivatives, more specifically to the compounds represented by the general formula (I) which have an inhibitory effect on nitric oxide synthase (hereunder abbreviated as NOS) to suppress the production of nitric oxide (hereunder abbreviated as NO) and thereby prove effective against the pathology in an acute phase of cerebrovascular disorders, in particular, occlusive cerebrovascular disorders in which NO or its metabolites would be involved, or pharmaceutically acceptable salts thereof. The invention also relates to preventives and therapeutics of such disorders and symptoms that comprise said compounds or pharmaceutically acceptable salts thereof as an effective ingredient.
BACKGROUND ART
In the brain region where blood flow is interrupted, cytotoxic brain edema occurs first, followed by vasogenic brain edema. Vasogenic brain edema developes several hours after the occurrence of cerebral ischemia and its progress continues for one week from the onset. Thereafter, brain edema decreases gradually and, depending on the focal range of infarction, the edema persists as an infarcted area for 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 (Siesjo, 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 effects and there is not much promise for the therapeutic efficacy to be finally achieved (Siesjo, J. Neurosurg. 77, 337-354, 1992). Therefore, it has been desirable to develop drugs that have an entirely different mechanism of action and which will prove effective in the treatment of ischemic cerebrovascular disorders.
The present inventors previously found that N.sup.G -nitro-L-arginine (L-NNA), a NOS inhibitor, was capable of ameliorating cerebral edema and infarction that were developed after focal cerebral ischemia (Nagafuji et al., Neurosci. Lett., 147, 159-162, 1992), as well as the neuronal cell death that was also developed after transient global cerebral ischemia (Nagafuji et al., Eur. J. Pharmacol. Env. Tox., 248, 325-328, 1993). However, it has also been reported that relatively high doses of NOS inhibitors are not only ineffective against ischemic brain damage but also they sometimes aggravate it (Iadecola et al., J. Cereb. Blood Flow Metab., 14, 175-192, 1994).
A presently dominant theory based on genetic DNA analyses holds that NOS exists in at least three isoforms, namely, N-cNOS which is mainly present constitutively in neurons, E-cNOS which is mainly present constitutively in vascular endothelial cells, and iNOS which is induced from transcriptional level on stimulation by cytokines and/or endotoxins in macrophages and other cells. Among these three isoforms, N-cNOS and E-cNOS are calcium-dependent whereas iNOS is not calcium-dependent (Nathan et al., FASEB J., 16, 3051-3064, 1992).
A mechanism that has been proposed as being most probable for explaining disorders in the brain tissue which accompany cerebral ischemia is a pathway comprising the sequence of elevation in the extracellular glutamic acid level, hyperactivation of glutamic acid receptors on the post-synapses, elevation in the intracellular calcium level and abnormal activation of calcium-dependent enzymes (Siesjo, J. Cereb. Blood Flow Metab. 1, 155-185, 1981; Siesjo, J. Neurosurg. 60, 883-908, 1984; Choi, Trends Neurosci. 11, 465-469, 1988; Siesjo and Bengstsson,
REFERENCES:
patent: 5364881 (1994-11-01), Griffith et al.
Narayanan et al., "Synthesis of L-Thiocitrulline, L-Homothiocitrulline, and S-Methyl-L-thiocitrulline: A New Class of Potent Nitric Oxide Synthase inhibitors", J. Med. Chem., vol. 37, pp. 885-887, (Apr. 1994).
Feldman, Synthesis of the Putative L-Arginine Metabolite L-N-Hydroxyarginine, Tetrahedron Letters, vol. 32 No. 7, pp. 875-878 (Apr. 1991).
Narayanan et al., "S-Alkyl-L-thiocitrullines", The Journal of Biological Chemistry, vol. 270, No. 19 pp. 11103-11110, (Aug. 1995).
Nagafuji et al., "Blockade of Nitric Oxide Formation by N.sup.W -Nitro-L-Arginine Mitigates Ischemic Brain Edema and Subsequent Cerebral Infarction in Rats", Neuroscience Letters, vol. 147, pp. 159-162, May 1992.
Nagafuji et al., "A Narrow Therapeutical Window of a Nitric Oxide Synthase Inhibitor Against Transient Ischemic Brain Injury", European Journal of Pharmacology, vol. 248, pp. 325-328, Jun. 1993.
Feldman, "Synthesis of the Putative L-Arginine Metabolite L-N.sup.G -Hydroxyarginine", Tetrahedron Letters, vol. 32, No. 7, pp. 875-878, Apr. 1991.
Nagafuji et al., "Temporal Profiles of Ca.sup.2+ /Calmodulin-Dependent and -Independent Nitric Oxide Synthase Activity in the Rat Brain Microvessels Following Cerebral Ischemia", Acta Neuochir, vol. 60, pp. 285-288, Dec. 1994.
Narayanan et al., "Synthesis of L-Thiocitrulline, L-Homothiocitrulline, and S-Methyl-L-thiocitrulline: A New Class of Potent Nitric Oxide Synthase Inhibitors", Journal of Medicinal Chemistry, vol. 37, No. 7, pp. 885-887, Jun. 1994.
Makino Toshihiko
Nagafuji Toshiaki
Barts Samuel
Chugai Seiyaku Kabushiki Kaisha
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