Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-19
2003-11-25
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S471000, C549S432000, C568S666000
Reexamination Certificate
active
06653344
ABSTRACT:
TECHNICAL FIELD
The present invention relates to the use of a dibenzocyclooctane lignan derivative of the following general formula (I) for prevention and treatment of neurodegenerative disorders and pharmaceutical preparations containing the same as active ingredient.
wherein R
1
is H or C
1-4
lower alkyl, R
2
, R
3
, R
4
and R
5
is respectively H, OH, C
1-4
lower alkyl, C
1-4
lower alkoxy, or R
2
and R
3
or R
4
and R
5
are respectively combined to form the group of —OCH
2
O—.
Among the compound of the above formula (I), the compound in which R
1
is H, R
2
R
3
, R
4
and R
5
is deoxyshizandrin: compound 1), the compound in which R
1
is H, R
2
and R
3
are combined to form the group of —OCH
2
O—, and R
4
and R
5
are each methoxy is gomisin N: compound 2), and the compound in which R
1
is H, and R
2
and R
3
, and R
4
and R
5
are each combined to form the group of —OCH
2
O— is wuweizisu C: compound 3).
The above ingredients are known compounds which are contained in
Schizandra chinensis
BACKGROUND OF THE TECHNOLOGY
The population distribution of the present society changes rapidly to venerable ages. Accordingly, invasion rate of neurodegenerative disorder in relation to venerable ages such as stroke or arthymia is increasing. The death rate for nervy craniales disease is annually increasing. When the death etiology of our country is analysed, the death rate for the nervy craniales disease is the second following to cancer. The world death rate of nervy craniales disease is 2-3rd. However, any drug or treatment method for the diseases has not been suggested until now. The social and economical loss is gradually increasing. The neurodegenerative disease can occur by neurodegeneration caused by concussion of the brain and aging, 2nd phenomena like circulatory disorders and neurodegenerative disorders caused by various physical or mechanical factors like traffic accident, workman's accident, CO-poisoning. (Rothman S M, Trhrston J H and Hauhart R E (1987) Delayed neurotoxicity of excitatory amino acids in vitro. Neuroscience 22: 1884-1891; and Weiloch, T. (1985) Hypoglycemia-induced neuronal damage prevented by NMDA antagonists. Science 230: 681-683).
When brain tissue is damaged, it leads to brain nervous cell-death. The mechanism of nervous cell-death is classified into two distinctive forms. The one is by glutamate existing in central excitatory neurotransmission material. Glutamate in normal state acts as neurotransmission material. When it is excessively secreted, it leads to nervous cell-death. Such neurotoxicity caused by glutamate is classified into acute and chronic forms of response. (Choi D W (1988) Glutamate neurotoxicity and disease of the nervous system. Neuron 1: 623-634). Acute neurotoxicity appears to be mediated by the entry of Na and K into neurons resulting in cell swelling which leads to cell death. In delayed toxicity, N-methyl-D-aspartate, the receptor of glutamate is activated and Ca is flowed into cell and Ca dependent enzyme is over-activated and leads to cell death. (Rothman S M, Thurston J H and Hauhart R E (1987) Delayed neurotoxicity of excitatory amino acids in vitro. Neuroscience 22: 1884-1891; Strijbos P J L M, Leach M J and Garthwaite J (1996) Vicious cycle involving Na+channels, glutamate release and NMDA receptors mediates delayed neurodegeneration through nitric oxide formation. J. Neurosci. 16: 5004-5013; and Coyle J T and Purrfarcken P (1993) Oxidative stress, glutamate and neurodegenerative disorders. Science 262: 689-695).
Second is injury by direct oxidative stress. In the brain, contents of unsaturated fatty acid and consumption of oxygen is high. The formation of oxygen radical is high and the content of antioxidative enzyme is relatively low. The danger of injury caused by free radical including oxygen radical is very high. A study for neurocell death mechanism in relation to neurodegenerative disorders is carried out actively worldwide.
TECHNICAL SUBJECT TO BE ACCOMPLISHED BY THE INVENTION
Preliminary studies in our laboratory indicated that a methanolic extract of dried Schizandra fruit (
S. chinensis
) attenuated neurotoxicity in primary cultures of rat cortical cells induced by L-glutamate. Thus, we attempted to isolate the active constituents of the methanolic extract of the fruits. In the present study, we report that five lignans were obtained from this fruit and identified as deoxyschizandrin, gomisin A, gomisin N, schizandrin and wuweizisu C, respectively. We also report that deoxyschizandrin, gomisin N and wuweizisu C exhibited neuroprotective activities against glutamate-induced neurotoxicity in primary cultures of rat cortical cells. Since early times in orient, Schizandra fruit (
S. chinensis
) have been used as a tonic and in order to protect the liver and have compounds of dibenzocyclooctane lignam. Various studies were carried out for the activity of the compounds. (Nakajima K, Taguchi H, Ikeya Y, Endo Y and Yosioka I (1983) The constituents of Schizandra chinensis Baill. XIII. Quantitative analysis of lignans in the fruits of
Schizandra chinensis
Baill. by high performance liquid chromatography. Yakugaku Zasshi 103: 743-749; Liu G T (1985) In: Advances in Chinese medical materials research (Chang H M et al. Eds) pp.257-268, World Scientific Publishing Co. Singapore). The important activities of dibenzocy clooctane lignan are liver-protecting activity (Hikino H, Kiso Y, Taguchi H and Ikeya Y (1984) Antihepatotoxic actions of lignoids from Schizandra chinensis Fruits. Planta Med. 50: 213-218; Kiso Y, Tohkin M, Hikino H, Ikeya Y and Taguchi H (1985) Mechanism of antihepatotoxic activity of wuweizisu C and gomisin A. Planta Med. 51: 331-334; and Yamada S, Murawaki Y and Kawasaki H (1993) Preventive effect of gomisin A, a lignan component of Schizandra fruits, on acetaminophen-induced hepatotoxicity in rats. Biochem. Pharmacol. 46: 1081-1085), anticancer activity (Yasukawa K, Ikeya Y, Mitsuhashi, Iwasaki M, Abursda M, Nakagawa S, Takeuchi M and Takido M (1992) Gomisin A inhibits tumor promotion by 12-o-tetra-decanoylphorbol-13-acetate in two-stage carcinogenesis in mouse skin. Oncology 49: 68-71), antiinflamation activity (Wang J P, Raung S L, Hsu M F and Chen C C (1994) Inhibitory by gomisin C (a lignan from
Schizandra chinensis
) of the respiratory burst of rat neutrophils. Brit. J. Pharmacol. 113: 945-953), antiviral activity (Fujihashi T, Hara H, Sakata T, Mori K, Higuchi H, Tanaka A, Kaji H and Kaji A (1995) Anti-human immunodeficiency virus (HIV) activities of halogenated gomisin J derivatives, new nonnucleotide inhibitors of HIV type 1 reverse transcriptase. Antimicrob. Agents Chemother. 39:2000-2007). However, no report appeared that those compounds have phycological activity in neurosystem.
We investigated the neuro-protective activity and mechanims of the dibenzocyclooctane lignan, the important ingredients of Schizandra fruit and ascertained that the dibenzocyclooctane lignan have neuroprotective activity and therefore, the compound can be used as a drug for prevent and treatment of neurodegenerative disorders such as stroke or Alzheimer's disease.
CONSTITUTION OF THE INVENTION
The present invention is more in detail by the following example and experiments.
REFERENCES:
Chemical Abstracts vol. 89 No. 24193, Liu et al , Studies on the constituents fo Hua-Zong-Wu-Wei-Zi and related compounds (1976).
Gu Gyeong-A
Jeong Won-Ju
Kim So-Ra
Kim Young-Joong
Lee Mi-Gyeong
Corless Peter F.
Covington Raymond
Edwards & Angell LLP
Elcom Bio Technology Co., Ltd.
O'Day Christine C.
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