Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-11-29
2003-03-11
Henley, III, Raymond (Department: 1614)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C514S025000, C514S168000
Reexamination Certificate
active
06531582
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel 2-O-(9z,12z-octadecadienoyl)-3-O-[&agr;-D-galactopyranosyl-(1″-6′)-O-&agr;-D-galactopyranosyl]glycerol having an excellent effect on arthritis, osteoporosis and ruptured disc, and to a pharmaceutical composition containing the same
BACKGROUND ART
At present, it has been known that in Korea patients suffering from various bone diseases are on an increasing tendency annually. However, chemotherapy, operative therapy, etc. which have been currently used for the purpose of treating bone diseases have fail to realize the complete success as yet. Such bone diseases are advanced to chronic and degenerative state due to ageing, and fturther impose a great medical burden on a patient. Therefore, the development of novel materials which can be generally utilized in the clinical field is still urgently required.
It has been known that rheumatoid arthritis and degenerative arthritis known as typical adult diseases and geriatric diseases are an intractable disease (
FIG. 2
a
), and are caused by a mechanism based on the activation of synovial cells in joint and the ageing due to such activation and the autoimmunological factors (
FIG. 2
b
). It is expected that rheumatoid arthritis and degenerative arthritis can be cured by development of a drug which can kill or inhibit arthritic cells or inhibit or repress the expression of cyclooxygenase II (COX-II) as the enzyme produced by such arthritic cells (
FIG. 2
c
).
The constituent drugs contained in the galenic composition developed by the present inventors have been described in “Dongeubogam” and “Sinnongbonchokyung” as having various pharmacological activities including hematopoiesis, tonic, diuresis, bone marrow formation, recruitment of vitality and virility, effects on pre- and post-partum joint, lumbago, stomachic, anti-inflammatory, promotion of blood circulation and removal of blood stasis, elimination of nervous disorders, detoxication, hemostasis, effect of alleviating climacteric disorders, emmenagogic effect, nutritive effect, hematic activity, etc. Further, other activities have also been disclosed in prior reference.
Throughout the whole world, the study of bone diseases has been actively conducted, and as a result, according to an increase of a series of immunological knowledge the etiology and mechanism of arthritic invasion have been revealed so that some agents for treatment of osteoporosis have been developed in recent days. Specifically, allendrate, tamoxifen, vitamin D
3
, parathyroid hormone (PTH) and COX-II inhibitor as an agent for treatment of rheumatoid arthritis have already been successfully commercialized. Further, as an anti-inflammatory agent sulfasalazine (Becker K, Gromer S, Schirmer R H, Muller S., Thioredoxin reductase as a pathophysiological factor and drug target.
Eur. J Biochem
., 2000 Oct., 15; 267(20):6118-6125) and thioredoxin reductase (a pathophysiological factor and drug target.
Eur. J. Biochem
., 2000 Oct., 15; 267(20):6118-6125) have been known and are under either clinical trials or research and development. Meanwhile, as an agent for treatment of osteoporosis alendronate, raloxifene, calcitonin (Moraghan T J, Perez E A. Mayo Clin Proc. 2000 Aug.; 75(8):821-9), estradiol (An-dersson T L, Stehle B, Davidsson B, Hoglund P. Maturitas. 2000 Jun. 30; 35(3): 245-52), genistein (Mazurek A P, Polkowski K, Acta Pol Pharm. 2000 Mar-Apr; 57(2):135-55), 1,25-dihydroxyvitamin D
3
(Am. J. Physiol. Endocrinol. Metab. 2000 Jul; 279(1):E213-20), patathyroid hormone (Hunziker J, Wronski T J, Miller S C, J. Dent. Res. 2000 Jun; 79(6): 1431-8), alendronate (Kashyap A S, Kashyap S. Postgrad Med J. 2000 Jul; 76(897):417-8), estrogen receptor modulators, calcitonin, and bisphosphonates (Wimal-Awansa SJ. J. Clin. Densitom. 2000 Summer; 3(2):187-201) have been also disclosed.
Thus, in consideration of the problems caused in applying the prior drugs for the clinical purpose and involved in the toxic side effects, the present inventors have obtained the solvent fractions of
Cibotii rhizoma
(
Cibotium barometz
J. Smith) as a medicinal plant used in the complex Chinese medicine, and then observed the inhibitory activity of respective fractions against proliferation of synovial cells in joint portion. As a result, we have demonstrated that butanol fraction (CBB fraction) of
Cibotii rhizoma
is effective.
Cibotii rhizoma
is
Cibotium barometz
J. Smith of which the rhizoma is used for the medicinal purpose and which inhabits a tropical region and is a medicinal plant belonging to Dicksoniaceae. According to the reference relating to Chinese medicines,
Cibotii rhizoma
has an effect of alleviating the joint pain and strengthening muscles and skeleton and has been disclosed that it has been used as a popular remedy. It has been known that
Cibotii rhizoma
contains onitin, onitin 4-O-□-D-allopyranoside, onitin 4-O-□-di-glucopyranoside and pterosin R (4-deoxy, 4-chloro onitin) and further, onitin has an activity for relaxing smooth muscle [Murakami, Takao; Satake, Toshiko; Ninomiya, Katsumi; Iida, Hideki; Yamauchi, Kazuhiko; Tanaka, Nobotoshi; Saiki, Yasuhisa; Chen, Chiu-Ming, Pterosin-derivate aus der Famile Pteridaceae.
Phytochemistry
, 19, 1743 1980]. Yang, Meei-Shieu, Studies on the Twian fork medicine VI. Studies on onitin.
Planta Medica
, p25 (1986)].
The present inventors divided the butanol fraction (CBB fraction) of
Cibotii rhizoma
into three sub-fractions CBB-10, CBB-20 and CBB-30 by chromatography on Sephadex LH-20 and conducted the animal test using three sub-fractions to identify that all of them are effective. CBB-20 is sugar-containing fraction of which the effective component could not be isolated, and CBB-30 contains polyphenolic compounds so that the effective component could not be isolated. However, from CBB-10 sub-fraction three kinds of a single material, i.e. CBB-11, CBB-12 and CBB-13 could be separated and purified. According to the result of determination on chemical structures, CBB-11 is onitin, CBB-12 is daucosterol as the previously known compound, and CBB-13 is the novel compound which is named chinbarometin. This novel compound has the following structure and its chemical name is 2-O-(9z,12z-octadecadienyl)-3-O-[&agr;-galactopyranosyl-(1″-6′)-O-&agr;-D-galactopyranosyl]glycerol:
Structure of CBB-13 (Shinbarometin, Novel Compound)
The compounds having the similar structure as CBB-13 (shinbarometin) have been separated from Arisaematis rhizoma (
Arisaema amurense
Max.) and reported [Jung, Jee H.; Lee, Hongkun; Kang, Sam Sik, Diacyglycerylgalactosides from
Arisaema amurense. Phytochemistry
, 42(2), 447(1996)]. In such reported compounds various saturated fatty acids or unsaturated fatty acids are combined by ester linkage at position 1 and 2 whereas CBB-13 (shinbarometin) is a compound having no ester linkage of saturated or unsaturated fatty acids at position I of glycerol and therefore, is determined as a novel compound.
DISCLOSURE OF INVENTION
The present inventors have examined the effect of the compound separated and purified from
Cibotii rhizoma
on arthritis. As a result thereof, it was demonstrated that CBB-13 (shinbarometin, novel) exhibits the most excellent pharmacological effect and CBB-11 (onitin) has a moderate pharmacological effect.
Therefore, the object of the present invention is to identify that the component having an anti-arthritic effect in Cibotii rgizoma is shinbarometin as the novel compound.
Therefore, the present invention relates to a novel 2-O-(9z,12z-octadecadienoyl)-3-O-[&agr;-D-galactopyranosyl-(1″-6′)-O-&agr;-D-galactopyranosyl]glycerol having excellent effect on arthritis, osteoporosis and ruptured disc, and to a pharmaceutical composition containing said compound as an effective component.
REFERENCES:
patent: 6123946 (2000-09-01), Wei
Chem Abstract AN No. 1999:317548 of Chinese Patent No. 1067556 (2001).
Han Yong Nam
Kim Sang Tae
Shin Joon Shik
Birch & Stewart Kolasch & Birch, LLP
Henley III Raymond
Shin Joon Shik
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