Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1997-02-24
2003-06-24
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S027000, C514S035000
Reexamination Certificate
active
06583118
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to an agent for protecting cartilage, i.e., a chondroprotective agent, more particularly, a chondroprotective agent containing a flavonoid compound or a stereoisomer thereof, or a naturally occurring glycoside thereof.
2. Description of the Related Art
There are various types of arthropathy, for example, rheumatoid arthritis, rheumatic fever, and osteoarthritis. Many people particularly suffer from rhematoid arthritis and osteoarthritis. These diseases have been studied as the major types of arthropathy. There are congenital and secondary osteoarthritis, and further primary osteoarthritis caused by degeneration of the articular cartilage along with aging. Patients suffering from primary osteoarthritis have recently been increasing along with the increase in the population of the aged.
Although there are considerable differences of the causes and conditions between rheumatoid arthritis and osteoarthritis, the articular function becomes eventually obstructed by the destruction of the cartilage in both of rheumatoid arthritis and osteoarthritis.
The first choice of medicines for the treatment of rheumatic diseases such as rheumatoid arthritis, rheumatic fever, systemic lupus erythematosus, and osteoarthritis are analgesic and anti-inflammatory agents, for example, aspirin or indometacin. Further, gold compounds such as Shiosol, immunomodulators, steroids, or D-penicillamine are used as medicines for the treatment of rheumatoid arthritis.
The above conventional analgesic and anti-inflammatory agents, however, were not effective against the destruction of the articular cartilage, and in fact, sometimes exhibited adverse effect in experiments using chondrocytes. Further, no inhibitory effect on articular cartilage destruction was also observed in the above-mentioned medicines for the treatment of rheumatoid arthritis.
It is known that flavonoids may be used as an agent for protecting a blood vessel and further in the following pharmaceutical applications: a virus genome deactivating agent for apigenin, chrysin, morin, fisetin, and baicalein [Japanese Unexamined Patent Publication (Kokai) No. 2-101013], an agent for determining the function of polymorphonuclear leukocyte for flavonoids [Japanese Unexamined Patent Publication (Kokai) No. 63-253254], an oral agent for suppressing smoking for flavonoids [Japanese Unexamined Patent Publication (Kokai) No. 4-46119], treatment of high protein edema for rutin, diosmin, and the like (U.S. Pat. No. 5,096,887), an anti-tumor agent containing flavonoids [Japanese Unexamined Patent Publication (Kokai) No. 3-275625], an anti-tumor agent containing apigenin (Japanese Examined Patent Publication (Kokoku) No. 3-616441, an agent for suppressing the formation of peroxylipid for hesperetin, kaempferol, and the like [Japanese Unexamined Patent Publication (Kokai) No. 3-5423], an anti-tumor agent containing kaempferol [Japanese Unexamined Patent Publications (Kokai) No. 4-103529 and No. 4-103532], a calcium antagonist for hesperidin and luteolin [Japanese Unexamined Patent Publication (Kokai) No. 4-243822], a sialidase inhibitor for luteolin [Japanese Unexamined Patent Publication (Kokai) No. 64-42427], an anti-retrovirus agent for luteolin [Japanese Unexamined Patent Publication (Kokai) No. 3-7224], an anti-HBV (hepatitus B virus) agent for quercetin [Japanese Unexamined Patent Publication (Kokai) No. 4-234320], and the like.
Flavonoids have not, however, been known to be useful as chondroprotective agents.
SUMMARY OF THE INVENTION
The present inventors engaged in intensive research to develop a chondroprotective agent for suppressing the destruction of the articular cartilage and as a result found that the particular flavonoid compounds and stereoisomers thereof, and the naturally occurring known glycosides thereof showed significant inhibition of the depletion of proteoglycan which is a major component of the cartilage matrix, and therefore, are useful as a chondroprotective agent for prohibiting the destruction of the articular cartilage.
Accordingly, the object of the present invention is to provide a chondroprotective agent containing as an active ingredient a particular flavonoid compound or a stereoisomer thereof, or a naturally occurring known glycoside thereof.
Other objects and effects of the present invention will be clear from the following description.
The present invention relates to a chondroprotective agent comprising a flavonoid compound of the general formula (I):
wherein R
1
to R
9
are, independently, a hydrogen atom, hydroxyl group, or methoxyl group and X is a single bond or a double bond, or a stereoisomer thereof, or a naturally occurring glycoside thereof (hereinafter referred to as “the present substance”).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The active ingredient of the chondroprotective agent according to the present invention is a flavonoid, which is widely present in the vegetable kingdom. Typical flavonoid compounds include flavones, flavonols, flavanones, and flavanonols. Flavanones contain an asymmetric carbon atom at the 2-position, and flavanonols contain asymmetric carbon atoms at the 2- and 3-positions, and such compounds may be present as the stereoisomers. These stereoisomers can also be used in the present invention. Further, the saccharides present in the above naturally occurring glycosides are not particularly limited. As examples of the naturally occurring glycosides, there may be mentioned glucoside, galactoside, fructoside, rhamnoside, rutinoside (that is, rhamnoglucoside), arabinoside, xyloside, apioglucoside, and robinobioside.
In the present invention, any naturally occurring flavonoids may be used as the above present substance. The flavonoid compounds and naturally occurring glycosides thereof shown in the following Table 1 are preferable.
TABLE 1
No.
Name
R
1
R
2
R
3
R
4
R
5
R
6
R
7
R
8
R
9
X
1
Flavone
H
H
H
H
H
H
H
H
H
Double
2
Chrysin
H
OH
H
OH
H
H
H
H
H
″
3
Toringin
H
OH
H
OGlu
H
H
H
H
H
″
4
Primetin
OH
H
H
OH
H
H
H
H
H
″
5
Apigenin
H
OH
H
OH
H
H
H
OH
H
″
6
Cosmosiin
H
OGlu
H
OH
H
H
H
OH
H
″
7
Apiin
H
OApg
H
OH
H
H
H
OH
H
″
8
Luteolin
H
OH
H
OH
H
H
OH
OH
H
″
9
Galuteolin
H
OH
H
OGlu
H
H
OH
OH
H
″
10
Glucoluteolin
H
OGlu
H
OH
H
H
OH
OH
H
″
11
Acacetin
H
OH
H
OH
H
H
H
OCH
3
H
″
12
Linarin
H
ORut
H
OH
H
H
H
OCH
3
H
″
13
Diosmetin
H
OH
H
OH
H
H
OH
OCH
3
H
″
14
Diosmin
H
ORut
H
OH
H
H
OH
OCH
3
H
″
15
Baicalein
H
OH
OH
OH
H
H
H
H
H
″
16
Fisetin
H
OH
H
H
OH
H
H
OH
H
″
17
Kaempferol
H
OH
H
OH
OH
H
H
OH
H
″
18
Trifolin
H
OH
H
OH
OGal
H
H
OH
H
″
19
Astragalin
H
OH
H
OH
OGlu
H
H
OH
H
″
20
Robinin
H
ORha
H
OH
ORob
H
H
OH
H
Double
21
Kaempferitrin
H
ORha
H
OH
ORha
H
H
OH
H
″
22
Quercetin
H
OH
H
OH
OH
H
OH
OH
H
″
23
Quercitrin
H
OH
H
OH
ORha
H
OH
OH
H
″
24
Isoquercitrin
H
OH
H
OH
OGlu
H
OH
OH
H
″
25
Rutin
H
OH
H
OH
ORut
H
OH
OH
H
″
26
Morin
H
OH
H
OH
OH
OH
H
OH
H
″
27
Myricetin
H
OH
H
OH
OH
H
OH
OH
OH
″
28
Myricitrin
H
OH
H
OH
ORha
H
OH
OH
OH
″
29
Datiscetin
H
OH
H
OH
OH
OH
H
H
H
″
30
Quercetagetin
H
OH
OH
OH
OH
H
OH
OH
H
″
31
Quercetagitrin
H
OGlu
OH
OH
OH
H
OH
OH
H
″
32
Rhamnetin
H
OCH
3
H
OH
OH
H
OH
OH
H
″
33
Isorhamnetin
H
OH
H
OH
OH
H
OCH
3
OH
H
″
34
Pinocembrin
H
OH
H
OH
H
H
H
H
H
Single
35
Naringenin
H
OH
H
OH
H
H
H
OH
H
″
36
Salipurpin
H
OH
H
OGlu
H
H
H
OH
H
″
37
Prunin
H
OGlu
H
OH
H
H
H
OH
H
″
38
Naringin
H
ORha
H
OH
H
H
H
OH
H
″
39
Sakuranetin
H
OCH
3
H
OH
H
H
H
OH
H
″
40
Sakuranin
H
OCH
3
H
OGlu
H
H
H
OH
H
″
41
Hesperetin
H
OH
H
OH
H
H
OH
OCH
3
H
″
42
Hesperidin
H
ORut
H
OH
H
H
OH
OCH
3
H
″
43
Eriodictyol
H
OH
H
OH
H
H
OH
OH
H
″
44
Eriodictin
H
ORha
H
OH
H
H
OH
OH
H
″
45
Pinobanksin
H
OH
H
OH
OH
H
H
H
H
″
Niimura Koichi
Umekawa Kiyonori
Watanabe Koju
Kureha Chemical Industry Co. Ltd.
Peselev Elli
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