Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-11-17
2003-11-11
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...
C549S332000
Reexamination Certificate
active
06645996
ABSTRACT:
FIELD OF INDUSTRIAL APPLICATION
The present invention relates to a novel bioactive substance which is effective in the prevention or treatment of various diseases accompanied by abnormal angiogenesis.
PRIOR ART
Angiogenesis is a biological phenomenon which is essential for the formation of a vascular arbor during fetal period and is also essential in the morphological and functional development of each organ. Newly blood vessels are constructed by way of plural processes such as the migration and proliferation of endothelial cells and tube formation. It is reported that in these processes, the participation of mast cells, lymph corpuscles, interstitial cells and others play an important role (J. Folkman and Y. Shing, J. Biol. Chem., 267, 10931, 1992). In adult, the angiogenesis occurs only in the female menstrual cycle and a morbid increase of angiogenesis is involved in various diseases and their progression. Given as specific examples of diseases accompanied by abnormal angiogenesis are cancers, rheumatic arthritis, atherosclerosis, diabetic retinopathy, hemangioma and psoriasis (J. Folkman, N. Engl. J. Med., 333, 1757, 1995).
It is reported that the growth of, particularly, solid cancers depends upon the angiogenesis and an antiangiogenic agent is expected to be a new chemotherapy for intractable solid cancers (Folkman J., J. Natl. Cancer Inst., 82, 4, 1990).
In the case of the rheumatic arthritis, it is reported that over production of angiogenesis factors from infiltrated macrophage/lymphatic cells leads to the induction of angiogenesis in the segments (Kahn J., Proc. Am. Soc. Clin. Oncol., 12, 50, abstract, 1993) and that an antiangiogenic agent AGM-470 inhibits arthritis in a collagen arthritis model (Peacock D J., J. Exp. Med. 175, 1135-8, 1992). These reports suggest that the inhibition of angiogenesis in inflammatory diseases results in the therapy for the diseases.
In the atherosclerosis, it is clarified that excess production of a vascular endothelial growth factor (VEGF) induced at hypoxia causes angiogenesis in an atheromatous macula (Stavri G T., FEBS Lett., 358 , 311-5, 1995) and it is said that angiogenesis is necessary for the extension of the atheromatous macula like in the case where angiogenesis is necessary for the growth of tumors (O'Brien E R., Am. J. Pathol., 146, 1029-39, 1994). For hemangioma which is sometimes related with life or death of the newborn, curing using IFN-&agr;2a known to have an antiangiogenic effect has been attempted (White C W., N. Engl. J. Med. 320, 1197-200, 1989) As remedies for these diseases, new antiangiogenic agents are desired eagerly.
There have been reports concerning several antiangiogenic substances so far. However, no effective substance which is fit for actual use has not been found yet (JP-A 3-109324, JP-A 3-236324 and JP-A 3-2148).
The present invention is to isolate a novel substance having an antiangiogenic effect to thereby provide an agent for preventing or treating various diseases accompanied by abnormal angiogenesis.
DISCLOSURE OF THE INVENTION
In view of the above situation, the inventors of the present invention have carried out research screening of antiangiogenic compound and as a result, found that an antiangiogenic compound is produced in a culture broth of microorganisms belonging to the genus Streptomyces. The active substance was isolated to determine the structure and as a result, it was clarified that this active substance was a novel active substance. Then the mechanism of action of the active substance was analyzed and as a result, found that this active substance had an inhibitory effect of the expression of adhesion molecule on endothelial cells as one of the mechanisms of inhibitory effects. Specifically, the substance showed a clear inhibitory effect on the expression of VCAM-1 and E-selectin of an endothelial cell. It is suggested that VCAM-1 and E-selectin are involved in the migration of endothelial cells and formation of lumens which are essential for angiogenesis (A. E. Koch et al, Nature, 376, 517, 1995). It is reported that the both are also involved in the adhesion of an endothelial cell to the lymph corpuscle. It is hence considered that the active substance is expected to be remedies for various diseases, specifically, autoimmune diseases, e.g., collagen diseases and graft rejection, cardiac infarction and arterial sclerosis, caused by an abnormal reaction of activated lymph corpuscles besides the diseases caused by an angiogenesis.
That is, the present invention relates to a chemical compound represented by the formula (1):
(wherein, R
1
represents hydrogen atom, aldehyde group or a lower acyl group, R
2
and R
3
are the same as or different from each other and represent hydrogen atom or a lower alkoxy group or are combined to represent an oxygen atom, R
4
represents a lower alkyl group and R
5
represents hydrogen atom or a lower alkyl group, provided that compounds in which R
1
is aldehyde group, R
2
and R
3
are different from each other and are hydrogen atom or methoxy group, R
4
is ethyl group and R
5
is hydrogen atom are excluded), a salt therof or a hydrate thereof.
More specifically, it relates to a compound, a salt thereof or a hydrate thereof, in which, in the formula (1) R
1
represents hydrogen atom, aldehyde group or acetyl group, R
2
and R
3
are the as same or different from each other and represent hydrogen atom or methoxy group or are combined to represent an oxygen atom, R
4
represents ethyl group, normal propyl group or isopropyl group and R
5
represents hydrogen atom or methyl group, provided that compounds in which R
1
is aldehyde group, R
2
and R
3
which are different from each other and are hydrogen atom or methoxy group, R
4
is ethyl group and R
5
is hydrogen atom are excluded;
a compound, a salt thereof or a hydrate thereof, wherein, in the formula (1), R
1
represents aldehyde group, R
2
and R
3
are the same as each other and represent hydrogen atoms, R
4
represents ethyl group and R
5
represents hydrogen atom or methyl group;
a compound, a salt thereof or a hydrate thereof, wherein, in the formula (1), R
1
represents aldehyde group, R
2
and R
3
are the same as each other and represent hydrogen atoms, R
4
represents normal propyl group or isopropyl group and R
5
represents hydrogen atom;
a compound, a salt thereof or a hydrate thereof, wherein, in the formula (1), R
1
represents aldehyde group, R
2
and R
3
are different from each other and represent hydrogen atom or methoxy group, R
4
represents normal propyl group or isopropyl group and R
5
represents hydrogen atom;
a compound, a salt thereof or a hydrate thereof, wherein, in the formula (1), R
1
represents hydrogen atom, R
2
and R
3
are the same as each other and are combined to represent an oxygen atom, R
4
represents ethyl group or isopropyl group and R
5
represents hydrogen atom;
a compound, a salt thereof or a hydrate thereof, wherein, in the formula (1), R
1
represents acetyl group, R
2
and R
3
are the same as each other and represent hydrogen atoms, R
4
represents ethyl group and R
5
represents hydrogen atom;
a medicament which comprises the above compounds or the compound in which, in the formula (1), R
1
represents aldehyde group, R
2
and R
3
are different from each other and represent hydrogen atom or methoxy group, R
4
represents ethyl group and R
5
represents hydrogen atom, a salt thereof or a hydrate thereof as the active ingredient; and
a method of producing the above compounds or a salt thereof, which comprises culturing Streptomyces sp. Mer-VD1207, FERM P-15889 in a nutrient medium and collecting the above compounds or a salt thereof from the culture broth.
The present invention provides a medical composition which comprises a pharmacologically effective amount of the above compounds, a salt or a hydrate thereof and a pharmacologically acceptable carrier; a method for treating a disease against which an antiangiogenic effect or an effect of inhibiting the expression of an adhesion molecules VCAM-1 or/and E-selectin is efficacious, which co
Dobashi Kazuyuki
Fujita Masanori
Funahashi Yasuhiro
Kawase Rena
Naruse Nobuaki
Mercian Corporation and Eisai Co., Ltd.
Robinson Binta
Rotman Alan L.
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