Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-02-26
2002-09-17
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S287000
Reexamination Certificate
active
06451846
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel isocoumarin derivatives inhibiting angiogenesis, a method for preparation thereof and pharmaceutical compositions comprising the said derivatives as pharmaceutically active ingredients.
More particularly, the present invention relates to novel isocoumarin derivatives represented by formula 1, especially 6,8-dihydroxy-4-acetyl-isocoumarin, a method for preparing 6,8-dihydroxy-4-acetyl-isocoumarin from fungi, and pharmaceutical compositions comprising the compounds and/or 6,8-dihydroxy-4-acetyl-isocoumarin as pharmaceutically active ingredients, which would be effective for the treatment of angiogenic diseases such as cancers, rheumatoid arthritis and diabetic retinopathy
<Formula 1>
Wherein,
R
1
is a hydrogen, alkyl or allylalkyl group; R
2
and R
3,
which may be the same or different, each is hydrogen or an alkyl group.
BACKGROUND
Angiogenesis is a complex process in which capillary blood vessels grow in a complex physiological processes (J. Folkman and M. Klagsbrun et al.,
Science
, Vol. 235, pp 442-447, 1987; J. Folkman and Y. Shing, J. et al.,
Biol. Chem
., Vol. 267, pp. 10931-10934, 1992). Angiogenesis is driven by a complex array of, soluble mediators, matrix molecules and accessory cells that function to fine-tune and coordinate the response in both time and space. The initiation of angiogenesis is mediated by multiple molecules that are released from a number of sources including inflammatory cells, such as mast cells and macrophage as well as a variety of tumor cells. These molecules activate the normally quiescent vascular endothelium by binding to their respective receptors. These activated endothelial cells have a characteristic set of traits which include increased cellular proliferation, elevated expression of cell adhesion molecules, increased secretion of proteolytic enzymes, increased cellular migration and invasion, and differentiation to capillary tube. These complex cellular processes should be successfully accomplished to complete angiogenesis.
Angiogenesis is plays important role in a variety of normal physiological events, including trophoblast implantation, wound healing and embryonic development. Uncontrolled angiogenesis, however, can contribute to a number of pathological processes such as rheumatoid arthritis, diabetic retinopathy, and tumor growth and metastasis.
Malignancies are characterized by the growth and spread of tumors. One crucial factor is angiogenesis. Once a tumor has appeared, every increase in tumor cell population must be preceded by an increase in new capillaries that converge on the tumor and supply the cells with oxygen and nutrients (J. Folkman,
Perspect. in Biol. and Med
., Vol 29, p. 10-36, 1985; N. Weidner, et al.,
Amer. J. Pathol
., Vol. 143, pp. 401-409, 1993). Tumors may thus remain harmless and confined to their tissue of origin, as long as angiogenesis is prevented from being activated. Therefore inhibition of tumor-associated angiogenesis is a most promising approach in cancer therapy (M. S. O'Reilly, et al.,
Cell
, Vol. 79, pp. 316-328, 1994).
Many experimental evidence supports the hypothesis that tumor angiogenesis is fundamental for the growth and metastasis of solid tumors (M. S. O'Reilly, et al., ibid. 1994; N. Weidner, et al.,
N. Eng. J. Med
., Vol. 324, pp. 1-8, 1991). Indeed, the majority of solid tumors are not even clinically detectable until after the occurrence of neovascularization, whose induction in solid tumors is mediated by one or more angiogenic factors (J. Folkman and Y. Shing,
J. Biol. Chem
., Vol. 267, pp. 10931-10934, 1992). Furthermore, angiogenesis is also important in a number of other pathological processes, including arthritis, psoriasis, diabetic retinopathy, and chronic inflammation (J. Folkman,
Nature Medicine
, Vol 1, p. 27-31, 1995; J. W. Miller, et al.,
J. Pathol
., Vol. 145, pp. 574-584, 1994; A. P. Adamid, et al.,
Amer. J. Ophthal
., Vol. 118, pp. 445-450, 1994; K. Takahashi, at al.,
J. Clin. Invest
., Vol.93, pp.2357-2364, 1994; D. J. Peacock, et al.,
J. Exp. Med
., Vol. 175, pp. 1135-1138, 1992; B. J. Nickoloff, et al.,
Amer. J. Pathol
., Vol. 44, pp. 820-828, 1994). Thus, clearly methods of blocking the mechanism of angiogenesis are necessary to treat, so called, angiogenic diseases.
In vitro angiogenesis assays are important for identification of potential angiogenic inhibitors and rapid screening for pharmacological inhibitors. As noted above, differentiation of endothelial cells to capillary-like structure on Matrigel is essential processes for the mechanism of angiogenesis. When endothelial cells are plated on Matrigel, a reconstituted basement membrane protein derived from the Engelbreth-Holm-Swarm mouse tumor, the cells stop proliferating and display high motility and cell-cell communication. Moreover, the cells align and form tubes proposed as models of endothelial cell differentiation, the final step of angiogenesis. These tubes are morphologically similar to capillaries in that the cells that form these tubes are polarized and a central lumen is observed. This in vitro angiogenesis assay is very useful method to evaluate antiangiogenic activity of various compounds.
In order to treat angiogenesis-related diseases, several inhibitors of the above mechanism of angiogenesis are being studied, including platelet factor 4, the fumagillin derivative AGM 1470, Interferon-alpha, thrombospondin, angiostatic steroids, and angiostatin (J. Folkman, et al., ibid., 1995; M. S. O'Reilly, et al., ibid., 1994; V. Castle, et al.,
J. Clin. Invest
., Vol. 87, pp.1183-1888; D. Ingber, et al.,
Nature,
Vol. 348, pp. 555-557). All of these compounds have disadvantages. For example, endostatin and angiostatin are proteins, so that they have all of the disadvantages of proteins, including the requirement for being administered parenterally. Therefore, a non-protein inhibitor, which would selectively block the underlying mechanism of angiogenesis without adversely affecting other physiological functions, and which could be administered by many different routes, would be extremely useful. Therefore continuous development of angiogenesis inhibitors having less toxicity and more excellent effect is further required.
Based on the above, the present inventors have performed extensive screening of microbial metabolites to solve the problems described above using in vitro angiogenesis assays, and as a result, discovered 6,8-dihydroxy-4-(1-hydroxyethyl)-isocoumarin and a novel 6,8-dihydroxy-4-acetyl-isocoumarin from a fungal strain of soil. These, two isocoumarin derivatives are highly effective in inhibiting angiogenesis in vitro and in vivo. Finally, the inventors of the present invention found these compounds and their general alkyl or allyl derivatives as therapeutics of angiogenic diseases.
SUMMARY OF THE INVENTION
The invention provides novel isocoumarin derivatives inhibiting angiogensis represented by formula 1, including a method for preparing isocoumarin derivatives.
The invention also provides pharmaceutical compositions comprising isocoumarin derivatives as pharmaceutically active ingredients.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The present invention provides novel isocoumarin derivatives inhibiting angiogensis represented by the formula 1;
<Formula 1>
Wherein,
R
1
is a hydrogen, alkyl or allylalkyl group; R
2
and R
3
, which may be the same or different, each is hydrogen or an alkyl group.
In addition, the present invention provides 6,8-dihydroxy-4-acetyl-isocoumarin represented by formula 2 as a preferable embodiment of angiogenesis-inhibiting isocoumarin derivatives.
The 6,8-dihydroxy-4-acetyl-isocoumarin can be prepared from fungus, Sesquicllium sp. Y70832, of soil.
The present invention provides a method of purification the active ingredients from a culture broth of the Sesquicillium sp. Y70832 using solvent extraction, column chromatography, and high performance liquid chromatography.
Additionally, the present invention provides pharmaceutical compositions comprising as
Hong Young-Soo
Kim Hang-Sub
Lee Jeong-Hyung
Lee Jung Joon
Park Yun Joo
Korea Research Institute of Bioscience and Biotechnology
Owens Amelia
LandOfFree
Isocoumarin derivatives inhibiting angiogenesis does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Isocoumarin derivatives inhibiting angiogenesis, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Isocoumarin derivatives inhibiting angiogenesis will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2861579