Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-09-23
2004-11-16
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S410000, C549S475000, C514S473000, C435S119000
Reexamination Certificate
active
06818664
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel compounds which are useful as active ingredients of medicaments such as angiogenesis inhibitors and antitumor agents.
BACKGROUND ART
Recently, angiogenesis has been elucidated as an important physiological phenomenon in proliferation and metastasis of various progressive solid cancers. The angiogenesis is completed through steps including, for example, (1) stimulation by vascular endothelial growth factor (VEGF) secreted from tumor cells; (2) disengagement of peritheliocyte or decomposition or digestion of extracellular matrix such as basal membrane; (3) migration and proliferation of vascular endothelial cells; (4) formation of tubule by the endothelial cells, formation of basal membrane, and maturation of blood vessel. In tumorous angiogenesis, the generated new vessels have a role of supplying oxygen and nutriment to tumors to accelerate their growth and serving as a route for infiltration and metastasis of tumor cells to other tissues.
Among them, the vascular endothelial growth factor has variety of functions in the blood, vessel, and coagulation system such as for induction of proliferation and survival and maintenance of vascular endothelial cells, acceleration of blood vessel permeability, platelet migration, and chemotaxis of macrophage, as well as for angiogenesis. Therefore, novel compounds inhibiting chemotaxis that is induced by VEGF derived from vascular endothelial cells are expected to be useful as angiogenesis inhibitors, antitumor agents, agents inhibiting metastasis, and agents for treatment of rheumatic arthritis (Eur. J. Cancer, 32A, 2534-2539, 1996; Nature Med., 1, 27-31, 1995, Immunity, 12, 121, 2000).
In addition, angiogenesis inhibitors are potential therapeutic medicament for diabetic retinopathy as one of complications of diabetic vascular diseases. At present, treatments for diabetic retinopathy are given basically as symptomatic treatments, and since late treatments often result in ablepsia, effective medicaments are desired which are effective in preventive and therapeutic treatments. In recent years, angiogenesis inhibitors based on variety of modes of actions have been clinically developed. Under the circumstances, novel compounds as potential lead compounds have always been desired strongly.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide novel compounds which exert angiogenesis inhibitory activity, antitumor activity, and metastasis inhibitory activity by inhibiting chemotaxis of vascular endothelial cells. Another object of the present invention is to provide a method for preparing a novel compound having the aforementioned features and a medicament comprising said compound as an active ingredient.
The inventors of the present invention conducted various studies to achieve the foregoing objects. As a result, they found that novel compounds isolated from a culture of a microorganism belonging to genus Neosartorya, a filamentous fungus, has angiogenesis inhibitory activity and antitumor activity. The present invention was achieved on the basis of the findings.
The present invention thus provides a compound represented by the following formula (I) or a salt thereof.
According to preferred embodiment of the invention, provided is a compound represented by the following formula (II) or a salt thereof.
According to another aspect of the present invention, provided is a medicament which comprises the aforementioned compound or a physiologically acceptable salt thereof as an active ingredient. The medicament can be used as a medicament for preventive and/or therapeutic treatment of diseases with excess angiogenesis or diseases resulting from excess angiogenesis, therapeutic treatment of malignant tumors, inhibition of metastasis of malignant tumors, preventive and/or therapeutic treatment of diabetes and complication of diabetes, and preventive and/or therapeutic treatment of inflammatory diseases. The present invention further provides an angiogenesis inhibitor which comprises the aforementioned compound or a physiologically acceptable salt thereof as an active ingredient; an inhibitor against chemotaxis of vascular endothelial cells which comprises the aforementioned compound or a physiologically acceptable salt thereof as an active ingredient; an antitumor agent which comprises the aforementioned compound or a physiologically acceptable salt thereof as an active ingredient; and an inhibitor against metastasis of malignant tumors which comprises the aforementioned compound or a physiologically acceptable salt thereof as an active ingredient. The angiogenesis inhibitor can be administered, for example, for preventive and/or therapeutic treatment of diabetic retinopathy.
As a further aspect of the present invention, there is provided a method for preparing the aforementioned compound or a salt thereof, which comprise the step of separating and collecting the aforementioned compound or a salt thereof from a culture obtained by culturing a microorganism belonging to genus Neosartorya which can produce the aforementioned compound. The present invention also provides a method for therapeutic treatment of malignant tumors which comprises the step of administering a therapeutically effective amount of the aforementioned compound or a physiologically acceptable salt thereof to a mammal including a human; a method for inhibition of metastasis of malignant tumors which comprises the step of administering a therapeutically effective amount of the aforementioned compound or a physiologically acceptable salt thereof to a mammal including a human; a method for angiogenesis inhibition in tumor tissues which comprises the step of administering a therapeutically effective amount of the aforementioned compound or a physiologically acceptable salt thereof to a mammal including a human; a method for suppression of abnormal acceleration of angiogenesis which comprises the step of administering a therapeutically effective amount of the aforementioned compound or a physiologically acceptable salt thereof to a mammal including a human; a method for preventive and/or therapeutic treatment of diabetic retinopathy which comprises the step of administering a therapeutically effective amount of the aforementioned compound or a physiologically acceptable salt thereof to a mammal including a human; and a method for inhibition of chemotakis of vascular endpthelial cells which comprises the step of administering a therapeutically effective amount of the aforementioned compound or a physiologically acceptable salt thereof to a mammal including a human.
BEST MODE FOR CARRYING OUT THE INVENTION
The compound represented by the formula (I) or (II) according to the present invention (either or both of them are hereinafter referred to as “the compound of the present invention”) has asymmetric carbon atoms, and stereoisomers such as optical isomers and diastereomers based on the asymmetric carbon atoms exist. The stereoisomers in a pure form as well as mixtures of any stereoisomers or racemates fall within the scope of the present invention. The compound of the present invention has plural olefinic double bonds, and geometrical isomers based on each double bond may exist. The geometrical isomers in a pure form as well as mixtures of any geometric isomers fall within the scope of the present invention. An example of a preferred geometrical isomer is the compound represented by the formula (II).
The compound of the present invention in a free form, as well as a salt of the aforementioned compound, preferably a physiologically acceptable salt, falls within the scope of the present invention. The form of the salt is not particularly limited. A salt such as a sodium salt may sometimes be formed with the hydroxyl groups in the molecule. A hydrate or a solvate of the aforementioned compound or a salt thereof also falls within the scope of the present invention. A preferred example of the compound of the present invention includes the compound represented by the formula (II). This particular compound may sometim
Kakeya Hideaki
Kanazawa Susumu
Konno Hiroshi
Osada Hiroyuki
Greenblum & Bernstein P.L.C.
McKane Joseph K.
Riken
Shameem Golam M M
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