Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-28
2002-04-02
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S229500, C514S229800, C514S543000, C514S544000, C514S452000, C544S065000, C548S131000, C548S218000, C549S358000, C549S360000, C549S383000, C549S387000
Reexamination Certificate
active
06365610
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel urokinase production inhibitors, angiogenesis inhibitors and a preventive or therapeutic method with use of the inhibitor.
BACKGROUND ART
Urokinase (urine-type plasminogen activator, i.e., uPA) is a protease which is highly specific to a single peptide linkage in plasminogen. Urokinase converts plasminogen to plasmin which is an active fibrinolytic enzyme. Activated plasmin acts on fibrin, fibronectin and laminin, converts inactive matrix metalloprotease (MMP) to active MMP and promotes liquefaction of collagen, a component of the basement membrane. In addition to the function of a protease, urokinase also has activity to promote the migration of vascular endothelial cells and to promote tube formation on Matrigel, serving an important function in angiogenesis.
The physiological processes in which urokinase participates include, for example, angiogenesis, osteoanagenesis, nidation, infiltration of immunocytes into inflammatory sites, ovulation, spermatogenesis, anagenesis for the repair of wounds and differentiation of organs, local infiltration of fibrosis and tumor into adjacent regions, metastatic spread of tumor cells from the primary site to a secondary site, and disorganization in arthritis. Accordingly urokinase inhibitors have activities against angiogenesis, arthritis, inflammation, invasion, metastasis, osteoporosis and retinopathy (angiogenesis-dependent retinopathy), contraceptive activity and activity to inhibit growth of tumor. It is therefore expected to develop medicinals which will act on urokinase as a molecular target. Reports are made on useful effects of anti-urokinase monoclonal antibodies and some urokinase inhibitors. For example, it is reported that anti-urokinase monoclonal antibodies block the invasiveness of tumor cells in vitro [Cancer Res., 51, 3690-3695(1991); Exp. Cell Res., 192, 453-459(1991)]. Reportedly, amiloride, a known urokinase inhibitor having medium efficacy, blocks the metastasis of tumors in vivo [Anticancer Res., 8, 1373-1376(1988)], and prevents angiogenesis or development of capillary reticular structures in vitro [J. Cell Biol. 115(3 Pt 2):402a(1991)].
The ozonide derivatives according to the present invention include some compounds which are known [for example, J. Am. Chem. Soc. (1984), 106(10), 2932-6, J. Org. Chem. (1985), 50(9), 1504-9, J. Org. Chem. (1990), 55(13), 4221-2, Ann. Chim. (Paris) 9 (7-8), 359-97(1964), J. Am. Chem. Soc. (1983), 105(8), 2414-26, J. Org. Chem. (1993), 58(1), 135-41, J. Org. Chem. (1985), 50(2), 275-7, etc.]. However, the literature relates only to preparation processes and optochemical properties, and nothing has been known about the fact that these compounds have high activity to inhibit production of urokinase and are useful as urokinase production inhibitors and angiogenesis inhibitors.
An object of the present invention is to provide novel urokinase production inhibitors and angiogenesis inhibitors, and a preventive or therapeutic method with use of such an inhibitor.
DISCLOSURE OF THE INVENTION
The present invention provides a urokinase production inhibitor comprising as an active component an ozonide derivative represented by the formula (1)
wherein A is an oxygen atom or N—R (wherein R is phenyl or phenyl having as a substituent lower alkyl having 1 to 6 carbon atoms, lower alkoxyl having 1 to 6 carbon atoms or a halogen atom); B is an oxo group or —R
4
; and (1) when A is an oxygen atom, R
1
is a hydrogen atom, lower alkyl having 1 to 6 carbon atoms, phenyl or phenyl having as a substituent lower alkyl having 1 to 6 carbon atoms, lower alkoxyl having 1 to 6 carbon atoms, lower alkoxycarbonyl having 2 to 7 carbon atoms or a halogen atom, R
2
is phenyl or phenyl having as a substituent lower alkyl having 1 to 6 carbon atoms, lower alkoxyl having 1 to 6 carbon atoms or a halogen atom, R
3
is a hydrogen atom, lower alkyl having 1 to 6 carbon atoms, lower alkoxyl having 1 to 6 carbon atoms or a halogen atom, B is an oxo group or —R
4
, R
4
is a hydrogen atom, lower alkyl having 1 to 6 carbon atoms, a halogen atom, lower alkanoyl having 2 to 6 carbon atoms or phenyl, and R
5
is a hydrogen atom, lower alkyl having 1 to 6 carbon atoms, lower alkoxyl having 1 to 6 carbon atoms or a halogen atom or forms an aromatic 6-membered ring when combined with R
4
; or (2) when A is N—R, R
1
is a hydrogen atom, lower alkyl having 1 to 6 carbon atoms, phenyl or phenyl having as a substituent lower alkyl having 1 to 6 carbon atoms, lower alkoxyl having 1 to 6 carbon atoms or a halogen atom, R
2
is a hydrogen atom or lower alkyl having 1 to 6 carbon atoms, R
3
is a hydrogen atom, lower alkyl having 1 to 6 carbon atoms, lower alkoxyl having 1 to 6 carbon atoms or a halogen atom, B is —R
4
, R
4
is a hydrogen atom, phenyl or phenyl having as a substituent lower alkyl having 1 to 6 carbon atoms, lower alkoxyl having 1 to 6 carbon atoms or a halogen atom, and R
5
is a hydrogen atom, lower alkyl having 1 to 6 carbon atoms, lower alkoxyl having 1 to 6 carbon atoms or a halogen atom or forms an aromatic 6-membered ring when combined with R
4
.
The invention further provides a urokinase production inhibitor composition containing an ozonide derivative represented by the formula (1) and a pharmacologically acceptable carrier.
The invention further proposes use of an ozonide derivative represented by the formula (1) for preparing a urokinase production inhibitor.
The invention further provides a method of inhibiting production of urokinase by administering to a human an effective amount of an ozonide derivative represented by the formula (1).
The invention further provides an angiogenesis inhibitor comprising as an active component an ozonide derivative represented by the formula (1).
The invention further provides an angiogenesis inhibitor composition containing an ozonide derivative represented by the formula (1) and a pharmacologically acceptable carrier.
The invention further proposes use of an ozonide derivative represented by the formula (1) for preparing an angiogenesis inhibitor.
The invention further provides a method of preventing or treating a disease accompanying angiogenesis by administering to a human an effective amount of an ozonide derivative represented by the formula (1).
The invention further provides an agent for preventing or treating a malignant tumor comprising as an active component an ozonide derivative represented by the formula (1).
The invention further provides a composition for preventing or treating a malignant tumor containing an ozonide derivative represented by the formula (1) and a pharmacologically acceptable carrier.
The invention further proposes use of an ozonide derivative represented by the formula (1) for preparing an agent for preventing or treating a malignant tumor.
The invention further provides a method of preventing or treating a malignant tumor by administering to a human an effective amount of an ozonide derivative represented by the formula (1).
The invention further provides an agent for preventing or treating metastasis of a tumor comprising as an active component an ozonide derivative represented by the formula (1).
The invention further provides a composition for preventing or treating metastasis of a tumor containing an ozonide derivative represented by the formula (1) and a pharmacologically acceptable carrier.
The invention further proposes use of an ozonide derivative represented by the formula (1) for preparing an agent for preventing or treating metastasis of a tumor.
The invention further provides a method of preventing or treating metastasis of a tumor by administering to a human an effective amount of an ozonide derivative represented by the formula (1).
The compounds serving as the active component of the invention and represented by the formula (1) have the following basic structures (A) to (D).
According to the invention, the group B included in the formula (1) is an oxo group or a group represented by —R
4
, and the group B is combined with a ring b
Nojima Masatomo
Sasaki Takuma
Arent Fox Kintner Plotkin & Kahn
Higel Floyd D.
Taiho Pharmaceutical Company Ltd.
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