Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-10-20
1999-10-05
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
A61K 3153
Patent
active
059624540
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a neovascularization inhibitor composition.
BACKGROUND ART
The blood vessels, together with the heart and the lymph vessels, constitute a vasculature which is indispensable for sustained metabolism of tissues and, hence, functional homeostasis of an organism. The chief constituent cells of a blood vessel are endothelial cells and smooth muscle cells. Proliferation of endothelial cells in the established vascular system is usually observed in the neovascularization process giving rise to a new network of capillary blood vessels chiefly from venules and the repair process following exfoliation of vascular endothelial cells. As it has recently been made clear that neovascularization is closely involved in pathology of growth of solid tumors, arteriosclerosis, hyperplasia of panni in rheumatoid arthritis, ophthalmic diseases such as diabetic proliferative retinopathy, psoriasis vulgaris, etc., there is a mounting interest in neovascularization.
The mechanism of neovascularization in cancers, rheumatoid arthritis, diabetic retinopathy, etc. is known to begin with a disruption of extracellular matrix which triggers migration of endothelial cells to form a tube which, in turn, is followed by the migration and proliferation of vascular smooth muscle cells around the tube to complete a new blood vessel.
Several compounds (e.g. D-penicillamine, heparin, 15-deoxyspergaulin, eponemycin AGM-1470, tecogalan sodium (DS-4152), herbimycin A, and interferon-alpha) are known to inhibit neovascularization. Those compounds are either biological component-related substances or substances of the natural origin and, therefore, the source of their supply is too limited for practical utilization.
The antitumor agent irsogladine maleate structurally close to the compound of the invention, reportedly inhibits neovascularization (FEBS, 322(2), 155-158, 1993). However, the 2-amino-4-substituted amino-6-(2,5-dichlorophenyl)-1,3,5-triazine derivative which is theoretically available upon substitution of one of the amino groups by alkyl, aralkyl, arylalkenyl, or aryl is not known to have neovascularization inhibitory activity.
Meanwhile, the inventors of the present invention previously discovered that the 2-amino-4-substituted amino-6-(2,5-dichlorophenyl)-1,3,5-triazine derivative has antihepatitis activity and is useful as a therapeutic agent for hepatitis and already filed a patent application (WO 96/04914).
DISCLOSURE OF INVENTION
The object of the present invention is to provide an excellent medicine with low toxicity which is effective in inhibiting neovascularization.
The inventors of the present invention found that the compound of the activity with extremely low toxicity and have completed the present invention. ##STR2## wherein R.sup.1 represents hydrogen, optionally substituted alkyl, aralkyl, arylalkenyl, or aryl; R.sup.2 represents optionally substituted alkyl, aralkyl, arylalkenyl, or aryl; or R.sup.1 and R.sup.2 conjoinedly and taken together with the adjacent N atom, i.e. in the form of NR.sup.1 R.sup.2, represent a 4- through 8-membered cyclic amino group optionally containing nitrogen, oxygen, or sulfur as a ring member in addition to said N atom and being further substituted.
The present invention, therefore, is directed to a neovascularization salt thereof, or a solvate thereof, as an active ingredient.
The present invention is predicated on the finding that the 2-amino-4-substituted amino-6-(2,5-dichlorophenyl-1,3,5-triazine derivative, which has antihepatitis activity as mentioned above, additionally has neovascularization inhibitory activity which is quite unrelated to the first-mentioned activity.
As demonstrated in the experimental examples presented hereinafter, the compound of the invention has by far higher neovascularization inhibitory activity than irsogladine maleate.
The present invention is now described in further detail.
The "alkyl" mentioned for R.sup.1 and R.sup.2 includes straight-chain or branched alkyl groups of 1-10 carbon atoms, such as methy
REFERENCES:
FEBS, vol. 322, No. 2, 155-158 Irsogladine is a potent inhibitor of angogenesis-Yasufumi Sato et al. (1989).
Katoh Fumitaka
Ueda Fusao
Henley III Raymond
Nippon Shinyaku Co. Ltd.
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