This application is a 371 of Pct/JP97/00354 filed on Feb. 12, 1997.
The present invention relates to a pharmaceutical composition which is useful as a neovascularization inhibitor.
More particularly, the present invention relates to an agent for the prevention or treatment of diseases associated with neovascularization which comprises as the active ingredient N-(3,4-dimethoxycinnamoyl)anthranilic acid represented by the formula: 
or a pharmaceutically acceptable salt thereof.
Diseases associated with neovascularization which can be treated in accordance with this invention include, various diseases which occur by participation of neovascularization as one of the causes thereof for examples include, diabetic retinopathy, senile discoid macular degeneration, retinopathy of prematurity, sickle-cell retinopathy, retinal vein occlusion, neovascularization after corneal transplantation or cataract extraction, neovascular glaucoma, rubeosis iridis, rheumatic arthritis, psoriasis, scleredema, tumors, overgrowth of capillary blood vessels in atherosclerosis adventitia and corneal neovascularization caused by long wear of cantact lens.
In general, neovascularization is a phenomena accompanying degradation of the basement membrane by proteolytic enzymes, chemotaxis and proliferation of endothelial cells, tube formation by endothelial cell differentiation and reorganization of blood vessels. Neovascularization occurs in luteinization and placentation physiologically and in the diseases described above pathologically. For example, in retinopathy, retinal tissues lying between preexisting basement membrane around retinal vessels and vitreous are degraded. Subsequently endothelial cells of preexisting vessels migrate from junctions of the degraded retinal tissues and endothelial cells proliferate to fill up spaces left by the migrated endothelial cells migrated, and the endothelial cells migrated to vitreoretina reorganize new vessels, leading to neovascularization.
Neovascularization is correlated with various diseases, and, for example, neovascularization plays a close part in the process of the onset and progress of the above diseases. Therefore, extensive studies to find compounds having an inhibitory activity on neovascularization have been actively promoted for the prevention or treatment of these diseases. Although, for example, neovascularization inhibitors such as fumagillin analogues, which are microbial metabolites having an inhibitory activity on endothelial cell proliferation, tetracycline antibiotics, which can inhibit a collagenase activity, and microorganism-derived D-gluco-galactan sulfate, which can interfere with binding of heparin-binding angiogenic factors to their receptors, are known, there is no satisfying drug clinically. In addition, there is no procedure enough to treat the above diseases. Specially, if patients with diabetic retinopathy do not undergo surgical treatment, involution of neogenetic vessels can not be observed, and therefore, visual loss caused by a discharge of blood from neogenetic vessels has become a problem. Thus, development of drugs having an excellent effect on neovascularization has been greatly desired.
N-(3,4-Dimethoxycinnamoyl)anthranilic acid (generic name: Tranilast) represented by the above formula (I) of the present invention has been used widely as a drug for the treatment of allergic disorders such as bronchial asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis, and cutaneous disorders such as keloid and hypertrophic scar. For example, it has been known that Tranilast has inhibitory activities on chemical mediator release caused by an allergic reaction, excessive collagen accumulation by fibroblast cells in cutaneous tissues and excessive proliferation of smooth muscle cells in coronary artery vessels.
However, it is disclosed in no way that Tranilast suppresses proliferation and chemotaxis of microvascular endothelial cells and tube formation of microvascular endothelial cells, and it is not known at all that Tranilast is useful as a neovascularization inhibitor.
The present invention relates to a neovascularization inhibitor which comprises as the active ingredient N-(3,4-dimethoxycinnamoyl)anthranilic acid represented by the formula: 
or a pharmaceutically acceptable salt thereof.
The present invention relates to a method for the prevention and treatment of diseases associated with neovascularization which comprises administering N-(3,4-dimethoxycinnamoyl)anthranilic acid represented by the above formula (I) or a pharmaceutically acceptable salt thereof.
The present invention relates to a use of N-(3,4-dimethoxycinnamoyl)anthranilic acid represented by the above formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the prevention and treatment of diseases associated with neovascularization.
Furthermore, the present invention relates to a use of N-(3,4-dimethoxycinnamoyl)anthranilic acid represented by the above formula (I) or a pharmaceutically acceptable salt thereof as a neovascularization inhibitor.