Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-28
2001-07-31
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S213010, C514S220000
Reexamination Certificate
active
06268359
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition for preventing or treating visual function disorders caused by disorders of ocular circulation such as intraocular blood circulation and aqueous humor circulation, as well as ciliary muscle tension and the like.
BACKGROUND OF THE INVENTION
In intraocular blood circulation, ophthalmic artery enters into orbit and branches to central retinal artery, lacrimal artery, posterior ciliary artery and anterior ciliary artery. Then, the blood circulation flows out of the eye through retinal central vein, vortex vein and ophthalmic vein. Anterior ciliary artery connects to blood vessel systems of choroid, optic disk, iris, ciliary body and the like. Therefor, it is known that, when the blood vessel systems are damaged, diseases such as glaucoma (in particular, open angle glaucoma and normal pressure glaucoma), pigmentary retinal degeneration, macular degeneration, ischemic optic neuropathy, choroid diseases following iridocyclitis, and retinochoroiditis are induced, and visual functions are damaged.
As hitherto known factors which cause intraocular blood circulatory disorders, among physiological active substances produced in vascular endothelial cells, there are those contacting blood vessel smooth muscle cells such as endothelin, thromboxane A2, angiotensin II and endogenous amines (dopamine, epinephrine, serotonin and the like). However, ocular blood flow varies largely due to difference in species, individuals and ocular tissues. In addition, ocular circulation measurement is still developing. Then, factors which cause intraocular blood circulatory disorders have not yet been fully elucidated.
Currently, for chemotherapy of diseases accompanied with ocular blood circulatory disorders, tocopherol nicotinate which is vitamin E medicine, micro-circulatory improving medicine such as pentoxifyline, and various steroids are administrated orally. However, there are problems such as insufficient ocular circulatory improving activity, and side effects, for example, hypotension and gastrointestinal disorders. It is also known that diseases such as ocular hypertension and closed angle glaucoma are caused by aqueous humor circulatory disorders. In glaucoma, the ocular hypertension causes disorders of the axon of optic nerve, which results in visual function disorders such as disorders of optic disk and abnormal visual field. For treatment of glaucoma, there are instillation of cholinergic agents whose typical example is pilocarpin which contracts ciliary muscle to stimulate outflow of aqueous humor; instillation of sympathomimetic agents such as epinephrine and dipivefrine which inhibit production of aqueous humor; and instillation of sympathomimetic &bgr;-blockers such as timolol, pindolol and carteolol; as well as oral administration of carbonic anhydrase inhibitors such as acetazolamide; and instillation of prostaglandin derivatives which promote uveoscleral outflow of aqueous humor by relaxing of ciliary muscle to promote outflow of aqueous humor. However, these drugs have problems such as various side effects depending on their respective activities.
Further, recently, many persons have been required to continue working at a short visual range as a factor of the living environment. This has caused ciliary muscle tension, resulting in visual function disorders such as refractive errors, for example, tonic accommodative myopia and myopia. Although instillation of control paralytic agents such as atropine and tropicamide have been tried to inhibit progress of myopia, this treatment is not popularized in the clinical field because of unreliability of effects and side effects such as mydriasis.
OBJECTS OF THE INVENTION
An object of the present invention is to provide a pharmaceutical composition for preventing or treating visual function disorders caused by ocular circulatory disorders, ciliary muscle tension, and the like, which improves the above problems. The term “ocular circulation” used herein means “intraocular blood circulation” and “aqueous humor circulation”.
SUMMARY OF THE INVENTION
The present inventors have studied intensively to develop a pharmaceutical composition for preventing or treating visual function disorders which have both excellent ocular circulation improving and ciliary muscle relaxing activities and are highly safe. As a result, it has been found that vasopressin antagonists exhibit the desired ocular circulation improving activity and ciliary muscle relaxing activity.
That is, vasopressin is known as a substance in a living body which contracts blood vessel smooth muscle, and its antagonists are proposed to be useful for prevention or treatment of diseases caused by blood circulatory disorders. However, it has not been reported heretofore in the prior art that vasopressin antagonists improve ocular circulation, exhibit intraocular pressure reducing activity and improve myopia. Further, no report of the application of vasopressin antagonists to the opthalomological field involving glaucoma has been found.
For example, JP 2-19397 A and JP 2-32098 A disclose the use of peptide derivatives, which are useful for vasopressin antagonists, as hypotensors and the like, and JP 3-127732 A discloses the use of indole derivatives, which are useful for vasopressin antagonists, as agents for preventing and treating hypertension, circulatory disfunction and the like. However, they do not disclose any application thereof in the ophthalmological field. JP 4-321669 A discloses that benzo-heterocyclic compounds are useful as vasopressin antagonists and can be used as vasodepressors, hypotensors, diuretics, platelet agglutination depressors and the like. JP 5-4984 A discloses the use of carbostyril derivatives, which are useful as vasopressin antagonists, as hypotensors. However, there is no disclosure of the use thereof in the ophthalmological field. JP 5-112600 A discloses cyclic hexapeptide oxytocin antagonists, and JP 5-294961 A and JP 5-230027 A disclose spiro-indanyl-camphorsulfonyl oxytocin antagonists. However, they disclose only the use thereof as repressors of premature delivery and the like. Although JP 6-135992 A discloses endothelin receptor antagonists from microorganisms which are also useful as vasopressin antagonists, they disclose only the use thereof in treatment of cardiovascular disorder and the like. JP 6-211800 A discloses benzo-heterocyclic compounds and their use for preventing and treating hypertension, premature delivery and the like. However, no use in the ophthalmological field is disclosed.
JP 7-233073 A discloses a vasopressin antagonist composition comprising as active component an amino acid, but it discloses only the use thereof in prevention and treatment of kidney function disorders, hepatocirrhosis and the like. JP 7-242625 A discloses piperidinyl-camphorsulfonyl oxytocin antagonist, but it discloses only the use thereof in prevention and treatment of hypertension, premature delivery and the like. JP 7-247269 A discloses indole derivatives useful for vasopressin antagonists, but it discloses only the use thereof in treatment of diseases in cardiovascular, kidney, stomach and the like.
WO95/03305 discloses nitrogen-containing aromatic 5-membered ring-condensed benzazepine derivatives, JP 8-198879 A discloses a novel method for producing the benzazepine derivatives, and JP 8-231403 A discloses a stable aqueous solution using one of the benzazepine derivatives. However, they do not suggest the use of vasopressin antagonists in the ophthalmological field, either.
Further, it is reported that, when desmopressin which is a vasopressin derivative is administrated intravenously, intraocular pressure is increased due to acceleration of aqueous humor production (Investigative Ophthalmology Visual Science, Vol. 29, 406-410, 1988). Then, there is a possibility that vasopressin may be one of factors that control intraocular pressure. However, there is no suggestion of improvement of ocular circulation, intraocular pressure reducing activity and improvement of myopia by vasopressi
Ogawa Takahiro
Waki Mitsunori
Watanabe Noriko
Fay Zohreh
Kwon Brian-Yong
Senju Pharmaceutical Co. Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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