Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-03-01
2002-05-14
Moezie, Minna (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S912000, C514S913000
Reexamination Certificate
active
06387889
ABSTRACT:
DESCRIPTION
This application is a 371 of PCT/JP99/04709 filed Aug. 31, 1999.
1. Technical Field
The present invention relates to medicinal compositions for treating eye diseases, which are useful for treating eye diseases accompanying increased ocular tension and/or optic neuropathy, such as glaucoma and hypertonia oculi.
2. Background Art
Glaucoma and hypertonia oculi are eye diseases which can occur in all mammals (e.g., primates), and are also intractable eye diseases which are characterized by optic neuropathy attributed to an increase in intraocular pressure (increase in ocular tension) or autoregulation dysfunction of aqueous humor and intraocular blood circulation. Symptoms of glaucoma include eye pain, headaches, rainbow symptoms, nephelopsia, decrease in visual acuity, eye congestion, nausea, vomiting, bradycardia, sweating, and visual field anomaly. In some cases, subjective symptoms of glaucoma do not arise until the disease is in its advanced stages.
Increase in ocular tension is caused by imbalance between the secretion rate of aqueous humor, which is secreted from the ciliary epithelium to the posterior chamber, and the elimination rate of aqueous humor, which is eliminated from the anterior chamber mainly through the Schlemm's canal. In many cases, this imbalance is considered to be caused by increase in the flow resistance of aqueous humor which does not circulate at the gonio-portion.
Conventionally, glaucoma had been considered to be caused by mechanical optic neuropathy due to increase in ocular tension. However, according to a recent convincing theory, glaucoma is considered to be caused by secretion of aqueous humor in the ciliary body; elimination of aqueous humor from the gonio-trabecule to the Schlemm's canal; or neurovascular disturbance due to autoregulation dysfunction of blood circulation at the optic papilla. Therefore, although increase in ocular tension is the major dysfunction factor, all factors related to embrittlement of the optic papilla or hematogenic disorder at the optic papilla are considered risk factors.
Recently, normal ocular tension glaucoma has become widely known, and ocular tension is not an absolute factor in the diagnosis of glaucoma. However, regardless of whether ocular tension is high or normal, controlling of ocular tension, which is the major risk factor for glaucoma, is most important for the treatment of glaucoma.
Glaucoma is a significant disease, and the number of patients suffering from glaucoma has been increasing year by year in developed countries experiencing aging of their populations. In such societies, the need for glaucoma remedies is expected to increase in the future.
At the present time, &bgr;-blockers, prostaglandin derivatives, and carbonate dehydrogenase inhibitors are known as glaucoma remedies. These drugs are known to exhibit the effect of lowering ocular tension through controlling secretion or elimination of aqueous humor.
Recently, an adenosine derivative which is an adenosine A2 receptor agonist: CGS-21680 [2-((4-(2-carboxyethyl)phenylethyl)amino)adenosine-5′-N-ethyluronamide] has been reported to have the effect of lowering ocular tension (J. Pharmacol. Exp. Ther. 273, 320-326 (1995)). However, this effect is not satisfactory, and there has been much demand for the development of more effective drugs.
DISCLOSURE OF THE INVENTION
In general, since the affinity to an adenosine receptor correlates with the hypotensive effect, an adenosine derivative is considered to exhibit the effect of lowering blood pressure through vasodilation in connection with an adenosine receptor (J. Pharmacol. Exp. Ther. 247, 882-888, 1988 and Eur. J. Pharmacol. 196, 69-76, 1991). For example, CGS-21680 has been reported to have affinity to an adenosine A2 receptor, and to exhibit the effect of lowering blood pressure. Also, 2-octynyladenosine has been reported to have affinity to an adenosine A2 receptor, to exhibit the effect of lowering blood pressure, and to be useful as a hypotensive drug, a preventive drug or a remedy for ischemic heart or brain diseases, and a preventive drug or a remedy for arteriosclerosis (Japanese Patent Publication (kokoku) Nos. 1-33477 and 2-17526, Japanese Patent No. 2774169, and Japanese Patent Application Laid-Open (kokai) No. 3-287537).
In view of the foregoing, the present inventors have anticipated that, similar to CGS-21680, other adenosine derivatives having affinity to an adenosine receptor may exhibit the effect of lowering ocular tension, although such derivatives have not yet been researched on the treatment of eye diseases. The present inventors have performed extensive studies on the relation between the affinity to an adenosine receptor and the effect of lowering ocular tension. Consequently, they have found that, surprisingly, the affinity of the adenosine derivatives to an adenosine receptor is not proportional to the effect of lowering ocular tension; that differences in the physical properties of compounds greatly affect the distribution of absorption; and that affinity to an adenosine receptor cannot serve as the basis for screening compounds with regard to whether or not they have the effect of lowering ocular tension. Therefore, the present inventors have carried out random screening of a variety of adenosine derivatives on the basis of the effect of lowering ocular tension. As a result, they have found that 2-alkynyladenosine derivatives having an acetylene union at the 2-position of the adenine base exhibit an excellent and long-lasting effect of lowering ocular tension, as compared with CGS-21680; and that such derivatives are useful as remedies for eye diseases such as glaucoma and hypertonia oculi. The present invention has been accomplished on the basis of these findings.
Accordingly, the present invention provides a medicinal composition for treating eye diseases, which comprises, as an active ingredient, a 2-alkynyladenosine derivative having an acetylene union at the 2-position of the adenine base.
The present invention also provides use of a 2-alkynyladenosine derivative having an acetylene union at the 2-position of the adenine base for the production of a medicinal composition for treating eye diseases.
The present invention also provides a method for the treatment of eye diseases, which comprises administration of a 2-alkynyladenosine derivative having an acetylene union at the 2-position of the adenine base.
REFERENCES:
patent: 5039797 (1991-08-01), Clack et al.
patent: 5593975 (1997-01-01), Cristalli
patent: 1-146895 (1989-06-01), None
patent: WO93/22328 (1993-11-01), None
T. Abiru, et al., European Journal of Pharmacology, vol. 196, No. 1, pp. 69-76, “The Antihypertensive Effect of 2-Alkynyladenosines and Their Selective Affinity for Adenosine A2Receptors”, 1991.
C. E. Crosson, The Journal of Pharmacology and Experimental Therapeutics, vol. 273, No. 1, pp. 320-326, “Adenosine Receptor Activation Modulates Intraocular Pressure in Rabbits”, 1995.
Abiru Toichi
Endo Kazuki
Hosokawa Tomokazu
Konno Takashi
Misawa Miwa
Bahar Mojdeh
Moezie Minna
Yamasa Corporation
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