JP2001240543A - Medicine for treatment and/or prevention of ischemic retinopathy and disease of retina or optic nerve - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine acting on the optic nerve directly to protect it and effective for treatment and/or prevention of ischemic retinopathy and diseases of a retina, optic nerve and the like. SOLUTION: The medicine for the treatment and/or prevention of ischemic retinopaty and the diseases of the retina, optic nerve, and the like contains a compound of a 4-acylaminotetrahydrofuro(2,3-b)quinoline derivative, its salt adduct, these hydrate or solvate as an active component. The preferable quinoline derivative is 2-(2-oxopyrrolidin-1-y1)-N-(2,3-dimethyl-5,6,7,8- tetrahydrofuo[2,3-b]quinolin-4-y1)acetamide.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to ischemic retinal diseases comprising a 4-acylaminotetrahydrofuro [2,3-b] quinoline derivative, an acid addition salt thereof or a hydrate or solvate thereof as an active ingredient, and The present invention relates to a drug for treating and / or preventing retinal and optic nerve disorders.

[0002]

BACKGROUND OF THE INVENTION In the field of ophthalmology, optic nerve protection is of great importance in maintaining vision. In recent years, diabetic retinopathy, glaucoma, and cataract account for most of the causative diseases that cause loss of vision, but there are no effective optic nerve protection / treatment drugs at present. Surgically, visual acuity preservation is measured for these diseases by vascular growth suppression by laser light, intraocular pressure reduction by filtration, vitreous replacement, and the like. As optic nerve protection / therapeutic agents being studied to date, there are compounds that are expected to improve retinal blood flow and to avoid glucose toxicity due to aldose reductase inhibition, but none of them directly protect the optic nerve. No, it is considered that the effect is very low, and none of them has been put to practical use.

By the way, it is known that a 4-acylaminotetrahydrofuro [2,3-b] quinoline derivative improves the reduced high-affinity choline uptake ability (JP-A-3-218361). No use has been previously known for the treatment and / or prevention of ischemic retinal diseases and retinal and optic nerve disorders.

[0004]

Means for Solving the Problems The present inventors have intensively studied to develop a drug effective against ischemic retinal disease, retinal and optic nerve disorders, and the like. As a result, 4-acylaminotetrahydrofuro [2] , 3-b] quinoline derivatives, acid addition salts thereof, or hydrates or solvates thereof, have an action of directly protecting the optic nerve, which has not been seen in optic nerve protection / therapeutic agents hitherto known. It was found for the first time, and the present invention was completed.

That is, the gist of the present invention is as follows:

[0006]

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[Wherein, R ¹ is a C2-C6 alkyl group;

[0008]

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Or the following general formula (III)

[0010]

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(In the above formula, R ⁴ represents a hydrogen atom or a C1 to C6 alkyl group.) R ² and R ³ each independently represent a hydrogen atom or a C1 to C4 alkyl group. . 4-isylaminotetrahydrofuro [2,3-b] quinoline derivative, an acid addition salt thereof or a hydrate or solvate thereof as an active ingredient for ischemic retinal diseases and retinal and optic nerve disorders Therapeutic and / or prophylactic agents.

Further, as a preferred embodiment of the present invention, the ischemic retinal disease is selected from glaucoma, diabetic retinopathy, and retinal artery / vein obstruction. Retinal and optic nerve disorders. In another preferred embodiment of the present invention, the active ingredient is represented by the above general formula, wherein R ¹ is

[0013]

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And 2- (2-oxopyrrolidin-1-yl) -N- (2,3-dimethyl-5,6,7,8-tetrahydrofuro [2,3-b] (Quinolin-4-yl) acetamide, an acid addition salt thereof, or a hydrate or solvate thereof.

[0015]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.

The R ¹ of the 4-acylaminotetrahydrofuro [2,3-b] quinoline derivative used in the present invention includes a C2 to C6 alkyl group, preferably an ethyl group, an n-propyl group, C2 such as isopropyl group, n-butyl group, sec-butyl group and tert-butyl group
To C4 alkyl groups. R ² and R ³ represent a hydrogen atom, a methyl group, an ethyl group, an n-propyl group,
Isopropyl group, n-butyl group, sec-butyl group, t
and C1-C4 alkyl groups such as ert-butyl group. Examples of R ⁴ include a hydrogen atom and a C1-C6 alkyl group. Preferred examples of the alkyl group include a methyl group,
C1 such as ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group and tert-butyl group
To C4 alkyl groups.

The acid in the acid addition salt of the 4-acylaminotetrahydrofuro [2,3-b] quinoline derivative of the above general formula (I) includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphorus Examples include inorganic acids such as acids, and organic acids such as oxalic acid, maleic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, benzoic acid, methanesulfonic acid, and camphorsulfonic acid. The acid addition salt administered is pharmaceutically acceptable.

The 4-acylaminotetrahydrofuro [2,3-b] quinoline derivative of the above formula (I) and its acid addition salt may be present in the form of a hydrate or a solvate. Hydrates and solvates of are also included in the compounds of the present invention.

The method for producing the 4-acylaminotetrahydrofuro [2,3-b] quinoline derivative of the above general formula (I) of the present invention is not particularly limited.
According to the method described in JP 8361, the compound of the present invention can be easily synthesized.

The 4-acylaminotetrahydrofuro [2,3-b] quinoline derivative of the above general formula (I) has an optic nerve protective action as shown in the examples described later. Therefore, the 4-acylaminotetrahydrofuro [2,3-b] quinoline derivative of the above general formula (I) having such an action is used as a therapeutic and / or prophylactic agent for ischemic retinal diseases and retinal and optic nerve disorders. More preferably, it can be used as a therapeutic and / or prophylactic agent for glaucoma, diabetic retinopathy, ischemic retinal diseases such as retinal artery / venous obstruction, and retinal and optic nerve disorders during trauma or surgery.

When the 4-acylaminotetrahydrofuro [2,3-b] quinoline derivative of the above formula (I) is used as a therapeutic or prophylactic agent, it is administered alone or in combination with a pharmaceutically acceptable carrier. Its composition is determined by the solubility, chemical properties, route of administration, dosing regimen, etc., of the compound. For example, it may be orally administered in the form of granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions or liquids, or it may be administered intravenously as an injection. It may be administered internally, intramuscularly, or subcutaneously.

The powder for injection may be used after being adjusted at the time of use. Pharmaceutical organic or inorganic, solid or liquid carriers or diluents suitable for oral, enteral, parenteral or topical administration can be combined with 4-acylaminotetrahydrofuro [2,3-b] of the above general formula (I) It can be used together with a quinoline derivative or the like. As an excipient used for producing a solid preparation, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like are used. Liquid preparations for oral administration, ie emulsions, syrups, suspensions, solutions and the like, contain commonly used inert diluents, such as water or vegetable oils. The formulation may contain, in addition to the inert diluent, auxiliaries such as wetting agents, suspending auxiliaries, sweetening agents, fragrances, coloring agents or preservatives. Liquid preparations may be included in capsules of absorbable substances such as gelatin. Examples of the solvent or suspending agent used for parenteral administration preparations, ie, preparations such as injections, include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like.
The preparation method of the preparation may be according to a conventional method.

In the present invention, it can be administered as an eye perfusion solution, an eye drop, or an infusion.

The eye perfusion solution of the present invention can be produced by dissolving the above compound in sterilized purified water or the like. At this time, pharmaceutically acceptable additives such as a tonicity agent and a buffer can be added as necessary. Specifically, glucose, sodium chloride, potassium chloride, calcium chloride, magnesium sulfate, sodium hydrogen carbonate and the like can be added.

The eye drops of the present invention are aqueous eye drops, non-aqueous eye drops, suspension eye drops, and emulsion eye drops. The production of the ophthalmic solution of the present invention uses sterilized purified water as an aqueous solvent, physiological saline, or the like, or a vegetable oil such as cottonseed oil, soybean oil, sesame oil, peanut oil, or the like as a non-aqueous solvent, and dissolves or suspends the above compound in these. It is done by doing. At this time, pharmaceutically acceptable additives such as isotonicity agents, pH adjusters, thickeners, suspending agents, emulsifiers, and preservatives can be added as necessary. Specific tonicity agents include sodium chloride, boric acid, sodium nitrate, potassium nitrate, D-mannitol, glucose and the like. As a pH regulator,
Examples include boric acid, anhydrous sodium sulfite, hydrochloric acid, citric acid, sodium citrate, acetic acid, potassium acetate, sodium carbonate, borax and the like. Examples of the thickener include methylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, chondroitin sulfate sodium, and polyvinylpyrrolidone. Examples of the suspending agent include polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and polyoxy hydrogenated castor oil. Emulsifiers include egg yolk lecithin, polysorbate 80, and the like, and preservatives include benzalkonium chloride, benzethonium chloride, chlorobutanol, phenylethyl alcohol, and paraoxybenzoates.

The infusion solution of the present invention is an aqueous injection solution or an emulsion injection solution. The production of the infusion solution of the present invention uses distilled water for injection, physiological saline, Ringer's solution and the like as a solvent,
Alternatively, the reaction is carried out by using a small amount of a water-soluble organic solvent such as ethanol or glycerin and dissolving the above compound in the solvent. At this time, a tonicity agent,
Pharmaceutically acceptable additives such as pH adjusters, emulsifiers and preservatives can be added as needed. Specific tonicity agents include sodium chloride, glucose, D-sorbitol, D-mannitol and the like. Examples of the pH regulator include anhydrous sodium sulfite, hydrochloric acid, citric acid, sodium citrate and the like. Emulsifiers include egg yolk lecithin, polysorbate 80 and the like, and preservatives include benzalkonium chloride, benzethonium chloride, and paraoxybenzoates.

The oral dose of the compound of the present invention is generally 1 to 2000 m / day for an adult.
g, preferably 1 to 500 mg,
It is more preferable that the dose be appropriately increased or decreased depending on the disease state and the presence or absence of simultaneous administration. The dose may be administered once a day, divided into two or three times a day at appropriate intervals, or may be administered intermittently. When administered as an injection, the daily dose for an adult is 0.1 to 100 mg, preferably 0.1 to 50 mg. In the case of ophthalmic administration, the concentration of the compound of the present invention in the perfusate when added to the eye drops having a concentration of about 0.1 mg / ml to 6 mg / ml of the above-mentioned compound is 0.01 μg / ml. It may be 〜0.6 mg / ml.

[0028]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples unless it exceeds the gist. In addition, 4 of the above-mentioned general formula (I)
As an acylaminotetrahydrofuro [2,3-b] quinoline derivative, 2- (2-oxopyrrolidin-1-yl) -N- (2,3-dimethyl) was prepared according to the method described in JP-A-3-218361. -5,6,7,8-Tetrahydrofuro [2,3-b] quinolin-4-yl) acedamide was synthesized and used in the following experiments.

Example 1 Inhibitory effect of the compound of the present invention on retinal ganglion cell death by glutamate Method of Otori et al. (Investigative O.)
phthalology & Visual Scie
nce, Vol. 39, no. 6, 1998), retinal ganglion cells were isolated from a 7-day-old Long Evans rat, and were inserted into a 24-well culture plate.
Diameter 12 with L-lysine and laminin coating
The cells were seeded on a 200 mm cover glass so that the number of cells became about 200. These were divided into four groups of 6 holes, 1) no treatment group, 2) control group, 3) 10 ^-5 M compound administration group, and 4) 10 ^-6 M compound administration group, and the following culture solutions were used respectively. 2
Cultured for days.

1) Untreated group-Basic culture solution 2) Control group-Basic culture solution + 25 μM glutamic acid 3) 10 ^-5 M compound administration group-Basic culture solution + 25 μM
Glutamic acid +10 ⁻⁵ M compound of the present invention 4) 10 ⁻⁶ M compound administration group-basic culture solution +25 μM
Glutamic acid +10 ^-6 M compound of the present invention The basic culture solution was Neurobasal (Gi
A culture solution obtained by adding 1 mM glutamine, 10 μg / ml gentamicin, 40 ng / ml BDGF, CNTF and bovine FGF to Bco was used.

After culturing them for 2 days, they were stained with 1 μM calcein-acetoxymethyl ester and, under a fluorescence microscope, aneurites having a length twice or more the cell diameter were obtained.
FIG. 1 shows the results of counting the number of cells, with the cells extending tes) as viable cells. FIG. 1 shows the percentage of the number of surviving cells in each group relative to the number of surviving cells in the untreated group. The values are the mean (%) of each group, the bar is the standard error, and * is the significant difference from the control group (p < 0.05). The number of cases used in the experiment was 6 in each group.

The results in FIG. 1 show that the compound of the present invention has a dose-dependent inhibitory effect on retinal ganglion cell death caused by glutamate.

Example 2 Inhibitory effect of the compound of the present invention on retinal degeneration in ocular hypertension-treated eyes A male Wister rat weighing about 200 g was subjected to a sufficient heat preservation treatment using a heat preservation plate under anesthesia. To fix the head. According to the method of Akaike (Journal of the Pharmacological Society of Japan 111: 97-104, 1998), an intraocular perfusion solution was obtained from a bottle held at a height of 174 cm above the eyeball using an infusion tube and a 30G injection needle. Intraocular injection into the anterior chamber results in an intraocular pressure of 13
It was kept at 0 mmHg for 60 minutes (high intraocular pressure treatment). A normal group, a control group, and a compound group of the present invention were provided, and the right eye of the control group and the compound group of the present invention were subjected to ocular hypertension treatment, and both eyes of the control group, the left eye of the compound group of the present invention, and the normal group were untreated And The compound of the present invention was orally administered at a dose of 10 mg / 5 ml / kg 30 minutes before and 3 hours after the treatment with the compound of the present invention. The control group was orally administered 5 ml / kg of the base at the same administration time. One week after the treatment, the animals were sacrificed under anesthesia, the eyes were enucleated, and light microscope specimens were prepared for horizontal sections of the retina. Under a microscope, the thickness of the retina (the total thickness of the inner plexiform layer, the outer plexiform layer, and the outer granular layer) was measured using a micrometer.
The results are shown in FIGS.

FIG. 2 shows the retinal thickness (total thickness of the inner plexiform layer, the outer plexiform layer and the outer granular layer) after the treatment for ocular hypertension. The values are the average value (μm) of each group, and the bar is the standard value. Error, * indicates a significant difference from the control group (p <0.05). The number of cases used in the experiment was 10 in the normal group, and 11 in the control group and the compound-administered group.

FIG. 3 is a graph showing the relationship between the retinal thickness (the total thickness of the inner plexiform layer, the outer plexiform layer, and the outer granular layer) of the untreated eye (left eye) for each individual after the ocular hypertension treatment. The percentage of the retinal thickness of the (right eye) is shown, the value is the average value (μm) of each group, the bar is the standard error, and * is the significant difference from the control group (p <0.05).
The number of cases used in the experiment is 11 cases.

From the results shown in FIGS. 2 and 3, the compound of the present invention is:
It can be seen that it has an inhibitory effect on retinal degeneration in eyes treated with high intraocular pressure.

[0037]

EFFECT OF THE INVENTION Since the 4-acylaminotetrahydrofuro [2,3-b] quinoline derivative of the present invention has an effect of directly protecting the optic nerve, it is used for the treatment and / or treatment of ischemic retinal diseases and retinal and optic nerve disorders. Very useful as a prophylactic.

[Brief description of the drawings]

FIG. 1 is a drawing showing the inhibitory effect of the compound of the present invention on retinal ganglion cell death by glutamate.

FIG. 2 is a graph showing the inhibitory effect of the compound of the present invention on retinal degeneration in eyes treated with high intraocular pressure.

FIG. 3 is a graph showing the inhibitory effect of the compound of the present invention on retinal degeneration in eyes treated with high intraocular pressure.

Claims (5)

[Claims] 1. A compound of the general formula (I) [In the above general formula, R ¹ is a C2 to C6 alkyl group, the following general formula (II): Or the following general formula (III): (In the above general formula, R ⁴ represents a hydrogen atom or a C1 to C6 alkyl group.), And R ² and R ³ each independently represent a hydrogen atom or a C1 to C4 alkyl group. 4-isylaminotetrahydrofuro [2,3-b] quinoline derivative, an acid addition salt thereof or a hydrate or solvate thereof as an active ingredient for ischemic retinal diseases and retinal and optic nerve disorders A therapeutic and / or prophylactic agent. 2. The therapeutic and / or prophylactic agent according to claim 1, wherein the ischemic retinal disease is selected from glaucoma, diabetic retinopathy, and retinal artery / vein obstruction. 3. The retinal and optic neuropathy according to claim 1, wherein the retinal and optic neuropathy are trauma or operative retinal and optic neuropathy.
The therapeutic and / or prophylactic agent according to the above. 4. An active ingredient wherein R ¹ in the general formula (I) is The therapeutic and / or prophylactic agent according to any one of claims 1 to 3, which is a compound of the formula: 5. The method according to claim 1, wherein the active ingredient is 2- (2-oxopyrrolidine-).
1-yl) -N- (2,3-dimethyl-5,6,7,8
5. Tetrahydrofuro [2,3-b] quinolin-4-yl) acetamide, an acid addition salt thereof or a hydrate or solvate thereof. A therapeutic and / or prophylactic agent.