JPH09316002A - Preparation for ophthalmic disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject preparation consisting of a serotonin receptor 1A (5-HT1 A receptor) ligand of a specific structure, having an excellent intraocular tension lowering effect as an active ingredient, and especially useful for a treating agent for high intraocular tension glaucoma, etc. SOLUTION: This preparation for an ophthalmic disease consists of an alkylenedioxybenzene derivative of the formula [(m) is an integer of 2-5; (n) is an integer of 1-3], etc., e.g. 5-[3- (2S)-(1,4-benzodioxan-2-yl-methyl) amino}propoxy]-1,3-benzodioxole hydrochloride as an active ingredient. The compound is a known compound and synthesized by a publicly known process. The amount of administration of the compound is usually 0.05-3mg/kg body weight/day preferably.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an ophthalmic drug, and more particularly to an ophthalmic drug containing a serotonin receptor 1A ligand having a specific structure as an active ingredient, for example, a therapeutic agent for glaucoma and an ocular hypotensive agent. Eye diseases such as glaucoma are becoming more and more socially important as one of the adult diseases particularly in the advanced nations that are facing the aging society.

[0002]

2. Description of the Related Art Ocular diseases such as glaucoma are a group of diseases in which intraocular tissues, particularly optic nerve function, are impaired due to lesions that cause abnormal intraocular pressure. In general, the mechanisms that induce lesions are thought to be mainly caused by ischemic symptoms and optic nerve axon flow disorder due to circulatory disturbance in the optic disc caused by an increase in intraocular pressure. Pharmacotherapy has been attempted and has been successful (for example,
k No. 9, 1979. Treatment of glaucoma, see Kinbara Publishing Co., Ltd.). However, the mechanism of the increase in intraocular pressure is still unknown, and the development of a better therapeutic agent is strongly desired.

On the other hand, serotonin receptor ligands are known to exhibit various pharmacological actions such as vasoconstrictor action, sympathomimetic action, antidepressant action, antihypertensive action, and platelet aggregation inhibitory action. It is used as an anxiolytic agent, an antihypertensive agent, etc. for the treatment of diseases. In addition, among these serotonin receptor ligands, certain alkylenedioxybenzene derivatives are selective ligands for serotonin receptor 1A (hereinafter this may be abbreviated as "5-HT _1A receptor"). Therefore, it is known to have a blood pressure lowering action, an anxiolytic action, etc. (JP-A-57-108088, JP-A-3-264528, and JP-A-4-288).
072).

[0004]

DISCLOSURE OF THE INVENTION The object of the present invention is to provide more excellent drugs for ophthalmic diseases such as therapeutic agents for glaucoma and agents for reducing intraocular pressure.

[0005]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that a serotonin receptor 1A ligand, for example, an alkylenedioxybenzene derivative having a specific structure has excellent intraocular pressure. It has been found that it has a lowering action and can be a therapeutic drug for eye diseases such as glaucoma, and has completed the present invention. That is, the present invention provides a drug for eye diseases which comprises a serotonin receptor 1A (5-HT _1A receptor) ligand as an active ingredient. Furthermore, according to a preferred embodiment of the present invention, the 5-HT _1A receptor ligand has the following formula (I):

[0006]

Embedded image

(In the formula, m is an integer of 2 to 5, and n is 1
Represents an integer of 1 to 3. ), An alkylenedioxybenzene derivative represented by the formula (1), a racemate thereof or an acid addition salt thereof; the above-mentioned drug; wherein the alkylenedioxybenzene derivative is represented by the following formula (II):

[0008]

Embedded image

The above-mentioned drug which is a compound represented by the above formula; the above-mentioned drug wherein said drug for eye diseases is a therapeutic agent for glaucoma; the above-mentioned drug whose drug for eye diseases is an intraocular pressure-lowering agent; The above-mentioned drug which is the above-mentioned drug; the above-mentioned drug whose said drug for eye diseases is an injection;

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the present invention will be described below. The 5-HT _1A receptor ligand used as an active ingredient of the drug for eye diseases of the present invention includes 5-HT
Any compound may be used as long as it is a compound that specifically binds to the _1A receptor and has an action of lowering intraocular pressure. Specifically, for example, Neuropharmac
logic Vol. 26, No. 2/3, pp. 139
-146 (1987), 8-hydroxy-2- (N, N-dipropylamino) -tetralin (hereinafter this may be referred to as "8-OH-DPAT"), 2- (4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl) -1,2-benzisothiazol-3- (2H) one-1,1-dioxide-hydrochloride (hereinafter referred to as “TVX Q 7821”) The alkylenedioxybenzene derivative represented by the formula (I), a racemate thereof, an acid addition salt thereof or an arbitrary hydrate thereof can be mentioned. Among these 5-HT _1A receptor ligands, the compounds represented by the above formula (I), their racemic forms, their acid addition salts or any hydrates thereof are preferable.

In the alkylenedioxybenzene derivative of the above formula (I), m is an integer of 2 to 5, and m is 1 to
Although it shows an integer of 3, a compound in which m represents an integer of 3 or 4 and n represents an integer of 1 to 3 is more preferable, and a compound in which m is 3 and n is 1 is most preferable. preferable. Specific examples of preferred compounds among the compounds used in the present invention are shown in Tables 1 and 2 below.

[0012]

[Table 1]

[0013]

[Table 2]

Examples of the acid in the compound represented by the above formula (I) or its racemic acid addition salt include inorganic acids such as hydrochloric acid, oxalic acid, sulfuric acid, phosphoric acid and nitric acid; acetic acid, succinic acid and adipine. Organic acids such as acids, propionic acid, tartaric acid, fumaric acid, maleic acid, oxalic acid, citric acid, benzoic acid, toluenesulfonic acid and methanesulfonic acid can be mentioned.
Among these, it is preferable to use the hydrochloride salt of the above-mentioned compound. Among the above compounds, the compound No.
1, that is, the compound of the above formula (II) is most preferable, and the hydrochloric acid addition salt of this compound is herein referred to as MKC-24.
Sometimes referred to as 2.

The alkylenedioxybenzene derivative of the general formula (I), the racemate thereof and the acid addition salt thereof used in the present invention are known compounds, for example, JP-A-57-108088. It can be easily synthesized by the method described in Kaihei 4-288072 or a method similar thereto. The drug for eye diseases of the present invention is the above-mentioned 5
It contains an HT _1A receptor ligand as an active ingredient, and can be made into various preparation forms such as an oral preparation, an injection, an eye drop or an ointment by a commonly used method known per se. In the case of oral preparations, they are used in the form of tablets, capsules, powders, solutions, elixirs and the like.
When used in such form, solid or liquid non-toxic pharmaceutical carriers can be included in the composition.

Examples of the solid carrier include cellulose, mannitol, lactose, starch, polyvinylpyrrolidone, starch derivatives such as sodium starch glycolate, and the like.
Sodium lauryl sulfate is used. The active ingredient is filled into gelatin type capsules with or without adjuvants, tableted by tableting or the like, or powder-packed.
These capsules, tablets and powders are generally 5% to 95%,
It preferably contains from 25 to 90% by weight of active ingredient. That is,
5 to 500 m per administration in these administration modes
It may contain g, preferably 25-250 mg of active ingredient. As the liquid carrier, for example, water or petroleum, peanut oil, soybean oil, mineral oil, sesame oil, or other animal or vegetable origin or synthetic oil is used.

In general, physiological saline, dextrose or similar sucrose solution, and glycols such as propylene glycol and polyethylene glycol are preferable as the liquid carrier. Particularly, in the case of an injectable solution using physiological saline, it is usually 0.5. -20%, preferably 1-10% by weight of active ingredient. 0.5 for orally administered drugs
A suspension or syrup containing from 10% by weight of the active ingredient is preferred. In this case, an aqueous excipient such as a flavor, syrup, or a pharmaceutical micelle is used as the carrier. To prepare an eye drop, the following various additives may be appropriately added to a solution of the 5-HT _1A receptor ligand in water.

As the buffer, for example, phosphate buffer, borate buffer, citrate buffer, tartaric acid buffer, acetate buffer, amino acid and the like are used. As the isotonicity agent, for example, saccharides such as sorbitol, glucose and mannitol, polyhydric alcohols such as glycerin and propylene glycol, and salts such as sodium chloride are used. Preservatives include, for example, quaternary ammonium salts such as benzalkonium chloride and benzethonium chloride;
Paraoxybenzoic acid esters such as methyl paraoxybenzoate and ethyl paraoxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid and salts thereof, thimerosal, chlorobutanol and the like are used. As the thickener, for example, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof are used.

The ointment is prepared by evenly mixing the 5-HT _1A receptor ligand with a suitable base such as petrolatum and, if necessary, adding a preservative, a stabilizer, or other suitable additives. To be done. Other forms of the pharmaceutical composition can be prepared by methods well known to those skilled in the art, and the form of the drug which is one aspect of the medicament of the present invention is not limited to the above.

5-H contained in the drug for eye diseases of the present invention
The dose of the T _1A receptor ligand varies depending on the age, body weight, symptom, severity of disease, etc. of the patient, and should be finally determined by the clinician, but generally 0.00
1 to 10.0 mg / kg body weight / day is administered for one day or more. Specifically, when the 5-HT _1A receptor ligand is an alkylenedioxybenzene derivative of the formula (I), the dose is usually preferably 0.05 to 3 mg / kg / body weight / day, and in the case of an oral preparation Contains an alkylenedioxybenzene derivative in an amount of usually 0.5 to 500 mg, preferably 1 to 100 mg to prepare a unit dosage form.
For example, the usual dose is 5 mg, which is usually taken 1 to 3 times a day.
In the case of an injection, the alkylenedioxybenzene derivative is usually contained in an amount of 0.5 to 20%, preferably 1 to 10% by weight to give a unit dosage form, which is, for example, 0.03 to 3
mg / dose, usually 1 to 4 times a day. In the case of eye drops, the concentration of the alkylenedioxybenzene derivative is 0.
Prepare an eye drop that is 1-1% and apply it 1-4 times daily.

The drug for eye diseases of the present invention is the above-mentioned 5-HT.
Based on the intraocular pressure-lowering effect of the _1A receptor ligand, it can be widely applied to diseases in the ophthalmological field. The agent of the present invention containing a 5-HT _1A receptor ligand as an active ingredient is useful for prevention and treatment of eye diseases such as glaucoma and ocular hypertension. In addition, glaucoma includes high-tension glaucoma, and low-tension glaucoma, which exhibits normal intraocular pressure and glaucomatous papillary abnormalities and visual field changes, and the drug of the present invention is effective for both. It is effective for high tension glaucoma.

[0022]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples. However, the following examples should be regarded as helping to obtain a specific recognition of the present invention, and do not limit the scope of the present invention. Production Example 1 5- [3-{(2S)-(1,4-benzodioxane-
2-ylmethyl) amino} propoxy] -1,3-ben
Zodioxole hydrochloride (hydrochloric acid of compound No. 1 in Table 1
Salt; synthesis of MKC-242) 5- (3-aminopropoxy) -1,3-benzodioxole 5.86 g and (2R) -2-tosyloxymethyl-
1,4-Benzodioxane (Journalof Me
dicinal Chemistry, 20 , 880,
3.20 g (synthesized according to 1977) was dissolved in 100 ml of acetonitrile and 2.77 ml of triethylamine was dissolved.
Was added, and the mixture was stirred with heating under reflux for 12 hours. After the reaction was completed, water was added and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The chloroform layer was concentrated and purified by silica gel column chromatography (chloroform-methanol) to give 5- [3-{(2s)
-(1,4-benzodioxan-2-ylmethyl) amino} propoxy] -1,3-benzodioxole 2.
68 g were obtained. This was dissolved in ethyl acetate and 26% hydrochloric acid / isopropanol was added. The generated crystals are collected by filtration,
2.37 g of the title compound was obtained.

Melting point 212-218 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 9.16 (2H,
m), 6.89 (5H, m), 6.63 (1H, d, J
= 2.4 Hz), 6.37 (1H, dd, J = 7.5,
2.5 Hz), 5.95 (2H, s), 4.65 (1
H, m), 4.37 (1H, dd, J = 12.5, 2.
3Hz), 4.02 (3H, m), 3.25 (4H,
m), 2.10 (2H, m). The optically active substance obtained above and a racemate separately synthesized (synthesized according to the method described in JP-A-57-108088) are amidated with (S) -methoxytrifluoromethylphenylacetic acid chloride in pyridine. After that, it was analyzed by high performance liquid chromatography (column: Waters Novapack C18) and the optical purity was determined by the comparison.
e. It was more than e.

Example 1 Eight male Japanese white rabbits having a body weight of about 2 kg were placed in a holding can and acclimated for about 1 hour, and then used in the test. After acclimatization, the initial intraocular pressure was measured, and the left eye of each of the four rabbits was treated with a 0.2% MKC-242 aqueous solution, and the left eye of each of the other four rabbits was treated with 50 parts of distilled water.
μl eye drops were applied. 0.5, 1, 2, 3 and 4 for drug instillation
After a lapse of time, intraocular pressure was measured. The measurement of the intraocular pressure is made by Alcon Corporation, Applanation Pneumaton.
ograph). The same test was carried out 5 days later, and distilled water was used for the rabbits instilled with the 0.2% MKC-242 solution in the first test, and 0. 0 for the rabbits instilled with the distilled water.
50 μl of 2% MKC-242 was instilled in each left eye. Note that MKC-242 was dissolved in distilled water so as to have a concentration of 0.2% using ultrasonic treatment and a test tube mixer.

The results are shown in FIG. As is clear from FIG. 1, a rabbit (contr) instilled with distilled water as a control was used.
ol), the initial intraocular pressure was 20.8 mmHg and the intraocular pressure after 4 hours from instillation was 22.8 mmHg, which increased with time. On the other hand, in the eye instilled with the 0.2% MKC-242 solution, the intraocular pressure dropped from 30 minutes after the instillation, and 1 to 2 hours after the instillation.
Shows a minimum intraocular pressure of 8.0 mmHg, initial intraocular pressure of 20.8 m
2.8 mmHg compared to mHg (1 and 2 hours after instillation), 4.9 m compared to the intraocular pressure of control rabbits
The maximum intraocular pressure lowering effect of mHg (2 hours after instillation) was observed. In addition, a maximum intraocular pressure-lowering effect of 3.9 mmHg (2 hours after instillation) was recognized as compared with the opposite eye (right eye) in which no instillation was performed.

Example 2 Eight male Japanese white rabbits weighing about 3 kg were placed in a holding can and acclimated for about 1 hour before use in the test. After acclimation, the initial intraocular pressure was measured, and 30 rabbits of MKC-242 suspended in 0.5% CMC (carboxymethylcellulose) were used in 4 rabbits.
5 ml / kg body weight, 0.5% CMC for the other 4 rabbits
Was orally administered at 5 ml / kg body weight. Intraocular pressure was measured 0.5 hours after oral administration, 1 hour after 1 hour and every 24 hours. The measurement of intraocular pressure was carried out in Example 1.
In the same manner as described above, MKC-242 is 0.6% (30%
It was suspended in a 0.5% CMC solution by stirring and sonication so that the concentration became 5 mg (5 mg).

The results are shown in FIG. As is clear from FIG. 2, the initial intraocular pressure was 21.9 mmH in the control rabbit orally administered with 0.5% CMC solution.
g, and then fluctuated in the range of 19.8 to 23.0 during the measurement time. In contrast, MKC-242 is 30 mg / kg
In rabbits given orally, intraocular pressure dropped 30 minutes after administration,
A minimum intraocular pressure of 10.5 mmHg was shown 2 hours after administration.
The intraocular pressure gradually increased from 3 hours after administration, but even at 7 hours after administration, the intraocular pressure was maintained at 14.3 mmHg, which was lower than the initial intraocular pressure and control.
Twenty-four hours after administration, it became almost equal to the initial intraocular pressure.

Example 3 A male white rabbit weighing about 2 to 2.5 kg was placed in a retaining can and acclimated for about 1 hour, and then used in the test. After acclimation, the initial intraocular pressure was measured and 1% 8-OH-DPAT was applied to one eye of 5 rabbits.
An aqueous solution (manufactured by Funakoshi Co., Ltd.) was instilled into the opposite eye with 50 μl of distilled water, and the intraocular pressure was measured 0.5, 1, 2 and 3 hours after instillation. The intraocular pressure was measured in the same manner as in Example 1. The results are shown in Fig. 3. As is clear from FIG. 3, 8-OH-DPAT significantly lowered the rabbit intraocular pressure by instillation of 1%.

[Brief description of drawings]

FIG. 1 is a diagram showing the intraocular pressure-lowering effect of MKC-242 by instillation. In the figure, the measurement points and bars are the average value of the intraocular pressure of 8 animals +/− S. E. FIG. , # Indicates a significant difference from the initial intraocular pressure (P <0.01), and * indicates a significant difference from the intraocular pressure of the control group (P <0.01).

FIG. 2 is a diagram showing the intraocular pressure-lowering effect of oral administration of MKC-242. In the figure, the measurement points and bars are the average value of the intraocular pressure of 4 animals +/- S. E. FIG. , # Indicates a significant difference from the initial intraocular pressure (P <0.05), and * indicates a significant difference from the control group (P <0.01).

FIG. 3 is a diagram showing the intraocular pressure-lowering effect of 8-OH-DPAT by instillation. In the figure, the measurement points and bars are the average value of the intraocular pressure of 5 animals +/− S. E. FIG. , And * and ** are significant differences from the initial intraocular pressure (P <0.05 and P <0.01, respectively).
Is shown.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location // C07D 319/20 C07D 319/20 407/12 317 407/12 317 319 319

Claims (8)

[Claims] 1. A drug for eye diseases, which comprises a serotonin receptor 1A ligand as an active ingredient. 2. A serotonin receptor 1A ligand is represented by the following formula (I): (In the formula, m represents an integer of 2 to 5, and n represents an integer of 1 to 3.) An alkylenedioxybenzene derivative, a racemate thereof, or an acid addition salt thereof. The described drug for eye diseases. 3. An alkylenedioxybenzene derivative represented by the following formula (II): The drug for eye diseases according to claim 2, which is a compound represented by: 4. The ophthalmic drug according to claim 1, which is a therapeutic agent for glaucoma. 5. The agent for eye diseases according to claim 1, which is an intraocular pressure-lowering agent. 6. An oral agent according to any one of claims 1 to 5.
The drug for eye diseases according to the item. 7. The method according to claim 1, which is an injection.
The drug for eye diseases according to the item. 8. The eye drop according to claim 1, which is an eye drop.
The drug for eye diseases according to the item.