JPH10120569A - Preventive and therapeutic agent for eye disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicinal preparation which contains a specific piperazine derivative manifesting dose-dependent protective action for retinal ganglion cell disorder, as an active ingredient and can prevent and treat eye diseases, particularly retinopathy such as diabetic retinopathy, vascular occlusion of retina and glaucoma. SOLUTION: This preparation contains, as an active ingredient, 1,4-(diphenylalkyl)piperazene derivative of formula I (R<1> is a lower alkoxy; R<2> is a lower alkoxy; A is a lower alkylene; B is a lower alkylene) or its salt, typically a compound of formula II. This preparation is orally given in an amount of 1mg-1,000mg/day in one-several portions in usual cases, in the form of ophthalmic solution, a solution of 0.001-3w/v% is given once to several times a day. Thus, the compound of formula I which is useful as a therapeutic agent for cranial nerve dysfunction and immunopathy can be expected to be used for a variety of eye diseases.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to the prevention or treatment of ophthalmic diseases containing a 1,4- (diphenylalkyl) piperazine derivative as an active ingredient, particularly retinal diseases such as diabetic retinopathy or retinal vascular occlusion or glaucoma. It is about useful drugs.

[0002]

2. Description of the Related Art The retina plays an important role in visual function, and retinal nerve cells present in the retina play an important role in information transmission in the eye. When retinal nerve cells are damaged, information transmission is abnormal and various eye diseases are caused. Therefore, protecting retinal nerve cells from damage and maintaining their normal function is important as one of preventive or therapeutic methods for eye diseases.

[0003] Retinal nerve cell damage is caused by a variety of causes, such as diabetes and retinal ischemia. As a result, eye diseases such as diabetic retinopathy, retinal vascular occlusion, and glaucoma are caused (Ophthalmology, 29 , 311-318 (19)
87), Journal of the Nikki Society, 99, 1361-1376 (199)
5)).

[0004] The 1,4- (diphenylalkyl) piperazine derivative, which is an active ingredient of the present invention, has a strong affinity for a sigma receptor, and has cerebral nerve functions such as dementia, depression, schizophrenia, and anxiety. Disorders, disorders associated with immune and endocrine disorders,
It has been reported that it is useful as a therapeutic agent for gastrointestinal ulcers and the like (JP-A-7-89949).

[0005]

The study of the application of 1,4- (diphenylalkyl) piperazine derivatives to eye diseases has not yet been made, and the study of pharmacological effects in the eyes is a very interesting subject. .

[0006]

Means for Solving the Problems The present inventors have made 1,4-
After diligent research to find new pharmacological effects of (diphenylalkyl) piperazine derivatives, 1,4-
It has been found that (diphenylalkyl) piperazine derivatives show a protective effect against retinal neuronal damage in a dose-dependent manner. That is, they have found that 1,4- (diphenylalkyl) piperazine derivatives are useful as agents for preventing or treating eye diseases, particularly retinal diseases such as diabetic retinopathy and retinal vascular occlusion, and glaucoma.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention relates to a preventive or therapeutic agent for eye diseases comprising a compound represented by the following general formula [I] or a salt thereof as an active ingredient.

[0008]

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[Wherein, R ¹ represents a lower alkoxy group.
R ² represents a lower alkoxy group. A represents a lower alkylene group. B represents a lower alkylene group. The groups defined above will be described in more detail. Lower alkoxy refers to lower alkoxy having 1 to 6 carbon atoms such as methoxy group, ethoxy group, propoxy group and butoxy group, and lower alkylene refers to carbon atom such as methylene group, ethylene group, propylene group and butylene group. Represents 1 to 6 lower alkylenes.

Among the above compounds, preferred examples include the following.

In the above general formula [I], A represents 2 carbon atoms
Compounds having from 4 to 4 lower alkylenes and salts thereof.

In the above general formula [I], B is 2 carbon atoms
Compounds having from 4 to 4 lower alkylenes and salts thereof.

Particularly preferred examples include the following.

In the above general formula [I], A is-(CH
_{2) 3} -, B is - (CH _{2) 2} - compounds and salts thereof showing the.

In the above general formula [I], R ¹ and R
Compounds wherein ² represents a methoxy group and salts thereof.

Specific examples of particularly preferred compounds include 1- [2- (3,4-dimethoxyphenyl) ethyl] -4- (3-phenylpropyl) piperazine represented by the following formula [II] or salts thereof. .

[0017]

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The above salts may be pharmaceutically acceptable salts, and include, for example, hydrochloride, sulfate, phosphate, lactate, maleate, fumarate, oxalate and the like. Further, the above compound may be in the form of a hydrate.

The present invention can be widely applied to eye diseases caused by disorders of retinal nerve cells, and is particularly useful for retinal diseases such as diabetic retinopathy or retinal vascular occlusion or glaucoma.

Although retinal nerve cell damage is caused by various causes, a retinal nerve cell damage model induced by administration of glutamate has been reported as an experimental disease model (Invest. Ophthalmol. Vis. Sci. , 36 , 2048-
2053 (1995)). The present inventors examined the protective effect of a 1,4- (diphenylalkyl) piperazine derivative on retinal neuronal damage using this glutamic acid-induced retinal neuronal damage model. The details will be described in the section on pharmacological tests. However, 1,4- (diphenylalkyl) piperazine derivatives show an excellent protective effect on retinal nerve cells, and ocular diseases caused by retinal nerve cell damage, particularly diabetic retinal cells. Has been found to be useful in the prevention or treatment of retinopathy, retinal vascular occlusion or glaucoma.

Examples of the dosage form of the drug include oral preparations such as tablets, capsules and granules, injections, eye drops and the like.
These formulations can be prepared using commonly used techniques. For example, tablets, capsules, oral preparations such as granules, if necessary, lactose, starch, crystalline cellulose,
Extender such as vegetable oil, lubricating agent such as magnesium stearate, talc, binder such as hydroxypropylcellulose, polyvinylpyrrolidone, disintegrant such as calcium carboxymethylcellulose, coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin It can be formulated using a gelatin film agent.
Further, eye drops include isotonic agents such as sodium chloride and concentrated glycerin, buffering agents such as sodium phosphate and sodium acetate, polyoxyethylene sorbitan monooleate (hereinafter referred to as polysorbate 80), and polyoxyl 40 stearate. And a surfactant such as polyoxyethylene hydrogenated castor oil, a stabilizer such as sodium citrate and sodium edetate, and a preservative such as benzalkonium chloride and paraben, if necessary. The pH of the eye drops may be within the range acceptable for ophthalmic preparations, but is preferably in the range of 4 to 8.

The dosage is appropriately selected depending on the condition, age, dosage form and the like.
000 mg may be administered once or in several divided doses. For eye drops, 0.001 to 3% (w / v) may be administered in 1 dose.
It may be applied once to several times a day.

Hereinafter, a pharmacological test will be described as an example.

[0024]

[Pharmacological test] Report by Akaike et al. (Invest. Ophthalmol. Vis.
Sci., 36 , 2048-2053 (1995)), a glutamate-induced rat retinal nerve cell injury model was prepared, and the injury model was used to produce 1,4- (diphenylalkyl) piperazine according to the method described in the above-mentioned literature. The protective effect of the derivative on retinal nerve cells was examined.

(Embodiment 1) Preparation of cultured retinal neurons (1) Confirmed pregnant rats (Wistar / S
Remove the fetus from T).

(2) The eyeball is removed from the obtained fetus.

(3) The retina is removed from the obtained eyeball under a microscope.

(4) The excised retina is cut into small pieces, and cultured as a cell suspension in Eagle MEM medium supplemented with fetal calf serum for one week (the medium is replaced every two days).

(5) On the 6th day from the start of the culture, arabinocytosine (about 10 μM) is added.

(6) After one week, the Eagle MEM medium supplemented with fetal bovine serum is replaced with an Eagle MEM medium supplemented with horse serum, and cultured.

2. Preparation of culture solution Eagle MEM medium powder (9400 mg), sodium bicarbonate (2000 mg), L-glutamine (290 m
g), glucose (1000 mg) and HEPES g
After dissolving wood buffer (2380 mg) in milli-Q water to make 1 liter, bubbling 95% O ₂ + 5% CO ₂ mixed gas for 30 minutes or more, and pH with 1N NaOH.
Is adjusted to 7.2.

The culture solution prepared as described above is referred to as a culture solution A. Culture solution B is prepared by adding a test compound to culture solution A to a concentration of 100 μM. Culture solution C was prepared by adding L-glutamic acid to culture solution A to a concentration of 500 μM. Culture solution A is prepared by adding a test compound (required amount) and L-glutamic acid to culture solution A to a concentration of 500 μM.

3. Effect measurement test (Test compound addition group) After incubating the cultured retinal nerve cells in the culture solution B for 10 minutes at 37 ° C. in a 5% CO ₂ atmosphere, the culture solution B is exchanged for the culture solution D, and a 5% CO ₂ atmosphere Incubated at 37 ° C for 10 minutes. Further, the culture solution D was replaced with the culture solution B, and the mixture was heated at 37 ° C. in a 5% CO ₂ atmosphere.
For 60 minutes. 1. Remove the removed cells
After staining with a 5% trypan blue solution and fixing with a 10% neutral formalin solution, the number of live cells and the number of dead cells were measured under a microscope.

(Control group) Cultured retinal nerve cells were incubated in culture medium A at 37 ° C. for 10 minutes in a 5% CO ₂ atmosphere, and then replaced with a new culture medium A and replaced with 5% CO _2.
Incubated at 37 ° C. for 10 minutes under an atmosphere. Further, this culture solution was replaced with a new culture solution A and incubated at 37 ° C. for 60 minutes in a 5% CO ₂ atmosphere. Then, the number of viable cells and the number of dead cells were measured in the same manner as in the test compound addition group.

(Glutamate-treated group) Cultured retinal nerve cells were incubated in culture medium A at 37 ° C. for 10 minutes in a 5% CO ₂ atmosphere, and then culture medium A was replaced with culture medium C.
Incubation was carried out at 37 ° C. for 10 minutes in a% CO ₂ atmosphere. Further, the culture solution C was exchanged for the culture solution A, and the mixture was incubated at 37 ° C. for 60 minutes in a 5% CO ₂ atmosphere.

4. Results As an example of the test compound, 1- represented by the following formula [III]
[2-3,4- (dimethoxyphenyl) ethyl] -4-
Table 1 shows the results of experiments conducted using (3-phenylpropyl) piperazine dihydrochloride (hereinafter, referred to as compound A).

[0037]

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The survival rate of retinal nerve cells was calculated according to the following equation.

Survival rate (%) = [number of living cells / (number of living cells +
Dead cells)] x 100

[Table 1]

5. Discussion The effect on retinal nerve cells was evaluated using cell viability as an index.

As shown in Table 1, the survival rate of retinal nerve cells was 90.4% in the control group, whereas the survival rate was 41.10% by adding L-glutamic acid and treating for 10 minutes. 3% (glutamic acid treated group), L-glutamic acid causes significant damage to retinal nerve cells. On the other hand, when Compound A was added, the survival rate of retinal nerve cells increased in a dose-dependent manner, reaching 81.5% at a concentration of 100 μM, and clearly inhibited retinal nerve cell damage.

From the above results, it has been clarified that Compound A has excellent protective and therapeutic effects on retinal nerve cell damage induced by glutamate.

[0043]

As described above, the 1,4- (diphenylalkyl) piperazine derivative has an excellent protective and therapeutic effect on retinal nerve cell damage, and is useful for eye diseases, particularly diabetic retinopathy. It was found to be useful as an agent for preventing or treating retinal diseases such as retinal vascular occlusion and glaucoma.

Claims (9)

[Claims] 1. A prophylactic or therapeutic agent for ocular diseases comprising a 1,4- (diphenylalkyl) piperazine derivative represented by the following general formula [I] or a salt thereof as an active ingredient. Embedded image [Wherein, R ¹ represents a lower alkoxy group. R ² represents a lower alkoxy group. A represents a lower alkylene group. B represents a lower alkylene group. ] 2. The preventive or therapeutic agent for ophthalmic diseases according to claim 1, wherein A is lower alkylene having 2 to 4 carbon atoms. 3. The method according to claim 1, wherein B is lower alkylene having 2 to 4 carbon atoms. 4. A is — (CH ₂ ) ₃ — and B is — (CH
₂ ) The agent for preventing or treating eye diseases according to claim 1, which is _2- . 5. The preventive or therapeutic agent for ophthalmic diseases according to claim 1, wherein R ¹ and R ² are methoxy groups. 6. A prophylactic or therapeutic agent for eye diseases comprising a compound represented by the following formula [II] or a salt thereof as an active ingredient: Embedded image 7. The preventive or therapeutic agent for an eye disease according to claim 1, wherein the eye disease is a retinal disease. 8. The preventive or therapeutic agent for an ocular disease according to claim 7, wherein the retinal disease is diabetic retinopathy or retinal vascular occlusion. 9. The preventive or therapeutic agent for an eye disease according to claim 1, wherein the eye disease is glaucoma.