WO2001058487A1 - Therapeutic and/or preventive agents for optic nerve diseases and retinal diseases - Google Patents

Abstract

Therapeutic and/or preventive agents for optic nerve diseases or retinal diseases, containing serotonin receptor ligands as the active ingredient. The serotonin receptor ligands include aminoalkoxy- bibenzyls of the general formula (1), salts of the same, and hydrates and solvates of both: wherein R?1, R2 and R3¿ are each hydrogen or the like; and R4 is -N(R5)(R6) (wherein R?5 and R6¿ are each independently hydrogen or the like).

Description

 Specification

 Treatment and prevention of optic nerve disease and retinal disease

 TECHNICAL FIELD The present invention relates to a therapeutic and / or prophylactic agent for optic nerve disease and retinal disease comprising a serotonin receptor ligand as an active ingredient.

 Regarding neuronal cell death and neuroprotection in ophthalmology, recent research has revealed that apoptosis-induced neuronal cell death occurs in many retinal and optic nerve diseases. To date, it has been clarified that apoptosis plays a large role in many optic nerve diseases such as retinochoroidal degeneration, retinal detachment due to retinal detachment, retinal circulation disorder, and glaucoma.

 At the same time, most treatments for glaucoma at present include reducing the intraocular pressure, the largest risk factor, with pharmacotherapy or surgery. Although its effectiveness has been proven in many studies, there are many cases where intraocular pressure cannot be sufficiently reduced, and there are also cases where intraocular pressure reduction is ineffective. In other words, the existence of glaucoma independent of intraocular pressure (normal tension glaucoma) has become clear. In the long run, there is a danger of blindness with a considerable probability of treatment. Against this background, in the treatment of glaucoma, it is desired to establish a treatment strategy that emphasizes not only the effect of lowering intraocular pressure but also direct optic nerve protection from the viewpoint of improving blood flow and suppressing cell death. Exp. Eye Res. 69, 331-342 1999 etc.).

On the other hand, aminoalkoxybibenzyls or salts thereof, or hydrates or solvates thereof, are disclosed in Japanese Patent Publication No. 8 — 3 2 8 4 7 US Nos. 4,595,419, U.S. Pat.No. 4,485,258 and European Patent Publication No. and this has the effect of enhancing the coagulation and prostaglandin I ₂ action are described. In addition, the fact that they are effective as vasoconstriction inhibitors based on serotonin antagonism has been disclosed in Japanese Patent Application Laid-Open No. Hei 2 (1994) -304022, US Pat. It is described in Japanese Patent Application Publication No. 3983226. Further, regarding ophthalmic application of these compounds, the fact that these compounds have an intraocular pressure lowering effect and are therefore effective for treating glaucoma is disclosed in JP-A-8-20531. And U.S. Pat. No. 5,658,950 and European Patent Application Publication No. 6,955,455. The fact that these compounds have a lacrimal secretion promoting action is disclosed in Japanese Patent Application Laid-Open No. H10-67684, US Pat. No. 5,925,677 and European Patent Application Publication No. 8 It is described in each of the publications No. 1 378 78. However, there is no disclosure that these compounds are effective for optic nerve disease and retinal disease. Disclosure of the invention

Since optic nerve disease and retinal disease both show severe visual impairment and there is no appropriate treatment, there is a need for a good therapeutic agent. The present invention aims to provide a new therapeutic and / or prophylactic agent for optic nerve disease and retinal disease.The present inventors have further studied the mechanism of apoptosis of retinal nerve cells, We thought that the development of a therapeutic method (neuroprotection therapy) that would suppress cell death would improve the therapeutic results of these intractable diseases, and we worked diligently to solve the above-mentioned problems. As a result, the above-mentioned aminoalkoxybibenzyls or salts thereof, or hydrates or solutions thereof, are obtained. Serotonin receptor ligands, such as solvates, have a protective effect on retinal ganglion cells and an inhibitory effect on retinal degeneration, and are useful for the treatment and Z or prevention of optic nerve diseases and retinal diseases. They have found that they are useful, and have completed the present invention.

 That is, the gist of the present invention is a therapeutic and / or prophylactic agent for normotensive glaucoma containing a serotonin receptor ligand as an active ingredient, and an optic nerve disease containing a serotonin receptor ligand as an active ingredient. And a therapeutic and / or prophylactic agent for a disease selected from retinal diseases.

 In another aspect of the present invention, there is provided a method for treating and / or preventing normal tension glaucoma using a serotonin receptor ligand; an optic nerve disease or a nervous system disease using a serotonin receptor ligand. A method for treating and preventing or preventing a retinal disease; a retinal ganglion cell death inhibitor containing a serotonin receptor ligand as an active ingredient; a retinal ganglion containing a serotonin receptor ligand as an active ingredient Cytoprotective agent; method of inhibiting retinal ganglion cell death using serotonin receptor ligand; method of protecting retinal ganglion cell using serotonin receptor ligand; serotonin receptor And a method for inhibiting retinal degeneration using a serotonin receptor ligand as an active ingredient. In a preferred embodiment, the retinal degeneration is retinal degeneration caused by retinal ischemia.

In a preferred embodiment of the present invention, the serotonin receptor ligand is a serotonin receptor type 2 ligand; the serotonin receptor ligand is a serotonin receptor. The receptor gonist of receptor type 2; the receptor gonist of serotonin receptor type 2 has the following general formula (1)

[In the above formula, R ¹ represents a hydrogen atom, a halogen atom, a C 1 -C 5 alkoxy group or a C 2 -C 6 dialkylamino group, and R ² represents a hydrogen atom, an octogen atom or a C l- R ³ represents a hydrogen atom, a hydroxyl group, —O— (CH 2) n -COOH (wherein n represents an integer of 1 to 5), or C 5 represents an alkoxy group of C 5; One O — CO — (CH 2) 1 — COOH (where 1 represents an integer from;! To 3), and R ⁴ represents one

^{N (R 5) (R 6} ) ( wherein, R ⁵ and R ⁶ each independently represent a hydrogen atom or an alkyl group of C 1 ~ C 8.) Or other one NA

(In the formula, A represents a C3-C5 alkylene group which may be substituted with a carbonyl group.) And m represents an integer of 0-5. ]

An aminoalkoxybibenzyl or a salt thereof, or a hydrate or solvate thereof represented by the following formula: , The following formula

で表されるアミ ノ アルコキシビベンジル類も しく はその塩、 またはそれらの水和物も しく はそれらの溶媒和物である こ と が挙げられ、 上記式 （ 2 ) で表される化合物のう ち、 塩酸塩 である こ とがさ らに好ま しい態様と して挙げられる。 また、 セロ トニン受容体タイ プ 2 のアン夕ゴニス 卜が、 下記式 （ 3 ) (2) (2)

Or a salt thereof, or a hydrate or solvate thereof, and a compound represented by the above formula (2). That is, a more preferred embodiment is a hydrochloride. In addition, the serotonin receptor type 2 angel gonist is represented by the following formula (3)

An aminoalkoxybibenzyl or a salt thereof, or a hydrate or a solvate thereof represented by the following formula: the optic nerve disease is an inflammatory disease or a disease caused by circulatory disorders; Optic nerve compression, optic nerve disorders, optic nerve toxic diseases, optic nerve disorders, and diseases selected from normal tension glaucoma. Preferred examples thereof include optic nerve diseases, ischemic optic neuropathy and normal. A more preferred embodiment is selected from tension glaucoma. The retinal disease is selected from diabetic retinopathy, retinal circulation disorder, retinal disorder, macular disease, retinal degenerative disease, retinal detachment and retinal damage caused by toxic drugs to the retina. More preferably, the retinal disease is a disease selected from diabetic retinopathy, retinal vein occlusion and retinal artery occlusion. It is mentioned. Furthermore, a preferred embodiment of the above-mentioned therapeutic and / or Z-prophylactic agent of the present invention is any one of an oral preparation, an injection, an eye drop and an ointment. BRIEF DESCRIPTION OF THE FIGURES

 FIG. 1 is a diagram showing the results of the inhibitory effect on retinal ganglion cell death by MCI-9042 (described later) in Example 1; FIG. The percentage of the number of surviving cells in the group is shown. Values represent the mean (%) of each group, and bars represent standard errors. The number of cases was 5 in each group, and * indicates a significant difference (p 0.01) from the control group.

 FIG. 2 is a diagram showing the results of the inhibitory effect on retinal ganglion cell death by M-1 (described later) in Example 1. The figure shows the percentage of the number of surviving cells in each group to the number of surviving cells in the untreated group. The value indicates the average value (%) of each group, and the bar indicates the standard error. The number of cases was 3 in each group, and * indicates a significant difference (p-0.01) from the control group.

FIG. 3 is a graph showing the results of Example 2 on the inhibitory effect on retinal degeneration by MCI-9042 (described later). The figure shows the ratio of the retinal thickness between the untreated eye and the hypertensive eye after 7 days of hypertensive treatment (retinal thickness of the hypertensive eye Z and retinal thickness of the untreated eye This indicates the thickness from the reticular layer to the outer granular layer). The values indicate the mean (%) of each group, and the bar indicates the standard error. The number of cases was 10 in each case, and * indicates a significant difference (p 0.01) from the control group. BEST MODE FOR CARRYING OUT THE INVENTION

 To explain the present invention in detail, extensive research has been carried out on serotonin receptors, and one of the results is that serotonin receptor ligands have various physiological effects. (PHARMACOLOGICALREVIEW S, Vol. 44 (3), 401). However, it has not yet been reported that the serotonin receptor ligand has an inhibitory effect on retinal ganglion cell death and an inhibitory effect on retinal degeneration as shown in the present invention, as far as the present inventors know. It has been found for the first time by the present inventors.

Serotonin receptors are classified into several types, and a number of ligands are known for each type of receptor. In the present invention, any of these ligands can be used, and among them, the receptor type 2 ligand is preferably used. An example of some of these ligands is the agonist 1 — (2, 5 — dimethoxy 4 — bromophenenyl) 1 2 — aminopropane (DOB), 1 1 (2, 5 —Dimethoxyl 4-diphenyl) 2 —Aminopropane (D〇I), N- (3—Trifluoromethylphenyl) Piperazine (YFMPP) Chloropromazine, ritanserin, ritanserin, ketanserin, cinanserin, butacramorille (butac 1 amo 1), meteregorin (metergo 1 ine), etc. (PHARMACOLOGICALREVIEW S, Vol. 44 (3), 401). Among the above, preferred are amino alkoxybibenzyls, which are serotonin receptor type 2 antagonists, represented by the following formula (1), or salts thereof. Or a solvate thereof (in the present specification, the salt has a broad meaning including an ester).

(1)

Wherein R ¹ represents a hydrogen atom, a halogen atom, a C 1 -C 5 alkoxy group or a C 2 -C 6 dialkylamino group, and R ² represents a hydrogen atom, a halogen atom or a C 1 -C 5 represents an alkoxy group, R ³ represents a hydrogen atom, a hydroxyl group, —O— (CH 2) n —COOH (wherein, n represents an integer of 1 to 5), or —CO— (CH 2) 1 represents one COOH (where 1 represents an integer of 1 to 3), and R represents — N (R ⁵ ) (R ⁶ ) (where R ⁵ and R ⁶ represent Each independently represents a hydrogen atom or a C 1 -C 8 alkyl group.) Or one NA (where A represents a C 3 -C 5 alkylene group which may be substituted by a carbonyl group) ) And m represents an integer of 0 to 5. ]

As described above, the compound represented by the above general formula (1) is used as a serotonin antagonist in various forms based on thrombus formation and vasoconstriction in diseases such as cerebral circulatory disorder, ischemic heart disease and peripheral circulatory disorder. It is known to be effective in improving microcirculatory disorders, and is also known to be effective in treating glaucoma and lowering intraocular pressure. However, when this compound is used in retinal ganglion cells as shown in the examples below. It is completely unexpected that it has an inhibitory action on vesicle death and an inhibitory action on retinal degeneration.

More specifically, the compound represented by the above general formula (1) is as follows: In the formula, R ¹ is a hydrogen atom; a halogen atom such as a chlorine atom or an iodine atom; a methoxy group, an ethoxy group, or a butoxy group. And a C 1 -C 5 alkoxy group; a C 2 -C 6 dialkylamino group such as a dimethylamino group, a getylamino group, a methylethylamino group and the like.

R ² represents a hydrogen atom; a halogen atom as described above; and a C 1 to C 5 alkoxy group as described above.

R ³ is a hydrogen atom; a hydroxyl group; one 0 _ (CH 2) 2 —COOH, one O — (CH 2) 3 — COOH, etc. one 0 _ (CH 2) n -CO 0 H (wherein, n represents an integer of 1 to 5.); — O — CO — (CH 2) 2 -COOH, — O — CO — (CH 2) 3 — COOH, etc. — O — CO — (CH 2) 1- COOH (wherein, 1 represents an integer of 1 to 3).

R ⁴ is a C 1 -C 1 group such as an amino group or a methylamino group, an ethylamino group, a butylamino group, a hexylamino group, a heptylamino group, a dimethylamino group, a getylamino group, a methylethylamino group, etc. Represents an amino group having 1 to 2 alkyl groups of 8 or a ring such as a trimethyleneamino group, a pentamethyleneamino group, or a 3-hydroxylopentamethyleneamino group.

Represents a 4- to 6-membered polymethyleneamino group which may be substituted by a poxyl group.

一 1 (つづさ） Table 11 shows some of the compounds represented by the general formula (1), which are preferred for use in the present invention.

One 1 (continued)

これらのなかでも、 アミ ノ アルコキシ基ー O C H 2 C ( R 3 ) H — ( C H 2 ) m — R がフエニル基の 2 —位に結合 しているのが好ま しい。 また、 R ¹ は水素原子、 C 1 〜 C 5 のアルコキシ基、 又は C 2 〜 C 6 のジアルキルアミ ノ 基 が好ま し く 、 R ² は水素原子が好ま し く 、 R ⁴ は少な く と も 1 個の C 1 〜 C 8 のアルキル基を有するアミ ノ基または ト リ メチレン基ないしはペンタメチレン基を有する 4 〜 6 員 のポリ メチレンアミ ノ基であるのが好ま し く 、 mは 0 〜 2 の 整数である のが好ま しい。 特に好ま しいのは、 R ¹ がメ ト キシ基であ り 、 R ² が水素原子であ り 、 R ³ が水酸基であ り 、 R ⁴ がジメチルァミ ノ基である N o . 1 5 の化合物 （本 発明においては、 これを 「 M— 1 」 という こ と もある） 及び そのコハク酸エステルである N O . 1 4 の化合物である。

Among these, it is preferable that the aminoalkoxy group-OCH2C (R3) H- (CH2) m-R be bonded to the 2-position of the phenyl group. R ¹ is preferably a hydrogen atom, a C 1 -C 5 alkoxy group or a C 2 -C 6 dialkylamino group, R ² is preferably a hydrogen atom, and R ⁴ is at least It is preferably an amino group having one C 1 -C 8 alkyl group or a 4- to 6-membered polymethylene amino group having a trimethylene group or a pentamethylene group, and m is 0 to 2. Preferably it is an integer. Particularly preferred is a compound of No. 15 wherein R ¹ is a methoxy group, R ² is a hydrogen atom, R ³ is a hydroxyl group, and R ⁴ is a dimethylamino group ( In the present invention, this is sometimes referred to as “M-1”), and the succinic ester NO.14 compound.

In the present invention, a pharmaceutically acceptable salt of the compound represented by the above general formula (1) can also be used. Acids that form such salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, succinic acid, adipic acid, propionic acid, Tartaric acid, maleic acid, oxalic acid, citric acid, benzoic acid, toluenesulfonic acid, methanesulfonic acid and the like are used. Further, a solvate or hydrate of the compound represented by the general formula (1) or a salt thereof can also be used. Of these, particularly preferred is (Sat) 1-11 [0— [2— (m-methoxyphenyl) ethyl] phenoxy] 13— (dimethylami) represented by the following formula (4). No.) —2-Hydrochloride of propyl hydrogen succinate (this may be referred to as “MCI—9042” in the present invention).

本発明で用いる一般式 （ 1 ) のアミ ノ アルコキシビベンジ ル類は前述の如く 公知化合物であ り 、 特開昭 5 8 — 3 2 8 4 7号、 特開昭 5 8 — 3 2 8 4 7 号、 米国特許第 4 5 9 9 4 1 9号、 米国特許第 4 4 8 5 2 5 8 号及び欧州特許出願公開第 7 2 9 4 2号各号公報に記載の方法またはそれに準じた方法 によ り 、 容易に合成できる。

The aminoalkoxybibenzyls of the general formula (1) used in the present invention are known compounds as described above, and are disclosed in JP-A-58-32847 and JP-A-58-32884. No. 7, U.S. Pat.No. 4,599,419, U.S. Pat.No. 4,485,258 and European Patent Application Publication No. 729442, or a method analogous thereto Thus, it can be easily synthesized.

In the present invention, optic nerve diseases include, for example, inflammatory diseases such as optic neuritis, diseases due to circulatory disorders such as ischemic optic neuropathy, optic nerve compression due to surgery, trauma and tumors, optic nerve disorders such as edema, It indicates toxic diseases of the optic nerve caused by ethanol or alcohol, optic nerve damage in refractive surgery, normotensive glaucoma, etc. In the present invention, the ischemic optic nerve It is preferable to use it for normal tension glaucoma, especially for normal tension glaucoma.

 Also, retinal diseases include, for example, retinal circulation disorders due to diabetic retinopathy, retinal vein occlusion and retinal artery occlusion, retinal disorders due to surgery or trauma, and retinal disorders caused by viruses, bacteria, fungi, etc. Disorders, macular diseases such as age-related macular degeneration, retinal degenerative diseases such as retinitis pigmentosa, retinal detachment, retinal disorders caused by toxic drugs to the retina such as phenothiazine, etc. . In the present invention, it is preferably used for a disease selected from diabetic retinopathy, retinal vein occlusion and retinal artery occlusion.

 The therapeutic and / or Z- or prophylactic agent for optic nerve disease and retinal disease according to the present invention can be administered, for example, as an oral preparation, injection, eye drop or ointment. In the case of oral preparations, they are used in the form of tablets, capsules, pills, granules, fine granules, powders, solutions, elixirs and the like. When used in such form, solid or liquid non-toxic pharmaceutical carriers can be included in the composition.

 As an example of the solid carrier, a normal gelatin type capsule is used. The active ingredient is tabletted or packaged with or without adjuvants.

 These tablets, capsules, pills, granules, fine granules and powders generally contain from 5 to 95%, preferably from 10 to 90% by weight of active ingredient.

 Thus, these dosage forms may contain from 5 to 500 mg, preferably from 25 to 25 mg of active ingredient per dose.

As a liquid carrier, water or petroleum oil, peanut oil, soybean oil, mineral oil, sesame oil, or other animal or plant derived or synthetic oil is used. Yes.

 In general, saline, dextroses or similar sucrose solutions, and darcols such as propylene glycol and polyethylene glycol are preferred as liquid carriers, particularly in the case of injections using physiological saline. The active ingredient usually contains 0.5 to 20%, preferably 1 to 10% by weight of active ingredient. '' For oral solutions, a suspension or syrup containing 0.5 to 10% by weight of active ingredient is preferred. As a carrier in this case, an aqueous excipient such as a flavor, syrup, or pharmaceutical micelle is used.

 For the preparation of eye drops, for example, the following various additives may be appropriately added to a solution of the aminoalkoxybibenzyl represented by the general formula (1) in water.

 As the buffer, for example, a phosphate buffer, a borate buffer, a citrate buffer, a tartrate buffer, an acetate buffer, an amino acid and the like are used.

 Examples of the tonicity agent include sugars such as sorbitol, glucose, and mannitol; polyhydric alcohols such as glycerin and propylene glycol; and salts such as sodium chloride. .

 Examples of the preservatives include quaternary ammonium salts such as benzalkonium chloride and benzenetonium chloride, paraoxybenzoic acid esters such as methyl paraoxybenzoate and ethyl parahydroxybenzoate, benzyl alcohol, phenethyl alcohol, and the like. Sorbic acid and salts thereof, thimerosal, chlorobutanol and the like are used.

Examples of the thickener include hydroxyshethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, and carboxymethyl cellulose. And their salts and the like.

 The ointment is prepared, for example, by uniformly mixing the aminoalkoxybibenzyl represented by the above general formula (1) with a suitable base such as cellulose, and, if necessary, a preservative or stabilizer. Or other suitable additives.

 The dosage of the aminoalkoxybibenzyls of the above general formula (1) which can be contained in the preparation of the present invention varies depending on the age, weight, symptoms, severity of the disease, etc. of the patient, and ultimately depends on the clinical condition. It should be determined by a physician. Generally, it is 0.5 to 5 Omg / kg body weight / day, usually l to 30 mg / kg body weight / day, and is administered for one or more days. In the case of a drug, 50 mg or 100 mg of aminoalkoxybibenzyls are added to make a unit dosage form, which is usually taken as 100 mg at a time and usually taken 1 to 3 times a day. . In the case of injections, aminoalkoxybibenzyls are usually administered 10 to 3 OmgZ times 1 to 4 times a day. In the case of eye drops, prepare an eye drop with a concentration of aminoalkoxybibenzyls of 0.1 to 1% and apply it 1 to 4 times a day. Although these examples have been described using the aminoalkoxybibenzyls represented by the general formula (1) as an active ingredient, the same applies when other active ingredients are used. For reference, it is possible to appropriately determine the age, weight, symptoms, severity of the disease, and the like of the patient. Example

Hereinafter, the present invention will be described in more detail by way of Examples, but these are not intended to limit the scope of the present invention. MCI-9042 and M-1 used below were synthesized according to the description in JP-A-58-32847. <Example 1>

Inhibitory effect of daltamate on retinal ganglion cell death

 According to the method of Otori et al. (Investigative Ophthalmology Visual Science, Vol. 39, No. 6, 1998), retinal ganglion cells were isolated from a 6-day-old wister-type rat and cultured in 24 wells. Oly-L-lysine and laminin coated in a plate were inoculated on a 12 mm-diameter cover glass so as to have about 200 cells, and cultured for 24 hours. These were divided into 2 wells each, untreated group, control group, and drug group. The untreated and control groups contained the basic culture solution, and the drug group contained various concentrations of MCI-9042 or M-1. After 4 hours of incubation, 25 M glutamate was added to all groups except the untreated group, and further cultured for 48 hours. After culturing for 48 hours, the cells were stained with 1 tM calcein-acetooxymetyl ester, and the number of cells was counted under a fluorescence microscope, with the cells growing neurites having a length of at least twice the cell diameter as viable cells. The test was performed on three to five cases, with the average value of the two holes being one case.

Drug ^{group: 10- 6 M, 10- 7 M} , 10- 8 M MCI- 9042 (n = 5)

^{10- 7 M, 1 (T 8} M, 1 (T 9 M, 10- 10 M M- 1 (n = 3) Basic culture: Neurobasal (Gibco, Grand Island, NY) in ImM glutanine, 10 ng / ml Medium containing gentamic in, 40ng / ml BDGF, CNTF and b-FGF

 As a result, as shown in FIGS. 1 and 2, MCI-9042 and M-1 significantly suppressed retinal ganglion cell death induced by glutamate. Example 2>

Inhibitory effects on retinal degeneration in transient ischemic eyes

A male Wistar rat weighing approximately 200 g was used. Under anesthesia, perform a sufficient warming treatment using a warming plate. To fix the head. According to Akaike's method (Japanese Pharmacological Journal, Vol. 111, pp. 97-104, 1998), the intraocular site was infused with an infusion tube and a 30G injection needle from a bottle held at a height of 174 cm above the eyeball. By injecting the perfusate transcorneally into the anterior chamber, the intraocular pressure was maintained at 130 mmHg for 50 minutes (high intraocular pressure treatment), and transient retinal ischemia was induced. Ocular hypertension was applied only to the right eye, and the left eye was left untreated. At 30 minutes before and 30 minutes after the intraocular pressure treatment, physiological saline, 3 mg / kg dose or 30 mg / kg dose of MCI-9042 was intraperitoneally injected. (7) Seven days after intraocular pressure treatment, the animals were sacrificed by 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 thickness from the inner plexiform layer to the outer granular layer) was measured using a micrometer.

 As a result, as shown in Fig. 3, MCI-9042 significantly reduced the retinal degeneration induced by transient retinal ischemia, and had industrial applicability.

 The therapeutic and / or prophylactic agent for optic nerve disease and retinal disease of the present invention is effective as evident from its inhibitory action on retinal degeneration induced by transient retinal ischemia and its protective effect on retinal ganglion cells. It has a therapeutic and / or preventive effect on various optic and retinal diseases. In addition, this application was filed by claiming the priority of Japanese Patent Application No. 2000-0-31543.

Claims

The scope of the claims 1. A therapeutic and / or prophylactic agent for normotensive glaucoma comprising a serotonin receptor ligand as an active ingredient. 2. The therapeutic and / or prophylactic agent according to claim 1, wherein the serotonin receptor ligand is a serotonin receptor type 2 ligand. 3. The therapeutic and / or Z- or prophylactic agent according to claim 1, wherein the serotonin receptor ligand is a serotonin receptor type 2 agonite. 4. Angiogonists of serotonin receptor type 2 have the following general formula (1)

[In the above formula, R ¹ represents a hydrogen atom, a hydrogen atom, a halogen atom, a C 1 -C 5 alkoxy group or a C 2 -C 6 dialkylamino group, and R ² represents a hydrogen atom, a halogen atom or a C alkoxy groups of l ~ C 5 to Table Wa, R ³ is a hydrogen atom, human de Rokishiru group one O- (CH 2) n - COOH , ( wherein, n represents an integer of 1-5.) Or one 0— CO— (CH 2) 1 one COOH Wherein 1 represents an integer of 1 to 3. R ⁴ represents —N (R ⁵ ) (R ⁶ ) (where R ⁵ and R ⁶ are each independently a hydrogen atom or C 1 ~ Represents an alkyl group of C8.) Or one NA (In the formula, A represents a C3-C5 alkylene group which may be substituted with a carbonyl group.) And m represents an integer of 0-5. ] 4. The therapeutic and / or preventive agent according to claim 3, which is an aminoalkoxybibenzyl represented by the formula: or a salt thereof, or a hydrate or solvate thereof. 5. Angiogonist of serotonin receptor type 2 is represented by the following formula (2)

The therapeutic and / or prophylactic agent according to claim 3, which is an aminoalkoxybibenzyl represented by the formula: or a salt thereof, or a hydrate or solvate thereof. 6. The therapeutic and / or prophylactic agent according to claim 5, wherein the salt is a hydrochloride. 7. The serotonin receptor type 2 angel gonist has the following formula:

The therapeutic, Z or prophylactic agent according to claim 3, which is an aminoalkoxybibenzyl represented by the formula: or a salt thereof, or a hydrate or a solvate thereof. 8. A therapeutic and / or prophylactic agent for a disease selected from optic nerve disease and retinal disease, comprising a serotonin receptor ligand as an active ingredient. 9. The therapeutic and / or prophylactic agent according to claim 8, wherein the serotonin receptor ligand is a serotonin receptor type 2 ligand. 10. The therapeutic and / or prophylactic agent according to claim 8, wherein the serotonin receptor ligand is an agonite of serotonin receptor Eve2. 1 1. Angiogonist of serotonin receptor type 2 has the following general formula (1)

(In the above formula, R ¹ represents a hydrogen atom, a halogen atom, a C 1 -C 5 alkoxy group or a C 2 -C 6 dialkylamino group, and R ² represents a hydrogen atom, an octogen atom or a C 1 -C 5 5 represents an alkoxy group, R ³ represents a hydrogen atom, a hydroxyl group, 100_ (CH 2) n -COOH (where n represents an integer of 1 to 5), or 10 —CO— (CH 2) l—COOH (where 1 represents an integer of 1 to 3), and R ⁴ represents — N (R ⁵ ) (R ⁶ ) (where R ⁵ and R ⁶ each independently represents a hydrogen atom or a C 1 to C 8 alkyl group.) -N A (In the formula, A represents a C3-C5 alkylene group which may be substituted with a carboxyl group.), And m represents an integer of 0-5. ] 10. The therapeutic, Z or prophylactic agent according to claim 10, which is an aminoalkoxybibenzyl represented by the formula: or a salt thereof, or a hydrate or solvate thereof. 1 2. Angiogonist of serotonin receptor type 2 has the following formula (2) (2)

The therapeutic and / or prophylactic agent according to claim 10, which is an aminoalkoxybibenzyl represented by the formula: or a salt thereof, or a hydrate or solvate thereof. 13. The therapeutic and / or Z- or prophylactic agent according to claim 12, wherein the salt is a hydrochloride. 1 4. The serotonin receptor type 2 enzymatic gonist has the following formula (3)

The therapeutic and / or prophylactic agent according to claim 10, which is an aminoalkoxybibenzyl represented by the formula: or a salt thereof, or a hydrate or solvate thereof. 1 5. Optic nerve disease, inflammatory disease, circulatory disorder, optic nerve compression, optic nerve disorder, optic nerve toxic disease, optic neuropathy The therapeutic and / or prophylactic agent according to any one of claims 8 to 14, which is a disease selected from harm and normal tension glaucoma. 16. The therapeutic and / or prophylactic agent according to any one of claims 8 to 14, wherein the optic nerve disease is selected from ischemic optic neuropathy and normal tension glaucoma. 17. The retinal disease is a disease selected from diabetic retinopathy, retinal circulation disorder, retinal disorder, macular disease, retinal degenerative disease, retinal detachment and retinal disorder caused by toxic drugs to the retina. Item 16. The therapeutic and / or prophylactic agent according to any one of Items 8 to 14. 18. The therapeutic and / or prophylactic agent according to any one of claims 8 to 14, wherein the retinal disease is selected from diabetic retinopathy, retinal vein occlusion and retinal artery occlusion. 19. The therapeutic and / or prophylactic agent according to any one of claims 1 to 18, which is any one of an oral preparation, an injection, an eye drop and an ointment. 20. A method for treating and preventing or preventing normal tension glaucoma using a serotonin receptor ligand. 21. A method for treating and / or preventing optic nerve disease or retinal disease using a serotonin receptor ligand. 22. A retinal ganglion cell death inhibitor containing a serotonin receptor ligand as an active ingredient. 23. Protective agent for retinal ganglion cells containing a serotonin receptor ligand as an active ingredient. 24. A method for inhibiting retinal ganglion cell death using a serotonin receptor ligand. 25 5. A method for protecting retinal ganglion cells using a serotonin receptor ligand. 26. An inhibitor of retinal degeneration containing a serotonin receptor ligand as an active ingredient. 27. The retinal degeneration inhibitor according to claim 26, wherein the retinal degeneration is induced by retinal ischemia. 28. A method for inhibiting retinal degeneration using a serotonin receptor ligand as an active ingredient. 29. The method according to claim 28, wherein the retinal degeneration is caused by retinal ischemia.