WO2009110526A1 - Prophylactic or therapeutic agent for optic nerve disorders comprising 3',5-di-2-propenyl-(1,1'-biphenyl)-2,4'-diol as active ingredient - Google Patents

Abstract

Disclosed is a compound which is useful as a prophylactic or therapeutic agent for optical nerve disorders, an inhibitor of the cell death of retinal ganglion cells or an agent for recovering the expression level of a neurofilament light chain, particularly a compound which can exhibit the above-mentioned physiological activity when administered orally. Specifically disclosed is 3'-5-di-2-propenyl- (1,1'-biphenyl)-2,4'-diol, an ester thereof, or a salt of the compound or the ester. The compound, the ester or the salt can significantly prevent the reduction in the number of cells in a retinal ganglion cell layer in an NMDA-induced retinal disorder model rat when administered orally to the model rat and can recover the reduction in the expression level of a neurofilament light chain in a retina in the model rat when administered intravitreally to the model rat. Therefore, the compound, the ester or the salt is useful as a prophylactic or therapeutic agent for optical nerve disorders, an inhibitor of the cell death of retinal ganglion cells or an agent for recovering the expression level of a neurofilament light chain.

Description

Prophylactic or therapeutic agent for optic neuropathy containing 3 ', 5-di-2-propenyl- (1,1'-biphenyl) -2,4'-diol as an active ingredient

Prevention or treatment of optic neuropathy containing as an active ingredient at least one of 3 ', 5-di-2-propenyl- (1,1'-biphenyl) -2,4'-diol, an ester thereof or a salt thereof The present invention relates to an agent, a retinal neuronal cell death inhibitor, or a neurofilament light chain expression level recovery agent.

The retina consists of 10 layers: inner boundary membrane, nerve fiber layer, ganglion cell layer, inner reticular layer, inner granular layer, outer reticular layer, outer granular layer, outer boundary membrane, photoreceptor layer and retinal pigment epithelial layer The tissue is 0.1 to 0.5 mm in size, and includes retinal neurons such as photoreceptor cells, bipolar cells, ganglion cells, horizontal cells and amacrine cells.

Retinal neurons play an important role in the reception and transmission of visual information, such as converting light stimuli into electrical signals and transmitting them to the brain.

When the transmission mechanism is described in detail, visual information entered from the eyes is converted into an electrical signal by the photoreceptor cell and transmitted to the ganglion cell after passing through the horizontal cell, the bipolar cell and / or the amacrine cell. The electrical signal is then transmitted to the brain via the optic nerve, which is a bundle of optic nerve fibers containing ganglion cell axons.

By the way, when the optic nerve is damaged due to various causes, the homeostasis of the optic nerve cannot be maintained, and transmission of visual information to the brain is hindered, resulting in visual field disorders such as blindness and visual field narrowing.

There are various possible causes of optic nerve damage, but the main causes include 1) increased intraocular pressure, 2) retinal blood flow circulatory disorder / retinal ischemia, 3) increased excitatory amino acids, etc. It is thought that the optic nerve is impaired by the activation of the accompanying glutamate signal cascade, axonal damage of retinal ganglion cells, and subsequent apoptosis of retinal neurons.
Therefore, by blocking a part of the glutamate signal cascade, an agent that suppresses apoptosis of retinal neurons and protects the retinal neurons, that is, a glutamate neurotoxicity inhibitor, N-methyl-D-aspartate (hereinafter referred to as “N-methyl-D-aspartate”) Drugs such as receptor blockers and nitric oxide synthesis inhibitors are thought to be useful as preventive or therapeutic agents for optic neuropathy and associated eye diseases, and various studies have been made. Yes.

For example, Patent Document 1 discloses a retinal nerve cell protective agent containing nipradilol, which is one of β-blockers, as an active ingredient. Patent Document 2 discloses optic ganglion cell protection containing an interleukin-1 receptor antagonist protein as an active ingredient. Patent Document 3 discloses an optic ganglion cell protective agent containing an α ₁ receptor blocker such as bunazosin as an active ingredient, and Patent Document 4 discloses retinal nerve cell protection containing a fluorinated prostaglandin F2α derivative as an active ingredient. Patent Document 5 discloses a retinal nerve cell protective agent containing an indazole derivative as an active ingredient.

Representative eye diseases with optic neuropathy include glaucoma, glaucomatous visual field stenosis, glaucomatous optic nerve atrophy, glaucomatous optic neuropathy, central retinal artery occlusion, branch retinal artery occlusion, central retinal vein occlusion, retina Venous branch occlusion, diabetic retinopathy, macular degeneration (age-related macular degeneration such as dry age-related macular degeneration), retinitis pigmentosa, retinopathy of prematurity, retinal detachment, retinal pigment Examples include glaucomatous diseases such as epithelial detachment, label disease, and ischemic optic neuropathy, retinal diseases, and ischemic disorders.

On the other hand, 3 ′, 5-di-2-propenyl- [1,1′-biphenyl] -2,4′-diol is contained in herbal medicine [bark of magnolia obovata etc.] It is a component and is generally known as honokiol. As its pharmacological action, non-patent document 1, non-patent document 2 or non-patent document 3 show persistent central inhibitory action such as sedation, movement inhibitory action, central muscle relaxation action, spinal cord reflex inhibition, etc. Non-patent document 4 or non-patent document 5 discloses an anti-gastric ulcer effect in non-patent document 6, anti-bacterial activity against gram-positive bacteria disclosed in non-patent document 7, and cranial nerve cell protective effect disclosed in non-patent document 8. .

Further, Patent Document 6 discloses an angiogenesis inhibitory action of a honokiol type compound, and Patent Document 7 discloses a cell growth inhibitory action.

Furthermore, Non-Patent Document 9 discloses that magnolol (one component contained in the herbal medicine), which is a structural isomer of honokiol, has an action of lowering intraocular pressure.

However, in any literature, 3 ′, 5-di-2-propenyl- (1,1′-biphenyl) -2,4′-diol, its ester or a salt thereof is effective for preventing or treating optic neuropathy. Such a specific description is not made.
International publication 2001/056606 pamphlet International Publication 2003/004058 Pamphlet JP 59-1418 International Publication 2006/106915 Pamphlet International Publication 2006/112313 Pamphlet Japan J. Pharmacol., 25,605 (1975) Planta Med., 49, 103 (1983) J. Pharm. Dyn., 6, 184 (1983) Journal of Japanese Pharmacology, 106,888 (1986) Life Sci., 47, 1153 (1990) Japanese and Chinese Journal of Medicine, 4,100 (1987) Herbal medicine journal, 36, 222 (1982) Bioorg.Med.Chem.Lett., 12,1163 (2002) International Publication No. 2002/076393 Pamphlet International Publication 2006/107451 Pamphlet Chinese Pharm.J., 58, 115 (2006)

It is an interesting problem to find a compound useful as an agent for preventing or treating optic neuropathy, an inhibitor of retinal neuronal cell death, or an agent for recovering the expression level of a neurofilament light chain, and in particular, a compound that expresses the pharmacological effect by oral administration. Finding is a very interesting task.

In order to find a compound useful as a prophylactic or therapeutic agent for optic neuropathy, an inhibitor of retinal neuronal cell death, or a recovery agent for the expression level of neurofilament light chain, the present inventors have identified NMDA-induced rats. The effect on the retinopathy model was examined. As a result, 3 ′, 5-di-2-propenyl- (1,1′-biphenyl) -2,4′-diol, an ester thereof or a salt thereof was obtained as follows: Significantly suppresses the decrease in the number of cells in the retinal nerve cell layer upon oral administration in an NMDA-induced rat retinal disorder model,
2. Reduced expression of neurofilament light chain in the retina (a major component of the optic nerve axon and an important component for maintaining the shape of the optic nerve axon) during intravitreal administration in a NMDA-induced rat retinal injury model Recovering,
The present invention was completed.

In the present invention, “3 ′, 5-di-2-propenyl- (1,1′-biphenyl) -2,4′-diol” means a compound represented by the following general formula (1):

The “ester” means a compound in which one or both of the two hydroxy groups in the general formula (1) are esterified, and there is no particular limitation as long as the hydroxy group site is esterified. In the case of forming an ester, the hydroxy group, a lower alkyl carboxylic acid which may have a substituent, a lower alkyl sulfinic acid which may have a substituent, a lower alkyl which may have a substituent Preference is given to esters formed from alkyl sulfonic acids, optionally substituted aryl carboxylic acids, optionally substituted aryl sulfinic acids or optionally substituted aryl sulfonic acids. An ester formed from a hydroxy group and an optionally substituted lower alkyl carboxylic acid is preferred.

The “salt thereof” means a pharmaceutically acceptable salt of “3 ′, 5-di-2-propenyl- [1,1′-biphenyl] -2,4′-diol or ester thereof”. However, there is no particular limitation as long as it is a pharmaceutically acceptable salt. In addition, when forming a salt, the salt formed with alkali metals, such as lithium, sodium, and potassium, is preferable.

A prophylactic or therapeutic agent for optic neuropathy, an inhibitor of retinal neuronal cell death, comprising at least one of these compounds (hereinafter also referred to as “the present compound”), preferably one of those compounds, as an active ingredient, or The agent for recovering the expression level of a neurofilament light chain is the present invention.

The “optic neuropathy” in the present invention means an optic neuropathy and / or an eye disease accompanied by an optic neuropathy.

Here, the “eye disease with optic neuropathy” is not particularly limited as long as it is an eye disease with optic neuropathy, but examples include glaucomatous diseases, retinal diseases, ischemic disorders, and the like. , Glaucomatous visual field stenosis, glaucomatous optic nerve atrophy, glaucomatous optic neuropathy, central retinal artery occlusion, branch retinal artery occlusion, central retinal vein occlusion, branch retinal vein occlusion, diabetic retinopathy, macular degeneration ( Age-related macular degeneration such as dry age-related macular degeneration, wet age-related macular degeneration), retinitis pigmentosa, retinopathy of prematurity, retinal detachment, retinal pigment epithelial detachment, label disease, ischemic optic neuropathy .

“Glaucomatous optic neuropathy” in the present invention is not particularly limited as long as it is an optic neuropathy caused by glaucoma. Specifically, it means glaucoma and / or an eye disease associated with glaucoma, more specifically. Glaucoma and glaucomatous visual field stenosis, glaucomatous optic nerve atrophy, glaucomatous eye diseases such as glaucomatous optic neuropathy.

The “retinal nerve cell” in the present invention means a nerve cell involved in transmission of a visual signal to the brain, and specifically means a photoreceptor cell, a horizontal cell, a bipolar cell, an optic ganglion cell, an amacrine cell, and the like.

“Retinal nerve cell death” in the present invention means apoptosis and / or necrosis of retinal neurons.

The term “neurofilament light chain expression level recovery agent” in the present invention means an agent that suppresses and / or increases the decrease in the expression level of the neurofilament light chain in the retina. This neurofilament light chain is one of the main components of the optic nerve axon and is an important component for maintaining the morphology of the optic nerve axon.

In the present invention, “halogen” refers to fluorine, chlorine, bromine or iodine.

In the present invention, “lower alkyl” refers to straight-chain or branched alkyl having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl groups and the like.

In the present invention, “lower alkoxy” refers to a hydroxy hydrogen atom substituted with lower alkyl. Specific examples include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexyloxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentoxy group and the like.

In the present invention, “aryl” refers to aryl having 6 to 10 carbon atoms. Specific examples include phenyl and naphthyl.

In the present invention, “aryloxy” refers to a hydroxy hydrogen atom substituted with aryl. Specific examples include phenyloxy and naphthyloxy.

The “lower alkyl which may have a substituent” in the present invention refers to an alkyl having one or more substituents selected from the group consisting of halogen, lower alkoxy, aryl and aryloxy.

The “aryl optionally having substituent (s)” in the present invention refers to aryl having one or more substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, aryl and aryloxy.

The “plurality” in the present invention may be the same or different, and the number is preferably 2 or 3, particularly preferably 2.

This compound may take the form of a hydrate or a solvate.

Further, when a crystalline polymorph exists in the present compound, the crystalline polymorph is also included in the scope of the present invention.

The compound can be administered either orally or parenterally. Examples of dosage forms include oral administration, topical ocular administration (instillation administration, intraconjunctival sac administration, intravitreal administration, subconjunctival administration, subtenon administration, etc.), intravenous administration, transdermal administration, etc. A pharmaceutically acceptable additive can be appropriately selected and used, and can be formulated into a dosage form suitable for the administration form.

Examples of the dosage form include tablets, capsules, granules, powders and the like in the case of oral preparations, and examples of parenterals include injections, eye drops, eye ointments, patches, gels, inserts and the like. Can be mentioned.

For example, in the case of oral preparations such as tablets, capsules, granules, powders, etc., excipients such as lactose, glucose, D-mannitol, anhydrous calcium hydrogen phosphate, starch, sucrose; carboxymethylcellulose, carboxymethylcellulose calcium, cloth Disintegrants such as carmellose sodium, crospovidone, starch, partially pregelatinized starch, low substituted hydroxypropylcellulose; binders such as hydroxypropylcellulose, ethylcellulose, gum arabic, starch, partially pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol ; Lubricants such as magnesium stearate, calcium stearate, talc, hydrous silicon dioxide, hydrogenated oil; refined sucrose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methyl Cellulose, ethyl cellulose, coating agents such as polyvinyl pyrrolidone; citric acid, aspartame, ascorbic acid, flavoring agents such as menthol, etc. selected and used appropriately according to need, can be formulated.

Injections (aqueous, oily, suspendable) are: isotonic agents such as sodium chloride; solvents or solubilizers such as soybean oil and macrogol; buffering agents such as sodium phosphate; surface activity such as polysorbate 80 Agents: Thickeners such as carmellose sodium and methylcellulose, etc., soothing agents such as benzyl alcohol, etc. can be appropriately selected and used as necessary, and their pH is acceptable for injections. If it is within the range, there is no particular problem, and a pH range of 4 to 8 is desirable.

Eye drops (aqueous, oily, suspendable) are castor oil, glycerol, alcohol, solvents or solubilizers such as ether compounds of polyglycerol and alcohol, isotonic agents such as sodium chloride and concentrated glycerin; phosphoric acid Buffers such as salts and carbonates; surfactants such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil; stabilizers such as sodium citrate and sodium edetate; benzalco chloride In antiseptics such as nium and parabens, and suspension eye drops, a dispersing agent such as a water-soluble polymer, a tonicity agent such as sodium chloride and concentrated glycerin; a buffering agent such as phosphate and carbonate; a polysorbate 80, surfactants such as polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 60; sodium citrate, ede Stabilizers such as sodium acid; preservatives such as benzalkonium chloride and paraben can be appropriately selected and used as necessary, and their pH is acceptable for ophthalmic eye drops. If it is within the range, there is no particular problem, and a pH range of 4 to 8 is desirable.

The eye ointment can be formulated using a commonly used base such as white petrolatum or liquid paraffin.

The intercalator can be formulated using biodegradable polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, polyacrylic acid, etc., if necessary, excipients, binders, stable An agent, a pH adjuster, and the like can be appropriately selected and used as necessary.

The intraocular implant preparation is prepared using a biodegradable polymer such as polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, lactic acid-caprolactone copolymer, polyanhydride, polyorthoester, polyepsilon caprolactone, etc. If necessary, excipients, binders, stabilizers, pH adjusters and the like can be appropriately selected and used as necessary. It can also be formulated using non-biodegradable polymers such as ethylene vinyl acetate copolymer, and if necessary, excipients, binders, stabilizers, etc. are appropriately selected as necessary. Can be used.

The dosage of the present compound can be appropriately selected depending on the dosage form, patient symptoms, age, body weight and the like. For example, in the case of oral administration, 0.01 to 5000 mg, preferably 0.1 to 2500 mg, particularly preferably 0.5 to 1000 mg can be administered in 1 to several times per day. In the case of an injection, 0.00001 to 2000 mg, preferably 0.0001 to 1500 mg, particularly preferably 0.001 to 500 mg can be administered in 1 to several times per day. In the case of eye drops, 0.00001 to 10% (w / v), preferably 0.0001 to 5% (w / v), particularly preferably 0.001 to 1%, is applied once to several times a day. can do. In the case of an eye ointment, one containing 0.0001 to 2000 mg can be applied. In the case of an insertion agent or a preparation for intraocular implant, one containing 0.0001 to 2000 mg can be inserted or implanted.

As will be described in detail in the section of the pharmacological test described later, this compound significantly suppressed the decrease in the number of cells in the retinal nerve cell layer in the oral administration test in the NMDA-induced rat retinal disorder model. Moreover, in the intravitreal administration test in the same model, the decrease in the expression level of the neurofilament light chain in the retina was recovered.

Based on the above, the present compound is useful as an agent for preventing or treating optic neuropathy, an inhibitor of retinal neuronal cell death, or a recovery agent for the expression level of neurofilament light chain, and more particularly a prophylactic or therapeutic agent for glaucomatous optic neuropathy. Specifically, it is useful as a preventive or therapeutic agent for glaucomatous eye diseases such as glaucoma, glaucomatous visual field stenosis, glaucomatous optic nerve atrophy, glaucomatous optic neuropathy and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

The results of the pharmacological test of the present invention and formulation examples are shown below. In addition, these illustrations are for understanding this invention better, and do not limit the scope of the present invention.

[Pharmacological test]

1. Test using NMDA-induced rat retinal disorder model (retinal section evaluation by oral administration of test compound)
Using NMDA-induced rat retinal injury model (Invest. Ophthalmol. Vis. Sci., 2003; 44: 385-392), which is widely used as an optic neuropathy model, the usefulness of this compound (retinal neuronal cell death inhibitory effect) was evaluated. did.

(Method for producing NMDA-induced rat retinal injury model)
Rat [Slc: SD, male, about 7 weeks old] 100% (V / V) oxygen 0.5 L / min and 100% (V / V) nitrous oxide 1.5 L / min mixed gas 2 L / min Gas or air vaporized with 3% (V / V) halothane Inhalation of 3-4% (V / V) isoflurane gas at 1 to 1.5 L / min and general anesthesia, 1% ( Maintenance anesthesia was performed under conditions of (V / V) halocene or 2-3% (V / V) isoflurane. Thereafter, a NMDA (manufactured by Sigma, [catalog number: M3262]) solution dissolved in a 10% (V / V) dimethyl sulfoxide-containing phosphate buffer (hereinafter also referred to as “DMSO-containing PBS”) so as to be 2 mmol / L. 5 μL (10 nmol as NMDA) was administered intravitreally.

(Preparation and evaluation methods for retinal sections)
Rats 7 days after intravitreal administration of the NMDA solution were intraperitoneally administered with a 100 mg / kg pentobarbital sodium injection solution, and the eyes were removed. The extracted eyeball was fixed with a mixed solution of 25% (W / V) glutaraldehyde: 10% (W / V) neutral buffered formalin = 1: 9. The fixed eyeball was embedded in paraffin, and then sliced to prepare a retinal section (3 μm thickness), which was stained with hematoxylin-eosin. Eight retinal sections were prepared at 45 μm intervals so that the optic papilla could enter each eye. Three sections were arbitrarily selected from the eight sections, and a photograph of the retina between 1 to 1.5 mm from the optic nerve head was taken for the selected sections, and the number of cells in the retinal ganglion cell layer was calculated (average value) . The number of cases in each group is 3 (5-6 eyes).

(Method of administration)
[PBS intravitreal group]
5 μL of PBS containing 10% (V / V) DMSO was administered intravitreally.

[NMDA intravitreal administration + base oral administration group]
NMDA solution 5 μL (10 nmol as NMDA) dissolved in PBS containing 10% (V / V) DMSO was administered into the vitreous body. In addition, a 1% (W / V) aqueous solution of methylcellulose was orally administered once a day at a dose of 10 mL / kg for 7 days from the NMDA intravitreal administration date to 6 days later. On the day of intravitreal administration of NMDA, a 1% (W / V) aqueous solution of methylcellulose was orally administered 30 to 60 minutes before intravitreal administration of NMDA.

[NMDA intravitreal administration + test compound oral administration group]
NMDA solution 5 μL (10 nmol as NMDA) dissolved in PBS containing 10% (V / V) DMSO was administered into the vitreous body. In addition, the test compound suspended in 1% (W / V) methylcellulose solution was administered at a dose of 10 mg / kg for 7 days from the day of intravitreal administration of NMDA for 7 days at a dose of 10 mL / kg per day. Oral administration was repeated twice. On the day of intravitreal administration of NMDA, a test compound suspended in a 1% (W / V) methylcellulose solution was orally administered at a dose of 10 mg / kg 30 to 60 minutes before NMDA administration.

(Test results)
As an example of the test compound, the test results when 3 ′, 5-di-2-propenyl- (1,1′-biphenyl) -2,4′-diol (hereinafter also referred to as “honokiol”) was used. Table 1 shows. As is apparent from Table 1, honokiol significantly suppressed the decrease in the number of cells in the ganglion cell layer in the retina, which occurred in the NMDA-induced rat retinal injury model.

(Discussion)
From the test results, the present compound containing honokiol has the effect of preventing or treating optic neuropathy and the effect of suppressing retinal nerve cell death in systemic exposure dosage forms such as oral administration. In particular, it has the effect of preventing or treating glaucomatous optic neuropathy.

2. Test using NMDA-induced rat retinal injury model (quantitative polymerase chain reaction (hereinafter also referred to as PCR) evaluation by intravitreal administration of test compound)
(Evaluation method by quantitative PCR)
In the NMDA-induced rat retinal injury model, the amount of expression in the retinal tissue of a neurofilament light chain (hereinafter also referred to as “NFL”), which is a main component of the optic nerve axon and important for maintaining the shape of the axon, As an index, the effectiveness of the test compound was evaluated.

(Evaluation methods)
One day after intravitreal administration of NMDA, a 100 mg / kg sodium pentobarbital injection solution was intraperitoneally administered to the rat and general anesthesia was performed. Then, the eyeball was removed and the retina was isolated. The isolated retina was homogenized, and total RNA was extracted using QIAzol Lysis Reagent (manufactured by QIAGEN [catalog number: 79306]) and RNeasy 96 Kit (250) (manufactured by QIAGEN [catalog number: 74106]), and PrimeScript (registered trademark) ) CDNA was synthesized using RT reagent Kit (manufactured by TAKARA [catalog number: RR037B]). QuantTect Multiplex PCR Master Mix, synthesized cDNA, NFL primer / probe according to the instructions attached to QuantTect Multiplex PCR Kit (1000) (manufactured by QIAGEN, [Cat. No. 204545]) (manufactured by Sigma [custom made]) And a primer probe of glyceraldehyde 3-phosphate dehydrogenase (hereinafter also referred to as “GAPDH”) (AppliedBiosystems, [Catalog No .: 4352338E]), and a quantitative PCR apparatus (AppliedBiosystems [Cat #: 7500- 03]), and the expression levels of NFL and GAPDH were measured.

From the obtained expression levels of NFL and GAPDH, the expression level of NFL was calculated by correcting the expression level of NFL with the expression level of GAPDH, which is a housekeeping gene, according to Equation 1. Thereafter, according to Formula 2, the group administered with 10% (V / V) DMSO-containing PBS intravitreal was set to 100%, and the group administered with 10 nmol NMDA intravitreal was set to 0%. NFL recovery rate (%) was calculated. The number of cases in each group is 2 to 3 (4 to 6 eyes).

The NFL primer / probe sequences used in the present invention are as follows.

[Formula 1]
Relative NFL expression level = (NFL expression level / GAPDH expression level)
[Formula 2]
NFL recovery rate (%) = (E _X −E ₀ ) / (E _P −E ₀ ) × 100
E _P : 10% (V / V) DMSO containing PBS Intravitreal administration relative NFL expression level E ₀ : 10 nmol NMDA Intravitreal administration relative NFL expression level E _X : 10 nmol NMDA Relative NFL expression level of the group in which oral administration of the drug was administered to the intravitreal administration (administration method)
[10% (V / V) DMSO-containing PBS intravitreal administration group]
5 μL of PBS containing 10% (V / V) DMSO was administered intravitreally.

[NMDA intravitreal administration group]
NMDA solution 5 μL (10 nmol as NMDA) dissolved in PBS containing 10% (V / V) DMSO was administered into the vitreous body.

[Intravitreal group of each compound]
5 μL of a mixed solution of NMDA and test compound dissolved in PBS containing 10% (V / V) DMSO (10 nmol as NMDA and 0.025 nmol as the test compound) was administered intravitreally.

(result)
Table 3 shows test results when honokiol and its structural isomer, magnolol (which is basically known to have the same action as honokiol), are used as an example of the test compound. As is apparent from Table 3, honokiol restores the decrease in the expression level of NFL that occurs in the NMDA-induced rat retinal injury model, whereas honokiol, a structural isomer of honokiol, is at the same concentration as honokiol. It did not recover the decrease in the expression level of NFL, but rather showed an exacerbation tendency.

(Discussion)
From the test results, the present compound containing honokiol has a prophylactic or therapeutic effect on optic neuropathy even in the form of local administration, and also has a recovery effect on the expression level of NFL.

Furthermore, in magnolol which is a structural isomer of honokiol, the effect of recovering the decrease in the expression level of NFL was not recognized, but rather showed an exacerbation tendency. It is thought that it has a big influence on expression.

[Formulation example]
The typical formulation example of this compound is shown below.

1) Tablet (in 150mg)
This compound 10mg
Lactose 90mg
Corn starch 40mg
Carboxymethylcellulose calcium 5.5mg
Hydroxypropylcellulose 4mg
Magnesium stearate 0.5mg
A tablet of the above formulation can be coated with 3 mg of a coating agent (for example, a coating agent such as hydroxypropylmethylcellulose, macrogol, talc, titanium oxide, silicone resin) to obtain the intended tablet. Moreover, a desired tablet can also be obtained by changing suitably the kind and / or quantity of this compound and an additive.

2) Capsule (in 150mg)
50 mg of this compound
Lactose 90mg
Carboxymethylcellulose calcium 4.5mg
Hydroxypropylcellulose 4mg
Magnesium stearate 1.5mg
Desired capsules can be obtained by appropriately changing the type and / or amount of the compound of the present invention and additives.

3) Water-soluble ophthalmic solution (in 100 ml)
100 mg of this compound
1-O-n-dodecyl-3-O-methyl-2-O-2 ′, 3′-dihydroxypropylglycerol 7000 mg
Ethanol 5mL
Sodium chloride 900mg
Sterile purified water appropriate amount Desired aqueous eye drops can be obtained by appropriately changing the type and / or amount of the present compound and additives.

4) Oily ophthalmic solution (in 100 ml)
100 mg of this compound
Castor oil Appropriate amount A desired oily eye drop can be obtained by appropriately changing the type and / or amount of the present compound and additives.

5) Suspension ophthalmic solution (in 100 ml)
100 mg of this compound
Sodium chloride 750mg
Benzalkonium chloride 5mg
Polysorbate 80 Appropriate amount Hydroxypropyl methylcellulose Appropriate amount Sodium edetate Appropriate amount Sodium hydrogen phosphate Appropriate amount Sodium dihydrogen phosphate Appropriate amount of sterilized purified water Appropriate amount By appropriately changing the type and / or amount of this compound and additives, desired suspension instillation An agent can be obtained.

6) Aqueous injection (in 100 ml)
100 mg of this compound
Sodium chloride 750mg
Macrogol 400 1000mg
Sodium hydroxide Appropriate amount Hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount A desired aqueous injection can be obtained by appropriately changing the type and / or amount of the present compound and additives.

7) Oily injection (in 100 ml)
100 mg of this compound
Appropriate amount of soybean oil A desired oily injection can be obtained by appropriately changing the type and / or amount of the present compound and additives.

8) Suspension injection (in 100 ml)
100 mg of this compound
Sodium chloride 750mg
Carmellose sodium 750mg
Polysorbate 80 40mg
Benzyl alcohol 40mg
Sodium hydroxide Appropriate hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount By appropriately changing the type and / or amount of the present compound and additives, a desired suspension injection can be obtained.

The present compound is useful as a preventive or therapeutic agent for optic neuropathy, an inhibitor of retinal neuronal cell death, or a recovery agent for the expression level of neurofilament light chain, and in particular, a prophylactic or therapeutic agent for glaucomatous optic neuropathy, more specifically It is useful as a prophylactic or therapeutic agent for glaucomatous eye diseases such as glaucoma, glaucomatous visual field stenosis, glaucomatous optic nerve atrophy, glaucomatous optic neuropathy.

Claims (24)

1. 3 ', 5-di-2-propenyl- (1,1'-biphenyl) -2,4'-diol, an ester thereof, or a salt thereof as an active ingredient .
2. The preventive or therapeutic agent according to claim 1, wherein the optic neuropathy is glaucomatous optic neuropathy.
3. The preventive or therapeutic agent according to claim 2, wherein the glaucomatous optic neuropathy is glaucoma, glaucomatous visual field stenosis, glaucomatous optic atrophy or glaucomatous optic neuropathy.
4. The prophylactic or therapeutic agent according to claim 1, wherein the optic neuropathy is an axonal flow disorder of retinal ganglion cells.
5. Inhibitor of retinal neuronal cell death comprising at least one of 3 ', 5-di-2-propenyl- (1,1'-biphenyl) -2,4'-diol, an ester thereof or a salt thereof as an active ingredient .
6. The inhibitor of claim 5, wherein the retinal nerve cell death is retinal ganglion cell death.
7. Expression amount of neurofilament light chain containing as an active ingredient at least one of 3 ′, 5-di-2-propenyl- (1,1′-biphenyl) -2,4′-diol, an ester thereof or a salt thereof Recovery agent.
8. The preventive or therapeutic agent according to any one of claims 1 to 7, which exhibits drug efficacy by oral administration.
9. Administering to a patient a therapeutically effective amount of at least one of 3 ′, 5-di-2-propenyl- (1,1′-biphenyl) -2,4′-diol, an ester thereof or a salt thereof. A method for preventing or treating optic neuropathy.
10. The method for prevention or treatment according to claim 9, wherein the optic neuropathy is glaucomatous optic neuropathy.
11. The method for prevention or treatment according to claim 10, wherein the glaucomatous optic neuropathy is glaucoma, glaucomatous visual field stenosis, glaucomatous optic atrophy or glaucomatous optic neuropathy.
12. The method for prevention or treatment according to claim 9, wherein the optic neuropathy is an axonal flow disorder of retinal ganglion cells.
13. Administering to a patient a therapeutically effective amount of at least one of 3 ′, 5-di-2-propenyl- (1,1′-biphenyl) -2,4′-diol, an ester thereof or a salt thereof. A method for suppressing retinal neuronal cell death.
14. The method according to claim 13, wherein the retinal nerve cell death is retinal ganglion cell death.
15. Administering to a patient a therapeutically effective amount of at least one of 3 ′, 5-di-2-propenyl- (1,1′-biphenyl) -2,4′-diol, an ester thereof or a salt thereof. A method for recovering the expression level of a neurofilament light chain.
16. The method according to claims 9 to 15, wherein the administration is carried out orally.
17. At least one of 3 ', 5-di-2-propenyl- (1,1'-biphenyl) -2,4'-diol, an ester thereof or a salt thereof for the prevention or treatment of optic neuropathy.
18. 18. The 3 ′, 5-di-2-propenyl- (1,1′-biphenyl) -2,4′-diol, an ester thereof, or a salt thereof according to claim 17, wherein the optic neuropathy is glaucomatous optic neuropathy. One.
19. The 3 ′, 5-di-2-propenyl- (1,1′-biphenyl) -2 according to claim 18, wherein the glaucomatous optic neuropathy is glaucoma, glaucomatous visual field stenosis, glaucomatous optic atrophy or glaucomatous optic neuropathy. At least one of 4′-diol, an ester thereof or a salt thereof.
20. The 3 ′, 5-di-2-propenyl- (1,1′-biphenyl) -2,4′-diol, an ester thereof or the like according to claim 17, wherein the optic neuropathy is an axonal flow disorder of retinal ganglion cells. At least one of the salts.
21. At least one of 3 ', 5-di-2-propenyl- (1,1'-biphenyl) -2,4'-diol, an ester thereof or a salt thereof for suppressing retinal neuronal cell death.
22. 23. The 3 ′, 5-di-2-propenyl- (1,1′-biphenyl) -2,4′-diol, its ester or a salt thereof according to claim 21, wherein the retinal neuronal cell death is retinal ganglion cell death. At least one of
23. At least one of 3 ', 5-di-2-propenyl- (1,1'-biphenyl) -2,4'-diol, an ester thereof or a salt thereof for recovering the expression level of the neurofilament light chain.
24. The 3 ', 5-di-2-propenyl- (1,1'-biphenyl) -2,4'-diol, an ester thereof or a salt thereof according to claim 17 to 23 formulated into an orally administered agent One.