WO2007108292A1

WO2007108292A1 - Neurite elongation inducer

Info

Publication number: WO2007108292A1
Application number: PCT/JP2007/053918
Authority: WO
Inventors: Makoto Makishima; Hideo Takahashi; Tomoko Koike; Shinichi Yokota
Original assignee: Kaneka Corporation; Nihon University
Priority date: 2006-03-20
Filing date: 2007-03-01
Publication date: 2007-09-27
Also published as: JP2009132622A

Abstract

Disclosed is a compound having a neurite elongation-inducing activity and a neuroprotective activity. It is now found that a compound represented by the formula (I) such as KNK437 has a neurite elongation-inducing activity and a neuroprotective activity and that the compound can exert a synergistic effect when used in combination with a nerve growth factor. [Chemical formula 1] wherein X represents -CH2- and R1 represents an alkyl group having 1 or 2 carbon atoms, a formyl group, an acetyl group, a hydrogen atom or a halogen atom; or X represents -(CH2)2- and R1 represents an alkyl group having 1 to 3 carbon atoms, a formyl group, an acetyl group, a hydrogen atom or a halogen atom.

Description

Specification

Neurite outgrowth inducer

Technical field

The present invention relates to a neurite outgrowth inducer and neuroprotective agent for nerve cells, or a composition for preventing and treating diseases based on the action thereof.

Background art

[0002] To form a neural network, neurite outgrowth from nerve cells is first required. In neurological diseases such as dementia and Alzheimer's disease, neuronal neurite loss has been observed, and treatment with neurite outgrowth induction is considered useful. Diseases and effects for which treatment by inducing neurite outgrowth may be useful include diabetic neuropathy, motor and sensory disturbances associated with peripheral neuropathies such as amyotrophic lateral sclerosis, or Alzheimer's disease Central nervous system disorders such as spinal cord injury, Parkinson's disease, Huntington's disease, or dementia, improved brain function, improved memory impairment.

[0003] Neurotrophic factors such as nerve growth factor (NGF) are known as substances that induce neurite outgrowth. However, since neurotrophic factors are proteins, there is a need for low molecular weight compounds that cannot pass through the blood-brain barrier and have a neurite outgrowth-inducing action. Methods for inducing neurite outgrowth other than neurotrophic factors include using growth hormone-free peptides (see Patent Document 1), using heat shock protein 90 (see Patent Document 2), and using polyalkoxyflavonoids. A method (see Patent Document 3) has been reported, and the neurite outgrowth action of epicarocatechin gallate has also been reported (see Non-Patent Document 1).

[0004] Dementia and Alzheimer's disease are progressive, always progressive neurodegenerative diseases with clinical symptoms centered on decreased memory and cognitive dysfunction. There are more than 25 million people with dementia, including Alzheimer's disease, worldwide, and the prevalence tends to increase with age. The new treatment and prevention methods are particularly desired to be developed as the population ages.

[0005] N-Forminolet 3, 4-Methylenedioxybenzylidene γ-Buchiguchi Ratatam (ΚΝΚ43 7) and its analogs are compounds that inhibit the activation of heat shock factor (HSF), which is a transcription factor, and heat shock induced by proteins induced by HSF activation, such as heat and chemical substances. Suppresses induction of protein (HSP) expression (see Patent Document 4 and Non-Patent Document 2). KNK437 is effective in inhibiting the acquisition of thermotolerance during cancer thermotherapy due to its inhibitory effect on HSP expression (see Patent Document 5, Non-Patent Documents 2 and 3). In addition, animal model tests have proved effective in stress-related diseases such as depression (see Patent Document 6).

[0006] However, it is generally known that induction of HSP expression acts as a cytoprotective action. For this reason, KNK437, which inhibits HSF activation and suppresses HSP expression, usually does not have a cytoprotective action, and conversely is thought to weaken cellular stress tolerance. Thus, although it is a well-known fact that induction of heat shock protein is effective in protecting cells due to ischemia, etc., even though undifferentiated PC12 cells are induced to express HSP by heat shock, they are differentiated by NGF pretreatment. It has been reported that PC12 cells thus induced do not induce HSP expression by heat shock (see Non-Patent Document 4), that is, heat shock proteins contribute to neuroprotection in differentiated neurons. In addition, there is a report that HSP induction after ischemia does not contribute to neuroprotection in a cerebral ischemia model, and that expression of HSP70 is not necessary for the development of ischemic tolerance (see Non-Patent Document 5).

[0007] Previous reports suggest that KNK437, which inhibits heat shock protein induction by inhibiting heat shock factor activity, normally does not have a positive effect on neurite outgrowth and neuronal protection. There is also a report that HSP is not involved, and its neuroprotective action and neurite outgrowth-inducing action were unknown.

[0008] In addition, hypothermia therapy that contributes to neuroprotection by various brain injuries is known to protect the brain from ischemic injury, and hypothermia therapy suppresses induction of HSP70 by ischemic stress. In hypothermia, KNK437, which inhibits heat shock protein induction, could never be expected to protect neurons, and so far there have been no reports on KNK437's neurite outgrowth-inducing action and neuroprotective effects. Les.

Patent Document 1: JP 2005-239712 A

Patent Document 2: Japanese Patent Laid-Open No. 8-245413

Patent Document 3: Japanese Patent Application Laid-Open No. 2002-60340 Patent Document 4: U.S. Patent 6,613,780

Patent Document 5: U.S. Patent 6,903,116

Patent Document 6: U.S. Patent 6, 281, 229

Non-Patent Document 1: J. Neurochemistry, 93, 1157-1167, (2005)

Non-Patent Document 2: Cancer Res., 60, 2942-2948. (2000)

Non-Patent Document 3: Clin. Cancer Res. 7, 215—219, (2001)

Non-Patent Document 4: Neurochem. Res. 21, 659-666, (1996)

Non-Patent Document 5: Neurosci. Lett. 295, 54—58, (2000)

Disclosure of the invention

Problems to be solved by the invention

[0009] An object of the present invention is to provide a compound having a neurite outgrowth-inducing action and a neuroprotective action.

Means for solving the problem

[0010] The present inventors show that a compound represented by the following formula (I) such as KNK437 has a neurite outgrowth-inducing action and a neuroprotective action, and further exhibits a synergistic effect when combined with a nerve growth factor. As a result, the present invention has been completed. Until now, it was not known at all that KNK437 had the above effects. That is, the present invention provides the following.

[1] Formula (I)

[0011] [Chemical 1]

(Wherein X is —CH— and R ¹ is an alkyl group having 1 or 2 carbon atoms, formyl group,

2

Represents a til group, a hydrogen atom or a halogen atom, or X is — (CH 2) —, and

twenty two

R ¹ is an alkyl group having 1 to 3 carbon atoms, a forminole group, a acetyl group, a hydrogen atom, or a halogen atom. A neurite outgrowth inducer comprising a compound represented by the formula:

[2] The neurite outgrowth inducer according to [1], wherein X is —CH— and R ¹ is a formyl group.

2

[3] The neurite outgrowth inducer according to [1], wherein X is —CH— and R ¹ is a hydrogen atom.

2

[4] The neurite outgrowth inducer according to [1], wherein X is —CH— and R ¹ is a acetyl group.

2

[5] The neurite outgrowth inducer according to [1], wherein X is _ (CH 3) 1 and R ¹ is a hydrogen atom.

twenty two

[6] The neurite outgrowth inducer according to [1], wherein X is _ (CH 3) — and R ¹ is a formyl group.

twenty two

[7] The neurite outgrowth inducer according to [1], wherein the compound represented by the formula (I) is an E form.

[8] The neurite outgrowth inducer according to [1], wherein the compound represented by the formula (I) is a Z form.

[9] The neurite outgrowth inducer according to any one of [1] to [8], further comprising a nerve growth factor

[10] The neurite outgrowth-inducing agent according to [9], comprising an amount of the compound represented by formula (I) that can synergistically increase the action of nerve growth factor.

[11] [1] to [10] Any force A therapeutic or prophylactic agent for dementia, Alzheimer's disease, or neurological disorder comprising the neurite outgrowth inducer according to 1.

[12] A neuroprotective agent comprising a compound represented by formula (I) according to any one of [1] to [8] as an active ingredient.

[13] The neuroprotective agent according to [12], further comprising nerve growth factor.

[14] A therapeutic or prophylactic agent for neuroprotection during cerebral ischemia, comprising the neuroprotective agent according to [12] or [13].

[15] A therapeutic or prophylactic agent for neuroprotection during hypothermia therapy, comprising the neuroprotective agent according to [12] or [13].

[16] Formula (I)

[0013] [Chemical 2]

(Wherein X is —CH— and R ¹ is an alkyl group having 1 or 2 carbon atoms, formyl group, Represents a til group, a hydrogen atom or a halogen atom, or X is — (CH 2) 1 and

twenty two

A method of inducing neurite outgrowth using a compound wherein R ¹ represents an alkyl group having 1 to 3 carbon atoms, a formyl group, a acetyl group, a hydrogen atom or a halogen atom.

[17] A method for treating or preventing dementia, Alzheimer's disease, or a neurological disorder using the neurite outgrowth inducer according to any one of [1] to [: 10].

[18] A method for protecting a nerve using a compound represented by the formula (I) according to any one of [1] to [8].

[19] A therapeutic or prophylactic method for the purpose of neuroprotection during cerebral ischemia using the neuroprotective agent according to [12] or [13].

[20] A method of performing neuroprotection during hypothermia therapy using the neuroprotective agent according to [12] or [13].

Hereinafter, embodiments of the present invention will be described in detail.

The present invention relates to a neurite outgrowth inducer comprising a compound represented by the above formula (I) (compound (I)).

Examples of the alkyl group having 1 or 2 carbon atoms in R ¹ of the above formula (I) include a methyl group and an ethyl group.

Examples of the halogen atom for R ¹ include a fluorine atom and a chlorine atom.

In addition, examples of the alkyl group having 1 to 3 carbon atoms in R ¹ of the formula (I) include a methyl group, an ethyl group, and a propyl group.

In a preferred embodiment, a compound in which X is —CH—, R ¹ is a formyl group, X is —C

2

A compound in which R ¹ is a hydrogen atom, X is —CH—, and R ¹ is a acetyl group.

twenty two

In another preferred embodiment, X is — (CH 2) — and R ¹ is a hydrogen atom.

twenty two

And a compound in which X is — (CH 2) — and R ¹ is a formyl group.

twenty two

Further, the compound represented by the above formula (I) may be an E-form or a Z-form. In a more preferred embodiment, X in the formula (I) is —CH— and R ¹ is formyl basic force X is — (C

2

H) — and R ¹ is hydrogen nuclear, or is — (CH) — and R ¹ is a formyl group, and

2 2 2 2

, E-form or Z-form compound.

As an example of the above compound (I), N-forminore-1,4-methylenedioxybenzylidene _γ -butyrolactam (KNK437).

[0017] The method for producing the compound represented by the formula (I) is not particularly limited. For example, when ΚΝΚ437 is given as a specific example, it can be obtained by the following method. First, a solution of ァ -acetyl-2-pyrrolidone (70.0 g, 0.55 mol) and piperonal (82.0 g, 0.55 mol) in tetrahydrofuran (500 ml) was added to sodium hydride (60./. Mineral oil). Suspension, 63.0 g, 1.57 mol) in tetrahydrofuran (1000 ml) is added dropwise under argon and with ice cooling, and the reaction is stirred overnight at room temperature. The resulting reaction solution is neutralized with dilute sulfuric acid, extracted with black mouth form, washed with saturated brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The obtained reaction product was recrystallized from 2_propanol to obtain N-formyl-1,3,4-methylenedibenzylidene-1-γ-butyrate ratatam (ΚΝΚ437) (79.0 g, yield 65%). You can get power.

[0018] The neurite outgrowth inducer of the present invention preferably further contains nerve growth factor (NGF), and further contains an amount of compound (I) capable of synergistically increasing the action of NGF. preferable.

The compound represented by the formula (I) alone has a nerve protrusion elongation-inducing action without NGF treatment or heat shock treatment, and can further enhance the action of NGF. In addition, a combination of an amount of compound (I) that is hardly effective alone and an amount of NGF that is hardly effective alone can provide a synergistic effect in inducing neurite outgrowth. the above

The “amount capable of synergistically increasing the action of GF” means that the amount of compound (I) relative to NGF is 100 mass% or more.

When NGF is further contained, as a preferred embodiment of the compound (I), X is —CH—, R ¹

In another preferred embodiment, wherein 2 is a formyl group, X is — (CH 2) —,

twenty two

Examples include compounds in which R ¹ is a hydrogen atom.

The neurite as used in the present invention is a protrusion extending from a nerve cell, and refers to a dendrite and an axon.

The neurite outgrowth inducing action as used in the present invention is synonymous with neurite outgrowth action and neurite outgrowth action. In addition, neurite outgrowth-inducing action also means neuronal differentiation-inducing action because neurites are elongated in the process of generating neurons, and the number of neurites is increased. Doing is also included in the neurite outgrowth-inducing action.

The effect of inducing neurite outgrowth can be evaluated using, for example, PC12 cells derived from rat brown cells. PC12 cells are widely used as a model system for neuronal differentiation and neurite outgrowth. For example, the neurite outgrowth-inducing action can be quantitatively expressed by the ratio of the number of cells having neurites to the total number of cells by the method of calculating the number of cells having neurites by microscopic observation. Other methods may be used other than

[0020] Rat brown cell-derived PC12 cells have been used for the analysis of neural factors such as NGF. The ability of PC12 cells to protect against heat shock stress by increasing the expression of HSPs such as HSP70 and HSP60 PC12 cells differentiated by NGF have the characteristic of not expressing HSP against heat shock. In other words, the compound represented by the formula (I) including KNK437 having an HSP inhibitory action is effective if the neurite outgrowth-inducing action is not known, or is not involved in neuronal cell protection and died on the contrary. It was speculated that it would let me. However, according to the present invention, it has been clarified that the compound represented by formula (I) such as KNK437 alone effectively induces neurite outgrowth of PC12 cells, and the effect of low-dose NGF treatment is neurite outgrowth. It was revealed that synergistic increase in induction and, consequently, neuroprotective effect.

[0021] Thus, PC12 cells can be used for confirming the neurite outgrowth-inducing action. The present invention is not limited to this cell, and other nerve cells capable of performing the same test may be used. At that time, the reactivity may vary depending on the number of times the nerve cells are transplanted, and the neurite outgrowth action of the nerve cells may differ even if the sampnore used is treated at the same concentration. In order to solve this problem, it is possible to show the relative properties of NGF and other positive subjects with clear neurite outgrowth-inducing effects.

[0022] The neurite outgrowth induction mechanism of the compound represented by the formula (I) such as KNK437 may be partially mediated by signal transduction systems such as MAP kinase, p38 and GSK3β.

The difference from NGF is that NGF shows an increase in acetylcholinesterase (AchE) activity, but KNK437 has no effect. When KNK437 is used, NGF induces AchE. It is presumed that the inner mechanism is working. [0023] Since the neurite outgrowth inducer of the present invention has an effect of promoting neurite outgrowth from nerve cells, it can be used for the manufacture of a therapeutic or prophylactic agent for dementia, Alzheimer's disease, or neurological disorders. it can.

[0024] The neuroprotective agent of the present invention comprises a compound represented by the above formula (I) as an active ingredient.

Specific examples and preferred embodiments of compound (I) are the same as described above. The neuroprotective agent of the present invention preferably further contains nerve growth factor (NGF).

Cerebral ischemia is a condition in which there is insufficient blood circulation in the brain, and sufficient oxygen and nutrients are not supplied to the brain tissue, which also causes cerebral infarction. The nervous system is known to be sensitive to many stresses such as cerebral ischemia. Normally, the expression of HSP that protects nerves is induced by physiological and chemical reactions including heat shock, heavy metals, chemical reagents, and ischemia, and the expression of HSP70 in nerve cells is also pathophysiological conditions such as ischemia. Induced under. That is, HSP has a neuroprotective function, and compound (I) such as KNK437 that suppresses the expression of HSP was expected to inhibit instead of neuroprotective action. However, Compound (I) has an action of protecting nerves from induction of nerve cell differentiation and damage even in a state where HSP expression is suppressed. The neuroprotective agent of the present invention can be used for the manufacture of a therapeutic or prophylactic agent for the purpose of neuroprotection during cerebral ischemia because compound (I) has an excellent neuroprotective action.

[0025] Since the neuroprotective agent of the present invention also has an excellent neuroprotective action even in a state where HSP is suppressed, the neuroprotective agent of the present invention can be used for the manufacture of a therapeutic or prophylactic agent for the purpose of neuroprotection during hypothermia therapy. Can do.

Hypothermia therapy is a treatment for head trauma that lowers body temperature to 32 to 33 degrees for severely injured head trauma patients, and is well known to contribute to neuroprotection by brain damage in laboratory animals and cardiac arrest patients. It has been. Regarding the relationship between HSP expression and hypothermia treatment, it is known that after ischemia, hypothermia treatment protects neurons without HSP70 induction in animal models. Furthermore, in the ischemic tolerance model, short-term ischemia induces resistance to subsequent serious injury, but HSP70 expression is not necessary for induction of ischemic tolerance. Thus, HSP is expressed in accordance with the subsequent stress, but its association with neuroprotective activity is considered to be weak. The exact mechanism of neuroprotection by hypothermia and whether stress-induced suppression of HSP expression is effective is unknown. For the first time according to the present invention, It has been clarified that compound (I) such as KNK437 having a harmful effect has the ability as a neuroprotective agent and induces neurogenesis.

[0026] As the administration method of the neurite outgrowth inducer, neuroprotective agent, therapeutic or prophylactic agent of the present invention, any of oral, enteral or other parenteral administration methods can be selected. There are no particular limitations on the form of the preparation, and oral preparations such as tablets, powders, capsules, granules, fine granules, syrups, suspensions, and emulsions are used depending on the purpose and route of administration. It is possible to raise parenterals such as suppositories, ointments, injections, drops, topically applied creams or eye drops.

There are no particular restrictions on the amount, but it can be selected appropriately within the range that produces the desired effect.

[0027] The carrier of the preparation according to the present invention may contain any component of an organic or inorganic solid or liquid suitable for oral, enteral or other parenteral administration. As optional components, additives such as binders, excipients, lubricants, disintegrants, stabilizers, emulsifiers, buffers and the like that are generally used in formulations can be contained. Preferable examples of the binder include starch, trehalose, dextrin, gum arabic and the like. Preferable examples of the excipient include sucrose, lactose, glucose, corn starch, mannitol, crystalline cellulose, gelatin, calcium phosphate, calcium sulfate, vegetable and animal fats and oils, pectin and the like. Preferable examples of the lubricant include stearic acid, talc, wax, polyethylene glycol and the like. Preferable examples of the disintegrant include starch, carboxymethyl cellulose, corn starch and the like. Preferable examples of the stabilizer include fats and oils, propylene glycol and the like. Preferable examples of the emulsifier include an anionic surfactant, a nonionic surfactant, polybulal alcohol and the like. Preferable examples of the buffer include a buffer solution such as phosphate, carbonate, citrate. When the neurite outgrowth inducer and neuroprotective agent of the present invention are formulated and used as quasi-drugs, other additives are added as necessary, for example, ointment, liniment ij, aerosol It can be used in preparations, creams, sarcophagus, facial cleansers, whole body cleansers, lotions, lotions, bath preparations, etc., and can be used locally.

[0028] The compound (I) of the present invention can be contained in the preparation in an amount of 0.001 to 100% by weight. Contains The amount is preferably 0. 01: 100 weight ^_0/0, more preferably from 0 ·:! ~ 90 weight ^_0/0.

The dosage of these preparations is the number of doses per day for each adult in terms of the compound (I), preferably from 0.001 to 1000 mg / kg body weight, more preferably from 0.01 to 200 mg / kg body weight. Dosage in divided doses.

Further, the neurite outgrowth inducer and neuroprotective agent of the present invention can contain other medicaments. In this case, the compound (I) of the present invention is not necessarily the main component in the preparation. The invention's effect

[0029] According to the present invention, a neurite outgrowth inducer and a neuroprotective agent can be obtained. These are effective for the treatment or prevention of dementia or Alzheimer's disease, neurological disorders, and neuroprotection during cerebral ischemia and hypothermia, and can be used as pharmaceuticals or quasi drugs.

BEST MODE FOR CARRYING OUT THE INVENTION

[0030] The present invention will be described more specifically with reference to the following examples. However, the scope of the present invention is not limited to these examples.

(Example 1)

Effects of KNK437 and NGF on neurite outgrowth using PC12 cells

PC12 cells (available from RIKEN CELL BANK) using DMEM medium containing 5% fetal calf serum, 5% horse serum, lOOunit / ml penicillin, 100 mg / ml streptomycin The cells were cultured under conditions of 100% humidity containing 5% carbon dioxide gas. Prior to treatment with NGF (Alomone Labs Ltd., Jerusalem, Is rael) or KNK437, the medium was replaced with medium containing 2% fetal calf serum. PC12 cells are cultured in DMSO-only medium, medium containing NGF (50 ng / ml), or medium containing KNK437 (5, 25, 50, 100, 150, 200 / i M) for 5 days. Then, the number of cells with extended nephew processes was counted every day. The value is shown as the average value soil SD. The results are shown in Figure 1. KNK437 showed neurite outgrowth-inducing action in a concentration-dependent manner.

(Example 2)

Synergistic neurite outgrowth-inducing effect of KNK437 and NGF using PC12 cells

PC12 cells with 5% fetal bovine serum, 5% horse serum, lOOunit / ml penicillin, 100mg / m 1 DMEM medium containing streptomycin was used and cultured under conditions of 100% humidity and 5% carbon dioxide. The medium was replaced with medium containing 2% fetal calf serum before treatment with NGF or KNK437. NGF (10ng / ml) alone, ΚΝΚ437 (50 μΜ) alone or NGF (10ng / ml) and KNK437 (50 μΜ) in both medium for 5 days Counted. The value is shown as the average value soil SD. * * *: Ρ <0. 001. The result is shown in figure 2. The medium containing both ΚΝΚ437 and NGF synergistically showed neurite outgrowth-inducing action at concentrations that did not individually show neurite outgrowth.

Industrial applicability

[0031] According to the present invention, a neurite outgrowth inducer and a neuroprotective agent can be obtained. These are effective for the treatment or prevention of dementia or Alzheimer's disease, neurological disorders, and neuroprotection during cerebral ischemia and hypothermia, and can be used as pharmaceuticals or quasi drugs.

Brief Description of Drawings

[0032] FIG. 1 shows the effect of ΚΝΚ437 and NGF on neurite outgrowth using PC 12 cells. The value is shown as the average value soil SD.

FIG. 2 shows the synergistic effect of KNK437 and NGF using PC12 cells. The value is shown as the average value soil SD. * * *: P <0. 001.

Claims

Claim [1] Formula (I)

[Chemical 1]

2

twenty two

A neurite outgrowth inducer comprising as an active ingredient a compound in which R ¹ represents a C 13 alkyl group, forminole group, acetyl group, hydrogen atom or halogen atom.

2. The neurite outgrowth inducer according to claim ^{1, wherein} X is —CH R ¹ is a formyl group.

2

[3] The neurite outgrowth inducer according to claim ¹ , wherein X is —CH R ¹ is a hydrogen atom.

2

[4] The neurite outgrowth inducer according to claim ¹ , wherein X is —CH R ¹ is a acetyl group.

2

[5] The neurite outgrowth inducer according to claim ¹ , wherein X is — (CH 2) R ¹ is a hydrogen atom.

twenty two

6. The neurite outgrowth inducer according to claim 1, wherein X is — (CH 2) —R ¹ is a formyl group.

twenty two

7. The neurite outgrowth inducer according to claim 1, wherein the compound represented by the formula (I) is an E form.

8. The neurite outgrowth inducing agent according to claim 1, wherein the compound represented by the formula (I) is a Z form.

[9] The neurite outgrowth inducer according to any one of [8] to [8], further comprising a nerve growth factor.

10. The neurite outgrowth inducer according to claim 9, comprising an amount of the compound represented by formula (I) that can synergistically increase the action of nerve growth factor.

[11] Claims: A therapeutic or prophylactic agent for dementia, Alzheimer's disease, or neurological disorder, comprising the neurite outgrowth inducer according to any one of claims 10 to 10.

[12] A neuroprotective agent comprising, as an active ingredient, the compound represented by the formula (I) according to [1], wherein [8].

13. The neuroprotective agent according to claim 12, further comprising a nerve growth factor.

[14] A treatment for neuroprotection during cerebral ischemia, comprising the neuroprotective agent according to claim 12 or 13. Therapeutic or preventive medicine.

[15] A therapeutic or prophylactic agent for neuroprotection during hypothermia therapy, comprising the neuroprotective agent according to claim 12 or 13.

[16] Formula (I)

[Chemical 2]

2

twenty two

A method of inducing neurite outgrowth using a compound wherein R ¹ represents an alkyl group having 1 to 3 carbon atoms, a forminole group, a acetyl group, a hydrogen atom or a halogen atom.

[17] A method for treating or preventing dementia, Alzheimer's disease, or neurological disorder using the neurite outgrowth inducer according to any one of [10] to [10].

[18] A method for protecting a nerve using the compound represented by formula (I) according to any one of [1] to [8].

[19] A method of treatment or prevention using the neuroprotective agent according to claim 12 or 13 for the purpose of neuroprotection during cerebral ischemia.

[20] A method for performing neuroprotection during hypothermia therapy using the neuroprotective agent according to claim 12 or 13.