Therapeutic and / or prophylactic agent for epilepsy, and pharmaceutical composition containing same

Abstract

Provided are: a therapeutic and / or prophylactic agent for at least one type of epilepsy selected from the group consisting of epilepsy after brain injury and epilepsy after the formation of compensatory brain areas; and a pharmaceutical composition containing the same.　This therapeutic and / or prophylactic agent for epilepsy after brain injury comprises a compound represented by general formula (1) or a salt thereof. (R1 and R2 are the same or different and represent one or more groups selected from a hydrogen atom, a halogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted aryl group, an optionally substituted C1-6 alkoxy group, an optionally substituted aryloxy group, an optionally substituted C1-6 alkylthio group, an optionally substituted arylthio group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkenyloxy group, an optionally substituted C1-6 alkylamino group, an optionally substituted C1-6 alkylsulfonyl group, an optionally substituted arylsulfonyl group, an optionally substituted carbamoyl group, an optionally substituted heterocyclic group, an optionally protected amino group, an optionally protected hydroxyl group, an optionally protected carboxyl group, a nitro group, and an oxo group; R3 represents an optionally substituted C1-6 alkylamino group, an optionally protected amino group, or an optionally protected hydroxyl group; and m and n are the same or different and each represent an integer of 1-6.)

Description

Agents for the treatment and / or prevention of epilepsy, and pharmaceutical compositions containing the same.

[0001] The present invention relates to a therapeutic and / or prophylactic agent for at least one type of epilepsy selected from the group consisting of epilepsy after brain injury and epilepsy after formation of the compensatory area of ​​the brain, and a pharmaceutical composition containing the same.

[0002] Several inventions claiming to have a preventative effect against the onset of epilepsy have been reported in the past. For example, Patent Documents 1 and 2 claim a preventative effect through the administration of specific compounds, and Patent Document 3 claims a preventative effect through the administration of antisense oligonucleotides. However, many aspects of their mechanism of action and pathogenesis remain unclear.

[0003] On the other hand, functional recovery from brain damage caused by various factors such as stroke is a plastic change in the brain. In particular, epilepsy following brain damage caused by various factors such as stroke jeopardizes the course of rehabilitation, and its prevention is an extremely important clinical issue. The glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) plays an important role in nerve function as a core molecule of excitatory synaptic transmission, and AMPAR synaptic transport is a fundamental mechanism of synaptic plasticity.

[0004] Special table 2011-510978 publication Special table 2022-503784 publication Special table 2015-516953 publication

[0005] ABE, H., JITSUKI, S., NAKAJIMA, W., MURATA, Y., JITSUKI-TAKAHASHI, A., KATSUNO, Y., TADA, H., SANO, A., SUYAMA, K., MOCHIZUKI, N., KOMORI, T., MASUYAMA, H., OKUDA, T., GOSHIMA, Y., HIGO, N. & TAKAHASHI, T. 2018. CRMP2-binding compound, edonerpic maleate, accelerates motor function recovery from brain damage. Science, 360, 50-57.

[0006] The present inventors have recently identified ednerpic maleate (also known as "ednerpic maleate") as a compound that binds to collagen response mediator protein 2 (CRMP2) (Non-Patent Literature 1). Ednerpic maleate is a synaptic plasticity promoter that can enhance rehabilitation-dependent functional recovery from brain injury by promoting experience-dependent synaptic translocation of AMPAR. On the other hand, after brain injury for any reason, a compensatory area, so-called compensatory area, is formed to compensate for the injury. In the aforementioned reports on existing epilepsy research, the causal relationship between the process of compensatory area formation after brain injury and the onset of epilepsy has not been clear. Moreover, there have been no reports showing that an imbalance in excitation and inhibition in that area causes epileptogenesis.

[0007] The present invention has been made in view of the above findings and aims to provide a therapeutic and / or prophylactic agent for at least one type of epilepsy selected from the group consisting of epilepsy after brain injury and epilepsy after formation of the compensatory area of ​​the brain, and a pharmaceutical composition containing the same.

[0008] The inventors first hypothesized that a functional compensation process could cause epileptic dysfunction in the brain due to increased excitation of compensatory brain regions. They identified compensatory brain regions in animals that recovered from cryogenic brain injury and found that AMPAR in these regions mediates recovery, that increased AMPAR expression around the injury is required to maintain recovered function in the formation of the compensatory area after brain injury, and that an imbalance in the excitation-inhibition balance (bias towards excitation) in the compensatory area is directly linked to the susceptibility to developing epilepsy (lowering of the onset threshold). They then found that a compound represented by the following general formula [1] or a salt thereof increases and balances both excitatory and inhibitory synaptic inputs in the compensatory area, thereby having a preventive effect against seizures in the injury recovery process, such as epilepsy, after brain injury caused by various factors such as stroke. The present invention was completed based on the above findings. Specifically, the present invention is as follows.

[0009] <1> A therapeutic and / or prophylactic agent for epilepsy after brain injury, comprising a compound represented by the following general formula [1] or a salt thereof. (In the formula, R １ and R ２ are the same or different and each represents a hydrogen atom, a halogen atom, an optionally substituted C １－６ alkyl group, an optionally substituted aryl group, an optionally substituted C １－６ alkoxy group, an optionally substituted aryloxy group, an optionally substituted C １－６ alkylthio group, an optionally substituted arylthio group, an optionally substituted C ２－６ alkenyl group, an optionally substituted C ２－６ alkenyloxy group, an optionally substituted C １－６ alkylamino group, an optionally substituted C １－６ alkylsulfonyl group, an optionally substituted arylsulfonyl group, an optionally substituted carbamoyl group, an optionally substituted heterocyclic group, an optionally protected amino group, an optionally protected hydroxyl group, an optionally protected carboxyl group, a nitro group and an oxo group; R ３ is an optionally substituted C １－６ alkylamino group, an optionally protected amino group or an optionally protected hydroxyl group; m and n are the same or different and each represents an integer of 1 to 6. ) <2> A therapeutic and / or prophylactic agent for epilepsy after formation of the brain compensation area, comprising a compound represented by the following general formula [1] or a salt thereof. (In the formula, R １ and R ２ are the same or different and each represents a hydrogen atom, a halogen atom, an optionally substituted C １－６ alkyl group, an optionally substituted aryl group, an optionally substituted C １－６ alkoxy group, an optionally substituted aryloxy group, an optionally substituted C １－６ alkylthio group, an optionally substituted arylthio group, an optionally substituted C ２－６ alkenyl group, an optionally substituted C ２－６ alkenyloxy group, an optionally substituted C１－６ Alkylamino group, optionally substituted C １－６ One or more groups selected from alkylsulfonyl groups, optionally substituted arylsulfonyl groups, optionally substituted carbamoyl groups, optionally substituted heterocyclic groups, optionally protected amino groups, optionally protected hydroxyl groups, optionally protected carboxyl groups, nitro groups, and oxo groups; R ３ C may be substituted. １－６ (An alkylamino group, an optionally protected amino group, or an optionally protected hydroxyl group; m and n are the same or different integers from 1 to 6, respectively.) <3> The agent according to <1> or <2> above, wherein the compound represented by the general formula [1] or a salt thereof is an agent for regulating and / or improving the excitatory / inhibitory [E / I] balance of nerve cells. <4> The agent according to <1> or <3> above, wherein the brain injury is a brain injury resulting from a stroke. <5> The agent according to any one of <1> to <4> above, wherein the epilepsy is epilepsy after the formation of a compensatory area of ​​the brain following brain injury. <6> R １ and R ２ However, they may be the same or different hydrogen atoms, halogen atoms, or C １－６ It is an alkoxy group, m is 2, n is 2 or 3, R ３ The agent according to any one of <1> to <5> above, wherein the hydroxyl group is protected. <7> The agent according to any one of <1> to <6> above, wherein the compound represented by the general formula [1] is 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidine-3-ol. <8> A pharmaceutical composition comprising the agent according to any one of <1> to <7> above.

[0010] According to the present invention, it is possible to provide a therapeutic and / or prophylactic agent for at least one type of epilepsy selected from the group consisting of epilepsy after brain injury and epilepsy after formation of the compensatory area of ​​the brain, and a pharmaceutical composition containing the same.

[0011] This figure shows that CNQX injection into the compensatory region attenuated functional recovery in both spontaneously recovering rats and ednerpycmalate-induced recovery rats. This figure shows that CNQX injection into the compensatory region attenuated functional recovery in both spontaneously recovering rats and ednerpycmalate-induced recovery rats. This figure shows that CNQX injection into the compensatory region attenuated functional recovery in both spontaneously recovering rats and ednerpycmalate-induced recovery rats. This figure shows that CNQX injection into the compensatory region attenuated functional recovery in both spontaneously recovering rats and ednerpycmalate-induced recovery rats. This figure shows that CNQX injection into the compensatory region attenuated functional recovery in both spontaneously recovering rats and ednerpycmalate-induced recovery rats. This figure shows that CNQX injection into the compensatory region attenuated functional recovery in both spontaneously recovering rats and ednerpycmalate-induced recovery rats. This figure shows that CNQX injection into the compensatory region attenuated functional recovery in both spontaneously recovering rats and ednerpycmalate-induced recovery rats. This figure shows that CNQX injection into the compensatory area attenuated functional recovery in both spontaneously recovering rats and ednerpycmaleate-induced recovering rats. This figure shows that CNQX injection into the compensatory area attenuated functional recovery in both spontaneously recovering rats and ednerpycmaleate-induced recovering rats. This figure shows that CNQX injection into the compensatory area attenuated functional recovery in both spontaneously recovering rats and ednerpycmaleate-induced recovering rats. This figure shows that in cases of severe cortical hypothermia, forelimb motor function recovered only in the ednerpycmaleate-administered group. This figure shows that ednerpycmaleate balances excitatory and inhibitory synaptic input to pyramidal neurons in the compensatory cortical area during functional recovery after brain injury. This figure shows that ednerpycmaleate balances excitatory and inhibitory synaptic input to pyramidal neurons in the compensatory cortical area during functional recovery after brain injury. This figure shows the results demonstrating that ednerpic maleate balances excitatory and inhibitory synaptic inputs to pyramidal neurons in compensatory cortical regions during functional recovery after brain injury.This figure shows the results demonstrating that ednerpicmaleate balances excitatory and inhibitory synaptic inputs to pyramidal neurons in the compensatory cortical region during functional recovery after brain injury. This figure shows the results demonstrating that ednerpicmaleate balances excitatory and inhibitory synaptic inputs to pyramidal neurons in the compensatory cortical region during functional recovery after brain injury. This figure shows the results demonstrating that ednerpicmaleate balances excitatory and inhibitory synaptic inputs to pyramidal neurons in the compensatory cortical region during functional recovery after brain injury. This figure shows the results demonstrating that ednerpicmaleate balances excitatory and inhibitory synaptic inputs to pyramidal neurons in the compensatory cortical region during functional recovery after brain injury. This figure shows the results demonstrating that ednerpicmaleate balances excitatory and inhibitory synaptic inputs to pyramidal neurons in the compensatory cortical region during functional recovery after brain injury. This figure shows the results demonstrating that the balance of spontaneous mEPSC / mIPSSC frequencies is disrupted in naturally recovering rats, while it is maintained in ednerpikmalate-induced recovery rats. This figure shows the results demonstrating that the balance of spontaneous mEPSC / mIPSSC frequencies is disrupted in naturally recovering rats, while it is maintained in ednerpikmalate-induced recovery rats. This figure shows the results demonstrating that the balance of spontaneous mEPSC / mIPSSC frequencies is disrupted in naturally recovering rats, while it is maintained in ednerpikmalate-induced recovery rats. This figure shows the results demonstrating that the balance of spontaneous mEPSC / mIPSSC frequencies is disrupted in naturally recovering rats, while it is maintained in ednerpikmalate-induced recovery rats. This figure shows the results demonstrating that the balance of spontaneous mEPSC / IPSSC frequencies is disrupted in naturally recovering rats, while it is maintained in ednerpikmalate-induced recovery rats. This figure shows the results demonstrating that the balance of spontaneous mEPSC / IPSSC frequencies is disrupted in naturally recovering rats, while it is maintained in ednerpikmalate-induced recovery rats.This figure shows the results demonstrating that the balance of spontaneous mEPSC / IPSC frequencies is disrupted in naturally recovering rats, while it is maintained in ednerpikmalate-induced recovery rats. This figure shows the results demonstrating that the balance of spontaneous mEPSC / IPSC frequencies is disrupted in naturally recovering rats, while it is maintained in ednerpikmalate-induced recovery rats. This figure shows the results demonstrating that the E / I ratio was disrupted in naturally recovering rats, while it was not disrupted in ednerpikmalate-induced recovery rats. This figure shows the results demonstrating that the E / I ratio was disrupted in naturally recovering rats, while it was not disrupted in ednerpikmalate-induced recovery rats. This figure shows the results demonstrating that the E / I ratio was disrupted in naturally recovering rats, while it was not disrupted in ednerpikmalate-induced recovery rats. This figure shows the results of ednerpicmaleate preventing epileptic seizures during the recovery phase from brain injury, and CNQX inhibition of AMPA receptor function in the compensatory region of naturally recovering animals downregulating susceptibility to picrotoxin-induced epilepsy. This figure shows the results of ednerpicmaleate preventing epileptic seizures during the recovery phase from brain injury, and CNQX inhibition of AMPA receptor function in the compensatory region of naturally recovering animals downregulating susceptibility to picrotoxin-induced epilepsy. This figure shows the results of ednerpicmaleate preventing epileptic seizures during the recovery phase from brain injury, and CNQX inhibition of AMPA receptor function in the compensatory region of naturally recovering animals downregulating susceptibility to picrotoxin-induced epilepsy. This figure shows the results of ednerpicmaleate preventing epileptic seizures during the recovery phase from brain injury, and CNQX inhibition of AMPA receptor function in the compensatory region of naturally recovering animals downregulating susceptibility to picrotoxin-induced epilepsy.

[0012] The embodiments of the present invention will be described in detail below, but the present invention is not limited in any way to the embodiments described below, and can be implemented with appropriate modifications within the scope of the object of the present invention.

[0013] <A therapeutic and / or prophylactic agent for at least one type of epilepsy selected from the group consisting of epilepsy after brain injury and epilepsy after the formation of a compensatory area of ​​the brain> The first aspect of the present invention is a therapeutic and / or prophylactic agent for epilepsy after brain injury, comprising a compound represented by the above general formula [1] or a salt thereof. The second aspect of the present invention is a therapeutic and / or prophylactic agent for epilepsy after the formation of a compensatory area of ​​the brain, comprising a compound represented by the above general formula [1] or a salt thereof. The therapeutic and / or prophylactic agent according to the first aspect can treat and / or prevent epileptic seizures (e.g., post-stroke epileptic seizures) in brain injury caused by various factors such as stroke (preferably during the recovery process in brain injury) by balancing excitatory and inhibitory synaptic inputs in the compensatory area formed after brain injury. The therapeutic and / or prophylactic agent according to the second embodiment can treat and / or prevent epileptic seizures (e.g., post-stroke epileptic seizures) that occur after the formation of a compensatory area following brain injury due to various factors such as stroke (preferably during the recovery process in brain injury), by balancing excitatory and inhibitory synaptic inputs. The fact that the therapeutic and / or prophylactic agents according to the first and second embodiments balance excitatory and inhibitory synaptic inputs is demonstrated in the examples section described later, where, in the pyramidal cells of the cerebral cortex in the compensatory area of ​​the brain, only excitatory synaptic input was enhanced in the spontaneously recovering animal group that was not administered the compound represented by the general formula [1] or its salt, resulting in a disruption of the balance between excitation and inhibition, whereas in the group administered the compound represented by the general formula [1] or its salt, both excitatory and inhibitory synaptic inputs were enhanced. Furthermore, this has been demonstrated by the fact that in the spontaneously recovering animal group that was not administered the compound represented by the general formula [1] or its salt, the threshold for drug-induced epilepsy was significantly lower compared to the animal group that was administered the compound represented by the general formula [1] or its salt.

[0014] Brain injury refers to a condition in which a part of the brain is damaged, regardless of the cause. Examples of brain injuries include stroke, cerebral infarction, cerebral hemorrhage, traumatic brain injury, head injury, cerebral contusion, acquired brain injury, brain tumor, brain tumor removal, and encephalitis.

[0015] In the therapeutic and / or prophylactic agents according to the first and second embodiments, the compound represented by the general formula [1] or a salt thereof can regulate and / or improve the ratio of excitatory and inhibitory transmission efficiency in nerve cells and neural circuits, and preferably balances excitatory and inhibitory synaptic input to pyramidal neurons in the compensatory cortical region by promoting synaptic translocation of not only AMPAR but also GABAR (γ-aminobutyric acid receptor) during the functional recovery process after brain injury. This makes it possible to treat and / or prevent at least one type of epilepsy selected from the group consisting of epilepsy after brain injury and epilepsy after the formation of the compensatory cortex. The compound represented by the above general formula [1] or a salt thereof is preferably a modulatory and / or improving agent for the excitation / inhibitory balance (Excitatory / Inhibitory [E / I] balance) of nerve cells (preferably neural circuits) in vivo and / or in vitro, more preferably a modulatory and / or improving agent that corrects an imbalance in the excitation / inhibitory balance in nerve cells (preferably neural circuits) (for example, an increase in excitatory synaptic input relative to a decrease, no change, or no increase in inhibitory synaptic input), and even more preferably an agent that modulates and / or improves the above balance so that the activity of nerve cells (preferably neural circuits) does not become too biased towards the excitatory side. The present invention also relates to a modulatory and / or improving agent for the excitation / inhibitory balance (Excitatory / Inhibitory [E / I] balance) of nerve cells (preferably neural circuits), comprising the compound represented by the above general formula [1] or a salt thereof.

[0016] (The compound represented by the general formula [1] above or its salt) A halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. C １－６ Alkyl groups are linear or branched C groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl groups. １－６ It means alkyl group. ２－６ Alkenyl groups are C groups such as vinyl, propenyl, butenyl, pentenyl, and hexenyl. ２－６ This refers to the alkenyl group. (Acyl C) １－６Alkyl compounds include acyl C compounds such as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methoxybenzoylmethyl, and 1-benzoylethyl. １－６ It means alkyl group. Acyloxy C １－６ Alkyl compounds include acyloxymethyl, such as acetoxymethyl, propionyloxymethyl, and pivaloyloxymethyl. １－６ It means alkyl group. １－６ Alkyl groups refer to groups such as phenylsulfenylmethyl and 2-(p-nitrophenylsulfenyl)ethyl.

[0017] Arylsulfonyl C １－６ Alkyl compounds include, for example, arylsulfonyl C compounds such as p-toluenesulfonyl ethyl. １－６ This refers to alkyl groups. Nitrogen-containing heterocyclic C １－６ Alkyl compounds are nitrogen-containing heterocyclic C molecules, such as phthalimidomethyl and succinimidomethyl. １－６ It means alkyl group. ３－８ Cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. ３－８ This refers to a cycloalkyl group. １－６ Alkylthio C １－６ Alkyl compounds include, for example, methylthiomethyl, ethylthiomethyl, and propylthiomethyl. １－６ Alkylthio C １－６ It means alkyl group. １－６ Alkoxy C １－６ Alkyl alkyl groups include, for example, methoxymethyl and 1-ethoxyethyl C １－６ Alkyloxy C １－６ This refers to alkyl groups. (Aryl C) １－６ Alkyloxy C １－６ Alkyl compounds include aryl C compounds such as benzyloxymethyl and phenethyloxymethyl. １－６ Alkyloxy C １－６ It means alkyl group.

[0018] C １－６ Alkoxy groups are linear or branched C groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, and hexyloxy groups. １－６ This refers to an alkyloxy group. ２－６ Alkenyloxy groups include C13 groups such as vinyloxy, propenyloxy, butenyloxy, pentenyloxy, and hexenyloxy. ２－６ This refers to an alkenyloxy group.

[0019] C １－６ Alkylthio groups include C13, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, and hexylthio. １－６ It means an alkylthio group.

[0020] An aryl group refers to a phenyl, naphthyl, indanyl, or indenyl group. An aryloxy group refers to a phenyloxy, naphthyloxy, indanyloxy, or indenyloxy group. Aryl C １－６ Alkyl groups include aryl C groups such as benzyl, diphenylmethyl, trityl, and phenethyl groups. １－６ This refers to an alkyl group. An arylthio group refers to a phenylthio, naphthylthio, indanylthio, or indenylthio group.

[0021] Acyl groups include C groups such as formyl, acetyl, isovaleil, propionyl, and pivaloyl. ２－６ Alkanoyl groups, aryl C groups such as benzylcarbonyl １－６ This refers to an alkylcarbonyl group or an alloyl group such as benzoyl and naphthoyl. １－６ Alkyloxycarbonyl groups are linear or branched carbon atoms such as methoxycarbonyl, ethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 2-ethylhexyloxycarbonyl, tert-butoxycarbonyl, and tert-pentyloxycarbonyl. １－６ This refers to an alkyloxycarbonyl group.１－６ Alkyloxycarbonyl groups include, for example, aryl C groups such as benzyloxycarbonyl and phenethyloxycarbonyl. １－６ This refers to an alkyloxycarbonyl group. An aryloxycarbonyl group refers to a group such as phenyloxycarbonyl. A heterocyclic oxycarbonyl group refers to a group such as 2-furfuryloxycarbonyl and 8-quinolyloxycarbonyl.

[0022] C １－６ Alkyl sulfonyl groups include, for example, methylsulfonyl, ethylsulfonyl, and propylsulfonyl. １－６ This refers to an alkylsulfonyl group. An arylsulfonyl group refers to a phenylsulfonyl, p-toluenesulfonyl, or naphthylsulfonyl group, among others.

[0023] C １－６ Alkylamino groups include mono- or di-C groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, diisopropylamino, and dibutylamino. １－６ It means alkylamino group.

[0024] Heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, homopiperidinyl, morpholyl, thiomorpholyl, tetrahydroquinolinyl, tetrahydroisoquinolyl, quinuclidinyl, imidazolinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, quinolyl, quinolidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, prinyl, furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, isoxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, be This refers to heterocyclic groups of five-membered or six-membered rings, fused rings, or bridging rings containing at least one heteroatom selected from nitrogen, oxygen, or sulfur atoms, such as nzothiazolyl, quinoxalyl, dihydroquinoxalyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3-4H-1-thianaphthyl, 2,3-dihydrobenzofuranyl, benzo[b]dioxanyl, imidazo[2,3-a]pyridyl, benzo[b]piperazinyl, clomenyl, isothiazolyl, isoxazolyl, oxadiazolyl, pyridadinyl, isoindolyl, isoquinolyl, 1,3-benzodioxonyl, and 1,4-benzodioxanyl groups.

[0025] Oxygen-containing heterocyclic groups refer to groups such as 2-tetrahydropyranyl and 2-tetrahydrofuranyl. Sulfur-containing heterocyclic groups refer to groups such as tetrahydrothiopyranyl. Substituted silyl groups refer to groups such as trimethylsilyl, triethylsilyl, and tributylsilyl. C １－６ Alkylsilyl C １－６ An alkyl group refers to a group such as 2-(trimethylsilyl)ethyl.

[0026] The amino protecting group includes all groups that can be used as a protecting group for a normal amino group. For example, it includes groups described in W. Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pages 696 - 868, 2007, John Wiley & Sons, INC. Specifically, for example, an acyl group, C １－６ an alkyloxycarbonyl group, an aryl C １－６ alkyloxycarbonyl group, an aryloxycarbonyl group, an aryl C １－６ alkyl group, C １－６ an alkoxy C １－６ alkyl group, an aryl C １－６ alkyloxy C １－６ alkyl group, an arylthio group, C １－６ an alkylsulfonyl group, an arylsulfonyl group, and a substituted silyl group, etc. are included.

[0027] The hydroxyl protecting group includes all groups that can be used as a protecting group for a normal hydroxyl group. For example, it includes groups described in W. Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pages 16 - 299, 2007, John Wiley & Sons, INC. Specifically, for example, an acyl group, C １－６ an alkyloxycarbonyl group, an aryl C １－６ alkyloxycarbonyl group, a heterocyclic oxycarbonyl group, C １－６ alkyl group, C ２－６ an alkenyl group, an aryl C １－６ alkyl group, an oxygen-containing heterocyclic group, a sulfur-containing heterocyclic group, C １－６ an alkoxy C １－６ alkyl group, an aryl C １－６ alkyloxy C １－６ alkyl group, C １－６Examples include an alkylsulfonyl group, an arylsulfonyl group, and a substituted silyl group.

[0028] Examples of the carboxyl protecting group include all groups that can be used as a protecting group for a normal carboxyl group. For example, groups described in W. Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 533 - 643, 2007, John Wiley & Sons, INC. Specifically, for example, a C １－６ alkyl group, a C ２－６ alkenyl group, an aryl group, an arylC １－６ alkyl group, an acylC １－６ alkyl group, an arylthioC １－６ alkyl group, an arylsulfonylC １－６ alkyl group, an oxygen-containing heterocyclic group, a C １－６ alkylsilylC １－６ alkyl group, an acyloxyC １－６ alkyl group, a nitrogen-containing heterocyclicC １－６ alkyl group, a C ３－８ cycloalkyl group, a C １－６ alkoxyC １－６ alkyl group, an arylC １－６ alkyloxyC １－６ alkyl group, a C １－６ alkylthioC １－６ alkyl group, a substituted silyl group, and the like.

[0029] R １ and R ２ In the C １－６ alkyl group, aryl group, arylC １－６ alkyl group, C １－６ alkoxy group, aryloxy group, C １－６ alkylthio group, arylthio group, C ２－６ alkenyl group, C ２－６ alkenyloxy group, C １－６ alkylamino group, C １－６Alkylsulfonyl groups, arylsulfonyl groups, carbamoyl groups and heterocyclic groups, as well as R ３ C in １－６ The substituents of the alkylamino group include halogen atoms and C １－６ alkyl group, C ３－８ Cycloalkyl groups, aryl groups, C １－６ Alkoxy group, aryloxy group, C １－６ Alkylthio group, arylthio group, C ２－６ Alkenyl group, C １－６ Alkyl sulfonyl group, aryl sulfonyl group, C １－６ Examples of groups include alkylamino groups, optionally protected amino groups, optionally protected hydroxyl groups, optionally protected carboxyl groups, acyl groups, and heterocyclic groups.

[0030] Examples of salts of compounds represented by general formula [1] include salts at basic groups such as amino groups or acidic groups such as hydroxyl or carboxyl groups, which are commonly known. Examples of salts at basic groups include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid; salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid, and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid.

[0031] Examples of salts in acidic groups include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-efenamine, and N,N'-dibenzylethylenediamine.

[0032] Among the salts mentioned above, preferred salts include those that are pharmacologically acceptable, and maleic acid is a more preferred salt.

[0033] In the case of a compound represented by general formula [1] or a salt thereof, if isomers (for example, optical isomers, geometric isomers, and tautomers) exist, the present invention encompasses all of these isomers, as well as hydrates, solvates, and all crystalline forms.

[0034] The following compounds are preferred as compounds represented by the above general formula [1] or salts thereof: R １ However, hydrogen atoms, halogen atoms or C １－６ Compounds with an alkoxy group are preferred, R １ However, compounds containing hydrogen atoms are more preferable. ２ However, hydrogen atoms, halogen atoms or C １－６ Compounds with an alkoxy group are preferred, R ２ However, compounds containing hydrogen atoms are more preferable. ３ However, a compound with a protected hydroxyl group is preferred, R ３ However, compounds with a hydroxyl group are more preferred. Compounds where m is 2 and n is 2 or 3 are preferred, and compounds where m is 2 and n is 3 are more preferred.

[0035] As a compound represented by the above general formula [1] or a salt thereof, R １ and R ２ However, they may be the same or different hydrogen atoms, halogen atoms, or C １－６ It is an alkoxy group, m is 2, n is 2 or 3, R ３ However, compounds or salts thereof that have a hydroxyl group that may be protected are particularly preferred.

[0036] It is particularly preferable that the compound represented by general formula [1] is 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidine-3-ol (i.e., ednerpic).

[0037] The compound represented by the above general formula [1] or a salt thereof can be produced by methods known in themselves or by appropriate combinations thereof, and by the method described in International Publication No. 03 / 035647.

[0038] Another aspect of the present invention is a compound represented by the above general formula [1] or a salt thereof for use in the treatment and / or prevention of at least one type of epilepsy selected from the group consisting of epilepsy after brain injury and epilepsy after the formation of the brain compensatory area. Another aspect of the present invention is the use of a compound represented by the above general formula [1] or a salt thereof for producing a therapeutic and / or prophylactic agent for at least one type of epilepsy selected from the group consisting of epilepsy after brain injury and epilepsy after the formation of the brain compensatory area. Another aspect of the present invention is a method for the treatment and / or prevention of at least one type of epilepsy selected from the group consisting of epilepsy after brain injury and epilepsy after the formation of the brain compensatory area, comprising administering to a patient in need of treatment and / or prevention an effective amount of the compound represented by the above general formula [1] or a salt thereof.

[0039] <Pharmaceutical composition comprising therapeutic and / or preventive agents according to the first and second embodiments> The third embodiment of the present invention is a pharmaceutical composition comprising therapeutic and / or preventive agents according to the first and second embodiments. The pharmaceutical composition according to the third embodiment can treat and / or prevent epileptic seizures (e.g., post-stroke epileptic seizures) in brain injury caused by various factors such as stroke (preferably during the recovery process in brain injury).

[0040] The therapeutic and / or prophylactic agents according to the first and second embodiments can be compounded with various pharmaceutical additives such as excipients, binders, disintegrants, disintegration inhibitors, caking / adhesion inhibitors, lubricants, absorbent / adsorbent carriers, solvents, bulking agents, isotonic agents, solubilizers, emulsifiers, suspending agents, thickeners, coating agents, absorption enhancers, gelling / coagulation enhancers, light stabilizers, preservatives, moisture-proofing agents, emulsifying / suspending / dispersion stabilizers, color inhibitors, deoxidizing / oxidizing agents, flavoring / odorizing agents, colorants, foaming agents, defoaming agents, analgesics, antistatic agents, buffering / pH adjusters, etc., to form pharmaceutical compositions (pharmaceutical preparations) according to the third embodiment, such as oral preparations (tablets, capsules, powders, granules, fine granules, pills, suspensions, emulsions, liquids, syrups, etc.), injections, eye drops, etc. These various drugs are formulated by conventional methods.

[0041] Oral solid preparations such as tablets, powders, and granules contain excipients such as lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, anhydrous dicalcium phosphate, partially pregelatinized starch, corn starch, and alginic acid; binders such as simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, sodium alginate, acacia gum, hydroxypropyl methylcellulose, hydroxypropylcellulose, water, and ethanol; disintegrants such as dried starch, alginic acid, agar powder, starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, calcium carboxymethylcellulose, and sodium starch glycolate; and stearyl alcohol. The solid formulation can be prepared using pharmaceutical additives for solid formulation, such as disintegration inhibitors like sodium, stearic acid, cocoa butter, and hydrogenated oil; anticaking and anti-adhesion agents like aluminum silicate, calcium hydrogen phosphate, magnesium oxide, talc, and anhydrous silicic acid; lubricants like carnauba wax, light anhydrous silicic acid, aluminum silicate, magnesium silicate, hydrogenated oil, hydrogenated vegetable oil derivatives, sesame oil, bleached beeswax, titanium dioxide, dried aluminum hydroxide gel, stearic acid, calcium stearate, magnesium stearate, talc, calcium hydrogen phosphate, sodium lauryl sulfate, and polyethylene glycol; absorption enhancers like quaternary ammonium salts, sodium lauryl sulfate, urea, and enzymes; and absorption and adsorption carriers like starch, lactose, kaolin, bentonite, anhydrous silicic acid, hydrated silicon dioxide, magnesium aluminometasilicate, and colloidal silicic acid, according to conventional methods. Furthermore, tablets may, if necessary, be coated with a conventional casing, such as sugar-coated tablets, gelatin-coated tablets, gastric-soluble coated tablets, enteric-coated tablets, and water-soluble film-coated tablets. Capsules are prepared by mixing the various pharmaceuticals exemplified above and filling them into hard gelatin capsules, soft capsules, etc.Furthermore, various liquid formulation additives such as solvents, bulking agents, isotonic agents, solubilizers, emulsifiers, suspending agents, and thickeners mentioned above can be used to prepare aqueous or oily suspensions, solutions, syrups, and elixirs according to conventional methods.

[0042] Injectable preparations may be prepared according to conventional methods using, for example, diluents such as water, ethyl alcohol, macrogol, propylene glycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid, and sodium hydroxide; pH adjusters and buffers such as sodium citrate, sodium acetate, and sodium phosphate; stabilizers such as sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid, and thiolactic acid; isotonic agents such as sodium chloride, glucose, mannitol, or glycerin; solubilizers such as sodium carboxymethylcellulose, propylene glycol, sodium benzoate, benzyl benzoate, urethane, ethanolamine, and glycerin; analgesics such as calcium gluconate, chlorobutanol, glucose, and benzyl alcohol; and pharmaceutical additives for liquid formulation, such as local anesthetics.

[0043] Eye drops may be prepared by appropriately blending preservatives such as chlorobutanol, sodium dehydroacetate, benzalkonium chloride, cetylpyridium chloride, phenethyl alcohol, methyl parahydroxybenzoate, and benzethonium chloride; buffering agents such as borax, boric acid, and potassium dihydrogen phosphate; thickeners such as methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, sodium carboxymethylcellulose, and chondroitin sulfate; solubilizers such as polysorbate 80 and polyoxyethylene hydrogenated castor oil 60; stabilizers such as sodium edetate and sodium bisulfite; and isotonic agents such as sodium chloride, potassium chloride, and glycerin, in accordance with conventional methods.

[0044] The pharmaceutical composition according to the third embodiment can treat and / or prevent epileptic seizures (e.g., post-stroke epileptic seizures) in brain damage caused by various factors such as stroke (preferably during the recovery process in brain damage).

[0045] The target population for the therapeutic and / or prophylactic agents according to the first and second embodiments, and the pharmaceutical composition according to the third embodiment, includes mammals such as humans, cattle, horses, dogs, cats, pigs, sheep, rats, and mice, and is preferably humans. The method of administering the therapeutic and / or prophylactic agents according to the first and second embodiments, and the pharmaceutical composition according to the third embodiment, is not particularly limited, but is appropriately determined according to the form of the formulation, the age, sex and other conditions of the target population (e.g., patient), and the severity of the symptoms of the target population (e.g., patient). There are no particular restrictions on the mode of administration of the therapeutic and / or prophylactic agents according to the first and second embodiments, and the pharmaceutical composition according to the third embodiment, and may be administered to the target population by routes such as oral, intramuscular, intravenous, transdermal, nasal, and inhalation. Such routes of administration are appropriately selected by those skilled in the art. The dosage, frequency of administration, duration of administration, etc., are also appropriately determined by those skilled in the art based on the type of target population, sex, age, symptoms, etc. The dosage of the active ingredient in the therapeutic and / or prophylactic agent according to the first and second embodiments, and the pharmaceutical composition according to the third embodiment, is appropriately selected according to the method of use, the age and sex of the recipient (e.g., patient), the form of the disease, and other conditions. However, for the recipient (e.g., adult), it is usually sufficient to administer 0.1 to 1000 mg per day in one to several divided doses, preferably 40 to 500 mg per day in one to several divided doses.

[0046] (A method for treating and / or preventing at least one type of epilepsy selected from the group consisting of epilepsy after brain injury and epilepsy after the formation of a compensatory brain area) The present invention also relates to a method for treating and / or preventing at least one type of epilepsy selected from the group consisting of epilepsy after brain injury and epilepsy after the formation of a compensatory brain area. The method for treating and / or preventing at least one type of epilepsy selected from the group consisting of epilepsy after brain injury and epilepsy after the formation of a compensatory brain area comprises administering a compound represented by the above general formula [1] or a salt thereof to a target. It is preferable that the above administration adjusts and / or improves the excitation / inhibitory balance (Excitatory / Inhibitory [E / I] balance) of nerve cells (preferably neural circuits). In the above method for treatment and / or prevention, the adjustment and / or improvement of the excitation / inhibitory balance (Excitatory / Inhibitory [E / I] balance) of nerve cells (preferably neural circuits) is the same as described above for the treatment and / or preventive agents according to the first and second embodiments. In the above-described treatment and / or preventive methods, the target recipients and methods of administration are the same as those described above for the treatment and / or preventive agents related to the first and second embodiments, and for the pharmaceutical compositions related to the third embodiment.

[0047] The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited to these examples.

[0048] <<Examples>> 1. Materials and Methods Long-Evans male rats (280-300g, 8 weeks old) were purchased from SLC Japan. All animals were kept in a 12-hour light-dark cycle, and water and food were provided ad libitum. All animal experiments were conducted in accordance with the "Guidelines for the Rearing and Use of Laboratory Animals" of Yokohama City University. The research protocol was approved by the Animal Welfare Committee of Yokohama City University (Approval Number: F-A-22-053). All surgical procedures were performed under anesthesia, and every effort was made to minimize pain.

[0049] <Reaching Task> All behavioral experiments were conducted in a soundproof room under dim lighting conditions (20-25 lux). Rats were allowed to acclimate to the room 30 minutes before each behavioral session. During the acclimatization, learning, and rehabilitation training periods, the rats underwent food restriction (5 g / day / animal body weight) only one day before each session, but water was available freely. A food pellet stand 3 cm high was installed in the reaching task apparatus (13.1 cm wide, 40 cm high, 27 cm deep). Furthermore, slits measuring 1.3 cm wide and 20 cm high were placed in the lower center or on either side of the device (XU, T., YU, X., PERLIK, AJ, TOBIN, WF, ZWEIG, JA, TENNANT, K., JONES, T. & ZUO, Y. 2009. Rapid formation and selective stabilization of synapses for enduring motor memories. Nature, 462, 915-9). All rats were handled for 5 minutes each for 3 days. All rats were accustomed to the device for 4 days: rats were allowed to move freely within the device for 10 minutes, and pellets were placed on the feeding platform. On the 4th day, the rats' dominant paw was assessed. After acclimatization was complete, the learning period was started. During the learning period, pellets were placed diagonally in front of the slits, and the rats were instructed to use their dominant forelimb in each session. Each session consisted of either 60 trials or 20 minutes over 5 days. Success was defined as being able to retrieve the pellet in one reach without dropping it. Failure was defined as dropping the pellet after taking it out, failing to reach it despite multiple attempts, turning the pellet over, or using the other forelimb (uninjured limb). The success rate was calculated by dividing the number of successful attempts by the total number of attempts. Only rats with a success rate of 40% or higher on the final day of learning were used in the experiment (Non-Patent Literature 1).

[0050] <Cryogenic Injury> After the motor learning phase of the reaching task was completed, cryogenic injury was induced in the motor cortex of rats using an ophthalmic surgical cryosystem (Keeler Instruments) (TABUSE, M., YAGUCHI, M., OHTA, S., KAWASE, T. & TODA, M. 2010. A simple behavioral test for locomotor function after brain injury in mice. J Clin Neurosci, 17, 1412-6). Briefly, rats were deeply anesthetized with a 4% isoflurane / 96% oxygen mixture. The skin on the skull was cut and gently pushed sideways. As shown in Figure 1A, which will be detailed later, the rostral forelimb region (RFA) and caudal forelimb region (CFA) were identified, and the area above the motor cortex (mild injury: 2.5 mm anterior to bregma, 2.5 mm lateral to bregma, 0 mm anterior to bregma, 2.5 mm lateral to bregma; severe injury: 2.5 mm anterior to bregma, 2.5 mm lateral to bregma) was gently punctured with a trefin (5.0 mm in diameter) (TENNANT, KA, ADKINS, DL, DONLAN, NA, ASAY, AL, THOMAS, N., KLEIM, JA & JONES, TA 2011. The organization of the forelimb representation of the C57BL / 6 mouse motor cortex as defined by intracortical microstimulation and cytoarchitecture. Cereb Cortex, 21, 865-76., STARKEY, ML, BLEUL, C., ZoRNER, B., LINDAU, NT, MUEGGLER, T., RUDIN, M. & SCHWAB, ME 2012. Back seat driving: hindlimb corticospinal neurons assume forelimb control following ischaemic stroke. Brain, 135, 3265-81.).

[0051] A metal probe cooled with carbon dioxide was applied to each rat for 30 seconds at a time. For minor injuries (spontaneous recovery model), 3 points were applied for two cycles, and for severe injuries (ednerpic maleate administration recovery model), 2 points were applied for four cycles. After the procedure, the skin was sutured. During the procedure, the rats were placed on a heating pad and returned to their original cages after their mobility recovered. An animal was defined as having suffered an injury if its success rate decreased by 45% or more compared to before the injury (final day of learning).

[0052] <Rehabilitation Training> Rehabilitation can be achieved by restoring and / or reducing functional impairments. Functional impairments that can be restored and / or reduced by rehabilitation refer to functional impairments resulting from brain injury, and specifically include motor function impairments, sensory function impairments, and language function impairments. Preferably, motor function impairments and language function impairments are included, and more preferably, motor function impairments are included. Even more preferably, motor function impairments of the limbs are included. During the rehabilitation training period, rats were placed in the device for 30 minutes, and several pellets were placed on a platform in front of the slit so that they could reach the pellets with the forelimb of the affected limb. During the rehabilitation period, ednerpicmaleate (84 mg / kg body weight) or vehicle (distilled water) was administered daily 30 minutes before training (Non-Patent Literature 1). Ednerpicmaleate was administered using an oral tube.

[0053] <Motor Function Assessment> For the assessment of forelimb motor function, the relative recovery rate (RRR) in the reaching task was used. The RRR was calculated as follows: Relative recovery rate (RRR) = (Success rate at the time of assessment [POD3, 10, 17, etc.] - Success rate at the post-injury assessment [POD3]) / (Success rate on the last learning day [pre-injury] - Success rate at the post-injury assessment [POD3]) Here, POD means post-operation days.

[0054] (1) Spontaneously recovering rats (Figures 1A-1I, 3A-3D, 4A-4D, 5A and 5B, and 6B and 6C): After the learning period (i.e., before rehabilitation training), rats were induced with cryogenic injury (mild injury), and their reaching movements were tested on postoperative days 3, 10, and 17 (POD 3, 10, and 17). With this mild injury, approximately 60% of the rats recovered forelimb function through rehabilitation training. (2) Ednerpycmaleate-administered rats (Figures 1B-1D, 1J, 2, 3E-3H, 4E-4H, 5C and 5D, and 6B and 6D): After the learning period, rats were induced with cryogenic injury (severe injury), and they were tested with a reaching task on PODs 3, 10, and 17. In this severe injury, the rats were unable to recover forelimb function without rehabilitation training and administration of ednerpycmaleate. The rats were tested 30 minutes after administration of ednerpycmaleate (84 mg / kg body weight) or the solvent (vehicle).

[0055] <Electrophysiological analysis> Electrophysiological analysis was performed as previously reported (JITSUKI, S., TAKEMOTO, K., KAWASAKI, T., TADA, H., TAKAHASHI, A., BECAMEL, C., SANO, A., YUZAKI, M., ZUKIN, RS, ZIFF, EB, KESSELS, HW & TAKAHASHI, T. 2011. Serotonin mediates cross-modal reorganization of cortical circuits. Neuron, 69, 780-92., ABE, H., JITSUKI, S., NAKAJIMA, W., MURATA, Y., JITSUKI-TAKAHASHI, A., KATSUNO, Y., TADA, H., SANO, A., SUYAMA, K., MOCHIZUKI, N., KOMORI, T., MASUYAMA, H., The procedure was carried out according to OKUDA, T., GOSHIMA, Y., HIGO, N. & TAKAHASHI, T. 2018. CRMP2-binding compound, edonerpic maleate, accelerates motor function recovery from brain damage. Science, 360, 50-57.). After the final assessment of forelimb motor function, the rats were anesthetized with isoflurane / oxygen mixed gas, and the brains were immediately removed and gas (95% Oxygen) was administered. ２ and 5% CO ２The cells were transferred to ice-cold dissection buffer via a refrigerant. The cells were then sliced ​​into coronary brain slices (400 μm, Leica VT1200) in the dissection buffer. Next, the slices were incubated in gas-passed artificial cerebrospinal fluid (ACSF). Patch recording pipettes (3–7 MΩ) were filled with intracellular solution as previously reported (JITSUKI, S., TAKEMOTO, K., KAWASAKI, T., TADA, H., TAKAHASHI, A., BECAMEL, C., SANO, A., YUZAKI, M., ZUKIN, RS, ZIFF, EB, KESSELS, HW & TAKAHASHI, T. 2011. Serotonin mediates cross-modal reorganization of cortical circuits. Neuron, 69, 780-92., MIYAZAKI, T., TAKASE, K., NAKAJIMA, W., TADA, H., OHYA, D., SANO, A., GOTO, T., HIRASE, H., MALINOW, R. & TAKAHASHI, T. 2012. Disrupted cortical function underlies behavior dysfunction due to social isolation. J Clin Invest, 122, 2690-701., NAKAJIMA, W., JITSUKI, S., SANO, A. & TAKAHASHI, T. 2016. Sustained Enhancement of Lateral Inhibitory Circuit Maintains Cross Modal Cortical Reorganization. PLoS One, 11, e0149068.).

[0056] (Recording of spontaneously occurring microexcitatory postsynaptic currents and spontaneously occurring microinhibitory postsynaptic currents) Spontaneous microexcitatory postsynaptic currents and spontaneously occurring microinhibitory postsynaptic currents are considered indicators of the characteristics (excitability and inhibitory properties) of nerve cells, respectively. Here, "spontaneous" refers to a state in which no stimulation is applied (a state in which input from other nerve cells is blocked, and the characteristics of the nerve cell itself that was recorded). "Microexcitatory postsynaptic currents" will also be simply referred to as "mEPSC" (miniature excitatory post-synaptic current) below, and "microinhibitory postsynaptic currents" will also be simply referred to as "mIPSC" (miniature inhibitory post-synaptic current) below. For both mEPSC and mIPSSC, amplitude is considered an indicator that primarily reflects "the number and function of postsynaptic receptors (AMPA receptors in the case of excitatory (mEPSC) and GABA receptors in the case of inhibitory (mIPSSC))," while frequency is an indicator that primarily reflects "the probability of neurotransmitter release from the presynaptic terminal (glutamate, etc. in the case of excitatory neurotransmitters, GABA, etc. in the case of inhibitory neurotransmitters)."

[0057] For recording mEPSCs and mIPSCs in layer 5 pyramidal neurons or layer 2 / 3 pyramidal neurons of the surrounding cortex, we selected sections corresponding to Figures 11-14 of Paxinos & Watson's *The Rat Brain in Stereotaxic Coordinates (compact sixth edition)* (PAXINOS, G. & WATSON, C. 2009. *The Rat Brain in Stereotaxic Coordinates*, Elsevier / Academic.; PAXINOS, G. & WATSON, C. 2006. *The rat brain in stereotaxic coordinates: hard cover edition*, Elsevier.). The recording chamber was perfused with artificial cerebrospinal fluid (ACSF) containing 0.5 μM tetrodotoxin (TTX), as previously reported (MITSUSHIMA, D., SANO, A. & TAKAHASHI, T. 2013. A cholinergic trigger drives learning-induced plasticity at hippocampal synapses. Nat Commun, 4, 2760.). The detection threshold for mEPSC was set to 2 × RMS (root mean square) noise. mEPSC and mIPSC were acquired from essentially the same neurons using inversion potentials, although for some neurons only mEPSC was recorded due to time constraints. The E / I ratio was calculated by dividing the mEPSC value of each recorded cell by the mIPSSC value.

[0058] <Inhibition of Compensatory Area Function Using AMPA Receptor Inhibitor (CNQX)> Rats with a RRR of more than 0.40 as assessed by the above motor function evaluation after 14 days of rehabilitation training (POD 17) were used in this study. A mixture of 40 μM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor inhibitor, and a fluorescent dye marker (Alexa 546), 0.2 μl of which was locally injected into the damaged cortex (compensatory area) at POD 18 (microinjection using a stereotactic device), and motor function was evaluated 30 minutes later. Two to three days later (POD 20-21), 0.2 μl of 0.2% dimethyl sulfoxide (DMSO) was locally injected into the same site in the same rats as the control group, and motor function was evaluated 30 minutes later. In this example, the compensatory area corresponds to the primary somatosensory cortex and jaw region (S1J) in normal animals. The injection sites were determined by aligning the tip of a glass needle, tilted at a 30-degree angle to the horizontal plane, 5.0 mm outward (on the injured side) from the bregma. Three injection sites were then administered anteriorly (1.1 mm, 1.6 mm, and 2.1 mm), and three additional injection sites were created by advancing the needle 1.5 mm, 2.5 mm, and 3.5 mm in the direction of the tilt from each of these sites, for a total of nine injection sites. In the control experiment, the same injections were administered on the opposite side of the injury.

[0059] <Insertion of jugular vein catheter for drug (picrotoxin) administration> Transvenous catheters were inserted in spontaneously recovering rats and ednerpicmaleate-administered rats after 14 days of rehabilitation training. A medical tube (Silascon, manufactured by Kaneka Medix) with an inner diameter of 0.3 mm and an outer diameter of 0.64 mm was cut to a length of 12.5 cm, and a 16 cm silk suture (manufactured by Natsume Seisakusho) was tied perpendicular to the tube 2.5 cm from the tip and secured with adhesive. The rats were anesthetized with isoflurane / oxygen mixed gas and the jugular vein near the atrium was exposed. After puncturing the jugular vein with a needle attached to a catheter, the catheter was removed from the needle, and the tip of the catheter (2.5 cm) was inserted into the jugular vein (FURUTA, M., FUNABASHI, T. & KIMURA, F. 2001. Intracerebroventricular administration of ghrelin rapidly suppresses pulsatile luteinizing hormone secretion in ovariectomized rats. Biochem Biophys Res Commun, 288, 780-5.). To prevent blood clotting within the catheter, 1% heparinized saline was administered, and after ensuring reflux blood flow and negative pressure in the catheter, a silk suture was tied to the muscle near the jugular vein. The other end of the catheter was led out of the body through subcutaneous tissue on the back. A plug was inserted into the tip of the catheter to prevent blood from flowing back into the catheter. The skin was sutured postoperatively. During the surgery, the rats were held on a heated pad and returned to their original cages after their mobility recovered.

[0060] <Epilepsy induction using picrotoxin> Picrotoxin (γ-aminobutyric acid type A receptor (GABA) ＡChemical seizure induction was performed using an antagonist (R). In spontaneously recovered rats, ednerpicmaleate-treated rats, and control (sham-operated) rats, 0.5 mg of picrotoxin per kg of body weight was administered via a jugular vein catheter implanted on POD 17. The level of induced epileptic seizures was then observed (PERICIC, D. & BUJAS, M. 1997. Sex differences in the response to GABA antagonists depend on the route of drug administration. Exp Brain Res, 115, 187-90.). To assess the stage of epilepsy, the Racine classification (RACINE, RJ 1972. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol, 32, 281-94., CELA, E., MCFARLAN, AR, CHUNG, AJ, WANG, T., CHIERZI, S., MURAI, KK & SJoSTRoM, PJ 2019. An Optogenetic Kindling Model of Neocortical Epilepsy. Sci Rep, 9, 5236.) was used. Similar experiments were conducted in rats with and without inhibition of AMPA receptor function in the compensatory cortex using CNQX.

[0061] <Statistics and Graphs> For comparisons between two independent groups, the Mann-Whitney U test or Student t's test was used. For comparisons between three or more independent groups, one-way ANOVA followed by Fisher's LSD test was used. Pearson correlation analysis was used to examine the relationship between two variables. A p < 0.05 was considered statistically significant. Statistical analysis was performed using GraphPad Prism 8 (GraphPad Software). In the graphs, error bars represent the standard error (SEM) of the mean.

[0062] 2. Results <Characteristics of the compensatory cortical region in animals (rats) that recovered from cold injury> In a previous report, it was reported that ednerpic maleate promotes the recovery of motor function from brain injury caused by cold injury in mice (Non-Patent Literature 1). In recovered mice, it was found that the compensatory brain region was located near the site of injury. In this example, first, as shown in Figure 1A, the compensatory brain region of rats in which cold injury was introduced into the motor cortex was examined.

[0063] Figures 1A to 1J show the results of CNQX injection into compensatory brain regions attenuating functional recovery in both spontaneously recovering rats and ednerpycmaleate-induced recovering rats. Figure 1A is a schematic diagram of cortical cryo-injury, where CFA represents the caudal forelimb area and RFA represents the rostral forelimb area in the left panel of Figure 1A. The middle panel of Figure 1A shows a schematic diagram of brain coordinates in cryo-injury. The right panel of Figure 1A is a representative photograph of the brain of a rat that underwent cryo-injury. Figure 1B is a representative photograph of a rat performing a reaching task. Figure 1C shows the time-series change in the average success rate of the rat reaching task (n=27). Figure 1D shows the experimental design and schedule for evaluating forelimb motor function before and after cryo-injury. In Figure 1D, CNQX represents an AMPA receptor inhibitor, and DMSO represents dimethyl sulfoxide (solvent of CNQX) as a control.

[0064] Figure 1E shows the time course of the mean relative recovery rate (RRR) in spontaneously recovering rats after cryo-injury (n=23). Figure 1F shows the correlation between injury area and RRR on postoperative day 17 (POD17) (n=23). In Figure 1F, injury area (%) = (injury area / whole brain area) × 100. Data were analyzed using Pearson correlation coefficient. Figure 1G shows representative images of the cortical cryo-injury area and the CNQX injection area (visualized with red fluorescence of co-injected Alexa 546). Scale bar: 500 μm. Figure 1H shows that CNQX injection into the compensatory area suppressed functional recovery in spontaneously recovering rats. One-way ANOVA and Fisher's LSD test were used (*p < 0.05). Figure 1I shows that CNQX injection on the contralateral side of the cryo-injury did not affect functional recovery in spontaneously recovering rats. A paired t-test was used. Figure 1J shows that CNQX injection into the compensatory area attenuated functional recovery in ednerpycmaleate-induced recovery rats. After one-way ANOVA, Fisher's LSD test was performed (*p < 0.05).

[0065] As shown in Figures 1A to 1C, cryogenic injury was induced in the forelimb region (motor cortex) of the rat cerebral cortex. As shown in Figure 1C, forelimb function was evaluated by the success rate of correctly reaching for and picking up food pellets. As shown in Figure 1D, rehabilitation training for picking up food pellets was performed on the injured animals (rats) after the introduction of cryogenic injury. As shown in Figure 1E, in the mild injury (spontaneous recovery model), after two weeks of forelimb rehabilitation, some individuals recovered their success rate in picking up food pellets, while others did not. This was independent of the area of ​​injury in our experimental system, as shown in Figure 1F.

[0066] Based on a previous report (Non-Patent Literature 1) demonstrating that the compensatory brain regions of recovered animals administered ednerpic maleate are located near the injury site in mice, we hypothesized that the compensatory brain regions of rats with cortical cryo-injury are located near the injury site.

[0067] As shown in Figure 1G, CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), an antagonist of AMPAR, was injected into a brain region near the injury site in spontaneously recovering rats that had not been administered ednelpic maleate. Local injection of CNQX into this region resulted in a reduction in the function of the recovered forelimb, as shown in Figure 1H, suggesting that this area is a compensatory brain region. As shown in Figures 1D and 1H, 2-3 days after the CNQX injection, when the function of the recovered forelimb was reduced, the animals recovered to a level equivalent to that before the injection, and additional injection of DMSO into the same brain region as the CNQX injection did not hinder functional recovery. These results indicate that excitatory synaptic transmission function via AMPAR in the compensatory brain region is necessary for functional recovery after brain injury. As shown in Figure 1I, injecting CNQX on the opposite side of the injury maintained the motor function of the recovered forelimb, further demonstrating that the CNQX injection site close to the injury site is a compensatory brain region for recovery.

[0068] Figure 2 shows the results of forelimb motor function recovery only in the ednerpikmaleate-administered group in cases of severe cortical cryo-injury. It shows the time course of the mean RRR after rehabilitation and severe cortical cryo-injury in rats administered ednerpikmaleate (n=9) or vehicle (n=6). An unpaired t-test was used between groups in the same POD (p < 0.05). As shown in Figure 2, to identify the compensatory brain region in ednerpikmaleate-induced recovery rats, severe cryo-injury that could not be recovered without ednerpikmaleate was induced in rats. CNQX was injected into the brain region near the cryo-injury site in rats that recovered with ednerpikmaleate. As shown in Figure 1J, this treatment worsened the motor function of the recovered forelimb, while injection of DMSO into the same site did not affect the function of the recovered forelimb. This further reinforces the idea that the region near the injury site is a compensatory brain region where AMPAR mediates functional recovery.

[0069] <Analysis of microcircuits in compensatory cortical regions of rats recovering from cryo-injury> We further investigated how enhanced synaptic plasticity by ednerpycmaleate alters microcircuits in cortical regions responsible for functional compensation after brain injury.

[0070] Figures 3A to 3H show the results demonstrating that ednerpycmaleate balances excitatory and inhibitory synaptic inputs to pyramidal neurons in the compensatory cortical region during functional recovery after brain injury. The upper left panel in Figure 3A shows representative spontaneous mEPSCs from layer 5 pyramidal neurons in the compensatory cortex after two weeks of rehabilitation training in mildly injured rats that "did not recover" (relative recovery rate [RRR]: 0.00). The lower left panel in Figure 3A shows representative spontaneous mEPSCs from layer 5 pyramidal neurons in the compensatory cortex after two weeks of rehabilitation training in mildly injured rats that "spontaneously recovered" (RRR: 0.89). The right panel in Figure 3A shows the correlation between mEPSC amplitude (pA) and RRR in mildly injured rats. Circles represent plots for rats that "did not recover (RRR < 0.4)", and triangles represent plots for rats that "recovered (RRR ≥ 0.4)" (Figure 3C is similar). The data was analyzed using the Pearson correlation coefficient.

[0071] Figure 3B shows the average amplitude of spontaneous mIPSCs. This is a comparison between rats that did not recover (n=9 rats, 11 cells) and rats that recovered (n=8 rats, 14 cells). An unpaired t-test was used (**p < 0.01). The upper left panel in Figure 3C shows representative values ​​of spontaneous mIPSCs from layer 5 pyramidal neurons in the compensatory area two weeks after rehabilitation training in mildly injured rats that did not recover (RRR: 0.00). The lower left panel in Figure 3C shows representative spontaneous mIPSCs from layer 5 pyramidal neurons in the compensatory area two weeks after rehabilitation training in mildly injured rats that recovered spontaneously (RRR: 0.89). The right panel in Figure 3C shows the correlation between mIPSC amplitude (pA) and RRR in mildly injured rats. Data were analyzed using the Pearson correlation coefficient. Figure 3D shows the average amplitude of spontaneous mIPSCs, comparing rats that did not recover (n=7 rats, 7 cells) and rats that recovered (n=5 rats, 8 cells). n. s. indicates no statistically significant difference.

[0072] The upper left panel in Figure 3E shows representative spontaneous mEPSCs from pyramidal neurons in the 2 / 3 layer of the compensatory cortex after two weeks of rehabilitation training in severely injured control rats (RRR: 0.07). The lower left panel in Figure 3E shows representative spontaneous mEPSCs from the 2 / 3 layer of pyramidal neurons in the compensatory cortex after two weeks of rehabilitation training in severely injured rats (administered ednerpycmaleate) (RRR: 0.56). The right panel in Figure 3E shows the correlation between mEPSC amplitude (pA) and RRR in severely injured rats. Circles represent plots for "vehicle-treated control (RRR < 0.4)" rats, and squares represent plots for "ednerpycmaleate-induced recovery (RRR ≥ 0.4)" rats (Figure 3G is similar). Data were analyzed using Pearson correlation coefficients. Figure 3F shows the mean amplitude of spontaneous mIPSCs, comparing vehicle-treated control rats (n=5, 12 cells) and ednerpycmaleate-induced recovery rats (n=4, 9 cells). An unpaired t-test was used (**p < 0.01). The upper left panel in Figure 3G shows representative values ​​of spontaneous mIPSCs from pyramidal neurons in the 2 / 3 layer of the compensatory cortex after 2 weeks of rehabilitation training in control rats (RRR: 0.07). The lower left panel in Figure 3G shows representative values ​​of spontaneous mIPSCs from pyramidal neurons in the 2 / 3 layer of the compensatory cortex after 2 weeks of rehabilitation training in ednerpycmaleate-induced recovery rats (RRR: 0.56). The right panel in Figure 3G shows the correlation between mIPSC amplitude (pA) and RRR in severely injured rats. Data were analyzed using Pearson correlation coefficients. Figure 3H shows the mean amplitude of spontaneous mIPSSCs, comparing the control group (n=5 rats, 12 cells) with the ednerpycmaleate-induced recovery rat group (n=4 rats, 9 cells). An unpaired t-test was used (**p < 0.01).

[0073] Figures 4A-H show the results demonstrating that the balance between spontaneous mEPSC / mIPSSC frequencies is disrupted in spontaneously recovering rats, while it is maintained in ednerpycmaleate-induced recovery rats. Figure 4A shows the correlation between mEPSC frequency (Hz) and RRR in mildly injured rats. Circles represent plots of mildly injured rats that "did not recover (RRR < 0.4)," and triangles represent plots of mildly injured rats that "recovered (RRR ≥ 0.4)" (Figure 4C is similar). The data were analyzed using the Pearson correlation coefficient. Figure 4B shows the average frequency of spontaneous mEPSC, comparing mildly injured rats that did not recover (n = 9 rats, 11 cells) with mildly injured rats that recovered (n = 8 rats, 14 cells). An unpaired t-test was used (**p < 0.01). Figure 4C shows the correlation between mIPSSC frequency (Hz) and RRR in mildly injured rats, and the data were analyzed using the Pearson correlation coefficient. Figure 4D shows the average frequency of spontaneous mIPSCs, comparing mildly injured rats that did not recover (n=7 rats, 7 cells) with mildly injured rats that recovered (n=5 rats, 8 cells). n.s. indicates no significant difference. Figure 4E shows the correlation between mIPSC frequency (Hz) and RRR in severely injured rats. Circles represent plots for "vehicle-treated control (RRR < 0.4)" rats, and squares represent plots for "ednerpycmaleate-induced recovery (RRR ≥ 0.4)" rats (Figure 4G is similar). Data were analyzed using Pearson correlation coefficients. Figure 4F shows the average frequency of spontaneous mIPSCs, comparing vehicle-treated controls (n=5 rats, 12 cells) with ednerpycmaleate-induced recovery rats (n=4 rats, 9 cells). n.s. indicates no significant difference. Figure 4G shows the correlation between mIPSC frequency (Hz) and RRR in severely injured rats. The data were analyzed using Pearson correlation coefficients. Figure 4H shows the average frequency of spontaneous mIPSSCs, comparing control (n=5 rats, 12 cells) with ednerpycmaleate-induced recovery rats (n=4 rats, 9 cells). n.s. indicates no significant difference.

[0074] We prepared acute cortical slices and performed whole-cell recordings from layer 5 pyramidal neurons in the aforementioned latent functional compensation areas, as shown in Figures 3A to 3D. As a result, as shown in Figure 3A, a significant positive correlation was observed between mEPSC amplitude and functional recovery rate in rats that were not administered ednerpic maleate. Consistent with this observation, as shown in Figure 3B, the mEPSC amplitude was increased in these brain regions of recovered animals compared to non-recovered rats. Furthermore, as shown in Figures 4A and 4B, differences were detected in the mEPSC frequency of these neurons between recovered and non-recovered rats. As shown in Figure 3C, no correlation was observed between mEPSC amplitude and functional recovery in these pyramidal neurons, and as shown in Figures 3D, 4C, and 4D, no differences were detected in either the amplitude or frequency of mEPSCs of these neurons between recovered and non-recovered animals.

[0075] Next, we examined the changes in microcircuits in the compensatory brain regions of rats treated with ednerpycmaleate. When more severe cold injury was induced than in the above rats that were not treated with ednerpycmaleate, the injured animals treated with the vehicle did not recover, whereas ednerpycmaleate administration induced a significant recovery, as shown in Figure 2, similar to what has been previously reported in mice and non-human primates (Non-Patent Literature 1).

[0076] We prepared acute cortical slices, induced severe cryo-induced injury, and administered ednerpic maleate to the compensatory cortical brain regions characterized by the above experiment. Whole-cell recordings were performed from layer 2 / 3 pyramidal neurons, as shown in Figures 3E-3H. As a result, a significant positive correlation was detected between mEPSC amplitude / frequency and functional recovery rate, as shown in Figures 3E and 4E. Furthermore, as shown in Figure 3F, the mEPSC amplitude in these neurons of recovered animals administered ednerpic maleate increased compared to non-recovered animals administered the vehicle. On the other hand, as shown in Figure 4F, there was no change in mEPSC frequency between these two groups.

[0077] As shown in Figure 3G, interestingly, a positive correlation was detected between mIPSC amplitude and the rate of functional recovery. Furthermore, as shown in Figure 3H, in recovery rats administered ednerpic maleate, the amplitude of mIPSCs in pyramidal neurons of layers 2 / 3 of the compensatory brain region was observed to be increased compared to non-recovery rats administered the vehicle, while the frequency remained unchanged in these rats, as shown in Figures 4G and 4H.

[0078] Figures 5A to 5D show the results demonstrating that the E / I ratio was disrupted in spontaneously recovering rats, while it was not disrupted in ednerpycmaleate-induced recovering rats. Figure 5A shows the E / I ratio of postsynaptic current amplitude in mildly injured rats, comparing non-recovering rats (n=7 rats, 7 cells) with recovering rats (n=5 rats, 8 cells). An unpaired t-test (*p < 0.05) was used. Figure 5B shows the E / I ratio of postsynaptic current frequency in mildly injured rats, comparing non-recovering rats (n=7 rats, 7 cells) with recovering rats (n=5 rats, 8 cells). An unpaired t-test (*p < 0.05) was used. Figure 5C shows the E / I ratio of postsynaptic current amplitude in severely injured rats, comparing vehicle-treated controls (n=5 rats, 12 cells) with ednerpycmaleate-induced recovering rats (n=4 rats, 9 cells). n. s. No significant difference is indicated. Figure 5D shows the E / I ratio of postsynaptic current frequencies in severely injured rats, comparing vehicle-treated controls (n=5 rats, 12 cells) with ednerpycmaleate-induced recovery rats (n=4 rats, 9 cells). No significant difference is indicated.

[0079] As shown in Figures 5A and 5B, the E / I ratio of postsynaptic current amplitude and frequency was significantly increased in spontaneously recovering rats. In contrast, as shown in Figures 5C and 5D, it was maintained in ednerpycmaleate-induced recovery rats. These results indicate that the compound represented by the general formula [1] or its salt (e.g., ednerpycmaleate) balances excitatory / inhibitory synaptic input to pyramidal neurons in compensatory cortical regions by promoting synaptic translocation of not only AMPAR but also GABAR (γ-aminobutyric acid receptor) during the functional recovery process after brain injury.

[0080] <Treatment or prevention of epileptic seizures during the recovery period from brain injury with compounds represented by the general formula [1] or salts thereof> Post-stroke epileptic seizures hinder recovery through rehabilitation. As mentioned above, as shown in Figures 3A to 3D, in animals that recovered spontaneously from cerebral cortical hypothermia without administration of ednerpicmaleate, an increase in mEPSC amplitude was observed in pyramidal neurons of the compensatory brain region layer 5, but not in mIPSSC. In contrast, as shown in Figures 3E to 3H, in animals administered ednerpicmaleate, both mEPSC and mIPSSC increased in these neurons. Therefore, we hypothesized that the threshold for epilepsy onset might be lowered in spontaneously recovering animals (where only the excitability of the compensatory region increased). In control animals (sham-operated animals) or animals that recovered spontaneously from cerebral cortical hypothermia without administration of ednerpicmaleate, picrotoxin (inhibitory GABA) was administered. Ａ We injected a receptor inhibitor and examined the level of epilepsy induced.

[0081] Figures 6A to 6D show the results of ednerpicmaleate preventing epileptic seizures during the recovery phase from brain injury, and CNQX inhibition of AMPA receptor function in the compensatory region of spontaneously recovering animals downregulating susceptibility to picrotoxin-induced epilepsy. Figure 6A shows the Racine classification used for epilepsy stage assessment (RACINE, RJ 1972. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol, 32, 281-94., CELA, E., MCFARLAN, AR, CHUNG, AJ, WANG, T., CHIERZI, S., MURAI, KK & SJoSTRoM, PJ 2019. An Optogenetic Kindling Model of Neocortical Epilepsy. Sci Rep, 9, 5236.). Figure 6B shows the epileptic stages of POD17 in picrotoxin-administered animals (sham-operated, spontaneous recovery [rehabilitation training only], ednerpicmaleate-induced recovery [ednerpicmaleate administration + rehabilitation training], spontaneous recovery + CNQX injection rats). Each group n=7. One-way ANOVA and Fisher's LSD test were used. Different letters indicate significant differences between groups (p < 0.05). Figure 6C shows the time course of mean RRR in spontaneously recovering rats after cryogenic injury. Figure 6D shows the time course of mean RRR after cryogenic injury in ednerpicmaleate-induced recovery rats.

[0082] As shown in Figures 6A, 6B, and 6C, spontaneously recovered animals that were not administered ednerpicmaleate were found to be more susceptible to inducing epileptic seizures from picrotoxin injections (more prone to epilepsy) compared to animals that underwent sham surgery.

[0083] As shown in Figures 3E to 3H, pyramidal neurons in the second and third layers of the compensatory brain regions of animals recovered by ednerpicmaleate administration showed increased amplitude in both mEPSC and mIPSSC. This suggests that recovered animals treated with ednerpicmaleate were less prone to epilepsy. Consistent with this hypothesis, as shown in Figures 6A, 6B, and 6D, the seizure grade (epilepsy stage) of these animals injected with picrotoxin was lower than that of animals not injected with ednerpicmaleate and was comparable to that of the sham surgery control group.

[0084] To investigate whether increased excitability due to increased postsynaptic currents mediated by AMPAR in the compensatory region of animals that spontaneously recovered without ednerpicmaleate administration is involved in epilepsy development, CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), a competitive antagonist of the AMPAR / kainate receptor, was injected into the compensatory region of the animals, and epileptic seizures were induced by injecting picrotoxin. As shown in Figure 6B, administration of CNQX reduced susceptibility to epilepsy induction by picrotoxin, suggesting that increased postsynaptic currents mediated by AMPAR and unchanged inhibitory synaptic input (disruption of the excitation / inhibition balance) in the compensatory brain region are involved in epilepsy development.

[0085] These results suggest that administration of the compound represented by the general formula [1] or its salt (e.g., ednerpycmaleate) not only promotes motor function recovery in brain-injured animals but also treats or prevents epileptic seizures during the recovery process.

[0086] 3. Discussion Epileptic seizures during the recovery process from brain injury such as stroke are serious events that should be avoided and can often hinder the recovery process. We have previously shown that AMPAR is translocated to synapses in compensatory cortical regions during the recovery process, and that this process is necessary for functional recovery (JITSUKI, S., TAKEMOTO, K., KAWASAKI, T., TADA, H., TAKAHASHI, A., BECAMEL, C., SANO, A., YUZAKI, M., ZUKIN, RS, ZIFF, EB, KESSELS, HW & TAKAHASHI, T. 2011. Serotonin mediates cross-modal reorganization of cortical circuits. Neuron, 69, 780-92., Non-patent Literature 1).

[0087] The postsynaptic transfer of AMPAR may increase the excitability of compensatory brain regions that could trigger epileptic seizures during the recovery phase after brain injury. Indeed, as shown in Figures 3B, 3D, and 6B, in compensatory brain regions of animals that spontaneously recovered from low-temperature motor cortical injuries without ednerpicmaleate administration, postsynaptic currents (excitatory input) mediated by AMPAR increased, but postsynaptic currents (inhibitory input) mediated by GABAR did not increase, which lowered the threshold for inducing epileptic seizures in response to picrotoxin injection. How compensatory brain regions change from "functional" to "epileptic" is still unclear. On the other hand, as shown in Figure 6B, injured animals administered ednerpicmaleate had lower susceptibility to epileptic seizure induction by picrotoxin (they were less prone to epilepsy).

[0088] As shown in Figures 3F and 3H, in animals recovering from cryo-injury treated with ednerpic maleate, both mEPSC amplitude and mIPSSC amplitude were increased. This suggests that GABAR-mediated current downregulation in compensatory brain regions may be changing these regions from "functional" to "epileptic." Further research is needed to understand the underlying mechanisms of the potential downregulation of inhibitory synaptic function in compensatory brain regions.

[0089] In this example, two different levels of injury were used. One was a "mild injury (i.e., a spontaneous recovery model)" to mimic and verify brain changes during the spontaneous recovery process, and the other was a "severe injury" to examine the effects of ednerpikmaleate. As described in Section 1. Materials and Methods above, these severely injured rats could not recover forelimb function without ednerpikmaleate administration accompanied by rehabilitation training (see also Figure 2). A technical limitation was that the layers from which mEPSCs and mIPSSCs were recorded differed between the mild injury model (layer 5) and the severe injury model (layers 2 / 3). While it would be desirable to conduct the experiment in the same layer, unfortunately, it was technically impossible to record mEPSCs and mIPSSCs from layer 5 onwards in the ednerpikmaleate (or vehicle)-administered rats due to their severe injury. However, pyramidal neurons in layers 2 / 3 and layer 5 have been reported to show similar morphological changes (a decrease in dendritic spines) after focal ischemic stroke (BROWN, CE, WONG, C. & MURPHY, TH 2008. Rapid morphologic plasticity of peri-infarct dendritic spines after focal ischemic stroke. Stroke, 39, 1286-91.).

[0090] These results suggest a therapeutic or prophylactic effect of ednerpicmaleate on epileptic seizures during the recovery process from brain injury. As shown in Figures 3F and 3H, administration of ednerpicmaleate can enhance not only AMPAR but also GABAR-mediated currents in compensatory brain regions. This suggests that ednerpicmaleate affects a common molecule / pathway that controls the transfer of AMPAR and GABAR, or that it independently controls them. While AMPAR and GABAR have different functions in neuronal excitability, their dynamics in neurons are very similar (LI, S., HUANG, H., WEI, X., YE, L., MA, M., LING, M. & WU, Y. 2022. The recycling of AMPA receptors / GABAa receptors is related to neuronal excitation / inhibition imbalance and may be regulated by KIF5A. Ann Transl Med, 10, 1103.). Both receptors are synthesized in the endoplasmic reticulum (ER) and assembled in the Golgi apparatus. Afterward, both receptors are transported to the synapse via vesicles, often mediated by motor proteins such as myosin along actin and kinesin or dynein along microtubules (SCHLAGER, MA & HOOGENRAAD, CC 2009. Basic mechanisms for recognition and transport of synaptic cargos. Mol Brain, 2, 25., etc.). Internalization of AMPAR and GABAR into the cytoplasm is mediated by clathrin, and recycling of AMPAR and GABAR is regulated by kinesin superfamily proteins (KIFs). Ednerpycmaleate is a compound that binds to CRMP2, which in turn mediates functional recovery by ednerpycmaleate (i.e., the translocation of AMPAR to the synapse) via the activation of actin depolymerization factor (ADF) / cofilin.Considering its function as an enhancer of neuroplasticity, it is reasonable that GABAR is also affected by the compound represented by the general formula [1] or its salt (e.g., ednerpikmaleate). The main target molecules / pathways of the compound represented by the general formula [1] or its salt (e.g., ednerpikmaleate) that upregulate GABAR should be clarified in future research. Therefore, the compound represented by the general formula [1] or its salt (e.g., ednerpikmaleate), which may promote functional recovery after stroke, can treat or prevent the development of epilepsy after stroke by balancing excitatory and inhibitory synaptic functions.

Claims

1. A therapeutic and / or preventive agent for epilepsy after brain injury, comprising a compound represented by the following general formula [1] or a salt thereof. (In the formula, R １ and R ２ are the same or different and are each independently selected from one or more groups consisting of a hydrogen atom, a halogen atom, an optionally substituted C １－６ alkyl group, an optionally substituted aryl group, an optionally substituted C １－６ alkoxy group, an optionally substituted aryloxy group, an optionally substituted C １－６ alkylthio group, an optionally substituted arylthio group, an optionally substituted C ２－６ alkenyl group, an optionally substituted C ２－６ alkenyloxy group, an optionally substituted C １－６ alkylamino group, an optionally substituted C １－６ alkylsulfonyl group, an optionally substituted arylsulfonyl group, an optionally substituted carbamoyl group, an optionally substituted heterocyclic group, an optionally protected amino group, an optionally protected hydroxyl group, an optionally protected carboxyl group, a nitro group, and an oxo group; R ３ is an optionally substituted C １－６ alkylamino group, an optionally protected amino group or an optionally protected hydroxyl group; m and n are the same or different and each represents an integer of 1 to 6.) 2. A therapeutic and / or prophylactic agent for epilepsy after the formation of compensatory areas of the brain, comprising a compound represented by the following general formula [1] or a salt thereof. (In the formula, R １ and R ２ These are the same or different hydrogen atoms, halogen atoms, or optionally substituted C atoms. １－６ Alkyl groups, optionally substituted aryl groups, optionally substituted C １－６ Alkoxy group, optionally substituted aryloxy group, optionally substituted C １－６ Alkylthio group, optionally substituted arylthio group, optionally substituted C ２－６ Alkenyl group, may be substituted C ２－６ Alkenyloxy group, may be substituted C １－６ Alkylamino group, optionally substituted C １－６ One or more groups selected from alkylsulfonyl groups, optionally substituted arylsulfonyl groups, optionally substituted carbamoyl groups, optionally substituted heterocyclic groups, optionally protected amino groups, optionally protected hydroxyl groups, optionally protected carboxyl groups, nitro groups, and oxo groups; R ３ C may be substituted. １－６ (An alkylamino group, an optionally protected amino group, or an optionally protected hydroxyl group; m and n are the same or different integers from 1 to 6, respectively.) 3. The agent according to claim 1 or 2, wherein the compound represented by the general formula [1] or a salt thereof is an agent for regulating and / or improving the excitation / inhibitory [E / I] balance of nerve cells.

4. The agent according to claim 1, wherein the brain injury is a brain injury caused by a stroke.

5. The agent according to claim 1 or 2, wherein the epilepsy is epilepsy that occurs after the formation of a compensatory area in the brain following brain injury.

6. R １ and R ２ However, they may be the same or different hydrogen atoms, halogen atoms, or C １－６ It is an alkoxy group, m is 2, n is 2 or 3, R ３ The agent according to claim 1 or 2, wherein the hydroxyl group is optionally protected.

7. The agent according to claim 1 or 2, wherein the compound represented by the general formula [1] is 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidine-3-ol.

8. A pharmaceutical composition comprising the agent described in claim 1 or 2.

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