JP2024026905A - Therapeutic agent for epilepsy - Google Patents
Therapeutic agent for epilepsy Download PDFInfo
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- JP2024026905A JP2024026905A JP2020195053A JP2020195053A JP2024026905A JP 2024026905 A JP2024026905 A JP 2024026905A JP 2020195053 A JP2020195053 A JP 2020195053A JP 2020195053 A JP2020195053 A JP 2020195053A JP 2024026905 A JP2024026905 A JP 2024026905A
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- epilepsy
- gat
- compound
- focal
- focal seizures
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- PBJUNZJWGZTSKL-MRXNPFEDSA-N tiagabine Chemical compound C1=CSC(C(=CCCN2C[C@@H](CCC2)C(O)=O)C2=C(C=CS2)C)=C1C PBJUNZJWGZTSKL-MRXNPFEDSA-N 0.000 description 1
- 229960002410 tiagabine hydrochloride Drugs 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229960004453 trimethadione Drugs 0.000 description 1
- IRYJRGCIQBGHIV-UHFFFAOYSA-N trimethadione Chemical compound CN1C(=O)OC(C)(C)C1=O IRYJRGCIQBGHIV-UHFFFAOYSA-N 0.000 description 1
- 208000009999 tuberous sclerosis Diseases 0.000 description 1
- 210000003135 vibrissae Anatomy 0.000 description 1
- PJDFLNIOAUIZSL-UHFFFAOYSA-N vigabatrin Chemical compound C=CC(N)CCC(O)=O PJDFLNIOAUIZSL-UHFFFAOYSA-N 0.000 description 1
- 229960005318 vigabatrin Drugs 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 229960002911 zonisamide Drugs 0.000 description 1
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 1
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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Abstract
Description
本発明は、ＧＡＢＡトランスポーター１（以下、ＧＡＴ－１と称す）阻害作用を有する、Ｎ－［（１Ｓ）－２，２，５，７－テトラフルオロ－２，３－ジヒドロ－１Ｈ－インデン－１－イル］スルファミドまたはその薬剤学的に許容される塩を含有する、難治てんかんを含む種々てんかんの治療剤に関する。 The present invention provides N-[(1S)-2,2,5,7-tetrafluoro-2,3-dihydro-1H-inden- The present invention relates to a therapeutic agent for various types of epilepsy, including intractable epilepsy, which contains sulfamide or a pharmaceutically acceptable salt thereof.
てんかんは最も頻度の高い中枢神経疾患の１つであり、全世界で約５，０００万人以上の患者が存在している。世界保健機関の定義では「種々の病因によってもたらされる慢性の脳疾患であり、大脳ニューロンの過剰な放電から由来する反復性の発作（てんかん発作）を主徴とし、それに変異に富んだ臨床ならびに検査所見の表出が伴う」とされる。 Epilepsy is one of the most common central nervous system diseases, and there are approximately 50 million or more patients worldwide. The World Health Organization defines it as ``a chronic brain disease caused by various etiologies, characterized by repeated seizures (epileptic seizures) resulting from excessive discharge of cerebral neurons, and characterized by a variety of clinical and laboratory tests. "It involves the expression of findings."
国際抗てんかん連盟（ＩＬＡＥ）により２０１７年に改訂された新たなてんかん分類では、てんかんは発作型、てんかん病型、てんかん症候群の３つの異なるレベルで分類される。発作型には焦点起始発作、全般起始発作、起始不明発作がある。てんかん病型には焦点てんかん、全般てんかん、全般焦点合併てんかん、病型不明てんかんがある。てんかん症候群の代表例として、Ｗｅｓｔ症候群、Ｌｅｎｎｏｘ－Ｇａｓｔａｕｔ症候群、Ｄｒａｖｅｔ症候群、脆弱Ｘ症候群、結節性硬化症、海馬硬化を伴う内側側頭葉てんかんなどがある。てんかんの治療は、抗てんかん薬（ＡＥＤ）による薬物療法が中心である。てんかん治療の目標はてんかん発作の消失と治療に伴う副作用を発現させないことである。抗てんかん薬物を用いた治療は原則として単剤より始められる。単剤治療は通常２－３種類の異なる薬剤で順次行い、それでも奏功しない場合には、多剤併用治療を行う。新たに発病したてんかん患者の約７０％は抗てんかん薬治療で発作の寛解が期待できる。しかしながら、残りの約３０％の患者については既存薬剤による多剤併用療法によっても、てんかん発作は抑制され難いことが知られている。 In the new epilepsy classification revised in 2017 by the International League Against Epilepsy (ILAE), epilepsy is classified into three different levels: seizure type, epilepsy type, and epilepsy syndrome. Seizure types include focal onset seizures, generalized onset seizures, and seizures of unknown origin. Epilepsy types include focal epilepsy, generalized epilepsy, generalized focal combined epilepsy, and epilepsy of unknown type. Representative examples of epilepsy syndromes include West syndrome, Lennox-Gastaut syndrome, Dravet syndrome, fragile X syndrome, tuberous sclerosis, and mesial temporal lobe epilepsy with hippocampal sclerosis. The main treatment for epilepsy is drug therapy using antiepileptic drugs (AEDs). The goals of epilepsy treatment are to eliminate epileptic seizures and to prevent side effects associated with treatment. As a general rule, treatment with antiepileptic drugs can be started with a single drug. Monotherapy is usually done with 2-3 different drugs in sequence, and if that doesn't work, multidrug therapy is used. Approximately 70% of newly diagnosed epilepsy patients can expect their seizures to be alleviated by antiepileptic drug treatment. However, it is known that for the remaining approximately 30% of patients, epileptic seizures are difficult to be suppressed even by multidrug therapy using existing drugs.
てんかんの治療用に上市されている薬物として、例えばカルバマゼピン、エトサクシミド、フェノバルビタール、フェニトイン、プリミドン、バルプロ酸ナトリウム、ゾニサミド、フェルバメート、ガバペンチン、ラモトリギン、トピラマート、チアガビン、レベチラセタム、オクスカルバゼピン、エスリカルバゼピン、プレガバリン、ラコサミド、ルフィナミド、トリメタジオン、スルチアム、アセタゾラミド、ビガバトリン、ベンゾジアゼピン系薬物（クロナゼパム、クロバザム、ニトラゼパム、ジアゼパム）、ペランパネル、レチガビンなどがある（非特許文献１）。これら既存の抗てんかん薬は、神経細胞の過剰興奮を抑制することにより効果を発現するものである。過剰興奮を抑制するアプローチとして、興奮性機能を抑えるアプローチと抑制性機能を増強させるアプローチがある。興奮性機能を抑えるアプローチの例として、ナトリウムチャネル、カルシウムチャネル、ＡＭＰＡ受容体の抑制がある。抑制性機能を増強させるアプローチの例としてＧＡＢＡＡ受容体の活性化がある。さらに、ＧＡＢＡＡ受容体を活性化させる手法として、ＧＡＢＡＡ受容体を直接活性化させる手法と、ＧＡＢＡＡ受容体のリガンドであるＧＡＢＡを増やすことによって間接的にＧＡＢＡＡ受容体を活性化させる手法がある。ＧＡＴ－１は主に神経細胞に発現しており、シナプス間隙のＧＡＢＡを取り込む機能を有している。したがって、ＧＡＴ－１を阻害することで、シナプス間隙のＧＡＢＡを増やすことができ、抗てんかん効果を発現することが期待できる。 Drugs marketed for the treatment of epilepsy include, for example, carbamazepine, etosuximide, phenobarbital, phenytoin, primidone, sodium valproate, zonisamide, felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, eslicarba. Examples include zepine, pregabalin, lacosamide, rufinamide, trimethadione, sultiam, acetazolamide, vigabatrin, benzodiazepine drugs (clonazepam, clobazam, nitrazepam, diazepam), perampanel, retigabine, etc. (Non-Patent Document 1). These existing antiepileptic drugs exert their effects by suppressing hyperexcitation of nerve cells. There are two approaches to suppressing hyperexcitation: one that suppresses excitatory functions and one that enhances inhibitory functions. Examples of approaches to suppress excitatory function include inhibition of sodium channels, calcium channels, and AMPA receptors. An example of an approach to enhance inhibitory function is activation of GABA A receptors. Furthermore, there are two methods for activating GABA A receptors: one is to directly activate GABA A receptors, and the other is to indirectly activate GABA A receptors by increasing GABA, the ligand for GABA A receptors. There is. GAT-1 is mainly expressed in nerve cells and has the function of taking up GABA from the synaptic cleft. Therefore, by inhibiting GAT-1, it is possible to increase GABA in the synaptic cleft, and it is expected that antiepileptic effects will be exhibited.
抗てんかん薬による薬物療法の重大な課題の１つに、神経機能抑制による毒性症状（めまい、眼振、複視、眠気、嘔吐、運動失調、精神症状、倦怠感、意欲の消失などの症状）がある。これらは、ほとんどの従来の抗てんかん薬において用量依存的に出現する副作用であり、治療薬選択・用量の制限につながる重大な課題である。また、これらは長期服用を必要とするてんかん患者の生活の質を大きく低下させる。よって、有効用量と神経毒性用量との乖離が大きい薬剤が見出せれば、前述の薬剤治療に抵抗性の症例のみならず、てんかんの症例全般に対して安全で効果的な薬物療法の提供につながることが期待できる。 One of the important issues with drug therapy using antiepileptic drugs is the toxicity symptoms caused by suppression of nerve function (symptoms such as dizziness, nystagmus, double vision, drowsiness, vomiting, ataxia, psychotic symptoms, malaise, and loss of motivation). There is. These are side effects that occur in a dose-dependent manner with most conventional antiepileptic drugs, and are serious issues that lead to limitations in therapeutic drug selection and dosage. In addition, these drugs greatly reduce the quality of life of epilepsy patients who require long-term use. Therefore, if a drug with a large discrepancy between the effective dose and the neurotoxic dose can be found, it will lead to the provision of safe and effective drug therapy not only for cases resistant to the above-mentioned drug treatments, but also for epilepsy cases in general. We can expect that.
ここで、式（Ｉ）で表される、Ｎ－［（１Ｓ）－２，２，５，７－テトラフルオロ－２，３－ジヒドロ－１Ｈ－インデン－１－イル］スルファミド（以下、「化合物（Ｉ）」ともいう。）は、てんかんのモデルであるマウスキンドリングモデルにおける発作抑制作用（ＥＤ５０）とロータロッド試験での神経毒性作用（ＴＤ５０）を比較した治療係数（ＴＤ５０／ＥＤ５０）が対照化合物に比して高く、より安全性が高いてんかん治療剤としての利用可能性を有することが報告されている（特許文献１）。また、化合物（Ｉ）は各種動物モデルでの鎮痛作用を示し、疼痛治療および／または予防剤としての利用可能性を有することが報告されている（特許文献２）。さらに、化合物（Ｉ）とＡＭＰＡ型グルタミン酸受容体拮抗剤とを併用することでてんかんの症例全般に対して安全で効果的な薬物療法の提供につながることが期待できることも報告されている（特許文献３）。
本発明の課題は、薬効と副作用のマージンが広く、薬剤治療に抵抗性の症例のみならず、てんかんの症例全般に対する利用可能性を有する、安全で効果的なてんかん治療剤を提供することにある。 An object of the present invention is to provide a safe and effective anti-epileptic drug that has a wide margin between efficacy and side effects and can be used not only for cases resistant to drug treatment but also for all epilepsy cases. .
本発明者らは、上記課題を解決すべく、鋭意検討して種々けいれん動物モデルに対して、化合物（Ｉ）がＧＡＴ－１の不競合阻害作用を示すことで、生理的なシナプスには影響が少なく、過剰興奮状態のシナプス選択的に作用することで抗けいれん効果を発揮することを見出し、本発明を完成した。 In order to solve the above problems, the present inventors conducted extensive studies and found that Compound (I) exhibits an uncompetitive inhibitory effect on GAT-1 in various convulsive animal models, and has no effect on physiological synapses. The present invention has been completed based on the discovery that anticonvulsant effects can be exerted by selectively acting on synapses in hyperexcited states.
すなわち、本発明は以下＜１＞から＜３１＞に関する。
＜１＞式（Ｉ）で表される化合物、Ｎ－［（１Ｓ）－２，２，５，７－テトラフルオロ－２，３－ジヒドロ－１Ｈ－インデン－１－イル］スルファミド：
またはその薬剤学的に許容される塩を含有する、てんかん治療剤。
＜２＞てんかんが焦点発作を有するてんかんである、＜１＞に記載のてんかん治療剤。
＜３＞焦点発作を有するてんかんが内側側頭葉てんかん（ＭＴＬＥ）、限局性皮質異形成症（ＦＣＤ）、または難治性焦点発作を有するてんかんである、＜２＞に記載のてんかん治療剤。
＜４＞式（Ｉ）で表される化合物、Ｎ－［（１Ｓ）－２，２，５，７－テトラフルオロ－２，３－ジヒドロ－１Ｈ－インデン－１－イル］スルファミド：
またはその薬剤学的に許容される塩を、それを必要とする患者に投与する、てんかんの治療方法。
＜５＞てんかんが焦点発作を有するてんかんである、＜４＞に記載の治療方法。
＜６＞焦点発作を有するてんかんがＭＴＬＥ、ＦＣＤ、または難治性焦点発作を有するてんかんである、＜５＞に記載の治療方法。
＜７＞式（Ｉ）で表される化合物、Ｎ－［（１Ｓ）－２，２，５，７－テトラフルオロ－２，３－ジヒドロ－１Ｈ－インデン－１－イル］スルファミド：
またはその薬剤学的に許容される塩および賦形剤を含む、てんかん治療のための医薬組成物。
＜８＞てんかんが焦点発作を有するてんかんである、＜７＞に記載の医薬組成物。
＜９＞焦点発作を有するてんかんがＭＴＬＥ、ＦＣＤ、または難治性焦点発作を有するてんかんである、＜８＞に記載の医薬組成物。
＜１０＞てんかん治療剤製造のための式（Ｉ）で表される化合物、Ｎ－［（１Ｓ）－２，２，５，７－テトラフルオロ－２，３－ジヒドロ－１Ｈ－インデン－１－イル］スルファミド：
またはその薬剤学的に許容される塩の使用。
＜１１＞てんかんが焦点発作を有するてんかんである、＜１０＞に記載の使用。
＜１２＞焦点発作を有するてんかんがＭＴＬＥ、ＦＣＤ、または難治性焦点発作を有するてんかんである、＜１１＞に記載の使用。
＜１３＞てんかん治療における使用のための、式（Ｉ）で表される化合物、Ｎ－［（１Ｓ）－２，２，５，７－テトラフルオロ－２，３－ジヒドロ－１Ｈ－インデン－１－イル］スルファミド：
またはその薬剤学的に許容される塩。
＜１４＞てんかんが焦点発作を有するてんかんである、＜１３＞に記載の使用のための化合物またはその薬剤学的に許容される塩。
＜１５＞焦点発作を有するてんかんがＭＴＬＥ、ＦＣＤ、または難治性焦点発作を有するてんかんである、＜１４＞に記載の使用のための化合物またはその薬剤学的に許容される塩。
＜１６＞ 式（Ｉ）で表される化合物、Ｎ－［（１Ｓ）－２，２，５，７－テトラフルオロ－２，３－ジヒドロ－１Ｈ－インデン－１－イル］スルファミド：
またはその薬剤学的に許容される塩を含有するＧＡＴ－１阻害剤。
＜１７＞てんかんの治療に用いるための、＜１６＞に記載のＧＡＴ－１阻害剤。
＜１８＞てんかんが焦点発作を有するてんかんである、＜１７＞に記載のＧＡＴ－１阻害剤。
＜１９＞焦点発作を有するてんかんがＭＴＬＥ、ＦＣＤ、または難治性焦点発作を有するてんかんである、＜１８＞に記載のＧＡＴ－１阻害剤。
＜２０＞＜１６＞に記載のＧＡＴ－１阻害剤を、それを必要とする患者に投与する、てんかんの治療方法。
＜２１＞てんかんが焦点発作を有するてんかんである、＜２０＞に記載の治療方法。
＜２２＞焦点発作を有するてんかんがＭＴＬＥ、ＦＣＤ、または難治性焦点発作を有するてんかんである、＜２１＞に記載の治療方法。
＜２３＞＜１６＞に記載のＧＡＴ－１阻害剤および賦形剤を含む、てんかん治療のための医薬組成物。
＜２４＞てんかんが焦点発作を有するてんかんである、＜２３＞に記載の医薬組成物。
＜２５＞焦点発作を有するてんかんがＭＴＬＥ、ＦＣＤ、または難治性焦点発作を有するてんかんである、＜２４＞に記載の医薬組成物。
＜２６＞てんかん治療剤製造のための＜１６＞に記載のＧＡＴ－１阻害剤の使用。
＜２７＞てんかんが焦点発作を有するてんかんである、＜２６＞に記載の使用。
＜２８＞焦点発作を有するてんかんがＭＴＬＥ、ＦＣＤ、または難治性焦点発作を有するてんかんである、＜２７＞に記載の使用。
＜２９＞てんかん治療における使用のための、＜１６＞に記載のＧＡＴ－１阻害剤。
＜３０＞てんかんが焦点発作を有するてんかんである、＜２９＞に記載の使用のためのＧＡＴ－１阻害剤。
＜３１＞焦点発作を有するてんかんがＭＴＬＥ、ＦＣＤ、または難治性焦点発作を有するてんかんである、＜３０＞に記載の使用のためのＧＡＴ－１阻害剤。
That is, the present invention relates to <1> to <31> below.
<1> Compound represented by formula (I), N-[(1S)-2,2,5,7-tetrafluoro-2,3-dihydro-1H-inden-1-yl]sulfamide:
or a pharmaceutically acceptable salt thereof, for the treatment of epilepsy.
<2> The epilepsy therapeutic agent according to <1>, wherein the epilepsy is epilepsy having focal seizures.
<3> The therapeutic agent for epilepsy according to <2>, wherein the epilepsy with focal seizures is mesial temporal lobe epilepsy (MTLE), focal cortical dysplasia (FCD), or epilepsy with intractable focal seizures.
<4> Compound represented by formula (I), N-[(1S)-2,2,5,7-tetrafluoro-2,3-dihydro-1H-inden-1-yl]sulfamide:
A method for treating epilepsy, which comprises administering or a pharmaceutically acceptable salt thereof to a patient in need thereof.
<5> The treatment method according to <4>, wherein the epilepsy is epilepsy with focal seizures.
<6> The treatment method according to <5>, wherein the epilepsy with focal seizures is MTLE, FCD, or epilepsy with intractable focal seizures.
<7> Compound represented by formula (I), N-[(1S)-2,2,5,7-tetrafluoro-2,3-dihydro-1H-inden-1-yl]sulfamide:
or a pharmaceutical composition thereof for the treatment of epilepsy, comprising a pharmaceutically acceptable salt thereof and an excipient.
<8> The pharmaceutical composition according to <7>, wherein the epilepsy is epilepsy with focal seizures.
<9> The pharmaceutical composition according to <8>, wherein the epilepsy with focal seizures is MTLE, FCD, or epilepsy with intractable focal seizures.
<10> Compound represented by formula (I) for production of epilepsy therapeutic agent, N-[(1S)-2,2,5,7-tetrafluoro-2,3-dihydro-1H-indene-1- ] Sulfamide:
or the use of pharmaceutically acceptable salts thereof.
<11> The use according to <10>, wherein the epilepsy is epilepsy with focal seizures.
<12> The use according to <11>, wherein the epilepsy with focal seizures is MTLE, FCD, or epilepsy with intractable focal seizures.
<13> Compound represented by formula (I), N-[(1S)-2,2,5,7-tetrafluoro-2,3-dihydro-1H-indene-1, for use in epilepsy treatment -il] sulfamide:
or a pharmaceutically acceptable salt thereof.
<14> The compound or a pharmaceutically acceptable salt thereof for use according to <13>, wherein the epilepsy is epilepsy with focal seizures.
<15> The compound or a pharmaceutically acceptable salt thereof for use according to <14>, wherein the epilepsy with focal seizures is MTLE, FCD, or epilepsy with intractable focal seizures.
<16> Compound represented by formula (I), N-[(1S)-2,2,5,7-tetrafluoro-2,3-dihydro-1H-inden-1-yl]sulfamide:
or a GAT-1 inhibitor containing a pharmaceutically acceptable salt thereof.
<17> The GAT-1 inhibitor according to <16> for use in treating epilepsy.
<18> The GAT-1 inhibitor according to <17>, wherein the epilepsy is epilepsy with focal seizures.
<19> The GAT-1 inhibitor according to <18>, wherein the epilepsy with focal seizures is MTLE, FCD, or epilepsy with intractable focal seizures.
<20> A method for treating epilepsy, which comprises administering the GAT-1 inhibitor according to <16> to a patient in need thereof.
<21> The treatment method according to <20>, wherein the epilepsy is epilepsy with focal seizures.
<22> The treatment method according to <21>, wherein the epilepsy with focal seizures is MTLE, FCD, or epilepsy with intractable focal seizures.
<23> A pharmaceutical composition for treating epilepsy, comprising the GAT-1 inhibitor according to <16> and an excipient.
<24> The pharmaceutical composition according to <23>, wherein the epilepsy is epilepsy with focal seizures.
<25> The pharmaceutical composition according to <24>, wherein the epilepsy with focal seizures is MTLE, FCD, or epilepsy with intractable focal seizures.
<26> Use of the GAT-1 inhibitor according to <16> for producing a therapeutic agent for epilepsy.
<27> The use according to <26>, wherein the epilepsy is epilepsy with focal seizures.
<28> The use according to <27>, wherein the epilepsy with focal seizures is MTLE, FCD, or epilepsy with refractory focal seizures.
<29> The GAT-1 inhibitor according to <16> for use in epilepsy treatment.
<30> The GAT-1 inhibitor for use according to <29>, wherein the epilepsy is epilepsy with focal seizures.
<31> The GAT-1 inhibitor for use according to <30>, wherein the epilepsy with focal seizures is MTLE, FCD, or epilepsy with intractable focal seizures.
本発明は、ＧＡＴ－１の不競合阻害作用を有する、Ｎ－［（１Ｓ）－２，２，５，７－テトラフルオロ－２，３－ジヒドロ－１Ｈ－インデン－１－イル］スルファミドまたはその薬剤学的に許容される塩を含有する薬剤を提供する。かかる薬剤は、顕著な抗てんかん作用を示し、薬効と副作用のマージンが広く、安全で効果的なてんかんの治療剤としての利用可能性を有している。 The present invention provides N-[(1S)-2,2,5,7-tetrafluoro-2,3-dihydro-1H-inden-1-yl]sulfamide or its A drug containing a pharmaceutically acceptable salt is provided. Such drugs exhibit remarkable antiepileptic effects, have a wide margin between efficacy and side effects, and have the potential to be used as safe and effective therapeutic agents for epilepsy.
以下、本発明の内容について詳細に説明する。 Hereinafter, the content of the present invention will be explained in detail.
化合物（Ｉ）またはその薬剤学的に許容される塩は、例えば、特許文献１に記載された方法により製造することができる。 Compound (I) or a pharmaceutically acceptable salt thereof can be produced, for example, by the method described in Patent Document 1.
「薬剤学的に許容される塩」とは、本発明に係る化合物と塩を形成されるものであれば特に限定されず、具体的には例えば、無機酸塩、有機酸塩または酸性アミノ酸塩等の酸付加塩が挙げられる。 "Pharmaceutically acceptable salt" is not particularly limited as long as it forms a salt with the compound according to the present invention, and specifically includes, for example, an inorganic acid salt, an organic acid salt, or an acidic amino acid salt. Examples include acid addition salts such as.
無機酸との塩の一態様としては、例えば塩酸、臭化水素酸、硫酸、硝酸、リン酸などとの塩が挙げられる。有機酸との塩の一態様としては、例えば酢酸、コハク酸、フマル酸、マレイン酸、酒石酸、クエン酸、乳酸、ステアリン酸、安息香酸、メタンスルホン酸、エタンスルホン酸、ｐ－トルエンスルホン酸などとの塩が挙げられる。 Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of salts with organic acids include acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc. Examples include salt.
酸性アミノ酸との塩の一態様としては、例えばアスパラギン酸、グルタミン酸などとの塩が挙げられる。 Examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like.
本発明のてんかん治療剤は、薬剤学的に許容される添加物を、化合物（Ｉ）またはその薬剤学的に許容される塩と混和することにより製造することができる。本発明のてんかん治療剤は例えば第十七改正日本薬局方の製剤総則に記載の方法など既知の方法に従って製造することができる。 The therapeutic agent for epilepsy of the present invention can be produced by mixing a pharmaceutically acceptable additive with compound (I) or a pharmaceutically acceptable salt thereof. The therapeutic agent for epilepsy of the present invention can be manufactured according to known methods such as those described in the General Preparations of the 17th Edition of the Japanese Pharmacopoeia.
本発明のてんかん治療剤は、その剤形に応じて適切に患者に投与することができる。 The therapeutic agent for epilepsy of the present invention can be appropriately administered to patients depending on its dosage form.
本発明のてんかん治療剤において、化合物（Ｉ）またはその薬剤学的に許容される塩の投与量は、症状の程度、患者の年齢、性別、体重、感受性差、投与方法、投与時期、医薬製剤の種類等に応じて異なるが、通常、成人（体重６０ｋｇ）に対して経口投与する場合、１日あたり１００μｇ～５ｇ、一態様としては３００μｇ～３ｇ、別の態様としては１ｍｇ～１ｇを、注射投与する場合、１日あたり３０μｇ～１ｇ、一態様としては３０μｇ～５００ｍｇ、別の態様としては５０μｇ～３００ｍｇを１回または数回に分けて投与する。 In the therapeutic agent for epilepsy of the present invention, the dosage of Compound (I) or a pharmaceutically acceptable salt thereof is determined based on the degree of symptoms, patient age, sex, body weight, sensitivity difference, administration method, administration timing, pharmaceutical formulation, etc. Although it differs depending on the type, etc., when orally administered to adults (body weight 60 kg), the injection amount is usually 100 μg to 5 g per day, in one embodiment 300 μg to 3 g, and in another embodiment 1 mg to 1 g. When administered, the dose is 30 μg to 1 g per day, in one embodiment 30 μg to 500 mg, and in another embodiment 50 μg to 300 mg, once or in divided doses.
〔薬理試験例〕
本発明者らは、けいれんに対する抑制効果を確認するために６Ｈｚ精神運動発作モデルマウスを用いて研究を行った。また、化合物（Ｉ）の作用機序を確認するために化合物（Ｉ）のトリチウムラベル体を用いた結合試験およびＧＡＴ－１，ＧＡＢＡ ｔｒａｎｓｐｏｒｔｅｒ ２（ＧＡＴ－２），ＧＡＢＡ ｔｒａｎｓｐｏｒｔｅｒ ３（ＧＡＴ－３），Ｂｅｔａｉｎｅ／ＧＡＢＡ ｔｒａｎｓｐｏｒｔｅｒ（ＢＧＴ－１）の各強制発現細胞を用いたＧＡＢＡ取込み阻害試験を行った。
[Pharmacology test example]
The present inventors conducted research using a 6Hz psychomotor seizure model mouse to confirm the suppressive effect on convulsions. In addition, in order to confirm the mechanism of action of Compound (I), we conducted a binding test using tritium-labeled Compound (I) and GAT-1, GABA transporter 2 (GAT-2), and GABA transporter 3 (GAT-3). , Betaine/GABA transporter (BGT-1).
［試験例１］６Ｈｚ精神運動発作モデルマウスを用いたけいれんに対する抑制効果確認試験
けいれんに対する抑制効果を確認するため、６Ｈｚ精神運動発作モデルマウスを用いた試験を実施した。このモデルは、薬剤抵抗性の焦点発作モデルとして知られている（非特許文献２）。
＜方法＞
５週齢の雄性Ｓｃｌ：ｄｄＹマウス（日本エスエルシー（株））を試験に供した（各処置でｎ＝１０）。角膜を介する電気刺激（４４ｍＡ，６Ｈｚ，０．２ｍｓ ｒｅｃｔａｎｇｕｌａｒ ｐｕｌｓｅ ｗｉｄｔｈ，３ｓ ｄｕｒａｔｉｏｎ）によって誘発されるけいれんの有無を評価の指標とした。次の４つの内、１つ以上の行動を示す個体をけいれん有りと判定した（ｓｔｕｎ，ｆｏｒｅｌｉｍｂ ｃｌｏｎｕｓ，ｔｗｉｔｃｈｉｎｇ ｏｆ ｔｈｅ ｖｉｂｒｉｓｓａｅ，Ｓｔｒａｕｂ－ｔａｉｌ；非特許文献２）。
化合物（Ｉ）またはレベチラセタム（東京化成工業（株）、カタログ番号Ｌ０２３４、以下、化合物（Ａ）という）を、それぞれ１０ｍＬ／ｋｇの投与容量になるように０．４５％メチルセルロース／４．５％クレモフォール／１０％ジメチルスルホキシド溶液に溶解して検体を調製し、経口投与した。ネガティブコントロールとして、化合物を含まない上記混合溶液（Ｖｅｈｉｃｌｅ）を使用した。群構成は表１の通りである。検体投与６０分後に角膜を介する電気刺激を行い、けいれんを誘発させた。電気刺激終了後３０秒間、各個体を観察することでけいれんの有無を評価した。各投与群１０匹中、けいれんを示した個体数をカウントした（図１）。
上記けいれん個体数を基に、化合物（Ｉ）および化合物（Ａ）の５０％有効用量（それぞれ化合物（Ｉ） ＥＤ５０，化合物（Ａ） ＥＤ５０）をｐｒｏｂｉｔ ａｎａｌｙｓｉｓにより算出した。
＜結果＞
６Ｈｚ精神運動発作モデルマウスにおける各投与群のＥＤ５０を表２に示す。化合物（Ｉ）は用量依存的に抗けいれん効果を示し、５０ｍｇ／ｋｇでは１００％の阻害効果を示すのに対し、既存の抗てんかん薬である化合物（Ａ）は１００ｍｇ／ｋｇおよび２００ｍｇ／ｋｇで部分的な阻害効果しか示さないことが明らかとなった。この結果は、本発明に係る薬剤のけいれんに対する顕著な抑制効果を示すものである。
[Test Example 1] Test to confirm the inhibitory effect on convulsions using a 6Hz psychomotor seizure model mouse In order to confirm the inhibitory effect on convulsions, a test was conducted using a 6Hz psychomotor seizure model mouse. This model is known as a drug-resistant focal seizure model (Non-Patent Document 2).
<Method>
Five-week-old male Scl:ddY mice (Japan SLC Co., Ltd.) were subjected to the test (n=10 for each treatment). The presence or absence of convulsions induced by electrical stimulation (44 mA, 6 Hz, 0.2 ms rectangular pulse width, 3 s duration) via the cornea was used as an evaluation index. Individuals exhibiting one or more of the following four behaviors were determined to have convulsions (stun, forelimb clonus, twitching of the vibrissae, Straub-tail; Non-Patent Document 2).
Compound (I) or levetiracetam (Tokyo Kasei Kogyo Co., Ltd., catalog number L0234, hereinafter referred to as compound (A)) was mixed with 0.45% methylcellulose/4.5% cremo to give a dosage volume of 10 mL/kg. A sample was prepared by dissolving it in Fol/10% dimethyl sulfoxide solution and administered orally. As a negative control, the above mixed solution (vehicle) containing no compound was used. The group composition is shown in Table 1. 60 minutes after administration of the sample, electrical stimulation was performed through the cornea to induce convulsions. The presence or absence of convulsions was evaluated by observing each individual for 30 seconds after the end of electrical stimulation. Among the 10 animals in each administration group, the number of animals that showed convulsions was counted (Figure 1).
Based on the above numbers of convulsing individuals, the 50% effective doses of Compound (I) and Compound (A) (Compound (I) ED 50 and Compound (A) ED 50 , respectively) were calculated by probit analysis.
<Results>
Table 2 shows the ED50 of each administration group in the 6Hz psychomotor seizure model mouse. Compound (I) shows anticonvulsant effects in a dose-dependent manner, showing 100% inhibitory effect at 50 mg/kg, whereas compound (A), an existing antiepileptic drug, shows anticonvulsant effects at 100 mg/kg and 200 mg/kg. It was revealed that only a partial inhibitory effect was exhibited. These results demonstrate the remarkable inhibitory effect of the drug according to the present invention on convulsions.
［試験例２］ＧＡＴ－１ノックアウトマウス全脳サンプルを用いた結合試験
ＧＡＴ－１ノックアウトマウス全脳サンプルにおける化合物（Ｉ）の結合活性を確認するため、本試験を実施した。
＜方法＞
１０週齢の雄性ホモ接合型ＧＡＴ－１ノックアウトマウス、ヘテロ接合型ＧＡＴ－１ノックアウトマウス、野生型リッターメイトマウス（Ｄｅｌｔａｇｅｎ社）から既報（非特許文献３及び４）に基づいて調製した脳シナプトソーム膜画分を試験に供した（ｎ＝３）。
各群におけるＧＡＴ－１タンパク質発現はウェスタンブロッティングにより確認した。１次抗体としてｒａｂｂｉｔ ａｎｔｉ－ＧＡＴ１ ｍｏｎｏｃｌｏｎａｌ ａｎｔｉｂｏｄｙ（Ａｂｃａｍ社）あるいはｒａｂｂｉｔ ａｎｔｉ－ｇｌｙｃｅｒａｌｄｅｈｙｄｅ－３－ｐｈｏｓｐｈａｔｅ ｄｅｈｙｄｒｏｇｅｎａｓｅ（ＧＡＰＤＨ）ｍｏｎｏｃｌｏｎａｌ ａｎｔｉｂｏｄｙ（Ｃｅｌｌ Ｓｉｇｎａｌｉｎｇ Ｔｅｃｈｎｏｌｏｇｙ社）を使用した。２次抗体としてｈｏｒｓｅｒａｄｉｓｈ ｐｅｒｏｘｉｄａｓｅ（ＨＲＰ）－ｌｉｎｋｅｄ ａｎｔｉ－ｒａｂｂｉｔ ＩｇＧ（ＧＥ Ｈｅａｌｔｈｃａｒｅ社）を使用した。ＨＲＰ基質の添加により生じた化学発光強度を定量し、サンプルごとにＧＡＴ－１タンパク質発現レベル（＝ＧＡＴ－１特異的な化学発光強度／ＧＡＰＤＨ特異的な化学発光強度）を算出した。野生型リッターメイト群におけるＧＡＴ－１タンパク質発現レベルの平均値を１００％としたときの、各群におけるＧＡＴ－１タンパク質発現レベルの平均値を算出した。野生型リッターメイト群に対する各群の統計学的有意性について、Ｄｕｎｎｅｔｔ検定により解析した。有意水準は両側５％とした。
各群に対する化合物（Ｉ）の結合活性は、化合物（Ｉ）のトリチウムラベル体を用いたラジオアイソトープ結合実験により確認した。Ｔｏｔａｌ Ｂｉｎｄｉｎｇ（ＴＢ）測定用に、各アッセイチューブに各脳シナプトソーム膜画分（タンパク質量０．４ｍｇ／チューブ）と化合物（Ｉ）のトリチウムラベル体（最終濃度２００ｎｍｏｌ／Ｌ）を加え、４℃で２時間インキュベートした。Ｎｏｎｓｐｅｃｉｆｉｃ Ｂｉｎｄｉｎｇ（ＮＳＢ）測定用に、各アッセイチューブに各脳シナプトソーム膜画分（タンパク質量０．４ｍｇ／チューブ）と化合物（Ｉ）のトリチウムラベル体（最終濃度２００ｎｍｏｌ／Ｌ）、化合物（Ｉ）（最終濃度１ｍｍｏｌ／Ｌ）を加え、４℃で２時間インキュベーションした。ＴＢ測定用およびＮＳＢ測定用の反応溶液をガラスフィルターに通し、５０ｍｍｏｌ／Ｌ Ｔｒｉｓ－ＨＣｌ ｂｕｆｆｅｒで３回洗浄した。ガラスフィルターを液体シンチレーション測定用バイアルに移し、液体シンチレーターを添加後３時間以上インキュベーションした。液体シンチレーションカウンターで放射能を測定し、サンプルごとに化合物（Ｉ）のトリチウムラベル体の特異的結合（Ｓｐｅｃｉｆｉｃ Ｂｉｎｄｉｎｇ（ＳＢ）＝ＴＢ－ＮＳＢ）を算出した。野生型リッターメイト群における化合物（Ｉ）のトリチウムラベル体のＳＢの平均値を１００％としたときの、各群における化合物（Ｉ）のトリチウムラベル体のＳＢの平均値を算出した。野生型リッターメイト群に対する各群の統計学的有意性について、Ｄｕｎｎｅｔｔ検定により解析した。有意水準は両側５％とした。
＜結果＞
ホモ接合型ＧＡＴ－１ノックアウトマウス、ヘテロ接合型ＧＡＴ－１ノックアウトマウス、野生型リッターメイトマウスの脳シナプトソーム膜画分におけるＧＡＴ－１タンパク質発現レベルを図２に示す。野生型リッターメイト群におけるＧＡＴ－１タンパク質発現レベルの平均値を１００％としたときの、ヘテロ接合型ＧＡＴ－１ノックアウト群およびホモ接合型ＧＡＴ－１ノックアウト群におけるＧＡＴ－１タンパク質発現レベルの平均値はそれぞれ４５．２％および０．０％であった。また、各群における化合物（Ｉ）のトリチウムラベル体の特異的結合を図３に示す。ＧＡＴ－１タンパク質発現レベルの低下とともに、化合物（Ｉ）のトリチウムラベル体の特異的結合も低下した（野生型リッターメイト群における特異的結合の平均値を１００％としたときの、ヘテロ接合型ＧＡＴ－１ノックアウト群およびホモ接合型ＧＡＴ－１ノックアウト群における特異的結合の平均値はそれぞれ５４．０％および８．０％）。これらの結果は、化合物（Ｉ）が、ＧＡＴ－１に特異的に結合することを示すものである。
[Test Example 2] Binding test using GAT-1 knockout mouse whole brain sample This test was conducted to confirm the binding activity of compound (I) in a GAT-1 knockout mouse whole brain sample.
<Method>
Brain synaptosomal membranes prepared from 10-week-old male homozygous GAT-1 knockout mice, heterozygous GAT-1 knockout mice, and wild-type Litter Mate mice (Deltagen) based on previous reports (Non-patent Documents 3 and 4). Fractions were tested (n=3).
GAT-1 protein expression in each group was confirmed by Western blotting. Rabbit anti-GAT1 monoclonal antibody (Abcam) or rabbit anti-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) monoclonal antibody was used as the primary antibody. body (Cell Signaling Technology) was used. Horseradish peroxidase (HRP)-linked anti-rabbit IgG (GE Healthcare) was used as a secondary antibody. The chemiluminescence intensity generated by the addition of the HRP substrate was quantified, and the GAT-1 protein expression level (=GAT-1-specific chemiluminescence intensity/GAPDH-specific chemiluminescence intensity) was calculated for each sample. The average value of the GAT-1 protein expression level in each group was calculated, taking the average value of the GAT-1 protein expression level in the wild type littermate group as 100%. The statistical significance of each group relative to the wild type litter mate group was analyzed by Dunnett's test. The significance level was set at 5% on both sides.
The binding activity of Compound (I) to each group was confirmed by a radioisotope binding experiment using a tritium-labeled compound (I). For Total Binding (TB) measurement, each brain synaptosome membrane fraction (protein amount 0.4 mg/tube) and tritium-labeled compound (I) (final concentration 200 nmol/L) were added to each assay tube and incubated at 4°C. Incubated for 2 hours. For nonspecific binding (NSB) measurement, each brain synaptosome membrane fraction (protein amount 0.4 mg/tube), tritium-labeled compound (I) (final concentration 200 nmol/L), compound (I) ( A final concentration of 1 mmol/L) was added and incubated at 4°C for 2 hours. The reaction solutions for TB measurement and NSB measurement were passed through a glass filter and washed three times with 50 mmol/L Tris-HCl buffer. The glass filter was transferred to a vial for liquid scintillation measurement, and after addition of liquid scintillator, it was incubated for 3 hours or more. Radioactivity was measured using a liquid scintillation counter, and the specific binding (Specific Binding (SB) = TB-NSB) of the tritium-labeled compound (I) was calculated for each sample. The average value of SB of the tritium-labeled form of Compound (I) in each group was calculated, with the average value of SB of the tritium-labeled form of Compound (I) in the wild-type Littermate group being taken as 100%. The statistical significance of each group relative to the wild type litter mate group was analyzed by Dunnett's test. The significance level was set at 5% on both sides.
<Results>
Figure 2 shows the GAT-1 protein expression levels in the brain synaptosomal membrane fractions of homozygous GAT-1 knockout mice, heterozygous GAT-1 knockout mice, and wild-type litter mate mice. Average value of GAT-1 protein expression level in heterozygous GAT-1 knockout group and homozygous GAT-1 knockout group when the average value of GAT-1 protein expression level in wild type litter mate group is taken as 100% were 45.2% and 0.0%, respectively. Further, the specific binding of the tritium-labeled compound of compound (I) in each group is shown in FIG. As the GAT-1 protein expression level decreased, the specific binding of the tritium-labeled compound (I) also decreased (heterozygous GAT The average values of specific binding in the -1 knockout group and the homozygous GAT-1 knockout group were 54.0% and 8.0%, respectively). These results demonstrate that compound (I) specifically binds to GAT-1.
［試験例３］ＧＡＴ－１，ＧＡＴ－２，ＧＡＴ－３，ＢＧＴ－１の各強制発現細胞を用いたＧＡＢＡ取込み阻害試験
化合物（Ｉ）のＧＡＴ－１に対する機能的な作用を確認するため、ＧＡＴ－１，ＧＡＴ－２，ＧＡＴ－３，ＢＧＴ－１の各強制発現細胞を用いたＧＡＢＡ取込み阻害試験を実施した。
＜方法＞
ヒトＧＡＴ－１，ヒトＧＡＴ－２，ヒトＧＡＴ－３，ヒトＢＧＴ－１の各強制発現細胞をそれぞれ９６－ｗｅｌｌ ｍｉｃｒｏｔｉｔｅｒ ｐｌａｔｅに４．０×１０４ｃｅｌｌｓ／２００μＬ／ｗｅｌｌの密度で播き、３７℃、５％ＣＯ２で１日培養した。細胞をａｓｓａｙ ｂｕｆｆｅｒで洗浄後、化合物（Ｉ）（０．０１２８－１０００μｍｏｌ／Ｌ）と［３Ｈ］ＧＡＢＡ（５０μｍｏｌ／Ｌ）を加え、３７℃、５％ＣＯ２で５分間インキュベーションした。この時、ヒトＧＡＴ－１強制発現細胞を用いた試験においては、細胞をａｓｓａｙ ｂｕｆｆｅｒで洗浄後、化合物（Ｉ）（０．０１２８－１０００μｍｏｌ／Ｌ）あるいはチアガビン塩酸塩（東京化成工業（株）、カタログ番号Ｔ３１６５、以下、化合物（Ｂ）という、（０．２５６ｎｍｏｌ／Ｌ－１００μｍｏｌ／Ｌ））と、［３Ｈ］ＧＡＢＡ（０．０１－５００μｍｏｌ／Ｌ）を加え、３７℃、５％ＣＯ２で５分間インキュベーションした。細胞をｃｏｌｄ ａｓｓａｙ ｂｕｆｆｅｒで洗浄後、液体シンチレーターを加え、室温で１時間以上インキュベーションした。液体シンチレーションカウンターで放射能を測定し、化合物を添加していないｃｏｎｔｒｏｌ ｗｅｌｌの放射能を１００％としたときの、各ｗｅｌｌの放射能を算出した。これらの値を基に、化合物（Ｉ）のヒトＧＡＴ－１，ヒトＧＡＴ－２，ヒトＧＡＴ－３，ヒトＢＧＴ－１に対する５０％ＧＡＢＡ取込み阻害濃度（ＩＣ５０）を算出した。
＜結果＞
［３Ｈ］ＧＡＢＡ（５０μｍｏｌ／Ｌ）条件下の化合物（Ｉ）のヒトＧＡＴ－１，ヒトＧＡＴ－２，ヒトＧＡＴ－３，ヒトＢＧＴ－１に対する阻害曲線を図４に、５０％ＧＡＢＡ取込み阻害濃度を表３に示す。化合物（Ｉ）はヒトＧＡＴ－１選択的に阻害効果を示すことが明らかとなった。また、［３Ｈ］ＧＡＢＡ濃度を０．０１－５００μｍｏｌ／Ｌの範囲で変化させたときの、化合物（Ｉ）および化合物（Ｂ）のヒトＧＡＴ－１に対する阻害曲線を図５に示す。ＧＡＴ－１を選択的に阻害することが知られている既存の抗てんかん薬である化合物（Ｂ）（日本では未承認）は、ＧＡＢＡ濃度によらずＧＡＴ－１に対する阻害強度が一定であるのに対し、化合物（Ｉ）はＧＡＢＡ濃度の上昇とともにＧＡＴ－１に対する阻害強度も上昇することが明らかとなった。これらの結果は、化合物（Ｉ）がＧＡＴ－１の選択的な不競合阻害剤であることを示すものである。
[Test Example 3] GABA uptake inhibition test using forced expression cells of GAT-1, GAT-2, GAT-3, and BGT-1 In order to confirm the functional effect of compound (I) on GAT-1, A GABA uptake inhibition test was conducted using cells forced to express GAT-1, GAT-2, GAT-3, and BGT-1.
<Method>
Forced expression cells of human GAT-1, human GAT-2, human GAT-3, and human BGT-1 were seeded on a 96-well microtiter plate at a density of 4.0 × 10 4 cells/200 μL/well, and incubated at 37°C. , and cultured for 1 day in 5% CO2 . After washing the cells with assay buffer, compound (I) (0.0128-1000 μmol/L) and [ 3 H]GABA (50 μmol/L) were added and incubated at 37° C. and 5% CO 2 for 5 minutes. At this time, in the test using human GAT-1 forced expression cells, after washing the cells with assay buffer, compound (I) (0.0128-1000 μmol/L) or tiagabine hydrochloride (Tokyo Kasei Kogyo Co., Ltd.), Catalog number T3165, hereinafter referred to as compound (B) (0.256 nmol/L-100 μmol/L)) and [ 3 H]GABA (0.01-500 μmol/L) were added, and the mixture was heated at 37°C with 5% CO 2 and incubated for 5 minutes. After washing the cells with cold assay buffer, a liquid scintillator was added and incubated at room temperature for over 1 hour. Radioactivity was measured with a liquid scintillation counter, and the radioactivity of each well was calculated, taking the radioactivity of a control well to which no compound was added as 100%. Based on these values, the 50% GABA uptake inhibition concentration (IC 50 ) of compound (I) against human GAT-1, human GAT-2, human GAT-3, and human BGT-1 was calculated.
<Results>
Figure 4 shows the inhibition curve of Compound (I) against human GAT-1, human GAT-2, human GAT-3, and human BGT-1 under [ 3 H]GABA (50 μmol/L) conditions. The concentrations are shown in Table 3. It was revealed that compound (I) selectively inhibits human GAT-1. Further, FIG. 5 shows the inhibition curves of Compound (I) and Compound (B) against human GAT-1 when the [ 3 H]GABA concentration was varied in the range of 0.01-500 μmol/L. Compound (B), an existing antiepileptic drug known to selectively inhibit GAT-1 (not approved in Japan), has a constant inhibition strength against GAT-1 regardless of GABA concentration. On the other hand, it was revealed that the inhibitory strength of compound (I) against GAT-1 increases as the GABA concentration increases. These results demonstrate that Compound (I) is a selective, uncompetitive inhibitor of GAT-1.
Claims (15)
またはその薬剤学的に許容される塩を含有する、てんかん治療剤。 Compound represented by formula (I), N-[(1S)-2,2,5,7-tetrafluoro-2,3-dihydro-1H-inden-1-yl]sulfamide:
or a pharmaceutically acceptable salt thereof, for the treatment of epilepsy.
またはその薬剤学的に許容される塩を、それを必要とする患者に投与する、てんかんの治療方法。 Compound represented by formula (I), N-[(1S)-2,2,5,7-tetrafluoro-2,3-dihydro-1H-inden-1-yl]sulfamide:
A method for treating epilepsy, which comprises administering or a pharmaceutically acceptable salt thereof to a patient in need thereof.
またはその薬剤学的に許容される塩および賦形剤を含有する、てんかん治療のための医薬組成物。 Compound represented by formula (I), N-[(1S)-2,2,5,7-tetrafluoro-2,3-dihydro-1H-inden-1-yl]sulfamide:
or a pharmaceutical composition thereof for the treatment of epilepsy, containing a pharmaceutically acceptable salt thereof and an excipient.
またはその薬剤学的に許容される塩の使用。 Compound represented by formula (I), N-[(1S)-2,2,5,7-tetrafluoro-2,3-dihydro-1H-inden-1-yl]sulfamide for the production of epilepsy therapeutic agent :
or the use of pharmaceutically acceptable salts thereof.
またはその薬剤学的に許容される塩。 Compounds of formula (I), N-[(1S)-2,2,5,7-tetrafluoro-2,3-dihydro-1H-inden-1-yl] for use in the treatment of epilepsy Sulfamide:
or a pharmaceutically acceptable salt thereof.
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