WO2019181854A1 - てんかん治療剤 - Google Patents
てんかん治療剤 Download PDFInfo
- Publication number
- WO2019181854A1 WO2019181854A1 PCT/JP2019/011184 JP2019011184W WO2019181854A1 WO 2019181854 A1 WO2019181854 A1 WO 2019181854A1 JP 2019011184 W JP2019011184 W JP 2019011184W WO 2019181854 A1 WO2019181854 A1 WO 2019181854A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pyrano
- dihydro
- oxo
- fluoro
- dipyridin
- Prior art date
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Images
Classifications
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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Definitions
- the present invention relates to a therapeutic agent for epilepsy comprising a combination of an indan-1-ylsulfamide derivative and an AMPA glutamate receptor antagonist. More specifically, N-[(1S) -2,2,5,7-tetrafluoro-2,3-dihydro-1H-inden-1-yl] sulfamide (or a pharmaceutically acceptable salt thereof) And an epilepsy treatment agent in combination with an AMPA-type glutamate receptor antagonist.
- Epilepsy is one of the most common central nervous diseases, and there are more than 50 million patients worldwide. According to the definition of the World Health Organization, it is a chronic brain disease caused by various etiologies, and it is characterized by recurrent seizures (epileptic seizures) derived from excessive discharge of cerebral neurons, and clinical and examinations rich in mutations It is accompanied by the presentation of findings. "
- Epilepsy seizures include, for example, partial seizures, complex seizures and secondary generalized seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures, weakness seizures, etc. are known.
- intractable epilepsy West syndrome, Lennox-Gastaut syndrome, tuberous sclerosis, Dravet syndrome, fragile X syndrome and the like are known.
- Treatment of epilepsy is centered on pharmacotherapy with antiepileptic drugs (AED).
- AED antiepileptic drugs
- the goal of epilepsy treatment is to eliminate epileptic seizures and prevent side effects associated with treatment. In principle, treatment with antiepileptic drugs starts with a single agent.
- Drugs marketed for the treatment of epilepsy include carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone, sodium valproate, zonisamide, felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, eslicarbabe Zepin, pregabalin, lacosamide, rufinamide, trimetadione, sultiam, acetazolamide, vigabatrin, benzodiazepine drugs (clonazepam, clobazam, nitrazepam, diazepam), peranpanel, retigabine and the like (Non-patent Document 1). These existing antiepileptic drugs exhibit an effect by suppressing excessive excitement of nerve cells.
- AMPA-type glutamate receptors are considered to play an important role in the generation of epilepsy waves and propagation through synapses.
- AMPA-type glutamate receptor antagonists inhibit epileptic seizures by inhibiting the activation of post-synaptic AMPA-type glutamate receptors by glutamate and suppressing neural hyperexcitability. Many AMPA-type glutamate receptor antagonists have been reported so far.
- peranpanel (3- (2-cyanophenyl) -5- (2-pyridyl) -1-phenyl-1,2-dihydropyridine represented by the formula (II): -2-one) (hereinafter also referred to as “compound (II)”) is an AMPA-type glutamate receptor antagonist.
- pyranodipyridine compound groups including the compound represented by the formula (III) (hereinafter also referred to as “compound (III)”) have an AMPA glutamate receptor antagonistic activity and can be used as a therapeutic agent for epilepsy. It is reported that it has the property (patent document 2).
- An object of the present invention is to provide a concomitant drug that exhibits a strong anticonvulsant action and has the potential to be used as a therapeutic agent for epilepsy.
- the present inventors have energetically studied using a mouse sound-induced convulsion model and a lithium-pilocarpine stacked convulsion model rat. As a result, it was found that sound-induced convulsions were significantly suppressed by combining an indan-1-ylsulfamide derivative and an AMPA-type glutamate receptor antagonist in a mouse sound-induced convulsion model. In addition, as a result of examination using a lithium-pilocarpine stacked convulsion model rat, it was found that by combining an indan-1-ylsulfamide derivative and an AMPA glutamate receptor antagonist, the convulsive seizure was remarkably suppressed. Was completed.
- the present invention relates to ⁇ 1> to ⁇ 14> below.
- ⁇ 1> N-[(1S) -2,2,5,7-tetrafluoro-2,3-dihydro-1H-inden-1-yl] sulfamide
- a therapeutic agent for epilepsy wherein a pharmaceutically acceptable salt thereof and an AMPA glutamate receptor antagonist are used in combination.
- ⁇ 2> N-[(1S) -2,2,5,7-tetrafluoro-2,3-dihydro-1H-inden-1-yl] sulfamide
- a therapeutic agent for epilepsy wherein a pharmaceutically acceptable salt thereof and an AMPA glutamate receptor antagonist are administered simultaneously or separately.
- a therapeutic agent for epilepsy comprising a pharmaceutically acceptable salt thereof and an AMPA glutamate receptor antagonist.
- a compound in which the AMPA-type glutamate receptor antagonist is selected from the following group: 3- (2-cyanophenyl) -5- (2-pyridyl) -1-phenyl-1,2-dihydropyridin-2-one, 9- (2-chlorophenyl) -7- (pyridin-3-yl) -6H-pyrano [3,2-b: 5,4-b ′] dipyridin-8 (7H) -one, 2-Fluoro-6- (7- (5-methoxypyridin-3-yl) -8-oxo-7,8-dihydro-6H-pyrano [3,2-b: 5,4-b ′] dipyridine-9 -Yl) benzonitrile, 2-Fluoro-6- (7- (6-methylpyridin-3-yl) -8-oxo-7,8-dihydro-6H-pyrano [3,2-b: 5,4-b ′] dipyridine-9 -Yl) benzonitrile, 2-
- AMPA-type glutamate receptor antagonist is 3- (2-cyanophenyl) -5- (2-pyridyl) -1-phenyl-1,2-dihydropyridin-2-one
- the epilepsy therapeutic agent according to any one of the above ⁇ 1> to ⁇ 3>, which is a pharmaceutically acceptable salt thereof.
- a compound in which the AMPA glutamate receptor antagonist is selected from the following group: 9- (2-chlorophenyl) -7- (pyridin-3-yl) -6H-pyrano [3,2-b: 5,4-b ′] dipyridin-8 (7H) -one, 2-Fluoro-6- (7- (5-methoxypyridin-3-yl) -8-oxo-7,8-dihydro-6H-pyrano [3,2-b: 5,4-b ′] dipyridine-9 -Yl) benzonitrile, 2-Fluoro-6- (7- (6-methylpyridin-3-yl) -8-oxo-7,8-dihydro-6H-pyrano [3,2-b: 5,4-b ′] dipyridine-9 -Yl) benzonitrile, 9- (2-Chloro-3-fluorophenyl) -7- (6-methylpyridin-3-yl) -6H-pyrano [3,2-
- AMPA-type glutamate receptor antagonist is a 2-fluoro-6- (3-fluoro-8-oxo-7- (pyridin-3-yl) -7,8-dihydro-6H-pyrano [3,2 -B: 5,4-b '] dipyridin-9-yl) benzonitrile
- the epilepsy therapeutic agent according to any one of the above ⁇ 1> to ⁇ 3>, which is a pharmaceutically acceptable salt thereof.
- a method for treating epilepsy using a pharmaceutically acceptable salt thereof and an AMPA glutamate receptor antagonist a method for treating epilepsy using a pharmaceutically acceptable salt thereof and an AMPA glutamate receptor antagonist.
- a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof, an AMPA glutamate receptor antagonist and an excipient.
- kits comprising a pharmaceutical composition comprising a pharmaceutically acceptable salt and an excipient thereof and a pharmaceutical composition comprising an AMPA glutamate receptor antagonist and an excipient.
- a kit comprising a pharmaceutical composition comprising a pharmaceutically acceptable salt and an excipient thereof and a pharmaceutical composition comprising an AMPA glutamate receptor antagonist and an excipient.
- a pharmaceutical composition comprising a pharmaceutically acceptable salt and an excipient thereof
- a pharmaceutical composition comprising an AMPA glutamate receptor antagonist and an excipient.
- an AMPA-type glutamate receptor antagonist for the manufacture of a therapeutic agent for epilepsy in combination with a pharmaceutically acceptable salt thereof.
- the present invention provides a drug comprising a combination of an indan-1-ylsulfamide derivative and an AMPA glutamate receptor antagonist.
- a drug exhibits a remarkable antiepileptic effect as compared with the case where each drug is used alone, and has applicability as a therapeutic agent for epilepsy.
- Test Example 2 the combined effect of the compound (Ia) and the compound (II) in a lithium-pilocarpine stacked convulsion model rat is shown.
- Test Example 3 the combined effect of compound (Ia) and compound (XVI) in a lithium-pilocarpine stacked convulsion model rat is shown.
- Compound (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof can be produced, for example, by the method described in Patent Document 1.
- Compound (II) or a pharmaceutically acceptable salt thereof can be produced, for example, by the method described in International Publication No. 2006/004100.
- compound (III)-(XXIV) or a pharmaceutically acceptable salt thereof can be produced, for example, by the method described in Patent Document 2.
- “Pharmaceutically acceptable salt” is not particularly limited as long as it forms a salt with the compound according to the present invention. Specifically, for example, inorganic acid salt, organic acid salt or acidic amino acid salt And acid addition salts such as
- Examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
- Examples of the salt with an organic acid include, for example, 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. And the salt.
- salt with acidic amino acid examples include salts with aspartic acid, glutamic acid and the like.
- the therapeutic agent for epilepsy of the present invention comprises compound (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof, an AMPA glutamate receptor antagonist, that is, compound (II) and compound (III).
- -A compound selected from the group consisting of (XXIV) or a pharmaceutically acceptable salt thereof may be formulated separately and both may be administered simultaneously or separately. Moreover, it is good also as what is called a kit formulation by putting two formulations in one package. Furthermore, both compounds may be contained in one preparation.
- the epilepsy therapeutic agent of the present invention comprises a pharmaceutically acceptable additive, compound (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof and / or compound (II) and a compound It can be produced by mixing with a compound selected from the group consisting of (III)-(XXIV) or a pharmaceutically acceptable salt thereof.
- the therapeutic agent for epilepsy of the present invention can be produced according to a known method such as the method described in the general rules for preparations of the 16th revision Japanese Pharmacopoeia.
- the therapeutic agent for epilepsy of the present invention can be appropriately administered to a patient according to its dosage form.
- the dose of compound (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof depends on the degree of symptoms, patient age, sex, body weight, sensitivity difference, Usually, when administered orally to an adult (body weight 60 kg), 100 ⁇ g to 5 g per day, one mode 300 ⁇ g to 3 g, another mode In the case of administration by administration of 1 mg to 1 g, 30 ⁇ g to 1 g per day, 30 ⁇ g to 500 mg in one embodiment, and 50 ⁇ g to 300 mg in another embodiment are administered in one or several divided doses.
- the dose of a compound selected from the group consisting of compound (II) and compound (III)-(XXIV) or a pharmaceutically acceptable salt thereof is appropriately selected as described above.
- can do when administered orally to an adult (body weight 60 kg), 10 ⁇ g to 500 mg per day, 30 ⁇ g to 300 mg as one aspect, 50 ⁇ g to 100 mg as another aspect, 3 ⁇ g per day when administered as an injection 100 mg, in one aspect, 10 ⁇ g to 100 mg, and in another aspect, 10 ⁇ g to 50 mg are administered once or in several divided doses.
- the therapeutic agent for epilepsy of the present invention comprises a dose of compound (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof, and compound (II) and compounds (III)-(XXIV)
- the dose of a compound selected from the group or a pharmaceutically acceptable salt thereof varies depending on the degree of symptoms, patient age, sex, body weight, sensitivity difference, administration method, administration time, type of pharmaceutical preparation, etc. .
- compound (II) when orally administered to an adult (body weight 60 kg), 100 ⁇ g to 5 g of compound (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof per day, compound (II) And a compound selected from the group consisting of Compound (III)-(XXIV) or a pharmaceutically acceptable salt thereof is orally administered in a dose of 10 ⁇ g to 500 mg per day in one or several divided doses.
- compound (II) and A compound selected from the group consisting of compounds (III)-(XXIV) or a pharmaceutically acceptable salt thereof is orally administered at 30 ⁇ g to 300 mg per day in one or several divided doses.
- 1 mg to 1 g of compound (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof per day for an adult (body weight 60 kg), compound (II) And a compound selected from the group consisting of Compound (III)-(XXIV) or a pharmaceutically acceptable salt thereof is orally administered in a dose of 50 ⁇ g to 100 mg per day in one or several divided doses.
- a compound selected from the group consisting of II) and compounds (III)-(XXIV) or a pharmaceutically acceptable salt thereof is administered by injection at a dose of 3 ⁇ g to 100 mg per day in one or several divided doses.
- compound (II) and A compound selected from the group consisting of compounds (III)-(XXIV) or a pharmaceutically acceptable salt thereof is administered by injection at a dose of 10 ⁇ g to 100 mg per day in one or several divided doses.
- a compound selected from the group consisting of Compound (III)-(XXIV) or a pharmaceutically acceptable salt thereof is administered at a dose of 10 ⁇ g to 50 mg per day in one or several divided doses.
- the dose at which the effective rate is 50% for each of the compound (Ia) single administration group, the compound (II) single administration group, and the combination group of compound (Ia) and compound (II) were calculated by regression analysis.
- the theoretical value (ED50add) of additive ED50 is calculated according to the method of literature (Epilepsia, 44, p1003-1013 (2003)), and the ratio of ED50mix to ED50add is less than 0.7 by isobologram analysis.
- lithium chloride dose 127 mg / kg, dose volume 1 mL / kg
- pilocarpine hydrochloride dose 30 mg / kg, dose volume 5 mL / kg
- (-)-scopolamine methylbromide dose 5 mg / kg, dose volume 1 mL / kg
- Table 4 shows the correspondence between the convulsion score and the symptoms.
- the vehicle or sample was administered into the tail vein (dosing volume: 1 mL / kg, infusion rate: flush).
- the group structure is as shown in Table 5.
- EEG recording was continued until 1 hour after vehicle or sample administration.
- Total power ( ⁇ V 2 ) was calculated for each set epoch (4 seconds / epoch) from the electroencephalogram data (analysis target frequency: 5 Hz to less than 100 Hz) of each individual using electroencephalogram analysis software SleepSign (Kissei Comtech, Nagano). .
- FIG. 1 shows the combined effect of compound (Ia) and compound (II) in a lithium-pilocarpine stacked convulsion model rat. The combined group of compound (Ia) and compound (II) showed a significant anticonvulsant effect on the vehicle group.
- FIG. 2 shows the combined effect of compound (Ia) and compound (XVI) in a lithium-pilocarpine stacked convulsion model rat. The combined group of compound (Ia) and compound (XVI) showed a significant anticonvulsant effect on the vehicle group.
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Abstract
Description
<1>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
<2>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
<3>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
<4>AMPA型グルタミン酸受容体拮抗剤が、以下の群から選ばれる化合物:
3-(2-シアノフェニル)-5-(2-ピリジル)-1-フェニル-1,2-ジヒドロピリジン-2-オン、
<5>AMPA型グルタミン酸受容体拮抗剤が、3-(2-シアノフェニル)-5-(2-ピリジル)-1-フェニル-1,2-ジヒドロピリジン-2-オン
<6>AMPA型グルタミン酸受容体拮抗剤が、以下の群から選ばれる化合物:
9-(2-クロロフェニル)-7-(ピリジン-3-イル)-6H-ピラノ[3,2-b:5,4-b’]ジピリジン-8(7H)-オン、
<7>AMPA型グルタミン酸受容体拮抗剤が、2-フルオロ-6-(3-フルオロ-8-オキソ-7-(ピリジン-3-イル)-7,8-ジヒドロ-6H-ピラノ[3,2-b:5,4-b’]ジピリジン-9-イル)ベンゾニトリル
<8>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
<9>AMPA型グルタミン酸受容体拮抗剤と併用することによるてんかんの治療のための、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
<10>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
<11>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
<12>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
<13>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
<14>AMPA型グルタミン酸受容体拮抗剤と併用することによるてんかん治療剤製造のための、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
なお、上記式(III)-(XXIV)で表される化合物を、以下まとめて「化合物(III)-(XXIV)」という。
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。
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マウス音誘発けいれんモデルを用いて研究を行った。また、けいれん重積発作に対する抑制効果を確認するためにリチウム-ピロカルピン重積けいれんモデルラットを用いて研究を行った。
けいれんに対する抑制効果を確認するため、マウス音誘発けいれんモデル試験を実施した。このモデルでは、音刺激によって誘導される強直性けいれんが評価指標となる(European Journal of Pharmacology,222,p193-203(1992))。
<方法>
3週齢の雄性DBA/2JJclマウス(日本クレア(株))を試験に供した(各処置でn=5を計2回実施)。音刺激によって誘発される強直性けいれんを評価の指標とした(上記文献)。
化合物(Ia)および/または化合物(II)を、それぞれ20mL/kgの投与容量になるように0.4%メチルセルロース/5%クレモフォール/5% 1N塩酸/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30分後に音刺激(11kHz、115dB、duration:30秒)を行い、けいれんを誘発させた。音刺激終了直後、後肢伸展の有無を観察することで強直性けいれんを評価した。投与群ごとに強直性けいれんを示した割合(%Tonic convulsion)を算出した。
上記算出した%Tonic convulsionを基に、化合物(Ia)単独投与群、化合物(II)単独投与群、化合物(Ia)と化合物(II)の併用群ごとに有効率が50%となる用量(それぞれ化合物(Ia) ED50、化合物(II) ED50、ED50mix)を回帰分析により算出した。文献(Epilepsia,44,p1003-1013(2003))の方法に従い、相加的なED50の理論値(ED50add)を算出し、アイソボログラム解析法により、ED50mixとED50addの比が0.7未満の場合は相乗、0.7以上1.3以下の場合は相加、1.3を超える場合は拮抗と判定した。
<結果>
マウス音誘発けいれんモデルにおける各投与群のED50を表2に示す。相加的なED50の理論値(ED50add)は、26mg/kgと算出された。その結果、ED50mixとED50addの比は0.58となったことから(表3)、化合物(Ia)と化合物(II)を併用することにより相乗的な抗けいれん効果を示す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。
けいれん重積発作に対する抑制効果を確認するため、リチウム-ピロカルピン重積けいれんモデルラット試験を実施した。このモデルでは、薬剤によって誘導される連続した脳波上の棘波の程度が評価指標となる(Journal of Neuroscience Methods,172,p143-157(2008))。
<方法>
三種混合麻酔(2mg/kg ミダゾラム、0.15mg/kg 塩酸メデトミジン、2.5mg/kg 酒石酸ブトルファノール、皮下投与)下に脳波用電極を頭蓋骨に埋め込んだ。手術後2日以上回復させた後、塩化リチウム(投与量127mg/kg、投与容量1mL/kg)を腹腔内投与した。1日後にピロカルピン塩酸塩(投与量30mg/kg、投与容量5mL/kg)と(-)-スコポラミンメチルブロミド(投与量5mg/kg、投与容量1mL/kg)を連続で腹腔内投与してけいれんを惹起した。けいれんスコア4以上のけいれんを発現した動物のみを実験に使用した。なお、けいれんスコアと症状との対応を表4に示す。けいれんスコアが4以上であることを目視で確認した30分後に、媒体あるいは検体を尾静脈内投与した(投与容量:1mL/kg、注入速度:フラッシュ)。群構成は表5の通りである。媒体あるいは検体投与1時間後まで脳波の記録を継続した。脳波解析ソフトウェアSleepSign(キッセイコムテック、長野県)を用いて、各個体の脳波データ(解析対象周波数:5Hz以上100Hz未満)から設定エポック(4秒/エポック)ごとにTotal power(μV2)を算出した。動物の動作に起因するノイズを含むエポックを除外後、投与前10分間を対象として、周波数ごとに1エポックあたりの平均power(μV2)を算出した後、全周波数帯分を合計し、各個体のPre total power(μV2)とした。同様に投与後から1時間分を対象としてFFT解析を実施して各個体のPost total power(μV2)を算出した。Pre total powerに対するPost total powerの百分率(%)((Post total power/Pre total power)×100)を個体ごとに算出し、統計解析を実施した。媒体群と、化合物(Ia)と化合物(II)の併用群との間の統計学的有意性について、対応のないt検定を実施した。また、化合物(Ia)単独投与群および化合物(II)単独投与群と、化合物(Ia)と化合物(II)の併用群との間の統計学的有意性について、1元配置分散分析後、有意の場合FisherのLSD検定を実施した。有意水準はいずれも両側5%とした。
<結果>
リチウム-ピロカルピン重積けいれんモデルラットにおける化合物(Ia)と化合物(II)の併用効果を図1に示す。化合物(Ia)と化合物(II)の併用群は媒体群に対して、有意にけいれん抑制作用を示した。また、化合物(Ia)と化合物(II)の併用群は化合物(Ia)単独投与群および化合物(II)単独投与群に対しても、有意にけいれん抑制作用の増強を示した。これらの結果は、本発明に係る薬剤が、けいれん重積発作に対する顕著なけいれん抑制効果を有することを示すものである。
けいれん重積発作に対する抑制効果を確認するため、リチウム-ピロカルピン重積けいれんモデルラット試験を実施した。
<方法>
6週齢の雄性SDラット(日本チャールス・リバー(株))を試験に供した。塩化リチウム(投与量127mg/kg、投与容量1mL/kg)を腹腔内投与した。1日後にピロカルピン塩酸塩(投与量30mg/kg、投与容量5mL/kg)と(-)-スコポラミンメチルブロミド(投与量5mg/kg、投与容量1mL/kg)を連続で腹腔内投与してけいれんを惹起した。けいれんスコア4以上のけいれんを発現した動物のみを実験に使用した。なお、けいれんスコアと症状との対応を表4に示す。けいれんスコアが4以上であることを目視で確認した30分後に、媒体あるいは検体を尾静脈内投与した(投与容量:1-4mL/kg、注入速度:フラッシュ)。群構成は表6の通りである。化合物投与1時間後、表4に従いけいれんをスコア化した。化合物(Ia)単独投与群および化合物(XVI)単独投与群および化合物(Ia)と化合物(XVI)の併用群と、媒体群との間の統計学的有意性について、Holm-Sidak検定を実施した。化合物(Ia)単独群および化合物(XVI)単独群と、化合物(Ia)と化合物(XVI)の併用群との間の統計学的有意性について、Holm-Sidak検定を実施した。有意水準はいずれも両側5%とした。
<結果>
リチウム-ピロカルピン重積けいれんモデルラットにおける化合物(Ia)と化合物(XVI)の併用効果を図2に示す。化合物(Ia)と化合物(XVI)の併用群は媒体群に対して、有意にけいれん抑制作用を示した。また、化合物(Ia)と化合物(XVI)の併用群は化合物(Ia)単独投与群および化合物(XVI)単独投与群に対しても、有意にけいれん抑制作用の増強を示した。これらの結果は、本発明に係る薬剤が、けいれん重積発作に対する顕著なけいれん抑制効果を有することを示すものである。
Claims (7)
- AMPA型グルタミン酸受容体拮抗剤が、以下の群から選ばれる化合物:
3-(2-シアノフェニル)-5-(2-ピリジル)-1-フェニル-1,2-ジヒドロピリジン-2-オン、
- AMPA型グルタミン酸受容体拮抗剤が、以下の群から選ばれる化合物:
9-(2-クロロフェニル)-7-(ピリジン-3-イル)-6H-ピラノ[3,2-b:5,4-b’]ジピリジン-8(7H)-オン、
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WO2023210617A1 (ja) * | 2022-04-27 | 2023-11-02 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | パーキンソン病治療用医薬組成物 |
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WO2022113778A1 (ja) * | 2020-11-25 | 2022-06-02 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | てんかん治療剤 |
WO2023210617A1 (ja) * | 2022-04-27 | 2023-11-02 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | パーキンソン病治療用医薬組成物 |
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