JP6061956B2 - 痛みを治療・緩和する物質 - Google Patents
痛みを治療・緩和する物質 Download PDFInfo
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- JP6061956B2 JP6061956B2 JP2014556911A JP2014556911A JP6061956B2 JP 6061956 B2 JP6061956 B2 JP 6061956B2 JP 2014556911 A JP2014556911 A JP 2014556911A JP 2014556911 A JP2014556911 A JP 2014556911A JP 6061956 B2 JP6061956 B2 JP 6061956B2
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- pain
- receptor
- gaba
- subunit
- aminobutyric acid
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- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
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Description
(1)完全のGABAA受容体機能を有するα5-GABAA受容体を含むシステムを提供する工程と、
(2)候補物質を工程(1)のシステムに投与し、候補物質とα5-GABAA受容体の結合の状況を観察し、候補物質がα5-GABAA受容体と結合する場合、当該候補物質を痛みを予防、改善または治療する潜在薬物とする工程と、
を含む、痛みを予防、改善または治療する薬物を選別する方法を提供する。
ここで用いられるように、「α5サブユニットを含有するγ-アミノ酪酸A受容体」、「α5-GABAA受容体」、「α5サブユニットを含有するGABAA受容体」は、入れ替えて使用することができる。
α5-GABAA受容体の逆作動薬に対する研究は既に十数年が経ち、次々と新規な化合物が合成され、以前の研究では、学習記憶(認知)に関連する疾患を治療することができると思われる。
α5-GABAA受容体の逆作動薬が選択的にα5-GABAA受容体と結合することによって、痛みを抑制する作用を発揮することが知られた以上、この特徴に基づいてα5-GABAA受容体と結合する物質を選別することができる。その後、前述の物質から、痛みの抑制に本当に有用な薬物を見つけることができる。
本発明は、痛みを治療する方法を提供することによって、安全で有効な急性痛と慢性痛の治療に満足する。本発明によって提供される痛みを治療する方法によれば、このような治療を必要とする患者に有効量のα5-GABAA受容体の逆作動薬を投与することを含む。
本発明の化合物は、薬物組成物を製造することができ、薬用担体は、固体または液体でもよく、固体製剤は、散剤、錠剤、丸剤、カプセル、カシェ剤、坐剤および分散可能な顆粒剤を含み、固体担体は、一種または複数種の物質でもよく、希釈剤、矯味剤、粘着剤、防腐剤、錠剤崩壊剤またはコーティング剤としてもよい。散剤において、担体は、微細の固体で、本発明の化合物と微細の活性成分が混合物に存在する。錠剤において、この化合物は必要な粘着担体と適切な比率で混合し、且つ必要な形状と大きさにプレスする。散剤と錠剤には、好ましくは5〜70%の活性化合物を含有するが、適切な担体は、炭酸マグネシウム、ステアリン酸マグネシウム、タルク、糖、乳糖、ペクチン、デキストリン、デンプン、ゼラチン、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、低融点ワックスやココア脂などである。同様に、カシェ剤または錠剤、タブレット剤、散剤、カプセル、丸剤、カシェ剤と錠剤は、経口投与に適する固体剤型である。
(1)動物
オスSDラット(200-250g)を6匹ずつカゴに入れ、動物をすべて12時間明暗循環(即ち、毎日12時間の照明と12時間の暗黒)に置き、任意に食べ物と水を食べさせた。全部の試験は、いずれも観察者が薬物治療を知らない状態で行われる。
神経部分損傷モデル(SNI): 10%抱水クロラールを腹腔注射してラットを麻酔し、ラットの後肢上縁で皮膚を切開し、縦に筋肉を分離し、坐骨神経の主幹およびその下の分枝―脛骨神経、総腓骨神経および腓腹神経を露出させ、脛骨神経と総腓骨神経を結紮して切断し、細い腓腹神経を残し、同時に一切の損傷を避けた。筋肉、皮膚を順番に縫合し、さらに抗菌予防のために抗生物質を腹腔注射し、具体的な方法は、非特許文献10を参照する。
免疫組織化学の実験において、異なる時点でモデルラットを手術して固定液で灌注した後、1.5時間固定し、10%ショ糖で24時間以上浸漬した組織を低温保持装置でスライサーによって14μmの切片に切り、-20℃の冷蔵庫で保存した。切片を抗体(抗α5-GABAA受容体(Santa Cruz)ヤギ由来抗体、有効希釈比1:100〜200)と一晩インキュベートした後、0.01MのPBSで3回洗浄し、さらに第二抗体を入れて40分間インキュベートした後、0.01MのPBSで3回洗浄し、光を避けて保存した。最後に、顕微鏡で観察し、写真を撮った。免疫蛍光強度は、Image-pro定量分析の免疫蛍光強度とした。
ラットの熱痛覚過敏の定量検出法: ラットの足裏にCFA液を注射して24時間後から始め、熱痛覚過敏の定量検出法によってラットの熱放射刺激に対する足逃避反応を測定した。ラットの熱痛閾値を検出するため、ラットを透明ガラス板を有する有機ガラス箱に置き、熱放射装置(BME-410C、CAMS)でラットの足裏を刺激した。熱痛閾値は、ラットの足裏に光を照射してから、ラットが反射して逃避するまでの時間とした。
MRK 016、C2、C3、C4、C5、C6、C7、C8等の化合物またはα5IA(A5I)を70%(PGE400:水=70:30の体積比)のPGE400に溶解させ、剤量は、MRK 016が2 mg/kgまたはA5Iが3 mg/kg、C2、C3、C4、C5、C6、C7、C8化合物の剤量が3 mg/kg体重とし、注射剤にした。
EX500に記載の方法に従い、siRNAを注射可能な溶液に調製した。次に、ラットを麻酔し、さらにsiRNA溶液を第5または第6腰椎の位置から脊髄に注射した。siRNA注射から3日後、第5または第6腰椎の後根神経節を採取し、GABAA受容体のα5サブユニットのタンパク質の発現強度を検出した。
行動学のデータ統計方法は、unpaired t-testで、*p<0.05は、有意差を表す。
実施例1、GABAA受容体のα5サブユニットのSNIモデル条件における発現の上昇
SNIモデルにおいて、免疫組織化学の実験とイムノブロットの実験によってGABAA受容体のα5サブユニットのタンパク質の発現状況を測定し、結果を図1に示す。
イムノブロットの実験から、SNIモデルにおいて、時間の経過に従って、GABAA受容体のα5サブユニットのタンパク質の合計量が顕著に上昇したことが示され、図1Bに示す。
CFAで誘導された炎症性疼痛モデルにおいて、免疫組織化学の実験とイムノブロットの実験によってGABAA受容体のα5サブユニットのタンパク質の発現状況を測定し、結果を図2に示す。
坐骨神経と後根神経の結紮モデルにおいて、GABAA受容体のα5サブユニットのタンパク質量の状況を観察し、結果を図3に示す。
SNIモデルは、直接に外傷や圧傷による、あるいは間接に感染、癌、代謝疾患、毒素、栄養欠乏、免疫機能障害や筋肉・骨格の変化(musculoskeletal changes)のような一連の疾患による神経損傷に関連する神経因性疼痛を模擬した。神経因性疼痛は、現在、臨床で最も治療しにくい痛みの一つで、患者の生活品質に大きく影響する。ガバペンチンは、いま神経因性疼痛を治療する第一線の薬物であるが、眠気、目眩、歩行不安定や疲労感などの副作用に繋がる。
炎症性疼痛は、通常、組織または器官の病変による炎症で生じる痛みで、急性痛と慢性痛がある。動物試験において、組織損傷性病理疼痛モデルは、臨床炎性疼痛と類似のモデルで、中では、CFAで誘導された炎症性疼痛モデルは、臨床における慢性炎症性疼痛の各指標を反映する。このモデルにおいて、CFA注射後2-3時間で注射部位の皮膚に炎症反応が生じ、6-24時間でピークに達し、痛覚過敏と水腫が1-2週間続く(非特許文献12)が、このモデルでは、炎症性疼痛の特徴が顕著で、持続時間が長い。本発明者は、化合物MRK016およびその代謝物MRK016-M3は、有効に炎症性疼痛を抑制できることを見出した。
α5IA(A5I)は、MSD(Merk)社によって開発されたα5-GABAA受容体に対する特異的な逆作動薬である。臨床II期実験で、当該薬物は、水溶性の問題によって、ある程度の毒性問題が生じたことがわかった。
(1)細胞レベルの選別
ヒト腎上皮細胞系293細胞系またはL(tk-)細胞系を含む細胞系でGABAA受容体の異なるサブユニットを発現させた。前述細胞を培地で培養し、この細胞を痛みを抑制する薬物の選別のための細胞モデルとした。完全の機能型GABAA受容体を構成するには、一つのαサブユニット、βサブユニットおよびγサブユニットが不可欠である。
(a)293細胞系で同時にα5サブユニット(タンパク質配列はGenBank登録番号NM_001165037.1を参照)、β3サブユニット(タンパク質配列はGenBank登録番号NM_021912.4を参照)およびγ2サブユニット(タンパク質配列はGenBank登録番号NM_198904.2を参照)を発現させ、α5-GABAA受容体を構成した。
(b)293細胞系で同時にα1サブユニット(タンパク質配列はGenBank登録番号NM_001127648.1を参照)、β3サブユニットおよびγ2サブユニットを発現させ、α1サブユニットを含有するGABAA受容体を構成した。
(c)293細胞系で同時にα2サブユニット(タンパク質配列はGenBank登録番号NM_000813.2を参照)、β3サブユニットおよびγ2サブユニットを発現させ、α2サブユニットを含有するGABAA受容体を構成した。
(d)293細胞系で同時にα3サブユニット(タンパク質配列はGenBank登録番号NM_000808.3を参照)、β3サブユニットおよびγ2サブユニットを発現させ、α3サブユニットを含有するGABAA受容体を構成した。
上述(a)-(d)は、いずれも完全の機能を有するGABAA受容体を構成することができる。
候補物質を皮下注射、腹腔注射(または経口投与)によって動物に投与し、処理後の適切な時点で、候補物質の動物体内の分布を測定した。以下の二種類の方法で被検化合物の中枢α5-GABAA受容体との結合効率を測定することができる。
中間体1: 4-t-ブチル-3-ホルミル-1H-ピラゾール 4-トルエンスルホナート
(a)3-t-ブチル-4-ヒドロキシ-2(5H)-フラノン(3-tert-butyl-4-hydroxyfuran-2(5H)
-one)
(4-tert-butyl-3-(hydroxymethyl)-1H-pyrazol-5-ol)
4-tert-butyl-3-(hydroxymethyl)-1H-pyrazol-5-yl 4-methylbenzenesulfonate)
(4-tert-butyl-3-formyl-1H-pyrazol-5-yl 4-methylbenzenesulfonate)
(a)(2-メチル-2H-1,2,4,-トリアゾール-3-イル)メタノール
[(2-methyl-2H-1,2,4-triazol-3-yl)methanol ]
[5-(chloromethyl)-1-methyl-1H-1,2,4- triazole]
(a)5-ヒドロキシメチルイソオキサゾール-3-カルボン酸エチル
(ethyl 5-(hydroxymethyl) wasoxazole-3- carboxylate)
(5-(hydroxymethyl)wasoxazole-3-carbohydrazide)
[5-((tert-butyldimethylsilyloxy)methyl)isoxazole-3-carbohydrazide]
(a)3-t-ブチル-7-(5-((t-ブチルジメチルシリルオキシ)メチル)イソオキサゾール-3-イル)ピラゾロ[1,5-d][1,2,4]トリアジン-2-イル 4-トルエンスルホナート
(3-tert-butyl-7-(5-((tert-butyldimethylsilyloxy)methyl)isoxazol-3-yl)pyrazolo
[1,5-d][1,2,4]triazin-2-yl 4-methylbenzenesulfonate)
[1,2,4]トリアジン-2-オール(3-tert-butyl-7-(5-(hydroxymethyl)isoxazol-3-yl)pyrazolo[1,5-d][1,2,4] triazin
-2-ol)
[1,2,4]triazin-7-yl)isoxazol-5-yl)methanol)
3-t-ブチル-7-(5-(ヒドロキシメチル)イソオキサゾール-3-イル)ピラゾロ[1,5-d][1,2,4]トリアジン-2-オールと2-クロロメチルピリジン塩酸塩を使用し、上述と類似の方法で以下の化合物(C2)(3-(3-t-ブチル-2-(2-ピリジルメトキシ)-3,3a-2H-ピリゾロ[1,5-d][1,2,4]トリアジン-7-イル)イソオキサゾール-5-イル)メタノールを合成することができるが、以下の図の通りである。 m/z 381 [M+H]+.
C2、C3、C4化合物をそれぞれ70%(PGE400:水=70:30の体積比)のPGE400に溶解させ、剤量が3 mg/kgとし、注射剤にした。
図7Aは、化合物C2、C3、C4の化学構造式を示す。
図7Bでは、C2、C3、C4化合物の腹腔注射は、有効に神経因性疼痛を治療できたことが示された。この実験において、SNIモデルの構築から14日後、それぞれC2、C3、C4化合物(3mg/kg体重)を皮下注射し、投与1時間後ラットの疼痛閾値を検出したところ、このような化合物は神経因性疼痛を有効に治療できることが証明された。
中間体1: 1-(1-クロロフタラジン-4-イル)
(a)1,4-ジクロロフタラジン(1,4-dichlorophthalazine)
(1-(1-chlorophthalazin-4-yl)hydrazine)
(5-(hydroxymethy)isozazole-3-carboxylic acid)
(a)N'-(1-クロロフタラジン-4-イル)-5-(ヒドロキシメチル)イソオキサゾール-3-カルボヒドラジド(N'-(1-chlorophthalzin-4-yl)-5-(hydroxymethy)isoxazole-3-carbohydrazide)
上述実施例で合成された化合物C5、C6、C7およびC8をそれぞれ70%PGE400に溶解させ、剤量がそれぞれ3 mg/kg体重とし、注射剤にした。
本発明者は、C5、C6、C7およびC8化合物のSNIモデルと炎症性疼痛モデルにおける鎮痛作用を測定した。
図8Aは、化合物C5、C6、C7およびC8の化学構造式を示す。
図8Bでは、C5、C6、C7およびC8化合物の腹腔注射は、有効に神経因性疼痛を治療できたことが示された。この実験において、SNIモデルの構築から14日後、それぞれC5、C6、C7およびC8化合物(3mg/kg体重)を皮下注射し、投与1時間後ラットの疼痛閾値を検出したところ、このような化合物は神経因性疼痛を有効に治療できることが証明された。
α5-GABAA受容体の逆作動薬は、学習記憶に関連する疾患の治療に広く使用されており、F.H.L.社は、一連の関連化合物を出願し、且つ文献では、
Claims (8)
- 痛みを予防、改善または治療する薬物の製造において、α5サブユニットを含有するγ−アミノ酪酸A受容体の逆作動薬またはその薬学的に許容されるその塩の使用であって、γ−アミノ酪酸A受容体の逆作動薬または薬学的に許容されるその塩は、次の化学構造式の化合物から選ばれることを特徴とする使用。
- 前記α5サブユニットを含有するγ-アミノ酪酸A受容体の逆作動薬は、選択的に前記受容体のベンゾジアゼピン結合部位と結合するリガンドであることを特徴とする請求項1に記載の使用。
- . 前記の痛みは、末梢神経に関連する慢性痛であることを特徴とする請求項1に記載の使用。
- 前記慢性痛は、神経因性疼痛、炎症性疼痛および癌性疼痛であることを特徴とする請求項1に記載の使用。
- 前記痛みの病症としては、頭痛、面部痛、頚痛、肩痛、背痛、胸痛、腹痛、背部痛、腰痛、下肢痛、筋肉・骨格痛、体躯痛、血管痛、痛風、関節炎痛、身体表現性障害に関連する痛み、内臓痛、感染病による痛み、多箇所骨痛、鎌状赤血球貧血、自己免疫疾患、多発性硬化症または炎症に関連する痛み、急・慢性炎症痛、癌性疼痛、神経因性疼痛、損傷または手術による痛み、癌性痛、侵害受容性疼痛、糖尿病、末梢神経障害、疱疹後神経痛、三叉神経痛、腰部または子宮頚神経根障害、舌咽神経痛、自律神経反射性疼痛、反射性交感神経性ジストロフィー、神経根裂離、癌、化学損傷、毒素、栄養失調、ウイルスまたは細菌感染、退行性骨関節症、あるいはこれらの組み合わせを含むことを特徴とする請求項1に記載の使用。
- (1)完全のγ-アミノ酪酸A受容体機能を有するα5サブユニットを含有するγ-アミノ酪酸A受容体を含むシステムを提供する工程と、
(2)候補物質を工程(1)のシステムに投与し、候補物質とα5サブユニットを含有するγ-アミノ酪酸A受容体の結合の状況を観察し、候補物質がα5サブユニットを含有するγ-アミノ酪酸A受容体と結合する場合、前記候補物質を痛みを予防、改善または治療する潜在薬物とする工程と、
を含む、痛みを予防、改善または治療する薬物を選別する方法。 - 工程(1)は、γ-アミノ酪酸A受容体が完全のγ-アミノ酪酸A受容体機能を有する、α1サブユニットを含有するγ-アミノ酪酸A受容体を含むシステム、α2サブユニットを含有するγ-アミノ酪酸A受容体を含むシステム及び/又はα3サブユニットを含有するγ-アミノ酪酸A受容体を含むシステムから選ばれる対照群を設ける工程を含み、
工程(2)で、前述方法は、α5サブユニットを含有するγ-アミノ酪酸A受容体を含むシステムで候補物質とα5サブユニットを含有するγ-アミノ酪酸A受容体の結合の状況を検出し、対照群と比較し、候補物質とα5サブユニットを含有するγ-アミノ酪酸A受容体の結合の阻害定数Kiが統計学的に候補物質とα1、α2またはα3サブユニットを含有するγ-アミノ酪酸A受容体の結合の阻害定数Kiよりも低い場合、前記候補物質を痛みを予防、改善または治療する潜在薬物とすることを含む、を含むことを特徴とする請求項6に記載の方法。 - 工程(1)は、γ-アミノ酪酸A受容体が完全のγ-アミノ酪酸A受容体機能を有する、α1サブユニットを含有するγ-アミノ酪酸A受容体を含むシステム、α2サブユニットを含有するγ-アミノ酪酸A受容体を含むシステム及び/又はα3サブユニットを含有するγ-アミノ酪酸A受容体を含むシステムから選ばれる対照群を設ける工程を含み、
工程(2)で、前記方法は、電気生理的方法によって候補物質のγ−アミノ酪酸がγ-アミノ酪酸A受容体によって誘導する電量に対する抑制を検出し、被検物質がα5サブユニットを含有するγ-アミノ酪酸A受容体による電流を顕著に抑制するが、α1またはα2またはα3を含有するγ-アミノ酪酸A受容体によって誘導する電流を顕著に抑制しない場合、前記候補物質を痛みを予防、改善または治療する潜在薬物とすることを含む、を含むことを特徴とする請求項6に記載の方法。
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Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX2016007808A (es) * | 2013-12-20 | 2016-09-07 | Agenebio Inc | Derivados de benzodiazepina, composiciones, y metodos para tratar el deterioro congnitivo. |
CA2990004C (en) | 2015-06-19 | 2024-04-23 | Agenebio, Inc. | Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment |
CN106854207B (zh) | 2015-12-08 | 2019-10-29 | 上海赛默罗生物科技有限公司 | 呔嗪类衍生物、其制备方法、药物组合物和用途 |
CN107344938B (zh) * | 2016-05-06 | 2022-05-06 | 上海赛默罗生物科技有限公司 | 吡唑-三嗪类衍生物、其制备方法、药物组合物和用途 |
CN107344936B (zh) * | 2016-05-06 | 2022-06-03 | 上海赛默罗生物科技有限公司 | 三唑哒嗪类衍生物、其制备方法、药物组合物和用途 |
US20180170941A1 (en) * | 2016-12-19 | 2018-06-21 | Agenebio, Inc. | Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment |
BR112019012821A2 (pt) | 2016-12-19 | 2019-11-26 | Agenebio Inc | derivados de benzodiazepina, composições e métodos para o tratamento do comprometimento cognitivo |
CA3055215A1 (en) * | 2017-03-12 | 2018-09-20 | Xiaodong Wang | Polycyclic amines as opioid receptor modulators |
WO2019174577A1 (zh) | 2018-03-12 | 2019-09-19 | 上海赛默罗生物科技有限公司 | 酞嗪异噁唑烷氧基衍生物、其制备方法、药物组合物和用途 |
MX2020013927A (es) | 2018-06-19 | 2021-03-02 | Agenebio Inc | Derivados de benzodiazepina, composiciones y metodos para tratar el deterioro cognitivo. |
CN112979655A (zh) | 2019-12-16 | 2021-06-18 | 上海赛默罗生物科技有限公司 | 三唑并哒嗪类衍生物、其制备方法、药物组合物和用途 |
CN111812314B (zh) * | 2020-07-09 | 2023-03-10 | 嘉兴市第二医院 | 一种完全弗氏佐剂诱导的冻结肩动物模型建立方法 |
EP4385988A1 (en) | 2021-08-12 | 2024-06-19 | Shanghai Simr Biotechnology Co., Ltd. | Substituted triazole derivative, preparation method therefor, pharmaceutical composition thereof, and use thereof |
CN115137829A (zh) * | 2022-08-08 | 2022-10-04 | 山东大学 | 用于减轻放疗诱导的肠道损伤的药物 |
CN116008442B (zh) * | 2023-03-27 | 2023-06-30 | 上海赛默罗生物科技有限公司 | α5-GABAA受体调节剂的合成中间体的杂质检测方法 |
CN116008443B (zh) * | 2023-03-28 | 2023-06-30 | 上海赛默罗生物科技有限公司 | α5-GABAA受体调节剂类药物中有关物质的检测方法 |
Family Cites Families (116)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9112504D0 (en) | 1991-06-11 | 1991-07-31 | Merck Sharp & Dohme | Cell line |
AU680852B2 (en) | 1992-12-10 | 1997-08-14 | Merck Sharp & Dohme Limited | Stably transfected cell lines expressing GABA-A receptors |
EE03355B1 (et) | 1994-09-14 | 2001-02-15 | Neurosearch A/S | Indool-2,3-dioon-3-oksiimi derivaadid, nende valmistamine ja kasutamine |
GB9503601D0 (en) | 1995-02-23 | 1995-04-12 | Merck Sharp & Dohme | Method of treatment and method of manufacture of medicament |
WO1998004560A1 (en) | 1996-07-25 | 1998-02-05 | Merck Sharp & Dohme Limited | SUBSTITUTED TRIAZOLO PYRIDAZINE DERIVATIVES AS INVERSE AGONISTS OF THE GABAAα5 RECEPTOR SUBTYPE |
GB9622370D0 (en) | 1996-10-28 | 1997-01-08 | Merck Sharp & Dohme | Therapeutic agents |
GB9625398D0 (en) | 1996-12-06 | 1997-01-22 | Merck Sharp & Dohme | Method of treatment,manufacture,compositions and compounds |
ES2179490T3 (es) | 1997-05-08 | 2003-01-16 | Merck Sharp & Dohme | Derivados de 1,2,4-triazolo(3,4-a)ftalazina sustituidos como ligandos de gaba alfa 5. |
GB9716345D0 (en) | 1997-08-01 | 1997-10-08 | Merck Sharp & Dohme | Therapeutic compounds |
GB9716347D0 (en) | 1997-08-01 | 1997-10-08 | Merck Sharp & Dohme | Therapeutic compounds |
GB9716344D0 (en) | 1997-08-01 | 1997-10-08 | Merck Sharp & Dohme | Therapeutic compounds |
US6297235B1 (en) | 1997-08-28 | 2001-10-02 | Merck Sharp & Dohme Ltd. | Triazolopyridazine derivatives for treating anxiety and enhancing cognition |
GB9812038D0 (en) | 1998-06-04 | 1998-07-29 | Merck Sharp & Dohme | Therapeutic compound |
CA2346289A1 (en) * | 1998-10-16 | 2000-04-27 | Merck Sharp & Dohme Limited | Pyrazolo-triazine derivatives as ligands for gaba receptors |
AU1816900A (en) | 1998-11-12 | 2000-05-29 | Merck & Co., Inc. | Therapeutic polymorphs of a gaba-a alpha-5 inverse agonist and pamoate formulations of the same |
GB9824897D0 (en) | 1998-11-12 | 1999-01-06 | Merck Sharp & Dohme | Therapeutic compounds |
GB9900222D0 (en) | 1999-01-06 | 1999-02-24 | Merck Sharp & Dohme | Therapeutic compounds |
ATE277927T1 (de) | 1999-04-02 | 2004-10-15 | Neurogen Corp | Aryl- und heteroaryl-kondensierte aminoalkyl- imidazol-derivate: selektive modulatoren der gabaa-rezeptoren |
US6297256B1 (en) | 1999-06-15 | 2001-10-02 | Neurogen Corporation | Aryl and heteroaryl substituted pyridino derivatives GABA brain receptor ligands |
CN1372546A (zh) | 1999-08-31 | 2002-10-02 | 神经原公司 | 稠合的吡咯甲酰胺:gaba脑受体的配体 |
GB9921351D0 (en) | 1999-09-09 | 1999-11-10 | Merck Sharp & Dohme | Therapeutic agents |
MXPA02004735A (es) | 1999-11-12 | 2003-01-28 | Orive Javier Uhthoff | Compuestos heteroaromaticos, biciclicos y triciclicos. |
US6355638B1 (en) | 1999-11-25 | 2002-03-12 | Merck Sharp & Dohme Ltd. | Pyrazolo[1,5-d][1,2,4] triazines for enhancing cognition |
GB9929569D0 (en) | 1999-12-14 | 2000-02-09 | Merck Sharp & Dohme | Therapeutic agents |
GB0000564D0 (en) | 2000-01-11 | 2000-03-01 | Merck Sharp & Dohme | Therapeutic agents |
EP1294723A1 (en) | 2000-05-24 | 2003-03-26 | MERCK SHARP & DOHME LTD. | 3-phenyl-imidazo-pyrimidine derivatives as ligands for gaba receptors |
AU2001264932A1 (en) | 2000-05-26 | 2001-12-11 | Neurogen Corporation | Oxo-imidazopyrimidine-carboxamides and their use as gaba brain receptor ligands |
US6528649B2 (en) | 2000-05-30 | 2003-03-04 | Neurogen Corporation | Imidazoloisoquinolines |
US6828329B2 (en) | 2000-06-26 | 2004-12-07 | Neurogen Corporation | Aryl fused substituted 4-oxy-pyridines |
US6552037B2 (en) | 2000-06-30 | 2003-04-22 | Neurogen Corporation | 2-Substituted imidazo[1,2-A]pyridine derivatives |
GB0017518D0 (en) | 2000-07-17 | 2000-08-30 | Merck Sharp & Dohme | Therapeutic agents |
GB0017543D0 (en) | 2000-07-17 | 2000-09-06 | Merck Sharp & Dohme | Therapeutic agents |
JP2004505942A (ja) | 2000-08-07 | 2004-02-26 | ニューロゲン コーポレイション | Gabaa受容体の配位子としての複素環式化合物 |
MXPA03001945A (es) | 2000-09-06 | 2003-09-10 | Neurogen Corp | Tetrahidroindazoles sustituidos con arilo y su uso como ligandos para el receptor gaba-a. |
US6743817B2 (en) | 2000-09-06 | 2004-06-01 | Neurogen Corporation | Substituted fused pyrroleimines and pyrazoleimines |
GB0117277D0 (en) | 2001-07-16 | 2001-09-05 | Merck Sharp & Dohme | Therapeutic agents |
TWI239333B (en) | 2000-11-16 | 2005-09-11 | Hoffmann La Roche | Benzodiazepine derivatives as GABA A receptor modulators |
GB0028583D0 (en) | 2000-11-23 | 2001-01-10 | Merck Sharp & Dohme | Therapeutic compounds |
PA8535601A1 (es) | 2000-12-21 | 2002-11-28 | Pfizer | Derivados benzimidazol y piridilimidazol como ligandos para gabaa |
TWI248936B (en) | 2001-03-21 | 2006-02-11 | Merck Sharp & Dohme | Imidazo-pyrimidine derivatives as ligands for GABA receptors |
ES2271221T3 (es) | 2001-03-23 | 2007-04-16 | MERCK SHARP & DOHME LTD. | Derivados imidazo-pirimidina como ligandos para receptores gaba. |
JP2004525937A (ja) | 2001-03-27 | 2004-08-26 | ニューロジェン コーポレイション | (オキソ−ピラゾロ[1,5a]ピリミジン−2−イル)アルキル−カルボキサミド |
GB0108475D0 (en) | 2001-04-04 | 2001-05-23 | Merck Sharp & Dohme | New compounds |
US6686352B2 (en) | 2001-05-18 | 2004-02-03 | Hoffmann-La Roche Inc. | Substituted imidazo [1,5-a] pyrimido [5,4-d] [1] benzazepine derivatives |
JP2005506056A (ja) | 2001-06-06 | 2005-03-03 | ニューロサーチ、アクティーゼルスカブ | カチオン伝導gabaaレセプターおよびその使用 |
US6861529B2 (en) | 2001-07-06 | 2005-03-01 | Pfizer Inc | Cycloalkypyrrole-3-carboxylic acid derivatives and heterocycloalkylpyrrole-3-carboxylic acid derivatives |
IL159811A0 (en) | 2001-07-13 | 2004-06-20 | Neurogen Corp | Heteroaryl substituted fused bicyclic heteroaryl compounds as gabaa receptor ligands |
GB0125086D0 (en) | 2001-10-18 | 2001-12-12 | Merck Sharp & Dohme | Novel compounds |
WO2003044018A1 (en) | 2001-11-19 | 2003-05-30 | Neurogen Corporation | 1h-pyrrolo[3,2-b]pyridine-3-carboxylic acid amides |
GB0128160D0 (en) | 2001-11-23 | 2002-01-16 | Merck Sharp & Dohme | Novel compounds |
GB0128499D0 (en) | 2001-11-28 | 2002-01-23 | Merck Sharp & Dohme | Therapeutic agents |
JP2005525333A (ja) | 2002-02-07 | 2005-08-25 | ニューロジェン コーポレイション | 置換縮合ピラゾールカルボン酸アリールアミド及び関連化合物 |
JP2005525392A (ja) | 2002-03-28 | 2005-08-25 | ウィシス テクノロジー ファウンデーション,インコーポレイティド | 減少された鎮静及び失調効果を有する抗不安薬剤 |
GB0208394D0 (en) | 2002-04-11 | 2002-05-22 | Merck Sharp & Dohme | Therapeutic agents |
GB0208392D0 (en) | 2002-04-11 | 2002-05-22 | Merck Sharp & Dohme | Therapeutic compounds |
EP1499608A1 (en) | 2002-05-02 | 2005-01-26 | Neurogen Corporation | Substituted imidazole derivatives: gaba a receptor ligands |
GB0210127D0 (en) | 2002-05-02 | 2002-06-12 | Merck Sharp & Dohme | Therapeutic agents |
GB0210124D0 (en) | 2002-05-02 | 2002-06-12 | Merck Sharp & Dohme | Therapeutic agents |
EP1501825A2 (en) | 2002-05-08 | 2005-02-02 | Neurogen Corporation | Substituted imidazolylmethyl pyridine and pyrazine derivatives: gaba a receptor ligands |
JP2006502974A (ja) | 2002-05-17 | 2006-01-26 | ニューロジェン コーポレイション | 置換環縮合イミダゾール誘導体:gabaa受容体リガンド |
GB0212049D0 (en) | 2002-05-24 | 2002-07-03 | Merck Sharp & Dohme | Therapeutic agents |
GB0212048D0 (en) | 2002-05-24 | 2002-07-03 | Merck Sharp & Dohme | Therapeutic agents |
DE60325865D1 (de) | 2002-08-13 | 2009-03-05 | Merck Sharp & Dohme | Phenylpyridazin derivative als liganden für gaba-rezeptoren |
GB0218876D0 (en) | 2002-08-13 | 2002-09-25 | Merck Sharp & Dohme | Therapeutic agents |
CN100579579C (zh) | 2002-10-01 | 2010-01-13 | 诺华疫苗和诊断公司 | 抗癌及抗感染性疾病组合物及其使用方法 |
GB0225501D0 (en) | 2002-11-01 | 2002-12-11 | Merck Sharp & Dohme | Therapeutic agents |
ATE335732T1 (de) | 2002-11-08 | 2006-09-15 | Neurogen Corp | 4-imidazol-1-ylmethylpyrimidinderivate als liganden für gabaa-rezeptoren |
GB0226462D0 (en) | 2002-11-13 | 2002-12-18 | Merck Sharp & Dohme | Therapeutic agents |
GB0301350D0 (en) | 2003-01-21 | 2003-02-19 | Merck Sharp & Dohme | Therapeutic agents |
CA2508731A1 (en) | 2003-02-19 | 2004-09-02 | Neurogen Corporation | Aryl acid pyrimidinyl methyl amides, pyridazinyl methyl amides and related compounds |
WO2004076452A1 (en) | 2003-02-26 | 2004-09-10 | Merck Sharp & Dohme Limited | 5,8-DIFLUOROIMIDAZO[1,2-a]PYRIDINES AS GABA-A α2/α3 LIGANDS FOR TREATING ANXIETY AND/OR DEPRESSION |
AU2004222540B2 (en) | 2003-03-11 | 2009-10-01 | Trophos | Use of derivatives of cholest-4-en-3-one as medicaments, pharmaceutical compositions containing same, novel derivatives and preparation method thereof |
WO2004087137A1 (en) | 2003-04-03 | 2004-10-14 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the gabaa receptor complex |
CA2524376A1 (en) | 2003-05-05 | 2004-12-16 | Neurogen Corporation | Substituted imidazolopyrazine and triazolopyrazyne derivatives: gabaa receptor ligands |
GB0311859D0 (en) | 2003-05-22 | 2003-06-25 | Merck Sharp & Dohme | Therapeutic agents |
EP1713784A1 (en) | 2004-02-12 | 2006-10-25 | Neurogen Corporation | Imidazo-pyridazines, triazolo-pyridazines and related benzodiazepine receptor ligands |
US20050277639A1 (en) | 2004-03-02 | 2005-12-15 | Phil Skolnick | 2-Pyridinyl[7-(substituted-pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]methanones |
US20050245517A1 (en) | 2004-04-29 | 2005-11-03 | Phil Skolnick | 2-pyridinyl[7-(substituted-pyridin-4-yl) pyrazolo[1,5-a]pyrimidin-3-yl]methanones |
JP5002452B2 (ja) | 2004-05-06 | 2012-08-15 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 置換エナミノン類、それらの誘導体およびそれらの使用 |
EP1809297B1 (en) | 2004-10-12 | 2008-07-30 | F. Hoffmann-Roche AG | Imidazo[1,5a]triazolo[1,5d]benzodiazepine derivatives for the treatment of cognitive disorders |
MX2007004639A (es) | 2004-10-20 | 2007-06-08 | Hoffmann La Roche | Derivados de imidazo-benzodiazepina. |
JP4751398B2 (ja) | 2004-10-20 | 2011-08-17 | エフ.ホフマン−ラ ロシュ アーゲー | ハロゲン置換ベンゾジアゼピン誘導体 |
BRPI0515800A (pt) | 2004-12-14 | 2008-08-05 | Hoffmann La Roche | imidazo-benzodiazepinas tetracìclicas como moduladores de receptores de gaba |
US20080132510A1 (en) | 2005-01-21 | 2008-06-05 | Bingsong Han | Imidazolylmethyl and Pyrazolylmethyl Heteroaryl Derivatives |
US20080167324A1 (en) | 2005-03-02 | 2008-07-10 | Yuelian Xu | Thiazolymethyl and Oxazolylmethyl Heteroaryl Derivatives |
JP2009508905A (ja) | 2005-09-19 | 2009-03-05 | エフ.ホフマン−ラ ロシュ アーゲー | GABAAα5逆アゴニストとしてのイソオキサゾロ誘導体 |
AU2006301376A1 (en) | 2005-10-11 | 2007-04-19 | F. Hoffmann-La Roche Ag | Isoxazole derivatives |
JP4885967B2 (ja) | 2005-10-11 | 2012-02-29 | エフ.ホフマン−ラ ロシュ アーゲー | イミダゾベンゾジアゼピン誘導体 |
CA2628667A1 (en) | 2005-11-09 | 2007-05-18 | F. Hoffmann-La Roche Ag | 3-aryl-isoxazole-4-carbonyl-benzofuran derivatives |
BRPI0620146A2 (pt) | 2005-12-23 | 2011-11-01 | Hoffmann La Roche | derivados de aril-isoxazolo-4-il-oxadiazol, processo para a preparação dos referidos derivados, medicamento que os contém e usos de um desses derivados |
ES2376357T3 (es) | 2005-12-27 | 2012-03-13 | F. Hoffmann-La Roche Ag | Derivados de aril-isoxazol-4-il-imidazo[1,5-a]piridina. |
ATE527255T1 (de) | 2005-12-27 | 2011-10-15 | Hoffmann La Roche | Aryl-isoxazol-4-yl-imidazol-derivate |
CA2636112A1 (en) | 2006-01-17 | 2007-07-26 | F.Hoffmann-La Roche Ag | Aryl-isoxazol-4-yl-imidazo[1,2-a]pyridine derivatives useful for the treatment of alzheimer's disease via gaba receptors |
AU2007267183B2 (en) | 2006-05-31 | 2011-10-20 | F. Hoffmann-La Roche Ag | Aryl-4-ethynyl-isoxazole derivatives |
ATE544344T1 (de) | 2007-06-08 | 2012-02-15 | Helicon Therapeutics Inc | Therapeutische pyrazolochinolinderivate |
BRPI0812369A2 (pt) | 2007-06-08 | 2016-08-09 | Helicon Therapeutics Inc | composto e composição farmacêutica e métodos de modulação de um ou mais subtipos de gabaa e de tratamento de deficiência orgânica cognitiva, de desordem psiquiátrica e de de aumento da função congnitiva em animal e usos de composto ou de composição farmacêutica. |
EP2164328B8 (en) | 2007-06-08 | 2013-09-11 | Dart Neuroscience (Cayman) Ltd | Therapeutic pyrazoloquinoline urea derivatives |
KR101228194B1 (ko) | 2007-06-22 | 2013-01-30 | 에프. 호프만-라 로슈 아게 | 아이속사졸-이미다졸 유도체 |
EP2229383B1 (en) | 2007-12-04 | 2017-01-18 | F. Hoffmann-La Roche AG | Isoxazolo-pyrazine derivatives |
JP5301557B2 (ja) | 2007-12-04 | 2013-09-25 | エフ.ホフマン−ラ ロシュ アーゲー | イソオキサゾロ−ピリジン誘導体 |
US7943619B2 (en) | 2007-12-04 | 2011-05-17 | Hoffmann-La Roche Inc. | Isoxazolo-pyridazine derivatives |
WO2010002451A1 (en) | 2008-07-01 | 2010-01-07 | Concert Pharmaceuticals, Inc. | Naphthyridin derivatives |
CN102123703A (zh) | 2008-09-10 | 2011-07-13 | 莫茨药物股份两合公司 | 用于治疗耳鸣中认知损害的1-氨基-烷基环己烷衍生物 |
TW201033201A (en) | 2009-02-19 | 2010-09-16 | Hoffmann La Roche | Isoxazole-isoxazole and isoxazole-isothiazole derivatives |
US8389550B2 (en) | 2009-02-25 | 2013-03-05 | Hoffmann-La Roche Inc. | Isoxazoles / O-pyridines with ethyl and ethenyl linker |
JP2012519731A (ja) | 2009-03-09 | 2012-08-30 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | ニコチン受容体およびgabaa受容体のアロステリックモジュレーターとしての置換複素環およびそれらの使用 |
US8222246B2 (en) | 2009-04-02 | 2012-07-17 | Hoffmann-La Roche Inc. | Substituted isoxazoles |
US20100280019A1 (en) | 2009-04-30 | 2010-11-04 | Roland Jakob-Roetne | Isoxazoles |
JP5478716B2 (ja) | 2009-05-05 | 2014-04-23 | エフ.ホフマン−ラ ロシュ アーゲー | 認識障害の処置において使用するためのgabaa受容体逆アゴニストとしてのイソオキサゾール−チアゾール誘導体 |
MX2011011477A (es) | 2009-05-05 | 2011-11-18 | Hoffmann La Roche | Derivados de isoxazol-piridazina. |
AU2010244553A1 (en) | 2009-05-05 | 2011-12-01 | F. Hoffmann-La Roche Ag | Isoxazole-pyridine derivatives |
KR101384829B1 (ko) | 2009-05-05 | 2014-04-15 | 에프. 호프만-라 로슈 아게 | 이속사졸-피라졸 유도체 |
SG175318A1 (en) | 2009-05-07 | 2011-11-28 | Hoffmann La Roche | Isoxazole-pyridine derivatives as gaba modulators |
WO2011020044A1 (en) * | 2009-08-14 | 2011-02-17 | Concert Pharmaceuticals, Inc. | Substituted triazolophthalazine derivatives |
EP2298296A1 (en) * | 2009-08-25 | 2011-03-23 | CNRS Centre National De La Recherche Scientifique | Composition and method for treating cognitive impairments in down syndrome subjects |
HU230031B1 (hu) | 2010-03-01 | 2015-05-28 | Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság | Pregabalint és izomaltot tartalmazó stabilizált gyógyszerkészítmény |
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2013
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- 2013-02-07 WO PCT/CN2013/071515 patent/WO2013120438A1/zh active Application Filing
- 2013-02-07 CN CN201310050017.3A patent/CN103239720B/zh active Active
- 2013-02-07 EP EP13749318.5A patent/EP3025716B1/en active Active
- 2013-02-07 JP JP2014556911A patent/JP6061956B2/ja active Active
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US20150374705A1 (en) | 2015-12-31 |
CN103239720A (zh) | 2013-08-14 |
EP3025716A4 (en) | 2016-10-19 |
CN103239720B (zh) | 2016-03-16 |
EP3025716A1 (en) | 2016-06-01 |
EP3025716B1 (en) | 2018-04-04 |
WO2013120438A1 (zh) | 2013-08-22 |
JP2015509935A (ja) | 2015-04-02 |
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