JP6224097B2 - フェニルトリアゾール誘導体及びgabaa受受容体複合体を調節するための該フェニルトリアゾール誘導体の使用 - Google Patents
フェニルトリアゾール誘導体及びgabaa受受容体複合体を調節するための該フェニルトリアゾール誘導体の使用 Download PDFInfo
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
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Description
本発明の第1の態様では、本発明は以下の構造(I):
本発明の式(I)のフェニルトリアゾール誘導体を、意図した投与に適したいずれの形態において提供できる。適した形態は、本発明の化合物の薬学的に(即ち生理学的に)許容可能な塩を含む。
本発明の式(I)のフェニルトリアゾール誘導体は、その標識形態又は非標識形態において使用してよい。本発明の文脈において、標識化合物は、通常自然に発見される原子質量又は質量数とは異なる原子質量又は質量数を有する原子で置換された1つ又は複数の原子を有する。標識づけにより、上記化合物の定量検出が容易になる。
本発明の式(I)のフェニルトリアゾール誘導体は、その重水素化類似体の形態で提供できる。重水素化形態は炭素と結合し、この結合波比較的低い周波数で振動し、よってC−H結合よりも強い。従って、「重水素」(ジュウテリウム)型の薬剤は、分解に対してより安定であり、生体においてより長く存続する。
本発明の式(I)のフェニルトリアゾール誘導体は、例えば実施例に記載されるもの等の化学合成のための従来の方法によって調製してよい。本出願に記載のプロセスのための開始材料は公知であるか、又は従来の方法によって市販の化学物質から容易に調製できる。
本発明の式(I)のフェニルトリアゾール誘導体は、α5サブユニットを含有するGABAA受容体を調節できる。よって更なる態様では、本発明の式(I)のフェニルトリアゾール誘導体は、特に中枢神経系における、α5サブユニットを含有するGABAA受容体の調節に反応する疾患、障害又は健康状態の治療、予防又は緩和に有用であると考えられる。
別の態様では、本発明は、治療的に有効な量の本発明の式(I)のフェニルトリアゾール誘導体を含む新規の医薬組成物を提供する。
別の態様では、本発明は、ヒトを含む動物の生体の疾患又は障害又は健康状態の治療、予防又は緩和のための方法を提供し、上記疾患若しくは障害若しくは健康状態はα5サブユニットを含有するGABAA受容体の調節に反応するものである。上記方法は、上記方法を必要とする、ヒトを含む動物の生体に、治療的に有効な量の本発明の式(I)のフェニルトリアゾール誘導体又はその薬学的に許容可能な塩を投与することを含む。
1-{6-[5-(2-フルオロ-フェニル)-3-メチル-3H-[1,2,3]トリアゾール-4-イルメトキシ]-ピリジン-3-イル}-1H-イミダゾール-4-カルボニトリル(化合物7)の調製
THF(1500ml)中のジイソプロピルアミン(193.13g、1899.04mmol)の予備冷却(−78℃、内部温度−70℃)した溶液に、n−ブチルリチウム(759.617ml、1899.04mmol、ヘキサン中の2.5M溶液)を添加し、90分間撹拌した。次に、THF(500ml)中のN,N−ジメチルニトロソアミド(化合物2)(134.57g、1816.48mmol)を、30分かけて一部分ずつカニューレ処置し、1時間撹拌した。続いてTHF(500ml)中の2−フルオロベンゾニトリル(化合物1)(100.0g、825.671mmol)の溶液を、30分かけて一部分ずつカニューレ処置し、−78℃(内部温度−70℃)で1時間撹拌した。冷却浴を除去し、室温で2時間撹拌した。TLC及びUPLCで反応を監視した。上記反応物を、塩化アンモニウム飽和溶液(2000ml)を用いてゆっくりとクエンチし、水性層をジクロロメタン(5×2000ml)で抽出した。化学結合した有機層を硫化ナトリウム上で乾燥させ、濾過及び濃縮して、粗物質を得た(170.0g、物質収支116.21%)。これを重力カラムにより、溶離剤としてポリエチレンエーテル中の30%酢酸エチルを用いて精製し、所望の産物4−(2−フルオロフェニル)−1−メチル−1H−1,2,3−トリアゾールを赤みがかったガムとして得た(64.52g、物質収支44.10%)。これを、メチルtert−ブチルエーテル(1000ml)及びヘキサン(500ml)を用いて粉砕し、上澄層をデカンタして固体を乾燥させ、所望の産物4−(2−フルオロフェニル)−1−メチル−1H−1,2,3−トリアゾールを黄色がかった固体として得た(32.9g、22.49%)。
窒素雰囲気下のTHF(1200ml)中の4−(2−フルオロフェニル)−1−メチル−1H−1,2,3−トリアゾール(化合物3)(51g、287.84mmol)の予備冷却(−70℃〜−78℃)した溶液に、n−ブチルリチウム(138.16ml、345.41mmol、ヘキサン中の2.5M溶液)を添加し、2時間撹拌した。次に、DMF(1200ml、14794.844mmol)を添加して、−78℃で30分間撹拌した。TLC及びUPLCで反応を監視した。上記反応混合物を、氷冷却水(1000ml)を用いてゆっくりとクエンチし、水性層を酢酸エチル(5×1000ml)で抽出した。化学結合した有機層を硫化ナトリウム上で乾燥させ、濾過及び濃縮して、粗物質を得た(50g、物質収支84.66%)。これを重力カラムにより、溶離剤としてポリエチレンエーテル中の20%酢酸エチルを用いて精製し、所望の産物4−(2−フルオロフェニル)−1−メチル−1H−1,2,3−トリアゾール−5−カルバルデヒドを赤みがかった固体として得た(40、物質収支67.72%)。これを、tert−ブチルエーテル(1000ml)及びヘキサン(500ml)を用いて粉砕し、上澄層をデカンタして固体を乾燥させ、所望の産物4−(2−フルオロフェニル)−1−メチル−1H−1,2,3−トリアゾール−5−カルバルデヒドを白色固体として得た(32g、収率54.18%)。
メタノール(300ml)中に4−(2−フルオロフェニル)−1−メチル−1H−1,2,3−トリアゾール−5−カルバルデヒド(化合物4)(38g、185.19mmol)を窒素雰囲気下で撹拌した溶液に、水素化ホウ素ナトリウム(8.407g、222.23mmol)を0℃において一部分ずつ添加し、反応物を20分間撹拌した。TLC及びUPLCで反応を監視した。反応混合物を、水(500ml)を用いてクエンチし、濃縮してメタノール及び水を除去した。次にこれを酢酸エチル(4×500ml)で抽出し、化学結合した有機層を食塩水(50ml)で洗浄し、硫化ナトリウム上で乾燥させ、濾過及び濃縮して、粗物質を得た(34g、物質収支88.6%)。この固体をヘキサン(3×100ml)を用いて粉砕し、上澄層をデカンタして固体を乾燥させ、所望の産物(4−(2−フルオロフェニル)−1−メチル−1H−1,2,3−トリアゾール−5−イル)メタノールを灰白色固体として得た(31g、80.77%)。
0℃かつN2雰囲気下のDMF(10ml)中のNaH(0.73g、18.1mmol、無機油中に60%)の懸濁液に、[5-(2-フルオロ-フェニル)-3-メチル-3H-[1,2,3]トリアゾール-4-イル]-メタノール(2.5g、12.06mmol)を添加し、1時間撹拌した。続いて2−クロロ−5−ヨードピリジン(3.17g、13.27mmol)を添加し、反応混合物を室温までゆっくりと加熱し、4時間撹拌した。TLCで反応を監視した。反応混合物を、氷水を用いてクエンチし、酢酸エチル(50ml)で抽出し、食塩水(10ml)で洗浄し、Na2SO4上で乾燥させ、減圧下で濃縮して、粗物質を得た(4.4g、物質収支88.9%)。これをヘキサンを用いて粉砕し、固体を濾過して真空下で乾燥させ、
2-[5-(2-フルオロ-フェニル)-3-メチル-3H-[1,2,3]トリアゾール-4-イルメトキシ]-5−ヨード-ピリジンを黄色の固体として得た(2.4g、48.48%)。
DMF(10ml)中の、2-[5-(2-フルオロ-フェニル)-3-メチル-3H-[1,2,3]トリアゾール-4-イルメトキシ]-5−ヨード-ピリジン(0.5g、1.22mmol)、1H−イミダゾール−4−カルボニトリル(0.170g、1.82mmol)、炭酸セシウム(0.79g、2.43mmol)、酸化銅(I)(0.017g、0.12282mmol)、アセチルアセトン酸鉄(0.129g、0.36582mmol)の混合物を、90℃で20時間加熱した。TLC及びUPLCで反応を監視した。反応混合物を減圧下で濃縮し、水を添加し、酢酸エチル(3×50ml)で抽出した。化学結合した有機層を食塩水(15ml)で洗浄し、Na2SO4上で乾燥させ、減圧下で濃縮して、粗物質を得た(500mg、物質収支109%)。これを、溶離剤としてクロロホルム中の2%メタノールを使用して、Graceカラム中で精製し、所望の1-{6-[5-(2-フルオロ-フェニル)-3-メチル-3H-[1,2,3]トリアゾール-4-イルメトキシ]-ピリジン-3-イル)-1H-イミダゾール-4-カルボニトリルを灰白色固体として得た(0.180g、39.38%)。
ヒトGABAAα5β3*γ2S受容体を発現するHEK細胞を結合する3H−フルマゼニル(3H−Ro 15−1788)のインビトロ阻害
ベンゾダイアゼピンモジュレータユニットを、アンタゴニストである3H‐フルマゼニルによって選択的に標識化できる。
組換型ヒトGABAAα5β3*γ2S受容体(プラスミドH46/E9B10)の安定した発現を有するHEK−293細胞株を、T175ポリスチレンフラスコ又はローラボトル(1700cm2,Fisher Scientific CCI−431 191)に播種し、10%のウシ胎仔血清及び以下の抗生物質:ハイグロマイシンB(50μg/ml;γ2サブユニット)又はG418(0.5mg/ml;α5サブユニット)のうちの一方又は両方を補充したGlutaMAX(登録商標)培地を有するダルベッコ改変イーグル培地(Dulbecco’s Modified Eagle Medium:DMEM)に培養した。
実験の日に、細胞膜調製物を解凍し、2℃で10分間27,000xgで遠心分離した。Ultra−Turraxホモジナイザーを用いて、ペレットをトリス−クエン酸緩衝液に、1回のアッセイあたり15〜50μgのタンパク質まで再懸濁し、結合アッセイのために使用した。
1)Brandel Cell harvesterを用いたワットマンGF/Cガラス繊維濾紙上での急速濾過、その後1mlの氷冷緩衝液による5回の洗浄;又は
2)Tomtec cell harvesterを用いたUniFilter GF/Cガラス繊維濾紙上での急速濾過、その後約5mlの氷冷緩衝液を用いた洗浄。
1)別個の大きな濾紙の場合、Tri−Carb(登録商標)カウンタ(PerkinElmer Life and Analytical Sciences);又は
2)96‐ウェル濾板の場合、Topcount(登録商標)カウンタ(PerkinElmer Life and Analytical Sciences)。特異的結合は結合全体から非特異的結合を引いたものである。
IC50(3H‐フマルゼニルの特異的結合を50%まで阻害する試験化合物の濃度(μM))の計算の前に、特異的結合の25〜75%の阻害が得られなければならない。
医薬組成物
本発明の式(I)のフェニルトリアゾール誘導体は、いずれの形態の組成物に適用してよく、いずれの所望の量で投与してよい。この実施例は、標準的なカプセル処方の製剤を示す。
式(I)の医薬品原料(API)をカプセル1つあたり1mg含有するカプセルは、以下の組成を用いて得られる:
図1は、アフリカツメガエル卵母細胞における、本発明の式(I)の化合物によるα5β2γ2GABAA受容体の調節の流れを示す。化合物(1)(遊離塩基としての式(I)の化合物)の調節有効性は、Mirzaら(J Pharmacol Exp Ther.2008;327:954−68)に記載の同様の技術によって決定した。簡潔に言うと、卵母細胞に、1:1:2の比率のヒトGABAA受容体サブユニットα5、β2、γ2のためのcRNAを接種し、調節有効性はGABAcontrolと呼ばれる準最大EC5-20GABA濃度(0.5μM)との同時投与によって上昇した。5つの濃度(3.16、0.316、0.0316、0.00316、0.000316μΜ)の上記化合物を、濃度が最も低いものから初めて、各卵母細胞に対して試験した。バックグラウンドを差し引いたピーク電流振幅を各GABAcontrol電流に対して正規化し、%変化に変換し、上昇する化合物の濃度の関数として±S.E.M.を表した。プロットしたデータポイントは実験に基づいたヒルの式に一致した。最大有効性に関する95%の信頼区間(Bottom)及び効力(LogEC50)がこのフィッティングルーチンによって導かれた。
Claims (8)
- 1−[6−[[5−(2−フルオロフェニル)−3−メチル−トリアゾール−4−イル]メトキシ]−3−ピリジル]イミダゾール−4−カルボニトリル;又は
その薬学的に許容可能な塩、多形体若しくは水和物
である、フェニルトリアゾール誘導体。 - 治療的に有効な量の請求項1に記載のフェニルトリアゾール誘導体、又はその薬学的に許容可能な塩、多形体若しくは水和物を、少なくとも1つの薬学的に許容可能な担体、賦形剤又は希釈剤と共に含む医薬組成物。
- α5サブユニットを含有するGABAA受容体の調節に反応する、ヒトを含む哺乳類の
疾患若しくは障害若しくは健康状態の治療、予防又は緩和において使用するための、1−[6−[[5−(2−フルオロフェニル)−3−メチル−トリアゾール−4−イル]メトキシ]−3−ピリジル]イミダゾール−4−カルボニトリル;又はその薬学的に許容可能な塩、多形体若しくは水和物である、フェニルトリアゾール誘導体。 - 請求項3に記載の化合物を含む、α5サブユニットを含有するGABAA受容体の調節
に反応する、ヒトを含む哺乳類の疾患若しくは障害若しくは健康状態の治療のための医薬
。 - 前記疾患、障害又は健康状態は、急性及び慢性神経障害、認知障害、アルツハイマー病、記憶欠損、統合失調症、統合失調症に関連する陽性症状、陰性症状及び/又は認知症状、双極性障害、自閉症、ダウン症、神経線維腫症1型、睡眠障害、概日リズム障害、筋萎縮性側索硬化症、エイズに起因する認知症、精神異常、物質誘導性精神異常、不安障害、全般性不安障害、パニック障害、妄想性障害、強迫性障害、急性ストレス障害、薬物依存、運動障害、パーキンソン病、下肢静止不能症候群、認知欠損障害、多発梗塞性認知症、気分障害、うつ病、神経精神状態、精神病、注意欠陥多動性障害、神経障害性疼痛、脳卒中、注意欠陥障害、摂食障害、拒食症、神経性食欲不振、悪液質、体重減少、筋萎縮、疼痛状態、慢性疼痛、侵害受容性疼痛、術後疼痛、骨関節炎性疼痛、リウマチ性関節炎性疼痛、筋骨格痛、火傷の痛み、眼の痛み、炎症による痛み、骨折による痛み、痛覚過敏、神経障害性疼痛、ヘルペス関連の痛み、HIV関連の神経障害性疼痛、外傷性神経損傷、脳卒中後の痛み、局所貧血後の痛み、線維筋痛症、慢性頭痛、偏頭痛、緊張型頭痛、糖尿病性神経障害性疼痛、幻肢痛、内臓痛、皮膚痛の群から選択される
請求項3に記載の化合物。 - 前記疾患、障害又は健康状態は、急性及び慢性神経障害、認知障害、アルツハイマー病、記憶欠損、統合失調症、統合失調症に関連する陽性症状、陰性症状及び/又は認知症状、双極性障害、自閉症、ダウン症、神経線維腫症1型、睡眠障害、概日リズム障害、筋萎縮性側索硬化症、エイズに起因する認知症、精神異常、物質誘導性精神異常、不安障害、全般性不安障害、パニック障害、妄想性障害、強迫性障害、急性ストレス障害、薬物依存、運動障害、パーキンソン病、下肢静止不能症候群、認知欠損障害、多発梗塞性認知症、気分障害、うつ病、神経精神状態、精神病、注意欠陥多動性障害、神経障害性疼痛、脳卒中、注意欠陥障害、摂食障害、拒食症、神経性食欲不振、悪液質、体重減少、筋萎縮、疼痛状態、慢性疼痛、侵害受容性疼痛、術後疼痛、骨関節炎性疼痛、リウマチ性関節炎性疼痛、筋骨格痛、火傷の痛み、眼の痛み、炎症による痛み、骨折による痛み、痛覚過敏、神経障害性疼痛、ヘルペス関連の痛み、HIV関連の神経障害性疼痛、外傷性神経損傷、脳卒中後の痛み、局所貧血後の痛み、線維筋痛症、慢性頭痛、偏頭痛、緊張型頭痛、糖尿病性神経障害性疼痛、幻肢痛、内臓痛、皮膚痛の群から選択される
請求項4に記載の医薬。 - 前記疾患、障害又は健康状態は、アルツハイマー病、統合失調症、統合失調症に関連する陽性症状、陰性症状及び/又は認知症状、ダウン症からなる群
から選択される、請求項3に記載の化合物。 - 前記疾患、障害又は健康状態は、アルツハイマー病、統合失調症、統合失調症に関連する陽性症状、陰性症状及び/又は認知症状、ダウン症からなる群
から選択される、請求項4に記載の医薬。
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BR102019014802A2 (pt) | 2018-07-20 | 2020-02-04 | Boehringer Ingelheim Int | difluorometil-fenil triazóis |
HU231223B1 (hu) | 2018-09-28 | 2022-01-28 | Richter Gedeon Nyrt. | GABAA A5 receptor modulátor hatású biciklusos vegyületek |
EP3858965B1 (en) * | 2020-01-28 | 2022-05-11 | The Procter & Gamble Company | Cleaning product |
WO2021191837A1 (en) | 2020-03-26 | 2021-09-30 | Richter Gedeon Nyrt. | 1,3-dihydro-2h-pyrrolo[3,4-c]pyridine derivatives as gabaa α5 receptor modulators |
TW202202495A (zh) * | 2020-03-26 | 2022-01-16 | 匈牙利商羅特格登公司 | 作為gamma-胺基丁酸A受體次單元alpha 5受體調節劑之㖠啶及吡啶并〔3,4-c〕嗒𠯤衍生物 |
IL310708A (en) * | 2021-08-12 | 2024-04-01 | Shanghai Simr Biotechnology Co Ltd | The history of converted triazole, a method for its preparation, its pharmaceutical preparation and its use |
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KR101022082B1 (ko) | 2005-10-11 | 2011-03-17 | 에프. 호프만-라 로슈 아게 | 아이소옥사졸 유도체 |
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PL1968973T3 (pl) | 2005-12-27 | 2012-03-30 | Hoffmann La Roche | Pochodne aryloizoksazol-4-iloimidazolu |
ES2376357T3 (es) | 2005-12-27 | 2012-03-13 | F. Hoffmann-La Roche Ag | Derivados de aril-isoxazol-4-il-imidazo[1,5-a]piridina. |
AU2007267183B2 (en) | 2006-05-31 | 2011-10-20 | F. Hoffmann-La Roche Ag | Aryl-4-ethynyl-isoxazole derivatives |
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IL236041A (en) | 2016-09-29 |
CA2876778A1 (en) | 2014-01-03 |
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EP2877463B1 (en) | 2018-11-07 |
JP2015521642A (ja) | 2015-07-30 |
CN104411699A (zh) | 2015-03-11 |
MX357504B (es) | 2018-07-12 |
EP2877463A1 (en) | 2015-06-03 |
AU2013283487B2 (en) | 2017-05-25 |
AU2013283487A1 (en) | 2015-01-22 |
IL236041A0 (en) | 2015-02-01 |
US9206160B2 (en) | 2015-12-08 |
US9931329B2 (en) | 2018-04-03 |
MX2014014871A (es) | 2015-06-17 |
AU2013283487C1 (en) | 2018-01-18 |
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