JP2018514524A - 5−芳香族アルキニル基置換ベンズアミド系化合物並びにその製造方法、薬物組成物及び使用 - Google Patents
5−芳香族アルキニル基置換ベンズアミド系化合物並びにその製造方法、薬物組成物及び使用 Download PDFInfo
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- JP2018514524A JP2018514524A JP2017554023A JP2017554023A JP2018514524A JP 2018514524 A JP2018514524 A JP 2018514524A JP 2017554023 A JP2017554023 A JP 2017554023A JP 2017554023 A JP2017554023 A JP 2017554023A JP 2018514524 A JP2018514524 A JP 2018514524A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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Abstract
Description
グルタミン酸は哺乳動物の中枢神経系における最も主要な興奮性神経伝達物質で、神経系の正常機能の維持に重要な作用を果たし、疼痛、神経退行性病変や癲癇などの多くの病理・生理的過程においても重要な作用を発揮する。同時に、グルタミン酸の神経系における大量の放出と蓄積は多くの神経細胞損傷と神経変性疾患の病理的原因で、すなわちグルタミン酸の神経毒作用で、最終的にニューロンの死亡につながる。グルタミン酸のその受容体に対する活性化による興奮毒性および細胞膜におけるグルタミン酸/システイン輸送体に対する抑制による酸化毒性は、脳虚血、パーキンソン病、癲癇などの多くの神経系疾患の発病要因であるため、グルタミン酸受容体は既にこれらの疾患の治療標的の一つになっている。
このように、本分野では新たなmGluR5陰性アロステリック調節剤の開発が切望されている。
本発明の目的は、新たなmGluR5陰性アロステリック調節剤、特に選択性が改善されたmGluR5陰性アロステリック調節剤を提供することである。
R1は水素、ハロゲン、C1-C6アルキル基、ハロゲン置換のC1-C6アルキル基、シアノ基からなる群から選ばれる。
R2およびR3はそれぞれ独立に水素、置換または無置換のフェニル基、置換または無置換の3-7員ヘテロアリール基、置換または無置換の5-7員アリール基-メチレン基、3-7員複素環基-メチレン基からなる群から選ばれ、各複素環基はそれぞれ独立に酸素、硫黄および窒素から選ばれる1〜4個のヘテロ原子を含有し、かつ前記のR2およびR3の少なくとも一方は水素ではない。あるいは、R2およびR3は連結するN原子とともに置換または無置換の5-20員スピロ複素環、もしくは置換または無置換の4-20員縮合複素環からなる群から選ばれる基を構成する。ここで、前記の置換とは基における一つまたは複数の水素原子がハロゲン、C1-C6アルキル基、ハロゲン置換のC1-C6アルキル基、C1-C6アルコキシ基、C1-C6アルコキシカルボニル基、ハロゲン置換のC1-C6アルコキシ基、C2-C6アルケニル基、C2-C6アルキニル基、C3-C8シクロアルキル基、シアノ基、ニトロ基、アミノ基、ヒドロキシ基、ヒドロキシメチル基、カルボキシ基、メルカプト基、スルホニル基、C6-C10アリール基、および3-12員複素環基からなる群から選ばれる置換基で置換されることをいう。ここで、前記のスピロ複素環、縮合複素環または複素環基はそれぞれ独立に酸素、硫黄および窒素から選ばれる1〜4個のヘテロ原子を含有する。
前記のハロゲンは、F、Cl、BrまたはIである。)
もう一つの好適な例において、前記のR2およびR3はそれぞれ独立に水素、置換または無置換のフェニル基、置換または無置換の3-7員ヘテロアリール基、置換または無置換の5-7員アリール基-メチレン基、3-7員複素環基-メチレン基からなる群から選ばれ、各複素環基はそれぞれ独立に酸素、硫黄および窒素から選ばれる1〜4個のヘテロ原子を含有し、R2およびR3の少なくとも一方は水素ではないか、
R3はHであるか、
あるいはR2およびR3は連結するN原子とともに置換または無置換の、
ここで、R9、R10、R11、R12、R13はそれぞれ環の任意の位置における1-4個の置換基を表し、かつ各置換基はそれぞれ独立にハロゲン、C1-C6アルキル基、ハロゲン置換のC1-C6アルキル基、C1-C6アルコキシ基、シアノ基、ニトロ基、アミノ基、ヒドロキシ基からなる群から選ばれる。
もう一つの好適な例において、前記のR1はH、F、Cl、CH3、CNからなる群から選ばれる。
もう一つの好適な例において、前記の化合物は表Aで示される化合物である。
もう一つの好適な例において、前記薬物組成物は、中枢神経系および精神系の関連疾患、好ましくは脆弱X症候群、パーキンソン病におけるレボドパ誘発ジスキネジー(PD-LID)、胃食道逆流症(GERD)、自閉症、疼痛、不安障害、うつ病、薬物依存症、不安障害からなる群から選ばれる疾患の治療に使用される。
もう一つの好適な例において、前記の薬物組成物は経口投与製剤である。
本発明の第三の側面では、上記一般式Iで表される構造を有する5-芳香族アルキニル基置換ベンズアミド系化合物、その薬用可能な塩、ラセミ体、R-異性体、S-異性体、またはこれらの組み合わせを含むmGluR5陰性アロステリック調節剤を提供する。
もう一つの好ましい例において、前記のmGluR5陰性アロステリック調節剤は選択的にmGluR5を抑制する。
もう一つの好ましい例において、前記のmGluR5陰性アロステリック調節剤はmGluR1に対して抑制作用がない(好ましくはmGluR5に対するIC50値とmGluR1に対するIC50値の比は≧1000、より好ましくは≧2000、さらに好ましくは≧5000、最も好ましくは≧10000である)。
もう一つの好適な例において、前記の疾患は、中枢神経系および精神系の関連疾患、好ましくは脆弱X症候群、パーキンソン病におけるレボドパ誘発ジスキネジー(PD-LID)、胃食道逆流症(GERD)、自閉症、疼痛、不安障害、うつ病、薬物依存症、不安障害からなる群から選ばれる疾患である。
本発明者は長期間にわたって深く研究したところ、式Iで表されるmGluR5陰性アロステリック調節剤を提供したが、前記の調節剤は高い選択性でmGluR5を抑制しながら、ほかの相同性のある代謝型グルタミン酸受容体に抑制作用が生じないか、抑制作用が弱いため、mGluR5に関連する疾患、たとえば中枢神経系および精神系の関連疾患の治療に使用することができる。上記の知見に基づき、発明者らは本発明を完成させた。
本明細書で用いられるように、ハロゲンはF、Cl、BrまたはIである。
本明細書で用いられるように、用語「C1〜C6アルキル基」とは炭素原子を1〜6個有する直鎖または分岐鎖のアルキル基で、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、sec-ブチル基、t-ブチル基、ペンチル基やヘキシル基などを含むが、これらに限定されない。
本明細書で用いられるように、用語「C1-C6アルコキシ基」とは炭素原子を1〜6個有する直鎖または分岐鎖のアルコキシ基で、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基やブトキシ基などを含むが、これらに限定されない。
本明細書で用いられるように、用語「C2-C6アルキニル基」とは炭素原子を2〜6個有し、三重結合を一つ含有する直鎖または分岐鎖のアルキニル基で、エチニル基、プロパギル基、ブチニル基、イソブチニル基、ペンチニルやヘキシニル基などを含むが、これらに限定されない。
本明細書で用いられるように、用語「C3-C10シクロアルキル基」とは、環に炭素原子を3〜10個有する環状アルキル基で、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、シクロオクチル基やシクロデシル基などを含むが、これらに限定されない。用語「C3-C8シクロアルキル基」、「C3-C7シクロアルキル基」、および「C3-C6シクロアルキル基」は類似の意味を持つ。
本明細書で用いられるように、用語「3-12員複素環基」とは環に酸素、硫黄および窒素から選ばれるヘテロ原子を1〜3個含有する飽和または不飽和の3〜12員環基で、たとえばジオキサシクロペンチル基などが挙げられる。用語「3-7員複素環基」は類似の意味を持つ。
用語「4-20員縮合複素環」とはN、OまたはSから選ばれるヘテロ原子を1〜4個有する飽和または不飽和の芳香族縮合環である。
本発明において、特別に説明しない限り、用いられる用語は、本分野の技術者に公知の通常の意味を持つ。
脆弱X症候群(fragile X syndrome、FXS)は、マーチン-ベル症候群とも呼ばれ、よく見られる遺伝性精神遅滞性疾患で、その発症率は男性は約1/1250で、女性は1/2500で、非特異性精神遅滞の2%-6%を占め、X連鎖精神遅滞の40%を占め、臨床症状は異なる程度の精神遅滞、注意欠陥、多動、不安が伴う情緒不安定、強迫症、自閉症と現れ、また運動協調障害や癲癇の罹患率の増加、およびほかの非神経系症状、たとえば顔異形、大きな耳、関節の過展や思春期後巨睾丸症等などが現れることもある。Verkerk(1991)らはその病原性遺伝子であるFMR1のクローニングに成功し、当該遺伝子の5’末端の(CGG)nの三ヌクレオチド反復配列の異常増幅およびその隣接部位のCpGアイランドの異常メチル化はFMR1遺伝子の転写および翻訳を終わらせ、コーディング産物であるFMRP、すなわち脆弱X精神遅滞タンパク質(fragile X mental retardation protein、FMRP)の減少または欠失につながる。1994年にFMR1遺伝子ノックアウトマウスの出現は脆弱X症候群の一つの里程標である。BakkerらはFMR1遺伝子領域にネオマイシン断片を挿入することによって、当該遺伝子はFMRPを発現することができなくなり、脆弱X症候群のマウスモデルができた。FMR1遺伝子ノックアウトマウスの多くの行動学的所見は脆弱X症候群患者と非常に類似で、最も顕著なのは自発的な活動の増加、オープンフィールド適応能力の低下、聴覚性痙攣発作の感受性の増強を含み、軽度の学習能力欠陥もある。
本発明は、以下の式Iで表される構造を有する5-芳香族アルキニル基置換ベンズアミド系化合物、及びそのラセミ体、R-異性体、S-異性体、薬用可能な塩またはこれらの混合物を提供する。
XはCHまたはNである。
R1は水素、ハロゲン、C1-C6アルキル基、ハロゲン置換のC1-C6アルキル基、シアノ基からなる群から選ばれる。
かつR1がHである場合、
前記のハロゲンは、F、Cl、BrまたはIである。)
あるいは、R2およびR3は連結するN原子とともに置換または無置換のスピロ複素環、もしくは置換または無置換の縮合複素環からなる群から選ばれる基を構成し、ここで、前記の置換とは基における一つまたは複数の水素原子がハロゲン、C1-C6アルキル基、C1-C6アルコキシ基、ハロゲン置換のC1-C6アルコキシ基、シアノ基、ニトロ基、アミノ基、ヒドロキシ基、ヒドロキシメチル基、カルボキシ基、メルカプト基、スルホニル基、トリフルオロメチル基からなる群から選ばれる置換基で置換されることをいう。
R3は、Hである。
ここで、R9、R10、R11、R12、R13はそれぞれ環の任意の位置における1-4個の置換基を表し、かつ各置換基はそれぞれ独立にハロゲン、C1-C6アルキル基、ハロゲン置換のC1-C6アルキル基、C1-C6アルコキシ基、シアノ基、ニトロ基、アミノ基、ヒドロキシ基からなる群から選ばれる。
もう一つの好適な例において、前記のR1はH、F、Cl、CH3、CNからなる群から選ばれる。
もう一つの好適な例において、前記の
本発明は、一般式I化合物の薬用可能な塩を提供し、具体的に、一般式I化合物と無機酸または有機酸が反応して通常の薬用可能な塩を形成する。たとえば、通常の薬用可能な塩は、一般式I化合物と無機酸または有機酸が反応することによって得られ、前記無機酸は、塩酸、臭化水素酸、硫酸、硝酸、アミノスルホン酸やリン酸などを含み、そして前記有機酸は、クエン酸、酒石酸、乳酸、ピルビン酸、酢酸、ベンゼンスルホン酸、p-トルエンスルホン酸、メタンスルホン酸、ナフタレンスルホン酸、エタンスルホン酸、ナフタレンジスルホン酸、マレイン酸、リンゴ酸、マロン酸、フマル酸、コハク酸、プロパン酸、シュウ酸、トリフルオロ酢酸、ステアリン酸、パモ酸、ヒドロキシマレイン酸、フェニル酢酸、安息香酸、サリチル酸、グルタミン酸、アスコルビン酸、p-アミノベンゼンスルホン酸、2-アセチルオキシ安息香酸やヒドロキシエタンスルホン酸を含み、あるいは一般式I化合物と無機塩基が形成したナトリウム塩、カリウム塩、カルシウム塩、アルミニウム塩またはアンモニウム塩でもよく、あるいは一般式I化合物と有機塩基が形成したメチルアミン塩、エチルアミン塩またはエタノールアミン塩でもよい。
本発明のもう一つは、一般式Iで表される化合物の製造方法を提供し、当該製造方法は以下のスキーム(例示)で行われる。
工程b: 化合物2を有機溶媒に溶解させ、チオアセトアミドを入れ、完全に反応するまで撹拌し、化合物3を得る。前記有機溶媒は、テトラヒドロフラン、エチルエーテル、ジメチルホルムアミド、エチレングリコールジメチルエーテル、エチレングリコールジエチルエーテル、ジオキサン、エタノール、メタノール、酢酸エチル、ジクロロメタンまたはこれらの混合物である。
工程d: 化合物5に塩化チオニルを入れ、加熱して還流させ、中間体6を得る。加熱温度の範囲は60〜80℃である。
ほかの化合物は異なる原料を選択することによって、類似の方法で製造することができる。
本発明化合物は、優れたmGluR5陰性アロステリック調節の活性を有するため、本発明化合物およびその各種の結晶型、薬学的に許容される無機・有機塩、水和物もしくは溶媒和物、並びに本発明化合物を主要活性成分として含有する薬物組成物はmGluR5陰性アロステリック調節に関連する疾患、たとえば中枢神経系および精神系の関連疾患などの治療、予防および緩和に有用である。
活性化合物の他、懸濁液は、懸濁剤、たとえば、エトキシ化イソオクタデカノール、ポリオキシエチレンソルビトールやソルビタンエステル、微晶質セルロース、メトキシアルミニウムや寒天またはこれらの物質の混合物などを含んでもよい。
局部投与のための本発明化合物の剤形は、軟膏剤、散剤、湿布剤、噴霧剤や吸入剤を含む。活性成分は、無菌条件で生理学的に許容される担体および任意の防腐剤、緩衝剤、または必要よって駆出剤と一緒に混合される。
薬物組成物を使用する場合、安全な有効量の本発明化合物を治療の必要のある哺乳動物(たとえばヒト)に使用し、使用の際の用量は薬学上で効果があるとされる投与量で、体重60kgのヒトの場合、毎日の投与量は、通常1〜2000mg、好ましくは6〜600mgである。勿論、具体的な投与量は、さらに投与の様態、患者の健康状況などの要素を考えるべきで、すべて熟練の医者の技能範囲以内である。
1.1 2-フルオロ-5-ヨードベンゾイルクロリドの合成
50mlナスフラスコに500mgの2-フルオロ-5-ヨード安息香酸を入れ、さらに3mlの塩化チオニルを入れ、77℃で加熱して2h還流させ、薄層クロマトグラフィー(TLC)によって反応をモニタリングした。反応終了後室温に冷却し、回転乾燥で塩化チオニルを除去し、524mgの無色液体を得たが、2-フルオロ-5-ヨードベンゾイルクロリドであった。
200mgの4-フルオロアニリンを5mlの酢酸エチルに溶解させ、260μlのトリエチルアミンを入れ、氷浴の条件で2-フルオロ-5-ヨードベンゾイルクロリドの酢酸エチル溶液を滴下し、1.5時間後完全に反応させた。10mlの酢酸エチルを入れて希釈し、20mlの水を入れて抽出し、酢酸エチルで3回抽出し、飽和食塩水で1回洗浄し、無水硫酸ナトリウムで乾燥し、回転乾燥して淡黄色固体620mgを得たが、2-フルオロ-N-(4-フルオロフェニル)-5-ヨードベンズアミドであった。
625mgの2-フルオロ-N-(4-フルオロフェニル)-5-ヨードベンズアミドをトルエンに溶解させ、1.5eqの2-エチニルピリジン、2.2eqのトリエチルアミンを入れ、sらに0.2eqびヨウ化第一銅、0.2eqのビス(トリフェニルホスフィン)パラジウムジクロリドを入れ、不活性ガスの保護下において、100℃で加熱して6時間撹拌した。反応液を回転乾燥し、精製して褐色固体460mgを得たが、ZD001で、収率は79%であった。1H NMR (400 MHz, CDCl3) δ 10.61 (s, 1H), 8.62 (d, J = 4.1 Hz, 1H), 7.95 - 7.80 (m, 3H), 7.78 - 7.71 (m, 2H), 7.68 (d, J = 7.8 Hz, 2H), 7.51 - 7.41 (m, 2H), 7.22 (t, J = 8.9 Hz, 2H). LRMS (EI) m/z 335(M+).
2-フルオロ-5-ヨード安息香酸を2-クロロ-5-ヨード安息香酸に、4-フルオロアニリンを7-オキサ-2-アザスピロ[3.5]ノナンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD002を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 8.62 (m, J = 4.9, 1.8, 0.9 Hz, 1H), 7.70 (m, J = 7.7, 1.8 Hz, 1H), 7.56 - 7.55 (m, 1H), 7.54 - 7.50 (m, 2H), 7.40 (dd, J = 8.1, 0.7 Hz, 1H), 7.30 - 7.26 (m, 1H), 3.94 (s, 4H), 3.65 - 3.49 (m, 4H), 1.89 - 1.70 (m, 4H). LRMS (EI) m/z367(M+).
2-フルオロ-5-ヨード安息香酸を2-クロロ-5-ヨード安息香酸に、4-フルオロアニリンを8-オキサ-2-アザスピロ[4.5]デカンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD003を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 4.1 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.57 - 7.49 (m, 3H), 7.43 - 7.38 (m, 1H), 7.28 (d, J = 7.5 Hz, 1H), 3.83 - 3.65 (m, 4H), 3.44 (dd, J = 104.9, 12.7 Hz, 2H), 1.87 (dt, J = 27.5, 7.2 Hz, 3H), 1.64 (t, J = 5.3 Hz, 2H), 1.60 - 1.48 (m, 3H).LRMS (EI) m/z 381(M+).
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD004を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 8.34 (dd, J = 7.5, 2.1 Hz, 1H), 7.68 (dd, J = 5.4, 3.1 Hz, 1H), 7.65 - 7.58 (m, 2H), 7.41 (s, 1H), 7.18 (dd, J = 11.7, 8.6 Hz, 1H), 7.08 (t, J = 8.6 Hz, 2H), 2.75 (s, 3H).LRMS (EI) m/z 355(M+)。
2-フルオロ-5-ヨード安息香酸を2-クロロ-5-ヨード安息香酸に変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD036を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.99 (s, 2H), 7.80 (s, 1H), 7.63 (d, J = 8.3 Hz, 4H), 7.45 (d, J = 8.1 Hz, 1H), 7.37 (s, 1H), 7.08 (t, J = 8.3 Hz, 2H).LRMS (EI) m/z 351(M+)
2-フルオロ-5-ヨード安息香酸を2-クロロ-5-ヨード安息香酸に、2-エチニルピリジンを4-エチニル-2-メチルチアゾールに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD037を得たが、収率は80%であった。1H NMR (400 MHz, DMSO) δ 10.63 (s, 1H), 7.96 (s, 1H), 7.79 (d, J = 1.7 Hz, 1H), 7.76 - 7.70 (m, 2H), 7.67 (dt, J = 15.5, 5.2 Hz, 2H), 7.21 (t, J = 8.9 Hz, 2H), 2.68 (s, 3H).LRMS (EI) m/z 371(M+)
2-エチニルピリジンを3-エチニルピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD038を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 9.28 - 8.51 (s, 1H), 8.47 - 8.30 (m, 2H), 7.85 (d, J = 7.8 Hz, 1H), 7.73 - 7.55 (m, 3H), 7.53 - 7.32 (m, 1H), 7.21 (dd, J = 11.7, 8.6 Hz, 1H), 7.08 (t, J = 8.6 Hz, 2H).LRMS (EI) m/z 335(M+)
2-エチニルピリジンを4-エチニルピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD039を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 8.44 - 8.34 (m,3H), 7.93 - 7.79 (m, 1H), 7.70 (s, 1H), 7.63 (dd, J = 8.6, 4.6 Hz, 3H), 7.24 - 7.18 (m, 1H), 7.09 (t, J = 8.5 Hz,3H).LRMS (EI) m/z 335(M+)
2-フルオロ-5-ヨード安息香酸を2-メチル-5-ヨード安息香酸に変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD040を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 4.3 Hz, 1H), 8.23 (s, 1H), 7.73 - 7.57 (m, 4H), 7.49 (td, J = 6.7, 3.2 Hz, 2H), 7.25 - 7.20 (m, 2H), 7.02 (t, J = 8.6 Hz, 2H), 2.47 (s, 3H).LRMS (EI) m/z 331(M+)
2-フルオロ-5-ヨード安息香酸を2-メチル-5-ヨード安息香酸に、2-エチニルピリジンを4-エチニル-2-メチルチアゾールに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD041を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.66 (s, 1H), 7.60 (dd, J = 8.5, 4.7 Hz, 2H), 7.49 (s, 1H), 7.36 (s, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.05 (t, J = 8.5 Hz, 2H), 2.74 (s,3H), 2.50 (s, 3H).LRMS (EI) m/z 351(M+)
4-フルオロアニリンを3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD042を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 8.72 (d, J = 13.1 Hz, 2H), 8.65 - 8.59 (m, 1H), 8.41 (d, J = 3.5 Hz, 1H), 8.31 (dd, J = 7.4, 2.2 Hz, 2H), 7.74 - 7.68 (m, 2H), 7.53 (dt, J = 7.8, 1.0 Hz, 1H), 7.35 (dd, J = 8.3, 4.7 Hz, 1H), 7.30 - 7.26 (m, 1H), 7.19 (dd, J = 11.5, 8.6 Hz, 1H).LRMS (EI) m/z 318(M+)
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、4-フルオロアニリンを3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD043を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.67 (d, J = 13.8 Hz, 1H), 8.41 (s, 1H), 8.33 (d, J = 8.1 Hz, 1H), 8.27 (dd, J = 7.4, 2.2 Hz, 1H), 7.67 (ddd, J = 8.4, 4.9, 2.3 Hz, 1H), 7.40 (s, 1H), 7.36 (s, 1H), 7.17 (dd, J = 11.6, 8.6 Hz, 1H), 2.73 (s, 3H).LRMS (EI) m/z 338(M+)
4-フルオロアニリンを4-シアノアニリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD044を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 14.4 Hz, 1H), 8.35 (d, J = 7.2 Hz, 1H), 7.82 (d, J = 8.7 Hz, 2H), 7.75 (s, 2H), 7.67 (d, J = 8.6 Hz, 2H), 7.62 - 7.50 (m, 1H), 7.39 - 7.27 (m, 1H), 7.21 (dd, J = 11.6, 8.5 Hz, 1H).LRMS (EI) m/z 342(M+)
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、4-フルオロアニリンを4-シアノアニリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD045を得たが、収率は80%であった。1H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.91 - 7.88 (m, 2H), 7.85 (s, 1H), 7.83 (s, 1H), 7.82 - 7.77 (m, 1H), 7.47 (s, 1H), 2.68 (s, 3H).LRMS (EI) m/z 362(M+)
4-フルオロアニリンを3,4-ジヒドロイソキノリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD046を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.73 - 7.61 (m, 3H), 7.54 - 7.49 (m, 1H), 7.30 - 7.26 (m, 1H), 7.25 - 7.17 (m, 3H), 7.14 (dd, J = 11.5, 6.5 Hz, 2H), 4.72 (d, J = 170.6 Hz, 2H), 3.58 (t, J = 5.8 Hz, 2H), 2.93 (dt, J = 42.1, 5.6 Hz, 2H).LRMS (EI) m/z 357(M+)
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、4-フルオロアニリンを3,4-ジヒドロイソキノリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD047を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 7.62 - 7.56 (m, 2H), 7.36 (d, J = 7.0 Hz, 1H), 7.25 - 7.16 (m, 3H), 7.12 (t, J = 9.0 Hz, 2H), 4.71 (d, J = 171.9 Hz, 2H), 3.57 (t, J = 5.8 Hz, 2H), 2.92 (d, J = 43.6 Hz, 2H), 2.73 (d, J = 3.6 Hz, 3H).LRMS (EI) m/z 377(M+)
4-フルオロアニリンを1-メチル-3,4-ジヒドロイソキノリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD048を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 4.7 Hz, 1H), 7.74 - 7.59 (m, 3H), 7.51 (d, J = 7.8 Hz, 1H), 7.25 - 7.23 (m, 1H), 7.23 - 7.09 (m,5H), 5.81 (d, J = 6.7 Hz, 1H), 3.72 - 3.42 (m, 2H), 2.73 (d, J = 16.0 Hz, 2H), 1.60 (d, J = 6.8 Hz, 3H).LRMS (EI) m/z 371(M+)
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、4-フルオロアニリンを1-メチル-3,4-ジヒドロイソキノリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD049を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 7.62 - 7.55 (m, 2H), 7.37 (s, 1H), 7.18 (ddd, J = 11.5, 9.2, 5.7 Hz, 3H), 7.11 (dd, J = 11.8, 5.7 Hz, 2H), 5.80 (d, J = 6.7 Hz, 1H), 3.54 (dd, J = 50.6, 6.1 Hz, 2H), 3.34 - 2.81 (m, 2H), 2.73 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H).LRMS (EI) m/z 391(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、4-フルオロアニリンを3-アミノピリジンに、2-フルオロ-5-ヨード安息香酸を2-フルオロ-5-ヨードピリジンカルボン酸に変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD050を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.699 (s,1H), 2.501 (s,3H), 8.869 (1H,d), 8.894 (d, 1H), 8.402 (ddd, 1H), 7.476 (ddd,1H), 7.316 (ddd, 1H,), 8.404 (ddd, 1H). LRMS (EI) m/z 339(M+)。
2-フルオロ-5-ヨード安息香酸を2-フルオロ-5-ヨードピリジンカルボン酸安息香酸に変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD051を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ8.719 (1H, d), 8.813 (1H, d), 7.743 (1H, ddd), 7.743 (1H, ddd), 7.017 (1H, ddd), 7.017 (1H, ddd), 7.492 (1H, ddd), 8.729 (1H, ddd), 7.848 (1H, ddd), 7.221 (1H, ddd). LRMS (EI) m/z 336(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、4-フルオロアニリンを3,4-ジヒドロイソキノリンに、2-フルオロ-5-ヨード安息香酸を2-フルオロ-5-ヨードピリジンカルボン酸に変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD052を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.264 (1H), 2.455 (s,3H), 8.688 (1H, d), 8.758 (1H, d), 4.354 (1H, d), 4.467 (1H, d), 3.658 (1H, ddd), 3.359 (1H, ddd), 2.926 (1H, ddd), 3.020 (1H, ddd), 6.866 (1H, ddd), 7.240 (1H, ddd), 7.041 (1H, ddd), 7.168 (1H, ddd). LRMS (EI) m/z 378(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、2-フルオロ-5-ヨード安息香酸を2-フルオロ-5-ヨードピリジンカルボン酸に変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD053を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.265 (s, 1H), 2.454 (s,3H), 8.690 (1H, d), 8.766 (1H, d), 7.743 (1H, ddd), 7.743 (1H, ddd), 7.017 (1H, ddd), 7.017 (1H, ddd). LRMS (EI) m/z 356(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、2-フルオロ-5-ヨード安息香酸を2-クロロ-5-ヨードピリジンカルボン酸に変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD054を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ8.690 (1H, d), 8.703 (1H, d), 7.744 (1H, ddd), 7.744 (1H, ddd), 7.018 (1H, ddd), 7.018 (1H, ddd), 7.284 (s, 1H), 2.408 (s, 3H). LRMS (EI) m/z 373(M+)。
2-フルオロ-5-ヨード安息香酸を2-フルオロ-5-ヨードピリジンカルボン酸安息香酸に、4-フルオロアニリンを3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD055を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ8.719 (1H, d), 8.813 (1H, d), 8.402 (1H, ddd), 7.476 (1H, ddd), 7.315 (1H, ddd), 7.492 (1H, ddd), 8.404 (1H, ddd), 8.729 (1H, ddd), 7.848 (1H, ddd), 7.221 (1H, ddd). LRMS (EI) m/z 319(M+)。
2-フルオロ-5-ヨード安息香酸を2-フルオロ-5-ヨードピリジンカルボン酸安息香酸に、4-フルオロアニリンを3,4-ジヒドロイソキノリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD056を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ8.718 (1H, d), 8.807 (1H, d), 4.356 (1H, d), 4.468 (1H, d), 3.659 (1H, ddd), 3.359 (1H, ddd), 2.926 (1H, ddd), 3.020 (1H, ddd), 6.866 (1H, ddd), 7.492 (1H, ddd), 7.240 (1H, ddd), 7.041 (1H, ddd), 8.729 (1H, ddd), 7.848 (1H, ddd), 7.168 (1H, ddd), 7.221 (1H, ddd). LRMS (EI) m/z 358(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、4-フルオロアニリンをアニリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD057を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.264 (s, 1H), 2.406 (s, 3H), 8.503 (1H, dd), 7.857 (1H, dd), 7.401 (1H, dd), 7.481 (1H, dddd), 7.481 (1H, dddd), 7.272 (1H, dddd), 7.272 (1H, dddd), 7.069 (1H, tt). LRMS (EI) m/z 337(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、2-フルオロ-5-ヨード安息香酸を2-シアノ-5-ヨードピリジンカルボン酸に、4-フルオロアニリンを3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD058を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.411 (s, 1H), 2.554 (s, 3H), 8.561 (1H, dd), 7.793 (1H, dd), 8.051 (1H, dd), 8.404 (1H, ddd), 7.455 (1H, ddd), 7.317 (1H, ddd), 8.405 (1H, ddd). LRMS (EI) m/z 345(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、2-フルオロ-5-ヨード安息香酸を2-トリフルオロメチル-5-ヨードピリジンカルボン酸に、4-フルオロアニリンを3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD059を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.461 (s, 1H), 2.478 (s, 3H), 8.585 (1H, dd), 7.899 (1H, dd), 7.781 (1H, dd), 8.404 (1H, ddd), 7.455 (1H, ddd), 7.317 (1H, ddd,), 8.405 (1H, ddd). LRMS (EI) m/z 388(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、2-フルオロ-5-ヨード安息香酸を2-トリフルオロメチル-5-ヨードピリジンカルボン酸に変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD060を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.461 (s, 1H), 2.478 (s, 3H), 8.585 (1H, dd), 7.899 (1H, dd), 7.781 (1H, dd), 7.745 (1H, ddd), 7.746 (1H, ddd), 7.018 (1H, ddd), 7.018 (1H, ddd). LRMS (EI) m/z 405(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、2-フルオロ-5-ヨード安息香酸を2-シアノ-5-ヨードピリジンカルボン酸に変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD061を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.379 (s, 1H), 8.556 (1H, dd), 7.794 (1H, dd), 8.044 (1H, dd), 7.745 (1H, ddd), 7.745 (1H, ddd), 7.018 (1H, ddd), 7.018 (1H, ddd). LRMS (EI) m/z 362(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、2-フルオロ-5-ヨード安息香酸を2-シアノ-5-ヨードピリジンカルボン酸に、4-フルオロアニリンを3,4-ジヒドロイソキノリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD062を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.410 (s, 1H), 2.554 (s, 3H), 8.544 (1H, dd), 7.790 (1H, dd), 8.046 (1H, dd), 4.330 (1H, d), 4.474 (1H, d), 3.665 (1H, ddd), 3.375 (1H, ddd), 2.928 (1H, ddd), 3.023 (1H, ddd), 6.867 (1H, ddd), 7.240 (1H, ddd), 7.042 (1H, ddd), 7.168 (1H, ddd). LRMS (EI) m/z 384(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、2-フルオロ-5-ヨード安息香酸を2-トリフルオロメチル-5-ヨードピリジンカルボン酸に、4-フルオロアニリンを3,4-ジヒドロイソキノリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD063を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.459 (s, 1H), 2.477 (s, 3H), 8.567 (1H, dd), 7.896 (1H, dd), 7.779 (1H, dd), 4.325 (1H, d), 4.467 (1H, d), 3.663 (1H, ddd), 3.374 (1H, ddd), 2.928 (1H, ddd), 3.023 (1H, ddd), 6.867 (1H, ddd), 7.240 (1H, ddd), 7.042 (1H, ddd), 7.168 (1H, ddd). LRMS (EI) m/z 427(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、4-フルオロアニリンを2-フルオロアニリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD064を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.264 (s, 1H), 2.406 (s, 3H), 8.504 (1H, dd), 7.858 (1H, dd), 7.401 (1H, dd), 8.107 (1H, ddd), 7.025 (1H, ddd), 7.235 (1H, ddd), 7.035 (1H, ddd). LRMS (EI) m/z 355(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、4-フルオロアニリンを3-フルオロアニリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD065を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.264 (s, 1H), 2.406 (s, 3H), 8.503 (1H, dd), 7.858 (1H, dd), 7.401 (1H, dd), 7.722 (1H, ddd), 7.533 (1H, ddd), 7.335 (1H, ddd), 7.013 (1H, ddd). LRMS (EI) m/z 355(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、4-フルオロアニリンを3,4-ジフルオロアニリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD066を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.264 (s, 1H), 2.406 (s, 3H), 8.504 (1H, dd), 7.858 (1H, dd), 7.401 (1H, dd), 7.725 (1H, dd), 7.278 (1H, dd), 7.299 (1H, dd). LRMS (EI) m/z 373(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、4-フルオロアニリンを2,4-ジフルオロアニリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD067を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.566 (s, 1H), 2.523 (s, 3H), 7.887 (1H, dd), 7.988 (1H, dd), 7.516 (1H, dd), 7.538 (1H, dd), 7.397 (1H, dd), 6.877 (1H, dd). LRMS (EI) m/z 373(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、4-フルオロアニリンを4-クロロアニリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD068を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.417 (1H, ddd), 7.417 (1H, ddd), 7.750 (1H, ddd), 7.750 (1H, ddd), 8.503 (1H, dd), 7.392 (1H, dd), 7.903 (1H, dd), 7.264 (s, 1H), 2.406 (s, 3H). LRMS (EI) m/z 372(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、4-フルオロアニリンを4-トリフルオロメチルアニリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD069を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.264 (s, 1H), 2.406 (s, 3H), 8.503 (1H, dd), 7.858 (1H, dd), 7.401 (1H, dd), 7.251 (1H, ddd), 7.251 (1H, ddd), 7.573 (1H, ddd), 7.573 (1H, ddd). LRMS (EI) m/z 405(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、4-フルオロアニリンを4-メトキシアニリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD070を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.264 (s, 1H), 2.406 (s, 3H), 8.503 (1H, dd), 7.858 (1H, dd), 7.401 (1H, dd), 7.277 (1H, ddd), 7.277 (1H, ddd), 6.636 (1H, ddd), 6.636 (1H, ddd), 3.760 (s, 3H). LRMS (EI) m/z 367(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、4-フルオロアニリンを2-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD071を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.265 (s, 1H), 2.406 (s, 3H), 8.507 (1H, dd), 7.859 (1H, dd), 7.402 (1H, dd), 7.661 (1H, ddd), 8.404 (1H, ddd), 7.755 (1H, ddd), 7.106 (1H, ddd). LRMS (EI) m/z 338(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、4-フルオロアニリンを4-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD072を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.264 (s, 1H), 2.406 (s, 3H), 8.505 (1H, dd), 7.858 (1H, dd), 7.401 (1H, dd), 7.971 (1H, ddd), 7.971 (1H, ddd), 8.501 (1H, ddd), 8.500 (1H, ddd). LRMS (EI) m/z 338(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、4-フルオロアニリンを6-フルオロ-3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD073を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.264 (s, 1H), 2.406 (s, 3H), 8.504 (1H, dd), 7.858 (1H, dd), 7.400 (1H, dd), 7.805 (1H, dd), 7.410 (1H, dd), 7.284 (1H, dd). LRMS (EI) m/z 356(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、4-フルオロアニリンを6-クロロ-3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD074を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.303 (1H, dd), 7.929 (1H, dd), 7.423 (1H, dd), 8.504 (1H, dd), 7.391 (1H, dd), 7.902 (1H, dd), 7.264 (s, 1H), 2.406 (s, 3H). LRMS (EI) m/z 373(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、4-フルオロアニリンを6-メチル-3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD075を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.264 (s, 1H), 2.406 (s, 3H), 8.503 (1H, dd), 7.857 (1H, dd), 7.401 (1H, dd), 7.186 (1H, ddd), 7.187 (1H, ddd), 7.079 (1H, ddd), 7.079 (1H, ddd), 2.210 (s, 3H). LRMS (EI) m/z 351(M+)。
2-エチニルピリジンを4-エチニルチアゾールに、4-フルオロアニリンを3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD076を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ8.388 (1H, d), 7.214 (1H, d), 8.514 (1H, dd), 7.858 (1H, dd), 7.411 (1H, dd), 8.402 (1H, ddd), 7.474 (1H, ddd), 7.315 (1H, ddd), 8.404 (1H, ddd). LRMS (EI) m/z 324(M+)。
2-エチニルピリジンを4-エチニル-2-フルオロチアゾールに、4-フルオロアニリンを3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD077を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.139 (s, 1H), 8.503 (1H, dd), 7.858 (1H, dd), 7.401 (1H, dd), 8.402 (1H, ddd), 7.474 (1H, ddd), 7.315 (1H, ddd), 8.404 (1H, ddd). LRMS (EI) m/z 342(M+)。
2-エチニルピリジンを4-エチニル-2-クロロチアゾールに、4-フルオロアニリンを3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD078を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.174 (s, 1H), 8.505 (1H, dd), 7.858 (1H, dd), 7.403 (1H, dd), 8.402 (1H, ddd), 7.474 (1H, ddd), 7.315 (1H, ddd), 8.404 (1H, ddd). LRMS (EI) m/z 359(M+)。
2-エチニルピリジンを4-エチニル-2-トリフルオロメチルチアゾールに、4-フルオロアニリンを3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD079を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.236 (s, 1H), 8.515 (1H, dd), 7.858 (1H, dd), 7.412 (1H, dd), 8.402 (1H, ddd), 7.474 (1H, ddd), 7.315 (1H, ddd), 8.404 (1H, ddd). LRMS (EI) m/z 392(M+)。
2-エチニルピリジンを2-エチニル-6-メチルピリジンに、4-フルオロアニリンを3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD080を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.567 (1H, dd), 8.587 (1H, dd), 7.954 (1H, dd), 8.402 (1H, ddd), 7.474 (1H, ddd), 7.315 (1H, ddd), 8.404 (1H, ddd), 7.294 (1H, dd), 7.653 (1H, dd), 7.008 (1H, dd), 2.565 (s, 3H). LRMS (EI) m/z 332(M+)。
2-エチニルピリジンを2-エチニル-6-フルオロピリジンに、4-フルオロアニリンを3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD081を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.660 (1H, dd), 7.723 (1H, dd), 7.396 (1H, dd), 8.605 (1H, dd), 7.784 (1H, dd), 7.571 ( 1H, dd), 8.402 (1H, ddd), 7.474 (1H, ddd), 7.315 (1H, ddd), 8.404 (1H, ddd). LRMS (EI) m/z 336(M+)。
2-エチニルピリジンを2-エチニル-6-クロロピリジンに、4-フルオロアニリンを3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD082を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.455 (1H, dd), 7.718 (1H, dd), 7.426 (1H, dd), 8.604 (1H, dd), 7.780 (1H, dd), 7.572 (1H, dd), 8.402 (1H, ddd), 7.474 (1H, ddd), 7.315 (1H, ddd), 8.404 (1H, ddd). LRMS (EI) m/z 353(M+)。
2-エチニルピリジンを2-エチニル-6-トリフルオロメチルピリジンに、4-フルオロアニリンを3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD083を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.572 (1H, dd), 8.615 (1H, dd), 7.961 (1H, dd), 8.402 (1H, ddd), 7.474 (1H, ddd), 7.315 (1H, ddd), 8.404 (1H, ddd), 7.331 (1H, dd), 7.916 (1H, dd), 7.346 (1H, dd). LRMS (EI) m/z 386(M+)。
2-エチニルピリジンを2-エチニル-6-シアノピリジンに、4-フルオロアニリンを3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD084を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.575 (1H, dd), 8.647 (1H, dd), 7.783 (1H, dd), 8.402 (1H, ddd), 7.474 (1H, ddd,), 7.315 (1H, ddd), 8.404 (1H, ddd), 7.507 (1H, dd), 7.892 (1H, dd), 7.780 (1H, dd). LRMS (EI) m/z 343(M+)。
2-エチニルピリジンを5-エチニルピリミジンに、4-フルオロアニリンを3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD085を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.645 (1H, dd), 8.552 (1H, dd), 7.859 (1H, dd), 8.402 (1H, ddd), 7.474 (1H, ddd), 7.315 (1H, ddd), 8.404 (1H, ddd), 9.058 ( 1H, dd), 8.767 (1H, dd), 8.849 (1H, dd). LRMS (EI) m/z 319(M+)。
2-エチニルピリジンを2-メチル-5-エチニルピリミジンに、4-フルオロアニリンを3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD086を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.640 (1H, dd), 8.552 (1H, dd), 7.859 (1H, dd), 8.402 (1H, ddd), 7.474 (1H, ddd), 7.315 (1H, ddd), 8.404 (1H, ddd), 8.751 (1H, d), 8.726 (1H, d), 2.603 (s, 3H). LRMS (EI) m/z 333(M+)。
2-エチニルピリジンを2-メチル-5-エチニルピリミジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD087を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.640 (1H, dd), 8.552 (1H, dd), 7.859 (1H, dd), 7.741 (1H, ddd), 7.741 (1H, ddd), 7.017 (1H, ddd), 7.018 (1H, ddd), 8.751 (1H, d), 8.726 (1H, d), 2.603 (s, 3H). LRMS (EI) m/z 350(M+)。
2-エチニルピリジンを2-メチル-5-エチニルピリミジンに、4-フルオロアニリンを3,4-ジヒドロイソキノリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD088を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.614 (1H, dd), 8.513 (1H, dd), 7.856 (1H, dd), 4.270 (1H, d), 4.461 (1H, d), 3.652 (1H, ddd), 3.376 (1H, ddd), 2.927 (1H, ddd), 3.020 (1H, ddd), 6.867 (1H, ddd), 7.240 (1H, ddd), 7.042 (1H, ddd), 8.751 (1H, d), 8.727 (1H, d), 7.168 (1H, ddd), 2.603 (s, 3H). LRMS (EI) m/z 372(M+)。
2-エチニルピリジンを2-メチル-4-エチニルオキサゾールに、4-フルオロアニリンを3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD089を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.392 (1H, dd), 8.492 (1H, dd), 7.892 (1H, dd), 8.402 (1H, ddd), 7.474 (1H, ddd), 7.315 (1H, ddd), 8.404 (1H, ddd), 7.383 (s, 1H), 2.547 (s, 3H). LRMS (EI) m/z 322(M+)。
2-エチニルピリジンを2-メチル-4-エチニルオキサゾールに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD090を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.393 (1H, dd), 8.492 (1H, dd), 7.892 (1H, dd), 7.741 (1H, ddd), 7.741 (1H, ddd), 7.017 (1H, ddd), 7.018 (1H, ddd), 7.383 (s, 1H), 2.547 (s, 3H). LRMS (EI) m/z 339(M+)。
2-エチニルピリジンを2-メチル-4-エチニルオキサゾールに、4-フルオロアニリンを3,4-ジヒドロイソキノリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD091を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.390 (1H, dd), 8.481 (1H, dd), 7.847 (1H, dd), 4.269 (1H, d), 4.460 (1H, d), 3.651 (1H, ddd), 3.353 (1H, ddd,), 2.927 (1H, ddd), 3.034 ( 1H, ddd), 6.867 (1H, ddd), 7.240 (1H, ddd), 7.042 ( 1H, ddd), 7.382 (1H), 7.168 (1H, ddd), 2.547 (s,3H). LRMS (EI) m/z 361(M+)。
2-エチニルピリジンを3,5-ジメチル-4-エチニルイソオキサゾールに、4-フルオロアニリンを3,4-ジヒドロイソキノリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD092を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.380 (1H, dd), 8.483 ( 1H, dd), 7.895 (1H, dd), 4.269 (1H, d), 4.460 (1H, d), 3.652 (1H, ddd), 3.375 (1H, ddd), 2.927 (1H, ddd), 3.020 (1H, ddd), 6.867 (1H, ddd), 7.240 (1H, ddd), 7.042 (1H, ddd), 7.168 (1H, ddd), 2.546 (s,3H), 2.234 (s,3H). LRMS (EI) m/z 375(M+)。
2-エチニルピリジンを3,5-ジメチル-4-エチニルイソオキサゾールに、4-フルオロアニリンを3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD093を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.382 (1H, dd), 8.495 (1H, dd), 7.899 (1H, dd), 8.402 (1H, ddd), 7.474 (1H, ddd), 7.315 (1H, ddd), 8.404 (1H, ddd), 2.546 (s,3H), 2.234 (s,3H). LRMS (EI) m/z 336(M+)。
2-エチニルピリジンを3,5-ジメチル-4-エチニルイソオキサゾールに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD094を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ7.383 (1H, dd), 8.494 (1H, dd), 7.899 (1H, dd, J=8.455), 7.741 (1H, ddd), 7.741 (1H, ddd), 7.017 (1H, ddd), 7.018 (1H, ddd), 2.546 (s,3H), 2.234 (s,3H). LRMS (EI) m/z 353(M+)。
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、2-フルオロ-5-ヨード安息香酸を3-ヨード安息香酸に変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD009を得たが、収率は80%であった。1H NMR (400 MHz, DMSO) δ 10.41 (s, 1H), 8.16 (s, 1H), 8.02 - 7.95 (m, 2H), 7.79 (m, J = 10.9, 8.1, 6.4 Hz, 3H), 7.61 (t, J = 7.8 Hz, 1H), 7.20 (dd, J = 12.3, 5.5 Hz, 2H), 2.69 (s, 3H). LRMS (EI) m/z 336(M+)
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、2-フルオロ-5-ヨード安息香酸を3-ヨード安息香酸に、4-フルオロアニリンを3,4-ジヒドロイソキノリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD012を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 7.61 (m J = 4.0, 1.6 Hz, 2H), 7.42 (d, J = 6.8 Hz, 2H), 7.38 (d, J = 3.2 Hz, 1H), 7.24 - 7.12 (m, 4H), 4.74 (d, J = 123.5 Hz, 2H), 3.81 (d, J = 140.1 Hz, 2H), 2.93 (d, J = 36.6 Hz, 2H), 2.74 (s, 3H). LRMS (EI) m/z 358(M+)
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、2-フルオロ-5-ヨード安息香酸を3-ヨード安息香酸に、4-フルオロアニリンを3-アミノピリジンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD013を得たが、収率は80%であった。1H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 8.94 (s, 1H), 8.33 (d, J = 4.0 Hz, 1H), 8.21 (d, J = 11.1 Hz, 2H), 8.02 (d, J = 7.8 Hz, 1H), 7.97 (s, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.41 (dd, J = 8.2, 4.7 Hz, 1H), 2.69 (s, 3H). LRMS (EI) m/z 319(M+)
2-エチニルピリジンを4-エチニル-2-メチルチアゾールに、2-フルオロ-5-ヨード安息香酸を3-ヨード安息香酸に、4-フルオロアニリンをアニリンに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD014を得たが、収率は80%であった。1H NMR (400 MHz, DMSO) δ 10.36 (s, 1H), 8.17 (s, 1H), 7.99 (dd, J = 5.3, 4.2 Hz, 1H), 7.97 (s, 1H), 7.78 (dd, J = 12.4, 4.4 Hz, 3H), 7.61 (t, J = 7.8 Hz, 1H), 7.36 (t, J = 7.9 Hz, 2H), 7.12 (t, J = 7.4 Hz, 1H), 2.72 - 2.65 (m, 3H). LRMS (EI) m/z 318(M+)
2-フルオロ-5-ヨード安息香酸を3-ヨード安息香酸に、4-フルオロアニリンを3-トリフルオロメチル-5,6,7,8-テトラヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジンに、2-エチニルピリジンを4-エチニル-2-メチルチアゾールに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD005を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.65 (s, 1H), 7.47 (d, J = 5.6 Hz,2H), 7.41 (s, 1H), 5.06 (s, 2H), 4.26 (s, 2H), 4.12 (s,2H), 2.74 (s, 3H).LRMS (EI) m/z 418(M+)。
2-エチニルピリジンを5-エチニル1H-インダゾールに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD006を得たが、収率は80%であった。1H NMR (400 MHz, DMSO) δ 13.31 (s, 1H), 10.58 (s, 1H), 8.14 (s, 1H), 8.04 (s, 1H), 7.86 (dd, J = 6.7, 2.2 Hz, 1H), 7.79 - 7.72 (m, 3H), 7.60 (d, J = 8.6 Hz, 1H), 7.53 - 7.48 (m, 1H), 7.47 - 7.40 (m, 1H), 7.21 (dd, J = 12.2, 5.6 Hz, 2H).LRMS (EI) m/z 374(M+)。
2-フルオロ-5-ヨード安息香酸を3-ヨード安息香酸に、4-フルオロアニリンを7-オキサ-2-アザスピロ[3.5]ノナンに、2-エチニルピリジンを4-エチニル-2-メチルチアゾールに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD007を得たが、収率は80%であった。1H NMR (400 MHz, DMSO) δ 7.95 (s, 1H), 7.77 (s, 2H), 7.52 (t, J = 7.7 Hz, 2H), 4.08 (s, 4H), 3.79 (t, 4H), 2.68 (s, 3H), 1.71 (s, 4H).LRMS (EI) m/z 353(M+)
2-フルオロ-5-ヨード安息香酸を3-ヨード安息香酸に、4-フルオロアニリンを8-オキサ-2-アザスピロ[4.5]デカンに、2-エチニルピリジンを4-エチニル-2-メチルチアゾールに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD008を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.51 - 7.46 (m, 1H), 7.39 (m, J = 7.2, 4.2 Hz, 2H), 3.80 - 3.61 (m, 4H), 3.60 - 3.45 (m, 4H), 2.73 (s, 3H), 1.69 - 1.43 (m, 6H). LRMS (EI) m/z 367(M+)
2-フルオロ-5-ヨード安息香酸を3-ヨード安息香酸に、4-フルオロアニリンを4-シアノアニリンに、2-エチニルピリジンを4-エチニル-2-メチルチアゾールに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD010を得たが、収率は80%であった。1H NMR (400 MHz, DMSO) δ 10.74 (s, 1H), 8.17 (s, 1H), 7.99 (t, J = 9.4 Hz,4H), 7.82 (dd, J = 15.8, 8.2 Hz, 3H), 7.61 (dd, J = 20.0, 12.4 Hz, 1H), 2.69 (s, 3H).LRMS (EI) m/z 344(M+)
2-フルオロ-5-ヨード安息香酸を3-ヨード安息香酸に、4-フルオロアニリンを1-メチル-3,4-ジヒドロイソキノリンに、2-エチニルピリジンを4-エチニル-2-メチルチアゾールに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD011を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 7.64 - 7.53 (m, 2H), 7.39 (d, J = 7.5 Hz, 3H), 7.24 - 7.06 (m, 4H), 5.77 (d, J = 6.0 Hz, 1H), 4.81 (s, 1H), 3.75 (s, 1H), 3.53 - 2.90 (m, 2H), 2.74 (s, 3H), 1.70 - 1.53 (m, 3H).LRMS (EI) m/z373 (M+)
2-フルオロ-5-ヨード安息香酸を3-ヨード安息香酸に、4-フルオロアニリンを4-トリフルオロメチルアニリンに、2-エチニルピリジンを4-エチニル-2-メチルチアゾールに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD015を得たが、収率は80%であった。1H NMR (400 MHz, DMSO) δ 10.68 (s, 1H), 8.18 (s, 1H), 8.02 (t, J = 6.3 Hz, 3H), 7.97 (s, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.63 (t, J = 7.8 Hz, 1H), 2.69 (s, 3H).LRMS (EI) m/z387 (M+)
2-フルオロ-5-ヨード安息香酸を3-ヨード安息香酸に、4-フルオロアニリンを3-フルオロアニリンに、2-エチニルピリジンを4-エチニル-2-メチルチアゾールに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD017を得たが、収率は80%であった。1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.87 (dd, J = 7.9, 1.3 Hz, 1H), 7.72 - 7.65 (m, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.41 (s, 1H), 7.32 - 7.30 (m, 1H), 6.85 (m, J = 9.5 Hz, 2H), 6.69 (s, 1H), 2.76 (s, 3H). LRMS (EI) m/z 337(M+)
2-フルオロ-5-ヨード安息香酸を3-ヨード安息香酸に、4-フルオロアニリンを3-シアノアニリンに、2-エチニルピリジンを4-エチニル-2-メチルチアゾールに変更し、ほかの必要な原料、試薬および製造方法は実施例1と同様で、産物ZD019を得たが、収率は80%であった。1H NMR (400 MHz, DMSO) δ 10.66 (s, 1H), 8.26 (d, J = 1.1 Hz, 1H), 8.18 (d, J = 1.5 Hz, 1H), 8.06 (m, J = 6.0, 3.6, 2.2 Hz, 1H), 8.03 - 7.99 (m, 1H), 7.97 (s, 1H), 7.82 - 7.77 (m, 1H), 7.66 - 7.57 (m, 3H), 2.69 (s, 3H).LRMS (EI) m/z 344(M+)
実施例1. 化合物の物理化学的属性のパラメーター
結果から、このような化合物の物理化学的属性(LogP、CLogPやtPSAなど)は陽性薬物に相当し、優れた薬らしさも有することが示された。
実験材料:HEK293/mGluR5細胞系、Fluo-8カルシウムイオン蛍光色素、陽性コントロールのMPEP、CTEP
実験装置:FLIPR Tetraリアルタイム蛍光イメージング分析システム
実験方法:HDB Fluo-8カルシウム蛍光検出法
実験原理:HDB Fluo-8カルシウムイオン蛍光検出法は快速で簡便で信頼性のある、細胞内のカルシウムイオン濃度の変化を検出する蛍光検出方法である。Fluo 8-AM蛍光色素はFluo 8のアセチルメチルエステル誘導体で、培養によって、簡単に細胞膜を通過し、細胞中に入ることができる。当該蛍光色素が細胞に入った後細胞内のエステラーゼによって加水分解され、生成するFluo 8は極性分子であるため、脂質二分子膜を透過しにくく、細胞内に残され、その後カルシウムイオン(Ca2+)と結合して蛍光を放出する。
実験材料:HEK293/mGluR5細胞系、HEK293/mGluR1細胞系、Fluo-8カルシウムイオン蛍光色素、陽性コントロールのJNJ16259685
前期のmGluR5のIC50が比較的に良い化合物を選んで選択性テストを行い、結果を表3に示す。
実験原理: 脆弱X症候群は人体内のX染色体の形成過程における突然変異によるよく見られる遺伝病で、自閉症や精神遅滞の最も見られる遺伝病因でもあり、臨床の主な所見は中、重度の精神遅滞、たとえば学習能力欠失、認知障害や癲癇の高感受性などが挙げられる。その病原性遺伝子がFmr1遺伝子であると確認されたが、臨床においてまだ有効な干与・治療手段がない。
本研究はFmr1遺伝子ノックアウトマウスの聴原性癲癇誘導動物モデルを利用し、癲癇の発作潜伏期、発作レベルおよび癲癇死亡率を評価指標とし、化合物ZD043に対して薬物効果の評価を行った。
種属、品種:Fmr1遺伝子ノックアウトマウス、FVB.129P2-Pde6b+ Tyrc-ch Fmr1tm1Cgr/J(品種番号004624)
年齢:19-21日齢
体重:7-10g程度
性別:メスとオス
動物数:24匹
被験物および調製方法:実験前に2.0mgのZD043を量って2mL遠心管に置き、精密ピペットで10uLのDMSOを取ってZD043粉末を溶解させ、さらに10uLのTween80を入れ、均一に混合した後980uLの生理食塩水を入れ、十分に混合して懸濁液とした。
溶媒コントロール:1% DMSO、1% Tween80を含有する0.9% NaCl溶液
主要実験装置:円柱形透明有機ガラス桶(直径10cm、高さ25cm)
映像監視システム:上海全景数字技術有限公司、型番:IPC-5201-BNS
大音量サイレンメーカー(≧120デシベル):AIDEXIN社、型番:ES626
デシベル計:泰克曼電子儀器控股有限公司、型番:TM824
癲癇発作の潜伏期が短ければ、発作レベルが高ければ、癲癇になりやすく、薬物干与後潜伏期の延長および癲癇レベルの低下は当該化合物が癲癇の発生に対する抑制または癲癇の発作レベルの低下を示す。
投与プラン:
体重150〜200gの健康なラット6匹を無作為に3群に3匹ずつ分けた。ZD043をそれぞれ胃内投与と静脉注射で投与し、投与体積は10 mL/kgで、投与量は胃内20 mg/kg、静脉注射10 mg/kgで、薬物はDMSO/ツイン80/生理食塩水(5:5:90、v/v/v)で調製した。 試験前、12h断食し、水を自由に飲ませた。薬物を投与してから2h後、一緒に食事をさせた。
サンプリング時点およびサンプルの処理:
以上の所定の時点でラットの眼球後静脈叢から血0.3 mLを取り、ヘパリンで処理した試験管に置き、11000 rpmで5 min遠心し、血漿を分離し、-20℃の冷蔵庫で冷凍した。
以上の実験結果から、ラットの薬物動態学実験において、化合物ZD043は優れた絶対生物利用能を表し、31.6%に達したことがわかる。
実験手順:
体重150〜200gの健康なラット6匹を無作為に3群に3匹ずつ分けた。ZD043をそれぞれ胃内投与と静脉注射で投与し、投与体積は10 mL/kgで、投与量は胃内20 mg/kg、静脉注射10 mg/kgで、薬物はDMSO/ツイン80/生理食塩水(5:5:90、v/v/v)で調製した。 試験前、12h断食し、水を自由に飲ませた。薬物を投与してから2h後、一緒に食事をさせた。
重量体積比が1:10の生理食塩水を入れ、ホモジナイザーで充分に均質化させた。均質化液100 uLを取り、ジクロロメタン:メタノール(3:2)溶液300 uLを入れ、ボルテックスで均一に混合し、14000 rpmで10 min遠心し、下清液を取り、窒素ガスで吹いて乾燥し、4℃の冷蔵庫で保存して使用に備えた。
投与後、化合物ZD043はすぐ吸収され、かつ血液脳関門を通過した脳組織に到達し、薬物の脳内と血漿における濃度比は1/2に達した。このように、化合物ZD043は優れた脳への標的性を有することがわかる。
実験原理:尾懸垂実験(Tail Suspension Test、TST)は典型的で快速に抗うつ薬、興奮薬、安定薬の薬物効果を評価する方法である。その原理は、マウスの尾を釣り上げた後、逃げようとするが逃げられず、足掻くのを諦め、特有のうつの無動状態に入り、実験過程で動物の無動時間を記録してうつ状態を反映し、抗うつ薬、興奮薬は顕著にその状態を短縮させることができる。
実験方法:体重20〜24gのオスマウスを選び、その尾の先端から2cmの部位を水平の木棒に貼り、動物を逆さ吊りの状態にし、その頭部は台表面から約5cm離れ、両側に板を掛けて動物の視線を阻んだ。投与群とコントロール群の6min内の無動時間を比較した。
実験結論:陽性コントロールであるフロキセチンは顕著にマウス尾懸垂実験の過程における「無動時間」を改善することができる。被験化合物ZD043は20 mg/kgの投与量でマウス尾懸垂実験の過程における「無動時間」を改善することができる。
実験原理:頭部強制回旋試験(Head Thrust Test,、HTT)のモデルは最初にCorneらによって1963年に提出され、5-HT受容体の興奮による頭部強制回旋症候群は5-HT2受容体が介することがあるマウスにおける5-HTPによる頭部強制回旋行為は異なる作用機序を有する抗うつ薬のいずれにも敏感である。たとえばシタロプラム、フルボキサミンなどの5-HT再取り込み阻害薬、デシプラミン、マプロチリン、ノミフェンシンなどのNA再取り込み阻害薬および5-HTとNA系に混合作用するイミプラミンが挙げられる。
実験結論:陽性コントロールであるフロキセチンは顕著にマウス頭部強制回旋実験の過程における「頭部強制回旋回数」を増加することができる。被験化合物ZD043は20 mg/kgの投与量でマウス頭部強制回旋実験の過程における「頭部強制回旋回数」を増加することができ、優れた体内薬効学を表す。
実験原理:マウス強制水泳実験(Forced Swimming Test,、FST)の原理は、マウスを限られた逃げられない空間内に置いて泳がせることで、動物の無動状態を誘導することができ、この状態は動物の絶望行為を反映する。
実験名称:マウス水泳うつ実験
実験目的:被験化合物のマウスうつ状況に対する影響を観察する
実験動物:ICRマウス、20〜28 g、メスとオスを兼用した
サンプル処理:被験化合物のいずれも1% CMC(カルメロースナトリウム)水溶液で研磨し、均一な溶液とした。体内薬効の投与は5mg/kg、10mg/kgおよび20mg/kgを選択し、0.1 ml/10 g体重体積で化合物を経口投与した。陽性コントロール薬(アミトリプチリンおよびフロキセチン)はいずれも0.9% 生理食塩水で溶解させ、体内投与量は10 mg/kgを選択し、0.1ml/10g体重体積で腹腔注射した。(注:化合物を投与する前にマウスを8時間断食させたが、水を取らせた。)
Claims (10)
- 一般式I:
Xは、CHまたはNである;
R1、は水素、ハロゲン、C1-C6アルキル基、ハロゲン置換のC1-C6アルキル基、シアノ基からなる群から選ばれる;
R2およびR3は、それぞれ独立に水素、置換または無置換のフェニル基、置換または無置換の3-7員ヘテロアリール基、置換または無置換の5-7員アリール基-メチレン基、3-7員複素環基-メチレン基からなる群から選ばれ、各複素環基は、それぞれ独立に酸素、硫黄および窒素から選ばれる1〜4個のヘテロ原子を含有する;かつ前記のR2およびR3は、同時には水素ではない;あるいは、R2およびR3は、連結するN原子とともに置換または無置換の5-20員スピロ複素環、もしくは置換または無置換の4-20員縮合複素環からなる群から選ばれる基を構成する;ここで、前記の置換とは、基における一つまたは複数の水素原子が、ハロゲン、C1-C6アルキル基、ハロゲン置換のC1-C6アルキル基、C1-C6アルコキシ基、C1-C6アルコキシカルボニル基、ハロゲン置換のC1-C6アルコキシ基、C2-C6アルケニル基、C2-C6アルキニル基、C3-C8シクロアルキル基、シアノ基、ニトロ基、アミノ基、ヒドロキシ基、ヒドロキシメチル基、カルボキシ基、メルカプト基、スルホニル基、C6-C10アリール基、および3-12員複素環基からなる群から選ばれる置換基で置換されることをいう;ここで、前記のスピロ複素環、縮合複素環または複素環基は、それぞれ独立に酸素、硫黄および窒素から選ばれる1〜4個のヘテロ原子を含有する;
かつR1が、Hである場合、
前記のハロゲンは、F、Cl、BrまたはIである、前記化合物。 - 前記のR2およびR3が、それぞれ独立に水素、置換または無置換のフェニル基、置換または無置換の3-7員ヘテロアリール基、置換または無置換の5-7員アリール基-メチレン基、3-7員複素環基-メチレン基からなる群から選ばれ、各複素環基が、それぞれ独立に酸素、硫黄および窒素から選ばれる1〜4個のヘテロ原子を含有する;R2およびR3が、同時に水素ではない;
あるいは、R2およびR3が、連結するN原子とともに置換または無置換のスピロ複素環、もしくは置換または無置換の縮合複素環からなる群から選ばれる基を構成し;ここで、前記の置換とは、基における一つまたは複数の水素原子が、ハロゲン、C1-C6アルキル基、C1-C6アルコキシ基、ハロゲン置換のC1-C6アルコキシ基、シアノ基、ニトロ基、アミノ基、ヒドロキシ基、ヒドロキシメチル基、カルボキシ基、メルカプト基、スルホニル基、トリフルオロメチル基からなる群から選ばれる置換基で置換されることをいう、請求項1に記載の化合物。 - 前記の
- 前記のR2が、置換または無置換のフェニル基、置換または無置換のピリジル基、置換または無置換のピラジニル基からなる群から選ばれる;ここで、前記の置換とは、基における水素原子(単数または複数)が、ハロゲン、C1-C6アルキル基、ハロゲン置換のC1-C6アルキル基、C1-C6アルコキシ基、シアノ基、ニトロ基、アミノ基、ヒドロキシ基からなる群から選ばれる置換基(単数または複数)で置換されることをいう;
R3が、Hである;
あるいは、R2およびR3が、連結するN原子とともに置換または無置換の、
ここで、R9、R10、R11、R12、R13が、それぞれ環のいずれかの位置における1-4個の置換基を表し、かつ各置換基が、それぞれ独立にハロゲン、C1-C6アルキル基、ハロゲン置換のC1-C6アルキル基、C1-C6アルコキシ基、シアノ基、ニトロ基、アミノ基、ヒドロキシ基からなる群から選ばれる、請求項1に記載の化合物。 - 前記の
- 前記の化合物が、以下の群から選ばれる、請求項1に記載の化合物。
- (a)治療有効量の、式Iで表される5-芳香族アルキニル基置換ベンズアミド系化合物、またはその薬学的に許容される塩、ラセミ体、R-異性体、S-異性体、またはこれらの組み合わせと、(b)薬学的に許容される担体とを含む、薬物組成物。
- 上記一般式Iで表される構造を有する5-芳香族アルキニル基置換ベンズアミド系化合物、その薬用可能な塩、ラセミ体、R-異性体、S-異性体、またはこれらの組み合わせを含む、mGluR5陰性アロステリック調節剤。
- 前記のmGluR5陰性アロステリック調節剤が、選択的にmGluR5を抑制する、請求項8に記載のmGluR5陰性アロステリック調節剤。
- mGluR5(代謝型グルタミン酸受容体サブタイプ5)に関連する疾患を治療する薬物の製造における、請求項1に記載の式Iで表される化合物、またはその薬学的に許容される塩、ラセミ体、R-異性体、S-異性体またはこれらの混合物の使用。
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