JP6491679B2 - Gabaa受容体活性のモジュレーターとしてのイミダゾピリダジン誘導体 - Google Patents
Gabaa受容体活性のモジュレーターとしてのイミダゾピリダジン誘導体 Download PDFInfo
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- JP6491679B2 JP6491679B2 JP2016572302A JP2016572302A JP6491679B2 JP 6491679 B2 JP6491679 B2 JP 6491679B2 JP 2016572302 A JP2016572302 A JP 2016572302A JP 2016572302 A JP2016572302 A JP 2016572302A JP 6491679 B2 JP6491679 B2 JP 6491679B2
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- 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
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Description
R1は、Hおよび(C1〜C3)アルキルから選択され、
R2は、Hおよび(C1〜C3)アルキルから選択され、かつR3は、Hであるか、または
R2およびR3は一緒に、−CH2−であり、
R4は、H、FおよびOCH3から選択され、
R5は、HおよびFから選択され、
R6は、(C2〜C4)アルキル、(C3〜C5)シクロアルキルおよびメチル置換(C3〜C5)シクロアルキルから選択され、
環Bは、環Aに3、4および5位のいずれか1つで結合しており;
R4は、環Aに2、3、4および5位のいずれか1つで結合しており、
ただし、R4および環Bの両方が、環Aに同じ位置で結合することはできないことを条件とする]
または薬学的に許容できるその塩を提供する。
R1、R2、R3、R4、R5およびR6は、実施形態E1において定義したとおりであり、
R4は、環Aに2、3および5位のいずれか1つで結合している]
または薬学的に許容できるその塩を提供する。
R1、R2、R3、R4、R5およびR6は、実施形態E1において定義したとおりであり、
R4は、環Aに2、4および5位のいずれか1つで結合している]
または薬学的に許容できるその塩を提供する。
5−[5−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−2−フルオロ−フェニル]−6−メトキシ−2−メチル−2,3−ジヒドロ−イソインドール−1−オン、
5−[2−フルオロ−5−(7−イソプロピル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−フェニル]−2−メチル−2,3−ジヒドロ−イソインドール−1−オン、
5−[5−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−2−フルオロ−フェニル]−2−メチル−2,3−ジヒドロ−イソインドール−1−オン、
5’−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−2’−フルオロ−ビフェニル−3−カルボキサミド、
6−[5−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−2−フルオロ−フェニル]−2−メチル−2,3−ジヒドロ−イソインドール−1−オン、および
5’−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−5,2’−ジフルオロ−N−メチル−ビフェニル−3−カルボキサミド
ならびに薬学的に許容できるその塩が含まれる。
(i)式(I)の化合物を所望の酸または塩基と反応させることによる方法;
(ii)所望の酸または塩基を使用して、式(I)の化合物の適切な前駆体から、酸または塩基に不安定な保護基を除去することによる方法;または
(iii)適切な酸もしくは塩基と反応させることにより、または適切なイオン交換カラムを用いて、式(I)の化合物のある塩を別の塩に変換することによる方法。
・例えば、以下でさらに検討するとおり、急性疼痛、慢性疼痛、神経障害性疼痛、侵害受容性(炎症性を含む)疼痛、体性疼痛、内臓疼痛、および機能障害性疼痛を含めた疼痛を処置するための、ならびに特に、根底にある機序に脳または脊髄成分が存在する疼痛状態のための鎮痛薬として;
・例えば、Lennox−Gastaut症候群、Dravet病、および熱性発作陽性(GEFS+)の全身てんかんを含めたてんかんおよびてんかん関連障害を処置するための抗痙攣薬として;
・例えば、パニック障害、全般性不安障害、心的外傷後ストレス障害、急性ストレス障害および物質誘発性ストレス障害などのストレス障害、広場恐怖症、社会恐怖症および動物恐怖症などの恐怖症、ならびに強迫性障害を処置するための抗不安薬として;ならびに
・例えば、筋肉痙攣、ジストニア、痙縮(全身および限局性痙縮を含む)および本態性振戦を処置するための筋弛緩薬として使用することができる。
・WO2008/118758に開示されている化合物などの選択的Nav1.3チャネルモジュレーター;
・WO2010/079443に開示されている化合物などの選択的Nav1.7チャネルモジュレーター、例えば、4−[2−(5−アミノ−1H−ピラゾール−4−イル)−4−クロロフェノキシ]−5−クロロ−2−フルオロ−N−1,3−チアゾール−4−イルベンゼンスルホンアミドもしくは4−[2−(3−アミノ−1H−ピラゾール−4−イル)−4−(トリフルオロメチル)フェノキシ]−5−クロロ−2−フルオロ−N−1,3−チアゾール−4−イルベンゼンスルホンアミド、または薬学的に許容できるいずれかの塩;
・選択的なNav1.8チャネルモジュレーター;
・選択的なNav1.9チャネルモジュレーター;
・ブピバカイン、カルバマゼピン、ラモトリジン、リドカイン、メキシレチンまたはフェニトインなどの非選択的モジュレーターを含めた、1種を超えるNavチャネルにおいて活性をモジュレートする化合物;
・NGFに結合して、NGFシグナル伝達により媒介されるNGF生物学的活性および/または下流の経路(複数可)を阻害する薬剤(例えば、タネズマブ)、TrkAアンタゴニストもしくはp75アンタゴニスト、またはNGF刺激TrkAまたはP75シグナル伝達に関する下流のシグナル伝達を阻害する薬剤などの神経成長因子(NGF)シグナル伝達の任意の阻害薬;
・その阻害が、(a)神経成長因子(NGF)(例えば、タネズマブ、ファシヌマブ(fasinumab)またはフルラヌマブ(fulranumab))、脳由来神経栄養因子(BDNF)、ニューロトロフィン−3(NT−3)もしくはニューロトロフィン−4(NT−4)に結合する薬剤、または1種を超える上述のニューロトロフィンに結合する薬剤(例えば、可溶性P75);または(b)オルソステリック部位においてか、アロステリック部位においてか、または受容体(複数可)の触媒活性の阻害により、TrKA、TrKB、TrKCまたはP75の1種または複数において受容体機能を阻害する薬剤により達成される神経栄養経路の阻害薬;
・脂肪酸アミドヒドロラーゼ阻害(FAAH)活性またはモノアシルグリセロールリパーゼ(MAGL)活性を有する化合物などの、エンドカンナビノイドのレベルを上昇させる化合物;
・鎮痛薬、特に、パラセタモール;
・ブプレノルフィン、ブトルファノール、コカイン、コデイン、ジヒドロコデイン、フェンタニール、ヘロイン、ヒドロコドン、ヒドロモルホン、レバロルファン レボルファノール、メペリジン、メタドン、モルヒネ、ナルメフェン、ナロルフィン、ナロキソン、ナルトレキソン、ナルブフィン、オキシコドン、オキシモルホン、プロポキシフェンまたはペンタゾシンなどのオピオイド鎮痛薬;
・TRV130など、ベータアレスチン動員とは対照的に、特異的細胞内経路、例えば、Gタンパク質を優先的に刺激するオピオイド鎮痛薬;ノルアドレナリン(ノルエピネフリン)再取り込み阻害(NRI)活性(例えば、タベンタドール);セロトニンおよびノルエピネフリン再取り込み阻害(SNRI)活性(例えば、トラマドール);またはノシセプチン受容体(NOP)アゴニスト活性(GRT6005など)などの追加の薬理を有するオピオイド鎮痛薬;
・非選択的シクロオキシゲナーゼ(COX)阻害薬などの非ステロイド系抗炎症薬(NSAID)、例えば、アスピリン、ジクロフェナク、ジフルシナル、エトドラク、フェンブフェン、フェノプロフェン、フルフェニサル、フルルビプロフェン、イブプロフェン、インドメタシン、ケトプロフェン、ケトロラック、メクロフェナム酸、メフェナム酸、メロキシカム、ナブメトン、ナプロキセン、ニメスリド、ニトロフルルビプロフェン、オルサラジン、オキサプロジン、フェニルブタゾン、ピロキシカム、スルファサラジン、スリンダク、トルメチンもしくはゾメピラク;またはCOX−2選択的阻害薬、例えば、セレコキシブ、デラコキシブ、エトリコキシブ、マヴァコキシブ(mavacoxib)またはパレコキシブ;
・プロスタグランジンE2サブタイプ4(EP4)アンタゴニスト;
・ミクロソームプロスタグランジンEシンテターゼ1型(mPGES−1)阻害薬;
・グルテチミド、メプロバメート、メタクワロンまたはジクロラールフェナゾンなどの鎮静薬;
・クロルジアゼポキシド、アルプラゾラム、ジアゼパム、ロラゼパム、オキサゼパム、テマゼパム、トリアゾラム、クロナゼパムまたはクロバザムなどの、ベンゾジアゼピン結合部位により媒介される幅広いサブタイプモジュレート効果を有するGABAAモジュレーター;
・TPA023、TPA023B、L−838,417、CTP354またはNSD72などの、有害作用の低減を伴う、ベンゾジアゼピン結合部位により媒介されるサブタイプ選択的モジュレート効果、例えば、鎮静を有するGABAAモジュレーター;
・バルビツレート、例えば、アモバルビタール、アプロバルビタール、ブタビタール(butabital)、メホバルビタール、メトヘキシタール、ペントバルビタール、フェノバルチタール(phenobartital)、セコバルビタール、またはチオペンタールなどの受容体上の代替的結合部位により作用するGABAAモジュレーター;アルファキサロン、アルファドロンまたはガナキソロン(ganaxolone)などの神経ステロイド;エチホキシンなどのβ−サブユニットリガンド;またはガボキサドール(gaboxadol)などのδ−選択的リガンド;
・GlyR3アゴニストまたは陽性アロステリックモジュレーター;
・骨格筋弛緩薬、例えば、バクロフェン、カリソプロドール、クロルゾキサゾン、シクロベンザプリン、メタキソロン(metaxolone)、メトカルバモールまたはオルフレナジン(orphrenadine);
・NMDA受容体アンタゴニストなどのグルタミン酸受容体アンタゴニストまたは陰性アロステリックモジュレーター、例えば、デキストロメトルファン、デキストロルファン、ケタミン、もしくはメマンチン;またはmGluRアンタゴニストもしくはモジュレーター;
・クロニジン、グアンファシンまたはデクスメタトミジン(dexmetatomidine)などのアルファ−アドレナリン作用薬;
・プロプラノロールなどのベータ−アドレナリン作用薬;
・三環系抗うつ薬、例えば、デシプラミン、イミプラミン、アミトリプチリンまたはノルトリプチリン;
・アプレピタントまたはマロピタント(maropitant)などのタキキニン(NK)アンタゴニスト;
・ムスカリン様アンタゴニスト、例えば、オキシブチニン、トルテロジン、プロピベリン、塩化トロプシウム(tropsium chloride)、ダリフェナシン、ソリフェナシン、テミベリンおよびイプラトロピウム;
・イスプロニクリン(TC−1734)、バレニクリンまたはニコチンなどのコリン作動性(ニコチン作動性)鎮痛薬;
・一過性受容体電位V1(TRPV1)受容体アゴニスト(例えば、レシンフェラトキシン(resinferatoxin)またはカプサイシン)またはアンタゴニスト(例えば、カプサゼピンまたはマヴァトラップ(mavatrap));
・一過性受容体電位A1(TRPA1)受容体アゴニスト(例えば、シンナムアルデヒドまたはカラシ油)またはアンタゴニスト(例えば GRC17536またはCB−625);
・一過性受容体電位M8(TRPM8)受容体アゴニスト(例えば、メントールまたはイシリン(icilin))またはアンタゴニスト;
・一過性受容体電位V3(TRPV3)受容体アゴニストまたはアンタゴニスト(例えば、GRC−15300);
・デキサメタゾンなどのコルチコステロイド;
・エレトリプタン、スマトリプタン、ナラトリプタン、ゾルミトリプタンまたはリザトリプタンなどの5−HT受容体アゴニストまたはアンタゴニスト、特に、5−HT1B/1Dアゴニスト;
・5−HT2A受容体アンタゴニスト;
・シルデナフィル、タダラフィルまたはバルデナフィルなどのPDEV阻害薬;
・ガバペンチン、ガバペンチンエナカルビルまたはプレガバリンなどのアルファ−2−デルタリガンド;
・セルトラリン、デメチルセルトラリン、フルオキセチン、ノルフルオキセチン、フルボキサミン、パロキセチン、シタロプラム、デスメチルシタロプラム、エスシタロプラム、d,l−フェンフルラミン、フェモキセチン、イフォキセチン(ifoxetine)、シアノドチエピン、リトキセチン(litoxetine)、ダポキセチン、ネファゾドン、セリクラミン(cericlamine)およびトラゾドンなどのセロトニン再取り込み阻害薬(SRI);
・マプロチリン、ロフェプラミン、ミルタゼピン(mirtazepine)、オキサプロチリン、フェゾラミン(fezolamine)、トモキセチン、ミアンセリン、ブプロプリオン、ブプロプリオン代謝産物ヒドロキシブプロプリオン、ノミフェンシンおよびビロキサジンなどのNRI、特に、レボキセチンなどの選択的ノルアドレナリン再取り込み阻害薬;
・ベンラファキシン、O−デスメチルベンラファキシン、クロミプラミン、デスメチルクロミプラミン、デュロキセチン、ミルナシプランおよびイミプラミンなどのSNRI;
・誘導型酸化窒素シンターゼ(iNOS)阻害薬;
・ロイコトリエンB4アンタゴニスト;
・ジロートンなどの5−リポキシゲナーゼ阻害薬;
・KCNQ/Kv7の開口薬または陽性モジュレーターなどのカリウムチャネル開口薬または陽性モジュレーター(例えば、レチガビンまたはフルピルチン)、サブファミリーA(例えば、Kv1.1)、サブファミリーB(例えば、Kv2.2)またはサブファミリーK(例えば、TASK、TREKまたはTRESK)のメンバーなどのGタンパク質共役型内向き整流性カリウムチャネル(GIRK)、カルシウム活性化カリウムチャネル(Kca)またはカリウム電位開口型チャネル;
・P2X3受容体アンタゴニスト(例えば、AF219)、またはP2X2/3ヘテロマー受容体などの、そのサブユニットの1つとしてP2X3サブユニットを含有する受容体のアンタゴニスト;
・ジコノチドなどのCaV2.2カルシウムチャネル遮断薬(N型);ならびに
・エトスクシミドなどのCaV3.2カルシウムチャネル遮断薬(T型)。
AcOHは酢酸であり;
aqは、水溶液であり;
brは、ブロードであり;
℃は、摂氏温度であり
CDCl3は、重水素−クロロホルムであり;
Cs2CO3は、炭酸セシウムであり;
δは、化学シフトであり;
dは、二重線であり;
DCMは、ジクロロメタン;塩化メチレンであり;
DIPEAは、N−エチルジイソプロピルアミン、N,N−ジイソプロピルエチルアミンであり;
DMFは、N,N−ジメチルホルムアミドであり;
DMSOは、ジメチルスルホキシドであり;
EDCI.HClは、1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミドヒドロクロリドであり;
ELSDは、蒸発光散乱検出器であり;
EtOAcは、酢酸エチルであり;
EtOHは、エタノールであり;
gは、グラムであり;
HClは、塩酸であり;
HOBtは、N−ヒドロキシベンゾトリアゾール水和物であり;
HPLCは、高圧液体クロマトグラフィーであり;
Lは、リットルであり
LCMSは、液体クロマトグラフィー質量分析法(Rt=保持時間)であり;
mは、多重線であり;
Mは、モル濃度であり;
MeCNは、アセトニトリルであり;
MeOHは、メタノールであり;
mgは、ミリグラムであり;
MgSO4は、硫酸マグネシウムであり;
MHzは、メガヘルツであり;
minは、分であり;
mLは、ミリリットルであり;
mmolは、ミリモルであり;
molは、モルであり;
MS m/zは、質量スペクトルピークであり;
NaHは、水素化ナトリウムであり;
NaHCO3は、炭酸水素ナトリウムであり;
Na2CO3は、炭酸ナトリウムであり;
NaOHは、水酸化ナトリウムであり;
Na2SO4は、硫酸ナトリウムであり;
NBSは、N−ブロモスクシンイミドであり
NH4OHは、水酸化アンモニウムであり;
NMMは、N−メチルモルホリンであり;
NMRは、核磁気共鳴であり;
ODSは、オクタデシルシリルであり;
pHは、水素イオン指数であり;
POCl3は、オキシ塩化リンであり;
ppmは、百万分率であり;
qは、四重線であり;
Rtは、保持時間であり;
sは、一重線であり;
SCXは、強カチオン交換であり;
tは、三重線であり;
TBMEは、tert−ブチルジメチルエーテルであり;
TFAは、トリフルオロ酢酸であり;
THFは、テトラヒドロフランであり;
TLCは、薄層クロマトグラフィーであり;
μLは、マイクロリットルであり;
μmolは、マイクロモルである。
単体の化合物を分取HPLCにより精製する場合に、使用する方法には、以下に示す2種がある。
方法1 酸性条件
カラム Gemini NX C18、5um 21.2×100mm
温度 周囲温度
検出 ELSD−MS
移動相A 水中0.1%ギ酸
移動相B アセトニトリル中0.1%ギ酸
勾配 初期0%B、1分−5%B;7分−98%B;9分−98%B;9.1分−5%B;10分−5%B
流速 18mL/分
注入体積 1000uL
方法2 塩基性条件
カラム Gemini NX C18、5um 21.2×100mm
温度 周囲温度
検出 ELSD−MS
移動相A 水中0.1%ジエチルアミン
移動相B アセトニトリル中0.1%ジエチルアミン
勾配 初期0%B、1分−5%B;7分−98%B;9分−98%B;9.1分−5%B;10分−5%B
流速 18mL/分
注入体積 1000uL
5−[5−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−2−フルオロフェニル]−6−メトキシ−2−メチル−2,3−ジヒドロ−1H−イソインドール−1−オン
1H NMR
(400 MHz, CDCl3): δ ppm 1.70 (t, 3H), 3.24
(s, 3H), 3.89 (s, 3H), 4.39 (s, 2H), 4.58 (q, 2H), 7.36 (t, 1H), 7.42 (s, 1H),
7.47 (s, 1H), 8.21 (dd, 1H), 8.29-8.33 (m, 2H), 9.39 (s, 1H).
19F NMR
(400 MHz, CDCl3): δ ppm -110.37
MS m/z 418 [M+H]+
5−{2−フルオロ−5−[7−(プロパン−2−イル)−7H−イミダゾ[4,5−c]ピリダジン−4−イル]フェニル}−2−メチル−2,3−ジヒドロ−1H−イソインドール−1−オン
1H NMR
(400 MHz, CDCl3): δ ppm 1.77 (d, 6H), 3.24
(s, 3H), 4.46 (s, 2H), 5.24 (m, 1H), 7.37 (m, 1H), 7.70-7.73 (m, 2H), 7.94 (d,
1H), 8.21 (m, 1H), 8.33 (s, 1H), 8.37 (m, 1H), 9.38 (s, 1H).
MS m/z 402 [M+H]+
精製方法A:DCM中の0〜20%MeOHで溶離するシリカゲルカラムクロマトグラフィー
精製方法B:分取HPLC
精製方法C:DCM中の2%MeOHで溶離する分取TLC
5−[5−(7−シクロプロピル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−2−フルオロフェニル]−2−メチル−2,3−ジヒドロ−1H−イソインドール−1−オン
1H NMR
(400 MHz, CDCl3): δ ppm 1.25-1.28 (m, 2H),
1.34-1.39 (m, 2H), 3.23 (s, 3H), 3.70-3.78 (m, 1H), 4.48 (s, 2H), 7.40 (t, 1H),
7.69-7.72 (m, 2H), 7.94 (d, 1H), 8.17-8.20 (m, 1H), 8.28 (s, 1H), 8.35 (d, 1H),
9.40 (s, 1H).
MS m/z 400 [M+H]+
5’−(7−シクロプロピル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−2’−フルオロ−N−メチルビフェニル−4−カルボキサミド
MS m/z 388 [M+H]+
2’−フルオロ−5’−[7−(プロパン−2−イル)−7H−イミダゾ[4,5−c]ピリダジン−4−イル]ビフェニル−4−カルボキサミド
1H NMR
(400 MHz, CDCl3): δ ppm 1.67 (d, 6H), 5.12
(m, 1H), 6.05 (br s, 1H), 7.00 (br s, 1H), 7.25 (m, 1H), 7.62 (m, 2H), 7.90 (m,
2H), 8.04-8.22 (m, 1H), 8.18-8.37 (m, 2H), 9.27 (s, 1H).
MS m/z 376 [M+H]+
5’−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−2’−フルオロ−N,N−ジメチルビフェニル−4−カルボキサミド
1H NMR
(400 MHz, CDCl3): δ ppm 1.66 (t, 3H), 3.08
(d, 6H), 4.57 (q, 2H), 7.34 (t, 1H), 7.52 (d, 2H), 7.66 (d, 2H), 8.18 (m, 1H),
8.29 (s, 1H), 8.32 (dd, 1H), 9.36 (s, 1H).
MS m/z 390 [M+H]+
分取HPLC法B:水酸化アンモニウム中の29〜59%アセトニトリル(pH=10)の勾配で溶離するPhenomenex Gemini C18。勾配時間:9分、保持時間:1分、流速:25mL/分。
LCMS QC:
A:水中の0.0375%TFA;B:MeCN中の0.01875%TFA
カラム:Welch XB−C18 2.1×50mm 5μm
勾配:1分で99%[A]および1%[B]から95%[A]および5%[B]に、さらに4.0分で100%[B]に、最終的に、4.30分で当初条件に戻す。流速0.8mL/分。
分取HPLC:水中の0.225%ギ酸中の31〜61%アセトニトリルの勾配で溶離するBoston Symmetrix ODS−H 150mm×30mm×5um。勾配時間:10分、保持時間:1.5分、流速:25mL/分。生成物は、TFA塩として単離された。
LCMS QC:
A:水中の0.0375%TFA;B:MeCN中の0.01875%TFA
カラム:Welch XB−C18 2.1×50mm 5μm
勾配:1分で99%[A]および1%[B]から95%[A]および5%[B]に、さらに4.0分で100%[B]に、最終的に、4.30分で当初条件に戻す。流速0.8mL/分。
5’−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−2’−フルオロ−2−メトキシ−N−メチルビフェニル−4−カルボキサミド
1H NMR
(400 MHz, CDCl3): δ ppm 1.69 (t, 3H), 3.05
(d, 3H), 3.89 (s, 3H), 4.55-4.60 (q, 2H), 6.22 (br s, 1H), 7.30-7.42 (m, 3H),
7.54 (s, 1H), 8.19-8.23 (m, 1H), 8.27-8.32 (m, 2H), 9.38 (s, 1H).
MS m/z 406 [M+H]+
5’−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−2’−フルオロ−2−メトキシ−N,N−ジメチルビフェニル−4−カルボキサミド
1H NMR
(400 MHz, CDCl3): δ ppm 1.70 (t, 3H), 3.08
(s, 3H), 3.15 (s, 3H), 3.85 (s, 3H), 4.56-4.61 (q, 2H), 7.06-7.11 (m, 2H),
7.32-7.39 (m, 2H), 8.20-8.24 (m, 1H), 8.28-8.33 (m, 1H), 8.37 (s, 1H), 9.41 (s,
1H).
MS m/z 420 [M+H]+
5’−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−2’−フルオロ−6−メトキシ−N,N−ジメチルビフェニル−3−カルボキサミド
1H NMR
(400 MHz, CDCl3): δ ppm 1.69 (t, 3H), 3.12
(s, 6H), 3.86 (s, 3H), 4.58 (q, 2H), 7.04 (d, 1H), 7.34 (t, 1H), 7.48 (s, 1H),
7.55 (m, 1H), 8.22 (m, 1H), 8.24-8.32 (m, 2H), 9.39 (s, 1H).
MS m/z 420 [M+H]+
3−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)ベンゼンボロン酸
THF(400mL)中の2−[3−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−フェニル]−2,3−ジヒドロ−1H−1,3−ジアザ−2−ボラフェナレン(調製例2、10.5g、26.9mmol)の室温溶液に、5N塩化水素水溶液(110mL、0.55mol)を加え、その結果生じた反応混合物を16時間にわたって還流において撹拌した。室温に冷却した後に、反応混合物を濾過し、濾液を、pH=6まで炭酸カリウムで中和した。その結果生じた沈澱物を濾過し、濾過ケークを、少量のEtOAcで洗浄した。収集した固体を真空下で乾燥させて、表題化合物をオフホワイト色の固体(4.5g、62%)として得た。そのまま次のステップに持ち越した。
2−[3−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)フェニル]−2,3−ジヒドロ−1H−1,3−ジアザ−2−ボラフェナレン
ジオキサン(160mL)および水(13mL)中の2−[3−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)フェニル]−2,3−ジヒドロ−1H−1,3−ジアザ−2−ボラフェナレン(調製例31、7.8g、21.1mmol)、4−クロロ−7−エチル−7H−イミダゾ[4,5−c]ピリダジン(調製例17、2.6g、14.1mmol)、および炭酸セシウム(13.8g、42.3mmol)の室温溶液を脱気した。次いで、1,1’−ビス(ジ−tert−ブチルホスフィノ)フェロセンパラジウムジクロリド(0.91g、1.4mmol)を1回で加え、反応混合物を脱気し、その結果生じた溶液を16時間にわたって還流において撹拌した。反応混合物を室温に冷却し、次いで、濾過し、真空中で濃縮した。残渣を、50:1のDCM:MeOHで溶離するシリカゲルカラムクロマトグラフィーにより精製して、表題化合物を黄色の固体(4.6g、84%)として得た。
1H NMR
(400 MHz, CDCl3): δ ppm 1.69 (t, 3H), 4.58
(q, 2H), 6.23 (s, 2H), 6.44 (d, 2H), 7.06 (d, 2H), 7.12-7.16 (m, 2H), 7.61-7.65
(m, 1H), 7.76 (d, 1H), 8.21 (d, 1H) 8.28 (s, 1H), 8.45 (s, 1H), 9.39 (s, 1H).
7−シクロプロピル−4−[4−フルオロ−3−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)フェニル]−7H−イミダゾ[4,5−c]ピリダジン
ジオキサン(20mL)中の4−(3−ブロモ−4−フルオロフェニル)−7−シクロプロピル−7H−イミダゾ[4,5−c]ピリダジン(調製例8、820mg、2.461mmol)、ビスピナコラトジボロン(938mg、3.692mmol)および酢酸カリウム(483mg、4.922mmol)の混合物を窒素で脱気し、その後、1,1’−ビス(ジ−フェニルホスフィノ)フェロセンパラジウム(II)ジクロリド(201mg、0.246mol)を加えた。反応物を3時間にわたって100℃に加熱し、その後、冷却し、セライトを通して濾過し、EtOAcで洗浄した。濾液を真空中で濃縮し、EtOAc中の0〜2%MeOHで溶離するシリカゲルカラムクロマトグラフィーを使用して精製し、続いて、EtOAcで摩砕して、表題化合物をオフホワイト色の固体(510mg、55%)として得た。
1H NMR
(400 MHz, CDCl3): δ ppm 1.25-1.34 (m, 4H),
1.39 (s, 12H), 3.67-3.73 (m, 1H), 7.21-7.26 (s, 1H), 8.25 (s, 1H), 8.40-8.44
(m, 2H), 9.40 (s, 1H).
MS m/z 299 [M+H]+ ボロン酸, MS m/z 381 [M+H]+ ボロン酸エステル
7−エチル−4−[4−フルオロ−3−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)フェニル]−7H−イミダゾ[4,5−c]ピリダジン
表題化合物を、調製例3に従って、4−(3−ブロモ−4−フルオロ−フェニル)−7−エチル−7H−イミダゾ[4,5−c]ピリダジン(調製例5)を使用して、淡茶色の固体(2.47g、62%)として調製した。
1H NMR
(400 MHz, CDCl3): δ ppm 1.36 (s, 12H), 1.66
(t, 3H), 4.55 (q, 2H), 7.19-7.24 (m, 1H), 8.25 (s, 1H), 8.41-8.44 (m, 2H), 9.36
(s, 1H).
4−(3−ブロモ−4−フルオロ−フェニル)−7−エチル−7H−イミダゾ[4,5−c]ピリダジン
濃硫酸(66g、0.67mol)を、氷浴に囲まれた7−エチル−4−(4−フルオロフェニル)−7H−イミダゾ[4,5−c]ピリダジン(調製例12、2.3g、9.5mmol)に慎重に加え、その結果生じた反応混合物を、均一な溶液が観察されるまで、室温において穏やかに撹拌した。この溶液に、1,3−ジブロモ−5,5−ジメチルヒダントイン(2.7g、9.5mmol)を少量ずつ加え、撹拌を2時間にわたって0℃において継続した。反応混合物を、亜硫酸水素ナトリウム水溶液(200mL)に慎重に注ぎ、次いで、温度を20℃未満に維持しながら、水酸化ナトリウム水溶液(2M)で、pH=8まで塩基性にした。EtOAc(50mL)を加え、層を分離した。水性層をEtOAc(2×50mL)で抽出した。合わせた有機相を飽和ブライン溶液で洗浄し、Na2SO4上で脱水し、真空中で濃縮した。残渣を、1:1の石油エーテル:DCMで溶離するシリカゲルカラムクロマトグラフィーにより精製し、続いて、EtOAcと共に摩砕して、表題化合物を白色の固体(1.25g、41%)として得た。
1H NMR
(400 MHz, CDCl3): δ ppm 1.70 (t, 3H), 4.58
(q, 2H), 7.26-7.34 (m, 1H), 8.16-8.25 (m, 1H), 8.31 (s, 1H), 8.44-8.50 (m, 1H),
9.32 (s, 1H).
MS m/z 323 [M81Br+H]+
ジオキサン(60mL)中の2−(3−ブロモ−4−フルオロフェニル)−4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン(調製例13、6.1g、16.28mmol)の混合物に、4−ヨード−7−エチル−7H−イミダゾ[4,5−c]ピリダジン(調製例15、.5g、13.28mmol)および炭酸ナトリウム(4.2g、39.8mmol)を加えた。混合物を脱気し、窒素を再装入した。テトラキス(トリフェニルホスフィン)パラジウム(0)(1.5g、1.3mmol)を加え、混合物を24時間にわたって窒素雰囲気下で80℃に加熱した。混合物を酢酸エチル(200mL)で希釈し、飽和塩化アンモニウム溶液(400mL)、水およびブライン(それぞれ200mL)で洗浄した。有機層を蒸発させ、その結果生じた茶色の固体をアセトニトリルから摩砕して、表題化合物を白色の固体(2.2g、51%)として得た。
7−エチル−4−(4−フルオロ−3−ヨードフェニル)−7H−イミダゾ[4,5−c]ピリダジン
濃縮硫酸(10mL)を、氷浴に囲まれた7−エチル−4−(4−フルオロフェニル)−7H−イミダゾ[4,5−c]ピリダジン(調製例12、825mg、2.4mmol)に慎重に加え、その結果生じた反応混合物を、均一な溶液が観察されるまで、室温において穏やかに撹拌した。これに、1,3−ジヨード−5,5−ジメチルヒダントイン(1.36g、3.58mmol)を少量ずつ加え、撹拌を5分間にわたって継続した。次いで、粘稠性の混合物を、撹拌しながら0℃において水酸化ナトリウム水溶液(1M、10mL)にゆっくりと注いだ。黒色の懸濁液がゆっくりと溶けて、青色の溶液が得られた。DCM(20mL)を加え、層を分離した。有機層を飽和亜硫酸水素ナトリウム水溶液(20mL)で洗浄し、次いで、真空中で濃縮した。残渣を、1:1〜0:100のヘプタン:EtOAcで溶離するシリカゲルカラムクロマトグラフィーを使用して精製して、表題化合物を白色の固体(1.19g、95%)として得た。
1H-NMR
(400 MHz, CDCl3): δ
ppm 1.70 (t, 3H), 4.58 (q, 2H), 7.25 (m, 1H), 8.19-8.23 (m, 1H), 8.29 (s, 1H),
8.65 (dd, 1H), 9.32 (s, 1H).
MS m/z 369 [M127I+H]+
7−エチル−4−(4−フルオロ−3−クロロフェニル)−7H−イミダゾ[4,5−c]ピリダジン
4−クロロ−7−エチル−7H−イミダゾ[4,5−c]ピリダジン(調製例17、1g、5.48mmol)、(3−クロロ−4−フルオロフェニル)ボロン酸(0.95g、5.48mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0)(633mg、0.548mmol)および炭酸ナトリウム(1.74g、16.44mmol)をジオキサン(55mL)および水(20mL)に溶かした。混合物を窒素で10分間にわたって脱気し、その後、24時間にわたって加熱還流した。反応物を冷却し、酢酸エチルで希釈し、その後、セライトのパッドを通して濾過した。濾液を減圧下で蒸発させ、その結果生じた残渣をSCX−2カートリッジを通して溶離して、表題化合物を淡い茶色の固体(1.52g、99%)として得た。
1H NMR
(400 MHz, CDCl3): δ ppm 1.68 (t, 3H), 4.58
(q, 2H), 7.34 (t, 1H), 8.11 (m, 1H), 8.30 (s, 1H), 8.35 (dd, 1H), 9.32 (s, 1H).
MS m/z 277 [M35Cl+H]+
4−(3−ブロモ−4−フルオロフェニル)−7−シクロプロピル−7H−イミダゾ[4,5−c]ピリダジン
表題化合物を、調製例5について記載した方法に従って、7−シクロプロピル−4−(4−フルオロフェニル)−7H−イミダゾ[4,5−c]ピリダジン(調製例11、450mg、1.77mmol)および1,3−ジブロモ−5,5−ジメチルヒダントイン(253mg、0.885mmol)を使用して調製して、白色の固体(500mg、25%)を得た。
1H NMR
(400 MHz, DMSO-d6):δ ppm 1.18-1.24 (m, 4H),
3.77-3.78 (m, 1H), 7.63 (t, 1H), 8.45-8.51 (m, 1H), 8.82-8.85 (m, 2H), 9.58 (s,
1H).
MS m/z 333 [M79Br+H]+
4−(3−クロロ−4−フルオロフェニル−7−(プロパン−2−イル))−7H−イミダゾ[4,5−c]ピリダジン
ジオキサン/水(20mL/7mL)中の4−クロロ−7−イソプロピル−7H−イミダゾ[4,5−c]ピリダジン(調製例14、1.04g、5.29mmol)、3−クロロ−4−フルオロフェニルボロン酸(1.01g、5.82mmol)および炭酸セシウム(3.45g、10.6mmol)の溶液を30分間にわたって窒素で脱気した。テトラキス(トリフェニルホスフィン)パラジウム(0)(305mg、0.265mmol)を加え、反応物を16時間にわたって85℃に加熱した。反応物を冷却し、水(20mL)で希釈し、EtOAc(40mL)に抽出した。有機層を真空中で濃縮し、DCM中の20%EtOAcで溶離するシリカゲルカラムクロマトグラフィーを使用して精製して、表題化合物をオレンジ色の粉末(1.12g、73%)として得た。
1H NMR
(400 MHz, CDCl3): δ ppm 1.78 (d, 6H), 5.21
(m, 1H), 7.36 (t, 1H), 8.12 (m, 1H), 8.34-8.38 (m, 2H), 9.31 (s, 1H).
MS m/z 291 [M35Cl+H]+
メチル5’−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−2’−フルオロ−2−メトキシビフェニル−4−カルボキシラートおよび5’−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−2’−フルオロ−2−メトキシビフェニル−4−カルボン酸
7−エチル−4−(4−フルオロ−3−クロロフェニル)−7H−イミダゾ[4,5−c]ピリダジン(調製例7、200mg、0.723mmol)、メチル−3−メトキシ−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ベンゾアート(調製例29、300mg、1.027mmol)、ジシクロヘキシル(2’,4’,6’−トリイソプロピル−[1,1’−ビフェニル]−2−イル)ホスフィン(35mg、0.073mmol)、酢酸パラジウム(II)(8mg、0.036mmol)および炭酸カリウム(280mg、2.029mmol)を2−メチル−2−ブタノール(6mL)および水(3mL)中、窒素下で混合し、18時間にわたって110℃に加熱した。反応物を冷却し、水(50mL)およびEtOAc(50mL)の間で分配した。水層を分離し、EtOAc(10mL)でさらに抽出した。合わせた有機層を硫酸ナトリウム上で脱水し、真空中で濃縮した。残渣をtert−ブチルメチルエーテル(2mL)で摩砕して、メチル5’−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−2’−フルオロ−2−メトキシビフェニル−4−カルボキシラート(125mg、43%)を得た。
1H NMR
(400 MHz, CDCl3): δ ppm 1.69 (t, 3H), 3.89
(s, 3H), 3.96 (s, 3H), 4.55-4.61 (q, 2H), 7.35 (t, 1H), 7.43 (d, 1H), 7.69 (s,
1H), 7.75 (d, 1H), 8.22-8.24 (dd, 1H), 8.28-8.33 (m, 2H), 9.39 (s, 1H).
19F NMR
(376 MHz, CDCl3): δ ppm -110.5
MS m/z 407 [M+H]+
1H NMR
(400 MHz, DMSO-d6): δ ppm 1.53 (t, 3H), 3.82
(s, 3H), 4.46-4.52 (q, 2H), 7.46-7.53 (m, 2H), 7.62-7.68 (m, 2H), 8.44-8.49 (m,
2H), 8.85 (s, 1H), 9.54 (s, 1H).
19F NMR
(376 MHz, CDCl3): δ ppm -111.5
MS m/z 393 [M+H]+
7−シクロプロピル−4−(4−フルオロフェニル)−7H−イミダゾ[4,5−c]ピリダジン
ジオキサン(20mL)中の4−クロロ−7−シクロプロピル−7H−イミダゾ[4,5−c]ピリダジン(調製例16、1.00g、5.1mmol)の室温溶液に、4−フルオロベンゼンボロン酸(1.08g、7.71mmol)およびNa2CO3の溶液(2.72g、水12.8mL中25.7mmol)を加えた。反応混合物を脱気した。次いで、テトラキス(トリフェニルホスフィン)パラジウム(0)(297mg、0.26mmol)を加え、混合物を16時間にわたって加熱還流した。溶媒を真空中で除去し、水性残渣を濾過し、EtOAcで溶離するシリカゲルカラムクロマトグラフィーにより精製して、表題化合物を赤色の固体(949mg、73%)として得た。
1H-NMR
(400 MHz, CDCl3): δ ppm 1.25-1.37 (m, 4H),
3.69-3.73 (m, 1H), 7.24-7.28 (m, 2H), 8.19-8.23 (m, 2H), 8.25 (s, 1H), 9.36 (s,
1H).
MS m/z 255 [M+H]+
7−エチル−4−(4−フルオロフェニル)−7H−イミダゾ[4,5−c]ピリダジン
ジオキサン(300mL)中の4−クロロ−7−エチル−7H−イミダゾ[4,5−c]ピリダジン(調製例17、9.6g、52.4mmol)の室温溶液に、4−フルオロベンゼンボロン酸(8.8g、63mmol)およびNa2CO3の水溶液(1M、260mL、262mmol)を加えた。反応混合物を脱気し、テトラキス(トリフェニルホスフィン)パラジウム(0)(1.2g、1.0mmol)を加え、混合物を4時間にわたって加熱還流した。有機溶媒を真空中で除去し、その結果生じた水性混合物を濾過した。濾過ケークを真空下で乾燥させて、表題化合物を黄色の固体(7g、55%)として得た。
1H NMR
(400 MHz, CDCl3): δ ppm 1.62 (t, 3H), 4.50
(q, 2H), 7.19 (t, 2H), 8.14-8.18 (m, 2H), 8.21 (s, 1H), 9.27 (s, 1H).
2−(3−ブロモ−4−フルオロフェニル)−4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン
ジオキサン(75mL)中の2−ブロモ−1−フルオロ−4−ヨードベンゼン(5.0g、16.62mmo)の混合物に、ビス(ピナコラト)ジボロン(4.2g、16.62mmol)および炭酸カリウム(3.3g、33.2mmol)を加えた。混合物を脱気し、窒素を再装入した。ビス(トリフェニルホスフィン)パラジウム(II)ジクロリド(0.60g、0.83mmol)を加え、混合物を窒素雰囲気下で18時間にわたって100℃に加熱した。混合物を酢酸エチル(300mL)で希釈し、飽和塩化アンモニウム溶液、水およびブライン(各200mL)で洗浄した。有機層を蒸発させて、表題化合物を暗赤色のオイル(6.1g)として得、これをさらに精製せずに使用した。
1H NMR
(400 MHz, CDCl3): δ ppm 1.33 (s, 12H), 7.10
(t, 1H), 7.72-7.65 (m, 1H), 8.00 (dd, 1H) ppm.
4−クロロ−7−イソプロピル−7H−イミダゾ[4,5−c]ピリダジン
オルトギ酸トリエチル(36mL)中の5−クロロ−N3−イソプロピルピリダジン−3,4−ジアミン(調製例19、14.4mmol)の溶液を2.5時間にわたって145℃に加熱し、次いで、冷却した。溶液を真空中で濃縮し、EtOAc(100mL)を加えた。溶液を濾過し、濾液を真空中で濃縮した。粗製の残渣を、ヘプタン中の50〜100%EtOAcで溶離するシリカゲルカラムクロマトグラフィーにより精製して、表題化合物を薄茶色の粉末(1.04g、2ステップで22%)として得た。
1H NMR
(400 MHz, CDCl3): δ ppm 1.97 (d, 6H),
5.18 (m, 1H), 8.33 (s, 1H), 9.14 (s, 1H).
MS m/z 197 [M35Cl+H]+
4−ヨード−7−エチル−7H−イミダゾ[4,5−c]ピリダジン
ヨウ化水素酸(130mL、55%水溶液)中の4−クロロ−7−エチル−7H−イミダゾ[4,5−c]ピリダジン(調製例17、7.80g、42.7mmol)の混合物に、ヨウ化ナトリウム(12.8g、85.4mmol)を加え、混合物を1時間にわたって70℃に加熱した。黄色の沈澱物がほぼ直ちに形成した。混合物のpHを、固体NaHCO3でpH7に調整した(激しいガス発生)。その結果生じた水層をDCMで抽出して、表題化合物を黄色の固体として得、これは、放置すると緑色になった(9.90g、85%)。
1H NMR
(400 MHz, CDCl3): δ ppm 1.66 (t, 3H), 4.53
(q, 2H), 8.33 (d, 1H), 9.40 (s, 1H).
4−クロロ−7−シクロプロピル−7H−イミダゾ[4,5−c]ピリダジン
5−クロロ−N3−シクロプロピルピリダジン−3,4−ジアミン(調製例20、10.0g、54mmol)およびオルトギ酸トリエチル(120mL)の混合物を3時間にわたって加熱還流した。反応混合物を真空中で濃縮し、残渣を、98:2のDCM:MeOHで溶離するシリカゲルカラムクロマトグラフィーにより精製して、表題化合物を茶色の固体(5g、48%)として得た。
1H NMR
(400 MHz, DMSO-d6): δ ppm 1.05-1.30 (m, 4H),
3.75-3.85 (m, 1H), 8.88 (s, 1H), 9.26 (s, 1H.
MS m/z 195 [M35Cl+H]+
4−クロロ−7−エチル−7H−イミダゾ[4,5−c]ピリダジン
5−クロロ−N3−エチル−ピリダジン−3,4−ジアミン(調製例18、10.0g、58mmol)およびオルトギ酸トリエチル(60mL)の混合物を、4時間にわたって加熱還流した。反応混合物を真空中で濃縮し、残渣をEtOAc(50mL)に溶かし、濾過した。濾過ケークをEtOAcで洗浄し、次いで、有機層を飽和ブライン溶液で洗浄し、Na2SO4上で脱水し、真空中で濃縮して、表題化合物を黄色の固体(4.8g、45%)として得た。そのまま次のステップに入れた。
5−クロロ−N3−エチルピリダジン−3,4−ジアミン
3,5−(ジクロロピリダジン−4−イル)アミン(調製例21、15g、92mmol)および無水エチルアミン(50mL)の混合物を、48時間にわたって密封管内で120℃に加熱した。反応混合物を室温に冷却し、次いで、水(500mL)およびEtOAc(50mL)の混合物に加えた。その結果生じた沈澱物を濾過により分離し、濾過ケークをtBMEで洗浄し、真空下で乾燥させて、表題化合物をオフホワイト色の固体(8.1g、51%)として得た。
1H-NMR
(400 MHz, DMSO-d6): δ ppm 1.18 (t, 3H), 3.41
(q, 2H), 6.08-6.11 (m, 3H), 8.09 (s, 1H).
5−クロロ−N3−イソプロピルピリダジン−3,4−ジアミン
イソプロピルアミン(16mL)および水(5mL)中の3,5−ジクロロピリダジン−4−アミン(調製例21、4g、14.4mmol)の溶液を16時間にわたって150℃に加熱した。反応物を冷却し、水(20mL)を加え、反応物をEtOAc(3×30mL)に抽出した。合わせた抽出物を真空中で濃縮して、表題化合物を得た。
1H NMR
(400 MHz, CDCl3): δ ppm 1.24 (d, 6H), 4.38
(m, 1H), 4.80 (s, 1H), 4.97 (s, 2H), 8.27 (s, 1H).
5−クロロ−N3−シクロプロピルピリダジン−3,4−ジアミン
3,5−ジクロロピリダジン−4−アミン(調製例21、5.12g、31.2mmol)をステンレス鋼製密封容器(100mL容量)内でシクロプロピルアミン(37.0g、650mmol)に加えて、均一な溶液を得た。混合物を12時間にわたって120℃において加熱し、その後、室温に冷却し、真空中で蒸発させた。残渣を、音波処理および撹拌でEtOAc(150mL)に溶かした。このEtOAc溶液を10%炭酸カリウム水溶液(2×200mL)で洗浄し、無水MgSO4上で脱水し、次いで、濾過し、真空中で蒸発させた。混合物をDCMに再び溶かし、DCM(100mL)、次いで、EtOAc(150mL)で溶離するシリカゲルカラムクロマトグラフィーを使用して精製して、表題化合物を薄いオレンジ色の固体(4.2g、73%収率)として得た。
1H NMR
(400 MHz, DMSO-d6): δ ppm 0.2-0.5 (m, 2H),
0.38-0.40 (m, 2H), 2.85-2.95 (m, 1H), 5.75 (b s, 2H), 6.0-6.05 (b s, 1H), 7.80
(s, 1H).
3,5−ジクロロピリダジン−4−アミン
EtOH(5.5mL)およびNH4OH(5.5mL)中の3,4,5−トリクロロピリダジン(調製例22、500mg、2.73mmol)の混合物を、25分間にわたってマイクロ波照射下で、120℃において加熱した。反応物を真空中で濃縮し、アセトン:ジクロロメタン(0〜15%アセトン)で溶離するシリカゲルカラムクロマトグラフィーを使用して精製して、表題化合物(163mg、36%)を得た。
1H NMR
(400 MHz, CDCl3): δ ppm 5.11 (br s, 2H),
8.74 (s, 1H).
MS m/z 164 [M35Cl35Cl+H]+
3,4,5−トリクロロピリダジン
POCl3(60mL、642mmol)中の4,5−ジクロロピリダジン−3(2H)−オン(10.0g、60.6mmol)を、18時間にわたって110℃において撹拌した。反応物を、トルエンと共に共沸させて真空中で濃縮した。EtOAc(200mL)および水を、その結果生じた残渣に加え、有機層を水およびブラインで洗浄し、MgSO4上で脱水し、真空中で濃縮して、表題化合物をオフホワイト色の固体(10g、90%)として得た。
1H NMR
(400 MHz, CDCl3): δ ppm 9.10 (d, 1H).
6−メトキシ−2−メチル−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)イソインドリン−1−オン
1,4−ジオキサン(15mL)中の5−クロロ−6−メトキシ−2−メチルイソインドリン−1−オン(調製例24、500mg、2.36mmol)、4,4,4’,4’,5,5,5’,5’−オクタメチル−2,2’−ビ(1,3,2−ジオキサボロラン)(780mg、3.07mmol)および酢酸カリウム(463mg、4.72mmol)の溶液を室温において窒素で脱気した。1時間後に、トリシクロヘキシルホスフィン(165mg、0.590mmol)およびトリス(ジベンジリデンアセトン)ジパラジウム(0)(108mg、0.150mmol)を順に加え、反応物を110℃に加熱した。18時間後に、反応物を室温に冷却し、溶液を、セライトを通して濾過し、酢酸エチル(3×50mL)で洗浄し、真空中で濃縮した。残渣を、ヘプタン中の20〜100%酢酸エチルで溶離するシリカゲルカラムクロマトグラフィーを使用して精製し、続いて、ヘプタン中の50%EtOAc中で摩砕して、表題化合物を無色の固体(93mg、13%)として得た。
1H NMR
(400 MHz, CDCl3): δ ppm 1.37 (s, 12H), 3.20
(s, 3H), 3.89 (s, 3H), 4.29 (s, 2H), 7.29 (s, 1H), 7.69 (s, 1H).
MS m/z 222 [M+H]+ ボロン酸.
5−クロロ−6−メトキシ−2−メチルイソインドール−1−オン
0℃のTHF(3mL)中の5−クロロ−6−メトキシイソインドリン−1−オン(調製例25、105mg、0.53mmol)の懸濁液に、NaH(オイル中の60%分散液、22mg、0.55mmol)を加え、反応物をこの温度で10分間にわたって、続いて、室温において10分間にわたって撹拌した。反応物を0℃に再び冷却し、ヨードメタン(38μL、0.61mmol)を加え、反応物を18時間にわたって室温に加温して撹拌した。反応物を、水(数滴)の添加によりクエンチし、EtOAc(40mL)および塩化アンモニウム水溶液(30mL)の間で分配した。有機層を収集し、Na2SO4上で脱水し、真空中で濃縮して、表題化合物をベージュ色の粉末(102mg、91%)として得た。
1H NMR
(400 MHz, CDCl3): δ ppm 3.19 (s, 3H), 3.96
(s, 3H), 4.30 (s, 2H), 7.37 (s, 1H), 7.45 (s, 1H).
MS m/z 212 [M35Cl+H]+
5−クロロ−6−メトキシイソインドリン−1−オン
メチル4−クロロ−2−シアノ−5−メトキシベンゾアート(調製例26、180mg、0.798mmol)を、穏やかに加熱することによりMeOH(20mL)およびEtOAc(5mL)に溶かした。880アンモニア水溶液(0.5mL)を加え、反応物をラネーニッケル(150mg)上、45psiで5時間にわたって水素化した。反応物を、セライトを通して濾過し、真空中で濃縮した。残渣をDCM中の0.5〜2%MeOHで溶離するシリカゲルカラムクロマトグラフィーを使用して精製して、表題化合物をオフホワイト色の粉末(105mg、67%)として得た。
1H NMR
(400 MHz, CDCl3): δ ppm 3.97 (s, 3H), 4.39
(s, 2H), 6.46 (br s, 1H), 7.40 (s, 1H), 7.50 (s, 1H).
MS m/z 198 [M35Cl+H]+
メチル4−クロロ−2−シアノ−5−メトキシベンゾアート
メチル2−ブロモ−4−クロロ−5−メトキシベンゾアート(調製例27、1.00g、3.58mmol)およびシアン化銅(0.39g、4.29mmol)をDMF(15mL)に溶かし、2時間にわたって150℃に加熱した。室温に冷却した後に、反応物をEtOAc(30mL)で希釈し、10分間にわたって撹拌した。その結果生じた懸濁液を濾過し、濾液を1M NaOH水溶液(2×50mL)、ブライン(50mL)で洗浄し、MgSO4上で脱水し、真空中で濃縮した。残渣を、ヘプタン中の20%EtOAcで溶離するシリカゲルカラムクロマトグラフィーを使用して精製し、続いて、EtOAc/ヘプタンから再結晶化させて、表題化合物を無色の固体(320mg、40%)として得た。
1H NMR
(400 MHz, CDCl3): δ ppm 4.01 (s, 6H), 7.64
(s, 1H), 7.77 (s, 1H).
メチル2−ブロモ−4−クロロ−5−メトキシベンゾアート
AcOH(10mL)および水(10mL)中のメチル4−クロロ−3−メトキシベンゾアート(調製例41、2.61g、13.0mmol)の懸濁液に、臭素(1mL、20mmol)を10分かけて滴下添加した。反応物を1時間にわたって60℃に加熱した。反応物を室温に冷却し、その結果生じた沈澱物を濾過し、水(2×20mL)で洗浄し、乾燥させて、表題化合物を黄色の固体(3.60g、99%)として得た。
1H NMR
(400 MHz, CDCl3): δ ppm 3.93 (s, 3H), 3.94
(s, 3H), 7.38 (s, 1H), 7.66 (s, 1H).
2’,6−ジフルオロ−N−メチル−5’−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ビフェニル−3−カルボキサミド
表題化合物を、調製例3について記載した方法に従って、5’−ブロモ−2’,6−ジフルオロ−N−メチルビフェニル−3−カルボキサミド(調製例40)を100℃において15時間にわたって使用して調製した。反応物を冷却し、水で希釈し、EtOAcで抽出した。有機層を収集し、水、ブラインで洗浄し、Na2SO4上で脱水し、真空中で濃縮した。残渣を、ヘキサン中の25〜30%EtOAcで溶離するシリカゲルカラムクロマトグラフィーを使用して精製して、表題化合物(4.89g、87%)を得た。
1H NMR
(400 MHz, CDCl3): δ ppm 1.33 (s, 12H), 3.00
(d, 3H), 4.11 (q, 1H), 7.13-7.25 (m, 2H), 7.77-7.85 (m, 4H).
メチル−3−メトキシ−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ベンゾアート
表題化合物を、調製例3について記載した方法に従って、メチル−4−ブロモ−3−メトキシベンゾアート(500mg、2.04mmol)を100℃において6時間にわたって使用して調製した。反応物を冷却し、真空中で濃縮し、残渣を、ヘプタン中の25〜50%EtOAcで溶離するシリカゲルカラムクロマトグラフィーを使用して精製して、無色のゴムを得た。
1H NMR
(400 MHz, CDCl3): δ ppm 1.34 (s, 12H), 3.88
(s, 3H), 3.92 (s, 3H), 7.50 (d, 1H), 7.58-7.61 (dd, 1H), 7.70 (d, 1H).
MS m/z 293 [M+H]+
2’−フルオロ−5’−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ビフェニル−4−カルボキサミド
表題化合物を、調製例3について記載した方法に従って、5’−ブロモ−2’−フルオロビフェニル−4−カルボキサミド(調製例39)をDMSO中、85℃において、マイクロ波照射下で、20分間にわたって使用して調製した。さらなるビスピナコラトジボロン(66mg、0.261mmol)、酢酸カリウム(41mg、0.41mmol)および[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)のジクロロメタンとの錯体(5mg、0.06mmol)を加え、反応を80℃において、マイクロ波照射下で10分間にわたって加熱して継続した。反応物を冷却し、真空中で濃縮し、ヘプタン中の0〜60%EtOAcで溶離するシリカゲルカラムクロマトグラフィーを使用して精製して、黄色の固体(170mg、81%)を得た。
1H NMR
(400 MHz, CDCl3): δ ppm 1.36 (s, 12H), 1.54-1.62
(m, 2H), 7.15-7.21 (m, 1H), 7.66-7.70 (m, 2H), 7.79-7.85 (m, 1H), 7.89 (m, 3H).
2−[3−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)フェニル]−2,3−ジヒドロ−1H−1,3−ジアザ−2−ボラフェナレン
表題化合物を、調製例3について記載した方法に従って、2−(3−ブロモフェニル)−2,3−ジヒドロ−1H−1,3−ジアザ−2−ボラフェナレン(調製例38)、トリシクロヘキシルホスフィンおよびビス(ジベンジリデンアセトン)ジパラジウムを還流において16時間にわたって使用して調製した。反応混合物を室温に冷却し、次いで、真空中で濃縮した。残渣を、5:1の石油エーテル:EtOAcで溶離するシリカゲルカラムクロマトグラフィーにより精製して、黄色の固体(16g、61%)を得た。
1H NMR
(400 MHz, CDCl3): δ ppm 1.37 (s, 12H), 6.12
(d, 2H), 6.43 (d, 2H), 7.04-7.16 (m, 4H), 7.41-7.42 (m, 1H), 7.72-7.77 (m, 1H),
7.89-7.90 (m, 1H), 8.09 (s, 1H).
6−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−2,3−ジヒドロ−1H−イソインドール−1−オン
MeOH(0.5L)中のメチル2−(アミノメチル)−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ベンゾアート(調製例33、45g、0.15mmol)の溶液を還流において3時間にわたって撹拌した。反応物を冷却し、真空中で濃縮し、残渣を水(2×50mL)およびメタノール(2×100mL)で洗浄して、表題化合物(35g、90%)を得た。
1H NMR
(400 MHz, DMSO-d6): δ ppm 1.31 (s, 12H),
4.40 (s, 2H), 7.60 (d, 1H), 7.88 (d, 1H), 7.93 (s, 1H), 8.59 (br s, 1H).
メチル2−(アミノメチル)−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ベンゾアート
MeOH(0.5L)中のメチル2−(ブロモメチル)−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ベンゾアート(調製例36、60g、0.17mmol)の懸濁液をアンモニアでパージした。反応が完了したら、混合物を真空中で濃縮した。残渣をEtOAc(300mL)で希釈し、ブライン(500mL)で洗浄し、真空中で濃縮して、表題化合物を茶色の固体(45g、91%)として得、これをそのまま、次のステップに入れた。
2−メチル−6−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−2,3−ジヒドロ−1H−イソインドール−1−オン
アセトニトリル(0.5L)中のメチル2−[(メチルアミノ)メチル]−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ベンゾアート(調製例35、40g、0.14mol)の溶液を2時間にわたって加熱還流した。反応物を冷却し、真空中で濃縮した。残渣をEtOAc(500mL)で希釈し、ブライン(2×100mL)で洗浄し、真空中で濃縮して、表題化合物を灰色の固体(35g、99%)として得た。
1H NMR
(400 MHz, CDCl3): δ ppm 1.35 (s, 12H), 3.20
(s, 3H), 4.38 (s, 2H), 7.42 (d, 1H), 7.90 (d, 1H), 8.30 (s, 1H).
MS m/z 274 [M+H]+
メチル2−[(メチルアミノ)メチル]−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ベンゾアート
MeOH(0.5L)中のメチル2−(ブロモメチル)−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ベンゾアート(調製例36、56g、0.16mol)の溶液に、メチルアミン(21g、0.6mol)を、続いて、トリエチルアミン(73g、0.68 mol)を加え、反応物を2時間にわたって加熱還流した。反応物を冷却し、真空中で濃縮した。残渣をEtOAc(1L)に入れ、濾過した。濾液を真空中で濃縮し、その結果生じた固体をエーテル(500mL)で洗浄して、表題化合物(40g、80%)を得、これをそのまま、次のステップに入れた。
メチル2−(ブロモメチル)−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ベンゾアート
四塩化炭素(1L)中のメチル2−メチル−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ベンゾアート(調製例37、60g、0.22mol)およびNBS(71g、0.40mol)の溶液に、過酸化ベンゾイル(5g)を加え、反応物を2時間にわたって80℃に加熱した。反応物を冷却し、濾過した。濾液を収集し、水で洗浄し、有機層をNa2SO4上で脱水し、真空中で濃縮して、表題化合物(56g、72%)を得、これをそのまま、次のステップに入れた。
メチル2−メチル−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ベンゾアート
DMF(800mL)中のメチル5−ヨード−2−メチルベンゾアート(調製例42、69g、0.25 mol)の溶液に、ビスピナコラトジボロン(100g、0.40mol)および酢酸カリウム(92g、0.93mol)を加え、続いて、窒素で脱気した。[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)のジクロロメタンとの錯体(6g)を加え、反応物を18時間にわたって100℃に加熱した。反応物を冷却し、セライトを通して濾過し、EtOAc(3×1L)で十分に洗浄した。濾液を合わせ、ブライン(3×500mL)で洗浄し、Na2SO4上で脱水し、真空中で濃縮した。残渣を石油エーテル(2×500mL)で洗浄し、濾過し、乾燥させて、表題化合物を黄色の粉末(60g、87%)として得、これをそのまま、次のステップに入れた。
2−(3−ブロモフェニル)−2,3−ジヒドロ−1H−1,3−ジアザ−2−ボラフェナレン
無水トルエン(600mL)中の3−ブロモベンゼンボロン酸(20g、0.1mol)およびナフタレン−1,8−ジアミン(17.3g、0.11mol)の溶液を、16時間にわたって加熱還流した。反応混合物を室温に冷却し、真空中で濃縮した。残渣を、5:1の石油エーテル:EtOAcで溶離するシリカゲルカラムクロマトグラフィーにより精製して、表題化合物を灰色の固体(23g、54%)として得た。
1H NMR
(400 MHz, CDCl3): δ ppm 5.91 (s, 2H), 6.35
(d, 2H), 7.00 (d, 2H), 7.06-7.09 (m, 2H), 7.24-7.26 (m, 1H), 7.47-7.55 (m, 2H),
7.69 (s, 1H).
5’−ブロモ−2’−フルオロビフェニル−4−カルボキサミド
ジオキサン(3.5mL)中の4−カルバモイルベンゼンボロン酸(204mg、1.2mmol)および1−フルオロ−2−ヨード−4−ブロモベンゼン(361mg、1.2mmol)の溶液に、[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)のジクロロメタンとの錯体(34mg、0.042mmol)を、続いて、水(1mL)中の炭酸ナトリウム(382mg)の溶液を加えた。反応物をマイクロ波照射下で20分間にわたって90℃に加熱した。反応物を冷却し、EtOAcで希釈し、硫酸ナトリウム上で脱水し、真空中で濃縮した。残渣を、ヘプタン中の0〜50%EtOAcで溶離するシリカゲルカラムクロマトグラフィーを使用して精製して、表題化合物をオフホワイト色の固体(180mg、51%)として得た。
1H NMR
(400 MHz, CDCl3): δ ppm 2.38 (s, 2H), 6.99
(m, 2H), 7.38 (m, 1H), 7.45-7.57 (m, 2H), 7.76-7.97 (m, 2H).
5’−ブロモ−2’,6−ジフルオロ−N−メチルビフェニル−3−カルボキサミド
ジオキサン(175mL)中の3−ブロモ−6−フルオロ−ヨードベンゼン(7.29g、36.5mmol)の溶液に、2−フルオロ−5−(メチルカルバモイル)ベンゼンボロン酸(10g、33.2mmol)を、続いて、水中の1M Na2CO3水溶液(166mL)を加えた。混合物を脱気し、その後、テトラキス(トリフェニルホスフィン)パラジウム(0)(1.92g、1.66mmol)を加えた。反応物を16時間にわたって110℃に加熱し、その後、冷却した。反応物を濾過し、真空中で濃縮し、ヘキサン中の60%EtOAcで溶離するシリカゲルカラムクロマトグラフィーを使用して精製して、表題化合物を得た。
1H NMR
(400 MHz, CDCl3): δ ppm 3.00 (s, 3H), 6.12
(br s, 1H), 7.06 (m, 1H), 7.23 (m, 1H), 7.50 (m, 2H), 7.79 (m, 2H).
MS m/z 326 [M79Br+H]+
メチル4−クロロ−3−メトキシベンゾアート
4−クロロ−3−メトキシ安息香酸(2.5g、13mmol)をメタノール(40mL)に溶かし、続いて、硫酸(0.3mL)を加え、48時間にわたって加熱還流した。反応物を冷却し、真空中で濃縮した。残渣をEtOAc(15mL)および水(15mL)の間で分配し、有機層を収集し、1M NaOH水溶液(15mL)で洗浄し、硫酸マグネシウム上で脱水し、真空中で濃縮して、表題化合物(2.61g、100%)を得た。
1H NMR
(400 MHz, CDCl3): δ ppm 3.86 (s, 3H), 3.89
(s, 3H), 7.34 (d, 1H), 7.48-7.52 (m, 2H).
メチル5−ヨード−2−メチルベンゾアート
MeOH(0.5L)中の5−ヨード−2−メチル安息香酸(86g、0.57mol)の溶液に、塩化チオニル(74g、0.62mol)を0℃において滴下添加し、添加の完了後に、反応物を2時間にわたって加熱還流した。反応物を冷却し、真空中で濃縮し、水で希釈し、EtOAc(2×300mL)に抽出した。有機層を合わせ、ブラインで洗浄し、Na2SO4上で脱水し、真空中で濃縮して、表題化合物を得、これをそのまま、次のステップに入れた(69g、73%)。
細胞系の構築および維持
ヒト胎児由来腎臓(HEK)細胞に、標準的な技法を使用してGABRA2−GABRB2−GABRG2構築物をトランスフェクトした。GABRA2−GABRB2−GABRG2構築物を安定発現する細胞を、ジェネテシンG−418(320μg/ml)、ハイグロマイシン(160μg/ml)およびゼオシン(40μg/ml)に対するそれらの耐性により同定した。クローンを、BD Pathway 855イメージングシステム(BD Biosciences、Rockville、MD、USA)およびQ Patch自動電気生理プラットフォーム(Sophion、Copenhagen、Denmark)を使用して、発現についてスクリーニングした。
GABRA2−GABRB2−GABRG2を安定的にトランスフェクトしたHEK細胞を、ジェネテシンG−418(320μg/ml)、ハイグロマイシン(160μg/ml)およびゼオシン(40μg/ml)と共にEarle塩、10%FBS、1×L−Glutamax、1% mM非必須アミノ酸(MEM)、および1mMピルビン酸ナトリウムを含むMEM培地中、インキュベーター内、37℃において、5%CO2の加湿雰囲気下で維持した。Q Patch電気生理試験のために、細胞を、酵素的解離によりフラスコから採取し、血清非含有培地に再懸濁させた。細胞を典型的には、分割後24〜72時間以内に、電気生理学的実験のために使用した。
被験化合物の親和性を、既知の化合物[3H]Ro−15−1788(フルマゼニル)(Perkin Elmer、85.4Ci/mmol)、ならびにアルファ2、ベータ2、およびガンマ3サブユニットを含有するヒト組換えGABA A受容体を使用して放射性リガンド競合結合アッセイにより決定した。
GABRA2−GABRB2−GABRG2を発現するHEK細胞を含有する細胞懸濁液を、血清非含有培地中で、Q Patch機器の細胞攪拌機内に設置した。この機器は、細胞外緩衝液を使用して細胞を一度洗浄し、次いで、それらを、3〜4000000/mlの濃度で、Q Plate HT測定プレートに分配した。細胞外溶液は、次の組成からなった:137mM NaCl、1.8mM CaCl2、4mM KCl、1mM MgCl2、10mMグルコース、および10mM HEPES、pH7.4、NaOH含有、300〜310mOsm/kg。Q Plate測定プレートの内側に、次の組成の細胞内溶液を充填した:90mM KCl、50mM KF、1mM MgCl2、10mM HEPES、11mM EGTA、および2mM Mg−ATP、pH7.35、KOH含有、295〜305mOsm/kg。記録はすべて、室温(22〜24℃)において取った。
[((モジュレーター電流振幅のピーク−漏れ)−(GABA電流振幅−漏れ))/(GABA電流振幅−漏れ)]×100
[式中、「漏れ」は、−60mVにおける漏れ電流であり、「モジュレーター電流振幅のピーク」は、ガンマ−アミノ酪酸および被験化合物の同時適用により誘発された電流であり、「GABA電流振幅」は、ガンマ−アミノ酪酸の単独適用により誘発された電流である]。
Claims (10)
- 式(I)による化合物
R1は、Hおよび(C1〜C3)アルキルから選択され、
R2は、Hおよび(C1〜C3)アルキルから選択され、かつR3は、Hであるか、または
R2およびR3は一緒に、−CH2−であり、
R4は、H、FおよびOCH3から選択され、
R5は、HおよびFから選択され、
R6は、(C2〜C4)アルキル、(C3〜C5)シクロアルキルおよびメチル置換(C3〜C5)シクロアルキルから選択され、
環Bは、環Aに3、4および5位のいずれか1つで結合しており;
R4は、環Aに2、3、4および5位のいずれか1つで結合しており、
ただし、R4および環Bの両方が、環Aに同じ位置で結合することはあり得ないことを条件とする]
または薬学的に許容できるその塩。 - R4がHおよびOCH3から選択される、請求項1から3のいずれか一項に記載の化合物、または薬学的に許容できるその塩。
- R5がFである、請求項1から4のいずれか一項に記載の化合物、または薬学的に許容できるその塩。
- 5−[5−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−2−フルオロ−フェニル]−6−メトキシ−2−メチル−2,3−ジヒドロ−イソインドール−1−オン、
5−[2−フルオロ−5−(7−イソプロピル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−フェニル]−2−メチル−2,3−ジヒドロ−イソインドール−1−オン、
5−[5−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−2−フルオロ−フェニル]−2−メチル−2,3−ジヒドロ−イソインドール−1−オン、
5’−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−2’−フルオロ−ビフェニル−3−カルボキサミド、
6−[5−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−2−フルオロ−フェニル]−2−メチル−2,3−ジヒドロ−イソインドール−1−オン、および
5’−(7−エチル−7H−イミダゾ[4,5−c]ピリダジン−4−イル)−5,2’−ジフルオロ−N−メチル−ビフェニル−3−カルボキサミド
から選択される化合物、または薬学的に許容できるその塩。 - 請求項1から6のいずれか一項に記載の化合物または薬学的に許容できるその塩と、薬学的に許容できる添加剤とを含む医薬組成物。
- 疼痛の処置のための、請求項7に記載の医薬組成物。
- 疼痛の処置のための医薬の製造における、請求項1から6のいずれか一項に記載の化合物または薬学的に許容できるその塩の使用。
- 請求項1から6のいずれか一項に記載の化合物または薬学的に許容できるその塩と、第2の薬学的活性薬剤とを含む医薬組成物。
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EP1838152A2 (en) * | 2005-01-21 | 2007-10-03 | Neurogen Corporation | Imidazolylmethyl and pyrazolylmethyl heteroaryl derivatives |
EP1995241B1 (en) | 2007-03-23 | 2010-03-17 | ICAgen, Inc. | Inhibitors of ion channels |
RS53941B1 (en) | 2009-01-12 | 2015-08-31 | Pfizer Limited | SULFONAMID DERIVATIVES |
SG175090A1 (en) | 2009-05-07 | 2011-11-28 | Astrazeneca Ab | Substituted 1-cyanoethylheterocyclylcarboxamide compounds 750 |
UA112028C2 (uk) * | 2012-12-14 | 2016-07-11 | Пфайзер Лімітед | Похідні імідазопіридазину як модулятори гамка-рецептора |
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2015
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- 2015-06-03 EP EP15730284.5A patent/EP3154979B1/en not_active Not-in-force
- 2015-06-03 US US15/316,552 patent/US9802945B2/en active Active
- 2015-06-03 JP JP2016572302A patent/JP6491679B2/ja active Active
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US9802945B2 (en) | 2017-10-31 |
EP3154979A1 (en) | 2017-04-19 |
WO2015189744A1 (en) | 2015-12-17 |
CA2951497A1 (en) | 2015-12-17 |
EP3154979B1 (en) | 2018-03-07 |
JP2017517538A (ja) | 2017-06-29 |
CA2951497C (en) | 2019-04-09 |
US20170197965A1 (en) | 2017-07-13 |
ES2664810T3 (es) | 2018-04-23 |
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