JP2016508505A - ピリダジノン−アミド誘導体 - Google Patents
ピリダジノン−アミド誘導体 Download PDFInfo
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- JP2016508505A JP2016508505A JP2015556421A JP2015556421A JP2016508505A JP 2016508505 A JP2016508505 A JP 2016508505A JP 2015556421 A JP2015556421 A JP 2015556421A JP 2015556421 A JP2015556421 A JP 2015556421A JP 2016508505 A JP2016508505 A JP 2016508505A
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Abstract
Description
キナーゼは、抗炎症薬の開発のための重要な治療標的であり(Cohen, 2009. Current Opinion in Cell Biology 21, 1-8)、例えば適応性の先天性免疫応答の編成に関与するキナーゼである。特に関心の集まるキナーゼ標的は、IRAKファミリーのメンバーである。
本発明の別の側面によれば、IRAKに関連する障害の処置および/または予防に適した、式(I)で表される化合物が提供される。
本発明の別の側面によれば、哺乳動物、特にヒトの疾患状態におけるIRAKの活性または機能を調節すること、特に阻害することができる、化合物が提供される。
本発明の別の側面によれば、以下から選択される障害の処置および/または予防のための方法が提供される:自己免疫、炎症性疾患、心血管疾患、神経変性疾患、細菌およびウイルス感染、アレルギー、喘息、膵炎、多臓器不全、腎疾患、血小板凝集、癌、移植、精子運動性、赤血球欠乏、移植片拒絶反応、肺損傷、呼吸器疾患および虚血状態。
本発明の別の側面によれば、少なくとも1種の式(I)の化合物を、好ましくは免疫調節剤と組み合わせて含む、キットまたはセットが提供される。
好ましくは、キットは、次の個別のパックから構成される:
(a)式(I)の化合物および/またはその薬学的に使用可能な誘導体または互変異性体、溶媒和物、塩、水和物および立体異性体、ならびに全ての比率でのそれらの混合物の有効量、および
(b)さらなる医薬活性成分の有効量。
本発明の別の側面によれば、式(I)および関連する式の化合物の合成方法が提供される。
一態様において、本発明は、式(I):
Zは、基
Xは、CHまたはNであり、
Yは、CHまたはNであり、
Ra、Rc、R1は、それぞれ独立してH、Hal、またはA1を表し、
Rbは、Hまたはアルキルであり、
A1は、1〜12個のC原子を有する分枝状もしくは直鎖状アルキルであり、ここで1または2以上、例えば1〜7個など、の水素原子は、Hal、ORb、COORb、CNまたはN(Rb)2により置き換えられていてもよく、ここで1または2以上の、好ましくは1から5のCH2基はO、CO、NRbまたはS、SO、SO2、1,2−、1,3−もしくは1,4−フェニレン、−CH=CH−または−C≡C−により置き換えられていてもよく、
および
Halは、F、Cl、Br、Iを表す、
で表される化合物、およびその薬学的に許容な誘導体、溶媒和物、互変異性体、塩、水和物および立体異性体、ならびに全ての比率でのそれらの混合物を提供する。
特記しない場合、アルキルは、1〜12個の炭素原子、好ましくは1〜8個の炭素原子、および最も好ましくは1〜6個の炭素原子を有する炭素鎖を表す。アルキルは非常に好ましくはメチルを、さらにエチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチルまたはtert−ブチル、さらにまたペンチル、1−、2−もしくは3−メチルブチル、1,1−、1,2−もしくは2,2−ジメチルプロピル、1−エチルプロピル、ヘキシル、1−、2−、3−もしくは4−メチルペンチル、1,1−、1,2−、1,3−、2,2−、2,3−、もしくは3,3−ジメチルブチル、1−もしくは2−エチルブチル、1−エチル−1−メチルプロピル、1−エチル−2−メチルプロピル、1,1,2−もしくは1,2,2−トリメチルプロピルを表す。
Oアルキル基は、好ましくはメトキシおよびエトキシを表す。
Raは、好ましくはH、Hal、ORdまたはアルキル、ここでRdは、H、アルキルもしくはCORbである。
R1は、好ましくはH、アルキル、Hal、Oアルキル、ORd、または(CH2)nCONHRbまたは(CH2)nCOORbであり、式中nは、0、1、2、3、4、5または6であり、Rbは上記で定義した通りであり、式中Rdは、H、アルキルまたはCORbである。
Rbは、好ましくはH、メチルまたはエチルである。
Zは、好ましくはピリジニルまたはピリミジニルを表す。
上記および下記の、全てのラジカルおよび指数は、明示的に別段の記載がない限り、一般構造式の下に示されている意味を有する。
一般に、式Iの化合物は、それらがより好ましい置換基を担持するほど、より好ましい。
式(I)の好ましい化合物No.1〜17を、それらの活性と共に以下に記す(IC50値は、実施例18に記載したIRAK1およびIRAK4酵素アッセイに従って得た)。
Ac(アセチル)、BINAP(2,2’−ビス(ジフェニルホスフィノ)−1,1’−ビナフタレン)、dba(ジベンジリデンアセトン)、Bu(ブチル)、tBu(tert−ブチル)、DCE(ジクロロエタン)、DCM(ジクロロメタン)、DIEA(ジイソプロピルエチルアミン)、DMA(ジメチルアセトアミド)、DMSO(ジメチルスルホキシド)、DMF(N,N−ジメチルホルムアミド)、Dppf(1,1’−ビス(ジフェニルホスフィンフェロセン))、EtOAc(酢酸エチル)、EtOH(エタノール)、g(グラム)、cHex(シクロヘキサン)、HATU(N−[(ジメチルアミノ)(3H−[1,2,3]トリアゾロ[4,5−b]ピリジン−3−イルオキシ)メチレン]−N−メチルメタンアミニウムヘキサフルオロホスフェート)、HBTU(N,N,N’,N’−テトラメチル−O−(1H−ベンゾトリアゾール−1−イル)ウロニウムヘキサフルオロホスフェート)、HPLC(高速液体クロマトグラフィー)、hr(時間)、LC(液体クロマトグラフィー)、LDA(リチウムジイソプロピルアミン)、LiHMDS(リチウムビス(トリメチルシリル)アミド)、MHz(メガヘルツ)、MeOH(メタノール)、min(分)、mL(ミリリットル)、mmol(ミリモル)、mM(ミリモーラー)、mp(融点)、MS(質量分析)、MW(マイクロ波)、NMM(N−メチルモルホリン)、NMP(N−メチルピロリジン)、NMR(核磁気共鳴)、O/N(一晩)、PBS(リン酸緩衝生理食塩水)、PPh3(トリフェニルホスフィン)、RT(室温)、TEA(トリエチルアミン)、TFA(トリフルオロ酢酸)、THF(テトラヒドロフラン)、TLC(薄層クロマトグラフィー)、oToL(オルト−トリル)、T3P(プロピルホスホン酸無水物)、UV(紫外線)。
式(I)の化合物は、一般式(II)のカルボン酸化合物のカップリングによって調製することができ、この式中、Aは、スキーム1に概説されるように、H、Li、NaまたはKおよびR1およびRbが上記で定義した通りである一般式(III)で表されるアミノベンゾイミダゾールである。かかる反応のための一般的なプロトコルは、当業者に周知の条件および方法を用いて、実施例において以下に示す。標準的なカップリング剤、例えばHBTU、EDC、T3Pまたはクロロギ酸イソブチルなどを、DMF、アセトニトリル、THFまたはDCMなどの適切な溶媒中、HOBtなどの添加剤およびDIEA、TEAまたはNMMなどの塩基の存在下または不在下で、約0℃から50℃の上昇温度で、使用することができる。代替的に、カルボン酸誘導体(例えば、塩化アシル)を、当業者に周知の条件および方法を用いて、トルエン、DCM、THFまたはDMFなどの適切な溶媒中で、ピリジンまたはDIEAなどの塩基の存在下で、約0℃からRTまでの上昇温度で、好ましくはRTで、数時間反応させることができる。
酸性中心を含有する式(I)の化合物の薬学的に許容し得るカチオン塩は、従来の方法で調製することができる。例えば、遊離酸の溶液を、適切な塩基で、ニートまたは適切な溶液のいずれかで処理して、得られた塩を、濾過または真空下で反応溶媒を蒸発させて単離することができる。いくつかのケースにおいて、塩は、酸の溶液を、アルカリまたはアルカリ土類塩の溶液(例えばエチルヘキサン酸ナトリウム、オレイン酸マグネシウム)と、式(I)の化合物の所望のアルカリまたはアルカリ土類塩が沈殿する溶媒を用いて混合することにより調製可能であり、または濃縮および非溶剤の添加によって単離することができる。
使用条件に応じて、反応時間は一般に数分から14日の間である。反応温度は、約−30℃〜約140℃の間、通常は−10℃〜90℃の間、特に約0℃〜70℃の間である。式(I)および関連する式はまた、これらの化合物の光学的に活性な形態(立体異性体)、鏡像異性体、ラセミ体、ジアステレオマーおよび水和物および溶媒和物を包含する。用語「化合物の溶媒和物」とは、それらの相互の引力により形成される、不活性溶媒分子の化合物への付加を意味する。溶媒和物は、例えば一もしくは二水和物またはアルコラートである。
用語「薬学的に許容し得る誘導体」とは、例えば、式Iの化合物の塩および、いわゆるプロドラッグ化合物を意味する。
式(I)および関連する式は、式Iの化合物の混合物も含み、例えば、2つのジアステレオマーの、例えば、1:1、1:2、1:3、1:4、1:5、1:10、1:100または1:1000の比率での混合物である。
これらは特に好ましくは、立体異性体化合物の混合物である。
医薬製剤は、投与単位あたり所定量の活性成分を含む投与単位の形態で投与することができる。かかる単位は、処置する疾患の状態、投与方法、患者の年齢、体重および状態に応じて、例えば0.5mg〜1gの、好ましくは1mg〜700mgの、特に好ましくは5mg〜100mgの、本発明の化合物を含むことができ、または医薬製剤は、投与単位あたり所定量の活性成分を含む投与単位の形態で投与することができる。好ましい投与単位製剤は、上述したように、日用量または部分用量を、または活性成分の対応するその画分を含むものである。さらに、この種類の医薬製剤は、医薬分野で一般的に知られている方法を用いて調製することができる。
経口投与に適した医薬製剤は、個別の単位として、例えば、カプセルまたは錠剤;粉剤または顆粒剤;水性または非水性液体中の液剤または懸濁剤;食用発泡体もしくは発泡体食品;または水中油型液体エマルジョンまたは油中水型液体エマルジョンとして、投与することができる。
カプセル剤は、上記のように粉末混合物を調製し、成形したゼラチン殻にこれを充填することにより製造される。滑剤および潤滑剤、例えば高度に分散した固体形態のケイ酸、タルク、ステアリン酸マグネシウム、ステアリン酸カルシウムまたはポリエチレングリコールを、充填操作の前に粉末混合物に添加することができる。崩壊剤または可溶化剤、例えば寒天、炭酸カルシウムまたは炭酸ナトリウムも、同様に、カプセルが摂取された後の医薬の有効性を改善するために、添加することができる。
経口投与用の投与単位製剤は、所望に応じて、マイクロカプセルに封入することができる。製剤はまた、例えば、コーティングまたはポリマー、ワックス等に粒子状物質を埋め込むことにより、放出を延長または遅延するように調製することもできる。
式(I)および関連式の化合物、およびそれらの塩、溶媒和物および生理学的に機能的な誘導体、ならびに他の活性成分はまた、モノクローナル抗体を本発明の化合物分子が結合した個別の担体として用いて、送達することができる。化合物はまた、標的薬物担体としての可溶性ポリマーに結合させることができる。かかるポリマーとしては、パルミトイル基で置換された、ポリビニルピロリドン、ピランコポリマー、ポリヒドロキシプロピル−メタクリルアミドフェノール、ポリヒドロキシエチルアスパルタミド−フェノールまたはポリエチレンオキシドポリリジンを包含することができる。化合物はさらに、医薬の制御放出を達成するのに適した生分解性ポリマーのクラスに結合することができ、例えば、ポリ乳酸、ポリ−イプシロン−カプロラクトン、ポリヒドロキシ酪酸、ポリ−オルトエステル、ポリアセタール、ポリジヒドロキシピラン、ポリシアノアクリレート、およびヒドロゲルの架橋性または両親媒性ブロックコポリマーである。
局所投与に適合された医薬化合物は、軟膏、クリーム剤、懸濁液、ローション剤、粉剤、液剤、ペースト剤、ゲル剤、スプレー剤、エアロゾル剤または油剤として製剤化することができる。
眼または他の外部組織、例えば口および皮膚の処置のために、製剤は、好ましくは局所的軟膏またはクリーム剤として適用する。軟膏を与える製剤の場合、活性成分は、パラフィン系または水混和性クリーム基剤のいずれかと共に使用することができる。代替的に、活性成分は、水中油型クリーム基剤または油中水型基剤を有するクリーム剤を得るよう、製剤化することができる。
口中への局所適用に適合された医薬品製剤としては、トローチ剤、パステル剤およびうがい薬が含まれる。
直腸投与に適合された医薬製剤は、坐剤または浣腸剤の形態で投与することができる。
担体物質が固体である、経鼻投与に適した医薬製剤は、例えば20〜500ミクロンの範囲の粒径を有する粗粉末を含み、これは、鼻呼吸の様式で、すなわち、鼻の近くに保持された粉末を含む容器から、鼻道を経由した迅速な吸入により、投与される。液体を担体とした鼻スプレーまたは点鼻剤としての投与に適した製剤は、水または油中の活性成分溶液を含む。
膣内投与に適合された医薬製剤は、ペッサリー、タンポン、クリーム剤、ゲル剤、パスタ剤、フォーム(foams)またはスプレー製剤として投与することができる。
非経口投与に適合された医薬製剤は、以下を含む:抗酸化剤、緩衝剤、静菌剤および溶質を含む水性および非水性滅菌注射溶液、これにより、製剤は、処置されるべきレシピエントの血液と等張にされる;懸濁媒体および増粘剤を含み得る、水性および非水性滅菌懸濁液。製剤は単一用量または複数用量容器中、例えば、密封アンプルおよびバイアルで投与され、およびフリーズドライ(凍結乾燥)状態で保存されて、注射のためには、例えば水などの無菌の担体液体の添加のみが、使用する直前に必要である。処方箋に従って調製される注射溶液および懸濁液は、滅菌粉末、顆粒および錠剤から調製することができる。
式(I)および関連式の化合物、および他の活性成分の治療有効量は、動物の年齢および体重、処置を必要とする正確な疾患状態およびその重症度、製剤の性質および投与の方法を含む、多数の要因に依存し、これは最終的には治療する医師または獣医師により決定される。しかし、化合物の有効量は一般に、1日当たり0.1〜100mg/レシピエント(哺乳動物)体重1kgの範囲であり、特に典型的には、1日当たり1〜10mg/体重kgである。したがって、体重70kgの成体哺乳動物に対する1日当たりの実際量は、通常70〜700mgの間であり、ここでこの量は、1日あたりの個別の用量として、または通常1日当たりの一連の部分用量(例えば2、3、4、5または6回)として投与することができ、したがって総日用量は同一である。塩または溶媒和物またはこれらの生理学的に機能的な誘導体の有効量は、その化合物自体の有効量の小部分として決定することができる。
式(I)および関連式の好ましい化合物は、IRAKへの結合のIC50として、約5μM未満、好ましくは約1μM未満、およびさらにより好ましくは約0.100μM未満の値を示す。
以下では、本発明を実施例を用いて説明するが、これら実施例は、本発明の範囲を限定するものと見なすとは解釈されない。
一般:
以下の実施例において提供されるHPLCデータは、次のようにして得た。
Method A:カラムWaters Xbridge(登録商標)C8 50mm×4.6mm、流量2mL/分;8分の勾配 H2O:CH3CN:TFAを100:0:0.1%から0:100:0.05%まで。
UV検出:最大プロットまたは指定された波長。
以下の実施例において提供されるLC/MSデータは、次のようにして得た。
Method A:カラムWaters Xbridge(登録商標)C8 50mm×4.6mm、流量2mL/分;8分の勾配 H2O:CH3CN:TFAを100:0:0.1%から0:100:0.05%まで。
Method B:カラムWaters Xbridge(登録商標)C8 50mm×4.6mm、流量1mL/分;8分の勾配 H2O:CH3CN:NH4HCO3を100:0:0.1%から0:100:0.05%まで。
UV検出:最大プロットまたは指定された波長。
後述する実施例において提供されるNMRデータは、Bruker AV−400MHzを用いて得た。
本発明の化合物は、プログラムAutonomで使用される標準に従って命名されている。
式(I)の化合物は、容易に入手可能な出発物質から、いくつかの合成アプローチにより、溶液相および固相の化学プロトコルまたは混合溶液と固相のプロトコルの両方を使用して、調製することができる。合成経路の例は、実施例に説明されている。特に明記しない限り、ラセミ混合物として得られる式(I)および関連式の化合物を分離して、鏡像異性的に富化された混合物または純粋な鏡像異性体を提供することができる。別に報告がない限り、以下の実験の説明で使用される市販の出発物質は、AldrichまたはSigmaまたはABCRから購入した。
ステップ1:3−(6−オキソ−3−ピリジン−3−イル−6H−ピリダジン−1−イルメチル)安息香酸メチルエステルの形成
ステップ1:2−(ベンゾ[c][1,2,5]チアジアゾール−5−イル)−N,N−ジメチルアセトアミドの形成
ステップ1:3−[3−(6−ヒドロキシメチル−ピリジン−3−イル)−6−オキソ−6H−ピリダジン−1−イルメチル]−安息香酸メチルエステルの形成
ステップ1:3−(4−メチル−6−オキソ−3−ピリジン−3−イル−6H−ピリダジン−1−イルメチル)−安息香酸メチルエステルの形成
LC/MS: (Method A) 181.0 (M-82, boronic acid), RT. 0.42 min, 97.09% (Max).
IRAK1酵素アッセイ:
IRAK1は、ヒトの精製組換え酵素である(His−TEV−IRAK1 (194−712))。このアッセイにおいて、IRAK−1はATPを加水分解し、自己リン酸化する。
IRAK−1阻害の測定は、ストレプトアビジンを被覆した384ウェルのFlashPlate(PerkinElmer #SMP410A)で実施する。
DMSO(20μM〜1nMの濃度範囲)中の、His−TEV−IRAK1(15ng/ウェル)、ATP(1μM、[33P]ATP 0.25μCi/ウェル)および化合物、または対照(2%DMSO)を、アッセイ緩衝液(HepespH7.0、50mM、脂肪酸フリーのBSA0.1%、ジチオスレイトールDTT2mM、MgCl2 10mM、EGTA0.5mM、Triton-X-100 0.01%)中で、30℃で3時間インキュベートする。キナーゼ反応はEDTAの添加により停止させる。上清を廃棄し、プレートを150mMのNaClで3回洗浄し、次に放射活性をMicrobeta Triluxリーダーで測定する。
IRAK4は、ヒトの精製組換え酵素である(His−TEV−IRAK1(194−712))。IRAK4はATPを加水分解し、自己リン酸化し、セリン/スレオニン一般的ペプチド基質をリン酸化する(STK: 61ST1BLC、CisBio Internationalより、based in Bagnols/Ceze FR)。
IRAK−4阻害の測定は、ストレプトアビジンを被覆した384ウェルのFlashPlate(PerkinElmer #SMP410A)で実施する。DMSO(20μM〜1nMの濃度範囲)中の、His−TEV−IRAK4(20ng/ウェル)、ATP(2μM、[33P]ATP 0.25μCi/ウェル)、STK1−ビオチンペプチド(300nM)および化合物、または対照(2%DMSO)を、アッセイ緩衝液(HepespH7.0、50mM、脂肪酸フリーのBSA0.1%、ジチオスレイトールDTT2mM、MgCl2 10mM、EGTA0.5mM、Tween-20 0.01%、MnCl2 5mM)中で、30℃で3時間インキュベートする。
キナーゼ反応はEDTAの添加により停止させる。上清を廃棄し、プレートを150mMのNaClで3回洗浄し、次に放射活性をMicrobeta Triluxリーダーで測定する。
製剤1―錠剤
式(I)の化合物を乾燥粉末として、乾燥ゼラチン結合剤と約1:2の重量比で混合する。少量のステアリン酸マグネシウムを滑沢剤として添加する。この混合物を、錠剤プレスで240〜270mgの錠剤に形成する(錠剤当たり本発明の活性化合物80〜90mg)。
製剤2―カプセル剤
式(I)の化合物を乾燥粉末として、澱粉希釈剤と約1:1の重量比で混合する。混合物を250mgのカプセルに充填する(カプセル当たり本発明の活性化合物125mg)。
式(I)の化合物(1250mg)、スクロース(1.75g)およびキサンタンガム(4mg)を配合し、メッシュNo.10のU.S.篩に通し、微結晶性セルロースとナトリウムカルボキシメチルセルロース(11:89、50mg)の予め調製した水溶液と混合する。安息香酸ナトリウム(10mg)、香料、および着色剤を水で希釈し、撹拌しながら添加する。次いで十分な水を添加して、5mLの総容積を生成する。
製剤4―錠剤
式(I)の化合物を乾燥粉末として、乾燥ゼラチン結合剤と約1:2の重量比で混合する。少量のステアリン酸マグネシウムを滑沢剤として添加する。この混合物を、錠剤プレスで450〜900mgの錠剤に形成する(本発明の活性化合物150〜300mg)。
製剤5―注射剤
式(I)の化合物を、緩衝化無菌食塩水の注射可能な水性媒体中に、約5mg/mlの濃度で溶解する。
Claims (15)
- 式(I):
Zは、基
Xは、CHまたはNであり、
Yは、CHまたはNであり、
Ra、Rc、R1は、それぞれ独立してH、Hal、またはA1を表し、
Rbは、Hまたはアルキルであり、
A1は、1〜12個のC原子を有する分枝状もしくは直鎖状アルキルであり、ここで1または2以上、例えば1〜7個などの水素原子は、Hal、ORb、COORb、CNまたはN(Rb)2により置き換えられていてもよく、ここで1または2以上の、好ましくは1から5のCH2基はO、CO、NRbまたはS、SO、SO2、1,2−、1,3−もしくは1,4−フェニレン、−CH=CH−または−C≡C−により置き換えられていてもよく、
および
Halは、F、Cl、Br、Iを表す、
で表される化合物、またはその薬学的に許容な誘導体、溶媒和物、互変異性体、塩、水和物または立体異性体、または全ての比率でのそれらの混合物。 - Raが、Hal、ORdまたはアルキルであり、ここでRdがH、アルキルまたはCOHもしくはCOアルキルである請求項1に記載の式(I)で表される化合物。
- R1が、H、アルキル、Hal、Oアルキル、ORd、または(CH2)nCONHRbもしくは(CH2)nCOORbを表し、ここでnは、0、1、2、3、4、5、または6であり、およびRbは、上記で定義した通りであり、ここでRdが、H、アルキルまたはCORbである、請求項1または2に記載の式(I)で表される化合物。
- Zが、ピリジニルまたはピリミジニルである請求項1〜3のいずれか一項に記載の式(I)で表される化合物。
- 以下の群から選択される、式(I)で表される化合物:
- 医薬として使用するための、請求項1〜5のいずれか一項に記載の式(I)で表される化合物、またはその薬学的に許容な誘導体、溶媒和物、互変異生体、塩、水和物または立体異性体、または全ての比率でのそれらの混合物。
- 炎症性疾患、自己免疫疾患、癌、または多発性硬化症および関連疾患の、処置または予防における使用のための、請求項6に記載の化合物。
- 自己免疫疾患が以下からなる群から選択される、請求項7に記載の化合物:喘息、関節リウマチ、急性散在性脳脊髄炎(ADEM)、アジソン病、円形脱毛症、強直性脊椎炎、抗リン脂質抗体症候群(APS)、自己免疫性溶血性貧血、自己免疫性肝炎、自己免疫性内耳疾患、水疱性類天疱瘡、ベーチェット病、セリアック病、抗トランスグルタミナーゼ、シャーガス病、慢性閉塞性肺疾患、クローン病、皮膚筋炎、1型糖尿病、子宮内膜症、グッドパスチャー症候群、グレーブス病、ギラン・バレー症候群(GBS)、橋本病、汗腺膿瘍、川崎病、IgA腎症、特発性血小板減少性紫斑病、間質性膀胱炎、エリテマトーデス、混合性結合組織病、限局性強皮症、多発性硬化症(MS)、重症筋無力症、ナルコレプシー、神経ミオトニー、尋常性天疱瘡、悪性貧血、乾癬、乾癬性関節炎、多発性筋炎、原発性胆汁性肝硬変、関節リウマチ、統合失調症、強皮症、シェーグレン症候群、スティッフパーソン症候群、全身性硬化症、側頭動脈炎、潰瘍性大腸炎、血管炎、白斑、ウェゲナー肉芽腫症。
- 疾患が以下からなる群から選択される、請求項7に記載の化合物:関節リウマチ、乾癬性関節炎、変形性関節症、全身性エリテマトーデス、ループス腎炎、強直性脊椎炎、骨粗鬆症、全身性硬化症、多発性硬化症、乾癬、I型糖尿病、II型糖尿病、炎症性腸疾患(クローン病および潰瘍性大腸炎)、高免疫グロブリン血症Dおよび自己炎症症候群、クリオピリン関連周期性症候群、シュニッツラー症候群、全身性若年性特発性関節炎、成人発症スティル病、痛風、偽痛風、SAPHO症候群、キャッスルマン病、敗血症、脳卒中、アテローム性動脈硬化症、セリアック病、DIRA(IL−1受容体アンタゴニスト欠損症)、アルツハイマー病、パーキンソン病、癌。
- 疾患が、関節リウマチ、ループス腎炎、全身性エリテマトーデスから選択される、請求項6に記載の化合物。
- IRAKの過剰発現に関連する疾患の予防および/または処置のための、請求項1に記載の式(I)で表される化合物。
- 次の個別のパックからなるキット:
(a)式(I)の化合物、および/またはその薬学的に使用可能な誘導体、溶媒和物、塩、水和物および立体異性体、ならびに全ての比率でのそれらの混合物の、有効量、および
(b)さらなる医薬活性成分の有効量。 - 請求項1〜5のいずれか一項に記載の式(I)で表される化合物、および/またはその薬学的に使用可能な誘導体、溶媒和物、塩および立体異性体、ならびに全ての比率でのそれらの混合物、の少なくとも1種を含む医薬組成物。
- 炎症性疾患または免疫疾患の処置に使用される少なくとも1種のさらなる医薬を追加して含む、請求項13に記載の医薬組成物。
- 少なくとも1種のさらなる免疫調節剤を追加して含む、請求項14に記載の医薬組成物。
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- 2014-02-06 WO PCT/EP2014/000316 patent/WO2014121931A1/en active Application Filing
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- 2014-02-06 CA CA2900431A patent/CA2900431C/en not_active Expired - Fee Related
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JP2022506687A (ja) * | 2018-11-06 | 2022-01-17 | エッジワイズ セラピューティクス, インコーポレイテッド | ピリダジノン化合物およびその使用 |
JP7162132B2 (ja) | 2018-11-06 | 2022-10-27 | エッジワイズ セラピューティクス, インコーポレイテッド | ピリダジノン化合物およびその使用 |
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US9567320B2 (en) | 2017-02-14 |
KR20150118981A (ko) | 2015-10-23 |
ES2634627T3 (es) | 2017-09-28 |
WO2014121931A1 (en) | 2014-08-14 |
CA2900431A1 (en) | 2014-08-14 |
PT2953944T (pt) | 2017-08-01 |
IL240290B (en) | 2019-06-30 |
SI2953944T1 (sl) | 2017-08-31 |
HUE032863T2 (en) | 2017-11-28 |
HRP20171076T1 (hr) | 2017-10-06 |
AU2014214321A1 (en) | 2015-09-17 |
EP2953944B1 (en) | 2017-04-26 |
US20150376167A1 (en) | 2015-12-31 |
RU2666899C2 (ru) | 2018-09-13 |
JP6483624B2 (ja) | 2019-03-13 |
KR102293952B1 (ko) | 2021-08-26 |
SG11201506100XA (en) | 2015-09-29 |
MX364486B (es) | 2019-04-29 |
RU2015137757A (ru) | 2017-03-13 |
IL240290A0 (en) | 2015-09-24 |
CN104968658B (zh) | 2017-08-01 |
BR112015018663A2 (pt) | 2017-07-18 |
RS56331B1 (sr) | 2017-12-29 |
US20170071936A1 (en) | 2017-03-16 |
HK1215708A1 (zh) | 2016-09-09 |
CN104968658A (zh) | 2015-10-07 |
EP2953944A1 (en) | 2015-12-16 |
LT2953944T (lt) | 2017-07-10 |
DK2953944T3 (en) | 2017-07-10 |
AU2014214321B2 (en) | 2018-04-19 |
MX2015010125A (es) | 2016-04-25 |
CA2900431C (en) | 2021-05-04 |
PL2953944T3 (pl) | 2017-09-29 |
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