JP2021512163A - (1−(3−フルオロ−2(トリフルオロメチル)イソニコチニル)ピぺリジン―4−オン)を作製するためのプロセス及び中間体 - Google Patents
(1−(3−フルオロ−2(トリフルオロメチル)イソニコチニル)ピぺリジン―4−オン)を作製するためのプロセス及び中間体 Download PDFInfo
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- 238000001356 surgical procedure Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000004489 tear production Effects 0.000 description 1
- JBOTYFLJTLOKTI-UHFFFAOYSA-N tert-butyl 3-(cyanomethyl)-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC1(CC#N)N1N=CC(C=2C=3C=CNC=3N=CN=2)=C1 JBOTYFLJTLOKTI-UHFFFAOYSA-N 0.000 description 1
- 229950011008 tetrachloroethylene Drugs 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 108091006106 transcriptional activators Proteins 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
Description
式中、Z1はHまたは保護基である。
本発明は、とりわけ、式Iの化合物を作製するためのプロセス及び中間体を提供する。したがって、一態様において、式IIIの化合物:
式中、Z1はHまたは保護基である。
式中、Z1はHまたは保護基である。
式Iの化合物である{1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリルは、JAK(例えばJAK1、JAK2)の阻害物質である。JAK阻害物質は、様々なJAK関連の疾患または障害の治療において有用である。JAK関連疾患の例としては、例えば移植臓器拒絶(例えば同種異系移植片拒絶及び移植片対宿主病)を包含する、免疫系に関与する疾患が挙げられる。JAK関連疾患のさらなる例としては、多発性硬化症、関節リウマチ、若年性関節炎、乾癬性関節炎、1型糖尿病、狼瘡、乾癬、炎症性大腸疾患、潰瘍性大腸炎、クローン病、重症筋無力症、免疫グロブリンA腎症、心筋炎、自己免疫性甲状腺疾患、慢性閉塞性肺疾患(COPD)、及び同種のもの等の自己免疫疾患が挙げられる。いくつかの実施形態において、自己免疫疾患は、尋常性天疱瘡(PV)または水疱性類天疱瘡(BP)等の自己免疫性水疱性皮膚障害である。
スキームI
スキームII
スキームIII
スキームIV
スキームV
スキームVI
スキームVII
スキームVIII
スキームIX
式Iの化合物を、Park et al.,Analytical Biochemistry 1999,269,94−104中で記載される以下のインビトロアッセイに従って、JAK標的の阻害活性について試験した。N末端Hisタグを備えたヒトJAK1(アミノ酸837〜1142)及びJAK2(アミノ酸828〜1132)の触媒ドメインを、昆虫細胞中でバキュロウイルスを使用して発現させ、精製した。JAK1及びJAK2の触媒活性を、ビオチン化ペプチドのリン酸化の測定によってアッセイした。リン酸化ペプチドを均一系時間分解蛍光(HTRF)によって検出した。100mMのNaCl、5mMのDTT及び0.1mg/mL(0.01%)のBSAを含む50mMのトリス(pH7.8)バッファー中の、酵素、ATP及び500nMのペプチドを含む40μLの反応物において、各々のキナーゼについて化合物のIC50を測定した。1mMのIC50測定について、反応中のATP濃度は1mMであった。反応を室温で1時間実行し、次いで20μLのアッセイバッファー(Perkin Elmer、Boston、MA)中の、45mMのEDTA、300nMのSA−APC、6nMのEu−Py20により停止した。ユウロピウム標識抗体への結合を40分間行い、HTRFシグナルをFusionプレートリーダー(Perkin Elmer、Boston、MA)上で測定した。式Iの化合物及びアジピン酸塩は≦5nMのJAK1でIC50を有し(1mMのATPで測定した)、>10のJAK2/JAK1比であった(1mMのATPで測定した)。
増殖についてサイトカイン及びしたがってJAK/STATシグナル形質導入に依存する癌細胞株は、RPMI 1640、10%のFBS、及び1nG/mLの適切なサイトカイン中で1ウェル(96ウェルプレートフォーマット)あたり6000細胞でプレーティングすることができる。化合物をDMSO/培地(0.2%のDMSOの最終濃度)中で細胞へ添加し、37℃、5%のCO2で72時間インキュベーションすることができる。細胞生存率に対する化合物の効果を、CellTiter−Glo Luminescent Cell Viability Assay(Promega)、続いてTopCount(Perkin Elmer、Boston、MA)の定量を使用して査定する。化合物の可能性のあるオフターゲット効果を、非JAK駆動性の細胞株を使用して、同じアッセイのリードアウトにより並列して測定する。すべての実験を典型的には二重で遂行する。
本明細書における化合物は、免疫不全マウス中のヒト腫瘍異種移植モデルにおいて評価することができる。例えば、INA−6形質細胞腫細胞株の腫瘍形成性バリアントを使用して、SCIDマウスに皮下接種することができる(Burger,R.,et al.Hematol J.2:42−53,2001)。次いで担がん動物を薬物処置群またはベヒクル処置群へと無作為化し、異なる用量の化合物を、経口、腹腔内、または植込み可能なポンプを使用する連続点滴を含む、いくつかの通常の経路によって投与することができる。腫瘍増殖を、キャリパーを使用して経時的に追跡する。さらに、上で記載されるような分析(実施例B)のために、腫瘍サンプルを処理の開始後の任意の時間で収穫して、JAK活性及び下流のシグナル経路に対する化合物効果を評価することができる。加えて、化合物(複数可)の選択性を、他の公知のキナーゼ(例えばBcr−Abl)によって駆動される、K562腫瘍モデル等の異種移植腫瘍モデルを使用して査定することができる。
本明細書における化合物を、T細胞駆動性のマウスの遅延型過敏性の試験モデルにおける(JAK標的の阻害の)有効性についても試験することができる。マウスの皮膚接触遅延型過敏性(DTH)応答は、臨床的な接触性皮膚炎、及び乾癬等の他のTリンパ球媒介性の皮膚の免疫障害の有効なモデルであるとみなされている(Immunol Today.1998 Jan;19(1):37−44)。マウスのDTHは、免疫浸潤、炎症性サイトカインの付随する増加、及びケラチノサイト過剰増殖を含む、複数の特徴を乾癬と共有している。さらに、クリニックでの乾癬の治療において有効な多くのクラスの薬剤が、マウスにおけるDTH応答の有効な阻害物質でもある(Agents Actions.1993 Jan;38(1−2):116−21)。
本明細書における化合物は、単一または複雑な炎症応答を再現するように設計された齧歯動物モデルまたは非齧歯動物モデルにおいて評価することができる。例えば、関節炎の齧歯類モデルを使用して、予防的にまたは治療的に投薬した化合物の処置可能性を評価することができる。これらのモデルとしては、マウスまたはラットのコラーゲン誘発関節炎、ラットのアジュバント誘発関節炎、及びコラーゲン抗体誘発関節炎が挙げられるがこれらに限定されない。多発性硬化症、1型糖尿病、ぶどう膜網膜炎、甲状腺炎、重症筋無力症、免疫グロブリン腎症、心筋炎、気道感作(喘息)、狼瘡または大腸炎が挙げられるがこれらに限定されない自己免疫疾患を使用して、本明細書における化合物の治療可能性を評価することができる。これらのモデルは研究コミュニティーにおいて十分に確立されており、当業者は精通している(Current Protocols in Immunology,Vol 3.,Coligan,J.E.et al,Wiley Press.、Methods in Molecular Biology:Vol.225,Inflammation Protocols.,Winyard,P.G.and Willoughby,D.A.,Humana Press,2003.)。
薬剤は、ウサギのコンカナバリンA(ConA)涙腺モデル、マウスのスコポラミンモデル(皮下または経皮)、マウスのBotulinumn涙腺モデル、または眼腺機能不全をもたらすいくつかの自然発生する齧歯類自己免疫モデル(例えばNOD−SCID、MRL/lprまたはNZB/NZW)のいずれかが挙げられるがこれらに限定されない、1つまたは複数の当業者に公知のドライアイの前臨床モデルにおいて評価することができる(Barabino et al.,Experimental Eye Research 2004,79,613−621及びSchrader et al.,Developmental Opthalmology,Karger 2008,41,298−312、その各々の全体は参照により本明細書に援用される)。これらのモデルにおけるエンドポイントとしては、眼腺及び眼(角膜など)の組織病理学、ならびに場合によっては涙液産生を測定する古典的Schirmer試験またはその修飾バージョン(Barabino et al.)が挙げられ得る。活性は、複数の投与経路(例えば全身的または局所的)を経由して投薬することによって査定することができ、それは測定可能な疾患が存在する前またはその後に開始することができる。
化合物は、骨減少症、骨粗鬆症、または当業者に公知の骨吸収の様々な前臨床モデルにおいて評価することができる。例えば、卵巣切除歯動物を使用して、化合物が骨の再形成及び/または密度の徴候及びマーカーに影響する能力を評価することができる(W.S.S.Jee and W.Yao,J Musculoskel.Nueron.Interact.,2001,1(3),193−207、その全体は参照により本明細書に援用される)。あるいは、骨の密度及び構造を、コントロールまたは化合物により処置した、治療(例えばグルココルチコイド)誘発骨減少症のモデルにおける齧歯動物で評価することができる(Yao,et al.Arthritis and Rheumatism,2008,58(6),3485−3497、及び同上58(11),1674−1686、その両方の全体は参照することによって本明細書に援用される)。加えて、骨の吸収及び密度に対する化合物の効果は、上で考察された関節炎の齧歯類のモデル(実施例E)において評価することができる。これらのすべてのモデルについてのエンドポイントは、変化し得るが、多くの場合、組織学的査定及び放射線学的査定に加えて、骨再形成の免疫組織学及び適切な生化学的マーカーを含み得る。
Claims (44)
- 前記4−ヒドロキシピペリジンとの反応が、塩基の存在下において遂行される、請求項1に記載のプロセス。
- 前記塩基が第三級アミンである、請求項2に記載のプロセス。
- 前記第三級アミンがN,N−ジイソプロピルエチルアミンである、請求項3に記載のプロセス。
- 前記4−ヒドロキシピペリジンとの反応が、ジクロロメタンを含む溶媒構成要素中で遂行される、請求項1〜4のいずれか1項に記載のプロセス。
- 前記4−ヒドロキシピペリジンとの反応が約25℃〜約35℃の温度で遂行される、請求項1〜5のいずれか1項に記載のプロセス。
- 前記塩化オキサリルとの前記式IIの化合物の反応が、触媒量のジメチルホルムアミド(DMF)の存在下において遂行される、請求項7に記載のプロセス。
- 前記塩化オキサリルとの前記式IIの化合物の反応が、ジクロロメタンを含む溶媒構成要素中で遂行される、請求項7または8のプロセス。
- 前記塩化オキサリルとの前記式IIの化合物の反応が、約15℃〜約25℃の温度で遂行される、請求項7〜9のいずれか1項に記載のプロセス。
- 前記酸化条件が第1の酸化剤を含む、請求項11に記載のプロセス。
- 前記酸化条件が第2の酸化剤を含む、請求項12に記載のプロセス。
- 前記第1の酸化剤がトリクロロイソシアヌル酸(TCIC)である、請求項12または13に記載のプロセス。
- 前記TCICが、前記式IVの化合物に関して、約0.5〜約0.7モル当量の間で存在する、請求項14に記載のプロセス。
- 前記第2の酸化剤が2,2,6,6−テトラメチル−1−ピペリジニルオキシ(TEMPO)である、請求項13〜15のいずれか1項に記載のプロセス。
- 前記TEMPOが、前記式IVの化合物に関して、約0.015〜約0.025モル当量の間で存在する、請求項16に記載のプロセス。
- 前記酸化条件下での前記式IVの化合物の反応が、重炭酸ナトリウム、炭酸ナトリウム及び臭化ナトリウムのうちの1つまたは複数をさらに含む、請求項11〜17のいずれか1項に記載のプロセス。
- 前記酸化条件下での前記式IVの化合物の反応が、ジクロロメタンを含む溶媒構成要素をさらに含む、請求項11〜18のいずれか1項に記載のプロセス。
- 前記溶媒構成要素が水をさらに含む、請求項19に記載のプロセス。
- 前記酸化条件が、トリクロロイソシアヌル酸を、前記式IVの化合物及びTEMPOを含む溶液へ約0℃〜約5℃の温度で添加することを含む、請求項11に記載のプロセス。
- 前記トリクロロイソシアヌル酸の添加が、少なくとも2つの小分けでトリクロロイソシアヌル酸を添加することを含む、請求項21に記載のプロセス。
- 前記溶液が、前記添加後に約0℃〜約5℃の温度で約30分間撹拌される、請求項21または22に記載のプロセス。
- 前記撹拌後に、前記溶液を約20℃〜約25℃の温度へ約1時間〜約2時間の時間で暖めることをさらに含む、請求項23に記載のプロセス。
- Z1がHである、請求項25に記載のプロセス。
- 前記還元剤が、水素化シアノホウ素ナトリウムまたは水素化トリアセトキシホウ素ナトリウムである、請求項25または26に記載のプロセス。
- 前記4−ピペリドンまたはその塩が、4−ピペリドン塩酸塩である、請求項28に記載のプロセス。
- 前記4−ピペリドンまたはその塩が、4−ピペリドン塩酸塩一水和物である、請求項28に記載のプロセス。
- 前記反応が塩基をさらに含む、請求項28〜30のいずれか1項に記載のプロセス。
- 前記塩基が炭酸ナトリウムである、請求項31に記載のプロセス。
- 前記4−ピペリドンとの前記式IIIの化合物の前記反応が、ジクロロメタンを含む溶媒構成要素中で遂行される、請求項28〜32のいずれか1項に記載のプロセス。
- 前記4−ピペリドンとの前記式IIIの化合物の前記反応が、約0℃〜約5℃の温度で遂行される、請求項28〜33のいずれか1項に記載のプロセス。
- 前記塩化オキサリルとの前記式IIの化合物の反応が、触媒量のジメチルホルムアミド(DMF)の存在下において遂行される、請求項35に記載のプロセス。
- 前記塩化オキサリルとの前記式IIの化合物の反応が、ジクロロメタンを含む溶媒構成要素中で遂行される、請求項35または36のプロセス。
- 塩化オキサリルとの前記式IIの化合物の反応が、約15℃〜約25℃の温度で遂行される、請求項35〜37のいずれか1項に記載のプロセス。
- 前記式IIIの化合物が、前記式IIIの化合物を4−ピペリドンと反応させる前に単離されない、請求項35〜38のいずれか1項に記載のプロセス。
- 塩化オキサリルとの前記式IIの化合物の反応及び4−ピペリドンとの前記式IIIの化合物の反応が、単一反応器中で遂行される、請求項35〜39のいずれか1項に記載のプロセス。
- Z1がHである、請求項41に記載のプロセス。
- 前記還元剤が、水素化シアノホウ素ナトリウムまたは水素化トリアセトキシホウ素ナトリウムである、請求項41または42に記載のプロセス。
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