JP2017531681A - Nik阻害剤としての新規化合物 - Google Patents
Nik阻害剤としての新規化合物 Download PDFInfo
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- JP2017531681A JP2017531681A JP2017522168A JP2017522168A JP2017531681A JP 2017531681 A JP2017531681 A JP 2017531681A JP 2017522168 A JP2017522168 A JP 2017522168A JP 2017522168 A JP2017522168 A JP 2017522168A JP 2017531681 A JP2017531681 A JP 2017531681A
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Chemical & Material Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
1496358821539_0
et al.J Biol.Chem.2011,285,39511−39522)。
国際公開第2009/158011号パンフレットには、キナーゼ阻害剤としてアルキニルアルコールが記載されている。
国際公開第2012/123522号パンフレットには、6,5−複素環プロパルギルアルコール化合物およびその使用が記載されている。
その互変異性体および立体異性形態、ならびにその薬学的に許容される付加塩および溶媒和物に関する。
本発明の化合物が、NF−κB誘導キナーゼ(NIK−MAP3K14としても知られる)を阻害することが明らかとなった。本発明による化合物、およびそのような化合物を含む医薬組成物は、癌、炎症性疾患、代謝異常(肥満および糖尿病など)、および自己免疫性疾患などの病気の治療または予防に有用であり得る。特に、本発明による化合物およびその医薬組成物は、血液系腫瘍または固形腫瘍の治療に有用であり得る。特定の実施形態においては、前記血液系腫瘍は、多発性骨髄腫、ホジキンリンパ腫、T細胞白血病、粘膜関連リンパ組織リンパ腫、びまん性大細胞型B細胞性リンパ腫およびマントル細胞リンパ腫からなる群から選択され、ある特定の実施形態において、マントル細胞リンパ腫である。本発明の他の特定の実施形態においては、固形腫瘍は、膵臓癌、乳癌、黒色腫および非小細胞肺癌からなる群から選択される。
−アミホスチン、カルボプラチンまたはオキサリプラチンと任意選択的に組み合わせた、白金配位化合物、例えばシスプラチン;
−タキサン化合物、例えば、パクリタキセル、タンパク質結合パクリタキセル粒子(AbraxaneTM)またはドセタキセル;
−カンプトテシン化合物などのトポイソメラーゼI阻害剤、例えばイリノテカン、SN−38、トポテカン、トポテカンhcl;
−抗腫瘍性エピポドフィロトキシンまたはポドフィロトキシン誘導体などのトポイソメラーゼII阻害剤、例えばエトポシド、リン酸エトポシドまたはテニポシド;
−抗腫瘍性ビンカアルカロイド、例えばビンブラスチン、ビンクリスチンまたはビノレルビン;
−抗腫瘍性ヌクレオシド誘導体、例えば5−フルオロウラシル、ロイコボリン、ゲムシタビン、ゲムシタビンhcl、カペシタビン、クラドリビン、フルダラビン、ネララビン;
−ナイトロジェン・マスタードまたはニトロソ尿素などのアルキル化剤、例えば、シクロホスファミド、クロラムブシル、カルマスティン、チオテパ、メファラン(メルファラン)、ロムスチン、アルトレタミン、ブスルファン、ダカルバジン、エストラムスチン、任意選択によりメスナと組み合わせたイホスファミド、ピポブロマン、プロカルバジン、ストレプトゾシン、テモゾロマイド、ウラシル;
−抗腫瘍性アントラサイクリン誘導体、例えばダウノルビシン、任意選択によりデクスラゾキサンと組み合わせたドキソルビシン、ドキシル、イダルビシン、ミトキサントロン、エピルビシン、エピルビシンhcl、バルルビシン;
−IGF−1受容体を標的とする分子、例えばピクロポドフィリン;
−テトラカルシン誘導体、例えばテトロカルシンA;
−グルココルチコイド、例えばプレドニゾン;
−抗体、例えばトラスツズマブ(HER2抗体)、リツキシマブ(CD20抗体)、ゲムツズマブ、ゲムツズマブ・オゾガマイシン、セツキシマブ、ペルツズマブ、ベバシズマブ、アレムツズマブ、エクリズマブ、イブリツモマブ・チウキセタン、ノフェツモマブ、パニツムマブ、トシツモマブ、CNTO 328;
−エストロゲン受容体アンタゴニストまたは選択的エストロゲン受容体調節剤あるいはエストロゲン合成の阻害剤、例えば、タモキシフェン、フルベストラント、トレミフェン、ドロロキシフェン、フェソロデックス、ラロキシフェンまたはレトロゾール;
−エキセメスタン、アナストロゾール、レトラゾール、テストラクトンおよびボロゾールなどの、アロマターゼ阻害剤;
−レチノイド、ビタミンDまたはレチノイン酸などの分化剤およびレチノイン酸代謝遮断剤(RAMBA)、例えばアキュテイン;
−DNAメチルトランスフェラーゼ阻害剤、例えばアザシチジンまたはデシタビン;
−抗葉酸剤、例えば、ペメトレキセド二ナトリウム;
−抗生物質、例えばアンチノマイシンD、ブレオマイシン、マイトマイシンC、ダクチノマイシン、カルミノマイシン、ダウノマイシン、レバミソール、プリカマイシン、ミトラマイシン;
−代謝拮抗薬、例えばクロファラビン、アミノプテリン、シトシンアラビノシドまたはメトトレキサート、アザシチジン、シタラビン、フロクスウリジン、ペントスタチン、チオグアニン;
−Bcl−2阻害剤などのアポトーシス誘導剤および抗血管新生薬、例えば、YC137、BH312、ABT737、ゴシポール、HA14−1、TW37またはデカン酸;
−チューブリン結合剤、例えばコンブレスタチン、コルヒチンまたはノコダゾール;
−キナーゼ阻害剤(例えばEGFR(上皮成長因子受容体)阻害剤、MTKI(マルチターゲット型キナーゼ阻害剤)、mTOR阻害剤)、例えばフラボペリドール、メシル酸イマチニブ、エルロチニブ、ゲフィチニブ、ダサチニブ、ラパチニブ、ラパチニブジトシラート、ソラフェニブ、ソラフェニブ、スニチニブ、リンゴ酸スニチニブ、テムシロリムス;
−ファルネシルトランスフェラーゼ阻害剤、例えばチピファルニブ;
−ヒストンデアセチラーゼ(HDAC)阻害剤、例えば酪酸ナトリウム、スベロイルアニリドヒドロキサム酸(SAHA)、デプシペプチド(FR901228)、NVP−LAQ824、R306465、クイジノスタット、トリコスタンチンA、ボリノスタット;
−ユビキチン−プロテアソーム経路阻害剤、例えばPS−341、MLN.41またはボルテゾミブ;
−Yondelis;
−テロメラーゼ阻害剤、例えばテロメスタチン;
−マトリックスメタロプロテアーゼ阻害剤、例えばバチマスタット、マリマスタット、プリノスタットまたはメタスタット;
−組換えインターロイキン、例えばアルデスロイキン、デニロイキンジフチトクス、インターフェロンアルファ2a、インターフェロンアルファ2b、ペグインターフェロンアルファ2b;
−MAPK阻害剤;
−レチノイド、例えばアリトレチノイン、ベキサロテン、トレチノイン;
−三酸化砒素;
−アスパラギナーゼ;
−ステロイド類、例えばプロピオン酸ドロモスタノロン、酢酸メゲストロール、ナンドロロン(ドカノエート、フェンプロピオネート)、デキサメタゾン;
−ゴナドトロピン放出ホルモン作動薬または拮抗薬、例えばアバレリックス、酢酸ゴセレリン、酢酸ヒストレリン、酢酸リュープロリド;
−サリドマイド、レナリドマイド;
−メルカプトプリン、ミトーテン、パミドロネート、ペガデマーセ、ペガスパルガーゼ、ラスブリカーゼ;
−BH3模倣体、例えばABT−737;
−MEK阻害剤、例えばPD98059、AZD6244、CI−1040;
−コロニー刺激因子類似物、例えばフィルグラスチム、ペグフィルグラスチム、サルグラモスチム;エリスロポエチンまたはその類似物(例えばダルベポエチンアルファ);インターロイキン11;オプレルベキン;ゾレドロネート、ゾレドロン酸;フェンタニール;ビスホスホネート;パリフェルミン。
−ステロイド性チトクロームP450 17アルファ−ヒドロキシラーゼ−17、20−リアーゼ阻害剤(CYP17)、例えばアビラテロン、酢酸アビラテロン。
組み合わせとして与えられるとき、本発明による化合物と1種以上の他の抗癌剤との重量比は、当業者であれば決定し得る。前記比と、正確な投与量および投与頻度とは、当業者によく知られている通り、使用する本発明による個々の化合物および他の抗癌剤、治療する個々の病態、治療する病態の重症度、個々の患者の年齢、体重、性別、食事、投与時期および全身の健康状態、投与方法、ならびにその個体が摂取している可能性がある他の医薬によって異なる。さらに、治療対象の応答に応じて、かつ/または本発明の化合物を処方する医師の評価に応じて、有効1日量が低減または増加され得ることは明らかである。グループAの本化合物と別の抗癌剤との具体的な重量比は、1/10〜10/1、より特には1/5〜5/1、さらにより特には1/3〜3/1の範囲であり得る。
1治療コースで、体表面積1平方メートル当たり0.1〜400mg(mg/m2)、例えば1〜300g/m2の投与量で、具体的には、イリノテカンでは約100〜350mg/m2の投与量で、またトポテカンでは約1〜2mg/m2の投与量で投与することが有利である。
1治療コースで、体表面積1平方メートル当たり2〜30mg(mg/m2)の投薬量で、具体的には、ビンブラスチンでは約3〜12mg/m2の投与量で、ビンクリスチンでは約1〜2mg/m2の投与量で、またビノレルビンでは約10〜30mg/m2の投与量で投与することが有利である。
1500mg/m2の投よ量で、具体的には、5−FUでは200〜500mg/m2の投よ量で、ゲムシタビンでは約800〜1200mg/m2の投よ量で、カペシタビンでは約1000〜
2500mg/m2の投与量で投与することが有利である。
実施例A1
a)中間体1の調製
窒素雰囲気中、周囲温度で撹拌した5−ブロモ−1H−ピロロ[2,3−c]ピリジン(2.0g、10.2mmol)の無水DMF(80ml)溶液を、水素化ナトリウム(0.49g、12.2mmol、鉱油中60%)により何回かに分けて処理した。20分間撹拌した後、2−ヨードプロパン(1.1ml、11.2mmol)を滴下し、得られた混合物を18時間撹拌した。混合物を真空中で濃縮し、残渣を水とEtOAcとの間で分配した。有機相を塩水で洗浄し、Na2SO4で乾燥し、真空中で濃縮した。シリカゲルカラムクロマトグラフィにより、EtOAcとペンタンの混合物(体積で1:9〜1:1)で溶出して残渣を精製し、茶色の油として所期の生成物(1.87g、77%)を得た。
LCMS(方法C):Rt=3.19min,m/z[M+H]+=239/241.
周囲温度で撹拌した中間体1(1.87g、7.81mmol)、塩化アルミニウム(2.08g、15.6mmol)および無水DCM(40ml)の混合物を、塩化アセチル(1.1ml、15.6mmol)の滴下により処理し、得られた混合物を4時間撹拌した。混合物を、順次、MeOH(2.0ml)、15M水酸化アンモニウム水溶液(10ml)および水で処理した。分離した水層をDCMで抽出し、まとめた有機相をNa2SO4で乾燥し、真空中で濃縮した。シリカゲルカラムクロマトグラフィにより、EtOAcとシクロヘキサンとの混合物(体積で1:9〜1:0)で溶出して残渣を精製し、淡黄色固体として所期の生成物(1.67g、76%)を得た。
LCMS(方法B):Rt=2.88min,m/z[M+H]+=281/283.
中間体2(1.66g、5.92mmol)とtert−ブトキシビス(ジメチルアミノ)メタン(2.44ml、11.8mmol)の混合物を100℃で30分間撹拌した。混合物を周囲温度にまで冷却し、真空中で濃縮して、淡黄色固体として所期の生成物(1.99g、100%)を得た。
LCMS(方法C):Rt=2.80min,m/z[M+H]+=336/338.
窒素雰囲気中、0℃で撹拌したグアジニン塩化水素塩(5.65g、59.2mmol)と1−ブタノール(40ml)の混合物を、ナトリウムメトキシド(3.20g、59.2mmol)により何回かに分けて処理した。30分間撹拌した後、中間体3(1.99g、5.92mmol)を加え、得られた混合物を100℃で18時間加熱した。混合物を周囲温度にまで冷却し、真空中で濃縮した。残渣を水とEtOAcとの間で分配した。有機相を塩水で洗浄し、Na2SO4で乾燥し、真空中で濃縮した。残渣をEt2Oで沈澱させ、無色の固体として所期の生成物(1.77g、90%)を得た。
LCMS(方法C):Rt=2.04min,m/z[M+H]+=332/334.
中間体4(1.62g、4.88mmol)、N−ヨードスクシンイミド(1.65g、7.32mmol)およびDMF(35ml)の混合物を、55℃で2.5時間撹拌した。この混合物を周囲温度にまで冷却し、水とEtOAcの間で分配した。有機相を塩水で洗浄し、Na2SO4で脱水し、真空中で濃縮した。残渣をDCMで沈澱させて、黄色の固体として所期の生成物(1.18g、53%)を得た。濾液を真空中で濃縮し、シリカゲルカラムクロマトグラフィにより、EtOAcとペンタンの混合物(体積で0:1〜1:0)で溶出して精製し、第2のバッチの初期生成物(0.36g、16%)を得た。
LCMS(方法C):Rt=3.24min,m/z[M+H]+=458/460.
a)中間体6の調製
0℃で撹拌した5,7−ジブロモ−1H−ピロロ[2,3−c]ピリジン(2.24g、8.12mmol)のDCM(34ml)懸濁液を、4−ジメチルアミノピリジン(0.06g、0.49mmol)、トリエチルアミン(2.26ml、12.2mmol)および二炭酸ジ−tert−ブチル(2.13g、9.74mmol)で順次処理した。得られた混合物を周囲温度にまで加温し、1時間撹拌した。この混合物をDCMと水との間で分配した。有機相をNa2SO4で乾燥し、真空中で濃縮した。シリカゲルカラムクロマトグラフィにより、DCMとペンタンの混合物(体積で0:1〜4:2)で溶出して残渣を精製し、白色固体として所期の生成物(2.66g、87%)を得た。
LCMS(方法C):Rt=4.05min,m/z[M−(tBu)+H]+=319/321/323.
窒素雰囲気中、周囲温度で撹拌した中間体6(5.29g、14.07mmol)とテトラキス(トリフェニルホスフィン)パラジウム(0.81g、0.703mmol)の無水THF(54ml)懸濁液を、臭化シクロプロピル亜鉛の0.5MTHF溶液(42.2ml、21.10mmol)溶液で処理し、得られた混合物を4時間撹拌した。混合物をEtOAcと飽和炭酸水素ナトリウム水溶液の間で分配した。有機相をNa2SO4乾燥し、真空中で濃縮した。シリカゲルカラムクロマトグラフィにより、DCMとペンタンの混合物(体積で0:1〜7:3)で溶出して残渣を精製し、白色固体として所期の生成物(4.0g、84%)を得た。
LCMS(方法C):Rt=4.61min,m/z[M+H]+=337/339.
アルゴン雰囲気下、周囲温度で、脱ガスした中間体7(4.0g、11.9mmol)、4,4−ジ−tert−ブチル−2,2−ジピリジル(0.32g、1.19mmol)およびシクロヘキサン(53ml)の混合物を、ジ−μ−メトキソビス(1,5−シクロオクタジエン)ジイリジウム(0.39g、0.59mmol)および4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン(8.6ml、59.3mmol)で順次処理した。得られた混合物を60℃で45時間撹拌した。この混合物を周囲温度にまで冷却し、濾過し、得られた濾液を真空中で濃縮した。シリカゲルカラムクロマトグラフ法により、DCMとペンタンの混合物(体積で0:1〜7:3)で溶出して残渣を精製し、白色固体として所期の生成物(4.74g、86%)を得た。
LCMS(方法D):Rt=4.62min,m/z[M−(tert−ブチル)+H]+=407/409.
中間体8(4.74g、10.2mmol)、4−クロロ−5−フルオロピリミジン−2−アミン(3.78g、25.6mmol)、テトラキス(トリフェニルホスフィン)パラジウム(1.18g、1.02mmol)、2.0M炭酸ナトリウム水溶液(20.5ml、40.9mmol)、トルエン(126ml)およびMeOH(17m)の混合物を、アルゴン雰囲気下、85℃で3時間撹拌した。この混合物を周囲温度にまで冷却し、水とEtOAcの間で分配した。有機相を塩水で洗浄し、Na2SO4で乾燥し、真空中で濃縮した。シリカゲルカラムクロマトグラフィにより、EtOAcとペンタンとの混合物(体積で0:1〜1:1)で溶出して残渣を精製し、白色固体として所期の生成物(2.30g、50%)を得た。
LCMS(方法D):Rt=3.81min,m/z[M−(tert−ブチル)+H]+=392/394.
窒素雰囲気下、周囲温度で、撹拌した中間体9(0.98g、2.19mmol)のDCM(25ml)溶液を、TFA(12ml、157mmol)で処理し、得られた混合物を6時間撹拌した。この混合物を真空中で濃縮し(2×、TFAと共沸混合物を作るトルエンを使用)、残渣をMeOHで沈澱させ、淡黄色固体として所期の生成物(0.62g、80%)を得た。
LCMS(方法B):Rt=2.91min,m/z[M+H]+=348/350.
a)中間体24の調製
中間体12(0.50g、0.76mmol)、4−(2−ヒドロキシエチル)モルホリン(10ml、82.6mmol)、1,10−フェナンスロリン(0.11g、0.61mmol)、ヨウ化銅(I)(0.058g、0.30mmol)およびCs2CO3(0.50mmol、1.52mmol)の混合物をマイクロ波照射により110℃で0.5時間加熱した。この混合物を周囲温度にまで冷却し、水とEtOAcの間で分配した。有機相を塩水で洗浄し、Na2SO4で乾燥し、真空中で濃縮した。残渣を、シリカゲルカラムクロマトグラフィにより、EtOAcとペンタンの混合物(体積で0:1〜1:0)、続いて2.0Mアンモニア・MeOH溶液とDCM(体積で0:1〜1:9)で溶出して精製し、黄色も油として所期の生成物(0.50g、100%)を得た。
LCMS(方法C):Rt=2.51min,m/z[M+H]+=561/563.
a)中間体25の調製
周囲温度で撹拌した中間体17(3.00g、9.74mmol)、Cs2CO3(9.5g、29.2mmol)およびDMF(45ml)の混合物を、3−メタンスルホニルオキシ−ピロリジン−1−カルボン酸tert−ブチルエステル(3.87g、14.6mmol)で処理し、得られた混合物を80℃で20時間加熱した。この混合物を周囲温度にまで冷却し、水とEtOAcの間で分配した。有機相を塩水で洗浄し、Na2SO4で乾燥し、真空中で濃縮した。残渣をEt2Oで沈澱させ、茶色の固体として所期の生成物(3.60g、77%)を得た。
a)中間体29の調製
窒素雰囲気中、周囲温度で撹拌した、中間体18(0.20g、0.53mmol)をMeOH(11ml)と1,2−ジクロロエタン(6.2ml)の混合物に溶解した溶液を、酢酸ナトリウム(0.06g、0.69mmol)、アセトン(0.077ml、1.06mmol)およびナトリウムトリアセトキシボロヒドリド(0.225g、1.06mmol)で順次処理し、得られた混合物を2時間撹拌した。この混合物を、ISOLUTE(登録商標)SCX−2SPEカラムにより、MeOHと、2.0Mアンモニア・MeOH溶液との混合物(体積で1:0〜0:1)で溶出して精製し、黄色固体として所期の生成物(0.22mg、99%)を得た。
LCMS(方法A):Rt=2.03min,m/z[M+H]+=419/421.
a)中間体34の調製
周囲温度で撹拌した中間体18(0.30g、0.79mmol)、DIPEA(0.70mL、1.59mmol)、THF(8.0ml)および DMF(4ml)の混合物を、1−ブロモ−3−メトキシ−プロパン(0.18ml、1.59mmol)で処理し、得られた混合物を70℃で18時間加熱した。混合物を周囲温度にまで冷却し、真空中で濃縮した。残渣を水とDCMの間で分配した。有機相を塩水で洗浄し、Na2SO4で乾燥し、真空中で濃縮した。残渣をシリカゲルカラムクロマトグラフィにより、MeOHとDCMとの混合物(体積で0:1〜2:23)で溶出して精製し、白色固体として所期の生成物(0.15g、51%)を得た。
LCMS(方法C):Rt=0.34/1.65/1.82min,m/z[M+H]+=449/451.
a)中間体36の調製
窒素雰囲気中、周囲温度で撹拌した、中間体19(3.2g、6.71mmol)をMeOH(63ml)と酢酸(32ml)の混合物に溶解した溶液を、(1−エトキシシクロプロポキシ)トリメチルシラン(6.74ml、33.5mmol)で処理した。10分間撹拌した後、混合物をシアノ水素化ホウ素ナトリウム(2.53g、40.2mmol)で処理し、得られた混合物を55℃で2時間撹拌した。混合物を周囲温度にまで冷却し、DCMと飽和重炭酸ナトリウム水溶液の間で分配した。有機相をNa2SO4で乾燥し、真空中で濃縮した。残渣をシリカゲルフラッシュクロマトグラフィにより、DCMとMeOHとの混合物(体積で1:0〜19:1)で溶出して精製した。さらに、シリカゲルカラムクロマトグラフィにより、2.0Mアンモニア・MeOH溶液とDCMとの混合物(体積で0:1〜1:9)で溶出して精製し、白色固体として所期の生成物(0.85g、31%)を得た。
LCMS(方法C):Rt=1.86min,m/z[M+H]+=403/405.
a)中間体37の調製
窒素雰囲気下、周囲温度で撹拌した中間体17(1.00g、3.25mmol)、水酸化カリウム粉末(0.55g、9.74mmol)、トルエン(20ml)およびDMF(2.0ml)の混合物を、3−メタンスルホニルオキシ−ピペリジン−1−カルボン酸tert−ブチルエステル(1.37g、4.90mmol)で処理し、得られた混合物を90℃で18時間加熱した。この混合物を周囲温度にまで冷却し、EtOAcと水の間で分配した。有機相をNa2SO4で脱水し、真空中で濃縮した。残渣をシリカゲルカラムクロマトグラフィにより、2.0Mアンモニア・MeOH溶液とDCMとの混合物(体積で0:1〜1:19)で溶出して精製した。さらに、シリカゲルフラッシュクロマトグラフィにより、EtOAcとペンタンとの混合物(体積で0:1〜1:0)で溶出して精製し、淡黄色の固体として所期の生成物(0.17g、10%)を得た。
LCMS(方法C):Rt=3.53min,m/z[M+H]+=491/493.
a)中間体38の調製
アルゴン雰囲気下、−78℃で、撹拌した(メチルジフェニルシリル)アセチレン(80.0g、359.8mmol)の無水THF(1200ml)溶液を、温度を−70℃未満に維持しながら、n−ブチルリチウム(23.5g、367.0mmol)で処理した。この混合物を1時間撹拌した後、1−シクロプロピル−エタノン(36.3g、432.0mmol)で処理し、得られた混合物を0℃で1.5時間撹拌した。混合物に水を加えて反応を停止させ、水とEtOAcの間で分配した。有機相を塩水で洗浄し、Na2SO4で乾燥し、真空中で濃縮した。残渣を、キラル分取SFCにより次の条件で精製した:カラム、ChiralPak IC、300×50mm、10μm;移動相、CO2(90%)、およびヘプタンおよびイソプロパノールとの混合物(体積で1:1)(10%);流速200ml/分、背圧100bar;検出器、UV220nm;カラム温度38℃。第1の溶出鏡像異性体がオフホワイト色の固体(20.2g、47.5%)として単離された。第2の溶出鏡像異性体(中間体38;RまたはS鏡像異性体)がオフホワイト色の固体(20.2g、47.5%)として単離された。
a)中間体39の調製
アルゴン雰囲気下、−78℃で、撹拌した(メチルジフェニルシリル)アセチレン(4.95ml、22.5mmol)の無水テトラヒドロフラン(80ml)溶液を、1.6Mのn−ブチルリチウム・ヘキサン溶液(15.5ml、24.8mmol)で、温度を−70℃未満に維持しながら処理した。1時間後、混合物をアセトン−d6(1.95ml、27.0mmol)で処理し、得られた混合物を0℃で1.5時間撹拌した。混合物に水を加えて反応を停止させ、水とEtOAcの間で分配した。有機相を塩水で洗浄し、Na2SO4で乾燥し、真空中で濃縮した。残渣を、シリカゲルカラムクロマトグラフィにより、EtOAcとシクロヘキサンとの混合物(体積で0:1〜2:3)で溶出して精製し、無色の油として所期の生成物(6.31g、98%)を得た。
本明細書に示す化合物中の酸含有量(例えば、ギ酸または酢酸)の値は、実験的に得たものであり、異なる分析法を用いれば変化し得る。本明細書で報告するギ酸または酢酸の含有量は、1H NMRの積分により決定されたものであり、1H NMRの結果と共に報告する。酸含有量が0.5当量未満の化合物は、遊離塩基と見なし得る。
a)化合物1の調製
中間体10(0.20g、0.57mmol)、2−シクロプロピル−ブタ−3−イン−2−オール(0.13g、1.15mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0.13g、0.11mmol)、ヨウ化銅(I)(0.01mg、0.05mmol)、トリエチルアミン(0.53ml、3.78mmol)およびMeCN(12ml)の混合物をマイクロ波照射により100℃で1時間加熱した。混合物を周囲温度にまで冷却し、真空中で濃縮した。残渣を、シリカゲルカラムクロマトグラフィにより、2.0Mアンモニア・MeOH溶液とDCMとの混合物(体積で0:1〜3:97)で溶出して精製した。さらに、逆相分取HPLCにより、MeCNと、0.1%水酸化アンモニウム含有水との混合物(体積で1:19〜3:2、20分かけて)で溶出して精製し、淡黄色固体として所期の生成物(0.072g、33%)を得た。
1H NMR(400MHz,DMSO−d6):12.64(br.s,1H),8.35(s,1H),8.25−8.24(m,2H),6.58(s,2H),5.30(s,1H),2.68−2.58(m,1H),1.53(s,3H),1.21−1.12(m,1H),1.12−1.07(m,2H),1.06−1.01(m,2H),0.59−0.48(m,2H),0.46−0.35(m,2H).
LCMS(方法E):Rt=2.73min,m/z[M+H]+=378.
a)化合物2の調製
脱ガスした、中間体20(0.20g、0.62mmol)、中間体38(0.29g、0.93mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0.14g、0.12mmol)、ヨウ化銅(I)(0.012mg、0.06mmol)、トリエチルアミン(0.61ml、4.35mmol)およびMeCN(7.5ml)の混合物を、1.0MのTBAF・THF(0.31ml、0.31mmol)で処理した。得られた混合物を100℃で30時間加熱した。混合物を周囲温度にまで冷却し、真空中で濃縮した。残渣を、シリカゲルカラムクロマトグラフィにより、2.0Mアンモニア・MeOH溶液とDCMとの混合物(体積で0:1〜1:9)で溶出して精製した。残渣を、ISOLUTE(登録商標)SCX−2 SPEカラムで、MeOHと2.0Mアンモニア・MeOH溶液との混合物(体積で1:0〜0:1)で溶出して精製した。さらに、逆相分取HPLCにより、MeCNと0.1%水酸化アンモニウム含有水との混合物(体積で1:9〜7:3、20分かけて)で溶出して精製し、白色固体として所期の生成物(0.11g、49%)を得た。
1H NMR(400MHz,DMSO−d6)δ ppm:12.43(br.s,1H),8.42(s,1H),8.24(d,J=3.8Hz,1H),8.21(d,J=2.9Hz,1H),6.59(s,2H),5.30(s,1H),2.68(s,3H),1.54(s,3H),1.21−1.13(m,1H),0.59−0.50(m,2H),0.45−0.38(m,2H).
LCMS(方法E):Rt=2.44min,m/z[M+H]+=352.
a)化合物24および25の調製
化合物12(0.12g、0.27mmol)をキラルSFCにより、次の条件で精製した:カラム、YMC Cellulose−C;移動相、CO2(75%)、1%ジエチルアミン含有IPA(25%)、検出器、UV240nm。これにより、白色固体として化合物24(第1の溶出鏡像異性体)(0.050g、40%)、および白色固体として化合物25(第2の溶出鏡像異性体)(0.023g、19%)を得た。
a)化合物26および27の調製
化合物11(0.06g、0.13mmol)をキラルSFCにより次の条件で精製した:カラム、YMC Cellulose−C;移動相、CO2(70%)、1%ジエチルアミン含有IPA(30%)、検出器、UV240nm。これにより、白色固体として化合物26(第1の溶出ジアステレオ異性体)(0.018g、29%)、および白色固体として化合物27(第2の溶出ジアステレオ異性体)(0.016g、26%)を得た。
a)化合物28および29の調製
化合物14(0.04g、0.09mmol)をキラルSFCにより、次の条件で精製した:カラム、YMC Cellulose−C;移動相、CO2(70%)、1%ジエチルアミン含有IPA(30%)、検出器、UV240nm。これにより、淡黄色固体として化合物28(第1の溶出鏡像異性体)(0.018g、45%)および淡黄色固体として化合物29(第2の溶出鏡像異性体)(0.016g、39%)を得た。
化合物30および31の調製
化合物19(0.06g、0.17mmol)をキラルSFCにより、次の条件で精製した:カラム、YMC Amylose−C;移動相、CO2(75%)、1%ジエチルアミン含有IPA(25%);検出器、UV240nm。これにより、黄色固体として化合物30(第1の溶出鏡像異性体)(0.022g、35%)および淡黄色固体として化合物31(第2の溶出鏡像異性体)(0.017g、27%)を得た。
化合物32および33の調製
化合物18(0.06g、0.16mmol)をキラルSFCにより、次の条件で精製した:カラム、LUX Cellulose−4;移動相、CO2(50%)、1%ジエチルアミン含有IPA(50%);検出器、UV240nm。これにより、オフホワイト色固体として化合物32(第1の溶出鏡像異性体)(0.017g、28%)および淡黄色固体として化合物33(第2の溶出鏡像異性体)(0.014g、23%)を得た。
LCMS
保持時間と関連質量のイオンを決定するために、以下の方法を用いて質量分析(LCMS)実験を行った。
本明細書のNMR実験は、周囲温度において400MHzで作動する、標準的なパルスシーケンスを有するVarian Unity Inovaスペクトロメータを用いて行った。化学シフト(δ)を、内部標準として使用したテトラメチルシラン(TMS)より低磁場側の百万分率(ppm)で報告する。CDCl3(重水素化クロロホルム)またはDMSO−d6(重水素化DMSO、ジメチル−d6スルホキシド)を溶媒として使用した。
1H NMR(400MHz,DMSO−d6):9.14(d,J=1.0Hz,1H),8.58(d,J=0.9Hz,1H),8.50(d,J=2.5Hz,1H),8.26(d,J=3.8Hz,1H),6.63(s,2H),5.38−5.30(m,2H),3.19−3.12(m,2H),2.75(dd,J=7.1, 10.6Hz,1H),2.56−2.45(m,2H),2.42−2.34(m,1H),2.00−1.89(m,1H),1.55(s,3H),1.22−1.14(m,1H),1.12(d,J=6.4Hz,3H),1.09(d,J=6.3Hz,3H),0.62−0.49(m,2H),0.48−0.39(m,2H).
LCMS(方法E):Rt=2.26min,m/z[M+H]+=449.
化合物4
1H NMR(400MHz,DMSO−d6)δ ppm 8.96(d,J=1.0Hz,1H),8.69(d,J=1.0Hz,1H),8.64(s,1H),8.11(s,1H),6.16(s,2H),5.32(s,1H),5.05−4.96(m,1H),4.19(t,J=5.4Hz,2H),3.59(t,J=4.6Hz,4H),2.79(t,J=5.4Hz,2H),2.49−2.44(m,4H),1.59−1.54(m,9H),1.22−1.14(m,1H),0.62−0.49(m,2H),0.48−0.36(m,2H).
LCMS(方法E):Rt=2.05min,m/z[M+H]+=491.
化合物5
1H NMR(400MHz,DMSO−d6)δ ppm:9.05(d,J=1.0Hz,1H),8.58(d,J=1.0Hz,1H),8.50(d,J=2.2Hz,1H),8.29(d,J=3.7Hz,1H),6.66(s,2H),5.41−5.32(m,2H),3.82(t,J=7.7Hz,2H),3.56−3.51(m,2H),2.79(t,J=7.2Hz,2H),2.45−2.31(m,2H),1.55(s,3H),1.22−1.14(m,1H),0.60−0.50(m,2H),0.45−0.38(m,2H).
LCMS(方法E):Rt=2.61min,m/z[M+H]+=489.
化合物6
1H NMR(400MHz,DMSO−d6)δ ppm:9.13(d,J=0.9Hz,1H),8.59(d,J=0.9Hz,1H),8.48(d,J=2.5Hz,1H),8.25(d,J=3.8Hz,1H),6.63(s,2H),5.41−5.35(m,1H),5.34(s,1H),3.20−3.10(m,2H),2.64−2.52(m,2H),2.48−2.39(m,2H),2.25(q,J=8.7Hz,1H),2.00−1.89(m,1H),1.55(s,3H),1.54−1.48(m,2H),1.25−1.14(m,1H),0.95(t,J=7.4Hz,3H),0.60−0.50(m,2H),0.46−0.38(m,2H).
LCMS(方法E):Rt=2.30min,m/z[M+H]+=449.
化合物7
1H NMR(400MHz,DMSO−d6)δ ppm:9.11(d,J=1.0Hz,1H),8.58(d,J=1.0Hz,1H),8.45(d,J=2.4Hz,1H),8.26(d,J=3.8Hz,1H),6.63(s,2H),5.40−5.32(m,2H),3.51(t,J=5.8Hz,2H),3.28(s,3H),3.22−3.14(m,2H),2.79−2.60(m,3H),2.56−2.52(m,1H),2.37(q,J=8.5Hz,1H),1.99−1.88(m,1H),1.55(s,3H),1.22−1.14(m,1H),0.60−0.50(m,2H),0.46−0.39(m,2H).
LCMS(方法E):Rt=2.26min,m/z[M+H]+=465.
化合物8
1H NMR(400MHz,DMSO−d6)δ ppm:9.11(d,J=0.9Hz,1H),8.59(d,J=1.0Hz,1H),8.45(d,J=2.5Hz,1H),8.26(d,J=3.8Hz,1H),6.64(s,2H),5.42−5.36(m,1H),5.34(s,1H),3.45−3.40(m,2H),3.24(s,3H),3.20−3.10(m,2H),2.65−2.53(m,4H),2.26(q,J=8.7Hz,1H),2.01−1.89(m,1H),1.79−1.67(m,2H),1.55(s,3H),1.22−1.14(m,1H),0.60−0.50(m,2H),0.46−0.39(m,2H).
LCMS(方法E):Rt=2.32min,m/z[M+H]+=479.
化合物9
1H NMR(400MHz,DMSO−d6):9.02(d,J=1.1Hz,1H),8.64(d,J=1.1Hz,1H),8.46(d,J=2.3Hz,1H),8.28(d,J=3.7Hz,1H),6.68(s,2H),5.50(d,J=4.4Hz,1H),5.37−5.29(m,1H),4.68−4.60(m,1H),3.87(t,J=7.7Hz,2H),3.63−3.57(m,2H),2.13−2.07(m,1H),1.44(d,J=6.6Hz,3H),0.44−0.38(m,2H),0.34−0.29(m,2H).
LCMS(方法E):Rt=1.87min,m/z[M+H]+=393.
化合物10
1H NMR(400MHz,DMSO−d6)δ ppm:8.57(d,J=2.4Hz,1H),8.51(s,1H),8.24(d,J=4.0Hz,1H),6.61(s,2H),5.52−5.48(m,1H),5.31(s,1H),3.25(d,J=10.9Hz,1H),3.15(dt,J=2.8, 8.8Hz,1H),2.89(s,3H),2.65−2.53(m,3H),2.48−2.44(m,1H),2.25(q,J=8.7Hz,1H),1.93−1.83(m,1H),1.54(s,3H),1.21−1.11(m,4H),0.60−0.49(m,2H),0.45−0.38(m,2H).
LCMS(方法E):Rt=2.06min,m/z[M+H]+=449.
化合物11(ギ酸0.8当量)
1H NMR(400MHz,DMSO−d6)δ ppm:9.12(d,J=1.0Hz,1H),8.59(d,J=1.0Hz,1H),8.46(d,J=2.5Hz,1H),8.26(d,J=3.8Hz,1H),8.16(s,0.8H),6.63(s,2H),5.40−5.32(m,2H),3.19−3.10(m,2H),2.65−2.52(m,3H),2.48−2.41(m,1H),2.25(q,J=8.7Hz,1H),1.99−1.89(m,1H),1.55(s,3H),1.53−1.35(m,4H),1.22−1.14(m,1H),0.92(t,J=7.3Hz,3H),0.60−0.50(m,2H),0.46−0.38(m,2H).
LCMS(方法E):Rt=2.48min,m/z[M+H]+=463.
化合物12
1H NMR(400MHz,CDCl3)δ ppm:8.81(s,1H),8.69(d,J=0.9Hz,1H),8.45(s,1H),8.15(d,J=3.7Hz,1H),5.02(s,2H),4.71−4.62(m,1H),3.12−3.07(m,1H),2.78−2.71(m,1H),2.56(t,J=9.4Hz,1H),2.42−2.33(m,4H),2.19−2.12(m,1H),1.97−1.76(m,3H),1.59−1.52(m,2H),0.93(t,J=7.4Hz,3H).
LCMS(方法E):Rt=2.14min,m/z[M+H]+=443.
化合物13
1H NMR(400MHz,DMSO−d6)δ ppm:12.62(br.s,1H),8.35(s,1H),8.26−8.24(m,2H),6.59(s,2H),5.31(s,1H),2.66−2.58(m,1H),1.53(s,3H),1.21−1.13(m,1H),1.13−1.00(m,4H),0.60−0.50(m,2H),0.48−0.37(m,2H).
LCMS(方法E):Rt=2.71min,m/z[M+H]+=378.
化合物14
1H NMR(400MHz,DMSO−d6)δ ppm:9.03(d,J=1.0Hz,1H),8.62(d,J=1.0Hz,1H),8.47(d,J=2.2Hz,1H),8.29(d,J=3.6Hz,1H),7.78(d,J=3.2Hz,1H),7.69(d,J=3.3Hz,1H),7.07(br.s,1H),6.67(s,2H),5.38−5.30(m,1H),3.87(t,J=7.7Hz,2H),3.62−3.57(m,2H),2.13−2.07(m,1H),1.94(s,3H),0.44−0.38(m,2H),0.34−0.28(m,2H).
LCMS(方法E):Rt=2.20min,m/z[M+H]+=476.
化合物15
1H NMR(400MHz,DMSO−d6)δ ppm:9.04(d,J=1.0Hz,1H),8.64(d,J=1.0Hz,1H),8.47(d,J=2.2Hz,1H),8.29(d,J=3.7Hz,1H),6.74(s,1H),6.67(s,2H),5.39−5.31(m,1H),3.88(t,J=7.6Hz,2H),3.63−3.58(m,2H),2.63(s,3H),2.13−2.07(m,1H),1.89(s,3H),0.45−0.38(m,2H),0.34−0.29(m,2H).
LCMS(方法E):Rt=2.13min,m/z[M+H]+=475.
化合物16
1H NMR(400MHz,DMSO−d6)δ ppm:9.03(d,J=1.0Hz,1H),8.63(d,J=1.0Hz,1H),8.47(d,J=2.2Hz,1H),8.29(d,J=3.7Hz,1H),6.68(s,2H),6.54(br.s,1H),6.39(d,J=0.9Hz,1H),5.38−5.30(m,1H),3.90−3.85(m,2H),3.63−3.57(m,2H),2.42(d,J=0.8Hz,3H),2.13−2.07(m,1H),1.85(s,3H),0.44−0.38(m,2H),0.34−0.30(m,2H).
LCMS(方法E):Rt=2.28min,m/z[M+H]+=474.
化合物17
1H NMR(400MHz,DMSO−d6)δ ppm:9.00(d,J=0.9Hz,1H),8.90(d,J=4.8Hz,2H),8.59(d,J=1.0Hz,1H),8.45(d,J=2.2Hz,1H),8.28(d,J=3.7Hz,1H),7.51(t,J=4.8Hz,1H),6.66(s,2H),6.17(s,1H),5.37−5.29(m,1H),3.87(t,J=7.7Hz,2H),3.62−3.57(m,2H),2.13−2.06(m,1H),1.92(s,3H),0.44−0.37(m,2H),0.34−0.28(m,2H).
LCMS(方法E):Rt=1.96min,m/z[M+H]+=471.
化合物18
1H NMR(400MHz,DMSO−d6)δ ppm:12.48(br.s,1H),8.80(d,J=1.1Hz,1H),8.63(d,J=1.1Hz,1H),8.31(d,J=2.7Hz,1H),8.25(d,J=3.8Hz,1H),6.63(s,2H),6.52(s,1H),6.39(d,J=0.9Hz,1H),2.42(d,J=0.8Hz,3H),1.85(s,3H).
LCMS(方法E):Rt=2.42min,m/z[M+H]+=379.
化合物19
1H NMR(400MHz,DMSO−d6)δ ppm:12.45(br.s,1H),8.79(d,J=1.1Hz,1H),8.62(d,J=1.0Hz,1H),8.31(d,J=2.9Hz,1H),8.25(d,J=3.8Hz,1H),7.78(d,J=3.3Hz,1H),7.69(d,J=3.3Hz,1H),7.05(s,1H),6.62(s,2H),1.94(s,3H).
LCMS(方法E):Rt=2.32min,m/z[M+H]+=381.
化合物20
1H NMR(400MHz,DMSO−d6)δ ppm:12.41(br.s,1H),8.78(d,J=1.1Hz,1H),8.59(d,J=1.1Hz,1H),8.30(d,J=2.8Hz,1H),8.24(d,J=3.9Hz,1H),6.62(s,2H),5.32(s,1H),1.99−1.92(m,4H),1.81−1.68(m,4H).
LCMS(方法E):Rt=2.40min,m/z[M+H]+=338.
化合物21
1H NMR(400MHz,DMSO−d6)δ ppm:9.01(d,J=0.9Hz,1H),8.60(d,J=0.8Hz,1H),8.45(d,J=2.2Hz,1H),8.28(d,J=3.7Hz,1H),6.67(s,2H),5.36−5.30(m,2H),3.87(t,J=7.6Hz,2H),3.63−3.57(m,2H),2.14−2.06(m,1H),1.99−1.94(m,4H),1.79−1.68(m,4H),0.45−0.38(m,2H),0.34−0.30(m,2H).
LCMS(方法E):Rt=2.26min,m/z[M+H]+=433.
化合物22
1H NMR(400MHz,DMSO−d6)δ ppm:12.63(br.s,1H),8.39(s,1H),8.24(d,J=2.7Hz,2H),6.60(s,2H),5.30(s,1H),2.66−2.59(m,1H),1.97−1.91(m,4H),1.79−1.67(m,4H),1.13−1.08(m,2H),1.07−1.00(m,2H).
LCMS(方法E):Rt=2.72min,m/z[M+H]+=378.
化合物23
1H NMR(400MHz,DMSO−d6)δ ppm:12.67(br.s,1H),8.41(s,1H),8.27−8.23(m,2H),6.59(s,2H),6.49(s,1H),6.38(d,J=0.9Hz,1H),2.67−2.59(m,1H),2.41(s,3H),1.84(s,3H),1.13−1.07(m,2H),1.07−1.00(m,2H).
LCMS(方法E):Rt=2.75min,m/z[M+H]+=419.
化合物24
1H NMR(400MHz,CDCl3)δ ppm:8.82(d,J=0.9Hz,1H),8.69(d,J=0.9Hz,1H),8.45(s,1H),8.15(d,J=3.6Hz,1H),5.04(s,2H),4.71−4.62(m,1H),3.14−3.07(m,1H),2.77−2.71(m,1H),2.58−2.53(m,1H),2.47(s,1H),2.42−2.33(m,3H),2.19−2.10(m,1H),1.97−1.74(m,3H),1.59−1.51(m,2H),0.94(t,J=7.4Hz,3H).
LCMS(方法E):Rt=2.14min,m/z[M+H]+=443.
化合物25
1H NMR(400MHz,CDCl3)δ ppm:8.81(d,J=0.7Hz,1H),8.69(d,J=1.0Hz,1H),8.45(s,1H),8.15(d,J=3.7Hz,1H),5.02(s,2H),4.71−4.62(m,1H),3.12−3.09(m,1H),2.77−2.71(m,1H),2.60−2.54(m,1H),2.42−2.33(m,4H),2.19−2.10(m,1H),1.97−1.76(m,3H),1.56−1.50(m,2H),0.94(t,J=7.4Hz,3H).
LCMS(方法E):Rt=2.15min,m/z[M+H]+=443.
化合物26
1H NMR(400MHz,DMSO−d6)δ ppm:9.13(d,J=1.0Hz,1H),8.59(d,J=1.0Hz,1H),8.46(d,J=2.5Hz,1H),8.26(d,J=3.8Hz,1H),6.63(s,2H),5.41−5.36(m,1H),5.35(s,1H),3.19−3.10(m,2H),2.64−2.53(m,2H),2.48−2.41(m,2H),2.25(q,J=8.7Hz,1H),1.99−1.89(m,1H),1.55(s,3H),1.53−1.36(m,4H),1.22−1.14(m,1H),0.92(t,J=7.3Hz,3H),0.60−0.50(m,2H),0.46−0.38(m,2H).
LCMS(方法E):Rt=2.46min,m/z[M+H]+=463.
化合物27
1H NMR(400MHz,DMSO−d6)δ ppm:9.12(d,J=0.9Hz,1H),8.59(d,J=0.9Hz,1H),8.46(d,J=2.5Hz,1H),8.26(d,J=3.8Hz,1H),6.63(s,2H),5.39−5.36(m,1H),5.34(s,1H),3.20−3.10(m,2H),2.64−2.53(m,2H),2.48−2.41(m,2H),2.25(q,J=8.8Hz,1H),2.00−1.89(m,1H),1.55(s,3H),1.53−1.36(m,4H),1.22−1.14(m,1H),0.92(t,J=7.3Hz,3H),0.60−0.50(m,2H),0.46−0.38(m,2H).
LCMS(方法E):Rt=2.46min,m/z[M+H]+=463.
化合物28
1H NMR(400MHz,DMSO−d6)δ ppm:9.03(d,J=1.1Hz,1H),8.62(d,J=1.1Hz,1H),8.47(d,J=2.2Hz,1H),8.29(d,J=3.7Hz,1H),7.78(d,J=3.2Hz,1H),7.69(d,J=3.3Hz,1H),7.07(s,1H),6.67(s,2H),5.38−5.30(m,1H),3.90−3.84(m,2H),3.62−3.57(m,2H),2.13−2.06(m,1H),1.94(s,3H),0.44−0.38(m,2H),0.33−0.30(m,2H).
LCMS(方法E):Rt=2.19min,m/z[M+H]+=476.
化合物29
1H NMR(400MHz,DMSO−d6)δ ppm:9.03(d,J=1.0Hz,1H),8.62(d,J=1.0Hz,1H),8.47(d,J=2.3Hz,1H),8.28(d,J=3.7Hz,1H),7.78(d,J=3.2Hz,1H),7.69(d,J=3.3Hz,1H),7.06(s,1H),6.67(s,2H),5.38−5.30(m,1H),3.87(t,J=7.6Hz,2H),3.62−3.57(m,2H),2.13−2.07(m,1H),1.94(s,3H),0.44−0.38(m,2H),0.33−0.29(m,2H).
LCMS(方法E):Rt=2.19min,m/z[M+H]+=476.
化合物30
1H NMR(400MHz,DMSO−d6)δ ppm:12.42(br.s,1H),8.79(d,J=1.1Hz,1H),8.61(d,J=1.1Hz,1H),8.31(d,J=2.7Hz,1H),8.24(d,J=3.8Hz,1H),7.78(d,J=3.2Hz,1H),7.69(d,J=3.3Hz,1H),7.04(s,1H),6.61(s,2H),1.94(s,3H).
LCMS(方法E):Rt=2.32min,m/z[M+H]+=381.
化合物31
1H NMR(400MHz,DMSO−d6)δ ppm:12.45(br.s,1H),8.78(d,J=1.1Hz,1H),8.61(d,J=1.0Hz,1H),8.31(d,J=2.9Hz,1H),8.23(d,J=3.8Hz,1H),7.78(d,J=3.2Hz,1H),7.69(d,J=3.2Hz,1H),7.04(s,1H),6.59(s,2H),1.94(s,3H).
LCMS(方法E):Rt=2.32min,m/z[M+H]+=381.
化合物32
1H NMR(400MHz,DMSO−d6)δ ppm:12.43(br.s,1H),8.79(d,J=1.1Hz,1H),8.63(d,J=1.1Hz,1H),8.31(d,J=2.7Hz,1H),8.25(d,J=3.8Hz,1H),6.62(s,2H),6.51(s,1H),6.39(d,J=0.9Hz,1H),2.42(d,J=0.8Hz,3H),1.85(s,3H).
LCMS(方法E):Rt=2.42min,m/z[M+H]+=379.
化合物33
1H NMR(400MHz,DMSO−d6)δ ppm:12.33(br.s,1H),8.80(d,J=1.1Hz,1H),8.63(d,J=1.1Hz,1H),8.31(d,J=2.7Hz,1H),8.25(d,J=3.8Hz,1H),6.62(s,2H),6.51(s,1H),6.39(d,J=0.9Hz,1H),2.42(d,J=0.7Hz,3H),1.85(s,3H).
LCMS(方法E):Rt=2.41min,m/z[M+H]+=379.
生物学的アッセイA
組み換えヒトNF−kappaB−誘導キナーゼ(NIK/MAP3K14)の自己リン酸化活性の阻害(AlphaScreen(登録商標))
AlphaScreen(登録商標)(αスクリーン)フォーマット(Perkin Elmer)を使用して、NIK/MAP3K14の自己リン酸化活性を測定した。試験した全化合物は、ジメチルスルホキシド(DMSO)に溶解させ、アッセイ緩衝液でさらに希釈した。アッセイ中の最終のDMSO濃度は1%(体積/体積)であった。アッセイ緩衝液は、1mM EGTA(エチレングリコール四酢酸)、1mM DTT(ジチオスレイトール)、0.1mM Na3VO4、5mM MgCl2、0.01%Tween(登録商標)20を含有するpH7.5の50mM Trisとした。アッセイは、384ウェルAlphaplates(Perkin Elmer)中で行った。インキュベーションは、化合物、25マイクロMアデノシン−5’−三リン酸(ATP)および0.2nM NIK/MAP3K14から構成された。インキュベーションは、GST−タグ付きNIK/MAP3K14酵素の添加により開始させ、25℃で1時間行ない、anti−phospho−IKK Ser176/180抗体を含有する停止緩衝液の添加により停止させた。プロテインA受容体およびグルタチオンドナービーズを加え、EnVision(登録商標)Multilabel Plate Reader(Perkin Elmer)を使用して読み取った。試料を含まないウェルで得た信号を、その他の全ウェルから減じ、コントロールの%阻害対Log10化合物濃度にシグモイド曲線をフィッティングしてIC50を決定した。
L363細胞におけるP−IKKα値に対する化合物の効果
試験した全化合物は、DMSOに溶解させ、培養液でさらに希釈した。細胞アッセイ中の最終DMSO濃度は1%(体積/体積)であった。ヒトL363細胞(ATCC)は、GlutaMaxおよび10%ウシ胎児血清を加えたRPMI 1640培地(PAA)で培養した。細胞は、加湿した5%CO2雰囲気中、37℃で、1ml当たり0.2×106個〜1×106個の密度に常に維持した。細胞は週に2回継代培養を行い、分割して低密度のものを得た。細胞は、1ウェル当たり75μlの体積の培養液および25μlの1μg/ml濃度組み換えヒトB−細胞活性化因子(BAFF/BLyS/TNFSF13B)の1ml当たり2×106個の割合で、96ウェルプレート(Nunc 167008)に播種した。播種した細胞を、加湿した5%CO2雰囲気中、37℃で24時間インキュベートした。薬剤および/または溶媒(20μl)を加えて最終体積を120μlにした。2時間処理した後、プレートをインキュベータから取り出し、30lの5×溶解緩衝液を添加して細胞を溶解させた後、プレート振盪器により4℃で10分間振盪した。このインキュベーションの最後に、4℃で20分間、800xgの遠心分離を行い、溶解物に対し、抗ウサギ抗体を付着させたMesoscaleプレートでサンドイッチイムノアッセイを行いP−IKKα値を評価した。実験では、各処理の結果は2つの複製ウェルの平均とした。初期スクリーニングの目的では、8点希釈曲線(連続1:3希釈)を使用して化合物を試験した。各実験では、コントロール(MG132およびBAFFを含むが、試験用薬剤は含まない)およびブランクのインキュベーション(MG132、BAFFおよび10μM ADS125117を含有、完全阻害を示すことが知られている試験濃度)も並行して試験した。全てのコントロールおよび試料値からブランクのインキュベーション値を減じた。IC50を決定するために、コントロールのP−IKKα値の%阻害対Log10化合物濃度のプロットにシグモイド曲線をフィッティングした。
LP−1、L−363およびJJN−3細胞に対する抗増殖活性の決定
試験化合物は全て、DMSOに溶解し、培養液でさらに希釈した。細胞抗増殖アッセイ中の最終のDMSO濃度は0.3%(体積/体積)であった。CellTiter−Glo細胞生存率アッセイキット(Promega)を使用して生存率を評価した。2mM L−グルタミンおよび10%ウシ胎児血清(PAA)で補強したRPMI1640培養液で、LP−1、L−363およびJJN−3細胞(DSMZ)を培養した。細胞は、37℃、加湿した5%CO2雰囲気中、常に懸濁細胞として維持した。細胞は、週に2回、0.2×106/mlの播種密度で継代培養を行った。黒色組織培養液処理96ウェルプレート(Perkin Elmer)中に細胞を播種した。播種に用いた密度は、全体積75μlの培養液中へ、ウェル当たり2,000〜6,000細胞の範囲であった。24時間後、薬剤および/または溶媒(25μl)を加えて最終体積を100μlにした。72時間の処理後、インキュベータからプレートを取り出し、約10分間室温と平衡化させた。各ウェルに100μlのCellTiter−Glo試薬を加えてカバー(Perkin Elmer Topseal)をし、プレート振盪器で10分間振盪した。HTS Topcount(Perkin Elmer)で発光を測定した。実験では、各処理の結果は2つの複製ウェルの平均とした。初期スクリーニングの目的では、化合物は9点希釈曲線(連続1:3希釈)を使用して試験した。各実験では、コントロール(薬剤を含まない)およびブランクインキュベーション(化合物の添加時に読み取られる細胞を含有)を並行して試験した。全てのコントロールおよび試料値からブランク値を減じた。各試料について、細胞増殖の平均値(相対的な光の単位で)を、コントロールの細胞増殖の平均値に対する百分率で表した。
これらの例全体を通して使用される「有効成分」(a.i.)は、任意の互変異性体または立体異性形態を含むグループAの化合物、あるいはその薬学的に許容される付加塩または溶媒和物に関し;特に例示した化合物のいずれか1つに関する。
1.錠剤
有効成分 5〜50mg
ジ−リン酸カルシウム 20mg
ラクトース 30mg
タルク 10mg
ステアリン酸マグネシウム 5mg
ジャガイモデンプン 合計で200mgになるまで
2.懸濁剤
水性懸濁液を、経口投与用に、1ミリリットル当たり1〜5mgの有効成分、50mgのカルボキシメチルセルロースナトリウム、1mgの安息香酸ナトリウム、500mgのソルビトールおよび水1mlまでの残部を含有するように調製する。
3.注射剤
非経口組成物を、NaClの0.9%水溶液またはプロピレングリコールの10体積%水溶液中、1.5%(重量/体積)の有効成分を撹拌して調製する。
4.軟膏剤
有効成分 5〜1000mg
ステアリルアルコール 3g
ラノリン 5g
白色ワセリン 15g
水 合計で100gになるまで
この例において、有効成分は、同量の本発明による化合物のいずれかに、特に同量の例示した化合物のいずれかに変更することができる。
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KR20170066473A (ko) | 2017-06-14 |
IL251780B (en) | 2020-08-31 |
MX2017005282A (es) | 2017-08-15 |
KR102500071B1 (ko) | 2023-02-14 |
US20170334906A1 (en) | 2017-11-23 |
CA2960336C (en) | 2023-03-07 |
BR112017008045A2 (pt) | 2017-12-19 |
CN107074855A (zh) | 2017-08-18 |
EA201790688A1 (ru) | 2017-08-31 |
US10005776B2 (en) | 2018-06-26 |
MX371153B (es) | 2020-01-20 |
JP6676048B2 (ja) | 2020-04-08 |
ES2718557T3 (es) | 2019-07-02 |
IL251780A0 (en) | 2017-06-29 |
EP3209662B1 (en) | 2019-01-09 |
EP3209662A1 (en) | 2017-08-30 |
CN107074855B (zh) | 2019-11-05 |
CA2960336A1 (en) | 2016-04-28 |
AU2015334917B2 (en) | 2019-08-29 |
EA030908B1 (ru) | 2018-10-31 |
AU2015334917A1 (en) | 2017-03-23 |
WO2016062792A1 (en) | 2016-04-28 |
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