JP2011507907A - A2arアゴニストとしての置換4−{3−[6−アミノ−9−(3,4−ジヒドロキシ−テトラヒドロ−フラン−2−イル)−9h−プリン−2−イル]−プロプ−2−イニル}−ピペリジン−1−カルボン酸エステル - Google Patents
A2arアゴニストとしての置換4−{3−[6−アミノ−9−(3,4−ジヒドロキシ−テトラヒドロ−フラン−2−イル)−9h−プリン−2−イル]−プロプ−2−イニル}−ピペリジン−1−カルボン酸エステル Download PDFInfo
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Abstract
Description
本発明は、米国国立衛生研究所からの米国助成金番号1 R41 AR052960の下での政府の支援により行った。政府は本発明に対して一定の権利を有し得る。
本発明は、A2Aアデノシン受容体(AR)の選択的アゴニストである、置換4-{3-[6-アミノ-9-(3,4-ジヒドロキシ-テトラヒドロ-フラン-2-イル)-9H-プリン-2-イル]-プロプ-2-イニル}-ピペリジン-1-カルボン酸エステルおよび薬学的組成物に関する。これらの化合物および組成物は医用薬剤として有用である。
放射性リガンド結合アッセイおよび生理応答に基づいて、A2Aアデノシン受容体(AR)のアゴニストとしてますます強力かつ/または選択的な化合物の漸進的開発がなされてきた。例えば、Lindenらに対する米国特許第6,232,297号(特許文献1)では、下記一般式を有する化合物が記載されている:
式中、各RはHであり得、Xはエチルアミノカルボニルであり得、R1は4-メトキシカルボニルシクロヘキシルメチル(DWH-146e)であり得る。これらの化合物はA2Aアゴニストであると報告されている。
式中、R7はHであり得、Xはエーテルまたはアミドであり得、CR1R2はCH2であり得、Zは複素環であり得る。これらの化合物はA2Aアゴニストであると報告されている。
式中、R7はHであり得、Xはシクロアルキル置換のエーテルまたはアミドであり得、CR1R2はCH2であり得、Zは複素環であり得る。これらの化合物はA2Aアゴニストであると報告されている。
式中、NR1R2はNH2であり得、R4はエーテルまたはアミドであり得、R5はエチニルであり得、YはOまたはNR1であり得、Zはアリールまたはヘテロアリールであり得る。これらの化合物はA2Aアゴニストであると報告されている。
本発明は、アデノシンA2A受容体においてアゴニストとして作用する新規置換4-{3-[6-アミノ-9-(3,4-ジヒドロキシ-テトラヒドロ-フラン-2-イル)-9H-プリン-2-イル]-プロプ-2-イニル}-ピペリジン-1-カルボン酸エステル、ならびに、A2A受容体が関与しておりかつ該受容体のアゴニズムが治療上の利点を与える疾患および状態を処置する方法において該化合物を使用するための方法を提供する。例えば、哺乳動物組織における炎症活動の処置、または鎌状赤血球症の処置のために、化合物を使用することができる。炎症組織活性は、病理学的作用物質が原因であり得るか、あるいは、物理的外傷、化学的外傷もしくは熱的外傷、あるいは臓器移植、組織移植もしくは細胞移植などの医学的手順、血管形成術(PCTA)、虚血/再灌流後の炎症、または移植術の外傷が原因であり得る。本発明の化合物は、他の抗炎症治療薬との組み合わせ、または抗病原体薬との組み合わせで使用することもできる。
式中、
R1およびR2はHおよびC1-3アルキルより独立して選択され;
Zはシクロプロピル、シクロブチル、シクロペンチル、テトラヒドロフラニル、アゼチジン-2-オニル、ピロリジニルおよびピロリジン-2-オニルより選択され;
Zは0〜2個のZ2で置換され;
Z1はテトラヒドロフラニル、アゼチジン-2-オニル、ピロリジニルおよびピロリジン-2-オニルより選択され;
Z1は0〜2個のZ2で置換され;
Z2はF、C1-4アルキル、CF3、OCF3、(CH2)aOR3、(CH2)aNR3R3、NO2、(CH2)aCN、(CH2)aCO2R3および(CH2)aCONR3R3より独立して選択され;
R3はHおよびC1-6アルキルより独立して選択され;
R4はCH2ORおよびC(O)NRRより選択され;
各RはH、C1-4アルキル、シクロブチルおよび(CH2)aシクロプロピルより独立して選択され;
aは0、1および2より選択され;
qは1、2および3より選択される。
R1およびR2がHであり;
Z2がF、C1-2アルキル、CF3、OCF3およびOR3より独立して選択され;
R3がHおよびC1-2アルキルより独立して選択され;
R4がC(O)NRRであり;
各RがH、C1-4アルキル、シクロプロピル、シクロブチルおよび-CH2-シクロプロピルより独立して選択され;
qが1である、
新規化合物を提供する。
R1およびR2がHであり;
Zが0〜1個のZ2で置換され;
Z2がF、C1-2アルキル、CF3、OCF3およびOR3より独立して選択され;
R3がHおよびC1-2アルキルより独立して選択され;
R4がC(O)NRRであり;
各RがH、C1-4アルキル、シクロプロピル、シクロブチルおよび-CH2-シクロプロピルより独立して選択される、
新規化合物を提供する。
R1およびR2がHであり;
Z1が0〜1個のZ2で置換され;
Z2がF、C1-2アルキル、CF3、OCF3およびOR3より独立して選択され;
R3がHおよびC1-2アルキルより独立して選択され;
R4がC(O)NRRであり;
各RがH、C1-4アルキル、シクロプロピル、シクロブチルおよび-CH2-シクロプロピルより独立して選択され;
qが0である、
新規化合物を提供する。
R1およびR2がHであり;
Z1が0〜1個のZ2で置換され;
Z2がF、C1-2アルキル、CF3、OCF3およびOR3より独立して選択され;
R3がHおよびC1-2アルキルより独立して選択され;
R4がC(O)NRRであり;
各RがH、C1-4アルキル、シクロプロピル、シクロブチルおよび-CH2-シクロプロピルより独立して選択され;
qが1である、
新規化合物を提供する。
2-Aas 2-アルキニルアデノシン
125I-ABA N6-(4-アミノ-3-125ヨード-ベンジル)アデノシン
APCI 大気圧化学イオン化
CCPA 2-クロロ-N6-シクロペンチルアデノシン;
Cl-IB-MECA N6-3-ヨード-2-クロロベンジルアデノシン-5'-N-メチルウロンアミド;
CPA N6-シクロペンチルアデノシン
DMF ジメチルホルムアミド
DMSO ジメチルスルホキシド
DMSO-d6 重水素化ジメチルスルホキシド
EtOAc 酢酸エチル
eq 当量
GPCR Gタンパク質共役受容体; hA2AAR 組換えヒトA2Aアデノシン受容体;
IADO 2-ヨードアデノシン
125I-APE 2-[2-(4-アミノ-3-[125I]ヨードフェニル)エチルアミノ]アデノシン;
NECA 5'-N-エチルカルボキサミドアデノシン;
IB-MECA N6-3-ヨードベンジルアデノシン-5'-N-メチルウロンアミド;
2-ヨードアデノシン 5-(6-アミノ-2-ヨード-プリン-9-イル)-3,4-ジヒドロキシテトラヒドロ-フラン-2カルボン酸エチルアミド
HPLC 高速液体クロマトグラフィー
HRMS 高分解能質量分析
125I-ZM241385 125I-4-(2-[7-アミノ-2-[2-フリル][1,2,4]トリアゾロ[2,3-a][1,3,5]トリアジン-5-イル-アミノ]エチル)フェノール;
INECA 2-ヨード-N-エチルカルボキサミドアデノシン
LC/MS 液体クロマトグラフィー/質量分析
m.p. 融点
MHz メガヘルツ
MRS 1220 N-(9-クロロ-2-フラン-2-イル-[1,2,4]トリアゾロ[1,5-c]キナゾリン-5-イル)-2-フェニルアセトアミド;
MS 質量分析
NECA N-エチルカルボキサミドアデノシン
NMR 核磁気共鳴
RP-HPLC 逆相高速液体クロマトグラフィー
TBAF フッ化テトラブチルアンモニウム
TBS tert-ブチルジメチルシリル
TBDMSCl tert-ブチルジメチルシリルクロリド
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
p-TSOH パラ-トルエンスルホン酸
XAC 8-(4-((2-アミノエチル)アミノカルボニル-メチルオキシ)フェニル)-1-3-ジプロピルキサンチン。
4-{3-[6-アミノ-9-(5-シクロプロピルカルバモイル-3,4-ジヒドロキシ-テトラヒドロ-フラン-2-イル)-9H-プリン-2-イル]-プロプ-2-イニル}-ピペリジン-1-カルボン酸シクロブチルエステル
THF中攪拌下のトリホスゲン(0.34当量)に、不活性雰囲気下0℃で、アルコール(1.0当量)およびジメチルアニリン(1.1当量)を乾燥THF中溶液としてゆっくりと加えた。10分後、反応液を室温に加温し、さらに3時間攪拌する。次に乾燥DCMを加え、混合物をN-ヒドロキシスクシンアミド(1.3当量)の乾燥DCM溶液に0℃でゆっくりと注いだ。反応液を室温にゆっくりと加温し、終夜攪拌した。水を混合物に加え、さらに3時間攪拌後、溶液をEtOAcで希釈した。有機層を水で3回、ブラインで1回洗浄した後、乾燥させ(MgSO4)、濃縮した。得られた油状物(炭酸塩と対称無水物との混合物であり得る)を次の工程に直接取り入れた。
LRMS ESI (M+H+) 540.35。
HPLC: 水中MeOH 20〜95%勾配、40℃で4分、合計6分。保持時間=3.04分(6分法)。
N-シクロプロピル2-{3-[1-((テトラヒドロフラン-3-イルオキシ)カルボニル)ピペリジン-4-イル]プロピン-1-イル}アデノシン-5'-ウロンアミド
実施例1に示すC-2カップリング用の一般的手順に従って、テトラヒドロフラン-3-イル4-(プロプ-2-イニル)ピペリジン-1-カルボキシレート(1.620g、6.83mmol)をN-シクロプロピル2-ヨードカルボキサミドアデノシン(0.101g、0.226mmol)の溶液に加えた。収量54mg、43%。LRMS ESI (M+H+) 556.3。HPLC室温 = 6.0分。
N-シクロプロピル2-{3-[1-((テトラヒドロ-2H-ピラン-4-イルオキシ)カルボニル)ピペリジン-4-イル]プロピン-1-イル}アデノシン-5'-ウロンアミド
実施例1に示すC-2カップリング用の一般的手順に従って、テトラヒドロ-2H-ピラン-4-イル4-(プロプ-2-イニル)ピペリジン-1-カルボキシレート(3.290g、13.09mmol)をN-シクロプロピル2-ヨードカルボキサミドアデノシン(0.100g、0.224mmol)の溶液に加えた。収量41mg、32%。LRMS ESI (M+H+) 570.3。HPLC室温 = 6.5分。
50% N2/50% O2の雰囲気下、10%ウシ胎仔血清、2.5μg/mlアムホテリシンBおよび50μg/mlゲンタマイシンを補充したグレース培地中でSf9細胞を培養した。ウイルス感染を2.5x106細胞/mLの密度で行い、使用する各ウイルスについて感染多重度を2とした。感染細胞を感染後3日間収集し、昆虫PBS(PBS pH6.3)中で2回洗浄した。次に、細胞を溶解緩衝液(20mM HEPES pH7.5、150mM NaCl、3mM MgCl2、1mM β-メルカプトエタノール(BME)、5μg/mLロイペプチン、5μg/mLペプスタチンA、1μg/mLアプロチニンおよび0.1mM PMSF)中で再懸濁させ、-80℃で貯蔵用にスナップ凍結させた。細胞を氷上で解凍し、溶解緩衝液中で全体積30mLにし、N2空洞化(600psi、20分間)により破裂させた。低速遠心分離を行って任意の未溶解細胞を除去した(1000 x g、10分間)後、高速遠心分離(17,000 x g、30分間)を行った。最終遠心分離からのペレットを、20mM HEPES pH8、100mM NaCl、1%グリセリン、2μg/mLロイペプチン、2μg/mLペプスタチンA、2 μg/mLアプロチニン、0.1mM PMSFおよび10μM GDPを含有する緩衝液中で、小さいガラスホモジナイザーを使用して均質化した後、26ゲージ針に通した。膜をアリコートし、液体N2中でスナップ凍結させ、-80℃で貯蔵した。ヒトA1 AR(CHO K1細胞)またはA3 AR(HEK 293細胞)を安定に発現させる細胞からの膜を(Robeva et al., 1996)記載のように調製した。
Sf9細胞膜中の組換えヒトA2A受容体に対する放射性リガンド結合を、放射標識アゴニスト125I-APE (Luthin et al., 1995)または放射標識アンタゴニスト125I-ZM241385(125I-ZM)のいずれかを使用して行った。A1およびA3 ARの高親和性GTPγS感受性状態を検出するために、本発明者らはアゴニスト125I-ABA(Linden et al., 1985; Linden et al., 1993)を使用した。結合実験を、1 U/mLアデノシンデアミナーゼおよび5mM MgCl2を有し、50μM GTPγSの有り無しでの、全体積0.1mLのHE緩衝液(20mM HEPESおよび1mM EDTA)中で、5μg(A2A)または25μg(A1およびA3)の膜タンパク質を用いて三つ組で行った。膜を放射性リガンドと共にMillipore Multiscreen(登録商標)96ウェルGF/Cフィルタープレート中、室温で3時間(アゴニストの場合)または2時間(アンタゴニストの場合)インキュベートし、細胞ハーベスター(Brandel、メリーランド州ゲイサーズバーグ)上での急速な濾過によりアッセイを終了させた後、氷冷10mM Tris-HCl(pH 7.4)、10mM MgCl2を用いて30秒間にわたって4 x 150μl洗浄を行った。非特異的結合を50μM NECAの存在下で測定した。競合結合アッセイを、0.5〜1nM 125I-APE、125I-ZM241385または125I-ABAを使用して(Robeva et al., 1996)記載のように行った。各段階希釈後にピペットチップを変えて強力な疎水性化合物のチップ上への移動を防ぐことが時として重要であることを、本発明者らは発見した。単一部位に対する競合化合物結合のKi値を、(Linden, 1982)に既に記載のように放射性リガンドおよび競合化合物の欠乏について補正したIC50値から導き出した。
好中球酸化活性の尺度であるルミノール増強化学発光は、スーパーオキシド産生と顆粒酵素ミエロペルオキシダーゼの動員との両方に依存する。活性化好中球が生成する次亜塩素酸および一重項酸素などの不安定な高エネルギー酸素種から発光する。
f-met-leu-phe(fMLP)、ルミノール、スーパーオキシドジスムターゼ、チトクロムC、フィブリノーゲン、アデノシンデアミナーゼおよびトリパンブルーをSigma Chemicalから得た。フィコール・ハイパックをICN(オハイオ州オーロラ)、ならびにCardinal Scientific(ニューメキシコ州サンタフェ)およびAccurate Chemicals and Scientific(ニューヨーク州Westerbury)から購入した。エンドトキシン(リポ多糖; 大腸菌K235)はList Biologicals(カリフォルニア州キャンベル)からのものとした。ハンクス平衡塩類溶液(HBSS)およびカブトガニ血球抽出物アッセイキットはBioWittaker(メリーランド州ウォーカーズビル)からのものとした。ヒト血清アルブミン(HSA)はCutter Biological(インディアナ州エルクハート)からのものとした。組換えヒト腫瘍壊死因子αは大日本製薬(株)(日本、大阪)が供給した。ZM241385(4-(2-[7-アミノ-2-(2-フリル)[1,2,4]トリアゾロ[2,3-a][1,3,5]トリアジン-5-イルアミノ]エチル)フェノール)は英国チェシャー州Zeneca PharmaceuticalsのSimon Poucherからの寄贈物であった。保存液(DMSO中1mMおよび10mM)を作製し、-20℃で貯蔵した。
好中球5個当たり血小板1個未満およびエンドトキシン50pg/ml(カブトガニ血球抽出物アッセイ)を含有する精製好中球(好中球約98%、トリパンブルー排除により95%超が生存可能)を、正常ヘパリン化(10 U/ml)静脈血から、1段階フィコール・ハイパック分離手順(A. Ferrante et al., J. Immunol. Meth., 36, 109 (1980))により得た。
化学発光
好中球酸化活性の尺度であるルミノール増強化学発光は、スーパーオキシド産生とリソソーム顆粒酵素ミエロペルオキシダーゼの動員との両方に依存する。活性化好中球が生成する不安定な高エネルギー酸素種から発光する。0.1%ヒト血清アルブミン(1ml)を試験A2Aアゴニストと共に、ロリプラムの有り無しでかつ腫瘍壊死因子α(1U/ml)の有り無しで含有するハンクス平衡塩類溶液中で、精製好中球(5〜10 x 105/ml)を、振盪水浴中37℃で30分間インキュベートした。次に、ルミノール(1 x 10-4 M)増強f-met-leu-phe(1 mcM)で刺激した化学発光を、Chronolog(登録商標)光度計(Crono-log Corp.、ペンシルベニア州ヘイバータウン)によって37℃で2〜4分間読み取った。腫瘍壊死因子αを有しかつアゴニストまたはロリプラムを有さない試料と比較した相対ピーク発光(=曲線の高さ)として化学発光を報告する。
Claims (17)
- 式I、IIもしくはIIIの化合物、またはその立体異性体もしくは薬学的に許容される塩:
式中、
R1およびR2はHおよびC1-3アルキルより独立して選択され;
Zはシクロプロピル、シクロブチル、シクロペンチル、テトラヒドロフラニル、アゼチジン-2-オニル、ピロリジニルおよびピロリジン-2-オニルより選択され;
Zは0〜2個のZ2で置換され;
Z1はテトラヒドロフラニル、アゼチジン-2-オニル、ピロリジニルおよびピロリジン-2-オニルより選択され;
Z1は0〜2個のZ2で置換され;
Z2はF、C1-4アルキル、CF3、OCF3、(CH2)aOR3、(CH2)aNR3R3、NO2、(CH2)aCN、(CH2)aCO2R3および(CH2)aCONR3R3より独立して選択され;
R3はHおよびC1-6アルキルより独立して選択され;
R4はCH2ORおよびC(O)NRRより選択され;
各RはH、C1-4アルキル、シクロブチルおよび(CH2)aシクロプロピルより独立して選択され;
aは0、1および2より選択され;
qは1、2および3より選択される。 - 式Iの化合物であり、
R1およびR2がHであり;
Z2がF、C1-2アルキル、CF3、OCF3およびOR3より独立して選択され;
R3がHおよびC1-2アルキルより独立して選択され;
R4がC(O)NRRであり;
各RがH、C1-4アルキル、シクロプロピル、シクロブチルおよび-CH2-シクロプロピルより独立して選択され;
qが1である、
請求項1記載の化合物。 - 式IIの化合物であり、式中、
R1およびR2がHであり;
Zが0〜1個のZ2で置換され;
Z2がF、C1-2アルキル、CF3、OCF3およびOR3より独立して選択され;
R3がHおよびC1-2アルキルより独立して選択され;
R4がC(O)NRRであり;
各RがH、C1-4アルキル、シクロプロピル、シクロブチルおよび-CH2-シクロプロピルより独立して選択される、
請求項1記載の化合物。 - 式IIIの化合物であり、
R1およびR2がHであり;
Z1が0〜1個のZ2で置換され;
Z2がF、C1-2アルキル、CF3、OCF3およびOR3より独立して選択され;
R3がHおよびC1-2アルキルより独立して選択され;
R4がC(O)NRRであり;
各RがH、C1-4アルキル、シクロプロピル、シクロブチルおよび-CH2-シクロプロピルより独立して選択され;
qが0である、
請求項1記載の化合物。 - 式IIIの化合物であり、
R1およびR2がHであり;
Z1が0〜1個のZ2で置換され;
Z2がF、C1-2アルキル、CF3、OCF3およびOR3より独立して選択され;
R3がHおよびC1-2アルキルより独立して選択され;
R4がC(O)NRRであり;
各RがH、C1-4アルキル、シクロプロピル、シクロブチルおよび-CH2-シクロプロピルより独立して選択され;
qが1である、
請求項1記載の化合物。 - 請求項1記載の化合物および薬学的に許容される担体を含む薬学的組成物。
- 医学的治療における使用のための、請求項1〜14のいずれか一項記載の化合物。
- 哺乳動物における疾患の処置に有用な医薬の製造のための、請求項1〜14のいずれか一項記載の化合物の使用。
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CN101068825B (zh) * | 2004-08-02 | 2013-05-08 | 弗吉尼亚大学专利基金会 | 具有a2a激动剂活性的具有修饰的5'-核糖基团的2-丙炔基腺苷类似物 |
WO2007120972A2 (en) * | 2006-02-10 | 2007-10-25 | University Of Virginia Patent Foundation | Method to treat sickle cell disease |
US8188063B2 (en) * | 2006-06-19 | 2012-05-29 | University Of Virginia Patent Foundation | Use of adenosine A2A modulators to treat spinal cord injury |
US8058259B2 (en) * | 2007-12-20 | 2011-11-15 | University Of Virginia Patent Foundation | Substituted 4-{3-[6-amino-9-(3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid esters as A2AR agonists |
EA027929B1 (ru) | 2012-05-25 | 2017-09-29 | Янссен Сайенсиз Айрлэнд Юси | Нуклеозиды на основе урацила и спирооксетана |
US9822141B2 (en) | 2012-08-01 | 2017-11-21 | Lewis And Clark Pharmaceuticals, Inc. | N-alkyl 2-(disubstituted)alkynyladenosine-5-uronamides as A2A agonists |
AU2013296420B2 (en) | 2012-08-01 | 2017-12-07 | Lewis And Clark Pharmaceuticals, Inc. | N-alkyl 2-(disubstituted)alkynyladenosine-5-uronamides as A2A agonists |
EP3421482A1 (en) | 2012-12-21 | 2019-01-02 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
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US8252767B2 (en) | 2012-08-28 |
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US8293720B2 (en) | 2012-10-23 |
US20110003765A1 (en) | 2011-01-06 |
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