JP2017500325A - 置換されたジアミノピリミジル化合物、それらの組成物、及びそれらによる治療方法 - Google Patents
置換されたジアミノピリミジル化合物、それらの組成物、及びそれらによる治療方法 Download PDFInfo
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- JP2017500325A JP2017500325A JP2016541143A JP2016541143A JP2017500325A JP 2017500325 A JP2017500325 A JP 2017500325A JP 2016541143 A JP2016541143 A JP 2016541143A JP 2016541143 A JP2016541143 A JP 2016541143A JP 2017500325 A JP2017500325 A JP 2017500325A
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- GTRWMSOHJOEGLM-UHFFFAOYSA-N tert-butyl 3-methyl-2-oxo-3h-indole-1-carboxylate Chemical compound C1=CC=C2C(C)C(=O)N(C(=O)OC(C)(C)C)C2=C1 GTRWMSOHJOEGLM-UHFFFAOYSA-N 0.000 description 1
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- HQXCHIODIJRHAT-UHFFFAOYSA-N tert-butyl n-(2-oxospiro[3.3]heptan-6-yl)carbamate Chemical compound C1C(NC(=O)OC(C)(C)C)CC21CC(=O)C2 HQXCHIODIJRHAT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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Abstract
Description
特定のアルキルヘテロアリール-ジアミノピリミジル化合物、そのような化合物の有効量を含有する組成物、及びこのようなアルキルヘテロアリール-ジアミノピリミジル化合物の有効量を、それを必要とする対象に投与することを含む、PKC-θ媒介性障害を治療又は予防する方法が、本明細書において提供される。
異常なタンパク質リン酸化と疾患の原因又は結果の間の結びつきは、20年以上周知のことである。従って、プロテインキナーゼは、非常に重要な薬物標的群となってきている。[Cohenの文献、Nature, 1:309-315 (2002);Gaestelらの文献、Curr.Med.Chem.14: 2214-223 (2007);Grimmingerらの文献、Nat. Rev. Drug Disc. 9(12):956-970 (2010)参照]。様々なプロテインキナーゼインヒビターが、癌、並びに、関節リウマチ及び乾癬を含む慢性炎症性疾患などの、多種多様な疾患の治療において、臨床で使用されている。[Cohenの文献、Eur. J. Biochem., 268:5001-5010 (2001);「疾患治療のためのプロテインキナーゼインヒビター:将来性と問題点(Protein Kinase Inhibitors for the Treatment of Disease: The Promise and the Problems)」、Handbook of Experimental Pharmacology, Springer Berlin Heidelberg, 167 (2005)参照]。
下記式(I)を有する化合物、又はそれらの医薬として許容し得る塩、互変異性体、アイソトポログ、又は立体異性体(式中、L、X、R1及びR2は、本明細書に定義されている。):
(定義)
「アルキル」基は、1〜10個の炭素原子、典型的には、1〜8個の炭素、又は一部の実施態様においては、1〜6個、1〜4個、若しくは2〜6個の炭素原子を有する、飽和した、部分的に飽和した、又は不飽和の直鎖又は分岐状非環式炭化水素である。代表的なアルキル基としては、-メチル、-エチル、-n-プロピル、-n-ブチル、-n-ペンチル、及び-n-ヘキシルが挙げられ;一方、飽和分岐アルキルとしては、-イソプロピル、-sec-ブチル、-イソブチル、-tert-ブチル、-イソペンチル、-ネオペンチル、tert-ペンチル、-2-メチルペンチル、-3-メチルペンチル、-4-メチルペンチル、-2,3-ジメチルブチルなどが挙げられる。不飽和アルキル基の例としては、特に、ビニル、アリル、-CH=CH(CH3)、-CH=C(CH3)2、-C(CH3)=CH2、-C(CH3)=CH(CH3)、-C(CH2CH3)=CH2、-C≡CH、-C≡C(CH3)、-C≡C(CH2CH3)、-CH2C≡CH、-CH2C≡C(CH3)、及び-CH2C≡C(CH2CH3)が挙げられるが、これらに限定されない。アルキル基は、置換されていても、置換されていなくてもよい。本明細書に記載のアルキル基が「置換されている」と言われるとき、それらは、本明細書に開示される例示的な化合物及び実施態様に見られるもの、並びにハロゲン(クロロ、ヨード、ブロモ、若しくはフルオロ);アルキル;ヒドロキシル;アルコキシ;アルコキシアルキル;アミノ;アルキルアミノ;カルボキシ;ニトロ;シアノ;チオール;チオエーテル;イミン;イミド;アミジン;グアニジン;エナミン;アミノカルボニル;アシルアミノ;ホスホネート;ホスフィン;チオカルボニル;スルフィニル;スルホン;スルホンアミド;ケトン;アルデヒド;エステル;ウレア;ウレタン;オキシム;ヒドロキシルアミン;アルコキシアミン;アラルコキシアミン;N-オキシド;ヒドラジン;ヒドラジド;ヒドラゾン;アジド;イソシアネート;イソチオシアネート;シアネート;チオシアネート;B(OH)2、又はO(アルキル)アミノカルボニルのような、任意の置換基(単数)又は置換基(複数)で置換されていてもよい。
下記式(I)を有する化合物、又はそれらの医薬として許容し得る塩、互変異性体、アイソトポログ、又は立体異性体を、本明細書において提供する:
Xは、CN又はCF3であり;
Lは、(C1-4アルキル)であり;
R1は、置換又は非置換のヘテロアリールであり;並びに
R2は、置換又は非置換のシクロアルキルである。)。
本ジアミノピリミジル化合物は、従来の有機合成及び市販の出発材料を用いて製造することができる。限定するものではない例として、式(I)のジアミノピリミジル化合物は、以下に示したスキーム1及び2、並びに以下に定める実施例に概略したように調製することができる。当業者は、所望の生成物に到達するために、例証的スキーム及び実施例に定めた手順を改変する方法を知っていることは留意されたい。
(式中、
Xは、CN又はCF3であり;
Lは、(C1-4アルキル)であり;
R1は、置換又は非置換のヘテロアリールであり;並びに
R2は、置換又は非置換のシクロアルキルである。)。
(式中、
Xは、CN又はCF3であり;
Lは、(C1-4アルキル)であり;
R1は、置換又は非置換のヘテロアリールであり;並びに
R2は、置換又は非置換のシクロアルキルであり;
Rxは、C1-2アルキルであり;並びに
mは、1又は2である。)。
本ジアミノピリミジル化合物は、動物又はヒトにおいて、状態を治療、予防又は改善するための医薬品としての有用性を有する。更に、本ジアミノピリミジル化合物は、プロテインキナーゼ、特にPKC-θに対して活性がある。従って、以下に定めるそれらの疾患の治療又は予防を含む、ジアミノピリミジル化合物の多くの用途が、本明細書において提供される。本明細書に提供される方法は、1種以上のジアミノピリミジル化合物(複数可)の有効量を、それを必要とする対象へ投与することを含む。
本ジアミノピリミジル化合物は、カプセル剤、マイクロカプセル、錠剤、顆粒剤、散剤、トローチ剤、丸剤、坐剤、注射剤、懸濁剤、シロップ剤、貼付剤、クリーム、ローション、軟膏、ゲル剤、スプレー、液剤及び乳剤などの、従来の調製品の形状で、経口、局所的又は非経口で、対象へ投与することができる。好適な製剤は、従来の有機又は無機添加物、例えば、賦形剤(例えば、スクロース、デンプン、マンニトール、ソルビトール、ラクトース、グルコース、セルロース、タルク、リン酸カルシウム、又は炭酸カルシウム)、結合剤(例えば、セルロース、メチルセルロース、ヒドロキシメチルセルロース、ポリプロピルピロリドン、ポリビニルピロリドン、ゼラチン、アラビアゴム、ポリエチレングリコール、スクロース、又はデンプン)、崩壊剤(例えば、デンプン、カルボキシメチルセルロース、ヒドロキシプロピルデンプン、低置換ヒドロキシプロピルセルロース、炭酸水素ナトリウム、リン酸カルシウム、又はクエン酸カルシウム)、滑沢剤(例えば、ステアリン酸マグネシウム、軽質無水ケイ酸、タルク、又はラウリル硫酸ナトリウム)、香味剤(例えば、クエン酸、メントール、グリシン、又はオレンジパウダー)、防腐剤(例えば、安息香酸ナトリウム、亜硫酸水素ナトリウム、メチルパラベン、又はプロピルパラベン)、安定化剤(例えば、クエン酸、クエン酸ナトリウム、又は酢酸)、懸濁化剤(例えば、メチルセルロース、ポリビニルピロリクロン(pyrroliclone)、又はステアリン酸アルミニウム)、分散剤(例えば、ヒドロキシプロピルメチルセルロース)、希釈剤(例えば、水)、及び基剤ワックス(例えば、カカオバター、白色ワセリン、又はポリエチレングリコール)を用いて、一般に利用される方法によって製造することができる。医薬組成物中のジアミノピリミジル化合物の有効量は、所望の効果を発揮するであろうレベル;例えば、経口投与と非経口投与の両方についての単位投薬量で対象の体重1kg当たり約0.005mgから対象の体重1kg当たり約10mgであってよい。
下記実施例は、限定ではなく、例証として提示されている。化合物は、Chemdraw Ultra 9.0 (Cambridgesoft)で提供される自動名称作製ツールを使用し命名したが、これは立体化学に関するカーン・インゴルド・プレローグ則の支援を受けて、化学構造に関して系統的に名称を作製する。当業者は、所望の生成物、例えば、表1及び2に列挙した化合物に到達するために、例証的実施例において定めた手順を改変することができる。
(実施例1:2-(((4-(2,2-ジフルオロプロポキシ)ピリミジン-5-イル)メチル)アミノ)-4-(((1R,4S)-4-ヒドロキシ-3,3-ジメチルシクロヘキシル)アミノ)ピリミジン-5-カルボニトリル)
、及び4-(((1R,4S)-4-ヒドロキシ-3,3-ジメチルシクロヘキシル)アミノ)-2-((2-((R)-3-メチル-2-オキソインドリン-3-イル)エチル)アミノ)ピリミジン-5-カルボニトリル(ピーク2:22.4mg, 0.052mmol, 収率6.6%, 99.1%e.e.)
を供した。
(生化学アッセイ)
(PKC-θアッセイ) 384-ウェルの時間分解蛍光アッセイを使用し、PKC-θ活性をモニタリングした。PKC-θアッセイは、下記のアッセイ緩衝液において試行した:50mM HEPES pH7.6、10mM MgCl2、1mM DTT、0.01%Triton X-100、0.01%BSA及び0.1mM EDTA。反応を開始するために、200nM Fam-標識したS6-由来のペプチド(Molecular Devices社)及び10μM ATPを、142pM His-PKC-θ(Invitrogen社)と、各ウェル中総アッセイ容積25μLで混合した。このアッセイ物を、室温で2時間インキュベーションし、検出結合溶液:70%IMAP段階的結合緩衝液A、30%IMAP段階的結合緩衝液B、1:600段階的結合試薬、及び1:400 TR-FRET Tbドナー(Molecular Devices社)の60μL/ウェル混合物を用いて終結した。次にこのアッセイプレートを、室温で一晩インキュベーションし、Perkin-Elmer Envision Reader上で測定した。IC50値は、蛍光シグナルのレベルを、そのシグナルウィンドウの50%まで減少する化合物の濃度として計算した。
(ジャーカット細胞アッセイ:CD3/CD8-刺激したIL-2分泌) 被験化合物濃度の範囲にわたるPKC-θの細胞内阻害を、ヒトジャーカット細胞において、IL-2サイトカイン産生を測定することにより、評価した。ATCCからのヒトジャーカットクローンE6-1を、これらの試験に使用した。細胞を、炎症誘発性サイトカインを発現するために、抗-CD3(Life Technologies/Invitrogen社)及び抗-ヒトCD28(BD Biosciences社)により、インビトロにおいて活性化した。ジャーカット細胞は、1.0mMピルビン酸ナトリウム、2mM L-グルタミン、10mM Hepes、1.0mM非必須アミノ酸、100IU/mLペニシリン、100μg/mLストレプトマイシン及び10%ウシ胎仔血清を補充したRPMI 1640培地内で培養した。細胞を、透明な96-ウェル丸底プレート上のRPMI完全培地(200μL/ウェル)中1ウェルにつき細胞50万個の密度で播種した。
(急性T細胞活性化モデル) マウスにおけるSEB媒介性サイトカイン放出。ブドウ球菌性エンテロトキシン(SEA、B、C、D及びE)は、T細胞の広いスペクトルに対するそれらの優れた効果のために、これらはスーパー抗原(sAg)と称される。これらは、ヒト、マウス及びウサギのT細胞に対し分裂促進性であり、且つIL-2、IFN-γ及びIL-6などのサイトカインの大量の放出を引き起こす。マウス及びラットのSEB媒介性T細胞活性化モデルは、T-細胞活性化を阻害する化合物を同定する迅速で信頼し得るモデルである。
表1及び2の各化合物を、1種以上の生化学アッセイにおいて試験し、その点で活性を有することがわかり、全ての化合物は、PKC-θアッセイにおいて10μM以下のIC50を有し、一部の化合物は100nM以下のIC50を有し(活性レベルD)、一部は100nM〜800nMのIC50を有し(活性レベルC)、一部は800nM〜2μMのIC50を有し(活性レベルB)、並びに他のものは2μM〜10μMのIC50を有する(活性レベルA)。これらの化合物はまた、PKC-δを上回るPKC-θの選択性を有することがわかり、その一部の化合物は、100倍超の選択性(選択性レベル=IC50 PKC-δ/IC50 PKC-θの比)(選択性レベルE)を示し、一部は20倍〜100倍の選択性(選択性レベルF)を、一部は5倍〜20倍の選択性(選択性レベルG)を、他のものは5倍以下の選択性レベル(選択性レベルH)を有する。
Claims (34)
- 前記Xが、CNである、請求項1記載の化合物。
- 前記Xが、CF3である、請求項1記載の化合物。
- 前記Lが、CH2、CH2CH2又はCH2CH2CH2である、請求項1記載の化合物。
- 前記R1が、置換又は非置換のピリジル、ピリジル-1-オキシド、又はピリミジルである、請求項1記載の化合物。
- 前記R1が、ハロゲン、-OR3、置換若しくは非置換のC1-4アルキル、又は置換若しくは非置換のアリールの1以上により置換され、ここで各R3は独立して、H、置換若しくは非置換のC1-6アルキル、又は置換若しくは非置換のアリールである、請求項5記載の化合物。
- 前記R1が、F、Cl、Br、I、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、t-ブチル、フェニル、ナフチル、-CH2F、-CHF2、-CF3、-CHFCH3、-CF2CH3、-C(CH3)2F、-OCH3、-OCH2F、-OCHF2、-OCF3、-OCH2CH3、-OCH2CH2F、-OCH2CHF2、-OCH2CF3、-OCH2CH(CH3)F、-OCH2C(CH3)2F、-OCH2C(CH3)F2、-OCH2CH2CF3、又は-O-フェニルの1以上により置換され、ここで各フェニルは、ハロゲン又は置換若しくは非置換のC1-4アルキルにより、任意に置換されている、請求項5記載の化合物。
- 前記R1が、F、Cl、メチル、エチル、イソプロピル、フェニル、-CF3、-CF2CH3、-C(CH3)2F、-OCH3、-OCH2CH3、-OCH2CF3、-OCH2CH2F、-OCH2CHF2、-OCH2C(CH3)F2、-OCH2CH2CF3、又は-O-フェニルの1以上により置換され、ここで各フェニルは、F又はメチルにより任意に置換されている、請求項5記載の化合物。
- 前記R1が、置換又は非置換のインドリル、インドリノニル、ベンゾオキサゾリル、ピロロピリジル、インダゾリル、ベンゾイミダゾリル、ジヒドロベンゾイミダゾロニル、又はキノリルである、請求項1記載の化合物。
- 前記R1が、ハロゲン、CN、-OR3、置換若しくは非置換のC1-4アルキル、又は置換若しくは非置換のアリールの1以上により置換され、ここで各R3は独立して、H、置換若しくは非置換のC1-6アルキル、又は置換若しくは非置換のアリールである、請求項9記載の化合物。
- 前記R1が、F、Cl、CN、メチル、エチル、-CH2SO2NHCH3、-OH、-OCH3、又はOCF3の1以上により置換されている、請求項9記載の化合物。
- 前記R1が、置換又は非置換のフラニル、ピロリル、チオフェニル、オキサゾリル、ピラゾリル、イミダゾリル、オキサジアゾリル、又はトリアゾリルである、請求項1記載の化合物。
- 前記R1が、ハロゲン、CN、-OR3、置換若しくは非置換のC1-4アルキル、又は置換若しくは非置換のアリールの1以上により置換され、ここで各R3は独立して、H、置換若しくは非置換のC1-6アルキル、又は置換若しくは非置換のアリールである、請求項12記載の化合物。
- 前記R1が、CN、メチル、エチル、-CF3、又は-CH2OCH3の1以上により置換されている、請求項12記載の化合物。
- 前記R2が、置換又は非置換のC3-12シクロアルキルである、請求項1記載の化合物。
- 前記R2が、置換又は非置換のシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、又はアダマンチルである、請求項15記載の化合物。
- 前記R2が、C1-4アルキル、-OR4、又は-C(=O)NR2の1以上により置換され、ここで各R4は独立して、H又はC1-6アルキルであり、並びに各Rは独立して、H又はC1-4アルキルである、請求項15記載の化合物。
- 前記R2が、メチル、エチル、プロピル、イソプロピル、-CH2OH、-CH(CH3)OH、-C(CH3)2OH、-OH、-OCH3、-OCH2CH3、-C(=O)NH2、-C(=O)NHCH3、又は-C(=O)N(CH3)2の1以上により置換されている、請求項15記載の化合物。
- 前記R2が、メチル、-CH2OH、-C(CH3)2OH、-OH、-OCH3、又は-C(=O)NHCH3の1以上により置換されている、請求項15記載の化合物。
- 前記R2が、置換又は非置換のスピロ[3.3]ヘプチル、又はビシクロオクチルである、請求項15記載の化合物。
- 前記R2が、C1-4アルキル、-OR4、-C(=O)NR2、又はトリアゾリルの1以上により置換され、ここで各R4は独立して、H又はC1-6アルキルであり、並びに各Rは独立して、H又はC1-4アルキルである、請求項15記載の化合物。
- 前記R2が、メチル、トリアゾリル、-CH2OH、-C(CH3)2OH、-OH、-OCH3、-C(=O)NH2、-C(=O)NHCH3、又は-C(=O)N(CH3)2の1以上により置換されている、請求項15記載の化合物。
- 10μMの濃度の前記化合物が、PKC-θを少なくとも約50%阻害する、請求項1記載の化合物。
- 前記化合物が、表1から選択される、請求項20記載の化合物。
- 表2から選択される化合物。
- 請求項1、24若しくは25記載の化合物、又はそれらの医薬として許容し得る塩、互変異性体、アイソトポログ、若しくは立体異性体の有効量、並びに医薬として許容し得る担体、賦形剤若しくはビヒクルを含有する、医薬組成物。
- キナーゼを発現している細胞において該キナーゼを阻害する方法であって、該細胞を、請求項1、24若しくは25記載の化合物、又はそれらの医薬として許容し得る塩、互変異性体、アイソトポログ、若しくは立体異性体の有効量と接触させることを含む、前記方法。
- 前記キナーゼが、PKC-θである、請求項27記載の方法。
- 前記化合物が、PKC-δを上回りPKC-θに選択性である、請求項28記載の方法。
- 前記化合物が、PKC-δ及びPKC-ηを上回りPKC-θに選択性である、請求項28記載の方法。
- 前記化合物が、PKC-δを上回りPKC-θに少なくとも5倍選択性である、請求項29記載の方法。
- 前記化合物が、PKC-δよりもPKC-θに100倍超選択性である、請求項29記載の方法。
- PKC-θ媒介性障害を治療又は予防する方法であって、請求項1、24若しくは25記載の化合物、又はそれらの医薬として許容し得る塩、互変異性体、アイソトポログ、若しくは立体異性体の有効量を、それを必要とする対象へ投与することを含む、前記方法。
- 前記PKC-θ媒介性障害が、移植片対宿主疾患、臓器移植拒絶反応、乾癬、デュシェンヌ型筋ジストロフィー、関節リウマチ、糖尿病、インスリン抵抗性、重症筋無力症、多発性硬化症、大腸炎、乾癬性関節炎、強直性脊椎炎、アトピー性皮膚炎、シェーグレン症候群、喘息又は狼瘡から選択される、請求項33記載の方法。
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