JP2013521295A - イムノプロテアソーム阻害のための化合物 - Google Patents
イムノプロテアソーム阻害のための化合物 Download PDFInfo
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- JP2013521295A JP2013521295A JP2012556160A JP2012556160A JP2013521295A JP 2013521295 A JP2013521295 A JP 2013521295A JP 2012556160 A JP2012556160 A JP 2012556160A JP 2012556160 A JP2012556160 A JP 2012556160A JP 2013521295 A JP2013521295 A JP 2013521295A
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- alkyl
- compound according
- compound
- hydrogen
- aralkyl
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- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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Abstract
プロテアソーム活性よりも優先的に阻害する阻害剤に関する。いくつかの実施態様では、本発明は、本発明の化合物を投与するステップを含む免疫関連疾患を処置する方法に関する。いくつかの実施態様では、本発明は、本発明の化合物を投与するステップを含む、癌の処置に関する。
Description
本願は、言及をもってその内容全体をここに援用することとする、2010年3月1日出願の米国仮出願第61/309,366号に基づく優先権を主張するものである。
真核生物においては、タンパク質分解は、破壊の標的となったタンパク質が76アミノ酸のポリペプチドであるユビキチンに連結されるユビキチン経路を通じて主に媒介される。標的に決定されたユビキチン化タンパク質は次に、その三つの主要なタンパク質分解活性の作用を通じてタンパク質を切断してより短いペプチドにする、多重触媒性プロテアーゼである26Sプロテアソームの基質として働く。細胞内タンパク質ターンオーバーにおいて一般的な機能を有しながらも、プロテアソーム媒介性分解はまた、主要組織適合性複合体 (MHC) クラスI提示、アポトーシス及び細胞生存、抗原プロセッシング、NFκB 活性化、及び炎症誘発シグナルの伝達など、数多くのプロセスで鍵となる役割を果たす。
kDa の筒状の多重触媒性プロテアーゼ複合体であり、4つに積層したヘプタマー環に並んだ、α-及びβ-タイプと分類される28個のサブユニットから成る。酵母及び他の真核生物においては、7種の異なるαサブユニットが外側の環を形成し、7種の異なるβサブユニットが内側の環を含む。αサブユニットは19S (PA700) 及び11S (PA28) 調節性複合体にとっての結合部位や、二つのβサブユニット環によって形成された内側のタンパク質分解チャンバーのための物理的障壁の役目をする。このように、in vivoでは、プロテアソームは 26S 粒子(「26S プロテアソーム」)として存在すると考えられる。In vivo実験では、プロテアソームの20S型の阻害を、26Sプロテアソームの阻害と容易に相関させることができることが示されている。
(PVA)、グルタミン PRPP アミドトランスフェラーゼ(GAT)、及び細菌性グリコシルアスパラギナーゼが含まれる。広汎発現性のβサブユニットに加え、より高等な脊椎動物は更に、それらの通常の相対物であるそれぞれβ5、β1及びβ2に替わる三つのインターフェロン-γ誘導性βサブユニット(LMP7、LMP2 及びMECLl)を持つ。三つのIFN-γ誘導性サブユニットの全てが存在する場合、そのプロテアソームは「イムノプロテアソーム」と呼ばれる。このように、真核細胞は二つの形のプロテアソームを様々な比率で持つことができる。
本発明の局面の一つは、イムノプロテアソーム活性を構成的プロテアソーム活性よりも優先的に阻害する阻害剤に関する。いくつかの実施態様では、本発明は、本発明の化合物を投与するステップを含む、免疫関連疾患の処置に関する。いくつかの実施態様では、本発明は、本発明の化合物を投与するステップを含む、癌の処置に関する。
から個別に選択され;あるいは
Aは、Zに隣接する場合には選択的に共有結合であり;
Y は存在しないか、又は
N(R7)(R8)であり;
M は存在しないか、又はC1-12アルキルであり;
各Z はO、S、NH、及びN-C1-6アルキルから個別に選択され;あるいは
Z はAに隣接する場合には選択的に共有結合であり、
R1 は水素、-C1-6アルキル-Y、C1-6ヒドロキシアルキル、C1-6アルコキシアルキル、アリール、及びC1-6アラルキルから選択され;
R2 はアリール、ヘテロアリール、C1-6アラルキル及びC1-6ヘテロアラルキルから選択され;
R3 はアリール、ヘテロアリール、C1-6ヘテロアラルキル、C1-6アラルキル及びC1-6アルキルから選択され;
R4 及びR5 はそれぞれ個別に水素、C1-6アラルキル、及びC1-6アルキルから選択され;あるいは 、
R4 及びR5 は共にC1-12アルキルであることで環を形成し;
R6 は水素、C1-6アルキル、C1-6アルケニル、C1-6アルキニル、カルボシクリル、ヘテロシクリル、N末端保護基、アリール、C1-6アラルキル、ヘテロアリール、C1-6ヘテロアラルキル、R9ZAZ-C1-8アルキル-、R12Z-C1-8アルキル-、(R9O)(R10O)P(=O)O-C1-8アルキル-ZAZ-C1-8アルキル-、9, ヘテロシクリルMZAZ-C1-8アルキル-、 (R9O)(R10O)P(=O)O-C1-8アルキル-、 (R11)2N-C1-12アルキル-、 (R11)3N+-C1-12アルキル-、 ヘテロシクリルM-、 カルボシクリルM-、 R12SO2C1-8アルキル-、及びR12SO2NHから選択され;
R7 は水素、 OH、及びC1-6アルキルから選択され;
R8 はN末端保護基であり、R7 及びR8 は個別に水素、 C1-6アルキル、及びC1-6アラルキルから選択され、好ましくは水素であり;
R9 及びR10
は個別に水素、金属陽イオン、 C1-6アルキル、 C1-6アルケニル、 C1-6アルキニル、 アリール、 ヘテロアリール、 C1-6アラルキル、及びC1-6ヘテロアラルキルから選択され、好ましくは水素、 金属陽イオン、及びC1-6アルキルから選択され、あるいはR11 及びR12 は共にC1-6アルキルであることで環を形成し;
各R11 は個別に水素およびC1-6アルキルから選択され、好ましくはC1-6アルキルであり;そして
R12 は個別に水素、 C1-6アルキル、 C1-6アルケニル、 C1-6アルキニル、 カルボシクリル、 ヘテロシクリル、
アリール、 ヘテロアリール、 C1-6アラルキル、及びC1-6ヘテロアラルキルから選択される。
本発明は酵素阻害剤として有用な化合物に関する。これらの化合物は、概して、N末端に求核性基を有する酵素を阻害するために有用である。例えばスレオニン、セリン、又はシステインなど、求核剤をそれらの側鎖に持つN末端アミノ酸を有する酵素又は酵素サブユニットの活性を、ここで解説する酵素阻害剤により成功裏に阻害することができる。例えば保護基又は糖など、それらのN末端に非アミノ酸求核性基を有する酵素又は酵素サブユニットの活性もまた、ここで解説する酵素阻害剤により成功裏に阻害することができる。
Organic Chemistry, Fox and Whitesell; Jones and Bartlett Publishers, Boston, MA
(1994); Section 5-6, pp 177-178に記載されている。ペプチドは骨格単位から延びる側鎖を持つ反復骨格構造を有する場合がある。一般的には、各骨格単位は、それに関連する側鎖を有し、場合によってはであるが、該側鎖は水素原子である。他の実施態様では、各骨格単位のすべてが、関連する側鎖を有するわけではない。
[-NH-CHR-C(=O)-]である。このような指示は、当業者には認識されるであろうが、天然発生型のアミノ酸プロリン、又は他の非天然発生型の環状二級アミノ酸を除外するものではない。
Hruby and Boteju, in “Molecular Biology and Biotechnology: A Comprehensive Desk
Reference”, ed. Robert A. Meyers, VCH Publishers (1995), pp. 658-664に論じられた他の修飾を含めることができる。
から選択され;あるいは
A はZに隣接する場合には選択的に共有結合であり;
Y は存在しないか、又はN(R7)(R8)であり;
Mは存在しないか、又はC1-12アルキルであり;
各Z は個別にO、S、NH、及びN-C1-6アルキルから選択され;あるいは
Z はAに隣接する場合には選択的に共有結合であり、
R1 は水素、-C1-6アルキル-Y、C1-6ヒドロキシアルキル、C1-6アルコキシアルキル、アリール、及びC1-6アラルキルから選択され;
R2 はアリール、ヘテロアリール、C1-6アラルキル及びC1-6ヘテロアラルキルから選択され;
R3 はアリール、ヘテロアリール、C1-6ヘテロアラルキル、C1-6アラルキル及びC1-6アルキルから選択され;
R4 及びR5 はそれぞれ個別に水素、 C1-6アラルキル、及びC1-6アルキルから選択され;あるいは
R4 及びR5 は共にC1-12アルキルであることで一個の環を形成し;
R6 は水素、 C1-6アルキル、 C1-6アルケニル、 C1-6アルキニル、 カルボシクリル、 ヘテロシクリル、N末端保護基、アリール、C1-6アラルキル、ヘテロアリール、C1-6ヘテロアラルキル、R9ZAZ-C1-8アルキル-、R12Z-C1-8アルキル-、(R9O)(R10O)P(=O)O-C1-8アルキル-ZAZ-C1-8アルキル-、9, ヘテロシクリルMZAZ-C1-8アルキル-、 (R9O)(R10O)P(=O)O-C1-8アルキル-、(R11)2N-C1-12アルキル-、(R11)3N+-C1-12アルキル-、ヘテロシクリルM-、カルボシクリルM-、R12SO2C1-8アルキル-、及びR12SO2NHから選択され;
R7 は水素、OH、及びC1-6アルキルから選択され;
R8 はN末端保護基でありR7 及び R8 は個別に水素、C1-6アルキル、及びC1-6アラルキルから選択され、好ましくは水素であり;
R9 及びR10
は個別に水素、金属陽イオン、C1-6アルキル、C1-6アルケニル、C1-6アルキニル、アリール、ヘテロアリール、C1-6アラルキル、及びC1-6ヘテロアラルキルから選択され、好ましくは水素、 金属陽イオン、及びC1-6アルキルから選択され、あるいはR11
及び R12 は共にC1-6アルキルであることで一個の環を形成し;
各R11 は個別に水素
及びC1-6アルキルから選択され、好ましくはC1-6アルキルであり;そして
R12 は個別に水素、C1-6アルキル、C1-6アルケニル、C1-6アルキニル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、C1-6アラルキル、及びC1-6ヘテロアラルキルから選択される。
はメチル、エチル、イソプロピル、カルボキシメチル、及びベンジルから選択され、好ましくはメチルである。
はC1-6アラルキル及びC1-6ヘテロアラルキルから選択される。いくつかのこのような実施態様では、R2
はC1-6アルキル-フェニル、C1-6アルキル-インドリル、C1-6アルキル-チエニル, C1-6アルキル-チアゾリル、及びC1-6アルキル-イソチアゾリルから選択され、この場合のアルキル部分は6個、5個、4個、3個、2個、又は1個の炭素原子を含有していてもよく、又は好ましくは1個又は2個の炭素原子を有していてもよい。いくつかのこのような実施態様では、R2 はヒドロキシ、ハロゲン、アミド、アミン、カルボン酸(又はその塩)、エステル(C1-6アルキルエステル、C1-5アルキルエステル、及びアリールエステルを含む)、チオール、又はチオエーテルから選択される一つ以上の置換基で置換される。いくつかのこのような実施態様では、R2 は、アルキル、トリハロアルキル、アルコキシ、ヒドロキシ、又はシアノ、好ましくはヒドロキシ又はアルコキシ、例えばメトキシ、から選択される置換基で置換される。いくつかの実施態様では、R2 は、C1-6アルキル-フェニル及びC1-6アルキル-インドリルから選択される。いくつかの好適な実施態様では、R2 は
は、C1-6アラルキル及びC1-6アルキルから選択される。いくつかの実施態様では、アルキル部分は6個、5個、4個、3個、2個、又は1個の炭素原子を含有してもよいが、好ましくは1個又は2個の炭素原子を含有するとよい。いくつかのこのような実施態様では、R3 は、ヒドロキシ、ハロゲン、アミド、アミン、カルボン酸(又はその塩)、エステル(C1-6アルキルエステル、C1-5アルキルエステル、及びアリールエステルを含む)、チオール、又はチオエーテルから選択される一つ以上の置換基で置換される。いくつかのこのような実施態様では、R3 は、アルキル、トリハロアルキル、アルコキシ、ヒドロキシ、又はシアノから選択される置換基で置換される。いくつかの実施態様では、R3はs C1-6アルキル-フェニルである。いくつかの好適なこのような実施態様では、R3 は、
及びR5 は個別に水素 及び及びC1-6アルキルから選択され、好ましくはR4 及びR5 は両者ともに水素であるとよい。いくつかの代替的な実施態様では、R4 及びR5 は共にC1-12アルキルであることで一個の環を形成する。いくつかの好適なこのような実施態様では、R4
及びR5 は二つの隣接する酸素原子及びホウ素と一緒になってピナコールボロネートエステルを形成する。
は、カルボシクリル、アリール、及びヘテロシクリルM-から選択される。いくつかのこのような実施態様では、R6 はカルボシクリル又はアリールである。いくつかのこのような実施態様では、R6
は、例えばメチルインデン、特に3-メチルインデンなどのインデンである。いくつかの代替的な実施態様では、R6
はヘテロシクリルM-であり、但しこの場合のヘテロシクリルはモルホリノ、ピペリジノ、ピペラジノ、及びピロリジノから選択され、好ましくはモルホリノである。いくつかの好適なこのような実施態様では、Mは C1-12アルキルである。
はそれぞれ個別に水素、アルキル、アルケニル、- (CH2)m-R8
を表し、あるいはR9 及びR10
は、これらが結合した先のN原子と一緒に捉えると、環構造内に4乃至8個の原子を有する複素環を完成し;R8 はアリール、シクロアルキル、シクロアルケニル、ヘテロシクリル又はポリシクリルを表し; そしてm はゼロであるか、又は1乃至8の整数である。好適な実施態様では、R9 又は R10
の一方のみがカルボニルであってよく、例えばR9、R10、及び窒素が一緒になってイミドを形成していないなどである。更により好適な実施態様では、R9 及びR10
(及び選択的にR10’)はそれぞれ個別に水素、アルキル、アルケニル、又は -(CH2)m-R8を表す。いくつかの実施態様では、アミノ基は塩基性であり、つまりそれがpKa > 7.00を有することを意味する。これらの官能基のプロトン化型は7.00を超えるpKas
を有する。
又は薬学的に許容可能な塩を表し、R11’ は水素、アルキル、アルケニル 又は -(CH2)m-R8を表す(この場合m 及びR8
は上に定義した通りである)。 X が酸素であり、そしてR11
又はR11’ が 水素でない場合、該式は「エステル」を表す。X が酸素であり、そしてR11
が水素である場合、該式は「カルボン酸」を表す。
感染の防止には、例えば、未処置のコントロール集団に比較して処置集団において感染の診断数を減少させること、及び/又は、未処置のコントロール集団に比較して処置集団において感染の症状発症を遅らせること、が含まれる。疼痛の防止には、例えば、未処置のコントロール集団に比較して処置集団において対象の経験する疼痛感の程度を低下させること又は代替的には遅らせることが含まれる。
プロテアソーム阻害の生物学的結果は多数である。プロテアソーム阻害は、限定はしないが、増殖性疾患、神経毒性/変性疾患、虚血状態、炎症、免疫関連疾患、HIV、癌、臓器移植拒絶、敗血性ショック、ウィルス及び寄生生物感染、アシドーシスに関連する状態、黄斑部変性、肺の状態、筋肉疲労疾患、線維性疾患、骨及び毛髪の成長疾患を含め、多数の疾患の防止及び/処置として示唆されてきた。
2006)。このような免疫関連状態の他の例には、狼瘡(例えば狼瘡腎炎及び全身性エリテマトーデス)、リウマチ様関節炎(例えば若年性リウマチ様関節炎及び乾癬性リウマチ様関節炎)、強皮症、強直性脊椎炎、皮膚筋炎、乾癬、多発性硬化症(再発性弛張性及び慢性進行性型の両者を含む)及び炎症性腸疾患(例えば潰瘍性腸炎及びクローン病)がある。組織/臓器移植片拒絶は、免疫系が、ホストの身体に導入されつつある細胞を誤って攻撃するときに起きる。移植片対宿主疾患 (GVHD)は異種移植が原因であり、ドナー組織由来のT細胞が攻撃的になり、ホストの組織を攻撃するときに生じる。自己免疫疾患、移植片拒絶及びGVHDという三つの状況の全てにおいて、本発明の化合物で対象を処置することで免疫系を調節すると、有益であろう。
FASEB J 18:39-51, 2004)。筋肉疲労は、癌、敗血症、腎不全、AIDS、飢餓、除神経、委縮、アシドーシス、糖尿病、廃用委縮及びうっ血性心不全を含め、生命を脅かす複数の疾患で症状発現する。いくつかの実施態様では、本発明は、ここに開示した通りの化合物を投与するステップを含む、悪液質又は筋肉疲労性疾患の処置に関する。本発明の化合物は、例えば癌、慢性感染性疾患、発熱、筋肉廃用(委縮)及び除神経、神経損傷、飢餓、アシドーシスに関連する腎不全、及び肝不全などの状態を処置するために有用であろう。例えばゴールドバーグ氏の米国特許第5,340,736号を参照されたい。
et al., Cell (1994) 78:773-785;
and Traenckner et al., EMBO J.
(1994) 13:5433-5441)。いくつかの実施態様では、本発明は、ここに記載した通りの化合物に細胞を接触させるステップを含む、IκB-α分解を阻害する方法に関する。
23:11653-1161, 2003)。更に分析したところ、主に変性中の神経細胞で亢進が起きていることが発見された。HDのマウスモデルを用い、この研究者たちは、脳の罹患及び凝集体含有領域、主に皮質及び線条体で、キモトリプシン様及びトリプシン様活性の両者に選択的増加があることをみとめた(Diaz-Hernandez et al, J Neurosci 23:11653-1161,
2003)。
阻害剤は骨量及び骨形成速度を70%を超えて上昇させた(Garrett, I. R. et al.,
J. Clin. Invest. (2003) 111: 1771-1782)ことから、ユビキチン-プロテアソーム機序が骨芽細胞分化及び骨形成を調節していることが示唆された。従って、開示されたプロテアソーム阻害剤組成物は、骨粗鬆症など、骨消失に関連する疾患の処置及び/又は防止において有用であろう。
ここに記載した通りに調製された化合物は、当業で公知の通り、処置しようとする障害、患者の年齢、状態、及び体重に応じて、様々な形で投与することができる。例えば、化合物を経口投与する場合、それらを錠剤、カプセル、顆粒、粉末、又はシロップとして調合してもよく;あるいは非経口投与の場合、それらを注射(静脈内、筋肉内、又は皮下)、液滴輸注製剤、又は座薬として調合してもよい。眼粘膜経路による適用の場合、それらは目薬又は眼用軟膏として調合してもよい。これらの調合物は従来の手段により調製することができ、そして必要であれば、活性成分をいずれの従来の添加剤又は医薬品添加物、例えば結合剤、崩壊剤、潤滑剤、推進薬、可溶化剤、懸濁補助剤、乳化剤、コーティング剤、シクロデキストリン及び/又は緩衝剤など、と混合してもよい。投薬量は、一般的には患者の症状、年齢及び体重、処置又は防止しようとする障害の性質及び重篤度、投与経路、並びに薬物の形に応じて様々であろうが、一日当たり0.01 乃至2000 mg の化合物投薬量が成人のヒトの患者には推奨され、これは単一の用量又は分割された用量で投与されてもよい。担体材料と組み合わせて一回分の剤形を作製することのできる活性成分量は、一般的には、治療効果を生じる化合物量であろう。
(1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66: 1-19.を参照されたい)。
Berge et al.を参照されたい)。
(BCNU)及び類似体、ストレプトゾシン);トラゼン(例えばダカルバジン(DTIC));抗増殖性/抗有糸***性抗代謝産物、例えば葉酸類似体(メトトレキセート)、ピリミジン類似体(フルオロウラシル、フロクスリジン、及びシタラビン)、プリン類似体及び関連阻害剤(メルカプトプリン、チオグアニン、ペントスタチン及び2-クロロデオキシアデノシン);アロマターゼ阻害剤(アナストロゾール、エクセメスタン、及びレトロゾール)、及びプラチナ配位錯体(シスプラチン、カルボプラチン);プロカルバジン;ヒドロキシウレア;ミトタン;アミノグルテチミド;ホルモン(例えばエストロゲン);及びホルモンアゴニスト、例えば黄体形成ホルモン分泌促進ホルモン (LHRH) アゴニスト(例えばゴセレリン、ロイプロリド及びトリプトレリン)がある。
スキーム1: 化合物1の合成
A (100 mg、0.4 mmol) 及び B (238 mg、0.6 mmol) を−10℃の10%
DMF/MeCN (10 mL) に溶かした溶液にHOBT (87
mg、0.6 mmol)、HBTU (245 mg、0.6 mmol) 及び DIEA (300 μL、1.7 mmol)を加えた。できた溶液を45分間、撹拌した。次に該反応混合液をEtOAc (50 mL) で希釈し、飽和NaHCO3
(3 x 25 mL) 及びブライン (1 x 25
mL) で洗浄し、MgSO4上で乾燥させ、ろ過し、減圧下で濃縮して泡を生じさせ、この泡をシリカによるクロマトグラフィーにかけて 1-5% MeOH/EtOAc を溶出させてCを油として生じさせた (26
mg、10.4%)。
C (26 mg、0.04 mmol) 及び2-メチルプロピルボロン酸 (10
mg、0.1 mmol) を2M HCl (0.4 mL)、MeOH (2 mL) 及びヘキサン (2 mL) に入れた混合液を16時間、撹拌した。次の層を分離し、ヘキサンをMeOH (3 x 2 mL)で洗浄した。配合したMeOH層を濃縮し、飽和NaHCO3 (15 mL)で希釈した。水層をEtOAc (3 x 5 mL) で抽出し、有機層をMgSO4 上で乾燥させ、ろ過し、減圧下で濃縮して化合物1を白色の固体として生じさせた (6.3 mg、29.1%)。
A (100 mg、0.4 mmol) 及びD (156 mg、0.6 mmol) を、−10℃の10% DMF/MeCN (10 mL) に溶かした溶液に、HOBT (87 mg、0.6 mmol)、HBTU (245 mg、0.6 mmol) 及び DIEA (300 μL、1.7 mmol)を加えた。できた溶液を45分間、撹拌した。次にこの反応液をEtOAc (50 mL) で希釈し、飽和NaHCO3
(3 x 25 mL) 及び (1 x 25 mL)で洗浄し、MgSO4上で乾燥させ、ろ過し、減圧下で濃縮して油を生成し、この油を、25-50% EtOAc/Hexを用いたシリカによるクロマトグラフィにかけてEを油として生じさせた (13 mg、4.9%)。
E (13 mg、0.02 mmol) 及び 2-メチルプロピルボロン酸 (10 mg、0.1 mmol)を2M HCl (0.4 mL)、MeOH (2 mL) 及びヘキサン(2 mL) に入れた混合液を16時間、撹拌した。次に層を分離し、ヘキサン層をMeOH (3 x 2
mL)で洗浄した。配合した MeOH 層を濃縮し、飽和 NaHCO3 (15 mL)で希釈した。次に水層を EtOAc (3 x 5 mL) で抽出し、有機層を MgSO4上で乾燥させ、ろ過し、減圧下で濃縮して化合物2を白色の固体として生じさせた (1.3 mg、11.2%)。
ある分子が構成的 (B5) 又はイムノプロテアソーム
(L7)のCT-Lを優先的に阻害するかどうかを判定するために用いることのできる生化学検定は、各サブユニットについてEC50をまず判定することに依拠する。これは、米国出願番号第09/569748号、実施例2及びStein et al., Biochem. (1996), 35,
3899-3908に開示されたものなど、判定用に90%を超える構成的プロテアソーム・サブユニット又はイムノプロテアソーム・サブユニットを持つ単離20S プロテアソーム標品を用いた酵素カイネティック・アッセイを用いて達成することができる。こうして、当該分子の阻害優先性は構成的プロテアソームの(イムノプロテアソームのそれに対する)キモトリプシン様活性のEC50比(20S比)に基づくことになる。
当業者であれば、ごく慣例的な実験を用いるのみで、ここに記載された化合物及びその使用法の均等物を数多く、認識され、あるいは確認できることであろう。このような均等物は、本発明の範囲内にあるとみなされ、また以下の請求の範囲の包含するところである。
Claims (32)
- 式(I):
但し式中、C=O、C=S、及びSO2 から個別に選択され;又は
A はZに隣接する場合には選択的に共有結合であり;
Y は存在しないか、又はN(R7)(R8)であり;
M は存在しないか、又はC1-12アルキルであり;
各Z はO、S、NH、及びN-C1-6アルキルから個別に選択され;又は
Z はAに隣接する場合には選択的に共有結合であり
R1 は水素、-C1-6アルキル-Y、C1-6ヒドロキシアルキル、C1-6アルコキシアルキル、アリール、及びC1-6アラルキルから選択され;
R2 はアリール、ヘテロアリール、C1-6アラルキル及び1-6ヘテロアラルキルから選択され;
R3 はアリール、ヘテロアリール、C1-6ヘテロアラルキル、C1-6アラルキル及びC1-6アルキルから選択され;
R4 及びR5 はそれぞれ個別に水素、C1-6アラルキル、及びC1-6アルキルから選択され;あるいは
R4 及びR5 は共に C1-12アルキルであることで一個の環を形成し;
R6 は水素、C1-6アルキル、C1-6アルケニル、C1-6アルキニル、カルボシクリル、ヘテロシクリル、N末端保護基、アリール、C1-6アラルキル、ヘテロアリール、C1-6ヘテロアラルキル、R9ZAZ-C1-8アルキル-、R12Z-C1-8アルキル-、(R9O)(R10O)P(=O)O-C1-8アルキル-ZAZ-C1-8アルキル-、9、ヘテロシクリルMZAZ-C1-8アルキル-、(R9O)(R10O)P(=O)O-C1-8アルキル-、(R11)2N-C1-12アルキル-、(R11)3N+-C1-12アルキル-、ヘテロシクリルM-、カルボシクリルM-、R12SO2C1-8アルキル-、及びR12SO2NHから選択され;
R7 は水素、OH、及びC1-6アルキルから選択され;
R8 はN末端保護基であり、R7 及びR8 は個別に水素、C1-6アルキル、及びC1-6アラルキルから選択され、好ましくは水素であり;
R9 及びR10
は個別に水素、金属陽イオン、C1-6アルキル、C1-6アルケニル、C1-6アルキニル、アリール、ヘテロアリール、C1-6アラルキル、及びC1-6ヘテロアラルキルから選択され、好ましくは水素、金属陽イオン、及びC1-6アルキルから選択され、あるいはR11 及び R12 は共にC1-6アルキルであることで一個の環を形成し;
各R11 は個別に水素及びC1-6アルキルから選択され、好ましくは
C1-6アルキルであり;そして
R12 は個別に水素、C1-6アルキル、C1-6アルケニル、C1-6アルキニル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、C1-6アラルキル、及びC1-6ヘテロアラルキルから選択される、
化合物。 - R1 が-C1-6アルキル-Yである、請求項1に記載の化合物。
- Yが存在せず、そしてR1 がメチル、エチル、イソプロピル、カルボキシメチル、及びベンジルから選択される、請求項2に記載の化合物。
- R1 がメチルである、請求項3に記載の化合物。
- R2 がC1-6アラルキル及びC1-6ヘテロアラルキルから選択される、請求項1乃至4のいずれかに記載の化合物。
- R2 がC1-6アルキル-フェニル、C1-6アルキル-インドリル、C1-6アルキル-チエニル、C1-6アルキル-チアゾリル、及びC1-6アルキル-イソチアゾリルから選択される、請求項5に記載の化合物。
- R2 が、選択的にアルキル、トリハロアルキル、アルコキシ、ヒドロキシ、又はシアノで置換されたC1-6アルキル-フェニル及びC1-6アルキル-インドリルから選択される、請求項6に記載の化合物。
- R3 がC1-6アラルキル及びC1-6アルキルから選択される、請求項1乃至7のいずれかに記載の化合物。
- R3 がC1-6アラルキルである、請求項8に記載の化合物。
- R3 がC1-6アルキル-フェニルである、請求項9に記載の化合物。
- R4 及びR5 が個別に水素及び及びC1-6アルキルから選択される、請求項1乃至10のいずれかに記載の化合物。
- R4 及びR5 が両者とも水素である、請求項11に記載の化合物。
- R4 及びR5 が共にC1-12アルキルであることで一個の環を形成する、請求項11に記載の化合物。
- R4 及びR5 が、二つの隣接する酸素原子及びホウ素と共に一個のピナコールボロネートエステルを形成する、請求項13に記載の化合物。
- R6 がカルボシクリル、アリール、及びヘテロシクリルM-から選択される、請求項1乃至14のいずれかに記載の化合物。
- R6 がカルボシクリル又はアリールである、請求項15に記載の化合物。
- R6 がインデンである、請求項16に記載の化合物。
- R6 が 3-メチリンデン(原語:methylindene)である、請求項17に記載の化合物。
- R6 がヘテロシクリルM-である、請求項15に記載の化合物。
- ヘテロシクリルがモルホリノ、ピペリジノ、ピペラジノ、及びピロリジノから選択される、請求項19に記載の化合物。
- ヘテロシクリルがモルホリノであり、そしてMがC1-12アルキルである、請求項20に記載の化合物。
- 請求項1乃至23のいずれかに記載の化合物を投与するステップを含む、免疫関連疾患を処置する方法。
- 請求項1に記載の化合物を投与するステップを含む、癌を処置する方法。
- 請求項1乃至23のいずれかに記載の化合物を投与するステップを含む、炎症を処置する方法。
- 請求項1乃至23のいずれかに記載の化合物を投与するステップを含む、感染を処置する方法。
- 請求項1乃至23のいずれかに記載の化合物を投与するステップを含む、増殖性疾患を処置する方法。
- 請求項1乃至23のいずれかに記載の化合物を投与するステップを含む、神経変性疾患を処置する方法。
- 構成的プロテアソーム活性の検定における化合物のEC50を、イムノプロテアソームの検定における化合物のEC50に比較したときの比が1.0を超える、請求項1乃至23のいずれかに記載の化合物。
- EC50比が3.0を超える、請求項30に記載の化合物。
- 薬学的に許容可能な担体又は希釈剤と、請求項1乃至23のいずれかに記載の化合物とを含む、医薬組成物。
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JP2021503471A (ja) * | 2017-11-16 | 2021-02-12 | プリンシピア バイオファーマ インコーポレイテッド | 免疫プロテアソーム阻害剤 |
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JP2018502048A (ja) * | 2014-10-01 | 2018-01-25 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングMerck Patent Gesellschaft mit beschraenkter Haftung | ボロン酸誘導体 |
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ECSP12012140A (es) | 2012-10-30 |
EP2542238B1 (en) | 2015-08-12 |
JP6042724B2 (ja) | 2016-12-14 |
KR20130075723A (ko) | 2013-07-05 |
ZA201206479B (en) | 2015-08-26 |
CA2791651A1 (en) | 2011-09-09 |
EA201290844A1 (ru) | 2013-03-29 |
EP2542238A1 (en) | 2013-01-09 |
CR20120451A (es) | 2012-10-16 |
CO6612265A2 (es) | 2013-02-01 |
BR112012022060A2 (pt) | 2018-05-08 |
DOP2012000238A (es) | 2013-01-15 |
US9359398B2 (en) | 2016-06-07 |
MA34133B1 (fr) | 2013-04-03 |
US20130072422A1 (en) | 2013-03-21 |
CN102892417A (zh) | 2013-01-23 |
CU20120125A7 (es) | 2012-11-15 |
AU2011223795A1 (en) | 2012-09-20 |
CA2791651C (en) | 2019-08-20 |
WO2011109355A1 (en) | 2011-09-09 |
SG183843A1 (en) | 2012-10-30 |
AU2011223795B2 (en) | 2015-11-05 |
MX2012010017A (es) | 2012-10-01 |
CL2012002404A1 (es) | 2012-12-21 |
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