JP7228571B2 - 免疫刺激因子トル様受容体7(tlr7)アゴニストとしての6-アミノ―7,9-ジヒドロ-8h-プリン-8-オン誘導体 - Google Patents
免疫刺激因子トル様受容体7(tlr7)アゴニストとしての6-アミノ―7,9-ジヒドロ-8h-プリン-8-オン誘導体 Download PDFInfo
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- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 238000006177 thiolation reaction Methods 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- WCNFFKHKJLERFM-UHFFFAOYSA-N thiomorpholinyl sulfone group Chemical group N1(CCSCC1)S(=O)(=O)N1CCSCC1 WCNFFKHKJLERFM-UHFFFAOYSA-N 0.000 description 1
- ZCAGUOCUDGWENZ-UHFFFAOYSA-N thiomorpholinyl sulfoxide group Chemical group N1(CCSCC1)S(=O)N1CCSCC1 ZCAGUOCUDGWENZ-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 238000007056 transamidation reaction Methods 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
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Description
(式中、R、R'およびR''は、構造可変基であり、R''は、通常、非置換または置換された芳香環またはヘテロ芳香環を含有している)
に関するプリン様骨格をベースとしている。
一態様において、本明細書は、式(I)または(II):
R1は、(C1-C5アルキル)O、(C1-C2アルキル)O(CH2)2-3O、(C1-C5アルキル)C(=O)O、(C1-C5アルキル)NH、(C1-C2アルキル)O(CH2)2-3NHまたは(C1-C5アルキル)C(=O)NHであり;
R2は、各々独立して、H、C1-C3アルキル、ハロ、O(C1-C3アルキル)、CNまたはNO2であり;
Xは、各々独立して、CR2またはNであり;および
Arは、ピロリル、フラニル、チオフェニル、ピラゾリル、イミダゾリル、オキサゾリル、イソオキサゾリル、1,2,3-トリアゾリル、1,2,4-トリアゾリル、テトラゾリル、1,2,4-オキサジアゾリル、1,2,4-チアジアゾリル、1,3,4-オキサジアゾリル、1,3,4-チアジアゾリル、1,2,5-オキサジアゾリル、1,2,5-チアジアゾリル、1,2,3,4-オキサチアゾリルおよび1,2,3,4-チアトリアゾリルから選択される5員環のヘテロ芳香族基である]
の構造を有する化合物を提供する。
「抗体」は、抗体全体およびあらゆる抗原結合フラグメント(即ち、「抗原結合部分」)またはその単鎖変異体を意味する。抗体全体は、ジスルフィド結合により相互に連結された少なくとも2つの重鎖(H)および2つの軽鎖(L)を含むタンパク質である。各重鎖は、3つのドメインCH1、CH2およびCH3を含む重鎖可変領域(VH)ならびに重鎖定常領域を含んでいる。各軽鎖は、1つのシングルドメインCLを含む軽鎖可変領域(VLまたはVk)および軽鎖定常領域を含む。VHおよびVL領域は、高度に保存されたフレームワーク領域(FR)と共に散在し得る超可変性領域、いわゆる相補性決定領域(CDRs)に更に細分化され得る。各々VHおよびVLは、3つのCDRおよび4つのFRを含み、アミノ末端からカルボキシ末端へと次の順番で配置されている:FR1、CDR1、FR2、CDR2、FR3、CDR3およびFR4。可変領域は、抗原と相互作用する結合ドメインを含有する。定常領域は、宿主の組織または因子[例えば、エフェクター細胞などの免疫系の様々な細胞および古典的補体系の第一成分(Clq)]への抗体の結合を媒介し得る。抗体が、5x10-8M未満のKD、より好ましくは1x10-8M未満のKD、より好ましくはKD、6x10-9M未満のKD、より好ましくは3x10-9M未満のKD、更により好ましくは2x10-9M未満のKDにて抗原Xに結合するならば、該抗体は、抗原Xに「特異的に結合する」といえる。抗体は、キメラ抗体、ヒト化抗体または好ましくはヒト抗体であり得る。重鎖定常領域を、グリコシル化の型またはその程度に影響を及ぼすように遺伝子設計して、抗体の半減期を延長させること、エフェクター細胞または補体系との相互作用を増強または低下させること、または別のある性質を調節することができる。遺伝子設計は、1以上のアミノ酸の置換、付加または削除によるか、あるドメインを別のイムノグロブリン型由来のドメインに置き換えるか、または前記組合せにより達成され得る。
であるか、またはRが、
であるという記載は、
を意味する。
は、
式(I)/(II)において、Ar基は所望により合成され得る。該置換基は、例えば、C1-C3アルキル、C3-C3シクロアルキル(CH2)1-3R3、(CH2)1-3C(=O)(CH2)0-3R3であってもよく、ここでR3は、ハロ、OH、CN、NH2、NH(C1-C5アルキル)、N(C1-C5アルキル)2、NH(C3-C6シクロアルキル)、NH(C4-C8ビシクロアルキル)、NH(C6-C10スピロシクロアルキル)、N(C3-C6シクロアルキル)2、NH(CH2)1-3(アリール)、N((CH2)1-3(アリール))2、構造:
を有する環状アミン基、6員の芳香族基またはヘテロ芳香族基、あるいは5員のヘテロ芳香族基であって;
ここで、アルキル、シクロアルキル、ビシクロアルキル、スピロシクロアルキル、環状アミン、6員の芳香族基またはヘテロ芳香族、あるいは5員のヘテロ芳香族基は、所望により、OH、ハロ、CN、(C1-C3アルキル)、O(C1-C3アルキル)、C(=O)(Me)、SO2(C1-C3アルキル)、C(=O)(Et)、NH2、NH(Me)、N(Me)2、NH(Et)、N(Et)2およびN(C1-C3アルキル)2から選択された1以上の置換基で置換されていてもよく;およびシクロアルキル、ビシクロアルキル、スピロシクロアルキルまたは環状アミン基は、O、S、NH、N(C1-C3アルキル)またはN(Boc)により置換されたCH2基を有していてもよい。
(式中、R1は、式(I)に関して上記に規定された通りであり、各X'は、独立して、CHまたはNであって、R4は、下記に規定される)
により示される。
(式中、R1は、式(I)に関して上記に規定された通りであり、各X'は、独立して、CHまたはNであって、R4は、下記に規定される)
により示される。
を有する環状アミン基、6員の芳香族基またはヘテロ芳香族基、あるいは5員ヘテロ芳香族基であり;
ここで、アルキル、シクロアルキル、ビシクロアルキル、スピロシクロアルキル、環状アミン、6員の芳香族基またはヘテロ芳香族基、あるいは5員のヘテロ芳香族基は、所望により、OH、ハロ、CN、(C1-C3アルキル)、O(C1-C3アルキル)、C(=O)(Me)、SO2(C1-C3アルキル)、C(=O)(Et)、NH2、NH(Me)、N(Me)2、NH(Et)、N(Et)2およびN(C1-C3アルキル)2から選択される1以上の置換基で置換されていてもよく;および、シクロアルキル、ビシクロアルキル、スピロシクロアルキルまたは環状アミン基は、O、S、NH、N(C1-C3アルキル)またはN(Boc)により置換されたCH2基を有する。
概要
本明細書に開示されたTLR7アゴニストは、局所投与またはターゲティング送達によるか、あるいはターゲティング基を含むコンジュゲートにより目的の作用部位に送達され得る。好ましくは、ターゲティング基とは、抗体またはその抗原結合部分であり、その抗原は目的とする作用付近に存在しており、例えば、目的とする作用部位が腫瘍(癌)であるならば腫瘍関連抗原である。好ましくは、腫瘍関連抗原は、正常細胞と比べると、癌細胞により特異的または過剰に発現される。腫瘍関連抗原は、癌細胞の表面に存在し得るか、その癌細胞周辺に癌細胞により分泌され得る。
[式中、Zは、ターゲティング基であり、Dは、本発明のアゴニストであり、-(XD)aC(XZ)b-は、ZおよびDを連結するという理由から、それらをまとめて「リンカー基」または「リンカー」と称される。リンカー内にて、Cは、Dの目的とする生物学的作用部位または部位付近で開裂されるように設計された開裂可能な基である;XDおよびXZは、DとC、およびCとZをそれぞれ空間的に分離するスペーサー基(または「スペーサー」)である;下付き文字a、bおよびcは、独立して、0または1(即ち、XD、XZおよびCの存在は任意である)である]
により示される本発明の化合物およびリガンドを含むコンジュゲートが提供される。下付き文字mは、1、2、3、4、5、6、7、8、9または10(好ましくは、1、2、3または4)である。D、XD、C、XZおよびZは、より詳細に後述される。
好ましくは、ターゲティング基Zは抗体である。便宜上かつ簡潔化のために、限定するものではないが、Zおよびそのコンジュゲートについての本明細書における詳細な説明は、それらが抗体であるという文脈で書かれているが、所望により変更して、Zの別のタイプをコンジュゲートし得ることも当業者には理解されよう。例えば、ターゲティング基として葉酸を含むコンジュゲートは、その表面上に葉酸受容体を有する細胞を標的とし得る(Leamon et al., Cancer Res. 2008, 68 (23), 9839)。同じ理由から、本明細書における詳細な説明は、主に、ZとD(m=1)が1:1の比として記載されている。
上記の通り、リンカーは、3つまでの要素:開裂可能な基Cおよび任意のスペーサーXZおよびXDを含む。
(ここで、下付き文字gは、0または1であり、下付き文字hは、1~24であり、好ましくは2~4である)
およびその組合せである。これらのセグメントを、下記に図示したように合わせることもできる:
本明細書において開示されたTLR7アゴニストのコンジュゲートは、好ましくは、Dおよびリンカー(XD)a(C)c(XZ)b(式中、XD、C、XZ、a、bおよびcは、式(II)に定義された通りである)を含む化合物を最初に製造して、
式(V):
により示される薬剤-リンカー化合物を形成して、コンジュゲートを形成することにより製造される。適切な基R31の例は、アミノ、アジド、チオール、シクロオクチン、
(式中、R32は、Cl、Br、F、メシレートまたはトシレートであり、R33は、Cl、Br、I、F、OH、-O-N-スクシンイミジル、-O-(4-ニトロフェニル)、-O-ペンタフルオロフェニルまたは-O-テトラフルオロフェニルである)
が包含される。適切な基:D-(XD)aC(XZ)b-R31を製造するために広く使用できる化学的手法は、Ng et al., US 7,087,600 B2 (2006);Ng et al., US 6,989,452 B2 (2006);Ng et al., US 7,129,261 B2 (2006);Ng et al., WO 02/096910 A1;Boyd et al., US 7,691,962 B2;Chen et al., US 7,517,903 B2 (2009);Gangwar et al., US 7,714,016 B2 (2010);Boyd et al., US 2008/0279868 A1;Gangwar et al., US 7,847,105 B2 (2010);Gangwar et al., US 7,968,586 B2 (2011);Sufi et al., US 8,461,117 B2 (2013);およびChen et al., US 8,664,407 B2 (2014)に開示されており、これらの開示内容は、出典明示によりその内容は本明細書に組み込まれる。
前記技術を用いて、TLR7アゴニストコンジュゲート、例えば下記に示されるコンジュゲートが、製造され得る:
ポリ(エチレングリコール)(PEG)鎖および薬剤(「PEG化」)の結合により、後者の薬物動態特性を改善することができる。薬剤の循環半減期は、時には一桁以上も増長されると同時に、目的とする治療効果を達成するのに必要な投薬量を低下することができる。また、PEG化により、薬剤の代謝分解を減らし、その免疫原性を低下させることもできる。概要として、Kolate et al., J. Controlled Release 2014, 192, 167を参照されたい。
本実施例および図1および7は、式(Ia)の化合物の合成に関する。
本実施例および図2は、式(Ib)の化合物の合成に関する。
本実施例および図3は、(Ic)の化合物の合成に関する。
本実施例は、本明細書に開示した化合物のTLR7アゴニスト活性をアッセイするための方法を記述するものである。
以下の方法を、アゴニスト-リンカー化合物(リンカーは、アミンドナーとして作用できるアミン基を有する)に関するトランスグルタミナーゼ媒介性コンジュゲーションのために用い得る。抗体は、トランスグルタミナーゼ反応性グルタミン、例えばN297AまたはN297Q置換を有する抗体であり得る。コンジュゲーションは、抗体:酵素の5:1のモル比にて組み換えバクテリアトランスグルタミナーゼにより行われる。コンジュゲーションは、50mM Tris緩衝液(pH8.0)中において終夜37℃でインキュベートした標準的プロトコールを用いて行われる。得られるコンジュゲートを、50mM Tris(pH8.0)を用いて事前平衡化したタンパク質Aカラムで精製した。コンジュゲートを、0.1M ナトリウムクエン酸塩緩衝液(pH3.5)で溶出した。溶出画分を、1M Tris(pH9.0)で中和した。コンジュゲートを、20mg/mLソルビトール、10mg/mLグリシン(pH5.0)中で製造され得る。
本実施例は、本明細書に開示された化合物によるインターロイキン6の誘導をアッセイするための方法を記述したものである。
第一著者(または発明者)および本明細書より過去の日付により省略形式で引用された以下の参考文献に対する全引用文献を以下に示します。これらの各参考文献は、参照によりすべての目的のために本明細書に組み込まれる。
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Claims (9)
- 式(Ia)、(Ib)または(Ic):
R1は、(C 1 -C 5 アルキル)O、(C 1 -C 2 アルキル)O(CH 2 ) 2-3 O、(C 1 -C 5 アルキル)C(=O)O、(C 1 -C 5 アルキル)NH、(C 1 -C 2 アルキル)O(CH 2 ) 2-3 NHまたは(C 1 -C 5 アルキル)C(=O)NHであり、
各X'は、独立して、CHまたはNであり、および
R4は、H、C1-C3アルキル、C3-C3シクロアルキル(CH2)1-3R3、(CH2)1-3C(=O)(CH2)0-3R3であり、ここでR3は、ハロ、OH、CN、NH2、NH(C1-C5アルキル)、N(C1-C5アルキル)2、NH(C3-C6シクロアルキル)、NH(C4-C8ビシクロアルキル)、NH(C6-C10スピロシクロアルキル)、N(C3-C6シクロアルキル)2、NH(CH2)1-3(アリール)、N((CH2)1-3(アリール))2、構造:
を有する環状アミン基、6員環の芳香族基またはヘテロ芳香族基、あるいは5員環のヘテロ芳香族基であり;ここで、アルキル、シクロアルキル、ビシクロアルキル、スピロシクロアルキル、環状アミン、6員環の芳香族基またはヘテロ芳香族基、あるいは5員環のヘテロ芳香族基は、所望により、OH、ハロ、CN、(C1-C3アルキル)、O(C1-C3アルキル)、C(=O)(Me)、SO2(C1-C3アルキル)、C(=O)(Et)、NH2、NH(Me)、N(Me)2、NH(Et)、N(Et)2およびN(C1-C3アルキル)2から選択された1以上の置換基で置換されていてもよく;および、シクロアルキル、ビシクロアルキル、スピロシクロアルキルまたは環状アミン基は、O、S、NH、N(C1-C3アルキル)またはN(Boc)により置換されたCH2基を有していてもよい]
により示される構造を有する、化合物。 - トル様受容体7の活性化により治療できる症状を治療する際に使用するための、請求項1記載の化合物。
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