JP2020505378A - 新規化合物(イムノヘリン−細胞内感染) - Google Patents
新規化合物(イムノヘリン−細胞内感染) Download PDFInfo
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Classifications
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Abstract
Description
GnRH I(ゴナドトロピン放出ホルモン又はLHRHとしても既知)は、構造pyroGlu−His−Trp−Ser−Tyr−Gly−Leu−Arg−Pro−Gly−NH2を有するデカペプチドである。それは、翻訳後に修飾されてアミノ末端にピログルタミン酸及びカルボキシル末端にカルボキサミドを有する最終ペプチドを形成する92アミノ酸プロペプチドとして産生される。それは、下垂体前葉からのFSH及びLHの放出の原因であることは長い間既知であり、通常は拍動的に視床下部から放出される。超生理学的レベルのGnRH Iは、すぐにFSH及びLH分泌の増加を誘発し、その後すぐにFSH及びLH分泌の阻害が続く。これは、高レベルのGnRH Iが下垂体前葉のI型GnRH受容体に対して阻害効果を有するという事実によるものである。したがって、高い非生理学的レベルでのGnRH Iの連続投与は、薬理学的去勢を誘発する(Fink 1998)。ホルモン感受性癌などの治療分野で使用するために、多数のGnRH Iアゴニスト及びアンタゴニストが合成されてきた。最初に、GnRH Iの塩が治療的に使用された(例えば、ゴナドレリン塩酸塩及びゴナドレリンジアセタート四水和物)。さらなる薬物の発見及び開発により、ブセレリン、トリプトレリン、ナファレリン、ヒストレリン、及びロイプロレリンを含む多種多様な薬剤の臨床使用がもたらされ、これらはそれぞれ、I型GnRH受容体の半減期の延長及びスーパーアゴニズムなどのゴナドレリンを超える改善を有する。
のペプチド又はその薬学的に許容される塩が提供され、式中、
R5=Me、Et、CH2CF3、iPr、nPr、nBu、iBu、sBu、tBu、シクロプロピル、CH2CONH2、又はNHCONH2である。
pGlu−His−Trp−Ser−AA1−AA2−AA3−AA4−Pro−X、
式中:
AA1は、His及びTyrから選択され、
AA2は、d−Ser(OtBu)、d−Trp、d−Nal、d−Bhi、及びd−Leuから選択され、
AA3は、Leu及びTrpから選択され、
AA4は、Arg及びTyrから選択され、
Xは、−NHMe、−NHEt、−NHCH2CF3、−NHiPr、−NHnPr、−NHnBu、−NHiBu、−NHsBu、−NHtBu、−NHシクロプロピル、−NH−NH−CONH2、及びNHCH2CONH2から選択される。
pGlu−His−Trp−Ser−AA1−AA2−AA3−AA4−Pro−X、式中、AA1は、Hisであり、AA3は、Trpであり、AA4は、Tyrであり、AA2は、D−Leu、D−tBu−Ser、及びD−Trpから選択され、Xは、−NHEt又はNH−NH−CONH2である。
式中、R1、R3、及びR4のうちの少なくとも1つは、II型から選択され、II型から選択されないR1、R3、及びR4のそれらは、I型から選択され、
式中、
であり、
式中、R5=Me、Et、CH2CF3、iPr、nPr、nBu、iBu、sBu、tBu、シクロプロピル、又はCH2CONH2である
pGlu−His−Trp−Ser−AA1−AA2−AA3−AA4−Pro−X、
式中、AA1、AA2、AA3、AA4、及びXは上で定義した通りであり、AA1、AA3、及びAA4のうちの少なくとも1つは、His、Trp、及びTyrから選択され;残りのAA1、AA3、及びAA4は、Tyr、Leu、Argから、かつ上で特定された化合物P1〜P15及び請求項1で放棄されたそれらの他の化合物を除いて選択される。
上記で特定された化合物P1〜P21を除く。
GnRH類似体は、ヒトを含む動物に投与したときに下垂体前葉の受容体に対するGnRHの作用を模倣する薬剤である。単一の低生理学的用量又は時間的に間隔を置いた単一の低生理学的用量でのGnRH類似体の投与は、下垂体前葉の受容体を刺激し、それによって受容体アゴニストとして作用するが、単位時間あたりの高い非生理学的用量でのGnRH類似体の連続投与は、下垂体前葉の受容体の最初の刺激後、FSH及びLHの分泌を阻害し、それによって受容体アンタゴニストとして作用する。
当業者は、本発明の化合物が既知の様式、種々の方法で調製され得ることを認識する。下記の経路は、式(I)の化合物の合成に用いることができるいくつかの方法の単なる例示である。
スキームI
スキームII
本明細書に記載の化合物は、医学、医学研究、又はそのような用途のための組成物の製造に使用することができる。さらに、本発明はまた、医学、医学研究、又はそのような用途のための組成物の製造における使用のための本明細書に記載の化合物P1〜P21に関する。したがって、以下において「本発明の化合物」という用語が医療用途又は医薬組成物に関連して使用される場合、これらの化合物がそのような用途について知られていない限り、その用語は、化合物P1〜P21も含むことが意図される。
−I型GnRH受容体と比較したII型GnRH受容体への結合の改善
−MHCクラスI刺激の改善
−MHCクラスII刺激の改善
−免疫調節の改善
−抗原提示細胞の活性化の改善
−T細胞応答の改善
−抗ウイルス活性の改善
−抗癌作用の改善
−MHC II抗原提示の改善
−MHC I抗原提示の改善
本発明はまた、本発明の化合物を1つ以上の薬学的に許容される希釈剤又は担体と一緒に含む医薬組成物を提供する。本章は、主に新規GnRH類似体の製剤化を対象とする。新規化合物が、望ましくなく、去勢又は類似の効果を引き起こすI型GnRH受容体に対する効果を有する場合、性ホルモンを含有する組成物は、当分野で既知であり、同時投与され得る。
配列表は、WIPO規格ST.25に従って調製される。配列表において、化合物1〜63及びP1〜P21の非天然アミノ酸は、以下のように対応する天然アミノ酸として表される:
WIPO規格ST.25の段落36を遵守するために、配列表の数値識別子<223>の下に含まれるフリーテキストは、ここで説明の主要部分において繰り返される:
冠詞「a」及び「an」は、冠詞の文法上の目的語の1つ又は2つ以上(すなわち少なくとも1つ)を指すために本明細書で使用される。例として、「類似体」は、1つの類似体又は複数の類似体を意味する。
一般的な生物学的方法
GnRH受容体に対する本発明の化合物の優先的効果は、以下に記載される方法のうちの1つ以上を使用して試験され得る:
ヒトナイーブT細胞及びメモリーT細胞を蛍光表面マーカー抗体CD45RA、CD45RO、及びCD4で標識し、フローサイトメトリーで分類した。全RNAをRnaeasyキット(Qiagen)で抽出し、iScript select cDNA合成キット(Biorad)で逆転写した。鋳型cDNAをSYBR Green(Applied Biosystem)で増幅し、CFX96 PCR(Biorad)で泳動した。I型GnRH受容体とII型GnRH受容体mRNAとの比は、選別されたナイーブT細胞又はメモリーT細胞におけるRNAポリメラーゼII発現に対して正規化された。MCF−7乳癌細胞株を陽性対照として使用した。
I型 GnRH受容体
fwd 5’−tgc ctc ttc atc atc cct ct−3’
rev 5’−gca aat gca acc gtc att tt−3’
II型 GnRH受容体
fwd 5’−act gtt caa tgg ctg gct gt−3’
rev 5’−gcc ccc aga agt ttc ctt ac−3’
トランスフェクションによってI型又はII型GnRH受容体を発現するように作製した細胞に対して化合物を試験した。細胞を標識GnRH化合物に曝露し、洗浄した後、細胞上の標識を測定することによって評価した。標識を直接的に(放射性同位体標識もしくは蛍光標識)又は間接的に(ビオチン標識ペプチド)測定した。
ヒト末梢血単核細胞(PBMC)を、フィコール−ハイパック密度遠心分離を用いて健康なドナーから精製した。細胞を、10%ウシ胎児血清、100μg/mLアンピシリン、及び100μg/mLストレプトマイシンを補充したRPMI−1640培地(Invitrogen)中、37℃、5%CO2中で24〜72時間培養した。細胞を本発明による化合物で刺激し、フローサイトメトリーを用いて細胞特異的表面マーカー及びMHCクラスII(BD Pharmingenからのモノクローナル抗体)の発現について分析した。
特に明記しない限り、以下の例で使用される全ての試薬は、商業的供給源から得られる。
材料及び方法
雄マウスは、細菌を含有するエアロゾルの吸入によって結核菌に感染させる。感染量は、マウス1匹あたり100〜1000細菌である。GnRHII又はGnRHI関連化合物(単独でもしくはテストステロンと一緒に)又はビヒクルは、いずれかの細菌による感染後、1〜2週間の間適切な用量で適切な経路により投与される。マウスを屠殺し、肺を取り出し、ホモジナイズし、結核菌の増殖を支持する培地を含有する細菌皿上にプレーティングする。3〜4週間のインキュベーション後、37℃の加熱キャビネット内で、マウスの肺の中の細菌の量をプレート上の細菌コロニーを数えることによって定量する。
この実験の予想結果は、対照ビヒクル処置マウスと比較して、GnRH化合物で処置されたマウスにおいて、マウスの肺中の結核菌細菌の量が減少することである。本発明者らはまた、この点でGnRHII関連化合物がGnRHI関連化合物よりも優れていると予想する。本発明者らは、テストステロンの同時投与がGnRH化合物の効果の程度に影響を与えるとは予想しない。
本発明の化合物によって誘発される去勢、ならびにその任意の補償は、関連性ホルモンの循環レベルの測定によって決定することができる。そのような測定を実行する方法は、当業者に既知である。
方法A
上記の図表に従って、標準Fmoc固相合成を使用してペプチドを調製した。保護アミノ酸(必要であればFmoc及びtBu又はTrt)を使用し、合成は、2−クロロトリチルポリスチレン樹脂上で実行した。反応は、A、B、Cの順序で行われ、続いて所望のペプチドを構築するためにB及びCが複数回繰り返される。最終アミノ酸(ピログルタマート−注意、反応Cは、アミノ酸がFmoc保護されていないがこれを行うために使用される)が添加されると、最後の2つの反応−D及びE−がその順序で行われ、本発明の化合物を生成する。
上記の図表に従って、標準Fmoc固相合成を使用してペプチドを調製した。保護アミノ酸(必要であればFmoc及びtBu又はTrt)を使用し、Ramage樹脂上で合成を実行した。反応は、A、B、Cの順序で行われ、続いて所望のペプチドを構築するためにB及びCが複数回繰り返される。最終アミノ酸(ピログルタマート−注意、反応Cは、アミノ酸がFmoc保護されていないがこれを行うために使用される)が添加されると、最後の2つの反応−D及びE−がその順序で行われ、本発明の化合物を生成する。
粗ペプチドをアセトニトリル/H2O(1:1、v/v)に個々に溶解し、水(0.1%TFA)−アセトニトリル(0.1%TFA)勾配を使用するC18カラムを用いた分取HPLCによって精製した。ペプチドの最終純度は、分析用HPLCにより確認した。−20℃で保存する前にペプチドを凍結乾燥した。
分析方法A
分析のために、化合物をメタノール:水(9:1、0.1mg/ml)に溶解し、150μl部分をHPLC微量バイアルに入れ、14000rpmで3分間遠心分離した。次いで、試料を、ダイオードアレイを用いた高速液体クロマトグラフィー(HPLC−DAD)及び質量分析(HPLC−MS)検出によって調査する。HPLC−DAD−MSは、Waters ZQ単一四重極質量分析計に連結された四次ポンプ、オートサンプラー、カラムオーブン、及びダイオードアレイ検出器を備えるAgilent 1100 HPLCシステムを使用して実行した。同じ逆相のWaters Xselect CSH C18、2.1mmx50mm、3.5μm粒径カラムを全ての化合物に使用し、Waters VanGuard CSH C18、2.1mmx5mm、3.5μm粒径ガードカラム及びWaters Acquity、0.2μmインラインカラムフィルターを装着した。カラムを60℃の温度に維持して1ml/分の流速で使用した。使用した溶媒は、95%アセトニトリル中の0.17%ギ酸、5%水中(溶媒B)及び10mMギ酸アンモニウム、水中0.2%ギ酸(溶媒A)であり、以下のような勾配であった:0〜0.2分の5%溶媒B、0.2〜9.3分の5〜50%溶媒B、9.3〜9.5分の50〜95%溶媒B、9.5〜11分の95%溶媒B、11〜11.05分の95〜5%溶媒B、及び11.05〜11.5分の5%溶媒Bとの再平衡化。窒素を補助ガス及びシースガスとして使用した。供給電圧は、3400Vに設定し、コーン電圧は、50L/時のガス流、550L/時の乾燥ガス流速、及び350℃の乾燥ガス温度で31Vに設定した。
分析方法B
溶解度及び安定性分析のために、化合物をリン酸緩衝溶液(PBS、10mM、pH7.4)に溶解し(0.2mg/ml)、室温で20分間振盪した。T=0時間の試料を採取し(80μl)、14000rpmで3分間遠心分離し、次いで上記のように分析方法Aによって分析した。バルク試料を37℃のTechne Roller−Blot HB−3Dローリングハイブリダイザーに入れ、T=4、24、及び96時間の時点で試料(80μl)を採取したときにのみ取り出した。試料を14000rpmで3分間遠心分離し、次いで上記のようにHPLC−DAD−MSによって分析した。280nmでの曲線下のUV面積を各時点で記録した。
例1−化合物合成
本発明の化合物は、一般的な合成方法に記載の方法に従って作製した。
本発明の化合物の溶解度を一般的な方法に記載の通りに試験した。次いで、溶解度を1〜5の等級に従って等級付けし、1が最も溶解性が高く、5が最も溶解性が低い。
水性媒体(PBS ph7.4)中の本発明の化合物の安定性を、一般的な方法に記載の通りに試験した。次いで、安定性は、t1/2>96分が+として示され、これよりも低い安定性が−として示される等級に従って等級付けした。
GnRHRを刺激する本発明の化合物の能力は、CHO−K1細胞(Genscript)を用いたカルシウムアッセイを使用することによって評価した。詳細については一般的な方法を参照のこと。次いで活性を1μMでの刺激百分率として記録した。
引用されたすべての参考文献は本願中に参照により組み入れられ、本願には特許及び特許出願が包含される。組み入れられる範囲は、可能な限り最も広範な範囲である。
Claims (21)
- 式(I)の化合物
又はその薬学的に許容される塩であって、式中、
式中、R5=Me、Et、CH2CF3、iPr、nPr、nBu、iBu、sBu、tBu、シクロプロピルCH2CONH2又はNHCONH2であり、
ただし、本発明は、以下の化合物を含まない、式(I)の化合物又はその薬学的に許容される塩。
- R1、R3、及びR4のうちの少なくとも1つが、下記のリストに従ってII型から選択され、II型から選択されないR1、R3、及びR4のものが下記のリストに従ってI型から選択される、請求項1に記載の化合物。
- R1、R3、及びR4のうちの少なくとも2つ又は3つが、下記のリストに従ってII型から選択される、請求項2に記載の化合物。
- R1、R3、及びR4のうちの1つが、下記のリストに従ってI型から選択され、R1、R3、及びR4のうちの2つが、下記のリストに従ってII型から選択される、請求項2に記載の化合物。
- R5=Et又はCH2CONH2である、請求項1〜4のいずれか一項に記載の化合物。
- R5=Me、iPr、nPr、nBu、iBu、sBu、又はtBuである、請求項1〜4のいずれか一項に記載の化合物。
- 式(I)の化合物が、以下から選択される、請求項1〜4のいずれか一項に記載の化合物:
- 請求項1〜6のいずれか一項に記載の化合物及び1つ以上の薬学的に許容される賦形剤を含む、医薬組成物。
- 医薬品に使用するための、請求項1〜7のいずれか一項に記載の化合物。
- 細胞内細菌、真菌、又は原虫感染の治療に使用するための、請求項1〜7のいずれか一項に記載の化合物。
- 細胞内細菌、真菌、又は原虫感染の治療に使用するための、請求項1に記載のP1〜P21から選択される化合物。
- 結核菌、非定型疾患を引き起こすマイコバクテリア、鳥型結核菌及びM.イントラセルレア(マイコバクテリウムアビウム(Mycobacterium avium)−イントラセルレア複合体、又はMACとしても既知)、M.カンサシ、M.マリナム、M.フォルトゥイタム、M.ゴルディナエ、マイコプラズマニューモニエ(Mycoplasma pneumoniae)、M.ゲニタリウム、M.ホミニス、ウレアプラズマウレアリチカム(Ureaplasma urealyticum)、U.パルブム、クラミドフィラニューモニエ(Chlamydophila pneumoniae)、サルモネラチフィムリウム(Salmonella typhimurium)、トキソプラズマゴンディ(Toxoplasma gondii)、熱帯熱マラリア原虫、P.ビバックス、クルーズトリパノソーマ、クリプトスポリジウム、リーシュマニア、ヒストプラスマカプスラーツム(Histoplasma capsulatum)、クリプトコックスネオフォルマンス(Cryptococcus neoformans)、及びエンセファリトゾーンクニクリ(Encephalitozoon cuniculi)から選択される、細胞内感染の治療に使用するための請求項10又は11に記載の化合物。
- 細胞内細菌、真菌、又は原虫感染によって引き起こされる疾患を治療又は予防する方法であって、それを必要とするヒト又は動物の対象に請求項1〜7のいずれか一項に記載の化合物の治療有効量を投与することを含む、方法。
- 細胞内細菌、真菌、又は原虫感染によって引き起こされる疾患を治療又は予防する方法であって、それを必要とするヒト又は動物の対象に請求項1に記載のP1〜P21から選択される化合物の治療有効量を投与することを含む、方法。
- 細胞内細菌、真菌、又は原虫感染によって引き起こされる疾患を治療又は予防する方法であって、それを必要とするヒト又は動物の対象に天然、半合成、又は合成の性ホルモンと組み合わせて、請求項1〜7のいずれか一項に記載の化合物の治療有効量を投与することを含む、方法。
- 細胞内細菌、真菌、又は原虫感染によって引き起こされる疾患を治療又は予防する方法であって、それを必要とするヒト又は動物の対象に天然、半合成、又は合成の性ホルモンと組み合わせて、請求項1に記載のP1〜P21から選択される化合物の治療有効量を投与することを含む、方法。
- 細胞内細菌又は原虫感染によって引き起こされる疾患を治療又は予防する方法であって、それを必要とする男性又は動物対象に天然、半合成、又は合成のエストロゲンと組み合わせて、請求項1〜7のいずれか一項に記載の化合物の治療的有効量を投与することを含み、かつ必要に応じて天然、半合成、又は合成のプロゲストゲンをさらに投与することを含む、方法。
- 細胞内細菌、真菌、又は原虫感染によって引き起こされる疾患を治療又は予防する方法であって、それを必要とするヒト又は動物の対象に天然、半合成、又は合成のエストロゲンと組み合わせて、請求項1に記載のP1〜P21から選択される化合物の治療有効量を投与することを含み、かつ必要に応じて天然、半合成、又は合成のプロゲストゲンをさらに投与することを含む、方法。
- 細胞内細菌、真菌、又は原虫感染によって引き起こされる疾患を治療又は予防する方法であって、それを必要とする男性又は動物対象に天然、半合成、又は合成のテストステロンと組み合わせて、請求項1〜7のいずれか一項に記載の化合物の治療有効量を投与することを含む、方法。
- 細胞内細菌、真菌、又は原虫感染によって引き起こされる疾患を治療又は予防する方法であって、それを必要とするヒト又は動物の対象に天然、半合成、又は合成のテストステロンと組み合わせて、請求項1に記載のP1〜P21から選択される化合物の治療有効量を投与することを含む、方法。
- 細胞内感染が、結核菌、非定型疾患を引き起こすマイコバクテリア、鳥型結核菌及びM.イントラセルレア(マイコバクテリウムアビウム(Mycobacterium avium)−イントラセルレア複合体、又はMACとしても既知)、M.カンサシ、M.マリナム、M.フォルトゥイタム、M.ゴルディナエ、マイコプラズマニューモニエ(Mycoplasma pneumoniae)、M.ゲニタリウム、M.ホミニス、ウレアプラズマウレアリチカム(Ureaplasma urealyticum)、U.パルブム、クラミドフィラニューモニエ(Chlamydophila pneumoniae)、サルモネラチフィムリウム(Salmonella typhimurium)、トキソプラズマゴンディ(Toxoplasma gondii)、熱帯熱マラリア原虫、P.ビバックス、クルーズトリパノソーマ、クリプトスポリジウム、リーシュマニア、ヒストプラスマカプスラーツム(Histoplasma capsulatum)、クリプトコックスネオフォルマンス(Cryptococcus neoformans)、及びエンセファリトゾーンクニクリ(Encephalitozoon cuniculi)から選択される、請求項13〜20のいずれか一項に記載の方法。
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US20190388497A1 (en) | 2019-12-26 |
AU2018209239A1 (en) | 2019-08-15 |
JP2022153565A (ja) | 2022-10-12 |
CA3050999A1 (en) | 2018-07-26 |
CN110431147A (zh) | 2019-11-08 |
US11564969B2 (en) | 2023-01-31 |
WO2018134373A1 (en) | 2018-07-26 |
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