JP5289706B2 - 免疫調節組成物 - Google Patents
免疫調節組成物 Download PDFInfo
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- JP5289706B2 JP5289706B2 JP2006500223A JP2006500223A JP5289706B2 JP 5289706 B2 JP5289706 B2 JP 5289706B2 JP 2006500223 A JP2006500223 A JP 2006500223A JP 2006500223 A JP2006500223 A JP 2006500223A JP 5289706 B2 JP5289706 B2 JP 5289706B2
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Description
本発明は、免疫調節ポリヒドロキシル化ピロリジジン化合物、およびそれらの薬剤での使用に関する。特に、本発明は、カスアリンおよびある種のカスアリン類似体の免疫調節(免疫刺激または免疫抑制)薬としての使用に関する。
免疫
免疫系が異種抗原によって攻撃されると、防御応答を起こすことによって応答する。この応答は、先天性および後天性免疫系の両方の調整相互作用を特徴とする。これらの系はかっては別々の独立したものと考えられていたが、現在は統合すると、相互に排他的な要件、すなわち敏速さ(先天性の系によって与えられる)および特異性(適応系によって与えられる)、を満足する2つの互いに依存する部分と認められている。
病原体侵襲に続いて最も早く見られるものは、先天性免疫系の細胞成分によって行われると考えられている。常在性組織マクロファージおよび樹状細胞(DC)が病原体に遭遇して、パターン認識受容体(PRR)と大きな群の微生物によって共有されている病原体関連分子パターン(PAMP)との相互作用によって生じるシグナルによって活性化されるときに、応答が開始する。活性化したマクロファージとDCは刺激されて、各種サイトカイン(ケモカインIL-8、MIP-1αおよびMIP-1βなど)を放出し、これらは「危険シグナル」を構成し、ナチュラルキラー(NK)細胞、マクロファージ、未成熟樹状細胞の組織への流入を誘発する。
適応免疫応答は、主として、2種類の独立した部分である細胞依存性(1型)免疫と抗体依存性または体液性(2型)免疫を介して行われる。
アルカロイドという用語は、本明細書では狭義で生物体に天然に存在する任意の塩基性の有機含窒素化合物を定義するのに用いられる。アルカロイドという用語は、本明細書では広義で天然に存在するアルカロイドだけでなく、それらの合成および半合成類似体および誘導体をも包含する一層広い群の化合物を定義するのにも用いられる。
(a) 緒論
樹状細胞(DC)は特徴的形態と広汎な組織分布を有する異種細胞個体群である(Steinman (1991) Ann. Rev. Immunol. 9: 271-296)。抗原提示に重要な役割を果たしており、抗原を捕捉し、プロセシングしてペプチドとした後、それらを(MHCの成分と共に)T細胞に提示する。次に、T細胞活性化を、高水準のMHCクラスIおよびII分子、接着分子、および補助的刺激分子のような細胞表面分子の発現によって伝達することができる。
未成熟(または静止)DCは、皮膚や粘膜のような非リンパ様組織に存在しており、食細胞性が高く、可溶性および顆粒状抗原を容易にインターナライズする。このような抗原に装填された未成熟DCが、食細胞性で移動性細胞からナイーブなT細胞の非食細胞性の高度に効率的な刺激因子へ形質転換する成熟過程を受けるのは、これらが炎症性刺激(成熟刺激)をも受けやすいときに限られる。
樹状細胞単細胞型によっては表されず、むしろ様々なクラスの細胞であってそれぞれが独特な個体発生を有するものの異種の集まりを含んでなる。少なくとも3種類の発生経路であって、特有の先祖から発生して特定のサイトカインの組合せによって別個の特殊化した機能を有するDCサブセットとするものが報告されている。
一つの樹状細胞に基づく治療パラダイム(Schuler et al. (2003) Current Opinion in Immunol 15: 138-147に概説されている)では、DC細胞は患者から(例えば、アフェレーシスによって)採取した後、特定の抗原または複数の抗原(例えば、(複数の)腫瘍抗原)を適用(プライミングまたは投与)する。次に、それらを自家細胞ワクチンとして再投与して、適当な免疫応答を増強する。
細胞傷害性Tリンパ球(CTL)を患者に投与して、特定の疾患または感染症(典型的には、癌)に対する免疫応答を付与しまたは追加することができる。例えば、腫瘍特異性T細胞を患者から(例えば、白血球搬出法によって)抽出し、選択的に膨張させ(例えば、テトラマーによって誘導されるクローニングによって: Dunbar et al. (1999) J Immunol 162: 6959-6962を参照)、次に自家細胞ワクチンとして再投与することができる。
樹状細胞は、免疫学的寛容の調節および維持にも関与しており、成熟の非存在下では、これらの細胞は抗原特異性サイレンシングまたは寛容を誘発する。
Granucci et al. (2002) Trends in Immunol. 23: 169-171には、微生物刺激後の樹状細胞におけるIL-2についてのmRNA転写体の一過性アップレギュレーションが報告されている。WO 03012078号明細書では、GranucciはT細胞活性化だけでなくNK細胞の活性化の伝達においてDCによって誘導されるIL-2が重要な役割を果たしていることを報告し、続けてDCによって誘導されるIL-2は先天性および適応免疫の調節および連結する重要な因子であることを示唆している。
本発明によれば、式
を有する、治療または予防に使用するための単離された免疫調節(例えば、免疫刺激)ポリヒドロキシル化ピロリジジン化合物、またはその薬学上許容可能な塩または誘導体が提供される。
を有する化合物、またはその薬学上許容可能な塩または誘導体である。
を有するポリヒドロキシル化ピロリジジン化合物、またはその薬学上許容可能な塩または誘導体を含んでなる組成物を患者に投与することを含んでなる、方法を提供する。
定義
本明細書で用いられ且つ特に断らない限りは、下記の用語は、当該技術分野でこれらの用語が持つことができる任意の一層広義の(または狭義の)意味に加えて、下記の意味を有することを意味する。
どのような理論によっても束縛されることを望むものではないが、本発明の化合物の免疫調節活性はイン・ビボでのサイトカインの刺激および/または抑制によって生じることがあると考えられる。特に、本発明の化合物の免疫調節活性は、インターロイキン2および/または12(IL-2および/またはIL-12)など1種類以上のサイトカイン(例えば、1種類以上のTh1サイトカイン)の分泌の刺激、および/または1種類以上のTh2サイトカイン(例えば、IL-5)の分泌の抑制によって生じると考えられる。
・腫瘍細胞グリコシル化(例えば、腫瘍抗原グリコシル化)の修飾、
・ウイルスタンパク質グリコシル化(例えば、ビリオン抗原グリコシル化)の修飾、
・感染宿主細胞における細胞-表面タンパク質グリコシル化の修飾、
・細菌細胞壁の修飾
のいずれかまたは全部が生じる可能性がある。
本発明は、医療、例えば、治療、予防および/または診断の方法に広汎な用途を見出している。
一般的考察
最初に述べたように、免疫応答は2種類の異なる型であるTh1応答(1型、細胞または細胞性免疫)およびTh2応答(2型、体液性または抗体依存性免疫)を含んでなる。
Th1関連疾患は、Th1細胞が疾患、障害、症候群、疾病または感染症の影響の予防、治癒または緩和に関与している疾患、障害、症候群、疾病または感染症である。
Th2関連疾患は、Th2細胞が疾患、障害、症候群、疾病または感染症の影響に関与する(例えば、支持し、引き起こしまたは伝達する)疾患、障害、症候群、疾病または感染症である。
本発明のピロリジジン化合物は脾臓および骨髄細胞増殖を増加し、脊髄増殖性 物質として作用することができる。従って、それらは、血液回復薬として応用することができる。
本発明のピロリジジン化合物を用いて、免疫系が部分的にまたは完全に抑制されまたは押し下げられている状態を緩和、制御または調節することができる。このような状態は、先天性(遺伝)疾患から生じ、(例えば、感染症または悪性腫瘍によって)獲得され、または(例えば、移植片または癌の処理の一部として故意に)誘導されることがある。
本発明のピロリジジン化合物を用いて、様々なインターロイキン(例えば、IL-2および/またはIL-12)などの様々なサイトカインをイン・ビボで誘発し、増強し、または活性化することができる。
本発明は、様々な癌および癌転移などの増殖性疾患の治療に用いることができる。例えば、本発明のピロリジジン化合物は、特に白血病、リンパ腫、黒色腫、アデノーマ、肉腫、固形組織の癌、黒色腫(目の黒色腫など)、膵臓癌、子宮頸部癌、腎臓、胃、肺、卵巣、直腸、乳、前立腺、腸、胃、肝臓、甲状腺、頸、子宮頸部、唾液腺、脚、舌、口唇、胆管、骨盤、縦隔、尿道、肺、膀胱、食道、および結腸癌、カポシ肉腫(例えば、AIDSに関連したとき)の治療に応用することができる。
本発明のピロリジジン化合物はワクチン補助薬として用いることができ、この態様では、抗原、特に内在性免疫原性が低い抗原に対する免疫応答を促進し、誘導し、または増強することができる。どのような理論によっても束縛されることを望むものではないが、本発明のピロリジジン化合物はサイトカイン放出によりB細胞およびCTL応答に対するT細胞の援助を促進することによってワクチン免疫原性を増強することができる。それらは、癌またはウイルス抗原のグリコシル化を変化させ、ワクチンの有効性を増加させることもできる。
上記のように、本発明のピロリジジン化合物は樹状細胞で持続的且つ顕著なサイトカイン産生(例えば、持続的且つ顕著なIL-12および/またはIL-2の産生)を誘導することができる。例えば、本発明の化合物は、樹状細胞においてサイトカイン産生の誘導を含んでなる、または樹状細胞におけるサイトカイン産生の誘導が指示されまたは必要とされる治療または予防の方法に応用することができる。
樹状細胞に基づく治療パラダイムでは、細胞に抗原または複数の抗原(例えば、(複数の)腫瘍抗原)をパルシング(プライミングまたはスパイク)した後、投与してTh1免疫応答を促進する。応答性T細胞としては、ヘルパー細胞、特に、(IFN-γを産生する)Th1CD4+細胞、およびキラー細胞(特に、CD8+細胞傷害性Tリンパ球)が挙げられる。樹状細胞は、他のクラスのリンパ球(B、NK、およびNKT細胞)によって応答を伝達することもできる。それらは、ワクチン接種の決定的目的であるT細胞記憶を誘発することもできる。
樹状細胞は、免疫学的寛容の調節および維持にも関与しており、成熟の非存在下では、細胞は抗原特異性サイレンシングまたは寛容を誘発する。例えば、別の樹状細胞に基づく治療パラダイムでは、細胞を自己免疫疾患と闘うようにデザインした免疫調節介入の一部として投与する。
本発明のピロリジジン化合物は、通常は非治癒性の感染性疾患モデルにおけるエクス・ビボでのTh2型脾臓細胞応答を逆転することができる。抗原特異性脾臓細胞IFN-γを、そのようなモデルで有意に増加させ且つIL-5産生を有意に減少させ、治癒性応答を示すことができる。
本発明のピロリジジン化合物は、経口、または静脈内、筋肉内、腹腔内、皮下、経皮、気道(エアゾール)、直腸、膣および局所(口内および舌下)投与などの非経口経路によって投与することができる。
本発明の組成物は、本発明のピロリジジン化合物を、場合によっては薬学上許容可能な賦形剤と共に含んでなる。
か213
本発明のピロリジジン化合物を薬学上許容可能な賦形剤と共に処方する態様では、任意の適当な賦形剤、例えば、不活性希釈剤、崩壊剤、結合剤、滑沢剤、甘味料、フレーバー剤、着色料、および防腐剤などを用いることができる。適当な不活性希釈剤としては、炭酸ナトリウムおよびカルシウム、リン酸ナトリウムおよびカルシウム、およびラクトースが挙げられ、一方トウモロコシ澱粉およびアルギン酸は適当な崩壊剤である。結合剤としては、澱粉およびゼラチンを挙げることができ、一方滑沢剤は、含まれる場合には、一般的にはステアリン酸マグネシウム、ステアリン酸、またはタルクである。
本発明を、具体例について説明する。これらは、単に例示的なものであり、説明を目的とするものであり、主張した独占権の範囲または記載した発明を制限しようとするものではない。これらの実施例は、本発明の実施について現在考えられる最良の様式を構成する。
マウス
通常の条件下でStrathclyde大学で飼育され、維持されたBALB/cの雄および雌マウスを、8週齢で使用した。
骨髄をマウスの大腿骨から得た。大腿骨を70%エタノールで洗浄し、清浄なペトリ皿に入れた。樹状細胞(DC)培地(RPMI-1640培地中、2.5%顆粒球-マクロファージコロニー刺激因子(GM-CSF)、10%熱および活性化ウシ胎仔血清、1%L-グルタミン、1%ペニシリン/ストレプトマイシン)を送液作用によって大腿骨の骨髄に投与し、細胞と培地を集めた。培地中の細胞1mlを、DC培地15mlを加えた75cm2フラスコに加えた。次に、フラスコを37℃、5%CO2でインキュベーションして、DCを増殖させて、発現させた。5日後、DC培地を更に10ml加えた。
骨髄をGM-CSFと共に10日間インキュベーションした後、樹状細胞を採取した。この工程は、組織培養フード(hood)で行った。フラスコの内容物を遠沈管に投入し、浮遊DCを確実に回収した。冷却したリン酸緩衝食塩水(PBS)約10mlをそれぞれの空のフラスコに加え、フラスコを緩やかに攪拌し、内容物を集めた。これにより、付着性DCを確実に回収した。回収したフラスコの内容物を200gで5分間遠心分離し、ペレットをGM-CSFを含まないDC培地2mlに再懸濁した。次に、細胞を計数した。
細胞を、血球計を用いて計数した。再懸濁した細胞約20μlを血球計のチャンバーにピペットで採取し、細胞を正確な細胞濃度(ウェル当たり約5x104で1x104以上)に調整した後、培養して分析した。
酵素結合イムノソーベントアッセイ(ELISA)を用いて、上清中のIL-12濃度を測定した。このアッセイに用いた総ての試薬は、PharMingen製であった。96ウェルの平底ELISAプレートに、50μl/ウェルでのPBS pH9.0中で希釈した2μg/mlの精製したラット抗マウスIL-12(p40/p70)MAb(カタログ番号554478)をコーティングした。次に、プレートを食品包装用ラップで被覆して、4℃でインキュベーションした。インキュベーションの後、プレートを洗浄用緩衝液で3回洗浄し、乾燥した。ブロッキング緩衝液(10%ウシ胎仔血清/PBS、pH7.0)200μlをそれぞれのウェルに加えた後、食品包装用ラップで被覆し、37℃で45分間インキュベーションした。プレートを3回洗浄し、乾燥した。形質転換マウスIL-12標準品を、10ng/mlから開始して、次いで5、2.5、1.25、0.625、0.31、0.156、0.078、0.039、0.020、0.010、0.005ng/mlで2個ずつのウェルに30μlを加えた。標準品を、ブロッキング緩衝液で希釈した。上清試料を50μl/ウェルで加えた。次に、プレートを食品包装用ラップで被覆し、37℃で2時間インキュベーションした。次いで、プレートを4回洗浄し、乾燥して、二次抗体を加えた。
IL-2の決定のための適当なMabおよび標準品を置換したことを除き、上記実施例1に記載のプロトコールを行った。結果を下表2.1に示す。
通常の条件下でStrathclyde大学で飼育され、維持されたBALB/cの雄および雌マウスを、様々な週齢で使用した。
マウス脾臓を無菌的に取り出し、5mlの完全培地(RPMI、1%L-グルタミン、1%ペニシリン/ストレプトマイシン、および10%ウシ胎仔血清)を含む滅菌ペトリ皿に入れた。細胞懸濁液を注射器の末端を用い、脾臓をワイヤーメッシュを通して粉砕することによって調製した。細胞懸濁液を、次に1000rpmで5分間遠心分離した。赤血球を除去するため、細胞ペレットをボイル溶液(Tris 0.17Mおよび塩化アンモニウム0.16M)に再懸濁し、再度5分間遠心分離した。次に、ペレットを培地で更に2回洗浄した後、3mlの培地に再懸濁した。次に、細胞計数を行った。
総ての脾臓細胞実験は、96ウェル組織培養プレートで行った。5x105個/ウェルの100μl分量を総てのウェルに加え、それぞれのウェルの最終容積を200μlとした。未刺激ウェルは、100μlの細胞と100μlの培地を含んでいた。刺激したウェルは100μlの細胞と、1μg/mlのLPSを50μlまたは0.5μg/mlの抗CD3を50μl、および50μlの培地を含んでいた。残りのウェルは、100μlの細胞、50μlのMNLP化合物、および50μlの抗CD3または培地のみを含んでいた。
適当なMabおよび標準品を、IL-12について記載したプロトコールに準じて用いた(上記の実施例1に記載)。結果を、下表3.1-3.3に示す。
総ての酵素は、適当なp-ニトロフェニル基質と同様に、Sigma社から購入した。アッセイは、マイクロタイタープレートで行った。酵素は、酵素についての最適pHで0.1Mクエン酸/0.1Mリン酸水素二ナトリウム(Mcllvaine)緩衝液中で分析した。総てのアッセイは20℃で行った。スクリーニングアッセイについては、インキュベーションアッセイは、10μlの酵素溶液、10μlのインヒビター溶液(水中で作成)、および酵素についての最適pHでのMcllvaine緩衝液中で作成した適当な5mM p-ニトロフェニル基質(3.57mM最終濃度)の50μlからなっていた。
マンノシダーゼおよびグルコシダーゼに関するスワインソニン(4)、カスアリン(8)およびカスアリングルコシド(9)のグリコシダーゼ阻害プロフィールを比較した。結果(総て、<0.1mg/ml)を、下表5.1に示す。
マウスは、3-4週齢のBALB/cであった。マウスに、頸部皮膚法を用いて104 p.f.u.のHSV-1(SG16)を接種した。この用量は致死量以下であるが、炎症(耳介の厚みの増加によって測定)などの臨床症状を生じる。
マウス(C57/bl6、腹腔内ケタミン麻酔下)に、0日目にマウス当たり100μlの最終容積の5x104個のB16-F10腫瘍細胞を静脈内(尾静脈)に投与した。試験化合物(50mg/kg、200μlの滅菌発熱性物質不含食塩水)を、2および4日目に皮下(右脇腹)に投与した。14日目に、マウスを屠殺して、肺を摘出し、インディアンインク溶液(150mlの2回蒸留水、30mlのインドインク、NH4OH4滴)で10分間染色した後、Fakete溶液(90mlの37%ホルムアルデヒド、900mlの70%EtOH、および45mlの氷酢酸)中で少なくとも24時間固定した。染色して固定した肺における転移を明視化し、計数し、写真撮影することができた。
細胞培養
MGF-7細胞(European Collection of Cell Cultures Ref. 86012803)を液体窒素ストックから取り出して、室温にて融解し、10% v/vウシ胎仔血清(FCS: BioWest Labsカタログ番号 S02755, Lot. No. S1800)を補足したHams F12、15mM HepesおよびL-グルタミンを有するダルベッコ改良イーグル培地(DMEM : Cambrexカタログ番号 BE12-719F)10mlに移した。FCSは、0.2μmの滅菌フィルターにより予備濾過した。
細胞を、非酵素的方法を用いて採取した。それぞれの時点に、細胞を倒立光学顕微鏡で観察し、その形態を評価した。採取前に、細胞を滅菌PBSで洗浄当たり7cm3で3回洗浄した。次に、細胞を滅菌スクレーパーを用いてフラスコからかき集め、Grenier試験管に移した。細胞を速やかに21 G2ゲージニードルを通過させ、細胞をバラバラにした。次に、細胞を1500gで5分間遠心分離してペレット化し、既知容積のPBSに再懸濁した。次に、細胞の数を血球計で計数し、 それぞれの細胞懸濁液0.1cm3をトリパンブルー溶液1滴と混合することによって細胞成長能力を評価した。それぞれの細胞ペレットを、グリカン放出および分析まで- 80℃で冷凍した。
細胞ペレットを氷水槽に入れ、融解させた。次に、ペレットを全量4cm3(脱イオン水でその容積にした)で均質化した。翼の速度を22,500rpmに設定したUltraturrax T25ホモジナイザージを、この目的に用いた。試料を氷上に保持し、それぞれの均質化段階の間に約1分間の時間を置いて泡を治め、それぞれ10秒間の3回のバーストを加えた。それぞれの試料の間には、翼を注意深く洗浄し、交差汚染を防止した。ホモジェネートを1cm3の分量で-80℃で保管した後、タンパク質アッセイおよびグリカン放出を行った。
BioRadタンパク質アッセイを用いて、製造業者の指示に従って評価を行った。BSAを標準品として用いた。それぞれのホモジェネート試料を、それぞれの時点から100μlの分量を用いて2回ずつ試験した。
62時間および86時間の時点について、タンパク質25μgの相当量を採取し、遠心エバポレーターで3時間(加熱せずに)乾燥した。初期の時点については、タンパク質濃度はタンパク質アッセイでは評価することができず、200μlを採取し、乾燥してグリカン放出の準備をした。放出は、ウシ胎仔血清からのフェチュイン25μgを用いて確認した。
グリカンを、Bigge et al.(1995) Anal. Biochem. 230 (2): 229-238に記載の方法によって65℃で2時間還元的アミノ化によって標識した。次に、インキュベーション混合物を「清浄化」して、試料をWhatman 3MM濾紙にスポットし、4:1:1のブタノール:エタノール:水の移動相を用いて降下式クロマトグラフィータンクで展開することによってあらゆる未接合蛍光団を除去した。次に、グリカンを0.5cm3メタノールおよび2x1cm3HPLC級水で溶出した後、0.2μmシリンジトップフィルターで濾過した。
グリカンは、サイズが4.6x25cmの正常相(親水性相互作用)HPLCカラム(LudgerSep N1アミド)上で分離した。
最初の採取時点および28時間の時点では、処理済および未処理細胞から放出したグリカンには明確な差異はなかった(データーは示さず)。しかしながら、62および86時間の時点では、未処理細胞はその処理済のものと比較して大きなN結合グリカンが著しく優勢となった(データーは示さず)。更に、全般的シグナル(蛍光標識グリカンの量)は、未処理群より大きかった。
カスアリン(8)およびカスタノスペルミン(20)のヒツジ腸の刷毛縁膜小胞へのNa+依存性D-グルコース摂取の初期速度に対する影響を、標識したD-グルコースを用いる競合アッセイで検討した。結果を、下表9.1に示す。
リーシュマニア症は、Th1疾患の古典的モデルであり、非治癒性皮膚障害は著しくTh2歪曲した免疫応答の好ましくない分極により生じる。
一般的実験
総ての反応は、特に断らない限り無水溶媒を用いてアルゴン雰囲気下で室温にて行った。無水溶媒はFluka Chemicalsから購入し、供給されたまま使用した。試薬はAldrich、FlukaおよびFisherから供給を受け、供給されたまま使用した。薄層クロマトグラフィー(Tlc)は、Merck 60 F254を前コーティングしたアルミニウムシート上で行い、紫外線およびエタノール中6%ホスホモリブデン酸を用いる染色により明視化した。シリカゲルクロマトグラフィーは、ポジティブ雰囲気下でSorbsil C60 40/60シリカゲルを用いて行った。強酸性イオン交換樹脂であるAmberlite IR-120は、樹脂を少なくとも2時間2M塩酸に浸漬した後、溶離液がpH5になるまで蒸留水で溶出することによって調製した。Dowex 50WX8-100は、樹脂を少なくとも2時間2M塩酸に浸漬した後、中性になるまで蒸留水で溶出することによって調製した。赤外スペクトルは、塩化ナトリウムプレート上のフィルムを用いてPerkin-Elmer 1750 IRフーリエ変換分光光度計上で記録した。特徴的ピークのみを記録する。旋光度は、光路長が1dmのPerkin-Elmer 241偏光計で測定した。濃度は、g/100mlで表した。核磁気共鳴スペクトルは、公認の重水素化溶媒中Bruker DQX 400分光計で記録した。総てのスペクトルは、周囲温度で記録した。化学シフト(δ)はppmで表し、標準品としての残留溶媒に対するものである。プロトンスペクトル(δH)は、400MHzで記録し、炭素スペクトル(δC)は100MHzで記録した。
5,6:7,8-ジ-O-イソプロピリデン-D-エリトロ-L-ガラクト-オクトノ-1,4-ラクトン(Qb)
シアン化ナトリウム(7.02g, 142ミリモル)を、D-グリセロ-D-グロ-ヘプトース(Qa, 21g, 100ミリモル)を水(300ml)に攪拌溶解したものに加えた。反応混合物を室温で48時間攪拌し、48時間加熱還流し、Amberlite IR-120(強酸性イオン交換樹脂, 300ml)を含むカラムを通過させた。溶離液を減圧濃縮し、残渣を24時間真空乾燥した。生成するフォームを、無水硫酸銅(10g, 62ミリモル)の存在下にてアセトン(500ml)と硫酸(5.4ml)で室温にて48時間処理した。T.l.c.分析は、2個の主要生成物の存在を示唆していた(酢酸エチル:シクロヘキサン, 1:1; Rf 0.72, 0.18)。反応混合物を濾過して、濾液を重炭酸ナトリウム(50g)で室温にて24時間処理した。固形残渣を濾別し、濾液を減圧濃縮した。生成する粗製の黄色シロップをシリカゲルクロマトグラフィーによって精製し、無色シロップ状の3:5,6:7,8-トリ-O-イソプロピリデン-D-エリトロ-L-タロ-オクトノ-1,4-ラクトン Qc (Rf 0.72; 7.672g; 21%)および透明油状の5,6:7,8-ジ-O-イソプロピリデン-D-エリトロ-L-ガラクト-オクトノ-1,4-ラクトン Qb(Rf 0.18; 8.105g; 25%)を得た。 2,3:5,6:7,8-トリ-O-イソプロピリデン-D-エリトロ-L-タロ-オクトノ-1,4-ラクトン Qc:δH(CDCl3) 1. 29, 1.33, 1.35, 1.38, 1.42, 1.48(6xs, 18H, 3xC(CH3)2), 3.93-3.99 (m, 2H, H-8a, H-7), 4.03-4.07 (m, 2H, H-5, H-6),4.15(dd, 1H, J8a,8b 8.7 J8b,7 6.1, H-8b), 4.75-4.78 (m, 3H, H-2, H-3, H-4); δC (CDCl3) 25.23, 25.51, 26.00, 26.71, 26.73, 27.16(3xC(CH3)2), 67.93, 74.93, 76.33, 76.69, 78.65, 79.40, 80.06, 109.95, 110.72, 113.19, 174.27;νmax (フィルム) 1793。5,6:7,8-ジ-O-イソプロピリデン-D-エリトロ-L-ガラクト-オクトノ-1,4-ラクトン Qb: δH (d6-アセトン) 1.28, 1.32, 1.34, 1.35(4s, 12H, 2xC(CH3)2), 3.92 (1H, m, H-8a), 3.98 (m, 1 H, H-7), 4.14 (m, 2H, H-5, H-8b), 4.23-4.25 (m, 2H, H-4, H-6), 4.35-4.40 (m, 2H, H-2, H-3); δC (d6-アセトン) 25.31, 25.87, 26.72, 27.31, 68.06, 75.15, 75.23, 77.51, 78.05, 78.41, 79.01, 110.06, 110.31, 174.25; νmax(フィルム) 1793, 3541。
2,3:5,6:7,8-トリ-O-イソプロピリデン-D-エリトロ-L-タロ-オクトノ-1,4-ラクトン(Qc, 3.8 g, 10.6ミリモル)を、酢酸:水(2:3, 100ml)で50℃にて2時間処理した。T.l.c.分析(酢酸エチル:シクロヘキサン, 1:1)は、出発材料(Rf 0.72)が消失し、一層極性の化合物(Rf 0.15)が存在することを示していた。溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィー(酢酸エチル:シクロヘキサン, 1:1-3:1)によって精製し、透明油状の2,3:5,6-ジ-O-イソプロピリデン-D-エリトロ-L-タロ-オクトノ-1,4-ラクトン Qd(3.23g, 94%)を得た。
δH (CD3OD) 1.28, 1.38, 1.43 (3xs, 12H, 2xC(CH3)2), 3.59 (dd, 1H, J8a,7 5.40 J8a,8b 11.41, H-8a), 3.66-3.69 (m, 1H, H-7), 3.74 (dd, 1H, J8b,72.90Hz, H-8b), 4.01 (ほぼt, 1H, J6,77.62Hz, H-6), 4.24 (dd, 1H, J5,68.17 Hz J5,40.89Hz, H-5), 4.79-4.81 (m, 2H, H-3, H-4), 4.89-4.91 (m, 1H, H-2); δC (CD3OD) 24.62, 25.42, 26.05, 26.49, 63.86, 73.81, 75.40, 75.91, 79.18, 79.90, 80.78, 110.53, 113.09, 175.76; νmax (フィルム) 1791, 3478; [α]D -35.7 (c 1, CHCl3)。
2,3:5,6-ジ-O-イソプロピリデン-D-エリトロ-L-タロ-オクトノ-1,4-ラクトン (Qd, 3.18g, 10ミリモル)をN,N-ジメチルホルムアミド(40ml)に溶解したものに、第三ブチルジメチルシリルクロリド(1.808g, 12ミリモル)とイミダゾール(1.361g, 20ミリモル)を加えた。反応混合物を室温で16時間攪拌した後、t.l.c.分析(酢酸エチル:シクロヘキサン, 1:1)では出発材料(Rf 0.15)が見られず、1個の主生成物(Rf; 0.63)が形成されていた。溶媒を減圧留去し、残渣を酢酸エチルと塩水とに分配した。水層を酢酸エチルで抽出し、合わせた有機層を乾燥し(MgSO4)、濾過して、溶媒を除去した。生成する淡青色油状生成物をシリカゲルクロマトグラフィー(酢酸エチル:シクロヘキサン, 0:1-1:2)によって精製し、透明油状の8-O-第三ブチルジメチルシリル-2,3:5,6-ジ-O-イソプロピリデン-D-エリトロ-L-タロ-オクトノ-1,4-ラクトン Qe(3.612g, 85%)を得た。
δH (CDCl3) 0.04 (br s, 6H, 2xCH3), 0.86 (s, 9H, C(CH3)3), 1.23, 1.30, 1.32, 1.41(4xs, 12H, 2xC(CH3)2), 3.63-3.67 (m, 2H, H-8a, H-7), 3.76 (brd, 1H, H-8b), 3.96 (ほぼt, J6,78.21 J6,57.98, H-6), 4.08 (br d, 1H, H-5), 4.72 (br s, 2H, H-2, H-3), 4.78 (br s, 1H, H-4); δC (CDCl3) -5.52, -5.45, 18.25, 25.51, 25.80, 25.93, 26.68, 27.18, 63.95, 72.97, 74.88, 74.93, 78.71, 79.63, 79.87, 110.34, 113.00, 174.42;νmax (フィルム) 1794, 3570;[α]D-20.1 (c 1, CHCl3)。
8-O-第三ブチルジメチルシリル-2,3:5,6-ジ-O-イソプロピリデン-D-エリトロ-L-タロ-オクトノ-1,4-ラクトン(Qe, 3.5g, 8.2ミリモル)をピリジン:ジクロロメタン混合物 (1:4, 25ml)に溶解したものを-30℃に冷却した。無水トリフルオロメタンスルホン酸(3.5g, 2.09ml, 12.4モル)を少量ずつ添加し、混合物を2時間攪拌した。T.l.c.分析(酢酸エチル:シクロヘキサン, 1:3)では、出発材料(Rf 0.38)が消失し、極性の小さな生成物(Rf 0.48)が存在することを示していた。反応混合物を減圧濃縮し、残渣を酢酸エチルと0.5M塩酸とに分配した。有機層を塩水で洗浄し、乾燥して(MgSO4)、濾過し、減圧濃縮した。生成する粗製の淡橙色残渣を、N,N-ジメチルホルムアミド(25ml)中ナトリウムアジド(807mg, 12.4ミリモル)で16時間処理した。T.l.c.分析(酢酸エチル:シクロヘキサン, 1:4)では、中間体のトリフレート(Rf 0.42)が消失し、極性の大きな化合物(Rf 0.40)が存在することを示していた。反応溶媒を真空留去し、残渣を酢酸エチルと塩水とに分配した。水層を酢酸エチルで抽出し、合わせた有機層を乾燥し(MgSO4)、濾過して、真空濃縮した。生成する粗製残渣をシリカゲルクロマトグラフィー(酢酸エチル:シクロヘキサン, 0:1-1:4)によって精製し、無色油状の7-アジド-8-O-第三ブチルジメチルシリル-7-デオキシ-2,3:5,6-ジ-O-イソプロピリデン-L-トレオ-L-タロ-オクトノ-1,4-ラクトン Qf(3.026g, 81%)を得た。
δH(CDCl3) 0.11 (2xs, 6H, 2xCH3), 0.91 (s, 9H, C(CH3)3), 1.30, 1.38, 1.41, 1.47(4xs, 12H, 2xC(CH3)2), 3.41-3.45 (m, 1H, H-7), 3.87 (dd,1H, J8a,75.37Hz J8a,8b10.81Hz, H-8a), 3.92 (dd, 1H, J8b,77.32Hz, H-8b), 4.19-4.24 (m, 2H, H-5, H-6), 4.61 (br s, 1H, H-4), 4.75-4.79 (m, 2H, H-2, H-3); δC(CDCl3) -5.59, -5.56, 18.14, 25.54, 25.73, 26.09, 26.71, 26.98, 61.61, 63.19, 67.94, 74.84, 74.94, 75.47, 78.36, 78.66, 110.90, 113.37, 174.02;νmax (フィルム) 1796, 2111 ; [α]D+36.7(c 1, CHCl3)。
7-アジド-8-O-第三ブチルジメチルシリル-7-デオキシ-2,3:5,6-ジ-O-イソプロピリデン-L-トレオ-L-タロ-オクトノ-1,4-ラクトン (Qf, 3.00g, 6.6ミリモル)をテトラヒドロフラン(40ml)に溶解し、0℃に冷却した。水素化ホウ素リチウム(216mg, 9.9ミリモル)を加え、混合物を0℃-室温で2時間攪拌した。T.l.c.分析(酢酸エチル:シクロヘキサン, 1:1)では、出発材料(Rf 0.76)が消失し、極性の大きな化合物(Rf 0.45)が存在することを示していた。反応を塩化アンモニウム(飽和水溶液)を加えて停止させ、酢酸エチルと塩水とに分配した。水層を酢酸エチル(2x)で抽出し、合わせた有機層を乾燥し(MgSO4)、濾過して、溶媒を除去した。生成する粗製残渣をシリカゲルクロマトグラフィー(酢酸エチル:シクロヘキサン, 1:3-1:1)によって精製し、無色シロップ状の7-アジド-8-O-第三ブチルジメチルシリル-7-デオキシ-2,3:5,6-ジ-O-イソプロピリデン-L-トレオ-L-タロ-オクチトール Qg(2.476g, 82%)を得た。
δH (CDCl3) 0.10 (s, 6H, 2xCH3), 0.91 (s, 9H, C(CH3)3), 1.36, 1.41, 1.42, 1.48(4xs, 12H, 2xC(CH3)2), 3.43-3.47 (m, 1H, H-7), 3.66(br d, 1H, H-4), 3.79-3.92 (m, 4H, H-1, H-1a, H-8, H-8a), 4.10-4.14 (m, 2H, H-2, H-3), 4.30-4.38 (m, 2H, H-5, H-6); δC (CDCl3) -5,61, -5.51, 18.14, 25.18, 25.71, 26.87, 27.07, 27.86. 60.65, 62.39, 63.66, 67.62, 75.90, 76.91, 77.18, 77.49. 108.63. 110.16;νmax(フィルム) 2109, 3536;
[α]D+46.6(c 1, CHCl3)。
7-アジド-8-O-第三ブチルジメチルシリル-7-デオキシ-2,3:5,6-ジ-O-イソプロピリデン-L-トレオ-L-タロ-オクチトール (Qg, 2.4g, 5.3ミリモル)をピリジン(20ml)に溶解し、4-ジメチルアミノピリジン(64mg, 0.53ミリモル)とメタンスルホニルクロリド(4.814g, 3.253ml, 42ミリモル)をピリジン(20ml)に溶解したものに加え、2時間攪拌した。T.l.c.分析(酢酸エチル:シクロヘキサン, 1:2, 二重溶出)では、出発材料(Rf 0.33)が消失し、疎水性の大きな生成物(Rf 0.43)が存在した。溶媒を減圧留去し、残渣を酢酸エチルと塩水とに分配した。水層を酢酸エチルで抽出し、合わせた有機層を乾燥し(MgSO4)、濾過して、減圧濃縮した。生成する粗製残渣をシリカゲルクロマトグラフィー(酢酸エチル:シクロヘキサン, 1:2)によって精製し、無色油状の7-アジド-8-O-第三ブチルジメチルシリル-7-デオキシ-2,3:5,6-ジ-O-イソプロピリデン-1,4-ジ-O-メタンスルホニル-L-トレオ-L-タロ-オクチトール Qh(2.973g, 92%)を得た。
δH (CDCl3) 0.11, 0.12 (2xs, 6H, 2xCH3), 0.91 (s, 9H, C(CH3)3), 1.41, 1.44, 1.46, 1.56 (4xs, 12H, 2xC(CH3)2), 3.08(s, 3H, SO2CH3), 3.21 (s, 3H, SO2CH3), 3.49 (ddd, 1H, J7,62.82Hz, J7,85.46Hz, J7,8a7.94Hz, H-7), 3.87-3.97 (m, 2H, H-8, H-8a), 4.19 (dd, 1H, J6,52.30Hz, H-6), 4.24-4.31 (m, 2H, H-1, H-5), 4.36 (dd, 1H, J3,42.96Hz, J3,26.62Hz, H-3), 4.49-4.53 (m, 1H, H-2), 4.69 (dd, 1H, J1a,22.39Hz, J1a,110.83Hz, H-1a), 5.11 (ほぼt, 1H, H-4); δC (CDCl3) -5,56, 18.18, 25.76, 26.24, 26.78, 26.89, 27.56, 37.75, 39.02, 60.90, 63.57, 70.44, 76.00, 76.07, 76.46, 77.18, 77.32, 109.01, 110.68; νmax(フィルム) 2113; [α]D-16.2 (c 1, CHCl3)。
7-アジド-8-O-第三ブチルジメチルシリル-7-デオキシ-2,3:5,6-ジ-O-イソプロピリデン-1,4-ジ-O-メタンスルホニル-L-トレオ-L-タロ-オクチトール (Qh, 2.90g, 4.7ミリモル)を、トリフルオロ酢酸:水混合物(1:1, 40ml)で3時間処理した。T.l.c.分析(酢酸エチル)では、出発材料(Rf 0.9)が消失し、極性の大きな生成物(Rf 0.12)が存在した。溶媒を減圧留去し、残渣をトルエンを用いて共沸蒸発させ、真空乾燥した。シリカゲルクロマトグラフィー(酢酸エチル:シクロヘキサン, 1:1-1:10)によって精製し、無色油状の7-アジド-7-デオキシ-1,4-ジ-O-メタンスルホニル-L-トレオ-L-タロ-オクチトール Qi(1.677g, 85%)を得た。
δH (CD3OD) 3.12 (s, 3H, SO2CH3), 3.21 (s, 3H, SO2CH3), 3.61-3.71 (m, 2H, H-7, H-8), 3.78-3.82 (m, 2H, H-6, H-8a), 3.98-4.05 (m, 2H, H-2, H-3), 4.11-4.13 (m, 1H, H-5), 4.34 (dd, 1H, J1,24.87Hz, J1,1a10.44Hz, H-1), 4.45 (dd, 1H, J1a,21.87Hz, H-1a), 5.00 (dd, 1H, J4,31.91Hz, J4,56.15Hz, H-4); δC (CDCl3) 36.17, 38.11, 61.84, 66.62, 69.09, 70.33, 70.45, 71.08, 72.55, 86.41; νmax(フィルム) 2113; [α]D-9.1 (c 1, H2O)。
7-アジド-7-デオキシ-1,4-ジ-O-メタンスルホニル-L-トレオ-L-タロ-オクチトール(Qi, 1.6g, 3.78ミリモル)を水(30ml)に溶解し、10%パラジウム/炭素(400mg)で水素雰囲気下にて16時間処理した。T.l.c.分析(酢酸エチル:メタノール, 9:1)では、出発材料(Rf 0.75)は消失し、極性の大きな生成物(Rf 0.05)の存在することを示していた。パラジウムを濾去し、濾液を酢酸ナトリウム(930mg, 11.34ミリモル)で60℃にて16時間処理した。反応混合物を冷却し、溶媒を真空留去した。粗製の褐色油状生成物をイオン交換クロマトグラフィー(Dowex 50WX8-100, 2M水酸化アンモニウムで溶出)によって精製し、褐色ガラス状の(1R,2R,3S,6S,7R,7aR)-3-(ヒドロキシメチル)-1,2,6,7-テトラヒドロキシピロリジジン [3,7-ジエピ-カスアリン] Qj (671mg, 87%)を得た。
δH(D2O) 2.81-2.92 (m, 2H, H-5, H-5a), 3.16 (dd, 1H, J3,2 5.91Hz, J3.810.74Hz, H-3), 3.30 (ほぼt, 1H, J3.78Hz, H-7a), 3.76 (dd, 1H, J8,8a6.35Hz, H-8), 3.87 (dd, 1H, H-8a), 4.01 (d, 1H, J2,13.55Hz, H-2), 4.04-4.12 (m, 2H, H-6, H-7), 4.29 (ほぼt, IH, H-1); δC(D2O) 49.32, 57.29, 63.78, 70.41, 72.59, 72.65, 74.47, 78.25; [α]D-21.1 (c 0.5. H2O)。
上記の説明は、本発明の現在の好ましい態様を詳述したものである。これらの説明を考察するとき、当業者には、それらの実施において多数の修飾および変更が予想される。これらの修飾および変更は、特許請求の範囲内に包含されると考えられる。
Claims (12)
- 単離された免疫調節ポリヒドロキシル化ピロリジジン化合物、またはその薬学上許容可能な塩、および薬学上許容可能な賦形剤を含んでなる、免疫調節のための医薬組成物であって、
ポリヒドロキシル化ピロリジジン化合物が
(a) 1R,2R,3R,6S,7S,7aR-3-(ヒドロキシメチル)-1,2,6,7-テトラヒドロキシピロリジジン(カスアリン)(但し、Rは水素である)であり且つ式
(b) カスアリングリコシド、
(c) 式
(d) 6-O-ブタノイルカスアリン、
(e) 3, 7-ジエピ-カスアリン、
(f) 7-エピ-カスアリン、
(g) 3,6,7-トリエピ-カスアリン、
(h) 6,7-ジエピ-カスアリン、
(i) 3-エピ-カスアリン、
(j) 3,7-ジエピ-カスアリン-6-α-D-グルコシド、
(k) 7-エピ-カスアリン-6-α-D-グルコシド、
(l) 3,6,7-トリエピ-カスアリン-6-α-D-グルコシド、
(m) 6,7-ジエピ-カスアリン-6-α-D-グルコシド、
(n) 3-エピ-カスアリン-6-α-D-グルコシド
または(a)〜(n)のいずれかの薬学上許容可能な塩である、免疫調節のための医薬組成物。 - 請求項1に記載のポリヒドロキシル化ピロリジジン化合物を、
(a) 免疫刺激薬、および/または
(b) 細胞傷害性物質、および/または
(c) 抗微生物薬、および/または
(d) 抗ウイルス薬、および/または
(e) 樹状細胞
と組み合わせて含み、任意に
薬学上許容可能な賦形剤を更に含んでなる、免疫調節のための組成物。 - 請求項1に記載のポリヒドロキシル化ピロリジジン化合物を抗原と組み合わせて含んでなり、化合物がワクチン接種時にアジュバント効果を生じるのに十分な量で存在する、免疫調節のためのワクチン。
- 請求項1に記載のポリヒドロキシル化ピロリジジン化合物を含んでなる成分の免疫調節のための医薬キットであって、任意に使用説明書を更に含んでなる免疫調節のための医薬キット。
- 治療または予防のための、請求項1〜2のいずれか1項に記載の組成物であって、治療または予防が黒色腫の治療であり、かつ化合物の免疫調節作用が介在する、組成物。
- ポリヒドロキシル化ピロリジジン化合物が1R,2R,3R,6S,7S,7aR-3-(ヒドロキシメチル)-1,2,6,7-テトラヒドロキシピロリジジン(カスアリン)である、請求項5に記載の組成物。
- ポリヒドロキシル化ピロリジジン化合物が3, 7-ジエピ-カスアリンである、請求項5に記載の組成物。
- 治療または予防が
(e) 増殖性疾患の治療、
(o) 細菌感染症の治療または予防、
(p) ウイルス感染症の治療または予防、
(s) 自己免疫疾患の治療または予防、
から選択され、かつ化合物の免疫調節作用が介在する、請求項5に記載の組成物。 - ウイルス感染症が、呼吸器シンシチウムウイルス(RSV)、B型肝炎ウイルス(HBV)、Epstein-Barrウイルス、C型肝炎ウイルス(HCV)、単純ヘルペス1および2型、陰部ヘルペス、ヘルペス角膜炎、ヘルペス脳炎、帯状疱疹、ヒト免疫不全症ウイルス(HIV)、インフルエンザA型ウイルス、ハンターンウイルス(出血熱)、ヒトパピローマウイルス(HPV)、および麻疹から選択される、請求項8(p)に記載の組成物。
- 自己免疫疾患が、重症筋無力症、慢性関節リウマチ、全身性エリテマトーデス、シェーグレン症候群、強皮症、多発性筋炎および皮膚骨化症、強直性脊椎炎、およびリウマチ熱、インスリン依存性糖尿病、甲状腺疾患(グレーヴズ病および橋本甲状腺炎を含む)、アジソン病、多発性硬化症、乾癬、炎症性腸疾患、潰瘍性大腸炎、および自己免疫男性不妊症および女性不妊症から選択される、請求項8(s)に記載の組成物。
- 治療または予防が、感染の危険性を減少させる全身性1型免疫刺激因子としての予防的使用を含む、請求項5に記載の組成物。
- ポリヒドロキシル化ピロリジジン化合物が免疫刺激である、請求項1〜11のいずれか1項に記載の免疫調節のための組成物、キットまたはワクチン。
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Also Published As
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CA2513881A1 (en) | 2004-08-05 |
US8557859B2 (en) | 2013-10-15 |
ES2394072T3 (es) | 2013-01-16 |
EP1587480B1 (en) | 2012-06-27 |
NZ541839A (en) | 2009-02-28 |
CN1761666A (zh) | 2006-04-19 |
CA2513881C (en) | 2013-04-02 |
AU2004206085B2 (en) | 2011-03-24 |
US20130209516A1 (en) | 2013-08-15 |
AU2004206085A1 (en) | 2004-08-05 |
US20070155814A1 (en) | 2007-07-05 |
US8383665B2 (en) | 2013-02-26 |
JP2006515357A (ja) | 2006-05-25 |
HK1084576A1 (en) | 2006-08-04 |
EP1587480A2 (en) | 2005-10-26 |
WO2004064715A3 (en) | 2004-12-23 |
WO2004064715A2 (en) | 2004-08-05 |
GB0301554D0 (en) | 2003-02-26 |
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