JP2020073636A - 放射線不透過性ポリマー - Google Patents
放射線不透過性ポリマー Download PDFInfo
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- JP2020073636A JP2020073636A JP2019170209A JP2019170209A JP2020073636A JP 2020073636 A JP2020073636 A JP 2020073636A JP 2019170209 A JP2019170209 A JP 2019170209A JP 2019170209 A JP2019170209 A JP 2019170209A JP 2020073636 A JP2020073636 A JP 2020073636A
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- beads
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- radiopaque
- iodine
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- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 229920003176 water-insoluble polymer Polymers 0.000 description 1
- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 description 1
- 229950009819 zotarolimus Drugs 0.000 description 1
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Abstract
Description
ZQ III
の基であり、
式中、
Zは、連結基であるか、Qが環状アセタールに直接結合するよう存在せず;
Zは、C1〜6アルキレン、C2〜6アルケニレン、C2〜6アルキニレン、C1〜6アルコキシレンまたはC1〜6アルコキシアルキレンであり、かつ任意選択で1つまたは複数のハロゲンによって置換されているか、存在せず;
Qは、C1〜6アルキル、C2〜6アルケニルまたはC2〜6アルキニル基であるか、C5〜C12アリール、もしくはヘテロアリールまたはC5〜12シクロアルキルであり;
Qは、1つまたは複数のハロゲンによって置換されている。
特に、Zは−CH2OCH2−または−CH2O−であるか存在せず、
Zは、好ましくはハロゲンによって置換されていない。
(a)1,2−ジオール基または1,3−ジオール基を有するポリマーを含む、予め形成されたヒドロゲルマイクロスフェアを、上記マイクロスフェアを膨潤させることができる溶媒中で膨潤させる段階;(b)膨潤させたマイクロスフェアを、酸性条件下で上記1,2ジオールまたは1,3ジオールと環状アセタールを形成できる放射線不透過性化学種の溶液と混合するか接触させる段階;および(c)マイクロスフェアを抽出または単離する段階。
X−A IV
の化合物であり、式中、
Xは上記の通りであり;
Aは、1,2ジオールまたは1,3ジオールと環状アセタールを形成できる基である。
好ましくは、Aは、−CHO、−CHOR1OR2 −CHOR1OH、−CHSR1OHまたは−CHSR1SR2であり、式中、R1およびR2は、C1〜4アルキル、好ましくはメチルまたはエチルから独立して選択される。
温度計、窒素バブラーおよびオーバーヘッドスターラーを装着した500ml三つ口平底フラスコ内で、窒素ブランケットおよび激しい攪拌条件下、室温でエタノール100mlにフェノール10gを溶かした。1.25モル当量の水酸化ナトリウムペレットを加え、窒素ブランケット下、ペレットが完全に溶解するまでスラリーを30分間攪拌した。次いで、温度を25℃に維持しながら1.1モル当量の2−ヨードエタノールを加え、15分間攪拌した。溶液をエタノールで加熱還流した。HPLC(実施例1の条件)によりフェノールの消費および2−(2,4,6−トリヨードフェノキシ)エタノールの形成を監視した。25時間後、0.27モル当量の2−ヨードエタノールを追加し、溶液を還流しながらさらに2時間攪拌した。溶液を室温に冷却した後、激しい攪拌条件下で脱イオン水150mlを急速に加えた。得られたスラリーを真空下でろ過し、母液、次いで脱イオン水30mlで3回、最後にエタノール5mlで洗浄した。得られた桃色のろ塊を酢酸エチル100ml中に溶かし、有機層を大量の水酸化ナトリウム溶液(pH14)で抽出し、硫酸マグネシウム酸で乾燥させ、ロータリーエバポレーターで濃縮して、オフピンクの固体5.9gを得て、これをSigma−Aldrich社から市販されている分析標準品との比較分析によって2−(2,4,6−トリヨードフェノキシ)エタノールと同定した。
温度計、窒素バブラーおよびオーバーヘッド攪拌機を装着した500ml三つ口平底フラスコ内で、窒素ブランケット下、無水DMSO 150ml中にアルコール5.9gを溶かした。この溶液を攪拌して40℃に加熱し、温度を40℃〜41℃に維持しながら1.6モル当量のT3P(EtOAcに溶かした50%w/w溶液)を徐々に加えた。高速液体クロマトグラフィーによりアルコールの消費およびアルデヒドの生成を経時的に監視した(実施例1の条件)。24時間後、シリンジポンプを用いて反応混合物に水150mlを2時間にわたって徐々に加えた。溶液からオフピンクの固体が沈殿し、真空下でろ過して桃色のろ塊が得られ、これを水で洗浄した。得られた不純物を含む凝集塊を酢酸エチル/ヘキサンに溶かした後、真空下、40℃で乾燥させて油を得て、1HNMR分析により2−(2,3,5−トリヨードフェノキシ)アセトアルデヒドと同定した。
国際公開第2004/071495号の実施例1に従って、架橋ヒドロゲルマイクロスフェアを調製した。この工程は、生成物を真空乾燥させて残留溶媒を除去する段階の後で終了させた。高AMPS形態および低AMPS形態の両方のポリマーを調製し、しかるべき大きさの範囲になるようビーズをふるい分けた。ビーズは乾燥状態または生理的食塩水中のいずれかで保管し、加圧滅菌した。高AMPS形態および低AMPS形態のいずれのポリマーを用いても良好な放射線不透過性の結果が得られる。
窒素をパージした500ml容器に乾燥PVA系ビーズ(実施例4を参照されたい―高AMPS型105〜150μm)5.0gおよび0.26当量のアルデヒド(7.27g)(実施例1に従って調製したもの)を入れた。窒素ブランケット下で無水DMSO 175mlを加え、攪拌してビーズを懸濁状態に保った。懸濁液を50℃に温め、メタンスルホン酸11mlを徐々に加えた。反応スラリーを50℃で27時間攪拌し、その間、HPLCによりアルデヒドの消費を監視した。次いで、反応スラリーを大量のDMSO/1%NaCl、次いで生理食塩水で洗浄した。得られたビーズは、ヨウ素濃度が141mg I/ml湿潤ビーズであり、放射線不透過性が4908HUであった。
実施例1に記載されている通りにT3PおよびDMSOを用いて、2,3,4,6−テトラヨードベンジルアルコール(ACES Pharma社;米国)を2,3,4,6テトラヨードベンズアルデヒドに変換した。次いで、窒素ブランケット下でDMSOと共にPVAヒドロゲルマイクロスフェア(実施例4を参照されたい―大きさ150〜250μmの高AMPS型)2.05gに0.6モル当量の2,3,4,6テトラヨードベンズアルデヒド(8.8g)を加えた。反応混合物を50℃に加熱し、数時間攪拌した。HPLCで反応を監視し、反応が完了したとき、ビーズをろ過し、DMSO、水、次いで0.9%生理食塩水で洗浄した。次いで、放射線不透過性ビーズを分析用に0.9%生理食塩水溶液中で保管した。ヨウ素含有量は30mg/ml湿潤ビーズと測定された。
大きさの範囲が150〜200μmの乾燥PVA−メタクリル酸ナトリウムコポリマーマイクロスフェア(Hepasphere(登録商標)(Merit Medical Systems社)0.1gを、無水DMSO 3.5mlに溶かした2,3,5−トリヨードベンズアルダイド(triiodobenzaldyde)0.1314gと混合した。反応物を窒素下で攪拌しながら50℃に加熱した。10分後、攪拌しながら、メタンスルホン酸0.22mlを加え、反応を50℃で24時間進行させた。次いで、ビーズを50℃にてDMSO 1%NaCl 20mlで5回洗浄し、各洗浄は10分間続けた。次いで、ビーズを0.9%生理食塩水20mlで10分間、振盪させながら洗浄した。
実施例(5および6)で作製されたビーズのうち典型的なものの光学顕微鏡像を図1に示す。
ビーズの固体含有量(%)×乾燥ビーズのヨウ素含有量(%)。
マイクロCTを用いて、上の実施例5に従って調製した放射線不透過性塞栓ビーズの試料の放射線不透過性を評価した。試料はNuncクライオチューブバイアル(Sigma−Aldrich社製品コードV7634、48mm×12.5mm)中で調製した。ビーズを0.5%アガロースゲル(Sigma−Aldrich社製品コードA9539を用いて調製したもの)に懸濁させた。得られた懸濁物は一般に、「ビーズファントム」と呼ばれる。これらのビーズファントムを調製するため、最初にアガロースの溶液(1%)を約50℃の温度まで上昇させる。次いで、既知の濃度のビーズを加え、溶液が凝固またはゲル化し始めるまで、この2つを穏やかに混合する。溶液は冷えるとゲル化し、ビーズはアガロースゲル内に均一に分散し懸濁した状態で維持される。
ソフトウェア:SkyScan1172バージョン1.5(ビルド14)
NReconバージョン1.6.9.6
CT Analyserバージョン1.13.1.1
光源の種類:10Mp Hamamatsu 100/250
カメラ解像度(ピクセル):4000×2096
カメラビニング:1×1
電源電圧kV:65
電源電流μA:153
画像ピクセルサイズ(μm):3.96
フィルター:Al 0.5mm
回転ステップ(度):0.280
出力フォーマット:8ビットBMP
ダイナミックレンジ:0.000〜0.140
平滑化:0
線質硬化:0
ポストアライメント:補正
リングアーチファクト:16
実施例13(a)ドキソルビシン
実施例5に従って調製したROビーズスラリー(大きさ100〜300μm、ヨウ素47mg I/ml湿潤ビーズ)1mLをメスシリンダーを用いて量り取り、液体を除去した。周囲温度で継続的に浸透しながら、ドキソルビシン溶液(25mg/mL)4mLを放射線不透過性ビーズと混合した。20時間装填した後、消耗された溶液を除去し、薬物が装填されたビーズを脱イオン水(10mL)で4〜5回洗浄した。消耗された装填溶液と洗浄溶液とを合わせたドキソルビシン濃度をUV分光光度計で483nmにおいて測定することにより、装填されたドキソルビシンが80mg/mLビーズであると算出された。放射線不透過性ビーズのドキソルビシン塩酸塩薬物装填容量は、ビーズ中のヨウ素含有量の非線形関数であると決定された。
ドキソルビシンの場合と同じ方法で、ROビーズ(実施例5に従って作製したもの)および非ROビーズ(大きさ70〜150μm)中にエピルビシンを装填した。ビーズ1mlを、装填溶液(25mg/mlエピルビシン)1.5mlを用いて装填した。90分後の放射線不透過性ビーズ中の最終的な装填量は37.49mg(装填効率99.97%)であり、非ROビーズでは36.43(装填効率97.43%)であった。
10mLメスフラスコ内で無水DMSOにスニチニブ粉末400mgを溶かすことにより、スニチニブDMSO溶液を調製した。ROビーズスラリー(70〜150μm、134.4mg I/ml湿潤ビーズ、実施例5に従って調製したもの)1mlをDMSO 10mlで3回予備洗浄して残留水を除去した。スニチニブ−DMSO溶液(40mg/mL)2.5mLをROビーズスラリーと混合し、1〜2時間混合させた。次いで、装填溶液を除去した後、ビーズスラリーに生理食塩水10mLを加えて、ビーズ内部にスニチニブを沈殿させた。洗浄溶液および薬物粒子をセルストレーナーでろ過し、洗浄を3〜4回繰り返した。非ROビーズ(100〜300μm、実施例4に従って調製したもの)を同じ方法で処理した。
RO PVAマイクロスフェア(大きさ70〜150μm、ヨウ素含有量134mgヨウ素/mlビーズ、実施例5に従って調製したもの)または非RO PVAマイクロスフェア(DC Bead(商標)100−300、Biocompatibles社;英国)1mlをDMSO 10mlで3回予備洗浄して残留水を除去した。ソラフェニブ/DMSO溶液(無水DMSO中39.8mg/mL)をビーズスラリー1mLと1時間混合した(放射線不透過性ビーズには2.5mL、非放射線不透過ビーズには2mL)。装填溶液を除去した後、ビーズスラリーに生理食塩水20mLを加えた。ビーズ懸濁液をセルストレーナーでろ過し、洗浄を3〜4回繰り返した。最終装填レベルを、ごく一部の水和ビーズのDMSO抽出およびHPLC(カラム:Kinetex 2.6u XB−C18 100A 75×4.60mm;移動相、水:アセトニトリル:メタノール:トリフルオロ酢酸=290:340:370:2(v/v);検出254nm;カラム温度40℃;流速:1mL/分)による薬物濃度の決定により決定した。
25mlの琥珀色メスフラスコ内で超音波処理を用いて、0.1M HCl 14mlにバンデタニブ500mgを溶かし、脱イオンを加えて25mlにすることによって、20mg/mlのバンデタニブ溶液を調製した。次いで、バンデタニブを以下のプロトコルに従ってRO PVAヒドロゲルマイクロスフェア(実施例5に従って調製したもの:大きさ70〜150μm;ヨウ素含有量147mg/mlビーズ)および非ROマイクロスフェア(DC Bead 100−300;Biocompatibles UK社)の両方に装填した:
各バイアル1mLの水和ROマイクロスフェア(大きさ70〜150μm、ヨウ素含有量134mgヨウ素/mlビーズ、実施例5に従って調製したもの)および非RO PVAマイクロスフェア(DC Bead 100−300、Biocompatibles社;英国)を1−メチル−2−ピロリジノン5mLで4回洗浄した。次いで、溶媒を除去した。ミリプラチン0.147gを1−メチル−2−ピロリジノン25mLと混合し、懸濁液を水浴中、75℃に加熱して、ミリプラチンを溶解させた。洗浄したビーズ中に薬液2mLを加え、混合物を75℃の水浴中に1時間置いた。ビーズ懸濁液をセルストレーナーでろ過して装填溶液を除去した後、生理食塩水約100mLで洗浄した。
非ROビーズ(100−300μm―実施例4の高AMPS型に従って作製したもの)およびROビーズ(100〜300μm、163mg I/mL、実施例5に従って作製したもの)の各ビーズ試料2mLをイリノテカン水溶液(10mg/mL)10mlと混合した。消耗された装填溶液中のイリノテカンレベルを384nmでのUV分光測定により決定することによって、装填量を測定した。非ROおよびROビーズはともに、90分以内に薬物のほぼ100%が装填された。
非ROビーズ(70〜150μm―実施例4の高AMPS型に従って作製したもの)およびROビーズ(70〜150μm、146mg I/mL、実施例5に従って作製したもの)の各ビーズ試料1mLをトポテカン水溶液(15.08mg/mL)と混合して、攪拌下で40mg(2.5ml)または80mg(5ml)の用量を装填した。約1.5時間後、消耗された装填溶液中のトポテカンレベルを384nmでのUV分光測定により上記のように決定することによって、トポテカンの装填量を測定した。表3は、ROビーズ試料にトポテカンが最大80mg装填されたことを示している。非ROビーズおよびROビーズはともに、40mgトポテカンの98%超が装填された。
実施例14(a)ドキソルビシン。
褐色瓶に入れたPBS 1000mlに実施例13(a)に従って調製したドキソルビシン装填ビーズ(70〜150μm、158mg I/ml、50mg/mlドキソルビシン)を室温で加えた。ビーズ懸濁液をマグネチックスターラーにより低速で攪拌した。試料採取時点で、溶出媒体1mLを5umのフィルター針で取り出し、483nmで標準物質に対するUVによって分析した。溶出プロファイルを図4に示した。
褐色瓶に入れたPBS 400ml、0.5g/L Tween 80に、実施例13(c)に従って調製したスニチニブ装填ビーズを水浴中、37℃で加えた。ビーズ懸濁液をマグネチックスターラーにより低速で攪拌した。1時間、2時間、3時間および4時間の試料採取時点で、HPLC分析(実施例13(c)の条件)用に溶出媒体10mLを5μmのフィルター針で取り出し、新鮮なPBS溶液10mLを加えて体積を補った。5時間、25時間、48時間および73時間の試料採取時点で、溶出媒体100mLを等体積の新鮮なPBS溶液と交換した。試料をHPLCにより分析した。溶出プロファイルを図6に示す。
褐色瓶に入れた0.5g/L Tween 80を含むPBS 400mLに、実施例13(d)に従って調製したソラフェニブ装填ビーズを水浴中、37℃で加えた。ビーズ懸濁液をマグネチックスターラーにより低速で攪拌した。1時間、2時間、4時間および6時間の試料採取時点で、HPLC分析用に溶出媒体10mLを5μmのフィルター針で取り出し、新鮮なPBS溶液10mLを加えて体積を400mLにした。8時間、24.5時間および31時間の試料採取時点で、溶出媒体100mLを等体積の新鮮なPBS溶液と交換した。各種類のビーズについて2回の反復試験を実施した。ROビーズおよび非ROビーズからのソラフェニブの溶出プロファイルを図6に示す。
実施例13(e)に従って調製したバンデチニブ(vandetinib)装填ROビーズおよび非ROビーズ(30mgバンデチニブ(vandetinib)/mlビーズのビーズ2ml、70〜150μmのビーズおよび141mg I/ml湿潤ビーズのROビーズ)を、PBS 500mLを含みマグネチックフリー(magnetic flea)を入れた琥珀色の瓶に周囲温度で入れた。各試料採取時点で、蠕動ポンプによってすべてのPBS溶出媒体を瓶からカニューレフィルターを通して取り出し、同じ体積の新鮮なPBSと交換した。溶出媒体5μlを、254nmで検出するC18逆相HPLCにより分析した。溶出プロファイルを図7に示す。
実施例13(f)に従って作製したミリプラチン装填ビーズを、100mL Duran(登録商標)瓶に入れた1%のTween 80を含むPBS 50mLに加えた。瓶を37℃の水浴中に浮かせ75rpmで回転させて、ビーズを攪拌した。1日、5日、11日、15日および22日の試料採取時点で、ICP分析用に溶出媒体20mLを取り出し、新鮮なPBS/Tween溶液20mLを加えて50mLの体積にした。ROビーズおよび非ROビーズからのミリプラチンの溶出プロファイルを図8に示す。
褐色瓶に入れたPBS 500mlに実施例13(g)で調製した試料163m I/mlを37℃で加え、マグネチックスターラーにより低速で攪拌した。試料採取時点で、溶出媒体1mlを5μmのフィルター針で取り出し、369nmで標準物質に対するUVによって分析した。溶出プロファイルを図9に示した。
国際公開第2012/101455号の実施例8に従って、45%ビス(アクリロイル)L−シチン(Cytine)−PVAビーズの試料を調製した。実施例5のプロトコルに以下の特異的な条件を用いて、これらのビーズを放射線不透過性にした。乾燥ビーズ1g、DMSO 35ml、メタンスルホン酸2.2ml、実施例1に従って作製したアルデヒド0.4当量(2.22g)。反応物を40℃になるまで1時間加熱し、次いで60℃になるまで1時間加熱した後、26時間のうちの残りの時間をかけて温度を50℃に低下させた。得られたヨウ素レベルは、ビーズ1mL当たりヨウ素289mgであった。
実施例13に従って調製したドキソルビシン装填ビーズの一部を、実施例12に記載されている通りにマイクロCT解析に供した。薬物装填ビーズは放射線不透過性であることがわかった。平均のビーズ放射線不透過性(グレースケール)は139(n=3)と決定された。
本発明のマイクロスフェアは、薬物装填の有無を問わず、国際公開第07/147902号(15ページ)に記載されているプロトコルに従い、Lyo Screen Control(LSC)パネルとPfeiffer DUO 10 Rotary Vane Vacuumポンプとを備えLyolog LL−1文書化ソフトウェアによって制御されるEpsilon 1−6D凍結乾燥機(Martin Christ Gefriertrocknungsanlagen社、オスターオーデ・アム・ハルツ、ドイツ)を用いて、以下に簡潔に記載する通りに凍結乾燥させ得る。
この試験には雄ヨークシャー交雑種家畜ブタ(約14週齢)を用いた。
Claims (25)
- 放射線不透過性化学種でアセタール化した1,3−ジオール基を含む、ポリビニルアルコール(以下、PVAと称する)ポリマーまたはPVAコポリマーであって、前記ポリマーが以下式Iの構造を含み、
式中、Xは式IIの基であり、
ZQ II
式中、Zは連結基であるか、またはQが環状アセタールに直接結合するようZが存在せず、
Zは、C1〜6アルキレン、C2〜6アルケニレン、C2〜6アルキニレン、C1〜6アルコキシレンまたはC1〜6アルコキシアルキレンであり、
Qは、C5〜C12アリール、もしくはヘテロアリールであり、
Qは、1つまたは複数のヨウ素によって置換されている、
PVAポリマーまたはPVAコポリマー。 - Qは、1つまたは複数のヨウ素によって置換されたフェニル基である、請求項1に記載のポリマー。
- Qは、2つ、3つまたは4つのヨウ素によって置換されたフェニル基である、請求項1に記載のポリマー。
- Qは、2,3,5もしくは2,4,6トリヨードフェニル基または2,3,4,6テトラヨードフェニル基である、請求項1に記載のポリマー。
- Qは、フェニル基であり、かつQが1つまたは複数のヨウ素によって置換されており、かつZは、存在しないか、あるいはC1〜6アルキレンまたは
基−(CH2) q−O−(CH2)p−であり、
式中、pは0、1または2であり、かつqは1または2である、請求項1に記載のポリマー。 - Qは、3つまたは4つのヨウ素によって置換されたフェニル基であり、かつZは、存在しないか、基−(CH2) q−O−(CH2)p−であり、式中、pは0または1である、請求項1に記載のポリマー。
- Qが環状アセタールに直接結合するよう、Zは存在しない、請求項1〜6のいずれか一項に記載のポリマー。
- Xは、ヨウ素化したフェニル基である、請求項1に記載のポリマー。
- 乾燥重量で少なくとも10%のヨウ素を含有する、請求項1〜8のいずれか一項に記載のポリマー。
- 乾燥重量で少なくとも20%のヨウ素を含有する、請求項1〜9のいずれか一項に記載のポリマー。
- 乾燥重量で少なくとも30%のヨウ素を含有する、請求項1〜10のいずれか一項に記載のポリマー。
- 架橋構造を有する、請求項1〜11のいずれか一項に記載のポリマー。
- 放射線不透過性のPVAポリマーまたはPVAコポリマーを調製する方法であって、
酸性条件下で、1,3−ジオール基を含有するPVAポリマーまたはPVAコポリマーを、前記1,3−ジオールと環状アセタールを形成できる放射線不透過性化学種と反応させる工程であって、前記放射線不透過性化学種は、式X−Aの化合物であり、
式中、Xは式IIであり、
ZQ II
式中、Zは連結基であるか、ZはC1〜6アルキレン、C2〜6アルケニレン、C2〜6アルキニレン、C1〜6 アルコキシレンまたはC1〜6アルコキシアルキレンであるか、存在せず、
Qは、C5〜C12アリール、もしくはヘテロアリール基であり、かつ
Qは、1つまたは複数のヨウ素によって置換されており、かつ
Aは、酸性条件下で1,3ジオールと環状アセタールを形成することができる基である、工程を含む、
方法。 - Qは、1つまたは複数のヨウ素によって置換されたフェニル基である、請求項13に記載の方法。
- Qは、2つ、3つ、または4つのヨウ素によって置換されたフェニル基である、請求項13に記載の方法。
- Qは、2,3,5もしくは2,4,6トリヨードフェニル基または2,3,4,6テトラヨードフェニル基である、請求項13に記載の方法。
- Qは、フェニル基であり、かつQは、1つまたは複数のヨウ素によって置換されており、かつZは、存在しないか、またはZは、C1〜6アルキレンまたは基−(CH2) q−O−(CH2)p−であり、式中、pは0、1または2であり、qは1または2である、請求項13に記載の方法。
- Qは、3つまたは4つのヨウ素によって置換されたフェニル基であり、かつZは、存在しないか、または基−(CH2) q−O−(CH2)p−であり、式中、pは0または1である、請求項13に記載の方法。
- Qが前記環状アセタールに直接結合するよう、Zは存在しない、請求項13に記載の方法。
- 前記放射線不透過性化学種が、ヨウ素化されたベンズアルデヒド、ヨウ素化されたフェニルアルデヒド、またはヨウ素化されたフェノキシアルデヒドである、請求項13に記載の方法。
- 前記反応が、25℃超の温度でかつ極性有機溶媒中で実施される、請求項13〜20のいずれか一項に記載の方法。
- Aは保護基を有するアルデヒドである、請求項13に記載の方法。
- Aはアルデヒド基、アセタール基、ヘミアセタール基、チオアセタール基、またはジチオアセタール基である、請求項13に記載の方法。
- Aは、Aは、−CHO、−CHOR1OR2−CHOR1OH、−CHSR1 OHまたは−CHSR1SR2であり、式中、R1およびR2は、C1〜4アルキルから独立して選択される、請求項23に記載の方法。
- 前記放射線不透過性化学種は、2,3,5−トリヨードベンズアルデヒド、 2,3,4,6−テトラヨードベンジアルデヒドおよび2−(2,4,6−トリヨードフ ェノキシ)アセトアルデヒドから成る群から選択される、請求項13に記載の方法。
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