JP2016525499A - デンドリマー組成物、合成方法、及びそれらの使用 - Google Patents
デンドリマー組成物、合成方法、及びそれらの使用 Download PDFInfo
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- JP2016525499A JP2016525499A JP2015563032A JP2015563032A JP2016525499A JP 2016525499 A JP2016525499 A JP 2016525499A JP 2015563032 A JP2015563032 A JP 2015563032A JP 2015563032 A JP2015563032 A JP 2015563032A JP 2016525499 A JP2016525499 A JP 2016525499A
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Classifications
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
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- A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/48—Polymers modified by chemical after-treatment
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
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- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
Abstract
Description
nは、0〜8の整数であり;
R1、R2及びR3は、独立して、H、NO2又はメチルを表し;
R′1及びR′2は、独立して、H、OH、メチル、エチル又はプロピルを表し;
金属Mの価数によって許容される、X1、X2及びX3は、独立して、φ、CO又はH2Oを表し;及び
Mは、Y、Zr、Nb、Mo、Tc、Ru、Rh、Pd、Ag、Cd、Re、In、又はSnから選択される遷移金属の放射性又は非放射性(コールド)同位体を表す。
Rは、直鎖状又は分岐鎖状のC1〜C6アルキル部又はC1〜C6ヘテロアルキル部、好ましくは、−Me、−CH2Ph又は−CH(CH3)OEtを表す。
(a)Aは、多価kのデンドリマーの核を表し、ここで、kは、デンドロン(樹)の数を表し、好ましくは3であり;
Aは、以下の構造を有する核シントンを表す。
i=0の場合、Miはφを表し、末端分岐BTは核シントン(合成等価体)Aに直接繋がり;
i>0の場合、Miは以下を表す。
記号*は、単量体Miと次の世代の単量体との結合点を示す
(c)BTは末端分岐鎖、tは末端部位の数を表し、ここで、
tは1〜3の整数、好ましくは、tは2又は3であり;
BTの各出現は、独立して、水素原子、カルボキシル部分(COOH)、カルボキシルエステル(COO−R)、ヒドロキシル基(OH)、チオール基(SH)又はチオールエステル部分を表し、ここでRの各出現は、独立して、C1〜C6アルキル基又はC6アリール基を表す。
Y(イットリウム);Zr(ジルコニウム);Nb(ニオブ);Mo(モリブデン);Tc(テクネチウム);Ru(ルテニウム);Rh(ロジウム);Pd(パラジウム);Ag(銀);Cd(カドミウム);Re(レニウム);In(インジウム);Sn(スズ)
処置用キット
等価物
例示
シクロトリホスファゼン−フェノキシメチル(メチルヒドラゾノ)デンドリマー(世代1.5)の代わりにポリリジンデンドリマーG5、及び配位子としてイミダゾールと結合したジチオカルボン酸2−メチル−1−アミノシクロペンテン型を有する四座配位子の代わりに、1−ニトロ−1H−イミダゾール−メチル−1,2,3−トリアゾール−メチル−ジ−(2−ピコリル)アミンを用いて実施例7を繰り返した。
Claims (31)
- 以下の構造を有するニトロイミダゾール配位子/金属錯体と複合体を形成したG2〜G10のポリリジンデンドリマーから成るデンドリマー複合体:
nは、0〜8の整数であり;
R1、R2及びR3は、独立して、H、NO2又はメチルを表し;
R′1及びR′2は、独立して、H、OH、メチル、エチル又はプロピルを表し;
金属Mの価数によって許容される、X1、X2及びX3は、独立して、φ、CO又はH2Oを表し;及び
Mは、Y、Zr、Nb、Mo、Tc、Ru、Rh、Pd、Ag、Cd、Re、In、又はSnから選択される遷移金属の放射性又は非放射性(コールド)同位体を表す。 - 前記複合体形成がイオン結合、金属結合、水素結合、又はファンデルワールス結合を含む、請求項1に記載のデンドリマー複合体。
- 前記デンドリマーが以下の構造:
- 前記ニトロイミダゾール配位子/金属錯体が以下の構造を有し、
- 前記複合体が、以下の構造を有し、
- がんの前記処置又は診断における薬剤として使用するための請求項1〜5のいずれか1項に記載のデンドリマー複合体。
- 請求項1〜5のいずれか1項に記載のデンドリマー複合体及び薬学的に許容される担体を含む医薬組成物。
- Mが186/188Reであり、前記組成物が放射性医薬組成物である、請求項7に記載の組成物。
- Mが99mTcであり、前記組成物が診断用組成物である、請求項7に記載の組成物。
- がんの処置又はその重症度の軽減のための方法であって、治療有効量の請求項7に記載の前記組成物を、前記がんを患う、又は前記がんに対して感受性である対象に投与することを含む方法。
- 前記がんが、リンパ腫、ホジキン病、非ホジキン病、多発性骨髄腫、ヴァルデンストレーム型マクログロブリン血症、重鎖病、固形腫瘍、肉腫及びがん腫、線維肉腫、粘液肉腫、脂肪肉腫、軟骨肉腫、骨原性肉腫、脊索腫、血管肉腫、内皮肉腫、リンパ管肉腫、リンパ管内皮肉腫、滑膜腫、中皮腫、ユーイング腫瘍、平滑筋肉腫、横紋筋肉腫、結腸がん、膵臓がん、脳がん、乳がん、卵巣がん、前立腺がん、扁平上皮がん、基底細胞がん、腺がん、汗腺がん、皮脂腺がん、乳頭がん、乳頭腺がん、嚢胞腺がん、髄様がん、気管支がん、腎細胞がん、肝がん、胆管がん、絨毛がん、精上皮腫、胎生期がん、ウィルムス腫瘍、子宮頸がん、子宮がん、精巣腫瘍、肺がん、小細胞肺がん、膀胱がん、上皮がん、神経膠腫、星状細胞腫、髄芽腫、頭蓋咽頭腫、上衣腫、松果体腫、血管芽腫、聴神経腫、乏突起、髄膜腫、黒色腫、神経芽細胞腫網膜芽細胞腫、及びすべての固形腫瘍からなる群から選択される、請求項10に記載の方法。
- 投与が、画像下治療による腫瘍内又は腫瘍周囲の動脈内への前記組成物の注入及び前記治療薬をその場沈着させる全ての投与を含む、請求項10又は11に記載の方法。
- 治療有効量の前記組成物の投与が、対象の体重1kg当たりである5.4×10−12モル金属/kgに相当する約37MBq/kgの188Reと対象の体重1kg当たりである9.96×10−12モル金属/kgに相当する約68MBq/kgの188Reとの間の用量を投与することを含む、請求項10〜12のいずれか1項に記載の方法。
- 対象の腫瘍増殖を変更する方法であって、a)請求項7に記載のデンドリマー複合体を含む組成物を提供すること、及びb)前記腫瘍増殖が変更されるような条件で治療有効量の前記組成物を、それを必要とする対象に投与することを含む方法。
- 前記変更が、前記対象の腫瘍増殖を阻害することを含む、請求項14に記載の方法。
- 前記変更が、前記対象の腫瘍のサイズを縮小させることを含む、請求項14に記載の方法。
- 前記腫瘍が、原発性腫瘍又は転移性腫瘍である、請求項14〜16のいずれか1項に記載の方法。
- デンドリマー複合体を含む前記組成物が化学療法剤又は抗発がん剤と同時に投与される、請求項14に記載の方法。
- 前記化学療法剤が、白金複合体、ベラパミル、ポドフィロトキシン、カルボプラチン、プロカルバジン、メクロレタミン、シクロホスファミド、カンプトテシン、イホスファミド、メルファラン、クロラムブシル、ビスルファン、ニトロソ尿素、アドリアマイシン、ダクチノマイシン、ダウノルビシン、ドキソルビシン、ブレオマイシン、プリカマイシン、マイトマイシン、ブレオマイシン、エトポシド、タモキシフェン、パクリタキセル、タキソール、トランスプラチナ、5−フルオロウラシル、ビンクリスチン、ビンブラスチン、及びメトトレキサートから成る群から選ばれる、請求項18に記載の方法。
- リンパ系画像化の方法であって、画像を向上させる量の請求項1〜5のいずれか1項に記載のデンドリマー複合体(前記金属Mが99mTc)を対象に投与すること;及び前記デンドリマー複合体を投与した後、少なくともリンパ系の一部の、転移性がん細胞の存在を示す画像信号強度の差を検出することを含む方法。
- 前記リンパ系の一部が、リンパ節を含む、請求項20に記載の方法。
- 投与が、静脈内又はリンパ管内に前記組成物を注入することを含む、請求項20又は21に記載の方法。
- 画像を向上させる量の前記デンドリマー複合体を投与が、対象の体重1kg当たりである0.6×10−12モル金属/kgに相当する約10.5MBq/kgの99mTcと対象の体重1kg当たりである1.5×10−12モル金属/kgに相当する約26.3MBq/kgの99mTcの間の用量を投与することを含む、請求項20〜請求項22のいずれか1項に記載の方法。
- がんの処置又はその重症度の軽減のための薬剤として使用するための請求項7に記載の組成物。
- 前記がんが、リンパ腫、ホジキン病、非ホジキン病、多発性骨髄腫、ヴァルデンストレーム型マクログロブリン血症、重鎖病、固形腫瘍、肉腫及びがん腫、線維肉腫、粘液肉腫、脂肪肉腫、軟骨肉腫、骨原性肉腫、脊索腫、血管肉腫、内皮肉腫、リンパ管肉腫、リンパ管内皮肉腫、滑膜腫、中皮腫、ユーイング腫瘍、平滑筋肉腫、横紋筋肉腫、結腸がん、膵臓がん、脳がん、乳がん、卵巣がん、前立腺がん、扁平上皮がん、基底細胞がん、腺がん、汗腺がん、皮脂腺がん、乳頭がん、乳頭腺がん、嚢胞腺がん、髄様がん、気管支がん、腎細胞がん、肝がん、胆管がん、絨毛がん、精上皮腫、胎生期がん、ウィルムス腫瘍、子宮頸がん、子宮がん、精巣腫瘍、肺がん、小細胞肺がん、膀胱がん、上皮がん、神経膠腫、星状細胞腫、髄芽腫、頭蓋咽頭腫、上衣腫、松果体腫、血管芽腫、聴神経腫、乏突起、髄膜腫、黒色腫、神経芽細胞腫網膜芽細胞腫、及びすべての固形腫瘍からなる群から選択される、請求項24に記載の薬剤として使用するための組成物。
- 対象の腫瘍増殖を変更するため薬剤として使用するための請求項7に記載の組成物。
- 前記変更が、前記対象の腫瘍増殖を阻害することを含む、請求項26に記載の薬剤として使用するための組成物。
- 前記変更が、前記対象の腫瘍のサイズを縮小させることを含む、請求項26に記載の薬剤として使用するための組成物。
- 前記腫瘍が、原発性腫瘍又は転移性腫瘍である、請求項26〜28に記載の薬剤として使用するための組成物。
- リンパ系画像化のための薬剤として使用するための請求項7に記載の組成物。
- 前記リンパ系の一部が、リンパ節を含む、請求項30に記載の薬剤として使用するための組成物。
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