JP2013504590A - 非放射性リン脂質化合物、組成物、及び使用方法 - Google Patents
非放射性リン脂質化合物、組成物、及び使用方法 Download PDFInfo
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- JP2013504590A JP2013504590A JP2012528915A JP2012528915A JP2013504590A JP 2013504590 A JP2013504590 A JP 2013504590A JP 2012528915 A JP2012528915 A JP 2012528915A JP 2012528915 A JP2012528915 A JP 2012528915A JP 2013504590 A JP2013504590 A JP 2013504590A
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- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
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- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/688—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols both hydroxy compounds having nitrogen atoms, e.g. sphingomyelins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
【選択図】なし
Description
Xは:a)ヨウ素の非放射性同位体、又はb)Hであり;
nは12〜30の整数であり;そして
Yは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物並びに
Xは:a)ヨウ素の非放射性同位体、又はb)Hであり;
nは12〜30の整数であり;
YはH、OH、COOH、COOR及びORからなる群から選択され;そして
Zは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物から選択される、治療有効量の非放射性リン脂質化合物を、当該方法を必要とする患者に投与する工程を含む。
Iはヨウ素の非放射性同位体である]
の化合物、又はその医薬として許容される塩である。この化合物は、本願中、「CLR1401」とも称される。
XはHであり;
nは12〜30の整数であり;そして
Yは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物並びに
XはHであり;
nは12〜30の整数であり;
YはH、OH、COOH、COOR及びORからなる群から選択され;そして
Zは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物から選択される非放射性リン脂質化合物を提供する。
Xはヨウ素の放射性同位体であり;
nは12〜30の整数であり;そして
Yは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物、又は
Xはヨウ素の放射性同位体であり;
nは12〜30の整数であり;
YはH、OH、COOH、COOR及びORからなる群から選択され;そして
Zは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物から選択される放射性リン脂質化合物を含有する。
Xはヨウ素の放射性同位体であり;
nは12〜30の整数であり;そして
Yは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物、又は
Xはヨウ素の放射性同位体であり;
nは12〜30の整数であり;
YはH、OH、COOH、COOR及びORからなる群から選択され;そして
Zは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物、又はそれらの医薬として許容される塩から選択される放射性リン脂質化合物、並びにb)タンパク質キナーゼB(Akt)阻害剤を含有する、組合せ医薬剤を提供する。
Xは:a)ヨウ素の非放射性同位体、又はb)Hであり;
nは12〜30の整数であり;そして
Yは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物並びに
Xは:a)ヨウ素の非放射性同位体、又はb)Hであり;
nは12〜30の整数であり;
YはH、OH、COOH、COOR及びORからなる群から選択され;そして
Zは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物から選択される非放射性リン脂質化合物、又はそれらの医薬として許容される塩である。
Iはヨウ素の非放射性同位体である]
の非放射性リン脂質化合物、及び
Iはヨウ素の放射性同位体である]
の放射性リン脂質化合物を含有する、組合せ医薬剤を提供する。
定義
「組成物」という用語は、特定の成分(そして示されている場合特定の量)を含有する生産物、及び直接的に又は間接的に特定の量の特定の成分を組み合わせてなる任意の生産物を含む。「医薬として許容される」とは、希釈剤、賦形剤又は担体が、製剤の他の成分と適合し、投与の対象にとって有害でないことを意味する。
一つの態様において、本発明は、固形癌を処置する方法を提供し、当該方法は:
Xは:a)ヨウ素の非放射性同位体、又はb)Hであり;
nは12〜30の整数であり;そして
Yは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物並びに
Xは:a)ヨウ素の非放射性同位体、又はb)Hであり;
nは12〜30の整数であり;
YはH、OH、COOH、COOR及びORからなる群から選択され;そして
Zは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物、又はこれらの医薬として許容される塩から選択される、治療有効量の非放射性リン脂質化合物を、当該方法を必要とする患者に投与する工程を含む。
他の態様において、本発明は:
XはHであり;
nは12〜30の整数であり;そして
Yは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物並びに
XはHであり;
nは12〜30の整数であり;
YはH、OH、COOH、COOR及びORからなる群から選択され;そして
Zは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物から選択される非放射性リン脂質化合物を提供する。
Xはヨウ素の放射性同位体であり;
nは12〜30の整数であり;そして
Yは、N+H2、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物又は
Xはヨウ素の放射性同位体であり;
nは12〜30の整数であり;
YはH、OH、COOH、COOR及びORからなる群から選択され;そして
Zは、N+H2、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物から選択される放射性リン脂質化合物、又はそれらの医薬として許容される塩である。
a):
Xはヨウ素の放射性同位体であり;
nは12〜30の整数であり;そして
Yは、N+H2、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物又は
Xはヨウ素の放射性同位体であり;
nは12〜30の整数であり;
YはH、OH、COOH、COOR及びORからなる群から選択され;そして
Zは、N+H2、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物から選択される放射性リン脂質化合物、又はそれらの医薬として許容される塩、並びにb)タンパク質キナーゼB(Akt)阻害剤を含有する、組合せ医薬剤を提供する。
Xは:a)ヨウ素の非放射性同位体、又はb)Hであり;
nは12〜30の整数であり;そして
Yは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物並びに
Xは:a)ヨウ素の非放射性同位体、又はb)Hであり;
nは12〜30の整数であり;
YはH、OH、COOH、COOR及びORからなる群から選択され;そして
Zは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物から選択される非放射性リン脂質化合物、又はそれらの医薬として許容される塩である。
Iがヨウ素の非放射性同位体である]
の非放射性リン脂質化合物である、CLR1401、及びb)式:
Iがヨウ素の放射性同位体である]
の放射性リン脂質化合物を含有する、組合せ医薬剤を提供する。
本発明の組成物は、単発の単位用量として、又は複数の単発単位用量として調製されてもよい。本明細書中で使用されるとき、「単位用量」という用語は、所定の量の活性成分を含有する組成物の個別の量を意味する。活性成分の量は、一般に、患者又はその分画(fraction)に投与される活性成分の用量に等しい。
a)127I-CLR1401(別名I-127-CLR1401)又はその医薬として許容される塩、及び
b)131I-CLR1404(別名I-131-CLR1404)若しくは125I-CLR1404(別名I-125-CLR1404)
を含有し、当該組合せ医薬剤は、単一の組成物として製剤化される。
a)127I-CLR1401又はその医薬として許容される塩、及び
b)131I-CLR1404若しくは125I-CLR1404
を含有し、当該組合せ医薬剤は、単一の組成物として製剤化され、そして127I-CLR1401と131I-CLR1404又は125I-CLR1404との重量比は、約10:1である。
他の態様において、本発明は、固形癌を処置するための方法を提供し、処置を必要とする患者に治療有効量の本発明の組合せ医薬剤を投与する工程を含む。
非小細胞肺癌及び前立腺癌細胞株における127I-CLR1401によるAkt活性化の阻害
American Type Culture Collection (ATCC)から入手したA549細胞は、ヒト非小細胞肺癌細胞腫である。A549細胞は野生型の機能性PTENを有する。
A549及びPC-3細胞を、200,000個/ウェルの密度で播種した。全ての処理は三重に実施された。A549及びPC-3細胞は、127I-CLR1401で24時間処理した。
・0,3,5,10μMの127I-CLR1401
・処理された細胞からタンパク質を単離した。
・活性化Aktのレベルを、酵素結合免疫吸着法(ELISA)によりSer473のリン酸化形態を試験することにより決定した。
・PathScan Phospho-Akt1 (Ser473) Sandwich ELISA Kit (Cell Signaling #7160)。
・ELISA対照
・陰性対照:A549及びPC-3を50μMのLY294,002で24時間処理した。LY294,002は、PI3Kにより生産されるホスファチジルイノシトール(3,4,5)三リン酸の量に影響を及ぼすことによりAktの活性化を阻害する、細胞浸透性ホスファチジルイノシトール3-キナーゼ(PI3K)阻害剤である。
・陽性対照:10μg/mlのインスリンで24時間刺激したA549及びPC-3細胞。
・陰性対照:無血清培地中のA549.
1)ELISAは、説明書に従って実施された。要するに、細胞ライゼートから回収した100μgのタンパク質を、予めコーティングした96ウェルプレート中、4℃で一昼夜インキュベートした。このウェルを1x洗浄緩衝液(付属)で4回洗浄した。そして、一次Akt抗体と、2時間、37℃、5%CO2大気下でインキュベーションした。当該一次インキュベーションの後、プレートを1x洗浄緩衝液で4回洗浄し、そしてHRP結合二次抗体と、1時間、37℃、5%CO2大気下でインキュベーションした。当該プレートを1x洗浄緩衝液で4回洗浄し、そして付属のTMB基質を使用して発色させた。TMB基質(テトラメチルベンジジン)は、ELISAアッセイで使用される比色分析基質(colormetric substrate)である。TMB(3,3',5,5'-テトラメチルベンジジン)は、過酸化水素により酸化されると(HRPにより触媒される)、主要な吸収スペクトルが370nm〜652nmの青色を発する色素原である。そしてその色は、硫酸又はリン酸の添加で最大の吸収スペクトルが450nmの黄色に変化する。これは、ホースラディッシュペルオキシダーゼタグを有する抗体に結合した標的タンパク質の検出に使用される。
・37℃で10分間インキュベーションした後、停止緩衝液(付属)を添加した反応を停止させた。そして、Synergy HTマイクロプレートリーダー(BioTek)を使用して、450nmの吸光度を測定した。データは450nmの吸光度として出力される。
2.127I-CLR1401による細胞増殖抑制
1) 127I-CLR1401による細胞増殖抑制は、MTT(3-(4,5-ジメチルチアゾール-2-イル)-2,5-ジフェニルテトラソディウムブロマイド)アッセイにより判定された。MTTは淡黄色の基質で、生きた細胞により切断されて、暗青色のホルマザン産物(formazan product)が生じる。このプロセスには生きたミトコンドリアを要し、たとえ死んだばかりの細胞であっても、顕著な量のMTTの切断は起こらない。
簡単に説明すると、6ウェルプレートに200,000個/ウェルのA549細胞を播種し、一昼夜置いて接着させた。この細胞を様々な濃度(0.0078, 0.392, 0.784, 1.568, 3.137, 4.705, 7.84, 39.2, 78.4μM)の127I-CLR1401で三重に処理し、その後、所定の時点でMTTアッセイ用に回収した。そして細胞を1xPBS中の0.5mg/ml MTTと、3時間、37℃、5%CO2大気中でインキュベーションした。
Synergy HTマイクロプレートリーダーを使用して、540nmの吸光度を測定した。540nmの吸光度の値は、存在する生存細胞の数に比例する。
図1は、127I-CLR1404が、A549細胞中のAktの活性化を阻害したことを示す。活性Akt(pAkt、S473)の量は、127I-CLR1401の用量の増大に依存して減少している。
127I-CLR1401の濃度の増大はA549細胞株におけるCLR1404の取り込み及び保持を促進させる
背景
127I-CLR1401は前立腺癌の処置における131I-CLR1404の有効性を増大させる
実験条件
127I-CLR1401及び131I-CLR1404は非小細胞肺癌の処置に有効である
実験条件:
127I-CLR1401及び131I-CLR1404は三重陰性乳癌の処置に効果的である
実験条件:
非小細胞肺癌の処置における127I-CLR1401の有効性のエルロチニブとの比較
実験条件:
Claims (17)
- 固形癌を処置する方法であり:
Xは:a)ヨウ素の非放射性同位体、又はb)Hであり;
nは12〜30の整数であり;そして
Yは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物並びに
Xは:a)ヨウ素の非放射性同位体、又はb)Hであり;
nは12〜30の整数であり;
YはH、OH、COOH、COOR及びORからなる群から選択され;そして
Zは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物、又はこれらの医薬として許容される塩から選択される、治療有効量の非放射性リン脂質化合物を、当該方法を必要とする患者に投与する工程を含む、前記方法。 - 前記非放射性リン脂質化合物が、18-(p-ヨードフェニル)オクタデシルホスホコリン、1-O-[18-(p-ヨードフェニル)オクタデシル]-1,3-プロパンジオール-3-ホスホコリン、及び1-O-[18-(p-ヨードフェニル)オクタデシル]-2-O-メチル-ラク-グリセロ-3-ホスホコリンからなる群から選択され、ここでヨウ素が非放射性同位体である、請求項1に記載の方法。
- 前記固形癌が、肺癌、乳癌、神経膠腫、扁平上皮癌、前立腺癌、黒色腫、腎臓癌、直腸結腸癌、卵巣癌、膵臓癌、肉腫及び胃癌からなる群から選択される、請求項1に記載の方法。
- 以下:
Xはヨウ素の放射性同位体であり;
nは12〜30の整数であり;そして
Yは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物又は
Xはヨウ素の放射性同位体であり;
nは12〜30の整数であり;
YはH、OH、COOH、COOR及びORからなる群から選択され;そして
Zは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物から選択される放射性リン脂質化合物、並びにタンパク質キナーゼB(Akt)阻害剤を含有する、組合せ医薬剤。 - 前記Akt阻害剤が:
Xは:a)ヨウ素の非放射性同位体、又はb)Hであり;
nは12〜30の整数であり;そして
Yは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物並びに
Xは:a)ヨウ素の非放射性同位体、又はb)Hであり;
nは12〜30の整数であり;
YはH、OH、COOH、COOR及びORからなる群から選択され;そして
Zは、N+H3、HN+(R)2、N+H2R、及びN+(R)3からなる群から選択され、ここでRは、アルキル又はアリールアルキル置換基である]
の化合物から選択される非放射性リン脂質化合物である、請求項5に記載の組合せ医薬剤。 - 前記ヨウ素の放射性同位体が、123I、124I、125I、及び131Iからなる群から選択される、請求項6に記載の組合せ医薬剤。
- 前記放射性リン脂質化合物が、18-(p-ヨードフェニル)オクタデシルホスホコリン、1-O-[18-(p-ヨードフェニル)オクタデシル]-1,3-プロパンジオール-3-ホスホコリン、及び1-O-[18-(p-ヨードフェニル)オクタデシル]-2-O-メチル-ラク-グリセロ-3-ホスホコリンからなる群から選択され、ここでヨウ素が放射性同位体である、請求項6に記載の組合せ医薬剤。
- 前記ヨウ素の放射性同位体が、125I及び131Iからなる群から選択される、請求項9に記載の組合せ医薬剤。
- 前記放射性リン脂質化合物及び前記非放射性化合物が、単一の組成物として製剤化される、請求項6に記載の組合せ医薬剤。
- 前記非放射性リン脂質化合物と前記放射性リン脂質化合物との重量比が、およそ10:1である、請求項11に記載の組合せ医薬剤。
- 前記放射性リン脂質化合物及び前記非放射性化合物が、個別の組成物として製剤化される、請求項6に記載の組合せ医薬剤。
- ヒト患者に投与されたとき、前記非放射性化合物の血清中濃度を約5μM〜約10μMに到達させることが出来る、請求項6に記載の組合せ医薬剤。
- 固形癌を処置する方法であり、治療有効量の請求項5又は9のいずれかに記載の組合せ医薬剤を当該方法を必要とする患者に投与する工程を含む、前記方法。
- 前記固形癌が、肺癌、乳癌、神経膠腫、扁平上皮癌、前立腺癌、黒色腫、腎臓癌、直腸結腸癌、卵巣癌、膵臓癌、肉腫及び胃癌からなる群から選択される、請求項15に記載の方法。
- 前記治療有効量が、約7 mCi〜約700 mCiである、請求項15に記載の方法。
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PCT/US2010/048351 WO2011031919A2 (en) | 2009-09-11 | 2010-09-10 | Non-radioactive phospholipid compounds, compositions, and methods of use |
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EP (1) | EP2475400A2 (ja) |
JP (1) | JP2013504590A (ja) |
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JP2007528374A (ja) | 2004-03-02 | 2007-10-11 | セレクター,リミティド ライアビリティ カンパニー | Diapeutic(登録商標)剤としてのリン脂質類似体、及びその方法 |
US8540968B2 (en) * | 2004-03-02 | 2013-09-24 | Cellectar, Inc. | Phospholipid ether analogs as agents for detecting and locating cancer, and methods thereof |
US20100316567A1 (en) | 2009-06-12 | 2010-12-16 | Weichert Jamey P | Ether and alkyl phospholipid compounds for treating cancer and imaging and detection of cancer stem cells |
US20110064661A1 (en) * | 2009-09-11 | 2011-03-17 | Pinchuk Anatoly | Non-radioactive phospholipid compounds, compositions, and methods of use |
EP4028018A4 (en) * | 2019-09-12 | 2023-10-11 | Cellectar Biosciences, Inc. | PHOSPHOLIPIDETHER CONJUGATES AS ANTI-CANCER CARRIERS |
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WO2011031919A3 (en) | 2014-03-27 |
US20120156133A1 (en) | 2012-06-21 |
RU2012114146A (ru) | 2013-10-20 |
US20110064661A1 (en) | 2011-03-17 |
EP2475400A2 (en) | 2012-07-18 |
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