JP5336082B2 - 抗腫瘍剤としてのイソホスホルアミドマスタードの塩及びその類似物 - Google Patents
抗腫瘍剤としてのイソホスホルアミドマスタードの塩及びその類似物 Download PDFInfo
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- JP5336082B2 JP5336082B2 JP2007538185A JP2007538185A JP5336082B2 JP 5336082 B2 JP5336082 B2 JP 5336082B2 JP 2007538185 A JP2007538185 A JP 2007538185A JP 2007538185 A JP2007538185 A JP 2007538185A JP 5336082 B2 JP5336082 B2 JP 5336082B2
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Description
本発明は国立癌研究所により与えられた許可番号5R44CA083552-03の下で政府の支援によりなされた。政府は本発明について一定の権利を有する。
技術分野
本開示はイソホスホルアミドマスタードの塩及びその類似物に関する。また、過増殖性疾患を治療するための医薬組成物及び該組成物の使用方法を開示する。
で表される化合物を開示する。
で表される化合物又はその製薬上許容される塩の除菌された医薬組成物を開示する。無菌の抗菌フィルターを使用することによって該組成物を除菌することを含む該組成物の製造する方法も開示する。ある実施形態においては、濾過は活性成分の分解率が10%未満、好ましくは5%、2%、更には1%未満となるように実施することができる。
“随意的な”又は“随意に”はこれに続いて記載される事象又は現象が必要ではないが起こり得ることを意味し、該記載は前記事象又は現象が起こる場合と起こらない場合を包含する。
“アミノ酸”は天然及び非天然のアミノ酸(α−アミノ酸を含む)の両方を指し、キラルアミノ酸についてはそれらのD及びL立体異性体の形態にあるものを含む。塩基性アミノ酸残基の例としてはアミノ基やグアニジノ基といった塩基性側鎖を有するものが挙げられる。塩基性アミノ酸残基としては、限定的ではないが、アルギニン、ヒスチジン、ホモアルギニン、リジン、ホモリジン及びオルニチンが挙げられる。
本発明においては、“脂肪族アミン”とは式NR1R2R3(式中、R1-3の少なくとも1つは脂肪族基である。)の化合物を指す。
“非環式脂肪族アミン”とは脂肪族基の少なくとも1つが非環式である上記脂肪族アミンを指す。
“複素環式アミン”とは式NR1R2R3(式中、R1-3の少なくとも1つは複素環基であるか、R1、R2及び/又はR3はそれらに共通の窒素原子と一緒に環を形成する。)の化合物を指す。
本発明に係る化合物及び組成物には1当量以上の塩基と共に処方されるIPM及びIPM類似物が含まれる。IPM及びその類似物は酸分解性であり酸性なので、ここで開示する化合物は優れた安定性及びその他の利点を与える。合成、安定性及び生物学的利用率の観点における本開示に係る処方物の利点は本開示から当業者に明らかであろう。
式中、Bは各nについて独立に選択される塩基性分子である。該式の一実施形態においては、Bは塩基性アミノ酸、非環式脂肪族アミン、ジ−及びトリ−アルキルアミン、複素環式脂肪族アミン、芳香族アミン、置換及び非置換のピリジン、環式及び非環式のグアニジン、並びに環式及び非環式のアミジンから選択することができる。典型的には、nは1〜約3(該式が異なる塩基性分子を含むように)である。また、式中、X及びYは脱離基である。当業者であれば図示したイソホスホルアミドマスタード構造が酸性プロトンを有し、生理学的pH及びBのような塩基の存在下においては、優勢的にその共役塩基として存在することを理解するだろう。同様に、塩基性基であるBは、生理学的pH及びイソホスホルアミドマスタード及びイソホスホルアミドマスタードの類似物の存在下においては、優勢的にその共役酸として存在する。本開示に係る化合物の具体例をTable1に示す。
式中、Bは任意の塩基性基、とりわけアミンとすることができる。上式は対応する塩として優勢的に存在し、次式で表される化合物を包含するであろうことが理解されるべきである。
で表すことができる。特定の実施形態においては、Gは塩基性アミノ酸であり、BH+は同一の又は異なる塩基性アミノ酸の共役酸を表す。
で表すことができる。
本開示の別の一側面は患者へ投与するために調製される医薬組成物、好ましくは除菌された医薬組成物を包含する。該医薬組成物は治療上有効量の本開示に係る化合物を1種以上含有する。該除菌された組成物はIPMの塩又はその類似物の溶液を無菌の抗菌フィルターで濾過することにより調製することができる。リン酸及びその塩並びに置換エチルアミンのような分解副生成物の存在を分析により測定して、該除菌された組成物は本発明の活性成分を10%未満の分解率、好ましくは5%、2%、更には1%未満の分解率で含むのが好ましい。
本開示に係る化合物組み込むことのできるDNA割込剤又は架橋剤には、限定的ではないが、シスプラチン、カルボプラチン、オキサリプラチン、マイトマイシン(例えばマイトマイシンC)、ブレオマイシン、クロラムブチル、シクロホスファミド並びにこれらの誘導体及び類似物が挙げられる。
本発明を、以下の非限定的な実施例により更に説明する。
本実施例では実施例2により製造したIPMからIPMリジン塩を調製する。L−リジンを秤量し(26.4g)、水を正確に計った(6L)。このL−リジンをこの水に撹拌しながら2〜8℃で加えた。原薬であるIPMを秤量し(20g)、このリジン溶液に撹拌しながら2〜8℃でゆっくりと加えた。
2〜8℃で溶解すると、該溶液は無菌の抗菌フィルター(0.22μm)を通過した。溶液を2〜8℃に維持し、無菌条件下でバイアル中に分散させた。
本実施例ではマウスに埋植した数種の癌細胞系に対するIPMの評価を実施する。マウスは各実験においてIPMによる腹膜内(IP)及び静脈内(IV)治療に対する耐容性性を充分にもっていた。検死によって観察された唯一の毒性物質は、人工癌に関連する器官病変であった。
まず、マウスに埋植した2種類のL1210変異体であるL1210/0及びL1210/CPA細胞系に対してIPMをIfosとの比較により評価した。IPMの用量はIfosの50%とした。L1210/0の治療グループにおいては、ILSが3種類の薬剤のすべてにおいて観察された。しかしながら、L1210/CPAモデルに対しては、IPMによる治療が他の2種類の薬剤(Ifos及びCPA)よりも優れていた。CPA耐性腫瘍系においては、IPMで治療した動物の生存率が2倍となり、腫瘍量の減少が7となった。L1210/0腫瘍モデルに対しては、IPMは少ない用量でCPA及びIfosと同等の活性を有する。この結果は、CPA耐性細胞はIPMに対して交叉耐性ではないことを示している。結果をTable2に示す。
本実験の結果をTable3に示す。IPMがルイス肺癌に対して有効であることが示される。
本実験の結果をTable4に示す。IPMが黒色腫に対して有効であることが示される。
本実施例では種々の過増殖性細胞系に対するIPMの効果とIPM・(LYS)2塩及びIPM・(NH4)2塩の効果を比較する。
(埋植後)6日目から始めて、20〜125mg/kg/日の用量としてIP経路で5日間毎日投与したときの、マウスのルイス肺癌に対するIPM、IPM・(LYS)2塩及びIPM・(NH4)2塩の効果を比較した。IPM及びそのリジン塩は同等の活性を有しており、親薬剤よりもこの塩のMTD(mg/kg/投与)は2倍増加していた。全比率は信頼限界値内であった。マウスはこれら塩のIP投与に対して充分に耐容性を示した。検死によって観察された唯一の毒性物質は、人工癌に関連する器官病変であった。
本実験の結果(Table10)はIPM・(LYS)2塩がマウスのルイス肺癌に対してIPMと同等の効果を有することを示しており、そして、IPM・(NH4)2塩がマウスのルイス肺癌に対して効果的であることを示している。
本実験の結果(Table11)はIPM・(LYS)2塩及びIPM・(NH4)2塩の双方がヒト乳癌細胞に対して顕著に優れた効果を有していることを示している。
本実施例では、毎日3日間マウスの静脈内(ボーラス)にイソホスホルアミドマスタードのリジン塩を注射した後の、急性毒性を評価する。本実験は二段階からなる。
全部で62匹の雄と61匹の雌のCrl:CD−l(lCR)BRマウス(生後約6週間)をCharles River Laboratories(ポーテージ、ミシガン州)から2003年4月21日に受け取った。7〜16日間の順化期間中は、動物の性別を確認し、体重を量り、健康全般及び病気の兆候を毎日2度観察した。受領時は、自動給水システムに順化させるために3〜4匹/カゴに動物を収容した。受領の3日後、動物を個別に収容した。実験に選ぶ前に、すべての動物を詳細な臨床的観察を行った。
実験に割り当てる前に、マウスの体重を量り、病気及びその他の身体的異常の有無を検査した。実験に割り当てられた動物は性別毎に平均体重の20%以内の体重を有していた。単純なランダム化手順を使用して、動物を治療グループに配置した。実験用に入手した余分の動物は二酸化炭素吸入により安楽死させて廃棄した。
4種類の範囲決定治療グループ(1匹のマウス/性別/グループ)が、100、200、400及び600mg/kgの各用量で1回/日として3日間連続でテスト品を静脈内(ボーラス)注射により投与される。すべての投与は、直近の体重をベースとして、15mL/kgの一定値とした。
罹患率、死亡率、怪我、並びに食物及び水の利用性の観察を全マウスに対して毎日2回実施した。
適宜、SAS(登録商標)のプロビット法(SAS Institute社、SAS/STAT(登録商標)ユーザーズガイド、バージョン6、第4版、第2巻. Cary NC: SAS Institute; 1989) in SAS (main study treated groups)を使用してLD50及びLD10及び95%信頼限界値を算出した(主たる実験の治療グループ)。
本実験の実施中に使用したコンピュータシステムをTable13に示す。
下記のデータは主たる実験段階の最終的な結果である。
死亡率のまとめをTable14に示す。全体的には、死亡率の結果は典型的な投与−応答効果を示している。IPMリジン塩は雄よりも雌において若干毒性が強かった。IPM親化合物を投与した対照標準グループは予想通りの死亡率を示し、雄よりも雌において高い毒性であった。これは従前の実験から得られたデータと相関している。
全体として、死亡率の結果は典型的な投与−応答効果を示しており、IPMリジン塩は雄よりも雌において若干毒性が強かった。50又は75mg/kgでは1匹の動物も死ななかった。100mg/kgでは10匹中1匹の動物が死んだ。200mg/kgでは10匹中3匹の動物の動物が死んだ。300mg/kgでは10匹中9匹の動物の動物が死んだ。400、500及び600mg/kgではすべての動物が死んだ。IPM親化合物を投与した対照標準グループは予想通りの死亡率(10匹中5匹)を示し、雄よりも雌において高い毒性であった。これは従前の実験から得られたデータと相関している。実験による死亡の開始は若干遅れ、最初に死亡したのは6日目であり、最後に死亡したのは12日目であった。死ぬ前のマウスの悪化状態を一般に反映する臨床上の兆候が両性において観察された。該臨床上の兆候には、瀕死の状態となること、不活発化、腫脹(尾、鼻/鼻づら、及び/又は顔)、呼吸が早くなる/遅くなる/浅くなる/困難になる/呼吸音が大きくなる、振顫、皮膚の低温化、乱れた外観、うずくまった姿勢、手足の障害、背中及び/又は肛門性器の辺りの毛の脱色、糞便が少ない/ない、排尿が減少するといった兆候が挙げられる。治療に関連して平均体重の増加量の減少(多くは体重の減少)が7日目までに生存した動物に認められ、実験終了時まで生存した動物においては14日目までに少なくとも部分的に回復した。検死では治療に関連した顕微鏡による所見は認められなかった。
本実施例はIPM及びそのリジン塩の毒性に関する広範囲にわたる前臨床データの結果を総括する。本データはヒトの臨床試験に対する投与計画を作成するのに使用する。
匹敵するヒトへのIV投与推定量をTable17に示す。
本実施例では転移性卵巣癌を罹患しているヒトの患者内の癌を治療する。
患者を静脈内点滴によりIPM500mg/m2で3日間連続して治療した。患者の血清電解質、例えばリン及び塩化物を補助的電解質で矯正し、7日後に中止した。RUN及びクレアチニンは正常値であった。
本実施例ではヒトの患者をIPM・(LYS)2で治療した結果を記載する。進行癌を罹患している4人の患者がIPM・(LYS)2の治療を受けた。
IPMリジン塩の初期用量を30mg/m2として3日間毎日静脈内投与した。一人の患者(コホート)については21〜28日毎に用量を増加させて、毒性が現れるのを観察した。深刻な中毒症状がない場合には用量を40%増加させた。4人の患者を―各用量で一人ずつ−30、42、59及び83mg/m2で3日間毎日IV投与して治療したところ、深刻な中毒症状はなかった。直腸癌の患者は、3日間毎日のIV投与により83mg/m2のIPM・(LYS)2を投与した後、病状が安定化した。
本実施例では転移・浸潤性の中程度に分化した腺癌へ進展した非小細胞肺癌を治療する。病状はCATスキャンにより確認することができる。
イソホスホルアミドマスタードリジン塩を毎日3日間静脈内に350mg/m2投与した。21日間の休息期間後、3日間の治療計画をもう一度繰り返した。治療期間中、血液流体化学及び血液学的検査の結果を毎日記録した。癌の状態をCATスキャンにより監視した。
Claims (36)
- A+はBH+を表し、Bは塩基性アミノ酸、ピリジン、N,N−ジメチルアミノピリジン、N−メチル−N−エチルアミン、ジエチルアミン、トリエチルアミン、ジイソプロピルエチルアミン、モノ−,ビス−若しくはトリス−(2−ヒドロキシエチル)アミン、2−ヒドロキシ−t−ブチルアミン、トリス(ヒドロキシメチル)メチルアミン、N,N−ジメチル−N−(2−ヒドロキシエチル)アミン、トリ−(2−ヒドロキシエチル)アミン及びN−メチル−D−グルカミンから選択される請求項1記載の化合物。
- Bがリジン、ホモリジン、アルギニン、ホモアルギニン、ヒスチジン及びオルニチンから選択される請求項2記載の化合物。
- Bがリジンである請求項2記載の化合物。
- X及びYは独立してハロゲン及びスルホネートより選択される請求項1〜4何れか一項記載の化合物。
- X及びYがハロゲンである請求項5記載の化合物。
- X及びYが塩素である請求項6記載の化合物。
- 請求項1の化合物と、アミンとを含有する化合物。
- 請求項1〜8何れか一項記載の化合物及び製薬上許容される担体を含有する医薬組成物。
- 前記組成物が単回用量当たり200mg〜1500mgの前記化合物を含有する請求項9記載の医薬組成物。
- ヒトの患者への投与用に処方された溶液を構成する組成物である請求項9記載の医薬組成物。
- 前記医薬組成物が0.1mg/mL〜250mg/mLの前記化合物を含有する請求項9記載の医薬組成物。
- 前記医薬組成物が20mg/mL〜100mg/mLの前記化合物を含有する請求項9記載の医薬組成物。
- A + がリジンの共役酸である請求項9記載の医薬組成物。
- 過増殖性疾患に罹患している患者を治療するための、請求項1〜8何れか一項記載の化合物。
- 10mg/m2/日〜700mg/m2/日の前記化合物を患者に投与するための請求項15記載の化合物。
- 100mg/m2/日〜500mg/m2/日の前記化合物を患者に投与するための請求項16記載の化合物。
- 過増殖性疾患には乳癌、膀胱癌、骨癌、子宮癌、結腸癌、中枢神経癌、食道癌、胆嚢癌、胃腸癌、頭部及び頸部癌、ホジキン病、非ホジキンリンパ腫、喉頭癌、白血病、肺ガン、黒色腫、神経芽細胞腫、卵巣癌、膵臓癌、前立腺癌、直腸癌、腎臓癌、網膜芽腫、胃癌、睾丸癌又はウィルムス腫瘍が含まれる請求項15記載の化合物。
- 過増殖性疾患には腺癌、黒色腫、皮膚腫瘍、肉腫、白血病又はリンパ腫が含まれる請求項15記載の化合物。
- 過増殖性疾患には卵巣癌、乳癌、肺癌、前立腺癌又は直腸癌が含まれる請求項15記載の化合物。
- 過増殖性疾患には肺癌が含まれ、肺癌は非小細胞又は小細胞癌である請求項20記載の化合物。
- 肺癌は非小細胞癌である請求項21記載の化合物。
- X及びYは塩素である請求項23記載の方法。
- アミン塩基がリジンである請求項23記載の方法。
- 請求項23記載の方法により製造された凍結乾燥物。
- 前記化合物が、水の存在下における半減期が水の存在下におけるイソホスホルアミドマスタードの半減期よりも長い、安定化されたイソホスホルアミドマスタードである請求項1記載の化合物。
- イソホスホルアミドマスタードを凍結乾燥させたものよりも安定である請求項26記載の凍結乾燥物。
- 請求項1記載の化合物と製薬上および生理学上許容される流体とを含有する除菌された組成物。
- 純粋なイソホスホルアミドマスタードの少なくとも2倍の貯蔵寿命を有する請求項29記載の組成物。
- 過増殖性疾患に罹患している患者を治療するための、請求項29に記載の組成物。
- 請求項1記載の化合物の塩を精製する方法であって、該化合物の溶液を無菌の抗菌フィルターで濾過し、精製された該化合物は濾過中に受ける分解率が10%未満である方法。
- 精製された該化合物は濾過中に受ける分解率が5%未満である請求項32記載の方法。
- 精製された該化合物は濾過中に受ける分解率が1%未満である請求項33記載の方法。
- 請求項32に記載の方法により製造された医薬組成物。
- 過増殖性疾患に罹患している患者を治療するための、請求項35に記載の組成物。
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US62208704P | 2004-10-25 | 2004-10-25 | |
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US67270705P | 2005-04-18 | 2005-04-18 | |
US60/672,707 | 2005-04-18 | ||
PCT/US2005/038523 WO2006047575A2 (en) | 2004-10-25 | 2005-10-25 | Salts of isophosphoramide mustard and analogs thereof as anti-tumor agents |
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EP (3) | EP2336139A3 (ja) |
JP (1) | JP5336082B2 (ja) |
KR (2) | KR20130041384A (ja) |
CN (3) | CN101087800B (ja) |
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CA (1) | CA2585125C (ja) |
DK (2) | DK1805192T3 (ja) |
ES (2) | ES2397165T3 (ja) |
HK (2) | HK1100945A1 (ja) |
IL (3) | IL182752A (ja) |
NO (1) | NO20072478L (ja) |
NZ (2) | NZ589418A (ja) |
PL (1) | PL1805192T3 (ja) |
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CN101087800B (zh) | 2004-10-25 | 2015-01-07 | 德克技术公司 | 作为抗肿瘤剂的异磷酰胺氮芥及其类似物的盐 |
US7964583B2 (en) | 2006-02-17 | 2011-06-21 | Ziopharm Oncology, Inc. | Salts of isophosphoramide mustard and analogs thereof as anti-tumor agents |
JP5659010B2 (ja) * | 2007-04-06 | 2015-01-28 | ジオファーム オンコロジー, インコーポレイテッドZiopharm Oncology,Inc. | イソホスホルアミドマスタードの塩およびそれらの類似体 |
EP2318013A4 (en) * | 2008-07-31 | 2013-07-24 | Ziopharm Oncology Inc | SYNTHESIS AND FORMULATION OF ISOPHOSPHORAMIDE MUSTARD SALTS AND THEIR ANALOGUES |
JP5779106B2 (ja) * | 2009-02-24 | 2015-09-16 | デック−テック, インコーポレイテッド | 抗腫瘍剤としての4−ヒドロペルオキシイホスファミドの錯体 |
CN102659841B (zh) * | 2012-04-24 | 2015-03-25 | 石家庄学院 | 多元酚磷酰胺衍生物及其制备方法与应用 |
CA2899206C (en) | 2013-01-24 | 2019-07-09 | Transderm, Inc. | Compositions for transdermal delivery of mtor inhibitors |
WO2017044453A1 (en) * | 2015-09-10 | 2017-03-16 | Becton, Dickinson And Company | Cyclophosphamide analogs for use as immunogens and assay conjugates for an immunoassay of cyclophosphamide and ifosfamide |
CN110520097B (zh) | 2017-01-06 | 2023-10-27 | 帕尔维拉治疗股份有限公司 | Mtor抑制剂的无水组合物及其使用方法 |
US11199529B2 (en) | 2017-09-21 | 2021-12-14 | Becton, Dickinson And Company | Hazardous contaminant collection kit and rapid testing |
JP2021530463A (ja) | 2018-07-02 | 2021-11-11 | パルヴェラ セラピューティクス、インク. | mTOR阻害剤の無水組成物および使用方法 |
CN112888698A (zh) * | 2018-09-25 | 2021-06-01 | 美国政府(由卫生和人类服务部的部长所代表) | 2’-卤代-4’-硫代-2’-脱氧-5-氮杂胞苷类似物及其使用方法 |
CN212748381U (zh) | 2019-01-28 | 2021-03-19 | 贝克顿·迪金森公司 | 一种有害污染物检测系统和一种有害污染物收集装置 |
CN111973583A (zh) * | 2020-07-29 | 2020-11-24 | 温州医科大学附属第二医院、温州医科大学附属育英儿童医院 | 芹菜素在制备促进缺血超长随意皮瓣存活药物的作用 |
CN111943979B (zh) | 2020-10-19 | 2020-12-22 | 南京卓康医药科技有限公司 | 一种异环磷酰胺中间体及其制备方法和应用 |
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EP2318013A4 (en) * | 2008-07-31 | 2013-07-24 | Ziopharm Oncology Inc | SYNTHESIS AND FORMULATION OF ISOPHOSPHORAMIDE MUSTARD SALTS AND THEIR ANALOGUES |
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