JPWO2015152393A1 - 悪性腫瘍転移抑制用医薬 - Google Patents
悪性腫瘍転移抑制用医薬 Download PDFInfo
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- JPWO2015152393A1 JPWO2015152393A1 JP2016511639A JP2016511639A JPWO2015152393A1 JP WO2015152393 A1 JPWO2015152393 A1 JP WO2015152393A1 JP 2016511639 A JP2016511639 A JP 2016511639A JP 2016511639 A JP2016511639 A JP 2016511639A JP WO2015152393 A1 JPWO2015152393 A1 JP WO2015152393A1
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- amino
- malonamide
- metastasis
- naphthylsulfonyl
- benzyl
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Abstract
Description
また、上皮系以外の悪性腫瘍(肉腫など)においても、悪性化して、運動能・浸潤能を獲得した腫瘍細胞が、血管等へ侵入し、遠隔組織の血管内皮への定着、及び組織内への浸潤を経て、転移巣が形成されることとなる。
本発明の医薬は、また、血管の炎症に伴う悪性腫瘍の転移の増悪及び/又は増大を抑制又は予防するのに有用である。本発明の医薬は、また、外科的手術による血管の炎症に伴う悪性腫瘍の転移の増悪及び/又は増大を抑制又は予防するのに有用である。
(i)悪性腫瘍の転移の抑制又は予防に使用するための、非ペプチド性のアンジオテンシン2型受容体アゴニスト(又は血管保護剤)。
(ii)抗癌剤及び/又は抗腫瘍剤による悪性腫瘍の転移の増悪及び/又は増大の抑制又は予防に使用するための、非ペプチド性のアンジオテンシン2型受容体アゴニスト(又は血管保護剤)。
(iii)非ペプチド性のアンジオテンシン2型受容体アゴニストを有効成分として含有する、血管内皮への悪性腫瘍細胞の定着又は浸潤を抑制又は予防するための医薬(又は血管保護剤)。
(iv)非ペプチド性のアンジオテンシン2型受容体アゴニスト又は血管保護剤(又はその有効量)を患者に投与することを含む、血管内皮への悪性腫瘍細胞の定着又は浸潤を抑制又は予防する方法。
(v)血管内皮への悪性腫瘍細胞の定着又は浸潤の抑制又は予防に使用するための、非ペプチド性のアンジオテンシン2型受容体アゴニスト(又は血管保護剤)。
R2、R3のいずれか一方は水素原子を示し、残りの一方はイソプロピル、イソブチル、ネオペンチル、アリル、−CH2−R5{式中、R5は置換されていてもよいC3−10シクロアルキル、置換されていてもよいヘテロサイクル、または−CO−NR6R7(式中、R6及びR7は、同一又は異なって水素原子、C1−6アルキル、置換されていてもよいアリール、または置換されていてもよいヘテロアリールを示し、あるいは、R5とR6はそれらが結合する窒素原子とともに、置換されていてもよい環状アミノを形成してもよい。)を示す。}、−(CH2)2−R5’(式中、R5’はシアノ、またはC1−6アルコキシを示す。)、または−(CH2)n−Ar(式中、nは1から3の整数を示し、Arは置換されていてもよいフェニルまたは置換されていてもよいヘテロアリールを示す。)を示し、あるいは、R2とR3はそれらが結合する炭素原子とともに、下式
R4はジ(C1−6アルキル)アミノまたは下式
N,N−ジエチル−2−{4−[(2,6−ジフルオロベンゾイル)アミノ]ベンジル}−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−[4−(ベンゾイルアミノ)ベンジル]−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−N,N−ジエチル−2−{4−[(2−フルオロベンゾイル)アミノ]ベンジル}−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−N,N−ジエチル−2−{4−[(3−フルオロベンゾイル)アミノ]ベンジル}−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−N,N−ジエチル−2−{4−[(2,4−ジフルオロベンゾイル)アミノ]ベンジル}−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−N,N−ジエチル−2−{4−[(4−メチルベンゾイル)アミノ]ベンジル}−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−N,N−ジエチル−N’−(2−ナフチルスルホニル)−2−{4−[(2−チエノイル)アミノ]ベンジル}マロンアミド、
(2S)−N,N−ジエチル−2−{4−[(2−フロイル)アミノ]ベンジル}−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−5−フルオロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−6−フルオロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−N,N−ジエチル−N’−(2−ナフチルスルホニル)−2−{4−[(2−ピリジルカルボニル)アミノ]ベンジル}マロンアミド、
(2S)−2−{4−[(2−アミノ−4−クロロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−5−クロロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−4,5−ジフルオロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−4−フルオロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−5−メチルベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
2−(4−フルオロベンジル)−N−イソプロピル−N−(3−ピリジル)−N’−((E)−スチリルスルホニル)マロンアミド、
2−アリル−N−(4−フルオロフェニル)−N−イソプロピル−N’−((E)−スチリルスルホニル)マロンアミド、
N−(4−フルオロフェニル)−2−イソブチル−N−イソプロピル−N’−((E)−スチリルスルホニル)マロンアミド、
N−(4−フルオロフェニル)−2−イソブチル−N−イソプロピル−N’−フェネチルスルホニルマロンアミド、
N−(4−フルオロフェニル)−2−イソブチル−N−イソプロピル−N’−(2−ナフチルスルホニル)マロンアミド、
(2Sまたは2R)−2−シクロプロピルメチル−N−(4−フルオロフェニル)−N−イソプロピル−N’−((E)−2−スチリルスルホニル)マロンアミド、
2−シクロプロピルメチル−N−(4−フルオロフェニル)−N−イソプロピル−N’−フェネチルスルホニルマロンアミド、および
2−シクロプロピルメチル−N−(4−フルオロフェニル)−N−イソプロピル−N’−(2−ナフチルスルホニル)マロンアミド
から選択される少なくとも1種の化合物またはその薬理的に許容される塩であってもよい。
本発明において、投与対象患者は、悪性腫瘍の切除手術を受けるか又は切除手術を受けた患者であってもよい。また、投与対象患者は、抗癌剤及び/又は抗腫瘍剤の投与を受けているか又は投与を受けた患者であってもよい。
また、非ペプチド性のアンジオテンシン2型受容体アゴニストは、前記の通り、抗癌剤及び/又は抗腫瘍剤による転移の増悪及び/又は増大を抑制又は予防するのに有用であるが、このような抑制又は予防機能を有効に発現するためには、投与対象患者に、抗癌剤及び/又は抗腫瘍剤を投与する前から(例えば、抗癌剤及び/又は抗腫瘍剤投与開始の1日以上前から)非ペプチド性のアンジオテンシン2型受容体アゴニストを投与するのが好ましい。
そのため、本発明の医薬(非ペプチド性のアンジオテンシン2型受容体アゴニスト又は血管保護剤)は、特に、経口投与用(経口投与用医薬、経口剤)であってもよい。
一般式(I)
R2、R3のいずれか一方は水素原子を示し、残りの一方はイソプロピル、イソブチル、ネオペンチル、アリル、−CH2−R5{式中、R5は置換されていてもよいC3−10シクロアルキル、置換されていてもよいヘテロサイクル、または−CO−NR6R7(式中、R6及びR7は、同一又は異なって水素原子、C1−6アルキル、置換されていてもよいアリール、または置換されていてもよいヘテロアリールを示し、あるいは、R5とR6はそれらが結合する窒素原子とともに、置換されていてもよい環状アミノを形成してもよい。)を示す。}、−(CH2)2−R5’(式中、R5’はシアノ、またはC1−6アルコキシを示す。)、または−(CH2)n−Ar(式中、nは1から3の整数を示し、Arは置換されていてもよいフェニルまたは置換されていてもよいヘテロアリールを示す。)を示し、あるいは、R2とR3はそれらが結合する炭素原子とともに、下式
R4はジ(C1−6アルキル)アミノまたは下式
C1−6アルキルとは、炭素数1ないし6の直鎖状又は分岐鎖状の炭化水素基を意味し、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル、ペンチル、イソペンチル、ネオペンチル、ヘキシル、イソヘキシル等が挙げられる。
さらに、上記ヘテロサイクルには芳香環が縮合していてもよい。該縮合環としては、例えば、インドリニル、イソインドリニル、1,2,3,4−テトラヒドロキノリル、1,2,3,4−テトラヒドロイソキノリル、スピロ[インダン−1,4’−ピペリジン]−1’−イル等が挙げられる。
N,N−ジエチル−2−{4−[(2,6−ジフルオロベンゾイル)アミノ]ベンジル}−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−[4−(ベンゾイルアミノ)ベンジル]−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−N,N−ジエチル−2−{4−[(2−フルオロベンゾイル)アミノ]ベンジル}−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−N,N−ジエチル−2−{4−[(3−フルオロベンゾイル)アミノ]ベンジル}−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−N,N−ジエチル−2−{4−[(2,4−ジフルオロベンゾイル)アミノ]ベンジル}−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−N,N−ジエチル−2−{4−[(4−メチルベンゾイル)アミノ]ベンジル}−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−N,N−ジエチル−N’−(2−ナフチルスルホニル)−2−{4−[(2−チエノイル)アミノ]ベンジル}マロンアミド、
(2S)−N,N−ジエチル−2−{4−[(2−フロイル)アミノ]ベンジル}−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−5−フルオロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−6−フルオロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−N,N−ジエチル−N’−(2−ナフチルスルホニル)−2−{4−[(2−ピリジルカルボニル)アミノ]ベンジル}マロンアミド、
(2S)−2−{4−[(2−アミノ−4−クロロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−5−クロロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−4,5−ジフルオロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−4−フルオロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−5−メチルベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
2−(4−フルオロベンジル)−N−イソプロピル−N−(3−ピリジル)−N’−((E)−スチリルスルホニル)マロンアミド、
2−アリル−N−(4−フルオロフェニル)−N−イソプロピル−N’−((E)−スチリルスルホニル)マロンアミド、
N−(4−フルオロフェニル)−2−イソブチル−N−イソプロピル−N’−((E)−スチリルスルホニル)マロンアミド、
N−(4−フルオロフェニル)−2−イソブチル−N−イソプロピル−N’−フェネチルスルホニルマロンアミド、
N−(4−フルオロフェニル)−2−イソブチル−N−イソプロピル−N’−(2−ナフチルスルホニル)マロンアミド、
(2Sまたは2R)−2−シクロプロピルメチル−N−(4−フルオロフェニル)−N−イソプロピル−N’−((E)−2−スチリルスルホニル)マロンアミド、
2−シクロプロピルメチル−N−(4−フルオロフェニル)−N−イソプロピル−N’−フェネチルスルホニルマロンアミド、または
2−シクロプロピルメチル−N−(4−フルオロフェニル)−N−イソプロピル−N’−(2−ナフチルスルホニル)マロンアミド。
なかでも、本発明における非ペプチド性のアンジオテンシン2型受容体アゴニストとして、好ましくは、以下の化合物またはその薬理的に許容しうる塩が好ましい。
(2S)−2−[4−(ベンゾイルアミノ)ベンジル]−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−6−フルオロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−4−クロロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
2−アリル−N−(4−フルオロフェニル)−N−イソプロピル−N’−((E)−スチリルスルホニル)マロンアミド、または
N−(4−フルオロフェニル)−2−イソブチル−N−イソプロピル−N’−((E)−スチリルスルホニル)マロンアミド。
このように宿主側へ作用することから、本発明は、悪性腫瘍(例えば癌)の種類によらず、全ての悪性腫瘍に対して優れた転移抑制効果を発揮することができる。
本発明の悪性腫瘍の転移を抑制又は予防する方法、及び治療若しくは予防方法は、血管内皮への悪性腫瘍細胞の定着又は浸潤を抑制又は予防するための方法としても好適である。
また、他の転移抑制薬としては、例えば、国際出願番号PCT/JP2013/077140号明細書に記載の(i)アンジオテンシンII受容体拮抗薬、(ii)HMG−CoA還元酵素阻害薬、(iii)グレリン又はその誘導体、(iv)アドレノメデュリン又はその誘導体から選択される少なくとも一種類の血管保護剤又はその薬理的に許容される塩を好適に用いることもできる。
アンジオテンシンII受容体拮抗薬は、アンジオテンシンII受容体(AT1受容体)にアンジオテンシンIIが結合するのを妨げる作用を有する。他の転移抑制薬の有効成分として用いるアンジオテンシンII受容体拮抗薬は、前記の作用を有するものであればよい。
HMG−CoA還元酵素阻害薬は、HMG−CoA還元酵素を特異的に阻害する作用を有する。他の転移抑制薬の有効成分として用いるHMG−CoA還元酵素阻害薬は、前記の作用を有するものであればよい。
グレリン(Ghrelin)は、成長ホルモン分泌促進因子レセプター1a(Growth Hormone Secretagogue- Receptor 1a:GHS-R1a)に作用し、下垂体からの成長ホルモン(Growth Hormone:GH)の分泌を亢進させる作用を有する。
: GSS(n-octanoyl)FLSPEHQRVQQRKESKKPPAKLQPR (配列番号1)
: GSS(n-octanoyl)FLSPEHQRVQRKESKKPPAKLQPR (配列番号2)
ラット(Rat)
: GSS(n-octanoyl)FLSPEHQKAQQRKESKKPPAKLQPR (配列番号3)
: GSS(n-octanoyl)FLSPEHQKAQRKESKKPPAKLQPR (配列番号4)
マウス(Mouse)
: GSS(n-octanoyl)FLSPEHQKAQQRKESKKPPAKLQPR (配列番号5)
ブタ(Porcine)
: GSS(n-octanoyl)FLSPEHQKVQQRKESKKPAAKLKPR (配列番号6)
ウシ(Bovine):
: GSS(n-octanoyl)FLSPEHQKLQRKEAKKPSGRLKPR (配列番号7)
ヒツジ(Ovine):
: GSS(n-octanoyl)FLSPEHQKLQRKEPKKPSGRLKPR (配列番号8)
イヌ(Canine)
: GSS(n-octanoyl)FLSPEHQKLQQRKESKKPPAKLQPR (配列番号9)
ウマ(Equine)
: GSS(n-butanoyl)FLSPEHHKVQHRKESKKPPAKLKPR (配列番号10)
(上記表記において、アミノ酸残基は一文字標記により表している。)
例えば、ヒトのグレリンは、配列番号1又は2に示されるアミノ酸配列を有するペプチドであって、アミノ末端から3番目のアミノ酸残基(セリン残基)はその側鎖(水酸基)が脂肪酸(n-オクタン酸)によりアシル化された修飾アミノ酸残基である。
(2)配列番号1〜10のいずれか1つに示されるアミノ酸配列において1〜数個のアミノ酸が欠失、置換及び/又は付加されたアミノ酸配列を有するペプチドであって、アミノ末端から3番目のアミノ酸残基はその側鎖が脂肪酸によりアシル化された修飾アミノ酸残基であるペプチド;及び
(3)配列番号1〜10のいずれか1つに示されるアミノ酸配列において、アミノ末端から少なくとも4番目までの配列が保存されており、かつ、当該保存配列以外の部分において1〜数個のアミノ酸が欠失、置換及び/又は付加されたアミノ酸配列を有するペプチドであり、さらに、アミノ末端から3番目のアミノ酸残基はその側鎖が脂肪酸によりアシル化された修飾アミノ酸残基であるペプチド。
その他のグレリンの誘導体は、例えば、Matsumoto らの文献(Structural similarity of ghrelin derivatives to peptidyl growth hormone secretagogues. Matsumoto M, Kitajima Y, Iwanami T, Hayashi Y, Tanaka S, Minamitake Y, Hosoda H, Kojima M, Matsuo H, Kangawa K. Biochem Biophys Res Commun. 2001 Jun 15;284(3):655-9.)等を適宜参照して設計することが出来る。
より詳細には、例えば、グレリン又はその誘導体を成長ホルモン分泌促進因子レセプター1aに接触せしめ、それが当該レセプターに結合することにより細胞内カルシウムイオン濃度を上昇させるかどうか、を試験し、細胞内カルシウムイオン濃度を上昇があればアゴニスト作用があると判断できる。
グレリン及びその誘導体は、天然の原料から単離することもできる。
アドレノメデュリンは、血管拡張作用及び降圧作用(血圧降下作用)を有するポリペプチドである。生体内で、アドレノメデュリンの前駆体より、生理活性を持つアドレノメデュリン(活性型アドレノメデュリン)及びPAMP(proadrenomedullin N-terminal 20 peptide)が生合成される(以下、PAMPはアドレノメデュリンの誘導体に含めることとする)。アドレノメデュリンは、血小板、血管内皮細胞及び平滑筋細胞の細胞内cAMPを増加させる作用、並びに血小板凝集抑制作用、強力な血管拡張作用及び降圧作用を発揮する。
配列番号11には、アドレノメデュリン前駆体のcDNAの塩基配列を示した。配列番号12には、アドレノメデュリン前駆体のアミノ酸配列を示した。配列番号12のアミノ酸配列は、配列番号11の塩基配列にコードされるアミノ酸配列である。また、配列番号13には、アドレノメデュリン(活性型)のアミノ酸配列を示した。また、配列番号14には、PAMPのアミノ酸配列を示した。
アドレノメデュリン誘導体の中には、アドレノメデュリンの前駆体も含まれる。また、アドレノメデュリン誘導体の中には、PAMPも含まれる。
(1)配列番号12、13又は14に示されるアミノ酸配列を有するポリペプチド;
(2)配列番号12、13又は14に示されるアミノ酸配列において1〜数個のアミノ酸が欠失、置換及び/又は付加されたアミノ酸配列を有するポリペプチド;及び
(3)配列番号11に示される塩基配列からなる核酸とストリンジェントな条件下においてハイブリダイズし得る核酸によりコードされるポリペプチド。
上記(3)において、核酸は、RNA、DNAのいずれでもよいが、DNAが好ましい。
通常、抗癌剤及び/又は抗腫瘍剤投与開始の約1日以上前(例えば、3日以上前)、好ましくは1週間以上前、さらに好ましくは約10日以上前から、本発明の医薬を投与(又は医薬の投与を開始)してもよい。また、抗癌剤及び/又は抗腫瘍剤投与の終了後、約1日以上(例えば、3日以上)、好ましくは1週間以上、好ましくは約10日以上、本発明の医薬の投与を継続するのが好ましい。
シスプラチン(CDDP)はシスプラチン注「マルコ」(日医工ファーマ)を使用した。
また、アンジオテンシン2型受容体アゴニストとしては、以下の化合物を使用した。
化合物A:(2S)−2−[4−(ベンゾイルアミノ)ベンジル]−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド
化合物B:(2S)-2-{4-[(2-アミノ-6-フルオロベンゾイル)アミノ]ベンジル}-N, N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド
化合物C:2-アリル-N-(4-フルオロフェニル)-N-イソプロピル-N’-((E)-スチリルスルホニル)マロンアミド
化合物D:N-(4-フルオロフェニル)-2-イソブチル-N-イソプロピル-N’-((E)-スチリルスルホニル)マロンアミド
化合物E:(2S)-2-{4-[(2-アミノ-4-クロロベンゾイル)アミノ]ベンジル}-N, N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド
マウスは8週齢の雄のC57BL6マウス(日本SLC株式会社より購入)を用いた。マウスメラノーマB16-F10はATCCより購入し、10% Fetal calf serum(FCS)を含む Dulbecco's Modified Eagle Medium(DMEM)(Life Technologies Corporation)にて37℃、5%CO2の条件下で培養し、セミコンフルエントの状態でEDTA-trypsin(0.01〜0.125%溶液)処理後、遠心し、3×106 cells/mLになるようserum free DMEMに懸濁した。100μL/mouseの用量で、3×105 個のメラノーマ細胞懸濁液をマウスの尾静脈より注入した。
アンジオテンシン2型受容体アゴニスト群には、化合物Aが30mg/kgの用量となるように調整された0.5%カルボキシメチルセルロース水溶液をCDDP投与4日前から実験終了(メラノーマ細胞の注入から14日後)まで前記用量で継続して経口摂取させた。
一方、コントロール群では、CDDPの注入を行わず、かつ薬剤が入っていない同水溶液のみを経口摂取させ、実験を行った。
また、比較のため、CDDPの注入を行わず、かつ化合物Aの経口摂取を行った実験、CDDPの注入を行い、かつ薬剤(化合物A)が入っていない同水溶液の経口摂取を行った実験についても、あわせて行った。
各群の例数は、n=5。
なお、図1及び図2において、「Control」は、コントロールの(CDDPの注入及び化合物Aの経口摂取のいずれも行わなかった)マウスの肺及び結節数(number of nodule)を、「AT2A」は、化合物Aの経口摂取のみを行ったマウスの肺及び結節数を、「CDDP」は、CDDPの注入のみを行ったマウスの肺及び結節数を、「AT2A+CDDP」は、CDDPの注入及び化合物Aの経口摂取を行ったマウスの肺及び結節数である。また、図1において、黒い部分は転移したメラノーマにより形成された結節(転移巣)である。
マウスは8週齢の雄のC57BL6マウス(日本SLC株式会社より購入)を用いた。リポポリサッカライド(LPS)を1mg/kgで尾静脈より注入し、その4-5時間後にマウスメラノーマB16-F10をマウスの尾静脈より注入した。この際、LPSを投与した尾静脈とは異なる側の尾静脈にマウスメラノーマを注入した。マウスメラノーマB16-F10はATCCより購入し、10% FCSを含む DMEM (Life Technologies Corporation)にて37℃、5%CO2の条件下で培養し、セミコンフルエントの状態でEDTA-trypsin(0.01〜0.125%溶液)処理後、遠心した。アンジオテンシン2型受容体アゴニストとして、化合物A〜Eを使用し、化合物A投与群では3×106 cells/mLになるように、また、化合物B〜E投与群では2×106 cells/mLになるように、それぞれserum free DMEMに懸濁した。100μL/mouseの用量で、化合物A投与群では3×105 個のメラノーマ細胞懸濁液を、また、化合物B〜E投与群では2×105 個のメラノーマ細胞懸濁液を、それぞれマウスの尾静脈より注入した。
一方、コントロール群ではLPSの注入を行わず、かつ薬剤(化合物A〜E)が入っていない同水溶液のみを経口摂取させ、実験を行った。
また、比較のため、LPSの注入を行わず、かつ化合物Aの経口摂取を行った実験、およびLPSの注入を行い、かつ薬剤(化合物A〜E)が入っていない同水溶液の経口摂取を行った実験についても、あわせて行った。
各群の例数は、n=5。
なお、図3において、上段左から1番目の肺はコントロール(LPSの注入及び化合物Aの経口摂取のいずれも行わなかった)のマウスの肺を、上段左から2〜5番目の肺はLPSの注入のみを行ったマウスの肺を、下段左から1番目の肺は化合物Aの経口摂取のみを行ったマウスの肺を、下段左から2〜5番目の肺はLPSの注入及び化合物Aの経口摂取を行ったマウスの肺である。また、図3において、黒い部分は転移したメラノーマにより形成された結節(転移巣)である。
マウスは4週齢の雄の野生型C57BL6マウスおよびアンジオテンシン2型受容体C57BL6ノックアウトマウス(いずれも日本チャールスリバー社より購入)を用いた。リポポリサッカライド(LPS)を1mg/kgで尾静脈より注入し、その4-5時間後にマウスメラノーマB16-F10をマウスの尾静脈より注入した。この際、LPSを投与した尾静脈とは異なる側の尾静脈にマウスメラノーマを注入した。マウスメラノーマB16-F10はATCCより購入し、10% FCSを含む DMEM (Life Technologies Corporation)にて37℃、5%CO2の条件下で培養し、セミコンフルエントの状態でEDTA-trypsin(0.01〜0.125%溶液)処理後、遠心し、2.5×106 cells/mLになるようserum free DMEMに懸濁した。100μL/mouseの用量で、2.5×105 個のメラノーマ細胞懸濁液をマウスの尾静脈より注入した。
アンジオテンシン2型受容体アゴニストとして、化合物Aを使用した。
一方、コントロール群ではLPSの注入を行わず、かつ薬剤が入っていない同水溶液のみを経口摂取させ、実験を行った。
また、比較のため、LPSの注入を行い、かつ薬剤(化合物A)が入っていない同水溶液の経口摂取を行った実験についても、あわせて行った。
各群の例数は、n=4。
なお、図10において、「WT」はコントロール(LPSの注入及び薬剤の経口摂取のいずれも行わなかった)の野生型マウスの肺を、「WT(LPS)」はLPSの注入のみ経口摂取を行った野生型マウスの肺を、「WT(AT2agonist+LPS)」はLPSの注入及び薬剤(化合物A)の経口摂取を行った野生型マウスの肺を、「AT2R-KO(cont)」はコントロールの(LPSの注入及び薬剤の経口摂取のいずれも行わなかった)アンジオテンシン2型受容体ノックアウトマウスの肺を、「AT2R-KO(LPS)」はLPSの注入のみ経口摂取を行ったアンジオテンシン2型受容体ノックアウトマウスの肺を、「AT2R-KO (AT2agonist+LPS)」はLPSの注入及び薬剤(化合物A)の経口摂取を行ったアンジオテンシン2型受容体ノックアウトマウスの肺である。また、図10において、黒い部分は転移したメラノーマにより形成された結節(転移巣)である。
以上の結果から、悪性腫瘍の肺転移の抑制にはアンジオテンシン2型受容体が関与していることが示唆され、アンジオテンシン2型受容体アゴニストは悪性腫瘍の転移の増悪及び/又は増大を抑制することが期待できる。
Claims (17)
- 非ペプチド性のアンジオテンシン2型受容体アゴニストを有効成分として含有することを特徴とする、悪性腫瘍の転移を抑制又は予防するための医薬。
- 非ペプチド性のアンジオテンシン2型受容体アゴニストを有効成分として含有することを特徴とする、抗癌剤及び/又は抗腫瘍剤による悪性腫瘍の転移の増悪及び/又は増大を抑制又は予防するための医薬。
- 非ペプチド性のアンジオテンシン2型受容体アゴニストを有効成分として含有することを特徴とする、血管の炎症に伴う悪性腫瘍の転移の増悪及び/又は増大を抑制又は予防するための医薬。
- 血管の炎症が外科的手術によるものである、請求項3に記載の医薬。
- 非ペプチド性のアンジオテンシン2型受容体アゴニストが、下記一般式(I)
R2、R3のいずれか一方は水素原子を示し、残りの一方はイソプロピル、イソブチル、ネオペンチル、アリル、−CH2−R5{式中、R5は置換されていてもよいC3−10シクロアルキル、置換されていてもよいヘテロサイクル、または−CO−NR6R7(式中、R6及びR7は、同一又は異なって水素原子、C1−6アルキル、置換されていてもよいアリール、または置換されていてもよいヘテロアリールを示し、あるいは、R5とR6はそれらが結合する窒素原子とともに、置換されていてもよい環状アミノを形成してもよい。)を示す。}、−(CH2)2−R5’(式中、R5’はシアノ、またはC1−6アルコキシを示す。)、または−(CH2)n−Ar(式中、nは1から3の整数を示し、Arは置換されていてもよいフェニルまたは置換されていてもよいヘテロアリールを示す。)を示し、あるいは、R2とR3はそれらが結合する炭素原子とともに、下式
R4はジ(C1−6アルキル)アミノまたは下式
で表される化合物またはその薬理的に許容される塩である請求項1〜4のいずれか1項に記載の医薬。 - 非ペプチド性のアンジオテンシン2型受容体アゴニストが、
N,N−ジエチル−2−{4−[(2,6−ジフルオロベンゾイル)アミノ]ベンジル}−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−[4−(ベンゾイルアミノ)ベンジル]−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−N,N−ジエチル−2−{4−[(2−フルオロベンゾイル)アミノ]ベンジル}−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−N,N−ジエチル−2−{4−[(3−フルオロベンゾイル)アミノ]ベンジル}−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−N,N−ジエチル−2−{4−[(2,4−ジフルオロベンゾイル)アミノ]ベンジル}−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−N,N−ジエチル−2−{4−[(4−メチルベンゾイル)アミノ]ベンジル}−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−N,N−ジエチル−N’−(2−ナフチルスルホニル)−2−{4−[(2−チエノイル)アミノ]ベンジル}マロンアミド、
(2S)−N,N−ジエチル−2−{4−[(2−フロイル)アミノ]ベンジル}−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−5−フルオロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−6−フルオロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−N,N−ジエチル−N’−(2−ナフチルスルホニル)−2−{4−[(2−ピリジルカルボニル)アミノ]ベンジル}マロンアミド、
(2S)−2−{4−[(2−アミノ−4−クロロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−5−クロロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−4,5−ジフルオロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−4−フルオロベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
(2S)−2−{4−[(2−アミノ−5−メチルベンゾイル)アミノ]ベンジル}−N,N−ジエチル−N’−(2−ナフチルスルホニル)マロンアミド、
2−(4−フルオロベンジル)−N−イソプロピル−N−(3−ピリジル)−N’−((E)−スチリルスルホニル)マロンアミド、
2−アリル−N−(4−フルオロフェニル)−N−イソプロピル−N’−((E)−スチリルスルホニル)マロンアミド、
N−(4−フルオロフェニル)−2−イソブチル−N−イソプロピル−N’−((E)−スチリルスルホニル)マロンアミド、
N−(4−フルオロフェニル)−2−イソブチル−N−イソプロピル−N’−フェネチルスルホニルマロンアミド、
N−(4−フルオロフェニル)−2−イソブチル−N−イソプロピル−N’−(2−ナフチルスルホニル)マロンアミド、
(2Sまたは2R)−2−シクロプロピルメチル−N−(4−フルオロフェニル)−N−イソプロピル−N’−((E)−2−スチリルスルホニル)マロンアミド、
2−シクロプロピルメチル−N−(4−フルオロフェニル)−N−イソプロピル−N’−フェネチルスルホニルマロンアミド、および
2−シクロプロピルメチル−N−(4−フルオロフェニル)−N−イソプロピル−N’−(2−ナフチルスルホニル)マロンアミド
から選択される少なくとも1種の化合物またはその薬理的に許容される塩である請求項1〜5のいずれか1項に記載の医薬。 - 悪性腫瘍の転移が、肺、骨、肝臓及び脳から選択される少なくとも1種への転移である、請求項1〜6のいずれか1項に記載の医薬。
- 悪性腫瘍の転移が、肺及び肝臓から選択される少なくとも1種への転移である、請求項1〜7のいずれか1項に記載の医薬。
- 悪性腫瘍が、上皮系悪性腫瘍、非上皮系悪性腫瘍及びメラノーマから選択される少なくとも1種の悪性腫瘍である、請求項1〜8のいずれか1項に記載の医薬。
- 悪性腫瘍が、メラノーマである、請求項1〜9のいずれか1項に記載の医薬。
- 投与対象患者が、悪性腫瘍の切除手術を受けるか又は切除手術を受けた患者である、請求項1〜10のいずれか1項に記載の医薬。
- 投与対象患者が、抗癌剤及び/又は抗腫瘍剤の投与を受けているか又は投与を受けた患者である、請求項1〜11のいずれか1項に記載の医薬。
- 抗癌剤及び/又は抗腫瘍剤とともに用いられるためのものである、請求項1〜12のいずれか1項に記載の医薬。
- 抗癌剤及び/又は抗腫瘍剤が白金系抗腫瘍剤である、請求項13に記載の医薬。
- 抗癌剤及び/又は抗腫瘍剤を投与する前から投与されるためのものである、請求項13または14に記載の医薬。
- 抗癌剤及び/又は抗腫瘍剤投与開始の1日以上前から投与されるためのものである、請求項15に記載の医薬。
- 経口投与用である、請求項1〜16のいずれか1項に記載の医薬。
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WO2017204163A1 (ja) * | 2016-05-23 | 2017-11-30 | 国立研究開発法人国立循環器病研究センター | 肺障害の予防または抑制用医薬 |
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AU2003286251A1 (en) | 2002-11-21 | 2004-06-15 | Vicore Pharma Ab | New bicyclic angiotensin ii agonists |
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- 2015-04-03 EP EP15773890.7A patent/EP3127554A4/en not_active Withdrawn
- 2015-04-03 JP JP2016511639A patent/JPWO2015152393A1/ja active Pending
- 2015-04-03 WO PCT/JP2015/060582 patent/WO2015152393A1/ja active Application Filing
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WO2015152393A1 (ja) | 2015-10-08 |
US20170014419A1 (en) | 2017-01-19 |
US10071099B2 (en) | 2018-09-11 |
EP3127554A1 (en) | 2017-02-08 |
EP3127554A4 (en) | 2017-12-06 |
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