JP2009504732A - Bnctに有用なホウ素化合物 - Google Patents
Bnctに有用なホウ素化合物 Download PDFInfo
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- JP2009504732A JP2009504732A JP2008526905A JP2008526905A JP2009504732A JP 2009504732 A JP2009504732 A JP 2009504732A JP 2008526905 A JP2008526905 A JP 2008526905A JP 2008526905 A JP2008526905 A JP 2008526905A JP 2009504732 A JP2009504732 A JP 2009504732A
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- Prior art keywords
- tumor
- compound
- formula
- boron
- compounds
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- 229910052796 boron Inorganic materials 0.000 claims abstract description 48
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- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 18
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- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 17
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 16
- -1 4- { [(2-Amino-4-oxo-3,4-dihydropteridin-6-yl) methyl] amino} benzoyl Chemical group 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 12
- 229910000085 borane Inorganic materials 0.000 claims description 9
- 235000019152 folic acid Nutrition 0.000 claims description 9
- 239000011724 folic acid Substances 0.000 claims description 9
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 8
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- LAJROZOGEYIBBN-LMRYEUCJSA-N B([C@@]([H])(BBBBBBB1)BB2)[C@]21CCCN[C@H](C(N)=O)CC(C(O)=O)C(=O)C(C=C1)=CC=C1NCC1=CN=C(N=C(N)NC2=O)C2=N1 Chemical compound B([C@@]([H])(BBBBBBB1)BB2)[C@]21CCCN[C@H](C(N)=O)CC(C(O)=O)C(=O)C(C=C1)=CC=C1NCC1=CN=C(N=C(N)NC2=O)C2=N1 LAJROZOGEYIBBN-LMRYEUCJSA-N 0.000 claims description 3
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- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 2
- UORVGPXVDQYIDP-BJUDXGSMSA-N borane Chemical group [10BH3] UORVGPXVDQYIDP-BJUDXGSMSA-N 0.000 claims description 2
- 229910017052 cobalt Inorganic materials 0.000 claims description 2
- 239000010941 cobalt Substances 0.000 claims description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical group [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 2
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- 239000003937 drug carrier Substances 0.000 claims description 2
- 229910052742 iron Chemical group 0.000 claims description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
【化1】
Description
本発明の目的は、ホウ素中性子捕獲療法(BNCT)に有用な化合物を提供することである。
R1およびR2の一方が、−NH−X−Y−Z、−O−X−Y−Zまたは−S−X−Y−Zであり、そして他方が−OH、−NH−X−Y−Z、−O−X−Y−Zまたは−S−X−Y−Zであり、
ここで、
Xが、−(CH2)m−(mは0、1、2、3または4である)または−(CH2)p−O−(CH2)q−(pおよびqは独立して、1、2、3または4である)であり;
Yが、ボランまたはカルボラン(少なくとも1つのホウ素原子は10Bである)であり;そして
Zが、Hまたはアミノメチル、2−アミノエチル、3−アミノプロピル、1,3−プロパンジオール−2−イル−メトキシル、エチレングリコキシルもしくはジエチレングリコキシルのような親水性基である)
の化合物ならびにそれらの薬学的に受容可能な塩、溶媒和物および立体異性体によって達成される。
本発明の目的はまた、式(I)の化合物および薬学的に受容可能な担体、希釈剤または補助剤を含有する医薬組成物によって達成される。
本発明の目的はまた、治療に使用するための式(I)の化合物によって、または腫瘍治療に使用するための医薬を製造するための式(I)の化合物の使用によって達成される。
(i)内科的腫瘍学において使用される場合、アルキル化剤(例えば、シス−プラチン、カルボプラチン、シクロホスファミド、ナイトロジェンマスタード、メルファラン、クロラムブシル、ブスルファンおよびニトロソウレア);代謝拮抗物質(例えば、5−フルオロウラシルおよびテガフルのようなフロオロピリミジン等の葉酸拮抗剤、ラルチトレキセド、メトトレキサート、シトシンアラビノシドおよびヒドロキシウレア);抗腫瘍抗生物質(例えば、アドリアマイシン、ブレオマイシン、ドキソルビシン、ダウノマイシン、エピルビシン、イダルビシン、マイトマイシン−C、ダクチノマイシンおよびミトラマイシンのようなアントラサイクリン);抗分裂剤(例えば、ビンクリスチン、ビンブラスチン、ビンデシンおよびビノレルビンのようなビンカアルカロイドならびにタクソールおよびタキソテールのようなタキソイド);およびトポイソメラーゼインヒビター(例えば、エトポシドおよびテニポシドのようなエピポドフィロトキシン、アムサクリン、トポテカンおよびカンプトセシン)のような抗増殖性物質/新生物治療薬およびそれらの組み合わせ;
(ii)抗エストロゲン剤(antioestrogen)(例えば、タモキシフェン、トレミフェン、ラロキシフェン、ドロロキシフェンおよびヨードキシフェン)、エストロゲン受容体ダウンレギュレーター(例えば、フルベストラント)、抗男性ホルモン物質(例えば、ビカルタミド、フルタミド、ニルタミドおよび酢酸シプロテロン)、LHRHアンタゴニストもしくはLHRHアゴニスト(例えば、ゴセレリン、リュープロレリンおよびブセレリン)、プロゲストゲン(例えば、酢酸メゲストロール)、アロマターゼインヒビター(例えば、アナストロゾール、レトロゾール、ボラゾール(vorazole)およびエキセメスタン)およびフィナステリドのような5α−レダクターゼのインヒビターのような細胞増殖抑制剤;
(iii)癌細胞浸潤を阻害する薬剤(例えば、マリマスタットのようなメタロプロテナーゼインヒビターおよびウロキナーゼプラスミノーゲンアクチベーター受容体機能のインヒビター);
(iv)成長因子機能のインヒビター(例えば、このようなインヒビターとしては、成長因子抗体、成長因子受容体抗体(例えば、抗−erbb2抗体トラスツズマブ[HerceptinTM]および抗−erbb1抗体セテュキマブ)、ファルネシルトランスフェラーゼインヒビター、チロシンキナーゼインヒビターおよびセリン/トレオニンキナーゼインヒビター(例えば、表皮成長因子ファミリーのインヒビター(例えば、N−(3−クロロ−4−フルオロフェニル)−7−メトキシ−6−(3−モルホリノプロポキシ)キナゾリン−4−アミン(ゲフィチニブ)、N−(3−エチニルフェニル)−6,7−ビス(2−メトキシエトキシ)キナゾリン−4−アミン(エルロチニブ)および6−アシルアミド−N−(3−クロロ−4−フルオロフェニル)−7−(3−モルホリノプロポキシ)キナゾリン−4−アミンのようなEGFRファミリーのチロシンキナーゼインヒビター)、例えば、血小板由来成長因子ファミリーのインヒビターおよび例えば、肝細胞成長因子ファミリーのインヒビター)が挙げられる);
(v)血管内皮成長因子の効果を阻害するもののような抗血管新生薬(例えば、抗血管内皮細胞成長因子抗体ベバシツマブ[AvastinTM]、国際特許出願WO 97/22596、WO 97/30035、WO 97/32856およびWO 98/13354に開示されているもののような化合物)および他の機構によって働く化合物(例えば、リノミド(linomide)、インテグリンαvβ3機能のインヒビターおよびアンギオスタチン);
(vi)Combretastatin A4および国際特許出願WO 99/02166、WO 00/40529、WO 00/41669、WO 01/92224、WO 02/04434およびWO 02/08213に開示されている化合物のような血管傷害性薬剤;
(vii)アンチセンス療法(例えば、ISIS 2503、 抗−rasアンチセンスのような上で列挙される標的に指向されるもの);
(viii)例えば、異常p53または異常BRCA1もしくはBRCA2のような異常遺伝子を置き換えるようなアプローチ、シトシンデアミナーゼ、チミジンキナーゼもしく細菌性ニトロレダクターゼ酵素を使用するもののようなGDEPT(遺伝子指向型酵素プロドラッグ療法(gene−directed enzyme pro−drug therapy))アプローチおよび多剤耐性遺伝子治療のような化学療法または放射線治療に対する患者の耐性を高めるアプローチを含む遺伝子治療アプローチ;および
(ix)例えば、インターロイキン2、インターロイキン4または顆粒球マクロファージコロニー刺激因子のようなサイトカインを用いるトランスフェクションのような患者の腫瘍細胞の免疫原性を高めるための生体外および生体内でのアプローチ、T細胞アネルギーを減少させるアプローチ、サイトカイントランスフェクト樹状細胞のようなトランスフェクト免疫細胞を使用するアプローチ、サイトカイントランスフェクト腫瘍細胞株を使用するアプローチおよび抗イディオタイプ抗体を使用するアプローチを含む免疫療法アプローチ。
使用する全ての溶媒は、分析等級であり、そして通常、市販される無水溶媒を日常的に反応に使用した。反応は、代表的に、窒素またはアルゴンの不活性雰囲気下で行った。
酸エチル、クロロホルム/メタノール/NH3(aq.)およびジクロロメタン/メタノール/NH3(aq.)の混合物であった。
DMAP 4−ジメチルアミノピリジン;
DMF N,N−ジメチルホルムアミド;
EDC 1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド;
EtOAc 酢酸エチル;
HCl 塩化水素;
CH2Cl2 ジクロロメタン;
CDCl3 重水素化クロロホルム(deuteriated chloroform);
Ether ジエチルエーテル;
MeCN アセトニトリル;
Na2CO3 炭酸ナトリウム;
NaOH 水酸化ナトリウム;
Na2SO4 硫酸ナトリウム;
QHSO4 硫酸水素テトラブチルアンモニウム;
r.t. 室温。
収率:62%(2.21g)。
1H NMR(400MHz,CDCl3):δ ppm 3.35(t,2H,J=7.07 Hz),2.62(s,1H),1.68−1.56(m,4H),1.49−1.44(m,18H)。
LC/MS(ESI)m/z 402(M+1)。
収率:76%(841mg)。
1H NMR(400MHz,CDCl3):δ ppm 2.62(s,1H),2.54−2.42(m,2H),1.69−1.58(m,2H),1.44−1.33(m,2H)。
LC/MS(ESI)m/z 202(M+1)。
−1−イル)−プロパン−1−アミン(839mg、4.17mmol)のDMF(40ml)溶液を添加し、そして混合物を1日間撹拌した。溶媒を真空で除去した。残留物をエーテル/CH2Cl2の混合物で2回洗浄した。粗物質を分取用HPLCで精製した。
収率:7.5%(190mg)。
両方の異性体についてLC/MS(ESI)m/z 623(M−1)。12分の保持時間。方法:8.48および8.78分。(この場合において、2.5mM酢酸水溶液を用いるアイソクラティック法を使用した。
ヒト由来の4つの異なる腫瘍細胞株(ヒトグリオーマ細胞株U343mga、ヒト肝癌細胞株Hep3B、ヒト乳腺癌細胞株MCF7およびヒト肉腫細胞株4SSを含む)を、実施例3からの精製物質(本明細書中の以下でBFと表す)の生体外試験をするために使用した。細胞を非コート化組織培養プラスチック皿にプレーティングし、加湿し、5% CO2で平衡化したインキュベーター中、37℃で培養した。それらを、10% FCSおよびPEST(ペニシリン 100IU/mlおよびストレプトマイシン100mg/ml)を追加した推奨される組織培養培地中で増殖させた。細胞移動のために、細胞をトリプシン−EDTA(0.25% トリプシン、カルシウムおよびマグネシウムを含まないリン酸緩衝生理食塩水(PBS)中の0.02% EDTA)でトリプシン処理(trypsinize)した。
U343mga細胞を、75%細胞密度でペトリ皿にプレーティングし、そしてホウ酸(BA)、ビタミンB12共役ホウ素(BB)、1−4−ジヒドロキシボリル−フェニルアラニン(BPA)またはBFのうちの1種を溶解した組織培養培地と共に6時間インキュベートした。4つ全てのホウ素化化合物をホウ素含有量について等モル濃度(5×10-4Mホウ素)で組織培養培地に添加し、そして溶解した。ホウ素含有組織培養培地を除去し、そして細胞から過剰な培地を洗浄するための冷PBS緩衝液を添加ことによってインキュベートを終了した。ゴム冠ポリスマンを使用してプラスチック皿から細胞を擦り取ることによって、細胞をすぐに回収した。それらを冷PBS中に回収し、そして遠心分離によって沈殿させた。
ヒト由来の4つの異なる腫瘍細胞株(U343mga、Hep3B、MCF7および4SS)を、40〜50%(低)および90〜100%(高)の細胞密度(密集度)でペトリ皿にプレーティングし、そして記載されるように、組織培養培地に溶解したBFと共に6時間インキュベートした。ホウ素含有培地を除去し、そして細胞から過剰な培地を洗浄するための冷PBS緩衝液を添加ことによってインキュベートを終了した。ゴム冠ポリスマンを使用してプラスチック皿の細胞を擦り取ることによって、細胞をすぐに回収し、冷PBS中に回収し、そして遠心分離によって沈殿させた。全タンパク質分析およびホウ素分析を標準的な手順に従って行った(上記を参照のこと)。
U343mga細胞を、75%細胞密度でペトリ皿にプレーティングし、そして1−4−ジヒドロキシボリル−フェニアルアラニン(BPA)またはBFのうち1種と共に細胞培養培地中で18時間インキュベートした。両方のホウ素化化合物をホウ素含有量に関して等モル濃度(5×10-4 Mホウ素)で細胞培養培地に添加した。ホウ素を含まない培養培地でホウ素含有培地を置き換えることによってインキュベートを終了した。ホウ素化化合物を18時間イキュベートしたすぐ後を0時間として、細胞サンプルを0、2および7時間の時点で回収した。
Claims (17)
- 式(I):
R1およびR2の一方が、−NH−X−Y−Z、−O−X−Y−Zまたは−S−X−Y−Zであり、そして他方が−OH、−NH−X−Y−Z、−O−X−Y−Zまたは−S−X−Y−Zであり、
ここで、
Xが、−(CH2)m−(mは0、1、2、3または4である)または−(CH2)p−O−(CH2)q−(pおよびqは独立して、1、2、3または4である)であり;
Yが、ボランまたはカルボラン(少なくとも1つのホウ素原子は10Bである)であり;そして
Zが、Hまたはアミノメチル、2−アミノエチル、3−アミノプロピル、1,3−プロパンジオール−2−イル−メトキシル、エチレングリコキシルもしくはジエチレングリコキシルのような親水性基である)
の化合物ならびにそれらの薬学的に受容可能な塩、溶媒和物および立体異性体。 - 化合物が、N2−(4−{[(2−アミノ−4−オキソ−3,4−ジヒドロプテリジン−6−イル)メチル]アミノ}ベンゾイル)−N−{3−[(1R,9S)−2,3,4,5,6,7,8,10,11,12−デカボラビシクロ[7.2.1]ドデカ−1−イル]プロピル}−α−グルタミンまたはN2−(4−{[(2−アミノ−4−オキソ−3,4−ジヒドロプテリジン−6−イル)メチル]アミノ}ベンゾイル)−N−[3−(2,3,4,5,6,7,8,10,11,12−デカボラビシクロ[7.2.1]ドデカ−1−イル)プロピル]−L−グルタミンである、請求項2に記載の化合物。
- R1がNH−X−Y−Z、−O−X−Y−Zまたは−S−X−Y−Zであり、そしてR2がOHである、請求項1または2に記載の化合物。
- 少なくとも1つの炭素原子が11Cである、請求項1〜4のいずれか1項に記載の化合物。
- 治療に使用するための請求項1〜5のいずれか1項に記載の化合物。
- 診断に使用するための請求項5に記載の化合物。
- 請求項1〜5のいずれか1項に記載の化合物および薬学的に受容可能な担体、希釈剤または補助剤を含有する医薬組成物。
- 腫瘍治療に使用するための医薬を製造するための請求項1〜5のいずれか1項に定義される式(I)に記載の化合物の使用。
- 腫瘍治療が、腫瘍のホウ素中性子捕獲療法である、請求項9に記載の使用。
- 腫瘍が、中枢神経系から発症する腫瘍、好ましくは、グリア芽腫、神経膠肉腫、未分化星状細胞腫、低悪性度星状細胞腫、毛様細胞性星状細胞腫、乏突起膠腫または脳幹膠腫のような神経膠腫;髄膜腫;末梢性神経上皮腫;未分化神経外胚葉性腫瘍;神経芽細胞腫;胚細胞腫;下垂体部腫瘍;転移性脳腫瘍;または動静脈奇形である、請求項9または10に記載の使用。
- 腫瘍が、悪性腫瘍または転移性腫瘍過程、好ましくは、黒色腫、前立腺癌、肝癌、肺癌、乳癌または肉腫である、請求項9または10に記載の使用。
- 陽電子放出断層撮影に使用するための医薬を製造するための請求項5に定義される式(I)に記載の化合物の使用。
- 式NH2−X−Y−Z、OH−X−Y−ZまたはSH−X−Y−Z(ここで、X、YおよびZは請求項1〜5のいずれか1項に定義される通りである)の化合物を、葉酸と反応させる、請求項1〜5のいずれか1項に定義される式(I)に記載の化合物の製造方法。
- 薬学的および薬理学的有効量の請求項1〜5のいずれか1項に定義される式(I)の化合物を、ホウ素中性子捕獲療法と併せて、このような治療が必要な被験体に投与する腫瘍治療方法。
- 腫瘍が、請求項11または12に定義される通りである、請求項15に記載の腫瘍治療方法。
- 薬学的および薬理学的有効量の請求項5に定義される式(I)の化合物を、陽電子放出断層撮影と併せて、診断されるべき被験体に投与する腫瘍診断方法。
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JP2018016590A (ja) * | 2016-07-28 | 2018-02-01 | ステラファーマ株式会社 | ホウ素含有化合物 |
KR20180060246A (ko) * | 2016-11-28 | 2018-06-07 | 가천대학교 산학협력단 | BSH 합성을 위한 티오피롤리딘을 이용한 Na2[B12H12] 반응 |
JP2019038778A (ja) * | 2017-08-25 | 2019-03-14 | 国立大学法人東京工業大学 | ホウ素含有葉酸誘導体 |
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DE102007026701A1 (de) * | 2007-06-01 | 2008-12-04 | Universität Leipzig | Neue chemische Verbindungen, deren Herstellung und deren Verwendung |
CN101713740B (zh) * | 2009-12-31 | 2012-05-02 | 中国原子能科学研究院 | 分光光度测量生物样品中bnct药物里硼含量的方法 |
CN104151339B (zh) * | 2013-05-17 | 2017-05-03 | 中国科学院近代物理研究所 | 含硼吖啶衍生物、其制备方法和应用 |
KR20220003507A (ko) * | 2019-03-04 | 2022-01-10 | 티에이이 라이프 사이언시스 | 붕소 중성자 포획 요법에서 사용하기 위한 보릴화된 아미노산 조성물 및 그의 방법 |
CN112358494B (zh) * | 2020-04-09 | 2021-09-28 | 南京大学 | 一种基于吖啶的碳硼烷衍生物及其在生物显影中的应用 |
CN112442095B (zh) * | 2020-12-01 | 2022-07-22 | 上海科黛生物科技有限公司 | 一种维生素b12的精制方法及所得产品的应用 |
CN112979686B (zh) * | 2021-02-08 | 2022-04-08 | 北京大学 | 一种新型硼携带剂、制备方法及其药物制剂 |
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