JP2018537452A - ペプチドチオ尿素誘導体、これを含有する放射線同位体標識化合物、およびこれを活性成分として含有する前立腺癌を処置または診断するための医薬組成物 - Google Patents
ペプチドチオ尿素誘導体、これを含有する放射線同位体標識化合物、およびこれを活性成分として含有する前立腺癌を処置または診断するための医薬組成物 Download PDFInfo
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- JP2018537452A JP2018537452A JP2018524818A JP2018524818A JP2018537452A JP 2018537452 A JP2018537452 A JP 2018537452A JP 2018524818 A JP2018524818 A JP 2018524818A JP 2018524818 A JP2018524818 A JP 2018524818A JP 2018537452 A JP2018537452 A JP 2018537452A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- 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
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
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Abstract
Description
本発明は、ペプチドチオ尿素誘導体、これを含む放射線同位体標識化合物、およびこれを活性成分として含む前立腺癌を処置または診断するための医薬組成物に関する。
前立腺癌は、世界中で最も一般的な泌尿生殖器腫瘍のうちの1つである。米国では、1997年に約380,000人が前立腺癌と診断され、そのうち41,800人が死亡し、このことは、この疾患の死亡率が肺癌についで二番目に高いことを示す。韓国では、前立腺癌は、高齢化および食事の西洋化に起因して、急速に増加している。したがって、前立腺癌の初期の画像診断および処置は、韓国だけでなく、世界中で大きな問題となっている。
[式1]
Xは、単結合、−O−または−S−であり;
nは、1〜5の整数であり;
Yは、−N(CH2COOH)(CH2)aCH2CH2−であり、
mは、1または2の整数であり;および
a、bおよびcは独立して、0または1の整数である)
[反応式1]
X、n、Y、m、a、b、およびcは、式1に定義されるとおりである)
本発明のペプチドチオ尿素誘導体は、インビボで投与される場合、ヒト血清中における安定性が優れており、前立腺癌において競合的に発現されるPSMAへの結合に優れているだけでなく、低濃度でPSMAを抑制するのにも優れている。そして、本発明の誘導体は、その高い水溶性に起因して、胆道ではなく腎臓に排泄されるので、前立腺癌組織において蓄積され、前立腺癌領域への放射線を放出し、このことは、本発明の誘導体が、前立腺癌を処置および診断するための医薬組成物として有効に使用できることを示唆する。
本明細書の以下において、本発明の例および実験例を具体的に記載および例示する。しかしながら、本発明は、以下の例および実験例によって限定されない。
工程1:(S)−ジ−tert−ブチル2−(1H−イミダゾール−1−カルボキシアミド)ペンタンジオアートの調製
1H-NMR (DMSO-d6, 600 MHz) δ 8.29 (s, 1H), 7.73 (s, 1H), 7.05 (s, 1H), 7.01 (s, 1H), 4.24 (m, 1H), 2.36 (t, J = 7.26 Hz, 2H), 2.03 (m, 1H), 1.87 (m, 1H), 1.42 (s, 9H), 1.39 (s, 9H)。
質量スペクトル(ESI+), m/z = 354 [M+H]+。
質量スペクトル(ESI+), m/z = 622 [M+H]+。
1H-NMR (DMSO-d6, 600 MHz) δ 8.43 (s, 1H), 8.10-7.10 (br, 1H), 6.50 (m, 2H), 4.01 (m, 1H), 3.92 (m, 1H), 2.69 (m, 2H), 2.17 (m, 2H), 1.83 (m, 1H), 1.70-1.49 (m, 4H), 1.38 (m, 27H), 1.29 (m, 2H)。
質量スペクトル(ESI+), m/z = 488 [M+H]+。
質量スペクトル(ESI+), m/z = 939 [M+H]+。
1H-NMR (DMSO-d6, 600 MHz) δ 12.4 (br, 6H), 9.45 (s, 1H), 7.69 (s, 1H), 7.38 (d, J = 8.10 Hz, 2H), 7.18 (d, J = 8.16 Hz, 2H) , 6.76 ~ 6.41 (br, 2H), 6.30 (m, 2H), 4.12-2.61 (m, 22H), 2.19 (m, 2H), 1.86 (m, 1H), 1.74-1.51 (m, 4H), 1.29 (m, 2H).: 質量スペクトル(ESI+), m/z = 770 [M+H]+。
1H-NMR (DMSO-d6, 600 MHz) δ 12.4 (br, 3H), 9.45 (s, 1H), 7.69 (s, 1H), 7.38 (d, J = 8.10 Hz, 2H), 7.18 (d, J = 8.16 Hz, 2H) , 6.76 ~ 6.41 (br, 2H), 6.30 (m, 2H), 4.12-2.61 (m, 22H), 2.19 (m, 2H), 1.89 (m, 1H), 1.74-1.51 (m, 4H), 1.29 (m, 2H). : 質量スペクトル(ESI+), m/z = 837 [M+H]+。
工程1:2,2’,2’’−(2−(4−(3−((S)−6−(tert−ブトキシ)−5−(3−((S)−1,5−ジ−tert−ブトキシ−1,5−ジオキソペンタン−2−イル)ウレイド)−6−オキソヘキシル)チオウレイド)ベンジル)−1,4,7,10−テトラアザシクロドデカン−1,4,7,10−テトリイル)四酢酸の調製
観察された質量スペクトル(ESI+), m/z = 1040 [M+H]+。
観察された質量スペクトル(ESI+), m/z = 871 [M+H]+。
本発明は、以下に詳細に説明される。
本発明は、以下の式1によって表される化合物またはその薬学的に許容し得る塩を提供する。
[式1]
Xは、単結合、−O−または−S−であり;
nは、1〜5の整数であり;
Yは、−N(CH2COOH)(CH2)aCH2CH2−であり、
mは、1または2の整数であり;および
a、bおよびcは、独立して、0または1の整数である)
(1)2−(3−(1−カルボキシ−5−(3−(4−((1,4,7−トリス(カルボキシメチル)−1,4,7−トリアゾナン−2−イル)メチル)フェニル)チオウレイド)フェニル)ウレイド)ペンタン二酸(GUL−SCN−NOTA);および
(2)2−(3−(1−カルボキシ−5−(3−(4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)チオウレイド)ペンチル)ウレイド)ペンタン二酸(GUL−SCN−DOTA)。
[反応式1]
X、n、Y、m、a、b、およびcは、式1に定義されるとおりである。
本明細書中の以下において、本発明の調製方法は、より詳細に記載される。
本明細書中の金属性放射線同位体は、好ましくは、67Ga、68Ga、62Cu、64Cu、67Cu、111In、90Y、177Lu、または117mSnである。
しかしながら、本開示を考慮して、本発明の精神および範囲内で改変および改善できることが当業者に理解される。
工程1:(S)−ジ−tert−ブチル2−(1H−イミダゾール−1−カルボキサアミド)ペンタンジオアートの調製
1H-NMR (DMSO-d6, 600 MHz) δ 8.29 (s, 1H), 7.73 (s, 1H), 7.05 (s, 1H), 7.01 (s, 1H), 4.24 (m, 1H), 2.36 (t, J = 7.26 Hz, 2H), 2.03 (m, 1H), 1.87 (m, 1H), 1.42 (s, 9H), 1.39 (s, 9H)。
質量スペクトル(ESI+), m/z = 354 [M+H]+。
質量スペクトル(ESI+), m/z = 622 [M+H]+。
1H-NMR (DMSO-d6, 600 MHz) δ 8.43 (s, 1H), 8.10-7.10 (br, 1H), 6.50 (m, 2H), 4.01 (m, 1H), 3.92 (m, 1H), 2.69 (m, 2H), 2.17 (m, 2H), 1.83 (m, 1H), 1.70-1.49 (m, 4H), 1.38 (m, 27H), 1.29 (m, 2H)。
質量スペクトル(ESI+), m/z = 488 [M+H]+。
質量スペクトル(ESI+), m/z = 939 [M+H]+。
1H-NMR (DMSO-d6, 600 MHz) δ 12.4 (br, 6H), 9.45 (s, 1H), 7.69 (s, 1H), 7.38 (d, J = 8.10 Hz, 2H), 7.18 (d, J = 8.16 Hz, 2H) , 6.76 ~ 6.41 (br, 2H), 6.30 (m, 2H), 4.12-2.61 (m, 22H), 2.19 (m, 2H), 1.86 (m, 1H), 1.74-1.51 (m, 4H), 1.29 (m, 2H).: 質量スペクトル(ESI+), m/z = 770 [M+H]+。
1H-NMR (DMSO-d6, 600 MHz) δ 12.4 (br, 3H), 9.45 (s, 1H), 7.69 (s, 1H), 7.38 (d, J = 8.10 Hz, 2H), 7.18 (d, J = 8.16 Hz, 2H) , 6.76 ~ 6.41 (br, 2H), 6.30 (m, 2H), 4.12-2.61 (m, 22H), 2.19 (m, 2H), 1.89 (m, 1H), 1.74-1.51 (m, 4H), 1.29 (m, 2H). : 質量スペクトル(ESI+), m/z = 837 [M+H]+。
工程1:2,2’,2’’−(2−(4−(3−((S)−6−(tert−ブトキシ)−5−(3−((S)−1,5−ジ−tert−ブトキシ−1,5−ジオキソペンタン−2−イル)ウレイド)−6−オキソヘキシル)チオウレイド)ベンジル)−1,4,7,10−テトラアザシクロドデカン−1,4,7,10−テトリイル)四酢酸の調製
観察された質量スペクトル(ESI+), m/z = 1040 [M+H]+。
観察された質量スペクトル(ESI+), m/z = 871 [M+H]+。
ヒト血清における安定性を、化合物がヒト血清と接触した際に、化合物の安定性を試験することによって調査した。インビボ安定性をインビトロで試験した。
ヒト血清中における本発明のGa−68−NOTA−SCN−GULの安定性を調査するために、例3で調製した、3.7MBq(100μL)のGa−68−NOTA−SCN−GULを、1mLのヒト血清に添加し、これを十分に混合し、続いて、36.5℃で振盪培養した。2時間後、反応混合物をITLCによって分析した。
その結果、Ga−68−NOTA−SCN−GULは、Ga−68に崩壊することなく、そのほとんどがそのまま存在することが確認された(図1c)。
ヒト血清中における本発明のGa−68−DOTA−SCN−GULの安定性を調査するために、例5で調製した3.7MBq(100μL)のGa−68−DOTA−SCN−GULを、1mLのヒト血清に添加し、これを十分に混合し、続いて、36.5℃で振盪培養した。2時間後、反応混合物をITLCによって分析した。
その結果、Ga−68−DOTA−SCN−GULのほとんどがそのまま存在し、9%のGa−68−DOTA−SCN−GULのみがGa−68に崩壊した(図2c)。
したがって、本発明のGa−68−NOTA−SCN−GULまたはGa−68−DOTA−SCN−GULは、血清中のプロテアーゼによって分解されないチオ尿素結合を含有し、アミド結合を含まず、その結果、ヒト血清中における安定性が優れており、明瞭な画像が得られる。
Ga−NOTA−SCN−GULのインビトロ競合阻害細胞細胞結合試験を実施するために、以下の実験を行った。
PSMA陽性前立腺癌細胞株22Rv1を、2x105細胞/ウェルの密度で、24ウェルプレートにロードし、続いて、37℃、5%CO2インキュベータで24時間培養した。例2で調製したGa−NOTA−SCN−GULを、0.5%ウシ血清アルブミンを含有する細胞培養培地で2倍に連続希釈した。希釈したサンプルを、培養細胞(0.5mL/ウェル)に添加し、これに、1.85kBq (S)−2−(3−((S)−1−カルボキシ−5−((4−ヨードベンジル)アミノ)ペンチル)ウレイド)ペンタン二酸(I−125−MIP−1072)を添加した(0.5mL/ウェル)。十分に混合した後、混合物を、37℃、5%CO2インキュベータで1時間培養した。培養培地を、廃棄し、細胞を新鮮な培地で二回洗浄し、これに、PBS中に溶解した0.5%ドデシル硫酸ナトリウム(SDS)を添加した(1mL/ウェル)。混合物を、完全な溶解のために穏やかに撹拌し、次いで、5mL使い捨てプラスチック試験管にロードした。次いで、放射活性を、ガンマカウンターで測定した。
したがって、本発明のGa−NOTA−SCN−GULは、前立腺癌細胞への競合的結合において優れているだけでなく、低濃度で前立腺癌細胞を抑制するのに優れていることが確認された。
本発明のGa−68−NOTA−SCN−GULを、前立腺癌を移植された動物に投与し、続いて、PET画像化し、以下のように癌組織標的化を調査した。
詳細には、5x106細胞の22Rv1細胞を含有する0.1mLのRPMI1640を、4週齢の雄性BALB/cヌードマウスの左側に皮下注射した。2〜3週間後、腫瘍組織は、適切なサイズを有することが確認され、実験に使用した。Ga−68−NOTA−SCN−GULを、注射可能な生理食塩水に希釈して、動物注射のための10.2MBq/100 μL溶液を得た。調製した溶液を、癌細胞を移植されたマウスの尾静脈に注射した。1時間後、動物で10分間、PET画像化を実施した。
したがって、本発明のGa−68−NOTA−SCN−GULGULは、PSMAに特異的に結合することができ、従って、前立腺癌を画像化するために効果的に使用できることが確認された。
本発明のGa−68−NOTA−SCN−GULまたはGa−68−DOTA−SCN−GULを、前立腺癌を移植された動物へ投与し、続いて、癌組織が実際にそこで観察されるか否かを調査するためにインビボ分布を行った。
詳細には、5x106細胞の22Rv1細胞を含有する0.1mLのRPMI1640を、4週齢の雄性BALB/cヌードマウスの左側に皮下注射した。2〜3週間後、腫瘍組織が、適切なサイズを有することを確認し、実験に使用した。例3で調製されたGa−68−NOTA−SCN−GULまたは例5で調製されたGa−68−DOTA−SCN−GULを、注射可能な生理食塩水中に希釈し、動物注射のための0.74MBq/100μL溶液を得た。調製された溶液を、癌細胞を移植されたマウスの尾静脈に注射した。1時間後、腫瘍、血液、筋肉、心臓、肺、肝臓、脾臓、胃、小腸、腎臓、および骨を抽出し、これらの重量および放射活性を測定した。このデータに基づいて、用量についての単位組織当たりの取り込み(%ID/g)を計算した。その結果を表2に示す。
したがって、本発明のGa−68−NOTA−SCN−GULまたはGa−68−DOTA−SCN−GULは、前立腺癌の画像化において効率的であるため、放射活性医薬品として効果的に使用できることが確認された。
Claims (10)
- 以下の式1によって表される化合物またはその薬学的に許容し得る塩
[式1]
Xは、単結合、−O−または−S−であり;
nは、1〜5の整数であり;
Yは、−N(CH2COOH)(CH2)aCH2CH2−であり、
mは、1または2の整数であり;および
a、bおよびcは、独立して、0または1の整数である)。 - Xが単結合であり;nが3であり;
- 式1によって表される化合物の調製方法であって、以下の反応式1:
[反応式1]
によって示されるように、式2によって表される化合物および式3によって表される化合物を反応させることによって、式1によって表される化合物を調製する工程(工程1)を含む、前記調製方法。 - 請求項1に記載の式1によって表される化合物またはその薬学的に許容し得る塩に金属性放射線同位体を配位させることによって調製された、標識化合物。
- 金属性放射線同位体が、67Ga、68Ga、62Cu、64Cu、67Cu、111In、90Y、177Lu、または117mSnである、請求項4に記載の標識化合物。
- 活性成分として請求項4に記載の標識化合物を含む、前立腺癌を処置または診断するための医薬組成物。
- 活性成分として、請求項1に記載の化合物またはその薬学的に許容し得る塩を含む、前立腺癌を画像化するための放射性医薬品。
- 請求項1に記載の化合物またはその薬学的に許容し得る塩を含む、前立腺癌を処置または診断するためのキット。
- pH1〜9および1μM〜10Mの濃度を有する緩衝液を含有する、請求項8に記載の前立腺癌を処置または診断するためのキット。
- 緩衝液が、酢酸、リン酸、クエン酸、フマル酸、アスコルビン酸、酪酸、コハク酸、酒石酸、炭酸、グルコヘプトン酸、グルコン酸、グルクロン酸、グルカル酸、ホウ酸またはそれらのナトリウム塩またはカリウム塩である、請求項9に記載の前立腺癌を処置または診断するためのキット。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20040044562A (ko) * | 2002-11-20 | 2004-05-31 | 임철부 | 항암 활성을 갖는 우레이도 또는 티오우레이도 유도체 및이 화합물을 함유하는 약학조성물 |
KR20120048250A (ko) * | 2010-11-05 | 2012-05-15 | 숙명여자대학교산학협력단 | 티오우레아계 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 항염증 조성물 |
JP2014524419A (ja) * | 2011-08-05 | 2014-09-22 | モレキュラー インサイト ファーマシューティカルズ | 放射標識された前立腺特異的膜抗原阻害剤 |
JP2015089881A (ja) * | 2013-11-06 | 2015-05-11 | 国立大学法人京都大学 | ウレア誘導体化合物、これを含有する放射性医薬 |
KR20150104092A (ko) * | 2012-11-15 | 2015-09-14 | 엔도사이트, 인코포레이티드 | Psma 발현 세포에 의해 야기되는 질병을 치료하기 위한 컨쥬게이트 |
Family Cites Families (4)
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PL2097111T3 (pl) | 2006-11-08 | 2016-01-29 | Molecular Insight Pharm Inc | Heterodimery kwasu glutaminowego |
HUE059436T2 (hu) | 2008-08-01 | 2022-11-28 | Univ Johns Hopkins | PSMA-kötõ szerek és alkalmazásaik |
EP2389361B1 (en) * | 2008-12-05 | 2016-08-24 | Molecular Insight Pharmaceuticals, Inc. | Technetium- and rhenium-bis(heteroaryl) complexes and methods of use thereof for inhibiting psma |
CN103930432B (zh) * | 2011-06-15 | 2017-06-23 | 癌靶技术有限责任公司 | 螯合的psma抑制剂 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20040044562A (ko) * | 2002-11-20 | 2004-05-31 | 임철부 | 항암 활성을 갖는 우레이도 또는 티오우레이도 유도체 및이 화합물을 함유하는 약학조성물 |
KR20120048250A (ko) * | 2010-11-05 | 2012-05-15 | 숙명여자대학교산학협력단 | 티오우레아계 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 항염증 조성물 |
JP2014524419A (ja) * | 2011-08-05 | 2014-09-22 | モレキュラー インサイト ファーマシューティカルズ | 放射標識された前立腺特異的膜抗原阻害剤 |
KR20150104092A (ko) * | 2012-11-15 | 2015-09-14 | 엔도사이트, 인코포레이티드 | Psma 발현 세포에 의해 야기되는 질병을 치료하기 위한 컨쥬게이트 |
JP2015089881A (ja) * | 2013-11-06 | 2015-05-11 | 国立大学法人京都大学 | ウレア誘導体化合物、これを含有する放射性医薬 |
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