JP7308366B2 - アクティブターゲティング型葉酸受容体近赤外蛍光分子及びその調製方法 - Google Patents
アクティブターゲティング型葉酸受容体近赤外蛍光分子及びその調製方法 Download PDFInfo
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- 230000008685 targeting Effects 0.000 title claims description 21
- 102000006815 folate receptor Human genes 0.000 title claims description 13
- 108020005243 folate receptor Proteins 0.000 title claims description 13
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 11
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N Vilsmeier-Haack reagent Natural products CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- NYDXNILOWQXUOF-UHFFFAOYSA-L disodium;2-[[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate Chemical compound [Na+].[Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)NC(CCC([O-])=O)C([O-])=O)C=C1 NYDXNILOWQXUOF-UHFFFAOYSA-L 0.000 claims description 6
- 229960003349 pemetrexed disodium Drugs 0.000 claims description 6
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- IOMZCWUHFGMSEJ-UHFFFAOYSA-N 4-(azaniumylamino)benzenesulfonate Chemical compound NNC1=CC=C(S(O)(=O)=O)C=C1 IOMZCWUHFGMSEJ-UHFFFAOYSA-N 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
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- ZAHGOULTAJWDGV-UQKRIMTDSA-N tert-butyl (2s)-2-amino-3-[4-[(2-methylpropan-2-yl)oxy]phenyl]propanoate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)[C@@H](N)CC1=CC=C(OC(C)(C)C)C=C1 ZAHGOULTAJWDGV-UQKRIMTDSA-N 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 2
- 230000001376 precipitating effect Effects 0.000 claims 1
- 229960004657 indocyanine green Drugs 0.000 description 13
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 13
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- SNZIFNXFAFKRKT-NSHDSACASA-N (2s)-2-azaniumyl-3-[4-[(2-methylpropan-2-yl)oxy]phenyl]propanoate Chemical compound CC(C)(C)OC1=CC=C(C[C@H]([NH3+])C([O-])=O)C=C1 SNZIFNXFAFKRKT-NSHDSACASA-N 0.000 description 1
- 125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 description 1
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- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 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 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
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- 239000002246 antineoplastic agent Substances 0.000 description 1
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
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- 125000000524 functional group Chemical group 0.000 description 1
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
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- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
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Description
Yは、Xのチロシン側鎖のフェノール部分とエーテル結合を形成することでXに結合する。
S0456を合成するステップS1と、
ペメトレキセド標的薬剤を合成、及びPemetrexed-Tyrを調製するステップS2と、
Pemetrexed-TyrとS0456を反応させてPemetrexed-Tyr-S0456を生成するステップS3と、を含む。
18~28℃でS0456の水溶液にpH10~12のPemetrexed-Tyrトリアニオン溶液を滴下するステップS31と、
反応混合物の温度を85-95℃に上昇させ、40-55分間攪拌し、7の生成をTLCにてモニターするステップS32と、
生成物の形成が完了したあと、反応混合物を室温まで冷却し、カニューレを介して攪拌中のアセトンに定常流で移し、緑色の沈殿物を得たステップS33と、
沈殿物を真空ポンプによる真空下で、焼結ロートを用いて濾過し、アセトンで洗浄したステップS34と、
緑色の粉末状の固体を乾燥させ、Pemetrexed-Tyr-S0456を得たテップS35と、を含む。
(1)4-ヒドラジノベンゼンスルホン酸(1.6g、31.9mmol)、3-メチル-2-ブタン(2.10ml、90mmol)および氷酢酸(50ml)を混合し、120°Cに加熱し、そして、窒素雰囲気下で18時間保持した。酢酸エチル中で沈殿させた後、ろ過してピンク色の固形物としての粗生成物を収集した。得られた生成物(6.5g、25.4mmol)をメタノール(50mL)に溶解した。温和な条件で、溶解液を、例えば水酸化カリウム(1.7g、30mmol)とイソプロパノール(20ml)の溶液に滴下し、粗混合物をろ過、洗浄して、収率が97%となる褐色の固形物を得た。褐色の固形物の構造式は、以下のとおりである。
ペメトレキセド二ナトリウム加水分解酸(1.05g、3.52mmol)をDMFに溶解し、溶解まで攪拌し、フラスコに、HATU(2.007g、5.28mmol)、O-tert-ブチル-L-チロシンtert-ブチルエステル塩酸塩(O-tert-butyl-L-tyrosine tert-butyl ester hydrochloride)(1.161g、3.52mmol)、DIEA(1.364g、10.56 mmol)を順に加え、完全に溶解するまで撹拌し、窒素雰囲気で室温で30分間反応させた。反応液を0.1N aq.HCl(1.0L、0.14M)中に滴下して、薄黄色の沈殿物を生成した。沈殿物を真空乾燥し、収率が95%となる2.04gの以下の固形物(4)を得た。固形物の構造式は、以下のとおりである。
23℃でS0456(2.909g、3.276mmol)を18mLの水に入れ、さらにpH11のPemetrexed-Tyr(1.507g、3.276mmol)トリアニオン溶液を滴下した。反応混合物の温度を90℃に上昇させ、45分間攪拌し、TLCにて以下の化合物(6)の生成をモニターした。生成物の形成が完了したあと、反応混合物を室温まで冷却し、カニューレを介して攪拌中のアセトン(0.5L)に定常流で移し、緑色の沈殿物を得た。その沈殿物を真空ポンプによる真空下で、焼結ロートを用いて濾過し、アセトン(3×500 mL)で洗浄した。緑色の粉末状の固体を高真空で12時間乾燥させ、定量的に化合物(6)(4.34g)を得た。
Claims (9)
- S0456を合成するステップS1と、
ペメトレキセド標的薬剤を合成、及び以下の式で表されるPemetrexed-Tyrを調製するステップS2と、
ステップS1は、ステップS11、ステップS12およびステップS13を含み、
ステップS11において、4-ヒドラジノベンゼンスルホン酸、3-メチル-2-ブタンおよび氷酢酸を混合して、110-130°Cに加熱し、そして、窒素雰囲気下で16-20時間還流させ、さらに酢酸エチル中で沈殿させた後、ろ過してピンク色の固形物としての粗生成物を収集し、得られた生成物をメタノールに溶解し、温和な条件で、溶解液を、例えば水酸化カリウムとイソプロパノールの溶液に滴下し、粗混合物をろ過、洗浄して、生成物1として褐色の固形物を得、
ステップS12において、生成物1および1,4-ブタンスルトンを、窒素雰囲気下でトルエン溶液に加え、100~120°Cで40~55時間加熱し、混合物を室温まで冷却した後、粗生成物を析出させ、粗混合物をメタノールに入れ、30分撹拌し、その後、沈殿、ろ過、収集した後、水:メタノール=2:1の液に再溶解し、滴下漏斗により溶解液をアセトニトリルにゆっくりと加え、更に沈殿物をろ過、収集し、生成物2としてピンク色の固形物を得、
ステップS13において、生成物2、Vilsmeier-Haack試薬および無水酢酸ナトリウムを、無水エタノール中で窒素雰囲気下で6~8時間還流加熱し、反応生成物を室温まで冷却した後、ろ過し、エタノールおよびメタノールで洗浄し、生成物3として緑色の固形物を収集した
ことを特徴とする、アクティブターゲティング型葉酸受容体近赤外蛍光分子の調整方法。 - 前記ステップS2は、ペメトレキセド標的薬剤を合成することは、
ペメトレキセド二ナトリウム加水分解酸をDMFに溶解し、フラスコに、HATU、O-tert-ブチル-L-チロシンtert-ブチルエステル塩酸塩、DIEAを順に加え、完全に溶解するまで撹拌し、窒素雰囲気で室温で25-35分間反応させた後、反応液をHCl溶液中に滴下して、薄黄色の沈殿物を生成し、その沈殿物を乾燥し、生成物4として固形物を得たことを含み、
Pemetrexed-Tyrを調製することは、
生成物4を丸底フラスコに入れ、トリフルオロ酢酸を加え、2時間撹拌した後、メチルtert-ブチルエーテルを入れ、沈殿、ろ過し、真空乾燥して、生成物5を得たことを含む
ことを特徴とする請求項2に記載のアクティブターゲティング型葉酸受容体近赤外蛍光分子の調整方法。 - 前記ステップS3は、
18~28℃でS0456の水溶液にpH10~12のPemetrexed-Tyrトリアニオン溶液を滴下するステップS31と、
反応混合物の温度を85-95℃に上昇させ、40-55分間攪拌し、7の生成をTLCにてモニターするステップS32と、
生成物の形成が完了したあと、反応混合物を室温まで冷却し、カニューレを介して攪拌中のアセトンに定常流で移し、緑色の沈殿物を得たステップS33と、
沈殿物を真空ポンプによる真空下で、焼結ロートを用いて濾過し、アセトンで洗浄したステップS34と、
緑色の粉末状の固体を乾燥させ、Pemetrexed-Tyr-S0456を得たステップS35と、
を含むことを特徴とする請求項2に記載のアクティブターゲティング型葉酸受容体近赤外蛍光分子の調整方法。
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