JP2016536292A - チオール標識のための3−アリールプロピオニトリル化合物 - Google Patents
チオール標識のための3−アリールプロピオニトリル化合物 Download PDFInfo
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- JP2016536292A JP2016536292A JP2016522652A JP2016522652A JP2016536292A JP 2016536292 A JP2016536292 A JP 2016536292A JP 2016522652 A JP2016522652 A JP 2016522652A JP 2016522652 A JP2016522652 A JP 2016522652A JP 2016536292 A JP2016536292 A JP 2016536292A
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- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- 229950002929 trinitrophenol Drugs 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical class [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Classifications
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- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/34—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring with cyano groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by unsaturated carbon chains
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- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/35—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
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- C07C255/37—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by etherified hydroxy groups
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- C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
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Abstract
Description
− 水素原子、
− O、NおよびSの中から選択された少なくとも1つのヘテロ原子によって場合により中断されたアルキル、アルケンまたはアルキン基、
− アリール基、
− アルコキシ基、
− ハロゲン原子、
− アミノ(−NRR’)基、式中、RおよびR’は、独立して、水素原子、以下に定義するアルキル、アルケン、アルキンまたはアリール基である、
− ヒドロキシルアミン(−ONH2)基、
− ヒドラジン(−NH−NH2)基、
− ニトロ(−NO2)基、
− アジド(−N3)基、
− 場合により対イオンの存在下にジアゾニウム(−N2 +)基、
− マレイミド基、
− アルキルまたはアリールカルボキシル(−C(=O)OR)基、式中、Rは、上記の通りである、
− アルキルまたはアリールカルボニル(−C(=O)R)基、式中、Rは、上記の通りである、
− ヒドロキシル(−OH)基、
− ホウ酸−B(OR”)2基、式中、R”は水素原子またはアルキル基である、
− ホスフィンまたはホスホニウム基、
− イソシアネート(−N=C=O)またはイソチオシアネート(−N=C=S)基、
− クロロスルホニル(−SO2Cl)基、
− −O−C(=O)−C(N2)−CF3基または−C(=O)−C(N2)−CF3基、
− 活性化エステル、例えば−C(=O)−NHS、式中、NHSは、N−ヒドロスクシンイミジル、過フッ素化エステル、およびアクリルウレアを表す、
− −C≡C−C≡N基、
− タグ、ならびに
− 先に列挙された基の少なくとも1つによって置換されたアルキル基
からなる群から独立して選択され、
R1〜R5の少なくとも1つが、タグ部位を含み、好ましくはタグ部位であり、
代替的には、R1〜R5のうち2つが、これらが連結するフェニル環の炭素原子と一緒になって、少なくとも1つのヘテロ原子、例えばP、OまたはSを場合により含む、飽和、不飽和または芳香族の単または多環式環を形成していてよい;
の化合物と接触させることを含む方法である。
− 化合物の検出、
− 化合物による対象薬剤のベクトル化、
− 化合物の可溶化、
− 化合物の安定化、
− 化合物の抽出および/または精製の改善、
− 化合物のADME(投与、分布、代謝、排泄)パラメータの少なくとも1つの変更;
− 化合物への生物活性の付加;
− クリック化学のための適切な官能性の付加。
− アルキン基、
− アミノ基、
− ヒドロキシルアミン(−ONH2)基、
− ヒドラジン(−NH−NH2)基、
− アジド(N3)基、
− 好ましくは対イオンの存在下にジアゾニウム(N2 +)基、
− マレイミド基、
− カルボン酸基、
− アルデヒド(−CHO)基、
− ホウ酸−B(OR”)2基、式中、R”は上記の通りである、および
− 活性化エステル;からなる群から独立して選択される。
本発明の式(I)または(II)の化合物は、例えば薗頭カップリングを介してプロパルギルアルコールとのカップリングによって、例えば、対応するヨードアレーンから二工程で合成され得る。カップリングには、好ましくは酸化が続く;例えば、酸化は、アンモニア溶液の存在下にMnO2によって実施されるタンデム酸化であってよい。代替的には、本発明の化合物は、アリールアルキンのシアノ化によって合成され得る。シアノ化は、例えば、CuCN、アリールイソシアネート、シアノベンゾトリアゾールまたはシアノイミダゾールによって実施されてよい。
式(I)の化合物は、少なくとも1つのチオールSH部位を含む化合物を標識するための方法において用いられ得る。好ましくは、本発明の方法は、式(I)の少なくとも1つの化合物を、少なくとも1つのチオールSH部位を含む化合物、またはかかる化合物を含む傾向にあるサンプルと接触させることを含む。好ましくは、サンプルは、生体サンプル、特に水性サンプルである。
− 水素原子、
− O、NおよびSの中から選択された少なくとも1つのヘテロ原子によって場合により中断されたアルキル、アルケンまたはアルキン基、
− アリール基、
− アルコキシ基、
− ハロゲン原子、
− アミノ(−NRR’)基、式中、RおよびR’は、独立して、水素原子、または先に定義したアルキル、アルケン、アルキンもしくはアリール基である、
− ヒドロキシルアミン(−ONH2)基、
− ヒドラジン(−NH−NH2)基、
− ニトロ(−NO2)基、
− アジド(−N3)基、
− 好ましくは対イオンの存在下にジアゾニウム(−N2 +)基、
− マレイミド基、
− アルキルまたはアリールカルボキシル(−C(=O)OR)基、
− アルキルまたはアリールカルボニル(−C(=O)R)基、
− ヒドロキシル(−OH)基、
− ホウ酸−B(OR”)2基、式中、R”は水素原子またはアルキル基である、
− ホスフィンまたはホスホニウム基、
− イソシアネート(−N=C=O)またはイソチオシアネート(−N=C=S)基、
− クロロスルホニル(−SO2Cl)基、
− O−C(=O)−C(N2)−CF3基または−C(=O)−C(N2)−CF3基、
− 活性化エステル、例えば−C(=O)−NHS、過フッ素化エステルおよびアクリルウレア、
− タグ、ならびに
− 先に列挙された基の少なくとも1つによって置換されたアルキル基;からなる群から独立して選択される;
の化合物も開示する。
式(II)の化合物の合成
式(I)または(II)の一連の化合物を以下の手順に従って合成し、特性決定した。
薗頭カップリング
A.適当なハロゲン化アリール(1当量、1mmol)のDMF(5mL)およびDIPEA(10当量、10mmol)脱気溶液に、予め混合したPdCl2(PPh3)2(0.03当量、30μmol)およびCuI(0.06当量、60μmol)を添加した。得られた反応塊を脱気し、さらに5分間撹拌し、続いてプロパルギルアルコール(1.2当量、1.2mmol)を添加した。反応塊を1〜24時間撹拌した(TLCによってモニタリングした)。1M HCl(50mL)を添加し(遊離アミノ基を含有するときには、代わりに50mLの水を添加し)、反応混合物を酢酸エチル(3×20mL)で抽出した。合わせた酢酸エチル画分を水で洗浄し(1×10mL)、MgSO4上で乾燥し、蒸発させて粗生成物を得た。生成物をフラッシュクロマトグラフィ(100%のシクロヘキサンから100%の酢酸エチルまで20分の勾配)によって精製した。
70℃のMnCl2・4H2O(1当量、1モル、200g)の水(2L)溶液を、フードにおいて60℃でKMnO4(1当量、1モル、160g)の水(2L)溶液に撹拌しながら10分間で徐々に添加した。激しい反応により、結果として塩素が発生した;懸濁液を2時間撹拌し、室温で一晩保持した。沈殿を濾去し、pHが6.5〜7となるまで水(4L)で完全に洗浄し、この洗浄により、無視できるほどの塩化物試験を与えた。次いでフィルタケーキを120〜130℃で18時間乾燥させ;これにより、チョコブラウン色の高分散アモルファス粉末を得た。
反応時間:18時間;収率:72%。
1H NMR(400MHz,メタノール−d4)δ7.36(dd,J=1.5,7.5Hz,1H),7.26−7.33(m,1H),6.97(d,J=8.3Hz,1H),6.86−6.93(m,1H),4.43(s,2H),3.84(s,3H);13C NMR(101MHz,メタノール−d4)δ161.6,134.5,131.0,121.5,113.4,112.0,92.7,82.0,56.2,51.5。
反応時間:16時間;収率:87%。
1H NMR(400MHz,メタノール−d4)δ7.15−7.24(pseudo−t,J=7.5Hz,1H),7.00(d,J=7.5Hz,1H),6.93−6.98(m,1H),6.87(dd,J=2.13,7.5Hz,1H),4.41(s,2H),3.73(s,3H);13C NMR(101MHz,メタノール−d4)δ160.9,130.6,125.4,125.1,117.8,115.7,88.8,85.6,55.9,51.4。
反応時間:16時間;収率:92%。
1H NMR(400MHz,クロロホルム−d)δ7.40(d,J=8.78Hz,2H),6.86(d,J=8.78Hz,2H),4.51(d,J=4.9Hz,2H),3.83(s,3H),1.78(t,J=4.9Hz,1H);13C NMR(101MHz,クロロホルム−d)δ159.8,133.2,114.6,114.0,85.9,85.7,55.3,51.7。
反応時間:24時間;収率:62%。
1H NMR(400MHz,メタノール−d4)δ7.19(dd,J=1.25,7.9Hz,1H),7.03−7.12(m,1H),6.75(d,J=7.9Hz,1H),6.56−6.65(m,1H),4.47(s,2H),4.26(s,2H);13C NMR(101MHz,メタノール−d4)δ150.3,133.0,130.6,118.2,115.6,93.8,78.9,69.5,51.0。
反応時間:18時間;収率:77%。
1H NMR(400MHz,クロロホルム−d)δ7.08(t,J=7.8Hz,1H),6.83(d,J=7.8Hz,1H),6.76(s,1H),6.64(dd,J=1.5,7.8Hz,1H),4.46(s,2H),2.17(s,1H);13C NMR(101MHz,クロロホルム−d)δ146.3,129.2,123.4,122.0,118.0,115.5,87.0,85.6,51.4。
反応時間:18時間;収率:42%。
1H NMR(400MHz,メタノール−d4)δ7.11−7.21(d,J=8.5Hz,2H),6.53−6.68(d,J=8.5Hz,2H),4.37(s,2H);13C NMR(101MHz,メタノール−d4)δ149.7,133.8,115.7,112.5,86.7,85.9,51.4;
反応時間:15時間;収率:35%。
1H NMR(400MHz,クロロホルム−d)δ7.97(d,J=8.0Hz,1H),7.54−7.60(d,J=8.0Hz,1H),7.46−7.54(t,J=8.0Hz,1H),7.36−7.44(t,J=8.0Hz,1H),4.49(s,2H),1.68(br.s.,1H);13C NMR(101MHz,クロロホルム−d)δ149.9,134.8,132.8,128.9,124.6,118.0,95.2,80.9,51.7。
反応時間:12時間;収率:91%。
1H NMR(400MHz,メタノール−d4)δ7.72−7.82(m,J=8.28Hz,2H),7.41−7.53(m,J=8.28Hz,2H),4.43(s,2H),2.92(s,3H);13C NMR(101MHz,メタノール−d4)δ169.9,135.2,132.7,128.3,127.6,91.5,84.7,51.3,27.1。
反応時間:18時間;収率:85%。
1H NMR(400MHz,メタノール−d4)δ7.56−7.64(d,J=8.8Hz,2H),7.47−7.56(d,J=8.8Hz,2H),4.74(s,2H),2.04(s,3H);13C NMR(101MHz,メタノール−d4)δ171.9,143.8,135.7,120.7,112.8,106.2,84.5,62.7,24.1。
反応時間:5時間;収率:70%。
1H NMR(400MHz,クロロホルム−d)δ7.40(d,J=7.5Hz,1H),7.11−7.24(m,3H),4.54(s,2H),2.43(s.,3H);13C NMR(101MHz,クロロホルム−d)δ138.2,131.2,128.4,128.0,119.3,115.3,86.5,85.2,51.2,21.2。
反応時間:24時間;収率:25%。
1H NMR(400MHz,クロロホルム−d)δ7.03(t,J=7.5Hz,1H),6.95(d,J=7.5Hz,2H),4.50(s,2H),2.34(s,7H);13C NMR(101MHz,クロロホルム−d)δ140.5,127.9,126.7,122.3,95.6,83.3,51.9,21.1。
反応条件:30℃、プロピルアミン、16時間;収率:38%。
1H NMR(400MHz,メタノール−d4)δ7.25(t,J=8.4Hz,1H),6.62(d,J=8.4Hz,2H),4.46(s,2H),3.84(s,6H);13C NMR(101MHz,メタノール−d4)δ163.0,131.0,104.7,102.5,97.0,78.1,56.4,51.7。
1H NMR(400MHz,メタノール−d4)δ7.51−7.65(m,2H),7.12(d,J=8.3Hz,1H),7.01(t,J=7.7Hz,1H),3.94(s,4H);13C NMR(101MHz,メタノール−d4)δ164.7,136.4,135.3,122.0,112.6,107.7,106.4,81.8,66.7,56.7;IR(ニートフィルム,cm−1):2946,2264,2142 1596,1490,1245,1164,1122,1047,1021,752,498;GC−ESI−HRMS:157.05276;実測値157.05044。
1H NMR(400MHz,メタノール−d4)δ7.38(t,J=7.8Hz,1H),7.27(d,J=7.8Hz,1H),7.20−7.24(m,1H),7.12−7.20(m,1H),3.83(s,3H);13C NMR(101MHz,メタノール−d4)δ161.2,131.4,127.1,120.0,119.4,119.2,106.0,84.1,62.7,56.1;IR(ニートフィルム,cm−1):2491,2264,2144,1595,1573,1488,1464,1420,1324,1294,1207,1178,1045,783,681,494;GC−ESI−HRMS:157.05276;実測値157.05298。
1H NMR(400MHz,クロロホルム−d)δ7.46−7.70(m,J=8。8Hz,2H),6.86−6.96(m,J=8.8Hz,2H),3.86(s,3H);13C NMR(101MHz,クロロホルム−d)δ161.4,134.4,113.7,108.2,104.8,82.7,61.5,54.5;IR(ニートフィルム,cm−1):2985,2358,2342,2263,2178,2149,1603,1514,1307,1270,1180,1028,835,808,669,424;GC−ESI−HRMS:157.05276;実測値157.05337。
1H NMR(400MHz,クロロホルム−d)δ7.38(t,J=8.5Hz,1H),6.53(d,J=8.5Hz,2H),3.88(s,6H);13C NMR(101MHz,クロロホルム−d)δ164.4,133.8,106.2,103.4,96.5,77.7,70.5,56.2;IR(ニートフィルム,cm−1):2847,2359,2259,2201,2139,1926,1586,1574,1478,1432,1302,1255,1188,1109,1025,778,727,648,632,545,506,488,420;GC−ESI−HRMS:187.06333;実測値184.06465。
1H NMR(500MHz,メタノール−d4)δ6.81(d,J=7.88Hz,1H),6.65−6.76(m,1H),6.08−6.19(m,2H),3.85(br.s.,1H);13C NMR(126MHz,クロロホルム−d)δ151.4,134.0,133.4,118.2,115.0,105.8,101.0,81.6,68.5;IR(ニートフィルム,cm−1):3413,3332,3211,2925,2853,2250,2136,1632,1600,1563,1486,1452,1312,1273,1252,1161,740,673,493;GC−ESI−HRMS:142.05310;実測値142.05458。
1H NMR(400MHz,クロロホルム−d)δ7.17(t,J=7.6Hz,1H),6.99(d,J=7.6Hz,1H),6.74−6.89(m,2H),3.85(br.s.,2H);13C NMR(101MHz,クロロホルム−d)δ146.8,129.8,123.6,118.7,118.7,118.0,105.7,83.7,62.3;IR(ニートフィルム,cm−1):3426,3340,2923,2852,2265,2142,1630,1594,1579,1513,1448,1326,1313,1300,1220,1164,993,882,862,784,680,534,456;GC−ESI−HRMS:142.05310;実測値142.05197。
1H NMR(400MHz,メタノール−d4)δ7.26(d,J=8.6Hz,2H),6.51(d,J=8.6Hz,2H);13C NMR(101MHz,メタノール−d4)δ152.5,135.1,113.6,105.6,102.3,86.3,60.2;IR(ニートフィルム,cm−1):3431,3333,3211,2250,2132,1632,1599,1513,1438,1303,1178,1043,949,826,814,526,495,452;GC−ESI−HRMS:142.05310;実測値142.05464。
1H NMR(400MHz,クロロホルム−d)δ7.47(d,J=7.78Hz,1H),7.28−7.36(m,1H),7.18(d,J=8.03Hz,1H),7.08−7.16(m,1H),2.39(s,3H);13C NMR(101MHz,クロロホルム−d)δ143.4,134.1,131.8,130.1,126.1,117.4,105.6,82.4,66.4,20.5;IR(ニートフィルム,cm−1):2295,2257,2141,1599,1484,1456,1383,1291,1199,1162,1116,1039,757,711,672,548,490,452;GC−ESI−HRMS:141.05785;実測値141.05926。
1H NMR(400MHz,クロロホルム−d)δ7.12−7.27(t,J=7.5Hz,1H),7.01(d,J=7.5Hz,2H),2.38(s,6H);13C NMR(101MHz,クロロホルム−d)δ143.8,131.2,127.3,117.6,105.6,81.5,70.2,20.8;IR(ニートフィルム,cm−1):2923,2856,2261,2138,1732,1595,1468,1381,1265,1168,1033,774,728,490;GC−ESI−HRMS:155.07350;実測値155.07507。
1H NMR(400MHz,メタノール−d4)δ8.28−8.35(m,1H),7.96−8.06(m,1H),7.81−7.90(m,2H);13C NMR(101MHz,メタノール−d4)δ151.9,138.3,135.2,134.1,126.6,114.2,105.7,79.0,68.6;IR(ニートフィルム,cm−1):2268,1604,1567,1528,1502,1480,1345,851,787,744,709,687,537,491;GC−ESI−HRMS:172.02728;実測値172.02869。
1H NMR(400MHz,メタノール−d4)δ7.56−7.63(m,J=8.8Hz,2H),7.49−7.56(m,J=8.8Hz,2H),2.04(s,3H);13C NMR(101MHz,メタノール−d4)δ171.9,143.8,135.7,120.7,112.8,106.2,84.5,62.7,24.1;IR(ニートフィルム,cm−1):3303,3174,3098,2278,2262,2139,1670,1594,1535,1407,1364,1321,1263,1177,834,534;GC−ESI−HRMS:184.06366;実測値184.06212。
1H NMR(400MHz,メタノール−d4)δ7.96−8.05(m,J=7.78Hz,2H),7.85−7.93(m,J=7.78Hz,2H),3.03(s,3H);13C NMR(101MHz,メタノール−d4)δ169.1,138.3,134.9,129.0,121.6,105.9,83.0,64.6,28.8;IR(ニートフィルム,cm−1):3348,2270,1641,1549,1502,1408,1392,1327,1303,1283,1162,854,760,617,488;GC−ESI−HRMS:184.06366;実測値184.06465。
1H NMR(400MHz,クロロホルム−d)δ=7.78(d,J=8.5Hz,2H),7.32(d,J=8.5Hz,3H);13C NMR(101MHz,クロロホルム−d)δ138.1,134.4,116.8,105.2,99.2,81.9,64.2。
化合物13を本発明による標識方法に用いることができる(放射性同位体125Iによる)。
1H NMR(400MHz,クロロホルム−d)δ=7.76(d,J=8.3Hz,2H),7.70(d,J=8.3Hz,2H)。
化合物14を、(放射性同位体18Fによる)本発明による標識方法に用いることができる。
1H NMR(400MHz,クロロホルム−d)δ=7.93(d,J=8.1Hz,2H),7.47(d,J=8.1Hz,2H),4.53(s,2H),1.60(s,9H);13C NMR(101MHz,クロロホルム−d)δ=165.1,131.7,131.4,129.3,126.6,89.8,85.1,81.4,51.6,28.1。
1H NMR(400MHz,DMSO−d6)δ=8.00(d,J=8.3Hz,2H),7.94(d,J=8.3Hz,2H),1.56(s,9H);13C NMR(101MHz,クロロホルム−d)δ=164.3,134.8,133.3,129.7,121.3,105.2,82.2,81.9,64.8,28.1。
1H NMR(400MHz,メタノール−d4)δ=8.12(d,J=8.3Hz,3H),7.83(d,J=8.3Hz,2H)。
1H NMR(400MHz,DMSO−d6)δ=8.29(d,J=8.3Hz,2H),8.08(d,J=8.3Hz,2H)。
化合物17を本発明によるバイオコンジュゲーション法に用いることができる。
1H NMR(400MHz,DMSO−d6)δ=8.31(d,J=6.3Hz,2H),8.09(d,J=6.3Hz,2H)。
化合物18を本発明によるバイオコンジュゲーション法に用いることができる。
1H NMR(400MHz,DMSO−d6)δ=8.59(br.s.,1H),8.34(d,J=7.3Hz,1H),8.33(s,1H)8.26(d,J=8.8Hz,1H),8.13(d,J=7.3Hz,1H),8.00(d,J=8.8Hz,2H),7.83(d,J=8.8Hz,2H),7.61−7.51(m,2H),7.18(d,J=7.5Hz,1H),4.21(s,2H),2.71(s,6H)。
13C NMR(101MHz,DMSO−d6)δ=151.2,144.8,138.4,135.7,135.6,129.4,128.9,128.8,128.6,127.8,123.4,121.3,119.9,119.0,116.0,114.9,105.3,82.5,63.1,44.9,37.6。
化合物20を、本発明による検出方法(例えば、染料による)に用いることができる。
1H NMR(400MHz,アセトニトリル−d3)δ=7.71(d,J=8.5Hz,2H),7.37(d,J=8.5Hz,2H)。
化合物21を本発明によるバイオコンジュゲーション法に用いることができる。
1H NMR(400MHz,メタノール−d4)δ=7.66(s,4H),3.65−3.54(m,12H),3.50(t,J=6.1Hz,2H),3.12(t,J=6.8Hz,2H),1.91(quin,J=6.1Hz,2H),1.72(quin,J=6.4Hz,2H),1.45(s,9H)。
13C NMR(101MHz,メタノール−d4)δ=182.0,158.5,144.6,135.6,106.4,84.8,80.0,71.6,71.5,71.3,71.3,70.0,68.2,63.0,38.8,31.0,29.8,29.0
1H NMR(400MHz,クロロホルム−d)δ=8.08(d,J=8.3Hz,2H),7.67(d,J=8.3Hz,2H)。
化合物23を本発明によるバイオコンジュゲーション法に用いることができる。
1H NMR(400MHz,メタノール−d4)δ=7.92(d,J=8.3Hz,2H),7.82(d,J=8.3Hz,2H),3.72−3.45(m,14H),3.12(t,J=6.8Hz,2H),1.90(quin,J=6.3Hz,2H),1.72(quin,J=6.4Hz,2H),1.44(s,9H)。
1H NMR(400MHz,クロロホルム−d)δ=7.90(d,J=8.3Hz,2H),7.67(d,J=8.3Hz,2H),7.48(br.s,1H),6.18(br.s,1H),3.71−3.45(m,14H),3.32(t,J=6.0Hz,2H),2.23(t,J=6.8Hz,4H),2.15(t,J=7.5Hz,2H),1.90(td,J=6.0,11.7Hz,2H),1.73(quin,J=6.1Hz,2H),1.65−1.42(m,6H),1.41−1.32(m,4H),1.32−1.19(m,22H),0.88(t,J=6.8Hz,3H)。
化合物25を、化合物を結合および/または固定化させるための本発明による標識(例えば光標識)方法に用いることができる。
1H NMR(400MHz,クロロホルム−d)δ=7.56(d,J=8.5Hz,2H),7.46(d,J=8.5Hz,2H),6.79(br.s.,1H),4.26(q,J=7.0Hz,2H),1.33(t,J=7.0Hz,3H)。
1H NMR(400MHz,メタノール−d4)δ=7.60(d,J=8.8Hz,2H),7.52(d,J=8.8Hz,2H),4.00(d,J=2.4Hz,2H),2.61(t,J=2.4Hz,1H)。
化合物27を本発明によるクリック化学に用いることができる。
1H NMR(400MHz,クロロホルム−d)δ=7.57(d,J=8.6Hz,2H),7.48(d,J=8.6Hz,2H),4.80(d,J=2.3Hz,2H),2.54(t,J=2.3Hz,1H)。
化合物28を、本発明によるクリック化学に用いることができる。
1H NMR(400MHz,クロロホルム−d)δ=7.55(d,J=8.8Hz,2H),7.47(d,J=8.8Hz,2H),7.09(br.s,1H),2.38−2.14(m,6H),1.67−1.51(m,2H),1.42(quin,J=8.7Hz,1H),1.04−0.91(m,2H)
化合物29を本発明によるクリック化学(例えば、歪促進クリック)に用いることができる。
1H NMR(400MHz,クロロホルム−d)δ=7.41(d,J=8.4Hz,2H),7.36(d,J=8.4Hz,2H),4.50(d,J=5.5Hz,2H),1.89(t,J=5.5Hz,1H),0.25(s,9H)。
1H NMR(400MHz,クロロホルム−d)δ=7.55(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),0.27(s,9H)。
13C NMR(101MHz,クロロホルム−d)δ=133.2,132.2,126.9,117.1,105.3,103.4,99.4,82.3,64.5,−0.3。
1H NMR(400MHz,クロロホルム−d)δ=7.20(t,J=1.3Hz,1H),6.98(d,J=1.3Hz,2H),4.02(br.s.,2H)。
13C NMR(101MHz,クロロホルム−d)δ=147.1,127.5,121.6,119.5,105.0,81.0,63.6。
化合物31を本発明による再架橋(ジAPN)に用いることができる。
1H NMR(400MHz,クロロホルム−d)δ=7.84(d,J=8.2Hz,2H),7.60(d,J=8.2Hz,2H),1.36(s,12H)。
1,2−ジヨージドベンゼン(1当量、661mg、0.262mL、2mmol)およびプロパルギルアルコール(2.3当量、272μL、4.61mmol)のブチルアミン(15.8mL)脱気溶液にPd(PPh3)4(4%,92.6mg、0.0801mmol)を添加し、得られた反応塊を一晩還流した。溶媒を蒸発させ、得られた粗生成物をフラッシュクロマトグラフィ(20分、勾配EtOAc/シクロヘキサン)によって精製し、33a(150mg、0.8mmol、40%)を褐色がかった固体として生成した。
1H NMR(400MHz,メタノール−d4)δ7.38−7.53(m,2H),7.25−7.38(m,2H),4.48(s,4H);13C NMR(101MHz,メタノール−d4)d135.6,131.9,129.2,95.6,86.6,53.9;ESI−MS:C12H11O2 +[M+H]+,187.1;実測値187.1。
化合物を標準のMnO2酸化プロトコールの唯一の生成物として得た。反応時間:75分間。褐色固体、収率:42%。
1H NMR(400MHz,メタノール−d4)δ7.89(dd,J=3.30,5.80Hz,2H),7.73(dd,J=3.30,5.80Hz,2H);13C NMR(101MHz,メタノール−d4)δ136.0,133.5,126.5,105.5,80.2,67.2;GC−ESI−MS:C12H5N2 +[M+H]+,177.0;実測値177.0。
33aの合成と同じ手段。褐色がかった固体、収率:55%。
1H NMR(400MHz,メタノール−d4)δ7.47(s,1H),7.36−7.43(m,2H),7.29−7.36(m,1H),4.41(s,4H);13C NMR(101MHz,メタノール−d4)δ135.3,132.5,129.8,124.8,89.7,84.5,51.2;ESI−MS:C12H11O2 +[M+H]+,187.1;実測値187.0。
化合物を標準のMnO2酸化プロトコールの唯一の生成物として得た。反応時間:2時間。褐色固体、収率:35%。
1H NMR(400MHz,メタノール−d4)δ8.10(d,J=1.50Hz,1H),7.93(dd,J=1.50,8.00Hz,1H),7.63(t,J=8.00Hz,2H);13C NMR(101MHz,メタノール−d4)δ139.3,137.8,131.2,120.0,105.7,81.7,64.2;GC−ESI−MS:C12H5N2 +[M+H]+,177.0;実測値177.1。
33aの合成と同じ手段であるが、72時間還流。褐色がかった固体、収率:35%。
1H NMR(400MHz,メタノール−d4)δ7.39(s,4H),4.41(s,4H);13C NMR(101MHz,メタノール−d4)δ132.6,124.3,101.4,90.8,84.9,51.2;ESI−MS:C12H11O2 +[M+H]+,187.1;実測値187.1。
化合物を標準のMnO2酸化プロトコールの唯一の生成物として得た。反応時間:2時間。褐色固体、収率:19%。
1H NMR(400MHz,メタノール−d4)δ7.94(s,4H);13C NMR(101MHz,メタノール−d4)δ135.0,121.6,105.5,82.0,65.9;GC−ESI−MS:C12H5N2 +[M+H]+,177.0;実測値177.0。
化合物33〜35を本発明による再架橋(ジAPN)に用いることができる。
1H NMR(400MHz,クロロホルム−d)δ7.03−7.18(m,3H),6.82−7.03(m,2H),4.87(d,J=7.28Hz,1H),4.24(d,J=7.03Hz,1H),2.65−2.95(m,2H),1.17(s,9H),1.21(s,9H)。
13C NMR(101MHz,クロロホルム−d)δ170.5,148.5,137.3,131.3,121.1,120.3,117.1,82.5,80.0,54.7,38.1,28.3,27.9。
1H NMR(400MHz,メタノール−d4)δ7.30−7.45(m,J=7.78Hz,2H),7.14−7.30(m,J=8.03Hz,2H),4.40(s,2H),4.18−4.32(m,1H),3.06(dd,J=6.27,13.80Hz,1H),2.91(dd,J=8.66,13.68Hz,1H),1.45−1.53(m,1H),1.42(d,J=3.26Hz,19H)。
1H NMR(400MHz,クロロホルム−d)δ=7.54(d,J=8.2Hz,2H),7.24(d,J=8.2Hz,2H),5.05(d,J=7.3Hz,1H),4.46(td,J=6.1,7.3Hz,1H),3.14(dd,J=6.1,13.7Hz,1H),3.05(dd,J=6.1,13.7Hz,1H),1.42(s,9H),1.41(s,9H)。
13C NMR(101MHz,クロロホルム−d)δ=170.3,154.9,141.4,133.4,130.1,115.9,105.5,82.9,82.5,79.9,63.2,54.5,38.8,28.3,27.9。
化合物36を本発明による精製および/または固定化に用いることができる。
1H NMR(400MHz,メタノール−d4)δ=7.92(d,J=8.5Hz,2H),7.81(d,J=8.5Hz,2H),4.49(dd,J=4.8,7.8Hz,1H),4.30(dd,J=4.5,7.8Hz,1H),3.71−3.56(m,8H),3.54(t,J=5.5Hz,2H),3.34(t,J=5.5Hz,2H),3.24−3.14(m,1H),2.92(dd,J=4.8,12.8Hz,1H),2.70(d,J=12.8Hz,1H),2.19(t,J=7.4Hz,2H),1.78−1.50(m,4H),1.48−1.35(m,2H)。
13C NMR(101MHz,メタノール−d4)δ=176.3,168.8,166.2,138.9,135.0,129.1,121.5,105.9,83.1,71.5,71.4,70.7,70.6,64.6,63.5,61.8,57.1,41.2,40.4,36.9,29.9,29.6,27.0。
Boc−GABA(1当量、0.928g、4.57mmol)、TEA(3当量、1.39g、1.9mL、13.7mmol)およびDMAP(0.05当量、0.0279g、0.228mmol)の0℃に冷却したDCM(11.7mL)溶液に、EDC(1当量、0.875g、4.57mmol)を添加した。得られた反応塊をさらに10分間0℃で撹拌し、氷浴を除去し、p−ヨードアニリン(1当量、1g、4.57mmol)を添加し、反応物を25℃で一晩放置した。得られた反応塊を1M HCl(2×20mL)、水(1×20mL)で洗浄し、Na2SO4上で乾燥して38d(1125mg、2.79mmol、61%)を得、これをさらに精製することなく用いた。
1H NMR(400MHz,クロロホルム−d)δ9.04(br.s.,1H),7.58−7.72(m,J=8.50Hz,2H),7.37−7.51(m,J=8.50Hz,2H),4.81(br.s.,1H),3.27(m,2H),2.30−2.50(m,2H),1.88(m,2H),1.49(s,9H);13C NMR(101MHz,クロロホルム−d)δ174.2,157.4,137.8,120.9,120.0,87.3,77.0,33.1,32.8,28.4,26.0;ESI−MS:C15H22N2O3 +[M+H]+,405.0;実測値405.1。
薗頭カップリングのプロトコールBに従って合成した。黄色がかった固体、収率:79%。
1H NMR(400MHz,メタノール−d4)δ7.54−7.58(m,J=8.50Hz,2H),7.34−7.38(m,J=8.50Hz,2H),4.40(s,2H),3.13(t,J=6.90Hz,2H),2.41(t,J=7.40Hz,2H),1.81−1.89(m,2H),1.44(s,9H);13C NMR(101MHz,メタノール−d4)δ174.0,158.6,140.1,133.2,120.8,119.5,88.3,85.3,80.1,51.3,40.9,35.3,28.8,27.1;ESI−MS:C18H25N2O4 +[M+H]+,332.1;実測値332.0。
MnO2酸化のプロトコールを用いて合成した。反応時間:1時間。白色固体、収率:85%。
1H NMR(400MHz,メタノール−d4)δ7.61−7.65(m,J=8.80Hz,2H),7.54−7.59(m,J=8.50Hz,2H),3.04(t,J=6.85Hz,2H),2.34(t,J=7.40Hz,2H),1.74−1.81(m,2H),1.34(s,9H);13C NMR(101MHz,メタノール−d4)δ174.3,159.1,143.8,135.7,120.8,112.8,106.3,84.6,62.7,40.8,35.3,34.8,28.8,26.9;ESI−MS:C18H22N3O3 +[M+H]+,328.1;実測値328.1。
38b(1当量、62.8mg、0.192mmol)のDCM(1mL)懸濁液に、TFA(20当量、285μL、3.83mmol)を添加し、得られた25℃で30分間撹拌した。反応塊の蒸発後に標的生成物38a(TFA塩、65.0mg、0.19mmol、99%)を得、さらに精製することなく次の工程に用いた。
1H NMR(400MHz,メタノール−d4)δ7.71−7.79(m,J=9.15Hz,2H),7.63−7.70(m,J=9.15Hz,2H),3.04(t,J=6.80Hz,2H),2.6(t,J=7.05Hz,2H),1.98−2.08(m,2H);13C NMR(101MHz,メタノール−d4)δ173.1,143.6,135.7,120.7,112.9,106.2,84.5,62.7,40.4,34.5,24.0;ESI−MS:C13H14N3O+[M+H]+,228.1;実測値228.1。
38a(1当量、10.1mg、0.0296mmol)のDMF(250μL)溶液に、TEA(1当量、4μL、0.0296mmol)を添加した。TMPP−Ac−OSu(1当量、22.7mg、0.0296mmol)を得られた溶液に添加し、反応塊を15分間室温で。粗生成物をHPLCによって精製し、38(9.9mg、0.0126mmol、42%)を主生成物として単離した。
1H NMR(400MHz,メタノール−d4)δ7.44−7.59(m,4H),6.13(d,J=4.52Hz,6H),3.75(s,9H),3.50(s,18H),3.00(td,J=7.91,15.31Hz,2H),2.26(t,J=6.90Hz,2H),1.64−1.75(m,2H),1.25−1.43(m,2H);13C NMR(101MHz,メタノール−d4)δ174.2,167.4,167.4,165.3,143.6,135.8,120.6,112.8,106.3,92.2(d,J=8Hz),84.5,62.7,56.5,56.2,37.5,29.4(d,J=64Hz),27.9,27.7,24.9;ESI−HRMS:C42H47N3O11P+[M]+,800.29427;実測値800.29401。
5−ブロモペンタン酸(1当量、2.85g、15.7mmol)およびSOCl2(1当量、1.87g、1.14mL、15.7mmol)のDCM(50mL)脱気溶液を3時間還流した。得られた反応塊を減圧下で蒸発させて39d(3.11g、100%)を黄色がかった油として得た。粗生成物を精製することなく次の工程に用いた。
39d(1当量、3.11g、15.7mmol)のDCM(50mL)溶液を、4−ヨードアニリン(1当量、3.45g、15.7mmol)およびDIPEA(1当量、2.03g、2.6mL、15.7mmol)の−78℃に冷却したDCM(50mL)溶液に注いだ。得られた反応塊を室温まで加温させ、さらに30分間撹拌し、1N HCl(2x25mL)、水(1×25mL)で洗浄し、Na2SO4上で乾燥し、蒸発させて、39c(5.60g、14.66mmol、93%)を褐色固体として得た。
1H NMR(400MHz,メタノール−d4)δ7.62−7.66(m,2H),7.38−7.43(m,2H),3.50(t,J=6.53Hz,2H),2.42(t,J=7.28Hz,2H),1.81−1.98(m,4H),1.37−1.42(m,1H);13C NMR(101MHz,メタノール−d4)δ174.0,140.5,138.9,123.1,87.6,36.9,33.8,33.4,25.3;ESI−MS:C11H14BrINO+[M+H]+,381.9;実測値381.8。
薗頭カップリングのプロトコールAに従って合成した。褐色固体、収率:92%。
1H NMR(400MHz,メタノール−d4)δ7.49−7.63(m,J=8.53Hz,2H),7.32−7.43(m,J=8.53Hz,2H),4.40(s,2H),4.26(s,1H),3.50(t,J=6.53Hz,2H),2.43(t,J=7.15Hz,2H),1.90−2.04(m,2H),1.74−1.90(m,2H),1.32(s,1H);13C NMR(101MHz,メタノール−d4)δ173.9,140.0,133.1,120.7,119.6,88.2,85.2,51.2,36.8,33.7,33.3,25.3;ESI−MS:C14H17BrNO+[M+H]+,310.0;実測値310.0。
NH3(4当量、94.8mg、5.56mmol)のIPA溶液(2M)および無水MgSO4(15当量、2511mg、20.9mmol)を39b(1当量、431mg、1.39mmol)のTHF(3.42mL)撹拌溶液に添加した。この溶液に活性化したMnO2(15当量、1814mg、20.9mmol)を添加し、得られた混合物を室温で4時間撹拌し(TLCによって制御、さらなる出発アルコールなし;NB:反応時間が長すぎて加水分解生成物が得られた)、DCM(13mL)で希釈した。混合物を濾過し、DCMで完全に洗浄し、合わせた濾液を減圧下に濃縮させた。固体残渣をフラッシュクロマトグラフィ(EtOAc−シクロヘキサン、20分間勾配、0〜100%のEtOAc)によって精製し、39を白色固体として得た(288mg、0.946mmol、68%)。
1H NMR(400MHz,メタノール−d4)δ7.69−7.79(m,J=8.78Hz,2H),7.59−7.69(m,J=8.78Hz,2H),3.50(t,J=6.53Hz,2H),1.79−1.99(m,4H),1.26(t,J=7.15Hz,2H);13C NMR(101MHz,メタノール−d4)δ174.3,143.8,135.7,120.7,112.8,106.2,101.4,84.6,37.0,33.7,33.4,25.2。ESI−MS:C14H14BrN2O+[M+H]+,304.0;実測値304.0。
39a(1当量、20mg、0.0655mmol)およびトリス(2,4,6−トリメトキシ−フェニル)ホスファン(TMPP、1.2当量、41.9mg、0.0786mmol)を乾燥トルエン(1mL)に溶解し、室温で一晩撹拌した。39(TFA塩、22mg、39%)を逆相HPLC後に白色固体として得た。
1H NMR(400MHz,メタノール−d4)δ7.51−7.55(m,4H),6.13(d,J=4.77Hz,6H),3.75(s,9H),3.50(s,18H),3.00(td,J=6.90,15.31Hz,2H),2.26(t,J=6.90Hz,2H),1.73(m,2H),1.22−1.45(m,2H);13C NMR(101MHz,メタノール−d4)δ174.2,167.4,165.3,143.6,135.8,120.6,112.8,106.2,93.6,92.3,92.2,84.5,62.7,56.3,37.5,29.7,27.7,24.9;ESI−HRMS:C41H46N2O10P+[M]+,757.28846;実測値757.29552。
4−ヨード安息香酸(1当量、1.45g、5.85mmol)をSOCl2(9当量、3.8mL、52.6mmol)中110℃で完全に溶解するまで(およそ15分)加熱した。過剰のSOCl2を真空中で除去し、得られた固体をDCM(15mL)に注ぎ、−78℃に冷却し、DIPEA(3.1当量、3mL、18.2mmol)を激しい撹拌下に添加した。得られた反応塊に3−ブロモプロピルアミンヒドロブロミド(1.5当量、1.90g、8.77mmol)を添加し、−78℃で5分間撹拌したままにし、さらに20分間撹拌しながら室温まで加温させた。酢酸エチル(100mL)を1M HCl(5mL)と共に添加し、得られた固体を濾過し(生成物)、水で洗浄し、乾燥して40c(2.09g、5.67mmol、97%)を白色固体として生成した。
1H NMR(400MHz,メタノール−d4)δ7.85(m,J=8.40Hz,2H),7.58(m,J=8.40Hz,2H),3.48−3.56(m,4H),2.12−2.23(m,2H);13C NMR(101MHz,メタノール−d4)δ160.1,139.2,136.0,132.8,102.4,50.1,43.2,23.0;ESI−MS:C10H12BrINO+[M+H]+,367.9;実測値368.0。
薗頭カップリングのプロトコールBに従って合成した。褐色固体、収率:81%。
1H NMR(400MHz,メタノール−d4)δ7.73(m,J=8.40Hz,2H),7.38(m,J=8.40Hz,2H),4.37(t,J=5.30Hz,2H),4.34(s,2H),3.51(t,J=5.80Hz,2H),1.92−1.98(m,2H);13C NMR(101MHz,メタノール−d4)δ159.2,134.2,132.4,128.2,127.1,91.2,84.8,67.2,51.2,43.3,22.5;ESI−MS:C13H15BrNO2 +[M+H]+,295.0;実測値295.0。
MnO2酸化のプロトコールを用いて合成した。反応時間:45分間。褐色固体、収率:52%。
1H NMR(400MHz,メタノール−d4)δ7.90(m,J=8.50Hz,2H),7.80(m,J=8.50Hz,2H),3.42−3.55(m,2H),3.25−3.35(m,2H),2.13−2.23(m,2H),1.92−1.98(m,2H);13C NMR(101MHz,メタノール−d4)δ168.7,138.8,134.9,128.9,121.4,105.8,83.0,67.3,41.9,39.8,22.8;ESI−MS:C13H12BrN2O+[M+H]+,291.0;実測値291.2。
40a(1当量、30mg、0.103mmol)およびトリス(2,4,6−トリメトキシフェニル)ホスファン(TMPP、1当量、54.9mg、0.103mmol)を乾燥トルエン(2mL)に溶解させた。得られた溶液を室温で一晩放置した。沈殿を濾過し、DMSOに再溶解させ、HPLCによって精製し、40(35mg、0.0409mmol、40%)を白色固体として得た。
1H NMR(400MHz,メタノール−d4)δ7.75(d,J=8.50Hz,2H),7.69(d,J=8.50Hz,2H),6.16(d,J=4.70Hz,2H),3.76(s,9H),3.51(s,18H),3.35(t,J=7.10Hz,2H),2.98−3.10(m,2H),1.53−1.64(m,2H);13C NMR(101MHz,メタノール−d4)δ168.5,167.5,165.3,138.7,134.9,128.8,121.2,105.8,94.0,92.9,92.3,82.9,64.5,56.5,41.7,27.8,25.7;ESI−HRMS:C40H44N2O10P+[M]+,743.22728;実測値743.23946。
化合物38〜40を本発明による検出および/または分離方法に用いることができる。
7(1当量、76.8mg、0.541mmol)のアセトン(2mL)溶液に、無水マレイン酸(2当量、106mg、1.08mmol)を添加した。約7時間の撹拌後、黄色がかった固体を得た。反応塊を蒸発させ、過剰の無水マレイン酸およびマレイン酸をメタノールで洗浄した。41a(127mg、0.53mmol、98%)を黄色がかった固体として得、さらに精製する必要はなかった。
1H NMR(400MHz,DMSO−d6)δ12.90(br.s.,1H),10.70(s,1H),7.62−7.90(m,4H),6.50(d,J=11.90Hz,1H),6.34(d,J=11.90Hz,1H);13C NMR(101MHz,DMSO−d6)δ166.8,163.8,142.4,135.0,131.7,130.1,119.3,110.2,105.6,84.3,61.9;ESI−MS:C13H7N2O3 −[M−H]−,239.0;実測値239.0。
41a(1当量、75mg、0.312mmol)の乾燥DMF(1.21mL)溶液に、無水トリフルオロ酢酸(2当量、86.9μL、0.624mmol)を添加した。室温でさらに5分間撹拌を継続し、K2CO3(3当量、129mg、0.937mmol)を添加した。反応塊をさらに60分間撹拌し、次いでHPLCによって直接精製し、41(65.9mg、0.297mmol、95%)を僅かに黄色の固体として得た。
1H NMR(400MHz,DMSO−d6)δ7.81(m,J=8.50Hz,2H),7.52(m,J=8.50Hz,2H),6.96(s,2H);13C NMR(101MHz,DMSO−d6)δ169.0,134.4,134.0,126.0,117.3,117.0,82.2,78.5,62.3;ESI−MS:C13H7N2O2 +[M+H]+,223.0;実測値229.9。
化合物41を本発明によるバイオコンジュゲーション法に用いることができる。
7(1当量、200mg、1.41mmol)のアセトン(1mL)溶液に、無水グルタル酸(2当量、321mg、2.81mmol)を添加した。得られた溶液を24時間室温で撹拌した。アセトンを蒸発させ、粗生成物をIPA−シクロヘキサンから再結晶し、42a(324mg、1.27mmol、90%)を灰色固体として得た。
1H NMR(400MHz,DMSO−d6)δ10.21(s,1H),8.15(br.s.,1H),7.60(d,J=8.72Hz,2H),7.52(d,J=8.72Hz,2H),2.52−2.62(m,4H),2.22−2.32(m,2H);13C NMR(101MHz,DMSO−d6)δ170.0,168.5,140.9,134.2,119.0,111.9,105.4,84.1,63.3,30.1,29.0,21.2;ESI−MS:C14H11N2O3 −[M−H]−,255.1;実測値255.1。
42a(1当量、18mg、0.0702mmol)のDCM(1mL)溶液に、DCC(1.02当量、14.8mg、0.0716mmol)およびTEA(1当量、6.52mg、0.00895mL、0.0644mmol)を添加した。得られた反応塊を5分間撹拌し、NHS(1当量、8.08mg、0.0702mmol)を添加した。得られた溶液をさらに2時間室温で撹拌した。粗生成物をフラッシュクロマトグラフィ(シクロヘキサン−EtOAc)によって精製し、42(6.45mg、0.0183mmol、26%)を白色固体として得た。
1H NMR(400MHz,クロロホルム−d)δ8.27(br.s.,1H),7.64(d,J=8.78Hz,2H),7.57(d,J=8.78Hz,2H),2.94(s,4H),2.74(t,J=6.53Hz,2H),2.52(t,J=6.90Hz,2H),2.23(m,2H);13C NMR(101MHz,クロロホルム−d)d170.3,169.5,168.2,141.3,134.6,119.4,112.4,105.7,83.2,62.9,35.6,29.9,25.7,21.2;ESI−MS:C18H16N3O5 +[M+H]+,353.1;実測値353.2。
化合物42を本発明によるバイオコンジュゲーション法に用いることができる。
1H NMR(400MHz,アセトニトリル−d3)δ7.58−7.81(m,J=8.78Hz,2H),7.11−7.26(m,J=8.78Hz,2H);13C NMR(101MHz,アセトニトリル−d3)δ144.9,136.0,120.4,113.6,105.9,83.4,62.9;GC−ESI−MS:C9H5N4 +[M+H]+,169.0;実測値169.0。
5−アジドペンタン酸(1当量、1.1g、6.99mmol)をSOCl2(10当量、5.1mL、69.9mmol)中で30分間還流した。過剰のSOCl2を真空中で除去し、得られた粗固体を精製することなく次の工程に用いた。
7(1当量、16.1mg、0.113mmol)およびTEA(1.5当量、24μL、0.17mmol)をDCM(3mL)に溶解させ、−78℃に冷却し、44a(1.1当量、20.1mg、0.125mmol)を反応混合物に添加し、次いで、これを、さらに1時間撹拌しながら室温まで加温させた。反応塊を1M HCl(2×1mL)、水(2mL)で洗浄し、Na2SO4上で乾燥し、蒸発させて粗生成物を得、これををフラッシュクロマトグラフィによって精製し、44(25.5mg、0.101mmol、89%)を灰色固体として得た。
1H NMR(400MHz,メタノール−d4)δ7.58−7.67(m,J=8.70Hz,2H),7.40−7.58(m,J=8.70Hz,2H),3.23−3.28(m,2H),2.34(t,J=7.28Hz,2H),1.61−1.72(m,2H),1.49−1.61(m,2H);13C NMR(101MHz,メタノール−d4)δ173.0,144.0,135.7,134.3,120.7,113.0,106.2,84.5,40.4,34.4,28.8,24.0;ESI−MS:C14H14N5O+[M+H]+,268.1;実測値268.1。
薗頭カップリングのプロトコールAを用いて合成した。黄色がかった固体、収率:88%。
1H NMR(400MHz,アセトニトリル−d3)δ7.25−7.49(m,J=8.03Hz,2H),7.04−7.25(m,J=8.03Hz,2H),4.34(d,J=6.02Hz,2H),3.31(t,J=6.02Hz,1H),2.32(s,3H);13C NMR(101MHz,アセトニトリル−d3)δ139.8,132.4,130.3,120.8,88.8,85.1,51.2,21.5;ESI−MS:C10H11O+[M+H]+,146.1;実測値146.0。
化合物を標準のMnO2酸化プロトコールの唯一の生成物として得た。反応時間:3時間。白色固体、収率:67%。
1H NMR(400MHz,メタノール−d4)δ7.37−7.59(m,J=8.03Hz,2H),7.02−7.31(m,J=8.03Hz,2H),2.29(s,3H);13C NMR(101MHz,メタノール−d4)143.2,133.3,129.5,114.0,104.8,83.2,61.3,20.4;ESI−MS:C10H8N+[M+H]+,141.1;実測値141.0。
45b(1当量、68mg、0.482mmol)のDCM(1mL)脱気溶液を5分間MW照射した(100℃)。反応混合物を蒸発させ、粗生成物を分取HPLCによって精製し、45a(42.4mg、0.193mmol、40%)を黄色がかった固体として得た。
1H NMR(400MHz,クロロホルム−d)δ7.56−7.71(m,J=8.28Hz,2H),7.40−7.49(m,J=8.28Hz,2H),4.48(s,2H);13C NMR(101MHz,クロロホルム−d)141.8,133.9,129.5,117.5,105.3,82.3,63.7,31.8;GC−ESI−MS:C10H7BrN+[M+H]+,219.0;実測値219.0。
45a(1当量、43.7mg、0.199mmol)およびTMTH(1.29当量、43mg、0.255mmol;上述の手順831に従って合成した)のDCM(1.34mL)脱気溶液に、LiOTf(11.6当量、360mg、2.31mmol)の蒸留かつ脱気したH2O(0.668mL)溶液を添加した。得られた二相混合物を25℃で5日間激しく撹拌した(1日に1回脱気)。二相を分離し、有機相をDCM(5×2mL)で洗浄した。合わせた有機分を蒸発させ、粗生成物をHPLCによって精製し、45(46.9mg、0.111mmol、56%)を無色油として得た(0℃でゆっくりと結晶化して白色固体を生成した)。
1H NMR(400MHz,クロロホルム−d)δ7.65−7.73(m,J=8.03Hz,2H),7.56−7.65(m,J=8.03Hz,2H),5.07(s,2H),4.12(d,J=12.30Hz,2H),3.72(d,J=12.30Hz,2H),1.36(s,6H),1.30(s,6H);13C NMR(101MHz,DMSO−d6)δ135.1,133.6,131.9,117.8,106.4,105.8,83.3,63.6,60.1,43.2,34.6,26.4,25.4;HR−ESI−MS:C20H22NS+[M]+,308.1;実測値308.1。
化合物43〜45を本発明によるクリック化学(例えば、反応クリック−アジド)に用いることができる。
化合物45を本発明による歪促進クリックに用いることができる。
TAMRA−5’−COOH(1当量、68.3mg、0.159mmol)のDMF(0.228mL)溶液に、HATU(1当量、60.3mg、0.159mmol)、DIPEA(6当量、123mg、0.157mL、0.952mmol)および二塩化シスタミン(5当量、178mg、0.793mmol)を続けて添加した;得られた溶液塊を一晩撹拌した。DTT(5当量、122mg、0.118mL、0.793mmol)のDCM(0.911mL)溶液を反応塊に添加し、撹拌を2時間継続させた。溶媒を蒸発させた;得られた粗塊をHPLCによって精製し、46a(33.5mg、0.0555mmol、35%)を暗紫色固体として生成した。
1H NMR(400MHz,DMSO−d6)δ9.06(t,J=5.4Hz,1H,8.70(d,J=1.8Hz,1H),8.30(dd,J=1.8,8.0Hz,1H),7.59(d,J=8.0Hz,1H),7.08−7.02(m,4H),6.95(s,2H),3.52−3.42(m,2H),3.26(s,12H),2.72(dt,J=6.8,8.0Hz,2H);13C NMR(101MHz,DMSO−d6)δ166.0,164.7,156.8,156.6,135.9,131.2,130.6,114.6,96.3,42.9,40.5,23.3;HR−ESI−MS:C27H27N3O4S:489.1722;実測値489.1723。
45(1当量、6.74mg、0.016mmol)のACN(1mL)溶液を46a(1当量、9.64mg、0.016mmol)のDMF(1mL)溶液と混合させた。次いでDIPEA(5当量、132μL、0.08mmol)を添加し、得られた反応塊を5分の反応後にHPLCに注入し、46(11.9mg、0.0149mmol、93%)を暗紫色固体として生成した。
1H NMR(400MHz,DMSO−d6)δ8.98(t,J=5.40Hz,1H),8.30(d,J=8.28Hz,1H),8.10−8.20(m,1H),7.85(s,1H),7.57−7.69(m,4H),6.97−7.15(m,5H),6.07(s,1H),4.85(s,2H),2.81−2.90(m,4H),3.28(br.s.,16H),1.25(s,6H),1.05(s,6H);13C NMR(101MHz,DMSO−d6)−情報なし(低い分割シグナル);HR−ESI−MS:C47H49N4O4S2 +,797.31897;実測値797.32739。
塩化ダブシル(1当量、100mg、0.309mmol)の0℃に冷却した乾燥ACN(3mL)溶液に、TEA(7当量、218mg、0.3mL、2.16mmol)および二塩酸シスタミン(5当量、347mg、1.54mmol)を続いて添加した。2時間の撹拌後、DTT(6当量、285mg、0.275mL、1.85mmol)を反応塊に添加した。得られた溶液をさらに2時間撹拌し、蒸発させ、得られた粗生成物をフラッシュクロマトグラフィ(シクロヘキサン−EtOAc)によって精製して47a(105.9mg、94%)を橙色固体として生成した。
46の合成と同じ手順。収率:94%。
1H NMR(400MHz,DMSO−d6)δ8.03(t,J=4.89Hz,1H),7.91(d,J=8.53Hz,2H),7.80−7.87(m,J=9.04Hz,2H),7.72−7.79(m,J=8.53Hz,2H),7.68(s,4H),6.87(d,J=9.04Hz,2H),6.08(s,1H),4.86(s,2H),3.92(d,J=12.05Hz,2H),3.84(d,J=12.30Hz,2H),3.10(s,6H),2.71−2.87(m,4H),1.32(s,6H),1.17(s,6H);13C NMR(101MHz,DMSO−d6)δ160.2,158.6,158.3,155.1,153.7,143.1,140.3,136.8,131.9,131.3,129.5,128.2,125.9,122.8,117.2,112.1,106.4,99.4,60.0,43.3,42.9,34.5,26.4,25.3;HR−ESI−MS:C36H42N5O2S3 +,672.24951;実測値672.25042。
化合物46〜47を、他の場合には到達可能でない化合物(TMTI)の調製に用いることができる。
この化合物を、先に報告したプロトコールに従って合成した。
48a(1当量、10mg、0.0123mmol)および77(1当量、3.12mg、0.0123mmol)のDMSO(0.472mL)溶液に、アスコルビン酸ナトリウム(10当量、24.4mg、0.123mmol)およびCuSO4・5H2O(5当量、15.4mg、0.0617mmol)の水溶液を添加した。得られた反応塊を脱気し、25℃で一晩撹拌した。反応塊をHPLCによって直接精製し、48(8.3mg、0.0078mmol、63%)を黄色固体として得た。
1H NMR(400MHz,メタノール−d4)δ7.78(br.s.,2H),7.72(d,J=8.28Hz,1H),7.67(s,1H),7.58(d,J=8.78Hz,2H),7.50(d,J=8.78Hz,2H),7.29(d,J=8.28Hz,1H),7.25(d,J=8.53Hz,1H),6.29(d,J=7.78Hz,1H),3.70−3.81(m,8H),3.62(d,J=4.77Hz,2H),3.58(d,J=5.02Hz,2H),3.48−3.53(m,2H),3.41−3.48(m,2H),3.01−3.07(m,6H),2.89−3.00(m,10H),2.78(dd,J=4.89,12.93Hz,1H),2.52−2.67(m,8H),2.33(t,J=7.28Hz,2H),2.09−2.19(m,2H),1.81−1.91(m,4H),1.65−1.78(m,2H),1.52−1.63(m,2H),1.42−1.52(m,1H),1.23−1.31(m,1H);HR−ESI−MS:C56H67N11O11S,1077.47422;実測値1077.45931。
VasselおよびSkelly(10.1002/0471264180.os035.09)によって先に記載されているように合成した。
3−(4−アミノフェニル)プロプ−2−インニトリル(1当量、66.3mg、0.466mmol)およびDIPEA(1.1当量、66.3mg、0.0848mL、0.513mmol)のDMF(1mL)溶液に、(2−クロロ−2−オキソエチル)トリメチルアザニウムクロリド(1.1当量、88.3mg、0.513mmol)の−20℃に冷却したDMF(1mL)溶液を添加した。得られた反応塊を25℃で10時間撹拌し、RPフラッシュクロマトグラフィによって精製し、49を黄色がかった固体として得た(39mg、0.110mmol、24%)。
1H NMR(400MHz,アセトニトリル−d3)δ11.14(br.s.,1H),7.70−7.83(m,J=8.78Hz,2H),7.56−7.70(m,J=8.78Hz,2H),4.33(s,2H),3.28(s,9H);13C NMR(101MHz,アセトニトリル−d3)δ163.5,142.5,135.8,121.2,113.5,106.5,84.4,66.3,63.1,55.2;ESI−MS:C14H16N3O+[M]+,242.13;実測値242.13。
1H NMR(400MHz,アセトニトリル−d3)δ8.41(s,1H),7.95−8.02(m,2H),7.88−7.94(m,2H),6.86(d,J=7.78Hz,1H),4.71(s,2H),4.49(td,J=6.71,8.41Hz,1H),3.68−3.76(m,3H),3.49−3.68(m,21H),2.53−2.64(m,5H),1.97(td,J=2.42,4.96Hz,15H);13C NMR(101MHz,アセトニトリル−d3)δ188.7,173.3,161.6,146.5,135.1,131.3,130.8,122.5,121.0,117.9,115.4,64.2,40.4,39.5,36.7,30.6;ESI−MS:C28H34N5O10 −[M−H]−,600.21;実測値600.23。
ESI−HRMS:C60H103N9O22,1301.72177;実測値1301.72204。
1H NMR(400MHz,アセトニトリル−d3)δ8.42(s,1H),7.95−8.02(m,J=9.03Hz,2H),7.86−7.95(m,J=8.78Hz,2H),7.30(br.s.,2H),7.19(br.s.,1H),4.71(s,2H),3.73−3.79(m,2H),3.65−3.73(m,7H),3.54−3.65(m,29H),3.51(t,J=5.40Hz,2H),3.34(q,J=5.35Hz,2H),3.13(d,J=4.52Hz,2H),2.37−2.46(m,2H),1.92−2.01(m,5H);13C NMR(126MHz,クロロホルム−d)δ177.5,151.3,144.6,140.7,140.7,140.6,127.2,126.0,125.9,125.8,122.4,110.5,87.2,75.4,75.3,75.3,75.2,75.2,75.1,75.1,75.1,75.0,74.9,74.8,74.8,72.2,71.9,68.9,68.5,45.0,44.2,41.6;ESI−MS:C35H55N6O11 +[M+H]+,735.39;実測値735.20。
1H NMR(400MHz,メタノール−d4)δ7.45−7.50(m,2H),7.41−7.45(m,2H),3.23−3.25(m,1H),3.04−3.11(m,2H),2.80(s,6H),1.77−1.91(m,2H);13C NMR(101MHz,メタノール−d4)δ156.5,143.7,134.4,118.0,109.3,105.0,83.7,61.0,55.2,42.1,35.9,25.3;ESI−MS:C15H20N4O+[M+H]+,271.16;実測値271.15。
1H NMR(400MHz,酸化重水素)δ7.45−7.67(m,2H),7.33(br.s.,2H),3.61(br.s.,4H),3.53(br.s.,1H),3.39(br.s.,2H),3.31(br.s.,2H),3.25(br.s.,2H),3.03(br.s.,7H),2.89(br.s.,7H),2.13(br.s.,1H),1.89(br.s.,7H),1.08(br.s.,2H);ESI−HRMS:C18H24N4O4S,392.15183;実測値392.15254。
化合物49〜54を、例えばADMEパラメータを変更するための(可溶化剤)本発明によるコンジュゲーション法に用いることができる。
1H NMR(400MHz,MeOD)δ8.58(s,1H),8.04(d,J=7.4Hz,2H),7.93(d,J=7.4Hz,2H),4.77(s,2H);ESI−MS:C12H9N4O+[M+H]+,225.08;実測値225.05。
1H NMR(400MHz,アセトニトリル−d3)δ8.44(s,1H),7.78−8.03(m,5H),4.74(s,2H);13C NMR(101MHz,クロロホルム−d)δ150.9,144.3,140.6,140.5,126.0,125.9,110.4,87.1,68.5,27.0;ESI−MS:C12H8BrN4 +[M+H]+,286.99;実測値287.08。
化合物56を本発明によるバイオコンジュゲーション法に用いることができる。
ESI−HRMS:C22H23N4S,375.16434;実測値375.16497。
化合物57を本発明によるクリック化学(歪促進クリック)に用いることができる。
1H NMR(400MHz,メタノール−d4)δ8.51(s,1H),8.33(d,J=8.28Hz,1H),8.16(dd,J=1.51,8.28Hz,1H),7.86−8.02(m,2H),7.64−7.86(m,3H),7.02−7.12(m,2H),6.84−7.02(m,4H),4.58−4.71(m,2H);ESI−HRMS:C37H29N7O4,635.22811;実測値635.22861。
ESI−HRMS:C21H17F3N2O5S,466.08103;実測値466.08221。
ESI−HRMS:C23H20N2O3,372.14739;実測値372.14735。
1H NMR(400MHz,クロロホルム−d)δ8.91(s,1H),8.26(d,J=8.03Hz,1H),7.79(dd,J=1.51,8.03Hz,1H),7.62(d,J=9.29Hz,1H),6.74(dd,J=2.63,9.16Hz,1H),6.51(d,J=2.51Hz,1H),6.35(s,1H),5.31(s,2H),3.49(q,J=7.11Hz,4H),1.09−1.36(m,6H);ESI−HRMS:C23H17N3O2,367.13208;実測値367.13145。
1H NMR(400MHz,クロロホルム−d)δ7.91(d,J=9.03Hz,2H),7.82−7.88(m,J=8.53Hz,2H),7.62−7.77(m,J=8.53Hz,2H),6.77(d,J=9.03Hz,2H),3.08−3.18(m,6H);13C NMR(101MHz,クロロホルム−d)δ154.7,153.2,143.7,134.4,125.8,122.5,117.3,111.6,105.6,83.3,64.2,40.3;ESI−HRMS:C17H14N4,274.12185;実測値274.12247。
化合物58〜60を、本発明による検出方法方法に用いることができる。
1H NMR(400MHz,クロロホルム−d)δ7.97(s,1H),7.74−7.81(m,J=8.78Hz,2H),7.67−7.74(m,J=8.78Hz,2H),4.41(d,J=6.02Hz,2H),1.32−1.41(m,9H);13C NMR(101MHz,クロロホルム−d)δ139.0,135.1,120.4,117.8,107.2,105.1,81.3,64.5,28.4;ESI−MS:C17H18N5O2 +[M+H]+,323.14;実測値323.13。
1H NMR(400MHz,メタノール−d4)δ8.74(s,1H),7.99−8.15(m,2H),7.85−7.97(m,2H),4.25−4.45(m,2H);13C NMR(101MHz,メタノール−d4)δ141.2,138.9,135.2,122.3,120.3,117.7,104.4,81.1,62.9,34.0;ESI−MS:C12H10N5 +[M]+,227.09;実測値227.10。
ESI−HRMS:C21H12F3N7O,435.10554;実測値435.10512。
化合物63を、例えばタンパク質の光標識のための本発明による標識方法に用いることができる。
1H NMR(400MHz,メタノール−d4)δ7.74−7.84(m,J=8.53Hz,2H),7.58−7.74(m,J=8.53Hz,2H),3.60(t,J=6.78Hz,2H),3.23−3.35(m,2H),2.85(t,J=6.78Hz,2H),2.71(t,J=6.90Hz,2H),1.32(s,9H);13C NMR(101MHz,メタノール−d4)δ167.3,157.0,137.3,133.5,127.5,120.1,104.4,81.5,78.8,63.1,39.3,39.1,37.8,27.4,26.6;ESI−MS:C19H24N3O3S2 +[M+H]+,406.12;実測値406.10。
ESI−HRMS:C14H16N3OS2 +,306.07293;実測値306.07312。
ESI−HRMS:C28H35N9O7 +,609.26594;実測値609.26417。
化合物66をキレート剤として用いることができる。
FastBlackKヘミ(塩化亜鉛)塩(実用等級、約30%の染料分)(7.76g)を冷水(150.0mL、0℃)に懸濁させ、20分間撹拌した。懸濁液を濾過し、赤色溶液を、水アセトン混合物(1:1)(150.0mL)中の4−(メチル(フェニル)アミノ)ブタン酸(1.33g、6.88mmol)、濃塩酸(3.1mL)および酢酸ナトリウム(3.6g、43.90mmol)の冷(0℃)混合物に滴加した。反応混合物を10℃で15分間および室温で2時間撹拌した。次いで、反応粗生成物を酢酸エチル(3×150mL)で抽出し、合わせた有機層をNa2SO4上で乾燥した。粗生成物をシリカゲル上のカラムクロマトグラフィ(100%EtOAc、次いで100%DCM〜DCM/MeOH(95:5))によって精製した。BHQ−2(1.36g、39%)を暗紫色固体として得た。
1H NMR(400MHz,メタノール−d4)δ8.31(d,J=9.0Hz,2H),8.00(d,J=9.0Hz,2H),7.86(d,J=9.0Hz,2H),7.45(s,1H),7.40(s,1H),6.77(d,J=9.0Hz,2H),4.05(s,3H),4.00(s,3H),3.5(t,J=7.1Hz,2H),2.36(t,J=7.1Hz,2H),1.98−1.90(m,2H);13C NMR(101MHz,メタノール−d4)δ176.2,157.1,154.3,153.0,151.4,149.0,147.4,145.0,142.6,126.9,125.3,124.2,112.1,101.7,100.7,57.2,52.3,39.0,31.6,22.9。
BHQ−2(1当量、92.2mg、0.182mmol)をDMF(5mL)およびDCM(10mL)の混合物に溶解させた。TEA(6当量、152μL、1.09mmol)および二塩化シスタミン(5当量、204mg、0.91mmol)を添加した。混合物を0℃に冷却し、HBTU(1当量、69mg、0.182mmol)を添加した。溶液を室温に到達させ、15時間撹拌した。全て転換したら、DTT(6当量、168mg、0.162mL、1.09mmol)を添加した。得られた混合物を室温で10分間撹拌した後、粗生成物を飽和NaHCO3溶液(75mL)で希釈し、EtOAc(2×50mL)で抽出した。有機層を合わせ、水(50mL)、塩水(50mL)で洗浄し、Na2SO4上で乾燥した。粗生成物をシリカゲル上のカラムクロマトグラフィ(DCM/MeOH、100:0〜95:5)によって精製して(BHQ−2)−SH(60.7mg、0.107mmol、59%)を暗紫色固体として生成した。
1H NMR(400MHz,クロロホルム−d)δ8.33(d,J=9.0Hz,2H),8.0(d,J=9.1Hz,2H),7.9(d,J=9.1Hz,2H),7.42(s,1H),7.42(s,1H),6.75(d,J=9.00Hz,2H),5.90(t,J=5.6Hz,1H),4.06(s,3H),4.01(s,3H),3.49(t,J=7.4Hz,2H),3.41(dt,J=6.2,6.4Hz,2H),2.64(td,J=6.4,8.47Hz,2H),2.24(t,J=7.4Hz,2H),2.01−1.94(m,2H);13C NMR(101MHz,クロロホルム−d)δ172.2,156.6,153.8,152.4,151.1,148.5,147.0,144.7,142.3,126.4,124.9,123.7,111.6,101.2,100.3,57.0,56.9,51.8,42.5,38.7,33.4,24.9,23.0;HR−ESI−MS:C27H31N7O5S,565.2107;実測値565.2105。
62a(1当量、17.3mg、0.0507mmol)およびTAMRA−5’−COOH(1当量、21.8mg、0.0507mmol)の0℃に冷却したDMF(1.4mL)脱気溶液に、HBTU(1当量、19.2mg)を0℃で添加した。得られた反応塊を5分間撹拌し、TEAを添加した。反応塊を25℃で1時間撹拌し、蒸発させ、HPLCによって精製し、65a(22mg、68%)を暗紫色固体として生成した。
1H NMR(400MHz,メタノール−d4)δ8.8(br.s,1H),8.7(s,1H),8.08−8.16(d,J=8.2Hz,1H),7.60−7.70(d,J=8.9Hz,2H),7.49−7.58(d,J=8.9Hz,2H),7.32−7.39(d,J=8.2,1H),δ7.01(s,4H),6.93(s,2H),3.48−3.58(m,2H),3.26(s,12H),2.44−2.54(t,J=7.17Hz,2H),1.98−2.12(m,2H);13C NMR(101MHz,メタノール−d4)−情報なし;HR−ESI−MS:639.24817;実測値639.24310。
BHQ−SH(1.13当量、2mg、0.00354mmol)のDCM(0.5mL)脱気溶液に、67(1当量、2mg、0.00313mmol)のメタノール(0.5mL)脱気溶液を添加した。TEA(4.6当量、2μL、0.0144mmol)を添加し、得られた反応塊を25℃で一晩放置した。溶媒を蒸発させ;粗生成物をDMSO(0.5mL)に再溶解させ、HPLCによって精製し、BHQ−APN−TAMRA(A,2.7mg、0.00225mmol、72%)を暗紫色固体として得た。
1H NMR(400MHz,メタノール−d4)δ8.63(d,J=2.0Hz,1H),8.34(d,J=8.8Hz,2H),8.22(dd,J=7.8,2.0Hz,1H),8.00(d,J=8.8Hz,2H),7.75(d,J=9.0Hz,2H),7.69(d,J=8.5Hz,2H),7.53(d,J=8.0Hz,1H),7.39(d,J=8.5Hz,2H),7.34(d,J=9.0Hz,2H),6.75−6.86(m,8H),5.48(s,1H),4.02(s,3H),3.92(s,3H),3.58−3.63(m,2H),3.45−3.52(m,2H),3.21(s,12H),3.16(t,J=6.9Hz,2H),3.08(s,3H),2.71(t,J=6.5Hz,2H),2.55(t,J=6.2Hz,2H),2.22(t,J=6.9Hz,2H),2.08−2.16(m,2H),1.88−1.96(m,2H),1.61(br.s,1H);13C NMR(101MHz,メタノール−d4)−情報なし;HR−ESI−MS:C65H65N12O10S+[M+H]+,1205.46618;実測値1205.46748。
この化合物を先に記載した手順に従って合成した。845
B−4(1当量、1.76g、10.7mmol)およびN−(3−ブロモプロピル)カルバミン酸tert−ブチル(2当量、5.07g、21.3mmol)のDMF(20mL)溶液に、K2CO3(1.2当量、1.77g、12.8mmol)を添加した。得られた反応塊を50℃で18時間加熱した。溶液を冷却させ;固体残渣を濾過してDMFで洗浄した。合わせた有機分を蒸発させ、ヘキサン(50mL)を添加してスラリー塊を得た。得られた懸濁液をさらなる時間にわたって撹拌し、濾過し、ヘキサンで洗浄してB−3(3.36g、10.4mmol、98%)を白色固体として得た。
1H NMR(400MHz,クロロホルム−d)δ6.49(s,2H),5.23(s,2H),3.52(t,J=6.5Hz,2H),2.96−3.09(m,2H),2.82(s,2H),1.66−1.75(m,2H),1.41(s,9H);13C NMR(101MHz,クロロホルム−d)δ176.5,155.9,136.5,81.0,79.3,47.5,37.1,36.0,28.4,27.8。
66c(1当量、243mg、0.754mmol)のトルエン(25mL)溶液を3時間還流した。トルエンを蒸発させ;得られた白色粗生成物をDCM(5mL)に再溶解させ、TFA(0.5mL)を添加した。撹拌を出発物質が完全に消失するまで(TLCによって制御)2時間継続させた。メタノール(3mL)によって反応をクエンチした後、溶媒を蒸発させた。得られた1−(3−アミノプロピル)−1H−ピロール−2,5−ジオン(B−2、TFA塩、190mg、94%)をさらに精製することなく用いた。
1H NMR(400MHz,メタノール−d4)δ6.76(s,2H),3.52(t,J=6.7Hz,2H),2.80−2.88(m,2H),1.76−1.88(m,2H);13C NMR(101MHz,メタノール−d4)δ170.6,135.6,38.5,35.4,28.0。
TAMRA−5’−COOH(1当量、71.5mg、0.166mmol)のDMF(3.21mL)溶液に、TEA(2.5当量、57.7μL、0.415mmol)およびHATU(1.12当量、70.7mg、0.186mmol)を添加した。得られた反応塊をさらに5分間撹拌し、B−2(1当量、71.5mg、0.166mmol)を添加した。撹拌を25分間継続し、反応塊を約1mLの体積になるまで減圧下で蒸発させ、反応塊を分取HPLCによって精製してTAMRA−マレイミド(B−1、34.8mg、0.0615mmol、37%)を桃色固体として得た。
1H NMR(400MHz,メタノール−d4)δ8.66(d,J=1.8Hz,1H),8.14(dd,J=1.8,8.0Hz,2H),7.41(d,J=8.0Hz,2H),7.02(d,J=9.5Hz,1H),6.92(dd,J=9.5,2.2Hz,2H),6.81(d,J=2.2Hz,2H),6.72(s,2H),3.52(t,J=6.8Hz,2H),3.34(t,J=7.0Hz,2H),3.17(s,12H),1.80−1.90(m,2H);13C NMR(101MHz,メタノール−d4)δ172.5,168.2,167.4,160.6,159.0,158.9,138.1,137.7,137.6,135.5,132.9,132.3,132.0,131.4,115.6,114.8,97.5,82.4,41.0,38.6,36.4,29.3。HR−ESI−MS:C32H30N4O6,566.21653;実測値566.21654。
BHQ−SH(1.15当量、4.6mg、0.00812mmol)のDCM(0.5mL)脱気溶液に、TAMRA−マレイミド(B−1)(1当量、4mg、0.00313mmol)のメタノール(0.5mL)脱気溶液を添加した。TEA(5当量、5μL、0.0353mmol)を添加し、得られた反応塊を25℃で一晩放置した。溶媒を蒸発させ;粗生成物をDMSO(0.5mL)に再溶解し、HPLCによって精製してB(7mg、0.00621mmol、88%)を暗紫色固体として得た。
1H NMR(400MHz,DMSO−d6)δ8.91(t,J=6.1Hz,1H),8.68(s,1H),8.43(d,J=9.1Hz,2H),8.31(d,J=8.9Hz,1H),8.01−8.10(m,3H),7.77(d,J=9.1Hz,2H),7.60(d,J=7.8Hz,1H),7.39(s,1H),7.33(s,1H),6.99(s,3H),6.89(s,1H),6.85(d,J=9.1Hz,2H),4.04(dd,J=3.9,8.9Hz,1H),3.98(s,3H),3.92(s,3H),3.41−3.45(m,2H),3.27−3.38(m,6H),3.23(m,12H),3.06(s,3H),2.85−2.95(m,1H),2.72−2.81(m,1H),2.52−2.56(m,2H),2.17(t,J=7.3Hz,2H),1.74−1.88(m,4H)。HR−ESI−MS:C59H62N11O11S+[M+H]+,1132.43455;実測値1132.43384。
985μLのPBS(1×、pH7.6)を含有するバイアルに、5μLのベンズアミド原液(水中10mM)、5μLのアリールプロピオニトリル原液(1−12、DMSO中10mM)および5μLのAcCysNHBn原液(7m、DMSO中10mM)を続けて添加した。反応混合物(50μL)のアリコートをHPLC(反応の0および30分で注入)によって分析した。出発物質および加水分解生成物のピーク下の面積を内部標準のピークの面積に従って正規化した。
得られた結果を以下の表2にまとめる。表2は、50μMの濃度の各試薬において25℃で7mの存在下に30分での化合物1〜12の転化率を提示する。反応は、プロピオニトリル基に対してオルト位の置換基に由来する立体障害(エントリー1、5、8〜9、4)、ならびに置換基:−Iおよび−M置換基;の電子効果の増加(エントリー10および12)に対して極めて感受性であるが、+M置換基は、化合物の反応性を低下させる(エントリー3および7)。
980μLのPBS(1×、pH7.6)を含有するバイアルに、10μLのベンズアミド原液および10μLの求電子剤原液(フェニルマレイミド1または
種々の条件における以下の化合物の安定性
「付加物」
以下の化合物A(本発明による)およびB(参照化合物)の安定性を種々の生体条件において調査した。
マウスからの正常な肝臓BNL CL.2細胞を、10%ウシ胎児血清(Perbio,Brebieres,France)、2mMのL−グルタミン、100U/mLのペニシリン、100μg/mLのストレプトマイシン(Eurobio)を補充した1g/lのグルコース(Eurobio,Les Ulis,France)を含むダルベッコMEM培地において成長させた。細胞を37℃で5%CO2湿気環境に維持した。
実験の24時間前に、ウエルあたり2.5×104のBNL CL.2細胞を8ウエルのLab-Tek IIチャンバーカバーガラス(参照番号155409,Nunc,Naperville,IL,USA)に播種した。所要量のプローブAおよびBをMEM完全培地において300μlまで希釈して1μMの最終濃度を得、次いで、上記細胞上に添加した。5μg/mlのHoechst118溶液を核マーカーとして用いた。細胞を、10%FBSフェノールレッドフリーイーグルMEM培地で洗浄した後、共焦点Leica TSC SPE II顕微鏡によって観察した。
実験前日、BNL CL.2細胞をダルベッコMEM完全培地中2.0×104細胞/ウエルで96プレート(Greiner Bio One,Frickenhausen,Germany)に播種した。両方のプローブ(AおよびB)をダルベッコMEM完全培地中1μMの濃度で調製し、種々の時間(2、6および24時間)の間、細胞上に添加した。PBS(Eurobio)で洗浄し、40μlのトリプシンで5分間インキュベーションし、160μLのPBS EDTA(5mM)を添加した後、細胞を、緑色レーザーによるPCA-96Guavaサイトメーター(Guava Technologies Merck Millipore,Billerica,MA,USA)におけるフローサイトメトリーによって分析した。
選択性についてのスクリーニングを、非保護アミノ酸のベンジルアミドにおいて行った。アミノ酸(TFA塩の形態)のベンジルアミドおよび求電子剤(フェニルプロピオニトリルおよびフェニルマレイミド)の100mMの原液をDMSO中で調製し、−20℃で保存した。100mMのベンズアミド原液(内部標準として使用)を蒸留水中で調製し、−20℃で保存した。反応混合物の分析をShimadzu LC with SunFire(商標)C18(5μMの4.6×150mmのカラム)によって行った(Waters)。HPLCパラメータは以下の通りであった:流量:1mL/分、勾配:5〜95%の移動相B、0〜20分、続いて95%の移動相で5分、およびポスト時間5分。移動相Aは0.05%TFA水溶液(mQ)(v/v)であり、移動相Bはアセトニトリル(HPLC等級)であった。データを、Shimadzu分析ソフトウェアを用いて分析した。シグナルを、内部標準(ベンズアミド)のピークの面積に従って正規化した。アミノ酸ベンジルアミドのピーク下の面積を用いて反応の際の転化率を算出した。
以下の式(II)の「リンカー」化合物の毒性をHaCaT細胞株におけるMTTアッセイによって検討した:
リゾチームのトリプシン消化物の標識
1nmolのリゾチームをNH4HCO3(25mM)に可溶化させ、1時間の間57℃で1mMのTCEPによって還元した。APN−TMPPの溶液(DMSO中1mM)を1:200のモル比でタンパク質に添加した。次いで、標識タンパク質をブタトリプシン(Promega V5111)によるタンパク質分解に供した。サンプルを25mM重炭酸アンモニウム中1:100(w/w)トリプシンによって35℃で一晩消化させた。反応に続いてナノLC−MS/MS分析を行った。得られたペプチド混合物を、ナノエレクトロスプレー源を備えたQ-TOF maXis(Bruker Daltonics,Bremen,Germany)質量分析器に連結されたnanoACQUITY Ultra-Performance-LC system(Waters,Milford,MA)においてC18逆相ナノHPLCによって分析した。クロマトグラフィ分離をnanoACQUITY Ultra-Performance-LCにおいて実施した。ペプチドをACQUITY UPLC(登録商標)BEH130 C18カラム(Waters Corp.)(75μm×200mm、1.7μm粒径)において分離した。溶媒系は、0.1%ギ酸の水溶液(溶媒A)および0.1%ギ酸のアセトニトリル溶液(溶媒B)からなった。トラッピングを、99%の溶媒Aおよび1%の溶媒Bによって5μL/分で3分間、20×0.18mmの5μmのSymmetry C18プレカラム(Waters Corp.)において実施した。溶離を、1〜50%勾配の溶媒Bを用いて300nL/分の流量で50℃において30分、続いて、80%(5分間)の溶媒Bにおいて高速上昇で実施した。完全系をHystar 3.2(Bruker Daltonics)によって完全に制御した。Q-TOF機器を以下の設定で操作した:電源温度を200℃に設定し、乾燥気体流量が4l/時間であり、ナノエレクトロスプレー電圧が4kVであった。TOFの質量検量線を50〜2200m/zの範囲においてポジティブモードでES-TOF Tuning Mix(Agilent Technologies)を用いて得た。タンデムMS実験では、系をm/z範囲[50〜2200]においてMSおよびMS/MSモードの両方の間での自動切り替えによって操作した。MSにおいて、総時間は0.2秒であった。MS/MSにおいて、総時間は、親イオン強度の関数において0.2秒と1.4秒との間で加重した。2つの最も豊富なペプチド(強度閾値400au)、好ましくは2、3、4または5つの電荷を有するイオンを各MSスペクトルにおいて選択してさらに単離し、衝突エネルギープロファイルを用いて設定された2つのエネルギーによりCIDフラグメント化した。衝突ガスとしてアルゴンを用いてフラグメント化を実施した。トリプシンペプチドを(初めから)手動で配列決定してその配列を確認し、APN-TMPPプローブによってタグ付けされたシステインを位置付けた。ペプチドを、算出されたペプチド配列のモノアイソトピック質量に基づいて、抽出されたイオンクロマトグラム(EIC)を用いて同定した。
(49によるCD38突然変異体の修飾の例における)実験の一般スキームを図6に示す。
300μLのCD38C275溶液(1mg/mL)に可溶化APN試薬(49〜54)の6μLの50mM DMSO溶液を添加した。平行して、対照として、300μLのCD38C275に、6μLのDMSOを添加した。両方のサンプルを25℃で15時間インキュベートし、次いで5回透析し(メンブレンカットオフ10k)、最終体積が30μL(10mg/mL)のそれぞれを得た。凝集物のサイズをDLSによって測定した。
a)本発明の化合物および対応するマレイミドの安定性
以下の化合物を合成した:
両方の化合物をCD38−C375突然変異体の2μM溶液と反応させた。
精製後のゲル電気泳動により、対応するマレイミド化合物によってよりも、本発明の化合物によって、より高い標識速度が得られ得ることが示された。図7は、精製前後に本発明の化合物およびマレイミドによって得られたゲル電気泳動を提示する。
実験の一般スキームを図8に示す。
トラスツズマブの溶液(100uL、50mMホウ酸緩衝液pH8.5中10mg/mL)に18の溶液(DMSO中10mg/mL)1.74μLを添加した。25℃で1時間インキュベーション後、0.69μLのTAMRA−SH(DMSO中100mM)を添加した。混合物を25℃で16時間インキュベートし、コンジュゲートをサイズ排除クロマトグラフィによって精製した。
18の代わりに4−(N−マレイミドメチル)シクロヘキサンカルボン酸N−ヒドロキシスクシンイミドエステル(SMCC)を用いて比較実験を行った。
得られたコンジュゲート(図9)のSDS−PAGE分析により、化合物18がSMCCと比較して高いレベルのコンジュゲーションを可能にすることが示された。
18を用いて調製したコンジュゲートのネイティブESI−MS分析(図10、図11)により、抗体あたり平均1分子のTAMRAがコンジュゲートしたことが示された。
SMCCを用いて調製したコンジュゲートのネイティブESI−MS分析(図12、図13)により、識別不能な種の複合混合物が示された。
実験により、化合物18が、一般に適用されるSMCCと比較して、より高いレベルのコンジュゲーションを可能にし、よりクリーンなコンジュゲート集団を与えることが示されている。
実験の一般スキームを図14に示す。
トラスツズマブの溶液(100uL、10mMのEDTAを含む50mM PBS(pH7.4)中10mg/mL)をTCEPの溶液(水中10mM、1.1または2.2当量)に添加した。混合物を37℃で2時間インキュベートし、次いで、58の溶液(8.25μL、DMSO中10mM)を添加した。混合物を25℃で16時間インキュベートし、コンジュゲートをサイズ排除クロマトグラフィによって精製した。
得られたコンジュゲートのSDS−PAGE分析(図15)により、化合物58が抗体に共有結合したことが示された。ESI−MS分析により、2.2当量のTCEPを用いて抗体あたり平均4分子がコンジュゲートしたことが示された。
実験の一般スキームを図16に示す。
トラスツズマブの溶液(100uL、10mMのEDTAを含む50mM PBS(pH7.4)中10mg/mL)を、TCEPの溶液(水中10mM、5当量)に添加した。混合物を37℃で2時間インキュベートし、次いで、33または34の溶液(DMSO中10mM、15当量)を添加した。得られた溶液を25℃で16時間インキュベートし、次いで、還元条件においてSDS−PAGEによって分析した。
SDS−PAGE分析により、抗体フラグメントが化合物33および34によって成功裏に架橋されたことが示された(図17)。
Claims (9)
- チオール部位を含む標識化合物の調製のための方法であって、チオール部位を含む化合物を、式(I):
− 水素原子、
− O、NおよびSの中から選択された少なくとも1つのヘテロ原子によって場合により中断されたアルキル、アルケンまたはアルキン基、
− アリール基、
− アルコキシ基、
− ハロゲン原子、
− アミノ(−NRR’)基、式中、RおよびR’は、独立して、水素原子、アルキル、アルケン、アルキンまたはアリール基である、
− ヒドロキシルアミン(−ONH2)基、
− ヒドラジン(−NH−NH2)基、
− ニトロ(−NO2)基、
− アジド(−N3)基、
− ジアゾニウム(−N2 +)基、
− マレイミド基、
− アルキルまたはアリールカルボキシル(−C(=O)OR)基、
− アルキルまたはアリールカルボニル(−C(=O)R)基、
− ヒドロキシル(−OH)基、
− ホウ酸−B(OR”)2基、式中、R”は水素原子またはアルキル基である、
− ホスフィンまたはホスホニウム基、
− イソシアネート(−N=C=O)またはイソチオシアネート(−N=C=S)基、
− クロロスルホニル(−SO2Cl)基、
− −O−C(=O)−C(N2)−CF3基または−C(=O)−C(N2)−CF3基、
− 活性化エステル、例えば−C(=O)−NHS、過フッ素化エステルおよびアシルウレア、
− −C≡C−C≡N基、
− タグ、ならびに
− 先に列挙された基の少なくとも1つによって置換されたアルキル基
からなる群から独立して選択され、
代替的には、R1〜R5のうち2つが、これらが連結するフェニル環の炭素原子と一緒になって、単または多環式環を形成していてよく、
R1〜R5の少なくとも1つが、以下:
− 化合物の検出、
− 化合物による対象薬剤のベクトル化、
− 化合物の可溶化、
− 化合物の安定化、
− 化合物の抽出および/または精製の改善、
− 化合物のADME(投与、分布、代謝、排泄)パラメータの少なくとも1つの変更;
− 化合物への生物活性の付加;ならびに
− クリック化学のための適切な官能性の付加;
のうち1つまたはいくつかを可能にするのに適切な化学基からなる群から選択されるタグ部位を含む;
の化合物と接触させることを含む方法。 - 式(I):
− 化合物の検出、
− 化合物による対象薬剤のベクトル化、
− 化合物の可溶化、
− 化合物の安定化、
− 化合物の抽出および/または精製の改善、
− 化合物のADME(投与、分布、代謝、排泄)パラメータの少なくとも1つの変更;
− 化合物への生物活性の付加;ならびに
− クリック化学のための適切な官能性の付加;
のうち1つまたはいくつかを可能にするのに適切な化学基からなる群から選択されるタグ部位を含む;
の化合物。 - 化合物が、以下:
- 式(II):
− 水素原子、
− O、NおよびSの中から選択された少なくとも1つのヘテロ原子によって場合により中断されたアルキル、アルケンまたはアルキン基、
− アリール基、
− アルコキシ基、
− ハロゲン原子、
− アミノ(−NRR’)基、式中、RおよびR’は、独立して、水素原子、アルキル、アルケン、アルキンまたはアリール基である、
− ヒドロキシルアミン(−ONH2)基、
− ヒドラジン(−NH−NH2)基、
− ニトロ(−NO2)基、
− アジド(−N3)基、
− ジアゾニウム(−N2 +)基、
− マレイミド基、
− アルキルまたはアリールカルボキシル(−C(=O)OR)基、
− アルキルまたはアリールカルボニル(−C(=O)R)基、
− ヒドロキシル(−OH)基、
− ホウ酸−B(OR”)2基、式中、R”は水素原子またはアルキル基である、
− ホスフィンまたはホスホニウム基、
− イソシアネート(N=C=O)またはイソチオシアネート(−N=C=S)基、
− クロロスルホニル(−SO2Cl)基、
− O−C(=O)−C(N2)−CF3基または−C(=O)−C(N2)−CF3基、
− 活性化エステル、例えば−C(=O)−NHS、過フッ素化エステルおよびアシルウレア、
− タグ、ならびに
− 先に列挙された基の少なくとも1つによって置換されたアルキル基
からなる群から独立して選択され、
代替的には、R1〜R5のうち2つが、これらが連結するフェニル環の炭素原子と一緒になって、単または多環式環を形成していてよく、
R1〜R5の少なくとも1つが、マレイミド、NHS−エステル、アジドまたはアルキン部位を含む;
の化合物。 - 化合物が、以下:
- 式(II):
− 水素原子、
− O、NおよびSの中から選択された少なくとも1つのヘテロ原子によって場合により中断されたアルキル、アルケンまたはアルキン基、
− アリール基、
− アルコキシ基、
− ハロゲン原子、
− アミノ(−NRR’)基、式中、RおよびR’は、独立して、水素原子、アルキル、アルケン、アルキンまたはアリール基である、
− ヒドロキシルアミン(−ONH2)基、
− ヒドラジン(−NH−NH2)基、
− ニトロ(−NO2)基、
− アジド(−N3)基、
− ジアゾニウム(−N2 +)基、
− マレイミド基、
− アルキルまたはアリールカルボキシル(−C(=O)OR)基、
− アルキルまたはアリールカルボニル(−C(=O)R)基、
− ヒドロキシル(−OH)基、
− ホウ酸−B(OR”)2基、式中、R”は水素原子またはアルキル基である、
− ホスフィンまたはホスホニウム基、
− イソシアネート(N=C=O)またはイソチオシアネート(−N=C=S)基、
− クロロスルホニル(−SO2Cl)基、
− O−C(=O)−C(N2)−CF3基または−C(=O)−C(N2)−CF3基、
− 活性化エステル、例えば−C(=O)−NHS、過フッ素化エステルおよびアシルウレア、
− タグ、ならびに
− 先に列挙された基の少なくとも1つによって置換されたアルキル基
からなる群から独立して選択され、
代替的には、R1〜R5のうち2つが、これらが連結するフェニル環の炭素原子と一緒になって、単または多環式環を形成していてよく、
R1〜R5の少なくとも1つが、フルオロフォア、少なくとも1つの放射性原子を含む原子の基、公知のマスの原子の基、リガンド、薬物、治療剤、生体分子、DNAフラグメント、ナノ対象物、または支持体からなる群から選択される対象化合物に結合している;
の化合物。 - 対象化合物が生体分子であり、生体分子が抗体またはタンパク質である、請求項6に記載の化合物。
- 式(III):
の化合物。 - 式(III):
の化合物。
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