JP2017535587A - 抗がん性化合物としての新規な2’および/または5’アミノ酸エステルホスホロアミダート3’−デオキシアデノシン誘導体 - Google Patents
抗がん性化合物としての新規な2’および/または5’アミノ酸エステルホスホロアミダート3’−デオキシアデノシン誘導体 Download PDFInfo
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- 125000002264 triphosphate group Chemical group [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 229960004441 tyrosine Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- ABDKAPXRBAPSQN-UHFFFAOYSA-N veratrole Chemical compound COC1=CC=CC=C1OC ABDKAPXRBAPSQN-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000001238 wet grinding Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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Abstract
Description
W1およびW2は、それぞれ独立に、−P(=O)(U)(V)およびHからなる群から選択され、ただし、W1およびW2のうち少なくとも1つは、−P(=O)(U)(V)であり、
W1およびW2それぞれについてのUおよびVは、独立に、以下のものからなる群から選択され:
(a)Uは−OArであり、それと合わせてVは−NR4−CR1R2−C(=O)OR3であり
Arは、C6〜30アリールおよび5〜30ヘテロアリールからなる群から選択され、そのそれぞれは、場合によって置換され;
R1およびR2はそれぞれ、独立に、H、およびC1〜20アルキル、C6〜30アリールC1〜6アルキル、C2〜20アルケニル、C1〜20アルコキシ、C1〜20アルコキシC1〜20アルキル、C1〜20アルコキシC6〜30アリール、C2〜20アルキニル、C3〜20シクロアルキルC6〜30アリール、C6〜30アリールオキシおよび5〜20ヘテロシクリルからなる群から選択され、そのいずれも、場合によっては置換され;
R3は、H、およびC1〜20アルキル、C6〜30アリールC1〜20アルキル、C2〜20アルケニル、C1〜20アルコキシC1〜20アルキル、C1〜20アルコキシC6〜30アリール、C2〜20アルキニル、C3〜20シクロアルキルC6〜30アリール、および5〜20ヘテロシクリルからなる群から選択され、そのいずれも、場合によっては置換され;
R4は、H、およびC1〜20アルキル、C6〜30アリールC1〜20アルキル、C2〜20アルケニル、C1〜20アルコキシ、C1〜20アルコキシC1〜20アルキル、C1〜20アルコキシC6〜30アリール、C2〜20アルキニル、C3〜20シクロアルキルC6〜30アリール、C6〜30アリールオキシおよび5〜20ヘテロシクリルからなる群から選択され、そのいずれも、場合によっては置換される;ならびに
(b)UおよびVはそれぞれ、独立に、−NR5R6から選択され、
R5は、HおよびC1〜6アルキルからなる群から選択され、R6は、−CR7R8CO2R9であり、R7およびR8は、独立に、Hを含めた、天然に存在するαアミノ酸の側鎖からなる群から選択され、R9は、H、およびC1〜20アルキル、C6〜30アリールC1〜20アルキル−、C2〜20アルケニル、C1〜20アルコキシC1〜20アルキル、C1〜20アルコキシC6〜30アリール、C2〜20アルキニル、C3〜20シクロアルキルC6〜30アリール、および5〜20ヘテロシクリルからなる群から選択され、そのいずれも、場合によっては置換され;または
R5およびR6は、それらが結合するN原子と一緒になって、5から8個の環原子を含む環部分を形成する;
Qは、O、SおよびCR10R11(式中、R10およびR11は、独立に、H、FおよびC1〜6アルキルから選択される)からなる群から選択され;
XおよびZはそれぞれ、独立に、H、OH、F、Cl、Br、I、C1〜6アルキル、−NR12R13(式中、R12およびR13はそれぞれ、独立に、HおよびC1〜6アルキルから選択される)、および−SR14(式中、R14は、HおよびC1〜6アルキルからなる群から選択される)からなる群から選択され;
Yは、H、OH、F、Cl、Br、I、−OC1〜6アルキル、C1〜6アルキル、C2〜8アルキニル、−NR15R16(式中、R15およびR16はそれぞれ、独立に、HおよびC1〜6アルキルから選択される)、および−SR17(式中、R17は、HおよびC1〜6アルキルからなる群から選択される)からなる群から選択される]、または式(Ia)の化合物の薬学的に許容される塩、エステル、エステルの塩、溶媒和物もしくはプロドラッグが提供される。
W1およびW2は、それぞれ独立に、−P(=O)(U)(V)およびHからなる群から選択され、ただし、W1およびW2のうち少なくとも1つは、−P(=O)(U)(V)であり、
W1およびW2それぞれについてのUおよびVは、独立に、以下のものからなる群から選択され:
(a)Uは、−OArであり、Vは、−NR4−CR1R2−C(=O)OR3であり
Arは、C6〜30アリールおよび5〜30ヘテロアリールからなる群から選択され、そのそれぞれは、場合によって置換され;
R1およびR2はそれぞれ、独立に、H、およびC1〜20アルキル、C6〜30アリールC1〜6アルキル、C2〜20アルケニル、C1〜20アルコキシ、C1〜20アルコキシC1〜20アルキル、C1〜20アルコキシC6〜30アリール、C2〜20アルキニル、C3〜20シクロアルキル、C6〜30アリール、C6〜30アリールオキシおよび5〜20ヘテロシクリルからなる群から選択され、そのいずれも、場合によっては置換され;
R3は、H、およびC1〜20アルキル、C6〜30アリールC1〜20アルキル、C2〜20アルケニル、C1〜20アルコキシC1〜20アルキル、C1〜20アルコキシC6〜30アリール、C2〜20アルキニル、C3〜20シクロアルキル、C6〜30アリール、および5〜20ヘテロシクリルからなる群から選択され、そのいずれも、場合によっては置換され;
R4は、H、およびC1〜20アルキル、C6〜30アリールC1〜20アルキル、C2〜20アルケニル、C1〜20アルコキシ、C1〜20アルコキシC1〜20アルキル、C1〜20アルコキシC6〜30アリール、C2〜20アルキニル、C3〜20シクロアルキル、C6〜30アリール、C6〜30アリールオキシおよび5〜20ヘテロシクリルからなる群から選択され、そのいずれも、場合によっては置換される;ならびに
(b)UおよびVはそれぞれ、独立に、−NR5R6から選択され
R5は、HおよびC1〜6アルキルからなる群から選択され、R6は、−CR7R8CO2R9であり、R7およびR8は、独立に、Hを含めた、天然に存在するαアミノ酸の側鎖からなる群から選択され、R9は、H、およびC1〜20アルキル、C6〜30アリールC1〜20アルキル−、C2〜20アルケニル、C1〜20アルコキシC1〜20アルキル、C1〜20アルコキシC6〜30アリール、C2〜20アルキニル、C3〜20シクロアルキル、C6〜30アリール、および5〜20ヘテロシクリルからなる群から選択され、そのいずれも、場合によっては置換され;または
R5およびR6は、それらが結合するN原子と一緒になって、5から8個の環原子を含む環部分を形成する;
Xは、NR12R13(式中、R12およびR13はそれぞれ、独立に、HおよびC1〜6アルキルから選択される);および−SR14(式中、R14は、HおよびC1〜6アルキルからなる群から選択される)から選択され;
Zは、独立に、H、OH、F、Cl、Br、I、C1〜6アルキル、−NR12R13、および−SR14(式中、R14は、HおよびC1〜6アルキルからなる群から選択される)からなる群から選択され;
Yは、H、OH、F、Cl、Br、I、−OC1〜6アルキル、C1〜6アルキル、C2〜8アルキニル、−NR15R16(式中、R15およびR16はそれぞれ、独立に、HおよびC1〜6アルキルから選択される)、および−SR17(式中、R17は、HおよびC1〜6アルキルからなる群から選択される)からなる群から選択される]、または式(Ib)の化合物の薬学的に許容される塩、エステル、エステルの塩、溶媒和物もしくはプロドラッグとなり得る。
(2S)−ベンジル2−(((((2S,4R,5R)−5−(6−アミノ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ナフタレン−1−イルオキシ)ホスホリル)アミノ)プロパノエート;
ベンジル2−(((((2S,4R,5R)−5−(6−アミノ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(フェノキシ)ホスホリル)アミノ)アセテート;
(2S)−ペンチル2−(((((2S,4R,5R)−5−(6−アミノ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ナフタレン−1−イルオキシ)ホスホリル)アミノ)−4−メチルペンタノエート;
メチル2−(((((2S,4R,5R)−5−(6−アミノ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ナフタレン−1−イルオキシ)ホスホリル)アミノ)−2−メチルプロパノエート;
(2S)−ベンジル2−(((((2S,4R,5R)−5−(6−アミノ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(2−(3−エトキシ−3−オキソプロピル)フェノキシ)ホスホリル)アミノ)プロパノエート;
(2S)−ベンジル2−(((((2R,3R,5S)−2−(6−アミノ−9H−プリン−9−イル)−5−(ヒドロキシメチル)テトラヒドロフラン−3−イル)オキシ)(フェノキシ)ホスホリル)アミノ)プロパノエート;
ベンジル2−(((((2S,4R,5R)−5−(6−アミノ−9H−プリン−9−イル)−4−((((1−(ベンジルオキシ)−1−オキソプロパン−2−イル)アミノ)(フェノキシ)ホスホリル)オキシ)テトラヒドロフラン−2−イル)メトキシ)(フェノキシ)ホスホリル)アミノ)プロパノエート;
(2S)−ベンジル2−(((((2R,3R,5S)−2−(6−アミノ−9H−プリン−9−イル)−5−(ヒドロキシメチル)テトラヒドロフラン−3−イル)オキシ)(ナフタレン−1−イルオキシ)ホホリル)アミノ)プロポネート;
ベンジル2−[({[5−(6−アミノ−9H−プリン−9−イル)−4−ヒドロキシオキソラン−2−イル]メトキシ}({[1−(ベンジルオキシ)−1−オキソプロパン−2−イル]アミノ})ホスホリル)アミノ]プロパノエート;
(2S)−ベンジル2−((((2S,4R,5R)−5−(6−アミノ−2−メトキシ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ナフタレン−1−イルオキシ)ホスホリルアミノ)プロパノエート;
(2S)−ベンジル2−((((2S,4R,5R)−5−(6−アミノ−2−メトキシ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(フェノキシ)ホスホリルアミノ)プロパノエート;
(2S)−ベンジル2−(((((2S,4R,5R)−5−(6−アミノ−2−フルオロ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(フェノキシ)ホスホリル)アミノ)プロパノエート;
(2S)−ヘキシル2−(((((2S,4R,5R)−5−(6−アミノ−2−フルオロ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(フェノキシ)ホスホリル)アミノ)プロパノエート;
(2R)−ベンジル2−((((2S,4R,5R)−5−(6−アミノ−2−クロロ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ナフタレン−1−イルオキシ)ホスホリルアミノ)プロパノエート;
3’−デオキシアデノシン−5’−O−[フェニル(ベンジルオキシ−L−アラニニル)]ホスフェート;
2−O−メチル−3’−デオキシアデノシン−5’−O−[1−ナフチル(1−ペンチルオキシ−L−ロイシニル)]ホスフェート;
2−O−メチル−3’−デオキシアデノシン−5’−O−[フェニル(1−ヘキシルオキシ−L−アラニニル)]ホスフェート;
2−フルオロ−3’−デオキシアデノシン−5’−O−[1−ナフチル(ベンジルオキシ−L−アラニニル)]ホスフェート;
2−フルオロ−3’−デオキシアデノシン−5’−O−[1−ナフチル(1−ペンチルオキシ−L−ロイシニル)]ホスフェート;
2−クロロ−3’デオキシアデノシン5’−O−[1−フェニル(2,2−ジメチルプロポキシ−L−アラニン)]ホスフェート;
2−クロロ−3’デオキシアデノシン5’−O−[1−ナフチル(2,2−ジメチルプロポキシ−L−アラニン)]ホスフェート;
2−クロロ−3’デオキシアデノシン5’−O−[1−フェニル(エトキシ−L−アラニン)]ホスフェート;および
(2S)−イソプロピル−2−(((((2S,4R,5R)−5−(6−アミノ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(フェノキシ)ホスホリル)アミノ)プロパノエート
および薬学的に許容されるそれらの塩、エステル、エステルの塩、溶媒和物またはプロドラッグが含まれる。
(2S)−イソプロピル−2−(((((2S,4R,5R)−5−(6−アミノ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(フェノキシ)ホスホリル)アミノ)プロパノアートでない。
(a)式Vの化合物:
(b)POCl3と、続いて、N+R5R6H2の塩[式中、W1、W2、Q、X、Y、Z、Ar、R1、R2、R3、R4、R5およびR6は、式(Ia)に関して、本明細書に記載される意味を有する]と反応させることにより式(Ia)の化合物
時折、他の場合で「腫瘍始原細胞」と称されるがん幹細胞は、当業者に周知である。本明細書で使用される場合、用語「がん幹細胞」は、広く認められた意味に従って解釈されるものであり、この細胞は、非対称性の分裂により自己再生する、腫瘍形成を開始する、分化により、より成熟した非幹細胞がんの後代を生じる能力を有する細胞である。
本発明は、本発明の化合物が、がん幹細胞を標的とするために用いることができるという第1の適応を提供する。本発明の化合物のがん幹細胞を標的とする能力は、本明細書において開示される実施例で例示される。
本発明は、本発明の化合物ががんの予防または治療のために用いられる医学的使用および治療の方法を提供する。本発明と関連して、がんの「予防」は、がんの発生前に用いられる本発明の化合物の予防的適用に関するものとして、およびがんが発生するのを停止させる狙いで考慮されるべきである。他方では、がんの「治療」は、がん細胞増殖および腫瘍成長を遅くするまたは停止させることによりがんを寛解させる目的で、がんが発生した後に本発明の化合物の使用に関係すると解釈することができる。有利には、がんの治療は、がん細胞数および腫瘍サイズの部分的なまたは全体的な減少をもたらすことができる。有効ながんの治療は、RECIST(Response Evaluation Criteria In Solid Tumours)ガイドラインに従って、「安定させる」または「応答する」疾患をもたらすことができる。
本発明によるがんの予防は、本明細書に記載した本発明の様々な態様または実施形態に従って、本発明の化合物を用いて前がん状態の治療によって実施することができる。
がんは、しばしば先行して前がん状態が発現し、この前がん状態はそれ自体がん性でないが、がんのリスクの増加を伴う。遺伝的またはエピジェネティックな変化が蓄積されることによって、以前は正常だった細胞が、がん幹細胞表現型を発現する恐れがある。したがって、がん幹細胞はまた、かかる前がん状態、ならびにがん性状態において存在することができる。
当業者は、がんの「治療」を評価することができる多くの測定があることを理解している。単なる例として、がん発生の任意の減少または予防、がんの進行、がんの再発、またはがん増殖は、有効ながんの治療を示すために考慮することができる。
本発明の化合物は、これらが由来する親ヌクレオシドと比較して、抗がん活性の増加を実証している。この抗がん活性の増加は、がん幹細胞およびがん非幹細胞に対する活性の増加の結果として示されると思われる。
上記で述べた通り、本発明のいくつかの態様および実施形態は、特に、再発性もしくは治療抵抗性がんの治療における本発明の化合物の使用に関する。
本発明の化合物の治療有効量は、がん細胞の死を誘導するのに十分な量となり得る。本発明の化合物の治療有効量は、がん幹細胞の死を誘導するのに十分な量となり得る。いくつかの実施形態、特に、再発性または治療抵抗性がんの治療に関するものでは、本発明の化合物の治療有効量は、がん幹細胞の死を誘導するおよびがん非幹細胞の死をも誘導するのに十分な量となり得る。
好適な実施形態では、本発明の化合物は、がんの一次治療としてがん幹細胞を標的指向化するために用いることができる。
本発明の化合物は、がんの予防または治療のための広範囲のさらなる治療薬と組み合わせて用いることができる。これには、がんの予防または治療のために用いることができる生物学的製剤、免疫療法薬、および化学療法薬が含まれる。
(a)抗血管新生薬(場合によっては、抗血管新生薬は、(i)VEGF経路の阻害薬、場合によっては、ベバシズマブ;(ii)チロシンキナーゼ阻害薬、場合によっては、ソラフェニブ、スニチニブもしくはパゾパニブ;または(iii)mTOR阻害薬、場合によっては、エベロリムスである);
(b)アルキル化剤;
(c)代謝拮抗剤;
(d)抗腫瘍抗生物質;
(e)トポイソメラーゼ;
(f)有糸分裂阻害剤;
(g)モノクローナル抗体;
(h)金属性薬剤;または
(i)能動もしくは受動免疫療法が含まれる。
本発明の化合物が、がん幹細胞を標的とすることができるという本発明者らの知見によって、ある特定の患者が、再発性または治療抵抗性がんなどの、がんの予防または治療において、本発明の化合物を投与することから恩恵を受ける可能性があるか否かを決定することができる多くの方法が可能になる。
本発明の化合物は、次の一般的な手順および模範的な合成手順に従ってまたはそれらと同じように作製することができる。
N−メチルイミダゾール(1.0mmol)および適切なホスホロクロリダート(0.6mmol)の無水THF(2mL)溶液を、3’−デオキシアデノシン(0.20mmol)または置換3’−デオキシアデノシンの無水THF(10mL)懸濁液に滴下し、反応混合物を16時間室温で撹拌した。カラムクロマトグラフィーおよび分取TLCにより精製して、白色固形物として所望の化合物を生成した。使用される構成成分の量は、変わることもあり、実際の量は下記の例において示す。
3’−デオキシアデノシン(0.80mmol)を、(CH3O)3PO(5mL)に懸濁し、POCl3(0.80mmol)を、−5℃で滴下した。反応混合物を室温にし、放置して4時間撹拌した。無水CH2Cl2(5mL)に溶解した適切なアミノ酸エステル塩(4.0mmol)の溶液を加え、その後、ジイソプロピルエチルアミン(8.0mmol)を−78℃で加えた。室温で20時間撹拌した後、水を加え、これらの層を分離した。水相をジクロロメタンで抽出し、有機相を食塩水で洗浄した。合わせた有機層を、Na2SO4で脱水し、濃縮した。残留物をカラムクロマトグラフィーにより精製して(勾配溶離がCH2Cl2/MeOH=100/0から93/7まで)、白色のフォームとして所望の生成物を得た。使用される構成成分の量は、変わることもあり、実際の量は、下記の例において示す。
3’−デオキシアデノシン(0.20mmol)を、無水THF(5mL)に懸濁し、tBuMgCl(THF中の1.0M溶液、0.22mmol)を室温で滴下した。適切なホスホロクロリダート(0.6mmol)の無水THF(2mL)溶液を滴下し、反応混合物を、16時間室温で撹拌した。カラムクロマトグラフィーおよび分取TLCにより精製して、白色固形物として所望の化合物を生成した。使用される構成成分の量は、変わることもあり、実際の量は下記の例において示す。
Tertブチルジメチルシリルクロリド(3.3mol/eq.)およびイミダゾール6.6(mol/eq)を適切な3’−デオキシアデノシン誘導体(1mol/eq)の無水DMF溶液に加え、反応混合物を、終夜(16〜20h)室温で撹拌した。次いで、NH4Clを混合物に加え、酢酸エチルで2回洗浄した。有機層を合わせ、Na2SO4で乾燥させ、溶媒を真空下で除去した。カラムクロマトグラフィーにより混合物を精製して、中間体C1を生成した。次いで、中間体C1を、THF/H2O/TFA4/1/1の水溶液(6ml/eq)に溶解し、0℃で4h撹拌した。次いで、溶液をNaHCO3の飽和水溶液で注意深く中和し、混合物を、酢酸エチルで2回洗浄した。有機層を合わせ、Na2SO4で乾燥し、溶媒を真空下で除去した。カラムクロマトグラフィーにより混合物を精製して、中間体C2を生成した。次いで、一般的な手順Bを適用し、中間体C3を生成した。中間体C3を、THF/H2O/TFA1/1/1の水溶液(6ml/eq)に0℃で溶解し、室温で24h撹拌した。クロマトグラフィーにより精製して、白色の固形物として所望の化合物を生成した。
H2O/CH3CN1:9の溶液、次いで、α−AIBBr(4.0mol/eq)を、乾燥したアデノシンまたは2−クロロアデノシンの無水CH3CN懸濁液に順次加え、室温(20℃)で撹拌を続けた。1時間後、NaHCO3の飽和溶液を、注意して加え、溶液を、EtOAcで抽出した。合わせた有機相を食塩水で洗浄した。水相をEtOAcで抽出し、合わせた有機相を、Na2SO4で脱水し、ろ過し、蒸発させて、白色のゴムを得た。粗混合物を、無水MeOHに溶解し、前もって無水MeOHで十分に洗浄したAmberlite(2×OH−)樹脂で1時間撹拌した。次いで、溶液をろ過し、樹脂を無水メタノールで注意深く洗浄した。合わせたろ液を蒸発させて、白色固形物として2’,3’−デヒドロアデノシンまたは2’,3’−デヒドロ−2−クロロアデノシンを生成した。
1H NMR (500 MHz, DMSO-d6) δ 8.37 (s, 1H, H8), 8.17 (s, 1H, H2), 7.29 (br s, 2H, NH2), 5.89 (d, J = 2.5 Hz, 1H, H1’), 5.68 (d, J = 4.5 Hz, 1H, OH-2’), 5.19 (t, J = 6.0 Hz, 1H, OH-5’), 4.63 - 4.58 (m, 1H, H2’), 4.40 - 4.34 (m, 1H, H4’), 3.71 (ddd, J = 12.0, 6.0, 3.0 Hz, 1H, H5’), 3.53-3.49 (ddd, J = 12.0, 6.0, 4.0 Hz, 1H, H5’), 2.30-2.23 (m, 1H, H3’), 1.98-1.90 (m, 1H, H3’). 13C NMR (125 MHz, DMSO-d6) δ 156.00 (C6), 152.41 (C2), 148.82 (C4), 139.09 (C8), 119.06 (C5), 90.79 (C1’), 80.66 (C4’), 74.56 (C2’), 62.61 (C5’), 34.02 (C3’).
1H NMR (500 MHz, CD3OD): δH 8.41 (s, 1H, H8), 5.93 (d, J = 2.5 Hz, 1H, H1’), 4.68-4.66 (m, 1H, H2’), 4.56-4.52 (m, 1H, H4’), 3.95 (dd, J = 3, 12.5 Hz, 1H, H5’), 3.70 (dd, J = 3, 12.5 Hz, 1H, H5’), 2.39-2.33 (m, 1H, H3’), 2.08-2.03 (m, 1H, H3’) 13C NMR (125 MHz, CD3OD): δC 158.14 (C6), 155.19 (C2), 151.15 (C4), 141.30 (C8), 119.56 (C5), 93.58 (C1’), 82.80 (C4’), 76.81 (C2’), 64.01 (C5’), 34.33 (C3’).
H2O/CH3CN(1:9;1.4mL)の溶液、次いでα−AIBBr(4.10mL、28.05mmol)を、乾燥した2−フルオロアデノシン(2.0g、7.01mmol)の無水CH3CN(50mL)懸濁液に順次加え、室温(20℃)で撹拌を続けた。1時間後、NaHCO3の飽和溶液を、注意して加え、溶液を、EtOAc(2×100mL)で抽出した。合わせた有機相を食塩水(1×50mL)で洗浄した。水相をEtOAc(2×50mL)で抽出し、合わせた有機相を、Na2SO4で脱水し、ろ過し、蒸発させて、白色のゴムを得た。粗混合物を、THF/H2O(4/1、50mL)の混合物に溶解し、(前もってTHFで十分洗浄した)Amberlite(2×OH−)樹脂60mLで1時間撹拌した。次いで、溶液をろ過し、樹脂をTHFで注意深く洗浄した。合わせたろ液を蒸発させて、EtOHから残留物を結晶化して、白色固形物として2’,3’−デヒドロ−2−フルオロアデノシンを得た(1.13g、60%)。
19F NMR (470 MHz, DMSO-d6): δF -52.19. 1H NMR (500 MHz, DMSO-d6) δH 8.34 (s, 1H, H8), 7.80 (br s, 2H, NH2), 5.78 (d, J = 2.25 Hz, 1H, H1’), 5.68 (br s, 1H, OH-2’), 5.01 (br s, 1H, OH-5’), 4.55-4.51 (m, 1H, H2’), 4.39-4.32 (m, 1H, H4’), 3.73-3.76 (m, 1H, H5’), 3.56-3.50 (m, 1H, H5’), 2.26-2.18 (m, 1H, H3’), 1.94-1.85 (m, 1H, H3’). 13C NMR (125 MHz, DMSO-d6) δC 158.51 (d, 1JC-F = 202.7 Hz, C2), 157.55 (d, 3JC-F = 21.2 Hz, C6), 150.11 (d, 3JC-F= 20.3 Hz, C4), 139.22 (d, 6JC-F = 2.2 Hz, C8), 117.37 (d, 4JC-F = 4.1 Hz, C5), 90.67 (C1’), 80.90 (C4’), 74.73 (C2’), 62.35 (C5’), 33.89 (C3’).
H2O/CH3CN(1:9;1.4mL)の溶液、次いで、α−AIBBr(4.10mL、28.05mmol)を、乾燥した2−フルオロアデノシン(2.0g、7.01mmol)の無水CH3CN(50mL)懸濁液に順次加え、室温(20℃)で撹拌を続けた。1時間後、NaHCO3の飽和溶液を注意して加え、溶液を、EtOAc(2×100mL)で抽出した。合わせた有機相を食塩水(1×50mL)で洗浄した。水相をEtOAc(2×50mL)で抽出し、合わせた有機相を、Na2SO4で脱水し、ろ過し、蒸発させて、白色のゴムを得た。粗混合物を無水MeOH(50mL)で溶解し、(前もって無水MeOHで十分に洗浄した)Amberlite(2×OH−)樹脂60mLで1時間撹拌した。次いで、溶液をろ過し、樹脂をTHFで注意深く洗浄した。合わせたろ液を蒸発させ、EtOHから残留物を結晶化して、白色固形物として2’,3’−デヒドロ−2−メトキシアデノシンを得た(1.57g、84%)。
1H NMR (500 MHz, CD3OD) δH 8.20 (s, 1H, H8), 5.90 (d, J = 2.4 Hz, 1H, H1’), 4.75-4.71 (m, 1H, H2’), 4.54-4.48 (m, 1H, H4’), 3.91 (dd, J = 12.3, 2.5 Hz, 1H, H5’), 3.69 (dd, J = 12.30, 4.0 Hz, 1H, H5’), 3.37 (s, 3H, OCH3), 2.43-2.35 (m, 1H, H3’), 2.08-2.02 (m, 1H, H3’). 13C NMR (125 MHz, CD3OD) δC 163.68 (C2), 158.12 (C6), 151.94 (C4), 139.71 (C8), 116.64 (C5), 93.36 (C1’), 82.53 (C4’), 76.59 (C2’), 64.24 (C5’), 55.29 (OCH3), 34.81 (C3’).
1H NMR (500 MHz, CD3OD): δH 8.26 (s, 0.5H, H8), 8.24 (s, 0.5H, H8), 8.22 (s, 0.5H, H2), 8.21 (s, 0.5H, H2), 7.34-7.25 (m, 7H, Ar), 7.21-7.13 (m, 3H, Ar), 6.01 (d, J = 2.9 Hz, 1H, H1’), 6.00 (d, J = 2.9 Hz, 1H, H1’), 5.15-5.04 (m, 2H, OCH2Ph), 4.73-4.63 (m, 2H, H2’, H4’), 4.43-4.35 (m, 1H, H5’), 4.27-4.20 (m, 1H, H5’), 4.03-3.91 (m, 1H, CHCH3), 2.35-2.28 (m, 1H, H3’), 2.09-2.02 (m, 1H, H3’), 1.32 (d, J = 7.4 Hz, 1.5 H, CHCH3), 1.28 (d, J = 7.4 Hz, 1.5 H, CHCH3).
13C NMR (125 MHz, CD3OD): δC 174.84 (d, 3JC-P = 4.5 Hz, C=O), 174.63 (d, 3JC-P = 4.5 Hz, C=O), 157.32 (C6), 157.31 (C6), 153.86 (C2), 153.84 (C2), 152.13 (C4), 152.07 (C4), 150.20 (C-Ar), 150.18 (C-Ar), 140.47 (C8), 137.26 (C-Ar), 137.19 (C-Ar), 130.76 (CH-Ar), 130.74 (CH-Ar), 129.57 (CH-Ar), 129.32 (CH-Ar), 129.31 (CH-Ar), 129.29 (CH-Ar), 129.26 (CH-Ar), 126.16 (CH-Ar), 126.14 (CH-Ar), 121.46 (d, 3JC-P = 4.7 Hz, CH-Ar), 121.38 (d, 3JC-P = 4.7 Hz, CH-Ar) 120.54 (C5), 120.53 (C5), 93.24 (C1’), 93.18 (C1’), 80.43 (d, 3JC-P = 3.6 Hz, C4’), 80.36 (d, 3JC-P = 3.6 Hz, C4’), 76.62 (C2’), 68.62 (d, 2JC-P = 5.3 Hz, C5’), 68.30 (d, 2JC-P = 5.3 Hz, C5’), 67.95 (OCH2Ph), 67.92 (OCH2Ph), 51.74 (CHCH3), 51.60 (CHCH3), 34.91 (C3’), 34.70 (C3’), 20.45 (d, 3JC-P = 7.0 Hz, CHCH3), 20.28 (d, 3JC-P = 7.0 Hz, CHCH3).
31P NMR (202 MHz, CD3OD): δP 3.9, 3.7.
31P NMR (202 MHz, CH3OD): δP 4.3 (s), 4.1 (s).
1H NMR (500 MHz, CH3OD): δH 8.24 (s, 0.5H, H8), 8.22 (s, 0.5H, H8), 8.20 (s, 0.5H, H2), 8.19 (s, 0.5H, H2), 8.14-8.09 (m, 1H, Ar), 7.89-7.85 (m, 1H, Ar), 7.70-7.67 (m, 1H, Ar), 7.53-7.42 (m, 3H, Ar), 7.39-7.34 (m, 1H, Ar), 7.31-7.25 (m, 5H, Ar), 5.99 (d, J = 2.0 Hz, 0.5H, H1’), 5.98 (d, J = 2.0 Hz, 0.5H, H1’), 5.10-5.01 (m, 2H, CH2Ph), 4.72-4.61 (m, 2H, H2’, H4’), 4.47-4.40 (m, 1H, H5’), 4.33-4.24 (m, 1H, H5’), 4.09-3.98 (m, 1H, CH ala) 2.35-2.26 (m, 1H, H3’), 2.07-1.98 (m, 1H, H3’), 1.30-1.24 (m, 3H, CH3).
13C NMR (125 MHz, CH3OD): δC 174.85 (d, 3JC-P= 3.7 Hz, C=O), 174.56 (d, 3JC-P = 3.7 Hz, C=O), 157.33 (C6), 157.31 (C6), 153.87 (C2), 153.85 (C2), 150.24 (C4), 150.23 (C4), 147.91 (d, 3JC-P = 7.5 Hz, 「イプソ」 Nap), 147.95, (d, 3JC-P = 7.5 Hz, 「イプソ」Nap), 140.56 (C8), 140.50 (C8), 137.22 (C-Ar), 137.17 (C-Ar), 136.28 (C-Ar), 129.55 (CH-Ar), 129.53 (CH-Ar), 129.30 (CH-Ar), 129.25 (CH-Ar), 128.88 (CH-Ar), 128.82 (CH-Ar), 127.91 (d, 2JC-P = 6.25 Hz, C-Ar), 127.83 (d, 2JC-P= 6.25 Hz, C-Ar), 127.77 (CH-Ar), 127.75 (CH-Ar), 127.49 (CH-Ar), 127.45 (CH-Ar), 126.48 (CH-Ar), 126.47 (CH-Ar), 126.02 (CH-Ar), 125.97 (CH-Ar), 122.77 (CH-Ar), 122.63 (CH-Ar), 120.58 (C5), 120.53 (C5), 116.35 (d, 3JC-P= 3.75 Hz, CH-Ar), 116.15 (d, 3JC-P = 3.75 Hz, CH-Ar), 93.22 (C1’), 93.20 (C1’), 80.30 (d, 3JC-P = 2.75 Hz, C4’), 80.24 (d, 3JC-P = 2.75 Hz, C4’), 76.51 (C2’), 76.44 (C2’), 68.87 (d, 2JC-P= 5.2 Hz, C5’), 68.64 (d, 2JC-P = 5.2 Hz, C5’), 67.93 (OCH2Ph), 51.82 (CH ala), 51.73 (CH ala), 35.01 (C-3’), 34.76 (C3’), 20.41 (d, 3JC-P = 6.7 Hz, CH3ala), 20.22 (d, 3JC-P = 6.7, CH3 ala).
31P NMR (202 MHz, CH3OD) δ 5.1, 4.9.
1H NMR (500 MHz, CH3OD) δ 8.27 (s, 0.5H, H8), 8.24 (s, 0.5H, H8), 8.22 (s, 0.5H, H2), 8.21 (s, 0.5H, H2), 7.37-7.26 (m, 7H, Ph), 7.22-7.13 (m, 3H, Ph), 6.02 (d, J = 1.8 Hz, 0.5H, H1’), 6.00 (d, J = 1.8 Hz, 0.5H, H1’), 5.14-5.11 (m, 2H, OCH2Ph), 4.73-4.64 (m, 2H, H2’, H4’), 4.50-4.39 (m, 1H, H5’), 4.36-4.24 (m, 1H, H5’), 3.53-3.71 (m, 2H, CH2 gly), 2.39-2.25 (m, 1H, H3’), 2.13-2.02 (m, 1H, H3’).
13C NMR (125 MHz, CH3OD) δ 172.30 (d, 3JC-P = 5.0 Hz, C=O), 172.27 (d, 3JC-P = 5.0 Hz, C=O), 157.34 (C6), 157.32 (C6), 153.88 (C2), 153.87 (C2), 152.08 (d, 3JC-P= 7.5 Hz, C-Ar), 152.05 (d, 3JC-P = 7.5 Hz, C-Ar), 150.20 (C4), 150.19 (C4), 140.52 (C8), 140.42 (C8), 137.15 (C-Ar), 130.79 (CH-Ar), 129.57 (CH-Ar), 129.55 (CH-Ar), 129.35 (CH-Ar), 129.34 (CH-Ar), 129.33 (CH-Ar), 126.22 (CH-Ar), 121.44 (d, JC-P = 3.7 Hz, CH-Ar), 121.40 (d, JC-P= 3.7 Hz, CH-Ar), 120.51 (C5), 120.49 (C5), 93.19, 93.14 (C1’), 80.46 (d, 3JC-P= 4.60 Hz, C4’), 80.39 (d, 3JC-P = 4.60, C4’), 76.66 (C2’), 68.68 (d, 2JC-P= 5.42 Hz, C5’), 68.24 (d, 2JC-P = 5.42 Hz, C5’), 67.95 (OCH2Ph), 67.93 (OCH2Ph), 43.90 (CH2 gly), 43.83 (CH2 gly), 34.83 (C3’), 34.54 (C3’).
31P NMR (202 MHz, CH3OD) δ 4.64, 4.37.
1H NMR (500 MHz, CH3OD) δ 8.28 (s, 0.5H, H-8), 8.25 (s, 0.5H, H-8), 8.21 (s, 0.5H, H-2), 8.20 (s, 0.5H, H-2), 8.17-8.12 (m, 1H, Nap), 7.88-7.83 (m, 1H, Nap), 7.69-7.66 (m, 1H, Nap), 7.54-7.42 (m, 3H, Nap), 7.40-7.35 (m, 1H, Nap), 7.31-7.26 (m, 5H, Ar), 6.01 (d, J = 2.1 Hz, 0.5H, H1’), 6.00 (d, J = 2.1 Hz, 0.5H, H1’), 4.47-4.67 (m, 2H, H2’, H4’), 4.55-4.44 (m, 1H, H5’), 4.43-4.31 (m, 1H, H5’), 4.00-3.87 (m, 3H, CH leu, CH2 Pen), 2.44-2.30 (m, 1H, H3’), 2.14-2.04 (m, 1H, H3’), 1.66-1.39 (m, 5H, CH2CH leu, CH2 Pen), 1.1.28-1.21 (m, 4H, CH2CH2Pen), 0.86-0.81 (m, 3H, CH3 Pen), 0.81-0.68 (m, 6H, (CH3)2leu).
13C NMR (125 MHz, CH3OD) δ 175.42 (d, 3JC-P = 2.5 Hz, C=O), 175.04 (d, 3JC-P = 2.5 Hz, C=O), 157.32 (C6), 153.87 (C2), 153.86 (C2), 150.23 (C4), 147.97 (d, 3JC-P= 6.2 Hz, 「イプソ」 Nap), 140.55 (C8), 136.30 (C-Ar), 136.29 (C-Ar), 128.89 (CH-Ar), 128.84 (CH-Ar), 127.95 (C-Ar), 127.91 (C-Ar), 127.84 (C-Ar), 127.78 (CH-Ar), 127.76 (CH-Ar), 127.46 (CH-Ar), 126.50 (C-Ar), 126.48 (C-Ar), 126.46 (C-Ar), 126.01 (CH-Ar), 125.91 (CH-Ar), 122.80 (CH-Ar), 122.70 (CH-Ar), 120.58 (C5), 120.56 (C5), 116.40 (d, 3JC-P= 3.7 Hz, CH-Ar), 116.01 (d, 3JC-P = 3.7 Hz, CH-Ar), 93.31 (C1’), 93.27 (C1’), 80.35 (d, 3JC-P = 3.5 Hz, C4’), 80.29 (d, 3JC-P = 3.5 Hz, C4’), 76.54 (C2’), 76.50 (C2’), 69.07 (d, 2JC-P = 5.5 Hz, C5’), 68.85 (d, 2JC-P = 5.5 Hz, C5’), 66.33 (CH2 Pent), 66.32 (CH2 Pent), 54.81 (CH leu), 54.71 (CH leu), 44.22 (d, 3JC-P = 7.6 Hz, CH2 leu), 43.93 (d, 3JC-P = 7.6 Hz, CH2 leu), 35.15 (C3’), 34.86 (C3’), 29.32 (CH2 pent), 29.30 (CH2 Pent), 29.11 (CH2 pent), 25.67 (CH leu), 25.45 (CH leu), 23.30 (CH2 pent), 23.12 (CH3 leu), 23.02 (CH3leu), 22.04 (CH3 leu), 21.78 (CH3 leu), 14.28 (CH3pent).
31P NMR (202 MHz, CH3OD) δ 2.73.
1H NMR (500 MHz, CH3OD) δ 8.28 (s, 0.5H, H8), 8.25 (s, 0.5H, H8), 8.21 (s, 0.5H, H2), 8.19 (s, 0.5H, H2), 8.18-8.14 (m, 1H, Nap), 7.90-7.84 (m, 1H, Nap), 7.71-7.66 (m, 1H, Nap), 7.53-7.47 (m, 3H, Nap), 7.41-7.35 (m, 1H, Nap), 6.03 (d, J = 2.1 Hz, 0.5H, H1’), 5.99 (d, J = 2.1 Hz, 0.5H, H1’), 4.76-4.67 (m, 2H, H2’, H4’), 4.52-4.44 (m, 1H, H5’), 4.42-4.33 (m, 1H, H5’), 3.65 (s, 1.5H, OCH3), 3.64 (s, 1.5H, OCH3), 2.48-2.41 (m, 0.5H, H3’), 2.37-2.30 (m, 0.5H, H3’), 2.15-2.09 (m, 0.5H, H3’), 2.08-2.02 (m, 0.5H, H3’), 1.47-1.44 (m, 6H, CH3).
13C NMR (125 MHz, CH3OD) δ 177.25 (d, 3JC-P = 3.7 Hz, C=O), 157.53 (C6), 157.51 (C6), 153.86 (C2), 150.28 (C4), 150.25 (C4), 148.06 (d, 3JC-P = 7.5 Hz, 「イプソ」 Nap), 148.04 (d, 3JC-P = 7.5, 「イプソ」 Nap), 140.67 (C8), 140.60 (C8), 136.28 (C-Ar), 136.27 (C-Ar), 128.82 (CH-Ar), 128.80 (CH-Ar), 127.93 (d, 2JC-P = 6.25 Hz, C-Ar), 127.92 (d, 2 JC-P= 6.25 Hz, C-Ar), 127.71 (CH-Ar), 127.69 (CH-Ar), 127.32 (CH-Ar), 126.44 (CH-Ar), 125.84 (CH-Ar), 122.93 (CH-Ar), 120.56 (C5), 120.50 (C5), 116.38 (d, 3JC-P= 3.75 Hz, CH-Ar), 116.36 (d, 3JC-P = 3.75 Hz, CH-Ar), 93.25 (C1’), 80.40 (d, 3JC-P= 8.0 Hz, C4’), 80.33 (d, 3JC-P = 8.0 Hz, C4’), 76.57 (C2’), 76.43 (C2’), 68.99 (d, 2JC-P = 5.5 Hz, C5’), 68.84 (d, 2JC-P = 5.5 Hz, C5’), 53.01 (OCH3), 35.22 (C-3’), 34.90 (C3’), 27.85 (d, 3JC-P = 6.0 Hz, CH3), 27.80 (d, 3JC-P = 6.0, CH3), 27.60 (d, 3JC-P= 6.0, CH3), 27.56 (d, 3JC-P = 6.0, CH3).
31P NMR (202 MHz, CH3OD): δP 3.95, 3.65.
1H NMR (500 MHz, CH3OD): δH 8.25 (s, 0.5H, H8), 8.21 (s, 1H, H8, H2), 8.20 (s, 0.5H, H2), 7.35-7.29 (m, 6H, Ph), 7.25-7.21 (m, 1H, Ph), 7.16-7.07 (m, 2H, Ar), 6.00 (d, J = 1.9 Hz, 0.5H, H1’), 5.98 (d, J = 1.9 Hz, 0.5H, H1’), 5.17-5.05 (m, 2H, OCH2Ph), 4.76-4.73 (m, 0.5H, H2’), 4.70-4.59 (m, 1.5H, H2’, H4’), 4.45-4.34 (m, 1H, H5’), 4.30-4.22 (m, 1H, H5’), 4.08-3.96 (m, 3H, CH2CH3, CH ala), 2.98-2.92 (m, 2H, CH2CH2), 2.62-2.56 (m, 2H, CH2CH2), 2.40-2.29 (m, 1H, H3’), 2.11-2.03 (m, 1H, H3’), 1.36 (d, J = 6.9 Hz, 1.5 H, CH3 ala), 1.33 (d, J = 6.9 Hz, 1.5 H, CH3 ala), 1.17 (t, J = 7.0 Hz, 1.5 H, CH2CH3), 1.16 (t, J = 7.0 Hz, 1.5 H, CH2CH3).
13C NMR (125 MHz, CH3OD): δC 174.82 (d, 3JC-P = 3.7 Hz, C=O), 174.62 (C=O), 174.58 (C=O), 174.55 (d, 3JC-P = 3.7 Hz, C=O), 157.34 (C6), 157.32 (C6), 153.86 (C2), 153.84 (C2), 150.48 (d, JC-P = 2.5 Hz, C-Ar), 150.44 (C4), 150.22 (d, JC-P = 2.5 Hz, C-Ar), 140.49 (C8), 137.29 (C-Ar), 137.21 (C-Ar), 133.09 (d, J = 7.5 Hz, C-Ar), 132.94 (d, J = 7.5 Hz, C-Ar), 131.62 (CH-Ar), 131.59 (CH-Ar), 129.58 (CH-Ar), 129.34 (CH-Ar), 129.31 (CH-Ar), 129.28 (CH-Ar), 128.70 (d, J = 5.0 Hz, CH-Ar), 128.69 (d, J = 5.0 Hz, CH-Ar), 126.18 (CH-Ar), 121.02 (d, J = 2.5 Hz, CH-Ar), 120.49 (d, J = 2.5 Hz, CH-Ar), 120.58 (C5), 93.28 (C1’), 93.24 (C1’), 80.32 (d, 3JC-P = 8.7 Hz, C4’), 76.57 (C2’), 68.86 (d, 2JC-P = 5.0 Hz, C5’), 68.53 (d, 2JC-P = 5.0 Hz, C5’), 67.98 (OCH2Ph), 67.95 (OCH2Ph), 61.57 (CH2CH3), 51.76 (CH ala), 51.65 (CH ala), 35.37 (CH2CH2), 35.30 (CH2CH2), 35.08 (C3’), 34.85 (C3’), 26.77 (CH2CH2), 26.72 (CH2CH2), 20.55 (d, 3JC-P = 6.2 Hz, CH3 ala), 20.33 (d, 3JC-P = 6.2 Hz, CH3 ala), 14.53 (CH2CH3).
31P NMR (202 MHz, CH3OD): δP 2.44 (s), 2.92 (s).
1H NMR (500 MHz, CH3OD): δH 8.41 (s, 0.5 H, H8), 8.28 (s, 0.5 H, H8), 8.19 (s, 0.5H, H2), 8.18 (s, 0.5H, H2), 7.39-7.30 (m, 4H, Ar), 7.28-7.18 (m, 4H, Ar), 7.17-7.11 (m, 1H, Ar), 7.08-7.03 (m, 1H, Ar), 6.23 (d, J = 2.0 Hz, 0.5H, H1’), 6.08 (d, J = 3.4 Hz, 0.5H, H1’), 5.52-5.43 (m, 1H, C2’), 5.19-5.12 (m, 1H, CH2Ph), 5.07-4.95 (m, 1H, CH2Ph), 4.48-4.42 (m, 1H, H4’), 4.05-3.97 (m, 1H, CH ala), 3.95-3.87 (m, 1H, H5’), 3.69-3.61 (m, 1H, H5’), 2.59-2.45 (m, 1H, H3’), 2.31-2.23 (m, 1H, H3’), 1.36-1.27 (m, 3H, CH3 ala).
13C NMR (125 MHz, CH3OH): δC 174.76 (d, 3JC-P= 5.0 Hz, C=O), 174.52 (d, 3JC-P = 5.0 Hz, C=O), 157.44 (C6), 153.76 (C2), 151.93 (C4), 150.06 (C-Ar), 149.93 (C-Ar), 141.38 (C8), 141.18 (C8), 137.33 (C-Ar), 137.10 (C-Ar), 130.69 (CH-Ar), 130.79 (CH-Ar), 129.61 (CH-Ar), 129.51 (CH-Ar), 129.40 (CH-Ar), 129.30 (CH-Ar), 129.23 (CH-Ar), 126.33 (CH-Ar), 126.16 (CH-Ar), 121.53 (d, 3JC-P = 4.5 Hz, CH-Ar), 121.20 (d, 3JC-P = 4.5 H, CH-Ar), 120.76 (C5), 91.56 (d, 3JC-P = 7.7 Hz, C1’), 91.45 (d, 3JC-P = 7.7 Hz, C1’), 82.78 (C4’), 82.28 (C4’), 81.83 (d, 2JC-P = 4.7 Hz, C2’), 80.96 (2 x d, 2JC-P = 4.7 Hz, C2’), 67.95 (OCH2Ph), 67.92 (OCH2Ph), 64.13 (C5’), 63.59 (C5’), 51.88 (CH ala), 51.75 (CH ala), 33.75 (d, 3JC-P = 3.0 Hz, C3’), 33.59 (d, 3JC-P = 3.0 Hz, C3’), 20.33 (d, 3JC-P = 7.1 CH3 ala), 20.18 (d, 3JC-P = 7.1 CH3 ala).
31P NMR (202 MHz, CH3OD): δP 3.98, 3.88, 3.59, 3.12, 3.05, 2.45, 2.32.
1H NMR (500 MHz, CH3OD): δH 8.24-8.13 (m, 2H, H8, H2), 7.39-7.08 (m, 20H, Ph), 6.27-6.23 (m, 0.5H, H1’), 6.16-6.13 (m, 0.5H, H1’), 5.61-5.48 (m, 1H, H2’), 5.17-4.91 (m, 4H, CH2Ph), 4.57-4.49 (m, 1H, H4’), 4.41-4.29 (m, 1H, H5’), 4.25-4.15 (m, 1H, H5’), 4.10-4.01 (m, 1H, CH ala), 3.99-3.89 (m, 1H, CH ala), 2.57-2.41 (m, 1H, H3’), 2.28-2.17 (m, 1H, H3’), 1.38-1.23 (m, 6H, CH3 ala).
13C NMR (125 MHz, CH3OD): δC 174.88 (C=O), 174.83 (C=O), 174.79 (C=O), 174.73 (C=O), 174.61 (C=O), 174.57 (C=O), 174.53 (C=O), 157.36 (C6), 157.34 (C6), 157.32(C6), 157.29 (C6), 154.04 (C2), 154.01 (C2), 153.97 (C2), 153.94 (C2), 152.09 (C4), 152.04 (C4), 152.02 (C4), 151.97 (C4), 150.31 (C-Ar), 150.29 (C-Ar), 150.16 (C-Ar), 140.98 (C8), 140.91 (C8), 140.81 (C8), 137.31 (C-Ar), 137.28 (C-Ar), 137.22 (C-Ar), 137.09 (C-Ar), 130.86 (CH-Ar), 130.78 (CH-Ar), 130.77 (CH-Ar), 129.65 (CH-Ar), 129.61 (CH-Ar), 129.58 (CH-Ar), 129.55 (CH-Ar), 129.44 (CH-Ar), 129.42 (CH-Ar), 129.38 (CH-Ar), 129.34 (CH-Ar), 129.32 (CH-Ar), 129.30 (CH-Ar), 129.28 (CH-Ar), 129.23 (CH-Ar), 129.21 (CH-Ar), 12.42 (CH-Ar), 126.23 (CH-Ar), 126.20 (CH-Ar), 126.17 (CH-Ar), 121.65 (CH-Ar), 121.63 (CH-Ar), 121.61 (CH-Ar), 121.59 (CH-Ar), 121.52 (CH-Ar), 121.50 (CH-Ar), 121.47 (CH-Ar), 121.46 (CH-Ar), 121.40 (CH-Ar), 121.39 (CH-Ar), 121.36 (CH-Ar), 121.35 (CH-Ar), 121.30 (CH-Ar), 121.28 (CH-Ar), 121.26 (CH-Ar), 121.24 (CH-Ar), 120.61 (C5), 120.57 (C5), 120.56 (C5), 120.54 (C5), 91.56 (C1’), 91.51 (C1’), 91.45 (C1’), 91.25 (C1’), 91.20 (C1’), 81.84 (C2’), 81.82 (C2’), 81.79 (C2’), 81.27 (C2’), 81.22 (C2’), 81.18 (C2’), 80.49 (C4’), 80.43 (C4’), 80.06 (C4’), 79.99 (C4’), 68.29 (C5’, OCH2Ph), 68.25 (C5’, OCH2Ph), 68.00 (C5’, OCH2Ph), 67.96 (C5’, OCH2Ph), 67.94 (C5’, OCH2Ph), 67.90 (C5’, OCH2Ph), 67.71 (C5’, OCH2Ph), 67.67 (C5’, OCH2Ph), 51.91 (CH ala), 51.74 (CH ala), 51.70 (CH ala), 51.59 (CH ala), 34.22 (C3’), 34.20 (C3’), 34.16 (C3’), 33.97 (C3’), 33.94 (C3’), 33.91 (C3’), 20.44 (CH3 ala), 20.43 (CH3 ala), 20.39 (CH3 ala), 20.29 (CH3ala), 20.27 (CH3 ala), 20.24 (CH3 ala), 20.21 (CH3ala), 20.19 (CH3 ala).
31P NMR (202 MHz, CH3OD): δP 3.27 (s), 2.75 (s).
1H NMR (500 MHz, CH3OD): δH 8.37 (s, 1H, H8), 8.18 (s, 1H, H8), 8.14 (s, 1H, H2), 8.13-8.11 (m, 0.5 H, Nap) 8.11 (s, 1H, H2), 7.94-7.90 (m, 0.5 H, Ar), 7.90-7.87 (m, 0.5 H, Ar), 7.86-7.82 (m, 0.5 H, Ar), 7.74-7.70 (m, 0.5 H, Ar), 7.66-7.61 (m, 0.5 H, Ar), 7.57-7.47 (m, 1.5 H, Ar), 7.46-7.37 (m, 2.5 H, Ar), 7.34-7.27 (m, 4 H, Ar), 7.25-7.17 (m, 1 H, Ar), 6.19 (d, J = 2.4 Hz, 0.5H, H1’), 6.04 (d, J = 2.4 Hz, 0.5H, H1’), 5.60-5.54 (m, 0.5H, H2’), 5.50-5.42 (m, 0.5H, H2’), 5.16-4.99 (m, 2H, OCH2Ph), 4.46-4.40 (m, 0.5H, H4’), 4.36-4.30 (m, 0.5H, H4’), 4.13-4.04 (m, 1H, CH ala), 3.90-3.83 (m, 1H, H5’), 3.64-3.56 (m, 1H, H5’), 2.61-2.54 (m, 0.5H, H3’), 2.49-2.41 (m, 0.5H, H3’), 2.35-2.27 (m, 0.5H, H3’), 2.22-2.16 (m, 0.5H, H3’), 1.35-1.24 (m, 3H, CH3 ala).
13C NMR (125 MHz, CH3OH): δC 174.52 (C=O), 174.49 (C=O), 157.27 (C6), 153.58 (C2), 149.97 (C4), 149.93 (C-4), 147.70 (d, 3JC-P= 7.5, 「イプソ」 Nap), 147.48 (d, 3JC-P= 7.5, 「イプソ」 Nap), 141.36 (C8), 141.19 (C8), 137.25 (C-Ar), 137.05 (C-Ar), 136.31 (C-Ar), 136.20 (C-Ar), 129.58 (CH-Ar), 129.48 (CH-Ar), 129.37 (CH-Ar), 129.26 (CH-Ar), 129.22 (CH-Ar), 128.88 (CH-Ar), 127.84 (CH-Ar), 127.75 (CH-Ar), 127.49 (CH-Ar), 127.44 (CH-Ar), 126.48 (CH-Ar), 126.39 (CH-Ar), 126.26 (CH-Ar), 126.05 (CH-Ar), 122.76 (CH-Ar), 122.38 (CH-Ar), 120.68 (C5), 120.61 (C5), 116.64 (d, 3JC-P = 3.75 Hz, CH-Ar), 116.13 (d, 3JC-P = 3.75, CH-Ar), 91.60 (d, 3JC-P= 7.5 Hz, C1’), 91.43 (d, 3JC-P = 7.5 Hz, C1’), 82.74 (C4’), 82.27 (C4’), 81.99 (d, 2JC-P = 5.5 Hz, C2’), 81.12 (d, 2JC-P = 5.5 Hz, C2’), 67.97 (OCH2Ph), 67.94 (OCH2Ph), 64.16 (C5’), 63.51 (C5’), 51.96 (CH ala), 51.89 (CH ala), 33.89 (d, 3JC-P = 7.5 Hz, CH3ala), 33.63 (d, 3JC-P = 7.5 Hz, CH3 ala).
31P NMR (202 MHz, CH3OD) δ 13.9.
1H NMR (500 MHz, CH3OD) δ 8.28 (s, 1H, H8), 8.22 (s, 1H, H2), 7.37-7.26 (m, 10H, Ph), 6.00 (d, J = 1.9 Hz, 1H, H1’), 5.15-5.05 (m, 4H, OCH2Ph), 4.74-4.70 (m, 1H, H2’), 4.63-4.56 (m, 1H, H4’), 4.24-4.18 (m, 1H, H5’), 4.11-4.05 (m, 1H, H5’), 3.97-3.87 (m, 1H, CH ala), 2.35-2.27 (m, 1H, H3’), 2.07-2.01 (m, 1H, H3’), 1.34-1.27 (m, 3H, CH3ala).
13C NMR (125 MHz, CH3OD) δ 175.40 (d, 3JC-P = 5.0 Hz, C=O), 175.36 (d, 3JC-P = 5.0 Hz, C=O), 157.36 (C6), 153.91 (C2), 150.25 (C4), 140.64 (C8), 137.33 (C-Ar), 137.29 (C-Ar), 129.58 (CH-Ar), 129.57 (CH-Ar), 129.33 (CH-Ar), 129.31 (CH-Ar), 129.29 (CH-Ar), 120.55 (C5), 93.18 (C1’), 80.67 (d, 3JC-P = 8.4 Hz, C4’), 76.59 (C2’), 67.90 (OCH2Ph), 67.47 (d, 2JC-P = 5.2 Hz, C5’), 51.14 (d, 2JC-P = 1.7 Hz, CH ala), 51.11 (d, 2JC-P = 1.7 Hz, CH ala), 35.08 (C3’), 20.77 (d, 3JC-P = 6.5 Hz, CH3ala), 20.59 (d, 3JC-P = 6.5 Hz, CH3 ala).
31P NMR (202 MHz, CD3OD): δP 4.38 (s), 4.08 (s). 1H NMR (500 MHz, CD3OD): δH 8.14-8.11 (d, J = 8.0Hz, 0.5H, Ar), 8.07 (d, J = 8.0Hz, 0.5H, Ar), 8.05 (s, 0.5H, H8), 8.02 (s, 0.5H, H8), 7.82-7.80 (m, 1H, Ar), 7.61 (d, J = 7.0Hz, Ar), 7.47-7.44 (m, 4H, Ar), 7.35-7.29 (m, 2H, Ar), 7.24-7.22 (m, 3H, Ar), 5.88 (s, 1H, H1’), 4.71-4.68 (m, 1H, H4’), 4.65-6.60 (m, 1H, H2’), 4.42-4.40 (m, 1H, H5’), 4.30-4.27 (m, 1H, H5’), 4.08-3.98 (m, 1H, CH ala) 3.88 (s, 1.5H, OCH3), 3.86 (s, 1.5H, OCH3), 2.37-2.33 (m, 1H, H3’), 2.04-2.01 (m, 1H, H3’), 1.27 (d J = 7.0 Hz, 1.5H, CH3), 1.24 (d J = 7.0 Hz, 1.5H, CH3). 13C NMR (125 MHz, CH3OD): δC 174.83 (d, 3JC-P = 3.7 Hz, C=O), 174.60 (d, 3JC-P= 3.7 Hz, C=O), 163.70 (C-2), 158.10 (C6), 151.95 (C4), 147.95 (d, 3JC-P= 7.5 Hz, 「イプソ」 Nap), 147.91, (d, 3JC-P= 7.5 Hz, 「イプソ」 Nap), 139.39 (C8), 139.37 (C8), 137.12, 137.17 (C-イプソ CH2Ph), 136.22 (C-Ar), 129.57, 129.54, 129.48, 129.32, 129.27, 129.12, 129.24 128.89, 128.83, (CH-Ar), 127.85 (d, 2JC-P = 6.25 Hz, C-Ar), 127.86, 127.76, 127.51, 127.48, 126.49, 126.00, 125.97, 122.73, 122.63 (CH-Ar), 116.86 (C5), 116.72 (C5), 116.29 (d, 3JC-P = 3.75 Hz, CH-Ar), 116.22 (d, 3JC-P= 3.75 Hz, CH-Ar), 93.33 (C1’), 93.31(C1’), 80.24 (d, 3JC-P = 2.75 Hz, C4’), 76.29 (C2’), 76.26 (C2’), 69.09 (d, 2JC-P = 5.0 Hz, C5’), 68.16 (d, 2JC-P = 8.2 Hz, C5’), 67.95 (OCH2Ph), 55.28, 55.32 (OCH3), 51.79 (CH ala), 51.71 (CH ala), 35.40 (C-3’), 35.12 (C3’), 20.49 (d, 3JC-P = 6.7 Hz, CH3ala), 20.35 (d, 3JC-P = 6.7, CH3 ala).
31P NMR (202 MHz, CD3OD) δ 3.97, 3.64. 1H NMR (500 MHz, CD3OD) δ 8.06 (s, 0.5H, H8), 8.04 (s, 0.5H, H8), 7.33-7.28 (m, 7H, Ph), 7.20-7.14 (m, 3H, Ph), 5.92 (d, J = 1.5 Hz, 0.5H, H1’), 5.90 (d, J = 1.5 Hz, 0.5H, H1’), 5.14-5.04 (m, 2H, OCH2Ph), 4.78-4.76 (m, 0.5H, H4’), 4.74-4.72 (m, 0.5H, H4’), 4.63-4.59 (m, 1H, H2’), 4.10-4.34 (m, 1H, H5’a), 4.25-4.20 (m, 1H, H5’b), 3.94, 3.95 (OCH3), 3.99-3.90 (m, 1H, CH ala), 2.40-2.37 (m, 1H, H3’), 2.07-2.04 (m, 1H, H3’), 1.31 (d J =7.0 Hz, CH3), 1.26 (d, J = 7.0 Hz, CH3). 13C NMR (125 MHz, CD3OD) δ 174.82 (d, 3JC-P = 3.7 Hz, C=O), 174.62 (d, 3JC-P = 3.7 Hz, C=O), 163.80 (C-2), 158.16, 158.13 (C6), 152.15 (C4), 152.05 (d, 3JC-P = 4.8 Hz, C-イプソ Ph), 152.00 (d, 3JC-P= 4.8 Hz, C-イプソ Ph), 139.39 (C8), 137.30, 137.21 (C-イプソCH2Ph), 130.72, 129.57, 129.31,129.27, 126.122 (CH-Ar), 121.42 (d, JC-P= 4.5 Hz, CH-Ar), 121.37 (d, JC-P = 4.5 Hz, CH-Ar), 116.72 (C5), 116.69 (C5), 93.33, 93.24 (C1’), 80.26 (d, 3JC-P = 8.87, C4’), 80.19 (d, 3JC-P = 8.87, C4’), 76.35 (C2’), 68.78 (d, 2JC-P= 5.0 Hz, C5’), 68.35 (d, 2JC-P = 5.0 Hz, C5’), 67.94 (OCH2Ph), 67.92 (OCH2Ph), 55.25, 55.28 (OCH3), 51.69, 51.57 (CH ala), 35.23 (C3’), 34.96 (C3’), 20.38 (d, 3JC-P= 6.7, CH3 ala), 20.26 (d, 3JC-P = 6.7, CH3ala).
31P NMR (202 MHz, CD3OD) δP 4.53, 4.28.
1H NMR (500 MHz, CD3OD) δH 8.04-7.96 (m, 1H, H8), 7.77-7.71 (m, 1H, Nap), 7.58-7.53 (m, 1H, Nap), 7.45-7.17 (m, 5H, Nap), 5.83-5.75 (m, 1H, H1’), 4.64-4.51 (m, 2H, H2’, H4’), 4.40-4.16 (m, 2H, H5’), 3.88-3.75 (m, 6H, OCH3, O(CH2)4CH3, CHCH2CH(CH3)2), 2.38-2.24 (m, 1H, H3’), 2.00-1.91 (m, 1H, H3’), 1.53-1.05 (m, 11H, O(CH2)4CH3, CHCH2CH(CH3)2), 0.77-0.55 (m, 9H, O(CH2)4CH3, CHCH2CH(CH3)2).
13C NMR (125 MHz, CD3OD) δC 175.02 (d, 3JC-P= 2.5 Hz, C=O), 174.78 (d, 3JC-P = 2.5 Hz, C=O), 163.76 (C2), 158.14 (C6), 151.03 (C4), 147.96 (d, 3JC-P = 7.2, 「イプソ」 Nap), 138.96 (C8), 136.30 (C-Ar), 136.28 (C-Ar), 136.22 (C-Ar), 128.93 (CH-Ar), 128.88 (CH-Ar), 128.81 (CH-Ar), 128.48 (CH-Ar), 127.77 (CH-Ar), 127.73 (CH-Ar), 127.44 (CH-Ar), 127.42 (CH-Ar), 127.06 (CH-Ar), 126.86 (CH-Ar), 126.45 (CH-Ar), 126.44 (CH-Ar), 126.31 (CH-Ar), 125.98 (CH-Ar), 125.88 (CH-Ar), 123.83 (CH-Ar), 123.43 (CH-Ar), 123.24 (CH-Ar), 122.81 (CH-Ar), 122.77 (CH-Ar), 122.69 (CH-Ar), 116.34 (d, 3JC-P = 3.7 Hz, CH-Ar), 116.02 (d, 3JC-P = 3.7 Hz, CH-Ar), 115.71 (C5), 93.42 (C1’), 93.32 (C1’), 80.22 (d, 3JC-P= 5.3 Hz, C4’), 80.15 (d, 3JC-P = 5.3 Hz, C4’), 76.29 (C2’), 76.27 (C2’), 69.22 (d, 2JC-P = 5.2 Hz, C5’), 69.028 (d, 2JC-P = 5.2 Hz, C5’), 66.31 (O(CH2)4CH3), 66.30 (O(CH2)4CH3), 55.29 (OCH3), 55.24 (OCH3), 54.79 (CHCH2CH(CH3)2), 54.68 (CHCH2CH(CH3)2), 44.20 (d, 3JC-P= 7.25 Hz, CHCH2CH(CH3)2), 43.93 (d, 3JC-P= 7.25 Hz, CHCH2CH(CH3)2), 35.49 (C3’), 35.17 (C3’), 29.31 (O(CH2)4CH3), 29.11 (O(CH2)4CH3), 25.67 (CHCH2CH(CH3)2), 25.44 (CHCH2CH(CH3)2), 23.30 (O(CH2)4CH3), 23.10 (CHCH2CH(CH3)2), 23.00 (CHCH2CH(CH3)2), 22.94 (CHCH2CH(CH3)2), 22.81 (CHCH2CH(CH3)2), 14.27 (O(CH2)4CH3).
31P NMR (202 MHz, CD3OD) δP 3.87, 3.65.
1H NMR (500 MHz, CD3OD) δH 8.08 (s, 0.5H, H8), 8.07 (s, 0.5H, H8), 7.36-7.29 (m, 2H, Ph), 7.24-7.14 (m, 3H, Ph), 5.94 (d, J = 2.0 Hz, 0.5H, H1’), 5.92 (d, J = 2.0 Hz, 0.5H, H1’), 4.81-4.76 (m, 1H, H2’), 4.71-4.62 (m, 1H, H4’), 4.48-4.43 (m, 0.5H, H5’), 4.42-4.36 (m, 0.5H, H5’), 4.33-4.25 (m, 1H, H5’), 4.10-3.83 (m, 6H, OCH3, O(CH2)5CH3, CHCH3), 2.48-2.40 (m, 1H, H3’), 2.13-2.07 (m, 1H, H3’), 1.61-1.51 (m, 2H, O(CH2)5CH3), 1.33-1.24 (m, 9H, O(CH2)5CH3, CHCH3), 0.89 (m, 3H, O(CH2)5CH3).
13C NMR (125 MHz, CD3OD) δC 175.13 (d, 3JC-P = 4.3 Hz, C=O), 174.94 (d, 3JC-P = 4.3 Hz, C=O), 163.80 (C2), 163.78 (C2), 158.17 (C6), 158.15 (C6), 152.17 (d, 2JC-P= 6.3 Hz, C-Ar), 152.15 (d, 2JC-P = 6.3 Hz, C-Ar), 152.03 (C4), 151.99 (C4), 139.42 (C8), 139.39 (C8), 130.75 (CH-Ar), 130.74 (CH-Ar), 126.13 (CH-Ar), 121.43 (CH-Ar), 121.41 (CH-Ar), 121.39 (CH-Ar), 121.37 (CH-Ar), 116.74 (C5), 116.69 (C5), 93.40 (C1’), 93.27 (C1’), 80.30 (C4’), 80.23 (C4’), 76.40 (C2’), 68.85 (d, 2JC-P = 5.2 Hz, C5’), 68.42 (d, 2JC-P = 5.2 Hz, C5’), 66.43 (O(CH2)5CH3), 55.30 (OCH3), 55.26 (OCH3), 51.64 (CHCH3), 51.54 (CHCH3), 35.30 (C3’), 35.04 (C3’), 32.58 (O(CH2)5CH3), 29.67 (O(CH2)5CH3), 29.64 (O(CH2)5CH3), 26.61 (O(CH2)5CH3), 23.59 (O(CH2)5CH3), 20.56 (d, 3JC-P = 6.4 Hz, CHCH3), 20.41 (d, 3JC-P = 6.4 Hz, CHCH3), 14.36 (O(CH2)5CH3).
31P NMR (202 MHz, CD3OD) δP 4.33, 4.08.
1H NMR (500 MHz, CD3OD) δH 8.17 (s, 0.5H, H8), 8.14 (s, 0.5H, H8), 8.14-8.09 (m, 1H, Ar), 7.89-7.85 (m, 1H, Ar), 7.70-7.66 (m, 1H, Ar), 7.54-7.42 (m, 4H, Ar), 7.40-7.24 (m, 5H, Ar), 5.89 (d, J = 2.3 Hz, 0.5H, H1’), 5.88 (d, J = 2.3 Hz, 0.5H, H1’), 5.08-5.01 (m, 2H, OCH2Ph), 4.70-4.60 (m, 2H, H2’, C4’), 4.46-4.39 (m, 1H, C5’), 4.32-4.24 (m, 1H, C5’), 4.09-3.97 (m, 1H, CHCH3), 2.36-2.25 (m, 1H, H3’), 2.06-1.98 (m, 1H, H3’), 1.32-1.25 (m, 3H, CHCH3).
13C NMR (125 MHz, CD3OD) δC 175.54 (CO), 175.22 (CO), 161.02 (d, 1JC-F = 207.3 Hz, C2), 160.89 (d, 1JC-F= 207.3 Hz, C2), 158.45 (d, 3JC-F = 18.2 Hz, C6), 158.23 (d, 3JC-F = 18.2 Hz, C6), 150.63 (d, 3JC-F= 18.4 Hz, C4), 140.67 (C8), 136.26 (C-Ar), 131.62, 131.54, 129.56 (CH-Ar), 129.52 (CH-Ar), 129.37 (CH-Ar), 129.31 (CH-Ar), 129.26 (CH-Ar), 128.87 (CH-Ar), 128.81 (CH-Ar), 128.29 (CH-Ar), 128.02 (CH-Ar), 127.79 (CH-Ar), 127.76 (CH-Ar), 127.51 (CH-Ar), 127.49 (CH-Ar), 127.47 (CH-Ar), 126.47 (CH-Ar), 126.33 (C-Ar), 126.27 (C-Ar), 125.97 (CH-Ar), 122.78 (CH-Ar), 122.74 (CH-Ar), 122.64 (CH-Ar), 122.62 (CH-Ar), 116.35 (d, 4JC-F = 3.0 Hz, C5), 116.15 (d, 4JC-F= 3.0 Hz, C5), 93.25 (C1’), 93.20 (C1’), 80.41 (d, 3JC-P = 7.5 Hz, C4’), 80.33 (d, 3JC-P = 7.5 Hz, C4’), 76.43 (C2’), 76.35 (C2’), 68.84 (d, 2JC-P = 5.5 Hz, C5’), 68.45 (d, 2JC-P = 5.5 Hz, C5’), 67.92 (OCH2Ph), 67.92 (OCH2Ph), 51.75 (CHCH3), 51.52 (CHCH3), 34.97 (C3’), 34.74 (C3’), 20.42 (d, 3JC-P = 6.7 Hz, CHCH3), 20.20 (d, 3JC-P = 6.7 Hz, CHCH3).
19F NMR (470 MHz, CD3OD) δF -53.14, -53.22.
19F NMR (470 MHz, CD3OD): δF -53.17, -53.23. 31P NMR (202 MHz, CD3OD): δP 3.95 (s), 3.67 (s). 1H NMR (500 MHz, CDCl3): δH 8.19 (s, 0.5H, H8), 8.16 (s, 0.5H, H8), 7.36-7.27 (m, 7H, Ar), 7.22-7.13 (m, 3H, Ar), 5.91 (d, J = 1.5 Hz, 0.5H, H1’), 5.89 (d, J = 1.7 Hz, 0.5H, H1’), 5.15-5.06 (m, 2H, OCH2Ph), 4.73-4.58 (m, 2H, H2’, H4’), 4.42-4.34 (m, 1H, H5’), 4.02-3.90 (m, 1H, H5’), 3.27-3.24 (m, 1H, H3’), 2.08-2.00 (m, 1H, H3’), 1.33 (d, J = 7.1 Hz, 1.5H, CH3 ala), 1.29 (d, J = 7.1 Hz, 1.5H, CH3ala). 13C NMR (125 MHz, CD3OD): δC 175.85 (d, 3JC-P = 3.7 Hz, C=O), 174.63 (d, 3JC-P = 5.0 Hz, C=O), 160.58 (d, 1JC-F = 207.5 Hz, C2), 160.53 (d, 1JC-F = 207.5 Hz, C2), 159.06 (d, 3JC-F= 18.7 Hz, C6), 159.05 (d, 3JC-F = 17.5 Hz, C6), 152.11 (d, 2JC-P = 8.75 Hz, C-Ar), 152.08 (d, 2JC-P= 8.7 Hz, C-Ar), 151.58 (d, 3JC-F = 19.7 Hz, C4), 151.56 (d, 3JC-F = 19.5 Hz, C4), 140.63 (C8), 137.28 (C-Ar), 137.21 (C-Ar), 130.78 (CH-Ar), 130.75 (CH-Ar), 129.58 (CH-Ar), 129.38 (CH-Ar), 129.34 (CH-Ar), 129.32 (CH-Ar), 129.28 (CH-Ar), 128.3 (CH-Ar), 128.02 (CH-Ar), 121.16 (CH-Ar), 121.18 (CH-Ar), 121.47 (CH-Ar), 121.51 (CH-Ar), 121.42 (CH-Ar), 121.39 (CH-Ar), 121.36 (CH-Ar), 118.75 (d, 4JC-F = 3.7 Hz, C5), 118.72 (d, 4JC-F= 3.7 Hz, C5), 93.25 (C1’), 93.18 (C1’), 80.48 (d, 3JC-P = 8.3 Hz, C4’), 80.46 (d, 3JC-P = 8.1 Hz, C4’), 76.51 (C2’), 76.49 (C2’), 68.54 (d, 2JC-P = 5.2 Hz, C5’), 68.18 (d, 2JC-P = 5.6 Hz, C5’), 67.94 (CH2 Bn), 67.91 (CH2 Bn), 51.71 (CH ala), 51.56 (CH ala), 34.85 (C3’), 34.64 (C3’), 20.42 (d, 3JC-P = 7.1 Hz, CH3ala), 20.25 (d, 3JC-P = 7.5 Hz, CH3 ala).
31P NMR (202 MHz, CD3OD): 4.60, 4.35.
1H NMR (500 MHz, CD3OD): δH 8.23 (s, 0.5H, H8), 8.20 (s, 0.5H, H8), 8.18-8.12 (m, 1H, Ar), 7.92-7.86 (m, 1H, Ar), 7.73-7.68 (m, 1H, Ar), 7.57-7.46 (m, 3H, Ar), 7.42-7.36 (m, 1H, Ar), 5.93-5.91 (m, 1H, H1’), 4.74-4.62 (m, 2H, H2’, H4’), 4.55-4.50 (m, 0.5H, H5’), 4.49-4.44 (m, 0.5H, H5’), 4.43-4.37 (m, 0.5H, H5’), 4.36-4.31 (m, 0.5H, H5’), 4.02-3.86 (m, 3H, CHCH2CH(CH3)2, O(CH2)4CH3), 2.43-2.29 (m, 1H, H3’), 2.12-2.04 (m, 1H, H3’), 1.67-1.20 (m, 11H, O(CH2)4CH3, CHCH2CH(CH3)2), 0.89-0.67 (m, 9H, O(CH2)4CH3, CHCH2CH(CH3)2)
13C NMR (125 MHz, CD3OD): δC 175.03 (d, 3JC-P= 2.5 Hz, C=O), 174.93 (d, 3JC-P = 2.5 Hz, C=O), 161.45 (d, 1JC-F = 205.5 Hz, C2), 160.39 (d, 1JC-F= 205.5 Hz, C2), 158.33 (C6), 151.60 (C4), 147.92 (C-Ar), 140.69 (C8), 136.30 (C-Ar), 128.88 (CH-Ar), 128.83 (CH-Ar), 127.80 (CH-Ar), 127.76 (CH-Ar), 127.49 (CH-Ar), 127.46 (CH-Ar), 126.48 (CH-Ar), 126.45 (CH-Ar), 126.02 (CH-Ar), 125.91 (CH-Ar), 123.03 (C-Ar), 122.81 (CH-Ar), 122.69 (CH-Ar), 116.39 (d, 3JC-P= 2.9 Hz, CH-Ar), 116.28 (C5), 116.26 (C5), 115.97 (d, 3JC-P= 2.9 Hz, CH-Ar), 93.29 (C1’), 93.23 (C1’), 80.45 (d, 3JC-P = 6.0 Hz, C4’), 80.38 (d, 3JC-P = 6.0 Hz, C4’), 76.45 (C2’), 76.41 (C2’), 68.99 (d, 2JC-P = 5.4 Hz, C5’), 68.78 (d, 2JC-P = 5.4 Hz, C5’), 66.31 (O(CH2)4CH3), 66.29 (O(CH2)4CH3), 54.78 (CHCH2CH(CH3)2), 54.66 (CHCH2CH(CH3)2), 44.16 (d, 3JC-P = 7.25 Hz, CHCH2CH(CH3)2), 43.84 (d, 3JC-P = 7.3 Hz, CHCH2CH(CH3)2), 35.09 (C3’), 34.79 (C3’), 29.31 (O(CH2)4CH3), 29.12 (O(CH2)4CH3), 25.65 (CHCH2CH(CH3)2), 25.41 (CHCH2CH(CH3)2), 23.33 (O(CH2)4CH3), 23.11 (CHCH2CH(CH3)2), 23.00 (CHCH2CH(CH3)2), 21.95 (CHCH2CH(CH3)2), 21.68 (CHCH2CH(CH3)2), 14.29 (O(CH2)4CH3).
19F NMR (470 MHz, CD3OD): δF -53.15, -53.20.
19F NMR (470 MHz, CD3OD): δF -53.15, -53.20. 31P NMR (202 MHz, CD3OD): 3.91 (s), 3.73 (s). 1H NMR (500 MHz, CDCl3): δH 8.21 (s, 0.5H, H8), 8.20 (s, 0.5H, H8), 7.37-7.29 (m, 7H, Ar), 7.26-7.13 (m, 3H, Ar), 5.94-5.91 (m, 1H, H1’), 4.76-4.64 (m, 2H, H2’, H4’), 4.49-4.44 (m, 0.5H, H5’), 4.43-4.37 (m, 0.5H, H5’), 4.33-4.26 (m, 1H, H5’), 4.11-3.99 (m, 2H, CH2 Hex), 3.97-3.83 (m, 1H, CH ala), 2.41-2.32 (m, 1H, H3’), 2.13-2.06 (m, 1H, H3’), 1.62-1.52 (m, 2H, CH2 Hex), 1.37-1.23 (m, 9H, CH3 ala, CH2 Hex), 0.92-0.85 (m, 3H, CH3Hex).
13C NMR (125 MHz, CD3OD): δC 175.15 (d, 3JC-P = 3.7 Hz, C=O), 174.96 (d, 3JC-P = 5.0 Hz, C=O), 160.59 (d, 1JC-F = 207.5 Hz, C2), 160.56 (d, 1JC-F= 207.5 Hz, C2), 159.09 (d, 3JC-F = 21.2 Hz, C6), 159.08 (d, 3JC-F = 20.0 Hz, C6), 152.16 (d, 2JC-P= 7.5 Hz, C-Ar), 152.14 (d, 2JC-P = 6.3 Hz, C-Ar), 151.71 (d, 3JC-F = 20.0 Hz, C4), 151.67 (d, 3JC-F= 20.0 Hz, C4), 140.70 (d, 5JC-F = 2.5 Hz, C8), 140.68 (d, 5JC-F = 2.5 Hz, C8), 130.77 (CH-Ar), 130.74 (CH-Ar), 126.16 (CH-Ar), 126.24 (CH-Ar), 121.48 (CH-Ar), 121.44 (CH-Ar), 121.41 (CH-Ar), 121.37 (CH-Ar), 118.80 (d, 4JC-F = 3.7 Hz, C5), 118.77 (d, 4JC-F = 3.7 Hz, C5), 93.37 (C1’), 93.25 (C1’), 80.52 (d, 3JC-P = 3.7 Hz, C4’), 80.45 (d, 3JC-P = 4.1 Hz, C4’), 76.52 (C2’), 76.49 (C2’), 68.69 (d, 2JC-P = 5.4 Hz, C5’), 68.30 (d, 2JC-P = 4.9 Hz, C5’), 66.46 (CH2 Hex), 51.68 (CH ala), 51.57 (CH ala), 35.02 (C3’), 34.80 (C3’), 32.58 (CH2 Hex), 29.65 (CH2 Hex), 26.61 (CH2 Hex), 23.59 (CH2 Hex), 20.60 (d, 3JC-P = 7.1 Hz, CH3 ala), 20.43 (d, 3JC-P = 7.5 Hz, CH3ala), 14.35 (CH3 Hex).
HPLC H2O/CH3CN 100/10から0/100までで30分、1ml/分、l=280nmで溶出した逆相HPLCから、tR 17.83分およびtR 18.02分でジアステレオマーの2つのピークを示した。
31P NMR (202 MHz, CD3OD): δP 4.39 (s), 4.12 (s); 1H NMR (500 MHz, CD3OD): δH 8.10 (s, 0.5 H, H8), 8.07 (s, 0.5 H, H8), 8.02-7.97 (m, 3H, CH2PhおよびNaph), 7.43-7.14 (m, 9H, CH2PhおよびNaph), 5.80-5.81 (m, 1H, H1’), 4.89-4.97 (m, 2H, CH2Ph) 4.49-4.53 (m, 2H, H4’およびH2’), 4.30-4.35 (m, 1H, H5’), 4.15-4.21 (m, 1H, H5’), 3.87-3.95 (m, 1H, CHCH3), 2.12-2.23 (m, 1H, H3’), 1.86-1.93 (m, 1H H3’), 1.14-1.17 (m, 3H, CHCH3); 13C NMR (125 MHz, CD3OD): δC 174.85 (d JCP = 4.0 Hz, C=O), 174.55 (d JCP= 4.3 Hz, C=O), 158.07, 158.04 (C6), 155.31, 155.28 (C2), 151.34, 151.31 (C4), 149.69 (C-Ar), 147.96 (d 3JCP = 7.25 Hz, C-イプソ Naph), 147.90 (d 3JCP= 7.0 Hz, C-イプソ Naph), 140.70 (C8), 137.21, 137.16 (C-イプソCH2Ph), 136.26 (C-Ar), 130.92, 130.80, 129.56, 129.53, 129.31, 129.27, 129.25, 128.88, 128.81 (CH-Ar), 127.78 (d JCP = 4.7 Hz, CH-Ar), 127.50 (d JCP = 6.2 Hz, CH-Ar), 126.48, 126.02, 125.97 (CH-Ar), 119.46, 119.42 (C5), 116.33 (d, JCP = 3.0, CH-Ar), 116.16 (d, JCP = 3.4, CH-Ar), 93.30, 93.27 (C1’), 80.56 (d J = 8.3 Hz, C4’), 80.51 (d J = 8.4 Hz, C4’), 76.61, 76.54 (C2’), 68.74 (d JCP= 5.3 Hz, C5’), 68.54 (d JCP= 5.1 Hz, C5’), 67.93, 67.90 (CH2Ph), 51.81, 51.70 (CHCH3), 34.79, 34.53 (C3’), 20.42 (d JCP = 6.5 Hz, CHCH3), 20.23 (d JCP = 7.7 Hz, CHCH3);
HPLC H2O/CH3CN 90/10から0/100までで30分、F=1ml/分、l=254nm、tR 18.03分で溶出した逆相HPLC。
31P NMR (202 MHz, CD3OD): δP 3.93, 3.72.
1H NMR (500 MHz, CD3OD): δH 8.12 (s, 0.5 H, H8), 8.10 (s, 0.5 H, H8), 7.19-7.23 (m, 2 H, Ph), 7.03-7.12 (m, 3 H, Ph), 5.84 (d J =2, 0.5 H, H1’), 5.83 (d J =2, 0.5 H, H1’), 4.54-4.60 (m, 2 H, H4’およびH2’), 4.34-4.38 (m, 0.5 H, H5’), 4.27-4.31 (m, 0.5 H, H5’), 4.16-4.23 (m, 1 H, H5’), 3.80-3.90 (m, 1 H, CHCH3), 3.57-3.73 (m, 2 H OCH2C(CH3)3), 2.18-2.28 (m, 1 H, H3’), 1.94-1.99 (m, 1 H, H3’), 1.20-1.24 (m, 3 H, CHCH3), 0.81 (s, 4.5 H OCH2(CH3)3), 0.79 (s, 4.5 H OCH2C(CH3)3).
13C NMR (125 MHz, CD3OD): δC 175.09 (d 3JCP= 4.75 Hz, C=O), 174.90 (d 3JCP = 5.37 Hz, C=O), 158.10, (C6), 155.31, 155.28 (C2), 152.14 (d 2JCP= 6.37 Hz, C-イプソ Ph), 152.13 (d 2JCP= 6.25 Hz, C-イプソ Ph), 151.33, 151.30 (C4), 140.87, 140.76 (C8), 130.78, 130.77 (CH-Ar), 126.17, 126.42 (CH-Ar), 121.45 (d 3JCP = 11.75 Hz, CH-Ar), 121.41 (d 3JCP = 11.75 Hz, CH-Ar), 119.52, 119.48 (C5), 93.49, 93.35 (C1’), 80.67 (d 3J = 8.62 Hz, C4’), 80.65 (d 3J = 8.25 Hz, C4’), 76.70, 76.67 (C2’), 75.43, (OCH2C(CH3)3), 68.68 (d 2JCP= 5.12 Hz, C5’), 68.42 (d 2JCP= 5.12 Hz, C5’), 51.77, 51.60 (CHCH3), 34.94, 34.67 (C3’), 32.36, 32.32 (OCH2C(CH3)3), 26.78, 26.76 (OCH2C(CH3)3), 20.83 (d JCP = 6.25 Hz, CHCH3), 20.61 (d JCP = 7.12 Hz, CHCH3).
31P NMR (202 MHz, CD3OD): δP 4.35, 4.20.
1H NMR (500 MHz, CD3OD): δH 8.23 (s, 0.5 H, H8), 8.21 (s, 0.5 H, H8), 8.11-8.16 (m, 1 H, Naph), 7.86-7.89 (m, 1 H, Naph), 7.69-7.70 (m, 1 H, Naph), 7.54-7.46 (m, 3 H, Naph), 7.37-7.41 (m, 1 H, Naph), 5.95 (d J = 2, 0.5 H, H1’), 5.94 (d J = 1.5, 0.5 H, H1’), 4.67-4.73 (m, 2 H, H4’およびH2’), 4.34-4.55 (m, 2 H, H5’), 4.00-4.08 (m, 1 H, CHCH3), 3.66-3.81 (m, 2 H OCH2C(CH3)3), 2.28-2.41 (m, 1 H, H3’), 2.03-2.10 (m, 1 H, H3’), 1.31-1.34 (m, 3 H, CHCH3), 0.90 (s, 4.5 H OCH2C(CH3)3), 0.89 (s, 4.5 H CH2(CH3)3).
13C NMR (125 MHz, CD3OD): δC 175.11 (d JCP= 4.1 Hz, C=O), 174.85 (d JCP = 5.0 Hz, C=O), 158.10, 158.04 (C6), 155.32, 155.30 (C2), 151.33 (C4), 147.96 (d 2JCP = 7.25 Hz, C-イプソ Naph), 147.93 (d 2JCP= 7.25 Hz, C-イプソ Naph), 140.84, 140.76 (C8), 136.29 (C-Ar), 128.87, 128.82 (CH-Ar), 127.85 (C-Ar), 127.77, 127.74, 127.48, 127.45, 126.47, 125.99, 125.96, 122.74, 122.66 (CH-Ar), 119.47 (C5), 116.29 (d 3JCP= 3.4 Hz, CH-Ar), 116.17 (d 3JCP = 2.9 Hz, CH-Ar), 93.42, 93.34 (C1’), 80.57 (d 3JCP = 8.1 Hz, C4’), 80.53 (d 3JCP = 5.1 Hz, C4’), 76.61, 76.53 (C2’), 75.41, 75.38 (OCH2C(CH3)3), 68.95 (d 2JCP= 5.3 Hz, C5’), 68.82 (d 2JCP= 5.2 Hz, C5’), 51.84, 51.73 (CHCH3), 35.04, 34.75 (C3’), 32.29 (OCH2C(CH3)3), 26.70 (OCH2C(CH3)3), 20.76 (d 3JCP = 6.4 Hz, CHCH3), 20.55 (d 3JCP = 7.2 Hz, CHCH3).
31P NMR (202 MHz, CD3OD): δP 3.93, 3.72.
1H NMR (500 MHz, CD3OD): δH 8.12 (s, 0.5 H, H8), 8.11 (s, 0.5 H, H8), 7.18-7.23 (m, 2 H, Ph), 7.03-7.12 (m, 3 H, Ph), 5.85 (d J =1.5, 0.5 H, H1’), 5.84 (d J =2, 0.5 H, H1’), 4.55-4.62 (m, 2 H, H4’およびH2’), 4.34-4.38 (m, 0.5 H, H5’), 4.28-4.32 (m, 0.5 H, H5’), 4.16-4.22 (m, 1 H, H5’), 3.93-4.03 (m, 2 H, OCH2CH3), 3.70-3.84 (m, 1 H, CHCH3), 2.20-2.28 (m, 1 H, H3’), 1.95-1.99 (m, 1 H, H3’), 1.15-1.21 (m, 3 H, CHCH3), 1.06-1.11 (m, 3 H, OCH2CH3).
13C NMR (125 MHz, CD3OD): δC 173.66 (d 3JCP= 4.5 Hz, C=O), 173.65 (d 3JCP = 5.3 Hz, C=O), 156.68, 156.70 (C6), 153.93, 153.88 (C2), 150.72 (d 2JCP= 6.7 Hz, C-イプソ Ph), 150.71 (d 2JCP= 6.5 Hz, C-イプソ Ph), 149.89, 149.94 (C4), 139.41, 139.35 (C8), 129.33 (CH-Ar), 124.74, 124.73 (CH-Ar), 120.03 (d 3JCP= 4.75 Hz, CH-Ar), 119.97 (d 3JCP = 4.87 Hz, CH-Ar), 118.07, 118.03 (C5), 92.02, 91.88 (C1’), 79.26, 79.19 (C4’), 75.26, 75.24 (C2’), 67.18 (d 2JCP= 5.25 Hz, C5’), 66.81 (d 2JCP= 5.12 Hz, C5’), 60.96 (OCH2CH3), 50.23, 50.12 (CHCH3), 33.46, 33.21 (C3’), 19.16 (d 3JCP = 6.3 Hz, CHCH3), 18.97 (d 3JCP = 7.2 Hz, CHCH3), 13.10, 13.07 (OCH2CH3).
31P NMR (202 MHz, CD3OD): δP 3.99 (s), 3.82 (s).
1H NMR (500 MHz, CD3OD): δH 8.16 (s, 0.5H, H8), 8.15 (s, 0.5H, H8), 8.11 (s, 1H, H-2) 7.23-7.20 (m, 2H, Ph), 7.11-7.03 (m, 3H, Ph), 5.91 (d J = 2.0Hz, 0.5H, H1’), 5.90 (d J = 2.0Hz, 0.5H, H1’), 4.85-4.79 (m, 1H, CH(CH3)2, 4.64-4.63 (m, 1H, H4’), 4.60-6.57 (m, 1H, H2’), 4.37-4.33 (m, 1H, H5’), 4.31-4.28 (m, 1H, H5’), 3.74-4.22-4.17 (m, 1H, H5’), 3.70 (m, 1H, CH ala), 2.02-1.97 (m, 1H, H3’), 2.04-2.01 (m, 1H, H3’), 1.18-1.14 (m, 3H, CH3), 1.24 (m,6H, CH(CH3)2)
予めコーティングされたアルミニウムで裏付けされたプレート(60 F254、0.2mm厚さ、Merck社)を、短波および長波の紫外線下で(254および366nm)または次のTLC指示薬を用いて燃焼させることにより可視化した。(i)モリブデン酸アンモニウムセリウムスルファート;(ii)過マンガン酸カリウム溶液である。分取TLCプレート(20cm×20cm、500〜2000μm)をMerck社から購入した。
本発明を具現する例示的な化合物を、これらの抗がん性の効力について以下の手順で評価した。
In vitro生死判別アッセイを実施して、72時間にわたり、選択された細胞株における化合物の細胞生存率に対する効果を、CellTiterGlo(CTG、Promega−G7573)アッセイを用いて評価した。これらの試験を、約72時間にわたって、9つの時点で、96穴プレートに3.16倍で滴定して化合物を処理することにより繰り返して実施した。化合物の開始濃度は198mMであった。96穴プレート中でCellTiterGloを用いた細胞生死判別アッセイを実施した。化合物の処理は、72時間、標準的な成長条件下で、2回であった。化合物を、100%解凍して40mMまで溶解した。化合物を、解凍済みのDMSOに3.16倍で連続的に希釈し、培地(2μl+200μl)に溶解する前に37℃まで加温した。化合物を培地に溶解した後、化合物を含有する培地を、インキュベーター中で−37℃まで加温し、次いで、培地中の化合物を、細胞プレート(50μl+50μl)に2回加えた。化合物の最終濃度は、198Mから19.9nMまでであった。すべての化合物の溶解度を調べ、再び記録し、次いで、これらのプレートをCO2組織培養インキュベーターに直ちに移し、3日間インキュベートした。DMSO最終濃度は、0.5%である。
拡大された用量範囲に対する急性ミエロイド白血病(AML)細胞株KG1aにおける化合物の毒性のさらなる比較分析を行い、用量範囲全体を通してKG1a細胞株内で白血病幹細胞(LSC)コンパートメントに対する化合物の相対的な効果を評価した。
KG1a細胞培養条件
KG1a細胞株を、ペニシリン100単位/ml,ストレプトマイシン100μg/mlおよび20%ウシ胎仔血清を補充したRPMI培地(Invitrogen社、Paisley、UK)で維持した。続いて、細胞を、96穴プレートに(105細胞/100μl)分注し、各シリーズの化合物について実験的に決定した濃度で、ヌクレオシドアナログおよびこれらのそれぞれのproTidesの存在下で、加湿した5%二酸化炭素雰囲気中37℃で72時間インキュベートした。さらに、対照培養を行い、これに薬物を加えなかった。続いて、細胞を、遠心により収集し、Annexin Vアッセイを用いたフローサイトメトリーにより分析した。
培養細胞を、遠心により収集し、次いで、カルシウムに富む緩衝液195μlに再懸濁した。続いて、Annexin V(Caltag Medsystems、Botolph Claydon、UK)5μlを、細胞懸濁液に加え、細胞を、洗浄前の10分間暗闇でインキュベートした。最後に、細胞を、ヨウ化プロピジウム10μlと共に、カルシウムに富む緩衝液190μlに再懸濁した。アポトーシスを前述の通り、二色免疫蛍光フローサイトメトリーにより評価した。続いて、LD50値(培養物中の細胞の50%を死滅させるのに必要とされる用量)を、各ヌクレオシドアナログおよびProTideについて算出した。
KG1a細胞を、アッセイした各化合物の広範囲の濃度の存在下で72時間培養した。次いで、細胞を収集し、抗系統抗体(PE−cy7)、抗CD34(FITC)、抗CD38(PE)および抗CD123(PERCP cy5)のカクテルで標識化した。続いて、LSC表現型を発現している部分集団を同定し、培養中で放置したすべての生存可能な細胞の百分率として表現した。次いで、残存する幹細胞の百分率を、用量−反応グラフでプロットし、化合物の効果を互いに比較し、親ヌクレオシドと比較した。
これらの実験において得られたデータを、一元配置ANOVAを用いて評価した。全データを、一様性K2検定を用いてガウスまたはガウス近似として確認した。LD50値を、非線形回帰およびS字状用量反応曲線の最良の当てはめの分析の直線から算出した。すべての統計解析を、Graphpad Prism 6.0ソフトウェア(Graphpad Software Inc.、San Diego、CA)を用いて行った。
in vitro薬物感受性を、Annexin V/ヨウ化プロピジウムアッセイを用いて測定した。化合物Aは、コルジセピンと比較した場合、より高いin vitroにおける効力を示した(P<0.0001)。2−F−コルジセピンは、コルジセピンよりも有意に強力であり(P<0.0001)、試験されたProTidesのすべては、親ヌクレオシドと比較した場合、効力の増加を示した(図1)。
本発明のいくつかの化合物を、本発明のいくつかの化合物の細胞毒性活性を試験し、また、4種の血液学的ながん細胞株に対するこれらの活性を測定するためにさらなる試験にかけた。
・TdT陽性CEM(ヒトALL)
・TdT陰性K562(ヒトCML)
・TdT陰性Hl−60(ヒトANLL)
・RL(CRL−2261)非−HDリンパ腫
細胞培養
アメリカ合衆国培養細胞株統保存機関(ATCC:American Type Culture Collection、Middlesex)から取得したHL−60(ATCC(登録商標)CCL−240(商標))、K562(ATCC(登録商標)CCL−243(商標))、CCRF−CEM(ATCC(登録商標)CRM−CCL−119(商標))およびRL(ATCC(登録商標)CRL−2261(商標))白血病細胞株。HL−60およびK562細胞株は、デオキシヌクレオチド転移酵素−陰性(TdT−ve)であり、CCRF−CEM細胞株は、TdT+veである。
HL−60、K562、CCRF−CEMおよびRL細胞株を、10%ウシ胎児血清(FBS)(PAA Laboratories社)、1%アムホテリシンB(5.5ml)および1%ペニシリン/ストレプトマイシン(5.5ml)(PAA Laboratories社)を補充した、RPMI−1640培地(Sigma Aldrich社、UK)で培養し、CO25%のインキュベーターで37℃においてフラスコ中で増殖させた。
ATPの量を、細胞数および細胞生存率の測定値として用いた。発光適合性の96穴プレート中で(細胞の初濃度は、1×104細胞/ウェルであった)、0、0.1、0.5、1、5および10μMの濃度でコルジセピンおよびProTidesで処理し、その後、CO25%のインキュベーターで37℃において72時間インキュベートした細胞中でATPを検出するATP ViaLightTM plus assay kit(Lonza、USA:製品番号LT07−121)。阻害薬試験の場合、NBTI10μMまたは1μM EHNAまたはA−134974を加え、薬物を加える前に5分間放置した(阻害薬についての詳細はセクション5を参照のこと)。
5×106細胞/mlの細胞株を用いた。細胞を、コルジセピンならびに化合物A、B、D、EおよびFをそれぞれ50μMの1μlで処理し、CO25%で37℃において2時間インキュベートした。インキュベーション後、細胞を遠心し(周囲温度、1200rpm、5分間)、培養培地の上澄みを除去し、細胞ペレットを、PBS1mlで洗浄し、遠心した(周囲温度、1200rpm、5分間)。上澄みを除去し;ペレットをPBS100μlおよび0.8M過塩素酸100μlに溶解し、ボルテックスで混合し、30分間氷上で維持した。次いで、遠心し(周囲温度、1200rpm、5分間)、上澄み180μlを新しい管に移し、分析の時間まで−80℃で保存した。
細胞株を、前述したものと同じやり方で処理したが、薬物による処理前に、いくつかの阻害薬を加えた。
1)ニトロベンジルチオイノシン(NBTI)(Sigma−Aldrich社、St.Louis、MO、製品番号N2255)ブロックスヌクレオシドトランスポーター
2)EHNA塩酸塩(Sigma−Aldrich社、St.Louis、MO、製品番号E114)ブロックスアデノシンデアミナーゼ
3)アデノシンキナーゼ阻害薬A−134974塩酸塩水和物(Sigma−Aldrich社、St.Louis、MO、製品番号A2846):ブロックスアデノシンキナーゼ
分析物を、Biobasic Ax5μm、50×2.1mmカラム(Thermo Electron Corporation、Murrieta、CA、USA)ならびにACN/H2O(30:70v/v)中の10mM NH4Ac(pH6.0)(A)、およびACN/H2O(30:70v/v)中の1mM NH4Ac(pH10.5)(B)の混合物からなる移動相を備えた超高速液体クロマトグラフィー系(Accela UPLC、Thermo Scientific社、UK)を用いて分離した。移動相の勾配を、0〜0.5分で緩衝液A=95%、1.25分にわたって95から0%まで、0%で1.75分間保持、0.1分にわたって0〜95%、2.9分間95%での終了を含めて使用し、すべて流速500μl/分である。
薬物の細胞毒性の用量反応曲線を、細胞生存百分率対濃度の非線形回帰分析を用いて決定し、EC50値を得た。細胞内アッセイを、各条件について5回実施した。細胞内アッセイを、3’ATP/ATP濃度の対t検定(両側)分析を用いて決定し、p値を得た。すべての分析について、Prismソフトウェアプログラム(GraphPad Software社)を用い、Microsoft Powerpoint(登録商標)2013を用いて、結果をプロットした。
Claims (26)
- 式(Ib)の化合物:
W1およびW2は、それぞれ独立に、−P(=O)(U)(V)およびHからなる群から選択され、ただし、W1およびW2のうち少なくとも1つは、−P(=O)(U)(V)であり、
W1およびW2それぞれについてのUおよびVは、独立に、以下のものからなる群から選択され:
(a)Uは、−OArであり、Vは、−NR4−CR1R2−C(=O)OR3であり
Arは、C6〜30アリールおよび5〜30ヘテロアリールからなる群から選択され、そのそれぞれは、場合によって置換され;
R1およびR2はそれぞれ、独立に、H、およびC1〜20アルキル、C6アリールC1〜6アルキル、C2〜20アルケニル、C1〜20アルコキシ、C1〜20アルコキシC1〜20アルキル、C1〜20アルコキシC6アリール、C2〜20アルキニル、C3〜20シクロアルキル、C6〜30アリール、C6〜30アリールオキシおよび5〜20ヘテロシクリルからなる群から選択され、そのいずれも、場合によっては置換され;
R3は、H、およびC1〜20アルキル、C6〜30アリールC1〜20アルキル、C2〜20アルケニル、C1〜20アルコキシC1〜20アルキル、C1〜20アルコキシC6〜30アリール、C2〜20アルキニル、C3〜20シクロアルキル、C6〜30アリール、および5〜20ヘテロシクリルからなる群から選択され、そのいずれも、場合によっては置換され;
R4は、H、およびC1〜20アルキル、C6〜30アリールC1〜20アルキル、C2〜20アルケニル、C1〜20アルコキシ、C1〜20アルコキシC1〜20アルキル、C1〜20アルコキシC6〜30アリール、C2〜20アルキニル、C3〜20シクロアルキル、C6〜30アリール、C6〜30アリールオキシおよび5〜20ヘテロシクリルからなる群から選択され、そのいずれも、場合によっては置換される;ならびに
(b)UおよびVはそれぞれ、独立に、−NR5R6から選択され
R5は、HおよびC1〜6アルキルからなる群から選択され、R6は、−CR7R8CO2R9であり、R7およびR8は、独立に、Hを含めた、天然に存在するαアミノ酸の側鎖からなる群から選択され、R9は、H、およびC1〜20アルキル、C6〜30アリールC1〜20アルキル−、C2〜20アルケニル、C1〜20アルコキシC1〜20アルキル、C1〜20アルコキシC6〜30アリール、C2〜20アルキニル、C3〜20シクロアルキル、C6〜30アリール、および5〜20ヘテロシクリルからなる群から選択され、そのいずれも、場合によっては置換され;または
R5およびR6は、それらが結合するN原子と一緒になって、5から8個の環原子を含む環部分を形成する;
Xは、NR12R13(式中、R12およびR13はそれぞれ、独立に、HおよびC1〜6アルキルから選択される);および−SR14(式中、R14は、HおよびC1〜6アルキルからなる群から選択される)から選択され;
Zは、独立に、H、OH、F、Cl、Br、I、C1〜6アルキル、−NR12R13、および−SR14(式中、R14は、HおよびC1〜6アルキルからなる群から選択される)からなる群から選択され;
Yは、H、OH、F、Cl、Br、I、−OC1〜6アルキル、C1〜6アルキル、C2〜8アルキニル、−NR15R16(式中、R15およびR16はそれぞれ、独立に、HおよびC1〜6アルキルから選択される)、および−SR17(式中、R17は、HおよびC1〜6アルキルからなる群から選択される)からなる群から選択される]、または式(Ib)の化合物の薬学的に許容される塩、エステル、エステルの塩、溶媒和物もしくはプロドラッグ。 - 式(Ib)の化合物が、式(II)の化合物:
- Arが、フェニルおよびナフチル(napthyl)から選択される、請求項1または請求項2に記載の化合物。
- Arが非置換である、請求項3に記載の化合物。
- Arが、ハロ、C1〜C4−アルキル、C1〜C4−アルコキシ、ニトロおよびシアノから選択される1個、2個、3個、4個または5個の置換基で置換される、請求項3に記載の化合物。
- R2が、C1〜C4−アルキルである、請求項1から4のいずれか一項に記載の化合物。
- R2がメチルである、請求項6に記載の化合物。
- R1およびR2を有するC原子が、L−アラニンと同じ絶対配置である、請求項7に記載の化合物。
- R3が、ベンジルおよび非置換のC1〜20アルキルからなる群から選択される、請求項1から8のいずれか一項に記載の化合物。
- R3が、ベンジル、非置換のメチルおよび非置換のn−ペンチルからなる群から選択される、請求項9に記載の化合物。
- R3がベンジルである、請求項10に記載の化合物。
- XがNH2である、請求項1から11のいずれか一項に記載の化合物。
- YがHである、請求項1から12のいずれか一項に記載の化合物。
- ZがHである、請求項1から13のいずれか一項に記載の化合物。
- ZがFである、請求項1から13のいずれか一項に記載の化合物。
- ZがClである、請求項1から13のいずれか一項に記載の化合物。
- ZがOMeである、請求項1から13のいずれか一項に記載の化合物。
- 式(Ib)の化合物が、(2S)−ベンジル2−(((((2S,4R,5R)−5−(6−アミノ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ナフタレン−1−イルオキシ)ホスホリル)アミノ)プロパノエート;
ベンジル2−(((((2S,4R,5R)−5−(6−アミノ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(フェノキシ)ホスホリル)アミノ)アセテート;
(2S)−ペンチル2−(((((2S,4R,5R)−5−(6−アミノ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ナフタレン−1−イルオキシ)ホスホリル)アミノ)−4−メチルペンタノエート;
メチル2−(((((2S,4R,5R)−5−(6−アミノ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ナフタレン−1−イルオキシ)ホスホリル)アミノ)−2−メチルプロパノエート;
(2S)−ベンジル2−(((((2S,4R,5R)−5−(6−アミノ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(2−(3−エトキシ−3−オキソプロピル)フェノキシ)ホスホリル)アミノ)プロパノエート;
(2S)−ベンジル2−(((((2R,3R,5S)−2−(6−アミノ−9H−プリン−9−イル)−5−(ヒドロキシメチル)テトラヒドロフラン−3−イル)オキシ)(フェノキシ)ホスホリル)アミノ)プロパノエート;
ベンジル2−(((((2S,4R,5R)−5−(6−アミノ−9H−プリン−9−イル)−4−((((1−(ベンジルオキシ)−1−オキソプロパン−2−イル)アミノ)(フェノキシ)ホスホリル)オキシ)テトラヒドロフラン−2−イル)メトキシ)(フェノキシ)ホスホリル)アミノ)プロパノエート;
(2S)−ベンジル2−(((((2R,3R,5S)−2−(6−アミノ−9H−プリン−9−イル)−5−(ヒドロキシメチル)テトラヒドロフラン−3−イル)オキシ)(ナフタレン−1−イルオキシ)ホホリル)アミノ)プロポネート;
ベンジル2−[({[5−(6−アミノ−9H−プリン−9−イル)−4−ヒドロキシオキソラン−2−イル]メトキシ}({[1−(ベンジルオキシ)−1−オキソプロパン−2−イル]アミノ})ホスホリル)アミノ]プロパノエート;
(2S)−ベンジル2−((((2S,4R,5R)−5−(6−アミノ−2−メトキシ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ナフタレン−1−イルオキシ)ホスホリルアミノ)プロパノエート;
(2S)−ベンジル2−((((2S,4R,5R)−5−(6−アミノ−2−メトキシ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(フェノキシ)ホスホリルアミノ)プロパノエート;
(2S)−ベンジル2−(((((2S,4R,5R)−5−(6−アミノ−2−フルオロ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(フェノキシ)ホスホリル)アミノ)プロパノエート;
(2S)−ヘキシル2−(((((2S,4R,5R)−5−(6−アミノ−2−フルオロ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(フェノキシ)ホスホリル)アミノ)プロパノエート;
(2R)−ベンジル2−((((2S,4R,5R)−5−(6−アミノ−2−クロロ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ナフタレン−1−イルオキシ)ホスホリルアミノ)プロパノエート;
3’−デオキシアデノシン−5’−O−[フェニル(ベンジルオキシ−L−アラニニル)]ホスフェート;
2−O−メチル−3’−デオキシアデノシン−5’−O−[1−ナフチル(1−ペンチルオキシ−L−ロイシニル)]ホスフェート;
2−O−メチル−3’−デオキシアデノシン−5’−O−[フェニル(1−ヘキシルオキシ−L−アラニニル)]ホスフェート;
2−フルオロ−3’−デオキシアデノシン−5’−O−[1−ナフチル(ベンジルオキシ−L−アラニニル)]ホスフェート;
2−フルオロ−3’−デオキシアデノシン−5’−O−[1−ナフチル(1−ペンチルオキシ−L−ロイシニル)]ホスフェート;
2−クロロ−3’デオキシアデノシン5’−O−[1−フェニル(2,2−ジメチルプロポキシ−L−アラニン)]ホスフェート;
2−クロロ−3’デオキシアデノシン5’−O−[1−ナフチル(2,2−ジメチルプロポキシ−L−アラニン)]ホスフェート;
2−クロロ−3’デオキシアデノシン5’−O−[1−フェニル(エトキシ−L−アラニン)]ホスフェート;および
(2S)−イソプロピル−2−(((((2S,4R,5R)−5−(6−アミノ−9H−プリン−9−イル)−4−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(フェノキシ)ホスホリル)アミノ)プロパノエートから選択される、請求項1に記載の化合物。 - 治療の方法において用いるための、請求項1から18のいずれか一項に記載の化合物。
- がんの予防または治療において用いるための、請求項19に記載の化合物。
- 前記がんが、白血病、リンパ腫、多発性骨髄腫、(非小細胞肺がんおよび小細胞肺がんを含む)肺がん、肝臓がん、乳がん、膀胱がん、前立腺がん、頭頚部がん、神経芽細胞腫、(ユーイング肉腫を含む)肉腫、甲状腺癌、(黒色腫を含む)皮膚がん、口腔扁平細胞癌、膀胱がん、ライディッヒ細胞腫、胆管細胞癌または胆管がんなどの胆道がん、膵がん、結腸がん、結腸直腸がんならびに卵巣がん、子宮体がんを含めた婦人科のがんからなる群から選択される、請求項20に記載の化合物。
- 前記がんが、白血病またはリンパ腫である、請求項21に記載の化合物。
- 前記白血病が、急性リンパ芽球性白血病、急性骨髄性白血病、急性前骨髄球性白血病、急性リンパ球性白血病、慢性骨髄性白血病、慢性リンパ球性白血病、単芽球性白血病、ヘアリー細胞白血病、ホジキンリンパ腫および非ホジキンリンパ腫を含む群から選択される、請求項22に記載の化合物。
- 前記白血病が、急性リンパ芽球性白血病である、請求項23に記載の化合物。
- がんの予防または治療の方法であって、そのような治療を必要としている患者に、請求項1から18のいずれか一項に記載の化合物の有効な用量を投与するステップを含む、がんの予防または治療の方法。
- 薬学的に許容される担体、希釈剤または賦形剤と組み合わせて、請求項1から18のいずれか一項に記載の化合物を含む医薬組成物。
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