JP5614858B2 - 新規コルチスタチンa類似体およびその用途 - Google Patents
新規コルチスタチンa類似体およびその用途 Download PDFInfo
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- JP5614858B2 JP5614858B2 JP2012534073A JP2012534073A JP5614858B2 JP 5614858 B2 JP5614858 B2 JP 5614858B2 JP 2012534073 A JP2012534073 A JP 2012534073A JP 2012534073 A JP2012534073 A JP 2012534073A JP 5614858 B2 JP5614858 B2 JP 5614858B2
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- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960005212 vindesine sulfate Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- Plural Heterocyclic Compounds (AREA)
Description
コルチスタチンAの類似体は、例えば特許文献1〜3に記載のものが知られている。しかし、特許文献1〜3に記載されているコルチスタチンA類似体の化学構造はコルチスタチンAと同様に複雑であり、合成に多工程を要するため、工業的な大量供給に適したものとは言えない。
[1]
一般式(M)
で示される化合物またはその薬学的に許容される塩。
[2]一般式(I)
で示される化合物またはその薬学的に許容される塩。
[3]R1が、ピリジル基、キノリル基またはイソキノリル基である前記[1]または[2]に記載の化合物またはその薬学的に許容される塩。
[4]式(II)
[5]前記[1]〜[4]のいずれかに記載の化合物またはその薬学的に許容される塩と、薬学的に許容される担体を含有してなる医薬組成物。
[6]前記[1]〜[4]のいずれかに記載の化合物またはその薬学的に許容される塩を有効成分として含有する血管内皮細胞増殖阻害剤。
[7]前記[1]〜[4]のいずれかに記載の化合物またはその薬学的に許容される塩を有効成分として含有する血管新生阻害剤。
[8]前記[1]〜[4]のいずれかに記載の化合物またはその薬学的に許容される塩を有効成分として含有する癌の予防または治療薬。
[9]化学療法剤、免疫療法剤またはホルモン療法剤と併用することを特徴とする前記[8]に記載の癌の予防または治療薬。
[10]放射線療法と併用することを特徴とする前記[8]に記載の癌の予防または治療薬。
[11]哺乳動物に対して、前記[1]〜[4]のいずれかに記載の化合物またはその薬学的に許容される塩の有効量を投与することを特徴とする癌の予防または治療方法。
[12]癌の予防または治療薬を製造するための、前記[1]〜[4]のいずれかに記載の化合物またはその薬学的に許容される塩の使用。
[13]癌の治療または予防に使用するための、前記[1]〜[4]のいずれかに記載の化合物またはその薬学的に許容される塩。
で示される化合物またはその薬学的に許容される塩を提供する。
で示される化合物またはその薬学的に許容される塩を提供する。
R3の「炭素数1〜4のアルキル基」としては、メチル基、エチル基、n−プロピル基、イソプロピル基、n−ブチル基、イソブチル基、sec−ブチル基、tert−ブチル基等が挙げられる。R3の「炭素数1〜4のアシル基」としては、ホルミル基、アセチル基、プロピオニル基、ブチリル基等が挙げられる。
R5の「炭素数1〜3のアルキル基」とは、メチル基、エチル基、n−プロピル基、イソプロピル基等が挙げられ、「炭素数1〜3のアシル基」とは、ホルミル基、アセチル基、プロピオニル基、マロニル基等が挙げられる。
本発明の化合物は、公知の手段、例えば、転溶、濃縮、溶媒抽出、分溜、液性変換、晶出、再結晶、クロマトグラフィー等によって単離、精製することができる。本発明の化合物が遊離化合物として得られた場合には、公知の方法により目的とする塩に変換することができ、逆に塩で得られた場合には、公知の方法により遊離体または目的とする他の塩に変換することができる。
本発明の化合物は、水和物または溶媒和物であってもよい。また、同位元素等で標識されていてもよい。
図1に示したスキームに従って、式(II)で示される化合物(以下、「CA−1」と記す。)を合成した。
Arガス雰囲気下、CuI(882 mg, 4.63 mmol)のTHF溶液(28 mL)に、−50℃でt−BuMgCl(1.0 M in THF, 6.02 mL, 6.02 mmol)を加え、20分撹拌した。反応液にHMPA(8.10 mL, 46.3 mmol)を加え、−50℃で20分撹拌した。化合物2(760 mg, 4.63 mmol)のTHF溶液を−78℃で、キャニュレーションによって加えた後、DIBAL−H(1.0 M in n-hexane, 7.41 mL, 7.41 mmol)、HMPA(4.05 mL, 23.2 mmol)のTHF溶液(9.0 mL)をキャニュレーションによってゆっくり滴下し、−78℃で30分撹拌した。−40℃までゆっくり昇温し、さらに3時間撹拌した。反応液を0℃にした後、5%HCl水溶液を加え、AcOEtで抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n-hexane/AcOEt = 2:1)にて精製し、化合物3(592 mg, 77%)を得た。
IR(KBr): 2959, 1738, 1711 cm-1. [α]D 21 +150.0 (c 1.70, CHCl3). 1H-NMR(500 MHz, CDCl3)δ: 2.55-2.50 (2H, m), 2.48-2.40 (3H, m), 2.22-2.14 (1H, m), 2.08-2.00 (1H, m), 1.96-1.90 (2H, m), 1.68 (1H, tt, J = 11.6, 8.5 Hz), 1.60 (1H, dd, J = 13.4, 9.2 Hz), 1.05 (3H, s).
化合物3(535 mg, 3.22 mmol)のCH3CN溶液(32 mL)に、0℃でethylene glycol(5.4 mL, 96.6 mmol)、oxalic acid dihydrate(203 mg, 1.61 mmol)を加え、室温で8時間撹拌した。反応液を0℃にした後、飽和NaHCO3溶液を加え、AcOEtで抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n-hexane/AcOEt = 2:1)にて精製し、化合物4(624 mg, 92%)を得た。
IR(KBr): 2953, 2887, 1732, 1068 cm-1. [α]D 21 +91.3 (c 1.28, CHCl3). 1H-NMR(500 MHz, CDCl3)δ: 3.92-3.86 (4H, m), 2.40 (1H, dd, J = 19.0, 9.2 Hz), 2.09 (1H, dt, J = 19.0, 11.0 Hz), 1.97-1.93 (1H, m), 1.83-1.80 (1H, m), 1.73-1.64 (5H, m), 1.57 (1H, tt, J = 12.5, 9.0 Hz), 1.44 (1H, td, J = 13.9, 5.7 Hz), 0.88 (3H, s). ESI MS: m/z 233 (M+Na)+. HR-ESI MS: m/z 233.1154, calcd for C12H18O3Na. Found: 233.1160.
化合物4(300 mg, 1.43 mmol)のTHF溶液(14 mL)に、−78℃でphenyl−N−triflimide(1.02 g, 2.86 mmol)、KHMDS(0.5 M in toluene, 4.3 mL, 2.15 mmol)を加え、30分撹拌した。反応液を0℃にした後、H2Oを加え、Et2Oで抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n-hexane/AcOEt = 4:1)にて精製し、化合物5(420 mg, 85%)を得た。
IR(KBr): 2955, 2885, 1421, 1213, 1141, 1055 cm-1. [α]D 20 +69.2 (c 1.41, CHCl3).
1H-NMR(500 MHz, CDCl3)δ: 5.57 (1H, dd, J = 3.3, 1.6 Hz), 3.92 (4H, m), 2.23-2.15 (2H, m), 2.05-2.02 (1H, m), 1.77-1.60 (7H, m), 1.02 (3H, s). ESI MS: m/z 365 (M+Na)+. HR-ESI MS: m/z 365.0647, calcd for C13H17O5F3NaS. Found: 365.0646.
化合物5(200 mg, 0.584 mmol)のDMF溶液(5.0 mL)に、室温で 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline(162 mg, 0.642 mmol)のDMF溶液(5.0 mL)、Pd(PPh3)4(100 mg, 0.0876 mmol)、K2CO3(239 mg, 1.75 mmol)を加え、50℃で30分撹拌した。反応液を0℃にした後、H2Oを加え、AcOEtで抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮して、化合物6を含む粗生成物を得た。
上記化合物6を含む粗生成物のacetone/H2O溶液(6.2 mL + 0.62 mL)に、0℃でp−toluenesulfonic acid monohydrate(237 mg, 1.23 mmol)を加え、室温で2時間撹拌した。反応液を0℃にした後、飽和NaHCO3溶液を加え、AcOEtで抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n-hexane/AcOEt = 1:2)にて精製し、化合物7(80 mg, 50% in 2 steps)を得た。
IR(KBr): 2935, 1707, 850 cm-1. [α]D 20 +94.0 (c 2.54, CHCl3). 1H-NMR(500 MHz, CDCl3)δ: 9.22 (1H, s), 8.49 (1H, d, J = 6.1 Hz), 7.92 (1H, s), 7.77 (1H, d, J = 9.8 Hz), 7.75 (1H, dd, J = 8.9, 1.5 Hz), 6.17 (1H, s), 2.62-2.50 (4H, m), 2.39-2.36 (4H, m), 2.28-2.21 (1H, m), 1.97-1.95 (1H, m), 1.32 (3H, s). ESI MS: m/z 278 (M+H)+. HR-ESI MS: m/z 278.1545, calcd for C19H20NO. Found: 278.1544.
化合物7(73 mg, 0.261 mmol)のAcOEt溶液(3.0 mL)に、室温でPd/C(21.9 mg)を加え、H2雰囲気下で12時間撹拌した。反応液をセライトろ過し、減圧濃縮することで、化合物8(71 mg, 98%)を得た。
IR(KBr): 2959, 1709, 852 cm-1. 1H-NMR(500 MHz, CDCl3)δ: 9.22 (1H, s), 8.48 (1H, d, J = 6.1 Hz), 7.80 (1H, s), 7.75 (1H, d, J = 7.9 Hz), 7.62 (1H, d, J = 6.1 Hz), 7.57 (1H, d, J = 8.5 Hz), 2.99 (1H, t, J = 9.8 Hz), 2.46-2.44 (1H, m), 2.37-2.30 (3H, m), 2.19-2.18 (1H, m), 2.12-2.10 (1H, m), 1.91-1.90 (1H, m), 1.78-1.75 (2H, m), 1.59-1.57 (1H, m), 0.75 (3H, s). ESI MS: m/z 280 (M+H)+. HR-ESI MS: m/z 280.1701, calcd for C19H22NO. Found: 280.1714.
化合物8(28 mg, 0.100 mmol)のCH3CN溶液(2.0 mL)に、0℃でHMDS(0.21 mL, 1.00 mmol)、NaI(75.2 mg, 0.500 mmol)、TMSCl(0.062 mL, 0.500 mmol)を加え、室温で3時間撹拌した。反応液を0℃にした後、飽和NH4Cl溶液を加え、CH2Cl2で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。得られた生成物のDMSO溶液(1.0 mL)に、0℃で2−ヨードキシ安息香酸(19.1 mg, 0.635 mmol)を加え、室温で8時間撹拌した。反応液を0℃にした後、飽和NaHCO3溶液を加え、CH2Cl2で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n-hexane/AcOEt = 1:2)にて精製し、化合物9(19 mg, 71% in 2 steps)を得た。
IR(KBr): 2962, 1672, 852 cm-1. [α]D 19 −3.95 (c 1.07, CHCl3). 1H-NMR(500 MHz, CDCl3)δ: 9.26 (1H, s), 8.52 (1H, d, J = 5.5 Hz), 7.85 (1H, s), 7.82 (1H, d, J = 8.5 Hz), 7.65-7.63 (2H, m), 7.07 (1H, d, J = 9.8 Hz), 5.90 (1H, d, J = 10.4 Hz), 3.24 (1H, t, J = 9.8 Hz), 2.62-2.58 (1H, m), 2.45-2.43 (2H, m), 2.33-2.28 (2H, m), 2.01-1.99 (1H, m), 1.74-1.72 (1H, m), 0.81 (3H, s). ESI MS: m/z 278 (M+H)+. HR-ESI MS: m/z 278.1545, calcd for C19H20NO. Found: 278.1544.
化合物9(100 mg, 0.361 mmol)のTHF溶液(3.6 mL)に、−78℃で、phenyl−N−triflimide(258 mg, 1.12 mmol)、KHMDS(0.5 M in toluene, 2.25 mL, 1.12 mmol)を加え、30分撹拌した。反応液を0℃にした後、H2Oを加え、AcOEtで抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n-hexane/AcOEt = 1:1)にて精製し、化合物10(138 mg, 94%)を得た。
IR(KBr): 2964, 1419, 1211, 1141 cm-1. 1H-NMR(500 MHz, CDCl3)δ: 9.22 (1H, s), 8.51 (1H, d, J = 6.1 Hz), 7.83 (1H, s), 7.80 (1H, d, J = 8.5 Hz), 7.64-7.62 (2H, m), 6.26 (1H, d, J = 9.8 Hz), 5.92 (1H, t, J = 2.5 Hz), 5.79 (1H, dd, J = 9.8, 2.2 Hz), 3.31 (1H, t, J = 10.1 Hz), 3.04-2.99 (1H, m), 2.37-2.34 (2H, m), 2.03-2.01 (1H, m), 1.88-1.86 (1H, m), 0.67 (3H, s). ESI MS: m/z 410 (M+H)+. HR-ESI MS: m/z 410.1038, calcd for C20H19NO3F3S. Found: 410.1024.
化合物10(265 mg, 0.648 mmol)のDMF溶液(20 mL)に、室温で、Pd(PPh3)4(75 mg, 0.0648 mmol)、MeOH(8.3 mL)、Et3N(1.45 mL, 9.72 mmol)を加え、一酸化炭素雰囲気下、40℃で3時間撹拌した。反応液を0℃にした後、H2Oを加え、AcOEtで抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n-hexane/AcOEt = 1:1)にて精製し、化合物11(200 mg, 98%)を得た。
IR(KBr): 2955, 1714, 1267 cm-1. [α]D 19 -88.6 (c 1.51, CHCl3). 1H-NMR(500 MHz, CDCl3)δ: 9.24 (1H, s), 8.50 (1H, d, J = 6.1 Hz), 7.84 (1H, s), 7.79 (1H, d, J = 8.5 Hz), 7.64 (2H, dd, J = 12.2, 3.7 Hz), 7.13 (1H, s), 6.34 (1H, d, J = 9.8 Hz), 6.17 (1H, d, J = 9.8 Hz), 3.77 (3H, s), 3.31 (1H, t, J = 9.8 Hz), 2.93-2.91 (1H, m), 2.39-2.33 (2H, m), 2.09-2.02 (1H, m), 1.89-1.88 (1H, m), 0.58 (3H, s). ESI MS: m/z 320 (M+H)+. HR-ESI MS: m/z 320.1651, calcd for C21H22NO2. Found: 320.1643.
化合物11(54.2 mg, 0.188 mmol)のCH2Cl2溶液(13 mL)に、−78℃で、DIBAL−H(1.0 M in n-hexane, 0.56 mL, 0.56 mmol)を加え、15分撹拌した。反応液を0℃にした後、15%NaOH水溶液を加え、セライトろ過し、減圧濃縮することで ((1R,3aS,7aS)-1-(Isoquinolin-7-yl)-7a-methyl-2,3,3a,7a-tetrahydro-1H-inden-5-yl)methanolを含む粗生成物(49 mg)を得た。得られた粗生成物のCH2Cl2溶液(3.4 mL)に、0℃でDess−Martin periodinane(107 mg, 0.254 mmol)、NaHCO3(71 mg, 0.847 mmol)を加え、室温で30分撹拌した。反応液を0℃にした後、飽和NaHCO3溶液を加え、CH2Cl2で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n-hexane/AcOEt = 1:4)にて精製し、化合物12(38 mg, 67% in 2 steps)を得た。
1H-NMR(500 MHz, CDCl3)δ: 9.44 (1H, s), 9.25 (1H, s), 8.50 (1H, d, J = 5.5 Hz), 7.85 (1H, s), 7.80 (1H, d, J = 8.5 Hz), 7.66-7.64 (2H, m), 6.95 (1H, s), 6.37 (1H, d, J = 9.8 Hz), 6.23 (1H, d, J = 9.8 Hz), 3.35 (1H, t, J = 9.8 Hz), 3.05 (1H, t, J = 10.0 Hz), 2.41-2.36 (2H, m), 2.08 (1H, s), 1.98-1.96 (1H, m), 0.58 (3H, s). ESI MS: m/z 290 (M+H)+.
化合物12(12 mg, 0.0415 mmol)のAcOEt溶液(4.0 mL)に、0℃で1,3−cyclohexanedione(11 mg, 0.083 mmol)、ethylenediamine(3.6 mL, 0.0498 mmol)を加え、室温で3時間撹拌した。反応液を0℃にした後、H2Oを加え、CH2Cl2で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n-hexane/AcOEt = 1:4)にて精製し、化合物1(15 mg, 97%)を得た。
IR(KBr): 2959, 1653, 1582, 1375 cm-1. [α]D 19 -101.7 (c 1.24, CHCl3). 1H-NMR(500 MHz, CDCl3)δ: 9.26 (1H, s), 8.51 (1H, d, J = 5.5 Hz), 7.85 (1H, s), 7.80 (1H, d, J = 8.5 Hz), 7.65 (2H, t, J = 6.4 Hz), 6.37 (1H, s), 6.05 (1H, d, J = 9.2 Hz), 5.90 (1H, d, J = 9.2 Hz), 4.86 (1H, d, J = 11.6 Hz), 3.23 (1H, t, J = 9.8 Hz), 2.57-2.28 (4H, m), 2.03-2.02 (2H, m), 1.84-1.81 (1H, m), 1.61-1.59 (1H, m), 1.20 (1H, m), 0.93-0.90 (2H, m), 0.68 (3H, s). ESI MS: m/z 384 (M+H)+.
式(II)で示されるCA−1を被験化合物とし、対照化合物に既存の抗がん剤であるドキソルビシン(doxorubicin)を用いた。被験化合物および対照化合物は、EtOHに溶解し、所定の濃度に調製した。細胞には、正常ヒト臍帯静脈血管内皮細胞HUVECおよびヒト咽頭上皮がん細胞KB3−1を使用した。
被験化合物のCA−1は、1%CMCを用いて所定の濃度に調製した。コントロール群には溶媒(1%CMC)を投与した。
被験化合物のCA−1は、1%CMCを用いて所定の濃度に調製した。コントロール群には溶媒(1%CMC)を投与した。
図6に示したスキームに従って、式(XVIII)で示される化合物(以下、「CA−2」と記す。)、式(XIX)で示される化合物(以下、「CA−3」と記す。)、式(XXIII)で示される化合物(以下、「CA−4」と記す。)を合成した。
化合物13(17 mg, 0.098 mmol)のDMF溶液(1.0 mL)に、0℃でimidazole(33 mg, 0.48 mmol)、TBDPSCl(80 μL, 0.31 mmol)を加え、0℃で30分間撹拌した。飽和NH4Cl水溶液を加え、CHCl3で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n-hexane/AcOEt = 10:1)にて精製し、化合物14(37.5 mg, 93%)を得た。
1H-NMR(500 MHz, CDCl3)δ: 7.71-7.69 (4H, m), 7.44-7.37 (6H, m), 4.73 (2H, d, J = 3.0 Hz), 3.56 (6H, s), 3.55 (2H, d, J = 7.5 Hz), 3.26-3.19 (1H, m), 2.84-2.74 (2H, m), 1.09 (9H, s).
化合物14(227 mg, 0.56 mmol)のTHF溶液(2.8 mL)に、1M HCl(0.55 mL)を加え、室温で1時間撹拌した。反応液をacetoneおよびtolueneで希釈し、減圧濃縮して、化合物15(198 mg, 94%)を得た。
1H-NMR(500 MHz, CDCl3)δ: 7.71-7.69 (4H, m), 7.44-7.37 (6H, m), 3.65-3.30 (3H, m), 2.75-2.30 (4H, m).
化合物12(実施例1および図1参照、56 mg, 0.19 mmol)のAcOEt/CH2Cl2溶液(1:3, 8.0 mL)に、0℃で化合物15(134 mg, 0.35 mmol)、ethylenediamine(16 μL, 0.23 mmol)を加え、室温で10時間撹拌した。反応液を0℃にした後、H2Oを加え、CH2Cl2で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n-hexane/AcOEt = 1:1)にて精製し、化合物16(57 mg, 45%)をジアステレオマー混合物(1:1)として得た。
1H-NMR(500 MHz, CDCl3)δ: 9.25 (1H, s), 8.51 (1H, d, J = 5.5 Hz), 7.85 (1H, s), 7.80 (1H, d, J = 8.5 Hz), 7.67-7.62 (5H, m), 7.47-7.35 (7H, m), 6.37 (1/2H, brs), 6.34 (1/2H, brs), 6.05 (1H, dd, J = 10.0, 1.0 Hz), 5.90 (1H, d, J = 10.0 Hz), 4.89 (1/2H, dd, J = 12.0, 2.0 Hz), 4.87 (1/2H, dd, J = 12.0, 2.0 Hz), 3.67-3.57 (2H, m), 3.23 (1H, t, J = 10.0 Hz), 2.60-2.20 (9H, m), 1.87-1.78 (1H, m), 1.08 (9/2H, s), 1.07 (9/2H, s), 0.69 (3H, s).
化合物16(42 mg, 0.066 mmol)のTHF溶液(0.7 mL)に、0℃でTBAF(1.0 M in THF, 0.13 mL, 0.13 mmol)とCH3COOH(4 μL)を加え、室温で終夜撹拌した。飽和食塩水と飽和NaHCO3水溶液を加え、CH2Cl2で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(AcOEtおよびAcOEt/MeOH = 10:1)にて精製し、化合物17(24.3 mg, 88%)をジアステレオマー混合物(1:1)として得た。
1H-NMR(500 MHz, CDCl3)δ: 9.25 (1H, s), 8.51 (1H, d, J = 5.5 Hz), 7.85 (1H, s), 7.80 (1H, d, J = 8.5 Hz), 7.66-7.63 (2H, m), 6.36 (1/2H, brs), 6.35 (1/2H, brs), 6.05 (1/2H, d, J = 9.0 Hz), 6.04 (1/2H, d, J = 9.0 Hz), 5.91 (1/2H, d, J = 9.0 Hz), 5.90 (1/2H, d, J = 9.0 Hz), 4.89 (1/2H, dd, J = 12.0, 2.0 Hz), 4.85 (1/2H, dd, J = 12.0, 2.0 Hz), 3.67-3.57 (3H, m), 3.23 (1H, t, J = 10.0 Hz), 2.60-2.20 (9H, m), 1.87-1.78 (1H, m), 0.68 (3H, s).
化合物17(4.2 mg, 0.01 mmol)のCH2Cl2溶液(0.2 mL)に、0℃でMsCl(4 μL, 0.05 mmol)とEt3N(8 μL, 0.10 mmol)を加え、室温で5時間撹拌した。H2Oを加え、CH2Cl2で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣のDMF溶液(0.2 mL)に、NaN3(6.4 mg, 0.10 mmol)を加え、室温で3日間撹拌した。H2Oを加え、CH2Cl2で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣のTHF/H2O溶液(0.4 mL + 0.1 mL)にPPh3(8.0 mg, 0.07 mmol)を加え、室温で5時間撹拌した。H2Oを加え、CH2Cl2で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(AcOEtおよびCH2Cl2/MeOH = 10:1)にて精製し、化合物18(2.3 mg, 42%)をジアステレオマー混合物(1:1)として得た。
1H-NMR(500 MHz, CDCl3)δ: 9.25 (1H, s), 8.51 (1H, d, J = 5.5 Hz), 7.84 (1H, s), 7.80 (1H, d, J = 8.5 Hz), 7.66-7.63 (2H, m), 6.33 (1H, brs), 6.03 (1H, d, J = 9.5 Hz), 5.91 (1H, d, J = 9.0 Hz), 4.85 (1H, d, J = 13.0 Hz), 3.65 (2H, brs), 3.23-3.16 (3H, m), 2.60-2.20 (9H, m), 1.87-1.78 (1H, m), 0.67 (3H, s).
化合物17(4.5 mg, 0.011 mmol)のCH2Cl2溶液(0.3 mL)に、0℃でDess−Martin periodinane(6.9 mg, 0.016 mmol)、NaHCO3(3.7 mg, 0.044 mmol)を加え、室温で1時間撹拌した。反応液を0℃にした後、飽和Na2S2O3溶液を加え、CH2Cl2で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣のt−BuOH溶液(0.2 mL)に、NaClO2(3.0 mg, 0.033 mmol)、2−methyl−2−butene(70 μL)、NaH2PO4水溶液(20%, 0.2 mL)を加え、室温で2時間撹拌した。反応液を0℃にした後、H2Oを加え、CH2Cl2で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(AcOEtおよびCH2Cl2/MeOH = 5:1)にて精製し、化合物19(1.1 mg, 25% in 2 steps)をジアステレオマー混合物(1:1)として得た。
1H-NMR(500 MHz, CDCl3)δ: 9.28 (1H, brs), 8.50 (1H, d, J = 6.0 Hz), 7.87 (1H, s), 7.81 (1H, d, J = 8.5 Hz), 7.67-7.63 (2H, m), 6.35 (1H, brs), 6.03 (1H, d, J = 9.5 Hz), 5.91 (1H, d, J = 9.0 Hz), 4.88 (1H, d, J = 11.0 Hz), 3.23-3.16 (2H, m), 2.60-2.20 (8H, m), 1.87-1.78 (1H, m), 0.67 (3H, s).
図7に示したスキームに従って、式(LIV)で示される化合物(以下、「CA−5」と記す。)を合成した。
化合物6(実施例1および図1参照、350 mg, 1.09 mmol)のTHF溶液(13.6 mL)に、BH3・THF(1.0M in THF, 3.3 mL, 3.3 mmol)を加え、室温で4時間撹拌した。反応液を0℃にした後、2N NaOH水溶液(17 mL)および30%H2O2水溶液(17 mL)を加え、室温で3日間撹拌した後、CH2Cl2で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をMeOH(10 mL)に溶解し、Na2CO3(800 mg)を加えて、7時間加熱還流した後、不溶物をろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(CHCl3/MeOH/H2O = 30:3:1 (lower phase))にて精製し、化合物20(258 mg, 70%)を得た。
1H-NMR(500 MHz, CDCl3)δ: 9.17 (1H, s), 8.46 (1H, d, J = 6.5 Hz), 7.79 (1H, s), 7.76 (1H, d, J = 8.5 Hz), 7.61 (1H, d, J = 6.5 Hz), 7.56 (1H, dd, J = 8.5, 1.5 Hz), 5.01 (1H, td, J = 9.0, 1.5 Hz), 4.00-3.95 (4H, m), 2.90 (1H, d, J = 7.5 Hz), 2.46-2.38 (1H, m), 2.02 (1H, td, J = 13.0, 8.5 Hz), 1.80-1.43 (7H, m), 0.63 (3H, s).
化合物20(209 mg, 0.62 mmol)のacetone/H2O溶液(10 mL + 2 mL)に、p−toluenesulfonic acid monohydrate(293 mg, 1.54 mmol)を加え、70℃で5時間撹拌した。反応液を0℃にした後、飽和NaHCO3溶液を加え、CHCl3で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(CHCl3/MeOH/H2O = 30:3:1 (lower phase))にて精製し、化合物21(174 mg, 96%)を得た。
1H-NMR(500 MHz, CDCl3)δ: 9.24 (1H, s), 8.51 (1H, d, J = 5.5 Hz), 7.85 (1H, s), 7.82 (1H, d, J = 8.5 Hz), 7.65 (1H, d, J = 5.5 Hz), 7.59 (1H, dd, J = 8.5, 1.5 Hz), 5.10 (1H, td, J = 9.0, 1.5 Hz), 3.64 (1H, s), 2.97 (1H, d, J = 8.0 Hz), 2.53-2.26 (5H, m), 2.15-2.08 (1H, m), 1.91 (1H, ddd, J = 14.5, 8.0, 2.0 Hz), 1.85 (1H, td, J = 12.0, 5.5 Hz), 1.75 (1H, ddd, J = 12.0, 6.5, 1.5 Hz), 0.83 (3H, s).
化合物21(214 mg, 0.73 mmol)のCH2Cl2溶液(7.3 mL)に、−78℃でTESOTf(180 μL, 0.80 mmol)および2,6−lutidine(110 μL, 0.95 mmol)を加え、−78℃で20分間撹拌した。飽和NH4Cl溶液を加え、CHCl3で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(CHCl3/MeOH/H2O = 100:3:1 (lower phase))にて精製し、化合物22(207 mg, 70%)を得た。
1H-NMR(500 MHz, CDCl3)δ: 9.25 (1H, s), 8.52 (1H, d, J = 5.5 Hz), 7.81-7.78 (2H, m), 7.65 (1H, d, J = 6.0 Hz), 7.58 (1H, dd, J = 8.5, 1.5 Hz), 4.95 (1H, td, J = 9.0, 2.0 Hz), 2.98 (1H, d, J = 7.5 Hz), 2.51-2.24 (5H, m), 2.04 (1H, td, J = 12.5, 8.5 Hz), 1.87-1.78 (2H, m), 1.69 (1H, ddd, J = 13.0, 7.5, 2.0 Hz), 0.83 (3H, s), 0.74 (9H, t, J = 8.0 Hz), 0.46-0.31 (6H, m).
化合物22(154 mg, 0.38 mmol)のCH3CN溶液(7.5 mL)に、0℃でHMDS(0.8 mL, 3.82 mmol)、NaI(280 mg, 1.87 mmol)、TMSCl(0.24 mL, 1.89 mmol)を加え、室温で1時間撹拌した。反応液を0℃にした後、飽和NH4Cl溶液を加え、CH2Cl2で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。得られた生成物のDMSO溶液(7.5 mL)に、0℃で2−ヨードキシ安息香酸(210 mg, 0.75 mmol)を加え、室温で9時間撹拌した。反応液を0℃にした後、飽和NaHCO3溶液および飽和Na2S2O3溶液を加え、CH2Cl2で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n-hexane/AcOEt = 1:1)にて精製し、化合物23(72 mg, 47%)を得た。
1H-NMR(500 MHz, CDCl3)δ: 9.25 (1H, s), 8.52 (1H, d, J = 5.5 Hz), 7.84-7.80 (2H, m), 7.66 (1H, d, J = 5.5 Hz), 7.61 (1H, dd, J = 8.5, 1.5 Hz), 6.96 (1H, d, J = 14.5 Hz), 5.86 (1H, d, J = 14.5 Hz), 4.88 (1H, t, J = 7.0 Hz), 3.16 (1H, d, J = 7.0 Hz), 2.87-2.78 (1H, m), 2.63 (1H, dd, J = 17.5, 4.0 Hz), 2.41 (1H, dd, J = 17.5, 15.0 Hz), 2.16 (1H, td, J = 13.5, 8.5 Hz), 1.90 (1H, dd, J = 13.5, 7.5 Hz), 0.86 (3H, s), 0.73 (9H, t, J = 8.0 Hz), 0.46-0.31 (6H, m).
化合物23(85.5 mg, 0.21 mmol)のTHF溶液(4.2 mL)に、−78℃で、phenyl−N−triflimide(300 mg, 0.84 mmol)、KHMDS(0.5 M in toluene, 1.7 mL, 0.85 mmol)を加え、150分撹拌した。反応液を0℃にした後、H2Oを加え、AcOEtで抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n-hexane/AcOEt = 3:1)にて精製し、化合物24(72 mg, 64%)を得た。
1H-NMR(500 MHz, CDCl3)δ: 9.25 (1H, s), 8.51 (1H, d, J = 6.0 Hz), 7.84 (1H, s), 7.83 (1H, d, J = 8.5 Hz), 7.69 (1H, d, J = 6.5 Hz), 7.62 (1H, d, J = 8.5 Hz), 6.16 (1H, d, J = 10.0 Hz), 5.90 (1H, s), 5.77 (1H, dd, J = 10.0, 2.0 Hz), 4.92 (1H, t, J = 7.0 Hz), 3.41-3.36 (1H, m), 3.24 (1H, d, J = 6.5 Hz), 2.30 (1H, td, J = 13.0, 8.5 Hz), 1.94 (1H, dd, J = 13.0, 8.0 Hz), 0.73 (3H, s), 0.73 (9H, t, J = 8.0 Hz), 0.46-0.31 (6H, m).
化合物24(8.3 mg, 0.015 mmol)のDMF溶液(0.5 mL)に、室温で、Pd(PPh3)4(2 mg, 0.002 mmol)、MeOH(0.2 mL)、Et3N(0.015 mL, 0.11 mmol)を加え、一酸化炭素雰囲気下、40℃で1時間撹拌した。反応液を0℃にした後、H2Oを加え、AcOEtで抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n-hexane/AcOEt = 2:1)にて精製し、化合物25(6.7 mg, 97%)を得た。
1H-NMR(500 MHz, CDCl3)δ: 9.25 (1H, s), 8.51 (1H, d, J = 6.0 Hz), 7.85 (1H, s), 7.81 (1H, d, J = 8.5 Hz), 7.67 (1H, d, J = 6.5 Hz), 7.63 (1H, d, J = 8.5 Hz), 7.10 (1H, d, J = 2.5 Hz), 6.32 (1H, d, J = 10.0 Hz), 6.05 (1H, d, J = 10.0 Hz), 4.93 (1H, t, J = 7.0 Hz), 3.77 (3H, s), 3.29 (1H, ddd, J = 12.0, 8.5, 2.5 Hz), 3.25 (1H, d, J = 6.5 Hz), 2.32 (1H, td, J = 13.0, 8.5 Hz), 1.95 (1H, dd, J = 13.0, 8.5 Hz), 0.73 (9H, t, J = 8.0 Hz), 0.62 (3H, s), 0.46-0.31 (6H, m).
化合物25(46 mg, 0.10 mmol)のCH2Cl2溶液(2.5 mL)に、−78℃で、DIBAL−H(1.0 M in n-hexane, 0.3 mL, 0.3 mmol)を加え、30分撹拌した。反応液を0℃にした後、CH2Cl2(5 mL)で希釈し、酒石酸ナトリウムカリウム水溶液(7 mL)を加え、6時間撹拌した後、CH2Cl2で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n-hexane/AcOEt = 1:1)にて精製し、化合物26(22.5 mg, 52%)を得た。
1H-NMR(500 MHz, CDCl3)δ: 9.24 (1H, s), 8.51 (1H, d, J = 6.0 Hz), 7.85 (1H, s), 7.81 (1H, d, J = 8.5 Hz), 7.65 (1H, d, J = 5.5 Hz), 7.63 (1H, dd, J = 8.5, 2.0 Hz), 6.03 (1H, d, J = 9.0 Hz), 5.90 (1H, brs), 5.89 (1H, dd, J = 9.0, 1.5 Hz), 4.93 (1H, t, J = 7.0 Hz), 4.16 (1H, d, J = 12.5 Hz), 4.11 (1H, d, J = 12.5 Hz), 3.24 (1H, d, J = 7.5 Hz), 3.24-3.19 (1H, m), 2.23 (1H, td, J = 13.5, 8.5 Hz), 1.88 (1H, dd, J = 12.0, 8.5 Hz), 0.73 (9H, t, J = 8.0 Hz), 0.63 (3H, s), 0.46-0.31 (6H, m).
化合物26(22.5 mg, 0.054 mmol)のCH2Cl2溶液(1.3 mL)に、0℃でDess−Martin periodinane(34.1 mg, 0.08 mmol)、NaHCO3(22.6 mg, 0.27 mmol)を加え、室温で30分撹拌した。反応液を0℃にした後、飽和NH4Cl溶液を加え、CH2Cl2で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮して、化合物27を含む混合物(27.5 mg)を得た。
上記生成物のAcOEt溶液(2.7 mL)に、0℃で1,3−cyclohexanedione(12 mg, 0.11 mmol)、ethylenediamine(4.3 μL, 0.064 mmol)を加え、室温で2時間撹拌した。反応液を0℃にした後、H2Oを加え、CH2Cl2で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n-hexane/AcOEt = 1:1)にて精製し、化合物28(16.5 mg, 60% in 2 steps)を得た。
1H-NMR(500 MHz, CDCl3)δ: 9.26 (1H, s), 8.51 (1H, d, J = 6.0 Hz), 7.83 (1H, s), 7.81 (1H, d, J = 8.5 Hz), 7.66 (1H, d, J = 5.5 Hz), 7.61 (1H, dd, J = 8.5, 1.5 Hz), 6.36 (1H, brs), 6.01 (1H, d, J = 9.0 Hz), 5.78 (1H, d, J = 9.0 Hz), 4.95 (1H, t, J = 7.0 Hz), 4.81 (1H, dd, J = 11.5, 2.5 Hz), 3.17 (1H, d, J = 6.5 Hz), 2.84 (1H, td, J = 13.5, 7.5 Hz), 2.57 (1H, ddd, J = 18.0, 9.0, 5.0 Hz), 2.50 (1H, dt, J = 18.0, 5.0 Hz), 2.44-2.40 (2H, m), 2.25 (1H, td, J = 13.5, 8.5 Hz), 2.12-1.95 (3H, m), 0.75 (3H, s), 0.73 (9H, t, J = 8.0 Hz), 0.46-0.31 (6H, m).
化合物26(4.7 mg, 0.009 mmol)のMeOH溶液(0.7 mL)に、0℃で5%HCl溶液(0.18 mL, 0.25 mmol)を加え、10分撹拌した。反応液にNaHCO3(64 mg)を加え、Na2SO4で乾燥後ろ過し、減圧濃縮した。残渣をCHCl3に溶解し、不溶物を綿栓ろ過し、減圧濃縮して、化合物29を含む混合物(5.4 mg)を得た。
上記生成物のCH2Cl2溶液(0.3 mL)に、0℃でDess−Martin periodinane(11.6 mg, 0.03 mmol)を加え、室温で30分撹拌した。反応液を0℃にした後、飽和NH4Cl溶液および飽和Na2S2O3溶液を加え、CH2Cl2で抽出した。有機層をNa2SO4で乾燥後ろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(CHCl3/MeOH/H2O = 100:3:1 (lower phase))にて精製し、化合物30(3.3 mg, 91% in 2 steps)を得た。
1H-NMR(500 MHz, CDCl3)δ: 9.26 (1H, s), 8.55 (1H, d, J = 5.5 Hz), 7.84 (1H, d, J = 8.5 Hz), 7.77 (1H, s), 7.67 (1H, d, J = 5.5 Hz), 7.46 (1H, d, J = 8.5 Hz), 6.47 (1H, brs), 6.16 (1H, d, J = 9.0 Hz), 5.97 (1H, d, J = 9.0 Hz), 4.99 (1H, d, J = 9.0 Hz), 3.71 (1H, s), 2.90-2.81 (2H, m), 2.61 (1H, ddd, J = 18.0, 9.5, 5.5 Hz), 2.56-2.44 (4H, m), 2.12-1.95 (2H, m), 0.80 (3H, s).
CA−1、CA−2、CA−3、CA−4およびCA−5について、正常ヒト臍帯静脈血管内皮細胞HUVECおよびヒト咽頭上皮がん細胞KB3−1に対する細胞増殖阻害活性を評価した。各被験化合物は、EtOHに溶解し、所定の濃度に調製した。HUVECおよびKB3−1をそれぞれ2×103cells/100μL/wellの濃度で96wellのマルチウェルプレートに播種し、37℃、5%CO2雰囲気下で24時間培養した。次に、各種濃度に調製した被検化合物または対照化合物のエタノール溶液1.0μLを添加し、同条件でさらに72時間培養した。72時間後、WST−8 [2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt] 試薬10μLを添加し、3時間培養後に生存細胞が形成する水溶性のformazanをOD450nmで比色定量し、化合物非添加群のそれと比較することにより生育阻害率を算出した。
実験は、投与経路を経口投与に変更したこと、50mg/kg群を設けたこと以外は、実施例3と同様に行った。
結果を図13および図14に示した。図13は、各群(25mg/kg群を除く)のマウスにおけるマトリゲル移植部位の写真であり、図14は、マトリゲル内に蓄積したヘモグロビン量を測定した結果を示すグラフである。図13および図14から明らかなように、CA−1投与群のマトリゲル内におけるヘモグロビンの蓄積量は、10mg/kg以上の用量で有意に抑制され、50mg/kg群では、血管新生促進因子であるbFGFを含有しないマトリゲルを用いて検討した場合とほぼ同程度の血管新生阻害活性を示した。これらのことから、被験化合物CA−1は、経口投与によってもin vivo血管新生阻害効果を示すことが明らかとなった。
実験は、投与経路を経口投与に変更したこと、5mg/kg群を設けずに50mg/kg群を設けたこと以外は、実施例3と同様に行った。
結果を図15および図16に示した。図15は、各群のマウスから摘出した腫瘍の大きさを示す写真であり、図16は、腫瘍重量を測定した結果を示すグラフである。図15および図16から明らかなように、CA−1投与群の腫瘍重量は、コントロール群に対して10mg/kg投与群で67%、25mg/kg投与群で50%、50mg/kg投与で25%に減少し、顕著な抗腫瘍活性を示した。また、いずれの投与群においてもマウスの体重減少や下痢、目視での臓器の異常は観察されなかった。
Claims (11)
- 一般式(M)
で示される化合物またはその薬学的に許容される塩。 - 一般式(I)
で示される化合物またはその薬学的に許容される塩。 - 式(II)
- 請求項1〜3のいずれかに記載の化合物またはその薬学的に許容される塩と、薬学的に許容される担体を含有してなる医薬組成物。
- 請求項1〜3のいずれかに記載の化合物またはその薬学的に許容される塩を有効成分として含有する血管内皮細胞増殖阻害剤。
- 請求項1〜3のいずれかに記載の化合物またはその薬学的に許容される塩を有効成分として含有する血管新生阻害剤。
- 請求項1〜3のいずれかに記載の化合物またはその薬学的に許容される塩を有効成分として含有する癌の予防または治療薬。
- 化学療法剤、免疫療法剤またはホルモン療法剤と併用することを特徴とする請求項7に記載の癌の予防または治療薬。
- 放射線療法と併用することを特徴とする請求項7に記載の癌の予防または治療薬。
- 癌の予防または治療薬を製造するための、請求項1〜3のいずれかに記載の化合物またはその薬学的に許容される塩の使用。
- 癌の予防または治療に使用するための、請求項1〜3のいずれかに記載の化合物またはその薬学的に許容される塩。
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