JP2008533191A - 癌の治療における使用のためのヌクレオシド化合物のホスホルアミデート誘導体 - Google Patents
癌の治療における使用のためのヌクレオシド化合物のホスホルアミデート誘導体 Download PDFInfo
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- JP2008533191A JP2008533191A JP2008502453A JP2008502453A JP2008533191A JP 2008533191 A JP2008533191 A JP 2008533191A JP 2008502453 A JP2008502453 A JP 2008502453A JP 2008502453 A JP2008502453 A JP 2008502453A JP 2008533191 A JP2008533191 A JP 2008533191A
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- compound
- compound according
- alkyl
- treatment
- naphthyl
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- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 14
- 238000011282 treatment Methods 0.000 title claims description 23
- 201000011510 cancer Diseases 0.000 title claims description 10
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- 208000032839 leukemia Diseases 0.000 claims abstract description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 102
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- 125000001624 naphthyl group Chemical group 0.000 claims description 29
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 125000001424 substituent group Chemical group 0.000 claims description 24
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- 230000001093 anti-cancer Effects 0.000 description 6
- ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical class OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
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- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229950002757 teoclate Drugs 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 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
- 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
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Genetics & Genomics (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
XおよびZの各々は、独立してH、OH、F、Cl、Br、I、C1‐6アルキル、およびNR5R6から選択され、ここでR5およびR6の各々は独立してHおよびC1‐6アルキルから選択され、
Yは、H、OH、F、Cl、Br、I、C1‐6アルキル、C2‐8アルキニル、およびNR5R6から選択され、ここでR5およびR6の各々は独立してHおよびC1‐6アルキルから選択され、
TおよびT′の各々は、独立してH、F、およびOHから選択されるが、但しTおよびT′の一方のみがOHとなりえ、
Qは、O、S、およびCR7R8から選択され、ここでR7およびR8は独立してHおよびC1‐6アルキルから選択され、
Arは、C6‐30アリールおよびC6‐30ヘテロアリールから選択され、その各々が場合により置換され、
R1およびR2の各々は、独立してH、および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、C5‐20ヘテロシクリルからなる群より選択され、そのいずれも場合により置換され、そして
R3およびR4の各々は、独立してH、および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、C5‐20ヘテロシクリルからなる群より選択され、そのいずれも場合により置換される〕。
X=NH2、Y=Cl、Z=H、Q=O、およびT=T′=Hを有し、そのためクラドリビンから誘導され、
X=Cl、Y=NH2、Z=H、Q=O、およびT=T′=Hを有し、そのためイソクラドリビンから誘導され、
X=NH2、Y=F、Z=H、Q=O、およびT=T′=Hを有し、そのためフルダラビンから誘導され、
X=NH2、Y=Cl、Z=H、Q=O、T=F、およびT′=Hを有し、そのためクロファラビンから誘導され、および
X=NH2、Y=C2‐8アルキニル、更に好ましくはC2‐6アルキニル、Z=H、Q=O、T=H、およびT′=OHを有する。
N‐メチルイミダゾール(NMI)(0.29g,3.50mmol,0.29mL)を無水THF(10mL)中2‐クロロ‐2′‐デオキシアデノシン(0.200g,0.70mmol)の攪拌懸濁液へ加えた。無水THF中1‐フェニル‐(メトキシ‐L‐アラニニル)ホスホロクロリデート(0.58g,2.10mmol)を−78℃において滴下した。15分後、反応液を室温まで上昇させた。反応をTLC(DCM/MeOH95/5)により追跡し、4時間後に更に1‐フェニル‐(メトキシ‐L‐アラニニル)〕ホスホクロリデート(0.28g,1.0mmol)を加え、反応液を一晩攪拌した。MeOHを加えて反応停止させ、揮発性物質を蒸発させ、残渣をフラッシュクロマトグラフィー(DCM/MeOH100/0〜95/5)および分取TLC(DCM/MeOH96/4)により精製して、白色泡状物として生成物を得た(0.008g,2%収率、クラドリビン回収率0.15g)。31P‐NMR(CDCl3,121MHz):δ4.56,4.21.1H‐NMR(CDCl3,300MHz):δ8.14,8.07(1H,2s,H‐8),7.52‐7.29(5H,m,Ph),6.56‐6.50(1H,m,H‐1′),6.18‐6.01(1H,bs,NH2),4.90‐4.77(1H,m,H‐3′),4.46‐4.56(2H,m,H‐5′),4.32‐4.26(1H,m,H‐4′),4.22‐4.02(1H,m,CHNH),3.85,3.83(3H,2s,CH3O),2.92‐2.61(2H,m,H‐2′),1.56‐1.44(3H,m,CH3CH).
NMI(0.29g,3.50mmol,0.29mL)を無水THF(10mL)中2‐クロロ‐2′‐デオキシアデノシン(0.200g,0.70mmol)の攪拌懸濁液へ加えた。無水THF中、1‐フェニル‐(ベンゾキシ‐L‐アラニニル)ホスホロクロリデート(0.74g,2.10mmol)を−78℃において滴下した。15分後、反応液を室温まで上昇させ、反応液を一晩攪拌した。MeOHを加えて反応停止させ、揮発性物質を蒸発させた。残渣をフラッシュクロマトグラフィー(DCM/MeOH100/0〜95/5)および分取TLC(DCM/MeOH96/4)により精製して、白色泡状物として生成物を得た(0.015g,4%収率)。31P‐NMR(MeOH,121MHz):δ5.11,4.81.1H‐NMR(MeOH,300MHz):δ8.12,8.10(1H,2s,H‐8),7.23‐7.04(10H,m,PhO,PhCH2),6.30‐6.24(1H,m,H‐1′),5.04‐5.00(2H,m,PhCH2),4.52‐4.48(1H,m,H‐3′),4.29‐4.15(2H,m,H‐5′),4.08‐4.04(1H,m,H‐4′),3.91‐3.81(1H,m,CHNH),2.63‐2.54(1H,m,H‐2′の一つ),2.41‐2.33(1H,m,H‐2′の一つ),1.24‐1.17(3H,m,CHCH3).13C‐NMR(MeOD,75MHz):δ20.6,20.8(CH3),41.2(C‐2′),52.0,52.1(CHCH3),67.7,68.1,68.2,68.3(C‐5′,CH2Ph),72.6(C‐3′),86.2,86.4(C‐1′),87.2,87.3(C‐4′),121.7,121.8,126.5,129.6,129.7,129.9,131.1,137.6,141.5(C‐5,C‐8,PhCH2,PhO,“イプソ”PhCH2),151.8,151.9(C‐6),152.4,152.5(“イプソ”PhO),155.7,155.8(C‐2),158.4(C‐4),175.0,175.2(COOCH2Ph).
NMI(0.29g,3.50mmol,0.29mL)を無水THF(6mL)中2‐クロロ‐2′‐デオキシアデノシン(0.200g,0.70mmol)の攪拌懸濁液へ加えた。無水THF(4mL)中、1‐ナフチル‐(ベンゾキシ‐L‐アラニニル)ホスホクロリデート(0.85g,2.10mmol)を−78℃において滴下した。15分後、反応液を室温まで上昇させ、一晩攪拌した。MeOHを加えて反応停止させ、揮発性物質を蒸発させた。残渣をフラッシュクロマトグラフィー(DCM/MeOH100/0〜95/5)および分取HPLC(H2O/CH3CN60/40)により精製して、白色泡状物として生成物を得た(混合26mg,速溶出11mg,遅溶出8mg)。
混合(CPF210)
31P‐NMR(CDCl3,202MHz):δ3.64,3.23(int.:1.00,0.97).
HPLC:Rt8.92,9.59min.1H‐NMR(CDCl3,500MHz):δ8.00‐7.98(1H,m,H‐8ナフチル),7.86(0.5H,s,1ジアステレオマーのH‐8の一つ),7.77(1H,d,H‐5ナフチル,3J=7.4Hz),7.75(0.5H,s,1ジアステレオマーのH‐8の一つ),7.56(1H,d,H‐4ナフチル,3J=8.3Hz),7.44‐7.40(3H,m,H‐2ナフチル,H‐6ナフチル,H‐7ナフチル),7.31‐7.15(6H,m,H‐3ナフチル,Ph),6.25‐6.21(1H,m,H‐1′),5.73(2H,bs,NH2),5.04(1H,s,1ジアステレオマーのCH2Ph),4.97(0.5H,d,2J=12.2Hz,1ジアステレオマーの一つのCH2Ph),4.94(0.5H,d,2J=12.2Hz,1ジアステレオマーの一つのCH2Ph),4.57‐4.54(0.5H,m,1ジアステレオマーのH‐3′),4.49‐4.46(0.5H,m,1ジアステレオマーのH‐3′),4.34‐4.23(2H,m,H‐5′),4.11‐4.00(2H,m,H‐4′,CHNH),3.91(0.5H,1ジアステレオマーのCHNH),3.90(0.5H,1ジアステレオマーのCHNH),3.13(0.5H,1ジアステレオマーのOH),3.01(0.5H,1ジアステレオマーのOH),2.56‐2.51(0.5H,m,1ジアステレオマーの一つのH‐2′),2.43‐2.29(1.5H,m,三つのH‐2′),1.27‐1.24(3H,2d,CHCH3).
13C‐NMR(CDCl3,125MHz):δ19.7,19.8(CH3),38.8(C‐2′),49.4,49.5(CHCH3),64.8,66.2,66.3(C‐5′,CH2Ph),69.8(C‐3′),83.0(C‐1′),83.9,84.0(C‐4′),113.9,114.0(C‐2ナフチル),117.6,120.2,120.3,123.9,124.5,125.2,125.4,125.5,125.7,126.8,127.1,127.4,127.5,127.6(C‐5,C‐8,PhCH2,C‐5aナフチル,C‐3ナフチル,C‐4ナフチル,C‐5ナフチル,C‐6ナフチル,C‐7ナフチル,C‐8ナフチル,C‐8aナフチル),133.6,133.7,134.1(“イプソ”PhCH2,C‐4aナフチル),145.3(C‐1ナフチル),149.3(C‐6),153.0(C‐2),155.13(C‐4),172.4(COOCH2Ph).
31P‐NMR(CDCl3,202MHz):δ3.60,3.22(int.:4.87,1.00).HPLC:Rt7.59,8.92min.1H‐NMR(CDCl3,500MHz):δ8.03(1H,d,3J=7.5Hz,H‐8ナフチル),7.92(0.2H,s,副ジアステレオマーのH‐8の一つ),7.80(0.8H,s,H‐8),7.79(1H,d,3J=7.4Hz,H‐5ナフチル),7.61(1H,d,H‐4ナフチル,3J=8.3Hz),7.47‐7.44(3H,m,H‐2ナフチル,H‐6ナフチル,H‐7ナフチル),7.35‐7.12(6H,m,H‐3ナフチル,Ph),6.29‐6.26(1H,m,H‐1′),5.88(2H,bs,NH2),5.08(0.4H,s,副ジアステレオマーのCH2Ph),5.05,4.97(1.6H,2d,2J=12.2Hz,CH2Ph),4.61‐4.58(0.2H,m,副ジアステレオマーのH‐3′),4.54‐4.51(0.8H,m,H‐3′),4.36‐4.32(2H,m,H‐5′),4.12‐4.06(2.2H,m,H‐4′,CHNH,副ジアステレオマーのCHNH),3.82(0.8H,CHNH),3.32(0.2H,副ジアステレオマーのOH),3.25(0.8H,OH),2.58‐2.53(0.2H,m,副ジアステレオマーの一つのH‐2′),2.46‐2.42(0.2H,m,副ジアステレオマーの一つのH‐2′),2.41‐2.33(1.6H,m,H‐2′),1.31‐1.29(3H,2d,CHCH3).
31P‐NMR(CDCl3,202MHz):δ3.64,3.25(int.:1.00,28.15).HPLC:Rt9.59,10.92min.1H‐NMR(CDCl3,500MHz):δ7.99‐7.97(1H,dd,H‐8ナフチル),7.87(1H,s,H‐8),7.77‐7.74(1H,m,H‐5ナフチル),7.57(1H,d,H‐4ナフチル,3J=8.3Hz),7.44‐7.40(3H,m,H‐2ナフチル,H‐6ナフチル,H‐7ナフチル),7.29‐7.20(6H,m,H‐3ナフチル,Ph),6.23(1H,m,H‐1′),5.81(2H,bs,NH2),5.03(2H,s,CH2Ph),5.00,4.92(d,2J=12.3Hz,副ジアステレオマーのCH2Ph),4.58‐4.55(1H,m,H‐3′),4.49,4.48(m,副ジアステレオマーのH‐3′),4.34‐4.23(2H,m,H‐5′),4.08‐3.99(3H,m,H‐4′,CHNH,CHNH),3.78(副ジアステレオマーのCHNH),3.31(1H,bs,OH),2.56‐2.50(1H,m,一つのH‐2′),2.42‐2.38(1H,m,一つのH‐2′),2.37‐2.31(m,副ジアステレオマーのH‐2′),1.26(3H,2d,CHCH3).
NMI(0.26g,3.20mmol,0.25mL)を無水THF(6mL)中2‐クロロ‐2′‐デオキシアデノシン(0.183g,0.64mmol)の攪拌懸濁液へ加えた。無水THF(4mL)中、4‐クロロ‐1‐ナフチル‐(ベンゾキシ‐L‐アラニニル)ホスホクロリデート(0.87g,1.92mmol)を−78℃において滴下した。15分後、反応液を室温まで上昇させ、一晩攪拌した。MeOHを加えて反応停止させ、揮発性物質を蒸発させた。残渣をフラッシュクロマトグラフィー(DCM/MeOH100/0〜95/5)および分取HPLC(H2O/CH3CN60/40)により精製して、白色泡状物として生成物を得た(15mg,3%)。
31P‐NMR(CDCl3,202MHz):δ3.45,3.26.HPLC:Rt7.92,10.20min.
1H‐NMR(CDCl3,500MHz):δ8.14‐8.10(1H,m,H‐5ナフチル),7.99‐7.96(1H,m,H‐8ナフチル),7.88(0.5H,s,1ジアステレオマーのH‐8の一つ),7.82(0.5H,s,1ジアステレオマーのH‐8の一つ),7.54‐7.49(1H,m,H‐6ナフチル),7.47‐7.40(1H,m,H‐7ナフチル),7.32‐7.14(7H,m,H‐2ナフチル,H‐3ナフチル,Ph),6.25‐6.22(1H,m,H‐1′),6.04(2H,bs,NH2),5.00(1H,s,1ジアステレオマーのCH2Ph),4.97(0.5H,d,2J=12.2Hz,1ジアステレオマーの一つのCH2Ph),4.90(0.5H,d,2J=12.2Hz,1ジアステレオマーの一つのCH2Ph),4.59‐4.54(1H,m,H‐3′),4.33‐4.19(2.5H,m,H‐5′,1ジアステレオマーのCHNH),4.08‐3.96(2.5H,m,H‐4′,CHNH,1ジアステレオマーのCHNH),3.61,3.57(1H,2bs,OH‐3′),3.01(0.5H,1ジアステレオマーのOH),2.59‐2.34(2H,m,H‐2′),1.25‐1.23(3H,m,CHCH3).
13C‐NMR(CDCl3,125MHz):δ20.8(CH3),39.7(C‐2′),50.5(CHCH3),66.2,66.3(C‐5′),67.4(CH2Ph),71.0(C‐3′),84.1(C‐1′),84.9,85.0,85.1(C‐4′),114.8,114.9,115.1,118.8,121.8,124.7,125.5,127.2,127.8,128.1,128.3,128.5,128.6,128.7(C‐2ナフチル,C‐3ナフチル,C‐4ナフチル,C‐5ナフチル,C‐6ナフチル,C‐7ナフチル,C‐8ナフチル,C‐8aナフチル,Ph),131.6(C‐4a),135.0(“イプソ”PhCH2),139.3,139.4(C‐8),145.3,145.4(C‐1ナフチル),150.4(C‐6),154.1(C‐2),156.1(C‐4),173.3(COOCH2Ph).
NMI(0.36g,4.40mmol,0.35mL)を−78℃において無水THF(10mL)中2‐アミノ‐6‐クロロ‐2′‐デオキシグアノシン(0.25g,0.88mmol)および1‐フェニル‐(ベンゾキシ‐L‐アラニニル)ホスホロクロリデート(0.93g,2.64mmol)の攪拌懸濁液へ加えた。15分後、反応液を室温まで上昇させ、反応液を一晩攪拌した。MeOHを加えて反応停止させ、揮発性物質を蒸発させた。残渣をフラッシュクロマトグラフィー(DCM/MeOH100/0〜96/4)および分取TLC(DCM/MeOH97/3)により精製して、白色泡状物として生成物を得た(0.145g,27.0%収率)。31P‐NMR(MeOH,121MHz):δ5.33,5.00.1H‐NMR(MeOH,300MHz):δ8.17,8.16(1H,2s,H‐8),7.32‐7.13(10H,m,PhO,PhCH2),6.37,6.32(1H,2d,H‐1′),5.11‐5.06(2H,m,PhCH2),4.61‐4.56(1H,m,H‐3′),4.41‐4.20(1H,m,H‐5′),4.18‐4.08(1H,m,H‐4′),4.00‐3.89(1H,m,CHNH),2.84‐2.68(1H,m,H‐2′の一つ),2.41‐2.30(1H,m,H‐2′の一つ),1.30‐1.24(3H,m,CHCH3).13C‐NMR(MeOD,75MHz):δ20.6,20.7,20.8(CH3),40.4,40.7(C‐2′),51.9,52.1(CHCH3),67.8,68.1,68.4(C‐5′,CH2Ph),72.8(C‐3′),86.4(C‐1′),87.1,87.3,87.4(C‐4′),121.7,121.8,125.8,126.5,129.7,129.9,131.1(PhCH2,PhO),137.5,137.6(“イプソ”PhCH2),143.2,143.3(C‐8),152.0(C‐6),152.4,152.5(“イプソ”PhO),155.0,155.1(C‐2),161.9(C‐4),175.0,175.2(COOCH2Ph).
9‐β‐D‐アラビノフラノシル‐2‐フルオロアデニン(50.0mg,0.175mmol)をトルエンと2回共蒸発させ、THF/ピリジン(各2:1混合物)6mLに溶解し、NMI(71.8mg,0.875mmol,70μL)を加えた。混合液を氷/塩浴中−17℃において冷却し、不活性雰囲気下においてフェニル‐(メトキシ‐L‐アラニニル)ホスホクロリデート(145.8mg,0.525mmol,525μL)のTHF中、1M溶液を1時間かけて滴下した。1時間後、反応液を室温まで上昇させ、16時間攪拌し、次いでメタノールにより反応停止させた。溶媒を減圧下において除去し、ジクロロメタン/メタノール(勾配溶出95/5〜85/5)を用いるフラッシュカラムクロマトグラフィーにより粗製物を精製した。単離された化合物を溶媒としてクロロホルム/メタノール(94/6)を用いる分取薄層クロマトグラフィーにより更に精製して、透明無色油状物として生成物を得たが、これはジエチルエーテルにより摩砕および共蒸発後に白色泡状物へ固化した(9.5mg,10.3%)。
19F‐NMR(MeOD,282MHz):δ−54.04.31P‐NMR(MeOD,121MHz):δ4.99.1H‐NMR(MeOD,300MHz):δ8.22,8.20(1H,2xs,H‐8),7.38‐7.19(5H,m,PhO),6.33,6.32(1H,2xd,3J=3.4Hz,H‐1′),4.89‐4.27(4H,m,H‐2′+H‐5′+H‐4′),4.17‐4.03(1H,m,H‐3′),4.00‐3.85(1H,m,CHCH3),3.66‐3.65(3H,2xs,CH 3 O),1.34,1.29(3H,2xd,3J=7.1Hz,CH 3 CH).13C‐NMR(MeOD,75MHz):δ20.7,20.8,20.9(CH3CH),51.9(CH3 CH),53.1,53.2(CH3O),67.4,67.5,67.8,67.9(C‐5′),77.3,77.4,77.6(C‐4′+C‐2′),84.0,84.1,84.2,84.3(C‐3′),86.5,86.7(C‐1′),118.2(アデノシン‐C),121.8,121.9(‘m’,PhO),126.5(‘p’,PhO),131.1(‘イプソ’,PhO),142.9,143.0(5J=2.9Hz,C‐8),142.8,142.9(C‐8),152.4,152.5,152.6(アデノシン‐C+“イプソ” PhO),159.2,159.4,159.6,162.4(アデノシン‐C),175.7,175.8,175.9(COOMe).
クロファラビン‐5′‐〔フェニル‐(ベンゾキシ‐L‐アラニニル)〕ホスフェート
31P‐NMR(MeOD,202MHz):δ3.77,3.64.19F‐NMR(MeOD,470MHz):δ−198.98,−199.01.1H‐NMR(MeOD,500MHz):δ8.17,8.16(1H,2s,H‐8),7.34‐7.15(10H,m,PhO,PhCH2),6.46‐6.40(1H,m,H‐1′),5.21‐5.07(3H,m,H‐2′,PhCH2),4.56,4.52(1H,2s,H‐3′),4.40‐4.39(2H,m,H‐5′),4.19‐4.16(1H,m,H‐4′),4.04‐4.01(1H,m,CHCH3),1.35,1.33(3H,2d,3J=8.5Hz,CHCH3).13C‐NMR(MeOD,75MHz):δ20.3,20.4,20.5(CH3),51.6,51.8(CHCH3),66.8,67.1(C‐5′),68.0(CH2Ph),75.0,75.1,75.3(C‐3′),83.6,83.7,83.8(C‐4′),84.3,84.4,84.5(C‐1′),95.6,97.2(C‐2′),118.6(C‐5),121.4,121.5,126.2,129.2,129.3,129.6,130.8(PhO,CH2Ph),137.2(“イプソ”CH2Ph),141.7,141.8(C‐8),151.7,152.2(“イプソ”PhO,C‐6),155.6(C‐4),158.1(C‐2),174.8,174.9(CO2CH2Ph).HPLC(H2O/CH3CN100/0〜0/100において20分間):tR11.76min.ESI MS(+):621〔M〕.
抗癌効果を評価するために、化合物CPF203、CPF204、CPF194、CPF210、CPF211、CPF212、CPF218、およびCPT2001を白血病細胞系において各々試験した。PromegaのMTSアッセイ試薬(CellTiter96 Aqueous One solution proliferation assay)を用いて各化合物を試験した。各化合物は4倍希釈により10μM〜0.002μMにおいて試験した。
Claims (31)
- 下記式Iの化合物ならびにその薬学上許容される塩、その溶媒和物、およびそのプロドラッグ:
XおよびZの各々は、独立してH、OH、F、Cl、Br、I、C1‐6アルキル、およびNR5R6から選択され、ここでR5およびR6の各々は独立してHおよびC1‐6アルキルから選択され、
Yは、H、OH、F、Cl、Br、I、C1‐6アルキル、C2‐8アルキニル、NR5R6から選択され、ここでR5およびR6の各々は独立してHおよびC1‐6アルキルから選択され、
TおよびT′の各々は、独立してH、F、およびOHから選択されるが、但しTおよびT′の一方のみがOHとなりえ、
Qは、O、S、およびCR7R8から選択され、ここでR7およびR8は独立してHおよびC1‐6アルキルから選択され、
Arは、C6‐30アリールおよびC6‐30ヘテロアリールから選択され、その各々が場合により置換され、
R1およびR2の各々は、独立してH、ならびに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C5‐20ヘテロシクリルからなる群より選択され、そのいずれも場合により置換され、
R3およびR4の各々は、独立してH、および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C5‐20ヘテロシクリルからなる群より選択され、そのいずれも場合により置換される〕。 - XおよびZの各々が独立してH、OH、F、Cl、およびNH2から選択され、YがH、OH、F、Cl、NH2、およびC2‐8アルキニルから選択される、請求項1に記載の化合物。
- XがNH2であり、YがClであり、およびZがHである、請求項2に記載の化合物。
- XがClであり、YがNH2であり、およびZがHである、請求項2に記載の化合物。
- XがNH2であり、YがFであり、およびZがHである、請求項2に記載の化合物。
- TおよびT′が各々Hである、先行する請求項のいずれか一項に記載の化合物。
- TおよびT′の一方または双方がFである、請求項1〜5のいずれか一項に記載の化合物。
- XがNH2であり、YがC2‐8アルキニルであり、ZがHであり、TがHであり、およびT′がOHである、請求項2に記載の化合物。
- QがOである、先行する請求項のいずれか一項に記載の化合物。
- R4がHである、先行する請求項のいずれか一項に記載の化合物。
- 部分‐N‐CR1R2‐COO‐が天然アミノ酸の場合に相当するようにR1およびR2が選択される、先行する請求項のいずれか一項に記載の化合物。
- R1およびR2の各々が独立してMeおよびHから選択される、先行する請求項のいずれか一項に記載の化合物。
- R1およびR2を有するC原子が天然アラニンのようなキラリティーLを有するように、R1およびR2の一方がMeであり、R1およびR2の一方がHである、請求項12に記載の化合物。
- Arが非置換である、先行する請求項のいずれか一項に記載の化合物。
- Arが、電子供与部分および電子求引部分を含む群から選択される1、2、3、4、5、またはそれ以上の置換基により置換される、請求項1〜13のいずれか一項に記載の化合物。
- Arがフェニル、ピリジル、ナフチル、およびキノリルを含む群から選択され、それら各々が置換されるかまたは非置換である、先行する請求項のいずれか一項に記載の化合物。
- ジアステレオマーRp、ジアステレオマーSp、またはジアステレオマーRpおよびSpの混合物を含んでなる、先行する請求項のいずれか一項に記載の化合物。
- 下記を含む群から選択される化合物:
2‐クロロ‐2′‐デオキシアデノシン‐5′‐〔フェニル‐(メトキシ‐L‐アラニニル)〕ホスフェート、
2‐クロロ‐2′‐デオキシアデノシン‐5′‐〔フェニル‐(ベンゾキシ‐L‐アラニニル)〕ホスフェート、
2‐クロロ‐2′‐デオキシアデノシン‐5′‐〔1‐ナフチル‐(メトキシ‐L‐アラニニル)〕ホスフェート、
2‐クロロ‐2′‐デオキシアデノシン‐5′‐〔4‐クロロ‐1‐ナフチル‐(ベンゾキシ‐L‐アラニニル)〕ホスフェート、
2‐アミノ‐6‐クロロプリン‐2′‐デオキシリボシド‐5′‐〔フェニル‐(メトキシ‐L‐アラニニル)〕ホスフェート、および
9‐β‐D‐アラビノフラノシル‐2‐フルオロアデニン‐5′‐〔フェニル‐(メトキシ‐L‐アラニニル)〕ホスフェート。 - 下記化合物:
2‐クロロ‐2′‐β‐フルオロ‐2′‐デオキシアデノシン‐5′‐〔フェニル‐(ベンゾキシ‐L‐(アラニニル)〕ホスフェート。 - 治療、適切には癌の予防または治療、更に適切には白血病の予防または治療における使用のための、請求項1〜18のいずれか一項に記載の化合物。
- 癌の予防または治療用の薬剤、好ましくは白血病の予防または治療用の薬剤の製造における、請求項1〜18のいずれか一項に記載の化合物の使用。
- 請求項1〜18のいずれか一項に記載の化合物の有効量を治療の必要な患者へ投与することからなる、癌、適切には白血病の予防または治療方法。
- 薬学上許容される担体、希釈剤、または賦形剤と組み合わされて、請求項1〜18のいずれか一項に記載の化合物を含んでなる、医薬組成物。
- 請求項1〜18のいずれか一項に記載の化合物を、薬学上許容される賦形剤、担体、または希釈剤と混合する工程を含んでなる、医薬組成物の製造方法。
- 治療、適切には癌の予防または治療、更に適切には白血病の予防または治療における使用のための、請求項19に記載の化合物。
- 癌の予防または治療用の薬剤、好ましくは白血病の予防または治療用の薬剤の製造における、請求項19に記載の化合物の使用。
- 請求項19に記載の化合物の有効量を治療の必要な患者へ投与することからなる、癌、適切には白血病の予防または治療方法。
- 薬学上許容される担体、希釈剤、または賦形剤と組み合わされて、請求項19に記載の化合物を含んでなる、医薬組成物。
- 請求項19に記載の化合物を、薬学上許容される賦形剤、担体、または希釈剤と混合する工程を含んでなる、医薬組成物の製造方法。
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JP2017504572A (ja) * | 2013-11-27 | 2017-02-09 | アイデニクス・ファーマシューティカルズ・エルエルシー | 肝臓癌治療のためのヌクレオチド類 |
JP2018533634A (ja) * | 2015-11-16 | 2018-11-15 | イコリオン セラピューティクス,インコーポレーテッド | 核酸プロドラッグ |
JP7019585B2 (ja) | 2015-11-16 | 2022-02-15 | アヴァロ セラピューティクス,インコーポレーテッド | 核酸プロドラッグ |
US11479576B2 (en) | 2015-11-16 | 2022-10-25 | Avalo Therapeutics, Inc. | Nucleic acid prodrugs |
JP2018538342A (ja) * | 2015-12-23 | 2018-12-27 | ニューカナ パブリック リミテッド カンパニー | ヌクレオシド薬剤のアミド亜リン酸エステル誘導体の製剤 |
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JP2020523381A (ja) * | 2017-06-14 | 2020-08-06 | ニューカナ パブリック リミテッド カンパニー | 3’−デオキシアデノシン−5’−o−[フェニル(ベンジルオシキ−l−アラニニル)]ホスフェート(nuc−7738)の合成 |
JP7248209B2 (ja) | 2017-06-14 | 2023-03-29 | ニューカナ パブリック リミテッド カンパニー | 3’-デオキシアデノシン-5’-o-[フェニル(ベンジルオシキ-l-アラニニル)]ホスフェート(nuc-7738)の合成 |
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DK1866324T3 (da) | 2010-09-27 |
US20090215715A1 (en) | 2009-08-27 |
JP5345381B2 (ja) | 2013-11-20 |
SI1866324T1 (sl) | 2010-10-29 |
ATE471334T1 (de) | 2010-07-15 |
CY1111538T1 (el) | 2015-08-05 |
IL186104A0 (en) | 2008-01-20 |
ZA200709011B (en) | 2009-01-28 |
JP2013173786A (ja) | 2013-09-05 |
CN103936807A (zh) | 2014-07-23 |
AU2006226182B2 (en) | 2011-09-01 |
US8263575B2 (en) | 2012-09-11 |
AU2006226182C1 (en) | 2012-06-14 |
EP1866324B1 (en) | 2010-06-16 |
BRPI0609704B8 (pt) | 2021-09-28 |
AU2006226182A1 (en) | 2006-09-28 |
JP5863702B2 (ja) | 2016-02-17 |
CA2602324A1 (en) | 2006-09-28 |
EP1866324A1 (en) | 2007-12-19 |
BRPI0609704B1 (pt) | 2020-12-01 |
DE602006014949D1 (de) | 2010-07-29 |
MX2007011666A (es) | 2007-11-14 |
CA2602324C (en) | 2015-02-24 |
ES2348741T3 (es) | 2010-12-13 |
IL186104A (en) | 2013-06-27 |
BRPI0609704A2 (pt) | 2010-04-20 |
WO2006100439A1 (en) | 2006-09-28 |
PT1866324E (pt) | 2010-09-16 |
GB0505781D0 (en) | 2005-04-27 |
CN101175763A (zh) | 2008-05-07 |
PL1866324T3 (pl) | 2010-12-31 |
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