CN1106017A - 核苷酸膦酸酯衍生物 - Google Patents
核苷酸膦酸酯衍生物 Download PDFInfo
- Publication number
- CN1106017A CN1106017A CN94109168A CN94109168A CN1106017A CN 1106017 A CN1106017 A CN 1106017A CN 94109168 A CN94109168 A CN 94109168A CN 94109168 A CN94109168 A CN 94109168A CN 1106017 A CN1106017 A CN 1106017A
- Authority
- CN
- China
- Prior art keywords
- compound
- record
- ethyl
- alkoxyl group
- trifluoroethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 97
- -1 Phenyl Chemical group 0.000 claims description 57
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 230000014509 gene expression Effects 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 2
- 239000000470 constituent Substances 0.000 claims 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 34
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- 238000006243 chemical reaction Methods 0.000 description 31
- 238000005160 1H NMR spectroscopy Methods 0.000 description 28
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- 150000003722 vitamin derivatives Chemical class 0.000 description 23
- 238000000034 method Methods 0.000 description 18
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
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- 210000002966 serum Anatomy 0.000 description 5
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical compound NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 description 4
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- 241000700605 Viruses Species 0.000 description 3
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
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- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
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- 125000001424 substituent group Chemical group 0.000 description 3
- RFLVMTUMFYRZCB-UHFFFAOYSA-N 1-methylguanine Chemical compound O=C1N(C)C(N)=NC2=C1N=CN2 RFLVMTUMFYRZCB-UHFFFAOYSA-N 0.000 description 2
- BNKDQKJMJDGFGA-UHFFFAOYSA-N 2-ethyl-7h-purin-6-amine Chemical compound CCC1=NC(N)=C2NC=NC2=N1 BNKDQKJMJDGFGA-UHFFFAOYSA-N 0.000 description 2
- ZKBQDFAWXLTYKS-UHFFFAOYSA-N 6-Chloro-1H-purine Chemical compound ClC1=NC=NC2=C1NC=N2 ZKBQDFAWXLTYKS-UHFFFAOYSA-N 0.000 description 2
- RYYIULNRIVUMTQ-UHFFFAOYSA-N 6-chloroguanine Chemical compound NC1=NC(Cl)=C2N=CNC2=N1 RYYIULNRIVUMTQ-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
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- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
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- 244000269722 Thea sinensis Species 0.000 description 2
- JLCHNBRGUPQWKF-UHFFFAOYSA-J [OH-].[C+4].[OH-].[OH-].[OH-] Chemical compound [OH-].[C+4].[OH-].[OH-].[OH-] JLCHNBRGUPQWKF-UHFFFAOYSA-J 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
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- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
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- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
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- 125000003729 nucleotide group Chemical group 0.000 description 2
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- 229940049954 penicillin Drugs 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
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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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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Abstract
本发明提供用下述通式(I)表示的核苷酸膦酸酯
衍生物或者其药用盐。
其中环A和R3、R4如说明书中所述。
本发明的核苷酸膦酸酯衍生物,具有优异的抗病毒活性及抗肿瘤活性,而且可以经口服给药。
Description
本发明涉及具有抗病毒活性的新的核苷酸膦酸酯衍生物或作为药剂允许而得到的其盐,具体地是涉及作为抗病毒剂,可经口服给药的核苷酸膦酸酯衍生物或作为药剂而允许得到的其盐。
感染性病毒疾病在医学上被认为是重要的问题,为了达到治疗这些疾病的目的,正在开发研究一种具有抗病毒活性,同时对正常细胞系的活性又不具有增殖阻碍作用的药剂。例如,核苷酸膦酸酯类,作为选择性的抗病毒剂正在被广泛地研究着。具体地说,曾报导了9-(2-膦酰甲氧基)乙基腺嘌呤(PMEA)、9-(2-磷酰甲氧基)乙基-2,6-二氨基嘌呤(PMDAP)等对于单纯疱疹1型及二型(HSV-1及HSV-2)、人体免疫缺陷病毒(H1V)、人体B型肝炎病毒(HBV)是有效的。(横田他、Antimicrob.Agents Chemother,35,394(1991);Votruba et al.Mol.Pharmacol.,32,524(1987))。
可是,这些核苷酸及离子性有机膦酸酯所存在的问题是它们不具有经口服给药的吸收性(De Clercq etal.Antimicrob.Agents Chemother.,33,185(1989))。因此,要想有效地发挥这些化合物的效果,为了在血中得到必要的浓度,就要采取静脉注射、肌肉注射等胃肠外给药方法。
可是这种胃肠外给药的治疗方法,对于未住院的患者是相当困难的,特别是对于需要长期治疗的AIDS和B型肝炎病毒等疾病的治疗不是一个好方法。所以,现在需要开发一种具有抗病毒活性,但又可经口服给药的药剂,但是一直尚未达到实用化阶段。
本发明者们为了解决上述这问题,不断地经过潜心研究,结果发现了通过特定的核苷酸膦酸酯类可以达到上述的目的,从而完成了本发明。
即,本发明的要点是用下记通式(1)表示的核苷酸膦酸酯衍生物或其药用盐,
(上述通式(1)中的环A表示,
R1及R2分别独立地表示氢原子、卤原子、羟基、巯基、C6-C10的芳硫基或氨基,R3表示C1-C4烷基或具有从氟原子、C1-C4烷氧基、苯氧基、C7-C10苯基烷氧基及C2-C5酰氧基中选出的1个或多个取代基的乙基、R4表示具有从氟原子、C1-C4的烷氧基、苯氧基、C7-C10的苯基烷氧基及C2-C5的酰氧基中选出来的1个或多个取代基的乙基,X、Y及Z分别独立地表示次甲基或氮原子)。
以下详细说明本发明。
本发明的核苷酸膦酸酯衍生物,用上述通式(1)表示。上述通式(1)中的R1及R2是卤原子时,可举出氟原子、氯原子、溴原子、碘原子等,作为C6-C10的芳硫基可举出苯硫基、甲苯硫基、萘硫基等。另外,作为C1-C4烷基的R3可举出甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基等,作为R3的乙基的取代基的C1-C4烷氧基可举出甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基等,作为C7-C10的苯基烷氧基可举出苄氧基、苯乙氧基、苯丙氧基等苯基C1-C4烷氧基,作为C2-C5的酰氧基可举出乙酰氧基、丙酰氧基、丁酰氧基、异丁酰氧基、戊酰氧基等。作为R4的乙基上取代基的C1-C4烷氧基、C7-C10的苯基烷氧基及C2-C5的酰氧基可与R3的乙基上的取代基相同。
上述的通式(1)中优选的环A是
(其中R1及R2各自代表氢、卤素、羟基、巯基、C6-C10芳硫基或氨基)。
最优选的环A是
(其中R1表示氢原子、氯原子、羟基、巯基、甲苯硫基或氨基、R2表示氢原子、氯原子、碘原子、羟基或氨基)、
(其中R1表示氨基、R2表示氢原子)、或
(其中R1及R2表示氨基)。
另外,作为R3,优选的是C1-C3的烷基、2,2,2-三氟乙基或者具有从C1-C3烷氧基、苯氧基、C7-C10的苯基烷氧基及C2-C5酰氧基中优选的出的1个取代基的乙基、特别优选的是C1-C3烷基或2,2,2-三氟乙基。
作为R4优选的是2,2,2-三氟乙基或者具有1个从C1-C3烷氧基、苯氧基、C7-C10苯基烷氧基及C2-C5酰氧基中选出的取代基的乙基,特别优选的是2,2,2-三氟乙基。
再者,R3或R4表示取代的乙基时,优选的是在乙基的2位上被取代,进而,R3及R4中的至少1个最好是2,2,2-三氟乙基。X及Z优选的是氮原子。
上述通式(1)表示的本发明的核苷酸膦酸酯衍生物可以形成其药用盐。作为这些盐的具体例子,当有酸性基存在时,可以形成锂盐、钠盐、钾盐、镁盐、钙盐等金属盐、铵盐、甲基铵盐、二甲基铵盐、三甲基铵基、二环已基铵盐等的铵盐;当存在有碱性基时,可以形成盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等无机酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、醋酸盐、丙酸盐、酒石酸盐、富马酸盐、马来酸盐、苹果酸盐、草酸盐、丁二酸盐、柠檬酸盐、苯甲酸盐、扁桃酸盐、肉桂酸盐、乳酸盐等有机酸盐。
另外,本发明的化合物,依取代基的种类可以形成酮-烯醇互变异构性的互变异构体,这些互变异构体也包括在本发明内。
本发明的化合物的具体例如下表1-7所示(表中的P、S是表示
在X、Y或Z的取代位置。另外,X、Y或Z的C表示-CH=)。
表-1(续)
表-1(续)
表-1(续)
表-1(续)
表-1(续)
表-1(续)
表-1(续)
本发明的化合物,例如可按下述反应路线(1)或(2)进行合成。反应路线(1)
(上述式中,R1-R4及环A如上述通式(1)中所定义,R5表示具有从氟原子、C1-C4烷氧基、苯氧基、C7-C10的苯基烷氧基、C2-C5的酰氧基、C1-C4的酰氨基及羟基中选出的1个或多个取代基的乙基。W表示卤原子、对甲苯磺酰氧基、甲磺酰氧基、三氟甲磺酰氧基等的离去基。)
首先将用(Ⅱ)式表示的化合物及(Ⅲ)式表示的化合物,在10-250℃,优选的是130-180℃温度下反应0.1-20小时,优选反应时间为3-15小时。
由上述反应得到的(Ⅳ)式化合物,根据需要,使用通常的分离、精制方法,例如,蒸馏、吸附、分配色谱等进行分离、精制。(Ⅳ)式的化合物虽然可用上述方法分离、精制,但也可以、不用精制直接供给下一步反应中。
继而,将(Ⅳ)式的化合物与用(Ⅴ)式表示的化合物,在碱,如,碳酸钠、碳酸钾、碳酸铯、氢化钠、氢化钾、三乙胺、二氮双环十一碳烯等存在下,在溶剂、如乙腈、四氢呋喃、二甲基亚砜、二甲基甲酰胺、甲基吡咯烷酮等的溶剂中,在10-200℃,优选的是50-150℃温度下反应0.1-100小时,最好是5-20小时,得到化合物(1)。
反应路线(2)
(上式中,R1-R4及环A,如通式(1)所定义,Me表示甲基、Et表示乙基。)
首先将(Ⅵ)式表示的化合物和三甲基甲硅烷基二乙基胺,在溶剂中,例如二氯甲烷、二氯乙烷、氯仿等含氯系列溶剂中,室温下反应小时左右。此时,对于1摩尔(Ⅵ)式化合物,三甲基甲硅烷基二乙基胺的使用量为2摩尔以上。
接着,将反应液浓缩至干后,溶解在二氯甲烷等含氯溶剂中,对于1摩尔的(Ⅵ)式化合物添加2摩尔以上的草酰氯,在催化剂量的二甲基甲酰胺存在下,冰冷下反应约1小时,室温下反应约1小时。
蒸出溶剂后,这样得到的化合物(Ⅶ),通常不用精制。在溶剂,例如,二氯甲烷等含氯溶剂、吡啶、乙腈、四氢呋喃、二甲基亚砜、二甲基甲酰胺、甲基吡咯烷酮等的溶剂中,在10-100℃,优选的是20-30℃的温度下,与R3OH,R4OH反应0.1-100小时,优选的是5-24小时,得到化合物(1)。
上述反应路线(1)或(2)得到的(1)式化合物根据需要,适宜地选择通常的核苷酸的分离、精制方法,例如重结晶、吸附、离子交换、分配色谱等方法,进行分离精制。这样得到的(1)式化合物,根据需要,用公知的方法衍生为各种的碱基衍生物。
此外,上述反应路线中(Ⅱ)、(Ⅲ)或(Ⅵ)式的化合物,可使用以试剂形成购入的商品,也可以按适宜的公知方法合成。
本发明的化合物,如下式试验例所示,作为可经口服给药的抗病毒剂,如其他离子性核苷酸膦酸酯类似物所看到的,可以期待具有抗肿瘤活性。对于作为治疗对象的病毒没有特殊的限制,具体地可以举出人体免疫缺陷病毒、流感病毒、C型肝炎病毒等的RNA病毒、以及单纯疱疹病毒Ⅰ、单纯疱疹病毒Ⅱ、细胞肥大病毒、水痘带状疱疹病毒、B型肝炎病毒等的DNA病毒,优选的是B型肝炎病毒。
本发明的化合物,对于人可经口服给药。给药量依患者的年令、健康状态、体重适当地确定,通常每日1-1000mg/kg体重,优选的是5-50mg/kg体重,可分为1次或几次给药。
本发明的化合物最好以含有通常使用的制剂用载体、赋形剂等药学上可允许的载体的组合形物式使用。作为这些载体,使用固体、液体都无妨。作为固体载体可举出如乳糖、白陶土(高岭土)蔗糖、结晶纤维素、玉米淀粉、滑石、琼脂、果胶、硬脂酸、硬脂酸镁、卵磷脂、氯化钠等,作为液体载体可举出如甘油,花生油、聚乙烯吡咯浣酮、橄榄油、乙醇、苄醇、丙二醇、生理食盐水、水等。
剂型可以作成各种形式。当使用固体载体时,可举出片剂、粉剂、颗粒剂、胶囊剂、药锭。使用液体作为载体时,可举出糖浆、软明胶胶囊、凝胶、膏剂等。
以下用实施例具体说明本发明,只要不超出本发明的范围,本发明不受以下实施例限制。
实施例1
9-[2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基]腺嘌呤(表-1中化合物No.309)的制备:
将2-氯乙基氯甲基醚1.96g(15.2mmol)及三(2,2,2-三氟乙基)亚磷酸酯5g(15.2mmol),在160℃下反应14小时,定量地得到2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基氯 5.15g。
将腺嘌呤2.07g(15.3mmol)悬浮在二甲基甲酰胺30ml中,与氢化钠(矿物油中,60%)0.61g,在100℃下反应1小时。接着,向上述反应液中加入2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基氯5.15g,在100℃下反应5小时。
反应后冷却至室温,浓缩至干。残渣溶解在氯仿中后,使之吸附在硅胶柱上,用5%的甲醇-氯仿洗脱,得到标题化合物2.77g(42%)。
m.p.∶111-113℃(醋酸乙酯-己烷)
1H-NMR(CDCl3,δ):3.91(d,J=8.0Hz,2H)
3.94(t,J=5.0Hz,2H)
4.30-4.39(m,6H)
6.00(br,2H)
7.83(s,1H)
8.31(s,1H)
实施例2
9-[2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基]-2,6-二氨基嘌呤(表1中化合物No.459)的制备。
在实施例1中,使用2,6-二氨基嘌呤代表腺嘌呤,其他与实施例1一样,得到标题化合物。
m.p.:108℃(乙醚)
1H-NMR(CDCl3,δ):3.91-3.95(m,4H)
4.24(t,J=5.1Hz,2H)
4.30-4.42(m,4H)
4.68(br,2H)
5.32(br,2H)
7.57(s,1H)
实施例3
9-[2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基]-2-氨基-6-氯嘌呤(表1中,化合物No.509)的制备。
在实施例1中,除了用2,6-二氨基嘌呤代替腺嘌呤外,其他与实施例1相同,得到标题化合物。
m.p.:132℃(乙醚)
1H-NMR(CDCl3,δ):3.91(t,J=4.7Hz,2H)
3.94(d,J=7.6Hz,2H)
4.30(t,J=4.7Hz,2H)
4.35-4.49(m,4H)
5.16(br,2H)
7.83(s,1H)
实施例4
7-[2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基]-2-氨基-6-氯嘌呤(表1中化合物No.510)的制备
在实施例1中,除了用2,6-二氨基-6-氯嘌呤代替腺嘌呤之外,其他与实施例1相同,得到标题化合物。
m.p.:无定形
1H-NMR(CDCl3,δ):3.93(t,J=5.1Hz,2H)
3.94(d,J=7.7Hz,2H)
4.24(t,J=5.1Hz,2H)
4.31-4.42(m,4H)
4.66(br,2H)
5.27(br,2H)
7.56(s,1H)
实施例5
9-[2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基]-8-氮杂-2,6-二氨基嘌呤(表1中化合物No.663)的制备
在实施例1中,除了用8-氮杂-2,6-二氨基嘌呤代替腺嘌呤外,其他与实施例一样,得到标题化合物。
m.p.:169℃(乙醇)
1H-NMR(Me2SO-d6,δ):
3.98(t,J=5.1Hz,2H)
4.11(d,J=7.8Hz,2H)
4.40-4.86(m,6H)
6.38(bs,2H)
7.18-8.00(m,2H)
实施例6
8-[2-[双(2,2,2-三氟乙基)磷酰甲基基]乙基]-8-氮杂-2,6-二氨基嘌呤(表1中化合物No.664)制备
在实施例1中,除了使用8-氮杂-2,6-二氨基嘌呤代替腺嘌呤外,其他与实施例1相同,得到标题化合物。
m.p.:128℃(二异丙基醚)
1H-NMR(Me2SO-d6,δ):4.03-4.15(m,4H)
4.55-4.71(m,4H)
6.05(br,2H)
7.50(br,2H)
实施例7
7-[2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基]茶硷(表3中化合物No.805)的制备
在实施例1中,除了用茶硷代替腺嘌呤之外,其他与实施例1相同,得到标题化合物。
m.p.:77℃(已烷)
1H-NMR(CDCl3,δ):3.41(s,3H)
3.60(s,3H)
3.93(d,J=8.1Hz,2H)
3.94(t,J=5.0Hz,2H)
4.31-4.48(m,4H)
4.52(t,J=5.0Hz,2H)
7.60(s,1H)
实施例8
9-[2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基]-2,6-二氯嘌呤(表1中,化合物No.559)的制备
在实施例1中,除了用2,6-二氯嘌呤代替腺嘌呤外,其他与实施例1相同,得到标题化合物。
m.p.:71-72℃(醋酸乙酯-己烷)
1H-NMR(CDCl3,δ):3.90-4.08(m,4H)
4.32-4.52(m,6H)
8.19(s,1H)
实施例9
9-[2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基]-3-脱氮-8-氮杂-2,6-二氨基嘌呤(表4中化合物No.838)的制备
在实施例1中,除了用3-脱氮-8-氮杂-2,6-二氨基嘌呤代替腺嘌呤外,其他与实施例1相同,得到标题化合物。
m.p.:116-122℃(乙醚)
1H-NMR(Me2SO-d6,δ):
3.94(t,J=5.2Hz,2H)
4.09(d,J=7.7Hz,2H)
4.46-4.78(m,6H)
5.55(s,2H)
5.57(s,1H)
6.66(s,2H)
实施例10
9-[2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基]-7-脱氮-8-氮杂-2,6-二氨基嘌呤(表1中,化合物No.734)的制备
在实施例1中,除了用7-脱氮-8-氮杂-2,6-二氨基嘌呤代替腺嘌呤外,其他与实施例1相同,得到标题化合物。
m.p.:54-64℃(乙醚)
1H-NMR(Me2SO-d6,δ):
3.91(t,J=5.3Hz,2H)
4.07(d,J=8.0Hz,2H)
4.27(t,J=5.3Hz,2H)
4.52-4.78(m,4H)
8.00(s,1H)
实施例11
9-2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基]-6-氯嘌呤(表1中的化合物No.1084)的制备
在实施例1中,除了用6-氯嘌呤代替腺嘌呤以外,其他以同样的方法,得到了标题化合物。
熔点:油
1H-NMR(CDCl3,δ):3.95(d,J=7.8Hz,2H)
4.00(t,J=4.9Hz,2H)
4.34-4.48(m,4H)
4.52(t,J=4.9Hz,2H)
8.20(s,1H)
8.75(s,1H)
实施例12:
9-[2-[甲基(2,2,2-三氟乙基)膦酰甲氧基]乙基]腺嘌呤(表-1中化合物No.303)的制备
将由实施例1得到的化合物1g(2.3mmol)溶于10ml甲醇中,并加入5g硅胶在50℃反应7小时后,进行浓缩至干,残留物用5%甲醇-氯仿洗脱,得到了目的化合物0.75g(88%)。
熔点:107-110℃(乙酸乙酯-己烷)
1H-NMR(CDCl3,δ):3.74(d,J=11.1Hz,3H)
3.83(d,J=8.3Hz,2H)
3.93(t,J=4.1Hz,2H)
4.30-4.39(m,4H)
5.65(br,2H)
7.86(s,1H)
8.33(s,1H)
实施例13
9-[2-[甲基(2,2,2-三氟乙基)膦酰甲氧基]乙基]-2,6-二氨基嘌呤(表-1中,化合物No.453)的制备
在实施例9中,除了使用由实施例2得到的化合物代替由实施例1得到的化合物以外,其他以同样的方法,得到了标题化合物。
熔点:无定形的(非晶形的)
1H-NMR(CDCl3,δ):3.77(d,J=11.0Hz,3H)
3.86(d,J=8.2Hz,2H)
3.91(t,J=5.0Hz,2H)
4.24(t,J=4.1Hz,2H)
4.25-4.42(m,2H)
4.69(br,2H)
5.35(br,2H)
7.60(s,1H)
实施例14
9-[[2-双(2-甲氧基乙基)膦酰甲氧基]乙基]腺嘌呤(表-1中,化合物No.313)的制备
将9-[(2-膦酰甲氧基)乙基]腺嘌呤1g(3.5mmol)悬浮于10ml的二氯甲烷中,与3ml的三甲基甲硅烷基二乙胺,在室温反应1小时,并浓缩至干。将其残渣溶解在10ml二氯甲烷中,然后加入0.05ml的二甲基甲酰胺以及0.9ml的乙二酰氯,并在冰冷下反应小时,再在室温反应1小时。馏出溶剂后,将残渣溶解在20ml吡啶中,之后在室温同2-甲氧基乙醇0.76g进行12小时反应。浓缩至干,将其残渣溶解于氯仿中,并吸附于硅胶柱色谱上,然后用5%-甲醇-氯仿洗脱,得到标题化合物0.3g(22%)。
熔点:90-93℃(乙酸乙酯-己烷)
1H-NMR(CDCl3,δ):3.35(s,6H)
3.55(d,J=4.6Hz,4H)
3.86(d,J=8.2Hz,2H)
3.95(t,J=4.9Hz,2H)
4.16-4.19(m,4H)
4.40(t,J=4.9Hz,2H)
5.67(br,2H)
7.98(s,1H)
8.35(s,1H)
实施例15
9-[[2-双(2-苯氧基乙基)膦酰甲氧基]乙基]腺嘌呤(表-1中的化合物No.323)的制备
在实施例11中,除了用2-苯氧基乙醇代替2-甲氧基乙醇之外,其余以同样的方法,得到了标题化合物。
熔点:112-115℃(已烷)
1H-NMR(CDCl3,δ):3.88(t,J=4.8Hz,2H)
3.95(d,J=8.0Hz,2H)
4.07(t,J=4.4Hz,4H)
4.21-4.26(m,4H)
4.30(t,J=4.8Hz,2H)
5.55(br,2H)
6.85-6.92(m,6H)
7.26(t,J=7.4Hz,4H)
8.06(s,1H)
8.12(s,1H)
实施例16
9-[[2-双(2-苄氧基乙基)膦酰甲氧基]乙基]腺嘌呤(表-1中,化合物No.331)的制备
在实施例11中,除了用2-苄氧基乙醇代替2-甲氧基乙醇外,其余以同样的方法,得到了标题化合物。
熔点:45-48℃(己烷)
1H-NMR(CDCl3,δ):3.61(d,J=4.6Hz,4H)
3.81(d,J=8.1Hz,2H)
3.84(t,J=5.0Hz,2H)
4.17-4.23(m,4H)
4.30(t,J=5.0Hz,2H)
4.51(s,4H)
5.49(br,2H)
7.29-7.33(m,10H)
7.91(s,1H)
8.35(s,1H)
实施例17
9-[[2-双(2-乙酰氧基乙基)膦酰甲氧基]乙基]腺嘌呤(表-1中,化合物No.343)的制备
在实施例11中,除了用2-乙酰氧基乙醇代替2-甲氧基乙醇之外,其余以同样的方法,得到了标题化合物。
熔点:68-70℃(乙酸乙酯-己烷)
1H-NMR(CDCl3,δ):2.08(s,6H)
3.84(d,J=8.3Hz,2H)
3.95(t,J=4.9Hz,2H)
4.22-4.26(m,8H)
4.42(t,J=4.9Hz,2H)
5.63(br,2H)
7.94(s,1H)
8.36(s,1H)
实施例18
9-[[2-双(2-戊酰氧基乙基)膦酰甲氧基]乙基]腺嘌呤(表-1中,化合物No.349)的制备
在实施例11中,除了用2-戊酰氧基乙醇代替2-甲氧基乙醇之外,其余以同样的方法,得到标题化合物。
熔点:油
1H-NMR(CDCl3,δ):
0.91(t,J=7.5Hz,6H)
1.36(qt,J=7.5Hz,4H)
1.60(tt,J=7.5Hz,4H)
2.33(t,J=7.5Hz,4H)
3.83(d,J=8.1Hz,2H)
3.95(t,J=5.0Hz,2H)
4.21-4.25(m,8H)
4.41(t,J=5.0Hz,2H)
5.73(br,2H)
7.94(s,1H)
8.35(s,1H)
实施例19
9-[2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基]-2-碘腺嘌呤(表-1中,化合物No.359)的制备
在实施例11中,除了用2,2,2-三氟乙醇代替2-甲氧基乙醇,且用9-[(2-膦酰甲氧基)乙基)-2-碘腺嘌呤代替9-[(2-膦酰甲氧基)乙基]腺嘌呤以外,其余以同样方法,得到了标题化合物。
熔点:179℃(氯仿)
1H-NMR(Me2SO-d6,δ):
3.88(t,J=5.0Hz,2H)
4.13(d,J=8.0Hz,2H)
4.28(t,J=5.0Hz,2H)
4.56-4.70(m,4H)
7.63(br,2H)
7.99(s,1H)
实施例20
9-[2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基]鸟嘌呤(表-1中,化合物No.259)的制备
在实施例1中,除了用能够以公知的方法合成的6-0-苄基鸟嘌呤代替腺嘌呤以外,其余以同样的方法,得到9-[2-[双-(2,2,2-三氟乙基)膦酰甲氧基]乙基-6-O-苄基鸟嘌呤。
将该化合物2.21g(4.07mmol)溶于20ml乙醇中,并加入环已烯20ml以及20%氢氧化钯-碳1.5g,在回流下反应2小时。滤去氢氧化钯-碳之后,浓缩溶液至干,使残渣溶解于氯仿中并吸附于硅胶柱上,然后用5%甲醇-氯仿洗脱,得到了标题化合物1.01g(55%)。
熔点:214℃(乙醇)
1H-NMR(Me2SO-d6,δ):
3.86(t,J=5.1Hz,2H)
4.13(d,J=8.1Hz,2H)
4.17(t,J=5.0Hz,2H)
4.58-4.70(m,4H)
6.61(br,2H)
8.06(s,1H)
10.88(br,1H)
实施例21
7-[2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基]鸟嘌呤(表-1中,化合物No.260)的制备
将1g鸟苷(3.53mmol)悬浮在10ml二甲基乙酰胺中,并加入2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基碘化物1.7g,在100℃反应2小时。将反应液浓缩至干,使残渣溶解于30%甲醇-水中,并吸附于十八烷基硅烷基硅胶柱上,用30%甲醇-水洗脱,得到标题化合物0.1g(6.3%)。
熔点:225℃(水)
1H-NMR(Me2SO-d6,δ):
3.89(t,J=5.0Hz,2H)
4.10(d,J=8.0Hz,2H)
4.40(t,J=5.0Hz,2H)
4.57-4.70(m,4H)
6.34(br,2H)
8.09(s,1H)
10.95(br,1H)
实施例22
9-[2-双(2,2,2-三氟乙基)膦酰甲氧基]乙基]腺嘌呤-1-N-氧化物(表-2中,化合物No.780)的制备
将实施例1的化合物8.12g(18.6mmol)溶于150ml的氯仿中,并加入m-氯过苯甲酸15g,在50℃反应2小时。滤除析出的沉淀后,吸附于硅胶柱上,用5%甲醇-氯仿洗脱,得到标题化合物3.42g(42%)。
熔点:186℃(乙酸乙酯)
1H-NMR(Me2SO-d6,δ):
3.88(t,J=5.0Hz,2H)
4.10(d,J=8.0Hz,2H)
4.36(t,J=5.0Hz,2H)
4.52-4.66(m,4H)
8.18(s,1H)
8.56(s,1H)
实施例23
9-[2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基]-6-硫鸟嘌呤(表-1中,化合物No.609)的制备
将实施例3的化合物800mg(1.7mmol)溶于15ml乙醇中,并加入硫脲157mg,在回流下反应4小时。反应后冷却无室温,浓缩至干。把残渣溶解于氯仿中,并吸附于硅胶柱上,然后以5%甲醇-氯仿洗脱,得到标题化合物252mg(32%)。
熔点:144℃(乙醇)
1H-NMR(Me2SO-d6,δ):
3.80(t,J=5.1Hz,2H)
4.06-4.16(m,4H)
4.49-4.68(m,4H)
6.73(br,2H)
7.76(s,1H)
11.88(br,1H)
实施例24
9-[2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基]-2-氨基-6-对甲苯基硫嘌呤(表-6中,化合物No.1030)的制备
将实施例3的化合物9.4g(20mmol)溶于DMF90ml中,并在室温下加入对甲硫酚5.23g及三乙胺2.8ml,然后在100℃反应4小时。反应后冷却至室温,并将反应液浓缩至干。残渣溶解于氯仿中,并吸附于硅胶柱上,然后用氯仿洗脱,得到标题化合物9.8g(88%)。
熔点:油
1H-NMR(CDCl3,δ):2.40(s,3H)
3.89-3.96(m,4H)
4.26(d,J=5.1Hz,2H)
4.39-4.47(m,4H)
4.79(br,2H)
7.23(d,J=9.8Hz,2H)
7.31(d,J=9.8Hz,2H)
7.71(s,1H)
实施例25
9-[2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基]-2-羟基-6-对甲苯基硫嘌呤(表-7中,化合物No.1055)的制备
将实施例21的化合物6.9g(12.3mmol)溶于50%乙酸水溶液120ml中,并加入亚硝酸钠12g,在50℃反应1小时,反应后冷却至室温,浓缩至干其残留物用氯仿-碳酸氢钠水溶液分配,用硫酸镁干燥氯仿层后过滤,浓缩至干,用乙醚进行结晶,得到标题化合物2.31g(34%)。
熔点:176℃(乙醚)
1H-NMR(Me2SO-d6,δ):2.33(s,3H)
3.85(t,J=5.1Hz,2H)
4.01(d,J=8.0Hz,2H)
4.25(d,J=5.1Hz,2H)
4.53-4.69(m,4H)
7.24(d,J=8.1Hz,2H)
7.43(d,J=8.1Hz,2H)
8.05(s,1H)
11.58(br,1H)
实施例26
9-[2-[双(2,2,2-三氟乙基)膦酰甲氧基]乙基]-1-甲基鸟嘌呤(表-5中,化合物No.1005)的制备
将实施例20的化合物500mg(1.1mmol)溶于DMF7ml中,然后加入碳酸钾150mg,分子筛(0.4nm)100mg以及碘甲烷203mg,在室温反应2小时。将其反应液过滤后进行浓缩至干,将其残渣溶解于氯仿中,并吸附于硅胶柱上,用5%甲醇-氯仿层洗脱,得到标题化合物30mg(5.8%)
熔点:油
1H-NMR(Me2SO-d6,δ):3.27(s,3H)
3.80(d,J=5.0Hz,2H)
4.05-4.11(m,4H)
4.52-4.68(m,4H)
6.98(br,2H)
7.59(s,1H)
参考例1
9-[[2-双(2-乙酰氨基乙基)膦酰甲氧基]乙基]腺嘌呤的制备
在实施例11中,除了用2-乙酰氨基乙醇代替2-甲氧基乙醇外,其余以同样的方法,得到了标题化合物。
熔点:油
1H-NMR(CDCl3,δ):2.02(s,6H)
3.41-3.53(m,4H)
3.81(d,J=8.5Hz,2H)
3.94(t,J=4.9Hz,2H)
3.97-4.21(m,4H)
4.43(t,J=4.9Hz,2H)
6.18(br,2H)
6.77(br,2H)
8.00(s,1H)
8.34(s,1H)
参考例2
9-[[2-双(2-羟乙基)膦酰甲氧基]乙基腺嘌呤的制备
将由实施例13得到的化合物1g(1.9mmol)溶于25ml乙醇中,并加入10%钯-碳0.1g,在氢气氛下,60℃反应7小时,滤除钯-碳之后,将溶液浓缩至干。将残渣溶解在氯仿中,并使之吸附于硅胶柱上,用5%甲醇-氯仿洗脱,得到标题化合物0.38g(55%)。
熔点:102-104℃(乙酸乙酯)
1H-NMR(Me2SO-d6,δ):
3.50(q,J=3.9Hz,4H)
3.86-3.96(m,8H)
4.32(t,J=5.1Hz,2H)
4.85(t,J=5.6Hz,2H)
7.21(br,2H)
8.09(s,1H)
8.13(s,1H)
试验例1
HBV增生抑制效果
将HB611细胞(生产HBV的重组人体肝癌细胞)2×104个,在含有10%牛胎儿血清,链霉素(100μg/ml),青霉素(100Iu/ml)以及G-418(0.2mg/ml)的dulbeccoME培养基中,在37℃进行培养。培养2日及5日后替换培养基,培养8日,11日,以及14日后,以含最终浓度为10μm的试样的培养基替代,培养17日后回收细胞的DNA。用Southern brott测定细胞内的HBV-DNA量,求出细胞内的HBV-DNA合成抑制率,而且求出死去HB611细胞的50%所需要的化合物浓度。结果示于下表-8中。
整理番号=940574 (101)
【表70】
表-8
化合物 HBV-DNA合成抑制率
HB611细胞的50%
(%) 细胞毒性浓度(μM)
実施例1 91.5 >1000
実施例2 99.9 840
実施例3 99.9 399
実施例5 97.2 -
実施例12 86.3 >1000
実施例13 100 >1000
実施例14 55.0 >1000
実施例15 59.7 174
実施例16 57.8 178
実施例17 66.2 >1000
実施例18 73.4 47
実施例20 99.9 -
実施例21 71.3 -
実施例22 76.2 -
実施例23 86.1 -
実施例24 99.9 -
実施例25 99.9 -
実施例26 99.9 -
参考例1 - >1000
参考例2 31.0 >1000
试验例2
经口服投药的大鼠或小鼠血清的HBV增生抑制效果
在一组由3只组成的大鼠上,试样以1g/kg或者0.5g/kg为一次口服量给药,给药1小时后采血,调制血清,或者在一组由3只而成的小鼠上,试样以0.3g/kg为一次口服量给药,给药30分钟后采血,调制血清。
将HB611细胞2×104个,在含10%牛胎儿血清,链霉素(100μg/ml),青霉素(100Iu/ml)以及G-418(0.2mg/ml)的dulbecco ME培养基中,在37℃进行培养。培养2日及5日后替换培养基,然后培养8日,11日以及14日后用含5%上述血清(将试样经口服后的大鼠或小鼠血清)的培养基替代,培养17日后回收细胞的DNA。用Southern brott测定细胞内的HBV-DNA量,并求出在细胞内HBV-DNA合成抑制率。为了参考,对于PMEA也进行了同样的试验。结果示于下表-9中。
整理番号=940574 (103)
【表71】
表-9
化合物 给药动物 经口服给药量 HBV-DNA
(g/kg) 合成抑制率(%)
実施例1 大鼠 1 89.9
実施例2 大鼠 1 71.9
実施例3 小鼠 0.3 99.9
実施例4 小鼠 0.3 36.3
実施例5 小鼠 0.3 87.2
実施例12 大鼠 1 92.9
実施例13 大鼠 1 77.7
実施例14 大鼠 0.5 25.4
実施例15 大鼠 0.5 38.5
実施例16 大鼠 0.5 43.6
実施例18 大鼠 0.5 61.4
実施例20 小鼠 0.3 99.9
実施例22 小鼠 0.3 15.2
参考例1 大鼠 0.5 0
参考例2 大鼠 0.5 0
PMEA 大鼠 1 35.5
本发明的核苷酸膦酸酯衍生物,具有优异的抗病毒活性及抗肿瘤活性,而且能够经口服给药。
Claims (12)
4、权利要求1记载的化合物,共中的环A是
(其中R1表示氨基、R2表示氢原子)。
6、权利要求1-5记载的化合物,其中的R3是C1-C3烷基、2,2,2-三氟乙基或具有从C1-C3的烷氧基、苯氧基、C7-C10的苯基烷氧基及C2-C5的酰氧基中选出的取代基的乙基。
7、权利要求1-5记载的化合物,其中的R3是C1-C3的烷基或2,2,2-三氟乙基。
8、权利要求1-7记载的化合物,其中R4是2,2,2-三氟乙基或具有从C1-C3的烷氧基、苯氧基、C7-C10的苯基烷氧基及C2-C5的酰氧基中选出来的取代基的乙基。
9、权利要求1-7记载的化合物,其中R4是2,2,2-三氟乙基。
10、权利要求1-9记载的化合物,其中的X及Z是氮原子。
11、医药组合物,其中含有权利要求1-10记载的化合物及药物上可允许的载体。
12、抗病毒剂,其中是以权利要求1-10记载的化合物为有效成分。
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Cited By (3)
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---|---|---|---|---|
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Families Citing this family (89)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2001401A1 (en) * | 1988-10-25 | 1990-04-25 | Claude Piantadosi | Quaternary amine containing ether or ester lipid derivatives and therapeutic compositions |
EP0702556B1 (en) * | 1993-06-10 | 2002-10-23 | Wake Forest University | (phospho)lipids for combatting hepatitis b virus infection |
US5798340A (en) * | 1993-09-17 | 1998-08-25 | Gilead Sciences, Inc. | Nucleotide analogs |
AU690587B2 (en) * | 1993-09-17 | 1998-04-30 | Gilead Sciences, Inc. | Method for dosing therapeutic compounds |
US5656745A (en) * | 1993-09-17 | 1997-08-12 | Gilead Sciences, Inc. | Nucleotide analogs |
US5962437A (en) | 1994-08-29 | 1999-10-05 | Wake Forest University | Lipid analogs for treating viral infections |
US7135584B2 (en) | 1995-08-07 | 2006-11-14 | Wake Forest University | Lipid analogs for treating viral infections |
WO1997000262A1 (fr) * | 1995-06-15 | 1997-01-03 | Mitsubishi Chemical Corporation | Nucleotides derives de phosphonates |
KR970015804A (ko) * | 1995-09-28 | 1997-04-28 | 이웅열 | 저수축 나일론 6 필라멘트사 및 그의 제조방법 |
DE19540798A1 (de) * | 1995-11-02 | 1997-05-07 | Hoechst Ag | Alkylxanthinphosphonate und Alkylxanthinphosphinoxide und deren Verwendung als Arzneimittel |
CA2195262C (en) * | 1996-01-18 | 2005-08-09 | Masaru Ubasawa | Phosphonate nucleotide compounds |
US5922695A (en) * | 1996-07-26 | 1999-07-13 | Gilead Sciences, Inc. | Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability |
CA2263286A1 (en) | 1996-08-13 | 1998-02-19 | Naoko Ueda | Phosphonate nucleotide compound |
AU6452098A (en) * | 1997-03-07 | 1998-09-22 | Metabasis Therapeutics, Inc. | Novel purine inhibitors of fructose-1,6-bisphosphatase |
EP1256584B1 (en) * | 1997-07-25 | 2004-09-29 | Gilead Sciences, Inc. | Process for preparing Adefovir Dipivoxil |
ATE228357T1 (de) * | 1997-07-25 | 2002-12-15 | Gilead Sciences Inc | Nukleotid-analoge zusammensetzung |
WO1999005150A1 (en) * | 1997-07-25 | 1999-02-04 | Gilead Sciences, Inc. | Nucleotide analog composition and synthesis method |
ZA986614B (en) | 1997-07-25 | 1999-01-27 | Gilead Sciences | Nucleotide analog composition |
US5935946A (en) * | 1997-07-25 | 1999-08-10 | Gilead Sciences, Inc. | Nucleotide analog composition and synthesis method |
JP2002524463A (ja) * | 1998-09-09 | 2002-08-06 | メタバシス・セラピューティクス・インコーポレイテッド | フルクトース−1,6−ビスホスファターゼの新規な芳香族インヒビター |
US7026469B2 (en) | 2000-10-19 | 2006-04-11 | Wake Forest University School Of Medicine | Compositions and methods of double-targeting virus infections and cancer cells |
EP1914237B1 (en) | 1999-12-03 | 2014-06-18 | The Regents of The University of California | Phosphonate ester antiviral compounds |
ATE385797T1 (de) | 1999-12-03 | 2008-03-15 | Univ California At San Diego | Phosphonatverbindungen |
US6965033B2 (en) * | 1999-12-22 | 2005-11-15 | Metabasis Therapeutics, Inc. | Bisamidate phosphonate prodrugs |
AU2001234174A1 (en) | 2000-02-29 | 2001-09-12 | Mitsubishi Pharma Corporation | Phosphonate nucleotide compound |
AU2001245532B2 (en) | 2000-03-08 | 2005-08-11 | Metabasis Therapeutics, Inc. | Novel aryl fructose-1,6-bisphosphatase inhibitors |
US7563774B2 (en) | 2000-06-29 | 2009-07-21 | Metabasis Therapeutics, Inc. | Combination of FBPase inhibitors and antidiabetic agents useful for the treatment of diabetes |
US7309696B2 (en) | 2000-10-19 | 2007-12-18 | Wake Forest University | Compositions and methods for targeting cancer cells |
MY141789A (en) * | 2001-01-19 | 2010-06-30 | Lg Chem Investment Ltd | Novel acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same. |
WO2003000187A2 (en) * | 2001-06-21 | 2003-01-03 | Ariad Pharmaceuticals, Inc. | Novel pyrazolo-and pyrrolo-pyrimidines and uses thereof |
WO2003028737A1 (en) * | 2001-08-30 | 2003-04-10 | Mitsubishi Pharma Corporation | Anti-viral agents and in-vitro method for the identification of candidates able to inhibit binding of polymerase to epsilon |
JP4714413B2 (ja) | 2001-08-31 | 2011-06-29 | トムソン ライセンシング | オーディオビジュアルストリームのためのシーケンスカウンタ |
AU2002343556A1 (en) * | 2001-12-07 | 2003-06-23 | Eli Lilly And Company | Use of phosphonate nucleotide analogue for treating hepatitis b virus infections |
EA008775B1 (ru) | 2002-04-26 | 2007-08-31 | Джилид Сайэнс, Инк. | Ингибиторы протеазы вич для лечения инфекции вич и фармацевтическая композиция |
IL164809A0 (en) | 2002-05-13 | 2005-12-18 | Metabasis Therapeutics Inc | Novel phosphonic acid basdrugs of pmea and its analogues |
AU2003235501A1 (en) | 2002-05-13 | 2003-11-11 | Metabasis Therapeutics, Inc. | PMEA and PMPA cyclic producing synthesis |
RU2005108601A (ru) * | 2002-09-26 | 2006-01-20 | Эл Джи Лайф Сайенсиз Лтд. (Kr) | (+)-транс-изомеры(1-фосфонометокси-2-алкилциклопропил)метилнуклеозидные производные, способ получения их стереоизомеров и применение указанных соединений в качестве противовирусных средств |
KR101115210B1 (ko) * | 2002-10-31 | 2012-04-12 | 메타베이시스 테라퓨틱스, 인크. | 신규 시타라빈 모노포스페이트 전구약물 |
SI1583542T1 (sl) | 2003-01-14 | 2008-12-31 | Gilead Sciences Inc | Sestavki in postopki za kombinacijsko antivirusnoterapijo |
JP2006524710A (ja) | 2003-04-25 | 2006-11-02 | ギリアード サイエンシーズ, インコーポレイテッド | キナーゼインヒビターホスホネート抱合体 |
WO2004096287A2 (en) | 2003-04-25 | 2004-11-11 | Gilead Sciences, Inc. | Inosine monophosphate dehydrogenase inhibitory phosphonate compounds |
US7407965B2 (en) | 2003-04-25 | 2008-08-05 | Gilead Sciences, Inc. | Phosphonate analogs for treating metabolic diseases |
US7300924B2 (en) | 2003-04-25 | 2007-11-27 | Gilead Sciences, Inc. | Anti-infective phosphonate analogs |
DK1628685T3 (da) | 2003-04-25 | 2011-03-21 | Gilead Sciences Inc | Antivirale phosphonatanaloge |
WO2005002626A2 (en) * | 2003-04-25 | 2005-01-13 | Gilead Sciences, Inc. | Therapeutic phosphonate compounds |
US7452901B2 (en) | 2003-04-25 | 2008-11-18 | Gilead Sciences, Inc. | Anti-cancer phosphonate analogs |
US7470724B2 (en) | 2003-04-25 | 2008-12-30 | Gilead Sciences, Inc. | Phosphonate compounds having immuno-modulatory activity |
US7432261B2 (en) | 2003-04-25 | 2008-10-07 | Gilead Sciences, Inc. | Anti-inflammatory phosphonate compounds |
US20050080053A1 (en) * | 2003-08-29 | 2005-04-14 | Biocryst Pharmaceuticals, Inc. | Nucleosides, preparation thereof and use as inhibitors of RNA viral polymerases |
JP2007508843A (ja) | 2003-10-24 | 2007-04-12 | ギリアード サイエンシーズ, インコーポレイテッド | 治療用化合物の同定のための方法および組成物 |
WO2005044279A1 (en) | 2003-10-24 | 2005-05-19 | Gilead Sciences, Inc. | Purine nucleoside phosphonate conjugates |
WO2005044308A1 (en) | 2003-10-24 | 2005-05-19 | Gilead Sciences, Inc. | Phosphonate analogs of antimetabolites |
GB0326168D0 (en) * | 2003-11-10 | 2003-12-17 | Arrow Therapeutics Ltd | Chemical compounds |
AU2004293013B2 (en) | 2003-11-19 | 2011-04-28 | Metabasis Therapeutics, Inc. | Novel phosphorus-containing thyromimetics |
MXPA06006899A (es) | 2003-12-22 | 2006-09-04 | Gilead Sciences Inc | Derivados de carbovir y abacavir 4'-sustituidos asi como compuestos relacionados con actividad antiviral de virus de inmunodeficiencia humana y virus de la hepatitis c. |
CN1921867B (zh) * | 2004-02-17 | 2010-05-05 | 株式会社Lg生命科学 | 用于治疗hiv感染的膦酸核苷衍生物 |
KR20070029196A (ko) | 2004-06-08 | 2007-03-13 | 메타베이시스 테라퓨틱스, 인크. | 고리 에스테르의 루이스 산 매개 합성 |
US7871991B2 (en) | 2004-07-27 | 2011-01-18 | Gilead Sciences, Inc. | Phosphonate analogs of HIV inhibitor compounds |
US20070225259A1 (en) * | 2004-08-18 | 2007-09-27 | Qun Dang | Novel Thiazole Inhibitors of Fructose 1,6-Bishosphatase |
WO2006110655A2 (en) | 2005-04-08 | 2006-10-19 | Chimerix, Inc. | Compounds, compositions and methods for the treatment of poxvirus infections |
TWI471145B (zh) | 2005-06-13 | 2015-02-01 | Bristol Myers Squibb & Gilead Sciences Llc | 單一式藥學劑量型 |
TWI375560B (en) | 2005-06-13 | 2012-11-01 | Gilead Sciences Inc | Composition comprising dry granulated emtricitabine and tenofovir df and method for making the same |
WO2007014491A1 (fr) * | 2005-08-03 | 2007-02-08 | Beijing Fu Kang Ren Bio-Pharm Tech.Co.Ltd. | Phosphonates de nucléotides acycliques et leur utilisation dans des agents antiviraux |
JP2009515887A (ja) | 2005-11-11 | 2009-04-16 | ザ スクリプス リサーチ インスティテュート | 神経系疾患のための治療薬としてのヒストンデアセチラーゼ阻害剤 |
WO2008005542A2 (en) | 2006-07-07 | 2008-01-10 | Gilead Sciences, Inc., | Antiviral phosphinate compounds |
CA2656356C (en) | 2006-07-07 | 2013-04-09 | Gilead Sciences, Inc. | Antiviral phosphinate compounds |
KR101538810B1 (ko) | 2007-02-09 | 2015-07-22 | 메타베이시스 테라퓨틱스, 인크. | 글루카곤 수용체의 길항제 |
CN101940571A (zh) | 2007-04-13 | 2011-01-12 | 南方研究所 | 抗血管生成剂和使用方法 |
WO2009023718A2 (en) | 2007-08-13 | 2009-02-19 | Metabasis Therapeutics, Inc. | Novel activators of glucokinase |
CA2713105C (en) | 2008-01-25 | 2016-06-07 | Chimerix, Inc. | Methods of treating viral infections |
TWI444384B (zh) * | 2008-02-20 | 2014-07-11 | Gilead Sciences Inc | 核苷酸類似物及其在治療惡性腫瘤上的用途 |
MX2011000306A (es) | 2008-07-08 | 2011-03-15 | Gilead Sciences Inc | Sales de compuestos inhibidores de hiv. |
CA2770298C (en) | 2008-08-13 | 2017-06-20 | Metabasis Therapeutics, Inc. | Glucagon antagonists |
WO2010078430A1 (en) | 2008-12-30 | 2010-07-08 | Arqule, Inc. | Substituted 1h-pyrazolo[3,4-d]pyrimidine-6-amine compounds |
WO2010114894A1 (en) | 2009-03-31 | 2010-10-07 | Arqule, Inc. | Substituted heterocyclic compounds |
US8614200B2 (en) | 2009-07-21 | 2013-12-24 | Chimerix, Inc. | Compounds, compositions and methods for treating ocular conditions |
PL2534150T3 (pl) | 2010-02-12 | 2017-09-29 | Chimerix, Inc. | Sposoby leczenia infekcji wirusowej |
US8940313B2 (en) | 2010-04-23 | 2015-01-27 | University Of Southern California | Tyrosine-based prodrugs of antiviral agents |
CA2797601A1 (en) | 2010-04-26 | 2011-11-10 | Chimerix, Inc. | Methods of treating retroviral infections and related dosage regimes |
CN103338754A (zh) | 2010-12-10 | 2013-10-02 | 西格玛制药实验有限责任公司 | 口服活性核苷酸类似物或口服活性核苷酸类似物前药的高度稳定组合物 |
WO2012154698A2 (en) | 2011-05-06 | 2012-11-15 | Mckenna Charles E | Method to improve antiviral activity of nucleotide analogue drugs |
DK2794624T3 (da) | 2011-12-22 | 2019-07-22 | Geron Corp | Guanin-analoger som telomerase-substrater og påvirkere af telomer-længde |
US10449210B2 (en) | 2014-02-13 | 2019-10-22 | Ligand Pharmaceuticals Inc. | Prodrug compounds and their uses |
JP2017519000A (ja) | 2014-06-12 | 2017-07-13 | リガンド・ファーマシューティカルズ・インコーポレイテッド | グルカゴンアンタゴニスト |
EP3164136A4 (en) | 2014-07-02 | 2018-04-04 | Ligand Pharmaceuticals, Inc. | Prodrug compounds and uses therof |
KR102589658B1 (ko) * | 2014-09-15 | 2023-10-13 | 더 리젠츠 오브 더 유니버시티 오브 캘리포니아 | 뉴클레오타이드 유사체 |
WO2017048956A1 (en) | 2015-09-15 | 2017-03-23 | The Regents Of The University Of California | Nucleotide analogs |
EP3960740B1 (en) | 2017-08-01 | 2023-11-15 | Gilead Sciences, Inc. | Crystalline forms of ethyl ((s)-((((2r,5r)-5-(6-amino-9h-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-l-alaninate (gs-9131) vanillate for treating viral infections |
RU2020126177A (ru) | 2018-01-09 | 2022-02-10 | Лиганд Фармасьютикалз, Инк. | Ацетальные соединения и их терапевтическое применение |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69129650T2 (de) * | 1990-09-14 | 1999-03-25 | Acad Of Science Czech Republic | Wirkstoffvorläufer von Phosphonaten |
GB9026164D0 (en) * | 1990-12-01 | 1991-01-16 | Beecham Group Plc | Pharmaceuticals |
CA2195262C (en) * | 1996-01-18 | 2005-08-09 | Masaru Ubasawa | Phosphonate nucleotide compounds |
-
1994
- 1994-06-23 AT AT94109742T patent/ATE199906T1/de not_active IP Right Cessation
- 1994-06-23 EP EP94109742A patent/EP0632048B1/en not_active Expired - Lifetime
- 1994-06-23 CA CA002126601A patent/CA2126601A1/en not_active Abandoned
- 1994-06-23 DE DE69426904T patent/DE69426904T2/de not_active Expired - Fee Related
- 1994-06-27 TW TW083105822A patent/TW302366B/zh active
- 1994-06-29 CN CN94109168A patent/CN1040761C/zh not_active Expired - Fee Related
- 1994-06-29 KR KR1019940015180A patent/KR100358327B1/ko not_active IP Right Cessation
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1997
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014026582A1 (zh) * | 2012-08-13 | 2014-02-20 | 洛阳聚慧投资股份有限公司 | 替诺福韦双酯类化合物、其制备方法、用途以及包含其的药物组合物 |
TWI642677B (zh) * | 2013-03-15 | 2018-12-01 | 美國加利福尼亞大學董事會 | 非環狀核苷膦酸二酯 |
CN103819472A (zh) * | 2014-03-18 | 2014-05-28 | 福建天泉药业股份有限公司 | 缬恩替卡韦酸式加成盐及其制备方法 |
Also Published As
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ATE199906T1 (de) | 2001-04-15 |
KR100358327B1 (ko) | 2003-03-03 |
CA2126601A1 (en) | 1994-12-30 |
TW302366B (zh) | 1997-04-11 |
US6037335A (en) | 2000-03-14 |
EP0632048A1 (en) | 1995-01-04 |
KR950000728A (ko) | 1995-01-03 |
CN1040761C (zh) | 1998-11-18 |
EP0632048B1 (en) | 2001-03-21 |
DE69426904T2 (de) | 2001-10-11 |
DE69426904D1 (de) | 2001-04-26 |
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