CN1398864A - 膦酸酯核苷酸化合物 - Google Patents
膦酸酯核苷酸化合物 Download PDFInfo
- Publication number
- CN1398864A CN1398864A CN02108501A CN02108501A CN1398864A CN 1398864 A CN1398864 A CN 1398864A CN 02108501 A CN02108501 A CN 02108501A CN 02108501 A CN02108501 A CN 02108501A CN 1398864 A CN1398864 A CN 1398864A
- Authority
- CN
- China
- Prior art keywords
- trifluoroethyl
- amino
- ethyl
- phosphonic acids
- methoxyl group
- 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
- -1 Phosphonate ester nucleotide compound Chemical class 0.000 title claims abstract description 85
- 239000002773 nucleotide Substances 0.000 title description 3
- 125000001495 ethyl group Chemical class [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 145
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- 239000003443 antiviral agent Substances 0.000 claims abstract description 8
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 4
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims abstract description 4
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 claims abstract description 3
- 239000012453 solvate Substances 0.000 claims abstract 18
- 150000001875 compounds Chemical class 0.000 claims description 145
- CLDKAKLHMYILJA-UHFFFAOYSA-N [S].C1=NC=C2NC=NC2=N1 Chemical compound [S].C1=NC=C2NC=NC2=N1 CLDKAKLHMYILJA-UHFFFAOYSA-N 0.000 claims description 45
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 40
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 33
- 125000005843 halogen group Chemical group 0.000 claims description 29
- 239000002904 solvent Substances 0.000 claims description 27
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 13
- NUQFGSPGRBZMJA-UHFFFAOYSA-N N1=CN=C2N=CNC2=C1.C(CC)OSC1=CC=CC=C1 Chemical compound N1=CN=C2N=CNC2=C1.C(CC)OSC1=CC=CC=C1 NUQFGSPGRBZMJA-UHFFFAOYSA-N 0.000 claims description 11
- BRXURIWVODSXCT-UHFFFAOYSA-N N1=CN=C2N=CNC2=C1.C(CCC)OSC1=CC=CC=C1 Chemical compound N1=CN=C2N=CNC2=C1.C(CCC)OSC1=CC=CC=C1 BRXURIWVODSXCT-UHFFFAOYSA-N 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- BLWRUXHYGMILCR-UHFFFAOYSA-N N1=CN=C2N=CNC2=C1.C1(=CC=CC=C1)[S].C(C(C)C)[O] Chemical compound N1=CN=C2N=CNC2=C1.C1(=CC=CC=C1)[S].C(C(C)C)[O] BLWRUXHYGMILCR-UHFFFAOYSA-N 0.000 claims description 9
- 241000700721 Hepatitis B virus Species 0.000 claims description 8
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- 239000000463 material Substances 0.000 claims description 7
- 239000000470 constituent Substances 0.000 claims description 6
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- 239000000654 additive Substances 0.000 claims description 4
- 230000000996 additive effect Effects 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- JPUPGEOKXACUQK-UHFFFAOYSA-N N1=CN=C2N=CNC2=C1.C1(=CC=CC=C1)SCC(C)C Chemical compound N1=CN=C2N=CNC2=C1.C1(=CC=CC=C1)SCC(C)C JPUPGEOKXACUQK-UHFFFAOYSA-N 0.000 claims 1
- 230000000840 anti-viral effect Effects 0.000 abstract description 6
- 239000001257 hydrogen Substances 0.000 abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 5
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 abstract description 2
- 150000002431 hydrogen Chemical group 0.000 abstract 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract 2
- 125000000229 (C1-C4)alkoxy group Chemical class 0.000 abstract 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 229910052757 nitrogen Chemical group 0.000 abstract 1
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- 125000001309 chloro group Chemical group Cl* 0.000 description 151
- 125000001246 bromo group Chemical group Br* 0.000 description 146
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 29
- 238000004519 manufacturing process Methods 0.000 description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 21
- 235000002639 sodium chloride Nutrition 0.000 description 20
- 238000000034 method Methods 0.000 description 19
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000001301 oxygen Substances 0.000 description 14
- 229910052760 oxygen Inorganic materials 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
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- 229910000041 hydrogen chloride Inorganic materials 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
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- 239000012141 concentrate Substances 0.000 description 10
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- 239000011737 fluorine Substances 0.000 description 10
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000008601 oleoresin Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000005864 Sulphur Substances 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
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- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 7
- 235000009421 Myristica fragrans Nutrition 0.000 description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 235000011167 hydrochloric acid Nutrition 0.000 description 7
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 7
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- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 244000183685 Citrus aurantium Species 0.000 description 5
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- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 5
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
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- CPHXLFKIUVVIOQ-UHFFFAOYSA-N 2-(trifluoromethoxy)benzaldehyde Chemical compound FC(F)(F)OC1=CC=CC=C1C=O CPHXLFKIUVVIOQ-UHFFFAOYSA-N 0.000 description 3
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Abstract
用通式(1)表示的膦酸酯核苷酸化合物或它的盐,或它们的水合物或溶剂物,用作抗病毒剂的有效成分。(式中R1表示氢原子、C1-C6的烷氧基、由1个以上的卤原子置取代的C1-C4的烷氧基、卤原子、氨基或硝基;R2和R3分别表示氢原子、C1-C22的烷基、酰氧甲基、酰硫乙基、或由1个以上的卤原子置换的基;R4表示氢原子,C1-C4的烷基、C1-C4的羟烷基,或由1个以上的卤原子取代的C1-C4的烷基;X表示碳原子或氮原子)。
Description
本申请申请人为1997年1月18日、申请号为97103169.X的
发明名称为“膦酸酯核苷酸化合物”的发明专利申请的分案申请。
本发明是关于一种新型的膦酸酯核苷酸化合物。更具体讲,是关于具有抗病毒活性,用作药品的新型膦酸酯核苷酸化合物和它的盐,以及它们的水合物和溶剂物。
感染性病毒疾病作为医学上重要的问题正在被认识,作为以治疗这种疾病为目的,正在研究开发一种药物,具有抗病毒活性,同时,对正常的细胞系统不具有阻碍增殖活性。例如,膦酸酯核苷酸类,作为选择性抗病毒剂,目前正在进行广泛地研究。具体讲,据报告9-(2-膦酸甲氧基)乙基腺嘌呤(PMEA)、9-(2-磷酸甲氧基)乙基-2,6-二氢基嘌呤(PMDAP)等,对单纯疱疹1型和2型(HSV-1和HSV-2)、人免疫不全病毒(HIV),人B型肝炎病毒(HBV)很有效(横田等人,Antimicrob.Agents Chemother.,35,394(1991);Votruba et al.,Mol.Pharmacol.,32,524(1987))。
然而,这些已知的磷酸酯核苷酸类,有可能对抑制骨髓细胞成长中代表性生物体显示毒性和变异原性等等安全性问题(Antiviral Research,16,77(1991))。这些化合物由于不具有经口腔吸收性(De Clercq et al.,Antimicrob.Agents Chemother.,33,185(1989)),为了发挥效果而获得必要的血中浓度,其问题是服用方法必须限定为静脉注射,筋皮注射等非经口腔的服用。不经口腔服用的治疗方法对于没有住院的患者是很困难的,也就没有理想的方法对于AIDS和B型肝炎病毒患者施以必要的长期治疗。
另外,本发明者们发现膦酸酯核苷酸的特定酯衍生物,虽能显示出很高的经口腔吸收性(EP632048号公报),但目前的现状是没有实用化。
本发明课题就是提供一种对于骨髓细胞的成长抑制和变异原性等有毒性的抗病毒剂。本发明的另一课题是提供一种经口腔吸收性特别好的抗病毒剂。
本发明者们为解决上述问题,经过大量的研究,结果发现,在上述EP632048号公报中没有具体公开的特定的2-氨基-6-芳基硫代嘌呤膦酸酯具有很高的抗病毒活性,并且,这些化合物比过去提出的化合物对生物体具有更高的安全性,经口服具有更高的吸收性,至此完成了本发明。
即本发明是以下述通式(I)表示的膦酸酯核苷酸化合物或它的盐,或它们的水合物或溶剂物,
(式中,R1表示氢原子、C1-C6的烷氧基、由1个以上的卤素原子取代的C1-C4的烷氧基、卤素原子、氨基或硝基;R2和R3分别表示氢原子、C1-C22的烷基、酰氧甲基、酰硫乙基、或由1个以上的卤素原子取代的乙基;R4表示氢原子、C1-C4的烷基、C1-C4的羟烷基,或由1个以上的卤素原子取代的C1-C4的烷基;X表示碳原子或氮原子)。
根据本发明的其它实施形式,提供的是含有从上述化合物或它的盐,及它们的水合物或溶剂物中选出的物质和药物学上容许的制剂用添加物的药物组合物;含有从上述化合物或它的盐,及它们的水合物或溶剂物中选出的物质作为有效成分的抗病毒剂。进而,根据本发明的再一实施形式,提供的是为制备上述药物组合物而从上述化合物或它的盐,及它们的水合物或溶剂物中选出之质的使用;以及病毒感染症的治疗方法,该方法将有效量的从上述化合物或它的盐,及它们的水合物或溶剂物中选出的物质,给于包括人类在内的哺乳类动物的包括投服工序的方法。
实施该发明的最佳形式
在上述通式(1)的膦酸酯核苷酸化合物中,作为用R1表示的C1-C6烷氧基,例举有甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基等。作为R1表示的用1个以上卤原子取代的C1-C4烷氧基,可以举出单氟甲氧基、二氟甲氧基、三氟甲氧基、单氟乙氧基、二氟乙氧基、三氟乙氧基、四氟乙氧基、五氟乙氧基、单氟丙氧基、二氟丙氧基、三氟丙氧基、四氟丙氧基、五氟丙氧基、六氟丙氧基、七氟丙氧基、单氟异丙氧基、二氟异丙氧基、三氟异丙氧基、四氟异丙氧基、五氟异丙氧基、六氟异丙氧基、七氟异丙氧基等。
作为用R2和R3表示的C1-C22烷基,例举有甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基、十九烷基、二十烷基、二十一烷基、二十二烷基等。作为用R2和R3表示的酰氧甲基,举例有乙酰氧甲基、丙酰氧甲基、丁酰氧甲基、异丁酰氧甲基、戊酰氧甲基、异戊酰氧甲基、特戊酰氧甲基等。
作为用R2和R3表示的酰硫乙基,举例有乙酰硫乙基、丙酰硫乙基、丁酰硫乙基、异丁酰硫乙基、戊酰硫乙基、异戊酰硫乙基、特成酰硫乙基等。在以R2和R3表示的用1个以上卤原子取代的乙基中,卤素原子的种类可以是氟原子、氯原子、溴原子或碘原子。作为用1个以上的卤原子取代的乙基,例举有1-氟乙基、2-氟乙基、1-氯乙基、2-氯乙基、2-溴乙基、2,2-二氟乙基、2,2-二氯乙基、2,2-二溴乙基、2,2,2-三氟乙基、2,2,2-三氟乙基,2,2,2-三溴乙基等。最好是在乙基第2位取代,作为卤原子最好是氟原子。R2和R3中,至少一个是用1个以上卤原子取代的乙基,特别好的是2,2,2-三氟乙基。
作为用R4表示的C1-C4烷基,有甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔-丁基等。作为用R4表示的C1-C4羟烷基,有羟甲基、1-羟乙基、2-羟乙基、1-羟丙基、2-羟丙基、3-羟丙基、1-羟丁基、2-羟丁基、3-羟丁基、4-羟丁基等。作为用R4表示的由1个以上的卤原子取代的C1-C4烷基,有氟原子、氯原子等卤原子结合在甲基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基等上的。作为具体实例有氟甲基、二氟甲基、三氟甲基、氟乙基、氯乙基、氟丙基、氯丙基、氟丁基、氯丁基等。
本发明中R1为氢原子或C1-C6的烷氧基,作为最理想化合物的第1个条件而举出。R1为氢原子或C1-C6的烷氧基、R2和R3分别是氢原子、C1-C22的烷基,或者由1个以上的卤原子取代的乙基,作为最理想化合物的第2个条件举出。进而,R1为氢原子或C1-C4的烷氧基、R2和R3分别是氢原子、C1-C22的烷基、或者2,2,2-三氟乙基、R4为氢原子或甲基,作为最理想化合物的第3个条件举出。R1为氢原子或C1-C4的烷氧基、R2和R3分别为氢原子或2,2,2-三氟乙基、R4为氢原子或甲基,作为最理想化合物的第4个条件常出。
例如:满足这些条件的具体理想化合物是以下化合物:2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对-甲氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-6-间甲氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻位甲氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基-6-对乙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对甲氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-甲氧苯基硫嘌呤;2-氨基-9-[2-[膦酸甲氧基]乙基]-6-苯基硫嘌呤;2-氨基-9-[2-[膦酸甲氧基]乙基]-6-对甲氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对异丙氧苯基硫嘌呤;和2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对异丁氧苯基硫嘌呤。
其它满足第4个条件的具体化合物是如下化合物:2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间乙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻乙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间异丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间异丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻异丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻异丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-间甲氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-邻甲氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对乙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-间乙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-邻乙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对异丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对异丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-间丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-间丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-间异丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-间异丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-邻丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-邻丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-邻异丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-邻异丁氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间甲氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻甲氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对乙氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间乙氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻乙氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对丁氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对丙氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对异丙苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对异丁苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间丁氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间丙氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间异丙氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间异丁氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻丁氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻丙氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻异丙氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻异丁氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对甲氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-间甲氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-邻甲氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对乙氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-间乙氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-邻乙氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对丁氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对丙氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对异丙氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对异丁氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-间丁氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-间丙氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-间异丙氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-间异丁氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-邻丁氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-邻丙氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-邻异丙氧苯基硫嘌呤;2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-邻异丁氧基硫嘌呤;2-氨基-9-[2-膦酸甲氧乙基]-6-间甲氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧乙基]-6-邻甲氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧乙基]-6-对乙氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧乙基]-6-间乙氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧乙基]-6-邻乙氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧乙基]-6-对丁氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧乙基]-6-对丙氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧乙基]-6-对异丙氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧乙基]-6-对异丁氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧乙基]-6-间丁氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧乙基]-6-间丙氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧乙基]-6-间异丙氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧乙基]-6-间异丁氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧乙基]-6-邻丁氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧乙基]-6-邻丙氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧乙基]-6-邻异丙氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧乙基]-6-邻异丁氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧丙基]-6-苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧丙基]-6-对甲氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧丙基]-6-间甲氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧丙基]-6-邻甲氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧丙基]-6-对乙氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧丙基]-6-间乙氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧丙基]-6-邻乙氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧丙基]-6-对丁氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧丙基]-6-对丙氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧丙基]-6-对异丙氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧丙基]-6-对异丁氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧丙基]-6-间丁氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧丙基]-6-间丙氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧丙基]-6-间异丙氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧丙基]-6-间异丁氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧丙基]-6-邻丁氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧丙基]-6-邻丙氧苯基硫嘌呤;2-氨基-9-[2-膦酸甲氧丙基]-6-邻异丙氧苯基硫嘌呤;和2-氨基-9-[2-膦酸甲氧丙基]-6-邻异丁氧苯基硫嘌呤。
进而,R1是氢原子或C1-C4的烷氧基,R2和R3是2,2,2-三氟乙基,R4是氢原子或甲基时作为理想化合物的第5个条件。作为满足该条件的具体理想化合物为以下化合物:2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对甲氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间甲氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻甲氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对乙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对甲氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对异丙氧苯基硫嘌呤;和2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对异丁氧苯基硫嘌呤。
除此之外,作为满足第5个条件的具体化合物有以下化合物:2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间乙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻乙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间异丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间异丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻异丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻异丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-间甲氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-邻甲氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对乙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-间乙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-邻乙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对异丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对异丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-间丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-间丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-间异丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间异丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-邻丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-邻丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-邻异丙氧苯基硫嘌呤;和2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-邻异丁氧苯基硫嘌呤。
进而举出,R1为氢原子或C1-C4的烷氧基,R2和R3为2,2,2-三氟乙基,R4为氢原子,作为理想化合物的第6个条件。满足该条件的具体理想化合物是以下化合物:2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对甲氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间甲氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻甲氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对乙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对异丙氧苯基硫嘌呤;和2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对异丁氧苯基硫嘌呤。
除此之外,作为满足第6个条件的具体化合物有以下化合物:2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间乙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻乙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间异丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间异丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻丁氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻丙氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻异丙氧苯基硫嘌呤;和2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻异丁氧苯基硫嘌呤。
进而举出,R1为氢原子或C1-C2的烷氧基,R2和R3为2,2,2-三氟乙基,R4为氢原子时作为理想化合物的第7个条件。满足该条件的具体理想化合物有以下化合物:2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对甲氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间甲氧苯基硫嘌呤;2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻甲氧苯基硫嘌呤;和2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对乙氧苯基硫嘌呤。
除此之外,作为满足第7个条件的化合物有以下化合物:2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间乙氧苯基硫嘌呤;和2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻乙氧苯基硫嘌呤。
用以上通式(I)表示的本发明膦酸酯核苷酸化合物,作为盐存在时,上述化合物无论形成那种盐都包含在本发明范围之内。作为这种盐,例如可举出医药上所容许的盐。例如,在存在酸性基时,酸性基可形成的盐有锂盐、钠盐、钾盐、镁盐、钙盐等金属盐、铵盐、甲基铵盐、二甲基铵盐、三甲基铵盐、二环己铵盐等的铵盐,等等。在有氨基存在时,可形成的盐有氯酸盐、溴酸盐、硫酸盐、硝酸盐、磷酸盐、偏磷酸盐等矿物酸盐、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、琥珀酸盐、柠檬酸盐、苯甲酸盐、杏仁酸盐、鲸皮酸盐、乳酸、伯希尔酸、吉草酸、硬酯酸、油酸、乳糖醛酸、红霉素丁二酸、半琥珀酸、丁酸、棕榈酸、胭脂红酸、葡萄糖酸、月桂酸、水杨酸、ラォクル酸、单宁酸、丁基磺酸盐等有机酸盐等。
以上述通式(I)表示的本发明膦酸酯核苷酸化合物和它的盐可以以水合物或溶剂物的形式存在。含有上述所谈到的具体理想化合物,用上述通式(I)表示的本发明的膦酸酯核苷酸化合物或它的盐所形成的任意水合物或溶剂物,无论那一种都包括在本发明的范围之内。作为获得的溶剂物的溶剂,有甲醇、乙醇、异丙醇、丙酮、醋酸乙酯、二氯甲烷、二异丙醚等。
下表示出了本发明化合物的具体实例(表中,Me表示甲基、Et表示乙基、n-Pr-表示正丙基、i-Pr-表示异丙基、n-Bu表示正丁基,i-Bu表示异丁基、t-Bu表示叔丁基)。
表1
No. R1 R2 R3 R4 X
1 H CF3CH2- CF3CH2- H C
2 o-OCH3 CF2CH2- CF3CH2- H C
3 m-OCH3 CF3CH2- CF3CH2- H C
4 p-OCH3 CF3CH2- CF3CH2- H C
5 o-Cl CF3CH2- CF3CH2- H C6 m-Cl CF3CH2- CF3CH2- H C7 p-Cl CF3CH2- CF3CH2- H C8 o-Br CF3CH2- CF3CH2- H C9 m-Br CF3CH2- CF3CH2- H C10 p-Br CF3CH2- CF3CH2- H C11 o-NH2 CF3CH2- CF3CH2- H C12 m-NH2 CF3CH2- CF3CH2- H C13 p-NH2 CF3CH2- CF3CH2- H C14 o-NO2 CF3CH2- CF3CH2- H C15 m-NO2 CF3CH2- CF3CH2- H C16 p-NO2 CF3CH2- CF3CH2- H C17 o-OC2H5 CF3CH2- CF3CH2- H C18 m-OC2H5 CF3CH2- CF3CH2- H C19 p-OC2H5 CF3CH2- CF3CH2- H C20 p-I CF3CH2- CF3CH2- H C21 o-O-n-Pr CF3CH2- CF3CH2- H C22 m-O-n-Pr CF3CH2- CF3CH2- H C23 p-O-n-Pr CF3CH2- CF3CH2- H C24 o-O-i-Pr CF3CH2- CF3CH2- H C25 m-O-i-Pr CF3CH2- CF3CH2- H C26 p-O-i-Pr CF3CH2- CF3CH2- H C27 o-O-n-Bu CF3CH2- CF3CH2- H C28 m-O-n-Bu CF3CH2- CF3CH2- H C29 p-O-n-Bu CF3CH2- CF3CH2- H C30 o-O-i-Bu CF3CH2- CF3CH2- H C31 m-O-i-Bu CF3CH2- CF3CH2- H C32 p-O-i-Bu CF3CH2- CF3CH2- H C33 o-OCF3 CF3CH2- CF3CH2- H C34 m-OCF3 CF3CH2- CF3CH2- H C35 p-OCF3 CF3CH2- CF3CH2- H C36 H CF3CH2- CF3CH2- H N37 o-OCH3 CF3CH2- CF3CH2- H N38 m-OCH3 CF3CH2- CF3CH2- H N39 p-OCH3 CF3CH2- CF3CH2- H N40 o-Cl CF3CH2- CF3CH2- H N41 m-Cl CF3CH2- CF3CH2- H N42 p-Cl CF3CH2- CF3CH2- H N43 o-Br CF3CH2- CF3CH2- H N44 m-Br CF3CH2- CF3CH2- H N45 p-Br CF3CH2- CF3CH2- H N46 o-NH2 CF3CH2- CF3CH2- H N47 m-NH2 CF3CH2- CF3CH2- H N48 p-NH2 CF3CH2- CF3CH2- H N49 o-NO2 CF3CH2- CF3CH2- H N50 m-NO2 CF3CH2- CF3CH2- H N51 p-NO2 CF3CH2- CF3CH2- H N52 o-OC2H5 CF3CH2- CF3CH2- H N53 m-OC2H5 CF3CH2- CF3CH2- H N54 p-OC2H5 CF3CH2- CF3CH2- H N55 p-I CF3CH2- CF3CH2- H N56 o-O-n-Pr CF3CH2- CF3CH2- H N57 m-O-n-Pr CF3CH2- CF3CH2- H N58 p-O-n-Pr CF3CH2- CF3CH2- H N59 o-O-i-Pr CF3CH2- CF3CH2- H N60 m-O-i-Pr CF3CH2- CF3CH2- H N61 p-O-i-Pr CF3CH2- CF3CH2- H N62 o-O-n-Bu CF3CH2- CF3CH2- H N63 m-O-n-Bu CF3CH2- CF3CH2- H N64 p-O-n-Bu CF3CH2- CF3CH2- H N65 o-O-i-Bu CF3CH2- CF3CH2- H N66 m-O-i-Bu CF3CH2- CF3CH2- H N67 p-O-i-Bu CF3CH2- CF3CH2- H N68 o-OCF3 CF3CH2- CF3CH2- H N69 m-OCF3 CF3CH2- CF3CH2- H N70 p-OCF3 CF3CH2- CF3CH2- H N71 H CF3CH2- Me- H C72 o-OCH3 CF3CH2- Me- H C73 m-OCH3 CF3CH2- Me- H C74 p-OCH3 CF3CH2- Me- H C75 o-Cl CF3CH2- Me- H C76 m-Cl CF3CH2- Me- H C77 p-Cl CF3CH2- Me- H C78 o-Br CF3CH2- Me- H C79 m-Br CF3CH2- Me- H C80 p-Br CF3CH2- Me- H C81 o-NH2 CF3CH2- Me- H C82 m-NH2 CF3CH2- Me- H C83 p-NH2 CF3CH2- Me- H C84 o-NO2 CF3CH2- Me- H C85 m-NO2 CF3CH2- Me H C86 p-NO2 CF3CH2- Me- H C87 o-OC2H5 CF3CH2- Me- H C88 m-OC2H5 CF3CH2- Me- H C89 p-OC2H5 CF3CH2- Me- H C90 p-I CF3CH2- Me- H C91 o-O-n-Pr CF3CH2- Me- H C92 m-O-n-Pr CF3CH2- Me- H C93 p-O-n-Pr CF3CH2- Me- H C94 o-O-i-Pr CF3CH2- Me- H C95 m-O-i-Pr CF3CH2- Me- H C96 p-O-i-Pr CF3CH2- Me- H C97 o-O-n-Bu CF3CH2- Me- H C98 m-O-n-Bu CF3CH2- Me- H C99 p-O-n-Bu CF3CH2- Me- H C100 o-O-i-Bu CF3CH2- Me- H C101 m-O-i-Bu CF3CH2- Me- H C102 p-O-i-Bu CF3CH2- Me- H C103 o-OCF3 CF3CH2- Me- H C104 m-OCF3 CF3CH2- Me- H C105 p-OCF3 CF3CH2- Me- H C106 H CF3CH2- Me- H N107 o-OCH3 CF3CH2- Me- H N108 m-OCH3 CF3CH2- Me- H N109 p-OCH3 CF3CH2- Me- H N110 o-Cl CF3CH2- Me- H N111 m-Cl CF3CH2- Me- H N112 p-Cl CF3CH2- Me- H N113 o-Br CF3CH2- Me- H N114 m-Br CF3CH2- Me- H N115 p-Br CF3CH2- Me- H N116 o-NH2 CF3CH2- Me- H N117 m-NH2 CF3CH2- Me- H N118 p-NH2 CF3CH2- Me- H N119 o-NO2 CF3CH2- Me- H N120 m-NO2 CF3CH2- Me- H N121 p-NO2 CF3CH2- Me- H N122 o-OC2H5 CF3CH2- Me- H N123 m-OC2H5 CF3CH2- Me- H N124 p-OC2H5 CF3CH2- Me- H N125 p-I CF3CH2- Me- H N126 o-O-n-Pr CF3CH2- Me- H N127 m-O-n-Pr CF3CH2- Me- H N128 p-O-n-Pr CF3CH2- Me- H N129 o-O-i-Pr CF3CH2- Me- H N130 m-O-i-Pr CF3CH2- Me- H N131 p-O-i-Pr CF3CH2- Me- H N132 o-O-n-Bu CF3CH2- Me- H N133 m-O-n-Bu CF3CH2- Me- H N134 p-O-n-Bu CF3CH2- Me- H N135 o-O-i-Bu CF3CH2- Me- H N136 m-O-i-Bu CF3CH2- Me- H N137 p-O-i-Bu CF3CH2- Me- H N138 o-OCF3 CF3CH2- Me- H N139 m-OCF3 CF3CH2- Me- H N140 p-OCF3 CF3CH2- Me- H N141 H CF3CH2- Et- H C142 o-OCH3 CF3CH2- Et- H C143 m-OCH3 CF3CH2- Et- H C144 p-OCH3 CF3CH2- Et- H C145 o-Cl CF3CH2- Et- H C146 m-Cl CF3CH2- Et- H C147 p-Cl CF3CH2- Et- H C148 o-Br CF3CH2- Et- H C149 m-Br CF3CH2- Et- H C150 p-Br CF3CH2- Et- H C151 o-NH2 CF3CH2- Et- H C152 m-NH2 CF3CH2- Et- H C153 p-NH2 CF3CH2- Et- H C154 o-NO2 CF3CH2- Et- H C155 m-NO2 CF3CH2- Et- H C156 p-NO2 CF3CH2- Et- H C157 o-OC2H5 CF3CH2- Et- H C158 m-OC2H5 CF3CH2- Et- H C159 p-OC2H5 CF3CH2- Et- H C160 p-I CF3CH2- Et- H C161 o-O-n-Pr CF3CH2- Et- H C162 m-O-n-Pr CF3CH2- Et- H C163 p-O-n-Pr CF3CH2- Et- H C164 o-O-i-Pr CF3CH2- Et- H C165 m-O-i-Pr CF3CH2- Et- H C166 p-O-i-Pr CF3CH2- Et- H C167 o-O-n-Bu CF3CH2- Et- H C168 m-O-n-Bu CF3CH2- Et- H C169 p-O-n-Bu CF3CH2- Et- H C170 o-O-i-Bu CF3CH2- Et- H C171 m-O-i-Bu CF3CH2- Et- H C172 p-O-i-Bu CF3CH2- Et- H C173 o-OCF3 CF3CH2- Et- H C174 m-OCF3 CF3CH2- Et- H C175 p-CF3 CF3CH2- Et- H C176 H CF3CH2- Et- H N177 o-OCH3 CF3CH2- Et- H N178 m-OCH3 CF3CH2- Et- H N179 p-OCH3 CF3CH2- Et- H N180 o-Cl CF3CH2- Et- H N181 m-Cl CF3CH2- Et- H N182 p-Cl CF3CH2- Et- H N183 o-Br CF3CH2- Et- H N184 m-Br CF3CH2- Et- H N185 p-Br CF3CH2- Et- H N186 o-NH2 CF3CH2- Et- H N187 m-NH2 CF3CH2- Et- H N188 p-NH2 CF3CH2- Et- H N189 o-NO2 CF3CH2- Et- H N190 m-NO2 CF3CH2- Et- H N191 p-NO2 CF3CH2- Et- H N192 o-OC2H5 CF3CH2- Et- H N193 m-OC2H5 CF3CH2- Et- H N194 p-OC2H5 CF3CH2- Et- H N195 p-I CF3CH2- Et- H N196 o-O-n-Pr CF3CH2- Et- H N197 m-O-nPr CF3CH2- Et- H N198 p-O-n-Pr CF3CH2- Et- H N199 o-O-i-Pr CF3CH2- Et- H N200 m-O-i-Pr CF3CH2- Et- H N201 p-O-i-Pr CF3CH2- Et- H N202 o-O-n-Bu CF3CH2- Et- H N203 m-O-n-Bu CF3CH2- Et- H N204 p-O-n-Bu CF3CH2- Et- H N205 o-O-i-Bu CF3CH2- Et- H N206 m-O-i-Bu CF3CH2- Et- H N207 p-O-i-Bu CF3CH2- Et- H N208 o-OCF3 CF3CH2- Et- H N209 m-OCF3 CF3CH2- Et- H N210 p-OCF3 CF3CH2- Et- H N211 H CF3CH2- H H C212 o-OCH3 CF3CH2- H H C213 m-OCH3 CF3CH2- H H C214 p-OCH3 CF3CH2- H H C215 o-Cl CF3CH2- H H C216 m-Cl CF3CH2- H H C217 p-Cl CF3CH2- H H C218 o-Br CF3CH2- H H C219 m-Br CF3CH2- H H C220 p-Br CF3CH2- H H C221 o-NH2 CF3CH2- H H C222 m-NH2 CF3CH2- H H C223 p-NH2 CF3CH2- H H C224 o-NO2 CF3CH2- H H C225 m-NO2 CF3CH2- H H C226 p-NO2 CF3CH2- H H C227 o-OC2H5 CF3CH2- H H C228 m-OC2H5 CF3CH2- H H C229 p-OC2H5 CF3CH2- H H C230 p-I CF3CH2- H H C231 o-O-n-Pr CF3CH2- H H C232 m-O-n-Pr CF3CH2- H H C233 p-O-n-Pr CF3CH2- H H C234 o-O-i-Pr CF3CH2- H H C235 m-O-i-Pr CF3CH2- H H C236 p-O-i-Pr CF3CH2- H H C237 o-O-n-Bu CF3CH2- H H C238 m-O-n-Bu CF3CH2- H H C239 p-On-Bu CF3CH2- H H C240 o-O-i-Bu CF3CH2- H H C241 m-O-i-Bu CF3CH2- H H C242 p-O-i-Bu CF3CH2- H H C243 o-OCF3 CF3CH2- H H C244 m-OCF3 CF3CH2- H H C245 p-OCF3 CF3CH2- H H C246 H CF3CH2- H H N247 o-OCH3 CF3CH2- H H N248 m-OCH3 CF3CH2- H H N249 p-OCH3 CF3CH2- H H N250 o-Cl CF3CH2- H H N251 m-Cl CF3CH2- H H N252 p-Cl CF3CH2- H H N253 o-Br CF3CH2- H H N254 m-Br CF3CH2- H H N255 p-Br CF3CH2- H H N256 o-NH2 CF3CH2- H H N257 m-NH2 CF3CH2- H H N258 p-NH2 CF3CH2- H H N259 o-NO2 CF3CH2- H H N260 m-NO2 CF3CH2- H H N261 p-NO2 CF3CH2- H H N262 o-OC2H5 CF3CH2- H H N263 m-OC2H5 CF3CH2- H H N264 p-OC2H5 CF3CH2- H H N265 p-I CF3CH2- H H N266 o-O-n-Pr CF3CH2- H H N267 m-O-n-Pr CF3CH2- H H N268 p-O-n-Pr CF3CH2- H H N269 o-O-i-Pr CF3CH2- H H N270 m-O-i-Pr CF3CH2- H H N271 p-O-i-Pr CF3CH2- H H N272 o-O-n-Bu CF3CH2- H H N273 m-O-n-Bu CF3CH2- H H N274 p-O-n-Bu CF3CH2- H H N275 o-O-i-Bu CF3CH2- H H N276 m-O-i-Bu CF3CH2- H H N277 p-O-i-Bu CF3CH2- H H N278 o-OCF3 CF3CH2- H H N279 m-OCF3 CF3CH2- H H N280 p-OCF3 CF3CH2- H H N281 H H H H C282 o-OCH3 H H H C283 m-OCH3 H H H C284 p-OCH3 H H H C285 o-Cl H H H C286 m-Cl H H H C287 p-Cl H H H C288 o-Br H H H C289 m-Br H H H C290 p-Br H H H C291 o-NH2 H H H C292 m-NH2 H H H C293 p-NH2 H H H C294 o-NO2 H H H C295 m-NO2 H H H C296 p-NO2 H H H C297 o-OC2H5 H H H C298 m-OC2H5 H H H C299 p-OC2H5 H H H C300 p-I H H H C301 o-O-n-Pr H H H C302 m-O-n-Pr H H H C303 p-O-n-Pr H H H C304 o-O-i-Pr H H H C305 m-O-i-Pr H H H C306 p-O-i-Pr H H H C30 o-O-n-Bu H H H C308 m-O-n-Bu H H H C309 p-O-n-Bu H H H C310 o-O-i-Bu H H H C311 m-O-i-Bu H H H C312 p-O-i-Bu H H H C313 o-OCF3 H H H C314 m-OCF3 H H H C315 p-OCF3 H H H C316 H H H H N317 o-OCH3 H H H N318 m-OCH3 H H H N319 p-OCH3 H H H N320 o-Cl H H H N321 m-Cl H H H N322 p-Cl H H H N323 o-Br H H H N324 m-Br H H H N325 p-Br H H H N326 o-NH2 H H H N327 m-NH2 H H H N328 p-NH2 H H H N329 o-NO2 H H H N330 m-NO2 H H H N331 p-NO2 H H H N332 o-OC2H5 H H H N333 m-OC2H5 H H H N334 p-OC2H5 H H H N335 p-I H H H N336 o-O-n-Pr H H H N337 m-O-n-Pr H H H N338 p-O-n-Pr H H H N339 o-O-i-Pr H H H N340 m-O-i-Pr H H H N341 p-O-i-Pr H H H N342 o-O-n-Bu H H H N343 m-O-n-Bu H H H N344 p-O-n-Bu H H H N345 o-O-i-Bu H H H N346 m-O-i-Bu H H H N347 p-O-i-Bu H H H N348 o-OCF3 H H H N349 m-OCF3 H H H N350 p-OCF3 H H H N351 H CF3CH2- CF3CH2- Me- C352 o-OCH3 CF3CH2- CF3CH2- Me- C353 m-OCH3 CF3CH2- CF3CH2- Me- C354 p-OCH3 CF3CH2- CF3CH2- Me- C355 o-Cl CF3CH2- CF3CH2- Me- C356 m-Cl CF3CH2- CF3CH2- Me- C357 p-Cl CF3CH2- CF3CH2- Me- C358 o-Br CF3CH2- CF3CH2- Me- C359 m-Br CF3CH2- CF3CH2- Me- C360 p-Br CF3CH2- CF3CH2- Me- C361 o-NH2 CF3CH2- CF3CH2- Me- C362 m-NH2 CF3CH2- CF3CH2- Me- C363 p-NH2 CF3CH2- CF3CH2- Me- C364 o-NO2 CF3CH2- CF3CH2- Me- C365 m-NO2 CF3CH2- CF3CH2- Me- C366 p-NO2 CF3CH2- CF3CH2- Me- C367 o-OC2H5 CF3CH2- CF3CH2- Me- C368 m-OC2H5 CF3CH2- CF3CH2- Me- C369 p-OC2H5 CF3CH2- CF3CH2- Me- C370 p-I CF3CH2- CF3CH2- Me- C371 o-O-n-Pr CF3CH2- CF3CH2- Me- C372 m-O-n-Pr CF3CH2- CF3CH2- Me- C373 p-O-n-Pr CF3CH2- CF3CH2- Me- C374 o-O-i-Pr CF3CH2- CF3CH2- Me- C375 m-O-i-Pr CF3CH2- CF3CH2- Me- C376 p-O-i-Pr CF3CH2- CF3CH2- Me- C377 o-O-n-Bu CF3CH2- CF3CH2- Me- C378 m-O-n-Bu CF3CH2- CF3CH2- Me- C379 p-O-n-Bu CF3CH2- CF3CH2- Me- C380 o-O-i-Bu CF3CH2- CF3CH2- Me- C381 m-O-i-Bu CF3CH2- CF3CH2- Me- C382 p-O-i-Bu CF3CH2- CF3CH2- Me- C383 o-OCF3 CF3CH2- CF3CH2- Me- C384 m-OCF3 CF3CH2- CF3CH2- Me- C385 p-OCF3 CF3CH2- CF3CH2- Me- C386 H CF3CH2- CF3CH2- Me- N387 o-OCH3 CF3CH2- CF3CH2- Me- N388 m-OCH3 CF3CH2- CF3CH2- Me- N389 p-OCH3 CF3CH2- CF3CH2- Me- N390 o-Cl CF3CH2- CF3CH2- Me- N391 m-Cl CF3CH2- CF3CH2- Me- N392 p-Cl CF3CH2- CF3CH2- Me- N393 o-Br CF3CH2- CF3CH2- Me- N394 m-Br CF3CH2- CF3CH2- Me- N395 p-Br CF3CH2- CF3CH2- Me- N396 o-NH2 CF3CH2- CF3CH2- Me- N397 m-NH2 CF3CH2- CF3CH2- Me- N398 p-NH2 CF3CH2- CF3CH2- Me- N399 o-NO2 CF3CH2- CF3CH2- Me- N400 m-NO2 CF3CH2- CF3CH2- Me- N401 p-NO2 CF3CH2- CF3CH2- Me- N402 o-OC2H5 CF3CH2- CF3CH2- Me- N403 m-OC2H5 CF3CH2- CF3CH2- Me- N404 p-OC2H5 CF3CH2- CF3CH2- Me- N405 p-I CF3CH2- CF3CH2- Me- N406 o-O-n-Pr CF3CH2- CF3CH2- Me- N407 m-O-n-Pr CF3CH2- CF3CH2- Me- N408 p-O-n-Pr CF3CH2- CF3CH2- Me- N409 o-O-i-Pr CF3CH2- CF3CH2- Me- N410 m-O-i-Pr CF3CH2- CF3CH2- Me- N411 p-O-i-Pr CF3CH2- CF3CH2- Me- N412 o-O-n-Bu CF3CH2- CF3CH2- Me- N413 m-O-n-Bu CF3CH2- CF3CH2- Me- N414 p-O-n-Bu CF3CH2- CF3CH2- Me- N415 o-O-i-Bu CF3CH2- CF3CH2- Me- N406 m-O-i-Bu CF3CH2- CF3CH2- Me- N417 p-O-i-Bu CF3CH2- CF3CH2- Me- N418 o-OCF3 CF3CH2- CF3CH2- Me- N419 m-OCF3 CF3CH2- CF3CH2- Me- N420 p-OCF3 CF3CH2- CF3CH2- Me- N421 H CF3CH2- Me- Me- C422 o-OCH3 CF3CH2- Me- Me- C423 m-OCH3 CF3CH2- Me- Me- C424 p-OCH3 CF3CH2- Me- Me- C425 o-Cl CF3CH2- Me- Me- C426 m-Cl CF3CH2- Me- Me- C427 p-Cl CF3CH2- Me- Me- C428 o-Br CF3CH2- Me- Me- C429 m-Br CF3CH2- Me- Me- C430 p-Br CF3CH2- Me- Me- C431 o-NH2 CF3CH2- Me- Me- C432 m-NH2 CF3CH2- Me- Me- C433 p-NH2 CF3CH2- Me- Me- C434 o-NO2 CF3CH2- Me- Me- C435 m-NO2 CF3CH2- Me- Me- C436 p-NO2 CF3CH2- Me- Me- C437 o-OC2H5 CF3CH2- Me- Me- C438 m-OC2H5 CF3CH2- Me- Me- C439 p-OC2H5 CF3CH2- Me- Me- C440 p-I CF3CH2- Me- Me- C441 o-O-n-Pr CF3CH2- Me- Me- C442 m-O-n-Pr CF3CH2- Me- Me- C443 p-O-n-Pr CF3CH2- Me- Me- C444 o-O-i-Pr CF3CH2- Me- Me- C445 m-O-i-Pr CF3CH2- Me- Me- C446 p-O-i-Pr CF3CH2- Me- Me- C447 o-O-n-Bu CF3CH2- Me- Me- C448 m-O-n-Bu CF3CH2- Me- Me- C449 p-O-n-Bu CF3CH2- Me- Me- C450 o-O-i-Bu CF3CH2- Me- Me- C451 m-O-i-Bu CF3CH2- Me- Me- C452 p-O-i-Bu CF3CH2- Me- Me- C453 o-OCF3 CF3CH2- Me- Me- C454 m-OCF3 CF3CH2- Me- Me- C455 p-OCF3 CF3CH2- Me- Me- C456 H CF3CH2- Me- Me- N457 o-OCH3 CF3CH2- Me- Me- N458 m-OCH3 CF3CH2- Me- Me- N459 p-OCH3 CF3CH2- Me- Me- N460 o-Cl CF3CH2- Me- Me- N461 m-Cl CF3CH2- Me- Me- N462 p-Cl CF3CH2- Me- Me- N463 o-Br CF3CH2- Me- Me- N464 m-Br CF3CH2- Me- Me- N465 p-Br CF3CH2- Me- Me- N466 o-NH2 CF3CH2- Me- Me- N467 m-NH2 CF3CH2- Me- Me- N468 p-NH2 CF3CH2- Me- Me- N469 o-NO2 CF3CH2- Me- Me- N470 m-NO2 CF3CH2- Me- Me- N471 p-NO2 CF3CH2- Me- Me- N472 o-OC2H5 CF3CH2- Me- Me- N473 m-OC2H5 CF3CH2- Me- Me- N474 p-OC2H5 CF3CH2- Me- Me- N475 p-I CF3CH2- Me- Me- N476 o-O-n-Pr CF3CH2- Me- Me- N477 m-O-n-Pr CF3CH2- Me- Me- N478 p-O-n-Pr CF3CH2- Me- Me- N479 o-O-i-Pr CF3CH2- Me- Me- N480 m-O-i-Pr CF3CH2- Me- Me- N481 p-O-i-Pr CF3CH2- Me- Me- N482 o-O-n-Bu CF3CH2- Me- Me- N483 m-O-n-Bu CF3CH2- Me- Me- N484 p-O-n-Bu CF3CH2- Me- Me- N485 o-O-i-Bu CF3CH2- Me- Me- N486 m-O-i-Bu CF3CH2- Me- Me- N487 p-O-i-Bu CF3CH2- Me- Me- N488 o-OCF3 CF3CH2- Me- Me- N489 m-OCF3 CF3CH2- Me- Me- N490 p-OCF3 CF3CH2- Me- Me- N491 H CF3CH2- Et- Me- C492 o-OCH3 CF3CH2- Et- Me- C493 m-OCH3 CF3CH2- Et- Me- C494 p-OCH3 CF3CH2- Et- Me- C495 o-Cl CF3CH2- Et- Me- C496 m-Cl CF3CH2- Et- Me- C497 p-Cl CF3CH2- Et- Me- C498 o-Br CF3CH2- Et- Me- C499 m-Br CF3CH2- Et- Me- C500 p-Br CF3CH2- Et- Me- C501 o-NH2 CF3CH2- Et- Me- C502 m-NH2 CF3CH2- Et- Me- C503 p-NH2 CF3CH2- Et- Me- C504 o-NO2 CF3CH2- Et- Me- C505 m-NO2 CF3CH2- Et- Me- C506 p-NO2 CF3CH2- Et- Me- C507 o-OC2H5 CF3CH2- Et- Me- C508 m-OC2H5 CF3CH2- Et- Me- C509 p-OC2H5 CF3CH2- Et- Me- C510 p-I CF3CH2- Et- Me- C511 o-O-n-Pr CF3CH2- Et- Me- C512 m-O-n-Pr CF3CH2- Et- Me- C513 p-O-n-Pr CF3CH2- Et- Me- C514 o-O-i-Pr CF3CH2- Et- Me- C515 m-O-i-Pr CF3CH2- Et- Me- C516 p-O-i-Pr CF3CH2- Et- Me- C517 o-O-n-Bu CF3CH2- Et- Me- C518 m-O-n-Bu CF3CH2- Et- Me- C519 p-O-n-Bu CF3CH2- Et- Me- C520 o-O-i-Bu CF3CH2- Et- Me- C521 m-O-i-Bu CF3CH2- Et- Me- C522 p-O-i-Bu CF3CH2- Et- Me- C523 o-OCF3 CF3CH2- Et- Me- C524 m-OCF3 CF3CH2- Et- Me- C525 p-OCF3 CF3CH2- Et- Me- C526 H CF3CH2- Et- Me- N527 o-OCH3 CF3CH2- Et- Me- N528 m-OCH3 CF3CH2- Et- Me- N529 p-OCH3 CF3CH2- Et- Me- N530 o-Cl CF3CH2- Et- Me- N531 m-Cl CF3CH2- Et- Me- N532 p-Cl CF3CH2- Et- Me- N533 o-Br CF3CH2- Et- Me- N534 m-Br CF3CH2- Et- Me- N535 p-Br CF3CH2- Et- Me- N536 o-NH2 CF3CH2- Et- Me- N537 m-NH2 CF3CH2- Et- Me- N538 p-NH2 CF3CH2- Et- Me- N539 o-NO2 CF3CH2- Et- Me- N540 m-NO2 CF3CH2- Et- Me- N541 p-NO2 CF3CH2- Et- Me- N542 o-OC2H5 CF3CH2- Et- Me- N543 m-OC2H5 CF3CH2- Et- Me- N544 p-OC2H5 CF3CH2- Et- Me- N545 p-I CF3CH2- Et- Me- N546 o-O-n-Pr CF3CH2- Et- Me- N547 m-O-n-Pr CF3CH2- Et- Me- N548 p-O-n-Pr CF3CH2- Et- Me- N549 o-O-i-Pr CF3CH2- Et- Me- N550 m-O-i-Pr CF3CH2- Et- Me- N551 p-O-i-Pr CF3CH2- Et- Me- N552 o-O-n-Bu CF3CH2- Et- Me- N553 m-O-n-Bu CF3CH2- Et- Me- N554 p-O-n-Bu CF3CH2- Et- Me- N555 o-O-i-Bu CF3CH2- Et- Me- N556 m-O-i-Bu CF3CH2- Et- Me- N557 p-O-i-Bu CF3CH2- Et- Me- N558 o-OCF3 CF3CH2- Et- Me- N559 m-OCF3 CF3CH2- Et- Me- N560 p-OCF3 CF3CH2- Et- Me- N561 H CF3CH2- H Me- C562 o-OCH3 CF3CH2- H Me- C563 m-OCH3 CF3CH2- H Me- C564 p-OCH3 CF3CH2- H Me- C565 o-Cl CF3CH2- H Me- C566 m-Cl CF3CH2- H Me- C567 p-Cl CF3CH2- H Me- C568 o-Br CF3CH2- H Me- C569 m-Br CF3CH2- H Me- C570 p-Br CF3CH2- H Me- C571 o-NH2 CF3CH2- H Me- C572 m-NH2 CF3CH2- H Me- C573 p-NH2 CF3CH2- H Me- C574 o-NO2 CF3CH2- H Me- C575 m-NO2 CF3CH2- H Me- C576 p-NO2 CF3CH2- H Me- C577 o-OC2H5 CF3CH2- H Me- C578 m-OC2H5 CF3CH2- H Me- C579 p-OC2H5 CF3CH2- H Me- C580 p-I CF3CH2- H Me- C581 o-O-n-Pr CF3CH2- H Me- C582 m-O-n-Pr CF3CH2- H Me- C583 p-O-n-Pr CF3CH2- H Me- C584 o-O-i-Pr CF3CH2- H Me- C585 m-O-i-Pr CF3CH2- H Me- C586 p-O-i-Pr CF3CH2- H Me- C587 o-O-n-Bu CF3CH2- H Me- C588 m-O-n-Bu CF3CH2- H Me- C589 p-O-n-Bu CF3CH2- H Me- C590 o-O-i-Bu CF3CH2- H Me- C591 m-O-i-Bu CF3CH2- H Me- C592 p-O-i-Bu CF3CH2- H Me- C593 o-OCF3 CF3CH2- H Me- C594 m-OCF3 CF3CH2- H Me- C595 p-OCF3 CF3CH2- H Me- C596 H CF3CH2- H Me- N597 o-OCH3 CF3CH2- H Me- N598 m-OCH3 CF3CH2- H Me- N599 p-OCH3 CF3CH2- H Me- N600 o-Cl CF3CH2- H Me- N601 m-Cl CF3CH2- H Me- N602 p-Cl CF3CH2- H Me- N603 o-Br CF3CH2- H Me- N604 m-Br CF3CH2- H Me- N605 p-Br CF3CH2- H Me- N606 o-NH2 CF3CH2- H Me- N607 m-NH2 CF3CH2- H Me- N608 p-NH2 CF3CH2- H Me- N609 o-NO2 CF3CH2- H Me- N610 m-NO2 CF3CH2- H Me- N611 p-NO2 CF3CH2- H Me- N612 o-OC2H5 CF3CH2- H Me- N613 m-OC2H5 CF3CH2- H Me- N614 p-OC2H5 CF3CH2- H Me- N615 p-I CF3CH2- H Me- N616 o-O-n-Pr CF3CH2- H Me- N617 m-O-n-Pr CF3CH2- H Me- N618 p-O-n-Pr CF3CH2- H Me- N619 o-O-i-Pr CF3CH2- H Me- N620 m-O-i-Pr CF3CH2- H Me- N621 p-O-i-Pr CF3CH2- H Me- N622 o-O-n-Bu CF3CH2- H Me- N623 m-O-n-Bu CF3CH2- H Me- N624 p-O-n-Bu CF3CH2- H Me- N625 o-O-i-Bu CF3CH2- H Me- N626 m-O-i-Bu CF3CH2- H Me- N627 p-O-i-Bu CF3CH2- H Me- N628 o-OCF3 CF3CH2- H Me- N629 m-OCF3 CF3CH2- H Me- N630 p-OCF3 CF3CH2- H Me- N631 H H H Me- C632 o-OCH3 H H Me- C633 m-OCH3 H H Me- C635 p-OCH3 H H Me- C635 o-Cl H H Me- C636 m-Cl H H Me- C637 p-Cl H H Me- C638 o-Br H H Me- C639 m-Br H H Me- C640 p-Br H H Me- C641 o-NH2 H H Me- C642 m-NH2 H H Me- C643 p-NH2 H H Me- C644 o-NO2 H H Me- C645 m-NO2 H H Me- C646 p-NO2 H H Me- C647 o-OC2H5 H H Me- C648 m-OC2H5 H H Me- C649 p-OC2H5 H H Me- C650 p-I H H Me- C651 o-O-n-Pr H H Me- C652 m-O-n-Pr H H Me- C653 p-O-n-Pr H H Me- C654 o-O-i-Pr H H Me- C655 m-O-i-Pr H H Me- C656 p-O-i-Pr H H Me- C657 o-O-n-Bu H H Me- C658 m-O-n-Bu H H Me- C659 p-O-n-Bu H H Me- C660 o-O-i-Bu H H Me- C661 m-O-i-Bu H H Me- C662 p-O-i-Bu H H Me- C663 o-OCF3 H H Me- C664 m-OCF3 H H Me- C665 p-OCF3 H H Me- C666 H H H Me- N667 o-OCH3 H H Me- N668 m-OCH3 H H Me- N669 p-OCH3 H H Me- N670 o-Cl H H Me- N671 m-Cl H H Me- N672 p-Cl H H Me- N673 o-Br H H Me- N674 m-Br H H Me- N675 p-Br H H Me- N676 o-NH2 H H Me- N677 m-NH2 H H Me- N678 p-NH2 H H Me- N679 o-NO2 H H Me- N680 m-NO2 H H Me- N681 p-NO2 H H Me- N682 o-OC2H5 H H Me- N683 m-OC2H5 H H Me- N684 p-OC2H5 H H Me- N685 p-I H H Me- N686 o-O-n-Pr H H Me- N687 m-O-n-Pr H H Me- N688 p-O-n-Pr H H Me- N689 o-O-i-Pr H H Me- N690 m-O-i-Pr H H Me- N691 p-O-i-Pr H H Me- N692 o-O-n-Bu H H Me- N693 m-O-n-Bu H H Me- N694 p-O-n-Bu H H Me- N695 o-O-i-Bu H H Me- N696 m-O-i-Bu H H Me- N697 p-O-i-Bu H H Me- N698 o-OCF3 H H Me- N699 m-OCF3 H H Me- N700 p-OCF3 H H Me- N701 H CF3CH2- CF3CH2- -CH2F C702 o-OCH3 CF3CH2- CF3CH2- -CH2F C703 m-OCH3 CF3CH2- CF3CH2- -CH2F C704 p-OCH3 CF3CH2- CF3CH2- -CH2F C705 o-Cl CF3CH2- CF3CH2- -CH2F C706 m-Cl CF3CH2- CF3CH2- -CH2F C707 p-Cl CF3CH2- CF3CH2- -CH2F C708 o-Br CF3CH2- CF3CH2- -CH2F C709 m-Br CF3CH2- CF3CH2- -CH2F C710 p-Br CF3CH2- CF3CH2- -CH2F C711 o-NH2 CF3CH2- CF3CH2- -CH2F C712 m-NH2 CF3CH2- CF3CH2- -CH2F C713 p-NH2 CF3CH2- CF3CH2- -CH2F C714 o-NO2 CF3CH2- CF3CH2- -CH2F C715 m-NO2 CF3CH2- CF3CH2- -CH2F C716 p-NO2 CF3CH2- CF3CH2- -CH2F C717 o-OC2H5 CF3CH2- CF3CH2- -CH2F C718 m-OC2H5 CF3CH2- CF3CH2- -CH2F C719 p-OC2H5 CF3CH2- CF3CH2- -CH2F C720 p-I CF3CH2- CF3CH2- -CH2F C721 o-O-n-Pr CF3CH2- CF3CH2- -CH2F C722 m-O-n-Pr CF3CH2- CF3CH2- -CH2F C723 p-O-n-Pr CF3CH2- CF3CH2- -CH2F C724 o-O-i-Pr CF3CH2- CF3CH2- -CH2F C725 m-O-i-Pr CF3CH2- CF3CH2- -CH2F C726 p-O-i-Pr CF3CH2- CF3CH2- -CH2F C727 o-O-n-Bu CF3CH2- CF3CH2- -CH2F C728 m-O-n-Bu CF3CH2- CF3CH2- -CH2F C729 p-O-n-Bu CF3CH2- CF3CH2- -CH2F C730 o-O-i-Bu CF3CH2- CF3CH2- -CH2F C731 m-O-i-Bu CF3CH2- CF3CH2- -CH2F C732 p-O-i-Bu CF3CH2- CF3CH2- -CH2F C733 o-OCF3 CF3CH2- CF3CH2- -CH2F C734 m-OCF3 CF3CH2- CF3CH2- -CH2F C735 p-OCF3 CF3CH2- CF3CH2- -CH2F C736 H CF3CH2- CF3CH2- -CH2F N737 o-OCH3 CF3CH2- CF3CH2- -CH2F N738 m-OCH3 CF3CH2- CF3CH2- -CH2F N739 p-OCH3 CF3CH2- CF3CH2- -CH2F N740 o-Cl CF3CH2- CF3CH2- -CH2F N741 m-Cl CF3CH2- CF3CH2- -CH2F N742 p-Cl CF3CH2- CF3CH2- -CH2F N743 o-Br CF3CH2- CF3CH2- -CH2F N744 m-Br CF3CH2- CF3CH2- -CH2F N745 p-Br CF3CH2- CF3CH2- -CH2F N746 o-NH2 CF3CH2- CF3CH2- -CH2F N747 m-NH2 CF3CH2- CF3CH2- -CH2F N748 p-NH2 CF3CH2- CF3CH2- -CH2F N749 o-NO2 CF3CH2- CF3CH2- -CH2F N750 m-NO2 CF3CH2- CF3CH2- -CH2F N751 p-NO2 CF3CH2- CF3CH2- -CH2F N752 o-OC2H5 CF3CH2- CF3CH2- -CH2F N753 m-OC2H5 CF3CH2- CF3CH2- -CH2F N754 p-OC2H5 CF3CH2- CF3CH2- -CH2F N755 p-I CF3CH2- CF3CH2- -CH2F N756 o-O-n-Pr CF3CH2- CF3CH2- -CH2F N757 m-O-n-Pr CF3CH2- CF3CH2- -CH2F N758 p-O-n-Pr CF3CH2- CF3CH2- -CH2F N759 o-O-i-Pr CF3CH2- CF3CH2- -CH2F N760 m-O-i-Pr CF3CH2- CF3CH2- -CH2F N761 p-O-i-Pr CF3CH2- CF3CH2- -CH2F N762 o-O-n-Bu CF3CH2- CF3CH2- -CH2F N763 m-O-n-Bu CF3CH2- CF3CH2- -CH2F N764 p-O-n-Bu CF3CH2- CF3CH2- -CH2F N765 o-O-i-Bu CF3CH2- CF3CH2- -CH2F N766 m-O-i-Bu CF3CH2- CF3CH2- -CH2F N767 p-O-i-Bu CF3CH2- CF3CH2- -CH2F N768 o-OCF3 CF3CH2- CF3CH2- -CH2F N769 m-OCF3 CF3CH2- CF3CH2- -CH2F N770 p-OCF3 CF3CH2- CF3CH2- -CH2F N771 H CF3CH2- Me- -CH2F C772 o-OCH3 CF3CH2- Me- -CH2F C773 m-OCH3 CF3CH2- Me- -CH2F C774 p-OCH3 CF3CH2- Me- -CH2F C775 o-Cl CF3CH2- Me- -CH2F C776 m-Cl CF3CH2- Me- -CH2F C777 p-Cl CF3CH2- Me- -CH2F C778 o-Br CF3CH2- Me- -CH2F C779 m-Br CF3CH2- Me- -CH2F C780 p-Br CF3CH2- Me- -CH2F C781 o-NH2 CF3CH2- Me- -CH2F C782 m-NH2 CF3CH2- Me- -CH2F C783 p-NH2 CF3CH2- Me- -CH2F C784 o-NO2 CF3CH2- Me- -CH2F C785 m-NO2 CF3CH2- Me- -CH2F C786 p-NO2 CF3CH2- Me- -CH2F C787 o-OC2H5 CF3CH2- Me- -CH2F C788 m-OC2H5 CF3CH2- Me- -CH2F C789 P-OC2H5 CF3CH2- Me- -CH2F C790 p-I CF3CH2- Me- -CH2F C791 o-O-n-Pr CF3CH2- Me- -CH2F C792 m-O-n-Pr CF3CH2- Me- -CH2F C793 p-O-n-Pr CF3CH2- Me- -CH2F C794 o-O-i-Pr CF3CH2- Me- -CH2F C795 m-O-i-Pr CF3CH2- Me- -CH2F C796 p-O-i-Pr CF3CH2- Me- -CH2F C797 o-O-n-Bu CF3CH2- Me- -CH2F C798 m-O-n-Bu CF3CH2- Me- -CH2F C799 p-O-n-Bu CF3CH2- Me- -CH2F C800 o-O-i-Bu CF3CH2- Me- -CH2F C801 m-O-i-Bu CF3CH2- Me- -CH2F C802 p-O-i-Bu CF3CH2- Me- -CH2F C803 o-OCF3 CF3CH2- Me- -CH2F C804 m-OCF3 CF3CH2- Me- -CH2F C805 p-OCF3 CF3CH2- Me- -CH2F C806 H CF3CH2- Me- -CH2F N807 o-OCH3 CF3CH2- Me- -CH2F N808 m-OCH3 CF3CH2- Me- -CH2F N809 p-OCH3 CF3CH2- Me- -CH2F N810 o-Cl CF3CH2- Me- -CH2F N811 m-Cl CF3CH2- Me- -CH2F N812 p-Cl CF3CH2- Me- -CH2F N813 o-Br CF3CH2- Me- -CH2F N814 m-Br CF3CH2- Me- -CH2F N815 p-Br CF3CH2- Me- -CH2F N816 o-NH2 CF3CH2- Me- -CH2F N817 m-NH2 CF3CH2- Me- -CH2F N818 p-NH2 CF3CH2- Me- -CH2F N819 o-NO2 CF3CH2- Me- -CH2F N820 m-NO2 CF3CH2- Me- -CH2F N821 p-NO2 CF3CH2- Me- -CH2F N822 o-OC2H5 CF3CH2- Me- -CH2F N823 m-OC2H5 CF3CH2- Me- -CH2F N824 p-OC2H5 CF3CH2- Me- -CH2F N825 p-I CF3CH2- Me- -CH2F N826 o-O-n-Pr CF3CH2- Me- -CH2F N827 m-O-n-Pr CF3CH2- Me- -CH2F N828 p-O-n-Pr CF3CH2- Me- -CH2F N829 o-O-i-Pr CF3CH2- Me- -CH2F N830 m-O-i-Pr CF3CH2- Me- -CH2F N831 p-O-i-Pr CF3CH2- Me- -CH2F N832 o-O-n-Bu CF3CH2- Me- -CH2F N833 m-O-n-Bu CF3CH2- Me- -CH2F N834 p-O-n-Bu CF3CH2- Me- -CH2F N835 o-O-i-Bu CF3CH2- Me- -CH2F N836 m-O-i-Bu CF3CH2- Me- -CH2F N837 p-O-i-Bu CF3CH2- Me- -CH2F N838 o-OCF3 CF3CH2- Me- -CH2F N839 m-OCF3 CF3CH2- Me- -CH2F N840 p-OCF3 CF3CH2- Me- -CH2F N841 H CF3CH2- Et- -CH2F C842 o-OCH3 CF3CH2- Et- -CH2F C843 m-OCH3 CF3CH2- Et- -CH2F C844 p-OCH3 CF3CH2- Et- -CH2F C845 o-Cl CF3CH2- Et- -CH2F C846 m-Cl CF3CH2- Et- -CH2F C847 p-Cl CF3CH2- Et- -CH2F C848 o-Br CF3CH2- Et- -CH2F C849 m-Br CF3CH2- Et- -CH2F C850 p-Br CF3CH2- Et- -CH2F C851 o-NH2 CF3CH2- Et- -CH2F C852 m-NH2 CF3CH2- Et- -CH2F C853 p-NH2 CF3CH2- Et- -CH2F C854 o-NO2 CF3CH2- Et- -CH2F C855 m-NO2 CF3CH2- Et- -CH2F C856 p-NO2 CF3CH2- Et- -CH2F C857 o-OC2H5 CF3CH2- Et- -CH2F C858 m-OC2H5 CF3CH2- Et- -CH2F C859 p-OC2H5 CF3CH2- Et- -CH2F C860 p-I CF3CH2- Et- -CH2F C861 o-O-n-Pr CF3CH2- Et- -CH2F C862 m-O-n-Pr CF3CH2- Et- -CH2F C863 p-O-n-Pr CF3CH2- Et- -CH2F C864 o-O-i-Pr CF3CH2- Et- -CH2F C865 m-O-i-Pr CF3CH2- Et- -CH2F C866 p-O-i-Pr CF3CH2- Et- -CH2F C867 o-O-n-Bu CF3CH2- Et- -CH2F C868 m-O-n-Bu CF3CH2- Et- -CH2F C869 p-O-n-Bu CF3CH2- Et- -CH2F C870 o-O-i-Bu CF3CH2- Et- -CH2F C871 m-O-i-Bu CF3CH2- Et- -CH2F C872 p-O-i-Bu CF3CH2- Et- -CH2F C873 o-OCF3 CF3CH2- Et- -CH2F C874 m-OCF3 CF3CH2- Et- -CH2F C875 p-OCF3 CF3CH2- Et- -CH2F C876 H CF3CH2- Et- -CH2F N877 o-OCH3 CF3CH2- Et- -CH2F N878 m-OCH3 CF3CH2- Et- -CH2F N879 p-OCH3 CF3CH2- Et- -CH2F N880 o-Cl CF3CH2- Et- -CH2F N881 m-Cl CF3CH2- Et- -CH2F N882 p-Cl CF3CH2- Et- -CH2F N883 o-Br CF3CH2- Et- -CH2F N884 m-Br CF3CH2- Et- -CH2F N885 p-Br CF3CH2- Et- -CH2F N886 o-NH2 CF3CH2- Et- -CH2F N887 m-NH2 CF3CH2- Et- -CH2F N888 p-NH2 CF3CH2- Et- -CH2F N889 o-NO2 CF3CH2- Et- -CH2F N890 m-NO2 CF3CH2- Et- -CH2F N891 p-NO2 CF3CH2- Et- -CH2F N892 o-OC2H5 CF3CH2- Et- -CH2F N893 m-OC2H5 CF3CH2- Et- -CH2F N894 p-OC2H5 CF3CH2- Et- -CH2F N895 p-I CF3CH2- Et- -CH2F N896 o-O-n-Pr CF3CH2- Et- -CH2F N897 m-O-n-Pr CF3CH2- Et- -CH2F N898 p-O-n-Pr CF3CH2- Et- -CH2F N899 o-O-i-Pr CF3CH2- Et- -CH2F N900 m-O-i-Pr CF3CH2- Et- -CH2F N901 p-O-i-Pr CF3CH2- Et- -CH2F N902 o-O-n-Bu CF3CH2- Et- -CH2F N903 m-O-n-Bu CF3CH2- Et- -CH2F N904 p-O-n-Bu CF3CH2- Et- -CH2F N905 o-O-i-Bu CF3CH2- Et- -CH2F N906 m-O-i-Bu CF3CH2- Et- -CH2F N907 p-O-i-Bu CF3CH2- Et- -CH2F N908 o-OCF3 CF3CH2- Et- -CH2F N909 m-OCF3 CF3CH2- Et- -CH2F N910 p-OCF3 CF3CH2- Et- -CH2F N911 H CF3CH2- H -CH2F C912 o-OCH3 CF3CH2- H -CH2F C913 m-OCH3 CF3CH2- H -CH2F C914 p-OCH3 CF3CH2- H -CH2F C915 o-Cl CF3CH2- H -CH2F C916 m-Cl CF3CH2- H -CH2F C917 p-Cl CF3CH2- H -CH2F C918 o-Br CF3CH2- H -CH2F C919 m-Br CF3CH2- H -CH2F C920 p-Br CF3CH2- H -CH2F C921 o-NH2 CF3CH2- H -CH2F C922 m-NH2 CF3CH2- H -CH2F C923 p-NH2 CF3CH2- H -CH2F C924 o-NO2 CF3CH2- H -CH2F C925 m-NO2 CF3CH2- H -CH2F C926 p-NO2 CF3CH2- H -CH2F C927 o-OC2H5 CF3CH2- H -CH2F C928 m-OC2H5 CF3CH2- H -CH2F C929 p-OC2H5 CF3CH2- H -CH2F C930 p-I CF3CH2- H -CH2F C931 o-O-n-Pr CF3CH2- H -CH2F C932 m-O-n-Pr CF3CH2- H -CH2F C933 p-O-n-Pr CF3CH2- H -CH2F C934 o-O-i-Pr CF3CH2- H -CH2F C935 m-O-i-Pr CF3CH2- H -CH2F C936 p-O-i-Pr CF3CH2- H -CH2F C937 o-O-n-Bu CF3CH2- H -CH2F C938 m-O-n-Bu CF3CH2- H -CH2F C939 p-O-n-Bu CF3CH2- H -CH2F C940 o-O-i-Bu CF3CH2- H -CH2F C941 m-O-i-Bu CF3CH2- H -CH2F C942 p-O-i-Bu CF3CH2- H -CH2F C943 o-OCF3 CF3CH2- H -CH2F C944 m-OCF3 CF3CH2- H -CH2F C945 p-OCF3 CF3CH2- H -CH2F C946 H CF3CH2- H -CH2F N947 o-OCH3 CF3CH2- H -CH2F N948 m-OCH3 CF3CH2- H -CH2F N949 p-OCH3 CF3CH2- H -CH2F N950 o-Cl CF3CH2- H -CH2F N951 m-Cl CF3CH2- H -CH2F N952 p-Cl CF3CH2- H -CH2F N953 o-Br CF3CH2- H -CH2F N954 m-Br CF3CH2- H -CH2F N955 p-Br CF3CH2- H -CH2F N956 o-NH2 CF3CH2- H -CH2F N957 m-NH2 CF3CH2- H -CH2F N958 p-NH2 CF3CH2- H -CH2F N959 o-NO2 CF3CH2- H -CH2F N960 m-NO2 CF3CH2- H -CH2F N961 p-NO2 CF3CH2- H -CH2F N962 o-OC2H5 CF3CH2- H -CH2F N963 m-OC2H5 CF3CH2- H -CH2F N965 p-OC2H5 CF3CH2- H -CH2F N965 p-I CF3CH2- H -CH2F N966 o-O-n-Pr CF3CH2- H -CH2F N967 m-O-n-Pr CF3CH2- H -CH2F N968 p-O-n-Pr CF3CH2- H -CH2F N969 o-O-i-Pr CF3CH2- H -CH2F N970 m-O-i-Pr CF3CH2- H -CH2F N971 p-O-i-Pr CF3CH2- H -CH2F N972 o-O-n-Bu CF3CH2- H -CH2F N973 m-O-n-Bu CF3CH2- H -CH2F N974 p-O-n-Bu CF3CH2- H -CH2F N975 o-O-i-Bu CF3CH2- H -CH2F N976 m-O-i-Bu CF3CH2- H -CH2F N977 p-O-i-Bu CF3CH2- H -CH2F N978 o-OCF3 CF3CH2- H -CH2F N979 m-OCF3 CF3CH2- H -CH2F N980 p-OCF3 CF3CH2- H -CH2F N981 H H H -CH2F C982 o-OCH3 H H -CH2F C983 m-OCH3 H H -CH2F C984 p-OCH3 H H -CH2F C985 o-Cl H H -CH2F C986 m-Cl H H -CH2F C987 p-Cl H H -CH2F C988 o-Br H H -CH2F C989 m-Br H H -CH2F C990 p-Br H H -CH2F C991 o-NH2 H H -CH2F C992 m-NH2 H H -CH2F C993 p-NH2 H H -CH2F C994 o-NO2 H H -CH2F C995 m-NO2 H H -CH2F C996 p-NO2 H H -CH2F C997 o-OC2H5 H H -CH2F C998 m-OC2H5 H H -CH2F C999 p-OC2H5 H H -CH2F C1000 p-I H H -CH2F C1001 o-O-n-Pr H H -CH2F C1002 m-O-n-Pr H H -CH2F C1003 p-O-n-Pr H H -CH2F C1004 o-O-i-Pr H H -CH2F C1005 m-O-i-Pr H H -CH2F C1006 p-O-i-Pr H H -CH2F C1007 o-O-n-Bu H H -CH2F C1008 m-O-n-Bu H H -CH2F C1009 p-O-n-Bu H H -CH2F C1010 o-O-i-Bu H H -CH2F C1011 m-O-i-Bu H H -CH2F C1012 p-O-i-Bu H H -CH2F C1013 o-OCF3 H H -CH2F C1014 m-OCF3 H H -CH2F C1015 p-OCF3 H H -CH2F C1016 H H H -CH2F N1017 o-OCH3 H H -CH2F N1018 m-OCH3 H H -CH2F N1019 p-OCH3 H H -CH2F N1020 o-Cl H H -CH2F N1021 m-Cl H H -CH2F N1022 p-Cl H H -CH2F N1023 o-Br H H -CH2F N1024 m-Br H H -CH2F N1025 p-Br H H -CH2F N1026 o-NH2 H H -CH2F N1027 m-NH2 H H -CH2F N1028 p-NH2 H H -CH2F N1029 o-NO2 H H -CH2F N1030 m-NO2 H H -CH2F N1031 p-NO2 H H -CH2F N1032 o-OC2H5 H H -CH2F N1033 m-OC2H5 H H -CH2F N1034 p-OC2H5 H H -CH2F N1035 p-I H H -CH2F N1036 o-O-n-Pr H H -CH2F N1037 m-O-n-Pr H H -CH2F N1038 p-O-n-Pr H H -CH2F N1039 o-O-i-Pr H H -CH2F N1040 m-O-i-Pr H H -CH2F N1041 p-O-i-Pr H H -CH2F N1042 o-O-n-Bu H H -CH2F N1043 m-O-n-Bu H H -CH2F N1044 p-O-n-Bu H H -CH2F N1045 o-O-i-Bu H H -CH2F N1046 m-O-i-Bu H H -CH2F N1047 p-O-i-Bu H H -CH2F N1048 o-OCF3 H H -CH2F N1049 m-OCF3 H H -CH2F N1050 p-OCF3 H H -CH2F N1051 H CF3CH2- CF3CH2- -CH2OH C1052 o-OCH3 CF3CH2- CF3CH2- -CH2OH C1053 m-OCH3 CF3CH2- CF3CH2- -CH2OH C1054 p-OCH3 CF3CH2- CF3CH2- -CH2OH C1055 o-Cl CF3CH2- CF3CH2- -CH2OH C1056 m-Cl CF3CH2- CF3CH2- -CH2OH C1057 p-Cl CF3CH2- CF3CH2- -CH2OH C1058 o-Br CF3CH2- CF3CH2- -CH2OH C1059 m-Br CF3CH2- CF3CH2- -CH2OH C1060 p-Br CF3CH2- CF3CH2- -CH2OH C1061 o-NH2 CF3CH2- CF3CH2- -CH2OH C1062 m-NH2 CF3CH2- CF3CH2- -CH2OH C1063 p-NH2 CF3CH2- CF3CH2- -CH2OH C1064 o-NO2 CF3CH2- CF3CH2- -CH2OH C1065 m-NO2 CF3CH2- CF3CH2- -CH2OH C1066 p-NO2 CF3CH2- CF3CH2- -CH2OH C1067 o-OC2H5 CF3CH2- CF3CH2- -CH2OH C1068 m-OC2H5 CF3CH2- CF3CH2- -CH2OH C1069 p-OC2H5 CF3CH2- CF3CH2- -CH2OH C1070 p-I CF3CH2- CF3CH2- -CH2OH C1071 o-O-n-Pr CF3CH2- CF3CH2- -CH2OH C1072 m-O-n-Pr CF3CH2- CF3CH2- -CH2OH C1073 p-O-n-Pr CF3CH2- CF3CH2- -CH2OH C1074 o-O-i-Pr CF3CH2- CF3CH2- -CH2OH C1075 m-O-i-Pr CF3CH2- CF3CH2- -CH2OH C1076 p-O-i-Pr CF3CH2- CF3CH2- -CH2OH C1077 o-O-n-Bu CF3CH2- CF3CH2- -CH2OH C1078 m-O-n-Bu CF3CH2- CF3CH2- -CH2OH C1079 p-O-n-Bu CF3CH2- CF3CH2- -CH2OH C1080 o-O-i-Bu CF3CH2- CF3CH2- -CH2OH C1081 m-O-i-Bu CF3CH2- CF3CH2- -CH2OH C1082 p-O-i-Bu CF3CH2- CF3CH2- -CH2OH C1083 o-OCF3 CF3CH2- CF3CH2- -CH2OH C1084 m-OCF3 CF3CH2- CF3CH2- -CH2OH C1085 p-OCF3 CF3CH2- CF3CH2- -CH2OH C1086 H CF3CH2- CF3CH2- -CH2OH N1087 o-OCH3 CF3CH2- CF3CH2- -CH2OH N1088 m-OCH3 CF3CH2- CF3CH2- -CH2OH N1089 p-OCH3 CF3CH2- CF3CH2- -CH2OH N1090 o-Cl CF3CH2- CF3CH2- -CH2OH N1091 m-Cl CF3CH2- CF3CH2- -CH2OH N1092 p-Cl CF3CH2- CF3CH2- -CH2OH N1093 o-Br CF3CH2- CF3CH2- -CH2OH N1094 m-Br CF3CH2- CF3CH2- -CH2OH N1095 p-Br CF3CH2- CF3CH2- -CH2OH N1096 o-NH2 CF3CH2- CF3CH2- -CH2OH N1097 m-NH2 CF3CH2- CF3CH2- -CH2OH N1098 p-NH2 CF3CH2- CF3CH2- -CH2OH N1099 o-NO2 CF3CH2- CF3CH2- -CH2OH N1100 m-NO2 CF3CH2- CF3CH2- -CH2OH N1101 p-NO2 CF3CH2- CF3CH2- -CH2OH N1102 o-OC2H5 CF3CH2- CF3CH2- -CH2OH N1103 m-OC2H5 CF3CH2- CF3CH2- -CH2OH N1104 p-OC2H5 CF3CH2- CF3CH2- -CH2OH N1105 p-I CF3CH2- CF3CH2- -CH2OH N1106 o-O-n-Pr CF3CH2- CF3CH2- -CH2OH N1107 m-O-n-Pr CF3CH2- CF3CH2- -CH2OH N1108 p-O-n-Pr CF3CH2- CF3CH2- -CH2OH N1109 o-O-i-Pr CF3CH2- CF3CH2- -CH2OH N1110 m-O-i-Pr CF3CH2- CF3CH2- -CH2OH N1111 p-O-i-Pr CF3CH2- CF3CH2- -CH2OH N1112 o-O-n-Bu CF3CH2- CF3CH2- -CH2OH N1113 m-O-n-Bu CF3CH2- CF3CH2- -CH2OH N1114 p-O-n-Bu CF3CH2- CF3CH2- -CH2OH N1115 o-O-i-Bu CF3CH2- CF3CH2- -CH2OH N1116 m-O-i-Bu CF3CH2- CF3CH2- -CH2OH N1117 p-O-i-Bu CF3CH2- CF3CH2- -CH2OH N1118 o-OCF3 CF3CH2- CF3CH2- -CH2OH N1119 m-OCF3 CF3CH2- CF3CH2- -CH2OH N1120 p-OCF3 CF3CH2- CF3CH2- -CH2OH N1121 H CF3CH2- Me- -CH2OH C1122 o-OCH3 CF3CH2- Me- -CH2OH C1123 m-OCH3 CF3CH2- Me- -CH2OH C1124 p-OCH3 CF3CH2- Me- -CH2OH C1125 o-Cl CF3CH2- Me- -CH2OH C1126 m-Cl CF3CH2- Me- -CH2OH C1127 p-Cl CF3CH2- Me- -CH2OH C1128 o-Br CF3CH2- Me- -CH2OH C1129 m-Br CF3CH2- Me- -CH2OH C1130 p-Br CF3CH2- Me- -CH2OH C1131 o-NH2 CF3CH2- Me- -CH2OH C1132 m-NH2 CF3CH2- Me- -CH2OH C1133 p-NH2 CF3CH2- Me- -CH2OH C1134 o-NO2 CF3CH2- Me- -CH2OH C1135 m-NO2 CF3CH2- Me- -CH2OH C1136 p-NO2 CF3CH2- Me- -CH2OH C1137 o-OC2H5 CF3CH2- Me- -CH2OH C1138 m-OC2H5 CF3CH2- Me- -CH2OH C1139 p-OC2H5 CF3CH2- Me- -CH2OH C1140 p-I CF3CH2- Me- -CH2OH C1141 o-O-n-Pr CF3CH2- Me- -CH2OH C1142 m-O-n-Pr CF3CH2- Me- -CH2OH C1143 p-O-n-Pr CF3CH2- Me- -CH2OH C1141 o-O-i-Pr CF3CH2- Me- -CH2OH C1145 m-O-i-Pr CF3CH2- Me- -CH2OH C1146 p-O-i-Pr CF3CH2- Me- -CH2OH C1147 o-O-n-Bu CF3CH2- Me- -CH2OH C1148 m-O-n-Bu CF3CH2- Me- -CH2OH C1149 p-O-n-Bu CF3CH2- Me- -CH2OH C1150 o-O-i-Bu CF3CH2- Me- -CH2OH C1151 m-O-i-Bu CF3CH2- Me- -CH2OH C1152 p-O-i-Bu CF3CH2- Me- -CH2OH C1153 o-OCF3 CF3CH2- Me- -CH2OH C1154 m-OCF3 CF3CH2- Me- -CH2OH C1155 p-OCF3 CF3CH2- Me- -CH2OH C1156 H CF3CH2- Me- -CH2OH N1157 o-OCH3 CF3CH2- Me- -CH2OH N1158 m-OCH3 CF3CH2- Me- -CH2OH N1159 p-OCH3 CF3CH2- Me- -CH2OH N1160 o-Cl CF3CH2- Me- -CH2OH N1161 m-Cl CF3CH2- Me- -CH2OH N1162 p-Cl CF3CH2- Me- -CH2OH N1163 o-Br CF3CH2- Me- -CH2OH N1164 m-Br CF3CH2- Me- -CH2OH N1165 p-Br CF3CH2- Me- -CH2OH N1166 o-NH2 CF3CH2- Me- -CH2OH N1167 m-NH2 CF3CH2- Me- -CH2OH N1168 p-NH2 CF3CH2- Me- -CH2OH N1169 o-NO2 CF3CH2- Me- -CH2OH N1170 m-NO2 CF3CH2- Me- -CH2OH N1171 p-NO2 CF3CH2- Me- -CH2OH N1172 o-OC2H5 CF3CH2- Me- -CH2OH N1173 m-OC2H5 CF3CH2- Me- -CH2OH N1174 p-OC2H5 CF3CH2- Me- -CH2OH N1175 p-I CF3CH2- Me- -CH2OH N1176 o-O-n-Pr CF3CH2- Me- -CH2OH N1177 m-O-n-Pr CF3CH2- Me- -CH2OH N1178 p-O-n-Pr CF3CH2- Me- -CH2OH N1179 o-O-i-Pr CF3CH2- Me- -CH2OH N1180 m-O-i-Pr CF3CH2- Me- -CH2OH N1181 p-O-i-Pr CF3CH2- Me- -CH2OH N1182 o-O-n-Bu CF3CH2- Me- -CH2OH N1183 m-O-n-Bu CF3CH2- Me- -CH2OH N1184 p-O-n-Bu CF3CH2- Me- -CH2OH N1185 o-O-i-Bu CF3CH2- Me- -CH2OH N1186 m-O-i-Bu CF3CH2- Me- -CH2OH N1187 p-O-i-Bu CF3CH2- Me- -CH2OH N1188 o-OCF3 CF3CH2- Me- -CH2OH N1189 m-OCF3 CF3CH2- Me- -CH2OH N1190 p-OCF3 CF3CH2- Me- -CH2OH N1191 H CF3CH2- Et- -CH2OH C1192 o-OCH3 CF3CH2- Et- -CH2OH C1193 m-OCH3 CF3CH2- Et- -CH2OH C1194 p-OCH3 CF3CH2- Et- -CH2OH C1195 o-Cl CF3CH2- Et- -CH2OH C1196 m-Cl CF3CH2- Et- -CH2OH C1197 p-Cl CF3CH2- Et- -CH2OH C1198 o-Br CF3CH2- Et- -CH2OH C1199 m-Br CF3CH2- Et- -CH2OH C1200 p-Br CF3CH2- Et- -CH2OH C1201 o-NH2 CF3CH2- Et- -CH2OH C1202 m-NH2 CF3CH2- Et- -CH2OH C1203 p-NH2 CF3CH2- Et- -CH2OH C1204 o-NO2 CF3CH2- Et- -CH2OH C1205 m-NO2 CF3CH2- Et- -CH2OH C1206 p-NO2 CF3CH2- Et- -CH2OH C1207 o-OC2H5 CF3CH2- Et- -CH2OH C1208 m-OC2H5 CF3CH2- Et- -CH2OH C1209 p-OC2H5 CF3CH2- Et- -CH2OH C1210 p-I CF3CH2- Et- -CH2OH C1211 o-O-n-Pr CF3CH2- Et- -CH2OH C1212 m-O-n-Pr CF3CH2- Et- -CH2OH C1213 p-O-n-Pr CF3CH2- Et- -CH2OH C1214 o-O-i-Pr CF3CH2- Et- -CH2OH C1215 m-O-i-Pr CF3CH2- Et- -CH2OH C1216 p-O-i-Pr CF3CH2- Et- -CH2OH C1217 o-O-n-Bu CF3CH2- Et- -CH2OH C1218 m-O-n-Bu CF3CH2- Et- -CH2OH C1219 p-O-n-Bu CF3CH2- Et- -CH2OH C1220 o-O-i-Bu CF3CH2- Et- -CH2OH C1221 m-O-i-Bu CF3CH2- Et- -CH2OH C1222 p-O-i-Bu CF3CH2- Et- -CH2OH C1223 o-OCF3 CF3CH2- Et- -CH2OH C1224 m-OCF3 CF3CH2- Et- -CH2OH C1225 p-OCF3 CF3CH2- Et- -CH2OH C1226 H CF3CH2- Et- -CH2OH N1227 o-OCH3 CF3CH2- Et- -CH2OH N1228 m-OCH3 CF3CH2- Et- -CH2OH N1229 p-OCH3 CF3CH2- Et- -CH2OH N1230 o-Cl CF3CH2- Et- -CH2OH N1231 m-Cl CF3CH2- Et- -CH2OH N1232 p-Cl CF3CH2- Et- -CH2OH N1233 o-Br CF3CH2- Et- -CH2OH N1234 m-Br CF3CH2- Et- -CH2OH N1235 p-Br CF3CH2- Et- -CH2OH N1236 o-NH2 CF3CH2- Et- -CH2OH N1237 m-NH2 CF3CH2- Et- -CH2OH N1238 p-NH2 CF3CH2- Et- -CH2OH N1239 o-NO2 CF3CH2- Et- -CH2OH N1240 m-NO2 CF3CH2- Et- -CH2OH N1241 p-NO2 CF3CH2- Et- -CH2OH N1242 o-OC2H5 CF3CH2- Et- -CH2OH N1243 m-OC2H5 CF3CH2- Et- -CH2OH N1244 p-OC2H5 CF3CH2- Et- -CH2OH N1245 p-I CF3CH2- Et- -CH2OH N1246 o-O-n-Pr CF3CH2- Et- -CH2OH N1247 m-O-n-Pr CF3CH2- Et- -CH2OH N1248 p-O-n-Pr CF3CH2- Et- -CH2OH N1249 o-O-i-Pr CF3CH2- Et- -CH2OH N1250 m-O-i-Pr CF3CH2- Et- -CH2OH N1251 p-O-i-Pr CF3CH2- Et- -CH2OH N1252 o-O-n-Bu CF3CH2- Et- -CH2OH N1253 m-O-n-Bu CF3CH2- Et- -CH2OH N1254 p-O-n-Bu CF3CH2- Et- -CH2OH N1255 o-O-i-Bu CF3CH2- Et- -CH2OH N1256 m-O-i-Bu CF3CH2- Et- -CH2OH N1257 p-O-i-Bu CF3CH2- Et- -CH2OH N1258 o-OCF3 CF3CH2- Et- -CH2OH N1259 m-OCF3 CF3CH2- Et- -CH2OH N1260 p-OCF3 CF3CH2- Et- -CH2OH N1261 H CF3CH2- H -CH2OH C1262 o-OCH3 CF3CH2- H -CH2OH C1263 m-OCH3 CF3CH2- H -CH2OH C1264 p-OCH3 CF3CH2- H -CH2OH C1265 o-Cl CF3CH2- H -CH2OH C1266 m-Cl CF3CH2- H -CH2OH C1267 p-Cl CF3CH2- H -CH2OH C1268 o-Br CF3CH2- H -CH2OH C1269 m-Br CF3CH2- H -CH2OH C1270 p-Br CF3CH2- H -CH2OH C1271 o-NH2 CF3CH2- H -CH2OH C1272 m-NH2 CF3CH2- H -CH2OH C1273 p-NH2 CF3CH2- H -CH2OH C1274 o-NO2 CF3CH2- H -CH2OH C1275 m-NO2 CF3CH2- H -CH2OH C1276 p-NO2 CF3CH2- H -CH2OH C1277 o-OC2H5 CF3CH2- H -CH2OH C1278 m-OC2H5 CF3CH2- H -CH2OH C1279 p-OC2H5 CF3CH2- H -CH2OH C1280 p-I CF3CH2- H -CH2OH C1281 o-O-n-Pr CF3CH2- H -CH2OH C1282 m-O-n-Pr CF3CH2- H -CH2OH C1283 p-O-n-Pr CF3CH2- H -CH2OH C1284 o-O-i-Pr CF3CH2- H -CH2OH C1285 m-O-i-Pr CF3CH2- H -CH2OH C1286 p-O-i-Pr CF3CH2- H -CH2OH C1287 o-O-n-Bu CF3CH2- H -CH2OH C1288 m-O-n-Bu CF3CH2- H -CH2OH C1289 p-O-n-Bu CF3CH2- H -CH2OH C1290 o-O-i-Bu CF3CH2- H -CH2OH C1291 m-O-i-Bu CF3CH2- H -CH2OH C1292 p-O-i-Bu CF3CH2- H -CH2OH C1293 o-OCF3 CF3CH2- H -CH2OH C1294 m-OCF3 CF3CH2- H -CH2OH C1295 p-OCF3 CF3CH2- H -CH2OH C1296 H CF3CH2- H -CH2OH N1297 o-OCH3 CF3CH2- H -CH2OH N1298 m-OCH3 CF3CH2- H -CH2OH N1299 p-OCH3 CF3CH2- H -CH2OH N1300 o-Cl CF3CH2- H -CH2OH N1301 m-Cl CF3CH2- H -CH2OH N1302 p-Cl CF3CH2- H -CH2OH N1303 o-Br CF3CH2- H -CH2OH N1304 m-Br CF3CH2- H -CH2OH N1305 p-Br CF3CH2- H -CH2OH N1306 o-NH2 CF3CH2- H -CH2OH N1307 m-NH2 CF3CH2- H -CH2OH N1308 p-NH2 CF3CH2- H -CH2OH N1309 o-NO2 CF3CH2- H -CH2OH N1310 m-NO2 CF3CH2- H -CH2OH N1311 p-NO2 CF3CH2- H -CH2OH N1312 o-OC2H5 CF3CH2- H -CH2OH N1313 m-OC2H5 CF3CH2- H -CH2OH N1314 p-OC2H5 CF3CH2- H -CH2OH N1315 p-I CF3CH2- H -CH2OH N1316 o-O-n-Pr CF3CH2- H -CH2OH N1317 m-O-n-Pr CF3CH2- H -CH2OH N1318 p-O-n-Pr CF3CH2- H -CH2OH N1319 o-O-i-Pr CF3CH2- H -CH2OH N1320 m-O-i-Pr CF3CH2- H -CH2OH N1321 p-O-i-Pr CF3CH2- H -CH2OH N1322 o-O-n-Bu CF3CH2- H -CH2OH N1323 m-O-n-Bu CF3CH2- H -CH2OH N1324 p-O-n-Bu CF3CH2- H -CH2OH N1325 o-O-i-Bu CF3CH2- H -CH2OH N1326 m-O-i-Bu CF3CH2- H -CH2OH N1327 p-O-i-Bu CF3CH2- H -CH2OH N1328 o-OCF3 CF3CH2- H -CH2OH N1329 m-OCF3 CF3CH2- H -CH2OH N1330 p-OCF3 CF3CH2- H -CH2OH N1331 H H H -CH2OH C1332 o-OCH3 H H -CH2OH C1333 m-OCH3 H H -CH2OH C1334 p-OCH3 H H -CH2OH C1335 o-Cl H H -CH2OH C1336 m-Cl H H -CH2OH C1337 p-Cl H H -CH2OH C1338 o-Br H H -CH2OH C1339 m-Br H H -CH2OH C1340 p-Br H H -CH2OH C1341 o-NH2 H H -CH2OH C1342 m-NH2 H H -CH2OH C1343 p-NH2 H H -CH2OH C1344 o-NO2 H H -CH2OH C1345 m-NO2 H H -CH2OH C1346 p-NO2 H H -CH2OH C1347 o-OC2H2 H H -CH2OH C1348 m-OC2H5 H H -CH2OH C1349 p-OC2H5 H H -CH2OH C1350 p-I H H -CH2OH C1351 o-O-n-Pr H H -CH2OH C1352 m-O-n-Pr H H -CH2OH C1353 p-O-n-Pr H H -CH2OH C1354 o-O-i-Pr H H -CH2OH C1355 m-O-i-Pr H H -CH2OH C1356 p-O-i-Pr H H -CH2OH C1357 o-O-n-Bu H H -CH2OH C1356 m-O-n-Bu H H -CH2OH C1359 p-O-n-Bu H H -CH2OH C1360 o-O-i-Bu H H -CH2OH C1361 m-O-i-Bu H H -CH2OH C1362 p-O-i-Bu H H -CH2OH C1363 o-OCF3 H H -CH2OH C1364 m-OCF3 H H -CH2OH C1365 p-OCF3 H H -CH2OH C1366 H H H -CH2OH N1367 o-OCH3 H H -CH2OH N1368 m-OCH3 H H -CH2OH N1369 p-OCH3 H H -CH2OH N1370 o-Cl H H -CH2OH N1371 m-Cl H H -CH2OH N1372 p-Cl H H -CH2OH N1373 o-Br H H -CH2OH N1374 m-Br H H -CH2OH N1375 p-Br H H -CH2OH N1376 o-NH2 H H -CH2OH N1377 m-NH2 H H -CH2OH N1378 p-NH2 H H -CH2OH N1379 o-NO2 H H -CH2OH N1380 m-NO2 H H -CH2OH N1381 p-NO2 H H -CH2OH N1382 o-OC2H5 H H -CH2OH N1383 m-OC2H5 H H -CH2OH N1384 p-OC2H5 H H -CH2OH N1385 p-I H H -CH2OH N1386 o-O-n-Pr H H -CH2OH N1387 m-O-n-Pr H H -CH2OH N1388 p-O-n-Pr H H -CH2OH N1389 o-O-i-Pr H H -CH2OH N1390 m-O-i-Pr H H -CH2OH N1391 p-O-i-Pr H H -CH2OH N1392 o-O-n-Bu H H -CH2OH N1393 m-O-n-Bu H H -CH2OH N1394 p-O-n-Bu H H -CH2OH N1395 o-O-i-Bu H H -CH2OH N1396 m-O-i-Bu H H -CH2OH N1397 p-O-i-Bu H H -CH2OH N1398 o-OCF3 H H -CH2OH N1399 m-OCF3 H H -CH2OH N1400 p-OCF3 H H -CH2OH N1401 H -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1402 o-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1403 m-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1404 p-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1405 o-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1106 m-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1407 p-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1408 o-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1409 m-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1410 p-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1411 o-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1412 m-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1413 p-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1414 o-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1415 m-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1416 p-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1417 o-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1418 m-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1119 p-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1420 p-I -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1421 o-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1422 m-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1423 p-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1424 o-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1425 m-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1426 p-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1427 o-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1428 m-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1429 p-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1430 o-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1431 m-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1432 p-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1433 o-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1434 m-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1435 p-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H C1436 H -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1437 o-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1438 m-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1439 p-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1440 o-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1441 m-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1442 p-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1443 o-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1444 m-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1445 p-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1446 o-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1447 m-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1448 p-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1449 o-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1450 m-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1451 p-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1452 o-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1453 m-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1454 p-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1455 p-I -CH2O-CO-t-Bu -CH2O-CO-t-BH Me- C1456 o-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me C1457 m-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1458 p-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1459 o-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1460 m-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1461 p-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1462 o-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1463 m-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1464 p-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1465 o-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1466 m-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1467 p-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1468 o-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1469 m-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- C1470 p-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me C1471 H -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1472 o-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1473 m-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1474 p-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1475 o-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1476 m-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1477 p-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1478 o-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1479 m-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C148O p-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1481 o-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1482 m-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1483 p-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1484 o-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1485 m-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1486 p-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1487 o-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1488 m-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1489 p-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1490 p-I -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1491 o-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1492 m-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1493 p-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1494 o-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1495 m-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1496 p-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1497 o-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1498 m-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1499 p-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1500 o-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1501 m-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1502 p-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1503 o-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1504 m-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1505 p-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F C1506 H -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1507 o-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1508 m-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1509 p-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1510 o-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1511 m-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1512 p-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1513 o-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1514 m-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1515 p-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1516 o-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1517 m-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1518 p-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1519 o-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1520 m-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1521 p-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1522 o-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1523 m-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1524 p-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1525 p-I -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1526 o-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1527 m-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1528 p-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1529 o-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1530 m-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1531 p-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1532 o-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1533 m-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1534 p-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1535 o-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1536 m-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1537 p-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1538 o-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1539 m-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1540 p-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH C1541 H -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1542 o-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1543 m-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1544 p-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1545 o-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1546 m-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1547 p-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1548 o-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1549 m-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1550 p-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1551 o-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1552 m-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1553 p-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1554 o-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1555 m-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1556 p-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1557 o-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1558 m-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1559 p-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1560 p-I -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1561 o-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1562 m-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1563 p-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1564 o-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1565 m-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1566 p-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1567 o-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1568 m-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1569 p-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1570 o-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1571 m-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1572 p-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1573 o-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1574 m-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1575 p-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H C1576 H -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1577 o-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1578 m-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1579 p-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1580 o-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1581 m-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1582 p-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1583 o-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1584 m-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1585 p-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1586 o-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1587 m-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1588 p-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1589 o-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1590 m-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1591 p-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1592 o-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1593 m-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1594 p-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1595 p-I -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1596 o-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1597 m-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1598 p-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1599 o-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1600 m-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1601 p-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1602 o-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1603 m-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1604 p-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1605 o-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1606 m-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1607 p-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1608 o-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1609 m-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1610 p-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- C1611 H -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1612 o-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1613 m-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1614 p-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1615 o-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1616 m-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1617 p-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1618 o-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1619 m-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1620 p-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1621 o-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1622 m-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1623 p-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1624 o-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1625 m-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1626 p-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1627 o-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1628 m-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1629 p-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1630 p-I -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1631 o-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1632 m-O-n-Pr -CH2CH2S-CO-i-Pr -CH3CH2S-CO-i-Pr -CH2F C1633 p-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1634 o-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1635 m-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1636 p-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1637 o-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1638 m-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1639 p-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1640 o-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1641 m-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1642 p-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1643 o-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1644 m-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1645 p-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F C1646 H -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1647 o-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1648 m-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1649 p-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1650 o-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1651 m-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Fr -CH2OH C1652 p-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1653 o-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1654 m-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1655 p-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1656 o-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1657 m-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1658 p-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1659 o-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1660 m-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1661 p-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1662 o-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1663 m-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1664 p-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1665 p-I -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1666 o-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1667 m-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1668 p-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1669 o-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1670 m-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1671 p-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1672 o-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1673 m-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1674 p-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1675 0-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1676 m-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1677 p-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1678 o-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1679 m-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C1680 p-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH C
作为本发明化合物的制造方法,通式(1)化合物的R2和R3同是C1-C22的烷基或由1个以上的卤原子取代的乙基的化合物时,例如可根据下述反应路线(1)或(2)进行合成(下述图式中,R1、R4和X是已定义的,R5表示C1-C22的烷基或由1个以上的卤原子取代的乙基。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脱离基)。<反应路线(1)>
首先,将上述通式(II)的化合物和上述通式(III)的化合物,在10-250℃,最好130-200℃的温度下,反应0.1-100小时,最好3-24小时。根据上述反应得到的上述通式(IV)化合物,根据需要利用通常的分离精制手段,例如蒸馏、吸附、分配色层分析法,进行分离精制。上述通式(IV)的化合物虽然可以如上述那样进行分离精制,但也可以不必精制,直接供入以下反应。继续将由上述通式(IV)的化合物和上述通式(V)表示的化合物,在碱基的存在下,例如碳酸钠、碳酸钾、碳酸铯、氢化钠、氢化钾、三乙胺、二氮杂二环十一碳烯等存在下,乙腈、四氢呋喃、二甲基亚砜、二甲基甲酰胺、甲基吡咯烷酮等适当的溶剂中,在10-200℃,最好50-150℃下,反应0.1-100小时,最好1-10小时,得到上述通式(I′)的化合物。
反应路线(I)的原料,即上述通式(II)的化合物,上述通式(III)的化合物和上述通式(V)的化合物,其来源没有特殊限定,例如,可以使用市售试剂、或者通过已知方法适当合成。例如,上述通式(V)的化合物,可以将后述的通式(VI)化合物和式(VIII)化合物,在乙腈、二甲基亚砜等适当溶剂中,加热到50-100℃进行合成。
将由反应路线(1)得到的上述通式(IV)化合物和上述通式(VI)的化合物,例如,碳酸钠、碳酸钾、碳酸铯、氢化钠、氢化钾、三乙胺、二氮杂环十一碳烯等在碱的存在下,乙腈、四氢呋喃、二甲基亚砜、二甲基甲酰胺、甲基吡咯烷酮等适当的溶剂中,在10-200℃下,最好50-150℃下,反应0.1-100小时,最好0.5-10小时,得到上述通式(VII)的化合物。接着,将由上述通式(VII)的化合物和上述通式(VIII)表示的硫醇或它的盐,例如钠盐、钾盐、锂盐、三乙胺盐等,在如乙腈、四氢呋喃、二甲基亚砜、二甲基甲酰胺、甲基吡咯烷酮等适当的溶剂中,根据情况,在适当的三级胺存在下,于10-200℃,最好70-120℃的温度下,反应0.1-100小时,最好0.5-12小时,得到上述通式(I’)的化合物。该通式(I’)的化合物相当于通式(I)中R2和R3同时为C1-C22烷基或由1个以上的卤原子取代的乙基化合物。反应路线(2)的原料,即上述通式(VI)的化合物来源没有特殊限定,例如,可以使用市售的试剂,也可以使用按已知方法适当合成的。
通过进一步改变上述通式(I’)化合物的磷酸酯部分,可以获得将通式(I’)化合物的R5变换成其它取代基的通式(I)的化合物。例如,通式(I)中R2和R3同为氢原子的化合物,可将上述通式(I’)的化合物加水分解而获得。通式(1)中,R3为氢原子、C1-C22的烷基、酰硫乙基,或由1个以上的卤原子取代的乙基、R2为C1-C22的烷基或由1个以上的卤原子取代的乙基的化合物,将上述通式(I’)的化合物和通式(IX):R6OH(R6表示氢原子,C1-C22的烷基、酰硫乙基,或由1个以上的卤原子取代的乙基)表示的化合物在无溶剂或适当溶剂中,例如二氯甲烷等氯系溶剂、吡啶、乙腈、四氢呋喃、二甲基亚砜、二甲基甲酰胺、甲基吡咯烷酮等溶剂中,根据情况,在有酸或碱的存在下,于10-100℃,最好20-30℃下,反应0.1-100小时。最好5-12小时,而获得。
(上述图式中,R1、R4、R5、R6和X为如同已定义的)
在通式(I)中,R2和R3分别为氢原子、C1-C22的烷基、酰硫基、或由1个以上的卤原子取代的乙基所表示的化合物,可通过下述方法获得(下述图式中,R1、R4和X为如同已定义的,R7和R8分别为氢原子,C1-C22的烷基、酰硫乙基、或由1个以上的卤原子取代的乙基。但是,R7和R8不能同时为氢原子。)
首先,将上述(I’)的化合物和三甲基甲硅烷二乙基胺,在适当的溶剂中,如二氯甲烷、二氯乙烷、氯仿等氯系溶剂中,在接近于室温下反应1小时左右。这时,三甲基甲硅烷二乙胺,对于1mol上述通式(I”)的化合物,使用2mol以上。接着,将反应液浓缩干固后,将残渣溶解于适当的溶剂中,例如二氯甲烷等氯系溶剂中,对于1mol的上述通式(I”)化合物,再添加2mol以上的草酰氯化物(ォキザリルクロリド),在催化量的二甲基甲酰胺的存在下,于冰冷下反应1小时,接着于室温下反应1小时。
将除去溶剂得到的上述通式(X)化合物,通常不进行精制,在适当的溶剂中,例如,二氯甲烷等氯系溶剂、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,和通式(XI)的化合物和/或通式(XII)的化合物,于10-100℃,最好20-30℃的温度下,反应0.1-100小时,最好5-12小时。获得的通式(XIII)化合物,相当于通式(I)中,R2和R3分别为氢原子,C1-C22烷基、酰硫乙基、或由1个以上的卤原子取代的乙基化合物(但是,R2和R3不能同时为氢原子)。另外,成为上述反应原料的上述通式(I”)化合物,和已讲述的一样,可将通式(I’)的化合物加水分解而获得,将上述通式(I’)中,R5为C1-C22的烷基化合物,与三乙基碘硅烷、三甲基溴硅烷反应,可更有效地获得。
将在通式(I)中,R2和R3同为酰氧甲基的化合物,或一方是酰氧甲基,另一方是氢的化合物,将上述通式(I”)的化合物和下述通式(XIV):R9Y(R9表示酰氧甲基、Y表示氯原子、溴原子或磺原子)表示的酰氧甲基卤化物,在碱的存在下,例如碳酸钠、碳酸钾、碳酸铯、氢化钠,氢化钾、三乙胺、吡啶、二氮杂二环十一碳烯、N,N’-二环己基-4-吗啉カルボキサミジン的等的存在下,于乙腈、四氢呋喃、二甲基亚砜、二甲基甲酰胺、甲基吡咯烷酮等适当的溶剂中,0-200℃,最好10-100℃下,反应1-300小时,最好10-200小时,而获得。在R2和R3都为酰氧甲基化合物时,对于通式(I”)的化合物,最好与2倍摩尔的通式(XIV)化合物进行反应,对于一方是酰氧甲基化合物时,最好以等摩尔进行反应。
R2和R3,一方为酰氧甲基,另一方为C1-C22的烷基,酰硫乙基或由1个以上的卤原子取代的乙基化合物,首先制备R2和R3的一方为C1-C22的烷基、酰硫乙基,或由1个以上的卤原子取代的乙基,另一方为氢原子的化合物,接着,对该化合物,利用上述方法,与通式(XIV)的化合物反应而可以制备。
由通式(I)表示的化合物的盐可以合成,例如可按照下述方法合成。通过将通式(I’)的化合物,在醋酸乙酯、异丙醇、乙腈、四氢呋喃、二甲基亚砜、二甲基甲酰胺、甲基吡咯烷酮等适当溶剂中,于-10-100℃下,最好10-50℃下,和对应的酸搅拌下,反应0.1-20小时,最好0.3-1小时而可以合成。
上述制造方法,只是表示制造本发明的通式(I)化合物的方法之一例。本发明化合物的制造方法并不仅限于这些方法。在本说明书的实施例中,由于更具体地说明了本发明化合物的制造方法,所以,本领域的人员,根据上述说明和实施例的具体说明,根据需要,对此加以适当的修改,就能制造出包括在上述通式(I)中的化合物。另外,通过上述方法制造的上述通式(1)的化合物或它们的盐,根据需要,通过适当选择核苷酸的精制分离方法就能进行精制或分离,例如重结晶、吸附、离子交换、色谱分离等。
本发明的化合物可用作药品的有效成分,具体讲可用作后述试验例中所示的抗病毒剂的有效成分。另外,如所见到的其它离子性膦酸酯核苷酸类似体,希望具有抗肿瘤活性。本发明药物的适用对象病毒没有特殊限定,但具体讲,有人类免疫不全病毒、流行性感冒病毒、C(丙)型肝炎病毒等的RNA病毒和单纯疱疹病毒I、单纯疱疹病毒II、细胞肥大病毒、带状水痘疱疹病毒、B(乙)型肝炎病毒等的DNA病毒,适用于B型肝炎病毒更好。
本发明的化合物用作药物时,虽然它自身可单独服用,但最好是制成药物组合物服用,使用药学上容许的制剂用添加物,将上述化合物作为有效成分。医药组合物的构成。可根据化合物的溶解度、化学性质、服用途径、服用计划等来决定。例如经口服用可以制成颗粒剂、细粒剂、散剂、片剂、硬糖浆剂、软胶囊剂、糖片剂、糖浆剂、乳剂、软胶囊剂、凝胶剂、膏剂、悬浊剂、核糖微粒等。或者,作为注射剂,可进行静脉注射、肌肉注射,皮下注射。也可以制成注射用的粉末,进行使用。
作为药学容许的制剂用添加物,可以用适宜于经口、经肠、不经口或局部施用的有机或无机的固体或液体的载体。作为用于制造固形制剂时的固体载体,例如有乳糖、蔗糖、淀粉、滑石粉、纤维素、糊精、高岭土、碳酸钙、琼胶、果胶、腻硬脂酸、硬脂酸镁、卵磷脂、氯化钠等。作为制造口服液体制剂时所用的液体载体,有甘油、花生油、聚乙烯吡咯烷酮、橄榄油、乙醇、苯乙醇、丙二醇、生理盐水、水等。上述药物组合物除上述载体外也可含有补助剂,如湿润剂、悬浊辅助剂、苷味剂、芳香剂、着色剂和保存剂等。液体制剂可以含在像凝胶样的可吸收的物质胶囊中使用。不经口施用的制剂、即,作为用于注射剂等制造的溶剂或悬浊剂,例如可以举出水、丙二醇、聚乙烯二醇、苯甲醇、油酸乙酯、卵磷脂等。
本发明的化合物,特别是用通式(I’)表示的酯衍生物,因为具有后述试验例中所示的很高的口服吸收性,所以经口服用是本发明药物的最好施用路径。上述各制剂的调制可按常规方法进行。本发明药物的临床服用量,在用于口腔服用时,作为本发明化合物的重量,成人每日为0.1-500mg/kg,最好是1-50mg/kg。不过,上述服用量,可根据年令、病状、症状、是否同时服用等,作适当增减。上述1日的服用量,最好是1日内一次,或适当间隔1日内2~数次服用,也可以每数日内间断服用。用作注射剂时,作为本发明化合物的重量,成人每日为0.01-50mg/kg,最好为0.1-5mg/kg。
实施例
以下利用实施例更具体地说明本发明,但本发明并不仅限于以下实施例。另外,实施例中化合物编号与表1中化合物编号相对应。
实施例1
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-苯基硫嘌呤(化合物No.1)的制造
将87g(670mmol)2-氯乙基氯甲基醚和200g(610mmol)三(2,2,2-三氟乙基)磷化物,于160℃,反应7小时,定量地得到2-[二(2,2,2-三氟乙基]膦酸甲氧基]乙基氯化物。
将206g 2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基氯化物溶解于2000m/甲基乙酮中,和270g碘化钠,回流8小时。反应后,冷却到室温,浓缩干固。再将残渣溶解于氯仿/己烷中,在硅胶柱上吸附,再用氯仿/己烷洗脱,定量获得2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基碘化物。
将15.0g(88mmol)2-氨基-6-氯嘌呤,悬浮于360ml二甲基甲酰胺中,和13.9ml(93mmol)1,8-二氮杂二环[5.4.0]十一碳-7-烯,于80℃下反应1小时。接着向上述反应液中加入23.8ml 2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基碘化物,于100℃下反应5小时。反应后冷却到室温,浓缩干固。将残渣溶解于氯仿中,再用硅胶柱吸附,用5%-甲醇-氯仿洗脱,得到23.3g(收率56%)2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-氯嘌呤。
将2.1ml乙基胺和3.1ml硫酚添加到68ml 7.1g 2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-氯嘌呤的二甲基甲酰胺溶液中,于100℃下,搅拌2小时。将反应混合物冷却到室温,浓缩干固。用氯仿溶解残渣,再用硅胶柱吸附,用5%-甲醇-氯仿洗脱,得到5.0g(收率61%)2-氨基-9-[2-[二(2,2,2-三氟乙基)磷酸甲氧基]乙基]-6-苯基硫嘌呤。
m.p.:105-106℃(乙醇)
1H-NMR(CDCl3,δ):3.86-4.03(m,4H)、4.20-4.50(m,6H)、4.77(S,2H)、7.42-7.58(m,3H)、7.58-7.68(m,2H)、7.72(S,1H)
实施例2:
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对-硝苯基硫嘌呤(化合物No.16)的制造
用对硝基硫酚代替实施例1中的硫酚,其它和实施例1相同,得到标题化合物。
m.p.:114-116℃(二异丙醚)
1H-NMR(CDCl3,δ):3.87-4.02(m,4H)、4.22-4.46(m,6H)、4.83(s,2H)、7.75-7.85(m,2H)、8.20-8.28(m,2H)
实施例3
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对甲氧苯基硫嘌呤(化合物No.4)的制造
用对甲氧基硫酚代替实施例1中的硫酚,其它和实施例1相同,得到标题化合物。
m.p.:93-95℃(二异丙醚)
1H-NMR(CDCl3,δ):3.85(s,3H),3.92-4.00(m,3H)、4.24-4.45(m,6H)、4.75(s,2H)、6.95(d,J=9.0Hz,2H)、7.53(d,J=9.0Hz,2H)、7.71(s,1H)
实施例4
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间甲氧苯基硫嘌呤(化合物No.3)的制造
用间甲氧基硫酚代替实施例1中的硫酚,其它和实施例1相同,得标题化合物。
UV:λmax=291,328(0.01N-HCl/CH3OH)
λmax=242,315(0.01N-NaOH/CH3OH
1H-NMR(CDCl3,δ):3.82(s,3H)、3.88-3.97(m,4H)、4.24-4.45(m,6H)、4.81(s,2H)、6.92-7.00(m,1H)、7.18-7.40(m,4H)、7.72(s,1H)
实施例5
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻甲氧苯基硫嘌呤(化合物No.2)的制造
用邻甲氧基硫酚代替实施例1中的硫酚,其它和实施例1相同,得到标题化合物。
UV:λmax=332(0.01N-HCl/CH3OH)
λmax=314(0.01N-NaOH/CH3OH)
1H-NMR(CDCl3,δ):3.80(s,3H)、3.85-3.98(m,4H)、4.20-4.46(m,6H)、4.78(s,2H)、6.96-7.04(m,2H)、7.43(ddd,J=7.7,7.7和1.5Hz,1H)、7.59(dd,J=7.6和1.5Hz,1H)、7.69(s,1H)
实施例6
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对氨苯基硫嘌呤(化合物No.13)的制造
用对氨基硫酚代替实施例1中的硫酚,其它和实施例1相同,得标题化合物。
m.p.:130°-132℃(二异丙醚)
1H-NMR(CDCl3,δ):3.86-4.00(m,4H)、4.21-4.48(m,6H)、4.80(s,2H)、6.71(d,J=8.5Hz,2H)、7.38(d,J=8.5Hz,2H)、7.70(s,1H)
实施例7
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对氯苯基硫嘌呤(化合物No.7)的制造
用对氯基硫酚代替实施例1中的硫酚,其它和实施例1相同,得到标题化合物。
m.p.:108-110℃(二异丙醚/己烷)
1H-NMR(CDCl3,δ):3.87-4.00(m,4H)、4.22-4.47(m,6H)、4.77(s,2H)、7.39(d,J=8.5Hz,2H)、7.56(d,J=8.5Hz,2H)、7.76(s,1H)
实施例8
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对乙氧苯基硫嘌呤(化合物No.19)的制造
将25g对羟苯亚硫酰溶于155ml DMSO,搅拌4小时后,注入1l冰水,将析出的结晶进行减压干燥,定量得到二(对羟苯)二硫化物。
将2.2g碳酸钾、4.3g乙基碘化物添加到20ml 2.0g二(对羟基苯)二硫化物的DMF溶液中,于70℃下搅拌16小时后,注入到100ml冰水中,用500ml己烷萃取后,浓缩,得到1.8g(82%)二(对羟基苯)二硫化物。
向20ml 1.8g二(对羟基苯)二硫化物的1,4-二恶烷/5ml水溶液中,加入1.9g三苯基磷化氢、3滴浓盐酸,于40℃下,搅拌10小时后,注入到250ml氯仿中,用水洗涤2次后,浓缩,定量得到对乙氧苯基硫醇。用对乙氧苯基硫醇代替实施例1中的硫酚,其它相同,得到标题化合物。
m.p.:61-64℃(氯仿)
1H-NMR(CDCl3,δ):1.45(t,J=7.0Hz,3H)、3.84-3.98(m,4H)、4.08(q,J=7.0Hz,2H)、4.18-4.48(m,6H)、4.76(s,2H)、6.96(d,J=8.4Hz,2H)、7.52(d,J=8.4Hz,2H)、7.71(s,1H)
实施例9
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基-6-对丁氧苯基硫嘌呤(化合物No.29)的制造
用丁基碘化物代替实施例2中的乙基碘化物,其它相同,得到标题化合物。
m.p.:89-92℃
1H-NMR(CDCl3,δ):0.99(t,J=7.5Hz,3H),1.51(tq,J=8.1Hz和7.5Hz,2H)、1.79(tt,J=6.4Hz和8.1Hz,2H)、3.84-3.98(m,4H)、4.00(t,J=6.4Hz,2H)、4.20-4.48(m,6H)、4.76(s,2H)、6.94(d,J=8.8Hz,2H)、7.52(d,J=8.8Hz,2H)、7.71(s,1H)
实施例10
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对丙氧苯基硫嘌呤(化合物No.23)的制造
用丙基碘化物代替实施例8中的乙基碘化物,其它相同,得到标题化合物。
UV:λmax=229,331(0.01N-HCl/CH3OH)
λmax=223,314(0.01N-NaOH/CH3OH)
1H-NMR(CDCl3,δ):1.05(t,J-7.4Hz,3H)、1.84(tq,J=6.8Hz和7.4Hz,2H)、3.82-4.00(m,6H)、4.20-4.48(m,6H)、4.78(s,2H)、6.95(dJ=8.7Hz,2H)、7.51(d,J=8.7Hz,2H)、7.71(s,1H)
实施例11
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对异丙氧苯基硫嘌呤(化合物No.26)的制造
用对异丙基碘化物代替实施例8中的乙基碘化物,其它相同,得到标题化合物。
UV:λmax=230,330(0.01N-HCl/CH3OH)
λmax=223,314(0.01N-NaOH/CH3OH)
1H-NMR(CDCl3,δ):1.37(d,J=6.0Hz,6H)、3.85-3.98(m,4H)、4.18-4.48(m,6H)、4.60(septet,J=6.0Hz,1H)、4.77(s,2H)、6.93(d,J=8.7Hz、2H)、7.51(d,J=8.7Hz,2H)、7.71(s,1H)
实施例12
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对异丙氧苯基硫嘌呤(化合物No.32)的制造
用对异丙基碘化物代替实施例8中的乙基碘化物,其它相同,得到标题化合物。
UV:λmax=230,331(0.01N-HCl/CH3OH)
λmax=223,314(0.01N-NaOH/CH3OH)
1H-NMR(CDCl3,δ):1.05(d,J=6.8Hz,6H)、2.13(表观五重峰),J=6.5Hz,1H)、3.76(d,J=6.5Hz,2H)、3.83-3.97(m,4H)、4.20-4.45(m,6H)、4.77(s,2H)、6.94(d,J=8.9Hz,2H)、7.52(d,J=8.9Hz,2H)、7.71(s,1H)
实施例13
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对三氟甲氧苯基硫嘌呤(化合物No.35)的制造
将3.1g锌粉添加到1.36ml对三氟甲氧苯磺酰氯化物、3.4ml浓硫酸、20ml水的悬浮液中,0℃下搅拌18小时,回流6小时后,加入醋酸乙酯,用水,饱和碳酸氢钠水、饱和食盐水洗涤后,减压浓缩,得到0.73g(47%)对三氟甲氧苯硫醇
用对三氟甲氧苯硫醇代替实施例1中的硫酚,其它相同,得到标题化合物。
m.p.:128-130℃(氯仿)
1H-NMR(CDCl3,δ):3.86-3.98(m,4H)、4.22-4.48(m,6H)、4.78(s,2H)、7.27(d,J=8.7Hz,2H)、7.66(d,J=8.7Hz),2H)、7.73(s1H)
实施例14
2-氨基-9-[2-[(2,2,2-三氟乙基膦酸甲氧基)膦酸甲氧基]乙基]-6-苯基硫嘌呤(化合物No.211)的制造
将82μl 1N氢氧化钠水溶液加入到0.3ml 45mg 2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-苯基硫嘌呤的四氢呋喃溶液中,搅拌30分钟后,冷冻干燥,得到37mg(93%)2-氨基-9-[2-[二(2,2,2-三氟乙基]乙基]-6-苯基硫嘌呤
UV:λmax=325(0.01N-HCl/CH3OH)
λmax=244,316(0.01N-NaOH/CH3OH)
1H-NMR(D2O,δ):3.63(d,J=8.8Hz,2H)、3.81-4.04(m,4H)、4.23-4.34(m,2H)、7.40-7.66(m,5H)、8.01(s,1H)
实施例15
2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基-6-对甲氧苯基硫嘌呤(化合物No.214)的制造
用2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对甲氧苯基硫嘌呤代替实施例1 4中的2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-苯基硫嘌呤,其它相同,得到标题化合物。
UV:λmax=230,328(0.01N-HCl/CH3OH)
λmax=223,314(0.01N-NaOH/CH3OH)
1H-NMR(D2O,δ):3.69(d,J=8.8Hz,2H)、3.82-4.06(m,包围S在3.87,7H)、7.51(d,J=8.7Hz,2H),8.04(s,1H)
实施例16
2-氨基-9-[2-[膦酸甲氧基]乙基]-6-苯基硫嘌呤(化合物No.281)的制造
用三乙基磷化物代替实施例1中的三(2,2,2-三氟乙基)磷化物,其它相同,得到2-氨基-9-[2-[三乙基膦酸甲氧基]乙基]-6-苯基硫嘌呤。
将2.6ml溴三甲基硅烷添加到20ml 1.75g 2-氨基-9-[2-[二乙基膦酸甲氧基]乙基]-6-苯基硫嘌呤的乙腈溶液中,25℃下,搅拌22小时后,添加水,浓缩干固,利用丙酮/甲醇进行结晶,得到406mg(27%)2-氨基-9-[2-[膦酸甲氧基]乙基]-6-苯基硫嘌呤。
m.p.:163°-168°(dec,丙酮/甲醇)
1H-NMR(DMSO-d6,δ):3.58(d,J=8.7Hz,2H)、3.81(t,J=5.1Hz,2H),4.19(t,J=5.1Hz,2H)、7.40-7.50(m,3H)、7.55-7.66(m,2H)、8.02(s,1H)
实施例17
2-氨基-9-[2-膦酸甲氧乙基]-6-对甲氧苯基硫嘌呤(化合物No.284)的制造
用对甲氧基硫酚代替实施例16中的硫酚,其它相同,得到标题化合物。
UV:λmax=230,328(0.01N-HCl/CH3OH)
λmax=223,314(0.01N-NaOH/CH3OH)
1H-NMR(DMSO-d6,δ):3.58(d,J=8.6Hz,2H)、3.78-3.92(m包围s在3.79,5H)、4.18-4.30(m,2H)、7.02(d,J=8.7Hz,2H)、7.51(d,J=8.7Hz,2H)、8.14(s,1H)
实施例18
盐酸2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对甲氧苯基硫嘌呤的制造
将2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对甲氧苯基硫嘌呤的醋酸乙酯溶液滴加到氯化氢醋酸乙酯溶液中,搅拌30分钟后,减压下干燥析出的结晶,得到盐酸2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对甲氧苯基硫嘌呤。
m.p.:110°-115°(dec,醋酸乙酯)
1H-NMR(DMSO-d6,δ):3.79(s,3H)、3.87(t,J=4.8Hz,2H)、4.13(d,J=7.9Hz,2H)、4.23(t,J=4.8Hz,2H)、4.55-4.75(m,4H)、7.02(d,J=8.7Hz,2H)、7.49(d,J=8.7Hz,2H)、8.13(s,1H)
实施例19
盐酸2-氨基-9-[2-(二(2,2,2-三氟乙基)膦酸甲氧基]基-6-间甲氧苯基硫嘌呤的制造
将2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间甲氧苯基硫嘌呤的醋酸乙酯溶液滴加到氯化氢醋酸乙酯溶液中,搅拌30分钟后,减压干燥析出的结晶,得到盐酸2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对甲氧苯基硫嘌呤。
m.p.:130°-135°(dec,醋酸乙酯)
1H-NMR(DMSO-d6,δ):3.77(s,3H)、3.84-3.96(m,2H)、4.14(d,J=8.0Hz,2H)、4.20-4.36(m,2H)、4.56-4.76(m,4H)、6.99-7.09(m,1H)、7.12-7.24(m,2H)、7.36(dd,J=7.8Hz和8.3Hz,1H)、8.28(s,1H)
实施例20
盐酸2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻甲氧苯基硫嘌呤的制造
将2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻甲氧苯基硫嘌呤的醋酸乙酯溶液滴加到氯化氢醋酸乙酯溶液中,搅拌30分钟后,减压干燥析出的结晶,得到盐酸2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻甲氧苯基硫嘌呤。
m.p.:101°-106°(dec.醋酸乙酯)
1H-NMR(DMSO-d6,δ):3.74(s,3H)、3.84-3.98(m,2H)、4.14(d,J=7.9Hz,2H)、4.20-4.34(m,2H)、4.56-4.76(m,4H)、7.01(dd,J=7.5Hz,1H)、7.14(d,J=8.4Hz,1H)、7.42-7.60(m,2H)、8.27(s,1H)
实施例21
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-苯基硫嘌呤(化合物No.351)的制造
将25ml 1-氯-2-丙醇和11g多聚甲醛悬浮于50ml二氯甲烷中,冷却到0℃,一边通入盐酸气体,一边搅拌10小时。蒸馏除去二氯甲烷,在残留物中加入86.5g三(2,2,2-三氟乙基)磷化物,于160℃下加热5小时。将反应混合物进行减压蒸馏,得到2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基氯化物。
将15.0g(88mmol)2-氨基-6-氯嘌呤悬浮于360ml二甲基甲酰胺中,和13.9ml(93mmol)1,8-二氮杂环[5.4.0]十一碳烯-7-烯烃,于80℃下反应1小时。接着向上述反应液中加入36.1g 2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基氯化物,于100℃下,反应2小时。反应后冷却到室温,浓缩,向残渣中加入水,用醋酸乙酯进行萃取。用硫酸镁干燥有机层后,浓缩,将得到的浆液溶于醚中,除去不溶物,得到6g 2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-氯嘌呤。
向25ml 3g 2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-氯嘌呤的二甲基甲酰胺溶液中,添加1.1ml三乙基胺和1.53ml硫酚,于100℃下搅拌2小时。将反应混合物冷却到室温,浓缩。向残渣中加入碳酸氢钠水,用醋酸乙酯萃取,浓缩有机层。用氯仿溶解残渣,用硅胶柱子吸附,再用2%-甲醇-氯仿洗脱,得到0.77g(收率22%)2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-苯基硫嘌呤。
m.p.:119-120℃(二异丙醚)
1H-NMR(CDCl3,δ):1.25(d,J=5.9Hz,3H)、3.76-4.23(m,5H)、4.28-4.42(m,4H)、4.77(s,2H)、7.40-7.43(m,3H)、7.62-7.65(m,2H)、7.72(s,1H)
实施例22
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦甲氧基]丙基]-6-对甲氧苯基硫嘌呤(化合物No.354)的制造
用对甲氧基硫酚代替实施例21中的硫酚,其它和实施例21相同,得标题化合物。
m.p.:118-119℃(二异丙醚)
1H-NMR(CDCl3,δ):1.24(d,J=5.9Hz,3H)、3.81-4.02(m,5H)、3.85(s,3H)、4.31-4.40(m,4H)、4.75(s,2H)、6.95(d,J=8.7Hz,2H)、7.53(d,J=8.7Hz,2H)、7.71(s,1H)
试验例1
Hepatitis B Virus(HBV)增殖抑制效果
按照公知方法(K.UEDA,等人,VIROL OGY,169,213-216(1989))测定本发明化合物的HBV增殖抑制效果。将2×104个HB611细胞(生产的HBV组换成人肝癌细胞),在含有10%。牛胎儿血清、链霉素(100μg/ml)、青霉素(100IU/ml)和ジエネティシン(商标名、ラィフテクノロジ-ズ社制抗生物质)(0.2mg/ml)的ダルベッュME培养基中,于37℃下培养。在培养第2日和第5日交换培养基后,在培养8日、11日和14日后,将被验化合物置换在含最终浓度0.005-100μM的培养基中,在培养17日后,回收细胞DNA。用サザンブロット测定细胞内HBV-DNA的量,求出细胞内的HBV-DNA合成50%阻碍浓度。求出灭死50%HB611细胞所需要的化合物浓度。结果示于表2中。表中的化合物号对应于表1中的化合物号。另外,为了参考,将公知化合物PMEA的二特戊酰羟甲基酯(参考例1)和,EP 632048号公报中记载的9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-2-氨基-6-对甲苯酰基硫嘌呤(参考例2)进行同样试验,结果也一同记于表2中。
表2被验化合物 HBV-DNA 对HB611细胞
50%合成阻碍浓度(μM) 50%细胞毒性浓度(μM)No.1 0.01 >1,0002 0.08 >1,0003 0.04 >1,0004 0.05 >1,000参考例1a 18.8 11参考例2b 0.06 108a PMEA的二特戊酰氧甲基酯b 9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-2-氨基-6-对甲苯酰基硫嘌呤
试验例2:
经口服用老鼠血清的HBV增殖抑制效果
在一组3个老鼠群中,经口服用被验化合物,一次服用量为1g/kg或0.3g/kg,服用30分钟后,采取血样,调制血清,将2×104个HB611细胞,在10%牛胎儿血清、链霉素(100μg/ml)、青霉素(100IU/ml)和ジエネティジン(0.2mg/ml)的ダルバッコME培养基中,于37℃下,培养。在培养第2日和第5日交换培养基后,在培养8日、11日和14日后,将上述血清(经口服用后检体的大白鼠血清)置换含5%的培养基中,培养17日后,回收细胞DNA。用杀展布勒特测定细胞内HBV-DNA的量,求出细胞内的HBV-DNA合成阻碍率。为参考,对PMEA也进行同样试验,结果示于表3。
表3被验化合物 口服量 HBV-DNA
(g/kg) 合成阻碍率(%)No.1 0.3 60.74 0.3 95.2PMEA 1.0 35.5
本发明的膦酸酯核苷酸化合物具有优良的抗病毒活性,同时由于具有很高的口服吸收性和对生物体很高的安全性,所以可用作药物的有效成分。
Claims (19)
2、根据权利要求1记载的膦酸酯核苷酸化合物或它的盐,或它们的水合物或溶剂化物,其中R1为氢原子或C1-C6的烷氧基。
3、根据权利要求1记载的膦酸酯核苷酸化合物或它的盐,或它们的水合物或溶剂化物,其中R1为氢原子或C1-C4的烷氧基;R2和R3分别为氢原子,C1-C22烷基,或由1个以上的卤原子取代的乙基。
4、根据权利要求1记载的膦酸酯核苷酸化合物或它的盐,或它们的水合物或溶剂化物,其中R1为氢原子或C1-C4的烷氧基;R2和R3分别为氢原子,C1-C22的烷基,或2,2,2-三氟乙基;R4为氢原子或甲基。
5、根据权利要求1记载的膦酸酯核苷酸化合物或它的盐,或它们的水合物或溶剂化物,其中R1为氢原子或C1-C4的烷氧基;R2和R3分别为氢原子或2,2,2-三氟乙基;R4为氢原子或甲基。
6、根据权利要求5记载的膦酸酯核苷酸化合物或它的盐,或它们的水合物或溶剂化物,其中所述的化合物选自
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-苯基硫嘌呤;
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对甲氧苯基硫嘌呤;
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间甲氧苯基硫嘌呤;
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻甲氧苯基硫嘌呤;
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基-6-对乙氧苯基硫嘌呤;
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-苯基硫嘌呤;
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对甲氧苯基硫嘌呤;
2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基1-6-苯基硫嘌呤;
2-氨基-9-[ 2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对甲氧苯基硫嘌呤;
2-氨基-9-[2-[膦酸甲氧基]乙基]-6-苯基硫嘌呤;
2-氨基-9-[2-[膦酸甲氧基]乙基]-6-对甲氧苯基硫嘌呤;
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对丁氧苯基硫嘌呤;
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对丙氧苯基硫嘌呤;
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对异丙苯基硫嘌呤;和
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对异丁苯基硫嘌呤。
7、根据权利要求1记载的膦酸酯核苷酸化合物或它的盐,或它们的水合物或溶剂化物,其中的R1为氢原子或C1-C4的烷氧基;R2和R3为2,2,2-三氟乙基;R4是氢原子或甲基。
8、根据权利要求7记载的膦酸酯核苷酸化合物或它的盐,或它们的水合物或溶剂化物,其中所述的化合物选自
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-苯基硫嘌呤;
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对甲氧苯基硫嘌呤;
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间甲氧苯基硫嘌呤;
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻甲氧苯基硫嘌呤;
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对乙氧苯基硫嘌呤;
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-苯基硫嘌呤;
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对甲氧苯基硫嘌呤;
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对丁氧苯基硫嘌呤;
2-氨基-9-[ 2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对丙氧苯基硫嘌呤;
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对异丙氧苯基硫嘌呤;
2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]丙基]-6-对异丁氧苯基硫嘌呤。
9、根据权利要求1记载的膦酸酯核苷酸化合物或它的盐,或它们的水合物或溶剂化物,其中的R1为氢原子或C1-C4的烷氧基;R2和R3是2,2,2-三氟乙基;R4是氢原子。
10、根据权利要求9记载的膦酸酯核苷酸化合物或它的盐,或它们的水合物或溶剂物,其中所述的化合物选自
2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-苯基硫嘌呤;
2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对甲氧苯基硫嘌呤;
2-氨基-9-[ 2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间甲氧苯基硫嘌呤;
2-氨基-9-[ 2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻甲氧苯基硫嘌呤;
2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对乙氧苯基硫嘌呤;
2-氨基-9-[ 2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对丁氧苯基硫嘌呤;
2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对丙氧苯基硫嘌呤;
2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对异丙氧苯基硫嘌呤;和
2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对异丁氧苯基硫嘌呤。
11、根据权利要求1记载膦酸酯核苷酸化合物或它的盐,或它们的水合物或溶剂化物,其中的R1为氢原子或C1-C2的烷氧基;R2和R3为2,2,2-三氟乙基;R4为氢原子。
12、根据权利要求11记载的膦酸酯核苷酸化合物或它的盐,或它们的水合物或溶剂化物,其中所述的化合物是2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-苯基硫嘌呤。
13、根据权利要求11记载的膦酸酯核苷酸化合物或它的盐,或它们的水合物或溶剂化物,其中所述的化合物是2-氨基-9-[2-[二(2,2,2-三氟乙基)膦酸甲氧基]乙基-6-对甲氧苯基硫嘌呤。
14.根据权利要求11记载的膦酸酯核苷酸化合物或它的盐,或它们的水合物或溶剂化物,其中所述的化合物是2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-间甲氧苯基硫嘌呤。
15、根据权利要求11记载的膦酸酯核苷酸化合物或它的盐,或它们的水合物或溶剂化物,其中所述的化合物是2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-邻甲氧苯基硫嘌呤。
16、根据权利要求11记载的膦酸酯核苷酸化合物或它的盐,或它们的水合物或溶剂化物,其中所述的化合物是2-氨基-9-[2-[(2,2,2-三氟乙基)膦酸甲氧基]乙基]-6-对乙氧苯基硫嘌呤。
17、一种药物组合物,它包括从权利要求1-16中任一项中记载的化合物和它的盐,以及它们的水合物和溶剂化物组成的组中选出的物质和药学上容许的制剂添加物。
18、一种抗病毒剂,它包括作为有效成分的从权利要求1-16中任一项记载的化合物和它的盐,以及它们的水合物和溶剂化物组成的组中选出的物质。
19、根据权利要求18中记载的抗病毒剂,其中病毒是乙型肝炎病毒。
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EP0632048B1 (en) * | 1993-06-29 | 2001-03-21 | Mitsubishi Chemical Corporation | Phosphonate-nucleotide ester derivatives |
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1997
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US5840716A (en) | 1998-11-24 |
DE69704286D1 (de) | 2001-04-26 |
KR970059181A (ko) | 1997-08-12 |
EP0785208A1 (en) | 1997-07-23 |
DK0785208T3 (da) | 2001-04-23 |
CN1088712C (zh) | 2002-08-07 |
CA2195262C (en) | 2005-08-09 |
GR3035776T3 (en) | 2001-07-31 |
KR100366727B1 (ko) | 2003-03-15 |
EP0785208B1 (en) | 2001-03-21 |
ES2155219T3 (es) | 2001-05-01 |
TW369536B (en) | 1999-09-11 |
PT785208E (pt) | 2001-06-29 |
ATE199907T1 (de) | 2001-04-15 |
CA2195262A1 (en) | 1997-07-19 |
DE69704286T2 (de) | 2001-10-25 |
CN1164534A (zh) | 1997-11-12 |
CN1216060C (zh) | 2005-08-24 |
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