JP3148139B2 - Phosphonate nucleotide compounds - Google Patents
Phosphonate nucleotide compoundsInfo
- Publication number
- JP3148139B2 JP3148139B2 JP00557097A JP557097A JP3148139B2 JP 3148139 B2 JP3148139 B2 JP 3148139B2 JP 00557097 A JP00557097 A JP 00557097A JP 557097 A JP557097 A JP 557097A JP 3148139 B2 JP3148139 B2 JP 3148139B2
- Authority
- JP
- Japan
- Prior art keywords
- amino
- trifluoroethyl
- phosphonylmethoxy
- ethyl
- bis
- 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.)
- Expired - Fee Related
Links
- -1 Phosphonate nucleotide compounds Chemical class 0.000 title claims description 73
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 205
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 183
- 150000001875 compounds Chemical class 0.000 claims description 158
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 67
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 46
- 150000003839 salts Chemical class 0.000 claims description 34
- 125000005843 halogen group Chemical group 0.000 claims description 30
- 239000012453 solvate Substances 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 241000700721 Hepatitis B virus Species 0.000 claims description 10
- 125000005042 acyloxymethyl group Chemical group 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 8
- 239000003443 antiviral agent Substances 0.000 claims description 7
- 150000004677 hydrates Chemical class 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 5
- 241000700605 Viruses Species 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 230000000996 additive effect Effects 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- BSZWYNBCSAYJFI-UHFFFAOYSA-N C(C(C)C)OC1=NC2=NC(=NC=C2N1)SC1=CC=CC=C1 Chemical compound C(C(C)C)OC1=NC2=NC(=NC=C2N1)SC1=CC=CC=C1 BSZWYNBCSAYJFI-UHFFFAOYSA-N 0.000 claims 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 147
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
- 235000002639 sodium chloride Nutrition 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 7
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 7
- 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
- 230000002829 reductive effect Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 5
- 230000000840 anti-viral effect Effects 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 241000725303 Human immunodeficiency virus Species 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 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 4
- 150000002148 esters Chemical class 0.000 description 4
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 238000007911 parenteral administration Methods 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WADSJYLPJPTMLN-UHFFFAOYSA-N 3-(cycloundecen-1-yl)-1,2-diazacycloundec-2-ene Chemical compound C1CCCCCCCCC=C1C1=NNCCCCCCCC1 WADSJYLPJPTMLN-UHFFFAOYSA-N 0.000 description 3
- UOVCFJQNDWAJEY-UHFFFAOYSA-N C(CC)OC1=NC2=NC(=NC=C2N1)SC1=CC=CC=C1 Chemical compound C(CC)OC1=NC2=NC(=NC=C2N1)SC1=CC=CC=C1 UOVCFJQNDWAJEY-UHFFFAOYSA-N 0.000 description 3
- XNFFINJEDVMDKN-UHFFFAOYSA-N COC1=NC2=NC(=NC=C2N1)SC1=CC=CC=C1 Chemical compound COC1=NC2=NC(=NC=C2N1)SC1=CC=CC=C1 XNFFINJEDVMDKN-UHFFFAOYSA-N 0.000 description 3
- 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 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 230000009422 growth inhibiting effect Effects 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 3
- 229910000105 potassium hydride Inorganic materials 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- JHVNSRJPBXPZJU-UHFFFAOYSA-N 4-(trifluoromethoxy)benzenethiol Chemical compound FC(F)(F)OC1=CC=C(S)C=C1 JHVNSRJPBXPZJU-UHFFFAOYSA-N 0.000 description 2
- XGKGITBBMXTKTE-UHFFFAOYSA-N 4-[(4-hydroxyphenyl)disulfanyl]phenol Chemical compound C1=CC(O)=CC=C1SSC1=CC=C(O)C=C1 XGKGITBBMXTKTE-UHFFFAOYSA-N 0.000 description 2
- OXWOIUVGAWIZQQ-UHFFFAOYSA-N 4-ethoxybenzenethiol Chemical compound CCOC1=CC=C(S)C=C1 OXWOIUVGAWIZQQ-UHFFFAOYSA-N 0.000 description 2
- NIFAOMSJMGEFTQ-UHFFFAOYSA-N 4-methoxybenzenethiol Chemical compound COC1=CC=C(S)C=C1 NIFAOMSJMGEFTQ-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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000002105 Southern blotting Methods 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000002798 bone marrow cell Anatomy 0.000 description 2
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000010261 cell growth Effects 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
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 229960003750 ethyl chloride Drugs 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 231100000299 mutagenicity Toxicity 0.000 description 2
- 230000007886 mutagenicity Effects 0.000 description 2
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 238000004810 partition chromatography Methods 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- CHEANNSDVJOIBS-MHZLTWQESA-N (3s)-3-cyclopropyl-3-[3-[[3-(5,5-dimethylcyclopenten-1-yl)-4-(2-fluoro-5-methoxyphenyl)phenyl]methoxy]phenyl]propanoic acid Chemical compound COC1=CC=C(F)C(C=2C(=CC(COC=3C=C(C=CC=3)[C@@H](CC(O)=O)C3CC3)=CC=2)C=2C(CCC=2)(C)C)=C1 CHEANNSDVJOIBS-MHZLTWQESA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
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- 239000011707 mineral Chemical class 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003935 n-pentoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 125000001196 nonadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 125000005499 phosphonyl group Chemical group 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 102220240796 rs553605556 Human genes 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- PPLMQFARLJLZAO-UHFFFAOYSA-N triethyl(iodo)silane Chemical compound CC[Si](I)(CC)CC PPLMQFARLJLZAO-UHFFFAOYSA-N 0.000 description 1
- 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000004377 trifluoropropoxy group Chemical group FC(CCO*)(F)F 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- CBIQXUBDNNXYJM-UHFFFAOYSA-N tris(2,2,2-trifluoroethyl) phosphite Chemical compound FC(F)(F)COP(OCC(F)(F)F)OCC(F)(F)F CBIQXUBDNNXYJM-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
【０００１】[0001]
【発明の属する技術分野】本発明は新規なホスホナート
ヌクレオチド化合物に関するものである。より具体的に
は、抗ウイルス活性を有し、医薬品として有用な新規ホ
スホナートヌクレオチド化合物及びその塩、並びにそれ
らの水和物及び溶媒和物に関する。[0001] The present invention relates to a novel phosphonate nucleotide compound. More specifically, the present invention relates to novel phosphonate nucleotide compounds having antiviral activity and useful as pharmaceuticals, salts thereof, and hydrates and solvates thereof.
【０００２】[0002]
【従来の技術】感染性のウイルス疾患は医学上重要な問
題として認識されており、このような疾患を治療する目
的で、抗ウイルス活性を有し、同時に正常細胞系に対し
ては増殖阻害活性を持たない薬剤の開発が検討されてい
る。例えばホスホナートヌクレオチド類は、選択的抗ウ
イルス剤として現在盛んに研究が進められている。具体
的には、９−（２−ホスホニルメトキシ）エチルアデニ
ン（ＰＭＥＡ）、９−（２−ホスホニルメトキシ）エチ
ル−２，６−ジアミノプリン（ＰＭＤＡＰ）等は、単純
ヘルペス１型及び２型（ＨＳＶ−１及びＨＳＶ−２）、
ヒト免疫不全ウイルス（ＨＩＶ）、ヒトＢ型肝炎ウイル
ス（ＨＢＶ）に対して有効であることが報告されている
（横田他，Ａｎｔｉｍｉｃｒｏｂ．Ａｇｅｎｔｓ Ｃｈ
ｅｍｏｔｈｅｒ．，３５，３９４（１９９１）；Ｖｏｔ
ｒｕｂａ ｅｔ ａｌ．，Ｍｏｌ．Ｐｈａｒｍａｃｏ
ｌ．，３２，５２４（１９８７））。2. Description of the Related Art Infectious viral diseases are recognized as a medically important problem. For the treatment of such diseases, they have antiviral activity and, at the same time, have antiproliferative activity against normal cell lines. The development of a drug that does not have is considered. For example, phosphonate nucleotides are currently being actively studied as selective antiviral agents. Specifically, 9- (2-phosphonylmethoxy) ethyladenine (PMEA), 9- (2-phosphonylmethoxy) ethyl-2,6-diaminopurine (PMDAP), etc. are herpes simplex types 1 and 2. (HSV-1 and HSV-2),
It has been reported that it is effective against human immunodeficiency virus (HIV) and human hepatitis B virus (HBV) (Yokota et al., Antimicrob. Agents Ch.
emother. , 35, 394 (1991); Vot.
ruba et al. , Mol. Pharmaco
l. , 32, 524 (1987)).
【０００３】しかし、これらの既知ホスホナートヌクレ
オチド類は、骨髄細胞成長抑制に代表される生体に対す
る毒性及び変異原性を示す可能性があるなど、安全性に
問題がある（Ａｎｔｉｖｉｒａｌ Ｒｅｓｅａｒｃｈ，
１６，７７（１９９１））。また、これらの化合物は経
口吸収性を有していないので（Ｄｅ Ｃｌｅｒｃｑｅｔ
ａｌ．，Ａｎｔｉｍｉｃｒｏｂ．Ａｇｅｎｔｓ Ｃｈ
ｅｍｏｔｈｅｒ．，３３，１８５（１９８９））、効果
を発揮するのに必要な血中濃度を得るためには、投与方
法が静注、筋注等の非経口的投与に限定されるという問
題がある。非経口投与による治療は入院患者以外には困
難であり、長期治療が必要なＡＩＤＳやＢ型肝炎ウイル
ス疾患等の治療には好ましい方法ではなかった。一方、
本発明者らは先にホスホナートヌクレオチドの特定のエ
ステル誘導体が高い経口吸収性を示すことを見い出して
いるが（ＥＰ６３２０４８号公報）、未だに実用化され
ていないのが現状である。[0003] However, these known phosphonate nucleotides have safety problems such as the possibility of exhibiting toxicity and mutagenicity to living organisms represented by the inhibition of bone marrow cell growth (Antiviral Research,
16, 77 (1991)). In addition, since these compounds do not have oral absorbability (De Clercqet
al. , Antimicrob. Agents Ch
emother. , 33, 185 (1989)), there is a problem that the method of administration is limited to parenteral administration such as intravenous injection, intramuscular injection and the like in order to obtain the blood concentration necessary for exerting the effect. Treatment by parenteral administration is difficult except for inpatients, and is not a preferred method for treating AIDS or hepatitis B virus disease that requires long-term treatment. on the other hand,
The present inventors have previously found that a specific ester derivative of a phosphonate nucleotide exhibits high oral absorbability (EP6322048), but at present it has not been put to practical use yet.
【０００４】[0004]
【発明が解決しようとする課題】本発明の課題は、骨髄
細胞成長抑制や変異原性などの毒性のない抗ウイルス剤
を提供することにある。また、本発明の別の課題は、経
口吸収性に優れた抗ウイルス剤を提供することにある。SUMMARY OF THE INVENTION An object of the present invention is to provide an antiviral agent having no toxicity such as inhibition of bone marrow cell growth and mutagenicity. Another object of the present invention is to provide an antiviral agent having excellent oral absorbability.
【０００５】[0005]
【課題を解決するための手段】本発明者らは上記問題を
解決するべく鋭意検討を重ねてきた結果、前記ＥＰ６３
２０４８号公報には具体的に開示されていない特定の２
−アミノ−６−アリールチオプリンホスホナートが高い
抗ウイルス活性を有しており、かつ、これらの化合物が
従来提案されている化合物に比べて生体に対する安全性
が高く、高い経口吸収性を有することを見い出し、本発
明を完成するに至った。The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, the above-mentioned EP 63
JP-A-2048 discloses a specific 2 which is not specifically disclosed.
-Amino-6-arylthiopurine phosphonate has high antiviral activity, and these compounds have higher safety to the living body and higher oral absorbability than conventionally proposed compounds. And completed the present invention.
【０００６】すなわち本発明は、下記一般式（Ｉ）：That is, the present invention provides the following general formula (I):
【化２】 （式中、Ｒ1 は水素原子、Ｃ1 〜Ｃ6 のアルコキシ基、
１以上のハロゲン原子で置換されたＣ1 〜Ｃ4 のアルコ
キシ基、ハロゲン原子、アミノ基、又はニトロ基を表
し；Ｒ2 及びＲ3 はそれぞれ独立に水素原子、Ｃ1 〜Ｃ
22のアルキル基、アシルオキシメチル基、アシルチオエ
チル基、又は１以上のハロゲン原子で置換されたエチル
基を表し；Ｒ4 は水素原子、Ｃ1 〜Ｃ4 のアルキル基、
Ｃ1 〜Ｃ4 のヒドロキシアルキル基、又は１以上のハロ
ゲン原子で置換されたＣ1 〜Ｃ4 のアルキル基を表し；
ＸはＣＨ又は窒素原子を表す。）で表されるホスホナー
トヌクレオチド化合物若しくはその塩、又はそれらの水
和物若しくは溶媒和物を提供するものである。Embedded image (Wherein, R 1 is a hydrogen atom, a C 1 -C 6 alkoxy group,
Represents a C 1 -C 4 alkoxy group, a halogen atom, an amino group, or a nitro group substituted with one or more halogen atoms; R 2 and R 3 each independently represent a hydrogen atom, C 1 -C
22 represents an alkyl group, an acyloxymethyl group, an acylthioethyl group, or an ethyl group substituted with one or more halogen atoms; R 4 represents a hydrogen atom, a C 1 -C 4 alkyl group,
A C 1 -C 4 hydroxyalkyl group, or a C 1 -C 4 alkyl group substituted with one or more halogen atoms;
X represents CH or a nitrogen atom. ), A salt thereof, or a hydrate or solvate thereof.
【０００７】また、本発明の別の態様により、上記化合
物及びその塩、並びにそれらの水和物及び溶媒和物から
なる群から選ばれる物質と薬学的に許容され得る製剤用
添加物とを含む医薬組成物；上記化合物及びその塩、並
びにそれらの水和物及び溶媒和物からなる群から選ばれ
る物質を有効成分として含む抗ウイルス剤が提供され
る。さらに本発明の別の態様により、上記医薬組成物の
製造のための上記化合物及びその塩、並びにそれらの水
和物及び溶媒和物からなる群から選ばれる物質の使用；
並びに、ウイルス感染症の治療方法であって、上記化合
物及びその塩、並びにそれらの水和物及び溶媒和物から
なる群から選ばれる物質の有効量をヒトを含む哺乳類動
物に投与する工程を含む方法が提供される。According to another aspect of the present invention, there is provided a compound selected from the group consisting of the above compounds and salts thereof, and hydrates and solvates thereof, and a pharmaceutically acceptable additive for a pharmaceutical preparation. A pharmaceutical composition; an antiviral agent comprising, as an active ingredient, a substance selected from the group consisting of the above compounds and salts thereof, and hydrates and solvates thereof. According to yet another aspect of the present invention, use of a substance selected from the group consisting of the above compound and a salt thereof, and a hydrate and a solvate thereof for the manufacture of the above pharmaceutical composition;
And a method for treating a viral infection, comprising the step of administering to a mammal including humans an effective amount of a substance selected from the group consisting of the above compounds and salts thereof, and hydrates and solvates thereof. A method is provided.
【０００８】[0008]
【発明の実施の形態】上記一般式（Ｉ）のホスホナート
ヌクレオチド化合物において、Ｒ1 で表されるＣ1 〜Ｃ
6 のアルコキシ基としては、メトキシ基、エトキシ基、
ｎ−プロポキシ基、イソプロポキシ基、ｎ−ブトキシ
基、イソブトキシ基、ｓｅｃ−ブトキシ基、ｔｅｒｔ−
ブトキシ基、ｎ−ペンチルオキシ基、ｎ−ヘキシルオキ
シ基等が挙げられる。また、Ｒ1 で表わされる１以上の
ハロゲン原子で置換されたＣ1 〜Ｃ4 のアルコキシ基と
しては、モノフルオロメトキシ基、ジフルオロメトキシ
基、トリフルオロメトキシ基、モノフルオロエトキシ
基、ジフルオロエトキシ基、トリフルオロエトキシ基、
テトラフルオロエトキシ基、ペンタフルオロエトキシ
基、モノフルオロプロポキシ基、ジフルオロプロポキシ
基、トリフルオロプロポキシ基、テトラフルオロプロポ
キシ基、ペンタフルオロプロポキシ基、ヘキサフルオロ
プロポキシ基、ヘプタフルオロプロポキシ基、モノフル
オロイソプロポキシ基、ジフルオロイソプロポキシ基、
トリフルオロイソプロポキシ基、テトラフルオロイソプ
ロポキシ基、ペンタフルオロイソプロポキシ基、ヘキサ
フルオロイソプロポキシ基、ヘプタフルオロイソプロポ
キシ基等が挙げられる。BEST MODE FOR CARRYING OUT THE INVENTION In the above phosphonate nucleotide compound of the general formula (I), C 1 to C 1 represented by R 1
As the alkoxy group of 6 , methoxy group, ethoxy group,
n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-
Butoxy group, n-pentyloxy group, n-hexyloxy group and the like. Examples of the C 1 -C 4 alkoxy group substituted with one or more halogen atoms represented by R 1 include a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a monofluoroethoxy group, a difluoroethoxy group, Trifluoroethoxy group,
Tetrafluoroethoxy group, pentafluoroethoxy group, monofluoropropoxy group, difluoropropoxy group, trifluoropropoxy group, tetrafluoropropoxy group, pentafluoropropoxy group, hexafluoropropoxy group, heptafluoropropoxy group, monofluoroisopropoxy group, Difluoroisopropoxy group,
Examples include a trifluoroisopropoxy group, a tetrafluoroisopropoxy group, a pentafluoroisopropoxy group, a hexafluoroisopropoxy group, and a heptafluoroisopropoxy group.
【０００９】Ｒ2 及びＲ3 で表されるＣ1 〜Ｃ22のアル
キル基としては、メチル基、エチル基、ｎ−プロピル
基、イソプロピル基、ｎ−ブチル基、イソブチル基、ｓ
ｅｃ−ブチル基、ｔｅｒｔ−ブチル基、ペンチル基、ヘ
キシル基、ヘプチル基、オクチル基、ノニル基、デシル
基、ウンデシル基、ドデシル基、トリデシル基、テトラ
デシル基、ペンタデシル基、ヘキサデシル基、ヘプタデ
シル基、オクタデシル基、ノナデシル基、イコシル基、
ヘンイコシル基、ドコシル基等が挙げられる。Ｒ2 及び
Ｒ3 で表されるアシルオキシメチル基としては、アセチ
ルオキシメチル基、フロピオニルオキシメチル基、ブチ
リルオキシメチル基、イソブチリルオキシメチル基、バ
レリルオキシメチル基、イソバレリルオキシメチル基、
ピバロイルオキシメチル基等が挙げられる。The C 1 -C 22 alkyl groups represented by R 2 and R 3 include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and s.
ec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl Group, nonadecyl group, icosyl group,
A henycosyl group, a docosyl group and the like. The acyloxymethyl groups represented by R 2 and R 3 include acetyloxymethyl, flopionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, and isovaleryloxy. Methyl group,
And pivaloyloxymethyl group.
【００１０】Ｒ2 及びＲ3 で表されるアシルチオエチル
基としては、アセチルチオエチル基、プロピオニルチオ
エチル基、ブチリルチオエチル基、イソブチリルチオエ
チル基、バレリルチオエチル基、イソバレリルチオエチ
ル基、ピバロイルチオエチル基等が挙げられる。Ｒ2 及
びＲ3 で表される１以上のハロゲン原子で置換されたエ
チル基において、ハロゲン原子の種類はフッ素原子、塩
素原子、臭素原子、又はヨウ素原子のいずれでもよい。
１以上のハロゲン原子で置換されたエチル基としては、
１−フルオロエチル基、２−フルオロエチル基、１−ク
ロロエチル基、２−クロロエチル基、２−ブロモエチル
基、２，２−ジフルオロエチル基、２，２−ジクロロエ
チル基、２，２−ジブロモエチル基、２，２，２−トリ
フルオロエチル基、２，２，２−トリクロロエチル基、
２，２，２−トリブロモエチル基等が挙げられる。特に
エチル基の２位が置換されていることが好ましく、ハロ
ゲン原子としてはフッ素原子が好ましい。Ｒ2 及びＲ3
の少くとも一方は、１以上のハロゲン原子で置換された
エチル基、特に２，２，２−トリフルオロエチル基であ
ることが好ましい。The acylthioethyl groups represented by R 2 and R 3 include an acetylthioethyl group, a propionylthioethyl group, a butyrylthioethyl group, an isobutyrylthioethyl group, a valerylthioethyl group and an isovalerylthioethyl group. And a pivaloylthioethyl group. In the ethyl group substituted with one or more halogen atoms represented by R 2 and R 3 , the type of the halogen atom may be any of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
Examples of the ethyl group substituted with one or more halogen atoms include:
1-fluoroethyl group, 2-fluoroethyl group, 1-chloroethyl group, 2-chloroethyl group, 2-bromoethyl group, 2,2-difluoroethyl group, 2,2-dichloroethyl group, 2,2-dibromoethyl group A 2,2,2-trifluoroethyl group, a 2,2,2-trichloroethyl group,
Examples include a 2,2,2-tribromoethyl group. In particular, the 2-position of the ethyl group is preferably substituted, and the halogen atom is preferably a fluorine atom. R 2 and R 3
At least one is preferably an ethyl group substituted with one or more halogen atoms, particularly a 2,2,2-trifluoroethyl group.
【００１１】Ｒ4 で表されるＣ1 〜Ｃ4 のアルキル基と
しては、メチル基、エチル基、ｎ−プロピル基、イソプ
ロピル基、ｎ−ブチル基、イソブチル基、ｓｅｃ−ブチ
ル基、ｔｅｒｔ−ブチル基等が挙げられる。Ｒ4 で表さ
れるＣ1 〜Ｃ4 のヒドロキシアルキル基としては、ヒド
ロキシメチル基、１−ヒドロキシエチル基、２−ヒドロ
キシエチル基、１−ヒドロキシプロピル基、２−ヒドロ
キシプロピル基、３−ヒドロキシプロピル基、１−ヒド
ロキシブチル基、２−ヒドロキシブチル基、３−ヒドロ
キシブチル基、４−ヒドロキシブチル基等が挙げられ
る。Ｒ4 で表される１以上のハロゲン原子で置換された
Ｃ1 〜Ｃ4 のアルキル基としては、フッ素原子、塩素原
子等のハロゲン原子がメチル基、エチル基、ｎ−プロピ
ル基、イソプロピル基、ｎ−ブチル基、イソブチル基、
ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基等に結合したも
のが挙げられる。具体例としては、フロロメチル基、ジ
フロロメチル基、トリフロロメチル基、フロロエチル
基、クロロエチル基、フロロプロピル基、クロロプロピ
ル基、フロロブチル基、クロロブチル基等が挙げられ
る。The C 1 -C 4 alkyl group represented by R 4 includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. And the like. Examples of the C 1 -C 4 hydroxyalkyl group represented by R 4 include a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydroxypropyl group, a 2-hydroxypropyl group, and a 3-hydroxypropyl group. Group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group and the like. As the C 1 -C 4 alkyl group substituted with one or more halogen atoms represented by R 4 , a halogen atom such as a fluorine atom and a chlorine atom is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, n-butyl group, isobutyl group,
Those bonded to a sec-butyl group, a tert-butyl group and the like can be mentioned. Specific examples include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, a chloroethyl group, a fluoropropyl group, a chloropropyl group, a fluorobutyl group, a chlorobutyl group, and the like.
【００１２】本発明においては、Ｒ1 が水素原子または
Ｃ1 〜Ｃ6 のアルコキシ基であることが好ましい化合物
の第１の条件として挙げられる。また、Ｒ1 が水素原子
またはＣ1 〜Ｃ6 のアルコキシ基であり、Ｒ2 及びＲ3
がそれぞれ独立に水素原子、Ｃ1 〜Ｃ22のアルキル基、
又は１以上のハロゲン原子で置換されたエチル基である
ことが好ましい化合物の第２の条件として挙げられる。
さらに、Ｒ1 が水素原子またはＣ1 〜Ｃ4 のアルコキシ
基であり、Ｒ2 及びＲ3 がそれぞれ独立に水素原子、Ｃ
1 〜Ｃ22のアルキル基、又は２，２，２−トリフルオロ
エチル基であり、Ｒ4 が水素原子またはメチル基である
ことが好ましい化合物の第３の条件として挙げられる。
Ｒ1 が水素原子又はＣ1 〜Ｃ4 のアルコキシ基であり、
Ｒ2 及びＲ3 がそれぞれ独立に水素原子又は２，２，２
−トリフルオロエチル基であり、Ｒ4 が水素原子又はメ
チル基であることが好ましい化合物の第４の条件として
挙げられる。In the present invention, the first condition of the compound in which R 1 is preferably a hydrogen atom or a C 1 -C 6 alkoxy group is mentioned. R 1 is a hydrogen atom or a C 1 -C 6 alkoxy group, and R 2 and R 3
Are each independently a hydrogen atom, a C 1 -C 22 alkyl group,
Alternatively, the second condition of the compound, which is preferably an ethyl group substituted with one or more halogen atoms, is mentioned.
Further, R 1 is a hydrogen atom or a C 1 -C 4 alkoxy group, and R 2 and R 3 are each independently a hydrogen atom,
1 alkyl group -C 22, or a 2,2,2-trifluoroethyl group, and a third condition that is preferred compounds R 4 is a hydrogen atom or a methyl group.
R 1 is a hydrogen atom or a C 1 -C 4 alkoxy group,
R 2 and R 3 each independently represent a hydrogen atom or 2,2,2
A trifluoroethyl group, and R 4 is preferably a hydrogen atom or a methyl group.
【００１３】例えば、この条件を満たす具体的な好まし
い化合物として、以下の化合物：２−アミノ−９−［２
−［ビス（２，２，２−トリフルオロエチル）ホスホニ
ルメトキシ］エチル］−６−フェニルチオプリン；２−
アミノ−９−［２−［ビス（２，２，２−トリフルオロ
エチル）ホスホニルメトキシ］エチル］−６−ｐ−メト
キシフェニルチオプリン；２−アミノ−９−［２−［ビ
ス（２，２，２−トリフルオロエチル）ホスホニルメト
キシ］エチル］−６−ｍ−メトキシフェニルチオプリ
ン；２−アミノ−９−［２−［ビス（２，２，２−トリ
フルオロエチル）ホスホニルメトキシ］エチル］−６−
ｏ−メトキシフェニルチオプリン；２−アミノ−９−
［２−［ビス（２，２，２−トリフルオロエチル）ホス
ホニルメトキシ］エチル］−６−ｐ−エトキシフェニル
チオプリン；２−アミノ−９−［２−［ビス（２，２，
２−トリフルオロエチル）ホスホニルメトキシ］プロピ
ル］−６−フェニルチオプリン；２−アミノ−９−［２
−［ビス（２，２，２−トリフルオロエチル）ホスホニ
ルメトキシ］プロピル］−６−ｐ−メトキシフェニルチ
オプリン；２−アミノ−９−［２−［（２，２，２−ト
リフルオロエチル）ホスホニルメトキシ］エチル］−６
−フェニルチオプリン；２−アミノ−９−［２−
［（２，２，２−トリフルオロエチル）ホスホニルメト
キシ］エチル］−６−ｐ−メトキシフェニルチオプリ
ン；２−アミノ−９−［２−［ホスホニルメトキシ］エ
チル］−６−フェニルチオプリン；２−アミノ−９−
［２−［ホスホニルメトキシ］エチル］−６−ｐ−メト
キシフェニルチオプリン；２−アミノ−９−［２−［ビ
ス（２，２，２−トリフルオロエチル）ホスホニルメト
キシ］エチル］−６−ｐ−ブトキシフェニルチオプリ
ン；２−アミノ−９−［２−［ビス（２，２，２−トリ
フルオロエチル）ホスホニルメトキシ］エチル］−６−
ｐ−プロポキシフェニルチオプリン；２−アミノ−９−
［２−［ビス（２，２，２−トリフルオロエチル）ホス
ホニルメトキシ］エチル］−６−ｐ−イソプロポキシフ
ェニルチオプリン；及び２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］エチル］−６−ｐ−イソブトキシフェニルチオプリ
ンを挙げることができる。For example, specific preferred compounds satisfying this condition include the following compound: 2-amino-9- [2
-[Bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-phenylthiopurine; 2-
Amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-methoxyphenylthiopurine; 2-amino-9- [2- [bis (2 2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] Ethyl] -6-
o-methoxyphenylthiopurine; 2-amino-9-
[2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-ethoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2
2-trifluoroethyl) phosphonylmethoxy] propyl] -6-phenylthiopurine; 2-amino-9- [2
-[Bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-p-methoxyphenylthiopurine; 2-amino-9- [2-[(2,2,2-trifluoroethyl ) Phosphonylmethoxy] ethyl] -6
-Phenylthiopurine; 2-amino-9- [2-
[(2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-methoxyphenylthiopurine; 2-amino-9- [2- [phosphonylmethoxy] ethyl] -6-phenylthiopurine 2-amino-9-
[2- [phosphonylmethoxy] ethyl] -6-p-methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6 -P-butoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6
p-propoxyphenylthiopurine; 2-amino-9-
[2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-isopropoxyphenylthiopurine; and 2-amino-9- [2- [bis (2,2, 2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-isobutoxyphenylthiopurine.
【００１４】その他、第４の条件を満たす具体的な化合
物としては、以下の化合物：２−アミノ−９−［２−
［ビス（２，２，２−トリフルオロエチル）ホスホニル
メトキシ］エチル］−６−ｍ−エトキシフェニルチオプ
リン；２−アミノ−９−［２−［ビス（２，２，２−ト
リフルオロエチル）ホスホニルメトキシ］エチル］−６
−ｏ−エトキシフェニルチオプリン；２−アミノ−９−
［２−［ビス（２，２，２−トリフルオロエチル）ホス
ホニルメトキシ］エチル］−６−ｍ−ブトキシフェニル
チオプリン；２−アミノ−９−［２−［ビス（２，２，
２−トリフルオロエチル）ホスホニルメトキシ］エチ
ル］−６−ｍ−プロポキシフェニルチオプリン；２−ア
ミノ−９−［２−［ビス（２，２，２−トリフルオロエ
チル）ホスホニルメトキシ］エチル］−６−ｍ−イソプ
ロポキシフェニルチオプリン；２−アミノ−９−［２−
［ビス（２，２，２−トリフルオロエチル）ホスホニル
メトキシ］エチル］−６−ｍ−イソブトキシフェニルチ
オプリン；２−アミノ−９−［２−［ビス（２，２，２
−トリフルオロエチル）ホスホニルメトキシ］エチル］
−６−ｏ−ブトキシフェニルチオプリン；２−アミノ−
９−［２−［ビス（２，２，２−トリフルオロエチル）
ホスホニルメトキシ］エチル］−６−ｏ−プロポキシフ
ェニルチオプリン；２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］エチル］−６−ｏ−イソプロポキシフェニルチオプ
リン；２−アミノ−９−［２−［ビス（２，２，２−ト
リフルオロエチル）ホスホニルメトキシ］エチル］−６
−ｏ−イソブトキシフェニルチオプリン；２−アミノ−
９−［２−［ビス（２，２，２−トリフルオロエチル）
ホスホニルメトキシ］プロピル］−６−ｍ−メトキシフ
ェニルチオプリン；２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］プロピル］−６−ｏ−メトキシフェニルチオプリ
ン；２−アミノ−９−［２−［ビス（２，２，２−トリ
フルオロエチル）ホスホニルメトキシ］プロピル］−６
−ｐ−エトキシフェニルチオプリン；２−アミノ−９−
［２−［ビス（２，２，２−トリフルオロエチル）ホス
ホニルメトキシ］プロピル］−６−ｍ−エトキシフェニ
ルチオプリン；２−アミノ−９−［２−［ビス（２，
２，２−トリフルオロエチル）ホスホニルメトキシ］プ
ロピル］−６−ｏ−エトキシフェニルチオプリン；２−
アミノ−９−［２−［ビス（２，２，２−トリフルオロ
エチル）ホスホニルメトキシ］プロピル］−６−ｐ−ブ
トキシフェニルチオプリン；２−アミノ−９−［２−
［ビス（２，２，２−トリフルオロエチル）ホスホニル
メトキシ］プロピル］−６−ｐ−プロポキシフェニルチ
オプリン；２−アミノ−９−［２−［ビス（２，２，２
−トリフルオロエチル）ホスホニルメトキシ］プロピ
ル］−６−ｐ−イソプロポキシフェニルチオプリン；２
−アミノ−９−［２−［ビス（２，２，２−トリフルオ
ロエチル）ホスホニルメトキシ］プロピル］−６−ｐ−
イソブトキシフェニルチオプリン；２−アミノ−９−
［２−［ビス（２，２，２−トリフルオロエチル）ホス
ホニルメトキシ］プロピル］−６−ｍ−ブトキシフェニ
ルチオプリン；２−アミノ−９−［２−［ビス（２，
２，２−トリフルオロエチル）ホスホニルメトキシ］プ
ロピル］−６−ｍ−プロポキシフェニルチオプリン；２
−アミノ−９−［２−［ビス（２，２，２−トリフルオ
ロエチル）ホスホニルメトキシ］プロピル］−６−ｍ−
イソプロポキシフェニルチオプリン；２−アミノ−９−
［２−［ビス（２，２，２−トリフルオロエチル）ホス
ホニルメトキシ］プロピル］−６−ｍ−イソブトキシフ
ェニルチオプリン；２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］プロピル］−６−ｏ−ブトキシフェニルチオプリ
ン；２−アミノ−９−［２−［ビス（２，２，２−トリ
フルオロエチル）ホスホニルメトキシ］プロピル］−６
−ｏ−プロポキシフェニルチオプリン；２−アミノ−９
−［２−［ビス（２，２，２−トリフルオロエチル）ホ
スホニルメトキシ］プロピル］−６−ｏ−イソプロポキ
シフェニルチオプリン；２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］プロピル］−６−ｏ−イソブトキシフェニルチオプ
リン；２−アミノ−９−［２−［（２，２，２−トリフ
ルオロエチル）ホスホニルメトキシ］エチル］−６−ｍ
−メトキシフェニルチオプリン；２−アミノ−９−［２
−［（２，２，２−トリフルオロエチル）ホスホニルメ
トキシ］エチル］−６−ｏ−メトキシフェニルチオプリ
ン；２−アミノ−９−［２−［（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
エトキシフェニルチオプリン；２−アミノ−９−［２−
［（２，２，２−トリフルオロエチル）ホスホニルメト
キシ］エチル］−６−ｍ−エトキシフェニルチオプリ
ン；２−アミノ−９−［２−［（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｏ−
エトキシフェニルチオプリン；２−アミノ−９−［２−
［（２，２，２−トリフルオロエチル）ホスホニルメト
キシ］エチル］−６−ｐ−ブトキシフェニルチオプリ
ン；２−アミノ−９−［２−［（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
プロポキシフェニルチオプリン；２−アミノ−９−［２
−［（２，２，２−トリフルオロエチル）ホスホニルメ
トキシ］エチル］−６−ｐ−イソプロポキシフェニルチ
オプリン；２−アミノ−９−［２−［（２，２，２−ト
リフルオロエチル）ホスホニルメトキシ］エチル］−６
−ｐ−イソブトキシフェニルチオプリン；２−アミノ−
９−［２−［（２，２，２−トリフルオロエチル）ホス
ホニルメトキシ］エチル］−６−ｍ−ブトキシフェニル
チオプリン；２−アミノ−９−［２−［（２，２，２−
トリフルオロエチル）ホスホニルメトキシ］エチル］−
６−ｍ−プロポキシフェニルチオプリン；２−アミノ−
９−［２−［（２，２，２−トリフルオロエチル）ホス
ホニルメトキシ］エチル］−６−ｍ−イソプロポキシフ
ェニルチオプリン；２−アミノ−９−［２−［（２，
２，２−トリフルオロエチル）ホスホニルメトキシ］エ
チル］−６−ｍ−イソブトキシフェニルチオプリン；２
−アミノ−９−［２−［（２，２，２−トリフルオロエ
チル）ホスホニルメトキシ］エチル］−６−ｏ−ブトキ
シフェニルチオプリン；２−アミノ−９−［２−
［（２，２，２−トリフルオロエチル）ホスホニルメト
キシ］エチル］−６−ｏ−プロポキシフェニルチオプリ
ン；２−アミノ−９−［２−［（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｏ−
イソプロポキシフェニルチオプリン；２−アミノ−９−
［２−［（２，２，２−トリフルオロエチル）ホスホニ
ルメトキシ］エチル］−６−ｏ−イソブトキシフェニル
チオプリン；２−アミノ−９−［２−［（２，２，２−
トリフルオロエチル）ホスホニルメトキシ］プロピル］
−６−フェニルチオプリン；２−アミノ−９−［２−
［（２，２，２−トリフルオロエチル）ホスホニルメト
キシ］プロピル］−６−ｐ−メトキシフェニルチオプリ
ン；２−アミノ−９−［２−［（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］プロピル］−６−ｍ
−メトキシフェニルチオプリン；２−アミノ−９−［２
−［（２，２，２−トリフルオロエチル）ホスホニルメ
トキシ］プロピル］−６−ｏ−メトキシフェニルチオプ
リン；２−アミノ−９−［２−［（２，２，２−トリフ
ルオロエチル）ホスホニルメトキシ］プロピル］−６−
ｐ−エトキシフェニルチオプリン；２−アミノ−９−
［２−［（２，２，２−トリフルオロエチル）ホスホニ
ルメトキシ］プロピル］−６−ｍ−エトキシフェニルチ
オプリン；２−アミノ−９−［２−［（２，２，２−ト
リフルオロエチル）ホスホニルメトキシ］プロピル］−
６−ｏ−エトキシフェニルチオプリン；２−アミノ−９
−［２−［（２，２，２−トリフルオロエチル）ホスホ
ニルメトキシ］プロピル］−６−ｐ−ブトキシフェニル
チオプリン；２−アミノ−９−［２−［（２，２，２−
トリフルオロエチル）ホスホニルメトキシ］プロピル］
−６−ｐ−プロポキシフェニルチオプリン；２−アミノ
−９−［２−［（２，２，２−トリフルオロエチル）ホ
スホニルメトキシ］プロピル］−６−ｐ−イソプロポキ
シフェニルチオプリン；２−アミノ−９−［２−
［（２，２，２−トリフルオロエチル）ホスホニルメト
キシ］プロピル］−６−ｐ−イソブトキシフェニルチオ
プリン；２−アミノ−９−［２−［（２，２，２−トリ
フルオロエチル）ホスホニルメトキシ］プロピル］−６
−ｍ−ブトキシフェニルチオプリン；２−アミノ−９−
［２−［（２，２，２−トリフルオロエチル）ホスホニ
ルメトキシ］プロピル］−６−ｍ−プロポキシフェニル
チオプリン；２−アミノ−９−［２−［（２，２，２−
トリフルオロエチル）ホスホニルメトキシ］プロピル］
−６−ｍ−イソプロポキシフェニルチオプリン；２−ア
ミノ−９−［２−［（２，２，２−トリフルオロエチ
ル）ホスホニルメトキシ］プロピル］−６−ｍ−イソブ
トキシフェニルチオプリン；２−アミノ−９−［２−
［（２，２，２−トリフルオロエチル）ホスホニルメト
キシ］プロピル］−６−ｏ−ブトキシフェニルチオプリ
ン；２−アミノ−９−［２−［（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］プロピル］−６−ｏ
−プロポキシフェニルチオプリン；２−アミノ−９−
［２−［（２，２，２−トリフルオロエチル）ホスホニ
ルメトキシ］プロピル］−６−ｏ−イソプロポキシフェ
ニルチオプリン；２−アミノ−９−［２−［（２，２，
２−トリフルオロエチル）ホスホニルメトキシ］プロピ
ル］−６−ｏ−イソブトキシフェニルチオプリン；２−
アミノ−９−［２−ホスホニルメトキシエチル］−６−
ｍ−メトキシフェニルチオプリン；２−アミノ−９−
［２−ホスホニルメトキシエチル］−６−ｏ−メトキシ
フェニルチオプリン；２−アミノ−９−［２−ホスホニ
ルメトキシエチル］−６−ｐ−エトキシフェニルチオプ
リン；２−アミノ−９−［２−ホスホニルメトキシエチ
ル］−６−ｍ−エトキシフェニルチオプリン；２−アミ
ノ−９−［２−ホスホニルメトキシエチル］−６−ｏ−
エトキシフェニルチオプリン；２−アミノ−９−［２−
ホスホニルメトキシエチル］−６−ｐ−ブトキシフェニ
ルチオプリン；２−アミノ−９−［２−ホスホニルメト
キシエチル］−６−ｐ−プロポキシフェニルチオプリ
ン；２−アミノ−９−［２−ホスホニルメトキシエチ
ル］−６−ｐ−イソプロポキシフェニルチオプリン；２
−アミノ−９−［２−ホスホニルメトキシエチル］−６
−ｐ−イソブトキシフェニルチオプリン；２−アミノ−
９−［２−ホスホニルメトキシエチル］−６−ｍ−ブト
キシフェニルチオプリン；２−アミノ−９−［２−ホス
ホニルメトキシエチル］−６−ｍ−プロポキシフェニル
チオプリン；２−アミノ−９−［２−ホスホニルメトキ
シエチル］−６−ｍ−イソプロポキシフェニルチオプリ
ン；２−アミノ−９−［２−ホスホニルメトキシエチ
ル］−６−ｍ−イソブトキシフェニルチオプリン；２−
アミノ−９−［２−ホスホニルメトキシエチル］−６−
ｏ−ブトキシフェニルチオプリン；２−アミノ−９−
［２−ホスホニルメトキシエチル］−６−ｏ−プロポキ
シフェニルチオプリン；２−アミノ−９−［２−ホスホ
ニルメトキシエチル］−６−ｏ−イソプロポキシフェニ
ルチオプリン；２−アミノ−９−［２−ホスホニルメト
キシエチル］−６−ｏ−イソブトキシフェニルチオプリ
ン；２−アミノ−９−［２−ホスホニルメトキシプロピ
ル］−６−フェニルチオプリン；２−アミノ−９−［２
−ホスホニルメトキシプロピル］−６−ｐ−メトキシフ
ェニルチオプリン；２−アミノ−９−［２−ホスホニル
メトキシプロピル］−６−ｍ−メトキシフェニルチオプ
リン；２−アミノ−９−［２−ホスホニルメトキシプロ
ピル］−６−ｏ−メトキシフェニルチオプリン；２−ア
ミノ−９−［２−ホスホニルメトキシプロピル］−６−
ｐ−エトキシフェニルチオプリン；２−アミノ−９−
［２−ホスホニルメトキシプロピル］−６−ｍ−エトキ
シフェニルチオプリン；２−アミノ−９−［２−ホスホ
ニルメトキシプロピル］−６−ｏ−エトキシフェニルチ
オプリン；２−アミノ−９−［２−ホスホニルメトキシ
プロピル］−６−ｐ−ブトキシフェニルチオプリン；２
−アミノ−９−［２−ホスホニルメトキシプロピル］−
６−ｐ−プロポキシフェニルチオプリン；２−アミノ−
９−［２−ホスホニルメトキシプロピル］−６−ｐ−イ
ソプロポキシフェニルチオプリン；２−アミノ−９−
［２−ホスホニルメトキシプロピル］−６−ｐ−イソブ
トキシフェニルチオプリン；２−アミノ−９−［２−ホ
スホニルメトキシプロピル］−６−ｍ−ブトキシフェニ
ルチオプリン；２−アミノ−９−［２−ホスホニルメト
キシプロピル］−６−ｍ−プロポキシフェニルチオプリ
ン；２−アミノ−９−［２−ホスホニルメトキシプロピ
ル］−６−ｍ−イソプロポキシフェニルチオプリン；２
−アミノ−９−［２−ホスホニルメトキシプロピル］−
６−ｍ−イソブトキシフェニルチオプリン；２−アミノ
−９−［２−ホスホニルメトキシプロピル］−６−ｏ−
ブトキシフェニルチオプリン；２−アミノ−９−［２−
ホスホニルメトキシプロピル］−６−ｏ−プロポキシフ
ェニルチオプリン；２−アミノ−９−［２−ホスホニル
メトキシプロピル］−６−ｏ−イソプロポキシフェニル
チオプリン；及び２−アミノ−９−［２−ホスホニルメ
トキシプロピル］−６−ｏ−イソブトキシフェニルチオ
プリンを挙げることができる。Other specific compounds satisfying the fourth condition include the following compounds: 2-amino-9- [2-
[Bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-ethoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) ) Phosphonylmethoxy] ethyl] -6
-O-ethoxyphenylthiopurine; 2-amino-9-
[2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-butoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2
2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-propoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-isopropoxyphenylthiopurine; 2-amino-9- [2-
[Bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-isobutoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2
-Trifluoroethyl) phosphonylmethoxy] ethyl]
-6-o-butoxyphenylthiopurine; 2-amino-
9- [2- [bis (2,2,2-trifluoroethyl)
Phosphonylmethoxy] ethyl] -6-o-propoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-o-iso Propoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6
-O-isobutoxyphenylthiopurine; 2-amino-
9- [2- [bis (2,2,2-trifluoroethyl)
Phosphonylmethoxy] propyl] -6-m-methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-o-methoxy Phenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6
-P-ethoxyphenylthiopurine; 2-amino-9-
[2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-m-ethoxyphenylthiopurine; 2-amino-9- [2- [bis (2
2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-o-ethoxyphenylthiopurine;
Amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-p-butoxyphenylthiopurine; 2-amino-9- [2-
[Bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-p-propoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2
-Trifluoroethyl) phosphonylmethoxy] propyl] -6-p-isopropoxyphenylthiopurine; 2
-Amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-p-
Isobutoxyphenylthiopurine; 2-amino-9-
[2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-m-butoxyphenylthiopurine; 2-amino-9- [2- [bis (2
2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-m-propoxyphenylthiopurine; 2
-Amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-m-
Isopropoxyphenylthiopurine; 2-amino-9-
[2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-m-isobutoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2 -Trifluoroethyl) phosphonylmethoxy] propyl] -6-o-butoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl]- 6
-O-propoxyphenylthiopurine; 2-amino-9
-[2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-o-isopropoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2 2-trifluoroethyl) phosphonylmethoxy] propyl] -6-o-isobutoxyphenylthiopurine; 2-amino-9- [2-[(2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m
-Methoxyphenylthiopurine; 2-amino-9- [2
-[(2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-o-methoxyphenylthiopurine; 2-amino-9- [2-[(2,2,2-trifluoroethyl) Phosphonylmethoxy] ethyl] -6-p-
Ethoxyphenylthiopurine; 2-amino-9- [2-
[(2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-ethoxyphenylthiopurine; 2-amino-9- [2-[(2,2,2-trifluoroethyl) phospho Nylmethoxy] ethyl] -6-o-
Ethoxyphenylthiopurine; 2-amino-9- [2-
[(2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-butoxyphenylthiopurine; 2-amino-9- [2-[(2,2,2-trifluoroethyl) phospho Nylmethoxy] ethyl] -6-p-
Propoxyphenylthiopurine; 2-amino-9- [2
-[(2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-isopropoxyphenylthiopurine; 2-amino-9- [2-[(2,2,2-trifluoroethyl ) Phosphonylmethoxy] ethyl] -6
-P-isobutoxyphenylthiopurine; 2-amino-
9- [2-[(2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-butoxyphenylthiopurine; 2-amino-9- [2-[(2,2,2-
Trifluoroethyl) phosphonylmethoxy] ethyl]-
6-m-propoxyphenylthiopurine; 2-amino-
9- [2-[(2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-isopropoxyphenylthiopurine; 2-amino-9- [2-[(2
2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-isobutoxyphenylthiopurine; 2
-Amino-9- [2-[(2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-o-butoxyphenylthiopurine; 2-amino-9- [2-
[(2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-o-propoxyphenylthiopurine; 2-amino-9- [2-[(2,2,2-trifluoroethyl) phospho Nylmethoxy] ethyl] -6-o-
Isopropoxyphenylthiopurine; 2-amino-9-
[2-[(2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-o-isobutoxyphenylthiopurine; 2-amino-9- [2-[(2,2,2-
Trifluoroethyl) phosphonylmethoxy] propyl]
-6-phenylthiopurine; 2-amino-9- [2-
[(2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-p-methoxyphenylthiopurine; 2-amino-9- [2-[(2,2,2-trifluoroethyl) phospho Nylmethoxy] propyl] -6-m
-Methoxyphenylthiopurine; 2-amino-9- [2
-[(2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-o-methoxyphenylthiopurine; 2-amino-9- [2-[(2,2,2-trifluoroethyl) Phosphonylmethoxy] propyl] -6-
p-ethoxyphenylthiopurine; 2-amino-9-
[2-[(2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-m-ethoxyphenylthiopurine; 2-amino-9- [2-[(2,2,2-trifluoro Ethyl) phosphonylmethoxy] propyl]-
6-o-ethoxyphenylthiopurine; 2-amino-9
-[2-[(2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-p-butoxyphenylthiopurine; 2-amino-9- [2-[(2,2,2-
Trifluoroethyl) phosphonylmethoxy] propyl]
-2-p-propoxyphenylthiopurine; 2-amino-9- [2-[(2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-p-isopropoxyphenylthiopurine; Amino-9- [2-
[(2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-p-isobutoxyphenylthiopurine; 2-amino-9- [2-[(2,2,2-trifluoroethyl) Phosphonylmethoxy] propyl] -6
-M-butoxyphenylthiopurine; 2-amino-9-
[2-[(2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-m-propoxyphenylthiopurine; 2-amino-9- [2-[(2,2,2-
Trifluoroethyl) phosphonylmethoxy] propyl]
2-amino-9- [2-[(2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-m-isobutoxyphenylthiopurine; 2 -Amino-9- [2-
[(2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-o-butoxyphenylthiopurine; 2-amino-9- [2-[(2,2,2-trifluoroethyl) phospho Nylmethoxy] propyl] -6-o
-Propoxyphenylthiopurine; 2-amino-9-
[2-[(2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-o-isopropoxyphenylthiopurine; 2-amino-9- [2-[(2,2
2-trifluoroethyl) phosphonylmethoxy] propyl] -6-o-isobutoxyphenylthiopurine;
Amino-9- [2-phosphonylmethoxyethyl] -6
m-methoxyphenylthiopurine; 2-amino-9-
[2-phosphonylmethoxyethyl] -6-o-methoxyphenylthiopurine; 2-amino-9- [2-phosphonylmethoxyethyl] -6-p-ethoxyphenylthiopurine; 2-amino-9- [2 -Phosphonylmethoxyethyl] -6-m-ethoxyphenylthiopurine; 2-amino-9- [2-phosphonylmethoxyethyl] -6-o-
Ethoxyphenylthiopurine; 2-amino-9- [2-
Phosphonylmethoxyethyl] -6-p-butoxyphenylthiopurine; 2-amino-9- [2-phosphonylmethoxyethyl] -6-p-propoxyphenylthiopurine; 2-amino-9- [2-phosphonyl Methoxyethyl] -6-p-isopropoxyphenylthiopurine; 2
-Amino-9- [2-phosphonylmethoxyethyl] -6
-P-isobutoxyphenylthiopurine; 2-amino-
9- [2-phosphonylmethoxyethyl] -6-m-butoxyphenylthiopurine; 2-amino-9- [2-phosphonylmethoxyethyl] -6-m-propoxyphenylthiopurine; 2-amino-9- [2-phosphonylmethoxyethyl] -6-m-isopropoxyphenylthiopurine; 2-amino-9- [2-phosphonylmethoxyethyl] -6-m-isobutoxyphenylthiopurine; 2-
Amino-9- [2-phosphonylmethoxyethyl] -6
o-butoxyphenylthiopurine; 2-amino-9-
[2-phosphonylmethoxyethyl] -6-o-propoxyphenylthiopurine; 2-amino-9- [2-phosphonylmethoxyethyl] -6-o-isopropoxyphenylthiopurine; 2-amino-9- [ 2-phosphonylmethoxyethyl] -6-o-isobutoxyphenylthiopurine; 2-amino-9- [2-phosphonylmethoxypropyl] -6-phenylthiopurine; 2-amino-9- [2
-Phosphonylmethoxypropyl] -6-p-methoxyphenylthiopurine; 2-amino-9- [2-phosphonylmethoxypropyl] -6-m-methoxyphenylthiopurine; 2-amino-9- [2-phospho Nylmethoxypropyl] -6-o-methoxyphenylthiopurine; 2-amino-9- [2-phosphonylmethoxypropyl] -6
p-ethoxyphenylthiopurine; 2-amino-9-
[2-phosphonylmethoxypropyl] -6-m-ethoxyphenylthiopurine; 2-amino-9- [2-phosphonylmethoxypropyl] -6-o-ethoxyphenylthiopurine; 2-amino-9- [2 -Phosphonylmethoxypropyl] -6-p-butoxyphenylthiopurine; 2
-Amino-9- [2-phosphonylmethoxypropyl]-
6-p-propoxyphenylthiopurine; 2-amino-
9- [2-phosphonylmethoxypropyl] -6-p-isopropoxyphenylthiopurine; 2-amino-9-
[2-phosphonylmethoxypropyl] -6-p-isobutoxyphenylthiopurine; 2-amino-9- [2-phosphonylmethoxypropyl] -6-m-butoxyphenylthiopurine; 2-amino-9- [ 2-phosphonylmethoxypropyl] -6-m-propoxyphenylthiopurine; 2-amino-9- [2-phosphonylmethoxypropyl] -6-m-isopropoxyphenylthiopurine; 2
-Amino-9- [2-phosphonylmethoxypropyl]-
6-m-isobutoxyphenylthiopurine; 2-amino-9- [2-phosphonylmethoxypropyl] -6-o-
Butoxyphenylthiopurine; 2-amino-9- [2-
Phosphonylmethoxypropyl] -6-o-propoxyphenylthiopurine; 2-amino-9- [2-phosphonylmethoxypropyl] -6-o-isopropoxyphenylthiopurine; and 2-amino-9- [2- Phosphonylmethoxypropyl] -6-o-isobutoxyphenylthiopurine.
【００１５】さらに、Ｒ1 が水素原子またはＣ1 〜Ｃ4
のアルコキシ基であり、Ｒ2 及びＲ3 が２，２，２−ト
リフルオロエチル基であり、Ｒ4 が水素原子またはメチ
ル基であることが好ましい化合物の第５の条件として挙
げられる。この条件を満たす具体的な好ましい化合物と
しては、以下の化合物：２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］エチル］−６−フェニルチオプリン；２−アミノ−
９−［２−［ビス（２，２，２−トリフルオロエチル）
ホスホニルメトキシ］エチル］−６−ｐ−メトキシフェ
ニルチオプリン；２−アミノ−９−［２−［ビス（２，
２，２−トリフルオロエチル）ホスホニルメトキシ］エ
チル］−６−ｍ−メトキシフェニルチオプリン；２−ア
ミノ−９−［２−［ビス（２，２，２−トリフルオロエ
チル）ホスホニルメトキシ］エチル］−６−ｏ−メトキ
シフェニルチオプリン；２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］エチル］−６−ｐ−エトキシフェニルチオプリン；
２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］プロピル］−６−フ
ェニルチオプリン；２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］プロピル］−６−ｐ−メトキシフェニルチオプリ
ン；２−アミノ−９−［２−［ビス（２，２，２−トリ
フルオロエチル）ホスホニルメトキシ］エチル］−６−
ｐ−ブトキシフェニルチオプリン；２−アミノ−９−
［２−［ビス（２，２，２−トリフルオロエチル）ホス
ホニルメトキシ］エチル］−６−ｐ−プロポキシフェニ
ルチオプリン；２−アミノ−９−［２−［ビス（２，
２，２−トリフルオロエチル）ホスホニルメトキシ］エ
チル］−６−ｐ−イソプロポキシフェニルチオプリン；
及び２−アミノ−９−［２−［ビス（２，２，２−トリ
フルオロエチル）ホスホニルメトキシ］エチル］−６−
ｐ−イソブトキシフェニルチオプリンを挙げることがで
きる。Further, R 1 is a hydrogen atom or C 1 -C 4
Wherein R 2 and R 3 are a 2,2,2-trifluoroethyl group, and R 4 is preferably a hydrogen atom or a methyl group. Specific preferred compounds satisfying this condition include the following compound: 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-phenylthiopurine 2-amino-
9- [2- [bis (2,2,2-trifluoroethyl)
Phosphonylmethoxy] ethyl] -6-p-methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,
2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] Ethyl] -6-o-methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-ethoxyphenylthiopurine;
2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-phenylthiopurine; 2-amino-9- [2- [bis (2,2 , 2-Trifluoroethyl) phosphonylmethoxy] propyl] -6-p-methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl ] -6
p-butoxyphenylthiopurine; 2-amino-9-
[2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-propoxyphenylthiopurine; 2-amino-9- [2- [bis (2
2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-isopropoxyphenylthiopurine;
And 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6
p-Isobutoxyphenylthiopurine can be mentioned.
【００１６】その他、第５の条件を満たす具体的な化合
物としては、以下の化合物：２−アミノ−９−［２−
［ビス（２，２，２−トリフルオロエチル）ホスホニル
メトキシ］エチル］−６−ｍ−エトキシフェニルチオプ
リン；２−アミノ−９−［２−［ビス（２，２，２−ト
リフルオロエチル）ホスホニルメトキシ］エチル］−６
−ｏ−エトキシフェニルチオプリン；２−アミノ−９−
［２−［ビス（２，２，２−トリフルオロエチル）ホス
ホニルメトキシ］エチル］−６−ｍ−ブトキシフェニル
チオプリン；２−アミノ−９−［２−［ビス（２，２，
２−トリフルオロエチル）ホスホニルメトキシ］エチ
ル］−６−ｍ−プロポキシフェニルチオプリン；２−ア
ミノ−９−［２−［ビス（２，２，２−トリフルオロエ
チル）ホスホニルメトキシ］エチル］−６−ｍ−イソプ
ロポキシフェニルチオプリン；２−アミノ−９−［２−
［ビス（２，２，２−トリフルオロエチル）ホスホニル
メトキシ］エチル］−６−ｍ−イソブトキシフェニルチ
オプリン；２−アミノ−９−［２−［ビス（２，２，２
−トリフルオロエチル）ホスホニルメトキシ］エチル］
−６−ｏ−ブトキシフェニルチオプリン；２−アミノ−
９−［２−［ビス（２，２，２−トリフルオロエチル）
ホスホニルメトキシ］エチル］−６−ｏ−プロポキシフ
ェニルチオプリン；２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］エチル］−６−ｏ−イソプロポキシフェニルチオプ
リン；２−アミノ−９−［２−［ビス（２，２，２−ト
リフルオロエチル）ホスホニルメトキシ］エチル］−６
−ｏ−イソブトキシフェニルチオプリン；２−アミノ−
９−［２−［ビス（２，２，２−トリフルオロエチル）
ホスホニルメトキシ］プロピル］−６−ｍ−メトキシフ
ェニルチオプリン；２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］プロピル］−６−ｏ−メトキシフェニルチオプリ
ン；２−アミノ−９−［２−［ビス（２，２，２−トリ
フルオロエチル）ホスホニルメトキシ］プロピル］−６
−ｐ−エトキシフェニルチオプリン；２−アミノ−９−
［２−［ビス（２，２，２−トリフルオロエチル）ホス
ホニルメトキシ］プロピル］−６−ｍ−エトキシフェニ
ルチオプリン；２−アミノ−９−［２−［ビス（２，
２，２−トリフルオロエチル）ホスホニルメトキシ］プ
ロピル］−６−ｏ−エトキシフェニルチオプリン；２−
アミノ−９−［２−［ビス（２，２，２−トリフルオロ
エチル）ホスホニルメトキシ］プロピル］−６−ｐ−ブ
トキシフェニルチオプリン；２−アミノ−９−［２−
［ビス（２，２，２−トリフルオロエチル）ホスホニル
メトキシ］プロピル］−６−ｐ−プロポキシフェニルチ
オプリン；２−アミノ−９−［２−［ビス（２，２，２
−トリフルオロエチル）ホスホニルメトキシ］プロピ
ル］−６−ｐ−イソプロポキシフェニルチオプリン；２
−アミノ−９−［２−［ビス（２，２，２−トリフルオ
ロエチル）ホスホニルメトキシ］プロピル］−６−ｐ−
イソブトキシフェニルチオプリン；２−アミノ−９−
［２−［ビス（２，２，２−トリフルオロエチル）ホス
ホニルメトキシ］プロピル］−６−ｍ−ブトキシフェニ
ルチオプリン；２−アミノ−９−［２−［ビス（２，
２，２−トリフルオロエチル）ホスホニルメトキシ］プ
ロピル］−６−ｍ−プロポキシフェニルチオプリン；２
−アミノ−９−［２−［ビス（２，２，２−トリフルオ
ロエチル）ホスホニルメトキシ］プロピル］−６−ｍ−
イソプロポキシフェニルチオプリン；２−アミノ−９−
［２−［ビス（２，２，２−トリフルオロエチル）ホス
ホニルメトキシ］プロピル］−６−ｍ−イソブトキシフ
ェニルチオプリン；２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］プロピル］−６−ｏ−ブトキシフェニルチオプリ
ン；２−アミノ−９−［２−［ビス（２，２，２−トリ
フルオロエチル）ホスホニルメトキシ］プロピル］−６
−ｏ−プロポキシフェニルチオプリン；２−アミノ−９
−［２−［ビス（２，２，２−トリフルオロエチル）ホ
スホニルメトキシ］プロピル］−６−ｏ−イソプロポキ
シフェニルチオプリン；及び２−アミノ−９−［２−
［ビス（２，２，２−トリフルオロエチル）ホスホニル
メトキシ］プロピル］−６−ｏ−イソブトキシフェニル
チオプリンを挙げることができる。Other specific compounds satisfying the fifth condition include the following compounds: 2-amino-9- [2-
[Bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-ethoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) ) Phosphonylmethoxy] ethyl] -6
-O-ethoxyphenylthiopurine; 2-amino-9-
[2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-butoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2
2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-propoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-isopropoxyphenylthiopurine; 2-amino-9- [2-
[Bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-isobutoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2
-Trifluoroethyl) phosphonylmethoxy] ethyl]
-6-o-butoxyphenylthiopurine; 2-amino-
9- [2- [bis (2,2,2-trifluoroethyl)
Phosphonylmethoxy] ethyl] -6-o-propoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-o-iso Propoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6
-O-isobutoxyphenylthiopurine; 2-amino-
9- [2- [bis (2,2,2-trifluoroethyl)
Phosphonylmethoxy] propyl] -6-m-methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-o-methoxy Phenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6
-P-ethoxyphenylthiopurine; 2-amino-9-
[2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-m-ethoxyphenylthiopurine; 2-amino-9- [2- [bis (2
2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-o-ethoxyphenylthiopurine;
Amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-p-butoxyphenylthiopurine; 2-amino-9- [2-
[Bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-p-propoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2
-Trifluoroethyl) phosphonylmethoxy] propyl] -6-p-isopropoxyphenylthiopurine; 2
-Amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-p-
Isobutoxyphenylthiopurine; 2-amino-9-
[2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-m-butoxyphenylthiopurine; 2-amino-9- [2- [bis (2
2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-m-propoxyphenylthiopurine; 2
-Amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-m-
Isopropoxyphenylthiopurine; 2-amino-9-
[2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-m-isobutoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2 -Trifluoroethyl) phosphonylmethoxy] propyl] -6-o-butoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl]- 6
-O-propoxyphenylthiopurine; 2-amino-9
-[2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-o-isopropoxyphenylthiopurine; and 2-amino-9- [2-
[Bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-o-isobutoxyphenylthiopurine.
【００１７】さらに、Ｒ1 が水素原子又はＣ1 〜Ｃ4 の
アルコキシ基であり、Ｒ2 及びＲ3が２，２，２−トリ
フルオロエチル基であり、Ｒ4 が水素原子であることが
好ましい化合物としての第６の条件として挙げられる。
この条件を満たす具体的な好ましい化合物としては、以
下の化合物：２−アミノ−９−［２−［ビス（２，２，
２−トリフルオロエチル）ホスホニルメトキシ］エチ
ル］−６−フェニルチオプリン；２−アミノ−９−［２
−［ビス（２，２，２−トリフルオロエチル）ホスホニ
ルメトキシ］エチル］−６−ｐ−メトキシフェニルチオ
プリン；２−アミノ−９−［２−［ビス（２，２，２−
トリフルオロエチル）ホスホニルメトキシ］エチル］−
６−ｍ−メトキシフェニルチオプリン；２−アミノ−９
−［２−［ビス（２，２，２−トリフルオロエチル）ホ
スホニルメトキシ］エチル］−６−ｏ−メトキシフェニ
ルチオプリン；２−アミノ−９−［２−［ビス（２，
２，２−トリフルオロエチル）ホスホニルメトキシ］エ
チル］−６−ｐ−エトキシフェニルチオプリン；２−ア
ミノ−９−［２−［ビス（２，２，２−トリフルオロエ
チル）ホスホニルメトキシ］エチル］−６−ｐ−ブトキ
シフェニルチオプリン；２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］エチル］−６−ｐ−プロポキシフェニルチオプリ
ン；２−アミノ−９−［２−［ビス（２，２，２−トリ
フルオロエチル）ホスホニルメトキシ］エチル］−６−
ｐ−イソプロポキシフェニルチオプリン；及び２−アミ
ノ−９−［２−［ビス（２，２，２−トリフルオロエチ
ル）ホスホニルメトキシ］エチル］−６−ｐ−イソブト
キシフェニルチオプリンを挙げることができる。Further, it is preferred that R 1 is a hydrogen atom or a C 1 -C 4 alkoxy group, R 2 and R 3 are 2,2,2-trifluoroethyl groups, and R 4 is a hydrogen atom. The sixth condition as a preferable compound is mentioned.
Specific preferred compounds satisfying this condition include the following compound: 2-amino-9- [2- [bis (2,2,
2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-phenylthiopurine; 2-amino-9- [2
-[Bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-
Trifluoroethyl) phosphonylmethoxy] ethyl]-
6-m-methoxyphenylthiopurine; 2-amino-9
-[2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-o-methoxyphenylthiopurine; 2-amino-9- [2- [bis (2
2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-ethoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] Ethyl] -6-p-butoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-propoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6
p-isopropoxyphenylthiopurine; and 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-isobutoxyphenylthiopurine. Can be.
【００１８】その他、第６の条件を満たす具体的な化合
物として、以下の化合物：２−アミノ−９−［２−［ビ
ス（２，２，２−トリフルオロエチル）ホスホニルメト
キシ］エチル］−６−ｍ−エトキシフェニルチオプリ
ン；２−アミノ−９−［２−［ビス（２，２，２−トリ
フルオロエチル）ホスホニルメトキシ］エチル］−６−
ｏ−エトキシフェニルチオプリン；２−アミノ−９−
［２−［ビス（２，２，２−トリフルオロエチル）ホス
ホニルメトキシ］エチル］−６−ｍ−ブトキシフェニル
チオプリン；２−アミノ−９−［２−［ビス（２，２，
２−トリフルオロエチル）ホスホニルメトキシ］エチ
ル］−６−ｍ−プロポキシフェニルチオプリン；２−ア
ミノ−９−［２−［ビス（２，２，２−トリフルオロエ
チル）ホスホニルメトキシ］エチル］−６−ｍ−イソプ
ロポキシフェニルチオプリン；２−アミノ−９−［２−
［ビス（２，２，２−トリフルオロエチル）ホスホニル
メトキシ］エチル］−６−ｍ−イソブトキシフェニルチ
オプリン；２−アミノ−９−［２−［ビス（２，２，２
−トリフルオロエチル）ホスホニルメトキシ］エチル］
−６−ｏ−ブトキシフェニルチオプリン；２−アミノ−
９−［２−［ビス（２，２，２−トリフルオロエチル）
ホスホニルメトキシ］エチル］−６−ｏ−プロポキシフ
ェニルチオプリン；２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］エチル］−６−ｏ−イソプロポキシフェニルチオプ
リン；及び２−アミノ−９−［２−［ビス（２，２，２
−トリフルオロエチル）ホスホニルメトキシ］エチル］
−６−ｏ−イソブトキシフェニルチオプリンを挙げるこ
とができる。Other specific compounds satisfying the sixth condition include the following compound: 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl]- 6-m-ethoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6
o-ethoxyphenylthiopurine; 2-amino-9-
[2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-butoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2
2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-propoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-isopropoxyphenylthiopurine; 2-amino-9- [2-
[Bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-isobutoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2
-Trifluoroethyl) phosphonylmethoxy] ethyl]
-6-o-butoxyphenylthiopurine; 2-amino-
9- [2- [bis (2,2,2-trifluoroethyl)
Phosphonylmethoxy] ethyl] -6-o-propoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-o-iso Propoxyphenylthiopurine; and 2-amino-9- [2- [bis (2,2,2
-Trifluoroethyl) phosphonylmethoxy] ethyl]
-6-o-isobutoxyphenylthiopurine can be mentioned.
【００１９】さらに、Ｒ1 が水素原子又はＣ1 〜Ｃ2 の
アルコキシ基であり、Ｒ2 及びＲ3 が２，２，２−トリ
フルオロエチル基であり、Ｒ4 が水素原子であることが
好ましい化合物の第７の条件として挙げられる。この条
件を満たす具体的な好ましい化合物として、以下の化合
物：２−アミノ−９−［２−［ビス（２，２，２−トリ
フルオロエチル）ホスホニルメトキシ］エチル］−６−
フェニルチオプリン；２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］エチル］−６−ｐ−メトキシフェニルチオプリン；
２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｍ−
メトキシフェニルチオプリン；２−アミノ−９−［２−
［ビス（２，２，２−トリフルオロエチル）ホスホニル
メトキシ］エチル］−６−ｏ−メトキシフェニルチオプ
リン；及び２−アミノ−９−［２−［ビス（２，２，２
−トリフルオロエチル）ホスホニルメトキシ］エチル］
−６−ｐ−エトキシフェニルチオプリンを挙げることが
できる。Further, R1Is a hydrogen atom or C1~ CTwoof
An alkoxy group;TwoAnd RThree Is 2,2,2-bird
A fluoroethyl group, RFourIs a hydrogen atom
The seventh condition of a preferable compound is mentioned. This article
Specific preferred compounds satisfying the above conditions are the following compounds
Compound: 2-amino-9- [2- [bis (2,2,2-tri
Fluoroethyl) phosphonylmethoxy] ethyl] -6
Phenylthiopurine; 2-amino-9- [2- [bis
(2,2,2-trifluoroethyl) phosphonyl methoxy
[S] ethyl] -6-p-methoxyphenylthiopurine;
2-amino-9- [2- [bis (2,2,2-trifur
Oroethyl) phosphonylmethoxy] ethyl] -6-m-
Methoxyphenylthiopurine; 2-amino-9- [2-
[Bis (2,2,2-trifluoroethyl) phosphonyl
Methoxy] ethyl] -6-o-methoxyphenylthiop
Phosphorus; and 2-amino-9- [2- [bis (2,2,2
-Trifluoroethyl) phosphonylmethoxy] ethyl]
-6-p-ethoxyphenylthiopurine
it can.
【００２０】その他、第７の条件を満たす具体的な化合
物としては、以下の化合物：２−アミノ−９−［２−
［ビス（２，２，２−トリフルオロエチル）ホスホニル
メトキシ］エチル］−６−ｍ−エトキシフェニルチオプ
リン；及び２−アミノ−９−［２−［ビス（２，２，２
−トリフルオロエチル）ホスホニルメトキシ］エチル］
−６−ｏ−エトキシフェニルチオプリンを挙げることが
できる。Other specific compounds satisfying the seventh condition include the following compounds: 2-amino-9- [2-
[Bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-ethoxyphenylthiopurine; and 2-amino-9- [2- [bis (2,2,2
-Trifluoroethyl) phosphonylmethoxy] ethyl]
-6-o-ethoxyphenylthiopurine can be mentioned.
【００２１】上記一般式（Ｉ）で表される本発明のホス
ホナートヌクレオチド化合物は塩として存在する場合が
あるが、上記化合物が形成する塩はいずれも本発明の範
囲に包含される。このような塩としては、例えば、医薬
として許容され得る塩を挙げることができる。例えば、
酸性基が存在する場合には、酸性基はリチウム塩、ナト
リウム塩、カリウム塩、マグネシウム塩、カルシウム塩
等の金属塩、アンモニウム塩、メチルアンモニウム塩、
ジメチルアンモニウム塩、トリメチルアンモニウム塩、
ジシクロヘキシルアンモニウム塩等のアンモニウム塩な
どを形成することができる。また、アミノ基が存在する
場合には、塩酸塩、臭酸塩、硫酸塩、硝酸塩、リン酸、
メタリン酸塩等の鉱酸塩、メタンスルホン酸塩、ベンゼ
ンスルホン酸塩、パラトルエンスルホン酸塩、酢酸塩、
プロピオン酸塩、酒石酸塩、フマル酸塩、マレイン酸
塩、リンゴ酸塩、シュウ酸塩、コハク酸塩、クエン酸
塩、安息香酸塩、マンデル酸塩、ケイ皮酸塩、乳酸、ベ
シル酸、吉草酸、ステアリン酸、オレイン酸、ラクトビ
オン酸、エチルコハク酸、セミコハク酸、酪酸、パルミ
チン酸、カルバミン酸、グルコン酸、ラウリル酸、サリ
チル酸、ラオクル酸、タンニン酸、ブチルスルホン酸塩
等の有機酸塩などを形成することができる。The phosphonate nucleotide compound of the present invention represented by the above general formula (I) may exist as a salt, and any salt formed by the above compound is included in the scope of the present invention. Such salts include, for example, pharmaceutically acceptable salts. For example,
When an acidic group is present, the acidic group may be a metal salt such as a lithium salt, a sodium salt, a potassium salt, a magnesium salt, a calcium salt, an ammonium salt, a methylammonium salt,
Dimethyl ammonium salt, trimethyl ammonium salt,
An ammonium salt such as dicyclohexylammonium salt can be formed. When an amino group is present, hydrochloride, bromate, sulfate, nitrate, phosphoric acid,
Mineral salts such as metaphosphate, methanesulfonate, benzenesulfonate, paratoluenesulfonate, acetate,
Propionate, tartrate, fumarate, maleate, malate, oxalate, succinate, citrate, benzoate, mandelate, cinnamate, lactic acid, besylate, valley Organic acids such as valeric acid, stearic acid, oleic acid, lactobionic acid, ethyl succinic acid, semi-succinic acid, butyric acid, palmitic acid, carbamic acid, gluconic acid, lauric acid, salicylic acid, laucolic acid, tannic acid, butyl sulfonic acid salt, etc. Can be formed.
【００２２】上記一般式（Ｉ）で表される本発明のホス
ホナートヌクレオチド化合物及びその塩は、水和物又は
溶媒和物の形で存在することもある。上記に具体的に言
及した好ましい化合物を含めて、上記一般式（Ｉ）で表
される本発明のホスホナートヌクレオチド化合物又はそ
の塩が形成する任意の水和物又は溶媒和物は、いずれも
本発明の範囲に包含される。溶媒和物を形成し得る溶媒
としては、メタノール、エタノール、イソプロパノー
ル、アセトン、酢酸エチル、塩化メチレン、ジイソプロ
ピルエーテル等が挙げられる。The phosphonate nucleotide compound of the present invention represented by the above general formula (I) and a salt thereof may exist in the form of a hydrate or a solvate. Any of the hydrates or solvates formed by the phosphonate nucleotide compound of the present invention represented by the general formula (I) or a salt thereof, including the preferred compounds specifically mentioned above, Included in the scope of the invention. Solvents that can form solvates include methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride, diisopropyl ether and the like.
【００２３】本発明化合物の具体例を下記表１に示す
（表中、Ｍｅ−はメチル基、Ｅｔ−はエチル基、ｎ−Ｐ
ｒ−はノルマルプロピル基、ｉ−Ｐｒ−はイソプロピル
基、ｎ−Ｂｕはノルマルブチル基、ｉ−Ｂｕはイソブチ
ル基、ｔ−Ｂｕ−はターシャリーブチル基を表す）。Specific examples of the compound of the present invention are shown in Table 1 below (in the table, Me- is a methyl group, Et- is an ethyl group, n-P
r- is a normal propyl group, i-Pr- is an isopropyl group, n-Bu is a normal butyl group, i-Bu is an isobutyl group, and t-Bu- is a tertiary butyl group.
【表１】 No. R1 R2 R3 R4 X 1 H CF3CH2- CF3CH2- H CH 2 o-OCH3 CF3CH2- CF3CH2- H CH 3 m-OCH3 CF3CH2- CF3CH2- H CH 4 p-OCH3 CF3CH2- CF3CH2- H CH 5 o-Cl CF3CH2- CF3CH2- H CH 6 m-Cl CF3CH2- CF3CH2- H CH 7 p-Cl CF3CH2- CF3CH2- H CH 8 o-Br CF3CH2- CF3CH2- H CH 9 m-Br CF3CH2- CF3CH2- H CH 10 p-Br CF3CH2- CF3CH2- H CH 11 o-NH2 CF3CH2- CF3CH2- H CH 12 m-NH2 CF3CH2- CF3CH2- H CH 13 p-NH2 CF3CH2- CF3CH2- H CH 14 o-NO2 CF3CH2- CF3CH2- H CH 15 m-NO2 CF3CH2- CF3CH2- H CH 16 p-NO2 CF3CH2- CF3CH2- H CH 17 o-OC2H5 CF3CH2- CF3CH2- H CH 18 m-OC2H5 CF3CH2- CF3CH2- H CH 19 p-OC2H5 CF3CH2- CF3CH2- H CH 20 p-I CF3CH2- CF3CH2- H CH 21 o-O-n-Pr CF3CH2- CF3CH2- H CH 22 m-O-n-Pr CF3CH2- CF3CH2- H CH 23 p-O-n-Pr CF3CH2- CF3CH2- H CH 24 o-O-i-Pr CF3CH2- CF3CH2- H CH 25 m-O-i-Pr CF3CH2- CF3CH2- H CH 26 p-O-i-Pr CF3CH2- CF3CH2- H CH 27 o-O-n-Bu CF3CH2- CF3CH2- H CH 28 m-O-n-Bu CF3CH2- CF3CH2- H CH 29 p-O-n-Bu CF3CH2- CF3CH2- H CH 30 o-O-i-Bu CF3CH2- CF3CH2- H CH 31 m-O-i-Bu CF3CH2- CF3CH2- H CH 32 p-O-i-Bu CF3CH2- CF3CH2- H CH 33 o-OCF3 CF3CH2- CF3CH2- H CH 34 m-OCF3 CF3CH2- CF3CH2- H CH 35 p-OCF3 CF3CH2- CF3CH2- H CH 36 H CF3CH2- CF3CH2- H N 37 o-OCH3 CF3CH2- CF3CH2- H N 38 m-OCH3 CF3CH2- CF3CH2- H N 39 p-OCH3 CF3CH2- CF3CH2- H N 40 o-Cl CF3CH2- CF3CH2- H N 41 m-Cl CF3CH2- CF3CH2- H N 42 p-Cl CF3CH2- CF3CH2- H N 43 o-Br CF3CH2- CF3CH2- H N 44 m-Br CF3CH2- CF3CH2- H N 45 p-Br CF3CH2- CF3CH2- H N 46 o-NH2 CF3CH2- CF3CH2- H N 47 m-NH2 CF3CH2- CF3CH2- H N 48 p-NH2 CF3CH2- CF3CH2- H N 49 o-NO2 CF3CH2- CF3CH2- H N 50 m-NO2 CF3CH2- CF3CH2- H N 51 p-NO2 CF3CH2- CF3CH2- H N 52 o-OC2H5 CF3CH2- CF3CH2- H N 53 m-OC2H5 CF3CH2- CF3CH2- H N 54 p-OC2H5 CF3CH2- CF3CH2- H N 55 p-I CF3CH2- CF3CH2- H N 56 o-O-n-Pr CF3CH2- CF3CH2- H N 57 m-O-n-Pr CF3CH2- CF3CH2- H N 58 p-O-n-Pr CF3CH2- CF3CH2- H N 59 o-O-i-Pr CF3CH2- CF3CH2- H N 60 m-O-i-Pr CF3CH2- CF3CH2- H N 61 p-O-i-Pr CF3CH2- CF3CH2- H N 62 o-O-n-Bu CF3CH2- CF3CH2- H N 63 m-O-n-Bu CF3CH2- CF3CH2- H N 64 p-O-n-Bu CF3CH2- CF3CH2- H N 65 o-O-i-Bu CF3CH2- CF3CH2- H N 66 m-O-i-Bu CF3CH2- CF3CH2- H N 67 p-O-i-Bu CF3CH2- CF3CH2- H N 68 o-OCF3 CF3CH2- CF3CH2- H N 69 m-OCF3 CF3CH2- CF3CH2- H N 70 p-OCF3 CF3CH2- CF3CH2- H N 71 H CF3CH2- Me- H CH 72 o-OCH3 CF3CH2- Me- H CH 73 m-OCH3 CF3CH2- Me- H CH 74 p-OCH3 CF3CH2- Me- H CH 75 o-Cl CF3CH2- Me- H CH 76 m-Cl CF3CH2- Me- H CH 77 p-Cl CF3CH2- Me- H CH 78 o-Br CF3CH2- Me- H CH 79 m-Br CF3CH2- Me- H CH 80 p-Br CF3CH2- Me- H CH 81 o-NH2 CF3CH2- Me- H CH 82 m-NH2 CF3CH2- Me- H CH 83 p-NH2 CF3CH2- Me- H CH 84 o-NO2 CF3CH2- Me- H CH 85 m-NO2 CF3CH2- Me- H CH 86 p-NO2 CF3CH2- Me- H CH 87 o-OC2H5 CF3CH2- Me- H CH 88 m-OC2H5 CF3CH2- Me- H CH 89 p-OC2H5 CF3CH2- Me- H CH 90 p-I CF3CH2- Me- H CH 91 o-O-n-Pr CF3CH2- Me- H CH 92 m-O-n-Pr CF3CH2- Me- H CH 93 p-O-n-Pr CF3CH2- Me- H CH 94 o-O-i-Pr CF3CH2- Me- H CH 95 m-O-i-Pr CF3CH2- Me- H CH 96 p-O-i-Pr CF3CH2- Me- H CH 97 o-O-n-Bu CF3CH2- Me- H CH 98 m-O-n-Bu CF3CH2- Me- H CH 99 p-O-n-Bu CF3CH2- Me- H CH 100 o-O-i-Bu CF3CH2- Me- H CH 101 m-O-i-Bu CF3CH2- Me- H CH 102 p-O-i-Bu CF3CH2- Me- H CH 103 o-OCF3 CF3CH2- Me- H CH 104 m-OCF3 CF3CH2- Me- H CH 105 p-OCF3 CF3CH2- Me- H CH 106 H CF3CH2- Me- H N 107 o-OCH3 CF3CH2- Me- H N 108 m-OCH3 CF3CH2- Me- H N 109 p-OCH3 CF3CH2- Me- H N 110 o-Cl CF3CH2- Me- H N 111 m-Cl CF3CH2- Me- H N 112 p-Cl CF3CH2- Me- H N 113 o-Br CF3CH2- Me- H N 114 m-Br CF3CH2- Me- H N 115 p-Br CF3CH2- Me- H N 116 o-NH2 CF3CH2- Me- H N 117 m-NH2 CF3CH2- Me- H N 118 p-NH2 CF3CH2- Me- H N 119 o-NO2 CF3CH2- Me- H N 120 m-NO2 CF3CH2- Me- H N 121 p-NO2 CF3CH2- Me- H N 122 o-OC2H5 CF3CH2- Me- H N 123 m-OC2H5 CF3CH2- Me- H N 124 p-OC2H5 CF3CH2- Me- H N 125 p-I CF3CH2- Me- H N 126 o-O-n-Pr CF3CH2- Me- H N 127 m-O-n-Pr CF3CH2- Me- H N 128 p-O-n-Pr CF3CH2- Me- H N 129 o-O-i-Pr CF3CH2- Me- H N 130 m-O-i-Pr CF3CH2- Me- H N 131 p-O-i-Pr CF3CH2- Me- H N 132 o-O-n-Bu CF3CH2- Me- H N 133 m-O-n-Bu CF3CH2- Me- H N 134 p-O-n-Bu CF3CH2- Me- H N 135 o-O-i-Bu CF3CH2- Me- H N 136 m-O-i-Bu CF3CH2- Me- H N 137 p-O-i-Bu CF3CH2- Me- H N 138 o-OCF3 CF3CH2- Me- H N 139 m-OCF3 CF3CH2- Me- H N 140 p-OCF3 CF3CH2- Me- H N 141 H CF3CH2- Et- H CH 142 o-OCH3 CF3CH2- Et- H CH 143 m-OCH3 CF3CH2- Et- H CH 144 p-OCH3 CF3CH2- Et- H CH 145 o-Cl CF3CH2- Et- H CH 146 m-Cl CF3CH2- Et- H CH 147 p-Cl CF3CH2- Et- H CH 148 o-Br CF3CH2- Et- H CH 149 m-Br CF3CH2- Et- H CH 150 p-Br CF3CH2- Et- H CH 151 o-NH2 CF3CH2- Et- H CH 152 m-NH2 CF3CH2- Et- H CH 153 p-NH2 CF3CH2- Et- H CH 154 o-NO2 CF3CH2- Et- H CH 155 m-NO2 CF3CH2- Et- H CH 156 p-NO2 CF3CH2- Et- H CH 157 o-OC2H5 CF3CH2- Et- H CH 158 m-OC2H5 CF3CH2- Et- H CH 159 p-OC2H5 CF3CH2- Et- H CH 160 p-I CF3CH2- Et- H CH 161 o-O-n-Pr CF3CH2- Et- H CH 162 m-O-n-Pr CF3CH2- Et- H CH 163 p-O-n-Pr CF3CH2- Et- H CH 164 o-O-i-Pr CF3CH2- Et- H CH 165 m-O-i-Pr CF3CH2- Et- H CH 166 p-O-i-Pr CF3CH2- Et- H CH 167 o-O-n-Bu CF3CH2- Et- H CH 168 m-O-n-Bu CF3CH2- Et- H CH 169 p-O-n-Bu CF3CH2- Et- H CH 170 o-O-i-Bu CF3CH2- Et- H CH 171 m-O-i-Bu CF3CH2- Et- H CH 172 p-O-i-Bu CF3CH2- Et- H CH 173 o-OCF3 CF3CH2- Et- H CH 174 m-OCF3 CF3CH2- Et- H CH 175 p-OCF3 CF3CH2- Et- H CH 176 H CF3CH2- Et- H N 177 o-OCH3 CF3CH2- Et- H N 178 m-OCH3 CF3CH2- Et- H N 179 p-OCH3 CF3CH2- Et- H N 180 o-Cl CF3CH2- Et- H N 181 m-Cl CF3CH2- Et- H N 182 p-Cl CF3CH2- Et- H N 183 o-Br CF3CH2- Et- H N 184 m-Br CF3CH2- Et- H N 185 p-Br CF3CH2- Et- H N 186 o-NH2 CF3CH2- Et- H N 187 m-NH2 CF3CH2- Et- H N 188 p-NH2 CF3CH2- Et- H N 189 o-NO2 CF3CH2- Et- H N 190 m-NO2 CF3CH2- Et- H N 191 p-NO2 CF3CH2- Et- H N 192 o-OC2H5 CF3CH2- Et- H N 193 m-OC2H5 CF3CH2- Et- H N 194 p-OC2H5 CF3CH2- Et- H N 195 p-I CF3CH2- Et- H N 196 o-O-n-Pr CF3CH2- Et- H N 197 m-O-n-Pr CF3CH2- Et- H N 198 p-O-n-Pr CF3CH2- Et- H N 199 o-O-i-Pr CF3CH2- Et- H N 200 m-O-i-Pr CF3CH2- Et- H N 201 p-O-i-Pr CF3CH2- Et- H N 202 o-O-n-Bu CF3CH2- Et- H N 203 m-O-n-Bu CF3CH2- Et- H N 204 p-O-n-Bu CF3CH2- Et- H N 205 o-O-i-Bu CF3CH2- Et- H N 206 m-O-i-Bu CF3CH2- Et- H N 207 p-O-i-Bu CF3CH2- Et- H N 208 o-OCF3 CF3CH2- Et- H N 209 m-OCF3 CF3CH2- Et- H N 210 p-OCF3 CF3CH2- Et- H N 211 H CF3CH2- H H CH 212 o-OCH3 CF3CH2- H H CH 213 m-OCH3 CF3CH2- H H CH 214 p-OCH3 CF3CH2- H H CH 215 o-Cl CF3CH2- H H CH 216 m-Cl CF3CH2- H H CH 217 p-Cl CF3CH2- H H CH 218 o-Br CF3CH2- H H CH 219 m-Br CF3CH2- H H CH 220 p-Br CF3CH2- H H CH 221 o-NH2 CF3CH2- H H CH 222 m-NH2 CF3CH2- H H CH 223 p-NH2 CF3CH2- H H CH 224 o-NO2 CF3CH2- H H CH 225 m-NO2 CF3CH2- H H CH 226 p-NO2 CF3CH2- H H CH 227 o-OC2H5 CF3CH2- H H CH 228 m-OC2H5 CF3CH2- H H CH 229 p-OC2H5 CF3CH2- H H CH 230 p-I CF3CH2- H H CH 231 o-O-n-Pr CF3CH2- H H CH 232 m-O-n-Pr CF3CH2- H H CH 233 p-O-n-Pr CF3CH2- H H CH 234 o-O-i-Pr CF3CH2- H H CH 235 m-O-i-Pr CF3CH2- H H CH 236 p-O-i-Pr CF3CH2- H H CH 237 o-O-n-Bu CF3CH2- H H CH 238 m-O-n-Bu CF3CH2- H H CH 239 p-O-n-Bu CF3CH2- H H CH 240 o-O-i-Bu CF3CH2- H H CH 241 m-O-i-Bu CF3CH2- H H CH 242 p-O-i-Bu CF3CH2- H H CH 243 o-OCF3 CF3CH2- H H CH 244 m-OCF3 CF3CH2- H H CH 245 p-OCF3 CF3CH2- H H CH 246 H CF3CH2- H H N 247 o-OCH3 CF3CH2- H H N 248 m-OCH3 CF3CH2- H H N 249 p-OCH3 CF3CH2- H H N 250 o-Cl CF3CH2- H H N 251 m-Cl CF3CH2- H H N 252 p-Cl CF3CH2- H H N 253 o-Br CF3CH2- H H N 254 m-Br CF3CH2- H H N 255 p-Br CF3CH2- H H N 256 o-NH2 CF3CH2- H H N 257 m-NH2 CF3CH2- H H N 258 p-NH2 CF3CH2- H H N 259 o-NO2 CF3CH2- H H N 260 m-NO2 CF3CH2- H H N 261 p-NO2 CF3CH2- H H N 262 o-OC2H5 CF3CH2- H H N 263 m-OC2H5 CF3CH2- H H N 264 p-OC2H5 CF3CH2- H H N 265 p-I CF3CH2- H H N 266 o-O-n-Pr CF3CH2- H H N 267 m-O-n-Pr CF3CH2- H H N 268 p-O-n-Pr CF3CH2- H H N 269 o-O-i-Pr CF3CH2- H H N 270 m-O-i-Pr CF3CH2- H H N 271 p-O-i-Pr CF3CH2- H H N 272 o-O-n-Bu CF3CH2- H H N 273 m-O-n-Bu CF3CH2- H H N 274 p-O-n-Bu CF3CH2- H H N 275 o-O-i-Bu CF3CH2- H H N 276 m-O-i-Bu CF3CH2- H H N 277 p-O-i-Bu CF3CH2- H H N 278 o-OCF3 CF3CH2- H H N 279 m-OCF3 CF3CH2- H H N 280 p-OCF3 CF3CH2- H H N 281 H H H H CH 282 o-OCH3 H H H CH 283 m-OCH3 H H H CH 284 p-OCH3 H H H CH 285 o-Cl H H H CH 286 m-Cl H H H CH 287 p-Cl H H H CH 288 o-Br H H H CH 289 m-Br H H H CH 290 p-Br H H H CH 291 o-NH2 H H H CH 292 m-NH2 H H H CH 293 p-NH2 H H H CH 294 o-NO2 H H H CH 295 m-NO2 H H H CH 296 p-NO2 H H H CH 297 o-OC2H5 H H H CH 298 m-OC2H5 H H H CH 299 p-OC2H5 H H H CH 300 p-I H H H CH 301 o-O-n-Pr H H H CH 302 m-O-n-Pr H H H CH 303 p-O-n-Pr H H H CH 304 o-O-i-Pr H H H CH 305 m-O-i-Pr H H H CH 306 p-O-i-Pr H H H CH 307 o-O-n-Bu H H H CH 308 m-O-n-Bu H H H CH 309 p-O-n-Bu H H H CH 310 o-O-i-Bu H H H CH 311 m-O-i-Bu H H H CH 312 p-O-i-Bu H H H CH 313 o-OCF3 H H H CH 314 m-OCF3 H H H CH 315 p-OCF3 H H H CH 316 H H H H N 317 o-OCH3 H H H N 318 m-OCH3 H H H N 319 p-OCH3 H H H N 320 o-Cl H H H N 321 m-Cl H H H N 322 p-Cl H H H N 323 o-Br H H H N 324 m-Br H H H N 325 p-Br H H H N 326 o-NH2 H H H N 327 m-NH2 H H H N 328 p-NH2 H H H N 329 o-NO2 H H H N 330 m-NO2 H H H N 331 p-NO2 H H H N 332 o-OC2H5 H H H N 333 m-OC2H5 H H H N 334 p-OC2H5 H H H N 335 p-I H H H N 336 o-O-n-Pr H H H N 337 m-O-n-Pr H H H N 338 p-O-n-Pr H H H N 339 o-O-i-Pr H H H N 340 m-O-i-Pr H H H N 341 p-O-i-Pr H H H N 342 o-O-n-Bu H H H N 343 m-O-n-Bu H H H N 344 p-O-n-Bu H H H N 345 o-O-i-Bu H H H N 346 m-O-i-Bu H H H N 347 p-O-i-Bu H H H N 348 o-OCF3 H H H N 349 m-OCF3 H H H N 350 p-OCF3 H H H N 351 H CF3CH2- CF3CH2- Me- CH 352 o-OCH3 CF3CH2- CF3CH2- Me- CH 353 m-OCH3 CF3CH2- CF3CH2- Me- CH 354 p-OCH3 CF3CH2- CF3CH2- Me- CH 355 o-Cl CF3CH2- CF3CH2- Me- CH 356 m-Cl CF3CH2- CF3CH2- Me- CH 357 p-Cl CF3CH2- CF3CH2- Me- CH 358 o-Br CF3CH2- CF3CH2- Me- CH 359 m-Br CF3CH2- CF3CH2- Me- CH 360 p-Br CF3CH2- CF3CH2- Me- CH 361 o-NH2 CF3CH2- CF3CH2- Me- CH 362 m-NH2 CF3CH2- CF3CH2- Me- CH 363 p-NH2 CF3CH2- CF3CH2- Me- CH 364 o-NO2 CF3CH2- CF3CH2- Me- CH 365 m-NO2 CF3CH2- CF3CH2- Me- CH 366 p-NO2 CF3CH2- CF3CH2- Me- CH 367 o-OC2H5 CF3CH2- CF3CH2- Me- CH 368 m-OC2H5 CF3CH2- CF3CH2- Me- CH 369 p-OC2H5 CF3CH2- CF3CH2- Me- CH 370 p-I CF3CH2- CF3CH2- Me- CH 371 o-O-n-Pr CF3CH2- CF3CH2- Me- CH 372 m-O-n-Pr CF3CH2- CF3CH2- Me- CH 373 p-O-n-Pr CF3CH2- CF3CH2- Me- CH 374 o-O-i-Pr CF3CH2- CF3CH2- Me- CH 375 m-O-i-Pr CF3CH2- CF3CH2- Me- CH 376 p-O-i-Pr CF3CH2- CF3CH2- Me- CH 377 o-O-n-Bu CF3CH2- CF3CH2- Me- CH 378 m-O-n-Bu CF3CH2- CF3CH2- Me- CH 379 p-O-n-Bu CF3CH2- CF3CH2- Me- CH 380 o-O-i-Bu CF3CH2- CF3CH2- Me- CH 381 m-O-i-Bu CF3CH2- CF3CH2- Me- CH 382 p-O-i-Bu CF3CH2- CF3CH2- Me- CH 383 o-OCF3 CF3CH2- CF3CH2- Me- CH 384 m-OCF3 CF3CH2- CF3CH2- Me- CH 385 p-OCF3 CF3CH2- CF3CH2- Me- CH 386 H CF3CH2- CF3CH2- Me- N 387 o-OCH3 CF3CH2- CF3CH2- Me- N 388 m-OCH3 CF3CH2- CF3CH2- Me- N 389 p-OCH3 CF3CH2- CF3CH2- Me- N 390 o-Cl CF3CH2- CF3CH2- Me- N 391 m-Cl CF3CH2- CF3CH2- Me- N 392 p-Cl CF3CH2- CF3CH2- Me- N 393 o-Br CF3CH2- CF3CH2- Me- N 394 m-Br CF3CH2- CF3CH2- Me- N 395 p-Br CF3CH2- CF3CH2- Me- N 396 o-NH2 CF3CH2- CF3CH2- Me- N 397 m-NH2 CF3CH2- CF3CH2- Me- N 398 p-NH2 CF3CH2- CF3CH2- Me- N 399 o-NO2 CF3CH2- CF3CH2- Me- N 400 m-NO2 CF3CH2- CF3CH2- Me- N 401 p-NO2 CF3CH2- CF3CH2- Me- N 402 o-OC2H5 CF3CH2- CF3CH2- Me- N 403 m-OC2H5 CF3CH2- CF3CH2- Me- N 404 p-OC2H5 CF3CH2- CF3CH2- Me- N 405 p-I CF3CH2- CF3CH2- Me- N 406 o-O-n-Pr CF3CH2- CF3CH2- Me- N 407 m-O-n-Pr CF3CH2- CF3CH2- Me- N 408 p-O-n-Pr CF3CH2- CF3CH2- Me- N 409 o-O-i-Pr CF3CH2- CF3CH2- Me- N 410 m-O-i-Pr CF3CH2- CF3CH2- Me- N 411 p-O-i-Pr CF3CH2- CF3CH2- Me- N 412 o-O-n-Bu CF3CH2- CF3CH2- Me- N 413 m-O-n-Bu CF3CH2- CF3CH2- Me- N 414 p-O-n-Bu CF3CH2- CF3CH2- Me- N 415 o-O-i-Bu CF3CH2- CF3CH2- Me- N 416 m-O-i-Bu CF3CH2- CF3CH2- Me- N 417 p-O-i-Bu CF3CH2- CF3CH2- Me- N 418 o-OCF3 CF3CH2- CF3CH2- Me- N 419 m-OCF3 CF3CH2- CF3CH2- Me- N 420 p-OCF3 CF3CH2- CF3CH2- Me- N 421 H CF3CH2- Me- Me- CH 422 o-OCH3 CF3CH2- Me- Me- CH 423 m-OCH3 CF3CH2- Me- Me- CH 424 p-OCH3 CF3CH2- Me- Me- CH 425 o-Cl CF3CH2- Me- Me- CH 426 m-Cl CF3CH2- Me- Me- CH 427 p-Cl CF3CH2- Me- Me- CH 428 o-Br CF3CH2- Me- Me- CH 429 m-Br CF3CH2- Me- Me- CH 430 p-Br CF3CH2- Me- Me- CH 431 o-NH2 CF3CH2- Me- Me- CH 432 m-NH2 CF3CH2- Me- Me- CH 433 p-NH2 CF3CH2- Me- Me- CH 434 o-NO2 CF3CH2- Me- Me- CH 435 m-NO2 CF3CH2- Me- Me- CH 436 p-NO2 CF3CH2- Me- Me- CH 437 o-OC2H5 CF3CH2- Me- Me- CH 438 m-OC2H5 CF3CH2- Me- Me- CH 439 p-OC2H5 CF3CH2- Me- Me- CH 440 p-I CF3CH2- Me- Me- CH 441 o-O-n-Pr CF3CH2- Me- Me- CH 442 m-O-n-Pr CF3CH2- Me- Me- CH 443 p-O-n-Pr CF3CH2- Me- Me- CH 444 o-O-i-Pr CF3CH2- Me- Me- CH 445 m-O-i-Pr CF3CH2- Me- Me- CH 446 p-O-i-Pr CF3CH2- Me- Me- CH 447 o-O-n-Bu CF3CH2- Me- Me- CH 448 m-O-n-Bu CF3CH2- Me- Me- CH 449 p-O-n-Bu CF3CH2- Me- Me- CH 450 o-O-i-Bu CF3CH2- Me- Me- CH 451 m-O-i-Bu CF3CH2- Me- Me- CH 452 p-O-i-Bu CF3CH2- Me- Me- CH 453 o-OCF3 CF3CH2- Me- Me- CH 454 m-OCF3 CF3CH2- Me- Me- CH 455 p-OCF3 CF3CH2- Me- Me- CH 456 H CF3CH2- Me- Me- N 457 o-OCH3 CF3CH2- Me- Me- N 458 m-OCH3 CF3CH2- Me- Me- N 459 p-OCH3 CF3CH2- Me- Me- N 460 o-Cl CF3CH2- Me- Me- N 461 m-Cl CF3CH2- Me- Me- N 462 p-Cl CF3CH2- Me- Me- N 463 o-Br CF3CH2- Me- Me- N 464 m-Br CF3CH2- Me- Me- N 465 p-Br CF3CH2- Me- Me- N 466 o-NH2 CF3CH2- Me- Me- N 467 m-NH2 CF3CH2- Me- Me- N 468 p-NH2 CF3CH2- Me- Me- N 469 o-NO2 CF3CH2- Me- Me- N 470 m-NO2 CF3CH2- Me- Me- N 471 p-NO2 CF3CH2- Me- Me- N 472 o-OC2H5 CF3CH2- Me- Me- N 473 m-OC2H5 CF3CH2- Me- Me- N 474 p-OC2H5 CF3CH2- Me- Me- N 475 p-I CF3CH2- Me- Me- N 476 o-O-n-Pr CF3CH2- Me- Me- N 477 m-O-n-Pr CF3CH2- Me- Me- N 478 p-O-n-Pr CF3CH2- Me- Me- N 479 o-O-i-Pr CF3CH2- Me- Me- N 480 m-O-i-Pr CF3CH2- Me- Me- N 481 p-O-i-Pr CF3CH2- Me- Me- N 482 o-O-n-Bu CF3CH2- Me- Me- N 483 m-O-n-Bu CF3CH2- Me- Me- N 484 p-O-n-Bu CF3CH2- Me- Me- N 485 o-O-i-Bu CF3CH2- Me- Me- N 486 m-O-i-Bu CF3CH2- Me- Me- N 487 p-O-i-Bu CF3CH2- Me- Me- N 488 o-OCF3 CF3CH2- Me- Me- N 489 m-OCF3 CF3CH2- Me- Me- N 490 p-OCF3 CF3CH2- Me- Me- N 491 H CF3CH2- Et- Me- CH 492 o-OCH3 CF3CH2- Et- Me- CH 493 m-OCH3 CF3CH2- Et- Me- CH 494 p-OCH3 CF3CH2- Et- Me- CH 495 o-Cl CF3CH2- Et- Me- CH 496 m-Cl CF3CH2- Et- Me- CH 497 p-Cl CF3CH2- Et- Me- CH 498 o-Br CF3CH2- Et- Me- CH 499 m-Br CF3CH2- Et- Me- CH 500 p-Br CF3CH2- Et- Me- CH 501 o-NH2 CF3CH2- Et- Me- CH 502 m-NH2 CF3CH2- Et- Me- CH 503 p-NH2 CF3CH2- Et- Me- CH 504 o-NO2 CF3CH2- Et- Me- CH 505 m-NO2 CF3CH2- Et- Me- CH 506 p-NO2 CF3CH2- Et- Me- CH 507 o-OC2H5 CF3CH2- Et- Me- CH 508 m-OC2H5 CF3CH2- Et- Me- CH 509 p-OC2H5 CF3CH2- Et- Me- CH 510 p-I CF3CH2- Et- Me- CH 511 o-O-n-Pr CF3CH2- Et- Me- CH 512 m-O-n-Pr CF3CH2- Et- Me- CH 513 p-O-n-Pr CF3CH2- Et- Me- CH 514 o-O-i-Pr CF3CH2- Et- Me- CH 515 m-O-i-Pr CF3CH2- Et- Me- CH 516 p-O-i-Pr CF3CH2- Et- Me- CH 517 o-O-n-Bu CF3CH2- Et- Me- CH 518 m-O-n-Bu CF3CH2- Et- Me- CH 519 p-O-n-Bu CF3CH2- Et- Me- CH 520 o-O-i-Bu CF3CH2- Et- Me- CH 521 m-O-i-Bu CF3CH2- Et- Me- CH 522 p-O-i-Bu CF3CH2- Et- Me- CH 523 o-OCF3 CF3CH2- Et- Me- CH 524 m-OCF3 CF3CH2- Et- Me- CH 525 p-OCF3 CF3CH2- Et- Me- CH 526 H CF3CH2- Et- Me- N 527 o-OCH3 CF3CH2- Et- Me- N 528 m-OCH3 CF3CH2- Et- Me- N 529 p-OCH3 CF3CH2- Et- Me- N 530 o-Cl CF3CH2- Et- Me- N 531 m-Cl CF3CH2- Et- Me- N 532 p-Cl CF3CH2- Et- Me- N 533 o-Br CF3CH2- Et- Me- N 534 m-Br CF3CH2- Et- Me- N 535 p-Br CF3CH2- Et- Me- N 536 o-NH2 CF3CH2- Et- Me- N 537 m-NH2 CF3CH2- Et- Me- N 538 p-NH2 CF3CH2- Et- Me- N 539 o-NO2 CF3CH2- Et- Me- N 540 m-NO2 CF3CH2- Et- Me- N 541 p-NO2 CF3CH2- Et- Me- N 542 o-OC2H5 CF3CH2- Et- Me- N 543 m-OC2H5 CF3CH2- Et- Me- N 544 p-OC2H5 CF3CH2- Et- Me- N 545 p-I CF3CH2- Et- Me- N 546 o-O-n-Pr CF3CH2- Et- Me- N 547 m-O-n-Pr CF3CH2- Et- Me- N 548 p-O-n-Pr CF3CH2- Et- Me- N 549 o-O-i-Pr CF3CH2- Et- Me- N 550 m-O-i-Pr CF3CH2- Et- Me- N 551 p-O-i-Pr CF3CH2- Et- Me- N 552 o-O-n-Bu CF3CH2- Et- Me- N 553 m-O-n-Bu CF3CH2- Et- Me- N 554 p-O-n-Bu CF3CH2- Et- Me- N 555 o-O-i-Bu CF3CH2- Et- Me- N 556 m-O-i-Bu CF3CH2- Et- Me- N 557 p-O-i-Bu CF3CH2- Et- Me- N 558 o-OCF3 CF3CH2- Et- Me- N 559 m-OCF3 CF3CH2- Et- Me- N 560 p-OCF3 CF3CH2- Et- Me- N 561 H CF3CH2- H Me- CH 562 o-OCH3 CF3CH2- H Me- CH 563 m-OCH3 CF3CH2- H Me- CH 564 p-OCH3 CF3CH2- H Me- CH 565 o-Cl CF3CH2- H Me- CH 566 m-Cl CF3CH2- H Me- CH 567 p-Cl CF3CH2- H Me- CH 568 o-Br CF3CH2- H Me- CH 569 m-Br CF3CH2- H Me- CH 570 p-Br CF3CH2- H Me- CH 571 o-NH2 CF3CH2- H Me- CH 572 m-NH2 CF3CH2- H Me- CH 573 p-NH2 CF3CH2- H Me- CH 574 o-NO2 CF3CH2- H Me- CH 575 m-NO2 CF3CH2- H Me- CH 576 p-NO2 CF3CH2- H Me- CH 577 o-OC2H5 CF3CH2- H Me- CH 578 m-OC2H5 CF3CH2- H Me- CH 579 p-OC2H5 CF3CH2- H Me- CH 580 p-I CF3CH2- H Me- CH 581 o-O-n-Pr CF3CH2- H Me- CH 582 m-O-n-Pr CF3CH2- H Me- CH 583 p-O-n-Pr CF3CH2- H Me- CH 584 o-O-i-Pr CF3CH2- H Me- CH 585 m-O-i-Pr CF3CH2- H Me- CH 586 p-O-i-Pr CF3CH2- H Me- CH 587 o-O-n-Bu CF3CH2- H Me- CH 588 m-O-n-Bu CF3CH2- H Me- CH 589 p-O-n-Bu CF3CH2- H Me- CH 590 o-O-i-Bu CF3CH2- H Me- CH 591 m-O-i-Bu CF3CH2- H Me- CH 592 p-O-i-Bu CF3CH2- H Me- CH 593 o-OCF3 CF3CH2- H Me- CH 594 m-OCF3 CF3CH2- H Me- CH 595 p-OCF3 CF3CH2- H Me- CH 596 H CF3CH2- H Me- N 597 o-OCH3 CF3CH2- H Me- N 598 m-OCH3 CF3CH2- H Me- N 599 p-OCH3 CF3CH2- H Me- N 600 o-Cl CF3CH2- H Me- N 601 m-Cl CF3CH2- H Me- N 602 p-Cl CF3CH2- H Me- N 603 o-Br CF3CH2- H Me- N 604 m-Br CF3CH2- H Me- N 605 p-Br CF3CH2- H Me- N 606 o-NH2 CF3CH2- H Me- N 607 m-NH2 CF3CH2- H Me- N 608 p-NH2 CF3CH2- H Me- N 609 o-NO2 CF3CH2- H Me- N 610 m-NO2 CF3CH2- H Me- N 611 p-NO2 CF3CH2- H Me- N 612 o-OC2H5 CF3CH2- H Me- N 613 m-OC2H5 CF3CH2- H Me- N 614 p-OC2H5 CF3CH2- H Me- N 615 p-I CF3CH2- H Me- N 616 o-O-n-Pr CF3CH2- H Me- N 617 m-O-n-Pr CF3CH2- H Me- N 618 p-O-n-Pr CF3CH2- H Me- N 619 o-O-i-Pr CF3CH2- H Me- N 620 m-O-i-Pr CF3CH2- H Me- N 621 p-O-i-Pr CF3CH2- H Me- N 622 o-O-n-Bu CF3CH2- H Me- N 623 m-O-n-Bu CF3CH2- H Me- N 624 p-O-n-Bu CF3CH2- H Me- N 625 o-O-i-Bu CF3CH2- H Me- N 626 m-O-i-Bu CF3CH2- H Me- N 627 p-O-i-Bu CF3CH2- H Me- N 628 o-OCF3 CF3CH2- H Me- N 629 m-OCF3 CF3CH2- H Me- N 630 p-OCF3 CF3CH2- H Me- N 631 H H H Me- CH 632 o-OCH3 H H Me- CH 633 m-OCH3 H H Me- CH 634 p-OCH3 H H Me- CH 635 o-Cl H H Me- CH 636 m-Cl H H Me- CH 637 p-Cl H H Me- CH 638 o-Br H H Me- CH 639 m-Br H H Me- CH 640 p-Br H H Me- CH 641 o-NH2 H H Me- CH 642 m-NH2 H H Me- CH 643 p-NH2 H H Me- CH 644 o-NO2 H H Me- CH 645 m-NO2 H H Me- CH 646 p-NO2 H H Me- CH 647 o-OC2H5 H H Me- CH 648 m-OC2H5 H H Me- CH 649 p-OC2H5 H H Me- CH 650 p-I H H Me- CH 651 o-O-n-Pr H H Me- CH 652 m-O-n-Pr H H Me- CH 653 p-O-n-Pr H H Me- CH 654 o-O-i-Pr H H Me- CH 655 m-O-i-Pr H H Me- CH 656 p-O-i-Pr H H Me- CH 657 o-O-n-Bu H H Me- CH 658 m-O-n-Bu H H Me- CH 659 p-O-n-Bu H H Me- CH 660 o-O-i-Bu H H Me- CH 661 m-O-i-Bu H H Me- CH 662 p-O-i-Bu H H Me- CH 663 o-OCF3 H H Me- CH 664 m-OCF3 H H Me- CH 665 p-OCF3 H H Me- CH 666 H H H Me- N 667 o-OCH3 H H Me- N 668 m-OCH3 H H Me- N 669 p-OCH3 H H Me- N 670 o-Cl H H Me- N 671 m-Cl H H Me- N 672 p-Cl H H Me- N 673 o-Br H H Me- N 674 m-Br H H Me- N 675 p-Br H H Me- N 676 o-NH2 H H Me- N 677 m-NH2 H H Me- N 678 p-NH2 H H Me- N 679 o-NO2 H H Me- N 680 m-NO2 H H Me- N 681 p-NO2 H H Me- N 682 o-OC2H5 H H Me- N 683 m-OC2H5 H H Me- N 684 p-OC2H5 H H Me- N 685 p-I H H Me- N 686 o-O-n-Pr H H Me- N 687 m-O-n-Pr H H Me- N 688 p-O-n-Pr H H Me- N 689 o-O-i-Pr H H Me- N 690 m-O-i-Pr H H Me- N 691 p-O-i-Pr H H Me- N 692 o-O-n-Bu H H Me- N 693 m-O-n-Bu H H Me- N 694 p-O-n-Bu H H Me- N 695 o-O-i-Bu H H Me- N 696 m-O-i-Bu H H Me- N 697 p-O-i-Bu H H Me- N 698 o-OCF3 H H Me- N 699 m-OCF3 H H Me- N 700 p-OCF3 H H Me- N 701 H CF3CH2- CF3CH2- -CH2F CH 702 o-OCH3 CF3CH2- CF3CH2- -CH2F CH 703 m-OCH3 CF3CH2- CF3CH2- -CH2F CH 704 p-OCH3 CF3CH2- CF3CH2- -CH2F CH 705 o-Cl CF3CH2- CF3CH2- -CH2F CH 706 m-Cl CF3CH2- CF3CH2- -CH2F CH 707 p-Cl CF3CH2- CF3CH2- -CH2F CH 708 o-Br CF3CH2- CF3CH2- -CH2F CH 709 m-Br CF3CH2- CF3CH2- -CH2F CH 710 p-Br CF3CH2- CF3CH2- -CH2F CH 711 o-NH2 CF3CH2- CF3CH2- -CH2F CH 712 m-NH2 CF3CH2- CF3CH2- -CH2F CH 713 p-NH2 CF3CH2- CF3CH2- -CH2F CH 714 o-NO2 CF3CH2- CF3CH2- -CH2F CH 715 m-NO2 CF3CH2- CF3CH2- -CH2F CH 716 p-NO2 CF3CH2- CF3CH2- -CH2F CH 717 o-OC2H5 CF3CH2- CF3CH2- -CH2F CH 718 m-OC2H5 CF3CH2- CF3CH2- -CH2F CH 719 p-OC2H5 CF3CH2- CF3CH2- -CH2F CH 720 p-I CF3CH2- CF3CH2- -CH2F CH 721 o-O-n-Pr CF3CH2- CF3CH2- -CH2F CH 722 m-O-n-Pr CF3CH2- CF3CH2- -CH2F CH 723 p-O-n-Pr CF3CH2- CF3CH2- -CH2F CH 724 o-O-i-Pr CF3CH2- CF3CH2- -CH2F CH 725 m-O-i-Pr CF3CH2- CF3CH2- -CH2F CH 726 p-O-i-Pr CF3CH2- CF3CH2- -CH2F CH 727 o-O-n-Bu CF3CH2- CF3CH2- -CH2F CH 728 m-O-n-Bu CF3CH2- CF3CH2- -CH2F CH 729 p-O-n-Bu CF3CH2- CF3CH2- -CH2F CH 730 o-O-i-Bu CF3CH2- CF3CH2- -CH2F CH 731 m-O-i-Bu CF3CH2- CF3CH2- -CH2F CH 732 p-O-i-Bu CF3CH2- CF3CH2- -CH2F CH 733 o-OCF3 CF3CH2- CF3CH2- -CH2F CH 734 m-OCF3 CF3CH2- CF3CH2- -CH2F CH 735 p-OCF3 CF3CH2- CF3CH2- -CH2F CH 736 H CF3CH2- CF3CH2- -CH2F N 737 o-OCH3 CF3CH2- CF3CH2- -CH2F N 738 m-OCH3 CF3CH2- CF3CH2- -CH2F N 739 p-OCH3 CF3CH2- CF3CH2- -CH2F N 740 o-Cl CF3CH2- CF3CH2- -CH2F N 741 m-Cl CF3CH2- CF3CH2- -CH2F N 742 p-Cl CF3CH2- CF3CH2- -CH2F N 743 o-Br CF3CH2- CF3CH2- -CH2F N 744 m-Br CF3CH2- CF3CH2- -CH2F N 745 p-Br CF3CH2- CF3CH2- -CH2F N 746 o-NH2 CF3CH2- CF3CH2- -CH2F N 747 m-NH2 CF3CH2- CF3CH2- -CH2F N 748 p-NH2 CF3CH2- CF3CH2- -CH2F N 749 o-NO2 CF3CH2- CF3CH2- -CH2F N 750 m-NO2 CF3CH2- CF3CH2- -CH2F N 751 p-NO2 CF3CH2- CF3CH2- -CH2F N 752 o-OC2H5 CF3CH2- CF3CH2- -CH2F N 753 m-OC2H5 CF3CH2- CF3CH2- -CH2F N 754 p-OC2H5 CF3CH2- CF3CH2- -CH2F N 755 p-I CF3CH2- CF3CH2- -CH2F N 756 o-O-n-Pr CF3CH2- CF3CH2- -CH2F N 757 m-O-n-Pr CF3CH2- CF3CH2- -CH2F N 758 p-O-n-Pr CF3CH2- CF3CH2- -CH2F N 759 o-O-i-Pr CF3CH2- CF3CH2- -CH2F N 760 m-O-i-Pr CF3CH2- CF3CH2- -CH2F N 761 p-O-i-Pr CF3CH2- CF3CH2- -CH2F N 762 o-O-n-Bu CF3CH2- CF3CH2- -CH2F N 763 m-O-n-Bu CF3CH2- CF3CH2- -CH2F N 764 p-O-n-Bu CF3CH2- CF3CH2- -CH2F N 765 o-O-i-Bu CF3CH2- CF3CH2- -CH2F N 766 m-O-i-Bu CF3CH2- CF3CH2- -CH2F N 767 p-O-i-Bu CF3CH2- CF3CH2- -CH2F N 768 o-OCF3 CF3CH2- CF3CH2- -CH2F N 769 m-OCF3 CF3CH2- CF3CH2- -CH2F N 770 p-OCF3 CF3CH2- CF3CH2- -CH2F N 771 H CF3CH2- Me- -CH2F CH 772 o-OCH3 CF3CH2- Me- -CH2F CH 773 m-OCH3 CF3CH2- Me- -CH2F CH 774 p-OCH3 CF3CH2- Me- -CH2F CH 775 o-Cl CF3CH2- Me- -CH2F CH 776 m-Cl CF3CH2- Me- -CH2F CH 777 p-Cl CF3CH2- Me- -CH2F CH 778 o-Br CF3CH2- Me- -CH2F CH 779 m-Br CF3CH2- Me- -CH2F CH 780 p-Br CF3CH2- Me- -CH2F CH 781 o-NH2 CF3CH2- Me- -CH2F CH 782 m-NH2 CF3CH2- Me- -CH2F CH 783 p-NH2 CF3CH2- Me- -CH2F CH 784 o-NO2 CF3CH2- Me- -CH2F CH 785 m-NO2 CF3CH2- Me- -CH2F CH 786 p-NO2 CF3CH2- Me- -CH2F CH 787 o-OC2H5 CF3CH2- Me- -CH2F CH 788 m-OC2H5 CF3CH2- Me- -CH2F CH 789 p-OC2H5 CF3CH2- Me- -CH2F CH 790 p-I CF3CH2- Me- -CH2F CH 791 o-O-n-Pr CF3CH2- Me- -CH2F CH 792 m-O-n-Pr CF3CH2- Me- -CH2F CH 793 p-O-n-Pr CF3CH2- Me- -CH2F CH 794 o-O-i-Pr CF3CH2- Me- -CH2F CH 795 m-O-i-Pr CF3CH2- Me- -CH2F CH 796 p-O-i-Pr CF3CH2- Me- -CH2F CH 797 o-O-n-Bu CF3CH2- Me- -CH2F CH 798 m-O-n-Bu CF3CH2- Me- -CH2F CH 799 p-O-n-Bu CF3CH2- Me- -CH2F CH 800 o-O-i-Bu CF3CH2- Me- -CH2F CH 801 m-O-i-Bu CF3CH2- Me- -CH2F CH 802 p-O-i-Bu CF3CH2- Me- -CH2F CH 803 o-OCF3 CF3CH2- Me- -CH2F CH 804 m-OCF3 CF3CH2- Me- -CH2F CH 805 p-OCF3 CF3CH2- Me- -CH2F CH 806 H CF3CH2- Me- -CH2F N 807 o-OCH3 CF3CH2- Me- -CH2F N 808 m-OCH3 CF3CH2- Me- -CH2F N 809 p-OCH3 CF3CH2- Me- -CH2F N 810 o-Cl CF3CH2- Me- -CH2F N 811 m-Cl CF3CH2- Me- -CH2F N 812 p-Cl CF3CH2- Me- -CH2F N 813 o-Br CF3CH2- Me- -CH2F N 814 m-Br CF3CH2- Me- -CH2F N 815 p-Br CF3CH2- Me- -CH2F N 816 o-NH2 CF3CH2- Me- -CH2F N 817 m-NH2 CF3CH2- Me- -CH2F N 818 p-NH2 CF3CH2- Me- -CH2F N 819 o-NO2 CF3CH2- Me- -CH2F N 820 m-NO2 CF3CH2- Me- -CH2F N 821 p-NO2 CF3CH2- Me- -CH2F N 822 o-OC2H5 CF3CH2- Me- -CH2F N 823 m-OC2H5 CF3CH2- Me- -CH2F N 824 p-OC2H5 CF3CH2- Me- -CH2F N 825 p-I CF3CH2- Me- -CH2F N 826 o-O-n-Pr CF3CH2- Me- -CH2F N 827 m-O-n-Pr CF3CH2- Me- -CH2F N 828 p-O-n-Pr CF3CH2- Me- -CH2F N 829 o-O-i-Pr CF3CH2- Me- -CH2F N 830 m-O-i-Pr CF3CH2- Me- -CH2F N 831 p-O-i-Pr CF3CH2- Me- -CH2F N 832 o-O-n-Bu CF3CH2- Me- -CH2F N 833 m-O-n-Bu CF3CH2- Me- -CH2F N 834 p-O-n-Bu CF3CH2- Me- -CH2F N 835 o-O-i-Bu CF3CH2- Me- -CH2F N 836 m-O-i-Bu CF3CH2- Me- -CH2F N 837 p-O-i-Bu CF3CH2- Me- -CH2F N 838 o-OCF3 CF3CH2- Me- -CH2F N 839 m-OCF3 CF3CH2- Me- -CH2F N 840 p-OCF3 CF3CH2- Me- -CH2F N 841 H CF3CH2- Et- -CH2F CH 842 o-OCH3 CF3CH2- Et- -CH2F CH 843 m-OCH3 CF3CH2- Et- -CH2F CH 844 p-OCH3 CF3CH2- Et- -CH2F CH 845 o-Cl CF3CH2- Et- -CH2F CH 846 m-Cl CF3CH2- Et- -CH2F CH 847 p-Cl CF3CH2- Et- -CH2F CH 848 o-Br CF3CH2- Et- -CH2F CH 849 m-Br CF3CH2- Et- -CH2F CH 850 p-Br CF3CH2- Et- -CH2F CH 851 o-NH2 CF3CH2- Et- -CH2F CH 852 m-NH2 CF3CH2- Et- -CH2F CH 853 p-NH2 CF3CH2- Et- -CH2F CH 854 o-NO2 CF3CH2- Et- -CH2F CH 855 m-NO2 CF3CH2- Et- -CH2F CH 856 p-NO2 CF3CH2- Et- -CH2F CH 857 o-OC2H5 CF3CH2- Et- -CH2F CH 858 m-OC2H5 CF3CH2- Et- -CH2F CH 859 p-OC2H5 CF3CH2- Et- -CH2F CH 860 p-I CF3CH2- Et- -CH2F CH 861 o-O-n-Pr CF3CH2- Et- -CH2F CH 862 m-O-n-Pr CF3CH2- Et- -CH2F CH 863 p-O-n-Pr CF3CH2- Et- -CH2F CH 864 o-O-i-Pr CF3CH2- Et- -CH2F CH 865 m-O-i-Pr CF3CH2- Et- -CH2F CH 866 p-O-i-Pr CF3CH2- Et- -CH2F CH 867 o-O-n-Bu CF3CH2- Et- -CH2F CH 868 m-O-n-Bu CF3CH2- Et- -CH2F CH 869 p-O-n-Bu CF3CH2- Et- -CH2F CH 870 o-O-i-Bu CF3CH2- Et- -CH2F CH 871 m-O-i-Bu CF3CH2- Et- -CH2F CH 872 p-O-i-Bu CF3CH2- Et- -CH2F CH 873 o-OCF3 CF3CH2- Et- -CH2F CH 874 m-OCF3 CF3CH2- Et- -CH2F CH 875 p-OCF3 CF3CH2- Et- -CH2F CH 876 H CF3CH2- Et- -CH2F N 877 o-OCH3 CF3CH2- Et- -CH2F N 878 m-OCH3 CF3CH2- Et- -CH2F N 879 p-OCH3 CF3CH2- Et- -CH2F N 880 o-Cl CF3CH2- Et- -CH2F N 881 m-Cl CF3CH2- Et- -CH2F N 882 p-Cl CF3CH2- Et- -CH2F N 883 o-Br CF3CH2- Et- -CH2F N 884 m-Br CF3CH2- Et- -CH2F N 885 p-Br CF3CH2- Et- -CH2F N 886 o-NH2 CF3CH2- Et- -CH2F N 887 m-NH2 CF3CH2- Et- -CH2F N 888 p-NH2 CF3CH2- Et- -CH2F N 889 o-NO2 CF3CH2- Et- -CH2F N 890 m-NO2 CF3CH2- Et- -CH2F N 891 p-NO2 CF3CH2- Et- -CH2F N 892 o-OC2H5 CF3CH2- Et- -CH2F N 893 m-OC2H5 CF3CH2- Et- -CH2F N 894 p-OC2H5 CF3CH2- Et- -CH2F N 895 p-I CF3CH2- Et- -CH2F N 896 o-O-n-Pr CF3CH2- Et- -CH2F N 897 m-O-n-Pr CF3CH2- Et- -CH2F N 898 p-O-n-Pr CF3CH2- Et- -CH2F N 899 o-O-i-Pr CF3CH2- Et- -CH2F N 900 m-O-i-Pr CF3CH2- Et- -CH2F N 901 p-O-i-Pr CF3CH2- Et- -CH2F N 902 o-O-n-Bu CF3CH2- Et- -CH2F N 903 m-O-n-Bu CF3CH2- Et- -CH2F N 904 p-O-n-Bu CF3CH2- Et- -CH2F N 905 o-O-i-Bu CF3CH2- Et- -CH2F N 906 m-O-i-Bu CF3CH2- Et- -CH2F N 907 p-O-i-Bu CF3CH2- Et- -CH2F N 908 o-OCF3 CF3CH2- Et- -CH2F N 909 m-OCF3 CF3CH2- Et- -CH2F N 910 p-OCF3 CF3CH2- Et- -CH2F N 911 H CF3CH2- H -CH2F CH 912 o-OCH3 CF3CH2- H -CH2F CH 913 m-OCH3 CF3CH2- H -CH2F CH 914 p-OCH3 CF3CH2- H -CH2F CH 915 o-Cl CF3CH2- H -CH2F CH 916 m-Cl CF3CH2- H -CH2F CH 917 p-Cl CF3CH2- H -CH2F CH 918 o-Br CF3CH2- H -CH2F CH 919 m-Br CF3CH2- H -CH2F CH 920 p-Br CF3CH2- H -CH2F CH 921 o-NH2 CF3CH2- H -CH2F CH 922 m-NH2 CF3CH2- H -CH2F CH 923 p-NH2 CF3CH2- H -CH2F CH 924 o-NO2 CF3CH2- H -CH2F CH 925 m-NO2 CF3CH2- H -CH2F CH 926 p-NO2 CF3CH2- H -CH2F CH 927 o-OC2H5 CF3CH2- H -CH2F CH 928 m-OC2H5 CF3CH2- H -CH2F CH 929 p-OC2H5 CF3CH2- H -CH2F CH 930 p-I CF3CH2- H -CH2F CH 931 o-O-n-Pr CF3CH2- H -CH2F CH 932 m-O-n-Pr CF3CH2- H -CH2F CH 933 p-O-n-Pr CF3CH2- H -CH2F CH 934 o-O-i-Pr CF3CH2- H -CH2F CH 935 m-O-i-Pr CF3CH2- H -CH2F CH 936 p-O-i-Pr CF3CH2- H -CH2F CH 937 o-O-n-Bu CF3CH2- H -CH2F CH 938 m-O-n-Bu CF3CH2- H -CH2F CH 939 p-O-n-Bu CF3CH2- H -CH2F CH 940 o-O-i-Bu CF3CH2- H -CH2F CH 941 m-O-i-Bu CF3CH2- H -CH2F CH 942 p-O-i-Bu CF3CH2- H -CH2F CH 943 o-OCF3 CF3CH2- H -CH2F CH 944 m-OCF3 CF3CH2- H -CH2F CH 945 p-OCF3 CF3CH2- H -CH2F CH 946 H CF3CH2- H -CH2F N 947 o-OCH3 CF3CH2- H -CH2F N 948 m-OCH3 CF3CH2- H -CH2F N 949 p-OCH3 CF3CH2- H -CH2F N 950 o-Cl CF3CH2- H -CH2F N 951 m-Cl CF3CH2- H -CH2F N 952 p-Cl CF3CH2- H -CH2F N 953 o-Br CF3CH2- H -CH2F N 954 m-Br CF3CH2- H -CH2F N 955 p-Br CF3CH2- H -CH2F N 956 o-NH2 CF3CH2- H -CH2F N 957 m-NH2 CF3CH2- H -CH2F N 958 p-NH2 CF3CH2- H -CH2F N 959 o-NO2 CF3CH2- H -CH2F N 960 m-NO2 CF3CH2- H -CH2F N 961 p-NO2 CF3CH2- H -CH2F N 962 o-OC2H5 CF3CH2- H -CH2F N 963 m-OC2H5 CF3CH2- H -CH2F N 964 p-OC2H5 CF3CH2- H -CH2F N 965 p-I CF3CH2- H -CH2F N 966 o-O-n-Pr CF3CH2- H -CH2F N 967 m-O-n-Pr CF3CH2- H -CH2F N 968 p-O-n-Pr CF3CH2- H -CH2F N 969 o-O-i-Pr CF3CH2- H -CH2F N 970 m-O-i-Pr CF3CH2- H -CH2F N 971 p-O-i-Pr CF3CH2- H -CH2F N 972 o-O-n-Bu CF3CH2- H -CH2F N 973 m-O-n-Bu CF3CH2- H -CH2F N 974 p-O-n-Bu CF3CH2- H -CH2F N 975 o-O-i-Bu CF3CH2- H -CH2F N 976 m-O-i-Bu CF3CH2- H -CH2F N 977 p-O-i-Bu CF3CH2- H -CH2F N 978 o-OCF3 CF3CH2- H -CH2F N 979 m-OCF3 CF3CH2- H -CH2F N 980 p-OCF3 CF3CH2- H -CH2F N 981 H H H -CH2F CH 982 o-OCH3 H H -CH2F CH 983 m-OCH3 H H -CH2F CH 984 p-OCH3 H H -CH2F CH 985 o-Cl H H -CH2F CH 986 m-Cl H H -CH2F CH 987 p-Cl H H -CH2F CH 988 o-Br H H -CH2F CH 989 m-Br H H -CH2F CH 990 p-Br H H -CH2F CH 991 o-NH2 H H -CH2F CH 992 m-NH2 H H -CH2F CH 993 p-NH2 H H -CH2F CH 994 o-NO2 H H -CH2F CH 995 m-NO2 H H -CH2F CH 996 p-NO2 H H -CH2F CH 997 o-OC2H5 H H -CH2F CH 998 m-OC2H5 H H -CH2F CH 999 p-OC2H5 H H -CH2F CH 1000 p-I H H -CH2F CH 1001 o-O-n-Pr H H -CH2F CH 1002 m-O-n-Pr H H -CH2F CH 1003 p-O-n-Pr H H -CH2F CH 1004 o-O-i-Pr H H -CH2F CH 1005 m-O-i-Pr H H -CH2F CH 1006 p-O-i-Pr H H -CH2F CH 1007 o-O-n-Bu H H -CH2F CH 1008 m-O-n-Bu H H -CH2F CH 1009 p-O-n-Bu H H -CH2F CH 1010 o-O-i-Bu H H -CH2F CH 1011 m-O-i-Bu H H -CH2F CH 1012 p-O-i-Bu H H -CH2F CH 1013 o-OCF3 H H -CH2F CH 1014 m-OCF3 H H -CH2F CH 1015 p-OCF3 H H -CH2F CH 1016 H H H -CH2F N 1017 o-OCH3 H H -CH2F N 1018 m-OCH3 H H -CH2F N 1019 p-OCH3 H H -CH2F N 1020 o-Cl H H -CH2F N 1021 m-Cl H H -CH2F N 1022 p-Cl H H -CH2F N 1023 o-Br H H -CH2F N 1024 m-Br H H -CH2F N 1025 p-Br H H -CH2F N 1026 o-NH2 H H -CH2F N 1027 m-NH2 H H -CH2F N 1028 p-NH2 H H -CH2F N 1029 o-NO2 H H -CH2F N 1030 m-NO2 H H -CH2F N 1031 p-NO2 H H -CH2F N 1032 o-OC2H5 H H -CH2F N 1033 m-OC2H5 H H -CH2F N 1034 p-OC2H5 H H -CH2F N 1035 p-I H H -CH2F N 1036 o-O-n-Pr H H -CH2F N 1037 m-O-n-Pr H H -CH2F N 1038 p-O-n-Pr H H -CH2F N 1039 o-O-i-Pr H H -CH2F N 1040 m-O-i-Pr H H -CH2F N 1041 p-O-i-Pr H H -CH2F N 1042 o-O-n-Bu H H -CH2F N 1043 m-O-n-Bu H H -CH2F N 1044 p-O-n-Bu H H -CH2F N 1045 o-O-i-Bu H H -CH2F N 1046 m-O-i-Bu H H -CH2F N 1047 p-O-i-Bu H H -CH2F N 1048 o-OCF3 H H -CH2F N 1049 m-OCF3 H H -CH2F N 1050 p-OCF3 H H -CH2F N 1051 H CF3CH2- CF3CH2- -CH2OH CH 1052 o-OCH3 CF3CH2- CF3CH2- -CH2OH CH 1053 m-OCH3 CF3CH2- CF3CH2- -CH2OH CH 1054 p-OCH3 CF3CH2- CF3CH2- -CH2OH CH 1055 o-Cl CF3CH2- CF3CH2- -CH2OH CH 1056 m-Cl CF3CH2- CF3CH2- -CH2OH CH 1057 p-Cl CF3CH2- CF3CH2- -CH2OH CH 1058 o-Br CF3CH2- CF3CH2- -CH2OH CH 1059 m-Br CF3CH2- CF3CH2- -CH2OH CH 1060 p-Br CF3CH2- CF3CH2- -CH2OH CH 1061 o-NH2 CF3CH2- CF3CH2- -CH2OH CH 1062 m-NH2 CF3CH2- CF3CH2- -CH2OH CH 1063 p-NH2 CF3CH2- CF3CH2- -CH2OH CH 1064 o-NO2 CF3CH2- CF3CH2- -CH2OH CH 1065 m-NO2 CF3CH2- CF3CH2- -CH2OH CH 1066 p-NO2 CF3CH2- CF3CH2- -CH2OH CH 1067 o-OC2H5 CF3CH2- CF3CH2- -CH2OH CH 1068 m-OC2H5 CF3CH2- CF3CH2- -CH2OH CH 1069 p-OC2H5 CF3CH2- CF3CH2- -CH2OH CH 1070 p-I CF3CH2- CF3CH2- -CH2OH CH 1071 o-O-n-Pr CF3CH2- CF3CH2- -CH2OH CH 1072 m-O-n-Pr CF3CH2- CF3CH2- -CH2OH CH 1073 p-O-n-Pr CF3CH2- CF3CH2- -CH2OH CH 1074 o-O-i-Pr CF3CH2- CF3CH2- -CH2OH CH 1075 m-O-i-Pr CF3CH2- CF3CH2- -CH2OH CH 1076 p-O-i-Pr CF3CH2- CF3CH2- -CH2OH CH 1077 o-O-n-Bu CF3CH2- CF3CH2- -CH2OH CH 1078 m-O-n-Bu CF3CH2- CF3CH2- -CH2OH CH 1079 p-O-n-Bu CF3CH2- CF3CH2- -CH2OH CH 1080 o-O-i-Bu CF3CH2- CF3CH2- -CH2OH CH 1081 m-O-i-Bu CF3CH2- CF3CH2- -CH2OH CH 1082 p-O-i-Bu CF3CH2- CF3CH2- -CH2OH CH 1083 o-OCF3 CF3CH2- CF3CH2- -CH2OH CH 1084 m-OCF3 CF3CH2- CF3CH2- -CH2OH CH 1085 p-OCF3 CF3CH2- CF3CH2- -CH2OH CH 1086 H CF3CH2- CF3CH2- -CH2OH N 1087 o-OCH3 CF3CH2- CF3CH2- -CH2OH N 1088 m-OCH3 CF3CH2- CF3CH2- -CH2OH N 1089 p-OCH3 CF3CH2- CF3CH2- -CH2OH N 1090 o-Cl CF3CH2- CF3CH2- -CH2OH N 1091 m-Cl CF3CH2- CF3CH2- -CH2OH N 1092 p-Cl CF3CH2- CF3CH2- -CH2OH N 1093 o-Br CF3CH2- CF3CH2- -CH2OH N 1094 m-Br CF3CH2- CF3CH2- -CH2OH N 1095 p-Br CF3CH2- CF3CH2- -CH2OH N 1096 o-NH2 CF3CH2- CF3CH2- -CH2OH N 1097 m-NH2 CF3CH2- CF3CH2- -CH2OH N 1098 p-NH2 CF3CH2- CF3CH2- -CH2OH N 1099 o-NO2 CF3CH2- CF3CH2- -CH2OH N 1100 m-NO2 CF3CH2- CF3CH2- -CH2OH N 1101 p-NO2 CF3CH2- CF3CH2- -CH2OH N 1102 o-OC2H5 CF3CH2- CF3CH2- -CH2OH N 1103 m-OC2H5 CF3CH2- CF3CH2- -CH2OH N 1104 p-OC2H5 CF3CH2- CF3CH2- -CH2OH N 1105 p-I CF3CH2- CF3CH2- -CH2OH N 1106 o-O-n-Pr CF3CH2- CF3CH2- -CH2OH N 1107 m-O-n-Pr CF3CH2- CF3CH2- -CH2OH N 1108 p-O-n-Pr CF3CH2- CF3CH2- -CH2OH N 1109 o-O-i-Pr CF3CH2- CF3CH2- -CH2OH N 1110 m-O-i-Pr CF3CH2- CF3CH2- -CH2OH N 1111 p-O-i-Pr CF3CH2- CF3CH2- -CH2OH N 1112 o-O-n-Bu CF3CH2- CF3CH2- -CH2OH N 1113 m-O-n-Bu CF3CH2- CF3CH2- -CH2OH N 1114 p-O-n-Bu CF3CH2- CF3CH2- -CH2OH N 1115 o-O-i-Bu CF3CH2- CF3CH2- -CH2OH N 1116 m-O-i-Bu CF3CH2- CF3CH2- -CH2OH N 1117 p-O-i-Bu CF3CH2- CF3CH2- -CH2OH N 1118 o-OCF3 CF3CH2- CF3CH2- -CH2OH N 1119 m-OCF3 CF3CH2- CF3CH2- -CH2OH N 1120 p-OCF3 CF3CH2- CF3CH2- -CH2OH N 1121 H CF3CH2- Me- -CH2OH CH 1122 o-OCH3 CF3CH2- Me- -CH2OH CH 1123 m-OCH3 CF3CH2- Me- -CH2OH CH 1124 p-OCH3 CF3CH2- Me- -CH2OH CH 1125 o-Cl CF3CH2- Me- -CH2OH CH 1126 m-Cl CF3CH2- Me- -CH2OH CH 1127 p-Cl CF3CH2- Me- -CH2OH CH 1128 o-Br CF3CH2- Me- -CH2OH CH 1129 m-Br CF3CH2- Me- -CH2OH CH 1130 p-Br CF3CH2- Me- -CH2OH CH 1131 o-NH2 CF3CH2- Me- -CH2OH CH 1132 m-NH2 CF3CH2- Me- -CH2OH CH 1133 p-NH2 CF3CH2- Me- -CH2OH CH 1134 o-NO2 CF3CH2- Me- -CH2OH CH 1135 m-NO2 CF3CH2- Me- -CH2OH CH 1136 p-NO2 CF3CH2- Me- -CH2OH CH 1137 o-OC2H5 CF3CH2- Me- -CH2OH CH 1138 m-OC2H5 CF3CH2- Me- -CH2OH CH 1139 p-OC2H5 CF3CH2- Me- -CH2OH CH 1140 p-I CF3CH2- Me- -CH2OH CH 1141 o-O-n-Pr CF3CH2- Me- -CH2OH CH 1142 m-O-n-Pr CF3CH2- Me- -CH2OH CH 1143 p-O-n-Pr CF3CH2- Me- -CH2OH CH 1144 o-O-i-Pr CF3CH2- Me- -CH2OH CH 1145 m-O-i-Pr CF3CH2- Me- -CH2OH CH 1146 p-O-i-Pr CF3CH2- Me- -CH2OH CH 1147 o-O-n-Bu CF3CH2- Me- -CH2OH CH 1148 m-O-n-Bu CF3CH2- Me- -CH2OH CH 1149 p-O-n-Bu CF3CH2- Me- -CH2OH CH 1150 o-O-i-Bu CF3CH2- Me- -CH2OH CH 1151 m-O-i-Bu CF3CH2- Me- -CH2OH CH 1152 p-O-i-Bu CF3CH2- Me- -CH2OH CH 1153 o-OCF3 CF3CH2- Me- -CH2OH CH 1154 m-OCF3 CF3CH2- Me- -CH2OH CH 1155 p-OCF3 CF3CH2- Me- -CH2OH CH 1156 H CF3CH2- Me- -CH2OH N 1157 o-OCH3 CF3CH2- Me- -CH2OH N 1158 m-OCH3 CF3CH2- Me- -CH2OH N 1159 p-OCH3 CF3CH2- Me- -CH2OH N 1160 o-Cl CF3CH2- Me- -CH2OH N 1161 m-Cl CF3CH2- Me- -CH2OH N 1162 p-Cl CF3CH2- Me- -CH2OH N 1163 o-Br CF3CH2- Me- -CH2OH N 1164 m-Br CF3CH2- Me- -CH2OH N 1165 p-Br CF3CH2- Me- -CH2OH N 1166 o-NH2 CF3CH2- Me- -CH2OH N 1167 m-NH2 CF3CH2- Me- -CH2OH N 1168 p-NH2 CF3CH2- Me- -CH2OH N 1169 o-NO2 CF3CH2- Me- -CH2OH N 1170 m-NO2 CF3CH2- Me- -CH2OH N 1171 p-NO2 CF3CH2- Me- -CH2OH N 1172 o-OC2H5 CF3CH2- Me- -CH2OH N 1173 m-OC2H5 CF3CH2- Me- -CH2OH N 1174 p-OC2H5 CF3CH2- Me- -CH2OH N 1175 p-I CF3CH2- Me- -CH2OH N 1176 o-O-n-Pr CF3CH2- Me- -CH2OH N 1177 m-O-n-Pr CF3CH2- Me- -CH2OH N 1178 p-O-n-Pr CF3CH2- Me- -CH2OH N 1179 o-O-i-Pr CF3CH2- Me- -CH2OH N 1180 m-O-i-Pr CF3CH2- Me- -CH2OH N 1181 p-O-i-Pr CF3CH2- Me- -CH2OH N 1182 o-O-n-Bu CF3CH2- Me- -CH2OH N 1183 m-O-n-Bu CF3CH2- Me- -CH2OH N 1184 p-O-n-Bu CF3CH2- Me- -CH2OH N 1185 o-O-i-Bu CF3CH2- Me- -CH2OH N 1186 m-O-i-Bu CF3CH2- Me- -CH2OH N 1187 p-O-i-Bu CF3CH2- Me- -CH2OH N 1188 o-OCF3 CF3CH2- Me- -CH2OH N 1189 m-OCF3 CF3CH2- Me- -CH2OH N 1190 p-OCF3 CF3CH2- Me- -CH2OH N 1191 H CF3CH2- Et- -CH2OH CH 1192 o-OCH3 CF3CH2- Et- -CH2OH CH 1193 m-OCH3 CF3CH2- Et- -CH2OH CH 1194 p-OCH3 CF3CH2- Et- -CH2OH CH 1195 o-Cl CF3CH2- Et- -CH2OH CH 1196 m-Cl CF3CH2- Et- -CH2OH CH 1197 p-Cl CF3CH2- Et- -CH2OH CH 1198 o-Br CF3CH2- Et- -CH2OH CH 1199 m-Br CF3CH2- Et- -CH2OH CH 1200 p-Br CF3CH2- Et- -CH2OH CH 1201 o-NH2 CF3CH2- Et- -CH2OH CH 1202 m-NH2 CF3CH2- Et- -CH2OH CH 1203 p-NH2 CF3CH2- Et- -CH2OH CH 1204 o-NO2 CF3CH2- Et- -CH2OH CH 1205 m-NO2 CF3CH2- Et- -CH2OH CH 1206 p-NO2 CF3CH2- Et- -CH2OH CH 1207 o-OC2H5 CF3CH2- Et- -CH2OH CH 1208 m-OC2H5 CF3CH2- Et- -CH2OH CH 1209 p-OC2H5 CF3CH2- Et- -CH2OH CH 1210 p-I CF3CH2- Et- -CH2OH CH 1211 o-O-n-Pr CF3CH2- Et- -CH2OH CH 1212 m-O-n-Pr CF3CH2- Et- -CH2OH CH 1213 p-O-n-Pr CF3CH2- Et- -CH2OH CH 1214 o-O-i-Pr CF3CH2- Et- -CH2OH CH 1215 m-O-i-Pr CF3CH2- Et- -CH2OH CH 1216 p-O-i-Pr CF3CH2- Et- -CH2OH CH 1217 o-O-n-Bu CF3CH2- Et- -CH2OH CH 1218 m-O-n-Bu CF3CH2- Et- -CH2OH CH 1219 p-O-n-Bu CF3CH2- Et- -CH2OH CH 1220 o-O-i-Bu CF3CH2- Et- -CH2OH CH 1221 m-O-i-Bu CF3CH2- Et- -CH2OH CH 1222 p-O-i-Bu CF3CH2- Et- -CH2OH CH 1223 o-OCF3 CF3CH2- Et- -CH2OH CH 1224 m-OCF3 CF3CH2- Et- -CH2OH CH 1225 p-OCF3 CF3CH2- Et- -CH2OH CH 1226 H CF3CH2- Et- -CH2OH N 1227 o-OCH3 CF3CH2- Et- -CH2OH N 1228 m-OCH3 CF3CH2- Et- -CH2OH N 1229 p-OCH3 CF3CH2- Et- -CH2OH N 1230 o-Cl CF3CH2- Et- -CH2OH N 1231 m-Cl CF3CH2- Et- -CH2OH N 1232 p-Cl CF3CH2- Et- -CH2OH N 1233 o-Br CF3CH2- Et- -CH2OH N 1234 m-Br CF3CH2- Et- -CH2OH N 1235 p-Br CF3CH2- Et- -CH2OH N 1236 o-NH2 CF3CH2- Et- -CH2OH N 1237 m-NH2 CF3CH2- Et- -CH2OH N 1238 p-NH2 CF3CH2- Et- -CH2OH N 1239 o-NO2 CF3CH2- Et- -CH2OH N 1240 m-NO2 CF3CH2- Et- -CH2OH N 1241 p-NO2 CF3CH2- Et- -CH2OH N 1242 o-OC2H5 CF3CH2- Et- -CH2OH N 1243 m-OC2H5 CF3CH2- Et- -CH2OH N 1244 p-OC2H5 CF3CH2- Et- -CH2OH N 1245 p-I CF3CH2- Et- -CH2OH N 1246 o-O-n-Pr CF3CH2- Et- -CH2OH N 1247 m-O-n-Pr CF3CH2- Et- -CH2OH N 1248 p-O-n-Pr CF3CH2- Et- -CH2OH N 1249 o-O-i-Pr CF3CH2- Et- -CH2OH N 1250 m-O-i-Pr CF3CH2- Et- -CH2OH N 1251 p-O-i-Pr CF3CH2- Et- -CH2OH N 1252 o-O-n-Bu CF3CH2- Et- -CH2OH N 1253 m-O-n-Bu CF3CH2- Et- -CH2OH N 1254 p-O-n-Bu CF3CH2- Et- -CH2OH N 1255 o-O-i-Bu CF3CH2- Et- -CH2OH N 1256 m-O-i-Bu CF3CH2- Et- -CH2OH N 1257 p-O-i-Bu CF3CH2- Et- -CH2OH N 1258 o-OCF3 CF3CH2- Et- -CH2OH N 1259 m-OCF3 CF3CH2- Et- -CH2OH N 1260 p-OCF3 CF3CH2- Et- -CH2OH N 1261 H CF3CH2- H -CH2OH CH 1262 o-OCH3 CF3CH2- H -CH2OH CH 1263 m-OCH3 CF3CH2- H -CH2OH CH 1264 p-OCH3 CF3CH2- H -CH2OH CH 1265 o-Cl CF3CH2- H -CH2OH CH 1266 m-Cl CF3CH2- H -CH2OH CH 1267 p-Cl CF3CH2- H -CH2OH CH 1268 o-Br CF3CH2- H -CH2OH CH 1269 m-Br CF3CH2- H -CH2OH CH 1270 p-Br CF3CH2- H -CH2OH CH 1271 o-NH2 CF3CH2- H -CH2OH CH 1272 m-NH2 CF3CH2- H -CH2OH CH 1273 p-NH2 CF3CH2- H -CH2OH CH 1274 o-NO2 CF3CH2- H -CH2OH CH 1275 m-NO2 CF3CH2- H -CH2OH CH 1276 p-NO2 CF3CH2- H -CH2OH CH 1277 o-OC2H5 CF3CH2- H -CH2OH CH 1278 m-OC2H5 CF3CH2- H -CH2OH CH 1279 p-OC2H5 CF3CH2- H -CH2OH CH 1280 p-I CF3CH2- H -CH2OH CH 1281 o-O-n-Pr CF3CH2- H -CH2OH CH 1282 m-O-n-Pr CF3CH2- H -CH2OH CH 1283 p-O-n-Pr CF3CH2- H -CH2OH CH 1284 o-O-i-Pr CF3CH2- H -CH2OH CH 1285 m-O-i-Pr CF3CH2- H -CH2OH CH 1286 p-O-i-Pr CF3CH2- H -CH2OH CH 1287 o-O-n-Bu CF3CH2- H -CH2OH CH 1288 m-O-n-Bu CF3CH2- H -CH2OH CH 1289 p-O-n-Bu CF3CH2- H -CH2OH CH 1290 o-O-i-Bu CF3CH2- H -CH2OH CH 1291 m-O-i-Bu CF3CH2- H -CH2OH CH 1292 p-O-i-Bu CF3CH2- H -CH2OH CH 1293 o-OCF3 CF3CH2- H -CH2OH CH 1294 m-OCF3 CF3CH2- H -CH2OH CH 1295 p-OCF3 CF3CH2- H -CH2OH CH 1296 H CF3CH2- H -CH2OH N 1297 o-OCH3 CF3CH2- H -CH2OH N 1298 m-OCH3 CF3CH2- H -CH2OH N 1299 p-OCH3 CF3CH2- H -CH2OH N 1300 o-Cl CF3CH2- H -CH2OH N 1301 m-Cl CF3CH2- H -CH2OH N 1302 p-Cl CF3CH2- H -CH2OH N 1303 o-Br CF3CH2- H -CH2OH N 1304 m-Br CF3CH2- H -CH2OH N 1305 p-Br CF3CH2- H -CH2OH N 1306 o-NH2 CF3CH2- H -CH2OH N 1307 m-NH2 CF3CH2- H -CH2OH N 1308 p-NH2 CF3CH2- H -CH2OH N 1309 o-NO2 CF3CH2- H -CH2OH N 1310 m-NO2 CF3CH2- H -CH2OH N 1311 p-NO2 CF3CH2- H -CH2OH N 1312 o-OC2H5 CF3CH2- H -CH2OH N 1313 m-OC2H5 CF3CH2- H -CH2OH N 1314 p-OC2H5 CF3CH2- H -CH2OH N 1315 p-I CF3CH2- H -CH2OH N 1316 o-O-n-Pr CF3CH2- H -CH2OH N 1317 m-O-n-Pr CF3CH2- H -CH2OH N 1318 p-O-n-Pr CF3CH2- H -CH2OH N 1319 o-O-i-Pr CF3CH2- H -CH2OH N 1320 m-O-i-Pr CF3CH2- H -CH2OH N 1321 p-O-i-Pr CF3CH2- H -CH2OH N 1322 o-O-n-Bu CF3CH2- H -CH2OH N 1323 m-O-n-Bu CF3CH2- H -CH2OH N 1324 p-O-n-Bu CF3CH2- H -CH2OH N 1325 o-O-i-Bu CF3CH2- H -CH2OH N 1326 m-O-i-Bu CF3CH2- H -CH2OH N 1327 p-O-i-Bu CF3CH2- H -CH2OH N 1328 o-OCF3 CF3CH2- H -CH2OH N 1329 m-OCF3 CF3CH2- H -CH2OH N 1330 p-OCF3 CF3CH2- H -CH2OH N 1331 H H H -CH2OH CH 1332 o-OCH3 H H -CH2OH CH 1333 m-OCH3 H H -CH2OH CH 1334 p-OCH3 H H -CH2OH CH 1335 o-Cl H H -CH2OH CH 1336 m-Cl H H -CH2OH CH 1337 p-Cl H H -CH2OH CH 1338 o-Br H H -CH2OH CH 1339 m-Br H H -CH2OH CH 1340 p-Br H H -CH2OH CH 1341 o-NH2 H H -CH2OH CH 1342 m-NH2 H H -CH2OH CH 1343 p-NH2 H H -CH2OH CH 1344 o-NO2 H H -CH2OH CH 1345 m-NO2 H H -CH2OH CH 1346 p-NO2 H H -CH2OH CH 1347 o-OC2H5 H H -CH2OH CH 1348 m-OC2H5 H H -CH2OH CH 1349 p-OC2H5 H H -CH2OH CH 1350 p-I H H -CH2OH CH 1351 o-O-n-Pr H H -CH2OH CH 1352 m-O-n-Pr H H -CH2OH CH 1353 p-O-n-Pr H H -CH2OH CH 1354 o-O-i-Pr H H -CH2OH CH 1355 m-O-i-Pr H H -CH2OH CH 1356 p-O-i-Pr H H -CH2OH CH 1357 o-O-n-Bu H H -CH2OH CH 1358 m-O-n-Bu H H -CH2OH CH 1359 p-O-n-Bu H H -CH2OH CH 1360 o-O-i-Bu H H -CH2OH CH 1361 m-O-i-Bu H H -CH2OH CH 1362 p-O-i-Bu H H -CH2OH CH 1363 o-OCF3 H H -CH2OH CH 1364 m-OCF3 H H -CH2OH CH 1365 p-OCF3 H H -CH2OH CH 1366 H H H -CH2OH N 1367 o-OCH3 H H -CH2OH N 1368 m-OCH3 H H -CH2OH N 1369 p-OCH3 H H -CH2OH N 1370 o-Cl H H -CH2OH N 1371 m-Cl H H -CH2OH N 1372 p-Cl H H -CH2OH N 1373 o-Br H H -CH2OH N 1374 m-Br H H -CH2OH N 1375 p-Br H H -CH2OH N 1376 o-NH2 H H -CH2OH N 1377 m-NH2 H H -CH2OH N 1378 p-NH2 H H -CH2OH N 1379 o-NO2 H H -CH2OH N 1380 m-NO2 H H -CH2OH N 1381 p-NO2 H H -CH2OH N 1382 o-OC2H5 H H -CH2OH N 1383 m-OC2H5 H H -CH2OH N 1384 p-OC2H5 H H -CH2OH N 1385 p-I H H -CH2OH N 1386 o-O-n-Pr H H -CH2OH N 1387 m-O-n-Pr H H -CH2OH N 1388 p-O-n-Pr H H -CH2OH N 1389 o-O-i-Pr H H -CH2OH N 1390 m-O-i-Pr H H -CH2OH N 1391 p-O-i-Pr H H -CH2OH N 1392 o-O-n-Bu H H -CH2OH N 1393 m-O-n-Bu H H -CH2OH N 1394 p-O-n-Bu H H -CH2OH N 1395 o-O-i-Bu H H -CH2OH N 1396 m-O-i-Bu H H -CH2OH N 1397 p-O-i-Bu H H -CH2OH N 1398 o-OCF3 H H -CH2OH N 1399 m-OCF3 H H -CH2OH N 1400 p-OCF3 H H -CH2OH N 1401 H -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1402 o-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1403 m-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1404 p-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1405 o-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1406 m-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1407 p-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1408 o-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1409 m-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1410 p-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1411 o-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1412 m-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1413 p-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1414 o-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1415 m-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1416 p-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1417 o-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1418 m-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1419 p-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1420 p-I -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1421 o-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1422 m-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1423 p-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1424 o-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1425 m-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1426 p-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1427 o-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1428 m-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1429 p-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1430 o-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1431 m-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1432 p-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1433 o-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1434 m-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1435 p-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu H CH 1436 H -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1437 o-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1438 m-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1439 p-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1440 o-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1441 m-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1442 p-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1443 o-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1444 m-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1445 p-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1446 o-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1447 m-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1448 p-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1449 o-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1450 m-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1451 p-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1452 o-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1453 m-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1454 p-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1455 p-I -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1456 o-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1457 m-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1458 p-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1459 o-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1460 m-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1461 p-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1462 o-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1463 m-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1464 p-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1465 o-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1466 m-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1467 p-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1468 o-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1469 m-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1470 p-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu Me- CH 1471 H -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1472 o-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1473 m-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1474 p-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1475 o-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1476 m-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1477 p-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1478 o-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1479 m-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1480 p-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1481 o-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1482 m-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1483 p-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1484 o-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1485 m-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1486 p-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1487 o-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1488 m-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1489 p-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1490 p-I -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1491 o-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1492 m-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1493 p-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1494 o-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1495 m-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1496 p-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1497 o-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1498 m-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1499 p-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1500 o-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1501 m-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1502 p-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1503 o-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1504 m-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1505 p-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2F CH 1506 H -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1507 o-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1508 m-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1509 p-OCH3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1510 o-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1511 m-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1512 p-Cl -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1513 o-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1514 m-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1515 p-Br -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1516 o-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1517 m-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1518 p-NH2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1519 o-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1520 m-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1521 p-NO2 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1522 o-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1523 m-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1524 p-OC2H5 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1525 p-I -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1526 o-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1527 m-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1528 p-O-n-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1529 o-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1530 m-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1531 p-O-i-Pr -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1532 o-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1533 m-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1534 p-O-n-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1535 o-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1536 m-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1537 p-O-i-Bu -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1538 o-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1539 m-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1540 p-OCF3 -CH2O-CO-t-Bu -CH2O-CO-t-Bu -CH2OH CH 1541 H -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1542 o-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1543 m-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1544 p-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1545 o-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1546 m-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1547 p-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1548 o-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1549 m-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1550 p-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1551 o-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1552 m-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1553 p-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1554 o-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1555 m-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1556 p-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1557 o-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1558 m-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1559 p-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1560 p-I -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1561 o-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1562 m-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1563 p-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1564 o-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1565 m-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1566 p-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1567 o-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1568 m-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1569 p-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1570 o-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1571 m-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1572 p-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1573 o-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1574 m-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1575 p-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr H CH 1576 H -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1577 o-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1578 m-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1579 p-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1580 o-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1581 m-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1582 p-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1583 o-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1584 m-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1585 p-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1586 o-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1587 m-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1588 p-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1589 o-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1590 m-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1591 p-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1592 o-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1593 m-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1594 p-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1595 p-I -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1596 o-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1597 m-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1598 p-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1599 o-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1600 m-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1601 p-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1602 o-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1603 m-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1604 p-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1605 o-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1606 m-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1607 p-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1608 o-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1609 m-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1610 p-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr Me- CH 1611 H -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1612 o-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1613 m-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1614 p-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1615 o-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1616 m-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1617 p-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1618 o-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1619 m-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1620 p-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1621 o-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1622 m-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1623 p-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1624 o-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1625 m-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1626 p-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1627 o-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1628 m-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1629 p-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1630 p-I -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1631 o-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1632 m-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1633 p-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1634 o-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1635 m-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1636 p-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1637 o-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1638 m-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1639 p-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1640 o-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1641 m-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1642 p-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1643 o-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1644 m-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1645 p-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2F CH 1646 H -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1647 o-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1648 m-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1649 p-OCH3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1650 o-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1651 m-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1652 p-Cl -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1653 o-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1654 m-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1655 p-Br -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1656 o-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1657 m-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1658 p-NH2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1659 o-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1660 m-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1661 p-NO2 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1662 o-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1663 m-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1664 p-OC2H5 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1665 p-I -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1666 o-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1667 m-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1668 p-O-n-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1669 o-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1670 m-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1671 p-O-i-Pr -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1672 o-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1673 m-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1674 p-O-n-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1675 o-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1676 m-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1677 p-O-i-Bu -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1678 o-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1679 m-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH 1680 p-OCF3 -CH2CH2S-CO-i-Pr -CH2CH2S-CO-i-Pr -CH2OH CH [Table 1] No. R 1 R Two R Three R Four X 1 H CF Three CH Two -CF Three CH Two -H CH 2 o-OCH Three CF Three CH Two -CF Three CH Two -H CH 3 m-OCH Three CF Three CH Two -CF Three CH Two -H CH 4 p-OCH Three CF Three CH Two -CF Three CH Two -H CH 5 o-Cl CF Three CH Two -CF Three CH Two -H CH 6 m-Cl CF Three CH Two -CF Three CH Two -H CH 7 p-Cl CF Three CH Two -CF Three CH Two -H CH 8 o-Br CF Three CH Two -CF Three CH Two -H CH 9 m-Br CF Three CH Two -CF Three CH Two -H CH 10 p-Br CF Three CH Two -CF Three CH Two -H CH 11 o-NH Two CF Three CH Two -CF Three CH Two -H CH 12 m-NH Two CF Three CH Two -CF Three CH Two -H CH 13 p-NH Two CF Three CH Two -CF Three CH Two -H CH 14 o-NO Two CF Three CH Two -CF Three CH Two -H CH 15 m-NO Two CF Three CH Two -CF Three CH Two -H CH 16 p-NO Two CF Three CH Two -CF Three CH Two -H CH 17 o-OC Two H Five CF Three CH Two -CF Three CH Two -H CH 18 m-OC Two H Five CF Three CH Two -CF Three CH Two -H CH 19 p-OC Two H Five CF Three CH Two -CF Three CH Two -H CH 20 pI CF Three CH Two -CF Three CH Two -H CH 21 oOn-Pr CF Three CH Two -CF Three CH Two -H CH 22 mOn-Pr CF Three CH Two -CF Three CH Two -H CH 23 pOn-Pr CF Three CH Two -CF Three CH Two -H CH 24 oOi-Pr CF Three CH Two -CF Three CH Two -H CH 25 mOi-Pr CF Three CH Two -CF Three CH Two -H CH 26 pOi-Pr CF Three CH Two -CF Three CH Two -H CH 27 oOn-Bu CF Three CH Two -CF Three CH Two -H CH 28 mOn-Bu CF Three CH Two -CF Three CH Two -H CH 29 pOn-Bu CF Three CH Two -CF Three CH Two -H CH 30 oOi-Bu CF Three CH Two -CF Three CH Two -H CH 31 mOi-Bu CF Three CH Two -CF Three CH Two -H CH 32 pOi-Bu CF Three CH Two -CF Three CH Two -H CH 33 o-OCF Three CF Three CH Two -CF Three CH Two -H CH 34 m-OCF Three CF Three CH Two -CF Three CH Two -H CH 35 p-OCF Three CF Three CH Two -CF Three CH Two -H CH 36 H CF Three CH Two -CF Three CH Two -HN 37 o-OCH Three CF Three CH Two -CF Three CH Two -HN 38 m-OCH Three CF Three CH Two -CF Three CH Two -HN 39 p-OCH Three CF Three CH Two -CF Three CH Two -HN 40 o-Cl CF Three CH Two -CF Three CH Two -HN 41 m-Cl CF Three CH Two -CF Three CH Two -HN 42 p-Cl CF Three CH Two -CF Three CH Two -HN 43 o-Br CF Three CH Two -CF Three CH Two -HN 44 m-Br CF Three CH Two -CF Three CH Two -HN 45 p-Br CF Three CH Two -CF Three CH Two -HN 46 o-NH Two CF Three CH Two -CF Three CH Two -HN 47 m-NH Two CF Three CH Two -CF Three CH Two -HN 48 p-NH Two CF Three CH Two -CF Three CH Two -HN 49 o-NO Two CF Three CH Two -CF Three CH Two -HN 50 m-NO Two CF Three CH Two -CF Three CH Two -HN 51 p-NO Two CF Three CH Two -CF Three CH Two -HN 52 o-OC Two H Five CF Three CH Two -CF Three CH Two -HN 53 m-OC Two H Five CF Three CH Two -CF Three CH Two -HN 54 p-OC Two H Five CF Three CH Two -CF Three CH Two -HN 55 pI CF Three CH Two -CF Three CH Two -HN 56 oOn-Pr CF Three CH Two -CF Three CH Two -HN 57 mOn-Pr CF Three CH Two -CF Three CH Two -HN 58 pOn-Pr CF Three CH Two -CF Three CH Two -HN 59 oOi-Pr CF Three CH Two -CF Three CH Two -HN 60 mOi-Pr CF Three CH Two -CF Three CH Two -HN 61 pOi-Pr CF Three CH Two -CF Three CH Two -HN 62 oOn-Bu CF Three CH Two -CF Three CH Two -HN 63 mOn-Bu CF Three CH Two -CF Three CH Two -HN 64 pOn-Bu CF Three CH Two -CF Three CH Two -HN 65 oOi-Bu CF Three CH Two -CF Three CH Two -HN 66 mOi-Bu CF Three CH Two -CF Three CH Two -HN 67 pOi-Bu CF Three CH Two -CF Three CH Two -HN 68 o-OCF Three CF Three CH Two -CF Three CH Two -HN 69 m-OCF Three CF Three CH Two -CF Three CH Two -HN 70 p-OCF Three CF Three CH Two -CF Three CH Two -HN 71 H CF Three CH Two -Me- H CH 72 o-OCH Three CF Three CH Two -Me- H CH 73 m-OCH Three CF Three CH Two -Me- H CH 74 p-OCH Three CF Three CH Two -Me- H CH 75 o-Cl CF Three CH Two -Me- H CH 76 m-Cl CF Three CH Two -Me- H CH 77 p-Cl CF Three CH Two -Me- H CH 78 o-Br CF Three CH Two -Me- H CH 79 m-Br CF Three CH Two -Me- H CH 80 p-Br CF Three CH Two -Me- H CH 81 o-NH Two CF Three CH Two -Me- H CH 82 m-NH Two CF Three CH Two -Me- H CH 83 p-NH Two CF Three CH Two -Me- H CH 84 o-NO Two CF Three CH Two -Me- H CH 85 m-NO Two CF Three CH Two -Me- H CH 86 p-NO Two CF Three CH Two -Me- H CH 87 o-OC Two H Five CF Three CH Two -Me- H CH 88 m-OC Two H Five CF Three CH Two -Me- H CH 89 p-OC Two H Five CF Three CH Two -Me- H CH 90 pI CF Three CH Two -Me- H CH 91 oOn-Pr CF Three CH Two -Me- H CH 92 mOn-Pr CF Three CH Two -Me- H CH 93 pOn-Pr CF Three CH Two -Me- H CH 94 oOi-Pr CF Three CH Two -Me- H CH 95 mOi-Pr CF Three CH Two -Me- H CH 96 pOi-Pr CF Three CH Two -Me- H CH 97 oOn-Bu CF Three CH Two -Me- H CH 98 mOn-Bu CF Three CH Two -Me- H CH 99 pOn-Bu CF Three CH Two -Me- H CH 100 oOi-Bu CF Three CH Two -Me- H CH 101 mOi-Bu CF Three CH Two -Me- H CH 102 pOi-Bu CF Three CH Two -Me- H CH 103 o-OCF Three CF Three CH Two -Me- H CH 104 m-OCF Three CF Three CH Two -Me- H CH 105 p-OCF Three CF Three CH Two -Me- H CH 106 H CF Three CH Two -Me- HN 107 o-OCH Three CF Three CH Two -Me- HN 108 m-OCH Three CF Three CH Two -Me- HN 109 p-OCH Three CF Three CH Two -Me- HN 110 o-Cl CF Three CH Two -Me- HN 111 m-Cl CF Three CH Two -Me- HN 112 p-Cl CF Three CH Two -Me- HN 113 o-Br CF Three CH Two -Me- HN 114 m-Br CF Three CH Two -Me- HN 115 p-Br CF Three CH Two -Me- HN 116 o-NH Two CF Three CH Two -Me- HN 117 m-NH Two CF Three CH Two -Me- HN 118 p-NH Two CF Three CH Two -Me- HN 119 o-NO Two CF Three CH Two -Me- HN 120 m-NO Two CF Three CH Two -Me- HN 121 p-NO Two CF Three CH Two -Me- HN 122 o-OC Two H Five CF Three CH Two -Me- HN 123 m-OC Two H Five CF Three CH Two -Me- HN 124 p-OC Two H Five CF Three CH Two -Me- HN 125 pI CF Three CH Two -Me- HN 126 oOn-Pr CF Three CH Two -Me- HN 127 mOn-Pr CF Three CH Two -Me- HN 128 pOn-Pr CF Three CH Two -Me- HN 129 oOi-Pr CF Three CH Two -Me- HN 130 mOi-Pr CF Three CH Two -Me- HN 131 pOi-Pr CF Three CH Two -Me- HN 132 oOn-Bu CF Three CH Two -Me- HN 133 mOn-Bu CF Three CH Two -Me-HN 134 pOn-Bu CF Three CH Two -Me- HN 135 oOi-Bu CF Three CH Two -Me- HN 136 mOi-Bu CF Three CH Two -Me- HN 137 pOi-Bu CF Three CH Two -Me- HN 138 o-OCF Three CF Three CH Two -Me- HN 139 m-OCF Three CF Three CH Two -Me- HN 140 p-OCF Three CF Three CH Two -Me- HN 141 H CF Three CH Two -Et-H CH 142 o-OCH Three CF Three CH Two -Et-H CH 143 m-OCH Three CF Three CH Two -Et-H CH 144 p-OCH Three CF Three CH Two -Et-H CH 145 o-Cl CF Three CH Two -Et-H CH 146 m-Cl CF Three CH Two -Et-H CH 147 p-Cl CF Three CH Two -Et-H CH 148 o-Br CF Three CH Two -Et-H CH 149 m-Br CF Three CH Two -Et-H CH 150 p-Br CF Three CH Two -Et-H CH 151 o-NH Two CF Three CH Two -Et-H CH 152 m-NH Two CF Three CH Two -Et-H CH 153 p-NH Two CF Three CH Two -Et-H CH 154 o-NO Two CF Three CH Two -Et-H CH 155 m-NO Two CF Three CH Two -Et-H CH 156 p-NO Two CF Three CH Two -Et-H CH 157 o-OC Two H Five CF Three CH Two -Et-H CH 158 m-OC Two H Five CF Three CH Two -Et-H CH 159 p-OC Two H Five CF Three CH Two -Et-H CH 160 pI CF Three CH Two -Et-H CH 161 oOn-Pr CF Three CH Two -Et-H CH 162 mOn-Pr CF Three CH Two -Et-H CH 163 pOn-Pr CF Three CH Two -Et-H CH 164 oOi-Pr CF Three CH Two -Et-H CH 165 mOi-Pr CF Three CH Two -Et-H CH 166 pOi-Pr CF Three CH Two -Et-H CH 167 oOn-Bu CF Three CH Two -Et-H CH 168 mOn-Bu CF Three CH Two -Et-H CH 169 pOn-Bu CF Three CH Two -Et-H CH 170 oOi-Bu CF Three CH Two -Et-H CH 171 mOi-Bu CF Three CH Two -Et-H CH 172 pOi-Bu CF Three CH Two -Et-H CH 173 o-OCF Three CF Three CH Two -Et-H CH 174 m-OCF Three CF Three CH Two -Et-H CH 175 p-OCF Three CF Three CH Two -Et-H CH 176 H CF Three CH Two -Et-HN 177 o-OCH Three CF Three CH Two -Et-HN 178 m-OCH Three CF Three CH Two -Et-HN 179 p-OCH Three CF Three CH Two -Et-HN 180 o-Cl CF Three CH Two -Et-HN 181 m-Cl CF Three CH Two -Et-HN 182 p-Cl CF Three CH Two -Et-HN 183 o-Br CF Three CH Two -Et-HN 184 m-Br CF Three CH Two -Et-HN 185 p-Br CF Three CH Two -Et-HN 186 o-NH Two CF Three CH Two -Et-HN 187 m-NH Two CF Three CH Two -Et-HN 188 p-NH Two CF Three CH Two -Et-HN 189 o-NO Two CF Three CH Two -Et-HN 190 m-NO Two CF Three CH Two -Et-HN 191 p-NO Two CF Three CH Two -Et-HN 192 o-OC Two H Five CF Three CH Two -Et-HN 193 m-OC Two H Five CF Three CH Two -Et-HN 194 p-OC Two H Five CF Three CH Two -Et-HN 195 pI CF Three CH Two -Et-HN 196 oOn-Pr CF Three CH Two -Et-HN 197 mOn-Pr CF Three CH Two -Et-HN 198 pOn-Pr CF Three CH Two -Et-HN 199 oOi-Pr CF Three CH Two -Et-HN 200 mOi-Pr CF Three CH Two -Et-HN 201 pOi-Pr CF Three CH Two -Et-HN 202 oOn-Bu CF Three CH Two -Et-HN 203 mOn-Bu CF Three CH Two -Et-HN 204 pOn-Bu CF Three CH Two -Et-HN 205 oOi-Bu CF Three CH Two -Et-HN 206 mOi-Bu CF Three CH Two -Et-HN 207 pOi-Bu CF Three CH Two -Et-HN 208 o-OCF Three CF Three CH Two -Et-HN 209 m-OCF Three CF Three CH Two -Et-HN 210 p-OCF Three CF Three CH Two -Et-HN 211 H CF Three CH Two -HH CH 212 o-OCH Three CF Three CH Two -HH CH 213 m-OCH Three CF Three CH Two -HH CH 214 p-OCH Three CF Three CH Two -HH CH 215 o-Cl CF Three CH Two -HH CH 216 m-Cl CF Three CH Two -HH CH 217 p-Cl CF Three CH Two -HH CH 218 o-Br CF Three CH Two -HH CH 219 m-Br CF Three CH Two -HH CH 220 p-Br CF Three CH Two -HH CH 221 o-NH Two CF Three CH Two -HH CH 222 m-NH Two CF Three CH Two -HH CH 223 p-NH Two CF Three CH Two -HH CH 224 o-NO Two CF Three CH Two -HH CH 225 m-NO Two CF Three CH Two -HH CH 226 p-NO Two CF Three CH Two -HH CH 227 o-OC Two H Five CF Three CH Two -HH CH 228 m-OC Two H Five CF Three CH Two -HH CH 229 p-OC Two H Five CF Three CH Two -HH CH 230 pI CF Three CH Two -HH CH 231 oOn-Pr CF Three CH Two -HH CH 232 mOn-Pr CF Three CH Two -HH CH 233 pOn-Pr CF Three CH Two -HH CH 234 oOi-Pr CF Three CH Two -HH CH 235 mOi-Pr CF Three CH Two -HH CH 236 pOi-Pr CF Three CH Two -HH CH 237 oOn-Bu CF Three CH Two -HH CH 238 mOn-Bu CF Three CH Two -HH CH 239 pOn-Bu CF Three CH Two -HH CH 240 oOi-Bu CF Three CH Two -HH CH 241 mOi-Bu CF Three CH Two -HH CH 242 pOi-Bu CF Three CH Two -HH CH 243 o-OCF Three CF Three CH Two -HH CH 244 m-OCF Three CF Three CH Two -HH CH 245 p-OCF Three CF Three CH Two -HH CH 246 H CF Three CH Two -HHN 247 o-OCH Three CF Three CH Two -HHN 248 m-OCH Three CF Three CH Two -HHN 249 p-OCH Three CF Three CH Two -HHN 250 o-Cl CF Three CH Two -HHN 251 m-Cl CF Three CH Two -HHN 252 p-Cl CF Three CH Two -HHN 253 o-Br CF Three CH Two -HHN 254 m-Br CF Three CH Two -HHN 255 p-Br CF Three CH Two -HHN 256 o-NH Two CF Three CH Two -HHN 257 m-NH Two CF Three CH Two -HHN 258 p-NH Two CF Three CH Two -HHN 259 o-NO Two CF Three CH Two -HHN 260 m-NO Two CF Three CH Two -HHN 261 p-NO Two CF Three CH Two -HHN 262 o-OC Two H Five CF Three CH Two -HHN 263 m-OC Two H Five CF Three CH Two -HHN 264 p-OC Two H Five CF Three CH Two -HHN 265 pI CF Three CH Two -HHN 266 oOn-Pr CF Three CH Two -HHN 267 mOn-Pr CF Three CH Two -HHN 268 pOn-Pr CF Three CH Two -HHN 269 oOi-Pr CF Three CH Two -HHN 270 mOi-Pr CF Three CH Two -HHN 271 pOi-Pr CF Three CH Two -HHN 272 oOn-Bu CF Three CH Two -HHN 273 mOn-Bu CF Three CH Two -HHN 274 pOn-Bu CF Three CH Two -HHN 275 oOi-Bu CF Three CH Two -HHN 276 mOi-Bu CF Three CH Two -HHN 277 pOi-Bu CF Three CH Two -HHN 278 o-OCF Three CF Three CH Two -HHN 279 m-OCF Three CF Three CH Two -HHN 280 p-OCF Three CF Three CH Two -HHN 281 HHHH CH 282 o-OCH Three HHH CH 283 m-OCH Three HHH CH 284 p-OCH Three HHH CH 285 o-Cl HHH CH 286 m-Cl HHH CH 287 p-Cl HHH CH 288 o-Br HHH CH 289 m-Br HHH CH 290 p-Br HHH CH 291 o-NH Two HHH CH 292 m-NH Two HHH CH 293 p-NH Two HHH CH 294 o-NO Two HHH CH 295 m-NO Two HHH CH 296 p-NO Two HHH CH 297 o-OC Two H Five HHH CH 298 m-OC Two H Five HHH CH 299 p-OC Two H Five HHH CH 300 pI HHH CH 301 oOn-Pr HHH CH 302 mOn-Pr HHH CH 303 pOn-Pr HHH CH 304 oOi-Pr HHH CH 305 mOi-Pr HHH CH 306 pOi-Pr HHH CH 307 oOn-Bu HHH CH 308 mOn-Bu HHH CH 309 pOn-Bu HHH CH 310 oOi-Bu HHH CH 311 mOi-Bu HHH CH 312 pOi-Bu HHH CH 313 o-OCF Three HHH CH 314 m-OCF Three HHH CH 315 p-OCF Three HHH CH 316 HHHHN 317 o-OCH Three HHHN 318 m-OCH Three HHHN 319 p-OCH Three HHHN 320 o-Cl HHHN 321 m-Cl HHHN 322 p-Cl HHHN 323 o-Br HHHN 324 m-Br HHHN 325 p-Br HHHN 326 o-NH Two HHHN 327 m-NH Two HHHN 328 p-NH Two HHHN 329 o-NO Two HHHN 330 m-NO Two HHHN 331 p-NO Two HHHN 332 o-OC Two H Five HHHN 333 m-OC Two H Five HHHN 334 p-OC Two H Five HHHN 335 pI HHHN 336 oOn-Pr HHHN 337 mOn-Pr HHHN 338 pOn-Pr HHHN 339 oOi-Pr HHHN 340 mOi-Pr HHHN 341 pOi-Pr HHHN 342 oOn-Bu HHHNH-N 343 mOn-Bu oOi-Bu HHHN 346 mOi-Bu HHHN 347 pOi-Bu HHHN 348 o-OCF Three HHHN 349 m-OCF Three HHHN 350 p-OCF Three HHHN 351 H CF Three CH Two -CF Three CH Two -Me- CH 352 o-OCH Three CF Three CH Two -CF Three CH Two -Me- CH 353 m-OCH Three CF Three CH Two -CF Three CH Two -Me- CH 354 p-OCH Three CF Three CH Two -CF Three CH Two -Me- CH 355 o-Cl CF Three CH Two -CF Three CH Two -Me- CH 356 m-Cl CF Three CH Two -CF Three CH Two -Me- CH 357 p-Cl CF Three CH Two -CF Three CH Two -Me- CH 358 o-Br CF Three CH Two -CF Three CH Two -Me- CH 359 m-Br CF Three CH Two -CF Three CH Two -Me- CH 360 p-Br CF Three CH Two -CF Three CH Two -Me- CH 361 o-NH Two CF Three CH Two -CF Three CH Two -Me- CH 362 m-NH Two CF Three CH Two -CF Three CH Two -Me- CH 363 p-NH Two CF Three CH Two -CF Three CH Two -Me- CH 364 o-NO Two CF Three CH Two -CF Three CH Two -Me- CH 365 m-NO Two CF Three CH Two -CF Three CH Two -Me- CH 366 p-NO Two CF Three CH Two -CF Three CH Two -Me- CH 367 o-OC Two H Five CF Three CH Two -CF Three CH Two -Me- CH 368 m-OC Two H Five CF Three CH Two -CF Three CH Two -Me- CH 369 p-OC Two H Five CF Three CH Two -CF Three CH Two -Me- CH 370 pI CF Three CH Two -CF Three CH Two -Me- CH 371 oOn-Pr CF Three CH Two -CF Three CH Two -Me- CH 372 mOn-Pr CF Three CH Two -CF Three CH Two -Me- CH 373 pOn-Pr CF Three CH Two -CF Three CH Two -Me- CH 374 oOi-Pr CF Three CH Two -CF Three CH Two -Me- CH 375 mOi-Pr CF Three CH Two -CF Three CH Two -Me- CH 376 pOi-Pr CF Three CH Two -CF Three CH Two -Me- CH 377 oOn-Bu CF Three CH Two -CF Three CH Two -Me- CH 378 mOn-Bu CF Three CH Two -CF Three CH Two -Me- CH 379 pOn-Bu CF Three CH Two -CF Three CH Two -Me- CH 380 oOi-Bu CF Three CH Two -CF Three CH Two -Me- CH 381 mOi-Bu CF Three CH Two -CF Three CH Two -Me- CH 382 pOi-Bu CF Three CH Two -CF Three CH Two -Me- CH 383 o-OCF Three CF Three CH Two -CF Three CH Two -Me- CH 384 m-OCF Three CF Three CH Two -CF Three CH Two -Me- CH 385 p-OCF Three CF Three CH Two -CF Three CH Two -Me- CH 386 H CF Three CH Two -CF Three CH Two -Me-N 387 o-OCH Three CF Three CH Two -CF Three CH Two -Me-N 388 m-OCH Three CF Three CH Two -CF Three CH Two -Me-N 389 p-OCH Three CF Three CH Two -CF Three CH Two -Me-N 390 o-Cl CF Three CH Two -CF Three CH Two -Me-N 391 m-Cl CF Three CH Two -CF Three CH Two -Me-N 392 p-Cl CF Three CH Two -CF Three CH Two -Me-N 393 o-Br CF Three CH Two -CF Three CH Two -Me-N 394 m-Br CF Three CH Two -CF Three CH Two -Me-N 395 p-Br CF Three CH Two -CF Three CH Two -Me-N 396 o-NH Two CF Three CH Two -CF Three CH Two -Me- N 397 m-NH Two CF Three CH Two -CF Three CH Two -Me-N 398 p-NH Two CF Three CH Two -CF Three CH Two -Me-N 399 o-NO Two CF Three CH Two -CF Three CH Two -Me- N 400 m-NO Two CF Three CH Two -CF Three CH Two -Me-N 401 p-NO Two CF Three CH Two -CF Three CH Two -Me- N 402 o-OC Two H Five CF Three CH Two -CF Three CH Two -Me- N 403 m-OC Two H Five CF Three CH Two -CF Three CH Two -Me-N 404 p-OC Two H Five CF Three CH Two -CF Three CH Two -Me-N 405 pI CF Three CH Two -CF Three CH Two -Me-N 406 oOn-Pr CF Three CH Two -CF Three CH Two -Me-N 407 mOn-Pr CF Three CH Two -CF Three CH Two -Me-N 408 pOn-Pr CF Three CH Two -CF Three CH Two -Me-N 409 oOi-Pr CF Three CH Two -CF Three CH Two -Me- N 410 mOi-Pr CF Three CH Two -CF Three CH Two -Me-N 411 pOi-Pr CF Three CH Two -CF Three CH Two -Me-N 412 oOn-Bu CF Three CH Two -CF Three CH Two -Me-N 413 mOn-Bu CF Three CH Two -CF Three CH Two -Me-N 414 pOn-Bu CF Three CH Two -CF Three CH Two -Me-N 415 oOi-Bu CF Three CH Two -CF Three CH Two -Me-N 416 mOi-Bu CF Three CH Two -CF Three CH Two -Me-N 417 pOi-Bu CF Three CH Two -CF Three CH Two -Me-N 418 o-OCF Three CF Three CH Two -CF Three CH Two -Me- N 419 m-OCF Three CF Three CH Two -CF Three CH Two -Me- N 420 p-OCF Three CF Three CH Two -CF Three CH Two -Me- N 421 H CF Three CH Two -Me- Me- CH 422 o-OCH Three CF Three CH Two -Me- Me- CH 423 m-OCH Three CF Three CH Two -Me- Me- CH 424 p-OCH Three CF Three CH Two -Me- Me- CH 425 o-Cl CF Three CH Two -Me- Me- CH 426 m-Cl CF Three CH Two -Me- Me- CH 427 p-Cl CF Three CH Two -Me- Me- CH 428 o-Br CF Three CH Two -Me- Me- CH 429 m-Br CF Three CH Two -Me- Me- CH 430 p-Br CF Three CH Two -Me- Me- CH 431 o-NH Two CF Three CH Two -Me- Me- CH 432 m-NH Two CF Three CH Two -Me- Me- CH 433 p-NH Two CF Three CH Two -Me- Me- CH 434 o-NO Two CF Three CH Two -Me- Me- CH 435 m-NO Two CF Three CH Two -Me- Me- CH 436 p-NO Two CF Three CH Two -Me- Me- CH 437 o-OC Two H Five CF Three CH Two -Me- Me- CH 438 m-OC Two H Five CF Three CH Two -Me- Me- CH 439 p-OC Two H Five CF Three CH Two -Me- Me- CH 440 pI CF Three CH Two -Me- Me- CH 441 oOn-Pr CF Three CH Two -Me- Me- CH 442 mOn-Pr CF Three CH Two -Me- Me- CH 443 pOn-Pr CF Three CH Two -Me- Me- CH 444 oOi-Pr CF Three CH Two -Me- Me- CH 445 mOi-Pr CF Three CH Two -Me- Me- CH 446 pOi-Pr CF Three CH Two -Me- Me- CH 447 oOn-Bu CF Three CH Two -Me- Me- CH 448 mOn-Bu CF Three CH Two -Me- Me- CH 449 pOn-Bu CF Three CH Two -Me- Me- CH 450 oOi-Bu CF Three CH Two -Me- Me- CH 451 mOi-Bu CF Three CH Two -Me- Me- CH 452 pOi-Bu CF Three CH Two -Me- Me- CH 453 o-OCF Three CF Three CH Two -Me- Me- CH 454 m-OCF Three CF Three CH Two -Me- Me- CH 455 p-OCF Three CF Three CH Two -Me- Me- CH 456 H CF Three CH Two -Me- Me- N 457 o-OCH Three CF Three CH Two -Me- Me- N 458 m-OCH Three CF Three CH Two -Me- Me- N 459 p-OCH Three CF Three CH Two -Me- Me- N 460 o-Cl CF Three CH Two -Me- Me- N 461 m-Cl CF Three CH Two -Me- Me- N 462 p-Cl CF Three CH Two -Me- Me- N 463 o-Br CF Three CH Two -Me- Me- N 464 m-Br CF Three CH Two -Me- Me- N 465 p-Br CF Three CH Two -Me- Me- N 466 o-NH Two CF Three CH Two -Me- Me- N 467 m-NH Two CF Three CH Two -Me- Me- N 468 p-NH Two CF Three CH Two -Me- Me- N 469 o-NO Two CF Three CH Two -Me- Me- N 470 m-NO Two CF Three CH Two -Me- Me- N 471 p-NO Two CF Three CH Two -Me- Me- N 472 o-OC Two H Five CF Three CH Two -Me- Me- N 473 m-OC Two H Five CF Three CH Two -Me- Me- N 474 p-OC Two H Five CF Three CH Two -Me- Me- N 475 pI CF Three CH Two -Me- Me- N 476 oOn-Pr CF Three CH Two -Me- Me- N 477 mOn-Pr CF Three CH Two -Me- Me- N 478 pOn-Pr CF Three CH Two -Me- Me- N 479 oOi-Pr CF Three CH Two -Me- Me- N 480 mOi-Pr CF Three CH Two -Me- Me- N 481 pOi-Pr CF Three CH Two -Me- Me- N 482 oOn-Bu CF Three CH Two -Me- Me- N 483 m On-Bu CF Three CH Two -Me- Me- N 484 pOn-Bu CF Three CH Two -Me- Me- N 485 oOi-Bu CF Three CH Two -Me- Me- N 486 mOi-Bu CF Three CH Two -Me- Me- N 487 pOi-Bu CF Three CH Two -Me- Me- N 488 o-OCF Three CF Three CH Two -Me- Me- N 489 m-OCF Three CF Three CH Two -Me- Me- N 490 p-OCF Three CF Three CH Two -Me- Me- N 491 H CF Three CH Two -Et- Me- CH 492 o-OCH Three CF Three CH Two -Et- Me- CH 493 m-OCH Three CF Three CH Two -Et- Me- CH 494 p-OCH Three CF Three CH Two -Et- Me- CH 495 o-Cl CF Three CH Two -Et- Me- CH 496 m-Cl CF Three CH Two -Et- Me- CH 497 p-Cl CF Three CH Two -Et- Me- CH 498 o-Br CF Three CH Two -Et- Me- CH 499 m-Br CF Three CH Two -Et- Me- CH 500 p-Br CF Three CH Two -Et- Me- CH 501 o-NH Two CF Three CH Two -Et- Me- CH 502 m-NH Two CF Three CH Two -Et- Me- CH 503 p-NH Two CF Three CH Two -Et- Me- CH 504 o-NO Two CF Three CH Two -Et- Me- CH 505 m-NO Two CF Three CH Two -Et- Me- CH 506 p-NO Two CF Three CH Two -Et- Me- CH 507 o-OC Two H Five CF Three CH Two -Et- Me- CH 508 m-OC Two H Five CF Three CH Two -Et- Me- CH 509 p-OC Two H Five CF Three CH Two -Et- Me- CH 510 pI CF Three CH Two -Et- Me- CH 511 oOn-Pr CF Three CH Two -Et- Me- CH 512 mOn-Pr CF Three CH Two -Et- Me- CH 513 pOn-Pr CF Three CH Two -Et- Me- CH 514 oOi-Pr CF Three CH Two -Et- Me- CH 515 mOi-Pr CF Three CH Two -Et- Me- CH 516 pOi-Pr CF Three CH Two -Et- Me- CH 517 oOn-Bu CF Three CH Two -Et- Me- CH 518 mOn-Bu CF Three CH Two -Et- Me- CH 519 pOn-Bu CF Three CH Two -Et- Me- CH 520 oOi-Bu CF Three CH Two -Et- Me- CH 521 mOi-Bu CF Three CH Two -Et- Me- CH 522 pOi-Bu CF Three CH Two -Et- Me- CH 523 o-OCF Three CF Three CH Two -Et- Me- CH 524 m-OCF Three CF Three CH Two -Et- Me- CH 525 p-OCF Three CF Three CH Two -Et- Me- CH 526 H CF Three CH Two -Et-Me-N 527 o-OCH Three CF Three CH Two -Et-Me-N 528 m-OCH Three CF Three CH Two -Et-Me-N 529 p-OCH Three CF Three CH Two -Et-Me-N 530 o-Cl CF Three CH Two -Et-Me-N 531 m-Cl CF Three CH Two -Et-Me-N 532 p-Cl CF Three CH Two -Et-Me-N 533 o-Br CF Three CH Two -Et-Me-N 534 m-Br CF Three CH Two -Et-Me-N 535 p-Br CF Three CH Two -Et-Me-N 536 o-NH Two CF Three CH Two -Et-Me-N 537 m-NH Two CF Three CH Two -Et-Me-N 538 p-NH Two CF Three CH Two -Et-Me-N 539 o-NO Two CF Three CH Two -Et-Me-N 540 m-NO Two CF Three CH Two -Et-Me-N 541 p-NO Two CF Three CH Two -Et-Me-N 542 o-OC Two H Five CF Three CH Two -Et-Me-N 543 m-OC Two H Five CF Three CH Two -Et-Me-N 544 p-OC Two H Five CF Three CH Two -Et-Me-N 545 pI CF Three CH Two -Et-Me-N 546 oOn-Pr CF Three CH Two -Et-Me-N 547 mOn-Pr CF Three CH Two -Et-Me-N 548 pOn-Pr CF Three CH Two -Et-Me-N 549 oOi-Pr CF Three CH Two -Et-Me-N 550 mOi-Pr CF Three CH Two -Et-Me-N 551 pOi-Pr CF Three CH Two -Et-Me-N 552 oOn-Bu CF Three CH Two -Et-Me-N 553 mOn-Bu CF Three CH Two -Et-Me-N 554 pOn-Bu CF Three CH Two -Et-Me-N 555 oOi-Bu CF Three CH Two -Et-Me-N 556 mOi-Bu CF Three CH Two -Et-Me-N 557 pOi-Bu CF Three CH Two -Et-Me-N 558 o-OCF Three CF Three CH Two -Et-Me-N 559 m-OCF Three CF Three CH Two -Et-Me-N 560 p-OCF Three CF Three CH Two -Et-Me-N 561 H CF Three CH Two -H Me- CH 562 o-OCH Three CF Three CH Two -H Me- CH 563 m-OCH Three CF Three CH Two -H Me- CH 564 p-OCH Three CF Three CH Two -H Me- CH 565 o-Cl CF Three CH Two -H Me- CH 566 m-Cl CF Three CH Two -H Me- CH 567 p-Cl CF Three CH Two -H Me- CH 568 o-Br CF Three CH Two -H Me- CH 569 m-Br CF Three CH Two -H Me- CH 570 p-Br CF Three CH Two -H Me- CH 571 o-NH Two CF Three CH Two -H Me- CH 572 m-NH Two CF Three CH Two -H Me- CH 573 p-NH Two CF Three CH Two -H Me- CH 574 o-NO Two CF Three CH Two -H Me- CH 575 m-NO Two CF Three CH Two -H Me- CH 576 p-NO Two CF Three CH Two -H Me- CH 577 o-OC Two H Five CF Three CH Two -H Me- CH 578 m-OC Two H Five CF Three CH Two -H Me- CH 579 p-OC Two H Five CF Three CH Two -H Me- CH 580 pI CF Three CH Two -H Me- CH 581 oOn-Pr CF Three CH Two -H Me- CH 582 mOn-Pr CF Three CH Two -H Me- CH 583 pOn-Pr CF Three CH Two -H Me- CH 584 oOi-Pr CF Three CH Two -H Me- CH 585 mOi-Pr CF Three CH Two -H Me- CH 586 pOi-Pr CF Three CH Two -H Me- CH 587 oOn-Bu CF Three CH Two -H Me- CH 588 mOn-Bu CF Three CH Two -H Me- CH 589 pOn-Bu CF Three CH Two -H Me- CH 590 oOi-Bu CF Three CH Two -H Me- CH 591 mOi-Bu CF Three CH Two -H Me- CH 592 pOi-Bu CF Three CH Two -H Me- CH 593 o-OCF Three CF Three CH Two -H Me- CH 594 m-OCF Three CF Three CH Two -H Me- CH 595 p-OCF Three CF Three CH Two -H Me- CH 596 H CF Three CH Two -H Me- N 597 o-OCH Three CF Three CH Two -H Me- N 598 m-OCH Three CF Three CH Two -H Me- N 599 p-OCH Three CF Three CH Two -H Me- N 600 o-Cl CF Three CH Two -H Me- N 601 m-Cl CF Three CH Two -H Me- N 602 p-Cl CF Three CH Two -H Me- N 603 o-Br CF Three CH Two -H Me- N 604 m-Br CF Three CH Two -H Me- N 605 p-Br CF Three CH Two -H Me- N 606 o-NH Two CF Three CH Two -H Me- N 607 m-NH Two CF Three CH Two -H Me- N 608 p-NH Two CF Three CH Two -H Me- N 609 o-NO Two CF Three CH Two -H Me- N 610 m-NO Two CF Three CH Two -H Me- N 611 p-NO Two CF Three CH Two -H Me- N 612 o-OC Two H Five CF Three CH Two -H Me- N 613 m-OC Two H Five CF Three CH Two -H Me- N 614 p-OC Two H Five CF Three CH Two -H Me- N 615 pI CF Three CH Two -H Me- N 616 oOn-Pr CF Three CH Two -H Me- N 617 mOn-Pr CF Three CH Two -H Me- N 618 pOn-Pr CF Three CH Two -H Me- N 619 oOi-Pr CF Three CH Two -H Me- N 620 mOi-Pr CF Three CH Two -H Me- N 621 pOi-Pr CF Three CH Two -H Me-N 622 oOn-Bu CF Three CH Two -H Me- N 623 mOn-Bu CF Three CH Two -H Me- N 624 pOn-Bu CF Three CH Two -H Me-N 625 oOi-Bu CF Three CH Two -H Me- N 626 mOi-Bu CF Three CH Two -H Me- N 627 pOi-Bu CF Three CH Two -H Me- N 628 o-OCF Three CF Three CH Two -H Me- N 629 m-OCF Three CF Three CH Two -H Me- N 630 p-OCF Three CF Three CH Two -H Me- N 631 HHH Me- CH 632 o-OCH Three HH Me- CH 633 m-OCH Three HH Me- CH 634 p-OCH Three HH Me- CH 635 o-Cl HH Me- CH 636 m-Cl HH Me- CH 637 p-Cl HH Me- CH 638 o-Br HH Me- CH 639 m-Br HH Me- CH 640 p-Br HH Me- CH 641 o-NH Two HH Me- CH 642 m-NH Two HH Me- CH 643 p-NH Two HH Me- CH 644 o-NO Two HH Me- CH 645 m-NO Two HH Me- CH 646 p-NO Two HH Me- CH 647 o-OC Two H Five HH Me- CH 648 m-OC Two H Five HH Me- CH 649 p-OC Two H Five HH Me- CH 650 pI HH Me- CH 651 oOn-Pr HH Me- CH 652 mOn-Pr HH Me- CH 653 pOn-Pr HH Me- CH 654 oOi-Pr HH Me- CH 655 mOi-Pr HH Me- CH 656 pOi-Pr HH Me- CH 657 oOn-Bu HH Me- CH 658 mOn-Bu HH Me- CH 659 pOn-Bu HH Me- CH 660 oOi-Bu HH Me- CH 661 mOi-Bu HH Me- CH 662 pOi-Bu HH Me- CH 663 o-OCF Three HH Me- CH 664 m-OCF Three HH Me- CH 665 p-OCF Three HH Me- CH 666 HHH Me- N 667 o-OCH Three HH Me- N 668 m-OCH Three HH Me- N 669 p-OCH Three HH Me- N 670 o-Cl HH Me- N 671 m-Cl HH Me- N 672 p-Cl HH Me- N 673 o-Br HH Me- N 674 m-Br HH Me- N 675 p-Br HH Me -N 676 o-NH Two HH Me- N 677 m-NH Two HH Me- N 678 p-NH Two HH Me- N 679 o-NO Two HH Me- N 680 m-NO Two HH Me- N 681 p-NO Two HH Me- N 682 o-OC Two H Five HH Me- N 683 m-OC Two H Five HH Me- N 684 p-OC Two H Five HH Me-N 685 pI HH Me-N 686 oOn-Pr HH Me-N 687 mOn-Pr HH Me-N 688 pOn-Pr HH Me-N 689 oOi-Pr HH Me-N 690 mOi-Pr HH Me- N 691 pOi-Pr HH Me- N 692 oOn-Bu HH Me- N 693 mOn-Bu HH Me- N 694 pOn-Bu HH Me- N 695 oOi-Bu HH Me- N 696 mOi-Bu HH Me- N 697 pOi -Bu HH Me- N 698 o-OCF Three HH Me- N 699 m-OCF Three HH Me- N 700 p-OCF Three HH Me- N 701 H CF Three CH Two -CF Three CH Two --CH Two F CH 702 o-OCH Three CF Three CH Two -CF Three CH Two --CH Two F CH 703 m-OCH Three CF Three CH Two -CF Three CH Two --CH Two F CH 704 p-OCH Three CF Three CH Two -CF Three CH Two --CH Two F CH 705 o-Cl CF Three CH Two -CF Three CH Two --CH Two F CH 706 m-Cl CF Three CH Two -CF Three CH Two --CH Two F CH 707 p-Cl CF Three CH Two -CF Three CH Two --CH Two F CH 708 o-Br CF Three CH Two -CF Three CH Two --CH Two F CH 709 m-Br CF Three CH Two -CF Three CH Two --CH Two F CH 710 p-Br CF Three CH Two -CF Three CH Two --CH Two F CH 711 o-NH Two CF Three CH Two -CF Three CH Two --CH Two F CH 712 m-NH Two CF Three CH Two -CF Three CH Two --CH Two F CH 713 p-NH Two CF Three CH Two -CF Three CH Two --CH Two F CH 714 o-NO Two CF Three CH Two -CF Three CH Two --CH Two F CH 715 m-NO Two CF Three CH Two -CF Three CH Two --CH Two F CH 716 p-NO Two CF Three CH Two -CF Three CH Two --CH Two F CH 717 o-OC Two H Five CF Three CH Two -CF Three CH Two --CH Two F CH 718 m-OC Two H Five CF Three CH Two -CF Three CH Two --CH Two F CH 719 p-OC Two H Five CF Three CH Two -CF Three CH Two --CH Two F CH 720 pI CF Three CH Two -CF Three CH Two --CH Two F CH 721 oOn-Pr CF Three CH Two -CF Three CH Two --CH Two F CH 722 mOn-Pr CF Three CH Two -CF Three CH Two --CH Two F CH 723 pOn-Pr CF Three CH Two -CF Three CH Two --CH Two F CH 724 oOi-Pr CF Three CH Two -CF Three CH Two --CH Two F CH 725 mOi-Pr CF Three CH Two -CF Three CH Two --CH Two F CH 726 pOi-Pr CF Three CH Two -CF Three CH Two --CH Two F CH 727 oOn-Bu CF Three CH Two -CF Three CH Two --CH Two F CH 728 mOn-Bu CF Three CH Two -CF Three CH Two --CH Two F CH 729 pOn-Bu CF Three CH Two -CF Three CH Two --CH Two F CH 730 oOi-Bu CF Three CH Two -CF Three CH Two --CH Two F CH 731 mOi-Bu CF Three CH Two -CF Three CH Two --CH Two F CH 732 pOi-Bu CF Three CH Two -CF Three CH Two --CH Two F CH 733 o-OCF Three CF Three CH Two -CF Three CH Two --CH Two F CH 734 m-OCF Three CF Three CH Two -CF Three CH Two --CH Two F CH 735 p-OCF Three CF Three CH Two -CF Three CH Two --CH Two F CH 736 H CF Three CH Two -CF Three CH Two --CH Two FN 737 o-OCH Three CF Three CH Two -CF Three CH Two --CH Two FN 738 m-OCH Three CF Three CH Two -CF Three CH Two --CH Two FN 739 p-OCH Three CF Three CH Two -CF Three CH Two --CH Two FN 740 o-Cl CF Three CH Two -CF Three CH Two --CH Two FN 741 m-Cl CF Three CH Two -CF Three CH Two --CH Two FN 742 p-Cl CF Three CH Two -CF Three CH Two --CH Two FN 743 o-Br CF Three CH Two -CF Three CH Two --CH Two FN 744 m-Br CF Three CH Two -CF Three CH Two --CH Two FN 745 p-Br CF Three CH Two -CF Three CH Two --CH Two FN 746 o-NH Two CF Three CH Two -CF Three CH Two --CH Two FN 747 m-NH Two CF Three CH Two -CF Three CH Two --CH Two FN 748 p-NH Two CF Three CH Two -CF Three CH Two --CH Two FN 749 o-NO Two CF Three CH Two -CF Three CH Two --CH Two FN 750 m-NO Two CF Three CH Two -CF Three CH Two --CH Two FN 751 p-NO Two CF Three CH Two -CF Three CH Two --CH Two FN 752 o-OC Two H Five CF Three CH Two -CF Three CH Two --CH Two FN 753 m-OC Two H Five CF Three CH Two -CF Three CH Two --CH Two FN 754 p-OC Two H Five CF Three CH Two -CF Three CH Two --CH Two FN 755 pI CF Three CH Two -CF Three CH Two --CH Two FN 756 oOn-Pr CF Three CH Two -CF Three CH Two --CH Two FN 757 mOn-Pr CF Three CH Two -CF Three CH Two --CH Two FN 758 pOn-Pr CF Three CH Two -CF Three CH Two --CH Two FN 759 oOi-Pr CF Three CH Two -CF Three CH Two --CH Two FN 760 mOi-Pr CF Three CH Two -CF Three CH Two --CH Two FN 761 pOi-Pr CF Three CH Two -CF Three CH Two --CH Two FN 762 oOn-Bu CF Three CH Two -CF Three CH Two --CH Two FN 763 mOn-Bu CF Three CH Two -CF Three CH Two --CH Two FN 764 pOn-Bu CF Three CH Two -CF Three CH Two --CH Two FN 765 oOi-Bu CF Three CH Two -CF Three CH Two --CH Two FN 766 mOi-Bu CF Three CH Two -CF Three CH Two --CH Two FN 767 pOi-Bu CF Three CH Two -CF Three CH Two --CH Two FN 768 o-OCF Three CF Three CH Two -CF Three CH Two --CH Two FN 769 m-OCF Three CF Three CH Two -CF Three CH Two --CH Two FN 770 p-OCF Three CF Three CH Two -CF Three CH Two --CH Two FN 771 H CF Three CH Two -Me- -CH Two F CH 772 o-OCH Three CF Three CH Two -Me- -CH Two F CH 773 m-OCH Three CF Three CH Two -Me- -CH Two F CH 774 p-OCH Three CF Three CH Two -Me- -CH Two F CH 775 o-Cl CF Three CH Two -Me- -CH Two F CH 776 m-Cl CF Three CH Two -Me- -CH Two F CH 777 p-Cl CF Three CH Two -Me- -CH Two F CH 778 o-Br CF Three CH Two -Me- -CH Two F CH 779 m-Br CF Three CH Two -Me- -CH Two F CH 780 p-Br CF Three CH Two -Me- -CH Two F CH 781 o-NH Two CF Three CH Two -Me- -CH Two F CH 782 m-NH Two CF Three CH Two -Me- -CH Two F CH 783 p-NH Two CF Three CH Two -Me- -CH Two F CH 784 o-NO Two CF Three CH Two -Me- -CH Two F CH 785 m-NO Two CF Three CH Two -Me- -CH Two F CH 786 p-NO Two CF Three CH Two -Me- -CH Two F CH 787 o-OC Two H Five CF Three CH Two -Me- -CH Two F CH 788 m-OC Two H Five CF Three CH Two -Me- -CH Two F CH 789 p-OC Two H Five CF Three CH Two -Me- -CH Two F CH 790 pI CF Three CH Two -Me- -CH Two F CH 791 oOn-Pr CF Three CH Two -Me- -CH Two F CH 792 mOn-Pr CF Three CH Two -Me- -CH Two F CH 793 pOn-Pr CF Three CH Two -Me- -CH Two F CH 794 oOi-Pr CF Three CH Two -Me- -CH Two F CH 795 mOi-Pr CF Three CH Two -Me- -CH Two F CH 796 pOi-Pr CF Three CH Two -Me- -CH Two F CH 797 oOn-Bu CF Three CH Two -Me- -CH Two F CH 798 mOn-Bu CF Three CH Two -Me- -CH Two F CH 799 pOn-Bu CF Three CH Two -Me- -CH Two F CH 800 oOi-Bu CF Three CH Two -Me- -CH Two F CH 801 mOi-Bu CF Three CH Two -Me- -CH Two F CH 802 pOi-Bu CF Three CH Two -Me- -CH Two F CH 803 o-OCF Three CF Three CH Two -Me- -CH Two F CH 804 m-OCF Three CF Three CH Two -Me- -CH Two F CH 805 p-OCF Three CF Three CH Two -Me- -CH Two F CH 806 H CF Three CH Two -Me- -CH Two FN 807 o-OCH Three CF Three CH Two -Me- -CH Two FN 808 m-OCH Three CF Three CH Two -Me- -CH Two FN 809 p-OCH Three CF Three CH Two -Me- -CH Two FN 810 o-Cl CF Three CH Two -Me- -CH Two FN 811 m-Cl CF Three CH Two -Me- -CH Two FN 812 p-Cl CF Three CH Two -Me- -CH Two FN 813 o-Br CF Three CH Two -Me- -CH Two FN 814 m-Br CF Three CH Two -Me- -CH Two FN 815 p-Br CF Three CH Two -Me- -CH Two FN 816 o-NH Two CF Three CH Two -Me- -CH Two FN 817 m-NH Two CF Three CH Two -Me- -CH Two FN 818 p-NH Two CF Three CH Two -Me- -CH Two FN 819 o-NO Two CF Three CH Two -Me- -CH Two FN 820 m-NO Two CF Three CH Two -Me- -CH Two FN 821 p-NO Two CF Three CH Two -Me- -CH Two FN 822 o-OC Two H Five CF Three CH Two -Me- -CH Two FN 823 m-OC Two H Five CF Three CH Two -Me- -CH Two FN 824 p-OC Two H Five CF Three CH Two -Me- -CH Two FN 825 pI CF Three CH Two -Me- -CH Two FN 826 oOn-Pr CF Three CH Two -Me- -CH Two FN 827 mOn-Pr CF Three CH Two -Me- -CH Two FN 828 pOn-Pr CF Three CH Two -Me- -CH Two FN 829 oOi-Pr CF Three CH Two -Me- -CH Two FN 830 mOi-Pr CF Three CH Two -Me- -CH Two FN 831 pOi-Pr CF Three CH Two -Me- -CH Two FN 832 oOn-Bu CF Three CH Two -Me- -CH Two FN 833 mOn-Bu CF Three CH Two -Me- -CH Two FN 834 pOn-Bu CF Three CH Two -Me- -CH Two FN 835 oOi-Bu CF Three CH Two -Me- -CH Two FN 836 mOi-Bu CF Three CH Two -Me- -CH Two FN 837 pOi-Bu CF Three CH Two -Me- -CH Two FN 838 o-OCF Three CF Three CH Two -Me- -CH Two FN 839 m-OCF Three CF Three CH Two -Me- -CH Two FN 840 p-OCF Three CF Three CH Two -Me- -CH Two FN 841 H CF Three CH Two -Et- -CH Two F CH 842 o-OCH Three CF Three CH Two -Et- -CH Two F CH 843 m-OCH Three CF Three CH Two -Et- -CH Two F CH 844 p-OCH Three CF Three CH Two -Et- -CH Two F CH 845 o-Cl CF Three CH Two -Et- -CH Two F CH 846 m-Cl CF Three CH Two -Et- -CH Two F CH 847 p-Cl CF Three CH Two -Et- -CH Two F CH 848 o-Br CF Three CH Two -Et- -CH Two F CH 849 m-Br CF Three CH Two -Et- -CH Two F CH 850 p-Br CF Three CH Two -Et- -CH Two F CH 851 o-NH Two CF Three CH Two -Et- -CH Two F CH 852 m-NH Two CF Three CH Two -Et- -CH Two F CH 853 p-NH Two CF Three CH Two -Et- -CH Two F CH 854 o-NO Two CF Three CH Two -Et- -CH Two F CH 855 m-NO Two CF Three CH Two -Et- -CH Two F CH 856 p-NO Two CF Three CH Two -Et- -CH Two F CH 857 o-OC Two H Five CF Three CH Two -Et- -CH Two F CH 858 m-OC Two H Five CF Three CH Two -Et- -CH Two F CH 859 p-OC Two H Five CF Three CH Two -Et- -CH Two F CH 860 pI CF Three CH Two -Et- -CH Two F CH 861 oOn-Pr CF Three CH Two -Et- -CH Two F CH 862 mOn-Pr CF Three CH Two -Et- -CH Two F CH 863 pOn-Pr CF Three CH Two -Et- -CH Two F CH 864 oOi-Pr CF Three CH Two -Et- -CH Two F CH 865 mOi-Pr CF Three CH Two -Et- -CH Two F CH 866 pOi-Pr CF Three CH Two -Et- -CH Two F CH 867 oOn-Bu CF Three CH Two -Et- -CH Two F CH 868 mOn-Bu CF Three CH Two -Et- -CH Two F CH 869 pOn-Bu CF Three CH Two -Et- -CH Two F CH 870 oOi-Bu CF Three CH Two -Et- -CH Two F CH 871 mOi-Bu CF Three CH Two -Et- -CH Two F CH 872 pOi-Bu CF Three CH Two -Et- -CH Two F CH 873 o-OCF Three CF Three CH Two -Et- -CH Two F CH 874 m-OCF Three CF Three CH Two -Et- -CH Two F CH 875 p-OCF Three CF Three CH Two -Et- -CH Two F CH 876 H CF Three CH Two -Et- -CH Two FN 877 o-OCH Three CF Three CH Two -Et- -CH Two FN 878 m-OCH Three CF Three CH Two -Et- -CH Two FN 879 p-OCH Three CF Three CH Two -Et- -CH Two FN 880 o-Cl CF Three CH Two -Et- -CH Two FN 881 m-Cl CF Three CH Two -Et- -CH Two FN 882 p-Cl CF Three CH Two -Et- -CH Two FN 883 o-Br CF Three CH Two -Et- -CH Two FN 884 m-Br CF Three CH Two -Et- -CH Two FN 885 p-Br CF Three CH Two -Et- -CH Two FN 886 o-NH Two CF Three CH Two -Et- -CH Two FN 887 m-NH Two CF Three CH Two -Et- -CH Two FN 888 p-NH Two CF Three CH Two -Et- -CH Two FN 889 o-NO Two CF Three CH Two -Et- -CH Two FN 890 m-NO Two CF Three CH Two -Et- -CH Two FN 891 p-NO Two CF Three CH Two -Et- -CH Two FN 892 o-OC Two H Five CF Three CH Two -Et- -CH Two FN 893 m-OC Two H Five CF Three CH Two -Et- -CH Two FN 894 p-OC Two H Five CF Three CH Two -Et- -CH Two FN 895 pI CF Three CH Two -Et- -CH Two FN 896 oOn-Pr CF Three CH Two -Et- -CH Two FN 897 mOn-Pr CF Three CH Two -Et- -CH Two FN 898 pOn-Pr CF Three CH Two -Et- -CH Two FN 899 oOi-Pr CF Three CH Two -Et- -CH Two FN 900 mOi-Pr CF Three CH Two -Et- -CH Two FN 901 pOi-Pr CF Three CH Two -Et- -CH Two FN 902 oOn-Bu CF Three CH Two -Et- -CH Two FN 903 mOn-Bu CF Three CH Two -Et- -CH Two FN 904 pOn-Bu CF Three CH Two -Et- -CH Two FN 905 oOi-Bu CF Three CH Two -Et- -CH Two FN 906 mOi-Bu CF Three CH Two -Et- -CH Two FN 907 pOi-Bu CF Three CH Two -Et- -CH Two FN 908 o-OCF Three CF Three CH Two -Et- -CH Two FN 909 m-OCF Three CF Three CH Two -Et- -CH Two FN 910 p-OCF Three CF Three CH Two -Et- -CH Two FN 911 H CF Three CH Two -H -CH Two F CH 912 o-OCH Three CF Three CH Two -H -CH Two F CH 913 m-OCH Three CF Three CH Two -H -CH Two F CH 914 p-OCH Three CF Three CH Two -H -CH Two F CH 915 o-Cl CF Three CH Two -H -CH Two F CH 916 m-Cl CF Three CH Two -H -CH Two F CH 917 p-Cl CF Three CH Two -H -CH Two F CH 918 o-Br CF Three CH Two -H -CH Two F CH 919 m-Br CF Three CH Two -H -CH Two F CH 920 p-Br CF Three CH Two -H -CH Two F CH 921 o-NH Two CF Three CH Two -H -CH Two F CH 922 m-NH Two CF Three CH Two -H -CH Two F CH 923 p-NH Two CF Three CH Two -H -CH Two F CH 924 o-NO Two CF Three CH Two -H -CH Two F CH 925 m-NO Two CF Three CH Two -H -CH Two F CH 926 p-NO Two CF Three CH Two -H -CH Two F CH 927 o-OC Two H Five CF Three CH Two -H -CH Two F CH 928 m-OC Two H Five CF Three CH Two -H -CH Two F CH 929 p-OC Two H Five CF Three CH Two -H -CH Two F CH 930 pI CF Three CH Two -H -CH Two F CH 931 oOn-Pr CF Three CH Two -H -CH Two F CH 932 mOn-Pr CF Three CH Two -H -CH Two F CH 933 pOn-Pr CF Three CH Two -H -CH Two F CH 934 oOi-Pr CF Three CH Two -H -CH Two F CH 935 mOi-Pr CF Three CH Two -H -CH Two F CH 936 pOi-Pr CF Three CH Two -H -CH Two F CH 937 oOn-Bu CF Three CH Two -H -CH Two F CH 938 mOn-Bu CF Three CH Two -H -CH Two F CH 939 pOn-Bu CF Three CH Two -H -CH Two F CH 940 oOi-Bu CF Three CH Two -H -CH Two F CH 941 mOi-Bu CF Three CH Two -H -CH Two F CH 942 pOi-Bu CF Three CH Two -H -CH Two F CH 943 o-OCF Three CF Three CH Two -H -CH Two F CH 944 m-OCF Three CF Three CH Two -H -CH Two F CH 945 p-OCF Three CF Three CH Two -H -CH Two F CH 946 H CF Three CH Two -H -CH Two FN 947 o-OCH Three CF Three CH Two -H -CH Two FN 948 m-OCH Three CF Three CH Two -H -CH Two FN 949 p-OCH Three CF Three CH Two -H -CH Two FN 950 o-Cl CF Three CH Two -H -CH Two FN 951 m-Cl CF Three CH Two -H -CH Two FN 952 p-Cl CF Three CH Two -H -CH Two FN 953 o-Br CF Three CH Two -H -CH Two FN 954 m-Br CF Three CH Two -H -CH Two FN 955 p-Br CF Three CH Two -H -CH Two FN 956 o-NH Two CF Three CH Two -H -CH Two FN 957 m-NH Two CF Three CH Two -H -CH Two FN 958 p-NH Two CF Three CH Two -H -CH Two FN 959 o-NO Two CF Three CH Two -H -CH Two FN 960 m-NO Two CF Three CH Two -H -CH Two FN 961 p-NO Two CF Three CH Two -H -CH Two FN 962 o-OC Two H Five CF Three CH Two -H -CH Two FN 963 m-OC Two H Five CF Three CH Two -H -CH Two FN 964 p-OC Two H Five CF Three CH Two -H -CH Two FN 965 pI CF Three CH Two -H -CH Two FN 966 oOn-Pr CF Three CH Two -H -CH Two FN 967 mOn-Pr CF Three CH Two -H -CH Two FN 968 pOn-Pr CF Three CH Two -H -CH Two FN 969 oOi-Pr CF Three CH Two -H -CH Two FN 970 mOi-Pr CF Three CH Two -H -CH Two FN 971 pOi-Pr CF Three CH Two -H -CH Two FN 972 oOn-Bu CF Three CH Two -H -CH Two FN 973 mOn-Bu CF Three CH Two -H -CH Two FN 974 pOn-Bu CF Three CH Two -H -CH Two FN 975 oOi-Bu CF Three CH Two -H -CH Two FN 976 mOi-Bu CF Three CH Two -H -CH Two FN 977 pOi-Bu CF Three CH Two -H -CH Two FN 978 o-OCF Three CF Three CH Two -H -CH Two FN 979 m-OCF Three CF Three CH Two -H -CH Two FN 980 p-OCF Three CF Three CH Two -H -CH Two FN 981 HHH -CH Two F CH 982 o-OCH Three HH -CH Two F CH 983 m-OCH Three HH -CH Two F CH 984 p-OCH Three HH -CH Two F CH 985 o-Cl HH -CH Two F CH 986 m-Cl HH -CH Two F CH 987 p-Cl HH -CH Two F CH 988 o-Br HH -CH Two F CH 989 m-Br HH -CH Two F CH 990 p-Br HH -CH Two F CH 991 o-NH Two HH -CH Two F CH 992 m-NH Two HH -CH Two F CH 993 p-NH Two HH -CH Two F CH 994 o-NO Two HH -CH Two F CH 995 m-NO Two HH -CH Two F CH 996 p-NO Two HH -CH Two F CH 997 o-OC Two H Five HH -CH Two F CH 998 m-OC Two H Five HH -CH Two F CH 999 p-OC Two H Five HH -CH Two F CH 1000 pI HH -CH Two F CH 1001 oOn-Pr HH -CH Two F CH 1002 mOn-Pr HH -CH Two F CH 1003 pOn-Pr HH -CH Two F CH 1004 oOi-Pr HH -CH Two F CH 1005 mOi-Pr HH -CH Two F CH 1006 pOi-Pr HH -CH Two F CH 1007 oOn-Bu HH -CH Two F CH 1008 mOn-Bu HH -CH Two F CH 1009 pOn-Bu HH -CH Two F CH 1010 oOi-Bu HH -CH Two F CH 1011 mOi-Bu HH -CH Two F CH 1012 pOi-Bu HH -CH Two F CH 1013 o-OCF Three HH -CH Two F CH 1014 m-OCF Three HH -CH Two F CH 1015 p-OCF Three HH -CH Two F CH 1016 HHH -CH Two FN 1017 o-OCH Three HH -CH Two FN 1018 m-OCH Three HH -CH Two FN 1019 p-OCH Three HH -CH Two FN 1020 o-Cl HH -CH Two FN 1021 m-Cl HH -CH Two FN 1022 p-Cl HH -CH Two FN 1023 o-Br HH -CH Two FN 1024 m-Br HH -CH Two FN 1025 p-Br HH -CH Two FN 1026 o-NH Two HH -CH Two FN 1027 m-NH Two HH -CH Two FN 1028 p-NH Two HH -CH Two FN 1029 o-NO Two HH -CH Two FN 1030 m-NO Two HH -CH Two FN 1031 p-NO Two HH -CH Two FN 1032 o-OC Two H Five HH -CH Two FN 1033 m-OC Two H Five HH -CH Two FN 1034 p-OC Two H Five HH -CH Two FN 1035 pI HH -CH Two FN 1036 oOn-Pr HH -CH Two FN 1037 mOn-Pr HH -CH Two FN 1038 pOn-Pr HH -CH Two FN 1039 oOi-Pr HH -CH Two FN 1040 mOi-Pr HH -CH Two FN 1041 pOi-Pr HH -CH Two FN 1042 oOn-Bu HH -CH Two FN 1043 mOn-Bu HH -CH Two FN 1044 pOn-Bu HH -CH Two FN 1045 oOi-Bu HH -CH Two FN 1046 mOi-Bu HH -CH Two FN 1047 pOi-Bu HH -CH Two FN 1048 o-OCF Three HH -CH Two FN 1049 m-OCF Three HH -CH Two FN 1050 p-OCF Three HH -CH Two FN 1051 H CF Three CH Two -CF Three CH Two --CH Two OH CH 1052 o-OCH Three CF Three CH Two -CF Three CH Two --CH Two OH CH 1053 m-OCH Three CF Three CH Two -CF Three CH Two --CH Two OH CH 1054 p-OCH Three CF Three CH Two -CF Three CH Two --CH Two OH CH 1055 o-Cl CF Three CH Two -CF Three CH Two --CH Two OH CH 1056 m-Cl CF Three CH Two -CF Three CH Two --CH Two OH CH 1057 p-Cl CF Three CH Two -CF Three CH Two --CH Two OH CH 1058 o-Br CF Three CH Two -CF Three CH Two --CH Two OH CH 1059 m-Br CF Three CH Two -CF Three CH Two --CH Two OH CH 1060 p-Br CF Three CH Two -CF Three CH Two --CH Two OH CH 1061 o-NH Two CF Three CH Two -CF Three CH Two --CH Two OH CH 1062 m-NH Two CF Three CH Two -CF Three CH Two --CH Two OH CH 1063 p-NH Two CF Three CH Two -CF Three CH Two --CH Two OH CH 1064 o-NO Two CF Three CH Two -CF Three CH Two --CH Two OH CH 1065 m-NO Two CF Three CH Two -CF Three CH Two --CH Two OH CH 1066 p-NO Two CF Three CH Two -CF Three CH Two --CH Two OH CH 1067 o-OC Two H Five CF Three CH Two -CF Three CH Two --CH Two OH CH 1068 m-OC Two H Five CF Three CH Two -CF Three CH Two --CH Two OH CH 1069 p-OC Two H Five CF Three CH Two -CF Three CH Two --CH Two OH CH 1070 pI CF Three CH Two -CF Three CH Two --CH Two OH CH 1071 oOn-Pr CF Three CH Two -CF Three CH Two --CH Two OH CH 1072 mOn-Pr CF Three CH Two -CF Three CH Two --CH Two OH CH 1073 pOn-Pr CF Three CH Two -CF Three CH Two --CH Two OH CH 1074 oOi-Pr CF Three CH Two -CF Three CH Two --CH Two OH CH 1075 mOi-Pr CF Three CH Two -CF Three CH Two --CH Two OH CH 1076 pOi-Pr CF Three CH Two -CF Three CH Two --CH Two OH CH 1077 oOn-Bu CF Three CH Two -CF Three CH Two --CH Two OH CH 1078 mOn-Bu CF Three CH Two -CF Three CH Two --CH Two OH CH 1079 pOn-Bu CF Three CH Two -CF Three CH Two --CH Two OH CH 1080 oOi-Bu CF Three CH Two -CF Three CH Two --CH Two OH CH 1081 mOi-Bu CF Three CH Two -CF Three CH Two --CH Two OH CH 1082 pOi-Bu CF Three CH Two -CF Three CH Two --CH Two OH CH 1083 o-OCF Three CF Three CH Two -CF Three CH Two --CH Two OH CH 1084 m-OCF Three CF Three CH Two -CF Three CH Two --CH Two OH CH 1085 p-OCF Three CF Three CH Two -CF Three CH Two --CH Two OH CH 1086 H CF Three CH Two -CF Three CH Two --CH Two OH N 1087 o-OCH Three CF Three CH Two -CF Three CH Two --CH Two OH N 1088 m-OCH Three CF Three CH Two -CF Three CH Two --CH Two OH N 1089 p-OCH Three CF Three CH Two -CF Three CH Two --CH Two OH N 1090 o-Cl CF Three CH Two -CF Three CH Two --CH Two OH N 1091 m-Cl CF Three CH Two -CF Three CH Two --CH Two OH N 1092 p-Cl CF Three CH Two -CF Three CH Two --CH Two OH N 1093 o-Br CF Three CH Two -CF Three CH Two --CH Two OH N 1094 m-Br CF Three CH Two -CF Three CH Two --CH Two OH N 1095 p-Br CF Three CH Two -CF Three CH Two --CH Two OH N 1096 o-NH Two CF Three CH Two -CF Three CH Two --CH Two OH N 1097 m-NH Two CF Three CH Two -CF Three CH Two --CH Two OH N 1098 p-NH Two CF Three CH Two -CF Three CH Two --CH Two OH N 1099 o-NO Two CF Three CH Two -CF Three CH Two --CH Two OH N 1100 m-NO Two CF Three CH Two -CF Three CH Two --CH Two OH N 1101 p-NO Two CF Three CH Two -CF Three CH Two --CH Two OH N 1102 o-OC Two H Five CF Three CH Two -CF Three CH Two --CH Two OH N 1103 m-OC Two H Five CF Three CH Two -CF Three CH Two --CH Two OH N 1104 p-OC Two H Five CF Three CH Two -CF Three CH Two --CH Two OH N 1105 pI CF Three CH Two -CF Three CH Two --CH Two OH N 1106 oOn-Pr CF Three CH Two -CF Three CH Two --CH Two OH N 1107 mOn-Pr CF Three CH Two -CF Three CH Two --CH Two OH N 1108 pOn-Pr CF Three CH Two -CF Three CH Two --CH Two OH N 1109 oOi-Pr CF Three CH Two -CF Three CH Two --CH Two OH N 1110 mOi-Pr CF Three CH Two -CF Three CH Two --CH Two OH N 1111 pOi-Pr CF Three CH Two -CF Three CH Two --CH Two OH N 1112 oOn-Bu CF Three CH Two -CF Three CH Two --CH Two OH N 1113 mOn-Bu CF Three CH Two -CF Three CH Two --CH Two OH N 1114 pOn-Bu CF Three CH Two -CF Three CH Two --CH Two OH N 1115 oOi-Bu CF Three CH Two -CF Three CH Two --CH Two OH N 1116 mOi-Bu CF Three CH Two -CF Three CH Two --CH Two OH N 1117 pOi-Bu CF Three CH Two -CF Three CH Two --CH Two OH N 1118 o-OCF Three CF Three CH Two -CF Three CH Two --CH Two OH N 1119 m-OCF Three CF Three CH Two -CF Three CH Two --CH Two OH N 1120 p-OCF Three CF Three CH Two -CF Three CH Two --CH Two OH N 1121 H CF Three CH Two -Me- -CH Two OH CH 1122 o-OCH Three CF Three CH Two -Me- -CH Two OH CH 1123 m-OCH Three CF Three CH Two -Me- -CH Two OH CH 1124 p-OCH Three CF Three CH Two -Me- -CH Two OH CH 1125 o-Cl CF Three CH Two -Me- -CH Two OH CH 1126 m-Cl CF Three CH Two -Me- -CH Two OH CH 1127 p-Cl CF Three CH Two -Me- -CH Two OH CH 1128 o-Br CF Three CH Two -Me- -CH Two OH CH 1129 m-Br CF Three CH Two -Me- -CH Two OH CH 1130 p-Br CF Three CH Two -Me- -CH Two OH CH 1131 o-NH Two CF Three CH Two -Me- -CH Two OH CH 1132 m-NH Two CF Three CH Two -Me- -CH Two OH CH 1133 p-NH Two CF Three CH Two -Me- -CH Two OH CH 1134 o-NO Two CF Three CH Two -Me- -CH Two OH CH 1135 m-NO Two CF Three CH Two -Me- -CH Two OH CH 1136 p-NO Two CF Three CH Two -Me- -CH Two OH CH 1137 o-OC Two H Five CF Three CH Two -Me- -CH Two OH CH 1138 m-OC Two H Five CF Three CH Two -Me- -CH Two OH CH 1139 p-OC Two H Five CF Three CH Two -Me- -CH Two OH CH 1140 pI CF Three CH Two -Me- -CH Two OH CH 1141 oOn-Pr CF Three CH Two -Me- -CH Two OH CH 1142 mOn-Pr CF Three CH Two -Me- -CH Two OH CH 1143 pOn-Pr CF Three CH Two -Me- -CH Two OH CH 1144 oOi-Pr CF Three CH Two -Me- -CH Two OH CH 1145 mOi-Pr CF Three CH Two -Me- -CH Two OH CH 1146 pOi-Pr CF Three CH Two -Me- -CH Two OH CH 1147 oOn-Bu CF Three CH Two -Me- -CH Two OH CH 1148 mOn-Bu CF Three CH Two -Me- -CH Two OH CH 1149 pOn-Bu CF Three CH Two -Me- -CH Two OH CH 1150 oOi-Bu CF Three CH Two -Me- -CH Two OH CH 1151 mOi-Bu CF Three CH Two -Me- -CH Two OH CH 1152 pOi-Bu CF Three CH Two -Me- -CH Two OH CH 1153 o-OCF Three CF Three CH Two -Me- -CH Two OH CH 1154 m-OCF Three CF Three CH Two -Me- -CH Two OH CH 1155 p-OCF Three CF Three CH Two -Me- -CH Two OH CH 1156 H CF Three CH Two -Me- -CH Two OH N 1157 o-OCH Three CF Three CH Two -Me- -CH Two OH N 1158 m-OCH Three CF Three CH Two -Me- -CH Two OH N 1159 p-OCH Three CF Three CH Two -Me- -CH Two OH N 1160 o-Cl CF Three CH Two -Me- -CH Two OH N 1161 m-Cl CF Three CH Two -Me- -CH Two OH N 1162 p-Cl CF Three CH Two -Me- -CH Two OH N 1163 o-Br CF Three CH Two -Me- -CH Two OH N 1164 m-Br CF Three CH Two -Me- -CH Two OH N 1165 p-Br CF Three CH Two -Me- -CH Two OH N 1166 o-NH Two CF Three CH Two -Me- -CH Two OH N 1167 m-NH Two CF Three CH Two -Me- -CH Two OH N 1168 p-NH Two CF Three CH Two -Me- -CH Two OH N 1169 o-NO Two CF Three CH Two -Me- -CH Two OH N 1170 m-NO Two CF Three CH Two -Me- -CH Two OH N 1171 p-NO Two CF Three CH Two -Me- -CH Two OH N 1172 o-OC Two H Five CF Three CH Two -Me- -CH Two OH N 1173 m-OC Two H Five CF Three CH Two -Me- -CH Two OH N 1174 p-OC Two H Five CF Three CH Two -Me- -CH Two OH N 1175 pI CF Three CH Two -Me- -CH Two OH N 1176 oOn-Pr CF Three CH Two -Me- -CH Two OH N 1177 mOn-Pr CF Three CH Two -Me- -CH Two OH N 1178 pOn-Pr CF Three CH Two -Me- -CH Two OH N 1179 oOi-Pr CF Three CH Two -Me- -CH Two OH N 1180 mOi-Pr CF Three CH Two -Me- -CH Two OH N 1181 pOi-Pr CF Three CH Two -Me- -CH Two OH N 1182 oOn-Bu CF Three CH Two -Me- -CH Two OH N 1183 mOn-Bu CF Three CH Two -Me- -CH Two OH N 1184 pOn-Bu CF Three CH Two -Me- -CH Two OH N 1185 oOi-Bu CF Three CH Two -Me- -CH Two OH N 1186 mOi-Bu CF Three CH Two -Me- -CH Two OH N 1187 pOi-Bu CF Three CH Two -Me- -CH Two OH N 1188 o-OCF Three CF Three CH Two -Me- -CH Two OH N 1189 m-OCF Three CF Three CH Two -Me- -CH Two OH N 1190 p-OCF Three CF Three CH Two -Me- -CH Two OH N 1191 H CF Three CH Two -Et- -CH Two OH CH 1192 o-OCH Three CF Three CH Two -Et- -CH Two OH CH 1193 m-OCH Three CF Three CH Two -Et- -CH Two OH CH 1194 p-OCH Three CF Three CH Two -Et- -CH Two OH CH 1195 o-Cl CF Three CH Two -Et- -CH Two OH CH 1196 m-Cl CF Three CH Two -Et- -CH Two OH CH 1197 p-Cl CF Three CH Two -Et- -CH Two OH CH 1198 o-Br CF Three CH Two -Et- -CH Two OH CH 1199 m-Br CF Three CH Two -Et- -CH Two OH CH 1200 p-Br CF Three CH Two -Et- -CH Two OH CH 1201 o-NH Two CF Three CH Two -Et- -CH Two OH CH 1202 m-NH Two CF Three CH Two -Et- -CH Two OH CH 1203 p-NH Two CF Three CH Two -Et- -CH Two OH CH 1204 o-NO Two CF Three CH Two -Et- -CH Two OH CH 1205 m-NO Two CF Three CH Two -Et- -CH Two OH CH 1206 p-NO Two CF Three CH Two -Et- -CH Two OH CH 1207 o-OC Two H Five CF Three CH Two -Et- -CH Two OH CH 1208 m-OC Two H Five CF Three CH Two -Et- -CH Two OH CH 1209 p-OC Two H Five CF Three CH Two -Et- -CH Two OH CH 1210 pI CF Three CH Two -Et- -CH Two OH CH 1211 oOn-Pr CF Three CH Two -Et- -CH Two OH CH 1212 mOn-Pr CF Three CH Two -Et- -CH Two OH CH 1213 pOn-Pr CF Three CH Two -Et- -CH Two OH CH 1214 oOi-Pr CF Three CH Two -Et- -CH Two OH CH 1215 mOi-Pr CF Three CH Two -Et- -CH Two OH CH 1216 pOi-Pr CF Three CH Two -Et- -CH Two OH CH 1217 oOn-Bu CF Three CH Two -Et- -CH Two OH CH 1218 mOn-Bu CF Three CH Two -Et- -CH Two OH CH 1219 pOn-Bu CF Three CH Two -Et- -CH Two OH CH 1220 oOi-Bu CF Three CH Two -Et- -CH Two OH CH 1221 mOi-Bu CF Three CH Two -Et- -CH Two OH CH 1222 pOi-Bu CF Three CH Two -Et- -CH Two OH CH 1223 o-OCF Three CF Three CH Two -Et- -CH Two OH CH 1224 m-OCF Three CF Three CH Two -Et- -CH Two OH CH 1225 p-OCF Three CF Three CH Two -Et- -CH Two OH CH 1226 H CF Three CH Two -Et- -CH Two OH N 1227 o-OCH Three CF Three CH Two -Et- -CH Two OH N 1228 m-OCH Three CF Three CH Two -Et- -CH Two OH N 1229 p-OCH Three CF Three CH Two -Et- -CH Two OH N 1230 o-Cl CF Three CH Two -Et- -CH Two OH N 1231 m-Cl CF Three CH Two -Et- -CH Two OH N 1232 p-Cl CF Three CH Two -Et- -CH Two OH N 1233 o-Br CF Three CH Two -Et- -CH Two OH N 1234 m-Br CF Three CH Two -Et- -CH Two OH N 1235 p-Br CF Three CH Two -Et- -CH Two OH N 1236 o-NH Two CF Three CH Two -Et- -CH Two OH N 1237 m-NH Two CF Three CH Two -Et- -CH Two OH N 1238 p-NH Two CF Three CH Two -Et- -CH Two OH N 1239 o-NO Two CF Three CH Two -Et- -CH Two OH N 1240 m-NO Two CF Three CH Two -Et- -CH Two OH N 1241 p-NO Two CF Three CH Two -Et- -CH Two OH N 1242 o-OC Two H Five CF Three CH Two -Et- -CH Two OH N 1243 m-OC Two H Five CF Three CH Two -Et- -CH Two OH N 1244 p-OC Two H Five CF Three CH Two -Et- -CH Two OH N 1245 pI CF Three CH Two -Et- -CH Two OH N 1246 oOn-Pr CF Three CH Two -Et- -CH Two OH N 1247 mOn-Pr CF Three CH Two -Et- -CH Two OH N 1248 pOn-Pr CF Three CH Two -Et- -CH Two OH N 1249 oOi-Pr CF Three CH Two -Et- -CH Two OH N 1250 mOi-Pr CF Three CH Two -Et- -CH Two OH N 1251 pOi-Pr CF Three CH Two -Et- -CH Two OH N 1252 oOn-Bu CF Three CH Two -Et- -CH Two OH N 1253 mOn-Bu CF Three CH Two -Et- -CH Two OH N 1254 pOn-Bu CF Three CH Two -Et- -CH Two OH N 1255 oOi-Bu CF Three CH Two -Et- -CH Two OH N 1256 mOi-Bu CF Three CH Two -Et- -CH Two OH N 1257 pOi-Bu CF Three CH Two -Et- -CH Two OH N 1258 o-OCF Three CF Three CH Two -Et- -CH Two OH N 1259 m-OCF Three CF Three CH Two -Et- -CH Two OH N 1260 p-OCF Three CF Three CH Two -Et- -CH Two OH N 1261 H CF Three CH Two -H -CH Two OH CH 1262 o-OCH Three CF Three CH Two -H -CH Two OH CH 1263 m-OCH Three CF Three CH Two -H -CH Two OH CH 1264 p-OCH Three CF Three CH Two -H -CH Two OH CH 1265 o-Cl CF Three CH Two -H -CH Two OH CH 1266 m-Cl CF Three CH Two -H -CH Two OH CH 1267 p-Cl CF Three CH Two -H -CH Two OH CH 1268 o-Br CF Three CH Two -H -CH Two OH CH 1269 m-Br CF Three CH Two -H -CH Two OH CH 1270 p-Br CF Three CH Two -H -CH Two OH CH 1271 o-NH Two CF Three CH Two -H -CH Two OH CH 1272 m-NH Two CF Three CH Two -H -CH Two OH CH 1273 p-NH Two CF Three CH Two -H -CH Two OH CH 1274 o-NO Two CF Three CH Two -H -CH Two OH CH 1275 m-NO Two CF Three CH Two -H -CH Two OH CH 1276 p-NO Two CF Three CH Two -H -CH Two OH CH 1277 o-OC Two H Five CF Three CH Two -H -CH Two OH CH 1278 m-OC Two H Five CF Three CH Two -H -CH Two OH CH 1279 p-OC Two H Five CF Three CH Two -H -CH Two OH CH 1280 pI CF Three CH Two -H -CH Two OH CH 1281 oOn-Pr CF Three CH Two -H -CH Two OH CH 1282 mOn-Pr CF Three CH Two -H -CH Two OH CH 1283 pOn-Pr CF Three CH Two -H -CH Two OH CH 1284 oOi-Pr CF Three CH Two -H -CH Two OH CH 1285 mOi-Pr CF Three CH Two -H -CH Two OH CH 1286 pOi-Pr CF Three CH Two -H -CH Two OH CH 1287 oOn-Bu CF Three CH Two -H -CH Two OH CH 1288 mOn-Bu CF Three CH Two -H -CH Two OH CH 1289 pOn-Bu CF Three CH Two -H -CH Two OH CH 1290 oOi-Bu CF Three CH Two -H -CH Two OH CH 1291 mOi-Bu CF Three CH Two -H -CH Two OH CH 1292 pOi-Bu CF Three CH Two -H -CH Two OH CH 1293 o-OCF Three CF Three CH Two -H -CH Two OH CH 1294 m-OCF Three CF Three CH Two -H -CH Two OH CH 1295 p-OCF Three CF Three CH Two -H -CH Two OH CH 1296 H CF Three CH Two -H -CH Two OH N 1297 o-OCH Three CF Three CH Two -H -CH Two OH N 1298 m-OCH Three CF Three CH Two -H -CH Two OH N 1299 p-OCH Three CF Three CH Two -H -CH Two OH N 1300 o-Cl CF Three CH Two -H -CH Two OH N 1301 m-Cl CF Three CH Two -H -CH Two OH N 1302 p-Cl CF Three CH Two -H -CH Two OH N 1303 o-Br CF Three CH Two -H -CH Two OH N 1304 m-Br CF Three CH Two -H -CH Two OH N 1305 p-Br CF Three CH Two -H -CH Two OH N 1306 o-NH Two CF Three CH Two -H -CH Two OH N 1307 m-NH Two CF Three CH Two -H -CH Two OH N 1308 p-NH Two CF Three CH Two -H -CH Two OH N 1309 o-NO Two CF Three CH Two -H -CH Two OH N 1310 m-NO Two CF Three CH Two -H -CH Two OH N 1311 p-NO Two CF Three CH Two -H -CH Two OH N 1312 o-OC Two H Five CF Three CH Two -H -CH Two OH N 1313 m-OC Two H Five CF Three CH Two -H -CH Two OH N 1314 p-OC Two H Five CF Three CH Two -H -CH Two OH N 1315 pI CF Three CH Two -H -CH Two OH N 1316 oOn-Pr CF Three CH Two -H -CH Two OH N 1317 mOn-Pr CF Three CH Two -H -CH Two OH N 1318 pOn-Pr CF Three CH Two -H -CH Two OH N 1319 oOi-Pr CF Three CH Two -H -CH Two OH N 1320 mOi-Pr CF Three CH Two -H -CH Two OH N 1321 pOi-Pr CF Three CH Two -H -CH Two OH N 1322 oOn-Bu CF Three CH Two -H -CH Two OH N 1323 mOn-Bu CF Three CH Two -H -CH Two OH N 1324 pOn-Bu CF Three CH Two -H -CH Two OH N 1325 oOi-Bu CF Three CH Two -H -CH Two OH N 1326 mOi-Bu CF Three CH Two -H -CH Two OH N 1327 pOi-Bu CF Three CH Two -H -CH Two OH N 1328 o-OCF Three CF Three CH Two -H -CH Two OH N 1329 m-OCF Three CF Three CH Two -H -CH Two OH N 1330 p-OCF Three CF Three CH Two -H -CH Two OH N 1331 HHH -CH Two OH CH 1332 o-OCH Three HH -CH Two OH CH 1333 m-OCH Three HH -CH Two OH CH 1334 p-OCH Three HH -CH Two OH CH 1335 o-Cl HH -CH Two OH CH 1336 m-Cl HH -CH Two OH CH 1337 p-Cl HH -CH Two OH CH 1338 o-Br HH -CH Two OH CH 1339 m-Br HH -CH Two OH CH 1340 p-Br HH -CH Two OH CH 1341 o-NH Two HH -CH Two OH CH 1342 m-NH Two HH -CH Two OH CH 1343 p-NH Two HH -CH Two OH CH 1344 o-NO Two HH -CH Two OH CH 1345 m-NO Two HH -CH Two OH CH 1346 p-NO Two HH -CH Two OH CH 1347 o-OC Two H Five HH -CH Two OH CH 1348 m-OC Two H Five HH -CH Two OH CH 1349 p-OC Two H Five HH -CH Two OH CH 1350 pI HH -CH Two OH CH 1351 oOn-Pr HH -CH Two OH CH 1352 mOn-Pr HH -CH Two OH CH 1353 pOn-Pr HH -CH Two OH CH 1354 oOi-Pr HH -CH Two OH CH 1355 mOi-Pr HH -CH Two OH CH 1356 pOi-Pr HH -CH Two OH CH 1357 oOn-Bu HH -CH Two OH CH 1358 mOn-Bu HH -CH Two OH CH 1359 pOn-Bu HH -CH Two OH CH 1360 oOi-Bu HH -CH Two OH CH 1361 mOi-Bu HH -CH Two OH CH 1362 pOi-Bu HH -CH Two OH CH 1363 o-OCF Three HH -CH Two OH CH 1364 m-OCF Three HH -CH Two OH CH 1365 p-OCF Three HH -CH Two OH CH 1366 HHH -CH Two OH N 1367 o-OCH Three HH -CH Two OH N 1368 m-OCH Three HH -CH Two OH N 1369 p-OCH Three HH -CH Two OH N 1370 o-Cl HH -CH Two OH N 1371 m-Cl HH -CH Two OH N 1372 p-Cl HH -CH Two OH N 1373 o-Br HH -CH Two OH N 1374 m-Br HH -CH Two OH N 1375 p-Br HH -CH Two OH N 1376 o-NH Two HH -CH Two OH N 1377 m-NH Two HH -CH Two OH N 1378 p-NH Two HH -CH Two OH N 1379 o-NO Two HH -CH Two OH N 1380 m-NO Two HH -CH Two OH N 1381 p-NO Two HH -CH Two OH N 1382 o-OC Two H Five HH -CH Two OH N 1383 m-OC Two H Five HH -CH Two OH N 1384 p-OC Two H Five HH -CH Two OH N 1385 pI HH -CH Two OH N 1386 oOn-Pr HH -CH Two OH N 1387 mOn-Pr HH -CH Two OH N 1388 pOn-Pr HH -CH Two OH N 1389 oOi-Pr HH -CH Two OH N 1390 mOi-Pr HH -CH Two OH N 1391 pOi-Pr HH -CH Two OH N 1392 oOn-Bu HH -CH Two OH N 1393 mOn-Bu HH -CH Two OH N 1394 pOn-Bu HH -CH Two OH N 1395 oOi-Bu HH -CH Two OH N 1396 mOi-Bu HH -CH Two OH N 1397 pOi-Bu HH -CH Two OH N 1398 o-OCF Three HH -CH Two OH N 1399 m-OCF Three HH -CH Two OH N 1400 p-OCF Three HH -CH Two OH N 1401 H -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1402 o-OCH Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1403 m-OCH Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1404 p-OCH Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1405 o-Cl -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1406 m-Cl -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1407 p-Cl -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1408 o-Br -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1409 m-Br -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1410 p-Br -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1411 o-NH Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1412 m-NH Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1413 p-NH Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1414 o-NO Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1415 m-NO Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1416 p-NO Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1417 o-OC Two H Five -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1418 m-OC Two H Five -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1419 p-OC Two H Five -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1420 pI -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1421 oOn-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1422 mOn-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1423 pOn-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1424 oOi-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1425 mOi-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1426 pOi-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1427 oOn-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1428 mOn-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1429 pOn-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1430 oOi-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1431 mOi-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1432 pOi-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1433 o-OCF Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1434 m-OCF Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1435 p-OCF Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu H CH 1436 H -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1437 o-OCH Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1438 m-OCH Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1439 p-OCH Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1440 o-Cl -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1441 m-Cl -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1442 p-Cl -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1443 o-Br -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1444 m-Br -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1445 p-Br -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1446 o-NH Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1447 m-NH Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1448 p-NH Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1449 o-NO Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1450 m-NO Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1451 p-NO Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1452 o-OC Two H Five -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1453 m-OC Two H Five -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1454 p-OC Two H Five -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1455 pI -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1456 oOn-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1457 mOn-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1458 pOn-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1459 oOi-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1460 mOi-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1461 pOi-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1462 oOn-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1463 mOn-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1464 pOn-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1465 oOi-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1466 mOi-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1467 pOi-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1468 o-OCF Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1469 m-OCF Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1470 p-OCF Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu Me- CH 1471 H -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1472 o-OCH Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1473 m-OCH Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1474 p-OCH Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1475 o-Cl -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1476 m-Cl -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1477 p-Cl -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1478 o-Br -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1479 m-Br -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1480 p-Br -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1481 o-NH Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1482 m-NH Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1483 p-NH Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1484 o-NO Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1485 m-NO Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1486 p-NO Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1487 o-OC Two H Five -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1488 m-OC Two H Five -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1489 p-OC Two H Five -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1490 pI -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1491 oOn-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1492 mOn-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1493 pOn-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1494 oOi-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1495 mOi-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1496 pOi-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1497 oOn-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1498 mOn-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1499 pOn-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1500 oOi-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1501 mOi-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1502 pOi-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1503 o-OCF Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1504 m-OCF Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1505 p-OCF Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two F CH 1506 H -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1507 o-OCH Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1508 m-OCH Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1509 p-OCH Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1510 o-Cl -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1511 m-Cl -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1512 p-Cl -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1513 o-Br -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1514 m-Br -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1515 p-Br -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1516 o-NH Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1517 m-NH Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1518 p-NH Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1519 o-NO Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1520 m-NO Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1521 p-NO Two -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1522 o-OC Two H Five -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1523 m-OC Two H Five -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1524 p-OC Two H Five -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1525 pI -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1526 oOn-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1527 mOn-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1528 pOn-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1529 oOi-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1530 mOi-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1531 pOi-Pr -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1532 oOn-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1533 mOn-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1534 pOn-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1535 oOi-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1536 mOi-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1537 pOi-Bu -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1538 o-OCF Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1539 m-OCF Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1540 p-OCF Three -CH Two O-CO-t-Bu -CH Two O-CO-t-Bu -CH Two OH CH 1541 H -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1542 o-OCH Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1543 m-OCH Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1544 p-OCH Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1545 o-Cl -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1546 m-Cl -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1547 p-Cl -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1548 o-Br -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1549 m-Br -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1550 p-Br -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1551 o-NH Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1552 m-NH Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1553 p-NH Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1554 o-NO Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1555 m-NO Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1556 p-NO Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1557 o-OC Two H Five -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1558 m-OC Two H Five -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1559 p-OC Two H Five -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1560 pI -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1561 oOn-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1562 mOn-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1563 pOn-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1564 oOi-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1565 mOi-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1566 pOi-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1567 oOn-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1568 mOn-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1569 pOn-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1570 oOi-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1571 mOi-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1572 pOi-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1573 o-OCF Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1574 m-OCF Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1575 p-OCF Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr H CH 1576 H -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1577 o-OCH Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1578 m-OCH Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1579 p-OCH Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1580 o-Cl -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1581 m-Cl -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1582 p-Cl -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1583 o-Br -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1584 m-Br -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1585 p-Br -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1586 o-NH Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1587 m-NH Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1588 p-NH Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1589 o-NO Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1590 m-NO Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1591 p-NO Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1592 o-OC Two H Five -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1593 m-OC Two H Five -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1594 p-OC Two H Five -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1595 pI -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1596 oOn-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1597 mOn-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1598 pOn-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1599 oOi-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1600 mOi-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1601 pOi-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1602 oOn-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1603 mOn-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1604 pOn-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1605 oOi-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1606 mOi-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1607 pOi-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1608 o-OCF Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1609 m-OCF Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1610 p-OCF Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr Me- CH 1611 H -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1612 o-OCH Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1613 m-OCH Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1614 p-OCH Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1615 o-Cl -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1616 m-Cl -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1617 p-Cl -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1618 o-Br -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1619 m-Br -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1620 p-Br -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1621 o-NH Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1622 m-NH Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1623 p-NH Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1624 o-NO Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1625 m-NO Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1626 p-NO Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1627 o-OC Two H Five -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1628 m-OC Two H Five -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1629 p-OC Two H Five -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1630 pI -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1631 oOn-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1632 mOn-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1633 pOn-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1634 oOi-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1635 mOi-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1636 pOi-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1637 oOn-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1638 mOn-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1639 pOn-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1640 oOi-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1641 mOi-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1642 pOi-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1643 o-OCF Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1644 m-OCF Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1645 p-OCF Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two F CH 1646 H -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1647 o-OCH Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1648 m-OCH Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1649 p-OCH Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1650 o-Cl -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1651 m-Cl -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1652 p-Cl -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1653 o-Br -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1654 m-Br -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1655 p-Br -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1656 o-NH Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1657 m-NH Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1658 p-NH Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1659 o-NO Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1660 m-NO Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1661 p-NO Two -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1662 o-OC Two H Five -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1663 m-OC Two H Five -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1664 p-OC Two H Five -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1665 pI -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1666 oOn-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1667 mOn-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1668 pOn-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1669 oOi-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1670 mOi-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1671 pOi-Pr -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1672 oOn-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1673 mOn-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1674 pOn-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1675 oOi-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1676 mOi-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1677 pOi-Bu -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1678 o-OCF Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1679 m-OCF Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH 1680 p-OCF Three -CH Two CH Two S-CO-i-Pr -CH Two CH Two S-CO-i-Pr -CH Two OH CH
【００２４】本発明の化合物の製造方法としては、一般
式（Ｉ）の化合物のＲ2 及びＲ3 が共にＣ1 〜Ｃ22のア
ルキル基又は１以上のハロゲン原子で置換されたエチル
基である化合物の場合は、例えば下記反応ルート（１）
又は（２）に従って合成することができる（下記スキー
ム中、Ｒ1 、Ｒ4 、及びＸは既に定義したとおりであ
り、Ｒ5 はＣ1 〜Ｃ22のアルキル基又は１以上のハロゲ
ン原子で置換されたエチル基を表わす。Ｗはハロゲン原
子、パラトルエンスルホニルオキシ基、メタンスルホニ
ルオキシ基、トリフルオロメタンスルホニルオキシ基等
の脱離基を表す。）According to the method for producing the compound of the present invention, R 2 and R 3 of the compound of the formula (I) are both a C 1 -C 22 alkyl group or an ethyl group substituted with one or more halogen atoms. In the case of a compound, for example, the following reaction route (1)
Or (2) wherein R 1 , R 4 and X are as defined above, and R 5 is substituted with a C 1 -C 22 alkyl group or one or more halogen atoms. W represents a leaving group such as a halogen atom, a paratoluenesulfonyloxy group, a methanesulfonyloxy group, and a trifluoromethanesulfonyloxy group.)
【００２５】＜反応ルート（１）＞<Reaction route (1)>
【化３】 Embedded image
【００２６】まず上記一般式（II）の化合物及び上記一
般式（III)の化合物を、１０〜２５０℃、好ましくは１
３０〜２００℃の温度で、０．１〜１００時間、好まし
くは３〜２４時間反応させる。上記反応により得られる
上記一般式（IV）の化合物は、必要に応じて通常の分離
精製手段、例えば蒸留、吸着、分配クロマトグラフィー
等により分離精製することができる。上記一般式（IV）
の化合物は上記のようにして分離精製してもよいが、そ
のまま精製することなく以下の反応に供してもよい。引
き続き、上記一般式（IV）の化合物及び上記一般式
（Ｖ）で表される化合物を、塩基、例えば炭酸ナトリウ
ム、炭酸カリウム、炭酸セシウム、水素化ナトリウム、
水素化カリウム、トリエチルアミン、ジアザビシクロウ
ンデセン等の存在下、アセトニトリル、テトラヒドロフ
ラン、ジメチルスルホキシド、ジメチルホルムアミド、
メチルピロリドン等の適当な溶媒中、１０〜２００℃、
好ましくは５０〜１５０℃の温度で、０．１〜１００時
間、好ましくは１〜１０時間反応させ、上記一般式
（Ｉ′）の化合物を得ることができる。First, the compound of the above general formula (II) and the compound of the above general formula (III) are reacted at 10 to 250 ° C., preferably 1 to 250 ° C.
The reaction is carried out at a temperature of 30 to 200 ° C. for 0.1 to 100 hours, preferably 3 to 24 hours. The compound of the general formula (IV) obtained by the above reaction can be separated and purified by a usual separation and purification means, for example, distillation, adsorption, partition chromatography and the like, if necessary. The above general formula (IV)
May be separated and purified as described above, or may be subjected to the following reaction without purification. Subsequently, the compound represented by the general formula (IV) and the compound represented by the general formula (V) are converted into a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride,
In the presence of potassium hydride, triethylamine, diazabicycloundecene, etc., acetonitrile, tetrahydrofuran, dimethylsulfoxide, dimethylformamide,
10 to 200 ° C. in a suitable solvent such as methylpyrrolidone,
The reaction is carried out preferably at a temperature of 50 to 150 ° C. for 0.1 to 100 hours, preferably 1 to 10 hours, to obtain the compound of the above general formula (I ′).
【００２７】反応ルート（１）の原料である上記一般式
（II）の化合物、上記一般式（III)の化合物、及び上記
一般式（Ｖ）の化合物の由来は特に限定されず、例え
ば、試薬として市販されているものを使用するか、それ
自体既知の方法により適宜合成して使用することができ
る。例えば、上記一般式（Ｖ）の化合物は、後述の一般
式（VI）の化合物と一般式（VIII）の化合物とを、アセ
トニトリル、ジメチルスルホキシド等の適当な溶媒中
で、５０〜１００℃の範囲で加熱することによって合成
できる。The source of the compound of the general formula (II), the compound of the general formula (III) and the compound of the general formula (V), which are the raw materials of the reaction route (1), is not particularly limited. Can be used, or can be appropriately synthesized and used by a method known per se. For example, the compound of the above general formula (V) can be prepared by combining a compound of the following general formula (VI) and a compound of the general formula (VIII) in a suitable solvent such as acetonitrile, dimethyl sulfoxide or the like in a temperature range of 50 to 100 ° C. Can be synthesized by heating.
【００２８】上記一般式（Ｉ′）の化合物は、下記の方
法によっても製造できる（下記スキーム中、Ｒ1 、
Ｒ4 、Ｒ5 、Ｘ、及びＷは既に定義したとおりであ
る）。 ＜反応ルート（２）＞The compound of the above general formula (I ') can also be produced by the following method (in the following scheme, R 1 ,
R 4 , R 5 , X, and W are as previously defined). <Reaction route (2)>
【化４】 Embedded image
【００２９】反応ルート（１）で得られた上記一般式
（IV）の化合物及び上記一般式（VI）の化合物を、塩
基、例えば炭酸ナトリウム、炭酸カリウム、炭酸セシウ
ム、水素化ナトリウム、水素化カリウム、トリエチルア
ミン、ジアザビシクロウンデセン等の存在下、アセトニ
トリル、テトラヒドロフラン、ジメチルスルホキシド、
ジメチルホルムアミド、メチルピロリドン等の適当な溶
媒中、１０〜２００℃、好ましくは５０〜１５０℃の温
度で、０．１〜１００時間、好ましくは０．５〜１０時
間反応させ、上記一般式（VII)の化合物を得る。次い
で、上記一般式（VII)の化合物及び上記一般式（VIII）
で表されるメルカプタン又はその塩、例えばナトリウム
塩、カリウム塩、リチウム塩、トリエチルアミン塩等
を、例えばアセトニトリル、テトラヒドロフラン、ジメ
チルスルホキシド、ジメチルホルムアミド、メチルピロ
リドン等の適当な溶媒中で、場合によっては適当な３級
アミンの存在下、１０〜２００℃、好ましくは７０〜１
２０℃の温度で、０．１〜１００時間、好ましくは０．
５〜１２時間反応させ、上記一般式（Ｉ′）の化合物を
得ることができる。この一般式（Ｉ′）の化合物は、一
般式（Ｉ）においてＲ2 及びＲ3 が共にＣ1 〜Ｃ22のア
ルキル基又は１以上のハロゲン原子で置換されたエチル
基である化合物に相当する。反応ルート（２）の原料で
ある上記一般式（VI）の化合物の由来は特に限定され
ず、例えば、試薬として市販されているものを使用する
か、それ自体既知の方法により適宜合成して使用するこ
とができる。The compound of the above general formula (IV) and the compound of the above general formula (VI) obtained by the reaction route (1) is converted into a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride , In the presence of triethylamine, diazabicycloundecene, etc., acetonitrile, tetrahydrofuran, dimethylsulfoxide,
The reaction is carried out in a suitable solvent such as dimethylformamide, methylpyrrolidone or the like at a temperature of 10 to 200 ° C, preferably 50 to 150 ° C for 0.1 to 100 hours, preferably 0.5 to 10 hours. ) Is obtained. Then, the compound of the above general formula (VII) and the above general formula (VIII)
In a suitable solvent such as acetonitrile, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, methylpyrrolidone, etc., a mercaptan represented by or a salt thereof, for example, a sodium salt, a potassium salt, a lithium salt, a triethylamine salt, etc. 10 to 200 ° C, preferably 70 to 1 in the presence of a tertiary amine
At a temperature of 20 ° C., for 0.1 to 100 hours, preferably 0.1 to 100 hours.
After reacting for 5 to 12 hours, the compound of the above general formula (I ') can be obtained. The compound of the general formula (I ′) corresponds to a compound of the general formula (I) in which R 2 and R 3 are both a C 1 -C 22 alkyl group or an ethyl group substituted with one or more halogen atoms. . The source of the compound of the above general formula (VI), which is a raw material of the reaction route (2), is not particularly limited. For example, a commercially available reagent may be used, or the compound may be appropriately synthesized by a method known per se. can do.
【００３０】上記一般式（Ｉ′）の化合物の燐酸エステ
ル部分を更に変化させることにより、一般式（Ｉ′）の
化合物のＲ5 を他の置換基に変換した一般式（Ｉ）の化
合物を得ることができる。例えば一般式（Ｉ）において
Ｒ2 及びＲ3 が共に水素原子である化合物は、上記一般
式（Ｉ′）の化合物を加水分解して得られる。また、一
般式（Ｉ）において、Ｒ3 が水素原子、Ｃ1 〜Ｃ22のア
ルキル基、アシルチオエチル基、又は１以上のハロゲン
原子で置換されたエチル基であり、Ｒ2 がＣ1〜Ｃ22の
アルキル基又は１以上のハロゲン原子で置換されたエチ
ル基である化合物は、上記一般式（Ｉ′）の化合物と一
般式（IX）：Ｒ6 ＯＨ（Ｒ6 は水素原子、Ｃ1 〜Ｃ22の
アルキル基、アシルチオエチル基，又は１以上のハロゲ
ン原子で置換されたエチル基を表す）で表される化合物
とを、無溶媒又は適当な溶媒、例えばジクロロメタン等
の塩素系溶媒、ピリジン、アセトニトリル、テトラヒド
ロフラン、ジメチルスルホキシド、ジメチルホルムアミ
ド、メチルピロリドン等の中で、場合により酸またはア
ルカリの存在下で、１０〜１００℃、好ましくは２０〜
３０℃の範囲の温度で、０．１〜１００時間、好ましく
は５〜１２時間反応させて得られる。By further changing the phosphate moiety of the compound of the above general formula (I '), the compound of the general formula (I) obtained by converting R 5 of the compound of the general formula (I') to another substituent is obtained. Obtainable. For example, a compound in which R 2 and R 3 in Formula (I) are both hydrogen atoms can be obtained by hydrolyzing the compound of Formula (I ′). In the general formula (I), R 3 is a hydrogen atom, a C 1 to C 22 alkyl group, an acylthioethyl group, or an ethyl group substituted with one or more halogen atoms, and R 2 is a C 1 to The compound which is an alkyl group of C 22 or an ethyl group substituted with one or more halogen atoms may be a compound of the above general formula (I ′) and a compound of the general formula (IX): R 6 OH (R 6 is a hydrogen atom, C 1 alkyl -C 22, acylthioethyl ethyl, or 1 or more and a compound represented by a halogen atom represent a substituted ethyl group), without solvent or in a suitable solvent, for example chlorinated solvents such as dichloromethane, In pyridine, acetonitrile, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, methylpyrrolidone and the like, optionally in the presence of an acid or alkali, 10 to 100 ° C, preferably 20 to 100 ° C.
It is obtained by reacting at a temperature in the range of 30 ° C. for 0.1 to 100 hours, preferably 5 to 12 hours.
【００３１】[0031]
【化５】 （上記スキーム中、Ｒ1 、Ｒ4 、Ｒ5 、Ｒ6 及びＸは、
既に定義したとおりである。）Embedded image (In the above scheme, R 1 , R 4 , R 5 , R 6 and X are
As defined above. )
【００３２】一般式（Ｉ）において、Ｒ2 及びＲ3 がそ
れぞれ独立して水素原子、Ｃ1 〜Ｃ22のアルキル基、ア
シルチオエチル基、又は１以上のハロゲン原子で置換さ
れたエチル基で表される化合物は、下記の方法によって
も得られる（下記スキーム中、Ｒ1 、Ｒ4 、及びＸは既
に定義したとおりであり、Ｒ7 及びＲ8 はそれぞれ独立
して水素原子、Ｃ1 〜Ｃ22のアルキル基、アシルチオエ
チル基、又は１以上のハロゲン原子で置換されたエチル
基を表す。ただし、Ｒ7 及びＲ8 が同時に水素原子を表
すことはない。）In the general formula (I), R 2 and R 3 are each independently a hydrogen atom, a C 1 -C 22 alkyl group, an acylthioethyl group, or an ethyl group substituted with one or more halogen atoms. The compound represented can also be obtained by the following method (in the following scheme, R 1 , R 4 , and X are as defined above, and R 7 and R 8 are each independently a hydrogen atom, C 1 to alkyl C 22, represent the acylthioethyl ethyl, or one or more substituted ethyl group by a halogen atom. However, R 7 and R 8 never represent a hydrogen atom simultaneously.)
【化６】 Embedded image
【００３３】まず上記一般式（Ｉ″）の化合物とトリメ
チルシリルジエチルアミンとを、適当な溶媒、例えばジ
クロロメタン、ジクロロエタン、クロロホルム等の塩素
系溶媒中、室温付近で１時間程度反応させる。このと
き、トリメチルシリルジエチルアミンは、上記一般式
（Ｉ″）の化合物１モルに対し２モル以上使用する。次
いで、反応液を濃縮乾固した後、残渣を適当な溶媒、例
えばジクロロメタン等の塩素系溶媒に溶かし、オキザリ
ルクロリドを上記一般式（Ｉ″）の化合物１モルに対し
て２モル以上添加し、触媒量のジメチルホルムアミドの
存在下に、氷冷下で約１時間、次いで室温付近で約１時
間反応させる。First, the compound of the above formula (I ″) is reacted with trimethylsilyldiethylamine in a suitable solvent, for example, a chlorinated solvent such as dichloromethane, dichloroethane or chloroform at about room temperature for about 1 hour. Is used in an amount of 2 mol or more per 1 mol of the compound of the above general formula (I ″). Next, the reaction solution is concentrated to dryness, and the residue is dissolved in an appropriate solvent, for example, a chlorinated solvent such as dichloromethane, and oxalyl chloride is added in an amount of 2 mol or more per 1 mol of the compound of the above general formula (I ″). The reaction is carried out in the presence of a catalytic amount of dimethylformamide under ice cooling for about 1 hour and then at about room temperature for about 1 hour.
【００３４】溶媒留去して得られる上記一般式（Ｘ）の
化合物を、通常は精製することなく、適当な溶媒、例え
ばジクロロメタン等の塩素系溶媒、ピリジン、アセトニ
トリル、テトラヒドロフラン、ジメチルスルホキシド、
ジメチルホルムアミド、メチルピロリドン等の中で、一
般式（XI）の化合物及び／又は一般式（XII)の化合物
と、１０〜１００℃、好ましくは２０〜３０℃の温度範
囲で、０．１〜１００時間、好ましくは５〜１２時間反
応させる。得られた一般式（XIII）の化合物は、一般式
（Ｉ）においてＲ2 及びＲ3 がそれぞれ独立して水素原
子、Ｃ1 〜Ｃ22のアルキル基、アシルチオエチル基、又
は１以上のハロゲン原子で置換されたエチル基である化
合物に相当する（ただし、Ｒ2 及びＲ3 が同時に水素原
子を表すことはない）。なお、上記反応で原料となる上
記一般式（Ｉ″）の化合物は、既に述べた様に、一般式
（Ｉ′）の化合物を加水分解して得ることもできるが、
上記一般式（Ｉ′）においてＲ5 がＣ1 〜Ｃ22のアルキ
ル基である化合物にトリエチルヨードシラン、トリメチ
ルブロモシラン等を反応させると効率よく得られる。The compound of the above formula (X) obtained by distilling off the solvent is usually purified without purification, using a suitable solvent such as a chlorinated solvent such as dichloromethane, pyridine, acetonitrile, tetrahydrofuran, dimethyl sulfoxide,
Among dimethylformamide, methylpyrrolidone and the like, the compound of the general formula (XI) and / or the compound of the general formula (XII) is added at a temperature of 10 to 100 ° C, preferably 20 to 30 ° C, in a temperature range of 0.1 to 100 ° C. The reaction is carried out for a time, preferably 5 to 12 hours. The obtained compound of the general formula (XIII) is a compound of the general formula (I) wherein R 2 and R 3 are each independently a hydrogen atom, a C 1 to C 22 alkyl group, an acylthioethyl group, or one or more halogen atoms. This corresponds to a compound that is an ethyl group substituted with an atom (however, R 2 and R 3 do not simultaneously represent a hydrogen atom). As described above, the compound of the general formula (I ″) as a raw material in the above reaction can be obtained by hydrolyzing the compound of the general formula (I ′).
The compound can be efficiently obtained by reacting a compound in which R 5 is an alkyl group of C 1 to C 22 in the general formula (I ′) with triethyliodosilane, trimethylbromosilane, or the like.
【００３５】一般式（Ｉ）においてＲ2 及びＲ3 が共に
アシルオキシメチル基である化合物、又は一方がアシル
オキシメチル基であり、他方が水素である化合物は、上
記一般式（Ｉ″）の化合物と下記一般式（XIV)：Ｒ9 Ｙ
（Ｒ9 はアシルオキシメチル基、Ｙは塩素原子、臭素原
子又はヨウ素原子を表す）で表されるアシルオキシメチ
ルハライドとを、塩基、例えば炭酸ナトリウム、炭酸カ
リウム、炭酸セシウム、水素化ナトリウム、水素化カリ
ウム、トリエチルアミン、ピリジン、ジアザビシクロウ
ンデセン、Ｎ，Ｎ′−ジクロヘキシル−４−モルホリン
カルボキサミジン等の存在下、アセトニトリル、テトラ
ヒドロフラン、ジメチルスルホキシド、ジメチルホルム
アミド、メチルピロリドン等の適当な溶媒中、０〜２０
０℃、好ましくは１０〜１００℃の温度で、１〜３００
時間、好ましくは１０〜２００時間反応させて得られ
る。Ｒ2 及びＲ3 の双方がアシルオキシメチル基である
化合物の場合には、一般式（Ｉ″）の化合物に対して一
般式（XIV)の化合物を２倍モル反応させればよく、一方
がアシルオキシメチル基である化合物の場合には等モル
反応させればよい。In the general formula (I), a compound in which R 2 and R 3 are both an acyloxymethyl group, or a compound in which one is an acyloxymethyl group and the other is hydrogen is the same as the compound of the above general formula (I ″) The following general formula (XIV): R 9 Y
(R 9 represents an acyloxymethyl group, Y represents a chlorine atom, a bromine atom or an iodine atom) and a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride , In the presence of triethylamine, pyridine, diazabicycloundecene, N, N'-diclohexyl-4-morpholinecarboxamidine, etc., in an appropriate solvent such as acetonitrile, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, methylpyrrolidone, etc. 20
At a temperature of 0 ° C, preferably 10-100 ° C,
It is obtained by reacting for a time, preferably 10 to 200 hours. In the case of a compound in which both R 2 and R 3 are an acyloxymethyl group, the compound of the general formula (I ″) may be reacted with the compound of the general formula (XIV) twice by mole, and one of them is an acyloxymethyl group. In the case of a compound having a methyl group, the reaction may be carried out in equimolar amounts.
【００３６】また、Ｒ2 及びＲ3 の一方がアシルオキシ
メチル基であり、他方がＣ1 〜Ｃ22のアルキル基、アシ
ルチオエチル基又は１以上のハロゲン原子で置換された
エチル基である化合物は、先ずＲ2 及びＲ3 の一方がＣ
1 〜Ｃ22のアルキル基、アシルチオエチル基、又は１以
上のハロゲン原子で置換されたエチル基であり、他方が
水素原子である化合物を調製し、次いでこの化合物に対
して上記方法により一般式（XIV)の化合物を反応させる
ことにより製造できる。A compound in which one of R 2 and R 3 is an acyloxymethyl group and the other is a C 1 -C 22 alkyl group, an acylthioethyl group or an ethyl group substituted with one or more halogen atoms. First, one of R 2 and R 3 is C
Alkyl group of 1 -C 22, acylthioethyl ethyl group, or a one or more ethyl group substituted with a halogen atom and the other to prepare a compound having a hydrogen atom, then the general formula by the method described above for this compound It can be produced by reacting the compound of (XIV).
【００３７】一般式（Ｉ）で表わされる化合物の塩は、
例えば、下記方法に従って合成することができる。一般
式（Ｉ’）の化合物を−１０〜１００℃、好ましくは１
０〜５０℃の温度で、０．１〜２０時間、好ましくは
０．３〜１時間、酢酸エチル、イソプロパノール、アセ
トニトリル、テトラヒドロフラン、ジメチルスルフォキ
シド、ジメチルフォルムアミド、メチルピロリドン等の
適当な溶媒中、対応する酸と撹拌下、反応させることに
よって合成することができる。The salt of the compound represented by the general formula (I) is
For example, it can be synthesized according to the following method. The compound of the general formula (I ′) is treated at -10 to 100 ° C., preferably 1
0.1 to 20 hours, preferably 0.3 to 1 hour at a temperature of 0 to 50 ° C. in a suitable solvent such as ethyl acetate, isopropanol, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, methylpyrrolidone and the like. By reacting with a corresponding acid under stirring.
【００３８】上記の製造方法は本発明の一般式（Ｉ）の
化合物を製造する方法の一例として示したものであり、
本発明の化合物の製造方法がこれらの方法に限定される
ことはない。本明細書の実施例には、さらに具体的に本
発明の化合物の製造方法が説明されているので、当業者
は、上記の一般的な説明及び実施例の具体的な説明に従
って、必要に応じてそれらに適宜の改変と修飾を加える
ことにより、上記一般式（Ｉ）に包含される化合物を製
造することができる。なお、上記方法により製造される
上記一般式（Ｉ）の化合物又はそれらの塩は、必要に応
じて通常のヌクレオチドの分離精製手段、例えば再結
晶、吸着、イオン交換、分配クロマトグラフィー等を適
宜選択して適用することにより分離・精製することがで
きる。The above production method is shown as an example of the method for producing the compound of the general formula (I) of the present invention,
The method for producing the compound of the present invention is not limited to these methods. In the examples of the present specification, the method of producing the compound of the present invention is more specifically described. Those skilled in the art will be able to use the above-described general description and the specific description of the examples as necessary. The compounds included in the above general formula (I) can be produced by appropriately modifying and modifying them. The compound of the general formula (I) or a salt thereof produced by the above method may be appropriately selected from ordinary nucleotide separation / purification means, for example, recrystallization, adsorption, ion exchange, partition chromatography, etc., as necessary. Separation / purification can be performed by applying it.
【００３９】本発明の化合物は医薬の有効成分として有
用であり、具体的には、後述の試験例に示す通り抗ウイ
ルス剤の有効成分として有用である。また、他のイオン
性ホスホナートヌクレオチド類似体に見られるように、
抗腫瘍活性を有することが期待される。本発明の医薬の
適用対象であるウイルスは特に制限されないが、具体的
には、ヒト免疫不全ウイルス、インフルエンザウイル
ス、Ｃ型肝炎ウイルス等のＲＮＡウイルスや単純ヘルペ
スウイルスＩ、単純ヘルペスウイルスII、サイトメガロ
ウイルス、水痘帯状疱疹ウイルス、Ｂ型肝炎ウイルス等
のＤＮＡウイルスが挙げられ、より好ましくはＢ型肝炎
ウイルスが挙げられる。The compound of the present invention is useful as an active ingredient of a medicament, and specifically, as an active ingredient of an antiviral agent as shown in Test Examples described later. Also, as found in other ionic phosphonate nucleotide analogs,
It is expected to have antitumor activity. The virus to which the medicament of the present invention is applied is not particularly limited, and specifically, RNA viruses such as human immunodeficiency virus, influenza virus, hepatitis C virus, herpes simplex virus I, herpes simplex virus II, cytomegalovirus, and the like. Virus, DNA virus such as varicella-zoster virus and hepatitis B virus, and more preferably hepatitis B virus.
【００４０】本発明の化合物を医薬として用いる場合、
それ自体を単独で投与してもよいが、薬学的に許容され
得る製剤用添加物を用いて上記化合物を有効成分として
含む医薬組成物を製造して投与するのが好適である。医
薬組成物の組成は、化合物の溶解度、化学的特質、投与
経路、投与計画等によって決定される。例えば、顆粒
剤、細粒剤、散剤、錠剤、硬シロップ剤、軟カプセル
剤、トローチ剤、シロップ剤、乳剤、軟ゼラチンカプセ
ル剤、ゲル剤、ペースト剤、懸濁剤、リポソーム等の剤
形にして経口的に投与するか、又は注射剤として静脈内
投与、筋肉内投与、皮下投与することができる。また、
注射用の粉末にして用時調製して使用することもでき
る。When the compound of the present invention is used as a medicine,
Although it may be administered alone, it is preferable to produce and administer a pharmaceutical composition containing the compound as an active ingredient using a pharmaceutically acceptable pharmaceutical additive. The composition of a pharmaceutical composition will be determined by the solubility of the compound, the chemical nature, the route of administration, the dosage regimen, and the like. For example, granules, fine granules, powders, tablets, hard syrups, soft capsules, troches, syrups, emulsions, soft gelatin capsules, gels, pastes, suspensions, liposomes, etc. Or intravenously, intramuscularly or subcutaneously as an injection. Also,
It can also be used as a powder for injection, prepared at the time of use.
【００４１】薬学的に許容され得る製剤用添加物として
は、経口、経腸、非経口もしくは局所投与に適した有機
又は無機の固体又は液体の担体を用いることができる。
固形製剤を製造する際に用いられる固体担体としては、
例えば乳糖、ショ糖、デンプン、タルク、セルロース、
デキストリン、カオリン、炭酸カルシウム、寒天、ペク
チン、ステアリン酸、ステアリン酸マグネシウム、レシ
チン、塩化ナトリウム等が挙げられる。また経口投与の
ための液体製剤を製造する際に用いられる液体担体とし
ては、例えばグリセリン、落花生油、ポリビニルピロリ
ドン、オリーブ油、エタノール、ベンジルアルコール、
プロピレングリコール、生理食塩水、水等が挙げられ
る。上記の医薬組成物は、上記担体以外に、補助剤、例
えば湿潤剤、懸濁補助剤、甘味剤、芳香剤、着色剤、及
び保存剤等を含むこともできる。また液体製剤は、ゼラ
チンのような吸収され得る物質のカプセル中に含ませて
使用してもよい。非経口剤投与の製剤、即ち注射剤等の
製造に用いられる溶剤又は懸濁化剤としては、例えば
水、プロピレングリコール、ポリエチレングリコール、
ベンジルアルコール、オレイン酸エチル、レシチン等が
挙げられる。As a pharmaceutically acceptable additive for pharmaceutical preparation, an organic or inorganic solid or liquid carrier suitable for oral, enteral, parenteral or topical administration can be used.
As a solid carrier used when producing a solid preparation,
For example, lactose, sucrose, starch, talc, cellulose,
Dextrin, kaolin, calcium carbonate, agar, pectin, stearic acid, magnesium stearate, lecithin, sodium chloride and the like. Further, as a liquid carrier used in producing a liquid preparation for oral administration, for example, glycerin, peanut oil, polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol,
Examples include propylene glycol, physiological saline, and water. In addition to the above carriers, the pharmaceutical composition can also contain adjuvants such as wetting agents, suspending aids, sweetening agents, flavoring agents, coloring agents, preservatives, and the like. Liquid preparations may also be used in capsules of absorbable substances such as gelatin. Preparations for parenteral administration, that is, as a solvent or a suspending agent used in the production of injections and the like, for example, water, propylene glycol, polyethylene glycol,
Benzyl alcohol, ethyl oleate, lecithin and the like.
【００４２】本発明の化合物、特に前記一般式（Ｉ′）
で表されるエステル誘導体は、後述の試験例に示す通り
高い経口吸収性を有することから、経口投与は本発明の
医薬の好ましい投与経路である。なお、上記各製剤の調
製は、常法に従って行うことができる。本発明の医薬の
臨床投与量は、経口投与により用いる場合には、本発明
化合物重量として、一般には成人１日あたり０．１〜５
００ｍｇ／ｋｇ、好ましくは１〜５０ｍｇ／ｋｇであ
る。もっとも、上記投与量は、年齢、病状、症状、同時
投与の有無等により適宜増減してもよい。前記１日投与
量を１日に１回、または適当な間隔をおいて１日に２〜
数回に分けて投与しても良いし、数日毎に間欠投与して
も良い。注射剤として用いる場合には、本発明化合物重
量として、成人１日あたり０．０１〜５０ｍｇ／ｋｇで
あり、好ましくは０．１〜５ｍｇ／ｋｇである。The compounds of the present invention, in particular, those of the aforementioned general formula (I ')
Oral administration is a preferred route for administering the medicament of the present invention since the ester derivative represented by has high oral absorbability as shown in the test examples described below. The preparation of each of the above preparations can be carried out according to a conventional method. The clinical dose of the medicament of the present invention, when used by oral administration, is generally 0.1 to 5 per adult per day as the weight of the compound of the present invention.
00 mg / kg, preferably 1 to 50 mg / kg. However, the above dosage may be appropriately increased or decreased depending on the age, medical condition, symptom, presence or absence of simultaneous administration, and the like. The daily dose may be taken once a day or at appropriate intervals for 2 to 3 days a day.
It may be administered in several divided doses, or may be administered intermittently every few days. When used as an injection, the compound of the present invention is used in an amount of 0.01 to 50 mg / kg, preferably 0.1 to 5 mg / kg, per day for an adult.
【００４３】[0043]
【実施例】以下、本発明を実施例によりさらに具体的に
説明するが、本発明は以下の実施例に限定されるもので
はない。なお、実施例中の化合物番号は、表１における
化合物番号に対応させてある。EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to the following examples. The compound numbers in the examples correspond to the compound numbers in Table 1.
【００４４】実施例１：２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］エチル］−６−フェニルチオプリン（化合物Ｎｏ．
１）の製造 ２−クロロエチルクロロメチルエーテル８７ｇ（６７０
ｍｍｏｌ）とトリス（２，２，２−トリフルオロエチ
ル）ホスファイト２００ｇ（６１０ｍｍｏｌ）とを、１
６０℃で７時間反応させ、２−［ビス（２，２，２−ト
リフルオロエチル）ホスホニルメトキシ］エチルクロリ
ドを定量的に得た。２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチルクロリド２０
６ｇをメチルエチルケトン２０００ｍｌに溶解し、ヨウ
化ナトリウム２７０ｇと８時間還流した。反応後室温ま
で冷却し、濃縮乾固した。残渣をクロロホルム／ヘキサ
ンに溶解させてシリカゲルカラムに吸着させ、クロロホ
ルム／ヘキサンにて溶出させ、２−［ビス（２，２，２
−トリフルオロエチル）ホスホニルメトキシ］エチルヨ
ージドを定量的に得た。Example 1 2-Amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-phenylthiopurine (Compound No.
Preparation of 1) 87 g of 2-chloroethylchloromethyl ether (670 g)
mmol) and 200 g (610 mmol) of tris (2,2,2-trifluoroethyl) phosphite.
The reaction was performed at 60 ° C. for 7 hours to quantitatively obtain 2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl chloride. 2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl chloride 20
6 g was dissolved in 2000 ml of methyl ethyl ketone and refluxed with 270 g of sodium iodide for 8 hours. After the reaction, the mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in chloroform / hexane, adsorbed on a silica gel column, eluted with chloroform / hexane, and purified with 2- [bis (2,2,2
-Trifluoroethyl) phosphonylmethoxy] ethyl iodide was obtained quantitatively.
【００４５】２−アミノ−６−クロロプリン１５．０ｇ
（８８ｍｍｏｌ）をジメチルホルムアミド３６０ｍｌに
懸濁し、１，８−ジアザビシクロ［５．４．０］ウンデ
ス−７−エン１３．９ｍｌ（９３ｍｍｏｌ）と８０℃で
１時間反応させた。次に２−［ビス（２，２，２−トリ
フルオロエチル）ホスホニルメトキシ］エチルヨージド
２３．８ｍｌを上記反応液に加え、１００℃で５時間反
応させた。反応後室温まで冷却し、濃縮乾固した。残渣
をクロロホルムに溶解させてシリカゲルカラムに吸着さ
せ、５％−メタノール−クロロホルムで溶出させ、２−
アミノ−９−［２−［ビス（２，２，２−トリフルオロ
エチル）ホスホニルメトキシ］エチル］−６−クロロプ
リン２３．３ｇ（収率５６％）を得た。15.0 g of 2-amino-6-chloropurine
(88 mmol) was suspended in 360 ml of dimethylformamide, and reacted with 13.9 ml (93 mmol) of 1,8-diazabicyclo [5.4.0] undes-7-ene at 80 ° C. for 1 hour. Next, 23.8 ml of 2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl iodide was added to the above reaction solution and reacted at 100 ° C. for 5 hours. After the reaction, the mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in chloroform, adsorbed on a silica gel column, and eluted with 5% methanol-chloroform.
23.3 g (56% yield) of amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-chloropurine was obtained.
【００４６】２−アミノ−９−［２−［ビス（２，２，
２−トリフルオロエチル）ホスホニルメトキシ］エチ
ル］−６−クロロプリン７．１ｇのジメチルフォルムア
ミド６８ｍｌ溶液に、トリエチルアミン２．１ｍｌとチ
オフェノール３．１ｍｌを添加し、１００℃で２時間撹
拌した。反応混合物を室温まで冷却し、濃縮乾固した。
残渣をクロロホルムに溶解させてシリカゲルカラムに吸
着させ、５％−メタノール−クロロホルムで溶出させ、
２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−フェ
ニルチオプリン５．０ｇ（収率６１％）を得た。 ｍ．ｐ．：１０５−１０６℃（エタノール）1 Ｈ−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，１
Ｈ）2-amino-9- [2- [bis (2,2,
To a solution of 7.1 g of 2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-chloropurine in 68 ml of dimethylformamide, 2.1 ml of triethylamine and 3.1 ml of thiophenol were added, followed by stirring at 100 ° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated to dryness.
The residue was dissolved in chloroform, adsorbed on a silica gel column, and eluted with 5% methanol-chloroform.
5.0 g (61% yield) of 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-phenylthiopurine was obtained. m. p. : 105-106 ° C (ethanol) 1 H-NMR (CDCl 3 , 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, 1
H)
【００４７】実施例２：２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］エチル］−６−ｐ−ニトロフェニルチオプリン（化
合物Ｎｏ．１６）の製造 実施例１において、チオフェノールに代えてｐ−ニトロ
チオフェノールを用いる他は実施例１と同様にして、表
題化合物を得た。 ｍ．ｐ．：１１４−１１６℃（ジイソプロピルエーテ
ル）1 Ｈ−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）Example 2: 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-nitrophenylthiopurine (Compound No. 16) The title compound was obtained in the same manner as in Example 1 except that p-nitrothiophenol was used instead of thiophenol. m. p. : 114-116 ° C (diisopropyl ether) 1 H-NMR (CDCl 3 , δ): 3.87-4.02
(M, 4H), 4.22-4.46 (m, 6H);
83 (s, 2H), 7.75-7.85 (m, 2H),
8.20-8.28 (m, 2H)
【００４８】実施例３：２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］エチル］−６−ｐ−メトキシフェニルチオプリン
（化合物Ｎｏ．４）の製造 実施例１において、チオフェノールに代えてｐ−メトキ
シチオフェノールを用いる他は実施例１と同様にして、
表題化合物を得た。 ｍ．ｐ．：９３−９５℃（ジイソプロピルエーテル）1 Ｈ−ＮＭＲ（ＣＤＣｌ3 ，δ）：３．８５（ｓ，３
Ｈ）、３．９２−４．００（ｍ，４Ｈ）、４．２４−
４．４５（ｍ，６Ｈ）、４．７５（ｓ，２Ｈ）、６．９
５（ｄ，Ｊ＝９．０Ｈｚ，２Ｈ）、７．５３（ｄ，Ｊ＝
９．０Ｈｚ，２Ｈ）、７．７１（ｓ，１Ｈ）Example 3 2-Amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-methoxyphenylthiopurine (Compound No. 4) In the same manner as in Example 1 except that p-methoxythiophenol was used instead of thiophenol in Example 1,
The title compound was obtained. m. p. : 93-95 ° C (diisopropyl ether) 1 H-NMR (CDCl 3 , δ): 3.85 (s, 3)
H), 3.92-4.00 (m, 4H), 4.24-
4.45 (m, 6H), 4.75 (s, 2H), 6.9
5 (d, J = 9.0 Hz, 2H), 7.53 (d, J =
9.0Hz, 2H), 7.71 (s, 1H)
【００４９】実施例４：２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］エチル］−６−ｍ−メトキシフェニルチオプリン
（化合物Ｎｏ．３）の製造 実施例１において、チオフェノールに代えてｍ−メトキ
シチオフェノールを用いる他は実施例１と同様にして、
表題化合物を得た。 ＵＶ：λmax ＝２９１， ３２８（０．０１Ｎ−ＨＣｌ／ＣＨ3 ＯＨ） λmax ＝２４２， ３１５（０．０１Ｎ−ＮａＯＨ／ＣＨ3 ＯＨ）1 Ｈ−ＮＭＲ（ＣＤＣｌ3 ，δ）：３．８２（ｓ，３
Ｈ）、３．８８−３．９７（ｍ，４Ｈ）、４．２４−
４．４５（ｍ，６Ｈ）、４．８１（ｓ，２Ｈ）、６．９
２−７．００（ｍ，１Ｈ）、７．１８−７．４０（ｍ，
４Ｈ）、７．７２（ｓ，１Ｈ）Example 4: 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-methoxyphenylthiopurine (Compound No. 3) In Example 1, except that m-methoxythiophenol was used instead of thiophenol,
The title compound was obtained. UV: λ max = 291, 328 (0.01 N HCl / CH 3 OH) λ max = 242, 315 (0.01 N NaOH / CH 3 OH) 1 H-NMR (CDCl 3 , δ): 3.82 (S, 3
H), 3.88-3.97 (m, 4H), 4.24-
4.45 (m, 6H), 4.81 (s, 2H), 6.9
2-7.00 (m, 1H), 7.18-7.40 (m, 1H)
4H), 7.72 (s, 1H)
【００５０】実施例５：２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］エチル］−６−ｏ−メトキシフェニルチオプリン
（化合物Ｎｏ．２）の製造 実施例１において、チオフェノールに代えてｏ−メトキ
シチオフェノールを用いる他は実施例１と同様にして、
表題化合物を得た。 ＵＶ：λmax ＝３３２ （０．０１Ｎ−ＨＣｌ／ＣＨ3 ＯＨ） λmax ＝３１４ （０．０１Ｎ−ＮａＯＨ／ＣＨ3 ＯＨ）1 Ｈ−ＮＭＲ（ＣＤＣｌ3 ，δ）：３．８０（ｓ，３
Ｈ）、３．８５−３．９８（ｍ，４Ｈ）、４．２０−
４．４６（ｍ，６Ｈ）、４．７８（ｓ，２Ｈ）、６．９
６−７．０４（ｍ，２Ｈ）、７．４３（ｄｄｄ，Ｊ＝
７．７， ７．７ ａｎｄ １．５Ｈｚ，１Ｈ）、７．
５９（ｄｄ，Ｊ＝７．６ ａｎｄ １．５Ｈｚ，１
Ｈ）、７．６９（ｓ，１Ｈ）Example 5 2-Amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-o-methoxyphenylthiopurine (Compound No. 2) In the same manner as in Example 1 except that o-methoxythiophenol was used instead of thiophenol in Example 1,
The title compound was obtained. UV: λ max = 332 (0.01 N HCl / CH 3 OH) λ max = 314 (0.01 N NaOH / CH 3 OH) 1 H-NMR (CDCl 3 , δ): 3.80 (s, 3)
H) 3.85-3.98 (m, 4H), 4.20-
4.46 (m, 6H), 4.78 (s, 2H), 6.9
6-7.04 (m, 2H), 7.43 (ddd, J =
7.7, 7.7 and 1.5 Hz, 1H), 7.
59 (dd, J = 7.6 and 1.5 Hz, 1
H), 7.69 (s, 1H)
【００５１】実施例６：２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］エチル］−６−ｐ−アミノフェニルチオプリン（化
合物Ｎｏ．１３）の製造 実施例１において、チオフェノールに代えてｐ−アミノ
チオフェノールを用いる他は実施例１と同様にして、表
題化合物を得た。 ｍ．ｐ．：１３０−１３２℃（ジイソプロピルエーテ
ル）1 Ｈ−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，２
Ｈ）、７．３８（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ）、７．７
０（ｓ，１Ｈ）Example 6: 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-aminophenylthiopurine (Compound No. 13) The title compound was obtained in the same manner as in Example 1 except that p-aminothiophenol was used instead of thiophenol. m. p. : 130-132 ° C (diisopropyl ether) 1 H-NMR (CDCl 3 , δ): 3.86-4.00
(M, 4H), 4.21-4.48 (m, 6H), 4.
80 (s, 2H), 6.71 (d, J = 8.5 Hz, 2
H), 7.38 (d, J = 8.5 Hz, 2H), 7.7
0 (s, 1H)
【００５２】実施例７：２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］エチル］−６−ｐ−クロロフェニルチオプリン（化
合物Ｎｏ．７）の製造 実施例１において、チオフェノールに代えてｐ−クロロ
チオフェノールを用いる他は実施例１と同様にして、表
題化合物を得た。 ｍ．ｐ．：１０８−１１０℃（ジイソプロピルエーテル
／ヘキサン）1 Ｈ−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，２
Ｈ）、７．５６（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ）、７．７
６（ｓ，１Ｈ）Example 7: Preparation of 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-chlorophenylthiopurine (Compound No. 7) Production The title compound was obtained in the same manner as in Example 1 except that p-chlorothiophenol was used instead of thiophenol. m. p. : 108-110 ° C (diisopropyl ether / hexane) 1 H-NMR (CDCl 3 , δ): 3.87-4.00
(M, 4H), 4.22-4.47 (m, 6H);
77 (s, 2H), 7.39 (d, J = 8.5 Hz, 2
H), 7.56 (d, J = 8.5 Hz, 2H), 7.7
6 (s, 1H)
【００５３】実施例８：２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］エチル］−６−ｐ−エトキシフェニルチオプリン
（化合物Ｎｏ．１９）の製造 ｐ−ヒドロキシベンゼンチオール２５ｇをＤＭＳＯ１５
５ｍｌに溶解し、４時間撹拌後、氷水１Ｌに注ぎ、析出
する結晶を減圧乾燥し、ビス（ｐ−ヒドロキシフェニ
ル）ジスルフィドを定量的に得た。ビス（ｐ−ヒドロキ
シフェニル）ジスルフィド２．０ｇのＤＭＦ２０ｍｌ溶
液に炭酸カリウム２．２ｇ、エチルヨージド４．３ｇを
添加し、７０°にて１６時間撹拌後、氷水１００ｍｌに
注ぎ、ヘキサン５００ｍｌで抽出後、濃縮し、ビス（ｐ
−エトキシフェニル）ジスルフィド１．８ｇ（８２％）
を得た。Example 8 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-ethoxyphenylthiopurine (Compound No. 19) Preparation of 25 g of p-hydroxybenzenethiol in DMSO 15
The crystals were dissolved in 5 ml, stirred for 4 hours, poured into 1 L of ice water, and the precipitated crystals were dried under reduced pressure to quantitatively obtain bis (p-hydroxyphenyl) disulfide. 2.2 g of potassium carbonate and 4.3 g of ethyl iodide were added to a solution of 2.0 g of bis (p-hydroxyphenyl) disulfide in 20 ml of DMF, stirred at 70 ° for 16 hours, poured into 100 ml of ice water, extracted with 500 ml of hexane, and concentrated. And screw (p
1.8 g (82%) of -ethoxyphenyl) disulfide
I got
【００５４】ビス（ｐ−エトキシフェニル）ジスルフィ
ド１．８ｇの１，４−ジオキサン２０ｍｌ／水５ｍｌ溶
液にトリフェニルホスフィン１．９ｇ、濃塩酸３滴を加
え、４０°で１０時間撹拌後、クロロホルム２５０ｍｌ
に注ぎ、水で２回洗浄後、濃縮し、ｐ−エトキシベンゼ
ンチオールを定量的に得た。ｐ−エトキシベンゼンチオ
ールを実施例１においてチオフェノールに代えて用いる
他は同様にして表題化合物を得た。 ｍ．ｐ．：６１−６４℃（クロロホルム）1 Ｈ−ＮＭＲ（ＣＤＣｌ3 ，δ）：１．４５（ｔ，Ｊ
＝７．０Ｈｚ，３Ｈ）、３．８４−３．９８（ｍ，４
Ｈ）、４．０８（ｑ，Ｊ＝７．０Ｈｚ，２Ｈ）、４．１
８−４．４８（ｍ，６Ｈ）、４．７６（ｓ，２Ｈ）、
６．９４（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ）、７．５２
（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ）、７．７１（ｓ，１Ｈ）1.9 g of triphenylphosphine and 3 drops of concentrated hydrochloric acid were added to a solution of 1.8 g of bis (p-ethoxyphenyl) disulfide in 20 ml of 1,4-dioxane / 5 ml of water, and the mixture was stirred at 40 ° C. for 10 hours and then 250 ml of chloroform.
, Washed twice with water, and concentrated to obtain p-ethoxybenzenethiol quantitatively. The title compound was obtained in the same manner as in Example 1, except that p-ethoxybenzenethiol was used in place of thiophenol in Example 1. m. p. : 61-64 ° C (chloroform) 1 H-NMR (CDCl 3 , δ): 1.45 (t, J
= 7.0 Hz, 3H), 3.84-3.98 (m, 4
H), 4.08 (q, J = 7.0 Hz, 2H), 4.1
8-4.48 (m, 6H), 4.76 (s, 2H),
6.94 (d, J = 8.4 Hz, 2H), 7.52
(D, J = 8.4 Hz, 2H), 7.71 (s, 1H)
【００５５】実施例９：２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］エチル］−６−ｐ−ブトキシフェニルチオプリン
（化合物Ｎｏ．２９）の製造 実施例２においてエチルヨージドに代えてブチルヨージ
ドを用いる他は同様にして表題化合物を得た。 ｍ．ｐ．：８９−９２℃（クロロホルム）1 Ｈ−ＮＭＲ（ＣＤＣｌ3 ，δ）：０．９９（ｔ，Ｊ＝
７．５Ｈｚ，３Ｈ）、１．５１（ｔｑ，Ｊ＝８．１Ｈｚ
ａｎｄ ７．５Ｈｚ，２Ｈ）、１．７９（ｔｔ，Ｊ＝
６．４Ｈｚ ａｎｄ ８．１Ｈｚ，２Ｈ）、３．８４−
３．９８（ｍ，４Ｈ）、４．００（ｔ，Ｊ＝６．４Ｈ
ｚ，２Ｈ）、４．２０−４．４８（ｍ，６Ｈ）、４．７
６（ｓ，２Ｈ）、６．９４（ｄ，Ｊ＝８．８Ｈｚ，２
Ｈ）、７．５２（ｄ，Ｊ＝８．８Ｈｚ，２Ｈ）、７．７
１（ｓ，１Ｈ）Example 9 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-butoxyphenylthiopurine (Compound No. 29) The title compound was obtained in the same manner as in Example 2, except that butyl iodide was used instead of ethyl iodide. m. p. : 89-92 ° C (chloroform) 1 H-NMR (CDCl 3 , δ): 0.99 (t, J =
7.5 Hz, 3H), 1.51 (tq, J = 8.1 Hz)
and 7.5 Hz, 2H), 1.79 (tt, J =
6.4 Hz and 8.1 Hz, 2H), 3.84-
3.98 (m, 4H), 4.00 (t, J = 6.4H)
z, 2H), 4.20-4.48 (m, 6H), 4.7
6 (s, 2H), 6.94 (d, J = 8.8 Hz, 2
H), 7.52 (d, J = 8.8 Hz, 2H), 7.7
1 (s, 1H)
【００５６】実施例１０：２−アミノ−９−［２−［ビ
ス（２，２，２−トリフルオロエチル）ホスホニルメト
キシ］エチル］−６−ｐ−プロポキシフェニルチオプリ
ン（化合物Ｎｏ．２３）の製造 実施例８において エチルヨージドに代えてプロピルヨ
ージドを用いる他は同にして表題化合物を得た。 ＵＶ：λmax ＝２２９， ３３１（０．０１Ｎ−ＨＣｌ／ＣＨ3 ＯＨ） λmax ＝２２３， ３１４（０．０１Ｎ−ＮａＯＨ／ＣＨ3 ＯＨ）1 Ｈ−ＮＭＲ（ＣＤＣｌ3 ，δ）：１．０５（ｔ，Ｊ＝
７．４Ｈｚ，３Ｈ）、１．８４（ｔｑ，Ｊ＝６．８Ｈｚ
ａｎｄ ７．４Ｈｚ，２Ｈ）、３．８２−４．００
（ｍ，６Ｈ）、４．２０−４．４８（ｍ，６Ｈ）、４．
７８（ｓ，２Ｈ）、６．９５（ｄ，Ｊ＝８．７Ｈｚ，２
Ｈ）、７．５１（ｄ，Ｊ＝８．７Ｈｚ，２Ｈ）、７．７
１（ｓ，１Ｈ）Example 10: 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-propoxyphenylthiopurine (Compound No. 23) The title compound was obtained in the same manner as in Example 8, except that propyl iodide was used instead of ethyl iodide. UV: λ max = 229, 331 (0.01 N HCl / CH 3 OH) λ max = 223, 314 (0.01 N NaOH / CH 3 OH) 1 H-NMR (CDCl 3 , δ): 1.05 (T, J =
7.4 Hz, 3H), 1.84 (tq, J = 6.8 Hz)
and 7.4Hz, 2H), 3.82-4.00
(M, 6H), 4.20-4.48 (m, 6H), 4.
78 (s, 2H), 6.95 (d, J = 8.7 Hz, 2
H), 7.51 (d, J = 8.7 Hz, 2H), 7.7
1 (s, 1H)
【００５７】実施例１１：２−アミノ−９−［２−［ビ
ス（２，２，２−トリフルオロエチル）ホスホニルメト
キシ］エチル］−６−ｐ−イソプロポキシフェニルチオ
プリン（化合物Ｎｏ．２６）の製造 実施例８においてエチルヨージドに代えてｐ−イソプロ
ピルヨージドを用いる他は同様にして表題化合物を得
た。 ＵＶ：λmax ＝２３０， ３３０（０．０１Ｎ−ＨＣｌ／ＣＨ3 ＯＨ） λmax ＝２２３， ３１４（０．０１Ｎ−ＮａＯＨ／ＣＨ3 ＯＨ）1 Ｈ−ＮＭＲ（ＣＤＣｌ3 ，δ）：１．３７（ｄ，Ｊ＝
６．０Ｈｚ，６Ｈ）、３．８５−３．９８（ｍ，４
Ｈ）、４．１８−４．４８（ｍ，６Ｈ）、４．６０（ｓ
ｅｐｔｅｔ，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，１
Ｈ）Example 11 2-Amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-isopropoxyphenylthiopurine (Compound No. 26) The title compound was obtained in the same manner as in Example 8 except that p-isopropyl iodide was used instead of ethyl iodide. UV: λ max = 230, 330 (0.01 N-HCl / CH 3 OH) λ max = 223, 314 (0.01 N-NaOH / CH 3 OH) 1 H-NMR (CDCl 3 , δ): 1.37 (D, J =
6.0 Hz, 6H), 3.85-3.98 (m, 4
H), 4.18-4.48 (m, 6H), 4.60 (s
eptet, J = 6.0 Hz, 1H), 4.77 (s,
2H), 6.93 (d, J = 8.7 Hz, 2H), 7.
51 (d, J = 8.7 Hz, 2H), 7.71 (s, 1
H)
【００５８】実施例１２：２−アミノ−９−［２−［ビ
ス（２，２，２−トリフルオロエチル）ホスホニルメト
キシ］エチル］−６−ｐ−イソブトキシフェニルチオプ
リン（化合物Ｎｏ．３２ ）の製造 実施例８においてエチルヨージドに代えてｐ−イソブチ
ルヨージドを用いる他は同様にして表題化合物を得た。 ＵＶ：λmax ＝２３０， ３３１（０．０１Ｎ−ＨＣｌ／ＣＨ3 ＯＨ） λmax ＝２２３， ３１４（０．０１Ｎ−ＮａＯＨ／ＣＨ3 ＯＨ）1 Ｈ−ＮＭＲ（ＣＤＣｌ3 ，δ）：１．０５（ｄ，Ｊ＝
６．８Ｈｚ，６Ｈ）、２．１３（ａｐｐａｒｅｎｔ ｑ
ｕｉｎｔｅｔ，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，２
Ｈ）、７．５２（ｄ，Ｊ＝８．９Ｈｚ，２Ｈ）、７．７
１（ｓ，１Ｈ）Example 12: 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-isobutoxyphenylthiopurine (Compound No. 32) The title compound was obtained in the same manner as in Example 8 except that p-isobutyl iodide was used instead of ethyl iodide. UV: λ max = 230, 331 (0.01 N HCl / CH 3 OH) λ max = 223, 314 (0.01 N NaOH / CH 3 OH) 1 H-NMR (CDCl 3 , δ): 1.05 (D, J =
6.8 Hz, 6H), 2.13 (appr. Q
uintet, J = 6.5 Hz, 1H), 3.76
(D, J = 6.5 Hz, 2H), 3.83-3.97
(M, 4H), 4.20-4.45 (m, 6H), 4.
77 (s, 2H), 6.94 (d, J = 8.9 Hz, 2
H), 7.52 (d, J = 8.9 Hz, 2H), 7.7
1 (s, 1H)
【００５９】実施例１３：２−アミノ−９−［２−［ビ
ス（２，２，２−トリフルオロエチル）ホスホニルメト
キシ］エチル］−６−ｐ−トリフルオロメトキシフェニ
ルチオプリン（化合物Ｎｏ．３５）の製造 ｐ−トリフルオロメトキシベンゼンスルホニルクロリド
１．３６ｍｌ、濃硫酸３．４ｍｌ、水２０ｍｌサスペン
ジョンに亜鉛粉末３．１ｇ添加し０°で１８時間撹拌、
６時間還流後、酢酸エチルを加え、水、飽和重曹水、飽
和食塩水で洗浄後、減圧濃縮しｐ−トリフルオロメトキ
シベンゼンチオール０．７３ｇ（４７％）を得た。実施
例１においてｐ−トリフルオロメトキシベンゼンチオー
ルをチオフェノールに代えて用いる他は同様にして表題
化合物を得た。 ｍ．ｐ．：１２８−１３０℃（クロロホルム）1 Ｈ−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，２
Ｈ）、７．６６（ｄ，Ｊ＝８．７Ｈｚ，２Ｈ）、７．７
３（ｓ，１Ｈ）Example 13: 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-trifluoromethoxyphenylthiopurine (Compound No. 35) Production 1.36 ml of p-trifluoromethoxybenzenesulfonyl chloride, 3.4 ml of concentrated sulfuric acid, 20 ml of water 3.1 g of zinc powder was added to a suspension, and the mixture was stirred at 0 ° for 18 hours.
After refluxing for 6 hours, ethyl acetate was added, and the mixture was washed with water, saturated aqueous sodium hydrogen carbonate and saturated saline, and concentrated under reduced pressure to obtain 0.73 g (47%) of p-trifluoromethoxybenzenethiol. The title compound was obtained in the same manner as in Example 1, except that p-trifluoromethoxybenzenethiol was used instead of thiophenol. m. p. : 128-130 ° C (chloroform) 1 H-NMR (CDCl 3 , δ): 3.86-3.98
(M, 4H), 4.22-4.48 (m, 6H);
78 (s, 2H), 7.27 (d, J = 8.7 Hz, 2
H), 7.66 (d, J = 8.7 Hz, 2H), 7.7
3 (s, 1H)
【００６０】実施例１４：２−アミノ−９−［２−
［（２，２，２−トリフルオロエチル）ホスホニルメト
キシ］エチル］−６−フェニルチオプリン（化合物Ｎ
ｏ．２１１）の製造 ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−フェ
ニルチオプリン４５ｍｇのテトラヒドロフラン溶液０．
３ｍｌに１Ｎ水酸化ナトリウム水溶液８２μｌを加え、
３０分撹拌後、凍結乾燥して２−アミノ−９−［２−
［（２，２，２−トリフルオロエチル）ホスホニルメト
キシ］エチル］−６−フェニルチオプリン３７ｍｇ（９
３％）を得た。 ＵＶ：λmax ＝３２５ （０．０１Ｎ−ＨＣｌ／ＣＨ3 ＯＨ） λmax ＝２４４， ３１６（０．０１Ｎ−ＮａＯＨ／ＣＨ3 ＯＨ）1 Ｈ−ＮＭ Ｒ（Ｄ2 Ｏ ，δ）：３．６３（ｄ，Ｊ＝
８．８Ｈｚ，２Ｈ）、３．８１−４．０４（ｍ，４
Ｈ）、４．２３−４．３４（ｍ，２Ｈ）、７．４０−
７．６６（ｍ，５Ｈ）、８．０１（ｓ，１Ｈ）Example 14: 2-amino-9- [2-
[(2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-phenylthiopurine (Compound N
o. Preparation of 2111) A solution of 45 mg of 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-phenylthiopurine in tetrahydrofuran.
82 μl of 1N aqueous sodium hydroxide solution was added to 3 ml,
After stirring for 30 minutes, the mixture was freeze-dried to give 2-amino-9- [2-
[(2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-phenylthiopurine 37 mg (9
3%). UV: λ max = 325 (0.01 N HCl / CH 3 OH) λ max = 244, 316 (0.01 N NaOH / CH 3 OH) 1 H-NM R (D 2 O, δ): 3.63 (D, J =
8.8 Hz, 2H), 3.81-4.04 (m, 4
H), 4.23-4.34 (m, 2H), 7.40-
7.66 (m, 5H), 8.01 (s, 1H)
【００６１】実施例１５：２−アミノ−９−［２−
［（２，２，２−トリフルオロエチル）ホスホニルメト
キシ］エチル］−６−ｐ−メトキシフェニルチオプリン
（化合物Ｎｏ．２１４）の製造 実施例１４において２−アミノ−９−［２−［ビス
（２，２，２−トリフルオロエチル）ホスホニルメトキ
シ］エチル］−６−フェニルチオプリンに代えて２−ア
ミノ−９−［２−［ビス（２，２，２−トリフルオロエ
チル）ホスホニルメトキシ］エチル］−６−ｐ−メトキ
シフェニルチオプリンを用いる他は同様にして表題化合
物を得た。 ＵＶ：λmax ＝２３０， ３２８（０．０１Ｎ−ＨＣｌ／ＣＨ3 ＯＨ） λmax ＝２２３， ３１４（０．０１Ｎ−ＮａＯＨ／ＣＨ3 ＯＨ）1 Ｈ−ＮＭＲ（Ｄ2 Ｏ ，δ）：３．６９（ｄ，Ｊ＝
８．８Ｈｚ，２Ｈ）、３．８２−４．０６（ｍ ｉｎｖ
ｏｌｖｉｎｇ ｓ ａｔ ３．８７，７Ｈ）、４．２８
−４．３８（ｍ，２Ｈ）、７．０５（ｄ，Ｊ＝８．７Ｈ
ｚ，２Ｈ）、７．５１（ｄ，Ｊ＝８．７Ｈｚ，２Ｈ）、
８．０４（ｓ，１Ｈ）Example 15: 2-amino-9- [2-
Preparation of [(2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-methoxyphenylthiopurine (Compound No. 214) In Example 14, 2-amino-9- [2- [bis Instead of (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-phenylthiopurine, 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonyl] Methoxy] ethyl] -6-p-methoxyphenylthiopurine was used in a similar manner except that the title compound was obtained. UV: λ max = 230, 328 (0.01 N HCl / CH 3 OH) λ max = 223, 314 (0.01 N NaOH / CH 3 OH) 1 H-NMR (D 2 O, δ): 3. 69 (d, J =
8.8 Hz, 2H), 3.82-4.06 (minv
olving sat 3.87, 7H), 4.28
-4.38 (m, 2H), 7.05 (d, J = 8.7H)
z, 2H), 7.51 (d, J = 8.7 Hz, 2H),
8.04 (s, 1H)
【００６２】実施例１６：２−アミノ−９−［２−［ホ
スホニルメトキシ］エチル］−６−フェニルチオプリン
（化合物Ｎｏ．２８１）の製造 実施例１においてトリス（２，２，２−トリフルオロエ
チル）ホスファイトに代えてトリエチルホスファイトを
用いる他は同様にして２−アミノ−９−［２−［ジエチ
ルホスホニルメトキシ］エチル］−６−フェニルチオプ
リンを得た。２−アミノ−９−［２−［ジエチルホスホ
ニルメトキシ］エチル］−６−フェニルチオプリン１．
７５ｇのアセトニトリル２０ｍｌ溶液にブロモトリメチ
ルシラン２．６ｍｌを添加し、２５℃で２２時間撹拌
後、水を添加、濃縮乾固し、アセトン／メタノールより
結晶化し、２−アミノ−９−［２−［ホスホニルメトキ
シ］エチル］−６−フェニルチオプリン４０６ｍｇ（２
７％）を得た。 ｍ．ｐ．：１６３°−１６８°（ｄｅｃ．アセトン／メ
タノール）1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6 ，δ）：３．５８（ｄ，
Ｊ＝８．７Ｈｚ，２Ｈ）、３．８１（ｔ，Ｊ＝５．１Ｈ
ｚ，２Ｈ）、４．１９（ｔ，Ｊ＝５．１Ｈｚ，２Ｈ）、
７．４０−７．５０（ｍ，３Ｈ）、７．５５−７．６６
（ｍ，２Ｈ）、８．０２（ｓ，１Ｈ）Example 16: Preparation of 2-amino-9- [2- [phosphonylmethoxy] ethyl] -6-phenylthiopurine (Compound No. 281) 2-amino-9- [2- [diethylphosphonylmethoxy] ethyl] -6-phenylthiopurine was obtained in the same manner except that triethyl phosphite was used in place of (fluoroethyl) phosphite. 2-amino-9- [2- [diethylphosphonylmethoxy] ethyl] -6-phenylthiopurine
2.6 ml of bromotrimethylsilane was added to a solution of 75 g of acetonitrile in 20 ml, stirred at 25 ° C. for 22 hours, water was added, concentrated to dryness, crystallized from acetone / methanol, and 2-amino-9- [2- [ Phosphonylmethoxy] ethyl] -6-phenylthiopurine 406 mg (2
7%). m. p. 163 ° -168 ° (dec. Acetone / methanol) 1 H-NMR (DMSO-d 6 , δ): 3.58 (d,
J = 8.7 Hz, 2H), 3.81 (t, J = 5.1H)
z, 2H), 4.19 (t, J = 5.1 Hz, 2H),
7.40-7.50 (m, 3H), 7.55-7.66
(M, 2H), 8.02 (s, 1H)
【００６３】実施例１７：２−アミノ−９−［２−ホス
ホニルメトキシエチル］−６−ｐ−メトキシフェニルチ
オプリン（化合物Ｎｏ．２８４）の製造 実施例１６においてチオフェノールに代えてｐ−メトキ
シチオフェノールを用いる他は同様にして表題化合物を
得た。 ＵＶ：λmax ＝２３０， ３２８（０．０１Ｎ−ＨＣｌ／ＣＨ3 ＯＨ） λmax ＝２２３， ３１４（０．０１Ｎ−ＮａＯＨ／ＣＨ3 ＯＨ）1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6 ，δ）：３．５８（ｄ，
Ｊ＝８．６Ｈｚ，２Ｈ）、３．７８−３．９２（ｍ ｉ
ｎｖｏｌｖｉｎｇ ｓ ａｔ ３．７９，５Ｈ）、４．
１８−４．３０（ｍ，２Ｈ）、７．０２（ｄ，Ｊ＝８．
７Ｈｚ，２Ｈ）、７．５１（ｄ，Ｊ＝８．７Ｈｚ，２
Ｈ）、８．１４（ｓ，１Ｈ）Example 17: Preparation of 2-amino-9- [2-phosphonylmethoxyethyl] -6-p-methoxyphenylthiopurine (Compound No. 284) In Example 16, p-methoxy was used in place of thiophenol. The title compound was obtained in the same manner except that thiophenol was used. UV: λ max = 230, 328 (0.01 N HCl / CH 3 OH) λ max = 223, 314 (0.01 N NaOH / CH 3 OH) 1 H-NMR (DMSO-d 6 , δ): 3 .58 (d,
J = 8.6 Hz, 2H), 3.78-3.92 (mi
3. nvolving sat at 3.79, 5H);
18-4.30 (m, 2H), 7.02 (d, J = 8.
7 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2
H), 8.14 (s, 1H)
【００６４】実施例１８：塩酸 ２−アミノ−９−［２
−［ビス（２，２，２−トリフルオロエチル）ホスホニ
ルメトキシ］エチル］−６−ｐ−メトキシフェニルチオ
プリンの製造 ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
メトキシフェニルチオプリンの酢酸エチル溶液を塩化水
素酢酸エチル溶液に滴下し、３０分撹拌後、析出した結
晶を減圧下乾燥して、塩酸 ２−アミノ−９−［２−
［ビス（２，２，２−トリフルオロエチル）ホスホニル
メトキシ］エチル］−６−ｐ−メトキシフェニルチオプ
リンを得た。 ｍ．ｐ．：１１０°−１１５°（ｄｅｃ．酢酸エチル）1 Ｈ−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，４
Ｈ）、７．０２（ｄ，Ｊ＝８．７Ｈｚ，２Ｈ）、７．４
９（ｄ，Ｊ＝８．７Ｈｚ，２Ｈ）、８．１３（ｓ，１
Ｈ）Example 18 2-amino-9- [2 hydrochloride
Preparation of-[bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-methoxyphenylthiopurine 2-amino-9- [2- [bis (2,2,2-triphenyl) Fluoroethyl) phosphonylmethoxy] ethyl] -6-p-
A solution of methoxyphenylthiopurine in ethyl acetate was added dropwise to the solution of hydrogen chloride in ethyl acetate. After stirring for 30 minutes, the precipitated crystals were dried under reduced pressure to give 2-amino-9- [2-hydrochloric acid.
[Bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-methoxyphenylthiopurine was obtained. m. p. : 110 ° -115 ° (dec. Ethyl acetate) 1 H-NMR (DMSO-d 6 , δ): 3.79 (s,
3H), 3.87 (t, J = 4.8 Hz, 2H);
13 (d, J = 7.9 Hz, 2H), 4.23 (t, J
= 4.8 Hz, 2H), 4.55-4.75 (m, 4
H), 7.02 (d, J = 8.7 Hz, 2H), 7.4
9 (d, J = 8.7 Hz, 2H), 8.13 (s, 1
H)
【００６５】実施例１９：塩酸 ２−アミノ−９−［２
−［ビス（２，２，２−トリフルオロエチル）ホスホニ
ルメトキシ］エチル］−６−ｍ−メトキシフェニルチオ
プリンの製造 ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｍ−
メトキシフェニルチオプリンの酢酸エチル溶液を塩化水
素酢酸エチル溶液に滴下し、３０分撹拌後、析出した結
晶を減圧下乾燥して、塩酸 ２−アミノ−９−［２−
［ビス（２，２，２−トリフルオロエチル）ホスホニル
メトキシ］エチル］−６−ｍ−メトキシフェニルチオプ
リンを得た。 ｍ．ｐ．：１３０°−１３５°（ｄｅｃ．酢酸エチル）1 Ｈ−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．
９９−７．０８（ｍ，１Ｈ）、７．１２−７．２４
（ｍ，２Ｈ）、７．３６（ｄｄ，Ｊ＝７．８Ｈｚａｎｄ
８．３Ｈｚ，１Ｈ）、８．２８（ｓ，１Ｈ）Example 19: 2-amino-9- [2 hydrochloride
Preparation of-[bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-methoxyphenylthiopurine 2-amino-9- [2- [bis (2,2,2-triphenyl) Fluoroethyl) phosphonylmethoxy] ethyl] -6-m-
A solution of methoxyphenylthiopurine in ethyl acetate was added dropwise to the solution of hydrogen chloride in ethyl acetate. After stirring for 30 minutes, the precipitated crystals were dried under reduced pressure to give 2-amino-9- [2-hydrochloric acid.
[Bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-methoxyphenylthiopurine was obtained. m. p. : 130 ° -135 ° (dec. Ethyl acetate) 1 H-NMR (DMSO-d 6 , δ): 3.77 (s,
3H), 3.84-3.96 (m, 2H), 4.14
(D, J = 8.0 Hz, 2H), 4.20-4.36
(M, 2H), 4.56-4.76 (m, 4H), 6.
99-7.08 (m, 1H), 7.12-7.24
(M, 2H), 7.36 (dd, J = 7.8 Hzand)
8.3 Hz, 1H), 8.28 (s, 1H)
【００６６】実施例２０：塩酸 ２−アミノ−９−［２
−［ビス（２，２，２−トリフルオロエチル）ホスホニ
ルメトキシ］エチル］−６−ｏ−メトキシフェニルチオ
プリンの製造 ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｏ−
メトキシフェニルチオプリンの酢酸エチル溶液を塩化水
素酢酸エチル溶液に滴下し、３０分撹拌後、析出した結
晶を減圧下乾燥して、塩酸 ２−アミノ−９−［２−
［ビス（２，２，２−トリフルオロエチル）ホスホニル
メトキシ］エチル］−６−ｏ−メトキシフェニルチオプ
リンを得た。 ｍ．ｐ．：１０１°−１０６°（ｄｅｃ．酢酸エチル）1 Ｈ−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，２
Ｈ）、８．２７（ｓ，１Ｈ）Example 20 2-amino-9- [2 hydrochloride
Production of-[bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-o-methoxyphenylthiopurine 2-amino-9- [2- [bis (2,2,2-triphenyl) Fluoroethyl) phosphonylmethoxy] ethyl] -6-o-
A solution of methoxyphenylthiopurine in ethyl acetate was added dropwise to the solution of hydrogen chloride in ethyl acetate. After stirring for 30 minutes, the precipitated crystals were dried under reduced pressure to give 2-amino-9- [2-hydrochloric acid.
[Bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-o-methoxyphenylthiopurine was obtained. m. p. : 101 ° -106 ° (dec. Ethyl acetate) 1 H-NMR (DMSO-d 6 , δ): 3.74 (s,
3H), 3.84-3.98 (m, 2H), 4.14
(D, J = 7.9 Hz, 2H), 4.20-4.34
(M, 2H), 4.56-4.76 (m, 4H), 7.
01 (dd, J = 7.5 Hz, 1H), 7.14 (d,
J = 8.4 Hz, 1H), 7.42-7.60 (m, 2
H), 8.27 (s, 1H)
【００６７】実施例２１：２−アミノ−９−［２−［ビ
ス（２，２，２−トリフルオロエチル）ホスホニルメト
キシ］プロピル］−６−フェニルチオプリン（化合物Ｎ
ｏ．３５１）の製造 １−クロロ−２−プロパノール２５ｍｌとパラホルムア
ルデヒド１１ｇをジクロロメタン５０ｍｌに懸濁させ、
０℃に冷却して、塩酸ガスを通しながら１０時間攪拌し
た。ジクロロメタンを留去し、残留物にトリス（２，
２，２−トリフルオロエチル）ホスファイト８６．５ｇ
を加え、１６０℃で５時間加熱した。反応混合物より減
圧蒸留して２−［ビス（２，２，２−トリフルオロエチ
ル）ホスホニルメトキシ］プロピルクロリドを得た。２
−アミノ−６−クロロプリン１５．０ｇ（８８ｍｍｏ
ｌ）をジメチルホルムアミド３６０ｍｌに懸濁し、１，
８−ジアザビシクロ［５．４．０］ウンデス−７−エン
１３．９ｍｌ（９３ｍｍｏｌ）と８０℃で１時間反応さ
せた。次に２−［ビス（２，２，２−トリフルオロエチ
ル）ホスホニルメトキシ］プロピルクロリド３６．１ｇ
を上記反応液に加え、１００℃で２時間反応させた。反
応後室温まで冷却し、濃縮した。残渣に水を加え、酢酸
エチルで抽出した。有機層を硫酸マグネシウムで乾燥
後、濃縮し、得られたシロップをエーテルに溶かして不
溶物を除き、２−アミノ−９−［２−［ビス（２，２，
２−トリフルオロエチル）ホスホニルメトキシ］プロピ
ル］−６−クロロプリン６ｇを得た。Example 21: 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-phenylthiopurine (compound N
o. Production of 351) 25 ml of 1-chloro-2-propanol and 11 g of paraformaldehyde were suspended in 50 ml of dichloromethane.
The mixture was cooled to 0 ° C and stirred for 10 hours while passing hydrochloric acid gas. Dichloromethane was distilled off and the residue was tris (2,2
86.5 g of 2,2-trifluoroethyl) phosphite
And heated at 160 ° C. for 5 hours. The reaction mixture was distilled under reduced pressure to obtain 2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl chloride. 2
-Amino-6-chloropurine 15.0 g (88 mmol
l) was suspended in 360 ml of dimethylformamide,
It was reacted with 13.9 ml (93 mmol) of 8-diazabicyclo [5.4.0] undes-7-ene at 80 ° C. for 1 hour. Then, 36.1 g of 2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl chloride.
Was added to the above reaction solution and reacted at 100 ° C. for 2 hours. After the reaction, the mixture was cooled to room temperature and concentrated. Water was added to the residue and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The obtained syrup was dissolved in ether to remove insolubles, and 2-amino-9- [2- [bis (2,2,2
6 g of 2-trifluoroethyl) phosphonylmethoxy] propyl] -6-chloropurine were obtained.
【００６８】２−アミノ−９−［２−［ビス（２，２，
２−トリフルオロエチル）ホスホニルメトキシ］プロピ
ル］−６−クロロプリン３ｇのジメチルフォルムアミド
２５ｍｌ溶液に、トリエチルアミン１．１ｍｌとチオフ
ェノール１．５３ｍｌを添加し、１００℃で２時間撹拌
した。反応混合物を室温まで冷却して濃縮した。残渣に
重曹水を加え酢酸エチルで抽出し、有機層を濃縮した。
残渣をクロロホルムに溶解させてシリカゲルカラムに吸
着させ、２％−メタノール−クロロホルムで溶出させ、
２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］プロピル］−６−フ
ェニルチオプリン０．７７ｇ（収率２２％）を得た。 ｍ．ｐ．：１１９−１２０℃（ジイソプロピルエーテ
ル）1 Ｈ−ＮＭＲ（ＣＤＣｌ3 ，δ）：１．２５（ｄ，Ｊ＝
５．９Ｈｚ，３Ｈ）、３．７６−４．２３（ｍ，５
Ｈ）、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）2-amino-9- [2- [bis (2,2,
To a solution of 3 g of 2-trifluoroethyl) phosphonylmethoxy] propyl] -6-chloropurine in 25 ml of dimethylformamide, 1.1 ml of triethylamine and 1.53 ml of thiophenol were added, and the mixture was stirred at 100 ° C for 2 hours. The reaction mixture was cooled to room temperature and concentrated. Aqueous sodium bicarbonate was added to the residue, extracted with ethyl acetate, and the organic layer was concentrated.
The residue was dissolved in chloroform, adsorbed on a silica gel column, and eluted with 2% methanol-chloroform,
0.77 g (yield 22%) of 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-phenylthiopurine was obtained. m. p. 119-120 ° C (diisopropyl ether) 1 H-NMR (CDCl 3 , δ): 1.25 (d, J =
5.9 Hz, 3H), 3.76-4.23 (m, 5
H) 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)
【００６９】実施例２２：２−アミノ−９−［２−［ビ
ス（２，２，２−トリフルオロエチル）ホスホニルメト
キシ］プロピル］−６−ｐ−メトキシフェニルチオプリ
ン（化合物Ｎｏ．３５４）の製造 実施例２１において、チオフェノールに代えてｐ−メト
キシチオフェノールを用いる他は実施例２１と同様にし
て、表題化合物を得た。 ｍ．ｐ．：１１８−１１９℃（ジイソプロピルエーテ
ル）1 Ｈ−ＮＭＲ（ＣＤＣｌ3 ，δ）：１．２４（ｄ，Ｊ＝
５．９Ｈｚ，３Ｈ）、３．８１−４．０２（ｍ，５
Ｈ）、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＝８．７Ｈ
ｚ，２Ｈ）、７．７１（ｓ，１Ｈ）Example 22: 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-p-methoxyphenylthiopurine (Compound No. 354) The title compound was obtained in the same manner as in Example 21 except that p-methoxythiophenol was used instead of thiophenol. m. p. : 118-119 ° C (diisopropyl ether) 1 H-NMR (CDCl 3 , δ): 1.24 (d, J =
5.9 Hz, 3H), 3.81-4.02 (m, 5
H), 3.85 (s, 3H), 4.31-4.40
(M, 4H), 4.75 (s, 2H), 6.95 (d,
J = 8.7 Hz, 2H), 7.53 (d, J = 8.7H)
z, 2H), 7.71 (s, 1H)
【００７０】試験例１：Ｈｅｐａｔｉｔｉｓ Ｂ ｖｉ
ｒｕｓ（ＨＢＶ）増殖抑制効果 本発明の化合物のＨＢＶ増殖抑制効果を公知の方法
（Ｋ．ＵＥＤＡ，ｅｔ ａｌ．，ＶＩＲＯＬＯＧＹ，１
６９，２１３−２１６（１９８９））に従い測定した。
ＨＢ６１１細胞（ＨＢＶを生産する組換えヒト肝癌細
胞）２×１０4 個を、１０％、牛胎児血清、ストレプト
マイシン（１００μｇ／ｍｌ）、ペニシリン（１００Ｉ
Ｕ／ｍｌ）及びジェネテイシン（商標名、ライフテクノ
ロジーズ社製抗生物質）（０．２ｍｇ／ｍｌ）を含むダ
ルベッコＭＥ培地中、３７℃で培養した。培養２日目及
び５日目に培地を交換した後、培養８日、１１日及び１
４日後に被験化合物を最終濃度で０．００５〜１００μ
Ｍ含む培地で置換し、培養１７日後に細胞のＤＮＡを回
収した。細胞内のＨＢＶ−ＤＮＡ量をサザンブロットで
測定し、細胞内でのＨＢＶ−ＤＮＡ合成５０％阻害濃度
を求めた。また、ＨＢ６１１細胞の５０％が死滅するの
に要する化合物濃度を求めた。結果を表２に示す。表中
の化合物番号は表１の化合物番号に対応させてある。な
お、表２には、参考のため、公知化合物であるＰＭＥＡ
のジピパロイルオキシメチルエステル（参考例１）と、
ＥＰ６３２０４８号公報に記載されている９−［２−
［ビス（２，２，２−トリフルオロエチル）ホスホニル
メトキシ］エチル］−２−アミノ−６−ｐ−トルイルチ
オプリン（参考例２）について、同様の試験を行った結
果も併記した。Test Example 1: Hepatitis B vi
rus (HBV) growth inhibitory effect The HBV growth inhibitory effect of the compound of the present invention can be determined by a known method (K. UEDA, et al., VIROLOGY, 1).
69, 213-216 (1989)).
HB611 cells (recombinant human hepatoma cells producing HBV) (2 × 10 4 cells), 10%, fetal calf serum, streptomycin (100 μg / ml), penicillin (100I)
U / ml) and Geneticin (trade name, antibiotics manufactured by Life Technologies) (0.2 mg / ml) in Dulbecco's ME medium at 37 ° C. After the medium was changed on the second and fifth days of culture, the culture was replaced on days 8, 11 and 1 of culture.
Four days later, the test compound was added to a final concentration of 0.005 to 100 μm.
The medium was replaced with a medium containing M, and the DNA of the cells was recovered after 17 days of culture. The amount of HBV-DNA in the cells was measured by Southern blot, and the concentration of 50% inhibition of HBV-DNA synthesis in the cells was determined. Further, the compound concentration required for killing 50% of the HB611 cells was determined. Table 2 shows the results. The compound numbers in the table correspond to the compound numbers in Table 1. Table 2 shows the known compound PMEA for reference.
Dipiparoyloxymethyl ester (Reference Example 1),
9- [2-] described in EP6322048
The results of the same test for [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -2-amino-6-p-toluylthiopurine (Reference Example 2) are also shown.
【００７１】[0071]
【表２】 ───────────────────────────────── 被験化合物 ＨＢＶ−ＤＮＡ ＨＢ６１１細胞に対する ５０％合成阻害濃度（μＭ） ５０％細胞毒性濃度（μＭ） ───────────────────────────────── Ｎｏ．１ ０．０１ ＞１，０００ ２ ０．０８ ＞１，０００ ３ ０．０４ ＞１，０００ ４ ０．０５ ＞１，０００ 参考例１a １８．８ １１ 参考例２b ０．０６ １０８ ─────────────────────────────────a ＰＭＥＡのジピパロイルオキシメチルエステルb ９−［２−［ビス（２，２，２−トリフルオロエチル）ホスホニルメトキシ］ エチル］−２−アミノ−６−ｐ−トルイルチオプリン[Table 2] Test compound HBV-DNA 50% synthesis inhibitory concentration against HB611 cells (ΜM) 50% cytotoxic concentration (μM) ───────────────────────────────── No. 1 0.01> 1,000 2 0.08> 1,000 3 0.04> 1,000 4 0.05> 1,000 Reference Example 1 a 18.8 11 Reference Example 2 b 0.06 108 ── ─────────────────────────────── a PMEA di Pi Palo yloxymethyl ester b 9- [2- [bis (2 , 2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -2-amino-6-p-toluylthiopurine
【化７】 Embedded image
【００７２】試験例２：経口投与マウス血清のＨＢＶ増
殖抑制効果 一群３匹よりなるマウスに、被験化合物を１ｇ／ｋｇ又
は０．３ｇ／ｋｇの１回経口用量を与え、投与３０分後
に採血し、血清を調製した。ＨＢ６１１細胞２×１０4
個を、１０％牛胎児血清、ストレプトマイシン（１００
μｇ／ｍｌ）、ペニシリン（１００ＩＵ／ｍｌ）及びジ
ェネテイシン（０．２ｍｇ／ｍｌ）を含むダルベッコＭ
Ｅ培地中、３７℃で培養した。培養２日目及び５日目に
培地を交換した後、培養８日、１１日及び１４日後に上
記血清（検体を経口投与後のラット血清）を５％含む培
地で置換し、培養１７日後に細胞のＤＮＡを回収した。
細胞内のＨＢＶ−ＤＮＡ量をサザンブロットで測定し、
細胞内でのＨＢＶ−ＤＮＡ合成阻害率を求めた。参考の
ため、ＰＭＥＡについても同様の試験を行った。結果を
表３に示す。Test Example 2: HBV Growth Inhibitory Effect of Orally Administered Mouse Serum A group of three mice was given a single oral dose of 1 g / kg or 0.3 g / kg of the test compound, and blood was collected 30 minutes after administration. , Serum was prepared. HB611 cells 2 × 10 4
Individuals were treated with 10% fetal calf serum, streptomycin (100
μg / ml), Dulbecco M containing penicillin (100 IU / ml) and geneticin (0.2 mg / ml)
The cells were cultured in E medium at 37 ° C. After the medium was changed on the second and fifth days of the culture, the medium was replaced with a medium containing 5% of the above serum (rat serum after oral administration of the specimen) on the eighth, 11 and 14 days of the culture. Cell DNA was recovered.
The amount of HBV-DNA in the cells was measured by Southern blot,
The rate of HBV-DNA synthesis inhibition in cells was determined. For reference, a similar test was performed for PMEA. Table 3 shows the results.
【００７３】[0073]
【表３】 [Table 3]
【００７４】[0074]
【発明の効果】本発明のホスホナートヌクレオチド化合
物は、優れた抗ウイルス活性を有するとともに、高い経
口吸収性と生体に対する高い安全性を有しているので、
医薬の有効成分として有用である。Industrial Applicability The phosphonate nucleotide compound of the present invention has excellent antiviral activity, high oral absorbability and high safety for living organisms.
It is useful as an active ingredient of a medicine.
フロントページの続き (72)発明者 上田 直子 神奈川県横浜市青葉区鴨志田町1000番地 三菱化学株式会社横浜総合研究所内 (72)発明者 湯浅 聡 神奈川県横浜市青葉区鴨志田町1000番地 三菱化学株式会社横浜総合研究所内 (72)発明者 神谷 直洋 神奈川県横浜市青葉区鴨志田町1000番地 三菱化学株式会社横浜総合研究所内 (56)参考文献 特開 平７−70159（ＪＰ，Ａ) (58)調査した分野(Int.Cl.7，ＤＢ名) C07F 9/6561 A01N 57/24 103 A01N 57/24 104 A61K 31/675 A61P 31/12 ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)Continued on the front page (72) Inventor Naoko Ueda 1000 Kamoshita-cho, Aoba-ku, Yokohama-shi, Kanagawa Prefecture Inside Mitsubishi Chemical Research Institute (72) Inventor Satoshi Yuasa 1000 Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa Mitsubishi Chemical Corporation Inside Yokohama Research Laboratory (72) Inventor Naohiro Kamiya 1000 Kamoshita-cho, Aoba-ku, Aoba-ku, Yokohama-shi, Kanagawa Prefecture Mitsubishi Research Institute Yokohama Research Laboratory (56) References JP-A-7-70159 (JP, A) (58) Field (Int.Cl. 7 , DB name) C07F 9/6561 A01N 57/24 103 A01N 57/24 104 A61K 31/675 A61P 31/12 CA (STN) REGISTRY (STN)
Claims (19)
１以上のハロゲン原子で置換されたＣ1 〜Ｃ4 のアルコ
キシ基、ハロゲン原子、アミノ基、又はニトロ基を表
し；Ｒ2 及びＲ3 はそれぞれ独立に水素原子、Ｃ1 〜Ｃ
22のアルキル基、アシルオキシメチル基、アシルチオエ
チル基、又は１以上のハロゲン原子で置換されたエチル
基を表し；Ｒ4 は水素原子、Ｃ1 〜Ｃ4 のアルキル基、
Ｃ1 〜Ｃ4 のヒドロキシアルキル基、又は１以上のハロ
ゲン原子で置換されたＣ1 〜Ｃ4 のアルキル基を表し；
ＸはＣＨ又は窒素原子を表す。）で表されるホスホナー
トヌクレオチド化合物若しくはその塩、又はそれらの水
和物若しくは溶媒和物。1. The following general formula (I): (Wherein, R 1 is a hydrogen atom, a C 1 -C 6 alkoxy group,
Represents a C 1 -C 4 alkoxy group, a halogen atom, an amino group, or a nitro group substituted with one or more halogen atoms; R 2 and R 3 each independently represent a hydrogen atom, C 1 -C
22 represents an alkyl group, an acyloxymethyl group, an acylthioethyl group, or an ethyl group substituted with one or more halogen atoms; R 4 represents a hydrogen atom, a C 1 -C 4 alkyl group,
A C 1 -C 4 hydroxyalkyl group, or a C 1 -C 4 alkyl group substituted with one or more halogen atoms;
X represents CH or a nitrogen atom. Or a hydrate or solvate thereof.
キシ基である請求項１記載のホスホナートヌクレオチド
化合物若しくはその塩、又はそれらの水和物若しくは溶
媒和物。2. The phosphonate nucleotide compound according to claim 1 , wherein R 1 is a hydrogen atom or a C 1 -C 6 alkoxy group, a salt thereof, or a hydrate or solvate thereof.
キシ基であり；Ｒ2 及びＲ3 がそれぞれ独立に水素原
子、Ｃ1 〜Ｃ22のアルキル基、又は１以上のハロゲン原
子で置換されたエチル基である請求項１記載のホスホナ
ートヌクレオチド化合物若しくはその塩、又はそれらの
水和物若しくは溶媒和物。3. R 1 is a hydrogen atom or a C 1 -C 4 alkoxy group; R 2 and R 3 are each independently a hydrogen atom, a C 1 -C 22 alkyl group, or one or more halogen atoms. The phosphonate nucleotide compound according to claim 1, which is a substituted ethyl group, a salt thereof, or a hydrate or solvate thereof.
キシ基であり；Ｒ2 及びＲ3 がそれぞれ独立に水素原
子、Ｃ1 〜Ｃ22のアルキル基、又は２，２，２−トリフ
ルオロエチル基であり；Ｒ4 が水素原子又はメチル基で
ある請求項１記載のホスホナートヌクレオチド化合物若
しくはその塩、又はそれらの水和物若しくは溶媒和物。R 1 is a hydrogen atom or a C 1 -C 4 alkoxy group; R 2 and R 3 are each independently a hydrogen atom, a C 1 -C 22 alkyl group, or 2,2,2- The phosphonate nucleotide compound according to claim 1, wherein R 4 is a hydrogen atom or a methyl group, a salt thereof, or a hydrate or solvate thereof.
キシ基であり；Ｒ2 及びＲ3 がそれぞれ独立に水素原子
又は２，２，２−トリフルオロエチル基であり；Ｒ4 が
水素原子又はメチル基である請求項１記載のホスホナー
トヌクレオチド化合物若しくはその塩、又はそれらの水
和物若しくは溶媒和物。Wherein R 1 is an alkoxy group of a hydrogen atom or a C 1 ~C 4; R 2 and R 3 are each independently a hydrogen atom or a 2,2,2-trifluoroethyl group; R 4 is The phosphonate nucleotide compound according to claim 1, which is a hydrogen atom or a methyl group, a salt thereof, or a hydrate or solvate thereof.
−［２−［ビス（２，２，２−トリフルオロエチル）ホ
スホニルメトキシ］エチル］−６−フェニルチオプリ
ン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
メトキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｍ−
メトキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｏ−
メトキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
エトキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］プロピル］−６−フ
ェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］プロピル］−６−ｐ
−メトキシフェニルチオプリン； ２−アミノ−９−［２−［（２，２，２−トリフルオロ
エチル）ホスホニルメトキシ］エチル］−６−フェニル
チオプリン； ２−アミノ−９−［２−［（２，２，２−トリフルオロ
エチル）ホスホニルメトキシ］エチル］−６−ｐ−メト
キシフェニルチオプリン； ２−アミノ−９−［２−［ホスホニルメトキシ］エチ
ル］−６−フェニルチオプリン； ２−アミノ−９−［２−［ホスホニルメトキシ］エチ
ル］−６−ｐ−メトキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
ブトキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
プロポキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
イソプロポキシフェニルチオプリン；及び ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
イソブトキシフェニルチオプリンから選ばれる請求項５
記載のホスホナートヌクレオチド化合物若しくはその
塩、又はそれらの水和物若しくは溶媒和物。6. A group consisting of the following compounds: 2-amino-9
-[2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-phenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoro Ethyl) phosphonylmethoxy] ethyl] -6-p-
Methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-
Methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-o-
Methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-
Ethoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-phenylthiopurine; 2-amino-9- [2- [ Bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-p
2-methoxy-9- [2-[(2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-phenylthiopurine; 2-amino-9- [2- [ (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-methoxyphenylthiopurine; 2-amino-9- [2- [phosphonylmethoxy] ethyl] -6-phenylthiopurine; 2-amino-9- [2- [phosphonylmethoxy] ethyl] -6-p-methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonyl Methoxy] ethyl] -6-p-
Butoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-
Propoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-
Isopropoxyphenylthiopurine; and 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-
6. The method according to claim 5, wherein the compound is selected from isobutoxyphenylthiopurine.
Or a salt or hydrate or solvate thereof.
キシ基であり；Ｒ2 及びＲ3 が２，２，２−トリフルオ
ロエチル基であり；Ｒ4 が水素原子又はメチル基である
請求項１記載のホスホナートヌクレオチド化合物若しく
はその塩、又はそれらの水和物若しくは溶媒和物。7. R 1 is a hydrogen atom or a C 1 -C 4 alkoxy group; R 2 and R 3 are a 2,2,2-trifluoroethyl group; R 4 is a hydrogen atom or a methyl group 2. The phosphonate nucleotide compound according to claim 1, or a salt thereof, or a hydrate or solvate thereof.
オロエチル）ホスホニルメトキシ］エチル］−６−フェ
ニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
メトキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｍ−
メトキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｏ−
メトキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
エトキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］プロピル］−６−フ
ェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］プロピル］−６−ｐ
−メトキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
ブトキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
プロポキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
イソプロポキシフェニルチオプリン；及び ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
イソブトキシフェニルチオプリンから選ばれる請求項７
記載のホスホナートヌクレオチド化合物若しくはその
塩、又はそれらの水和物若しくは溶媒和物。8. A group consisting of the following compounds: 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-phenylthiopurine; 2-amino- 9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-
Methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-
Methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-o-
Methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-
Ethoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-phenylthiopurine; 2-amino-9- [2- [ Bis (2,2,2-trifluoroethyl) phosphonylmethoxy] propyl] -6-p
-Methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-
Butoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-
Propoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-
Isopropoxyphenylthiopurine; and 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-
8. The method of claim 7, wherein the isobutoxyphenylthiopurine is selected from the group consisting of:
Or a salt or hydrate or solvate thereof.
キシ基であり；Ｒ2 及びＲ3 が２，２，２−トリフルオ
ロエチル基であり；Ｒ4 が水素原子である請求項１記載
のホスホナートヌクレオチド化合物若しくはその塩、又
はそれらの水和物若しくは溶媒和物。9. The method according to claim 9, wherein R 1 is a hydrogen atom or a C 1 -C 4 alkoxy group; R 2 and R 3 are 2,2,2-trifluoroethyl groups; and R 4 is a hydrogen atom. 2. The phosphonate nucleotide compound according to 1, or a salt thereof, or a hydrate or solvate thereof.
オロエチル）ホスホニルメトキシ］エチル］−６−フェ
ニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
メトキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｍ−
メトキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｏ−
メトキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
エトキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
ブトキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
プロポキシフェニルチオプリン； ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
イソプロポキシフェニルチオプリン；及び ２−アミノ−９−［２−［ビス（２，２，２−トリフル
オロエチル）ホスホニルメトキシ］エチル］−６−ｐ−
イソブトキシフェニルチオプリンから選ばれる請求項９
記載のホスホナートヌクレオチド化合物若しくはその
塩、又はそれらの水和物若しくは溶媒和物。10. A group consisting of the following compounds: 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-phenylthiopurine; 2-amino- 9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-
Methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-
Methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-o-
Methoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-
Ethoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-
Butoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-
Propoxyphenylthiopurine; 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-
Isopropoxyphenylthiopurine; and 2-amino-9- [2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-
10. The composition of claim 9, wherein the composition is selected from isobutoxyphenylthiopurine.
Or a salt or hydrate or solvate thereof.
コキシ基であり；Ｒ2 及びＲ3 が２，２，２−トリフル
オロエチル基であり；Ｒ4 が水素原子である請求項１記
載のホスホナートヌクレオチド化合物若しくはその塩、
又はそれらの水和物若しくは溶媒和物。11. The method according to claim 11, wherein R 1 is a hydrogen atom or a C 1 -C 2 alkoxy group; R 2 and R 3 are 2,2,2-trifluoroethyl groups; and R 4 is a hydrogen atom. The phosphonate nucleotide compound or a salt thereof according to 1,
Or hydrates or solvates thereof.
２，２−トリフルオロエチル）ホスホニルメトキシ］エ
チル］−６−フェニルチオプリンである請求項１１記載
のホスホナートヌクレオチド化合物若しくはその塩、又
はそれらの水和物若しくは溶媒和物。12. A compound of the formula 2-amino-9- [2- [bis (2,
The phosphonate nucleotide compound according to claim 11, which is 2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-phenylthiopurine, a salt thereof, or a hydrate or solvate thereof.
２，２−トリフルオロエチル）ホスホニルメトキシ］エ
チル］−６−ｐ−メトキシフェニルチオプリンである請
求項１１記載のホスホナートヌクレオチド化合物若しく
はその塩、又はそれらの水和物若しくは溶媒和物。13. A method of producing 2-amino-9- [2- [bis (2,
The phosphonate nucleotide compound according to claim 11, which is 2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-methoxyphenylthiopurine, a salt thereof, or a hydrate or solvate thereof.
２，２−トリフルオロエチル）ホスホニルメトキシ］エ
チル］−６−ｍ−メトキシフェニルチオプリンである請
求項１１記載のホスホナートヌクレオチド化合物若しく
はその塩、又はそれらの水和物若しくは溶媒和物。14. A compound of the formula 2-amino-9- [2- [bis (2,
The phosphonate nucleotide compound according to claim 11, which is 2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-m-methoxyphenylthiopurine, a salt thereof, or a hydrate or solvate thereof.
２，２−トリフルオロエチル）ホスホニルメトキシ］エ
チル］−６−ｏ−メトキシフェニルチオプリンである請
求項１１記載のホスホナートヌクレオチド化合物若しく
はその塩、又はそれらの水和物若しくは溶媒和物。15. A compound of the formula 2-amino-9- [2- [bis (2,
The phosphonate nucleotide compound according to claim 11, which is 2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-o-methoxyphenylthiopurine, a salt thereof, or a hydrate or solvate thereof.
２，２−トリフルオロエチル）ホスホニルメトキシ］エ
チル］−６−ｐ−エトキシフェニルチオプリンである請
求項１１記載のホスホナートヌクレオチド化合物若しく
はその塩、又はそれらの水和物若しくは溶媒和物。16. A compound of the formula 2-amino-9- [2- [bis (2,
The phosphonate nucleotide compound according to claim 11, which is 2,2-trifluoroethyl) phosphonylmethoxy] ethyl] -6-p-ethoxyphenylthiopurine, a salt thereof, or a hydrate or solvate thereof.
の化合物及びその塩、並びにそれらの水和物及び溶媒和
物からなる群から選ばれる物質と薬学的に許容され得る
製剤用添加物とを含む医薬組成物。17. A compound selected from the group consisting of the compound according to any one of claims 1 to 16 and salts thereof, and hydrates and solvates thereof, and a pharmaceutically acceptable additive for a pharmaceutical preparation. And a pharmaceutical composition comprising:
の化合物及びその塩、並びにそれらの水和物及び溶媒和
物からなる群から選ばれる物質を有効成分として含む抗
ウイルス剤。18. An antiviral agent comprising as an active ingredient a substance selected from the group consisting of the compound according to any one of claims 1 to 16, a salt thereof, and a hydrate or solvate thereof.
求項１８に記載の抗ウイルス剤。19. The antiviral agent according to claim 18, wherein the virus is hepatitis B virus.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP00557097A JP3148139B2 (en) | 1996-01-18 | 1997-01-16 | Phosphonate nucleotide compounds |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8-6480 | 1996-01-18 | ||
| JP648096 | 1996-01-18 | ||
| JP00557097A JP3148139B2 (en) | 1996-01-18 | 1997-01-16 | Phosphonate nucleotide compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH09255695A JPH09255695A (en) | 1997-09-30 |
| JP3148139B2 true JP3148139B2 (en) | 2001-03-19 |
Family
ID=26339536
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP00557097A Expired - Fee Related JP3148139B2 (en) | 1996-01-18 | 1997-01-16 | Phosphonate nucleotide compounds |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3148139B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010018531A (en) * | 2008-07-09 | 2010-01-28 | Sumitomo Seika Chem Co Ltd | Method for producing 3-benzyloxybenzenethiol |
| CN102093422B (en) * | 2009-12-10 | 2015-02-25 | 中国人民解放军军事医学科学院毒物药物研究所 | Acyclic nucleoside phosphonate derivative and medicinal application thereof |
-
1997
- 1997-01-16 JP JP00557097A patent/JP3148139B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH09255695A (en) | 1997-09-30 |
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