PT1013661E - 2'-o,4'-c-metileno-biciclonucleósidos - Google Patents
2'-o,4'-c-metileno-biciclonucleósidos Download PDFInfo
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- PT1013661E PT1013661E PT98905804T PT98905804T PT1013661E PT 1013661 E PT1013661 E PT 1013661E PT 98905804 T PT98905804 T PT 98905804T PT 98905804 T PT98905804 T PT 98905804T PT 1013661 E PT1013661 E PT 1013661E
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- Portugal
- Prior art keywords
- group
- compound
- nucleic acid
- pyrimidine
- derivative
- Prior art date
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- -1 purine nucleic acid Chemical group 0.000 claims abstract description 48
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 31
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 31
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims abstract description 24
- 125000000714 pyrimidinyl group Chemical group 0.000 claims abstract description 9
- 229940127073 nucleoside analogue Drugs 0.000 claims description 21
- 239000002777 nucleoside Substances 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 14
- 125000002103 4,4'-dimethoxytriphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)(C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H])C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 13
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 12
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 10
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 8
- 229940104302 cytosine Drugs 0.000 claims description 6
- 229940035893 uracil Drugs 0.000 claims description 6
- 229930024421 Adenine Natural products 0.000 claims description 5
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 5
- 229960000643 adenine Drugs 0.000 claims description 5
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 claims description 4
- 229960003495 thiamine Drugs 0.000 claims description 4
- 235000019157 thiamine Nutrition 0.000 claims description 4
- 239000011721 thiamine Substances 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims description 2
- 125000001990 thiamine group Chemical group 0.000 claims 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical group CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims 2
- 229940113082 thymine Drugs 0.000 claims 1
- 108091034117 Oligonucleotide Proteins 0.000 abstract description 36
- 238000001727 in vivo Methods 0.000 abstract description 5
- 108091081021 Sense strand Proteins 0.000 abstract description 4
- 108091033319 polynucleotide Proteins 0.000 abstract description 4
- 102000040430 polynucleotide Human genes 0.000 abstract description 4
- 239000002157 polynucleotide Substances 0.000 abstract description 4
- 102000004190 Enzymes Human genes 0.000 abstract description 2
- 108090000790 Enzymes Proteins 0.000 abstract description 2
- 230000000692 anti-sense effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- 239000000243 solution Substances 0.000 description 57
- 150000001875 compounds Chemical class 0.000 description 49
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 39
- 230000015572 biosynthetic process Effects 0.000 description 39
- 238000003786 synthesis reaction Methods 0.000 description 36
- 238000005481 NMR spectroscopy Methods 0.000 description 34
- 239000000203 mixture Substances 0.000 description 34
- 125000003729 nucleotide group Chemical group 0.000 description 31
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 30
- 239000002904 solvent Substances 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- 229910052757 nitrogen Inorganic materials 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 28
- 239000012043 crude product Substances 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- 238000010898 silica gel chromatography Methods 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 108020004414 DNA Proteins 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
- 238000004821 distillation Methods 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 239000000843 powder Substances 0.000 description 17
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 15
- 239000012267 brine Substances 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- 235000011152 sodium sulphate Nutrition 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 13
- 239000002773 nucleotide Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 150000007523 nucleic acids Chemical class 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 6
- KWQCNAXZKYMWAL-DLTWYDFYSA-N 1-[(1r,4s,6r,7s)-4-(hydroxymethyl)-7-phenylmethoxy-2,5-dioxabicyclo[2.2.1]heptan-6-yl]pyrimidine-2,4-dione Chemical compound N1([C@@H]2O[C@]3(CO[C@@]2([C@@H]3OCC=2C=CC=CC=2)[H])CO)C=CC(=O)NC1=O KWQCNAXZKYMWAL-DLTWYDFYSA-N 0.000 description 6
- KNLNWXXWKDEEFW-JIOCBJNQSA-N 1-[(1r,4s,6r,7s)-7-hydroxy-4-(hydroxymethyl)-2,5-dioxabicyclo[2.2.1]heptan-6-yl]pyrimidine-2,4-dione Chemical compound N1([C@@H]2O[C@]3(CO[C@@]2([C@@H]3O)[H])CO)C=CC(=O)NC1=O KNLNWXXWKDEEFW-JIOCBJNQSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 229940126657 Compound 17 Drugs 0.000 description 6
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 101710163270 Nuclease Proteins 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 229940126214 compound 3 Drugs 0.000 description 5
- 229940125898 compound 5 Drugs 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 5
- 229940045145 uridine Drugs 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 4
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 4
- 108020004394 Complementary RNA Proteins 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 238000010533 azeotropic distillation Methods 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 229940126142 compound 16 Drugs 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 4
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- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
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Description
ΡΕ1013661 1
DESCRIÇÃO "2'-Ο,4'-C-METILENO-BICICLONUCLEOSIDOS"
Esta invenção diz respeito a análogos de nucleó-sidos inovadores e à sua utilização em análogos de nucleótidos e, mais especificamente, em análogos de nucleó-tidos apropriados para serem utilizados como moléculas de sentido reverso.
TÉCNICA ANTERIOR
Em 1978, relatou-se pela primeira vez que uma molécula de sentido reverso inibia infecções provocadas pelo vírus da grupe. Desde então, emitiram-se relatórios que defendiam que as moléculas de sentido reverso inibiam a expressão de oncogenes e a infecção com SIDA. Nos últimos anos, oligonucleótidos de sentido reverso têm-se tornado nuns dos produtos farmacêuticos mais promissores, uma vez que controlam especificamente a expressão de genes indesej áveis. 0 método de sentido reverso encontra-se baseado na ideia de controlar uma corrente unidireccional sendo designado por dogma central, i.e., ADN ARN -► proteína, por intermédio da utilização de um oligonucleótido de sentido reverso. 2 ΡΕ1013661
No entanto, ao aplicar-se um oligonucleótido disponível na natureza a este método, como molécula de sentido reverso, este decompôs-se com várias nucleases em vivo, ou a sua permeação através da membrana celular não foi elevada. Para se resolverem estes problemas, sintetizaram-se vários derivados e análogos de ácido nucleico, e levaram-se a cabo os seus respectivos estudos. Os exemplos de produtos sintetizados incluem um fosforotioato, tendo um átomo de enxofre em substituição de um átomo de oxigénio no átomo de fósforo, e um metilfosfonato tendo um grupo de metilo de substituição. Recentemente, sintetizaram-se produtos em que o átomo de fósforo também tem sido substituído por um átomo de carbono, ou em que a estrutura da porção se modificou, ou em que a base de ácido nucleico se modificou. No entanto, quaisquer derivados ou análogos resultantes não têm sido plenamente satisfatórios em termos da estabilidade em vivo, da facilidade de síntese, e da especificidade da sequência (a propriedade em que se controla selectivamente a expressão de um gene específico isoladamente).
Obika et al. ("Properties of Novel Oligonucleo-tide Analogues Containing an Acyclic Nucleoside and a Carbamate Linkage", Bioorganic & Medicinal Chemistry Letters, 6(12) (1996) p.1357-1360) descrevem heterodímeros contendo um nucleósido acíclico e uma ligação de carbamato na posição 3' incorporada em oligonucleótidos. Estudaram-se as temperaturas de fusão dos dímeros de ADN-ADN e ADN-ARN 3 ΡΕ1013661 bem como a resistência da nuclease dos oligonucleótidos modificados.
Nestas circunstâncias, tem surgido procura para a criação de uma molécula de sentido reverso que se decomponha minimamente com uma nuclease em vivo, se ligue ao mensageiro-alvo do ARN com afinidade elevada, tenha especificidade elevada e que, assim, possa controlar eficientemente a expressão de um gene especifico.
DESCRIÇÃO DA INVENÇÃO
Os inventores da invenção presente conceberam um análogo de ácido nucleico com configuração imobilizada da porção de açúcar presente num ácido nucleico, que teria utilidade no método de sentido reverso. Sintetizaram um análogo de nucleósido que irá, portanto, ser uma estrutura unitária, e confirmaram que um análogo de oligonucleótido preparado com a sua utilização provou ser muito útil como molécula de sentido reverso.
BREVE DESCRIÇÃO DAS FIGURAS A Fig. 1 apresenta um gráfico que representa o decurso no tempo da absorção ultravioleta (260 nm) de um oligonucleótido decomposto com uma exonuclease; e A Fig. 2 apresenta um gráfico que representa o decurso no tempo da absorção ultravioleta (260 nm) de um 4 ΡΕ1013661 oligonucleótido preparado com a utilização de um análogo de nucleósido análogo ao da invenção presente (X2) decomposto com uma exonuclease.
Em seguida descrevem-se os detalhes das invenção presente. A estrutura de um análogo de nucleósido de acordo com a invenção presente é um análogo de nucleósido com a fórmula geral (I) seguinte
X—O· d) em que B seja uma base de ácido nucleico de pirimidina ou de purina, ou um seu análogo, e X e Y sejam idênticos ou diferentes, e cada um destes representa um átomo de hidrogénio, um grupo alquilo, um grupo alcenilo, um grupo alcinilo, um grupo cicloalquilo, um grupo aralquilo, um grupo arilo, um grupo acilo, ou um grupo sililo, ou um seu derivado de amidito. 0 grupo alquilo representa um grupo alquilo, de cadeia linear ou cadeia ramificada, com 1 a 20 átomos de carbono. Os seus exemplos incluem metilo, etilo, n-propilo, 5 ΡΕ1013661 i-propilo, n-butilo, t-butilo, pentilo, hexilo, heptilo, octilo, nonilo e decilo. 0 grupo alcenilo representa um grupo alcenilo, de cadeia linear ou cadeia ramificada, com 2 a 20 átomos de carbono. Os seus exemplos incluem vinilo, alilo, butenilo, pentenilo, geranilo, e farnesilo. O grupo alcinilo representa um grupo alcinilo, de cadeia linear ou cadeia ramificada, com 2 a 20 átomos de carbono. Os seus exemplos incluem etinilo, propinilo, e butinilo. 0 grupo cicloalquilo representa um grupo cicloalquilo, com 3 a 8 átomos de carbono, e inclui, por exemplo, ciclopropilo, ciclobutilo, ciclopentilo, ciclo-hexilo, ciclo-heptilo, e ciclo-octilo. Outro exemplo é um grupo heterociclico em que um ou mais grupos metileno arbitrários no anel do grupo cicloalquilo foram substituídos por um átomo de oxigénio, um átomo de enxofre, ou um átomo de azoto alquilo-substituído. Este será, por exemplo, um grupo tetra-hidropiranilo. 0 grupo arilo diz respeito a um substituinte monovalente formado pela remoção de um átomo de hidrogénio a partir de um grupo heterociclico aromático ou um grupo hidrocarboneto aromático. De preferência, este representa um substituinte monovalente formado pela remoção de um átomo de hidrogénio a partir de um grupo heterociclico 6 ΡΕ1013661 aromático ou um grupo hidrocarboneto aromático, e inclui, por exemplo, fenilo, toluilo, xililo, bifenilo, naftilo, antrilo, e fenantrilo. 0 átomo de carbono no anel do grupo arilo pode ser substituído por um ou mais de entre um átomo de halogéneo, um grupo alquilo inferior, um grupo hidroxilo, um grupo alcoxilo, um grupo amino, um grupo nitro, e um grupo trifluorometilo. Neste caso o substituinte será, por exemplo, um átomo de halogéneo, um grupo hidroxilo, um grupo amino, um grupo alcoxilo, ou um grupo ariloxilo. 0 grupo aralquilo diz respeito a um grupo alquilo ligado a um grupo arilo, e que pode ser substituído. 0 grupo aralquilo que pode ser substituído representa um grupo alquilo ligado a um grupo arilo, com um ou mais átomos de hidrogénio arbitrários do grupo arilo e do grupo alquilo a serem substituídos opcionalmente pelos substituintes seguintes: Os exemplos de substituintes são acilo, amino, arilo, alquilo, cicloalquilo, alcoxilo, hidroxilo, nitro, e halogéneo. 0 grupo amino não necessita ser substituído, embora o grupo amino uma vez substituído inclua, por exemplo, alquilamino, arilamino, e acilamino. Os exemplos de grupos alcoxilo são metoxilo, etoxilo, n-propoxilo, i-propoxilo, n-butoxilo, i-butoxilo, s-butoxilo, t-butoxilo, pentiloxilo, hexiloxilo, e fenoxilo. Os exemplos de átomos de halogéneo são flúor, cloro, bromo, e iodo. 7 ΡΕ1013661
Os exemplos preferidos do grupo aralquilo são tritilo, benzilo, fenetilo, tritilmetilo, difenilmetilo, naftilmetilo, e 4,4'-dimetoxitritilo (DMTr). 0 grupo DMTr é especialmente preferido.
Tal como os grupos acilo, acetilo, formilo, propionilo, benzoilo, e benziloxicarbonilo se podem exemplificar. Um exemplo do grupo sililo é um grupo trial-quilsililo, de preferência trimetilsililo, trietilsililo, tri-isopropilsililo, t-butildimetilsililo ou t-butildife-nilsililo, e de preferência trimetilsililo. 0 análogo de nucleótido preparado a partir dos análogos de nucleósido da invenção presente é um análogo de oligonucleótido ou de polinucleótido tendo uma ou mais estruturas com a fórmula geral (Ia)
( la) em que B seja uma base de ácido nucleico de pirimidina ou de purina, ou um seu análogo, ou um análogo de oligonucleótido ou polinucleótido com a fórmula geral (II) ΡΕ1013661
em que B1 e B sejam idênticos ou diferentes, e cada qual representa uma base de ácido nucleico de pirimidina ou de purina, ou um seu análogo, R seja um átomo de hidrogénio, um grupo hidroxilo, um átomo de halogéneo, ou um grupo alcoxilo, W1 e W2 sejam idênticos ou diferentes, e cada qual representa um átomo de hidrogénio, um grupo alquilo, um grupo alcenilo, um grupo alcinilo, um grupo cicloalquilo, um grupo aralquilo, um grupo arilo, um grupo acilo, um grupo sililo, um resíduo de ácido fosfórico, um nucleósido que ocorre na natureza ou um nucleósido sintético ligado através de uma ligação fosfodiéster, ou um oligonucleótido ou polinucleótido contendo o nucleósido, n1 ou n2 sejam idênticos ou diferentes, e cada qual indica um número inteiro de 0 a 50, desde que os n1 ou n2 não sejam zero ao mesmo tempo, e desde que nem todos os n2 sejam zero ao mesmo tempo, n3 indica um número de 1 a 50, desde que quando n1 e/ou n2 sejam ou seja 2 ou seja 2 ou mais, B1 e B não têm que ser idênticos, e os R' não têm que ser necessariamente idênticos. A base de ácido nucleico de pirimidina ou de purina da invenção presente diz respeito a tiamina, ura-cilo, citosina, adenina, guanina, ou um seu derivado. 9 ΡΕ1013661 0 análogo de nucleósido da invenção presente pode ser sintetizado do modo abaixo descrito. (1) Síntese do análogo de nucleósido
7 B
Tratou-se o Composto 1, sintetizado a partir de uridina de acordo com a literatura [1) J.A. Secrist et al., J. Am. Chem. Soc., 101, 1554 (1979); 2) G.H. Jones et al., J. Org. Chem., 44, 1309 (1979)], com cloreto de tosilo (TsCl) para ser tosilado apenas um dos dois alcoóis primários, conduzindo ao Composto 2. 0 Composto 2 foi hidrolisado com ácido para se obter um triol, Composto 3. Condensou-se o Composto 3 com benzaldeido na presença de um catalisador ácido para se formar um benzilideno, Composto 4. Levou-se a cabo a redução do Composto 4 com cianoboro-hidreto de sódio (NaBH3CN) na presença de tetracloreto de 10 ΡΕ1013661 titânio (TiCl4) para se obter o Composto 5. Fez-se reagir este composto com hexametildisilazida de sódio (NaHMDS) em tetra-hidrofurano (THF) para se obter um biciclo, Composto 6 (Composto I: B = uracilo (U) , X = Η, Y = benzilo). Quando se efectuou cataliticamente a redução do Composto 6 na presença de um catalisador de paládio sobre carbono, obteve-se um diol, Composto 7 (Composto (I): B=U, X=Y= H) . Do tratamento posterior do Composto 7 com cloreto de 4,4'-dimetoxitritilo (DMTrCl) resultou num tritilo, Composto 8 (Composto I: B = U, X = DMTr, Y = H) . Os Compostos 6, 7 e 8 poderão ser utilizados como materiais de partida para a obtenção de vários compostos I.
Os compostos (I) tendo várias bases de ácido nucleico, tanto naturais como não naturais, que não a uridina, poderão ser sintetizados recorrendo a qualquer um dos três métodos seguintes: 0 primeiro método configura a conversão a partir do Composto 8. Isto é, acetila-se o Composto 8 para se obter o Composto 9, e em seguida faz-se reagir com 1,2,4-triazole para se formar o Composto 10. A hidrólise deste composto proporciona o Composto 11 (Composto (I): B = citosina (C) , X = DMTr, Y = H) . O Composto 12 (Composto (I) : B = benzoilcitosina (CBz) , X = DMTr, Y = Η) , que se irá tornar numa matéria de partida para a síntese de oligonucleótidos, poderá obter-se facilmente pela benzoilação do Composto 11. 11 ΡΕ1013661
0 segundo método é um método que se leva a cabo através do Composto 13 que se poderá obter facilmente a partir de D-ribose de acordo com a literatura [3 ) A.G.M. Barrett et al., J. Org. Chem., 55, 3853 (1990); 4) G.H. Jones et al., ibid. , 44, 1309 ( 1979) ] . Isto é, o Composto 13 foi conduzido ao Composto 16 em três passos, e ciclizado sob condições básicas para se obter um metilglicosilo desejado, Composto 17. 0 grupo OMe na posição 1 deste composto poderá ser substituído por diversas bases naturais de ácidos nucleicos ou bases não naturais análogas às dos ácidos nucleicos seguindo um de vários métodos que já foram desenvolvidos anteriormente. Por exemplo, pode aplicar-se um método tal como se representa por um esquema que vai do Composto 17 ao Composto 20.
HO
OH
OH OH 0-ribOSe c. HO reflux. 19 hr (SO %)
MeOH, aceona
Cr03f Py CH2CI2 rt, 20 <riin
H
1) p-dioxane rt 15 hr ( 37 %. 2 steps ) HCHO aq., NaOH aq.
2) (3 °X° 12 ΡΕ1013661 12 ΤΒθΡ3θ/80Ρ3°]^ο^ΟΟΗ3 TiCUOMAP TSOPSO-|^o-^ aaN/CH,C«z JW rsJrí 2\ rt. 13 hr ( 70 %) 14 ( 38 %) X ts
TTFA-HjO TH0P3ai NaHMOS THF rt, 20 min (77%)
Jp Ts<V OH OH THF rt, 1 hr TBOPSO.. OCHj TBDPSO· 16 (35%) 17
'0 OH (43 %) >8 OCH3
OTMS N
Me.
(7
AcgO TBOPSO·» oCH3 O MAPI Py rt, 3 hr ( 86 %) 'N- OTMS TMSOTT/ 1,1-dichloroethane CHjCN rt, 18 hr (ca. 70 %) - cy mFo 15
O terceiro método tem início em acetona-D-glucose, que se obtém a partir de D-glucose num só passo e se encontra disponível no comércio. Preparou-se o Composto 31 de acordo com a referência 5) R.D. Youssefyeh, J.P.H. Verheyden e J.G. Moffatt., J. Org. Chem., 44, 1301-1309 (1979) . Em seguida, tratou-se o Composto 31 tal como se representa pelo esquema seguinte para se protegerem os dois grupos hidroxilo primários com um grupo t-butildifenil-sililo e um grupo p-toluenossulfonilo, progressivamente. Acetilou-se o composto protegido para se obter o Composto 13 ΡΕ1013661
TBDPSOk _ HGT OSn 32
TsC)/ DM AP / Et3N TBOPSCk, CH2q2 f f L TsCT 97% iBn 33
AcOH / Ac20/ conc. H^SOí rt 86% TBDPS* Ts( iriíiAc 34
Condensou-se o Composto 34, separadamente, com tiamina, benzoiladenina, e isobutirilguanina activada por trimetilsililação (referidos como 2TMS*T, 2TMS*ABz, e 3TMS*GlBu, respectivamente) , para se obterem os Compostos 35, 40 e 44 com elevados rendimentos, tal como se representa no esquema colocado abaixo. Em seguida, sujeitaram-se estes condensados à desacetilação (Compostos 36, 41, 45), formação de anéis com cinco membros (Compostos 37, 42, 46), des-sililação (Compostos 38, 43, 47), e mais desbenzilação para se formarem os Compostos 39 pretendidos.
34 2TMS · T or 2TMS · A®* or 3TMS · G®u
TMS OTI/CIC HjCH jCI TBOPS' Ts< aq. K2C03 / MeOH "7t ~ rt. (70-97%) 35: 8=T 40: 8»Aa* 44: 8*Gi0u (64-92%) 14 ΡΕ1013661
B TBDPSl
TsOr ôsn OH
NaHMOS/THF TBOPi TBAF/THF rt. 38: B=.T +1: B=ASl 45: B»QISu (44-100%) (83-100%)
37: B=T At B=ABi 48: B=G®U
Htf 20%Pd(OH)a-C HO· MeOH rl 96% 38: B=T -Μίβ-Α31 47: BbGí6m ai iSu
39a: B=>T 39b: B=A 39c: B=G (2) Síntese do análogo de oligonucleótido
Faz-se reagir o Composto 8 com 2-cianoetil-N,N, N'N'-tetraisopropilfosforamidito para se obter um amidito, Composto 21. Combina-se este composto com amidito nucleósi-do que ocorre na natureza, e sujeita-se a um sintetizador de ADN para se sintetizarem vários análogos de oligonucleó-tidos. Purificam-se os produtos impuros sintetizados uma coluna cromatográfica de fase reversa (Oligo-Pak). Analisa-se o grau de pureza do produto purificado por HPLC, altura em que se poderá confirmar quanto à formação de um análogo de oligonucleótido. jtaidfc de nadeàskkí natai
21 15 ΡΕ1013661
Pelo menos uma unidade de monómero sob a forma de Composto 8 pode ser contida no análogo de oligonucleótido. Alternativamente, as unidades de monómero podem estar presentes em duas ou mais localizações no análogo de oligonucleótido de tal forma que se separem de cada qual através de um ou mais nucleótidos que ocorrem na natureza. A invenção presente torna possível sintetizar uma molécula de sentido reverso incorporando um número necessário de análogos de nucleótido (análogos de nucleósido) da invenção (um comprimento necessário do análogo de nucleótido ou nucleósido) numa localização necessária. 0 comprimento da totalidade do análogo de oligonucleótido é de 2 a 50, 10 a 30 de preferência, unidades de nucleósido.
Um tal análogo de nucleótido (molécula de sentido reverso) é minimamente degradável por várias nucleases, e pode existir em vivo durante um longo período de tempo após a sua administração. Esta molécula de sentido reverso opera, por exemplo, na formação de uma dupla hélice estável em conjunto com um ARN mensageiro, inibindo assim a biossíntese de uma proteína potencialmente patogénica; ou forma uma tripla hélice em combinação com ADN de cadeia dupla num genoma para se inibir a transcrição para ARN mensageiro. O análogo de oligonucleótido também poderá suprimir a proliferação de um vírus que tenha provocado a infecção. À luz destas revelações, torna-se expectável que um análogo de nucleótido (molécula de sentido reverso) 16 ΡΕ1013661 utilizando um análogo de nucleósido da invenção presente tenha utilidade sob a forma de medicamentos, incluindo os antineoplásicos e os antivirais, para tratamento de doenças por inibição das acções especificas dos genes. A molécula de sentido reverso que utiliza o análogo de nucleótido (nucleósido) da invenção presente pode ser formulada sob a forma de preparações parentéricas ou preparações de lipossomas pela incorporação auxiliares habituais tais como tampões e/ou estabilizadores. Sob a forma de preparações para aplicação tópica, esta poderá ser misturada com veículos farmacêuticos utilizados habitualmente para a preparação de unguentos, cremes, líquidos ou emplastros. A síntese dos análogos de nucleósido da invenção presente e dos análogos de nucleótido da invenção presente será descrita mais detalhadamente por intermédio dos Exemplos e Exemplos de Produção seguintes. Nestes Exemplos, o uracilo é utilizado principalmente como uma base, mas à sua semelhança também se poderão utilizar outras bases de purina de ácido nucleico.
[Exemplo 1] Síntese de um análogo de nucleósido (1) Síntese de 2',3'-O-ciclo-hexilideno-4'-(p-toluenossulfoniloximetil)uridina (Composto 2)
Adicionou-se cloreto de p-toluenossulfonilo (771 17 ΡΕ1013661 mg, 4,05 mmoles) a uma solução de piridina anidra (13,5 mL) do Composto 1 (956 mg, 2,70 mmoles) conhecida na litera tura, à temperatura ambiente numa corrente de azoto, e agitou-se a mistura durante 5 horas a 60°C.
Adicionou-se uma solução de bicarbonato de sódio à mistura reaccional, extraindo-se o sistema reaccional de seguida com benzeno por 3 vezes. Lavou-se a fase orgânica uma vez com uma solução saturada de cloreto de sódio, e secou-se por sobre MgS04 anidro. Retiraram-se os solventes por destilação sob pressão reduzida, e sujeitou-se o resíduo a uma destilação azeotrópica com benzeno, por 3 vezes. Purificou-se o produto impuro resultante por croma-tografia em coluna sobre silicagel (CHCl3:MeOH = 15:1), e em seguida precipitou-se novamente a partir de benzeno-hexano para se obter um pó branco (Composto 2) (808 mg, 1,59 mmo1e s, 59%).
Composto 2: Pó branco, p.f. 104-106°C (benzeno-hexano) . IV v (KBr) : 3326, 2929, 2850, 1628, 1577, 1544, 1437, 1311, 1244 cm1. RMN de ^ (d6-acetona) : δ 1,45-1,67 (1 OH , m) , • 2,45 ( 3H, s) , 3 ,71 (2H, ABq, J = 12 H. z) , 4 ,20 (2H, ABq, J = 11 Hz) , 4 ,92 (1H, d, J’ = 6 Hz), 5, 05, 5 , 06 (1H, dd, J = 4, 6 Hz) , 5, 60 (1H, d, J = 7 Hz ), 5,75 (1H t d, J = 4 Hz) , 7,48 ( :2h, d, J = = 8 Hz), 7,77 ( 1H , d, J = 8 H z) , \—1 co (2H, , d, J = = 8 Hz) t 10,10 (1H, s,) • RMN de 13c ( d6- acetona): δ 21,5, 24, Λ, 24, 5, 25,5, 34,8, 36 i,9, 63, 5, 69 ,7, 82,5 , 84, 7, 87,8, 92 ,9, 102,9, 115 ,4, 128 ,8 , 130,8 , 133 ,9, 142, 7, 14 5,9, 151 ,3, 163 ,5. Massa ( EI): m/z 481 (M+- -h2o) 18 ΡΕ1013661
Anál. Calculado. para C23H28N2O9S · 1/3 H20: C, 53,69; H, 5,61; N, 5,44; S, 6,22. Determinado: C, 53,99;H, 5,48; N, 5, 4 2 ; S, 6,10. (2) Síntese de 4'-(p-toluenossulfoniloximetil)-uridina (Composto 3)
Agitou-se o Composto 2 acima (107 mg, 0,21 mmole) em TFA-H20 (98:2, 1 mL) durante 10 minutos à temperatura ambiente. Retirou-se a mistura reaccional por destilação sob pressão reduzida, e adicionou-se EtOH ao resíduo, seguindo-se a realização de uma destilação azeotrópica por 3 vezes. Purificou-se o produto impuro resultante por cromatografia em coluna sobre silicagel (CHCl3:MeOH = 10:1) para se obter o Composto 3 (85.0 mg, 0.20 mmole, 94%).
Composto 3: Pó branco, p.f. 119-120°C. IV v (KBr): 3227, 3060, 2932, 2837, 1709, 1508, 1464, 1252, 978, 835, 763, 556 cm-1. RMN de 1H (d6~acetona) : δ 2,31 (3H, s) , 2,84 (3H, s) , 3, 71 (2H, s) , 4, 13, 4,20 (2H, ABq, J = 11 Hz) , 4, 28, 4,31 (1H, dd, J' = 9, 6 Hz ) , 4 ,36 ( 1H, d, J’ = = 6 Hz) , 5, 54 (1H, d, J' = 8 Hz) , 5,75 ( 1H, d, J = 7 Hz), 7, , 32 (2H, d, J = 8 Hz) 7 , 67 (2H, d, J = 8 Hz ), 7, 70 (1H, d, J’ = 8 Hz ) , 10, 14 (1H, s) . RMN de 13C (d6- -acetona) : δ 21, ,5, 63,7, 70, 8, 72,7, 74, 6, 86, 8, 88, 8, 103, 1, 128,8, 130,7, 133, 9, 141,7, 145, 8, 151,8, 163, 9. Massa (EI): m/z 256 (M+- OTs) . 19 ΡΕ1013661 (3) Síntese de 2',3'-O-benzilideno-4'-(p-tolue-nossulfoniloximetil)uridina (Composto 4)
Numa corrente de azoto, adicionaram-se benzal-deído (2.4 mL, em excesso) e cloreto de zinco (670 mg, 5,0 mmoles) ao Composto 3 acima (400 mg, 0,93 mmoles), e agitou-se a mistura durante 5 horas à temperatura ambiente. Após terminada a reacção com a adição de solução saturada de bicarbonato de sódio, extraiu-se a mistura reaccional com clorofórmio, e lavou-se com uma solução saturada de bicarbonato de sódio, água, e uma solução saturada de cloreto de sódio. Secou-se a fase orgânica sobre sulfato de sódio anidro. Retiraram-se os solventes por destilação sob pressão reduzida, e purificou-se o resíduo por cromato- grafia em coluna sobre silicagel (CHCl3:MeOH = 40:1) para se obter o Composto 4 (380 mg, 0,74 mmol, 80%).
Composto 4: Pó branco, p.f. 99-102°C (CH2CI2- hexano) . [a]D23-26, 7 ° (c = 1,0, CHC13) . IV v (KBr) : 3059, 1691, 1460, 1362, 1269, 1218, 1177 cnT1. RMN de XH (CDC13) : δ 2,41 (3H, s), 3,25 (1H, lg) , 3,79 (2H, m) , 4,19 (2H, s) ,
5, 09 (1H, cr C-l II ^1 Hz) , 5,28 (1H, dd, J = 3, 7 Hz), 5 , 60 (1H, d, J = 4 Hz), 5, 73 (1H, N CO II l~D ), 5, 94 (1H, s) , 7,24 (1H, d, J = 8 Hz) , 7,38 (2H, d, J = 9 Hz) ), 7,42 ( 5H, lg), 7, 69 (2H, d, J = 9 Hz) , 9,11 (1H, lg) . RMN de 13C (CDCL3) : δ 21, 6, 63,5, 68,3, 77,2, 82,8, 84,2, 87,7, 94, 9, 102, 6, 107,5, 126, 5, 127,9, 128,5, 129, 7, 132,2, 135, 0, 143,0, 145,0, 150,4, 163,5. 20 ΡΕ1013661
Anál. Calculado. para C24H24N2O9S· 1/3 H20: C, 55,17; H, 4,76; N, 5,36; S, 6,14. Determinado: C, 55,19; H, 4,66; N, 5,29; S, 5,98. (4) Síntese de 3'-O-benzil-4'-(p-toluenossulfo-niloximetil)uridina (Composto 5)
Adicionou-se cianoboro-hidreto de sódio (92 mg, 1,5 mmoles) a uma solução de acetonitrilo (3 mL) do Composto 4 (150 mg, 0,29 mmole) à temperatura ambiente numa corrente de azoto. Em seguida, adicionou-se tetracloreto de titânio (0,16 mL, 1,5 mmoles) gota-a-gota sob arrefecimento com gelo, e agitou-se a mistura durante 15 horas à temperatura ambiente. Diluiu-se a mistura reaccional com clorofórmio, e lavou-se com uma solução saturada de bicarbonato de sódio, água, e uma solução saturada de cloreto de sódio. Em seguida, secou-se a fase orgânica sobre sulfato de sódio anidro. Após se retirarem os solventes por destilação, purificou-se o resíduo por cromatografia em coluna sobre silicagel (CHCl3:MeOH = 25:1) para se obter o Composto 5 (112 mg, 0,22 mmole, 75%).
Composto 5: Cristais incolores. P.f. 195-197°C (AcOEt-hexano) . [a]D23-14,6° (c = 1,0, CHC13) . IV v (KBr) : 3033, 2885, 2820, 1726, 1470, 1361, 1274, 1175, 1119 cm-1. RMN de ^ (CDCI3) δ: 2,40 (3H, s), 3,59-3,77 (3H, m) , 4,10, 4,24 (2H, AB, J = 11 Hz), 4,32 (1H, d, J = 6 Hz), 4,56 (2H, m) , 4,69 (1H, d, J = 11 Hz), 5,52 (1H, d, J = 6 Hz), 5,67 (1H, d, J = 8 Hz), 7,24-7,29 (7H, m) , 7,48 (1H, d, J = 8 21 ΡΕ1013661
Hz), 7,70 (2H, d, J = 9 Hz), 9,91 (1H, s). RMN de 13C (CDC13) : δ 21, 6, 63,2, 69, 2, 73, 6, 74, 6, 78, 1, 86, 6, 92,9, 102,5, 127,9, 128,2, 128,3, 128, 6, 129, 9, 132,3, 136, 9, 142,4, 145,2, 150,7, 163,8.
Anál. Calculado, para C24H26N2O9S: C, 55, 59; H, 5,05; N, 5,40; S, 6,18, Determinado: C, 55,41;H, 5,02;N, 5,32;S, 6,15. (5) Síntese de 3'-O-benzil-2'-O,4'-C-metileno-uridina (Composto 6)
Adicionou-se uma suspensão anidra de benzeno (0,7 mL) de NaHDMS (3,2 mmoles) a uma solução anidra de THF (1,5 mL) do Composto 5 (80 mg, 0.16 mmole) , à temperatura ambi ente numa corrente de azoto, e agitou-se a mistura durante 20 horas à temperatura ambiente. Adicionou-se uma solução saturada de bicarbonato de sódio à mistura reaccional, seguindo-se a extracção da mistura com CHC13. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e em seguida secou-se sobre sulfato de sódio anidro. Após se retirarem os solventes por destilação sob pressão reduzida, purificou-se o produto impuro resultante por cromatografia de coluna sobre silicagel (CHCl3:MeOH = 10:1), and recristalizou-se em seguida a partir de MeOH para se obter o Composto 6 (41 mg, 0,10 mmole, 61%).
Composto 6: Cristais incolores. P.f. 217-219°C (MeOH). [oí]d23° +108,4° (c = 0,3, MeOH). IV v (KBr) : 3059, 22 ΡΕ1013661 2951, 1688, 1459, : 1271, 1053 cm 1. RMN de 1H (d6-DMSO) δ: 3,75, 3,85 (2H, AB, J = 8 Hz) , 3, 77 (2H, d, J = 5 Hz) , 3, 92 (1H, s), 4,44 (1H, s) , 4, 60 (2h, s; ), 5 ,39 (1H, t, J = 5 Hz) , 5,48 (1H, s) , 7,31 (5H, m) , 7, 72 ( 1H, d, J = 8 Hz ) , 11,37 (1H, s). RMN de 13C (d6 -DMSO) δ: 56,0, 71,1, 71, 6, 75,8, 76, 5, 86, 5, 8 8,3, 100,9, 127,4 , 127, 6, 128,2, 137, 9, 139, 0 , 150, 0, 163,3 . Massa (EI ) : m/z 346 (M+, 1.1) .
Anál. Calculado para C17H18N2O6: C, 58,96; H, 5,24; N, 8,09.
Determinado: C, 58,67; H, 5,23; N, 8,05. (6) Síntese de 2'-O,4'-C-metileno-uridina (Composto 7)
Adicionou-se 10% Pd-C (25 mg) a uma solução de metanol (2,5 mL) do Composto 6 (25 mg, 0, 072 mmole) , e agitou-se a mistura reaccional durante 15 horas à pressão atmosférica numa corrente de azoto. Filtrou-se a mistura reaccional, e retirou-se o solvente por destilação. Em seguida, purificou-se o resíduo por cromatografia de coluna sobre silicagel (CHCl3:MeOH = 10:1, 5:1 em seguida) para se obter o Composto 7 (18,3 mg, quant.).
Composto 7: Cristais incolores. P.f. 239-243 °C (MeOH) . [a] d23° +92.2° ( O II 0 CO MeOH). IV v (KBr) : 3331, 3091, 3059, 2961, 1689 , 1463, 1272, 1049 cm1. RMN de 1H (CD3OD) δ: 3,76, 3,96 (2H, AB, J = 8 Hz), 3,90 (2H, s), 23 ΡΕ1013661 4,04 (1Η, s), 4,28 (1H, s), 5,55 (1H, s), 5,69 (1H, d, J = 8 Hz), 7,88 (1H, d, J = 8 Hz).
Anál. Calculado para C10H12N2O6: C, 46, 88; H, 4,72; N, 10,93.
Determinado: C, 46,74; H, 4,70; N, 10,84. (7) 5'-O-(4,4'-dimetoxitritil)-2'-O,4'-C-metile- no-uridina (Composto 8)
Adicionou-se piridina anidra ao Composto 7 (140 mg, 0,53 mmole), seguindo-se uma destilação azeotrópica da mistura por 3 vezes. Em seguida, converteu-se o produto numa solução anidra de piridina (1,5 mL), e adicionaram-se cloreto de 4,4'-dimetoxitritilo (210 mg, 0,63 mmole) e DMAP (6,5 mg, 0,053 mmole) à temperatura ambiente numa corrente de azoto. Agitou-se a mistura durante 5 horas à temperatura ambiente. Adicionou-se uma solução saturada de bicarbonato de sódio à mistura reaccional, seguindo-se a extracção com CH2CI2. Lavou-se a fase orgânica com água e com uma solução saturada de cloreto de sódio, e secou-se em seguida sobre sulfato de sódio anidro. Após se retirarem os solventes por destilação sob pressão reduzida, purificou-se o produto impuro resultante por cromatografia de coluna sobre sili-cagel (CHCl3:MeOH = 40:1) para se obter o Composto 8 (230 mg, 0,34 mmole, 66%).
Composto 8: Pó branco. P.f. 117-120°C (CHC13) . 24 ΡΕ1013661 [oí] d23° +17,2° (c = 1,0, CHC13) . IV v (KBr) : 3393, 3101, 2885, 1689, 1464, 1272, 1047 cm-1. RMN de ^ (CDC13) δ: 2,59 (1H, lg) , 3,56 (2H, q, J = 7, 11 Hz), 3,87 (1H, d, J = 7
Hz), 4,26 (1H, s), 4,47 (1H, s), 5,60 (1H, d, J = 9 Hz), 5,63 (1H, s), 5,84 (4H, d, J = 9 Hz), 7,22-7,45 (9H, m) , 7,93 (1H, d, J = 9 Hz) .
[Exemplo 2] Síntese de um análogo de nucleósido (1) Síntese de metil=5-0-(t-butildifenilsilil) -4-hidroximetil-2,3-0-isopropilideno-p-D-ribofuranosida (Composto 14)
Numa corrente de azoto, adicionaram-se EtsN (2,62 mL, 18,8 mmoles) e cloreto de t-butildifenilsililo (4,88 mL, 18,8 mmoles) a uma solução anidra de CH2CI2 (40 mL) do Composto 13 (2,00 g, 8,54 mmoles) conhecido da literatura sob arrefecimento com gelo, e agitou-se a mistura durante 13 horas à temperatura ambiente. À mistura reaccional, adicionou-se uma solução saturada de bicarbonato de sódio, e extraiu-se o sistema reaccional em seguida com AcOEt por 3 vezes. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e secou-se em seguida sobre Na2S04. Retiraram-se os solventes sob pressão reduzida, e purificou-se o produto impuro resultante por cromatografia de coluna sobre silicagel (hexano:AcOEt = 5:1) para se obter um material oleoso incolor (Composto 14) (2,82 g, 5,98 mmo1e s, 7 0%). 25 ΡΕ1013661 [a] 17° D -16,2° (c — 0,52, CHCI3) • IV v ( KBr) : 3510, 3061, 2938 , 2852, 1465, 1103 cm 1. RMN de Oí (CDC1 3) δ: 1,09 (9H, s) , 1, 28 ( 3H , s) , 1,49 (3H, s) , 3,22 (3H, s: ), 3, 67, 3,76 ( 2H, AB, J = 11 Hz) , co co 00 3,93 (: 2H, AB, J = 11 Hz), 4,49 (1H, d, J = 6 Hz) , 4,57 (1H, d, J = = 6 Hz) r 4, 93 (1H, s), 7,38-7, 43 ( 6H , m) , 7, 67 (4H, d, J = 7 Hz) . RMN de 13C ( CDCI3 ) δ: 19,2, 24,4, 25, 9 t 26,9, 55, 0, 62, 9, 64, 8 , 82,2 r 85 , 9, 88,7, 108, 6, 112, 6, 127,8, 129, 9, r 133,0, 135 >,7.
Anál. Calculado para C26H36O6S1 · 1/4 H20: C, 65,45; H, 7,71.
Determinado: C, 65,43; H, 7,59. (2) Síntese de metil=5-0-(t-butildifenilsilil)-2,3-0-isopropylideno-4-(p-toluenossulfoniloximetil)-β-ribofuranósido (Composto 15)
Numa corrente de azoto, adicionaram-se EtsN (3,92 g, 28,0 mmoles), cloreto de p-toluenossulfonilo (1.34 g, 7,22 mmoles), e 4-dimetilaminopiridina (90 mg, 0,72 mmole) a uma solução anidra de CH2CI2 (15 mL) do Composto 14 (2,13 g, 4,51 mmoles), e agitou-se a mistura durante 17 horas à 26 ΡΕ1013661 temperatura ambiente. Adicionou-se uma solução saturada de bicarbonato de sódio à mistura reaccional, e em seguida extraiu-se o sistema reaccional com AcOEt por 3 vezes. Lavou-se uma vez a fase orgânica com solução saturada de cloreto de sódio, e secou-se sobre Na2S04 anidro. Retiraram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto impuro resultante por cromato-grafia de coluna sobre silicagel (hexano:AcOEt = 10:1) para se obter um material oleoso incolor, Composto 15 (2,76 g, 4,42 mmo1e s, 98%).
[a] d17° -3.82o (c = 0,56, CHC13) . IV v (KBr) : 2934, 2852, 1369, 1104 cm'1. RMN de 3H (CDCls) δ: 1,02 (9H, s) , 1, 20 (3H, s) , 1,32 (3H, s) , 2,41 ( :3h, s), 3, 09 (3H, s) , 3 ,51 , 3 ,77 (2H, AB, J = 1 0 Hz ), 4,34 (1H, d, J = 6 Hz) , 4 ,25, 4, 39 (2H, AB, J = 9 Hz) , 4, 47 (1H, d, J = 6 H z) , 4,77 (: 1H, s) , 7, 28, 7, 81 (4H, AB, J = 9 Hz) , 7,39 - 7,4 4 ( 6H, m) , 7, 62 - 7 , 65 (4H, m) , 7 ,81 (2H, d, J = 9 Hz) . 13c- NMR (CDCI3) δ: 19 ,2, 21, 6, 24,. 5, 25, 8, 2 6,8, 54,9 f 62, 7, 68,8, 8: 1,9, 85 , 6, 87 ,5, 108 ,7, 112,8 , 12 7,7, 127, 8 , 12 8,2, 129, 6, 129,9, 132 ,9, 135 , 6, 144 f 4 .
Anál. Calculado para C33H42O8SSÍ: C, 63,23; H, 6,75; S, 5,11.
Determinado: C, 62,99; H, 6,53; S, 5,13. 27 ΡΕ1013661 (3) Síntese de metil=5-0-(t-butildifenylsilil)-4-(p-toluenossulfoniloximetil)-β-D-ribofuranósido (Composto 16)
Adicionou-se ácido trifluoroacético (14 mL) a uma solução de THF-H20 [11 mL, 8:3 em volume] do Composto 15 (645 mg, 1,03 mmoles) à temperatura ambiente, e agitou-se a mistura durante 20 minutos à temperatura ambiente. Retiraram-se os solventes por destilação sob pressão reduzida e purificou-se o produto impuro resultante por cromatografia de coluna sobre silicagel (hexano: AcOEt = 5: 1) para se obter um material oleoso incolor, Composto 16 (464 mg, 0,79 mmole, 77%).
[a] d17° -35.8° (c=l, 90, CHC13) IV v (KBr): 3499, 3051, 2931, 2840, 1594, 1468, 1362, 1109 crrf1. RMN de ^ (CDCI3) δ: 1,02 (9H,s), 2,42 (3H,s), 3,16 (3H,s), 3,54, 3,70 (2H,AB,J=10Hz ) , 3,97 (1H,d,J=5Hz), 4,18 (1H,d,J=5Hz) , 4,26, 4,39 (2H,AB,J=10Hz) , 4,73 (lH,s), 7,30 (2H,d,J=8Hz), 7,36-7,44 (6H,m), 7,59-7,66 (4H,m), 7,78 (2H,d,J=8Hz). RMN de 13C-NMR (CDCI3) δ: 19, 2, 21, 6, 26, 7, 55, 2, 66, 5, 69, 6, 74, 0, 75, 2, 76, 5, 84, 8, 107,5, 127,7, 128,0, 129, 8, 132, 6, 132,7, 132,8, 135, 5, 135, 6, 144,9. 28 ΡΕ1013661
Anál. Calculado para C3oH38SSi08· 1/4 H20: C, 60, 94; H, 6,56.
Determinado: C, 60,94; H, 6,43. (4) Síntese de metil=5-0-(t-butildifenilsilil)-2-O,4-C-metileno-p-D-ribofuranósido (Composto 17) e metil=5-0-(t-butildifenilsilil)-3-0,4-C-metileno-p-D-ribofuranósido (Composto 18)
Numa corrente de azoto, adicionou-se uma suspensão de benzeno (1,6 mL) de NaHMDS (3,30 mmoles) a uma solução anidra de THF (4 mL) do Composto 16 (194 mg, 0,33 mmol) à temperatura ambiente, e agitou-se a mistura durante 1 hora à temperatura ambiente. Após a adição de uma solução saturada de bicarbonato de sódio à mistura reaccional, retiraram-se os solventes por destilação, e extraiu-se o resíduo com AcOEt por 3 vezes. Lavou-se a fase orgânica uma vez com uma solução saturada de cloreto de sódio, e secou-se em seguida sobre Na2S04 anidro. Retirou-se o solvente por destilação sob pressão reduzida, e purificou-se o produto impuro resultante por cromatografia de coluna sobre silicagel (hexano:AcOEt = 5:1) para se obter um material oleoso incolor, Composto 17 (48 mg, 0,116 mmole, 35%) e um material oleoso incolor, Composto 18 (59 mg, 0,142 mmole, 43%) . ΡΕ1013661 29
Composto 17: IV v (KBr) : 3438, 3064, 1103, 1036 cm 1. RMN de 1H (CDC13) δ: 1,08 (9H,s), 2,04 (1H, s lg) , 3,39 (3H,s), 3, 65, 3, 98 (2 Η, AB, J= 8 H z ) , 3,95, 4,02 (2 Η, AB, J= 12 H z ) , 4,02 (lH,s), 4,30 (lH,s), 4,79 (lH,s), 7,38-7,46 (6H,m), 7,65-7,69(4H,m). RMN de 13C (CDC13) δ: 19, 2, 26, 7, 55, 0, 60,7, 71,2, 73, 1, 79, 9, 85, 5, 104,3, 127,8, 129, 9, 130, 0, 132,9, 135, 6, 135, 7.
Anál. Calculado para C23H30O5SÍ · 1/4 H20: C, 65, 68; H, 7,34.
Determinado: C, 65,98; H, 7,23.
Composto 18: IV v (KBr): 3456, 3058, 2938, 2852, 1467, 1108crrf1. RMN de 3Η (CDC13)õ: 1,10 (9H,s), 3,26 (3H,s), 3,71 (2H,s), 4,02 (1H, d, J=6Hz ) , 4,35, 4,95 (2H, d, J=7Hz ) , 5,01 (1H,s) , 5,11 (1H, d,J=6Hz) , 7,38-7,44 (6H,m), 7,66 (4H, d, J=7Hz) . RMN de 13C (CDC13) δ: 19, 3, 26, 8, 55, 4, 63,7, 75, 1, 77,9, 84,5, 86, 3, 111,9, 127,8, 128,0, 129, 9, 132,9, 133, 0, 135, 6, 135, 8, 135, 9. 30 ΡΕ1013661
Anál. Calculado para C23H30O5S1 · 1/4 H20: C, 65,91; H, 7,34.
Determinado: C, 66,07; H, 7,14. (5) Sintese de metil=3-0-acetil-5-0-(t-butildi-fenilsilil)-2-0,4-C-metileno-p-D-ribofuranósido (Composto 19)
Numa corrente de azoto, adicionaram-se anidrido acético (0,38 mL, 4,08 mmoles) e 4-dimetilaminopiridina (21 mg, 0,170 mmoles) a uma solução em piridina anidra (10 mL) do Composto 17 (704 mg, 1,70 mmoles) à temperatura ambi ente, e agitou-se a mistura durante 3 horas à temperatura ambiente. Após a adição de uma solução saturada de bicarbonato de sódio à mistura reaccional, extraiu-se o sistema com AcOEt por 3 vezes. Lavou-se uma vez a fase orgânica com uma solução saturada de cloreto de sódio, and secou-se em seguida sobre Na2S04 anidro. Retiraram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto impuro resultante por cromatografia de coluna sobre sili-cagel (hexano:AcOEt = 7:1) para se obter um material oleoso incolor, Composto 19 (665 mg, 1,46 mmoles, 86%).
[a]D17° -34.3° (c=0, 93, CHC13) IV v (KBr) : 3438, 3064, 2934, 1749, 1468, 1103, 103 6 cm-1. 31 ΡΕ1013661 RMN de 1H (CDC13) δ: 0,99 (9H,s), 1,97 (3H,s), 3,34 (3H,s), 3, 69, 3, 86 (2H, AB, J=8Hz) , 3,86 (2H,s), 4,17 (1H,s) , 4,77 (1H,s), 5,06 (lH,s), 7,28-7,39 (6H,m), 7,58- 7,63 (4H, m) . RMN de 13C (CDC13) õc: 19, 3, 20, 9, 26, 7, 55, 0, 60, 3, 72,0, 73, 6, 78,3, 85, 3, 104,4, 127,7, 129, 8, 133, 0, 135, 6, 169, 8.
Anál. Calculado para C25H3206Si· 1/4 H20: C, 65,12/ H, 7,10.
Determinado: C, 65,27; H, 7,00. (6) Síntese de 5'-O-(t-butildifenilsilil)-2'-O,4'-C-metileno-5-metiluridina (Composto 20)
Numa corrente de azoto, adicionou-se Ο,Ο'-bis-trimetilsililtimina (154 mg, 0,598 mmoles) a uma solução anidra de CH3CN (2 mL) do Composto 19 (109,2 g, 0,239 mmole) à temperatura ambiente. Em seguida, adicionou-se sob arrefecimento com gelo uma solução de 1,1-dicloroetano (0,31 mL) de trifluorometanossulfonato de trimetilsililo (0,82 mL, 8,74 mmoles), e agitou-se a mistura durante 18 horas à temperatura ambiente. Diluiu-se a mistura reacci-onal com CH2C12, e adicionou-se uma solução saturada de bicarbonato de sódio, seguindo-se a extracção do sistema com AcOEt por 3 vezes. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e secou-se em seguida 32 ΡΕ1013661 sobre Na2S04 anidro. Retiraram-se os solventes sob pressão reduzida, e purificou-se o produto impuro resultante por cromatografia de coluna sobre silicagel (hexano:AcOEt = 3:1) para se obter um material oleoso incolor, Composto 20 (87,7 mg, 0,173 mmole, 70%). IV v (KBr): 3048, 2935, 2852, 1749, 1466, 1369, 1234, 1108, 1040 cm1. RMN de ^ (CDC13) δ: 1,06 (9H,s), 1.94 (3H,s), 2,98 (1H,br s), 3, 63, 4, 00 (2H,AB,J=10Hz), 3,72 (1H,d,J=7Hz), 3,82-3,84 (2H,m), 4,30 (lH,s), 5,25 (lH,s), 7,40-7,46 (6H,m), 7,60 (4H, d, J=6Hz) , 7,66 (lH,s), 9,68 (1H,s lg).
[Exemplo 3] Síntese de análogo de nucleósido (método diferente) (1) Síntese de 3-0-benzil-5-0-t-butildifenilsi-lil-4-(hidroximetil)-1,2-O-isopropilideno-a-D-eritropento-furanose (Composto 32)
Sob uma corrente de azoto, adicionaram-se tri-etilamina (3,71 mL, 26,6 mmol) e cloreto de t-butildife-nilsililo (6,94 mL, 26,7 mmol), sob arrefecimento com gelo, a uma solução em cloreto de metileno (50 mL) do Composto 31 (2,50 g, 8,08 mmol) preparada consoante a referência 5) mencionada acima. Agitou-se a mistura durante 10,5 horas à temperatura ambiente. Em seguida adicionou-se uma solução 33 ΡΕ1013661 saturada de bicarbonato de sódio à mistura reaccional, extraiu-se o sistema com acetato de etilo. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Separaram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (AcOEt-hexano: = 1:4 — 1:3) para se obter um sólido branco, Composto 32 (2,97 g, 5,41 mmol, 67%) . P.f. 98-99°C (hexano) . [oí]d20 +54,8°(c = 1,12, acetona). IV vmax (KBr) : 3553, 2936, 1463 , 137 9, 1107 cm 1. RMN de 2H (CDC13) δ: 1, 13 (9H, s) , 1,50 (: 3H, s ) , 1,78 (3H, s), 2,56 (1H, t, J = = 7 Hz) , 3, 82, 3 ,92 (2H , AB, J = 11 Hz) , 3, 94 (2H, t, J = 6 Hz) , 4 ,57 (1H, d, J = 5 Hz ) , 4, 64, 4,95 (2H, AB, J = 12 Hz) , 4, 83 (1H, dd, , J = 4, 5 Hz) , 5, 95 (1H, d, J = 4 Hz) , 7,44-7, , 55 (11H, m) , 7, 72-7, 78 (4H, m) . RMN de 13C (CDC13) 5C: 19 72, 26, 2 , 26,5, 26, 8, 63,2, 65, 4, 72,5, 77,9, 79,1 , 87,4, , 104,4, 113,7, 127, 6, 127,7 , 12 :8, 0, 128,5, 129, 5, 129,7, 132,9, 133,1, 134, 7, 135,5, 137,2.
Anál, Calculado para C32H4o06Si : C, 70, 04; H, 7,38. Determinado: C, 70,19; H, 7,35. 34 ΡΕ1013661 (2) Síntese de 3-0-benzil-5-0-(t-butildifenilsi-lil)-4-(p-toluenossulfoniloximetil)-1,2-a-D-eritropentofu-ranose (Composto 33)
Sob uma corrente de azoto, adicionaram-se tri-etilamina (395 pL, 2,83 mmol) , cloreto de p-toluenossul-fonilo (139,2 mg, 0,730 mmol), e 4-dimetilaminopiridina (8,92 mg, 0, 0730 mmol), sob arrefecimento com gelo, a uma solução em cloreto de metileno do Composto 32 (250 mg, 0,456 mmol). Agitou-se a mistura durante 15,5 horas à temperatura ambiente. Depois de se adicionar um solução saturada de bicarbonato de sódio à mistura reaccional, extraiu-se o sistema com acetato de etilo. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Separaram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (AcOEt-hexano: = 1:6) para se obter um material oleoso amarelo claro, Composto 33 (310,6 mg, 0,442 mmol, 97%).
[a]D20 +16,0° (c = 0,44, acetona). IV vmax (KBr) : 2935, 1595, 1462, 1363, 1174, 1106 cm-1. RMN de XH (CDC13) δ co 0 \—1 (9H , s) O \—1 (3H, s ) , 1/ 46 (3H, S) , 2, 48 (3H, s) , 3 , 68, 3 , 83 (2H, AB, J = 11 Hz ) , 4, 45 (2H, dd, J = 4 , 5 Hz), 4 ,64, 4 ,81 (2H, AB, J = 12 Hz ) , 4, 68 (1H, dd, J = 4, 5 Hz) f 5, 81 (1H, d, J = 4 Hz) , 7, 32 (2H, d, J = 8 Hz) , 7,42 -7,72 (15H, m) , 7,82, (2H, d, J 8 Hz ) , 7, 66 (4H, m) , 7,72 (2H, f d, J = 8 Hz) . 35 ΡΕ1013661 RMN de 13C (CDC13) õc: 19, 1, 21,5, 26,1, 26, 4, 26,7, 64,4,70 , 0, 72,5, 78, 1, 78,9, 85,4, 104,2, 113, 6, 127,3, 127,7, 127,9, 128,0, 128,4, 129, 6, 129, 7, 129, 8, 132,7, 132,8, 135,5, 137,2, 144,4. MS (EI) m/z : 646 (M+-t-Bu) . HRMS(EI): Calculado para C35H37O8SS1 (M+-t-Bu) : 645, 1978, Determinado: 645, 1969. (3) Síntese de 1,2-di-0-acetil-3-0-benzil-5-0-t-butildifenilsilil-4-(p-toluenossulfoniloximetil)-a- e -β-D-ribofuranose (Composto 34)
Sob uma corrente de azoto, adicionou-se anidrido acético (6,0 mL, 63,6 mmol) e ácido sulfúrico concentrado (56 pL, 1,10 μπιοί) a uma solução em ácido acético (56 mL) do Composto 34 (3, 70 g, 5,27 mmol) . Agitou-se a mistura durante 2 horas à temperatura ambiente. Verteu-se a mistura reaccional sobre água gelada (300 mL), e agitou-se durante 30 minutos. Depois de se lhe adicionar uma solução saturada de cloreto de sódio, extraiu-se a mistura com acetato de etilo. Em seguida secou-se a fase orgânica sobre sulfato de magnésio. Separaram-se os solventes por destilação, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (AcOEt-hexano, a 2:1) para se obter um material oleoso amarelo, Composto 34 (3,36 g, 4,53 mmol, 86%), sob a forma de uma mistura α-β (a 1:4). ΡΕ1013661 36 IV vmax (KBr) : 2934, 2863, 1751, 1365, 1217, 1106 cm RMN de 1H (CDCI3) [configuração β] δ: 1,02 (9H, s) , 1,77 (3H, s ) , CO \—1 (3H, s), 2, 39 (3H, s ) , 3 , 61, 3,76 (2H, AB, J = 11 Hz) , 4, 21-4,58 (5H, m) , 5,26 (1H, d, J = 5 Hz) , 5, 94 (1H, s) , 7,15-7,59 (13H, m) , 7,58- 7, 66 (4H, m) , 7,72 (2H, d, J = 8 Hz) [configuração cí] δ: 1,02 (9H, s) , co \—1 (3H, s) , 2, 36 (3H, s), 3,48, 3, 58 (2H, AB, J = 11 Hz) , 4,21 -4,58 (5H , m) , 5, 12 (1H, dd, J = : 5, 6 Hz), . 6,33 (1H , d, j = 5 Hz) , 7, 15- 7,59 (13H, m) , 7,58- 7,66 (4H, m) , 7,72 (2H, d, J = 8 Hz). RMN de 13C (CDCI3) 5C: 14,2, 19,3, 20,5, 20, 8, 21, 6, 26,7, 26 ,8, 60,3, 64,8 , 69,1 , 73, 6, 74, 1, 78, 6, 85, 3, 97,4, 127,4, 127, ,6, 127,7, 127, 8, 127,9, 128, 0, 128, 2, 128,3, 128,4, 129 ,5, 129,6, 1289 , 8, 129, 9, 132,4, 132, 8, 132,9, 135,4, 135, 5, 135,6, 136, 9, 144,5, 168,7, 169, 4 . HRMS (FAB) : Calculado para C^H^OioSSiNa (M++Na) : 769,2479, Determinado: 769,2484. (4) Síntese de 2'-O-acetil-3'-O-benzil-5'-O-t-butildifenilsilil-4'-p-toluenossulfoniloximetil-5-metiluri-dina (Composto 35)
Sob uma corrente de azoto, adicionaram-se 2TMS»T (1,04 g, 4,03 mmol) e trifluorometanossulfonato de trime-tilsililo (730 pL, 4,03 mmol), sob arrefecimento com gelo, 37 ΡΕ1013661 a uma solução em 1,2-dicloroetano (26 mL) do Composto 34 (1,88 g, 2,52 mmol), e agitou-se a mistura durante 17 horas à temperatura ambiente. Adicionou-se uma solução saturada de bicarbonato de sódio à mistura reaccional, e filtrou-se o sistema através de Celite, extraindo-se as águas-mães em seguida com clorofórmio. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Removeram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (AcOEt-hexano, a 2:3) para se obter um pó branco, Composto 35 (2,00 g, 2,44 mmol, 97%). P.f. 70-71,5°C. [a] D24 +4,58° (c = 1,25, acetona). IV vmax (KBr) : 3059, 2934, 1694, 1465, 1368, 704 cnf1. RMN de ^ (CDC13) δ: 1,11 3 (9H, s) , 1,63 (3H, d, = 1H z) , 2, 10 (3H, s ) , 2,42 (3H , s) , 3,73 , 3,8 6 (2H, AB , J : 11 H z) , 4, 12, 4,20 (2H , ab, J = 11 Hz) , 4,44, 4,57 i !2H , AB J = 11 Hz) , 4 ,45 (1H, d, J = 6 Hz) , 5, 38 (1H, t, J = = 6 Hz) 6, 02 ( 1H, d, J = 6 Hz) ', 7, 21-' 7, 60 (13H, m) , 7,62-7, 69 (7H m) , 8, 91 ( 1H, s lg) • RMN de 13 !C (CDC1 3 ) õc: 11,9, 19, 3 , 20, 6 f 21, 6 27,0 f 65, 3, 68, 6, 74 :,1, 74, 8, 1 77,2, 77,3, , 86,0, f 86, 4 111, 6, 12 7,9, 128, 0, 128, 2, 128, 5, 12 9,7, 130,1, 1 30,2 131, 8, 132,3, 132, 5, 135, 3, 135, 5, 135,6, 136,8, 1 44,9 150, 2, 163 !,4, 170,2 * 38 ΡΕ1013661 MS (FAB) m/z : 813 (M++H).
Anál, Calculado para C43H48N2O10SS1 ·2H20: C, 60,83; H, 6,17; N, 3,30. Determinado: C, 60,55; H, 5,78; N, 3,22. (5) Síntese de 3'-O-benzil-5'-O-t-butildifenil-silil-4'-p-toluenossulfoniloximetil-5-metiluridina (Composto 36)
Adicionaram-se carbonato de potássio (12,75 mg, 0,0923 mmol) e água (0,5 mL), sob arrefecimento com gelo, a uma solução em metanol (4 mL) do Composto 35 (250 mg, 0,308 mmol), e agitou-se a mistura durante 22 horas à temperatura ambiente. Sob arrefecimento com gelo, adicionou-se ácido acético à mistura reaccional para a neutralizar, e depois separou-se o solvente por destilação sob pressão reduzida. Depois de se adicionar água ao resíduo, extraiu-se a mistura com acetato de etilo. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Separou-se o solvente por destilação sob pressão reduzida, e purificou-se o produto em bruto resultante por cromatografia em coluna sobre gel (AcOEt-hexano, a 3:2) para se obter um pó branco, Composto 36 (216,7 mg, 0,283 mmol, 92%). p. f. . 74 - 77 °C. [a] d23 + 5,15° (c = 1,23, CHC13) . IV vmax (KBr) : 3048, 2934, 1695, 1363, 1181, 1108, 977, 819, 704 cm-1. 39 ΡΕ1013661 RMN de XH (CDCI3) δ: 1,05 (9H, s), 1, 65 (3H, d, J = 1 Hz) , 2,39 (3H, s), 3,04 (1H, d lg, J = 9 Hz) , 3, 72 (2H, s) t 4, 17 (2H, s) , 4,18 (1H, d, J = 5 Hz), 4,24 -4,32 (1H, m) f 4,54, 4, 62 (2H, AB, J = 11 Hz), 5,62 (1H , d, J = 6 Hz) , 7, 19 -7, 69 (2 0H , m) , 8,46 (1H, s lg) φ RMN 13C (CDC13) õc: 12,1, 19, 4, 26, 9, 58,8, 72,0, 72.2, 75,8, 76,7, 87,4, 88,8, 110,4, 127,7, 12,79, 128,1, 128.2, 128,5, 128,7, 129,8, 130,0, 130,1, 132,2, 134,3, 135.3, 135,5, 136,8, 149,8, 163,9. MS(FAB) m/z : 771 (N++H) .
Anál. Calculado para C41H46N2O9SSÍ: C, 63,41; H, 6,16; N, 3,51; S, 3,95.
Determinado: C, 63,87; H, 6,01; N, 3,63; S, 4,16. (6) Síntese de 3'-O-benzil-5'-O-t-butildifenil-silil-2'-O,4'-C-metileno-5-metiluridina (Composto 37)
Numa corrente de azoto, adicionou-se bis(trime-tilsilil) amideto de sódio (1,0 M em THF, 8,47 mL, 8,47 mmol), sob arrefecimento com gelo, a uma solução em tetra-hidrofurano (30 mL) do Composto 36 (1,86 g, 2,42 mmol), e agitou-se a mistura durante 1 hora à temperatura ambiente. Adicionou-se uma solução saturada de bicarbonato de sódio (14 mL) à mistura reaccional, e depois destilou-se o solvente sob pressão reduzida. Adicionou-se água ao resí- 40 ΡΕ1013661 duo, extraiu-se a mistura com clorofórmio. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Separaram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (AcOEt-hexano, 2:3) para se obter um pó branco, Composto 37 (1,42 g, 2,37 mmol, 98%). P.f. 7 0,5-72 °C. [a]D22+52.47 (c= 1,025, acetona). IV vmax (KBr) : 2936, 1694, 1465, 1275, 1106, 1055, 809, 7040101. RMN de 1H (CDC13 ) δ: 1,21 (9H, s) , 1,76 (3H 3, 88, 4,07(2H, AB, J = 8 Hz) , 4,07, 4,15 (2H, AB, J Hz) , 4,16 (1H, s), 4, 66, 4, 80 (2H, AB, J = 11 Hz), (1H, s), 7,34-7,79 (16H, m) , 10,0 (1H, s lg) . MS (FAB) m/z : 599 (M++H) .
Anál. Calculado para C34H38N206Si · 2H20: C, 64,33; H, 6,03; N, 4,41, Determinado: C, 64,58; H, 6,15; N, 4,28. (7) Sintese de 3'-O-benzil-2'-O,4'-C-metileno-5-metiluridina (Composto 38)
Em corrente de azoto, adicionou-se fluoreto de tetrabutilamónio (1,0 M em THF, 379 pL, 0,379 pmol) a uma solução em tetra-hidrofurano (1 mL) do Composto 37 (188,7 mg, 0,316 mmol), e agitou-se a mistura durante 2,5 horas à 41 ΡΕ1013661 temperatura ambiente. Destilou-se a mistura reaccional sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (AcOEt-hexano, 1:1-+1:0) para se obter um pó branco, Composto 38 (94,6 mg, 0, 262 itimol, 83%). IV vmax (KBr) : 3424, 3183, 3063, 2950, 1691, 1463, 1273, 1057, 7340101. RMN de XH (CDC13) δ: 1,90 ( 3H, d, J = 1 Hz) , 3, 83, . 4,05 (2H, AB, J = 8 Hz) , 3,93, 4 , 02 (2H, AB, J = 12 Hz) , 3,94 (1H, s), 4 ,53 (1H, s), 4,56, 4,58 (2H, AB, J = 12 Hz) , 5, 65 (1H, s) , 7,32 (5H, s) 1, 7,44 (1H, d, J = 1 Hz) . HRMS (EI): Calculado para Ci8H2oN06 (M+) : 360, 1321,
Determinado: 360,1312. (8) Síntese de 2'-O,4'-C-metileno-5-metiluridina (Composto 39a)
Adicionou-se a uma solução em álcool metílico (4 mL) do Composto 38 (86, 5 mg, 0,240 mmol) , Pd(0H)2 a 20 % sobre C (86,5 mg), e agitou-se a mistura durante 14,5 horas à pressão atmosférica em corrente de hidrogénio. Filtrou-se a mistura reaccional, e depois separou-se o solvente por destilação sob pressão reduzida para se obterem cristais incolores, Composto 39 (62,5 mg, 0,230 mmol, 96%).
p.f. 194-195°C. [a] D20 + 53, 7° (c =1,02, EtOH) . IV vmax (KBr) : 3323, 3163, 3027, 2889, 2826, 1689, 1471, 1276, 1057 cm1. 42 ΡΕ1013661 RMN de (CD3OD) δ: 1,89 (3H, q, J = 1 3,74, 3,95 (2H, AB, J = 8 Hz ), 3,90 (1H, s) , 4,07 (1H 4,26 (1H, s), 5,53 ( 1H, s) , 7,74 (1H, d, J = 1 Hz) RMN de 13C (CD3OD) õc: 12, 6, 57, 6, 70, 3, 72, 4, 80,8, 88,3, 90,4, 110,7, 136,8, 151,8, 166,5.
[Exemplo 4] (1) Síntese de 2'-O-acetil-3'-O-benzil-5'-O-t-butildifenilsilil-4'-p-toluenossulfoniloximetil-N6-benzoíladenosina (Composto 40)
Numa corrente de azoto, adicionaram-se uma solução em 1,2-dicloroetano (5,0 mL) do Composto 34 (250 mg, 0,336 mmol) e trifluorometanossulfonato de trimetilsililo (6,7 pL, 0,0336 mmol), à temperatura ambiente, a 2TMS*ABz (128,7 mg, 0,336 mmol) preparado de acordo com a referência 6) (H. Vorbrggen, K. Krolikiewicz e B. Bennua, Chem., Ber., 114, 1234-1255 (1981)). Aqueceu-se a mistura ao refluxo durante 26 horas. Depois de se adicionar uma solução saturada de bicarbonato de sódio à mistura reaccional, extraiu-se 3 vezes o sistema com cloreto de metileno. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Separaram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (CHCl3-MeOH, a 1:3) para se obter um pó branco, Composto 40 (234,5 mg, 0,253 mmol, 75%). 43 ΡΕ1013661 P.f. 77-7 8°C (AcOEt/hexano) . [oí]d24 - 13,2° (c = 1,00, CHC13) . IV vmax (KBr) : 3058, 2934, 1749, 1703, 1606, 1105 cm-1. RMN de 3H (CDCI3) δ: 0,99 ( 9H, s ), 2 ,04 (3H, s) , 2,38 (3H, s) , 3, 7 4, 3, 85 (2H, AB, J = 11 Hz) , 4,31, 4,43 (2H, AB, J = 11 Hz) , 4, 52, 4,58 (2H, AB, J = 11 Hz), 4,81 (1H, d, J = 6 Hz ) , 5, 94 (1H , d, J = 6 Hz) , 6, 04 (1H, d, J = 5 Hz' >, 7, 18 - 7, 61 ( 2 0H, m ), 7,69 (2H, d, J = 8 Hz) , 7,99 (1H, s), 8,01 (2H, d, J = 7 Hz), 8,56 (1H, s), 8,99 (1H, s ig) · RMN de 13C (CDCI3 ) δ: 19, 1, 2 0,5 , 21 ,5, 26 ,7, 64, 1 f 00 4,0, 74 ,6, 77, «·. to 00 σΤ 57, to co 64, 123, 4, 127 ,7, 127, 8, 127,9, 128 /1/ 128,5 , 128, 8, 129, 6, 129, 9, 132 ,0, 132, 3, 132,6, 132 ,7, 133, 5 , 135, 4, 135, 5, 136, 8, 142 ,0, 144, 7, 149, 6, 151, 2, 152,6, 164,5, 169,8. MS ( FAB) m/z : 926 (M++H) . (2) Síntese de 3'-O-benzil-5'-O-t-butildifenil-silil-4 ' -p-toluenossulfoniloximetil-N6-benzoíladenosina (Composto 41)
Adicionou-se a uma solução em metanol (3,0 mL) do Composto 40 (167,9 mg, 0,182 mmol), carbonato de potássio (15,0 mg, 0,109 mmol) à temperatura ambiente, e agitou-se a mistura durante 15 minutos à temperatura ambiente. Adicionou-se ácido clorídrico concentrado à mistura reaccional para a neutralizar, em seguida extraiu-se o sistema 3 vezes 44 ΡΕ1013661 com cloreto de metileno. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Removeram-se os solventes sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (CHC13-MeOH, a 30:1) para se obter um pó branco, Composto 41 (140,5 mg, 0,160 mmo1, 88%). P.f. 82-83°C (AcOEt-hexano) . [a]D25 - 6, 02° (c = 0,96, CHCI3) . IV vmax (KBr) : 3306, 3066, 2935, 2859, 1701, 1611 cm-1. RMN de XH (CDCI3) δ: 0,98 ( :9H, ; S) , 2,37 (3H, s ) , 3,76 (2H, s), 4, 39, 4,45 (1H, AB, J = 11 Hz) , 4,54 ( 1H, d, II 1~D Hz), 4,67, 4, 76 (2H, AB / J = 1 1 Hz) , 4 , 85 (1H, dd, J = 5, 6 Hz), 5 ,79 (1H, d, J = 5 Hz) , 7,20 - 7,58 (21H, m ) , 7,73 (2H, d, J = 8 Hz), 7,80 (1H, s ), 7, 96 (2H, d, J = 8 NI 8,49 (1H, s) , 9,18 (1H, s ig) . RMN de 13C (CDCI3) δ: 19, 1, 2 1, 6 , 26 ,8, 64, 4, 68,9, 74,1, 7 4, 6 , 7 9, 2, 86, 8, 89,8, 123, 127, 7, 127, 8, 128,0 , 128,2, 12 CO C\J \—1 00 128,8, 129, 7, 130, 0, 132, 1, 132,5 , 132,6, 132,8, 133,4, 135,4, 135, 5, 136, 8, 142, 1, 144,8 , 149,4, 152 ,3, 164,5. (3) Síntese de 3'-O-benzil-5'-O-t-butildifenil-silil-2 ' -0,4 ' -C-metileno-N6-benziladenosina (Composto 42)
Sob uma corrente de azoto, adicionou-se bis(tri- 45 ΡΕ1013661 metilsilil) amideto de sódio (1,0 M em THF, 0,58 mL, 0,572 mmol) a uma solução em tetra-hidrofurano (8,0 mL) do Composto 41 (210,5 mg, 0,238 mmol) à temperatura ambiente, e agitou-se a mistura durante 3 horas à temperatura ambiente. Adicionou-se uma solução saturada de bicarbonato de sódio à mistura reaccional, e depois extraiu-se o sistema 3 vezes com cloreto de metileno. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Destilaram-se os solventes sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (CHCI3-MeOH, a 30:1) para se obter um pó branco, Composto 42 (169,5 mg, 0,238 mmol, quant.). P .f . 80-81° C. IV ^max (KBr): 3259, 3064, 2932, 2858 , 1703, 1 607 cnf1. RMN de 1H (CDC13) δ: 1,07 (9H, s), 3,95, 4, 10 (2H, AB, J = 8 Hz) , 4, 02 (2H, d, J = 8 Hz), 4,56, 4, 64 (2H, AB, J = 12 Hz), 4,26 ( 1H, s ), 4,86 (1H, s ), 6,14 (1H, S) , 7,26 - 7, ,70 (18H , m) , 8,04 (2 H, d, J = 7 Hz) , 8,22 (1H, s) , 8, 78 (1H, s) , 9,18 (1H, s lg) . RMN de 13C (CDCI3) δ: 19,2, 26,5 , 26,8, 29, 7 59,2, 72,4, 72 , 6, 7 6, 5, 76, 8, 86,7, 88,6, 123,4, 127,7 127,8, 127,9, 128,1, 128,4, 128,8, 129, 5, 130,0, 132,4 132,5, 132,8, 133,5, 134,8, 135,2, 135,5, 135,6, 136, 8 140,4, 152,7. 46 ΡΕ1013661 (4) Síntese de 3'-O-benzil-2'-O,4'-C-metileno-N6-benzoíladenosina (Composto 43)
Adicionou-se fluoreto de tetrabutilamónio (1,0 M em THF, 1,0 mL, 1,0 mmol) , à temperatura ambiente, a uma solução em tetra-hidrofurano (7,0 mL) do Composto 42 (173,6 mg, 0,244 mmol), e agitou-se a mistura durante 25 minutos à temperatura ambiente. Destilou-se a mistura reaccional sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (CHC13-MeOH, 15:1) para se obter um pó branco, Composto 43 (115,4 mg, 0,244 mmol, quant.). p.f. 154 - 155°C (Et20) . IV vmax (KBr) : 3339, 2944, 1701, 1611 cm-1. RMN de 1H (CDC13) δ: 3, 91, 4,13 ( 2H, AB, J = 8 Hz) , 3, 93 , 4, 01 (2H, , AB, J = 12 Hz) , 4,38 (1H , s) r 4, 64 (1H, s) t 4,85 (1H, s) , 6,08 l :ih, s) , 7,29 (1H, , s) r 7,51 (2H, d, J = 8 Hz), 7, ,58 (1H, d, j = 7 Hz), 8, , 05 (2H, d, J = 7 Hz), 8,14 (1H, s), 8,75 (1H, s), 9,50 (1H, s lg). RMN de 13C (CDC13) δ: 57,1, 72,4, 77, 0, 77, 1, 86, 9, 88, 6, 122,9, 127, 6, 128,0, 128,1, 128,4, 128,7, 132,8, 133, 5, 136, 9, 140, 5, 149, 8, 150, 5, 152, 8, 165, 0. 47 ΡΕ1013661 [Exemplo 5] (1) Síntese de 2'-0-acetil-3'-0-benzil-5'-0-t-butildifenilsilil-4'-p-toluenossulfoniloximetil-N2-isobutirilguanosina (Composto 44)
Sob uma corrente de azoto, adicionou-se uma solução em 1,2-dicloroetileno (5,0 mL) do Composto 4 (250 mg, 0,336 mmol) e trifluorometanossulfonato de trimetilsililo (6,7 pL, 0, 0336 mmol), à temperatura ambiente, a 3TMS*GlBu (146,8 mg, 0,336 mmol) preparado de acordo com a referência 6 mencionada acima). Aqueceu-se a mistura ao refluxo durante 15 horas. Em seguida adicionou uma solução saturada de bicarbonato de sódio à mistura reaccional, extraiu-se o sistema 3 vezes com cloreto de metileno. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Separaram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (CHCl3-MeOH, a 30:1) para se obter um pó branco, Composto 44 (213,6 mg, 0,235 mmol, 70 %). P. f. 96-97°C (AcOEt-hexano). [«]d24° -11,09° (c = 0, 97, CHC13) . IV vmax (KBr) : 3152, 3065 , 2934 , 1746, 1681, 160 6 cm 1. RMN de XH (CDCI3) δ: 0,96 (9H, s), 1 .,10 (3H, d, J = 9 Hz), 1, 13 (3H, d, J = 9 Hz), 1,98 (3H, s), 2,36 (3H, s), 2,48 (1H, m), 3,65, 3, 72 (2H, AB, J = 11 Hz), 4,23, 4,43 (2H, AB, J = 11 Hz), 4 ,47 (2H, s), 4, 63 (1H, d, J = 6 48 ΡΕ1013661
Hz) , 5 ,74 (1H , t, J = 6 Hz) , 5,96 (1H, d, J = 6 Hz), 7, 14 - 7,68 ( 20H, m) , 9,15 (1H, s) , 12, 2 :o (1H, s) . RMN de 13C (CDCI3) δ: 19 ,1, 19, 3, 19,4, 20, 8, 21,9, 27,0, 27,2, 36, 5, 64,5, 68 ,9, 74, 4, 74,9, 76, 7, 86,1, 86,7, 122,0, 127,6, 12 7, 7, 127 ,9, 128,1, 128, 3, 128,4, 128,8, 130, 1, 130, 4, 132, -3, 132 ,7, 132,9, 135, 7, 135,8, 137,3, 137, 8, 145, 2, 147, -8, 148 ,5, 156,2, 170, 2, 178,8. (2) Síntese de 3'-O-benzil-5'-O-t-butildifenilsi-lil-4 ' -p-toluenossulfoniloximetil-N2-isobutirilguanosina (Composto 45)
Adicionou-se a uma solução em álcool metilico (3,0 mL) do Composto 44 (137,0 mg, 0,151 mmol), carbonato de potássio (15,8 mg, 0,113 mmol), à temperatura ambiente, e agitou-se a mistura durante 45 minutos à temperatura ambiente. Adicionou-se ácido clorídrico concentrado à mistura reaccional para a neutralizar, e em seguida extraiu-se o sistema por 3 vezes com cloreto de metileno. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Separaram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (CHCl3-MeOH, 30:1) para se obter um pó branco, Composto 45 (83,4 mg, 0,097 mmol, 64%). p.f. 102-103°C (AcOEt-hexano) [a]D25 -2,00° (c = 0,40, CHC13) . IV vmax( KBr) : 3166, 2932, 1684, 1607 cm-1. 49 ΡΕ1013661 RMN de 1H (CDCI3) δ: 0, 90 ( 9H, s) , 1, 09 (3H, d , J = 7 Hz) , 1,13 (3H, d, J = 7 Hz), 2, , 30 (1H, , m ), 2,37 ( 3H, s) , 3, 71, 3,76 (2H, AB, J = = 11 Hz) , L 1,32, 4, 48 (2H, AB , J = 11 Hz) , 4 ,35 (1H, d , J = 6 Hz) , 4,63 , 4, 90 (2H , AB, J = 12 Hz) , 4 , 96 (1H, t, J = 6 H z) , 5,67 ( 1H, d, J = 7 Hz) , 7 ,17 - 7, 71 (21 OH, m) , 8, í 32 (1H, s) , 12,05 (1H, s Ig) • RMN de 13C (CDCI3) δ: 18,7, 19,0, , 21,6, 26, 5, 36 ,2, 63, 5 f 69, 1, 73,7, 74,3, 78,8 , 86,2 , 89,5, 127,7, 127 ,8, 128, 0, 12 : 8, 1, 128,. 5, 129, 7, 130,0, 132 '! 0, 132,6, 132 ,7, 135, 3, 135,4, 137,4, 138,2, 144 ,8, 146 5,9, 155 ,5, 178,5. (3) Síntese de 3'-O-benzil-5'-O-t-butildifenilsi-lil-2 ' -0,4 ' -C-metileno-N2-isobutirilguanosina (Composto 46)
Sob uma corrente de azoto, adicionou-se bis (tri-metilsilil) amideto de sódio (1,0 M em THF, 0,31 mL, 0,315 mmol) a uma solução em tetra-hidrofurano (3,0 mL) do Composto 45 (92,1 mg, 0,102 mmol), à temperatura ambiente, e agitou-se a mistura durante 3 horas à temperatura ambiente. Adicionou-se uma solução saturada de bicarbonato de sódio à mistura reaccional, e depois extraiu-se o sistema por 3 vezes com cloreto de metileno. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Removeram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (CHCI3, MeOH, a 25:1) para se obter um pó branco, Composto 46 (31,4 mg, 0,160 mmol, 44%). 50 ΡΕ1013661 p.f. 99-100 °C. IV vmax (KBr) : 3162, 3068, 2932, 1683, 1610 cnf1. RMN de 3H (CDC13) δ: 1,0 6 (9H, s), 1,25 (3H , d , J = 7 Hz :) , 1,27 (3H, d, J = 7 Hz) , 2,64 (1H, m) , 3 , 83 , 4 ,01 (2H, AB, J = 8 Hz) , 3, 97 ( 2H, d, J = 7 Hz), 4,18 (1H, s) , 4,51 ( 1H, s) , 4,54 (2H , d, J = 2 Hz), 5,77 (1H, s) , 7, 17- 7,42 ( 5H, m) , 7, 64 - ' 7, 72 ( 10H , m) , 7,84 (1H, s) , 9,03 ( 1H, s) , 12 , 08 (1H, s lg) • RMN de 13( C ( :cdci 3) δ: 18,9, 19,0 , 19, a, 26 ,5, 26, 7 t 36, , 4, 59,1, 72, 4, 72, 5, 76, 8, 77,5 , 86, ,3, 88 ,3, 121, 7, 12 !7, 6, 127,7 , 127, 8, 127 ,9, 128,1, 128, 4, 129 ,6, 130, o, 132,36, 132,42, 134, 8, 135, 45, 135, 54, 135, 8, 136 ,8, 146, 8, 14 7,7, 155,4, 17 8, 6. (4) Síntese de 3'-O-benzil-2'-O,4'-C-metileno-N2-isobutirilguanosina (Composto 47)
Adicionou-se fluoreto de tetrabutilamónio (1,0 M em THF, 0,90 mL, 0,90 mmol), à temperatura ambiente, a uma solução em tetra-hidrofurano (3,0 mL) do Composto 46 (41,3 mg, 0,060 mmol), e agitou-se a mistura durante 1 hora à temperatura ambiente. Destilou-se a mistura reaccional sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (AcOH-EtOH, a 20:1) para se obter um pó branco, Composto 47 (27,1 mg, 0,060 mmol, quant.). 51 ΡΕ1013661 P. f. 228 - 229°C (Et20) . [a] d25 +32,90° (c = 0, 875 , CHCls) . IR v max (KBr) : 3162 , 2934, 1683, 1608 cnT1. RMN de 1H (CDC13) δ: 1,24 (3H, d, J = 7 Hz), 1,26 (3H, d, J = 7 Hz), 2, 76 (1H, m) , 3, 83, 4,03 1 I2H, AB, J = 8 Hz) , 3,92, 4, 02 (2H, AB, J = 13 Hz), 4,33 (1H, s), 4,55 (1H, s), 4,62 (2H, s ), 5,80 (1H, s), 7,25 (5H, s), 7,91 (1H, s) , 9,85 (1H, s), . 12,05 (1H, s) . RMN de 13C (CDCI3) δ: 19,19, 19,25 , 36,4, 57,4, 72,5, 77, 0, 77,5, 86, 5, 88,8 , 121,0, 127,8, 128,1, 128,2, 128,3 , 128,4, 128,6, 137,1, 137,5, 147,5, 148,2, 155,7, 179,9.
[Exemplo de Referência 1] Síntese de um análogo de um oligonucleótido
CMTQ
J&, 'RÍ
1 Sinfetizader de AON
Diversos Anâiops Olqomdã駱s de P · "rM 21
$'-&asxrmT9CTx3' pera s^csrrxmscT^· rrsxrsj y^csrmsTFscT-y rrssní r-acGTTTmfQCT,3< ítss} s^csxxrmàcr^ ^ecsrnocrrscT-y h&aim s'-<jCsmTxxQCT-a’ í?mi «‘-scaxxtxxxscT-y im sN^TmTTTradc^ 'pes 52 ΡΕ1013661 (1) 3'-O-[2-cianoetoxi(di-isopropilamino)fosfi- no]-5'-O-(4,4'-dimetoxitritil)-2'-0,4'-metano-uridina (Composto 21)
Submeteram-se a uma destilação azeotrópica o Composto 8 (200 mg, 0,31 mmol) tetrazolido de di- isopropilamónio (39,6 mg, 0,23 mmol) com CH3CN anidro, três vezes, e depois transformou-se o sistema numa solução em CH3CN anidro-THF anidro (a 3:1, 4 mL) . Numa corrente de azoto, adicionou-se 2-cianoetil-N,N,Ν',Ν'-tetraisopropil-fosforodiamidito (0,12 mL, 0,37 mmol), e agitou-se a mistura durante 90 minutos à temperatura ambiente. Separaram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto resultante em bruto por croma-tografia em coluna sobre silicagel (AcOEt:hexano:Et3N = 75:25:1). Em seguida, voltou a precipitar-se o produto purificado a partir de AcOEt-hexano para se obter um composto amidito, 21 (181 mg, 0,25 mmol, 81%). P.f. 71-74°C (AcOEt-hexano). RMN de 31P (CDC13) : δ 149, 6, 149, 5, 149, 4, 149, 3, 149,2. (2) Síntese geral de análogos de oligonucleótidos A síntese de um oligómero foi conduzida recorrendo ao sintetizador de ADN da Pharmacia, Gene Assembler 53 ΡΕ1013661
Plus, a uma escala de 0,2 pmol. As concentrações de solventes, reagentes, e fosforamidito eram as mesmas que se utilizaram para a síntese de ADN natural. Desprotegeu-se um grupo DMTr da 5'-O-DMTr-timidina (0,2 pmol) contendo um grupo 3'-hidroxilo ligado a um suporte CPG, com ácido tricloroacético. No seu grupo 5'-hidroxilo, repetiu-se a reacção de condensação utilizando um amidito que incluía quatro bases para síntese de ácido nucleico de ADN natural e Composto 21, para se sintetizarem análogos oligonucleo-tídicos das sequências respectivas. O ciclo sintético era como se segue:
Ciclo sintético (escala de 0,2 ymole) 1) Destritilação 2) Acoplamento 3) Terminação 4) Oxidação 1% de CCI3COOH em CH2C1CH2C1, 6 s fosforamidito 0,1 M (25 equiv.), lH-tetrazole 0,5 M (500 equiv.) em MeCN, 2 minutos 3% de 4-(dimetilamino)piridina, 10 % de Ac2Oi em MeCN, 18 s I2 0,01 M em 2,4,6-colidina/H20/ MeCN (1:5:11), 6 s
Clivou-se o oligómero sintetizado do suporte por tratamento com solução aquosa concentrada de amoníaco, do modo habitual. Ao mesmo tempo, clivou-se o grupo protector cianoetilo do átomo de fósforo, e também se removeram os grupos protectores das adenina, guanina e citosina. 54 ΡΕ1013661
Retirou-se ao análogo de oligonucleótido 5'-0-dimetoxitritilado o grupo DMTr usando 5 mL de ácido trifluoroacético numa coluna cromatográfica de fase reversa (Millipore, 01igo-Pak™SP) , e purificou-se mais para se obter o análogo de oligonucleótido pretendido.
De acordo com o método geral de síntese acima, sintetizaram-se os seguintes oligonucleótidos: (2) 5'-GCGXTTTTTGCT-3' (XT5)
Rendimento 0,06 pmole (rendimento de 30%) (3) 5'-GCGTTXTTTGCT-3' (T2XT3)
Rendimento 0,05 pmole (rendimento de 25%) (4) 5'-GCGTTTXTTGCT-3' (T3XT2)
Rendimento 0,03 pmole (rendimento de 15%) (5) 5'-GCGTTTTTXGCT-3' (T5X)
Rendimento 0,06 pmole (rendimento de 30%) (6) 5'-GCGXXTTTTGCT-3' (X2T4)
Rendimento 0,06 pmole (rendimento de 30%) (7) 5'-GCGTTXXTTGCT-3' (T2X2T2)
Rendimento 0,05 pmole (rendimento de 25%) (8) 5'-GCGTTTTXXGCT-3' (T4X2)
Rendimento 0,06 pmole (rendimento de 30%) (9) 5'-GCGXXXXXXGCT-3' (X6)
Rendimento 0,06 pmole (rendimento de 30%) (10) -5'-GTTTTTTTTXXC-3' (X2)
Rendimento 0,07 pmole (rendimento de 35%) 55 ΡΕ1013661 [Exemplo de Referência 2] Medição da temperatura de fusão (Tm)
Mediram-se as temperaturas de fusão (Tm) dos produtos de recozimento entre as estirpes de sentido reverso, que eram os diversos análogos de oligonucleótidos sintetizados no Exemplo 2, e cadeias baseadas em ADN ou ARN naturais de sentido directo, para se investigar a capacidade hibridizante doa análogos a oligonucleótidos da invenção presente para ADN e ARN complementares.
Cada solução de amostra (500 pL) com concentrações finais de 100 mM em NaCl, 10 mM em tampão de fosfato de sódio (pH 7,2), 4 μΜ em cadeia de sentido reverso, e 4 μΜ em cadeia de sentido directo, respectivamente, foi banhada em água a ferver, e lentamente arrefecida até à temperatura ambiente ao longo de 10 horas. Arrefeceu-se a solução de amostra gradualmente até 5°C, manteve-se a 5°C durante mais um período de 20 minutos, e depois começou a medir-se, passando-se uma corrente de azoto através da câmara com a célula de um espectrofotómetro (UV-2100PC, Shimadzu) para evitar a condensação de humidade. Aumentou-se a temperatura a uma taxa de 0,2°C/minuto até aos 90°C, e mediu-se a absorção no ultravioleta a 260 nm a intervalos de 0,1°C. Para evitar alterações da concentração das amostras com os aumentos de temperatura, a célula tinha uma tampa, e aplicou-se uma gota de óleo mineral sobre a superfície da solução de cada amostra durante a medição. ΡΕ1013661 56
Os resultados estão listados na tabela seguinte.
Tabela 1 Temperaturas de fusão (Tm) de Análogos de Oligonu-cleótidos de sentido reverso para ADN e ARN Complementares
Molécula de sentido reverso Tm para o ADNa> complementar (ATm/mod.) Tm para o ARNb) complementar (ATm/mod.) 5'-GCGTTTTTTGCT-3’ (natural) O O 45°C 5'-GCGXTTTTTGCT-3' (XT5) 50°C (+3°C) 49°C ( + 4 °C) 5'-GCGTTXTTTGCT-3' (T2XT3) 49°C ( + 2 °C) 49°C ( + 4 °C) 5’-GCGTTTXTTGCT-3' (T3XT2) 49°C ( + 2 °C) 50°C (+5°C) 5'-GCGTTTTTXGCT-3’ (T5X) 52 °C ( + 4 °C) 51°C (+6°C) 5'-GCGXXTTTTGCT-3' (X2T4) 51°C (+2 °C) 53°C (+4°C) 5'-GCGTTXXTTGCT-3’ (T2X2T2) 49°C (+1°C) 53°C ( + 4 °C) 5'-GCGTTTTXXGCT-3' (T4X2) 54 °C (+3,5°C) 55°C (+5°C) 5'-GCGXXXXXXGCT-3' (X6) 58 °C ( + 1,8 °C) 71.°C (+4,3°C) a): 3'-CGCAAAAAACGA-5' . b) : 3 ' -r(CGCAAAAAAC
Tal como se ilustra na tabela, no caso do oligómero contendo uma ou duas unidades (X) do análogo de nucleósido da invenção presente (fórmula geral (Ia)) introduzidas numa cadeia de ADN natural, a capacidade de se hibridizarem com o oligómero de ADN complementar, avaliada através da Tm, aumentou 2 a 7 graus (cerca de 2 graus por resíduo modificado) em comparação com a cadeia natural. Com o oligómero com todos os T substituídos por X (X6), o 57 ΡΕ1013661 aumento da capacidade foi tão elevado como 11 graus. Quando a capacidade de se hibridizar com o ARN complementar foi avaliada, o oligómero que incorporava um ou dois X apresentava um aumento em Tm de 4 - 10 graus (4 a 6 graus por resíduo modificado) ao longo da cadeia modificada. No caso de X6, a capacidade de se hibridizar com o ARN complementar era mais aumentada, mostrando um aumento de Tm de mais do que 25 graus (4 graus por resíduo modificado) . Não houve nenhum exemplo de análogos sofrendo estes aumentos em Tm em comparação com estirpes naturais, e a afinidade do oligómero era maior para o ARN do que para o ADN. Estes factos significam que o análogo de oligonucleótido constituído pelo análogo de biciclo-oligonucleósido da invenção presente tem um desempenho extremamente elevado a título de molécula de sentido reverso, e é útil como material para produtos farmacêuticos.
[Exemplo de Referência 3] Medição da resistência à nuclease
Misturou-se uma solução tampão (0,003 U/mL, 400 pL) de uma fosfodiesterase de um veneno de cobra com uma solução tampão (10 μΜ, 400 pL) do oligonucleótido mantendo-se a 37 °C durante 15 minutos. Colocou-se a mistura de soluções numa células em quartzo (800 pL) mantida a 37°C, e mediram-se os aumentos na absorção no ultravioleta (a 260 nm) devidos á decomposição do oligonucleótido ao longo do tempo usando um SHIMADZU UV-2100PC. O tampão utilizando incluía Tris-HCl 0,1 M (pH 8,6), NaClO,1 M, e MgCl2 14 mM, e foi suficientemente desgaseifiçado antes da medição. ΡΕ1013661 58
Medição da vida média (11/2) :
Calculou-se a média dos valores da absorção no UV medidos no inicio da medição (t=0) e a média medida na altura em que não se notou qualquer aumento deste parâmetro. 0 período correspondente a esta média foi designado como vida média (11/2) ·
Sequência de Oligonucleótido_ti/2 (segundos) 5’-GTTTTTTTTTTTC-3' (de tipo natural) 260 5’-GTTTTTTTTT-XX-C-3' (X2) 850
Apresentam-se a título de Fig. 1 gráficos mostrando o decurso temporal da absorção no ultravioleta (cadeia natural) e também na Fig. 2 (X2) . A absorção no ultravioleta atingiu um patamar em cerca de 30 minutos para a estirpe natural, e em cerca de 90 minutos para X2, após iniciação da reacção enzimática.
APLICABILIDADE INDUSTRIAL A utilização deste análogo proporciona um análogo de um oligonucleótido, molécula de sentido reverso, que é minimamente hidrolisável com um enzima em vivo, tem uma elevada capacidade para se ligar a uma cadeia de sentido directo, e se sintetiza facilmente. 59 ΡΕ1013661
Listagem de Sequências
Nome do requerente: Takeshi Imanishi
Titulo da invenção: Biciclonucleósido novo e análogo de oligonucleótido Referência N.°:
Pedido N.°:
Data do pedido: Março, 1998 Prioridade N.°: JPA 53409/97 Data de prioridade: 7 de Março, 1997 Número de sequências: 11 N.° ID Seq.: 1
Comprimento da sequência: 12 Tipo de sequência: Nucleótido Número de cadeias: Cadeia simples Topologia: Linear Sequência: 5'-GCGTTTTTTGCT-3' N.0 ID Seq.: 2
Comprimento da sequência: 12
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples Topologia: Linear Sequência: 5'-GCGXTTTTTGCT-3' N.° ID Seq.: 3
Comprimento da sequência: 12
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples 60 ΡΕ1013661
Topologia: Linear Sequência: 5'-GCGTTXTTTGCT-3' N.° ID Seq.: 4
Comprimento da sequência: 12
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples Topologia: Linear Sequência: 5'-GCGTTTXTTGCT-3' N.° ID Seq.: 5
Comprimento da sequência: 12
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples Topologia: Linear Sequência: 5'-GCGTTTTTXGCT-3' N.° ID Seq.: 6 Comprimento da sequência: 12
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples Topologia: Linear Sequência: 5'-GCGXXTTTTGCT-3' N.° ID Seq.: 7
Comprimento da sequência: 12
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples Topologia: Linear 61 ΡΕ1013661
Sequência: 5' 1-GCGTTXXTTGCT-3' N.0 ID Seq.: 8
Comprimento da sequência: 12
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples Topologia: Linear
Sequência: 5' 1-GCGTTTTXXGCT-3’ N.° ID Seq.: 9
Comprimento da sequência: 12
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples Topologia: Linear
Sequência: 5' 1-GCGXXXXXXGCT-3' N.° ID Seq.: 10
Comprimento da sequência: 13
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples Topologia: Linear
Sequência: 5' ,-gtttttttttttc-3' N.0 ID Seq.: 11
Comprimento da sequência: 13
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples Topologia: Linear Sequência: 5' -GTTTTTTTTXXTC-3' 62 ΡΕ1013661
Listagem de Sequências <110> <12 0> <130> Imanishi, Takeshi Biciclonucleósido inovador e análogo de oligonucleótido <14 0> <141> <150> <151> <160> 98905804.5 1998-03-09 JPA 53409/97 1997-03-07 11 <210> <211> 1 12
<212> ADN <213> <22 0> <221> <222> <223> Sequência Artificial Λ o o V gcgttttttgct <210> 2 <211> 12
<212> ADN <213> <22 0> Sequência Artificial <221> <222> <223> base modificada <400> gcgntttttgct <210> <211> 3 12
<212> ADN
<213> <22 0> Sequência Artificial <221> <222> <223> base modificada <400> gcgttntttgct <210> <211> 4 12 <212> <213> <22 0> <221> ADN Sequência Artificial <222> <223> base modificada <400> gcgtttnttgct <210> <211> 5 12 <212> ADN 63 ΡΕ1013661 <213> Sequência Artificial <22 0> <221> base modificada <222> <223> <400> gcgtttttngct
<210> 6 <211> 12 <212> ADN <213> Sequência Artificial <22 0> <221> <222> base modificada <223> <400> gcgnnttttgct
<210> 7 <211> 12 <212> ADN <213> Sequência Artificial <22 0> <221> <222> base modificada <223> <400> gcgttnnttgct
<210> 8 <211> 12 <212> ADN <213> Sequência Artificial <22 0> <221> <222> base modificada <223> <400> gcgttttnngct
<210> 9 <211> 12 <212> ADN <213> Sequência Artificial <22 0> <221> <222> base modificada <223> <400> gcgnnnnnngct
<210> 10 <211> 13 <212> ADN <213> Sequência Artificial <22 0> <221> <222> <223> 64 ΡΕ1013661 Λ o o V gtttttttttttc <210> 11 <211> 13 <212> ADN <213> Sequência Artificial <22 0> <221> <222> base modificada <223> Λ o o V gttttttttnntc
Lisboa, 15 de Março de 2012
Claims (16)
- ΡΕ1013661 1 REIVINDICAÇÕES 1. Um análogo do nucleósido com a fórmula geral (I) seguinte(D em que B seja uma base de ácido nucleico de pirimidina ou de purina, ou um seu análogo, e X e Y sejam idênticos ou diferentes, e cada um destes representa um átomo de hidrogénio, um grupo alquilo, um grupo alcenilo, um grupo alcinilo, um grupo cicloalquilo, um grupo aral-quilo, um grupo arilo, um grupo acilo, ou um grupo sililo, ou um seu derivado de amidito.
- 2. Um análogo de nucleósido de acordo com a reivindicação 1, em que a base de ácido nucleico de pirimidina ou de purina seja seleccionada de entre tiamina, uracilo, citosina, adenina, guanina, ou um seu derivado.
- 3. Um análogo de nucleósido de acordo com a reivindicação 1, em que a base de ácido nucleico de pirimidina ou de purina seja tiamina, ou um seu derivado.
- 4. Um análogo de nucleósido de acordo com a 2 ΡΕ1013661 reivindicação 1, em que a base de ácido nucleico de pirimidina ou de purina seja uracilo, ou um seu derivado.
- 5. Um análogo de nucleósido de acordo com a reivindicação 1, em que a base de ácido nucleico de pirimidina ou de purina seja citosina, ou um seu derivado.
- 6. Um análogo de nucleósido de acordo com a reivindicação 1, em que a base de ácido nucleico de pirimidina ou de purina seja adenina, ou um seu derivado.
- 7. Um análogo de nucleósido de acordo com a reivindicação 1, em que a base de ácido nucleico de pirimidina ou de purina seja guanina, ou um seu derivado.
- 8. Um análogo de nucleósido de acordo com qualquer uma das reivindicações 1-3 com a fórmula geral (li) seguinteem que B seja uma base de ácido nucleico de pirimidina ou de purina, ou um seu análogo, e X e Y sejam idênticos ou diferentes, e cada um destes representa um átomo de hidrogénio, um grupo alquilo, 3 ΡΕ1013661 um grupo alcenilo, um grupo alcinilo, um grupo cicloal-quilo, um grupo aralquilo, um grupo arilo, um grupo acilo, ou um grupo sililo, ou um seu derivado; em que a referida base de ácido nucleico de pirimidina ou de purina seja timina.
- 9. Um análogo de nucleósido de acordo com qualquer uma das reivindicações 1, 2 e 4 com a fórmula geral (Iii) seguinteem que B seja uma base de ácido nucleico de pirimidina ou de purina, ou um seu análogo, e X e Y sejam idênticos ou diferentes, e cada um destes representa um átomo de hidrogénio, um grupo alquilo, um grupo alcenilo, um grupo alcinilo, um grupo cicloalquilo, um grupo aralquilo, um grupo arilo, um grupo acilo, ou um grupo sililo, ou um seu derivado de amidito; em que a referida base de ácido nucleico de pirimidina ou de purina seja uracilo.
- 10. Um análogo de nucleósido de acordo com qualquer uma das reivindicações 1, 2 e 5 com a fórmula geral (Iiii) seguinte 4 ΡΕ1013661em que B seja uma base de ácido nucleico de pirimidina ou de purina, ou um seu derivado, e X e Y sejam idênticos ou diferentes, e cada um destes representa um átomo de hidrogénio, um grupo alquilo, um grupo alcenilo, um grupo alcinilo, um grupo ciclo-alquilo, um grupo aralquilo, um grupo arilo, um grupo acilo, ou um grupo sililo, ou um seu derivado de amidito; em que a referida base de ácido nucleico de pirimidina ou de purina seja citosina.
- 11. Um análogo de nucleósido de acordo com qualquer uma das reivindicações 1, 2 e 6 com a fórmula geral (Iiv) seguinteem que B seja uma base de ácido nucleico de pirimidina ou de purina, ou um seu derivado, e 5 ΡΕ1013661 X e Y sejam idênticos ou diferentes, e cada um destes representa um átomo de hidrogénio, um grupo alquilo, um grupo alcenilo, um grupo alcinilo, um grupo cicloal-quilo, um grupo aralquilo, um grupo arilo, um grupo acilo, ou um grupo sililo, ou um seu derivado de amidito; em que a referida base de ácido nucleico de pirimidina ou de purina seja adenina.
- 12. Um análogo de nucleósido de acordo com qualquer uma das reivindicações 1, 2 e 7 com a fórmula geral (Iv) seguinteem que B seja uma base de ácido nucleico de pirimidina ou de purina, ou um seu derivado, e X e Y sejam idênticos ou diferentes, e cada um destes representa um átomo de hidrogénio, um grupo alquilo, um grupo alcenilo, um grupo alcinilo, um grupo cicloal-quilo, um grupo aralquilo, um grupo arilo, um grupo acilo, ou um grupo sililo, ou um seu derivado de amidito; em que a referida base de ácido nucleico de pirimidina ou de purina seja guanina. 6 ΡΕ1013661
- 13. Um análogo de nucleósido tal como se reivindica em qualquer uma das reivindicações 1 a 12, em que X e Y representem cada qual um átomo de hidrogénio.
- 14. Um análogo de nucleósido tal como se reivindica em qualquer uma das reivindicações 1 a 12 que seja um derivado de amidito de mononucleósido, em que X seja 4,4-dimetoxitritilo (DMTr), e Y seja um grupo 2-cianoetoxi(di-isopropilamino)fosfino (grupo amidito).
- 15. Um análogo de nucleósido tal como se reivindica na reivindicação 1, em que o grupo aralquilo seja seleccionado de entre tritilo, benzilo, fenetilo, tritil-metilo, difenilmetilo, naftilmetilo e 4,4'-dimetoxitritilo (DMTr).
- 16. Um análogo de nucleósido de acordo com a reivindicação 1 que seja seleccionado de entre os seguintes :ΡΕ1013661 7 οTBDPSOv. . »Βη 37:Β-Τ 42:3mABx 4β: 8=G®U 38: Β=Τ 43: ΒβΑ®* 47: B-G10" 39a: Β«=Τ 39b: BaA02 39c: BaGíaj Lisboa, 15 de Março de 2012
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| JP5340997 | 1997-03-07 |
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| PT101729713T PT2295441E (pt) | 1997-03-07 | 1998-03-09 | Novo biciclonucleosido e análogo de oligonucleotido |
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| EP (3) | EP2361921B1 (pt) |
| JP (1) | JP3756313B2 (pt) |
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| AU (1) | AU720472B2 (pt) |
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| DE (1) | DE98905804T1 (pt) |
| DK (3) | DK1013661T4 (pt) |
| ES (3) | ES2485716T3 (pt) |
| PT (2) | PT1013661E (pt) |
| WO (1) | WO1998039352A1 (pt) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5859221A (en) * | 1990-01-11 | 1999-01-12 | Isis Pharmaceuticals, Inc. | 2'-modified oligonucleotides |
| JPH0953409A (ja) † | 1995-08-15 | 1997-02-25 | Mitsubishi Heavy Ind Ltd | ガスタービン用セラミック静翼 |
| GB9612600D0 (en) * | 1996-06-13 | 1996-08-21 | Ciba Geigy Ag | Chemical compounds |
| JP3756313B2 (ja) † | 1997-03-07 | 2006-03-15 | 武 今西 | 新規ビシクロヌクレオシド及びオリゴヌクレオチド類縁体 |
| EP1015469B2 (en) | 1997-09-12 | 2015-11-18 | Exiqon A/S | Bi- and tri-cyclic nucleoside, nucleotide and oligonucleoide analogues |
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1998
- 1998-03-06 JP JP05511498A patent/JP3756313B2/ja not_active Expired - Lifetime
- 1998-03-09 ES ES10172971.3T patent/ES2485716T3/es not_active Expired - Lifetime
- 1998-03-09 AU AU61209/98A patent/AU720472B2/en not_active Expired
- 1998-03-09 AT AT98905804T patent/ATE541576T2/de active
- 1998-03-09 CA CA002283509A patent/CA2283509C/en not_active Expired - Lifetime
- 1998-03-09 DE DE98905804T patent/DE98905804T1/de active Pending
- 1998-03-09 PT PT98905804T patent/PT1013661E/pt unknown
- 1998-03-09 EP EP10011863.7A patent/EP2361921B1/en not_active Expired - Lifetime
- 1998-03-09 PT PT101729713T patent/PT2295441E/pt unknown
- 1998-03-09 DK DK98905804.5T patent/DK1013661T4/en active
- 1998-03-09 ES ES10011863.7T patent/ES2545211T3/es not_active Expired - Lifetime
- 1998-03-09 DK DK10011863.7T patent/DK2361921T3/en active
- 1998-03-09 EP EP10172971.3A patent/EP2295441B1/en not_active Expired - Lifetime
- 1998-03-09 EP EP98905804.5A patent/EP1013661B2/en not_active Expired - Lifetime
- 1998-03-09 WO PCT/JP1998/000945 patent/WO1998039352A1/ja not_active Ceased
- 1998-03-09 DK DK10172971.3T patent/DK2295441T3/da active
- 1998-03-09 ES ES98905804T patent/ES2380354T5/es not_active Expired - Lifetime
- 1998-03-09 US US09/380,638 patent/US6268490B1/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| EP2361921A3 (en) | 2012-06-27 |
| US6268490B1 (en) | 2001-07-31 |
| ES2380354T5 (es) | 2019-04-02 |
| ES2380354T3 (es) | 2012-05-10 |
| ES2545211T3 (es) | 2015-09-09 |
| DK1013661T4 (en) | 2019-01-21 |
| EP2295441A3 (en) | 2011-10-26 |
| EP2295441B1 (en) | 2014-05-07 |
| CA2283509A1 (en) | 1998-09-11 |
| EP2361921A2 (en) | 2011-08-31 |
| EP1013661B1 (en) | 2012-01-18 |
| HK1154590A1 (en) | 2012-04-27 |
| EP2361921B1 (en) | 2015-06-03 |
| AU720472B2 (en) | 2000-06-01 |
| DK1013661T3 (da) | 2012-03-19 |
| ATE541576T2 (de) | 2012-02-15 |
| DK2361921T3 (en) | 2015-09-14 |
| WO1998039352A1 (en) | 1998-09-11 |
| JP3756313B2 (ja) | 2006-03-15 |
| EP1013661A4 (en) | 2000-11-22 |
| DK2295441T3 (da) | 2014-07-21 |
| AU6120998A (en) | 1998-09-22 |
| DE98905804T1 (de) | 2010-08-26 |
| ES2485716T3 (es) | 2014-08-14 |
| PT2295441E (pt) | 2014-07-25 |
| EP2295441A2 (en) | 2011-03-16 |
| JPH10304889A (ja) | 1998-11-17 |
| CA2283509C (en) | 2005-01-04 |
| EP1013661A1 (en) | 2000-06-28 |
| EP1013661B2 (en) | 2018-10-24 |
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