TW470748B

TW470748B - Nucleotide analogs

Nucleotide analogs Download PDF

Info

Publication number: TW470748B
Authority: TW; Taiwan
Prior art keywords: twenty; compound; cns; ministry; pmpa
Prior art date: 1996-07-26

Application number

TW089123708A

Other languages

English (en)

Chinese (zh)

Inventor

Murty N Arimilli

Kenneth C Cundy

Joseph P Dougherty

Reza Oliyai

Choung Un Kim

Original Assignee

Gilead Sciences Inc

Priority date

1996-07-26

Filing date

1997-08-21

Publication date

2002-01-01

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26696272&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=TW470748(B) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

1997-08-21 Application filed by Gilead Sciences Inc filed Critical Gilead Sciences Inc

2002-01-01 Application granted granted Critical

2002-01-01 Publication of TW470748B publication Critical patent/TW470748B/zh

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125000003729 nucleotide group Chemical group 0.000 title description 7
150000001875 compounds Chemical class 0.000 claims abstract description 217
230000000840 anti-viral effect Effects 0.000 claims abstract description 17
230000002079 cooperative effect Effects 0.000 claims description 39
125000000217 alkyl group Chemical group 0.000 claims description 16
238000006467 substitution reaction Methods 0.000 claims description 2
-1 alkyenylaryl Chemical group 0.000 abstract description 91
125000003118 aryl group Chemical group 0.000 abstract description 19
238000002360 preparation method Methods 0.000 abstract description 15
239000000543 intermediate Substances 0.000 abstract description 14
150000002148 esters Chemical class 0.000 abstract description 12
125000000623 heterocyclic group Chemical group 0.000 abstract description 12
125000003342 alkenyl group Chemical group 0.000 abstract description 11
125000000304 alkynyl group Chemical group 0.000 abstract description 8
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 8
108091034117 Oligonucleotide Proteins 0.000 abstract description 6
125000002877 alkyl aryl group Chemical group 0.000 abstract description 6
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 6
229910052760 oxygen Inorganic materials 0.000 abstract description 6
239000001301 oxygen Substances 0.000 abstract description 6
125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 abstract description 5
150000004649 carbonic acid derivatives Chemical class 0.000 abstract 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 abstract description 2
150000004657 carbamic acid derivatives Chemical class 0.000 abstract description 2
125000004400 (C1-C12) alkyl group Chemical group 0.000 abstract 3
125000005025 alkynylaryl group Chemical group 0.000 abstract 2
125000005018 aryl alkenyl group Chemical group 0.000 abstract 2
125000003710 aryl alkyl group Chemical group 0.000 abstract 2
125000005015 aryl alkynyl group Chemical group 0.000 abstract 2
125000001475 halogen functional group Chemical group 0.000 abstract 2
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238000011321 prophylaxis Methods 0.000 abstract 1
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239000000203 mixture Substances 0.000 description 54
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238000000034 method Methods 0.000 description 23
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IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 21
239000000047 product Substances 0.000 description 21
BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 19
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
239000002585 base Substances 0.000 description 18
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 17
239000007787 solid Substances 0.000 description 17
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
239000000460 chlorine Substances 0.000 description 14
239000007788 liquid Substances 0.000 description 14
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
238000004128 high performance liquid chromatography Methods 0.000 description 13
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
210000002700 urine Anatomy 0.000 description 13
229910052799 carbon Inorganic materials 0.000 description 12
238000003756 stirring Methods 0.000 description 12
230000015572 biosynthetic process Effects 0.000 description 11
229910052757 nitrogen Inorganic materials 0.000 description 11
239000003921 oil Substances 0.000 description 11
235000019198 oils Nutrition 0.000 description 11
229940002612 prodrug Drugs 0.000 description 11
239000000651 prodrug Substances 0.000 description 11
239000002904 solvent Substances 0.000 description 11
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
229910052739 hydrogen Inorganic materials 0.000 description 10
125000004430 oxygen atom Chemical group O* 0.000 description 10
239000011541 reaction mixture Substances 0.000 description 10
239000000725 suspension Substances 0.000 description 10
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 9
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
239000013078 crystal Substances 0.000 description 9
239000001257 hydrogen Substances 0.000 description 9
239000012535 impurity Substances 0.000 description 9
239000000126 substance Substances 0.000 description 9
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
239000006071 cream Substances 0.000 description 8
125000004122 cyclic group Chemical group 0.000 description 8
150000002314 glycerols Chemical class 0.000 description 8
238000001990 intravenous administration Methods 0.000 description 8
238000004519 manufacturing process Methods 0.000 description 8
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 8
238000003786 synthesis reaction Methods 0.000 description 8
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GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 7
241001465754 Metazoa Species 0.000 description 7
WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 7
229960000643 adenine Drugs 0.000 description 7
238000001914 filtration Methods 0.000 description 7
229910052943 magnesium sulfate Inorganic materials 0.000 description 7
235000019341 magnesium sulphate Nutrition 0.000 description 7
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
230000002829 reductive effect Effects 0.000 description 7
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
125000004432 carbon atom Chemical group C* 0.000 description 6
230000000694 effects Effects 0.000 description 6
239000000706 filtrate Substances 0.000 description 6
125000005843 halogen group Chemical group 0.000 description 6
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
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239000007937 lozenge Substances 0.000 description 6
239000012071 phase Substances 0.000 description 6
UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 6
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210000000813 small intestine Anatomy 0.000 description 6
125000001424 substituent group Chemical group 0.000 description 6
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125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 5
GCOFRXOOFANVPB-SNVBAGLBSA-N 9-[(2r)-2-(diethoxyphosphorylmethoxy)propyl]purin-6-amine Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCC)OCC)C=NC2=C1N GCOFRXOOFANVPB-SNVBAGLBSA-N 0.000 description 5
241000282472 Canis lupus familiaris Species 0.000 description 5
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KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 5
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JYWJULGYGOLCGW-UHFFFAOYSA-N chloromethyl chloroformate Chemical compound ClCOC(Cl)=O JYWJULGYGOLCGW-UHFFFAOYSA-N 0.000 description 5
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 5
239000012065 filter cake Substances 0.000 description 5
239000011261 inert gas Substances 0.000 description 5
238000002347 injection Methods 0.000 description 5
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125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
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239000004816 latex Substances 0.000 description 5
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125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
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125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 4
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 4
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101100167062 Caenorhabditis elegans chch-3 gene Proteins 0.000 description 4
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SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
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238000007259 addition reaction Methods 0.000 description 4
150000001412 amines Chemical class 0.000 description 4
239000008346 aqueous phase Substances 0.000 description 4
239000007864 aqueous solution Substances 0.000 description 4
239000007853 buffer solution Substances 0.000 description 4
NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 4
125000004093 cyano group Chemical group *C#N 0.000 description 4
150000005690 diesters Chemical class 0.000 description 4
LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 4
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238000000605 extraction Methods 0.000 description 4
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CFYRHPJXXCHEFX-UHFFFAOYSA-L hydrogen phosphate;tetrabutylazanium Chemical compound OP([O-])([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC CFYRHPJXXCHEFX-UHFFFAOYSA-L 0.000 description 4
208000015181 infectious disease Diseases 0.000 description 4
150000002632 lipids Chemical class 0.000 description 4
210000004185 liver Anatomy 0.000 description 4
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JFVZFKDSXNQEJW-UHFFFAOYSA-N [1-(6-aminopurin-9-yl)propan-2-yloxymethyl-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate Chemical compound N1=CN=C2N(CC(C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-UHFFFAOYSA-N 0.000 description 3
238000010521 absorption reaction Methods 0.000 description 3
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MBUCWFHXWNITCQ-UHFFFAOYSA-N butyl chloromethyl carbonate Chemical compound CCCCOC(=O)OCCl MBUCWFHXWNITCQ-UHFFFAOYSA-N 0.000 description 3
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