JP5046219B2 - １，３−プロパン−１−アリールジオールの新規環状リン酸ジエステルおよびそのプロドラッグへの使用 - Google Patents
１，３−プロパン−１−アリールジオールの新規環状リン酸ジエステルおよびそのプロドラッグへの使用 Download PDFInfo
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- JP5046219B2 JP5046219B2 JP2004550353A JP2004550353A JP5046219B2 JP 5046219 B2 JP5046219 B2 JP 5046219B2 JP 2004550353 A JP2004550353 A JP 2004550353A JP 2004550353 A JP2004550353 A JP 2004550353A JP 5046219 B2 JP5046219 B2 JP 5046219B2
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- alkyl
- salt
- amino
- halogen
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- -1 cyclic phosphodiester Chemical class 0.000 title claims description 132
- 229940002612 prodrug Drugs 0.000 title abstract description 53
- 239000000651 prodrug Substances 0.000 title abstract description 53
- 150000001875 compounds Chemical class 0.000 claims abstract description 84
- 150000003839 salts Chemical class 0.000 claims abstract description 65
- 229960000684 cytarabine Drugs 0.000 claims abstract description 36
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims abstract description 17
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims abstract description 16
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 16
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 13
- 239000001301 oxygen Substances 0.000 claims abstract description 8
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000011574 phosphorus Substances 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 123
- 239000000203 mixture Substances 0.000 claims description 114
- 238000000034 method Methods 0.000 claims description 113
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 96
- 238000006243 chemical reaction Methods 0.000 claims description 86
- 239000002777 nucleoside Substances 0.000 claims description 77
- 229910052736 halogen Inorganic materials 0.000 claims description 68
- 150000002367 halogens Chemical group 0.000 claims description 61
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 claims description 60
- 239000002904 solvent Substances 0.000 claims description 56
- 125000003118 aryl group Chemical group 0.000 claims description 55
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 52
- 239000002585 base Substances 0.000 claims description 52
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 49
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 43
- 125000001424 substituent group Chemical group 0.000 claims description 42
- 125000003545 alkoxy group Chemical group 0.000 claims description 39
- 229910052799 carbon Inorganic materials 0.000 claims description 38
- 125000003282 alkyl amino group Chemical group 0.000 claims description 36
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 35
- 229910052757 nitrogen Inorganic materials 0.000 claims description 31
- 230000008569 process Effects 0.000 claims description 31
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 29
- 238000006317 isomerization reaction Methods 0.000 claims description 29
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 28
- 239000000460 chlorine Substances 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 21
- 125000004104 aryloxy group Chemical group 0.000 claims description 20
- 238000010438 heat treatment Methods 0.000 claims description 19
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 17
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 235000000346 sugar Nutrition 0.000 claims description 17
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 16
- 125000003835 nucleoside group Chemical group 0.000 claims description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 15
- 229920000166 polytrimethylene carbonate Polymers 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 239000011777 magnesium Substances 0.000 claims description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 9
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 claims description 7
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 6
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 6
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 claims description 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- XPYQFIISZQCINN-QVXDJYSKSA-N 4-amino-1-[(2r,3e,4s,5r)-3-(fluoromethylidene)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one;hydrate Chemical compound O.O=C1N=C(N)C=CN1[C@H]1C(=C/F)/[C@H](O)[C@@H](CO)O1 XPYQFIISZQCINN-QVXDJYSKSA-N 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 5
- ZDTFMPXQUSBYRL-PTSYZVBVSA-N (3s,4s,5r)-2-(2,6-diaminopurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C12=NC(N)=NC(N)=C2N=CN1C1O[C@H](CO)[C@@H](O)[C@@H]1O ZDTFMPXQUSBYRL-PTSYZVBVSA-N 0.000 claims description 4
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 4
- GIMSJJHKKXRFGV-BYPJNBLXSA-N 4-amino-1-[(2r,3s,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-iodopyrimidin-2-one Chemical compound C1=C(I)C(N)=NC(=O)N1[C@H]1[C@@H](F)[C@H](O)[C@@H](CO)O1 GIMSJJHKKXRFGV-BYPJNBLXSA-N 0.000 claims description 4
- CKTSBUTUHBMZGZ-CHKWXVPMSA-N 4-amino-1-[(2s,4r,5s)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 CKTSBUTUHBMZGZ-CHKWXVPMSA-N 0.000 claims description 4
- HSBKFSPNDWWPSL-VDTYLAMSSA-N 4-amino-5-fluoro-1-[(2s,5r)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@@H]1C=C[C@H](CO)O1 HSBKFSPNDWWPSL-VDTYLAMSSA-N 0.000 claims description 4
- QBEIABZPRBJOFU-VDTYLAMSSA-N 4-amino-5-fluoro-1-[(2s,5r)-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)CC1 QBEIABZPRBJOFU-VDTYLAMSSA-N 0.000 claims description 4
- SWFJAJRDLUUIOA-IBCQBUCCSA-N 5-ethyl-1-[(2r,3s,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(CC)=CN1[C@H]1[C@@H](F)[C@H](O)[C@@H](CO)O1 SWFJAJRDLUUIOA-IBCQBUCCSA-N 0.000 claims description 4
- RTRQQBHATOEIAF-UHFFFAOYSA-N AICA riboside Natural products NC1=C(C(=O)N)N=CN1C1C(O)C(O)C(CO)O1 RTRQQBHATOEIAF-UHFFFAOYSA-N 0.000 claims description 4
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 4
- RLAHNGKRJJEIJL-RFZPGFLSSA-N [(2r,4r)-4-(2,6-diaminopurin-9-yl)-1,3-dioxolan-2-yl]methanol Chemical compound C12=NC(N)=NC(N)=C2N=CN1[C@H]1CO[C@@H](CO)O1 RLAHNGKRJJEIJL-RFZPGFLSSA-N 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 125000000328 arabinofuranosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 4
- 235000010300 dimethyl dicarbonate Nutrition 0.000 claims description 4
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 claims description 4
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 claims description 4
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 4
- ODZBBRURCPAEIQ-PIXDULNESA-N helpin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(\C=C\Br)=C1 ODZBBRURCPAEIQ-PIXDULNESA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 claims description 4
- IPVFGAYTKQKGBM-BYPJNBLXSA-N 1-[(2r,3s,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-iodopyrimidine-2,4-dione Chemical compound F[C@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 IPVFGAYTKQKGBM-BYPJNBLXSA-N 0.000 claims description 3
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 claims description 3
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 claims description 3
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 claims description 3
- LJIRBXZDQGQUOO-KVTDHHQDSA-N 6-amino-3-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,4-dihydro-1,3,5-triazin-2-one Chemical compound C1NC(N)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 LJIRBXZDQGQUOO-KVTDHHQDSA-N 0.000 claims description 3
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 claims description 3
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 3
- 229960002756 azacitidine Drugs 0.000 claims description 3
- 229960004396 famciclovir Drugs 0.000 claims description 3
- DSWNRHCOGVRDOE-UHFFFAOYSA-N n,n-dimethylmethanimidamide Chemical compound CN(C)C=N DSWNRHCOGVRDOE-UHFFFAOYSA-N 0.000 claims description 3
- 125000002524 organometallic group Chemical group 0.000 claims description 3
- 229960000329 ribavirin Drugs 0.000 claims description 3
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 3
- 125000005270 trialkylamine group Chemical group 0.000 claims description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 239000011737 fluorine Chemical group 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- LMJVXGOFWKVXAW-OXOINMOOSA-N oxetanocin A Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@H]1CO LMJVXGOFWKVXAW-OXOINMOOSA-N 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims 6
- QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 claims 2
- 239000003513 alkali Substances 0.000 claims 2
- 150000004678 hydrides Chemical class 0.000 claims 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims 2
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 claims 2
- AHNJTQYTRPXLLG-UHFFFAOYSA-N lithium;diethylazanide Chemical compound [Li+].CC[N-]CC AHNJTQYTRPXLLG-UHFFFAOYSA-N 0.000 claims 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 2
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 claims 2
- RTRQQBHATOEIAF-UUOKFMHZSA-N acadesine Chemical compound NC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 RTRQQBHATOEIAF-UUOKFMHZSA-N 0.000 claims 1
- 229940124675 anti-cancer drug Drugs 0.000 claims 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000001369 canonical nucleoside group Chemical group 0.000 claims 1
- 238000006482 condensation reaction Methods 0.000 claims 1
- 230000000174 oncolytic effect Effects 0.000 claims 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 21
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 198
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 153
- 239000000243 solution Substances 0.000 description 144
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 126
- 230000015572 biosynthetic process Effects 0.000 description 115
- 238000003786 synthesis reaction Methods 0.000 description 113
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 99
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 87
- 238000005160 1H NMR spectroscopy Methods 0.000 description 76
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 72
- 239000007787 solid Substances 0.000 description 64
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 63
- 239000003153 chemical reaction reagent Substances 0.000 description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
- 238000003756 stirring Methods 0.000 description 49
- 230000002829 reductive effect Effects 0.000 description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- 239000010410 layer Substances 0.000 description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 38
- 239000011541 reaction mixture Substances 0.000 description 37
- 229910019142 PO4 Inorganic materials 0.000 description 36
- 239000010452 phosphate Substances 0.000 description 34
- 238000004128 high performance liquid chromatography Methods 0.000 description 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 32
- 230000000865 phosphorylative effect Effects 0.000 description 29
- 125000002947 alkylene group Chemical group 0.000 description 26
- 150000002009 diols Chemical class 0.000 description 26
- 238000006366 phosphorylation reaction Methods 0.000 description 26
- 239000012044 organic layer Substances 0.000 description 24
- 125000004122 cyclic group Chemical group 0.000 description 23
- 235000021317 phosphate Nutrition 0.000 description 22
- 238000001816 cooling Methods 0.000 description 20
- 230000026731 phosphorylation Effects 0.000 description 20
- 238000001914 filtration Methods 0.000 description 19
- 125000003710 aryl alkyl group Chemical group 0.000 description 18
- 239000003795 chemical substances by application Substances 0.000 description 18
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 17
- 238000001514 detection method Methods 0.000 description 17
- 239000003921 oil Substances 0.000 description 17
- 239000012071 phase Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
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- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 1
- 229960003962 trifluridine Drugs 0.000 description 1
- QHUNJMXHQHHWQP-UHFFFAOYSA-N trimethylsilyl acetate Chemical compound CC(=O)O[Si](C)(C)C QHUNJMXHQHHWQP-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229960003636 vidarabine Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Genetics & Genomics (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US42321102P | 2002-10-31 | 2002-10-31 | |
| US42325902P | 2002-10-31 | 2002-10-31 | |
| US60/423,211 | 2002-10-31 | ||
| US60/423,259 | 2002-10-31 | ||
| PCT/US2003/034709 WO2004041834A2 (en) | 2002-10-31 | 2003-10-31 | Novel cyclic phosphate diesters of 1,3-propane-1-aryl diols and their use in preparing prodrugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2006504791A JP2006504791A (ja) | 2006-02-09 |
| JP5046219B2 true JP5046219B2 (ja) | 2012-10-10 |
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| JP2004550339A Expired - Fee Related JP4689274B2 (ja) | 2002-10-31 | 2003-10-31 | 新規なシタラビン・モノホスフェートプロドラッグ |
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| JP2004550339A Expired - Fee Related JP4689274B2 (ja) | 2002-10-31 | 2003-10-31 | 新規なシタラビン・モノホスフェートプロドラッグ |
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| EP (2) | EP1556393B1 (enExample) |
| JP (2) | JP5046219B2 (enExample) |
| KR (2) | KR101115210B1 (enExample) |
| AT (1) | ATE442375T1 (enExample) |
| AU (2) | AU2003287389B2 (enExample) |
| BR (2) | BR0315795A (enExample) |
| CA (2) | CA2503729C (enExample) |
| DE (1) | DE60329211D1 (enExample) |
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| MX (2) | MXPA05004504A (enExample) |
| PL (2) | PL376474A1 (enExample) |
| WO (2) | WO2004041834A2 (enExample) |
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| PL376474A1 (en) * | 2002-10-31 | 2005-12-27 | Metabasis Therapeutics, Inc. | Novel cyclic phosphate diesters of 1,3-propane-1-aryl diols and their use in preparing prodrugs |
| US20050182252A1 (en) * | 2004-02-13 | 2005-08-18 | Reddy K. R. | Novel 2'-C-methyl nucleoside derivatives |
| MXPA06014013A (es) | 2004-06-08 | 2007-03-15 | Metabasis Therapeutics Inc | Sintesis mediada por acidos de lewis de esteres ciclicos. |
| EP1915053A2 (en) * | 2005-08-12 | 2008-04-30 | Merck & Co., Inc. | Novel 2'-c-methyl and 4'-c-methyl nucleoside derivatives |
| US20070241502A1 (en) * | 2006-04-14 | 2007-10-18 | Campbell Darrell C | Poker game and apparatus for play thereof |
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| KR20050055630A (ko) | 2002-06-28 | 2005-06-13 | 이데닉스 (케이만) 리미티드 | 플라비비리다에 감염 치료를 위한 1'-, 2'- 및 3'-변형된뉴클레오시드 유도체 |
| AU2003247084B9 (en) | 2002-06-28 | 2018-07-26 | Centre National De La Recherche Scientifique | Modified 2' and 3'-nucleoside prodrugs for treating flaviridae infections |
| KR20050035194A (ko) | 2002-06-28 | 2005-04-15 | 이데닉스 (케이만) 리미티드 | 플라비비리다에 감염 치료용 2'-ｃ-메틸-3'-ｏ-ｌ-발린에스테르 리보푸라노실 사이티딘 |
| PL376474A1 (en) | 2002-10-31 | 2005-12-27 | Metabasis Therapeutics, Inc. | Novel cyclic phosphate diesters of 1,3-propane-1-aryl diols and their use in preparing prodrugs |
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