JPH08512039A - メチルホスホン酸エステル、その製造方法およびその使用 - Google Patents
メチルホスホン酸エステル、その製造方法およびその使用Info
- Publication number
- JPH08512039A JPH08512039A JP7503269A JP50326995A JPH08512039A JP H08512039 A JPH08512039 A JP H08512039A JP 7503269 A JP7503269 A JP 7503269A JP 50326995 A JP50326995 A JP 50326995A JP H08512039 A JPH08512039 A JP H08512039A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- independent
- alkyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 66
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 title description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- 239000002253 acid Substances 0.000 claims abstract description 4
- 108091034117 Oligonucleotide Proteins 0.000 claims description 52
- 125000003729 nucleotide group Chemical group 0.000 claims description 27
- 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 claims description 24
- 239000002773 nucleotide Substances 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 239000002777 nucleoside Substances 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 235000000346 sugar Nutrition 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 229940127073 nucleoside analogue Drugs 0.000 claims description 8
- 125000005499 phosphonyl group Chemical group 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 239000012634 fragment Substances 0.000 claims description 5
- 241001024304 Mino Species 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 150000001413 amino acids Chemical class 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 3
- 229940002612 prodrug Drugs 0.000 claims description 3
- 239000000651 prodrug Substances 0.000 claims description 3
- 229940122498 Gene expression inhibitor Drugs 0.000 claims description 2
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 claims description 2
- 239000012190 activator Substances 0.000 claims description 2
- 125000000524 functional group Chemical group 0.000 claims description 2
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 claims description 2
- 229960000367 inositol Drugs 0.000 claims description 2
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 claims description 2
- 150000003431 steroids Chemical class 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- 239000011800 void material Substances 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 61
- 238000002360 preparation method Methods 0.000 abstract description 14
- 150000002148 esters Chemical class 0.000 abstract description 4
- 238000001727 in vivo Methods 0.000 abstract description 4
- 229910052740 iodine Inorganic materials 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
- -1 compound compounds Chemical class 0.000 description 39
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- 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 description 12
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 12
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- 239000002609 medium Substances 0.000 description 10
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- XKKCQTLDIPIRQD-JGVFFNPUSA-N 1-[(2r,5s)-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)CC1 XKKCQTLDIPIRQD-JGVFFNPUSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 108010071563 Proto-Oncogene Proteins c-fos Proteins 0.000 description 8
- 102000007568 Proto-Oncogene Proteins c-fos Human genes 0.000 description 8
- 230000000692 anti-sense effect Effects 0.000 description 8
- 230000004048 modification Effects 0.000 description 8
- 238000012986 modification Methods 0.000 description 8
- 150000008300 phosphoramidites Chemical class 0.000 description 8
- 239000006228 supernatant Substances 0.000 description 8
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000000074 antisense oligonucleotide Substances 0.000 description 7
- 238000012230 antisense oligonucleotides Methods 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- 229940104230 thymidine Drugs 0.000 description 7
- 229960002555 zidovudine Drugs 0.000 description 7
- 239000001431 2-methylbenzaldehyde Substances 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 150000003833 nucleoside derivatives Chemical class 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 238000012546 transfer Methods 0.000 description 6
- CMWKITSNTDAEDT-UHFFFAOYSA-N 2-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC=C1C=O CMWKITSNTDAEDT-UHFFFAOYSA-N 0.000 description 5
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 5
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 5
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 230000000840 anti-viral effect Effects 0.000 description 5
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 5
- 239000000178 monomer Substances 0.000 description 5
- 102000039446 nucleic acids Human genes 0.000 description 5
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- BTFQKIATRPGRBS-UHFFFAOYSA-N o-tolualdehyde Chemical compound CC1=CC=CC=C1C=O BTFQKIATRPGRBS-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 4
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- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
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- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
- ZILXIZUBLXVYPI-UHFFFAOYSA-N 2,4-dinitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C([N+]([O-])=O)=C1 ZILXIZUBLXVYPI-UHFFFAOYSA-N 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
-
- 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
-
- 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
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
Claims (1)
- 【特許請求の範囲】 1)式I 〔式中、 YはOH、SH、OAcまたはSAc(ここでAc=(C1〜C18)−アシルであって、場合に より1〜3回不飽和である)であり、 R′はアリール、ヘテロアリールまたはアルキルであり、 Wは医薬的に活性な化合物の基であり、 RはWの意味を有する(ここでRおよびWは同一であるかまたは相異なるこ とができる)かまたはRは場合により置換されたアルキル基であり、または WおよびRはそれらを結合しているホスホネート基と一緒になってオリゴヌ クレオチドを形成し、ここでWは下記の式IIの基でありそしてRは下記の式II′ {上記式中、Xはオキシ、フルファンジイルまたはメチレンであ り、 Bは互いに独立していて、ヌクレオチド塩基であり、 nは互いに独立していて、0〜50の整数であり、 R1およびR2は互いに独立していて、H(C1〜C18)−アシルまたは式 (ここでR4はO-、S-、CH3またはCHYR′(ここでR′およびYは前述の定義を有 する)でありそしてR5は場合により置換された(C1〜C18)−アルキル基である )の基であり、 R3は互いに独立していて、H、O(C1〜C18)−アルキル、O(C1〜C18)− アシル、F、Cl、N3、NH2またはNHR6(ここでR6は(C1〜C6)−アルキルまたは (C1〜C6)−アシルである)であり、 そして括弧はR3および隣接ホスホニル基が2′または3′の位置にあることが できることを示している}の基である〕で表される化合物。 2)Yは0H、SH、OAcまたはSAc(ここでAc=(C1〜C8)−アシルであって、場合 により1〜3回不飽和である)であり、 R′は(C1〜C5)−アルキル、ハロゲン、NO2、CN、(C1〜C6)−アルコキシ 、アミノ、(C1〜C4)−アルキルアミノ、(C1〜C8)−ジアルキルアミノからな る群より選択される互いに独立した3個までの基で場合により置換されている( C6〜C14)−アリール{ここでCH2基がオキシによりさらに置換されうる(C3〜C8 )−アルキレン基がさらにこのアリール基に縮合することも可能であ る}; N、OおよびSからなる群より選択される3個までのヘテロ原子を有する( C3〜C13)−ヘテロアリール;または (C1〜C16)−アルキル(これは分枝鎖または非分枝鎖状、飽和または1〜3 回不飽和であって、ハロゲン、CN、NO2および(C1〜C3)−アルコキシからなる群 より選択される3個までの互いに独立した置換基で場合により置換されている) であり、 Wは医薬的に活性な化合物の基であり、 RはWの意味を有する(ここでRおよびWは同一であるかまたは相異なるこ とができる)かまたはRは〔空隙〕または(C1〜C16)−アルキル基(これは分枝 鎖または非分枝鎖状であることができ、そしてハロゲン、CN、(C1〜C8)−アシ ルオキシ、(C1〜C18)−アルコキシからなる群より選択される3個までの互い に独立した基で場合により置換されている)であり、または WおよびRはそれらを結合しているホスホネート基と一緒になってオリゴヌ クレオチドを形成し、ここでWは式IIの基でありそしてRは式II′{各式中、X はオキシまたはスルファンジイルであり、 Bは互いに独立していて、ヌクレオチド塩基であり、 nは互いに独立していて、0〜30の整数であり、 R1およびR2は互いに独立していて、H(C1〜C12)−アシルまたは式 (ここでR4はO、S、CH3またはCHYR′(ここでR′およびYは前述 の定義を有する)でありそしてR5は場合により置換された(C1〜C12)−アルキ ルである)の基であり、 R3は互いに独立していて、H、O(C1〜C12)−アルキル、O(C1〜C12)−ア シル、Cl、N3、NH2またはNHR6(ここでR6は(C1〜C3)−アルキルまたは(C1〜C3 )−アシルである)であり、 そして括弧はR3および隣接ホスホニル基が2′または3′の位置にあることが できることを示している}の基である請求項1記載の式Iの化合物。 3)YはOH、SH、OAcまたはSAc(ここでAC=(C1〜C3)−アシルであって、場合 により1〜3回不飽和である)であり、 R′は(C1〜C3)−アルキル、F、Cl、NO2、CN、(C1〜C4)−アルコキシ、 アミノ、(C1〜C3)−アルキルアミノ、(C1〜C6)−ジアルキルアミノからな る群より選択される互いに独立した3個までの基で場合により置換されている(C6 〜C14)−アリール{ここでCH2基がオキシによりさらに置換されうる(C3〜C8)− アルキレン基がさらにこのアリール基に縮合することも可能である}; N、OおよびSからなる群より選択される3個までのヘテロ原子を有する( C3〜C6)−ヘテロアリール;または (C1〜C8)−アルキル(これは分枝鎖または非分枝鎖状、飽和または1〜3 回不飽和であって、Cl、CN、NO2および(C1〜C3)−アルコキシからなる群より選 択される3個までの互いに独立した置換基で場合により置換されている)であり 、 Wはステロイド、糖、イノシトールまたはペプチド(少なくとも1個のアミ ノ酸SerまたはTyrを有しかつ合計20個までの天然アミノ酸を有する)の5′−、3 ′−または2′−ヌクレオシド類似体で あり、 RはWの意味を有するかまたは(C1〜C8)−アルキル基(これは分枝鎖また は非分枝鎖状であることができ、そしてハロゲン、CN、(C3〜C6)−アシルオキ シ、(C8〜C18)−アルコキシからなる群より選択される2個までの基で場合に より置換されている)であり、または WおよびRはそれらを結合しているホスホネート基と一緒になってオリゴヌ クレオチドを形成し、ここでWは式IIの基でありそしてRは式II′{各式中、X はオキシであり、 Bは互いに独立していて、ヌクレオチド塩基であり、 nは互いに独立していて、0〜20の整数であり、 R1およびR2は互いに独立していて、H(C1〜C8)−アシルまたは式 (ここでR4はO、S、CH3またはCHYR′(ここでR′およびYは前述の定義を有 する)でありそしてR5は場合により置換された(C1〜C8)−アルキルである)の 基であり、 R3は互いに独立していて、H、O(C1〜C8)−アルキル、O(C1〜C8)−アシル 、ClまたはN3であり、 そして括弧はR3および隣接ホスホニル基が2′または3′の位置にあることが できることを示している}の基である請求項1または2に記載の式Iの化合物。 4)YはOHであり、 R′は(C1〜C3)−アルキル、F、Cl、NO2、CN、(C1〜C4)−ア ルコキシ、アミノ、(C1〜C3)−アルキルアミノ、(C1〜C6)−ジアルキルア ミノからなる群より選択される互いに独立した3個までの基で場合により置換さ れているC6-アリールにこでCH2基がオキシによりさらに置換されうる(C3〜C6) −アルキレン基がさらにこのアリール基に縮合することも可能である}; N、OおよびSからなる群より選択される3個までのヘテロ原子を有する( C3〜C6)−ヘテロアリール;または (C1〜C8)−アルキル(これは分枝鎖または非分枝鎖状、飽和または1〜3回 不飽和、好ましくはα−位で不飽和結合を有する共役形態で不飽和であり、Cl、 CN、NO2および(C1〜C3)−アルコキシからなる群より選択される3個までの互 いに独立した置換基で場合により置換されている)であり、 Wは5′−または3′−ヌクレオシド類似体であり、 RはWの意味を有するかまたは(C1〜C4)−アルキル基(これは分枝鎖または 非分枝鎖状であることができる)であり、または WおよびRはそれらを結合しているホスホネート基と一緒になってオリゴヌ クレオチドを形成し、ここでWは式IIの基でありそしてRは式II′{各式中、X はオキシであり、 Bは互いに独立していて、ヌクレオチド塩基であり、 nは互いに独立していて、0〜15の整数であり、 R1およびR2は互いに独立していて、H(C1〜C4)−アシルまたは式 (ここでR4はO、S、CH3またはCHYR′(ここでR′およびYは前述 の定義を有する)でありそしてR5は場合により置換された(C1〜C3)−アルキル 基である)の基であり、 R3は互いに独立していて、H、O(C1〜C3)−アルキル、O(C1〜C3)−アシル 、ClまたはN3であり、 そして括弧はR3および隣接ホスホニル基が2′または3′の位置にあることが できることを示している}の基である請求項1〜3のいずれか1項に記載の式I の化合物。 5)YはOHであり、 Wは5′−または3′−ヌクレオシド類似体であり、 RはWの意味を有するかまたは(C1〜C4)−アルキル基(これは分枝鎖また は非分枝鎖状であることができる)であり、 R′はCl、NO2、CN、(C1〜C3)−アルコキシ、アミノおよび(C1〜C3)−アル キルアミノからなる群より選択される互いに独立した3個までの基で場合により 置換されているC6−アリールである請求項1〜4のいずれか1項に記載の式Iの 化合物。 6)請求項1〜5のいずれか1項に記載の化合物の製造において、 a)式IIIの化合物を式IVの化合物と反応させるか、 または b)式Vの化合物をいずれか所望の順序で、縮合剤を用いて式VIの化合物と反 応させるか、 または c)式Vの化合物をいずれか所望の順序で、縮合剤を用いて式VIの化合物およ び式VIIの化合物と反応させるか、 (式中、SGは保護基であって、場合により式Iの化合物を得るために除去され る)、または 3′(2′)−末端H−ホスホネート基および保護された5′−ヒドロキシ基を 有するヌクレオチド単位を活性化剤の存在下で遊離5′−ヒドロキシ基および保 護された3′(2′)−ヒドロキシ基を有するさらに別のヌクレオチド単位と反応さ せてH−ホスホネートヌクレオシドを得、これをアルデヒドと縮合してジヌクレ オシドα−ヒドロキシアルキル(アリール)ホスホネートを得、それをその活性 誘導体を得るための反応後にさらに別の(オリゴ)ヌクレオチド断片と反応させ てオリゴヌクレオチドを得、次いで一時的に導入した保護基を除去する、すなわ ち i)3′(2′)−末端リン(III)またはリン(V)基を有するヌクレオチド 単位を縮合剤の存在下でさらに別のヌクレオチド単位または成長するオリゴヌク レオチド鎖の遊離5′−ヒドロキシ基と反応させるか、または ii)その活性誘導体またはオリゴヌクレオチド類似体を同じ手法で断片中に 作成し、その他の官能基保護のためにi)またはii)によって得られたオリゴヌク レオチド中に一時的に導入した保護基を除去し、こうして得られた式Iのオリゴ ヌクレオチド類似体 (ここでWは式IIの基でありそしてRは式II′の基である)を場合によりそれら の生理学的に許容し得る塩に変換することを特徴とする前記の製造方法。 7)遺伝子発現阻害剤としての請求項1〜5のいずれか1項に記載のオリゴヌク レオチド類似体の使用。 8)請求項1〜5のいずれか1項に記載の1種以上の式Iの化合物を含有する医 薬。 9)医薬として使用するための請求項1〜5のいずれか1項に記載の式Iの化合 物。 10)プロドラッグ作用を有する医薬を製造するための請求項1〜5のいずれか1 項に記載の式Iの化合物。
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DE4321946A DE4321946A1 (de) | 1993-07-01 | 1993-07-01 | Methylphosphonsäureester, Verfahren zu deren Herstellung und deren Verwendung |
DE4321946.2 | 1993-07-01 | ||
PCT/EP1994/002121 WO1995001363A1 (de) | 1993-07-01 | 1994-06-29 | Methylphosphonsäureester, verfahren zu deren herstellung und deren verwendung |
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US (1) | US6028182A (ja) |
EP (1) | EP0707591B1 (ja) |
JP (1) | JP3831407B2 (ja) |
AT (1) | ATE206130T1 (ja) |
AU (1) | AU698928B2 (ja) |
CA (1) | CA2165971C (ja) |
DE (2) | DE4321946A1 (ja) |
DK (1) | DK0707591T3 (ja) |
ES (1) | ES2165391T3 (ja) |
FI (1) | FI115399B (ja) |
NO (1) | NO319860B1 (ja) |
PT (1) | PT707591E (ja) |
WO (1) | WO1995001363A1 (ja) |
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1993
- 1993-07-01 DE DE4321946A patent/DE4321946A1/de not_active Withdrawn
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1994
- 1994-06-29 EP EP94919670A patent/EP0707591B1/de not_active Expired - Lifetime
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- 1994-06-29 AT AT94919670T patent/ATE206130T1/de not_active IP Right Cessation
- 1994-06-29 AU AU70735/94A patent/AU698928B2/en not_active Ceased
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1995
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Cited By (3)
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JP2011528654A (ja) * | 2008-06-26 | 2011-11-24 | プロリンクス エルエルシー | 制御された薬剤放出速度を有するプロドラッグ及び薬剤−高分子のコンジュゲート |
JP2015172078A (ja) * | 2008-06-26 | 2015-10-01 | プロリンクス エルエルシー | 制御された薬剤放出速度を有するプロドラッグ及び薬剤−高分子のコンジュゲート |
US9387254B2 (en) | 2008-06-26 | 2016-07-12 | Prolynx Llc | Prodrugs and drug-macromolecule conjugates having controlled drug release rates |
Also Published As
Publication number | Publication date |
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ES2165391T3 (es) | 2002-03-16 |
ATE206130T1 (de) | 2001-10-15 |
FI115399B (fi) | 2005-04-29 |
FI956341A (fi) | 1996-02-19 |
EP0707591A1 (de) | 1996-04-24 |
NO955352D0 (no) | 1995-12-29 |
NO319860B1 (no) | 2005-09-26 |
EP0707591B1 (de) | 2001-09-26 |
US6028182A (en) | 2000-02-22 |
WO1995001363A1 (de) | 1995-01-12 |
JP3831407B2 (ja) | 2006-10-11 |
FI956341A0 (fi) | 1995-12-29 |
NO955352L (no) | 1996-02-14 |
PT707591E (pt) | 2002-03-28 |
DE59409880D1 (de) | 2001-10-31 |
AU7073594A (en) | 1995-01-24 |
CA2165971A1 (en) | 1995-01-12 |
AU698928B2 (en) | 1998-11-12 |
DK0707591T3 (da) | 2002-01-21 |
DE4321946A1 (de) | 1995-01-12 |
CA2165971C (en) | 2006-05-30 |
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