WO1997000262A1 - Nucleotides derives de phosphonates - Google Patents
Nucleotides derives de phosphonates Download PDFInfo
- Publication number
- WO1997000262A1 WO1997000262A1 PCT/JP1996/001631 JP9601631W WO9700262A1 WO 1997000262 A1 WO1997000262 A1 WO 1997000262A1 JP 9601631 W JP9601631 W JP 9601631W WO 9700262 A1 WO9700262 A1 WO 9700262A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- alkyl group
- compound
- solvate
- hydrate
- Prior art date
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- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 title description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 128
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 41
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 38
- 125000005843 halogen group Chemical group 0.000 claims abstract description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 5
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 5
- 125000005042 acyloxymethyl group Chemical group 0.000 claims abstract description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 3
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 239000012453 solvate Substances 0.000 claims description 19
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 150000004677 hydrates Chemical class 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
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims description 3
- 230000002458 infectious effect Effects 0.000 claims description 3
- 230000003612 virological effect Effects 0.000 claims description 3
- 230000001548 androgenic effect Effects 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 230000000840 anti-viral effect Effects 0.000 abstract description 9
- 229910052757 nitrogen Chemical group 0.000 abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 abstract 3
- 239000001257 hydrogen Substances 0.000 abstract 3
- 150000002431 hydrogen Chemical group 0.000 abstract 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract 2
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 abstract 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 105
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 104
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 100
- -1 ester derivative of phosphonate nucleotide Chemical class 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 17
- 239000002904 solvent Substances 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- GHILAORILZRWPO-UHFFFAOYSA-N 6-n,6-n-dimethyl-7h-purine-2,6-diamine Chemical compound CN(C)C1=NC(N)=NC2=C1NC=N2 GHILAORILZRWPO-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 6
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 6
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- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
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- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
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- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 4
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 4
- 229960003750 ethyl chloride Drugs 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- BVIAOQMSVZHOJM-UHFFFAOYSA-N DMPURH Natural products CN(C)C1=NC=NC2=C1N=CN2 BVIAOQMSVZHOJM-UHFFFAOYSA-N 0.000 description 3
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- 125000001309 chloro group Chemical group Cl* 0.000 description 3
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- 230000002401 inhibitory effect Effects 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
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- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- LUTWEKBTDWRTSE-UHFFFAOYSA-N 1-chloro-2-(chloromethoxy)ethane Chemical compound ClCCOCCl LUTWEKBTDWRTSE-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
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- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
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- WCZNSRQVTJYMRQ-UHFFFAOYSA-N n-phenyl-7h-purin-6-amine Chemical compound N=1C=NC=2N=CNC=2C=1NC1=CC=CC=C1 WCZNSRQVTJYMRQ-UHFFFAOYSA-N 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
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- 239000001814 pectin Substances 0.000 description 1
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- 229920001277 pectin Polymers 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
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- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
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- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
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- 239000008117 stearic acid Substances 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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- 239000000196 tragacanth Substances 0.000 description 1
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- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
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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
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Definitions
- the present invention relates to novel phosphonate nucleotide derivatives. More specifically, the present invention relates to a novel phosphonate nucleotide derivative having antiviral activity and useful as an active ingredient of a medicine. Background art
- Infectious viral diseases are recognized as an important medical problem, and in order to treat these diseases, the development of drugs that have antiviral activity and at the same time do not show growth inhibitory activity against normal cell lines has been developed.
- drugs that have antiviral activity and at the same time do not show growth inhibitory activity against normal cell lines has been developed.
- phosphonate nucleotides are a group of compounds that are currently being actively studied as compounds having selective toxicity to viruses.
- 9- (2-phosphonylmethoxy) ethyladenine (PMEA), 91- (2-phosphonylmethoxy) ethyl-2,6-diaminopurine (PMDAP), etc. are simple herpes 1 Has been reported to be effective against type 2 and type 2 (HSV-1 and HSV-2), human immunodeficiency virus (HIV), and human hepatitis B virus (HBV) (Yokota et al. , Antimicrob. Agents Chemother ther., 35, 394 (1991); Votrubaetal., MoI. Pharmacol., 32, 524 (1998)).
- the present inventors have made intensive studies to solve the above problems, and as a result, phosphonate nucleotides having a specific novel structure have a higher antiviral activity than the conventionally proposed compounds. In addition, they have found that they are safer and have higher oral absorbability for living bodies, and have completed the present invention.
- the present invention provides a compound represented by the following general formula (I):
- R 1 represents a Ararukiru group hydrogen atom, an alkyl group or a C 7 -C 1 of -C 6 (), the alkyl group for R 2 ⁇ C 6, C 7 ⁇ C 1 () Represents an aralkyl group or a phenyl group, wherein R 3 and R 4 are each independently a hydrogen atom,
- a medicine comprising these substances, and a pharmaceutical composition and an antiviral agent containing these substances as an active ingredient.
- a method for treating an infectious virus disease comprising the use of the above substance for producing a pharmaceutical composition having an antiviral action, and the step of administering a therapeutically effective amount of the above substance to a patient.
- the alkyl groups of R 1 , R 2 , R 3 , and R 4 are methyl, ethyl, n-propyl, isopropyl, Examples include n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group and the like. ⁇
- the R 1 preferably a hydrogen atom or an alkyl group ⁇ C 4, the R 2, Ji alkyl group ⁇ to c 4, benzyl or Fuweniru group, are preferred.
- the R 2, an alkyl group or a phenyl group -C lambda are particularly preferred.
- the alkyl group of R 5 to C 4 include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group.
- R 3 and R 4 include an acetyloxymethyl group, a propylionyloxymethyl group, a butyryloxymethyl group, an isoptyryloxymethyl group, and a valeryloxymethyl group. And an isono-rreloxymethyl group, a bivaloyloxymethyl group and the like.
- the acetylthioethyl groups for R 3 and R 4 include acetylthioethyl, propionylthioethyl, butyrylthioethyl, isobutyrylthioethyl, valerylthioethyl, isovalerylthioethyl, and vivaloylthioethyl. And a tyl group.
- the halogen atom includes a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like.
- the ethyl group substituted with one or more halogen atoms include 1-fluoroethyl group, 2-fluoroethyl group, 1 monochloroethyl group, 2-chloroethyl group, 2-bromoethyl group, and 2,2-difluoroethyl group.
- the 2-position of the ethyl group is preferably substituted, and the halogen atom is preferably a fluorine atom.
- R 3 and R 4 are preferably an alkyl group of -C or an ethyl group substituted with one or more halogen atoms, and particularly preferably a 2,2,2-trifluoroethyl group.
- Examples of the hydroxyalkyl group of R 5 to C 4 include a hydroxymethyl group, a 1-hydroxyl group, a 2-hydroxyl group, a 1-hydroxylpropyl group, a 2-hydroxypropyl group and a 3-hydroxypropyl group. And a 1-hydroxybutyl group, a 2-hydroxybutyl group, a 3-hydroxybutyl group and a 4-hydroxybutyl group.
- examples of the halogen atom include a fluorine atom and a chlorine atom
- examples of the alkyl group for C j — include a methyl group, an ethyl group, Examples include n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group and tert-butyl group.
- Examples of the C i -c 4 alkyl group substituted with one or more halogen atoms include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, a chloroethyl group, a fluoropropyl group, a chloropropyl group, and a fluorobutyl group. Group, chlorobutyl group and the like.
- R 5 is preferably a hydrogen atom or a C 1 -C 4 alkyl group.
- the antiviral activity of the compound of the present invention is enhanced by making the amino group at the 6-position of the pyridine ring a substituted amino group, as compared with the compound described in EP632048. However, it is characterized by higher safety for living bodies and higher oral absorbability.
- a compound wherein R 2 is a phenyl group is characterized in that R 2 is less toxic than I ⁇ of Arukinore group or Ararukiru group, Compounds in which R 5 is an alkyl group have been found to be less toxic than compounds in which R 5 is a hydrogen atom, a hydroxyalkyl group, or a halogen-substituted alkyl group.
- Particularly preferred compounds among the compounds of the present invention include the following compounds.
- the phosphonate nucleotide derivative of the present invention represented by the above general formula (I) can form a pharmacologically and pharmaceutically acceptable salt.
- a salt include a metal salt such as a lithium salt, a sodium salt, a potassium salt, a magnesium salt, a calcium salt, an ammonium salt, a methyl ammonium salt, and a dimethyl ammonium salt when an acidic group is present.
- ammonium salts such as trimethylammonium salt, dicyclohexylammonium salt and the like.
- mineral salts such as hydrochloride, bromate, sulfate, nitrate, and phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, Acetate, propionate, tartrate, fumarate, maleate, malate, oxalate, succinate, kuninate, benzoate, mandelate, gay cinnamate, lactate, etc. Can be formed.
- the phosphonate nucleotide derivative of the present invention represented by the above general formula (I) or a salt thereof may exist in the form of a hydrate or a solvate.
- Solvents that can form solvates include, for example, methanol, ethanol, isopropanol , Acetone, ethyl acetate, dimethylene chloride and the like. It goes without saying that the free form compound represented by the above general formula (I) and salts thereof, and hydrates and solvates thereof are all encompassed in the present invention.
- Table 1 below shows specific examples of the compound of the present invention.
- Me is a methyl group
- Et is an ethyl group
- n—Pr is an n-propyl group
- i—Pr is an isopropyl group
- n—Bu is an n-butyl group
- t—Bu is a A short butyl group and Ph represent a phenyl group.
- R 4 is an alkyl group of ⁇ c 6 or an ethyl substituted with one or more halogen atoms.
- the compound as a group can be synthesized, for example, according to the following reaction route (1) or (2).
- R 1 , R 2 , R 5 and X are as defined above, and R 6 represents a 1-C 4 alkyl group or an ethyl group substituted with one or more halogen atoms.
- R 6 represents a 1-C 4 alkyl group or an ethyl group substituted with one or more halogen atoms.
- the compound of the above general formula ( ⁇ ) and the compound of the above general formula ( ⁇ ⁇ ) are reacted at a temperature of 10 to 250 ° C., preferably 130 to 180 ° C. for 0.1 to 20 hours, The reaction is preferably performed for 3 to 6 hours.
- the compound of the above general formula (IV) obtained by the above reaction can be separated and purified, if necessary, by ordinary separation and purification means, for example, distillation, adsorption, distribution chromatography and the like.
- the compound of the above general formula (IV) may be separated and purified as described above and used in the next step, but may be directly subjected to the following reaction without purification.
- the compound represented by the general formula (IV) and the compound represented by the general formula (V) are converted into a base, for example, sodium carbonate, carbonated lime, cesium carbonate, sodium hydride, potassium hydride, In the presence of triethylamine, diazabicycloundecene, etc.
- a suitable solvent such as acetonitrile, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, methylpyrrolidone, etc.
- the reaction is carried out for up to 100 hours, preferably for 5 to 20 hours, to obtain the compound of the above general formula (I ′).
- the method of obtaining the compound of the above general formula ( ⁇ ), the compound of the above general formula ( ⁇ ), and the compound of the above general formula (IV), which are the raw materials of the reaction route (1) is not particularly limited. Commercially available ones can be used, or they can be appropriately synthesized and used by a method known per se. Further, the compound of the above general formula (V) can be prepared by mixing a compound of the following general formula (VI) and a compound of the general formula (VIII) in a suitable solvent such as acetonitrile, dimethyl sulfoxide or the like at 50 to 100 ° C. Obtained by heating.
- a suitable solvent such as acetonitrile, dimethyl sulfoxide or the like
- R 1 , R 2 , R 5 , R 6 , X and W are as defined above. You. )
- the compound of the above general formula (IV) and the compound of the above general formula (VI) obtained in the reaction route (1) is converted into a base, for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, hydrogenation 10-20 in a suitable solvent such as acetonitril, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, methylpyrrolidone in the presence of potassium, triethylamine, diazabicycloundenecene, etc.
- a suitable solvent such as acetonitril, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, methylpyrrolidone in the presence of potassium, triethylamine, diazabicycloundenecene, etc.
- a suitable solvent such as acetonitril, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, methylpyrrolidone in the presence of potassium, tri
- the compound of the above general formula (VII) and the amine of the above general formula (VIII) or a hydrochloride thereof are converted into an appropriate compound such as acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, methylpyrrolidone or the like.
- an appropriate compound such as acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, methylpyrrolidone or the like.
- the reaction is carried out for 512 hours to obtain the compound of the above general formula (I ′).
- the compound of the general formula (I ′) is a compound represented by the general formula (I) in which R 3 and R 4 are each an alkyl group of ⁇ C 6 or an ethyl group substituted
- the method for obtaining the compound of the above general formula (VI), which is a raw material of the reaction route (2), is not particularly limited, and a commercially available reagent may be used, or the compound may be appropriately synthesized by a method known per se. It can also be used.
- R 3 of the compounds of general formula (I) is a hydrogen atom, an alkyl group of ⁇ CP, is represented by Echiru group substituted with Ashiruchi Oechiru group or one or more halogen atoms, R 4 is ⁇ C.
- the compound represented by the alkyl group of formula (I) or an ethyl group substituted by one or more halogen atoms is a compound of the above general formula (I ′) and the following general formula (IX)
- R 7 OH (IX) R 7 represents a hydrogen atom, a C 4 alkyl group, an acylthioethyl group or an ethyl group substituted with one or more halogen atoms.
- the compound of formula (IX) is reacted at a temperature in the range of 10 to 100 ° C, preferably 20 to 30 ° C, for 0.1 to 100 hours, preferably 5 to 12 hours in the presence of Obtained.
- R 3 and R 4 are each independently a hydrogen atom, an alkyl group of Ci to C, an acylthioethyl group or an ethyl group substituted with one or more halogen atoms, It is obtained by the following method.
- R 1 , R 2 ⁇ ", R 5 , and X are as defined above, and R 8 or R J are each independently an alkyl group, an acylthioethyl group, or one or more Represents an ethyl group substituted with a halogen atom.
- the compound of the above general formula (I ′′) is reacted with trimethylsilyl getylamine in a suitable solvent, for example, a chlorinated solvent such as dichloromethane, dichloroethane, and chloroform for about 1 hour at about room temperature.
- a suitable solvent for example, a chlorinated solvent such as dichloromethane, dichloroethane, and chloroform
- trimethylsilyl getylamine should be used in an amount of 2 mol or more per 1 mol of the compound of the above general formula (I ′′).
- an appropriate solvent for example, a chlorinated solvent such as dichloromethane, and oxalyl chloride is added to this solution based on 1 mol of the compound of the above general formula (1 ''). Add 2 mol or more, and react in the presence of catalytic amount of dimethylformamide for about 1 hour under ice-cooling and about 1 hour near room temperature.
- the obtained compound of the above general formula (X) is usually purified, without purification, using a suitable solvent, for example, a chlorinated solvent such as dichloromethane, pyridine, acetonitrile, tetrahydrofuran, dimethylsulfoxyl. , Dimethylformamide, methylbi Among loridone and the like, a compound of the general formula (XI) and a compound of the general formula (XII) and a compound of the general formula (XII) at a temperature of 10 to 100 ° C., preferably 20 to 30 ° C .; The reaction is carried out for 100 hours, preferably for 5 to 12 hours.
- a suitable solvent for example, a chlorinated solvent such as dichloromethane, pyridine, acetonitrile, tetrahydrofuran, dimethylsulfoxyl. , Dimethylformamide, methylbi Among loridone and the like, a compound of the general formula (XI
- R 3 and R 4 of the compound of the general formula (I) each independently represent a hydrogen atom, an alkyl group of up to C 4 , an acylthioethyl group or one or more halogen atoms. It is a compound represented by a substituted ethyl group.
- the compound of the general formula (I ′′), which is a raw material in the above reaction, can be obtained by hydrolyzing the compound of the general formula (I ′) as described above. )),
- a compound of the above general formula (I ′) is obtained from a compound in which R 6 is an alkyl group of ⁇ C 4 , and this is efficiently obtained by reacting the compound with triethylodosilane, trimethylbutamosilane or the like.
- R 1 () represents an acyloxymethyl group
- Y represents a chlorine atom, a bromine atom, or an iodine atom.
- a base such as sodium carbonate, carbon dioxide rim, and carbonic acid
- cesium sodium hydride, potassium hydride, triethylamine, pyridine, diazabicyclocundenecene, N, N'-dicyclohexyl-41-morpholinecarboxamidine, acetonitril, tetrahydrofuran
- a suitable solvent such as dimethyl sulfoxide, dimethylformamide, methylpyrrolidone, etc. at a temperature of 0 to 200 ° C, preferably 10 to 100 ° C. It is obtained by reacting for 300 hours, preferably for 10-200 hours.
- the compound of the above general formula (I) thus obtained can be used, if necessary, by appropriately selecting ordinary means for separating and purifying nucleotides, for example, recrystallization, adsorption, ion exchange, distribution chromatography and the like. Can be separated and purified.
- the compounds of the present invention have antitumor activity, as shown in the test examples below, as an antiviral agent and as found in other ionic phosphonate nucleotide analogs.
- RNA viruses such as human immunodeficiency virus, influenza virus, hepatitis C virus, simple virus I, simple virus II, and virus Examples include DNA viruses such as tomegalovirus, varicella-zoster virus, and hepatitis B virus, and more preferably, hepatitis B virus.
- the compound of the present invention or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof is used as a pharmaceutical
- the compound is administered alone or in combination with a pharmaceutically acceptable carrier.
- the type of pharmaceutical composition is determined by the solubility, chemical properties, route of administration, dosage regimen, and the like, of the compound. For example, granules, fine granules, powders, tablets, hard syrups, soft capsules, troches, syrups, emulsions, soft gelatin capsules, gels, pastes, suspensions, ribosomes, etc. It can be administered orally in the form of an injection, or it can be administered intravenously, intramuscularly, or subcutaneously as an injection, or it can be used as an injection, prepared from powder for injection You can also.
- a pharmaceutically acceptable carrier is a pharmaceutical organic or inorganic solid or liquid suitable for oral, enteral, parenteral or topical administration.
- the solid carrier used in producing a solid pharmaceutical composition include lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate, agar, pectin, and stearic acid. , Magnesium stearate, lecithin, sodium chloride and the like.
- the liquid carrier used for producing a liquid pharmaceutical composition for oral administration include glycerin, peanut oil, polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, and physiology. Saline, water and the like.
- the pharmaceutical composition of the present invention may contain, in addition to the above carriers, auxiliary agents such as wetting agents, suspending agents, sweetening agents, fragrances, coloring agents and preservatives.
- Liquid pharmaceutical compositions may also be used in capsules of absorbable substances such as gelatin.
- the solvent or suspending agent used for the production of a pharmaceutical composition for parenteral administration, ie, an injection include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like.
- C 97002 The compound of the present invention, in particular, the ester derivative represented by the above general formula (I ′) has a high oral absorbability as shown in the test examples described later. Is a preferred composition.
- the above pharmaceutical compositions can be prepared according to a conventional method.
- the dose When used by oral administration, the dose is generally 1 to 500 mgZkg per day, preferably 5 to 5 OmgZkg per day in terms of the compound of the present invention, which is an active ingredient for adults.
- the dosage may be increased or decreased as appropriate depending on the disease state, symptoms, presence / absence of co-administered drugs, and the like.
- the above-mentioned daily dose may be administered once a day, divided into two to several times a day at appropriate intervals, or may be administered intermittently.
- it When used as an injection, it is generally 0.1 to 5 OmgZkg per day, preferably 0.1 to 5 mgZkg per day in terms of the compound of the present invention, which is an active ingredient for adults. is there.
- 2-amino-6- (dimethylamino) purin 7.1 (40 mmo1) was suspended in 300 ml of dimethylsulfoxide, and 1,8-diazabicyclo [5.4.0] ENDES—7—6,6 ml (4 4 mmo 1) and 100. The reaction was performed at C for 1 hour. Next, 11.5 ml of 2- [bis (2,2,2-trifluoroethyl) phosphonylmethoxyl] ethyl chloride was added to the above reaction solution, and the mixture was reacted at 100 ° C. for 2 hours. After the reaction, the mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in black-mouthed form, adsorbed on a silica gel column, and eluted with 5% methanol-chloroform to give 2.35 g (12%) of the title compound having the following physical properties.
- Example 2 dimethylamine hydrochloride was used instead of methyl-1-propylamine.
- the title compound having the following physical properties was obtained in the same manner as described above except that the compound was used.
- Example 1 a 2-amino-6- (methylphenylamino) purine was used in place of 2-amino-6- (dimethylamino) purine, and a similar method was used.
- the title compound having the following physical properties was obtained.
- Example 1 the property of Byonia was determined in the same manner except that 2-amino-6- (phenylamino) purine was used instead of 2-amino-6- (dimethylamino) purine. The title compound shown was obtained.
- Example 1 1-chloroisopropyl chloromethyl ether was used in place of 2-chloroethylchloromethyl ether, and 2-amino-6- (dimethylamino) purine was used instead of 2-amino-6- (dimethylamino) purine.
- the title compound having the following physical properties was obtained in the same manner except that phenylamino) purine was used.
- the HBV proliferation inhibitory effect was measured according to a known method (K. UEDA, eta1., VIROLOGY, 169, 213-216 (1989)).
- HB611 cells (recombinant human hepatoma cells that produce HBV) 2 x 10 4 cells were transfected with 10% fetal bovine serum, streptomycin (100 / zg / ml), penicillin (1001 The cells were cultured at 37 ° C. in Dulbecco's ME medium containing U / m 1) and dineticin (trade name, an antibiotic manufactured by Life Techno Kuchizu Co., Ltd.) (0.2 mg / m 1). After the medium was changed on the 2nd and 5th days of culture, the samples were replaced with a medium containing 10 / M or 1 / M at the final concentration on the 8th, 11th and 14th days of the culture. ⁇ DNA was recovered.
- the amount of HBV-DNA in the cells was measured using a Southern blot, and the rate of HBV-DNA synthesis inhibition in the cells was determined.
- the compound concentration required for killing 50% of the HB611 cells was also determined.
- PME A and its bis (pivaloyloxymethyl ester) were also determined.
- the results are shown in Table 1 below. The compound numbers correspond to the compound numbers in Table-1.
- a single oral dose of 1 gZkg or 0.3 g / kg was given to a rat consisting of three rats per group, and blood was collected 1 hour after administration to prepare serum.
- the cells were cultured at 37 ° C in Dulbecco's ME medium containing (100 ⁇ g / m 1), penicillin (100 I UZm 1), and dieneticin (0.2 mg / m 1). After the medium was changed on the second and fifth days of culture, the medium was replaced with a medium containing 5% of the above serum (rat serum after oral administration of the sample) after 8, 11, and 14 days of culture. After 17 days of culture, the DNA of the cells was recovered. The amount of HBV-DNA in the cells was measured by Southern blot, and the rate of HBV-DNA synthesis inhibition in the cells was determined. For reference, a similar test was performed for PME A. The results are shown in Table 13 below. Compound No. is the compound in Table-1 Table 1 3 compounds corresponding to No. Oral dosage HB V—DNA synthesis inhibition rate
- the test substance was administered to mice at a dose of 1,000 and 2,000 OmgZkg, and bone marrow smears were prepared 24, 30, 48, and 72 hours after the administration.
- the negative control group (0.5% tragacanth aqueous solution) and the positive control group [2 mg / kg of mitomycin C (MMC) was intraperitoneally administered once
- bone marrow smears were prepared 24 hours after administration.
- Specimens were stained with Giemsa by a conventional method, and 2,000 polychromatic erythrocytes were observed per animal, and the number and appearance frequency (%) of those with micronuclei were determined.
- significance tests were performed between the negative control group and the test substance-administered group on the polychromatic erythrocytes having micronuclei by the Kasternbaurn and Bowman estimation methods.
- the phosphonate nucleotide derivative of the present invention has excellent antiviral activity. Since it exhibits high oral absorption, it is expected to be useful as a pharmaceutical.
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Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP96917686A EP0832896A4 (en) | 1995-06-15 | 1996-06-14 | NUCLEOTIDES DERIVED FROM PHOSPHONATES |
US08/973,762 US6197775B1 (en) | 1995-06-15 | 1996-06-14 | Phosphonate nucleotide derivatives |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP14901495 | 1995-06-15 | ||
JP7/149014 | 1995-06-15 |
Publications (1)
Publication Number | Publication Date |
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WO1997000262A1 true WO1997000262A1 (fr) | 1997-01-03 |
Family
ID=15465793
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1996/001631 WO1997000262A1 (fr) | 1995-06-15 | 1996-06-14 | Nucleotides derives de phosphonates |
Country Status (6)
Country | Link |
---|---|
US (1) | US6197775B1 (ja) |
EP (1) | EP0832896A4 (ja) |
KR (1) | KR19990022752A (ja) |
CN (1) | CN1078593C (ja) |
CA (1) | CA2224710A1 (ja) |
WO (1) | WO1997000262A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9593137B2 (en) | 2011-12-22 | 2017-03-14 | Geron Corporation | Guanine analogs as telomerase substrates and telomere length affectors |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2394654A1 (en) | 1999-12-17 | 2001-06-21 | Manfred Weigele | Proton pump inhibitors |
EP1248790A1 (en) * | 1999-12-17 | 2002-10-16 | Ariad Pharmaceuticals, Inc. | Proton pump inhibitors |
DE60028253T2 (de) * | 1999-12-17 | 2007-03-08 | Ariad Pharmaceuticals, Inc., Cambridge | Neue purine |
WO2003028737A1 (en) * | 2001-08-30 | 2003-04-10 | Mitsubishi Pharma Corporation | Anti-viral agents and in-vitro method for the identification of candidates able to inhibit binding of polymerase to epsilon |
HUP0501070A2 (en) * | 2001-11-14 | 2006-04-28 | Biocryst Pharmaceuticals | Nucleosides preparation thereof and use as inhibitors of rna viral polymerases |
KR20050044587A (ko) * | 2001-12-07 | 2005-05-12 | 미쯔비시 웰 파마 가부시키가이샤 | B형 간염 바이러스 감염 치료용 포스포네이트뉴클레오타이드 유사체의 용도 |
US20060111324A1 (en) * | 2002-09-26 | 2006-05-25 | Lg Life Sciences | (+)-Ttrans-isomers of (1-phosphonomethoxy-2-alkylcyclopropyl)methyl nucleoside derivatives, process for the preparation of stereoisomers thereof, and use of antiviral agents thereof |
US20050065171A1 (en) * | 2003-06-25 | 2005-03-24 | Shakespeare William C. | Substituted purine derivatives |
EP1831235B1 (en) * | 2004-12-16 | 2013-02-20 | The Regents of The University of California | Lung-targeted drugs |
US20060188559A1 (en) * | 2005-02-18 | 2006-08-24 | E. T. Browne Drug Co. | Topical cosmetic compositions comprising alpha arbutin |
WO2006130217A2 (en) * | 2005-04-01 | 2006-12-07 | The Regents Of The University Of California | Substituted phosphate esters of nucleoside phosphonates |
LT2970346T (lt) | 2013-03-15 | 2018-11-26 | The Regents Of The University Of California | Acikliniai nukleozido fosfonato diesteriai |
SI3194411T1 (sl) | 2014-09-15 | 2022-07-29 | The Regents Of The University Of California | Nukleotidni analogi |
EP3875462A1 (en) | 2015-09-15 | 2021-09-08 | The Regents of The University of California | Nucleotide analogs |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994003467A2 (en) * | 1992-08-05 | 1994-02-17 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiretroviral enantiomeric nucleotide analogs |
JPH0770159A (ja) * | 1993-06-29 | 1995-03-14 | Mitsubishi Chem Corp | ホスホナートヌクレオチドエステル誘導体 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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DE69426904T2 (de) * | 1993-06-29 | 2001-10-11 | Mitsubishi Chemical Corp., Tokio/Tokyo | Phosphonat-Nukleotid Ester-Derivate |
US5977061A (en) * | 1995-04-21 | 1999-11-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | N6 - substituted nucleotide analagues and their use |
-
1996
- 1996-06-14 CA CA002224710A patent/CA2224710A1/en not_active Abandoned
- 1996-06-14 EP EP96917686A patent/EP0832896A4/en not_active Withdrawn
- 1996-06-14 US US08/973,762 patent/US6197775B1/en not_active Expired - Fee Related
- 1996-06-14 CN CN96196228A patent/CN1078593C/zh not_active Expired - Fee Related
- 1996-06-14 KR KR1019970709194A patent/KR19990022752A/ko not_active Application Discontinuation
- 1996-06-14 WO PCT/JP1996/001631 patent/WO1997000262A1/ja not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994003467A2 (en) * | 1992-08-05 | 1994-02-17 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiretroviral enantiomeric nucleotide analogs |
JPH0770159A (ja) * | 1993-06-29 | 1995-03-14 | Mitsubishi Chem Corp | ホスホナートヌクレオチドエステル誘導体 |
Non-Patent Citations (1)
Title |
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See also references of EP0832896A4 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9593137B2 (en) | 2011-12-22 | 2017-03-14 | Geron Corporation | Guanine analogs as telomerase substrates and telomere length affectors |
US10035814B2 (en) | 2011-12-22 | 2018-07-31 | Geron Corporation | Guanine analogs as telomerase substrates and telomere length affectors |
US10562926B2 (en) | 2011-12-22 | 2020-02-18 | Geron Corporation | Guanine analogs as telomerase substrates and telomere length affectors |
US11279720B2 (en) | 2011-12-22 | 2022-03-22 | Geron Corporation | Guanine analogs as telomerase substrates and telomere length affectors |
Also Published As
Publication number | Publication date |
---|---|
EP0832896A1 (en) | 1998-04-01 |
CA2224710A1 (en) | 1997-01-03 |
US6197775B1 (en) | 2001-03-06 |
EP0832896A4 (en) | 1998-11-25 |
CN1192744A (zh) | 1998-09-09 |
CN1078593C (zh) | 2002-01-30 |
KR19990022752A (ko) | 1999-03-25 |
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