WO2007101371A1 - Préparation et utilisation d'esters d'acide purine bis-aminés - Google Patents
Préparation et utilisation d'esters d'acide purine bis-aminés Download PDFInfo
- Publication number
- WO2007101371A1 WO2007101371A1 PCT/CN2006/000663 CN2006000663W WO2007101371A1 WO 2007101371 A1 WO2007101371 A1 WO 2007101371A1 CN 2006000663 W CN2006000663 W CN 2006000663W WO 2007101371 A1 WO2007101371 A1 WO 2007101371A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ethyl
- acid
- adenine
- bis
- tert
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title abstract description 48
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 title abstract 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
- 150000003839 salts Chemical class 0.000 claims abstract description 49
- 239000003814 drug Substances 0.000 claims abstract description 31
- 230000003612 virological effect Effects 0.000 claims abstract description 9
- 125000003277 amino group Chemical group 0.000 claims abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 139
- -1 bismuth compound bisphenols Chemical class 0.000 claims description 127
- 229960000643 adenine Drugs 0.000 claims description 88
- 229930024421 Adenine Natural products 0.000 claims description 87
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 44
- 238000006243 chemical reaction Methods 0.000 claims description 41
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 36
- 239000002253 acid Substances 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 27
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 25
- 241000700721 Hepatitis B virus Species 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 208000035473 Communicable disease Diseases 0.000 claims description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- 235000015165 citric acid Nutrition 0.000 claims description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 11
- SUPKOOSCJHTBAH-UHFFFAOYSA-N adefovir Chemical compound NC1=NC=NC2=C1N=CN2CCOCP(O)(O)=O SUPKOOSCJHTBAH-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 235000001014 amino acid Nutrition 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 9
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 8
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 8
- 239000012346 acetyl chloride Substances 0.000 claims description 8
- ZWRUINPWMLAQRD-UHFFFAOYSA-N nonan-1-ol Chemical compound CCCCCCCCCO ZWRUINPWMLAQRD-UHFFFAOYSA-N 0.000 claims description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- 239000000010 aprotic solvent Substances 0.000 claims description 7
- 239000012454 non-polar solvent Substances 0.000 claims description 7
- 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 6
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 6
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 6
- 208000015181 infectious disease Diseases 0.000 claims description 6
- 239000011976 maleic acid Substances 0.000 claims description 6
- 235000011007 phosphoric acid Nutrition 0.000 claims description 6
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 5
- 229910000037 hydrogen sulfide Inorganic materials 0.000 claims description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 5
- 239000011707 mineral Substances 0.000 claims description 5
- 239000002798 polar solvent Substances 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003444 phase transfer catalyst Substances 0.000 claims description 4
- 235000011054 acetic acid Nutrition 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 150000001622 bismuth compounds Chemical class 0.000 claims description 3
- 239000003880 polar aprotic solvent Substances 0.000 claims description 3
- 150000003431 steroids Chemical class 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- 239000004475 Arginine Substances 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- LTKLGLUBPGQLSZ-UHFFFAOYSA-N ClC(C(=O)OCC(C)C)CCCCCCCC Chemical compound ClC(C(=O)OCC(C)C)CCCCCCCC LTKLGLUBPGQLSZ-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 2
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
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- XTHPWXDJESJLNJ-UHFFFAOYSA-M chlorosulfate Chemical compound [O-]S(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-M 0.000 claims description 2
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- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
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- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
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- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 3
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- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 claims 1
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical class NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 claims 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims 1
- 229930185605 Bisphenol Natural products 0.000 claims 1
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- 239000004480 active ingredient Substances 0.000 claims 1
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- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
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- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 1
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- 229920002258 tannic acid Polymers 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- PRDUHXPVDHDGKN-UHFFFAOYSA-N tetrachloromethane;hydrate Chemical compound O.ClC(Cl)(Cl)Cl PRDUHXPVDHDGKN-UHFFFAOYSA-N 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
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- 239000012588 trypsin Substances 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
- 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
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
Definitions
- Hepatitis B is a disease caused by hepatitis B virus (HBV) that is seriously harmful to human health. According to statistics, there are about 350 million chronic HBV carriers in the world, and about 1 million people die each year from diseases caused by HBV. About 120 million people in China are carriers of hepatitis B virus, 28 million hepatitis B patients, and one-third of hepatitis B patients will evolve into chronic hepatitis, cirrhosis or primary liver cancer (HCC).
- HBV hepatitis B virus
- the main drugs for the treatment of chronic hepatitis B include interferons, nucleoside antiviral drugs and immunomodulators.
- Nucleoside antiviral drugs are inhibitors of viral DNA polymerases or reverse transcriptases that stop the synthesis of viral DNA strands and thereby inhibit viral replication.
- nucleoside anti-HBV drugs acyclic nucleoside phosphonates have an important role as analogs of nucleoside 5'-monophosphates, which can bypass rate limiting during nucleoside analog activation.
- the primary phosphorylation reaction therefore, also has an inhibitory effect on DNA viruses that do not encode viral thymidine kinase (TK), with a broader spectrum of antiviral activity (Erik De Clercq Nature Rev. 2002, 1, 13).
- TK viral thymidine kinase
- the structure of the compound is different from that of the L-nucleoside drug, no cross-resistance is generated between the clinically applied L-nucleoside anti-HBV drug such as lamivudine. (Doo E Gastroenterology 2001, 120:1000; Das, KJ Virol 2001, 75:4771) 0 Because of these characteristics, acyclic nucleoside phosphonates represent a class of highly promising antiviral drugs.
- Adefovir diputelohydroquinone (bis(POM)PMEA, abbreviated as ADV) is a double of 9-[2-(phosphonodecyloxy)ethyl]adenine adefovir (PMEA, Adefovir)
- PMEA Adefovir
- ADV has strong antiviral activity against hepatitis B virus (HBV), duck hepatitis B virus (DHBV), and variant hepatitis B virus (YMDD) resistant to lamivudine in vitro and in vivo (Yen MF. Expert Opin Pharmacother. 2004, 5 (11): 2361-7 )» Clinical studies have shown that this drug can significantly improve the liver histology of patients, reduce serum HBV-DNA and transaminase levels, increase the conversion of e antigen (HBeAg), and regardless of the state of HBeAg, Genotype, ethnic differences, or the presence or absence of a variant virus resistant to lamivudine did not affect ADV's anti-HBV activity (Anneke K Raney.
- ADV applications also have the following major defects: (1) Chemical instability, which is highly sensitive to serum enzyme-mediated hydrolysis and does not effectively increase drug concentration at the site of action (Pieter Annaert, Pharmaceutical Research. 1997, 14(4) : 492-496 ); (2) The transport of one molecule of nucleic acid requires the release of two equivalents of potentially toxic formaldehyde and pivalic acid (Jae-Taeg Hwang. Drugs of the Future 2004, 29(2); 163-177).
- the new generation of adefovir prodrugs are designed to increase the metabolic stability of the drug, prolong the duration of action, increase the bioavailability of the drug, and reduce the toxicity of the drug.
- Human peptide transporters are an integrated cytoplasmic membrane protein that mediates the absorption of di- and tripeptides in humans and belongs to the family of proton-dependent oligopeptide transporters. At present, two human peptide transporters (PepTl, PepT2) with transport activity are cloned and functionally confirmed. PepTl is called intestinal peptide transporter, which is mainly present on the comb membrane of intestinal epithelial cells, and mediates the reverse concentration. The gradient of the substrate-proton co-transport process, the natural L-amino acid is its suitable transport substrate (Isabbel Rubio-Aliaga TRENDS in Pharmacological Sciences, 2002, 23(9): 434-440).
- amino acid ester modification methods have been used for antiviral nucleoside derivatives to improve bioavailability and enhance drug efficacy, such as acyclovir and ganciclovir proline ester prodrugs L. -Valaciclovir and L-Valganciclovir increased the bioavailability of the original drug from 6% to 20% to 63% and 61%, respectively (Birger Brodin. Pharmacology & Toxicology. 2002, 90: 285-29; Raymund R Razonable, Expert Rev. Anti-infect. Ther. 2004, 2 (1): 27-42 ).
- the penicillin double L-valine and isoleucine ester derivatives developed by MEDIVIR AB can significantly improve the bioavailability of the original drug and make the drug resistant to varicella virus, scorpion virus and EB-virus.
- Role Per Engelhardt, US 0020188125
- the L-valine ester derivative BRL 44385 of 9-(3-hydroxypropyl-1-oxo)guanine developed by Smithline Beecham can improve the bioavailability of the original drug.
- the drug has a potent inhibitory effect on DNA viruses (parotid virus 1/2, varicella virus, cytomegalovirus, hepatitis B virus, etc.) (Harnden, Michael, WO9509855).
- One object of the present invention is to provide novel terpenoids having antiviral activity, particularly anti-hepatitis B (HBV) and AIDS (HIV) virus activity, and pharmaceutically acceptable salts thereof.
- Another object of the present invention is to provide a process for the preparation of the above novel anthraquinone compound having antiviral activity, particularly against hepatitis B and HIV virus activity, and a pharmaceutically acceptable salt thereof.
- a further object of the present invention is to provide the use of such compounds and their salts as active substances in the manufacture of a medicament for the treatment of infectious diseases caused by viral infectious diseases, in particular HBV and HIV viruses.
- the present invention provides an anthraquinone diaryl acid ester of the formula (I) and a pharmacologically acceptable inorganic or organic salt thereof:
- Ri is an amino group
- R 2 is an amino-protected or free L-form amino acid; n is 0 or 1; X is 0 or S.
- the present invention also provides two processes for preparing a bismuth compound bisamino acid ester having the structure of the above formula (I) and a salt thereof.
- Method 1 Perform Process I as follows:
- DCMC ⁇ , ⁇ '-dicyclohexyl-4-morphine-oxime
- DBU 1,8-two Azabicyclo[5,4,0]undec-7-ene
- N-tert-butoxy-reactive (BOC) L-amino acid ester N-tert-butoxycarbonyl L-amino acid and 2-bromoethanol in an aprotic solvent in the presence of dicyclohexylcarbodiimide (DCC) and indole, indole-diaminopyridine (DMAP), in 0 ⁇ Reacting at 25 ° C for 6-24 hours to obtain N-tert-butoxycarbonyl L-amino acid bromoethyl ester; or
- N-tert-butoxycarbonyl L-amino acid is reacted in isobutyl chloroformate, N-methylmorpholine, hydrogen sulfide gas at a low temperature of -20 - -10 ° C for 1-4 hours to obtain N-tert-butoxycarbonyl group.
- a corresponding pharmaceutically acceptable salt is prepared as needed.
- the guanidine compound trihydrochloride is freed with sodium hydrogencarbonate, sodium carbonate or the like and formed into a sulfate, a phosphate, a lemon with three equivalents of a mineral acid such as sulfuric acid, phosphoric acid and an organic acid such as citric acid or maleic acid.
- the citrate and maleate are prepared in a pharmaceutically acceptable manner according to methods known in the art. (Method 2: Flow II is carried out according to Scheme II below)
- a Oxalyl chloride, hydrazine, ⁇ '-diethyl hydrazide (DEF), 0 ⁇ 50 ° C, 0.5 ⁇ 4.5 hours; b. N, N-dimethylaminopyridine (DMAP), dicyclohexylcarba Amine (DCC), 0 ⁇ 25°C, 6 ⁇ 24 hours; c. Pyridine, triethylamine, 0 ⁇ 25°C, 1 - 10 hours; d. Saturated hydrogen chloride/1,4-dioxane or Acetyl chloride / sterol, -10 ⁇ 25 ° C, 0.5 ⁇ 6 hours.
- DMAP N-dimethylaminopyridine
- DCC dicyclohexylcarba Amine
- Method two includes the following steps: (1) 9-[ 2 _ (phosphonomethoxy)ethyl] adenine in an inert solvent in the presence of a halogenating agent oxalyl chloride and a catalyst, hydrazine, ⁇ '-diethyl hydrazide, 0 to 50 °C, the reaction is carried out for 0.5 to 4.5 hours to obtain a dichlorophosphonate of 9-[2-(phosphonomethoxy)ethyl]adenine.
- N-tert-butoxycarbonyl L-amino acid and ethylene glycol in an aprotic solvent in the presence of dicyclohexylcarbodiimide and indole, indole-diamidopyridine, at 0-25 ° C From 6 to 24 hours, N-tert-butoxycarbonyl L-amino acid-hydroxyethyl ester was obtained.
- the product compound obtained in the above step (3) is in a polar or non-polar solvent in the presence of hydrogen chloride-saturated 1, 4-dioxane or acetyl chloride/nonanol at -10 to 25°. C, the reaction is carried out for 0.5 to 6 hours to obtain a product compound.
- a corresponding pharmaceutically acceptable salt is prepared as needed.
- the guanidine compound trihydrochloride is freed with sodium hydrogencarbonate, sodium carbonate or the like and formed into a sulfate, a phosphate, and a triple equivalent of a mineral acid such as sulfuric acid, phosphoric acid, and an organic acid such as citric acid or maleic acid.
- Citrate and maleate salts and the like are prepared as pharmaceutically acceptable salts by methods known in the art.
- the present invention further provides the use of the adefovir bisphosphonate compound of the formula (I) and a salt thereof for the preparation of a medicament for treating an infectious disease caused by a viral infectious disease, particularly a hepatitis B virus.
- the pharmacologically acceptable salt of the compound of the present invention specifically includes a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid, and tannic acid, acetic acid, propionic acid, oxalic acid, and propylene.
- Acid succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid
- An acid addition salt of an acidic acid such as citric acid, picric acid, methanesulfonic acid or ethanesulfonic acid with an acidic amino acid such as aspartic acid or glutamic acid, or a salt formed with a base such as sodium, potassium, calcium or aluminum.
- a salt of an inorganic base an ammonium salt, a methylamine salt, an ethylamine salt, an ethanolamine salt or the like, or a salt formed with a basic amino acid such as lysine, arginine or ornithine.
- Representative examples of the compound of the formula (I) of the present invention are as follows:
- the steroid bi-amino acid esters and pharmacologically acceptable salts thereof claimed in the present invention have a function of treating infectious diseases caused by viral infectious diseases, particularly HBV and HIV viruses.
- the bismuth compound diamino acid ester and the pharmacologically acceptable salt thereof claimed in the present invention have activity similar to or stronger than those of the nucleoside small molecule anti-HBV drug of the prior art for treating viral infectious diseases. Therefore, these compounds are useful for the preparation of novel drugs for the treatment of viral infectious diseases, particularly infectious diseases caused by HBV and HIV viruses.
- BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be further illustrated by the following examples, but these examples are in no way intended to limit the invention.
- the compounds of the invention can be prepared by two methods.
- the compound of the invention is prepared according to method one:
- the optimum conditions are tetrahydrofuran as a solvent, and the reaction is carried out at -20 to 10 for 2 to 4 hours.
- the obtained product and 1,2-dibromoethane are in an aprotic solvent such as toluene, dichlorodecane, chloroform or tetrahydrofuran in the presence of sodium hydride, sodium t-butoxide, lithium t-butoxide, sodium ethoxide or the like.
- the reaction is carried out at -40 to 10 ° C for 0.5 to 10 hours.
- the optimum reaction conditions are as follows: tetrahydrofuran is used as a solvent in the presence of sodium hydride at -20 to 0 ° C for 2 to 5 hours.
- N-tert-Butoxycarbonyl L-aminothiocarboxylic acid-2-bromoethyl ester was obtained.
- N-tert-butoxycarbonyl (BOC) L-amino acid and bromochloromethane and chlorosulfonate should be obtained as chloropurinyl chlorosulfonate in an inert solvent-water two-phase system (dichloromethane-water, chloroform) - in water, carbon disulfide-water, carbon tetrachloride-water, etc., in the presence of phase transfer catalyst, tetra-n-butylammonium hydrogen sulfate, tetra-n-butylammonium bromide, react at -20 ⁇ 25 °C 0.5 ⁇ After 24 hours, a chloromethyl ester of N-tert-butoxycarbonyl L-amino acid was obtained.
- the optimum reaction conditions are dichloromethane-water as the reaction system, and tetra-n-butylammonium hydrogen sulfate as the phase transfer catalyst, and the reaction is carried out at 0 to 15 ° C for 6 to 12 hours.
- Compounds 1 to 10 are present in a polar solvent such as ethyl acetate, isopropyl acetate or 1,4-dioxane in the presence of hydrogen chloride saturated 1,4-dioxane or acetyl chloride/nonanol.
- the reaction is carried out at -20 - 25 ° C for 0.5-12 hours to obtain compounds 11-20.
- the optimum reaction conditions are as follows: 1,4-dioxane is used as a reaction solvent, and the reaction is carried out at 0 to 10 ° C for 3 to 6 hours in the presence of a hydrogen chloride-saturated 1,4-dioxane.
- the hydrazine compound trihydrochloride is freed with sodium hydrogencarbonate, sodium carbonate or the like and forms a sulfate, a phosphate, a citrate with three equivalents of a mineral acid such as sulfuric acid, phosphoric acid and an organic acid such as citric acid, maleic acid or the like.
- maleate or the like is prepared into a pharmaceutically acceptable salt by a conventional method.
- the compound of the invention is prepared according to method two:
- N-tert-butoxycarbonyl L-amino acid and ethylene glycol in a non-polar solvent such as toluene, dichlorodecane, chloroform or tetrahydrofuran, in 1 ⁇ ,: ⁇ -diaminopyridine, dicyclohexylcarbal The reaction is carried out at 0-25 °C for 6-24 hours in the presence of imine. The optimum conditions are to react with dichloromethane as solvent at 10-25 °C for 12-24 hours to obtain N-tert-butoxycarbonyl L-amino acid-hydroxyl. Ethyl ester. '
- Compounds 21 to 25 are saturated with 1, 4 - dioxane or B in a nonpolar solvent such as 1, 4-dioxane, ethyl acetate, isopropyl acetate or dichlorodecane.
- a nonpolar solvent such as 1, 4-dioxane, ethyl acetate, isopropyl acetate or dichlorodecane.
- the reaction is carried out at -10 to 100 ° C for 0.5-6 hours.
- the optimum reaction conditions are as follows: 1, 4-dioxane as solvent in hydrogen chloride saturation under 1, 4-dioxane conditions , reacting at 0 ⁇ 10 °C for 2 ⁇ 4 hours to obtain compounds 26 ⁇ 30.
- reaction solvent was evaporated to dryness under reduced pressure, and ethyl acetate (20 ml) was added to the residue, and the mixture was allowed to stand at -5 to 0 ° C for 6 hours, and the insoluble materials were filtered off, and the filtrate was washed with 1% citric acid, water and saturated brine, and anhydrous sodium sulfate. The mixture was dried, filtered, and the filtrate was evaporated,jjjjjjjjjjjjjj Yield: 15.17%.
- reaction solvent was evaporated to dryness under reduced pressure, and ethyl acetate (20 ml) was added to the residue, and the mixture was allowed to stand at -5 to 0 ° C for 6 hours, and the insoluble material was filtered off, and the filtrate was washed with 1% citric acid, 7 and saturated brine, anhydrous sodium sulfate. The mixture was dried, filtered, and the filtrate was evaporated,jjjjjjj Yield: 13.15%.
- the ⁇ -tert-butoxycarbonyl-L-proline (2.50 g, 0.0115 mol) was dissolved in 25 ml of dry tetrahydrofuran, cooled to -15 ° C with a water-salt bath, and N-methylmorpholine (11.54 g, 0.0575 mol) and isobutyl chlorodecanoate (1.74 g, 0.0126 mol), and the system was stirred for 30 minutes.
- the temperature is kept below -15 °C, and the hydrogen peroxide gas is introduced into the system.
- the aeration time lasts for 1.5-2 hours. After the hydrogen sulfide gas in the system is absorbed to saturation, the reaction is kept for 2 hours to complete the reaction. .
- reaction solvent was evaporated to dryness under reduced pressure, and ethyl acetate (20 ml, ethyl acetate) was added to the residue, and the mixture was allowed to stand at -5 to 0 ° C, and the insoluble materials were filtered off.
- the filtrate was washed with 10 ⁇ 2 ml of 1% citric acid, 7 J and saturated brine, dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated. EtOAc m. Yield: 13.09%.
- N-tert-butoxy-L-phenylalanine was used as a starting material, and was prepared in a similar manner to that of Example 3 to obtain a white amber compound ( 2S, 2' S ) -9- ⁇ 2-[0 , 0'-bis[(2-tert-butoxycarbonylamino-3-phenylpropionylthio)ethyl]phosphonohydrazide]ethyl ⁇ adenine 61 mg. Yield: 12.67 %.
- ⁇ -tert-Butoxycarbonyl-L-proline was used as a starting material, which was prepared in a similar manner to that of Example 3 to give a pale brown oily compound (2S, 2's) -9- ⁇ 2-[0,0 '-Bis[(1-tert-butoxycarbonyl-2-pyrrolidinylsulfonyl)ethyl]phosphonohydrazide]ethyl ⁇ adenine 55 mg, Yield: 18.61%.
- ⁇ -tert-butoxy-l-isoleucine was used as a starting material, and was prepared in a similar manner to that of Example 3 to give a white foamy compound (2S, 2's) -9- ⁇ 2-[0 , 0'-bis[(2-tert-butoxycarbonylamino-3-mercapto-valerylthio)ethyl]phosphonomethoxy]ethyl ⁇ adenine, 81 mg, Yield: 35.23%.
- Chlorochlorosulfonate (a) Chlorosulfonic acid (100 ml, 1.5 mol), bromochlorosilane ( 50 ml, 0.75 mol) was placed in a reaction flask, and the reaction system was slowly heated to reflux for 3 hours. After the reaction was completed, the system was cooled to room temperature, and then poured slowly into 500 g of crushed ice. After the water was melted, it was extracted with dichloromethane (400 ⁇ 2 ml, ), and the organic layer was separated, dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under normal pressure, and the residue was evaporated under reduced pressure to collect 45-50 ° C / 9-10 mmHg fractions. The product was obtained in 30.25 g, yield: 24.4%.
- N-tert-Butoxycarbonyl-L-proline (3.00 g, 0.0138 mol), sodium hydrogencarbonate (4.59 g, 0.0546 mol) and tetra-n-butylammonium hydrogen sulfate (0.47 g, 0.00138 mol) to 50 ml of water
- the water salt bath was cooled to 0 ° C, and a solution of chloropurinyl chlorosulfonate (a) (2.78 g, 0.0167 mol) in 14 ml of dichloromethane was slowly added dropwise with vigorous stirring. After the dropwise addition, the system naturally rose to room temperature and reacted for 12 hours.
- N-tert-butoxycarbonyl-L-leucine was used as a starting material, and was obtained in a similar manner to that of Example 8 to give a white foamy compound (2S, 2's) -9- ⁇ 2-[0,0 '-Bis[(2-tert-butoxycarbonylamino-4-indolylpentanoyloxy)methylene]phosphonohydrazide]ethyl ⁇ adenine 26 mg, yield: 9.56%.
- ⁇ -tert-butoxy-l-isoleucine was used as a starting material, and was prepared in a similar manner to that of Example 8 to give a white foamy compound (2S, 2's) - 9- ⁇ 2-[0, 0'-bis[(2-tert-butoxycarbonylamino-3-mercaptoloyloxy)methylene]phosphonomethoxy]ethyl ⁇ adenine 85 mg, yield: 15.56%.
- Example 2 The compound prepared in Example 1 (0.21 g, 0.267 mmol) was dissolved in 1 ml of dry 1,4-dioxane, and the system was cooled to 0 ° C with a salt bath under nitrogen, and slowly added dropwise with stirring at 15%. A solution of hydrogen chloride in 1, 4-dioxane (1 ml, 4 mmol) was incubated for 1 hour, and then reacted at room temperature for 3 hours until the product was fully converted. After standing for 30 minutes, the supernatant in the system was aspirated, and the solid was washed with 5 ⁇ 2 ml of ethyl acetate, and the mixture was allowed to stand for 5 times. The solvent was discarded, and the residue was sufficiently dried to give a white foamy solid, 0.176 g, yield: 95.24% .
- Acetyl chloride (0.077 ml, 1.06 mmol) and decyl alcohol (0.058 ml, 1.36 mmol) were placed in 1.6 ml of dry ethyl acetate, and the system was cooled to -5 to 0 ° C in a water salt bath for 30 minutes.
- the compound (30 mg, 0.0379 mmol) of the compound prepared in Example 3 was dissolved in ethyl acetate. After the dropwise addition, the reaction was allowed to stand for 2 hours, and then naturally raised to room temperature for 6 hours until the product was sufficiently converted.
- Example 14 ( 2S, 2' S ) -9- ⁇ 2- "0,0'-biguanide (2-amino-3-phenylpropionylsulfide)ethyl 1phosphonylmethoxy 1ethyl ⁇ gland Preparation of trihydrochloride (Compound 14) The compound prepared in Example 4 was used as a starting material to give a white powdery product (yield: 84.46%).
- Example 17 ( 2S, 2' S ) -9- ⁇ 2- "0,0'-bis"(2-amino-3-methylpentanoylthio)ethyl 1phosphonylmethoxy 1ethyl ⁇ gland
- the trihydrochloride salt (Compound 17 was prepared by the procedure of Example 13 using the compound obtained in Example 7 to give a white fluffy solid, 14 mg, yield: 50.26%.
- the resultant was dissolved in 2 ml of dry dichloromethane, cooled to 0 ° C in an ice salt bath, and 0.3 ml of pyridine was slowly added thereto, and kept at a low temperature (served below 0 ° C).
- Example 26 ( 2S, S ) -9- ⁇ 2-"0,0'-biguanide (2-amino-3-methylbutanoyloxy)ethyl 1phosphonomethoxylethyl) gland Preparation of Trihydrochloride (Compound 26) Using the compound prepared in Example 21 as a starting material, a procedure similar to that of Example 11 was afforded to afford white white solid (yield: 13.
- Example 30 ( 2S, 2' S ) -9- ⁇ 2- ⁇ , 0'-bis((2-amino-4-methylpentanoyloxy)ethyl 1phosphonylmethoxy 1ethyl adenine Preparation of Trihydrochloride (Compound 30) Using the compound prepared in Example 25 as a starting material, a procedure similar to that of Example 11 afforded a pale yellow semi-solid 46 mg, yield: 81.45%.
- 2 ul of viral DNA was placed in a 48 ⁇ l reaction mixture, including 5 mmol/L MgCl2, 0.2 mmol/L 2.5 U Gold Taq polymerase per dNTP, 0.2 U UNG enzyme and Each was 0.4 mmol/L and the probe was 0.15 mmol/L.
- the cells were denatured at 95 ° C for 3 min and 30 s, 94 ° C for 20 s, and 60 ° C for 40 s (fluorescence signal detection) for 41 cycles, and finally stored at 4 ° C.
- the Taqman probe sequence used was detected: 5TAM-CCAGCAGCGCCTCCTCCTGC-3 'TAMARA; Primer sequence: Forward primer: 5'-CCC TCAGGCTCAGGGCATA-3 ', Reverse primer: 5'- CTTCCTGACTGCCGATTGGT-3.
- Test cell line
- HepG 2215 cells cited in the Molecular Virus Laboratory of Fudan University.
- the cell line is obtained by transfecting the receptor cell HepG2 with two head-to-tail HBV DNA whole gene recombinant plasmids, which can stably secrete HBsAg, HBeAg and intact Dane particles in vitro, and can also produce a large number of replication intermediates ( RI).
- the cells were cultured in DMEM containing 10% fetal bovine serum.
- the positive control group was adefovir Dipivoxil.
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Abstract
L'invention concerne des esters d'acide purine bis-aminés représentés par la formule (I) et des sels inorganiques ou organiques pharmaceutiquement acceptables de ces derniers, où R1 est un groupe amino; R2 est un acide L-amino libre ou protégé par un amino; n est 0 ou 1; X est O ou S. L'invention se rapporte également à la préparation desdits composés et à leur utilisation comme principe actif dans la préparation d'un médicament destiné au traitement de maladies virales. (I)
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WO2013017564A2 (fr) | 2011-07-29 | 2013-02-07 | Straitmark Holding Ag | Procédé pour la fabrication de composés contenant un groupe alpha-oxy-phosphoré à l'aide de composants p-x |
US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
Citations (2)
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WO1995009855A1 (fr) * | 1993-10-01 | 1995-04-13 | Smithkline Beecham P.L.C. | Esters d'amino-acide de penciclovir et de brl 44385 |
WO1997030051A1 (fr) * | 1996-02-16 | 1997-08-21 | Medivir Ab | Derives de nucleosides acycliques |
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US5627165A (en) * | 1990-06-13 | 1997-05-06 | Drug Innovation & Design, Inc. | Phosphorous prodrugs and therapeutic delivery systems using same |
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WO1995009855A1 (fr) * | 1993-10-01 | 1995-04-13 | Smithkline Beecham P.L.C. | Esters d'amino-acide de penciclovir et de brl 44385 |
WO1997030051A1 (fr) * | 1996-02-16 | 1997-08-21 | Medivir Ab | Derives de nucleosides acycliques |
Non-Patent Citations (1)
Title |
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BALLATORE C. ET AL.: "Synthesis and evaluation of novel amidate prodrugs of PMEA and PMPA", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 11, no. 8, 2001, pages 1053 - 1056 * |
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WO2013017564A2 (fr) | 2011-07-29 | 2013-02-07 | Straitmark Holding Ag | Procédé pour la fabrication de composés contenant un groupe alpha-oxy-phosphoré à l'aide de composants p-x |
US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
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