WO2014000541A1 - Analogue nucléotidique acyclique, procédé de préparation s'y rapportant et son application - Google Patents

Analogue nucléotidique acyclique, procédé de préparation s'y rapportant et son application Download PDF

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Publication number
WO2014000541A1
WO2014000541A1 PCT/CN2013/076066 CN2013076066W WO2014000541A1 WO 2014000541 A1 WO2014000541 A1 WO 2014000541A1 CN 2013076066 W CN2013076066 W CN 2013076066W WO 2014000541 A1 WO2014000541 A1 WO 2014000541A1
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WO
WIPO (PCT)
Prior art keywords
compound
group
hydrogen
hydrazine
halogen
Prior art date
Application number
PCT/CN2013/076066
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English (en)
Chinese (zh)
Inventor
谢永美
魏于全
李炯
耿福能
Original Assignee
四川好医生攀西药业有限责任公司
四川大学
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Publication of WO2014000541A1 publication Critical patent/WO2014000541A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • 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
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
    • C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
    • C07F9/65846—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a six-membered ring which may be condensed with another ring system

Definitions

  • the invention belongs to the technical field of chemical synthetic drugs, and particularly relates to acyclic nucleotide analogs, a preparation method thereof and application in antiviral drugs.
  • TDF is effective against a variety of viruses, including those resistant to nucleoside reverse transcriptase inhibitors.
  • Tenofovir is approved by the FDA in 2001 and 2008 for the treatment of HIV and HBV infection. Recent studies have found that tenofovir disoproxil has a good therapeutic effect on HCV infection (Tuma P, Vispo E, Barrei) Ro P, Soriano V. Enferm Infecc Microbiol Clin. 2008, 26 (Suppl 8): 31 -37).
  • TDF can also cause viral resistance. Increasing the concentration of TDF in the in vitro MT-2 cell line produces a virus strain that survives in 2 ⁇ TDF.
  • tenofovir can cause acute renal failure, Fanconi syndrome, proteinuria or tubular necrosis.
  • R 3 is one of hydrogen, hydrazine, halogen, amino, nitro, nitrile, fluoromethyl, linear or branched ⁇ -alkylamino;
  • R4 is one of hydrogen, hydrazine, cyclopropyl, linear or branched or cyclic alkyl, fluoromethyl, hydroxymethyl; ,
  • R 6 , R 7 are independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, aryl or aralkyl, or R 6 , R 7 are independently 1 to 3 selected from alkylamino, alkyl Aminoalkyl, dialkylaminoalkyl, dialkylamino, hydroxy, oxo, halogen, amino, alkylthio, alkoxyalkyl, aryloxy, aryloxyalkyl, aryloxyoxy An alkyl group substituted with a substituent of an arylalkoxyalkyl group, a haloalkyl group, a nitro group, a nitroalkyl group, an azido group, an azidoalkyl group, an alkanoyl group, an alkanoylalkyl group, a carboxyl group or an alkanoylamino group Alkenyl, alkynyl, aryl or aralkyl;
  • hydrogen, halogen, amino, and nitrile groups preferably, hydrogen, hydrazine, halogen, and most preferably hydrogen and hydrazine.
  • hydrogen, hydrazine, halogen, or amino group preferred are hydrogen and halogen.
  • R4 is hydrogen, hydrazine, methyl or hydroxymethyl; preferred is hydrogen, hydrazine, methyl; and most preferred is methyl.
  • Z is 0, S or Se; preferably 0, and S; and most preferably 0.
  • R 7 is independently hydrogen
  • R6, R 7 is independently hydrogen, deuterium, x, X
  • Z is 0, and the structural formula is as follows:
  • R 5 is , which is a linear or branched or cyclic alkane, a substituted aryl group; preferably a substituted aryl group; preferably Z is 0, and the structural formula is as follows:
  • the invention also provides a process for the preparation of the acyclic nucleotide analogue of formula I:
  • R 5 is ⁇ 2 - ⁇ 3 ⁇ 4
  • the route is as follows:
  • Compound 1 and Compound 2 are condensed under basic conditions to obtain Compound 3, and Compound 3 and Compound 4 are alkylated under basic conditions to directly obtain Compound 5; or
  • Io Ru is independently alkyl, alkenyl, alkynyl, aryl or aralkyl; Xi, ⁇ 2 , ⁇ ⁇ 2 are independently 0, S or NH;
  • the present invention also provides the use of the above acyclic nucleotide analog for the preparation of a treatment for chronic hepatitis B, hepatitis C or AIDS.
  • the pharmaceutical composition is prepared by adding an auxiliary agent for the active ingredient to the drug;
  • the active ingredient is at least one of a pharmaceutically acceptable salt, a hydrate or a solvate thereof of the above acyclic nucleotide analog;
  • the pharmaceutically acceptable salt of the compound is an inorganic salt or an organic salt such as a hydrochloride, a sulfate, a fumarate, a methanesulfonate, a sulfonate or the like.
  • the acyclic nucleotide analog of the present invention has antiviral efficacy and provides a new choice for the development of antiviral drugs. detailed description
  • One of a baseoxy group or a substituted arylthio group preferred are hydrogen, hydrazine, halogen, amino group, hydroxyl group, more preferred are hydrogen, amino group, hydroxyl group, and most preferably an amino group.
  • R4 is hydrogen, hydrazine, cyclopropyl, linear or branched or cyclic, alkyl, fluoromethyl, hydroxymethyl; preferably hydrogen, hydrazine, methyl or hydroxymethyl, More preferred are hydrogen, hydrazine, methyl, and most preferred is methyl.
  • * indicates that the compound may be a racemate, R type or S type.
  • Xi X 2 is independently 0, S or NH;
  • Z is 0, S or Se; preferably O and S; most preferably O;
  • R 7 is independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, aryl or aralkyl, or R 7 is independently 1 to 3 selected from alkylamino, alkylaminoalkyl, Alkylaminoalkyl, dialkylamino, hydroxy, oxo, halogen, amino, alkylthio, alkoxyalkyl, aryloxy, aryloxyalkyl, aryloxyoxy, arylalkoxy Alkyl, alkenyl, alkyne substituted with a substituent of an alkyl group, a haloalkyl group, a nitro group, a nitroalkyl group, an azido group, an azidoalkyl group, an alkanoyl group, an alkanoylalkyl group, a carboxyl group or an alkanoylamino group Base, Fang
  • R 7 is independently hydrogen, helium,
  • the substituent is -H, halogen, aryl, -OH, -CF 3 ,
  • Re and R 7 are independently hydrogen , m ,
  • R 5 It is hydrogen, hydrazine, aryl, linear or branched dC 6 alkyl, linear or branched dC 6 haloalkyl, benzyl. It is one of a linear or branched or cyclic alkane, a substituted aromatic group; preferably a substituted aromatic group.
  • Compound 1 and Compound 2 are condensed under basic conditions to give Compound 3, and Compound 3 and Compound 4 are subjected to alkylation under basic conditions to give Compound 5 directly.
  • the compound 3 can be first reacted with the easily available starting material compound 6 to obtain the compound 7, and then deprotected to obtain the compound 8.
  • the compound 8 is reacted with a halogenated hydrocarbon, a phenol or an amine under certain conditions to obtain a compound 5.
  • Ru is independently an alkyl group, an alkenyl group, an alkynyl group, an aryl group or an aralkyl group.
  • ⁇ ⁇ 2 , ⁇ ⁇ 2 Independent is 0, S or NH.
  • the compound 9 and the compound 13, the organic base and the dehydrating agent are added to the solvent, and after reacting for a certain period of time, ethyl acetate is added, and the mixture is washed with water, sodium hydrogencarbonate and brine, dried, filtered, and evaporated. 14.
  • the reaction solvent is selected from the group consisting of hydrazine, hydrazine-dimethylformamide, hydrazine, hydrazine-dimethylacetamide, dimethyl sulfoxide, hydrazine-methylpyrrolidone, and the like;
  • the organic base is selected from 1,8-diazabicyclo[ 5.4.0] undec-7-ene, 4-dimethylaminopyridine, hydrazine, hydrazine-diisopropylethylamine, triethylamine, etc.
  • the dehydrating agent is selected from dicyclohexylcarbodiimide (DCC), ⁇ , ⁇ '-diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), HATU-O azobenzene And triazole]- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyl
  • the invention also provides the use of an acyclic nucleotide analog of formula I for the treatment of chronic hepatitis B, hepatitis C or AIDS.
  • the pharmaceutical composition is prepared by adding an excipient commonly used for the active ingredient to a drug; the active ingredient is at least one of a pharmaceutically acceptable salt, a hydrate or a solvate thereof of the compound of the formula I.
  • the pharmaceutically acceptable salt of the compound is an inorganic salt or an organic salt such as a hydrochloride, a sulfate, a fumarate, a methanesulfonate, a sulfonate or the like.
  • the mixture was separated by a cation exchange resin, and eluted with water until the effluent was neutral, and then the product was eluted with 10% ammonia water, and distilled to give a white solid 6.3 g.
  • the mixture was separated by an anion exchange resin, and the mixture was eluted with water and then evaporated to afford a neutral product of 10% glacial acetic acid.
  • the product was distilled off under reduced pressure to give a white solid 3.46 g. The total yield was 52.3%.
  • Example 11 the compound prepared in Example 7-10 was reacted with fumaric acid in isopropanol to give a compound as shown in Table 2.
  • SI Selectivity Index
  • nucleoside analog has a good inhibitory effect on the secretion of HBV DNA by HBV2.2.15 cells, and the selection index is much larger than 2, and the selection index of some of the compounds is much larger than that of the marketed drug tenofovir. Select the index.
  • the invention has obtained experimentally obtained compounds having better anti-hepatitis B virus, hepatitis C virus, HIV virus and herpes virus, and has good application prospects.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le domaine technique des médicaments chimiquement synthétisés et, en particulier, elle porte sur un analogue nucléotidique acyclique, sur un procédé de préparation s'y rapportant et sur une application de celui-ci dans un médicament antiviral. Le nouvel analogue nucléotidique acyclique selon l'invention a une structure représentée par la formule (I). L'analogue nucléotidique acyclique de la présente invention a une efficacité antivirale et offre un nouveau choix pour le développement de médicaments antiviraux.
PCT/CN2013/076066 2012-06-29 2013-05-22 Analogue nucléotidique acyclique, procédé de préparation s'y rapportant et son application WO2014000541A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201210220153.8 2012-06-29
CN201210220153.8A CN102887901B (zh) 2011-07-01 2012-06-29 无环核苷酸类似物及其制备方法和应用

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Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102887901B (zh) * 2011-07-01 2015-01-07 四川好医生攀西药业有限责任公司 无环核苷酸类似物及其制备方法和应用
MX2019007585A (es) 2016-12-22 2019-09-09 Merck Sharp & Dohme Profarmacos de ester alifatico antiviricos de tenofovir.
CN112961158B (zh) * 2020-03-05 2022-07-01 四川大学华西医院 氨基嘧啶并吡唑/吡咯类衍生物及其制备方法和用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1244200A (zh) * 1996-07-26 2000-02-09 吉里德科学公司 核苷酸类似物
CN101659676A (zh) * 2009-09-07 2010-03-03 徐奎 一种硫代阿德福韦、替诺福韦肝靶向酯前体药物
CN101781334A (zh) * 2010-03-04 2010-07-21 福建广生堂药业有限公司 替诺福韦酯的盐化合物，其制备方法和药物应用
CN102887901A (zh) * 2011-07-01 2013-01-23 四川大学 无环核苷酸类似物及其制备方法和应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1244200A (zh) * 1996-07-26 2000-02-09 吉里德科学公司 核苷酸类似物
CN101659676A (zh) * 2009-09-07 2010-03-03 徐奎 一种硫代阿德福韦、替诺福韦肝靶向酯前体药物
CN101781334A (zh) * 2010-03-04 2010-07-21 福建广生堂药业有限公司 替诺福韦酯的盐化合物，其制备方法和药物应用
CN102887901A (zh) * 2011-07-01 2013-01-23 四川大学 无环核苷酸类似物及其制备方法和应用

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