WO2013004141A1 - Composé de 2-pyrazinylformamide substitué en 3ème position par alcoxy et son utilisation - Google Patents

Composé de 2-pyrazinylformamide substitué en 3ème position par alcoxy et son utilisation Download PDF

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Publication number
WO2013004141A1
WO2013004141A1 PCT/CN2012/077679 CN2012077679W WO2013004141A1 WO 2013004141 A1 WO2013004141 A1 WO 2013004141A1 CN 2012077679 W CN2012077679 W CN 2012077679W WO 2013004141 A1 WO2013004141 A1 WO 2013004141A1
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WIPO (PCT)
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virus
fluoro
group
decanoylamide
preparation
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PCT/CN2012/077679
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English (en)
Chinese (zh)
Inventor
李松
李行舟
钟武
王莉莉
郑志兵
肖军海
周辛波
陈伟
赵国明
王晓奎
Original Assignee
中国人民解放军军事医学科学院毒物药物研究所
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Publication of WO2013004141A1 publication Critical patent/WO2013004141A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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

Definitions

  • the present invention relates to pyrazinamide compounds, processes for their preparation and their use for the preparation of antiviral drugs. Background technique
  • ⁇ 5 ⁇ 1105 It has been reported that ⁇ 705 alone or in combination with a neuraminidase inhibitor such as oseltamivir phosphate has a good anti-influenza effect (Antimicrobial Agents and Chemotherapy, 2007, Vol.51, No. 3, 845-851; Antimicrobial Agents and Chemotherapy, 2010, p. 126 133, PCT Patent: WO2000010569). T1105 exhibits a very good effect against foot-and-mouth disease virus in both in vivo and in vitro models (PCT patent: WO20071139081). In addition, T705 has a good effect on diseases caused by other RNA viruses.
  • T705 has a therapeutic effect on Western-type equine encephalitis in a mouse model (Antiviral Research 82 (2009) 169 171 ); T705 has a therapeutic effect on yellow fever in hamsters (Antimicrobial Agents and Chemotherapy, 2009, p. 202 209 ) T705 has therapeutic effects in vivo and in vitro against diseases caused by arenavirus and Bunia virus infection (Antimicrobial Agents and Chemotherapy, 2007, p. 3168 3176).
  • T705 has a therapeutic effect on rodents infected with West Nile virus ( Ant ivira l Research 80 (2008) 377 379 ); T705 has a therapeutic effect on venous viral infection ( Ant ivira l Research 86 (2010) 121 127 ).
  • T1105 and T705 have good antiviral effects in an in vitro model, both compounds have some undesirable pharmacokinetic properties, which are not conducive to their efficacy.
  • Tl 105 has poor oral absorption and rapid elimination in vivo. It exhibits excellent activity against foot-and-mouth disease virus in vitro, IC50 is 1. 6ug/mL, but pigs are administered orally, twice a day, to reach 200mg. The dose of /Kg can achieve the desired anti-foot-and-mouth disease effect.
  • T705 good oral absorption, but rapid elimination, short half-life problems exist, leading to larger dose, a daily dose of oral J 800mg -! 2400mg o Summary of the Invention
  • the present invention provides a structure having the structure of Formula I. - R! - 3 - 0-R 2 - 2 - pyrazine decanoyl compounds, which can be converted into T1105 or T705 in vivo to exert antiviral effects, and can significantly improve oral bioavailability of compounds. Degree, and prolong the duration of action of the compound in the body.
  • a first aspect of the invention relates to a compound having the structure of formula I, a pharmaceutically acceptable salt or solvate thereof,
  • ⁇ represents hydrogen or halogen; the halogen is fluorine, chlorine, bromine or iodine;
  • R 2 is selected from the group consisting of: an alkyl group; an alkoxy-substituted alkyl group; a cycloalkyl group; an aryl-substituted alkyl group or an aryl-substituted alkyl group having a substituent group selected from the group consisting of an alkoxy group, Alkyl, cycloalkyl, halogen, nitro, nitrile, hydroxy or amino, etc., preferably alkoxy; phenyl or substituted phenyl, said substituent being selected from alkane fL&, alkyl, cycloalkyl, halogen A nitro group, a nitrile group, a hydroxyl group or an amino group, etc., preferably an alkoxy group.
  • the compound according to the first aspect a pharmaceutically acceptable salt or solvate thereof, wherein the alkyl group is a d alkyl group, which is a linear or branched alkyl group having 1 to 10 carbon atoms, for example, a d- 6 alkyl group.
  • the alkyl group includes, but is not limited to, mercapto, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, n-octyl, and the like;
  • the cycloalkyl means a saturated or unsaturated but non-aromatic having from 3 to 12 carbon atoms and a cyclic alkyl group having one or more rings, for example, C 3 - 6 cycloalkyl, said ring
  • the alkyl group includes, for example, an adamantyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclooctyl group, a cyclohexenyl group, etc., preferably a cyclopentyl group and a cyclohexyl group;
  • the alkoxy group means "alkyl-0-", and the alkyl group is as defined above, and includes, for example, ⁇ fL&, ethoxy, n-propoxy, isopropyl fL&, n-butyl fL&, tert-butyl An oxy group, a sec-butoxy group, a n-pentyloxy group or the like, preferably a decyloxy group and an ethoxy group;
  • the aryl group means a monovalent aromatic carbocyclic group having 6 to 12 carbon atoms and having a single ring (for example, phenyl) or a plurality of fused rings (for example, naphthyl or anthracenyl), wherein the fused ring may be aromatic Or may not be aromatic (eg 2-benzoxazolinone, 2H-1, 4-benzoxazin-3(4H)-one-7-yl, etc.), provided that the point of attachment is an aryl group , preferably phenyl;
  • substitution may be a mono- or poly-substitution, and the poly-substitution is, for example, a di-substitution.
  • a second aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to any one of the first aspects of the invention, a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • composition according to the second aspect of the present invention which can be formulated into a solid preparation, an injection, an external preparation, a spray, a liquid preparation or a combination preparation, and the like.
  • a third aspect of the invention relates to a compound according to any one of the first aspects of the invention, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to any one of the second aspect of the invention, in the preparation of an antiviral drug Use or use in the manufacture of a medicament for preventing and/or treating a disease caused by a viral infection.
  • the medicament can be used in a mammal, such as a human or a cloven-hoofed animal, and the cloven-hoofed animal can be a pig, a cow or a sheep.
  • the virus mainly comprises various types
  • RNA virus including but not limited to the following viruses: Influenza Virus, Hepatitis C virus , Bunyavirus , Phlebovirus , Foot and Mouth Di sease Virus , Wes t Ni le virus , sand virus ( Arenavirus ) , Western equine encephalitis virus ( Wes tern Equine Encepha litis Virus ), or yellow fever disease Yel low Fever Virus ).
  • the diseases caused by viral infection are, for example, influenza, hepatitis C, dengue fever, hemorrhagic fever (for example, hemorrhagic fever with nephrotic syndrome), encephalitis, ferrets fever, foot and mouth disease, West Nile virus disease, lymphocytic choriomeningitis , Lazarus, Argentine hemorrhagic fever, Venezuelan hemorrhagic fever, Western equine encephalitis and yellow fever.
  • influenza hepatitis C
  • dengue fever for example, hemorrhagic fever with nephrotic syndrome
  • hemorrhagic fever for example, hemorrhagic fever with nephrotic syndrome
  • encephalitis ferrets fever
  • foot and mouth disease West Nile virus disease
  • lymphocytic choriomeningitis Lazarus
  • Argentine hemorrhagic fever Venezuelan hemorrhagic fever
  • a fourth aspect of the invention relates to the use of a compound according to any one of the first aspects of the invention, a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the prevention and/or treatment of foot and mouth disease in a mammal.
  • the mammal is, for example, a human or a cloven-hoofed animal, and the cloven-hoofed animal may be a pig, a cow or a sheep or the like.
  • a fifth aspect of the invention relates to a process for the preparation of a compound according to any of the first aspects of the invention, which comprises:
  • X is a halogen, including fluorine, chlorine, bromine or iodine
  • X is a halogen, including fluorine, chlorine, bromine or iodine.
  • the invention also relates to a method of preventing and/or treating a disease caused by a viral infection, the method comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound according to any one of the first aspects of the invention, which is Pharmaceutically acceptable salts or solvates or pharmaceutical compositions of the invention.
  • the viruses described therein mainly include various types of RM viruses including, but not limited to, the following viruses: Influenza Virus, Hepatitis C Virus, Bunyavirus, and Phlebovirus ) Foot and Mouth Disease Virus , West Ni le virus , Arenavirus , Western Equine Encephalitis Virus , or Yellow Fever ( Yellow Fever ) Virus ).
  • the diseases caused by viral infection are, for example, influenza, hepatitis C, dengue fever, hemorrhagic fever (for example, hemorrhagic fever with nephrotic syndrome), encephalitis, ferrets fever, foot and mouth disease, West Nile virus disease, lymphocytic choriomeningitis , Lazarus, Argentine hemorrhagic fever, Venezuelan hemorrhagic fever, Western equine encephalitis and yellow fever.
  • the individual in need thereof may be, for example, a mammal such as a human or a cloven-hoofed animal, and the cloven-hoofed animal may be a pig, a cow or a sheep.
  • the compound or pharmaceutical composition of the present invention can be used alone or mixed with drinking water or mixed with animal feed for the prevention and treatment of foot-and-mouth disease of cloven-hoofed animals such as pigs, cows, sheep and the like.
  • the compound of the present invention exerts an antiviral action by metabolizing to T1105 or T705 by an esterase or a P450 enzyme in vivo.
  • the compound of the formula I of the present invention has high bioavailability and in vivo action. The obvious advantages such as long time.
  • Figure 1 is a drug-time curve of T705 in vivo after administration of compound 14, 15, 16, 17 in mice.
  • Figure 2 is a drug-time curve of T1105 in vivo after administration of compound 1, 2, 3, 4, 5 in mice (T1105 was orally administered at a dose of 0. 0637 leg /10/10 ml/kg, and was not detected in plasma. T1105).
  • Example 5 Preparation of 3-n-pentyl-2-pyrazinylamide (Compound 4)
  • Example 13 3-(p-Oxyloxybenzyl)-2-pyrazinecarboxamide (Compound 12 The preparation method is the same as in Example 1, except that n-propanol is substituted for n-propanol to obtain the title compound, 1 ⁇ R(CDC1 3 ) ⁇ (ppm ) , 3.82 (3 ⁇ , s) , 5.51 (2 ⁇ , s) ) , 6.00 (1 ⁇ , brs) ,
  • Step 1 6 Preparation of fluoro-3-ethyl-yl-2-pyrazinecarbonitrile
  • Step 2 6 Preparation of fluoro-3-ethyl 2-pyrazinylamide (Compound 14)
  • 6-fluoro-3-ethyloxy-2-pyrazinium was added in a three-necked flask with a thermometer.
  • the nitrile (1020mg, 6 leg ol) was dissolved in 60mL of 95% ethanol, the ice water bath was reduced to 5 C, 30% H202 and 6N NaOH aqueous solution was added, the reaction was stirred for 2 hours in an ice water bath, and the pH was adjusted to neutral with 1 NHC.
  • the mixture was concentrated under reduced pressure to dryness.
  • the method was the same as in the step 2 of Example 15, except that 6-fluoro-3-butoxy-2-pyrazinecarbonitrile was used instead of fluorenyl-trifluoro- 3-ethyl-2-pyrazole nitrile to obtain 0-fluoro-3. —butyl-2-pyrazinium.
  • the method was the same as that in the second step of Example 15, except that 6-fluoro-3-benzyl-2-pyrazinecarbonitrile was substituted for 6-fluoro-3-ethyloxy-2-pyrazole nitrile to obtain 6-fluoro- 3-Benzyloxy-2-pyrazine ugly ammonia.
  • Step 2 6 Fluoro-3-(p-oxobenzyloxy)-2-pyrazinamide is prepared in the same manner as in Step 2 of Example 15, except that 6-fluoro-3-(p-oxobenzyl fU-2) -Pyrazinephthalonitrile instead of 6-fluoro-3-ethoxy-2-pyrazinonitrile gives 6-fluoro-3-(p-oxobenzyloxy)-2-pyrazinamide, 'H MR CDC ⁇ ) ⁇ 3.31 (3 ⁇ , s) , 5.49 (2 ⁇ , s) ,
  • the method is the same as in the first step of Example 15, except that the ethanol is replaced by n-hexanol to obtain 6-fluoro-3.
  • Step 1 6 Preparation of fluoro-3-(n-octyloxy)-2-pyrazinonitrile
  • Step 2 6 Preparation of fluorine - 3 - ( 3- ⁇ ⁇ benzyloxy) -2-pyrazin decanoyl (compound 20)
  • the method is the same as in Step 2 of Example 15, except that 6-fluoro-3-(3-fluorenylbenzyloxy)-2-pyrazinonitrile is substituted for 6-fluoro-3-ethoxy-2-pyrazinecarbonitrile.
  • Step 1 0-Fluoro-3-((3-ethoxypropyl)oxy]-2-pyrazinonitrile is prepared in the same manner as in Step 1 of Example 15, except that 3-ethoxypropanol is used instead of ethanol.
  • 6-Fluoro-3 - [(3-ethoxypropyl)oxy]-2-pyrazinonitrile, ⁇ NMR (CDCI3) ⁇ 1.19 (3 ⁇ , t, J 7.2 Hz), 2.13 (2H , m) , 3.51 (2H. q.
  • mice Twenty-four KM mice (male, 27 ⁇ 2 g) were randomly divided into 8 groups according to body weight, 3 in each group.
  • the test compound was administered orally by gavage at a dose of 0.0637 mmol/10 ml/kg (equivalent to 10 mg/10 ml/kg for T705 or T1105).
  • 20 ⁇ of blood was collected from the eyelids at different time points, 20 cation internal standard acetonitrile solution, 20 anion internal standard acetonitrile solution, 40 acetonitrile, shaking, 18000 g for 10 min, and the supernatant was taken by LC/MS/MS.
  • Table 1 is data of the blood concentration of T705 in vivo after administration of the compound T705 and the compound 14, 15, 16, 17, 18, 20, 21, etc. in the mice after intragastric administration.
  • Figure 1 is a drug-time curve of T705 in vivo after administration of compound 14, 15, 16, 17 in mice.
  • Compound 16 was shown to significantly extend the half-life of T705.
  • Table 2 is data of the plasma concentration of T1105 in vivo after administration of the compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 in mice.
  • Figure 2 is a drug-time curve of T1105 in vivo after administration of Compound 1-5 in mice. The results showed that Compound 1-11 could significantly improve the oral bioavailability of T1105 (T1105 was orally administered at a dose of 0.0637 mmol/10 ml/kg, and T1105 was not detected in plasma, indicating that T1105 was poorly absorbed orally.
  • Table 1 Data of T705 plasma concentration over time in mice after intragastric administration of compound T705 and compound 14, 15, 16, 17, 18, 20, 21, etc.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé de 2-pyrazinylformamide substitué en 3ème position par alcoxy présentant une structure représentée par la formule I et son utilisation dans la préparation de médications antivirales. Le composé divulgué exerce des effets antiviraux in vivo au moyen du métabolisme du T1105 ou T705 via un estérate ou l'enzyme P450.
PCT/CN2012/077679 2011-07-01 2012-06-28 Composé de 2-pyrazinylformamide substitué en 3ème position par alcoxy et son utilisation WO2013004141A1 (fr)

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CN111349049B (zh) * 2020-02-28 2022-11-11 江苏阿尔法药业股份有限公司 一种法匹拉韦及其中间体的合成工艺
CN113563273B (zh) * 2020-04-28 2023-12-26 中国人民解放军军事科学院军事医学研究院 一种抗病毒的吡嗪酰胺衍生物及其制备方法
CN116687932B (zh) * 2022-02-25 2024-03-29 中国人民解放军军事科学院军事医学研究院 ((3-氨甲酰-5-氟吡嗪-2-基)氧基)甲基异丁酸酯的医药用途
WO2023169119A1 (fr) * 2022-03-10 2023-09-14 中国人民解放军军事科学院军事医学研究院 Forme solide de composé, son procédé de préparation et son utilisation

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