WO2013004092A1 - Dérivés de 3-oxo-3,4-dihydro-2-pyrazineformamide, compositions pharmaceutiques les comprenant, leurs procédés de préparation et leurs utilisations - Google Patents

Dérivés de 3-oxo-3,4-dihydro-2-pyrazineformamide, compositions pharmaceutiques les comprenant, leurs procédés de préparation et leurs utilisations Download PDF

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WO2013004092A1
WO2013004092A1 PCT/CN2012/072534 CN2012072534W WO2013004092A1 WO 2013004092 A1 WO2013004092 A1 WO 2013004092A1 CN 2012072534 W CN2012072534 W CN 2012072534W WO 2013004092 A1 WO2013004092 A1 WO 2013004092A1
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oxo
dihydro
pyrazinecarboxamide
compound
virus
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PCT/CN2012/072534
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English (en)
Chinese (zh)
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李松
李行舟
钟武
张振清
张天宏
肖军海
王莉莉
郑志兵
周辛波
赵国明
王晓奎
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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 WO2013004092A1 publication Critical patent/WO2013004092A1/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
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • 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
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the invention belongs to the field of medicine and chemical industry, and relates to a 3-oxo- 3,4-dihydro-2-pyridazine formamide derivative, a pharmaceutical composition thereof, a preparation method thereof and use thereof. Background technique
  • T1105 3-oxo-3,4-dihydro-2-pyrazinecarboxamide
  • T705 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide
  • T1105 nucleoside derivative of T1105
  • T705 alone or in combination with a neuraminidase inhibitor has a good anti-influenza virus effect ( Ant imicrobial Agents and Chemotherapy, 2007, Vol. 51 , No.
  • T1105 exhibits a very good effect against foot-and-mouth disease virus in both in vivo and in vitro models (PCT patent: W020071139081).
  • T705 and T1106 have a good effect on diseases caused by other RNA viruses.
  • T705 has a therapeutic effect on Western-type equine encephalitis in a mouse model ( Ant iviral Research 82 (2009) 169-171); T705 and T1106 have a therapeutic effect on yellow fever in hamsters (Antipromial Agents and Chemotherapy, 2009, 202 - 209 ); T705 has therapeutic effects in vivo and in vitro against diseases caused by arenavirus and Bunia virus infection (Antipromial Agents and Chemotherapy, 2007, 3168-3176).
  • T705 has a therapeutic effect on rodents infected with West Nile virus (Ant iviral Research 80 (2008) 377 - 379 ); T705 has a therapeutic effect on venous viral infection ( Ant iviral (2010) 121 - 127).
  • the three compounds T1105 and T705, and the nucleoside derivative T1106 of T1105 have a similar mechanism of action, which can be converted into the corresponding nucleoside triphosphate form in vivo, by simulating the guanosine triphosphate (GTP) competition.
  • GTP guanosine triphosphate
  • the viral RNA polymerase is inhibited to exert an antiviral effect (ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2005, Vol. 49, No. 3, p. 981-986).
  • T705 have good antiviral effects in an in vitro model, both compounds have some undesirable pharmacokinetic properties that are not conducive to their efficacy.
  • the oral absorption of T1105 is very poor, and the elimination in vivo is also very fast.
  • IC50 is 1.6 ⁇ g/mL, but pigs are administered orally twice a day to achieve a dose of 200 mg/kg to achieve the desired anti-foot-and-mouth disease effect.
  • the elimination of T705 is faster, and there is a problem of short half-life, resulting in a large dosage of the oral dose of 800 mg - 2400 mg per day. Summary of the invention
  • One aspect of the invention relates to a compound of formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof
  • R 2 and R 3 are independently selected from the group consisting of: hydrogen, (d- 6 alkyl acyloxy)-d- 6 alkyl, 1-(d- 6 alkyl acyloxy)-d- 6 alkyl, tetrahydrofuranyl a tetrahydropyranyl group, and a hydroxy or halogen substituted d- 6 alkyl group;
  • the halogen is selected from the group consisting of fluorine, chlorine, bromine, and iodine, and
  • R 2 and R 3 are both hydrogen, they cannot be hydrogen or fluorine.
  • Example 17 demonstrates that the oral bioavailability of Compound 3 and Compound 12 administered orally by mice is significantly higher than that of ⁇ 705.
  • Example 18 demonstrates that the oral bioavailability of Compound 10 and Compound 12 administered orally by monkeys is significantly higher than that of ⁇ 705. Since the antiviral and antifungal effects of ⁇ 705 or T1105 are known in the art, those skilled in the art will be able to anticipate that the compounds of formula I also have antiviral and activity against foot and mouth disease.
  • Example 19 demonstrate that Compound 12 has a mortality rate and average life in mice.
  • the inhibitory effects of live, lung lesions and lung index were reproducible statistically significant, and the therapeutic effect was superior to the currently marketed influenza treatment drug oseltamivir phosphate.
  • the (d- 6 alkyl acyloxy)-d- 6 alkyl group is (d- 6 alkyl acyloxy)-methylene or (d- 6 alkyl acyloxy)-ethyl;
  • the 1-(d- 6 alkylacyloxy)-d- 6 alkyl group is 1-(d- 6 alkyl acyloxy)-methylene or 1-(d- 6 alkyl acyloxy) - Ethyl.
  • (1) is hydrogen or fluorine
  • R 2 is hydrogen, acetoxy-methylene, or 2-tetrahydrofuranyl
  • R 3 is hydrogen, acetoxy-methylene, hydroxymethyl, 2-tetrahydrofuranyl, pivaloyloxy-methylene, butyryloxy-methylene, isobutyryloxy- Methylene, acetoxy-ethyl.
  • the compound of formula I of the present invention is selected from the compounds shown in Table 1 below: Table 1: Partial specific compounds of the invention
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I according to any of the invention, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.
  • composition according to any one of the present invention, further comprising a pharmaceutically acceptable carrier or adjuvant; in particular, the pharmaceutical composition is a solid preparation, an injection, an external preparation, a spray, a liquid preparation, or a combination preparation.
  • the pharmaceutical composition usually contains from 0.1 to 90% by weight of the compound of the formula I and/or a pharmaceutically acceptable salt thereof and/or a hydrate thereof and/or a solvate thereof.
  • Pharmaceutical compositions can be prepared according to methods known in the art. When used for this purpose, if desired, a compound of formula I or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof, may be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants. It can be used as a suitable administration form or dosage form for mammals.
  • the compound of formula I or a pharmaceutical composition containing the same may be administered in unit dosage form, either parenterally or parenterally, such as orally, muscle, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum.
  • Formulations such as tablets, capsules, pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal agents, buccal tablets, suppositories, lyophilized powders Injection, etc. It may be a general preparation, a sustained release preparation, a controlled release preparation, and various microparticle delivery systems.
  • various carriers well known in the art can be widely used.
  • the carrier examples include, for example, a diluent and an absorbent such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline fiber.
  • a diluent and an absorbent such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline fiber.
  • wetting agent, aluminum silicate, etc. wetting agent and binder, such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, gum arabic, gelatin pulp, carboxy Methylcellulose sodium, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrating agents, such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and tannic acid, calcium carbonate , polyoxyethylene, sorbitan fatty acid ester, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenation Oil or the like; an absorption enhancer such as a quaternary ammonium salt, sodium lauryl sulfate or the like; a lubricant such as
  • Tablets may also be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
  • various carriers known in the art can be widely used.
  • the carrier are, for example, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc, etc.; binders such as acacia, tragacanth, gelatin , ethanol, honey, liquid sugar, rice paste or batter; etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, and the like.
  • the drug delivery unit in order to prepare the drug delivery unit as a suppository, various carriers well known in the art can be widely used.
  • the carrier are, for example, polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides and the like.
  • the active ingredient compound of the formula I or a stereoisomer thereof is mixed with the various carriers described above, and the resulting mixture is placed in a hard gelatin capsule or soft capsule.
  • the active ingredient of the compound of the formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof may be prepared as a micro-tank, suspended in an aqueous medium to form a suspension, or may be incorporated into a hard gelatin or may be prepared. Injection application.
  • an injectable preparation such as a solution, an emulsion, a lyophilized powder, and a suspension
  • all diluents conventionally used in the art for example, water, ethanol, polyethylene glycol, 1, 3 can be used.
  • an appropriate amount of sodium chloride, glucose or glycerin may be added to the preparation for injection, and a conventional cosolvent, a buffer, a pH adjuster or the like may be added.
  • a further aspect of the invention relates to a process for the preparation of a compound of formula I according to any one of the inventions, comprising the steps of any of the following methods (1) to (5)
  • R is a Cl-alkyl group
  • R 5 is hydrogen or d- 6 alkyl
  • X is fluorine, chlorine, bromine, or iodine
  • 6--3-oxo-3,4-dihydro-2-pyrazinecarboxamide is directly reacted with 2-d- 6 alkoxytetrahydrofuran under heating Reaction, preparation of 6-N-(tetrahydrofuran-2-yl)-3-oxo-3,4-dihydro-2-pyrazinecarboxamide, 6-1 ⁇ -4-(tetrahydrofuran-2-yl)- 3-oxo-3,4-dihydro-2-pyrazinecarboxamide, and 6-R-[N,4-di-(tetrahydrofuran-2-yl)]-3-oxo-3, 4- Dihydro-2-pyrazinecarboxamide,
  • R is a d- 6 alkyl group, preferably a tert-butyl group
  • the aprotic organic solvent is selected from one or more of dichloromethane, DMF, acetonitrile, DME, and THF;
  • the organic base is selected from one or more of triethylamine, DBU, and diisopropylethylamine;
  • the inorganic base is potassium carbonate or cesium carbonate
  • the halo is substituted with fluorine, chlorine, bromine or iodine.
  • the 2-d- 6 alkoxytetrahydrofuran is 2-tert-butoxytetrahydrofuran
  • the Lewis acid is selected from the group consisting of SnCl 4 , TiCl 4 , and tert-butyldimethylsilyl trifluoromethanesulfonate; and SnCl 4 is preferred.
  • a further aspect of the invention relates to a compound of formula I according to any one of the invention, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, or a pharmaceutical composition according to any of the inventions for the preparation of an antiviral Use in medicine.
  • the virus in the present invention is an RNA virus; specifically, an influenza virus (Influenza Virus), an HCV virus (Hepatitis C Virus), a Bimyavirus, a Phlebovirus, a foot-and-mouth disease virus ( Foot and Mouth Disease Virus ) , West Ni le virus , Arenavirus , Western Equine Encephalitis Virus , or Yellow Fever Virus ;
  • influenza virus is a methyl 1 (H1N1) influenza A virus.
  • a further aspect of the invention relates to a compound of formula I according to any one of the inventions, Use of a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, or a pharmaceutical composition according to any of the present invention, for the manufacture of a medicament for the treatment and/or mammalian foot-and-mouth disease; in particular, the mammal is a hoof The animal; specifically, the cloven-hoofed animal is a pig, a cow, or a sheep.
  • a further aspect of the invention relates to a method of antiviral in vivo or in vitro comprising administering to a subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof, or an effective amount of inclusion
  • a pharmaceutical composition of a compound I or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof is administered to a subject.
  • the subject is a mammal (eg, a human or a monkey), such as a cloven-hoofed animal (eg, pig, cow, or sheep).
  • a further aspect of the invention relates to a method of treating and/or preventing foot-and-mouth disease or influenza in a mammal comprising administering to the mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof, or an effective amount thereof
  • a step of a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof.
  • the mammal is a cloven-hoofed animal.
  • the cloven-hoofed animal is a pig, a cow, or a sheep.
  • a pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof, or an effective amount of a compound comprising a compound of formula I or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof, may be used alone or Mix with animal feed or drinking water.
  • the dose of a compound of formula I or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof depends on a number of factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight and individual response of the patient or animal. , the specific compound used, the route of administration and the number of administrations, and the like.
  • the above dosages may be administered in a single dosage form or divided into several, for example two, three or four dosage forms.
  • the actual dosage level of the active ingredient in the pharmaceutical compositions may be varied so that the amount of active compound obtained is effective to the particular patient, composition, and mode of administration Therapeutic response.
  • the dosage level will be selected based on the activity of the compound of formula I, the route of administration, the severity of the condition being treated, and the condition and past medical history of the patient to be treated. However, it is the practice in the art that the dosage of the compound be started from a level lower than that required to achieve the desired therapeutic effect, and the dosage is gradually increased until the desired effect is obtained.
  • a therapeutically and/or prophylactically effective amount of a compound of the invention may be administered in pure form, or in the form of a pharmaceutically acceptable ester or prodrug (in the presence of such forms) B) Application.
  • the compound can be administered as a pharmaceutical composition comprising the compound of interest and one or more pharmaceutically acceptable excipients.
  • prophylactically and/or therapeutically effective amount refers to a sufficient amount of a compound to treat a disorder with a reasonable effect/risk ratio applicable to any medical prophylaxis and/or treatment.
  • the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dosage level for any particular patient will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; Patient's age, weight, general health, sex and diet; time of administration, route of administration and excretion rate of the particular compound employed; duration of treatment; drug used in combination with or concurrent with the particular compound employed; Similar factors are known in the medical field. For example, it is a practice in the art to start at a dose lower than that required to achieve the desired therapeutic effect, gradually increasing the dosage until the desired effect is achieved. In general, the present invention
  • 011-10100 mg/kg body weight / day for example, between 0. 01-100 mg / kg body weight / day, for example between 0. 01-10 mg /kg body weight / day.
  • the compounds according to the present invention are effective for preventing and/or treating various diseases or conditions described in the present invention.
  • the term "effective amount" means that treatment can be achieved in a subject, The dosage of the disease or condition of the invention is prevented, alleviated and/or alleviated.
  • d-C 6 alkyl or "d- 6 alkyl” (including d- 6 alkyl acyloxy or (d- 6 alkyl acyloxy)-d- 6 alkyl or 1-(d- 6 alkyl acyloxy) -D-C6 alkyl according to any one D- 6 alkyl) means a straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl , isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, etc.
  • d- 6 alkyl oxy group can be similarly understood.
  • the (Cw of alkyl acyloxy) -d- 6 is alkyl (d-3-alkyl acyloxy) -d-3 alkyl or (C 4 - 6 alkyl Acyloxy)-C 4 -6 alkyl.
  • the 1-(Cw alkylacyloxy)-d- 6 alkyl group is 1-(da alkylacyloxy)-d-3 alkyl or 1-(C 4 - 6 alkyl acyloxy) - C 4 - 6 alkyl.
  • d-C 6 alkoxy or "d- 6 alkoxy” refers to a straight or branched alkoxy group having from 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy Base, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-oxopentyl, isooxypentyl, neopentyloxy, hexyloxy, 2-hexyloxy Base, 3-oxohexyl, 3-methylpentyloxy and the like.
  • the "C alkoxy” or "6 D- group” is an alkoxy group or a d- 3 (4 - 6 alkoxy beneficial effects of the invention
  • the compound of the present invention can be converted into the form of T1105 or T705 in vivo to exert an antiviral effect, and at the same time, the bioavailability of the compound can be remarkably improved, and the action time of the compound T705 or T1105 in vivo can be prolonged.
  • Fig. 1 Drugs for T705 after oral administration of compounds 3, 4, 6 and T705, respectively - time curve.
  • Fig. 2 The drug-time curve of T705 after oral administration of compounds 10, 11, 12, 13 and T705, respectively.
  • Fig. 3 Drug-time curve of T1105 after oral administration of compounds 7, 9 and T1105 in mice (T1105 was not detected in blood after oral administration of T1105).
  • Fig. 4 The drug-time curve of the macaques after oral administration of compounds 3, 10, 12, 11, 13 and T705 (in the case of drug testing, 3 monkeys, after giving 1 drug test, after not less than 3 days) During the cleaning period, the next test drug is given).
  • Example 1 N-[(Acetoxy)-methylene]-3-oxo-3,4-dihydro-2-pyrazinylamide (Compound 1) and 4-[(Acetoxy) - Preparation of methylene]-3-oxo-3,4-dihydro-2-pyrazinium amide (Compound 2)
  • Compound 2 Dissolve 1.39 g (l Ommo 1) of T1105 in 10 mL under nitrogen. In anhydrous DMF, after stirring at room temperature for 15 m in, a suspension was added, and 2.20 g (20 mmo 1) of chloromethyl acetate, potassium (2 mmol) and 3.03 g (30 mmol) of triethylamine were added dropwise. The solution is clarified.
  • Example 2 6-Fluoro-4-[(acetoxy)-methylene]-3-oxo-3,4-dihydro-2-pyrazinylamide (Compound 3) and 6-Fluoro- Preparation of 4-(hydroxyindenyl)-3-oxo-3,4-dihydro-2-pyrazinylamide (Compound 4)
  • Compound 4 Compound 3 The same procedure as in Synthesis Example 1, except that T705 was replaced by T705, and 6-fluoro-4-[(acetoxy)-methylene]-3-oxo-3,4-dihydro-2 was mainly obtained. Pyrazinylamide (Compound 3) and 6-fluoro-4-(hydroxymethyl)-3-oxo-3,4-dihydro-2-pyrazinecarboxamide (Compound 4).
  • Compound 12 was the same as in Synthesis Example 11, except that diisopropylethylamine was used instead of triethylamine to give 6-fluoro-4-(isobutyryloxymethylene)-3-oxo-3, 4- Dihydro-2-pyrazinecarboxamide (Compound 12).
  • Example 13 6-Fluoro-4-(isobutyryloxymethylene)-3-oxo-3,4-dihydro-2 -
  • mice Male, 27 ⁇ 2 g were randomly divided into 15 groups according to body weight, with 3 rats in each group.
  • Test compounds were administered orally in a dose of 0.0637 mmol/10 ml/kg (corresponding to 10 mg/10 ml/kg for T705 or T1105) (one group for each compound, i.e., 3 mice). 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 centrifugation for 10 min, and the supernatant was taken by LC/MS/MS. Corresponding test compound and concentration of T705 or T1105. Bioavailability [AUC ( ⁇ * ⁇ )] value calculated by T1105 when metabolized in mice.
  • T705 Bioavailability of T705 calculated by T705 and its derivative compounds 3, 4, 6, 10, 11, 12, 13 and the like when metabolized in mice and monkeys [AUC ( ⁇ * ⁇ ) ]
  • T1105 was orally administered at a dose of 0.0637 mmol/10 ml/kg, no T1105 was detected in mouse plasma, indicating that the oral bioavailability of T1105 was very low.
  • Example 18 Metabolic test in monkeys
  • the next test drug is administered.
  • Experimental drug Compound 12 was formulated into a colorless transparent solution using physiological saline. At the time of the experiment, the compound 12 was formulated into solutions of different concentrations and administered orally.
  • mice Kunming mice, the first and second batches of male and female, the third batch of females, 16-18 grams, provided by the rodent culture center of the Chinese Academy of Medical Sciences, Health certificate.
  • H1N1 Influenza virus A (H1N1) subtype A (FM1 strain) rat lung adaptor strain (provided by the Institute of Medical Biotechnology of Chinese Academy of Medical Sciences, other H1N1 influenza strains can also be purchased or used).
  • Toxicity LD50 to mice is about 10-5.
  • Control drug oseltamivir phosphate, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences.
  • Influenza virus A (H1N1) subtype A (FM1 strain) infection method After anesthetizing the mice with ether, a 40 ⁇ l appropriately diluted virus solution was intranasally dropped by a pipette.
  • the first batch of experiments Compound 12 dose: 30 mg/kg, 100 mg/kg, 300 mg/kg Three dose groups of the drug-administered group, 20 mice per group. Dosing is about 1 hour after infection. The infection control was treated with the same amount of physiological saline. The positive control drug oseltamivir phosphate (5 mg/kg) was given to the stomach once a day, and the administration time was the same as that of the treatment group.
  • the second batch of experiments Compound 12 dose: 30 mg / kg, 100 mg / kg, 300 mg / kg Three dose groups of the drug-administered group, 20 mice per group. Dosing is about 1 hour after infection. The infection control was treated with the same amount of physiological saline. The positive control drug oseltamivir phosphate (10 mg/kg) was given to the stomach once a day, and the administration time was the same as that of the treatment group.
  • the administration time was qd x 5 , and the virus LD50 was simultaneously titrated in each batch of experiments.
  • mice were infected with the appropriate amount of influenza virus FM-1, and the infected mice were divided into three groups, which were treated with 100 mg/kg of compound 12, oseltamivir phosphate 10 mg/kg, and physiological saline. 20 animals per group. Five rats from each group were sacrificed at 24 hours, 48 hours, 72 hours, and 96 hours after infection, and the lungs were aseptically taken. Weighed and stored in a -85 water tank. The lung tissue taken was added to 10 volumes of MEM and an appropriate amount of glass powder, and fully ground into a homogenate. The mixture was centrifuged at 12,000 rpm for 1 minute, and the supernatant was collected. The supernatant was diluted in equal proportions, and CPE was observed on MDCK cells at 24 and 48 hours. Titrate the TCID50 of each lung.
  • Lung lesions, lung index mice were fasted on the 4th day after infection, and the next day, the 5th day after infection, the mice were sacrificed in groups, and the lungs of the rats were taken out, and the degree of lung lesions was visually judged. 0 means no lung lesions, 1-4 is 25% lung lesions per grade. The weight and lung weight of each mouse were weighed, and the lung index of each mouse was calculated, and the average lung index of each group was determined, and compared and statistically processed. The lung index is the ratio of lung weight to rat weight.
  • Mortality mean life day: Daily observation, record the number of deaths per group for 2 weeks, calculate mortality and average life expectancy.
  • Statistical procedures were used to test drug toxicity results and lung index lesions by t-test analysis; lung lesions were examined by Ridi t test; Kaplan-Meier method was used to compare mortality and mean life days.
  • the average daily life index was observed experimentally.
  • the survival rate and average life-day test results of Compound 12 against mouse influenza A (H1N1) subtype A (FM1 strain) are shown in Table 4.
  • the experimental results of lung lesions and lung index are shown in Table 5.
  • Table 4 Pharmacodynamic test survival and average life-day results of compound I 2 against mouse model of influenza virus alpha 1 (H1N1) subtype A (FM1 strain) infection
  • Compound 12 showed reproducible statistical significance in the inhibition of mouse mortality, mean daily life, lung lesions, and lung index in both batches of experiments. This indicates that compound I 2 has a reproducible therapeutic effect on experimental infection of mouse influenza A (H1N1) subtype (FM1 strain), and the therapeutic effect is superior to the currently marketed influenza treatment drug oseltamivir phosphate.

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Abstract

L'invention porte sur des dérivés de 3-oxo-3,4-dihydro-2-pyrazineformamide, sur des compositions pharmaceutiques les comprenant, sur leurs procédés de préparation et sur leurs utilisations. Concrètement, l'invention porte sur les composés représentés par la formule I, leurs sels pharmaceutiquement acceptables, leurs hydrates ou leurs solvates, dans laquelle formule R1 représente H ou un atome d'halogène; R2 et R3 sont chacun indépendamment choisis parmi H ou un groupe (alkyl en C1-6)acyloxy(alkyl en C1-6), 1-((alkyl en C1‑6)acyloxy)(alkyl en C1-6), tétrahydrofuranyle, tétrahydropyranyle et alkyle en C1-6 substitué par OH ou un atome d'halogène, ledit atome d'halogène étant choisi parmi F, Cl, Br et I; et lorsque R2 et R3 représentent tous deux H, R1 ne peut pas être H ou F. Les composés de formule I peuvent être convertis en 6-R1-3-oxo-3,4-dihydro-2-pyrazineformamide correspondant in vivo pour le traitement antiviral. Par comparaison avec le 6-R1-3-oxo-3,4-dihydro-2-pyrazineformamide, les composés de formule I présentent une biodisponibilité supérieure et une plus longue durée d'effet in vivo.
PCT/CN2012/072534 2011-07-01 2012-03-19 Dérivés de 3-oxo-3,4-dihydro-2-pyrazineformamide, compositions pharmaceutiques les comprenant, leurs procédés de préparation et leurs utilisations WO2013004092A1 (fr)

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CN113563273A (zh) * 2020-04-28 2021-10-29 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
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

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