WO2017025031A1 - Dérivé d'alcaloïde spiro-dione pipérazine diazaoxa-hétérocyclique à activité antivirale et son procédé de préparation - Google Patents

Dérivé d'alcaloïde spiro-dione pipérazine diazaoxa-hétérocyclique à activité antivirale et son procédé de préparation Download PDF

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WO2017025031A1
WO2017025031A1 PCT/CN2016/094330 CN2016094330W WO2017025031A1 WO 2017025031 A1 WO2017025031 A1 WO 2017025031A1 CN 2016094330 W CN2016094330 W CN 2016094330W WO 2017025031 A1 WO2017025031 A1 WO 2017025031A1
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formula
compound
methyl
group
solvate
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PCT/CN2016/094330
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于跃
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于跃
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Priority to CN201680002296.8A priority Critical patent/CN106795174B/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
    • 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
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems

Definitions

  • the present invention relates to a bis-oxaoxacyclohexanedione piperazine alkaloid derivative and a preparation method thereof, and to the above-mentioned bis-oxaoxacyclohexanedione piperazine alkaloid derivative in the preparation of an antiviral drug application.
  • the diazoxide heterodone piperazine alkaloid derivative of the present invention has broad-spectrum antiviral activity and exhibits strong antiviral activity against both RNA virus and DNA virus, especially to respiratory syncytial virus (RSV).
  • Herpes simplex virus (HSV-1) and enterovirus 71 (EV71) have strong inhibitory activities.
  • Respiratory syncytial virus (RSV, also known as Paramyxoviridae) is an RNA virus belonging to the family Paramyxoviridae.
  • RSV infection can cause pneumonia and a variety of lower respiratory tract diseases. At least 3 million infants and young children worldwide are admitted to the hospital each year because of RSV infection. At least 160,000 of them die, so RSV is also known as child killer (Science, 2013, 342, 546). -547).
  • ribavirin ribavirin
  • ribavirin is the only chemotherapeutic drug used in clinical practice (J. Med. Chem. 2008, 51, 875–896).
  • Herpes simplex virus (HSV-1) is a wrapped DNA virus belonging to the herpes family virus, which can cause various diseases in humans, such as gingivostomatitis and keratoconjunctivitis. Encephalitis and infections of the reproductive system and neonates.
  • Enterovirus 71 is the main pathogen of hand, foot and mouth disease. It was first isolated from sputum specimens of infants with central nervous system diseases in California in 1969. It is a new enteric virus discovered by humans. Mainly infected with infants and young children, it can cause acute infections with fever, rash, herpes and herpes angina in the hands, feet, mouth and other parts. The infection is often accompanied by neurological complications, which can lead to children. death. At present, although there are some reports on EV71 replication cycle antiviral drugs, EV71 vaccine development, RNA, etc., no clinically effective prevention and treatment measures have been found.
  • the present invention provides a bis-oxaoxacyclohexanedione piperazine alkaloid compound of the formula I, a tautomer thereof, a stereoisomer thereof, a racemate thereof, and an enantiomer thereof A non-equal mixture, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, characterized in that the compound of formula I has the structure:
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, alkyl, cycloalkyl, alkyl acyl, alkoxy acyl, cycloalkyl acyl, alkenyl, alkenyl acyl, alkynyl, Alkynyl, aryl, arylalkyl, aryl acyl, heteroaryl, heteroarylalkyl, heteroaryl acyl, saturated or unsaturated heterocyclic, saturated or unsaturated heterocyclic alkyl, saturated Or an unsaturated heterocyclic acyl group; the above R 1 , R 2 , R 3 , R 4 groups are optionally hydroxy, hydroxymethyl, carboxy, acetylamino, C1-C4 alkyl (eg methyl, ethyl, propyl) , trifluoromethyl, trifluoroacetyl, decyl, halogen, nitro, amino, azido (
  • the compounds of formula I according to the invention do not include compounds 239 and 539 and their racemates, but may include stereoisomers thereof, non-isomeric mixtures of enantiomers thereof, geometric isomers thereof, solvates thereof, A solvate of a pharmaceutically acceptable salt or a salt thereof.
  • R 1 , R 2 , R 3 , R 4 are each independently selected from H, C1-C8 alkyl, C1-C8 alkyl acyl, C1-C8 alkoxy acyl, C3- C10 cycloalkyl, C3-C10 cycloalkyl acyl, C2-C8 alkenyl, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkynyl, C6-C10 aryl, C6-C10 aryl C1-C4 alkyl, C6-C10 aryl acyl, C5-C12 heteroaryl, C5-C12 heteroaryl C1-C4 alkyl, C5-C12 heteroaryl acyl, 4 to 12-membered saturated or unsaturated a heterocyclic group, a 4- to 12-membered saturated or unsaturated heterocyclic group C1-C4 alkyl group, a 4- to 12-membered
  • R 1 , R 2 , R 3 , R 4 are each independently selected from H, C1-C8 alkyl, C3-C10 cycloalkyl, C1-C8 haloalkyl, C1-C8 alkane.
  • R 3 and R 4 are each independently H, methyl, ethyl, isopropyl, C 5 H 11 , C 6 H 13 , C 8 H 17 , 3-hydroxy-propyl base 2-carboxy-ethyl P-chlorobenzyl, m-nitrobenzyl, phenyl, furan-3-yl, naphthalen-1-yl, quinoline-8-yl, trifluoromethyl, acetyl, chloroacetyl (ClCH 2 CO), Propionyl, valeryl, hexanoyl, heptanoyl, octanoyl, cyclopropanoyl, cyclohexanoyl, benzoyl, m-fluorobenzoyl, m-methoxybenzoyl, m-azidobenzoyl, tri Fluoroacetyl, allyl, ethynyl, propargyl,
  • R 1 , R 2 , R 3 , R 4 groups may be optionally a hydroxyl group, a hydroxymethyl group, a carboxyl group, an acetylamino group, C1-C4 alkyl (such as methyl, ethyl, propyl), fluor
  • R 3 and R 4 are each independently H, methyl, ethyl, isopropyl, C 5 H 11 , C 6 H 13 , C 8 H 17 , 3-hydroxy-propyl base 2-carboxy-ethyl P-chlorobenzyl, m-nitrobenzyl, phenyl, furan-3-yl, naphthalen-1-yl, quinoline-8-yl, trifluoromethyl, acetyl, chloroacetyl (ClCH 2 CO), Propionyl, valeryl, hexanoyl, heptanoyl, octanoyl, cyclopropanoyl, cyclohexanoyl, benzoyl, m-fluorobenzoyl, m-methoxybenzoyl, m-azidobenzoyl, tri Fluoroacetyl, allyl, ethynyl, propargyl,
  • R 3 and R 4 are each independently H, methyl, acetyl, trifluoroacetyl, trifluoromethyl, tert-butoxycarbonyl; the other definitions are the same as above.
  • the compound of formula I is selected from the group consisting of the compounds of Tables 1-5 or tautomers thereof, stereoisomers thereof, racemates thereof, non-equivalence of enantiomers thereof A mixture of the mixture, its geometric isomer, its solvate, its pharmaceutically acceptable salt or a salt thereof.
  • R 1 , R 2 , R 3 , R 4 are specific to the corresponding positions in the specific compounds 1-239, 301-539, 601-893, and 900-953 in Tables 1-5. Group.
  • the present invention provides a bisoxazinidine spirobiperazine alkaloid compound of the formula I-1, a tautomer thereof, a stereoisomer thereof, a racemate thereof, and an enantiomer thereof A non-equal mixture, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, characterized in that the compound of the formula I-1 has the structure:
  • R 1, R 2, R 3 , R 4 is defined above with various embodiments of the compound of formula I is R 1, R 2, R 3, R 4 is defined.
  • the compound of the formula I-1 of the present invention does not include And racemates of the two, but may include stereoisomers thereof, non-isomeric mixtures of enantiomers thereof, geometric isomers thereof, solvates thereof, pharmaceutically acceptable salts thereof or salts thereof Solvate.
  • the present invention provides a diisoxazole spirodione piperazine alkaloid compound of the formula I-2, a tautomer thereof, a stereoisomer thereof, a racemate thereof, and an enantiomeric thereof
  • R 1, R 2, R 3 , R 4 is defined above with various embodiments of the compound of formula I is R 1, R 2, R 3, R 4 is defined.
  • the present invention provides a bisoxazinidine spirobone piperazine alkaloid compound of the formula I-3, a tautomer thereof, a stereoisomer thereof, a racemate thereof, and an enantiomer thereof A non-equal mixture, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, characterized in that the compound of formula 1-3 has the following structure:
  • R 3 is 3, R 4 defined for the compound of formula I each of R in the above embodiments.
  • the present invention provides a bisisoxazoline spidinone piperazine alkaloid compound of the formula I-4, a tautomer thereof, a stereoisomer thereof, a racemate thereof, and an enantiomer thereof
  • R 3 is 3, R 4 defined for the compound of formula I each of R in the above embodiments.
  • the alkenyl group involved in the group contains one or more double bonds unless otherwise specified; the alkynyl group involved in the group contains one or more triple bonds, and any of the alkynyl groups involved Containing one or more double bonds; the alkyl group referred to in the group, for example, the alkyl group in the "alkyl group, alkyl acyl group, arylalkyl group, haloalkyl group, haloalkyl group" is a linear or branched alkyl group.
  • alkenyl groups involved in the group for example
  • the alkenyl group in the "alkenyl group, alkenyl group” is a linear or branched alkenyl group, and has one or more double bonds, preferably a C2-C8 straight or branched alkenyl group, and further preferably a vinyl group or a propylene group.
  • cycloalkyl group in the cycloalkyl acyl group is a C3-C10 cycloalkyl group, preferably a cycloprop
  • aryl group referred to in the group for example, "aryl” in the "aryl, arylalkyl, aryl acyl” is an aromatic hydrocarbon Base a monocyclic, bicyclic, fused ring aryl group, further preferably a monocyclic or bicyclic aryl group having 6 to 10 carbon atoms, further preferably a phenyl group or a naphthyl group; a heteroaryl group referred to in the group such as the "heteroaryl group”
  • the heteroaryl group in the "heteroarylalkyl group, heteroaryl acyl group” is an aryl group
  • Chemical bond in the compound of formula I, formula I-1, formula I-2, formula I-3, formula I-4 of the present invention Means pointing to the key in the paper at the same time Or point to the key outside the paper
  • pharmaceutically acceptable salt in the present invention means a non-toxic addition salt of an inorganic or organic acid and/or a base, see “Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201–217. These salts can be prepared in situ during the final isolation and purification of the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or by subjecting the base or acid functional groups to the appropriate organic or inorganic Prepared separately by acid or base reaction.
  • Representative salts include, but are not limited to, the following: acetate, adipic acid Salt, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, butyrate, camphorate, digluconate, cyclopentane propionate , dodecane sulfate, ethanesulfonate, glucoheptonate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydrogen iodine Acid salt, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectate, over Sulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thi
  • the basic nitrogen-containing group may be quaternized by a lower alkyl halide such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; dialkyl sulfate, For example, dimethyl, diethyl, dibutyl and dipentyl sulfate; long chain halides such as decyl, dodecyl, tetradecyl, octadecyl chloride, bromide and iodide An aralkyl halide such as benzyl and phenethyl bromide. Water or oil soluble or dispersible products are thus obtained.
  • a lower alkyl halide such as methyl, ethyl, propyl and butyl chloride, bromide and iodide
  • dialkyl sulfate For example, dimethyl, diethyl, dibutyl and dipentyl sulfate
  • Examples of the acid which can be used to form a pharmaceutically acceptable acid addition salt include the following acids: inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid; organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, lemon Acid, fumaric acid, glucuronic acid, formic acid, acetic acid, succinic acid.
  • inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid
  • organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, lemon Acid, fumaric acid, glucuronic acid, formic acid, acetic acid, succinic acid.
  • the basic addition salt can be prepared in situ during the final isolation and purification of the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or by reacting a carboxylic acid group with a suitable
  • the base e.g., a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation
  • ammonia or an organic primary, secondary or tertiary amine is prepared separately or reacted with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, alkali metal and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, aluminum salts, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, Ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.
  • solvate in the present invention means a solvate of the compound of the formula I, the formula I-1, the formula I-2, the formula I-3, the compound of the formula I-4 or a salt thereof and the organic solvent and/or water.
  • the organic solvent is preferably acetone, acetonitrile, methanol or ethanol
  • the solvate formed is preferably a monohydrate of the compound of the formula I, the formula I-1, the formula I-2, the formula I-3, the compound of the formula I-4 or a salt thereof, Hydrate, trihydrate, monomethanolate, dimethanolate, monoacetonitrile, diacetonitrile, monoacetone, diacetone, hemi-fumarate monohydrate, fumarate Dihydrate, fumarate monoethanolate, and the like. Further preferred are monohydrate, fumarate dihydrate, fumarate monoethanolate. Further preferred are compounds 1100-1105.
  • geometric isomer as used in the present invention means both Z and E geometric configurations when a compound having a double bond is contained in the compound of Formula I, Formula I-1, Formula I-2, Formula I-3, and Formula I-4. compound of.
  • the compounds of the formula I, the formula I-1, the formula I-2, the formula I-3 and the formula I-4 of the present invention exist in various tautomeric forms (in which the proton of one atom of the molecule is transferred to another atom, the molecular The chemical bonds between the atoms are then rearranged). See, for example, March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pp. 69-74 (1992).
  • tautomer as used herein. Refers to compounds produced by proton transfer, it being understood that all tautomeric forms (as long as they may be present) are included within the scope of the invention.
  • non-equal mixture of enantiomers refers to a mixture of two pairs of enantiomers in non-equimolar amounts, i.e., having an ee value greater than zero and less than 100%.
  • Compounds of the invention including compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or stereoisomers thereof, and any pharmaceutically acceptable salts, esters, metabolites thereof and
  • the drug may contain asymmetrically substituted carbon atoms.
  • Such asymmetrically substituted carbon atoms may allow the compounds of the invention to exist in enantiomers, diastereomers, and other stereoisomeric forms, which may be defined as, for example, (R)- or (based on absolute stereochemistry). S) - configuration.
  • the compound of formula I, formula I-1, formula I-2, formula I-3, formula I-4 is selected from the compounds of Tables 1-5 or tautomers thereof, stereoisomers thereof, and racemization thereof.
  • the solvate of the solvate or salt of the formula I and the formula I-1 is preferably a monohydrate, a fumarate dihydrate or a fumarate monoethanolate; further preferably a compound 1100-1105.
  • R 1 , R 2 , R 3 , and R 4 in the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, and Formula I-4 are the specific compounds in Tables 1-5. Specific groups at corresponding positions in 1-239, 301-539, 601-893, and 900-953.
  • Another embodiment of the present invention provides an antiviral agent, which comprises one or more of Formula I, Formula I-1, Formula I-2, Formula I-3, and Formula I-4.
  • Compounds or tautomers thereof, stereoisomers thereof, racemates thereof, non-isomeric mixtures of enantiomers thereof, geometric isomers thereof, solvates thereof, pharmaceutically acceptable thereof Any one or more of a salt of a salt or a salt thereof is used as an active ingredient.
  • Another embodiment of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any one or more of Formula I, Formula I-1, Formula I-2, Formula I-3, and Formula I-4.
  • Another embodiment of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any one or more of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or a compound thereof a tautomer, a stereoisomer thereof, a racemate thereof, a non-isomeric mixture of its enantiomers, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a salt thereof Any one or more of the solvates, and at least one other antiviral drug.
  • the pharmaceutical composition is preferably an injection, an oral preparation, a lyophilized powder injection, a suspension, or the like.
  • Another embodiment of the invention provides any one or more of the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or tautomers thereof, and stereoisomers thereof a solvate of a body, a racemate thereof, a non-equal mixture of its enantiomers, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a salt thereof, in the preparation of an antiviral drug use.
  • Another embodiment of the invention provides any one or more of the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or tautomers thereof, and stereoisomers thereof a treatment, and/or prevention of a body, a racemate thereof, a non-equal mixture of its enantiomers, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof Application in medicines for respiratory diseases, hand, foot and mouth disease, immune diseases, and inflammatory diseases.
  • Another embodiment of the invention provides any one or more of the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or tautomers thereof, and stereoisomers thereof a treatment, and/or prevention of a body, a racemate thereof, a non-equal mixture of its enantiomers, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof Application in medicines for diseases caused by RSV, HSV-1, EV71.
  • the disease is selected from the group consisting of: respiratory diseases, pneumonia, gingivitis, keratoconjunctivitis, encephalitis, reproductive system infections, rashes of the hands, feet, mouth, etc., herpes and herpetic angina.
  • Another embodiment of the invention provides any one or more of the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or tautomers thereof, and stereoisomers thereof, and stereoisomers thereof
  • the medicament is for the treatment of diseases caused by respiratory syncytial virus (RSV), herpes simplex virus (HSV-1), and enterovirus 71 (EV71).
  • RSV respiratory syncytial virus
  • HSV-1 herpes simplex virus
  • EV71 enterovirus 71
  • Another embodiment of the invention provides any one or more of the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or tautomers thereof, and stereoisomers thereof, and stereoisomers thereof
  • Application of EV71 drug lead compound is any one or more of the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or tautomers thereof, and stereoisomers thereof.
  • Another embodiment of the invention provides any one or more of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or each other An isomer, a stereoisomer thereof, a racemate thereof, a non-isomeric mixture of its enantiomers, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a salt thereof
  • An isomer, a stereoisomer thereof, a racemate thereof, a non-isomeric mixture of its enantiomers, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a salt thereof The use of solvates in the preparation of anti-RSV, HSV-1, EV71 drug candidates.
  • Another embodiment of the present invention provides a process for the preparation of a compound of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, comprising the steps of:
  • This step of the reaction can be carried out in accordance with the method disclosed in JP-A-2013-53115A or a similarly improved
  • Step (2) The compound of the formula II is refluxed in an organic solvent under the action of an oxidizing agent to give a compound of the formula III.
  • the oxidizing agent is preferably mCPBA or hydrogen peroxide; the oxidizing agent is preferably used in an amount of from 2.0 to 4.0 times, more preferably from 2.5 to 3.5 times, the molar amount of the compound of the formula II; and the organic solvent is preferably acetone, dichloromethane, chloroform or THF.
  • Step (3) The compound of the formula III is reacted in an organic solvent under the action of an initiator or a base to obtain a compound of the formula IV (that is, a compound of the formula I-3, I-4 when R 3 and R 4 are H).
  • the initiator is selected from the group consisting of Ag + containing compounds or TEMPO, preferably Ag 2 CO 3 , AgNO 3 , AgOAc, AgOTf, Ag 2 O; bases preferably alkali metal carbonates or alkali metal hydrogencarbonates such as Na 2 CO 3 , K 2 CO 3 , Rb 2 CO 3 , Cs 2 CO 3 ;
  • the organic solvent is preferably DMF, DMA, THF, acetonitrile, acetone, toluene; and the reaction temperature is 0 to 60 ° C, preferably 20 to 40 ° C.
  • R 4 is the same as the definition of R 3 and R 4 in any of the above aspects of the invention
  • the base is preferably an alkali metal carbonate (preferably Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 ), alkali metal hydroxide (preferably LiOH, NaOH, KOH), alkali metal hydride (preferably NaH, LiH or KH) or alkali metal al
  • Step (5) The compound of the formula V is reacted in an organic solvent under a reducing agent to give a compound of the formula VI (i.e., a compound of the formula I-1, I-2 when R 1 and R 2 are H).
  • the reducing agent is preferably H 2 and Pd/C, H 2 and PtO 2 , H 2 and Raney Nickel, sodium borohydride, sodium cyanoborohydride, borane (BH 3 , B 2 H 6 ).
  • the reaction temperature is preferably -20 ° C to reflux temperature.
  • the organic solvent is preferably dichloromethane, methanol, ethyl acetate, acetone, THF, acetonitrile or chloroform.
  • Step (6) the compound VI is subjected to an alkylation reaction or an acylation reaction to obtain a compound of the formula VII (ie, a compound of the formula I-1, I-2 when R 1 and R 2 are different at the same time), and the alkylation reaction conditions are in the art.
  • a compound of the formula VII ie, a compound of the formula I-1, I-2 when R 1 and R 2 are different at the same time
  • the alkylating agent is preferably R 1 X or R 2 X (halogenated hydrocarbon), wherein X is a halogen, preferably chlorine, bromine, iodine, R 1 ,
  • R 2 is the same as the definition of R 1 and R 1 in any of the above aspects of the invention
  • the base is preferably an alkali metal carbonate (preferably Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 ), an alkali metal hydroxide (preferably LiOH, NaOH, KOH), an alkali metal hydride (preferably NaH, LiH or KH) or an alkali metal alkoxide (preferably CH 3 ONa, EtONa, t-BuOK);
  • the acylation reaction conditions are also conventional in the art: In an organic solvent, the reaction is carried out under the action of a base and an acylating agent, wherein the acylating agent is
  • the organic solvent is preferably dichloromethane, acetonitrile, benzene, toluene, THF, diethyl ether, ethylene glycol dimethyl ether, DMF, dioxane or the like.
  • Step (1) The compound of the formula III is reacted in an organic solvent under a reducing agent to give a compound of the formula VIII.
  • the reducing agent is preferably H 2 and Pd/C, H 2 and PtO 2 , H 2 and Raney Nickel, sodium borohydride, sodium cyanoborohydride, borane (BH 3 , B 2 H 6 ).
  • the reaction temperature is preferably -20 ° C to reflux temperature.
  • the organic solvent is preferably dichloromethane, methanol, ethyl acetate, acetone, THF, acetonitrile or chloroform.
  • Step (2) The compound of the formula VIII is reacted in an organic solvent under the action of a base or a Mitsunobu reagent to obtain a compound of the formula IX (that is, the formula I-1, I when R 1 , R 2 , R 3 and R 4 are both H) -2 compound).
  • the base is preferably an alkali metal carbonate or an alkali metal hydrogencarbonate such as Na 2 CO 3 , K 2 CO 3 , Rb 2 CO 3 , Cs 2 CO 3 , an alkali metal hydroxide (preferably LiOH, NaOH, KOH), a base.
  • Metal hydride preferably NaH, LiH or KH
  • alkali metal alkoxide preferably CH 3 ONa, EtONa, t-BuOK
  • Mitsunobu reagents preferably DEAD and PPh 3 , DIAD and PPh 3 , DEAD and PEt 3 , DIAD and PEt 3
  • the organic solvent is preferably DMF, DMA, THF, acetonitrile, acetone, dichloromethane, chloroform; the reaction temperature is 0 to 60 ° C, preferably 20 to 40 ° C.
  • R 1 OR 1 , R 2 OR 2 , R 3 OR 3 or R 4 OR 4 (anhydride), wherein X is a halogen, preferably chlorine, bromine, iodine, the definitions of R 1 , R 2 , R 3 , R 4 are the same as the invention at any preceding for R 1, R 2, R 3 , R 4 is defined
  • the base is preferably an alkali metal hydroxide (e.g., NaOH, KOH), triethylamine, pyridine, sodium acetate, quinoline, imidazole, dimethylaniline, DMAP, 2,6- lutidine.
  • the organic solvent is preferably dichloromethane, acetonitrile, benzene, toluene, THF, diethyl ether, ethylene glycol dimethyl ether, DMF, dioxane or the like.
  • Method 3 Compounds 239 and 539 were obtained according to the method described in Chinese Patent (Application No.: 201510201548.7): Compounds 239 and 539 are then structurally modified by similar hydrocarbylation or acylation modification methods in methods one and two to provide a series of compounds falling within the scope of formula I and formula I-1.
  • a synthesis method of Formula IV, Formula V, Formula VI, Formula VII, and Formula IX is provided, which comprises Formula I, Formula I-1, Formula I-2, Formula I-3, and Formula I-4.
  • a method of synthesizing a compound is provided.
  • Another embodiment of the invention provides an intermediate compound of formula III, characterized in that formula III has the structure: a chemical bond in the diketopiperazine ring Means pointing to the key in the paper at the same time Or point to the key outside the paper Chemical bond in sulfhydryl Indicates a "Z" or "E” configuration with a double bond in the imine; n is 0 or 1.
  • Another embodiment of the invention provides an intermediate compound of formula VIII, characterized in that formula VIII has the structure: Chemical bond Means pointing to the key in the paper at the same time Or point to the key outside the paper n is 0 or 1.
  • the synthesis can be carried out according to the synthesis method described in JP-A-2013-53115A, WO2012109256A2, WO2010078373A1, WO2008003626A1; or according to the literature: Journal of Asian Natural Products Research, 2010, 12(1): 51-55 and Chinese Journal of Natural The method described in Medicines, 2011, 9(1): 0078-0080 gives eleutherazine B or cyclo-di-N ⁇ - acetyl-L-ornithyl, followed by hydrazine hydrate according to the literature Fitobib, 2014, Vol. 98, 91-97.
  • the hydrolyzed acyl method described herein hydrolyzes the corresponding acyl group to give the corresponding L-ornithine condensed 2,5-diketopiperazine derivative (compound 1001).
  • KHSO 4 -SiO 2 NaHSO 4 -SiO 2 , H 2 SO 4 -SiO 2 , HClO 4 -SiO 2 or TfOH-SiO 2
  • the above 0.16% KHSO 4 is reacted in a water or alcohol solution at a temperature of 30 to 120 ° C for 4 to 120 hours to obtain a compound 1001 in a yield of 40% to 60%.
  • the oxidizing agent in the above reaction may be replaced by hydrogen peroxide in a molar amount of 2.0 to 4.0 times that of the compound 1001, and the solvent may be replaced by dichloromethane, chloroform or THF; and the compound 1007 may be obtained in a yield of 45% to 75%.
  • reaction starting compound 1001 was replaced by the compound 1002-1006, and the compound 1008-1012 was obtained in a yield of 68%, 72%, 59%, 62%, 57%, respectively.
  • Ag 2 CO 3 may be replaced by Ag 2 CO 3 , AgNO 3 , AgOAc, AgOTf, Ag 2 O or TEMPO in a molar amount of 1.0-2.0 times that of the compound 1001, and K 2 CO 3 may be replaced by Na 2 CO. 3 , Rb 2 CO 3 , Cs 2 CO 3 ; solvent DMA can be replaced by DMF, THF, acetonitrile, acetone, toluene; reaction temperature can be between 0 and 60 ° C, yielding compound 1013 in 65% to 85% yield .
  • reaction starting compound 1007 was replaced with the compound 1008-1012, and the compounds 840, 1014, 900, 1015, 1016 were obtained in yields of 78%, 82%, 65%, 67%, and 65%, respectively.
  • reaction starting material compound 1014 was replaced with the compound 840, 1013, 900, 1015, 1016 to give the corresponding reduced product in a similar yield.
  • Example 4 (3) a method for synthesizing a compound which is modified in accordance with the different hydrocarbylation or different acylation or hydrocarbylation and acylation described in Example 4 (mainly related to Example 4 (4)) or a synthetic method similar thereto,
  • the products of the different hydrocarbylation or different acylation or hydrocarbylation and acylation in Table 1 can be prepared using the corresponding hydrocarbylation or acylating agents.
  • the 1-Boc-acridine-2-carboxylic acid used in the reaction is a racemate, and the corresponding isomer can also be prepared using 1-Boc-acridin-2-carboxylic acid in a single D or L configuration)
  • the single condensation product can be recondensed with the above carboxylic acid to form an asymmetric double condensation product, and then subjected to a hydrocarbylation, acylation, reduction, oxidation, click reaction, etc. according to the method of the present invention to obtain a corresponding substitution in Table 1.
  • the above Boc, Ac, Me, propargyl protected carboxylic acid can be prepared by reacting the corresponding carboxylic acid with Boc 2 O, Ac 2 O, MeI, propargyl bromide or the like.
  • Oxidation of side chain hydroxyl groups after condensation The product of the mono- or dicarboxyl group in the side chain can be obtained by oxidation with the Jones reagent in Example 4 (7).
  • compound 239 was obtained in the yield of 32% and 48%, respectively, under the action of Jones reagent, and the HPLC purity was 98% or more.
  • the methylation reaction was carried out by the methylation method described in Example 4, and then the benzoyl group was removed under MeONa-MeOH to obtain a compound 45-48 in a yield of 60%. about.
  • the compound 231 (1 mmol) was weighed, dissolved in 100 mL of dichloromethane, 2.2 equiv. azide methane (2.2 mmol), 8 mL of water, and a catalytic amount of sodium ascorbate and copper sulfate pentahydrate were added and reacted at 40 ° C for 4.5 h. , TLC detection showed that the reaction was completed, and the reaction mixture was extracted with 200 mL of dichloromethane, and washed successively with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The yield gave Compound 232 with a HPLC purity of 97.3%.
  • Table 1-5 can be prepared.
  • all of the above compounds were structurally confirmed by 1 H NMR, ESI-MS, and HPLC purity. Some of the compounds were confirmed by CD, 1 H- 1 H COSY, HMQC, HMBC, and NOESY. Due to space limitations, the present invention lists the ESI-MS data in Tables 1-5.
  • the acid chloride used in the synthesis process of the present invention can be prepared by the corresponding acid according to the conventional acid chloride preparation method in the art, that is, the corresponding acid is reacted with thionyl chloride or oxalyl chloride.
  • Antiviral activity test method The inhibitory activity of the compound of the present invention against respiratory syncytial virus (RSV), herpes simplex virus (HSV-1), enterovirus 71 (EV71) is tested according to the method described in the patent: CN104800212A; CN104774159A. of. Antiviral activity tests can also be performed according to the literature: Zhang, YJ; Stein, DA; Fan, SM; Wang, KY; Kroeker, AD; Meng, XJ; Iversen, PL; Matson, DOVet. Microbiol. 2006, 117 (2- 4), 117-129; the method described in CN104004042A is tested, or tested by other similar test methods in the prior art.
  • RSV respiratory syncytial virus
  • HSV-1 herpes simplex virus
  • EV71 enterovirus 71
  • the present invention tests the inhibitory activity of all compounds against respiratory syncytial virus (RSV), herpes simplex virus (HSV-1), enterovirus 71 (EV71), for the convenience of the present invention and for a more concise and intuitive understanding of the present invention.
  • RSV respiratory syncytial virus
  • HSV-1 herpes simplex virus
  • EV71 enterovirus 71
  • A indicates that the compound has a half-inhibitory concentration (IC 50 ) of 1-500 ng/mL
  • IC 50 half-inhibitory concentration
  • B indicates that the compound has a half-inhibitory concentration (IC 50 ) of 1.0-20 ⁇ g/mL
  • C indicates a compound.
  • the half-inhibitory concentration (IC 50 ) was greater than 50 ⁇ g/mL.
  • ClCH 2 C(O) represents a chloroacetyl group
  • CF 3 C(O) represents a trifluoroacetyl group
  • C n H 2n+1 represents an n-alkyl group (n is 4, 5, 6, 7, 8) );symbol And a bonding site of N in the structure of R 1 , R 2 , R 3 , and R 3 and a structure of Formula I, Formula I-2, Formula I-3, and Formula I-4;
  • the precipitate is collected by filtration. After drying, the obtained solid is placed at 25 ° C and 60% relative humidity. After two days, fumarate dihydrate 1102 (43 mg) and 1103 (40 mg) were obtained. No racemization of the solvate containing a chiral amino acid in the above solvate was observed by 1 H NMR, solid-state 13 C NMR or specific optical rotation.
  • the solvates or solvates 1100-1105 of the above salts were subjected to differential thermal analysis/thermogravimetric analysis, elemental analysis, infrared absorption spectroscopy, solid state 13 C-NMR analysis, respectively. Only the differential thermogravimetric analysis data is listed below: using Thermo plus TG8120 differential thermogravimetric analyzer (measured sample volume of 3-5mg, heating rate: 10 °C / min, reference material: alumina) for differential thermogravimetric analysis, endothermic peak: 72.1- There is an endothermic peak near 85.3 °C, and an endothermic peak near 177.2-180.3 °C.
  • Compounds 1100-1105 were stored at 40 ° C, 75% relative humidity (see Table 6 for results) and 50 ° C open containers, respectively, and storage stability after 2 months was measured. Regarding the storage stability, the purity of each test compound was measured by HPLC at the initial time and after storage for 2 months, and the results were compared (for the specific method, see the method described in WO2009128421A1).
  • the compounds of the formula I, I-1, I-2, I-3, and I-4 in addition to the compounds described in Tables 1-5 of the present invention may also be synthesized according to the methods described in Examples 1-10.
  • All of the diazoxide heterodoxadione piperazine alkaloid derivatives (Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4) of the present invention are for RSV, HSV-1, and EV71.
  • the half-inhibitory concentration (IC 50 ) is from 1 to 500 ng / mL, and the half-toxic concentration (TC 50 ) is in the range of 10-300 ⁇ g / mL, the compound of the present invention or its stereoisomer, its elimination
  • IC 50 the half-inhibitory concentration
  • TC 50 the half-toxic concentration
  • a non-equal mixture of a polar body, an enantiomer thereof, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, can be used for the preparation of a therapeutic and/or prophylactic respiratory disease, hand and foot.

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Abstract

La présente invention concerne un dérivé d'alcaloïde spiro-dione pipérazine diazaoxa-hétérocyclique à activité antivirale et son procédé de préparation. Ledit composé est un composé de formule (I), présente des activités anti-RSV, HSV-1 et EV71 et a la structure suivante : dans laquelle chacun des R1, R2, R3, R4 est indépendamment choisi parmi H, un alkyle, un cycloalkyle, un alkylacyle, un alcoxyacyle, un cycloalkylacyle, un alcényle, un alcénylacyle, un alcynyle, un alcynylacyle, un aryle, un arylalkyle, un arylacyle, un hétéroaryle, un hétéroarylalkyle, un hétéroarylacyle, éventuellement substitués, un hétérocyclyle saturé ou insaturé, un hétérocyclylalkyle saturé ou insaturé, un hétérocyclylacyle saturé ou insaturé; n est égal à 0 ou 1; et une liaison chimique (A) représente une liaison (B) qui pointe vers l'arrière ou une liaison (C) qui pointe vers l'avant. « ----- » indique une liaison simple ou pas de liaison, et lorsque « ----- » représente une liaison simple, R1 et R2 n'existent pas.
PCT/CN2016/094330 2015-08-10 2016-08-10 Dérivé d'alcaloïde spiro-dione pipérazine diazaoxa-hétérocyclique à activité antivirale et son procédé de préparation WO2017025031A1 (fr)

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WO2024075813A1 (fr) * 2022-10-07 2024-04-11 学校法人中部大学 Synthèse de polypeptides à l'aide d'un composé de dicétopipérazine

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