WO2017114509A1 - Aldéhyde et préparation et application associées - Google Patents

Aldéhyde et préparation et application associées Download PDF

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WO2017114509A1
WO2017114509A1 PCT/CN2016/113835 CN2016113835W WO2017114509A1 WO 2017114509 A1 WO2017114509 A1 WO 2017114509A1 CN 2016113835 W CN2016113835 W CN 2016113835W WO 2017114509 A1 WO2017114509 A1 WO 2017114509A1
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group
compound
synthesis
straight
substituted
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PCT/CN2016/113835
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Chinese (zh)
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柳红
年永
李建
希尔根菲尔德饶福
林岱宗
刘海龙
周宇
蒋华良
陈凯先
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中国科学院上海药物研究所
吕贝克大学生物化学学院
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Publication of WO2017114509A1 publication Critical patent/WO2017114509A1/fr

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    • 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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicinal chemistry and pharmacotherapeutics, and in particular to aldehyde-based compounds as enterovirus proteases or coronavirus main protease inhibitors, processes for their preparation, pharmaceutical compositions containing such compounds, and uses.
  • Infectious diseases caused by enteroviruses are common in children. Its clinical features are mild patient burnout, fatigue, low fever, etc. Severe patients can be infected with the whole body, and the vital organs such as brain, heart, liver and spinal cord are damaged, and the sequelae are worse and severe. These diseases are spread all over the world and have a high incidence in humid, warm, poorly populated areas and densely populated areas. Some viruses are often prevalent, and the prevalence in different years can be caused by different types of viruses, and some viruses have a periodicity.
  • EV71 and CVA16 are highly homologous in evolution. Both viruses belong to the family Picaraviridae, Enterovirus, and Human enterovirus A in their taxonomic status. Generally, the clinical symptoms caused by CVA16 infection are milder and less associated with neurological diseases. In addition to causing hand, foot and mouth disease, EV71 often causes serious central nervous system diseases such as encephalitis, meningitis, aseptic meningitis, and acute Delayed paralysis, etc., more serious can lead to pulmonary edema and heart failure, and the mortality rate is extremely high.
  • Enterovirus is a naked virion with a icosahedral structure. Because it is coated with a lipid-free outer membrane, conventional disinfectants are not effective in inactivating the virus. Although the two pathogens are sensitive to temperature, they are completely inactivated at 56 ° C for 30 min, but the virus can survive for several weeks at 4 ° C, and can survive for several years at -20 ° C, and can survive for a long time in the natural environment. Therefore, it is difficult to effectively prevent and control enterovirus infection.
  • the enterovirus is a single strand of sense strand RNA, which has 5'- and 3'-untranslated regions at both ends, and a viral protein coding region in the middle.
  • the coding region contains only one open reading frame, so the original translation product of the virus is a polyprotein precursor with a molecular weight of about 243 kDa.
  • the polyprotein needs to be further cleaved by the virus's own encoded 2A and 3C proteases and processed into 11 mature functional protein subunits (Vp1-Vp4, 2A-2C, 3A-3D) to complete viral replication and assembly.
  • the 2A protease is responsible for the cleavage of the Vp1/2A junction sequence; the 3C protease is responsible for the cleavage of the other 8 sites in the polyprotein (including Vp2/Vp3, Vp3/Vp1, 2A/2B, 2B/2C, 2C/3A, 3A).
  • /3B, 3B/3C, 3C/3D junction sequence because it can recognize multiple different sites, plays a major role in the processing of viral polyprotein precursors, so 3C protease is also called primary protease.
  • the 3C protease also has RNA binding activity. Shin-Ru13 et al.
  • EV71 3C can directly participate in viral replication by binding to the 5'-UTR of the viral genome through two functional motifs, "KFRDI” and "VGK".
  • 3C protease promotes virus proliferation by interacting with various host factors.
  • the host's own protein translation system is shut down by cleavage of the CstF-64 host factor, providing more raw material for viral protein synthesis.
  • the production of the host antiviral factor interferon beta (IFN-[beta]) is inhibited by binding to retinoic acid-inducible gene I (RIG-I).
  • 3C protease inhibitors have the potential to be used in clinical and treatment of diseases associated with enterovirus infections such as hand, foot and mouth disease.
  • the chiral carbon atoms C*, C* 2 , C* 3 are each independently S-type, R-type, or a combination thereof;
  • n 0 or 1;
  • X is CH 2 or NR 5 ;
  • R 1 is selected from the group consisting of unsubstituted or substituted with 1 to 3 substituents: C 3 -C 7 cycloalkyl, trifluoromethyl, C 2 -C 6 alkynyl, 4 to 7-membered heterocyclic, C 5 -C 7 An aryl group, a 5- to 7-membered heteroaryl group; the heteroaryl group having 1 to 3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; the substituents are each independently selected from the group consisting of halogen, C1 to C4 Linear or branched alkyl, C1-C4 straight or branched alkenyl, C2-C4 straight or branched alkynyl, C1-C4 straight or branched alkoxy, C1-C4 straight or branched Alkylcarbonyloxy, cyano, nitro, hydroxy, amino, hydroxymethyl, trifluoromethyl, carboxy, decyl, C1-C4 acyl
  • R 2 is selected from the group consisting of unsubstituted or substituted by 1 to 3 substituents: a C 3 -C 7 cycloalkyl group, a 5 to 12 membered heterocyclic group (preferably a 5 to 7 membered heterocyclic group or a 6-membered aryl group) And a 5- to 7-membered heterocyclic group), a C6-C12 aryl group, a 5- to 12-membered heteroaryl group, or a -Cbz; wherein each of the heterocyclic or heteroaryl groups has 1 to 3 selected from the group consisting of oxygen and sulfur.
  • the substituents are each independently selected from halogen, C1-C6 straight or branched alkyl, C2-C6 straight or branched alkenyl, C2-C6 straight or branched alkynyl , C1-C6 linear or branched alkoxy, C1-C6 straight or branched alkylcarbonyloxy, cyano, nitro, hydroxy, amino, hydroxymethyl, trifluoromethyl, carboxyl, fluorenyl, a C1-C4 acyl group, an amide group, a sulfonyl group, an aminosulfonyl group, a C1-C4 alkyl-substituted sulfonyl group, or two adjacent substituents together with a carbon atom to which they are attached constitute a 5-7 membered ring;
  • R 3 is a C1-C6 alkylene group which is unsubstituted or substituted by 1 to 3 substituents; the substituents are each independently selected from a C1 to C6 straight or branched alkyl group, a C1 to C6 straight chain or a branched alkoxy group, a substituted or unsubstituted C3 to C7 cycloalkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted 5-12 membered heteroaryl group, said heteroaryl group having 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; wherein the cycloalkyl, aryl and heteroaryl groups are one or more selected from halogen, C1-C6 straight or branched alkyl, cyano Substituting a group of a nitro group, an amino group, a hydroxyl group, a hydroxymethyl group, a trifluoro
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, C1-C6 straight or branched alkyl, C2-C6 straight or branched alkenyl, C2-C6 straight or branched alkynyl, a C3-C7 cycloalkyl group, a C1-C6 acyl group, a C5-C7 aryl group, a benzyl group or a 5- to 7-membered heteroaryl group; the heteroaryl group having 1-3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen;
  • the aryl, benzyl or 5- to 7-membered heteroaryl is optionally selected from one or more selected from the group consisting of halogen, C1-C6 straight or branched hydrocarbon, cyano, nitro, amino, hydroxy, hydroxy
  • R 1 is a substituted or unsubstituted phenyl group, preferably an unsubstituted phenyl group.
  • R 2 is a 5-6 membered heterocyclic group containing benzene, N, O or S, preferably a 5-6 membered heterocyclic group having a benzo N group.
  • Y is -CON(R 4 )R 3 -;
  • R 1 is selected from the group consisting of unsubstituted or substituted by 1 to 3 substituents: trifluoromethyl, alkynyl, cyclopropyl, cyclobutane, cyclopentyl, cyclohexane, phenyl , thienyl, pyrazolyl, thiazolyl, pyridyl, furyl.
  • the chiral carbon atoms C* and C* 2 are S-type, and the chiral carbon atom C* 3 is S-type, R-type, or a combination thereof;
  • R 3 is unsubstituted or substituted with 1-3 substituents of C1 ⁇ C6 alkylene; and the substituents are each independently selected from C1 ⁇ C6 straight or branched chain alkyl, C1 ⁇ C6 straight or Branched alkoxy, substituted or unsubstituted C3 to C7 cycloalkyl;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, a C1-C4 straight or branched alkyl group, a C2-C4 straight or branched alkenyl group, and a C2-C4 straight or branched alkynyl group.
  • n 1;
  • R 3 is a C1-C3 alkylene group which is unsubstituted or substituted with 1-3 substituents; the substituents are each independently selected from the group consisting of C1-C6 straight or branched alkyl groups, substituted or not Substituted C3-C6 cycloalkyl; said alkyl or cycloalkyl optionally being selected from one or more selected from the group consisting of halogen, C1-C4 straight or branched alkyl, cyano, nitro, amino, hydroxy
  • the group consisting of a methylol group, a trifluoromethyl group, a trifluoromethoxy group, a carboxyl group, a C1-C4 alkoxy group, a fluorenyl group, and a C1-C4 acyl group is substituted.
  • n 0;
  • X is NR 5 ;
  • R 1 is a group selected from the group consisting of unsubstituted or substituted with 1 to 3 substituents: cyclopentyl, cyclohexane, phenyl, thienyl;
  • R 2 is a group selected from the group consisting of phenyl, benzoheterocyclyl, 5- to 12-membered heteroaryl which is unsubstituted or substituted by 1 to 3 substituents; preferably, the benzoheterocycle And a 5- to 12-membered heteroaryl ring is selected from the group consisting of benzodioxole, hydrazine, isoxazole, 2-hydropropran, pyridine, pyrazole, dihydroimidazopyridine, imidazopyridine, benzo Thiophene, dihydrobenzodioxane, quinoxaline, benzofuran, carbazole, benzimidazole, quinoline;
  • R 5 is selected from the group consisting of hydrogen, a C1 to C4 linear or branched alkyl group, a C2 to C4 linear or branched alkenyl group, and a C2 to C4 linear or branched alkynyl group.
  • the aldehyde group compound is selected from the compounds shown in Table A.
  • the condensing agent is EDCI (1-ethyl-(3-dimethyl) Aminopropyl)carbodiimide hydrochloride);
  • each group is as defined in the first aspect of the invention.
  • the step (3) is carried out in the presence of a base, and the base is selected from the group consisting of sodium hydrogencarbonate or triethylamine.
  • a pharmaceutical composition comprising: a therapeutically effective amount of one or more compounds of the formula (I) according to the first aspect of the invention, or A pharmaceutically acceptable salt.
  • a pharmaceutical composition for the preparation of a disease associated with the treatment or prevention of an enterovirus infection in a third aspect of the invention, there is provided a pharmaceutical composition for the preparation of a disease associated with the treatment or prevention of an enterovirus infection.
  • the pharmaceutical composition is for inhibiting enterovirus and coronavirus replication; preferably, the pharmaceutical composition is for inhibiting enterovirus 3C protease.
  • the related diseases caused by the enterovirus infection include: respiratory tract infection, herpetic angina, epidemic rash, hand, foot and mouth disease or meningitis.
  • a compound of formula (I) according to the first aspect of the invention for the manufacture of a medicament for inhibiting replication of enteroviruses and coronaviruses.
  • the present inventors After long-term and intensive research, the present inventors have prepared a class of compounds of formula I which are capable of inhibiting the replication of enteroviruses and coronaviruses. And the compound has higher inhibitory activity than the enterovirus and coronavirus replication inhibiting compounds of the prior art. Based on the above findings, the inventors completed the present invention.
  • An object of the present invention is to provide an aldehyde group compound represented by the formula (I), a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer or a racemate.
  • Another object of the present invention is to provide a process for producing a compound of the above formula (I).
  • a further object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of the above formula (I) or a pharmaceutically acceptable salt thereof.
  • Still another object of the present invention is to provide a compound of the above formula (I) for the preparation of a disease associated with infection caused by an enterovirus, such as respiratory infection, herpetic angina, epidemic rash, hand, foot and mouth disease, Use in drugs such as meningitis.
  • an enterovirus such as respiratory infection, herpetic angina, epidemic rash, hand, foot and mouth disease
  • the compounds of the invention are useful for inhibiting enterovirus and coronavirus replication, particularly against enterovirus 3C protease.
  • substituted means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 10 naphthenic a group, a C 1 -C 10 alkoxy group, a halogen, a hydroxyl group, a carboxyl group (-COOH), a C 1 -C 10 aldehyde group, a C 2 -C 10 acyl group, a C 2 -C 10 ester group, an amino group, a phenyl group;
  • the phenyl group includes an unsubstituted phenyl group or a substituted phenyl group having 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 10 alkyl, cyano, OH, nitro, C 3 ⁇ C 10 cycloalkyl, C 1 -C 10 alkoxy, amino.
  • each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • C1-C6 alkyl refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, Tert-butyl, or a similar group.
  • 3-8 membered heterocyclic group refers to a group formed by a 3 to 8 membered saturated ring having from 1 to 3 hetero atoms selected from the group consisting of N, S, O; for example, pyrrolidinyl group, Piperidinyl, piperazinyl, morpholinyl, or the like.
  • 6-10 membered aryl refers to a group formed by the loss of one hydrogen atom of a 6 to 10 membered aryl group; for example, a phenyl group, a naphthyl group, or the like.
  • 5-10 membered heteroaryl refers to a group of 5 to 8 membered aryl groups having from 1 to 3 heteroatoms selected from the group consisting of N, S, and O, each of which is heteroaryl.
  • the cyclic system of the group may be monocyclic or polycyclic; for example, pyrrolyl, pyridyl, thienyl, furyl, imidazolyl, pyrimidinyl, benzothienyl, fluorenyl, imidazopyridyl, quinolyl Or a similar group.
  • C1-C6 alkoxy refers to a straight or branched alkoxy group having from 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso Butoxy, sec-butoxy, tert-butoxy, or the like.
  • halogen refers to F, Cl, Br and I.
  • the structural formulae described herein are intended to include all isomeric forms (such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers): for example, containing asymmetric centers R, S configuration, (Z), (E) isomers of the double bond and conformational isomers of (Z), (E).
  • isomeric forms such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers): for example, containing asymmetric centers R, S configuration, (Z), (E) isomers of the double bond and conformational isomers of (Z), (E).
  • a single stereochemical isomer of the compound of the invention or its enantiomer Mixtures of isomers, diastereomers or geometric isomers (or conformational isomers) are within the scope of the invention.
  • tautomer means that structural isomers having different energies can exceed the low energy barrier and thereby transform each other.
  • proton tautomers ie, proton shifts
  • the valence tautomers include interconversion through some bonding electron recombination.
  • C1 to C6 means that the group may have 1 to 6 carbon atoms, for example, 1, 2, 3, 4 or 5.
  • the present invention provides an aldehyde group compound represented by the formula (I), an enantiomer thereof, a diastereomer, a racemate, a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • each group is as described above.
  • n, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 are each independently the corresponding group corresponding to each specific compound in the examples.
  • aldehyde group compounds of the present invention are preferably selected from the compounds shown in Table A below:
  • the invention also provides a process for the synthesis of a compound of formula I, in particular, wherein the compound of formula I is prepared by the following scheme:
  • Step a dissolving dimethyl tert-butoxycarbonyl glutamate in a solvent, adding -78 ° C to the base to stir, then adding bromoacetonitrile, and stirring to obtain the compound I a ,
  • the solvent is tetrahydrofuran or dioxane;
  • the base is lithium hexamethyldisilazide or lithium diisopropylamide;
  • Step b dissolving I a in a solvent, adding a catalytic amount of platinum dioxide, stirring until the reaction of the starting material is complete, filtering, adding a base, and stirring under reflux to obtain a compound I b ;
  • the base is sodium carbonate or sodium acetate;
  • the solvent It is a mixed solvent of methanol and chloroform;
  • Step c dissolving I b in a solvent, stirring until the reaction is completed, and spinning the solvent to obtain a compound I c ;
  • the solvent is a mixed solvent of dichloromethane and trifluoroacetic acid;
  • Step d the substituted carboxylic acid and I c are dissolved in a solvent, and a condensation reaction is carried out with the aid of a condensing agent to obtain a compound I d ;
  • the solvent is dichloromethane or DMF;
  • Step e dissolving the compound I d in a solvent, adding sodium borohydride, and stirring to obtain a compound I e , the solvent is methanol, tetrahydrofuran, ethanol;
  • Step f dissolving compound I e in a solvent, adding an oxidizing agent, adding a base, and stirring to obtain a final product I f
  • the solvent is dichloromethane or tetrahydrofuran
  • the oxidizing agent is Dess-Martin oxidizing agent or dimethyl sulfoxide And oxalyl chloride
  • the base is sodium hydrogencarbonate or triethylamine
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount selected from the group consisting of aldehyde-based compounds represented by formula (I), pharmaceutically acceptable salts thereof, prodrugs thereof, and hydrates and solvates thereof
  • a pharmaceutically acceptable carrier useful for treating diseases associated with enterovirus and coronavirus replication.
  • the pharmaceutical composition can be prepared in various forms depending on the route of administration.
  • the pharmaceutical composition of the aldehyde group compound represented by (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, and one or more of the hydrates and solvates thereof can be used as an enterovirus 3C protease inhibitor for treatment Enterovirus infection or a disease associated with coronavirus infection.
  • the preparation of the pharmaceutically acceptable salt of the compound of the present invention can be carried out by direct salt formation reaction of the free base of the compound with an inorganic or organic acid.
  • the inorganic or organic acid may be selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, picric acid, citric acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonate. Acid and p-toluenesulfonic acid and the like.
  • the compound of the present invention Since the compound of the present invention has excellent inhibitory activity against enterovirus and coronavirus replication, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and the present invention
  • the pharmaceutical composition of the present invention as a main active ingredient can be used for the treatment, prevention, and alleviation of diseases associated with enterovirus and coronavirus replication, such as prevention and/or treatment of diseases associated with intestinal virus and coronavirus replication abnormalities.
  • the compounds of the present invention are useful for the treatment of respiratory tract infections, herpetic angina, epidemic rash, hand, foot and mouth disease, meningitis and the like.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 5 to 200 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) a slow solvent such as paraffin; (f) absorption Accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the compounds according to the invention as described above can be used clinically in mammals, including humans and animals, by route of administration to the mouth, nose, skin, lungs, or gastrointestinal tract, and more preferably orally.
  • the daily dose is preferably 0.01 to 200 mg/kg body weight, taken at once, or 0.01 to 100 mg/kg body weight in divided doses.
  • the optimal dosage for the individual should be based on the particular treatment. Usually starting with a small dose, gradually increase the dose until the most suitable dose is found. Of course, specific doses should also consider factors such as the route of administration, the health of the patient, etc. They are all within the skill of a skilled physician.
  • the analytical data of the samples were determined by the following instruments: NMR was determined by GEMINI-300, Bruker AMX-400 and INVOA-600 NMR, TMS (tetramethylsilane) was used as internal standard, and the chemical shift was in ppm. The constant unit is Hz; the mass spectra were determined by Finnigan Model MAT-711, MAT-95 and LCQ-DECA mass spectrometers and IonSpec 4.7 Tesla mass spectrometer.
  • N-tert-butoxycarbonyl-L-glutamic acid dimethyl ester (1-1) (6 g, 21.8 mmol) was dissolved in 60 mL of anhydrous tetrahydrofuran, and LiHMDS was slowly dropped at -78 °C.
  • the compound 1-5 (2.6 g) was dissolved in a solution of trifluoroacetic acid in dichloromethane (1/1, v/v), stirred at room temperature for 1 hour, concentrated, and then added with 100 ml of dichloromethane and washed with saturated sodium carbonate. The layer was dried over anhydrous sodium sulfate and evaporated.
  • the oily intermediate obtained in the above step was dissolved in a mixed solution of methanol/water (1:2, v/v), and 3 equivalents of a 1 M aqueous sodium hydroxide solution was added thereto, and stirred at room temperature. After the TLC monitoring (ultraviolet) reaction was completed, the pH was adjusted to -2, ethyl acetate was extracted, washed with saturated sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate and evaporated.
  • D-phenylalanine (5g, 30.3mmol) was dissolved in 60mL of 48% hydrobromic acid, cooled to 0 ° C, sodium nitrite (2.6g, 37.5mmol) was added in portions, stirred at temperature for 1 hour, raised to The reaction was continued for 10 hours at room temperature. After completion of the reaction, the mixture was extracted with EtOAc EtOAc.
  • the compound 12-3 (4 g) was dissolved in 30 mL of methanol, and 1 mL of concentrated sulfuric acid was added thereto, and the mixture was heated and heated to 70 ° C for 2 hours. The methanol was evaporated to dryness, and then evaporated, evaporated, evaporated, evaporated, evaporated.
  • the diisopropylaminolithium solution (2 equivalents of LDA tetrahydrofuran solution, 19 mL) was diluted with 10 mL of tetrahydrofuran, then argon-protected, cooled to -78 ° C, tert-butyl acetate (4.87 g, 42 mmol) was added and stirred for 1 hour.
  • Add L-benzyl The reaction solution of oxycarbonylproline and CDI was controlled at -78 ° C for 2 hours. After quenching with 2 mL of water, the mixture was evaporated to EtOAc.
  • the inhibitory activity of the compound on EV71-3C protease was determined: purified 3C protease and chemically synthesized fluorescent substrate polypeptide were used.
  • the coding sequence of EV71 virus 3C protease was cloned into pET-21a vector, and the hexahistidine tag was introduced into the C-terminus of the vector by E.coli.
  • the purification of the protease was carried out by Ni-NTA affinity chromatography and Superdex. 200 molecular exclusion chromatography was completed.
  • the substrate polypeptide will use a Dabcyl-KIGNTIEALFQGPPKFRE-Edans fluorescent polypeptide corresponding to the junction sequence between EV71 2C/3A, and the detection of polypeptide cleavage is excited by 340 nm excitation light, monitored by 490 nm emission light. Synthesis of compound at each concentration after mixing with a gradient of 3C protease inhibition was determined situation polypeptide cleavage efficiency; by three independent experiments for each compound is calculated 3C protease half maximal inhibitory concentration IC 50. The experimental results are shown in Table 1.
  • the inhibitory activity of the compound on SARS (Severe Acute Respiratory Syndrom) coronavirus main protease (SARS-CoV M pro ) was determined: the enzyme level inhibitory activity against the inhibitor of 3C protease was determined by fluorescence resonance energy transfer (FRET) technique. .
  • FRET fluorescence resonance energy transfer
  • the inhibitory activity of the compound against CVB3 (Coxsachievirus B3) 3C protease was determined: 20.0 ⁇ L of buffer (20 mM Tris, 100 mM NaCl, 1 mM EDTA, 10 mM DTT, pH 7.4) was added to each well in a 96-well plate while 2.5 ⁇ L of the compound was added. (final concentrations were 100 ⁇ M, 33 ⁇ M, 11 ⁇ M, 3.7 ⁇ M, 1.2 ⁇ M, 0.4 ⁇ M, 0.13 ⁇ M, 0.004 ⁇ M, respectively) and 2.5 ⁇ L CVB3 3Cpro (final concentration 3 ⁇ M). Incubate for 10 min at 37 °C.
  • Fluorescent substrate diluted in 25 ⁇ L of buffer was then added. Fluorescence parameters were measured using a Ge n5 fluorescence spectrometer with excitation and emission wavelengths of 340 nm and 490 nm, respectively, and maintained at 37 ° C for 15 min. A negative control was used in which no compound was added to the control and the rest were identical. The data obtained were processed using the software GraphPad Prism 6.0, and the experimental results are shown in Table 3.
  • the compound was assayed for replication inhibition activity of each virus: a 96 ⁇ l/well gradient concentration of the compound was added to the 96 well, followed by the addition of 50 ⁇ l/well of virus buffer, followed by the immediate addition of 50 ⁇ l/well of the cultured RD cells (rhabdomyosarcoma cells), 37 ° C. Incubate for 3-4 days until the maximum cytopathic effect is observed.
  • the medium was aspirated, 75 ⁇ l of 5% MTS phenol red medium was added, and cultured at 37 ° C, 5% CO 2 for 1.5 hours.
  • the fluorescence value of each well at a wavelength of 498 nM was measured, and a graph of the concentration of the compound and the cell reaction was plotted. Accelrys custom software calculates the EC 50 value of the compound.
  • Some compounds were selected to test the inhibition of EV68-WT virus replication. From the above experimental results, it can be seen that the compound has a good inhibitory effect on EV68-WT virus replication, and the activity reaches the nanomolar level.
  • the compound of the present invention also has a certain inhibitory effect on the replication of MNV-CW1 virus, and the activity of some compounds is better than that of the positive compound AG7088, and the EC 50 of compounds 56 and 48 is less than 1 ⁇ mol, and the therapeutic index TI>20.
  • Compound 18 of the present invention was administered by intragastric administration and intravenous injection respectively at a dose of 10 mg/kg, a dose of 10 mL/kg, and a drug of DMSO/Tween 80/normal saline (5:5:90, v/v/v). ) formulated. Fasting for 12 hours before the test, free to drink water. Uniformly eaten 2 hours after administration.
  • Subcutaneous administration 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after administration;
  • Intravenous administration 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after administration;
  • 0.3 mL of blood was taken from the posterior venous plexus of the rat eye, placed in a heparinized test tube, centrifuged at 11,000 rpm for 5 min, and the plasma was separated and frozen in a refrigerator at -20 °C.
  • the concentration of Compound 18 in rat plasma was determined by LC/MS/MS.
  • the plasma concentration peak time Tmax was 1 h
  • the peak concentration Cmax was 1919.4 ng/ml
  • the area under the curve was AUC0-t was 6876.0 ng ⁇ h/ml
  • the half-life t1/2 is 1.35 h.
  • AUC0-t was 23361.2 ng ⁇ h/ml
  • the absolute bioavailability of the rats after subcutaneous injection of 10 mg/kg of Compound 18 was 29.4%.

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  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne les domaines de la chimie thérapeutique et de la pharmacothérapie et concerne spécifiquement un composé représenté par la formule générale (I). Le composé est utilisé en tant qu'inhibiteur de protéase d'entérovirus, et exerce également une activité inhibitrice importante sur une protéase principale d'un coronavirus (tel que le SRAS), et peut être utilisé pour traiter des maladies associées. L'invention concerne également un procédé de préparation, une composition pharmaceutique, un sel pharmaceutique, un énantiomorphe, un diastéréomère et un mélange racémique de ce composé.
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US11124497B1 (en) 2020-04-17 2021-09-21 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
US11174231B1 (en) 2020-06-09 2021-11-16 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
US11351149B2 (en) 2020-09-03 2022-06-07 Pfizer Inc. Nitrile-containing antiviral compounds
CN115322130A (zh) * 2022-08-02 2022-11-11 南京正济医药研究有限公司 制备(s)-2-(boc-氨基)-3-[(s)-2-氧代-3-吡咯烷基]丙酸甲酯
WO2023044509A1 (fr) * 2021-09-20 2023-03-23 Pardes Biosciences, Inc. Procédé de production d'inhibiteurs de cystéine protéase et composés obtenus selon ce procédé
WO2023044171A1 (fr) * 2021-09-20 2023-03-23 Pardes Biosciences, Inc. Inhibiteurs de cystéine protéases et leurs méthodes d'utilisation

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WO2022268111A1 (fr) * 2021-06-25 2022-12-29 前沿生物药业(南京)股份有限公司 Composition pharmaceutique antivirale, son procédé de préparation et son application
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CN113773259A (zh) * 2021-07-14 2021-12-10 上海药明康德新药开发有限公司 病毒主蛋白酶抑制剂及其制备方法和用途
WO2023283831A1 (fr) * 2021-07-14 2023-01-19 上海药明康德新药开发有限公司 Inhibiteur de protéase principale virale, son procédé de préparation et son utilisation
CN114149415A (zh) * 2021-07-26 2022-03-08 中国药科大学 一种拟肽类化合物及其衍生物、制备方法、药物组合物和应用
CN114456211B (zh) * 2021-09-03 2024-03-26 中国药科大学 一种拟肽类化合物及其制备方法和应用
CN115490626A (zh) * 2021-11-26 2022-12-20 杭州科巢生物科技有限公司 一种pf-07321332的关键手性化合物及其制备方法
CN114605301B (zh) * 2022-03-23 2024-06-04 江苏恒沛药物科技有限公司 一种制备帕罗韦德中间体的方法
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US11124497B1 (en) 2020-04-17 2021-09-21 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
US11312704B2 (en) 2020-04-17 2022-04-26 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
US11472793B2 (en) 2020-04-17 2022-10-18 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
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US11524940B1 (en) 2020-06-09 2022-12-13 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
US11351149B2 (en) 2020-09-03 2022-06-07 Pfizer Inc. Nitrile-containing antiviral compounds
US11452711B2 (en) 2020-09-03 2022-09-27 Pfizer Inc. Nitrile-containing antiviral compounds
US11541034B2 (en) 2020-09-03 2023-01-03 Pfizer Inc. Nitrile-containing antiviral compounds
WO2023044509A1 (fr) * 2021-09-20 2023-03-23 Pardes Biosciences, Inc. Procédé de production d'inhibiteurs de cystéine protéase et composés obtenus selon ce procédé
WO2023044171A1 (fr) * 2021-09-20 2023-03-23 Pardes Biosciences, Inc. Inhibiteurs de cystéine protéases et leurs méthodes d'utilisation
CN115322130A (zh) * 2022-08-02 2022-11-11 南京正济医药研究有限公司 制备(s)-2-(boc-氨基)-3-[(s)-2-氧代-3-吡咯烷基]丙酸甲酯
CN115322130B (zh) * 2022-08-02 2024-05-14 南京正济医药研究有限公司 制备(s)-2-(boc-氨基)-3-[(s)-2-氧代-3-吡咯烷基]丙酸甲酯

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