WO2023011573A1 - Dérivé d'acétylène aromatique, son procédé de préparation et son utilisation - Google Patents

Dérivé d'acétylène aromatique, son procédé de préparation et son utilisation Download PDF

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WO2023011573A1
WO2023011573A1 PCT/CN2022/110172 CN2022110172W WO2023011573A1 WO 2023011573 A1 WO2023011573 A1 WO 2023011573A1 CN 2022110172 W CN2022110172 W CN 2022110172W WO 2023011573 A1 WO2023011573 A1 WO 2023011573A1
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Prior art keywords
phenyl
methyl
ethynyl
pyrimidin
bis
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PCT/CN2022/110172
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English (en)
Chinese (zh)
Inventor
郭阳辉
王鑫
曹琪
孟力陈
吴诺毅
邬澄飞
陈友喜
叶成
钱文建
陈磊
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浙江海正药业股份有限公司
上海昂睿医药技术有限公司
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Priority to CN202280052824.6A priority Critical patent/CN117751113A/zh
Publication of WO2023011573A1 publication Critical patent/WO2023011573A1/fr

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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
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to an aromatic acetylene derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and the use of the aromatic acetylene derivative or the pharmaceutical composition as a therapeutic agent, especially as an LPXC inhibitor.
  • UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase is a Zn2 + -dependent metalloenzyme that is the first step in lipid A synthesis
  • Lipid A is an important component of the outer membrane of Gram-negative bacteria, which can anchor lipopolysaccharide on the outer membrane of the cell and maintain the integrity of its own cells. At the same time, it acts as a hydrophobic external barrier, preventing external factors such as antibiotics from entering cells, and protecting bacteria from damage.
  • lipid A is also the active component of bacterial endotoxin, which enters the blood through the intestinal mucosa, activates the immune response of the human body, and even causes severe septic shock, which is also the cause of pathogenic infection caused by Gram-negative bacteria. Therefore, by inhibiting LPXC, the biosynthesis of lipid A of Gram-negative bacteria can be inhibited, thereby effectively controlling the infection of Gram-negative bacteria.
  • LPXC structure and characteristics of LPXC
  • the structures of these three different sources of LPXC are highly similar, all contain two domains, and the active region is located at the junction of the two domains.
  • Each domain contains an ⁇ -helix and a ⁇ -sheet, and the ⁇ -sheet sandwiches the ⁇ -helix, forming a sandwich structure of " ⁇ - ⁇ - ⁇ - ⁇ ".
  • amino acid sequences of these two domains are slightly different, they have the same spatial structure.
  • each structural domain has a corresponding insertion region, which is composed of ⁇ -sheets and forms different functional regions.
  • LPXC has high homology in Gram-negative bacteria and has no common sequence with various mammalian enzyme systems. From a biological point of view, due to its unique advantages of broad-spectrum and low toxicity, it can inhibit The target of LPXC will be an ideal direction for the research of antibacterial drugs.
  • the present invention provides a kind of aromatic acetylene derivative shown in a kind of general formula (I) or its stereoisomer, tautomer or its pharmaceutically acceptable salt:
  • X and Y are each independently selected from C or N, and X and Y are not N at the same time;
  • Ring A is selected from 4-6 membered heteroaryl or 4-6 membered heterocyclic group, preferably 5-membered heteroaryl or 5-membered heterocyclic group;
  • L 1 is selected from a single bond or -CH 2 -;
  • R 1 is the same or different, each independently selected from -G 1 -R 4 ;
  • R 2 are the same or different, each independently selected from hydroxyl, cyano, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl , heterocyclyl, aryl or heteroaryl are optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or alkoxy;
  • R 3 are the same or different, each independently selected from hydroxyl, cyano, halogen, alkyl, cycloalkyl, heterocyclyl, alkoxy or -C(O)R 5 , wherein the alkyl, cycloalkane
  • one or more substituents selected from halogen, hydroxy, cyano, alkoxy, -C(O)OR 5 or -C(O)NR 6 R 7 replaced by
  • R 4 is selected from cyano, halogen, alkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 5 , -C(O)OR 5 , - OC(O)R 5 , -NR 6 R 7 , -C(O)NR 6 R 7 , -SO 2 NR 6 R 7 or -NR 6 C(O)R 7 , wherein the alkoxy, alkane
  • the radical, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more RA ;
  • RA is selected from halogen, hydroxy, amino, hydroxyalkyl, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 5 , -C(O)OR 5.
  • alkyl , cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from one or more of halogen, hydroxy, amino, haloalkyl, hydroxyalkyl, alkoxy, alkyl, cycloalkyl, hetero Cyclic group, aryl group, heteroaryl group, -C(O)R 5 , -C(O)OR 5 , -OC(O)R 5 , -NR 6 R 7 , -C(O)NR 6 R 7 , Substituents of -SO 2 NR 6 R 7 or -NR 6 C(O)R 7 ;
  • R 8 , R 9 and R 10 are each independently selected from a hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl , aryl or heteroaryl are optionally further replaced by one or more selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , carboxyl or carboxylate substituents;
  • n 0, 1, 2 or 3;
  • n 0, 1 or 2, preferably n is 0;
  • p 0, 1 or 2.
  • a compound described in general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof which is a compound described in general formula (II) Or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • ring A, R 1 -R 3 , L 1 , m, n and p are defined as described in general formula (I).
  • a compound described in general formula (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof which is a compound described in general formula (III) Or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • RA is selected from haloalkyl, hydroxyalkyl, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, wherein said alkyl, cycloalkyl, heterocyclyl, Aryl and heteroaryl are optionally further substituted by carboxyl;
  • q 0, 1 or 2;
  • Ring A, G 1 , R 2 , R 3 , L 1 , n and p are as defined in general formula (I).
  • the compound described in general formula (I) is selected from:
  • the present invention provides a pharmaceutical composition, which contains an effective dose of the compound described in general formula (I), (II) or (III) or its stereoisomers, tautomers body or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides a compound described in general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition in the preparation of LPXC Use in inhibitors.
  • the present invention also provides a compound described in general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition
  • the disease mediated by LPXC is preferably a bacterial infection caused by Gram-negative bacteria
  • the disease mediated by LPXC is selected from the group consisting of Escherichia coli, green Pseudomonas, Proteus, Shigella, Klebsiella pneumoniae, Brucella, Salmonella typhi, Acinetobacter, Yersinia, Legionella pneumophila, Bordetella pertussis, Shigella, Pasteurella, Cholera Bacterial infection caused by gram-negative bacteria such as Vibrio and meningitidis.
  • the present invention further provides a compound described in general formula (I, (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition in the preparation of therapeutic Use in medicine for bacterial infections caused by Gram-negative bacteria.
  • the present invention provides a compound described in general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition in the preparation of large intestine Bacillus, Pseudomonas aeruginosa, Proteus, Shigella, Klebsiella pneumoniae, Brucella, Salmonella typhi, Acinetobacter, Yersinia, Legionella pneumophila, Bordetella pertussis, Shigella, Pasteurella
  • Bacillus Pseudomonas aeruginosa, Proteus, Shigella, Klebsiella pneumoniae, Brucella, Salmonella typhi, Acinetobacter, Yersinia, Legionella pneumophila, Bordetella pertussis, Shigella, Pasteurella
  • the application in the medicine of the bacterial infection caused by gram-negative bacteria such as genus, vibrio cholerae, meningoc
  • the present invention also provides a method for treating diseases mediated by LPXC, comprising administering the compound described in general formula (I), (II) or (III) or its stereoisomer, mutual variants or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.
  • the disease mediated by LPXC is a bacterial infection caused by Gram-negative bacteria; more preferably, the Gram-negative bacteria are selected from the group consisting of Escherichia coli, Pseudomonas aeruginosa, Proteus, Shigella, and Klebsiella pneumoniae , Brucella, Salmonella typhi, Acinetobacter, Yersinia, Legionella pneumophila, Bordetella pertussis, Shigella, Pasteurella, Vibrio cholerae, Neisseria meningitidis.
  • the Gram-negative bacteria are selected from the group consisting of Escherichia coli, Pseudomonas aeruginosa, Proteus, Shigella, and Klebsiella pneumoniae , Brucella, Salmonella typhi, Acinetobacter, Yersinia, Legionella pneumophila, Bordetella pertussis, Shigella, Pasteurella, Vibrio
  • Alkyl when used as a group or a part of a group refers to a C 1 -C 20 straight chain or branched aliphatic hydrocarbon group. It is preferably a C 1 -C 10 alkyl group, more preferably a C 1 -C 6 alkyl group or a C 1 -C 4 alkyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl wait.
  • Alkyl groups can be substituted or unsubstituted.
  • Cycloalkyl means a non-aromatic cyclic alkyl group in which one or more of the atoms forming the ring is a carbon atom, including monocyclic, polycyclic, fused, bridged and spiro rings, preferably having 3 to 7 members Monocyclic or 7-10 membered bicyclic or tricyclic.
  • Examples of “cycloalkyl” include, but are not limited to, cyclopropyl, cyclopentyl, cyclobutyl. Cycloalkyl groups can be substituted or unsubstituted. Preference is given to C 3 -C 7 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 7 cycloalkyl.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one carbon atom (called a spiro atom) shared between the single rings.
  • the ring contains one or more Aromatic systems with double bonds, but none of the rings have fully conjugated ⁇ electrons. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiro cycloalkyl group is divided into single spiro, double spiro or polyspiro cycloalkyl, preferably single spiro and double spiro cycloalkyl, preferably 4-membered/5-membered, 4-membered Yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan.
  • spirocycloalkyl include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.
  • “Fused cycloalkyl” refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more ring structures sharing a pair of carbon atoms with each other, and one or more rings may contain one or more double bonds, Aromatic systems where none of the rings have fully conjugated pi-electrons, preferably 6 to 12, more preferably 7 to 10 membered. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
  • fused cycloalkyl include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetrahydrophenanthrenyl.
  • “Bridged cycloalkyl” refers to a 5- to 18-membered, full-carbon polycyclic group that contains two or more ring structures and shares two carbon atoms that are not directly connected to each other.
  • One or more rings may contain one or more Aromatic systems with multiple double bonds but none of the rings having fully conjugated pi electrons are preferably 6 to 12 membered, more preferably 7 to 10 membered. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged cycloalkyl include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bis Cycloo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl.
  • a heteroatom such as oxygen, nitrogen or S(O) r (where r is selected from 0, 1 or 2), etc.
  • a 5 to 7 membered monocyclic ring or a 7 to 10 membered bicyclic or tricyclic ring which may contain 1, 2 or 3 members selected from nitrogen, oxygen and/or S(O) r (wherein r is selected from 0, 1 or 2 ) atoms.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl , piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1] Octyl, piperazinyl, hexahydropyrimidine,
  • a heterocyclyl group can be substituted or unsubstituted.
  • “Spiroheterocyclic group” refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the single rings.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spirocycloalkyl group can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclyl include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[4.4]nonyl, Heteraspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclyl include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1. 0]hexyl, octahydrobenzo[b][1,4]dioxine,
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.2]octyl, Cyclo[3.3.2]decyl.
  • Aryl means a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion.
  • aryl includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferred aryl groups are C 6 -C 10 aryl groups, more preferred aryl groups are phenyl and naphthyl, most preferably naphthyl.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl refers to an aromatic 5 to 6 membered monocyclic ring or 8 to 10 membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • Preferred heteroaryl groups are C 6 -C 10 heteroaryl groups containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl examples include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo Dioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzo Isothiazolyl, benzoxazolyl, benzisoxazolyl, isothiazolyl, 1H-1,2,
  • Alkoxy refers to a group of (alkyl-O-). Wherein, alkyl refers to relevant definitions herein. C 1 -C 6 or C 1 -C 4 alkoxy is preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Niro refers to a -NO2 group.
  • Haldroxy means an -OH group.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Benzyl means -CH2 -phenyl.
  • Carboxy refers to -C(O)OH.
  • Carboxylate group refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein the definitions of alkyl and cycloalkyl are as above.
  • Hydroalkyl means a hydroxy-substituted alkyl group, wherein alkyl is as defined above.
  • Aminoalkyl means an amino-substituted alkyl group, wherein alkyl is as defined above.
  • Haloalkyl means a halogen substituted alkyl wherein alkyl is as defined above.
  • Haloalkoxy means a halogen substituted alkoxy group, wherein alkoxy group is as defined above.
  • DMSO dimethylsulfoxide
  • THP refers to 2-tetrahydropyranyl
  • TFA trifluoroacetic acid
  • Ts refers to p-toluenesulfonyl.
  • leaving group an atom or functional group that is separated from a larger molecule in a chemical reaction, is a term used in nucleophilic substitution reactions and elimination reactions.
  • the reactant attacked by the nucleophile is called the substrate, and the atom or atomic group that breaks off with a pair of electrons from the substrate molecule is called the leaving group.
  • Groups that are easy to accept electrons and have strong ability to bear negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to detach from other molecules.
  • Common leaving groups include, but are not limited to, halogens, methanesulfonyl, -OTs, or -OH.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • R 8 , R 9 and R 10 are each independently selected from a hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl , aryl or heteroaryl are optionally further replaced by one or more selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , Carboxyl or carboxylate substituents are substituted.
  • “Pharmaceutically acceptable salt” refers to certain salts of the above compounds that can maintain their original biological activity and are suitable for medical use.
  • the pharmaceutically acceptable salt of the compound represented by the general formula (I) may be a metal salt or an amine salt with a suitable acid.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as a physiologically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • the present invention provides a preparation method of a compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, said method comprising:
  • the compound of general formula (I-a) and the compound of (I-b) undergo a coupling reaction under the action of a catalyst, and optionally further remove the protecting group to obtain the compound of general formula (I);
  • X is selected from halogen
  • Ring A, X, Y, R 1 to R 3 , L 1 , n, m and p are as defined in general formula (I).
  • the mass spectrum is measured by LC/MS instrument, and the ionization method can be ESI or APCI.
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • CD 3 OD deuterated methanol.
  • the argon atmosphere means that the reaction bottle is connected to an argon balloon with a volume of about 1 L.
  • the solution in the reaction refers to an aqueous solution.
  • the compound was purified by silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system was selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: two Chloromethane and ethyl acetate system; the volume ratio of the solvent varies according to the polarity of the compound, and can also be adjusted by adding a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine.
  • A petroleum ether and ethyl acetate system
  • B dichloromethane and methanol system
  • C two Chloromethane and ethyl acetate system
  • the volume ratio of the solvent varies according to the polarity of the compound, and can also be adjusted by adding a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine.
  • 4,5-bis(benzyloxy)-6-vinylpyrimidine 1d (1.1 g, 3.46 mmol, self-produced according to patent WO2020061375) and triethylamine (699.25 mg, 6.91 mmol, 957.87 ⁇ L) were dissolved in N, N-Dimethylformamide (14.04 mL), slowly dropwise added (Z)-N-hydroxy-4-iodobenzimidoyl chloride 1c (972.54 mg, 3.46 mmol) in N,N-dimethylformamide solution (10 mL), react at room temperature for 6 hours.
  • the di Bis(trichloromethyl)carbonate (2.58g, 8.70mmol) was added to the methyl chloride (80mL) solution, and reacted at low temperature for 20 minutes, then rose to room temperature and reacted overnight.
  • Di-tert-butyl dicarbonate (5.51g, 25.25mmol) was added to 50mL of dioxane in 3-amino-3-(4-iodophenyl)propionic acid 4b (4.9g, 16.83mmol), and then 50mL of Saturated sodium bicarbonate solution, stirred overnight at room temperature.
  • the reaction liquid Add 20mL of water, extract with ethyl acetate (20mL ⁇ 3), wash with saturated sodium chloride solution (20mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure, and the obtained residue is purified by silica gel column chromatography ( Eluent: System A) to obtain 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholine-4-carbonyl) Phenyl)ethynyl)phenyl)-2-oxoimidazoline-1-carboxylic acid tert-butyl ester 4f (60 mg), yield: 49.66%.
  • Potassium phosphate (6.50g, 30.60mmol), bis(triphenylphosphine)palladium dichloride (859.18mg, 1.22mmol), 4,5-dibenzyloxy-6-chloropyrimidine 5a (2.0g, 6.12mmol , self-made according to patent WO2020102572) and 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborane (4.11g, 24.48mmol) were sequentially added to tetrahydrofuran (20mL ) and water (4 mL), the argon gas was replaced three times, heated to 90° C., and reacted for 20 hours.
  • 4-ethynylbenzoic acid 17a (1g, 6.84mmol) and morpholine 17b (3.58g, 41.06mmol) were added to 5mL of dichloromethane, and 1-(3-dimethylaminopropyl)-3-ethyl Carbodiimide hydrochloride (2.10g, 10.95mmol), react overnight at room temperature.
  • reaction solution was extracted with dichloromethane (30ml ⁇ 2), the water layer was separated, and the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2) successively, dried over anhydrous sodium sulfate, filtered, and reduced pressure After concentration, the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain (4-ethynylphenyl)(morpholinyl)methanone 17c (600 mg, 40.74% yield).
  • reaction solution was extracted with ethyl acetate (30mlx2), and the water layer was separated. The combined organic phase was washed with saturated sodium chloride solution (30mLx2) successively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, and the combined organic phases were successively washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: System A and System B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4 -Iodophenyl)-4-methylpyrrolidin-2-one 20 g (130 mg, 214.71 ⁇ mol, 47.19% yield).
  • reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: system B) to obtain 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-methyl-4- (4-((4-(morpholinemethyl)phenyl)ethynyl)phenyl)pyrrolidin-2-one 20j (50 mg, 73.66 ⁇ mol, 55.75% yield).
  • reaction solution was concentrated under reduced pressure, 30 mL of saturated sodium bicarbonate solution was added to the residue, extracted with ethyl acetate (30 mL ⁇ 3), the combined organic phases were successively washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate , filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: eluent: system B) to obtain 1-((5,6-bis(benzyloxy)pyrimidine-4- yl)methyl)-4-(4-iodophenyl)imidazolin-2-one 21d (1 g, 1.69 mmol, 77.93% yield).
  • reaction solution was quenched by adding 20 mL of ice water, extracted with ethyl acetate (20 mL ⁇ 3), the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: system A) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodo Phenyl)-3-isopropylimidazolin-2-one 21e (450 mg, 709.21 ⁇ mol, 42.02% yield).
  • reaction solution was extracted with ethyl acetate (30mL ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: system B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-(( 4-(((1,1-dioxotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolin-2-one 21k (50mg, 66.14 ⁇ mol, 93.26% yield).
  • 4-(2-Trimethylsilylethynyl)benzaldehyde 22a (400 mg, 1.98 mmol) was dissolved in 1,2-dichloroethane (15 mL), and thiomorpholine 1,1-dioxide was added sequentially 22b (534.53mg, 3.95mmol) and acetic acid (1.25mL) were reacted at room temperature for 30 minutes, then sodium triacetoxyborohydride (1.26g, 5.93mmol) was added at 0°C, and reacted at room temperature for two hours.
  • reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: eluent: system B) to obtain 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-( 4-((4-((1,1-thiomorpholine dioxide)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolin-2-one 22e (26mg, 34.40 ⁇ mol, 48.50% yield).
  • 4-(2-Trimethylsilylethynyl)benzaldehyde 22a (400mg, 1.98mmol) was dissolved in 1,2-dichloroethane (20mL), and hexahydro-1H-furo[3,4 -c] Pyrrole 23a (335.57 mg, 2.97 mmol) and acetic acid (1.25 mL) were reacted at room temperature for 2 hours, then sodium triacetoxyborohydride (1.26 g, 5.93 mmol) was added and reacted at room temperature for 2 hours.
  • reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: system A) to obtain 5-(4-ethynylbenzyl)hexahydro-1H-furo[3,4-c]pyrrole 23c (311mg, 1.37mmol ,89.08% yield).
  • reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: system B) to obtain 4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)- 3-Isopropyl-2-oxoimidazolin-4-yl)phenyl)ethynyl)benzaldehyde 24b (230 mg, 361.22 ⁇ mol, 76.40% yield).
  • reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: system B) to obtain 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4 -(4-((6-(morpholinomethyl)pyridin-3-yl)ethynyl)phenyl)imidazolin-2-one 25d (55 mg, 77.59 ⁇ mol, 98.46% yield).
  • Example 1-36 According to the synthesis method of Example 1-36, the following compounds were prepared, including:
  • reaction was heated to 70°C and stirred for 5 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, and the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2) successively.
  • reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and reduced pressure Concentrate, and the obtained residue is purified by silica gel column chromatography (eluent: system A) to obtain 2-(4-ethynylphenoxy)ethan-1-ol 89d (120 mg, 739.90 ⁇ mol, 73.48% yield) .
  • reaction was heated to 70°C and stirred for 5 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, and the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2) successively.
  • 4-ethynyl benzoic acid 90a 500mg, 3.42mmol
  • 3-methoxy azacycline hydrochloride 90b 845.62mg, 6.84mmol
  • 1-(3 -Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 1.05g, 5.47mmol
  • 4-dimethylaminopyridine 41.80mg, 342.13 ⁇ mol
  • reaction solution was extracted with dichloromethane (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue Further separation and purification by silica gel column chromatography (eluent: system C) gave (4-ethynylphenyl)(3-methoxyazetidin-1-yl)methanone 90c (500mg, 2.32mmol, 67.90% yield).
  • reaction solution was extracted with ethyl acetate (30mL ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue Further separation and purification by silica gel column chromatography (eluent: system B) to obtain 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4 -(4-((4-(3-methoxyazetidine-1-carbonyl)phenyl)ethynyl)phenyl)imidazolin-2-one 90d (35mg, 48.49 ⁇ mol, 51.28% yield) .
  • 4-ethynylbenzoic acid 90a 150mg, 1.03mmol
  • thiomorpholine 1-oxide hydrochloride 36a 255.61mg, 1.64mmol
  • 1-(3-di Methylaminopropyl)-3-ethylcarbodiimide hydrochloride 314.82mg, 1.64mmol
  • 4-dimethylaminopyridine (12.54mg, 102.64 ⁇ mol
  • reaction solution was extracted with dichloromethane (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue Further separation and purification by silica gel column chromatography (eluent: system A) gave (4-ethynylphenyl)(1-oxythiomorpholine)methanone 91a (100 mg, 404.35 ⁇ mol, 39.39% yield).
  • reaction was warmed to 70°C and stirred for 5 hours.
  • the reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl- 4-(4-((4-(1-Oxothiomorpholine-4-carbonyl)phenyl)ethynyl)phenyl)imidazolin-2-one 91b (30 mg, 39.79 ⁇ mol, 50.50% yield).
  • reaction solution was extracted with dichloromethane (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and reduced pressure Concentration, the obtained residue was further separated and purified by silica gel column chromatography (eluent: system C) to obtain N-(4-ethynylbenzyl)-2-hydroxyacetamide 92c (300mg, 1.59mmol, 44.30% yield ).
  • N-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4- yl)phenyl)ethynyl)benzyl)-2-hydroxyacetamide 92d (20mg, 28.74 ⁇ mol) was added to 1.5mL dichloromethane, boron trichloride (0.8mL) was added, and the reaction was carried out at room temperature for 1 hour.
  • reaction solution was extracted with dichloromethane (30ml ⁇ 2), the water layer was separated, and the combined organic phase was washed successively with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain 4-ethynyl-N-(2-methoxyethyl)benzamide 93b (360mg, 1.77mmol, 51.77% yield ).
  • Example 1-93 According to the synthesis method of Example 1-93, the following compounds were prepared, including:
  • Test example 1 compound of the present invention is to LpxC enzymatic activity inhibitory assay
  • the following method is used to determine the inhibitory degree of the compounds of the present invention to the enzymatic activity of recombinant Pseudomonas aeruginosa LpxC under in vitro conditions.
  • test compound was first dissolved in DMSO to prepare a 10 mM stock solution.
  • the reaction was carried out in a 96-well microwell plate.
  • 20 ⁇ L of recombinant Pseudomonas aeruginosa LpxC purchased from Signalway Antibody, catalog number AP74647-2 was added to the wells with a final concentration of 5 nM; 5 ⁇ L of the test compound was added, and the compound was diluted 4 times.
  • the concentration range is 0.61-10000nM; add 5 ⁇ L LpxC substrate UDP-3-O-(R-3-hydroxydecanoyl)-GlcNAc (purchased from Biosynth Carbosynth, product number is mu75071), the final concentration of the substrate is 10 ⁇ M , and incubated at 25°C for 120 minutes.
  • Example 15 Compound number IC 50 /nM Example 7 42.45 Example 9 13.12 Example 10 22.99 Example 11 8.00 Example 13 15.72 Example 15 33.17 Example 16 24.69 Example 17 23.17 Example 22 36.1 Example 23 32.08 Example 24 20.58
  • the compound of the present invention has an inhibitory IC50 of less than 100nM on the enzyme activity of recombinant Pseudomonas aeruginosa LpxC, and has a significant inhibitory effect on the enzyme activity of LpxC.
  • Test example 2 the antibacterial activity evaluation of the compound of the present invention
  • test compound was dissolved in DMSO to prepare a 12.8 mg/mL stock solution, and then DMSO was used to prepare 11 double-diluted 100 ⁇ high-concentration working solutions (the final concentration of the system was 64 ⁇ g/mL-0.06 ⁇ g/mL).
  • the minimum drug concentration for cell growth is the minimum inhibitory concentration (MIC) of the compound, as shown in Table 2 below.
  • the compound of the present invention has good inhibitory effect on K. pneumoniae (K.Pneumoniae ATCC13883) and Escherichia coli (E.coli ATCC 25922).
  • ND means not determined.
  • the LC/MS/MS method was used to determine the compound 13 of the present invention administered to the mice intravenously or intragastrically, and to measure the drug concentration in plasma at different times, and to study the pharmacological effects of the compound of the present invention in mice. Kinetic features.
  • ICR mice male, 29.0-33.8 g, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • Intravenous injection group Weigh an appropriate amount of medicine, add 10% HP- ⁇ -CD aqueous solution, vortex, and sonicate for 60 minutes. Add 10 ⁇ L of 1M HCl, vortex, mix well, pH 3.5-4.0, filter with (Rephile, Nylon, 0.45 ⁇ m) to obtain a colorless solution, and prepare the final concentration of 0.2 mg/mL;
  • Oral gavage group Weigh an appropriate amount of medicine, add 10% Solutol HS15-20% HP- ⁇ -CD, vortex, and sonicate for 30 minutes to obtain a colorless solution, and prepare a final concentration of 0.5 mg/kg.
  • ICR mice each compound to be tested was divided into intravenous injection group (nine in each group) and gavage group (nine in each group), orbital intravenous injection administration (administration dose 1mg/kg, give Drug volume 5mL/kg) and intragastric administration (administration dose 5mg/kg, administration volume 10mL/kg), take food 4 hours after administration.

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Abstract

La présente invention concerne un dérivé d'acétylène aromatique, son procédé de préparation, et une utilisation médicale d'une composition pharmaceutique contenant le dérivé. Plus particulièrement, la présente invention concerne un dérivé d'acétylène aromatique représenté par la formule générale (I), un procédé de préparation associé, un sel pharmaceutiquement acceptable de celui-ci, et une utilisation de celui-ci en tant qu'agent thérapeutique, en particulier un inhibiteur de LPXC, la définition de chaque substituant dans la formule générale (I) étant la même que sa définition dans la description.
PCT/CN2022/110172 2021-08-05 2022-08-04 Dérivé d'acétylène aromatique, son procédé de préparation et son utilisation WO2023011573A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024083177A1 (fr) * 2022-10-21 2024-04-25 浙江海正药业股份有限公司 Dérivé d'acétylène aromatique, son procédé de préparation et son utilisation médicale

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101365677A (zh) * 2005-12-01 2009-02-11 先灵公司 治疗炎性病症和微生物疾病的化合物
CN101528711A (zh) * 2006-08-31 2009-09-09 先灵公司 可用作抗细菌剂的乙内酰脲衍生物
WO2010017060A1 (fr) * 2008-08-04 2010-02-11 Schering Corporation Dérivés d'urée en tant qu'agents antibactériens
CN101765585A (zh) * 2007-06-12 2010-06-30 尔察祯有限公司 抗菌剂
WO2010100475A1 (fr) * 2009-03-02 2010-09-10 Astrazeneca Ab Dérivés de l'acide hydroxamique en tant qu'agents contre des bactéries à gram négatif
US20180327365A1 (en) * 2015-11-09 2018-11-15 Forge Therapeutics, Inc. Hydroxypyridinone and hydroxypyrimidinone based compounds for treating bacterial infections
WO2020102572A1 (fr) * 2018-11-14 2020-05-22 Forge Therapeutics, Inc. Composés antibactériens
CN113166077A (zh) * 2018-09-20 2021-07-23 福至治疗公司 抗细菌化合物

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101365677A (zh) * 2005-12-01 2009-02-11 先灵公司 治疗炎性病症和微生物疾病的化合物
CN101528711A (zh) * 2006-08-31 2009-09-09 先灵公司 可用作抗细菌剂的乙内酰脲衍生物
CN101765585A (zh) * 2007-06-12 2010-06-30 尔察祯有限公司 抗菌剂
WO2010017060A1 (fr) * 2008-08-04 2010-02-11 Schering Corporation Dérivés d'urée en tant qu'agents antibactériens
WO2010100475A1 (fr) * 2009-03-02 2010-09-10 Astrazeneca Ab Dérivés de l'acide hydroxamique en tant qu'agents contre des bactéries à gram négatif
US20180327365A1 (en) * 2015-11-09 2018-11-15 Forge Therapeutics, Inc. Hydroxypyridinone and hydroxypyrimidinone based compounds for treating bacterial infections
CN113166077A (zh) * 2018-09-20 2021-07-23 福至治疗公司 抗细菌化合物
WO2020102572A1 (fr) * 2018-11-14 2020-05-22 Forge Therapeutics, Inc. Composés antibactériens

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024083177A1 (fr) * 2022-10-21 2024-04-25 浙江海正药业股份有限公司 Dérivé d'acétylène aromatique, son procédé de préparation et son utilisation médicale

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