WO2017211307A1 - Benzene derivative, and manufacturing method and pharmaceutical application thereof - Google Patents

Benzene derivative, and manufacturing method and pharmaceutical application thereof Download PDF

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Publication number
WO2017211307A1
WO2017211307A1 PCT/CN2017/087484 CN2017087484W WO2017211307A1 WO 2017211307 A1 WO2017211307 A1 WO 2017211307A1 CN 2017087484 W CN2017087484 W CN 2017087484W WO 2017211307 A1 WO2017211307 A1 WO 2017211307A1
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Prior art keywords
group
alkyl
membered
hydroxy
heterocyclic group
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PCT/CN2017/087484
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French (fr)
Chinese (zh)
Inventor
秦琳琳
魏用刚
刘国亮
王伟
任磊
万松林
Original Assignee
四川海思科制药有限公司
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Priority to CN201780020343.6A priority Critical patent/CN109071392B/en
Publication of WO2017211307A1 publication Critical patent/WO2017211307A1/en

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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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
    • C07C39/17—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings containing other rings in addition to the six-membered aromatic rings, e.g. cyclohexylphenol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds

Definitions

  • the present invention relates to a benzene ring derivative represented by the formula (A), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a preparation method thereof and a drug combination thereof And the use of the compounds of the invention in the field of central nervous system.
  • the GABA A receptor is the major inhibitory neurotransmitter receptor in the central nervous system.
  • the GABA A receptor consists of a pentamer of transmembrane polypeptide subunits, and 19 different subunits make up a variety of different GABA A receptor subtypes.
  • GABA A receptors are involved in the pathogenesis and diagnosis and treatment of various diseases such as anesthesia, depression, anxiety, epilepsy, memory disorders, and drug dependence. Therefore, the GABA A receptor is a pharmacological and clinically important drug target. Propofol and its derivatives are an important class of compounds targeting GABA A.
  • Propofol activates a variety of GABA A receptor subtypes and is a clinically mature intravenous anesthetic widely used for the induction and maintenance of general anesthesia.
  • Clinical dose-related propofol directly activates the GABA A receptor-chloride channel complex in mammalian neurons, increases chloride conduction, reduces neural network excitability, and causes general anesthesia (Manami Hara et al. (1993) .Anesthesiology, 79, 781-788).
  • the remarkable pharmacokinetic and pharmacodynamic properties of propofol are fast onset, short duration and fast reversible.
  • propofol After intravenous administration, propofol rapidly enters the high perfusion area such as heart, lung and liver from the blood. The high fat solubility makes propofol easily cross the blood-brain barrier and enter the brain to exert general anesthesia.
  • propofol also has obvious limitations and disadvantages. It is reported that about 70% of patients have a certain degree of pain or discomfort when taking propofol (Pascale Picard (2000). Anesthesia & Analgesia, 90, 963-969), which has been reported to be caused by propofol in the aqueous phase of lipid emulsions.
  • Propofol has been shown to reduce systolic blood pressure, diastolic blood pressure and mean arterial blood pressure, thus causing hypotension in the clinic.
  • respiratory depression is also a risk that cannot be ignored when using propofol.
  • These adverse reactions have largely hampered the use of propofol in a number of clinical cases, such as cardiovascular disease, brain damage and chronic hypotension.
  • the object of the present invention is to provide a novel, effective, safe, orally administrable GABA A receptor agonist, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, preparation method and pharmaceutical composition And its use in the central nervous system to promote sedative and hypnosis, to treat and prevent anxiety, nausea, vomiting, migraine, convulsions, epilepsy, neurodegenerative diseases, brain protection, and central nervous system-related diseases to provide more and better Drug selection route.
  • the present invention relates to a compound of the formula (A), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or eutectic thereof:
  • R is selected from F, Cl, Br, I, OR 4 or Optimal
  • R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, C 1-8 alkyl, C 1-8 alkoxy a 3 to 8 membered carbocyclic group or a 3 to 8 membered heterocyclic group, which is further optionally 0 to 5 selected from the group consisting of F, Cl, Br, Substituted by a substituent of 1 , a hydroxyl group, a C 1-8 alkyl group, a C 1-8 alkoxy group, a 3 to 8 membered carbocyclic group or a 3 to 8 membered heterocyclic group, said heterocyclic group having 1 to 2 a hetero atom selected from N, O or S, and R 1 , R 2 and R 3 are not simultaneously H;
  • R 1 and R 2 , R 2 and R 3 , R 1 and R 3 , R 8 and R 9 or any of R 10 and R 11 may form a 3 to 8 member with the carbon atom to which they are attached.
  • Carbocyclyl or 3 to 8 membered heterocyclic group, said 3 to 8 membered carbocyclic group or 3 to 8 membered heterocyclic group optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, C a 1-8 alkyl group, a C 1-8 alkoxy group, a 3 to 8 membered carbocyclic group or a 3 to 8 membered heterocyclic group, the heterocyclic group having 1 to 2 selected from N, O or S Hetero atom
  • R 4 is selected from H, C 2-8 alkyl, 3 to 8 membered carbocyclic group or 3 to 8 membered heterocyclic group, and the alkyl group, carbocyclic group or heterocyclic group is optionally further 0 to 5 Substituted with a substituent selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, 3 to 8 membered carbocyclic or 3 to 8 membered heterocyclic,
  • the heterocyclic group contains 1 to 2 hetero atoms selected from N, O or S;
  • R 5 or R 6 are each independently selected from H, F, Cl, Br, I, C 1-8 alkyl, C 1-8 alkoxy, 3 to 8 membered carbocyclyl or 3 to 8 membered heterocyclic,
  • the alkyl, alkoxy, carbocyclic or heterocyclic group is further optionally from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-8 alkyl, C 1-8 alkoxy
  • R 5 and R 6 may form a 3 to 8 membered ring with a carbon atom to which they are attached, and the 3 to 8 membered ring may have 0 to 2 hetero atoms selected from N, O or S, and The formed 3 to 8 membered ring may be optionally further substituted with 0 to 4 R 12 ;
  • R 7 is selected from H, F, Cl, Br, I, hydroxy or C 1-8 alkoxy
  • R 12 is selected from the group consisting of F, Cl, Br, I, C 1-8 alkyl, C 1-8 alkoxy, hydroxy, -COOH, amino, carboxylate, amide, 3 to 8 membered carbocyclyl or a 3- to 8-membered heterocyclic group containing 1 to 2 hetero atoms selected from N, O or S;
  • X is selected from a hydroxyl group or NR a R b ;
  • W 1 or W 2 are each independently selected from NR yc , O, S or absent;
  • R ya or R yb are each independently selected from H or C 1-6 alkyl
  • R yc is selected from H, C 1-6 alkyl, C 3-8 carbocyclic or 3 to 8 membered heterocyclic, and the alkyl, carbocyclic or heterocyclic group may be further further 0 to 5
  • n 0, 1, 2 or 3;
  • n is selected from 1, 2 or 3, preferably 1 or 2, more preferably 1.
  • Preferred embodiments of the invention include compounds of the formula (A-I) or (A-II), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or eutectic thereof:
  • R is selected from F, Cl, Br, I, OR 4 or Optimal
  • R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, C 1-6 alkyl, C 1-6 alkoxy a 3 to 6 membered carbocyclic group or a 3 to 6 membered heterocyclic group, preferably H, F, Cl, C 1-6 alkyl or a 3 to 6 membered carbocyclic group, said alkyl group, alkoxy group, carbon
  • the cyclo or heterocyclic group is optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, 3 to 6 membered carbocyclic or 3 Substituted to a 6-membered heterocyclic group containing 1 to 2 heteroatoms selected from N, O or S, and R 1 , R 2 and R 3 are not simultaneously H;
  • R 1 and R 2 , R 2 and R 3 , R 1 and R 3 , R 8 and R 9 or any of R 10 and R 11 may form a 3 to 6 member with the carbon atom to which they are attached.
  • Carbocyclyl or 3 to 6 membered heterocyclic group, said 3 to 6 membered carbocyclic group or 3 to 6 membered heterocyclic group optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, C Substituted by 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered carbocyclic or 3 to 6 membered heterocyclic, preferably further 0 to 5 selected from F, Cl, Br, C 1- a 6 alkyl group, a C 1-6 alkoxy group or a 3 to 6 membered carbocyclic group, the heterocyclic group having 1 to 2 selected from N, O or S;
  • R 4 is selected from H, C 2-6 alkyl, 3 to 6 membered carbocyclic group or 3 to 6 membered heterocyclic group, and the alkyl group, carbocyclic group or heterocyclic group is optionally further 0 to 5 Substituted with a substituent selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, a 3 to 6 membered carbocyclic group or a 3 to 6 membered heterocyclic group,
  • the heterocyclic group contains 1 to 2 hetero atoms selected from N, O or S;
  • R 5 or R 6 are each independently selected from H, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered carbocyclic or 3 to 6 membered heterocyclic,
  • the alkyl, alkoxy, carbocyclic or heterocyclic group is further optionally from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-6 alkyl, C 1-6 alkoxy Substituted by a substituent of a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group containing 1 to 2 hetero atoms selected from N, O or S, and R 5 and R 6 is not H at the same time;
  • R 5 and R 6 may form a 3 to 6 membered ring with a carbon atom to which they are attached, and the 3 to 6 membered ring may have 0 to 2 hetero atoms selected from N, O or S, and The formed 3- to 6-membered ring may be optionally further substituted with 0 to 4 R 12 ;
  • R 7 is selected from H, F, Cl, Br, I, hydroxy or C 1-6 alkoxy
  • R 12 is selected from the group consisting of F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, -COOH, amino, carboxylate, amide, 3 to 6 membered carbocyclyl or a 3- to 6-membered heterocyclic group containing 1 to 2 hetero atoms selected from N, O or S;
  • W 1 and W 2 are each independently selected from NR yc , O, S or absent;
  • R ya , R yb are each independently selected from H or C 1-6 alkyl
  • R yc is selected from H, C 1-6 alkyl, C 3-6 carbocyclyl or 3 to 6 membered heterocyclic, and the alkyl, carbocyclyl or heterocyclic group may be further further 0 to 5 One selected from the group consisting of H, F, Cl, Br, I, hydroxy, amino, cyano, -COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclyl or 3 to 6 Substituted by a substituent of a heterocyclic group containing from 1 to 2 heteroatoms selected from N, O or S;
  • n 0, 1, 2 or 3;
  • n is selected from 1, 2 or 3, preferably 1 or 2, more preferably 1.
  • Preferred embodiments of the invention include compounds of the formula (A-I) or (A-II), or all of them Stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or eutectic:
  • R is selected from F, Cl, Br, I, OR 4 or Optimal
  • R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of H, F, Cl, Br, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, N-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and R 1 , R 2 and R 3 are not At the same time, H;
  • R 1 and R 2 , R 2 and R 3 , R 1 and R 3 , R 8 and R 9 or any of R 10 and R 11 may form a cyclopropyl group or a ring with a carbon atom bonded thereto.
  • R 4 is selected from the group consisting of H, CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, hydroxyethyl, cyclopropyl, Cyclobutyl, cyclopentyl or cyclohexyl;
  • R 5 and R 6 are each independently selected from the group consisting of H, F, Cl, Br, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, methyl, ethyl, n-propyl, Isopropyl, n-butyl, sec-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy a group, a tert-butoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, and R 5 and R 6 are not simultaneously H;
  • R 5 and R 6 may form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group with a carbon atom to which they are attached;
  • R 7 is selected from the group consisting of H, F, Cl, Br, I, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy or tert-butoxy;
  • R 12 is selected from the group consisting of F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy , isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, hydroxy, -COOH, amino, carboxylate, amide, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ;
  • R yc is selected from the group consisting of H, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl , tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxybenzene Base, 3-methoxyphenyl or 4-methoxyphenyl;
  • n 0, 1, 2 or 3;
  • n is selected from 1, 2 or 3, preferably 1 or 2, more preferably 1.
  • Preferred embodiments of the invention include compounds of the formula (A-I) or (A-II), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or eutectic thereof:
  • R is selected from
  • R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, and R 1 , R 2 and R 3 are not H at the same time;
  • R 5 and R 6 are each independently selected from H, methyl, ethyl, n-propyl or isopropyl, and R 5 and R 6 are not simultaneously H;
  • R 7 is selected from H
  • W 1 and W 2 are each independently selected from NR yc , O, S or absent;
  • R ya , R yb are each independently selected from H or C 1-6 alkyl
  • R yc is selected from H, C 1-6 alkyl, C 3-6 carbocyclyl or 3 to 6 membered heterocyclic, and the alkyl, carbocyclyl or heterocyclic group may be further further 0 to 5 One selected from the group consisting of H, F, Cl, Br, I, hydroxy, amino, cyano, -COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclyl or 3 to 6 Substituted by a substituent of a heterocyclic group containing from 1 to 2 heteroatoms selected from N, O or S;
  • n 0, 1, 2 or 3;
  • n is selected from 1.
  • Preferred embodiments of the invention include compounds of the formula (AI) or (A-II), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or eutectic thereof:
  • R is selected from
  • R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, and R 1 , R 2 and R 3 are not H at the same time;
  • R 5 and R 6 are each independently selected from H, methyl, ethyl, n-propyl or isopropyl, and R 5 and R 6 are not simultaneously H;
  • R 7 is selected from H
  • Y is selected from H
  • R yc is selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, phenyl;
  • n is selected from 1.
  • Preferred embodiments of the invention include compounds of the formula (A-I) or (A-II), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or eutectic thereof:
  • R is selected from
  • R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are each independently selected from H, methyl or cyclopropyl, and R 1 , R 2 and R 3 are not simultaneously H;
  • R 5 and R 6 are each independently selected from H or methyl, and R 5 and R 6 are not H at the same time;
  • R 7 is selected from H
  • Y is selected from H
  • R yc is selected from H, methyl or phenyl
  • n is selected from 1.
  • the prodrug compound of the present invention is selected from, but not limited to:
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (A) or all stereoisomers, solvates, metabolites thereof, pharmaceutically acceptable salts thereof, Crystal or prodrug, and one or more pharmaceutically acceptable carriers and/or excipients.
  • the present invention relates to a compound of the formula (A), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof, for the preparation and maintenance of an animal or Human anesthesia, use in promoting sedative hypnosis, brain protection, stroke, treatment and/or prevention of anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions or epilepsy in animals or humans, preferably in preparation Use in the induction and maintenance of anesthetic drugs in animals or humans.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopic conditions, and the carbons involved in the groups and compounds of the present invention.
  • Hydrogen, oxygen, sulfur or nitrogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C and 14 C, and the hydrogen isotopes include helium (H), helium (D, Also known as heavy hydrogen), ⁇ (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • Alkyl means a straight or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, further preferably An alkyl group of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various Branched isomers.
  • Alkoxy means -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropane Oxyl and cyclobutoxy. .
  • Amino means -NH 2 .
  • Alkylamino means an amino group having one or two alkyl substituents.
  • Carboxyl means -COOH.
  • Carboxylic acid ester group means -COOR 14 wherein R 14 is C 1-6 alkyl.
  • “Amido” means -CONR 15 R 16 wherein R 15 and R 16 are each independently selected from H, alkyl or carbocyclyl.
  • Carbocyclyl means a saturated or unsaturated aromatic or non-aromatic ring.
  • the aromatic or non-aromatic ring may be a 3 to 8 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered tricyclic ring system.
  • the ring group may be attached to a bridged ring or a spiro ring, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, Cyclohexene,
  • Heterocyclyl means a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 8 membered monocyclic ring, a 4 to 12 membered bicyclic ring or 10 to 15 a tricyclic ring system, and comprising 1 to 3 hetero atoms selected from N, O or S, preferably a 3 to 8 membered heterocyclic group, and optionally substituted N, S in the ring of the heterocyclic group can be oxidized into various Oxidation state.
  • the heterocyclic group may be attached to a hetero atom or a carbon atom, and the heterocyclic group may be bonded to a bridged or spiro ring, and non-limiting examples include epoxyethyl, azacyclopropyl, oxetanyl, aza.
  • Cyclobutyl 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxohexyl, azepanyl, pyridyl, furyl, thienyl, pyridyl Cyclol, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithia, Dihydrofuranyl, dihydropyranyl, dithiapentanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl , pyrrolopyridyl, benzod
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” means that the compound of the invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is passed through with a non-toxic inorganic base or An organic base, a salt obtained by reacting a free base with a non-toxic inorganic or organic acid.
  • Non-limiting examples of the inorganic base include Al, Ca, Li, Mg, K, Na, and Zn; non-limiting examples of the organic base include ammonia, isopropylamine, trimethylamine, Diethylamine, triethylamine, tripropylamine, tetramethylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine , procaine, choline, betaine, phenicillin, ethylenediamine, glucosamine, N-methylmethylglucamine, theobromine, triethanolamine, tromethamine, hydrazine, piperazine, piperazine Pyridine, N-ethylpiperidine and polyamine resins; non-limiting examples of the inorganic and organic acids include sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic
  • “Pharmaceutical composition” means a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts thereof or prodrugs and other chemical components, wherein “other chemical components” means pharmaceutically acceptable Accepted carriers, excipients, and/or one or more additional therapeutic agents.
  • Carrier means a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
  • Excipient means an inert substance that is added to a pharmaceutical composition to facilitate administration of the compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, bonding Agent and disintegrant.
  • Prodrug means a compound of the invention that can be converted to biological activity by metabolism in vivo.
  • Prodrugs of the invention are prepared by modifying a phenolic group in a compound of the invention which can be removed by conventional procedures or in vivo to provide the parent compound.
  • the prodrug is cleaved to form a free hydroxyl group.
  • Cyctic crystal refers to a crystal in which an active pharmaceutical ingredient (API) and a eutectic former (CCF) are combined by hydrogen bonding or other non-covalent bonds, wherein the pure state of API and CCF is at room temperature. Solid, and there is a fixed stoichiometric ratio between the components. Eutectic is a multi-component crystal that contains both a binary eutectic formed between two neutral solids and a multi-eutectoid formed from a neutral solid with a salt or solvate.
  • API active pharmaceutical ingredient
  • CCF eutectic former
  • Animal is meant to include mammals, such as humans, companion animals, zoo animals, and domestic animals, preferably humans, horses, or dogs.
  • Stepoisomer refers to isomers resulting from the spatial arrangement of atoms in a molecule, including cis and trans isomers, enantiomers and conformational isomers.
  • heterocyclic group optionally substituted by an alkyl group means that the alkyl group may be, but not necessarily, the description includes the case where the heterocyclic group is substituted by an alkyl group, and the heterocyclic group thereof is not substituted with an alkyl group.
  • R a and R b are each independently selected from alkyl, alkoxy; as an alternative, R a and R b form an aromatic ring", denoted R relationship between a and R b form an aromatic ring and R a and R b each independently selected from alkyl or alkoxy is a parallel, with each other is not limited definition.
  • Anesthesia induction time and anesthesia maintenance time start timing after administration, and closely observe the general symptoms of the animal and the local and respiratory changes. If a normal animal pushes it down or is lying on its back, it can be turned over immediately. This reflection is judged as a normal reflection. On the contrary, it is regarded as the disappearance of the righting reflection, and the reflection disappearance time is recorded. When the animal reappears the righting reflection, the reflection recovery time is recorded. The time from the end of administration to the righting reflex was recorded as the anesthesia onset time, and the disappearance of the righting reflex to the reflex recovery time was recorded as the anesthesia maintenance time.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD). ), the internal standard is tetramethylsilane (TMS);
  • HPLC HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm, 3.5 ⁇ M);
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.20mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm;
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anike Chemical, Shanghai Demo, Chengdu Kelon Chemical, Suiyuan Chemical Technology, Belling Technology, etc. the company;
  • the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume;
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume;
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and operated three times;
  • reaction is carried out under a nitrogen atmosphere
  • the solution means an aqueous solution
  • the temperature in the reaction is room temperature, and the most suitable reaction temperature at room temperature is 20 ° C to 30 ° C;
  • SPF grade ICR mice SCXY (chuan)-2008-24-Chengdu Dashuo Biotechnology Co., Ltd.
  • the general anesthetic effect of the test compound was studied using a mature mouse anesthesia model (Ratnakumari Lingamaneni et al. (2001). Anesthesiology, 2001, 94, 1050-7).
  • the test compound is formulated to the desired concentration with physiological saline.
  • the experimental animals were fasted for 12 hours after acclimation in a laboratory environment. After oral administration at 50, 100 mg/kg the next day, the disappearance time of righting reflex was recorded. The time from the disappearance of the righting reflex after administration was the induction time of anesthesia.
  • the time when the righting reflex disappeared until the recovery of righting reflex was the duration of anesthesia.
  • the anesthesia induction time and the duration of anesthesia indicate the strength of anesthesia.
  • the anesthesia effect was evaluated by indicators such as anesthesia induction time, anesthesia maintenance time, and righting reflex disappearance rate.
  • the righting reflex disappears: the righting reflex disappears, making it in the supine position and lasting for 60s;
  • Righting reflex recovery time The ability to correct the righting reflex is restored so that it is less than 2s in the supine position.
  • mice can produce significant anesthetic effects after oral administration, indicating that the compounds of the present invention have good pharmacodynamic activity and oral characteristics.

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Abstract

The present invention relates to a benzene derivative, and a manufacturing method and pharmaceutical application thereof. The invention specifically relates to a benzene derivative as represented by formula (A), or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt, or cocrystal thereof, a manufacturing method of the derivative, a pharmaceutical composition comprising the derivative, and an application of a compound or the composition in the field of central nervous system. Definitions for each substituent in the formula (A) are identical to the definitions provided in the specification.

Description

苯环衍生物及其制备方法和在医药上的应用Benzene ring derivative, preparation method thereof and application in medicine 技术领域Technical field
本发明涉及一种通式(A)所示的苯环衍生物，或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或者共晶，其制备方法、药物组合物以及本发明化合物在中枢神经领域的用途。The present invention relates to a benzene ring derivative represented by the formula (A), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a preparation method thereof and a drug combination thereof And the use of the compounds of the invention in the field of central nervous system.
背景技术Background technique
GABAA受体是中枢神经系统中主要的抑制性神经递质受体。GABAA受体由跨膜多肽亚基的五聚体构成，19种不同的亚基组成了多种不同的GABAA受体亚型。GABAA受体涉及麻醉、抑郁、焦虑、癫痫、记忆障碍、药物依赖等多种疾病的发病机制和诊断治疗。因此，GABAA受体是药理学和临床上重要的药物作用靶点。丙泊酚及其衍生物即是一类重要的以GABAA为靶点的化合物。The GABA A receptor is the major inhibitory neurotransmitter receptor in the central nervous system. The GABA A receptor consists of a pentamer of transmembrane polypeptide subunits, and 19 different subunits make up a variety of different GABA A receptor subtypes. GABA A receptors are involved in the pathogenesis and diagnosis and treatment of various diseases such as anesthesia, depression, anxiety, epilepsy, memory disorders, and drug dependence. Therefore, the GABA A receptor is a pharmacological and clinically important drug target. Propofol and its derivatives are an important class of compounds targeting GABA A.
丙泊酚可激活多种GABAA受体亚型，是一个临床上成熟的静脉麻醉药，广泛用于全身麻醉的诱导和维持。临床剂量相关的丙泊酚可直接激活哺乳动物神经元中的GABAA受体-氯离子通道复合体，增加氯离子传导，降低神经网络的兴奋性，进而引起全身麻醉(Manami Hara等(1993).Anesthesiology,79,781-788)。丙泊酚的显著药代动力学和药效学性质是起效快，维持时间短和快速可逆。静脉给药后，丙泊酚迅速从血液进入心、肺和肝等高灌注区，高脂溶性使丙泊酚容易跨越血脑屏障进入大脑发挥全身麻醉作用。Propofol activates a variety of GABA A receptor subtypes and is a clinically mature intravenous anesthetic widely used for the induction and maintenance of general anesthesia. Clinical dose-related propofol directly activates the GABA A receptor-chloride channel complex in mammalian neurons, increases chloride conduction, reduces neural network excitability, and causes general anesthesia (Manami Hara et al. (1993) .Anesthesiology, 79, 781-788). The remarkable pharmacokinetic and pharmacodynamic properties of propofol are fast onset, short duration and fast reversible. After intravenous administration, propofol rapidly enters the high perfusion area such as heart, lung and liver from the blood. The high fat solubility makes propofol easily cross the blood-brain barrier and enter the brain to exert general anesthesia.
然而，丙泊酚也有显而易见的局限性和缺点。据报道，约70％的病人在注射丙泊酚时有一定程度的疼痛或者不适(Pascale Picard(2000).Anesthesia&Analgesia,90,963-969)，有报道认为是脂质乳剂水相中的丙泊酚导致的注射疼痛(Klement W等，1991，Br J Anaesth 67，281)，几项研究报道了与DIPRIVAN的水相中的丙泊酚含量相比，当丙泊酚的水相浓度降低时注射疼痛显著降低(Doenicke AW等，1996，Anesth Analg 82，472；Ueki R等，2007，J Anesth 21，325)。虽然有报道用其他药物预处理或者联合用药的方法可降低丙泊酚注射疼痛的发生率和严重程度(C.H.Tan等(1998).Anaesthesia,53,302–305)，但这种疼痛仍难以避免。丙泊酚已被证明可降低收缩压，舒张压和平均动脉血压，因此在临床上会引起低血压。同时，呼吸抑制也是使用丙泊酚时不可忽视的风险。这些不良反应很大程度上阻碍了丙泊酚在一些临床病例中的应用，如心血管疾病，脑损伤和慢性低血压。However, propofol also has obvious limitations and disadvantages. It is reported that about 70% of patients have a certain degree of pain or discomfort when taking propofol (Pascale Picard (2000). Anesthesia & Analgesia, 90, 963-969), which has been reported to be caused by propofol in the aqueous phase of lipid emulsions. Injection pain (Klement W et al., 1991, Br J Anaesth 67, 281), several studies have reported significant injection pain when the aqueous phase concentration of propofol is reduced compared to the propofol content in the aqueous phase of DIPRIVAN Reduction (Doenicke AW et al, 1996, Anesth Analg 82, 472; Ueki R et al, 2007, J Anesth 21, 325). Although it has been reported that pretreatment with other drugs or combination therapy can reduce the incidence and severity of propofol injection pain (C.H. Tan et al. (1998). Anaesthesia, 53, 302–305), this pain is still difficult to avoid. Propofol has been shown to reduce systolic blood pressure, diastolic blood pressure and mean arterial blood pressure, thus causing hypotension in the clinic. At the same time, respiratory depression is also a risk that cannot be ignored when using propofol. These adverse reactions have largely hampered the use of propofol in a number of clinical cases, such as cardiovascular disease, brain damage and chronic hypotension.
鉴于丙泊酚的局限性和缺点，需要开发新的具有更好药代动力学和药效学特性，且有较少副作用的GABAA受体激动剂。 In view of the limitations and shortcomings of propofol, it is desirable to develop new GABA A receptor agonists with better pharmacokinetic and pharmacodynamic properties with fewer side effects.
发明内容Summary of the invention
本发明的目的在于提供一种结构新颖、药效好、安全、可口服的GABAA受体激动剂，或者其立体异构体、药学上可接受的盐或前药，制备方法、药物组合物以及其在中枢神经领域上的用途，以便促进镇静催眠，治疗和预防焦虑、恶心、呕吐、偏头痛、惊厥、癫痫、神经变性疾病、脑保护以及中枢神经系统相关的疾病提供更多更优的药物选择途径。The object of the present invention is to provide a novel, effective, safe, orally administrable GABA A receptor agonist, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, preparation method and pharmaceutical composition And its use in the central nervous system to promote sedative and hypnosis, to treat and prevent anxiety, nausea, vomiting, migraine, convulsions, epilepsy, neurodegenerative diseases, brain protection, and central nervous system-related diseases to provide more and better Drug selection route.
本发明涉及一种通式(A)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶：The present invention relates to a compound of the formula (A), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or eutectic thereof:
Figure PCTCN2017087484-appb-000001
Figure PCTCN2017087484-appb-000001
其中：among them:
R选自F、Cl、Br、I、OR4或者
Figure PCTCN2017087484-appb-000002
优选
Figure PCTCN2017087484-appb-000003
R is selected from F, Cl, Br, I, OR 4 or
Figure PCTCN2017087484-appb-000002
Optimal
Figure PCTCN2017087484-appb-000003
R1、R2、R3、R8、R9、R10和R11各自独立选自H、F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基，所述的烷基、烷氧基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子，且R1、R2和R3不同时为H；R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, C 1-8 alkyl, C 1-8 alkoxy a 3 to 8 membered carbocyclic group or a 3 to 8 membered heterocyclic group, which is further optionally 0 to 5 selected from the group consisting of F, Cl, Br, Substituted by a substituent of 1 , a hydroxyl group, a C 1-8 alkyl group, a C 1-8 alkoxy group, a 3 to 8 membered carbocyclic group or a 3 to 8 membered heterocyclic group, said heterocyclic group having 1 to 2 a hetero atom selected from N, O or S, and R 1 , R 2 and R 3 are not simultaneously H;
作为选择，R1与R2、R2与R3、R1与R3、R8与R9或者R10与R11任意一组可以与同其相连接的碳原子形成一个3至8元碳环基或者3至8元杂环基，所述3至8元碳环基或者3至8元杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；Alternatively, R 1 and R 2 , R 2 and R 3 , R 1 and R 3 , R 8 and R 9 or any of R 10 and R 11 may form a 3 to 8 member with the carbon atom to which they are attached. Carbocyclyl or 3 to 8 membered heterocyclic group, said 3 to 8 membered carbocyclic group or 3 to 8 membered heterocyclic group optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, C a 1-8 alkyl group, a C 1-8 alkoxy group, a 3 to 8 membered carbocyclic group or a 3 to 8 membered heterocyclic group, the heterocyclic group having 1 to 2 selected from N, O or S Hetero atom
R4选自H、C2-8烷基、3至8元碳环基或者3至8元杂环基，所述的烷基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；R 4 is selected from H, C 2-8 alkyl, 3 to 8 membered carbocyclic group or 3 to 8 membered heterocyclic group, and the alkyl group, carbocyclic group or heterocyclic group is optionally further 0 to 5 Substituted with a substituent selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, 3 to 8 membered carbocyclic or 3 to 8 membered heterocyclic, The heterocyclic group contains 1 to 2 hetero atoms selected from N, O or S;
R5或者R6各自独立选自H、F、Cl、Br、I、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基，所述的烷基、烷氧基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子，且R5和R6不同时为H； R 5 or R 6 are each independently selected from H, F, Cl, Br, I, C 1-8 alkyl, C 1-8 alkoxy, 3 to 8 membered carbocyclyl or 3 to 8 membered heterocyclic, The alkyl, alkoxy, carbocyclic or heterocyclic group is further optionally from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-8 alkyl, C 1-8 alkoxy Substituted by a substituent of a 3- to 8-membered carbocyclic group or a 3- to 8-membered heterocyclic group containing 1 to 2 hetero atoms selected from N, O or S, and R 5 and R 6 is not H at the same time;
作为选择，R5与R6可以与同其相连接的碳原子形成一个3至8元环，所述3至8元环可以含有0至2个选自N、O或者S的杂原子，且形成的3至8元环可以任选进一步被0至4个R12所取代；Alternatively, R 5 and R 6 may form a 3 to 8 membered ring with a carbon atom to which they are attached, and the 3 to 8 membered ring may have 0 to 2 hetero atoms selected from N, O or S, and The formed 3 to 8 membered ring may be optionally further substituted with 0 to 4 R 12 ;
R7选自H、F、Cl、Br、I、羟基或者C1-8烷氧基；R 7 is selected from H, F, Cl, Br, I, hydroxy or C 1-8 alkoxy;
R12选自F、Cl、Br、I、C1-8烷基、C1-8烷氧基、羟基、-COOH、氨基、羧酸酯基、酰胺基、3至8元碳环基或者3至8元杂环基，所述的杂环基含有1至2个选自N、O或者S的杂原子；R 12 is selected from the group consisting of F, Cl, Br, I, C 1-8 alkyl, C 1-8 alkoxy, hydroxy, -COOH, amino, carboxylate, amide, 3 to 8 membered carbocyclyl or a 3- to 8-membered heterocyclic group containing 1 to 2 hetero atoms selected from N, O or S;
X选自羟基或者NRaRb；X is selected from a hydroxyl group or NR a R b ;
Y选自H、F或者-(CRyaRyb)m-(W1)-C(＝O)(W2Ryc)，且X为羟基时，Y不为H、F或者-COOH；Y is selected from H, F or -(CR ya R yb ) m -(W 1 )-C(=O)(W 2 R yc ), and when X is a hydroxyl group, Y is not H, F or -COOH;
Ra或者Rb各自独立地选自H、C1-8烷基或者-C(＝O)(W2Ryc)；R a or R b are each independently selected from H, C 1-8 alkyl or -C(=O)(W 2 R yc );
W1或者W2各自独立地选自NRyc、O、S或者不存在；W 1 or W 2 are each independently selected from NR yc , O, S or absent;
Rya或者Ryb各自独立的选自H或者C1-6烷基；R ya or R yb are each independently selected from H or C 1-6 alkyl;
Ryc选自H、C1-6烷基、C3-8碳环基或者3至8元杂环基，所述的烷基、碳环基或者杂环基可以任选进一步被0至5个选自H、F、Cl、Br、I、羟基、氨基、氰基、-COOH、C1-6烷基、C1-6烷氧基、C3-8碳环基或者3至8元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；R yc is selected from H, C 1-6 alkyl, C 3-8 carbocyclic or 3 to 8 membered heterocyclic, and the alkyl, carbocyclic or heterocyclic group may be further further 0 to 5 One selected from the group consisting of H, F, Cl, Br, I, hydroxy, amino, cyano, -COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 carbocyclyl or 3 to 8 Substituted by a substituent of a heterocyclic group containing from 1 to 2 heteroatoms selected from N, O or S;
m选自0、1、2或者3；m is selected from 0, 1, 2 or 3;
n选自1、2或者3，优选1或者2，更优选1。n is selected from 1, 2 or 3, preferably 1 or 2, more preferably 1.
本发明优选方案，包括通式(A-I)或者(A-II)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶：Preferred embodiments of the invention include compounds of the formula (A-I) or (A-II), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or eutectic thereof:
Figure PCTCN2017087484-appb-000004
Figure PCTCN2017087484-appb-000004
其中：among them:
R选自F、Cl、Br、I、OR4或者
Figure PCTCN2017087484-appb-000005
优选
Figure PCTCN2017087484-appb-000006
R is selected from F, Cl, Br, I, OR 4 or
Figure PCTCN2017087484-appb-000005
Optimal
Figure PCTCN2017087484-appb-000006
R1、R2、R3、R8、R9、R10和R11各自独立选自H、F、Cl、Br、I、羟基、C1-6烷基、C1-6烷氧基、3至6元碳环基或者3至6元杂环基，优选H、F、Cl、C1-6烷基或者3至6元碳环基，所述的烷基、烷氧基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至6元碳环基或者3至6元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子，且R1、R2和R3不同时为H； R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, C 1-6 alkyl, C 1-6 alkoxy a 3 to 6 membered carbocyclic group or a 3 to 6 membered heterocyclic group, preferably H, F, Cl, C 1-6 alkyl or a 3 to 6 membered carbocyclic group, said alkyl group, alkoxy group, carbon The cyclo or heterocyclic group is optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, 3 to 6 membered carbocyclic or 3 Substituted to a 6-membered heterocyclic group containing 1 to 2 heteroatoms selected from N, O or S, and R 1 , R 2 and R 3 are not simultaneously H;
作为选择，R1与R2、R2与R3、R1与R3、R8与R9或者R10与R11任意一组可以与同其相连接的碳原子形成一个3至6元碳环基或者3至6元杂环基，所述3至6元碳环基或者3至6元杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-6烷基、C1-6烷氧基、3至6元碳环基或者3至6元杂环基所取代，优选进一步被0至5个选自F、Cl、Br、C1-6烷基、C1-6烷氧基或者3至6元碳环基所取代，所述的杂环基含有1至2个选自N、O或者S；Alternatively, R 1 and R 2 , R 2 and R 3 , R 1 and R 3 , R 8 and R 9 or any of R 10 and R 11 may form a 3 to 6 member with the carbon atom to which they are attached. Carbocyclyl or 3 to 6 membered heterocyclic group, said 3 to 6 membered carbocyclic group or 3 to 6 membered heterocyclic group optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, C Substituted by 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered carbocyclic or 3 to 6 membered heterocyclic, preferably further 0 to 5 selected from F, Cl, Br, C 1- a 6 alkyl group, a C 1-6 alkoxy group or a 3 to 6 membered carbocyclic group, the heterocyclic group having 1 to 2 selected from N, O or S;
R4选自H、C2-6烷基、3至6元碳环基或者3至6元杂环基，所述的烷基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-6烷基、C1-6烷氧基、3至6元碳环基或者3至6元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；R 4 is selected from H, C 2-6 alkyl, 3 to 6 membered carbocyclic group or 3 to 6 membered heterocyclic group, and the alkyl group, carbocyclic group or heterocyclic group is optionally further 0 to 5 Substituted with a substituent selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, a 3 to 6 membered carbocyclic group or a 3 to 6 membered heterocyclic group, The heterocyclic group contains 1 to 2 hetero atoms selected from N, O or S;
R5或者R6各自独立选自H、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、3至6元碳环基或者3至6元杂环基，所述的烷基、烷氧基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-6烷基、C1-6烷氧基、3至6元碳环基或者3至6元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子，且R5和R6不同时为H；R 5 or R 6 are each independently selected from H, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered carbocyclic or 3 to 6 membered heterocyclic, The alkyl, alkoxy, carbocyclic or heterocyclic group is further optionally from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-6 alkyl, C 1-6 alkoxy Substituted by a substituent of a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group containing 1 to 2 hetero atoms selected from N, O or S, and R 5 and R 6 is not H at the same time;
作为选择，R5与R6可以与同其相连接的碳原子形成一个3至6元环，所述3至6元环可以含有0至2个选自N、O或者S的杂原子，且形成的3至6元环可以任选进一步被0至4个R12所取代；Alternatively, R 5 and R 6 may form a 3 to 6 membered ring with a carbon atom to which they are attached, and the 3 to 6 membered ring may have 0 to 2 hetero atoms selected from N, O or S, and The formed 3- to 6-membered ring may be optionally further substituted with 0 to 4 R 12 ;
R7选自H、F、Cl、Br、I、羟基或者C1-6烷氧基；R 7 is selected from H, F, Cl, Br, I, hydroxy or C 1-6 alkoxy;
R12选自F、Cl、Br、I、C1-6烷基、C1-6烷氧基、羟基、-COOH、氨基、羧酸酯基、酰胺基、3至6元碳环基或者3至6元杂环基，所述的杂环基含有1至2个选自N、O或者S的杂原子；R 12 is selected from the group consisting of F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, -COOH, amino, carboxylate, amide, 3 to 6 membered carbocyclyl or a 3- to 6-membered heterocyclic group containing 1 to 2 hetero atoms selected from N, O or S;
Y’选自-(CRyaRyb)m-(W1)-C(＝O)(W2Ryc)，且Y’不为-COOH；Y' is selected from -(CR ya R yb ) m -(W 1 )-C(=O)(W 2 R yc ), and Y' is not -COOH;
Y选自H、F或者-(CRyaRyb)m-(W1)-C(＝O)(W2Ryc)；Y is selected from H, F or -(CR ya R yb ) m -(W 1 )-C(=O)(W 2 R yc );
Ra、Rb各自独立地选自H、C1-6烷基或者-C(＝O)(W2Ryc)；R a , R b are each independently selected from H, C 1-6 alkyl or -C(=O)(W 2 R yc );
W1、W2各自独立地选自NRyc、O、S或者不存在；W 1 and W 2 are each independently selected from NR yc , O, S or absent;
Rya、Ryb各自独立的选自H或者C1-6烷基；R ya , R yb are each independently selected from H or C 1-6 alkyl;
Ryc选自H、C1-6烷基、C3-6碳环基或者3至6元杂环基，所述的烷基、碳环基或者杂环基可以任选进一步被0至5个选自H、F、Cl、Br、I、羟基、氨基、氰基、-COOH、C1-6烷基、C1-6烷氧基、C3-6碳环基或者3至6元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；R yc is selected from H, C 1-6 alkyl, C 3-6 carbocyclyl or 3 to 6 membered heterocyclic, and the alkyl, carbocyclyl or heterocyclic group may be further further 0 to 5 One selected from the group consisting of H, F, Cl, Br, I, hydroxy, amino, cyano, -COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclyl or 3 to 6 Substituted by a substituent of a heterocyclic group containing from 1 to 2 heteroatoms selected from N, O or S;
m选自0、1、2或者3；m is selected from 0, 1, 2 or 3;
n选自1、2或者3，优选1或者2，更优选1。n is selected from 1, 2 or 3, preferably 1 or 2, more preferably 1.
本发明优选方案，包括通式(A-I)或者(A-II)所示的化合物，或者其所有的 立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶：Preferred embodiments of the invention include compounds of the formula (A-I) or (A-II), or all of them Stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or eutectic:
其中：among them:
R选自F、Cl、Br、I、OR4或者
Figure PCTCN2017087484-appb-000007
优选
Figure PCTCN2017087484-appb-000008
R is selected from F, Cl, Br, I, OR 4 or
Figure PCTCN2017087484-appb-000007
Optimal
Figure PCTCN2017087484-appb-000008
R1、R2、R3、R8、R9、R10和R11各自独立地选自H、F、Cl、Br、CH2F、CHF2、CF3、CH2CH2F、CHFCH3、CHFCH2F、羟基、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、羟基甲基、羟基乙基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、环丙基、环丁基、环戊基或者环己基，且R1、R2和R3不同时为H；R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of H, F, Cl, Br, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, N-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and R 1 , R 2 and R 3 are not At the same time, H;
作为选择，R1与R2、R2与R3、R1与R3、R8与R9或者R10与R11任意一组可以与同其相连接的碳原子形成环丙基、环丁基、环戊基或者环己基；Alternatively, R 1 and R 2 , R 2 and R 3 , R 1 and R 3 , R 8 and R 9 or any of R 10 and R 11 may form a cyclopropyl group or a ring with a carbon atom bonded thereto. Butyl, cyclopentyl or cyclohexyl;
R4选自H、CH2CH2F、CHFCH3、CHFCH2F、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、羟基乙基、环丙基、环丁基、环戊基或者环己基；R 4 is selected from the group consisting of H, CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, hydroxyethyl, cyclopropyl, Cyclobutyl, cyclopentyl or cyclohexyl;
R5和R6各自独立选自H、F、Cl、Br、CH2F、CHF2、CF3、CH2CH2F、CHFCH3、CHFCH2F、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、羟基甲基、羟基乙基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、环丙基、环丁基、环戊基或者环己基，且R5和R6不同时为H；R 5 and R 6 are each independently selected from the group consisting of H, F, Cl, Br, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, methyl, ethyl, n-propyl, Isopropyl, n-butyl, sec-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy a group, a tert-butoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, and R 5 and R 6 are not simultaneously H;
作为选择，R5与R6可以与同其相连接的碳原子形成环丙基、环丁基、环戊基或者环己基；Alternatively, R 5 and R 6 may form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group with a carbon atom to which they are attached;
R7选自H、F、Cl、Br、I、羟基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基或者叔丁氧基；R 7 is selected from the group consisting of H, F, Cl, Br, I, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy or tert-butoxy;
R12选自F、Cl、Br、I、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、羟基、-COOH、氨基、羧酸酯基、酰胺基、环丙基、环丁基、环戊基或者环己基；R 12 is selected from the group consisting of F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy , isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, hydroxy, -COOH, amino, carboxylate, amide, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ;
Y’选自-C(＝O)(Ryc)、-CH(CH3)C(＝O)(Ryc)、-CH2CH2C(＝O)(Ryc)、-OC(＝O)(Ryc)、-CH2OC(＝O)(Ryc)、-CH(CH3)OC(＝O)(Ryc)、-CH2CH2OC(＝O)(Ryc)、-NRycC(＝O)(Ryc)、-CH2NRycC(＝O)(Ryc)、-CH(CH3)NRycC(＝O)(Ryc)、-CH2CH2NRycC(＝O)(Ryc)、-C(＝O)(ORyc)、-CH2C(＝O)(ORyc)、-CH(CH3)C(＝O)(ORyc)、-CH2CH2C(＝O)(ORyc)、-C(＝O)(NRycRyc)、-CH2C(＝O)(NRycRyc)、-CH(CH3)C(＝O)(NRycRyc)或者-CH2CH2C(＝O)(NRycRyc)，且Y’不为-COOH；Y' is selected from -C(=O)(R yc ), -CH(CH 3 )C(=O)(R yc ), -CH 2 CH 2 C(=O)(R yc ), -OC(= O)(R yc ), -CH 2 OC(=O)(R yc ), -CH(CH 3 )OC(=O)(R yc ), -CH 2 CH 2 OC(=O)(R yc ) , -NR yc C(=O)(R yc ), -CH 2 NR yc C(=O)(R yc ), -CH(CH 3 )NR yc C(=O)(R yc ), -CH 2 CH 2 NR yc C(=O)(R yc ), -C(=O)(OR yc ), -CH 2 C(=O)(OR yc ), -CH(CH 3 )C(=O)( OR yc ), -CH 2 CH 2 C(=O)(OR yc ), -C(=O)(NR yc R yc ), -CH 2 C(=O)(NR yc R yc ), -CH( CH 3 )C(=O)(NR yc R yc ) or -CH 2 CH 2 C(=O)(NR yc R yc ), and Y′ is not —COOH;
Y选自H、F、-C(＝O)(Ryc)、-CH(CH3)C(＝O)(Ryc)、-CH2CH2C(＝O)(Ryc)、-OC(＝O)(Ryc)、-CH2OC(＝O)(Ryc)、-CH(CH3)OC(＝O)(Ryc)、-CH2CH2OC(＝O)(Ryc)、-NRycC(＝O)(Ryc)、-CH2NRycC(＝O)(Ryc)、-CH(CH3)NRycC(＝O)(Ryc)、 -CH2CH2NRycC(＝O)(Ryc)、-C(＝O)(ORyc)、-CH2C(＝O)(ORyc)、-CH(CH3)C(＝O)(ORyc)、-CH2CH2C(＝O)(ORyc)、-C(＝O)(NRycRyc)、-CH2C(＝O)(NRycRyc)、-CH(CH3)C(＝O)(NRycRyc)或者-CH2CH2C(＝O)(NRycRyc)；Y is selected from H, F, -C(=O)(R yc ), -CH(CH 3 )C(=O)(R yc ), -CH 2 CH 2 C(=O)(R yc ), - OC(=O)(R yc ), -CH 2 OC(=O)(R yc ), -CH(CH 3 )OC(=O)(R yc ), -CH 2 CH 2 OC(=O)( R yc ), -NR yc C(=O)(R yc ), -CH 2 NR yc C(=O)(R yc ), -CH(CH 3 )NR yc C(=O)(R yc ), -CH 2 CH 2 NR yc C(=O)(R yc ), -C(=O)(OR yc ), -CH 2 C(=O)(OR yc ), -CH(CH 3 )C(= O) (OR yc ), -CH 2 CH 2 C(=O)(OR yc ), -C(=O)(NR yc R yc ), -CH 2 C(=O)(NR yc R yc ), -CH(CH 3 )C(=O)(NR yc R yc ) or -CH 2 CH 2 C(=O)(NR yc R yc );
Ra、Rb各自独立地选自H、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、或者-C(＝O)(Ryc)；R a , R b are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, or -C(=O)(R yc );
Ryc选自H、CH2F、CHF2、CF3、CH2CH2F、CHFCH3、CHFCH2F、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基、苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-甲氧基苯基、3-甲氧基苯基或者4-甲氧基苯基；R yc is selected from the group consisting of H, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl , tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxybenzene Base, 3-methoxyphenyl or 4-methoxyphenyl;
m选自0、1、2或者3；m is selected from 0, 1, 2 or 3;
n选自1、2或者3，优选1或者2，更优选1。n is selected from 1, 2 or 3, preferably 1 or 2, more preferably 1.
本发明优选方案，包括通式(A-I)或者(A-II)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶：Preferred embodiments of the invention include compounds of the formula (A-I) or (A-II), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or eutectic thereof:
其中：among them:
R选自
Figure PCTCN2017087484-appb-000009
R is selected from
Figure PCTCN2017087484-appb-000009
R1、R2、R3、R8、R9、R10和R11各自独立地选自H、甲基、乙基、正丙基、异丙基、环丙基或者环丁基，且R1、R2和R3不同时为H；R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, and R 1 , R 2 and R 3 are not H at the same time;
R5和R6各自独立选自H、甲基、乙基、正丙基或异丙基，且R5和R6不同时为H；R 5 and R 6 are each independently selected from H, methyl, ethyl, n-propyl or isopropyl, and R 5 and R 6 are not simultaneously H;
R7选自H；R 7 is selected from H;
Y’选自-(CRyaRyb)m-(W1)-C(＝O)(W2Ryc)，且Y’不为-COOH；Y' is selected from -(CR ya R yb ) m -(W 1 )-C(=O)(W 2 R yc ), and Y' is not -COOH;
Y选自H、F或者-(CRyaRyb)m-(W1)-C(＝O)(W2Ryc)；Y is selected from H, F or -(CR ya R yb ) m -(W 1 )-C(=O)(W 2 R yc );
Ra、Rb各自独立地选自H、C1-6烷基或者-C(＝O)(W2Ryc)；R a , R b are each independently selected from H, C 1-6 alkyl or -C(=O)(W 2 R yc );
W1、W2各自独立地选自NRyc、O、S或者不存在；W 1 and W 2 are each independently selected from NR yc , O, S or absent;
Rya、Ryb各自独立的选自H或者C1-6烷基；R ya , R yb are each independently selected from H or C 1-6 alkyl;
Ryc选自H、C1-6烷基、C3-6碳环基或者3至6元杂环基，所述的烷基、碳环基或者杂环基可以任选进一步被0至5个选自H、F、Cl、Br、I、羟基、氨基、氰基、-COOH、C1-6烷基、C1-6烷氧基、C3-6碳环基或者3至6元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；R yc is selected from H, C 1-6 alkyl, C 3-6 carbocyclyl or 3 to 6 membered heterocyclic, and the alkyl, carbocyclyl or heterocyclic group may be further further 0 to 5 One selected from the group consisting of H, F, Cl, Br, I, hydroxy, amino, cyano, -COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclyl or 3 to 6 Substituted by a substituent of a heterocyclic group containing from 1 to 2 heteroatoms selected from N, O or S;
m选自0、1、2或者3；m is selected from 0, 1, 2 or 3;
n选自1。n is selected from 1.
本发明优选方案，包括通式(A-I)或者(A-II)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶： Preferred embodiments of the invention include compounds of the formula (AI) or (A-II), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or eutectic thereof:
其中：among them:
R选自
Figure PCTCN2017087484-appb-000010
R is selected from
Figure PCTCN2017087484-appb-000010
R1、R2、R3、R8、R9、R10和R11各自独立地选自H、甲基、乙基、正丙基、异丙基、环丙基或者环丁基，且R1、R2和R3不同时为H；R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, and R 1 , R 2 and R 3 are not H at the same time;
R5和R6各自独立选自H、甲基、乙基、正丙基或异丙基，且R5和R6不同时为H；R 5 and R 6 are each independently selected from H, methyl, ethyl, n-propyl or isopropyl, and R 5 and R 6 are not simultaneously H;
R7选自H；R 7 is selected from H;
Y’选自-OC(＝O)(Ryc)、-NRycC(＝O)(Ryc)或-CH2CH2C(＝O)(ORyc)；Y' is selected from -OC(=O)(R yc ), -NR yc C(=O)(R yc ) or -CH 2 CH 2 C(=O)(OR yc );
Y选自H；Y is selected from H;
Ryc选自H、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、环丙基、苯基；R yc is selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, phenyl;
n选自1。n is selected from 1.
本发明优选方案，包括通式(A-I)或者(A-II)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶：Preferred embodiments of the invention include compounds of the formula (A-I) or (A-II), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or eutectic thereof:
其中：among them:
R选自
Figure PCTCN2017087484-appb-000011
R is selected from
Figure PCTCN2017087484-appb-000011
R1、R2、R3、R8、R9、R10和R11各自独立地选自H、甲基、或者环丙基，且R1、R2和R3不同时为H；R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are each independently selected from H, methyl or cyclopropyl, and R 1 , R 2 and R 3 are not simultaneously H;
R5和R6各自独立选自H或者甲基，且R5和R6不同时为H；R 5 and R 6 are each independently selected from H or methyl, and R 5 and R 6 are not H at the same time;
R7选自H；R 7 is selected from H;
Y’选自-OC(＝O)(Ryc)、-NRycC(＝O)(Ryc)或-CH2CH2C(＝O)(ORyc)；Y' is selected from -OC(=O)(R yc ), -NR yc C(=O)(R yc ) or -CH 2 CH 2 C(=O)(OR yc );
Y选自H；Y is selected from H;
Ryc选自H、甲基或者苯基；R yc is selected from H, methyl or phenyl;
n选自1。n is selected from 1.
本发明优选方案，本发明涉及的前药化合物选自，但不限于：In a preferred embodiment of the present invention, the prodrug compound of the present invention is selected from, but not limited to:
Figure PCTCN2017087484-appb-000012
Figure PCTCN2017087484-appb-000012
Figure PCTCN2017087484-appb-000013
Figure PCTCN2017087484-appb-000013
本发明涉及一种药物组合物，所述的药物组合物包括通式通式(A)所述的化合物或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药，和一种或者多种药学上可接受的载体和/或者赋形剂。The present invention relates to a pharmaceutical composition comprising a compound of the formula (A) or all stereoisomers, solvates, metabolites thereof, pharmaceutically acceptable salts thereof, Crystal or prodrug, and one or more pharmaceutically acceptable carriers and/or excipients.
本发明涉及一种通式(A)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药，在制备诱导和维持动物或者人类的麻醉、促进动物或者人类的镇静催眠、脑保护、脑卒中、治疗和/或者预防焦虑、抑郁、失眠、恶心、呕吐、偏头痛、精神分裂、惊厥或者癫痫药物中的用途，优选在制备诱导和维持动物或者人类的麻醉药物中的用途。The present invention relates to a compound of the formula (A), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof, for the preparation and maintenance of an animal or Human anesthesia, use in promoting sedative hypnosis, brain protection, stroke, treatment and/or prevention of anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions or epilepsy in animals or humans, preferably in preparation Use in the induction and maintenance of anesthetic drugs in animals or humans.
本发明使用的术语具有下述含义。The terms used in the present invention have the following meanings.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或者F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或者氮任选进一步被一个或者多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素包括17F和19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopic conditions, and the carbons involved in the groups and compounds of the present invention. Hydrogen, oxygen, sulfur or nitrogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C and 14 C, and the hydrogen isotopes include helium (H), helium (D, Also known as heavy hydrogen), 氚 (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
“烷基”是指1至20个碳原子的直链或者支链饱和脂肪族烃基，优选为1至8个碳原子的烷基，更优选为1至6个碳原子的烷基，进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体。"Alkyl" means a straight or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, further preferably An alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various Branched isomers.
“烷氧基”是指-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。。"Alkoxy" means -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropane Oxyl and cyclobutoxy. .
“氨基”是指-NH2。"Amino" means -NH 2 .
“烷基氨基”是指具有一个或者两个烷基取代基的氨基基团。"Alkylamino" means an amino group having one or two alkyl substituents.
“羟基”是指-OH。"Hydroxy" means -OH.
“羧基”是指-COOH。"Carboxyl" means -COOH.
“羰基”是指-(C＝O)-。 "Carbonyl" means -(C=O)-.
“羧酸酯基”是指-COOR14，其中R14为C1-6烷基。"Carboxylic acid ester group" means -COOR 14 wherein R 14 is C 1-6 alkyl.
“酰胺基”是指-CONR15R16，其中R15和R16各自独立选自H、烷基或者碳环基。"Amido" means -CONR 15 R 16 wherein R 15 and R 16 are each independently selected from H, alkyl or carbocyclyl.
“＝O”为本领域通常习惯用法，是指以双键相连的氧原子，譬如羰基中与碳原子相连的双键氧原子。"=O" is a commonly used practice in the art and refers to an oxygen atom bonded by a double bond, such as a double bond oxygen atom to a carbon atom in a carbonyl group.
“碳环基”是指饱和或者不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，碳环基可以连接有桥环或者螺环，非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基和环十二烷基、环己烯、
Figure PCTCN2017087484-appb-000014
"Carbocyclyl" means a saturated or unsaturated aromatic or non-aromatic ring. The aromatic or non-aromatic ring may be a 3 to 8 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered tricyclic ring system. The ring group may be attached to a bridged ring or a spiro ring, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, Cyclohexene,
Figure PCTCN2017087484-appb-000014
“杂环基”是指取代的或者未取代的饱和或者不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，且包含1至3个选自N、O或者S的杂原子，优选3至8元杂环基，杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。"Heterocyclyl" means a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 8 membered monocyclic ring, a 4 to 12 membered bicyclic ring or 10 to 15 a tricyclic ring system, and comprising 1 to 3 hetero atoms selected from N, O or S, preferably a 3 to 8 membered heterocyclic group, and optionally substituted N, S in the ring of the heterocyclic group can be oxidized into various Oxidation state. The heterocyclic group may be attached to a hetero atom or a carbon atom, and the heterocyclic group may be bonded to a bridged or spiro ring, and non-limiting examples include epoxyethyl, azacyclopropyl, oxetanyl, aza. Cyclobutyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxohexyl, azepanyl, pyridyl, furyl, thienyl, pyridyl Cyclol, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithia, Dihydrofuranyl, dihydropyranyl, dithiapentanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl , pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]decyl, oxatricyclo[5.3.1.1] Alkyl, azaadamantyl and oxaspiro[3.3]heptanyl.
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。所述的无机碱的非限制性实施例包括Al、Ca、Li、Mg、K、Na和Zn；所述的有机碱的非限制性实施例包括氨、异丙基胺、三甲基胺、二乙胺、三乙胺、三丙基胺、四甲基胺、二乙醇胺、乙醇胺、二甲基乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己基胺、咖啡碱、普鲁卡因、胆碱、甜菜碱、苯明青霉素、乙二胺、葡萄糖胺、N-甲基甲基葡糖胺、可可碱、三乙醇胺、氨丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶和聚胺树脂；所述的无机酸和有机酸的非限制性实施例包括硫酸、磷酸、硝酸、氢溴酸、盐酸、甲酸、乙酸、丙酸、苯磺酸、苯甲酸、苯乙酸、水杨酸、褐藻酸、氨茴酸、樟脑酸、柠檬酸、乙烯磺酸、蚁酸、富马酸、糠酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、乙醇酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、粘液酸、双羟萘酸、泛酸、硬脂酸、琥珀酸、磺胺酸、酒石酸、对甲苯磺酸、丙二酸、2-羟基丙酸、草酸、羟乙酸、葡萄糖醛酸、半乳糖醛酸、枸橼酸、 赖氨酸、精氨酸、门冬氨酸、肉桂酸、对甲苯磺酸、甲磺酸、乙磺酸和三氟甲磺酸。"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the compound of the invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is passed through with a non-toxic inorganic base or An organic base, a salt obtained by reacting a free base with a non-toxic inorganic or organic acid. Non-limiting examples of the inorganic base include Al, Ca, Li, Mg, K, Na, and Zn; non-limiting examples of the organic base include ammonia, isopropylamine, trimethylamine, Diethylamine, triethylamine, tripropylamine, tetramethylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine , procaine, choline, betaine, phenicillin, ethylenediamine, glucosamine, N-methylmethylglucamine, theobromine, triethanolamine, tromethamine, hydrazine, piperazine, piperazine Pyridine, N-ethylpiperidine and polyamine resins; non-limiting examples of the inorganic and organic acids include sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid , benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinyl sulfonic acid, formic acid, fumaric acid, citric acid, gluconic acid, glucuronic acid, glutamic acid, ethanol Acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, Carbenoxolone, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxy propionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, Lysine, arginine, aspartic acid, cinnamic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid and trifluoromethanesulfonic acid.
“药物组合物”是指一种或者多种本发明所述化合物、其药学上可接受的盐或者前药和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或者一种或者多种其它治疗剂。"Pharmaceutical composition" means a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts thereof or prodrugs and other chemical components, wherein "other chemical components" means pharmaceutically acceptable Accepted carriers, excipients, and/or one or more additional therapeutic agents.
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。"Carrier" means a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。"Excipient" means an inert substance that is added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, bonding Agent and disintegrant.
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的酚基团来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。当本发明的前药被施予哺乳动物个体时，前药被割裂形成游离的羟基。"Prodrug" means a compound of the invention that can be converted to biological activity by metabolism in vivo. Prodrugs of the invention are prepared by modifying a phenolic group in a compound of the invention which can be removed by conventional procedures or in vivo to provide the parent compound. When a prodrug of the invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group.
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或者其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与盐或者溶剂化物形成的多元共晶。"Cyctic crystal" refers to a crystal in which an active pharmaceutical ingredient (API) and a eutectic former (CCF) are combined by hydrogen bonding or other non-covalent bonds, wherein the pure state of API and CCF is at room temperature. Solid, and there is a fixed stoichiometric ratio between the components. Eutectic is a multi-component crystal that contains both a binary eutectic formed between two neutral solids and a multi-eutectoid formed from a neutral solid with a salt or solvate.
“动物”是指包括哺乳动物，例如人、陪伴动物、动物园动物和家畜，优选人、马或者犬。"Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and domestic animals, preferably humans, horses, or dogs.
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。"Stereoisomer" refers to isomers resulting from the spatial arrangement of atoms in a molecule, including cis and trans isomers, enantiomers and conformational isomers.
“任选”或者“任选地”或者“选择性的”或者“选择性地”是指随后所述的事件或者状况可以但未必发生，该描述包括其中发生该事件或者状况的情况及其中未发生的情况。例如，“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在，该描述包括其中杂环基被烷基取代的情况，及其中杂环基未被烷基取代的情况。"Optional" or "optionally" or "optional" or "optionally" means that the subsequently described event or condition may, but does not necessarily, occur, including where the event or condition occurred and What happened. For example, "heterocyclic group optionally substituted by an alkyl group" means that the alkyl group may be, but not necessarily, the description includes the case where the heterocyclic group is substituted by an alkyl group, and the heterocyclic group thereof is not substituted with an alkyl group. Happening.
本文所述“作为选择”是指一种并列的存在关系，比如“Ra与Rb各自独立选自烷基、烷氧基；作为选择，Ra与Rb形成芳环”，表示的Ra与Rb形成芳环与Ra与Rb各自独立选自烷基或烷氧基是一种并列的关系，不受彼此定义的限制。As used herein, "as an option" refers to a juxtaposed existence relationship, such as "R a and R b are each independently selected from alkyl, alkoxy; as an alternative, R a and R b form an aromatic ring", denoted R relationship between a and R b form an aromatic ring and R a and R b each independently selected from alkyl or alkoxy is a parallel, with each other is not limited definition.
麻醉诱导时间和麻醉维持时间：给药后开始计时，密切观察动物一般症状和给药局部、呼吸的变化。如正常动物将其推倒或者呈背位仰卧时，能立即翻正过来，这种反射判为翻正反射。反之，则视为翻正反射消失，记录反射消失时间，待动物重新出现翻正反射时，记录反射恢复时间。将给药结束至翻正反射的时间记为麻醉起效时间，自翻正反射消失至反射恢复时间记为麻醉维持时间。 Anesthesia induction time and anesthesia maintenance time: start timing after administration, and closely observe the general symptoms of the animal and the local and respiratory changes. If a normal animal pushes it down or is lying on its back, it can be turned over immediately. This reflection is judged as a normal reflection. On the contrary, it is regarded as the disappearance of the righting reflection, and the reflection disappearance time is recorded. When the animal reappears the righting reflection, the reflection recovery time is recorded. The time from the end of administration to the righting reflex was recorded as the anesthesia onset time, and the disappearance of the righting reflex to the reflex recovery time was recorded as the anesthesia maintenance time.
具体实施方式detailed description
以下结合附图及实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes but is not limited thereto.
化合物的结构是通过核磁共振(NMR)或者(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)；The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD). ), the internal standard is tetramethylsilane (TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；For the determination of MS (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm，3.5μM)；HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm, 3.5 μM);
薄层层析硅胶板使用烟台黄海HSGF254或者青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm；Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.20mm. The specification for thin layer chromatography separation and purification is 0.4mm. ~0.5mm;
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体；Column chromatography generally uses Yantai Yellow Sea silica gel 200 ~ 300 mesh silica gel as a carrier;
本发明的己知起始原料可以采用或者按照本领域已知的方法来合成，或者可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司；The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anike Chemical, Shanghai Demo, Chengdu Kelon Chemical, Suiyuan Chemical Technology, Belling Technology, etc. the company;
氮气氛是指反应瓶连接一个约1L容积的氮气气球；The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume;
氢气氛是指反应瓶连接一个约1L容积的氢气气球；The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume;
氢化反应通常抽真空，充入氢气，反复操作3次；The hydrogenation reaction is usually evacuated, filled with hydrogen, and operated three times;
实施例中无特殊说明，反应在氮气氛下进行；Unless otherwise stated in the examples, the reaction is carried out under a nitrogen atmosphere;
实施例中无特殊说明，溶液是指水溶液；There is no special description in the examples, and the solution means an aqueous solution;
实施例中无特殊说明，反应的温度为室温，室温最适宜的反应温度，为20℃～30℃；The temperature in the reaction is room temperature, and the most suitable reaction temperature at room temperature is 20 ° C to 30 ° C;
DMSO，二甲基亚砜。DMSO, dimethyl sulfoxide.
实施例1Example 1
[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]甲酸酯(化合物1)[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]formate (Compound 1)
[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]formate[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]formate
Figure PCTCN2017087484-appb-000015
Figure PCTCN2017087484-appb-000015
Figure PCTCN2017087484-appb-000016
Figure PCTCN2017087484-appb-000016
第一步：3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯甲醛(1B)First step: 3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-benzaldehyde (1B)
3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-benzaldehyde3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-benzaldehyde
Figure PCTCN2017087484-appb-000017
Figure PCTCN2017087484-appb-000017
反应瓶加入2-[(1R)-1-环丙基乙基]-6-异丙基-苯酚(1A)(10g，48.94mmol)和醋酸(100mL)，搅拌均匀后分批加入乌洛托品(54.89g，391.56mmol)，加完后加热到100℃反应20小时。向反应液中加入水(500mL)，用乙酸乙酯(100mL x3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)＝20:1)得到黄色固体产物3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯甲醛(1B)(3.5g，收率：30.78％)。Add 2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenol (1A) (10g, 48.94mmol) and acetic acid (100mL) to the reaction flask, stir well and add to Ulotto in batches. The product (54.89 g, 391.56 mmol) was heated to 100 ° C for 20 hours after the addition. Water (500 mL) was added to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated Ethyl acetate (V/V) = 20:1) gave the product as a yellow solid, 3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-benzaldehyde (1B) (3.5 g, yield: 30.78%).
第二步：[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]甲酸酯(化合物1)Second step: [3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]formate (Compound 1)
[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]formate[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]formate
Figure PCTCN2017087484-appb-000018
Figure PCTCN2017087484-appb-000018
向反应瓶加入加入3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯甲醛(1B)(10.0g，43.04mmol)和二氯甲烷(200mL)，搅拌均匀后分批加间氯过氧苯甲酸(11.14g，64.57mmol)，加完后室温反应4小时。向反应液中加入水(500mL)，分液，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)＝20:1)得到黄色固体[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]甲酸酯(化合物1)(7.5g，收率：70.17％)。To the reaction flask was added 3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-benzaldehyde (1B) (10.0 g, 43.04 mmol) and dichloromethane (200 mL) After stirring uniformly, m-chloroperoxybenzoic acid (11.14 g, 64.57 mmol) was added in portions, and the mixture was reacted at room temperature for 4 hours. Water (500 mL) was added to the reaction mixture, and the organic layer was dried over anhydrous sodium sulfate. 20:1) A yellow solid [3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]carboxylate (Compound 1) (7.5 g, yield : 70.17%).
MS m/z(ESI):247.1(M-1).MS m/z (ESI): 247.1 (M-1).
1HNMR:(400MHz,CDCl3):δ8.30(s,1H),6.89(d,1H),6.81(d,1H),4.92(s,1H),3.19-3.12(m,1H),2.50-2.46(m,1H),1.29(d,3H),1.25(dd,6H),1.04-0.96(m,1H),0.62-0.45(m,2H),0.26-0.14(m,1H). 1 H NMR: (400 MHz, CDCl 3 ): δ 8.30 (s, 1H), 6.89 (d, 1H), 6.81 (d, 1H), 4.92 (s, 1H), 3.19-3.12 (m, 1H), 2.50 -2.46 (m, 1H), 1.29 (d, 3H), 1.25 (dd, 6H), 1.04-0.96 (m, 1H), 0.62-0.45 (m, 2H), 0.26-0.14 (m, 1H).
实施例2Example 2
[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]甲酸酯(化合物2)[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]formate (Compound 2)
[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]formate [3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]formate
Figure PCTCN2017087484-appb-000019
Figure PCTCN2017087484-appb-000019
第一步：3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯甲醛(2B)First step: 3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-benzaldehyde (2B)
3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-benzaldehyde3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-benzaldehyde
Figure PCTCN2017087484-appb-000020
Figure PCTCN2017087484-appb-000020
反应瓶中加入2,6-二[(1R)-1-环丙基乙基]苯酚(2A)(4.0g，17.36mmol)和醋酸(50mL)，搅拌均匀后分批加入乌洛托品(19.47g，138.92mmol)，加完后加热到100℃反应20小时。向反应液中加入水(100mL)，用乙酸乙酯(50mL x 3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)＝20:1)得到黄色固体3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯甲醛(2B)(1.5g，收率：33.43％)。2,6-bis[(1R)-1-cyclopropylethyl]phenol (2A) (4.0 g, 17.36 mmol) and acetic acid (50 mL) were added to the reaction flask, and the mixture was uniformly stirred, and then urotropine was added in portions. 19.47 g, 138.92 mmol), heated to 100 ° C for 20 hours after the addition. Water (100 mL) was added to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated /ethyl acetate (V / V) = 20:1) to give a yellow solid 3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-benzaldehyde (2B) (1.5 g, Rate: 33.43%).
第二步：[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]甲酸酯(化合物2)Second step: [3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]formate (Compound 2)
[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]formate[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]formate
Figure PCTCN2017087484-appb-000021
Figure PCTCN2017087484-appb-000021
反应瓶中加入加入3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯甲醛(2B)(1.0g，3.87mmol)和二氯甲烷(20mL)，搅拌均匀后分批加入间氯过氧苯甲酸(1.0g，5.81mmol)，加完后室温反应4小时。向反应液中加入水(50mL)，分液，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)＝20:1)得到黄色固体[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]甲酸酯(化合物2)(0.7g，收率：65.92％)。Add 3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-benzaldehyde (2B) (1.0 g, 3.87 mmol) and dichloromethane (20 mL) to the reaction flask and mix well. After the addition of m-chloroperoxybenzoic acid (1.0 g, 5.81 mmol), the mixture was reacted at room temperature for 4 hours. Water (50 mL) was added to the reaction mixture, and the organic layer was dried over anhydrous sodium sulfate. 20:1) A yellow solid [3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]carboxylate (Compound 2) (0.7 g, yield: 65.92%) ).
MS m/z(ESI):273.1(M-1).MS m/z (ESI): 273.1 (M-1).
1HNMR:(400MHz,CDCl3):δ8.31(s,1H),6.90(d,2H),5.03(s,1H),2.50-2.45(m,2H),1.28(d,6H),1.01-0.97(m,2H),0.58-0.45(m,4H),0.24-0.16(m,4H). 1 H NMR: (400MHz, CDCl 3 ): δ 8.31 (s, 1H), 6.90 (d, 2H), 5.03 (s, 1H), 2.50-2.45 (m, 2H), 1.28 (d, 6H), 1.01 -0.97 (m, 2H), 0.58-0.45 (m, 4H), 0.24-0.16 (m, 4H).
实施例3 Example 3
3-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]丙酸甲酯(化合物3)Methyl 3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]propanoate (Compound 3)
Methyl-3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]propanoateMethyl-3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]propanoate
Figure PCTCN2017087484-appb-000022
Figure PCTCN2017087484-appb-000022
第一步：3-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]丙烯酸甲酯(3B)First step: 3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]acrylate methyl ester (3B)
methyl-3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]prop-2-enoateMethyl-3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]prop-2-enoate
Figure PCTCN2017087484-appb-000023
Figure PCTCN2017087484-appb-000023
反应瓶中加入3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯甲醛(1B)(0.7g，3.0mmol)，甲苯(10mL)和甲氧甲酰基亚甲基三苯基膦(3.0g，9.0mmol)，升温至100℃反应14小时，冷却至室温后将反应液浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)＝30:1)得到无色油状液体3-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]丙烯酸甲酯(3B)(0.8g，产率：90％)。3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-benzaldehyde (1B) (0.7 g, 3.0 mmol), toluene (10 mL) and methoxy Formylmethylenetriphenylphosphine (3.0 g, 9.0 mmol), and the mixture was heated to 100 ° C for 14 hours. After cooling to room temperature, the reaction mixture was concentrated. V/V)=30:1) Obtained methyl 3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]acrylate as a colorless oily liquid ( 3B) (0.8 g, yield: 90%).
第二步：3-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]丙酸甲酯(化合物3)Second step: methyl 3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]propanoate (Compound 3)
Methyl-3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]propanoateMethyl-3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]propanoate
Figure PCTCN2017087484-appb-000024
Figure PCTCN2017087484-appb-000024
反应瓶中依次加入3-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]丙烯酸甲酯(3B)(0.8g，2.8mmol)，甲醇(8mL)和Pd/C(0.24g，30％(w％))，室温反应4小时。反应液经硅藻土过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)＝20:1)得到无色油状液体3-[3-[(1R)-1-环丙基乙基]-4- 羟基-5-异丙基-苯基]丙酸甲酯(化合物3)(0.75g，产率：93％)。Methyl 3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]acrylate (3B) (0.8 g, 2.8 mmol) was added to the reaction flask. Methanol (8 mL) and Pd/C (0.24 g, 30% (w%)) were reacted at room temperature for 4 hours. The reaction mixture was filtered through celite (EtOAc) (EtOAc) (HHHHHHHHHHHHH 1R)-1-cyclopropylethyl]-4- Methyl hydroxy-5-isopropyl-phenyl]propanoate (Compound 3) (0.75 g, Yield: 93%).
MS m/z(ESI):289.1(M-1).MS m/z (ESI): 289.1 (M-1).
1HNMR(400MHz,CDCl3):δ6.93(d,1H,J＝2.4Hz),6.88(d,1H,J＝2.0Hz),4.82(brs,1H),3.68(s,3H)，3.15-3.12(m,1H),2.89(t,2H,J＝7.8Hz),2.63-2.59(m,2H),2.48-2.45(m,1H),1.29-1.24(m,9H),1.04-1.02(m,1H),0.56-0.45(m,2H),0.22-0.15(m,2H). 1 H NMR (400 MHz, CDCl 3 ): δ 6.93 (d, 1H, J = 2.4 Hz), 6.88 (d, 1H, J = 2.0 Hz), 4.82 (brs, 1H), 3.68 (s, 3H), 3.15 -3.12(m,1H),2.89(t,2H,J=7.8Hz),2.63-2.59(m,2H),2.48-2.45(m,1H),1.29-1.24(m,9H),1.04-1.02 (m, 1H), 0.56-0.45 (m, 2H), 0.22-0.15 (m, 2H).
实施例4Example 4
3-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]丙酸(化合物4)3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]propanoic acid (Compound 4)
3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]propanoic acid3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]propanoic acid
Figure PCTCN2017087484-appb-000025
Figure PCTCN2017087484-appb-000025
第一步：3-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]丙酸(化合物4)First step: 3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]propanoic acid (Compound 4)
3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]propanoic acid3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]propanoic acid
Figure PCTCN2017087484-appb-000026
Figure PCTCN2017087484-appb-000026
反应瓶中放入3-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]丙酸甲酯(化合物3)(0.75g，2.6mmol)，甲醇(5mL)和水(2mL)，加入NaOH(0.31g，7.7mmol)，于70℃反应3小时，将反应液冷却后浓缩，残留物中加入水(10mL)，用4M的HCl调节pH为5至6，用二氯甲烷(10mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(二氯甲烷/乙酸乙酯(V/V)＝30:1)得到无色油状液体3-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]丙酸(化合物4)(0.55g，产率：77％)。3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]propanoic acid methyl ester (Compound 3) was placed in the reaction flask (0.75 g, 2.6 Methanol) (5 mL) and water (2 mL), NaOH (0.31 g, 7.7 mmol), EtOAc (0.31 g, 7.7 mmol). The pH was adjusted to 5 to 6 and extracted with dichloromethane (10 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated. Ethyl ester (V/V) = 30:1) to give 3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]propyl as a colorless oil Acid (Compound 4) (0.55 g, Yield: 77%).
MS m/z(ESI):275.1(M-1).MS m/z (ESI): 275.1 (M-1).
1HNMR(400MHz,CDCl3):δ6.95(d,1H,J＝2.0Hz),6.89(d,1H,J＝2.4Hz),3.17-3.10(m,1H),2.90(t,2H,J＝8.0Hz),2.67-2.64(m,2H,),2.48-2.45(m,1H),1.29-1.24(m,9H),1.05-1.03(m,1H),0.57-0.46(m,2H),0.21-0.15(m,2H). 1 HNMR (400MHz, CDCl 3) : δ6.95 (d, 1H, J = 2.0Hz), 6.89 (d, 1H, J = 2.4Hz), 3.17-3.10 (m, 1H), 2.90 (t, 2H, J=8.0 Hz), 2.67-2.64 (m, 2H,), 2.48-2.45 (m, 1H), 1.29-1.24 (m, 9H), 1.05-1.03 (m, 1H), 0.57-0.46 (m, 2H) ), 0.21-0.15 (m, 2H).
实施例5Example 5
3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙酸甲酯(化合物5)Methyl 3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]propanoate (Compound 5)
methyl 3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]propanoateMethyl 3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]propanoate
Figure PCTCN2017087484-appb-000027
Figure PCTCN2017087484-appb-000027
第一步：3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙烯酸甲酯(5B)First step: 3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]acrylate methyl ester (5B)
Methyl 3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]prop-2-enoateMethyl 3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]prop-2-enoate
Figure PCTCN2017087484-appb-000028
Figure PCTCN2017087484-appb-000028
反应瓶中放入3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯甲醛(2B)(1.1g，4.3mmol)和甲苯(6mL)，加入甲氧甲酰基亚甲基三苯基膦(4.3g，13.0mmol)，升温至100℃反应14小时。冷却至室温后将反应液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)＝30:1)得到无色油状液体3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙烯酸甲酯(5B)(1.0g，产率：75％)。3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-benzaldehyde (2B) (1.1 g, 4.3 mmol) and toluene (6 mL) were placed in a reaction flask, and methoxy group was added. Acylmethylenetriphenylphosphine (4.3 g, 13.0 mmol) was heated to 100 ° C for 14 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjjjjjjj Methyl (1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]acrylate (5B) (1.0 g, yield: 75%).
第二步：3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙酸甲酯(化合物5)Second step: 3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]propanoic acid methyl ester (Compound 5)
methyl 3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]propanoateMethyl 3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]propanoate
Figure PCTCN2017087484-appb-000029
Figure PCTCN2017087484-appb-000029
反应中依次加入3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙烯酸甲酯(5B)(1.0g，3.2mmol)，甲醇(8mL)和Pd/C(0.3g，30％(w％))，室温搅拌4小时。反应液经硅藻土过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)＝20:1)得到无色油状液体3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙酸甲酯(化合物5)(0.9g，产率：90％)。Methyl 3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]acrylate (5B) (1.0 g, 3.2 mmol), methanol (8 mL) And Pd/C (0.3 g, 30% (w%)), stirred at room temperature for 4 hours. The reaction mixture was filtered through EtOAc (EtOAc) (EtOAc) (HHHHHHHHHHHHH Methyl [(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]propanoate (Compound 5) (0.9 g, yield: 90%).
MS m/z(ESI):315.3(M-1).MS m/z (ESI): 315.3 (M-1).
1HNMR(400MHz,CDCl3):δ6.94(s,2H),4.97(s,1H),3.68(s,3H)，2.91- 2.87(m,2H),2.64-2.60(m,2H),2.50-2.43(m,2H),1.28(d，6H,J＝7.2Hz),1.05-1.00(m，2H)，0.55-0.54(m,2H),0.46-0.44(m,2H),0.20-0.15(m,4H). 1 H NMR (400 MHz, CDCl 3 ): δ 6.94 (s, 2H), 4.97 (s, 1H), 3.68 (s, 3H), 2.91 - 2.87 (m, 2H), 2.64 - 2.60 (m, 2H), 2.50-2.43 (m, 2H), 1.28 (d, 6H, J = 7.2 Hz), 1.05-1.00 (m, 2H), 0.55-0.54 (m, 2H), 0.46-0.44 (m, 2H), 0.20- 0.15 (m, 4H).
实施例6Example 6
3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙酸(化合物6)3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]propionic acid (Compound 6)
3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]propanoic acid3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]propanoic acid
Figure PCTCN2017087484-appb-000030
Figure PCTCN2017087484-appb-000030
第一步：3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙酸(化合物6)First step: 3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]propionic acid (compound 6)
3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]propanoic acid3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]propanoic acid
Figure PCTCN2017087484-appb-000031
Figure PCTCN2017087484-appb-000031
反应瓶中加入3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙酸甲酯(化合物5)(0.4g，1.3mmol)，甲醇(5mL)，水(2mL)和氢氧化钠(0.15g，3.8mmol)，70℃反应3小时。将反应液冷却后浓缩，加入水(10mL)，用4M的HCl调节pH为5至6，用二氯甲烷(10mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(二氯甲烷/乙酸乙酯(V/V)＝30:1)得到无色油状液体3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙酸(化合物6)(0.35g，产率：92％)。To the reaction flask was added methyl 3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]propanoate (Compound 5) (0.4 g, 1.3 mmol), methanol (5 mL), water (2 mL) and sodium hydroxide (0.15 g, 3.8 mmol). The reaction mixture was cooled and concentrated, water (10 mL) was added, and the pH was adjusted to 5 to 6 with 4M HCl, extracted with dichloromethane (10 mL x 2), and the organic phase was combined, dried over anhydrous sodium sulfate Concentration by pressure, the residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate (V/V) = 30:1) to give 3-[3,5-bis[(1R)-1- ring as a colorless oil. Propylethyl]-4-hydroxy-phenyl]propionic acid (Compound 6) (0.35 g, yield: 92%).
MS m/z(ESI):301.2(M-1).MS m/z (ESI): 301.2 (M-1).
1HNMR(400MHz,CDCl3):δ6.96(s,2H),2.92-2.88(m,2H),2.69-2.65(m,2H),2.50-2.43(m,2H),1.28(d，6H,J＝7.2Hz),1.06-1.00(m，2H)，0.56-0.55(m,2H),0.46-0.45(m,2H),0.20-0.14(m,4H). 1 H NMR (400 MHz, CDCl 3 ): δ 6.96 (s, 2H), 2.92-2.88 (m, 2H), 2.69-2.65 (m, 2H), 2.50-2.43 (m, 2H), 1.28 (d, 6H) , J = 7.2 Hz), 1.06-1.00 (m, 2H), 0.56-0.55 (m, 2H), 0.46-0.45 (m, 2H), 0.20-0.14 (m, 4H).
实施例7Example 7
N-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]乙酰胺(化合物7)N-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]acetamide (Compound 7)
N-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]acetamide N-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]acetamide
Figure PCTCN2017087484-appb-000032
Figure PCTCN2017087484-appb-000032
第一步：2,6-二[(1R)-1-环丙基乙基]-4-异亚硝基-2,5-二烯环己酮(7B)First step: 2,6-bis[(1R)-1-cyclopropylethyl]-4-isonitroso-2,5-dicyclohexanone (7B)
2,6-bis[(1R)-1-cyclopropylethyl]-4-hydroxyimino-cyclohexa-2,5-dien-1-one2,6-bis[(1R)-1-cyclopropylethyl]-4-hydroxyimino-cyclohexa-2,5-dien-1-one
Figure PCTCN2017087484-appb-000033
Figure PCTCN2017087484-appb-000033
反应瓶中加入2,6-二[(1R)-1-环丙基乙基]苯酚(2A)(2.0g，8.7mmol)和无水乙醇(18mL)，将体系冷却至-10℃，加入浓盐酸(1.2mL，14.8mmol)，搅拌下滴加亚硝酸钠(0.66g，9.6mmol)溶于水(3.3mL)的溶液，加毕缓慢升至0℃反应5小时。向反应液中加入饱和碳酸氢钠溶液以调节pH为8至9，减压浓缩除去乙醇，加入水(20mL)，用二氯甲烷(20mL x 2)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)＝5:1)得到浅棕色固体2,6-二[(1R)-1-环丙基乙基]-4-异亚硝基-2,5-二烯环己酮(7B)(1.8g，产率：80％)。2,6-bis[(1R)-1-cyclopropylethyl]phenol (2A) (2.0 g, 8.7 mmol) and absolute ethanol (18 mL) were added to the reaction flask, and the system was cooled to -10 ° C and added. Concentrated hydrochloric acid (1.2 mL, 14.8 mmol) was added dropwise with a solution of sodium nitrite (0.66 g, 9.6 mmol) dissolved in water (3.3 mL), and the mixture was slowly warmed to 0 ° C for 5 hours. Saturated sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 8 to 9 and concentrated under reduced pressure to remove ethanol. Water (20 mL) was added and extracted with dichloromethane (20 mL x 2), dried over anhydrous sodium sulfate The organic layer was concentrated under reduced pressure. EtOAcjjjjjjjjjj 4-Isonitroso-2,5-diene cyclohexanone (7B) (1.8 g, yield: 80%).
MS m/z(ESI):260.2(M+1).MS m/z (ESI): 260.2 (M + 1).
第二步：4-胺基-2,6-二[(1R)-1-环丙基乙基]苯酚(7C)Second step: 4-amino-2,6-bis[(1R)-1-cyclopropylethyl]phenol (7C)
4-amino-2,6-bis[(1R)-1-cyclopropylethyl]phenol4-amino-2,6-bis[(1R)-1-cyclopropylethyl]phenol
Figure PCTCN2017087484-appb-000034
Figure PCTCN2017087484-appb-000034
反应瓶中加入2,6-二[(1R)-1-环丙基乙基]-4-异亚硝基-2,5-二烯环己酮(7B)(0.67g，2.6mmol)，甲醇(10mL)和Pd/C(0.2g，30％(w％))，体系用氢气置换3次，常温下氢化4小时。反应液经硅藻土过滤，滤液减压浓缩得棕色固体粗品4-胺基-2,6-二[(1R)-1-环丙基乙基]苯酚(7C)(0.63g)，所得粗品直接用于下步反应。 2,6-bis[(1R)-1-cyclopropylethyl]-4-isonitroso-2,5-dicyclohexanone (7B) (0.67 g, 2.6 mmol) was added to the reaction flask. Methanol (10 mL) and Pd/C (0.2 g, 30% (w%)), the system was replaced with hydrogen three times, and hydrogenated at normal temperature for 4 hours. The reaction mixture was filtered through EtOAc (EtOAc m.) (EtOAcjjjjjjjj Used directly in the next step of the reaction.
MS m/z(ESI):246.3(M+1).MS m/z (ESI): 246.3 (M + 1).
第三步：N-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]乙酰胺(化合物7)The third step: N-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]acetamide (compound 7)
N-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]acetamideN-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]acetamide
Figure PCTCN2017087484-appb-000035
Figure PCTCN2017087484-appb-000035
反应瓶中加入粗品4-胺基-2,6-二[(1R)-1-环丙基乙基]苯酚(7C)(0.63g，2.6mmol)和二氯甲烷(5mL)，加入三乙胺(1.1mL，7.7mmol)，缓慢滴加乙酸酐(0.58g，5.6mmol)，加完后室温搅拌16小时。反应液用水(5mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)＝10:1-3:1)得到白色固体粗品(1.8g)，加入甲醇(5mL)使之溶解，加入碳酸钾(0.3g，4.9mmol)，室温搅拌16小时。减压浓缩除去甲醇，加入水(20mL)，用二氯甲烷(20mL x 2)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)＝10:1)得到白色固体N-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]乙酰胺(化合物7)(0.57g，产率：82％)。The reaction flask was charged with crude 4-amino-2,6-bis[(1R)-1-cyclopropylethyl]phenol (7C) (0.63 g, 2.6 mmol) and dichloromethane (5 mL). The amine (1.1 mL, 7.7 mmol) was slowly added dropwise with acetic acid (0.58 g, 5.6 mmol). The reaction solution was washed with water (5 mL). A crude white solid (1.8 g) was obtained, which was dissolved in methanol (5 mL), The mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. The ester (V/V) = 10:1) gave the white solid N-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]acetamide (Compound 7) ( 0.57 g, yield: 82%).
MS m/z(ESI):288.2(M+1).MS m/z (ESI): 288.2 (M+1).
1HNMR(400MHz,CDCl3):δ7.26(s,1H),7.14(s,1H),2.51-2.44(m,2H),2.14(s,3H),1.28(d，6H,J＝6.8Hz),1.04-1.00(m，2H),0.56-0.55(m,2H),0.46-0.45(m,2H),0.21-0.16(m,4H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.26 (s, 1H), 7.14 (s, 1H), 2.51-2.44 (m, 2H), 2.14 (s, 3H), 1.28 (d, 6H, J = 6.8 Hz), 1.04-1.00 (m, 2H), 0.56-0.55 (m, 2H), 0.46-0.45 (m, 2H), 0.21-0.16 (m, 4H).
实施例8Example 8
N-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]苯甲酰胺(化合物8)N-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]benzamide (Compound 8)
N-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]benzamideN-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]benzamide
Figure PCTCN2017087484-appb-000036
Figure PCTCN2017087484-appb-000036
第一步：N-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]苯甲酰胺(化合物8)First step: N-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]benzamide (Compound 8)
N-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]benzamideN-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]benzamide
Figure PCTCN2017087484-appb-000037
Figure PCTCN2017087484-appb-000037
反应瓶中加入4-胺基-2,6-二[(1R)-1-环丙基乙基]苯酚(7C)(0.82g，3.3mmol)，二氯甲烷(10mL)和三乙胺(0.9mL，6.7mmol)，缓慢滴加苯甲酰氯(0.52g，3.7mmol)，加完后室温反应16小时。反应液用水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)＝10:1-3:1)得到白色固体粗品(1.2g)，加入甲醇(6mL)和碳酸钾(1.0g，7.2mmol)，50℃搅拌5小时。减压浓缩除去甲醇，加入水(20mL)，用二氯甲烷(30mL x 2)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)＝3：1)得到类白色固体N-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]苯甲酰胺(化合物8)(0.35g，产率：30％)。To the reaction flask was added 4-amino-2,6-bis[(1R)-1-cyclopropylethyl]phenol (7C) (0.82 g, 3.3 mmol), dichloromethane (10 mL) and triethylamine ( 0.9 mL, 6.7 mmol), benzoyl chloride (0.52 g, 3.7 mmol) was slowly added dropwise, and the mixture was reacted at room temperature for 16 hours. The reaction solution was washed with water (10 mL). A crude white solid (1.2 g) was obtained. EtOAc (EtOAc) The mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. Ester (V/V) = 3:1) gave an off-white solid N-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]benzamide (Compound 8 (0.35 g, yield: 30%).
MS m/z(ESI):350.2(M+1).MS m/z (ESI): 350.2 (M + 1).
1HNMR(400MHz,CDCl3):δ7.88(d，2H,J＝7.2Hz),7.72(s,1H),7.55-7.42(m,5H),5.00(s,1H),2.54-2.47(m,2H),1.31(d，6H,J＝6.8Hz),1.09-1.03(m，2H),0.58-0.57(m,2H),0.49-0.48(m,2H),0.23-0.19(m,4H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.88 (d, 2H, J = 7.2 Hz), 7.72 (s, 1H), 7.55-7.42 (m, 5H), 5.00 (s, 1H), 2.54-2.47 ( m, 2H), 1.31 (d, 6H, J = 6.8 Hz), 1.09-1.03 (m, 2H), 0.58-0.57 (m, 2H), 0.49-0.48 (m, 2H), 0.23-0.19 (m, 4H).
实施例9Example 9
N-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]乙酰胺(化合物9)N-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]acetamide (Compound 9)
N-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]acetamideN-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]acetamide
Figure PCTCN2017087484-appb-000038
Figure PCTCN2017087484-appb-000038
第一步：2-[(1R)-1-环丙基乙基]-4-异亚硝基-6-异丙基-2,5-二烯环己酮(9B)First step: 2-[(1R)-1-cyclopropylethyl]-4-isonitroso-6-isopropyl-2,5-diene cyclohexanone (9B)
2-[(1R)-1-cyclopropylethyl]-4-hydroxyimino-6-isopropyl-cyclohexa-2,5-dien-1-one 2-[(1R)-1-cyclopropylethyl]-4-hydroxyimino-6-isopropyl-cyclohexa-2,5-dien-1-one
Figure PCTCN2017087484-appb-000039
Figure PCTCN2017087484-appb-000039
反应瓶中加入2-[(1R)-1-环丙基乙基]-6-异丙基-苯酚(1A)(5.0g，24.5mmol)和无水乙醇(25mL)，体系降至-10℃，加入浓盐酸(3.5mL,41.6mmol)，搅拌下滴加亚硝酸钠(1.9g，26.9mmol)溶于水(10mL)的溶液，加完后缓慢升至0℃反应5小时。反应液中加入饱和碳酸氢钠溶液调节pH为8至9，减压浓缩除去乙醇，加入水(20mL)，用二氯甲烷(20mL x 2)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩得到浅棕色固体2-[(1R)-1-环丙基乙基]-4-异亚硝基-6-异丙基-2,5-二烯环己酮(9B)(5.5g，产率：96％)，直接用于下一步反应。2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenol (1A) (5.0 g, 24.5 mmol) and absolute ethanol (25 mL) were added to the reaction flask, and the system was dropped to -10 Concentrated hydrochloric acid (3.5 mL, 41.6 mmol) was added thereto, and a solution of sodium nitrite (1.9 g, 26.9 mmol) dissolved in water (10 mL) was added dropwise with stirring, and the mixture was slowly warmed to 0 ° C for 5 hours. The reaction mixture was diluted with sodium hydrogen carbonate, and the mixture was adjusted to pH 8 to 9 and concentrated under reduced pressure to remove ethanol. Water (20 mL) was added and extracted with dichloromethane (20 mL x 2), dried over anhydrous sodium sulfate Concentration gave 2-[(1R)-1-cyclopropylethyl]-4-isonitroso-6-isopropyl-2,5-dicyclohexanone (9B) (5.5 g, Yield: 96%), used directly in the next reaction.
第二步：4-胺基-2-[(1R)-1-环丙基乙基]-6-异丙基苯酚(9C)Second step: 4-amino-2-[(1R)-1-cyclopropylethyl]-6-isopropylphenol (9C)
4-amino-2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenol4-amino-2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenol
Figure PCTCN2017087484-appb-000040
Figure PCTCN2017087484-appb-000040
反应瓶中加入2-[(1R)-1-环丙基乙基]-4-异亚硝基-6-异丙基-2,5-二烯环己酮(9B)(1.5g，6.4mmol)，甲醇(20mL)，Pd/C(0.45g，30％(w％))，体系用氢气置换3次，常温下氢化反应4小时。反应液经硅藻土过滤，滤液减压浓缩得到棕色固体粗品4-胺基-2-[(1R)-1-环丙基乙基]-6-异丙基苯酚(9C)(1.4g)，所得粗品直接用于下步反应。2-[(1R)-1-cyclopropylethyl]-4-isonitroso-6-isopropyl-2,5-dicyclohexanone (9B) (1.5 g, 6.4) was added to the reaction flask. Methyl acetate (20 mL), Pd/C (0.45 g, 30% (w%)), the system was replaced with hydrogen three times, and hydrogenated at room temperature for 4 hours. The reaction mixture was filtered over EtOAc EtOAc (EtOAc m.) The crude product obtained was used directly in the next step.
第三步：N-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]乙酰胺(化合物9)The third step: N-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]acetamide (Compound 9)
N-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]acetamideN-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]acetamide
Figure PCTCN2017087484-appb-000041
Figure PCTCN2017087484-appb-000041
反应瓶中加入4-胺基-2-[(1R)-1-环丙基乙基]-6-异丙基苯酚(9C)(1.4g，6.4mmol)，二氯甲烷(10mL)和三乙胺(2.7mL,19.2mmol)，缓慢滴加乙酸酐(1.4g，14.0mmol)，加毕于室温搅拌16小时。反应液用水(15mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)＝10:1-3:1)得到白色固体粗品(1.0g)，加入甲醇(10mL)和碳酸钾(1.0g，7.2mmol)，室温下搅拌16小时。减压浓缩除去甲醇，加入水(30mL)，用4M的HCl调节pH为7，用二氯甲烷(20mL x 2)萃取，水相中析出白色固体，抽 滤，得到N-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]乙酰胺(化合物9)(0.61g，产率：71％)。4-Amino-2-[(1R)-1-cyclopropylethyl]-6-isopropylphenol (9C) (1.4 g, 6.4 mmol), dichloromethane (10 mL) and Ethylamine (2.7 mL, 19.2 mmol) was slowly added dropwise with acetic acid (1.4 g, 14.0 mmol), and stirred at room temperature for 16 hours. The reaction solution was washed with water (15 mL), dried over anhydrous NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH A crude white solid (1.0 g) was obtained. MeOH (10 mL) and EtOAc. The methanol was concentrated under reduced pressure, and water (30 mL) was then evaporated, and the mixture was adjusted to pH 7 with 4M HCl, and extracted with dichloromethane (20 mL x 2). Filtration gave N-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]acetamide (Compound 9) (0.61 g, yield: 71% ).
MS m/z(ESI):262.2(M+1).MS m/z (ESI): 262.2 (M+1).
1HNMR(400MHz,CD3OD):δ7.16(d，1H,J＝2.8Hz),7.08(d,1H,J＝2.4Hz),3.20-3.14(m,1H),2.40-2.33(m,1H),1.97(s,3H),1.15-1.08(m,9H),0.91-0.89(m，1H)，0.43-0.41(m,1H),0.26-0.25(m,1H),0.08-0.05(m,2H). 1 H NMR (400 MHz, CD 3 OD): δ 7.16 (d, 1H, J = 2.8 Hz), 7.08 (d, 1H, J = 2.4 Hz), 3.20 - 3.14 (m, 1H), 2.40 - 2.33 (m) ,1H), 1.97(s,3H),1.15-1.08(m,9H),0.91-0.89(m,1H),0.43-0.41(m,1H),0.26-0.25(m,1H),0.08-0.05 (m, 2H).
实施例10Example 10
N-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]苯甲酰胺(化合物10)N-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]benzamide (Compound 10)
N-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]benzamideN-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]benzamide
Figure PCTCN2017087484-appb-000042
Figure PCTCN2017087484-appb-000042
第一步：N-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]苯甲酰胺(化合物10)First step: N-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]benzamide (Compound 10)
N-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]benzamideN-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]benzamide
Figure PCTCN2017087484-appb-000043
Figure PCTCN2017087484-appb-000043
反应瓶中依次加入4-胺基-2-[(1R)-1-环丙基乙基]-6-异丙基苯酚(9C)(1.4g，2.6mmol)，二氯甲烷(10mL)和三乙胺(1.8mL，13.0mmol)，缓慢滴加苯甲酰氯(1.0g，7.0mmol)，加完后室温搅拌16小时。反应液用水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)＝10:1-3:1)得到得白色固体粗品(2.0g)，加入甲醇(10mL)和碳酸钾(1.0g，7.2mmol)，升温至50℃搅拌5小时。减压浓缩除去甲醇，加 入水(20mL)，用二氯甲烷(30mL x 2)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)＝3：1)得到类白色固体N-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]苯甲酰胺(化合物10)(0.61g，产率：40％)。4-Amino-2-[(1R)-1-cyclopropylethyl]-6-isopropylphenol (9C) (1.4 g, 2.6 mmol), dichloromethane (10 mL) and Triethylamine (1.8 mL, 13.0 mmol) was slowly added dropwise with benzoyl chloride (1.0 g, 7.0 mmol). The reaction solution was washed with water (10 mL). A crude white solid (2.0 g) was obtained, and methanol (10 mL) and potassium carbonate (1.0 g, 7.2 mmol) were added, and the mixture was warmed to 50 ° C and stirred for 5 hours. Concentrated under reduced pressure to remove methanol, plus The mixture was poured into water (20 mL), EtOAc (EtOAc)EtOAc. 3:1) Obtained off-white solid N-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]benzamide (Compound 10) (0.61 g , yield: 40%).
MS m/z(ESI):324.2(M+1).MS m/z (ESI): 324.2 (M+1).
1HNMR(400MHz,CDCl3):δ7.89(d，2H,J＝7.2Hz),7.71(s,1H),7.54-7.46(m,3H),7.41(s,1H),7.33(s,1H),4.87(s,1H),3.22-3.15(m,1H),2.54-2.47(m,1H)，1.32-1.26(m，9H),1.09-1.06(m，1H)，0.57-0.50(m,2H),0.23-0.19(m,2H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.89 (d, 2H, J = 7.2 Hz), 7.71 (s, 1H), 7.54-7.46 (m, 3H), 7.41 (s, 1H), 7.33 (s, 1H), 4.87 (s, 1H), 3.22-3.15 (m, 1H), 2.54-2.47 (m, 1H), 1.32-1.26 (m, 9H), 1.09-1.06 (m, 1H), 0.57-0.50 ( m, 2H), 0.23-0.19 (m, 2H).
实施例11Example 11
2,6-双[(1R)-1-环丙基乙基]苯胺(化合物11)2,6-bis[(1R)-1-cyclopropylethyl]aniline (Compound 11)
2,6-bis[(1R)-1-cyclopropylethyl]aniline2,6-bis[(1R)-1-cyclopropylethyl]aniline
Figure PCTCN2017087484-appb-000044
Figure PCTCN2017087484-appb-000044
第一步：2,6-双(1-环丙基乙烯基)苯胺(11B)First step: 2,6-bis(1-cyclopropylvinyl)aniline (11B)
2,6-bis(1-cyclopropylvinyl)aniline2,6-bis(1-cyclopropylvinyl)aniline
Figure PCTCN2017087484-appb-000045
Figure PCTCN2017087484-appb-000045
向反应瓶中依次加入2,6-二溴苯胺(11A)(10.0g，39.9mmol)，2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(23.2g，120.0mmol)，七水磷酸钾(40.5g，120.0mmol)，甲苯(100mL)和水(50mL)，用水泵抽真空，氮气置换3次，加入醋酸钯(0.45g，2.0mmol)和2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(Ruphos，1.86g，4.0mmol)，再次用水泵抽真空，氮气置换3次，升温至90℃，氮气氛围下反应8小时。冷却至室温，过滤后分液，水相用乙酸乙酯(50mL x 3)萃取，合并有机相，用水(150mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(V/V)＝50:1-20:1)得到淡黄色油状液体2,6-双(1-环丙基乙烯基)苯胺(11B)(7.58g，产率：84.4％)。2,6-dibromoaniline (11A) (10.0 g, 39.9 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1 was added to the reaction flask in that order. 3,2-dioxaborane (23.2 g, 120.0 mmol), potassium phosphate heptahydrate (40.5 g, 120.0 mmol), toluene (100 mL) and water (50 mL). Palladium acetate (0.45 g, 2.0 mmol) and 2-dicyclohexylphos-2',6'-diisopropoxy-1,1'-biphenyl (Ruphos, 1.86 g, 4.0 mmol), pumped again with water pump The mixture was replaced with a vacuum of nitrogen three times, heated to 90 ° C, and reacted for 8 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and evaporated. EtOAcjjjjjjjjjjjjjjjjj Chromatographic separation and purification (petroleum ether / ethyl acetate (V / V) = 50:1 - 20:1) to give a pale yellow oily liquid 2,6-bis(1-cyclopropylvinyl)aniline (11B) (7.58 g) , yield: 84.4%).
1HNMR(400MHz,CDCl3):δ6.87(d,2H),6.64(dd,1H),5.19(d,2H),4.94(d,2H),4.00(s,2H),1.68-1.62(m,2H),0.74-0.69(m,4H),0.48-0.45(m,4H). 1 H NMR (400 MHz, CDCl 3 ): δ 6.87 (d, 2H), 6.64 (dd, 1H), 5.19 (d, 2H), 4.94 (d, 2H), 4.00 (s, 2H), 1.68-1.62 ( m, 2H), 0.74-0.69 (m, 4H), 0.48-0.45 (m, 4H).
第二步：2,6-双[(1R)-1-环丙基乙基]苯胺(化合物11)Second step: 2,6-bis[(1R)-1-cyclopropylethyl]aniline (Compound 11)
2,6-bis[(1R)-1-cyclopropylethyl]aniline2,6-bis[(1R)-1-cyclopropylethyl]aniline
Figure PCTCN2017087484-appb-000046
Figure PCTCN2017087484-appb-000046
室温下，向250mL的高压反应釜中加入2,6-双(1-环丙基乙烯基)苯胺(11B)(4.0g，17.8mmol)和二氯甲烷(30mL)，加入催化剂[(R)-2,2'-双(二苯基膦)-1,1'-联萘]二乙酸钌(0.7g，0.83mmol)，加完后将高压釜装置拧紧密封，用氢气置换3次，充入氢气，高压釜上的压力表压力显示为22atm，室温下反应30小时。减压浓缩除去溶剂，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(V/V)＝30:1)得到白色固体2,6-双[(1R)-1-环丙基乙基]苯胺(化合物11)(3.2g，产率：78.6％，手性HPLC：93.0％)。2,6-bis(1-cyclopropylvinyl)aniline (11B) (4.0 g, 17.8 mmol) and dichloromethane (30 mL) were added to a 250 mL autoclave at room temperature, and the catalyst was added [(R) -2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]diacetate (0.7 g, 0.83 mmol), after the addition, the autoclave device was tightly sealed and replaced with hydrogen for 3 times. Hydrogen was introduced, and the pressure of the gauge on the autoclave was shown to be 22 atm, and the reaction was carried out at room temperature for 30 hours. The solvent was concentrated under reduced pressure, and the residue was purified (jjjjjjjjjjjjjj Aniline (Compound 11) (3.2 g, yield: 78.6%, chiral HPLC: 93.0%).
MS m/z(ESI):230.2(M+1).MS m/z (ESI): 230.2 (M+1).
1HNMR(400MHz,CDCl3):δ7.14(d,2H),6.80(t,1H),3.62(s,2H),2.27-2.34(m,2H),1.29(d,6H),1.04-1.12(m,2H),0.52-0.59(m,2H),0.41-0.48(m,2H),0.06-0.17(m,4H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.14 (d, 2H), 6.80 (t, 1H), 3.62 (s, 2H), 2.27-2.34 (m, 2H), 1.29 (d, 6H), 1.04 1.12 (m, 2H), 0.52-0.59 (m, 2H), 0.41-0.48 (m, 2H), 0.06-0.17 (m, 4H).
实施例12Example 12
2,6-双[(1S)-1-环丙基乙基]苯胺(化合物12)2,6-bis[(1S)-1-cyclopropylethyl]aniline (Compound 12)
2,6-bis[(1S)-1-cyclopropylethyl]aniline2,6-bis[(1S)-1-cyclopropylethyl]aniline
Figure PCTCN2017087484-appb-000047
Figure PCTCN2017087484-appb-000047
第一步：2,6-双[(1S)-1-环丙基乙基]苯胺(化合物12)First step: 2,6-bis[(1S)-1-cyclopropylethyl]aniline (compound 12)
2,6-bis[(1S)-1-cyclopropylethyl]aniline2,6-bis[(1S)-1-cyclopropylethyl]aniline
Figure PCTCN2017087484-appb-000048
Figure PCTCN2017087484-appb-000048
250mL的高压反应釜中室温下加入2,6-双(1-环丙基乙烯基)苯胺(11B)(4.0g，17.8mmol)，二氯甲烷(30mL)和[(S)-2,2'-双(二苯基膦)-1,1'-联萘]二乙酸钌(0.7g，0.83mmol)，加毕将高压釜装置拧紧密封，用氢气置换3次后充入氢气，高压釜上的压力表压力显示为22atm，室温下反应30小时。减压浓缩除去溶剂，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(V/V)＝30:1)得到淡黄色油状液体2,6-双[(1S)-1-环丙基乙基]苯胺(化合物12)(3.3g，产率：81.0％，手性 HPLC：92.7％)。2,6-bis(1-cyclopropylvinyl)aniline (11B) (4.0 g, 17.8 mmol), dichloromethane (30 mL) and [(S)-2,2 were added to a 250 mL autoclave at room temperature. '-Bis(diphenylphosphino)-1,1'-binaphthyl]diacetate (0.7g, 0.83mmol), after the addition, the autoclave device was tightly sealed, replaced with hydrogen for 3 times and then charged with hydrogen, autoclave The upper gauge pressure was shown to be 22 atm and reacted at room temperature for 30 hours. The solvent was concentrated under reduced pressure. Ethylethyl]aniline (Compound 12) (3.3 g, yield: 81.0%, chiral HPLC: 92.7%).
MS m/z(ESI):230.2(M+1).MS m/z (ESI): 230.2 (M+1).
1HNMR(400MHz,CDCl3):δ7.14(d,2H),6.82(t,1H),3.62(s,2H),2.27-2.34(m,2H),1.31(d,6H),1.04-1.12(m,2H),0.52-0.59(m,2H),0.41-0.48(m,2H),0.06-0.17(m,4H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.14 (d, 2H), 6.82 (t, 1H), 3.62 (s, 2H), 2.27-2.34 (m, 2H), 1.31 (d, 6H), 1.04- 1.12 (m, 2H), 0.52-0.59 (m, 2H), 0.41-0.48 (m, 2H), 0.06-0.17 (m, 4H).
实施例13Example 13
2-[(1R)-1-环丙基乙基]-6-异丙基苯胺(化合物13)2-[(1R)-1-cyclopropylethyl]-6-isopropylaniline (Compound 13)
2-[(1R)-1-cyclopropylethyl]-6-isopropyl-aniline2-[(1R)-1-cyclopropylethyl]-6-isopropyl-aniline
Figure PCTCN2017087484-appb-000049
Figure PCTCN2017087484-appb-000049
第一步：2-(1-环丙基乙基)-6-异丙基苯胺(13B)First step: 2-(1-cyclopropylethyl)-6-isopropylaniline (13B)
2-(1-cyclopropylvinyl)-6-isopropyl-aniline2-(1-cyclopropylvinyl)-6-isopropyl-aniline
Figure PCTCN2017087484-appb-000050
Figure PCTCN2017087484-appb-000050
向反应瓶中依次加入2-溴-6-异丙基苯胺(13A)(6.70g，31.29mmol)，2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(9.10g，46.88mmol))，七水磷酸钾(31.76g，93.87mmol)，甲苯(100mL)和水(50mL)，用水泵抽真空，氮气置换3次，加入醋酸钯(0.35g，1.56mmol)和2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(Ruphos，1.46g，3.12mmol)，再次用水泵抽真空，氮气置换3次，升温至90℃，氮气氛围下反应4小时。冷却至室温，过滤后分液，水相用乙酸乙酯(50mL x 3)萃取，合并有机相，用水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(V/V)＝50:1-20:1)得到淡黄色油状液体2-(1-环丙基乙基)-6-异丙基苯胺(13B)(4.86g，产率：77.1％)。2-bromo-6-isopropylaniline (13A) (6.70 g, 31.29 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl was added sequentially to the reaction flask. -1,3,2-dioxaborane (9.10 g, 46.88 mmol)), potassium phosphate heptahydrate (31.76 g, 93.87 mmol), toluene (100 mL) and water (50 mL). Three times, palladium acetate (0.35 g, 1.56 mmol) and 2-dicyclohexylphos-2',6'-diisopropoxy-1,1'-biphenyl (Ruphos, 1.46 g, 3.12 mmol) were added. The pump was again evacuated with a water pump, replaced with nitrogen three times, heated to 90 ° C, and reacted for 4 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and evaporated. EtOAcjjjjjjjjjjjjjjjj Chromatographic separation and purification (petroleum ether / ethyl acetate (V / V) = 50:1 - 20:1) to give a pale yellow oily liquid 2-(1-cyclopropylethyl)-6-isopropylaniline (13B) (4.86 g, yield: 77.1%).
MS m/z(ESI):202.2(M+1).MS m/z (ESI): 202.2 (M+1).
1HNMR(400MHz,CDCl3):δ7.07(dd,1H),6.82(dd,1H),6.72(dd,1H),5.22(dd,1H),4.94(d,1H),3.83(s,2H),2.95-2.84(m,1H),1.68-1.62(m,1H),1.26(d,6H),0.73-0.68(m,2H),0.47-0.43(m,2H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.07 (dd, 1H), 6.82 (dd, 1H), 6.72 (dd, 1H), 5.22 (dd, 1H), 4.94 (d, 1H), 3.83 (s, 2H), 2.95-2.84 (m, 1H), 1.68-1.62 (m, 1H), 1.26 (d, 6H), 0.73-0.68 (m, 2H), 0.47-0.43 (m, 2H).
第二步：2-[(1R)-1-环丙基乙基]-6-异丙基苯胺(化合物13) Second step: 2-[(1R)-1-cyclopropylethyl]-6-isopropylaniline (Compound 13)
2-[(1R)-1-cyclopropylethyl]-6-isopropyl-aniline2-[(1R)-1-cyclopropylethyl]-6-isopropyl-aniline
Figure PCTCN2017087484-appb-000051
Figure PCTCN2017087484-appb-000051
250mL的高压反应釜中室温下加入2-(1-环丙基乙基)-6-异丙基苯胺(13B)(2.0g，9.94mmol)，二氯甲烷(20mL)和[(R)-2,2'-双(二苯基膦)-1,1'-联萘]二乙酸钌(0.34g，0.40mmol)，加毕将高压釜装置拧紧密封，用氢气置换3次，充入氢气，高压釜上的压力表压力显示为20atm，室温下反应30小时。减压浓缩除去溶剂，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(V/V)＝30:1)得到淡黄色油状液体2-[(1R)-1-环丙基乙基]-6-异丙基苯胺(化合物13)(1.52g，产率：75.3％，手性HPLC：98.53％)。In a 250 mL autoclave, 2-(1-cyclopropylethyl)-6-isopropylaniline (13B) (2.0 g, 9.94 mmol), dichloromethane (20 mL) and [(R)- 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]diacetate (0.34 g, 0.40 mmol), after completion, the autoclave device was tightly sealed, replaced with hydrogen three times, and charged with hydrogen. The pressure gauge pressure on the autoclave was shown to be 20 atm and reacted at room temperature for 30 hours. The solvent was concentrated under reduced pressure. EtOAc (EtOAc m. -6-isopropylaniline (Compound 13) (1.52 g, yield: 75.3%, chiral HPLC: 98.53%).
MS m/z(ESI):204.2(M+1).MS m/z (ESI): 204.2 (M+1).
1HNMR(400MHz,CDCl3):δ7.14(dd,1H),7.04(dd,1H),6.81(dd,1H),3.74(s,2H),2.98-2.90(m,1H),2.36-2.29(m,1H),1.30(d,3H),1.27(d,6H),1.12-1.04(m,1H),0.59-0.52(m,1H),0.48-0.41(m,1H),0.18-0.07(m,2H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.14 (dd, 1H), 7.04 (dd, 1H), 6.81 (dd, 1H), 3.74 (s, 2H), 2.98-2.90 (m, 1H), 2.36- 2.29 (m, 1H), 1.30 (d, 3H), 1.27 (d, 6H), 1.12-1.04 (m, 1H), 0.59-0.52 (m, 1H), 0.48-0.41 (m, 1H), 0.18- 0.07 (m, 2H).
实施例14Example 14
2-[(1S)-1-环丙基乙基]-6-异丙基苯胺(化合物14)2-[(1S)-1-cyclopropylethyl]-6-isopropylaniline (Compound 14)
2-[(1S)-1-cyclopropylethyl]-6-isopropyl-aniline2-[(1S)-1-cyclopropylethyl]-6-isopropyl-aniline
Figure PCTCN2017087484-appb-000052
Figure PCTCN2017087484-appb-000052
第一步：2-[(1S)-1-环丙基乙基]-6-异丙基苯胺(化合物14)First step: 2-[(1S)-1-cyclopropylethyl]-6-isopropylaniline (Compound 14)
2-[(1S)-1-cyclopropylethyl]-6-isopropyl-aniline2-[(1S)-1-cyclopropylethyl]-6-isopropyl-aniline
Figure PCTCN2017087484-appb-000053
Figure PCTCN2017087484-appb-000053
室温下，250mL的高压反应釜中室温下加入2-(1-环丙基乙基)-6-异丙基苯胺(13B)(2.0g，9.94mmol)，二氯甲烷(20mL)和[(S)-2,2'-双(二苯基膦)-1,1'-联萘]二乙酸钌(0.34g，0.40mmol)，加毕将高压釜装置拧紧密封，置换氢气3次后充入氢气，高压釜上的压力表压力显示为20atm，室温下反应30小时。减压浓缩除去溶剂，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(V/V)＝30:1)得到淡黄色油状液体2-[(1S)-1-环丙基乙基]-6-异丙基苯胺(化合物14)(1.54g，产 率：76.2％，手性HPLC：96.95％)。At room temperature, a 250 mL autoclave was charged with 2-(1-cyclopropylethyl)-6-isopropylaniline (13B) (2.0 g, 9.94 mmol), dichloromethane (20 mL) and [ S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]diacetate (0.34 g, 0.40 mmol), after the addition, the autoclave device was tightly sealed, and the hydrogen was replaced 3 times. Hydrogen was introduced, and the pressure on the autoclave was shown to be 20 atm, and the reaction was carried out at room temperature for 30 hours. The solvent was concentrated under reduced pressure. EtOAc (EtOAc m. ]-6-isopropylaniline (Compound 14) (1.54g, produced Rate: 76.2%, chiral HPLC: 96.95%).
MS m/z(ESI):204.2(M+1).MS m/z (ESI): 204.2 (M+1).
1HNMR(400MHz,CDCl3):δ7.14(dd,1H),7.03(dd,1H),6.80(dd,1H),3.74(s,2H),2.98-2.89(m,1H),2.36-2.29(m,1H),1.30(d,3H),1.27(d,6H),1.15-1.04(m,1H),0.59-0.52(m,1H),0.48-0.41(m,1H),0.18-0.07(m,2H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.14 (dd, 1H), 7.03 (dd, 1H), 6.80 (dd, 1H), 3.74 (s, 2H), 2.98-2.89 (m, 1H), 2.36- 2.29 (m, 1H), 1.30 (d, 3H), 1.27 (d, 6H), 1.15.10.04 (m, 1H), 0.59-0.52 (m, 1H), 0.48-0.41 (m, 1H), 0.18- 0.07 (m, 2H).
实施例15Example 15
N-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]乙酰胺(化合物15)N-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]acetamide (Compound 15)
N-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]acetamideN-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]acetamide
Figure PCTCN2017087484-appb-000054
Figure PCTCN2017087484-appb-000054
第一步：N-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]乙酰胺(化合物15)First step: N-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]acetamide (Compound 15)
N-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]acetamideN-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]acetamide
Figure PCTCN2017087484-appb-000055
Figure PCTCN2017087484-appb-000055
反应瓶中加入2-[(1R)-1-环丙基乙基]-6-异丙基苯胺(化合物13)(0.61g，3.0mmol)和干燥的二氯甲烷(20mL)，冷却至0℃，加入三乙胺(0.46g，4.50mmol)，滴加乙酰氯(0.26g，3.30mmol)，自然升至室温反应1小时。加入水(20mL)，分液，水相用二氯甲烷(20mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用石油醚(20mL)打浆，过滤后得到白色固体N-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]乙酰胺(化合物15)(0.45g，产率：61.4％)。2-[(1R)-1-Cyclopropylethyl]-6-isopropylaniline (Compound 13) (0.61 g, 3.0 mmol) and dry dichloromethane (20 mL) Triethylamine (0.46 g, 4.50 mmol) was added dropwise, and acetyl chloride (0.26 g, 3.30 mmol) was added dropwise, and the mixture was allowed to react to room temperature for 1 hour. After adding water (20 mL), EtOAc (EtOAc m. After filtration, N-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]acetamide (Compound 15) (0.45 g, yield: 61.4%).
MS m/z(ESI):246.1(M+1).MS m/z (ESI): 246.1 (M+1).
1HNMR(400MHz,DMSO-d6):δ9.09(s,1H),7.28-7.22(dd,2H),7.15-7.12(dd,1H),3.09-3.00(m,1H),2.21-2.14(m,1H),2.01(s,3H),1.25-1.12(m,9H),1.04-0.94(m,1H),0.52-0.45(m,1H),0.28-0.22(m,1H),0.15-0.08(m,2H). 1 H NMR (400 MHz, DMSO-d6): δ 9.09 (s, 1H), 7.28-7.22 (dd, 2H), 7.15-7.12 (dd, 1H), 3.09-3.00 (m, 1H), 2.21-2.14 ( m, 1H), 2.01 (s, 3H), 1.25-1.12 (m, 9H), 1.04-0.94 (m, 1H), 0.52-0.45 (m, 1H), 0.28-0.22 (m, 1H), 0.15- 0.08 (m, 2H).
实施例16 Example 16
N-[2-[(1S)-1-环丙基乙基]-6-异丙基-苯基]乙酰胺(化合物16)N-[2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenyl]acetamide (Compound 16)
N-[2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenyl]acetamideN-[2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenyl]acetamide
Figure PCTCN2017087484-appb-000056
Figure PCTCN2017087484-appb-000056
第一步：N-[2-[(1S)-1-环丙基乙基]-6-异丙基-苯基]乙酰胺(化合物16)First step: N-[2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenyl]acetamide (Compound 16)
N-[2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenyl]acetamideN-[2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenyl]acetamide
Figure PCTCN2017087484-appb-000057
Figure PCTCN2017087484-appb-000057
反应瓶中加入2-[(1S)-1-环丙基乙基]-6-异丙基苯胺(化合物14)(0.61g，3.0mmol)和干燥的二氯甲烷(20mL)中，冷却至0℃，加入三乙胺(0.46g，4.50mmol)后滴加乙酰氯(0.26g，3.30mmol)，自然升至室温反应1小时，加水(20mL)，分液，水相用二氯甲烷(20mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用石油醚(20mL)打浆，过滤得到白色固体N-[2-[(1S)-1-环丙基乙基]-6-异丙基-苯基]乙酰胺(化合物16)(0.56g，产率：76.1％)。Add 2-[(1S)-1-cyclopropylethyl]-6-isopropylaniline (Compound 14) (0.61 g, 3.0 mmol) and dry dichloromethane (20 mL) After adding triethylamine (0.46 g, 4.50 mmol) at 0 ° C, acetyl chloride (0.26 g, 3.30 mmol) was added dropwise, and the mixture was allowed to react to room temperature for 1 hour, water (20 mL) was added, and the aqueous phase was separated with dichloromethane. The mixture was extracted with EtOAc (3 mL). Cyclopropylethyl]-6-isopropyl-phenyl]acetamide (Compound 16) (0.56 g, Yield: 76.1%).
MS m/z(ESI):246.2(M+1).MS m/z (ESI): 246.2 (M+1).
1HNMR(400MHz,DMSO-d6):δ9.08(s,1H),7.27-7.24(dd,2H),7.15-7.12(dd,1H),3.08-3.00(m,1H),2.19-2.13(m,1H),2.01(s,3H),1.23-1.12(m,9H),1.03-0.95(m,1H),0.51-0.45(m,1H),0.27-0.22(m,1H),0.14-0.07(m,2H). 1 HNMR (400MHz, DMSO-d6 ): δ9.08 (s, 1H), 7.27-7.24 (dd, 2H), 7.15-7.12 (dd, 1H), 3.08-3.00 (m, 1H), 2.19-2.13 ( m,1H), 2.01 (s, 3H), 1.23-1.12 (m, 9H), 1.03-0.95 (m, 1H), 0.51-0.45 (m, 1H), 0.27-0.22 (m, 1H), 0.14- 0.07 (m, 2H).
实施例17Example 17
N-[2,6-双[(1R)-1-环丙基乙基]苯基]乙酰胺(化合物17)N-[2,6-bis[(1R)-1-cyclopropylethyl]phenyl]acetamide (Compound 17)
N-[2,6-bis[(1R)-1-cyclopropylethyl]phenyl]acetamideN-[2,6-bis[(1R)-1-cyclopropylethyl]phenyl]acetamide
Figure PCTCN2017087484-appb-000058
Figure PCTCN2017087484-appb-000058
将2,6-双[(1R)-1-环丙基乙基]苯胺(化合物11)(0.700g，3.0mmol)溶于10mL干燥的二氯甲烷中，加入干燥的三乙胺(0.52mL，3.7mmol)，0℃氮气保护下滴加乙酰氯(0.25mL，3.5mmol)，加完后自然升至室温反应5个小时。加入20mL水，搅拌1分钟后倒入分液漏斗中分层，水层用二氯甲烷萃取(10mLx2)，合并有机相，饱和氯化钠洗(10mLx1)，无水硫酸钠干燥，过滤，减压浓缩后柱层析(石油醚:乙酸乙酯(V/V)＝20:1)得白色固体化合物N-[2,6-双[(1R)-1-环丙基乙基]苯基]乙酰胺(化合物17)及其互变异构(0.69g，收率83.3％，HPLC:95.53％)。2,6-Bis[(1R)-1-cyclopropylethyl]aniline (Compound 11) (0.700 g, 3.0 mmol) was dissolved in 10 mL of dry dichloromethane and dried triethylamine (0.52 mL) , 3.7 mmol), acetyl chloride (0.25 mL, 3.5 mmol) was added dropwise under a nitrogen atmosphere at 0 ° C. After the addition, the mixture was allowed to react to room temperature for 5 hours. Add 20mL of water, stir for 1 minute, then pour into the separatory funnel and layer, the aqueous layer is extracted with dichloromethane (10mLx2), the organic phase is combined, washed with saturated sodium chloride (10mLx1), dried over anhydrous sodium sulfate, filtered, reduced Column chromatography (petroleum ether: ethyl acetate (V/V) = 20:1) to give white compound N-[2,6-bis[(1R)-1-cyclopropylethyl]phenyl Acetamide (Compound 17) and its tautomerism (0.69 g, yield 83.3%, HPLC: 95.53%).
化合物17与化合物17-1为互变异构体。Compound 17 and Compound 17-1 are tautomers.
MS m/z(ESI):270.1[M-1]-.MS m/z (ESI): 270.1 [M-1] - .
1H NMR(400MHz,CDCl3):δ7.40-7.35(m,1H),7.31-7.27(m,2H),6.79(s,0.4H),6.72(brs,0.6H),2.49-2.41(m,0.6H),2.28-2.21(m,1.4H),2.14(s,1.8H),1.70(s,1.2H),1.30(d,J＝7.0Hz,1.2H),1.24-1.19(m,4.8H),1.10-0.95(m,1.6H),0.93-0.84(m,0.4H),0.67-0.60(m,0.4H),0.57-0.45(m,2H),0.47-0.25(m,2H),0.19-0.05(m,3H),[0.03-(-0.04)](m,0.6H). 1 H NMR (400MHz, CDCl3) : δ7.40-7.35 (m, 1H), 7.31-7.27 (m, 2H), 6.79 (s, 0.4H), 6.72 (brs, 0.6H), 2.49-2.41 (m , 0.6H), 2.28-2.21 (m, 1.4H), 2.14 (s, 1.8H), 1.70 (s, 1.2H), 1.30 (d, J = 7.0 Hz, 1.2H), 1.24-1.19 (m, 4.8H), 1.10-0.95 (m, 1.6H), 0.93-0.84 (m, 0.4H), 0.67-0.60 (m, 0.4H), 0.57-0.45 (m, 2H), 0.47-0.25 (m, 2H) ), 0.19-0.05 (m, 3H), [0.03-(-0.04)] (m, 0.6H).
实施例18Example 18
N-[2,6-双[(1S)-1-环丙基乙基]苯基]乙酰胺(化合物18)N-[2,6-bis[(1S)-1-cyclopropylethyl]phenyl]acetamide (Compound 18)
N-[2,6-bis[(1S)-1-cyclopropylethyl]phenyl]acetamideN-[2,6-bis[(1S)-1-cyclopropylethyl]phenyl]acetamide
Figure PCTCN2017087484-appb-000059
Figure PCTCN2017087484-appb-000059
将2,6-双[(1S)-1-环丙基乙基]苯胺(化合物12)(0.700g，3.0mmol)溶于10mL干燥的二氯甲烷中，加入干燥的三乙胺(0.52mL，3.7mmol)，0℃氮气保护下滴加乙酰氯(0.25mL，3.5mmol)，加完后自然升至室温反应5个小时。加入20mL水，搅拌1分钟后倒入分液漏斗中分层，水层用二氯甲烷萃取(10mLx 2)，合并有机相，饱和氯化钠洗(10mLx 1)，无水硫酸钠干燥，过滤，减压浓缩后柱层析(石油醚:乙酸乙酯(V/V)＝20:1)得白色固体化合物N-[2,6-双[(1S)-1-环丙基乙基]苯基]乙酰胺(化合物18)及其互变异构体(0.69g，收率83.3％，HPLC:99.81％)。2,6-bis[(1S)-1-cyclopropylethyl]aniline (Compound 12) (0.700 g, 3.0 mmol) was dissolved in 10 mL of dry dichloromethane and dried triethylamine (0.52 mL) , 3.7 mmol), acetyl chloride (0.25 mL, 3.5 mmol) was added dropwise under a nitrogen atmosphere at 0 ° C. After the addition, the mixture was allowed to react to room temperature for 5 hours. Add 20 mL of water, stir for 1 minute, then pour into a separatory funnel and separate the layers. The aqueous layer is extracted with dichloromethane (10 mL×2), and the organic phase is combined, washed with saturated sodium chloride (10 mL×1), dried over anhydrous sodium sulfate After concentration under reduced pressure, EtOAc (EtOAc/EtOAc (EtOAc/EtOAc) Phenyl]acetamide (Compound 18) and its tautomer (0.69 g, yield 83.3%, HPLC: 99.81%).
化合物18与化合物18-1为互变异构体。Compound 18 and Compound 18-1 are tautomers.
MS m/z(ESI):270.1[M-1]-.MS m/z (ESI): 270.1 [M-1] - .
1H NMR(400MHz,CDCl3):δ7.41-7.32(m,1H),7.31-7.22(m,2H),6.77(brs,0.4H),6.72(brs,0.6H),2.48-2.41(m,0.4H),2.29-2.16(m,1.6H),2.14(s,1.8H),1.70(s,1.2H),1.30(d,J＝7.0Hz,1.2H),1.24-1.17(m,4.8H),1.10-0.96(m,1.6H),0.93-0.84(m, 0.6H),0.66-0.59(m,0.4H),0.57-0.45(m,2H),0.41-0.25(m,2H),0.17-0.05(m,3H),[0.01-(-0.02)](m,0.4H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.41 - 7.32 (m, 1H), 7.31 - 7.22 (m, 2H), 6.77 (brs, 0.4H), 6.72 (brs, 0.6H), 2.48-2.41 (m) , 0.4H), 2.29-2.16 (m, 1.6H), 2.14 (s, 1.8H), 1.70 (s, 1.2H), 1.30 (d, J = 7.0 Hz, 1.2H), 1.24-1.17 (m, 4.8H), 1.10-0.96 (m, 1.6H), 0.93-0.84 (m, 0.6H), 0.66-0.59 (m, 0.4H), 0.57-0.45 (m, 2H), 0.41-0.25 (m, 2H) ), 0.17-0.05 (m, 3H), [0.01-(-0.02)] (m, 0.4H).
生物测试例Biological test case
1、小鼠翻正反射实验1. Mouse righting reflex experiment
SPF级ICR小鼠(SCXY(川)-2008-24-成都达硕生物科技有限公司)，18-22g，雌雄各半。利用成熟的小鼠麻醉模型研究受试化合物的全身麻醉效果(Ratnakumari Lingamaneni等(2001).Anesthesiology,2001,94,1050-7)。用生理盐水将待测化合物配制为所需浓度备用。将实验动物在实验室环境中适应后禁食12小时。次日以50、100mg/kg口服给药后，记录翻正反射消失时间，给药后到翻正反射消失的时间为麻醉诱导时间，翻正反射消失到翻正反射恢复的时间为麻醉持续时间，以麻醉诱导时间和麻醉持续时间表示麻醉作用的强弱。以麻醉诱导时间、麻醉维持时间、翻正反射消失率等指标评价麻醉效果。SPF grade ICR mice (SCXY (chuan)-2008-24-Chengdu Dashuo Biotechnology Co., Ltd.), 18-22g, male and female. The general anesthetic effect of the test compound was studied using a mature mouse anesthesia model (Ratnakumari Lingamaneni et al. (2001). Anesthesiology, 2001, 94, 1050-7). The test compound is formulated to the desired concentration with physiological saline. The experimental animals were fasted for 12 hours after acclimation in a laboratory environment. After oral administration at 50, 100 mg/kg the next day, the disappearance time of righting reflex was recorded. The time from the disappearance of the righting reflex after administration was the induction time of anesthesia. The time when the righting reflex disappeared until the recovery of righting reflex was the duration of anesthesia. The anesthesia induction time and the duration of anesthesia indicate the strength of anesthesia. The anesthesia effect was evaluated by indicators such as anesthesia induction time, anesthesia maintenance time, and righting reflex disappearance rate.
翻正反射消失时间：翻正反射消失，使之处于仰卧位并能够持续60s的时间；The righting reflex disappears: the righting reflex disappears, making it in the supine position and lasting for 60s;
翻正反射恢复时间：翻正反射能力恢复，使之处于仰卧位翻正时间小于2s。Righting reflex recovery time: The ability to correct the righting reflex is restored so that it is less than 2s in the supine position.
实验结果如表1所示：The experimental results are shown in Table 1:
表1 小鼠翻正反射实验数据Table 1 Experimental data of mouse righting reflex
Figure PCTCN2017087484-appb-000060
Figure PCTCN2017087484-appb-000060
结论：小鼠通过口服给药后能够产生明显的麻醉效果，表明本发明化合物具有良好的药效活性和口服特性。 Conclusion: The mice can produce significant anesthetic effects after oral administration, indicating that the compounds of the present invention have good pharmacodynamic activity and oral characteristics.

Claims (8)

  1. 一种通式(A)所示的化合物，或者其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶：a compound of the formula (A), or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof:
    其中：among them:
    Figure PCTCN2017087484-appb-100001
    Figure PCTCN2017087484-appb-100001
    R选自F、Cl、Br、I、OR4或者
    Figure PCTCN2017087484-appb-100002
    R is selected from F, Cl, Br, I, OR 4 or
    Figure PCTCN2017087484-appb-100002
    R1、R2、R3、R8、R9、R10和R11各自独立选自H、F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基，所述的烷基、烷氧基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子，且R1、R2和R3不同时为H；R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, C 1-8 alkyl, C 1-8 alkoxy a 3 to 8 membered carbocyclic group or a 3 to 8 membered heterocyclic group, which is further optionally 0 to 5 selected from the group consisting of F, Cl, Br, Substituted by a substituent of 1 , a hydroxyl group, a C 1-8 alkyl group, a C 1-8 alkoxy group, a 3 to 8 membered carbocyclic group or a 3 to 8 membered heterocyclic group, said heterocyclic group having 1 to 2 a hetero atom selected from N, O or S, and R 1 , R 2 and R 3 are not simultaneously H;
    作为选择，R1与R2、R2与R3、R1与R3、R8与R9或者R10与R11任意一组可以与同其相连接的碳原子形成一个3至8元碳环基或者3至8元杂环基，所述3至8元碳环基或者3至8元杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；Alternatively, R 1 and R 2 , R 2 and R 3 , R 1 and R 3 , R 8 and R 9 or any of R 10 and R 11 may form a 3 to 8 member with the carbon atom to which they are attached. Carbocyclyl or 3 to 8 membered heterocyclic group, said 3 to 8 membered carbocyclic group or 3 to 8 membered heterocyclic group optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, C a 1-8 alkyl group, a C 1-8 alkoxy group, a 3 to 8 membered carbocyclic group or a 3 to 8 membered heterocyclic group, the heterocyclic group having 1 to 2 selected from N, O or S Hetero atom
    R4选自H、C2-8烷基、3至8元碳环基或者3至8元杂环基，所述的烷基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；R 4 is selected from H, C 2-8 alkyl, 3 to 8 membered carbocyclic group or 3 to 8 membered heterocyclic group, and the alkyl group, carbocyclic group or heterocyclic group is optionally further 0 to 5 Substituted with a substituent selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, 3 to 8 membered carbocyclic or 3 to 8 membered heterocyclic, The heterocyclic group contains 1 to 2 hetero atoms selected from N, O or S;
    R5、R6各自独立选自H、F、Cl、Br、I、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基，所述的烷基、烷氧基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子，且R5和R6不同时为H；R 5 and R 6 are each independently selected from H, F, Cl, Br, I, C 1-8 alkyl, C 1-8 alkoxy, 3 to 8 membered carbocyclic group or 3 to 8 membered heterocyclic group. The alkyl, alkoxy, carbocyclic or heterocyclic group is further optionally from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-8 alkyl, C 1-8 alkoxy Substituted by a substituent of a 3- to 8-membered carbocyclic group or a 3- to 8-membered heterocyclic group containing 1 to 2 hetero atoms selected from N, O or S, and R 5 and R 6 is not H at the same time;
    作为选择，R5与R6可以与同其相连接的碳原子形成一个3至8元环，所述3至8元环可以含有0至2个选自N、O或者S的杂原子，且形成的3至8元环可以任选进一步被0至4个R12所取代；Alternatively, R 5 and R 6 may form a 3 to 8 membered ring with a carbon atom to which they are attached, and the 3 to 8 membered ring may have 0 to 2 hetero atoms selected from N, O or S, and The formed 3 to 8 membered ring may be optionally further substituted with 0 to 4 R 12 ;
    R7选自H、F、Cl、Br、I、羟基或者C1-8烷氧基；R 7 is selected from H, F, Cl, Br, I, hydroxy or C 1-8 alkoxy;
    R12选自F、Cl、Br、I、C1-8烷基、C1-8烷氧基、羟基、-COOH、氨基、羧 酸酯基、酰胺基、3至8元碳环基或者3至8元杂环基，所述的杂环基含有1至2个选自N、O或者S的杂原子；R 12 is selected from the group consisting of F, Cl, Br, I, C 1-8 alkyl, C 1-8 alkoxy, hydroxy, -COOH, amino, carboxylate, amide, 3 to 8 membered carbocyclyl or a 3- to 8-membered heterocyclic group containing 1 to 2 hetero atoms selected from N, O or S;
    X选自羟基或者NRaRb；X is selected from a hydroxyl group or NR a R b ;
    Y选自H、F或者-(CRyaRyb)m-(W1)-C(＝O)(W2Ryc)，且X为羟基时，Y不为H、F或者-COOH；Y is selected from H, F or -(CR ya R yb ) m -(W 1 )-C(=O)(W 2 R yc ), and when X is a hydroxyl group, Y is not H, F or -COOH;
    Ra或者Rb各自独立地选自H、C1-8烷基或者-C(＝O)(W2Ryc)；R a or R b are each independently selected from H, C 1-8 alkyl or -C(=O)(W 2 R yc );
    W1或者W2各自独立地选自NRyc、O、S或者不存在；W 1 or W 2 are each independently selected from NR yc , O, S or absent;
    Rya或者Ryb各自独立的选自H或者C1-6烷基；R ya or R yb are each independently selected from H or C 1-6 alkyl;
    Ryc选自H、C1-6烷基、C3-8碳环基或者3至8元杂环基，所述的烷基、碳环基或者杂环基可以任选进一步被0至5个选自H、F、Cl、Br、I、羟基、氨基、氰基、-COOH、C1-6烷基、C1-6烷氧基、C3-8碳环基或者3至8元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；R yc is selected from H, C 1-6 alkyl, C 3-8 carbocyclic or 3 to 8 membered heterocyclic, and the alkyl, carbocyclic or heterocyclic group may be further further 0 to 5 One selected from the group consisting of H, F, Cl, Br, I, hydroxy, amino, cyano, -COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 carbocyclyl or 3 to 8 Substituted by a substituent of a heterocyclic group containing from 1 to 2 heteroatoms selected from N, O or S;
    m选自0、1、2或者3；m is selected from 0, 1, 2 or 3;
    n选自1、2或者3。n is selected from 1, 2 or 3.
  2. 根据权利要求1所述的的化合物，或者其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶，其中该化合物选自通式(A-I)或者(A-II)所示的化合物：A compound according to claim 1, or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the group consisting of formula (AI) or (A- II) Compounds shown:
    Figure PCTCN2017087484-appb-100003
    Figure PCTCN2017087484-appb-100003
    其中：among them:
    R选自F、Cl、Br、I、OR4或者
    Figure PCTCN2017087484-appb-100004
    R is selected from F, Cl, Br, I, OR 4 or
    Figure PCTCN2017087484-appb-100004
    R1、R2、R3、R8、R9、R10和R11各自独立选自H、F、Cl、C1-6烷基或者3至6元碳环基，所述的烷基、碳环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至6元碳环基或者3至6元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子，且R1、R2和R3不同时为H；R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are each independently selected from H, F, Cl, C 1-6 alkyl or a 3 to 6 membered carbocyclic group, said alkyl group Carbocyclyl optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, 3 to 6 membered carbocyclyl or 3 to 6 Substituted by a substituent of a heterocyclic group, the heterocyclic group having 1 to 2 hetero atoms selected from N, O or S, and R 1 , R 2 and R 3 are not simultaneously H;
    作为选择，R1与R2、R2与R3、R1与R3、R8与R9或者R10与R11任意一组可以与同其相连接的碳原子形成一个3至6元碳环基或者3至6元杂环基，所述3至6元碳环基或者3至6元杂环基任选进一步被0至5个选自F、Cl、Br、C1-6烷基、C1-6烷氧基或者3至6元碳环基所取代，所述的杂环基含有1至2个选自N、O或者S；Alternatively, R 1 and R 2 , R 2 and R 3 , R 1 and R 3 , R 8 and R 9 or any of R 10 and R 11 may form a 3 to 6 member with the carbon atom to which they are attached. Carbocyclyl or 3 to 6 membered heterocyclic group, said 3 to 6 membered carbocyclic group or 3 to 6 membered heterocyclic group optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, C 1-6 alkane Substituted, C 1-6 alkoxy or 3 to 6 membered carbocyclic group, said heterocyclic group containing 1 to 2 selected from N, O or S;
    R4选自H、C2-6烷基、3至6元碳环基或者3至6元杂环基，所述的烷基、 碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-6烷基、C1-6烷氧基、3至6元碳环基或者3至6元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；R 4 is selected from H, C 2-6 alkyl, 3 to 6 membered carbocyclic or 3 to 6 membered heterocyclic, and the alkyl, carbocyclic or heterocyclic group is optionally further further 0 to 5 Substituted with a substituent selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, a 3 to 6 membered carbocyclic group or a 3 to 6 membered heterocyclic group, The heterocyclic group contains 1 to 2 hetero atoms selected from N, O or S;
    R5或者R6各自独立选自H、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、3至6元碳环基或者3至6元杂环基，所述的烷基、烷氧基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-6烷基、C1-6烷氧基、3至6元碳环基或者3至6元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子，且R5和R6不同时为H；R 5 or R 6 are each independently selected from H, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered carbocyclic or 3 to 6 membered heterocyclic, The alkyl, alkoxy, carbocyclic or heterocyclic group is further optionally from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-6 alkyl, C 1-6 alkoxy Substituted by a substituent of a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group containing 1 to 2 hetero atoms selected from N, O or S, and R 5 and R 6 is not H at the same time;
    作为选择，R5与R6可以与同其相连接的碳原子形成一个3至6元环，所述3至6元环可以含有0至2个选自N、O或者S的杂原子，且形成的3至6元环可以任选进一步被0至4个R12所取代；Alternatively, R 5 and R 6 may form a 3 to 6 membered ring with a carbon atom to which they are attached, and the 3 to 6 membered ring may have 0 to 2 hetero atoms selected from N, O or S, and The formed 3- to 6-membered ring may be optionally further substituted with 0 to 4 R 12 ;
    R7选自H、F、Cl、Br、I、羟基或者C1-6烷氧基；R 7 is selected from H, F, Cl, Br, I, hydroxy or C 1-6 alkoxy;
    R12选自F、Cl、Br、I、C1-6烷基、C1-6烷氧基、羟基、-COOH、氨基、羧酸酯基、酰胺基、3至6元碳环基或者3至6元杂环基，所述的杂环基含有1至2个选自N、O或者S的杂原子；R 12 is selected from the group consisting of F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, -COOH, amino, carboxylate, amide, 3 to 6 membered carbocyclyl or a 3- to 6-membered heterocyclic group containing 1 to 2 hetero atoms selected from N, O or S;
    Y’选自-(CRyaRyb)m-(W1)-C(＝O)(W2Ryc)，且Y’不为-COOH；Y' is selected from -(CR ya R yb ) m -(W 1 )-C(=O)(W 2 R yc ), and Y' is not -COOH;
    Y选自H、F或者-(CRyaRyb)m-(W1)-C(＝O)(W2Ryc)；Y is selected from H, F or -(CR ya R yb ) m -(W 1 )-C(=O)(W 2 R yc );
    Ra、Rb各自独立地选自H、C1-6烷基或者-C(＝O)(W2Ryc)；R a , R b are each independently selected from H, C 1-6 alkyl or -C(=O)(W 2 R yc );
    W1、W2各自独立地选自NRyc、O、S或者不存在；W 1 and W 2 are each independently selected from NR yc , O, S or absent;
    Rya、Ryb各自独立的选自H或者C1-6烷基；R ya , R yb are each independently selected from H or C 1-6 alkyl;
    Ryc选自H、C1-6烷基、C3-6碳环基或者3至6元杂环基，所述的烷基、碳环基或者杂环基可以任选进一步被0至5个选自H、F、Cl、Br、I、羟基、氨基、氰基、-COOH、C1-6烷基、C1-6烷氧基、C3-6碳环基或者3至6元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；R yc is selected from H, C 1-6 alkyl, C 3-6 carbocyclyl or 3 to 6 membered heterocyclic, and the alkyl, carbocyclyl or heterocyclic group may be further further 0 to 5 One selected from the group consisting of H, F, Cl, Br, I, hydroxy, amino, cyano, -COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclyl or 3 to 6 Substituted by a substituent of a heterocyclic group containing from 1 to 2 heteroatoms selected from N, O or S;
    m选自0、1、2或者3；m is selected from 0, 1, 2 or 3;
    n选自1、2或者3。n is selected from 1, 2 or 3.
  3. 根据权利要求2所述的化合物，或者其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶，其中该化合物选自通式(A-I)或者(A-II)所示的化合物：A compound according to claim 2, or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the group consisting of formula (AI) or (A-II) ) the compound shown:
    其中：among them:
    R选自
    Figure PCTCN2017087484-appb-100005
    R is selected from
    Figure PCTCN2017087484-appb-100005
    R1、R2、R3、R8、R9、R10和R11各自独立地选自H、甲基、乙基、正丙基、异丙基、环丙基或者环丁基，且R1、R2和R3不同时为H； R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, and R 1 , R 2 and R 3 are not H at the same time;
    R5和R6各自独立选自H、甲基、乙基、正丙基或异丙基，且R5和R6不同时为H；R 5 and R 6 are each independently selected from H, methyl, ethyl, n-propyl or isopropyl, and R 5 and R 6 are not simultaneously H;
    R7选自H；R 7 is selected from H;
    Y’选自-(CRyaRyb)m-(W1)-C(＝O)(W2Ryc)，且Y’不为-COOH；Y' is selected from -(CR ya R yb ) m -(W 1 )-C(=O)(W 2 R yc ), and Y' is not -COOH;
    Y选自H、F或者-(CRyaRyb)m-(W1)-C(＝O)(W2Ryc)；Y is selected from H, F or -(CR ya R yb ) m -(W 1 )-C(=O)(W 2 R yc );
    Ra、Rb各自独立地选自H、C1-6烷基或者-C(＝O)(W2Ryc)；R a , R b are each independently selected from H, C 1-6 alkyl or -C(=O)(W 2 R yc );
    W1、W2各自独立地选自NRyc、O、S或者不存在；W 1 and W 2 are each independently selected from NR yc , O, S or absent;
    Rya、Ryb各自独立的选自H或者C1-6烷基；R ya , R yb are each independently selected from H or C 1-6 alkyl;
    Ryc选自H、C1-6烷基、C3-6碳环基或者3至6元杂环基，所述的烷基、碳环基或者杂环基可以任选进一步被0至5个选自H、F、Cl、Br、I、羟基、氨基、氰基、-COOH、C1-6烷基、C1-6烷氧基、C3-6碳环基或者3至6元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；R yc is selected from H, C 1-6 alkyl, C 3-6 carbocyclyl or 3 to 6 membered heterocyclic, and the alkyl, carbocyclyl or heterocyclic group may be further further 0 to 5 One selected from the group consisting of H, F, Cl, Br, I, hydroxy, amino, cyano, -COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclyl or 3 to 6 Substituted by a substituent of a heterocyclic group containing from 1 to 2 heteroatoms selected from N, O or S;
    m选自0、1、2或者3；m is selected from 0, 1, 2 or 3;
    n选自1。n is selected from 1.
  4. 根据权利要求3所述的的化合物，或者其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶，其中该化合物选自通式(A-I)或者(A-II)所示的化合物：A compound according to claim 3, or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the group consisting of formula (AI) or (A- II) Compounds shown:
    其中：among them:
    R选自
    Figure PCTCN2017087484-appb-100006
    R is selected from
    Figure PCTCN2017087484-appb-100006
    R1、R2、R3、R8、R9、R10和R11各自独立地选自H、甲基、乙基、正丙基、异丙基、环丙基或者环丁基，且R1、R2和R3不同时为H；R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, and R 1 , R 2 and R 3 are not H at the same time;
    R5和R6各自独立选自H、甲基、乙基、正丙基或异丙基，且R5和R6不同时为H；R 5 and R 6 are each independently selected from H, methyl, ethyl, n-propyl or isopropyl, and R 5 and R 6 are not simultaneously H;
    R7选自H；R 7 is selected from H;
    Y’选自-OC(＝O)(Ryc)、-NRycC(＝O)(Ryc)或-CH2CH2C(＝O)(ORyc)；Y' is selected from -OC(=O)(R yc ), -NR yc C(=O)(R yc ) or -CH 2 CH 2 C(=O)(OR yc );
    Y选自H；Y is selected from H;
    Ryc选自H、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、环丙基、苯基。R yc is selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, phenyl.
  5. 根据权利要求1至4中任一项所述的化合物，或者其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶，其中所述的化合物选自： The compound according to any one of claims 1 to 4, or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the group consisting of:
    Figure PCTCN2017087484-appb-100007
    Figure PCTCN2017087484-appb-100007
  6. 一种药物组合物，所述药物组合物包含权利要求1-5中任一项所述的化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药，和一种或者多种药学上可接受的载体和/或者赋形剂。A pharmaceutical composition comprising the compound of any one of claims 1 to 5 or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug thereof And one or more pharmaceutically acceptable carriers and/or excipients.
  7. 根据权利要求1-5中任一项所述的化合物、或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药，在制备诱导和维持动物或者人类的麻醉、促进动物或者人类的镇静催眠、治疗和/或者预防焦虑、抑郁、失眠、恶心、呕吐、偏头痛、精神分裂、惊厥和癫痫药物中的用途。A compound according to any one of claims 1 to 5, or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof, for the preparation and maintenance of an animal or human Use in anesthesia, sedative hypnosis, treatment and/or prevention of anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions and epilepsy in animals or humans.
  8. 根据权利要求7所述的在制备诱导和维持动物或者人类的麻醉、促进动物或者人类的镇静催眠、治疗和/或者预防焦虑、抑郁、失眠、恶心、呕吐、偏头痛、精神分裂、惊厥和癫痫药物中的用途，其特征在于通过口服给药。 The preparation, induction and maintenance of anesthesia in an animal or human, the sedative hypnosis of an animal or human, the treatment and/or prevention of anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions and epilepsy according to claim 7. The use in medicine is characterized by oral administration.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021122645A1 (en) 2019-12-20 2021-06-24 Syngenta Crop Protection Ag Pesticidally active azole-amide compounds
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1206934A1 (en) * 2000-11-15 2002-05-22 B. Braun Melsungen Ag Blockade of sodium channels by phenol derivatives
CN1627939A (en) * 2002-01-31 2005-06-15 法玛氏公司 Bicyclic CB2 cannabinoid receptor ligands
CN101151234A (en) * 2005-03-31 2008-03-26 三共农业株式会社 Process for producing cyclopropylphenol derivative
WO2009140275A1 (en) * 2008-05-12 2009-11-19 Pharmacofore, Inc. Analogs of propofol, preparation thereof and use as anesthetics
CN103896743A (en) * 2012-12-28 2014-07-02 四川海思科制药有限公司 2,6-diisopropyl-4-fluorophenol or salt and crystal form thereof as well as preparation method and application thereof
WO2014180305A1 (en) * 2013-05-09 2014-11-13 四川海思科制药有限公司 Phenol derivative and preparation method and use in medicine thereof
WO2016034079A1 (en) * 2014-09-04 2016-03-10 四川海思科制药有限公司 Use of gabaa receptor reinforcing agent in preparation of sedative and anesthetic medicament

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1206934A1 (en) * 2000-11-15 2002-05-22 B. Braun Melsungen Ag Blockade of sodium channels by phenol derivatives
CN1627939A (en) * 2002-01-31 2005-06-15 法玛氏公司 Bicyclic CB2 cannabinoid receptor ligands
CN101151234A (en) * 2005-03-31 2008-03-26 三共农业株式会社 Process for producing cyclopropylphenol derivative
WO2009140275A1 (en) * 2008-05-12 2009-11-19 Pharmacofore, Inc. Analogs of propofol, preparation thereof and use as anesthetics
CN103896743A (en) * 2012-12-28 2014-07-02 四川海思科制药有限公司 2,6-diisopropyl-4-fluorophenol or salt and crystal form thereof as well as preparation method and application thereof
WO2014180305A1 (en) * 2013-05-09 2014-11-13 四川海思科制药有限公司 Phenol derivative and preparation method and use in medicine thereof
WO2016034079A1 (en) * 2014-09-04 2016-03-10 四川海思科制药有限公司 Use of gabaa receptor reinforcing agent in preparation of sedative and anesthetic medicament

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5
WO2021122645A1 (en) 2019-12-20 2021-06-24 Syngenta Crop Protection Ag Pesticidally active azole-amide compounds

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