WO2022052998A1 - Magnolol derivative, magnolol derivative and salts thereof, preparation method therefor and use thereof - Google Patents

Magnolol derivative, magnolol derivative and salts thereof, preparation method therefor and use thereof Download PDF

Info

Publication number
WO2022052998A1
WO2022052998A1 PCT/CN2021/117535 CN2021117535W WO2022052998A1 WO 2022052998 A1 WO2022052998 A1 WO 2022052998A1 CN 2021117535 W CN2021117535 W CN 2021117535W WO 2022052998 A1 WO2022052998 A1 WO 2022052998A1
Authority
WO
WIPO (PCT)
Prior art keywords
enyl
group
oct
amino
hept
Prior art date
Application number
PCT/CN2021/117535
Other languages
French (fr)
Chinese (zh)
Inventor
张平平
刘晔
于国坤
赵强峰
Original Assignee
北京红惠新医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 北京红惠新医药科技有限公司 filed Critical 北京红惠新医药科技有限公司
Publication of WO2022052998A1 publication Critical patent/WO2022052998A1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
    • C07C37/18—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms by condensation involving halogen atoms of halogenated compounds
    • 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
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention relates to the technical field of biomedicine, in particular, to a honokiol derivative, a honokiol derivative and a salt thereof, a preparation method and an application thereof.
  • Magnolol and honokiol have broad pharmacological effects such as antibacterial, anti-inflammatory, antitumor, muscle relaxation, cholesterol lowering and anti-aging (Chinese herbal medicine; 2005, 36, 10, 1591-1594), but honokiol and and The poor water solubility of magnolol severely limits its wide application in medicine and needs to be improved. Later, the water solubility of magnolol and honokiol was improved by chemical derivatization (CN103113264B), and the patent gave the laboratory preparation method of water-soluble magnolol derivatives and honokiol derivatives. However, the traditional pharmacokinetic study of this kind of drugs found that its metabolism is fast and the recovery rate is low, which is not conducive to scientific researchers to fully understand the whole process of absorption, distribution, metabolism and excretion of this kind of drugs in the body.
  • the present invention aims to provide a honokiol derivative, a honokiol derivative and a salt thereof, a preparation method and an application, so as to solve the problem that it is difficult to monitor the honokiol derivative, the honokiol derivative and the same in the prior art.
  • Technical issues of the whole process of salt absorption, distribution, metabolism and excretion in the body are considered to be a honokiol derivative, a honokiol derivative and a salt thereof, a preparation method and an application, so as to solve the problem that it is difficult to monitor the honokiol derivative, the honokiol derivative and the same in the prior art.
  • a magnolol derivative having the structure shown in the following formula (I),
  • R 1 and R 4 are independently selected from hydrocarbon groups containing 1 to 8 carbons;
  • R 5 is an amino acid, a peptide or an amino group modified by a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons, wherein the amino acid, the peptide or a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons
  • the salt-formable amino group may be partially or completely in the form of a salt
  • R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl;
  • the benzene ring marked by * is a deuterated label, it has the structure shown in formula (II), Formula (II), D is a deuterium atom (labeled atom), R 2 and R 3 are independently deuterium or hydroxyl, and R 2 , R 3 are not simultaneously deuterium or hydroxyl;
  • R 1 and R 4 are not allyl groups at the same time, R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl; salt
  • salt In the form of honokiol derivatives, and pharmaceutically acceptable salts such as fumarate, oxalate or trifluoroacetate salts of honokiol derivatives.
  • the hydrocarbon group containing 1 to 8 carbons is an alkyl group or an alkenyl group, preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a vinyl group, a propenyl group, an alkene group Propyl, but-1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent-3-enyl, pentyl -4-enyl (pentenyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl (hexenyl) , hept-1-enyl, hept-2-enyl, hept-3
  • the amino acid is lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, glycine, histidine, arginine, proline , glutamic acid, aspartic acid, cystine or cysteine;
  • the peptide is composed of the above amino acids, and the molecular weight is less than or equal to 2500Da.
  • the magnolol derivative, the magnolol derivative and its salt are preferably 3',5-diallyl-3-[(S)-2,6-diamino-1-hexanoyl]amide Base-2,4'-dihydroxy-1,1'-[1'-phenyl-C14]biphenyl and its hydrochloride, 3',5-diallyl-2',5',6' -Trideutero-3-[(S)-2,6-diamino-1-hexanoyl]amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3', 5-Diallyl-3-[(S)-2-amino-4-methylthio-1-butyryl]amino-2,4'-dihydroxy-1,1'-[1'-benzene Base-C14]biphenyl and its hydrochloride, 3',5-diallyl-2',5',6'-tri
  • a magnolol derivative a magnolol derivative and the application of its salt in drug metabolism research, wherein, the magnolol derivative, the magnolol derivative and the same
  • the salt has the structure shown in the following formula (I),
  • R 1 and R 4 are independently selected from hydrocarbon groups containing 1 to 8 carbons;
  • R 5 is an amino group modified by an amino acid, a peptide or a nitrogen-containing acyl group of a non-amino acid formula containing 1 to 8 carbons, a salt-forming amino group in an amino acid, a peptide or a nitrogen-containing acyl group of a non-amino acid formula containing 1 to 8 carbons may be partly or wholly in the form of a salt;
  • R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl;
  • the hydrocarbon group containing 1 to 8 carbons is an alkyl group or an alkenyl group, preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a vinyl group, a propenyl group, an alkene group Propyl, but-1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent-3-enyl, pentyl -4-enyl (pentenyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl (hexenyl) , hept-1-enyl, hept-2-enyl, hept-3
  • the amino acid is lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, glycine, histidine, arginine, proline , glutamic acid, aspartic acid, cystine or cysteine;
  • the peptide is composed of the above amino acids, and the molecular weight is less than or equal to 2500Da.
  • honokiol derivatives, honokiol derivatives and salts thereof are 3',5-diallyl-3-[(S)-2,6-diamino-1-hexanoyl]amino groups -2,4'-Dihydroxy-1,1'-[1'-phenyl-C14]biphenyl and its hydrochloride, 3',5-diallyl-2',5',6'- Trideutero-3-[(S)-2,6-diamino-1-hexanoyl]amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5 -Diallyl-3-[(S)-2-amino-4-methylthio-1-butyryl]amino-2,4'-dihydroxy-1,1'-[1'-phenyl -C14] Biphenyl and its hydrochloride and 3',5-diallyl-2',5',5
  • honokiol derivatives, and honokiol derivatives and salts thereof are provided for brain protection applications in ischemic injury.
  • the magnolol derivative, the magnolol derivative and the salt thereof have the structure shown in the following formula (I),
  • R 1 and R 4 are independently selected from hydrocarbon groups containing 1 to 8 carbons;
  • R 5 is an amino acid, a peptide or an amino group modified by a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons, wherein the amino acid, the peptide or a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons
  • the salt-formable amino group may be partially or completely in the form of a salt
  • R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl;
  • the hydrocarbon group containing 1 to 8 carbons is an alkyl group or an alkenyl group, preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, heptyl, vinyl, propenyl, alkene Propyl, but-1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent-3-enyl, pentyl -4-enyl (pentenyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl (hexenyl) , hept-1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl
  • the amino acid is lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, glycine, histidine, arginine, proline , glutamic acid, aspartic acid, cystine or cysteine;
  • the peptide is composed of the above amino acids, and the molecular weight is less than or equal to 2500Da.
  • honokiol derivatives are 3',5-dipropyl-3-[(S)-2,6-diamino-1-hexanoyl]amino- 2,4'-Dihydroxy-1,1'-biphenyl. Hydrochloride.
  • a preparation method of the above-mentioned magnolol derivative, and a magnolol derivative and a salt thereof comprises the following steps:
  • R 1 is selected from hydrocarbon groups containing 1 to 8 carbons, preferably alkyl or alkenyl, more preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, heptyl, ethylene base, propenyl, allyl, but-1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent- 3-enyl, pent-4-enyl (enpenthexyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-ene (hexenyl), hept-1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-1-enyl,
  • R 4 is selected from an electron-donating substituent hydrocarbon group containing 1 to 8 carbons; when the benzene ring marked by * contains one C14 atom, R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 , R 3 is not hydrogen or hydroxyl at the same time; when the benzene ring marked by * is a deuterated label, it has the structure shown in formula (V) D is a deuterium atom, R 2 and R 3 are independently deuterium or hydroxyl, and R 2 and R 3 are not simultaneously deuterium or hydroxyl; when the benzene ring marked by * does not contain a marked atom, R2 and R3 are independently is hydrogen or hydroxyl, and R 2 and R 3 are not hydrogen or hydroxyl at the same time;
  • the compound of formula (III) and the compound of formula (IV) are formed by Suzuki reaction to obtain the compound of formula 1, wherein the amino acid, peptide or nitrogen-containing acyl group of non-amino acid formula with 1 to 8 carbons used is tert-butyl Oxycarbonyl protection.
  • a pharmaceutical composition for resisting cerebral ischemia injury is provided.
  • the pharmaceutical composition is composed of an effective amount of the above magnolol derivatives, honokiol derivatives and salts thereof, and pharmaceutically acceptable carriers and/or excipients.
  • Figure 1 shows a graph of the content of the prolonged drug in plasma over time in Example 12;
  • Figure 2 shows a schematic diagram of the experimental results of the compound in Example 13 reducing the volume of cerebral infarction in the mouse ischemic stroke tMCAO model.
  • a magnolol derivative having the structure shown in the following formula (I),
  • R 1 and R 4 are selected from hydrocarbon groups containing 1 to 8 carbons (N, O, S heteroatom substituted hydrocarbon groups Examples: -CH 2 CH 2 OCH 3 , - CH 2 CH 2 SMe, - CH 2 CH 2 NMe 2 );.
  • R 5 is an amino acid, a peptide or an amino group modified by a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons, wherein the amino acid, the peptide or a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons Salt-forming amino groups can be partially or completely in the form of salts; other compounds other than amino acids containing 1 to 8 carbons and both acyl and amino groups are referred to in the present invention as "non-amino acid formulas containing 1 to 8 carbons""nitrogen-containing acyl group", for example: NH 2 -CH 2 -CH 2 -O-CH 2 -CH 2 COOH.
  • R 2 and R 3 are each independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl;
  • the benzene ring marked by * is a deuterated label, it has the structure shown in formula (II), Formula (II), D is a deuterium atom, R 2 , R 3 are independently deuterium or hydroxyl, and R 2 , R 3 are not simultaneously deuterium or hydroxyl;
  • R 1 and R 4 are not allyl groups at the same time, R2 and R3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl;
  • the salts are honokiol derivatives and honokiol derivatives.
  • pharmaceutically acceptable salts such as hydrochloride, fumarate, oxalate or trifluoroacetate.
  • the hydrocarbon group containing 1 to 8 carbons is an alkyl group or an alkenyl group; preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent-3-enyl, Pent-4-enyl (enpenthexyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl (hexenyl ), hept-1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl
  • the amino acid is lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, glycine, histidine , arginine, proline, glutamic acid, aspartic acid, cystine or cysteine.
  • the peptide consists of the above-mentioned amino acids and has a molecular weight of ⁇ 2500 Da. These are all amino acids contained in the human body and play an important role in regulating life activities.
  • the honokiol derivatives, honokiol derivatives and their salts are 3',5-diallyl-3-[(S)-2,6-diamino-1-hexanoyl]amino groups -2,4'-Dihydroxy-1,1'-[1'-phenyl-C14]biphenyl and its hydrochloride, 3',5-diallyl-2',5',6'- Trideutero-3-[(S)-2,6-diamino-1-hexanoyl]amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5 -Diallyl-3-[(S)-2-amino-4-methylthio-1-butyryl]amino-2,4'-dihydroxy-1,1'-[1'-phenyl -C14] Biphenyl and its hydrochloride, 3', 5-diallyl-2', 5
  • honokiol derivatives and honokiol derivatives and their salts can enhance the traceability in drug metabolism.
  • C14 is radioactive, and radioactive tracking technology can be used to detect the disposition process of drugs in the body, which cannot be achieved by traditional mass spectrometry detection. of.
  • the labeled compounds in the present invention are useful for clarifying the drug metabolism of honokiol derivatives, and honokiol derivatives and salts thereof
  • the process is very important, but in general, the raw materials for the synthesis of labeled compounds are expensive and difficult to obtain, so the development of labeled compounds as therapeutic drugs is obviously too expensive.
  • unlabeled honokiol derivatives, and honokiol derivatives and their salts in this application have obvious brain protective effects in ischemic injury, and corresponding labeled compounds can be used to explain unlabeled honokiol derivatives , and the metabolic process of honokiol derivatives and their salts, the two complement each other, which is beneficial to the discovery of ischemic cerebral protective drugs.
  • a honokiol derivative and the application of honokiol derivative and salt thereof in drug metabolism research are provided, wherein, the honokiol derivative, and the honokiol derivative
  • the compound and its salt have the structure shown in the following formula (I),
  • R 1 and R 4 are independently selected from hydrocarbon groups containing 1 to 8 carbons;
  • R 5 is an amino acid, a peptide or an amino acid modified by a nitrogen-containing acyl group having a non-amino acid formula of 1 to 8 carbons, wherein the amino acid, the peptide or a nitrogen-containing acyl group of a non-amino acid formula of 1 to 8 carbons
  • the salt-formable amino group may be partially or completely in the form of a salt
  • R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl;
  • the hydrocarbon group containing 1 to 8 carbons is an alkyl group or an alkenyl group, preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a vinyl group, a propenyl group, an alkene group Propyl, but-1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent-3-enyl, pentyl -4-enyl (pentenyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl (hexenyl) , hept-1-enyl, hept-2-enyl, hept-3
  • the amino acid is lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, glycine, histidine, arginine, proline , glutamic acid, aspartic acid, cystine or cysteine;
  • the peptide is composed of the above amino acids, and the molecular weight is less than or equal to 2500Da.
  • the magnolol derivative, the magnolol derivative and its salt are preferably 3',5-diallyl-3-[(S)-2,6-diamino-1-hexanoyl]amide Base-2,4'-dihydroxy-1,1'-[1'-phenyl-C14]biphenyl and its hydrochloride, 3',5-diallyl-2',5',6' -Trideutero-3-[(S)-2,6-diamino-1-hexanoyl]amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3', 5-Diallyl-3-[(S)-2-amino-4-methylthio-1-butyryl]amino-2,4'-dihydroxy-1,1'-[1'-benzene Base-C14]biphenyl and its hydrochloride and 3',5-diallyl-2',5',6'-tri
  • honokiol derivatives, and honokiol derivatives and salts thereof are provided for brain protection applications in ischemic injury.
  • the magnolol derivative, the magnolol derivative and the salt thereof have the structure shown in the following formula (I),
  • R 1 and R 4 are independently selected from hydrocarbon groups containing 1 to 8 carbons;
  • R 5 is an amino acid, a peptide or an amino group modified by a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons, wherein the amino acid, the peptide or a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons
  • the salt-formable amino group may be partially or completely in the form of a salt
  • R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl;
  • the hydrocarbon group containing 1 to 8 carbons is alkyl or alkenyl, preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, alkene Propyl, but-1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent-3-enyl, pentyl -4-enyl (pentenyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl (hexenyl) , hept-1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl (
  • the amino acid is lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, glycine, histidine, arginine, proline , glutamic acid, aspartic acid, cystine or cysteine; the peptide is composed of the above amino acids, and the molecular weight is less than or equal to 2500Da.
  • honokiol derivatives, honokiol derivatives and their salts are 3',5-dipropyl-3-[(S)-2,6-diamino-1-hexanoyl]amine Base-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride.
  • a preparation method of the above-mentioned magnolol derivative, and a magnolol derivative and a salt thereof is provided.
  • the preparation method comprises the following steps:
  • R 1 is a hydrocarbon group containing 1 to 8 carbons, preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, butyl -1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-ene Hex-1-enyl (enpentenyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl (hexenyl), hept-1 -alkenyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl (hexenyl), hept-1
  • R 5 is amino acid modified by amino acid, peptide or nitrogen-containing acyl group containing 1-8 carbon non-amino acid formula, the amino acid, peptide or containing All amino groups in the nitrogen-containing acyl groups of 1 to 8 carbons that are not amino acids are protected with tert-butoxycarbonyl;
  • R 4 is a hydrocarbon group containing 1 to 8 carbons, preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, butyl -1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-ene Hex-1-enyl (enpentenyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl (hexenyl), hept-1 -alkenyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl (hexenyl), hept-1
  • the specific synthesis circuit diagram of the preparation method is as follows:
  • reaction solution was evaporated to dryness, 250 ml of water was added, the aqueous phase was extracted twice with 250 ml of n-hexane, the n-hexane phases were combined, washed with 100 ml of 10% aqueous sodium hydroxide solution, washed with 100 ml of saturated aqueous sodium chloride solution, and dried with anhydrous sodium sulfate ,filter.
  • the organic phase was evaporated to dryness and the residue was placed in an oil bath at 200°C, heated for 4h, and then lowered to room temperature.
  • P-bromophenol-D4 (2.05g, 12mmol) was added in a 50ml single-neck flask, 25ml of acetone was added, stirred, anhydrous potassium carbonate (10.4g, 75mmol) and 3-bromopropene (2.8g, 24mmol) were added, and the reaction was heated under reflux. 3h.
  • the aqueous phase was adjusted to pH 6-7 with 4N hydrochloric acid, and extracted with 180 ml of dichloromethane.
  • the radiolabeled compound was successfully prepared, and then it was applied to the drug metabolism study in rats and mice.
  • the recovery results showed that part of the drug was deposited with the protein, and it was speculated that the drug had a binding effect with the protein, which successfully explained the drug of formula I in traditional non-radioactive drugs.
  • the problem of low drug recovery rate in the pharmacokinetic experiment the results of the drug-time curve measurement perfectly reflect the metabolic trend of compound 9 in vivo. It can be seen that the honokiol derivatives, and the honokiol derivatives and their hydrochloride salts can be used in formula I Preclinical animal pharmacokinetic studies and clinical human pharmacokinetic studies on the absorption, tissue distribution, metabolism, and excretion of the indicated drugs.
  • mice Male KM mice (body weight 26-30 g) were selected and randomly divided into: sham operation group (Sham), normal saline group (Vehicle), compound 12, and all drugs were administered at a dose of 100 ⁇ g/kg.
  • mice were fixed in a supine position on a constant temperature operating table at 37°C. An incision of about 1 cm was made in the middle of the neck to the right, and the muscle space between the sternocleidomastoid and sternohyoid muscles was bluntly separated, and the common carotid artery (CCA), internal carotid artery (ICA) and external carotid artery were exposed and separated. (ECA).
  • CCA common carotid artery
  • ICA internal carotid artery
  • ECA external carotid artery
  • a slip-knot was tied on the CCA, the distal end of the ECA was ligated, and a slip-knot was tied at its proximal end, and the ICA was clamped with an arterial clip.
  • the branch vessels on the ECA were coagulated, a small incision was made at the distal end of the ECA (between the two knots), a nylon suture was slowly inserted through the incision to the proximal end of the ECA, and the slip knot at the proximal end of the ECA was slightly tied to prevent
  • loosen the arterial clip of the ICA coagulate the distal end of the ECA (outside the distal node), pull the ECA to a straight line with the ICA, and insert the suture through the CCA bifurcation into the ICA.
  • the average insertion line is 10 ⁇ 2mm.
  • MCA middle cerebral artery
  • the patients were anesthetized with 5% chloral hydrate, perfused with cold normal saline (NS) through the left atrium, and then rapidly removed by craniotomy and placed on a glass slide, frozen at -20°C for 20-25 minutes. Sectioned along the coronal plane, cut into 5 pieces of uniform thickness, placed in a petri dish containing 2ml of 1% TTC solution at 37°C and incubated in the dark for 30 minutes (flip once in 15 minutes to make the staining uniform). After staining, the brain slices were fixed in 4% paraformaldehyde at 4°C overnight. Normal brain tissue is bright red and infarcted brain tissue is white.
  • NS normal saline
  • the infarct area of each brain slice was measured using photoshop software.
  • the proportion of infarcted area was calculated according to the following formula: ⁇ [infarct volume-(whole brain volume-contralateral hemibrain volume ⁇ 2)]/contralateral hemibrain volume ⁇ 100%.
  • Figure 2 shows representative brain slices stained with TTC at 24 h after reperfusion in mice with transient middle cerebral artery occlusion, with white areas representing infarcts and red areas representing viable tissue. The results indicated that the tested compounds play a role in brain protection and are potential therapeutic drugs for clinical ischemic stroke.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Vascular Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Disclosed are a magnolol derivative, a magnolol derivative and salts thereof, a preparation method therefor and use thereof. The magnolol derivative, the magnolol derivative and salts thereof have a structure represented by formula (I). By using the technical solution of the present invention, the magnolol derivative, the magnolol derivative and salts thereof are prepared in a modularized manner by using a method of chemical synthesis. C14 atom markers and D atom markers can be used for drug metabolism research of the magnolol derivative, the magnolol derivative and salts thereof. The use of C14 labeling technology can solve the problem of low drug recovery rate in traditional drug metabolism experiments, and make it convenient to clarify processes related to absorption, distribution, metabolism and excretion of such drugs in vivo.

Description

厚朴酚衍生物、和厚朴酚衍生物及其盐、制备方法及应用Magnolol derivatives, and honokiol derivatives and salts thereof, preparation method and application 技术领域technical field
本发明涉及生物医药技术领域，具体而言，涉及一种厚朴酚衍生物、和厚朴酚衍生物及其盐、制备方法及应用。The invention relates to the technical field of biomedicine, in particular, to a honokiol derivative, a honokiol derivative and a salt thereof, a preparation method and an application thereof.
背景技术Background technique
厚朴酚
Figure PCTCN2021117535-appb-000001
以及和厚朴酚
Figure PCTCN2021117535-appb-000002
是中国传统中药厚朴的主要活性成分。1930年日本杉井首先从中国厚朴树皮中分离得到了厚朴酚(中草药；2005，36,10,1591-1594)。1989年中国的孟丽珍等也从厚朴分离到和厚朴酚(中成药：1989,11(8)：223.)。 Magnolol
Figure PCTCN2021117535-appb-000001
and Honokiol
Figure PCTCN2021117535-appb-000002
It is the main active ingredient of the traditional Chinese medicine Magnolia officinalis. In 1930, Japanese Sugii first isolated honokiol from the bark of Magnolia officinalis (Chinese herbal medicine; 2005, 36, 10, 1591-1594). In 1989, Meng Lizhen in China also isolated Honokiol from Magnolia officinalis (Chinese Patent Medicine: 1989, 11(8): 223.).
厚朴酚以及和厚朴酚具有抗菌，抗炎，抗肿瘤，肌肉松弛，降胆固醇和抗衰老等广泛的药理作用(中草药；2005，36,10,1591-1594)，但是厚朴酚以及和厚朴酚的水溶性很差，严重限制了其在医药上的广泛应用，有待改进。后来厚朴酚以及和厚朴酚的水溶性通过化学衍生化得以改进(CN103113264B)，该专利给出了水溶性厚朴酚衍生物以及和厚朴酚衍生物的实验室制备方法。但是该类药物的传统药物代谢动力学研究发现其代谢速度较快且回收率低，不利于科研工作者充分了解该类药物在体内吸收、分布、代谢和排泄的全过程。Magnolol and honokiol have broad pharmacological effects such as antibacterial, anti-inflammatory, antitumor, muscle relaxation, cholesterol lowering and anti-aging (Chinese herbal medicine; 2005, 36, 10, 1591-1594), but honokiol and and The poor water solubility of magnolol severely limits its wide application in medicine and needs to be improved. Later, the water solubility of magnolol and honokiol was improved by chemical derivatization (CN103113264B), and the patent gave the laboratory preparation method of water-soluble magnolol derivatives and honokiol derivatives. However, the traditional pharmacokinetic study of this kind of drugs found that its metabolism is fast and the recovery rate is low, which is not conducive to scientific researchers to fully understand the whole process of absorption, distribution, metabolism and excretion of this kind of drugs in the body.
发明内容SUMMARY OF THE INVENTION
本发明旨在提供一种厚朴酚衍生物、和厚朴酚衍生物及其盐、制备方法及应用，以解决现有技术中难以监控厚朴酚衍生物、和厚朴酚衍生物及其盐在体内吸收、分布、代谢和排泄的全过程的技术问题。The present invention aims to provide a honokiol derivative, a honokiol derivative and a salt thereof, a preparation method and an application, so as to solve the problem that it is difficult to monitor the honokiol derivative, the honokiol derivative and the same in the prior art. Technical issues of the whole process of salt absorption, distribution, metabolism and excretion in the body.
为了实现上述目的，根据本发明的一个方面，提供了一种厚朴酚衍生物、和厚朴酚衍生 物及其盐，具有如下式(I)所示结构，
Figure PCTCN2021117535-appb-000003
In order to achieve the above object, according to one aspect of the present invention, there is provided a magnolol derivative, a magnolol derivative and a salt thereof, having the structure shown in the following formula (I),
Figure PCTCN2021117535-appb-000003
其中，R 1和R 4分别独立的选自含有1～8个碳的烃基； wherein, R 1 and R 4 are independently selected from hydrocarbon groups containing 1 to 8 carbons;
R 5为氨基酸、肽或具有1～8个碳的非氨基酸式的含氮酰基所修饰的氨基，所述氨基酸、所述肽或具有1～8个碳的非氨基酸式的含氮酰基中的可成盐氨基可以部分或全部为盐形式； R 5 is an amino acid, a peptide or an amino group modified by a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons, wherein the amino acid, the peptide or a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons The salt-formable amino group may be partially or completely in the form of a salt;
当*所标记的苯环含有一个C14原子，R 2、R 3分别独立地为氢或羟基，且R 2、R 3不同时为氢或羟基； When the benzene ring marked by * contains a C14 atom, R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl;
或当*所标记的苯环为氘代标记物时，具有式(II)所示的结构，
Figure PCTCN2021117535-appb-000004
式(II)，D为氘原子(标记原子)，R 2和R 3分别独立地为氘或羟基，且R 2、R 3不同时为氘或羟基； Or when the benzene ring marked by * is a deuterated label, it has the structure shown in formula (II),
Figure PCTCN2021117535-appb-000004
Formula (II), D is a deuterium atom (labeled atom), R 2 and R 3 are independently deuterium or hydroxyl, and R 2 , R 3 are not simultaneously deuterium or hydroxyl;
当*所标记的苯环不含标记原子时，R 1和R 4不同时为烯丙基，R2和R3分别独立地为氢或羟基，且R 2、R 3不同时为氢或羟基；盐为厚朴酚衍生物、和厚朴酚衍生物的富马酸盐、草酸盐或三氟乙酸盐等药学上可接受的盐的形式。 When the benzene ring marked by * does not contain marked atoms, R 1 and R 4 are not allyl groups at the same time, R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl; salt In the form of honokiol derivatives, and pharmaceutically acceptable salts such as fumarate, oxalate or trifluoroacetate salts of honokiol derivatives.
进一步地，含有1～8个碳的烃基为烷基或烯基，优选为甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、丁-3烯基(烯丁基)、 戊-1-烯基、戊-2-烯基、戊-3-烯基、戊-4-烯基(烯戊己)、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基、己-5-烯基(己烯基)、庚-1-烯基、庚-2-烯基、庚-3-烯基、庚-4-烯基、庚-5-烯基、庚-6-烯基(庚烯基)、辛1-烯基、辛-2-烯基、辛-3-烯基、辛-4-烯基、辛-5-烯基、辛-6-烯基或辛-7-烯基(辛烯基)。Further, the hydrocarbon group containing 1 to 8 carbons is an alkyl group or an alkenyl group, preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a vinyl group, a propenyl group, an alkene group Propyl, but-1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent-3-enyl, pentyl -4-enyl (pentenyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl (hexenyl) , hept-1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl (heptenyl), oct-1 -alkenyl, oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl or oct-7-enyl (octenyl) .
进一步地，氨基酸为赖氨酸、蛋氨酸、色氨酸、缬氨酸、丙氨酸、苯丙氨酸、亮氨酸、异亮氨酸、甘氨酸、组氨酸、精氨酸、脯氨酸、谷氨酸、天冬氨酸、胱氨酸或半胱氨酸；肽由上述氨基酸组成，且分子量≤2500Da。Further, the amino acid is lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, glycine, histidine, arginine, proline , glutamic acid, aspartic acid, cystine or cysteine; the peptide is composed of the above amino acids, and the molecular weight is less than or equal to 2500Da.
进一步地，厚朴酚衍生物、和厚朴酚衍生物及其盐优选为3'，5-二烯丙基-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-[1'-苯基-C14]联苯及其盐酸盐、3'，5-二烯丙基-2',5',6'-三氘-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-联苯及其盐酸盐、3'，5-二烯丙基-3-[(S)-2-氨基-4-甲硫基-1-丁酰]胺基-2，4'-二羟基-1，1'-[1'-苯基-C14]联苯及其盐酸盐，3'，5-二烯丙基-2',5',6'-三氘-3-[(S)-2-氨基-4-甲硫基-1-丁酰]胺基-2，4'-二羟基-1，1'-联苯及其盐酸盐和3'，5-二丙基-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-联苯及其盐酸盐。Further, the magnolol derivative, the magnolol derivative and its salt are preferably 3',5-diallyl-3-[(S)-2,6-diamino-1-hexanoyl]amide Base-2,4'-dihydroxy-1,1'-[1'-phenyl-C14]biphenyl and its hydrochloride, 3',5-diallyl-2',5',6' -Trideutero-3-[(S)-2,6-diamino-1-hexanoyl]amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3', 5-Diallyl-3-[(S)-2-amino-4-methylthio-1-butyryl]amino-2,4'-dihydroxy-1,1'-[1'-benzene Base-C14]biphenyl and its hydrochloride, 3',5-diallyl-2',5',6'-trideutero-3-[(S)-2-amino-4-methylthio -1-Butyryl]amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride and 3',5-dipropyl-3-[(S)-2,6- Diamino-1-hexanoyl]amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride.
根据本发明的另一个方面，提供一种厚朴酚衍生物、和厚朴酚衍生物及其盐在药物代谢研究中的应用，其中，厚朴酚衍生物、和厚朴酚衍生物及其盐具有如下式(I)所示结构，According to another aspect of the present invention, there is provided a magnolol derivative, a magnolol derivative and the application of its salt in drug metabolism research, wherein, the magnolol derivative, the magnolol derivative and the same The salt has the structure shown in the following formula (I),
Figure PCTCN2021117535-appb-000005
Figure PCTCN2021117535-appb-000005
其中，R 1和R 4分别独立的选自含有1～8个碳的烃基；； wherein, R 1 and R 4 are independently selected from hydrocarbon groups containing 1 to 8 carbons;
R 5为氨基酸、肽或含1～8个碳的非氨基酸式的含氮酰基所修饰的氨基，氨基酸、肽或含1～8个碳的非氨基酸式的含氮酰基中的可成盐氨基可以部分或全部为盐形式； R 5 is an amino group modified by an amino acid, a peptide or a nitrogen-containing acyl group of a non-amino acid formula containing 1 to 8 carbons, a salt-forming amino group in an amino acid, a peptide or a nitrogen-containing acyl group of a non-amino acid formula containing 1 to 8 carbons may be partly or wholly in the form of a salt;
当*所标记的苯环含有一个C14原子，R 2、R 3分别独立地为氢或羟基，且R 2、R 3不同时为氢或羟基； When the benzene ring marked by * contains a C14 atom, R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl;
或当*所标记的苯环为氘代标记物时，具有式(II)所示的结构，
Figure PCTCN2021117535-appb-000006
式(II)，D为氘原子，R2和R3分别独立地为氘或羟基，且R 2、R 3不同时为氘或羟基。 Or when the benzene ring marked by * is a deuterated label, it has the structure shown in formula (II),
Figure PCTCN2021117535-appb-000006
In formula ( II ), D is a deuterium atom, R2 and R3 are each independently deuterium or hydroxyl, and R2 and R3 are not simultaneously deuterium or hydroxyl.
进一步地，含有1～8个碳的烃基为烷基或烯基，优选为甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、丁-3烯基(烯丁基)、戊-1-烯基、戊-2-烯基、戊-3-烯基、戊-4-烯基(烯戊己)、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基、己-5-烯基(己烯基)、庚-1-烯基、庚-2-烯基、庚-3-烯基、庚-4-烯基、庚-5-烯基、庚-6-烯基(庚烯基)、辛1-烯基、辛-2-烯基、辛-3-烯基、辛-4-烯基、辛-5-烯基、辛-6-烯基或辛-7-烯基(辛烯基)。Further, the hydrocarbon group containing 1 to 8 carbons is an alkyl group or an alkenyl group, preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a vinyl group, a propenyl group, an alkene group Propyl, but-1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent-3-enyl, pentyl -4-enyl (pentenyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl (hexenyl) , hept-1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl (heptenyl), oct-1 -alkenyl, oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl or oct-7-enyl (octenyl) .
进一步地，氨基酸为赖氨酸、蛋氨酸、色氨酸、缬氨酸、丙氨酸、苯丙氨酸、亮氨酸、异亮氨酸、甘氨酸、组氨酸、精氨酸、脯氨酸、谷氨酸、天冬氨酸、胱氨酸或半胱氨酸；肽由上述氨基酸组成，且分子量≤2500Da。Further, the amino acid is lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, glycine, histidine, arginine, proline , glutamic acid, aspartic acid, cystine or cysteine; the peptide is composed of the above amino acids, and the molecular weight is less than or equal to 2500Da.
进一步地，厚朴酚衍生物、和厚朴酚衍生物及其盐为3'，5-二烯丙基-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-[1'-苯基-C14]联苯及其盐酸盐、3'，5-二烯丙基-2',5',6'-三氘-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-联苯及其盐酸盐、3'，5-二烯丙基-3-[(S)-2-氨基-4-甲硫基-1-丁酰]胺基-2，4'-二羟基-1，1'-[1'-苯基-C14]联苯及其盐酸盐和3'，5-二烯丙基-2',5',6'-三氘-3-[(S)-2-氨基-4-甲硫基-1-丁酰]胺基-2，4'-二羟基-1，1'-联苯及其盐酸盐。Further, honokiol derivatives, honokiol derivatives and salts thereof are 3',5-diallyl-3-[(S)-2,6-diamino-1-hexanoyl]amino groups -2,4'-Dihydroxy-1,1'-[1'-phenyl-C14]biphenyl and its hydrochloride, 3',5-diallyl-2',5',6'- Trideutero-3-[(S)-2,6-diamino-1-hexanoyl]amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5 -Diallyl-3-[(S)-2-amino-4-methylthio-1-butyryl]amino-2,4'-dihydroxy-1,1'-[1'-phenyl -C14] Biphenyl and its hydrochloride and 3',5-diallyl-2',5',6'-trideutero-3-[(S)-2-amino-4-methylthio- 1-Butyryl]amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride.
根据本发明的又一个方面，提供厚朴酚衍生物、和厚朴酚衍生物及其盐在缺血性损伤中的脑保护应用。其中，所述厚朴酚衍生物、和厚朴酚衍生物及其盐具有如下式(I)所示结构，According to yet another aspect of the present invention, honokiol derivatives, and honokiol derivatives and salts thereof are provided for brain protection applications in ischemic injury. Wherein, the magnolol derivative, the magnolol derivative and the salt thereof have the structure shown in the following formula (I),
Figure PCTCN2021117535-appb-000007
Figure PCTCN2021117535-appb-000007
其中，R 1和R 4分别独立的选自含有1～8个碳的烃基； wherein, R 1 and R 4 are independently selected from hydrocarbon groups containing 1 to 8 carbons;
R 5为氨基酸、肽或具有1～8个碳的非氨基酸式的含氮酰基所修饰的氨基，所述氨基酸、所述肽或具有1～8个碳的非氨基酸式的含氮酰基中的可成盐氨基可以部分或全部为盐形式； R 5 is an amino acid, a peptide or an amino group modified by a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons, wherein the amino acid, the peptide or a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons The salt-formable amino group may be partially or completely in the form of a salt;
*所标记的苯环不含标记原子，R 2和R 3分别独立地为氢或羟基，且R 2、R 3不同时为氢或羟基； *The marked benzene ring does not contain marked atoms, R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl;
进一步地，含有1～8个碳的烃基为烷基或烯基，优选为甲基、乙基、丙基、丁基、戊基、己基、辛基、庚基、乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、丁-3烯基(烯丁基)、戊-1-烯基、戊-2-烯基、戊-3-烯基、戊-4-烯基(烯戊己)、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基、己-5-烯基(己烯基)、庚-1-烯基、庚-2-烯基、庚-3-烯基、庚-4-烯基、庚-5-烯基、庚-6-烯基(庚烯基)、辛1-烯基、辛-2-烯基、辛-3-烯基、辛-4-烯基、辛-5-烯基、辛-6-烯基或辛-7-烯基(辛烯基)。Further, the hydrocarbon group containing 1 to 8 carbons is an alkyl group or an alkenyl group, preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, heptyl, vinyl, propenyl, alkene Propyl, but-1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent-3-enyl, pentyl -4-enyl (pentenyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl (hexenyl) , hept-1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl (heptenyl), oct-1 -alkenyl, oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl or oct-7-enyl (octenyl) .
进一步地，氨基酸为赖氨酸、蛋氨酸、色氨酸、缬氨酸、丙氨酸、苯丙氨酸、亮氨酸、异亮氨酸、甘氨酸、组氨酸、精氨酸、脯氨酸、谷氨酸、天冬氨酸、胱氨酸或半胱氨酸；肽由上述氨基酸组成，且分子量≤2500Da。Further, the amino acid is lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, glycine, histidine, arginine, proline , glutamic acid, aspartic acid, cystine or cysteine; the peptide is composed of the above amino acids, and the molecular weight is less than or equal to 2500Da.
进一步地，厚朴酚衍生物、和厚朴酚衍生物及其盐为3'，5-二丙基-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-联苯﹒盐酸盐。Further, honokiol derivatives, honokiol derivatives and salts thereof are 3',5-dipropyl-3-[(S)-2,6-diamino-1-hexanoyl]amino- 2,4'-Dihydroxy-1,1'-biphenyl﹒ Hydrochloride.
根据本发明的再一个方面，提供一种上述厚朴酚衍生物、和厚朴酚衍生物及其盐的制备方法。该制备方法包括以下步骤：According to yet another aspect of the present invention, there is provided a preparation method of the above-mentioned magnolol derivative, and a magnolol derivative and a salt thereof. The preparation method comprises the following steps:
制备具有式(III)的化合物
Figure PCTCN2021117535-appb-000008
其中，R 1选自含有1～8个碳的烃基，优选为烷基或烯基，更优选为甲基、乙基、丙基、丁基、戊基、己基、辛基、庚基、乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、丁-3烯基(烯丁基)、戊-1-烯基、戊-2-烯基、戊-3-烯基、戊-4-烯基(烯戊己)、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基、己-5-烯基(己烯基)、庚-1-烯基、庚-2-烯基、庚-3-烯基、庚-4-烯基、庚-5-烯基、庚-6-烯基(庚烯基)、辛1-烯基、辛-2-烯基、辛-3-烯基、辛-4-烯基、辛-5-烯基、辛-6-烯基或辛-7-烯基(辛烯基)，R 5为氨基酸、肽或具有1～8个碳的非氨基酸式的含氮酰基所修饰的氨基，氨基酸、肽或具有1～8个碳的非氨基酸式的含氮酰基中的氨基全部用叔丁氧羰基保护； Preparation of compounds of formula (III)
Figure PCTCN2021117535-appb-000008
Wherein, R 1 is selected from hydrocarbon groups containing 1 to 8 carbons, preferably alkyl or alkenyl, more preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, heptyl, ethylene base, propenyl, allyl, but-1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent- 3-enyl, pent-4-enyl (enpenthexyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-ene (hexenyl), hept-1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl (hept-6-enyl) alkenyl), oct-1-enyl, oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl or oct-7-ene Base (octenyl), R 5 is amino acid, peptide or amino group modified by nitrogen-containing acyl group of non-amino acid formula with 1 to 8 carbons, amino acid, peptide or nitrogen-containing nitrogen of non-amino acid formula with 1 to 8 carbons All amino groups in the acyl group are protected with tert-butoxycarbonyl;
制备具有式(IV)的化合物
Figure PCTCN2021117535-appb-000009
其中，R 4选自含有1～8个碳的给电子取代基烃基；当*所标记的苯环含有一个C14原子时，R 2、R 3分别独立地为氢或羟基，且R 2、R 3不同时为氢或羟基；当*所标记的苯环为氘代标记物时，具有式(V)所示的结构
Figure PCTCN2021117535-appb-000010
D为氘原子，R 2、R 3分别独立地为氘或羟基，且R 2、R 3不同时为氘或羟基；当*所标记的苯环不含标记原子时，R2和R3分别独立地为氢或羟基，且R 2、R 3不同时为氢或羟基； Preparation of compounds of formula (IV)
Figure PCTCN2021117535-appb-000009
Wherein, R 4 is selected from an electron-donating substituent hydrocarbon group containing 1 to 8 carbons; when the benzene ring marked by * contains one C14 atom, R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 , R 3 is not hydrogen or hydroxyl at the same time; when the benzene ring marked by * is a deuterated label, it has the structure shown in formula (V)
Figure PCTCN2021117535-appb-000010
D is a deuterium atom, R 2 and R 3 are independently deuterium or hydroxyl, and R 2 and R 3 are not simultaneously deuterium or hydroxyl; when the benzene ring marked by * does not contain a marked atom, R2 and R3 are independently is hydrogen or hydroxyl, and R 2 and R 3 are not hydrogen or hydroxyl at the same time;
具有式(III)的化合物与具有式(IV)的化合物通过Suzuki反应形成得到式1化合物，其中，所用到的氨基酸、肽或具有1～8个碳的非氨基酸式的含氮酰基用叔丁氧羰基保护。The compound of formula (III) and the compound of formula (IV) are formed by Suzuki reaction to obtain the compound of formula 1, wherein the amino acid, peptide or nitrogen-containing acyl group of non-amino acid formula with 1 to 8 carbons used is tert-butyl Oxycarbonyl protection.
进一步地，制备方法的具体合成线路图如下：Further, the specific synthesis circuit diagram of the preparation method is as follows:
Figure PCTCN2021117535-appb-000011
Figure PCTCN2021117535-appb-000011
根据本发明的另一个方面，提供一种抗脑缺血损伤的药物组合物。该药物组合物由有效量的上述厚朴酚衍生物、和厚朴酚衍生物及其盐和在药学上可接受的载体和/或赋型剂组成。According to another aspect of the present invention, a pharmaceutical composition for resisting cerebral ischemia injury is provided. The pharmaceutical composition is composed of an effective amount of the above magnolol derivatives, honokiol derivatives and salts thereof, and pharmaceutically acceptable carriers and/or excipients.
应用本发明的技术方案，利用化学合成的方法模块化制备厚朴酚衍生物、和厚朴酚衍生物及其盐碳14标记物和氘标记物，两者可用于厚朴酚衍生物、和厚朴酚衍生物及其盐的药物代谢研究。其中利用C14标记技术物可以很好的解决传统药物代谢实验中药物回收率低所带来的问题，方便阐明该类药物体内吸收、分布、代谢和排泄相关的过程，没有放射性标记的厚朴酚衍生物、和厚朴酚衍生物及其盐对脑缺血性损伤具有优异的保护作用。Apply the technical scheme of the present invention, utilize the method of chemical synthesis to modularly prepare honokiol derivatives, and honokiol derivatives and their salt carbon 14 labels and deuterium labels, both of which can be used for honokiol derivatives, and Drug Metabolism Studies of Magnolol Derivatives and Their Salts. Among them, the use of C14-labeled technical substances can well solve the problem of low drug recovery in traditional drug metabolism experiments, and facilitate the elucidation of the processes related to the absorption, distribution, metabolism and excretion of such drugs in vivo. There is no radiolabeled honokiol. Derivatives, and honokiol derivatives and their salts have excellent protective effects on cerebral ischemic injury.
附图说明Description of drawings
构成本申请的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。在附图中：The accompanying drawings forming a part of the present application are used to provide further understanding of the present invention, and the exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the attached image:
图1示出了实施例12中随时间的延长药物在血浆中含量曲线图；Figure 1 shows a graph of the content of the prolonged drug in plasma over time in Example 12;
图2示出了实施例13中化合物在小鼠缺血性脑卒中tMCAO模型中减少脑梗死体积的实验结果示意图。Figure 2 shows a schematic diagram of the experimental results of the compound in Example 13 reducing the volume of cerebral infarction in the mouse ischemic stroke tMCAO model.
具体实施方式detailed description
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将参考附图并结合实施例来详细说明本发明。It should be noted that the embodiments in the present application and the features of the embodiments may be combined with each other in the case of no conflict. The present invention will be described in detail below with reference to the accompanying drawings and in conjunction with the embodiments.
本发明中所涉及到的缩略术语：Abbreviated terms involved in the present invention:
EA：乙酸乙酯EA: Ethyl acetate
Hexane：正己烷Hexane: n-hexane
MeOH：甲醇MeOH: methanol
DCM：二氯甲烷DCM: dichloromethane
TLC:薄层色谱TLC: Thin Layer Chromatography
根据本发明一种典型的实施方式，提供一种厚朴酚衍生物、和厚朴酚衍生物及其盐，具有如下式(I)所示结构，
Figure PCTCN2021117535-appb-000012
According to a typical embodiment of the present invention, there is provided a magnolol derivative, a magnolol derivative and a salt thereof, having the structure shown in the following formula (I),
Figure PCTCN2021117535-appb-000012
其中，R 1和R 4选自含有1～8个碳的烃基(N、O、S杂原子取代烃基示例：-CH 2CH 2OCH 3，-CH 2CH 2SMe，-CH 2CH 2NMe 2)；。 Wherein, R 1 and R 4 are selected from hydrocarbon groups containing 1 to 8 carbons (N, O, S heteroatom substituted hydrocarbon groups Examples: -CH 2 CH 2 OCH 3 , - CH 2 CH 2 SMe, - CH 2 CH 2 NMe 2 );.
R 5为氨基酸、肽或具有1～8个碳的非氨基酸式的含氮酰基所修饰的氨基，所述氨基酸、所述肽或具有1～8个碳的非氨基酸式的含氮酰基中的可成盐氨基可以部分或全部为盐形式；含有1～8碳且同时含有酰基和氨基的除了氨基酸外的其他化合物，这些化合物在本发明中称为“含1～8个碳的非氨基酸式的含氮酰基”，例如：NH 2-CH 2-CH 2-O-CH 2-CH 2COOH。 R 5 is an amino acid, a peptide or an amino group modified by a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons, wherein the amino acid, the peptide or a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons Salt-forming amino groups can be partially or completely in the form of salts; other compounds other than amino acids containing 1 to 8 carbons and both acyl and amino groups are referred to in the present invention as "non-amino acid formulas containing 1 to 8 carbons""nitrogen-containing acyl group", for example: NH 2 -CH 2 -CH 2 -O-CH 2 -CH 2 COOH.
当*所标记的苯环含有一个C14原子时，R 2、R 3分别独立地为氢或羟基，且R 2、R 3不同时为氢或羟基； When the benzene ring marked by * contains one C14 atom, R 2 and R 3 are each independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl;
当*所标记的苯环为氘代标记物时，具有式(II)所示的结构，
Figure PCTCN2021117535-appb-000013
式(II)，D为氘原子，R 2、R 3分别独立地为氘或羟基，且R 2、R 3不同时为氘或羟基；当*所标记的苯环不含标记原子时，R 1和R 4不同时为烯丙基，R2和R3分别独立地为氢或羟基，且R 2、R 3不同时为氢或羟基；盐为厚朴酚衍生物、和厚朴酚衍生物的盐酸盐、富马酸盐、草酸盐或三氟乙酸盐等药学上可接受的盐的形式。 When the benzene ring marked by * is a deuterated label, it has the structure shown in formula (II),
Figure PCTCN2021117535-appb-000013
Formula (II), D is a deuterium atom, R 2 , R 3 are independently deuterium or hydroxyl, and R 2 , R 3 are not simultaneously deuterium or hydroxyl; When the marked benzene ring does not contain a marked atom, R 1 and R 4 are not allyl groups at the same time, R2 and R3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl; the salts are honokiol derivatives and honokiol derivatives. In the form of pharmaceutically acceptable salts such as hydrochloride, fumarate, oxalate or trifluoroacetate.
应用本发明的技术方案，利用化学合成的方法模块化制备厚朴酚衍生物、和厚朴酚衍生物及其盐碳14标记物和氘标记物，两者可用于厚朴酚衍生物、和厚朴酚衍生物及其盐的药物代谢研究。其中利用C14标记技术物可以很好的解决传统药物代谢实验中药物回收率低所带来的问题，方便阐明该类药物体内吸收、分布、代谢和排泄相关的过程。Apply the technical scheme of the present invention, utilize the method of chemical synthesis to modularly prepare honokiol derivatives, and honokiol derivatives and their salt carbon 14 labels and deuterium labels, both of which can be used for honokiol derivatives, and Drug Metabolism Studies of Magnolol Derivatives and Their Salts. Among them, the use of C14-labeled technical substances can well solve the problem of low drug recovery in traditional drug metabolism experiments, and facilitate the elucidation of the processes related to the absorption, distribution, metabolism and excretion of such drugs in vivo.
优选的，含有1～8个碳的烃基为烷基或烯基，；优选自甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、丁-3烯基(烯丁基)、戊-1-烯基、戊-2-烯基、戊-3-烯基、戊-4-烯基(烯戊己)、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基、己-5-烯基(己烯基)、庚-1-烯基、庚-2-烯基、庚-3-烯基、庚-4-烯基、庚-5-烯基、庚-6-烯基(庚烯基)、辛1-烯基、辛-2-烯基、辛-3-烯基、辛-4-烯基、辛-5-烯基、辛-6-烯基或辛-7-烯基(辛烯基)。在本发明一种典型的实施方式中，氨基酸为赖氨酸、蛋氨酸、色氨酸、缬氨酸、丙氨酸、苯丙氨酸、亮氨酸、异亮氨酸、甘氨酸、组氨酸、精氨酸、脯氨酸、谷氨酸、天冬氨酸、胱氨酸或半胱氨酸。所述肽由上述氨基酸组成，且分子量≤2500Da。这些都是人体中所含有氨基酸，对生命活动起着重要的调节作用。优选的，厚朴酚衍生物、和厚朴酚衍生物及其盐为3'，5-二烯丙基-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-[1'-苯基-C14]联苯及其盐酸盐、3'，5-二烯丙基-2',5',6'-三氘-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-联苯及其盐酸盐、3'，5-二烯丙基-3-[(S)-2-氨基-4-甲硫基-1-丁酰]胺基-2，4'-二羟基-1，1'-[1'-苯基-C14]联苯及其盐酸盐、3'，5-二烯丙基-2',5',6'-三氘-3-[(S)-2-氨基-4-甲硫基-1-丁酰]胺基-2，4'-二羟基-1，1'-联苯及其盐酸盐和3'，5-二丙基-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-联苯及其盐酸盐。这些厚朴酚衍生物、和厚朴酚衍生物及其盐可以增强药物代谢中的可追踪性，如C14有放射性，可以用放射性追踪技术检测药物在体内的处置过程，是传统质谱检测无法实现的。本发明中的标记化合物(例如，C14或氘标记的厚朴酚衍生物、和厚朴酚衍生 物及其盐)对于明确厚朴酚衍生物、和厚朴酚衍生物及其盐的药物代谢过程至关重要，但一般来说标记化合物合成原料价格昂贵，不易得，故将标记化合物开发为治疗药物显然成本过高；相比而言，非标记化合物合成原料简单易得，容易开发为治疗药物；本申请中的非标记厚朴酚衍生物、和厚朴酚衍生物及其盐在缺血性损伤中具有明显的脑保护作用，相应标记化合物可以用于解释非标记厚朴酚衍生物、和厚朴酚衍生物及其盐的代谢过程，两者相辅相成，有利于缺血性脑保护药物的发现。Preferably, the hydrocarbon group containing 1 to 8 carbons is an alkyl group or an alkenyl group; preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent-3-enyl, Pent-4-enyl (enpenthexyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl (hexenyl ), hept-1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl (heptenyl), octyl 1-enyl, oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl or oct-7-enyl (octenyl ). In a typical embodiment of the present invention, the amino acid is lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, glycine, histidine , arginine, proline, glutamic acid, aspartic acid, cystine or cysteine. The peptide consists of the above-mentioned amino acids and has a molecular weight of ≤2500 Da. These are all amino acids contained in the human body and play an important role in regulating life activities. Preferably, the honokiol derivatives, honokiol derivatives and their salts are 3',5-diallyl-3-[(S)-2,6-diamino-1-hexanoyl]amino groups -2,4'-Dihydroxy-1,1'-[1'-phenyl-C14]biphenyl and its hydrochloride, 3',5-diallyl-2',5',6'- Trideutero-3-[(S)-2,6-diamino-1-hexanoyl]amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5 -Diallyl-3-[(S)-2-amino-4-methylthio-1-butyryl]amino-2,4'-dihydroxy-1,1'-[1'-phenyl -C14] Biphenyl and its hydrochloride, 3', 5-diallyl-2', 5', 6'-trideutero-3-[(S)-2-amino-4-methylthio- 1-Butyryl]amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride and 3',5-dipropyl-3-[(S)-2,6-diphenyl Amino-1-hexanoyl]amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride. These honokiol derivatives, and honokiol derivatives and their salts can enhance the traceability in drug metabolism. For example, C14 is radioactive, and radioactive tracking technology can be used to detect the disposition process of drugs in the body, which cannot be achieved by traditional mass spectrometry detection. of. The labeled compounds in the present invention (eg, C14- or deuterium-labeled honokiol derivatives, and honokiol derivatives and salts thereof) are useful for clarifying the drug metabolism of honokiol derivatives, and honokiol derivatives and salts thereof The process is very important, but in general, the raw materials for the synthesis of labeled compounds are expensive and difficult to obtain, so the development of labeled compounds as therapeutic drugs is obviously too expensive. Drugs; unlabeled honokiol derivatives, and honokiol derivatives and their salts in this application have obvious brain protective effects in ischemic injury, and corresponding labeled compounds can be used to explain unlabeled honokiol derivatives , and the metabolic process of honokiol derivatives and their salts, the two complement each other, which is beneficial to the discovery of ischemic cerebral protective drugs.
根据本发明的一种典型的实施方式，提供一种厚朴酚衍生物、和厚朴酚衍生物及其盐在药物代谢研究中的应用，其中，厚朴酚衍生物、和厚朴酚衍生物及其盐具有如下式(I)所示结构，
Figure PCTCN2021117535-appb-000014
According to a typical embodiment of the present invention, a honokiol derivative, and the application of honokiol derivative and salt thereof in drug metabolism research are provided, wherein, the honokiol derivative, and the honokiol derivative The compound and its salt have the structure shown in the following formula (I),
Figure PCTCN2021117535-appb-000014
其中，R 1和R 4分别独立的选自含有1～8个碳的烃基； wherein, R 1 and R 4 are independently selected from hydrocarbon groups containing 1 to 8 carbons;
R 5为氨基酸、肽或具有1～8个碳的非氨基酸式的含氮酰基所修饰的氨基酸，所述氨基酸、所述肽或具有1～8个碳的非氨基酸式的含氮酰基中的可成盐氨基可以部分或全部为盐形式； R 5 is an amino acid, a peptide or an amino acid modified by a nitrogen-containing acyl group having a non-amino acid formula of 1 to 8 carbons, wherein the amino acid, the peptide or a nitrogen-containing acyl group of a non-amino acid formula of 1 to 8 carbons The salt-formable amino group may be partially or completely in the form of a salt;
当*所标记的苯环含有一个C14原子，R 2、R 3分别独立地为氢或羟基，且R 2、R 3不同时为氢或羟基； When the benzene ring marked by * contains a C14 atom, R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl;
或当*所标记的苯环为氘代标记物时，具有式(II)所示的结构，
Figure PCTCN2021117535-appb-000015
式(II)，D为氘原子，R2和R3分别独立地为氘或羟基，且R 2、R 3不同时为氘或羟基。 Or when the benzene ring marked by * is a deuterated label, it has the structure shown in formula (II),
Figure PCTCN2021117535-appb-000015
In formula ( II ), D is a deuterium atom, R2 and R3 are each independently deuterium or hydroxyl, and R2 and R3 are not simultaneously deuterium or hydroxyl.
进一步地，含有1～8个碳的烃基为烷基或烯基，优选为甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、丁-3烯基(烯丁基)、戊-1-烯基、戊-2-烯基、戊-3-烯基、戊-4-烯基(烯戊己)、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基、己-5-烯基(己烯基)、庚-1-烯基、庚-2-烯基、庚-3-烯基、庚-4-烯基、庚-5-烯基、庚-6-烯基(庚烯基)、辛1-烯基、辛-2-烯基、辛-3-烯基、辛-4-烯基、辛-5-烯基、辛-6-烯基或辛-7-烯基(辛烯基)。进一步地，氨基酸为赖氨酸、蛋氨酸、色氨酸、缬氨酸、丙氨酸、苯丙氨酸、亮氨酸、异亮氨酸、甘氨酸、组氨酸、精氨酸、脯氨酸、谷氨酸、天冬氨酸、胱氨酸或半胱氨酸；肽由上述氨基酸组成，且分子量≤2500Da。Further, the hydrocarbon group containing 1 to 8 carbons is an alkyl group or an alkenyl group, preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a vinyl group, a propenyl group, an alkene group Propyl, but-1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent-3-enyl, pentyl -4-enyl (pentenyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl (hexenyl) , hept-1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl (heptenyl), oct-1 -alkenyl, oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl or oct-7-enyl (octenyl) . Further, the amino acid is lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, glycine, histidine, arginine, proline , glutamic acid, aspartic acid, cystine or cysteine; the peptide is composed of the above amino acids, and the molecular weight is less than or equal to 2500Da.
进一步地，厚朴酚衍生物、和厚朴酚衍生物及其盐优选为3'，5-二烯丙基-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-[1'-苯基-C14]联苯及其盐酸盐、3'，5-二烯丙基-2',5',6'-三氘-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-联苯及其盐酸盐、3'，5-二烯丙基-3-[(S)-2-氨基-4-甲硫基-1-丁酰]胺基-2，4'-二羟基-1，1'-[1'-苯基-C14]联苯及其盐酸盐和3'，5-二烯丙基-2',5',6'-三氘-3-[(S)-2-氨基-4-甲硫基-1-丁酰]胺基-2，4'-二羟基-1，1'-联苯及其盐酸盐。Further, the magnolol derivative, the magnolol derivative and its salt are preferably 3',5-diallyl-3-[(S)-2,6-diamino-1-hexanoyl]amide Base-2,4'-dihydroxy-1,1'-[1'-phenyl-C14]biphenyl and its hydrochloride, 3',5-diallyl-2',5',6' -Trideutero-3-[(S)-2,6-diamino-1-hexanoyl]amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3', 5-Diallyl-3-[(S)-2-amino-4-methylthio-1-butyryl]amino-2,4'-dihydroxy-1,1'-[1'-benzene Base-C14]biphenyl and its hydrochloride and 3',5-diallyl-2',5',6'-trideutero-3-[(S)-2-amino-4-methylthio -1-Butyryl]amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride.
根据本发明的又一个方面，提供厚朴酚衍生物、和厚朴酚衍生物及其盐在缺血性损伤中的脑保护应用。其中，所述厚朴酚衍生物、和厚朴酚衍生物及其盐具有如下式(I)所示结构，According to yet another aspect of the present invention, honokiol derivatives, and honokiol derivatives and salts thereof are provided for brain protection applications in ischemic injury. Wherein, the magnolol derivative, the magnolol derivative and the salt thereof have the structure shown in the following formula (I),
Figure PCTCN2021117535-appb-000016
Figure PCTCN2021117535-appb-000016
其中，R 1和R 4分别独立的选自含有1～8个碳的烃基； wherein, R 1 and R 4 are independently selected from hydrocarbon groups containing 1 to 8 carbons;
R 5为氨基酸、肽或具有1～8个碳的非氨基酸式的含氮酰基所修饰的氨基，所述氨基酸、所述肽或具有1～8个碳的非氨基酸式的含氮酰基中的可成盐氨基可以部分或全部为盐形式； R 5 is an amino acid, a peptide or an amino group modified by a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons, wherein the amino acid, the peptide or a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons The salt-formable amino group may be partially or completely in the form of a salt;
*所标记的苯环不含标记原子，R 2和R 3分别独立地为氢或羟基，且R 2、R 3不同时为氢或羟基； *The marked benzene ring does not contain marked atoms, R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl;
优选的，含有1～8个碳的烃基为烷基或烯基，优选为甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、丁-3烯基(烯丁基)、戊-1-烯基、戊-2-烯基、戊-3-烯基、戊-4-烯基(烯戊己)、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基、己-5-烯基(己烯基)、庚-1-烯基、庚-2-烯基、庚-3-烯基、庚-4-烯基、庚-5-烯基、庚-6-烯基(庚烯基)、辛1-烯基、辛-2-烯基、辛-3-烯基、辛-4-烯基、辛-5-烯基、辛-6-烯基或辛-7-烯基(辛烯基)。Preferably, the hydrocarbon group containing 1 to 8 carbons is alkyl or alkenyl, preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, alkene Propyl, but-1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent-3-enyl, pentyl -4-enyl (pentenyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl (hexenyl) , hept-1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl (heptenyl), oct-1 -alkenyl, oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl or oct-7-enyl (octenyl) .
优选的，氨基酸为赖氨酸、蛋氨酸、色氨酸、缬氨酸、丙氨酸、苯丙氨酸、亮氨酸、异亮氨酸、甘氨酸、组氨酸、精氨酸、脯氨酸、谷氨酸、天冬氨酸、胱氨酸或半胱氨酸；肽由上述氨基酸组成，且分子量≤2500Da。Preferably, the amino acid is lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, glycine, histidine, arginine, proline , glutamic acid, aspartic acid, cystine or cysteine; the peptide is composed of the above amino acids, and the molecular weight is less than or equal to 2500Da.
更有选的，厚朴酚衍生物、和厚朴酚衍生物及其盐为3'，5-二丙基-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-联苯及其盐酸盐。More preferably, honokiol derivatives, honokiol derivatives and their salts are 3',5-dipropyl-3-[(S)-2,6-diamino-1-hexanoyl]amine Base-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride.
根据本发明的一种典型的实施方式，提供一种上述厚朴酚衍生物、和厚朴酚衍生物及其盐的制备方法。该制备方法包括以下步骤：According to a typical embodiment of the present invention, a preparation method of the above-mentioned magnolol derivative, and a magnolol derivative and a salt thereof is provided. The preparation method comprises the following steps:
制备具有式(III)的化合物
Figure PCTCN2021117535-appb-000017
其中，R 1为含有1～8个碳的烃基，优选自甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、丁-3烯基(烯丁基)、戊-1-烯基、戊-2-烯基、戊-3-烯基、戊-4-烯基(烯戊己)、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基、己-5-烯基(己烯基)、庚-1-烯基、庚-2-烯基、庚-3-烯基、庚-4-烯基、庚-5-烯基、庚-6-烯基(庚烯基)、辛1-烯基、辛-2-烯基、辛-3-烯基、辛-4-烯基、辛-5-烯基、辛-6-烯基或辛-7-烯基(辛烯基)等含有1～8个碳的烷基或含有1～8个碳的烯基，R 5为氨基酸、肽或含1-8个碳的非氨基酸式的含氮酰基所修饰的氨基，所述氨基酸、肽或含1～8个碳的非氨基酸式的含氮酰基中的氨基全部用叔丁氧羰基保护； Preparation of compounds of formula (III)
Figure PCTCN2021117535-appb-000017
Wherein, R 1 is a hydrocarbon group containing 1 to 8 carbons, preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, butyl -1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-ene Hex-1-enyl (enpentenyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl (hexenyl), hept-1 -alkenyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl (heptenyl), oct-1-enyl, Oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl or oct-7-enyl (octenyl), etc. contain 1- 8-carbon alkyl group or 1-8 carbon alkenyl group, R 5 is amino acid modified by amino acid, peptide or nitrogen-containing acyl group containing 1-8 carbon non-amino acid formula, the amino acid, peptide or containing All amino groups in the nitrogen-containing acyl groups of 1 to 8 carbons that are not amino acids are protected with tert-butoxycarbonyl;
制备具有式(IV)的化合物
Figure PCTCN2021117535-appb-000018
其中，R 4为含有1～8个碳的烃基，优选自甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、丁-3烯基(烯丁基)、戊-1-烯基、戊-2-烯基、戊-3-烯基、戊-4-烯基(烯戊己)、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基、己-5-烯基(己烯基)、庚-1-烯基、庚-2-烯基、庚-3-烯基、庚-4-烯基、庚-5-烯基、庚-6-烯基(庚烯基)、辛1-烯基、辛-2-烯基、辛-3-烯基、辛-4-烯基、辛-5-烯基、辛-6-烯基或辛-7-烯基(辛烯基)等含有1～8个碳的烷基或含有1～8个碳的烯基；当*所标记的苯环含有一个C14原子时，R 2、R 3分别独立地为氢或羟基，且R 2、R 3不同时为氢或羟基；当*所标记的苯环为氘代标记物时，具有式(V)所示的结构
Figure PCTCN2021117535-appb-000019
D为氘原子，R 2、R 3分别独立地为氘或羟基，且 R 2、R 3不同时为氘或羟基；当*所标记的苯环不含标记原子时，R 2和R 3分别独立地为氢或羟基，且R 2、R 3不同时为氢或羟基； Preparation of compounds of formula (IV)
Figure PCTCN2021117535-appb-000018
Wherein, R 4 is a hydrocarbon group containing 1 to 8 carbons, preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, butyl -1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-ene Hex-1-enyl (enpentenyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl (hexenyl), hept-1 -alkenyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl (heptenyl), oct-1-enyl, Oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl or oct-7-enyl (octenyl), etc. contain 1- 8-carbon alkyl group or 1-8 carbon alkenyl group; when the benzene ring marked by * contains one C14 atom, R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not At the same time, it is hydrogen or hydroxyl; when the benzene ring marked by * is a deuterated label, it has the structure shown in formula (V)
Figure PCTCN2021117535-appb-000019
D is a deuterium atom, R 2 and R 3 are independently deuterium or hydroxyl, and R 2 and R 3 are not both deuterium or hydroxyl; when the benzene ring marked by * does not contain a marked atom, R 2 and R 3 are respectively are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl;
具有式(III)的化合物与具有式(IV)的化合物通过Suzuki反应形成得到式1化合物，其中，所用到的氨基酸或肽用叔丁氧羰基保护。Compounds of formula (III) and compounds of formula (IV) are formed by Suzuki reaction to give compounds of formula 1, wherein the amino acid or peptide used is protected with a tert-butoxycarbonyl group.
优选的，制备方法的具体合成线路图如下：Preferably, the specific synthesis circuit diagram of the preparation method is as follows:
Figure PCTCN2021117535-appb-000020
Figure PCTCN2021117535-appb-000020
下面将结合实施例进一步说明本发明的有益效果。The beneficial effects of the present invention will be further described below in conjunction with the embodiments.
实施例1Example 1
2-烯丙基-4-溴苯酚(化合物1)的制备Preparation of 2-allyl-4-bromophenol (compound 1)
将对溴苯酚(17.2g，100mmol)加入500ml单口瓶中，加入丙酮180ml，搅拌，加入无水碳酸钾(89.7g，650mmol)和3-溴丙烯(24.2g，200mmol)，加热回流反应过夜。将反应液蒸干，加入250ml水，水相用正己烷250ml提取两次，合并正己烷相，用10％的氢氧化钠水溶液100ml洗涤，饱和氯化钠水溶液100ml洗涤，用无水硫酸钠干燥，过滤。有机相蒸干残留置于200℃的油浴中，加热4h，降至室温。反应液中加入10％氢氧化钠水溶液180ml，水溶液 用正己烷洗涤，收集水相。水相用4N盐酸调节PH为6-7，用二氯甲烷180ml萃取。有机相用饱和氯化钠100ml洗涤，无水硫酸钠干燥，蒸干，残留经柱层析得到淡黄色油状物(11g，收率51％)。P-bromophenol (17.2g, 100mmol) was added to a 500ml single-neck flask, 180ml of acetone was added, stirred, anhydrous potassium carbonate (89.7g, 650mmol) and 3-bromopropene (24.2g, 200mmol) were added, and the reaction was heated under reflux overnight. The reaction solution was evaporated to dryness, 250 ml of water was added, the aqueous phase was extracted twice with 250 ml of n-hexane, the n-hexane phases were combined, washed with 100 ml of 10% aqueous sodium hydroxide solution, washed with 100 ml of saturated aqueous sodium chloride solution, and dried with anhydrous sodium sulfate ,filter. The organic phase was evaporated to dryness and the residue was placed in an oil bath at 200°C, heated for 4h, and then lowered to room temperature. To the reaction solution was added 180 ml of a 10% aqueous sodium hydroxide solution, the aqueous solution was washed with n-hexane, and the aqueous phase was collected. The aqueous phase was adjusted to pH 6-7 with 4N hydrochloric acid, and extracted with 180 ml of dichloromethane. The organic phase was washed with 100 ml of saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated to dryness, and the residue was subjected to column chromatography to obtain a pale yellow oil (11 g, yield 51%).
化合物1： 1H-NMR(400MHz，CDCl 3)δ7.23-7.21(2H，q)，6.70(1H，d)，6.02-5.92(1H，m)，5.20-5.14(2H，m)，4.91(1H，s)3.36(2H，d) Compound 1: 1 H-NMR (400 MHz, CDCl 3 ) δ 7.23-7.21 (2H, q), 6.70 (1H, d), 6.02-5.92 (1H, m), 5.20-5.14 (2H, m), 4.91 (1H,s)3.36(2H,d)
实施例2Example 2
2-烯丙基-4-溴苯酚-D4(化合物2)的制备Preparation of 2-allyl-4-bromophenol-D4 (compound 2)
将对溴苯酚-D4(2.05g，12mmol)加入50ml单口瓶中，加入丙酮25ml，搅拌，加入无水碳酸钾(10.4g，75mmol)和3-溴丙烯(2.8g，24mmol)，加热回流反应3h。将反应液蒸干，加入50ml水，正己烷10mlx2提取两次，合并有机相，用10％的氢氧化钠水溶液25mlx2洗涤，饱和氯化钠水溶液50ml洗涤，无水硫酸钠干燥，过滤，有机相蒸干残留置于200℃的油浴中，加热4h，降至室温。反应液中加入10％氢氧化钠水溶液180ml，水溶液用正己烷洗涤，收集水相。水相用4N盐酸调节PH为6-7，用二氯甲烷180ml萃取。有机相用饱和氯化钠100ml洗涤，无水硫酸钠干燥，蒸干，残留经柱层析(Hexane:EA＝40:1)得到淡黄色油状物(0.63g，收率25％)。P-bromophenol-D4 (2.05g, 12mmol) was added in a 50ml single-neck flask, 25ml of acetone was added, stirred, anhydrous potassium carbonate (10.4g, 75mmol) and 3-bromopropene (2.8g, 24mmol) were added, and the reaction was heated under reflux. 3h. Evaporate the reaction solution to dryness, add 50ml of water, extract twice with n-hexane 10mlx2, combine the organic phases, wash with 25mlx2 of 10% aqueous sodium hydroxide solution, wash with 50ml of saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter, and the organic phase The residue was evaporated to dryness and placed in an oil bath at 200°C, heated for 4h, and then lowered to room temperature. 180 ml of a 10% aqueous sodium hydroxide solution was added to the reaction solution, the aqueous solution was washed with n-hexane, and the aqueous phase was collected. The aqueous phase was adjusted to pH 6-7 with 4N hydrochloric acid, and extracted with 180 ml of dichloromethane. The organic phase was washed with 100 ml of saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated to dryness, and the residue was subjected to column chromatography (Hexane:EA=40:1) to obtain a pale yellow oil (0.63 g, yield 25%).
化合物2：C 9H 6D 3BrO＝216.0MS:214和216[M-H] - Compound 2 : C9H6D3BrO = 216.0 MS: 214 and 216 [MH] -
实施例3Example 3
4-烯丙基苯酚(化合物3)的制备Preparation of 4-allylphenol (compound 3)
将4-烯丙基苯甲醚(22g，0.148mmol)溶于二氯甲烷(150ml)中，N2保护，干冰浴降温。三溴化硼(47.5g，0.19mmol)缓慢加入反应液中，保持温度低于-10℃，加完后继续反应，温度低于0度反应1h，TLC监测反应完毕，将反应液倒入200ml冰水中，加入乙酸乙酯300ml，分液，水相用EA100mlx2萃取，合并有机相，饱和氯化钠洗涤，无水硫酸钠干燥，浓缩，残留物柱层析得到黄色油状物化合物3(16.1g，80.8％)。4-Allylanisole (22 g, 0.148 mmol) was dissolved in dichloromethane (150 ml), protected with N2, and cooled in a dry ice bath. Boron tribromide (47.5g, 0.19mmol) was slowly added to the reaction solution, keeping the temperature lower than -10°C, the reaction was continued after the addition, the temperature was lower than 0°C and the reaction was performed for 1h, TLC monitoring was completed, and the reaction solution was poured into 200ml In ice water, 300 ml of ethyl acetate was added, the layers were separated, the aqueous phase was extracted with EA 100 ml×2, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to column chromatography to obtain compound 3 (16.1 g) as a yellow oil. , 80.8%).
化合物3：C 9H 10O＝134.18,GC-MS:134[M] +。 Compound 3: C 9 H 10 O = 134.18, GC-MS: 134 [M] + .
实施例4Example 4
4-烯丙基-2-硝基-6-溴苯酚(化合物4)的制备Preparation of 4-allyl-2-nitro-6-bromophenol (compound 4)
化合物3(16.1g，0.12mmol)溶于二氯甲烷(160ml)，搅拌降温至0℃，分批加入NBS(39g,0.22mmol)，两小时加完，TLC监测反应完毕，加入2mol/L盐酸水溶液(100ml),分液，有机相用饱和氯化钠水溶液(100ml)洗涤，无水硫酸钠干燥，浓缩得到淡黄色油状物28.5g。将上述粗品溶于醋酸(150ml)中，搅拌，亚硝酸钠(13.4g,0.19mol)溶于水(20ml)中加入到上述醋酸溶液中，加完后室温反应1h，将反应液倒冰水中，二氯甲烷(150mlx3)萃取水相，合并有机相，先后用饱和碳酸氢钠和饱和氯化钠水溶液洗涤，合并有机相，无水硫酸钠干燥，浓缩后得到黄色油状物，后经柱层析(洗脱剂PE)得到黄色蜡状固体化合物4(10.2g，33％)。Compound 3 (16.1 g, 0.12 mmol) was dissolved in dichloromethane (160 ml), stirred and cooled to 0 ° C, NBS (39 g, 0.22 mmol) was added in batches, the addition was completed in two hours, and the reaction was monitored by TLC, and 2 mol/L hydrochloric acid was added. The aqueous solution (100ml) was separated, and the organic phase was washed with saturated aqueous sodium chloride solution (100ml), dried over anhydrous sodium sulfate, and concentrated to obtain 28.5g of pale yellow oil. The above crude product was dissolved in acetic acid (150ml), stirred, sodium nitrite (13.4g, 0.19mol) was dissolved in water (20ml) and added to the above acetic acid solution, after adding, the reaction was performed at room temperature for 1h, and the reaction solution was poured into ice water , the aqueous phase was extracted with dichloromethane (150ml×3), the organic phases were combined, washed successively with saturated sodium bicarbonate and saturated aqueous sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oil, which was passed through the column layer Analysis (eluent PE) gave compound 4 (10.2 g, 33%) as a yellow waxy solid.
化合物4：C 9H 8BrNO 3＝258.07，GC-MS 257和259。 1H-NMR(400MHz，CDCl 3)δ11.02(1H，s)，7.91(1H，s)，7.71(1H，s)，5.93-5.83(1H，m)，5.19-5.06(1H，m)，3.36(2H，d)。 Compound 4 : C9H8BrNO3 = 258.07, GC-MS 257 and 259. 1 H-NMR (400 MHz, CDCl 3 ) δ 11.02 (1H, s), 7.91 (1H, s), 7.71 (1H, s), 5.93-5.83 (1H, m), 5.19-5.06 (1H, m) , 3.36(2H, d).
实施例5Example 5
4-烯丙基-2-氨基-6-溴苯酚(化合物5)的制备Preparation of 4-allyl-2-amino-6-bromophenol (compound 5)
将化合物4(18g，23mmol)溶于无水乙醇(150ml)中，加入氯化亚锡(18g，79mmol)，加入浓盐酸(0.5ml)，搅拌回流反应1h，浓缩，加入乙酸乙酯(200ml)，先后用饱和氯化钠(100mlx3)洗涤和碳酸氢钠水溶液洗涤，有机相无水硫酸钠干燥，加硅藻土过滤，滤液浓缩后得到棕色固体化合物5(4.7g，收率30％)Compound 4 (18g, 23mmol) was dissolved in absolute ethanol (150ml), stannous chloride (18g, 79mmol) was added, concentrated hydrochloric acid (0.5ml) was added, the reaction was stirred and refluxed for 1h, concentrated, and ethyl acetate (200ml) was added. ), washed with saturated sodium chloride (100ml×3) and washed with aqueous sodium bicarbonate successively, the organic phase was dried over anhydrous sodium sulfate, filtered with celite, and the filtrate was concentrated to obtain a brown solid compound 5 (4.7g, yield 30%)
化合物5：C 9H 10BrNO＝228.09，MS 228[M+H] +和230[M+H] +。 Compound 5 : C9H10BrNO= 228.09 , MS 228 [M+H] + and 230 [M+H] + .
实施例6Example 6
4-烯丙基-2-[(S)-2,6-二氨基-1-己酰]胺基-6-溴苯酚(化合物6)(英文名di-tert-butyl(6-((5-allyl-3-bromo-2-hydoxyphenyl)amino)-6-oxohexane-1,5-diyl)(R)-dicarbamate)的制备4-allyl-2-[(S)-2,6-diamino-1-hexanoyl]amino-6-bromophenol (compound 6) (English name di-tert-butyl(6-((5 Preparation of -allyl-3-bromo-2-hydoxyphenyl)amino)-6-oxohexane-1,5-diyl)(R)-dicarbamate)
化合物5(4.7g，20.7mmol)和Boc-L-lys(Boc)-OH(7.54g，22.7mmol)溶于二氯甲烷(200ml)中，0℃搅拌，DCC(4.7g，22.7mmol)溶于二氯甲烷(50ml)中加入到上述反应液中反应2h。过滤，滤液用1N盐酸洗涤至酸性，分液，有机相用饱和氯化钠洗涤，无水硫酸钠干燥，过滤浓缩后残留进行柱层析(hexane:EA＝10:1-3:1)，得到泡沫状黄色固体化合物6(6.1g，53％)。Compound 5 (4.7 g, 20.7 mmol) and Boc-L-lys(Boc)-OH (7.54 g, 22.7 mmol) were dissolved in dichloromethane (200 ml), stirred at 0°C, and dissolved in DCC (4.7 g, 22.7 mmol) Dichloromethane (50ml) was added to the above reaction solution to react for 2h. After filtration, the filtrate was washed with 1N hydrochloric acid until acidic, and the layers were separated. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to column chromatography (hexane:EA=10:1-3:1), Compound 6 (6.1 g, 53%) was obtained as a foamy yellow solid.
化合物6：C 25H 38BrN 3O 6＝556.50，MS 556[M+H] +和558[M+H] +。 Compound 6 : C25H38BrN3O6 = 556.50 , MS 556 [M+H] + and 558 [M+H] + .
实施例7Example 7
5-烯丙基-3-[(S)-2,6-二氨基-1-己酰]胺基-2-羟基苯硼酸(化合物7)的制备Preparation of 5-allyl-3-[(S)-2,6-diamino-1-hexanoyl]amino-2-hydroxyphenylboronic acid (compound 7)
在氮气保护下，将化合物6(C2.9g，5.2mmol)和联硼频那醇酯(22.7g，10.4mmol)溶于二氧六环(50ml中)，加醋酸钾(1.6g，15.8mmol)和催化剂Pd(pddf)Cl2(200mg，0.28mmol)，搅拌，加热至80℃反应2h。降至室温，浓缩，加入EA(100ml)，有机相用饱和氯化钠洗涤(100mlx2)，无水硫酸钠干燥，过滤，滤液浓缩，残留经柱层(MeOH:DCM＝1:5)析得白色固体化合物7(1.2g，38％)，纯度96％Under nitrogen protection, compound 6 (C 2.9 g, 5.2 mmol) and biboron pinacol ester (22.7 g, 10.4 mmol) were dissolved in dioxane (50 ml), and potassium acetate (1.6 g, 15.8 mmol) was added. ) and catalyst Pd(pddf)Cl2 (200 mg, 0.28 mmol), stirred, heated to 80° C. to react for 2 h. It was cooled to room temperature, concentrated, EA (100ml) was added, the organic phase was washed with saturated sodium chloride (100ml×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was precipitated by column layer (MeOH:DCM=1:5). White solid compound 7 (1.2 g, 38%), purity 96%
化合物7：C 31H 50BN 3O 8＝603.56，MS 604[M+H] +, 1H-NMR(400MHz，CDCl 3)δ8.29(1H，s)，8.03(1H，s)，7.14(1H，s)，5.93-5.83(1H，m)，5.20(1H，s),5.09-5.01(2H，m)，4.21(1H，t),3.31(2H，d),3.12(2H，t)。 Compound 7: C 31 H 50 BN 3 O 8 =603.56, MS 604 [M+H] + , 1 H-NMR (400 MHz, CDCl 3 ) δ 8.29 (1H, s), 8.03 (1H, s), 7.14 (1H, s), 5.93-5.83 (1H, m), 5.20 (1H, s), 5.09-5.01 (2H, m), 4.21 (1H, t), 3.31 (2H, d), 3.12 (2H, t) ).
实施例8Example 8
3'，5-二烯丙基-3-[(S)-2,6-N-叔丁氧羰基-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-[1'-苯基 -C14]联苯(化合物8)的制备3',5-Diallyl-3-[(S)-2,6-N-tert-butoxycarbonyl-diamino-1-hexanoyl]amino-2,4'-dihydroxy-1,1 Preparation of '-[1'-phenyl-C14]biphenyl (Compound 8)
将C14标记化合物1(487mg，2.3mmol))、化合物7(1.0g，1.92mmol)和碳酸钠(610mg，5.76mmol)溶于1,4-二氧六环(50ml)和水(5ml)，搅拌，置换氮气，加入PdCl 2(dppf) 2(140mg,0.19mmol)，80℃反应3h。浓缩，加入50ml水和乙酸乙酯(50ml)分层，分液，水相乙酸乙酯(50ml)萃取，合并有机相用饱和食盐水(50ml)洗涤，有机相用无水硫酸钠干燥，减压浓缩，柱层析(Hexane:EA＝2:1)得C14标记化合物8(350mg，收率30％)。 C14-labeled compound 1 (487 mg, 2.3 mmol)), compound 7 (1.0 g, 1.92 mmol) and sodium carbonate (610 mg, 5.76 mmol) were dissolved in 1,4-dioxane (50 ml) and water (5 ml), Stir, replace nitrogen, add PdCl 2 (dppf) 2 (140 mg, 0.19 mmol), and react at 80° C. for 3 h. Concentrate, add 50ml of water and ethyl acetate (50ml) to separate layers, separate the layers, extract the aqueous phase with ethyl acetate (50ml), combine the organic phases and wash with saturated brine (50ml), dry the organic phase with anhydrous sodium sulfate, reduce Concentrated under pressure, column chromatography (Hexane:EA=2:1) gave C14-labeled compound 8 (350 mg, yield 30%).
化合物8：C 34H 47N 3O 7＝611.75，MS：612[M+H] +。 1H NMR(300MHz，CDCl 3)δ8.65(1H，s)，7.31(1H，s)，7.20(2H，d)6.87(2H，d)，6.09(1H，s)，6.02-5.86(2H，m)，5.36(1H，s)，5.18-5.00(4H，m)，4.67(1H，s)，4.28(1H，t)，3.42(2H，d)，3.29(2H，d)，3.11(2H，t),1.92(2H,m),1.460(22H,m)。 Compound 8 : C34H47N3O7 = 611.75 , MS: 612 [M+H] + . 1 H NMR (300 MHz, CDCl 3 ) δ 8.65(1H,s), 7.31(1H,s), 7.20(2H,d) 6.87(2H,d), 6.09(1H,s), 6.02-5.86(2H , m), 5.36 (1H, s), 5.18-5.00 (4H, m), 4.67 (1H, s), 4.28 (1H, t), 3.42 (2H, d), 3.29 (2H, d), 3.11 ( 2H, t), 1.92 (2H, m), 1.460 (22H, m).
实施例9Example 9
3'，5-二烯丙基-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-联苯﹒盐酸盐(化合物9)的制备3',5-Diallyl-3-[(S)-2,6-diamino-1-hexanoyl]amino-2,4'-dihydroxy-1,1'-biphenyl﹒ Preparation of hydrochloride (compound 9)
0℃，化合物8(125mg，0.21mmol)溶于4M HCl(gas)乙酸乙酯溶液(10ml)，搅拌5h，加正己烷20ml,过滤，滤饼溶于5ml水柱层析(C18柱，水：乙醇＝100:15)得固体(41mg，41％)。At 0°C, compound 8 (125 mg, 0.21 mmol) was dissolved in 4M HCl (gas) ethyl acetate solution (10 ml), stirred for 5 h, added with 20 ml of n-hexane, filtered, and the filter cake was dissolved in 5 ml of water column chromatography (C18 column, water: ethanol=100:15) to give a solid (41 mg, 41%).
化合物9：C 24H 33Cl 2N 3O 3＝482.44，MS：410[M+H] +(游离态)。 1H-NMR(400MHz，DMSO)δ10.43(1H,s),δ9.46(1H,s),δ8.61(1H,s)，δ8.43(3H,s)，7.99(3H,s)，7.33(1H,s)，7.16(2H,t)，6.86(2H,d),5.99(2H,m)，5.09(4H,m)，4.15(1H,d)，3.29(4H,m)，2.77(2H,t),1.89(2H,q),1.63(2H,m),1.47(2H,m) Compound 9 : C24H33Cl2N3O3 = 482.44 , MS: 410 [ M +H] + (free). 1 H-NMR (400MHz, DMSO) δ10.43(1H,s), δ9.46(1H,s), δ8.61(1H,s), δ8.43(3H,s), 7.99(3H,s) ), 7.33(1H,s), 7.16(2H,t), 6.86(2H,d), 5.99(2H,m), 5.09(4H,m), 4.15(1H,d), 3.29(4H,m) , 2.77(2H,t), 1.89(2H,q), 1.63(2H,m), 1.47(2H,m)
实施例10Example 10
3'，5-二烯丙基-2',5',6'-三氘-3-[(S)-2,6-N-叔丁氧羰基-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-联苯(化合物10)的制备3',5-Diallyl-2',5',6'-trideutero-3-[(S)-2,6-N-tert-butoxycarbonyl-diamino-1-hexanoyl]amino Preparation of -2,4'-dihydroxy-1,1'-biphenyl (compound 10)
将氘标记化合物2(300mg，1.39mmol))、化合物7(1.24g，2.08mmol)和碳酸钠(438mg，4.16mmol)溶于1,4-二氧六环(10ml)和水(5ml)，搅拌，置换氮气，加入PdCl 2(dppf) 2(48mg,0.07mmol)，80℃反应6h。浓缩，加入30ml水和乙酸乙酯(50ml)分层，分液，水相乙酸乙酯(50ml)萃取，合并有机相用饱和食盐水(50ml)洗涤，有机相用无水硫酸钠干燥，减压浓缩，柱层析(Hexane:EA＝2:1)得氘标记化合物8(210mg，收率20％)。 Deuterium-labeled compound 2 (300 mg, 1.39 mmol)), compound 7 (1.24 g, 2.08 mmol) and sodium carbonate (438 mg, 4.16 mmol) were dissolved in 1,4-dioxane (10 ml) and water (5 ml), Stir, replace nitrogen, add PdCl 2 (dppf) 2 (48 mg, 0.07 mmol), and react at 80° C. for 6 h. Concentrate, add 30ml of water and ethyl acetate (50ml) to separate the layers, separate the layers, extract the aqueous phase with ethyl acetate (50ml), combine the organic phases and wash with saturated brine (50ml), dry the organic phase with anhydrous sodium sulfate, reduce Concentrated under pressure, column chromatography (Hexane:EA=2:1) gave deuterium-labeled compound 8 (210 mg, yield 20%).
化合物10：C 34H 44D 3N 3O 77＝612.78，MS：613[M+H] + Compound 10 : C34H44D3N3O77 = 612.78 , MS: 613 [M+H] +
实施例11Example 11
3'，5-二烯丙基-2',5',6'-三氘-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-联苯﹒盐酸盐(化合物11)的制备3',5-Diallyl-2',5',6'-trideutero-3-[(S)-2,6-diamino-1-hexanoyl]amino-2,4'-di Hydroxy-1,1'-biphenyl﹒ Preparation of hydrochloride (compound 11)
0℃，化合物8(210mg，0.34mmol)溶于4M HCl(gas)乙酸乙酯溶液(5ml)，搅拌5h，加正己烷20ml,过滤，滤饼溶于5ml水HPLC(C18柱，水：甲醇＝100:15)得固体(24mg，14％)。0°C, compound 8 (210mg, 0.34mmol) was dissolved in 4M HCl (gas) ethyl acetate solution (5ml), stirred for 5h, added n-hexane 20ml, filtered, the filter cake was dissolved in 5ml water HPLC (C18 column, water: methanol =100:15) to give a solid (24 mg, 14%).
化合物11：C 24H 33Cl 2N 3O 3＝C 24H 30D 3Cl 2N 3O 3，MS：413[M+H] +(游离态)。 1H-NMR(400MHz，D 2O)δ7.22(1H,s)，6.99(1H,s),6.05-5.90(2H,m)，5.05-4.96(4H,m)，4.20(1H,t)，3.33-3.26(4H,dd)，2.92(2H,t),1.96(2H,m),1.72(2H,m),1.53(2H,m)。 Compound 11 : C24H33Cl2N3O3 = C24H30D3Cl2N3O3 , MS : 413 [ M + H] + ( free ) . 1 H-NMR (400MHz, D 2 O) δ 7.22(1H,s), 6.99(1H,s), 6.05-5.90(2H,m), 5.05-4.96(4H,m), 4.20(1H,t) ), 3.33-3.26(4H,dd), 2.92(2H,t), 1.96(2H,m), 1.72(2H,m), 1.53(2H,m).
实施例12Example 12
本发明化合物的药物代谢回收率测定实验及药时曲线测定实验。The drug metabolism recovery rate determination experiment and the drug time curve determination experiment of the compound of the present invention.
一、供试化合物：1. Test compounds:
3'，5-二烯丙基-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-联苯﹒盐酸盐(化合物9)3',5-Diallyl-3-[(S)-2,6-diamino-1-hexanoyl]amino-2,4'-dihydroxy-1,1'-biphenyl﹒ hydrochloride (compound 9)
二、实验方法：2. Experimental method:
2.1药物代谢回收率测定实验2.1 Determination experiment of drug metabolism recovery rate
向新鲜大鼠和小鼠全血中加入少量化合物9，混合均匀，取300uL进行沉淀蛋白预处理，上层上清液和下层沉淀的蛋白分别测定含有的放射量。A small amount of compound 9 was added to fresh rat and mouse whole blood, mixed well, and 300 uL was taken for pretreatment of precipitated protein.
2.2药时曲线测定实验2.2 Drug-time curve determination experiment
4只SD雄性大鼠尾静脉注射化合物的生理盐水1mg/ml溶液，给用剂量2mg/kg，分别于给药后0.05h、0.25h、0.5h、1h、2h、5h、24h取血，利用液体闪烁计数法测定血浆中总放射性活度，并计算药物浓度。Four SD male rats were injected with a 1 mg/ml solution of the compound in physiological saline through the tail vein at a dose of 2 mg/kg. Total radioactivity in plasma was determined by liquid scintillation counting, and drug concentrations were calculated.
三、实验结果：3. Experimental results:
3.1实验结果如下表1和表2所示，大鼠全血实验中32％的药物随蛋白沉降，上清液中仅含有68％的药物；小鼠全血实验中42％的药物随蛋白沉降，上清液中仅含有58％的药物；实验结果揭示了化合物9及其非放射性标记物3'，5-二烯丙基-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-联苯·盐酸盐在药物代谢实验中可能与全血中某些蛋白作用并随之沉降的特点。3.1 The experimental results are shown in Tables 1 and 2 below. In the rat whole blood experiment, 32% of the drug was precipitated with protein, and the supernatant only contained 68% of the drug; in the mouse whole blood experiment, 42% of the drug was precipitated with protein. , the supernatant contained only 58% of the drug; the experimental results revealed compound 9 and its non-radioactive label 3',5-diallyl-3-[(S)-2,6-diamino-1- Hexoyl]amino-2,4'-dihydroxy-1,1'-biphenyl·hydrochloride may interact with some proteins in whole blood in drug metabolism experiments and then sediment.
表1Table 1
Figure PCTCN2021117535-appb-000021
Figure PCTCN2021117535-appb-000021
表2Table 2
Figure PCTCN2021117535-appb-000022
Figure PCTCN2021117535-appb-000022
3.2实验结果如图1所示，随时间的延长药物在血浆中含量逐渐降低，24h血浆中药物完全消失。3.2 The experimental results are shown in Figure 1, the content of the drug in the plasma gradually decreased with the prolongation of time, and the drug completely disappeared in the plasma within 24 hours.
3.3实验结果如表3给出了血浆中药物相关物质的药动学参数，其中雄性大鼠药物的T 1/2为11.42h，雌性大鼠药物的T 1/2为10.66h。 3.3 Experimental results The pharmacokinetic parameters of drug-related substances in plasma are shown in Table 3, wherein the T 1/2 of the drug in male rats is 11.42h, and the T 1/2 of the drug in female rats is 10.66h.
表3table 3
Figure PCTCN2021117535-appb-000023
Figure PCTCN2021117535-appb-000023
从以上的描述中，可以看出，本发明上述的实施例实现了如下技术效果：From the above description, it can be seen that the above-mentioned embodiments of the present invention achieve the following technical effects:
成功制备了放射性标记化合物，进而将其应用于大、小鼠的药物代谢研究，回收率结果显示部分药物随蛋白沉降，推测药物与蛋白有结合作用，这成功解释了式Ⅰ药物在传统非放射性药代实验中药物回收率较低的问题，药时曲线测定结果完美体现了化合物9体内的代谢趋势，可见，厚朴酚衍生物、和厚朴酚衍生物及其盐酸盐可用于式Ⅰ所示药物的吸收、组织 分布、代谢、排泄等临床前动物药代研究以及临床人体药代研究。The radiolabeled compound was successfully prepared, and then it was applied to the drug metabolism study in rats and mice. The recovery results showed that part of the drug was deposited with the protein, and it was speculated that the drug had a binding effect with the protein, which successfully explained the drug of formula I in traditional non-radioactive drugs. The problem of low drug recovery rate in the pharmacokinetic experiment, the results of the drug-time curve measurement perfectly reflect the metabolic trend of compound 9 in vivo. It can be seen that the honokiol derivatives, and the honokiol derivatives and their hydrochloride salts can be used in formula I Preclinical animal pharmacokinetic studies and clinical human pharmacokinetic studies on the absorption, tissue distribution, metabolism, and excretion of the indicated drugs.
实施例13Example 13
非标记化合物的脑神经保护实验Brain neuroprotective experiments with unlabeled compounds
一.供试化合物1. Test compounds
3'，5-二丙基-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-联苯﹒盐酸盐(化合物12)3',5-Dipropyl-3-[(S)-2,6-diamino-1-hexanoyl]amino-2,4'-dihydroxy-1,1'-biphenyl﹒ hydrochloride (compound 12)
Figure PCTCN2021117535-appb-000024
Figure PCTCN2021117535-appb-000024
3'，5-二丙烯基-3-[(S)-2-氨基-6-羟基-1-己酰]胺基-2，4'-二羟基-1，1'-联苯盐酸盐(化合物13)3',5-Dipropenyl-3-[(S)-2-amino-6-hydroxy-1-hexanoyl]amino-2,4'-dihydroxy-1,1'-biphenyl hydrochloride (Compound 13)
Figure PCTCN2021117535-appb-000025
Figure PCTCN2021117535-appb-000025
二、实验方法：2. Experimental method:
选用雄性KM小鼠(体重26-30g),随机分别为：假手术组(Sham)、生理盐水组(Vehicle)、化合物12，所有药物的给药剂量均为100μg/kg。Male KM mice (body weight 26-30 g) were selected and randomly divided into: sham operation group (Sham), normal saline group (Vehicle), compound 12, and all drugs were administered at a dose of 100 μg/kg.
用5％水合氯醛(500mg/kg，i.p.)麻醉，制备tMCAO模型：将小鼠仰卧位固定于37℃恒温手术台上。颈部正中偏右剪开约1cm的切口，钝性分离胸锁乳突肌和胸骨舌骨肌间的肌间隙，暴露分离出颈总动脉(CCA)，颈内动脉(ICA)和颈外动脉(ECA)。在CCA上系一活结，将ECA的远心端结扎，并在其近心端系一活结，ICA用动脉夹夹闭。将ECA上的分支血管凝断，在ECA远心端(两结之间)剪一小口，将一根尼龙栓线经切口处缓慢插向ECA近心端，略微系紧ECA近心端的活结以防止出血，松开ICA的动脉夹，凝断ECA远心端(远心端结外)，将ECA拉向与ICA呈直线，将栓线经CCA分叉处插入ICA。以CCA分叉处为标记，平均进线10±2mm，感到轻微阻力时，即达到大脑中动脉(MCA)的起始点处，停止进线，收紧ECA根部的活结，固定栓线。阻断MCA血液供应90min后，撤出栓线，结扎动脉残端，松开CCA上的活结，缝合皮肤，完成缺血再灌注损伤手术。假手术组只分离血管，不插入栓线。Anesthetize with 5% chloral hydrate (500 mg/kg, i.p.) to prepare the tMCAO model: the mice were fixed in a supine position on a constant temperature operating table at 37°C. An incision of about 1 cm was made in the middle of the neck to the right, and the muscle space between the sternocleidomastoid and sternohyoid muscles was bluntly separated, and the common carotid artery (CCA), internal carotid artery (ICA) and external carotid artery were exposed and separated. (ECA). A slip-knot was tied on the CCA, the distal end of the ECA was ligated, and a slip-knot was tied at its proximal end, and the ICA was clamped with an arterial clip. The branch vessels on the ECA were coagulated, a small incision was made at the distal end of the ECA (between the two knots), a nylon suture was slowly inserted through the incision to the proximal end of the ECA, and the slip knot at the proximal end of the ECA was slightly tied to prevent To prevent bleeding, loosen the arterial clip of the ICA, coagulate the distal end of the ECA (outside the distal node), pull the ECA to a straight line with the ICA, and insert the suture through the CCA bifurcation into the ICA. Taking the CCA bifurcation as the mark, the average insertion line is 10±2mm. When a slight resistance is felt, that is, the starting point of the middle cerebral artery (MCA) is reached. After blocking the blood supply of the MCA for 90 minutes, the suture was withdrawn, the arterial stump was ligated, the slip knot on the CCA was loosened, and the skin was sutured to complete the ischemia-reperfusion injury surgery. In the sham-operated group, only the blood vessels were separated and no suture was inserted.
再灌注24h后，用5％水合氯醛麻醉，用冷的生理盐水(NS)经左心房进行灌注，然后快速开颅取出全脑置于载玻片上，于-20℃冷冻20-25分钟。沿冠状面切片，切成均匀厚度的5片，置于盛有2ml 1％TTC溶液的培养皿中37℃避光孵育30分钟(15分钟翻面一次使其染色均匀)。染色结束后，将脑片置于4％多聚甲醛中4℃固定过夜。正常脑组织呈鲜红色，梗 死脑组织呈白色。用数码相机(PowerShot G12,Canon)照相后，利用photoshop软件测量各脑片梗死面积。根据以下公式算得梗死区域所占比例：{[梗死体积-(全脑体积–对侧半脑体积×2)]/对侧半脑体积}×100％。After 24 hours of reperfusion, the patients were anesthetized with 5% chloral hydrate, perfused with cold normal saline (NS) through the left atrium, and then rapidly removed by craniotomy and placed on a glass slide, frozen at -20°C for 20-25 minutes. Sectioned along the coronal plane, cut into 5 pieces of uniform thickness, placed in a petri dish containing 2ml of 1% TTC solution at 37°C and incubated in the dark for 30 minutes (flip once in 15 minutes to make the staining uniform). After staining, the brain slices were fixed in 4% paraformaldehyde at 4°C overnight. Normal brain tissue is bright red and infarcted brain tissue is white. After taking pictures with a digital camera (PowerShot G12, Canon), the infarct area of each brain slice was measured using photoshop software. The proportion of infarcted area was calculated according to the following formula: {[infarct volume-(whole brain volume-contralateral hemibrain volume×2)]/contralateral hemibrain volume}×100%.
三、实验结果3. Experimental results
结果如下表3所示，化合物12和化合物13在小鼠缺血性脑卒中tMCAO模型中能明显减少脑梗死体积，图1小鼠缺血-再灌注后24h时经TTC染色的代表性，两者都说明供试化合物起到脑保护用，是潜在的临床缺血性脑卒中的治疗药物。The results are shown in Table 3 below. Compound 12 and Compound 13 can significantly reduce the volume of cerebral infarction in the mouse ischemic stroke tMCAO model. Figure 1. Representative of TTC staining at 24h after ischemia-reperfusion in mice All of them indicated that the test compound can protect the brain and is a potential clinical drug for the treatment of ischemic stroke.
表3table 3
Figure PCTCN2021117535-appb-000026
Figure PCTCN2021117535-appb-000026
图2示出了短暂性大脑中动脉堵塞的小鼠再灌注后24h时经TTC染色的代表性脑片，白色区域表示梗死部分，红色区域表示存活的组织。结果说明供试化合物起到脑保护用，是潜在的临床缺血性脑卒中的治疗药物。Figure 2 shows representative brain slices stained with TTC at 24 h after reperfusion in mice with transient middle cerebral artery occlusion, with white areas representing infarcts and red areas representing viable tissue. The results indicated that the tested compounds play a role in brain protection and are potential therapeutic drugs for clinical ischemic stroke.
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims (12)

  1. 一种厚朴酚衍生物、和厚朴酚衍生物及其盐，具有如下式(I)所示结构，
    Figure PCTCN2021117535-appb-100001
    A magnolol derivative, a magnolol derivative and a salt thereof, having the structure shown in the following formula (I),
    Figure PCTCN2021117535-appb-100001
    其中，R 1和R 4分别独立的选自含有1～8个碳的烃基； wherein, R 1 and R 4 are independently selected from hydrocarbon groups containing 1 to 8 carbons;
    R 5为氨基酸、肽或具有1～8个碳的非氨基酸式的含氮酰基所修饰的氨基，所述氨基酸、所述肽或具有1～8个碳的非氨基酸式的含氮酰基中的可成盐氨基可以部分或全部为盐形式； R 5 is an amino acid, a peptide or an amino group modified by a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons, wherein the amino acid, the peptide or a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons The salt-formable amino group may be partially or completely in the form of a salt;
    当*所标记的苯环含有一个C14原子，R 2、R 3分别独立地为氢或羟基，且R 2、R 3不同时为氢或羟基； When the benzene ring marked by * contains a C14 atom, R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl;
    当*所标记的苯环为氘代标记物时，具有式(II)所示的结构，
    Figure PCTCN2021117535-appb-100002
    D为氘原子，R 2和R 3分别独立地为氘或羟基，且R 2、R 3不同时为氘或羟基；     When the benzene ring marked by * is a deuterated label, it has the structure shown in formula (II),
    Figure PCTCN2021117535-appb-100002
    D is a deuterium atom, R 2 and R 3 are independently deuterium or hydroxyl, and R 2 and R 3 are not simultaneously deuterium or hydroxyl;
    当*所标记的苯环不含标记原子时，R 1和R 4不同时为烯丙基，R 2和R 3分别独立地为氢或羟基，且R 2、R 3不同时为氢或羟基。 When the benzene ring marked by * does not contain marked atoms, R 1 and R 4 are not allyl at the same time, R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl .
  2. 根据权利要求1所述的厚朴酚衍生物、和厚朴酚衍生物及其盐，其特征在于，所述盐为厚朴酚衍生物、和厚朴酚衍生物的盐酸盐、富马酸盐、草酸盐或三氟乙酸盐。The honokiol derivative according to claim 1, and the honokiol derivative and salt thereof, wherein the salt is the honokiol derivative, and the hydrochloride of the honokiol derivative, fumaric acid salt, oxalate or trifluoroacetate.
  3. 根据权利要求1所述的厚朴酚衍生物、和厚朴酚衍生物及其盐，其特征在于，所述含有1～8个碳的烃基为烷基或烯基，优选为甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、丁-3烯基(烯丁基)、戊-1-烯基、戊-2-烯基、戊-3-烯基、戊-4-烯基(烯戊己)、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基、己-5-烯基(己烯基)、庚-1-烯基、庚-2-烯基、庚-3-烯基、庚-4-烯基、庚-5-烯基、庚-6-烯基(庚烯基)、辛1-烯基、辛-2-烯基、辛-3-烯基、辛-4-烯基、辛-5-烯基、辛-6-烯基或辛-7-烯基(辛烯基)。The magnolol derivative, magnolol derivative and salt thereof according to claim 1, wherein the hydrocarbon group containing 1 to 8 carbons is an alkyl group or an alkenyl group, preferably a methyl group, an ethyl group base, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, but-3-enyl (ene butyl), pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl (pentenyl), hex-1-enyl, hex-2-enyl , hex-3-enyl, hex-4-enyl, hex-5-enyl (hexenyl), hept-1-enyl, hept-2-enyl, hept-3-enyl, hept- 4-enyl, hept-5-enyl, hept-6-enyl (heptenyl), oct-1-enyl, oct-2-enyl, oct-3-enyl, oct-4-enyl , oct-5-enyl, oct-6-enyl or oct-7-enyl (octenyl).
  4. 根据权利要求1所述的厚朴酚衍生物、和厚朴酚衍生物及其盐，其特征在于，所述氨基酸为赖氨酸、蛋氨酸、色氨酸、缬氨酸、丙氨酸、苯丙氨酸、亮氨酸、异亮氨酸、甘氨酸、组氨酸、精氨酸、脯氨酸、谷氨酸、天冬氨酸、胱氨酸或半胱氨酸；所述肽由上述氨基酸组成，且分子量≤2500Da。The honokiol derivative, honokiol derivative and salt thereof according to claim 1, wherein the amino acid is lysine, methionine, tryptophan, valine, alanine, benzene Alanine, leucine, isoleucine, glycine, histidine, arginine, proline, glutamic acid, aspartic acid, cystine or cysteine; Amino acid composition, and molecular weight≤2500Da.
  5. 根据权利要求3所述的厚朴酚衍生物、和厚朴酚衍生物及其盐，其特征在于，所述厚朴酚衍生物、和厚朴酚衍生物及其盐为3'，5-二烯丙基-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-[1'-苯基-C14]联苯及其盐酸盐、3'，5-二烯丙基-2',5',6'-三氘-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-联苯及其盐酸盐、3'，5-二烯丙基-3-[(S)-2-氨基-4-甲硫基-1-丁酰]胺基-2，4'-二羟基-1，1'-[1'-苯基-C14]联苯及其盐酸盐、3'，5-二烯丙基-2',5',6'-三氘-3-[(S)-2-氨基-4-甲硫基-1-丁酰]胺基-2，4'-二羟基-1，1'-联苯及其盐酸盐或3'，5-二丙基-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-联苯及其盐酸盐。The honokiol derivative according to claim 3, and the honokiol derivative and salt thereof, wherein the honokiol derivative, the honokiol derivative and the salt thereof are 3',5- Diallyl-3-[(S)-2,6-diamino-1-hexanoyl]amino-2,4'-dihydroxy-1,1'-[1'-phenyl-C14]biphenyl Benzene and its hydrochloride, 3',5-diallyl-2',5',6'-trideutero-3-[(S)-2,6-diamino-1-hexanoyl]amino -2,4'-Dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5-diallyl-3-[(S)-2-amino-4-methylthio-1 -Butyryl]amino-2,4'-dihydroxy-1,1'-[1'-phenyl-C14]biphenyl and its hydrochloride, 3',5-diallyl-2', 5',6'-trideutero-3-[(S)-2-amino-4-methylthio-1-butyryl]amino-2,4'-dihydroxy-1,1'-biphenyl and Its hydrochloride or 3',5-dipropyl-3-[(S)-2,6-diamino-1-hexanoyl]amino-2,4'-dihydroxy-1,1'-bi Benzene and its hydrochloride.
  6. 厚朴酚衍生物、和厚朴酚衍生物及其盐在药物代谢研究中的应用，其中，所述厚朴酚衍生物、和厚朴酚衍生物及其盐具有如下式(I)所示结构，
    Figure PCTCN2021117535-appb-100003
    Application of honokiol derivatives, and honokiol derivatives and salts thereof in drug metabolism research, wherein the honokiol derivatives, honokiol derivatives and their salts have the following formula (I) structure,
    Figure PCTCN2021117535-appb-100003
    其中，R 1和R 4分别独立的选自含有1～8个碳的烃基； wherein, R 1 and R 4 are independently selected from hydrocarbon groups containing 1 to 8 carbons;
    R 5为氨基酸、肽或具有1～8个碳的非氨基酸式的含氮酰基所修饰的氨基，所述氨基酸、所述肽或具有1～8个碳的非氨基酸式的含氮酰基中的可成盐氨基可以部分或全部为盐形式； R 5 is an amino acid, a peptide or an amino group modified by a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons, wherein the amino acid, the peptide or a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons The salt-formable amino group may be partially or completely in the form of a salt;
    当*所标记的苯环含有一个C14原子，R 2、R 3分别独立地为氢或羟基，且R 2、R 3不同时为氢或羟基； When the benzene ring marked by * contains a C14 atom, R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl;
    当*所标记的苯环为氘代标记物时，具有式(II)所示的结构，
    Figure PCTCN2021117535-appb-100004
    D为氘原子，R 2和R 3分别独立地为氘或羟基，且R 2、R 3不同时为氘或羟基。     When the benzene ring marked by * is a deuterated label, it has the structure shown in formula (II),
    Figure PCTCN2021117535-appb-100004
    D is a deuterium atom, R 2 and R 3 are each independently deuterium or hydroxyl, and R 2 and R 3 are not simultaneously deuterium or hydroxyl.
  7. 根据权利要求6所述的应用，其特征在于，所述含有1～8个碳的烃基为烷基或烯基，优选为甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、丁-3烯基(烯丁基)、戊-1-烯基、戊-2-烯基、戊-3-烯基、戊-4-烯基(烯戊己)、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基、己-5-烯基(己烯基)、庚-1-烯基、庚-2-烯基、庚-3-烯基、庚-4-烯基、庚-5-烯基、庚-6-烯基(庚烯基)、辛1-烯基、辛-2-烯基、辛-3-烯基、辛-4-烯基、辛-5-烯基、辛-6-烯基或辛-7-烯基(辛烯基)。The application according to claim 6, wherein the hydrocarbon group containing 1 to 8 carbons is an alkyl group or an alkenyl group, preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, and a heptyl group. base, octyl, vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2 -alkenyl, pent-3-enyl, pent-4-enyl (enpenthexyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl , hex-5-enyl (hexenyl), hept-1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept- 6-enyl (heptenyl), oct-1-enyl, oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl or oct-7-enyl (octenyl).
  8. 根据权利要求6所述的应用，其特征在于，所述氨基酸为赖氨酸、蛋氨酸、色氨酸、缬氨酸、丙氨酸、苯丙氨酸、亮氨酸、异亮氨酸、甘氨酸、组氨酸、精氨酸、脯氨酸、谷氨酸、天冬氨酸、胱氨酸或半胱氨酸；所述肽由上述氨基酸组成，且分子量≤2500Da；The application according to claim 6, wherein the amino acid is lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, glycine , histidine, arginine, proline, glutamic acid, aspartic acid, cystine or cysteine; the peptide is composed of the above amino acids, and the molecular weight is less than or equal to 2500Da;
    优选的，所述厚朴酚衍生物、和厚朴酚衍生物及其盐为3'，5-二烯丙基-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-[1'-苯基-C14]联苯及其盐酸盐、3'，5-二烯丙基-2',5',6'-三氘-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-联苯及其盐酸盐、3'，5-二烯丙基-3-[(S)-2-氨基-4-甲硫基-1-丁酰]胺基-2，4'-二羟基-1，1'-[1'-苯基-C14]联苯及其盐酸盐和3'，5-二烯丙基-2',5',6'-三氘-3-[(S)-2-氨基-4-甲硫基-1-丁酰]胺基-2，4'-二羟基-1，1'-联苯及其盐酸盐。Preferably, the magnolol derivative, magnolol derivative and its salt are 3',5-diallyl-3-[(S)-2,6-diamino-1-hexanoyl] Amino-2,4'-dihydroxy-1,1'-[1'-phenyl-C14]biphenyl and its hydrochloride, 3',5-diallyl-2',5',6 '-Trideutero-3-[(S)-2,6-diamino-1-hexanoyl]amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3' , 5-Diallyl-3-[(S)-2-amino-4-methylthio-1-butyryl]amino-2,4'-dihydroxy-1,1'-[1'- Phenyl-C14]biphenyl and its hydrochloride and 3',5-diallyl-2',5',6'-trideutero-3-[(S)-2-amino-4-methylthio yl-1-butyryl]amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride.
  9. 厚朴酚衍生物、和厚朴酚衍生物及其盐在制备缺血性损伤中的脑保护的药物方面的应用，其中，所述厚朴酚衍生物、和厚朴酚衍生物及其盐具有如下式(I)所示结构，Use of honokiol derivatives, and honokiol derivatives and salts thereof in the preparation of medicaments for brain protection in ischemic injury, wherein the honokiol derivatives, and honokiol derivatives and salts thereof It has the structure shown in the following formula (I),
    Figure PCTCN2021117535-appb-100005
    Figure PCTCN2021117535-appb-100005
    其中，R 1和R 4分别独立的选自含有1～8个碳的烃基； wherein, R 1 and R 4 are independently selected from hydrocarbon groups containing 1 to 8 carbons;
    R 5为氨基酸、肽或具有1～8个碳的非氨基酸式的含氮酰基所修饰的氨基，所述氨基酸、所述肽或具有1～8个碳的非氨基酸式的含氮酰基中的可成盐氨基可以部分或全部为盐形式； R 5 is an amino acid, a peptide or an amino group modified by a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons, wherein the amino acid, the peptide or a nitrogen-containing acyl group with a non-amino acid formula of 1 to 8 carbons The salt-formable amino group may be partially or completely in the form of a salt;
    *所标记的苯环不含标记原子，R 2和R 3分别独立地为氢或羟基，且R 2、R 3不同时为氢或羟基； *The marked benzene ring does not contain marked atoms, R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl;
    优选的，所述含有1～8个碳的烃基为烷基或烯基，优选为甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、丁-3烯基(烯丁基)、戊-1-烯基、戊-2-烯基、戊-3-烯基、戊-4-烯基(烯戊己)、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基、己-5-烯基(己烯基)、庚-1-烯基、庚-2-烯基、庚-3-烯基、庚-4-烯基、庚-5-烯基、庚-6-烯基(庚烯基)、辛1-烯基、辛-2-烯基、辛-3-烯基、辛-4-烯基、辛-5-烯基、辛-6-烯基或辛-7-烯基(辛烯基)；Preferably, the hydrocarbon group containing 1 to 8 carbons is an alkyl group or an alkenyl group, preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a vinyl group, and a propenyl group , allyl, but-1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent-3-enyl , pent-4-enyl (pentenyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl (hexene base), hept-1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl (heptenyl), oct-1-enyl, oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl or oct-7-enyl (octene base);
    优选的，所述氨基酸为赖氨酸、蛋氨酸、色氨酸、缬氨酸、丙氨酸、苯丙氨酸、亮氨酸、异亮氨酸、甘氨酸、组氨酸、精氨酸、脯氨酸、谷氨酸、天冬氨酸、胱氨酸或半胱氨酸；所述肽由上述氨基酸组成，且分子量≤2500Da；Preferably, the amino acid is lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, glycine, histidine, arginine, pro amino acid, glutamic acid, aspartic acid, cystine or cysteine; the peptide is composed of the above amino acids, and the molecular weight is less than or equal to 2500Da;
    更优选的，所述厚朴酚衍生物、和厚朴酚衍生物及其盐为3'，5-二丙基-3-[(S)-2,6-二氨基-1-己酰]胺基-2，4'-二羟基-1，1'-联苯及其盐酸盐。More preferably, the magnolol derivative, magnolol derivative and its salt are 3',5-dipropyl-3-[(S)-2,6-diamino-1-hexanoyl] Amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride.
  10. 一种权利要求1至6中任一项所述的厚朴酚衍生物、和厚朴酚衍生物及其盐的制备方法，其特征在于，包括以下步骤：A preparation method of magnolol derivative described in any one of claim 1 to 6 and magnolol derivative and salt thereof, is characterized in that, comprises the following steps:
    制备具有式(III)的化合物
    Figure PCTCN2021117535-appb-100006
    其中，R 1选自含有1～8个碳的烃基，优选自甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、丁-3烯基(烯丁基)、戊-1-烯基、戊-2-烯基、戊-3-烯基、戊-4-烯基(烯戊己)、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基、己-5-烯基(己烯基)、庚-1-烯基、庚-2-烯基、庚-3-烯基、庚-4-烯基、庚-5-烯基、庚-6-烯基(庚烯基)、辛1-烯基、辛-2-烯基、辛-3-烯基、辛-4-烯基、辛-5-烯基、辛-6-烯基或辛-7-烯基(辛烯基)，R 5为氨基酸、肽或具1～8个碳的非氨基酸式的含氮酰基所修饰的氨基，所述氨基酸、所述肽或具1～8个碳的非氨基酸式的含氮酰基中的氨基全部用叔丁氧羰基保护；     Preparation of compounds of formula (III)
    Figure PCTCN2021117535-appb-100006
    Wherein, R 1 is selected from hydrocarbon groups containing 1 to 8 carbons, preferably from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, But-1-enyl, but-2-enyl, but-3-enyl (alkenyl), pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4- Alkenyl (enpenthexyl), hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl (hexenyl), hept- 1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl (heptenyl), oct-1-enyl , oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl or oct-7-enyl (octenyl), R 5 Amino group modified by amino acid, peptide or nitrogen-containing acyl group of non-amino acid formula with 1 to 8 carbons, all amino groups in said amino acid, said peptide or nitrogen-containing acyl group of non-amino acid formula with 1 to 8 carbons Protected with tert-butoxycarbonyl;
    制备具有式(IV)的化合物
    Figure PCTCN2021117535-appb-100007
    其中，R 4选自含有1～8个碳的烃基；当*所标记的苯环含有一个C14原子时，R 2、R 3分别独立地为氢或羟基，且R 2、R 3不同时为氢或羟基；当*所标记的苯环为氘代标记物时，具有式(V)所示的结构
    Figure PCTCN2021117535-appb-100008
    D为氘原子，R 2、R 3分别独立地为氘或羟基，且R 2、R 3不同时为氘或羟基；当*所标记的苯环不含标记原子时，R 2和R 3分别独立地为氢或羟基，且R 2、R 3不同时为氢或羟基；     Preparation of compounds of formula (IV)
    Figure PCTCN2021117535-appb-100007
    Wherein, R 4 is selected from hydrocarbon groups containing 1 to 8 carbons; when the benzene ring marked by * contains one C14 atom, R 2 and R 3 are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously Hydrogen or hydroxyl; when the benzene ring marked by * is a deuterated label, it has the structure shown in formula (V)
    Figure PCTCN2021117535-appb-100008
    D is a deuterium atom, R 2 and R 3 are independently deuterium or hydroxyl, and R 2 and R 3 are not both deuterium or hydroxyl; when the benzene ring marked by * does not contain a marked atom, R 2 and R 3 are respectively are independently hydrogen or hydroxyl, and R 2 and R 3 are not simultaneously hydrogen or hydroxyl;
    具有式(III)的化合物与具有式(IV)的化合物通过Suzuki反应形成得到式1化合物，其中，所用到的氨基酸、肽或具有1～8个碳的非氨基酸式的含氮酰基用叔丁氧羰基保护。The compound of formula (III) and the compound of formula (IV) are formed by Suzuki reaction to obtain the compound of formula 1, wherein the amino acid, peptide or nitrogen-containing acyl group of non-amino acid formula with 1 to 8 carbons used is tert-butyl Oxycarbonyl protection.
  11. 根据权利要求10所述的制备方法，其特征在于，所述制备方法的具体合成线路图如下：The preparation method according to claim 10, wherein the specific synthesis circuit diagram of the preparation method is as follows:
    Figure PCTCN2021117535-appb-100009
    Figure PCTCN2021117535-appb-100009
  12. 一种抗脑缺血损伤的药物组合物，其特征在于，所述药物组合物由有效量的如权利要求1至5中任一项所述的厚朴酚衍生物、和厚朴酚衍生物及其盐和在药学上可接受的载体和/或赋型剂组成。A pharmaceutical composition against cerebral ischemia injury, characterized in that, the pharmaceutical composition is composed of an effective amount of the honokiol derivative as described in any one of claims 1 to 5, and the honokiol derivative and its salts and pharmaceutically acceptable carriers and/or excipients.
PCT/CN2021/117535 2020-09-11 2021-09-09 Magnolol derivative, magnolol derivative and salts thereof, preparation method therefor and use thereof WO2022052998A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010955391.8A CN112321452B (en) 2020-09-11 2020-09-11 Magnolol derivative, honokiol derivative and hydrochloride thereof, preparation method and application
CN202010955391.8 2020-09-11

Publications (1)

Publication Number Publication Date
WO2022052998A1 true WO2022052998A1 (en) 2022-03-17

Family

ID=74303849

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/117535 WO2022052998A1 (en) 2020-09-11 2021-09-09 Magnolol derivative, magnolol derivative and salts thereof, preparation method therefor and use thereof

Country Status (2)

Country Link
CN (1) CN112321452B (en)
WO (1) WO2022052998A1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112321452B (en) * 2020-09-11 2022-11-29 北京红惠新医药科技有限公司 Magnolol derivative, honokiol derivative and hydrochloride thereof, preparation method and application
CN116139115A (en) * 2021-11-19 2023-05-23 北京红惠新医药科技有限公司 Application of magnolol and/or honokiol aromatic ring amino substituted derivatives in resisting hypoxia/anoxia injury and pharmaceutical composition

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1215990A (en) * 1995-02-17 1999-05-05 史密丝克莱恩比彻姆公司 IL-8 receptor antagonists
CN103113264A (en) * 2013-01-22 2013-05-22 北京红惠新医药科技有限公司 Magnolol derivative, honokiol derivative and preparation method and application thereof
CN110343033A (en) * 2018-04-02 2019-10-18 四川大学 Magnolol series derivates and its preparation method and application
CN112321452A (en) * 2020-09-11 2021-02-05 北京红惠新医药科技有限公司 Magnolol derivative, honokiol derivative and hydrochloride thereof, preparation method and application

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100892596B1 (en) * 2007-02-12 2009-04-09 바이오스펙트럼 주식회사 Biphenyl Diol Derivatives and Compositions Comprising the Same as an Active Ingredient

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1215990A (en) * 1995-02-17 1999-05-05 史密丝克莱恩比彻姆公司 IL-8 receptor antagonists
CN103113264A (en) * 2013-01-22 2013-05-22 北京红惠新医药科技有限公司 Magnolol derivative, honokiol derivative and preparation method and application thereof
CN110343033A (en) * 2018-04-02 2019-10-18 四川大学 Magnolol series derivates and its preparation method and application
CN112321452A (en) * 2020-09-11 2021-02-05 北京红惠新医药科技有限公司 Magnolol derivative, honokiol derivative and hydrochloride thereof, preparation method and application

Also Published As

Publication number Publication date
CN112321452B (en) 2022-11-29
CN112321452A (en) 2021-02-05

Similar Documents

Publication Publication Date Title
WO2022052998A1 (en) Magnolol derivative, magnolol derivative and salts thereof, preparation method therefor and use thereof
CN103113264B (en) Magnolol derivative, honokiol derivative and preparation method and application thereof
KR100900179B1 (en) Geranyl compounds
JPH06509335A (en) Acylmercaptoalkanoyl dipeptides, their production methods and their therapeutic uses
WO2023165015A1 (en) Near-infrared fluorescent probe specifically targeting tumor, synthesis method therefor, and use thereof
JPS6340199B2 (en)
WO1991016338A1 (en) S-(lower fatty acid)-substituted glutathione derivative
CN108727208B (en) Linker compound, polyethylene glycol-linker conjugate and derivative thereof, and polyethylene glycol-linker-drug conjugate
WO2020228789A1 (en) 3-aryloxyl-3-five-membered heteroaryl propylamine compound, and crystal form and use thereof
JP5279021B2 (en) Novel compound having GPR54 agonist activity
JP5958948B1 (en) p21-activated kinase inhibitor
JPS63233999A (en) Novel cystine compound, and its production and use
US20070048252A1 (en) Conjugates of the hydrophilic polymer and the molecules from boxwood extraction, and pharmaceutical compositions of the conjugates
WO2015096725A1 (en) Linear lipopeptide with end group having lipophilic structure, preparation method for the lopopeptide, and use thereof
JP4467985B2 (en) Novel opioid derivatives
CA3202303A1 (en) Trop2 targeting antibody-drug conjugate, and preparation method and use therefor
WO2024012157A1 (en) Polypeptide compound, and complex and use thereof
Dahiya et al. Synthesis and anthelmintic potential of a novel series of 2-mercaptobenzimidazolopeptides
CN107540725B (en) Water-soluble tanshinone IIA derivative and preparation and application thereof
WO2020249139A1 (en) Potassium salt crystal form b of phosphodiesterase type 5 inhibitor, and preparation method and use therefor
WO2023088062A1 (en) Anti-hypoxic/anoxic injury use of magnolol and/or honokiol aromatic ring amino-substituted derivative, and pharmaceutical composition
WO2024141104A1 (en) New pyridazine compound, and pharmaceutical composition and use thereof
CN115581690A (en) Application of magnolol or aromatic ring amino substituted derivative of honokiol in preparation of anti-myocardial ischemia drugs and pharmaceutical composition
CN107459556B (en) L-vitamin C-2-oxyacetyl-PAKPAK, its synthesis, activity and application
CN107459553B (en) Levovitamin C-2-oxyacetyl-PAK, its synthesis, activity and application

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21866050

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21866050

Country of ref document: EP

Kind code of ref document: A1