CN112321452A - Magnolol derivative, honokiol derivative and hydrochloride thereof, preparation method and application - Google Patents

Magnolol derivative, honokiol derivative and hydrochloride thereof, preparation method and application Download PDF

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CN112321452A
CN112321452A CN202010955391.8A CN202010955391A CN112321452A CN 112321452 A CN112321452 A CN 112321452A CN 202010955391 A CN202010955391 A CN 202010955391A CN 112321452 A CN112321452 A CN 112321452A
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张平平
刘晔
于国坤
赵强峰
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Beijing Honghui Meditech Co ltd
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Abstract

The invention discloses a magnolol derivative, a honokiol derivative, a hydrochloride thereof, a preparation method and an application. The magnolol derivative, the honokiol derivative and the hydrochloride thereof have the structures shown as the following formula (I),
Figure DDA0002678412860000011
the magnolol derivative, the honokiol derivative and the hydrochloride thereof are prepared in a modularized mode by using a chemical synthesis method, and the magnolol derivative, the hydrochloride thereof and the C14 atomic marker and the D atomic marker can be used for drug metabolism research of the magnolol derivative, the honokiol derivative and the hydrochloride thereof. Wherein C14 is utilizedThe labeling technical substance can well solve the problem caused by low drug recovery rate in the traditional drug metabolism experiment, and conveniently clarify the processes related to absorption, distribution, metabolism and excretion of the drugs in vivo.

Description

Magnolol derivative, honokiol derivative and hydrochloride thereof, preparation method and application
Technical Field
The invention relates to the technical field of biological medicines, and particularly relates to a magnolol derivative, a honokiol derivative and hydrochloride thereof, and a preparation method and application of the magnolol derivative and the hydrochloride thereof.
Background
Magnolol
Figure BDA0002678412840000011
And honokiol
Figure BDA0002678412840000012
Is the main active ingredient of the traditional Chinese medicine magnolia officinalis. In 1930, magnolol (Chinese herbal medicine; 2005, 36,10, 1591-. Honolizhen et al, China in 1989, also isolated honokiol from Magnolia officinalis (Chinese patent medicine: 1989,11 (8): 223.).
Magnolol and honokiol have wide pharmacological actions such as antibiosis, anti-inflammation, anti-tumor, muscle relaxation, cholesterol reduction and anti-aging (Chinese herbal medicine; 2005, 36,10, 1591-. Later the water solubility of magnolol and honokiol was improved by chemical derivatization (CN103113264B), which gives a laboratory preparation of water soluble magnolol derivatives and honokiol derivatives. However, the traditional pharmacokinetic research of the medicines shows that the medicines have high metabolic speed and low recovery rate, and are not beneficial to scientific researchers to fully understand the whole process of absorption, distribution, metabolism and excretion of the medicines in vivo.
Disclosure of Invention
The invention aims to provide a magnolol derivative, a honokiol derivative and a hydrochloride thereof, and a preparation method and application thereof, so as to solve the technical problem that the whole process of absorption, distribution, metabolism and excretion of the magnolol derivative, the honokiol derivative and the hydrochloride thereof in a body is difficult to monitor in the prior art.
To achieve the above object, according to one aspect of the present invention, there is provided a magnolol derivative, and a honokiol derivativeThe compound and the hydrochloride thereof have the structure shown as the following formula (I),
Figure BDA0002678412840000021
wherein R is1And R4Each independently selected from alkyl containing 1-8 carbon atoms or N, O, S heteroatom substituted alkyl;
R5amino modified by amino acid, peptide or non-amino acid-like nitrogen-containing acyl with 1-8 carbons, wherein part or all of salifiable amino groups in the amino acid, the peptide or the non-amino acid-like nitrogen-containing acyl with 1-8 carbons can be in the form of hydrochloride;
when the phenyl ring contains a C14 atom, R2、R3Each independently is hydrogen or hydroxy, and R2、R3Not hydrogen or hydroxyl at the same time;
or when the benzene ring marked by the mark is a deuterated marker, the structure is shown as a formula (II),
Figure BDA0002678412840000022
formula (II), D is a deuterium atom, R2And R3Each independently is deuterium or hydroxy, and R2、R3Is not deuterium or hydroxyl at the same time;
when the marked benzene ring does not contain a marker atom, R1And R4Not simultaneously allyl, R2 and R3 are each independently hydrogen or hydroxy, and R2、R3Not hydrogen or hydroxyl at the same time.
Further, the hydrocarbyl group containing 1-8 carbons or the N, O, S heteroatom-substituted hydrocarbyl group is an alkyl group or an alkenyl group, preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, a vinyl group, an allyl group, a butenyl group, a pentenyl group or a hexenyl group.
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 consists of the amino acids and has a molecular weight of less than or equal to 2500 Da.
Further, the magnolol derivative, honokiol derivative, and hydrochloride thereof are preferably 3', 5-diallyl-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1' - [1' -phenyl-C14 ] biphenyl hydrochloride, 3', 5-diallyl-2 ',5',6' -tridehydro-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1' -biphenyl hydrochloride, 3', 5-diallyl-3- [ (S) -2-amino-4-methylthio-1-butanoyl ] amino-2, 4 '-dihydroxy-1, 1' - [1 '-phenyl-C14 ] biphenyl-hydrochloride, 3', 5-diallyl-2 ',5',6 '-trideuterio-3- [ (S) -2-amino-4-methylsulfanyl-1-butyryl ] amino-2, 4' -dihydroxy-1, 1 '-biphenyl-hydrochloride and 3', 5-dipropyl-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4 '-dihydroxy-1, 1' -biphenyl-hydrochloride.
According to another aspect of the present invention, there is provided a magnolol derivative, a honokiol derivative, and a hydrochloride thereof, which are useful in drug metabolism research, wherein the magnolol derivative, the honokiol derivative, and the hydrochloride thereof have the structure shown in the following formula (I),
Figure BDA0002678412840000031
wherein R is1And R4Each independently selected from alkyl containing 1-8 carbon atoms or N, O, S heteroatom substituted alkyl; (ii) a
R5Amino modified by amino acid, peptide or non-amino acid nitrogen-containing acyl containing 1-8 carbon atoms, wherein part or all of salifiable amino in the amino acid, peptide or non-amino acid nitrogen-containing acyl containing 1-8 carbon atoms can be in a hydrochloride form;
when the phenyl ring contains a C14 atom, R2、R3Each independently is hydrogen or hydroxy, and R2、R3Not hydrogen or hydroxyl at the same time;
or when the benzene ring marked by the mark is a deuterated marker, the structure is shown as a formula (II),
Figure BDA0002678412840000041
formula (II), D is a deuterium atomR2 and R3 are each independently deuterium or hydroxy, and R2、R3Not deuterium or hydroxyl at the same time.
Further, the hydrocarbyl group containing 1-8 carbons or the N, O, S heteroatom-substituted hydrocarbyl group is an alkyl group or an alkenyl group, preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, a vinyl group, an allyl group, a butenyl group, a pentenyl group or a hexenyl group.
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 consists of the amino acids and has a molecular weight of less than or equal to 2500 Da.
Further, magnolol derivatives, honokiol derivatives and hydrochloride thereof are 3', 5-diallyl-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1' - [1' -phenyl-C14 ] biphenyl hydrochloride, 3', 5-diallyl-2 ',5',6' -tridedeuterium-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1' -biphenyl hydrochloride, 3', 5-diallyl-3- [ (S) -2-amino-4-methylthio-1-butyryl ] amino-2, 4' -dihydroxy-1, 1' - [1' -phenyl-C14 ] biphenyl hydrochloride and 3', 5-diallyl-2 ',5',6' -tridedeuterium-3- [ (S) -2-amino-4-methylsulfanyl-1-butyryl ] amino-2, 4' -dihydroxy-1, 1' -biphenyl hydrochloride.
According to a further aspect of the present invention there is provided a magnolol derivative, a honokiol derivative and a use of its hydrochloride salt for cerebral protection in ischemic injury. Wherein the magnolol derivative, the honokiol derivative and the hydrochloride thereof have the structures shown as the following formula (I),
Figure BDA0002678412840000051
wherein R is1And R4Each independently selected from alkyl containing 1-8 carbon atoms or N, O, S heteroatom substituted alkyl;
R5is an amino acid, a peptide or a non-amino group having 1 to 8 carbon atomsAmino modified by acid-like nitrogenous acyl, wherein part or all of salifiable amino in the amino acid, the peptide or the non-amino acid-like nitrogenous acyl with 1-8 carbons can be in the form of hydrochloride;
the benzene ring marked by R is free of marking atoms2And R3Each independently is hydrogen or hydroxy, and R2、R3Not hydrogen or hydroxyl at the same time;
further, the hydrocarbyl group containing 1-8 carbons or the N, O, S heteroatom-substituted hydrocarbyl group is an alkyl group or an alkenyl group, preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, a vinyl group, an allyl group, a butenyl group, a pentenyl group or a hexenyl group.
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 consists of the amino acids and has a molecular weight of less than or equal to 2500 Da.
Further, magnolol derivative, honokiol derivative, and its hydrochloride were 3', 5-dipropyl-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1'- [1' -phenyl-C14 ] biphenyl hydrochloride.
According to another aspect of the present invention, there is provided a method for preparing the above magnolol derivative, honokiol derivative and hydrochloride thereof. The preparation method comprises the following steps:
preparation of a Compound having formula (III)
Figure BDA0002678412840000052
Wherein R is1Selected from hydrocarbyl containing 1-8 carbon atoms or N, O, S heteroatom substituted hydrocarbyl, preferably alkyl or alkenyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, allyl, butenyl, pentenyl or hexenyl, R5Amino group modified by nitrogen-containing acyl group of amino acid, peptide or non-amino acid with 1-8 carbon atomsProtecting all amino groups in non-amino acid nitrogen-containing acyl groups with 1-8 carbon atoms by using tert-butyloxycarbonyl;
preparation of a Compound having formula (IV)
Figure BDA0002678412840000061
Wherein R is4Selected from an electron-donating substituent alkyl group containing 1-8 carbons or an N, O, S heteroatom substituted alkyl group; when the phenyl ring marked contains one C14 atom, R2、R3Each independently is hydrogen or hydroxy, and R2、R3Not hydrogen or hydroxyl at the same time; when the benzene ring marked by the mark is a deuterated marker, the structure has a structure shown in a formula (V)
Figure BDA0002678412840000062
D is a deuterium atom, R2、R3Each independently is deuterium or hydroxy, and R2、R3Is not deuterium or hydroxyl at the same time; when the phenyl ring is not containing a labelling atom, R2 and R3 are each independently hydrogen or hydroxy, and R2、R3Not hydrogen or hydroxyl at the same time;
the compound with the formula (III) and the compound with the formula (IV) are subjected to a Suzuki reaction to form the compound with the formula 1, wherein the amino acid, the peptide or the non-amino acid nitrogen-containing acyl with 1-8 carbons is protected by tert-butyloxycarbonyl.
Further, the specific synthetic route of the preparation method is as follows:
Figure BDA0002678412840000071
according to another aspect of the present invention, there is provided a pharmaceutical composition for treating cerebral ischemic injury. The pharmaceutical composition comprises an effective amount of the magnolol derivative, the honokiol derivative and the hydrochloride thereof, and a pharmaceutically acceptable carrier and/or excipient.
By applying the technical scheme of the invention, the magnolol derivative, the honokiol derivative and the hydrochloride carbon 14 marker and the deuterium marker thereof are prepared in a modularized manner by using a chemical synthesis method, and the magnolol derivative, the honokiol derivative and the hydrochloride thereof can be used for drug metabolism research. The C14 labeled technical material can be used for well solving the problem caused by low drug recovery rate in the traditional drug metabolism experiment, conveniently clarifying the processes related to absorption, distribution, metabolism and excretion of the drugs in vivo, and the radiolabeled-free magnolol derivative, the honokiol derivative and the hydrochloride thereof have excellent protective effect on cerebral ischemic injury.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate exemplary embodiments of the invention and, together with the description, serve to explain the invention and are not intended to limit the invention. In the drawings:
figure 1 shows a graph of the plasma levels of the drug in example 12 over time.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail below with reference to the embodiments with reference to the attached drawings.
The abbreviated terms referred to in the present invention:
EA: ethyl acetate
Hexane: n-hexane
MeOH: methanol
DCM: methylene dichloride
TLC thin layer chromatography
According to a typical embodiment of the present invention, there is provided a magnolol derivative, a honokiol derivative and a hydrochloride thereof, having a structure represented by the following formula (I),
Figure BDA0002678412840000081
wherein R is1And R4Selected from a C1-8 hydrocarbon group or an N, O, S hetero atom-substituted hydrocarbon group (N, O, S hetero atom-substituted hydrocarbon group is exemplified by-CH)2CH2OCH3，-CH2CH2SMe，-CH2CH2NMe2)；。
R5Amino modified by amino acid, peptide or non-amino acid-like nitrogen-containing acyl with 1-8 carbons, wherein part or all of salifiable amino groups in the amino acid, the peptide or the non-amino acid-like nitrogen-containing acyl with 1-8 carbons can be in the form of hydrochloride; other compounds containing 1 to 8 carbon atoms and both an acyl group and an amino group, in addition to the amino acid, are referred to as "non-amino acid-like nitrogen-containing acyl group containing 1 to 8 carbon atoms" in the present invention, and include, for example: NH (NH)2-CH2-CH2-O-CH2-CH2COOH。
When the phenyl ring marked by contains one C14 atom, R2、R3Each independently is hydrogen or hydroxy, and R2、R3When not all are hydrogen or hydroxy;
when the benzene ring marked by the mark is a deuterated marker, the structure has a structure shown in a formula (II),
Figure BDA0002678412840000091
formula (II), D is a deuterium atom, R2、R3Each independently is deuterium or hydroxy, and R2、R3Is not deuterium or hydroxyl at the same time; when the marked benzene ring does not contain a marker atom, R1And R4Not simultaneously allyl, R2 and R3 are each independently hydrogen or hydroxy, and R2、R3Not hydrogen or hydroxyl at the same time.
By applying the technical scheme of the invention, the magnolol derivative, the honokiol derivative and the hydrochloride carbon 14 marker and the deuterium marker thereof are prepared in a modularized manner by using a chemical synthesis method, and the magnolol derivative, the honokiol derivative and the hydrochloride thereof can be used for drug metabolism research. The C14 labeled technical material can be used for solving the problem caused by low drug recovery rate in the traditional drug metabolism experiment, and conveniently clarifying the processes related to absorption, distribution, metabolism and excretion of the drug in vivo.
Preferably, the hydrocarbyl or N, O, S heteroatom-substituted hydrocarbyl containing 1-8 carbons is an alkyl or alkenyl group; preferably from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, allyl, butenyl, pentenyl or hexenyl. In a typical embodiment of the 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 amino acids and has a molecular weight of less than or equal to 2500 Da. These are all amino acids contained in the human body, and play an important regulatory role in life activities. Preferably, the magnolol derivative, honokiol derivative and its hydrochloride are 3', 5-diallyl-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1' - [1' -phenyl-C14 ] biphenyl hydrochloride, 3', 5-diallyl-2 ',5',6' -trideutero-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1' -biphenyl hydrochloride, 3', 5-diallyl-3- [ (S) -2-amino-4-methylthio-1-butanoyl ] amino-2, 4 '-dihydroxy-1, 1' - [1 '-phenyl-C14 ] biphenyl-hydrochloride, 3', 5-diallyl-2 ',5',6 '-trideuterio-3- [ (S) -2-amino-4-methylsulfanyl-1-butyryl ] amino-2, 4' -dihydroxy-1, 1 '-biphenyl-hydrochloride and 3', 5-dipropyl-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4 '-dihydroxy-1, 1' -biphenyl-hydrochloride. The magnolol derivative, the honokiol derivative and the hydrochloride thereof can enhance the traceability in drug metabolism, for example, C14 has radioactivity, and the radioactive tracing technology can be used for detecting the treatment process of the drug in vivo, which cannot be realized by the traditional mass spectrometry. The labeled compound (for example, the magnolol derivative labeled with C14 or deuterium, the honokiol derivative and the hydrochloride thereof) is important for determining the drug metabolism process of the magnolol derivative, the honokiol derivative and the hydrochloride thereof, but generally, the synthetic raw materials of the labeled compound are expensive and not easy to obtain, so that the development of the labeled compound into a therapeutic drug is obviously too high in cost; in contrast, the non-labeled compound has simple and easily available synthetic raw materials and is easy to develop into a therapeutic drug; the non-labeled magnolol derivative, the honokiol derivative and the hydrochloride thereof have an obvious brain protection effect in ischemic injury, and the corresponding labeled compound can be used for explaining the metabolic processes of the non-labeled magnolol derivative, the honokiol derivative and the hydrochloride thereof, and the two supplement each other, so that the discovery of ischemic brain protection medicines is facilitated.
According to a typical embodiment of the invention, the application of magnolol derivative, honokiol derivative and hydrochloride thereof in drug metabolism research is provided, wherein the magnolol derivative, the honokiol derivative and the hydrochloride thereof have the structures shown as the following formula (I),
Figure BDA0002678412840000101
wherein R is1And R4Each independently selected from alkyl containing 1-8 carbon atoms or N, O, S heteroatom substituted alkyl;
R5the amino acid is an amino acid, a peptide or an amino acid modified by a non-amino acid-like nitrogen-containing acyl group with 1-8 carbons, wherein part or all of salifiable amino groups in the amino acid, the peptide or the non-amino acid-like nitrogen-containing acyl group with 1-8 carbons can be in the form of hydrochloride;
when the phenyl ring contains a C14 atom, R2、R3Each independently is hydrogen or hydroxy, and R2、R3Not hydrogen or hydroxyl at the same time;
or when the benzene ring marked by the mark is a deuterated marker, the structure is shown as a formula (II),
Figure BDA0002678412840000102
formula (II), D is a deuterium atom, R2 and R3 are each independently deuterium or hydroxy, and R2、R3Not deuterium or hydroxyl at the same time.
Further, the hydrocarbyl group containing 1-8 carbons or the N, O, S heteroatom-substituted hydrocarbyl group is an alkyl group or an alkenyl group, preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, a vinyl group, an allyl group, a butenyl group, a pentenyl group or a hexenyl group. 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 consists of the amino acids and has a molecular weight of less than or equal to 2500 Da.
Further, the magnolol derivative, honokiol derivative, and hydrochloride thereof are preferably 3', 5-diallyl-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1' - [1' -phenyl-C14 ] biphenyl hydrochloride, 3', 5-diallyl-2 ',5',6' -tridehydro-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1' -biphenyl hydrochloride, 3', 5-diallyl-3- [ (S) -2-amino-4-methylthio-1-butanoyl ] amino-2, 4' -dihydroxy-1, 1' - [1' -phenyl-C14 ] biphenyl hydrochloride and 3', 5-diallyl-2 ',5',6' -tridedeuterium-3- [ (S) -2-amino-4-methylsulfanyl-1-butyryl ] amino-2, 4' -dihydroxy-1, 1' -biphenyl hydrochloride.
According to a further aspect of the present invention there is provided a magnolol derivative, a honokiol derivative and a use of its hydrochloride salt for cerebral protection in ischemic injury. Wherein the magnolol derivative, the honokiol derivative and the hydrochloride thereof have the structures shown as the following formula (I),
Figure BDA0002678412840000111
wherein R is1And R4Each independently selected from alkyl containing 1-8 carbon atoms or N, O, S heteroatom substituted alkyl;
R5amino modified by amino acid, peptide or non-amino acid-like nitrogen-containing acyl with 1-8 carbons, wherein part or all of salifiable amino groups in the amino acid, the peptide or the non-amino acid-like nitrogen-containing acyl with 1-8 carbons can be in the form of hydrochloride;
the benzene ring marked by R is free of marking atoms2And R3Each independently is hydrogen or hydroxy, and R2、R3Not hydrogen or hydroxyl at the same time;
preferably, the hydrocarbyl group containing 1 to 8 carbons or the N, O, S heteroatom-substituted hydrocarbyl group is an alkyl group or an alkenyl group, preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, a vinyl group, an allyl group, a butenyl group, a pentenyl group or a hexenyl group.
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 consists of the amino acids and has a molecular weight of less than or equal to 2500 Da.
More preferably, magnolol derivative, honokiol derivative, and its hydrochloride are 3', 5-dipropyl-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1'- [1' -phenyl-C14 ] biphenyl hydrochloride.
According to a typical embodiment of the present invention, there is provided a method for preparing the above magnolol derivative, honokiol derivative and hydrochloride thereof. The preparation method comprises the following steps:
preparation of a Compound having formula (III)
Figure BDA0002678412840000121
Wherein R is1Is a C1-8 hydrocarbon group or a N, O, S hetero atom-substituted hydrocarbon group, preferably selected from a C1-8 alkyl group or a C1-8 alkenyl group such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, a vinyl group, an allyl group, a butenyl group, a pentenyl group or a hexenyl group, R5Amino modified by amino acid, peptide or non-amino acid-like nitrogen-containing acyl containing 1-8 carbon atoms, wherein all amino groups in the amino acid, peptide or non-amino acid-like nitrogen-containing acyl containing 1-8 carbon atoms are protected by tert-butyloxycarbonyl;
preparation of a Compound having formula (IV)
Figure BDA0002678412840000122
Wherein R is4Is a C1-8 hydrocarbon group or an N, O, S hetero atom-substituted hydrocarbon group, preferably selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, and,An alkyl group having 1 to 8 carbon atoms such as an allyl group, butenyl group, pentenyl group or hexenyl group, or an alkenyl group having 1 to 8 carbon atoms; when the phenyl ring marked by contains one C14 atom, R2、R3Each independently is hydrogen or hydroxy, and R2、R3Not hydrogen or hydroxyl at the same time; when the benzene ring marked by the mark is a deuterated marker, the structure has a structure shown in a formula (V)
Figure BDA0002678412840000131
D is a deuterium atom, R2、R3Each independently is deuterium or hydroxy, and R2、 R3Is not deuterium or hydroxyl at the same time; when the marked benzene ring does not contain a marker atom, R2And R3Each independently is hydrogen or hydroxy, and R2、R3Not hydrogen or hydroxyl at the same time;
the compound of formula (III) is reacted with a compound of formula (IV) by Suzuki reaction to form the compound of formula 1, wherein the amino acid or peptide used is protected with t-butyloxycarbonyl.
Preferably, the specific synthetic route of the preparation method is as follows:
Figure BDA0002678412840000132
the following examples are provided to further illustrate the advantageous effects of the present invention.
Example 1
Preparation of 2-allyl-4-bromophenol (Compound 1)
P-bromophenol (17.2g, 100mmol) was charged into a 500ml single-neck flask, acetone (180 ml) was added, stirring was conducted, anhydrous potassium carbonate (89.7g, 650mmol) and 3-bromopropene (24.2g, 200mmol) were added, and the reaction was refluxed overnight. The reaction mixture was evaporated to dryness, 250ml of water was added, the aqueous phase was extracted twice with 250ml of n-hexane, the n-hexane phases were combined, washed with 100ml of 10% aqueous sodium hydroxide solution, 100ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. Evaporating the organic phase to dryness, placing the residue in an oil bath at 200 ℃, heating for 4h, and cooling to room temperature. 180ml of a 10% aqueous solution of sodium hydroxide was added to the reaction mixture, and the aqueous solution was washed with n-hexane to collect the aqueous phase. The aqueous phase is adjusted to pH 6-7 with 4N hydrochloric acid and extracted with 180ml of dichloromethane. The organic phase was washed with 100ml of saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated to dryness and the residue was subjected to column chromatography to give a pale yellow oil (11g, yield 51%).
Compound 1:1H-NMR(400MHz，CDCl3)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)
example 2
Preparation of 2-allyl-4-bromophenol-D4 (Compound 2)
p-bromophenol-D4 (2.05g, 12mmol) was charged in a 50ml single-neck flask, acetone 25ml was added, stirring was conducted, anhydrous potassium carbonate (10.4g, 75mmol) and 3-bromopropene (2.8g, 24mmol) were added, and the mixture was heated under reflux for 3 hours. Evaporating the reaction solution to dryness, adding 50ml of water, extracting twice with n-hexane 10ml x2, combining organic phases, washing with 10% sodium hydroxide aqueous solution 25ml x2, washing with saturated sodium chloride aqueous solution 50ml, drying with anhydrous sodium sulfate, filtering, evaporating the organic phase to dryness, placing in an oil bath at 200 ℃, heating for 4h, and cooling to room temperature. 180ml of a 10% aqueous solution of sodium hydroxide was added to the reaction mixture, and the aqueous solution was washed with n-hexane to collect the aqueous phase. The aqueous phase is adjusted to pH 6-7 with 4N hydrochloric acid and extracted with 180ml of dichloromethane. The organic phase was washed with 100ml 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 give a pale yellow oil (0.63g, yield 25%).
Compound 1: c9H6D3BrO 216.0MS:214 and 216[ M-H [ ]]-
Example 3
Preparation of 4-allylphenol (Compound 3)
4-allylanisole (22g, 0.148mmol) was dissolved in dichloromethane (150ml), protected by N2 and cooled in a dry ice bath. Boron tribromide (47.5g, 0.19mmol) is slowly added into the reaction solution, the temperature is kept lower than-10 ℃, the reaction is continued after the addition, the reaction is carried out for 1h at the temperature lower than 0 ℃, TLC monitors that the reaction is finished, the reaction solution is poured into 200ml of ice water, 300ml of ethyl acetate is added, liquid separation is carried out, the water phase is extracted by EA100ml of 2, organic phases are combined, the organic phases are washed by saturated sodium chloride, dried by anhydrous sodium sulfate and concentrated, and the residue is subjected to column chromatography to obtain a yellow oily compound 1(16.1g, 80.8%).
Compound 1: c9H10O＝134.18,GC-MS:134[M]+。
Example 4
Preparation of 4-allyl-2-nitro-6-bromophenol (Compound 4)
Compound 3(16.1g, 0.12mmol) was dissolved in dichloromethane (160ml), stirred to cool to 0 deg.C, NBS (39g,0.22mmol) was added in portions over two hours, TLC monitored reaction completion, 2mol/L aqueous hydrochloric acid (100ml) was added, liquid separated, the organic phase was washed with saturated aqueous sodium chloride (100ml), dried over anhydrous sodium sulfate, and concentrated to give 28.5g of a pale yellow oil. Dissolving the crude product in acetic acid (150ml), stirring, dissolving sodium nitrite (13.4g,0.19mol) in water (20ml), adding into the acetic acid solution, reacting at room temperature for 1h, pouring the reaction solution into ice water, extracting the water phase with dichloromethane (150mlx3), combining the organic phases, washing with saturated sodium bicarbonate and saturated sodium chloride aqueous solution successively, combining the organic phases, drying with anhydrous sodium sulfate, concentrating to obtain yellow oily substance, and performing column chromatography (eluent PE) to obtain yellow waxy solid compound 4(10.2g, 33%).
Compound 4: c9H8BrNO3258.07, GC-MS 257 and 259.1H-NMR(400MHz，CDCl3)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)。
Example 5
Preparation of 4-allyl-2-amino-6-bromophenol (Compound 5)
Dissolving compound 4(18g, 23mmol) in anhydrous ethanol (150ml), adding stannous chloride (18g, 79mmol), adding concentrated hydrochloric acid (0.5ml), stirring and refluxing for 1h, concentrating, adding ethyl acetate (200ml), washing with saturated sodium chloride (100mlx3) and aqueous sodium bicarbonate solution, drying with organic phase anhydrous sodium sulfate, filtering with diatomite, and concentrating the filtrate to obtain brown solid compound 5(4.7g, yield 30%)
Compound 5: c9H10BrNO＝228.09，MS 228[M+H]+And 230[ M + H]+。
Example 6
Preparation of 4-allyl-2- [ (S) -2, 6-diamino-1-hexanoyl ] amino-6-bromophenol (Compound 6) (British name di-tert-butyl (6- ((5-allyl-3-bromo-2-hyoxyphenyl) amino) -6-oxohexane-1,5-diyl) (R) -dicarbamate)
Compound 5(4.7g, 20.7mmol) and Boc-L-lys (Boc) -OH (7.54g, 22.7mmol) were dissolved in dichloromethane (200ml), stirred at 0 ℃ and DCC (4.7g, 22.7mmol) was dissolved in dichloromethane (50ml) and reacted for 2 h. Filtration was performed, and the filtrate was washed with 1N hydrochloric acid to be acidic, followed by liquid separation, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated, and then column chromatography was performed on the residue (hexane: EA ═ 10:1-3:1) to obtain compound 6(6.1g, 53%) as a foamy yellow solid.
Compound 6: c25H38BrN3O6＝556.50，MS 556[M+H]+And 558[ M + H ]]+。
Example 7
Preparation of 5-allyl-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2-hydroxyphenylboronic acid (Compound 7)
Compound 6(C2.9g, 5.2mmol) and diboron pinacol ester (22.7g, 10.4mmol) were dissolved in dioxane (50ml) under nitrogen, potassium acetate (1.6g, 15.8mmol) and catalyst Pd (pddf) Cl2(200mg, 0.28mmol) were added, stirred and heated to 80 ℃ for 2 h. Cooling to room temperature, concentrating, adding EA (100ml), washing the organic phase with saturated sodium chloride (100ml x2), drying over anhydrous sodium sulfate, filtering, concentrating the filtrate, and separating the residue through a column (MeOH: DCM ═ 1:5) to give compound 7(1.2g, 38%) as a white solid with a purity of 96%
Compound 7: c31H50BN3O8＝603.56，MS 604[M+H]+,1H-NMR(400MHz，CDCl3)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)。
Example 8
Preparation of 3', 5-dipropenyl-3- [ (S) -2, 6-N-tert-butoxycarbonyl-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1'- [1' -phenyl-C14 ] biphenyl (Compound 8)
C14-labeled Compound 1(487mg, 2.3mmol), Compound 7(1.0g, 1.92mmol) and sodium carbonate (610mg, 5.76mmol) were dissolved in 1, 4-dioxane (50ml) and water (5ml), stirred, nitrogen was replaced, PdCl was added2(dppf)2(140mg,0.19mmol), reaction at 80 ℃ for 3 h. After concentration, 50ml of water and ethyl acetate (50ml) were added thereto, the layers were separated, the aqueous layer was extracted with ethyl acetate (50ml), the combined organic layers were washed with saturated brine (50ml), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (Hexane: EA ═ 2:1) to give C14-labeled compound 8(350mg, yield 30%).
Compound 8: c34H47N3O7＝611.75，MS：612[M+H]+。1H NMR(300MHz，CDCl3)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)。
Example 9
Preparation of 3', 5-dipropenyl-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1'- [1' -phenyl-C14 ] biphenyl hydrochloride (Compound 9)
Compound 8(125mg, 0.21mmol) was dissolved in 4M HCl (gas) ethyl acetate solution (10ml) at 0 ℃, stirred for 5h, n-hexane 20ml was added, filtered, and the filter cake was dissolved in 5ml water column chromatography (C18 column, water: ethanol ═ 100:15) to give a solid (41mg, 41%).
Compound 9: c24H33Cl2N3O3＝482.44，MS：410[M+H]+(free state).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)
Example 10
Preparation of 3', 5-dipropenyl-2', 5',6' -tridedeuterium-3- [ (S) -2, 6-N-tert-butoxycarbonyl-diamino-1-hexanoyl ] amino-2, 4 '-dihydroxy-1, 1' -biphenyl (Compound 10)
Deuterium-labeled compound 2(300mg, 1.39mmol), compound 7(1.24g, 2.08mmol) and sodium carbonate (438mg, 4.16mmol) were dissolved in 1, 4-dioxane (10ml) and water (5ml), stirred, nitrogen was replaced, PdCl was added2(dppf)2(48mg,0.07mmol) and reacted at 80 ℃ for 6 h. Concentrating, adding 30ml of water and ethyl acetate (50ml), separating, extracting an aqueous phase with ethyl acetate (50ml), combining organic phases, washing with saturated saline (50ml), drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (Hexane: EA ═ 2:1) to obtain deuterium-labeled compound 8(210mg, yield 20%).
Compound 10: c34H44D3N3O77＝612.78，MS：613[M+H]+
Example 11
Preparation of 3', 5-Dipropenyl-2', 5',6' -Trideuterium-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4 '-dihydroxy-1, 1' -biphenyl hydrochloride (Compound 11)
Compound 8(210mg, 0.34mmol) was dissolved in 4M HCl (gas) ethyl acetate solution (5ml) at 0 ℃, stirred for 5h, n-hexane 20ml was added, filtered and the filter cake was dissolved in 5ml water HPLC (C18 column, water: methanol ═ 100:15) to give a solid (24mg, 14%).
Compound 11: c24H33Cl2N3O3＝C24H30D3Cl2N3O3，MS：413[M+H]+(free state).1H-NMR(400MHz， D2O)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)。
Example 12
The test for measuring the drug metabolism recovery rate and the test for measuring the time curve of the drug of the compound are carried out.
First, test compound:
3', 5-Dipropenyl-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1'- [1' -phenyl-C14 ] biphenyl hydrochloride (Compound 9)
II, an experimental method:
2.1 drug metabolic recovery assay
Adding a small amount of compound 9 into fresh whole blood of rats and mice, mixing uniformly, taking 300uL for protein precipitation pretreatment, and measuring the radioactivity contained in the supernatant and the protein precipitated in the lower layer respectively.
2.2 time-of-use Curve measurement experiment
The compound was injected into the tail vein of 4 SD male rats in a 1mg/ml solution in normal saline at a dose of 2mg/kg, and blood was taken at 0.05h, 0.25h, 0.5h, 1h, 2h, 5h, and 24h after administration, respectively, and the total radioactivity in the plasma was measured by liquid scintillation counting, and the drug concentration was calculated.
Thirdly, experimental results:
3.1 results of the experiment As shown in tables 1 and 2 below, 32% of the drug in the rat whole blood experiment settled with the protein, and the supernatant contained only 68%. The medicament of (1); 42% of the drug in the mouse whole blood experiment is settled along with the protein, and the supernatant only contains 58% of the drug; the experimental results reveal that the compound 9 and the nonradioactive marker 3', 5-dipropenyl-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1' -biphenyl hydrochloride thereof can react with certain proteins in whole blood and settle along with the proteins in the drug metabolism experiment.
TABLE 1
Figure BDA0002678412840000181
TABLE 2
Figure BDA0002678412840000182
3.2 the results are shown in FIG. 1, and the content of the drug in the plasma gradually decreases with the time, and the drug in the plasma completely disappears within 24 h.
From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:
the radiolabeled compound is successfully prepared and then applied to drug metabolism research of rats and mice, the recovery rate result shows that part of the drug is settled along with protein, and the drug is presumed to have a binding effect with the protein, so that the problem of low drug recovery rate of the drug of the formula I in the traditional non-radioactive drug metabolism experiment is successfully explained, the curve measurement result during drug administration perfectly reflects the metabolic trend of the compound 9 in vivo, and thus, the magnolol derivative, the honokiol derivative and the hydrochloride thereof can be used for preclinical animal drug metabolism research and clinical human body drug metabolism research of absorption, tissue distribution, metabolism, excretion and the like of the drug of the formula I.
Example 13
Cerebral neuroprotection experiments with non-labeled Compounds
Test compounds
3', 5-dipropyl-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1' -biphenyl hydrochloride (Compound 12)
Figure BDA0002678412840000183
II, an experimental method:
male KM mice (body weight 26-30g) were selected, randomized as follows: sham (Sham), saline (Vehicle), compound 12, all drugs were administered at a dose of 100 μ g/kg.
A tMCAO model was prepared under anesthesia with 5% chloral hydrate (500mg/kg, i.p.): mice were fixed in the supine position on a 37 ℃ thermostatic operating table. An incision of approximately 1cm was made right medially of the neck, and the muscular space between the sternocleidomastoid and sternohyoid muscles was isolated bluntly, exposing and isolating the Common Carotid Artery (CCA), Internal Carotid Artery (ICA) and External Carotid Artery (ECA). A knot was tied to the CCA, the distal end of the ECA was tied and a knot was tied to the proximal end of the ECA, and the ICA was clamped closed with an arterial clamp. The method comprises the steps of coagulating and cutting off branch blood vessels on the ECA, cutting a small opening at the distal end (between two knots) of the ECA, slowly inserting a nylon plug thread through the incision to the proximal end of the ECA, slightly fastening a slipknot at the proximal end of the ECA to prevent bleeding, loosening an artery clamp of the ICA, coagulating and cutting off the distal end (outside the knot at the distal end) of the ECA, pulling the ECA to be in a straight line with the ICA, and inserting the plug thread into the ICA through the bifurcation of the CCA. Taking CCA bifurcation as a mark, averagely leading in 10 +/-2 mm, stopping leading in when slight resistance is felt, namely reaching the starting point of Middle Cerebral Artery (MCA), tightening loose knot at the root of ECA and fixing the embolism. After MCA blood supply is blocked for 90min, the thrombus thread is withdrawn, the artery stump is ligated, the slipknot on CCA is loosened, the skin is sutured, and the ischemia reperfusion injury operation is completed. The sham group only isolated the vessels and did not insert the plug wire.
After 24h of reperfusion, 5% chloral hydrate was used for anesthesia, perfusion was performed with cold physiological saline (NS) through the left atrium, then the whole brain was taken out by rapid craniotomy and placed on a glass slide, and frozen at-20 ℃ for 20-25 min. The slices were sliced along the coronal plane, cut into 5 slices of uniform thickness, and placed in a petri dish containing 2ml of 1% TTC solution and incubated for 30 minutes in the dark at 37 deg.C (the staining was uniform by turning over once for 15 minutes). After the staining was completed, the brain pieces were fixed in 4% paraformaldehyde at 4 ℃ overnight. The normal brain tissue is bright red, and the dead brain tissue is white. After photographing with a digital camera (PowerShot G12, Canon), infarct size of each brain piece was measured using photoshop software. The proportion of the infarcted area is calculated according to the following formula: { [ infarct volume- (whole brain volume-contralateral half brain volume x2) ]/contralateral half brain volume } × 100%.
Third, experimental results
The results are shown in the following table 3, and the compound 12 can obviously reduce the cerebral infarction volume in a mouse tMCAO model of ischemic stroke, thereby playing a role in brain protection and being a potential therapeutic drug for clinical ischemic stroke.
TABLE 3
Figure BDA0002678412840000191
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (11)

1. A magnolol derivative, honokiol derivative and its hydrochloride have the structure shown in formula (I),
Figure FDA0002678412830000011
wherein R is1And R4Each independently selected from alkyl containing 1-8 carbon atoms or N, O, S heteroatom substituted alkyl;
R5amino modified by amino acid, peptide or non-amino acid-like nitrogen-containing acyl with 1-8 carbons, wherein part or all of salifiable amino groups in the amino acid, the peptide or the non-amino acid-like nitrogen-containing acyl with 1-8 carbons can be in the form of hydrochloride;
when the phenyl ring contains a C14 atom, R2、R3Each independently is hydrogen or hydroxy, and R2、R3Not hydrogen or hydroxyl at the same time;
when the benzene ring marked by the mark is a deuterated marker, the structure has a structure shown in a formula (II),
Figure FDA0002678412830000012
d is a deuterium atom, R2And R3Each independently is deuterium or hydroxy, and R2、R3Is not deuterium or hydroxyl at the same time;
when the marked benzene ring does not contain a marker atom, R1And R4Not simultaneously being allyl, R2And R3Each independently is hydrogen or hydroxy, and R2、R3Not hydrogen or hydroxyl at the same time.
2. The magnolol derivative, the honokiol derivative and the hydrochloride thereof according to claim 1, wherein the alkyl group containing 1-8 carbons or the N, O, S heteroatom-substituted alkyl group is an alkyl group or an alkenyl group, preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, a vinyl group, an allyl group, a butenyl group, a pentenyl group or a hexenyl group.
3. The magnolol derivative, the honokiol derivative, and the hydrochloride thereof according to claim 1, 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 consists of the amino acids and has a molecular weight of less than or equal to 2500 Da.
4. The magnolol derivative, the honokiol derivative and the hydrochloride thereof according to claim 2, wherein the magnolol derivative, the honokiol derivative and the hydrochloride thereof are 3', 5-diallyl-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1' - [1' -phenyl-C14 ] biphenyl hydrochloride, 3', 5-diallyl-2 ',5',6' -tridedeuterium-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1' -biphenyl hydrochloride, 3', 5-diallyl-3- [ (S) -2-amino-4-methylthio-1- Butyryl ] amino-2, 4 '-dihydroxy-1, 1' - [1 '-phenyl-C14 ] biphenyl-hydrochloride, 3', 5-diallyl-2 ',5',6 '-trideutero-3- [ (S) -2-amino-4-methylthio-1-butyryl ] amino-2, 4' -dihydroxy-1, 1 '-biphenyl-hydrochloride or 3', 5-dipropyl-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4 '-dihydroxy-1, 1' -biphenyl-hydrochloride.
5. Application of magnolol derivatives, honokiol derivatives and hydrochlorides thereof in drug metabolism research, wherein the magnolol derivatives, the honokiol derivatives and the hydrochlorides thereof have structures shown as the following formula (I),
Figure FDA0002678412830000021
wherein R is1And R4Each independently selected from alkyl containing 1-8 carbon atoms or N, O, S heteroatom substituted alkyl;
R5amino modified by amino acid, peptide or non-amino acid-like nitrogen-containing acyl with 1-8 carbons, wherein part or all of salifiable amino groups in the amino acid, the peptide or the non-amino acid-like nitrogen-containing acyl with 1-8 carbons can be in the form of hydrochloride;
when the phenyl ring contains a C14 atom, R2、R3Each independently is hydrogen or hydroxy, and R2、R3Not hydrogen or hydroxyl at the same time;
when the benzene ring marked by the mark is a deuterated marker, the structure has a structure shown in a formula (II),
Figure FDA0002678412830000031
d is a deuterium atom, R2And R3Each independently is deuterium or hydroxy, and R2、R3Not deuterium or hydroxyl at the same time.
6. The use according to claim 5, wherein the hydrocarbyl group containing 1 to 8 carbons or N, O, S heteroatom-substituted hydrocarbyl group is an alkyl or alkenyl group, preferably a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, allyl, butenyl, pentenyl or hexenyl group.
7. The use according to claim 5, 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 consists of the amino acids and has a molecular weight of less than or equal to 2500 Da;
preferably, the magnolol derivative, honokiol derivative and hydrochloride thereof are 3', 5-diallyl-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1' - [1' -phenyl-C14 ] biphenyl hydrochloride, 3', 5-diallyl-2 ',5',6' -tridedeuterium-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1' -biphenyl hydrochloride, 3', 5-diallyl-3- [ (S) -2-amino-4-methylthio-1-butyryl ] amino-2, 4' -dihydroxy-1, 1' - [1' -phenyl-C14 ] biphenyl hydrochloride and 3', 5-diallyl-2 ',5',6' -tridedeuterium-3- [ (S) -2-amino-4-methylsulfanyl-1-butyryl ] amino-2, 4' -dihydroxy-1, 1' -biphenyl hydrochloride.
8. The magnolol derivative, the honokiol derivative and the hydrochloride thereof have the structures shown in the following formula (I),
Figure FDA0002678412830000041
wherein R is1And R4Each independently selected from alkyl containing 1-8 carbon atoms or N, O, S heteroatom substituted alkyl;
R5amino modified by amino acid, peptide or non-amino acid-like nitrogen-containing acyl with 1-8 carbons, wherein part or all of salifiable amino groups in the amino acid, the peptide or the non-amino acid-like nitrogen-containing acyl with 1-8 carbons can be in the form of hydrochloride;
the benzene ring marked by R is free of marking atoms2And R3Each independently is hydrogen or hydroxy, and R2、R3Not hydrogen or hydroxyl at the same time;
preferably, the hydrocarbyl group containing 1 to 8 carbons or the N, O, S heteroatom-substituted hydrocarbyl group is an alkyl group or an alkenyl group, preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, a vinyl group, an allyl group, a butenyl group, a pentenyl group or a hexenyl group;
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 consists of the amino acids and has a molecular weight of less than or equal to 2500 Da;
more preferably, the magnolol derivative, honokiol derivative, and hydrochloride thereof are 3', 5-dipropyl-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1' -biphenyl hydrochloride.
9. A process for the preparation of magnolol derivatives, honokiol derivatives and their hydrochlorides according to any of claims 1 to 4, characterized in that it comprises the following steps:
preparation of a Compound having formula (III)
Figure FDA0002678412830000051
Wherein R is1Selected from alkyl containing 1-8 carbon atoms or N, O, S heteroatom substituted alkyl, preferably selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, allyl, butenyl, pentenyl or hexenyl, R5Amino modified by amino acid, peptide or non-amino acid-like nitrogen-containing acyl with 1-8 carbon atoms, wherein all amino groups in the amino acid, the peptide or the non-amino acid-like nitrogen-containing acyl with 1-8 carbon atoms are protected by tert-butyloxycarbonyl;
preparation of a Compound having formula (IV)
Figure FDA0002678412830000052
Wherein R is4Selected from alkyl containing 1-8 carbon atoms or N, O, S heteroatom substituted alkyl; when the phenyl ring marked by contains one C14 atom, R2、R3Each independently is hydrogen or hydroxy, and R2、R3Not hydrogen or hydroxyl at the same time; when the benzene ring marked by the mark is a deuterated marker, the structure has a structure shown in a formula (V)
Figure FDA0002678412830000053
D is a deuterium atom, R2、R3Each independently is deuterium or hydroxy, and R2、R3Is not simultaneousIs deuterium or hydroxy; when the marked benzene ring does not contain a marker atom, R2And R3Each independently is hydrogen or hydroxy, and R2、R3Not hydrogen or hydroxyl at the same time;
the compound with the formula (III) and the compound with the formula (IV) are subjected to a Suzuki reaction to form the compound with the formula 1, wherein the amino acid, the peptide or the non-amino acid nitrogen-containing acyl with 1-8 carbons is protected by tert-butyloxycarbonyl.
10. The preparation method according to claim 9, wherein the specific synthetic route of the preparation method is as follows:
Figure RE-FDA0002856624830000061
11. a pharmaceutical composition for treating cerebral ischemic injury, which comprises an effective amount of the magnolol derivative, honokiol derivative and its hydrochloride of any one of claims 1 to 4, and a pharmaceutically acceptable carrier and/or excipient.
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