CN112745284B - Natural chalcone derivative and preparation method and application thereof - Google Patents

Natural chalcone derivative and preparation method and application thereof Download PDF

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CN112745284B
CN112745284B CN202011584817.XA CN202011584817A CN112745284B CN 112745284 B CN112745284 B CN 112745284B CN 202011584817 A CN202011584817 A CN 202011584817A CN 112745284 B CN112745284 B CN 112745284B
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吴文爽
张芮佳
叶昊宇
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West China Hospital of Sichuan University
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Abstract

The invention provides a natural chalcone derivative and a preparation method and application thereof, belonging to the technical field of chemical medicines. The natural chalcone derivative is a compound shown in a formula (I), or a salt, a stereoisomer or a hydrate thereof. The derivative has obvious inhibitory activity to IL-1 beta, can effectively inhibit the release of IL-1 beta, and has an inhibitory effect even superior to that of a compound with a similar structure in the prior art. Among them, compounds 19, 27, 30,32 and 40 had the best inhibitory effect on IL-1 beta. The derivative can be used as an IL-1 beta inhibitor, is used for preparing medicaments for treating inflammation and inflammation related diseases, such as preparing medicaments for treating diseases such as neurogenic inflammation, Alzheimer disease, systemic lupus erythematosus, atherosclerosis, allergic asthma, arthritis, colitis and the like, and has good application prospect.

Description

Natural chalcone derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of chemical medicines, and particularly relates to a natural chalcone derivative, and a preparation method and application thereof.
Background
The inflammatory reaction is one of the important defense mechanisms of the body against tissue cell damage caused by physical, chemical, immune or biological factors, and is also the basic pathological process for the development of various diseases, including Alzheimer's disease, systemic lupus erythematosus, atherosclerosis, allergic asthma, arthritis, colitis and other important diseases.
Chalcone and derivatives thereof are products of aromatic aldehyde ketone subjected to cross aldol condensation, and are important organic synthesis intermediates for synthesizing various natural compounds. The chalcone has great flexibility of molecular structure and can combine with different receptors, so that the chalcone has wide biological activity, such as tumor resistance, oxygen radical inhibition and elimination, inflammation resistance, virus resistance and the like.
A natural chalcone with certain inhibition effect on IL-1 beta can be separated from natural plant of Millettia speciosa. However, the activity of the compound has yet to be further improved so as to have potential clinical anti-inflammatory application value.
Disclosure of Invention
In order to solve the problems, the invention provides a natural chalcone derivative and a preparation method and application thereof.
The present invention provides a compound represented by formula (I), or a salt thereof, or a stereoisomer thereof, or a hydrate thereof:
Figure BDA0002865370240000011
wherein the content of the first and second substances,
R1is selected from
Figure BDA0002865370240000012
The dotted line is a bond or nothing;
when the dotted line is a bond, X is selected from-CRa-or-N-; when the dotted line is absent, X is selected from-CRaRb-or-NRa-；
Ra、RbEach independently selected from hydrogen, hydroxy, a and RcSubstituted 5-to 10-membered aryl or substituted a RcA substituted 5-to 10-membered heteroaryl;
a is 0, 1, 2 or 3;
Rceach independently selected from substituted or unsubstituted C1～C8Alkyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, 5-to 10-membered aryl or 5-to 10-membered heteroaryl; the substituent of the alkyl is halogen; the substituent of the alkoxy is halogen;
R3、R4、R5、R6each independently selected from hydrogen, substituted or unsubstituted C1～C8Alkyl, substituted or unsubstituted C1～C8Alkoxy, halogen or cyano; the substituent of the alkyl is halogen; the substituent of the alkoxy is halogen;
R11each independently selected from substituted or unsubstituted C1～C8Alkyl, substituted or unsubstituted C2～C8Alkenyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted 5-to 10-membered aryl or substituted b ReA substituted 5-to 10-membered heteroaryl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1～C8Alkyl radical, C1～C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd；
RdEach independently selected from substituted or unsubstituted C1～C8Alkyl, halogen or 3-to 8-membered cycloalkyl; the substituent of the alkyl is halogen;
R2selected from hydroxy, C2～C8Alkynyl, by n R7Substituted 5-to 10-membered aryl, substituted with n R7Substituted 5-to 10-membered heteroaryl, 3-to 8-membered cycloalkyl or-NR8R9；
n is 0, 1, 2 or 3;
R7each independently selected from substituted or unsubstituted C1～C8Alkyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, 5-to 10-membered aryl or 5-to 10-membered heteroaryl; the substituent of the alkyl is halogen; the substituent of the alkoxy is halogen;
R8、R9are independently selected from hydrogen, hydroxyl and m R10Substituted 5-to 10-membered aryl or substituted with m R10A substituted 5-to 10-membered heteroaryl;
m is 0, 1, 2 or 3;
R10each independently selected from substituted or unsubstituted C1～C8Alkyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, 5-to 8-membered aryl or 5-to 10-membered heteroaryl; the substituent of the alkyl is halogen; the substituent of the alkoxy is halogen;
when the dotted line is null, X is-CH2-，R2When it is phenyl, R3、R4Not hydrogen at the same time.
Further, the air conditioner is provided with a fan,
R1is selected from
Figure BDA0002865370240000021
The dotted line is a bond or nothing;
when the dotted line is a bond, X is selected from-CRa-or-N-; when the dotted line is absent, X is selected from-CRaRb-or-NRa-；
Ra、RbAre respectively and independently selected from hydrogen, hydroxyl,
Figure BDA0002865370240000031
Figure BDA0002865370240000032
a is 0, 1, 2 or 3;
Rcare each independently selected from C1～C8Alkyl radical, C1～C8Alkoxy, trifluoromethyl, cyano, halogen, hydroxy or amino;
R3、R4、R5、R6are respectively and independently selected from hydrogen and C1～C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R11each independently selected from substituted or unsubstituted C1～C8Alkyl, substituted or unsubstituted C2～C4Alkenyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted phenyl, substituted by b ReSubstituted pyridyl, thienyl, furyl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1～C8Alkyl radical, C1～C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd；
RdAre each independently selected from C1～C8Alkyl, 3-6 membered cycloalkyl, trifluoromethyl;
R2selected from hydroxy, C2～C8Alkynyl, -NR8R9、
Figure BDA0002865370240000033
Figure BDA0002865370240000034
n is 0, 1, 2 or 3;
R7are each independently selected from C1～C8Alkyl, trifluoromethyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
R8、R9are respectively and independently selected from hydrogen, hydroxyl,
Figure BDA0002865370240000035
Figure BDA0002865370240000036
m is 0, 1, 2 or 3;
R10are each independently selected from C1～C8Alkyl, trifluoromethyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
preferably, the first and second electrodes are formed of a metal,
when the dotted line is a bond, X is selected from-CH-or-N-; when the dotted line is absent, X is selected from-CH2-or-NRa-。
Further, the compound is a compound represented by the formula (II):
Figure BDA0002865370240000041
wherein the content of the first and second substances,
R1is selected from
Figure BDA0002865370240000042
X is selected from-CRaRb-or-NRa-；
Ra、RbAre respectively and independently selected from hydrogen, hydroxyl,
Figure BDA0002865370240000043
Figure BDA0002865370240000044
a is 0, 1, 2 or 3;
Rcare each independently selected from C1～C8Alkyl radical, C1～C8Alkoxy, trifluoromethyl, cyano, halogen, hydroxy or amino;
R3、R4、R5、R6are respectively and independently selected from hydrogen and C1～C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R11each independently selected from substituted or unsubstituted C1～C8Alkyl, substituted or unsubstituted C2～C4Alkenyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted phenyl, substituted by b ReSubstituted pyridyl, thienyl, furyl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1～C8Alkyl radical, C1～C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd；
RdAre each independently selected from C1～C8Alkyl, 3-6 membered cycloalkyl, trifluoromethyl;
R2selected from hydroxy, C2～C8Alkynyl, -NR8R9、
Figure BDA0002865370240000051
Figure BDA0002865370240000052
n is 0, 1, 2 or 3;
R7are each independently selected from C1～C8Alkyl, trifluoromethyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
R8、R9are respectively and independently selected from hydrogen, hydroxyl,
Figure BDA0002865370240000053
Figure BDA0002865370240000054
m is 0, 1, 2 or 3;
R10are each independently selected from C1～C8Alkyl, trifluoromethyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
preferably, the first and second electrodes are formed of a metal,
x is selected from-CH2-or-NRa-。
Further, the compound is a compound represented by the formula (III):
Figure BDA0002865370240000055
wherein the content of the first and second substances,
R1is selected from
Figure BDA0002865370240000056
R3、R4、R5、R6Are respectively and independently selected from hydrogen and C1～C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R11are independently selected fromSubstituted or unsubstituted C1～C8Alkyl, substituted or unsubstituted C2～C4Alkenyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted phenyl, substituted by b ReSubstituted pyridyl, thienyl, furyl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1～C8Alkyl radical, C1～C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd；
RdAre each independently selected from C1～C8Alkyl, 3-6 membered cycloalkyl, trifluoromethyl;
R2selected from hydroxy, C2～C8Alkynyl, -NR8R9、
Figure BDA0002865370240000061
Figure BDA0002865370240000062
n is 0, 1, 2 or 3;
R7are each independently selected from C1～C8Alkyl, trifluoromethyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
R8、R9are respectively and independently selected from hydrogen, hydroxyl,
Figure BDA0002865370240000063
Figure BDA0002865370240000064
m is 0, 1, 2 or 3;
R10are each independently selected from C1～C8Alkyl, trifluoromethyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen.
Further, the compound is a compound represented by the formula (IV):
Figure BDA0002865370240000065
wherein the content of the first and second substances,
R3、R4are respectively and independently selected from hydrogen and C1～C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R2selected from hydroxy, C2～C8Alkynyl, -NR8R9、
Figure BDA0002865370240000066
Figure BDA0002865370240000067
n is 0, 1, 2 or 3;
R7are each independently selected from C1～C8Alkyl, trifluoromethyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
R8、R9are respectively and independently selected from hydrogen, hydroxyl,
Figure BDA0002865370240000071
Figure BDA0002865370240000072
m is 0, 1, 2 or 3;
R10are each independently selected from C1～C8Alkyl, trifluoromethyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
alternatively, the compound is of formula (V):
Figure BDA0002865370240000073
wherein the content of the first and second substances,
R3、R4are respectively and independently selected from hydrogen and C1～C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R2selected from hydroxy, C2～C8Alkynyl, -NR8R9、
Figure BDA0002865370240000074
Figure BDA0002865370240000075
n is 0, 1, 2 or 3;
R7are each independently selected from C1～C8Alkyl, trifluoromethyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
R8、R9are respectively and independently selected from hydrogen, hydroxyl,
Figure BDA0002865370240000076
Figure BDA0002865370240000077
m is 0, 1, 2 or 3;
R10are each independently selected from C1～C8Alkyl, trifluoromethyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
alternatively, the compound is of formula (VI):
Figure BDA0002865370240000081
wherein the content of the first and second substances,
R5、R6are respectively and independently selected from hydrogen and C1～C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R11each independently selected from substituted or unsubstituted C1～C8Alkyl, substituted or unsubstituted C2～C4Alkenyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted phenyl, substituted by b ReSubstituted pyridyl, thienyl, furyl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1～C8Alkyl radical, C1～C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd；
RdAre each independently selected from C1～C8Alkyl, 3-6 membered cycloalkyl, trifluoromethyl;
R2selected from hydroxy, C2～C8Alkynyl, -NR8R9、
Figure BDA0002865370240000082
Figure BDA0002865370240000083
n is 0, 1, 2 or 3;
R7are each independently selected from C1～C8Alkyl, trifluoromethyl, substituted or unsubstituted C1～C8Alkoxy radicalYl, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
R8、R9are respectively and independently selected from hydrogen, hydroxyl,
Figure BDA0002865370240000084
Figure BDA0002865370240000085
m is 0, 1, 2 or 3;
R10are each independently selected from C1～C8Alkyl, trifluoromethyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen.
Further, the compound is a compound represented by the formula (VII):
Figure BDA0002865370240000091
wherein the content of the first and second substances,
R3、R4are respectively and independently selected from hydrogen and C1～C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R8independently selected from hydrogen, hydroxyl,
Figure BDA0002865370240000092
Figure BDA0002865370240000093
m is 0, 1, 2 or 3;
R10are each independently selected from C1～C8Alkyl, trifluoromethyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
alternatively, the compound is of formula (VIII):
Figure BDA0002865370240000094
wherein the content of the first and second substances,
R5、R6are respectively and independently selected from hydrogen and C1～C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R11each independently selected from substituted or unsubstituted C1～C8Alkyl, substituted or unsubstituted C2～C4Alkenyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted phenyl, substituted by b ReSubstituted pyridyl, thienyl, furyl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1～C8Alkyl radical, C1～C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd；
RdAre each independently selected from C1～C8Alkyl, 3-6 membered cycloalkyl, trifluoromethyl;
R8independently selected from hydrogen, hydroxyl,
Figure BDA0002865370240000095
Figure BDA0002865370240000101
m is 0, 1, 2 or 3;
R10are each independently selected from C1～C8Alkyl, trifluoromethyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
alternatively, the compound is of formula (IX):
Figure BDA0002865370240000102
wherein the content of the first and second substances,
Raindependently selected from hydrogen, hydroxyl,
Figure BDA0002865370240000103
Figure BDA0002865370240000104
a is 0, 1, 2 or 3;
Rcare each independently selected from C1～C8Alkyl radical, C1～C8Alkoxy, trifluoromethyl, cyano, halogen, hydroxy or amino;
R3、R4are respectively and independently selected from hydrogen and C1～C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
alternatively, the compound is a compound represented by formula (X):
Figure BDA0002865370240000105
wherein the content of the first and second substances,
Raindependently selected from hydrogen, hydroxyl,
Figure BDA0002865370240000106
Figure BDA0002865370240000107
a is 0, 1, 2 or 3;
Rcare each independently selected from C1～C8Alkyl radical, C1～C8Alkoxy, trifluoromethyl, cyano, halogen, hydroxy or amino;
R5、R6are respectively and independently selected from hydrogen and C1～C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R11each independently selected from substituted or unsubstituted C1～C8Alkyl, substituted or unsubstituted C2～C4Alkenyl, substituted or unsubstituted C1～C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted phenyl, substituted by b ReSubstituted pyridyl, thienyl, furyl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1～C8Alkyl radical, C1～C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd；
RdAre each independently selected from C1～C8Alkyl, 3-to 6-membered cycloalkyl, trifluoromethyl.
Further, the compound is one of the following compounds:
Figure BDA0002865370240000111
Figure BDA0002865370240000121
Figure BDA0002865370240000131
Figure BDA0002865370240000141
the invention also provides application of the compound or the salt thereof, or the stereoisomer thereof, or the hydrate thereof in preparing the IL-1 beta inhibitor.
The invention also provides the application of the compound, or the salt, the stereoisomer or the hydrate thereof in preparing medicaments for treating inflammation and inflammation-related diseases;
preferably, the medicament is a medicament for treating neurogenic inflammation, alzheimer's disease, systemic lupus erythematosus, atherosclerosis, allergic asthma, arthritis, colitis.
The invention also provides a medicament which is a preparation prepared by taking the compound, or the salt thereof, or the stereoisomer thereof, or the hydrate thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
In the invention, the room temperature is 25 +/-5 ℃; the overnight period was 12. + -.2 h.
The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The structures of the compounds in the invention are all structures capable of stably existing.
The minimum and maximum carbon atom contents of the hydrocarbon groups in the present invention are indicated by prefixes, e.g. prefix (C)a～Cb) Alkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C1～C10The alkyl refers to a straight chain or branched chain alkyl containing 1-10 carbon atoms; c1～C8The alkoxy group is an alkoxy group having 1 to 8 carbon atoms; c2～C10The alkenyl group means an alkenyl group having 2 to 10 carbon atoms; c2～C10Alkynyl isAn alkynyl group having 2 to 10 carbon atoms.
The cycloalkyl refers to a carbon ring which does not contain double bonds and heteroatoms, the cycloalkyl can be monocyclic, condensed rings, bridged rings or spiro rings, and the 3-8-membered cycloalkyl refers to the carbon ring containing 3-8 carbon atoms.
Aryl in the present invention means a carbocyclic ring containing at least one double bond and no heteroatom, and the aryl may be monocyclic, fused, bridged or spiro, such as phenyl, naphthyl, anthracenyl and the like; the 6-to 10-membered aromatic group means that the carbon ring contains 6 to 10 carbon atoms.
Heteroaryl in the present invention refers to a carbocyclic ring containing at least one double bond and containing a heteroatom, which heteroatom aromatic group may be monocyclic, fused, bridged or spiro ring, the heteroatom is selected from O, S or N, the number of heteroatoms is 1, 2, 3, 4, 5 or 6, which heteroaryl group may be selected from benzoheterocyclyl; the 5-to 10-membered hetero-atom aromatic group means that the sum of the number of hetero atoms and carbon atoms in the carbon ring is 5 to 10.
In the present invention, halogen is fluorine, chlorine, bromine or iodine.
In the present invention, -S (O) RdIs structured as
Figure BDA0002865370240000151
-NHS(O)(O)RdIs structured as
Figure BDA0002865370240000152
The invention provides a natural chalcone derivative which has obvious inhibitory activity on IL-1 beta, can effectively inhibit the release of the IL-1 beta, and has an inhibitory effect even superior to that of a compound with a similar structure in the prior art. Of these, compounds 19, 27, 30, 32 and 40 had the best inhibitory effect on IL-1 β. The derivative can be used as an IL-1 beta inhibitor, is used for preparing medicaments for treating inflammation and inflammation related diseases, such as preparing medicaments for treating diseases such as neurogenic inflammation, Alzheimer disease, systemic lupus erythematosus, atherosclerosis, allergic asthma, arthritis, colitis and the like, and has good application prospect.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products. To facilitate the subsequent description of the exemplary synthetic routes and methods, the abbreviations for some of the starting materials or reagents used in the examples are given in Table 1 below.
TABLE 1 abbreviations for some of the starting materials or reagents used in the examples
Reagent Abbreviations
Ethyl acetate EtOAc
Methanol MeOH
Ethanol EtOH
N, N-dimethylformamide DMF
Hydrochloric acid HCl
Anhydrous sodium sulfate Na2SO4
Potassium carbonate K2CO3
Nitrogen gas N2
Petroleum ether PE
Methylene dichloride DCM
Water (W) H2O
Sodium bicarbonate NaHCO3
Dimethyl sulfoxide DMSO
Sodium sulfate Na2SO4
Trifluoroacetic acid TFA
Boron tribromide BBr3
Triethylamine Et3N
4-dimethylaminopyridine DMAP
1, 3-bis (diphenylphosphino) propane DPPP
EXAMPLE 1 preparation of (E) -3- (4, 7-Dimethoxybenzofuran-5-yl) -1-phenyl-prop-2-en-1-one
Figure BDA0002865370240000161
Step 1: preparation of intermediate 1
Figure BDA0002865370240000171
Commercially available QINLIN (1equiv, furochromone, CAS number: 82-02-0) was stirred in 10mL of distilled water for 10min at room temperature, 10mL of an aqueous solution prepared by slowly adding potassium hydroxide (6equiv) dropwise, followed by stirring at 120 ℃ for 9-11h, and the reaction was monitored by TLC. After completion of the reaction, it was cooled to room temperature, the reaction solution was extracted three times with DCM (50mL), and the organic layer was collected and Na anhydrous2SO4After drying and concentration under reduced pressure to remove the solvent, purification by silica gel column chromatography gave yellow solid 1 (intermediate 1).1H NMR(400MHz,CDCl3)δ13.09(s,1H),7.50(d,J＝2.3Hz,1H),6.90(d,J＝2.4Hz,1H),4.14(s,3H),4.04(s,3H),2.73(s,3H).Exact mass calcd for C12H12O5[M+H]+:236.0685；found 236.0681.
Step 2: preparation of intermediate 2
Figure BDA0002865370240000172
Intermediate 1(1equiv) and DMAP (1.5equiv) were dissolved in 15mL DCM and trifluoromethanesulfonic anhydride (Tf) was slowly added dropwise at 0 deg.C2O,4.5equiv), after the addition was complete, the reaction was stirred at 0 ℃ for 10min, then at room temperature for 3-5h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to give compound 2 (intermediate 2) as a pale yellow oil.1H NMR(400MHz,CDCl3)δ7.71(d,J＝2.2Hz,1H),6.97(d,J＝2.2Hz,1H),4.20(s,3H),4.04(s,3H),2.59(s,3H).Exact mass calcd for C13H11F3O7S[M+H]+:368.0178；found 368.0172.
And step 3: preparation of intermediate 3
Figure BDA0002865370240000173
Mixing intermediate 2(1equiv) and PdCl2(dppf) (0.1equiv) and DPPP (1.5equiv) were dissolved in 10mL DMF, triethylamine (3equiv) and formic acid (2equiv) were added dropwise at room temperature, the reaction mixture was heated at 60 ℃ for 1-2h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, extracted three times with ethyl acetate (50mL), and the organic layer was collected and washed with anhydrous Na2SO4After drying and concentration under reduced pressure to remove the solvent, the product was purified by silica gel column chromatography to obtain white solid 3 (intermediate 3).1H NMR(400MHz,CDCl3)δ7.64(d,J＝2.2Hz,1H),7.25(s,1H),6.97(d,J＝2.2Hz,1H),4.07(s,3H),4.00(s,3H),2.70(s,3H).Exact mass calcd for C12H12O4[M+H]+:220.0736；found 220.0732.
And 4, step 4: preparation of intermediate 4
Figure BDA0002865370240000181
Dissolving intermediate 3(1equiv) in a mixture of 10mL of distilled water and 10mL of 1, 4-dioxane, adding25mL NaOCl were added. The mixture was stirred at 120 ℃ for 3-4h and the reaction was monitored by TLC. After completion of the reaction, it was cooled to room temperature, the reaction mixture was poured into 125mL of distilled water, the pH was adjusted to 2 with concentrated hydrochloric acid solution, a white solid was precipitated, filtered under suction, washed with anhydrous ether, and dried under vacuum to give white solid 4 (intermediate 4).1H NMR(400MHz,DMSO-d6)δ12.64(s,1H),7.96(d,J＝2.2Hz,1H),7.12(s,1H),7.09(d,J＝2.2Hz,1H),3.86(s,3H),3.85(s,3H).Exact mass calcd for C11H10O5[M+H]+:222.0528；found 222.0523.
And 5: preparation of intermediate 5
Figure BDA0002865370240000182
Intermediate 4(1equiv) was dissolved in 15mL of anhydrous THF, lithium aluminum hydride (1.5equiv) was added slowly at 0 deg.C, the reaction mixture was stirred at room temperature for 3-4h, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was poured into 125mL of ice water, suction-filtered, the filtrate was extracted with ethyl acetate (50mL) three times, and the organic layer was collected and Na anhydrous2SO4After drying and concentration under reduced pressure to remove the solvent, the product was purified by silica gel column chromatography to obtain white solid 5 (intermediate 5).1H NMR(400MHz,DMSO-d6)δ7.97(d,J＝2.2Hz,1H),7.12(d,J＝2.2Hz,1H),7.00(s,1H),4.62(s,2H),3.95(s,3H),3.93(s,3H).Exact mass calcd for C11H12O4[M+H]+:208.0736；found 208.0734.
Step 6: preparation of intermediate 6
Figure BDA0002865370240000191
Intermediate 5(1equiv) was dissolved in 15mL toluene, manganese dioxide (5equiv) was added and the reaction mixture was stirred at 120 ℃ for 6-8h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed by concentrating the reaction mixture under reduced pressure, followed by purification by silica gel column chromatography to give a white solid 6 (medium)Intermediate 6).1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.04(d,J＝2.2Hz,1H),7.31(d,J＝2.2Hz,1H),7.08(s,1H),4.07(s,3H),3.86(s,3H).Exact mass calcd for C11H10O4[M+H]+:206.0579；found 206.0575.
And 7: preparation of Compound A1
Figure BDA0002865370240000192
Intermediate 6(1equiv) and acetophenone (1.2equiv) were dissolved in 15mL of methanol, 3mL of 3M NaOH solution was added dropwise, the reaction mixture was stirred at room temperature for 4-5h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was neutralized with 5% HCl, extracted with ethyl acetate, and the organic phase was washed with water and anhydrous Na2SO4After drying and concentration under reduced pressure to remove the solvent, the product was purified by silica gel column chromatography to obtain product A1.1H NMR(400MHz,CDCl3)δ8.22(d,J＝15.8Hz,1H),8.08–8.01(m,2H),7.62(d,J＝2.2Hz,1H),7.60–7.54(m,1H),7.49(d,J＝15.8Hz,1H),7.54–7.48(m,2H),7.05(s,1H),6.95(d,J＝2.2Hz,1H),4.04(d,J＝5.1Hz,6H).13C NMR(101MHz,CDCl3)δ191.18,148.23,147.54,145.13,142.11,140.48,138.75,132.69,128.71,128.71,128.66,128.66,121.83,121.63,120.90,105.49,105.12,61.65,56.67.Exact mass calcd for C19H16O4Na,331.0946；[M+Na]+:331.0940.
EXAMPLE 2 preparation of (E) -3- (4, 7-dimethoxybenzofuran-5-yl) -1- (3',4',5' -trimethoxyphenyl) -prop-2-en-1-one
Figure BDA0002865370240000193
The method comprises the following specific steps:
Figure BDA0002865370240000201
will be intermediateBody 6(1equiv) and 3',4',5' -trimethoxyacetophenone (1.2equiv) were dissolved in 15mL of methanol, 3mL of 3M NaOH solution was added dropwise, the reaction mixture was stirred at room temperature for 4-5h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was neutralized with 5% HCl, extracted with ethyl acetate, and the organic phase was washed with water and anhydrous Na2SO4After drying and concentration under reduced pressure to remove the solvent, the product was purified by silica gel column chromatography to obtain product A2.1H NMR(400MHz,DMSO-d6)δ8.14(d,J＝15.7Hz,1H),8.04(d,J＝2.2Hz,1H),7.86(d,J＝15.7Hz,1H),7.51(s,1H),7.42(s,2H),7.26(d,J＝2.3Hz,1H),4.05(s,3H),4.03(s,3H),3.92(s,6H),3.79(s,3H).13C NMR(101MHz,DMSO-d6)δ188.75,153.38,153.38,148.00,147.38,146.50,142.41,141.92,139.02,133.85,121.58,120.99,120.37,106.79,106.29,106.19,105.96,61.69,60.70,57.06,56.75,56.54.Exact mass calcd for C22H22O7[M+Na]+:421.1264；found 421.1251.
EXAMPLE 3 preparation of (E) -3- (4, 7-dimethoxybenzofuran-5-yl) -1- (3' -trifluoromethylphenyl) -prop-2-en-1-one
Figure BDA0002865370240000202
The method comprises the following specific steps:
Figure BDA0002865370240000203
intermediate 6(1equiv) and 3' -trifluoromethylacetophenone (1.2equiv) were dissolved in 15mL of methanol, 3mL of 3M NaOH solution was added dropwise, the reaction mixture was stirred at room temperature for 4-5h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was neutralized with 5% HCl, extracted with ethyl acetate, and the organic phase was washed with water and anhydrous Na2SO4After drying and concentration under reduced pressure to remove the solvent, the product was purified by silica gel column chromatography to obtain product A3.1H NMR(400MHz,CDCl3)δ8.27(s,1H),8.23(d,J＝15.8Hz,1H1H),8.20(d,J＝7.8Hz,1H),7.84(d,J＝7.8Hz,1H),7.67(d,J＝7.7Hz,1H),7.63(d,J＝2.3Hz,1H),7.46(d,J＝15.8Hz,1H),7.05(s,1H),6.96(d,J＝2.2Hz,1H),4.06(d,J＝2.1Hz,6H).13C NMR(101MHz,CDCl3)δ189.81,148.40,147.75,145.08,142.03,141.71,139.22,131.67,131.32,129.23,128.91,125.38,122.49,121.38,120.96,120.35,105.42,105.13,60.62,54.92..Exact mass calcd for C20H15F3O4[M+Na]+:399.0820；found 399.0817.
EXAMPLE 4 preparation of (E) -3- (4, 7-Dimethoxybenzofuran-5-yl) -1- (2' -fluorophenyl) -prop-2-en-1-one
Figure BDA0002865370240000211
The method comprises the following specific steps:
Figure BDA0002865370240000212
intermediate 6(1equiv) and 2' -fluoroacetophenone (1.2equiv) were dissolved in 15mL of methanol, 3mL of 3M NaOH solution was added dropwise, the reaction mixture was stirred at room temperature for 4-5h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was neutralized with 5% HCl, extracted with ethyl acetate, and the organic phase was washed with water and anhydrous Na2SO4After drying and concentration under reduced pressure to remove the solvent, the product was purified by silica gel column chromatography to obtain product A4.1H NMR(400MHz,CDCl3)δ8.16(dd,J＝15.8,1.8Hz,1H),7.81(td,J＝7.5,1.9Hz,1H),7.61(d,J＝2.2Hz,1H),7.55-7.48(m,1H),7.36(dd,J＝15.9,2.7Hz,1H),7.26-7.24(m,1H),7.17(dd,J＝9.7,8.2Hz,1H),7.02(s,1H),6.93(d,J＝2.2Hz,1H),4.03(d,J＝3.3Hz,6H).13C NMR(101MHz,CDCl3)δ189.58,162.34(159.83),148.26,147.57,145.01,142.01,140.45,133.65(133.57),131.01(130.99),125.09,125.03,124.48,121.46,120.59,116.58(116.36),105.35,104.87,61.58,56.44.Exact mass calcd for C19H15FO4[M+Na]+:349.0852；found 349.0851.
EXAMPLE 5 preparation of (E) -3- (4, 7-Dimethoxybenzofuran-5-yl) -1- (3' -fluorophenyl) -prop-2-en-1-one
Figure BDA0002865370240000221
The method comprises the following specific steps:
Figure BDA0002865370240000222
intermediate 6(1equiv) and 3' -fluoroacetophenone (1.2equiv) were dissolved in 15mL of methanol, 3mL of 3M NaOH solution was added dropwise, the reaction mixture was stirred at room temperature for 4-5h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was neutralized with 5% HCl, extracted with ethyl acetate, and the organic phase was washed with water and anhydrous Na2SO4After drying and concentration under reduced pressure to remove the solvent, the product was purified by silica gel column chromatography to obtain product A5.1H NMR(400MHz,CDCl3)δ8.24(d,J＝15.8Hz,1H),7.81(dt,J＝7.8,1.2Hz,1H),7.71(ddd,J＝9.5,2.7,1.6Hz,1H),7.62(d,J＝2.2Hz,1H),7.50(dd,J＝8.1,5.5Hz,1H),7.44(d,J＝15.8Hz,1H),7.29(ddd,J＝8.3,2.6,0.9Hz,1H),7.04(s,1H),6.95(d,J＝2.2Hz,1H),4.05(d,J＝1.8Hz,6H).13C NMR(101MHz,CDCl3)δ189.64,164.12(161.66),148.31,147.61,145.05,141.99,141.14,140.79(140.73),130.26(130.18),124.20,121.40,121.03,120.47,119.63(119.42),115.44(115.22),105.41,104.98,61.50,56.54.Exact mass calcd for C19H15FO4[M+Na]+:349.0852；found 349.0857.
Examples 6 to 27
The synthesis methods of other natural chalcone derivatives are the same as those in examples 1-5, except that the types of the aromatic methyl ketone are changed. The aromatic methyl ketone starting material, the structural formula of the obtained compound and the nuclear magnetic results of the obtained compound are shown in table 2.
TABLE 2 raw materials for preparing compounds, structural formula of the obtained compounds and nuclear magnetic results of the compounds
Figure BDA0002865370240000223
Figure BDA0002865370240000231
Figure BDA0002865370240000241
Figure BDA0002865370240000251
Figure BDA0002865370240000261
Figure BDA0002865370240000271
Figure BDA0002865370240000281
Figure BDA0002865370240000291
EXAMPLE 28 preparation of (E) -3- (4, 7-dimethoxybenzofuran-5-yl) -1- (6-phenylpyridin-2-yl) -prop-2-en-1-one
Figure BDA0002865370240000292
The method comprises the following specific steps:
Figure BDA0002865370240000301
mixing compound A12(1equiv), pinacol phenylboronate (1.2equiv), PdCl2(dppf)(0.1equiv), potassium carbonate (2equiv) in a mixed solution of 7mL dioxane, 3mL ethanol, and 4mL water, N2The reaction mixture was stirred at 80 ℃ for 1-2 hours under protection and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product A28.1H NMR(400MHz,CDCl3)δ8.69(d,J＝3.5Hz,2H),8.42(d,J＝15.8Hz,1H),8.44–8.36(m,2H),8.20(d,J＝4.4Hz,2H),7.88(d,J＝2.2Hz,1H),7.79(d,J＝15.8Hz,1H),7.82 7.69(m,3H),7.46(s,1H),7.22(d,J＝2.2Hz,1H),4.33(s,6H).13C NMR(101MHz,CDCl3)δ189.92,156.40,154.47,148.45,147.60,145.03,142.04,140.11,138.86,137.95,129.52,128.97,128.97,127.11,127.11,123.35,121.58,121.41,121.34,120.78,105.51,105.33,61.72,56.55.Exact mass calcd for C24H19NO4[M+Na]+:408.1212；found 408.1214.
EXAMPLE 29 preparation of (E) -3- (4, 7-dimethoxybenzofuran-5-yl) -1- (6-thienylpyridin-2-yl) -prop-2-en-1-one
Figure BDA0002865370240000302
The method comprises the following specific steps:
Figure BDA0002865370240000303
mixing compound A12(1equiv), thiophene-2-boronic acid pinacol ester (1.2equiv), PdCl2(dppf) (0.1equiv), potassium carbonate (2equiv) in a mixed solution of 7mL dioxane, 3mL ethanol and 4mL water, N2The reaction mixture was stirred at 80 ℃ for 1-2 hours under protection and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product A29.1H NMR(400MHz,CDCl3)δ8.15(d,J＝3.3Hz,2H),7.79(dd,J＝7.4,1.2Hz,1H),7.60(t,J＝7.7Hz,1H),7.56(dd,J＝7.9,1.2Hz,1H),7.40(dd,J＝3.7,1.1Hz,1H),7.36(d,J＝2.2Hz,1H),7.19(dd,J＝5.0,1.1Hz,1H),6.97(s,1H),6.89(dd,J＝5.1,3.7Hz,1H),6.70(d,J＝2.2Hz,1H),3.83(d,J＝4.3Hz,6H).13C NMR(101MHz,CDCl3)δ189.22,154.01,151.69,148.39,147.48,144.92,144.59,141.95,139.89,137.76,128.25,128.13,125.04,121.48,121.27,121.27,120.89,120.40,105.43,105.13,61.64,56.36.Exact mass calcd for C22H17NO4S[M+Na]+:417.0776；found 417.0764.
EXAMPLE 30 preparation of (E) -3- (4-bromo-2, 5-dimethoxyphenyl) -1- (4-fluorophenyl) -prop-2-en-1-one
Figure BDA0002865370240000311
The method comprises the following specific steps:
Figure BDA0002865370240000312
commercially available 4-bromo-2, 5-dimethoxybenzaldehyde (1equiv) and 4-fluoroacetophenone (1.2equiv) were dissolved in 15mL of methanol, 3mL of 3M NaOH solution was added dropwise, the reaction mixture was stirred at room temperature for 4-5h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was neutralized with 5% HCl, extracted with ethyl acetate, and the organic phase was washed with water and anhydrous Na2SO4After drying and concentration under reduced pressure to remove the solvent, the product was purified by silica gel column chromatography to obtain product A30.1H NMR(400MHz,CDCl3)δ8.33–8.28(m,2H),8.25(d,J＝15.8Hz,1H),7.83(d,J＝15.8Hz,1H),7.46–7.41(m,3H),7.38(s,1H),4.16(d,J＝11.4Hz,6H).13C NMR(101MHz,CDCl3)δ189.51,164.44,153.50,150.37,139.95,134.81,131.32,131.23,123.62,123.16,117.12,115.96,115.74,115.23,112.44,57.11,56.51.Exact mass calcd for C17H14BrFO3Na,387.0008；[M+Na]+:387.0006.
EXAMPLE 31 preparation of (E) -3- (2,5-2' -methyl- [1,1' -biphenyl ] -4-yl) -1- (4' -fluorophenyl) -prop-2-en-1-one
Figure BDA0002865370240000321
The method comprises the following specific steps:
Figure BDA0002865370240000322
mixing compound A30(1equiv), methylbenzene-2-boric acid (1.2equiv), PdCl2(dppf) (0.1equiv), potassium carbonate (2equiv) in a mixed solution of 7mL dioxane, 3mL ethanol and 4mL water, N2The reaction mixture was stirred at 80 ℃ for 1-2 hours under protection and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product A31.1H NMR(400MHz,CDCl3)δ8.07(d,J＝15.8Hz,1H),8.05–7.99(m,2H),7.57(d,J＝15.8Hz,1H),7.25–7.19(m,3H),7.18–7.09(m,4H),6.74(s,1H),3.83(s,3H),3.73(s,3H),2.13(s,3H).13C NMR(101MHz,CDCl3)δ189.79,166.89(164.36),153.33,150.89,140.78,138.03,136.83,135.01,134.97,131.31,131.22,129.95,129.75,127.97,125.73,123.19,122.60,115.90,115.69,114.82,111.59,56.31,56.31,20.07.Exact mass calcd for C24H21FO3Na,399.1372；[M+Na]+:399.1371.
The synthesis methods of examples 32 to 40 were the same as in example 31 except that the type of boric acid was changed. The boric acid species, structural formula of the obtained compound and nuclear magnetic results of the obtained compound are shown in table 3.
TABLE 3 raw materials for preparing compounds, structural formula of the obtained compounds and nuclear magnetic results of the compounds
Figure BDA0002865370240000323
Figure BDA0002865370240000331
Figure BDA0002865370240000341
Figure BDA0002865370240000351
Figure BDA0002865370240000361
EXAMPLE 41 (E) -N- (4-fluorophenyl) -3-oxoprop-1-en-1-yl) -2, 5-dimethoxyphenylmethanesulfonamide
Figure BDA0002865370240000362
The method comprises the following specific steps:
Figure BDA0002865370240000363
compound A30(1equiv), methylsulfonamide (1.2equiv), [ Pd (allyl) Cl]2(0.1equiv), t-BuXPhos (0.13equiv), Potassium carbonate (2equiv) in 7mL 2-methyltetrahydrofuran, N2The reaction mixture was stirred at 80 ℃ for 8-10 hours under protection and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product A41.1H NMR(400MHz,DMSO)δ8.18–8.12(m,2H),8.06(d,J＝15.2Hz,1H),7.43(d,J＝15.2Hz,1H),7.36–7.29(m,2H),7.16(s,1H),6.90(s,1H),3.73(d,J＝10.3Hz,6H),2.68(s,3H).13C NMR(101MHz,DMSO)δ186.84,165.70(163.22),155.64,146.09,140.47,135.71,130.93,130.84,129.72,115.58,115.37,112.88,109.42,109.18,100.52,55.88,55.58,48.52.Exact mass calcd for C18H18FNO5SNa,402.0787；[M+Na]+:402.0783.
EXAMPLE 42 (E) -N- (4-fluorophenyl) -3-oxoprop-1-en-1-yl) -2, 5-dimethoxyphenylcyclopropanesulfonamide
Figure BDA0002865370240000364
The method comprises the following specific steps:
Figure BDA0002865370240000371
compound A30(1equiv), cyclopropanesulfonamide (1.2equiv), [ Pd (allyl) Cl]2(0.1equiv), t-BuXPhos (0.13equiv), Potassium carbonate (2equiv) in 7mL 2-methyltetrahydrofuran, N2The reaction mixture was stirred at 80 ℃ for 8-10 hours under protection and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product A42.1H NMR(400MHz,CDCl3)δ8.03(d,J＝15.8Hz,1H),8.08–7.97(m,2H),7.52(d,J＝15.8Hz,1H),7.28(s,1H),7.17(t,J＝8.6Hz,2H),7.11(s,1H),3.91(d,J＝4.9Hz,6H),2.57–2.47(m,1H),1.23(dd,J＝6.8,4.8Hz,2H),0.99(dd,J＝7.9,3.2Hz,2H).Exact mass calcd for C20H20FNO5SNa,428.0944；[M+Na]+:428.0949.
EXAMPLE 43 (E) -N- (4-fluorophenyl) -3-oxoprop-1-en-1-yl) -2, 5-dimethoxyphenyl trifluoromethanesulfonamide
Figure BDA0002865370240000372
The method comprises the following specific steps:
Figure BDA0002865370240000373
compound A30(1equiv), trifluoromethylsulfonamide (1.2equiv), [ Pd (allyl) Cl]2(0.1equiv), t-BuXPhos (0.13equiv), Potassium carbonate (2equiv) in 7mL 2-methyltetrahydrofuran, N2The reaction mixture was stirred at 80 ℃ for 8-10 hours under protection and the reaction was monitored by TLC. Reaction ofAfter completion, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product A43.1H NMR(400MHz,MeOD-d4)δ8.12(d,J＝15.7Hz,1H),8.19–8.05(m,2H),7.67(d,J＝15.7Hz,1H),7.32(s,1H),7.30–7.21(m,2H),7.13(s,1H),3.87(d,J＝2.9Hz,6H).Exact mass calcd for C18H15F4NO5SNa,456.0505；[M+Na]+:456.0503.
EXAMPLE 44 preparation of (E) -3- (benzofuran-5-yl) -1-phenyl-prop-2-en-1-one
Figure BDA0002865370240000381
The method comprises the following specific steps:
Figure BDA0002865370240000382
commercially available 1-benzofuran-5-carbaldehyde (1equiv) and acetophenone (1.2equiv) were dissolved in 15mL of methanol, 3mL of 3M NaOH solution was added dropwise, the reaction mixture was stirred at room temperature for 4-5h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was neutralized with 5% HCl, extracted with ethyl acetate, and the organic phase was washed with water and anhydrous Na2SO4After drying and concentration under reduced pressure to remove the solvent, the product was purified by silica gel column chromatography to obtain product A44.1H NMR(400MHz,CDCl3)δ8.34–8.26(m,2H),8.20(d,J＝15.8Hz,1H),8.14(d,J＝1.8Hz,1H),7.92(d,J＝2.3Hz,1H),7.89–7.70(m,6H),7.07(d,J＝2.3Hz,1H).13C NMR(101MHz,CDCl3)δ190.63,156.36,146.25,145.53,138.51,132.81,130.13,128.73,128.73,128.60,128.60,128.28,124.71,122.35,121.12,112.14,106.94.Exact mass calcd for C17H12F4O2Na,271.0735；[M+Na]+:271.0729.
EXAMPLE 45 preparation of 3- (4, 7-Dimethoxybenzofuran-5-yl) -1-phenyl-propan-1-one
Figure BDA0002865370240000383
The method comprises the following specific steps:
Figure BDA0002865370240000384
1 particle of zinc particles (0.3g) and ammonium acetate (2equiv) were dissolved in a mixed solution of 5mL of distilled water and 5mL of ethanol, stirred at normal temperature for 30min, Compound A1(1equiv) was added to the reaction system, stirred at 55 ℃ for 5 to 8 hours, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product B1.1H NMR(400MHz,CDCl3)δ8.25(dd,J＝8.4,1.4Hz,2H),7.83(d,J＝2.1Hz,1H),7.82–7.76(m,1H),7.71(dd,J＝8.3,7.0Hz,2H),7.12(d,J＝2.2Hz,1H),6.92(s,1H),4.23(d,J＝2.0Hz,6H),3.56(dd,J＝8.8,6.7Hz,2H),3.37(dd,J＝8.6,6.8Hz,2H).Exact mass calcd for C19H18O4[M+Na]+:333.1103；found 333.1102.
EXAMPLE 46 preparation of 3- (4, 7-Dimethoxybenzofuran-5-yl) -1- (4' -fluorophenyl) -propan-1-one
Figure BDA0002865370240000391
The method comprises the following specific steps:
Figure BDA0002865370240000392
1 particle of zinc particles (0.3g) and ammonium acetate (2equiv) were dissolved in a mixed solution of 5mL of distilled water and 5mL of ethanol, stirred at normal temperature for 30min, Compound A19(1equiv) was added to the reaction system, stirred at 55 ℃ for 5 to 8 hours, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product B2.1H NMR(400MHz,CDCl3)δ8.30–8.24(m,2H),7.84(d,J＝2.2Hz,1H),7.38(dd,J＝9.6,7.7Hz,2H),7.12(d,J＝2.2Hz,1H),6.91(s,1H),4.23(d,J＝2.9Hz,6H),3.53(dd,J＝8.7,6.7Hz,2H),3.36(dd,J＝8.8,6.6Hz,2H).Exact mass calcd for C19H17FO4[M+Na]+:351.1009；found 351.1004.
EXAMPLE 47 preparation of 3- (4, 7-Dimethoxybenzofuran-5-yl) -1- (3' -trifluoromethylphenyl) -propan-1-one
Figure BDA0002865370240000393
The method comprises the following specific steps:
Figure BDA0002865370240000401
1 particle of zinc particles (0.3g) and ammonium acetate (2equiv) were dissolved in a mixed solution of 5mL of distilled water and 5mL of ethanol, stirred at normal temperature for 30min, Compound A3(1equiv) was added to the reaction system, stirred at 55 ℃ for 5 to 8 hours, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product B3.1H NMR(400MHz,CDCl3)δ8.49(s,1H),8.42(d,J＝7.8Hz,1H),8.07(d,J＝7.8Hz,1H),7.88–7.84(m,1H),7.84(d,J＝2.0Hz,1H),7.13(dd,J＝2.3,1.0Hz,1H),6.92(s,1H),4.23(t,J＝1.5Hz,6H),3.58(t,J＝7.7Hz,2H),3.38(dd,J＝8.5,6.7Hz,2H).13C NMR(101MHz,CDCl3)δ198.51,144.64,144.54,144.43,141.35,137.37,131.26,129.43,129.40,129.27,125.44,125.07(125.03),122.37,121.14,108.57,104.66,60.74,56.51,40.35,25.56.Exact mass calcd for C20H17F3O4Na,401.0979；[M+Na]+:401.0979.
EXAMPLE 48 preparation of 3- (4, 7-Dimethoxybenzofuran-5-yl) -1- (3' -aminophenyl) -propan-1-one
Figure BDA0002865370240000402
The method comprises the following specific steps:
Figure BDA0002865370240000403
1 particle of zinc particles (0.3g) and ammonium acetate (2equiv) were dissolved in a mixed solution of 5mL of distilled water and 5mL of ethanol, stirred at normal temperature for 30min, Compound A12(1equiv) was added to the reaction system, stirred at 55 ℃ for 5 to 8 hours, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product B4.1H NMR(400MHz,CDCl3)δ7.30(d,J＝2.2Hz,1H),7.25(t,J＝7.7Hz,1H),7.08(dd,J＝12.7,7.7Hz,2H),6.57(d,J＝2.2Hz,1H),6.36(s,1H),3.72(s,3H),3.67(s,3H),2.70–2.53(m,2H),1.73(dtd,J＝13.9,8.5,5.4Hz,2H).Exact mass calcd for C18H16BrNO4Na,412.0160；[M+Na]+:412.0162.
EXAMPLE 49 preparation of (E) -3- (4, 7-dimethoxybenzofuran-5-yl) -1-N-phenylacrylamide
Figure BDA0002865370240000411
The method comprises the following specific steps:
Figure BDA0002865370240000412
dissolving compound A25(1equiv), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (1.5equiv) and triethylamine (1.5equiv) in 10mL of DMF, stirring at room temperature for 30min, dissolving aniline (1.2equiv) in a small amount of DMF, slowly dropping into the reaction system, stirring at room temperature for 1-2h, and monitoring the reaction by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain a product C1.1H NMR(400MHz,CDCl3)δ7.85(d,J＝15.6Hz,1H),7.38(d,J＝7.9Hz,2H),7.34(d,J＝2.2Hz,1H),7.21(s,1H),7.09(t,J＝7.9Hz,2H),6.87(t,J＝7.4Hz,1H),6.66(d,J＝2.3Hz,2H),6.34(d,J＝15.7Hz,1H),3.74(d,J＝4.8Hz,6H).Exact mass calcd for C19H17NO4Na,346.1055；[M+Na]+:346.1056.
EXAMPLE 50 preparation of (E) -3- (4, 7-dimethoxybenzofuran-5-yl) -1-N- (4' -fluorophenyl) -acrylamide
Figure BDA0002865370240000413
The method comprises the following specific steps:
Figure BDA0002865370240000421
compound a25(1equiv), 2- (7-benzotriazole oxide) -N, N '-tetramethylurea Hexafluorophosphate (HATU) (1.5equiv), triethylamine (1.5equiv) were dissolved in 10mL DMF, stirred at room temperature for 30min, 4' -fluoroaniline (1.2equiv) was dissolved in a small amount of DMF and then slowly dropped into the reaction system, stirred at room temperature for 1-2h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain a product C2.1H NMR(400MHz,DMSO-d6)δ7.84(d,J＝2.2Hz,1H),7.73(d,J＝15.8Hz,1H),7.59–7.53(m,2H),7.04(d,J＝2.3Hz,1H),7.00(t,J＝8.9Hz,2H),6.93(s,1H),6.65(d,J＝15.8Hz,1H),3.81(d,J＝12.8Hz,6H).Exact mass calcd for C19H16FNO4[M+Na]+:364.0961；found 364.0961.
EXAMPLE 51 preparation of (E) -3- (4, 7-dimethoxybenzofuran-5-yl) -1-N- (3' -trifluoromethylphenyl) -acrylamide
Figure BDA0002865370240000422
The method comprises the following specific steps:
Figure BDA0002865370240000423
compound a25(1equiv), 2- (7-benzotriazole oxide) -N, N '-tetramethylurea Hexafluorophosphate (HATU) (1.5equiv), triethylamine (1.5equiv) were dissolved in 10mL DMF, stirred at room temperature for 30min, 3' -trifluoromethylaniline (1.2equiv) was dissolved with a small amount of DMF and then slowly dropped into the reaction system, stirred at room temperature for 1-2h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain a product C3.1H NMR(400MHz,CDCl3)δ8.14(d,J＝15.7Hz,1H),7.95(s,1H),7.84(d,J＝8.2Hz,1H),7.61(d,J＝2.2Hz,1H),7.52–7.44(m,2H),7.38(d,J＝7.9Hz,1H),6.94(d,J＝2.2Hz,1H),6.92(s,1H),6.58(d,J＝15.6Hz,1H),4.02(d,J＝5.6Hz,6H).Exact mass calcd for C20H16F3NO4Na:414.0929；[M+Na]+:414.0934.
EXAMPLE 52 preparation of (E) -N- (6-bromopyridin-2-yl) -3- (4, 7-dimethoxybenzofuran-5-yl) -acrylamide
Figure BDA0002865370240000431
The method comprises the following specific steps:
Figure BDA0002865370240000432
compound a25(1equiv), 2- (7-benzotriazole oxide) -N, N' -tetramethylurea Hexafluorophosphate (HATU) (1.5equiv), triethylamine (1.5equiv) were dissolved in 10mL DMF, stirred at room temperature for 30min, 2-amino-6-bromopyridine (1.2equiv) was dissolved in a small amount of DMF and then slowly dropped into the reaction system, stirred at room temperature for 1-2h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain a product C4.1H NMR(400MHz,CDCl3)δ8.75(dd,J＝4.5,1.4Hz,1H),8.50(d,J＝16.1Hz,1H),8.45(dd,J＝8.4,1.4Hz,1H),7.65(d,J＝2.2Hz,1H),7.46(dd,J＝8.4,4.5Hz,1H),7.00(s,1H),6.98(d,J＝2.2Hz,1H),6.77(d,J＝16.1Hz,1H),4.09(s,3H),4.05(s,3H).13C NMR(101MHz,CDCl3)δ163.47,151.85,149.00,146.99,145.36,142.18,141.16,135.25,129.69,120.95,119.11,116.07,109.41,105.79,105.52,105.00,61.58,56.61.Exact mass calcd for C18H15BrN2O4Na:425.0113；[M+Na]+:425.0114.
EXAMPLE 53 preparation of N- ((4, 7-Dimethoxybenzofuran-5-yl) methyl) -N-phenylacrylamide
Figure BDA0002865370240000433
Step 1: preparation of intermediate 7
Figure BDA0002865370240000441
The intermediate 6(1equiv) and aniline (1.2equiv) were dissolved in 10mL DCM, 1mL glacial acetic acid and anhydrous sodium sulfate (1.5equiv) were added, stirring was carried out at room temperature for 1h, suction filtration was carried out, the filtrate was concentrated under reduced pressure to remove the solvent, the solid obtained by spin-drying was dissolved in 10mL methanol, sodium cyanoborohydride (2.5equiv) was slowly added under ice bath, stirring was carried out for 2-3h, and the reaction was monitored by TLC. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and then purified by silica gel column chromatography to obtain intermediate 7.1H NMR(400MHz,CDCl3)δ7.56(d,J＝2.2Hz,1H),7.32–7.27(m,3H),7.04–6.99(m,2H),6.90(s,1H),6.78(d,J＝2.2Hz,1H),5.56(t,J＝5.5Hz,2.1Hz,1H),5.16(s,2H),3.96(s,3H),3.51(s,3H)
Step 2: preparation of Compound D1
Figure BDA0002865370240000442
The intermediate 7(1equiv) and triethylamine (1.5equiv) were dissolved in 10mL of Dichloromethane (DCM), acryloyl chloride (2equiv) was slowly added dropwise under ice bath, after the addition was completed, stirring was carried out for 2-3h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain a product D1.1H NMR(400MHz,CDCl3)δ7.56(d,J＝2.2Hz,1H),7.32–7.27(m,3H),7.04–6.99(m,2H),6.90(s,1H),6.78(d,J＝2.2Hz,1H),6.45(dd,J＝16.8,2.1Hz,1H),6.05(dd,J＝16.8,10.3Hz,1H),5.56(dd,J＝10.3,2.1Hz,1H),5.16(s,2H),3.96(s,3H),3.51(s,3H).13C NMR(101MHz,CDCl3)δ165.79,145.23,144.97,144.36,144.36,141.71,129.31,129.31,128.83,128.57,127.82,127.77,122.30,120.69,108.12,104.87,60.67,56.50,56.47,46.50.Exact mass calcd for C20H19NO4Na:360.1212；[M+Na]+360.1204.
EXAMPLE 54 preparation of N- ((4, 7-dimethoxybenzofuran-5-yl) methyl) -N- (4-fluorophenyl) -acrylamide
Figure BDA0002865370240000451
Step 1: preparation of intermediate 8
Figure BDA0002865370240000452
The intermediate 6(1equiv) and 4-fluoroaniline (1.2equiv) were dissolved in 10mL of DCM, 1mL of glacial acetic acid and anhydrous sodium sulfate (1.5equiv) were added, stirring was carried out at room temperature for 1h, suction filtration was carried out, the filtrate was concentrated under reduced pressure to remove the solvent, the solid obtained by spin-drying was dissolved in 10mL of methanol, sodium cyanoborohydride (2.5equiv) was slowly added under ice bath, stirring was carried out for 2-3h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and then purified by silica gel column chromatography to obtain intermediate 8.1H NMR(400MHz,CDCl3)δ7.82(d,J＝2.2Hz,1H),7.26–7.20(m,4H),7.12(s,1H),7.04(d,J＝2.2Hz,1H),5.30(t,J＝5.4Hz,1H),5.37(s,2H),4.21(s,3H),3.81(s,3H).Exact mass calcd for C17H16FNO3Na:324.1012；[M+Na]+324.1015.
Step 2: preparation of Compound D2
Figure BDA0002865370240000453
The intermediate 8(1equiv) and triethylamine (1.5equiv) were dissolved in 10mL of Dichloromethane (DCM), acryloyl chloride (2equiv) was slowly added dropwise under ice bath, after the addition was completed, stirring was carried out for 2-3h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain a product D2.1H NMR(400MHz,CDCl3)δ7.82(d,J＝2.2Hz,1H),7.26–7.20(m,4H),7.12(s,1H),7.04(d,J＝2.2Hz,1H),6.70(dd,J＝16.8,2.1Hz,1H),6.26(dd,J＝16.8,10.3Hz,1H),5.83(dd,J＝10.3,2.0Hz,1H),5.37(s,2H),4.21(s,3H),3.81(s,3H).13C NMR(101MHz,CDCl3)δ165.79,163.06(160.59),145.31,145.06,144.46,141.73,137.64,130.33,130.25,128.54,128.14,121.89,120.63,116.31,116.08,108.18,104.89,60.67,56.53,46.50.Exact mass calcd for C20H18FNO4Na:378.1118；[M+Na]+378.1115.
EXAMPLE 55 preparation of N- ((4, 7-Dimethoxybenzofuran-5-yl) methyl) -N- (4-fluorophenyl) -acrylamide
Figure BDA0002865370240000461
Step 1: preparation of intermediate 9
Figure BDA0002865370240000462
The intermediate 6(1equiv) and 3-trifluoromethylaniline (1.2equiv) were dissolved in 10mL of DCM, 1mL of glacial acetic acid and anhydrous sodium sulfate (1.5equiv) were added, stirring was carried out at room temperature for 1h, suction filtration was carried out, the filtrate was concentrated under reduced pressure to remove the solvent, the solid obtained by spin-drying was dissolved in 10mL of methanol, sodium cyanoborohydride (2.5equiv) was slowly added under ice bath, stirring was carried out for 2-3h, and the reaction was monitored by TLC. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and then purified by silica gel column chromatography to obtain intermediate 9.1H NMR(500MHz,CDCl3)δ7.56–7.50(m,2H),7.40(t,J＝7.9Hz,1H),7.34(s,1H),7.14(d,J＝7.9Hz,1H),6.85(s,1H),6.77(d,J＝2.2Hz,1H),5.43(t,J＝5.5Hz,1H),5.13(s,2H),3.93(s,3H),3.56(s,3H).Exact mass calcd for C18H16F3NO3Na:374.0980；[M+Na]+374.0981.
Step 2: preparation of Compound D3
Figure BDA0002865370240000463
Intermediate 9(1equiv) and triethylamine (1.5equiv) were dissolved in 10mL of Dichloromethane (DCM), acryloyl chloride (2equiv) was slowly added dropwise while cooling on ice, after the addition was completed, stirring was carried out for 2-3h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain a product D3.1H NMR(400MHz,CDCl3)δ7.56–7.50(m,2H),7.40(t,J＝7.9Hz,1H),7.34(s,1H),7.14(d,J＝7.9Hz,1H),6.85(s,1H),6.77(d,J＝2.2Hz,1H),6.46(dd,J＝16.7,2.0Hz,1H),5.98(t,J＝13.5Hz,1H),5.60(dd,J＝10.3,1.9Hz,1H),5.13(s,2H),3.93(s,3H),3.56(s,3H).Exact mass calcd for C21H18F3NO4Na:428.1086；[M+Na]+:428.1080.
EXAMPLE 56 preparation of N- (6-bromopyridin-2-yl) -N- ((4, 7-dimethoxybenzofuran-5-yl) methyl) -acrylamide
Figure BDA0002865370240000471
Step 1: preparation of intermediate 10
Figure BDA0002865370240000472
The intermediate 6(1equiv) and 2-amino-6-bromopyridine (1.2equiv) were dissolved in 10mL of DCM, 1mL of glacial acetic acid and anhydrous sodium sulfate (1.5equiv) were added, stirring was carried out at room temperature for 1h, suction filtration was carried out, the filtrate was concentrated under reduced pressure to remove the solvent, the solid obtained by spin-drying was dissolved in 10mL of methanol, sodium cyanoborohydride (2.5equiv) was slowly added under ice bath, stirring was carried out for 2-3h, and the reaction was monitored by TLC. After the reaction is finished, concentrating under reduced pressureAfter removal of the solvent, purification by silica gel column chromatography gave intermediate 10.1H NMR(400MHz,CDCl3)δ7.80(d,J＝2.2Hz,1H),7.73(t,J＝7.8Hz,1H),7.58(d,J＝7.8Hz,1H),7.34(d,J＝7.8Hz,1H),7.14(s,1H),7.06(d,J＝2.2Hz,1H),5.43(t,J＝5.5Hz,1H),5.56(s,2H),4.19(s,3H),4.08(s,3H).Exact mass calcd for C16H15BrN2O3Na:385.0164；[M+Na]+:385.0168.
Step 2: preparation of Compound D4
Figure BDA0002865370240000473
The intermediate 10(1equiv) and triethylamine (1.5equiv) were dissolved in 10mL of Dichloromethane (DCM), acryloyl chloride (2equiv) was slowly added dropwise under ice bath, after the addition was completed, stirring was carried out for 2-3h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain a product D4.1H NMR(400MHz,CDCl3)δ7.80(d,J＝2.2Hz,1H),7.73(t,J＝7.8Hz,1H),7.58(d,J＝7.8Hz,1H),7.34(d,J＝7.8Hz,1H),7.14(s,1H),7.06(d,J＝2.2Hz,1H),6.72(dd,J＝16.7,2.0Hz,1H),6.58(dd,J＝16.7,10.2Hz,1H),5.94(dd,J＝10.2,2.0Hz,1H),5.56(s,2H),4.19(s,3H),4.08(s,3H).Exact mass calcd for C19H17BrN2O4Na:439.0269；[M+Na]+:439.0272.
The advantageous effects of the present invention are demonstrated by specific test examples below.
Test example 1 pharmacological test of the Compound of the present invention
The invention also provides a pharmacological activity screening experiment of the partial compounds, namely an in-vitro IL-1 beta inhibition experiment. THP-1 is a human myeloid leukemia monocyte originally derived from acute monocytic leukemia patients. THP-1 is an acute monocytic leukemia cell line commonly used in various laboratories, and is an ideal cell for researching immunity and inflammation.
Materials: LPS, nigericin, PMA.
Preparation of the compound: 1) preparing a compound into a mother solution of 10mmol/L by using 100% DMSO; 2) preparing LPS into 1mg/ml mother solution by using Opti-MEM; 3) preparing Nigericin into 10mM mother liquor by using absolute ethyl alcohol; 4) PMA was prepared as a stock solution at 100. mu.g/ml in 100% DMSO.
The method comprises the following steps: THP-1 cells (3X 10)3) The cells were inoculated in 48-well plates and cultured with PMA (100ng/ml) for 24 hours, then the medium was changed to Opti-MEM and treated with LPS (concentration 1mg/ml) for 3 hours, then with 2. mu.M of the compound for 40min, and finally with nigericin (concentration 10mM) for 40min, and the supernatant was collected. IL-1. beta. was detected in the supernatant by ELISA kit.
Reading and recording the raw data of each hole, and performing corresponding conversion on the raw data.
As a result: table 4 shows the inhibitory activity of the compounds of the present invention on IL-1 β, wherein at 2 μ M, the inhibition rate > 80% is indicated as "+++", the inhibition rate < 50% < 80% is indicated as "+++", and the inhibition rate < 50% is indicated as "+".
TABLE 4 inhibitory Activity of Compounds of the present invention on IL-1 beta
Figure BDA0002865370240000481
Figure BDA0002865370240000491
The structural formula of curcumin is as follows:
Figure BDA0002865370240000492
the structural formula of chalcone is:
Figure BDA0002865370240000493
control compound 1 and control compound 2 are known compounds, and control compound 1 has the formula:
Figure BDA0002865370240000494
control compound 2 has the structural formula:
Figure BDA0002865370240000495
as can be seen from table 4 above: the compound of the invention has obvious inhibitory activity to IL-1 beta, can effectively inhibit the release of IL-1 beta, and has the inhibitory effect even better than that of compounds such as curcumin, chalcone, a control compound 1, a control compound 2 and the like. Of these, compounds 19, 27, 30, 32 and 40 had the best inhibitory effect on IL-1 β. The compound can be used for preparing IL-1 beta inhibitor and treating diseases related to IL-1 beta.
In conclusion, the invention provides a natural chalcone derivative, which has obvious inhibitory activity on IL-1 beta, can effectively inhibit the release of IL-1 beta, and has an inhibitory effect even superior to that of a compound with a similar structure in the prior art. Of these, compounds 19, 27, 30, 32 and 40 had the best inhibitory effect on IL-1 β. The derivative can be used as an IL-1 beta inhibitor, is used for preparing medicaments for treating inflammation and inflammation related diseases, such as preparing medicaments for treating diseases such as neurogenic inflammation, Alzheimer disease, systemic lupus erythematosus, atherosclerosis, allergic asthma, arthritis, colitis and the like, and has good application prospect.

Claims (5)

1. A compound, or a salt thereof, characterized in that: the compound is one of the following compounds:
Figure FDA0003556762830000011
Figure FDA0003556762830000021
Figure FDA0003556762830000031
Figure FDA0003556762830000041
2. use of a compound of claim 1, or a salt thereof, for the preparation of an IL-1 β inhibitor.
3. Use of the compound according to claim 1, or a salt thereof, for the manufacture of a medicament for the treatment of inflammation associated with IL-1 β and inflammation-related disorders.
4. Use according to claim 3, characterized in that: the medicine is used for treating neurogenic inflammation, Alzheimer disease, systemic lupus erythematosus, atherosclerosis, allergic asthma, arthritis and colitis.
5. A medicament, characterized by: the compound or the salt thereof as the active ingredient of the compound or the salt thereof as the active ingredient is added with pharmaceutically acceptable auxiliary materials or auxiliary ingredients to prepare the preparation.
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