CN112694392A - TRPV3 inhibitor and preparation method thereof - Google Patents
TRPV3 inhibitor and preparation method thereof Download PDFInfo
- Publication number
- CN112694392A CN112694392A CN202011520551.2A CN202011520551A CN112694392A CN 112694392 A CN112694392 A CN 112694392A CN 202011520551 A CN202011520551 A CN 202011520551A CN 112694392 A CN112694392 A CN 112694392A
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- Prior art keywords
- trpv3
- compound
- solution
- added
- propyl
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Classifications
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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Abstract
The invention discloses a TRPV3 inhibitor,from R1Group, R group and R2The groups are connected in sequence to form the compound, and the molecular structural general formula of the compound is shown as formula 1. The invention also discloses a preparation method and application of the TRPV3 inhibitor. The TRPV3 inhibitor can specifically inhibit TRPV3 ion channel, and has great scientific research and clinical values.
Description
The technical field is as follows:
the invention relates to the technical field of ion channels and organic compound synthesis, in particular to a TRPV3 inhibitor and a preparation method thereof.
Background art:
transient Receptor Potential cation channels (TRPs) are an important class of nonselective cation channel superfamilies located on the cell membrane and are expressed in almost all cells in various organs of the human body. TRP channels are divided into 6 subfamilies: TRPC (Canonical, TRPC1-7), TRPV (Vanilloid, TRPV1-6), TRPM (Melastatin, TRPM1-8), TRPP (Polycysteine, TRPP2, TRPP3, TRPP5), TRPML (Mucolipin, TRPML1-3) and TRPA (Ankyrin, TRPA 1). The functions involved in these pathways include vision, hearing, olfaction, taste and somatic sensation (e.g., pain sensation, mechanical stimulation, temperature sensation, etc.). Among them, the temperature-sensitive transient receptor potential channels including TRPV1, TRPV2, TRPV3, TRPV4, TRPM8 and TRPA1 are expressed in cutaneous sensory neurons on the skin for sensing changes in external temperature, while TRPV1 and TRPV3 are highly expressed in keratinocytes and are likely to be associated with skin inflammation and skin barrier formation.
The Transient Receptor Potential cation channel, subfamily V, member 3(Transient Receptor Potential channel, subfamily V, member 3, TRPV3) gene is located on human chromosome 17P13.2, is mainly expressed in human skin keratinocytes, can regulate skin sensation, and affects epidermal keratinocytes and hair growth. TRPV3 was first discovered in keratinocytes in 2002 and has 38% and 32% homology to TRPV l and TRPV2, respectively. The TRPV protein has the structural commonality that the TRPV protein contains 6 transmembrane domains, the amino terminal (N terminal) and the carboxyl terminal (C terminal) of the TRPV protein are positioned in cells, and the 5 th and 6 th transmembrane domains jointly form a non-selective cation channel. Studies have shown that the main function of TRPV3 protein is to regulate intracellular Ca as a non-selective cation channel2+Balance, plays an important role in a variety of biological processes such as temperature sensing, inflammation, cell signaling, secretion of enzymes and hormones, cell proliferation, differentiation, and apoptosis.
TRPV3 belongs to the 3 rd thermosensitive channel and is activated at a temperature ranging from 33 ℃ to 37 ℃. However, the gating mechanism of the temperature-dependent TRPV3 channel is not well understood to date. Like most TRP channels, TRPV3 is simultaneously activated by a range of non-thermal stimuli; ruthenium Red (RR), on the other hand, is an inhibitor of TRPV3, which inhibits the activity of its ion channel. The thermal sensitivity of TRPV3 is also regulated by the extracellular calcium ion concentration.
TRPV3 plays a direct role as a cation channel in many signaling processes. First, TRPV3 is an important pathway for intracellular calcium signaling. Ca2+As a very important intracellular second messenger, it is widely involved in signal transduction processes and plays an important role in various biological activities such as muscle contraction, neurotransmission, secretion of enzymes and hormones, cell cycle regulation, and cell differentiation and apoptosis. Extracellular Ca when TRPV3 channel located in cell membrane is opened2+Enter into cells to make intracellular Ca2+The concentration is greatly increased, activating the downstream pathway in the form of an intracellular flux of extracellular cations, which mainly consists of two phases: a slow first phase followed by a second phase of rapid influx of intracellular Ca2+The concentration is greatly increased, producing a calcium signal. Meanwhile, the N-terminus of the TRPV3 channel contains multiple ankyrin binding sites, and interaction of ankyrin with the TRP channel inhibits inositol triphosphate (IP 3) receptor and ranoladine receptor-mediated intracellular calcium pool Ca2+And (4) releasing. However, excessive calcium loading in cells can trigger cell death and skin exfoliation, resulting in abnormal skin hyperkeratosis, dermatitis and hair growth phenotypes. In addition, the research finds that NO generated under extreme hypoxia and acidic conditions can be used as an unstable signal molecule to activate TRPV3 ion channel of keratinocytes and generate a nitrite-independent signal transduction pathway.
In addition, TRPV3 on the membrane of keratinocytes can also pass Ca2+Channel and turnMetagrowth factor a (TGF-a), Epidermal Growth Factor Receptor (EGFR), form a complex TGF-alpha/TGFR signaling complex. Activation of TGFR will result in an increase in TRPV3 channel activity, thereby stimulating TGF-a release. Neurotransmitters, TGF-a and EGF, etc., act on G protein-coupled receptors and receptor tyrosine kinases, respectively, and activate phosphatidylinositol (IPs) signaling pathways via PLC, producing a second signal, IP3 and Diacylglycerol (DAG). It is currently believed that both of these signal pathways activate the TRPV3 channel. Activation of TRPV3 channel and signal transduction process also requires activation and involvement of transglutaminase 1 (TGM 1), which is a calcium ion-dependent crosslinking enzyme essential in the proliferation and differentiation process of keratinocytes. Menthol, cinnamaldehyde, camphor, and the like, which activate the TRPV channel, can regulate phospholipase C signaling, resulting in an alteration in cell function.
As TRPV3 is most abundantly expressed in the skin, particularly in the epidermis and hair follicle keratinocytes. Thus regulating and influencing the proliferation and differentiation of epidermal keratinocytes, hair growth, the development of sensitive dermatitis and keratoderma. TRPV3 receptors in keratinocytes when stimulated release inflammatory mediators including ATP, prostaglandins PGE2 and IL-1b, support skin inflammatory signaling and pain transmission, and have therapeutic potential. Thus, TRPV3 in keratinocytes, when activated, promotes the release of a variety of factors, including ATP, PGE2, IL-1 α, NO, TGF- α and NGF, which exacerbate the inflammatory process and which also dominate the cutaneous itchy fibers, resulting in cutaneous pruritus. Therefore, the TRP channel abnormality is closely related to human diseases, and the development of a high-efficiency and specific TRPV3 inhibitor is necessary for the diseases, but the lack of specific inhibitor in the prior art leads to slow progress of the research on the physiological function of TRPV 3.
The invention content is as follows:
the invention aims to provide an organic compound capable of specifically inhibiting TRPV3 and a preparation method thereof.
The invention provides a TRPV3 inhibitor, consisting of1Group, R group and R2The groups are connected in sequence to form the compound, and the molecular structural general formula of the compound is shown as formula 1：
R1the radical structural formula is selected from
One of (1), R3Is a halo group; r4One selected from hydroxyl, alkoxy or alkoxy ether; r is a group
R2The radicals being selected from
One of (1), R5Selected from hydroxy or alkoxyether groups, R6One selected from halo, trifluoroalkoxy or trichloroalkoxy; r7One selected from alkyl, halo, trifluoroalkoxy or trichloroalkoxy; r8Is one selected from hydroxyl, alkoxy or alkoxy ether.
In one embodiment according to the invention, R1Is selected from
In one embodiment according to the invention, said R2Is selected from
Any one of the above.
Preferably (E) -1- (2-fluorophenyl) -3- (4-fluorophenyl) propyl-2-en-1-one, (E) -1-cyclopropyl-3- (3-hydroxyphenyl) propyl-2-en-1-one, (E) -1-cyclopropyl-3- (3- (methoxymethoxy) phenyl) propyl-2-en-1-one, (E) -1- (3, 5-dimethoxy-4- (methoxymethoxy) phenyl) -3- (3- (methoxymethoxy) phenyl) propyl-2-en-1-one, (E) -1- (4-hydroxy-3, 5-dimethoxyphenyl) -3- (3-hydroxyphenyl) propyl-2-en-1-one, (E) -1- (4-fluorophenyl) -3- (4- (trifluoromethoxy) phenyl) propyl-2-en-1-one, or (E) -1-cyclopropyl-3- (4- (trifluoromethoxy) phenyl) propyl-2-en-1-one.
The invention also provides a preparation method of the TRPV3 inhibitor, which comprises the following steps:
1) will contain R1Dissolving the acetophenone compounds in an organic solvent, adding dilute alkali liquor, and uniformly mixing to obtain a mixed solution;
2) will contain R2Adding a group benzaldehyde compound into the mixed solution, and stirring at room temperature until the mixed solution reacts overnight;
3) extracting, washing, drying and filtering to obtain a crude product of the TRPV3 inhibitor.
In one embodiment according to the present invention, further comprising: 4) purifying the obtained ester compound by column chromatography to obtain the TRPV3 inhibitor.
In one embodiment according to the invention, the eluent in step 4) is ethyl acetate.
In one embodiment according to the present invention, step 2) further comprises saturating the sample with an appropriate amount of NaHCO3The reaction was quenched with aqueous solution.
In one embodiment according to the present invention, the dilute alkali solution is a 10% concentration NaOH solution or KOH solution; the organic solvent is absolute ethyl alcohol.
In one embodiment of the invention, the molar ratio of the acetophenone compound dilute alkali solution is 1: 2.5-3; the molar ratio of the acetophenone figures to the benzaldehyde compounds is 1: 1-1.5.
The invention also provides application of the TRPV3 inhibitor in preparing a reagent for inhibiting TRPV3 ion channel.
The invention further provides application of the TRPV3 inhibitor in preparing a reagent for inhibiting TRPV3 ion channel.
The invention has the beneficial effects that:
the TRPV3 inhibitor provided by the invention can specifically inhibit a TRPV3 ion channel, can be beneficial to preparing a specific inhibition reagent of the TRPV3 ion channel, and has a great promoting effect on the research on the properties and characteristics of the TRPV3 ion channel. Meanwhile, the compound can also be used for preparing medicaments for treating diseases caused by enhancement of the activity of the TRPV3 ion channel. Therefore, the TRPV3 inhibitor provided by the invention has great value for scientific research and clinical research.
The specific implementation mode is as follows:
the following detailed description of the preferred embodiments of the present invention is provided to enable those skilled in the art to more readily understand the advantages and features of the present invention and to clearly define the scope of the invention.
Dissolving acetophenone compounds in absolute ethanol at room temperature, adding 10% sodium hydroxide solution, stirring for 10 min, adding benzaldehyde compounds, and stirring overnight. After the reaction is finished, extracting the mixture for three times by using ethyl acetate, washing the mixture by using saturated sodium chloride aqueous solution, drying the mixture by using anhydrous sodium sulfate, filtering the mixture, and purifying the mixture by using a silica gel chromatography to obtain a series of alpha, beta-unsaturated carbonyl compounds. The specific structure, name and synthetic route are shown in the following examples:
EXAMPLE 1 Synthesis of (E) -1- (2-fluorophenyl) -3- (4-fluorophenyl) propyl-2-en-1-one
(E) -1- (2-fluorophenyl) -3- (4-fluorophenyl) propyl-2-en-1-one
(E)-1-(2-fluorophenyl)-3-(4-fluorophenyl)prop-2-en-1-one
Product(s)1H NMR(500MHz,CDCl3)δ7.78(d,J＝15.7Hz,1H),7.66–7.62(m, 2H),7.59(d,J＝7.7Hz,1H),7.54(s,1H),7.44(d,J＝10.4Hz,1H),7.42–7.39(m, 1H),7.15–7.10(m,3H),3.89(s,3H).13C NMR(101MHz,DMSO)δ189.36, 165.28,162.80,161.93,159.43,143.89,134.78,134.69,131.75,131.66,131.42, 131.39,130.98,130.95,127.41,127.27,125.93,125.34,125.31,117.22,117.00, 116.65,116.43.[M+H]+＝245.0772.
The synthetic route is as follows:
to a solution of m-fluoroacetophenone (200mg,1.45mmol) in absolute ethanol (5mL) was added 10% NaOH (3.6mmol) at room temperature, and after stirring for 10 minutes, p-fluorobenzaldehyde (188.7mg,1.52mmol) was added and the mixture was stirred at room temperature overnight. Extraction with ethyl acetate (3X 20mL), organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:60 to give the compound as a white powder in 87% yield.
EXAMPLE 2 Synthesis of (E) -3- (4-fluorophenyl) -1- (3-methoxyphenyl) propyl-2-en-1-one
(E) -3- (4-fluorophenyl) -1- (3-methoxyphenyl) propyl-2-en-1-one
(E)-3-(4-fluorophenyl)-1-(3-methoxyphenyl)prop-2-en-1-one
Product(s)1H NMR(500MHz,CDCl3)δ7.78(d,J＝15.7Hz,1H),7.65–7.63(m, 2H),7.59(d,J＝7.7Hz,1H),7.55–7.53(m,1H),7.44(d,J＝10.4Hz,1H),7.42– 7.39(m,1H),7.15–7.10(m,3H),3.89(s,3H).13C NMR(101MHz,DMSO)δ
196.15,162.13,161.16,145.17,130.97,130.83,130.44,130.32,130.26,121.38, 120.13,115.48,115.32,114.86,114.01,55.84.[M+H]+＝257.0980.
The synthetic route is as follows:
to a solution of m-methoxyacetophenone (200mg,1.33mmol) in absolute ethanol (5mL) was added 10% NaOH (3.33mmol) at room temperature, and after stirring for 10 minutes, p-fluorobenzaldehyde (173.5mg,1.4mmol) was added and the mixture was stirred at room temperature overnight. Extraction with ethyl acetate (3X 20mL), organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:60 to give the compound as a white powder in 83% yield.
EXAMPLE 3 Synthesis of (E) -1- (p-tolyl) -3- (2,4, 5-trimethoxyphenyl) propyl-2-en-1-one
(E) -1- (p-tolyl) -3- (2,4, 5-trimethoxyphenyl) propyl-2-en-1-one
(E)-1-(p-tolyl)-3-(2,4,5-trimethoxyphenyl)prop-2-en-1-one)
Product(s)1H NMR(500MHz,CDCl3)δ8.33(d,J＝16.1Hz,1H),7.84–7.82(m, 1H),7.45–7.44(m,2H),7.28–7.26(m,1H),7.42(d,J＝16.1Hz,1H),6.71(s,1H), 6.42(s,1H),3.85(s,1H),3.84(s,1H),3.83(s,1H),2.34(s,3H).13C NMR(101MHz, DMSO)δ189.74,150.02,144.23,142.03,141.04,135.75,134.96,129.84,129.57, 129.52,129.37,121.38,110.48,108.28,98.74,56.24,56.18,56.11,21.36. [M+H]+＝313.1446.
The synthetic route is as follows:
to p-methyl phenethyl at room temperatureTo a solution of ketone (200mg,1.49mmol) in absolute ethanol (5mL) was added 10% NaOH (3.7mmol), and after stirring for 10 minutes, p-fluorobenzaldehyde (307mg,1.56mmol) was added and the mixture was stirred at room temperature overnight. Extraction with ethyl acetate (3X 20mL), organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give pure product as a yellow solid in 85% yield.
EXAMPLE 4 Synthesis of (E) -1- (3-methoxyphenyl) -3- (2,4, 5-trimethoxyphenyl) propyl-2-en-1-one
(E) -1- (3-methoxyphenyl) -3- (2,4, 5-trimethoxyphenyl) propyl-2-en-1-one
(E)-1-(3-methoxyphenyl)-3-(2,4,5-trimethoxyphenyl)prop-2-en-1-one
Product(s)1H NMR(500MHz,CDCl3)δ8.33(d,J＝16.1Hz,1H),7.84–7.82(m, 1H),7.45–7.44(m,2H),7.28–7.26(m,1H),7.42(d,J＝16.1Hz,1H),6.71(s,1H), 6.42(s,1H),3.85(s,1H),3.84(s,1H),3.83(s,1H),3.82(s,1H).13C NMR(101MHz, DMSO)δ196.15,161.13,150.05,142.07,141.02,135.78,130.94,130.27,121.34, 120.14,114.82,114.05,110.47,108.23,98.73,56.25,56.16,56.12,55.83. [M+H]+＝329.1386.
The synthetic route is as follows:
to a solution of m-methoxyacetophenone (200mg,1.33mmol) in absolute ethanol (5mL) was added 10% NaOH (3.33mmol) at room temperature, and after stirring for 10 minutes, p-fluorobenzaldehyde (274mg,1.4mmol) was added and the mixture was stirred at room temperature overnight. Extraction with ethyl acetate (3X 20mL), organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. After the filtrate is concentrated,the product is separated and purified by column chromatography, and the eluent is EtOAc (petroleum ether) ═ 1:5, so that the pure product is obtained as yellow solid, and the yield is 83%.
EXAMPLE 5 Synthesis of (E) -1-cyclopropyl-3- (3-hydroxyphenyl) propyl-2-en-1-one
(E) -1-cyclopropyl-3- (3-hydroxyphenyl) propyl-2-en-1-one
(E)-1-cyclopropyl-3-(3-hydroxyphenyl)prop-2-en-1-one
Product(s)1H NMR(500MHz,CDCl3)δ7.58(d,J＝16.1Hz,1H),7.27–7.24(m, 1H),7.12–7.10(m,2H),6.93–6.89(m,1H),6.85(d,J＝16.1Hz,1H),2.30–2.23 (m,1H),1.21–1.16(m,2H),1.03–0.99(m,2H).13C NMR(101MHz,DMSO)δ 200.71,158.45,142.84,135.48,130.04,126.28,121.14,117.63,115.18,42.93,14.83, 14.69.[M+H]+＝189.0918.
The synthetic route is as follows:
m-hydroxybenzaldehyde (500mg,4.09mmol) was dissolved in 10mL DMF at 0 deg.C, sodium hydride (196.3mg,4.9mmol) was added, and after stirring for 15 minutes chloromethyl methyl ether (410.6mg,5.1mmol) was added and the reaction stirred for 1 hour. Saturated NaHCO3The reaction was quenched with aqueous solution (20mL), extracted with ethyl acetate (3X 20mL), the organic phases combined and washed with saturated aqueous NaCl solution (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:10 to give the compound as an oil. To a solution of cyclopropylmethyl ketone (429mg,2.58mmol) in absolute ethanol (5mL) was added 10% NaOH (6.15mmol) at room temperature, and after stirring for 10 minutes, 3- (methoxymethoxy) benzaldehyde (207mg,2.46mmol) was added and the mixture was stirred at room temperature overnight. Extraction with ethyl acetate (3X 20mL), organic phases were combined and washed with saturated aqueous NaCl (2X 20mL) and filteredFiltering with anhydrous Na2SO4And (5) drying. The filtrate is concentrated and separated and purified by column chromatography, and the eluent is EtOAc, petroleum ether 1:5, to obtain the pure product as oily compound. This product (230mg,0.99mmol) was dissolved in 8mL of methanol solution, and 3N HCl (2.97mmol) was added dropwise with stirring, and reacted for 3 hours. Saturated NaHCO3The reaction was quenched with aqueous solution (20mL), extracted with ethyl acetate (3X 20mL), the organic phases combined and washed with saturated aqueous NaCl solution (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give the compound as a white solid. The yield thereof was found to be 73%.
EXAMPLE 6 Synthesis of (E) -1-cyclopropyl-3- (3- (methoxymethoxy) phenyl) propyl-2-en-1-one
(E) -1-cyclopropyl-3- (3- (methoxymethoxy) phenyl) propyl-2-en-1-one
(E)-1-cyclopropyl-3-(3-(methoxymethoxy)phenyl)prop-2-en-1-one
Product(s)1H NMR(400MHz,CDCl3)δ7.50(d,J＝16.1Hz,1H),7.23(d,J＝7.9 Hz,1H),7.20–7.12(m,2H),7.02–6.96(m,1H),6.78(d,J＝16.1Hz,1H),5.13(s, 2H),3.42(s,3H),2.26–2.11(m,1H),1.12–1.04(m,2H),0.93–0.88(m,2H).13C NMR(101MHz,DMSO)δ200.71,160.53,142.84,135.08,129.64,126.28,120.84, 113.51,113.26,94.93,55.62,42.93,14.83,14.69.[M+H]+＝233.1176.
The synthetic route is as follows:
m-hydroxybenzaldehyde (500mg,4.09mmol) was dissolved in 10mL DMF at 0 deg.C, sodium hydride (196.3mg,4.9mmol) was added, and after stirring for 15 minutes chloromethyl methyl ether (410.6mg,5.1mmol) was added and the reaction stirred for 1 hour. Saturated NaHCO3Aqueous solutionThe reaction was quenched (20mL), extracted with ethyl acetate (3X 20mL), the organic phases combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:10 to give the compound as an oil. To a solution of cyclopropylmethyl ketone (429mg,2.58mmol) in absolute ethanol (5mL) was added 10% NaOH (6.15mmol) at room temperature, and after stirring for 10 minutes, 3- (methoxymethoxy) benzaldehyde (207mg,2.46mmol) was added and the mixture was stirred at room temperature overnight. Extraction with ethyl acetate (3X 20mL), organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give the pure compound as an oil in 81% yield.
EXAMPLE 7 Synthesis of (E) -1- (3, 5-dimethoxy-4- (methoxymethoxy) phenyl) -3- (3- (methoxymethoxy) phenyl) propyl-2-en-1-one
(E) -1- (3, 5-dimethoxy-4- (methoxymethoxy) phenyl) -3- (3- (methoxymethoxy) phenyl) propyl-2-en-1-one
(E)-1-(3,5-dimethoxy-4-(methoxymethoxy)phenyl)-3-(3-(methoxymethoxy)phenyl)pr op-2-en-1-one
Product(s)1H NMR(500MHz,CDCl3)δ7.76(d,J＝15.6Hz,1H),7.47(d,J＝15.6 Hz,1H),7.30–7.25(m,1H),7.22–7.15(m,2H),6.92(dd,J＝8.0,1.6Hz,1H), 6.38(s,1H),6.08(s,1H),5.21(s,4H),3.93(s,6H),3.60(s,3H),3.49(s,3H).13C NMR(101MHz,DMSO)δ189.73,160.54,153.68,153.47,145.14,140.03,135.06, 129.63,128.54,121.38,120.84,113.58,113.27,99.48,99.27,98.24,94.92,56.18, 56.01,55.63,55.39.[M+H]+＝389.1602.
The synthetic route is as follows:
m-hydroxybenzaldehyde (200mg,1.64mmol) was dissolved in 5mL DMF at 0 deg.C, sodium hydride (78.6mg,1.96mmol) was added, and after stirring for 15 minutes chloromethyl methyl ether (161mg,2mmol) was added and the reaction stirred for 1 hour. Saturated NaHCO3The reaction was quenched with aqueous solution (20mL), extracted with ethyl acetate (3X 20mL), the organic phases combined and washed with saturated aqueous NaCl solution (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:10 to give compound a as an oil. Acetylsyringone (200mg,1mmol) was dissolved in 10mL of DMF at 0 ℃ and sodium hydride (48mg,1.2mmol) was added, followed by stirring for 15 minutes, chloromethyl methyl ether (100.6mg,1.25mmol) was added, and the reaction was stirred for 1 hour. Saturated NaHCO3The reaction was quenched with aqueous solution (20mL), extracted with ethyl acetate (3X 20mL), the organic phases combined and washed with saturated aqueous NaCl solution (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:10 to give compound B as an oil. To a solution of compound B (287mg,1.19mmol) in absolute ethanol (8mL) was added 10% NaOH (2.98mmol) at room temperature, and after stirring for 10 minutes, compound A (208mg, 1.25mmol) was added and the mixture was stirred at room temperature overnight. Extraction with ethyl acetate (3X 20mL), organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:6 to give the pure compound as a yellow oil in 74% yield.
EXAMPLE 8 Synthesis of (E) -1- (4-hydroxy-3, 5-dimethoxyphenyl) -3- (3-hydroxyphenyl) propyl-2-en-1-one
(E) -1- (4-hydroxy-3, 5-dimethoxyphenyl) -3- (3-hydroxyphenyl) propyl-2-en-1-one
(E)-1-(4-hydroxy-3,5-dimethoxyphenyl)-3-(3-hydroxyphenyl)prop-2-en-1-one
Product(s)1H NMR(500MHz,CDCl3)δ7.76(d,J＝15.6Hz,1H),7.47(d,J＝15.6 Hz,1H),7.30–7.25(m,1H),7.22–7.15(m,2H),6.92(dd,J＝8.0,1.6Hz,1H), 6.38(s,1H),6.08(s,1H),3.96(s,6H).13C NMR(101MHz,DMSO)δ189.72, 158.44,148.69,148.49,145.17,143.24,135.47,130.01,128.83,121.38,121.17, 117.63,115.18,99.84,99.69,56.17,56.03.[M+H]+＝301.1075.
The synthetic route is as follows:
m-hydroxybenzaldehyde (200mg,1.64mmol) was dissolved in 5mL DMF at 0 deg.C, sodium hydride (78.6mg,1.96mmol) was added, and after stirring for 15 minutes chloromethyl methyl ether (161mg,2mmol) was added and the reaction stirred for 1 hour. Saturated NaHCO3The reaction was quenched with aqueous solution (20mL), extracted with ethyl acetate (3X 20mL), the organic phases combined and washed with saturated aqueous NaCl solution (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:10 to give compound a as an oil. Acetylsyringone (200mg,1mmol) was dissolved in 10mL of DMF at 0 ℃ and sodium hydride (48mg,1.2mmol) was added, followed by stirring for 15 minutes, chloromethyl methyl ether (100.6mg,1.25mmol) was added, and the reaction was stirred for 1 hour. Saturated NaHCO3The reaction was quenched with aqueous solution (20mL), extracted with ethyl acetate (3X 20mL), the organic phases combined and washed with saturated aqueous NaCl solution (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:10 to give compound B as an oil. To a solution of compound B (287mg,1.19mmol) in absolute ethanol (8mL) was added 10% NaOH (2.98mmol) at room temperature, and after stirring for 10 minutes, compound A (208mg, 1.25mmol) was added and the mixture was stirred at room temperature overnight. Extraction with ethyl acetate (3X 20mL), organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. Concentrating the filtrate, separating and purifying by column chromatography,the eluent was EtOAc, petroleum ether 1:6, to give pure compound as a yellow oil. This product (170mg,0.44mmol) was dissolved in 6mL of methanol solution, and 3N HCl (2.6mmol) was added dropwise with stirring, and reacted for 3 hours. Saturated NaHCO3The reaction was quenched with aqueous solution (20mL), extracted with ethyl acetate (3X 20mL), the organic phases combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give the compound as an oily liquid in 73% yield.
EXAMPLE 9 Synthesis of (E) -1- (4-fluorophenyl) -3- (3-hydroxyphenyl) propyl-2-en-1-one
(E) -1- (4-fluorophenyl) -3- (3-hydroxyphenyl) propyl-2-en-1-one
(E)-1-(4-fluorophenyl)-3-(3-hydroxyphenyl)prop-2-en-1-one
Product(s)1H NMR(500MHz,CDCl3)δ7.78(d,J＝15.7Hz,1H),7.65–7.63(m, 2H),7.59(d,J＝7.7Hz,1H),7.55–7.53(m,1H),7.44(d,J＝15.7Hz,1H),7.42– 7.39(m,1H),7.15–7.10(m,3H).13C NMR(101MHz,DMSO)δ189.76,168.73, 158.54,145.16,135.48,133.52,131.59,131.48,130.03,121.14,121.03,117.69, 116.02,115.93,115.12.[M+H]+＝243.0820.
The synthetic route is as follows:
m-hydroxybenzaldehyde (200mg,1.64mmol) was dissolved in 4mL DMF at 0 deg.C, sodium hydride (78.6mg,1.92mmol) was added, and after stirring for 15 minutes chloromethyl methyl ether (161mg,2mmol) was added and the reaction stirred for 1 hour. Saturated NaHCO3The reaction was quenched with aqueous solution (20mL), extracted with ethyl acetate (3X 20mL), the organic phases combined and washed with saturated aqueous NaCl solution (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:10 to give the compound as an oil. To a solution of 4-fluoroacetophenone (214mg,1.3mmol) in absolute ethanol (5mL) was added 10% NaOH (3mmol) at room temperature, and after stirring for 10 minutes, 3- (methoxymethoxy) benzaldehyde (169mg, 1.2mmol) was added and the mixture was stirred at room temperature overnight. Extraction with ethyl acetate (3X 20mL), organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:15 to give pure compound as an oil. This product (286mg,1mmol) was dissolved in methanol solution and 3N HCl (3mmol) was added dropwise with stirring and reacted for 3 hours. Saturated NaHCO3The reaction was quenched with aqueous solution (20mL), extracted with ethyl acetate (3X 20mL), the organic phases combined and washed with saturated aqueous NaCl solution (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:10 to give the compound as a white solid. The yield thereof was found to be 73%.
EXAMPLE 10 Synthesis of (E) -1- (4-fluorophenyl) -3- (4- (trifluoromethoxy) phenyl) propyl-2-en-1-one
(E) -1- (4-fluorophenyl) -3- (4- (trifluoromethoxy) phenyl) propyl-2-en-1-one
(E)-1-(4-fluorophenyl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one
Product(s)1H NMR(500MHz,CDCl3)δ7.84(d,J＝16.0Hz,1H),7.87(d,J＝7.5 Hz,2H),7.62(d,J＝7.5Hz,2H),7.43(d,J＝8.0Hz,2H),6.94(d,J＝8.2Hz,2H), 6.57(d,J＝16.0Hz,1H).13C NMR(101MHz,DMSO)δ189.75,168.72,149.85, 145.14,133.52,131.59,131.47,130.27,130.03,129.73,127.57,121.38,116.05, 115.89,114.23,114.05.[M+H]+＝311.0693.
The synthetic route is as follows:
to a solution of p-fluoroacetophenone (200mg,1.45mmol) in absolute ethanol (5mL) was added 10% NaOH (3.6mmol) at room temperature, and after stirring for 10 minutes, p-trifluoromethoxybenzaldehyde (289mg,1.52mmol) was added, and the mixture was stirred at room temperature for 6 hours. EtOAc (3X 20mL) extraction, organic phase combination and washing with saturated aqueous NaCl solution (2X 20mL), filtration and anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:80 to give pure product as a white solid in 86% yield.
EXAMPLE 11 Synthesis of (E) -1-cyclopropyl-3- (4- (trifluoromethoxy) phenyl) propyl-2-en-1-one
(E) -1-cyclopropyl-3- (4- (trifluoromethoxy) phenyl) propyl-2-en-1-one
(E)-1-cyclopropyl-3-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one
Product(s)1H NMR(500MHz,CDCl3)δ7.60(d,J＝16.1Hz,1H),7.27–7.24(m, 1H),7.12–7.10(m,2H),6.95–6.93(m,1H),6.91(d,J＝16.1Hz,1H),2.30–2.23 (m,1H),1.21–1.16(m,2H),1.03–0.99(m,2H).13C NMR(101MHz,DMSO)δ 200.74,149.83,142.83,130.48,130.28,130.19,129.74,126.28,114.24,114.15, 42.98,14.86,14.68.[M+H]+＝257.0788.
The synthetic route is as follows:
to a solution of cyclopropylmethyl ketone (200mg,2.4mmol) in absolute ethanol (5mL) was added 10% NaOH (5.9mmol) at room temperature, and after stirring for 10 minutes, p-trifluoromethoxybenzaldehyde (475mg,2.5mmol) was added and the mixture was stirred at room temperature for 6 hours. EtOAc (3X 20mL)Extraction, combined organic phases, washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. Concentrating the filtrate, and separating and purifying by column chromatography, wherein the eluent is EtOAc (1: 60-1: 40) to obtain a pure product which is a white solid, and the yield is 88%. EXAMPLE 12 Synthesis of (E) -1- (2-bromophenyl) -3- (4-fluorophenyl) propyl-2-en-1-one
(E) -1- (2-bromophenyl) -3- (4-fluorophenyl) propyl-2-en-1-one
(E)-1-(2-bromophenyl)-3-(4-fluorophenyl)prop-2-en-1-one
Product(s)1H NMR(400MHz,CDCl3)δ7.64(d,J＝7.8Hz,1H),7.58–7.52(m, 2H),7.44–7.37(m,3H),7.36–7.31(m,1H),7.12–7.06(m,2H),7.02(d,J＝16.1 Hz,1H).13C NMR(101MHz,CDCl3)δ194.50,165.54,163.03,145.19,141.09, 133.48,131.46,130.61,130.52,129.19,127.41,125.90,125.87,119.50,116.35, 116.13.[M+H]+＝304.9982.
The synthetic route is as follows:
to a solution of o-bromoacetophenone (200mg,1mmol) in absolute ethanol (5mL) was added 10% NaOH (2.5mmol) at room temperature, and after stirring for 10 minutes, p-fluorobenzaldehyde (131mg,1.06mmol) was added and the mixture was stirred at room temperature overnight. EtOAc (3X 20mL) extraction, organic phase combination and washing with saturated aqueous NaCl solution (2 in a production line)
20mL), filtered and then treated with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:30 to give pure product as a clear oily liquid in 82% yield.
EXAMPLE 13 Synthesis of (E) -1- (4-bromophenyl) -3- (4-fluorophenyl) propyl-2-en-1-one
(E) -1- (4-bromophenyl) -3- (4-fluorophenyl) propyl-2-en-1-one
(E)-1-(4-bromophenyl)-3-(4-fluorophenyl)prop-2-en-1-one
Product(s)1H NMR(400MHz,CDCl3)δ7.91–7.86(m,2H),7.78(d,J＝15.7Hz, 1H),7.68–7.61(m,4H),7.40(d,J＝15.7Hz,1H),7.17–7.08(m,2H).13C NMR (101MHz,CDCl3)δ189.17,165.46,162.95,144.10,136.85,131.98,130.98,130.51, 130.02,128.00,121.15,116.34,116.12.[M+H]+＝304.9980.
The synthetic route is as follows:
to a solution of p-bromoacetophenone (200mg,1mmol) in absolute ethanol (5mL) was added 10% NaOH (2.5mmol) at room temperature, and after stirring for 10 minutes, p-fluorobenzaldehyde (131mg,1.06mmol) was added and the mixture was stirred at room temperature overnight. EtOAc (3X 20mL) extraction, organic phase combination and washing with saturated aqueous NaCl solution (2 in a production line)
20mL), filtered and then treated with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:30 to give pure product as a white solid in 82% yield.
EXAMPLE 14 Synthesis of (E) -1- (2-chlorophenyl) -3- (4-fluorophenyl) propyl-2-en-1-one
(E) -1- (2-chlorophenyl) -3- (4-fluorophenyl) propyl-2-en-1-one
(E)-1-(2-chlorophenyl)-3-(4-fluorophenyl)prop-2-en-1-one
Product(s)1H NMR(400MHz,CDCl3)δ7.59–7.54(m,2H),7.50–7.44(m,3H), 7.44–7.40(m,1H),7.39–7.34(m,1H),7.13–7.03(m,3H).13C NMR(101MHz, CDCl3)δ189.17,165.46,162.95,144.10,136.85,131.98,130.98,130.51,130.02, 128.00,121.15,116.34,116.12.[M+H]+＝261.0488.
The synthetic route is as follows:
to a solution of o-chloroacetophenone (200mg,1.3mmol) in absolute ethanol (5mL) was added 10% NaOH (3.23mmol) at room temperature, and after stirring for 10 min, p-fluorobenzaldehyde (168.6mg,1.4mmol) was added and the mixture was stirred at room temperature overnight. EtOAc (3X 20mL) extraction, organic phase combination and washing with saturated aqueous NaCl solution (2X 20mL), filtration and anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:30 to give a pure white solid in 83% yield.
EXAMPLE 15 Synthesis of (E) -1- (4-chlorophenyl) -3- (4-fluorophenyl) propyl-2-en-1-one
(E) Synthesis of (E) -1- (4-chlorophenyl) -3- (4-fluorophenyl) propyl-2-en-1-one
(E)-1-(4-chlorophenyl)-3-(4-fluorophenyl)prop-2-en-1-one
Product(s)1H NMR(400MHz,CDCl3)δ7.99–7.93(m,2H),7.79(d,J＝15.7Hz, 1H),7.68–7.61(m,2H),7.52–7.46(m,2H),7.41(d,J＝15.7Hz,1H),7.16–7.09 (m,2H).13C NMR(101MHz,CDCl3)δ188.55,166.97,164.44,143.55,136.59, 134.39,134.36,133.26,131.17,131.08,129.63,129.31,121.97,115.95,115.73. [M+H]+＝261.0482.
The synthetic route is as follows:
to a solution of p-chloroacetophenone (200mg,1.3mmol) in absolute ethanol (5mL) was added 10% NaOH (3.23mmol) at room temperature, and after stirring for 10 minutes, p-fluorobenzaldehyde (168.6mg,1.4mmol) was added and the mixture was stirred at room temperature overnight. EtOAc (3X 20mL) extraction, organic phase combination and washing with saturated aqueous NaCl solution (2X 20mL), filtration and anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:30 to give a pure white solid in 83% yield.
EXAMPLE 16 Synthesis of (E) -3- (4-bromophenyl) -1- (4-fluorophenyl) propyl-2-en-1-one
(E) -3- (4-bromophenyl) -1- (4-fluorophenyl) propyl-2-en-1-one
(E)-3-(4-bromophenyl)-1-(4-fluorophenyl)prop-2-en-1-one
Product(s)1H NMR(400MHz,CDCl3)δ8.09–8.01(m,2H),7.75(d,J＝15.7Hz, 1H),7.58–7.54(m,2H),7.53–7.47(m,3H),7.22–7.15(m,2H).13C NMR(101 MHz,CDCl3)δ188.53,166.98,164.44,143.61,134.37,134.34,133.69,132.27, 131.17,131.08,129.83,124.96,122.06,115.95,115.74.[M+H]+＝304.9979.
The synthetic route is as follows:
to a solution of p-fluoroacetophenone (200mg,1.45mmol) in anhydrous ethanol (5mL) was added 10% NaOH (3.62mmol) at room temperature, and after stirring for 10 minutes, p-bromobenzaldehyde (281mg,1.52mmol) was added and the mixture was stirred at room temperature overnight. EtOAc (3X 20mL) extraction, organic phase combination and washing with saturated aqueous NaCl solution (2X 20mL), filtration and anhydrous Na2SO4And (5) drying. Concentrating the filtrate, and performing column chromatographySeparating and purifying, wherein an eluent is EtOAc (petroleum ether) ═ 1:30, and a pure product is obtained as a white solid, and the yield is 85%.
EXAMPLE 17 Synthesis of (E) -3- (4-chlorophenyl) -1- (4-fluorophenyl) propyl-2-en-1-one
(E) -3- (4-chlorophenyl) -1- (4-fluorophenyl) propyl-2-en-1-one
(E)-3-(4-chlorophenyl)-1-(4-fluorophenyl)prop-2-en-1-one
Product(s)1H NMR(400MHz,CDCl3)δ8.08–8.03(m,2H),7.76(d,J＝15.7Hz, 1H),7.60–7.56(m,2H),7.48(d,J＝15.7Hz,1H),7.42–7.38(m,2H),7.22–7.15 (m,2H).13C NMR(101MHz,CDCl3)δ188.55,166.97,164.44,143.55,136.59, 134.39,134.36,133.26,131.17,131.08,129.63,129.31,121.97,115.95,115.73. [M+H]+＝261.0482.
The synthetic route is as follows:
to a solution of p-fluoroacetophenone (200mg,1.45mmol) in anhydrous ethanol (5mL) was added 10% NaOH (3.62mmol) at room temperature, and after stirring for 10 minutes, p-chlorobenzaldehyde (281mg,1.52mmol) was added and the mixture was stirred at room temperature overnight. EtOAc (3X 20mL) extraction, organic phase combination and washing with saturated aqueous NaCl solution (2X 20mL), filtration and anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:30 to give pure product as a white solid in 85% yield.
EXAMPLE 18 Synthesis of (E) -1, 3-bis (4-fluorophenyl) propyl-2-en-1-one
(E) -1, 3-bis (4-fluorophenyl) propyl-2-en-1-one
(E)-1,3-bis(4-fluorophenyl)prop-2-en-1-one
Product(s)1H NMR(400MHz,CDCl3)δ8.08–8.02(m,2H),7.78(d,J＝15.7Hz, 1H),7.67–7.61(m,2H),7.43(d,J＝15.6Hz,1H),7.21–7.15(m,2H),7.15–7.08 (m,2H).13C NMR(101MHz,CDCl3)δ188.60,166.92,165.39,164.39,162.88, 143.73,134.47,134.44,131.14,131.04,130.45,130.36,121.27,121.25,116.30, 116.08,115.90,115.69.[M+H]+＝245.0780.
The synthetic route is as follows:
to a solution of p-fluoroacetophenone (200mg,1.45mmol) in anhydrous ethanol (5mL) was added 10% NaOH (3.62mmol) at room temperature, and after stirring for 10 minutes, p-fluorobenzaldehyde (189mg,1.52mmol) was added and the mixture was stirred at room temperature overnight. EtOAc (3X 20mL) extraction, organic phase combination and washing with saturated aqueous NaCl solution (2X 20mL), filtration and anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:30 to give pure product as a white solid in 82% yield.
Example 19 inhibitory Activity assay
Performing an inhibitory activity test of a TRPV3 channel on a compound by using a whole-cell patch clamp technology, planting HEK-293 cells into a dish, performing hTRPV3 plasmid transient transfection on the HEK-293 cells in the dish the next day, changing the solution after 4 hours, placing the solution in a 37 ℃ and 5% CO2 incubator for culture overnight, performing whole-cell current recording by using a patch clamp amplification system on the third day, perfusing extracellular fluid containing 2-APB (50 mu M), and then perfusing the extracellular fluid containing inhibitors with different concentrations and 2-APB (50 mu M). Recording the maximum outward current mediated by mTRPV3 channel induced by 2-APB and the outward current mediated by hTRPV3 channel under the simultaneous action of inhibitor and 2-APB, and calculating the half effective concentration (IC50) according to the outward current inhibition rate of the whole cell current mediated by hTRPV3 channel.
The results of the test compounds for their inhibitory activity on TRPV3 channel are shown below, with forsythoside B (inhibitory activity IC50 ═ 7 μ M) as a positive control. The results are shown in Table 1.
Table 1 TRPV3 inhibitory activity of the compounds obtained in examples 1 to 18:
| compound numbering | Inhibition ratio (%) | Compound numbering | Inhibition ratio (%) | Compound numbering | Inhibition ratio (%) |
| 1 | 78.4 | 7 | 70.7 | 13 | 41.2 |
| 2 | 58.3 | 8 | 72.3 | 14 | 53.6 |
| 3 | 50.3 | 9 | 83.6 | 15 | 42.4 |
| 4 | 56.8 | 10 | 87.3 | 16 | 50.8 |
| 5 | 82.6 | 11 | 89.4 | 17 | 40.4 |
| 6 | 71.5 | 12 | 47.6 | 18 | 56 |
From the inhibition at a single concentration of 50. mu.M, the inhibition of compounds 1-30 was all very good at a concentration of 50. mu.M, with compounds 1, 5, 6, 7, 8, 9, 10 and 11 showing the best inhibition of TRPV3 at this concentration.
TABLE 2 inhibition of TRPV1 at a single concentration (50. mu.M) by the compounds
| Compound numbering | Inhibition ratio (%) | Compound numbering | Inhibition ratio (%) | Compound numbering | Inhibition ratio (%) |
| 1 | 3.2 | 7 | 2.7 | 13 | 3.6 |
| 2 | 4.4 | 8 | 2.5 | 14 | 3.1 |
| 3 | 2.5 | 9 | 3.1 | 15 | 3.9 |
| 4 | 3.7 | 10 | 2.6 | 16 | 2.5 |
| 5 | 3.5 | 11 | 3.8 | 17 | 3.6 |
| 6 | 2.7 | 12 | 2.3 | 18 | 3.5 |
As can be seen from Table 2, the compounds 1 to 30 had a low inhibitory rate against TRPV1 at a concentration of 50. mu.M, and therefore, the compounds 1 to 18 had a weak inhibitory activity against TRPV 1.
TABLE 3 inhibition of TRPV4 at a single concentration (50. mu.M) by the compounds
| Compound numbering | Inhibition ratio (%) | Compound numbering | Inhibition ratio (%) | Compound numbering | Inhibition ratio (%) |
| 1 | 3.2 | 7 | 2.4 | 13 | 1.8 |
| 2 | 1.4 | 8 | 2.5 | 14 | 2.4 |
| 3 | 2.4 | 9 | 3.3 | 15 | 3.8 |
| 4 | 2.6 | 10 | 3.6 | 16 | 4.2 |
| 5 | 3.7 | 11 | 2.1 | 17 | 3.9 |
| 6 | 4.7 | 12 | 2.6 | 18 | 2.5 |
As can be seen from Table 3, compounds 1 to 18 had low inhibitory rates against TRPV4 at a concentration of 50. mu.M, and therefore, compound 118 had weak inhibitory activity against TRPV 4.
As is apparent from tables 2 and 3, the 1-30 compounds have little inhibitory activity against TRPV1 and TRPV4, indicating that the compounds can be used as a specific, highly potent TRPV3 inhibitor and can be applied as a candidate drug against skin itch and inflammation caused by overexpression of TRPV 3.
The above summary and the detailed description are intended to demonstrate the practical application of the technical solutions provided by the present invention, and should not be construed as limiting the scope of the present invention. Various modifications, equivalent substitutions, or improvements may be made by those skilled in the art within the spirit and principles of the invention. The scope of the invention is to be determined by the appended claims.
Claims (10)
1. A TRPV3 inhibitor characterized by consisting of R1Group, R group and R2The groups are connected in sequence to form the compound, and the molecular structural general formula of the compound is shown as formula 1:
R1the radicals being selected from
One of (1), R3Is a halo group; r4One selected from hydroxyl, alkoxy or alkoxy ether; r is a group
R2Is selected from
One of (1), R5Selected from hydroxy or alkoxyether groups, R6One selected from halo, trifluoroalkoxy or trichloroalkoxy; r7One selected from alkyl, halo, trifluoroalkoxy or trichloroalkoxy; r8Is one selected from hydroxyl, alkoxy or alkoxy ether.
2. The TRPV3 inhibitor according to claim 1, wherein R is1Is selected from
Any one of the above.
3. The TRPV3 inhibitor according to claim 1, wherein R is2Is selected from
Any one of the above.
4. The method for preparing the TRPV3 inhibitor according to claim 1, comprising:
1) will contain R1Dissolving the acetophenone compounds in an organic solvent, adding dilute alkali liquor, and uniformly mixing to obtain a mixed solution;
2) will contain R2Radical (I)Adding the benzaldehyde compound into the mixed solution, and stirring at room temperature until the mixture reacts overnight;
3) extracting, washing, drying and filtering to obtain a crude product of the TRPV3 inhibitor.
5. The method of claim 4, further comprising: 4) purifying the obtained ester compound by column chromatography to obtain the TRPV3 inhibitor.
6. The method according to claim 5, wherein the eluent in step 4) is ethyl acetate.
7. The method of claim 4, wherein step 2) further comprises saturating the sample with an amount of NaHCO3The reaction was quenched with aqueous solution.
8. The method of claim 4, wherein the dilute alkali solution is NaOH solution or KOH solution with concentration of 10%; the organic solvent is absolute ethyl alcohol.
9. The method according to claim 4, wherein the molar ratio of the acetophenone compound dilute alkali solution is 1: 2.5-3; the molar ratio of the acetophenone figures to the benzaldehyde compounds is 1: 1.5.
10. use of an inhibitor of TRPV3 as defined in claims 1 to 3 in the manufacture of a reagent for inhibiting the TRPV3 ion channel.
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