CN112694392B - TRPV3 inhibitor and preparation method thereof - Google Patents
TRPV3 inhibitor and preparation method thereof Download PDFInfo
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- CN112694392B CN112694392B CN202011520551.2A CN202011520551A CN112694392B CN 112694392 B CN112694392 B CN 112694392B CN 202011520551 A CN202011520551 A CN 202011520551A CN 112694392 B CN112694392 B CN 112694392B
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- propyl
- fluorophenyl
- trpv3
- phenyl
- mixture
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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, consisting of R 1 Group, R group and R 2 The 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 channels, 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, TRPC 1-7), TRPV (Vanilloid, TRPV 1-6), TRPM (Melastatin, TRPM 1-8), TRPP (Polycystin, TRPP2, TRPP3, TRPP 5), TRPML (Mucolipin, TRPML 1-3) 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.). Wherein, the temperature-sensitive transient receptor potential channel comprises TRPV1, TRPV2, TRPV3, TRPV4, TRPM8 and TRPA1, which is expressed in skin sensory neurons for sensing the change of external temperature, while the TRPV1 and TRPV3 are highly expressed in keratinocytes and may be related to skin inflammation and skin barrier formation.
The Transient Receptor Potential cation channel, subfamily V, member 3 (Transient Receptor Potential channel, subfamily V, member 3, TRPV 3) gene is located in 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 found 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 protein are positioned in cells, and the 5 th and the 6 th transmembrane domains jointly form a non-selective cation channel. Studies have shown that the main function of TRPV3 proteins is to regulate intracellular Ca as a non-selective cation channel 2+ 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 range of 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 concentration of extracellular calcium ions.
TRPV3 plays a direct role as a cation channel in many signaling processes. First, TRPV3 is an important pathway for intracellular calcium signaling. Ca 2+ 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 opened 2+ Enter intoIntracellular Ca-inducing 2+ 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 Ca 2+ 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 can inhibit inositol triphosphate (IP 3) receptor and ranoladine receptor-mediated intracellular calcium pool Ca 2+ 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, research shows that NO generated under extreme hypoxia and acidic conditions can be used as an unstable signal molecule to activate TRPV3 ion channels of keratinocytes and generate a nitrite-independent signal transduction pathway.
In addition, TRPV3 on the keratinocyte membrane can also pass Ca 2+ The channel forms a complex TGF-alpha/TGFR signaling complex with transforming growth factor a (TGF-a), epidermal Growth Factor Receptor (EGFR). Activation of TGFR will result in increased 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 second signals IP3 and Diacylglycerol (DAG). It is currently believed that both signal pathways can activate the TRPV3 channel. The activation and signal transduction process of TRPV3 channel also requires the activation and participation of transglutaminase 1 (transglutaminase 1, tgm 1), which is an essential calcium ion-dependent cross-linking enzyme 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, especially in the epidermis and hair follicle keratinocytes. Thus regulating and influencing the proliferation and differentiation of epidermal keratinocytes, hair growth, the development of skin conditions which lead to sensitive dermatitis and keratodermia. When stimulated, TRPV3 receptors in keratinocytes 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 itchy fibers of the skin, resulting in itchy skin. Therefore, the TRP channel abnormality is closely related to human diseases, and the development of a highly effective and specific TRPV3 inhibitor for the diseases is very necessary, 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 purpose of the present invention is to provide an organic compound capable of specifically inhibiting TRPV3 and a method for preparing the same.
The invention provides a TRPV3 inhibitor, consisting of 1 Group, R group and R 2 The groups are connected in sequence to form the compound, and the molecular structural general formula of the compound is shown as formula 1:
R 1 the radical structural formula is selected from
One of (1), R 3 Is a halo group; r 4 One selected from hydroxyl, alkoxy or alkoxy ether; r is a group
R 2 The radicals being selected from
One of (1), R 5 Selected from hydroxy or alkoxyether groups, R 6 One selected from halo, trifluoroalkoxy or trichloroalkoxy; r 7 One selected from alkyl, halo, trifluoroalkoxy or trichloroalkoxy; r 8 Selected from hydroxy, alkoxy or alkoxyether groupsOne kind of the method.
In one embodiment according to the invention, R 1 Is selected from
In one embodiment according to the invention, said R 2 Is 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 -a ketone.
The invention also provides a preparation method of the TRPV3 inhibitor, which comprises the following steps:
1) Will contain R 1 Dissolving the acetophenone compounds in an organic solvent, adding a dilute alkali solution, and uniformly mixing to obtain a mixed solution;
2) Will contain R 2 Adding a group 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.
In one embodiment according to the present invention, further comprising: 4) Purifying the obtained purified 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 NaHCO 3 The 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; the molar ratio of the acetophenone figures to the benzaldehyde compounds is 1-1.5.
The invention also provides application of the TRPV3 inhibitor in preparation of a reagent for inhibiting the TRPV3 ion channel.
The present invention further provides use of the TRPV3 inhibitor described above in the preparation of an agent for inhibiting a 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 TRPV3 ion channel activity. 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.
At room temperature, the acetophenone compound is taken and dissolved in absolute ethyl alcohol, 10 percent sodium hydroxide solution is added for stirring for 10 minutes, and then the benzaldehyde compound is added for 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 dried mixture, concentrating the filtered mixture, and purifying the concentrated 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) 1 H NMR(500MHz,CDCl 3 )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). 13 C 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:
adding 10% NaOH (3.6 mmol) to a solution of m-fluoroacetophenone (200mg, 1.45mmol) in anhydrous ethanol (5 mL) at room temperature, stirring for 10 minutes, adding p-fluorobenzaldehyde (188.7 mg, 1.52mmol), and stirring at room temperature overnight. Extraction with ethyl acetate (3X 20 mL), combination of the organic phases and washing with saturated aqueous NaCl (2X 20 mL), filtration and application of anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc/petroleum ether =1 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) 1 H NMR(500MHz,CDCl 3 )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). 13 C 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 (5 mL) was added 10% NaOH (3.33 mmol) at room temperature, and after stirring for 10 minutes, p-fluorobenzaldehyde (173.5 mg,1.4 mmol) was added and the mixture was stirred at room temperature overnight. Extraction with ethyl acetate (3X 20 mL), combination of the organic phases and washing with saturated aqueous NaCl (2X 20 mL), filtration and application of anhydrous Na 2 SO 4 And (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) 1 H NMR(500MHz,CDCl 3 )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). 13 C 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 a solution of p-methylacetophenone (200mg, 1.49mmol) in absolute ethanol (5 mL) was added 10% NaOH (3.7 mmol) at room temperature, and after stirring for 10 minutes, p-fluorobenzaldehyde (307 mg, 1.56mmol) was added, and the mixture was stirred at room temperature overnight. Extraction with ethyl acetate (3X 20 mL), combination of the organic phases, washing with saturated aqueous NaCl (2X 20 mL), filtration and application of anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc/petroleum ether =1 to give the 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) 1 H NMR(500MHz,CDCl 3 )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). 13 C 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 (5 mL) was added 10% NaOH (3.33 mmol) 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 20 mL), combination of the organic phases and washing with saturated aqueous NaCl (2X 20 mL), filtration and application of anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc/petroleum ether =1 to give the pure product as a yellow solid in 83% yield.
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) 1 H NMR(500MHz,CDCl 3 )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). 13 C NMR(101MHz,DMSO)δ200.71,158.45,142.84,135.48,130.04,126.28,121.14,117.63,115.18,42.93,14.83,14.69.[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, 4.9 mmol) was added, and after stirring for 15 minutes chloromethyl methyl ether (410.6 mg, 5.1mmol) was added and the reaction stirred for 1 hour. Saturated NaHCO 3 The reaction was quenched with aqueous solution (20 mL), extracted with ethyl acetate (3X 20 mL), the organic phases combined and washed with saturated aqueous NaCl (2X 20 mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc/petroleum ether =1 to give the compound as an oil. To a solution of cyclopropylmethyl ketone (429mg, 2.58mmol) in absolute ethanol (5 mL) was added NaOH (10% (6.15 mmol) 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 20 mL), combination of the organic phases and washing with saturated aqueous NaCl (2X 20 mL), filtration and application of anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc/petroleum ether =1 to give pure product as an oily compound. This product (230mg, 0.99mmol) was dissolved in 8mL of methanol solution, and 3N HCl (2.97 mmol) was added dropwise with stirring, and reacted for 3 hours. Saturated NaHCO 3 The reaction was quenched with aqueous solution (20 mL), extracted with ethyl acetate (3X 20 mL), the organic phases combined and washed with saturated aqueous NaCl (2X 20 mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc in petrileum ether =1 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) 1 H NMR(400MHz,CDCl 3 )δ7.50(d,J＝16.1Hz,1H),7.23(d,J＝7.9Hz,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). 13 C 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, 4.9 mmol) was added, and after stirring for 15 minutes chloromethyl methyl ether (410.6 mg, 5.1mmol) was added and the reaction stirred for 1 hour. Saturated NaHCO 3 The reaction was quenched with aqueous solution (20 mL), extracted with ethyl acetate (3X 20 mL), the organic phases combined and washed with saturated aqueous NaCl (2X 20 mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether = 1. To a solution of cyclopropylmethyl ketone (429mg, 2.58mmol) in absolute ethanol (5 mL) was added NaOH (10% (6.15 mmol) 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 20 mL), combination of the organic phases and washing with saturated aqueous NaCl (2X 20 mL), filtration and application of anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether =1, to give the pure product as an oily compound 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)prop-2-en-1-one
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.76(d,J＝15.6Hz,1H),7.47(d,J＝15.6Hz,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). 13 C 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 (78.6 mg, 1.96mmol) was added, and after stirring for 15 min chloromethyl methyl ether (161mg, 2mmol) was added and the reaction stirred for 1 h. Saturated NaHCO 3 The reaction was quenched with aqueous solution (20 mL), extracted with ethyl acetate (3X 20 mL), the organic phases combined and washed with saturated aqueous NaCl (2X 20 mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether = 1. Acetylsyringone (200mg, 1mmol) was dissolved in 10mL of DMF at 0 ℃ and sodium hydride (48mg, 1.2mmol) was added thereto, followed by stirring for 15 minutes, chloromethyl methyl ether (100.6mg, 1.25mmol) was added thereto, and the reaction was stirred for 1 hour. Saturated NaHCO 3 The reaction was quenched with aqueous solution (20 mL), extracted with ethyl acetate (3X 20 mL), the organic phases combined and washed with saturated aqueous NaCl (2X 20 mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc/petroleum ether =1 to give compound B as an oil. Adding NaOH (10% in terms of content of NaOH (2.98 mmol) to a solution of Compound B (287mg, 1.19mmol) in anhydrous ethanol (8 mL) at room temperature, stirring for 10 minutes, and adding Compound A (2)08mg, 1.25mmol), stirred at room temperature overnight. Extraction with ethyl acetate (3X 20 mL), combination of the organic phases, washing with saturated aqueous NaCl (2X 20 mL), filtration and application of anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc/petroleum ether =1 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) 1 H NMR(500MHz,CDCl 3 )δ7.76(d,J＝15.6Hz,1H),7.47(d,J＝15.6Hz,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). 13 C 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 of DMF at 0 deg.C, sodium hydride (78.6 mg, 1.96mmol) was added, and after stirring for 15 minutes, chloromethyl methyl ether (161mg, 2mmol) was added, and the reaction was stirred for 1 hour. Saturated NaHCO 3 The reaction was quenched with aqueous solution (20 mL), extracted with ethyl acetate (3X 20 mL), the organic phases combined and washed with saturated aqueous NaCl (2X 20 mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc/petroleum ether =1 to give compound a as an oil. At 0 ℃ ofAcetosyringone (200mg, 1mmol) was dissolved in 10mL of DMF, sodium hydride (48mg, 1.2mmol) was added, and after stirring for 15 minutes, chloromethyl methyl ether (100.6mg, 1.25mmol) was added, and the reaction was stirred for 1 hour. Saturated NaHCO 3 The reaction was quenched with aqueous solution (20 mL), extracted with ethyl acetate (3X 20 mL), the organic phases combined and washed with saturated aqueous NaCl (2X 20 mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether = 1. To a solution of compound B (287mg, 1.19mmol) in anhydrous ethanol (8 mL) at room temperature was added 10% NaOH (2.98 mmol), 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 20 mL), combination of the organic phases, washing with saturated aqueous NaCl (2X 20 mL), filtration and application of anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc/petroleum ether =1 to give the pure compound as a yellow oil. This product (170mg, 0.44mmol) was dissolved in 6mL of methanol solution, and 3N HCl (2.6 mmol) was added dropwise with stirring, and reacted for 3 hours. Saturated NaHCO 3 The reaction was quenched with aqueous solution (20 mL), extracted with ethyl acetate (3X 20 mL), the organic phases combined and washed with saturated aqueous NaCl (2X 20 mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc/petroleum ether =1 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) 1 H NMR(500MHz,CDCl 3 )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). 13 C 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 (78.6 mg, 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 NaHCO 3 The reaction was quenched with aqueous solution (20 mL), extracted with ethyl acetate (3X 20 mL), the organic phases combined and washed with saturated aqueous NaCl (2X 20 mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether = 1. To a solution of 4-fluoroacetophenone (214mg, 1.3 mmol) in anhydrous ethanol (5 mL) was added 10% NaOH (3 mmol) at room temperature, and after stirring for 10 minutes, 3- (methoxymethoxy) benzaldehyde (1699 mg,1.2 mmol) was added and the mixture was stirred at room temperature overnight. Extraction with ethyl acetate (3X 20 mL), combination of the organic phases and washing with saturated aqueous NaCl (2X 20 mL), filtration and application of anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc/petroleum ether =1 to give pure product as an oily compound. This product (286mg, 1mmol) was dissolved in a methanol solution, and 3N HCl (3 mmol) was added dropwise with stirring for 3 hours. Saturated NaHCO 3 The reaction was quenched with aqueous solution (20 mL), extracted with ethyl acetate (3X 20 mL), the organic phases combined and washed with saturated aqueous NaCl (2X 20 mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc/petroleum ether =1 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) 1 H NMR(500MHz,CDCl 3 )δ7.84(d,J＝16.0Hz,1H),7.87(d,J＝7.5Hz,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). 13 C 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 (5 mL) was added 10% NaOH (3.6 mmol) 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 20 mL) extraction, combination of organic phases and washing with saturated aqueous NaCl solution (2X 20 mL), filtration and anhydrous Na 2 SO 4 And (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) 1 H NMR(500MHz,CDCl 3 )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). 13 C NMR(101MHz,DMSO)δ200.74,149.83,142.83,130.48,130.28,130.19,129.74,126.28,114.24,114.15,42.98,14.86,14.68.[M+H] + ＝257.0788.
The synthetic route is as follows:
to a solution of cyclopropylmethyl ketone (200mg, 2.4 mmol) in absolute ethanol (5 mL) was added 10% NaOH (5.9 mmol) 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 20 mL) extraction, combination of organic phases and washing with saturated aqueous NaCl solution (2X 20 mL), filtration and anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc in petrileum ether (1. 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) 1 H NMR(400MHz,CDCl 3 )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＝16.1Hz,1H). 13 C NMR(101MHz,CDCl 3 )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:
10% NaOH (2.5 mmol) was added to a solution of o-bromoacetophenone (200mg, 1mmol) in absolute ethanol (5 mL) 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 20 mL) extraction, combination of organic phases and washing with saturated aqueous NaCl solution (2 in a production line)
20 mL), filtered and then treated with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc/petroleum ether =1 to give a 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) 1 H NMR(400MHz,CDCl 3 )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). 13 C NMR(101MHz,CDCl 3 )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 (5 mL) at room temperature was added 10% NaOH (2.5 mmol), and after stirring for 10 minutes, p-fluorobenzaldehyde (131mg, 1.06mmol) was added, and the mixture was stirred at room temperature overnight. EtOAc (3X 20 mL) extraction, and the combined organic phase was washed with saturated aqueous NaCl solution (2. The product of the extraction)
20 mL), filtered and thenWith anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc/petroleum ether =1 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) 1 H NMR(400MHz,CDCl 3 )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). 13 C NMR(101MHz,CDCl 3 )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, 1.3 mmol) in absolute ethanol (5 mL) was added 10% NaOH (3.23 mmol) at room temperature, followed by stirring for 10 minutes, p-fluorobenzaldehyde (168.6 mg,1.4 mmol) was added, and the mixture was stirred at room temperature overnight. EtOAc (3X 20 mL) extraction, combined organic phases and washed with saturated aqueous NaCl solution (2X 20 mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc in petrileum ether =1 to give a pure product as a 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) 1 H NMR(400MHz,CDCl 3 )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). 13 C NMR(101MHz,CDCl 3 )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, 1.3 mmol) in anhydrous ethanol (5 mL) was added 10% NaOH (3.23 mmol) at room temperature, followed by stirring for 10 minutes, and then p-fluorobenzaldehyde (168.6 mg,1.4 mmol) was added, followed by stirring at room temperature overnight. EtOAc (3X 20 mL) extraction, combined organic phases and washed with saturated aqueous NaCl solution (2X 20 mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc in petrileum ether =1 to give a pure product as a 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) 1 H NMR(400MHz,CDCl 3 )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). 13 C NMR(101MHz,CDCl 3 )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 absolute ethanol (5 mL) was added 10% NaOH (3.62 mmol) 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 20 mL) extraction, combined organic phases and washed with saturated aqueous NaCl solution (2X 20 mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc in pelculeum ether =1 to give pure product as a white solid in 85% yield.
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) 1 H NMR(400MHz,CDCl 3 )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). 13 C NMR(101MHz,CDCl 3 )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 p-fluoroacetophenone (200mg, 1.45mmol) in absolute ethanol at room temperatureNaOH (3.62 mmol) was added to the solution (5 mL) in an amount of 10%, and after stirring for 10 minutes, p-chlorobenzaldehyde (281mg, 1.52mmol) was added and the mixture was stirred at room temperature overnight. EtOAc (3X 20 mL) extraction, combination of organic phases and washing with saturated aqueous NaCl solution (2X 20 mL), filtration and anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc in pelculeum ether =1 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) 1 H NMR(400MHz,CDCl 3 )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). 13 C NMR(101MHz,CDCl 3 )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 absolute ethanol (5 mL) was added 10% NaOH (3.62 mmol) 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 20 mL) extraction, combination of organic phases and washing with saturated aqueous NaCl solution (2X 20 mL), filtration and anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc in pelculeum ether =1 to give pure product as a white solid in 82% yield.
Example 19 inhibitory Activity test
Performing TRPV3 channel inhibitory activity test on compounds by using a whole-cell patch clamp technology, inoculating HEK-293 cells into a small dish, performing hTRPV3 plasmid transient transfection on the HEK-293 cells in the small dish the next day, changing the solution after 4 hours, culturing at 37 ℃ in a CO2 incubator at 5 ℃ overnight, performing whole-cell current recording on the third day by using a patch clamp amplification system, and perfusing extracellular fluid containing 2-APB (50 mu M) firstly and then different concentrations of an inhibitor and 2-APB (50 mu M) extracellular fluid. 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 (IC 50) according to the outward current inhibition rate of hTRPV3 channel mediated whole cell current.
The results of the inhibitory activity of the test compounds on TRPV3 channel are shown below, and the positive control is forsythoside B (its inhibitory activity IC50=7 μ M). 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 number | 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 low inhibition rates of TRPV1 at a concentration of 50. Mu.M, and therefore, the compounds 1 to 18 had weak inhibitory activities against TRPV 1.
TABLE 3 inhibition of TRPV4 at a single concentration (50. Mu.M) by the compounds
| Compound number | 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 inhibition rates of TRPV4 at a concentration of 50. Mu.M, and thus, compound 118 had weak inhibitory activity against TRPV 4.
As is apparent from tables 2 and 3, the compounds 1 to 30 have little inhibitory activity on 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 defined by the appended claims.
Claims (3)
1. A TRPV3 inhibitor, wherein the TRPV3 inhibitor has the formula:
2. a method for preparing the TRPV3 inhibitor according to claim 1, wherein the method for preparing the TRPV3 inhibitor comprises: dissolving acetophenone compounds in absolute ethyl alcohol at room temperature, adding 10% sodium hydroxide solution, stirring for 10 minutes, then 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.
3. The use of the following compounds in the preparation of an agent for inhibiting a TRPV3 ion channel,
(E) -1- (2-fluorophenyl) -3- (4-fluorophenyl) propyl-2-en-1-one
(E) -3- (4-fluorophenyl) -1- (3-methoxyphenyl) propyl-2-en-1-one
(E) -1- (p-tolyl) -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-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- (3-hydroxyphenyl) propyl-2-en-1-one
(E) -1- (4-fluorophenyl) -3- (4- (trifluoromethoxy) phenyl) propyl-2-en-1-one
(E) -1-cyclopropyl-3- (4- (trifluoromethoxy) phenyl) propyl-2-en-1-one
(E) -1- (2-bromophenyl) -3- (4-fluorophenyl) propyl-2-en-1-one
(E) -1- (4-bromophenyl) -3- (4-fluorophenyl) propyl-2-en-1-one
(E) -1- (2-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) -3- (4-bromophenyl) -1- (4-fluorophenyl) propyl-2-en-1-one
(E) -3- (4-chlorophenyl) -1- (4-fluorophenyl) propyl-2-en-1-one
(E) -1, 3-bis (4-fluorophenyl) propyl-2-en-1-one.
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