CN110776486B - Benzofuran micromolecule P2Y14Receptor inhibitors, their preparation and use - Google Patents

Benzofuran micromolecule P2Y14Receptor inhibitors, their preparation and use Download PDF

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CN110776486B
CN110776486B CN201911011418.1A CN201911011418A CN110776486B CN 110776486 B CN110776486 B CN 110776486B CN 201911011418 A CN201911011418 A CN 201911011418A CN 110776486 B CN110776486 B CN 110776486B
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benzofuran
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CN110776486A (en
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胡庆华
李环球
刘春晓
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Abstract

The invention discloses a benzofuran derivative shown in a formula (I), and a preparation method and application thereof. Experimental results show that the benzofuran derivative provided by the invention has better P2Y14Inhibiting activity and antiinflammatory activity, and can be used for preparing P2Y14A therapeutic agent for receptor-related inflammatory diseases.

Description

Benzofuran micromolecule P2Y14Receptor inhibitors, their preparation and use
Technical Field
The invention belongs to small molecule P2Y14The technical field of receptor inhibitors, in particular to a benzofuran micromolecule P2Y14Receptor inhibitors, their preparation and use.
Background
P2Y14The receptors belong to the delta-branch of rhodopsin-like G protein-coupled receptors (GPCRs). It inhibits the production of 3', 5' -cyclic adenosine monophosphate (cAMP) by Gi proteins and is activated by uridine-5 ' -diphosphate glucose (UDPG) and other endogenous UDP-sugars. P2Y14Receptors are mainly present in the heart, placenta, adipose tissue, gastrointestinal tract, and peripheral immune cells, and are involved in pro-inflammatory and immune response processes, the activation of which enhances neutrophil chemotaxis and promotes the release of mediators from mast cells. Recent studies have shown that the activity of the enzyme is shown at P2Y14In receptor knockout mice, P2Y14Antagonism of the receptor has potential therapeutic effects on diabetes. There are also reports of UDPG activating P2Y as a ligand14The receptor has a great relationship with immune inflammation related diseases. Thus, P2Y14Receptors are considered as potential targets for inflammation-related diseases such as asthma, aseptic inflammation, diabetes, neurodegenerative diseases, and the like.
For P2Y at present14Receptor inhibitor studies have only reported 3 structural classes of compounds (pyrimido)Piperidines, 2-naphthoates, and 3-substituted benzoates), all in the preclinical stage of study. The 2-naphthoic acid inhibitor has the highest activity and selectivity, but the currently reported 2-naphthoic acid inhibitor has the defects of poor solubility, low oral bioavailability, great difficulty in synthesis and purification and the like, and brings great difficulty for further discussion of structure-activity relationship and biological evaluation. Thus finding a new structure type of P2Y14Receptor antagonist, which can improve the problems of poor drug formation and the like of 2-naphthoic acid inhibitor, and has strong activity and good selectivity, is the discovery of P2Y14Novel strategies for receptor inhibitors.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the technical problems, the invention provides a benzofuran small molecule P2Y14Receptor inhibitors, their preparation and use. The invention provides benzofuran derivatives as P2Y14The receptor inhibitor has good activity and good pharmaceutical property.
The technical scheme is as follows: in order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:
a benzofuran derivative has a structure represented by formula (I):
Figure BDA0002244312090000011
Figure BDA0002244312090000021
wherein, the
Figure BDA0002244312090000022
Is a substituted or unsubstituted C4-C5 heterocyclic group, or is a substituted or unsubstituted phenyl group, or is
Figure BDA0002244312090000023
n is 1 or 2.
Preferably, the substituted phenyl is phenyl substituted by halogen, C1-C4 alkyl or C1-C4 alkoxy, the C1-C4 alkyl or C1-C4 alkoxy, wherein 0-3 hydrogen atoms are substituted by halogen.
Preferably, the substituted phenyl group is a monosubstituted phenyl group.
Preferably, the
Figure BDA0002244312090000024
Is an unsubstituted five-or six-membered heterocyclic group containing a heteroatom of N, S or O, or is monosubstituted phenyl, or is
Figure BDA0002244312090000025
n is 1 or 2.
Further preferably, the
Figure BDA0002244312090000026
Is thienyl, tetrahydropyranyl, 4-butoxyphenyl, 4-tert-butylphenyl, 3, 4- (methylenedioxy) ylphenyl, 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl.
More preferably, the benzofuran derivative is selected from the following compounds:
Figure BDA0002244312090000027
Figure BDA0002244312090000031
the preparation method of the benzofuran derivative comprises the step of reacting a compound with a structure shown in a formula (II) with a compound with a structure shown in a formula (III) to obtain a compound with a structure shown in a formula (I);
Figure BDA0002244312090000032
wherein, the
Figure BDA0002244312090000033
As described above.
Preparation of the benzofuran derivative P2Y14The use of inhibitors.
Alternatively, the benzofuran derivative is used in preparation of P2Y14The application of the medicine in treating the inflammatory diseases related to the receptor.
The technical effects are as follows: compared with the prior art, the invention provides the benzofuran derivative and the preparation method and application thereof, and experimental results show that the benzofuran derivative provided by the invention has better P2Y14Inhibiting activity and anti-inflammatory activity, and can be used for preparing P2Y14A therapeutic agent for receptor-related inflammatory diseases.
Detailed Description
The following will be clearly and completely described in conjunction with the technical scheme of the embodiment of the invention, and the preparation reaction process is as follows:
Figure BDA0002244312090000041
example 1
(1) Synthesis of 2- (4-nitrophenyl) benzofuran:
Figure BDA0002244312090000042
salicylaldehyde (1.92mL), p-nitrobenzyl bromide (3.888g), potassium carbonate (2.484g),20mL N, N-Dimethylformamide (DMF) were added to a 50mL round bottom flask, heated to reflux at 80 ℃ overnight, monitored by TLC spotting, quenched after the reaction was complete by addition of water, added 400mL water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and rotary evaporated. The product was treated with petroleum ether: and (3) passing ethyl acetate (PE: EA) 10:1 through a column to obtain a yellow solid, namely the product.
1H NMR(600MHz,DMSO)δ8.33(d,J＝8.7Hz,2H),8.16(d,J＝8.8Hz,2H),7.77(s, 1H),7.72(d,J＝7.8Hz,1H),7.67(d,J＝8.3Hz,1H),7.39(t,J＝7.5Hz,1H),7.30(t,J＝ 7.5Hz,1H).
(2) Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (4-methoxyphenyl) acetamide:
Figure BDA0002244312090000043
2- (4-nitrophenyl) benzofuran, iron powder and ammonium chloride are added into 20mL of ethanol and water in a volume ratio of 1:10:3, the mixture is heated and refluxed at 80 ℃, the reaction is monitored by TLC, and the reaction is completed after 1 h. Filtering, extracting and drying, and passing PE (ethylene oxide) EA (20: 1) through a column to obtain 4- (benzofuran-2-yl) aniline which is light yellow solid. Adding the obtained product, 4-methoxyphenylacetic acid, EDCI, HOBt and DIPEA into 10mL of DMF at a molar ratio of 1:1:1.5:1.5:3, monitoring the reaction by TLC, adding water after the reaction is finished, quenching, extracting, drying and spin-drying. Adding a small amount of ethyl acetate to separate out a product, filtering and drying.
1H NMR(400MHz,DMSO)δ7.86(d,J＝8.7Hz,2H),7.74(d,J＝8.8Hz,2H),7.65– 7.58(m,2H),7.32–7.24(m,5H),6.90(d,J＝8.7Hz,2H),3.74(s,3H),3.60(s,2H).
13C NMR(101MHz,DMSO)δ169.69,158.07,155.23,154.07,139.85,130.13,129.00, 127.73,125.33,124.53,124.25,123.18,120.92,119.29,113.77,110.97,100.82,55.04,42.49, 39.52.
Example 2
Figure BDA0002244312090000051
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (4-chlorophenyl) acetamide:
the synthesis method is shown in example 1 by taking 4-chlorophenylacetic acid as a raw material.
1H NMR(600MHz,DMSO)δ7.84(d,J＝8.7Hz,2H),7.71(d,J＝8.7Hz,2H),7.60(d, J＝7.4Hz,1H),7.57(d,J＝8.0Hz,1H),7.36(dt,J＝18.3,5.3Hz,4H),7.29–7.25(m,2H), 7.24–7.20(m,1H),3.66(s,2H).
13C NMR(101MHz,DMSO)δ168.94,155.18,154.07,139.68,134.80,131.33,131.08, 128.98,128.24,125.34,124.65,124.26,123.18,120.92,119.34,110.96,100.87,42.46,39.52.
Example 3
Figure BDA0002244312090000052
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (4-bromophenyl) acetamide:
starting from 4-bromobenzeneacetic acid, the synthesis is described in example 1.
1H NMR(400MHz,DMSO)δ7.88–7.85(m,2H),7.74(d,J＝8.8Hz,2H),7.62(ddd, J＝14.5,4.9,0.8Hz,2H),7.55–7.52(m,2H),7.30(ddd,J＝10.7,5.7,2.0Hz,4H),7.25(td, J＝7.4,1.2Hz,1H),3.68(s,2H).
13C NMR(101MHz,DMSO)δ168.87,155.19,154.08,139.67,135.23,131.46,131.17, 128.98,125.35,124.66,124.26,123.18,120.92,119.81,119.34,110.96,100.87,42.53,40.15, 39.94,39.73,39.52,39.31,39.10,38.89.
Example 4
Figure BDA0002244312090000061
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (p-tolyl) acetamide:
the synthesis method of the compound is shown in example 1 by taking 4-methylphenylacetic acid as a raw material.
1H NMR(400MHz,DMSO)δ7.88–7.85(m,2H),7.74(d,J＝8.8Hz,2H),7.62(ddd, J＝14.1,5.0,0.8Hz,2H),7.32–7.28(m,2H),7.25(dd,J＝11.0,4.7Hz,3H),7.14(d,J＝ 7.9Hz,2H),3.62(s,2H),2.28(s,3H).
13C NMR(101MHz,DMSO)δ169.49,155.22,154.07,139.82,135.60,132.76,128.97, 128.89,125.32,124.55,124.24,123.17,120.91,119.30,110.96,100.82,42.99,40.15,39.94, 39.73,39.52,39.31,39.10,38.89,20.65.
Example 5
Figure BDA0002244312090000062
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (thiophen-2-yl) acetamide:
the synthesis method is shown in example 1 by taking 2-thiopheneacetic acid as a raw material.
1H NMR(400MHz,DMSO)δ7.89–7.86(m,2H),7.75(d,J＝8.8Hz,2H),7.63(ddd, J＝13.4,4.9,0.7Hz,2H),7.41(dd,J＝5.0,1.4Hz,1H),7.32(t,J＝1.2Hz,1H),7.31–7.23 (m,2H),7.03–6.98(m,2H),3.92(s,2H).
13C NMR(101MHz,DMSO)δ168.23,155.17,154.08,139.60,136.91,128.98,126.69, 126.43,125.37,125.13,124.73,124.28,123.18,120.93,119.37,110.98,100.92,39.52,37.58.
Example 6
Figure BDA0002244312090000063
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (4-butoxyphenyl) acetamide:
the synthesis was carried out as described in example 1, starting from 4-butoxyphenylacetic acid.
1H NMR(400MHz,DMSO)δ7.86(d,J＝8.7Hz,2H),7.75(d,J＝8.8Hz,2H),7.65– 7.58(m,2H),7.31–7.27(m,2H),7.25(d,J＝8.5Hz,3H),6.89(d,J＝8.6Hz,2H),3.93(t,J ＝6.5Hz,2H),3.59(s,2H),1.68(dd,J＝9.5,5.3Hz,2H),1.42(dd,J＝15.0,7.4Hz,2H), 0.92(t,J＝7.4Hz,3H).
13C NMR(151MHz,DMSO)δ169.67,157.48,155.21,154.05,139.83,130.08,128.98, 127.58,125.30,124.52,124.22,123.15,120.89,119.28,114.29,110.94,100.80,67.06,42.50, 39.94,39.80,39.66,39.52,39.38,39.24,39.10,30.75,18.73,13.68.
Example 7
Figure BDA0002244312090000071
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (tetrahydro-2H-pyran-4-yl) acetamide:
the synthesis method of tetrahydropyran 4-acetic acid used as a raw material is shown in example 1.
1H NMR(600MHz,DMSO)δ7.82(d,J＝8.7Hz,2H),7.71(d,J＝8.7Hz,2H),7.58 (dd,J＝19.8,7.7Hz,2H),7.28–7.24(m,2H),7.23–7.20(m,1H),3.80(dd,J＝11.4,2.6Hz, 2H),3.28(d,J＝1.6Hz,1H),3.26(d,J＝1.7Hz,1H),2.25(d,J＝7.1Hz,2H),1.57(dd,J＝ 12.8,1.6Hz,2H),1.23(ddd,J＝24.6,11.9,4.2Hz,2H).
13C NMR(101MHz,DMSO)δ170.21,155.26,154.05,139.76,128.99,125.27,124.42, 124.19,123.14,120.87,119.26,110.93,100.73,66.85,43.64,40.15,39.94,39.73,39.52, 39.31,39.10,38.89,32.39,32.07.
Example 8
Figure BDA0002244312090000072
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (4- (tert-butyl) phenyl) acetamide:
the synthesis process is described in example 1, using 4-tert-butyl phenylacetic acid as the starting material.
1H NMR(400MHz,DMSO)δ7.86(d,J＝8.7Hz,2H),7.74(d,J＝8.7Hz,2H),7.61 (dd,J＝14.4,7.6Hz,2H),7.35(d,J＝8.3Hz,2H),7.31(s,1H),7.29–7.22(m,4H),3.63(s, 2H),1.27(s,9H).
13C NMR(101MHz,DMSO)δ169.48,155.21,154.06,148.90,139.82,132.79,128.99, 128.76,125.32,125.09,124.55,124.24,123.17,120.91,119.28,110.96,100.82,42.94,39.52, 34.14,31.16.
Example 9
Figure BDA0002244312090000081
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (benzo [ d ] [1,3] dioxol-5-yl) acetamide:
the synthesis method of the compound is shown in example 1 by using 3, 4- (methylenedioxy) phenylacetic acid as a raw material.
1H NMR(400MHz,DMSO)δ7.86(d,J＝8.8Hz,2H),7.74(d,J＝8.8Hz,2H),7.65– 7.58(m,2H),7.32–7.27(m,2H),7.25(td,J＝7.4,1.1Hz,1H),6.92(d,J＝1.5Hz,1H), 6.87(d,J＝7.9Hz,1H),6.80(dd,J＝8.0,1.6Hz,1H),5.99(s,2H),3.58(s,2H).
13C NMR(101MHz,DMSO)δ169.44,155.22,154.08,147.17,145.96,139.79,129.41, 128.99,125.33,124.57,124.25,123.17,122.16,120.91,119.32,110.96,109.56,108.10, 100.81,42.93,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
Example 10
Figure BDA0002244312090000082
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (4- (trifluoromethyl) phenyl) acetamide:
the synthesis method of the compound is shown in example 1 by taking 4-trifluoromethyl phenylacetic acid as a raw material.
1H NMR(400MHz,DMSO)δ7.88(d,J＝8.8Hz,2H),7.73(dd,J＝12.8, 8.5Hz,4H),7.64(dd,J＝7.5,0.9Hz,1H),7.59(t,J＝7.6Hz,3H),7.33–7.28 (m,2H),7.25(td,J＝7.4,1.1Hz,1H),3.82(s,2H).
13C NMR(151MHz,DMSO)δ168.57,155.16,154.07,140.62,139.60,130.09,128.97, 127.46,127.25,125.35,125.13,124.72,124.26,123.16,120.91,119.37,110.95,100.89, 42.91,39.94,39.80,39.66,39.52,39.38,39.24,39.10.
Example 11
Figure BDA0002244312090000083
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (4- (trifluoromethoxy) phenyl) acetamide:
the synthesis method of the compound is shown in example 1 by taking 4-trifluoromethoxy phenylacetic acid as a raw material.
1H NMR(400MHz,DMSO)δ7.87(d,J＝8.8Hz,2H),7.74(d,J＝8.8Hz,2H),7.65– 7.58(m,2H),7.47(d,J＝8.7Hz,2H),7.35–7.27(m,4H),7.25(td,J＝7.4,1.1Hz,1H), 3.74(s,2H).
13C NMR(101MHz,DMSO)δ168.93,155.19,154.09,147.17,139.67,135.33,131.08, 128.99,125.35,124.69,124.27,123.18,121.39,120.93,119.36,118.84,110.97,100.89, 42.39,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
Example 12
Figure BDA0002244312090000091
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (2-bromophenyl) acetamide:
starting from 2-bromobenzeneacetic acid, the synthesis is described in example 1.
1H NMR(400MHz,DMSO)δ7.88(d,J＝8.7Hz,2H),7.75(d,J＝8.8Hz,2H),7.65– 7.59(m,3H),7.44(dd,J＝7.6,1.7Hz,1H),7.38(td,J＝7.5,1.1Hz,1H),7.32(s,1H),7.31– 7.27(m,1H),7.24(dt,J＝7.9,1.7Hz,2H),3.90(s,2H).
13C NMR(101MHz,DMSO)δ168.07,155.23,154.07,139.78,135.58,132.27,129.00, 128.84,127.62,125.37,124.60,124.56,124.25,123.18,120.91,119.27,110.97,100.83, 43.30,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
Example 13
Figure BDA0002244312090000092
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (o-tolyl) acetamide:
the synthesis method of the compound is shown in example 1 by taking 2-methylphenylacetic acid as a raw material.
1H NMR(400MHz,DMSO)δ7.87(d,J＝8.7Hz,2H),7.76(d,J＝8.7Hz,2H),7.65–7.59(m,2H),7.33–7.29(m,2H),7.28–7.25(m,2H),7.19–7.15(m,3H),3.73(s,2H), 2.32(s,3H).
13C NMR(101MHz,DMSO)δ169.27,155.24,154.08,139.82,136.69,134.52,129.99, 129.90,129.00,126.73,125.78,125.35,124.56,124.25,123.18,120.92,119.33,110.97, 100.82,41.00,40.15,39.94,39.73,39.52,39.31,39.10,38.89,19.40.
Example 14
Figure BDA0002244312090000101
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (2-chlorophenyl) acetamide:
the synthesis method is shown in example 1 by taking 2-chlorophenylacetic acid as a raw material.
1H NMR(400MHz,DMSO)δ7.88(d,J＝8.7Hz,2H),7.75(d,J＝8.7Hz,2H),7.62 (dd,J＝14.3,7.6Hz,2H),7.46(td,J＝5.9,2.1Hz,2H),7.34–7.28(m,4H),7.26(dd,J＝ 10.9,4.0Hz,1H),3.89(s,2H).
13C NMR(101MHz,DMSO)δ168.13,155.23,154.08,139.77,133.81,133.71,132.24, 129.01,128.64,127.07,125.37,124.58,124.25,123.17,120.91,119.28,110.97,100.83, 40.86,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
Example 15
Figure BDA0002244312090000102
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (2- (trifluoromethyl) phenyl) acetamide:
the synthesis method of 2-trifluoromethyl phenylacetic acid used as a raw material is shown in example 1.
1H NMR(400MHz,DMSO)δ7.88(d,J＝8.8Hz,2H),7.75–7.72(m,3H),7.68–7.59 (m,3H),7.57–7.49(m,2H),7.32(d,J＝0.6Hz,1H),7.31–7.23(m,2H),3.97(s,2H).
13C NMR(101MHz,DMSO)δ168.21,155.22,154.08,139.71,133.77,133.48,132.25, 129.00,127.73,127.44,127.35,125.66,125.61,125.38,124.60,124.25,123.18,120.92, 119.29,110.97,100.85,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
Example 16
Figure BDA0002244312090000103
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (3-methoxyphenyl) acetamide:
the synthesis method of 3-methoxyphenylacetic acid used as a raw material is shown in example 1.
1H NMR(400MHz,DMSO)δ7.89–7.85(m,2H),7.75(d,J＝8.8Hz,2H),7.65–7.62 (m,1H),7.62–7.59(m,1H),7.31(dd,J＝7.2,1.1Hz,2H),7.28–7.26(m,1H),7.26–7.23 (m,1H),6.93(t,J＝4.2Hz,2H),6.85–6.82(m,1H),3.76(s,3H),3.65(s,2H).
13C NMR(151MHz,DMSO)δ169.15,159.21,155.20,154.06,139.75,137.23,129.33, 128.97,125.32,124.59,124.24,123.16,121.32,120.90,119.32,114.93,111.95,110.95, 100.83,54.98,43.41,39.94,39.80,39.66,39.52,39.38,39.24,39.10.
Example 17
Figure BDA0002244312090000111
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (3- (trifluoromethoxy) phenyl) acetamide:
3-trifluoromethoxy phenylacetic acid is used as a raw material, and the synthesis method is shown in example 1.
1H NMR(400MHz,DMSO)δ7.90–7.86(m,2H),7.75(d,J＝8.8Hz,2H),7.65–7.62 (m,1H),7.62–7.59(m,1H),7.49(t,J＝7.9Hz,1H),7.40–7.36(m,2H),7.33–7.29(m, 2H),7.29–7.23(m,2H),3.78(s,2H).
13C NMR(101MHz,DMSO)δ168.63,155.17,154.07,148.29,139.60,138.42,130.12, 128.96,128.40,125.34,124.70,124.24,123.15,121.67,120.90,119.37,119.08,110.94, 100.88,42.61,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
Example 18
Figure BDA0002244312090000112
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (3-chlorophenyl) acetamide:
the synthesis method is shown in example 1 by taking 3-chlorophenylacetic acid as a raw material.
1H NMR(400MHz,DMSO)δ7.89–7.86(m,2H),7.75(d,J＝8.8Hz,2H),7.62(ddd, J＝13.8,4.9,0.7Hz,2H),7.44(s,1H),7.40–7.36(m,1H),7.35(t,J＝1.8Hz,1H),7.33– 7.30(m,3H),7.28–7.25(m,1H),3.72(s,2H).
13C NMR(101MHz,DMSO)δ168.74,155.18,154.08,139.64,138.20,132.84,130.13, 129.12,128.98,127.98,126.60,125.36,124.70,124.27,123.18,120.93,119.37,110.97, 100.89,42.68,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
Example 19
Figure BDA0002244312090000121
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (m-tolyl) acetamide:
the synthesis method of 3-methyl phenylacetic acid used as a raw material is shown in example 1.
1H NMR(400MHz,DMSO)δ7.87(d,J＝8.7Hz,2H),7.75(d,J＝8.7Hz,2H),7.62 (dd,J＝13.8,7.6Hz,2H),7.31(d,J＝6.3Hz,2H),7.26(dd,J＝7.6,3.3Hz,2H),7.17(dt,J ＝6.6,4.7Hz,3H),3.72(s,2H),2.31(s,3H).
13C NMR(101MHz,DMSO)δ169.26,155.24,154.08,139.81,136.69,134.51,129.99, 129.90,129.00,126.73,125.78,125.35,124.56,124.24,123.18,120.91,119.33,110.96, 100.82,41.00,40.15,39.94,39.73,39.52,39.31,39.10,38.89,19.40.
Example 20
Figure BDA0002244312090000122
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (3-bromophenyl) acetamide:
starting from 3-bromobenzeneacetic acid, the synthesis is described in example 1.
1H NMR(400MHz,DMSO)δ7.87(d,J＝8.6Hz,2H),7.74(d,J＝8.6Hz,2H),7.65– 7.57(m,3H),7.47(d,J＝7.7Hz,1H),7.37–7.31(m,3H),7.30–7.23(m,2H),3.71(s,2H).
13C NMR(101MHz,DMSO)δ168.76,155.18,154.08,139.63,138.49,131.98,130.45, 129.49,128.98,128.36,125.36,124.70,124.27,123.18,121.48,120.93,119.36,110.97, 100.90,42.63,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
Example 21
Figure BDA0002244312090000131
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (2-methoxyphenyl) acetamide:
the synthesis method of the compound is shown in example 1 by taking 2-methoxyphenylacetic acid as a raw material.
1H NMR(400MHz,DMSO)δ7.87(d,J＝8.6Hz,2H),7.76(d,J＝8.6Hz,2H),7.62 (dd,J＝13.3,7.6Hz,2H),7.32–7.28(m,2H),7.27–7.22(m,3H),6.99(d,J＝8.1Hz,1H), 6.92(t,J＝7.4Hz,1H),3.78(s,3H),3.67(s,2H).
13C NMR(101MHz,DMSO)δ169.31,157.24,155.28,154.05,139.96,130.81,128.99, 128.05,125.30,124.37,124.18,124.02,123.13,120.86,120.15,119.21,110.92,110.71, 100.70,55.41,39.52,37.76.
Example 22
Figure BDA0002244312090000132
Synthesis of N- (4- (benzofuran-2-yl) phenyl) -2- (3- (trifluoromethyl) phenyl) acetamide:
the synthesis method of 3-trifluoromethyl phenylacetic acid used as a raw material is shown in example 1.
1H NMR(400MHz,DMSO)δ7.88(d,J＝8.7Hz,2H),7.77–7.72(m,3H),7.66(d,J＝9.7Hz,2H),7.63–7.59(m,3H),7.33–7.29(m,2H),7.28–7.23(m,1H),3.84(s,2H).
13C NMR(101MHz,DMSO)δ168.68,155.15,154.07,139.58,137.12,133.45,129.28, 128.95,125.85,125.81,125.33,124.70,124.23,123.36,123.33,123.14,120.89,119.37, 110.92,100.86,42.61,39.52.
Example 23
Compounds of formula I as P2Y14Evaluation of inhibitory Activity of receptor inhibitors test methods:
stable rotation P2Y14The recipient HEK293 cell line was cultured in DMEM medium (containing 10% fetal bovine serum, 100U/ml penicillin and 100. mu.g/ml streptomycin), and inoculated on 384 culture plates one day before the experiment at an inoculation density of 1X 104Cell/well, cell at 37 ℃ 95% O2、5％CO2Culturing under humidity condition. Prior to the experiment, the medium was discarded, serum-free medium was used instead, and IBMX (500. mu.M) and Ro 20-1724 (100. mu.M) were added to inhibit PDEs activity to ensure cAMP at a higher level. The AC agonist Forskolin (30. mu.M) was used to stimulate cellular cAMP production, and varying concentrations of test compounds (0.01, 0.1, 1, 10, 100nM) were pre-added, with PPTN as a positive control. At the same time, 10. mu.M of P2Y was added14Receptor agonist UDPG, Glo according to cAMP after 30minTMThe Assay kit (PROMEGA co. ltd, usa) instructions were used to measure intracellular cAMP levels. Calculation of IC from the inhibition of cAMP content50The results are shown in Table 1, and Table 1 shows the cAMP inhibition ratios (100nM) and IC of the compounds obtained in examples 1 to 22 of the present invention50The value is obtained.
TABLE 1
Figure BDA0002244312090000141

Claims (3)

1. Benzofuran derivative, characterized in that it is chosen from the following compounds:
Figure FDA0003562803100000011
2. use of benzofuran derivatives according to claim 1 in the preparation of P2Y14The use of inhibitors.
3. Use of benzofuran derivatives according to claim 1 in the preparation of P2Y14The application of the medicine in treating the inflammatory diseases related to the receptor.
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