CN110776486A - Benzofuran micromolecule P2Y 14Receptor inhibitors, their preparation and use - Google Patents

Benzofuran micromolecule P2Y 14Receptor inhibitors, their preparation and use Download PDF

Info

Publication number
CN110776486A
CN110776486A CN201911011418.1A CN201911011418A CN110776486A CN 110776486 A CN110776486 A CN 110776486A CN 201911011418 A CN201911011418 A CN 201911011418A CN 110776486 A CN110776486 A CN 110776486A
Authority
CN
China
Prior art keywords
benzofuran
dmso
nmr
phenyl
synthesis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201911011418.1A
Other languages
Chinese (zh)
Other versions
CN110776486B (en
Inventor
胡庆华
李环球
刘春晓
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
China Pharmaceutical University
Original Assignee
China Pharmaceutical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by China Pharmaceutical University filed Critical China Pharmaceutical University
Priority to CN201911011418.1A priority Critical patent/CN110776486B/en
Publication of CN110776486A publication Critical patent/CN110776486A/en
Application granted granted Critical
Publication of CN110776486B publication Critical patent/CN110776486B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a benzofuran derivative shown as a formula (I), and a preparation method and application thereof. Experimental results show that the benzofuran derivative provided by the invention has better P2Y 14Inhibitory Activity and antiHaving inflammatory activity, can be used for preparing P2Y 14A therapeutic agent for receptor-related inflammatory diseases.

Description

Benzofuran micromolecule P2Y 14Receptor inhibitors, their preparation and use
Technical Field
The invention belongs to a small molecule P2Y 14The technical field of receptor inhibitors, in particular to a benzofuran micromolecule P2Y 14Receptor inhibitors, their preparation and use.
Background
P2Y 14The receptors belong toDelta-branching 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. P2Y 14Receptors 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 P2Y 14In receptor knockout mice, P2Y 14Antagonism of the receptor has potential therapeutic effects on diabetes. There are also reports of UDPG activating P2Y as a ligand 14The receptor has a great relationship with immune inflammation related diseases. Thus, P2Y 14Receptors are considered as potential targets for inflammation-related diseases such as asthma, aseptic inflammation, diabetes, neurodegenerative diseases, and the like.
For P2Y at present 14Receptor inhibitor studies only reported that 3 structural classes of compounds (pyrimidopiperides, 2-naphthoates and 3-substituted benzoic acids) were in preclinical phase. 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 P2Y 14The receptor antagonist solves the problems of poor drug forming property and the like of the 2-naphthoic acid inhibitor, and is found to be P2Y with strong activity and good selectivity 14Novel 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 P2Y 14Receptor inhibitors, their preparation and use. The invention provides benzofuran derivatives as P2Y 14The 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 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 has 0-3 hydrogen atoms 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-tris (methylene dioxy) phenylFluoromethylphenyl, 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 P2Y 14The use of inhibitors.
Alternatively, the benzofuran derivative is used in preparation of P2Y 14The 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 P2Y 14Inhibiting activity and anti-inflammatory activity, and can be used for preparing P2Y 14A 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:
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
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
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 P2Y 14Evaluation of inhibitory Activity of receptor inhibitors test methods:
stable rotation P2Y 14The 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 the 384 plates one day before the experiment at a density of 1X 10 4Cell/well, cell at 37 ℃ 95% O 2、5％CO 2Culturing under humidity condition. Medium was discarded before the experiment, 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 added 14Receptor agonist UDPG, Glo according to cAMP after 30min TMThe Assay kit (PROMEGA co. ltd, usa) instructions were used to measure intracellular cAMP levels. Calculation of IC from the inhibition of cAMP content 50The 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 invention 50The value is obtained.
TABLE 1
Figure BDA0002244312090000141

Claims (8)

1. A benzofuran derivative having the structure shown in formula (I):
Figure FDA0002244312080000011
wherein, the
Figure FDA0002244312080000012
Is a substituted or unsubstituted C4-C5 heterocyclic group, or is a substituted or unsubstituted phenyl group, or is
Figure FDA0002244312080000013
n is 1 or 2.
2. The benzofuran derivative according to claim 1, wherein said substituted phenyl is phenyl substituted by halogen, alkyl of C1-C4 or alkoxy of C1-C4, alkyl of C1-C4 or alkoxy of C1-C4, wherein 0-3 hydrogen atoms are substituted by halogen.
3. Benzofuran derivative according to claim 1, wherein said substituted phenyl group is a monosubstituted phenyl group.
4. Benzofuran derivative according to claim 1, wherein said compound is selected from the group consisting of
Figure FDA0002244312080000014
Is an unsubstituted five-or six-membered heterocyclic group containing a heteroatom of N, S or O, or is monosubstituted phenyl, or is
Figure FDA0002244312080000015
n is 1 or 2.
5. Benzofuran derivative according to claim 1, selected from the group consisting of:
Figure FDA0002244312080000016
。
6. the process for preparing benzofuran derivative according to any one of claims 1 to 5, comprising reacting a compound having the structure of formula (II) with a compound having the structure of formula (III) to obtain a compound having the structure of formula (I);
Figure FDA0002244312080000022
wherein, the
Figure FDA0002244312080000023
As described in any one of claims 1 to 5.
7. Use of benzofuran derivatives as claimed in any one of claims 1 to 5 in the preparation of P2Y 14The use of inhibitors.
8. Use of benzofuran derivatives as claimed in any one of claims 1 to 5 in the preparation of P2Y 14The application of the medicine in treating the inflammatory diseases related to the receptor.
CN201911011418.1A 2019-10-23 2019-10-23 Benzofuran micromolecule P2Y14Receptor inhibitors, their preparation and use Active CN110776486B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201911011418.1A CN110776486B (en) 2019-10-23 2019-10-23 Benzofuran micromolecule P2Y14Receptor inhibitors, their preparation and use

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201911011418.1A CN110776486B (en) 2019-10-23 2019-10-23 Benzofuran micromolecule P2Y14Receptor inhibitors, their preparation and use

Publications (2)

Publication Number Publication Date
CN110776486A true CN110776486A (en) 2020-02-11
CN110776486B CN110776486B (en) 2022-05-20

Family

ID=69386520

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201911011418.1A Active CN110776486B (en) 2019-10-23 2019-10-23 Benzofuran micromolecule P2Y14Receptor inhibitors, their preparation and use

Country Status (1)

Country Link
CN (1) CN110776486B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116444482A (en) * 2023-06-14 2023-07-18 中国药科大学 Thiophene-2-carboxylic acid derivative, preparation method and medical application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070117853A1 (en) * 2004-07-02 2007-05-24 Santen Pharmaceutical Co., Ltd Inhibitor of pain threshold decrease
CN1989122A (en) * 2004-05-18 2007-06-27 拜耳医药保健股份公司 Novel cylopenta[b]benzofuran derivatives and the utilization thereof
US20080171786A1 (en) * 2004-11-20 2008-07-17 Ulf Bruggemeier Substituted [(Phenylethanoyl)Amino]Benzamides
CN109574949A (en) * 2018-12-27 2019-04-05 苏州大学 Benzoxazoles derivative and its preparation method and application

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1989122A (en) * 2004-05-18 2007-06-27 拜耳医药保健股份公司 Novel cylopenta[b]benzofuran derivatives and the utilization thereof
US20070117853A1 (en) * 2004-07-02 2007-05-24 Santen Pharmaceutical Co., Ltd Inhibitor of pain threshold decrease
US20080171786A1 (en) * 2004-11-20 2008-07-17 Ulf Bruggemeier Substituted [(Phenylethanoyl)Amino]Benzamides
CN109574949A (en) * 2018-12-27 2019-04-05 苏州大学 Benzoxazoles derivative and its preparation method and application

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
COLUMBUS, OHIO, US REGISTRY[ONLINE]: "STN检索报告", 《STN REGISTRY》 *
王杰 等: "基于P2Y1受体药物研究进展", 《药物生物技术》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116444482A (en) * 2023-06-14 2023-07-18 中国药科大学 Thiophene-2-carboxylic acid derivative, preparation method and medical application thereof
CN116444482B (en) * 2023-06-14 2023-09-22 中国药科大学 Thiophene-2-carboxylic acid derivative, preparation method and medical application thereof

Also Published As

Publication number Publication date
CN110776486B (en) 2022-05-20

Similar Documents

Publication Publication Date Title
KR101094003B1 (en) Ep4 receptor antagonists
AU2007269572A1 (en) 3,4-di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
EP1532113A2 (en) Substituted hihydroquinolines as glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
WO2005058883A1 (en) 2, 6 bisheteroaryl-4-aminopyrimidines as adenosine receptor antagonists
KR101312198B1 (en) New compounds as adenosine a1 receptor antagonists
WO2003059871A1 (en) N-alkylsulfonyl-substituted amide derivatives
KR100779324B1 (en) Substituted 3-cyanothiophene acetamides as glucagon receptor antagonists
CA2726449A1 (en) Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
MX2014003958A (en) Novel disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases.
JP2023537271A (en) Thiophene HSD17B13 inhibitors and uses thereof
JP4409935B2 (en) Aminoquinoline and aminopyridine derivatives and their use as adenosine A3 ligands
CN110776486B (en) Benzofuran micromolecule P2Y14Receptor inhibitors, their preparation and use
CZ13393A3 (en) Oxime derivatives, process of their preparation and a pharmaceutical composition in which said derivatives are comprised
WO2012038904A1 (en) Nicotinamide derivatives, preparation thereof and therapeutic use thereof
CN106414434B (en) Isothiazole derivatives as GPR120 agonists for the treatment of type II diabetes
FI89492B (en) For the preparation of pharmacologically active substances tetrahydro-6H-thiazolo / 5,4-d / azepine
EP1023269A1 (en) Beta3-adrenoreceptor agonists, agonist compositions and methods of using
JP2015214527A (en) Imidazole derivative
CN114478511B (en) Benzoxazole compound and preparation method, pharmaceutical composition and application thereof
CN105037305A (en) 5-hydroxy-2 '-nitro aurone or 5-hydroxy-4' -nitro aurone derivative and application thereof
US7411076B2 (en) Coumarin derivative
CN113493433B (en) Benzopyrone derivative capable of serving as GPR35 receptor agonist, preparation method and application thereof
JPH03193746A (en) Substituted alkylamine derivative
WO2020114290A1 (en) 3-carboxyl coumarin derivative capable of being used as a gpr35 agonist, preparation method, and application
WO2020253352A1 (en) Compound, preparation method therefor and use thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant