CN109879772B - Benzylaminoyl derivative and application thereof in preparation of anti-inflammatory drugs - Google Patents
Benzylaminoyl derivative and application thereof in preparation of anti-inflammatory drugs Download PDFInfo
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Abstract
The invention provides a compound shown as a formula A, or pharmaceutically acceptable salt or solvate thereof, and application thereof in preparing anti-inflammatory drugs. Experiments prove that the compound shown in the formula A can obviously inhibit NO generation induced by LPS, has strong anti-inflammatory capability and low cytotoxicity, and can be applied to preparation of clinical anti-inflammatory drugs.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a benzylaminoyl derivative and application thereof in preparing an anti-inflammatory medicament.
Background
Inflammation is a vital pathological process in the human body that is itself an autoimmune response as a stimulus to foreign or foreign bodies. When this response is deregulated or over-responsive, it results in self-injury to the body, which becomes inflammatory. Most diseases are accompanied by the mediation and occurrence of inflammation, which in turn aggravates the damage to the body, such as acute lung injury, rheumatoid arthritis, diabetic complications, cancer, atherosclerosis, inflammatory bowel disease, and the like. In these processes, proinflammatory factors such as TNF- α, IL-6, IL-1 β, etc. play an important role.
At present, the prior art has more treatment drugs aiming at inflammation, and most drugs used comprise steroids and non-steroidal anti-inflammatory drugs, but have side effects or drug resistance. For example, indomethacin, a classical anti-inflammatory drug, has good anti-inflammatory activity, but because it is a non-selective COX-2 inhibitor, patients are often associated with severe gastrointestinal adverse reactions, such as nausea, vomiting, abdominal pain, diarrhea, ulcers, and sometimes gastric bleeding and perforation; patent US5506224 reports an N-acyl-derivative of hydroxylamine, suitable for the therapeutic treatment of pathological conditions characterized by: degranulation of mast cells (degranulation) due to neurogenic and/or immunogenic hyperstimulation. However, administration of the compounds disclosed therein may be accompanied by an increase in the levels of nitrite/nitrate in the blood which is considered undesirable. Therefore, the development of a drug with high efficiency, broad-spectrum anti-inflammatory effect and few adverse reactions becomes a technical problem to be solved urgently by the technical personnel in the field.
Disclosure of Invention
In order to solve the problems, the invention provides benzylaminoyl derivatives and application thereof in anti-inflammatory drugs.
The present invention provides a compound represented by formula a, or a pharmaceutically acceptable salt thereof, or a solvate thereof:
wherein:
l is selected from C1～2Alkylene, or a mixture thereof,
R1、R2Each independently selected from H, C1～6Alkyl or-C (O) R4；
n is an integer of 0 to 10;
R3selected from H, C1～6Alkyl radical, C1～6Alkoxy, aryl, heteroaryl, cycloalkyl or heterocycloalkyl;
R4is C1～6An alkyl group.
Further, the air conditioner is provided with a fan,
the structure of the compound is shown as formula I:
wherein:
R1、R2each independently selected from H, C1～6Alkyl or-C (O) R4；
n is an integer of 0 to 10;
R3selected from H, C1～6Alkyl radical, C1～6Alkoxy, aryl, heteroaryl, cycloalkyl or heterocycloalkyl;
R4is C1～4An alkyl group.
Further, R1、R2Each independently selected from H, methyl or-C (O) CH3。
Further, R3Selected from H, methyl, isopropyl or phenyl.
Further, the compound has the following structure:
further, the air conditioner is provided with a fan,
the structure of the compound is shown as formula II:
wherein R1, R2, n have the same meanings as defined in claim 1.
Further, the air conditioner is provided with a fan,
the structure of the compound is shown as follows:
the invention also provides a preparation method of the compound or the pharmaceutically acceptable salt or the solvate thereof, which is characterized in that: comprises the following steps:
(a) reacting the raw material A with N, N' -carbonyl diimidazole to obtain a compound B;
(b) directly adding 3, 4-dimethoxyphenyl primary amine into the compound B obtained in the step (a) without separation for reaction, extracting by ethyl acetate after the reaction is finished, and separating by silica gel column chromatography to obtain a compound C;
(c) adding compound C to BBr in ice bath3Reacting at room temperature, decomposing a reaction product by citric acid after the reaction is finished, extracting by ethyl acetate, and separating by silica gel column chromatography to obtain a compound D;
(d) reacting the compound D with acetic anhydride in the presence of pyridine, after the reaction is finished, extracting a reaction product by ethyl acetate, decomposing by citric acid, and separating by silica gel column chromatography to obtain a compound E;
wherein the raw material A has the following structural formula:
compound B has the following structural formula:
compound C has the following structural formula:
compound D has the following structural formula:
compound E has the following structural formula:
the invention also provides application of the compound, or pharmaceutically acceptable salt or solvate thereof in preparing anti-inflammatory drugs.
The invention also provides an anti-inflammatory pharmaceutical composition, which is characterized in that: the compound, the pharmaceutically acceptable salt thereof or the solvate thereof according to any one of claims 1 to 8, and pharmaceutically acceptable auxiliary materials.
In the present invention, "substituted" means that a hydrogen atom in a molecule is replaced with another different atom or molecule.
In the present invention, the minimum and maximum carbon atom content of a hydrocarbon group is indicated by a prefix, e.g., the prefix Ca-b alkyl indicates any alkyl group containing "a" to "b" carbon atoms, including straight chain and branched chain alkyl groups. Thus, for example, C1～6The alkyl group refers to a straight-chain alkyl group and a branched-chain alkyl group having 1 to 6 carbon atoms.
In the present invention, the substituent "-C (O) R4The structural formula is
In the present invention, the "pharmaceutically acceptable salt" refers to a salt formed by the compound of the present invention with an acid or a base, which is suitable for use as a medicament. Pharmaceutically acceptable salts include inorganic and organic salts.
As used herein, "solvate" refers to a compound of the present invention that forms a solvate with a pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable solvent includes (but is not limited to): water, ethanol, methanol, isopropanol, propylene glycol, tetrahydrofuran, and dichloromethane.
The pharmaceutically acceptable auxiliary material has certain physiological activity, but the addition of the component does not change the dominance of the medicinal composition in the process of treating diseases, but only plays an auxiliary effect, and the auxiliary effects are only utilization of the known activity of the component and are auxiliary treatment modes which are commonly used in the field of medicine. If the auxiliary components are used together with the pharmaceutical composition of the present invention, the protection scope of the present invention still remains.
The invention provides benzylaminoyl derivatives shown in formula I and application thereof, wherein the benzylaminoyl derivatives can obviously inhibit generation of nitrogen monoxide (NO) induced by LPS, have strong anti-inflammatory capability and low cytotoxicity, and can be applied to preparation of clinical anti-inflammatory drugs.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a graph showing the inhibition rate of intracellular NO by the compounds of the present invention.
FIG. 2 is a cytotoxicity assay of compounds of the invention.
FIG. 3 is a graph showing the concentration dependence of intracellular NO on the compound of the present invention, and IC of the compound of the present invention50The value is obtained.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
Experimental example 1 Synthesis of Compound of the present invention
Compound 2:
n- (3,4-dimethoxybenzyl) nonanamide (0.154g, 0.5mmol) was dissolved in anhydrous dichloromethane (10mL), boron tribromide (57. mu.L, 0.6mmol) was added to the solution, the reaction was carried out at room temperature for 2 hours, 30mL of water, 50mL of ethyl acetate and 0.5g of citric acid were added, the reaction was stirred for 2 hours, the ethyl acetate solution was dehydrated over anhydrous sodium sulfate, ethyl acetate was recovered, and the residue was subjected to silica gel column chromatography (petroleum ether-ethyl acetate (3: 1)) to obtain Compound 2(0.112g, 80%). 1H NMR (400MHz, CDCl)3)δ8.44(s,1H),6.86(d,J＝1.9Hz,1H),6.83(d,J＝8.0Hz,1H),6.64(dd,J＝8.0,2.0Hz,1H),6.26(s,1H,OH),6.01(s,1H,OH),4.32(d,J＝5.9Hz,2H),2.32–2.17(m,2H),1.70–1.55(m,2H),1.27(q,J＝7.5,6.7Hz,10H),0.89(t,J＝6.9Hz,3H)；13C NMR(101MHz,DMSO-D6)δ172.4,145.5,144.5,131.0,118.6,115.7,115.4,42.1,35.9,31.7,29.2,29.2,29.1,25.8,22.6,14.4。
Compound 3:
dissolving synthesized capsaicin (0.147g, 0.5mmol) in anhydrous pyridine (5mL), adding acetic anhydride (1.0 mL), reacting overnight, adding water to dilute 30mL, ethyl acetate (50 mL), washing ethyl acetate layer with 2% citric acid aqueous solution, discarding water solution, dehydrating ethyl acetate solution with anhydrous sodium sulfate, recovering ethyl acetate, and performing silica gel column chromatography (petroleum ether-ethyl acetate (4: 1)) on the residue to obtain compound 3.1H NMR(400MHz,Chloroform-d)δ6.98(d,J＝8.1Hz,1H),6.90(d,J＝1.9Hz,1H),6.84(dd,J＝8.0,1.9Hz,1H),5.68(s,1H),4.42(d,J＝5.7Hz,2H),3.82(s,3H),2.31(s,3H),2.21(t,J＝7.6Hz,2H),1.65(q,J＝7.3Hz,2H),1.28(d,J＝13.1Hz,13H),0.87(t,J＝6.7Hz,3H)；13C NMR(101MHz,CDCl3)δ173.01,169.14,151.20,139.06,137.44,122.84,120.02,112.16,55.89,43.42,36.82,31.81,29.34,29.32,29.15,25.78,22.64,20.65,14.08.
Compound 4:
dissolving compound 2(0.140g, 0.5mmol) in anhydrous pyridine (5mL), adding acetic anhydride 1.0mL, reacting overnight, diluting with water 30mL, ethyl acetate 50mL, extracting, washing ethyl acetate layer with 2% citric acid aqueous solution, discarding water solution, dehydrating ethyl acetate solution with anhydrous sodium sulfate, recovering ethyl acetate, and performing silica gel column chromatography (petroleum ether-ethyl acetate (4: 1)) on the residue to obtain compound 4(0.149g, 82%).1H NMR(400MHz,CDCl3)δ7.23–7.17(m,2H),7.15(d,J＝4.6Hz,1H),5.75(s,1H),4.46(d,J＝5.8Hz,2H),2.31(s,6H),2.28–2.19(m,2H),1.72–1.62(m,2H),1.34–1.22(m,10H),0.90(td,J＝6.6,4.1Hz,3H)；13C NMR(101MHz,CDCl3)δ173.1,168.4,168.3,142.1,141.3,137.4,126.1,123.6,122.8,42.8,36.7,31.9,29.5,29.4,29.3,25.7,22.7,20.6,20.6,14.1。
Compound 5: n- (3,4-dimethoxybenzyl) -3-methylbutanamide
Accurately sucking 10mL of an anhydrous tetrahydrofuran solution (9.7mg/mL) of CDI into a 100mL flask (CDI0.097g, 0.6mmol), adding isovaleric acid (0.051g, 0.5mmol), stirring at room temperature for reaction for 3h, adding 3, 4-dimethoxybenzylamine (0.083g, 0.5mmol), stirring for reaction overnight, rotary evaporating tetrahydrofuran, adding 40mL of ethyl acetate and 50mL of water to the residue, extracting the ethyl acetate solution with anhydrous sodium sulfate, recovering ethyl acetate, and performing silica gel column chromatography on the residue (petroleum ether-ethyl acetate (5: 1) to obtain compound 5(0.101g, 80%).1H NMR(400MHz,CDCl3)δ7.03(d,J＝1.0Hz,1H),6.78(s,2H),4.34(d,J＝5.7Hz,2H),3.82(s,3H),3.80(s,3H),2.07(s,2H),0.93(d,J＝6.4Hz,6H)；13CNMR(101MHz,CDCl3)δ172.7,149.1,148.3,135.2,131.1,120.0,111.1,55.9,55.8,46.1,43.3,26.3,22.5。
Compound 6: n- (3,4-dimethoxybenzyl) pentanamide
Accurately sucking 10mL of an anhydrous tetrahydrofuran solution (9.7mg/mL) of CDI into a 100mL flask (CDI0.097g, 0.6mmol), adding n-pentanoic acid (0.052g, 0.5mmol), stirring at room temperature for reaction for 3h, adding 3, 4-dimethoxybenzylamine (0.085g, 0.5mmol), stirring for reaction overnight, rotary evaporating tetrahydrofuran, adding 40mL of ethyl acetate and 50mL of water to the residue for extraction, dehydrating the ethyl acetate solution with anhydrous sodium sulfate, recovering ethyl acetate, and performing silica gel column chromatography on the residue (petroleum ether-ethyl acetate (5: 1) to obtain compound 6(0.109g, 86%).1H NMR(400MHz,CD3OD)δ6.99–6.90(m,1H),6.90(s,1H),6.85(d,J＝1.9Hz,1H),4.31(s,2H),3.83(d,J＝4.1Hz,6H),2.25(t,J＝7.5Hz,2H),1.72–1.52(m,2H),1.46–1.26(m,2H),0.95(t,J＝7.4Hz,3H)；13C NMR(101MHz,CD3OD)δ174.7,149.1,148.3,131.6,119.8,111.5,111.3,55.1,55.0,42.4,35.5,27.9,22.0,12.7。
Compound 8: n- (3,4-dimethoxybenzyl) octanamide
Weighing CDI (0.97g, 6mmol) and dissolving in anhydrous tetrahydrofuran (100mL) to obtain 9.7mg of tetrahydrofuran solution containing CDI per 1mL, sucking 10mL of the solution into a 100mL flask, adding octanoic acid (0.072g, 0.5mmol), stirring at normal temperature for reaction for 3h, adding 3, 4-dimethoxybenzylamine (0.083g, 0.5mmol), stirring for reaction overnight, evaporating tetrahydrofuran, adding 40mL of ethyl acetate and 50mL of water into the residue for extraction, dehydrating the ethyl acetate solution with anhydrous sodium sulfate, recovering ethyl acetate, and carrying out silica gel column chromatography (petroleum ether-ethyl acetate (5: 1) on the residue to obtain compound 8(0.125g, 85%).1H NMR(400MHz,CDCl3)δ6.79(s,3H),5.83(s,1H),4.34(d,J＝5.7Hz,2H),3.84(s,6H),2.25–2.12(m,2H),1.69–1.57(m,2H),1.26(dd,J＝11.3,4.7Hz,8H),0.93–0.77(m,3H)；13C NMR(101MHz,CDCl3)δ173.0,149.1,148.4,131.1,120.1,111.2,111.1,55.9,55.9,43.4,36.8,31.7,29.3,29.0,25.8,22.6,14.1。
Compound 9: n- (3,4-dimethoxybenzyl) decanoamide
Accurately sucking 10mL of CDI anhydrous tetrahydrofuran solution (9.7mg/mL) into a 100mL flask (CDI0.097g, 0.6mmol), adding n-decanoic acid (0.086g, 0.5mmol), stirring at room temperature for reaction for 3h, adding 3, 4-dimethoxybenzylamine (0.083g, 0.5mmol), stirring for reaction overnight, steaming tetrahydrofuran, adding 60mL of ethyl acetate and 50mL of water to the residue, extracting, filtering, dissolving the filter cake with ethyl acetate, dehydrating with anhydrous sodium sulfate, recovering ethyl acetate, and subjecting the residue to silica gel column chromatography (petroleum ether-ethyl acetate (5: 1) to obtain compound 9(0.142g, 88%).1H NMR(400MHz,CDCl3)δ6.80(s,3H),4.36(d,J＝5.7Hz,2H),3.86(s,6H),2.30–2.11(m,2H),1.68–1.57(m,2H),1.26(d,J＝15.5Hz,12H),0.86(t,J＝6.9Hz,3H)；13C NMR(101MHz,CDCl3)δ173.0,149.1,148.5,131.1,120.1,111.2,111.1,56.0,55.9,43.4,36.9,31.9,29.5,29.4,29.3,29.3,25.8,22.7,14.1。
Compound 10: n- (3,4-dimethoxybenzyl) -5-phenylpentanamide
Accurately sucking 10mL of an anhydrous tetrahydrofuran solution (9.7mg/mL) of CDI into a 100mL flask (CDI0.097g, 0.6mmol), adding phenylpentanoic acid (0.089g, 0.5mmol), stirring at room temperature for reaction for 3 hours, adding 3, 4-dimethoxybenzylamine (0.084g, 0.5mmol), stirring for reaction overnight, rotary evaporating tetrahydrofuran, adding 40mL of ethyl acetate and 50mL of water to the residue for extraction, dehydrating the ethyl acetate solution with anhydrous sodium sulfate, recovering ethyl acetate, and subjecting the residue to silica gel column chromatography (petroleum ether-ethyl acetate (5: 1) to obtain compound 10(0.137g, 83%).1H NMR(400MHz,CDCl3)δ7.26(t,J＝7.3Hz,2H),7.22–6.95(m,3H),6.79(d,J＝2.9Hz,3H),5.72(s,1H),4.35(d,J＝5.7Hz,2H),3.86(s,3H),3.82(s,3H),2.62(t,J＝7.3Hz,2H),2.21(t,J＝7.2Hz,2H),1.80–1.47(m,4H)；13C NMR(101MHz,CDCl3)δ172.6,149.2,148.5,142.2,131.0,128.4,128.3,125.8,120.1,111.2,56.0,55.9,43.4,36.7,35.7,31.1,25.4。
Compound 11: n- (3, 4-dihydrobenzinyl) -3-methylbutanamide
Compound 5(0.125g, 0.5mmol) was dissolved in anhydrous dichloromethane (10mL), boron tribromide (57. mu.L, 0.6mmol) was added to the mixture in ice bath to react at room temperature for 2 hours, 30mL of water was added, 50mL of ethyl acetate and 0.5g of citric acid were added to the mixture, the reaction was stirred for 2 hours, the ethyl acetate solution was dehydrated with anhydrous sodium sulfate, ethyl acetate was recovered, and the residue was subjected to silica gel column chromatography (petroleum ether-ethyl acetate (3: 1)) to give compound 16(0.087g, 78%).1H NMR(400MHz,CD3OD)δ6.79–6.66(m,2H),6.65–6.57(m,1H),4.22(d,J＝3.8Hz,2H),2.10(d,J＝2.1Hz,2H),1.07–0.83(m,6H)；13C NMR(101MHz,CD3OD)δ173.86,145.0,144.2,130.1,118.9,114.8,114.6,50.8,45.0,42.4,26.1,21.3；HRMSESI:[M+Na]+,found 246.10953,C12H17NO3Na,246.11061requires。
Compound 12: n- (3, 4-dihydrobenzinyl) pentanamide
Compound 6(0.126g, 0.5mmol) was dissolved in anhydrous dichloromethane (10mL), boron tribromide (57. mu.L, 0.6mmol) was added to the mixture in ice bath to react at room temperature for 2 hours, 30mL of water was added, 50mL of ethyl acetate and 0.5g of citric acid were added to the mixture, the mixture was stirred for reaction for 2 hours, the ethyl acetate solution was dehydrated with anhydrous sodium sulfate, ethyl acetate was recovered, and the residue was subjected to silica gel column chromatography (petroleum ether-ethyl acetate (3: 1)) to give compound 12(0.092g, 82%).1H NMR(400MHz,CD3OD)δ7.92(s,1H),6.81–6.67(m,2H),6.61(dd,J＝8.1,2.0Hz,1H),4.21(s,2H),2.23(t,J＝7.5Hz,2H),1.62(dd,J＝8.8,6.5Hz,2H),1.46–1.31(m,2H),0.95(t,J＝7.4Hz,3H)；13C NMR(101MHz,CD3OD)δ174.6,145.0,144.2,130.1,118.8,114.8,114.6,42.4,35.5,27.9,22.0,12.7。
Compound 14: n- (3, 4-dihydrobenzoyl) octanamide
Compound 8(0.146g, 0.5mmol) was dissolved in anhydrous dichloromethane (10mL), boron tribromide (57. mu.L, 0.6mmol) was added to the mixture in ice bath to react at room temperature for 2 hours, 30mL of water was added, 50mL of ethyl acetate and 0.5g of citric acid were added to the mixture, the reaction was stirred for 2 hours, the ethyl acetate solution was dehydrated with anhydrous sodium sulfate, ethyl acetate was recovered, and the residue was subjected to silica gel column chromatography (petroleum ether-ethyl acetate (3: 1)) to give compound 14(0.108g, 81%).1H NMR(400MHz,CD3OD)δ6.78–6.69(m,1H),6.61(dd,J＝8.1,2.1Hz,1H),4.21(s,1H),2.22(t,J＝7.5Hz,1H),1.64(d,J＝7.2Hz,1H),1.38–1.27(m,8H),0.91(d,J＝7.1Hz,1H)；13C NMR(101MHz,CD3OD)δ174.6,145.0,144.2,130.1,118.8,114.8,114.6,42.4,35.7,31.5,28.9,28.7,25.7,22.3,13.0。
Compound 15: n- (3, 4-dihydrobenzinyl) decanoamide
Compound 9(0.161g, 0.5mmol) was dissolved in anhydrous dichloromethane (10mL), boron tribromide (57. mu.L, 0.6mmol) was added to the mixture in ice bath to react at room temperature for 2 hours, 30mL of water was added, 50mL of ethyl acetate and 0.5g of citric acid were added to the mixture, the reaction was stirred for 2 hours, the ethyl acetate solution was dehydrated with anhydrous sodium sulfate, ethyl acetate was recovered, and the residue was subjected to silica gel column chromatography (petroleum ether-ethyl acetate (3: 1)) to give compound 15(0.121g, 82%).1H NMR(400MHz,DMSO-D6)δ8.81(s,2H),8.13(t,J＝5.7Hz,1H),6.65(d,J＝8.0Hz,2H),6.48(dd,J＝8.0,1.9Hz,1H),4.07(d,J＝5.8Hz,2H),2.09(t,J＝7.4Hz,2H),1.57–1.43(m,2H),1.25(s,12H),0.87(t,J＝6.8Hz,3H)；13C NMR(101MHz,DMSO-D6)δ172.3,145.5,144.5,131.0,118.6,115.7,115.4,42.1,35.8,31.8,29.4,29.3,29.2,29.2,25.8,22.6,14.45。
Compound 16: n- (3,4-dihydroxybenzyl) -5-phenylpentanamide
Compound 10(0.163g, 0.5mmol) was dissolved in anhydrous dichloromethane (10mL), boron tribromide (57. mu.L, 0.6mmol) was added to the mixture in ice bath to react at room temperature for 2 hours, 30mL of water was added, 50mL of ethyl acetate and 0.5g of citric acid were added to the mixture, the reaction was stirred for 2 hours, the ethyl acetate solution was dehydrated with anhydrous sodium sulfate, ethyl acetate was recovered, and the residue was subjected to silica gel column chromatography (petroleum ether-ethyl acetate (3: 1)) to give compound 16(0.117g, 78%).1H NMR(400MHz,DMSO-D6)δ8.84(s,1H,OH),8.75(s,1H,OH),8.16(t,J＝5.8Hz,1H),7.38–7.23(m,2H),7.18(d,J＝6.8Hz,3H),6.65(dd,J＝5.0,3.0Hz,2H),6.49(dd,J＝8.0,2.0Hz,1H),4.08(d,J＝5.8Hz,2H),2.57(t,J＝7.0Hz,2H),2.14(t,J＝6.8Hz,2H),1.55(t,J＝3.5Hz,4H)；13C NMR(101MHz,DMSO-D6)δ172.2,145.5,144.5,142.6,131.0,128.7,126.1,118.6,115.7,115.4,42.2,35.7,35.4,31.1,25.5。
Compound 17:
dissolving 6-phenylhexanedione (0.528g,3mmol) in 10mL tetrahydrofuran, adding 100 μ L pyrrolidine and 60 μ L glacial acetic acid, stirring at room temperature for 10min, adding 3, 4-dihydroxybenzaldehyde (0.138g, 1mmol), reacting at 50 ℃ for 20h under nitrogen protection, adding 80mL water, extracting with 80mL ethyl acetate for 2 times, combining ethyl acetate layers, drying the ethyl acetate layer with anhydrous sodium sulfate, recovering the ethyl acetate layer under reduced pressure, performing silica gel column chromatography, eluting with petroleum ether-ethyl acetate (4:1), and recovering the ethyl acetate layer under reduced pressure to obtain compound 17.1H NMR(400MHz,Chloroform-d)δ7.49(d,J＝16.1Hz,1H),7.29(t,J＝3.6Hz,2H+CHCl3),7.24–7.12(m,4H),7.03(dd,J＝8.2,2.0Hz,1H),6.91(d,J＝8.3Hz,1H),6.59(d,J＝16.1Hz,1H),2.68(dt,J＝10.0,6.6Hz,4H),1.72(dt,J＝10.4,3.5Hz,3H)；13C NMR(101MHz,CDCl3)δ201.86,146.98,144.07,143.71,142.16,128.40,128.33,127.32,125.78,123.84,122.96,115.50,114.45,40.40,35.73,31.04,24.18.
Compound 18: 4- ((3-methylbutanamido) methyl) -1,2-phenylene diacetate
Dissolving compound 11(0.111g, 0.5mmol) in anhydrous pyridine (5mL), adding acetic anhydride 1.0mL, reacting overnight, adding water 30mL, ethyl acetate 50mL, extracting, washing ethyl acetate layer with 2% citric acid aqueous solution, discarding water solution, dehydrating ethyl acetate solution with anhydrous sodium sulfate, recovering ethyl acetate, and performing silica gel column chromatography (petroleum ether-ethyl acetate (4: 1)) on the residue to obtain compound 18(0.122g, 79%).1H NMR(400MHz,CDCl3)δ7.15(d,J＝3.7Hz,2H),7.12(d,J＝2.7Hz,1H),4.41(d,J＝5.8Hz,2H),2.29(s,6H),2.20–1.88(m,2H),1.27(m,1H),1.06–0.85(m,6H)；13C NMR(101MHz,CDCl3)δ172.6,168.4,168.3,142.1,141.3,137.5,126.0,123.6,122.9,46.0,42.7,26.2,22.5,20.6；.
Compound 19: 4- (pentamidomethyl) -1,2-phenylene diacetate
Dissolving compound 12(0.111g, 0.5mmol) in anhydrous pyridine (5mL), adding acetic anhydride 1.0mL, reacting overnight, diluting with water 30mL, ethyl acetate 50mL, extracting, washing ethyl acetate layer with 2% citric acid aqueous solution, discarding water solution, dehydrating ethyl acetate solution with anhydrous sodium sulfate, recovering ethyl acetate, and performing silica gel column chromatography (petroleum ether-ethyl acetate (4: 1)) on the residue to obtain compound 19(0.129g, 84%).1H NMR(400MHz,CDCl3)δ7.19–7.11(m,2H),7.09(d,J＝4.8Hz,1H),5.96(s,1H),4.38(d,J＝5.8Hz,2H),2.27(d,J＝4.0Hz,6H),2.23–2.11(m,2H),1.62(q,J＝7.1Hz,2H),1.42–1.22(m,2H),0.90(t,J＝7.3Hz,3H)；13C NMR(101MHz,CDCl3)δ173.1,168.4,168.3,142.1,141.3,137.5,126.0,123.6,122.9,42.7,36.4,27.8,22.4,20.6,13.8；HRMSESI:[M+Na]+,found 330.13226,C16H21NO5Na,330.13174,requires。
Compound 21: 4- (octanamidomethyl) -1,2-phenylene diacetate
Dissolving compound 14(0.133g, 0.5mmol) in anhydrous pyridine (5mL), adding acetic anhydride 1.0mL, reacting overnight, diluting with water 30mL, ethyl acetate 50mL, extracting, washing the ethyl acetate layer with 2% citric acid aqueous solution, discarding the aqueous solution, dehydrating the ethyl acetate solution with anhydrous sodium sulfate, recovering ethyl acetate, and performing silica gel column chromatography (petroleum ether-ethyl acetate (4: 1)) on the residue to obtain compound 18(0.139g, 80%).1H NMR(400MHz,CDCl3)δ7.22–7.17(m,2H),7.16–7.12(m,1H),5.74(s,1H),4.46(d,J＝5.7Hz,2H),2.31(s,6H),2.28–2.14(m,2H),1.67(d,J＝7.5Hz,2H),1.31(d,J＝10.5Hz,2H),0.89(d,J＝7.0Hz,3H)；13C NMR(101MHz,CDCl3)δ173.1,168.3,168.3,142.1,141.3,137.5,126.1,123.6,122.9,42.7,36.8,36.7,31.7,29.3,29.0,25.7,22.6,20.6,14.1。
Compound 22: 4- (decanoamidomethyl) -1,2-phenylene diacetate
Dissolving compound 15(0.147g, 0.5mmol) in anhydrous pyridine (5mL), adding acetic anhydride 1.0mL, reacting overnight, adding water to dilute 30mL, ethyl acetate 50mL, washing ethyl acetate layer with 2% citric acid aqueous solution, discarding water solution, dehydrating ethyl acetate solution with anhydrous sodium sulfate, recovering ethyl acetate, and performing silica gel column chromatography (petroleum ether-ethyl acetate (4: 1)) on the residue to obtain compound 22(0.151g, 80%).1H NMR(400MHz,CDCl3)δ7.19–7.13(m,2H),7.13–7.10(m,1H),5.75(s,1H),4.42(d,J＝5.8Hz,2H),2.28(s,6H),2.24–2.11(m,2H),1.63(dd,J＝14.6,7.0Hz,2H),1.40–1.18(m,12H),0.87(d,J＝7.0Hz,3H)；13C NMR(101MHz,CDCl3)δ173.2,168.3,168.3,142.1,141.3,137.4,126.1,123.6,123.0,42.8,36.7,31.8,29.7,29.4,29.3,29.3,25.7,22.7,20.6,20.6,14.1；HRMSESI:[M+Na]+,found400.20990,C21H31NO5Na,400.20999requires。
Compound 23: 4- ((5-phenyl-pentanamido) methyl) -1, 2-phenyl-ene diacetate
Dissolving compound 16(0.150g, 0.5mmol) in anhydrous pyridine (5mL), adding acetic anhydride 1.0mL, reacting overnight, diluting with water 30mL, ethyl acetate 50mL, extracting, washing ethyl acetate layer with 2% citric acid aqueous solution, discarding water solution, dehydrating ethyl acetate solution with anhydrous sodium sulfate, recovering ethyl acetate, and performing silica gel column chromatography (petroleum ether-ethyl acetate (4: 1)) on the residue to obtain compound 23(0.158g, 82%).1H NMR(400MHz,CDCl3)δ7.30–7.23(m,2H),7.17(t,J＝6.9Hz,3H),7.12(s,2H),7.09(s,1H),5.84(s,1H),4.38(d,J＝5.8Hz,2H),2.63(t,J＝7.1Hz,2H),2.27(d,J＝3.7Hz,6H),2.21(t,J＝7.1Hz,2H),1.67(dt,J＝10.2,6.4Hz,4H)；13C NMR(101MHz,CDCl3)δ172.8,168.3,168.3,142.2,142.1,141.3,137.4,128.4,128.3,126.1,125.8,123.6,123.0,42.8,36.5,35.7,31.1,25.3,20.6；HRMSESI:[M+H]+,found 384.18030,C22H26NO5,384.18110requires。
The beneficial effects of the present invention are demonstrated by the following experimental examples.
Experimental example 1 anti-inflammatory Activity assay
1. The experimental method comprises the following steps:
(1) culture of test cells
Respectively placing DMEM high-sugar medium (complete medium) containing 10% fetal calf serum and 1% penicillin/streptomycin and PBS solution in water bath at 37 deg.C, preheating to 37 deg.C, taking out cells from liquid nitrogen tank, immediately placing in water bath at 37 deg.C for 3min, adding prepared 9mL complete medium and frozen fine cells into culture dishCell suspension 1mL, saturated humidity, 5% CO2And standing and incubating for at least 24h at 37 ℃ in a standard environment. The next day the fluid was changed and the cell status was checked.
Because RAW264.7 cells are vigorous in metabolism and fast in growth, PBS is needed to wash the cells for 2-3 times every day, and the cells are subcultured when the cells are fully spread on a culture dish to reach 80%. Abandoning the original culture medium before passage, washing for 2 times by using pre-warmed PBS, adding 3mL of complete culture medium, directly and lightly blowing to beat cells, mixing 10 mu L of cell suspension with 1:1 volume of 0.4 w/v% placenta blue, and counting the cells to ensure that the cell survival rate is more than 85%.
(2) Method for detecting anti-inflammatory activity
The anti-inflammatory activity of the compounds of the invention is determined by measuring the concentration of NO in the cells, which is determined by the Griess reagent method. RAW264.7 cells were seeded at 6X 104cells/well in 24-well cell culture plates, each set of 3 wells, and cultured overnight. Inducing with 1 μ g/mL LPS, extracting cell supernatant of each group after 24 hr, dissolving NO in water to form nitrite, and measuring Nitrite (NO) in supernatant2-) The content of (b) is the content of NO in the cell supernatant culture solution which can be indirectly reflected.
Nitrite (NO) measurement in supernatants of each group using Griess reagent2-) The specific operation steps of (1) are that the Griess reagent I and Griess reagent II are taken out from a refrigerator at 4 ℃ for 20min in advance to restore the room temperature, and then the people are protected from light. To plot the NO standard curve, the standard nitrite C nitrate) was diluted in a gradient (e.g., 100,50,25,12.5,6.25,3.125, 1.563. mu. mol/mL). In a dark environment, 50 mu L of diluted standard substance or sample to be detected is added into each reaction hole of a 96-hole plate, each reaction hole is provided with 3 multiple holes, then Griess reagent I is added into each reaction hole, 50 mu L/well of Griess reagent II is added, the excitation wavelength of a microplate reader is set to be 540nm, the absorption wavelength is set to be 670nm, and the absorption light value (OD value) of each reaction hole is measured within 30 min. And drawing an NO standard curve according to the concentration of the standard substance and the corresponding OD value, and calculating the NO content in the sample according to the standard curve.
2. The experimental results are as follows:
the experimental results are shown in fig. 1, and it can be seen that the compound of the present invention can effectively inhibit the NO production induced by LPS, wherein the inhibition effects of the compounds 3,4, 15, 17 and 23 are the most significant, which indicates that the compound of the present invention has strong anti-inflammatory ability.
Further, the half Inhibitory Concentration (IC) of the compound of the present invention against NO was calculated from the graph showing the dependence of NO content in cells on the concentration of the compound of the present invention shown in FIG. 250) It can be seen that IC of the compounds of the present invention50The value is 1.73-20.51 mu M, and the compound is further proved to be capable of effectively inhibiting the generation of NO induced by LPS, so that the compound has stronger anti-inflammatory capability.
Experimental example 2 cytotoxicity assay
1. The experimental method comprises the following steps:
in Experimental example 2, in the determination of NO concentration by Griess reagent method, after extracting cell supernatants from each group, the old culture medium in the test wells of the 96-well plate was replaced with 100. mu.L of culture medium containing 10% of ambue, and then returned to the cell incubator to incubate for 30min, and when the color of the new culture medium changed from indigo blue to pink, the detection was performed by using a fluorescence microplate reader, the excitation light wavelength was between 530 and 560nm, the emission light wavelength was 590nm, and the Relative Fluorescence Units (RFU) were recorded.
2. The experimental results are as follows:
the experimental result is shown in fig. 2, and it can be seen that the compound of the present invention has no obvious cytotoxicity, which indicates that the benzylaminoyl derivative provided by the present invention has little toxicity and good biological safety.
In conclusion, the invention provides benzylaminoyl derivatives shown in formula I, which can remarkably inhibit NO generation induced by LPS, have strong anti-inflammatory capability and small cytotoxicity, and can be applied to preparation of clinical anti-inflammatory drugs.
Claims (5)
1. The following compounds, or pharmaceutically acceptable salts thereof:
2. a process for preparing a compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized by: comprises the following steps:
(a) reacting the raw material A with N, N' -carbonyl diimidazole to obtain a compound B;
(b) directly adding 3, 4-dimethoxyphenyl primary amine into the compound B obtained in the step (a) without separation for reaction, extracting by ethyl acetate after the reaction is finished, and separating by silica gel column chromatography to obtain a compound C;
(c) adding compound C to BBr in ice bath3Reacting at room temperature, decomposing a reaction product by citric acid after the reaction is finished, extracting by ethyl acetate, and separating by silica gel column chromatography to obtain a compound D;
(d) reacting the compound D with acetic anhydride in the presence of pyridine, after the reaction is finished, extracting a reaction product by ethyl acetate, decomposing by citric acid, and separating by silica gel column chromatography to obtain a compound E;
wherein the raw material A has the following structural formula:
compound B has the following structural formula:
compound C has the following structural formula:
compound D has the following structural formula:
compound E has the following structural formula:
wherein n is 7 and R3Is methyl, or n is 4 and R3Is phenyl.
3. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of an anti-inflammatory medicament.
4. An anti-inflammatory pharmaceutical composition characterized by: the compound or the pharmaceutically acceptable salt thereof as claimed in claim 1, and pharmaceutically acceptable auxiliary materials.
5. Use of a compound, or a pharmaceutically acceptable salt thereof, in the manufacture of an anti-inflammatory medicament:
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4959503A (en) * | 1986-04-11 | 1990-09-25 | Warner-Lambert Company | Diarylalkanoids having activity as lipoxygenase inhibitors |
| CN106831383A (en) * | 2016-12-28 | 2017-06-13 | 中国科学院成都生物研究所 | Diarylheptanoids |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4959503A (en) * | 1986-04-11 | 1990-09-25 | Warner-Lambert Company | Diarylalkanoids having activity as lipoxygenase inhibitors |
| CN106831383A (en) * | 2016-12-28 | 2017-06-13 | 中国科学院成都生物研究所 | Diarylheptanoids |
Non-Patent Citations (2)
| Title |
|---|
| Analyses of Synthetic N-Acyl Dopamine Derivatives Revealing Different Structural Requirements for Their Anti-inflammatory and Transient-Receptor-Potential-Channel-of-the-Vanilloid-Receptor-Subfamily-Subtype-1 (TRPV1)-Activating Properties;Prama Pallavi等;《J. Med. Chem. 》;20180315;第61卷;第3126-3137页 * |
| 无;无;《STN Registry》;20180607;无 * |
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