CN114133336A - 4-methoxynaphthalene substituted aniline compound and preparation method and application thereof - Google Patents

4-methoxynaphthalene substituted aniline compound and preparation method and application thereof Download PDF

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CN114133336A
CN114133336A CN202010915170.8A CN202010915170A CN114133336A CN 114133336 A CN114133336 A CN 114133336A CN 202010915170 A CN202010915170 A CN 202010915170A CN 114133336 A CN114133336 A CN 114133336A
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methoxynaphthalen
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methoxynaphthalene
aniline compound
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CN114133336B (en
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刘永祥
付佳悦
梁启达
林斌
肖建勇
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Shenyang Pharmaceutical University
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    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
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Abstract

The invention belongs to the technical field of medicines, and relates to a 4-methoxynaphthalene substituted aniline compound, and a preparation method and application thereof. The compound or the pharmaceutically acceptable salt thereof is shown as a general formula M, wherein R1Hydrogen, C1-C6 alkoxy, halogen, C1-C6 alkyl, hydroxyl, nitro and amino; r2Hydrogen, C1-C6 alkyl, halogen, C1-C6 alkoxy. The 4-methoxynaphthalene-substituted aniline compound or the salt thereof has a good CAR agonist effect.

Description

4-methoxynaphthalene substituted aniline compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and relates to a 4-methoxynaphthalene substituted aniline compound, and a preparation method and application thereof.
Background
Insulin resistance, hyperlipidemia and fatty liver are all causes of blood and cerebral vascular diseases, are serious diseases threatening human health and life, and the finding and discovery of new drugs for treating and preventing cardiovascular and cerebrovascular diseases is a major topic currently facing.
Constitutive androstane receptors (CAR, NR1I3) and pregnane X receptors (PXR, NR1I2) are two important members of the nuclear receptor superfamily, playing a key role in heterologous chemical stimulation. The CARs induce the expression of various drug metabolizing enzymes (e.g., CYP2B6, CYP3a4, CYP2C9, and UGT1a1) and transporters. CARs are typically sequestered in the cytoplasmic region of untreated hepatocytes and translocate to the nucleus upon exposure to activators or ligands. Following nuclear translocation, the CAR binds to the response element in the promoter region of its target gene, forming a heterodimeric complex with retinoid AX receptor alpha (RXR α, NR2B 1). In contrast, exogenously expressed CARs accumulate in the nucleus without any stimulation. Because CARs have the potential to constitutively transactivate, nuclear CARs induce transcription of target genes in the absence of agonists. CARs have been reported to play important roles in energy homeostasis, such as affecting thyroid hormone metabolism, glucose production, and lipogenesis, which in turn have therapeutic effects on cardiovascular and cerebrovascular diseases. Most CAR agonists are synthesized by taking testosterone as a raw material, and have the defects of large side effect, complex synthesis and easy influence on other functional groups.
The research of the 4-methoxynaphthalene substituted aniline compound as a CAR agonist has not been reported.
Disclosure of Invention
The invention aims to design and synthesize a 4-methoxynaphthalene substituted aniline compound with good CAR agonist effect, and the prepared compound has good CAR agonist effect in vitro.
The present invention relates to compounds of general formula M defined below or a pharmaceutically acceptable salt thereof:
Figure BDA0002664759970000011
wherein the content of the first and second substances,
R1hydrogen, C1-C6 alkoxy, halogen, C1-C6 alkyl, hydroxyl, nitro and amino;
R2hydrogen, C1-C6 alkyl, halogen, C1-C6 alkoxy.
The present invention preferably defines a compound of the general formula M, or a pharmaceutically acceptable salt thereof, wherein,
R1hydrogen, C1-C4 alkoxy, halogen, C1-C4 alkyl, hydroxyl, nitro and amino;
R2hydrogen, C1-C4 alkyl, halogen, C1-C4 alkoxy.
The present invention preferably defines a compound of the general formula M, or a pharmaceutically acceptable salt thereof, wherein,
R1hydrogen, C1-C4 alkoxy, halogen;
R2hydrogen, C1-C4 alkyl, halogen;
the present invention preferably defines a compound of the general formula M or a pharmaceutically acceptable salt thereof as follows: wherein the content of the first and second substances,
R1when it is hydrogen, R2Is hydrogen, halogen, C1-C4 alkyl;
R1when it is C1-C4 alkoxy, R2Hydrogen, C1-C4 alkyl, halogen;
R1when it is halogen, R2Hydrogen, C1-C4 alkyl, halogen;
the present invention preferably defines a compound of the general formula M or a pharmaceutically acceptable salt thereof as follows: wherein the content of the first and second substances,
R1when it is hydrogen, R2Is H, Me, Cl, F;
R1when it is methoxy, R2Is H, Me, Cl, F;
R1when is chlorine or fluorine, R2Is H, Me, Cl, F;
preferred partial compounds of the present invention have the following structure:
compound 1
Figure BDA0002664759970000021
Compound 2
Figure BDA0002664759970000031
Compound 3
Figure BDA0002664759970000032
Compound 4
Figure BDA0002664759970000033
Compound 5
Figure BDA0002664759970000034
Compound 6
Figure BDA0002664759970000035
Compound 7
Figure BDA0002664759970000041
Compound 8
Figure BDA0002664759970000042
Compound 9
Figure BDA0002664759970000043
Compound 10
Figure BDA0002664759970000044
Compound 11
Figure BDA0002664759970000045
Compound 12
Figure BDA0002664759970000051
Compound 13
Figure BDA0002664759970000052
Compound 14
Figure BDA0002664759970000053
Compound 15
Figure BDA0002664759970000054
Compound 16
Figure BDA0002664759970000055
The synthetic route of the 4-methoxynaphthalene substituted aniline compound is as follows:
Figure BDA0002664759970000061
preparation of Compound A
Adding a proper amount of oxygen-free and dry tetrahydrofuran into an eggplant-shaped bottle filled with 2-bromo-5-substituted benzaldehyde, bis (triphenylphosphine) palladium dichloride and cuprous iodide, adding trimethylacetylene silicon and dry triethylamine under the protection of nitrogen, and continuously stirring until the terminal alkyne is completely consumed. After the reaction is finished, concentrating the reaction solution and carrying out column chromatography to obtain the compound A.
Preparation of Compound B
Adding the compound A into a dry eggplant-shaped bottle, adding dry diethyl ether, adding methyl magnesium bromide dropwise at-78 ℃ under the protection of nitrogen, heating the reaction solution to room temperature after the addition is finished, and continuously stirring for 2-4 hours. After the reaction is finished, adding saturated ammonium chloride solution for quenching, extracting by ethyl acetate, washing by water, drying by sodium sulfate, and concentrating to obtain a compound B.
Preparation of Compound C
Adding PCC into a dry eggplant-shaped bottle, adding dry dichloromethane, protecting with nitrogen, adding dichloromethane solution of compound B at 0 ℃, after adding, heating the reaction solution to room temperature, and stirring for more than 12 hours or overnight. And after the reaction is finished, enabling the reaction solution to pass through a sand funnel to obtain a compound C.
Preparation of Compound D
Compound C, potassium carbonate and methanol were added to an eggplant type bottle and stirred at room temperature for 2-4 hours. And after the reaction is finished, adding a saturated ammonium chloride solution for quenching, extracting by using dichloromethane, washing by using water, drying by using sodium sulfate, and concentrating to obtain a compound D.
Preparation of Compound E
Compound D, trimethyl orthoformate, p-toluenesulfonic acid, methanol were added to an eggplant type flask and stirred at room temperature for 3 to 5 hours. And after the reaction is finished, adding triethylamine for quenching, extracting by ethyl acetate, washing by a saturated sodium bicarbonate solution, washing by water, drying by sodium sulfate, and concentrating to obtain a compound E.
Preparation of Compound F
Adding the compound E, trimethylchlorosilane, benzoic acid and pyridine into an eggplant-shaped bottle, and stirring for more than 10 hours or overnight at 70-90 ℃. After the reaction is finished, 15 percent NaOH is added into the reaction solution at 0 ℃, ethyl acetate is used for extraction, copper sulfate solution is used for washing, water washing, sodium sulfate is used for drying, column chromatography is carried out after concentration, and the compound F is obtained.
Preparation of Compound H
Dissolving the compound G in a water-methanol solution (100: 3), adding sodium bicarbonate and iodine elementary substance, and stirring for 20-40 minutes at room temperature. After the reaction is finished, water is added for dilution, the pH value is adjusted to be neutral by hydrochloric acid (2M), ether is used for extraction, sodium thiosulfate is used for washing, sodium sulfate is used for drying, and after concentration, column chromatography is carried out to obtain a compound H.
Preparation of Compound I
Adding a proper amount of oxygen-free and dry tetrahydrofuran into an eggplant-shaped bottle filled with a compound H, bis (triphenylphosphine) palladium dichloride and cuprous iodide, adding a compound F and dry triethylamine under the protection of nitrogen, and continuing stirring until the terminal alkyne is completely consumed. After the reaction is finished, concentrating the reaction solution and carrying out column chromatography to obtain the compound I.
Preparation of Compound M
To a dry eggplant-type bottle, IPrAuCl and AgSbF were added6Drying dichloromethane to dissolve, stirring for 20-40 min at normal temperature, adding dichloromethane solution of compound I, and stirring for 2-4 hr. After the reaction is finished, concentrating the reaction solution, and carrying out column chromatography to obtain a compound M.
The invention also provides a pharmaceutical composition which comprises the 4-methoxynaphthalene substituted aniline compound or the salt thereof and a pharmaceutically acceptable carrier or excipient.
The 4-methoxynaphthalene-substituted aniline compound or the salt thereof has a good CAR agonist effect.
Drawings
FIG. 1 shows the agonism of CAR receptor after CITCO treatment of each compound
Detailed Description
The anhydrous tetrahydrofuran and anhydrous ether were distilled off by adding sodium strips under reflux in the presence of nitrogen. The anhydrous dichloromethane was obtained by distilling off under reflux with calcium hydride in the presence of nitrogen. The chemical reactions involved were all analyzed by TLC using F-254 thin silica gel plates. The extraction and separation of the reaction solution are realized by column chromatography with silica gel of 200-300 meshes as a filler.1H NMR and13c NMR was measured using Bruker Avance-III 600 using deuterated dimethyl sulfoxide as a solvent.
Example 1: preparation of 2- (4-methoxynaphthalen-2-yl) aniline (Compound 1)
An eggplant-shaped bottle filled with o-bromobenzaldehyde (5g, 0.0272mol), bis (triphenylphosphine) palladium dichloride (0.95g, 0.0014mol) and cuprous iodide (0.50g, 0.0026mol) is added with a proper amount of oxygen-free and dry tetrahydrofuran, and under the protection of nitrogen, trimethylethynyl silicon (6.67g, 0.0679mol) and dry triethylamine (19.1ml, 0.136mol) are added, and stirring is continued until the terminal alkyne is completely consumed. After the reaction is finished, the reaction solution is concentrated and subjected to column chromatography to obtain 2- ((trimethylsilyl) ethynyl) benzaldehyde with the yield of 99%.
2- ((trimethylsilyl) ethynyl) benzaldehyde (5.49g, 0.027mol) was added to a dry eggplant-type bottle, dried diethyl ether was added, under nitrogen protection, methyl magnesium bromide (9.66g, 0.081mol) was added dropwise at-78 deg.C, and after the addition, the reaction was allowed to warm to room temperature and stirring was continued for 3 hours. After the reaction is finished, adding saturated ammonium chloride solution for quenching, extracting by ethyl acetate, washing by water, drying by sodium sulfate, and concentrating to obtain the 1- (2- ((trimethylsilyl) ethynyl) phenyl) ethan-1-ol with the yield of 99%.
PCC (9.52g, 0.041mol) was charged into a dry eggplant type bottle, dried dichloromethane was added, nitrogen gas was added, a solution of 1- (2- ((trimethylsilyl) ethynyl) phenyl) ethan-1-ol (6.19g, 0.027mol) in dichloromethane was added at 0 ℃, and after the addition, the reaction solution was allowed to warm to room temperature and stirred overnight. After the reaction, the reaction solution was passed through a Shao funnel to obtain 1- (2- ((trimethylsilyl) ethynyl) phenyl) ethan-1-one in a yield of 99%.
To an eggplant type bottle were added 1- (2- ((trimethylsilyl) ethynyl) phenyl) ethan-1-one (5.83g, 0.027mol), potassium carbonate (0.37g, 0.0027mol) and methanol, and stirred at room temperature for 3 hours. After the reaction is finished, adding a saturated ammonium chloride solution for quenching, extracting by dichloromethane, washing by water, drying by sodium sulfate, and concentrating to obtain the 1- (2-ethynylphenyl) ethane-1-ketone with the yield of 99%.
To an eggplant type bottle were added 1- (2-ethynylphenyl) ethan-1-one (3.89g, 0.027mol), trimethyl orthoformate (7.16g, 0.0675mol), p-toluenesulfonic acid (0.94g, 0.0054mol), and methanol, and stirred at room temperature for 4 hours. After the reaction is finished, triethylamine is added for quenching, ethyl acetate is used for extraction, saturated sodium bicarbonate solution is used for washing, water washing is carried out, sodium sulfate is used for drying, and concentration is carried out to obtain 1-ethynyl-2- (2-methoxypropan-2-yl) benzene with the yield of 95 percent
To an eggplant-type flask were added 1-ethynyl-2- (2-methoxyprop-2-yl) benzene (4.47g, 0.026mol), chlorotrimethylsilane (7.18ml, 0.065mol), benzoic acid (0.57g, 0.00468mol), pyridine, and stirred at 80 ℃ overnight. After the reaction is finished, 15% NaOH is added into the reaction liquid at 0 ℃, ethyl acetate is used for extraction, copper sulfate solution is used for washing, water washing, sodium sulfate is used for drying, column chromatography is carried out after concentration, and 1-ethynyl-2- (1-methoxyvinyl) benzene is obtained with the yield of 86%.
Aniline (5g, 0.054mol) was dissolved in water-methanol solution (100: 3), and sodium hydrogencarbonate and iodine (10.9g, 0.0432mol) were added and stirred at room temperature for 30 minutes. After the reaction is finished, water is added for dilution, the pH value is adjusted to 7 by hydrochloric acid (2M), ether extraction is carried out, sodium thiosulfate is used for washing, sodium sulfate is used for drying, column chromatography is carried out after concentration, and o-iodoaniline is obtained, wherein the yield is 90%.
To an eggplant-shaped bottle containing o-iodoaniline (0.46g, 1.58mmol), bis (triphenylphosphine) palladium dichloride (0.022g, 0.032mmol) and cuprous iodide (0.011g, 0.063mmol) was added an appropriate amount of oxygen-free and dried tetrahydrofuran, under nitrogen protection, 1-ethynyl-2- (1-methoxyvinyl) benzene (0.1g, 0.63mmol) and dried triethylamine (0.44ml, 3.15mmol), and stirring was continued until the terminal alkyne was completely consumed. After the reaction is finished, the reaction solution is concentrated and subjected to column chromatography to obtain 2- ((2- (1-methoxyvinyl) phenyl) ethynyl) aniline with the yield of 92%.
To a dry eggplant type flask were added IPrAuCl (3.0mg, 0.005mmol) and AgSbF6(1.72mg, 0.005mmol), dissolved in dry dichloromethane, stirred at room temperature for 30 minutes, added a solution of 2- ((2- (1-methoxyvinyl) phenyl) ethynyl) aniline (25mg, 0.1mmol) in dichloromethane, and stirred for an additional 2 hours. After the reaction is finished, concentrating the reaction solution, and carrying out column chromatography to obtain the compound 1 with the yield of 92%.1H NMR(600MHz,DMSO-d6)δ8.14(d,J＝8.2Hz,1H),7.89(d,J＝8.0Hz,1H),7.55–7.51(m,1H),7.51–7.46(m,2H),7.13(dd,J＝7.5,1.5Hz,1H),7.10–7.06(m,1H),6.99(d,J＝1.1Hz,1H),6.79(dd,J＝8.0,0.9Hz,1H),6.67(td,J＝7.4,1.1Hz,1H),4.93(d,J＝16.7Hz,2H),4.00(s,3H)；13C NMR(150MHz,DMSO-d6)δ155.30,145.70,138.18,134.69,130.66,128.74,128.18,127.13,126.32,125.64,124.29,121.76,119.83,117.05,115.69,106.22,56.03。
Example 2: preparation of 2- (4-methoxynaphthalen-2-yl) -4-methylaniline (Compound 2)
To a dry eggplant type bottle were added IPrAuCl (3.0mg, 0.005mmol) and AgSbF6(1.72mg, 0.005mmol), the mixture was dissolved in dry dichloromethane, and stirred at ordinary temperature for 30 minutes, and a solution of 2- ((2- (1-methoxyvinyl) phenyl) ethynyl) -4-methylaniline (26mg, 0.1mmol) in dichloromethane prepared in the same manner as in example 1 was added and stirring was continued for 2 hours. After the reaction is finished, concentrating the reaction solution, and carrying out column chromatography to obtain the compound 2 with the yield of 93%.1H NMR(600MHz,DMSO-d6)δ8.14(d,J＝8.3Hz,1H),7.89(d,J＝8.0Hz,1H),7.55–7.51(m,1H),7.50–7.45(m,2H),7.00–6.94(m,2H),6.90(dd,J＝8.1,1.7Hz,1H),6.71(d,J＝8.1Hz,1H),4.70(s,2H),4.00(s,3H),2.21(s,3H)；13C NMR(150MHz,DMSO-d6)δ155.24,143.19,138.32,134.68,131.03,129.27,128.15,127.11,126.40,125.59,125.46,124.24,121.76,119.80,115.95,106.23,56.04,20.59。
Example 3: preparation of 4-chloro-2- (4-methoxynaphthalen-2-yl) aniline (Compound 3)
A dried eggplant-type flask was charged with IPrAuCl (3.0mg, 0.005mmol) and AgSbF6(1.72mg, 0.005mmol), dissolved in dry dichloromethane, stirred at ordinary temperature for 30 minutes, added with a dichloromethane solution of 4-chloro-2- ((2- (1-methoxyvinyl) phenyl) ethynyl) aniline (28mg, 0.1mmol) obtained in the same manner as in example 1, and stirred for further 2 hours. After the reaction is finished, concentrating the reaction solution, and carrying out column chromatography to obtain a compound 3 with the yield of 87%.1H NMR(600MHz,DMSO-d6)δ7.99(dd,J＝9.0,5.8Hz,1H),7.74(td,J＝10.7,2.7Hz,1H),7.54(s,1H),7.48–7.41(m,1H),7.04(s,1H),6.95(s,1H),6.92–6.88(m,1H),6.71(d,J＝8.1Hz,1H),4.71(s,2H),4.00(s,3H),2.21(s,3H)；13C NMR(150MHz,DMSO-d6)δ155.45,144.92,136.74,134.63,129.78,128.31,127.71,127.22,125.90,124.51,121.78,120.05,117.08,105.88,56.09。
Example 4: preparation of 4-fluoro-2- (4-methoxynaphthalen-2-yl) aniline (Compound 4)
To a dry eggplant type bottle were added IPrAuCl (3.0mg, 0.005mmol) andAgSbF6(1.72mg, 0.005mmol) was dissolved in dry dichloromethane, stirred at room temperature for 30 minutes, and a solution of 4-fluoro-2- ((2- (1-methoxyvinyl) phenyl) ethynyl) aniline (27mg, 0.1mmol) in dichloromethane prepared in the same manner as in example 1 was added and stirring was continued for 2 hours. After the reaction is finished, concentrating the reaction solution, and carrying out column chromatography to obtain a compound 4 with the yield of 90%.1H NMR(600MHz,DMSO-d6)δ8.15(d,J＝8.3Hz,1H),7.90(d,J＝7.9Hz,1H),7.57–7.48(m,3H),7.02–6.97(m,2H),6.94(td,J＝8.6,3.0Hz,1H),6.79(dd,J＝8.8,5.2Hz,1H),4.83(s,2H),4.01(s,3H)；13C NMR(150MHz,DMSO-d6)δ155.41,155.06(d,J＝229.5Hz),142.33,137.01,134.58,128.29,127.23,127.04(d,J＝7.1Hz),125.90,124.45,121.77,119.99,116.63,116.53(d,J＝15.8Hz),115.17(d,J＝21.8Hz),105.96,56.09。
Example 5: preparation of 2- (4, 6-dimethoxynaphthalen-2-yl) aniline (Compound 5)
A dried eggplant type bottle was charged with IPrAuCl (3.0mg, 0.005mmol) and AgSbF6(1.72mg, 0.005mmol), dissolved in dry dichloromethane, stirred at ordinary temperature for 30 minutes, added with a dichloromethane solution of 2- ((4-methoxy-2- (1-methoxyvinyl) phenyl) ethynyl) aniline (28mg, 0.1mmol) obtained in the same manner as in example 1, and stirred for further 2 hours. After the reaction is finished, concentrating the reaction solution, and carrying out column chromatography to obtain the compound 5 with the yield of 94%.1H NMR(600MHz,DMSO-d6)δ7.82(d,J＝8.9Hz,1H),7.47–7.43(m,2H),7.19(dt,J＝10.6,5.3Hz,1H),7.12(dd,J＝7.5,1.4Hz,1H),7.08–7.04(m,1H),6.98(d,J＝1.0Hz,1H),6.82–6.76(m,1H),6.66(td,J＝7.4,1.0Hz,1H),4.88(s,2H),4.00(s,3H),3.88(s,3H)；13C NMR(150MHz,DMSO-d6)δ157.47,154.43,145.68,135.56,130.66,129.96,128.53,126.47,125.19,119.73,119.41,117.07,115.64,106.68,100.31,55.96,55.62。
Example 6: preparation of 2- (4, 6-dimethoxynaphthalen-2-yl) -4-methylaniline (Compound 6)
IPrAuCl (3.0mg, 0.005mmol) and AgSbF6(1.72mg, 0.005mmol) were added to a dry eggplant type bottle, and dried dichloromethane was dissolved, and stirred at ordinary temperature for 30 minutes, to which was added 2- ((4-methoxy-2- (1-methoxyethylethyl) 2 prepared in the same manner as in example 1Alkenyl) phenyl) ethynyl) -4-methylaniline (29mg, 0.1mmol) in dichloromethane and stirring was continued for 2 h. After the reaction is finished, concentrating the reaction solution, and carrying out column chromatography to obtain the compound 6 with the yield of 89%.1H NMR(600MHz,DMSO-d6)δ7.81(d,J＝8.9Hz,1H),7.46–7.41(m,2H),7.18(dd,J＝8.9,2.6Hz,1H),6.95(dd,J＝17.5,1.4Hz,2H),6.88(dd,J＝8.1,1.7Hz,1H),6.69(d,J＝8.1Hz,1H),4.66(s,2H),3.99(s,3H),3.88(s,3H),2.20(s,3H)；13C NMR(150MHz,DMSO-d6)δ157.43,154.38,143.15,135.70,131.05,129.93,129.05,126.55,125.46,125.14,119.70,119.39,115.89,106.68,100.31,55.97,55.61,20.59。
Example 7: preparation of 4-chloro-2- (4, 6-dimethoxynaphthalen-2-yl) aniline (Compound 7)
To a dry eggplant type bottle were added IPrAuCl (3.0mg, 0.005mmol) and AgSbF6(1.72mg, 0.005mmol), the mixture was dissolved in dry dichloromethane, and stirred at ordinary temperature for 30 minutes, and a solution of 4-chloro-2- ((4-methoxy-2- (1-methoxyvinyl) phenyl) ethynyl) aniline (31mg, 0.1mmol) obtained in the same manner as in example 1 was added to the solution in dichloromethane, and stirring was continued for 2 hours. After the reaction is finished, concentrating the reaction solution, and carrying out column chromatography to obtain a compound 7. The yield thereof was found to be 95%.1H NMR(600MHz,DMSO-d6)δ7.84(d,J＝8.9Hz,1H),7.48–7.43(m,2H),7.20(dd,J＝8.9,2.6Hz,1H),7.13–7.07(m,2H),6.96(d,J＝1.0Hz,1H),6.79(d,J＝8.6Hz,1H),5.07(s,2H),4.00(d,J＝5.4Hz,3H),3.89(s,3H)；13C NMR(100MHz,DMSO-d6)δ157.67,154.57,144.88,134.12,130.03,129.92,129.77,128.10,127.89,125.47,120.09,119.90,119.49,117.01,106.33,100.37,56.04,55.65。
Example 8: preparation of 2- (4, 6-dimethoxynaphthalen-2-yl) -4-fluoroaniline (Compound 8)
A dried eggplant type bottle was charged with IPrAuCl (3.0mg, 0.005mmol) and AgSbF6(1.72mg, 0.005mmol), dissolved in dry dichloromethane, stirred at ordinary temperature for 30 minutes, added with a dichloromethane solution of 4-fluoro-2- ((4-methoxy-2- (1-methoxyvinyl) phenyl) ethynyl) aniline (30mg, 0.1mmol) obtained in the same manner as in example 1, and stirred for an additional 2 hours. After the reaction is finished, concentrating the reaction solution, and carrying out column chromatography to obtain a compound 8. The yield thereof was found to be 94%.1H NMR(600MHz,DMSO-d6)δ7.83(d,J＝8.9Hz,1H),7.48(s,1H),7.45(d,J＝2.6Hz,1H),7.20(dd,J＝8.9,2.6Hz,1H),7.00–6.95(m,2H),6.95–6.90(m,1H),6.78(dd,J＝8.8,5.2Hz,1H),4.82(s,2H),4.00(d,J＝6.3Hz,3H),3.88(s,3H)；13C NMR(150MHz,DMSO-d6)δ157.65,155.11(d,J＝229.5Hz),154.52,142.23,134.40,130.03,129.87,125.40,119.88,119.51,116.61,116.54,116.47,114.92(d,J＝21.7Hz),106.40,100.31,56.02,55.64(s)。
Example 9: preparation of 2- (6-chloro-4-methoxynaphthalen-2-yl) aniline (Compound 9)
A dried eggplant type bottle was charged with IPrAuCl (3.0mg, 0.005mmol) and AgSbF6(1.72mg, 0.005mmol), dissolved in dry dichloromethane, stirred at ordinary temperature for 30 minutes, added with a dichloromethane solution of 2- ((4-chloro-2- (1-methoxyvinyl) phenyl) ethynyl) aniline (28mg, 0.1mmol) obtained in the same manner as in example 1, and stirred for further 2 hours. After the reaction is finished, concentrating the reaction solution, and carrying out column chromatography to obtain a compound 9. The yield thereof was found to be 94%.1H NMR(600MHz,DMSO-d6)δ8.10(d,J＝2.1Hz,1H),7.96(d,J＝8.8Hz,1H),7.55(dd,J＝8.7,1.9Hz,2H),7.15–7.05(m,3H),6.82–6.78(m,1H),6.67(td,J＝7.4,1.0Hz,1H),4.95(s,2H),4.01(s,3H)；13C NMR(150MHz,DMSO-d6)δ154.47,145.74,138.91,133.07,130.67,130.53,130.33,128.92,127.56,125.88,124.86,120.66,119.73,117.06,115.77,107.49,56.23。
Example 10: preparation of 2- (6-chloro-4-methoxynaphthalen-2-yl) -4-methylaniline (Compound 10)
To a dry eggplant type bottle were added IPrAuCl (3.0mg, 0.005mmol) and AgSbF6(1.72mg, 0.005mmol), the mixture was dissolved in dry dichloromethane, and stirred at ordinary temperature for 30 minutes, and a solution of 2- ((4-chloro-2- (1-methoxyvinyl) phenyl) ethynyl) -4-methylaniline (30mg, 0.1mmol) in dichloromethane prepared in the same manner as in example 1 was added and stirring was continued for 2 hours. After the reaction is finished, concentrating the reaction solution, and carrying out column chromatography to obtain the compound 10. The yield thereof was found to be 92%.1H NMR(600MHz,DMSO-d6)δ8.10(d,J＝2.1Hz,1H),7.94(d,J＝8.8Hz,1H),7.53(dd,J＝7.9,3.0Hz,2H),7.06(d,J＝0.9Hz,1H),6.96(d,J＝1.5Hz,1H),6.91(dd,J＝8.1,1.7Hz,1H),6.72(d,J＝8.1Hz,1H),4.73(s,2H),4.00(s,3H),2.21(s,3H)；13C NMR(150MHz,DMSO-d6)δ154.42,143.23,139.06,133.06,131.02,130.47,130.28,129.47,127.53,125.99,125.51,124.82,120.67,119.70,116.05,107.48,56.22,20.56。
Example 11: preparation of 4-chloro-2- (6-chloro-4-methoxynaphthalen-2-yl) aniline (Compound 11)
To a dry eggplant type bottle were added IPrAuCl (3.0mg, 0.005mmol) and AgSbF6(1.72mg, 0.005mmol), the mixture was dissolved in dry dichloromethane, and stirred at ordinary temperature for 30 minutes, and a solution of 4-chloro-2- ((4-chloro-2- (1-methoxyvinyl) phenyl) ethynyl) aniline (32mg, 0.1mmol) obtained in the same manner as in example 1 was added to the solution in dichloromethane, and stirring was continued for 2 hours. After the reaction is finished, concentrating the reaction solution, and carrying out column chromatography to obtain the compound 11. The yield thereof was found to be 93%.1H NMR(600MHz,DMSO-d6)δ8.10(d,J＝2.2Hz,1H),7.97(d,J＝8.8Hz,1H),7.58–7.55(m,2H),7.16–7.09(m,2H),7.05(d,J＝1.2Hz,1H),6.80(d,J＝8.6Hz,1H),5.14(s,2H),4.02(d,J＝9.7Hz,3H)；13C NMR(150MHz,DMSO-d6)δ154.61,144.93,137.43,133.00,130.61,129.79,128.50,127.64,127.27,125.09,120.70,120.14,119.92,117.17,107.13,56.28。
Example 12: preparation of 2- (6-chloro-4-methoxynaphthalen-2-yl) -4-fluoroaniline (Compound 12)
To a dry eggplant type bottle were added IPrAuCl (3.0mg, 0.005mmol) and AgSbF6(1.72mg, 0.005mmol), the mixture was dissolved in dry dichloromethane, and stirred at ordinary temperature for 30 minutes, and a solution of 2- ((4-chloro-2- (1-methoxyvinyl) phenyl) ethynyl) -4-fluoroaniline (30mg, 0.1mmol) in dichloromethane prepared in the same manner as in example 1 was added and stirring was continued for 2 hours. After the reaction is finished, concentrating the reaction solution, and carrying out column chromatography to obtain the compound 12. The yield thereof was found to be 97%.1H NMR(600MHz,DMSO-d6)δ8.10(d,J＝2.1Hz,1H),7.95(t,J＝9.5Hz,1H),7.60–7.53(m,2H),7.08(d,J＝1.0Hz,1H),7.01–6.92(m,2H),6.79(dd,J＝8.8,5.2Hz,1H),4.86(s,2H),4.02(s,3H)；13C NMR(150MHz,DMSO-d6)δ155.06(d,J＝229.5Hz),154.57,142.37(d,J＝1.1Hz),137.73,132.96,130.62,130.60,127.66,126.58(d,J＝7.0Hz),125.03,120.68,119.91,116.72(d,J＝7.5Hz),116.56(d,J＝22.1Hz),115.37(d,J＝21.8Hz),107.24,56.29。
Example 13: preparation of 2- (6-fluoro-4-methoxynaphthalen-2-yl) aniline (Compound 13)
A dried eggplant type bottle was charged with IPrAuCl (3.0mg, 0.005mmol) and AgSbF6(1.72mg, 0.005mmol), dissolved in dry dichloromethane, stirred at ordinary temperature for 30 minutes, added with a dichloromethane solution of 2- ((4-fluoro-2- (1-methoxyvinyl) phenyl) ethynyl) aniline (27mg, 0.1mmol) obtained in the same manner as in example 1, and stirred for further 2 hours. After the reaction is finished, concentrating the reaction solution, and carrying out column chromatography to obtain a compound 13. The yield thereof was found to be 94%.1H NMR(600MHz,DMSO-d6)δ8.10(d,J＝2.1Hz,1H),7.95(t,J＝9.5Hz,1H),7.60–7.53(m,2H),7.08(d,J＝1.0Hz,1H),7.01–6.92(m,2H),6.79(dd,J＝8.8,5.2Hz,1H),4.86(s,2H),4.02(s,3H)；13C NMR(150MHz,DMSO-d6)δ160.28(d,J＝242.9Hz),154.81(d,J＝5.3Hz),145.74,137.63(d,J＝2.3Hz),131.84,131.21(d,J＝8.8Hz),130.68,128.80,126.04,124.85(d,J＝8.7Hz),119.84,117.09(d,J＝25.5Hz),117.05,115.72,107.27,105.44(d,J＝22.2Hz),56.17。
Example 14: preparation of 2- (6-fluoro-4-methoxynaphthalen-2-yl) -4-methylaniline (Compound 14)
To a dry eggplant type bottle were added IPrAuCl (3.0mg, 0.005mmol) and AgSbF6(1.72mg, 0.005mmol), the mixture was dissolved in dry dichloromethane, and the mixture was stirred at ordinary temperature for 30 minutes, and a solution of 2- ((4-fluoro-2- (1-methoxyvinyl) phenyl) ethynyl) -4-methylaniline (28mg, 0.1mmol) in dichloromethane prepared in the same manner as in example 1 was added and the stirring was continued for 2 hours. After the reaction is finished, concentrating the reaction solution, and carrying out column chromatography to obtain the compound 14. The yield thereof was found to be 95%.1H NMR(600MHz,DMSO-d6)δ7.99(dd,J＝9.0,5.8Hz,1H),7.74(td,J＝10.7,2.7Hz,1H),7.54(s,1H),7.48–7.41(m,1H),7.04(s,1H),6.95(s,1H),6.92–6.88(m,1H),6.71(d,J＝8.1Hz,1H),4.71(s,2H),4.00(s,3H),2.21(s,3H).13C NMR(150MHz,DMSO-d6)δ160.25(d,J＝242.9Hz),154.74(d,J＝5.2Hz),143.22,137.78(d,J＝2.5Hz),131.82,131.18(d,J＝8.8Hz),131.05,129.34,126.11,125.46,124.79(d,J＝8.7Hz),119.80,117.07(d,J＝25.0Hz),115.98,107.26,105.43(d,J＝22.2Hz),56.17,20.57。
Example 15: preparation of 4-chloro-2- (6-fluoro-4-methoxynaphthalen-2-yl) aniline (Compound 15)
A dried eggplant type bottle was charged with IPrAuCl (3.0mg, 0.005mmol) and AgSbF6(1.72mg, 0.005mmol), dissolved in dry dichloromethane, stirred at ordinary temperature for 30 minutes, added with a dichloromethane solution of 4-chloro-2- ((4-fluoro-2- (1-methoxyvinyl) phenyl) ethynyl) aniline (30mg, 0.1mmol) obtained in the same manner as in example 1, and stirred for an additional 2 hours. After the reaction is finished, concentrating the reaction solution, and carrying out column chromatography to obtain the compound 15. The yield thereof was found to be 96%.1H NMR(600MHz,DMSO-d6)δ8.01(dd,J＝9.0,5.8Hz,1H),7.76(dd,J＝10.6,2.5Hz,1H),7.58(d,J＝11.6Hz,1H),7.47(td,J＝8.8,2.7Hz,1H),7.14–7.08(m,1H),7.03(s,1H),6.80(d,J＝8.6Hz,1H),5.12(s,1H),4.01(s,2H)；13C NMR(150MHz,DMSO-d6)δ160.42(d,J＝243.3Hz),154.92(d,J＝5.1Hz),144.96,136.18,131.77,131.37(d,J＝8.9Hz),129.80,128.3,127.38,125.10(d,J＝8.8Hz),120.03,117.20(d,J＝25.0Hz),117.09,106.93,105.47(d,J＝22.2Hz),56.24。
Example 16: preparation of 4-fluoro-2- (6-fluoro-4-methoxynaphthalen-2-yl) aniline (Compound 16)
A dried eggplant type bottle was charged with IPrAuCl (3.0mg, 0.005mmol) and AgSbF6(1.72mg, 0.005mmol), dissolved in dry dichloromethane, stirred at ordinary temperature for 30 minutes, added with a dichloromethane solution of 4-fluoro-2- ((4-fluoro-2- (1-methoxyvinyl) phenyl) ethynyl) aniline (29mg, 0.1mmol) obtained in the same manner as in example 1, and stirred for an additional 2 hours. After the reaction is finished, concentrating the reaction solution, and carrying out column chromatography to obtain a compound 16. The yield thereof was found to be 96%.1H NMR(600MHz,DMSO-d6)δ8.01(dd,J＝9.0,5.7Hz,1H),7.76(dd,J＝10.6,2.6Hz,1H),7.60(s,1H),7.47(td,J＝8.8,2.7Hz,1H),7.06(s,1H),7.01–6.92(m,2H),6.79(dd,J＝8.8,5.2Hz,1H),4.84(s,2H),4.01(s,3H)；13C NMR(150MHz,DMSO-d6)δ160.41(d,J＝243.2Hz),155.04(d,J＝231.0Hz),154.89(d,J＝5.2Hz),142.37,136.47,131.73,131.35(d,J＝8.9Hz),126.73(d,J＝7.0Hz),125.05(d,J＝8.8Hz),120.01,117.21(d,J＝25.0Hz),116.65(d,J＝2.1Hz),116.56(d,J＝16.8Hz),115.24(d,J＝21.8Hz),107.00,105.47(d,J＝22.2Hz),56.23。
Example 17
Activity testing of Compounds of the invention as CAR agonists in vitro
Cell culture a HepTR/hCAR cell line derived from human liver cancer HepG2 cells was previously established using the T-REx system (Invitrogen/Thermo Fisher Scientific, Waltham, MA), where expression of hCAR can be induced by Tet treatment. A human hepatoma HepG2 cell line stably expressing hPXR (Hep/hPXR) was established by transfection with pCMV3tag 6-hPXR. HepTR/hCR HepG2 and Hep/hPXR cells were cultured in Dulbecco's modified Eagle's Medium (Wako, Osaka, Japan) containing 10% fetal bovine serum, penicillin and streptomycin at 5% CO2In a humid environment at 37 ℃. Differentiated HepaRG cells (KAC, Kyoto, Japan) were stored in Williams 'medium E (Life Technologies/Thermo Fisher Scientific, Greenland, N.Y.) and supplemented with 10% fetal bovine serum, 5mg/ml insulin and 50mM hydrocortisone (WAKO) (Osaka, Japan) at 37 deg.C, 5% CO according to the manufacturer's instructions2And 95% air.
Expression plasmids for the plasmids GAL/hCR LBD, GAL/hCR LBD SV2 and GAL/hCR LBD 3 a.a.. (Kanno and Inouye, 201035515-. GAL-responsive element (GALRE)/TATA box driven Gaussian luciferase reporter vector (GAL-Gaussia Luc.) (201910297788) has been previously constructed. The preparation of CYP3a4 XREM driven luciferase reporter plasmid (XREMluc.) has been previously described (201995120-.
Gauss luciferase assay HepG2 cells were transfected with the expression vector GAL/hCRAR LBD 3a.a. PEI Max Reagent (Polysciences inc., Warrington, PA) and GALRE driven gaussian luciferase reporter vectors were used. After overnight incubation, cells were treated with compound (10uM) or citciio (1uM) in this patent for 24 hours and gauss luciferase activity was measured using the BioLux gauss luciferase assay kit (BioRad, Hercules, CA).
With GAL/hCR LBD, GAL/hCR LBD SV2, GAL/hCR LBD 3a.a., pG5luc and pGL4.74 (hRluc/TK; Promega, Madison, Wis.); we used PEI Max Reagent (Polysciences Inc.). Similarly, Hep/hPXR cells were transfected with the CYP3A4 XREM-driven luciferase reporter plasmid and pGL4.74. After overnight incubation, cells were treated with compound and luciferase activity was measured using a dual luciferase reporter assay system (Promega). The activity of firefly luciferase was normalized to that of Renilla luciferase.
Quantitative reverse transcription polymerase chain reaction (RT-PCR) Total RNA from HepTR/hCR, Hep/hPXR and Hepall cells was isolated using ISOGEN II (Japanese Gene, Tokyo, Japan) and cDNA was synthesized using the ReverTraace qPCR RT kit (Toyobo). Osaka, japan). Quantitative PCR (qPCR) was performed on the 7500Fast system (Applied Biosystems, Foster City, Calif.) using Geneace SYBR qPCR Mix α Low ROX (Japan Gene, Tokyo, Japan) according to the manufacturer's protocol. The specific PCR primers used were as follows: CYP2B6(5'-AAG CGG ATT TGT CTT GGT GAA-3' and 5'-TGGAGG ATG GTG GTG AAG AAG3'), CYP3a4(5'-CCA AGC TAT GCT CTT CAC CG-3' and 5'-TCAGGC TCC ACT TAC GGT GC-3') and B-actin (5'-TCC TCCTGA GCG CAA GTA CTC-3' and 5'CTG CTT GCT GAT CCA CAT CTG-3'). Statistical analysis for statistical comparison, one-way analysis of variance was used, followed by Dunnett's multiple comparison test as a post-test, and the differences were considered statistically significant, # P < 0.05.

Claims (10)

1. 4-methoxy naphthalene substituted aniline compound with the general formula M or pharmaceutically acceptable salt thereof,
Figure FDA0002664759960000011
wherein the content of the first and second substances,
R1hydrogen, C1-C6 alkoxy, halogen, C1-C6 alkyl, hydroxyl, nitro and amino;
R2hydrogen, C1-C6 alkyl, halogen, C1-C6 alkoxy.
2. The 4-methoxynaphthalene-substituted aniline compound according to claim 1 or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
R1hydrogen, C1-C4 alkoxy, halogen, C1-C4 alkyl, hydroxyl, nitro and amino;
R2hydrogen, C1-C4 alkyl, halogen, C1-C4 alkoxy.
3. The 4-methoxynaphthalene-substituted aniline compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
R1when it is hydrogen, R2Is hydrogen, halogen, C1-C4 alkyl;
R1when it is C1-C4 alkoxy, R2Hydrogen, C1-C4 alkyl, halogen;
R1when it is halogen, R2Hydrogen, C1-C4 alkyl and halogen.
4. The 4-methoxynaphthalene-substituted aniline compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof,
compound 1
Figure FDA0002664759960000021
2- (4-methoxynaphthalen-2-yl) anilines
Compound 2
Figure FDA0002664759960000022
2- (4-methoxynaphthalen-2-yl) -4-methylaniline
Compound 3
Figure FDA0002664759960000023
4-chloro-2- (4-methoxynaphthalen-2-yl) aniline
Compound 4
Figure FDA0002664759960000024
4-fluoro-2- (4-methoxynaphthalen-2-yl) anilines
Compound 5
Figure FDA0002664759960000031
2- (4, 6-dimethoxynaphthalen-2-yl) aniline
Compound 6
Figure FDA0002664759960000032
2- (4, 6-Dimethoxynaphthalen-2-yl) -4-methylaniline
Compound 7
Figure FDA0002664759960000033
4-chloro-2- (4, 6-dimethoxynaphthalen-2-yl) aniline
Compound 8
Figure FDA0002664759960000034
2- (4, 6-Dimethoxynaphthalen-2-yl) -4-fluoroaniline
Compound 9
Figure FDA0002664759960000041
2- (6-chloro-4-methoxynaphthalen-2-yl) aniline
Compound 10
Figure FDA0002664759960000042
2- (6-chloro-4-methoxynaphthalen-2-yl) -4-methylaniline
Compound 11
Figure FDA0002664759960000043
4-chloro-2- (6-chloro-4-methoxynaphthalen-2-yl) aniline
Compound 12
Figure FDA0002664759960000044
2- (6-chloro-4-methoxynaphthalen-2-yl) -4-fluoroaniline
Compound 13
Figure FDA0002664759960000051
2- (6-fluoro-4-methoxynaphthalen-2-yl) aniline
Compound 14
Figure FDA0002664759960000052
2- (6-fluoro-4-methoxynaphthalen-2-yl) -4-methylaniline
Compound 15
Figure FDA0002664759960000053
4-chloro-2- (6-fluoro-4-methoxynaphthalen-2-yl) aniline
Compound 16
Figure FDA0002664759960000054
4-fluoro-2- (6-fluoro-4-methoxynaphthalen-2-yl) aniline.
5. A method for producing a 4-methoxynaphthalene-substituted aniline compound according to claim 1, which comprises:
Figure FDA0002664759960000061
wherein R is1、R2As claimed in claim 1.
6. A pharmaceutical composition comprising the 4-methoxynaphthalene substituted aniline compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
7. Use of a 4-methoxynaphthalene substituted aniline compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof for the preparation of a CAR agonist.
8. Use of a pharmaceutical composition according to claim 6 for the preparation of a CAR agonist.
9. Use of a 4-methoxynaphthalene-substituted aniline compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cardiovascular and cerebrovascular diseases.
10. The use of the pharmaceutical composition of claim 6 in the preparation of a medicament for the treatment of cardiovascular and cerebrovascular diseases.
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Citations (6)

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Publication number Priority date Publication date Assignee Title
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US5952350A (en) * 1996-10-24 1999-09-14 Eli Lilly And Company Naphthyl compounds and compositions, as estrogen receptor binding agents
US5929090A (en) * 1997-09-12 1999-07-27 Eli Lilly And Company 2-aryl-3-aminoaryloxynaphthy1 compounds, intermediates, compositions and methods
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