A class of 1,2,3,4-tetrahydro-9-aminoacridine compounds and their applications

Abstract

The present invention discloses a class of 1,2,3,4-tetrahydro-9-aminoacridine compounds and applications thereof, wherein the 1,2,3,4-tetrahydro-9-aminoacridine compounds have the following general structural formula: wherein R is selected from H, halogen, C1-C3 alkyl, aryl, carboxyl, C1-C3 alkoxy, methyl ester group, ethyl ester group or a five-membered aromatic heterocycle containing one O, S or N heteroatom. The 1,2,3,4-tetrahydro-9-aminoacridine compounds designed and synthesized by the present invention are a class of novel anti-inflammatory compounds, and the embodiments of the present invention have excellent anti-inflammatory effects through experimental verification, which is of great significance for exploring the mechanism of inflammatory reaction and developing safe and efficient novel anti-inflammatory drugs.

Description

Technical Field

[0001] The invention relates to a class of 1,2,3,4-tetrahydro-9-aminoacridine compounds and applications thereof. Background Art

[0002] Inflammation is a defense response of the body to stimulation, which manifests as redness, swelling, heat, pain and dysfunction. It is one of the most important defense responses of the human body to tissue damage or microbial invasion. Under normal physiological conditions, the immune response caused by inflammation is beneficial to the host, but excessive inflammation, especially chronic inflammation, can lead to immune system abnormalities. Common inflammations such as chronic hepatitis B, gastrointestinal inflammation, and osteoarthritis have a high incidence rate. For example, the new coronavirus, as an infectious pneumonia, spreads quickly and has strong infection ability. Various types of inflammation endanger human health. At present, the commonly used anti-inflammatory drugs in clinical practice are mainly non-steroidal anti-inflammatory drugs, but common non-steroidal anti-inflammatory drugs can cause obvious toxicity to the gastrointestinal tract and kidneys. Therefore, it is of great significance to explore the mechanism of inflammatory response and develop safe and efficient new anti-inflammatory drugs. Summary of the invention

[0003] In view of the above technical problems existing in the prior art, the object of the present invention is to provide a class of 1,2,3,4-tetrahydro-9-aminoacridine compounds and applications thereof.

[0004] The technical solution adopted by the present invention is as follows:

[0005] The 1,2,3,4-tetrahydro-9-aminoacridine compounds have the following general structural formula:

[0006]

[0007] Wherein R is selected from H, halogen, C1-C3 alkyl, aryl, carboxyl, C1-C3 alkoxy, carbomethoxy, carboethoxy or a five-membered aromatic heterocycle containing one O, S or N heteroatom.

[0008] Furthermore, the 1,2,3,4-tetrahydro-9-aminoacridine compound is specifically one of the following:

[0009]

[0010] The preparation method of the 1,2,3,4-tetrahydro-9-aminoacridine compound is to use 2-aminobenzonitrile derivatives 1a to 1i and cyclohexanone 2 as raw materials, p-toluenesulfonic acid as a catalyst, and reflux reaction in xylene to obtain compounds 3a to 3i. 3i is used as a raw material to obtain 3j through hydrolysis reaction. 3b is used as a raw material, and Suzuki coupling reaction with boronic acid derivative 4 is carried out under nitrogen protection to obtain 3k and 3l. The reaction equation is as follows:

[0011]

[0012] The invention relates to the use of the 1,2,3,4-tetrahydro-9-aminoacridine compounds and pharmaceutically acceptable salts thereof in the preparation of anti-inflammatory drugs.

[0013] By adopting the above technology, compared with the prior art, the beneficial effects of the present invention are as follows: the 1,2,3,4-tetrahydro-9-aminoacridine compounds designed and synthesized by the present invention are a new type of anti-inflammatory compounds, and the embodiments of the present invention have been verified by experiments to have excellent anti-inflammatory effects. DETAILED DESCRIPTION

[0014] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0015] 1. Preparation of intermediates and target compounds:

[0016] Example 1: 5-Bromo-1,2,3,4-tetrahydro-9-aminoacridine 3a

[0017]

[0018] Add 3.81mmol 2-amino-3-bromobenzonitrile, 11.43mmol cyclohexanone, 7.62mmol p-toluenesulfonic acid hydrate and 20mL xylene to the reaction bottle and reflux for 6h. After the reaction is completed, pour out the upper xylene solution, add appropriate amount of water to dilute, adjust the reaction solution to alkalinity with 10% sodium hydroxide solution, add dichloromethane to extract (20mL×3), combine the organic phases, wash the organic phases with saturated brine (20mL×3), and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (DCM: MeOH: TEA = 20: 10: 1, v / v / v) to obtain 629mg of light yellow solid, with a yield of 59.3%. 1 H NMR(500MHz,DMSO-d6)δ8.19(dd,J=8.4,1.3Hz,1H),7.88–7.84(m,1H),7.20–7.15(m,1H),6.56–6.43 (m,2H),2.59–2.53(m,2H),1.98–1.90(m,2H),1.85–1.80(m,2H),1.66–1.46(m,2H).ESI-MS:m / z[M+H] + 277.

[0019] Example 2: 6-Bromo-1,2,3,4-tetrahydro-9-aminoacridine 3b

[0020]

[0021] The synthesis steps of 6-bromo-1,2,3,4-tetrahydro-9-aminoacridine were the same as those of compound 3a in Example 1, except that 2-amino-3-bromobenzonitrile was replaced with an equal molar amount of 2-amino-4-bromobenzonitrile. A light yellow solid was obtained in a yield of 59.0%. 1 HNMR(500MHz,DMSO-d6)δ8.18(d,J=9.0Hz,1H),7.83(d,J=2.0Hz,1H),7.46(dd,J=8.9,2.0Hz,1H ),6.85(s,2H),2.84(t,J=5.8Hz,2H),1.87–1.75(m,5H),1.12(t,J=7.2Hz,1H).ESI-MS:m / z[M+H] + 277.

[0022] Example 3: 7-Bromo-1,2,3,4-tetrahydro-9-aminoacridine 3c

[0023]

[0024] The synthesis steps of 7-bromo-1,2,3,4-tetrahydro-9-aminoacridine are the same as the synthesis process of compound 3a in Example 1, except that 2-amino-3-bromobenzonitrile is replaced by an equal molar amount of 2-amino-5-bromobenzonitrile. The reaction gives a light yellow solid with a yield of 30.9%. 1 H NMR(500MHz,DMSO-d6)δ8.43(d,J=1.7Hz,1H),7.62–7.53(m,2H),6.46(s,2H),2 .81(t,J=6.0Hz,2H),2.54(t,J=6.4Hz,2H),1.86–1.77(m,4H).ESI-MS:m / z[M+H] + 277.

[0025] Example 4: 8-Bromo-1,2,3,4-tetrahydro-9-aminoacridine 3d

[0026]

[0027] The synthesis steps of 8-bromo-1,2,3,4-tetrahydro-9-aminoacridine are the same as the synthesis process of compound 3a in Example 1, except that 2-amino-3-bromobenzonitrile is replaced by an equal molar amount of 2-amino-6-bromobenzonitrile. The reaction obtains a brown-red solid with a yield of 38.6%. 1HNMR(500MHz,DMSO-d6)δ7.67(dd,J=8.5,1.3Hz,1H),7.59–7.57(m,1H),7.36–7.32(m,1H),6.62(d ,J=11.9Hz,2H),2.82(t,J=6.2Hz,2H),2.48(t,J=6.4Hz,2H),1.86–1.78(m,4H).ESI-MS:m / z[M+H] + 277.

[0028] Example 5: 6-Methoxy-1,2,3,4-tetrahydro-9-aminoacridine 3e

[0029]

[0030] The synthesis steps of 6-methoxy-1,2,3,4-tetrahydro-9-aminoacridine were the same as those of compound 3a in Example 1, except that 2-amino-3-bromobenzonitrile was replaced with an equal molar amount of 2-amino-4-methoxybenzonitrile. A brown solid was obtained in a yield of 59.4%. 1 HNMR(600MHz,DMSO-d6)δ7.34(t,J=8.1Hz,1H),7.20(dd,J=8.5,1.0Hz,1H),6.72(dd,J=7.9,1.1Hz,1H),6 .59(s,2H),3.95(s,3H),2.77(t,J=6.2Hz,2H),2.46(t,J=6.4Hz,2H),1.86–1.74(m,4H).ESI-MS:m / z[M+H] + 229.

[0031] Example 6: 8-Methoxy-1,2,3,4-tetrahydro-9-aminoacridine 3f

[0032]

[0033] The synthesis steps of 9-methoxy-1,2,3,4-tetrahydro-9-aminoacridine were the same as those of compound 3a in Example 1, except that 2-amino-3-bromobenzonitrile was replaced with an equal molar amount of 2-amino-6-methoxybenzonitrile. A light yellow solid was obtained in a yield of 29.2%. 1HNMR(500MHz,DMSO-d6)δ7.34(t,J=8.1Hz,1H),7.20(dd,J=8.5,1.1Hz,1H),6.72(dd,J=7.8,1.1Hz,1H),6 .59(s,2H),3.95(s,3H),2.77(t,J=6.2Hz,2H),2.46(t,J=6.3Hz,2H),1.86–1.76(m,4H).ESI-MS:m / z[M+H] + 229.

[0034] Example 7: 6-Fluoro-1,2,3,4-tetrahydro-9-aminoacridine 3 g

[0035]

[0036] The synthesis steps of 6-fluoro-1,2,3,4-tetrahydro-9-aminoacridine were the same as those of 3a, except that 2-amino-3-bromobenzonitrile was replaced with an equal molar amount of 2-amino-4-fluorobenzonitrile. A dark yellow solid was obtained in a yield of 26.9%. 1 HNMR(500MHz,DMSO-d6)δ7.48–7.40(m,2H),7.07–7.01(m,1H),6.19(d,J=4.1Hz,2 H),2.82(t,J=6.1Hz,2H),2.54–2.51(m,2H),1.87–1.77(m,4H).ESI-MS:m / z[M+H] + 217.

[0037] Example 8: 6-Chloro-1,2,3,4-tetrahydro-9-aminoacridine 3h

[0038]

[0039] The synthesis steps of 6-chloro-1,2,3,4-tetrahydro-9-aminoacridine were the same as those of 3a, except that 2-amino-3-bromobenzonitrile was replaced with an equal molar amount of 2-amino-4-chlorobenzonitrile. A yellow solid was obtained in a yield of 45.2%. 1 H NMR(500MHz,DMSO-d6)δ8.19(d,J=9.0Hz,1H),7.63(d,J=2.2Hz,1H),7.29(dd,J=9.0,2.2Hz,1H) ,6.50(s,2H),2.81(t,J=6.0Hz,2H),2.53(t,J=6.1Hz,2H),1.86–1.76(m,4H).ESI-MS:m / z[M+H] + 233.

[0040] Example 9: 9-amino-5,6,7,8-tetrahydroacridine-3-carboxylic acid methyl ester 3i

[0041]

[0042] The synthesis steps of 9-amino-5,6,7,8-tetrahydroacridine-3-carboxylic acid methyl ester are the same as those of 3a, except that 2-amino-3-bromobenzonitrile is replaced with an equal molar amount of compound 1i. The reaction yields a light yellow solid in a yield of 16.8%. 1 H NMR(500MHz,DMSO-d6)δ8.92(d,J=1.8Hz,1H),7.96(dd,J=8.8,1.9Hz,1H),7.66(d,J=8.8Hz,1H),6.75 (s,2H),3.90(s,3H),2.84(t,J=6.0Hz,2H),2.55(t,J=6.0Hz,2H),1.89–1.76(m,4H).ESI-MS:m / z[M+H] + 257.

[0043] Example 10: 9-amino-5,6,7,8-tetrahydroacridine-3-carboxylic acid 3j

[0044]

[0045] 0.14mmol of compound 3i, 4mL of tetrahydrofuran and 1mL of methanol solution were added to the reaction flask in sequence, and 0.55mmol of lithium hydroxide was dissolved in 2mL of aqueous solution and added to the reaction flask, and the reaction was carried out at room temperature for 0.5h. After the reaction was completed, 1mol / L hydrochloric acid solution was used to acidify to pH=5-6, diluted with water, and extracted with dichloromethane (20mL×3), the organic phases were combined, washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 28mg of light yellow solid, with a yield of 85.3%. 1 HNMR(500MHz,DMSO-d6)δ8.66(s,1H),8.02(d,J=8.6Hz,1H),7.47(d,J=8.6Hz,1H),6.30( s,2H),2.81(t,J=5.9Hz,2H),2.55(t,J=6.0Hz,2H),1.86–1.77(m,4H).ESI-MS:m / z[M+H] + 243.

[0046] Example 11: 6-phenyl-1,2,3,4-tetrahydro-9-aminoacridine 3k

[0047]

[0048] 0.36mmol of compound 3b, 0.72mmol of phenylboronic acid, 0.054mmol of tetrakis(triphenylphosphine)palladium, 0.72mmol of potassium carbonate, 10mL of 1,4-dioxane solution and 5mL of aqueous solution were added to the reaction flask, and the mixture was refluxed for 8h under nitrogen protection. After the reaction, water was added to dilute the reaction solution, extracted with ethyl acetate (20mL×3), the organic phases were combined, washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA:TEA=10:10:1, v / v / v) to obtain 41mg of light yellow solid with a yield of 41.4%. 1 H NMR (500MHz, DMSO-d6) δ8.24(d,J=8.8Hz,1H),7.90(d,J=1.9Hz,1H),7.84–7.78(m,2H),7.62(dd,J=8.7,2.0Hz,1H),7.50(t,J =7.7Hz,2H),7.42–7.37(m,1H),6.40(s,2H),2.85(t,J=6.0Hz,2H),2.58(t,J=6.1Hz,2H),1.89–1.78(m,4H).ESI-MS:m / z[M+H] + 275.

[0049] Example 12: 6-(3-Furan)-1,2,3,4-tetrahydro-9-aminoacridine 31

[0050]

[0051] The synthesis steps of 6-(3-furan)-1,2,3,4-tetrahydro-9-aminoacridine were the same as those of 3k, except that phenylboronic acid was replaced with an equal molar amount of 3-furanboronic acid. A light yellow solid was obtained in a yield of 39.7%. 1 H NMR (500MHz, DMSO-d6) δ8.32(t,J=1.2Hz,1H),8.15(d,J=8.7Hz,1H),7.86(d,J=1.8Hz,1H),7.77(t,J=1.7Hz,1H),7.57(d,J=2.1H z,1H),7.11(dd,J=1.9,0.9Hz,1H),6.33(s,2H),2.83(t,J=6.0Hz,2H),2.55(t,J=6.1Hz,2H),1.87–1.78(m,4H).ESI-MS:m / z[M+H] + 265.

[0052] 2. Test of TNF-α inhibitory activity:

[0053] After resuspending the RAW264.7 cells in a large dish, add 1×10 5 The cells were inoculated into a 96-well plate at a density of 100 ng / mL and cultured in a cell culture incubator at 37°C. When the cell density grew to 50% to 60%, the test compound was diluted with 1% fetal bovine serum DMEM medium and pre-administered with the test compound (the final concentration of the test compound was 10 μM), and an equal amount of 1% fetal bovine serum DMEM medium was added as a blank control, and the cells were returned to the incubator for culture for 12 hours. Then, LPS was added to each well at a final concentration of 100 ng / mL. After culturing in a cell culture incubator for 3 hours, 60 μL of cell supernatant was aspirated and the expression of TNF-α in the supernatant was determined by ELISA. The test results of compounds 3a to 3l are shown in Table 1:

[0054]

[0055] Table 1 Inhibitory activity of compounds 3a-31 on TNF-α

[0056]

[0057] The contents described in this specification are merely an enumeration of implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as being limited to the specific forms described in the embodiments.

Claims

1. Use of a class of 1,2,3,4-tetrahydro-9-aminoacridine compounds and pharmaceutically acceptable salts thereof in the preparation of anti-inflammatory drugs, characterized in that 1,2,3,4-Tetrahydro-9-aminoacridine compounds have one of the following two structures: ； ; Wherein, the anti-inflammatory drug is used to inhibit the expression of TNF-α.

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