Naproxen derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of development of anti-inflammatory drugs, and discloses a naproxen derivative as well as a preparation method and application thereof. The naphthoprim derivative is a compound with a structure as shown in a formula 2 or a pharmaceutically acceptable salt thereof. The naproxen derivative belongs to a novel compound, the compounds are designed and successfully synthesized for the first time, and the structure of the naproxen derivative is represented; the preparation method of the naproxen derivative is simple and convenient to operate, and the compounds can be rapidly synthesized; research finds that the naproxen derivative disclosed by the invention has good anti-inflammatory activity and shows a good application prospect in treatment of inflammation. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of anti-inflammatory drug development, and particularly relates to a naproxen derivative, a preparation method thereof, and an application thereof. Background Art

[0002] Naproxen, chemical name (+)-(S)-α-methyl-6-methoxy-2-naphthaleneacetic acid, has a molecular formula of C 14 H 14 O3, a molecular weight of 230.259, CAS number: 22204-53-1, and a structure as shown in Formula 1.

[0003]

[0004] Naproxen is a non-steroidal anti-inflammatory drug with anti-inflammatory, antipyretic, and analgesic effects. By inhibiting inducible cyclooxygenase-2 (COX-2) and alleviating the production of pro-inflammatory prostaglandins (mainly PEG-2), its curative effect on rheumatoid arthritis and osteoarthritis is similar to that of aspirin. Like other non-steroidal anti-inflammatory drugs, naproxen also has side effects such as gastrointestinal problems, and long-term use can cause kidney damage. Summary of the Invention

[0005] In order to overcome the disadvantages and deficiencies existing in the prior art, the primary object of the present invention is to provide a naproxen derivative that can enhance the anti-inflammatory activity of naproxen while reducing its toxic and side effects.

[0006] Another object of the present invention is to provide a preparation method of the above naproxen derivative; this method uses the terminal free carboxyl group of naproxen to connect with the amino group on the aminothiazole ring and branches different groups on the thiazole side chain to form a new compound, aiming to develop a naproxen hybrid molecule with enhanced anti-inflammatory activity and low toxic and side effects.

[0007] Another object of the present invention is to provide the application of the above naproxen derivative. Since this naproxen derivative has good in vitro anti-inflammatory activity, it is suitable as a new drug for inflammatory diseases.

[0008] The object of the present invention is achieved by the following technical solutions:

[0009] A naproxen derivative, wherein the derivative is a compound of the structure shown in Formula 2 or a pharmaceutically acceptable salt thereof:

[0010]

[0011] Wherein, R is one of the following groups:

[0012]

[0013] The specific induction of the above compounds is shown in Table 1:

[0014] Table 1 Compound numbers and specific groups

[0015]

[0016]

[0017] The R is more preferably one of the following groups:

[0018]

[0019] The pharmaceutically acceptable salt is a salt formed by the compound of the structure shown in Formula 2 and hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, glutamic acid or aspartic acid.

[0020] The preparation method of the above-mentioned naproxen derivative comprises the following operating steps:

[0021] (1) Dissolve thiosemicarbazide in acetone, stir evenly and then add chloroacetone derivative, stir and react at room temperature for 3 h until a solid precipitates in the reaction solution, carry out vacuum filtration using a Buchner funnel, wash the obtained solid with acetone, and finally dry the solid to obtain the thiazole intermediate of the structure shown in Formula 3, where R in the structure of Formula 3 is one of the following groups, with a yield of 75.24% - 90%;

[0022]

[0023] (2) Dissolve naproxen in N,N-dimethylformamide (DMF), add N,N-diisopropylethylamine under ice bath conditions and stir evenly, then add 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate for reaction. After fully generating the active ester, add the thiazole intermediate obtained in step (1) for condensation reaction to finally obtain the naproxen derivative of the structure shown in Formula 2.

[0024] In step (1), the molar ratio of thiosemicarbazide to chloroacetone derivative is 1:1.1.

[0025] In step (2), the molar ratio of naproxen, N,N-diisopropylethylamine, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and thiazole intermediate is 1:2:1.5:1.1.

[0026] The application of the above-mentioned naproxen derivative in the preparation of drugs for preventing and treating inflammatory diseases.

[0027] The synthetic route of the naproxen derivative is shown in the following equation, and the R group is the group in Table 1:

[0028]

[0029] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0030] (1) The naproxen derivatives provided by the present invention are novel types of compounds that have not been reported. The present invention designed and successfully synthesized these compounds for the first time and characterized their structures at the same time.

[0031] (2) The preparation method of the naproxen derivative of the present invention is simple and convenient to operate, and can quickly synthesize the target compound.

[0032] (3) Through extensive and in-depth research, the present invention synthesized a large number of naproxen derivatives with novel structures and having anti-inflammatory activities, and carried out anti-inflammatory activity screening. It was found for the first time that this type of compound has good in vitro anti-inflammatory activities and is suitable for use as a novel anti-inflammatory drug for preventing and treating inflammatory diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 It is the NMR spectrum diagram of Compound 1.

[0034] Figure 2 It is the NMR spectrum diagram of Compound 7.

[0035] Figure 3 It is the NMR spectrum diagram of Compound 9.

[0036] Figure 4 It is the NMR spectrum diagram of Compound 11.

[0037] Figure 5 It is the NMR spectrum diagram of Compound 13.

[0038] Figure 6 It is the NMR spectrum diagram of Compound 16.

[0039] Figure 7 It is the cytotoxicity test of naproxen and its derivatives on RAW264.7 cells measured by the MTT method.

[0040] Figure 8 It is the inhibitory effect of naproxen and its derivatives on the NO content in RAW264.7 cells measured by the Griess method.

[0041] Figure 9 It is the inhibitory effect of naproxen and its derivatives on the expression of iNOS protein in RAW264.7 cells analyzed by the Western blot method. DETAILED DESCRIPTION OF THE INVENTION

[0042] The present invention will be further described in detail below in conjunction with embodiments and the accompanying drawings, but the embodiments of the present invention are not limited thereto.

[0043] Example 1

[0044] Preparation of thiazole intermediate 1

[0045] In a clean single-necked round-bottom flask, 0.8 g (10.5 mmol) of thiosemicarbazide was dissolved in 20 mL of acetone. After stirring evenly, 1.7 g (11.6 mmol) of chloroacetophenone was added. The reaction was stirred at room temperature for 3 h until a large amount of white solid precipitated in the reaction solution. The solid was filtered under reduced pressure using a Buchner funnel, and the obtained solid was washed with an appropriate amount of acetone. Finally, the solid was dried to obtain thiazole intermediate A1 with the structure shown in Formula 3, and the yield was 87.65%.

[0046] According to the above method (the molar amounts of each reactant, reaction conditions, purification, etc. are the same), it was reacted with different chloroacetone derivatives to obtain intermediates A2 - A19 with the structure shown in Formula 3 (yields 75.24 - 90%). The structures of each intermediate are shown in Table 2, and the yields are shown in Table 3.

[0047] Table 2 Intermediates A1 - A19 and specific groups

[0048]

[0049]

[0050] Example 2

[0051] Synthesis of N-(4-isopropylthiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide (Compound 1)

[0052] In a single-diameter round-bottom flask, naproxen (1.0 g, 4.35 mmol) was added and dissolved in 10 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (DIPEA, 1.25 g, 9.7 mmol) was added to the flask, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 2.48 g, 6.525 mmol) was added under ice bath conditions. After 40 minutes, 2-amino-4-isopropylthiazole (Intermediate A1) (0.68 g, 4.785 mmol) obtained in Example 1 was added to the system. The mixture was transferred to room temperature and stirred for 3 hours. The reaction was monitored by TLC. After the reaction was completed, 100 ml of water and ethyl acetate were added to the system in sequence. The mixture was then transferred to a separatory funnel and shaken. The mixture was allowed to stand for separation. The organic phase was washed twice with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The organic phase was collected and rotary evaporated to obtain a crude product. The crude product was redissolved in ethyl acetate, and 2 g of 100-200 mesh silica gel was added and mixed thoroughly. The product compound 1 was purified by column chromatography with a yield of 56.4%. The NMR spectrum of the product is shown in FIG. Figure 1 As shown, the H NMR spectrum data is: 1 H NMR (600 MHz, DMSO-d6) δ 12.29 (s, 1H), 7.85–7.76 (m, 3H), 7.49 (dd, J = 8.5, 1.8 Hz, 1H), 7.28 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 8.9, 2.6 Hz, 1H), 6.71 (s, 1H), 4.10 (q, J = 7.0 Hz, 1H), 3.86 (s, 3H), 2.87 (hept, J = 6.9 Hz, 1H), 1.52 (d, J = 7.1 Hz, 3H), 1.19 (d, J = 1.0 Hz, 3H), 1.17 (d, J = 1.1 Hz, 3H). The number and displacement of hydrogen atoms in compound 1 were similar to those predicted.

[0053] Example 3

[0054] Synthesis of N-(4-(tert-butyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide (Compound 2)

[0055] The other steps were the same as those in Example 2, except that 2-amino-4-isopropylthiazole (Intermediate A1) obtained in Example 2 was used to replace 2-amino-4-tert-butylthiazole (Intermediate A2) in equal moles to obtain Compound 2: N-(4-(tert-butyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide, with a yield of 66.35%. The H NMR spectrum data were as follows: 1HNMR (600 MHz, DMSO-d6) δ 12.29 (s, 1H), 7.86–7.75 (m, 3H), 7.50 (dd, J = 8.5, 1.8 Hz, 1H), 7.28 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 8.9, 2.5 Hz, 1H), 6.71 (s, 1H), 4.12 (q, J = 7.0 Hz, 1H), 3.86 (s, 3H), 1.51 (d, J = 7.0 Hz, 3H), 1.23 (s, 9H). The number and chemical shift of hydrogen atoms in Compound 2 are similar to the prediction.

[0056] Example 4

[0057] Synthesis of 2-(6-methoxynaphthalen-2-yl)-N-(4-phenylthiazol-2-yl)propanamide (Compound 3)

[0058] Other steps are the same as in Example 2, except that 2-amino-4-isopropylthiazole (Intermediate A1) obtained in Example 2 is used to replace 2-amino-4-phenylthiazole (Intermediate A3) in equimolar amount to obtain Compound 3: 2-(6-methoxynaphthalen-2-yl)-N-(4-phenylthiazol-2-yl)propanamide, with a yield of 62.1%. The 1H NMR data are as follows: 1 HNMR (600 MHz, DMSO-d6) δ 12.50 (s, 1H), 7.91–7.86 (m, 2H), 7.85–7.74 (m, 3H), 7.60 (s, 1H), 7.52 (dd, J = 8.6, 1.9 Hz, 1H), 7.41 (t, J = 7.7 Hz, 2H), 7.33–7.27 (m, 2H), 7.16 (dd, J = 9.0, 2.6 Hz, 1H), 4.02 (d, J = 7.1 Hz, 1H), 3.86 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H).. The number and chemical shift of hydrogen atoms in Compound 3 are similar to the prediction.

[0059] Example 5

[0060] N-(4-(2-fluorophenyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide (Compound 4)

[0061] Other steps are the same as in Example 2, except that 2-amino-4-isopropylthiazole (Intermediate A1) obtained in Example 2 is used to replace 2-amino-4-phenylthiazole (Intermediate A4) in equimolar amount to obtain Compound 4: N-(4-(2-fluorophenyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide, with a yield of 59.23%. The 1H NMR data are as follows: 1HNMR (600 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.01 (td, J = 7.9, 1.7 Hz, 1H), 7.87–7.76 (m, 3H), 7.52 (dd, J = 8.7, 1.9 Hz, 2H), 7.38 (tdd, J = 7.1, 6.1, 1.8 Hz, 1H), 7.33–7.24 (m, 3H), 7.16 (dd, J = 9.0, 2.5 Hz, 1H), 4.18 (q, J = 7.0 Hz, 1H), 3.86 (s, 3H), 1.56 (d, J = 7.0 Hz, 3H). The number and chemical shifts of the hydrogens in Compound 4 are similar to the prediction.

[0062] Example 6

[0063] Synthesis of N-(4-(3-fluorophenyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide (Compound 5)

[0064] Other steps are the same as in Example 2, except that 2-amino-4-isopropylthiazole (Intermediate A1) obtained in Example 2 is used to replace 2-amino-4-(3-fluorophenyl)thiazole (Intermediate A5) in equimolar amounts to obtain Compound 5: N-(4-(3-fluorophenyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide, with a yield of 55.42%. The 1H NMR data are as follows: 1 HNMR (600 MHz, DMSO-d6) δ 12.52 (s, 1H), 7.85–7.82 (m, 2H), 7.80 (d, J = 8.6 Hz, 1H), 7.73 (dd, J = 7.9, 1.0 Hz, 2H), 7.67 (ddd, J = 10.7, 2.7, 1.5 Hz, 1H), 7.52 (dd, J = 8.5, 1.8 Hz, 1H), 7.46 (td, J = 8.0, 6.2 Hz, 1H), 7.29 (d, J = 2.5 Hz, 1H), 7.18–7.12 (m, 2H), 4.17 (q, J = 7.0 Hz, 1H), 3.86 (s, 3H), 1.56 (d, J = 7.0 Hz, 3H). The number and chemical shifts of the hydrogens in Compound 5 are similar to the prediction.

[0065] Example 7

[0066] N-(4-(4-fluorophenyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide (Compound 6)

[0067] Other steps were the same as in Example 2, except that 2-amino-4-isopropylthiazole (Intermediate A1) obtained in Example 2 was used to replace 2-amino-4-(4-fluorophenyl)thiazole (Intermediate A6) in equimolar amounts to obtain Compound 6: N-(4-(4-fluorophenyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide, with a yield of 67.83%. The 1H NMR data were as follows: 1 1H NMR (600 MHz, DMSO-d6) δ 12.34 (s, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 2.6 Hz, 1H), 6.93 (d, J = 9.0 Hz, 1H), 6.77 (s, 1H), 6.72 (dd, J = 9.0, 2.6 Hz, 1H), 3.84 (s, 2H), 3.75 (s, 3H), 2.28 (s, 3H), 1.98 (td, J = 8.3, 4.2 Hz, 1H), 0.86 (dt, J = 8.5, 3.1 Hz, 2H), 0.79–0.73 (m, 2H). The number and chemical shift of hydrogen atoms in Compound 6 were similar to the prediction.

[0068] Example 8

[0069] N-(4-(3,4-Difluorophenyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide (Compound 7)

[0070] Other steps were the same as in Example 2, except that 2-amino-4-isopropylthiazole (Intermediate A1) obtained in Example 2 was used to replace 2-amino-4-(3,4-difluorophenyl)thiazole (Intermediate A7) in equimolar amounts to obtain Compound 7: N-(4-(3,4-difluorophenyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide, with a yield of 61.25%. The NMR spectrum of Compound 7 was as shown in Figure 2 and the 1H NMR data were as follows: 1 1H NMR (600 MHz, DMSO-d6) δ 12.52 (s, 1H), 7.88 (ddd, J = 12.2, 7.8, 2.2 Hz, 1H), 7.84–7.79 (m, 3H), 7.75–7.72 (m, 1H), 7.71 (s, 1H), 7.53–7.46 (m, 2H), 7.29 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 9.0, 2.5 Hz, 1H), 4.17 (q, J = 7.0 Hz, 1H), 3.86 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H). The number and chemical shift of hydrogen atoms in Compound 7 were similar to the prediction.

[0071] Example 9

[0072] Synthesis of N-(4-(3-chlorophenyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide (Compound 8)

[0073] Other steps are the same as in Example 2, except that 2-amino-4-isopropylthiazole (Intermediate A1) obtained in Example 2 is used to replace 2-amino-4-(3-chlorophenyl)thiazole (Intermediate A8) in equimolar amounts to obtain Compound 8: N-(4-(3-chlorophenyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide, with a yield of 67.2%. The 1H NMR data are as follows: 1 1H NMR (600 MHz, DMSO-d6) δ 12.52 (s, 1H), 7.94 (t, J = 1.9 Hz, 1H), 7.87–7.82 (m, 3H), 7.80 (d, J = 8.6 Hz, 1H), 7.76 (s, 1H), 7.52 (dd, J = 8.6, 1.8 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.37 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 7.29 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 9.0, 2.5 Hz, 1H), 4.17 (t, J = 7.0 Hz, 1H), 3.86 (s, 3H), 1.56 (d, J = 7.0 Hz, 3H). The number and chemical shift of hydrogen atoms in Compound 8 are similar to the prediction.

[0074] Example 10

[0075] Synthesis of N-(4-(4-chlorophenyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide (Compound 9)

[0076] Other steps are the same as in Example 2, except that 2-amino-4-isopropylthiazole (Intermediate A1) obtained in Example 2 is used to replace 2-amino-4-(4-chlorophenyl)thiazole (Intermediate A9) in equimolar amounts to obtain Compound 9: N-(4-(4-chlorophenyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide, with a yield of 73.2%. The NMR spectrum of Compound 9 is as shown in Figure 3 and the 1H NMR data are as follows: 1HNMR (600 MHz, DMSO-d6) δ 12.52 (s, 1H), 7.90–7.88 (m, 2H), 7.84–7.82 (m, 2H), 7.80 (d, J = 8.6 Hz, 1H), 7.67 (s, 1H), 7.52 (dd, J = 8.5, 1.8 Hz, 1H), 7.49–7.46 (m, 2H), 7.29 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 9.0, 2.5 Hz, 1H), 4.16 (q, J = 7.0 Hz, 1H), 3.86 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H). The number and chemical shift of hydrogen atoms in Compound 9 are similar to the prediction.

[0077] Example 11

[0078] Synthesis of N-(4-(3-bromophenyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide (Compound 10)

[0079] Other steps are the same as in Example 2, except that 2-amino-4-isopropylthiazole (Intermediate A1) obtained in Example 2 is used to replace 2-amino-4-(3-bromophenyl)thiazole (Intermediate A10) in equimolar amount to obtain Compound 10: N-(4-(3-bromophenyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide, with a yield of 52.98%. The 1H NMR data are as follows 1 HNMR (600 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.09 (t, J = 1.8 Hz, 1H), 7.88 (dt, J = 7.8, 1.3 Hz, 1H), 7.83 (d, J = 8.9 Hz, 2H), 7.80 (d, J = 8.5 Hz, 1H), 7.76 (s, 1H), 7.53–7.49 (m, 2H), 7.38 (t, J = 7.9 Hz, 1H), 7.29 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 9.0, 2.6 Hz, 1H), 4.16 (q, J = 7.0 Hz, 1H), 3.86 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H). The number and chemical shift of hydrogen atoms in Compound 10 are similar to the prediction

[0080] Example 12

[0081] Synthesis of N-(4-(4-bromophenyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide (Compound 11)

[0082] Other steps are the same as those in Example 2, except that 2-amino-4-isopropylthiazole (Intermediate A1) obtained in Example 2 is used to replace 2-amino-4-(4-bromophenyl)thiazole (Intermediate A11) in an equimolar amount to obtain Compound 11: N-(4-(4-bromophenyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide, with a yield of 68.2%. The NMR spectrum of the product is as shown in Figure 4 shown, and the 1H NMR data are 1 1H NMR (600 MHz, DMSO-d6) δ 12.52 (s, 1H), 7.85–7.82 (m, 2H), 7.80 (d, J = 8.6 Hz, 1H), 7.73 (dd, J = 7.9, 1.0 Hz, 2H), 7.67 (ddd, J = 10.7, 2.7, 1.5 Hz, 1H), 7.52 (dd, J = 8.5, 1.8 Hz, 1H), 7.46 (td, J = 8.0, 6.2 Hz, 1H), 7.29 (d, J = 2.5 Hz, 1H), 7.18–7.12 (m, 2H), 4.17 (q, J = 7.0 Hz, 1H), 3.86 (s, 3H), 1.56 (d, J = 7.0 Hz, 3H). The number and chemical shift of hydrogen atoms in Compound 11 are similar to the prediction.

[0083] Example 13

[0084] 2-(6-Methoxynaphthalen-2-yl)-N-(4-(o-tolyl)thiazol-2-yl)propanamide (Compound 12)

[0085] Other steps are the same as those in Example 2, except that 2-amino-4-isopropylthiazole (Intermediate A1) obtained in Example 2 is used to replace 4-o-tolyl-2-aminothiazole (Intermediate A12) in an equimolar amount to obtain Compound 12: 2-(6-methoxynaphthalen-2-yl)-N-(4-(o-tolyl)thiazol-2-yl)propanamide, with a yield of 70.58%. The 1H NMR data are 1 1H NMR (600 MHz, DMSO-d6) δ 12.45 (s, 1H), 7.83 (dd, J = 5.4, 3.6 Hz, 2H), 7.80 (d, J = 8.5 Hz, 1H), 7.54 (dd, J = 14.7, 7.4, 1.9 Hz, 2H), 7.29 (d, J = 2.5 Hz, 1H), 7.26 (p, J = 2.7, 2.2 Hz, 1H), 7.23 (d, J = 5.7, 2.4 Hz, 3H), 7.16 (dd, J = 9.0, 2.5 Hz, 1H), 4.16 (q, J = 7.0 Hz, 1H), 3.86 (d, J = 1.2 Hz, 3H), 2.40 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H). The number and chemical shift of hydrogen atoms in Compound 12 are similar to the prediction.

[0086] Example 14

[0087] Synthesis of 2-(6-methoxynaphthalen-2-yl)-N-(4-(p-tolyl)thiazol-2-yl)propanamide (Compound 13)

[0088] Other steps were the same as in Example 2, except that 2-amino-4-isopropylthiazole (Intermediate A1) obtained in Example 2 was used to replace 4-(p-tolyl)-2-aminothiazole (Intermediate A13) in equimolar amounts to obtain Compound 13: 2-(6-methoxynaphthalen-2-yl)-N-(4-(p-tolyl)thiazol-2-yl)propanamide, with a yield of 65.33%. The NMR spectrum of the product is as Figure 5 shown, and the 1H NMR data are 1 1H NMR (600 MHz, DMSO-d6) δ 12.47 (s, 1H), 7.88–7.71 (m, 5H), 7.52 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 2.5 Hz, 1H), 7.24–7.09 (m, 3H), 4.16 (q, J = 7.0 Hz, 1H), 3.86 (s, 3H), 2.31 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H). The number and chemical shift of hydrogens in Compound 13 were similar to the prediction.

[0089] Example 15

[0090] 2-(6-methoxynaphthalen-2-yl)-N-(4-(2-methoxyphenyl)thiazol-2-yl)propanamide (Compound 14)

[0091] Other steps were the same as in Example 2, except that 2-amino-4-isopropylthiazole (Intermediate A1) obtained in Example 2 was used to replace 2-amino-4-(2-methoxyphenyl)thiazole (Intermediate A14) in equimolar amounts to obtain Compound 14: 2-(6-methoxynaphthalen-2-yl)-N-(4-(2-methoxyphenyl)thiazol-2-yl)propanamide, with a yield of 76.54%, and the 1H NMR data are: 11H NMR (600 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.04 (dd, J = 7.7, 1.8 Hz, 1H), 7.83 (dd, J = 5.4, 3.7 Hz, 2H), 7.80 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 0.7 Hz, 1H), 7.52 (dd, J = 8.5, 1.8 Hz, 1H), 7.31–7.28 (m, 2H), 7.16 (dd, J = 9.0, 2.6 Hz, 1H), 7.11 (dd, J = 8.3, 1.0 Hz, 1H), 7.01 (td, J = 7.5, 1.1 Hz, 1H), 4.16 (q, J = 6.9 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H). The number and chemical shift of hydrogen atoms of compound 14 are similar to the prediction.

[0092] Example 16

[0093] Synthesis of 2-(6-methoxynaphthalen-2-yl)-N-(4-(4-methoxyphenyl)thiazol-2-yl)propanamide (Compound 15)

[0094] Other steps are the same as in Example 2, except that 2-amino-4-isopropylthiazole (Intermediate A1) obtained in Example 2 is used to replace 2-amino-4-(4-methoxyphenyl)thiazole (Intermediate A15) in equimolar amounts to obtain Compound 15: 2-(6-methoxynaphthalen-2-yl)-N-(4-(4-methoxyphenyl)thiazol-2-yl)propanamide, with a yield of 63.25%. The 1H NMR data are as follows: 1 1H NMR (600 MHz, DMSO-d6) δ 12.45 (s, 1H), 7.85–7.82 (m, 2H), 7.82–7.78 (m, 3H), 7.52 (dd, J = 8.5, 1.8 Hz, 1H), 7.43 (d, J = 0.7 Hz, 1H), 7.29 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 9.0, 2.5 Hz, 1H), 7.00–6.95 (m, 2H), 4.16 (q, J = 7.0 Hz, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 1.55 (d, J = 6.9 Hz, 3H). The number and chemical shift of hydrogen atoms of compound 15 are similar to the prediction.

[0095] Example 17

[0096] Synthesis of 2-(6-methoxynaphthalen-2-yl)-N-(4-(2-nitrophenyl)thiazol-2-yl)propanamide (Compound 16)

[0097] Other steps are the same as in Example 2, except that 2-amino-4-isopropylthiazole (Intermediate A1) obtained in Example 2 is used to replace 2-amino-4-(2-nitrophenyl)thiazole (Intermediate A16) in equimolar amounts to obtain Compound 16: 2-(6-methoxynaphthalen-2-yl)-N-(4-(2-nitrophenyl)thiazol-2-yl)propanamide, with a yield of 66.89%. The NMR spectrum of the product is as shown in Figure 6 shown, and the 1H NMR data are as follows: 1 H NMR(600MHz, DMSO-d6)δ12.44(s, 1H), 7.88(dd, J = 8.1, 1.2Hz, 1H), 7.83–7.79(m, 3H), 7.75(dd, J = 7.8, 1.5Hz, 1H), 7.71(td, J = 7.5, 1.2Hz, 1H), 7.59(td, J = 7.7, 1.5Hz, 1H), 7.53(d, J = 0.6Hz, 1H), 7.50(dd, J = 8.4, 1.8Hz, 1H), 7.29(d, J = 2.5Hz, 1H), 7.16(dd, J = 8.9, 2.6Hz, 1H), 4.18(q, J = 7.0Hz, 1H), 3.86(s, 3H), 1.54(d, J = 6.9Hz, 3H). The number and chemical shift of hydrogens in Compound 16 are similar to the prediction.

[0098] Example 18

[0099] 2-(6-methoxynaphthalen-2-yl)-N-(4-(3-nitrophenyl)thiazol-2-yl)propanamide (Compound 17)

[0100] Other steps are the same as in Example 2, except that 2-amino-4-isopropylthiazole (Intermediate A1) obtained in Example 2 is used to replace 2-amino-4-(3-nitrophenyl)thiazole (Intermediate A17) in equimolar amounts to obtain Compound 17: 2-(6-methoxynaphthalen-2-yl)-N-(4-(3-nitrophenyl)thiazol-2-yl)propanamide, with a yield of 68.24%, and the 1H NMR data are as follows: 11H NMR (600 MHz, DMSO-d6) δ 12.61 (s, 1H), 8.72 (t, J = 2.0 Hz, 1H), 8.32 (dt, J = 7.9, 1.3 Hz, 1H), 8.16 (dd, J = 8.2, 2.3 Hz, 1H), 7.92 (s, 1H), 7.84 (dd, J = 5.4, 3.7 Hz, 2H), 7.81 (d, J = 8.6 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.53 (dd, J = 8.5, 1.8 Hz, 1H), 7.29 (d, J = 2.6 Hz, 1H), 7.17 (dd, J = 9.0, 2.5 Hz, 1H), 4.18 (q, J = 7.0 Hz, 1H), 3.86 (s, 3H), 1.57 (d, J = 7.1 Hz, 3H). The number and chemical shift of the hydrogens of Compound 17 are similar to the prediction.

[0101] Example 19

[0102] Synthesis of 2-(6-methoxynaphthalen-2-yl)-N-(4-(4-nitrophenyl)thiazol-2-yl)propanamide (Compound 18)

[0103] Other steps are the same as in Example 2, except that 2-amino-4-isopropylthiazole (Intermediate A1) obtained in Example 2 is used to replace 2-amino-4-(4-nitrophenyl)thiazole (Intermediate A18) in an equimolar amount to obtain Compound 18: 2-(6-methoxynaphthalen-2-yl)-N-(4-(4-nitrophenyl)thiazol-2-yl)propanamide, with a yield of 73.2%. The 1H NMR data are as follows: 1H NMR (600 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.31–8.27 (m, 2H), 8.15–8.12 (m, 2H), 7.98 (s, 1H), 7.83 (dd, J = 5.4, 3.7 Hz, 2H), 7.80 (d, J = 8.6 Hz, 1H), 7.52 (dd, J = 8.6, 1.8 Hz, 1H), 7.29 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 9.0, 2.5 Hz, 1H), 4.18 (q, J = 7.0 Hz, 1H), 3.86 (s, 3H), 1.56 (d, J = 7.0 Hz, 3H). The number and chemical shift of the hydrogens of Compound 18 are similar to the prediction.

[0104] Example 20

[0105] Synthesis of N-(4-(3-cyanophenyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide (Compound 19)

[0106] Other steps are the same as those in Example 2, except that 2-amino-4-isopropylthiazole (Intermediate A1) obtained in Example 2 is used to replace 3-(2-aminothiazol-4-yl)benzonitrile (Intermediate A19) in equimolar amounts to obtain Compound 19: N-(4-(3-cyanophenyl)thiazol-2-yl)-2-(6-methoxynaphthalen-2-yl)propanamide, with a yield of 77.67%. The nuclear magnetic resonance hydrogen spectrum data are as follows: 1 H NMR(600MHz, DMSO-d6)δ12.55(s, 1H), 8.31(s, 1H), 8.20(dt, J = 7.9, 1.4Hz, 1H), 7.86–7.82(m, 3H), 7.81–7.76(m, 2H), 7.64(t, J = 7.9Hz, 1H), 7.52(dd, J = 8.5, 1.8Hz, 1H), 7.29(d, J = 2.6Hz, 1H), 7.17(dd, J = 9.0, 2.6Hz, 1H), 5.76(s, 1H), 4.18(q, J = 7.0Hz, 1H), 3.87(s, 3H), 1.56(d, J = 7.0Hz, 3H). The number and chemical shift of hydrogen atoms in Compound 19 are similar to the prediction.

[0107] Table 3 Compound numbers and yields

[0108]

[0109]

[0110] Effect Example

[0111] 1. Experimental method

[0112] 1.1 Cytotoxicity experiment

[0113] Mouse mononuclear macrophages RAW264.7 were subcultured in DMEM medium containing 10% fetal bovine serum, 100 mg / L penicillin, and 100 mg / L streptomycin in a constant temperature incubator at 37°C and 5% CO2. RAW264.7 cells in the logarithmic growth phase were taken, and the cell density was adjusted to 1×10 4 cells / ml and inoculated into a 96-well plate, 100 μL per well. After the cells adhered for 12 h, the medium was replaced with DMEM without or containing 20 μmol / L of Compound 1-19, and 3 replicate wells were set for each concentration. After incubation for 24 h, 100 μL of MTT was added to each well and cultured for another 4 h. The supernatant was discarded, 150 μL of dimethyl sulfoxide (DMSO) was added to each well, and the plate was shaken on a shaker for 10 min. After the crystals were fully dissolved, the absorbance A was measured at 490 nm. The experiment was repeated 3 times. The cell survival rate (%) was calculated as (A detection well / A blank well) × 100%.

[0114] 1.2 Effect of the compound on NO content

[0115] Take the RAW264.7 cell suspension in the logarithmic growth phase, adjust the cell density to 5×10 5 cells / mL, inoculate into a 96-well plate, 100 μL per well. After adherent for 12 h, add 100 μL of each of compounds 1-19 with a concentration of 20 μmol / L and incubate for 3 h, then add 100 ng / L LPS and incubate for 12 h. Set up a blank group, an LPS group, and an LPS + drug administration group, with 3 replicate wells in each group. Detect the content of NO in the supernatant by the Griess method.

[0116] 1.3 Effect of the compound on the expression of iNOS protein

[0117] Take the RAW264.7 cell suspension in the logarithmic growth phase, adjust the cell density to 2×10 5 cells / mL, inoculate into a 12-well plate, 1 mL per well. After adherent for 12 h, add compounds 14, 18, and 21 with a concentration of 20 μmol / L and incubate for 3 h, then add 100 ng / L LPS and incubate for 12 h. Set up a blank group, an LPS group, and an LPS + drug administration group, with 3 replicate wells in each group. Detect the expression of iNOS protein by Western blot method.

[0118] 1.4 Data analysis

[0119] Use prism software for data analysis. The t-test is used for comparison between groups, and P < 0.05 indicates statistically significant differences.

[0120] 2. Results

[0121] According to the results of the MTT experiment, compounds 3, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19 have no obvious effect on the viability of RAW 264.7 cells, and the results are as Figure 7 shown. According to the results of the Griess experiment, compounds 12, 16, and 19 show significantly better effects in inhibiting the production of NO by RAW264.7 cells than other compounds, and the results are as Figure 8 shown. Study the effects of these 3 compounds on the expression of iNOS in LPS-induced RAW264.7 cells by WB experiment. The results of the WB experiment are as Figure 9 shown. Compounds 12, 16, and 19 can significantly inhibit the expression of iNOS protein in LPS-induced RAW264.7 cells.

[0122] The results showed that compounds 12, 16, and 19 of the present invention had no obvious cell inhibitory effect on RAW264.7, and at the same time could significantly reduce the release level of the inflammatory factor NO and the expression level of the inflammatory protein iNOS in RAW264.7 cells induced by LPS, had good anti-inflammatory activity, and could be used as the active ingredient of anti-inflammatory drugs.

[0123] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A naproxen derivative, characterized in that: The derivative is a compound of the structure shown in Formula 2 or a pharmaceutically acceptable salt thereof: Wherein, R is one of the following groups:

2. The naproxen derivative according to claim 1, wherein: R is one of the following groups:

3. The naproxen derivative according to claim 1, wherein: The pharmaceutically acceptable salt is a salt formed by the compound of the structure shown in Formula 2 and hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, glutamic acid or aspartic acid.

4. A method for preparing a naproxen derivative according to any one of claims 1-3, characterized in that It includes the following operation steps: (1) Dissolve thiosemicarbazide in acetone, stir evenly and then add the chloroacetone derivative. Stir and react at room temperature for 3 h until a solid precipitates in the reaction solution. Perform vacuum filtration using a Buchner funnel. Wash the obtained solid with acetone, and finally dry the solid to obtain the thiazole intermediate of the structure shown in Formula 3, with a yield of 75.24% - 90%; Wherein, R is one of the following groups (2) Dissolve naproxen in N,N-dimethylformamide, add N,N-diisopropylethylamine under ice bath conditions and stir evenly. Then add 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate to react. After fully generating the active ester, add the thiazole intermediate obtained in step (1) for condensation reaction to finally obtain the naproxen derivative of the structure shown in Formula 2.

5. The preparation method according to claim 4, characterized in that: In step (1), the molar ratio of thiosemicarbazide to the chloroacetone derivative is 1:1.

1.

6. The preparation method according to claim 4, characterized in that: In step (2), the molar ratio of naproxen, N,N-diisopropylethylamine, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and the thiazole intermediate is 1:2:1.5:1.

1.

7. Use of the naproxen derivative according to any one of claims 1 - 3 in the preparation of a drug for preventing and treating inflammatory diseases.

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