Lead compound of alpha-nitrogen modified ibuprofen amide non-steroidal anti-inflammatory drug

Abstract

The invention discloses an alpha-nitrogen modified ibuprofen amide non-steroidal anti-inflammatory drug lead compound and a preparation method thereof. The lead compound of the alpha-nitrogen modified ibuprofen non-steroidal anti-inflammatory drug comprises alpha-azide ibuprofen (or ketoprofen, naproxen, loxoprofen and flurbiprofen) amide, alpha-triazole ibuprofen (or ketoprofen, naproxen, loxoprofen and flurbiprofen) amide, alpha-phosphamide ibuprofen (or ketoprofen, naproxen, loxoprofen and flurbiprofen) amide, alpha-nitrogen modified ibuprofen (or ketoprofen, naproxen, loxoprofen and flurbiprofen) amide and alpha-nitrogen modified ibuprofen (or ketoprofen, naproxen, loxoprofen and flurbiprofen) amide. Animal experiments prove that the alpha-azide ibuprofen amide, the alpha-phosphamide ibuprofen amide and the like show anti-inflammatory and analgesic activity which is remarkably superior to that of ibuprofen, and a novel non-steroidal anti-inflammatory drug capable of replacing the ibuprofen is expected to be developed.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to synthesis of a lead compound of an alpha-nitrogen modified ibuprofen amide non-steroidal anti-inflammatory drug and its pharmaceutical activity in anti-inflammatory and analgesic aspects. BACKGROUND

[0002] Ibuprofen, as a non-steroidal anti-inflammatory drug, is widely used for fever, mild and moderate pain (including postoperative pain), menstrual pain, headache, and pain caused by kidney stones. Ibuprofen inhibits the activity of cyclooxygenase (COX), blocks the biosynthesis of arachidonic acid (AA) into prostaglandins (PGs), and reduces local vascular permeability and leukocyte infiltration, thereby inhibiting inflammatory response and reducing tissue swelling and redness. At the same time, ibuprofen reduces pain signal transmission by inhibiting the release of inflammatory mediators and the activation of neurons, thereby relieving pain perception; and by affecting the hypothalamic thermoregulatory center, ibuprofen reduces the synthesis of prostaglandins in the hypothalamus, thereby reducing body temperature. However, it has been reported that the cleavage of the carboxylic acid structure of ibuprofen often produces side effects such as gastrointestinal complications during long-term use. In order to improve the bioavailability of ibuprofen drugs, improve adverse reactions and find new targets, researchers have designed and synthesized many new ibuprofen derivatives through various methods. At present, the structural modification of ibuprofen mainly focuses on the carboxyl group, benzene ring and isobutyl structural unit (Figure 1). The ester bond and amide bond formed by chemical modification can improve the anti-gastrointestinal ulcer and other biological properties of ibuprofen drugs to some extent, but their analgesic, anti-inflammatory and antipyretic effects are often weaker than ibuprofen. Organic azide compounds are widely used as general precursors for drugs and the synthesis of various nitrogen-containing targets. Although the product of azidation of the isobutyl benzyl group of ibuprofen has been reported, the study on the pharmaceutical activity of alpha-azido ibuprofen amide compounds and their derived alpha-nitrogen modified ibuprofen amide compounds is still blank. SUMMARY

[0003] The present application relates to a novel alpha-nitrogen modified ibuprofen amide non-steroidal anti-inflammatory drug lead compound and its pharmaceutical activity in anti-inflammatory and analgesic aspects.

[0004] The inventors have demonstrated through in-depth analysis of various ibuprofen structural modification derivatives reported that the alpha-nitrogen modified ibuprofen amide compound as a novel non-steroidal anti-inflammatory drug lead compound has excellent anti-inflammatory and analgesic efficacy. Animal experiment results prove that the alpha-nitrogen modified ibuprofen amide non-steroidal anti-inflammatory drug lead compound shows excellent anti-inflammatory and analgesic activity in mouse experiments, and has a statistically significant difference (p < 0.01) compared with ibuprofen.

[0005] In order to achieve the object of the present application, the present application provides an alpha-nitrogen modified ibuprofen amide non-steroidal anti-inflammatory drug lead compound having a compound as shown in the general formula (I):

[0006]

[0007] wherein R is any one of , , , or .

[0008] Y is any one of , or .

[0009] Synthetic route:

[0010]

[0011] Further, the synthesis method of the alpha-nitrogen modified ibuprofen amide non-steroidal anti-inflammatory drug lead compound comprises the following steps:

[0012] (1) dissolving ibuprofen, naproxen drugs, 3-methyl-2-aminopyridine, EDC, HOBT in organic solvent tetrahydrofuran to obtain a mixed solution A; the molar ratio of the ibuprofen, naproxen drugs, 3-methyl-2-aminopyridine, EDC, HOBT is 1:1:1.2:1. The mixed solution A is stirred at room temperature for 24 hours to obtain a mixed solution B; the mixed solution B is filtered, the filtrate is concentrated, and column chromatography is performed to obtain a plurality of ibuprofen, naproxen amide derivatives.

[0013] (2) dissolving the amide derivative, Cu(OAc)2, IBA, TMSN3 in organic solvent 1,2-dichloroethane to obtain a mixed solution C; as preferred, the molar ratio of the amide, Cu(OAc)2, IBA, TMSN3 is 1:0.05:1.5:2; the mixed solution C is stirred at 80°C under N2 atmosphere for 6 hours to obtain a mixed solution D; the mixed solution D is filtered, the filtrate is concentrated, and column chromatography is performed to obtain a plurality of alpha-azide ibuprofen amide compounds.

[0014] (3) dissolving the alpha-azide ibuprofen amide compound, CuI, phenylacetylene in CH3CN to obtain a mixed solution E; as preferred, the molar ratio of the alpha-azide ibuprofen amide compound, CuI, phenylacetylene is 1:0.1:2; the mixed solution E is stirred at room temperature for 24 hours to obtain a mixed solution F; the mixed solution F is filtered, the filtrate is concentrated, and column chromatography is performed to obtain a plurality of alpha-triazole ibuprofen amide compounds.

[0015] (4) Dissolve α-azidoibuprofen amide compounds and triethyl phosphate in dichloromethane to obtain a mixture G; preferably, the molar ratio of the α-azidoibuprofen amide compounds and triethyl phosphate is 1:3; stir the mixture G at room temperature for 20 hours to obtain a mixture H; filter the mixture H, concentrate the filtrate, and obtain a variety of α-phosphamide ibuprofen amide compounds by column chromatography.

[0016] Compared with existing ibuprofen-modified compounds, the present invention has the following advantages: the invented α-azido-ibuprofenamide and α-phosphamide ibuprofenamide exhibit significantly better anti-inflammatory and analgesic activities than ibuprofen, and are expected to be developed into novel nonsteroidal anti-inflammatory drugs that can replace ibuprofen.

[0017] The use of the α-nitrogen-modified ibuprofen amide lead compound of the present invention in anti-inflammatory and analgesic effects falls within the scope of protection of the present invention. Attached Figure Description

[0018] Figure 1 This is a schematic diagram of the chemical modification of ibuprofen.

[0019] Figure 2 yes 1 ¹H NMR data of 2-azido-2-(4-isobutylphenyl)-N-(3-methylpyridin-2-yl)propenamide 1.

[0020] Figure 3 yes 13 A 1C NMR chromatogram of 2-azido-2-(4-isobutylphenyl)-N-(3-methylpyridin-2-yl)propenamide 1.

[0021] Figure 4 This is a HRMS (ESI) data graph of 2-azido-2-(4-isobutylphenyl)-N-(3-methylpyridin-2-yl)propanamide (±) 1.

[0022] Figure 5 yes 1 ¹H NMR data of 2-(4-isobutylphenyl)-N-(3-methylpyridin-2-yl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)propenamide 2.

[0023] Figure 6is a data plot of HRMS (ESI) of 2-(4-isobutylphenyl)-N-(3-methylpyridin-2-yl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)propanamide 2.

[0024] Figure 7 is a data plot of HRMS (ESI) of 2-(4-isobutylphenyl)-N-(3-methylpyridin-2-yl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)propanamide 2.

[0025] Figure 8 is 1 is a data plot of H NMR of Diethyl (R)-(2-(4-isobutylphenyl)-1-((3-methylpyridin-2-yl)amino)-1-oxopropan-2-yl)phosphoramidate 3

[0026]

[0027] Figure 9 is 13 is a data plot of C NMR of Diethyl (R)-(2-(4-isobutylphenyl)-1-((3-methylpyridin-2-yl)amino)-1-oxopropan-2-yl)phosphoramidate 3.

[0028] Figure 10 is a data plot of HRMS (ESI) of diethyl (R)-(2-(4-isobutylphenyl)-1-((3-methylpyridin-2-yl)amino)-1-oxopropan-2-yl)phosphoramidate 3.

[0029] Figure 11 is a comparative data plot of Example 4.

[0030] Figure 12 is a comparative data plot of Example 5. DETAILED DESCRIPTION

[0031] Example 1 α-Azidobuprofenamide (Compound 1) and its structural characterization

[0032] ​Dissolve 5 mmol ibuprofen, 5 mmol 3-methyl-2-aminopyridine, 6 mmol EDC, 5 mmol HOBT in 40 mL tetrahydrofuran, stir the mixture at room temperature for 24 hours to obtain a mixture, filter the mixture, concentrate the filtrate, and purify by column chromatography to obtain ibuprofen amide. Dissolve 1 mmol ibuprofen amide, 0.1 mmol copper acetate, 1.5 mmol IBA, 2 mmol TMSN3 in 20 mL 1,2-dichloroethane, stir the obtained reaction mixture at 80°C under N2for 6 hours, concentrate the filtrate, and purify by column chromatography to obtain α-azido ibuprofen amide (compound 1) with a yield of about 61%.

[0033] NMR monitoring data are as follows: Compound 1. 1 H NMR (600 MHz, CDCl3) δ8.74 (s, 1H), 8.23 (s, 1H), 7.51-7.48 (m, 3H), 7.18 (d, J = 7.8 Hz, 2H), 7.07(s, 1H), 2.47 (d, J = 7.1 Hz, 2H), 2.10 (s, 3H), 2.03 (s, 3H), 1.90-1.81 (m,1H), 0.90 (s, 3H), 0.89 (d, J = 6.6 Hz, 3H); 13 C NMR (151 MHz, CDCl3) δ 169.3,148.7, 146.0, 142.2, 139.8, 136.5, 129.6, 128.5, 125.7, 122.0, 69.6, 45.0,30.1, 22.7, 22.3, 17.8; ; HRMS (ESI): m / z [M+H] + calcd for C 19 H 24 N5O + 338.1975, found 338.1964.

[0034] As shown in Figure 2 ,

[0035] 1 Data graph of H NMR of 2-azido-2-(4-isobutylphenyl)-N-(3-methylpyridin-2-yl)propenamide 1.

[0036] As shown in Figure 3 ,

[0037] 13 Data plot of C NMR of 2-azido-2-(4-isobutylphenyl)-N-(3-methylpyridin-2- yl)propenamide 1.

[0038] As shown in Figure 4

[0039] Data plot of HRMS (ESI) of 2-azido-2-(4-isobutylphenyl)-N-(3-methylpyridin-2- yl)propanamide (±) 1.

[0040] Example 2 α-triazole ibuprofen amide (compound 2) and its structural characterization

[0041] Dissolve 1 mmol of α-azide ibuprofen amide (compound 1), 0.1 mmol of CuI, 2 mmol of phenylacetylene in CH3CN, stir the obtained reaction mixture at room temperature for 24 hours, concentrate the filtrate, and purify by column chromatography to obtain α-triazole ibuprofen amide (compound 2) with a yield of about 71%.

[0042] NMR monitoring data are as follows: Compound 2. 1 H NMR (600 MHz, CDCl3)δ 8.81 (s, 1H), 8.26 (s, 1H), 7.93 (s, 1H), 7.84 (d, J = 7.7 Hz, 2H), 7.52(d, J = 7.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.5 Hz, 1H), 7.22(d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.10-7.03 (m, 1H), 2.48 (d, J= 7.1 Hz, 2H), 2.43 (s, 3H), 2.19 (s, 3H), 1.90-1.83 (m, 1H), 0.90 (d, J =6.6 Hz, 6H); 13 ​C NMR (151 MHz, CDCl3) δ 167.7, 148.7, 147.2, 146.1, 142.8, 139.7, 137.4, 130.2, 129.9, 128.9, 128.4, 127.9, 126.1, 125.8, 121.9, 120.5, 72.1, 44.9, 30.0, 26.7, 22.4, 17.8; HRMS (ESI): m / z [M+H] + calcd for C 27 H 30 N5O + 440.2445, found 440.2431.

[0043] As Figure 5 shown,

[0044] 1 H NMR of 2-(4-isobutylphenyl)-N-(3-methylpyridin-2-yl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)propenamide 2 of the data graph.

[0045] As Figure 6 shown,

[0046] 13 C NMR of 2-(4-isobutylphenyl)-N-(3-methylpyridin-2-yl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)propenamide 2 of the data graph.

[0047] As Figure 7 shown,

[0048] HRMS (ESI) of 2-(4-isobutylphenyl)-N-(3-methylpyridin-2-yl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)propanamide 2 of the data graph.

[0049] Example 3 α-phosphoramidate ibuprofen amide (compound 3) and its structural characterization;

[0050] Dissolve 1 mmol of α-azide ibuprofen amide (compound 1), 3 mmol of triethyl phosphate in dichloromethane, stir the resulting reaction mixture at room temperature for 20 hours, concentrate the filtrate, and purify by column chromatography to obtain α-phosphoramidate ibuprofen amide (compound 3) at a yield of about 82%.

[0051] NMR monitoring data are as follows: Compound 3. 1 H NMR (600 MHz, CDCl3) δ8.38 (s, 1H), 8.10 (d, J = 4.8 Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.48 (d, J= 7.9 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H), 7.05 (dd, J = 7.5, 4.9 Hz, 1H), 5.04(d, J = 9.8 Hz, 1H), 3.95-3.85 (m, 3H), 3.73-3.65 (m, 1H), 2.47 (d, J = 7.2Hz, 2H), 2.10 (s, 3H), 2.07 (s, 3H), 1.88-1.81 (m, 1H), 1.19 (t, J = 7.1 Hz,3H), 1.12 (t, J = 7.1 Hz, 3H), 0.90 (d, J = 6.6 Hz, 6H); 13 C NMR (151 MHz,CDCl3) δ 173.1, 149.1, 145.7, 141.7, 140.0, 139.7, 129.4, 128.5, 126.5,121.8, 62.4, 62.3(dd, J = 14.0, 3.6 Hz), 62.3, 62.3, 45.0, 30.1, 25.1, 22.3(d, J = 2.2 Hz), 17.7, 16.1 (dd, J = 12.0, 7.2 Hz); HRMS (ESI): m / z [M+H] + calcd for C 23 H 35 N3O4P + 448.2360, found 448.2350.

[0052] As shown in Figure 8 ,

[0053] 1HNMR of Diethyl (R)-(2-(4-isobutylphenyl)-1-((3-methylpyridin-2-yl)amino)-1-oxopropan-2-yl)phosphoramidate 3.

[0054] As shown in Figure 9 ,

[0055] 13 C NMR of Diethyl (R)-(2-(4-isobutylphenyl)-1-((3-methylpyridin-2-yl)amino)-1-oxopropan-2-yl)phosphoramidate 3.

[0056] As shown in Figure 10 ,

[0057] HRMS (ESI) of diethyl (R)-(2-(4-isobutylphenyl)-1-((3-methylpyridin-2-yl)amino)-1-oxopropan-2-yl)phosphoramidate 3.

[0058] Example 4: Anti-inflammatory activity of compounds 1-3 was determined using mouse carrageenan-induced paw edema animal model

[0059] Carrageenan-induced paw edema animal model was performed in male Sprague-Dawley rats weighing 140-150 g for detecting anti-inflammatory activity. Hot plate test was performed in male C57BL / 6J mice weighing 20-22 g for detecting analgesic activity. Animals were housed in a constant temperature environment at 22°C, following a 12 / 12 hour light / dark cycle. All animal experiments were in accordance with the Tianjin Medical Experimental Animal Care Guidelines, and the animal experimental protocol was approved by the Institutional Animal Care and Use Committee of Yisen Source Gene Technology (Tianjin) Co., Ltd. (Agreement Number: YSY-DWLL-2025668). Animals were acclimated in the laboratory environment for one week before starting the experiment. Twelve hours before the experiment, animals only received water feeding to avoid the interference of food on the absorption of substances.

[0060] Animal model of carrageenan-induced paw swelling: Rats were randomly divided into 7 groups: drug group (4 ibuprofen-modified drugs), control group (0.5% carboxymethyl cellulose solution), ibuprofen group (positive control group), and indomethacin group (positive control group), with 7 rats in each group. One hour before carrageenan injection, rats were administered carrageenan by gavage at a dose of 100 mg / kg dissolved in 0.5% carboxymethyl cellulose solution (10 mL / kg). The control group was administered the solution by gavage only (0.5% carboxymethyl cellulose solution). Subsequently, 10 μL of 2% carrageenan suspension was injected subcutaneously into the right paw of the rats to induce edema. Paw thickness was measured before injection (T0) and at 2 h and 4 h after injection (Tt). Edema was calculated by subtracting the base volume from the treated paw thickness (mm) (ΔT = Tt – T0). For each animal, the anti-inflammatory effect of the drug was expressed as the percentage of edema inhibition. Inhibition rate (%) = [(control group ΔT - experimental group ΔT) / control group ΔT] × 100%.

[0061] Animal experiments showed that α-azidoibuprofenamide (compound 1) exhibited the highest anti-inflammatory activity (76%, 2h inhibition rate) compared to ibuprofen, with a statistically significant difference (P < 0.01). This result confirms that introducing an azido group at the α-site of ibuprofen can significantly enhance its anti-inflammatory activity. Furthermore, α-phosphatidyl-ibuprofenamide (compound 3) also significantly enhanced the anti-inflammatory activity of ibuprofen (P < 0.01).

[0062] Example 5: The analgesic activity of compounds 1-3 was determined using a mouse hot plate test.

[0063] Hot plate test: Mice were randomly divided into 6 groups: drug group (4 ibuprofen modified drugs), control group (0.5% carboxymethyl cellulose solution), and ibuprofen group (positive control), with 7 mice in each group. To determine nociceptive activity, a traditional hot plate test was used. One group of mice was placed alone on a hot plate at 55±0.5℃, and the mice were confined to the hot plate surface using an acrylic glass tube with a diameter of 12 cm and a height of 20 cm. The time to lick the forepaw or the jumping response (whichever appeared first) was recorded as an indicator of nociceptive sensation. Only mice exhibiting a nociceptive response within 60 seconds were used in the experiment. To avoid tissue damage, the maximum transection time was chosen to be 60 s. After obtaining the baseline reading (T0), mice were administered the test compound at a dose of 100 mg / kg, 0.5% carboxymethyl cellulose solution as a control, and ibuprofen as a positive control by gavage. The latency of response (T1) was measured at 0.5 h, 1 h, and 2 h after administration. If there was still no response after 60 s, the pain threshold of 60 s was used. The effect of the compound on the sense of injury was determined by the percentage of maximum possible effect (%MPE), calculated as follows: MPE(%) = (T1-T0) / (T2-T0)×100%, where the cutoff time (T2) is 60 s.

[0064] In tests 1 h and 2 h after administration, all compounds (compounds 1-3) significantly inhibited the hot plate licking paw response compared to the control group. Notably, the compound exhibiting the highest anti-inflammatory activity also showed the highest analgesic activity. In tests 0.5 h after administration, α-azidoibuprofenamide (compound 1) showed the highest analgesic activity compared to ibuprofen, with a statistically significant difference (P < 0.01). Meanwhile, α-phosphatidyl-ibuprofenamide (compound 3) showed the highest analgesic activity compared to ibuprofen in tests 1 h and 2 h after administration, with statistically significant differences (P < 0.01).

Claims

1. An alpha-nitrogen modified ibuprofen amide non-steroidal anti-inflammatory drug lead compound, characterized in that: a compound having the following structure: (1) dissolving ibuprofen, naproxen drugs, 3-methyl-2-aminopyridine, EDC, HOBT in organic solvent tetrahydrofuran to obtain mixed solution A; the molar ratio of ibuprofen, naproxen drugs, 3-methyl-2-aminopyridine, EDC, HOBT is 1:1:1.2:1; stirring mixed solution A at room temperature for 24 hours to obtain mixed solution B; filtering mixed solution B, concentrating the filtrate, and column chromatography to obtain a plurality of ibuprofen, naproxen amide derivatives; ； wherein R1 is any one of , , , or . Y is any one of , or . (2) dissolving the amide derivative, Cu(OAc)2, IBA, TMSN3 in organic solvent 1,2-dichloroethane to obtain mixed solution C; the molar ratio of the amide, Cu(OAc)2, IBA, TMSN3 is 1:0.05:1.5:2; stirring mixed solution C at 80°C under N2 atmosphere to obtain mixed solution D; filtering mixed solution D, concentrating the filtrate, and column chromatography to obtain a plurality of alpha-azide ibuprofen amide compounds; (3) dissolving the alpha-azide ibuprofen amide compound, CuI, phenylacetylene in CH3CN to obtain mixed solution E; the molar ratio of the alpha-azide ibuprofen amide compound, CuI, phenylacetylene is 1:0.1:2; stirring mixed solution E at room temperature to obtain mixed solution F; filtering mixed solution F, concentrating the filtrate, and column chromatography to obtain a plurality of alpha-triazole ibuprofen amide compounds; (4) dissolving the alpha-azide ibuprofen amide compound, triethyl phosphate in dichloromethane to obtain mixed solution G; the molar ratio of the alpha-azide ibuprofen amide compound, triethyl phosphate is 1:3; stirring mixed solution G at room temperature to obtain mixed solution H; filtering mixed solution H, concentrating the filtrate, and column chromatography to obtain a plurality of alpha-phosphoramide ibuprofen amide compounds. Azidation, triazole or phosphoramide modification of the alpha-position of ibuprofen drugs.

2. The lead compound of a- nitrogen modified ibuprofen amide non-steroidal anti-inflammatory drug according to claim 1, characterized by: The compound has anti-inflammatory activity better than ibuprofen, indomethacin, and shows a very significant difference p < 0.01 in animal tests.

3. The lead compound of a- nitrogen modified ibuprofen amide NSAIDs of claim 1, characterized in that: The compound has analgesic activity better than ibuprofen, and shows a very significant difference p < 0.01 in animal tests.

4. The lead compound of a- nitrogen modified ibuprofen amide NSAIDs of claim 1, characterized in that: ​

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