CN114853661A - Fluoroamidoibuprofen derivative and preparation method and application thereof - Google Patents

Fluoroamidoibuprofen derivative and preparation method and application thereof Download PDF

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CN114853661A
CN114853661A CN202210545881.XA CN202210545881A CN114853661A CN 114853661 A CN114853661 A CN 114853661A CN 202210545881 A CN202210545881 A CN 202210545881A CN 114853661 A CN114853661 A CN 114853661A
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ibuprofen
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张永强
徐缓
杨悦
马慧娟
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East China University of Science and Technology
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Abstract

The invention discloses a flutolanil ibuprofen derivative and a preparation method and application thereof. Aims to prepare the flutolanil ibuprofen derivative by using the condensation reaction of carboxylic acid and fluorinated aliphatic amine and research the anti-inflammatory activity of the flutolanil ibuprofen derivative. A series of flutolanil ibuprofen derivatives are designed and synthesized. The experimental result of the invention shows that most of the newly synthesized compounds show better anti-inflammatory activity than ibuprofen and are expected to become anti-inflammatory drugs with high efficiency and low toxicity.

Description

Fluoroamidoibuprofen derivative and preparation method and application thereof
Technical Field
The invention relates to a fluoroamide ibuprofen derivative, and belongs to the technical field of medicines.
Background
Ibuprofen (Ibuprofen, IBU) is one of the most widely used non-steroidal anti-inflammatory Drugs (NSAIDs). At present, the traditional Chinese medicine composition is mainly used as a symptomatic treatment medicine clinically, is used for relieving osteoarthritis, rheumatoid arthritis, various fever and various pain symptoms, and has good curative effect and safety. In recent years, the medicine also shows a certain application potential in the aspect of neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. However, the presence of carboxyl groups in the structure, as well as the non-selective inhibition of cyclooxygenase COX, results in the occurrence of gastrointestinal side effects upon prolonged use. In addition, relatively poor brain permeability limits its use in the treatment of central nervous system disorders.
Research shows that amidation of ibuprofen is an effective way to increase activity and reduce side effects. In previous studies, we have unexpectedly found that fluoroamide derivatives of 5-chlorothiophene-2-carboxylic acid exhibit anti-inflammatory activity comparable to that of itself. In the drug design, fluorine substitution is an effective strategy for regulating physicochemical properties, optimizing pharmacokinetic parameters and improving drug effects.
Inspired by this, a series of flutolanil ibuprofen derivatives were designed and synthesized in this study. A large number of experiments show that most of newly synthesized compounds show anti-inflammatory activity superior to ibuprofen and are expected to become high-efficiency and low-toxicity anti-inflammatory drugs.
Disclosure of Invention
The invention aims to prepare the flutolanil ibuprofen derivative by using the condensation reaction of carboxylic acid and fluorinated aliphatic amine and research the anti-inflammatory activity of the flutolanil ibuprofen derivative.
The structural general formula of the compound is as follows:
Figure BDA0003649392930000011
wherein the content of the first and second substances,
R 1 selected from hydrogen;
R 2 selected from fluoroalkyl, fluorocycloalkyl, fluoroazacycloalkyl, fluoroazacycloalkylmethyl;
the fluoroalkyl is C2-C8 fluoroalkyl;
the fluorinated cycloalkyl is C3-C10 fluorinated cycloalkyl;
the fluorinated azacycloalkyl is C3-C7 fluorinated azacycloalkyl;
the fluorinated azacycloalkylmethyl and azacycloalkyl is C3-C7 fluorinated azacycloalkyl.
Preferably, R in the general structural formula 1 And R 2 Bonded to each other to form a C3-C7 fluoroazacycloalkyl group, wherein,
R 1 selected from hydrogen;
R 2 selected from fluoroalkyl, fluorocycloalkyl, fluoroazacycloalkyl, fluoroazacycloalkylmethyl;
the fluoroalkyl is C2-C8 fluoroalkyl;
the fluorinated cycloalkyl is C3-C10 fluorinated cycloalkyl;
the fluorinated azacycloalkyl is C3-C7 fluorinated azacycloalkyl;
the fluorinated azacycloalkylmethyl and azacycloalkyl is C3-C7 fluorinated azacycloalkyl.
Preferably, the compounds of the present invention have the following general structural formula:
Figure BDA0003649392930000021
Figure BDA0003649392930000031
Figure BDA0003649392930000041
。
the flutolanil ibuprofen derivative is prepared by the following preparation method:
Figure BDA0003649392930000042
the invention also provides a preparation method of the derivative, which comprises the step of condensing ibuprofen and fluorinated aliphatic amine by using DCC/HOBT as a condensing agent to obtain S1-S18.
The invention has the beneficial effects that: most of the fluoroamide ibuprofen derivatives show in-vitro anti-inflammatory activity superior to that of ibuprofen, are expected to reduce side effects and improve the permeability of a central system so as to contribute to the development of further medicines for treating neurogenic inflammation, and specific experimental effects can be seen in figure 1 and table 1.
Drawings
FIG. 1 is a graph showing the in vitro nitric oxide inhibitory activity of the compounds S1-S18 of the present invention.
Detailed Description
Example 1: synthesis of Compound S1
Ibuprofen (103mg,0.5mmol,1.0equiv) was dissolved in 3mL of dichloromethane, dicyclohexylcarbodiimide (113mg,0.55mmol), HOBT (74mg,0.55mmol) were added sequentially at 0 ℃, stirred for 30min, 2-fluoroethylamine (50mg,0.5mmol,1.0equiv) was added to react, triethylamine (130 μ L,1mmol,2.0equiv), and then the mixture was moved to room temperature to react for 3h, by-product DCU was filtered off, the solvent was removed by rotary evaporation, water and dichloromethane were added to extract three times, saturated brine was washed, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by silica gel column chromatography (DCM: MeOH ═ 20:1) to give S1(93mg, 74%) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.19(d,J＝8.0Hz,2H),7.11(d,J＝7.9Hz,2H),5.87(s,1H),4.48–4.45(4.36–4.33)(m,2H),3.60–3.53(m,1H),349–3.43(m,2H),2.45(d,J＝7.2Hz,2H),1.88–1.82(m,1H),1.51(d,J＝7.2Hz,3H),0.90(d,J＝6.6Hz,6H). 19 F NMR(376MHz,CDCl 3 )δ-224.2–-224.6(m,1F). 13 C NMR(150MHz,CDCl 3 )δ174.7,140.9,138.2,129.7,127.3,83.3,82.2,46.7,45.0,40.0,30.2,22.4,18.5.HRMS(ESI)Calcd.for C 15 H 23 FNO + [(M+H) + ]252.1764,found 252.1763.
Example 2 Synthesis of Compound S2
The 2-fluoroethylamine was replaced with 2, 2', 2 "-trifluoroethylamine at the same equivalent ratio, and the remaining reagents and procedures were the same as those for the synthesis of S1, to give S2(124mg, 86%) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.10(d,J＝8.0Hz,2H),7.04(d,J＝8.0Hz,2H),5.87(s,1H),3.82–3.65(m,2H),3.58–3.51(m,1H),2.38(d,J＝7.2Hz,2H),1.85–1.72(m,1H),1.44(d,J＝7.2Hz,3H),0.82(d,J＝6.6Hz,6H). 19 F NMR(376MHz,CDCl 3 )δ-72.7(s,3F).HRMS(ESI)Calcd.for C 15 H 21 F 3 NO + [(M+H) + ]288.1575,found 288.1577.
Example 3 Synthesis of Compound S3
The 2-fluoroethylamine was replaced with 2-amino-1, 1, 1-trifluoropropane hydrochloride in the same equivalent ratio, and the remaining reagents and procedures were the same as those for the synthesis of S1 to give S3(120mg, 80%) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.17(t,J＝7.1Hz,2H),7.12(d,J＝8.1Hz,2H),5.55(d,J＝8.6Hz,1H),4.71–4.64(m,1H),3.61–3.54(m,1H),2.46(d,J＝7.2Hz,2H),1.87–1.784(m,1H),1.52–1.50(m,3H),1.22–1.15(m,3H),0.89(d,J＝6.6Hz,6H). 19 F NMR(376MHz,CDCl 3 )δ-77.7–-77.8(m,3F).HRMS(ESI)Calcd.for C 16 H 23 F 3 NO + [(M+H) + ]302.1732,found 302.1733.
Example 4 Synthesis of Compound S4
The 2-fluoroethylamine was replaced with 2, 2' -difluoropropylamine hydrochloride in the same equivalent ratio, and the remaining reagents and procedures were the same as those for the synthesis of S1, to give S4(116mg, 82%) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.19(d,J＝8.1Hz,2H),7.12(d,J＝8.1Hz,2H),5.77(s,1H),3.62–3.53(m,3H),2.46(d,J＝7.2Hz,2H),1.88–1.80(m,1H),1.53–1.51(m,3H),1.45(d,J＝18.6Hz,3H),0.89(d,J＝6.6Hz,6H). 19 F NMR(376MHz,CDCl 3 )δ-96.4–-96.5(m,2F).HRMS(ESI)Calcd.for C 16 H 24 F 2 NO + [(M+H) + ]284.1826,found 284.1827.
Example 5 Synthesis of Compound S5
Replacement of 3-fluoroethylamine by 2-fluoro-2-methyl-1-Propylamine hydrochloride, the remaining reagents and procedure were the same as those for the synthesis of S1, to give S5(124mg, 89%) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.20(d,J＝7.9Hz,2H),7.10(d,J＝8.0Hz,2H),5.73(s,1H),3.57(q,J＝7.2Hz,1H),3.40–3.31(m,2H),2.44(d,J＝7.2Hz,2H),1.87–1.80(m,1H),1.52(d,J＝7.2Hz,3H),1.28–1.16(m,6H),0.88(d,J＝6.6Hz,6H). 19 F NMR(376MHz,CDCl 3 )δ-144.3–-144.6(m,1F).HRMS(ESI)Calcd.for C 17 H 26 FNNaO + [(M+Na) + ]302.1896,found 302.1892.
Example 6 Synthesis of Compound S6
The 2-fluoroethylamine was replaced with 3, 3', 3 "-trifluoropropylamine hydrochloride at the same equivalent ratio, and the remaining reagents and procedures were the same as for the synthesis of S1, to give S6(145mg, 96%) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.16(d,J＝8.1Hz,2H),7.12(d,J＝8.1Hz,2H),5.63(s,1H),3.53(q,J＝7.2Hz,1H),3.42(q,J＝6.4Hz,2H),2.46(d,J＝7.2Hz,2H),2.28–2.25(m,2H),1.88–1.82(m,1H),1.51(d,J＝7.2Hz,3H),0.90(d,J＝6.6Hz,6H). 19 F NMR(376MHz,CDCl 3 )δ-65.2(t,J＝10.9Hz,3F).HRMS(ESI)Calcd.for C 16 H 23 F 3 NO + [(M+H) + ]302.1732,found 302.1733.
Example 7 Synthesis of Compound S7
The 3-fluoroethylamine was replaced with 2,2 ', 3, 3', 3 "-pentafluoropropylamine at the same equivalent ratio, and the remaining reagents and procedures were the same as for the synthesis of S1 to give S7 as a white solid (138mg, 82%). 1 H NMR(400MHz,CDCl 3 )δ7.18(d,J＝8.1Hz,2H),7.13(d,J＝8.0Hz,2H),5.78(s,1H),3.94–3.82(m,2H),3.61(q,J＝7.2Hz,1H),2.46(d,J＝7.2Hz,2H),1.88–1.80(m,1H),1.52(d,J＝7.2Hz,3H),0.89(d,J＝6.6Hz,6H). 19 F NMR(376MHz,CDCl 3 )δ-84.3(s,3F),-122.0–-122.1(m,2F).HRMS(ESI)Calcd.for C 16 H 21 F 5 NO + [(M+H) + ]338.1543,found 338.1545.
Example 8 Synthesis of Compound S8
Replacing 2-fluoroethylamine with 2,2 ', 3,3 ', 4,4 ' -heptafluorobutylamine under the same equivalent ratio, and using the rest of reagents and operationsAs a result of the synthesis of S1, S8(155mg, 80%) was obtained as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.24–7.17(m,2H),7.13–7.16(m,2H),5.99(s,1H),4.02–3.82(m,2H),3.63(q,J＝7.2Hz,1H),2.46(d,J＝7.2Hz,2H),1.91–1.80(m,1H),1.52(d,J＝7.2Hz,3H),0.89(d,J＝6.6Hz,6H). 19 F NMR(376MHz,CDCl 3 )δ-80.9(s,3F),-119.2–-119.3(m,2F),-127.9(s,2F).HRMS(ESI)Calcd.for C 17 H 21 F 7 NO + [(M+H) + ]388.1511,found 388.1510.
Example 9 Synthesis of Compound S9
The 3-fluoroethylamine was replaced with (1R,2S) -2-fluorocyclopropylamine p-toluenesulfonate at the same equivalent ratio, and the remaining reagents and procedures were the same as those for the synthesis of S1, to give S9(116mg, 88%) as a white solid. 1 H NMR(600MHz,CDCl 3 )δ7.19–7.17(m,2H),7.10(d,J＝7.8Hz,2H),5.61(s,1H),4.63–4.51(m,1H),3.58–3.53(m,1H),2.80–2.73(m,1H),2.44(d,J＝7.2Hz,2H),1.87–1.81(m,1H),1.52–1.50(m,3H),1.11–1.02(m,1H),0.89(d,J＝6.6Hz,6H),0.83–0.70(m,1H). 19 F NMR(376MHz,CDCl 3 )δ-277.1–-277.3(m,1F).HRMS(ESI)Calcd.for C 16 H 22 FNNaO + [(M+Na) + ]286.1583,found 286.1585.
Example 10 Synthesis of Compound S10
The 2-fluoroethylamine was replaced with 2, 2' -difluorocyclopropylamine hydrochloride at the same equivalent ratio, and the remaining reagents and procedures were the same as those for the synthesis of S1 to give S10(121mg, 86%) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.18–7.15(m,2H),7.13–7.10(m,2H),5.64(s,1H),3.59–3.51(m,1H),3.29–3.25(m,1H),2.45(d,J＝7.1Hz,2H),1.86–1.83(m,1H),1.75–1.70(m,1H),1.51(d,J＝7.2Hz,3H),1.24–1.15(m,1H),0.91–0.88(m,6H). 19 F NMR(376MHz,CDCl 3 )δ-131.2–-131.8(-143.9–-144.5)(m,2F).HRMS(ESI)Calcd.for C 16 H 22 F 2 NO + [(M+H) + ]282.1699,found 282.1668.
Example 11 Synthesis of Compound S11
3-fluoroethylamine is replaced with 3, 3' -difluorocyclobutylamine in the same equivalent ratio, whichThe remaining reagents and procedures were the same as those for the synthesis of S1, to give S11(117mg, 79%) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ 1 H NMR(400MHz,CDCl 3 )δ7.17(d,J＝8.1Hz,2H),7.11(d,J＝8.0Hz,2H),6.11(d,J＝6.4Hz,1H),4.22–4.15(m,1H),3.52(q,J＝7.1Hz,1H),2.94–2.85(m,2H),2.45(d,J＝7.2Hz,2H),2.40–2.30(m,2H),1.90–1.80(m,1H),1.48(d,J＝7.2Hz,3H),0.90(d,J＝6.6Hz,6H). 19 F NMR(376MHz,CDCl 3 )δ-84.7–-85.3(-96.8–-97.4)(m,2F).HRMS(ESI)Calcd.for C 17 H 24 F 2 NO + [(M+H) + ]296.1826,found 296.1827.
Example 12 Synthesis of Compound S12
The 2-fluoroethylamine was replaced with tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate in the same equivalent ratio and the remaining reagents and procedures were the same as those for the synthesis of S1 to give S12(177mg, 87%) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.16(d,J＝7.9Hz,2H),7.10–7.08(m,2H),5.58(s,1H),4.27–4.07(m,2H),4.06–4.07(m,1H),3.70(t,J＝12.4Hz,1H),3.54(q,J＝7.1Hz,1H),2.96–2.87(m,2H),2.43(d,J＝7.2Hz,2H),1.97–1.93(1.32–1.20)(m,2H),1.86–1.80(m,1H),1.49–1.47(m,3H),1.41(s,9H),0.87(d,J＝6.6Hz,6H). 19 F NMR(376MHz,CDCl 3 )δ-189.4–-189.8(m,1F).HRMS(ESI)Calcd.for C 23 H 35 FN 2 NaO 3 + [(M+Na) + ]429.2529,found 429.2527.
Example 13 Synthesis of Compound S13
The 3-fluoroethylamine was replaced with tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate in the same equivalent ratio, and the remaining reagents and procedures were the same as those for the synthesis of S1 to give S13(189mg, 90%) as a white solid. 1 H NMR(600MHz,CDCl 3 )δ7.18(d,J＝8.0Hz,2H),7.10(d,J＝8.0Hz,2H),5.70(t,J＝6.0Hz,1H),3.82(s,2H),3.55(q,J＝7.1Hz,1H),3.37(s,2H),3.01–2.95(m,2H),2.44(d,J＝7.2Hz,2H),1.85–1.80(m,1H),1.67–1.63(m,1H),1.56–1.50(s,6H),1.42(s,9H),0.87(d,J＝6.6Hz,6H). 19 F NMR(565MHz,CDCl 3 )δ-165.3(s,1F).HRMS(ESI)Calcd.for C 24 H 37 F 2 N 2 NaO 3 + [(M+Na) + ]443.2686,found 443.2687.
Example 14 Synthesis of Compound S14
The 2-fluoroethylamine was replaced with 3-fluoroazetidine hydrochloride at the same equivalent ratio, and the remaining reagents and procedures were the same as those used for the synthesis of S1, giving S14 as a white solid (94mg, 71%). 1 H NMR(400MHz,CDCl 3 )δ7.16–7.14(m,2H),7.10–7.07(m,2H),5.32–5.05(m,1H),4.31–3.84(m,4H),3.51(q,J＝7.0Hz,1H),2.44–2.43(m,2H),1.87–1.80(m,1H),1.41(d,J＝7.0Hz,3H),0.89(d,J＝6.6Hz,6H). 19 F NMR(376MHz,CDCl 3 )δ-181.2–-181.6(m,1F).HRMS(ESI)Calcd.for C 16 H 22 FNNaO + [(M+Na) + ]286.1583,found 286.1585.
Example 15 Synthesis of Compound S15
The 3-fluoroethylamine was replaced with 3, 3' -difluoroazetidine hydrochloride at the same equivalent ratio, and the remaining reagents and procedures were the same as for the synthesis of S1, to give S15(111mg, 79%) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.14(d,J＝8.1Hz,2H),7.10(d,J＝8.1Hz,2H),4.38–4.23(m,3H),4.02–3.99(m,1H),3.53(q,J＝7.0Hz,1H),2.45(d,J＝7.2Hz,2H),1.88–1.81(m,1H),1.44(d,J＝7.0Hz,3H),0.89(d,J＝6.6Hz,6H). 19 F NMR(376MHz,CDCl 3 )δ-100.9–-101.0(m,2F).HRMS(ESI)Calcd.for C 16 H 22 F 2 NO + [(M+H) + ]282.1699,found 282.1670.
Example 16 Synthesis of Compound S16
The 2-fluoroethylamine was replaced with 3, 3' -difluoropyrrole hydrochloride in the same equivalent ratio, and the other reagents and procedures were the same as those for the synthesis of S1, to give S16(121mg, 82%) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.14–7.13(m,2H),7.08(d,J＝7.9Hz,2H),3.89–3.54(m,4H),3.43–3.37(m,1H),2.43(d,J＝7.2Hz,2H),2.32–2.21(m,2H),1.87–1.80(m,1H),1.43(d,J＝5.7Hz,3H),0.88(d,J＝6.6Hz,6H). 19 F NMR(376MHz,CDCl 3 )δ-100.3–-103.3(m,2F).HRMS(ESI)Calcd.for C 17 H 23 F 2 NNaO + [(M+Na) + ]318.1645,found 318.1647.
Example 17 Synthesis of Compound S17
The 3-fluoroethylamine was replaced with 3, 3' -difluoropiperidine hydrochloride in the same equivalent ratio, and the remaining reagents and procedures were the same as those for the synthesis of S1, to give S17(127mg, 82%) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.10–7.06(m,4H),4.19–4.14(m,1H),3.89–3.81(m,1H),3.58–2.97(m,3H),2.43(d,J＝7.2Hz,2H),1.92–1.78(m,3H),1.76–1.71(1.09–1.06)(m,2H),1.42(d,J＝6.8Hz,3H),0.87(d,J＝6.5Hz,6H). 19 F NMR(376MHz,CDCl 3 )δ-101.3–-105.3(m,2F).HRMS(ESI)Calcd.for C 18 H 26 F 2 NO + [(M+H) + ]310.1982,found 310.1983.
Example 18 Synthesis of Compound S18
The 2-fluoroethylamine was replaced with 4, 4' -difluoropiperidine at the same equivalent ratio, and the remaining reagents and procedures were the same as those for the synthesis of S1, to give S18(144mg, 93%) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.11(d,J＝8.2Hz,2H),7.08(d,J＝8.2Hz,2H),4.12–4.09(3.56–3.53)(m,2H),3.84(q,J＝6.8Hz,1H),3.33(t,J＝11.4Hz,2H),2.43(d,J＝7.2Hz,2H),1.94–1.91(1.11–1.01)(m,2H),1.85–1.77(m,1H),1.73–1.63(m,2H),1.42(d,J＝6.8Hz,3H),0.86(d,J＝6.6Hz,6H). 19 F NMR(376MHz,CDCl 3 )δ-94.8–-100.5(m,2F).HRMS(ESI)Calcd.for C 18 H 26 F 2 NO + [(M+H) + ]310.1982,found 310.1983.
The synthetic narcotine derivative has inflammatory activity, and the pharmacological experiment result is as follows: the lipopolysaccharide induced inflammation model is used for carrying out corresponding analysis on the anti-nitric oxide release activity, and the specific operation is as follows:
1. cell lines: RAW 264.7
2. Culture medium: DMEM (high glucose) + 10% FBS
3. Other materials: full-wavelength multifunctional microplate reader: model number SpectraMax i3x, manufacturer USA MD company, import 96-well plate, nitric oxide fluorescent probe DAF-FM DA and the like.
4. The experimental method comprises the following steps:
preparing mouse macrophage RAW 264.7 into 2 x 10 5 Number of orThe method comprises the steps of inoculating a single cell suspension mL into a 96-well plate (180 mu L/well), culturing the 96-well plate paved with cells in a 5% carbon dioxide environment at 37 ℃ for 12 hours, stimulating the cells with 100 mu mol/L of drugs and 100ng/mL of LPS in each well, repeating three wells, simultaneously setting an LPS group and a blank control group, after incubating for 6 hours, sucking and removing a culture medium, adding 50 mu L of DAF-FM-DA with the concentration of 5 mu mol/L into each well, incubating for 20 minutes in a cell incubator at 37 ℃, washing the cells for three times by PBS (pH 7.4), removing the DAF-FM-DA which does not enter the cells, and detecting the fluorescence intensity by using a multifunctional microplate reader at the excitation wavelength of 495nm and the emission wavelength of 515 nm. The results of the in vitro nitric oxide inhibitory activity of the compounds of the present invention, S1-S18, are shown in Table 1 and FIG. 1.
TABLE 1 Fluoramidoibuprofen derivatives in vitro nitric oxide inhibitory Activity
Figure BDA0003649392930000121
From table 1 and fig. 1, we can find that: the flutolanil ibuprofen derivative generally has a larger influence on NO release induced by LPS, and the inhibition activity of a part of the derivative is far higher than that of ibuprofen, wherein the inhibition capacity of the optimized compound S6 is 2.5 times that of ibuprofen. The compound does not contain carboxyl, shows NO release inhibition capability superior to ibuprofen, and lays a foundation for development of anti-inflammatory drugs with low gastrointestinal irritation and other side effects.

Claims (5)

1. A compound of the formula:
Figure FDA0003649392920000011
wherein the content of the first and second substances,
R 1 selected from hydrogen;
R 2 selected from fluoroalkyl, fluorocycloalkyl, fluoroazacycloalkyl, fluoroazacycloalkylmethyl;
the fluoroalkyl is C2-C8 fluoroalkyl;
the fluorinated cycloalkyl is C3-C10 fluorinated cycloalkyl;
the fluorinated azacycloalkyl is C3-C7 fluorinated azacycloalkyl;
the fluorinated azacycloalkylmethyl and azacycloalkyl is C3-C7 fluorinated azacycloalkyl.
2. The compound of formula (la) according to claim 1, wherein R in the formula 1 And R 2 Bonded to each other to form a C3-C7 fluoroazacycloalkyl group, wherein,
R 1 selected from hydrogen;
R 2 selected from fluoroalkyl, fluorocycloalkyl, fluoroazacycloalkyl, fluoroazacycloalkylmethyl;
the fluoroalkyl is C2-C8 fluoroalkyl;
the fluorinated cycloalkyl is C3-C10 fluorinated cycloalkyl;
the fluorinated azacycloalkyl is C3-C7 fluorinated azacycloalkyl;
the fluorinated azacycloalkylmethyl and azacycloalkyl is C3-C7 fluorinated azacycloalkyl.
3. A compound of formula (la) according to claim 1, having the structure:
Figure FDA0003649392920000012
Figure FDA0003649392920000021
Figure FDA0003649392920000031
。
4. a compound of formula (la) according to claim 2, having the structure:
Figure FDA0003649392920000032
Figure FDA0003649392920000041
。
5. use of a compound according to any one of claims 1 to 4 in the preparation of a fluoroamide ibuprofen derivative.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101565393A (en) * 2009-06-02 2009-10-28 中国科学院上海有机化学研究所 3-(substituted bisulfonyl fluromethane)-1-propylene compound, synthetic method and applications thereof
CN108299340A (en) * 2018-03-08 2018-07-20 浙江工业大学 A method of synthesis 2- fluoro-N- substituted aryl acetamides

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
CN101565393A (en) * 2009-06-02 2009-10-28 中国科学院上海有机化学研究所 3-(substituted bisulfonyl fluromethane)-1-propylene compound, synthetic method and applications thereof
CN108299340A (en) * 2018-03-08 2018-07-20 浙江工业大学 A method of synthesis 2- fluoro-N- substituted aryl acetamides

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Title
ANA MARÍA CASAS FERREIRA, ET AL.: ""Headspace sampling with in situ carbodiimide-mediated derivatization for the determination of ibuprofen in water samples"", 《JOURNAL OF CHROMATOGRAPHY A》, vol. 1218, pages 4856 - 4862 *
HIROSHI MATSUZAWA ET AL.: ""Efficient enantiomeric resolution via introduction of a fluorous tag as a resolving reagent with -cyclodextrin columns: model study on fluorinated O-acetylmandelate and ibuprofen amide"", 《TETRAHEDRON LETTERS》, vol. 44, pages 6227 - 6230, XP004439052, DOI: 10.1016/S0040-4039(03)01538-7 *
M. HIMAJA ET AL.: ""SYNTHESIS, DOCKING AND ANTIOXIDANT ACTIVITY OF SOME NSAID DERIVATIVES OF AMINES"", 《INTERNATIONAL JOURNAL OF RESEARCH IN AYURVEDA AND PHARMACY》, vol. 3, no. 4, pages 548 - 551 *

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