CN114853661B - Fluoroamide ibuprofen derivative and preparation method and application thereof - Google Patents
Fluoroamide ibuprofen derivative and preparation method and application thereof Download PDFInfo
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- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical class CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 230000003110 anti-inflammatory effect Effects 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 abstract description 26
- 229960001680 ibuprofen Drugs 0.000 abstract description 12
- 150000001412 amines Chemical class 0.000 abstract description 3
- 229940124599 anti-inflammatory drug Drugs 0.000 abstract description 3
- 150000001735 carboxylic acids Chemical class 0.000 abstract description 2
- 238000006482 condensation reaction Methods 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 76
- 230000015572 biosynthetic process Effects 0.000 description 35
- 238000003786 synthesis reaction Methods 0.000 description 35
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- 238000004293 19F NMR spectroscopy Methods 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 239000003153 chemical reaction reagent Substances 0.000 description 17
- FURHRJBOFNDYTG-UHFFFAOYSA-N 2-fluoroethanamine Chemical compound NCCF FURHRJBOFNDYTG-UHFFFAOYSA-N 0.000 description 11
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 125000003709 fluoroalkyl group Chemical group 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 239000002158 endotoxin Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 229920006008 lipopolysaccharide Polymers 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- BEVHTVRRVVEMEF-UHFFFAOYSA-N [6'-acetyloxy-4-amino-2',7'-difluoro-5-(methylamino)-3-oxospiro[2-benzofuran-1,9'-xanthene]-3'-yl] acetate Chemical compound C12=CC(F)=C(OC(C)=O)C=C2OC2=CC(OC(C)=O)=C(F)C=C2C21OC(=O)C1=C(N)C(NC)=CC=C21 BEVHTVRRVVEMEF-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 102000006833 Multifunctional Enzymes Human genes 0.000 description 2
- 108010047290 Multifunctional Enzymes Proteins 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 125000005348 fluorocycloalkyl group Chemical group 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical class CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 description 1
- XUWZMHVPMZXIRU-LMLSDSMGSA-N (1r,2s)-2-fluorocyclopropan-1-amine;4-methylbenzenesulfonic acid Chemical compound N[C@@H]1C[C@@H]1F.CC1=CC=C(S(O)(=O)=O)C=C1 XUWZMHVPMZXIRU-LMLSDSMGSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- REOSCHXVONAVMN-UHFFFAOYSA-N 2-fluoro-2-methylpropan-1-amine;hydrochloride Chemical compound Cl.CC(C)(F)CN REOSCHXVONAVMN-UHFFFAOYSA-N 0.000 description 1
- PXFUWRWCKSLCLS-UHFFFAOYSA-N 3-fluoroazetidine;hydron;chloride Chemical compound Cl.FC1CNC1 PXFUWRWCKSLCLS-UHFFFAOYSA-N 0.000 description 1
- QZLSBOVWPHXCLT-UHFFFAOYSA-N 5-chlorothiophene-2-carboxylic acid Chemical class OC(=O)C1=CC=C(Cl)S1 QZLSBOVWPHXCLT-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 208000007920 Neurogenic Inflammation Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
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- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- FCYNTMBZASDPHJ-UHFFFAOYSA-N tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(F)(CN)CC1 FCYNTMBZASDPHJ-UHFFFAOYSA-N 0.000 description 1
- ZQRYPCAUVKVMLZ-UHFFFAOYSA-N tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(N)C(F)C1 ZQRYPCAUVKVMLZ-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a fluoroamide ibuprofen derivative and a preparation method and application thereof. The purpose is to prepare fluoroamide ibuprofen derivative by using condensation reaction of carboxylic acid and fluoroaliphatic amine, and to study the anti-inflammatory activity of the fluoroamide ibuprofen derivative. A series of fluoroamide ibuprofen derivatives are designed and synthesized. The experimental results of the invention show that most of the newly synthesized compounds show anti-inflammatory activity superior to that of ibuprofen, and are expected to become high-efficiency low-toxicity anti-inflammatory drugs.
Description
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 (Nonsteroidal Antiinflammatory Drugs, NSAIDs). At present, the traditional Chinese medicine composition is mainly used as symptomatic therapeutic medicine in clinic, 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 has 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, and 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.
Studies have shown 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 themselves. In the design of medicines, fluorine substitution is an effective strategy for adjusting physicochemical properties, optimizing pharmacokinetic parameters and improving the efficacy.
In light of this, the present study designed and synthesized a series of fluoroamide ibuprofen derivatives. A large number of experiments show that most of the newly synthesized compounds show anti-inflammatory activity superior to ibuprofen and are expected to be high-efficiency low-toxicity anti-inflammatory drugs.
Disclosure of Invention
The present invention aims at preparing fluoroamide ibuprofen derivative by means of condensation reaction of carboxylic acid and fluoroaliphatic amine and researching its anti-inflammatory activity.
The structural general formula of the compound is as follows:
Wherein,
R 1 is selected from hydrogen;
R 2 is selected from fluoroalkyl, fluorocycloalkyl, fluoroazacycloalkyl, fluoroazacycloakylmethyl;
The fluoroalkyl is a C2-C8 fluoroalkyl;
the fluorinated cycloalkyl is C3-C10 fluorinated cycloalkyl;
The fluoroazacycloalkyl is a C3-C7 fluoroazaalkyl;
The fluoro-azacycloalkyl is C3-C7 fluoro-azaalkyl.
Preferably, R 1 and R 2 in the general structural formula are bonded to each other to form a C3-C7 fluoroazacycloalkyl group, wherein,
R 1 is selected from hydrogen;
R 2 is selected from fluoroalkyl, fluorocycloalkyl, fluoroazacycloalkyl, fluoroazacycloakylmethyl;
The fluoroalkyl is a C2-C8 fluoroalkyl;
the fluorinated cycloalkyl is C3-C10 fluorinated cycloalkyl;
The fluoroazacycloalkyl is a C3-C7 fluoroazaalkyl;
The fluoro-azacycloalkyl is C3-C7 fluoro-azaalkyl.
Preferably, the compounds of the present invention have the general structural formula:
The fluoroamide ibuprofen derivative is obtained by the following preparation method:
the invention also provides a preparation method of the derivative, which uses DCC/HOBT as a condensing agent to condense ibuprofen and fluoroaliphatic amine to obtain S1-S18.
The invention has the beneficial effects that: most of the fluoroamide ibuprofen derivatives have in vitro anti-inflammatory activity superior to ibuprofen, have expected side effects to be reduced, and have improved permeability of the central system, so as to be beneficial to further development of medicaments for treating neurogenic inflammation, and specific experimental effects can be seen in the accompanying drawings 1 and the table 1.
Drawings
FIG. 1 is a graph showing the results of in vitro nitric oxide inhibitory activity of the compounds S1-S18 of the present invention.
Detailed Description
Example 1: synthesis of Compound S1
Ibuprofen (103 mg,0.5mmol,1.0 equiv) was dissolved in 3mL of dichloromethane, dicyclohexylcarbodiimide (113 mg,0.55 mmol), HOBT (74 mg,0.55 mmol) was added sequentially at 0deg.C, stirred for 30min, 2-fluoroethylamine (50 mg,0.5mmol,1.0 equiv) was added to react, triethylamine (130. Mu.L, 1mmol,2.0 equiv) was then allowed to react to room temperature 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 by rotary evaporation, and purified by silica gel column chromatography (DCM: meOH=20:1) to give a white solid S1(93mg,74％).1H NMR(400MHz,CDCl3)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).19F NMR(376MHz,CDCl3)δ-224.2–-224.6(m,1F).13C NMR(150MHz,CDCl3)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 C15H23FNO+[(M+H)+]252.1764,found 252.1763.
EXAMPLE 2 Synthesis of Compound S2
2-Fluoroethylamine is replaced by 2,2' -trifluoroethylamine with the same equivalent ratio, and the rest reagents and operations are the same as those of S1 synthesis, so that white solid is obtained S2(124mg,86％).1H NMR(400MHz,CDCl3)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).19F NMR(376MHz,CDCl3)δ-72.7(s,3F).HRMS(ESI)Calcd.for C15H21F3NO+[(M+H)+]288.1575,found 288.1577.
EXAMPLE 3 Synthesis of Compound S3
2-Fluoroethylamine is replaced by 2-amino-1, 1-trifluoropropane hydrochloride with the same equivalent ratio, and the rest reagents and operations are the same as those of S1 synthesis to obtain white solid S3(120mg,80％).1H NMR(400MHz,CDCl3)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).19F NMR(376MHz,CDCl3)δ-77.7–-77.8(m,3F).HRMS(ESI)Calcd.for C16H23F3NO+[(M+H)+]302.1732,found 302.1733.
EXAMPLE 4 Synthesis of Compound S4
2-Fluoroethylamine is replaced by 2,2' -difluoropropylamine hydrochloride with the same equivalent ratio, and the rest reagents and operations are the same as those of S1 synthesis to obtain white solid S4(116mg,82％).1H NMR(400MHz,CDCl3)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).19F NMR(376MHz,CDCl3)δ-96.4–-96.5(m,2F).HRMS(ESI)Calcd.for C16H24F2NO+[(M+H)+]284.1826,found 284.1827.
EXAMPLE 5 Synthesis of Compound S5
3-Fluoroethylamine is replaced by 2-fluoro-2-methyl-1-propylamine hydrochloride with the same equivalent ratio, and the rest reagents and operations are the same as those of S1 synthesis to obtain white solid S5(124mg,89％).1H NMR(400MHz,CDCl3)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).19F NMR(376MHz,CDCl3)δ-144.3–-144.6(m,1F).HRMS(ESI)Calcd.for C17H26FNNaO+[(M+Na)+]302.1896,found 302.1892.
EXAMPLE 6 Synthesis of Compound S6
2-Fluoroethylamine is replaced by 3,3' -trifluoropropylamine hydrochloride with the same equivalent ratio, and the rest reagents and operations are the same as those of S1 synthesis, so as to obtain white solid S6(145mg,96％).1H NMR(400MHz,CDCl3)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).19F NMR(376MHz,CDCl3)δ-65.2(t,J＝10.9Hz,3F).HRMS(ESI)Calcd.for C16H23F3NO+[(M+H)+]302.1732,found 302.1733.
EXAMPLE 7 Synthesis of Compound S7
3-Fluoroethylamine is replaced by 2,2', 3' -pentafluoropropylamine with the same equivalent ratio, and the rest reagents and operations are the same as those of S1 synthesis, so as to obtain white solid S7(138mg,82％).1H NMR(400MHz,CDCl3)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).19F NMR(376MHz,CDCl3)δ-84.3(s,3F),-122.0–-122.1(m,2F).HRMS(ESI)Calcd.for C16H21F5NO+[(M+H)+]338.1543,found 338.1545.
EXAMPLE 8 Synthesis of Compound S8
2-Fluoroethylamine is replaced by 2,2', 3', 4' -heptafluorobutylamine with the same equivalent ratio, and the rest reagents and operations are the same as those of S1 synthesis, so that a white solid is obtained S8(155mg,80％).1H NMR(400MHz,CDCl3)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).19F NMR(376MHz,CDCl3)δ-80.9(s,3F),-119.2–-119.3(m,2F),-127.9(s,2F).HRMS(ESI)Calcd.for C17H21F7NO+[(M+H)+]388.1511,found 388.1510.
EXAMPLE 9 Synthesis of Compound S9
3-Fluoroethylamine is replaced by (1R, 2S) -2-fluorocyclopropylamine p-toluenesulfonate with the same equivalent ratio, and the rest reagents and operations are the same as those of S1 synthesis to obtain white solid S9(116mg,88％).1H NMR(600MHz,CDCl3)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).19F NMR(376MHz,CDCl3)δ-277.1–-277.3(m,1F).HRMS(ESI)Calcd.for C16H22FNNaO+[(M+Na)+]286.1583,found 286.1585.
EXAMPLE 10 Synthesis of Compound S10
2-Fluoroethylamine is replaced by 2,2' -difluorocyclopropylamine hydrochloride with the same equivalent ratio, and the rest reagents and operations are the same as those of S1 synthesis, so as to obtain white solid S10(121mg,86％).1H NMR(400MHz,CDCl3)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).19F NMR(376MHz,CDCl3)δ-131.2–-131.8(-143.9–-144.5)(m,2F).HRMS(ESI)Calcd.for C16H22F2NO+[(M+H)+]282.1699,found 282.1668.
EXAMPLE 11 Synthesis of Compound S11
3-Fluoroethylamine is replaced by 3,3' -difluorocyclobutane with the same equivalent ratio, and the rest reagents and operations are the same as those of S1 synthesis, so that a white solid is obtained S11(117mg,79％).1H NMR(400MHz,CDCl3)δ1H NMR(400MHz,CDCl3)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).19F NMR(376MHz,CDCl3)δ-84.7–-85.3(-96.8–-97.4)(m,2F).HRMS(ESI)Calcd.for C17H24F2NO+[(M+H)+]296.1826,found 296.1827.
EXAMPLE 12 Synthesis of Compound S12
2-Fluoroethylamine is replaced by 4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester with the same equivalent ratio, and the rest reagents and operations are the same as those of S1 synthesis to obtain white solid S12(177mg,87％).1H NMR(400MHz,CDCl3)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).19F NMR(376MHz,CDCl3)δ-189.4–-189.8(m,1F).HRMS(ESI)Calcd.for C23H35FN2NaO3 +[(M+Na)+]429.2529,found 429.2527.
EXAMPLE 13 Synthesis of Compound S13
3-Fluoroethylamine is replaced by 4- (aminomethyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester with the same equivalent ratio, and the rest reagents and operations are the same as those of S1 synthesis to obtain white solid S13(189mg,90％).1H NMR(600MHz,CDCl3)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).19F NMR(565MHz,CDCl3)δ-165.3(s,1F).HRMS(ESI)Calcd.for C24H37F2N2NaO3 +[(M+Na)+]443.2686,found 443.2687.
EXAMPLE 14 Synthesis of Compound S14
The 2-fluoroethylamine is replaced by 3-fluoroazetidine hydrochloride with the same equivalent ratio, and the rest reagents and operations are the same as those of S1 synthesis, so that a white solid is obtained S14(94mg,71％).1H NMR(400MHz,CDCl3)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).19F NMR(376MHz,CDCl3)δ-181.2–-181.6(m,1F).HRMS(ESI)Calcd.for C16H22FNNaO+[(M+Na)+]286.1583,found 286.1585.
EXAMPLE 15 Synthesis of Compound S15
3-Fluoroethylamine is replaced by 3,3' -difluoro azetidine hydrochloride with the same equivalent ratio, and the rest reagents and operations are the same as those of S1 synthesis, thus obtaining white solid S15(111mg,79％).1H NMR(400MHz,CDCl3)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).19F NMR(376MHz,CDCl3)δ-100.9–-101.0(m,2F).HRMS(ESI)Calcd.for C16H22F2NO+[(M+H)+]282.1699,found 282.1670.
EXAMPLE 16 Synthesis of Compound S16
2-Fluoroethylamine is replaced by 3,3' -difluoropyrrole hydrochloride with the same equivalent ratio, and the rest reagents and operations are the same as those of S1 synthesis, so as to obtain white solid S16(121mg,82％).1H NMR(400MHz,CDCl3)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).19F NMR(376MHz,CDCl3)δ-100.3–-103.3(m,2F).HRMS(ESI)Calcd.for C17H23F2NNaO+[(M+Na)+]318.1645,found 318.1647.
EXAMPLE 17 Synthesis of Compound S17
3-Fluoroethylamine is replaced by 3,3' -difluoropiperidine hydrochloride with the same equivalent ratio, and the rest reagents and operations are the same as those of S1 synthesis, so as to obtain white solid S17(127mg,82％).1H NMR(400MHz,CDCl3)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).19F NMR(376MHz,CDCl3)δ-101.3–-105.3(m,2F).HRMS(ESI)Calcd.for C18H26F2NO+[(M+H)+]310.1982,found 310.1983.
EXAMPLE 18 Synthesis of Compound S18
The 2-fluoroethylamine is replaced by 4,4' -difluoropiperidine with the same equivalent ratio, and the rest reagents and operations are the same as those of the synthesis of S1, so that a white solid is obtained S18(144mg,93％).1H NMR(400MHz,CDCl3)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).19F NMR(376MHz,CDCl3)δ-94.8–-100.5(m,2F).HRMS(ESI)Calcd.for C18H26F2NO+[(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 activity of resisting nitric oxide release, 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 enzyme-labeled instrument: model SpectraMax i3x, manufacturer, MD, inlet 96-well plate, nitric oxide fluorescent probe DAF-FM DA, etc.
4. The experimental method comprises the following steps:
The preparation method comprises the steps of preparing 2X 10 5/mL single-cell suspensions of mouse macrophage RAW 264.7, inoculating the single-cell suspensions 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, resetting three wells, simultaneously arranging an LPS group and a blank control group, after co-incubation for 6 hours, absorbing and discarding a culture medium, adding 50 mu L of DAF-FM-DA with the concentration of 5 mu mol/into each well, incubating the cells in a cell incubator at 37 ℃ for 20 minutes, washing the cells for three times by PBS (pH 7.4), removing DAF-FM DA which does not enter the cells, and detecting fluorescence intensity at an excitation wavelength of 495nm and an emission wavelength of 515nm by using a multifunctional enzyme-labeled instrument. The results of the in vitro nitric oxide inhibitory activity of the compounds S1-S18 of the present invention are shown in Table 1 and FIG. 1.
TABLE 1 in vitro nitric oxide inhibitory Activity of fluoroamide ibuprofen derivatives
From table 1 and fig. 1 we can find that: the fluoroamide ibuprofen derivative has a large influence on NO release induced by LPS generally, and the inhibition activity of part of the derivative is far higher than that of ibuprofen, wherein the inhibition capacity of the optimal compound S6 is 2.5 times that of ibuprofen. The compound does not contain carboxyl, has NO release inhibition capability superior to ibuprofen, and lays a foundation for the development of anti-inflammatory drugs with low gastrointestinal irritation and other side effects.
Claims (2)
1. The fluoroamide ibuprofen derivative is characterized by specifically comprising the following structure:
2. use of a fluoroamide ibuprofen derivative according to claim 1 in the preparation of an anti-inflammatory medicament.
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| 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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| 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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