CN106117156B - compound containing 5-phenyl isoxazole stilbenoid group and preparation method thereof - Google Patents
compound containing 5-phenyl isoxazole stilbenoid group and preparation method thereof Download PDFInfo
- Publication number
- CN106117156B CN106117156B CN201610412031.7A CN201610412031A CN106117156B CN 106117156 B CN106117156 B CN 106117156B CN 201610412031 A CN201610412031 A CN 201610412031A CN 106117156 B CN106117156 B CN 106117156B
- Authority
- CN
- China
- Prior art keywords
- compound
- group
- stilbenoid
- compound containing
- dmso
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- MLJJRVMANUGETQ-UHFFFAOYSA-N 3-(chloromethyl)-5-phenyl-1,2-oxazole Chemical class O1N=C(CCl)C=C1C1=CC=CC=C1 MLJJRVMANUGETQ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- -1 5-phenylisoxazolylstilbene group Chemical group 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000008280 blood Substances 0.000 claims description 3
- 210000004369 blood Anatomy 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical group C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 125000003020 stilbenoid group Chemical group 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- 108090000371 Esterases Proteins 0.000 abstract description 2
- 230000002218 hypoglycaemic effect Effects 0.000 abstract description 2
- DCWXELXMIBXGTH-UHFFFAOYSA-N phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 abstract description 2
- 101001087394 Homo sapiens Tyrosine-protein phosphatase non-receptor type 1 Proteins 0.000 abstract 1
- 102100033001 Tyrosine-protein phosphatase non-receptor type 1 Human genes 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 238000001308 synthesis method Methods 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 102000002072 Non-Receptor Type 1 Protein Tyrosine Phosphatase Human genes 0.000 description 9
- 108010015847 Non-Receptor Type 1 Protein Tyrosine Phosphatase Proteins 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 7
- 150000003436 stilbenoids Chemical class 0.000 description 5
- SMEROWZSTRWXGI-UHFFFAOYSA-N Lithocholsaeure Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 SMEROWZSTRWXGI-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- SMEROWZSTRWXGI-HVATVPOCSA-N lithocholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 SMEROWZSTRWXGI-HVATVPOCSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000003472 antidiabetic agent Substances 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 2
- 229940125890 compound Ia Drugs 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 235000021286 stilbenes Nutrition 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YCVPRTHEGLPYPB-VOTSOKGWSA-N trans-pinosylvin Chemical compound OC1=CC(O)=CC(\C=C\C=2C=CC=CC=2)=C1 YCVPRTHEGLPYPB-VOTSOKGWSA-N 0.000 description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- MIJYXULNPSFWEK-GTOFXWBISA-N 3beta-hydroxyolean-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C MIJYXULNPSFWEK-GTOFXWBISA-N 0.000 description 1
- XZKIHKMTEMTJQX-UHFFFAOYSA-L 4-nitrophenyl phosphate(2-) Chemical compound [O-][N+](=O)C1=CC=C(OP([O-])([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-L 0.000 description 1
- JKLISIRFYWXLQG-UHFFFAOYSA-N Epioleonolsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4CCC3C21C JKLISIRFYWXLQG-UHFFFAOYSA-N 0.000 description 1
- YBRJHZPWOMJYKQ-UHFFFAOYSA-N Oleanolic acid Natural products CC1(C)CC2C3=CCC4C5(C)CCC(O)C(C)(C)C5CCC4(C)C3(C)CCC2(C1)C(=O)O YBRJHZPWOMJYKQ-UHFFFAOYSA-N 0.000 description 1
- MIJYXULNPSFWEK-UHFFFAOYSA-N Oleanolinsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C MIJYXULNPSFWEK-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- IIXHQGSINFQLRR-UHFFFAOYSA-N Piceatannol Natural products Oc1ccc(C=Cc2c(O)c(O)c3CCCCc3c2O)cc1O IIXHQGSINFQLRR-UHFFFAOYSA-N 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 229960000452 diethylstilbestrol Drugs 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000013537 high throughput screening Methods 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940100243 oleanolic acid Drugs 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- CDRPUGZCRXZLFL-OWOJBTEDSA-N piceatannol Chemical compound OC1=CC(O)=CC(\C=C\C=2C=C(O)C(O)=CC=2)=C1 CDRPUGZCRXZLFL-OWOJBTEDSA-N 0.000 description 1
- YCVPRTHEGLPYPB-UHFFFAOYSA-N pinosylvine Natural products OC1=CC(O)=CC(C=CC=2C=CC=CC=2)=C1 YCVPRTHEGLPYPB-UHFFFAOYSA-N 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- HZLWUYJLOIAQFC-UHFFFAOYSA-N prosapogenin PS-A Natural products C12CC(C)(C)CCC2(C(O)=O)CCC(C2(CCC3C4(C)C)C)(C)C1=CCC2C3(C)CCC4OC1OCC(O)C(O)C1O HZLWUYJLOIAQFC-UHFFFAOYSA-N 0.000 description 1
- 239000003801 protein tyrosine phosphatase 1B inhibitor Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 235000021283 resveratrol Nutrition 0.000 description 1
- 229940016667 resveratrol Drugs 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003429 steroid acids Chemical class 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a compound (I) containing a 5-phenylisoxazole stilbenoid group and a preparation method thereof. Is prepared by condensing substituted 4' -hydroxy stilbene-3-methyl formate (II) and substituted 5-phenyl 3-chloromethyl isoxazole (III) and hydrolyzing and acidifying. The compound I containing the 5-phenyl isoxazole stilbenoid group has the inhibitory activity of phosphotyrosine esterase 1B (PTP1B), and can be used for preparing a hypoglycemic medicament.
Description
Technical Field
the invention belongs to the field of compound preparation, and particularly relates to a compound containing a 5-phenyl isoxazole stilbenoid group, and a preparation method and application thereof.
background
Diabetes seriously threatens human health, and the number of patients increases year by year. Until now, no specific medicine for treating diabetes exists. Research shows that protein tyrosine phosphatase 1B (PTP1B) can down-regulate the expression of insulin, so that the inhibition of the activity of PTP1B is an effective means for treating diabetes by promoting the level of insulin.
research shows that various natural products including steroid compound lithocholic acid (LCA) have better PTP1B inhibition activity (IC)5012.7 μ M), the activity of PTP1B was significantly improved by a heterocycle-containing derivative obtained by modifying the structure thereof. However, the compound has strong structural rigidity and poor drug-like property, and has the risk of hormone-like drugs.
"skeletal migration" is a common structural design method used in drug design. In fact, the method was successfully used for many years in the design of diethylstilbestrol, an estradiol substitute. This also demonstrates that stilbene (stilbenoid) is an ideal replacement structure for the steroid ring. Stilbenoid is a common natural product fragment, and stilbenoid has many biological activities such as antibacterial, antitumor, antioxidant and antidiabetic, such as: the natural products resveratrol, pinosylvin and piceatannol are all stilbenoids. In addition, researches show that the incorporation of heterocycles such as pyrazole, oxazole, isoxazole and thiazole into the A ring of lithocholic acid (a steroid acid) can improve the inhibitory activity of lithocholic acid on PTP 1B. Therefore, a compound obtained by splicing a heterocycle with stilbene (stilbenoid) in combination with the backbone migration may also have a better PTP1B inhibitory activity.
Disclosure of Invention
The invention aims to provide a compound containing 5-phenyl isoxazole stilbenoid group with hypoglycemic activity, which has the following structure:
wherein R is H,2-Cl,2-OMe,3-Cl,3-F,3-Br,3-Me,3-NO2,4-Me,4-OMe,4-F,3,4-Cl2Or 3,4-F2。
A method for preparing compound containing 5-phenyl isoxazole stilbenoid group comprises performing condensation reaction between 4' -hydroxy stilbene-3-methyl formate (II) and substituted 5-phenyl 3-chloromethyl isoxazole (III) with cesium carbonate as acid-binding agent;
Hydrolyzing under the action of potassium hydroxide, acidifying by hydrochloric acid to obtain a compound containing 5-phenylisoxazole stilbenoid group,
wherein R is H,2-Cl,2-OMe,3-Cl,3-F,3-Br,3-Me,3-NO2,4-Me,4-OMe,4-F,3,4-Cl2Or 3,4-F2。
The compound containing 5-phenylisoxazole diethylstilbestrol group is used for preparing hypoglycemic drugs. The invention also aims to provide application of the compound in the general formula I in interfering enzyme formation in a blood sugar rising pathway, and the purpose of reducing blood sugar is achieved by inhibiting phosphotyrosine esterase 1B (PTP 1B).
Detailed Description
To facilitate a further understanding of the invention, the following examples are provided to illustrate it in more detail. These examples are provided for illustrative purposes only and are not intended to limit the scope or the principles of the invention.
Example 1: synthesis of Compound Ia (R ═ H)
Compound ii (1mmol), iiia (R ═ H,1mmol) and cesium carbonate (2mmol) were heated to 85 ℃ in DMSO (5mL) solvent and allowed to react for 8 hours while maintaining the temperature, and after lowering the reaction temperature to 60 ℃, 20% potassium hydroxide solution (2mL) was added and the reaction stirred at 60 ℃ for 4 hours. Cooling the reaction overnight to room temperature, acidifying with hydrochloric acid and diluting with water to give a large amount of precipitate, filtering and purifying by recrystallization from methanol to give compound Ia (R ═ H); yellow solid; 42 percent of Yield;1H NMR(DMSO-d6,400MHz)δ:13.15(brs,1H),8.12(s,1H),7.90(dd,J1＝8.0Hz,J2＝1.8Hz,2H),7.80(t,J＝7.5Hz,2H),7.62(d,J＝8.8Hz,2H),7.52～7.58(m,3H),7.47(t,J＝7.7Hz,1H),7.29(d,J＝16.4Hz,1H),7.22(d,J＝16.4Hz,1H),7.20(s,1H),7.10(d,J＝8.8Hz,2H),5.29(s,2H)；13C NMR(DMSO-d6,100MHz)δ:170.0,168.2,161.8,158.1,138.0,131.1,130.8,130.3,129.8(2C),129.3,129.2,128.5(2C),128.4,127.4,127.1,126.3,126.1(2C),115.6(2C),100.5,61.8；HRMS(ESI)calcd for C25H18NO4[M-H]-396.1236,found 396.1219.
example 2: synthesis of Compound Ib (R ═ 2-Cl)
Obtained by following the synthesis method of Ia in example 1, substituting iiib (R ═ 2 — Cl) for iiia (R ═ H). Yellow solid; 51 percent of Yield;1H NMR(DMSO-d6,400MHz)δ:12.98(brs,1H),8.13(s,1H),7.82～7.88(m,2H)，7.79(d,J＝8.1Hz,1H),7.62(d,J＝8.6Hz,2H),7.49～7.54(m,1H),7.35(d,J＝8.1Hz,2H),7.47(t,J＝7.7Hz,1H),7.28(d,J＝16.5Hz,1H),7.23(d,J＝16.5Hz,1H),7.10(d,J＝8.6Hz,2H),7.09(s,1H),5.27(s,2H),2.37(s,3H)；170.2,166.7,161.7,158.2,141.0,138.4,131.0,130.6,130.3(2C),129.7,129.6,128.6(2C)，127.3，126.1(2C)，125.9，124.4，115.6(2C)，99.9，61.8，21.5；HRMS(ESI)calcd for C25H17ClNO4[M-H]-430.0846,found 430.0831.
example 3: synthesis of Compound Ic (R ═ 2-OMe)
obtained by following the synthesis method of Ia in example 1, substituting iiic (R ═ 2-OMe) for iiia (R ═ H). Yellow solid; 47 percent of Yield;1H NMR(DMSO-d6,400MHz)δ:13.05(brs,1H),8.13(s,1H),7.79～7.83(m,2H),7.62(d,J＝8.8Hz,2H),7.46～7.52(m,3H),7.26(d,J＝16.4Hz,1H),7.20(d,J＝16.4Hz,1H),7.10～7.14(m,2H),6.99(s,1H),6.79(d,J＝8.8Hz,2H),5.29(s,2H)，3.96(s,3H)；13C NMR(DMSO-d6，100MHz)δ:167.8，166.2,161.5,158.2,138.4,138.2,131.7,130.7,130.5,130.0,129.4,129.4,128.6(2C),128.2,127.4,127.2,126.1,124.6,121.3,115.6(2C),103.6,61.8,56.3；HRMS(ESI)calcd for C26H20NO5[M-H]-426.1341,found 426.1376.
Example 4: synthesis of Compound Id (R ═ 3-Cl)
obtained by following the synthesis method of Ia in example 1, substituting iiid (R ═ 3 — Cl) for iiia (R ═ H). Yellow solid; 40 percent of Yield;1H NMR(DMSO-d6,400MHz)δ:13.05(brs,1H),8.12(s，1H),7.96(s,1H),7.80(t,J＝7.0Hz,2H),7.61～7.73(m，4H),7.41～7.49(m，2H),7.33(d,J＝16.5Hz,1H),7.25(d,J＝16.5Hz,1H),7.41(s,1H),7.10(d,J＝8.8Hz,2H),5.28(s，2H),2.39(s,3H)；13C NMR(DMSO-d6,100MHz)δ:170.2,168.1,161.7,158.1,139.2,138.0,131.7，130.7，130.3，129.7，129.3，129.2，128.5(2C)，128.4，127.4,127.0,126.5,126.3,123.3,115.6(2C),100.4,61.8,21.3；HRMS(ESI)calcd for C25H17ClNO4[M-H]-430.0846,found 430.0857.
Example 5: synthesis of Compound Ie (R ═ 3-F)
Obtained by following the synthesis method of Ia in example 1, substituting iiie (R ═ 3 — F) for iiia (R ═ H). Yellow solid; 48 percent of Yield;1H NMR(DMSO-d6,400MHz)δ:13.05(brs,1H),8.13(s,1H),7.76～7.84(m,4H)，7.58～7.64(m,3H)，7.49(t,J＝7.7Hz,1H),7.29～7.40(m,3H)，7.22(d,J＝16.4Hz,1H),7.10(d,J＝8.7Hz,2H),5.30(s，2H)；13C NMR(DMSO-d6，100MHz)δ:168.7,167.7,162.9(d,J＝145.6Hz),161.9，158.1，138.2,132.1，132.0,131.7,130.7,129.4,129.1,129.0,128.5(2C),128.4,127.4,126.2,122.3,118.2(d,J＝21.2Hz),115.6(2C),113.0(d,J＝23.7Hz)，101.6，61.7；HRMS(ESI)calcd for C25H17FNO4[M-H]-414.1142,found 414.1133.
example 6: synthesis of Compound If (R ═ 3-Br)
Obtained by following the synthesis method of Ia in example 1 with iii f (R ═ 3-Br) instead of iiia (R ═ H). Yellow solid; 51 percent of Yield;1H NMR(DMSO-d6,400MHz)δ:13.13(brs，1H)，8.14(s，1H),8.12(s，1H),7.89～7.93(m,1H),7.79(d,J＝7.6Hz,1H),7.71～7.73(m,1H),7.61(d,J＝8.7Hz,2H),7.49～7.58(m,2H),7.43(t,J＝7.6Hz,1H),7.27(d,J＝16.5Hz,1H),7.20(d,J＝16.5Hz，1H),7.19(s,1H),7.09(d,J＝8.7Hz,2H)，5.29(s，2H)；13C NMR(DMSO-d6，100MHz)δ:170.0，168.4，161.8,158.0,137.8,133.7,131.9,131.0,130.9,129.8,129.1,128.9,128.7,128.5(2C),127.4,126.6,126.1,125.0,123.0,115.6(2C),100.5,61.7；HRMS(ESI)calcd forC25H17BrNO4[M-H]-474.0341,found 474.0371.
example 7: synthesis of Compound Ig (R-3-Me)
Obtained by following the synthesis method of Ia in example 1, substituting iiig (R ═ 3-Me) for iiia (R ═ H). Yellow solid; 44 percent of Yield;1H NMR(DMSO-d6,400MHz)δ:13.12(brs,1H),8.13(s,1H),8.01(s,1H),7.78～7.82(m,2H),7.62(d,J＝8.6Hz,2H),7.58～7.59(m,2H),7.46～7.50(m,2H),7.33(s,1H),7.30(d,J＝16.4Hz,1H),7.22(d,J＝16.4Hz,1H),7.10(d,J＝8.6Hz,2H),5.30(s,2H)；13C NMR(DMSO-d6,100MHz)δ:168.5,167.9,161.9,158.1,138.2,134.5,131.7,130.8,130.6,130.0,129.4,129.0,128.5,127.4,126.2(2C),125.8,124.7,124.6,115.6(2C),101.7；HRMS(ESI)calcd for C26H20NO4[M-H]-410.1392,found 410.1388.
Example 8: compound Ih (R ═ 3-NO)2) Synthesis of (2)
With IIIh (R ═ 3-NO)2) Obtained by referring to the synthesis method of Ia in example 1 instead of iiia (R ═ H). Yellow solid; 38 percent of Yield;1H NMR(DMSO-d6,400MHz)δ:13.17(brs,1H),8.35(s,1H),8.13(s,1H),7.78～7.83(m,3H),7.63(d,J＝8.8Hz,2H),7.46～7.49(m,4H),7.28(d,J＝16.5Hz,1H),7.22(d,J＝16.5Hz,1H),7.11(d,J＝8.8Hz,2H),5.33(s,2H)；13C NMR(DMSO-d6,100MHz)δ:167.7,162.2,158.0,148.9,138.5,138.2,131.7,130.7,130.5,130.0,129.4,128.6(2C),128.4,127.4,127.2,126.2,125.4,124.6,120.7,115.6(2C),102.5,61.7；HRMS(ESI)calcdfor C25H17N2O6[M-H]-441.1087,found 441.1072.
Example 9: synthesis of Compound Ii (R ═ 4-Me)
Obtained by following the synthesis method of Ia in example 1, substituting iiii (R ═ H) for iiia (R ═ H). Yellow solid; 55 percent of Yield;1H NMR(DMSO-d6,400MHz)δ:13.02(s,1H),8.12(s,1H),7.99(d,J＝8.4Hz,1H),7.97(d,J＝5.5Hz,1H),7.78～7.85(m,3H),7.62(d,J＝8.4Hz,2H),7.46～7.51(m,2H),7.40(t,J＝8.7Hz,2H),7.30(d,J＝16.4Hz,1H),7.22(d,J＝16.4Hz,1H),7.18(s,1H),7.09(d,J＝8.4Hz,2H),5.28(s,2H)；13C NMR(DMSO-d6,100MHz)δ:168.6,167.3,161.3,157.6,137.7,131.2,130.2,128.9,128.2,128.1,128.1,128.0(2C),127.9,126.9,124.1,125.6,116.5,116.3,115.5,115.1(2C),99.9,61.3；HRMS(ESI)calcd for C26H20NO4[M-H]-410.1392,found 410.1373.
Example 10: synthesis of Compound Ij (R ═ 4-OMe)
Synthesis of Ia in reference example 1 with iii j (R ═ 4-OMe) instead of iiia (R ═ H)the method is used for preparing the compound. Yellow solid; 52 percent of Yield;1H NMR(DMSO-d6,400MHz)δ:13.04(brs,1H),8.12(s,1H),7.77～7.86(m,5H),7.62(d，J＝8.4Hz，2H),7.46～7.54(m，2H),7.30(d,J＝16.5Hz,1H),7.22(d,J＝16.5Hz,1H),7.09(d,J＝8.4Hz,2H),7.04(s，1H),5.26(s,2H)，3.83(s，3H)；13C NMR(DMSO-d6,100MHz)δ:167.7,166.1,161.5,158.2,138.4,138.2，131.7，130.7，130.7,130.0,129.4,128.6(2C),127.7,127.5,127.4,127.2,126.1，124.6,120.0，115.2(2C),100.0,61.8,55.7；HRMS(ESI)calcd for C26H20NO5[M-H]-426.1341,found 426.1365.
Example 11: synthesis of Compound Ik (R ═ 4-F)
obtained by following the synthesis method of Ia in example 1, substituting iiik (R ═ 4 — F) for iiia (R ═ H). Yellow solid; 37 percent of Yield;1H NMR(DMSO-d6,400MHz)δ:13.10(brs,1H),8.13(s，1H)，7.83～7.95(m，5H)，7.64(d,J＝8.5Hz,2H),7.48～7.55(m,2H)，7.31(d，J＝16.5Hz,1H),7.24(d,J＝16.5Hz,1H),7.21(s,1H),7.11(d,J＝8.4Hz,2H),5.33(s,2H)；13C NMR(DMSO-d6,100MHz)δ:168.1,166.7,161.5,158.8(d，J＝154.0Hz,2C)，158.1，139.4，132.5,132.4(2C),130.9,129.9,128.7(2C),128.5,128.2,127.9,127.3,126.2(d,J＝26.5Hz,2C),124.6,115.5(2C),104.8,61.8；HRMS(ESI)calcd for C25H17FNO4[M-H]-414.1142,found 414.1159.
Example 12: compound Il (R ═ 3, 4-Cl)2) Synthesis of (2)
With IIIl (R ═ 3, 4-Cl)2) Obtained by referring to the synthesis method of Ia in example 1 instead of iiia (R ═ H). Yellow solid; 52 percent of Yield;1H NMR(DMSO-d6,400MHz)δ:13.03(brs,1H),8.22(s,1H),8.12(s，1H),7.80～7.83(m，3H)，7.62(d,J＝8.7Hz,2H),7.45～7.52(m,2H),7.37(s，1H)，7.30(d，J＝16.4Hz，1H)，7.23(d，J＝16.4Hz，1H)，7.09(d,J＝8.7Hz,2H),5.30(s,2H)；13C NMR(DMSO-d6,100MHz)δ:167.3,167.1,161.5,157.5,137.7,133.1,132.2,131.6,131.3,130.5,130.3,130.2,130.1,129.1,128.9,128.1,128.0(2C),127.5,127.0,126.9,125.7,115.5,115.1(2C),101.6,61.2；HRMS(ESI)calcd for C25H16Cl2NO4[M-H]-464.0456,found 464.0438.
Example 13: compound Im (R ═ 3, 4-F)2) Synthesis of (2)
With IIIm (R ═ 3, 4-F)2) Obtained by referring to the synthesis method of Ia in example 1 instead of iiia (R ═ H). Yellow solid; 45 percent of Yield;1H NMR(DMSO-d6,400MHz)δ:13.13(brs,1H),8.12(s,1H),7.78～7.85(m,3H),7.62(d,J＝8.8Hz,2H),7.46～7.51(m,3H),7.30(d,J＝16.5Hz,1H),7.23(d,J＝16.5Hz,1H),7.09(d,J＝8.8Hz,2H),6.78(d,J＝7.9Hz,1H),5.30(s,2H)；13C NMR(DMSO-d6,100MHz)δ:170.6,169.1,162.5,158.6,150.7(d,J＝148.5Hz),150.0(d,J＝149.4Hz),138.0,137.7,131.2,130.3,130.0,129.5,128.9,128.6(2C),128.2,127.4,121.3,119.3(d,J＝8.2Hz),115.5(2C),115.0(d,J＝8.5Hz),103.6,61.8,56.3；HRMS(ESI)calcd forC25H16F2NO4[M-H]-432.1047,found 432.1083.
Example 14: in vitro inhibitory Activity test of Compound I on PTP1B
Materials and instruments
The substrate p-nitrophenylphosphate (pNPP) used in the test was purchased from Calbiochem (San Diego, Calif., USA); the automated sample application systems used were Biomek 2000 from Beckman (Fullerton, CA, u.s.a.) and Hydra96 from Robbins Scientific; the 96-well microplate and 96-well uv/vis spectrophotometers spectra max 340 and Flexstation ii 384 used were purchased from Greiner (Epsom, Surrey KT199AP, UK) and Molecular Devices (Sunnyvale, CA, u.s.a.), respectively.
sample preparation
1mg of the sample was dissolved in 200mL of DMSO, and the resulting solution was used as a stock solution of 5 g/mL. From this stock solution, 20mL was put into A2-H11 sample wells of a 96-well polypropylene plate, and 80mL of DMSO was added thereto and mixed well to serve as a 1g/mL sample master (Figure 26). The Biomek 2000 automated sample application system transferred 2mL of sample from this master plate to a 96-well polystyrene plate as a sample daughter plate for screening.
High throughput screening of PTP1B inhibitors
Oleanolic acid was used as a positive control, and 2ml of ldmso, but no other reagents or samples, was added to the sample wells as a blank control, and the assay was performed as described above.
After detection, the average value of the initial speeds of the enzyme reactions of 8 blank controls is calculated and taken as the total activity, then the relative activity of the enzyme reactions of each sample well is calculated, and finally the percentage of inhibition is obtained by subtracting the relative activity from the total activity (100%). After data processing by Excel software, the final results shown are the percent inhibition for each sample well. And then, selecting a sample with the inhibition rate of 50% from the primary screening result, and carrying out subsequent secondary screening.
Rescreening and IC50Measurement of (2)
2mL of the compound was collected from a 1mg/mL daughter plate and placed in a 96-well plate (the final concentration in the reaction system was 20g/mL), and two multiple wells were provided for each compound, and the inhibitory activity of the compound was tested again in the same manner as in the primary screening. Finally, the relative activity is plotted against the compound concentration, and IC is calculated by fitting Graphpad software50The value is obtained.
the activity results are shown in table 1:
TABLE 1 IC inhibition of PTP1B by Compounds Ia-Im50.
As shown in the table above, the compounds Ia to Im have different degrees of inhibition effects on the enzyme activity of PTP1B, and can be used as potential antidiabetic drugs.
Claims (3)
1. A compound containing a 5-phenylisoxazolylstilbene group, wherein the chemical structure formula of 5-phenylisoxazolylstilbene compound (I) is as follows:
Wherein R is H,2-Cl,2-OMe,3-Cl,3-F,3-Br,3-Me,3-NO2,4-Me,4-OMe,4-F,3,4-Cl2Or 3,4-F2。
2. A preparation method of a compound containing 5-phenylisoxazolyl stilbenoid group as claimed in claim 1, which is characterized in that 4' -hydroxystyrene-3-carboxylic acid methyl ester (II) as shown in formula (II) and substituted 5-phenyl 3-chloromethyl isoxazole (III) as shown in formula (III) are subjected to condensation reaction by using cesium carbonate as an acid-binding agent; hydrolyzing under the action of potassium hydroxide, acidifying by hydrochloric acid to obtain a compound containing 5-phenylisoxazole stilbenoid group,
Wherein R is H,2-Cl,2-OMe,3-Cl,3-F,3-Br,3-Me,3-NO2,4-Me,4-OMe,4-F,3,4-Cl2Or 3,4-F2。
3. Use of a compound containing a 5-phenylisoxazolyl stilbene group according to claim 1 for the preparation of a medicament for lowering blood sugar.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610412031.7A CN106117156B (en) | 2016-06-14 | 2016-06-14 | compound containing 5-phenyl isoxazole stilbenoid group and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610412031.7A CN106117156B (en) | 2016-06-14 | 2016-06-14 | compound containing 5-phenyl isoxazole stilbenoid group and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106117156A CN106117156A (en) | 2016-11-16 |
| CN106117156B true CN106117156B (en) | 2019-12-17 |
Family
ID=57270520
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610412031.7A Active CN106117156B (en) | 2016-06-14 | 2016-06-14 | compound containing 5-phenyl isoxazole stilbenoid group and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106117156B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101422450A (en) * | 2008-10-09 | 2009-05-06 | 广州市允中投资发展有限公司 | Cajanus cajan L. natural medicine with blood sugar reduction and weight reduction function |
| CN103351285A (en) * | 2013-06-27 | 2013-10-16 | 广州中医药大学热带医学研究所 | Diethylstilbestrol compound and application thereof in preparation of drug for treating osteoporosis and hyperlipemia |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090105240A1 (en) * | 2007-10-17 | 2009-04-23 | Tomas Mustelin | Methods for treating leukemia and myelodysplastic syndrome, and methods for identifying agents for treating same |
-
2016
- 2016-06-14 CN CN201610412031.7A patent/CN106117156B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101422450A (en) * | 2008-10-09 | 2009-05-06 | 广州市允中投资发展有限公司 | Cajanus cajan L. natural medicine with blood sugar reduction and weight reduction function |
| CN103351285A (en) * | 2013-06-27 | 2013-10-16 | 广州中医药大学热带医学研究所 | Diethylstilbestrol compound and application thereof in preparation of drug for treating osteoporosis and hyperlipemia |
Non-Patent Citations (2)
| Title |
|---|
| Design, synthesis, and evaluation of non-steroidal farnesoid X receptor (FXR) antagonist;Masahiko Kainuma et al.;《Bioorganic & Medicinal Chemistry》;20070131;第15卷;第2587-2600页 * |
| Discovery of new non-steroidal FXR ligands via a virtual screening workflow based on Phase shape and induced fit docking;Jing Fu et al.;《Bioorganic & Medicinal Chemistry Letters》;20120923;第22卷;第6848-6853页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106117156A (en) | 2016-11-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Elgazar et al. | Isolates from Alpinia officinarum Hance attenuate LPS‐induced inflammation in HepG2: Evidence from in silico and in vitro studies | |
| Yang et al. | Structure-based discovery of a selective KDM5A inhibitor that exhibits anti-cancer activity via inducing cell cycle arrest and senescence in breast cancer cell lines | |
| Aziz et al. | Synthesis, crystal structure, DFT studies and evaluation of the antioxidant activity of 3, 4-dimethoxybenzenamine Schiff bases | |
| Abdellatif et al. | Synthesis, characterization and biological evaluation of novel 4′-fluoro-2′-hydroxy-chalcone derivatives as antioxidant, anti-inflammatory and analgesic agents | |
| Wilhelm et al. | Syntheses and in vitro antiplasmodial activity of aminoalkylated chalcones and analogues | |
| Gaur et al. | Synthesis, antitubercular activity, and molecular modeling studies of analogues of isoliquiritigenin and liquiritigenin, bioactive components from Glycyrrhiza glabra | |
| Khumkhrong et al. | Crinamine induces apoptosis and inhibits proliferation, migration, and angiogenesis in cervical cancer SiHa cells | |
| Acuña et al. | Synthesis, anti-proliferative activity evaluation and 3D-QSAR study of naphthoquinone derivatives as potential anti-colorectal cancer agents | |
| Shahab et al. | Novel polyhydroquinoline Schiff’s base derivatives: synthesis, characterization, in vitro α-glucosidase inhibitory, and molecular docking studies | |
| Dyshlovoy et al. | Polyphenolic compounds from Lespedeza bicolor root bark inhibit progression of human prostate cancer cells via induction of apoptosis and cell cycle arrest | |
| Aboushanab et al. | Antioxidant and cytotoxic activities of kudzu roots and soy molasses against pediatric tumors and phytochemical analysis of isoflavones using HPLC-DAD-ESI-HRMS | |
| Iwaoka et al. | Characterization and identification of bioactive polyphenols in the Trapa bispinosa Roxb. pericarp extract | |
| Abbotto et al. | Virtual screening in the identification of sirtuins’ activity modulators | |
| Alminderej et al. | In vitro and in silico evaluation of antiproliferative activity of new isoxazolidine derivatives targeting EGFR: design, synthesis, cell cycle analysis, and apoptotic inducers | |
| Ximenis et al. | Natural polyhydroxy flavonoids, curcuminoids, and synthetic curcumin analogs as α7 nAChRs positive allosteric modulators | |
| CN106117156B (en) | compound containing 5-phenyl isoxazole stilbenoid group and preparation method thereof | |
| Puder et al. | Terphenylquinone inhibitors of the src protein tyrosine kinase from Stilbella sp. | |
| Yuen et al. | Tectoridin stimulates the activity of human dermal papilla cells and promotes hair shaft elongation in mouse vibrissae hair follicle culture | |
| Niu et al. | Discovery of matrinic thiadiazole derivatives as a novel family of anti-liver fibrosis agents via repression of the TGFβ/Smad pathway | |
| Chittimalla et al. | A detour route for meta functionalization of phenols | |
| Xiang et al. | Ovatodiolides: Scalable Protection‐Free Syntheses, Configuration Determination, and Biological Evaluation against Hepatic Cancer Stem Cells | |
| Khvostov et al. | Discovery of the first in class 9-N-berberine derivative as hypoglycemic agent with extra-strong action | |
| Kim et al. | Prenylated flavonoid glycosides with PCSK9 mRNA expression inhibitory activity from the aerial parts of Epimedium koreanum | |
| Morikawa et al. | Glucose tolerance-improving activity of helichrysoside in mice and its structural requirements for promoting glucose and lipid metabolism | |
| Geng et al. | Wogonin inhibits osteoclast differentiation by inhibiting NFATc1 translocation into the nucleus |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20201014 Address after: 226019 No.205, building 6, Nantong University, No.9, Siyuan Road, Nantong City, Jiangsu Province Patentee after: Center for technology transfer, Nantong University Address before: 226019 Jiangsu city of Nantong province sik Road No. 9 Patentee before: NANTONG University |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20201216 Address after: 8319 Yanshan Road, Bengbu City, Anhui Province Patentee after: Bengbu Lichao Information Technology Co.,Ltd. Address before: 226019 No.205, building 6, Nantong University, No.9, Siyuan Road, Nantong City, Jiangsu Province Patentee before: Center for technology transfer, Nantong University |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20211216 Address after: Room 503, building 3, No. 133, development avenue, Tongxiang Economic Development Zone, Tongxiang City, Jiaxing City, Zhejiang Province Patentee after: ZHEJIANG MAIZHI NETWORK TECHNOLOGY CO.,LTD. Address before: 8319 Yanshan Road, Bengbu City, Anhui Province Patentee before: Bengbu Lichao Information Technology Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20221114 Address after: No. 99, Gangcheng Road, Administrative Committee of Dongying Port Economic Development Zone, Dongying City, Shandong Province 257237 Patentee after: Dongying Ruigang Investment Promotion Service Co.,Ltd. Address before: Room 503, building 3, No. 133, development avenue, Tongxiang Economic Development Zone, Tongxiang City, Jiaxing City, Zhejiang Province Patentee before: ZHEJIANG MAIZHI NETWORK TECHNOLOGY CO.,LTD. |