CN101693674B - Oxime compound, preparation process and application thereof - Google Patents

Oxime compound, preparation process and application thereof Download PDF

Info

Publication number
CN101693674B
CN101693674B CN200910233389.3A CN200910233389A CN101693674B CN 101693674 B CN101693674 B CN 101693674B CN 200910233389 A CN200910233389 A CN 200910233389A CN 101693674 B CN101693674 B CN 101693674B
Authority
CN
China
Prior art keywords
compound
preparation
acid
adds
obtains
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.)
Expired - Fee Related
Application number
CN200910233389.3A
Other languages
Chinese (zh)
Other versions
CN101693674A (en
Inventor
朱海亮
骆银
李环球
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing University
Original Assignee
Nanjing University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Nanjing University filed Critical Nanjing University
Priority to CN200910233389.3A priority Critical patent/CN101693674B/en
Publication of CN101693674A publication Critical patent/CN101693674A/en
Application granted granted Critical
Publication of CN101693674B publication Critical patent/CN101693674B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Oxime compound is characterized in that the oxime compound is represented by the following general formula, wherein R1 is multi-hydroxyphenyl, and R2 is substituted benzyl. Oxime derivatives have obvious inhibition action on activated T cells and have weaker inhibition action on inactivated T cells, and then the oxime compound can be applied in preparation of immunosuppressive drug. Further, the invention discloses a process for preparing the oxime compound.

Description

A kind of oxime compounds and preparation method thereof and purposes
Technical field
The present invention relates to oxime compounds and preparation method thereof and immunosuppressive drug.
Background technology
Immunosuppressor is a kind of important clinical medicine for medical procedure, and it is used for comprising treatment such as systemic lupus erythematous, rheumatoid arthritis and the psoriasis of graft-rejection and autoimmune disorder.The T lymphocyte has been brought into play indispensable effect in graft-rejection, make ciclosporin A (CsA), and tacrolimus (FK506's) and sirolimus (rapamycin) are shown one's talent as immunosuppressant treatment.Although immunosuppressive drug has been successfully used to the clinical treatment of organ transplantation and autoimmune disorder, its side effect comprises that liver toxicity, renal toxicity, malignant tumour, infection, Cardiovascular Toxicity etc. can not be ignored.Therefore, seek new adjusting immune response, and efficient, the immunosuppressive compounds of the potential novel species of low toxicity can clinical will never the stopping of medicine.
According to research reports, the compound of flavones and osajin has obvious restraining effect to the T cell proliferation in the immune response.The deoxybenzoin compounds is the precursor of flavonoid compound, and it has similarly significant active such as anticancer, antibiotic etc. with flavones a lot of aspect active.Therefore, as the derivative of deoxybenzoin class, its research aspect immunosuppression has larger potentiality equally.
Summary of the invention
The object of the present invention is to provide a class novel oxime compounds and their preparation method and purposes.
Technical scheme of the present invention is as follows:
One class oxime compounds is characterized in that it has following general formula:
Figure G2009102333893D00011
In the formula: R 1-be:
Group;
R 2-be:
Figure G2009102333893D00023
Group.
A kind of method for preparing above-mentioned oxime compounds, it is comprised of the following step:
Step 1. is in boron trifluoride ether solution, add the compound of corresponding phenol and the compound of corresponding toluylic acid class, the ratio of the amount of substance of the compound of the compound of phenol and toluylic acid class is about 1: 1, be heated with stirring to 80-84 ℃, cool off behind the reaction 2h, under agitation pour in the aqueous solution of sodium acetate, then static, filter out solid behind the 24h, the solid that obtains is dissolved in the dehydrated alcohol recrystallization purifies
Solid after the purification that step 2. obtains step 1 is dissolved in dehydrated alcohol, adds sodium acetate, adds the oxammonium hydrochloride of Isoequivalent weight again, be heated with stirring to 60 ℃, approximately use the thin layer chromatography detection reaction behind the 3h, until react completely, cooled and filtered, the filtrate decompression evaporate to dryness obtains the compound of oximes.
Above-mentioned method for making, in the described step 1, boron trifluoride ether solution is that mass percentage concentration is the 47.0-47.7% boron trifluoride ether solution, its consumption is that the compound of every mmole phenol adds 1.0-1.5ml.
Above-mentioned method for making, in the step 2 described in the described step 2, the consumption of dehydrated alcohol is that every mmole oxammonium hydrochloride adds 1.0-1.5ml.
Oxime compounds of the present invention is to the obvious restraining effect of T cell of activation, and to the restraining effect of non-activated T cell a little less than, therefore oxime compounds of the present invention can be used in the preparation immunosuppressive drug.
Embodiment
Embodiment one: (E)-and the preparation of 2-(4-bromophenyl)-1-(3,4 dihydroxy phenyl) ethyl ketone oxime (compound 1)
Figure G2009102333893D00031
In the 100ml single necked round bottom flask, add pyrocatechol (10mmol) and to bromo-acid (10mmol), add again the boron trifluoride diethyl etherate (47.0-47.7%, in BF3, lower same) of 10ml.Stirring reaction is heated to 80-84 ℃ of back flow reaction and approximately cools off behind the 2h, adds in water (200ml) solution of sodium acetate (8g), and the limit edged stirs, and is then static, filters behind the 24h, obtains the solid of brown color.The product that obtains is put into the beaker of 100ml, added dehydrated alcohol to fully dissolving, then filter behind the recrystallization, obtain yellow lenticular material 2-(4-bromophenyl)-1-(3,4-dihydroxyl) Phenyl ethyl ketone.It is moved in the single necked round bottom flask of 100ml, sodium acetate and the oxammonium hydrochloride of the molar masss such as adding are dissolved in ethanol (10ml) again.Be heated with stirring to 60 ℃, reflux and approximately use the thin layer chromatography detection reaction behind the 3h, until react completely, cooled and filtered, the filtrate decompression evaporate to dryness obtains yellow particulate state compound, i.e. the target oxime compounds behind the recrystallization.Productive rate: 62%.Mp?144-145℃. 1H?NMR(300MHz,DMSO-d6),3.99(s,2H),6.67(d,J=8.2Hz,1H),6.92(dd,J=8.22,2.2Hz,2H),7.10(d,J=2.2Hz,1H),7.15(d,J=8.4Hz,1H),7.44(d,J=8.4Hz,1H),8.96(s,1H),9.09(s,1H),11.10(s,1H).ESI-MS:321.00([M+H]+).Anal.Calcd?for?C14H12BrNO3:C,52.20;H,3.75;Br,24.80;N,4.35;O,14.90%;found:C,52.11;H,3.70;Br,24.89;N,4.38;O,14.98%.
Embodiment two: (E)-and the preparation of 2-(4-bromophenyl)-1-(2,3,4-hydroxy phenyl) ethyl ketone oxime (compound 2)
Figure G2009102333893D00032
The preparation method is with embodiment one.Replace pyrocatechol with pyrogallol, obtain brown particle shape target compound.Productive rate 63%.Mp?143-1145℃. 1H?NMR(300MHz,DMSO-d6),4.14(s,2H),6.24(s,1H),6.39(d,J=9Hz,1H),6.90(d,J=8Hz,2H),7.08(d,J=9Hz,2H),7.88(d,J=9Hz,1H),8.71(s,1H),9.45(s,1H),10.11(s,1H),12.45(s,1H).ESI-MS:336.99([M+H]+).Anal.Calcd?for?C14H12BrNO4:C,49.73;H,3.58;Br,23.63;N,4.14;O,18.93%;found:C,49.71;H,3.56;Br,23.65;N,4.15;O,18.97%.
Embodiment three: (E)-and the preparation of 2-(4-p-methoxy-phenyl)-1-(2,4,6-hydroxy phenyl) ethyl ketone oxime (compound 3)
Figure G2009102333893D00041
The preparation method is with embodiment one.Replace pyrocatechol with Phloroglucinol monomethyl ether, replace bromo-acid with homoanisic acid, obtain brown ceramic powder shape target compound.Productive rate 60%.Mp?143-144℃. 1H?NMR(300MHz,DMSO-d6),3.93(s,2H),6.37(d,J=9Hz,1H),6.92(d,J=8Hz,2H),7.15(d,J=8Hz,2H),7.34(d,J=9Hz,1H),9.15(s,1H),10.34(s,1H),12.11(s,2H),12.98(s,1H).ESI-MS:289.10([M+H]+).Anal.Calcd?for?C15H15NO5:C,62.28;H,5.23;N,4.84;O,27.65%;found:C,62.24;H,5.22;N,4.85;O,27.67%.
Embodiment four: (E)-and the preparation of 1-(2,4 dihydroxy phenyl)-2-(4-fluorophenyl) ethyl ketone oxime (compound 4)
Figure G2009102333893D00042
The preparation method is with embodiment one.Replace bromo-acid with para-fluorophenylacetic acid, obtain brown ceramic powder shape target compound.Productive rate 58%.Mp?110-112℃. 1H?NMR(300MHz,DMSO-d6),4.02(s,2H),6.25(d,J=7.32,2H),7.10(t,J=9Hz,2H),7.28(t,J=8.8,3H),8.90(s,1H),9.08(s,1H),11.20(s,1H).ESI-MS:261.08([M+H]+).Anal.Calcd?for?C14H12FNO3:C,64.36;H,4.63;F,7.27;N,5.36;O,18.37%;found:C,64.34;H,4.60;F,7.29;N,5.39;O,18.38%.
Embodiment five: (E)-and the preparation of 2-(3-chloro-phenyl-)-1-(2,3,4-trihydroxy-phenyl) ethyl ketone oxime (compound 5)
Figure G2009102333893D00051
The preparation method is with embodiment one.Replace bromo-acid with a chlorobenzene acetic acid, pyrogallol replaces pyrocatechol, obtains the white powder target compound.Productive rate 64%.Mp?115-117℃. 1H?NMR(300MHz,DMSO-d6),4.17(s,2H),6.29(d,J=8.8,1H),6.83(d,J=8.8,1H),7.23(t,J=8.4,2H),7.31(t,J=7.7,2H),8.21(s,1H),9.25(s,1H),11.54(s,1H),11.63(s,1H).ESI-MS:293.05([M+H]+).Anal.Calcd?for?C14H12ClNO4:C,57.25;H,4.12;Cl,12.07;N,4.77;O,21.79%;fourd:C,57.22;H,4.11;Cl,12.09;N,4.74;O,21.81%.
Embodiment six: (E)-and the preparation of 2-(3-chloro-phenyl-)-1-(2,4-dihydroxy phenyl) ethyl ketone oxime (compound 6)
Figure G2009102333893D00052
The preparation method is with embodiment one.Replace pyrocatechol with Resorcinol, replace bromo-acid with a chlorobenzene acetic acid, obtain the white powder target compound.Productive rate 62%.Mp?121-122℃.1H?NMR(300MHz,DMSO-d6),4.18(s,2H)6.25(d,J=1.29,1H),6.26(s,1H),6.41(d,J=1.26,1H),7.23(dd,J=4.59,J=9.15,1H),7.30(d,J=1.65,1H),7.94(d,J=5.31,1H),8.16(s,1H),11.54(s,1H),11.63(s,1H),12.37(s,1H).MS(ESI):277.05([M+H]+).Anal.calc.for?C14H12ClNO3:C,60.55;H,4.36;Cl,12.77;N,5.04;O,17.28%;found:C,60.50;H,4.34;Cl,12.79;N,5.07;O,17.25%.
Embodiment seven: (E)-and the preparation of 2-(3-chloro-phenyl-)-1-(3,4-dihydroxy phenyl) ethyl ketone oxime (compound 7)
The preparation method is with embodiment one.Replace bromo-acid with a chlorobenzene acetic acid, obtain the white powder target compound.Productive rate 64%.Mp?120-122℃. 1H?NMR(300MHz,DMSO-d6),4.10(s,2H),6.68(d,J=8.22,1H),6.94(dd,J=2.19,J=8.22,1H),7.12(d,J=2.01,1H),7.22(d,J=5.31,2H),7.37(d,J=6.39,2H),8.97(s,1H),9.09(s,1H),11.13(s,1H).MS(ESI):277.05([M+H] +).Anal.calc.for?C14H12ClNO3:C,60.55;H,4.36;Cl,12.77;N,5.04;O,17.28%;found:C,60.57;H,4.37;Cl,12.75;N,5.03;O,17.27%.
Embodiment eight: (E)-and the preparation of 2-(3-p-methoxy-phenyl)-1-(2,3,4-trihydroxy-phenyl) ethyl ketone oxime (compound 8)
Figure G2009102333893D00062
The preparation method is with embodiment one.Replace pyrocatechol with pyrogallol, replace bromo-acid with the meta-methoxy toluylic acid, obtain yellow powder shape target compound.Productive rate 52%.Mp?120-121℃. 1H?NMR(300MHz,DMSO-d6),3.70(s,3H),4.07(s,2H),6.27(d,J=8.6,1H),6.75(d,J=7.1,1H),6.82(d,J=4.95,1H),7.18(t,J=7.68,3H),8.19(s,1H),9.15(s,1H),11.44(s,1H),11.73(s,1H).MS(ESI):275.12([M+H] +).Anal.calc.for?C15H17NO4:C,65.44;H,6.22;N,5.09;O,23.25%;found:C,65.47;H,6.20;N,5.07;O,23.26%.
Embodiment nine: (E)-and the preparation of 1-(2,4-dihydroxy phenyl)-2-(3-p-methoxy-phenyl) ethyl ketone oxime (compound 9)
Figure G2009102333893D00071
The preparation method is with embodiment one.Replace pyrocatechol with Resorcinol, the meta-methoxy toluylic acid replaces bromo-acid, obtains yellow powder shape target compound.Productive rate 49%.Mp?153-156℃. 1H?NMR(500MHz,DMSO-d6),3.70(s,3H),4.13(s,2H),6.24(s,1H),6.25(d,J=2.7,1H),6.75(dd,J=2.45,J=8.25,1H),6.81(s,1H),6.83(d,J=5.8,2H),7.18(t,J=7.65,1H),7.27(d,J=9.15,1H),9.18(s,1H),11.66(s,1H),11.76(s,1H).MS(ESI):273.10([M+H] +).Anal.calc.for?C15H15NO4:C,65.92;H,5.53;N,5.13;O,23.42;found:C,65.94;H,5.54;N,5.18;O,23.41.
Embodiment ten: (E)-and the preparation of 1-(3,4-dihydroxy phenyl)-2-(3-p-methoxy-phenyl) ethyl ketone oxime (compound 10)
Figure G2009102333893D00072
The preparation method is with embodiment one.Replace bromo-acid with the meta-methoxy toluylic acid, obtain yellow powder shape target compound.Productive rate 49%.Mp?153-156℃. 1H?NMR(500MHz,DMSO-d6),3.70(s,3H),4.13(s,2H),6.24(s,1H),6.25(d,J=2.7,1H),6.75(dd,J=2.45,J=8.25,1H),6.81(s,1H),6.83(d,J=5.8,2H),7.18(t,J=7.65,1H),7.27(d,J=9.15,1H),9.18(s,1H),11.66(s,1H),11.76(s,1H).MS(ESI):273.10([M+H] +).Anal.calc.forC15H15NO4:C,65.92;H,5.53;N,5.13;O,23.42%;found:C,65.94;H,5.54;N,5.18;O,23.41%.
Embodiment 11: (E)-and the preparation of 2-(3-bromophenyl)-1-(2,3,4-trihydroxy-phenyl) ethyl ketone oxime (compound 11)
Figure G2009102333893D00081
The preparation method is with embodiment one.Replace pyrocatechol with pyrogallol, replace bromo-acid with a bromo-acid, obtain the white powder target compound.Productive rate 62%.Mp?126-127℃. 1H?NMR(300MHz,DMSO-d6),4.09(s,2H),6.29(d,J=8.58,1H),6.82(d,J=8.76,1H),7.23(t,J=8.4,2H),7.31(d,J=7.7,1H),7.47(d,J=6.03,1H),8.20(s,1H),9.23(s,1H),11.50(s,1H),11.61(s,1H).MS(ESI):336.99([M+H] +).Anal.calc.for?C14H12BrNO4:C,49.73;H,3.58;Br,23.63;N,4.14;O,18.93%;found:C,49.75;H,3.60;Br,23.61;N,4.11;O,18.95%.
Embodiment 12: (E)-and the preparation of 2-(3-bromophenyl)-1-(3,4-dihydroxy phenyl) ethyl ketone oxime (compound 12)
Figure G2009102333893D00082
The preparation method is with embodiment one.Replace bromo-acid with a bromo-acid, obtain the white powder target compound.Productive rate 64%.Mp?120-122℃. 1H?NMR(300MHz,DMSO-d6),4.10(s,2H),6.68(d,J=8.22,1H),6.94(dd,J=2.19,J=8.22,1H),7.12(d,J=2.01,1H),7.22(d,J=5.31,2H),7.37(d,J=6.39,2H),8.97(s,1H),9.09(s,1H),11.13(s,1H).MS(ESI):321.00([M+H] +).Anal.calc.for?C14H12BrNO3:C,52.20;H,3.75;Br,24.80;N,4.35;O,14.90%;found:C,52.25;H,3.77;Br,24.77;N,4.32;O,14.88%.
Embodiment 13: (E)-and the preparation of 2-(3-bromophenyl)-1-(2,4-dihydroxy phenyl) ethyl ketone oxime (compound 13)
Figure G2009102333893D00091
The preparation method is with embodiment one.Replace pyrocatechol with Resorcinol, a bromo-acid replaces bromo-acid, obtains the white powder target compound.Productive rate 53%.Mp?118-119℃. 1H?NMR(300MHz,DMSO-d6),c4.17(s,2H),6.25(s,1H),7.25(d,J=5.49,2H),7.30(d,J=8.97,2H),7.38(d,J=8.65,1H),7.50(d,J=5.31,1H),9.71(s,1H),11.61(s,1H),11.50(s,1H).MS(ESI):321.00([M+H] +).Anal.calc.for?C14H12BrNO3:C,52.20;H,3.75;Br,24.80;N,4.35;O,14.90%;found:C,52.23;H,3.77;Br,24.82;N,4.30;O,14.88%.
Embodiment 14: (E)-and the preparation of 2-(4-chloro-phenyl-)-1-(2,3,4-trihydroxy-phenyl) ethyl ketone oxime (compound 14)
Figure G2009102333893D00092
The preparation method is with embodiment one.Replace pyrocatechol with pyrogallol, 4-Chlorophenylacetic acid replaces bromo-acid, obtains the white powder target compound.Productive rate 53%.Mp?145-147℃. 1H?NMR(300MHz,DMSO-d6),4.14(s,2H),6.24(s,1H),6.39(d,J=9Hz,1H),6.90(d,J=8Hz,2H),7.08(d,J=9Hz,2H),7.88(d,J=9Hz,1H),8.71(s,1H),9.45(s,1H),10.11(s,1H),12.45(s,1H).MS(ESI):293.05([M+H] +).Anal.calc.for?C14H12ClNO4:C,57.25;H,4.12;C1,12.07;N,4.77;O,21.79%;found:C,57.26;H,4.13;Cl,12.08;N,4.73;O,21.80%.
Embodiment 15: (E)-and the preparation of 2-(4-chloro-phenyl-)-1-(3,4-dihydroxy phenyl) ethyl ketone oxime (compound 15)
Figure G2009102333893D00101
The preparation method is with embodiment one.Replace bromo-acid with 4-Chlorophenylacetic acid, obtain the white powder target compound.Productive rate: 62%.Mp?144-145℃. 1H?NMR(300MHz,DMSO-d6),3.99(s,2H),6.67(d,J=8.2Hz,1H),6.92(dd,J=8.22,2.2Hz,2H),7.10(d,J=2.2Hz,1H),7.15(d,J=8.4Hz,1H),7.44(d,J=8.4Hz,1H),8.96(s,1H),9.09(s,1H),11.10(s,1H).ESI-MS:277.05([M+H]+).Anal.Calcd?for?C14H12ClNO3:C,60.55;H,4.36;Cl,12.77;N,5.04;O,17.28%;found:C,60.53;H,4.34;C1,12.78;N,5.05;O,17.30%.
Embodiment 16: (E)-and the preparation of 1-(3,4-dihydroxy phenyl)-2-(3-fluorophenyl) ethyl ketone oxime (compound 16)
Figure G2009102333893D00102
The preparation method is with embodiment one.Replace bromo-acid with a fluorophenylacetic acid, obtain the white powder target compound.Productive rate 64%.Mp?120-122℃. 1H?NMR(300MHz,DMSO-d6),4.10(s,2H),6.68(d,J=8.22,1H),6.94(dd,J=2.19,J=8.22,1H),7.12(d,J=2.01,1H),7.22(d,J=5.31,2H),7.37(d,J=6.39,2H),8.97(s,1H),9.09(s,1H),11.13(s,1H).MS(ESI):261.08([M+H] +).Anal.calc.for?C14H12FNO3:C,64.36;H,4.63;F,7.27;N,5.36;O,18.37%;found:C,64.35;H,4.64;F,7.23;N,5.35;O,18.39%.
Embodiment 17: (E)-and the preparation of 1-(2,4-dihydroxy phenyl)-2-(3-fluorophenyl) ethyl ketone oxime (compound 17)
Figure G2009102333893D00111
The preparation method is with embodiment one.Replace pyrocatechol with Resorcinol, a fluorophenylacetic acid replaces bromo-acid, obtains the white powder target compound.Productive rate 53%.Mp?118-119℃. 1H?NMR(300MHz,DMSO-d6),c4.17(s,2H),6.25(s,1H),7.25(d,J=5.49,2H),7.30(d,J=8.97,2H),7.38(d,J=8.65,1H),7.50(d,J=5.31,1H),9.71(s,1H),11.61(s,1H),11.50(s,1H).MS(ESI):261.08([M+H] +).Anal.calc.for?C14H12FNO3:C,64.36;H,4.63;F,7.27;N,5.36;O,18.37%;found:C,64.35;H,4.64;F,7.29;N,5.38;O,18.34%.
Embodiment 18: (E)-and the preparation of 2-(3-fluorophenyl)-1-(2,3,4-trihydroxy-phenyl) ethyl ketone oxime (compound 18)
The preparation method is with embodiment one.Replace pyrocatechol with pyrogallol, replace bromo-acid with a fluorophenylacetic acid, obtain the white powder target compound.Productive rate 62%.Mp?126-127℃. 1H?NMR(300MHz,DMSO-d6),4.09(s,2H),6.29(d,J=8.58,1H),6.82(d,J=8.76,1H),7.23(t,J=8.4,2H),7.31(d,J=7.7,1H),7.47(d,J=6.03,1H),8.20(s,1H),9.23(s,1H),11.50(s,1H),11.61(s,1H).MS(ESI):277.08([M+H] +).Anal.calc.for?C14H12FNO4:C,60.65;H,4.36;F,6.85;N,5.05;O,23.08%;found:C,60.67;H,4.37;F,6.84;N,5.06;O,23.09%.
Embodiment 19: (E)-and the preparation of 2-(4-nitrophenyl)-1-(2,3,4-trihydroxy-phenyl) ethyl ketone oxime (compound 19)
Figure G2009102333893D00121
The preparation method is with embodiment one.Replace pyrocatechol with pyrogallol, paranitrophenylacetic acid replaces bromo-acid, obtains the white powder target compound.Productive rate 53%.Mp?145-147℃. 1H?NMR(300MHz,DMSO-d6),4.14(s,2H),6.24(s,1H),6.39(d,J=9Hz,1H),6.90(d,J=8Hz,2H),7.08(d,J=9Hz,2H),7.88(d,J=9Hz,1H),8.71(s,1H),9.45(s,1H),10.11(s,1H),12.45(s,1H).MS(ESI):304.07([M+H] +).Anal.calc.for?C14H12N2O6:C,55.27;H,3.98;N,9.21;O,31.55%;found:C,55.26;H,3.99;N,9.20;O,31.53%.
Embodiment 20: (E)-and the preparation of 2-(4-nitrophenyl)-1-(2,3,4-trihydroxy-phenyl) ethyl ketone oxime (compound 20)
The preparation method is with embodiment one.Replace bromo-acid with paranitrophenylacetic acid, obtain the white powder target compound.Productive rate: 62%.Mp?144-145℃. 1H?NMR(300MHz,DMSO-d6),3.99(s,2H),6.67(d,J=8.2Hz,1H),6.92(dd,J=8.22,2.2Hz,2H),7.10(d,J=2.2Hz,1H),7.15(d,J=8.4Hz,1H),7.44(d,J=8.4Hz,1H),8.96(s,1H),9.09(s,1H),11.10(s,1H).ESI-MS:288.07([M+H]+).Anal.Calcd?for?C14H12N2O5:C,58.33;H,4.20;N,9.72;O,27.75%;found:C,58.32;H,4.22;N,9.73;O,27.77%.
Embodiment 21: the research of oxime compounds immunosuppressive activity
Adopt MTT[3-(4,5)-two methyl-2-thiazole-(2,5)-phenyl bromination tetrazole is blue] method measures oxime compounds to T cell and the non-activated T cell minimum inhibitory concentration (minimal inhibitoryconcentration, MIC) of activation.Adopt the method for flow cytometer and immunoblotting that the best compound of immunocompetence is carried out the mechanism of action detection.
(1) animal is prepared: available from the female BALB/c mouse in 6 to 8 ages in week of Jiangsu Province's Experimental Animal Center.Under 21 ± 2 ℃, mouse keep freely eating food and water, and kept for 12 little time/cycle secretly.Laboratory Animal Welfare and experimental arrangement are to carry out in strict accordance with treatment and laboratory animal guide (science and China, 200 years technical divisions) the ethics rules guide relevant with Nanjing University.Reduce to full capacity the misery of animal and reduce the quantity of using animal.
(2) cell is prepared with reagent: separate lymph-node cell from BALB/c mouse at 37 ℃, in the air of 5.0% carbonic acid gas humidification, cultivate in 1640 substratum that are aided with 10% foetal calf serum (foetal calf serum).Anti-CD3, anti-CD28 murine antibody is available from BD Pharmingen.Annexin V-FITC/PI test kit is available from the U.S. biotechnology of crystalline substance.Anti-caspase-3 antibody and the anti-PARP antibody of splitting is available from Santa Cruz biotech company.Anti-β-ribose antibody is available from Cell Signaling Technology, Inc..Every other chemical obtains Sigma chemical industry company limited.
(3) cell proliferation experiment: lymph-node cell is with 5 * 10 5The density of individual/plate is cultivated in 96 holes, with the compound of different concns with the anti-CD28 Co stituation of anti-CD3/, continue 72h.4h before cultivating end, every hole adds 20 μ l MTT, and the multiplicative stage begins.After the end, remove supernatant liquor after, add 20 μ l DMSO Rong Xie formazan crystallizations.With the absorbancy under the enzyme linked immunosorbent assay instrument test 540nm.
(4) cell toxicity test: with cell with 5 * 10 5The density in individual/hole adds in 96 orifice plates, and the compound that then adds gradient concentration is cultivated 72h.The every hole of 4h adds the MTT of 20 μ l before finishing cultivation.And then add the DMSO Rong Xie formazan crystal of 200 μ l.Survey at last the absorbance of 540nm.
(5) apoptosis detects: stimulate lymph-node cell with anti-CD3/anti-CD28 under the compound of different concns, continue 48 hours.Use again albumen V-fluorescence (fluorescein isothiocyanate) and propidium iodide (PI) to dye.With flow cytometer sample is analyzed at last.
(6) immunoblotting assay: after cultivating end, with phosphoric acid buffer and the lysate (Tris of 30mmol/L, pH value 7.5, the sodium-chlor of 150mmol/L, the phenylmethylsulfonyl fluoride of 1mmol/L, the sodium orthovanadate of 1mmol/L, 1%Nonidet P-40,10% glycerine and Phosphoric acid esterase and proteinase inhibitor) the washing lysing cell.The centrifugal 1O of 10,000 * g minute, use BCA TMProtein detection kit (Pierce, Rockford, IL) is determined the content of the protein of supernatant liquor.Separate this protein with the 10%SDS-PAGE cracking again, be placed on subsequently and carry out the electricity conversion on the polyvinylidene fluoride film.Film at room temperature seals 2h with 5% skimmed milk.The film of sealing, then resists in conjunction with two with horseradish peroxidase and hatches at 4 ℃ of probe marks that spend the night in order to the primary antibodie of mark.With the LumiGLO chemical luminescence substrate system result is detected again.
(7) statistical study
All experiments have all repeated 3-5 time, all obtain similar result.These two experimental group P values are tested with two tail student t-checks.It is 0.05 that significance level fixes on the P value.If applicable, data report is mean+SD (SD).
The calculating of inhibiting rate: the inhibiting rate of Growth of Cells calculates according to following formula:
Growth inhibition ratio=(1-survival rate) * 100%=[1-(OD Experiment-OD Blank)/(OD Contrast-OD Empty In vain)] * 100% (OD ExperimentThe average optical of expression testing drug group, OD ContrastThe average optical of expression control group, OD BlankThe average optical of expression control group).
Half-inhibition concentration (IC 50) be defined as the drug level when the survival of 50% tumour cell.According to the optical density(OD) (OD value) of measuring, make the typical curve of inhibitory rate of cell growth, try to achieve its corresponding drug level at typical curve.
The inhibition IC of T cell to activation of oxime compounds of the present invention 50Value sees Table 1, to the inhibition IC of non-activated T cell 50Value sees Table 2.
The inhibition IC of T cell to activation of the listed oxime compounds of table 1 the present invention 50Value (μ M)
Figure G2009102333893D00141
The inhibition IC to non-activated T cell of the listed oxime compounds of table 2 the present invention 50Value (μ M)
Figure G2009102333893D00151

Claims (5)

1. oxime compounds is characterized in that it has following general formula:
Figure FSB00000881016500011
In the formula: R 1For:
Figure FSB00000881016500012
R 2For:
Figure FSB00000881016500013
2. method for preparing oxime compounds claimed in claim 1 is characterized in that it is comprised of the following step:
Step 1. is in boron trifluoride ether solution, add the compound of corresponding phenol and the compound of corresponding toluylic acid class, the ratio of the amount of substance of the compound of the compound of phenol and toluylic acid class is 1: 1, be heated with stirring to 80-84 ℃, cool off behind the reaction 2h, under agitation pour in the aqueous solution of sodium acetate, then static, filter out solid behind the 24h, the solid that obtains is dissolved in the dehydrated alcohol recrystallization purifies
Solid after the purification that step 2. obtains step 1 is dissolved in dehydrated alcohol, adds sodium acetate, adds the oxammonium hydrochloride of Isoequivalent weight again, is heated with stirring to 60 ℃, until react completely, and cooled and filtered, the filtrate decompression evaporate to dryness obtains the compound of oximes.
3. method for making according to claim 2, it is characterized in that: in the described step 1, boron trifluoride ether solution is that mass percentage concentration is the 47.0-47.7% boron trifluoride ether solution, and its consumption is that the compound of every mmole phenol adds 1.0-1.5ml.
4. method for making according to claim 2, it is characterized in that: in the described step 2, the consumption of dehydrated alcohol is that every mmole oxammonium hydrochloride adds 1.0-1.5ml.
5. oxime compounds claimed in claim 1 is used in the preparation immunosuppressive drug.
CN200910233389.3A 2009-10-27 2009-10-27 Oxime compound, preparation process and application thereof Expired - Fee Related CN101693674B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN200910233389.3A CN101693674B (en) 2009-10-27 2009-10-27 Oxime compound, preparation process and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN200910233389.3A CN101693674B (en) 2009-10-27 2009-10-27 Oxime compound, preparation process and application thereof

Publications (2)

Publication Number Publication Date
CN101693674A CN101693674A (en) 2010-04-14
CN101693674B true CN101693674B (en) 2013-03-06

Family

ID=42092686

Family Applications (1)

Application Number Title Priority Date Filing Date
CN200910233389.3A Expired - Fee Related CN101693674B (en) 2009-10-27 2009-10-27 Oxime compound, preparation process and application thereof

Country Status (1)

Country Link
CN (1) CN101693674B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109772592B (en) * 2019-03-13 2021-03-23 广东省科学院资源综合利用研究所 Application of 2-hydroxy aronoxime compound as collecting agent in oxide ore flotation and flotation method

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4029704A (en) * 1972-08-25 1977-06-14 Imperial Chemical Industries Limited Oximes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4029704A (en) * 1972-08-25 1977-06-14 Imperial Chemical Industries Limited Oximes

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ACS.RN: 320741-23-9.《STN:REGISTRY》.2001, *
Huan-Qiu Li et al.Amines and oximes derived from deoxybenzoins as Helicobacter pylori urease inhibitors.《European Journal of Medicinal Chemistry》.2008,第44卷2246-2251. *
Medicinal Chemistry》.2007,第15卷3703-3710. *
Zhu-Ping Xiao et al.Polyphenols based on isoflavones as inhibitors of Helicobacter pylori urease.《Bioorganic & Medicinal Chemistry》.2007,第15卷3703-3710.
Zhu-Ping Xiao et al.Polyphenols based on isoflavones as inhibitors of Helicobacter pylori urease.《Bioorganic &amp *

Also Published As

Publication number Publication date
CN101693674A (en) 2010-04-14

Similar Documents

Publication Publication Date Title
CN103102283A (en) Preparation method of chalcone oxime compound and application of the same as novel immunosuppressant
Fang et al. EGCG inhibits proliferation, invasiveness and tumor growth by up-regulation of adhesion molecules, suppression of gelatinases activity, and induction of apoptosis in nasopharyngeal carcinoma cells
CN103664932B (en) One class indoles grafting thiazole hydrazone analog derivative and preparation method thereof and the inhibitory action to cancer cell tubulin polymerization
CN106831383A (en) Diarylheptanoids
CN101693674B (en) Oxime compound, preparation process and application thereof
Viswanathan et al. Battling Glioblastoma: A Novel Tyrosine Kinase Inhibitor with Multi-Dimensional Anti-Tumor Effect
CN108530435B (en) Quinoxaline-containing 1, 4-pentadiene-3-ketone derivative, preparation method and application
CN101932331B (en) Methods for in vitro maturation of ovarian follicles
CN103102331B (en) Pharmaceutical application of chalcone compound containing piperazine ring
CN105884645B (en) A kind of rhein compound and application thereof
CN104529987A (en) 4-hydroxyl bishydroxycoumarin compound and application thereof
CN104447436B (en) A kind of sulphur acylhydrazone, its preparation method and free radical resisting thereof or anti-tumor activity application
CN103936772A (en) Preparation method of binuclear copper complex with anti-tumor activity
JP4939761B2 (en) Ingredients of stone lotus flowers and their uses
CN105646476B (en) Biphenyl simultaneously [1,2,5] selenium oxadiazole derivative and its preparation method and application
CN107496428A (en) Calycosin derivative is preparing the application in promoting endothelial cell proliferation medicine
CN104961707B (en) Substituted thiazole ketone secretory protease inhibitors and preparation method thereof
CN102093191A (en) Resveratrol chalcone derivative and preparation method thereof
CN114671917A (en) Curcumin analogue, preparation method and application thereof in anti-cancer cell proliferation drugs
Fu et al. EDACO, a derivative of myricetin, inhibits the differentiation of Gaoyou duck embryonic osteoclasts in vitro
CN104173325B (en) Application of the palmitinic acid in preparation treatment liver cancer and anti-liver cancer and anti-diversion medicaments
CN104910074A (en) Hydroximic acid group-containing pyrazoles derivative, preparation method and purpose thereof
CN106588581A (en) Stilbenes derivative and application thereof
CN104922125B (en) 2- [3- cyano-[R1-R2-R3Azepine phenyl]-R4Thio-based compound and its pharmaceutical composition and its application
CN106544399A (en) The application of the high specific fluorescence probe of one class detection Cytochrome P450 1A1

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20130306

Termination date: 20151027

EXPY Termination of patent right or utility model