CN101693674B - Oxime compound, preparation process and application thereof - Google Patents
Oxime compound, preparation process and application thereof Download PDFInfo
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- 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
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- 238000002360 preparation method Methods 0.000 title claims abstract description 46
- -1 Oxime compound Chemical class 0.000 title claims abstract description 32
- 150000002923 oximes Chemical class 0.000 claims abstract description 14
- 239000003018 immunosuppressive agent Substances 0.000 claims abstract description 7
- 229940124589 immunosuppressive drug Drugs 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 43
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 229910015900 BF3 Inorganic materials 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- 239000001632 sodium acetate Substances 0.000 claims description 6
- 235000017281 sodium acetate Nutrition 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 5
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- 210000001744 T-lymphocyte Anatomy 0.000 abstract description 11
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- 238000004519 manufacturing process Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 40
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 26
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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
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:
In the formula: R
1-be:
Group;
R
2-be:
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
The inhibition IC to non-activated T cell of the listed oxime compounds of table 2 the present invention
50Value (μ M)
Claims (5)
1. oxime compounds is characterized in that it has following general formula:
In the formula: R
1For:
R
2For:
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.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4029704A (en) * | 1972-08-25 | 1977-06-14 | Imperial Chemical Industries Limited | Oximes |
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| US4029704A (en) * | 1972-08-25 | 1977-06-14 | Imperial Chemical Industries Limited | Oximes |
Non-Patent Citations (5)
| 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 & * |
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