CN107286101A - 1 aromatic aldehyde oxime uracil and preparation method thereof - Google Patents

1 aromatic aldehyde oxime uracil and preparation method thereof Download PDF

Info

Publication number
CN107286101A
CN107286101A CN201710622318.7A CN201710622318A CN107286101A CN 107286101 A CN107286101 A CN 107286101A CN 201710622318 A CN201710622318 A CN 201710622318A CN 107286101 A CN107286101 A CN 107286101A
Authority
CN
China
Prior art keywords
aromatic aldehyde
uracil
preparation
arh
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.)
Granted
Application number
CN201710622318.7A
Other languages
Chinese (zh)
Other versions
CN107286101B (en
Inventor
金毅
林军
赵舒悦
蒋昆明
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.)
Yunnan University YNU
Original Assignee
Yunnan University YNU
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 Yunnan University YNU filed Critical Yunnan University YNU
Priority to CN201710622318.7A priority Critical patent/CN107286101B/en
Publication of CN107286101A publication Critical patent/CN107286101A/en
Application granted granted Critical
Publication of CN107286101B publication Critical patent/CN107286101B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

A kind of 1 aromatic aldehyde oxime uracil and preparation method thereof, is related to drug field, is specifically a kind of suppression tumor cell growth activity, with 1 aromatic aldehyde oxime uracil for significantly suppressing thymidine phosphorylase and antitumor activity and preparation method thereof.The 1 aromatic aldehyde oxime uracil of the present invention, it is characterised in that the compound has following structure I：Wherein, R1For methyl or hydrogen, R2For chlorine, iodine, carboxyl or hydrogen, Ar is alkyl phenyl, halogenophenyl, alkoxyl phenyl, thienyl, furyl.1 aromatic aldehyde oxime uracil of the present invention and preparation method thereof, shows very high suppression tumor cell growth activity, with the effect for significantly suppressing thymidine phosphorylase and antitumor activity, preparation process is easy, feasibility is high, is easy to large-scale production, advantageously reduces production cost.

Description

1- aromatic aldehyde oxime uracils and preparation method thereof
Technical field
The present invention relates to drug field, be specifically it is a kind of suppress tumor cell growth activity, with significantly suppressing thymidine 1- aromatic aldehyde oxime uracils of phosphorylase and antitumor activity and preparation method thereof.
Background technology
Angiogenesis plays highly important role during growth and metastasis of tumours.Thymidine phosphorylase (TP), be it is a kind of be related to thymidine homeostasis and metabolism enzyme, due to its endothelial cell have can stimulating endothelial cell move The gravitaxis of shifting is so as to be considered as to rely on angiogenesis.The main function of this enzyme is can be with reversible by thymidine phosphorus It is acidified as thymidine and 2-deoxyribosyl -1- phosphate, and activates 5 FU 5 fluorouracil and precursor.Thymidine phosphorylase not only may be used To recognize that thymidine can also recognize BrdU and Pyrmidine nucleoside derivatives.According to Gene sequence comparison, the thymidine phosphates of the mankind Change enzyme equivalent to angiogenin protein, endothelial cell platelet derived growth factor.Thymidine phosphorylase and endothelial cell blood are small Growth factor this proteinoid in plate source all has with stomach cancer, renal cancer, uterine cancer, liomyoma, breast cancer, colon cancer and lung cancer Indivisible contact.
The migration of endothelial cell is a highly important step for angiogenesis, and the catalytic activity pair of thymidine phosphorylase It is again particularly significant in the migration of endothelial cell, thus in these years come have the thymidine phosphorylase of many various crystal structures and its The elaboration of analog.Recently, a series of thymidine phosphorylase inhibitors containing base or without base have been synthesized and delivered, And with potential anti-thymidine phosphorylase activity and Cancer therapy.On body, maximally effective thymidine phosphorylase Inhibitor is uracil derivative, it is contemplated that be combined to reach the effect of suppression with the site on thymidine.It is most effective at present Inhibitor be the chloro- 6- of 5- [1- (2- amino-pyrroles) methyl] uracil phosphate salt (TPI), its IC50 reaches 35nM, shown Good inhibitory activity.At the same time, a series of TP inhibitor without base have been synthesized and have been tested, to wherein one The mechanism of action of a little compounds is predicted that they are to suppress to make by realizing with the interaction of TP allosteric binding site With this is different from general substrate sites and combined.However, same TP inhibitor, which is clinically used for a long time, might have toxicity The side effects such as drug resistance.New a series of TP inhibitor should be further studied in order to solve this problem.
Amidoxime is the important organic matter of a class, and it has the structure of amide groups oxime, be used frequently as Material synthesis heterocycle and Related intermediate is so as to be widely used in pharmacy, antitumor agent, antiseptic, antiinflammatory etc..The end group and TPI of amidoxime Amino-pyrroles there is similitude, therefore we devise target molecule.In addition to uracil unit, new amidoxime structure has C =N, N-OH, N-H, C=O and different substituents, these are likely to be combined with avtive spot to realize that suppression is lived Property.
The content of the invention
In view of the deficiencies of the prior art, the present invention provides one kind suppresses tumor cell growth activity, with significantly suppressing 1- aromatic aldehyde oxime uracils of thymidine phosphorylase and antitumor activity and preparation method thereof.
The 1- aromatic aldehyde oxime uracils of the present invention, it is characterised in that the compound has following structure I：
Wherein, R1For methyl or hydrogen, R2For chlorine, iodine, carboxyl or hydrogen, Ar be alkyl phenyl, halogenophenyl, alkoxyl phenyl, Thienyl, furyl.
Described 1- aromatic aldehyde oxime uracils, are any one in following 24 kinds：
A kind of preparation method of 1- aromatic aldehyde oximes uracil, it is characterised in that the synthetic reaction formula of the preparation method is：
Specific preparation process is as follows：
(1) aromatic aldehyde is dissolved in methanol, stirred under normal temperature, after aromatic aldehyde is completely dissolved, by hydroxylamine hydrochloride and carbonic acid Potassium is added in methanol, is reacted 2-5h, after reaction completely, then extractive reaction liquid washed with saturated sodium bicarbonate solution, is used Methanol is reclaimed in anhydrous sodium sulfate drying, vacuum distillation, obtains fragrant aldoxime.
(2) fragrant aldoxime is dissolved in DMF, stirred under normal temperature, after fragrant aldoxime is completely dissolved, It is chlorosuccinimide to add NCS, and stirring at normal temperature 2-6h after reaction completely, is extracted, washed using saturated nacl aqueous solution, With anhydrous sodium sulfate drying, vacuum distillation removes solvent, obtains the fragrant aldoxime of adjacent chlorine；
(3) the fragrant aldoxime of adjacent chlorine, substituted uracil and alkali are dissolved in organic solvent 1, stirring at normal temperature 2-4h, question response After completely, after extraction, washing, 3- carboxyl benzaldehydes are added, stirring at normal temperature 6h separates out white solid, after filtering, washing, then used Anhydrous sodium sulfate drying, column chromatography for separation or recrystallization, you can obtain obtaining 1- aromatic aldehyde oxime uracils.
In described step (3), organic solvent 1 is methanol, ethanol, isopropanol, ethyl acetate, toluene, tetrahydrofuran, first Any two kinds or two kinds in benzene, dichloromethane, chloroform, 1,4- dioxane, N,N-dimethylformamide or dimethyl sulfoxide (DMSO) The mixed liquor of above solvent.
In described step (3), alkali be lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, potassium phosphate, One or more mixtures in cesium fluoride, triethylamine.
The 1- aromatic aldehyde oxime uracils of the present invention, it is characterised in that the compound is used as the inhibitor of thymidine phosphorylase, tool Have suppress thymidine phosphorylase activity, for treat stomach cancer, renal cancer, uterine cancer, liomyoma, breast cancer, colon cancer or Lung cancer.
1- aromatic aldehyde oxime uracils of the present invention and preparation method thereof, show very high suppression tumor cell growth activity, With the effect for significantly suppressing thymidine phosphorylase and antitumor activity, preparation process is easy, and feasibility is high, is easy to extensive Production, advantageously reduces production cost.
Embodiment
Embodiment 1：A kind of 1- aromatic aldehyde oximes uracil, with following structure I：
Wherein, R1 is methyl or hydrogen, and R2 is chlorine, iodine, carboxyl or hydrogen, and Ar is alkyl phenyl, halogenophenyl, alkoxy benzene Base, thienyl, furyl.
The 1- aromatic aldehyde oxime uracils, its structural formula is：
The preparation method of 1- aromatic aldehyde oxime uracils, its synthetic reaction formula is：
R1=CH3, H R2=Cl, I, COOH, H
Specific preparation process is as follows：
(1) 0.02mol aromatic aldehydes are dissolved in 25mL methanol, stirred under normal temperature, will after aromatic aldehyde is completely dissolved 0.02mol hydroxylamine hydrochlorides and 0.022mol potassium carbonate are added in methanol, react 3h, after reaction completely, extractive reaction liquid, Ran Houyong Saturated sodium bicarbonate solution is washed, and with anhydrous sodium sulfate drying, vacuum distillation reclaims methanol, obtains fragrant aldoxime.
(2) the fragrant aldoximes of 0.02mol are dissolved in 25mL DMFs, are stirred under normal temperature, treat fragrant aldoxime After being completely dissolved, 0.022mol NCS, stirring at normal temperature 4h are added, after reaction completely, extraction is washed using saturated nacl aqueous solution Wash, with anhydrous sodium sulfate drying, vacuum distillation removes solvent, obtain the fragrant aldoxime of adjacent chlorine；
(3) the fragrant aldoxime of the adjacent chlorine of 2.4mmol, 2mmol substituted uracils and 2.4mmol sodium hydroxides are dissolved in 10mL The in the mixed solvent of DMF and 10mL methanol, stirring at normal temperature 2-4h, after question response is complete, after extraction, washing, 3- carboxyl benzaldehydes are added, stirring at normal temperature 6h separates out white solid, after filtering, washing, then with anhydrous sodium sulfate drying, post layer Analysis separation is recrystallized, you can obtain obtaining 1- aromatic aldehyde oxime uracils.
(Z) -1- (phenyl) (oximido) methyl) -6- methylpyrimidines -2,4- (1H, 3H)-diketone (compound 1).
White solid；M.p.245-246℃；IR(KBr,νmax,cm-1):3451,2918,1731,1658,1459,1367, 1085,947,813,693,462；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.35(s,1H,NH),11.48(s,1H, ), OH 7.63-7.61 (m, J=2.0Hz, 2H, ArH), 7.48-7.46 (t, J=7.0Hz, 3H, ArH), 5.72 (s, 1H, CH), 1.89(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4,152.5,149.8,143.2,132.0, 130.7,129.6,125.5,101.5,18.3；HRMS(ESI-TOF,[M+Na]+):m/z calcd for C12H11N3O3, 268.0693；found,268.0687.
1st, anticancer experiment in vitro：
The positive reference compound used is 7- denitrifications xanthine (7DX) and the chloro- 6- of 5- [1- (2- amino-pyrroles) methyl] Uracil phosphate salt (TPI).
The thymidine phosphorylase inhibitory activity of the cell in vitro level of table 1
Pharmacological Results show that this kind of 1- aromatic aldehyde oximes uracil compound is the tumor growth inhibitors of a class high activity, tool There is the IC of the activity, especially compound 4,5,6,7,12 of very strong suppression thymidine phosphorylase50Value reaches 0.12-9.7 μM, display Go out very high inhibitory activity.
2nd, cytotoxic experiment
The reference compound used is cycloheximide.
The compound 4,5,6,12 to thymidine phosphorylase with preferable inhibitory activity is chosen, in Apoptosis On carried out cytotoxicity, growth inhibition capability evaluation.Experiment finds, all reactive compound within 50 μM of concentration all It is nontoxic.
Embodiment 2：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(Z) -1- ((2- fluorophenyls) (oximido) methyl) -6- methylpyrimidines -2,4- (1H, 3H)-diketone (compound 2).
White solid；M.p.248-249℃；IR(KBr,νmax,cm-1):3440,2919,1695,1432,1302,1179, 989,811,512；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.57(s,1H,NH),11.50(s,1H,OH),7.52- 7.47 (m, J=7.6Hz, 3H, ArH), 7.46-7.33 (m, 1H, ArH), 5.73 (s, 1H, CH), 1.89 (s, 3H, CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4,162.1,152.3,149.8,142.5(d,3JC–F=3Hz), 134.6 (d ,3JC–F=7.5Hz), 131.7 (d,3JC–F=7.5Hz), 121.7 (d,3JC–F=1.5Hz), 117.6 (d,2JC–F=21Hz), 112.3(d,2JC–F=24Hz), 101.8,18.3；HRMS(ESI-TOF,[M+H]+):m/z calcd for C12H10FN3O3, 264.0779；found,264.0776.
Embodiment 3：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(Z) -1- ((4- fluorophenyls) (oximido) methyl) -6- methylpyrimidines -2,4- (1H, 3H)-diketone (compound 3).
White solid；M.p.234-235℃；IR(KBr,νmax,cm-1):3419,2921,1706,1513,1459, 1159,841,605,538；1H NMR(500MHz,DMSO-d6)(δ,ppm):12.36(s,1H,NH),11.48(s,1H,OH), 7.70-7.67 (m, J=8.5Hz, 2H, ArH), 7.31-7.28 ((m, J=7Hz, 2H, ArH), 5.72 (s, 1H, CH), 1.89 (s,3H,CH3)；13C NMR(125MHz,DMSO-d6)(δ,ppm):163.4,162.7,152.4,149.8,142.5,128.7 (d,3JC–F=2.5Hz), 128.0 (d,3JC–F=8.8Hz), 116.7,116.5,101.6,18.3；HRMS(ESI-TOF,[M+H ]+):m/z calcd for C12H10FN3O3,264.0779；found,264.0776.
Embodiment 4：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(Z) -1- ((4- chlorphenyls) (oximido) methyl) -6- methylpyrimidines -2,4- (1H, 3H)-diketone (compound 4).
White solid；M.p.249-250℃；IR(KBr,νmax,cm-1):3445,2922,1673,1493,1312, 1093,942,836,705,504；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.50(s,1H,NH),11.51(s,1H, ), OH 7.66-7.64 (d, J=8.6Hz, 2H, ArH), 7.53-7.52 (d, J=8.6Hz, 2H, ArH), 5.73 (s, 1H, CH), 1.89(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4,152.4,149.8,142.5,135.3, 131.0,129.6,127.4,101.7,18.3；HRMS(ESI-TOF,[M+H]+):m/z calcd for C12H10ClN3O3, 280.0483；found,264.0480.
Embodiment 5：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(Z) -1- ((oximido) (p-methylphenyl) methyl) -6- methylpyrimidines -2,4- (1H, 3H)-diketone (compound 5).
White solid；M.p.256-257℃；IR(KBr,νmax,cm-1):3431,3287,2854,1671,1612,1408, 1303,1185,941,823,706,531；1H NMR(500MHz,DMSO-d6)(δ,ppm):12.17(s,1H,NH),11.42 (s, 1H, OH), 7.51-7.49 (d, J=8.5Hz, 2H, ArH), 7.28-7.26 (d, J=8Hz, 2H, ArH), 5.70 (s, 1H, CH),2.34(s,3H,CH3),1.88(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4,152.6, 149.8,143.2,140.5,130.1,129.5,125.5,101.4,21.3,18.3；HRMS(ESI-TOF,[M+Na]+):m/z calcd for C13H13N3O3,282.0849；found,282.0845.
Embodiment 6：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(Z) -1- ((4- ethylphenyls) (oximido) methyl) -6- methylpyrimidines -2,4- (1H, 3H)-diketone (compound 6).
White solid；M.p.256-257℃；IR(KBr,νmax,cm-1):3444,3242,2964,1720,1656,1462, 1370,1154,1020,950,849,526；1H NMR(500MHz,DMSO-d6)(δ,ppm):12.18(s,1H,NH),11.42 (s, 1H, OH), 7.53-7.52 (d, J=8Hz, 2H, ArH), 7.31-7.29 (d, J=8Hz, 2H, ArH), 5.70 (s, 1H, CH),2.65-2.64(m,2H,CH2),1.89(s,3H,CH3),1.21-1.18(m,3H,CH3)；13C NMR(125MHz,DMSO- d6)(δ,ppm):163.4,152.6,149.8,146.7,143.2,129.6,128.9,125.6,101.4,28.4,18.3, 15.8；HRMS(ESI-TOF,[M+H]+):m/z calcd for C14H15N3O3,274.1186；found,274.1182.
Embodiment 7：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(Z) -1- ((4- bromophenyls) (oximido) methyl) -6- methylpyrimidines -2,4- (1H, 3H)-diketone (compound 7).
White solid；M.p.261-262℃；IR(KBr,νmax,cm-1):3426,1697,1672,1409,1310,1182, 999,848,772,511；1H NMR(500MHz,DMSO-d6)(δ,ppm):12.51(s,1H,NH),11.51(s,1H,OH), 7.72-7.70 (m, J=8.5Hz, 2H, ArH), 7.63-7.62 (d, J=8.5Hz, 2H, ArH), 5.76 (s, 1H, CH), 1.94 (s,3H,CH3)；13C NMR(125MHz,DMSO-d6)(δ,ppm):163.4,152.4,149.8,142.6,132.5,131.7, 127.6,124.1,101.7,18.3；HRMS(ESI-TOF,[M+H]+):m/z calcd for C12H10BrN3O3, 323.9984；found,323.9978.
Embodiment 8：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(Z) -1- ((oximido) (3- methoxyphenyls) methyl) -6- methylpyrimidines -2,4- (1H, 3H)-diketone (compound 8)。
White solid；M.p.256-257℃；IR(KBr,νmax,cm-1):3427,3200,2922,1717,1659,1459, 1385,1310,1236,1018,815,704；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.37(s,1H,NH),11.47 (s, 1H, OH), 7.38-7.37 (m, J=8Hz, 1H, ArH), 7.16-7.14 (m, J=2Hz, 3H, ArH), 5.72-5.71 (d, 1H,CH),3.80(s,3H,CH3),1.89(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4, 160.1,152.5,149.8,143.1,133.5,130.8,118.0,116.4,110.5,101.5,55.7,18.3；HRMS (ESI-TOF,[M+H]+):m/z calcd for C13H13N3O4,276.0984；found,276.0978.
Embodiment 9：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(Z) -1- ((4- ethylphenyls) (oximido) methyl) -6- methylpyrimidines -2,4- (1H, 3H)-diketone (compound 9).
White solid；M.p.243-244℃；IR(KBr,νmax,cm-1):3436,2920,1730,1669,1608,1450, 1367,1181,1033,944,813,523；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.05(s,1H,NH),11.43 (s, 1H, OH), 7.55-7.54 (d, J=8.8Hz, 2H, ArH), 7.01-7.00 (d, J=8.8Hz, 2H, ArH), 5.69 (s, 1H,CH),3.80(s,3H,CH3),1.88(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4, 161.3,152.6,149.8,143.0,127.1,124.5,115.0,101.4,55.8,18.3；HRMS(ESI-TOF,[M+H ]+):m/z calcd for C13H13N3O4,276.0984；found,276.0982.
Embodiment 10：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(Z) -1- ((oximido) (tolyl) methyl) -6- methylpyrimidines -2,4- (1H, 3H)-diketone (compound 10).
White solid；M.p.246-247℃；IR(KBr,νmax,cm-1):3443,2920,1655,1480,1315,1022, 923,802,711,507；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.27(s,1H,NH),11.44(s,1H,OH), 7.43 (s, 1H, ArH), 7.41-7.40 (d, J=7.9Hz, 1H, ArH), 7.36-7.33 (t, J=7.7Hz, 1H, ArH), 7.30-7.29 (d, J=7.5Hz, 1H, ArH), 5.71 (s, 1H, CH), 2.35 (s, 3H, CH3),1.89(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4,152.6,149.8,143.3,138.9,132.1,131.4,129.4, 125.8,122.8,101.5,21.4,18.4；HRMS(ESI-TOF,[M+Na]+):m/z calcd for C13H13N3O3, 282.0849；found,282.0844.
Embodiment 11：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(Z) -1- ((3- fluorophenyls) (oximido) methyl) -6- methylpyrimidines -2,4- (1H, 3H)-diketone (compound 11).
White solid；M.p.255-256℃；IR(KBr,νmax,cm-1):3439,3155,2766,1712,1616,1432, 1296,1082,955,818,745,514；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.49(s,1H,NH),11.41 (s, 1H, OH), 7.45-7.42 (m, J=7.7Hz, 3H, ArH), 7.39-7.38 (m, J=7.3Hz, 1H, ArH), 7.28-7.26 (t, J=8Hz, 1H, ArH) 5.65 (s, 1H, CH), 1.81 (s, 3H, CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm): 163.4,162.1,152.3,149.8,142.5,134.7,131.8(d,3JC–F=7.5Hz), 121.7,117.6 (d,2JC–F= 21Hz),112.3(d,2JC–F=24Hz), 101.8,18.3；HRMS(ESI-TOF,[M+H]+):m/z calcd for C12H10FN3O3,264.0779；found,264.0776.
Embodiment 12：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(Z) -1- ((3,4- dichlorophenyls) (oximido) methyl) -6- methylpyrimidines -2,4- (1H, 3H)-diketone (compound 12)。
White solid；M.p.244-245℃；IR(KBr,νmax,cm-1):3428,2901,1755,1928,1367,1128, 1025,892,655,543；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.70(s,1H,NH),11.51(s,1H,OH), 7.89 (s, 1H, ArH), 7.74-7.73 (d, J=8.5Hz, 1H, ArH), 7.66-7.65 (d, J=8.5Hz, 1H, ArH), 5.73 (s,1H,CH),2.35(s,3H,CH3),1.90(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4, 152.2,149.9,141.8,133.3,132.9,132.5,131.8,127.2,125.8,102.0,18.3；HRMS(ESI- TOF,[M+H]+):m/z calcd for C12H9Cl2N3O3,314.0094；found,314.0088.
Embodiment 13：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(Z) -1- ((oximido) (thienyl) methyl) -6- methylpyrimidines -2,4- (1H, 3H)-diketone (compound 13).
Yellow solid；M.p.234-235℃；IR(KBr,νmax,cm-1):3452,2901,1822,1652,1331,839, 524；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.08(s,1H,NH),11.43(s,1H,OH),7.82-7.81(m, 1H,CH),7.67-7.65(m,1H,CH),7.42-7.41(m,1H,CH),5.69(s,1H,CH),1.90(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):163.5,152.3,149.7,140.6,134.7,128.7,126.3,124.9, 101.5,18.3。
Embodiment 14：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(E) -1- ((oximido) (p-methylphenyl) methyl) -5- iodine pyrimidines -2,4- (1H, 3H)-diketone (compound 14).
White solid；M.p.241-242℃；IR(KBr,νmax,cm-1):3438,3189,3049,2892,1720,1652, 1408,1283,1140,1018,950,826,605,492；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.14(s,1H, ), NH 11.90 (s, 1H, OH), 8.10 (s, 1H, CH), 7.51-7.49 (d, J=8.2Hz, 2H, ArH), 7.25-7.24 (d, J= 8.1Hz,2H,ArH),2.33(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):161.5,149.1,148.4, 143.8,140.4,129.8,128.9,126.0,70.3,21.4；HRMS(ESI-TOF,[M+H]+):m/z calcd for C12H10IN3O3,371.9840；found,371.9838.
Embodiment 15：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(E) -1- ((4- ethylphenyls) (oximido) methyl) -5- iodine pyrimidines -2,4- (1H, 3H)-diketone (compound 15).
White solid；M.p.238-240℃；IR(KBr,νmax,cm-1):3417,3187,3047,2965,2881,1720, 1651,1603,1411,1285,1140,1014,949,841,606,530；1H NMR(500MHz,DMSO-d6)(δ,ppm): 12.15 (s, 1H, NH), 11.92 (s, 1H, OH), 8.10 (s, 1H, CH), 7.54-7.52 (d, J=7.5Hz, 2H, ArH), 7.28-7.27 (d, J=7.5Hz, 2H, ArH), 2.65-2.61 (m, 2H, CH2),1.19-1.16(t,3H,CH3)；13C NMR (125MHz,DMSO-d6)(δ,ppm):161.5,149.2,148.4,146.7,143.8,129.2,128.7,126.1,70.3, 28.5,15.9；HRMS(ESI-TOF,[M+Na]+):m/z calcd for C12H11IN3O3,407.9821；found, 407.9816。
Embodiment 16：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(E) -1- ((2- fluorophenyls) (oximido) methyl) -5- iodine pyrimidines -2,4- (1H, 3H)-diketone (compound 16).
White solid；M.p.249-250℃；IR(KBr,νmax,cm-1):3441,3052,2882,1724,1652,1601, 1410,1306,1283,1139,1014,948,846,611,542；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.48 (s, 1H, NH), 11.91 (s, 1H, OH), 8.11 (s, 1H, CH), 7.49-7.48 (m, J=2.4Hz, 3H, ArH), 7.33-7.30 (m, J=2.4Hz, 1H, ArH)；13C NMR(150MHz,DMSO-d6)(δ,ppm):163.6,162.0,161.5,149.2, 148.1,143.1(d,3JC–F=3Hz), 134.3 (d,3JC–F=9Hz), 131.4 (d,3JC–F=9Hz), 122.3,117.5 (d,2JC–F=22.5Hz), 112.9 (d,2JC–F=24Hz), 70.7；HRMS(ESI-TOF,[M-H]-):m/z calcd for C11H7FIN3O3,373.9438；found,373.9442.
Embodiment 17：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(E) -1- ((4- chlorphenyls) (oximido) methyl) -5- iodine pyrimidines -2,4- (1H, 3H)-diketone (compound 17).
White solid；M.p.225-226℃；IR(KBr,νmax,cm-1):3440,3190,3048,2924,1727,1651, 1601,1410,1307,1287,1095,948,832,770,511；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.41 (s, 1H, NH), 11.94 (s, 1H, OH), 8.11 (s, 1H, CH), 7.66-7.65 (d, J=8.6Hz, 2H, ArH), 7.50-7.49 (m, J=1.8Hz, 2H, ArH)；13C NMR(150MHz,DMSO-d6)(δ,ppm):161.5,149.2,148.2,143.1, 135.2,130.7,129.3,127.9,70.7；HRMS(ESI-TOF,[M+H]+):m/z calcd for C11H7ClIN3O3, 391.9299；found,391.9294.
Embodiment 18：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(E) -1- ((4- fluorophenyls) (oximido) methyl) -5- iodine pyrimidines -2,4- (1H, 3H)-diketone (compound 18).
White solid；M.p.242-243℃；IR(KBr,νmax,cm-1):3440,3199,3052,2905,1728,1655, 1600,1444,1305,1285,1214,1023,842,794,678,550；1H NMR(500MHz,DMSO-d6)(δ,ppm): 12.29 (s, 1H, NH), 11.92 (s, 1H, OH), 8.12 (s, 1H, CH), 7.70-7.68 (m, J=8.5Hz, 2H, ArH), 7.29-7.26 (m, J=9Hz, 2H, ArH)；13C NMR(125MHz,DMSO-d6)(δ,ppm):164.5,162.8,161.5, 149.2,148.3,143.1,128.5(t,2JC–F=22.5Hz), 115.8 (d,2JC–F=17.5Hz), 70.5；HRMS(ESI- TOF,[M-H]-):m/z calcd for C11H7FIN3O3,373.9438；found,373.9444.
Embodiment 19：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(E) -1- ((oximido) (4- methoxyphenyls) methyl) -5- iodine pyrimidines -2,4- (1H, 3H)-diketone (compound 19).
Yellow solid；M.p.245-246℃；IR(KBr,νmax,cm-1):3189,3050,2894,1722,1655,1521, 1415,1345,1285,1178,1013,948,836,638,542；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.00 (s, 1H, NH), 11.89 (s, 1H, OH), 8.08 (s, 1H, CH), 7.56-7.54 (d, J=8.8Hz, 2H, ArH), 6.99-6.98 (d, J=8.9Hz, 2H, ArH), 3.79 (s, 3H, CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):161.5,161.3, 149.1,148.4,143.6,127.7,124.1,114.7,70.2,55.9；HRMS(ESI-TOF,[M+H]+):m/z calcd for C11H10IN3O4,387.9789；found,387.9787.
Embodiment 20：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(E) -1- ((oximido) (phenyl) methyl) -5- iodine pyrimidines -2,4- (1H, 3H)-diketone (compound 20).
White solid；M.p.253-254℃；IR(KBr,νmax,cm-1):3443,3087,3051,2916,1722,1649, 1439,1285,1015,949,781,610；1H NMR(500MHz,DMSO-d6)(δ,ppm):12.28(s,1H,NH),11.93 (s,1H,OH),8.13(s,1H,CH),7.62-7.61(d,2H,ArH),7.48-7.42(m,2H,ArH)；13C NMR (125MHz,DMSO-d6)(δ,ppm):161.5,149.2,148.4,143.8,131.7,130.6,129.3,126.1,70.5； HRMS(ESI-TOF,[M+Na]+):m/z calcd for C11H8IN3O3,379.9308；found,379.9504.
Embodiment 21：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(E) -1- ((oximido) (3- methoxyphenyls) methyl) -5- iodine pyrimidines -2,4- (1H, 3H)-diketone (compound 21).
Yellow solid；M.p.255-256℃；IR(KBr,νmax,cm-1):3478,3072,2894,1738,1608,1434, 1218,1138,1044,940,756,636,549；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.31(s,1H,NH), 11.92(s,1H,OH),8.11(s,1H,CH),7.36-7.35(t,1H,ArH),7.16-7.14(m,2H,ArH),7.07- 7.05(t,1H,ArH),3.79(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):161.9,151.7, 149.2,148.3,143.7,133.1,130.5,118.6,116.3,111.2,55.8；HRMS(ESI-TOF,[M-H]-):m/z calcd for C12H10IN3O4,385.9638；found,385.9645.
Embodiment 22：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(E) the chloro- 3- of -5- ((oximido) (p-methylphenyl) methyl) -4- picolines -2,6 (1H, 3H)-diketone (compound 22)。
White solid；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.32(s,1H,NH),11.05(s,1H,OH), 7.60-7.58 (d, J=8.2Hz, 2H, ArH), 7.27-7.26 (d, J=8.1Hz, 2H, ArH), 2.38-2.33 (m, 3H, CH3),2.20-2.19(d,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):159.3,148.9,148.3, 143.2,140.7,130.3,130.1,129.0,126.5,125.7,107.6,21.4,16.8.l。
Embodiment 23：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(E) -5- ((oximido) (p-methylphenyl) methyl) -2,6- diketone -1,2,5,6- tetrahydropyridine -3- carboxylic acid (compounds 23)。
White solid；1H NMR(600MHz,DMSO-d6)(δ,ppm):15.12(s,1H,COOH),12.32(s,1H, NH),11.05(s,1H,OH),8.13(s,1H,CH),7.72-7.70(d,2H,ArH),7.26-7.25(d,2H,ArH),2.57 (s,3H,CH3)。
Embodiment 24：A kind of 1- aromatic aldehyde oximes uracil, its structural formula is
(E) the fluoro- 3- of -5- ((oximido) (p-methylphenyl) methyl) pyridine -2,6- (1H, 3H)-diketone (compound 24).
White solid；1H NMR(600MHz,DMSO-d6)(δ,ppm):11.01(s,1H,NH),10.23(s,1H,OH), 7.56(s,1H,CH),7.28-7.27(m,2H,ArH),7.71-7.70(m,2H,ArH),2.57(s,3H,CH3)。

Claims (6)

1. a kind of 1- aromatic aldehyde oximes uracil, it is characterised in that the compound has following structure I：
Wherein, R1For methyl or hydrogen, R2For chlorine, iodine, carboxyl or hydrogen, Ar is alkyl phenyl, halogenophenyl, alkoxyl phenyl, thiophene Base, furyl.
2. 1- aromatic aldehyde oximes uracil as claimed in claim 1, it is characterised in that the compound is times in following 24 kinds Meaning is a kind of：
3. a kind of preparation method of 1- aromatic aldehyde oximes uracil, it is characterised in that the synthetic reaction formula of the preparation method is：
R1=CH3, H R2=Cl, l, COOH, H
Specific preparation process is as follows：
(1) aromatic aldehyde is dissolved in methanol, stirs, after aromatic aldehyde is completely dissolved, hydroxylamine hydrochloride and potassium carbonate are added under normal temperature Enter in methanol, react 2-5h, after reaction completely, then extractive reaction liquid washed with saturated sodium bicarbonate solution, with anhydrous Sodium sulphate is dried, and methanol is reclaimed in vacuum distillation, obtains fragrant aldoxime.
(2) fragrant aldoxime is dissolved in DMF, stirred under normal temperature, after fragrant aldoxime is completely dissolved, added NCS is chlorosuccinimide, and stirring at normal temperature 2-6h after reaction completely, is extracted, washed using saturated nacl aqueous solution, with nothing Aqueous sodium persulfate is dried, and vacuum distillation removes solvent, obtains the fragrant aldoxime of adjacent chlorine；
(3) the fragrant aldoxime of adjacent chlorine, substituted uracil and alkali are dissolved in organic solvent 1, stirring at normal temperature 2-4h, question response is complete Afterwards, after extracting, washing, 3- carboxyl benzaldehydes are added, stirring at normal temperature 6h separates out white solid, after filtering, washing, then with anhydrous Sodium sulphate is dried, column chromatography for separation or recrystallization, you can obtain obtaining 1- aromatic aldehyde oxime uracils.
4. the preparation method of 1- aromatic aldehyde oximes uracil as claimed in claim 3, it is characterised in that in described step (3), have Machine solvent 1 is methanol, ethanol, isopropanol, ethyl acetate, toluene, tetrahydrofuran, toluene, dichloromethane, chloroform, 1,4- dioxies The mixed liquor of two or more any solvent in six rings, N,N-dimethylformamide or dimethyl sulfoxide (DMSO).
5. the preparation method of 1- aromatic aldehyde oximes uracil as claimed in claim 3, it is characterised in that in described step (3), alkali For the one or more in lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, potassium phosphate, cesium fluoride, triethylamine Mixture.
6. 1- aromatic aldehyde oximes uracil as claimed in claim 1, it is characterised in that the compound as thymidine phosphorylase suppression Preparation, with the activity for suppressing thymidine phosphorylase, for treating stomach cancer, renal cancer, uterine cancer, liomyoma, breast cancer, knot Intestinal cancer or lung cancer.
CN201710622318.7A 2017-07-27 2017-07-27 1-aryl aldoxime uracil and its preparation method Expired - Fee Related CN107286101B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710622318.7A CN107286101B (en) 2017-07-27 2017-07-27 1-aryl aldoxime uracil and its preparation method

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710622318.7A CN107286101B (en) 2017-07-27 2017-07-27 1-aryl aldoxime uracil and its preparation method

Publications (2)

Publication Number Publication Date
CN107286101A true CN107286101A (en) 2017-10-24
CN107286101B CN107286101B (en) 2020-04-21

Family

ID=60103126

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710622318.7A Expired - Fee Related CN107286101B (en) 2017-07-27 2017-07-27 1-aryl aldoxime uracil and its preparation method

Country Status (1)

Country Link
CN (1) CN107286101B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111533700A (en) * 2020-05-20 2020-08-14 天津科技大学 5-substituted uracil derivative and preparation method and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1659148A (en) * 2002-06-10 2005-08-24 默克专利有限公司 Aryloximes
US20070244117A1 (en) * 2003-12-03 2007-10-18 Leo Pharma A/S Novel Hydroxamic Acid Esters and Pharmaceutical Use Thereof
CN102503953A (en) * 2011-10-20 2012-06-20 天津药物研究院 Oximes compound
CN106883217A (en) * 2017-04-01 2017-06-23 清华大学深圳研究生院 A kind of nucleoside base hydroxamic acid derivative compound and preparation method and application

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1659148A (en) * 2002-06-10 2005-08-24 默克专利有限公司 Aryloximes
US20070244117A1 (en) * 2003-12-03 2007-10-18 Leo Pharma A/S Novel Hydroxamic Acid Esters and Pharmaceutical Use Thereof
CN102503953A (en) * 2011-10-20 2012-06-20 天津药物研究院 Oximes compound
CN106883217A (en) * 2017-04-01 2017-06-23 清华大学深圳研究生院 A kind of nucleoside base hydroxamic acid derivative compound and preparation method and application

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111533700A (en) * 2020-05-20 2020-08-14 天津科技大学 5-substituted uracil derivative and preparation method and application thereof
CN111533700B (en) * 2020-05-20 2023-03-28 天津科技大学 5-substituted uracil derivative and preparation method and application thereof

Also Published As

Publication number Publication date
CN107286101B (en) 2020-04-21

Similar Documents

Publication Publication Date Title
CN104080455B (en) Certain chemical entities, composition and method
CN102099355B (en) Phenyl and benzodioxinyl substituted indazoles derivatives
KR102474640B1 (en) Carboxylic acid compound, method for preparation thereof, and use thereof
CN103998434B (en) Thiazole and application thereof as DHODH inhibitor
KR101866706B1 (en) 1-alkyl-6-oxo-1,6-dihydropyridin-3-yl compounds and use as sgrm modulators
WO2011106992A1 (en) Inhibitors of hepatitis c virus ns5b polymerase
PL212494B1 (en) Certain chemical entities, compositions, and methods
CA2985542A1 (en) Triazole agonists of the apj receptor
KR20060123208A (en) Pyrazine derivatives and pharmaceutical use thereof
BRPI0616939A2 (en) triarylcarboxylic acid derivative
JPWO2003064410A1 (en) New 1,2,4-triazole compounds
TW200536545A (en) Pyrazine derivatives and pharmaceutical use thereof
EP2661425B1 (en) Hedgehog antagonists having zinc binding moieties
CA2527586A1 (en) Pyridine n-oxides as antiviral agents
KR20150136294A (en) New Compound Having Inhibition Activity to Factor XIa
BR112019020075A2 (en) compound and pharmaceutical composition
US20200131144A1 (en) Amine or (thio)amide containing lxr modulators
Chaudhary et al. A review on novel synthesis approaches and biological activities of 1, 2, 4-oxadiazole and 1, 3, 4-oxadiazole tailored compounds
CN107286101A (en) 1 aromatic aldehyde oxime uracil and preparation method thereof
CN111072582A (en) N-hydroxy aromatic heterocyclic-2-formamide compound and preparation method and application thereof
JP2018502896A (en) Bifunctional compounds and uses to reduce uric acid levels
CN104844590B (en) A kind of N methyl Ciprofloxacin (rhodanine beta-unsaturated ketone) amide derivatives and its preparation method and application
EP3814331B9 (en) Novel lxr modulators with bicyclic core moiety
JP6533997B2 (en) Compound having ZNF143 inhibitory activity and use thereof
JP2009501158A (en) Heteroarylethenyl derivatives, process for their production and use as pharmaceuticals

Legal Events

Date Code Title Description
PB01 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
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20200421

Termination date: 20210727