CN102344476B - Thymidine cyclic phosphate compound and anticancer usage thereof - Google Patents
Thymidine cyclic phosphate compound and anticancer usage thereof Download PDFInfo
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- CN102344476B CN102344476B CN201010241506.3A CN201010241506A CN102344476B CN 102344476 B CN102344476 B CN 102344476B CN 201010241506 A CN201010241506 A CN 201010241506A CN 102344476 B CN102344476 B CN 102344476B
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- hydrogen
- cyclic phosphate
- thymidine
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- derivative
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- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Natural products O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 title claims abstract description 27
- 229940104230 thymidine Drugs 0.000 title claims abstract description 16
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 15
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 239000010452 phosphate Substances 0.000 title claims abstract description 15
- -1 Thymidine cyclic phosphate compound Chemical class 0.000 title abstract description 13
- 230000001093 anti-cancer Effects 0.000 title abstract description 3
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 239000000523 sample Substances 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000004122 cyclic group Chemical group 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 6
- 201000011510 cancer Diseases 0.000 claims 2
- 238000003745 diagnosis Methods 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 24
- 239000002246 antineoplastic agent Substances 0.000 abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 4
- 210000001541 thymus gland Anatomy 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 229910052698 phosphorus Inorganic materials 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-BJUDXGSMSA-N carbon-11 Chemical compound [11C] OKTJSMMVPCPJKN-BJUDXGSMSA-N 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 238000002050 diffraction method Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 0 C*(C(OC(C(C(*)C1)O[C@]1*1C=C(C2=O)N)=C1*2=C)=O)*(c1c(C)c(*=C)ccc1)=C Chemical compound C*(C(OC(C(C(*)C1)O[C@]1*1C=C(C2=O)N)=C1*2=C)=O)*(c1c(C)c(*=C)ccc1)=C 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- DTRYYPKLEYYJTH-UHFFFAOYSA-N I.OP(O)(O)=O Chemical compound I.OP(O)(O)=O DTRYYPKLEYYJTH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- FPISENDBCQYRQB-UHFFFAOYSA-N phenol;phosphoric acid Chemical compound OP(O)(O)=O.OC1=CC=CC=C1 FPISENDBCQYRQB-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- PNDPGZBMCMUPRI-HVTJNCQCSA-N 10043-66-0 Chemical compound [131I][131I] PNDPGZBMCMUPRI-HVTJNCQCSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 240000000203 Salix gracilistyla Species 0.000 description 2
- 102000006601 Thymidine Kinase Human genes 0.000 description 2
- 108020004440 Thymidine kinase Proteins 0.000 description 2
- PNDPGZBMCMUPRI-XXSWNUTMSA-N [125I][125I] Chemical compound [125I][125I] PNDPGZBMCMUPRI-XXSWNUTMSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000001412 amines Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000003983 crown ethers Chemical class 0.000 description 2
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004334 fluoridation Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 229940044173 iodine-125 Drugs 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- ZZDYHBFMDAYCRQ-UHFFFAOYSA-N [Cl].[P].OC1=C(C=CC=C1)O Chemical compound [Cl].[P].OC1=C(C=CC=C1)O ZZDYHBFMDAYCRQ-UHFFFAOYSA-N 0.000 description 1
- GJMMXPXHXFHBPK-UHFFFAOYSA-N [P].[Cl] Chemical compound [P].[Cl] GJMMXPXHXFHBPK-UHFFFAOYSA-N 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical compound OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- RKOKDYYBPOKUKF-UHFFFAOYSA-N phosphoric acid;hydrobromide Chemical compound Br.OP(O)(O)=O RKOKDYYBPOKUKF-UHFFFAOYSA-N 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- DZGUAKWKLLPSDK-UHFFFAOYSA-N pyrimidine;trifluoromethanesulfonic acid Chemical compound C1=CN=CN=C1.OS(=O)(=O)C(F)(F)F DZGUAKWKLLPSDK-UHFFFAOYSA-N 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Thymidine cyclic phosphate compound and anticancer usage thereof, the invention provides the preparation method of following general formula compound and the application as antitumor drug and nano-probe.
Description
Technical field:
The present invention relates to thymidine cyclic phosphate derivative and isotropic substance thereof that a class has good biological activity, be specifically related to derivative that five Yuans sugared ring 3 ' fluorine and Value linear replace and preparation method thereof and the application as antitumor drug and nano-probe.
Background technology:
Thimidine analogue is the most compounds effective of a class treatment HIV.The general modfel that this compounds works suppresses the ThermoScript II of HIV, namely embeds the DNA chain of growth, cause the termination of DNA chain.But many thimidine analogue are also inoperative, one of reason is that they can not be changed into 5 '-monophosphate ester derivatives by thymidine kinase (ThymidineKinase) phosphoric acid.Therefore, the compound designing thymidine 5 '-O phosphate derivative is used for permeates cell membranes produce biological activity in cell.Research shows, the upper cyclic phosphate of 5 '-thymidine connection can make increased activity 10-40 doubly in some cases.
1. Sun Wei swallow etc., CycloSaligenylPronucleotidesof5-Iodoand5-Trifluoromethyl-1-(2-deoxy-b-d-ribofuranosyl)-2,4-difluorobenzeneMimicsofThymidine:SynthesisandEvaluatio nofthisPronucleotideMonophosphateDeliverySystemforCompou ndswithPotentialAnticancerActivity:NUCLEOSIDES, NUCLEOTIDES & NUCLEICACIDSVol.22, No.12, pp.2121-2132, (2003)
2. Sun Wei swallow etc., PETRadiopharmaceuticalsattheCrossCancerInstitutePetCentr e:[
18f] FLTforinvivocellproliferationimaging, AlbertaCancerBoard2005AnnualResearchMeeting, BanffCanadaNov8-10, (2005)
3. Sun Wei swallow etc., Radiosynthesisof2 '-deoxy-2 '-[
18f] fluorothymidine ([
18f] FT), aputativePETagentforimagingHSV-TKexpression.CurrentRadio pharmaceuticals, 2 (1), 72-85, (2009)
Deoxythymidine (FLT) is an effective antiviral compound, and in order to allow FLT play stronger anti-tumor activity, we design and have prepared the FLT cyclic phosphate derivative of a class replacement and the marker of Value linear.We find that this compounds has very strong anti-tumor activity.This compounds is that unknown compound does not also have corresponding physical data and bibliographical information at present.
Summary of the invention:
An object of the present invention is to provide and there is antitumor FLT cyclic phosphate derivative.
An object of the present invention is to provide the preparation method of this analog derivative.
An object of the present invention is to provide the application of this analog derivative on antitumor drug.
An object of the present invention is to provide the application as nano-probe on antitumor drug of this analog derivative.
The invention provides a following general formula (I), 5-replaces the derivative of thymidine cyclic phosphate:
Wherein R
1=hydrogen or C
1-C
20straight or branched, saturated or unsaturated group, halogen;
R
3=hydrogen atom or C
1-C
20straight or branched alkyl or alkoxyl group or carbon isotope or halogen or halogen isotopes;
R
4=hydrogen atom or C
1-C
20straight or branched alkyl or alkoxyl group or carbon isotope or halogen or halogen isotopes;
X=halogen or halogen isotopes;
Y=hydrogen or halogen or leavings group;
N=0 or 1.
Present invention also offers 5-shown in above-mentioned general formula (I) and replace thymus pyrimidine-5 ' 8 kinds of preparation methods of-cyclic phosphate derivative, can be obtained by reacting by following one or several:
Method one, directly obtains general formula (I) compound by a step coupled reaction below:
By formula (II), substituted ring phosphoric acid or cyclic phosphorochloridate (Z=OH or Cl) and formula (III), replace the direct coupled reaction of thymus pyrimidine and obtain formula (I), 5-replaces thymus pyrimidine-5 '-cyclic phosphate derivative.
Method two, reoxidizes two-step reaction by first coupling below and obtains general formula (I) compound:
By formula (II), substituted ring phosphorus chlorine compound and formula (III), replace thymus pyrimidine direct coupled reaction and obtain an intermediate, oxidizedly further obtains formula (I), and 5-replaces thymus pyrimidine-5 '-cyclic phosphate derivative.
Method three, obtains general formula (I) compound by substitution reaction below:
By formula (V), 3 '-by leavings group replace thymidine cyclic phosphate compound directly and halogen be obtained by reacting formula (I), 5-replaces thymus pyrimidine-5 '-cyclic phosphate derivative.
Method four, obtains general formula (I) compound by ring-opening reaction below:
By formula (VI), 5 '-cyclic phosphate 2,3 '-thymus pyrimidine acid anhydride and halogen or halogen isotropic substance are under microwave heating condition, and obtain formula (I), 5-replaces thymus pyrimidine-5 '-cyclic phosphate derivative.
Method five, obtains carbon-11 tagged compound of general formula (I) compound by the methylation reaction on phenyl ring below:
By formula (VII), thymidine-5 '-cyclic phosphate phenol and carbon-11 methyl iodide be obtained by reacting formula (I) on LOOP, the 5-that carbon-11 marks replaces thymus pyrimidine-5 '-cyclic phosphate derivative.
Method six, obtains iodo-124 of general formula (I) compound, iodine-125, iodine-131 or bromo-75, bromo-76 tagged compounds by the halogen exchange reaction on phenyl ring below:
By formula (VIII), 3 '-(fluorine, bromine, iodine or OH) '-cyclic phosphate iodine and isotropic substance sodium iodide (iodo-124 or iodine-125 or iodine-131) microwave heating be obtained by reacting formula (I), the 5-of iodine labeling replaces thymus pyrimidine-the 5 '-cyclic phosphate derivative that replaces thymidine-5.
Also can by (VIII), 3 '-(fluorine, bromine, iodine or OH) '-cyclic phosphate bromine and isotropic substance Sodium Bromide (bromo-75 or bromo-76) microwave heating be obtained by reacting formula (I), the 5-of bromine mark replaces thymus pyrimidine-the 5 '-cyclic phosphate derivative that replaces thymidine-5.
Method seven, obtains the Value linear tagged compound of general formula (I) compound by the fluoridation on phenyl ring below:
By (IX), 3 '-(fluorine, bromine, iodine or OAc) ' benzene of-cyclic phosphate replace trifluoromethanesulfonic acid tetramethyl quaternary amine with K222 crown ether Value linear salt in the upper production (I) of full-automatic integrated ejector (intergratedfluidics), the 5-replacement thymus pyrimidine-5 of fluorine the mark '-cyclic phosphate derivative that replaces thymidine-5.
Method eight, obtains the Value linear tagged compound of general formula (I) compound by the fluoridation on 5-position side chain below:
By (X), 3 '-(fluorine, bromine, iodine or OH) replaces thymidine-5 ' p-toluenesulfonic esters of-cyclic phosphate-5-position side chain and K222 crown ether Value linear salt is at ASU (TracerLabFX
fN) thymus pyrimidine-5 of upper fully automated synthesis 5-position side chain Value linear mark '-cyclic phosphate derivative.
Embodiment:
Embodiment one:
3-cresotinic acid phosphoric acid acyl chlorides (1.2mol) is with the anhydrous THF of FLT (1mol), add pyridine to stir 4 hours at-20 DEG C, decompression removing organic solvent, residue is recrystallization in acetonitrile, and obtaining sterling compound (I) is P
rand P
sdL, its absolute configuration is determined by X diffraction method.
1HNMRδ11.4(1H)，7.70(1H)，7.10(1H)，6.95(1H)，6.22(1H)，5.40((2H)，5.29(1H)，4.14(1H)，3.62(2H)，2.37(2H)，2.30(3H)，1.78(3H)
31Pδ-8.70，-8.56
High resolution mass spectrum 426.3288 observed value 426.3286
Embodiment two:
Bigcatkin willow phosphoric acid acyl chlorides (1.2mol) is with the anhydrous pyridine of FLT (1mol), add the DMAP of catalytic amount, stir at 0 DEG C and spend the night, wash away excessive pyridine with HCl, decompression removing organic solvent, is extracted with ethyl acetate, dried over sodium sulfate, be concentrated in pulpous state, residue is recrystallization in ethanol-dichloromethane, and obtaining DL compound (I) is 50%P
rand 50%P
s, its absolute configuration is determined by X diffraction method.Concrete reference (KazueOhkuta, Sun Weiyan etc.
(2S)-2-[1-(2，4-Difluoro-5-indophenyl)-2-deoxy-β-D-ribofuranos-5-yloxy]-8-methyl-4H-1，3，2-benzodioxa-phosphole2-oxide，ActaCrystallographicaSectionC60，0789-91，(2004))
1HNMRδ11.38(1H)，7.71(1H)，7.26-7.36(1H)，7.02-7.16(3H)，5.28-5.50(4H)，4.12(1H)，3.60(2H)，2.36(2H)，1.80(3H)
31PNMRδ-9.06，-9.18
High resolution mass spectrum 412.3062 observed value 412.3068
Embodiment three:
Dihydroxy-benzene phosphorus chlorine (1.1mmol) is with the anhydrous pyridine of FLT (1mmol), add the DMAP of catalytic amount, stir 30 minutes at-20 DEG C, add hydrogen peroxide and continue stirring 60 minutes, wash away excessive pyridine with HCl, decompression removing organic solvent, by chloroform extraction, dried over sodium sulfate, be concentrated in pulpous state, residue is recrystallization in ethanol-dichloromethane, and obtaining DL compound (I) is 50%P
rand 50%P
s, its absolute configuration is determined by X diffraction method.Concrete reference (KazueOhkuta, Sun Weiyan etc.
(2S)-2-[1-(2，4-Difluoro-5-indophenyl)-2-deoxy-β-D-ribofuranos-5-yloxy]-8-methyl-4H-1，3，2-benzodioxa-phosphole2-oxide，ActaCrystallographicaSectionC60，0789-91，(2004))
1HNMRδ11.41(1H)，7.70(1H)，7.25-7.37(1H)，7.0-7.15(3H)，5.20-5.55(4H)，4.12(1H)，2.36(2H)，1.80(3H)
31PNMRδ-9.05，-9.16
High resolution mass spectrum 412.3062 observed value 412.3061
Embodiment four:
3-methoxysalicylic phosphoric acid-3 '-deoxidation thymus pyrimidine triflate (V) (1mmol) and normal-butyl fluoride amine (10mmol) anhydrous methylene chloride in, add the DMAP of catalytic amount, stir 5 minutes at-20 DEG C, add NaHCO
3saturated solution washes away excessive methylsulfonic acid, and decompression removing organic solvent, by chloroform extraction, dried over sodium sulfate, be concentrated in pulpous state, residue flash column purification, it is 50%P that methylene dichloride/ether wash-out obtains DL compound (I)
rand 50%P
s, its absolute configuration is determined by X diffraction method.Concrete reference (KazueOhkuta, Sun Weiyan etc. (2S)-2-[1-(2,4-Difluoro-5-indophenyl)-2-deoxy-β-D-ribofuranos-5-yloxy]-8-methyl-4H-1,3,2-benzodioxa-phosphole2-oxide, ActaCrystallographicaSectionC60,0789-91, (2004))
1HNMRδ11.37(1H)，7.58(1H)，7.10(1H)，6.94(1H)，6.69(1H)，5.42((2H)，5.29(1H)，4.14(1H)，3.90(3H)，3.62(2H)，2.38(2H)，2.29(3H)，1.81(3H)
High resolution mass spectrum 442.3322 observed value 442.3322
Embodiment five:
Bigcatkin willow phosphoric acid ester-2,3 '-deoxidation thymus pyrimidine acid anhydride (VI) (5 milligrams) is in anhydrous DMSO, by the K222 of Value linear (100Bq) negative ion that QMA captures, potassium bicarbonate solution, formula automatization joins in the chip of full-automatic integrated ejector (intergratedfluidics), and microwave heating to 165 DEG C reaction 10 minutes, is chilled to 40 DEG C and adds sterilized water, cross the alkaline standard column of FDG, Al
2o
3, C-18 reversed-phase column removing K
222rf value same as standard control
Embodiment six:
Thymidine cyclic phosphate phenol (VII) (1 milligram) reacts in DMSO solution with on LOOP carbon-11 methyl iodide being imported HPLC, is directly separated through HPLC after 5 minutes, can obtain the thymidine cyclic phosphate that purity is greater than the C-11 mark of 99%.Send into 2 kilometers of outer micro-PET centers with air gun pipeline, make further tumour PET image.
Embodiment seven:
Thymidine cyclic phosphate iodide (VIII) (250 microgram) incorporate CuSO
4(0.5M, 0.5mL), NH
4sO
4in the mixing solutions of (0.5M, 0.5mL), add Na
126i heating is by moisture evaporate to dryness, and microwave heating 140 DEG C reaction 4 hours, residue injects high-pressure liquid phase and is separated, and moving phase is water: methyl alcohol 85: 15, cut when collecting 29 minutes.Putting productive rate is 79%
Embodiment eight:
From magnetic resonance acceleator target obtain fluorine anion (95Bq) through QMA enrichment, use K
222naHCO
3solution (0.5mL) wash-out, on the program control chip being injected into full-automatic integrated ejector (intergratedfluidics), high-purity argon gas dewaters, inject the acetonitrile solution of thymidine cyclic phosphate quaternary amine (IX) (3mg), microwave heating to 170 DEG C maintains ten minutes, through aluminium sesquioxide post, C-18 post, disposable micro HPLC obtains the thymidine cyclic phosphate (I) of Value linear mark.Putting productive rate is 19.5%, and radiochemicsl purity is greater than 99%.The HPLC residence time is 12 minutes.
Claims (3)
1. the derivative of the thymidine cyclic phosphate of the replacement shown in general formula as described below (I):
Wherein, R
1for methyl, R
3for hydrogen, R
4for methyl, one in X and Y is hydrogen, another is F, n=1; Or,
R
1for methyl, R
3and R
4for hydrogen, one in X and Y is hydrogen, another is-F, n=1; Or,
R
1for methyl, R
3and R
4for hydrogen, one in X and Y is hydrogen, another is-F, n=0; Or,
R
1for methyl, R
3for hydrogen, R
4for-OCH
3, one in X and Y is hydrogen, another is-F, n=1; Or,
R
1for methyl, R
3and R
4for hydrogen, one in X and Y be hydrogen, another for-
18f, n=1; Or,
R
1for propyl group, R
3for-O
11cH
3, R
4for-OCH
3, one in X and Y be hydrogen, another for-
18f, n=1; Or,
R
1for-F, R
3for-
125i, R
4for hydrogen, one in X and Y is hydrogen, another is-F, n=1; Or,
R
1for hydrogen, R
3for-
18f, R
4for hydrogen, one in X and Y is hydrogen, another is-F.
2. the application of derivative in the medicine for the preparation of the treatment in tumor and cancer of the thymidine cyclic phosphate replaced described in claim 1.
3. in the derivative of the thymidine cyclic phosphate replaced described in claim 1, X/Y is the application of derivative in the nano-probe for the preparation of the diagnosis in tumor and cancer of the thymidine cyclic phosphate of the replacement of halogen isotopes.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050069495A1 (en) * | 2003-09-25 | 2005-03-31 | Janina Baranowska-Kortylewicz | Cancer specific radiolabeled conjugates regulated by the cell cycle for the treatment and diagnosis of cancer |
| US20090117041A1 (en) * | 2007-08-10 | 2009-05-07 | Kortylewicz Zbigniew P | Radiologic Agents for Monitoring Alzheimer's Disease Progression and Evaluating a Response to Therapy and Processes for the Preparation of Such Agents |
| WO2009121347A1 (en) * | 2008-04-04 | 2009-10-08 | Universität Hamburg | Method for the stereoselective synthesis of phosphorus compounds |
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2010
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050069495A1 (en) * | 2003-09-25 | 2005-03-31 | Janina Baranowska-Kortylewicz | Cancer specific radiolabeled conjugates regulated by the cell cycle for the treatment and diagnosis of cancer |
| US20090117041A1 (en) * | 2007-08-10 | 2009-05-07 | Kortylewicz Zbigniew P | Radiologic Agents for Monitoring Alzheimer's Disease Progression and Evaluating a Response to Therapy and Processes for the Preparation of Such Agents |
| WO2009121347A1 (en) * | 2008-04-04 | 2009-10-08 | Universität Hamburg | Method for the stereoselective synthesis of phosphorus compounds |
Non-Patent Citations (3)
| Title |
|---|
| Antiviral activity of cyclosaligenyl prodrugs of the nucleoside analogue bromovinyldeoxyuridine against herpes;Astrid et al.;《International Journal of Antimicrobial Agents》;20051231;第27卷(第5期);图1及表1 * |
| CycloSal-BVDUMP Pronucleotides: How to Convert an Antiviral-Inactive Nucleoside Analogue into a Bioactive Compound against EBV;Meier, Chris et al.;《Journal of Medicinal Chemistry》;20021231;第45卷(第23期);Scheme1及表1 * |
| Nucleotide delivery from cycloSaligenyl-3"-azido-3"-deoxythymidine monophosphates (cycloSal-AZTMP);Meier, Chris et al.;《European Journal of Organic Chemistry》;19981231(第5期);第838页 * |
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