CN102898421A - Pyridazinone compound containing polyethyleneglycol (PEG) modified benzyl triazolyl and preparation method and application thereof - Google Patents
Pyridazinone compound containing polyethyleneglycol (PEG) modified benzyl triazolyl and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a pyridazinone compound containing polyethyleneglycol (PEG) modified benzyl triazolyl. According to the pyridazinone compound, a molecular formula is Fmppn, and a structure is shown as a formula (1), wherein n is an integral number of 1 to 8; and F is 19F or 18F. The pyridazinone compound has the characteristics of simplicity in preparation, low using cost, high radiochemical yield and radiochemical purity, high stability and biological properties, high target-to-nontarget ratio, high myocardial intake value and the like, and is used as a novel fluorine-18 marked myocardial perfusion photographic developer to be applied to the technical fields of radiopharmaceutical chemistry and clinical nuclear medicine.
Description
Technical field
The present invention relates to one-class pyridazinone compounds, be specifically related to a kind of pyridazinone compound and preparation method and application that contain PEGization benzyl triazolyl.
Background technology
Although the diagnosis of coronary heart disease and methods for the treatment of development, worldwide, coronary heart disease is still and threatens the most serious disease of human health.In China, the sickness rate of coronary heart disease and mortality ratio are all in rising trend.China's Development of Health Service statistical communique showed in 2008, the specific death rate (1,/10 ten thousand) of heart trouble in China city, urban residents is respectively 121.00 and 87.10, account for respectively 19.65% and 14.11% of city and country Disease causation formation, become the second cause of death of China's morbidity.Estimate that according to the World Health Organization (WHO) to about the year two thousand twenty, China can welcome cardiovascular disorder (being mainly coronary heart disease) " popular " peak.Therefore, the early diagnosis of coronary heart disease and prognostic evaluation seem particularly important.
Myocardial perfusion imaging is used for the heart trouble noninvasive test and starts from the seventies in last century, and its huge diagnostic value worldwide is widely accepted, and becomes one of most important Imaging Method of present diagnosis of coronary heart disease, therapeutic evaluation and prognosis judgement.Heart muscle perfusion single photon emission computed tomography (SPECT) imaging technique is the current main method that is used for clinically the non-invasive perfusion imaging of coronary heart disease detection.But, to compare with SPECT, positron emission fault (PET) video picture has higher room and time resolving power, can effectively reduce the tissue decay, quantitatively myocardial blood flow and coronary flow reserve.In addition, the short-half-life of positron radionuclide can effectively reduce the radiation dose around the target tissue, and shortens tranquillization and motion video picture interval.Heart muscle perfusion PET developer commonly used comprises:
15O-H
2O,
13N-NH
3With
82Rb etc.But the above-mentioned developer transformation period is all shorter, and clinical application is very restricted.And
18F is with respect to other positron radionuclides, and the transformation period is grown (t
1/2=109.8min); Have lower positron energy (512keV), the radiation injury of normal tissue is less; Its van der Waals radius
With hydrogen
Similar, can not affect the biological activity of tagged compound, therefore, the myocardial perfusion imaging agent of fluoro-18 marks of development of new has important practical significance.
In the cardiac muscular tissue, mitochondrial weight accounts for 30%.The respiratory chain (electron transport chain) that is arranged in mitochondrial inner membrane is comprised of four kinds of Mitochondria complexes (MC-I, II, III, IV), wherein MC-I(NADH-ubiquinone oxide-reductase enzyme) be the beginning of this chain.It comprises NADH and H
+, start the electronics transmission by oxidation NADH.Several PET myocardial perfusion imaging agents of report are the MC-I inhibitor analogue recently, as
18F-FDHR(Robert C.Marshall, et al.J Nucl Med, 2004,45:1950-1959),
18F-4-(1, the 3-naphthyridines derivatives) (Ajay Purohit, et al.Bioorgan Med Chem Lett, 2007,17:4882-4885), BMS-747158-02(Padmaja Yalamanchili, et al.J Nucl Cardiol, 2007,14:782-788), [
18F] FP2OP(Tiantian Mou, et al.Bioorgan Med Chem, 2010,18:1312-1320), [
18F] FP1OP(Tiantian Mou, et al.J Nucl Med, 2012,53:472-478) etc.But there is poor stability in the aqueous solution in above developer, in cardiac muscle, remove too fast or in liver metabolism wait more slowly weak point.So design is synthetic new and positron myocardial perfusion imaging agent that performance is more excellent has actual demand.Pyridaben is one of inhibitor of MC-I, how pyridaben is carried out structural modification, be translated into the pyridazinone labelled precursor that can be used for fluoro-18 marks, and the pyridazinone myocardial perfusion imaging agent of preparation fluoro-18 marks is problem and main purposes that the present invention need to solve.
Summary of the invention
Primary and foremost purpose of the present invention is to provide that a class has good stability, biological property is good, the target to non-target ratio value high, the new pyridazinone compound of the high premium properties of heart uptake value, and this pyridazinone compound of radioactive fluorine-18 mark.
Another object of the present invention is to provide the preparation method of described compound.
A further object of the present invention provides the application of pyridazinone compound in the preparation myocardial perfusion imaging agent of described radioactive fluorine-18 mark.
In order to achieve the above object, the present invention is by the following technical solutions:
Provide a class to contain the pyridazinone compound of polyethyleneglycol modified (PEGization) benzyl triazolyl, its molecular formula is Fmppn, and its structure is as shown in the formula shown in (1):
Wherein, n gets the integer of 1-8, preferred n=1-3; F can be
19F or
18F.
The present invention also provides the preparation method of described pyridazinone compound.
F in described formula (1) is
19During F, its preparation method comprises the steps:
Synthesizing (1) integer of part mpp-nOTs(n=1-8):
(1.1) with 1,3-xylyl alcohol, the 2-tertiary butyl-4,5-dichloro pyridazinone (DCP), Cs
2CO
3With DMF in 10-80 ℃ the reaction 2-24h, obtain structure suc as formula the mIP-OH shown in (2);
(1.2) mIP-OH that step (1.1) is obtained carries out the sulfonic acid esterification, obtains structure suc as formula the mIP-OTs shown in (3), and then mIP-OTs is carried out azido reaction, obtains structure suc as formula the mIP-N shown in (4)
3
(1.3) with the integer of PEGn(n=1-8) in introduce first alkynyl, obtain structure suc as formula the P-nOH shown in (5), the wherein integer of n=1-8; And then with P-nOH and p-methyl benzene sulfonic chloride, DMAP, diisopropylethylamine and anhydrous methylene chloride 0-40 ℃ of reaction 1-5h, obtain structure suc as formula the P-nOTs shown in (6), the wherein integer of n=1-8;
(1.4) under nitrogen protection, the mIP-N that water, Salzburg vitriol, L-AA sodium, step (1.2) are obtained
3, the P-nOTs that obtains of step (1.3) and DMF stirred 1-4 days, obtains structure suc as formula the mpp-nOTs shown in (7), the wherein integer of n=1-8
(2) [
19F] integer of Fmppn(n=1-8) synthetic
The mpp-nOTs that step (1) is obtained and tetra-n-butyl Neutral ammonium fluoride (TBAF) add in the anhydrous acetonitrile, 70-100 ℃ of reaction 20-60min, obtain structure suc as formula shown in (8) [
19F] Fmppn, the wherein integer of n=1-8.
F in described formula (1) is
18During F, its preparation method comprises the steps:
With amino-polyether 4,7,13,16,21,24-six oxa-s-1,10-diazabicyclo [8,8,8] 26 carbon alkane (K
222), K
2CO
3,
18[F] F
-And the mpp-nOTs that obtains of above-mentioned steps (1) adds in the anhydrous acetonitrile, 70-100 ℃ of reaction 20-60min, obtain structure suc as formula shown in (9) [
18F] Fmppn, the wherein integer of n=1-8.
In the preferred scheme of the present invention, the integer of part mpp-nOTs(n=1-8) preferably prepare in accordance with the following methods:
A. under the ice bath, with the MnO of 120 ~ 130g
2With the furfural of 20 ~ 30g in 450 ~ 500mL concentrated hydrochloric acid in 20-100 ℃ of reaction 1-4h, cool overnight, suction filtration, recrystallization obtain mucochloric acid (DCA);
B. under the ice bath, mucochloric acid, 4 ~ 5gNa that 10 ~ 20g step a is obtained
2CO
3Add in 150 ~ 200mL water with 8 ~ 12g tertiary butyl hydrazine hydrochloride, stir 1-3h, suction filtration; Add 45 ~ 55mL benzene and 6 ~ 8g Glacial acetic acid in precipitation, 10-60 ℃ of reaction 3-6h obtains the 2-tertiary butyl-4,5-dichloro pyridazinone (DCP);
C. with 1 of 8 ~ 12mmol, the DCP that the step b of 3-xylyl alcohol, 8 ~ 12mmol obtains and the Cs of 8 ~ 12mmol
2CO
3, with 8 ~ 12mL dry DMF in 10-80 ℃ the reaction 2-24h, obtain mIP-OH;
D. 0-40 ℃ of reaction of the diisopropylethylamine of the p-methyl benzene sulfonic chloride of mIP-OH, the 6.0 ~ 6.5mmol that 5.0 ~ 5.5mmol step c is obtained, the DMAP of 6.0 ~ 6.5mmol, 6.0 ~ 6.5mmol and 45 ~ 55mL anhydrous methylene chloride 1-5h obtains mIP-OTs;
E. the mIP-OTs that 3.0 ~ 3.5mmol steps d is obtained, the NaN of 9.5 ~ 10.0mmol
3With 50 ~ 55mL alcohol reflux 1-8h, obtain mIP-N
3
F. with the integer of the PEGn(n=1-8 of 18 ~ 22mmol), 3-propargyl bromide 0-40 ℃ of reaction 0.5-2d in tetrahydrofuran (THF) of NaH, the 1.5 ~ 2.0g of 10 ~ 15mmol, obtain the integer of P-nOH(n=1-8);
G. the integer of the P-nOH(n=1-8 that 10 ~ 14mmol step f is obtained), the DMAP of 12 ~ 15mmol p-methyl benzene sulfonic chloride, 10 ~ 14mmol, diisopropylethylamine 0-40 ℃ of reaction 1-5h in methylene dichloride of 12 ~ 15mmol, obtain the integer of P-nOTs(n=1-8);
H. under nitrogen protection, the mIP-N that 4 ~ 5mL water, 1.5 ~ 2.0mmol Salzburg vitriol, 5.2 ~ 5.5mmol L-AA sodium, 3.5 ~ 3.8mmol step e are obtained
3, the P-nOTs(n=1-8 that obtains of 3.5 ~ 3.8mmol step g integer) in the DMF aqueous solution, stirred 1-4 days, obtain the integer of mpp-nOTs(n=1-8);
Its synthetic route is:
Chemosynthesis reagent used in the present invention all is commercial goods, and wide material sources obtain easily.
The present invention also provides the application of described pyridazinone compound in the preparation myocardial perfusion imaging agent.
The pyridazinone compound of PEGization benzyl triazolyl that contains provided by the invention is because its unique chemical structure has good stability, biological property is good, the target to non-target ratio value high, the high premium properties of heart uptake value.The pyridazinone compound that contains PEGization benzyl triazolyl of radioactive fluorine-18 mark especially of the present invention [
18F] integer of Fmppn(n=1-8), owing to contained radionuclide fluoro-18 in its structure, the above-mentioned many premium propertiess that have in conjunction with itself again are so that it can be used as the novel myocardial perfusion imaging agent of a class.
Compound of the present invention has the beneficial effect of following several respects than existing compound:
1.[
18F] integer of Fmppn(n=1-8) radioactive fluoro-18 in the molecule, can be used for positron emission computer tomography (PET).The PET imaging technique will obviously be better than at present single photon emission computed tomography (SPECT) commonly used clinically at resolving power, the aspect such as quantitative;
2.[
18F] integer of Fmppn(n=1-8) preparation simple, use cost is low, radiological chemistry productive rate and radiochemical purity are high.It is synthetic more to be conducive to automatization, and high yield is more conducive to commercial applications and the clinical expansion of radio-labeling product for short-lived nuclide.
3. new compound of the present invention has good vitro stability, and particularly the stability in the aqueous solution significantly improves.More be conducive to storage and the dispensing of tagged compound, be conducive to commercialization and the clinical expansion of product.
4. new compound of the present invention has the advantages that heart uptake is detained, liver is removed soon, the target to non-target ratio value is high.Compare with the positron myocardial perfusion imaging agent of having reported, its biological property is better, is conducive to obtain more clear reliable image, reaches better diagnosis effect.
Description of drawings
Fig. 1 be [
18F] radiochemical purity (A) of Fmpp2 and its room temperature in the aqueous solution place the HPLC analysis chart of (B) behind the 3h.
Fig. 2 be [
18F] integer of FPnOP(n=1-3) room temperature is placed the HPLC analysis chart behind the 1h in the aqueous solution.
Fig. 3 be [
18F] the total body opacification figure of Fmpp2 in normal Chinese miniature pig.
Fig. 4 be [
18F] the PET tomography figure of Fmpp2 in normal Chinese miniature pig.
Embodiment
The below describes the present invention in detail with concrete preparation example and embodiment.
One, preparation example:
Embodiment 1.
Synthesizing (1) part mpp-nOTs(n=1):
A. mucochloric acid (DCA) is synthetic
Under the ice bath, in the 1L four-hole bottle, add the 480mL concentrated hydrochloric acid.In the time of 0-10 ℃, add 80g MnO in batches
2, stir, slowly drip the 24g furfural.Behind the stirring at room 30min, slowly be warming up to 60 ℃.In the time of 60-80 ℃, add 42g MnO in batches
2, be warming up to 100 ℃.React become orange clear solution to liquid after, continue reaction 30min, cooling, suction filtration.Precipitation 40mL ether dissolution filters.Filtrate with 40mL water recrystallization, obtains the 31g mucochloric acid through revolving the steaming desolventizing, is the lightpink tabular crystal.Nuclear magnetic spectrogram: (
1HNMR, CDCl
3) δ: 6.085 (s, 1H, HO-C-H); (
13CNMR, CDCl
3) δ: 98.56,123.87,151.25,165.15.Infrared spectrum: (IR)/cm
-1: vOH:3407, vC=O:1770, vC=C:1638.
B.2-the tertiary butyl-4,5-dichloro pyridazinone (DCP) synthetic
Under the ice bath, the 15g mucochloric acid that step a is obtained is dissolved in the 150mL water, adds the 4.5g anhydrous Na
2CO
3, be stirred to the solution becomes clarification.Add 10g tertiary butyl hydrazine hydrochloride, stir 2.5h, suction filtration.Precipitation with cold water washing after, be transferred to the 100mL eggplant-shape bottle.Add 50mL benzene and 7g Glacial acetic acid, be heated to 35-45 ℃, reaction 4h.Add 20mL water, tell the benzene layer, use respectively 20mL 5%NaOH solution, 20mL 10%HCl solution and 20mL water washing, organic phase is through MgSO
4Drying is revolved to steam and is removed hold over night behind most of solvent.Separate out the 6.9g 2-tertiary butyl-4, the 5-dichloro pyridazinone is light yellow needle-like crystal.Nuclear magnetic spectrogram: (
1HNMR, CDCl
3) δ: 1.648 (s, 9H, N (CH
3)
3), 7.729 (s, 1H, N=C-H).Infrared spectrum: (IR)/cm
-1: vOH:3461, vC=O:1658.
C.mIP-OH's is synthetic
With 1.38g(10mmol) 1,3-benzhydrol, 2.58g(10mmol) step the b DCP, the 3.26g(10mmol that obtain) Cs
2CO
3Add in the 50mL eggplant-shape bottle 68 ℃ of oil bath reaction 12h with the 10mL dry DMF.Reaction solution is cooled to room temperature, with suction filtration after the dilution of 50mL ethyl acetate.Filtrate is transferred to the 250mL separating funnel, respectively with 50mL washing 5 times.Organic phase is through MgSO
4Drying is revolved behind the suction filtration and is steamed filtrate, and through 200-300 purpose silicagel column purifying, developping agent is sherwood oil: ethyl acetate=2:1, obtains mIP-OH.Nuclear magnetic spectrogram: (
1HNMR, CDCl
3) δ: 1.633 (s, 9H, N (CH
3)
3), 4.745 (s, 2H, CH
2OH), 5.320 (s, 2H, phenyl-O-CH
2), 7.295-7.431 (s, 4H, phenyl), 7.725 (s, 1H, N=C-H).Infrared spectrum: (IR)/cm
-1: vC=O:1635.
D.mIP-OTs's is synthetic
With 1.70g(5.3mmol) step the c mIP-OH, the 1.18g(6.2mmol that obtain) p-methyl benzene sulfonic chloride, 0.76g(6.2mmol) DMAP, 0.80g(6.2mmol) diisopropylethylamine and 50mL anhydrous methylene chloride add in the 100mL eggplant-shape bottle, stirs 2h.Revolve steam desolventize after, reaction solution 100mL acetic acid ethyl dissolution is transferred in the 250mL separating funnel, washes with 100mL 0.1M HCl and 100mL respectively.The organic phase anhydrous Na
2SO
4Drying is revolved behind the suction filtration and is steamed filtrate, and through 200-300 purpose silicagel column purifying, developping agent is sherwood oil: ethyl acetate=4:1, obtains mIP-OTs.Nuclear magnetic spectrogram: (
1HNMR, CDCl
3) δ: 1.636 (s, 9H, N (CH
3)
3), 2.450 (s, 3H, phenyl-CH
3), 5.068 (s, 2H, CH
2OS), 5.267 (s, 2H, O-CH
2-C=C-Cl), 7.274-7.7.818 (m, 8H, phenyl), 7.691 (s, 1H, N=C-H).Infrared spectrum: (IR)/cm
-1: vC=O:1651.
E.mIP-N
3Synthetic
With 1.54g(3.2mmol) the steps d mIP-OTs, the 0.63g(9.7mmol that obtain) NaN
3Add to reflux 2h in the 100mL flask with 50mL ethanol.After revolving the steaming desolventizing, add the 100mL methylene dichloride, suction filtration.Filtrate is used the 100mL water washing, through anhydrous Na
2SO
4Dry.Revolve behind the suction filtration and steam filtrate, through 200-300 purpose silicagel column purifying, developping agent is sherwood oil: ethyl acetate=2:1, obtains mIP-N
3Nuclear magnetic spectrogram: (
1HNMR, CDCl
3) δ: 1.562 (s, 9H, N (CH
3)
3), 4.315 (s, 2H, CH
2N
3), 5.257 (s, 2H, phenyl-O-CH
2), 7.250-7.396 (d, 4H, phenyl), 7.645 (s, 1H, N=C-H).Infrared spectrum: (IR)/cm
-1: vC=O:1634.
Synthesizing f.P-nOH(n=1)
Under 0 ℃ of nitrogen protection, 20mmol ethylene glycol is dissolved among the THF that heavily steams, slowly adds 0.31g(13mmol) NaH.After stirring 30min, slowly inject the toluene solution of the 3-propargyl bromide of 1.98g 80%, stir 2h.Stirring at room 20h is poured into water reaction solution, uses the 100mL dichloromethane extraction, and organic phase is through anhydrous Na
2SO
4Drying is spin-dried for, and obtains P-nOH(n=1).Infrared spectrum: (IR)/cm
-1: vO-H:3425; VC ≡ C:3287.
Synthesizing g.P-nOTs(n=1)
With 1.65g(12mmol) DMAP, 1.74g(13mmol) diisopropylethylamine adds in the 100mL there-necked flask, adds 20mL under the nitrogen protection and contain the P-nOH(n=1 that 12mmol step f obtains) and dichloromethane solution.Drip 30mL under the ice bath and contain 2.56g(13mmol) dichloromethane solution of Tosyl chloride, ice bath 50min, subsequently stirring at room 30min.Reactant is behind the 0.1M hydrochloric acid and frozen water washing of ice, through anhydrous Na
2SO
4Dry.Revolve behind the suction filtration and steam filtrate, through 200-300 purpose silicagel column purifying, obtain P-nOTs(n=1).Nuclear magnetic spectrogram: δ: 2.420 (t, 1H, C ≡ CH), 2.448 (s, 3H, CH
3-phenyl), 3.714-4.205 (m, 4H, OCH
2CH
2OS), 4.117 (d, C ≡ CCH
2), 7.343 (d, 2H, CH
3-phenyl), 7.804 (d, 2H, phenyl-SO
3).
Synthesizing h.mpp-nOTs(n=1)
Under nitrogen protection, 4mL water is added to 0.46g(1.8mmol) Salzburg vitriol and 1.46g(5.4mmol) in the L-AA sodium, be stirred to reaction solution and be brown color.Then add successively 1.5mL and contain 1.29g(3.7mmol) mIP-N that obtains of step e
3DMF solution and 1.5mL contain the P-nOTs(n=1 that the 3.7mmol step g obtains) DMF solution, under the sealed state stirring at room 1-2 days.Reaction solution is used the 100mL water washing after the dilution of 100mL methylene dichloride, organic phase is through anhydrous Na
2SO
4Dry.Revolve behind the suction filtration and steam filtrate, through 200-300 purpose silicagel column purifying, obtain mpp-nOTs(n=1).Nuclear magnetic spectrogram: (
1HNMR, CDCl
3) δ: 1.637 (s, 9H, N (CH
3)
3), 2.435 (s, 3H, phenyl-CH
3), 3.711-4.150 (m, 4H, (OCH
2CH
2), 4.651 (d, 2H, C ≡ CCH
2), 5.288 (s, 2H, CH
2OS), 5.571 (s, 2H, O-CH
2-C=C-Cl), 7.306-7.7.760 (m, 8H, phenyl), 7.573 (s, 1H, triazolyl), 7.717 (s, 1H, N=C-H).
(2) [
19F] Fmpp1 synthetic
The THF solution of 1mL 1mol/L tetra-n-butyl Neutral ammonium fluoride is added in the 25mL eggplant-shape bottle, and 110 ℃ of nitrogen dry up.Adding 1mL anhydrous acetonitrile is evaporated to dried, triplicate.The mpp-nOTs(n=1 that 250mg step (1) is obtained) is dissolved in the 3mL anhydrous acetonitrile, adds in the reaction flask backflow 40min.Reaction solution with the dissolving of 15mL methylene dichloride, and is transferred to the 100mL separating funnel after revolving the steaming desolventizing, use the 20mL water washing.Organic phase MgSO
4Drying is revolved behind the suction filtration and is steamed filtrate, and through 200-300 purpose silicagel column purifying, developping agent is sherwood oil: ethyl acetate=1:2.Obtain at last [
19F] Fmpp1.Nuclear magnetic spectrogram: (
1HNMR, CDCl
3) 1.640 (s, 9H, N (CH
3)
3), 3.787 (dt, 2H, OCH
2CH
2F), 4.562 (dt, 2H, CH
2F), 4.708 (s, 2H, OCH
2-triazolyl), 5.544 (s, 2H, triazolyl-CH
2-pyridyl), 5.561 (s, 2H, CH
2-O-C=C-Cl), 7.287-7.439 (m, 4H, phenyl), 7.541 (s, 1H, triazolyl), 7.718 (s, 1H, N=C-H); (
19FNMR, CDCl
3)-223.15.
(3) pyridazinone compound of fluoro-18 marks ([
18F] Fmpp1) synthetic
1.5mL is contained 6mg K
2CO
3With 11mg K
222. [
18F] F
-Solution adds in the 10mL reaction flask, and 120 ℃ of nitrogen dry up, and adding 0.5mL anhydrous acetonitrile is evaporated to dried, triplicate.The mpp-nOTs(n=1 that 2mg step (1) is obtained) is dissolved in the 1mL anhydrous acetonitrile, adds in the reaction flask, 90 ℃ of pins reactions 30 minutes.Reaction is cooled to room temperature after finishing, and injects the anti-phase semipreparative column of C-18 (10 * 250mm, Venusil MP-C18, Agela Technologies Inc.).Collecting retention time is the component of 19-21.5min, be [
18F] Fmpp1.The HPLC condition is: A is water mutually, and B is acetonitrile mutually; The drip washing gradient is: 0 ~ 5min:95%A, 5.01 ~ 8min:95%-60%A, 8.01-19min:60%-30%A, 19.01-40min:0%A; Flow velocity 5mL/min.
Identify by RP-HPLC, [
18F] retention time of Fmpp1 is 20.0min, radiochemical purity is greater than 98%.The stable reference compound [
19F] Fmpp1 retention time under the same conditions is 19.8min.
Embodiment 2.
Synthesizing (1) part mpp-nOTs(n=2):
A. mucochloric acid (DCA) is synthetic: with embodiment 1.
B.2-the tertiary butyl-4,5-dichloro pyridazinone (DCP) synthetic: with embodiment 1.
C.mIP-OH's is synthetic: with embodiment 1.
D.mIP-OTs's is synthetic: with embodiment 1.
E.mIP-N
3Synthetic: with embodiment 1.
Synthesizing f.P-nOH(n=2)
Under 0 ℃ of nitrogen protection, the 20mmol Diethylene Glycol is dissolved among the THF that heavily steams, slowly adds 0.31g(13mmol) NaH.After stirring 30min, slowly inject the toluene solution of the 3-propargyl bromide of 1.98g 80%, stir 2h.Stirring at room 20h is poured into water reaction solution, uses the 100mL dichloromethane extraction, and organic phase is through anhydrous Na
2SO
4Drying is spin-dried for, and obtains P-nOH(n=2).Nuclear magnetic spectrogram: (
1HNMR, CDCl
3) δ: 2.164 (s, 1H, O-H), 2.452 (t, 1H, C ≡ CH), 3.612-3.764 (m, 8H, (OCH
2CH
2) 2), 4.221 (d, 2H, C ≡ CCH
2).Infrared spectrum: (IR)/cm
-1: vO-H:3425; VC ≡ C:3287.
Synthesizing g.P-nOTs(n=2)
With 1.65g(12mmol) DMAP, 1.74g(13mmol) diisopropylethylamine adds in the 100mL there-necked flask, adds 20mL under the nitrogen protection and contain the P-nOH(n=2 that 12mmol step f obtains) and dichloromethane solution.Drip 30mL under the ice bath and contain 2.56g(13mmol) dichloromethane solution of Tosyl chloride, ice bath 50min, subsequently stirring at room 30min.Reactant is behind the 0.1M hydrochloric acid and frozen water washing of ice, through anhydrous Na
2SO
4Dry.Revolve behind the suction filtration and steam filtrate, through 200-300 purpose silicagel column purifying, obtain P-nOTs(n=2).Nuclear magnetic spectrogram: δ: 2.430 (t, 1H, C ≡ CH), 2.449 (s, 3H, CH
3-phenyl), 3.596-3.701 (m, 6H, OCH
2CH
2OCH
2CH
2OS), 4.158-4.182 (m, 4H, OCH
2CH
2OS, C ≡ CCH
2), 7.344 (d, 2H, CH
3-phenyl), 7.804 (d, 2H, phenyl-SO
3).Infrared spectrum: (IR)/cm
-1: vO-H:3425, vC ≡ C:3287.
Synthesizing h.mpp-nOTs(n=2)
Under nitrogen protection, 4mL water is added to 0.46g(1.8mmol) Salzburg vitriol and 1.46g(5.4mmol) in the L-AA sodium, be stirred to reaction solution and be brown color.Then add successively 1.5mL and contain 1.29g(3.7mmol) mIP-N that obtains of step e
3DMF solution and 1.5mL contain the P-nOTs(n=2 that the 3.7mmol step g obtains) DMF solution, under the sealed state stirring at room 1-2 days.Reaction solution is used the 100mL water washing after the dilution of 100mL methylene dichloride, organic phase is through anhydrous Na
2SO
4Dry.Revolve behind the suction filtration and steam filtrate, through 200-300 purpose silicagel column purifying, obtain mpp-nOTs(n=2).Nuclear magnetic spectrogram: (
1HNMR, CDCl
3) δ: 1.637 (s, 9H, N (CH
3)
3), 2.436 (s, 3H, phenyl-CH
3), 3.585-3.664 (m, 6H, (OCH
2CH
2)
2), 4.130 (d, 2H, C ≡ CCH
2), 5.271 (s, 2H, CH
2OS), 5.569 (s, 2H, O-CH
2-C=C-Cl), 7.310-7.7.768 (m, 8H, phenyl), 7.425 (s, 1H, triazolyl), 7.637 (s, 1H, N=C-H); Mass spectrum: C30H36ClN5O7S: calculated value: 645.2; Actual value: 646.8.
(2) [
19F] Fmpp2 synthetic
The THF solution of 1mL 1mol/L tetra-n-butyl Neutral ammonium fluoride is added in the 25mL eggplant-shape bottle, and 110 ℃ of nitrogen dry up.Adding 1mL anhydrous acetonitrile is evaporated to dried, triplicate.The mpp-nOTs(n=2 that 250mg step (1) is obtained) is dissolved in the 3mL anhydrous acetonitrile, adds in the reaction flask backflow 40min.Reaction solution with the dissolving of 15mL methylene dichloride, and is transferred to the 100mL separating funnel after revolving the steaming desolventizing, use the 20mL water washing.Organic phase MgSO
4Drying is revolved behind the suction filtration and is steamed filtrate, and through 200-300 purpose silicagel column purifying, developping agent is sherwood oil: ethyl acetate=1:2.Obtain at last [
19F] Fmpp2.[
19F] the Fmpp2 nuclear magnetic spectrogram: (
1HNMR, CDCl
3) 1.639 (s, 9H, N (CH
3)
3), 3.617-3.756 (m, 6H, OCH
2CH
2OCH
2CH
2F), 4.534 (dt, 2H, CH
2F), 4.689 (s, 2H, OCH
2-triazolyl), 5.280 (s, 2H, triazolyl-CH
2-pyridyl), 5.547 (s, 2H, CH
2-O-C=C-Cl), 7.274-7.431 (m, 4H, phenyl), 7.552 (s, 1H, triazoltl), 7.721 (s, 1H, N=C-H); Mass spectrum: C19H24ClFN2O4: calculated value: 493.2; Actual value: 494.6.
(3) pyridazinone compound of fluoro-18 marks ([
18F] Fmpp2) synthetic
1.5mL is contained 6mg K
2CO
3With 11mg K
222[
18F] F
-Solution adds in the 10mL reaction flask, and 120 ℃ of nitrogen dry up, and adding 0.5mL anhydrous acetonitrile is evaporated to dried, triplicate.The mpp-nOTs(n=2 that 2mg step (1) is obtained) is dissolved in the 1mL anhydrous acetonitrile, adds in the reaction flask, 90 ℃ of pins reactions 30 minutes.Reaction is cooled to room temperature after finishing, and injects the anti-phase semipreparative column of C-18 (10 * 250mm, Venusil MP-C18, Agela Technologies Inc.).Collecting retention time is the component of 19-21.5min, be [
18F] Fmpp2).The HPLC condition is: A is water mutually, and B is acetonitrile mutually; The drip washing gradient is: 0 ~ 5min:95%A, 5.01 ~ 8min:95%-60%A, 8.01-19min:60%-30%A, 19.01-40min:0%A; Flow velocity 5mL/min.
Identify by RP-HPLC, [
18F] retention time of Fmpp2 is 19.9min, radiochemical purity is greater than 98%.The stable reference compound [
19F] Fmpp2 retention time under the same conditions is 19.7min.
Embodiment 3.
Synthesizing (1) part mpp-nOTs(n=3):
A. mucochloric acid (DCA) is synthetic: with embodiment 1.
B.2-the tertiary butyl-4,5-dichloro pyridazinone (DCP) synthetic: with embodiment 1.
C.mIP-OH's is synthetic: with embodiment 1.
D.mIP-OTs's is synthetic: with embodiment 1.
E.mIP-N
3Synthetic: with embodiment 1.
Synthesizing f.P-nOH(n=3)
Under 0 ℃ of nitrogen protection, the 20mmol triethylene glycol is dissolved among the THF that heavily steams, slowly adds 0.31g(13mmol) NaH.After stirring 30min, slowly inject the toluene solution of the 3-propargyl bromide of 1.98g 80%, stir 2h.Stirring at room 20h is poured into water reaction solution, uses the 100mL dichloromethane extraction, and organic phase is through anhydrous Na
2SO
4Drying is spin-dried for, and obtains P-nOH(n=3).Nuclear magnetic spectrogram: (
1HNMR, CDCl
3) δ: 2.357 (s, 1H, O-H), 2.442 (t, 1H, C ≡ CH), 3.609-3.749 (m, 12H, (OCH
2CH
2)
3), 4.215 (d, 2H, C ≡ CCH
2).Infrared spectrum: (IR)/cm
-1: vO-H:3423; VC ≡ C:3287.
Synthesizing g.P-nOTs(n=3)
With 1.65g(12mmol) DMAP, 1.74g(13mmol) diisopropylethylamine adds in the 100mL there-necked flask, adds 20mL under the nitrogen protection and contain the P-nOH(n=3 that 12mmol step f obtains) and dichloromethane solution.Drip 30mL under the ice bath and contain 2.56g(13mmol) dichloromethane solution of Tosyl chloride, ice bath 50min, subsequently stirring at room 30min.Reactant is behind the 0.1M hydrochloric acid and frozen water washing of ice, through anhydrous Na
2SO
4Dry.Revolve behind the suction filtration and steam filtrate, through 200-300 purpose silicagel column purifying, obtain P-nOTs(n=3).Nuclear magnetic spectrogram: δ: 2.041 (s, 1H, O-H), 2.429 (t, 1H, C ≡ CH), 2.445 (s, 3H, CH
3-phenyl), 3.588-3.698 (m, 10H, (OCH
2CH
2)
2OCH
2CH
2OS), 4.106-4.190 (m, 4H, OCH
2CH
2OS, C ≡ CCH
2), 7.341 (d, 2H, CH
3-phenyl), 7.796 (d, 2H, phenyl-SO
3).Infrared spectrum: (IR)/cm
-1: vC ≡ C:3287.
Synthesizing h.mpp-nOTs(n=3)
Under nitrogen protection, 4mL water is added to 0.46g(1.8mmol) Salzburg vitriol and 1.46g(5.4mmol) in the L-AA sodium, be stirred to reaction solution and be brown color.Then add successively 1.5mL and contain 1.29g(3.7mmol) mIP-N that obtains of step e
3DMF solution and 1.5mL contain the Pn-OTs(n=3 that the 3.7mmol step g obtains) DMF solution, under the sealed state stirring at room 1-2 days.Reaction solution is used the 100mL water washing after the dilution of 100mL methylene dichloride, organic phase is through anhydrous Na
2SO
4Dry.Revolve behind the suction filtration and steam filtrate, through 200-300 purpose silicagel column purifying, obtain mpp-nOTs(n=3).Nuclear magnetic spectrogram: (
1HNMR, CDCl
3) δ: 1.640 (s, 9H, N (CH
3)
3), 2.439 (s, 3H, phenyl-CH
3), 3.558-3.695 (m, 10H, (OCH
2CH
2) 2), 4.131 (d, 2H, C ≡ CCH
2), 5.275 (s, 2H, CH
2OS), 5.559 (s, 2H, O-CH
2-C=C-Cl), 7.317-7.7.781 (m, 8H, phenyl), 7.609 (s, 1H, triazolyl), 7.720 (s, 1H, N=C-H).
(2) [
19F] Fmpp3 synthetic
The THF solution of 1mL 1mol/L tetra-n-butyl Neutral ammonium fluoride is added in the 25mL eggplant-shape bottle, and 110 ℃ of nitrogen dry up.Adding 1mL anhydrous acetonitrile is evaporated to dried, triplicate.The mpp-nOTs(n=3 that 250mg step (1) is obtained) is dissolved in the 3mL anhydrous acetonitrile, adds in the reaction flask backflow 40min.Reaction solution with the dissolving of 15mL methylene dichloride, and is transferred to the 100mL separating funnel after revolving the steaming desolventizing, use the 20mL water washing.Organic phase MgSO
4Drying is revolved behind the suction filtration and is steamed filtrate, and through 200-300 purpose silicagel column purifying, developping agent is sherwood oil: ethyl acetate=1:2.Obtain at last [
19F] Fmpp3).[
19F] the Fmpp3 nuclear magnetic spectrogram: (
1HNMR, CDCl
3) 1.561 (s, 9H, N (CH
3)
3), 3.550-3.690 (m, 10H, O (CH
2CH
2O)
2CH
2CH
2F), 4.459 (dt, 2H, CH
2F), 4.600 (s, 2H, OCH
2-triazolyl), 5.210 (s, 2H, triazolyl-CH
2-pyridyl), 5.472 (s, 2H, CH
2-O-C=C-Cl), 7.188-7.350 (m, 4H, phenyl), 7.498 (s, 1H, triazolyl), 7.666 (s, 1H, N=C-H); (
19FNMR, CDCl
3)-222.74.Mass spectrum: C19H24ClFN2O4: calculated value: 493.2; Actual value: 494.6.
(3) pyridazinone compound of fluoro-18 marks ([
18F] Fmpp3) synthetic
1.5mL is contained 6mg K
2CO
3With 11mg K
222[
18F] F
-Solution adds in the 10mL reaction flask, and 120 ℃ of nitrogen dry up, and adding 0.5mL anhydrous acetonitrile is evaporated to dried, triplicate.The mpp-nOTs(n=3 that 2mg step (1) is obtained) is dissolved in the 1mL anhydrous acetonitrile, adds in the reaction flask, 90 ℃ of pins reactions 30 minutes.Reaction is cooled to room temperature after finishing, and injects the anti-phase semipreparative column of C-18 (10 * 250mm, Venusil MP-C18, Agela Technologies Inc.).Collecting retention time is the component of 19-21.5min, be [
18F] Fmpp3.The HPLC condition is: A is water mutually, and B is acetonitrile mutually; The drip washing gradient is: 0 ~ 5min:95%A, 5.01 ~ 8min:95%-60%A, 8.01-19min:60%-30%A, 19.01-40min:0%A; Flow velocity 5mL/min.
Identify by RP-HPLC, [
18F] retention time of Fmpp3 is 19.6min, radiochemical purity is greater than 98%.The stable reference compound [
19F] Fmpp3 retention time under the same conditions is 19.3min.
Two, experimental example
With [
18F] Fmpp2 is example, the putting productive rate behind its decay correction is 45-65%, radiochemicsl purity〉99%.Experiment shows, [
18F] fundamental property of Fmpp2 measures and to be described below:
1.[
18F] the vitro stability experiment of Fmpp2
Radiochemical purity that above-mentioned preparation example 2 is made is greater than 99%
18The F tagged compound at room temperature places the aqueous solution to deposit different time.Then carry out the HPLC Analysis and Identification, method is the same.Relatively place the radiochemical purity behind the different time, analyze according to this stability of radio-labeled compound.The result shows: the present invention
18The F tagged compound can stable existence in the aqueous solution, place behind the 3h its outward appearance and radiochemical purity without considerable change (the HPLC analytical results is seen accompanying drawing 1).And known similar compound [
18F] integer of FPnOP(n=1-3) in the aqueous solution, place 1h after existing obviously assorted peak occur, the HPLC analytical results divides sees accompanying drawing 2(Tiantian Mou, et al.Bioorgan Med Chem, 2010,18:1312-1320; Tiantian Mou, et al.JNucl Med, 2012,53:472-478), visible the compounds of this invention has better stability.
2.[
18F] Fmpp2 bio distribution in the normal mouse body
Get 20 normal Kunming small white mouses, in the tail vein injection 0.1mL embodiment of the invention 2 preparation [
18F] Fmpp2 (about 0.185MBq).Sacrificed by decapitation after injection 2,15,30, behind the 60min.Take out the tissues such as the heart, liver, lung, kidney, muscle, bone, blood, weighing is also surveyed its radiocounting in gamma counter.[
18F] bio distribution of Fmpp2 in normal mouse see Table 1.
Table 1.[
18F] bio distribution (%ID/g ± SD, n=5) of Fmpp2 in Mice Body
Bio distribution result's demonstration in normal mouse, [
18F] Fmpp2 has very high initial picked-up and certain delay arranged in cardiac muscle.Behind the injection 2min, the heart uptake value is (44.19 ± 2.11) %ID/g, and behind the injection 60min, heart uptake still has (17.25 ± 0.26) %ID/g.Simultaneously, [
18F] liver of Fmpp2 remove very fast, 2-60min after the injection, the conscience ratio is about 4, can satisfy the video picture requirement.
3.[
18F] total body opacification of Fmpp2 in normal Chinese miniature pig
Get the Chinese miniature pig of the about 15kg of body weight, anaesthetize by intravenous injection ketamine (25mg/kg) and stable (1.1mg/kg).Then pig is prostrate on the PET/CT berth, the about 37MBq of 2mL [
18F] 5% ethanolic soln of Fmpp2 injects in the pig body by ductus venosus.PET/CT scanning is carried out respectively at injection rear 5min, 15min, 30min, 60min and 120min.Body scan comprises five continuous berths, and be 2min the sweep time of each berth.
The video picture result is referring to accompanying drawing 3.As can be seen from Fig. 3, different from the bio distribution of mouse, at the cardia of arrow indication, from injecting rear 5-120min higher picked-up is arranged all, illustrate [
18F] Fmpp2 has good picked-up and delay in the cardiac muscle of Chinese miniature pig.The removing of liver and other non-target organs is very obvious from injecting rear 15min simultaneously, and image 15-120min after injection has good signal to noise ratio, can satisfy clinical demand.
4.[
18F] the PET tomography of Fmpp2 in normal Chinese miniature pig
Get the Chinese miniature pig of the about 15kg of body weight, anaesthetize by intravenous injection ketamine (25mg/kg) and stable (1.1mg/kg).Then pig is prostrate on the PET/CT berth, the about 37MBq of 2mL [
18F] 5% ethanolic soln of Fmpp2 injects in the pig body by ductus venosus.PET/CT scans in the rear 70min of injection and carries out.
PET tomography result is referring to accompanying drawing 4.As can be seen from Figure 4, during 70min, myocardial contours is high-visible after the injection, in the image except gall-bladder, substantially without the interference of other non-target tissues.
With reported [
18F] integer of FPnOP(n=1-3) compare, [
18F] Fmpp2 has good vitro stability, is suitable for long-distance transport.Compare with the BMS747158-02 that enters clinical trial, [
18F] Fmpp2 has faster liver and removes, and can carry out in early days video picture, shortens patient's waiting time.With current at clinical widely used myocardial perfusion imaging agent
99mTc-MIBI compares, [
18F] Fmpp2 has significant advantage at aspects such as resolving power, target to non-target ratio values, and we think that this compounds is expected to develop into the novel myocardial perfusion imaging agent of a class accordingly.
Claims (8)
1. a class contains the pyridazinone compound of PEGization benzyl triazolyl, and its molecular formula is Fmppn, and its structure is as shown in the formula shown in (1):
Wherein, n gets the integer of 1-8; F is
19F or
18F.
2. pyridazinone compound claimed in claim 1, it is characterized in that: the F in the described formula (1) is
19F, its structural formula is:
3. pyridazinone compound claimed in claim 1, it is characterized in that: the F in the described formula (1) is
18F, its structural formula is:
4. pyridazinone compound claimed in claim 1, it is characterized in that: the n in the described formula (1) gets the integer of 1-3.
5. the preparation method of pyridazinone compound claimed in claim 1, in the described compound structure, F is
19F, this preparation method may further comprise the steps:
Synthesizing (1) integer of part mpp-nOTs(n=1-8):
(1.1) with 1,3-xylyl alcohol, the 2-tertiary butyl-4,5-dichloro pyridazinone (DCP), Cs
2CO
3With DMF in 10-80 ℃ the reaction 2-24h, obtain structure suc as formula the mIP-OH shown in (2);
(1.2) mIP-OH that step (1.1) is obtained carries out the sulfonic acid esterification, obtains structure suc as formula the mIP-OTs shown in (3), and then mIP-OTs is carried out azido reaction, obtains structure suc as formula the mIP-N shown in (4)
3
(1.3) be to introduce first alkynyl among the PEGn of integer of 1-8 with n, obtain structure suc as formula the P-nOH shown in (5), the wherein integer of n=1-8; And then with P-nOH and p-methyl benzene sulfonic chloride, DMAP, diisopropylethylamine and anhydrous methylene chloride 0-40 ℃ of reaction 1-5h, obtain structure suc as formula the P-nOTs shown in (6), the wherein integer of n=1-8;
(1.4) under nitrogen protection, the mIP-N that water, Salzburg vitriol, L-AA sodium, step (1.2) are obtained
3, the P-nOTs that obtains of step (1.3) and DMF stirred 1-4 days, obtains structure suc as formula the mpp-nOTs shown in (7), the wherein integer of n=1-8
(2) [
19F] integer of Fmppn(n=1-8) synthetic
The mpp-nOTs that step (1) is obtained and TBAF add in the anhydrous acetonitrile, 70-100 ℃ of reaction 20-60min, obtain structure suc as formula shown in (8) [
19F] Fmppn, the wherein integer of n=1-8
6. the preparation method of pyridazinone compound claimed in claim 1, in the described compound structure, F is
18F, this preparation method may further comprise the steps:
Synthesizing (1) integer of part mpp-nOTs(n=1-8):
(1.1) with 1,3-xylyl alcohol, the 2-tertiary butyl-4,5-dichloro pyridazinone (DCP), Cs
2CO
3With DMF in 10-80 ℃ the reaction 2-24h, obtain structure suc as formula the mIP-OH shown in (2);
(1.2) mIP-OH that step (1.1) is obtained carries out the sulfonic acid esterification, obtains structure suc as formula the mIP-OTs shown in (3), and then mIP-OTs is carried out azido reaction, obtains structure suc as formula the mIP-N shown in (4)
3
(1.3) be to introduce first alkynyl among the PEGn of integer of 1-8 with n, obtain structure suc as formula the P-nOH shown in (5), the wherein integer of n=1-8; And then will with P-nOH p-methyl benzene sulfonic chloride, DMAP, diisopropylethylamine and anhydrous methylene chloride 0-40 ℃ the reaction 1-5h, obtain structure suc as formula the P-nOTs shown in (6), the wherein integer of n=1-8;
(1.4) under nitrogen protection, the mIP-N that water, Salzburg vitriol, L-AA sodium, step (1.2) are obtained
3, the P-nOTs that obtains of step (1.3) and DMF stirred 1-4 days, obtains structure suc as formula the mpp-nOTs shown in (7), the wherein integer of n=1-8
(2) [
18F] integer of Fmppn(n=1-8) synthetic
With K
222, K
2CO
3,
18[F] F
-And the mpp-nOTs that obtains of step (1) adds in the anhydrous acetonitrile, 70-100 ℃ of reaction 20-60min, obtain structure suc as formula shown in (9) [
18F] Fmppn, the wherein integer of n=1-8
7. claim 5 or 6 described any one preparation methods is characterized in that step (1) prepares the integer of part mpp-nOTs(n=1-8 in accordance with the following methods):
A. under the ice bath, with the MnO of 120 ~ 130g
2With the furfural of 20 ~ 30g in 450 ~ 500mL concentrated hydrochloric acid in 20-100 ℃ of reaction 1-4h, cool overnight, suction filtration, recrystallization obtains mucochloric acid;
B. under the ice bath, mucochloric acid, 4 ~ 5gNa that 10 ~ 20g step a is obtained
2CO
3Add in 150 ~ 200mL water with 8 ~ 12g tertiary butyl hydrazine hydrochloride, stir 1-3h, suction filtration; Add 45 ~ 55mL benzene and 6 ~ 8g Glacial acetic acid in precipitation, 10-60 ℃ of reaction 3-6h obtains the 2-tertiary butyl-4, the 5-dichloro pyridazinone;
C. with 1 of 8 ~ 12mmol, the DCP that the step b of 3-xylyl alcohol, 8 ~ 12mmol obtains and the Cs of 8 ~ 12mmol
2CO
3, with 8 ~ 12mL dry DMF in 10-80 ℃ the reaction 2-24h, obtain mIP-OH;
D. 0-40 ℃ of reaction of the diisopropylethylamine of the p-methyl benzene sulfonic chloride of mIP-OH, the 6.0 ~ 6.5mmol that 5.0 ~ 5.5mmol step c is obtained, the DMAP of 6.0 ~ 6.5mmol, 6.0 ~ 6.5mmol and 45 ~ 55mL anhydrous methylene chloride 1-5h obtains mIP-OTs;
E. the mIP-OTs that 3.0 ~ 3.5mmol steps d is obtained, the NaN of 9.5 ~ 10.0mmol
3With 50 ~ 55mL alcohol reflux 1-8h, obtain mIP-N
3
F. be 3-propargyl bromide 0-40 ℃ of reaction 0.5-2d in tetrahydrofuran (THF) of NaH, 1.5 ~ 2.0g of PEGn, the 10 ~ 15mmol of the integer of 1-8 with the n of 18 ~ 22mmol, obtain P-nOH, wherein the integer of n=1-8;
G. the DMAP of the P-nOH that 10 ~ 14mmol step f is obtained, 12 ~ 15mmol p-methyl benzene sulfonic chloride, 10 ~ 14mmol, the diisopropylethylamine of 12 ~ 15mmol be 0-40 ℃ of reaction 1-5h in methylene dichloride, obtain P-nOTs, wherein the integer of n=1-8;
H. under nitrogen protection, the mIP-N that 4 ~ 5mL water, 1.5 ~ 2.0mmol Salzburg vitriol, 5.2 ~ 5.5mmol L-AA sodium, 3.5 ~ 3.8mmol step e are obtained
3, the P-nOTs that obtains of 3.5 ~ 3.8mmol step g stirred 1-4 days in the DMF aqueous solution, obtained mpp-nOTs, wherein the integer of n=1-8.
8. the application of pyridazinone compound claimed in claim 1 in the preparation myocardial perfusion imaging agent.
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|---|---|---|---|---|
| CN114478395A (en) * | 2022-04-08 | 2022-05-13 | 北京先通国际医药科技股份有限公司 | TCPB-OH single crystal |
| CN114478394A (en) * | 2022-04-08 | 2022-05-13 | 北京先通国际医药科技股份有限公司 | Preparation method of TCPB-OH single crystal and application of TCPB-OH single crystal |
| CN114456154A (en) * | 2022-04-12 | 2022-05-10 | 北京先通国际医药科技股份有限公司 | Impurity separated from compound 1 and application thereof |
| CN114835690A (en) * | 2022-07-04 | 2022-08-02 | 北京先通国际医药科技股份有限公司 | Preparation method and application of myocardial perfusion PET imaging agent |
| CN114835690B (en) * | 2022-07-04 | 2022-09-27 | 北京先通国际医药科技股份有限公司 | Preparation method of liquid composition containing compound I and application of liquid composition in myocardial perfusion PET imaging |
| WO2024008075A1 (en) * | 2022-07-04 | 2024-01-11 | 北京先通国际医药科技股份有限公司 | Preparation method for liquid composition containing compound i and use in myocardial perfusion pet imaging |
| CN115141183A (en) * | 2022-07-26 | 2022-10-04 | 北京先通国际医药科技股份有限公司 | Preparation method and application of myocardial perfusion developer precursor |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103113354B (en) | 2014-12-17 |
| CN103113354A (en) | 2013-05-22 |
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