CN101020698A - Benzothiazole aniline compound marked with Tc-99m and its prepn process and application - Google Patents
Benzothiazole aniline compound marked with Tc-99m and its prepn process and application Download PDFInfo
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Abstract
The present invention provides one kind of Tc-99m marked benzothiazole aniline compound in the structure as shown. The compound is obtained based on benzothiazole aniline and through coupling chelating ligand with carbon chain in certain length to the hydroxyl radical in the 6th place and Tc-99m marking the ligand. The compound has very high initial brain intake and certain brain elimination inside mouse body, and its Re ligand has very high sensitivity and selectivity in the selective combination with A-beta deposition in the brain of transgenic mouse and AD patient. The compound as the latent A-beta plaque developing agent may be used in clinical AD diagnosis. The present invention also provides the preparation process and application of the said compound.
Description
Technical field
The present invention relates to a kind of compound of Tc-99m mark, particularly a kind of benzothiazole amino benzenes compounds of Tc-99m mark, and preparation method thereof with this compound alzheimer's disease (Alzheimer ' s disease, AD) in the diagnosis as the application of beta amyloid patch developer.
Background technology
Alzheimer's disease (Alzheimer ' s disease is that a kind of what take place in the senium is the neurone degenerative disease of principal character with the dementia AD).Its main clinical manifestation is carrying out property cognition dysfunction and being losing one's memory, personality and behavior change, and judgement descends, human communication disorders, the self care ability forfeiture, final dead, the elderly's healthy and quality of life in serious harm.
This illness is in＞65 years old crowd according to estimates, and sickness rate is 8-10%; In＞75 years old crowd, sickness rate is 25%; And in＞95 years old crowd, sickness rate is up to 50%.The whole world has 2,500 ten thousand people to be subjected to influence (Mathis, the Wang﹠amp of AD approximately at present; Klunk, Cur.Pharm.Des., 2004,10:1469-1492.), in developed country, AD has become the fourth-largest killer after heart trouble, tumour, apoplexy.China have approximately at present 5,000,000 AD patients (Cheng Wufeng, geriatrics and health care, 2004,10:74-76.).
The diagnosis of AD at present also exists very big difficulty, and after death senile plaque and the neurofibrillary tangles in the postmortem brain is unique confirmation method (Mirra, Heyman, McKeel, Sumi, Crain, Brownlee, Vogel, Hughes, van Belle; Berg, Neurology, 1991,41:479-486.).Studying AT AD developer becomes current pressing for, and can and seek effective AD methods of treatment for the diagnosis of AD strong tool is provided.From present development, the development of the patch developer of positron type is relatively ripe, and the patch developer of the patch developer of single photon, particularly Tc-99m mark needs to be resolved hurrily.
It is Congo red that (Congo Red is the azo dyes of patch in a kind of AD brain tissue slice commonly used CR), and simultaneously, it also can dye to neurofibrillary tangles.(Bennhold, Munchen Med.Wochnschr's nineteen twenty-two Bennhold 1922 69:1537-1538.) just dye to the A beta plaque with CR, people (Puchtler, Sweat ﹠amp such as Puchtler in 1962; Levine, J.Histochem.Cytochem., 1962,10:355-364.) further developed this method.People (Han, Cho﹠amp such as Han in 1996; Lansbury, J.Am.Chem.Soc., 1996,118:4506-4507.) attempt first analogue and the isonitrile part of CR have been carried out the Tc-99m mark that is mixed, but this compounds is difficult to pass hemato encephalic barrier (BBB).1999, people such as Zhen (Zhen, Han, Anguiano, Lemere, Cho﹠amp; Lansbury, J.Med.Chem., 1999,42:2805-2815.) by monoamine monoamide (MAMA) bifunctional linking reagent CR has been carried out the Tc-99m mark, though this compound coordination center is neutral, fat-soluble too low, lipid P has only 0.12, and molecular weight surpasses 1000, faces the problem that can't pass BBB equally.
For Congo red class developer, subject matter still is can't or to be difficult to pass complete BBB at present.In addition the CR compounds in vivo the meta-bolites benzidine have carcinogenic activity, though the amount that radiological imaging agent finally is used for human body is seldom, this also is a unfavorable factor of such developer.Chrysamine-G class developer equally also exists the problem that is difficult to pass normal BBB.
People such as Zhang (Zhuang, Kung, Hou ﹠amp; Kung, J.Label.Compd.Radiopharm., 2005,48:S251.) employing coupled toluylene of PEG and Tc-99m coordination core, the compound of one of them has affinity external with Tg2576 transgenic mice brain section, and injection back 2min brain capture is at 1.79 ± 0.20%ID/g organ.People such as Zhuang (Zhuang, Kung, Hou, Ploessl ﹠amp; Kung, Nucl.Med.Biol., 2005,32:171-184.) report carries out the Tc-99m mark with biphenyl compound.
From present A beta plaque developer development, can't or be difficult to pass the main problem that hemato encephalic barrier is the development of restriction Tc-99m developer.Because part itself Congo red and chrysamine-G class just is difficult to pass BBB, thus be not suitable for the Tc-99m mark, based on the small molecules of thioflavin, as benzothiazole amino benzenes, toluylene etc., molecular volume is little, fat-soluble height, the space of modification is big, is more suitable for the mark in Tc-99m.Benzothiazole amino benzenes compounds is that research at present is more, an affinity compounds preferably, and comparatively successful example is the PIB of C-11 mark at present.But use the benzothiazole amino benzenes compounds developer of Tc-99m mark few at present, the result of existing minority bibliographical information is unsatisfactory, and the title complex brain capture is very low or the A beta plaque do not had affinity (Tzanopoulou, Patsis, Sagnou, Pirmettis, Papadopoulos﹠amp; Pelecanou, Technetium, Rhenium and Other Metals in Chemistry and Nuclear Medicine, 2006,7:103-104; Vanderghinste, Eeckhoudt﹠amp; Cleynhens, Technetium, Rhenium and Other Metals inChemistry and Nuclear Medicine, 2002,6:463-465.).
Summary of the invention
Under above-mentioned background, the object of the present invention is to provide a kind of have higher brain capture, sensitivity and the benzothiazole amino benzenes compounds of Tc-99m mark optionally, for the clinical diagnosis of AD provides more effective developer.
Technical scheme of the present invention is as follows:
The invention provides a kind of benzothiazole amino benzenes compounds of Tc-99m mark, have following structural formula:
Wherein, n gets 1～5, R
1And R
2Be H or CH
3, R
3For
Or
Described R
3Be preferably (I) or (II).
The present invention also provides 3 kinds of methods that prepare the benzothiazole amino benzenes compounds of above-mentioned Tc-99m mark.
Method 1 may further comprise the steps:
1) will be according to prior art synthetic structural formula
Compound 1 and (CH
2)
nBr
2Carry out condensation reaction, obtain structural formula and be
Compound 2; Wherein, n gets 1～5;
2) compound 2 and the compound MAMA-MBz that earlier step 1) is made carries out linked reaction, obtains structural formula and is
Compound 3, the nitro with compound 3 reduces with tin protochloride then, obtains structural formula to be
Compound 4, the protecting group of again compound 4 being taken off sulfydryl obtains structural formula and is
Compound 5;
3) in new system
99mAdding step 2 among the Tc-GH) ethanolic soln of the compound that finally makes is regulated pH=5.5, adds 40%
99mThe Tc-GH volume of ethanol, reaction mixture is at 100 ℃ of heating 30min, and dichloromethane extraction is used with the saturated sodium bicarbonate solution neutralization in the cooling back.
The step 2 of aforesaid method 1) can be with described compound 4 further with methyl iodide with amino methylization, obtain structural formula and be
Or
Compound 4 ', and then with the protecting group that compound 4 ' takes off sulfydryl, obtain structural formula and be
Or
Compound 5 '.
Method 2 may further comprise the steps:
1) after 1 method obtains compound 4 according to the method described above,, obtains structural formula and be further with the amide group borane reduction of compound 4
Compound 7; And then, obtain structural formula and be the protecting group that compound 7 is taken off sulfydryl
Compound 8;
2) according to the final compound for preparing of step 3) mark present method step 1) of method 1.
Aforesaid method 2 described steps 2) can also be with amide group borane reduction, obtain structural formula and be according to the compound 4 ' of the method for method 1 preparation
Or
Compound 7 '; And then, obtain structural formula and be the protecting group that compound 7 ' is taken off sulfydryl
Or
Compound 8 '.
Method 3 may further comprise the steps:
1) will with structural formula be according to the compound 2 of method 1 preparation
Compound 10 condensation under alkaline condition, obtain structural formula and be
Compound 11; Then compound 11 usefulness tin protochlorides being reduced into structural formula is
Compound 12; Wherein, described compound 10 is to use 2-amino
Picoline and ethyl bromoacetate condensation make;
2) with the acetonitrile solution of compound 12 with [
99mTc (CO)
3(H
2O)
3]
+Solution mix 80～90 ℃ of heating in back 30min, after the cooling, use dichloromethane extraction.
The step 2 of aforesaid method 3) can also be with described compound 12 further with methyl iodide with amino methylization, obtain structural formula and be
Or
Compound 12 '.
The present invention also provides the application of a kind of benzothiazole amino benzenes compounds of above-mentioned Tc-99m mark as beta amyloid patch developer.
The benzothiazole amino benzenes compounds of above-mentioned Tc-99m mark is the application at the diagnostic field of alzheimer's disease as the application of beta amyloid patch developer.
Compound-base of the present invention adopts the carbochain of certain-length to carry out coupled chelating ligand in the skeleton of benzothiazole aniline by 6 hydroxyls, and the part that obtains obtains above-claimed cpd through the mark of Tc-99m.Above-claimed cpd has very high initial brain capture in the mouse body and certain brain is removed.A β in the title complex of the corresponding Re of above-claimed cpd and transgenic mice and the patient's AD brain deposits optionally and combines, and has very high sensitivity and selectivity.Above-claimed cpd is potential A beta plaque developer, may be used for the clinical diagnosis of AD.
Using method:
But compound of the present invention is introduced tissue or patient with detection limit, and compound combines with amyloid deposition after adequate time, the tagged compound in the AT employing SPECT technology for detection patient.The result of video picture can position the amyloid deposition in the brain and be quantitative, to diagnose or to follow the tracks of the development of patient's alzheimer's disease.
Effect experiment and data
1. bio distribution experiment in the mouse body
The compound of the embodiment of the invention 1 of 0.1ml is injected into female ICR mouse (in 18～22g) bodies from the tail vein.Mouse different disconnected neck of time point after injection is put to death.Internal organs are cut and are measured weight in wet base, and the radioactivity in the internal organs is measured through automatic gamma counter (Wizard 1470).Radioactivity percent dose in each internal organs is calculated by the injected dose of more modest dilution, and data are expressed as radioactivity percent dose in every gram internal organs (%ID/g organ).The results are shown in Table 1.
The mouse brain picked-up of the compound of table 1 embodiment of the invention 1 and existing other compounds contrasts
| Radioactivity percent dose in every gram internal organs (%ID/g organ) | ||||
| The compound of the embodiment of the invention 1 | 99mTc-5-BTA-BAT | 99mTc-2′-BTA-BAT | 6-Me-BTA- 99mTc(CO) 3 | |
| 2min | 1.34±0.16 | 0.62 | 0.25 | N/A |
| 60min | 0.65±0.10 | 0.27 | 0.04 | N/A |
| Patch is in conjunction with activity | + | N/A | N/A | - |
As can be seen from the table, the initial brain capture of The compounds of this invention is very high, and injection back 2min reaches 0.62%ID/organ, and this numerical value is a very high numerical value for the neural developer of the mesencephalic centre of Tc-99m mark.At present unique mesencephalic centre neural system developer that successfully is used for clinical Tc-99m mark [
99mTc] the initial brain capture of mouse of TRODAT-1 is 0.43%ID/organ (2min).The brain capture of compound behind 60min after the injection reduced to half of 2min, has certain brain removing speed.Compound is mainly by the metabolism of liver system.
2. the fluorescent dye of transgenic mice brain section is observed
Fluorescent dye: the solution of preparing the corresponding Re compound of embodiment 1 and 3 prepared compounds respectively, the brain section of 12 male transgenic mices of monthly age of 5 μ m is taken off paraffin through the dimethylbenzene of 3 * 20min successively, then successively through 100% the ethanol of 2 * 5min, 95% the ethanol of 2 * 5min, 70% the washing with alcohol of 80% the ethanol of 5min and 5min, behind the flowing water flushing 10min, among the PBS (pH=7.6) as for 10mM.The brain section of APP transgenic mice is dipped in 10min in the solution of ThS (0.0125%, 40% ethanolic soln) and two compounds of the present invention respectively; Section is adopted fluorescence microscope through 50% washing with alcohol, fast after the differentiation.The results are shown in accompanying drawing 1A, B, C.
The compare compound of the visible embodiment of the invention 1 of Figure 1B and Figure 1A can equally with ThS selectively combine the A beta plaque, and bonded patch place sends tangible fluorescence, and is clear and legible; Almost do not combine with its hetero-organization of background, target/non-target contrast obviously.
The compare compound of the visible embodiment of the invention 3 of Fig. 1 C and Figure 1A can equally with ThS selectively combine the A beta plaque, and bonded patch place sends tangible fluorescence, and is clear and legible; Almost do not combine with its hetero-organization of background, target/non-target contrast obviously.
So as can be seen, compound of the present invention selectively combines with the A beta plaque from the tissue section strain picture, and higher sensitivity is arranged.
3.AD human brain section's fluorescent dye is observed
Fluorescent dye: the solution of preparing the corresponding Re compound of the prepared compound of embodiment 1 respectively, the section of the AD human brain of 5 μ m is taken off paraffin through the dimethylbenzene of 3 * 20min successively, then successively through 100% the ethanol of 2 * 5min, 95% the ethanol of 2 * 5min, 70% the washing with alcohol of 80% the ethanol of 5min and 5min, behind the flowing water flushing 10min, among the PBS (pH=7.6) as for 10mM.The section of AD human brain is dipped in 10min in the solution of compound of the present invention; Section is adopted fluorescence microscope through 50% washing with alcohol, fast after the differentiation.The results are shown in accompanying drawing 2.
The compound of the embodiment of the invention 1 selectively combines with A beta plaque in the human brain as can be seen from accompanying drawing 2, and all has high-intensity combination with different big or small patches, has very high sensitivity.
Compound among above-mentioned experimental observation explanation the present invention has very high brain capture, and compound has very high sensitivity and selectivity simultaneously, has potential in clinical application.
Description of drawings
Fig. 1 .A is the pallium district A beta plaque of standard substance ThS fluorescent mark transgenic mice.
Fig. 1 .B is the A beta plaque of selectivity fluorescent dye transgenic mice of corresponding rhenium compound of the compound of the embodiment of the invention 1.
Fig. 1 .C is the A beta plaque of corresponding rhenium compound selectivity fluorescent dye transgenic mice of the compound of the embodiment of the invention 3.
Fig. 2. be the A beta plaque of corresponding rhenium compound selectivity fluorescent dye AD human brain of the compound of the embodiment of the invention 1.
Embodiment
Following examples are used for embodying the embodiment of The compounds of this invention and preparation method thereof, but embodiments of the present invention are not limited to the following example.
Used chemical reagent is all available from chemical reagent company among the embodiment.
Embodiment 1
Work as R
1And R
2Be H, R
3Be I, n got 5 o'clock, and structural formula of compound of the present invention is:
This compound prepares according to following method:
1) according to reference C.A.Mathis, Y.Wang, D.P.Holt et al.J.Med.Chem.2003, the method synthetic compound of 46:2740-2754
The v concrete grammar is as follows:
A) 25g p-nitrobenzoic acid (0.15mol) is added in the 40ml sulfur oxychloride the about 25h of mixture heating up backflow.Separate out a large amount of faint yellow needle-like crystals after the cooling, be spin-dried for solvent, obtain the 27.49g paranitrobenzoyl chloride, productive rate is about 98%, and infrared spectrum and standard spectrogram are in full accord, are not further purified, and are directly used in next step reaction.IR：3109，1760，1605，1528，1349，1319，1195，1173，1113，1011，889，869，838，706，691，634 cm
-1。
B) 18.3g P-nethoxyaniline (0.15mmol) is dissolved in the 100ml exsiccant pyridine, adds the 150ml pyridine solution of 27g paranitrobenzoyl chloride (0.15mmol), N
2Reflux under the gas shiled has precipitation to separate out behind the 3h.Stop heating, reaction solution is poured in the 500ml water, suction filtration, filter cake be water, 5% sodium hydrogen carbonate solution, water washing successively.Natural air drying obtains structural formula
The yellow solid 36.04g of compound, productive rate is 89%.IR：3297，1645，1599，1532，1515，1348，1323，1249，1105，1028，829，705 cm
-1.
1H-NMR(500 MHz，DMSO-d
6)：δ8.36(d，J＝8.6Hz，2H)，8.16(d，J＝8.4Hz，2H)，7.67(d，J＝8.5Hz，2H)，6.95(d，J＝8.8Hz，2H)，3.75(s，3H).EI-MS：272.31；calcd：272.08。
C) with the 20g compound
(73.5mmol) be dissolved in the 80ml chlorobenzene with 17.8g Lawesson reagent (44mmol).Mixture heats in 130-140 ℃ of oil bath, and the gained brown-red solution continues reflux 4-5h, is cooled to room temperature, and suction filtration obtains in a large number
Orange red solid 17.7g, productive rate is 83%.Repeat this test more products.IR：3164，1608，1593，1519，1508，1347，1253cm
-1.
1H-NMR(500 MHz，DMSO-d
6)：δ8.29(d，J＝8.8Hz，2H)，7.98(d，J＝8.8Hz，2H)，7.77(d，J＝7.0Hz，2H)，7.01(d，J＝6.4Hz，2H)，3.79(s，3H).EI-MS：288.24；calcd：288.06。
D) 2ml ethanol is added the 13.6g compound
47.2mmol) in, add 30% the sodium hydroxide solution (8 times of equivalents) of 50ml then, in this henna solution, add the dilution of 100ml water again.Divide 30 minor ticks to join in one minute in 80-90 ℃ the 200ml potassium ferricyanide solution (62g, 4 times of equivalents) mixed solution of this 150ml.Reaction system is kept 80-90 ℃ of about 30min.Separate out a large amount of precipitations after the cooling, filter, wash with massive laundering, natural air drying obtains thick product 12.7g.Adopt normal hexane-ethyl acetate (6: 1) as eluent, silica gel column chromatography separates, and the product solvability is relatively poor, is combined in recrystallization in the tetrahydrofuran (THF), obtains
Faint yellow needle-like crystal, productive rate is 32%.Repeat this test more products.IR：1594，1552，1517，1476，1460，1436，1343，1315，1266，1220，1066，1030，968，849cm
-1.
1H-NMR(500 MHz，DMSO-d
6)：δ8.39(d，J＝8.2Hz，2H)，8.30(d，J＝8.4Hz，2H)，8.03(d，J＝8.9Hz，1H)，7.79(s，1H)，7.20(d，J＝8.1Hz，1H)，3.88(s，3H).EI-MS：286.06；calcd：286.04.Anal.Calcd for C
14H
10N
2O
3S：C，58.73；H，3.52，N，9.78；Found：C，58.20；H，3.77，N，9.80。
E) with the 4.6g compound
(16mmol) add in the 150ml exsiccant methylene dichloride, under nitrogen protection, be cooled to-70 ℃, dropwise drip the dichloromethane solution (1M) of the boron tribromide of 40ml in the mixture, last 1h.Slowly rise to room temperature reaction and spend the night behind-70 ℃ of lasting down stirring 1h, the hydrochloric acid soln cancellation reaction with 1M adds the saturated sodium bicarbonate solution neutralization.Mixed solution adds the 40ml methyl-sulphoxide with the ethyl acetate extraction of 6 * 50ml during extraction, merge organic phase, and anhydrous magnesium sulfate drying spends the night.When being concentrated into solvent and only remaining methyl-sulphoxide, add 80ml water, separate out a large amount of precipitations, suction filtration, drying obtains 4.1g
The orange solid, productive rate is 94%.IR：3447，1592，1519，1459，1342，1281，1238，1225，854cm
-1.
1H-NMR(500 MHz，DMSO-d
6)：δ8.38(d，J＝8.8Hz，2H)，8.27(d，J＝8.8Hz，2H)，7.95(d，J＝8.8Hz，1H)，7.49(d，J＝2.4Hz 1H)，7.07(dd，J
1＝8.8Hz，J
2＝2.4Hz，1H)，2.55(s，6H).EI-MS：272.27；calcd：272.03。
2) compound with the preparation of 2.0g step 1) is dissolved in the 10ml exsiccant acetonitrile, adds 3.21g pentamethylene bromide and Anhydrous potassium carbonate, and reaction mixture is 80～90 ℃ of reflux.Be spin-dried for acetonitrile, mixture adds entry, uses dichloromethane extraction, merges organic phase, anhydrous magnesium sulfate drying.Add the development of a large amount of normal hexanes when being concentrated into a small amount of solvent, separate out a large amount of glassy yellow solids, obtain the 2.47g structural formula and be
Glassy yellow solid (IR:2942,1594,1553,1519,1445,1344,1315,1268,1218, the 848cm of compound
-1.
1H-NMR (500 MHz, CDCl
3): δ 8.37 (d, J=8.8Hz, 2H), 8.25 (d, J=8.7Hz, 2H), 8.03 (d, J=8.9Hz, 1H), 7.40 (d, J=2.4Hz, 1H), 7.17 (dd, J
1=9.0 Hz, J
2=2.4Hz, 1H), 4.10 (t, J=6.3Hz, 2H), 3.49 (t, J=6.7Hz, 2H), 2.00 (p, J=7.3Hz, 2H), 1.90 (p, J=6.3Hz, 2H), 1.71 (m, 2H)).
3) with 840mg step 2) compound and the 1.3g compound MAMA-MBz of preparation be dissolved in the 8ml exsiccant acetonitrile, adds DIEA.80 ℃ of reacting by heating.Revolve to steam and remove solvent, resistates adds entry, uses dichloromethane extraction.Merge organic phase, concentrated filtrate.The employing silica gel column chromatography separates, and obtains the 956mg structural formula and is
Yellow solid (IR:3353,2934,2826,1679,1609,1594,1553,1516,1454,1344,1316,1302,1252,1219,1176,1107,1029,847,751, the 687cm of compound
-1.
1H-NMR (500 MHz, CDCl
3): δ 8.36 (d, J=8.7Hz, 2H), 8.22 (d, J=8.7Hz, 2H), 8.00 (d, J=9.0Hz, 1H), 7.83 (s, 1H), 7.38 (d, J=2.0Hz, 1H), 7.22 (d, J=8.3Hz, 4H), 7.15 (dd, J
1=9.0Hz, J
2=2.2Hz, 1H), 6.84 (t, J=8.4Hz, 4H), 4.05 (t, J=6.2Hz, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 3.67 (s, 4H), 3.45 (q, J=6.1Hz, 2H), 3.08 (s, 2H), 2.68 (m, 2H), 2.57 (t, J=6.4Hz, 2H), 2.54 (m, 4H), 1.85 (m, 2H), 1.52 (m, 4H)); With the 965mg compound
Join in the mixing solutions of 40ml ethanol and ethyl acetate, add the 1.67g tin protochloride, backflow 8h stops heating, revolves to steam and removes organic solvent, and resistates merges organic phase with ethyl acetate and sodium hydroxide solution extraction.Concentrate, adopt silica gel column chromatography to separate, collection obtains the 650mg structural formula and is
Faint yellow oily compound (IR:3447,3342,2933,1731,1665,1606,1511,1489,1455,1302,1284,1248,1176,1033,831.
1H-NMR (500 MHz, DMSO-d
6): δ 7.75 (d, J=8.6Hz, 1H), 7.68 (d, J=7.5Hz, 2H), 7.54 (s, 1H), 7.18 (t, J=8.5Hz, 4H), 7.01 (d, J=7.5Hz, 1H), 6.82 (t, J=7.5Hz, 4H), 6.65 (d, 2H), 3.99 (t, 2H), 3.69 (s, 3H), 3.68 (s, 3H), 3.65 (s, 2H), 3.63 (s, 2H), 3.25 (t, 2H), 2.96 (s, 2H), 2.64 (m, 2H), 2.45 (m, 6H), 1.71 (m, 2H), 1.40 (m, 4H)); With the 95.7mg compound
Be cooled to 0 ℃, add the 80mg methyl-phenoxide successively, 0.4ml methanesulfonic and 1ml trifluoroacetic acid, reaction mixture stirs 1h behind the stirring 20min down at 0 ℃ under room temperature.Revolve to steam and remove most of solvent, add frozen water in the resistates, use extracted with diethyl ether three times.Water with the extraction of methylene chloride-methanol mixed solution, merges organic phase with in the saturated sodium bicarbonate solution and back, and anhydrous sodium sulfate drying spends the night, and suction filtration concentrates and obtains the 47.2mg structural formula and be
The faint yellow oily thing of compound.
4) with the 0.5ml new system
99mThe ethanolic soln of the compound that adding 0.1ml step 3) finally prepares among the Tc-GH is regulated pH=5.5, adds the ethanol of 200 μ L.Reaction mixture is at 100 ℃ of heating 30min, and the cooling back makes compound of the present invention with the saturated sodium bicarbonate solution neutralization with the 1ml dichloromethane extraction, and structural formula is:
Embodiment 2
Work as R
1And R
2Be H, R
3Be II, n got 5 o'clock, and structural formula of compound of the present invention is:
This compound prepares according to following method:
1) with structural formula among the 600mg embodiment 1 is
Compound be dissolved in 20ml exsiccant tetrahydrofuran solution, drip the tetrahydrofuran solution 3ml of borine, reflux is spent the night, and adds the unreacted borine of water destruct behind the cool to room temperature, remove and desolvate, the hydrochloric acid soln that adds 10ml 10%, reflux 1 hour, cool to room temperature, be neutralized to pH value 10.0 with ammoniacal liquor, with methylene chloride (9: 1) extraction, organic phase drying, concentrated employing preparation chromatographic sheet separation (methylene chloride (9: 1)) obtains the 80mg structural formula and is
Compound;
2) adopt the deprotection identical and the method for mark, with compound with the foregoing description 1
Be prepared into compound
Embodiment 3
Work as R
1And R
2Be H, R
3Be III, n got 5 o'clock, and structural formula of compound of the present invention is:
This compound prepares according to following method:
1) method according to embodiment 1 prepares compound
2) 18.11mg 2-aminomethyl pyridine is dissolved in the 100ml exsiccant tetrahydrofuran (THF), ice bath to 0 ℃ is added dropwise to the 100ml anhydrous tetrahydrofuran solution of ethyl bromoacetate.Stirring at room 18h behind the reaction 30min under 0 ℃.The filtering white precipitate revolves to steam and removes organic solvent, remaining weak yellow liquid, and underpressure distillation obtains the 9.0g compound
Weak yellow liquid (IR:3332,2981,1739,1591,1570,1474,1434,1367,1199,1149,1097,1048,1028,995,759cm
-1.
1H-NMR (500 MHz, CDCl
3): δ 8.51 (d, J=2.3Hz, 1H), 7.59 (t, J=7.5Hz, 1H), 7.27 (s, 1H), 7.11 (t, J=5.9Hz, 1H), 4.14 (q, J=7.1Hz, 2H), 3.89 (s, 2H), 3.42 (s, 2H), 2.42 (s, 1H), 1.22 (t, J=7.1Hz, 3H)).
3) the 500mg step 1) is prepared
With 840mg step 2) preparation
Be dissolved in the 15ml exsiccant acetonitrile, add 400mg DIEA.Reaction mixture revolves to steam and removes solvent at 80 ℃ of heated and stirred 30h, and resistates adds in the 60ml water, uses dichloromethane extraction.Merge organic phase, anhydrous magnesium sulfate drying spends the night, and filters concentrated filtrate.The employing silica gel column chromatography separates, and obtains the 368mg compound
Yellow solid (IR:2939,2863,1737,1594,1553,15119,1475,1454,1435,1314,1267,1217,1185,849,751,687cm
-1); 300mg gained compound is joined in the mixing solutions of 10ml ethanol and ethyl acetate, add tin protochloride, backflow 8h stops heating, revolves to steam and removes organic solvent, and resistates merges organic phase with ethyl acetate and sodium hydroxide solution extraction.Concentrate, adopt silica gel column chromatography to separate, collection obtains the 650mg structural formula and is
Faint yellow oily compound.
4) acetonitrile solution and the 0.1ml[of the compound that the 0.1ml step 3) is made
99mTc (CO)
3(H
2O)
3]
+Solution mix 80～90 ℃ of heating in back 30min, after the cooling, use the 1ml dichloromethane extraction, make compound of the present invention, structural formula is
Embodiment 4.
Work as R
1And R
2Be H, R
3Be III, n got 3 o'clock, and structural formula of compound of the present invention is:
This compound prepares according to following method:
1) with the compound of 2.0g according to the method preparation of embodiment 1
Be dissolved in the 10ml exsiccant acetonitrile, add 3.0g 1,3-dibromo pentane and 1.52g Anhydrous potassium carbonate, reaction mixture is 80～90 ℃ of reflux, and henna initial reactant becomes faint yellow at last.Be spin-dried for acetonitrile, mixture adds 60ml water, uses dichloromethane extraction, merges organic phase, and anhydrous magnesium sulfate drying spends the night.Concentrate a large amount of normal hexanes of adding, separate out a large amount of glassy yellow solids, suction filtration obtains yellow solid.The employing petroleum ether-ethyl acetate is a developping agent, and after silica gel column chromatography separated, recrystallization obtained the 1.75g compound in the tetrahydrofuran (THF)
Glassy yellow solid (IR:1594,1553,1519,1477,1454,1343,1313,1266,1214,1107,848cm
-1.
1H-NMR (500 MHz, CDCl
3): δ 8.36 (d, J=8.8Hz, 2H), 8.24 (d, J=8.7Hz, 2H), 8.03 (d, J=9.0Hz, 1H), 7.43 (d, J=2.4Hz, 1H), 7.18 (dd, J
1=9.0Hz, J
2=2.5Hz, 1H), 4.24 (t, J=5.8Hz, 2H), 3.68 (t, J=6.3Hz, 2H), 2.41 (p, J=6.0Hz, 2H)).
2) with 1.75g above-mentioned steps 1) preparation compound
With 1.4g according to embodiment 3) step 2) and the preparation compound
Be dissolved among the 20ml exsiccant DMSO, add 0.863gDIEA and a small amount of KI.Reaction mixture is at N
2Under the gas shiled, 80 ℃ of reflux are poured reaction mixture in the water into after the cooling, use ethyl acetate extraction, merge organic phase, and anhydrous sodium sulfate drying spends the night, and adopt petroleum ether-ethyl acetate as eluent, and silica gel column chromatography separates, and obtains the 350mg compound
Yellow solid (IR:3440,2930,2850,1730,1592,1555,1522,1476,1452,1345,1313,1266,1215,1188,1056,1028,851,754,687cm
-1.
1H-NMR (500 MHz, CDCl
3): δ 8.53 (d, J=4.3Hz, 1H), 8.36 (d, J=8.7Hz, 2H), 8.23 (d, J=8.7Hz, 2H), 8.00 (d, J=8.9Hz, 1H), 7.59 (t, 1H), 7.54 (s, 1H), 7.36 (d, J=2.3Hz, 1H), 7.15 (t, J=5.6Hz, 1H), 7.07 (dd, J
1=9.0Hz, J
2=2.3Hz, 1H), 4.20 (q, J=7.2Hz, 2H), 4.13 (t, J=6.1Hz, 2H), 3.51 (s, 2H), 2.95 (t, J=6.4Hz, 2H), 2.05 (p, J=6.4Hz, 2H), 1.30 (t, J=7.1Hz, 2H)); With the 300mg compound
Join in the mixing solutions of 10ml ethanol and ethyl acetate, add tin protochloride, backflow 8h stops heating, revolves to steam and removes organic solvent, and resistates merges organic phase with ethyl acetate and sodium hydroxide solution extraction.Concentrate, adopt silica gel column chromatography to separate, collection obtains the 100mg structural formula and is
Compound.
3) with 0.1mg above-mentioned steps 2) acetonitrile solution of the compound that makes with [
99mTc (CO)
3(H
2O)
3]
+Solution mix 80～90 ℃ of heating in back 30min, after the cooling, use the 1ml dichloromethane extraction, make compound of the present invention, structural formula is
Claims (10)
1. the benzothiazole amino benzenes compounds of a Tc-99m mark has following structural formula:
Wherein, n gets 1～5, R
1And R
2Be H or CH
3, R
3For
Or
2. the benzothiazole amino benzenes compounds of Tc-99m mark according to claim 1 is characterized in that: described R
3For
Or
3. method for preparing the benzothiazole amino benzenes compounds of the described Tc-99m mark of claim 1 may further comprise the steps:
1) with the synthetic structural formula is
Compound 1 and (CH
2)
nBr
2Carry out condensation reaction, obtain structural formula and be
Compound 2; Wherein, n gets 1～5;
2) compound 2 and the compound MAMA-MBz that earlier step 1) is made carries out linked reaction, obtains structural formula and is
Compound 3, the nitro with compound 3 reduces with tin protochloride then, obtains structural formula to be
Compound 4, the protecting group of again compound 4 being taken off sulfydryl obtains structural formula and is
Compound 5;
3) in new system
99mAdding step 2 among the Tc-GH) ethanolic soln of the compound that finally makes is regulated pH=5.5, adds 40%
99mThe Tc-GH volume of ethanol, reaction mixture is at 100 ℃ of heating 30min, and dichloromethane extraction is used with the saturated sodium bicarbonate solution neutralization in the cooling back.
4. the method for the benzothiazole amino benzenes compounds of a kind of Tc-99m mark of preparation according to claim 3 is characterized in that: step 2) be with described compound 4 usefulness methyl iodide with amino methylization, obtain structural formula and be
Or
Compound 4 ', and then with the protecting group that compound 4 ' takes off sulfydryl, obtain structural formula and be
Compound 5 '.
5. method for preparing the benzothiazole amino benzenes compounds of the described Tc-99m mark of claim 1 may further comprise the steps:
1) with the synthetic structural formula is
Compound 1 and (CH
2)
nBr
2Carry out condensation reaction, obtain structural formula and be
Compound 2; Wherein, n gets 1～5;
2) compound 2 and the compound MAMA-MBz that earlier step 1) is made carries out linked reaction, obtains structural formula and is
Compound 3, the nitro with compound 3 reduces with tin protochloride then, obtains structural formula to be
Compound 4, again with the amide group borane reduction of compound 4, obtain structural formula and be
Compound 7; And then the guarantor that compound 7 is taken off sulfydryl expanded base, obtain structural formula and be
Compound 8;
3) in new system
99mAdding step 2 among the Tc-GH) ethanolic soln of the compound that finally makes is regulated pH=5.5, adds 40%
99mThe Tc-GH volume of ethanol, reaction mixture is at 100 ℃ of heating 30min, and dichloromethane extraction is used with the saturated sodium bicarbonate solution neutralization in the cooling back.
6. the method for the benzothiazole amino benzenes compounds of a kind of Tc-99m mark of preparation according to claim 5 is characterized in that: described step 2) be with described compound 4 usefulness methyl iodide with amino methylization, obtain structural formula and be
Or
Compound 4 '; And then, obtain structural formula and be the amide group borane reduction of compound 4 '
Or
Compound 7 ', the protecting group of again compound 7 ' being taken off sulfydryl obtains structural formula and is
Or
Compound 8 '.
7. method for preparing the benzothiazole amino benzenes compounds of the described Tc-99m mark of claim 1 may further comprise the steps:
1) with the synthetic structural formula is
Compound 1 and (CH
2)
nBr
2Carry out condensation reaction, obtain structural formula and be
Compound 2; Wherein, n gets 1～5;
2) compound 2 and the structural formula that earlier step 1) is prepared is
Compound 10 condensation under alkaline condition, obtain structural formula and be
Compound 11; Then compound 11 usefulness tin protochlorides being reduced into structural formula is
Compound 12; Wherein, described compound 10 usefulness 2-aminomethyl pyridines and ethyl bromoacetate condensation make;
3) with step 2) acetonitrile solution of the compound that finally makes with [
99mTc (CO)
3(H
2O)
3]
+Solution mix 80～90 ℃ of heating in back 30min, after the cooling, use dichloromethane extraction.
8. the method for the benzothiazole amino benzenes compounds of a kind of Tc-99m mark of preparation according to claim 7 is characterized in that: described step 2) be with described compound 12 usefulness methyl iodide with amino methylization, obtain structural formula and be
Or
Compound 12 '.
9. the benzothiazole amino benzenes compounds of the described Tc-99m mark of claim 1 is as the application of beta amyloid patch developer.
10. the benzothiazole amino benzenes compounds of Tc-99m mark according to claim 9 is characterized in that as the application of beta amyloid patch developer: described application is the application at the diagnostic field of alzheimer's disease.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101885744A (en) * | 2010-07-21 | 2010-11-17 | 北京师范大学 | Preparation method of 99mTc labeled hydrazinonicotinamide group-pteroyllysine coordination compound |
| WO2012017891A1 (en) * | 2010-08-06 | 2012-02-09 | 国立大学法人京都大学 | Pyridyl benzofuran derivative |
| CN103497217A (en) * | 2013-09-26 | 2014-01-08 | 北京师范大学 | 2-aryl benzothiazole compound with high affinity with A(beta) plaque and preparation method and application thereof |
| CN104059028A (en) * | 2014-06-06 | 2014-09-24 | 北京智博高科生物技术有限公司 | Fluoro-2-arylbenzoheterocyclic compounds with affinity with Abeta plaque, and preparation method and application thereof |
| CN106496275A (en) * | 2016-09-07 | 2017-03-15 | 北京师范大学 | There is the N of high-affinity with A β plaque block2S22 aryl benzothiazole compound of class and preparation method and application |
-
2007
- 2007-03-27 CN CNB2007100866199A patent/CN100543018C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101885744A (en) * | 2010-07-21 | 2010-11-17 | 北京师范大学 | Preparation method of 99mTc labeled hydrazinonicotinamide group-pteroyllysine coordination compound |
| CN101885744B (en) * | 2010-07-21 | 2012-12-19 | 北京师范大学 | Preparation method of 99mTc labeled hydrazinonicotinamide group-pteroyllysine complex |
| WO2012017891A1 (en) * | 2010-08-06 | 2012-02-09 | 国立大学法人京都大学 | Pyridyl benzofuran derivative |
| CN103497217A (en) * | 2013-09-26 | 2014-01-08 | 北京师范大学 | 2-aryl benzothiazole compound with high affinity with A(beta) plaque and preparation method and application thereof |
| CN103497217B (en) * | 2013-09-26 | 2016-07-06 | 北京师范大学 | With A β plaque block, there is the 2-aryl benzothiazole compound of affinity, its preparation method and application |
| CN104059028A (en) * | 2014-06-06 | 2014-09-24 | 北京智博高科生物技术有限公司 | Fluoro-2-arylbenzoheterocyclic compounds with affinity with Abeta plaque, and preparation method and application thereof |
| CN106496275A (en) * | 2016-09-07 | 2017-03-15 | 北京师范大学 | There is the N of high-affinity with A β plaque block2S22 aryl benzothiazole compound of class and preparation method and application |
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| Publication number | Publication date |
|---|---|
| CN100543018C (en) | 2009-09-23 |
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