CN115322197B - Imidazonaphthyridine compound with affinity with Tau protein, and preparation method and application thereof - Google Patents

Imidazonaphthyridine compound with affinity with Tau protein, and preparation method and application thereof Download PDF

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CN115322197B
CN115322197B CN202210744927.0A CN202210744927A CN115322197B CN 115322197 B CN115322197 B CN 115322197B CN 202210744927 A CN202210744927 A CN 202210744927A CN 115322197 B CN115322197 B CN 115322197B
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CN115322197A (en
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崔孟超
刘天晴
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Beijing Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Abstract

The invention relates to the technical fields of radiopharmaceuticals chemistry and clinical nuclear medicine, in particular to an imidazo naphthyridine compound with high affinity with Tau protein, and a preparation method and application thereof. The imidazonaphthyridine compound has a structure shown in a general formula (I). The compound and the derivative thereof can be used for nuclear medicine clinical diagnosis of neurodegenerative diseases after being marked by radionuclides, in particular for diagnosing diseases with Tau protein deposition characteristics including Alzheimer disease. The structure of the compound is shown as a general formula (I):

Description

Imidazonaphthyridine compound with affinity with Tau protein, and preparation method and application thereof
Technical Field
The invention relates to the technical fields of radiopharmaceuticals chemistry and clinical nuclear medicine, in particular to an imidazo naphthyridine compound with high affinity with Tau protein, and a preparation method and application thereof.
Background
Alzheimer's Disease (AD) is a neurodegenerative Disease which is mainly characterized by dementia, the Disease is progressive and irreversible, inorganic system treatment and accurate diagnosis are still carried out at present, and the Disease is aggravated from the beginning of diagnosis to the end of the life.
According to the 2018 world Alzheimer's disease report, about 5000 thousands of dementia patients worldwide, the number of 2050 is expected to increase to 1.52 billion. In China, there are 1507 ten thousand dementia patients in 60 years old and above, wherein the prevalence of Alzheimer's disease is 983 ten thousand, mild cognitive impairment is 15.54%, and the number of patients reaches 3877 ten thousand. AD has become a serious threat to human health following tumors, heart disease and stroke, diabetes. Therefore, early prevention and diagnosis of AD and other neurodegenerative diseases is essential for patients, and research in this regard is of great importance.
The pathogenesis of AD is complex, and studies indicate that two major pathological biomarkers of AD are plaques formed by deposition of amyloid β peptides (aβ) outside nerve cells and neurofibrillary tangles consisting of hyperphosphorylated Tau protein in nerve cells, respectively.
Currently, molecular probe studies targeting aβ are mature, but using aβ as a diagnostic standard often leads to false positives, because the extent of aβ deposition is not positively correlated with disease progression. In contrast, tau protein has a good correlation with the progression of the disease, and therefore Tau protein (neurofibrillary tangles in the brain) is considered as a more ideal target for diagnosis of AD than Abeta.
At present, molecular probes targeting Tau protein have been proposed, e.g. [ 18 F]T807，[ 18 F]MK6240，[ 11 C]PBB3 and [ 18 F]THK5351, and the like. However, they all have their own disadvantages, in clinical trials [ 18 F]T807，[ 18 F]MK6240 [ 18 F]THK5351 is off-target to MAO-B and [ 11 C]Although PBB3 has high activity and selectivity to Tau protein, it has unstable phenomenon in vivo. Thus, high activity and high purity are developedSelective and high affinity Tau protein molecular probes are the current research focus.
Disclosure of Invention
Aiming at the problems of the existing Tau protein molecular probes, the invention provides an imidazo naphthyridine compound with high affinity with Tau protein, and a preparation method and application thereof. The compound has higher affinity and selectivity to Tau protein, and can be used for nuclear medicine imaging after being marked by using proper radioactive isotopes, and is particularly suitable for diagnosing patients with neurodegenerative diseases including Alzheimer disease and having Tau protein deposition characteristics.
In a first aspect, the imidazonaphthyridine compound provided by the invention has a structure as shown in the following general formula (I):
wherein:
X 1 ～X 7 each independently represents N or CH;
R 1 at positions 1 and 2, R 2 The two parts are positioned at 3 and 4 positions;
R 1 and R is 2 Each of which independently represents H,wherein R is 3 Representation of 123/125/ 127 I， 18/19 F，OH，O 11/12 CH 3 ，(OCH 2 CH 2 ) m 18/19 F, m is an integer between 1 and 6.
The compound with naphthyridine imidazole structure as main body provided by the invention can be used as a radiopharmaceuticals with high affinity to neurofibrillary tangles (Tau protein deposition) 18 F， 11 C or 123/125 I, for PET or SPECT imaging), to achieve early diagnosis of Tau protein-related diseases, in particular Alzheimer's disease.
Preferably, the compound of formula (I) is selected from the following compounds:
wherein I in compounds 1-4, compounds 14-17 and compound 19 is 123 I， 125 I or 127 I；
Compounds 5-13 and 18 wherein F is 18 F or F 19 F。
The preferred compounds have higher activity, higher affinity and selectivity for Tau protein.
In a second aspect, the present invention provides a process for the preparation of a preferred imidazonaphthyridine compound, comprising:
when I is 123 I or 125 I, compounds 1 to 4, compounds 14 to 17, compound 19 are prepared from trialkyltin, trialkylsilicon, boric acid or borate precursor compounds and [123/125 ]]Reacting NaI solution in the presence of an oxidant to obtain the catalyst;
when F is 18 F, compounds 5-13, 18 are prepared from OTs, trimethyl quaternary ammonium salt, boric acid ester or high-valence iodine prosthetic precursor compound and [18F]F anions are obtained by reacting in the presence of a phase transfer catalyst.
In a third aspect, the invention also provides a derivative of the imidazonaphthyridine compound, which is a pharmaceutically acceptable salt, ester or amide compound or prodrug of the compound shown in the general formula (I).
In a fourth aspect, the present invention also provides a diagnostic or detection reagent for neurofibrillary tangle diseases caused by Tau protein deposition, wherein the active ingredient is a compound represented by formula (I), and/or a derivative thereof.
These diseases include, but are not limited to, alzheimer's disease, frontotemporal lobar degeneration, chronic traumatic encephalopathy, progressive supranuclear palsy, corticobasal degeneration, pick's disease, and the like.
In a fifth aspect, the present invention further provides the use of a compound of formula (I) and/or a derivative thereof in the preparation of a nuclear medicine imaging agent.
In particular, the nuclear medicine imaging agent is a PET or SPECT imaging agent.
Compared with the prior art, the invention has the following advantages:
the compound shown in the (I) has higher affinity and selectivity to Tau protein, can be used for nuclear medicine imaging after being marked by using proper radioactive isotopes, and is particularly suitable for diagnosing patients with neurodegenerative diseases including Alzheimer's disease and having Tau protein deposition characteristics.
Drawings
FIG. 1 is a schematic diagram of the synthetic process of the compounds of examples 1-20 according to the present invention, wherein the reactants and conditions involved are:
(a) Sodium bicarbonate, ethanol, reflux overnight; (b) N-hexabutylditin, tetra-triphenylphosphine palladium, toluene, 110 ℃ and nitrogen protection for 10 hours; (c) Na (Na) 125 I,3% hydrogen peroxide, 1M hydrochloric acid, room temperature, 15 minutes; (d) 18 F - Tetraethylammonium bicarbonate, cu (OTf) 2 (Py) 4 N-butanol, dimethylacetamide at 110 ℃ for 20 minutes; (e) 1-bromo-2 fluoroethane, cesium carbonate, DMF,80 ℃ overnight; (f) Bromoethanol or 2- (2-chloroethoxy) ethanol or chloro-di-polyethylene glycol, cesium carbonate, DMF,80 ℃ overnight; (g) P-toluenesulfonyl chloride, triethylamine, dichloromethane, room temperature for 7 hours; (h) Tetrabutylammonium fluoride, tetrahydrofuran, 60 ℃ for 2 hours; (i) 18 F - ，K 222 /K 2 CO 3 Acetonitrile, 100 ℃, for 10 minutes.
FIG. 2 is a schematic diagram showing the synthesis of the compounds of examples 21-30 according to the present invention, wherein the reagents and conditions involved are:
(a) Sodium bicarbonate, ethanol, reflux overnight; (b) Trimethylamine, trifluoroacetic anhydride, dichloromethane, room temperature, half an hour; (c) tetrabutylammonium fluoride, acetonitrile, 60 ℃ for 2 hours; (d) 18 F - Tetrabutylammonium bicarbonate, DMSO,100 ℃,6 minutes; (e) mCPBA, dichloromethane, room temperature, 2 hours;(f) (1) NaH, anhydrous tetrahydrofuran, ice bath for 1 hour; (2) diethylene glycol, 140 ℃, for 4 hours; (g) P-toluenesulfonyl chloride, triethylamine, dichloromethane, room temperature, 5 hours (h) 18 F - ，K 222 /K 2 CO 3 Acetonitrile, 100 ℃, for 5 minutes.
FIG. 3 is a schematic diagram showing the synthesis of the compounds of examples 31-39 according to the present invention, wherein the reagents and conditions involved are:
(a) Sodium bicarbonate, ethanol, reflux overnight; (b) trifluoroacetic acid, dichloromethane, room temperature, 3 hours; (c) 1-bromo-3-fluoropropane or 3-bromo-1-propanol, cesium carbonate, acetonitrile, 80 ℃ for 10 hours; (d) P-toluenesulfonyl chloride, triethylamine, dichloromethane, room temperature for 7 hours; (e) 18 F - ，K 222 /K 2 CO 3 Acetonitrile, 100 ℃, for 10 minutes; (f) mCPBA, dichloromethane, room temperature, 2 hours; (g) Trimethylamine, trifluoroacetic anhydride, dichloromethane, room temperature, half an hour; (h) tetrabutylammonium fluoride, acetonitrile, 60 ℃ for 2 hours; (i) 18 F - Tetrabutylammonium bicarbonate, DMSO,100 ℃,6 min.
FIG. 4 is a schematic diagram showing the synthesis of the compounds of examples 40-51 according to the present invention, wherein the reagents and conditions involved are:
(a) Ethanol, refluxing for 3 hours; (b) DMF,130 ℃,2 hours; (c) Sodium periodate, THF/H 2 O (1:1), room temperature, 24 hours; (d) iron powder, ethanol/water (10:1), concentrated hydrochloric acid; (e) potassium hydroxide, ethanol; (f) N-hexabutylditin, tetra-triphenylphosphine palladium, toluene, 110 ℃ and nitrogen protection for 10 hours; (g) Na (Na) 125 I,3% hydrogen peroxide, 1M hydrochloric acid, room temperature, 15 minutes.
FIG. 5 is a schematic diagram showing the synthesis of the compounds of examples 59-61 according to the present invention, wherein the reagents and conditions involved are:
(a) NBS, TMS-OTf, acetonitrile, 40 ℃ for half an hour; (b) Bis (triphenylphosphine) palladium chloride, potassium carbonate, dioxane, 110 ℃, overnight; (c) N-hexabutylditin, tetra-triphenylphosphine palladium, toluene, 110 ℃ and nitrogen protection for 10 hours; (d) Na (Na) 125 I,3% Hydrogen peroxide, 1M hydrochloric acid, room temperature, 15 min。
FIG. 6 shows a probe in example 62 of the present invention 125 I]1-3，[ 125 I]8，[ 125 I]54 and [ 125 I]60, example 64 Probe [ 18 F]4 results of autoradiography on brain tissue sections of AD patients and their corresponding silver staining or 6E10 staining (first row, female, 102 years old, temporal lobe), (second row, male, 95 years old, frontal lobe).
FIG. 7 shows a probe in example 62 of the present invention 125 I]1 from an enlarged view of brain tissue sections of AD patients and their corresponding silver staining or 6E10 staining (a and B, female, 102 years old, temporal lobe), (C and D, male, 95 years old, frontal lobe).
FIG. 8A probe in example 62 of the present invention 125 I]1 results of autoradiography in AD patients brain tissue sections (a, male, 95 years old, temporal lobe), (B, male, 97 years old, striatum), (C, male, 74 years old, frontal lobe), (D, male, 74 years old, temporal lobe), (E, male, 78 years old, temporal lobe), (F, male, 95 years old, hippocampus).
Detailed Description
The following examples are illustrative of the invention and are not intended to limit the scope of the invention.
Example 1: synthesis of Compound 1
The compound 8-amino-1, 7-naphthyridine (75.0 mg,0.5 mmol), 2' -bromo-4-iodoacetophenone (152.1 mg,0.7 mmol) and NaHCO 3 (70.2 mg,0.8 mmol) was dissolved in 20mL of ethanol, then heated under reflux with an oil bath at 90℃for 6 hours, after the reaction was completed, ethanol was distilled off under reduced pressure, water was added, and extraction was performed three times with ethyl acetate, and after removal of ethyl acetate by distillation under reduced pressure, column chromatography was carried out, with the volume ratio of the developing solvent being ethyl acetate: petroleum ether=9:1, to give 96.2mg of pale yellow solid. The yield was 40.5%. The structure is as follows: 1H-NMR (400 MHz, (CD) 3 ) 2 SO)δ8.87(d,J＝4.3Hz,1H),8.50(s,1H),8.39(d,J＝7.2Hz,1H),8.26(d,J＝8.0Hz,1H),7.79(s,4H),7.61(dd,J＝8.1,4.5Hz,1H),7.25(d,J＝7.1Hz,1H).
Example 2: synthesis of Compound 2
Compound 2 was synthesized according to the procedure of example 1 starting from 1-aminoisoquinoline to yield 15.2mg of pale yellow product in 29.0% yield. The structure is as follows: 1H-NMR (400 MHz, (CD) 3 ) 2 SO)δ8.48(d,J＝5.7Hz,1H),8.42(d,J＝2.3Hz,1H),8.30(dd,J＝7.2,2.3Hz,1H),7.84(d,J＝7.2Hz,1H),7.78(d,J＝2.2Hz,4H),7.68–7.58(m,2H),7.24(d,J＝7.2Hz,1H).
Example 3: synthesis of Compound 3
According to the method for synthesizing compound 1, compound 3 was synthesized using 2, 7-naphthyridin-1-amine as a raw material, 59.6mg of a earthy yellow solid was obtained in a yield of 37.1%. The structure is as follows: 1H-NMR (400 MHz, (CD) 3 ) 2 SO)δ9.70(s,1H),8.67(d,J＝5.4Hz,1H),8.54–8.50(m,2H),7.80(s,5H),7.27(d,J＝7.3Hz,1H).
Example 4: synthesis of Compound 4
The compound 8-amino-1, 7-naphthyridine (100.9 mg,0.7 mmol), 2' -bromo-4-fluoroacetophenone (152.0 mg,0.7 mmol) and NaHCO 3 (67.2 mg,0.8 mmol) was dissolved in 50mL of ethanol, then heated under reflux with an oil bath at 90 ℃ for 5 hours, after the reaction was completed, ethanol was distilled off under reduced pressure, water was added, and extraction was performed three times with ethyl acetate, and after removal of ethyl acetate by distillation under reduced pressure, column chromatography was carried out, and the volume ratio of the developing solvent to ethyl acetate: methanol=10:1, 110.8mg of a white solid was obtained. The yield was 79.4%. The structure is as follows: 1H-NMR (600 MHz, CDCl) 3 )δ9.00(d,J＝4.4Hz,1H),8.10–8.06(m,2H),8.02(d,J＝8.0Hz,1H),8.00(d,J＝7.1Hz,1H),7.87(s,1H),7.50(dd,J＝8.0,4.5Hz,1H),7.10(t,J＝8.6Hz,2H),7.01(d,J＝7.0Hz,1H).
Example 5: synthesis of labeled precursor Compound 5
Intermediate compound 1 (48.4 mg,0.1 mmol), tetrakis triphenylphosphine palladium (18.2 mg,0.016 mmol) and n-hexabutylditin (0.23 g,0.4 mmol) were dissolved in 8mL toluene and reacted overnight at 110 ℃, after the reaction was completed, toluene was distilled off under reduced pressure, methylene chloride was added, suction filtration was carried out, and after methylene chloride was distilled off under reduced pressure, column chromatography was separated, with the volume ratio of developing solvent being petroleum ether: ethyl acetate=3:2. 10.2mg of pale yellow solid was obtained in 18.7% yield. The structure is as follows: 1H-NMR (600 MHz, CDCl) 3 )δ8.09(t,J＝8.9Hz,1H),7.60(d,J＝5.6Hz,1H),7.57(s,1H),7.55(d,J＝6.3Hz,1H),7.37(d,J＝5.8Hz,2H),7.06(dd,J＝6.0,3.5Hz,1H),7.00(t,J＝7.0Hz,2H),6.73(d,J＝5.7Hz,1H),2.26–2.24(m,4H),2.09–2.05(m,7H),1.86(d,J＝6.3Hz,4H),1.70(t,J＝5.8Hz,12H).
Example 6: synthesis of labeled precursor Compound 6
Intermediate compound 2 (60.1 mg,0.16 mmol), tetraphenylphosphine palladium (28.1 mg,0.024 mmol) and n-hexabutylditin (0.36 g,0.65 mmol) were dissolved in 9mL toluene, and reacted overnight at 110℃under nitrogen, after the completion of the reaction, toluene was distilled off under reduced pressure, methylene chloride was added, suction filtration was performed, and after methylene chloride was distilled off under reduced pressure, column chromatography was separated, with a volume ratio of developing solvent being petroleum ether: ethyl acetate=3:1. 14.4mg of the product was obtained as a pale yellow oil in 16.4% yield. The structure is as follows: 1H-NMR (600 MHz, CDCl) 3 )δ7.96(d,J＝4.7Hz,2H),7.90(d,J＝7.1Hz,1H),7.82(s,1H),7.70(dd,J＝5.7,3.2Hz,1H),7.69(s,1H),7.64(s,1H),7.57(d,J＝7.5Hz,1H),7.54(d,J＝7.8Hz,2H),7.51(dd,J＝5.8,3.2Hz,1H),1.57–1.54(m,5H),1.35–1.32(m,6H),1.10–1.05(m,6H),0.89(t,J＝7.3Hz,11H).
Example 7: synthesis of labeled precursor Compound 7
Intermediate compound 3 (51.5 mg,0.14 mmol), tetrakis triphenylphosphine palladium (23.4 mg,0.02 mmol) and n-hexabutylditin (0.32 g,0.55 mmol) were dissolved in 10mL toluene and reacted overnight at 110℃under nitrogen, after the reaction was completed, toluene was distilled off under reduced pressure, methylene chloride was added, suction filtration was carried out, and after methylene chloride was distilled off under reduced pressure, column chromatography was separated with a volume ratio of developing solvent petroleum ether: ethyl acetate=8:1. 21mg of the product was obtained as a pale yellow oil in 28.1% yield. The structure is as follows: 1H-NMR (400 MHz, CDCl) 3 )δ10.06(s,1H),8.71(d,J＝5.5Hz,1H),8.14(d,J＝7.3Hz,1H),7.96(d,J＝8.0Hz,2H),7.92(s,1H),7.58(dd,J＝12.6,6.4Hz,3H),7.05(d,J＝7.2Hz,1H),1.58–1.53(m,5H),1.33(t,J＝8.3Hz,6H),1.11–1.05(m,5H),0.89(t,J＝7.3Hz,11H).
Example 8: synthesis of Compound 8
The compound 2-aminoquinoline (100.7 mg,0.7 mmol), 2' -bromo-4-iodoacetophenone (152.8 mg,0.7 mmol) and NaHCO 3 (67.0 mg,0.8 mmol) was dissolved in 30mL of ethanol, then heated under reflux with an oil bath at 90 ℃ for 7 hours, after the reaction was completed, ethanol was distilled off under reduced pressure, water was added, and extraction was performed three times with ethyl acetate, and after removal of ethyl acetate by distillation under reduced pressure, column chromatography was carried out, and the volume ratio of the developing solvent to ethyl acetate: methanol=10:1, to obtain 133.9mg of yellow solid. The yield was 51.4%. The structure is as follows: 1H-NMR (400 MHz, (CD) 3 ) 2 SO)δ9.17(s,1H),8.30(d,J＝8.4Hz,1H),7.95(d,J＝7.7Hz,1H),7.79(s,4H),7.72(dd,J＝14.7,8.7Hz,2H),7.52(dd,J＝15.7,8.4Hz,2H).
Example 9: synthesis of labeled precursor Compound 9
Intermediate compound 8 (78.3 mg,0.21 mmol), tetrakis triphenylphosphine palladium (37.6 mg,0.032 mmol) and n-hexabutylditin (0.48 g,0.84 mmol) were dissolved in 8mL toluene and reacted overnight at 110℃under nitrogen, after the reaction was completed, toluene was distilled off under reduced pressure, methylene chloride was added, suction filtration was carried out, and after methylene chloride was distilled off under reduced pressure, column chromatography was separated with a volume ratio of developing solvent petroleum ether: ethyl acetate=3:1. 18.1mg of pale yellow solid was obtained in 16.1% yield. The structure is as follows: 1H-NMR (400 MHz, CDCl) 3 )δ8.30(s,1H),7.94(t,J＝7.5Hz,3H),7.78(d,J＝7.9Hz,1H),7.62(dd,J＝16.4,8.3Hz,2H),7.55(d,J＝8.0Hz,2H),7.50(d,J＝9.5Hz,1H),7.44(t,J＝7.5Hz,1H),1.59(s,4H),1.37(d,J＝7.3Hz,6H),1.09(s,3H),0.91(q,J＝7.5Hz,14H).
Example 10: synthesis of labeled precursor Compound 10
The synthesis of labeled precursor compound 10 was followed by the synthesis of example 1 to yield 46.6mg of a white solid in 42.8% yield. The structure is as follows: 1H-NMR (400 MHz, CDCl) 3 )δ8.99(dd,J＝4.5,1.6Hz,1H),8.14(d,J＝8.1Hz,2H),8.02(dd,J＝8.0,1.5Hz,1H),7.99(d,J＝7.1Hz,1H),7.97(s,1H),7.88(d,J＝8.1Hz,2H),7.49(dd,J＝8.1,4.5Hz,1H),7.01(d,J＝7.1Hz,1H),1.36(s,12H).
Example 11: synthesis of intermediate Compound 11
The compound 8-amino-1, 7-naphthyridine (145.2 mg,1 mmol), 2' -bromo-4-hydroxyacetophenone (258.7 mg,1.2 mmol) and NaHCO 3 (168.4 mg,2 mmol) was dissolved in 20mL of ethanol, then heated under reflux with an oil bath at 90deg.C for 10 hours, after the reaction, ethanol was distilled off under reduced pressure, water was added, extraction was performed three times with ethyl acetate, and after removal of ethyl acetate by distillation under reduced pressure, column chromatography was performed, and the developer was usedThe volume ratio was ethyl acetate: petroleum ether=5:1, yielding 101.9mg of a pale yellow solid. The yield was 42.1%. The structure is as follows: 1H-NMR (400 MHz, (CD) 3 ) 2 SO)δ8.95(dd,J＝4.4,1.6Hz,1H),8.51(d,J＝7.1Hz,1H),8.43(s,1H),8.38(dd,J＝8.1,1.6Hz,1H),7.93–7.89(m,2H),7.70(dd,J＝8.1,4.5Hz,1H),7.34(d,J＝7.1Hz,1H),6.96–6.90(m,2H).
Example 12: synthesis of Compound 12
Intermediate compound 11 (50.2 mg,0.23 mmol), 1-bromo-2-fluoroethane (88.6 mg,0.69 mmol) and cesium carbonate (0.6 g,1.84 mmol) were dissolved in 4mL DMF, reacted at 80 ℃ for 13 hours, DMF was distilled off under reduced pressure, dichloromethane was added, cesium carbonate was removed by suction filtration after sonication, after removal of dichloromethane by distillation under reduced pressure, column chromatography was separated, the volume ratio of developing solvent was ethyl acetate: petroleum ether=1:4, to give 29.2mg of pale yellow solid with a yield of 41.3%. The structure is as follows: 1H-NMR (600 MHz, CDCl) 3 )δ8.99(dd,J＝4.5,1.5Hz,1H),8.05–8.01(m,4H),7.91(s,1H),7.50(dd,J＝8.0,4.5Hz,1H),7.02(d,J＝7.2Hz,1H),6.95(d,J＝8.7Hz,2H),4.83–4.80(m,1H),4.75–4.71(m,1H),4.28–4.25(m,1H),4.24–4.21(m,1H).
Example 13: synthesis of intermediate Compound 13
Intermediate compound 11 (50.3 mg,0.23 mmol), bromoethanol (88.3 mg,0.69 mmol) and cesium carbonate (0.6 g,1.84 mmol) were dissolved in 4mL DMF and reacted at 80 ℃ for 11 hours, DMF was distilled off under reduced pressure, water was added and extracted with ethyl acetate, and after removal of ethyl acetate by distillation under reduced pressure, column chromatography was carried out with a volume ratio of developing solvent of ethyl acetate: petroleum ether=6:1 to give 44.3mg as a yellow solid with a yield of 63.1%. The structure is as follows: 1H-NMR (400 MHz, (CD) 3 ) 2 SO)δ8.86(dd,J＝4.4,1.6Hz,1H),8.39(d,J＝7.2Hz,1H),8.35(s,1H),8.25(dd,J＝8.0,1.6Hz,1H),7.94–7.88(m,2H),7.59(dd,J＝8.0,4.5Hz,1H),7.22(d,J＝7.2Hz,1H),7.03–6.97(m,2H),4.01(t,J＝5.0Hz,2H),3.70(t,J＝4.9Hz,2H).
Example 14: synthesis of intermediate Compound 14
Intermediate compound 11 (457.3 mg,2 mmol), 2- (2-chloroethoxy) ethanol (752.2 mg,6 mmol) and cesium carbonate (5 g,15 mmol) were dissolved in 8mL DMF, reacted for 6 hours at 80℃and distilled off under reduced pressure, water was added and extracted with ethyl acetate, and after removal of ethyl acetate by distillation under reduced pressure, column chromatography was carried out with a volume ratio of developing solvent of ethyl acetate: methanol=9:1 to give 169.2mg of orange solid in 24.3% yield. The structure is as follows: 1H-NMR (400 MHz, (CD) 3 ) 2 SO)δ8.81(dd,J＝4.4,1.6Hz,1H),8.34(d,J＝7.1Hz,1H),8.30(s,1H),8.20(dd,J＝8.1,1.6Hz,1H),7.86(d,J＝8.7Hz,2H),7.54(dd,J＝8.1,4.5Hz,1H),7.17(d,J＝7.2Hz,1H),6.96(d,J＝8.9Hz,2H),4.06(dd,J＝5.4,3.9Hz,2H),3.68(dd,J＝5.2,3.9Hz,2H),3.43(s,4H).
Example 15: synthesis of intermediate Compound 15
Intermediate compound 11 (260.6 mg,1.2 mmol), 2- [2- (2-chloroethoxy) ethoxy]Ethanol (604.8 mg,3.6 mmol) and cesium carbonate (2.7 g,8 mmol) were reacted for 11 hours at 80℃in 6mL DMF, DMF was distilled off under reduced pressure, water was added and extracted with ethyl acetate, and after removal of ethyl acetate by distillation under reduced pressure, column chromatography was carried out with a volume ratio of developing solvent of ethyl acetate: methanol=9:1 to give 212.2mg of a colorless oily product in 45.1% yield. The structure is as follows: 1H-NMR (400 MHz, CDCl) 3 )δ8.98(dd,J＝4.5,1.6Hz,1H),8.02(dd,J＝8.0,5.7Hz,4H),7.89(s,1H),7.49(dd,J＝8.1,4.5Hz,1H),7.01(d,J＝7.2Hz,1H),6.95(d,J＝8.8Hz,2H),4.19–4.15(m,2H),3.90–3.86(m,2H),3.75–3.73(m,4H),3.66–3.60(m,4H).
Example 16: synthesis of labeled precursor Compound 16
Intermediate compound 13 (95.9 mg,0.31 mmol), p-toluenesulfonyl chloride (70.3 mg,0.36 mmol), triethylamine (0.15 mL,2 mmol) were dissolved in 5mL of dichloromethane, reacted at room temperature for 6 hours, after the reaction was completed, the dichloromethane was distilled off under reduced pressure, column chromatography was carried out, and the volume ratio of the developing solvent was petroleum ether: ethyl acetate=1:7, to give 29.4mg of an off-white solid with a yield of 20%. The structure is as follows: 1H-NMR (400 MHz, CDCl) 3 )δ9.04(dd,J＝4.4,1.5Hz,1H),8.19(d,J＝7.2Hz,2H),8.13(s,1H),7.97(d,J＝8.6Hz,2H),7.83(d,J＝8.3Hz,2H),7.59(dd,J＝8.1,4.5Hz,1H),7.36(d,J＝8.2Hz,2H),7.14(d,J＝7.0Hz,1H),6.67(d,J＝8.5Hz,2H),4.35(dd,J＝5.4,3.7Hz,2H),4.12–4.06(m,2H),2.46(s,3H).
Example 17: synthesis of labeled precursor Compound 17
Intermediate compound 14 (150.4 mg,0.43 mmol), p-toluenesulfonyl chloride (98.9 mg,0.52 mmol), triethylamine (0.2 mL,2.5 mmol) were dissolved in 6mL of dichloromethane, reacted at room temperature for 5 hours, after the reaction was completed, the dichloromethane was distilled off under reduced pressure, column chromatography was carried out, and the volume ratio of the developing solvent was petroleum ether: ethyl acetate=1:9 to give 57.1mg of a white solid with a yield of 26.3%. The structure is as follows: 1H-NMR (400 MHz, (CD) 3 ) 2 SO)δ8.91(dd,J＝4.5,1.7Hz,1H),8.46–8.39(m,2H),8.30(dd,J＝8.1,1.6Hz,1H),7.95(d,J＝8.7Hz,2H),7.78(d,J＝8.3Hz,2H),7.63(dd,J＝8.0,4.5Hz,1H),7.44(d,J＝8.1Hz,2H),7.27(d,J＝7.2Hz,1H),7.02(d,J＝8.8Hz,2H),4.19–4.13(m,2H),4.09–4.04(m,2H),3.72–3.64(m,4H),2.37(s,3H).
Example 18: synthesis of labeled precursor Compound 18
Intermediate compound 14 (240.6 mg,0.61 mmol), p-toluenesulfonyl chloride (139.4 mg,0.73 mmol), triethylamine (0.3 mL,2.8 mmol) were dissolved in 6mL of dichloromethane, reacted at room temperature for 5 hours, after the reaction was completed, the dichloromethane was distilled off under reduced pressure, column chromatography was carried out, and the volume ratio of the developing solvent was ethyl acetate: methanol=12:1, to obtain 116.1mg of pale yellow solid with a yield of 35.3%. The structure is as follows: 1H-NMR (400 MHz, CDCl) 3 )δ8.97(dd,J＝4.5,1.6Hz,1H),8.97(dd,J＝4.5,1.6Hz,1H),8.03–7.95(m,5H),7.81(s,1H),7.77(d,J＝8.3Hz,2H),7.47(dd,J＝7.9,4.5Hz,1H),7.30(d,J＝8.2Hz,2H),6.96(dd,J＝7.8,5.7Hz,3H),4.15(dd,J＝8.5,3.7Hz,5H),3.85–3.81(m,2H),3.70–3.67(m,2H),3.67–3.64(m,2H),3.63–3.58(m,2H),2.40(s,3H).
Example 19: synthesis of Compound 19
The synthesis of precursor compound 17 (25.3 mg,0.05 mmol) and TBAF (0.25 mL,0.25 mmol) in 5mL anhydrous tetrahydrofuran was reacted for 2 hours at 60 ℃, after completion of the reaction, tetrahydrofuran was removed by distillation under reduced pressure, column chromatography was separated, and the volume ratio of developing solvent to dichloromethane: methanol=12:1 to give 14mg of yellow solid in 81.6% yield. The structure is as follows: 1H-NMR (400 MHz, CDCl) 3 )δ8.98(dd,J＝4.5,1.6Hz,1H),8.01(ddd,J＝5.2,3.9,2.2Hz,4H),7.87(s,1H),7.48(dd,J＝8.1,4.5Hz,1H),7.00(d,J＝7.2Hz,1H),6.95(d,J＝8.9Hz,2H),4.68–4.64(m,1H),4.55–4.52(m,1H),4.20–4.15(m,2H),3.92–3.89(m,2H),3.89–3.85(m,1H),3.81–3.78(m,1H).
Example 20: synthesis of Compound 20
The synthesis of precursor 17 (61.6 mg,0.11 mmol) and TBAF (1 mL,1 mmol) in 5mL anhydrous tetrahydrofuran was reacted at 60℃for 3 hours, after the completion of the reaction, tetrahydrofuran was distilled off under reduced pressure, and column chromatography was performedThe resulting mixture was separated to give 12.5mg of yellow solid in 31.6% yield, based on methylene chloride: ethyl acetate: methanol=12:4:1 by volume. The structure is as follows: 1H-NMR (400 MHz, CDCl) 3 )δ8.96(dd,J＝4.5,1.5Hz,1H),7.99(dd,J＝10.5,4.2Hz,3H),7.95(d,J＝7.2Hz,1H),7.79(s,1H),7.46(dd,J＝8.0,4.5Hz,1H),6.96(d,J＝7.2Hz,3H),4.63–4.58(m,1H),4.52–4.46(m,1H),4.19–4.15(m,2H),3.90–3.85(m,2H),3.80–3.77(m,1H),3.73–3.68(m,4H),3.62(t,J＝5.8Hz,1H).
The schematic of the synthesis of the compounds of examples 1-20 above is shown in FIG. 1.
Example 21: synthesis of intermediate Compound 21
The compound 8-amino-1, 7-naphthyridine (290.4 mg,1 mmol), 3- (2-bromoacetyl) pyridine oxide (518.3 mg,2.4 mmol) and NaHCO 3 (252.5 mg,3 mmol) was dissolved in 20mL ethanol, then heated under reflux with an oil bath at 90 ℃ for 9 hours, after the reaction was completed, the ethanol was distilled off under reduced pressure, and the mixture was separated by column chromatography, wherein the volume ratio of the developing solvent was ethyl acetate: methanol=7:3, to obtain 173.5mg of yellow solid. The yield was 33.5%. The structure is as follows: 1H-NMR (400 MHz, (CD) 3 ) 2 SO)δ8.90(dd,J＝4.4,1.5Hz,1H),8.80(s,1H),8.67(s,1H),8.43(d,J＝7.2Hz,1H),8.30(dd,J＝8.1,1.4Hz,1H),8.15(d,J＝6.4Hz,1H),7.92(d,J＝7.9Hz,1H),7.64(dd,J＝8.0,4.4Hz,1H),7.49(dd,J＝7.8,6.6Hz,1H),7.30(d,J＝7.2Hz,1H).
Example 22: synthesis of labeled precursor Compound 22
Compound 21 (131.1 mg,0.5 mmol) was dissolved in 3mL of methylene chloride, then trimethylamine (1.5 mL,3 mmol) and trifluoroacetic anhydride (315.7 mg,1.5 mmol) were sequentially added to the reaction mixture, stirred at room temperature for half an hour, after the completion of the reaction, water was added, the aqueous phase was distilled off under reduced pressure, diethyl ether and acetonitrile were added, and ultrasonic washing was performed, followed by centrifugation to obtain the lower brown layer137.6mg of yellow solid was found to be 75.7% yield. The structure is as follows: 1H-NMR (600 MHz, (CD) 3 ) 2 SO)δ9.29(d,J＝2.3Hz,1H),8.94(d,J＝4.5Hz,1H),8.77(dd,J＝8.6,2.1Hz,1H),8.57(s,1H),8.36(d,J＝7.2Hz,1H),8.30(d,J＝8.1Hz,1H),8.05(d,J＝8.7Hz,1H),7.68(dd,J＝8.0,4.5Hz,1H),7.30(d,J＝7.2Hz,1H),3.68(s,9H).
Example 23: synthesis of Compound 23
Compound 22 (30.0 mg,0.07 mmol) and tetrabutylammonium fluoride (0.2 mL,0.21 mmol) were dissolved in 5mL acetonitrile and reacted at 60℃for two hours, after which the reaction was completed, the column chromatography was separated and the ratio of developing solvent was ethyl acetate: methanol=10:1 to give 13.3mg of pale yellow product with a yield of 67.3%. The structure is as follows: 1H-NMR (600 MHz, (CD) 3 ) 2 SO)δ8.89(dd,J＝4.4,1.2Hz,1H),8.84(d,J＝2.0Hz,1H),8.57(s,1H),8.53(td,J＝8.2,2.3Hz,1H),8.44(d,J＝7.1Hz,1H),8.29(dd,J＝8.1,1.0Hz,1H),7.63(dd,J＝8.0,4.4Hz,1H),7.30–7.26(m,2H).
Example 24: synthesis of intermediate Compound 24
Starting from intermediate compound 4 (131.3 mg,0.5 mmol) in 40mL of dichloromethane, mCPBA (127.2 mg,0.75 mmol) was added and reacted at room temperature for 3 hours, and the dichloromethane was distilled off under reduced pressure. 41.5mg of pale yellow solid was obtained in 50.2% yield. The structure is as follows: 1H-NMR (400 MHz, (CD) 3 ) 2 SO)δ8.53–8.47(m,3H),8.04(dd,J＝8.7,5.6Hz,2H),7.77(d,J＝8.0Hz,1H),7.52(dd,J＝8.1,6.4Hz,1H),7.32–7.26(m,3H).
Example 25: synthesis of labeled precursor Compound 25
The labeled precursor compound 25 was synthesized according to the synthesis method of example 22 starting from intermediate compound 24. 26.1mg of a brown-white solid was obtained in 68.6% yield. The structure is as follows: 1H-NMR (400 MHz, (CD) 3 ) 2 SO)δ8.74(d,J＝8.8Hz,1H),8.61(d,J＝4.5Hz,2H),8.31(d,J＝8.8Hz,1H),8.10–8.03(m,2H),7.43(d,J＝7.1Hz,1H),7.30(t,J＝8.1Hz,2H),3.71(s,9H).
Example 26: synthesis of Compound 26
Compound 26 was synthesized according to the procedure for the synthesis of example 22 starting from labeled precursor compound 25 to yield 9.7mg of a white solid with a yield of 78.5%. The structure is as follows: 1H-NMR (600 MHz, CDCl) 3 )δ8.16–8.12(m,1H),8.07(dd,J＝8.9,5.4Hz,2H),8.03(d,J＝7.1Hz,1H),7.90(s,1H),7.16(dd,J＝8.5,2.7Hz,1H),7.12(t,J＝8.7Hz,2H),7.05(d,J＝7.1Hz,1H).
Example 27: synthesis of intermediate Compound 27
Intermediate compound 34 was synthesized according to the procedure for the synthesis of example 1 starting from 8-amino-1, 7-naphthyridine and 5- (2-bromoacetyl) -2-chloropyridine to yield 172.8mg of white product in 61.3% yield. The structure is as follows: 1H-NMR (400 MHz, (CD) 3 ) 2 SO)δ9.06(d,J＝2.0Hz,1H),8.93(d,J＝4.5Hz,1H),8.67(s,1H),8.48(d,J＝7.2Hz,1H),8.44(dd,J＝8.5,1.5Hz,1H),8.33(d,J＝8.0Hz,1H),7.67(dd,J＝7.7,4.5Hz,1H),7.63(d,J＝8.3Hz,1H),7.33(d,J＝7.0Hz,1H).
Example 28: synthesis of intermediate Compound 28
Compound 28 (30.9 mg,0.1 mmol) was dissolved in 6mLDMF was added with NaH (50.1 mg,1.25 mmol) and stirred in an ice bath for half an hour, diethylene glycol (3 mL,5 mmol) was added, the mixture was heated at 130℃for 3 hours, water was added for quenching reaction, dichloromethane was added for extraction, dichloromethane was distilled off under reduced pressure, column chromatography was carried out, and the volume ratio of developing solvent was ethyl acetate to dichloromethane to methanol=10:2:1. 18.1mg of product was obtained in a yield of 51.7%. The structure is as follows: 1H-NMR (400 MHz, (CD) 3 ) 2 SO)δ8.88(dd,J＝4.5,1.6Hz,1H),8.77(d,J＝2.4Hz,1H),8.46(s,1H),8.43(d,J＝7.1Hz,1H),8.30–8.24(m,2H),7.61(dd,J＝7.3,3.7Hz,1H),7.26(d,J＝7.2Hz,1H),6.92(d,J＝8.6Hz,1H),4.42–4.37(m,2H),3.76–3.72(m,2H),3.47(t,J＝3.6Hz,4H).
Example 29: synthesis of labeled precursor Compound 29
Labeled precursor compound 29 was synthesized according to the synthesis method of example 16 starting from intermediate compound 28 to yield 50.3mg of a white product with a yield of 66.7%. The structure is as follows: 1H-NMR (600 MHz, CDCl) 3 )δ9.01(dd,J＝4.5,1.4Hz,1H),8.75(d,J＝2.4Hz,1H),8.42(dd,J＝8.6,2.3Hz,1H),8.07(t,J＝8.2Hz,2H),7.98(s,1H),7.79(d,J＝8.2Hz,2H),7.54(dd,J＝8.0,4.5Hz,1H),7.30(d,J＝8.4Hz,2H),7.08(d,J＝7.2Hz,1H),6.81(d,J＝8.6Hz,1H),4.44–4.40(m,2H),4.22–4.18(m,2H),3.80–3.77(m,2H),3.76–3.73(m,2H),2.40(s,3H).
Example 30: compound 30
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The synthesis precursor compound 29 (25.7 mg,0.05 mmol) and TBAF (0.25 mL,0.25 mmol) were reacted in 5mL anhydrous tetrahydrofuran at 60℃for 2 hours, after which the tetrahydrofuran was removed by distillation under reduced pressure, column chromatography was separated, and the volume ratio of the developing solvent to methylene chloride: methanol=12:1 to give 14.1mg of yellow solid in 81.6% yield. The structure is as follows: 1H-NMR (400 MHz, CDCl) 3 )δ9.01(dd,J＝4.5,1.4Hz,1H),8.69(d,J＝2.1Hz,1H),8.32(dd,J＝8.6,2.4Hz,1H),8.07(dd,J＝8.2,1.6Hz,1H),8.06–8.02(m,1H),7.94(s,1H),7.55(dd,J＝8.0,4.5Hz,1H),7.09(d,J＝7.2Hz,1H),6.79(d,J＝8.6Hz,1H),4.68–4.65(m,1H),4.57–4.53(m,1H),4.52–4.48(m,2H),3.93–3.89(m,2H),3.88–3.85(m,1H),3.81–3.77(m,1H).
The schematic of the synthesis of the compounds of examples 21-30 above is shown in FIG. 2.
Example 31: synthesis of intermediate Compound 31
Intermediate compound 31 was synthesized following the synthesis of example 1 to yield 167.9mg of product in approximately 62.7% yield. The next reaction was directly carried out without purification.
Example 32: synthesis of intermediate Compound 32
Intermediate compound 31 (1.2 g,3 mmol) was dissolved in 10mL of dichloromethane, 5mL of trifluoroacetic acid was added thereto and reacted at room temperature for 3 hours, after the completion of the reaction, dichloromethane and trifluoroacetic acid were distilled off under reduced pressure, diethyl ether was added, and suction filtration was performed to obtain 680.1mg of a white solid with a yield of about 91.3%. The next reaction was directly carried out without purification.
Example 33: synthesis of intermediate Compound 33
Intermediate compound 32 (490.3 mg,2 mmol), 3-bromo-1-propanol (1.9 g,12 mmol) and cesium carbonate (3.3 g,10 mmol) were dissolved in 25mL acetonitrile, and 90℃overnight to give 86.3mg of a pale yellow solid in about 14.0% yield. The next reaction was directly carried out without purification.
Example 34: synthesis of Compound 34
Compound 34 was synthesized according to the procedure for the synthesis of example 33 to yield 16.7mg of a pale yellow solid in 17.9% yield. The structure is as follows: 1H-NMR (600 MHz, CDCl) 3 )δ8.92(dd,J＝4.5,1.5Hz,1H),7.97(dd,J＝8.1,1.4Hz,1H),7.91(d,J＝7.0Hz,1H),7.44(dd,J＝8.0,4.6Hz,1H),7.35(s,1H),6.96–6.90(m,1H),4.55(t,J＝6.1Hz,1H),4.47(t,J＝6.0Hz,1H),3.02(d,J＝11.2Hz,2H),2.90(tt,J＝11.7,3.5Hz,1H),2.51(t,J＝7.4Hz,2H),2.24(d,J＝12.6Hz,2H),2.14(t,J＝11.2Hz,2H),1.98–1.86(m,2H),1.85–1.76(m,2H).
Example 35: synthesis of labeled precursor Compound 35
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The synthesis of labeled precursor compound 35 was followed by the synthesis of example 16 to give 12.5mg of a white solid in 10.0% yield. The structure is as follows: 1H-NMR (600 MHz, CD) 3 OD)δ8.94(dd,J＝4.5,1.5Hz,1H),8.01(dd,J＝8.0,1.5Hz,1H),7.97(d,J＝7.0Hz,1H),7.80(d,J＝8.0Hz,2H),7.61(s,1H),7.48(dd,J＝8.0,4.4Hz,1H),7.13(d,J＝8.0Hz,2H),6.97(d,J＝7.2Hz,1H),4.56(t,J＝8.4Hz,2H),4.38(t,J＝8.3Hz,2H),3.90(s,2H),3.88(d,J＝3.4Hz,1H),2.76–2.69(m,2H),2.44(s,1H),2.32(s,4H),1.71(s,3H).
Example 36: synthesis of intermediate Compound 36
Intermediate compound 36 was synthesized following the synthesis procedure of example 1 starting from 8-amino-1, 7-naphthyridine and chloroacetaldehyde. 177.5mg of white product was obtained in 71.3% yield. The structure is as follows: 1H-NMR (600 MHz, CD) 3 OD)δ8.94(dd,J＝4.3,1.3Hz,1H),8.01–7.98(m,2H),7.70(s,1H),7.63(d,J＝0.9Hz,1H),7.47(dd,J＝8.0,4.5Hz,1H),6.99(d,J＝7.2Hz,1H).
Example 37: synthesis of intermediate Compound 37
Intermediate compound 37 was synthesized following the synthesis procedure of example 24 starting from intermediate compound 36. 237.9mg of white solid was obtained in 87.8% yield. The next reaction was directly carried out without purification.
Example 38: synthesis of labeled precursor Compound 38
The synthesis of labeled precursor compound 38 was performed according to the synthesis method of example 22, starting from intermediate compound 37. 209.7mg of white powder was obtained in a yield of 49.1%. The structure is as follows: 1H-NMR (400 MHz, (CD) 3 ) 2 SO)δ8.75(d,J＝8.9Hz,1H),8.64(d,J＝7.2Hz,1H),8.30(d,J＝8.8Hz,1H),8.19(s,1H),7.75(s,1H),7.43(d,J＝7.2Hz,1H),3.68(s,9H).
Example 39: synthesis of Compound 39
Compound 39 was synthesized according to the synthesis method of example 23 starting from labeled precursor compound 38. 36.2mg of white solid was obtained in 50.3% yield. The structure is as follows: 1H-NMR (400 MHz, (CD) 3 ) 2 SO)δ8.48(dd,J＝12.9,7.2Hz,2H),8.07(s,1H),7.63(s,1H),7.40(d,J＝8.5Hz,1H),7.30(d,J＝7.0Hz,1H).
A schematic of the synthesis of the compounds of examples 31-39 above is shown in FIG. 3.
Example 40: intermediate compound 40
2-amino-3-nitro-4-methylpyridine (1.5 g,10 mmol) and chloroacetaldehyde (1.5 g,30 mmol) were dissolved in 25mL of ethanol, refluxed for 3 hours, distilled off under reduced pressure to remove the solvent, 100mL of water was added and extracted three times with dichloromethane, distilled off under reduced pressure to remove the solvent, and the crude product was obtained as a yellow solid, which was directly put into the next reaction without identification.
Example 41: synthesis of intermediate Compound 41
Starting from intermediate compound 40 (870.4 mg,5 mmol) and N, N-dimethylformamide dimethyl acetal (1.2 g,10 mmol) were dissolved in 15mL DMF and reacted at 130℃for 2 hours, the solvent was distilled off under reduced pressure, 100mL of water was added and extracted three times with dichloromethane, and the solvent was distilled off under reduced pressure to give a dark red solid crude product which was directly taken for the next reaction without identification.
Example 42: synthesis of intermediate Compound 42
Intermediate compound 41 (1.2 g,5 mmol) and sodium periodate (5.0 g,21 mmol) were dissolved in 45mL THF/45mL water and reacted at room temperature for 24 hours, then the solvent was distilled off under reduced pressure, 100mL water was added and extracted three times with methylene chloride, and the solvent was distilled off under reduced pressure to give a crude yellow solid product which was directly taken for the next reaction without identification.
Example 43: synthesis of intermediate Compound 43
Intermediate compound 42 (900.4 mg,5 mmol) and iron powder (560.2 mg,10 mmol) were dissolved in 30mL ethanol/3 mL water, five drops of concentrated hydrochloric acid were added dropwise to the stirred solution, and after reflux reaction for 3 hours, the solution was pumped outMost of the solvent was removed by filtration, distillation under reduced pressure, and when the pH was neutralized to neutrality by adding a saturated sodium bicarbonate solution, 100mL of water was added and extracted three times with methylene chloride, and the solvent was removed by distillation under reduced pressure to give compound 53 (388.2 mg,2.5 mmol) as a pale yellow solid, yield 51.4%. The structure is as follows: 1H-NMR (400 MHz, CDCl) 3 )δ9.80(s,1H),7.58(d,J＝0.6Hz,1H),7.52(d,J＝0.7Hz,1H),7.44(d,J＝6.9Hz,1H),6.83(d,J＝7.0Hz,1H).
Example 44: synthesis of Compound 44
Intermediate compound 43 (155.1 mg,1 mmol) and p-iodoacetophenone (258.6 mg,1 mmol) were dissolved in 30mL ethanol, 3g potassium hydroxide was added, after reflux reaction for 6 hours, 1M hydrochloric acid was added to neutralize to neutrality, the solvent was distilled off under reduced pressure, column chromatography was separated, and the developing solvent was ethyl acetate: dichloromethane: methanol=8:2:1 to give a pale yellow solid (100.9 mg,0.27 mmol), yield 27.2%, structure as follows: 1H-NMR (400 MHz, CDCl) 3 )δ8.34–8.31(m,2H),8.07(d,J＝8.4Hz,1H),7.99(dd,J＝7.8,3.6Hz,2H),7.75(d,J＝1.2Hz,1H),7.65(d,J＝1.2Hz,1H),7.49(d,J＝7.5Hz,1H),7.03(d,J＝7.1Hz,1H).
Example 45: synthesis of precursor Compound 45
The procedure of example 5 was followed, using intermediate compound 44 as a starting material, to synthesize labeled precursor compound 45, affording 20.3mg of a pale yellow solid in 39.1% yield. The structure is as follows: 1H-NMR (400 MHz, CDCl) 3 )δ8.25(d,J＝8.1Hz,2H),8.05(d,J＝8.4Hz,1H),7.97(d,J＝7.3Hz,2H),7.74(d,J＝1.2Hz,1H),7.64(d,J＝1.2Hz,1H),7.59(d,J＝8.1Hz,2H),7.02(d,J＝7.1Hz,1H),1.58–1.54(m,4H),1.36–1.31(m,4H),1.08(d,J＝6.3Hz,7H),0.93–0.88(m,12H).
Example 46: synthesis of intermediate Compound 46
Intermediate compound 57 was synthesized following the synthesis procedure of example 40 starting from 2-methyl-3-nitro-6-aminopyridine to afford a yellow solid crude product which was directly fed to the next reaction without purification.
Example 47: synthesis of intermediate Compound 47
According to the synthesis method of example 41, intermediate compound 46 was used as a starting material to synthesize intermediate compound 47, and a dark red solid crude product was obtained and directly subjected to the next reaction without purification and identification.
Example 48: synthesis of intermediate Compound 48
According to the synthesis method of example 42, intermediate compound 47 was used as a raw material to synthesize intermediate compound 59, and a brown yellow solid crude product was obtained and directly fed to the next reaction without purification and identification.
Example 49: synthesis of intermediate Compound 49
Intermediate compound 49 was synthesized according to the procedure for the synthesis of example 43 starting from intermediate compound 48 to yield 97.3mg of yellow solid in 42.1% yield. The structure is as follows: 1H-NMR (400 MHz, CD) 3 OD)δ10.19(s,1H),7.62(d,J＝9.6Hz,1H),7.41(d,J＝1.0Hz,1H),6.87(d,J＝9.6Hz,1H).
Example 50: synthesis of Compound 50
Compound 50 was synthesized according to the procedure for the synthesis of example 44, starting from intermediate compound 49, to yield 12.6mg of a yellow-green solid with a yield of 17.3%. The structure is as follows: 1H-NMR (600 MHz, (CD) 3 ) 2 SO)δ8.87(d,J＝8.7Hz,1H),8.73(s,1H),8.31(dd,J＝8.7,2.0Hz,1H),8.22(d,J＝7.4Hz,1H),8.03(d,J＝8.3Hz,1H),7.89(d,J＝8.3Hz,1H),7.81(d,J＝9.6Hz,1H),7.76(t,J＝9.9Hz,1H),7.68(s,1H),7.53(t,J＝7.5Hz,1H).
Example 51: synthesis of precursor Compound 51
According to the synthesis method of example 45, starting from compound 50, precursor compound 51 was synthesized to give 8.0mg of a pale yellow solid with a yield of 22.8%. The structure is as follows: 1H-NMR (600 MHz, CDCl) 3 )δ8.28(d,J＝8.7Hz,1H),8.07–8.03(m,4H),7.99(d,J＝8.7Hz,1H),7.82(t,J＝9.7Hz,3H),7.36(d,J＝4.3Hz,1H),1.61–1.54(m,4H),1.39–1.32(m,5H),1.13–1.07(m,9H),0.90(dd,J＝12.1,5.0Hz,8H).
A schematic of the synthesis of the compounds of examples 40-51 above is shown in FIG. 4.
Example 52: synthesis of Compound 52
According to the synthesis method of example 1, starting from 8-amino-1, 7-naphthyridine and α -bromometa-fluoroacetophenone, 33.2mg of a pale yellow solid are obtained, with a yield of 47.2%, the structure being as follows: 1H-NMR (600 MHz, CDCl) 3 )δ9.00(d,J＝4.3Hz,1H),8.01(d,J＝7.8Hz,1H),7.98(d,J＝7.1Hz,1H),7.89(s,1H),7.85(d,J＝7.8Hz,2H),7.49(dd,J＝8.0,4.5Hz,1H),7.38–7.34(m,1H),7.00(d,J＝7.0Hz,2H).
Example 53: synthesis of Compound 53
According to the synthesis method of example 1, starting from 8-amino-1, 7-naphthyridine and α -bromometa-iodoacetophenone, 12.1mg of a tan solid is obtained, with a yield of 30.9%, the structure being as follows: 1H-NMR (600 MHz, CDCl) 3 )δ9.00(s,1H),8.53(s,1H),8.03(d,J＝7.8Hz,2H),7.99(d,J＝7.1Hz,1H),7.90(s,1H),7.63(d,J＝7.7Hz,1H),7.51(s,1H),7.14(t,J＝7.7Hz,1H),7.01(s,1H).
Example 54: synthesis of Compound 54
According to the synthesis method of example 1, starting from 4-aminoquinazoline and 2' -bromo-4-iodoacetophenone, 29.2mg of a earthy yellow solid was obtained in 33.0% yield. The structure is as follows: 1H-NMR (400 MHz, (CD) 3 ) 2 SO)δ9.24(s,1H),8.53(s,1H),8.43(d,J＝7.7Hz,1H),7.90(d,J＝8.1Hz,1H),7.82(s,4H),7.75–7.68(m,2H).
Example 55: synthesis of precursor Compound 55
The procedure was as in example 5, starting from intermediate compound 53, to synthesize labeled precursor compound 55, affording 6.3mg of a pale yellow solid in 27.7% yield. The structure is as follows: 1H-NMR (400 MHz, CDCl) 3 )δ8.99(dd,J＝4.5,1.6Hz,1H),8.14(s,1H),8.08(d,J＝7.3Hz,1H),8.02(d,J＝7.3Hz,2H),7.93(s,1H),7.51–7.47(m,1H),7.41(d,J＝2.2Hz,1H),7.38(d,J＝7.2Hz,1H),7.01(d,J＝7.1Hz,1H),1.61–1.50(m,6H),1.36–1.30(m,6H),1.12–1.08(m,4H),0.92–0.85(m,11H).
Example 56: synthesis of precursor Compound 56
The procedure was as in example 5, starting from intermediate compound 54, to synthesize labeled precursor compound 56, giving 11.3mg of a pale yellow solid in 35.9% yield. The structure is as follows: 1H-NMR (400 MHz, CDCl) 3 )δ8.88(s,1H),8.67(s,1H),7.99–7.92(m,3H),7.89(s,1H),7.68(t,J＝7.0Hz,2H),7.56(d,J＝8.0Hz,2H),1.59(d,J＝7.2Hz,8H),1.38–1.32(m,8H),1.10(dd,J＝10.1,4.6Hz,5H),0.95–0.88(m,6H).
Example 57: synthesis of precursor Compound 57
Potassium peroxymonosulphonate (300.4 mg,1 mmol) at 53 (285.1 mg,0.75 mmol), 6.10-dioxaspiro [4.5 ]]The preparation method comprises the steps of dissolving 53 and potassium peroxymonosulfonate in 6mL of chloroform, dropwise adding 3.5mL of TFA, stirring at room temperature for half an hour, removing solvent by reduced pressure distillation after the reaction is finished, dissolving in ethanol, adding ketone, regulating the pH of the solution to be more than 10 by using a saturated solution of sodium bicarbonate, reacting at room temperature for 3 hours, removing the solvent by reduced pressure distillation, adding 20mL of water, extracting three times by using dichloromethane, removing the solvent by reduced pressure distillation, separating by column chromatography, wherein a developing solvent system is ethyl acetate, namely dichloromethane: methanol=8:4:1, and obtaining 19.4mg of white solid with the yield of 5.1%. The structure is as follows: 1H-NMR (400 MHz, CDCl) 3 )δ8.99(s,1H),8.60(s,1H),8.24(s,1H),8.03(dd,J＝18.1,7.5Hz,2H),7.95(s,1H),7.70(d,J＝6.2Hz,1H),7.53(dd,J＝7.0,4.1Hz,1H),7.41(s,1H),7.05(d,J＝7.0Hz,1H),2.17(s,4H),1.79(s,4H).
Example 58: synthesis of precursor Compound 58
The synthesis of labeled precursor compound 58 was followed by the synthesis of example 57 starting from compound 1 to give 21.9mg of a pale yellow solid with a yield of 8.3%. The structure is as follows: 1H-NMR (400 MHz, C)DCl 3 )δ9.01(d,J＝4.6Hz,1H),8.14(d,J＝8.4Hz,2H),8.06(d,J＝8.1Hz,1H),8.03–7.98(m,2H),7.92(d,J＝8.4Hz,2H),7.54(dd,J＝8.0,4.6Hz,1H),7.06(d,J＝7.3Hz,1H),2.16(s,4H),1.79(s,4H).
Example 59: synthesis of intermediate Compound 59
Starting from intermediate compound 36 (281.3 mg,1.7 mmol), N-bromosuccinimide (600.9 mg,3.5 mmol) was dissolved in 20mL acetonitrile, TMS-OTf (390.9 mg,1.8 mmol) was added dropwise and reacted at 40℃for half an hour to give 400.3mg as a pale yellow solid with a yield of 93.9%, the structure was as follows: 1H-NMR (400 MHz, (CD) 3 ) 2 SO)δ8.91(dd,J＝4.5,1.6Hz,1H),8.36(dd,J＝8.1,1.6Hz,1H),8.27(d,J＝7.3Hz,1H),7.76(s,1H),7.66(dd,J＝8.1,4.5Hz,1H),7.43(d,J＝7.3Hz,1H).
Example 60: synthesis of Compound 60
Starting from intermediate 59 (204.1 mg,0.8 mmol), 4-iodophenylboronic acid (202.3 mg,1 mmol) in 15mL dioxane, bis (triphenylphosphine) palladium chloride (49.5 mg,0.07 mmol) and potassium carbonate (350.8 mg,2.5 mmol) were added, nitrogen protection, overnight at 110 ℃, the reaction was completed, the solvent was distilled off under reduced pressure, column chromatography was separated, the developing solvent was ethyl acetate: dichloromethane=1:1, 67.7mg of pale yellow solid was obtained, yield 22.5%, structure was as follows: 1H-NMR (400 MHz, CDCl) 3 )δ8.99(dd,J＝4.5,1.6Hz,1H),8.10(d,J＝7.3Hz,1H),8.04(dd,J＝8.0,1.6Hz,1H),7.88(d,J＝8.5Hz,2H),7.76(s,1H),7.51(dd,J＝8.1,4.5Hz,1H),7.33(d,J＝8.4Hz,2H),7.04(d,J＝7.4Hz,1H).
Example 61: synthesis of precursor Compound 61
The synthesis of labeled precursor compound 61 was followed by the synthesis of example 5 starting from intermediate compound 60 to give 9.0mg of a pale yellow solid with a yield of 29.9%. The structure is as follows: 1H-NMR (400 MHz, CDCl) 3 )δ8.98(d,J＝4.4Hz,1H),8.20(d,J＝7.3Hz,1H),8.02(d,J＝8.0Hz,1H),7.76(s,1H),7.63(d,J＝7.8Hz,2H),7.53(d,J＝7.2Hz,3H),7.01(d,J＝7.4Hz,1H),1.61–1.55(m,6H),1.36(d,J＝7.3Hz,6H),1.12(d,J＝8.4Hz,5H),0.90(t,J＝7.3Hz,10H).
A schematic of the synthesis of the compounds of examples 59-61 above is shown in FIG. 5.
Example 62: 125 preparation of I-labeled compounds
(a) Compounds [ 125 I]1，[ 125 I]2，[ 125 I]3，[ 125 I]8，[ 125 I]44，[ 125 I]50，[ 125 I]53，[ 125 I]54 and [ 125 I]60 preparation
0.1mg of the labeled precursor compounds (compounds 5,6,7,9, 45, 51, 55, 56 and 61, respectively) were dissolved in 100. Mu.L of ethanol, and about 70. Mu. Ci Na was added 125 I solution, 100. Mu.L of hydrochloric acid (1M) and 50. Mu.L of 3% hydrogen peroxide solution, reacted at room temperature for 15 minutes, naHCO was added 3 To neutral pH. Then separating and purifying by HPLC under the following conditions: venusil MP C18 column (5 μm,4.6 mm. Times.250 mm), the effluent of the target product was collected, acetonitrile was removed with nitrogen, and the resulting product was formulated into the desired solution.
Example 63: 18 preparation of F-labelled compounds
(1) Compounds [ 18 F]4 preparation of the catalyst
(a)[ 18 F]F - Ion enrichment on QMA column, washing the QMA column with 3mL of methanol, and washing with 1mL of eluent (containing 0.5mg of TEAB in methanol) 18 F]F - Eluting from the QMA column. About 20mCi of fluoride ion solution was added to a 10mL glass reaction tube, heated in a metal bath at 120deg.C, and continuously introduced with N 2 Blow-drying to ensure that the reaction system is anhydrous. 3.5mg of the labeled precursor compound (Compound 10) and 6mg of Cu (OTf) 2 (Py) 4 Dissolved in 100. Mu.L 1Butanol and 200 μl DMA, and transferring the solution to a solution containing [ solution ] 18 F]F - Is provided. The reaction was heated at 110℃for 20 minutes. After cooling, 10mL of deionized water was added to dilute the reaction mixture. The mixture was purified by passing through a pretreated Sep-Pak C18 solid phase extraction cartridge, eluting the cartridge with 20mL deionized water to remove unreacted [ 18 F]F - Inorganic salts. The column was rinsed with 1mL of anhydrous acetonitrile, and the labeled compound, labeled precursor compound, etc. adsorbed on the column were eluted, concentrated, and then separated and purified by HPLC under the conditions of separation: venusil MP C18 reverse column (5 μm,10 mm. Times.250 mm), the effluent of the target product was collected, the solvent was dried with nitrogen, and the resulting product was dissolved in 10% ethanol and purified water to the desired concentration.
(b)[ 18 F]F - Ions were concentrated on QMA column and then eluted with 1mL of eluent (TEAB 2mg, acetonitrile/water=7/3) to give [ [ 18 F]F - Eluting from the QMA column. About 20mCi of fluoride ion solution was added to a 10mL glass reaction tube, heated in a metal bath at 120deg.C, and continuously introduced with N 2 Blow-drying to ensure that the reaction system is anhydrous. 2mg of the labeled precursor compound (Compound 58) was dissolved in 400. Mu.L of DMF, and the solution was transferred to a container [ containing ] 18 F]F - Is provided. The reaction was heated at 110℃for 10 minutes. After cooling, separation and purification by HPLC, separation conditions: venusil MP C18 reverse column (5 μm,10 mm. Times.250 mm), the effluent of the target product was collected, the solvent was dried with nitrogen, and the resulting product was dissolved in 10% ethanol and purified water to the desired concentration.
(2) Compounds [ 18 F]12，[ 18 F]19，[ 18 F]20，[ 18 F]40 and [ 18 F]34, preparation of the
[ 18 F]F - The ions were concentrated on a QMA column using 1mL of eluent (containing Kryptofix-2.2.2 13mg, K 2 CO 3 1.1mg, acetonitrile/water=4/1) will [ 18 F]F - Eluting from the QMA column. About 20mCi of fluoride ion solution was added to a 10mL glass reaction tube, heated in a metal bath at 120deg.C, and continuously introduced with N 2 Blow-drying to ensure the reaction bodyIs anhydrous. 1.5mg of the labeled precursor compounds (compounds 16, 17, 18, 29 and 35) were dissolved in 300. Mu.L of anhydrous acetonitrile, and the solution was transferred to a container [ containing ] 18 F]F - Is provided. Heating and reacting for 5-10 minutes at 100 ℃. After cooling, separation and purification by HPLC, separation conditions: venusil MP C18 reverse column (5 μm,10 mm. Times.250 mm), the effluent of the target product was collected, the solvent was dried with nitrogen, and the resulting product was dissolved in 10% ethanol and purified water to the desired concentration.
(3) Compounds [ 18 F]23，[ 18 F]26, sum [ 18 F]39 preparation
[ 18 F]F - Ion enrichment on QMA column, eluting with 1mL of eluent (containing TBAB 6.8mg, acetonitrile/water=7/3) [ 18 F]F - Eluting from the QMA column. About 20mCi of fluoride ion solution was added to a 10mL glass reaction tube, heated in a metal bath at 120deg.C, and continuously introduced with N 2 Blow-drying to ensure that the reaction system is anhydrous. 1mg of the labeled precursor compound (compounds 22, 25 and 38) was dissolved in 300. Mu.L of anhydrous DMSO, and the solution was transferred to a solution containing [ 18 F]F - Is provided. The reaction was heated at 100deg.C for 6 minutes. After cooling, separation and purification by HPLC, separation conditions: venusil MP C18 reverse column (5 μm,10 mm. Times.250 mm), the effluent of the target product was collected, the solvent was dried with nitrogen, and the resulting product was dissolved in 10% ethanol and purified water to the desired concentration.
(4) Compounds [ 18 F]52 preparation of the
[ 18 F]F - Ions were concentrated on QMA column and then eluted with 1mL of eluent (TEAB 2mg, acetonitrile/water=7/3) to give [ [ 18 F]F - Eluting from the QMA column. About 20mCi of fluoride ion solution was added to a 10mL glass reaction tube, heated in a metal bath at 120deg.C, and continuously introduced with N 2 Blow-drying to ensure that the reaction system is anhydrous. 2mg of the labeled precursor compound (compound 57) was dissolved in 400. Mu.L of DMF, and the solution was transferred to a container [ containing ] 18 F]F - Is provided. The reaction was heated at 110℃for 10 minutes. After cooling, separation and purification by HPLC, separation conditions: venThe usil MP C18 reverse column (5 μm,10 mm. Times.250 mm), the effluent of the target product was collected, the solvent was dried with nitrogen, and the resulting product was dissolved in 10% ethanol and purified water to the desired concentration.
Results of two experiments
[ 125 I]1，[ 125 I]2，[ 125 I]3，[ 18 F]4，[ 125 I]8，[ 18 F]12，[ 18 F]19，[ 18 F]20，[ 18 F]23，[ 18 F]26，[ 18 F]30，[ 18 F]34，[ 18 F]39，[ 125 I]44，[ 125 I]50，[ 18 F]52，[ 125 I]53，[ 125 I]54 and [ 125 I]60 is marked as follows, and the radiochemical purity is more than 95% after HPLC separation and purification. The column was a Venusil MP C18 reverse column (5 μm,10 mm. Times.250 mm) and the mobile phase flow rates were all 4mL/min, the labeling rates are shown in Table 1.
Table 1: labeling efficiency of labeling compound
Example 64: autoradiography experiment
The labeled products (10% ethanol solution) with certain concentration are respectively incubated with brain slices of AD patients for a certain time at room temperature, after incubation, the brain slices are exposed through a phosphorus screen, and then the images are analyzed by a phosphorus screen system.
1. The experimental steps are as follows:
(1) Preprocessing AD human brain slices;
(2) Covering AD human brain slices with 5 μCi/mL 125 I-labeled or 20. Mu. Ci/mL 18 1mL of F-labeled compound solution, and incubating for 1.5 hours or 1 hour at room temperature;
(3) Soaking with 50% ethanol solution for 30 min, or washing with 50% ethanol for 5 min;
(4) After being dried, the preservative film is coated under the phosphorus screen for exposure for 24 hours 125 Labeled compound I) or 1 hour% 18 F labeling compound), the image is analyzed with a phosphor screen system.
2. Experimental results:
the experimental results are shown in fig. 6,7 and 8, and fully illustrate that the compound provided by the invention can be used as an AD brain Tau protein imaging agent after being marked by radionuclides, and has potential application prospects in clinical diagnosis.
Example 65: in vivo biodistribution experiments in normal mice
1. The experimental steps are as follows:
5-10. Mu. Ci 18 F-labelled compound or 1-2. Mu. Ci 125 The I-labeled compound (100 μl of physiological saline solution containing 10% ethanol) was injected into normal mice (ICR, males, 18-20g,3-4 weeks old) from the tail vein (n=3 or 5), and relevant organs were dissected out at 2 minutes, 10 minutes, 30 minutes and 60 minutes after injection, respectively, and wet weights and radioactivity counts were measured. Data are expressed as percent radioactivity per gram of viscera (% ID/g).
2. Experimental results:
the experimental results are shown in Table 2, and the probe according to the present invention 125 I]1、[ 125 I]2、[ 18 F]4 can smoothly pass through the blood brain barrier, and the brain uptake reaches a peak value in 2 minutes and is cleared quickly in the brain of a normal mouse.
Table 2: animal distribution results of partial Compounds in Normal mice
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Example 66: determination of Tau Activity
1. The experimental steps are as follows:
(1) Preprocessing AD human brain slices;
(2) 10 μCi/mL of coverage on AD human brain sections 125 1mL of a solution of the labeled compound of I, to which stable cold ligand (final concentration of 0.1nM,1nM,5nM,10nM,50nM,100nM and 500 nM) was added, was incubated at room temperature for 2 hours;
(3) Soaking with 50% ethanol solution for 30 min, or washing with 50% ethanol solution for 5 min;
(4) After drying, the preservative film is coated under a phosphorus screen for exposure for 24 hours, and the image is analyzed by a phosphorus screen storage system to obtain a quantized value (Digital Light Unit/mm) of Region of interests (ROIs) 2 ，DLU/mm 2 ) Fitting a curve according to the values and the corresponding cold ligand concentrations, the half-inhibition constant (IC 50 ) And obtaining the product through fitting calculation.
2. Experimental results:
experimental results indicate that IC of Compound 1 50 IC with a value of 1.63nM, compound 4 50 The value was 8.22nM, and as shown in Table 3, the activity of some of the compounds was evaluated by inhibition experiments (final cold ligand concentration of 10 nM), indicating that the probes of the invention, particularly compounds 1 and 4, had particularly high activity against Tau protein.
Table 3: evaluation of partial Compound Tau Activity
Example 67: aβ Activity assay
1. Experimental procedure
(1) mu.L of radioligand ([ solution ]) was added 125 I]IMPY,100000 CPM/100. Mu.L), 100. Mu.L ethanol solutions of Compounds 1,4, 12, 19 and 20 (10 -4 M to 10 -10 M), 700. Mu.L BSA (0.1% PBS solution) and Abeta 1-42 The aggregates (100. Mu.L, final concentration 0.7. Mu.M) were sequentially added to borosilicate glass tubes.
(2) Incubate at 37℃for 2 hours with standing.
(3) The cells were isolated by filtration using MP-48T cell harvester from Brandel, U.S.A., and washed three times with 10% ethanol.
(4) Collecting the product containing Aβ 1-42 Aggregate-bound 125 The glass fiber filter paper of the I ligand was placed at the bottom of the numbered counting tube and the radioactivity count of each counting tube was measured using a Wizard2 2480 gamma counter from Perkinelmer, U.S.A. Semi-suppression constant (IC) 50 ) Obtained by fitting calculation, the inhibition constant (K i ) K is calculated according to the Cheng-Prusoff equation i ＝IC 50 /(1+[L]/K d )。
2. Experimental results
The experimental results are shown in Table 4, with compounds 1,4, 12, 19 and 20 having activity on Abeta (K i ) Substantially on the order of micromolar, substantially illustrates poor binding to aβ.
Table 4: some of the Compounds Aβ 1-42 Results of Activity test
Compounds of formula (I) Aβ Activity (nM)
1 985.07
4 441.19
12 ＞1000
19 ＞1000
20 ＞1000
Example 68: MAO-A/B Activity assay
1. Experimental procedure
(1) A substrate solution was prepared and 10. Mu.L of 4- (trifluoromethyl) benzylamine was dissolved in 9990. Mu.L of PBS (1X).
(2) A color development solution was prepared, and 2.03mg of 4-aminoantipyrine, 3.36mg of vanillic acid, and 400. Mu.L of an aqueous horseradish peroxidase solution (2 mg/mL) were dissolved in 19.6 mLPBS.
(3) An inhibitor solution, i.e. a 1000nM aqueous solution of selegiline and clofaline, was formulated.
(4) In a 96-well plate, 50 mu L of extracted enzyme solution and 50 mu L of inhibition solution are added, incubation is carried out for 30 minutes at 37 ℃,50 mu L of samples to be tested with different concentrations are added after incubation is finished, incubation is carried out for 30 minutes at 37 ℃,100 mu L of substrate and 40 mu L of chromogenic solution are added after incubation is finished, and incubation is carried out for 90 minutes at 37 ℃.
(5) After incubation, ultraviolet absorbance is measured at 490nm by an enzyme-labeled instrument, the abscissa is the negative logarithmic value of the final concentration of the sample to be measured, the ordinate is the absorbance, and IC is calculated by using one-site mode 50 Values.
2. Experimental results
Experimental results indicate that the IC's for Compounds 1,2,3,8, 44, 53, 54 and 60 50 Values above 1000nM, indicating that they are inactive with MAO-A/B, and that there is no corresponding non-target uptake in the brain.
While the invention has been described in detail in the foregoing general description and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed. The foregoing description is only illustrative of the preferred embodiments of the present invention and is not to be construed as limiting the scope of the invention, i.e., the invention is not to be limited to the details of the invention.

Claims (6)

1. An imidazonaphthyridine compound, characterized in that it is selected from the following compounds:
wherein I in compounds 1-4, compounds 14-17 and compound 19 is 123 I， 125 I or 127 I；
Compounds 5-13 and 18 wherein F is 18 F or F 19 F。
2. The process for the preparation of imidazonaphthyridines according to claim 1, wherein when I is 123 I or 125 I, compounds 1 to 4, 14 to 17, 19 from tri-n-butyltin or borate precursor Compounds with [ 123/125 I]Reacting NaI solution in the presence of an oxidant to obtain the catalyst;
when F is 18 F, compounds 5-13, compound 18 from OTs, trimethyl Quaternary ammonium salt or borate precursor Compounds with [ 18 F]F anions are obtained by reacting in the presence of a phase transfer catalyst.
3. The derivative of an imidazonaphthyridine compound according to claim 1, wherein said derivative is a pharmaceutically acceptable salt of said imidazonaphthyridine compound.
4. A diagnostic or diagnostic reagent for neurofibromatosis caused by Tau protein deposition, characterized in that the active ingredient is the imidazonaphthyridine compound according to claim 1 and/or the derivative according to claim 3.
5. The diagnostic or test agent of claim 4, wherein the disease comprises alzheimer's disease, frontotemporal degeneration, chronic traumatic encephalopathy, progressive supranuclear palsy, corticobasal degeneration, or pick's disease.
6. Use of an imidazonaphthyridine compound according to claim 1 or a derivative according to claim 3 for the preparation of a nuclear medicine imaging agent; i in the compound or derivative is 125 I or 123 I, F is 18 F。
CN202210744927.0A 2022-06-27 2022-06-27 Imidazonaphthyridine compound with affinity with Tau protein, and preparation method and application thereof Active CN115322197B (en)

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