CN118126009A - Coumarin derivative, preparation method and application - Google Patents
Coumarin derivative, preparation method and application Download PDFInfo
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- CN118126009A CN118126009A CN202211526408.3A CN202211526408A CN118126009A CN 118126009 A CN118126009 A CN 118126009A CN 202211526408 A CN202211526408 A CN 202211526408A CN 118126009 A CN118126009 A CN 118126009A
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- Prior art keywords
- compound
- synuclein
- pharmaceutically acceptable
- organic solvent
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- CFNMUZCFSDMZPQ-GHXNOFRVSA-N 7-[(z)-3-methyl-4-(4-methyl-5-oxo-2h-furan-2-yl)but-2-enoxy]chromen-2-one Chemical compound C=1C=C2C=CC(=O)OC2=CC=1OC/C=C(/C)CC1OC(=O)C(C)=C1 CFNMUZCFSDMZPQ-GHXNOFRVSA-N 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 126
- 108090000185 alpha-Synuclein Proteins 0.000 claims abstract description 57
- 229920000642 polymer Polymers 0.000 claims abstract description 25
- 238000003384 imaging method Methods 0.000 claims abstract description 22
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- 238000009206 nuclear medicine Methods 0.000 claims abstract description 10
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- 230000002799 radiopharmaceutical effect Effects 0.000 claims abstract description 4
- 102000003802 alpha-Synuclein Human genes 0.000 claims abstract 13
- 238000006243 chemical reaction Methods 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- 239000003960 organic solvent Substances 0.000 claims description 25
- 238000002156 mixing Methods 0.000 claims description 23
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 18
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 18
- 238000006467 substitution reaction Methods 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- -1 { 2- [ (2-fluoroethyl) oxy ] ethyl } oxy Chemical group 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 13
- ZOJAINJCZSVZGW-UHFFFAOYSA-N 6-aminochromen-2-one Chemical compound O1C(=O)C=CC2=CC(N)=CC=C21 ZOJAINJCZSVZGW-UHFFFAOYSA-N 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 238000002600 positron emission tomography Methods 0.000 claims description 9
- AUFVJZSDSXXFOI-UHFFFAOYSA-N 2.2.2-cryptand Chemical compound C1COCCOCCN2CCOCCOCCN1CCOCCOCC2 AUFVJZSDSXXFOI-UHFFFAOYSA-N 0.000 claims description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 8
- 238000001514 detection method Methods 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 8
- 206010067889 Dementia with Lewy bodies Diseases 0.000 claims description 7
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- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 6
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 5
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- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 claims description 4
- AIHIHVZYAAMDPM-MRVPVSSYSA-N [(2r)-oxiran-2-yl]methyl 3-nitrobenzenesulfonate Chemical compound [O-][N+](=O)C1=CC=CC(S(=O)(=O)OC[C@@H]2OC2)=C1 AIHIHVZYAAMDPM-MRVPVSSYSA-N 0.000 claims description 4
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 4
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- AIHIHVZYAAMDPM-QMMMGPOBSA-N [(2s)-oxiran-2-yl]methyl 3-nitrobenzenesulfonate Chemical compound [O-][N+](=O)C1=CC=CC(S(=O)(=O)OC[C@H]2OC2)=C1 AIHIHVZYAAMDPM-QMMMGPOBSA-N 0.000 claims description 3
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
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Landscapes
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention provides a coumarin derivative, a preparation method and application thereof, and belongs to the technical field of radiopharmaceuticals. The structural formula is shown as formula I: I, I. The invention provides a preparation method of a compound shown as a formula I. The compounds have high affinity with the alpha-synuclein polymer, and can be directly used as a diagnostic reagent for detecting the alpha-synuclein polymer in a tissue sample. The compounds are labeled with suitable radioisotopes and are useful in nuclear medicine imaging with alpha-synuclein deposition characteristics including, but not limited to, parkinson's disease.
Description
Technical Field
The invention relates to the technical fields of radiopharmaceutical chemistry and clinical nuclear medicine, in particular to coumarin derivatives, a preparation method and application.
Background
Alpha-synuclein (alpha-synuclein) is a soluble protein of 140 amino acids expressed in the presynaptic nerve endings of the central nervous system. In normal physiological environment, alpha-synuclein exists in vivo in three forms of unfolded monomer, different secondary structures and natural oligomer, and the contents of the three are maintained in a relatively balanced state through normal synthetic and degradation pathways. However, under the influence of pathological conditions, such as mutation of SNCA gene or dysfunction of autophagy lysosome system, the physiological balance can be destroyed by increasing the production of alpha-synuclein or blocking the degradation pathway of alpha-synuclein, resulting in the formation of alpha-synuclein oligomers and fibrils. Toxic α -synuclein polymers are secreted by different secretory pathways, further inducing aggregation of α -synuclein monomers. The alpha-synuclein polymer is a main component of a Lewy Body (LBs) and Lewy Neurites (LNs) in the brain of Parkinsonism (PD), and also appears in dementia with lewy bodies (DLB) and other alpha-synuclein deposition diseases such as Multiple System Atrophy (MSA), and is closely related to pathogenesis and dysfunction of related diseases. Therefore, the alpha-synuclein polymer is not only an important pathological marker of the related diseases of alpha-synuclein deposition, but also an ideal target for related disease diagnosis.
The molecular imaging technology realizes noninvasive imaging detection of cell and molecular level by means of probes of target recognition targets, wherein positron emission tomography imaging is an advanced clinical imaging technology in the field of nuclear medicine, and plays an important role in early diagnosis of tumor and brain diseases and evaluation of the curative effect of subclinical lesions. Although antibodies or polypeptides can specifically recognize specific amino acid sequences of alpha-synuclein polymers and have high specificity and sensitivity, the antibodies or polypeptides are not easy to penetrate through blood brain barrier into brain because of biological macromolecules, and are not beneficial to detection of alpha-synuclein polymers in brain. Compared with macromolecules, the organic micromolecular compound has moderate molecular structure and size, and is more beneficial to entering the brain through a blood brain barrier, so that development of an organic micromolecular ligand capable of specifically recognizing an alpha-synuclein polymer in the brain is urgently needed. Up to now, about 37 organic small molecules of the reported affinity α -synuclein polymer, about 23 compounds with radiolabeled are completed, but the research data are mainly in the preclinical evaluation stage, and the reported data show that the compounds still have problems of insufficient protein selectivity, protein affinity, brain entry and the like, which hinders further clinical research. Thus, there is a need to develop novel small organic molecule ligands for specific recognition of α -synuclein polymers in the brain.
Disclosure of Invention
To solve the problems in the background art, a first object of the present invention is to provide coumarin derivatives having affinity with α -synuclein polymers, having a structure represented by formula I,
I；
Wherein R is -OCH2CH2F、-(OCH2CH2)2F、-(OCH2CH2)3F、、/>；
Or a pharmaceutically acceptable form thereof;
Wherein F is 18 F or 19 F.
Further, the compound may be represented by formula IA:
IA；
or a pharmaceutically acceptable form thereof; for example, the compounds may be: 6- [ (1E) - {4- [ (2-fluoroethyl) oxy ] phenyl } ethanamenyl ] -2H-chromen-2-one;
Wherein F is 18 F or 19 F.
Further, the compound may also be represented by formula IB:
IB；
or a pharmaceutically acceptable form thereof; for example, the compounds may be: 6- [ (1E) - [4- ({ 2- [ (2-fluoroethyl) oxy ] ethyl } oxy) phenyl ] ethanamenyl ] -2H-chromen-2-one;
Wherein F is 18 F or 19 F.
Further, the compound may be represented by formula IC:
IC；
Or a pharmaceutically acceptable form thereof; for example, the compounds may be: 6- [ (1E) - {4- [ (8-fluoro-3, 6-dioxaoct-1-yl) oxy ] phenyl } ethanamenyl ] -2H-chromen-2-one;
Wherein F is 18 F or 19 F.
Further, the compound may be represented by formula ID:
ID；
Or a pharmaceutically acceptable form thereof; for example, the compounds may be: 6- [ (1E) - (4- { [ (2S) -2-hydroxybutyl ] oxy } phenyl) ethazinyl ] -2H-chromen-2-one fluoroalkane;
Wherein F is 18 F or 19 F.
Further, the compound may be represented by formula IE:
IE；
Or a pharmaceutically acceptable form thereof; for example, the compounds may be: 6- [ (1E) - (4- { [ (2R) -2-hydroxybutyl ] oxy } phenyl) ethazinyl ] -2H-chromen-2-one fluoroalkane;
Wherein F is 18 F or 19 F.
Further, the pharmaceutically acceptable form of the compound is selected from the group consisting of pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, nitrogen oxides, isotopic labels, metabolites and prodrugs.
The second object of the present invention is to provide a process for producing the coumarin derivative:
(a) When R is 、/>、/>When in use, the preparation method comprises the following steps:
Mixing 6-aminocoumarin with water and a first diazotizing agent sodium nitrite, adjusting pH to be acidic, and performing a first diazotizing reaction to obtain a first diazotizing reaction product system; adjusting the pH value of the first diazotization reaction product system to be neutral, adding phenol, mixing, and carrying out coupling reaction to obtain a first intermediate; notably, are: the source of the 6-aminocoumarin is not particularly limited, and the 6-aminocoumarin can be a commercial product or can be prepared by a method well known to a person skilled in the art; in the invention, the preparation method of the 6-aminocoumarin is preferably as follows: dissolving 6-nitrocoumarin in a methanol-water system, and carrying out reduction reaction with reduced iron powder under an acidic condition to generate 6-aminocoumarin.
The first intermediate structure is shown as formula Ia:
Ia；
Mixing the first intermediate, a chloro compound, an organic solvent and potassium carbonate, and carrying out substitution reaction to obtain a second intermediate; the chloro compound is ClCH 2CH2OH、ClCH2CH2-O-CH2CH2 OH or ClCH 2CH2-O-CH2CH2-O-CH2CH2 OH;
The second intermediate structure is shown as formulas Ib-1 to Ib-3:
Ib-1
Or (b)
Ib-2
Or (b)
Ib-3；
Mixing the second intermediate, diethylaminosulfur trifluoride and an organic solvent for substitution reaction to obtain coumarin derivatives with structures shown in formulas Ic-1 to Ic-3:
Ic-1
Or (b)
Ic-2
Or (b)
Ic-3。
(B) When R is、/>When in use, the preparation method comprises the following steps:
Dissolving the first intermediate in the step (a) and (R) -glycidyl-3-nitrobenzenesulfonate or (S) -glycidyl-3-nitrobenzenesulfonate in an organic solvent, and carrying out substitution reaction under the action of cesium fluoride serving as a first catalyst to obtain a third intermediate;
the third intermediate structure is shown as formulas Id-1 and Id-2:
Id-1
Or (b)
Id-2；
Dissolving the third intermediate in an organic solvent, and carrying out substitution reaction with tetrabutylammonium fluoride to obtain coumarin derivatives with structures shown in formulas Ie-1 and Ie-2:
Ie-1
Or (b)
Ie-2。
The invention also provides another preparation method of the coumarin derivative:
(a) When R is 、/>Or/>When in use, the preparation method comprises the following steps:
Dissolving the second intermediate in an organic solvent, mixing with 4-toluenesulfonyl chloride, and carrying out substitution reaction under the action of a third catalyst 4-dimethylaminopyridine to obtain a fourth intermediate;
The fourth intermediate structure is shown as formulas If-1 to If-3:
If-1
Or (b)
If-2
Or (b)
If-3；
Mixing the Kryptofix 222/K 2CO3 mixed solution and [ 18 F ] potassium fluoride solution, removing the solvent, mixing the obtained residue with a fourth intermediate and an organic solvent, and carrying out nucleophilic substitution reaction under anhydrous conditions to obtain coumarin derivatives with structures shown in formulas Ig-1 to Ig-3; the Kryptofix 222/K 2CO3 mixed solution is obtained by mixing 4,7,13,16,21, 24-hexaoxy-1, 10-diazabicyclo [8.8.8] hexacosane, K 2CO3 and an organic solvent;
Ig-1
Or (b)
Ig-2
Or (b)
Ig-3。
(B) When R is、/>When in use, the preparation method comprises the following steps:
Dissolving the first intermediate in an organic solvent, mixing with (R) - (-) -p-toluenesulfonic acid-2, 2-dimethyl-1, 3-dioxolanyl-4-methyl ester or (S) - (-) -p-toluenesulfonic acid-2, 2-dimethyl-1, 3-dioxolanyl-4-methyl ester, and carrying out substitution reaction under the action of cesium fluoride serving as a fourth catalyst to obtain a fifth intermediate;
The fifth intermediate structure is shown as formulas Ih-1 and Ih-2:
Ih-1
Or (b)
Ih-2；
Dissolving the fifth intermediate in an organic solvent, carrying out hydrolysis reaction with hydrochloric acid, and regulating pH to obtain a sixth intermediate;
the sixth intermediate structure is shown as formulas Ii-1 and Ii-2:
Ii-1
Or (b)
Ii-2；
Dissolving the sixth intermediate in an organic solvent, and carrying out substitution reaction with p-toluenesulfonyl chloride to generate a seventh intermediate;
the seventh intermediate structure is shown as formulas Ij-1 and Ij-2:
Ij-1
Or (b)
Ij-2；
Dissolving the seventh intermediate in an organic solvent, carrying out substitution reaction with 3, 4-dihydro-2H-pyrane under the action of 4-methylbenzenesulfonic acid pyridine (PPTS) to generate an eighth intermediate,
The eighth intermediate structure is shown as formulas Ik-1 and Ik-2:
Ik-1
Or (b)
Ik-2；
Mixing Kryptofix 222/K 2CO3 mixed solution and [ 18 F ] potassium fluoride solution, removing the solvent, mixing the obtained residue with an eighth intermediate, carrying out nucleophilic substitution reaction under anhydrous condition, cooling, adding hydrochloric acid solution, continuing to react at 100 ℃ to remove Boc protecting group, cooling, adding saturated NaHCO 3 solution, and regulating the reaction system to be weak alkaline to obtain coumarin derivatives with structures shown as formulas Il-1 and Il-2; the Kryptofix 222/K 2CO3 mixed solution is obtained by mixing 4,7,13,16,21, 24-hexaoxy-1, 10-diazabicyclo [8.8.8] hexacosane, K 2CO3 and an organic solvent.
Il-1
Or (b)
Il-2。
The invention provides application of the compound in preparing biological detection reagents, diagnostic reagents and diagnostic medicines of alpha-synuclein polymers.
The invention also provides application of the compound in preparing an imaging agent for related diseases caused by alpha-synuclein deposition, wherein the imaging mode is nuclear medicine imaging and magnetic resonance imaging. The related diseases caused by the alpha-synuclein deposition include but are not limited to Parkinson's disease, dementia with lewy bodies, multiple system atrophy and the like.
The invention also provides application of the compound in preparing radiopharmaceuticals of nuclear medicine imaging alpha-synuclein polymers, wherein the nuclear medicine imaging mode is positron emission tomography imaging.
The invention also provides a pharmaceutical composition comprising the compound or a pharmaceutically acceptable form thereof, and one or more pharmaceutically acceptable carriers, and the use of the pharmaceutical composition in the manufacture of a medicament for the prevention and/or treatment of a related disease or disorder caused at least in part by alpha-synuclein deposition.
The invention also provides the use of said compound or a pharmaceutically acceptable form thereof in the manufacture of a medicament for the prophylaxis and/or treatment of a disease or condition associated at least in part with alpha-synuclein deposition.
The invention also provides a composition for imaging alpha-synuclein aggregates, comprising the compound and a pharmaceutically acceptable carrier, the compound being radiolabeled, and the use of the composition in the manufacture of a medicament for inhibiting alpha-synuclein aggregation.
The invention also provides the use of a compound or pharmaceutically acceptable form thereof in the manufacture of a medicament for use in a method for detecting alpha-synuclein aggregation in a patient, the method comprising the steps of: administering a detectable amount of the drug, and detecting binding of the compound to the alpha-synuclein aggregates in the patient. Wherein the detection is performed by performing Positron Emission Tomography (PET) imaging, single Photon Emission Computed Tomography (SPECT), nuclear magnetic resonance imaging, or autoradiography.
Furthermore, the medicine can be used for diagnosing Parkinsonism (PD), dementia with lewy bodies (DLB), multiple System Atrophy (MSA) and other alpha-synuclein aggregation diseases.
Further, the medicament may be used for diagnosing familial parkinson's disease and monitoring treatment of familial parkinson's disease.
The compounds of the invention may also be used in the preparation and use of diagnostic kits.
Compared with the prior art, the invention has the following beneficial effects:
1. Compared with the Chinese patent CN112552272A, the compound provided by the invention is marked by 18 F or 19 F, has good marking stability, and can realize rapid and sufficient positioning marking of the brain-entering and brain-entering alpha-synuclein polymer by adjusting the side chain groups of benzene rings.
2. The compound mother nucleus structure in the compound has good brain entering capability, the whole structure of the compound has plane flexibility, the compound is suitable for protein aggregate combination with a folding structure, and nitrogen atoms contained in the structure are favorable for forming hydrogen bonds with alpha-synuclein polymer, so that affinity and protein selectivity are enhanced. According to the invention, diazobenzene structure is constructed by diazotization, side chain groups capable of performing radiolabeling are added on the side chain of a benzene ring, and the fat-solubility of the compound is regulated by changing the side chain groups of the benzene ring, so that proper brain metabolism and protein affinity are obtained. The compound provided by the invention can be directly used as a developer for detecting alpha-synuclein polymers in vivo or tissue samples, the dyeing time is quick and effective, and nuclear medicine imaging of alpha-synuclein aggregates in the brain can be directly carried out after the radioisotope is marked by adopting the marking precursor and the marking method provided by the invention.
Drawings
FIG. 1 shows the results of autoradiography of brain tissue sections of A53T transgenic mice with compound [ 18 F ]4 of test example 2;
FIG. 2 is a result of staining a brain tissue section of a patient suffering from Parkinson's disease with the compound [ 18 F ]4 of test example 3;
FIG. 3 is a PET/CT image of a compound [ 18 F ]4 of test example 5 in a single-sided striatal injection alpha-synuclein molding mouse (right) and a single-sided striatal injection physiological saline molding mouse (left).
Detailed Description
The invention also provides a synthetic method for the intermediate compound used for preparing the compound.
The compounds described herein can be prepared according to the following schemes and procedures of the examples using suitable materials and are further illustrated by the following specific examples. However, the compounds shown in the examples should not be construed as forming the only genus considered as the present invention. The examples further illustrate details for preparing the compounds of the present invention. Those skilled in the art will readily appreciate that known variations of the conditions and procedures of the following preparation operations may be used to prepare these compounds.
In some cases, the final product may be further modified, for example by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions commonly known to those skilled in the art. In some cases, the order in which the above-described reaction schemes are performed may be altered to promote the reaction or to avoid unwanted reaction products. The following examples are provided so that the present invention may be more fully understood. These examples are merely illustrative and should not be construed as limiting the invention in any way.
The preparation of the compounds of the invention may be carried out in sequential or convergent routes. The synthesis of the compounds of the invention is shown in the following schemes. The techniques required to carry out the reaction and purify the resulting product are known to those skilled in the art. Substituents and labels used in the following process descriptions have the meanings given herein, unless indicated to the contrary. In more detail, the compounds of the present invention can be produced by the methods given below, by the methods given in the examples, or by similar methods. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. The order of the reactions is not limited to that shown in the schemes, but the order of the reaction steps may be arbitrarily changed depending on the starting materials and their respective reactivities. The starting materials are commercially available or can be prepared by methods analogous to those given below, by methods described in the references cited in the specification or in the examples, or by methods known in the art.
In the present invention, the coumarin derivative may specifically be any one of the following compounds:
；
；；
；
；
；
；
；
；
。
In the present invention, the reaction schemes for synthesizing IA, IB, IC compounds and If-1, if-2, if-3 compounds are as follows:
The reaction reagents and conditions involved therein are: (a) Iron powder, hydrochloric acid, methanol and water, condensing and refluxing at 70 ℃ for 10 hours; (b) 0 ℃ sodium nitrite solution, hydrochloric acid, 20min; room temperature, phenol, sodium hydroxide, 1h; (c) Potassium carbonate, sodium iodide, 100 ℃, N-dimethylformamide, 2- (2-chloroethyl) ethanol, 8h; (d) diethylaminosulfur trifluoride, chloroform, 0 ℃ for 1h; (e) P-toluenesulfonyl chloride, triethylamine, 4-dimethylaminopyridine, 0 ℃ to room temperature for 18 h; (f) P-toluenesulfonyl chloride, cesium carbonate, acetonitrile, 25 ℃,10 h; (g) Tetrabutylammonium fluoride-1M tetrahydrofuran solution, condensing and refluxing at 90 ℃ for 6 hours.
The following will specifically describe examples 1 to 11 in connection with the above reaction scheme.
Example 1: synthetic intermediate 1 (6-aminocoumarin)
The synthesis of intermediate 1 comprises the following steps:
1.4g (7.35 mmol) of 6-nitrocoumarin, 120ml of water and 40ml of methanol are added to a 250ml round-bottomed flask, 1.232g (22.05 mmol) of a reducing Fe powder are added, and finally 1.4ml of hydrochloric acid (44.1 mmol) are added dropwise, condensed and refluxed at 70℃and reacted for 10 hours. After cooling to room temperature, the iron powder was removed by filtration, washed with 100ml of methanol and the filtrate was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and dried by spin to give a yellow solid in 83.5% yield.
The structural formula of the intermediate 1 is shown as follows:
The nuclear magnetic data of the synthetic intermediate 1 are shown below ：1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 9.5 Hz, 1H),7.08 (d, J = 8.8 Hz, 1H),6.80 (dd, J = 8.8, 2.8 Hz, 1H), 6.65 (d, J = 2.8 Hz, 1H),6.31 (d, J = 9.5 Hz, 1H), 3.67 (s, 2H).
Example 2: synthesis of intermediate 2
A synthetic intermediate 2 was prepared comprising the steps of:
Water was added to a 100ml round-bottomed flask at a rate of 1ml/1mmol of the starting material in an ice-water bath at 0℃and 1mmol of 6-aminocoumarin was added thereto, 1mmol of sodium nitrite was added dropwise thereto, the pH was adjusted to 2 with hydrochloric acid, and after stirring for 20 minutes, the pH was adjusted to 7 with sodium hydroxide solution, 1mmol of phenol was added, and stirring was carried out at room temperature for 1 hour. The precipitated solid was recrystallized from toluene. The product was a yellow solid, yield: 71.0%.
The structural formula of the intermediate 2 is shown as follows:
The nuclear magnetic data of intermediate 2 is shown below ：1H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 8.23 (d, J = 9.6 Hz, 1H), 8.20 (d, J = 2.4 Hz, 1H), 8.06 (dd, J = 8.8, 2.4 Hz, 1H), 7.83 (d, J = 8.7 Hz, 2H), 7.57 (d, J = 8.9 Hz, 1H), 6.97 (d, J = 8.7 Hz, 2H), 6.60 (d, J = 9.6 Hz, 1H).
Example 3: synthetic intermediate 3
The synthesis of intermediate 3 comprises the following steps:
1mmol of intermediate 2,2mmol of potassium carbonate and 1mmol of sodium iodide are added to a round-bottomed flask at 100 ℃, N-dimethylformamide and 2mmol of 2- (2-chloroethyl ether) ethanol solution are added in a proportion of 1ml/1mmol of raw materials, the mixture is continuously added dropwise to the solution in 1 hour, the reaction is carried out for 8 hours, after the reaction mixture is cooled to room temperature, the product is extracted with methylene chloride to form an organic phase, the organic phase is washed twice with 5% aqueous sodium hydroxide solution, the pH is adjusted to 7, the solvent is dried by spin, and the mixture is purified by column (ethyl acetate: petroleum ether=1:2). The product was a yellow solid, yield: 68.2%.
The structural formula of the intermediate 3 is shown as follows:
The nuclear magnetic data of intermediate 3 is shown below ：1H NMR (400 MHz, CDCl3) δ8.10 (dd, J = 8.9, 2.3 Hz, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.97 – 7.89 (m, 2H), 7.82 (d, J = 9.6 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.12 – 7.01 (m, 2H), 6.50 (d, J = 9.5 Hz, 1H), 4.28 – 4.18 (m, 2H), 3.96 – 3.89 (m, 2H), 3.80 (d, J = 5.4 Hz, 2H), 3.71 (dd, J = 5.3, 3.6 Hz, 2H), 2.10 (s, 1H).
Example 4: synthesis of Compound 4
Compound 4 was synthesized comprising the steps of:
In an ice-water bath at 0deg.C, 1mmol of intermediate 3 (0.23 mmol) was dissolved in 5mL chloroform, and 2mmol of diethylaminosulfur trifluoride (DAST, 61 μl,0.46 mmol) was added. The reaction was stirred for 1h, then poured into a saturated sodium bisulfite solution and extracted with chloroform. The organic phase was separated, dried over sodium sulfate, filtered, spin-dried and purified by column (ethyl acetate: petroleum ether=2:5). The product was a yellow solid, yield: 53.8%.
The structural formula of the compound 4 is shown as follows:
The nuclear magnetic data of the compound 4 are shown below ：1H NMR (400 MHz, CDCl3) δ8.03 (dd, J = 8.9, 2.3 Hz, 1H),7.95 (d, J = 2.3 Hz, 1H),7.90 – 7.82 (m, 2H),7.75 (d, J = 9.6 Hz, 1H),7.38 (d, J = 8.8 Hz, 1H),7.04 – 6.95 (m, 2H),6.43 (d, J = 9.6 Hz, 1H),4.64 – 4.54 (m, 1H),4.52 – 4.42 (m, 1H),4.18 (dd, J = 5.6, 3.9 Hz, 2H),3.91 – 3.84 (m, 2H),3.84 – 3.77 (m, 1H),3.80 – 3.66 (m, 1H).
Example 5: synthetic intermediate 5
The synthesis of intermediate 5 comprises the following steps:
1mmol of the synthesis intermediate 3 and triethylamine (0.5 mL/1mmol of the synthesis intermediate 3) were dissolved in methylene chloride (5 mL/1mmol of the synthesis intermediate 3) in a 0℃ice-water bath, 0.1mmol of 4-dimethylaminopyridine and 1.2mmol of p-toluenesulfonyl chloride were added to the reaction mixture, the solution was stirred at room temperature for 18 hours, the reaction was stopped with water (20 mL), the reaction solution was washed 2-3 times with 1M hydrochloric acid solution, saturated sodium carbonate solution, saturated brine in an appropriate amount, the organic layer was separated, dried over anhydrous sodium sulfate, the organic layer was filtered, the organic layer was concentrated under vacuum reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate=2:1 as eluent). The product was a yellow solid, yield: 57.6%.
The structural formula of the intermediate 5 is shown as follows:
The nuclear magnetic data of the intermediate 5 are shown below ：1H NMR (400 MHz, CDCl3) δ 8.03 (dd, J = 8.8, 2.3 Hz, 1H),7.94 (d, J = 2.3 Hz, 1H),7.89 – 7.80 (m, 2H),7.75 (d, J = 6.9 Hz, 1H),7.72 (dd, J = 5.7, 3.8 Hz, 2H),7.37 (d, J = 8.8 Hz, 1H),7.24 (d, J = 8.1 Hz, 2H),6.97 – 6.91 (m, 2H),6.42 (d, J = 9.6 Hz, 1H),4.16 – 4.12 (m, 2H),4.10 – 4.06 (m, 2H),3.79 – 3.75 (m, 2H),3.73 – 3.70 (m, 2H),2.34 (s, 3H).
Example 6: intermediate 6
Intermediate 6 was prepared from intermediate 2 according to the procedure for intermediate 3 to give a pale yellow solid. Yield: 65.0%, the structure of intermediate 6 is as follows:
The nuclear magnetic data of the intermediate 6 are shown below ：1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.2 Hz, 1H), 8.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.82 – 7.75 (m, 2H), 7.67 (d, J = 9.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.10 – 7.04 (m, 2H), 6.30 (d, J = 9.5 Hz, 1H), 4.22 (t, J = 4.7 Hz, 2H), 3.67 – 3.63 (m, 2H), 2.31 (t, J = 6.2 Hz, 1H).
Example 7: synthesis of Compound 7
Compound 7 was prepared from intermediate 6 according to the procedure for the synthesis of compound 4 to give a pale yellow solid. Yield: 64.1% of the compound 7 has the following structure:
/>
the nuclear magnetic data of the compound 7 are shown below ：1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.2 Hz, 1H), 8.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.81 – 7.77 (m, 2H), 7.67 (d, J= 9.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.11 – 7.05 (m, 2H), 6.30 (d, J = 9.5 Hz, 1H), 4.79 (t, J = 3.5 Hz, 1H), 4.69 (t, J = 3.5 Hz, 1H), 4.30 (t, J = 3.5 Hz, 1H), 4.26 (t, J = 3.5 Hz, 1H).
Example 8: synthetic intermediate 8
Intermediate 8 was prepared from intermediate 6 according to the procedure for the synthesis of intermediate 5 to give a pale yellow solid. Yield: 59.8%, the structure of intermediate 8 is as follows:
The nuclear magnetic data of the intermediate 8 are shown below ：1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.1 Hz, 1H), 8.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.80 – 7.76 (m, 2H), 7.74 – 7.70 (m, 2H), 7.67 (d, J = 9.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.39 – 7.34 (m, 2H), 7.09 – 7.05 (m, 2H), 6.30 (d, J = 9.5 Hz, 1H), 4.22 (t, J = 5.5 Hz, 2H), 3.95 (t, J = 5.5 Hz, 2H), 2.41 (d, J = 0.9 Hz, 3H).
Example 9: synthetic intermediate 9
Intermediate 9 was prepared from intermediate 2 according to the procedure for the synthesis of intermediate 3 to give a pale yellow solid. Yield: 63.3%, the structure of intermediate 9 is as follows:
The nuclear magnetic data of the intermediate 9 are shown below ：1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.1 Hz, 1H), 8.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.80 – 7.76 (m, 2H), 7.67 (d, J= 9.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.09 – 7.05 (m, 2H), 6.30 (d, J = 9.5 Hz, 1H), 4.11 (t, J = 5.0 Hz, 2H), 3.79 (d, J = 4.9 Hz, 2H), 3.75 – 3.70 (m, 4H), 3.67 – 3.63 (m, 2H), 3.59 (d, J = 4.6 Hz, 2H), 2.64 (t, J = 6.4 Hz, 1H).
Example 10: synthesis of Compound 10
Compound 10 was prepared from intermediate 9 according to the procedure for the synthesis of compound 4 to give a pale yellow solid. Yield: 57.3% of the compound 10 having the structure:
The nuclear magnetic data of the compound 10 are shown below ：1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.2 Hz, 1H), 8.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.79 – 7.77 (m, 2H), 7.67 (d, J= 9.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.08 – 7.06 (m, 2H), 6.30 (d, J = 9.5 Hz, 1H), 4.12 – 4.09 (m, 3H), 4.00 (t, J = 3.3 Hz, 1H), 3.79 (d, J = 4.9 Hz, 2H), 3.65 – 3.64 (m, 4H), 3.59 (t, J = 3.4 Hz, 1H), 3.55 (t, J = 3.4 Hz, 1H).
Example 11: synthetic intermediate 11
Intermediate 11 was prepared from intermediate 9 according to the procedure for the synthesis of intermediate 5 to give a pale yellow solid. Yield: 51.7% of intermediate 11, the structure of which is as follows:
The nuclear magnetic data of the intermediate 11 are as follows ：1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.1 Hz, 1H), 8.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.79 – 7.76 (m, 2H), 7.73 – 7.70 (m, 2H), 7.67 (d, J = 9.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.40 – 7.36 (m, 2H), 7.09 – 7.05 (m, 2H), 6.30 (d, J = 9.5 Hz, 1H), 4.11 (t, J = 5.0 Hz, 2H), 3.79 (t, J = 5.0 Hz, 2H), 3.72 – 3.68 (m, 4H), 3.67 – 3.64 (m, 4H), 2.41 (d, J = 0.9 Hz, 3H).
In the present invention, the reaction schemes for synthesizing (R) -12, (S) -12, (R) -13, (S) -13, (R) -14, (S) -14, (R) -15, (S) -15, (R) -16, (S) -16, (R) -17, and (S) -17 are as follows:
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The reaction reagents and conditions involved therein are: (h) (R) or (S) -glycidyl-3-nitrobenzenesulfonate, cesium fluoride, N, N-dimethylformamide at 65℃for 6h; (i) Tetrabutylammonium fluoride-1M tetrahydrofuran solution, condensing and refluxing at 90 ℃ for 6 hours; (j) (R) - (-) -p-toluenesulfonic acid-2, 2-dimethyl-1, 3-dioxolanyl-4-methyl ester, cesium fluoride, azomethide at 65℃for 6 hours; (k) Tetrahydrofuran, hydrochloric acid (1M), 90 ℃, reflux for 30 minutes, sodium bicarbonate; (l) P-toluenesulfonyl chloride, triethylamine, dichloromethane, room temperature for 6 hours; (m) 3, 4-dihydro-2H-pyran, 4-methylbenzenesulfonic acid pyridine (PPTS), dichloromethane, room temperature, 5 hours; (p) (S) - (-) -p-toluenesulfonic acid-2, 2-dimethyl-1, 3-dioxolanyl-4-methyl ester, cesium fluoride, azomethine formamide at 65℃for 6 hours.
The following will specifically describe examples 12 to 23 in connection with the above reaction scheme.
Example 12: synthetic intermediate (R) -12
The synthesis of intermediate (R) -12 comprises the following steps:
Intermediate 2 (1 mmol,266.2 mg) was dissolved in 5mL of N, N-dimethylformamide with (R) -glycidyl-3-nitrobenzenesulfonate (1.25 mmol,324.05 mg) and cesium fluoride (3 mmol,455.7 mg) was added with stirring and reacted at 65℃for 6 hours. After the reaction is finished, 100mL of deionized water is added after the reaction solution is cooled to room temperature, and the reaction solution is subjected to suction filtration after the product is separated out and placed in ultrasound for 30 minutes. The crude product was dried and separated by column chromatography using a developing solvent of petroleum ether: ethyl acetate=2:1 by volume. Obtained as a pale yellow solid, yield: 48.9%.
The structural formula of the intermediate (R) -12 is shown as follows:
The nuclear magnetic data of the intermediate (R) -12 are shown below:
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.2 Hz, 1H), 8.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.91 – 7.84 (m, 2H), 7.67 (d, J = 9.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 6.84 – 6.77 (m, 2H), 6.30 (d, J = 9.5 Hz, 1H), 4.74 (dd, J = 2.1, 1.2 Hz, 1H), 3.04 (dd, J = 8.1, 1.2 Hz, 1H), 2.79 (dd, J = 8.1, 2.2 Hz, 1H).
Example 13: synthetic intermediate (S) -12
Intermediate (S) -12 was prepared from intermediate 2 according to the procedure for the synthesis of intermediate (R) -12, affording a pale yellow solid. Yield 56.2%, structure of intermediate (S) -12 is as follows:
the nuclear magnetic data of intermediate (S) -12 are shown below:
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.2 Hz, 1H), 8.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.90 – 7.84 (m, 2H), 7.67 (d, J = 9.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 6.84 – 6.76 (m, 2H), 6.30 (d, J = 9.5 Hz, 1H), 4.74 (dd, J = 2.1, 1.2 Hz, 1H), 3.04 (dd, J = 8.1, 2.2 Hz, 1H), 2.79 (dd, J = 8.0, 1.1 Hz, 1H).
Example 14: synthesis of Compound (R) -13
The synthesis of compound (R) -13, comprising the steps of:
Intermediate (S) -12 (1 mmol,332.3 mg) was weighed into a 25ml round bottom flask, tetrabutylammonium fluoride-1M tetrahydrofuran solution (10 mmol,10 ml) was gradually added dropwise, and after the addition was completed, the mixture was heated in an oil bath at 90 ℃ for reflux reaction for 6 hours, after the reaction was completed, tetrahydrofuran was distilled off under reduced pressure, and was separated by column chromatography using a developing solvent having a volume ratio of petroleum ether: ethyl acetate=2:1. Obtained as a pale yellow solid in 64.3% yield. The structure of the compound (R) -13 is as follows:
the nuclear magnetic data of the compound (R) -13 are shown below:
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.1 Hz, 1H), 8.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.80 – 7.76 (m, 2H), 7.67 (d, J = 9.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.09 – 7.02 (m, 2H), 6.30 (d, J = 9.5 Hz, 1H), 4.42 – 4.37 (m, 1H), 4.36 – 4.27 (m, 1H), 4.16 – 4.02 (m, 1H), 3.90 (ddd, J = 11.7, 5.9, 3.5 Hz, 1H), 3.70 (ddd, J = 11.7, 5.9, 3.5 Hz, 1H), 3.64 – 3.62 (m, 1H).
example 15: synthesis of Compound (S) -13
According to the method for synthesizing compound (R) -13, compound (S) -13 was prepared from intermediate (R) -12 to give a pale yellow solid, yield: 63.1%. The structure of the compound (S) -13 is as follows:
the nuclear magnetic data of the compound (S) -13 are shown below:
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.1 Hz, 1H), 8.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.82 – 7.75 (m, 2H), 7.67 (d, J = 9.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.10 – 7.04 (m, 2H), 6.30 (d, J = 9.5 Hz, 1H), 4.69 – 4.55 (m, 1H), 4.45 – 4.37 (m, 1H), 4.36 – 4.32 (m, 1H), 3.93 (dt, J = 5.8, 3.7 Hz, 2H), 3.64 – 3.59 (m, 1H).
example 16: synthetic intermediate (R) -14
The synthesis of intermediate (R) -14 comprises the following steps:
Intermediate 2 (3.0 mmol) and (R) - (-) -p-toluenesulfonic acid-2, 2-dimethyl-1, 3-dioxolanyl-4-methyl ester (3.6 mmol) were dissolved in 5mL dimethylformamide, cesium fluoride (9.0 mmol) was added with stirring and reacted at 65℃for 6 hours. After the reaction is finished, 100mL of deionized water is added after the reaction solution is cooled to room temperature, yellow products are precipitated and placed in ultrasound for 30 minutes, the obtained solid is dissolved by methylene dichloride after suction filtration and then dried by anhydrous sodium sulfate, and pale yellow solid is obtained by column chromatography separation by using a developing agent with the volume ratio of petroleum ether to ethyl acetate=2:1, and the yield is 76.7%. The structure of the intermediate (R) -14 is as follows:
the nuclear magnetic data of the intermediate (R) -14 are shown below:
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.2 Hz, 1H), 8.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.80 – 7.76 (m, 2H), 7.67 (d, J = 9.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.09 – 7.05 (m, 2H), 6.30 (d, J = 9.5 Hz, 1H), 4.21 – 4.17 (m, 2H), 4.03 – 3.99 (m, 1H), 3.98 – 3.94 (m, 1H), 3.75 – 3.67 (m, 1H), 1.38 (s, 6H).
Example 17: synthetic intermediate (R) -15
The preparation of the synthetic intermediate (R) -15 comprises the following steps:
Intermediate (R) -14 (2 mmol) was dissolved in 10mL tetrahydrofuran and 1M hydrochloric acid was slowly added dropwise with stirring to pH 3, and after the addition was completed, the reaction was heated in an oil bath at 90℃for half an hour under reflux. After the reaction is finished, tetrahydrofuran is distilled off under reduced pressure, the reaction liquid p H is adjusted to be neutral and is placed in ultrasound for 30 minutes, a product can be separated out, light yellow solid 910.2mg can be obtained through suction filtration and drying, the yield is 85.6%, and the structure of the intermediate (R) -15 is as follows:
The nuclear magnetic data of the intermediate (R) -15 are shown below:
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.2 Hz, 1H), 8.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.82 – 7.76 (m, 2H), 7.67 (d, J = 9.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.09 – 7.04 (m, 2H), 6.30 (d, J = 9.5 Hz, 1H), 5.00 (t, J = 5.8 Hz, 1H), 3.99 (dp, J = 6.3, 5.4 Hz, 1H), 3.90 (dd, J = 12.1, 5.5 Hz, 1H), 3.70 (dd, J = 12.1, 5.3 Hz, 1H), 3.67 – 3.56 (m, 2H), 2.52 (d, J = 6.0 Hz, 1H).
Example 18: synthetic intermediate (S) -16
The synthesis of intermediate (S) -16 comprises the following steps:
intermediate (R) -15 (1.0 mmol) was dissolved in dichloromethane and p-toluenesulfonyl chloride (1.0 mmol) was slowly added with stirring, then 5mL of triethylamine was continuously slowly added dropwise, and the reaction was stirred at room temperature for 6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the yellow oily compound was separated by column chromatography using a developing solvent having a volume ratio of petroleum ether to ethyl acetate=1:1, and the yield was 21.6%. The structure of the intermediate (R) -16 is as follows:
The nuclear magnetic data of intermediate (S) -16 are shown below:
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.2 Hz, 1H), 8.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.80 – 7.77 (m,2H), 7.73 – 7.71 (m, 2H), 7.67 (d, J = 9.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.41 – 7.35 (m, 2H), 7.09 – 7.06 (m, 2H), 6.30 (d, J = 9.5 Hz, 1H), 4.26 – 4.21 (m, 1H), 4.16 – 4.09 (m, 2H), 3.92 – 3.88 (m, 1H), 3.73 – 3.68 (m, 1H), 2.54 – 2.51 (m, 1H), 2.41 (d, J = 0.9 Hz, 3H).
example 19: synthetic intermediate (S) -17
The synthesis of intermediate (S) -17 comprises the following steps:
Intermediate (S) -16 (0.1 mmol), dihydropyran (1.0 mmol) and pyridinium 4-methylbenzenesulfonate (0.2 mmol) were dissolved in anhydrous dichloromethane and stirred at room temperature for 5 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and 60.5mg of a pale yellow oily compound was obtained by column chromatography using a developing solvent having a volume ratio of petroleum ether to ethyl acetate=2:1, and the yield was 82.1%, and the structure of the intermediate (S) -17 was as follows:
the nuclear magnetic data of intermediate (S) -17 are shown below:
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.2 Hz, 1H), 8.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.81 – 7.75 (m, 2H), 7.75 – 7.70 (m, 2H), 7.67 (d, J = 9.5 Hz, 1H), 7.48 (s, 1H), 7.41 – 7.35 (m, 2H), 7.10 – 7.04 (m, 2H), 6.30 (d, J = 9.5 Hz, 1H), 4.70 (t, J = 3.6 Hz, 1H), 4.30 – 4.17 (m, 2H), 4.11 (dd, J = 12.6, 5.5 Hz, 1H), 3.98 – 3.88 (m, 2H), 3.91 – 3.84 (m, 1H), 3.48 (dddd, J = 11.1, 5.2, 3.9, 1.9 Hz, 1H), 2.41 (d, J = 0.9 Hz, 3H), 1.89 – 1.77 (m, 1H), 1.76 – 1.66 (m, 1H), 1.59 – 1.43 (m, 4H).
example 20: synthetic intermediate (S) -14
According to the method for synthesizing intermediate (R) -14, intermediate (S) -14 was prepared from intermediate 2 to give a pale yellow solid in 72.4% yield, the structure of intermediate (S) -14 being as follows:
the nuclear magnetic data of the intermediate (S) -14 are shown below:
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.2 Hz, 1H), 8.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.81 – 7.75 (m, 2H), 7.67 (d, J = 9.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.10 – 7.04 (m, 2H), 6.30 (d, J = 9.5 Hz, 1H), 4.23 – 4.15 (m, 2H), 4.08 – 4.00 (m, 1H), 3.99 – 3.93 (m, 1H), 3.70 (ddd, J = 12.0, 2.4, 1.1 Hz, 1H), 1.38 (s, 6H).
example 21: synthesis of intermediate (S) -15
According to the method for synthesizing intermediate (R) -15, intermediate (S) -17 was prepared from intermediate (S) -14 to give a pale yellow solid in 80.5% yield, the structure of intermediate (S) -15 was as follows:
the nuclear magnetic data of the intermediate (S) -15 are shown below:
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.2 Hz, 1H), 8.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.82 – 7.73 (m, 2H), 7.67 (d, J = 9.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.12 – 7.02 (m, 2H), 6.30 (d, J = 9.5 Hz, 1H), 5.00 (t, J = 5.8 Hz, 1H), 4.02 – 3.95 (m, 1H), 3.93 (dd, J = 5.4, 3.5 Hz, 2H), 3.63 – 3.54 (m, 1H), 3.33 (dt, J = 11.9, 5.5 Hz, 1H), 2.52 (d, J = 6.0 Hz, 1H).
example 22: synthetic intermediate (R) -16
According to the method for synthesizing intermediate (S) -16, intermediate (R) -16 was prepared from intermediate (S) -15 to give a pale yellow oil in 19.6% yield, the structure of intermediate (R) -16 was as follows:
the nuclear magnetic data of intermediate (R) -16 are shown below:
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.2 Hz, 1H), 8.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.81 – 7.76 (m, 2H), 7.74 – 7.71 (m, 2H), 7.67 (d, J = 9.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.40 – 7.37 (m, 2H), 7.10 – 7.06 (m, 2H), 6.30 (d, J = 9.5 Hz, 1H), 4.13 (dtd, J = 11.6, 6.1, 5.4 Hz, 1H), 4.03 (dd, J = 12.6, 6.2 Hz, 1H), 3.97 – 3.89 (m, 2H), 3.77 (dd, J = 12.6, 6.0 Hz, 1H), 2.52 (d, J = 6.1 Hz, 1H), 2.41 (d, J = 0.9 Hz, 3H).
example 23: synthetic intermediate (R) -17
According to the method for synthesizing intermediate (S) -17, intermediate (R) -17 was prepared from intermediate (R) -16 to give a pale yellow oil in 79.7% yield, the structure of intermediate (R) -17 was as follows:
the nuclear magnetic data of the intermediate (R) -17 are shown below:
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.1 Hz, 1H), 8.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.81 – 7.77 (m, 2H), 7.73 – 7.70 (m, 2H), 7.67 (d, J = 9.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.41 – 7.33 (m, 2H), 7.10 – 7.04 (m, 2H), 6.30 (d, J = 9.5 Hz, 1H), 4.70 (t, J = 3.6 Hz, 1H), 4.26 (tt, J = 5.7, 5.0 Hz, 1H), 4.01 (dd, J = 12.6, 5.6 Hz, 1H), 3.95 – 3.88 (m, 3H), 3.75 (dd, J = 12.6, 5.5 Hz, 1H), 3.53 – 3.45 (m, 1H), 2.41 (d, J = 0.9 Hz, 3H), 1.98 – 1.92 (m, 1H), 1.89 – 1.76 (m, 1H), 1.58 – 1.45 (m, 4H).
In the present invention, the reaction scheme for preparing compound [ 18F]4、(S)-[18F]18、(R)-[18 F ]18 is:
The reaction reagents and conditions involved therein are: (n) 18 F-ion, 4,7,13,21,24-hexa-1, 10-diazabicyclo [8, 8] -hexacosane, potassium carbonate, dimethyl sulfoxide, 132℃for 10min; (o) (1) 18F-ion, 4,7,13,21,24-hexaoxa-1, 10-diazabicyclo [8, 8] -hexacosane, potassium carbonate, 132℃for 10 minutes, (2) 1M hydrochloric acid, 100℃for 5 minutes.
The following is a specific description of the reaction scheme from example 24 to example 26.
Example 24: preparation of Compound [ 18 F ]4
The structure of the compound [ 18 F ]4 is as follows:
[ 18F]F- ] ion enrichment on QMA column [ 18F]F- ] was eluted from the QMA column with 1.0mL of a eluent (containing Kryptofix-2.2.2.5.0 mg, 1.1mg of potassium carbonate). About 20mCi of fluoride ion solution is added into a 10mL glass reaction tube, heated at 100 ℃, continuously introduced with nitrogen gas for drying, and then 1.0mL anhydrous acetonitrile is added for three times for azeotropic drying, so that the anhydrous reaction system is ensured. 2.0mg of intermediate 5 was dissolved in 500. Mu.L of anhydrous dimethyl sulfoxide, and the solution was transferred to a glass reaction tube containing [ 18F]F- ]. The reaction was heated at 120℃for 10 minutes and quenched by the addition of deionized water. The mixture was purified by passing through a pretreated Sep-Pak Plus C18 column, and the column was rinsed with 20mL deionized water to remove unreacted [ 18F]F- and inorganic salts. The column was rinsed with anhydrous acetonitrile (3 washes of 1mL each) to elute the labeled compound adsorbed to the column, and after concentration, the labeled compound was separated and purified by HPLC. Separation conditions: alltech Chrom BDS 10u (250 mm. Times.10 mm), acetonitrile: phosphate buffer (pH 8) =60:40, flow rate: and 4ml/min, collecting effluent liquid of the target product, and removing the solvent by rotary evaporation to obtain the target product.
Example 25: preparation of Compound (S) - [ 18 F ]18
The structure of the compound (S) - [ 18 F ]18 is as follows:
[ 18F]F- ] ion enrichment on QMA column [ 18F]F- ] was eluted from the QMA column with 1.0mL of eluent (containing Kryptofix-2.2.2.4.0 mg, 1.1mg K 2CO3). About 20mCi of fluoride ion solution is added into a 10mL glass reaction tube, heated at 100 ℃, continuously introduced with nitrogen gas for drying, and then 1.0mL anhydrous acetonitrile is added for three times for azeotropic drying, so that the anhydrous reaction system is ensured. 2.0mg (S) -17 was dissolved in 500. Mu.L of anhydrous dimethyl sulfoxide, and the solution was transferred to a glass reaction tube containing [ 18F]F- ]. Heating and reacting for 10 minutes at 130 ℃, cooling, adding 400 mu L of hydrochloric acid solution (1M), continuing to react for 5 minutes at 100 ℃ to remove the Boc protecting group, cooling, adding saturated NaHCO 3 solution to adjust the pH to 8-9, and adding 10mL of deionized water to dilute the reaction mixture. The mixture was purified by passing through a pretreated Sep-Pak Plus C18 column, and the column was rinsed with 20mL deionized water to remove unreacted [ 18F]F- and inorganic salts. The column was rinsed with anhydrous acetonitrile (3 times each of 1 mL), and the labeled compound, labeled precursor, and the like adsorbed on the column were eluted, concentrated, and then separated and purified by HPLC. Separation conditions: alltech Chrom BDS 10u (250 mm. Times.10 mm), acetonitrile: phosphate buffer (pH 8) =60:40, flow rate: and 4ml/min, collecting effluent liquid of the target product, and removing the solvent by rotary evaporation to obtain the target product.
Example 26: preparation of Compound (R) - [ 18 F ]18
The structure of the compound (R) - [ 18 F ]18 is as follows:
/>
[ 18F]F- ] ion enrichment on QMA column [ 18F]F- ] was eluted from the QMA column with 1.0mL of eluent (containing Kryptofix-2.2.2.4.0 mg, 1.1mg K 2CO3). About 20mCi of fluoride ion solution is added into a 10mL glass reaction tube, heated at 100 ℃, continuously introduced with nitrogen gas for drying, and then 1.0mL anhydrous acetonitrile is added for three times for azeotropic drying, so that the anhydrous reaction system is ensured. 2.0mg (R) -17 was dissolved in 500. Mu.L of anhydrous dimethyl sulfoxide, and the solution was transferred to a glass reaction tube containing [ 18F]F- ]. Heating and reacting for 10 minutes at 132 ℃, cooling, adding 400 mu L of hydrochloric acid solution (1M), continuing to react for 5 minutes at 100 ℃ to remove the Boc protecting group, cooling, adding saturated NaHCO 3 solution to adjust the pH to 8-9, and adding 10mL of deionized water to dilute the reaction mixture. The mixture was purified by passing through a pretreated Sep-Pak Plus C18 column, and the column was rinsed with 20mL deionized water to remove unreacted [ 18F]F- and inorganic salts. The column was rinsed with anhydrous acetonitrile (3 times each of 1 mL), and the labeled compound, labeled precursor, and the like adsorbed on the column were eluted, concentrated, and then separated and purified by HPLC. Separation conditions: alltech Chrom BDS 10u (250 mm. Times.10 mm), acetonitrile: phosphate buffer (pH 8) =60:40, flow rate: and 4ml/min, collecting effluent liquid of the target product, and removing the solvent by rotary evaporation to obtain the target product.
Test example 1 High Performance Liquid Chromatography (HPLC) to verify 18 F-labeled ligand
The labeling rate of [ 18 F ]4 obtained in example 24, (S) - [ 18 F ]18 obtained in example 25, and (R) - [ 18 F ]18 obtained in example 26 was 5% to 20%. After HPLC separation and purification, the radiochemical purity was greater than 95% and consistent with the retention time of the stable fluorinated ligand (table 1).
TABLE 1 18 F labeling ligands and retention time and purity of their stabilized ligands
。
Test example 2 autoradiography experiment of brain sections of A53T transgenic mice
The [ 18 F ]4 obtained in example 24, i.e.the fluoro-18 radiolabel of compound 4 obtained in example 4, was combined with frozen sections of A53T mouse brain tissue (24 months old, male, 16 μm) and then exposed through a phosphor screen and then imaged by analysis using a phosphor screen system.
1. The experimental steps are as follows:
(1) mu.L of 18 F-labeled compound solution covering 20. Mu. Ci on A53T mouse brain frozen sections was incubated for 60 min at room temperature;
(2) Eluting with 35% ethanol-water for 2min twice and eluting with pure water for 30s once;
(3) After the film is dried, the film is coated under a phosphorus screen for exposure for 40min, and the image is analyzed by a phosphorus screen storage system.
2. Experimental results:
As shown in figure 1, the radionuclide labeled compound [ 18 F ]4 effectively labels the region where the alpha-synuclein polymer of the A53T mouse brain slice is concentrated, and the experimental result shows that the radionuclide labeled compound can be combined with the alpha-synuclein polymer, and has potential application prospects in the aspects of detection, imaging, diagnosis drugs and the like of the alpha-synuclein polymer.
Test example 3 autoradiography of brain sections of Parkinson's disease patient
The [ 18 F ]4 obtained in example 24, i.e., the fluoro-18 radiolabel of compound 4 obtained in example 4, was combined with a slice of the temporal lobe (female, 80 years old, 6 μm) of a PD patient, exposed to light through a phosphor screen and then imaged by analysis using a phosphor screen system.
1. The experimental steps are as follows:
(1) mu.L of 18 F-labeled compound solution covered with 20. Mu. Ci on a slice of temporal lobe (female, 80 years old, 6 μm) of PD patient was incubated for 60 min at room temperature;
(2) Eluting with 35% ethanol-water for 2min twice and eluting with pure water for 30s once;
(3) After the film is dried, the film is coated under a phosphorus screen for exposure for 40min, and the image is analyzed by a phosphorus screen storage system.
2. Experimental results:
as shown in figure 2, the radionuclide labeled compound effectively labels the alpha-synuclein polymer in the temporal lobe (female, 80 years old, 6 mu m) of PD patients, and the experimental result shows that the radionuclide labeled compound can be combined with the alpha-synuclein polymer in the brain of the patients, and has potential application prospects in the aspects of detection, imaging, diagnosis medicaments and the like of the alpha-synuclein polymer.
Test example 4 Normal mouse biodistribution
The biodistribution of [ 18 F ]4 obtained in example 24 in various organ tissues of mice at various time points, in particular, initial brain uptake and brain clearance, was examined by biodistribution experiments.
1. The experimental steps are as follows:
5-10 μCi labeled compound [ 18 F ]4 (100 μL of physiological saline solution containing 10% ethanol) was injected from the tail vein into normal Kunming mice (female, 5 weeks old), and the mice were sacrificed at their decapitation at 2, 10, 30, and 60 minutes (5 mice per time point), respectively, and relevant organs were dissected out and wet weights and radioactivity counts were measured. Data are expressed as percent radioactivity per gram of viscera (% ID/g).
2. Experimental results:
the results of the experiment are shown in Table 2, and the radiolabeled ligand [ 18 F ]4 of the invention was able to enter the brain rapidly and cleared from the brain over time. In addition, the compounds do not undergo significant in vivo defluorination.
TABLE 2 Normal mouse biodistribution of Compound [ 18 F ]4
。
Test example 5 unilateral striatal injection of alpha synuclein molded mice micro PET/CT imaging
1. Experimental procedure
(1) The Kunming mice (females, five weeks old) were allowed to acclimate in the animal facility for one week prior to surgery. The anesthetized mice were intraperitoneally injected with 4% chloral hydrate at a dose of 8 ml/kg. After hair removal from the mice head, the mice were placed in a brain locator, and alpha-synuclein aggregates (5 μl,55 μΜ) were injected into the right striatum (ml= +2.0 mm, ap=0.8 mm, dv= -3.6 mm) using a stereo injector (TJ-1A, longer-Pump, UK). The mice of the negative control group were injected with 5 μl of physiological saline at the same position. Injection time of 10min was 0.5 μl per 1 min. Mice were kept in cages at 22℃and 40-60% humidity for 14 days with a light-dark period of 12:12 hours for further subsequent imaging experiments.
(2) The [ 18 F ]4 (100. Mu. Ci) obtained in example 24 was injected into the model mice obtained in (1) via the tail vein and subjected to dynamic scanning for 60min by micro PET-CT (IRIS XL PET/CT, france Inviscan). During the scanning, 1.5-2.0% isoflurane is used for anesthetizing the mice.
2. Experimental results
As shown in FIG. 3, the left and right panels are PET/CT images of normal saline model mice and alpha-synuclein aggregate model mice, respectively, 30min after probe injection. The right image shows that the brain of the protein modeling module has strong radiation signals consistent with modeling points, and the normal saline control group does not display obvious radiation signals at the same modeling position, which suggests that [ 18 F ]4 can target and display alpha-synuclein polymer in the brain.
Claims (27)
1. A compound of formula I:
I；
wherein R is -OCH2CH2F、-(OCH2CH2)2F、-(OCH2CH2)3F、 、/>；
Or a pharmaceutically acceptable form thereof;
Wherein F is 18 F or 19 F.
2. The compound of claim 1, represented by formula IA:
IA；
Or a pharmaceutically acceptable form thereof;
Wherein F is 18 F or 19 F.
3. The compound according to claim 1 or 2, wherein said compound is:
6- [ (1E) - {4- [ (2-fluoroethyl) oxy ] phenyl } ethanamenyl ] -2H-chromen-2-one.
4. The compound of claim 1, represented by formula IB:
IB；
Or a pharmaceutically acceptable form thereof;
Wherein F is 18 F or 19 F.
5. The compound according to claim 1 or 4, wherein said compound is:
6- [ (1E) - [4- ({ 2- [ (2-fluoroethyl) oxy ] ethyl } oxy) phenyl ] ethanamenyl ] -2H-chromen-2-one.
6. The compound of claim 1, represented by formula IC:
IC；
Or a pharmaceutically acceptable form thereof;
Wherein F is 18 F or 19 F.
7. The compound of claim 1 or 6, wherein the compound is:
6- [ (1E) - {4- [ (8-fluoro-3, 6-dioxaoct-1-yl) oxy ] phenyl } ethy-lamino ] -2H-chromen-2-one.
8. The compound of claim 1, represented by formula ID:
ID；
Or a pharmaceutically acceptable form thereof;
Wherein F is 18 F or 19 F.
9. A compound according to claim 1 or 8, wherein said compound is:
6- [ (1E) - (4- { [ (2S) -2-hydroxybutyl ] oxy } phenyl) ethanamenyl ] -2H-chromen-2-one fluoroalkane.
10. The compound of claim 1, represented by formula IE:
IE；
Or a pharmaceutically acceptable form thereof;
Wherein F is 18 F or 19 F.
11. A compound according to claim 1 or 10, wherein the compound is:
6- [ (1E) - (4- { [ (2R) -2-hydroxybutyl ] oxy } phenyl) ethanamenyl ] -2H-chromen-2-one fluoroalkane.
12. The compound of any one of claims 1-11, wherein the pharmaceutically acceptable form of the compound is selected from the group consisting of pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, nitrogen oxides, isotopic labels, metabolites and prodrugs.
13. A process for the preparation of a compound according to any one of claims 1 to 12, wherein:
(a) When R is 、/>、/>When in use, the preparation method comprises the following steps:
after diazotizing 6-aminocoumarin under an acidic condition, coupling reaction is carried out between the 6-aminocoumarin and phenol under a neutral condition to obtain a first intermediate;
Mixing the first intermediate, a chloro compound, an organic solvent and potassium carbonate, and carrying out substitution reaction to obtain a second intermediate; the chloro compound is ClCH 2CH2OH、ClCH2CH2-O- CH2CH2 OH or ClCH 2CH2-O- CH2CH2-O- CH2CH2 OH;
Mixing the second intermediate, diethylaminosulfur trifluoride and an organic solvent, and carrying out substitution reaction to obtain a compound with a structure shown in a formula I;
(b) When R is 、/>When in use, the preparation method comprises the following steps:
Dissolving the first intermediate in the step (a) and (R) -glycidyl-3-nitrobenzenesulfonate or (S) -glycidyl-3-nitrobenzenesulfonate in an organic solvent, and carrying out substitution reaction under the action of cesium fluoride serving as a first catalyst to obtain a third intermediate;
And dissolving the third intermediate in an organic solvent, and carrying out substitution reaction with tetrabutylammonium fluoride to obtain the compound with the structure shown in the formula I.
14. A process for the preparation of a compound according to any one of claims 1 to 12, wherein:
(a) When R is 、/>Or/>When in use, the preparation method comprises the following steps:
after diazotizing 6-aminocoumarin under an acidic condition, coupling reaction is carried out between the 6-aminocoumarin and phenol under a neutral condition to obtain a first intermediate;
Mixing the first intermediate, a chloro compound, an organic solvent and potassium carbonate, and carrying out substitution reaction to obtain a second intermediate; the chloro compound is ClCH 2CH2OH、ClCH2CH2-O- CH2CH2 OH or ClCH 2CH2-O- CH2CH2-O- CH2CH2 OH;
Dissolving the second intermediate in an organic solvent, mixing with 4-toluenesulfonyl chloride, and carrying out substitution reaction under the action of a third catalyst 4-dimethylaminopyridine to obtain a fourth intermediate;
Mixing the Kryptofix 222/K 2CO3 mixed solution with [ 18 F ] potassium fluoride solution, removing the solvent, mixing the obtained residue with a fourth intermediate and an organic solvent, and carrying out nucleophilic substitution reaction under anhydrous conditions to obtain a compound with a structure shown in a formula I; the Kryptofix 222/K 2CO3 mixed solution is obtained by mixing 4,7,13,16,21, 24-hexaoxy-1, 10-diazabicyclo [8.8.8] hexacosane, K 2CO3 and an organic solvent;
(b) When R is 、/>When in use, the preparation method comprises the following steps:
Dissolving the first intermediate in an organic solvent, mixing with (R) - (-) -p-toluenesulfonic acid-2, 2-dimethyl-1, 3-dioxolanyl-4-methyl ester or (S) - (-) -p-toluenesulfonic acid-2, 2-dimethyl-1, 3-dioxolanyl-4-methyl ester, and carrying out substitution reaction under the action of cesium fluoride serving as a fourth catalyst to obtain a fifth intermediate;
Dissolving the fifth intermediate in an organic solvent, carrying out hydrolysis reaction with hydrochloric acid, and regulating pH to obtain a sixth intermediate;
Dissolving the sixth intermediate in an organic solvent, and carrying out substitution reaction with p-toluenesulfonyl chloride to generate a seventh intermediate;
Dissolving the seventh intermediate in an organic solvent, and carrying out substitution reaction with 3, 4-dihydro-2H-pyrane under the action of 4-methylbenzenesulfonic acid pyridine (PPTS) to generate an eighth intermediate;
Mixing a Kryptofix 222/K 2CO3 mixed solution and a [ 18 F ] potassium fluoride solution, removing a solvent, mixing the obtained residue with an eighth intermediate, carrying out nucleophilic substitution reaction under anhydrous conditions, cooling, adding a hydrochloric acid solution, continuing to react at 100 ℃ to remove a Boc protecting group, cooling, adding a saturated NaHCO 3 solution, and regulating the reaction system to be weak alkaline to obtain a compound with a structure shown in a formula I; the Kryptofix 222/K 2CO3 mixed solution is obtained by mixing 4,7,13,16,21, 24-hexaoxy-1, 10-diazabicyclo [8.8.8] hexacosane, K 2CO3 and an organic solvent.
15. Use of a compound according to any one of claims 1-12 for the preparation of a biological detection and diagnostic reagent, diagnostic medicament for α -synuclein polymers.
16. Use of a compound according to any one of claims 1-12 for the preparation of an imaging agent for a disease associated with alpha-synuclein deposition, wherein the imaging modality is nuclear medicine imaging, magnetic resonance imaging.
17. The use according to claim 16, wherein the diseases associated with the deposition of α -synuclein include, but are not limited to parkinson's disease, dementia with lewy bodies and multiple system atrophy.
18. Use of a compound according to any one of claims 1-12 for the preparation of a radiopharmaceutical of a nuclear medicine imaging α -synuclein polymer, wherein the nuclear medicine imaging modality is positron emission tomography imaging.
19. A pharmaceutical composition comprising a compound according to any one of claims 1-12, or a pharmaceutically acceptable form thereof, and one or more pharmaceutically acceptable carriers.
20. Use of a compound according to any one of claims 1-12, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition according to claim 19, in the manufacture of a medicament for the prevention and/or treatment of a related disease or disorder caused at least in part by deposition of alpha-synuclein.
21. A composition for imaging an alpha-synuclein aggregate comprising a compound according to any of claims 1-12 and a pharmaceutically acceptable carrier, the compound being radiolabeled.
22. Use of a composition according to claim 21 in the manufacture of a medicament for inhibiting aggregation of α -synuclein.
23. Use of a compound of formula I according to claim 1 or a pharmaceutically acceptable form thereof for the manufacture of a medicament for use in a method for detecting alpha-synuclein aggregation in a patient, the method comprising the steps of: administering a detectable amount of the drug, and detecting binding of the compound of formula I to the α -synuclein aggregates in the patient.
24. The use of claim 23, wherein the detection is performed by performing positron emission tomography, single photon emission computed tomography, nuclear magnetic resonance imaging, or autoradiography.
25. The use according to claim 23, for the diagnosis of parkinson's disease, dementia with lewy bodies and multiple system atrophy and other treatment of alpha-synuclein aggregation diseases.
26. The use according to claim 23, wherein the medicament is useful for diagnosing familial parkinson's disease and monitoring treatment of familial parkinson's disease.
27. A composition or diagnostic kit comprising a compound according to any one of claims 1 to 12.
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