WO2020200283A1 - 芴酮类α7烟碱型乙酰胆碱受体的配体化合物及其应用 - Google Patents
芴酮类α7烟碱型乙酰胆碱受体的配体化合物及其应用 Download PDFInfo
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Definitions
- the present invention relates to the technical field of medicine, in particular to a ligand compound of fluorenone ⁇ 7 nicotinic acetylcholine receptor and its application.
- Nicotinic acetylcholine receptor is a type of gated-transmitter ion channel, which is ubiquitous in the central nervous system (CNS) and peripheral nervous system (PNS), and is related to a variety of physiological functions.
- nAChR is generally composed of ⁇ subunits (such as ⁇ 2- ⁇ 10) and ⁇ subunits ( ⁇ 2- ⁇ 4).
- ⁇ 7 nicotinic acetylcholine receptor ⁇ 7 nicotinic acetylcholine receptor
- ⁇ 7 nAChR is a homopentamer composed of 5 identical ⁇ subunits. It mainly exists in the hippocampus, thalamus and cerebral cortex, which are important for memory, learning, etc. area.
- ⁇ 7 nAChR protein density is found in the brains of patients with neurodegenerative diseases such as Alzheimer’s Disease (AD) and Parkinson’s disease.
- AD Alzheimer’s Disease
- sex ligands have shown that targeted ⁇ 7 nAChR ligands can improve cognitive ability and auditory gating defects, such as PNU-282987, PHA-543613 and A-582941 and other highly selective ⁇ 7 nAChR agonists.
- the cognitive functions of sensory-gating defects, short-term working memory, and memory curing models are improved.
- SPECT Single-Photon Emission Computed Tomography
- autopsy studies of AD patients it has been shown that the density of ⁇ 7 nAChR in the brains of healthy people and patients with neurodegenerative diseases is different . Therefore, ⁇ 7 nAChR can be used as a potential drug target for the early diagnosis and treatment of AD, and the use of radioligands to conduct non-invasive quantitative research on human ⁇ 7 nAChR will promote a better understanding of its effects in various central nervous systems.
- the role of system diseases which can simplify the development of drugs for the treatment of these diseases.
- the purpose of the embodiments of the present invention is to provide fluorenone ⁇ 7 nicotinic acetylcholine receptor ligand compounds and applications thereof.
- the specific technical solutions are as follows:
- the present invention first provides a fluorenone ⁇ 7 nicotinic acetylcholine receptor ligand compound represented by the following formula (I),
- X is a 6-10 membered nitrogen-containing heterocyclic group; the nitrogen-containing heterocyclic group is unsubstituted or substituted by a C 1-4 alkyl group;
- R 1 is selected from amino, halogen or a radioisotope of halogen
- R 2 is hydrogen
- R 1 is hydrogen
- R 2 is selected from amino, halogen or a radioactive isotope of halogen
- R 1 and R 2 are not selected from amino, fluorine and fluorine radioisotopes.
- halogen includes fluorine, chlorine, bromine or iodine.
- C 1 - 4 alkyl refers to a hydrocarbon moiety containing from 1 to 4 carbon atoms, a straight-chain or branched alkyl group removing one hydrogen atom chain-derived, such as methyl, ethyl, n-propyl , Isopropyl, n-butyl, etc.
- the 6-10 membered nitrogen-containing heterocyclic group is selected from
- the heterocyclic group can be selected from the chiral structure of the above group, for example
- R 1 is selected from fluorine, iodine or their radioactive isotopes
- R 2 is hydrogen
- R 1 is hydrogen
- R 2 is selected from fluorine, iodine or their radioactive isotopes.
- R 1 when X is When R 1 is only iodine or its radioactive isotope, R 2 is hydrogen; or R 1 is hydrogen, and R 2 is only iodine or its radioactive isotope.
- the radioisotope is selected from 18 F, 123 I, 124 I, 125 I, or 131 I.
- the aforementioned fluorenone ⁇ 7 nicotinic acetylcholine receptor ligand compound is selected from compounds of the following structures:
- the present invention also provides a precursor compound of the fluorenone ⁇ 7 nicotinic acetylcholine receptor ligand compound represented by formula (I),
- R 1 is 3,3-dibutyltriaz-1-en-1-yl
- R 2 is hydrogen
- X is R 1 is hydrogen and R 2 is tributylstannyl
- the precursor compound is selected from
- the ⁇ 7 nicotinic acetylcholine receptor ligand compound provided by the present invention can be used as an agonist of the ⁇ 7 nicotinic acetylcholine receptor.
- the ⁇ 7 nicotinic acetylcholine receptor ligand compound provided by the present invention can be used as a partial agonist of the ⁇ 7 nicotinic acetylcholine receptor.
- the “agonist” should be understood to be given its broadest meaning, that is, as any molecule that partially or fully activates the target (for example, ⁇ 7 nicotinic acetylcholine receptor) or at least one biological activity .
- the ligand compound of the ⁇ 7 nicotinic acetylcholine receptor provided by the present invention can specifically bind to the extracellular domain of the ⁇ 7 nicotinic acetylcholine receptor to induce intracellular signal transmission, thereby proving that it is effective in preventing or treating cognition. Obstacles and efficacy in neurological rehabilitation.
- ⁇ 7 nicotinic acetylcholine receptors play an important role in improving the cognitive function of learning, memory and attention.
- ⁇ 7 nicotinic acetylcholine receptors are associated with the following diseases: mild cognitive impairment, Alzheimer’s disease, age-related and other cognitive impairments, schizophrenia, attention deficit disorder, attention deficit hyperactivity Disorders (ADHD), dementia caused by injections or metabolic disorders, dementia with Lewy bodies, convulsions such as epilepsy, multiple cerebral infarctions, mood disorders, compulsive and addictive behaviors, inflammatory diseases, and control pain caused by these disorders Related diseases and conditions.
- the degree of activation of ⁇ 7 nicotinic acetylcholine receptors can be changed or adjusted by the administration of ⁇ 7 receptor ligands.
- Non-limiting examples of the ⁇ 7 receptor ligands are: antagonists, agonists, partial agonists and inverse agonists Agent.
- ⁇ 7 receptor ligands can be used to treat and prevent various types of cognitive impairment and other disorders or diseases, and its agonists and partial agonists can improve cognitive function and attention in rodents, non-human primates and humans force.
- the present invention also provides the use of the aforementioned fluorenone ⁇ 7 nicotinic acetylcholine receptor ligand compound in the preparation of drugs for preventing or treating cognitive disorders.
- the "cognitive impairment” refers to the large-scale degradation of animals in cognitive functions or cognitive domains, for example, in working memory, attention and alertness, language learning and memory, visual learning and memory, reasoning And problem solving, especially in terms of execution ability, task processing speed and/or social cognition.
- the known manifestations of cognitive impairment are attention deficit, thinking disorder, slow thinking reaction, difficulty understanding, poor concentration, loss of problem-solving ability, inaccurate memory, expressing thoughts and/or comprehensive thinking, and difficulty in feeling and behavior. Difficulty in eliminating unreasonable thinking.
- treatment has its general meaning, and specifically refers to the treatment of mammalian individuals (preferably humans) who have suffered from the cognitive impairment disease of the present invention with the medicament of the present invention in order to treat The disease has the effects of treatment, cure, alleviation, alleviation, etc.
- prevention has its general meaning, and specifically refers to mammals who may suffer from the cognitive impairment disease of the present invention or are at risk for the cognitive impairment disease of the present invention.
- the individual uses the medicine of the present invention for treatment in order to prevent, prevent, stop, block, and block the disease.
- the cognitive impairment is selected from the group consisting of early-onset Alzheimer's disease, senile dementia, micro-infarct dementia, AIDS-related dementia, HIV dementia, Lewy body Related dementia, Down syndrome related dementia, mild cognitive impairment, age-related memory impairment, recent short-term memory impairment, age-related cognitive impairment, drug-related cognitive impairment, immunodeficiency syndrome-related Cognitive impairment, cognitive dysfunction associated with vascular disease, schizophrenia, attention deficit disorder, attention deficit hyperactivity disorder, and learning deficit disorder.
- Alzheimer's disease can be Alzheimer's disease or Alzheimer's disease.
- Lewy body-related dementia may be Lewy body dementia.
- the present invention also provides the use of the fluorenone ⁇ 7 nicotinic acetylcholine receptor ligand compound represented by the following formula (I) in the preparation of a reagent for PET or SPECT imaging agent,
- X is a 6-10 membered nitrogen-containing heterocyclic group; the nitrogen-containing heterocyclic group is unsubstituted or substituted by a C 1-4 alkyl group;
- R 1 is single-photon radionuclide 123 I, 125 I, 131 I or positron radionuclide 124 I;
- R 2 is hydrogen; or
- R 1 is hydrogen,
- R 2 is single-photon radionuclide 123 I, 125 I, 131 I or positron radionuclide 124 I.
- the 6-10 membered nitrogen-containing heterocyclic group is selected from
- the structure of the ligand compound of the fluorenone ⁇ 7 nicotinic acetylcholine receptor is shown in the following formula:
- the present invention also provides the use of the ligand compound of the fluorenone ⁇ 7 nicotinic acetylcholine receptor shown in the following formula in the preparation of a PET imaging agent,
- the ligand compounds provided by the present invention have high affinity with ⁇ 7 nicotinic acetylcholine receptors, and are excellent ligand compounds for ⁇ 7 nicotinic acetylcholine receptors. Further, the ⁇ 7 cigarettes provided by the present invention After the basic acetylcholine receptor ligand compound is radiochemically labeled, it can be used as a PET imaging agent or a SPECT imaging agent, and has good affinity, strong specificity, high selectivity, brain uptake and metabolic rate Moderate characteristics, with clinical application value.
- Figure 1 is the HPLC spectrum of [ 125 I] TM-16 and TM-16 co-injection
- Figure 2 shows the HPLC spectrum of [ 125 I] TM-6 and TM-6 co-injection
- Figure 3 is the specific binding curve of [ 125 I] ⁇ -bgt and ⁇ 7 nAChRs membrane protein
- Figure 4 is the Hill straight line of [ 125 I] ⁇ -bgt binding to receptor membrane protein.
- Figure 5 shows the Scatchard straight line
- Figure 6 is an HPLC chart of the stability analysis of the radioligand [ 125 I]TM-16 after incubation in fetal calf serum for 2 hours;
- Figure 7 is an HPLC chart of the stability analysis of the radioligand [ 125 I]TM-16 after incubating for 2 hours in saline;
- Figure 8 is a SPECT image of the radioligand [ 125 I]TM-16 in mice.
- Figure 9 is an autoradiographic image of the radioligands [ 125 I]TM-6 and [ 125 I]TM-16 in the brain of mice.
- the synthetic route is as follows:
- chromium trioxide 138.0g, 1.38mol
- a mixed solution of 120mL water and 80mL acetic acid stir to dissolve all, and set aside; add 40.0g fluoranthene (3-5) (0.2mol) to the reaction flask And 500mL of acetic acid, and heated to 80-85 °C, then add the chromium trioxide solution dropwise to it, control the temperature of the reaction system in the reaction flask at 80-85 °C, after the addition is completed, the reaction system in the reaction flask is heated to After reacting at 110-120°C for 2 hours, cool to room temperature and pour into 3L water. A large amount of yellow solid precipitates out.
- the synthetic route is as follows:
- the synthetic route is as follows:
- the synthetic route is as follows:
- the intermediate compound 3-8 (9.0g), n-methyl homopiperazine (4.5g), Pd 2 (dba) 3 (1.0g), BINAP (1.3g), cesium carbonate (12.5g) were added to the reaction flask ), and toluene (270 mL), the reaction was replaced with nitrogen three times, and then heated to 80-85°C, and reacted for 16 hours.
- the synthetic route is as follows:
- step (1) in Example 1 the reaction substrate n-methylhomopiperazine was replaced with cis-2-methylhexahydropyrrolo[3,4-C]pyrrole for reaction to obtain the compound BocTM-2.
- the synthetic route is as follows:
- step (2) in Example 7 the intermediate compound 3-20 was reacted with the substrate cis-2-methylhexahydropyrrolo[3,4-C]pyrrole to obtain compound TM- 1.
- MS (M+H + ): m/z 323.15.
- step (2) in Example 7 the intermediate compound 3-20 and the substrate cis-3,7-diazabicyclo[3.3.0]octano[3,4-C]pyrrole The reaction is carried out to obtain compound TM-5.
- MS (M+H + ): m/z 309.13.
- step (2) in Example 7 the intermediate compound 3-20 was reacted with the substrate n-methylhomoperazine to obtain compound TM-8.
- MS (M+H + ): m/z 311.15.
- step (2) in Example 7 the intermediate compound 3-20 was reacted with the substrate homopiperazine to obtain compound TM-11.
- MS (M+H + ): m/z 283.12.
- step (2) in Example 7 the intermediate compound 3-20 was reacted with the substrate piperazine to obtain compound TM-18.
- MS (M+H + ): m/z 297.13.
- the synthetic route is as follows:
- Compound 4-2 (100 mg) was added to 50 mL of anhydrous toluene. After dissolution, 30 mg of tetrakistriphenylphosphine palladium and 455.5 mg of n-hexabutyl tin were added and heated to 90° C. and refluxed for 18 hours. After the reaction was detected by TLC, the product 4-3 (35 mg, 41.5%) was purified by silica gel column.
- the synthetic route is as follows:
- the radiochemical purity of the radioligand is greater than 98%, and the radiolabeling rate is about 63.1% (without decay correction); the purified [ 125 I]TM-16 and the unlabeled stable Compound TM-16 was co-injected for HPLC analysis.
- the retention times of [ 125 I]TM-16 and TM-16 are 7.257 min and 6.931 min, respectively. The retention times of the two match, confirming the accuracy of the radioligand .
- the column was washed with purified water (10 mL), the product was eluted with methanol (10 mL), and then the solvent was removed under vacuum.
- the final product was analyzed by high performance liquid chromatography using a 280nm ultraviolet detector and a radioactivity detector to determine the radiochemical purity of the synthesized compound (Figure 2).
- the total synthesis time is about 100 minutes, the radiochemical yield is 84.5% (uncorrected for decay), and the radiochemical purity is greater than 98%.
- the total volume of the reaction mixture in the total binding tube is 500 ⁇ L, including 100 ⁇ L of membrane protein solution (the final amount of protein in each tube is 1.5mg), 10 ⁇ L of different concentrations of radioligand [ 125 I] ⁇ -bgt and 390 ⁇ L of ice-cold 50mM Tris-HCl buffer solution, the order of sample addition is: membrane protein, Tris-HCl buffer solution and [ 125 I] ⁇ -bgt (Table 1).
- Non-specific binding is determined by 2 ⁇ M non-labeled ⁇ -bgt
- the reaction mixture in the test tube includes 100 ⁇ L membrane protein solution (the final amount of protein in each test tube is 1.5mg), 10 ⁇ L different concentrations of radioligand [ 125 I ] ⁇ -bgt, 100 ⁇ L 2 ⁇ M ⁇ -bgt and 290 ⁇ L ice-cold 50mM Tris-HCl buffer solution, the total volume is 500 ⁇ L
- the order of sample addition is: membrane protein, Tris-HCl buffer solution, ⁇ -bgt and [ 125 I] ⁇ -bgt (Table 2).
- MLA JMWard, VBCockcroft, GGLunt, FSSmillie, S. Wonnacott, Methyllycaconitine: a selective probe for neuronal alpha-bungarotoxin binding sites, FEBS LETT, 270 (1990) 45 -8.
- ⁇ 7 nAChRs with high selectivity and high affinity ligands is used as a reference ligand to determine its affinity with ⁇ 7 nAChRs in mouse brain.
- the preparation method and sample addition method of the ligand compound are shown in Table 3 and Table 4:
- the order of sample addition is: protein, Tris-HCl buffer solution, drug (ligand compound or MLA), [ 125 I] ⁇ -bgt.
- each ligand compound has an affinity for ⁇ 7 nAChR membrane protein, and the inhibition constant (K i ) is distributed in the range of 2.23-521.1 nM.
- K i the inhibition constant
- the compound TM-16 and TM-6 pair [ 125 I] ⁇ -bungaratoxin showed a strong inhibitory effect, with K i values of 2.23 ⁇ 0.56 nM and 9.26 ⁇ 0.37 nM, respectively.
- the in vitro stability of the radioligand is of great significance to its further in vivo studies.
- in vitro stability studies are carried out in physiological saline and animal serum.
- the specific method is: take 10 ⁇ Ci of radioligand [ 125 I]TM-16 purified by HPLC and incubate 100 ⁇ L of fetal bovine serum at 37°C for 1h and 2h respectively, add 200 ⁇ L of acetonitrile to it to fully precipitate the protein after incubation.
- the blood, brain, heart, lung, liver, spleen, lung, kidney, muscle, bone, intestine, stomach and tail were dissected. , Weigh the wet weight of each organ and use ⁇ -counter to measure its count.
- the data in the table is the average ⁇ standard deviation of five measurements
- the 125 I-labeled radioligand [ 125 I]TM-16 has a very high initial brain uptake in the mouse brain, and its uptake value reaches 6.47% ID/g for 15 minutes after 5 minutes of injection. It showed the highest brain uptake value of 9.49%ID/g; at the same time, the radioligand showed a suitable brain clearance rate. After 60min and 120min of administration, the brain uptake value dropped to 6.21%ID/g, respectively And 3.26% ID/g, which indicates that the compound has suitable brain dynamics; in addition, the uptake of [ 125 I]TM-16 in the blood is very low, showing a high brain/blood ratio. It was 8.11 and 8.87 at 15min and 60min, respectively.
- the radioligand [ 125 I]TM-16 (0.2mL, 60 ⁇ Ci) was injected into female Kunming mice (18-22g) by tail vein injection, and then the mice were anesthetized with 3% isoflurane to a coma Later, the mouse was fixed on a small animal micro-SPECT/CT imaging device (TriFoil imaging Triumph SPECT/CT) in a prone position, and 1% isoflurane was used to maintain the mouse in anesthesia during the scanning and imaging process. Images were collected 1min-60min after the administration, divided into 12 frames, one frame every 5 minutes, to observe the distribution of [ 125 I]TM-16 in the brain of the mouse.
- Figure 8 shows the coronal, sagittal, and cross-sectional micro-SPECT images of the brain of Kunming mice after 15min, 30min, 60min, and 90min injection of [ 125 I]TM-16. It can be seen from Figure 8 that [ 125 I]TM-16 has a higher uptake in the brain of mice, and its distribution in the brain is basically consistent with the results of the animal body distribution experiment of biological experiment example 3. The uptake is the highest at 30 minutes. With the extension of time, the concentration of radioligand gradually decreases, and at the same time, the retention in the brain is more suitable. A certain concentration of enrichment can still be observed after 60 minutes of administration. According to the above-mentioned good imaging results, [ 125 I]TM-16 can be used as a SPECT imaging agent for ⁇ 7 nAChR.
- the blood, brain, heart, lung, liver, spleen, lung, kidney, muscle, bone, intestine, stomach and tail were dissected. , Weigh the wet weight of each organ and use ⁇ -counter to measure its count.
- the data in the table is the average value of five measurements ⁇ standard deviation
- the 125 I-labeled radioligand [ 125 I]TM-6 has a very high initial brain uptake in the mouse brain, and its uptake value reaches 4.20%ID/g for 15 minutes after 5 minutes of injection. It showed the highest brain uptake value of 7.46% ID/g; at the same time, the radioligand showed a suitable brain clearance rate. After 60 minutes and 120 minutes of administration, the brain uptake value was reduced to 4.56% ID/g. And 2.84%ID/g, which indicates that the compound has suitable brain dynamic properties. In addition, the uptake of [ 125 I]TM-6 in the blood is very low, showing a high brain/blood ratio, which is 6.27 and 5.30 at 15 min and 60 min, respectively.
- the brain was quickly dissected and placed on ice, blood stains were removed with ice-cold normal saline, and the cortex was dissected in different regions.
- Striatum, hippocampus, hypothalamus, thalamus, cerebellum and afterbrain weigh the wet weight of each brain area and use ⁇ -counter to determine its radioactive count.
- the data in the table is the average ⁇ standard deviation of five measurements
- the rate of uptake and clearance of radioactivity in the cerebellum is very fast compared to other brain regions. During the entire experiment, the tissue/cerebellum ratio gradually increased and reached a peak value 90 minutes after the administration.
- the radioligand has good specific binding to ⁇ 7 nAChR.
- the brain was quickly dissected and placed on ice, blood stains were removed with ice-cold normal saline, and the cortex was dissected in different regions.
- Striatum, hippocampus, hypothalamus, thalamus, cerebellum and afterbrain weigh the wet weight of each brain area and use ⁇ -counter to determine its radioactive count.
- the data in the table is the average ⁇ standard deviation of five measurements
- the rate of uptake and clearance of radioactivity in the cerebellum is very fast compared to other brain regions. During the entire experiment, the tissue/cerebellum ratio gradually increased and reached a peak value 90 minutes after the administration.
- the radioligand has good specific binding to ⁇ 7 nAChR.
- [ 125 I]TM-6 or [ 125 I]TM-16 with an activity of 60 ⁇ Ci was injected into Kunming mice through the tail vein, and the mice were sacrificed 45 minutes later.
- methyl tauphine 0.1 mL, 1 mg/kg, containing 15% ethanol
- the mice were sacrificed 45 minutes after the tracer molecule injection, and the sections were embedded, and the operation was the same as above.
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Claims (12)
- 如权利要求1所述的芴酮类α7烟碱型乙酰胆碱受体的配体化合物,其中,R 1选自氟、碘或它们的放射性同位素,R 2为氢;或者R 1为氢,R 2选自氟、碘或它们的放射性同位素。
- 如权利要求1所述的芴酮类α7烟碱型乙酰胆碱受体的配体化合物,其中,所述放射性同位素选自 18F、 123I、 124I、 125I或 131I。
- 如权利要求1-5中任一项所述的芴酮类α7烟碱型乙酰胆碱受体的配体化合物在制备预防或治疗认知障碍的药物中的用途。
- 如权利要求7所述的用途,其中所述认知障碍选自下组:早发性阿尔茨海默病、老年性痴呆症、微小梗塞性痴呆症、AIDS相关痴呆症、HIV痴呆症、路易体相关痴呆症、唐氏综合征相关痴呆症、轻度认知功能障碍、与年龄相关的记忆障碍、最近短期记忆障碍、年龄相关认知障碍、药物相关的认知障碍、免疫缺陷综合征相关的认知障碍、血管疾病相关的认知功能障碍、精神分裂症、注意力缺陷障碍、注意缺陷多动障碍以及学习缺陷障碍。
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