N-cyclopropyl isoindole compound as well as preparation method and application thereof

Abstract

The invention discloses an N-cyclopropyl isoindole compound as well as a preparation method and application thereof, and relates to an N-cyclopropyl isoindole compound shown in a structure of a claimed formula I as well as a preparation method and pharmaceutical application of the N-cyclopropyl isoindole compound. The N-cyclopropyl isoindole compound provided by the invention not only has good inhibitory activity on a sigma-2 receptor, but also shows high selectivity on the sigma-2 receptor. Therefore, the N-cyclopropyl isoindole compound provided by the invention has a prospect of being developed into drugs for treating diseases which are prevented, treated or relieved by inhibiting the sigma-2 receptor, and the diseases which are prevented, treated or relieved by inhibiting the sigma-2 receptor comprise nervous system diseases and tumors, such as nervous system diseases and tumors. The nervous system diseases comprise Alzheimer's disease, schizophrenia and dementia with Lewy bodies. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and relates to the synthesis, preparation and application of new compounds, and specifically to an N-cyclopropylisoindole compound, a preparation method and application. Background Art

[0002] Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia among the elderly. The disease was first described in 1906 by German neurologist Alois Alzheimer, hence its name. Key features of AD include the death of nerve cells and loss of brain tissue, ultimately leading to significant cognitive impairment. Key features of AD include the abnormal accumulation of β-amyloid protein in the brain, forming plaques, which are considered a hallmark of AD. This likely causes neuronal damage and death in multiple brain regions, particularly those associated with memory and cognition. This neuronal death and tissue damage trigger progressive cognitive decline, ultimately leading patients to experience progressively worsening problems with memory, language, decision-making, and executive function. Currently, there is no effective treatment for AD, and clinical treatment focuses on alleviating symptoms and improving patients' quality of life.

[0003] Sigma-2 receptors are a type of receptor widely distributed in peripheral tissues such as the central nervous system, pancreas, liver, and gastrointestinal tract. They may be potential targets for the treatment of tumors, neurodegenerative diseases, and neuralgia. Studies have shown that some people will not develop AD even if they have AD-related pathological features in their brains (such as amyloid plaques and neurofibrillary tangles). This may be because the unique synaptic protein composition of these people is resistant to beta-amyloid protein and tau protein, thereby avoiding their damage to synaptic function. This phenomenon shows that as long as the treatment targets the synaptic toxicity of beta-amyloid protein deposition, good therapeutic effects may be achieved. Research by Cognition Therapeutic, a US company, has found that by inhibiting the sigma-2 receptor, the binding of Aβ oligomers to synaptic receptors can be unstable, resulting in the removal of Aβ oligomers from the synapse and restoring synaptic function. Based on this discovery, the company designed and synthesized the compound CT1812, which is currently in Phase II clinical trials (Alzheimers Dement. 2021, 17(8), 1365-1382) and has good prospects for the treatment of AD. Unfortunately, CT1812 has the disadvantages of poor selectivity for sigma-1 and sigma-2 receptors and poor oral bioavailability.

[0004] The applicant has discovered a compound that can selectively inhibit sigma-2 receptors and has proposed the present invention. Summary of the Invention

[0005] The present invention aims to overcome the deficiencies of the prior art. The first purpose is to provide an N-cyclopropylisoindole compound with strong inhibitory activity and high selectivity for sigma-2 receptors; the second purpose is to provide a method for preparing the N-cyclopropylisoindole compound; and the third purpose is to provide a pharmaceutical use of the N-cyclopropylisoindole compound.

[0006] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0007] An N-cyclopropylisoindole compound represented by formula I, or a pharmaceutically acceptable salt thereof:

[0008]

[0009] Wherein: R is hydrogen or an alcohol having 2 to 4 carbon atoms connected thereto or an alcohol having 2 to 4 carbon atoms connected thereto by fluorination.

[0010] Preferably, in the above-mentioned N-cyclopropylisoindole compounds, R is hydrogen, 3-hydroxypropyl or 2-F-3-hydroxypropyl.

[0011] The present invention provides a method for preparing the above-mentioned N-cyclopropylisoindole compounds, and the synthetic route is as follows:

[0012]

[0013] The specific steps of the above preparation method are as follows:

[0014] Step a: dissolving catechol in dichloromethane, adding a catalytic amount of concentrated sulfuric acid at -30°C, then slowly adding isobutylene dropwise, slowly returning to room temperature and stirring overnight, adding triethylamine to the reaction solution at -30°C to quench, evaporating the reaction solution to dryness, and separating by column chromatography to obtain a brown-yellow oil; dissolving the oil in methanol, adding potassium iodide and sodium hydroxide, then slowly adding sodium hypochlorite dropwise at 0°C, reacting at 0°C for 3 hours, adding saturated ammonium chloride to the reaction solution, extracting with ethyl acetate, and evaporating to dryness to obtain a brown oil; dissolving the oil in triethylamine, then adding 2-methylbut-3-yn-2-amine, bis(triphenylphosphine)palladium chloride, and cuprous iodide, reacting under nitrogen for 3 hours, then directly filtering and evaporating the reaction solution to dryness, and separating by column chromatography to obtain a yellow solid; dissolving the yellow solid in ethanol, then adding hydrazine hydrate, copper sulfate pentahydrate, and neocuproine, refluxing overnight, extracting with ethyl acetate, evaporating to dryness, and separating by column chromatography to obtain a yellow solid.

[0015] Step b: dissolving the brown oily substance 2-(tert-butoxy)-4-iodophenol obtained in the second step of step a in dimethylformamide, adding 3-bromo-propan-1-ol, potassium iodide and potassium carbonate, reacting at room temperature overnight under nitrogen protection, extracting, evaporating and column chromatography to obtain a brown oily substance; dissolving the brown oily substance in triethylamine, then adding 1-ethynylcyclopropane-1-amine hydrochloride, bis(triphenylphosphine)palladium chloride and cuprous iodide, reacting under nitrogen protection for 3 hours, directly filtering the reaction solution and evaporating to dryness, and separating by column chromatography to obtain a brown oily substance; dissolving the brown oily substance in ethanol, then adding hydrazine hydrate, copper sulfate pentahydrate and neocuproine, refluxing overnight, extracting with ethyl acetate, evaporating to dryness and separating by column chromatography to obtain a brown oily substance.

[0016] Step c: dissolving the brown oily substance 2-(tert-butoxy)-4-iodophenol obtained in the second step of step a in dimethylformamide, adding 3-bromo-2-fluoro-propan-1-ol, potassium iodide and potassium carbonate, reacting at room temperature overnight under nitrogen protection, extracting, evaporating and column chromatography to obtain a brown oily substance; dissolving the brown oily substance in triethylamine, then adding 1-ethynylcyclopropane-1-amine hydrochloride, bis(triphenylphosphine)palladium chloride and cuprous iodide, reacting under nitrogen protection for 3 hours, directly filtering the reaction solution and evaporating to dryness, and separating by column chromatography to obtain a brown oily substance; dissolving the brown oily substance in ethanol, then adding hydrazine hydrate, copper sulfate pentahydrate and neocuproine, refluxing overnight, extracting with ethyl acetate, evaporating to dryness and separating by column chromatography to obtain a brown oily substance.

[0017] Step d: o-xylene was dissolved in chloroform, chlorosulfonic acid was slowly added dropwise at 0°C, and stirred at room temperature for two days after the addition was complete. The reaction solution was added to ice water, extracted with dichloromethane, and evaporated to dryness to obtain a light yellow oil; the oil was dissolved in xylene, triphenylphosphine was added in batches, the reaction was allowed to react overnight at room temperature, petroleum ether was added after evaporation and the excess triphenylphosphine was removed by stirring at -10°C, the filtrate was evaporated to dryness, and the yellow-green oil was separated by column chromatography; the yellow-green oil was dissolved in anhydrous ethanol, sodium borohydride was added in batches, and then iodomethane was added to react overnight. The reaction solution was extracted with dichloromethane and directly subjected to the next step; m-chloroperbenzoic acid was added to the above dichloromethane solution at -30°C, and then at the same temperature. The reaction mixture was reacted for 3 hours under 400 nm temperature and 800 nm temperature conditions, and the reaction solution was returned to room temperature. A saturated sodium carbonate solution was added to adjust the pH to neutral, and the mixture was extracted with dichloromethane. The solvent was evaporated to dryness and separated by column chromatography to obtain a light yellow solid; the light yellow solid was dissolved in 1,2-dichloroethane, and N-bromosuccinimide and azobisisobutyronitrile were added. After nitrogen displacement, the reaction was refluxed overnight, extracted with dichloromethane, and purified by column chromatography to obtain a light yellow oil; the light yellow oil and the yellow solid obtained in step a (or b, or c) were dissolved in tetrahydrofuran, and triethylamine was added. The mixture was reacted at 50° C. under nitrogen protection for 18 hours, filtered, evaporated to dryness, and separated by column chromatography and purified by pre-HPLC (C18) to obtain the target compound.

[0018] The N-cyclopropylisoindole compounds are used for preparing drugs for treating diseases that can be prevented, treated or alleviated by inhibiting sigma-2 receptors.

[0019] Preferably, the diseases that are prevented, treated or alleviated by inhibiting sigma-2 receptors include nervous system diseases and tumors.

[0020] More preferably, the nervous system diseases include Alzheimer's disease, schizophrenia, dementia, ALS and Parkinson's disease.

[0021] More preferably, the tumor comprises ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, cervical cancer, bone metastatic cancer, papillary thyroid cancer, colon cancer, gastrointestinal stromal tumors, melanoma, mesothelioma, glioblastoma, osteosarcoma, multiple myeloma, hyperproliferative diseases, metastasis from a primary tumor site, myeloproliferative diseases, and leukemia.

[0022] Preferably, the diseases that are prevented, treated or alleviated by inhibiting sigma-2 receptors also include metabolic diseases, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, hypereosinophilic syndrome and mastocytosis.

[0023] Beneficial effects:

[0024] 1. The present invention provides an N-cyclopropylisoindole compound and a method for preparing the compound. The prior art does not disclose the structure of the compound and its preparation method.

[0025] 2. Activity tests have demonstrated that the N-cyclopropylisoindole compounds provided by the present invention not only have good sigma-2 receptor inhibitory activity but also exhibit high selectivity for sigma-2 receptors. Those skilled in the art are aware that sigma-2 receptors are widely distributed in peripheral tissues such as the central nervous system, pancreas, liver, and gastrointestinal tract, and are potential targets for the treatment of tumors, neurodegenerative diseases, and neuralgia. Taking AD as an example, on the one hand, in view of the strong inhibitory activity of the N-cyclopropylisoindole compounds of the present invention on the sigma-2 receptor, the N-cyclopropylisoindole compounds of the present invention bind to the sigma-2 receptor and allosterically regulate the sigma-2 receptor complex, thereby making the adjacent Aβ oligomers unstable in binding to the receptors on the synapse and then removed from the synapse, avoiding the damage of Aβ to the synapse, thereby exerting a therapeutic effect on AD; on the other hand, in view of the high selectivity of the N-cyclopropylisoindole compounds of the present invention for the sigma-2 receptor, the N-cyclopropylisoindole compounds of the present invention can reduce the undesirable effects brought about by the poor selectivity of compounds such as CT1812 in the prior art when binding to the sigma-1 receptor, and have strong selectivity. Therefore, the N-cyclopropylisoindole compounds provided by the present invention have the prospect of being developed into drugs for treating diseases that are prevented, treated or alleviated by inhibiting sigma-2 receptors. Diseases that are prevented, treated or alleviated by inhibiting sigma-2 receptors include nervous system diseases and tumors. Nervous system diseases include Alzheimer's disease, schizophrenia and Lewy body dementia. DETAILED DESCRIPTION

[0026] The essential contents of the present invention are described in detail below with reference to the embodiments, but the protection scope of the present invention is not limited thereto.

[0027] Example 1: Synthesis of 2-(tert-Butoxy)-4-(2-(1-(5-(methanesulfonyl)isoindol-2-yl)cyclopropyl)ethyl)phenol

[0028]

[0029] Step a:

[0030] Step 1: Add catechol (30.00 g, 272.45 mmol) and dichloromethane (150 ml) to a 500 ml three-necked flask. Then, add a catalytic amount of concentrated sulfuric acid (1.4 ml) at -35°C. Freshly prepared isobutylene (152.62 g, 2720 mmol) is slowly added dropwise. After the addition is complete, the reaction mixture is gradually allowed to warm to room temperature overnight. The reaction mixture is quenched by the addition of 3 ml of triethylamine. The reaction mixture is evaporated to dryness and separated by column chromatography (EA / PE = 1:10) to afford 30 g of a brownish-yellow oil, A, in a yield of 65.60%. LC-MS (ESI): m / z [M+H] +calcd for C 10 H 14 NaO2189.1; found 189.1.[M+H] +

[0031] Step 2: Add A (14.00 g, 84.23 mmol), potassium iodide (13.98 g), sodium hydroxide (3.37 g, 84.23 mmol), and methanol (80 ml) to a 500 ml three-necked flask. Slowly add sodium hypochlorite (83.86 ml, 84.23 mmol) dropwise at 0°C over 1 hour, then react at 0°C for 3 hours. Add 250 ml of saturated ammonium chloride solution to the reaction mixture, extract with ethyl acetate (250 ml x 2), wash once with saturated brine (400 ml), dry over anhydrous sodium sulfate, and evaporate to dryness to obtain 23.8 g of brown oil B, with a yield of 96.71%. LC-MS (ESI): m / z [MH] - calcd for C 10 H 12 IO2291.0;found 291.0.

[0032] Step 3: To a 100 ml single-necked flask, add B (0.3 g, 1.03 mmol), 1-ethynylcyclopropane-1-amine hydrochloride (1.69 g, 14.37 mmol), bis(triphenylphosphine)palladium chloride (0.014 g, 0.021 mmol), cuprous iodide (0.01 g, 0.05 mmol), and triethylamine (10 ml). React under nitrogen for 3 h. The reaction solution was directly evaporated to dryness and filtered. Column chromatography (EA / PE = 2:3) afforded 0.22 g of a brown oil, C, in a yield of 87.65%. LC-MS (ESI): m / z [M+H] + calcd for C 15 H 20 NO2246.1; found 246.1.

[0033] Step 4: To a 50ml single-necked flask, add C (0.25g, 1.02mmol), hydrazine hydrate (0.25g, 4.08mmol), copper sulfate pentahydrate (24mg, 0.1mmol), neocuproine (20mg, 0.17mmol), and anhydrous ethanol (10ml). The mixture was refluxed in air for 18h. After cooling to room temperature, the reaction solution was added with 20ml of water, extracted with ethyl acetate (15ml x 3), washed once with saturated brine (50ml), and dried over anhydrous sodium sulfate. Column chromatography (EA / PE = 2:3) afforded 0.15g of a brown oil, D, in a yield of 60.81%. LC-MS (ESI): m / z [M+H] + calcd for C15 H 30 NO2250.1; found 250.1.

[0034] Step d:

[0035] Step 1: Add o-xylene (30 g, 282.59 mmol) and chloroform (90 ml) to a 500 ml single-necked flask. Then, slowly add chlorosulfonic acid (72.55 g, 721.70 mmol) dropwise at 0°C. After the addition is complete, gradually return the reaction mixture to room temperature and stir for two days. Slowly add the reaction mixture to ice water, extract with dichloromethane (200 ml x 3), wash once with saturated brine (500 ml), and dry over anhydrous sodium sulfate. Evaporate the solvent to dryness to obtain 54.30 g of K as a light yellow oil, yield: 94.00%. LC-MS (ESI): m / z [MH] - calcd for C8H9O3S185.0; found 185.1.

[0036] Step 2: Compound K (10.00 g, 48.90 mmol) and xylene (80 ml) were added to a 250 ml single-necked flask. Triphenylphosphine (38.00 g, 146.60 mmol) was then added in portions at 0°C. After complete addition, the reaction mixture was allowed to warm to room temperature and allowed to react overnight. The reaction mixture was evaporated to dryness, 80 ml of petroleum ether was added, and the mixture was stirred at -10°C for 30 min. The excess triphenylphosphine was then removed by filtration. The filtrate was evaporated to dryness and separated by column chromatography (100% PE) to obtain 5.80 g of a yellow-green oil, L, in a yield of 86.60%. LC-MS (ESI): m / z [M+H] + calcd for C 16 H 19 S2275.1;found 275.1.

[0037] Step 3: Add L (0.5 g, 1.82 mmol) and anhydrous ethanol (20 ml) to a 100 ml two-necked flask. Then, add sodium borohydride (0.21 g, 5.47 mmol) in batches at 0°C. Stir for 30 min, then add iodomethane (0.57 g, 4.00 mmol). The reaction mixture is brought to room temperature and allowed to react for 3 h. Pour the reaction mixture into 20 ml of saturated ammonium chloride, extract with dichloromethane (20 ml x 3), wash once with saturated brine (50 ml), dry over anhydrous sodium sulfate, and filter the filtrate into a two-necked flask for direct use in the next reaction.

[0038] Step 4: The filtrate was cooled to -30°C, and then m-chloroperbenzoic acid (1.30 g, 7.28 mmol) was added in batches. The reaction was then allowed to react at this temperature for 3 h. The reaction solution was gradually returned to room temperature, and the pH was adjusted to neutral by adding saturated sodium carbonate solution. The reaction solution was transferred to a separatory funnel and extracted with dichloromethane (50 ml x 3), washed once with saturated brine (150 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness and separated by column chromatography (EA / PE = 1:4) to obtain 0.55 g of light yellow solid N, with a yield of 82.30%. LC-MS (ESI): m / z [M+H] + calcd for C9H 13 O2S185.1;found 185.1.

[0039] Step 5: To a 50ml single-necked flask, add N (2.7g, 14.65mmol), N-bromosuccinimide (5.13g, 28.71mmol), azobisisobutyronitrile (196.56mg, 1.17mmol), and 1,2-dichloroethane (70ml). Replace the atmosphere with nitrogen and reflux overnight. After cooling to room temperature, the reaction solution was poured into water, extracted with dichloromethane (30ml x 3), washed once with saturated brine (60ml), and dried over anhydrous sodium sulfate. Column chromatography (EA / PE = 1:8) yielded 3.69g of a light yellow oil (O), yield: 73.80%. LC-MS (ESI): m / z [M+H]+calcd for C9H 11 Br2O2S 340.9; found 340.9.

[0040] Step 6: To a 50 ml single-necked flask, add Compound D (0.10 g, 0.40 mmol), Compound O (0.17 g, 0.48 mmol), triethylamine (0.11 g, 1.12 mmol), and tetrahydrofuran (10 ml). The mixture was reacted at 50°C under nitrogen for 18 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was evaporated to dryness. The filtrate was separated by column chromatography (EA / DCM = 1:4) to afford 0.11 g of a light brown oil (yield: 61.45%). The product was further purified by pre-HPLC (C18, gradient elution: 10-40% methanol: 0.1% aqueous TFA) to afford 176 mg of the title compound (yield: 35.12%).

[0041] 1H NMR (400MHz, Chloroform-d) δ7.91(dd,J=8.1,1.6Hz,1H),7.84(d,J=1.9Hz,1H),7.49(d,J=8.0Hz,1H),6.80(d,J=8.1Hz,1H),6.64(d,J=2.1Hz,1H ),6.58(dd,J=8.2,2.1Hz,1H),4.86(s,4H),3.04(s,3H),2.41–2.33(m,2 H),2.02–1.93(m,2H),1.52–1.47(m,2H),1.35(s,9H),1.07–0.97(m,2H). 13 C NMR(101MHz,Chloroform-d)δ162.06,161.69,148.71,142.26,141.90,140.00,135.66,130.62,128.60,123.95,123 .56,122.25,122.17,115.19,80.94,56.35,56.18,46.89,44.57,30.87,30.57,28.91,10.41.LC-MS(ESI):m / z[M+H] + calcd for C 24 H 32 NO4S430.2;found 430.1.

[0042] Example 2: Synthesis of 3-(2-(tert-butoxy)-4-(2-(1-(5-(methylsulfonyl)isoindol-2-yl)cyclopropyl)ethyl)phenoxy)propan-1-ol

[0043]

[0044] Step b:

[0045] Step 1: To a 500ml three-necked flask, add Compound B (0.14g, 0.48mmol) from Example 1, 3-bromo-propan-1-ol (0.17g, 1.20mmol), potassium iodide (0.20g, 1.20mmol), potassium carbonate (0.14g, 1.03mmol), and N,N-dimethylformamide (10ml). The mixture was reacted at room temperature overnight under nitrogen. 20ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20ml x 2). The mixture was washed once with saturated brine (40ml), dried over anhydrous sodium sulfate, and separated by column chromatography (EA / PE = 1:9) to obtain 0.22g of a brown oil, E, in a yield of 61.23%. LC-MS (ESI): m / z [M+Na] + calcd for C 13 H19 IO3351.1;found352.1.

[0046] Step 2: To a 100 ml single-necked flask, add E (0.20 g, 0.57 mmol), 1-ethynylcyclopropane-1-amine hydrochloride (0.87 g, 7.42 mmol), bis(triphenylphosphine)palladium chloride (0.008 g, 0.011 mmol), cuprous iodide (0.005 g, 0.029 mmol), and triethylamine (10 ml). React under nitrogen for 3 h. The reaction solution was directly evaporated to dryness and filtered. Column chromatography (EA / PE = 2:3) afforded 0.11 g of a brown oil, F, in a yield of 64.71%. LC-MS (ESI): m / z [M+H] + calcd for C 18 H 26 NO3304.1; found 304.1.

[0047] Step 3: In a 50ml single-necked flask, add F (0.50g, 1.65mmol), hydrazine hydrate (0.39g, 6.6mmol), copper sulfate pentahydrate (41mg, 0.17mmol), neocuproine (34mg, 0.17mmol), and anhydrous ethanol (10ml). The mixture was refluxed in air for 18h. After cooling to room temperature, the reaction solution was added with 20ml of water, extracted with ethyl acetate (15ml x 3), washed once with saturated brine (50ml), and dried over anhydrous sodium sulfate. Column chromatography (EA / PE = 2:3) afforded 0.45g of a brown oil, G, in a yield of 88.21%. LC-MS (ESI): m / z [M+H] + calcd for C 15 H 30 NO2308.1; found 308.1.

[0048] Step d:

[0049] Compound G (0.10 g, 0.40 mmol), intermediate compound O from Example 1 (0.15 g, 0.48 mmol), triethylamine (0.11 g, 1.12 mmol), and tetrahydrofuran (10 ml) were added to a 50 ml single-necked flask and reacted at 50°C under nitrogen for 18 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was evaporated to dryness. Column chromatography (EA / DCM = 1:4) afforded 0.11 g of a light brown oil in a 61.45% yield. Further purification by pre-HPLC (C18, gradient elution with 10-40% 0.1% T methanol:FA solution) afforded 259 mg of the title compound as a white solid in a 33.12% yield.

[0050] 1H NMR (400MHz, Chloroform-d) δ7.90 (dd, J=7.9, 1.4Hz, 1H), 7.85 (s, 1H), 7.49 (d, J=8. 0Hz,1H),6.77(d,J=8.9Hz,1H),6.63(h,J=2.2Hz,2H),4.85(s,2H),4.83(s,2H),4.0 7(t,J=5.9Hz,2H),3.84(t,J=5.5Hz,2H),3.04(s,3H),2.42–2.32(m,2H),2.02(q,J= 5.6Hz,2H),1.98–1.90(m,2H),1.49(d,J=6.4Hz,2H),1.30(s,9H),1.05–0.96(m,2H). 13 C NMR(101MHz,Chloroform-d)δ162.32,161.93,151.96,144.78,141.83,140.20,135.84,131.80,128.51,125.06,123.95,123.4 9,122.22,113.72,80.34,67.78,61.18,56.32,56.14,46.84,44.57,31.87,30.68,30.38,28.72,10.46.LC-MS(ESI):m / z[M+H] + calcd for C 27 H 38 NO5S 488.2; found 488.1

[0051] Example 3: Synthesis of 3-(2-(tert-butoxy)-4-(2-(1-(5-(methylsulfonyl)isoindol-2-yl)cyclopropyl)ethyl)phenoxy)-2-fluoropropyl-1-ol

[0052]

[0053] Step c:

[0054] Step 1: To a 500ml three-necked flask, add Compound B from Example 1 (0.14g, 0.48mmol), 3-bromo-2-fluoro-propan-1-ol (0.19g, 1.20mmol), potassium iodide (0.20g, 1.20mmol), potassium carbonate (0.14g, 1.03mmol), and N,N-dimethylformamide (10ml). The mixture was reacted at room temperature overnight under nitrogen. 20ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20ml x 2). The mixture was washed once with saturated brine (40ml), dried over anhydrous sodium sulfate, and separated by column chromatography (EA / PE = 1:9) to obtain 0.12g of a brown oil H, with a yield of 66.30%. LC-MS (ESI): m / z [M+H] + calcd for C 13 H 19 FIO3369.2; found 369.1.

[0055] Step 2: To a 100 ml single-necked flask, add H (0.21 g, 0.57 mmol), 1-ethynylcyclopropane-1-amine hydrochloride (0.87 g, 7.42 mmol), bis(triphenylphosphine)palladium chloride (0.008 g, 0.011 mmol), cuprous iodide (0.005 g, 0.029 mmol), and triethylamine (10 ml). React under nitrogen for 3 h. The reaction solution was directly evaporated to dryness and filtered. Column chromatography (EA / PE = 2:3) yielded 0.12 g of a brown oil (I), yield: 65.21%. LC-MS (ESI): m / z [M+H] + calcd for C 18 H 25 FNO3322.1; found 322.1.

[0056] Step 3: To a 50ml single-necked flask, add I (0.53g, 1.65mmol), hydrazine hydrate (0.39g, 6.6mmol), copper sulfate pentahydrate (41mg, 0.17mmol), neocuproine (34mg, 0.17mmol), and anhydrous ethanol (10ml). The mixture was then refluxed in air for 18h. The reaction mixture was cooled to room temperature, added with 20ml of water, extracted with ethyl acetate (15ml x 3), washed once with saturated brine (50ml), and dried over anhydrous sodium sulfate. Column chromatography (EA / PE = 2:3) afforded 0.47g of J as a brown oil (yield: 87.15%). LC-MS (ESI): m / z [M+H] + calcd for C 18 H 29 FNO3326.2; found 326.1.

[0057] Step d:

[0058] Compound J (0.13 g, 0.40 mmol), intermediate compound O from Example 1 (0.15 g, 0.48 mmol), triethylamine (0.11 g, 1.12 mmol), and tetrahydrofuran (10 ml) were added to a 50 ml single-necked flask and reacted at 50°C under nitrogen for 18 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was evaporated to dryness. Column chromatography (EA / DCM = 1:4) afforded 0.11 g of a light brown oil in a yield of 57.16%. The product was further purified by pre-HPLC (C18, gradient elution of 10-40% methanol:0.1% aqueous TFA) to afford 347 mg of the title compound as a white solid in a yield of 23.12%.

[0059] 1 H NMR (400MHz, Chloroform-d) δ7.88 (dd, J=7.9, 1.4Hz, 1H), 7.80 (s, 1H), 7.46 (d, J=8. 0Hz,1H),6.71(d,J=8.9Hz,1H),6.58(h,J=2.2Hz,2H),4.84(s,2H),4.82(s,2H),4.7 6-4.67(m,2H),4.37(t,J=5.9Hz,2H),4.04(t,J=5.5Hz,2H),3.11(s,3H),2.42–2.32 (m,1H),2.06(q,J=5.6Hz,2H),1.49(d,J=6.4Hz,2H),1.30(s,9H),1.05–0.96(m,2H). 13 C NMR(101MHz,Chloroform-d)δ162.21,161.82,151.79,144.68,141.73,140.13,135.72,131.70,128.43,124.95,123.88,123.3 5,122.19,113.67,92.17,80.35,67.70,61.11,56.29,56.11,46.81,44.53,30.64,30.35,28.70,10.42.LC-MS(ESI):m / z[M+H] + calcd for C 27 H 37 FNO5S 506.2; found 506.1

[0060] Example 4: Sigma-1 / Sigma-2 Receptor Affinity Activity Test

[0061] In a 96-well plate, the test compound and the reference compound were diluted 4-fold in 8 points, 1 μL was added to each well, and the wells were arranged in duplicate. The starting concentration of the reference compound Haloperidol was 1 μM. 1 μL DMSO was added to the high signal control well (High control), and 1 μL 200 μM Haloperidol (final concentration 1 μM) was added to the low signal control well (Low control). 100 μL of sigma-1R or sigma-2R cell membrane diluted to the required concentration of the experiment with 50mM Tris-HCl (pH7.4, Sigma, Cat: T1503-1KG) buffer was added to each well. 100 μL of sigma-1R or sigma-2R cell membrane diluted to the required concentration of the experiment with 50mM Tris-HCl (pH7.4) buffer was added to each well. 3 H-DTG, the 96-well plate was sealed and incubated on a shaker at 300 rpm for 2 hours at room temperature. Simultaneously, 0.3% PEI (Polyethyleneimine, Sigma, Cat: P3143) was used to soak a GF / C filter plate (PerkinElmer, Cat: NET986250UC). After incubation, the cells were harvested onto the GF / C filter plate using a cell harvester (PerkinElmer, Model: C961961). The cells were washed four times with 50 mM Tris-HCl (pH 7.4) plate wash buffer and then dried in a 50°C oven for 1 hour. The bottom of the dried GF / C filter plate was sealed with film, 50 μL of scintillation fluid was added to each well, and the plate was sealed. The cells were read using a Microbeta (PerkinElmer, Model: 2450 Microplate Counter) and the percentage activity was calculated using Microsoft Excel software using the formula: % Activity = 100 × (Sample Raw Value - High Control Average) / (Low Control Average - High Control Average). The activity was analyzed using GraphPad Prism. 5. Data analysis software was used to fit the Dose-response-Stimulation—log[antagonist] vs.response—Variable slope model to obtain the IC of each test sample. 50 The values ​​are shown in Table 1.

[0062] Table 1 Sigma-1 / sigma-2 receptor inhibition and affinity activity results

[0063]

[0064] The above results show that compounds 1 to 3 provided by the present invention not only have good sigma-2 receptor inhibitory activity, but also show high selectivity for sigma-2 receptors. Those skilled in the art know that Sigma-2 receptors are widely distributed in peripheral tissues such as the central nervous system, pancreas, liver and gastrointestinal tract, and are potential targets for the treatment of tumors, neurodegenerative diseases and neuralgia. Taking AD as an example, on the one hand, in view of the strong inhibitory activity of compounds 1 to 3 on sigma-2 receptors, compounds 1 to 3 bind to sigma-2 receptors and allosterically regulate the sigma-2 receptor complex, making the adjacent Aβ oligomers unstable in binding to the receptors on the synapse and then removed from the synapse, avoiding Aβ damage to the synapse, thereby exerting a therapeutic effect on AD; on the other hand, in view of the high selectivity of compounds 1 to 3 for sigma-2 receptors, compounds 1 to 3 can reduce the undesirable effects of compounds such as CT1812 in the prior art due to poor selectivity when binding to sigma-1 receptors, and have strong selectivity. Therefore, the N-cyclopropylisoindole compounds provided by the present invention have the prospect of being developed into drugs for treating diseases that are prevented, treated or alleviated by inhibiting sigma-2 receptors, including nervous system diseases and tumors, and the nervous system diseases include Alzheimer's disease, schizophrenia and Lewy body dementia.

[0065] The purpose of the above embodiments is to specifically introduce the essential content of the present invention, but those skilled in the art should know that the protection scope of the present invention should not be limited to this specific embodiment.

Claims

1. An N-cyclopropylisoindole compound represented by formula I, or a pharmaceutically acceptable salt thereof: in: R is hydrogen or an alcohol having 2 to 4 carbon atoms connected thereto or a fluorinated alcohol having 2 to 4 carbon atoms connected thereto.

2. The N-cyclopropylisoindole compound according to claim 1, characterized in that: R is hydrogen, 3-hydroxypropyl or 2-F-3-hydroxypropyl.

3. The method for preparing the N-cyclopropylisoindole compound according to claim 2, characterized in that: The synthetic route is as follows:

4. Use of the N-cyclopropylisoindole compound according to claim 1 or 2 for preparing a medicament for treating a disease that can be prevented, treated or alleviated by inhibiting sigma-2 receptors.

5. The use according to claim 4, characterized in that: The diseases that can be prevented, treated or alleviated by inhibiting sigma-2 receptors include nervous system diseases and tumors.

6. The use according to claim 5, characterized in that: The neurological diseases include Alzheimer's disease, schizophrenia, dementia, ALS and Parkinson's disease.

7. The use according to claim 5, characterized in that: Such tumors include ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, cervical cancer, bone metastatic cancer, papillary thyroid cancer, colon cancer, gastrointestinal stromal tumors, melanoma, mesothelioma, glioblastoma, osteosarcoma, multiple myeloma, hyperproliferative diseases, metastases from a primary tumor site, myeloproliferative diseases, and leukemias.

8. The use according to claim 4, characterized in that: The diseases that can be prevented, treated or alleviated by inhibiting sigma-2 receptors also include metabolic diseases, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, hypereosinophilic syndrome and mastocytosis.

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