CN116640093A - Capsaicin-tacrine hybrid, and preparation method and application thereof - Google Patents

Capsaicin-tacrine hybrid, and preparation method and application thereof Download PDF

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CN116640093A
CN116640093A CN202310616098.2A CN202310616098A CN116640093A CN 116640093 A CN116640093 A CN 116640093A CN 202310616098 A CN202310616098 A CN 202310616098A CN 116640093 A CN116640093 A CN 116640093A
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formula
compound
capsaicin
tacrine
structure shown
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刘云
龙娟月
韦庆军
詹新立
蒋能
颜志明
廖世杰
谢天裕
唐海军
冯文宇
罗晓婷
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First Affiliated Hospital of Guangxi Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/08—Nitrogen atoms
    • C07D219/10—Nitrogen atoms attached in position 9
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The application discloses a series of capsaicin-tacrine hybrids and a preparation method and application thereof, and belongs to the technical field of medicines. The test result of the applicant shows that the capsaicin-tacrine hybrid provided by the application has good anticholinesterase activity, anti-BACE-1 activity and neuroprotection, is expected to be used for treating neurodegenerative diseases, particularly Alzheimer's disease, and has good potential medicinal value.

Description

Capsaicin-tacrine hybrid, and preparation method and application thereof
Technical Field
The application relates to capsaicin-tacrine hybrid, and a preparation method and application thereof, and belongs to the technical field of medicines.
Background
Alzheimer's Disease (AD) is a complex multifactorial neurodegenerative disease that worsens over time and whose pathogenesis is unknown, with major pathologies being represented by amyloid beta (Abeta) deposition, neurofibrillary tangles (NFT), amyloid plaque formation and tau abnormal expression. There are many hypotheses about AD, including cholinergic and amyloidogenic hypotheses.
Cholinergic hypothesis it is believed that there is a close relationship between cholinergic loss and decline in cognitive ability in AD patients, and that decreasing acetylcholine (ACh) metabolism is beneficial in improving memory and cognitive dysfunction. Studies have shown that the decrease in acetylcholinesterase activity in the brain is due to hydrolysis of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE or BChE). Of these, AChE is the primary cholinesterase (ChE), mainly from the synaptic junction and the adult cerebral cortex expressing strong activity, whereas BuChE is mainly from glial cells of the brain, regulating local ACh levels. With the progression of AD, the increase in BuChE activity in the hippocampal and temporal cortex can compensate for the decrease in AChE activity, playing a key role in the maintenance and progression of the disease. Thus, AChE and BuChE are both considered drug targets for AD. Currently, clinical treatment of AD is also mainly focused on ACh deficiency.
Another important hypothesis suggests that aβ plaques in the brain play a critical role in the pathogenesis of AD. The aβ peptide produced by hydrolysis of Amyloid Precursor Protein (APP) aggregates into monomers, oligomers and large aβ plaques, triggering pathogenic cascades, ultimately leading to neuronal loss and dementia. Thus, aβ production and clearance are critical in the pathogenesis of AD. BACE-1 is a protease that is widely expressed in various neuronal cell types and produces all monomeric forms of Aβ as desired. Increased concentration and activity of BACE-1 in AD brain and body fluids also supports the hypothesis that BACE-1 plays a key role in AD pathophysiology. In addition to the amyloidogenic pathway, BACE-1 has other substrates that may be important for synaptic plasticity and synaptic homeostasis. Previously, BACE-1 inhibitor compounds have entered the clinical development and testing stage and have been effective in reducing aβ concentrations in humans.
Due to the complexity of AD, it is not suitable to control the progression of AD by inhibiting a single underlying cause, and it is more suitable to consider simultaneous modulation of multiple targets. Thus, the design and synthesis of multi-target ligands (MTDL), which can inhibit multiple targets simultaneously, prevent or slow down disease progression, is viable as an effective strategy for treating AD. MTDL has many advantages over pharmaceutical combinations, in that it can improve therapeutic effects and reduce side effects by low dose synergy, thereby achieving a wider therapeutic window.
Capsaicin is a phenolic component that has been shown to have neuroprotective effects. Tacrine is an acetylcholinesterase inhibitor approved for the treatment of AD, with low molecular weights suitable for modification in MTDL design. By maintaining cholinesterase inhibitory properties and reducing hepatotoxicity, MTDL may be developed as a promising candidate for the treatment of AD.
At present, no report on synthesis of capsaicin or a derivative thereof and tacrine to obtain heterocyclic compounds with multi-target inhibition activity for treating AD is available.
Disclosure of Invention
The application aims to solve the technical problem of providing a series of capsaicin-tacrine hybrids with novel structure and obvious multi-target AChE, buChE and BACE-1 inhibition activity, and a preparation method and application thereof.
In order to solve the technical problems, the application adopts the following technical scheme:
the capsaicin-tacrine hybrid of the application is a compound with a structure shown in the following formula 6, formula 7 or formula 8 or pharmaceutically acceptable salt thereof:
wherein m=6 to 8, n=3 to 8.
In the capsaicin-tacrine hybrid having the structure shown in the above formula 6, preferably, m=6 to 8, and n=3 to 6; in the capsaicin-tacrine hybrid of the structure shown in formula 7, n=3 to 8 is preferable; in the capsaicin-tacrine hybrid of the structure shown in formula 8, n=3 to 8 is preferable.
The capsaicin-tacrine hybrid of the application is further preferably as follows:
the capsaicin-tacrine hybrid related in the application can be pharmaceutically acceptable salts, in particular hydrochloride, hydrobromide, phosphate, sulfate, fumarate, salicylate, benzenesulfonate, pyruvate, acetate, mandelate, basic metal cation salt or ammonium cation salt of the structural compound shown in the above formula 6, formula 7 or formula 8. Preferably an alkaline metal cation salt thereof.
The preparation method of the capsaicin-tacrine hybrid provided by the application comprises the following steps:
1) Taking a compound with a structure shown in the following formula 1, respectively placing the compound with a capsaicin derivative, dihydrocapsaicin or natural capsaicin with a structure shown in the formula 9 in a first organic solvent, and reacting in the presence of an acid binding agent to obtain a compound with a structure shown in the formula 3, formula 4 or formula 5;
2) Placing a compound with a structure shown in the following formula 2 and a compound with a structure shown in the formula 3, the formula 4 or the formula 5 in a second organic solvent respectively, and adding an alkaline reagent to react to obtain a compound with a structure shown in the formula 6, the formula 7 or the formula 8;
in step 1) of the above preparation method, the molar ratio of the compound of the structure represented by formula 1 to the capsaicin derivative, dihydrocapsaicin or natural capsaicin of the structure represented by formula 9 is a stoichiometric ratio. Wherein the structures of the dihydrocapsaicin and the natural capsaicin are respectively shown as follows:
in the step 1) of the preparation method, the selection and the dosage of the acid binding agent are all conventional choices in the prior art. In the present application, the acid-binding agent is preferably one or a combination of two or more selected from triethylamine, N-Diisopropylethylamine (DIEA), pyridine, sodium acetate, sodium carbonate, potassium carbonate, and the like. The amount of the acid-binding agent is preferably 1 to 2 times the molar amount of the capsaicin derivative, dihydrocapsaicin or natural capsaicin having the structure represented by formula 9.
In step 1) of the above preparation method, the reaction may be performed with or without heating, and the completion of the reaction may be detected by thin layer chromatography tracking. The reaction is more advantageously carried out under heating, more preferably at a temperature of greater than or equal to 50 ℃, even more preferably at a temperature between 65 ℃ and the boiling point of the solvent.
In step 2) of the above preparation method, the molar ratio of the compound of the structure represented by formula 2 to the compound of the structure represented by formula 3, formula 4 or formula 5 is a stoichiometric ratio. The alkaline agent involved in this step is a conventional choice in the art, more preferably sodium hydride or potassium hydride, or a combination thereof. The amount of the alkaline agent is preferably 1 to 2 times the molar amount of the compound having the structure represented by formula 3, formula 4 or formula 5. In this step, the reaction may be performed with or without heating, and the completion of the reaction may be detected by thin layer chromatography tracking. When sodium hydride or potassium hydride is the alkaline reagent of choice, the reaction is preferably carried out at ambient temperature or under ice bath conditions.
In the preparation method according to the present application, the first organic solvent and the second organic solvent are referred to as organic solvents, and the "first" and the "second" are merely used for distinguishing between the different organic solvents used in step 1) and step 2). Specifically, in step 1), the first organic solvent is preferably one or a combination of two or more selected from 1, 2-Dichloroethane (DCE), toluene and acetonitrile; acetonitrile is further preferred. In step 2), the second organic solvent is preferably N, N-Dimethylformamide (DMF) or Dimethylsulfoxide (DMSO), or a combination thereof; n, N-dimethylformamide is more preferable. The amount of the first organic solvent or the second organic solvent to be used is determined as needed, and it is preferable that the raw materials to be reacted in the corresponding step be sufficiently dissolved.
The above method is used for preparing the crude product of the target compound with the structure shown in the formula 6, the formula 7 or the formula 8, and therefore, the method also comprises the step of purifying the prepared crude product of the target compound. Specifically, it can be purified by conventional purification methods to increase the purity of each target compound, such as purification of the crude product by silica gel column chromatography. More preferably, the materials obtained by the reaction are extracted and then subjected to silica gel column chromatography, so that the burden of the silica gel column is reduced. The eluent used for elution in the column chromatography is preferably a mixed solvent of dichloromethane and methanol. In the mixed solvent, the volume ratio of dichloromethane to methanol is preferably 20:1 to 10:1. if extraction is involved, the extractant is typically a conventional extractant such as Dichloromethane (DCM) or Ethyl Acetate (EA).
In order to increase the yield of the target compound, it is preferable to purify the intermediate product obtained in step 1) before proceeding to the next step. The purification is usually carried out by silica gel column chromatography, more preferably by subjecting the reaction product to silica gel column chromatography after extraction. Wherein, in the column chromatography, the eluent used for elution is preferably petroleum ether and ethyl acetate according to the weight ratio of 1:1 by volume ratio. If extraction is involved, the extractant is typically a conventional extractant such as methylene chloride or ethyl acetate.
The applicant finds through experiments that the capsaicin-tacrine hybrid has good anticholinesterase activity, anti-BACE-1 activity and neuroprotection, and based on the capsaicin-tacrine hybrid or pharmaceutically acceptable salt thereof, the application also comprises application of the capsaicin-tacrine hybrid in preparing medicines for treating or preventing Alzheimer disease; furthermore, the application also comprises application of the capsaicin-tacrine hybrid or pharmaceutically acceptable salt thereof in preparing cholinesterase inhibitor, BACE-1 inhibitor or neuroprotectant.
Still further, the present application also includes a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of the capsaicin-tacrine hybrid of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
Compared with the prior art, the application provides a series of capsaicin-tacrine hybrids with novel structures and preparation methods thereof. The test result of the applicant shows that the capsaicin-tacrine hybrid provided by the application has good anticholinesterase activity, anti-BACE-1 activity and neuroprotection, is expected to be used for treating neurodegenerative diseases, particularly Alzheimer's disease, and has good potential medicinal value.
Drawings
FIG. 1 is a graph of the linear correlation between experimental and reported permeabilities of commercial drugs measured using the PAMPA-BBB.
FIG. 2 is a bar graph showing the results of measuring the viability of PC12 cells (A) and BV2 cells (B) using the CCK-8 method with different concentrations of Compound 7e or donepezil, wherein (A) is PC12 cells and (B) is BV2 cells.
Figure 3 is a body weight curve of mice given different doses of compound 7e orally over 14 days.
FIG. 4 is an image of HE staining of heart, liver, lung, kidney and brain of mice exposed to 0 and 2500mg/kg dose of Compound 7 e. Scale bar: 200 μm.
Fig. 5 shows the latency and the number of errors in hypotension test in the hypotension passive avoidance experiment of compound 7e, wherein (a) is latency and (B) is number of errors.
Detailed Description
In order to better explain the technical scheme of the present application, the present application will be described in further detail with reference to examples, but the embodiments of the present application are not limited thereto.
Example 1
Step 1: preparation of Compounds 3a,3b,3c,3d,3e,3f,3g,3h
3a：m＝6，n＝3
3b：m＝6，n＝4
3c：m＝6，n＝5
3d：m＝6，n＝6
3e：m＝7，n＝3
3f：m＝7，n＝4
3g：m＝8，n＝4
3h：m＝8，n＝6
Dissolving capsaicin derivative (0.5 mmol,1.0 equivalent) of formula 9 in CH 3 CN (3 mL) was added thereto a compound having the structure shown in formula 1 (0.5 mmol,1.0 equivalent), followed by K 2 CO 3 (0.65 mmol,1.3 eq.) is warmed to 70℃and reacted at reflux for 6 hours. After completion of the reaction, the mixture was extracted with DCM (3X 30 mL), and the combined organic phases were washed with saturated brine and then with anhydrous Na 2 SO 4 Dried, filtered and concentrated, and the resulting residue was purified by thin layer chromatography (developer: PE/EA,1/1, volume ratio) to give the corresponding compounds 3a,3b,3c,3d,3e,3f,3g,3h, respectively.
Step 2: preparation of Compounds 6a,6b,6c,6d,6e,6f,6g,6h
6a：m＝6，n＝3
6b：m＝6，n＝4
6c：m＝6，n＝5
6d：m＝6，n＝6
6e：m＝7，n＝3
6f：m＝7，n＝4
6g：m＝8，n＝4
6h：m＝8，n＝6
Compounds 3a,3b,3c,3d,3e,3f,3g or 3H (0.45 mmol,1.0 eq.) were taken and dissolved in DMF (5 mL), to which was added a compound of the structure shown in formula 2, followed by sodium hydride (0.9 mmol,2.0 eq.) and the reaction was stirred at room temperature for 3 hours, extracted with EA (3X 30 mL) and then H was added 2 O (3X 30 mL) was washed, and the combined organic phases were washed with saturated brine and with anhydrous Na 2 SO 4 Dried, filtered and concentrated, and the resulting residue was purified by thin layer chromatography (eluent: DCM/MeOH,15/1, vol) to give the corresponding target compound 6a,6b,6c,6d,6e,6f,6g,6h. The specific characteristics are as follows:
the compound N- (3-methoxy-4- (3- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) propoxy) benzyl) heptanamide (6 a): the yield thereof was found to be 37%; yellow solid; 1 H NMR(600MHz,CDCl 3 )δ8.46(d,J＝8.5Hz,1H),8.18(d,J＝8.6Hz,1H),7.67(t,J＝7.7Hz,1H),7.45–7.40(t,1H),6.76(s,1H),6.72(d,J＝8.2Hz,1H),6.66(d,J＝8.1Hz,1H),4.37(d,J＝6.0Hz,2H),4.19(m,J＝5.5Hz,2H),4.16(t,J＝5.4Hz,2H),3.66(s,3H),3.23–3.19(t,2H),2.63(t,J＝6.1Hz,2H),2.30(m,J＝9.4,6.0Hz,4H),1.83(m,J＝12.8,7.0Hz,4H),1.67(m,J＝7.6Hz,2H),1.30–1.27(m,6H),0.87(m,J＝2.3Hz,3H). 13 C NMR(150MHz,CDCl 3 )δ173.66,156.25,149.27,146.72,133.15,132.10,125.04,124.41,121.36,119.79,116.46,113.40,111.96,111.27,68.24,55.65,47.75,43.04,36.85,32.04,31.74,30.37,29.82,29.16,28.67,25.99,23.95,22.66,22.15,20.93,14.19.HRMS:calcd for C 31 H 41 N 3 O 3 [M+H] + 504.3221,found504.3280.
the compound N- (3-methoxy-4- (4- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) butoxy) benzyl) heptanamide (6 b): yield 29%; yellow solid; 1 H NMR(600MHz,CDCl 3 )δ8.38(m,J＝15.7,8.7Hz,1H),8.25(m,J＝8.7,4.5Hz,1H),7.63(m,J＝7.6,7.2Hz,1H),7.37(t,J＝7.9Hz,1H),6.82(s,1H),6.77(s,1H),6.69(d,J＝7.7Hz,1H),6.62(t,J＝8.2Hz,1H),4.34(t,J＝5.1Hz,2H),4.06(t,J＝6.7Hz,2H),4.01(m,J＝6.4,5.8Hz,2H),3.67(s,3H),3.16(m,J＝11.6,5.7Hz,2H),2.61(t,J＝6.0Hz,2H),2.27(t,J＝7.6Hz,2H),2.02(m,J＝6.7Hz,2H),1.91(m,J＝6.2Hz,2H),1.80(m,J＝12.9,7.2,6.6Hz,4H),1.63(m,J＝7.7Hz,2H),1.31–1.25(m,6H),0.85–0.83(m,3H). 13 C NMR(150MHz,CDCl 3 )δ173.55,155.81,151.49,149.21,146.86,138.79,132.34,125.32,124.09,121.04,119.89,116.13,112.68,111.25,111.03,68.77,55.75,47.59,43.14,36.88,31.73,29.82,29.15,28.48,28.14,25.97,25.70,24.01,22.65,22.07,20.74,14.19.HRMS:calcd for C 32 H 43 N 3 O 3 [M+H] + 518.3377,found 514.3438.
the compound N- (3-methoxy-4- ((5- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) pentyl) oxy) benzyl) heptanamide (6 c): yield 36%; yellow solid; 1 H NMR(600MHz,CDCl 3 )δ8.46(t,J＝9.1Hz,1H),8.18(d,J＝8.8,2.9Hz,1H),7.69–7.64(m,1H),7.41(m,1H),6.80(t,J＝2.6Hz,1H),6.73(m,1H),6.62(m,J＝8.2,2.6Hz,1H),6.46(d,J＝18.1Hz,1H),6.00(d,J＝56.2Hz,1H),4.36(m,J＝5.8,3.2Hz,2H),3.98(t,2H),3.93(m,J＝5.7Hz,2H),3.76(s,J＝3.1Hz,3H),3.19(m,J＝6.6Hz,2H),2.57(t,J＝6.2Hz,2H),2.25(m,J＝7.6,1.9Hz,2H),1.93(m,J＝7.4Hz,2H),1.85(m,2H),1.81–1.78(m,2H),1.68–1.64(m,4H),1.30–1.26(m,8H),0.86(m,J＝3.4Hz,3H). 13 C NMR(150MHz,CDCl 3 )δ173.42,155.63,149.54,147.49,132.53,132.17,125.35,124.17,121.37,120.11,115.90,113.15,111.71,110.94,68.79,56.02,48.54,43.25,36.94,32.06,31.73,30.68,29.84,29.15,28.51,28.43,25.97,23.19,22.83,22.66,21.96,20.72,14.19.HRMS:calcd for C 33 H 45 N 3 O 3 [M+H] + 532.3534,found 532.3596.
the compound N- (3-methoxy-4- ((6- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) hexyl) oxy) benzyl) heptanamide (6 d): yield 41%; yellow solid; 1 H NMR(600MHz,CDCl 3 )δ8.36(m,J＝8.3,5.0Hz,1H),8.23(d,J＝8.7Hz,1H),7.63–7.58(m,1H),7.38(m,1H),6.77(d,J＝2.1Hz,1H),6.72(m,J＝8.2,1.9Hz,1H),6.70–6.66(s,1H),6.64(d,J＝8.2Hz,1H),4.32(d,J＝5.9Hz,2H),3.92(t,J＝7.3Hz,2H),3.87(t,J＝6.5Hz,2H),3.71(s,3H),3.13(t,J＝6.3Hz,2H),2.61(t,J＝6.2Hz,2H),2.23(t,J＝7.6Hz,2H),1.88–1.81(m,4H),1.77(m,J＝12.1,6.0Hz,4H),1.60(m,J＝7.6Hz,2H),1.48(m,J＝7.4,6.9Hz,4H),1.31–1.22(m,6H),0.82(t,J＝6.7Hz,3H). 13 C NMR(150MHz,CDCl 3 )δ173.48,155.73,151.19,149.48,147.60,138.91,132.30,131.78,125.14,124.55,120.80,119.97,115.92,113.04,111.59,110.94,68.76,55.95,48.24,43.20,36.84,31.67,30.84,29.09,28.96,28.43,26.23,25.93,25.57,23.95,22.60,21.98,20.72,14.14.HRMS:calcd for C 34 H 47 N 3 O 3 [M+H] + 546.3690,found 546.3744.
n- (3-methoxy)Phenyl-4- (3- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) propoxy) benzyl) octanamide (6 e): the yield thereof was found to be 37%; yellow solid; 1 H NMR(600MHz,CDCl 3 )δ8.44(d,J＝8.5Hz,1H),8.19(m,J＝9.0,4.4Hz,1H),7.66(t,J＝7.6Hz,1H),7.42(t,J＝7.0Hz,1H),6.82(s,1H),6.76(s,1H),6.71(d,J＝7.8Hz,1H),6.65(m,J＝6.2Hz,1H),4.24–4.12(m,4H),3.66(s,3H),3.19(m,J＝6.7Hz,2H),2.64(t,J＝6.1Hz,2H),2.30(t,J＝7.5Hz,4H),1.86–1.78(m,4H),1.67(m,J＝7.5Hz,2H),1.35–1.27(m,8H),0.86(m,J＝1.5Hz,3H). 13 C NMR(150MHz,CDCl 3 )δ173.70,156.59,149.29,146.70,138.89,133.27,132.34,125.15,120.92,119.79,116.23,113.50,111.70,111.32,55.67,43.04,36.86,32.05,31.85,30.38,29.83,29.78,29.46,29.23,28.39,26.06,23.91,22.82,22.75,22.11,20.83,14.22.HRMS:calcd for C 32 H 43 N 3 O 3 [M+H] + 518.3377,found 518.3437.
n- (3-methoxy-4- (4- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) butoxy) benzyl) octanamide (6 f): yield 43%; yellow solid; 1 H NMR(600MHz,CDCl 3 )δ8.45–8.39(m,1H),8.24(d,J＝8.6Hz,1H),7.64(t,J＝8.4,3.7,2.0Hz,1H),7.41–7.35(t,1H),6.78(s,J＝2.0Hz,1H),6.71(d,J＝8.1Hz,2H),6.64(m,J＝7.1,3.8Hz,1H),4.35(d,J＝5.9Hz,2H),4.07(m,J＝5.9,5.2Hz,2H),4.02(m,J＝5.6,4.7Hz,2H),3.67(s,3H),3.19(t,J＝5.7Hz,2H),2.61(t,J＝6.0Hz,2H),2.27(t,J＝7.6Hz,2H),2.05–2.00(m,2H),1.92(m,J＝6.4Hz,2H),1.86–1.77(m,4H),1.64(m,J＝7.4Hz,2H),1.35–1.24(m,8H),0.87–0.82(t,3H). 13 C NMR(150MHz,CDCl 3 )δ173.61,155.84,151.29,149.21,146.86,138.77,132.28,125.26,124.25,120.82,119.86,116.14,112.70,111.25,68.72,60.51,55.75,47.55,43.11,36.84,31.82,29.80,29.42,29.19,28.48,27.94,26.01,25.76,24.09,22.71,22.07,20.74,14.19.HRMS:calcd for C 33 H 45 N 3 O 3 [M+H] + 532.3534,found 532.3588.
n- (3-methoxy-4- (4- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) butoxy) benzyl) nonanamide (6 g): yield 34%; yellow solid; 1 H NMR(600MHz,CDCl 3 )δ8.40(d,J＝8.5Hz,1H),8.24(d,J＝8.7Hz,1H),7.63(t,J＝7.7Hz,1H),7.38(t,J＝8.6,7.0Hz,1H),6.78(s,J＝2.0Hz,1H),6.71(d,J＝6.3Hz,1H),6.64(d,J＝8.1Hz,1H),4.35(d,J＝5.9Hz,2H),4.07(t,J＝6.6Hz,2H),4.02(t,J＝5.6Hz,2H),3.67(s,3H),3.17(t,J＝6.2Hz,2H),2.61(t,J＝6.1Hz,2H),2.27(t,J＝7.6Hz,2H),2.02(m,J＝6.7Hz,2H),1.92(m,J＝6.1Hz,2H),1.84–1.77(m,4H),1.66–1.62(m,2H),1.34–1.24(m,10H),0.85(t,J＝6.9Hz,3H). 13 C NMR(150MHz,CDCl 3 )δ173.61,155.82,151.35,149.21,146.87,138.80,132.27,132.23,125.23,124.21,120.89,119.85,116.16,112.69,111.25,68.71,55.75,47.54,43.11,36.85,32.02,31.93,29.80,29.49 29.29,28.50,27.96,26.02,25.79,24.11,22.75,22.08,20.75,14.21.HRMS:calcd for C 34 H 47 N 3 O 3 [M+H] + 546.3690,found 546.3751.
n- (3-methoxy-4- ((6- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) hexyl) oxy) benzyl) nonanamide (6 h): yield 42%; yellow solid; 1 H NMR(600MHz,Chloroform-d)δ8.37(m,J＝8.5,3.6Hz,1H),8.22(d,J＝8.7,2.6Hz,1H),7.61(m,J＝8.2,4.7Hz,1H),7.39(t,J＝8.4,4.3Hz,1H),6.77(s,J＝2.0Hz,1H),6.73(d,J＝7.9,2.8Hz,1H),6.66(m,J＝8.6,3.5Hz,1H),6.58(s,1H),4.33(t,J＝6.0,3.1Hz,2H),3.90(m,J＝17.1,6.6Hz,4H),3.72(s,J＝2.2Hz,3H),3.13(m,J＝6.2Hz,2H),2.63–2.58(t,2H),2.23(t,J＝7.7Hz,2H),1.84(m,J＝13.4,5.9Hz,4H),1.81–1.74(m,4H),1.64–1.59(m,2H),1.49(s,J＝6.2Hz,4H),1.32–1.22(m,10H),0.84(m,J＝7.1,3.6Hz,3H). 13 C NMR(150MHz,Chloroform-d)δ173.39,155.59,151.53,149.54,147.65,139.09,132.37,131.84,125.22,124.39,121.16,120.03,115.94,113.10,111.64,110.87,68.77,55.98,48.41,43.26,36.91,31.93,30.92,29.81,29.48,29.29,28.96,28.45,26.19,25.99,25.56,23.78,22.76,21.98,20.75,14.22.HRMS:calcd for C 36 H 51 N 3 O 3 [M+H] + 574.4003,found 574.4060.
example 2: preparation of Compounds 6a,6b
Compound 6a: example 1 was repeated except that step 2 was performed as follows:
compound 3a (0.45 mmol,1.0 eq.) was dissolved in DMSO (5 mL), to which was added the compound of formula 2, followed by potassium hydride (0.9 mmol,2.0 eq.) and reacted at room temperature to completion, the reaction mixture was extracted with EA (3X 30 mL) and then H 2 O (3X 30 mL) was washed, and the combined organic phases were washed with saturated brine and with anhydrous Na 2 SO 4 Dried, filtered and concentrated, and the resulting residue was purified by thin layer chromatography (developer: DCM/MeOH,15/1, vol) to give a yellow solid in 30% yield. And the compound is determined to be the compound 6a through nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum characterization.
Compound 6b: example 1 was repeated except that step 2 was performed as follows:
compound 3b (0.45 mmol,1.0 eq.) was dissolved in DMSO (5 mL), to which was added the compound of formula 2, followed by potassium hydride (0.9 mmol,2.0 eq.) and reacted at room temperature to completion, the reaction mixture was extracted with EA (3X 30 mL) and then H 2 O (3X 30 mL) was washed, and the combined organic phases were washed with saturated brine and with anhydrous Na 2 SO 4 Dried, filtered and concentrated, and the resulting residue was purified by thin layer chromatography (developer: DCM/MeOH,15/1, vol) to give a yellow solid in 39% yield. And the compound is determined to be the compound 6b through nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum characterization.
Example 3: preparation of Compounds 7a,7b,7c,7d,7e,7f
Step 1: the dihydrocapsaicin (0.5 mmol,1.0 eq.) was dissolved in CH 3 CN (3 mL) was added thereto a compound having the structure shown in formula 1 (0.5 mmol,1.0 equivalent), and K is added 2 CO 3 (0.65 mmol,1.3 eq.) is heated to 70℃and reacted at reflux for 6 hours. After completion of the reaction, the mixture was extracted with DCM (3X 30 mL), and the combined organic phases were washed with saturated brine and then with anhydrous Na 2 SO 4 Drying, filtration and concentration, the residue obtained is purified by thin layer chromatography (developer: PE/EA,1/1, volume ratio) to give the corresponding compounds 4a,4b,4c,4d,4e,4f, respectively.
Step 2: the compound 4a,4b,4c,4d,4e or 4f (0.45 mmol,1.0 eq.) was dissolved in DMF (5 mL), to which was added the compound of the structure shown in formula 2, followed by sodium hydride (0.9 mmol,2.0 eq.) and stirred at room temperature for 3 hours, the reaction mixture was extracted with EA (3X 30 mL) and then H was added 2 O (3X 30 mL) was washed, and the combined organic phases were washed with saturated brine and with anhydrous Na 2 SO 4 Dried, filtered and concentrated, and the resulting residue was purified by thin layer chromatography (eluent: DCM/MeOH,15/1, vol) to give the corresponding target compound 7a,7b,7c,7d,7e,7f. The specific characteristics are as follows:
n- (3-methoxy-4- (3- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) propoxy) benzyl) -8-methylnonanamide (7 a): yield 35%; yellow solid; 1 H NMR(600MHz,Chloroform-d)δ8.48(d,J＝8.5Hz,1H),8.16(d,J＝8.6Hz,1H),7.69(t,J＝7.9Hz,1H),7.43(t,J＝8.4Hz,1H),6.77(d,J＝1.9Hz,1H),6.74(d,J＝10.0Hz,1H),6.68(d,J＝8.1Hz,1H),6.62(t,J＝6.1Hz,1H),6.50(s,1H),4.38(d,J＝6.0Hz,2H),4.18(m,J＝10.7,5.5Hz,4H),3.67(s,3H),3.23(t,J＝6.1Hz,2H),2.62(t,J＝6.0Hz,2H),2.49(m,J＝15.6,7.5Hz,1H),2.29(m,J＝9.7,5.4Hz,4H),1.86–1.82(m,4H),1.68(m,J＝7.5Hz,2H),1.51–1.47(m,2H),1.34(m,J＝8.1Hz,2H),1.14(m,J＝7.0Hz,4H),0.85(d,J＝6.6Hz,6H). 13 C NMR(150MHz,Chloroform-d)δ173.63,156.50,151.70,149.32,146.71,138.99,133.30,132.39,125.17,124.36,121.15,119.83,116.24,113.57,111.69,111.34,68.45,55.68,47.98,43.08,39.11,36.89,32.06,30.40,29.84,29.57,28.41,28.09,27.41,26.06,22.78,22.12,20.84,14.27.HRMS:calcd for C 34 H 47 N 3 O 3 [M+H] + 546.3690,found 546.3748.
n- (3-methoxy-4- (4- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) butoxy) benzyl) -8-methylnonanamide (7 b): yield 42%; yellow solid; 1 H NMR(600MHz,Chloroform-d))δ8.48(d,J＝8.6Hz,1H),8.19(d,J＝8.7Hz,1H),7.68(t,J＝7.7Hz,1H),7.41(t,J＝7.8Hz,1H),6.78(s,1H),6.75(d,J＝8.2Hz,1H),6.69(d,J＝8.1Hz,1H),6.41(s,1H),4.38(d,J＝5.9Hz,2H),4.06(t,J＝5.6Hz,4H),3.69(s,3H),3.25(t,J＝6.0Hz,2H),2.59(t,J＝5.9Hz,2H),2.27(t,J＝7.6Hz,2H),2.01(m,J＝6.6Hz,2H),1.96–1.93(m,2H),1.85(m,J＝6.3,5.4Hz,6H),1.68–1.65(m,2H),1.51–1.48(m,1H),1.36–1.31(m,4H),1.14(t,J＝7.2Hz,2H),0.84(d,J＝6.7Hz,6H). 13 C NMR(150MHz,Chloroform-d)δ173.56,155.82,151.45,149.21,146.86,138.80,132.30,125.30,124.13,121.01,119.87,116.14,112.66,111.24,111.04,68.75,55.75,47.58,43.12,39.08,36.88,32.04,29.82,29.54,28.49,28.06,27.38,26.03,25.71,24.04,22.76,22.07,20.74,14.25.HRMS:calcd for C 35 H 49 N 3 O 3 [M+H] + 560.3847,found 560.3903.
n- (3-methoxy-4- ((5- ((1,22,3,4-tetrahydroacridin-9-yl) amino) pentyl) oxy) benzyl) -8-methylnonanamide (7 c): the yield thereof was found to be 39%; yellow solid; 1 H NMR(600MHz,Chloroform-d)δ8.41(d,J＝8.5Hz,1H),8.16(d,J＝8.8,1.1Hz,1H),7.65(m,J＝8.3,6.9,1.2Hz,1H),7.40(m,J＝8.4,6.9,1.2Hz,1H),6.80(d,J＝2.0Hz,1H),6.74(m,J＝8.2,2.0Hz,1H),6.64(d,J＝8.2Hz,1H),6.40(t,J＝4.8Hz,1H),4.36(d,J＝5.8Hz,2H),3.94(t,J＝6.4Hz,4H),3.77(s,3H),3.18(t,J＝6.2Hz,2H),2.58(t,J＝6.3Hz,2H),2.25(t,J＝7.6Hz,2H),1.93–1.89(m,2H),1.88–1.83(m,4H),1.82–1.78(m,2H),1.67–1.63(m,4H),1.50–1.46(m,1H),1.31(m,J＝7.4Hz,2H),1.28–1.25(m,4H),1.13(m,J＝10.3,4.6Hz,2H),0.84(d,J＝6.6Hz,6H). 13 C NMR(150MHz,Chloroform-d)δ173.40,149.53,147.51,132.31,132.11,125.25,124.11,121.72,120.11,116.14,113.12,111.69,111.19,68.78,56.02,48.57,43.27,39.09,36.95,32.06,30.74,29.84,29.81,29.54,28.67,28.54,28.08,27.40,26.01,23.69,23.22,22.77,22.01,20.84,14.26.HRMS:calcd for C 36 H 51 N3O 3 [M+H] + 574.4003,found 574.4063.
n- (3-methoxy-4- ((6- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) hexyl) oxy) benzyl) -8-methylnonanamide (7 d): yield 34%; yellow solid; 1 H NMR(600MHz,DMSO-d 6 )δ8.31(d,J＝8.7Hz,1H),8.20(t,J＝6.0Hz,1H),7.81–7.75(m,2H),7.50(m,J＝6.6Hz,1H),6.79(m,J＝5.2,3.1Hz,2H),6.67(d,J＝8.2,2.0Hz,1H),4.12(d,J＝5.9Hz,2H),3.83(m,J＝6.5Hz,2H),3.75(m,J＝7.0Hz,2H),3.65(s,3H),2.93(m,J＝5.6Hz,2H),2.62(m,J＝5.8Hz,2H),2.06(t,J＝7.4Hz,2H),1.78(m,J＝3.3Hz,4H),1.68(m,J＝7.2Hz,2H),1.63(m,J＝6.9Hz,2H),1.44(m,J＝13.2,6.4Hz,7H),1.35(m,J＝13.7,6.9Hz,6H),1.07(t,J＝6.9Hz,2H),0.79(d,J＝6.7Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ173.39,155.37,151.85,149.53,147.66,139.46,132.20,131.78,125.15,124.32,121.49,120.04,116.13,113.07,111.63,111.09,68.76,55.98,48.46,43.28,39.07,36.92,30.97,29.79,29.51,28.96,28.69,28.05,27.37,26.22,26.00,25.57,23.82,22.75,22.03,20.84,14.24.HRMS:calcd for C 37 H 53 N 3 O 3 [M+H] + 588.4160,foun588.4202.
n- (3-methoxy-4- ((7- ((1, 2,3, 4-tetrahydro)Acridin-9-yl) amino) heptyl) oxy) benzyl) -8-methylnonanamide (7 e): yield 45%; yellow solid; 1 H NMR(600MHz,Chloroform-d)δ8.04–7.97(m,2H),7.57(t,J＝8.3,6.8,1.3Hz,1H),7.35(t,J＝8.3,6.7,1.3Hz,1H),6.83–6.75(d,3H),5.84(s,1H),4.36(d,J＝5.7Hz,2H),3.97(t,J＝6.7Hz,2H),3.82(s,3H),3.58(t,J＝7.2Hz,2H),3.12–3.07(t,2H),2.67(t,J＝5.5Hz,2H),2.20(t,J＝7.6Hz,2H),1.91(m,J＝4.9Hz,4H),1.82(m,J＝7.4Hz,2H),1.72–1.68(m,2H),1.66–1.62(m,2H),1.49(m,J＝13.6,6.8Hz,3H),1.45–1.40(m,4H),1.33–1.29(m,4H),1.13(m,J＝8.8,5.6Hz,2H),0.85(d,J＝6.6Hz,6H). 13 C NMR(150MHz,Chloroform-d)δ173.33,155.48,151.66,149.57,147.78,139.21,132.38,131.63,125.23,124.34,121.30,120.09,115.95,113.08,111.65,110.88,69.06,56.04,48.58,43.34,39.07,36.94,31.03,29.78,29.50,28.98,28.80,28.52,28.05,27.37,26.51,25.98,23.75,22.75,22.00,20.78,14.25.HRMS:calcd for C 38 H 55 N 3 O 3 [M+H] + 602.4316,found 602.4368.
n- (3-methoxy-4- ((8- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) octyl) oxy) benzyl) -8-methylnonanamide (7 f): yield 38%; yellow solid; 1 H NMR(600MHz,Chloroform-d)δ8.51(t,J＝9.4Hz,1H),8.20–8.16(d,1H),7.67(t,J＝7.9Hz,1H),7.43(t,J＝8.4,6.9,1.2Hz,1H),6.81–6.74(m,3H),4.36(d,J＝5.8Hz,2H),3.95(t,J＝6.7Hz,2H),3.91(t,J＝7.2Hz,2H),3.81(s,3H),3.27(t,J＝6.3Hz,2H),2.59(t,J＝6.3Hz,2H),2.21(t,J＝7.6Hz,2H),1.91(m,J＝6.2,2.5Hz,2H),1.82(m,J＝14.7,7.5Hz,6H),1.64(m,J＝8.6,6.6Hz,2H),1.49(m,J＝13.4,6.7Hz,2H),1.47–1.43(m,4H),1.40–1.36(m,5H),1.33–1.29(m,4H),1.13(m,J＝7.2Hz,2H),0.84(d,J＝6.6Hz,6H). 13 C NMR(150MHz,Chloroform-d)δ173.29,155.44,151.66,149.56,147.84,139.29,132.28,131.46,125.16,124.36,121.30,120.09,116.01,113.02,111.65,110.95,69.07,56.05,48.64,43.36,39.05,36.93,31.16,29.76,29.48,29.19,29.14,29.08,28.62,28.04,27.35,26.64,25.96,23.83,22.74,22.04,20.82,14.23.HRMS:calcd for C 39 H 57 N 3 O 3 [M+H] + 616.4473,found 616.4531.
example 4: preparation of Compound 7a
Step 1: dihydrocapsaicin (0.5 mmol,1.0 eq.) was dissolved in toluene (3 mL), to which was added the compound of the structure shown in formula 1 (0.5 mmol,1.0 eq.) followed by potassium hydride (0.65 mmol,1.3 eq.) at room temperature until the reaction was complete. After completion of the reaction, the mixture was extracted with DCM (3X 30 mL), and the combined organic phases were washed with saturated brine and then with anhydrous Na 2 SO 4 Dried, filtered and concentrated, and the resulting residue was purified by thin layer chromatography (developer: PE/EtOAc,1/1, volume ratio) to give compound 4a.
Step 2: compound 4a (0.45 mmol,1.0 eq.) was dissolved in DMF (5 mL), to which was added the compound of formula 2, followed by potassium hydride (0.9 mmol,2.0 eq.) and reacted at room temperature until reaction was complete, the reaction mixture was extracted with EA (3X 30 mL) and then H was added 2 O (3X 30 mL) was washed, and the combined organic phases were washed with saturated brine and with anhydrous Na 2 SO 4 Dried, filtered and concentrated, and the resulting residue was purified by thin layer chromatography (developer: DCM/MeOH,15/1, vol) to give a yellow solid in 27% yield. The target compound 7a is determined by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum characterization.
Example 5: preparation of Compounds 8a,8b,8c,8d,8e,8f
Step 1: dissolving natural capsaicin (0.5 mmol,1.0 equivalent) in CH 3 CN (3 mL) was added thereto a compound having the structure shown in formula 1 (0.5 mmol,1.0 equivalent), followed by K 2 CO 3 (0.65 mmol,1.3 eq.) and heated to 70℃for 6 hours under reflux. After completion of the reaction, the mixture was extracted with DCM (3X 30 mL), and the combined organic phases were washed with saturated brine and then with anhydrous Na 2 SO 4 Dried, filtered and concentrated, and the resulting residue was purified by thin layer chromatography (developer: PE/EA,1/1, vol) to give the corresponding compounds 5a,5b,5c,5d,5e,5f, respectively.
Step (a)2: the compound 5a,5b,5c,5d,5e or 5f (0.45 mmol,1.0 eq.) was dissolved in DMF (5 mL), to which was added the compound of the structure shown in formula 2, followed by sodium hydride (0.9 mmol,2.0 eq.) and stirred at room temperature for 3 hours, the reaction mixture was extracted with EA (3X 30 mL) and then H was added 2 O (3X 30 mL) was washed, and the combined organic phases were washed with saturated brine and with anhydrous Na 2 SO 4 Dried, filtered and concentrated, and the resulting residue was purified by thin layer chromatography (eluent: DCM/MeOH,15/1, vol) to give the corresponding target compounds 8a,8b,8c,8d,8e,8f. The specific characteristics are as follows:
(E) -N- (3-methoxy-4- (3- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) propoxy) benzyl) -8-methylnon-6-enamide (8 a): the yield was 32%; yellow solid; 1 H NMR(600MHz,CDCl 3 )δ8.37(d,J＝8.5Hz,1H),8.13(d,J＝8.7Hz,1H),7.68(t,J＝7.7Hz,1H),7.42(t,J＝7.9Hz,1H),6.78(s,J＝1.9Hz,1H),6.75(d,J＝8.2,2.0Hz,1H),6.71(d,J＝8.1Hz,1H),5.38–5.31(m,2H),4.38(d,J＝5.9Hz,2H),4.18(t,J＝5.4Hz,2H),4.14(t,J＝5.7Hz,2H),3.68(s,3H),3.41(t,J＝6.79Hz,1H),3.20(t,J＝6.3Hz,2H),2.63(t,J＝5.8Hz,2H),2.34(m,J＝7.4Hz,2H),2.29–2.25(m,3H),2.20(m,J＝6.6Hz,2H),2.00(m,J＝7.2Hz,2H),1.87(m,J＝14.57,7.19Hz,4H),1.67(m,J＝2.6Hz,2H),0.95(d,J＝6.7Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ173.46,149.40,146.78,138.17,133.28,132.34,129.89,126.70,125.16,124.29,119.90,116.38,113.69,111.88,111.38,68.63,55.70,48.11,43.14,36.74,32.45,32.06,31.11,30.41,29.84,29.48,28.54,25.51,23.81,22.80,22.13,20.91,14.26.HRMS:calcd for C 34 H 45 N 3 O 3 [M+H] + 544.3534,found544.3594.
(E) -N- (3-methoxy-4- (4- (((1, 2))3, 4-tetrahydroacridin-9-yl) amino) butoxy) benzyl) -8-methylnon-6-enamide (8 b): the yield was 40%; yellow solid; 1 H NMR(600MHz,DMSO-d 6 )δ8.27(t,J＝6.0Hz,1H),7.87(d,J＝8.4Hz,1H),7.81(t,J＝7.7Hz,1H),7.48(t,J＝7.8Hz,1H),6.86–6.79(m,2H),6.70(d,J＝8.2,2.0Hz,1H),5.33(m,J＝15.5,7.5Hz,2H),4.16(d,J＝5.9Hz,2H),3.93(t,J＝6.1Hz,2H),3.88(m,J＝6.9Hz,2H),3.64(s,3H),2.97(t,J＝5.4Hz,2H),2.64(t,J＝5.4Hz,2H),2.19(m,J＝12.8,6.5Hz,1H),2.11(t,J＝7.3Hz,2H),1.93(m,J＝7.0Hz,2H),1.86(m,J＝7.2Hz,2H),1.80(s,J＝3.7Hz,4H),1.76(m,J＝13.8,7.0Hz,2H),1.50(m,J＝7.6Hz,2H),1.31–1.27(m,2H),0.90(d,6H). 13 C NMR(150MHz,DMSO-d 6 )δ172.02,148.81,146.72,137.36,132.43,126.62,124.84,119.15,112.93,111.26,79.23,79.01,78.78,70.02,67.86,55.34,47.03,42.04,40.06,35.24,31.70,31.31,30.39,29.04,28.70,26.75,25.94,24.93,24.05,22.55,22.12,21.59,20.55,13.93.HRMS:calcd for C 35 H 47 N 3 O 3 [M+H] + 558.3690,found 558.3749.
(E) -N- (3-methoxy-4- ((5- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) pentyl) oxy) benzyl) -8-methylnon-6-enamide (8 c): yield 31%; yellow solid; 1 H NMR(600MHz,DMSO-d 6 )δ8.22(t,J＝6.0Hz,1H),7.82(d,J＝8.8Hz,1H),7.78(t,J＝7.6Hz,1H),7.50(t,J＝7.7Hz,1H),6.80–6.75(m,2H),6.66(d,J＝8.3,2.0Hz,1H),5.29(m,J＝20.4,13.9,6.2Hz,2H),4.12(d,J＝5.9Hz,2H),3.84(t,J＝6.3Hz,2H),3.80(m,J＝6.9Hz,2H),3.64(s,3H),2.93(t,J＝5.6Hz,2H),2.62(t,J＝5.7Hz,2H),2.17–2.13(m,1H),2.07(t,J＝7.3Hz,2H),1.88(m,J＝7.0Hz,2H),1.78(m,J＝3.6,3.1Hz,4H),1.72(m,J＝7.5Hz,2H),1.66(m,J＝6.7Hz,2H),1.45(m,J＝12.4,6.6Hz,4H),1.24(m,J＝7.5Hz,2H),0.87(d,J＝6.7Hz,6H). 13 C NMR(150MHz,DMSO-d 6 )δ209.72,186.55,184.58,175.04,170.06,164.29,162.58,156.88,150.71,149.06,121.76,116.88,116.66,116.43,107.47,105.78,93.08,84.96,79.35,72.91,69.36,68.06,67.24,66.70,66.35,66.02,62.60,61.65,60.43,60.21,59.78,59.21,58.15,51.64,41.29.HRMS:calcd for C 36 H 49 N 3 O 3 [M+H] + 572.3847,found 572.3905.
(E) -N- (3-methoxy-4- ((6- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) hexyl) oxy) benzyl) -8-methylnon-6-enamide (8 d): yield 38%; yellow solid; 1 H NMR(600MHz,CDCl 3 )δ8.52(d,J＝8.5Hz,1H),8.18(d,J＝8.7Hz,1H),7.68(t,J＝7.7Hz,1H),7.43(t,J＝7.7Hz,1H),6.79(d,J＝1.9Hz,1H),6.76(m,J＝8.3,2.0Hz,1H),6.69(d,J＝8.2Hz,1H),6.33(d,J＝5.7Hz,1H),5.73(s,1H),5.34(m,J＝15.4,7.5Hz,2H),4.37(d,J＝5.8Hz,2H),3.95(m,J＝17.2,6.4Hz,4H),3.73(s,3H),3.22(t,J＝6.4Hz,2H),2.55(t,J＝6.4Hz,2H),2.25(t,J＝7.6Hz,2H),2.22–2.18(m,1H),1.98(m,J＝7.0Hz,2H),1.88(m,J＝6.3Hz,4H),1.82(m,J＝8.8,5.7,5.3Hz,4H),1.67–1.64(m,2H),1.55(m,J＝7.3,3.7Hz,4H),1.40–1.36(m,2H),0.94(d,J＝6.7Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ173.27,155.59,149.57,147.67,139.05,138.12,132.49,131.86,126.69,125.29,124.34,121.23,120.05,115.88,113.13,111.65,110.78,68.76,55.99,48.48,43.29,36.77,32.42,31.09,30.95,29.83,29.45,28.94,28.41,26.14,25.49,23.68,22.79,21.96,20.73,14.26.HRMS:calcd for C 37 H 51 N 3 O 3 [M+H] + 586.4003,found 586.4065.
(E) -N- (3-methoxy-4- ((7- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) heptyl) oxy) benzyl) -8-methylnon-6-enamide (8 e): yield 43%; yellow solid; 1 H NMR(600MHz,Chloroform-d)δ8.57–8.53(t,1H),8.18(d,J＝8.7Hz,1H),7.69(t,J＝8.0,6.6,3.8,1.9Hz,1H),7.44(t,J＝8.6,6.9,1.6Hz,1H),6.79(s,J＝1.9Hz,1H),6.76(d,J＝8.2,1.9Hz,1H),6.72(d,J＝8.1Hz,1H),6.15(s,1H),5.69(s,1H),5.33(m,J＝21.8,14.6,6.2Hz,2H),4.36(d,J＝5.7Hz,2H),3.94(t,J＝6.8,5.5Hz,4H),3.79(s,3H),3.28–3.23(t,2H),2.57(t,J＝5.7Hz,2H),2.24(t,J＝7.6Hz,2H),1.98(m,J＝7.0Hz,2H),1.91(m,J＝6.4,3.5Hz,2H),1.87–1.79(m,6H),1.67–1.64(m,2H),1.49(m,J＝7.3Hz,4H),1.46–1.42(m,2H),1.42–1.35(m,3H),0.94(d,J＝6.7Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ173.16,155.49,149.62,147.81,138.15,132.53,131.70,126.67,125.33,124.25,121.41,120.10,115.87,113.14,111.67,110.74,69.10,56.06,48.66,43.36,36.80,32.40,31.10,31.05,29.83,29.44,28.96,28.74,28.44,26.46,25.98,25.47,23.61,22.79,21.98,20.75,14.26.HRMS:calcd for C 38 H 53 N 3 O 3 [M+H] + 600.4160,found 600.4222.
(E) -N- (3-methoxy-4- ((8- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) octyl) oxy) benzyl) -8-methylnon-6-enamide (8 f): yield 38%; yellow solid; 1 H NMR(600MHz,DMSO-d 6 )δ8.34(d,J＝8.7Hz,1H),8.22(t,J＝6.0Hz,1H),7.81(m,J＝2.0Hz,2H),7.53(t,J＝8.6,6.2,2.2Hz,1H),6.83–6.78(m,2H),6.69(d,J＝8.3,2.0Hz,1H),5.30(m,J＝15.5,7.5Hz,2H),4.14(d,J＝5.9Hz,2H),3.84(t,J＝6.6Hz,2H),3.79(m,J＝7.0Hz,2H),3.67(s,3H),2.95(s,2H),2.62(s,2H),2.16(m,J＝13.9,6.8Hz,1H),2.08(t,J＝7.4Hz,2H),1.90(m,J＝7.0Hz,2H),1.80(s,J＝4.0Hz,4H),1.68(m,J＝7.5Hz,2H),1.62(m,J＝6.7Hz,2H),1.47(m,J＝7.7Hz,2H),1.32(m,J＝17.0,6.8Hz,4H),1.26(m,J＝7.7Hz,6H),0.89(d,J＝6.8Hz,6H). 13 C NMR(150MHz,DMSO-d 6 )δ172.04,148.90,148.56,146.99,137.39,132.34,126.66,124.96,119.26,113.01,111.39,79.25,79.03,78.81,68.29,55.43,47.36,41.71,40.06,35.26,31.74,31.35,30.44,29.87,29.08,28.78,28.71,28.66,28.59,26.05,25.48,24.97,22.59,22.16,21.56,20.52,16.95,14.02.HRMS:calcd for C 39 H 55 N 3 O 3 [M+H] + 614.4316,found 614.4364.
example 6: preparation of Compound 8a
Step 1: natural capsaicin (0.5 mmol,1.0 eq.) was dissolved in 1, 2-dichloroethane (5 mL), to which was added the compound of formula 1 (0.5 mmol,1.0 eq.) followed by sodium hydride (0.65 mmol,1.3 eq.) and reacted at ambient temperature to completion. After completion of the reaction, the mixture was extracted with DCM (3X 30 mL), and the combined organic phases were washed with saturated brine and then with anhydrous Na 2 SO 4 Drying, filtration and concentration, the resulting residue was purified by thin layer chromatography (developer: PE/EA,1/1, volume ratio) to give compound 5a.
Step 2: compound 5a (0.45 mmol,1.0 eq.) was dissolved in DMSO (5 mL), to which was added the compound of the structure shown in formula 2, followed by sodium hydride (0.9 mmol,2.0 eq.) and stirred at room temperature for 3 hours, the reaction mixture was extracted with EA (3X 30 mL) and then H was added 2 O (3X 30 mL) was washed, and the combined organic phases were washed with saturated brine and with anhydrous Na 2 SO 4 Dried, filtered and concentrated, and the resulting residue was purified by thin layer chromatography (developer: DCM/MeOH,15/1, vol) to give a yellow solid in 42% yield. The target compound 8a is determined by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum characterization.
Experimental example 1: the capsaicin-tacrine hybrid 6a,6b,6c,6d,6e,6f,6g,6h,7a,7b,7c,7d,7e,7f,8a,8b,8c,8d,8e,8f has anticholinesterase activity
1. Experimental part
The inhibitory activity of the designed compounds 6 a-h, 7 a-f and 8 a-f on ChEs was determined according to the method of Ellman. Electroeel (eeAChE) and human erythrocytes (hAChE). The target compound was dissolved in dimethyl sulfoxide and then buffered with Tris-HCl (50 mm, ph= 8.0,0.1M NaCl,0.02M MgCl) 2 ·H 2 O) diluted to different concentrations (dimethyl sulfoxide; 0.01%). Experimental protocols were performed in 96-well plates. For each test well, 160. Mu.L of DTNB (1.5 mM), 50. Mu.L of AChE (0.22U/mL eeAChE or 0.05U/mL hAChE) or 50. Mu.L of BuChE (0.12U/mL eqBuChE or 0.024U/mL hBuChE) and test compound at the corresponding concentration of 10. Mu.L were added and then mixedThe compounds were incubated at 37℃for 6 min. After that, 30. Mu.L of ATCI (15 mM) or BTCI (15 mM) was added rapidly. By IC 50 Value reporting inhibitory Activity of test Compounds, IC 50 The values were calculated as the concentration of compound that produced 50% inhibition of enzyme activity. Results are expressed as mean ± standard deviation of three independent experiments. Data analysis was performed using Graph Pad prism9.0.0 software (san diego, california, usa). Data have been expressed as mean ± standard error of mean (x±sd).
2. Results and discussion
2.1. Anticholinesterase activity of capsaicin-tacrine hybrids
To determine whether capsaicin-tacrine hybrids are active against ChEs, compounds 6 a-h, 7 a-f and 8 a-f were tested for their cholinesterase (ChE) inhibitory activity according to the spectrophotometric assay described by Ellman et al for electric eel acetylcholinesterase (eeAChE), butyrylcholinesterase (eqBuChE), human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBuChE). The cholinesterase inhibitor donepezil was used as a positive compound to reflect the inhibitory capacity of all the generated compounds. Experimental results are given by IC 50 (mu M) is shown in Table 1 below.
TABLE 1 anticholinergic activity of Compounds 6a to h,7a to f and 8a to f
Note that: a IC 50 values are expressed as three determinations, mean ± SD.
Of a series of hybrid compounds, compound 7e is the most potent and most balanced Inhibitor (IC) of hAChE and hBuChE 50 0.07 μm and 0.07 μm, respectively) which are more balanced in cholinesterase than the reference compound donepezil (IC 50 0.022. Mu.M and 2.31. Mu.M) as shown in Table 1. The inhibitory activity of compounds 6 a-h, 7 a-f and 8 a-f on eeAChE showed that the inhibitory activity was strongest among the same type of compounds when the number of carbon atoms between tacrine and the different capsaicin or capsaicin derivatives was 4. And the compoundComparison of the inhibitory activity of 6 a-h on eqBuChE shows that with increasing carbon chain between tacrine and capsaicin (from 3 carbon atoms to 5 carbon atoms), the compound activity increases, but with further increasing carbon chain (from 5 carbon atoms to 6 carbon atoms), the activity starts to decrease, and similar phenomenon exists for compounds 8 a-f. For hAChE, the inhibitory activity of compounds 5 a-5 s increases with increasing number of carbon atoms between tacrine and capsaicin. When the carbon number of the carbon chain is 4-7, the inhibition activity of the compounds 5 a-5 h on hBuChE is better than that of the compounds with 3 or 8 carbon atoms.
After studying the structure-activity relationship (SAR) of chain length, the applicant also explored the correlation between SAR and capsaicin lipophilic components of different structures. Most compounds having a chain amide structure show potent inhibitory activity against cholinesterase. As the number of carbon atoms of the amide moiety of capsaicin and its derivatives increases, the activity of the resulting compounds decreases. Furthermore, as shown in Table 1, the compounds containing the alkylamide structures (6 a to 6h and 7a to 7 f) exhibited stronger inhibitory effects on hAChE than the compounds (8 a to 8 f) having the enamide structure.
Experimental example 2: the capsaicin-tacrine hybrid 6a,6b,6h,7b,7d,7e,7f,8e anti-BACE-1 activity experiments
1. Experimental part
BACE-1 (Sigma) inhibition studies were performed using polypeptide M-2420 of the APP sequence (Bachem, germany). The following procedure was used: mu.L of test compound (or dimethyl sulfoxide in control wells) was pre-incubated with 175. Mu.L of enzyme (pH 4.5, containing 0.1% w/v CHAPS in 20mM sodium acetate) for 1 hour at room temperature; the substrate (3. Mu.M, final concentration) was then added and allowed to stand for 15 minutes. At lambda em ＝405nm(λ exc =320 nm) and the fluorescent signal was read. The concentration of dimethyl sulfoxide in the final mixture was kept below 5% (v/v) to prevent significant loss of enzyme activity. Background signals were measured in control wells containing all reagents except BACE-1 and subtracted. Fluorescence intensities with and without inhibitors were compared and the percent inhibition due to the presence of test compound was calculated by the following expression: 100- (IFi/IF)o×100), where IFi and IFo are the fluorescence intensities obtained for BACE-1 with and without inhibitor, respectively. To demonstrate the inhibitory effect on BACE-1 activity, a peptidomimetic inhibitor (β -secretase inhibitor IV, calbiochem) was serially diluted into the reaction wells. IC was calculated using a linear regression plot (GraphPad Prism9.0.0, graphPad-Software Inc.) 50 Values.
2. Results and discussion
2.1. anti-BACE-1 Activity of capsaicin-tacrine hybrids
In order to more reasonably evaluate the inhibitory activity of contemplated compounds on BACE-1, 8 compounds 6a,6b,6h,7b,7d,7e,7f and 8e with better inhibitory activity and selectivity on ChEs were selected for further determination of BACE-1, the results are shown in Table 2 below.
TABLE 2 anti-BACE-1 Activity of Compounds 6a,6b,6h,7b,7d,7e,7f and 8e
Note that: a the values for all compounds are the mean ± SD of three separate experiments.
As can be seen from Table 2, most of them still retain high inhibitory activity against BACE-1. In particular, compound 7e, which has the best inhibitory effect on hCHEs, also showed excellent inhibitory activity on BACE-1, showing 3.6. Mu.M IC 50 Values.
Experimental example 3: blood brain barrier permeability experiments of capsaicin-tacrine hybrids 6 a-h, 7 a-f and 8 a-f
1. Experimental part
Blood Brain Barrier (BBB) permeabilities of all synthetic compounds were determined by parallel artificial membrane permeabilities test (PAMPA). Experimental materials included porcine brain lipids (PBL, avanti Polar lipids), commercial drugs (Sigma and aladins), donor microwell plates (PVDF membrane, pore size 0.45 mm), acceptor microwell plates, and 96 Kong Zi outer line plates (Millipore). The commercial drug and the drug to be tested were dissolved in dimethyl sulfoxide, diluted with buffer solution (300 ml PBS/EtOH (7:3)) and PBL (4 ml) dodecane solution (20 mg/ml) was coated on the receptor 96-well plate filter. The receiving plate is placed such that the underside of the filter membrane is in contact with the buffer solution. After 18 hours of standing at 25, the drug absorbance in the acceptor plate and the donor plate was measured to calculate the drug concentration. At least three independent analyses were performed for each sample, and the results are expressed as mean ± standard deviation.
2. Results and discussion
2.1. Blood brain barrier permeability of capsaicin-tacrine hybrids
To assess the permeability of compounds to the Blood Brain Barrier (BBB) acting on the Central Nervous System (CNS), all compounds were used for parallel artificial membrane permeation assays of the blood brain barrier. The permeability experimental data of 10 commercial drugs and the reported data (table 3) have good linear correlation, P e (exp.) =1.065 Pe (bibl.) +0.1625 (r2=0.9967) (fig. 1).
TABLE 3 blood brain barrier permeabilities of Compounds 6 a-h, 7 a-f and 8 a-f
Note that: a permeability P e (×10 -6 cm/s) values are expressed as mean ± standard deviation of three independent experiments.
b CNS+ is predicted to be hyperglycemic brain barrier penetration, P e (×10 -6 cm/s)>4.42。
c CNS.+ -. Predicted as uncertain blood brain barrier penetration, 2.29<P e (×10 -6 cm/s)<4.42。
From the above linear equation and considering the limits established by Di et al for blood brain barrier permeation, applicants determined compounds with a blood brain barrier permeation range: (a) cns+ (predicted blood brain barrier high permeability): p (P) e (10 -6 cm/s)>4.42; (b) CNS- (predicted blood brain barrier low permeability): p (P) e (10 -6 cm/s)<2.29; (c) CNS ± (predicted blood brain barrier penetration uncertainty): 2.29<P e (10 -6 cm/s)<4.42 except that Compounds 6b and 8a showed uncertaintyP of all compounds outside the blood brain barrier penetration e (×10 -6 cm/s) are all above 4.42, indicating that these compounds can cross the blood brain barrier and exert biological effects in the central nervous system. After all of the above biological evaluations, overall blood brain barrier permeability and inhibition of che and BACE-1, compound 7e was selected for further study.
Experimental example 4: PC12 cell and BV2 cytotoxicity assay of Compound 7e
1. Experimental part
To evaluate the safety of compound 7e, the cytotoxicity test of PC12 cells and BV12 cells was determined and donepezil was used as a reference compound. PC12 cells were treated with compound 7e or donepezil at various concentrations for 24 hours and cell viability was determined by cell counting kit (CCK-8). PC12 cells and BV-2 cells in DMEM high glucose medium supplemented with 10% fetal bovine serum at 37 and 5% CO 2 Is cultured in a humid atmosphere. After the cell density reaches a certain level, the cells are planted in 96-well plates, and the density of each well is 1 multiplied by 10 4 Individual cells. When cell growth was satisfactory, cells were placed in 1% fetal bovine serum DMEM high glucose medium and incubated for 24 hours at 37 ℃ with compound 7e and positive control drug donepezil (0.625, 1.25, 2.5, 5, 10 μm) at different concentrations. Cell viability was measured using the CCK-8 method according to the instructions. Each experiment was repeated three times and the experimental results were expressed as mean ± standard deviation.
2. Results and discussion
2.1. PC12 cell and BV2 cytotoxicity experiments of capsaicin-tacrine hybrids
The results are shown in FIG. 2. As can be seen from FIG. 2, when the concentration reached 10. Mu.M, compound 7e had no significant toxic damage to PC12 cells (compound 7e:80.28%; donepezil: 98.20%). However, when the test concentration of compound 7e in BV2 cells exceeded 5 μm, cell viability was significantly reduced. This suggests that compound 7e has a moderate therapeutic safety margin and requires further evaluation in vivo.
Experimental example 5: acute toxicity test of Compound 7e
1. Experimental part
40 Kunming mice (18-22 g, male and female halves) were purchased from Hunan four-A laboratory animal Co. All mice were kept in standard animal houses at a constant temperature of 23.+ -. 2 ℃ and a relative humidity of 55.+ -. 5% and were light-dark cycled for 12h. Distilled water and sterilized food were supplied to mice. Mice were randomly divided into four groups (n=10, male 5, female 5 per group) according to the experimental dose of compound 7e: control (0.5% carboxymethyl cellulose sodium salt solution), high dose (2500 mg/kg), medium dose (1250 mg/kg) and low dose (625 mg/kg). Compound 7e was suspended in 0.5% sodium carboxymethyl cellulose (CMC-Na) salt solution and delivered to the test animals by oral administration. All groups were fasted overnight before the experiment and allowed free water. Following dosing, animals were continuously observed for any abnormal behavioral changes or death during the first 4 hours, then intermittently during the next 24 hours, with occasional observation of any delay effects occurring during the following 14 days. On day 14, all mice were sacrificed and examined for pathological changes in heart, liver, lung, brain and kidneys.
2. Results and discussion
The safety of candidate compound 7e was further evaluated by the mouse acute toxicity test. After 4 hours of administration of 625, 1250 and 2500mg/kg at the different doses, no abnormal behaviour was observed, nor was the mice died, eating down or otherwise observed. Thereafter, the mice were observed for 14 consecutive days. The study found that the body weight change at the three doses was similar to the placebo group with no significant acute toxicity (fig. 3). In addition, the analyzed mouse tissues showed lung, liver, brain, kidney and heart of the high dose control group and the blank control group, respectively (fig. 4). The results show that at a dose of 2500mg/kg of compound 7e, compound 7e had no significant damage to mice and was well tolerated.
Experimental example 6: antihypertensive passive avoidance experiment of Compound 7e
1. Experimental part
The Kunming mice were placed in the diving platform box for 5 minutes to familiarize the mice with the internal environment of the diving platform box, then the power switch of the diving platform was turned on, the current stimulus intensity at the bottom of the diving platform box was set to 0.5mA (24V), and the mice were trained. The compound was uniformly dispersed in a 0.5% CMC-Na solution to prepare three concentrations of drug solutions of 20mg/kg, 10mg/kg and 5mg/kg, respectively. The test animals were randomly divided into six groups of six animals each. 1 hour prior to the experiment, compound CMC Na solution and donepezil Ji Rongye (10 mg/kg) were administered by gavage. The blank group was given the same dose of CMC-Na solution. After 30 minutes, rats were intraperitoneally injected with scopolamine hydrobromide injection (3 mg/kg) for modeling. The trained animals are returned to the platform box. After familiarity with 5 minutes, current stimulation (0.5 ma,24 v) was again performed, the time of the first jump of the mouse (latency period) and the number of jumps (number of errors) within 5 minutes were recorded, and the in vivo efficacy was evaluated based on latency period and number of errors. One-way anova was used to measure differences between groups.
2. Results and discussion
The superior therapeutic results of the above studies indicate that compound 7e is necessary to determine whether it can improve memory impairment in vivo. Compound 7e, donepezil, was tested using a scopolamine-induced cognition deficit mouse model as a positive reference, and a hypotensive passive avoidance test was performed to evaluate the effect of cognitive improvement. As shown in FIG. 5, the model group showed shorter latency and more errors than the control group ### P<0.001). In addition to the low dose group of compound 7e, the latency and the number of errors in the high dose group and the medium dose group showed significant differences compared to the model group (P<0.001 and P<0.001). After treatment with compound 7e, latency and number of errors was reversed. The high dose group (20 mg/kg) showed a longer latency period (139.8 s vs 120.7 s) than the donepezil group (10 mg/kg). The high dose group (20 mg/kg) and the medium dose group (10 mg/kg) showed less errors (1.36, 1.24, vs 3.4) than the donepezil group (10 mg/kg). The low dose group (5 mg/kg) did not differ significantly from the model group, but the latency and the number of errors were improved (98.7s vs 66.2s,3.21 vs 4.2). This in vivo study further demonstrates that compound 7e may be a promising compound for the treatment of AD.

Claims (10)

1. Capsaicin-tacrine hybrids having the structure shown in the following formula 6, formula 7 or formula 8 or pharmaceutically acceptable salts thereof:
wherein m=6 to 8, n=3 to 8.
2. A capsaicin-tacrine hybrid according to claim 1, wherein,
in the formula 6, m=6 to 8, and n=3 to 6; in formula 7, n=3 to 8; in formula 8, n=3 to 8.
3. A process for the preparation of the capsaicin-tacrine hybrid of claim 1, comprising the steps of:
1) Taking a compound with a structure shown in the following formula 1, respectively placing the compound with a capsaicin derivative, dihydrocapsaicin or natural capsaicin with a structure shown in the formula 9 in a first organic solvent, and reacting in the presence of an acid binding agent to obtain a compound with a structure shown in the formula 3, formula 4 or formula 5;
2) Placing a compound with a structure shown in the following formula 2 and a compound with a structure shown in the formula 3, the formula 4 or the formula 5 in a second organic solvent respectively, and adding an alkaline reagent to react to obtain a compound with a structure shown in the formula 6, the formula 7 or the formula 8;
4. a process according to claim 3, wherein,
in the step 1), the first organic solvent is one or more than two selected from 1, 2-dichloroethane, toluene and acetonitrile;
in the step 2), the second organic solvent is N, N-dimethylformamide or dimethyl sulfoxide, or a combination thereof.
5. A process according to claim 3, wherein in step 1), the reaction is carried out under heating.
6. A process according to claim 3, wherein in step 2) the alkaline agent is sodium hydride or potassium hydride or a combination thereof.
7. The method according to any one of claims 3 to 6, further comprising a step of purifying the produced compound of the structure represented by formula 6, formula 7 or formula 8.
8. Use of a capsaicin-tacrine hybrid or a pharmaceutically acceptable salt thereof of claim 1, in the manufacture of a medicament for treating or preventing alzheimer's disease.
9. The use of a capsaicin-tacrine hybrid or pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a cholinesterase inhibitor, or in the preparation of a BACE-1 inhibitor, or in the preparation of a neuroprotectant.
10. A pharmaceutical composition comprising as an active ingredient a therapeutically effective dose of the capsaicin-tacrine hybrid of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
CN202310616098.2A 2023-05-29 2023-05-29 Capsaicin-tacrine hybrid, and preparation method and application thereof Pending CN116640093A (en)

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