Oxime compound and preparation and use thereof

Abstract

The present invention relates to the field of pharmaceutical chemistry, and in particular, to an oxime compound and preparation and use thereof. The oxime compound not only selectively acts on a small molecule ligand of a Sigma-1 receptor, but also has low pharmacological toxicity. Marketed drugs for treating neuropsychiatric diseases have been reported to act non-selectively on the Sigma-1 receptor. However, to date, no drug that selectively acts on the Sigma-1 receptor has been successfully marketed. The aryl oxime compound disclosed previously is a Sigma-1 receptor ligand with selectivity. However, as a drug, in addition to selectively acting on the Sigma-1 receptor, this compound also needs to have pharmacological safety. The oxime compound of the present invention selectively acts on the small molecule ligand of the Sigma-1 receptor, has low pharmacological toxicity, and can be used in the preparation of a variety of drugs for treating diseases of the central nervous system.

Description

An oxime compound and its preparation and application Technical Field

[0001] This invention relates to the field of medicinal chemistry, and more particularly to an oxime compound and its preparation and application, which not only selectively acts on small molecule ligands of Sigma-1 receptors, but also has low pharmacological toxicity. Background Technology

[0002] The Sigma receptor (σ1R) is a membrane protein that can be divided into two subtypes: Sigma-1 and Sigma-2 receptors. Studies have found that the Sigma-1 receptor is a binding protein for various specific psychotropic drugs, and as a receptor-type molecular chaperone, it performs physiological functions including regulating ion channels (K+). + Ca 2+ Na + Sigma-1 receptors regulate mitochondrial function and neurotransmitter release by acting on ion channels, neurotransmitter function, and downstream receptors (such as inositol triphosphate (IP3) receptors and NMDAR). The physiological functions of Sigma-1 receptors in the central nervous system mainly include improving drug addiction and motor disorders, protecting nerves, and regulating cognition. Peripheral Sigma-1 receptors are mainly distributed in lymphatic tissues, where their primary role is in regulating the body's immune function. Sigma-1 receptors are widely distributed throughout the central nervous system, most abundantly in the hippocampus and thalamus, followed by the striatum, cerebellum, dorsal raphe nucleus, and locus coeruleus. By regulating ion channels, neurotransmitter function, and mitochondrial function, they play an important regulatory role in cholinergic, GABAergic, and dopaminergic nervous systems, thereby exerting analgesic, memory-improving, anti-epileptic, antidepressant, and neuroprotective effects.

[0003] To date, many marketed drugs for treating neuropsychiatric disorders have been reported to act non-selectively on the Sigma-1 receptor; however, no drug selectively acting on the Sigma-1 receptor has yet been successfully marketed. The applicant previously disclosed an aryl oxime compound, a class of ligands with selective Sigma-1 receptor action. However, as a drug, in addition to selective action on the Sigma-1 receptor, pharmacological safety is also required, and this existing compound needs improvement. Therefore, it is necessary to develop new oxime compounds that are small-molecule ligands selectively acting on the Sigma-1 receptor with low pharmacological toxicity, which is of great significance for the treatment of neuropsychiatric disorders such as Alzheimer's disease, depression, epilepsy, Parkinson's disease, stroke, pain, and drug addiction. Summary of the Invention

[0004] To address the aforementioned technical problems, the present invention aims to provide an oxime compound, its pharmaceutically acceptable salt, ester, or hydrate, and its preparation and application. The oxime compound of the present invention selectively acts on small molecule ligands of the Sigma-1 receptor and has low pharmacological toxicity, and can be used to prepare a variety of drugs for treating diseases of the central nervous system.

[0005] The present invention adopts the following technical solution.

[0006] An oxime compound has the following general chemical structural formula:

[0007] Wherein, R1 is selected from one or more of halogenated alkyl, halogenated acyl, alkoxy or halogen; R2 is selected from alkyl, or forms a ring with Ar; Ar is selected from benzene ring or aromatic heterocycle; n is selected from 1 to 5; m and p are selected from 0 to 6; R3 and R4 are independently selected from one of hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, methanesulfonyl, alkoxyalkyl, hydroxy, hydroxyalkyl, deuterium, or both of them form a 3 to 8 membered ring with the C atom attached to them.

[0008] Preferably, R1 is selected from one or more of trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethanesulfonyl, alkoxy or halogen, and the substitution is 1 to 3 substitutions;

[0009] R2 is selected from methyl groups, or forms a 4- to 8-membered ring with Ar;

[0010] n is selected from any integer from 1 to 3, such as 1, 2, 3; m and p are selected from any integer from 0 to 4, such as 0, 1, 2, 3, 4;

[0011] More preferably, n = 1 or 2, m = p = 2.

[0012] In an even more preferred configuration, when m = p = 2 and Ar is a benzene ring, R3 and R4 are not both H.

[0013] Preferred fragments Selected from:

[0014] Preferred fragments Selected from:

[0015] Preferably, the oxime compound is selected from any of the following compounds:

[0016] In this invention, halogens include fluorine, chlorine, and bromine.

[0017] This invention discloses the above-mentioned oxime compounds, and their pharmaceutically acceptable salts, esters or hydrates.

[0018] Furthermore, the pharmaceutically acceptable salt is a salt formed by the above-mentioned oxime compound with an inorganic or organic acid, the pharmaceutically acceptable ester is an ester formed by the above-mentioned oxime compound with an acid (carboxylic acid or inorganic oxyacid) or an alcohol, and the pharmaceutically acceptable hydrate is a hydrous compound formed by the above-mentioned oxime compound with water via a coordinate or covalent bond.

[0019] This invention discloses a method for preparing the above-mentioned oxime compounds, comprising the following steps: using chlorides and amines as raw materials, reacting to prepare oxime compounds;

[0020] The general chemical structural formula of chlorides is as follows:

[0021] The general chemical structural formula of amines is as follows:

[0022] In this invention, the substituents and the number of repeating units in chlorides and amines are the same as those in oxime compounds.

[0023] In this invention, the reaction is carried out in the presence of an inorganic base, which includes potassium salts, sodium salts, calcium salts, etc., such as carbonates.

[0024] In this invention, the reaction is carried out in an organic solvent, which is a conventionally chosen organic solvent.

[0025] In this invention, the reaction temperature is 70–100°C and the reaction time is 0.5–5 hours; preferably, the reaction temperature is 80–90°C and the reaction time is 1–3 hours.

[0026] In this invention, the molar ratio of chloride to amine is 1:(1-3), preferably 1:(1.5-2.5).

[0027] In this invention, the molar ratio of chloride to inorganic base is 1:(1-3), preferably 1:(1.5-2.5).

[0028] This invention discloses a pharmaceutical composition in which the active ingredient is the above-mentioned oxime compound, its pharmaceutically acceptable salt, ester or hydrate.

[0029] This invention discloses the use of the above-mentioned oxime compounds, their pharmaceutically acceptable salts, esters or hydrates in the preparation of drugs.

[0030] This invention discloses the use of the above-mentioned oxime compounds, their pharmaceutically acceptable salts, esters or hydrates in the preparation of drugs for Sigma-1 related diseases.

[0031] This invention discloses the use of the above-mentioned oxime compounds, their pharmaceutically acceptable salts, esters or hydrates as Sigma-1 ligands in the preparation of drugs for the prevention and / or treatment of Sigma-1 related diseases.

[0032] Furthermore, diseases associated with Sigma-1 include neuropsychiatric disorders.

[0033] Preferably, neuropsychiatric disorders include epilepsy, depression, Alzheimer's disease, Parkinson's disease, ischemic stroke, neuropathic pain, or drug addiction.

[0034] The purpose of this invention is to provide an oxime compound, its pharmaceutically acceptable salt, ester, or hydrate, and its preparation and application. The oxime compounds of this invention selectively act on small molecule ligands of the Sigma-1 receptor and exhibit low pharmacological toxicity, particularly low hERG potassium channel inhibitory activity, IC50... 50 The value is as high as 21.59 μM, which indicates that it has a low risk of cardiotoxicity and shows good cardiac safety. It can be used to prepare a variety of drugs for treating diseases of the central nervous system.

[0035] The above description is merely an overview of the technical solution of the present invention. In order to better understand the technical means of the present invention and to implement it in accordance with the contents of the specification, the preferred embodiments of the present invention are described in detail below with reference to the accompanying drawings. Attached Figure Description

[0036] Figure 1 shows the treatment of σ1RLgBiT / BiPSmBiT cell lines with DMSO or the specified σ1R ligand (10 μM) for 10 minutes (A) or 16 hours (B).

[0037] Figure 2 shows the effects of compound C17 on cognitive function and spatial memory in normal mice, including the familiarity stage (A), memory index (B), and (C).

[0038] Figure 3 shows the effect of compound C31 on acetic acid-induced writhing in mice. Detailed Implementation

[0039] The purpose of this invention is to provide an oxime compound, its pharmaceutically acceptable salt, ester, or hydrate, and its preparation and application. The oxime compounds of this invention selectively act on small molecule ligands of the Sigma-1 receptor and exhibit low pharmacological toxicity, particularly low hERG potassium channel inhibitory activity, IC50... 50 The value is as high as 21.59 μM, which indicates that it has a low risk of cardiotoxicity and shows good cardiac safety. It can be used to prepare a variety of drugs for treating diseases of the central nervous system.

[0040] This invention discloses an oxime compound, its pharmaceutically acceptable salt, ester, or hydrate, the general chemical structural formula of which is as follows:

[0041] Wherein, R1 is selected from one or more of halogenated alkyl, halogenated acyl, alkoxy or halogen; R2 is selected from alkyl, or forms a ring with Ar; Ar is selected from benzene ring or aromatic heterocycle; n is selected from 1 to 5; m and p are independently selected from 0 to 6; R3 and R4 are independently selected from one of hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, methanesulfonyl, alkoxyalkyl, hydroxy, hydroxyalkyl, deuterium, or both of them form a 3 to 8 membered ring with the C atom attached to them.

[0042] Preferably, R1 is selected from one or more of trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethanesulfonyl, alkoxy or halogen, and the substitution is 1 to 3 substitutions;

[0043] R2 is selected from methyl groups, or forms a 4- to 8-membered ring with Ar;

[0044] n is selected from any integer from 1 to 3, such as 1, 2, 3; m and p are independently selected from any integer from 0 to 4, such as 0, 1, 2, 3, 4;

[0045] More preferably, n = 1 or 2, m = p = 2.

[0046] In an even more preferred configuration, when m = p = 2 and Ar is a benzene ring, R3 and R4 are not both H.

[0047] In this invention, halogens include fluorine, chlorine, and bromine.

[0048] Preferred fragments Selected from:

[0049] Preferred fragments Selected from:

[0050] The specific embodiments of the present invention will be further described in detail below with reference to the accompanying drawings and examples. The following examples are for illustrative purposes only and are not intended to limit the scope of the invention. All reagents used are existing products, and the specific preparation operations and performance tests are all conventional techniques. Animal experiments comply with the relevant requirements of Soochow University.

[0051] In the following embodiments of the present invention, the general preparation route of oxime compounds is shown below:

[0052] The specific general steps are as follows:

[0053] Oxime synthesis: 0.25 mmol of an existing ketone was dissolved in 10 mL of ethanol, and 0.5 mmol of hydroxylamine hydrochloride and 0.5 mmol of potassium carbonate were added. The mixture was refluxed at 90 °C for 2 h. After the reaction was complete, the solvent was evaporated to dryness, diluted with 15 mL of water, and then extracted with dichloromethane (15 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the oxime.

[0054] Synthesis of chloride: 0.25 mmol of oxime was dissolved in 15 mL of dichloromethane. The corresponding haloalkane (1.25 mmol), CTMAB (cetyltrimethylammonium bromide, 0.06 mmol), and 5 mL of 5N NaOH aqueous solution were added. The mixture was refluxed overnight at 50 °C. After the reaction was complete, the solvent was evaporated to dryness, diluted with 15 mL of water, and then extracted with 15 mL × 2 of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the chloride.

[0055] Synthesis of oxime compounds: Chloride (0.25 mmol) was dissolved in acetonitrile (10 mL), potassium carbonate (69 mg, 0.5 mmol) and the corresponding amine (0.5 mmol) were added, and the mixture was refluxed at 85 °C for 2 h. After the reaction was complete, the solvent was evaporated to dryness, diluted with water (15 mL), and then extracted with dichloromethane (15 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the oxime compounds.

[0056] Example 1

[0057] The obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with 4-fluoropiperidine according to the general procedure to give compound C1. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 68% yield. Its 1H NMR, 1C NMR, and mass spectrometry results are as follows: 1 H NMR(400MHz, CDCl3)δ7.75(d,J=8.2Hz,2H),7.61(d,J=8.2Hz,2H),4.76–4.71(m,0.5H),4.64–4.59(m,0.5H),4 .25(t,J=6.4Hz,2H),2.62–2.58(m,2H),2.50–2.46(m,2H),2.43–2.38(m,2H),2.23(s,3H),1.98–1.85(m,6H). 13 C NMR(101MHz,CDCl3)δ153.3,140.2,130.9(q,J C-F =32.8Hz), 126.4, 125.4(q,J)C-F =3.9Hz), 124.2(q,J C-F =273.4Hz),73.8,55.4,49.8,49.7,31.7,31.5,27.1,12.7.HRMS(CI)calcd for C 17 H 22 F4N2O[M+H] + :347.1747,found 347.1753.

[0058] Following standard procedures, the obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with 4-trifluoromethylpiperidine to give compound C2. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 68% yield. The 1H NMR, 1C NMR, and mass spectrometry results are as follows: 1 H NMR (300MHz, CDCl3) δ7.75(d,J=7.0Hz,2H),7.61(d,J=7.8Hz,2H),4.26(t,J=5.2Hz,2H),3 .03(d,J=8.9Hz,2H),2.50–2.43(m,2H),2.23(s,3H),2.02–1.80(m,8H),1.76–1.52(m,1H). 13 C NMR(101MHz,CDCl3)δ153.2,140.2,130.9(q,J C-F =97.0Hz), 126.4, 125.4(q,J) C-F =3.7Hz), 124.9(q,J C-F =280.78Hz), 124.2(q,J C-F =272.7Hz),72.9,55.4,52.7,40.6(q,J C-F =27.1Hz),27.1,24.8(q,J) C-F =2.7Hz), 12.6.LC-Ms:369.2.

[0059] The obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with 4-methylpiperidine according to the general procedure to give compound C3. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. The 1H NMR, 1C NMR, and mass spectrometry results are as follows: 1H NMR (300MHz, CDCl3) δ7.75(d,J=8.1Hz,2H),7.60(d,J=8.2Hz,2H),4.26(t,J=6.5Hz, 2H),2.52–2.47(m,6H),2.23(s,3H),1.96(p,J=6.5Hz,2H),1.41(s,4H),0.26(s,4H). 13 C NMR(101MHz,CDCl3)δ153.2,140.3,130.8(q,J C-F =32.7Hz), 126.4, 125.4(q,J) C-F =3.9Hz), 124.2(q,J C-F =273.1Hz),73.2,55.9,53.5,35.2,27.1,17.7,12.6,11.6.HRMS(CI)calcd for C 19 H 27 F3N2O[M+H] + :354.1919,found 354.1917.

[0060] The obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with 4-difluoromethylpiperidine according to the general procedure to give compound C4. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 72% yield. Its 1H NMR and mass spectrometry results are as follows: 1 H NMR (300MHz, CDCl3) δ7.75(d,J=8.2Hz,2H),7.61(d,J=8.1Hz,2H),5.56(td,J=56.9,4.5Hz,1H),4.25(t,J=6.4Hz,2H),3.00(d,J=11.1H z,2H),2.61–2.38(m,2H),2.23(s,3H),1.96(d,J=3.8Hz,1H),1.91(s,2H),1.83–1.69(m,4H),1.48(q,J=10.8,9.0Hz,2H).LC-Ms:378.2.

[0061] Following standard procedures, the obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with 4-cyanopiperidine to give compound C5. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 65% yield. The 1H NMR, 1C NMR, and mass spectrometry results are as follows: 1H NMR (300MHz, CDCl3) δ7.75–7.71(m,2H),7.61–7.56(m,2H),4.23(q,J=6.0Hz,2H),2.64( s,3H),2.48–2.43(m,2H),2.33(s,2H),2.24–2.17(m,3H),1.88(dt,J=11.9,5.7Hz,6H). 13 C NMR(101MHz,CDCl3)δ153.2,140.2,130.9(q,J C-F =32.5Hz), 126.3, 125.4(q,J) C-F =3.8Hz), 124.2(q,J C-F =271.9Hz),121.9,72.8,55.4,51.5,28.9,26.9,26.3,12.6.LC-Ms:353.2.

[0062] The obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with 4-(methylsulfonyl)piperidine according to the general procedure to give compound C6. Silica gel column chromatography using elution (PE:EA = 3:1) yielded a colorless oil in 70% yield. Its 1H NMR and mass spectrometry results are as follows: 1 H NMR (500MHz, CDCl3) δ7.74(d,J=10.5Hz,2H),7.68(d,J=10.5Hz,2H),3.93(t,J=6.9Hz,2H),3.35–3.24(m,1H),2.97(s,3H),2.8 1–2.72(m,2H),2.63(t,J=6.1Hz,2H),2.55–2.46(m,2H),2.15–2.04(m,2H),1.99–1.89(m,2H),1.87–1.78(m,2H).LC-Ms:406.2

[0063] The obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with 4-methoxypiperidine according to the general procedure to give compound C7. Silica gel column chromatography using elution (PE:EA = 3:1) yielded a colorless oil in 70% yield. Its 1H NMR and mass spectrometry results are as follows: 1H NMR (300MHz, CDCl3) δ7.76(d,J=8.2Hz,2H),7.61(d,J=8.2Hz,2H),4.25(t,J=6.4Hz,2H),3.34(s,3H),3.22(dt,J=8.0,4.4Hz,1H),2.81–2 .67(m,2H),2.46(t,J=7.6Hz,2H),2.23(s,3H),2.13(dd,J=23.7,13.8Hz,2H),1.92(q,J=6.8Hz,4H),1.61(q,J=9.0Hz,2H).LC-Ms:358.2.

[0064] The obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with 4-(methoxymethyl)piperidine according to the general procedure to give compound C8. Silica gel column chromatography using elution (PE:EA = 3:1) yielded a colorless oil in 70% yield. Its 1H NMR and mass spectrometry results are as follows: 1 H NMR (300MHz, CDCl3) δ7.74(d,J=7.6Hz,2H),7.59(d,J=7.9Hz,2H),4.24(t,J=6.2Hz,2H),3.32(s,3H),3.21(d,J=6.4Hz,2H),2.95(d,J=9 .3Hz,2H),2.51–2.38(m,2H),2.22(s,3H),2.00–1.84(m,4H),1.73(d,J=11.7Hz,2H),1.65–1.52(m,1H),1.37–1.19(m,2H).LC-Ms:372.2.

[0065] The obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with 3-methoxypiperidine according to the general procedure to give compound C9. Silica gel column chromatography using elution (PE:EA = 3:1) yielded a colorless oil in 70% yield. The 1H NMR and mass spectrometry results are as follows: 1H NMR (300MHz, CDCl3) δ7.75(d,J=8.1Hz,2H),7.59(d,J=8.1Hz,2H),4.24(t,J=6.4Hz,2H) ,3.36(s,3H),3.29(dt,J=8.2,4.0Hz,1H),2.90(d,J=8.5Hz,1H),2.70–2.59(m,1H),2.53 –2.44(m,2H),2.22(s,3H),2.13–2.00(m,2H),1.93(dt,J=13.2,6.3Hz,3H),1.75(dd,J= 8.9, 4.3Hz, 1H), 1.51 (dd, J=10.2, 3.3Hz, 1H), 1.26 (q, J=10.8, 9.3Hz, 1H). LC-Ms: 358.2.

[0066] Following standard procedures, the obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-bromoethyl)oxime was reacted with 4-hydroxypiperidine to give compound C10. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. The 1H NMR and mass spectrometry results are as follows: 1 H NMR (600MHz, CDCl3) δ7.75(d,J=8.1Hz,2H),7.61(d,J=8.1Hz,2H),4.36(t,J=5.9Hz,2H),3.71(s,1H),2.86(dt,J=10.5 ,4.5Hz,2H),2.76(t,J=6.0Hz,2H),2.33–2.26(m,2H),2.24(s,3H),1.95–1.88(m,2H),1.65–1.58(m,3H).LC-Ms:330.2.

[0067] Following standard procedures, the obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with 4-hydroxypiperidine to give compound C11. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. The 1H NMR, 1C NMR, and mass spectrometry results are as follows: 1 H NMR(600MHz, CDCl3) δ7.75(d,J=8.1Hz,2H),7.61(d,J=8.2Hz,2H),4.25(t,J=6.4Hz,2H), 3.76(s,1H),2.89–2.78(m,2H),2.54(s,2H),2.23(s,3H),1.98(s,4H),1.73–1.60(m,2H). 13C NMR (101MHz, CDCl3) δ156.1, 134.9, 132.6 (q, J = 32.1Hz), 127.4 (q, J = 1.9Hz), 126.24 (q, J=4.1Hz),123.9(q,J=268.0Hz),73.1,67.5,54.4,50.6,34.0,25.0,14.1.LC-Ms:calcd for C 17 H 23 F3N2O2[M]+:344.1712, found 344.1718.

[0068] The obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with 4-hydroxymethylpiperidine according to the general procedure to give compound C12. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. The 1H NMR and mass spectrometry results are as follows: 1 H NMR (300MHz, CDCl3) δ7.75(d,J=8.1Hz,2H),7.60(d,J=8.1Hz,2H),4.24(t,J=6.3Hz,2H),3.48(d,J=6.2Hz,2H),2.96(d,J=11.1Hz,2 H), 2.53–2.40 (m, 2H), 2.23 (s, 3H), 1.94 (t, J = 7.7Hz, 4H), 1.73 (d, J = 12.7Hz, 2H), 1.50 (s, 1H), 1.28 (q, J = 11.9Hz, 2H). LC-Ms: 358.2.

[0069] The obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with 2-hydroxymethylpiperidine according to the general procedure to give compound C13. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. The 1H NMR and mass spectrometry results are as follows: 1 H NMR (500MHz, CDCl3) δ7.74(d,J=10.5Hz,2H),7.68(d,J=10.5Hz,2H),3.95(t,J=6.6Hz,2H),3.61–3.48(m,3H),2.82–2.74 (m,1H),2.72–2.64(m,3H),2.57(dt,J=12.5,6.2Hz,1H),2.31(s,3H),1.90–1.73(m,3H),1.61–1.41(m,3H).LC-Ms:358.2

[0070] The obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with 4,4-dimethylpiperidine according to the general procedure to give compound C14. Silica gel column chromatography using elution (PE:EA = 3:1) yielded a colorless oil in 70% yield. The 1H NMR, 1C NMR, and mass spectrometry results are as follows: 1 H NMR (300MHz, CDCl3) δ7.75(d,J=8.2Hz,2H),7.60(d,J=8.2Hz,2H),4.25(t,J=6.3Hz,2H), 2.65–2.41(m,6H),2.23(s,3H),1.98(p,J=6.5Hz,2H),1.45(t,J=5.6Hz,4H),0.93(s,6H). 13 C NMR(101MHz,CDCl3)δ153.3,140.2,130.9(d,J C-F =32.6Hz), 126.4, 125.4 (d, J) C-F =3.8Hz), 124.2(d,J C-F =272.1Hz),72.9,55.7,50.1,38.4,28.5,26.8,12.6.LC-Ms:356.2.

[0071] Following standard procedures, the obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with 7-azaspiro[3.5]nonane to give compound C15. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil with a yield of 70%. Its 1H NMR, 1C NMR, and mass spectrometry results are as follows: 1 H NMR (300MHz, CDCl3) 1 H NMR (300MHz, CDCl3) δ7.75(d,J=8.1Hz,2H),7.60(d,J=8.2Hz,2H),4.24(t,J=6.4Hz,2H),2.45–2.35(m,2H),2.32(s ,3H),2.22(s,3H),2.16(s,1H),1.98–1.90(m,2H),1.89–1.80(m,2H),1.72(t,J=7.0Hz,4H),1.60(t,J=5.0Hz,4H). 13 C NMR(101MHz,CDCl3)δ153.1,140.3,130.8(q,J C-F =32.6Hz), 126.4, 125.4(q,J) C-F =3.8Hz), 124.2(q,J C-F=272.0Hz),73.2,55.8,50.7,37.8,37.8,32.1,27.2,15.3,12.6.LC-Ms:368.2.

[0072] The obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with 6-azaspiro[3.5]octane according to the general procedure to give compound C16. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil with a yield of 70%. Its 1H NMR, 1C NMR, and mass spectrometry results are as follows: 1 H NMR (300MHz, CDCl3) δ7.75(d,J=8.1Hz,2H),7.60(d,J=8.2Hz,2H),4.26(t,J=6.4Hz, 2H),2.55–2.38(m,6H),2.23(s,3H),1.96(p,J=6.5Hz,2H),1.41(s,4H),0.26(s,4H). 13 C NMR(101MHz,CDCl3)δ153.2,140.3,130.8(q,J C-F =32.5Hz), 126.4, 125.4(q,J) C-F =3.7Hz), 124.2(q,J C-F =272.0Hz),73.2,55.9,53.5,35.2,27.1,17.7,12.6,11.6.LC-Ms:354.2.

[0073] The obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-bromoethyl)oxime was reacted with 4,4-difluoropiperidine according to the general procedure to give compound C17. Silica gel column chromatography using elution (PE:EA = 3:1) yielded a colorless oil in 70% yield. The 1H NMR, 1C NMR, and mass spectrometry results are as follows: 1 H NMR (400MHz, CDCl3) δ7.76(d,J=8.1Hz,2H),7.62(d,J=8.1Hz,2H),4.35(t,J=6.0Hz,2H) ,2.82(t,J=5.7Hz,2H),2.68(t,J=5.7Hz,4H),2.24(s,3H),2.01(tt,J=12.9,5.7Hz,4H). 13 C NMR(101MHz,CDCl3)δ153.6,140.0,131.0(q,J C-F =32.5Hz), 126.4, 125.5(q,J) C-F =3.8Hz), 124.2(q,JC-F =272.0Hz), 122.0(q,J C-F =241.4Hz),72.8,56.4,50.5(t,J C-F =5.4Hz), 34.2(t,J C-F =22.9Hz),12.9.LC-Ms:350.2.

[0074] The obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with 4,4-difluoropiperidine according to general procedures to give compound C18. Silica gel column chromatography using elution (PE:EA = 3:1) yielded a colorless oil in 70% yield. The 1H NMR, 1C NMR, and mass spectrometry results are as follows: 1 H NMR (300MHz, CDCl3) δ7.76(d,J=8.1Hz,2H),7.61(d,J=8.1Hz,2H),4.26(t,J=6.4Hz,2H),2.55(dt,J=14.4,6.6Hz,6H),2.24(s,3H),2.12–1.85(m,6H). 13 C NMR(101MHz,CDCl3)δ153.3,140.2,130.9(q,J C-F =32.5Hz), 126.4, 125.4(q,J) C-F =3.8Hz), 124.2(q,J C-F =272.1Hz), 122.2(t,J) C-F =241.4Hz),72.8,54.5,50.2(t,J C-F =5.3Hz), 34.2(t,J C-F =22.9Hz),27.3,12.6.LC-Ms:364.2.

[0075] The obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with 2,2-dideuterium piperidine according to the general procedure to give compound C19. Silica gel column chromatography using elution (PE:EA = 3:1) yielded a colorless oil in 70% yield. The 1H NMR, 1C NMR, and mass spectrometry results are as follows: 1 H NMR (300MHz, CDCl3) δ7.75(d,J=8.2Hz,2H),7.61(d,J=8.2Hz,2H),4.26(t,J=6.2Hz, 2H),2.73–2.52(m,4H),2.23(s,3H),2.10(p,J=6.5Hz,2H),1.75(s,4H),1.51(s,2H).13 C NMR(151MHz,CDCl3)δ153.6,140.1,131.0(d,J C-F =32.4Hz), 126.4, 125.4(q,J) C-F =3.8Hz), 124.2(q,J C-F =271.8Hz),72.5,55.9,54.3,25.9,24.9,24.7,23.7,12.7.LC-Ms:330.2.

[0076] The obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-bromoethyl)oxime was reacted with 8-oxa-2-aza[4.5]decane according to the general procedure to give compound C20. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil with a yield of 70%. Its 1H NMR and mass spectrometry results are as follows: 1 H NMR: 1 H NMR (600MHz, CDCl3) δ7.76(d,J=8.1Hz,2H),7.61(d,J=8.2Hz,2H),4.36(t,J=6.0Hz,2H),3.64(t,J=5.3Hz,4H),2.82(t,J=6.0Hz,2H),2.70 (t,J=6.9Hz,2H),2.55(s,2H),2.25(s,3H),1.70(t,J=6.9Hz,2H),1.62(dt,J=13.5,5.5Hz,2H),1.57(dt,J=13.3,5.1Hz,2H).LC-Ms:370.2.

[0077] Following standard procedures, the obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-bromoethyl)oxime was reacted with 7-oxa-2-aza[4.5]nonane to give compound C21. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. Its 1H NMR and mass spectrometry results are as follows: 1 H NMR (600MHz, CDCl3) δ7.76(d,J=8.1Hz,2H),7.61(d,J=8.2Hz,2H),4.24(t,J=5.7Hz,2H),3.59(t,J =5.3Hz,24H),3.14(s,4H),2.83(t,J=5.8Hz,2H),2.24(s,3H),1.76(t,J=5.3Hz,4H).LC-Ms:356.2.

[0078] The obtained (E)-1-(4-(trifluoromethyl)phenyl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with 7-oxa-2-aza[4.5]nonane according to the general procedure to give compound C22. Silica gel column chromatography with eluent (PE:EA = 3:1) yielded a colorless oil with a yield of 70%. Its 1H NMR and mass spectrometry results are as follows: 1 H NMR (500MHz, CDCl3) δ7.74(d,J=10.5Hz,1H),7.68(d,J=10.5Hz,1H),3.93(t, J=6.9Hz,1H),3.61(dd,J=5.4,2.7Hz,1H),3.56(dd,J=5.4,2.7Hz,1H),2.77( s,1H),2.66(t,J=4.9Hz,1H),2.64(s,1H),2.31(s,1H),1.83(tt,J=6.9,4.8H z, 1H), 1.71 (dd, J = 5.5, 2.7Hz, 1H), 1.63 (dd, J = 5.5, 2.6Hz, 1H). LC-Ms: 370.2.

[0079] Following standard procedures, the obtained (E)-6-(trifluoromethyl)-3,4-dihydronaphthyl-1(2H)-one O-(3-chloropropyl)oxime was reacted with piperidine to give compound C23. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. The 1H NMR, 1C NMR, and mass spectrometry results are as follows: 1 H NMR(300MHz, CDCl3)δ8.04(d,J=8.2Hz,1H),7.43–7.37(m,2H),4.26(t,J=6.1Hz, 2H),2.88–2.68(m,10H),2.26–2.15(m,2H),1.92–1.79(m,6H),1.64–1.50(m,2H). 13 C NMR (151MHz, CDCl3) δ153.2,139.9,134.2,130.6(d,J C-F =32.2Hz), 125.6(d,J C-F =4.1Hz), 124.9, 124.2 (d, J) C-F =272.2Hz), 123.1(d,J C-F =3.9Hz),72.4,55.9,54.2,29.8,25.8,24.7,24.3,23.6,21.2.HRMS(CI)calcd for C 19 H 26 F3N2O[M+H] +:355.1996,found 355.1997.

[0080] The obtained (E)-7-(trifluoromethyl)chromane-4-one O-(3-chloropropyl)oxime was reacted with piperidine according to the general procedure to give compound C24. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. The 1H NMR, 1C NMR, and mass spectrometry results are as follows: 1 H NMR(300MHz, CDCl3)δ7.99(d,J=8.3Hz,1H),7.18–7.11(m,2H),4.23(t,J=6.3Hz,4H),2.91( t,J=6.2Hz,2H),2.52–2.36(m,6H),2.00–1.90(m,2H),1.66–1.57(m,4H),1.49–1.40(m,2H). 13 C NMR(151MHz,CDCl3)δ156.3,147.1,132.4(q,J C-F =32.8Hz), 125.0, 123.8(q,J) C-F =273.3Hz), 122.0, 117.8 (d, J) C-F =3.9Hz), 115.2(q,J C-F =4.1Hz),73.3,65.3,56.1,54.7,26.8,25.9,24.4,23.9.HRMS(CI)calcd for C 18 H 24 F3N2O2[M+H] + :357.1789,found 357.1790.HPLC:99.7%(λ=254nm,t R =13.32min).

[0081] Following standard procedures, the obtained (E)-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one O-(3-chloropropyl)oxime was reacted with piperidine to give compound C25. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. The 1H NMR, 1C NMR, and mass spectrometry results are as follows: 1H NMR (300MHz, CDCl3) δ7.76(d,J=8.1Hz,1H),7.55(s,1H),7.49(d,J=8.1Hz,1H),4.23(t,J=6.3Hz,2H),3.14–3 .03(m,2H),2.97–2.85(m,2H),2.57–2.35(m,6H),1.97(q,J=7.0Hz,2H),1.68–1.58(m,4H),1.50–1.41(m,2H). 13 C NMR (151MHz, CDCl3) δ161.2,148.5,140.0,131.9(d,J C-F =32.0Hz), 124.3(d,J C-F =272.3Hz), 124.2(d,J C-F =4.0Hz), 122.7(q,J C-F =4.0Hz),121.9,73.2,56.2,54.8,28.7,27.0,26.6,26.1,24.6.HRMS(CI)calcd for C 18 H 24 F3N2O[M+H] + :341.1839, found 341.1841.HPLC:96.3% (λ=254nm,t R =12.93min).

[0082] Following standard procedures, the obtained (E)-1-(pyridin-2-yl)ethyl-1-one O-(2-bromoethyl)oxime was reacted with piperidine to give compound C26. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. Its 1H NMR and mass spectrometry results are as follows: 1 H NMR (300MHz, DMSO-d6) δ8.85(d,J=4.9Hz,1H),8.16(d,J=8.1Hz,1H),7.92(t,J=6.9Hz,1H),7.55–7.47(m,1H),4.66(t,J=6. 0Hz, 2H), 3.03 (t, J = 6.0Hz, 2H), 2.83–2.75 (m, 4H), 2.59 (s, 3H), 1.89 (p, J = 5.6Hz, 4H), 1.71 (p, J = 6.1Hz, 2H). LC-Ms: 347.2.

[0083] Following standard procedures, the obtained (E)-1-(pyridin-2-yl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with piperidine to give compound C27. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. Its 1H NMR and mass spectrometry results are as follows: 1 H NMR (300MHz, CDCl3) δ8.58(d,J=5.0Hz,1H),7.88(d,J=8.0Hz,1H),7.66(t,J=7.7Hz,1H),7.28–7.19(m,1H),4.28(t, J=6.1Hz,2H),2.80–2.64(m,6H),2.31(s,3H),2.24–2.08(m,2H),1.89–1.75(m,4H),1.62–1.47(m,2H).LC-Ms:361.2.

[0084] The obtained (E)-1-(pyridin-4-yl)ethyl-1-one O-(2-bromoethyl)oxime was reacted with piperidine according to the general procedure to give compound C28. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. Its 1H NMR and mass spectrometry results are as follows: 1 H NMR (300MHz, CDCl3) δ8.55(d,J=4.8Hz,2H),7.47(d,J=5.1Hz,2H),4.32(t,J=4.6Hz,2H),2.75–2.58( m,2H),2.48–2.37(t,J=5.4Hz,4H),2.15(s,3H),1.59–1.48(m,2H),1.43–1.33(m,4H).LC-Ms:347.2.

[0085] The obtained (E)-1-(pyridin-3-yl)ethyl-1-one O-(2-bromoethyl)oxime was reacted with piperidine according to the general procedure to give compound C29. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. Its 1H NMR and mass spectrometry results are as follows: 1 H NMR (300MHz, CDCl3) δ8.86(s,1H),8.58(d,J=4.5Hz,2H),7.95(d,J=7.6Hz,2H),7.40–7.25(m,1H),4.36(t,J=6.1H z,2H),2.72(t,J=6.1Hz,2H),2.59–2.44(m,4H),2.24(s,3H),1.66–1.55(m,4H),1.46–1.36(m,2H).LC-Ms:347.2.

[0086] The obtained (E)-1-(pyrimidin-4-yl)ethyl-1-one O-(2-bromoethyl)oxime was reacted with piperidine according to the general procedure to give compound C30. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. Its 1H NMR and mass spectrometry results are as follows: 1 H NMR (300MHz, CDCl3) δ9.16 (s, 1H), 8.63 (d, J = 5.3Hz, 1H), 7.82 (d, J = 5.6Hz, 1H), 4.39 (t, J = 6.0Hz, 2H), 2. 72(t,J=6.0Hz,2H),2.62–2.40(m,4H),2.25(s,3H),1.68–1.53(m,4H),1.50–1.34(m,2H).LC-Ms:348.2.

[0087] Following standard procedures, the obtained (E)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl-1-one O-(2-bromoethyl)oxime was reacted with piperidine to give compound C31. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. The 1H NMR and mass spectrometry results are as follows: 1 H NMR (300MHz, CDCl3) δ8.96(s,1H),8.11(d,J=7.7Hz,1H),7.66(d,J=8.2Hz,1H),4.39(t,J=6.0Hz,2H),2.74(t ,J=6.0Hz,2H),2.50(t,J=5.3Hz,4H),2.25(s,3H),1.61(p,J=5.5Hz,4H),1.43(p,J=5.7Hz,2H).LC-Ms:315.2.

[0088] Following standard procedures, the obtained (E)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with piperidine to give compound C32. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. The 1H NMR and mass spectrometry results are as follows: 1 H NMR (300MHz, CDCl3) δ8.94 (s, 1H), 8.09 (d, J = 8.4Hz, 1H), 7.63 (d, J = 8.2Hz, 1H), 4.25 (t, J = 6.4Hz, 2H), 2.58–2.34(m,6H),2.22(s,3H),2.04–1.83(m,2H),1.72–1.51(m,4H),1.49–1.36(m,2H).LC-Ms:329.2.

[0089] Following standard procedures, the obtained (E)-1-(5-(trifluoromethyl)pyridin-2-yl)ethyl-1-one O-(2-bromoethyl)oxime was reacted with piperidine to give compound C33. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. Its 1H NMR and mass spectrometry results are as follows: 1 H NMR (600MHz, CDCl3) δ8.82–8.79(m,1H),8.02(d,J=8.5Hz,1H),7.86–7.81(m,1H),4.41(t,J=6.0Hz,2H),2.77 (t,J=6.0Hz,2H),2.60–2.47(m,4H),2.30(s,3H),1.61(p,J=5.6Hz,4H),1.43(p,J=6.0Hz,2H).LC-Ms:315.2.

[0090] Following standard procedures, the obtained (E)-1-(5-(trifluoromethyl)pyridin-2-yl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with piperidine to give compound C34. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. Its 1H NMR and mass spectrometry results are as follows: 1 H NMR (300MHz, DMSO-d6) δ8.83(s,1H),8.04(d,J=7.6Hz,1H),7.86(d,J=7.4Hz,1H),4.29(t,J=6.1Hz,2H),2.50 (q,J=7.2,5.5Hz,9H),2.31(s,3H),2.01(p,J=6.5Hz,3H),1.74–1.57(m,5H),1.54–1.40(m,3H).LC-Ms:329.2.

[0091] The obtained (E)-1-(quinolin-6-yl)ethyl-1-one O-(3-chloropropyl)oxime was reacted with piperidine according to the general procedure to give compound C35. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. Its 1H NMR and mass spectrometry results are as follows: 1H NMR (300MHz, CDCl3) δ8.91(d,J=4.3Hz,1H),8.19(d,J=8.3Hz,1H),8.09(q,J=8.9Hz,2H),7.99(s,1H),7.42(dd,J=8.4,4.3Hz ,1H),4.31(t,J=6.0Hz,2H),2.97–2.83(m,6H),2.34(s,3H),2.33–2.18(m,2H),1.99–1.85(m,4H),1.60(s,2H).LC-Ms:311.2.

[0092] The obtained (E)-1-(quinolin-6-yl)ethyl-1-one O-(2-bromoethyl)oxime was reacted with piperidine according to the general procedure to give compound C36. Silica gel column chromatography using eluent (PE:EA = 3:1) yielded a colorless oil in 70% yield. Its 1H NMR and mass spectrometry results are as follows: 1 H NMR (400MHz, CDCl3) δ8.88(dd,J=4.3,1.7Hz,1H),8.19–8.11(m,1H),8.10(dd,J=8.9,2.0Hz,1H),8.03(d,J=8.9Hz,1H),7.95(d,J=2.0Hz,1H),7.39(dd, J=8.3,4.3Hz,1H),4.56(t,J=5.4Hz,2H),3.05(t,J=5.4Hz,2H),2.87–2.77( m,4H),2.31(s,3H),1.80(p,J=5.4Hz,4H),1.56–1.45(m,2H).LC-Ms:297.2.

[0093] The chemical structural formulas of the above products are shown in Table 1. The left part is the raw material ketone, which can be obtained by replacing C=N with C=O.

[0094] Example 2

[0095] The bioactivity of the compounds prepared above was tested using the following methods:

[0096] The protein was diluted to 200 mg / mL using Kreb's solution. 3 H(+)-pentazocine. The reaction system consists of 100 μL of membrane protein and 20 μL of... 3The mixture consisted of H(+)-pentazocine, 20 μL of the test drug, and 60 μL of Kreb's solution. After incubation at 30 °C for 150 min, the free radioligand and the receptor-bound radioligand were separated by filtration. The activity of the receptor-bound isotope was detected using a liquid scintillation analyzer. Non-specific binding activity was determined using 10 μM BD1047. Specific binding activity without the addition of the test compound was defined as 100%.

[0097] As shown in Table 1, at a concentration of 10 μM, if the inhibition rate of a compound on the binding of the radioligand to the Sigma-1 receptor is less than 50%, the compound is considered to have no affinity for the Sigma-1 receptor. For compounds with an inhibition rate higher than 85%, further testing was conducted at a concentration of 1 μM to determine the inhibition rate of the compound on the binding of the radioligand to the Sigma-1 receptor and the K0. i The results showed that both substituents (R3 and R4) and the length of the intermediate carbon chain (n) affected the affinity of the compounds for sigma-1. Compounds C1, C3, C4, C6, C12, C13, C17, C20, C27, C28, C31, and C35 exhibited strong affinity for the sigma-1 receptor, with Ki values ​​below 30 nM. Compounds C2, C9, C11, C23, C24, C25, C26, C29, C30, C32, C33, and C36 also showed relatively strong affinity for the sigma-1 receptor, with Ki values ​​ranging from 30 to 90 nM.

[0098] Compounds with high affinity for the Sigma-1 receptor were selected for Sigma-2 receptor binding experiments, and the procedure was similar to that for the Sigma-1 receptor: the Sigma-2 receptor ligand was labeled with... 3 H-DTG. 10 μM BD1047 was added to the reaction system to block the binding activity of Sigma-1. Non-specific binding activity was determined using 10 μM haloperidol. Specific binding activity without the addition of the test compound was defined as 100%. If, at a concentration of 10 μM, the compound exhibited an inhibition rate of more than 75% against the binding of the radioligand to the Sigma-2 receptor, it was considered to have low affinity for the Sigma-2 receptor. The results are shown in Table 2; all compounds demonstrated superior Sigma-2 receptor selectivity.

[0099] Replacing the benzene rings of the compounds in Table 1 with heterocycles revealed that the compounds also exhibited high sigma-1 acceptor affinity and selectivity.

[0100] Table 1. Results of Sigma-1 receptor affinity tests for different compounds.

[0101] Table 2. Results of Sigma-1 receptor affinity tests for different compounds.

[0102] Example 3: Functional determination of sigma-1 receptor small molecule ligands

[0103] The sigma-1 receptor allosteric modulator phenytoin can differentially modulate the affinity of sigma-1 ligands. The aforementioned radiolabeled receptor affinity assay will be used to determine the function of the compound, i.e., whether it is a sigma-1 receptor agonist or antagonist. Typically, phenytoin (250 μM) enhances the receptor binding affinity of sigma-1 agonists, i.e., phenytoin-free K... i / K containing phenytoin (σ1Rratios) i A value >1 indicates a sigma-1 receptor agonist; while phenytoin (250 μM) has no effect on or slightly reduces the receptor binding affinity of sigma-1 antagonists, i.e., K+ without phenytoin. i K containing phenytoin i A σ1R ratio ≤ 1 indicates a sigma-1 receptor antagonist. As shown in Table 3, C9, C6, C12, C17, and C27 have σ1R ratios ≥ 1.77, suggesting they may be sigma-1 receptor agonists with potential therapeutic effects on Alzheimer's disease, schizophrenia, depression, anxiety, Parkinson's disease, drug addiction, motor disorders caused by anti-Parkinson's / schizophrenia drugs, and cognitive impairment caused by neuropsychiatric diseases, and also have nootropic effects. On the other hand, C30 has a σ1R ratio of 0.99, suggesting it may be a sigma-1 receptor antagonist and a potential analgesic. However, the mean values ​​of the σ1R ratios for C2, C25, C28, C29, C31, C35, and C36 are between 1 and 1.37, and the SEM values ​​are between 0.04 and 0.22, suggesting these compounds may be either agonists or antagonists, thus requiring further experimental confirmation.

[0104] Table 3 Functional determination of sigma-1 receptor small molecule ligands

[0105] Example 4: Determination of the effect of the compound on the binding of σ1R to BiP

[0106] A rapid and sensitive NanoBiT assay for detecting the interaction between σ1R and Bip was used to verify the functional activity of the compound for σ1R. The specific procedure was as follows: HEK-293-σ1RLgBiT-BIPSmBiT cells were sputtered at 100,000 cells / cm². 2Cells were seeded at a density in white 96-well plates (Corning, flat-bottomed microplates used for cell culture). The specified concentration of the test compound was added before (16-hour treatment) or after (10-minute treatment) the addition of 10 μL of 10 μM amylopectin 400a solution (NanoLight Technologies, Pinetop, AZ, USA) to each well. After 1 minute incubation, the fluorescence intensity was measured using a BioTek microplate reader and recorded as integrated relative fluorescence units (RLU). RFP fluorescence expressed in HEK-293 cells served as an internal control.

[0107] The test results are shown in Figure 1A. After 10 minutes of treatment, compounds C27, C28, and C29, containing two carbon chains and unsubstituted pyridine, are similar to σ1R agonist B1, containing three carbon chains and 4-trifluoromethylphenyl, as described in patent CN111848549B. The interaction between σ1R-LgBiT and BiP-SmBiT is weakened, resulting in a decrease in relative fluorescence intensity, indicating that compounds C27, C28, and C29 are also agonists. However, as shown in Figure 1B, after 16 hours of treatment, compound C31, containing only two carbon chains and 6-trifluoromethylpyridine, is similar to the well-known σ1R antagonist BD1047, enhancing this interaction and resulting in an increase in relative fluorescence intensity, indicating that compound C31 is an antagonist. These results suggest that changes in carbon chain length n, the type of Ar ring, and the substituent R1 all have a significant impact on the function of σ1R. In other words, it is impossible to predict the impact of changes in compound structure (even minor changes) on its functional activity based on existing literature data, and thus it is impossible to predict its potential clinical applications.

[0108] Example 5: Determination of hERG potassium ion channel inhibition rate

[0109] The inhibitory effect of compound S4 on hERG potassium channels was detected using a fully automated electrophysiological patch-clamp QPatch assay. The specific procedures were as follows: The cells used in this experiment were CHO cell lines (provided by Sophion Bioscience) transfected with hERG cDNA and stably expressing hERG channels, at passage number P30. After achieving a fully thawed, whole-cell configuration at the initial stage, cells were recorded for 120 seconds to reach stability. Then, throughout the process, cells were clamped at -80 mV. The cell clamping voltage was depolarized to +20 mV to activate hERG potassium channels, and then clamped again to -50 mV after 2.5 seconds to eliminate inactivation and generate an outward tail current. This voltage pattern was applied to the cells every 15 seconds. Only stable cells were allowed to proceed with the drug treatment process during the above parameter threshold recording. An extracellular solution containing 0.1% dimethyl sulfoxide (solvent) was applied to the cells to establish a baseline, and the current was allowed to stabilize for another 3 minutes. After compound addition, cells were held in the test environment until the effect of the compound reached a stable state or was limited to 4 minutes. In the compound concentration gradient tests, the compound was added to the clamped cells at increasingly higher concentrations. After each compound test, the cells were washed with an external solution until the current returned to a stable state. A positive control (cisapride) was used to ensure normal cell response and reliable cell quality. Unless otherwise specified, all experiments were conducted at normal room temperature (~25°C). Experimental data were analyzed using Qpatch analysis software and Excel provided by Sophion.

[0110] Test results show that, compared with the representative compound B1 in the aryl oxime compounds and their preparation and application patent CN111848549B filed in 2019, the compound of this invention has a lower hERG potassium ion channel inhibition effect, IC50... 50 The values ​​ranged from 2.10 to 21.59 μM, indicating a low risk of cardiotoxicity and good cardiac safety.

[0111] Example 6: Compound Recognition Experiment

[0112] Studies have found that sigma-1 agonists are beneficial in the treatment of neurodegenerative diseases (such as Alzheimer's disease, stroke, Parkinson's disease, and bulbar palsy), epilepsy, and depression. Therefore, we used a novel object recognition (NOR) experiment to evaluate the potential application of the sigma-1 receptor agonist C17 in Alzheimer's disease.

[0113] The novel object recognition experiment is an experimental method that evaluates the cognitive memory level of experimental animals by measuring the time they spend exploring old (previously encountered) objects and new (never encountered) objects. Specifically: Mice are placed in an empty experimental device at the same location and allowed to move freely for 10 minutes; no video is recorded during this phase. Two identical objects, A and B, are placed symmetrically, approximately 10 cm from the four walls, ensuring sufficient exploration space for the animals. Exploration is defined as the mouse touching the object with its mouth or nose or coming within approximately 2-3 cm of the object; video is recorded for 10 minutes, and the exploration time for the two objects during this phase is recorded. In the next phase, no video is recorded; the mice are isolated using a book or a special isolation device to forget the recently experienced event for 5 minutes. One of the objects is replaced with an object of completely different shape and color. The mice are placed in the same location and allowed to move freely for 10 minutes; the exploration time for the new and old objects during this phase is recorded. The exploration time of new objects and old objects during the statistical test period is called exploration time. The preference ratio is calculated as (exploration time of new objects - exploration time of old objects) / (exploration time of new objects + exploration time of old objects), which is (NF) / (N+F).

[0114] As shown in Figure 2, to investigate the effects of the Sigma-1 receptor agonist C17 on the cognitive function and spatial memory of normal mice, a novel object recognition experiment was conducted at doses of 3 mg / kg and 10 mg / kg. In the novel object recognition experiment: during the familiarization phase (Figure 2A), there was no difference in the exploration time for two identical objects, indicating that the mice did not exhibit positional preference. During the testing phase, there was a significant difference in the exploration time for both new and old objects, as shown in Figure 2B, indicating that the cognitive abilities of the mice in each group were normal, manifested by spending more time exploring new objects. In the memory index (Figure 2B) and (Figure 2C), both treatment groups (3 mg / kg and 10 mg / kg) showed significantly higher scores than the control group (P < 0.0001 vs. VEH group). These results indicate that both 3 mg / kg and 10 mg / kg of C17 can improve the cognitive abilities of mice, suggesting its potential in combating Alzheimer's disease.

[0115] Example 7: Compound Acetic Acid Writhing Analgesia Experiment

[0116] Studies have found that sigma-1 antagonists are beneficial in relieving pain and drug addiction (such as alcohol and methamphetamine). The acetic acid writhing test is an economical, rapid, and reproducible primary screening model for analgesic activity, so we used this model to evaluate the therapeutic potential of the sigma-1 receptor antagonist C31 for pain.

[0117] The specific experimental procedure was as follows: Five minutes after intraperitoneal injection of C31, a 0.6% acetic acid solution (0.1 mL / 10 g) was injected into the peritoneum of each mouse. After injection, the mice's writhing response was closely observed and recorded, and the number of writhing responses within 25 minutes was recorded.

[0118] As shown in Figure 3, the Sigma-1 receptor antagonist C31 significantly reduced the number of acetic acid-induced writhing movements in mice at doses of 0.01-0.3 mg / kg, thus C31 has an analgesic effect.

[0119] In summary, the vast majority of compounds exhibited moderate to high activity towards Sigma-1 receptors and low activity towards Sigma-2 receptors. In particular, compounds C17 and C31 showed high affinity for Sigma-1 receptors and almost no activity towards Sigma-2 receptors, and demonstrated therapeutic effects in improving cognition or relieving pain in animal studies. This indicates that the present invention provides a class of novel and highly selective Sigma-1 receptor ligands. These oxime compounds will be of great significance for treating diseases of the central nervous system, such as Alzheimer's disease, schizophrenia, depression, anxiety disorders, Parkinson's disease, pain, drug addiction, motor disorders caused by anti-Parkinson's / schizophrenia drugs, and cognitive impairment caused by neuropsychiatric diseases.

[0120] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the technical principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. An oxime compound, or a pharmaceutically acceptable salt, ester, or hydrate of said oxime compound, characterized in that, The general chemical structural formula of the oxime compounds is as follows: Wherein, R1 is selected from one or more of halogenated alkyl, halogenated acyl, alkoxy or halogen; R2 is selected from alkyl, or forms a ring with Ar; Ar is selected from benzene ring or aromatic heterocycle; n is selected from 1 to 5; m and p are selected from 0 to 6; R3 and R4 are independently selected from one of hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, methanesulfonyl, alkoxyalkyl, hydroxy, hydroxyalkyl, deuterium, or both of them form a 3 to 8 membered ring with the C atom attached to them.

2. The oxime compound according to claim 1, characterized in that, R1 is selected from one or more of trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethanesulfonyl, alkoxy or halogen, with 1 to 3 substitutions; R2 is selected from methyl, or forms a 4 to 8-membered ring with Ar; n is selected from any integer from 1 to 3; m and p are selected from any integer from 0 to 4.

3. The oxime compound according to claim 2, characterized in that, n = 1 or 2, m = p = 2.

4. The oxime compound according to claim 3, characterized in that, When m = p = 2 and Ar is a benzene ring, R3 and R4 are not both H.

5. The oxime compound according to claim 1, characterized in that, Excerpt Selected from:

6. The oxime compound according to claim 1, characterized in that, Excerpt Selected from:

7. The oxime compound according to claim 1, characterized in that, The oxime compounds are selected from any of the following compounds:

8. A method for preparing the oxime compound of claim 1, comprising the following steps: Oxime compounds were prepared by reaction using chlorides and amines as raw materials; The general chemical structural formula of chlorides is as follows: The general chemical structural formula of amines is as follows:

9. The method for preparing the oxime compound according to claim 8, characterized in that, The reaction is carried out in the presence of an inorganic base and an organic solvent; the reaction temperature is 70–100 °C and the reaction time is 1–3 hours.

10. The method for preparing the oxime compound according to claim 8, characterized in that, The molar ratio of chloride to amine is 1:(1-3).

11. A pharmaceutical composition wherein the active ingredient is the oxime compound of claim 1, or a pharmaceutically acceptable salt, ester, or hydrate thereof.

12. The use of the oxime compound of claim 1, its pharmaceutically acceptable salt, ester or hydrate, in the preparation of a medicament.

13. The use of the oxime compound of claim 1, its pharmaceutically acceptable salt, ester or hydrate, in the preparation of Sigma-1 related disease medicaments.

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