Application of o-piperidinyl cyclohexylamine ester compound in preparation of anti-tumor metastasis drugs

Abstract

The invention belongs to the technical field of medicines, and relates to application of o-piperidinyl cyclohexylamine ester compounds in preparation of anti-tumor metastasis medicines. The invention specifically relates to application of o-piperidinyl cyclohexylamine ester compounds or pharmaceutically acceptable salts thereof as PI3K gamma kinase selective inhibitors in preparation of drugs for inhibiting tumor metastasis. The o-piperidinyl cyclohexylamine ester compound or the pharmaceutically acceptable salt of the o-piperidinyl cyclohexylamine ester compound inhibits polarization of M2 type TAMs by targeting PI3K gamma kinase in the M2 type TAMs so as to inhibit migration and invasion of breast cancer cells mediated by the M2 type TAMs, and the o-piperidinyl cyclohexylamine ester compound or the pharmaceutically acceptable salt of the o-piperidinyl cyclohexylamine ester compound plays a role in resisting tumor metastasis by increasing the proportion of CD8 < + > cytotoxic T lymphocytes. The o-piperidinyl cyclohexylamine ester compound or a pharmaceutically acceptable structure thereof is shown in the specification, wherein R1 is shown in the claims and the specification.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to the application of o-piperidine cyclohexylamine esters in the preparation of anti-tumor metastasis drugs. Specifically, it relates to the application of o-piperidine cyclohexylamine esters as selective inhibitors of PI3Kγ kinase in the preparation of anti-tumor metastasis drugs. Background Technology

[0002] Cancer has become a major challenge in the global public health field. Data from the World Health Organization shows that the annual incidence of malignant tumors continues to rise, and traditional treatment models face significant limitations: surgical treatment is invasive and has limited applicability; although chemotherapy and radiotherapy are widely used, they are accompanied by serious adverse reactions such as bone marrow suppression and organ toxicity, and it is difficult to overcome the problems of tumor recurrence and metastasis.

[0003] Tumor metastasis involves several steps, including tumor cell shedding, spread through the lymphatic system or blood circulation, invasion of blood vessels / tissues, and the establishment of new lesions. Anti-tumor metastasis treatment refers to preventing or inhibiting the spread (metastasis) of existing tumor cells from the primary site to other parts of the body, such as the lungs, liver, bones, and brain, to form new metastatic lesions.

[0004] Immunotherapy holds immense potential—by activating or enhancing the patient's own immune system's ability to specifically recognize and eliminate tumor cells, it represents a shift in treatment philosophy from "directly killing tumors" to "rebooting immune surveillance." This innovative therapy boasts two core advantages: first, it significantly reduces systemic toxicity caused by traditional treatments, improving patients' quality of life; second, it forms long-term protection through immune memory effects, effectively controlling tumor recurrence and metastasis. With a deepening understanding of the tumor immune microenvironment, immunotherapy is evolving from single-therapy approaches to combination strategies, providing a new pathway to overcome existing treatment bottlenecks.

[0005] Phosphatidylinositol 3-kinases (PI3Ks) are a class of lipid phosphokinases that play a crucial role in numerous physiological processes such as cell proliferation, migration, and angiogenesis. Among the PI3K family, class I PI3Ks are the most extensively studied. Based on different catalytic subunits, class I PI3Ks are divided into four subtypes: PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ, each with different distributions and functions in vivo. PI3Kα and PI3Kβ subtypes are widely expressed in tissue cells, while PI3Kγ and PI3Kδ are mainly found in hematopoietic cells and immune cells. PI3Kγ is the only class IB subtype in the PI3K kinase family; it is highly expressed in bone marrow-derived immune cells (such as neutrophils and macrophages) but lowly expressed in most solid tumor cells.

[0006] Tumor metastasis is the result of the interaction between tumor cells and immune cells in the tumor microenvironment. High-density infiltration of tumor-associated macrophages (TAMs) in the tumor microenvironment is closely related to tumor metastasis and resistance to immune checkpoint inhibitors.

[0007] There are no existing reports on the use of o-piperidine cyclohexylamine esters in the treatment of tumor metastasis. Summary of the Invention

[0008] In order to overcome the shortcomings of the prior art, the first objective of the present invention is to provide the use of o-piperidine cyclohexylamine esters or salts thereof in the preparation of antitumor metastasis drugs.

[0009] The tumors mentioned are any one or more of the following: breast cancer, cervical cancer, ovarian cancer, lung cancer, leukemia, malignant lymphoma, multiple myeloma, thyroid cancer, nasopharyngeal carcinoma, meningeal carcinoma, pituitary adenoma, oral cancer, craniopharyngioma, thalamic and brainstem tumors, vascular tumors, intracranial metastases, liver cancer, gastric cancer, esophageal cancer, colorectal cancer, rectal cancer, colon cancer, pancreatic cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, bone cancer, malignant melanoma, glioma, and skin cancer.

[0010] Preferably, the tumor is breast cancer; Furthermore, the tumor metastasis mentioned is lung metastasis of breast cancer.

[0011] A second objective of this invention is to provide the use of ortho-piperidine cyclohexylamine esters or their salts in the preparation of PI3Kγ inhibitors.

[0012] A third objective of this invention is to provide the use of ortho-piperidine cyclohexylamine esters or salts thereof in the preparation of medicaments for the prevention or treatment of diseases related to abnormal activation of PI3Kγ, such as immune-related diseases.

[0013] Furthermore, the aforementioned o-piperidine cyclohexylamine ester compounds or their salts exert their anti-tumor metastasis effect by inhibiting PI3Kγ kinase activity.

[0014] The aforementioned piperocyclohexylamine ester compounds or their salts inhibit M2-type TAMs polarization by targeting PI3Kγ kinase in M2-type TAMs, thereby inhibiting M2-type TAMs-mediated breast cancer cell migration and invasion, and ultimately exerting an anti-tumor metastasis effect.

[0015] The aforementioned o-piperidine cyclohexylamine esters or their salts increase CD8 + The proportion of cytotoxic T lymphocytes plays a role in preventing tumor metastasis.

[0016] The aforementioned piperonylcyclohexylamine esters or their salts inhibit the infiltration of M2 type TAMs in lung tissue and increase CD8 levels. + The increased T-cell ratio activates the immune response, thereby exerting an anti-breast cancer lung metastasis effect.

[0017] The aforementioned o-piperidine cyclohexylamine ester compounds or their salts have the structure of Formula I:

[0018] Wherein, R1 is H, C1-C6 alkyl, or C1-C6 alkoxy, preferably H, C1-C4 alkyl, or C1-C4 alkoxy.

[0019] Furthermore, the o-piperidine cyclohexylamine ester compound or its salt may be one or two of the following compounds;

[0020] Preferred options are:

[0021] The o-piperidine cyclohexylamine ester compounds or their salts of the present invention can selectively inhibit the kinase activity of PI3Kγ. The IC50 of CDF-06 on the inhibitory activity of PI3Kγ kinase is... 50 The value is 0.84 µM.

[0022] CDF-06 can also inhibit lung metastasis of breast cancer by inhibiting PI3Kγ kinase.

[0023] The aforementioned o-piperidine cyclohexylamine ester compounds or their salts can be prepared into pharmaceutical compositions with pharmaceutically acceptable carriers or excipients.

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention is the first to discover that o-piperidine cyclohexylamine esters or their salts, especially CDF-06 or its salts, or pharmaceutical compositions containing them, exhibit significant anti-tumor metastasis effects at low doses (2.5-10 mg / kg), and can be used to prepare drugs for the treatment of tumor metastasis. The aforementioned compounds or compositions can also effectively inhibit the kinase activity of PI3Kγ (IC50). 50 =0.84µM), while it has no inhibitory activity against the other three isoforms of PI3K (PI3Kα, PI3Kβ and PI3Kδ) (IC50). 50 (>1000 µM), which can be used to prepare PI3Kγ kinase inhibitors.

[0025] Cellular experiments demonstrated that CDF-06 significantly inhibited M2-type TAMs-mediated breast cancer cell migration and invasion. Animal experiments showed that oral administration of CDF-06 did not inhibit tumor growth, but it effectively inhibited lung metastasis of breast cancer in mice; its mechanism may be related to inhibiting PI3Kγ kinase activity, thereby inhibiting M2-type TAM polarization in lung tissue and increasing CD8+. + It is related to the proportion of cytotoxic T lymphocytes. Attached Figure Description

[0026] Figure 1 This refers to the effect of CDF-06 on the growth of breast cancer in mice in Example 2.

[0027] Figure 2 This is the effect of CDF-06 on lung metastasis of breast cancer in mice in Example 2.

[0028] Figure 3 The effect of CDF-06 on mouse body weight and organ index in Example 2.

[0029] Figure 4 This is the effect of CDF-06 on the polarization of M2 type TAMs in mouse lung tissue in Example 2.

[0030] Figure 5 The CDF-06 cytotoxic T lymphocytes (CD86) in mouse lung tissue, as shown in Example 2. + The influence of the proportion.

[0031] Figure 6 This is the effect of CDF-06 on the migration ability of M2-type TAMs-mediated mouse breast cancer cells in Example 3.

[0032] Figure 7 This is the effect of CDF-06 on the downstream pathway of the PI3Kγ pathway in M2 type TAMs in Example 5. Detailed Implementation

[0033] The following description, in conjunction with the accompanying drawings, uses embodiments of the present invention to further illustrate the substantive content of the invention, but does not limit the invention thereto.

[0034] The preparation of the o-piperidine cyclohexylamine ester compounds or their salts described in this invention is based on Chinese Patent CN115677714A.

[0035] Example 1: Preparation of CDF-06: CDF-06 was prepared according to the method in Example 6 of Chinese Patent CN115677714A.

[0036]

[0037] 1H NMR (600 MHz, CDCl3) δ (ppm) 7.30 – 7.23 (m, 4H), 7.23 – 7.17 (m,7H), 7.16 – 7.10 (m, 5H), 6.95 (d, J = 6.7 Hz, 2H), 6.40 (d, J = 41.9 Hz, 2H), 5.86 (s, 2H), 4.56 (d, J = 11.7 Hz, 1H), 4.44 (d, J = 11.7 Hz, 2H), 4.39 – 4.32(m, 2H), 4.27 – 4.18 (m, 1H), 4.09 (d, J = 11.7 Hz, 1H), 3.98 – 3.90 (m, 3H), 3.83 (s, 1H), 3.71 (s, 1H), 3.66 (s, 3H), 3.50 (s, 1H), 2.88 (d, J = 11.3 Hz, 1H), 2.75 (d, J = 7.9 Hz, 1H), 1.62 (s, 1H), 1.06 (s, 3H). HRMS (ESI) (m / z): [M+Na] + calcd for C 37 H 39 NO8Na + 648.2573, found648.2568.

[0038] Example 2: Effects of CDF-06 on breast cancer growth and lung metastasis in mice 1. Experimental Methods: Mouse breast cancer 4T1 cells were used, and the cell concentration was adjusted to 1×10⁻⁶. 7Cells were inoculated at a rate of 100 μL / mL into the fourth pair of mammary pads of mice, with each mouse receiving 100 μL of cells. Experimental groups included a solvent control group (2% DMSO, 15% PEG400, 5% Tween 80, and 78% PBS), CDF-06 2.5 mg / kg, CDF-06 5 mg / kg, CDF-06 10 mg / kg, and a positive control group (Eganelisib (IPI549)). Eight mice were used in each group. Mice in each group were administered the solvent, CDF-06 (2.5, 5, 10 mg / kg), and IPI549 (10 mg / kg) daily via gavage, respectively. Four weeks later, mice were euthanized by cervical dislocation, and 15% Indian ink was instilled into the lungs via trachea. After staining and fixation, the number of metastatic nodules in the lungs was observed. The spleen, liver, and kidneys were immediately removed, weighed, fixed, and their organ indices were calculated. Spleen index (mg / g) = spleen weight (mg) / tumor-free mouse body weight (g); Liver / kidney index (mg / g) = liver and kidney weight (mg) / tumor-free mouse body weight (g). Additionally, flow cytometry was used to detect CD8 infiltrating lung tissue. + The proportion of T cells and M2 type TAMs.

[0039] 2. Experimental Results: 2.1 At the end of the experiment, the tumor was photographed and weighed. The tumor weighing results showed that CDF-06 had no inhibitory effect on tumor growth. Figure 1 Lung ink staining results showed that the solvent control group mice had significant lung metastases, with the highest number of metastatic nodules in the lungs. The CDF-06 administration group mice showed a significant reduction in the number of lung metastatic nodules in a dose-dependent manner. Figure 2 The inhibition rates of lung metastasis in the CDF-06 administration groups of 2.5 mg / kg, 5 mg / kg and 10 mg / kg were 64.49%, 81.16% and 91.30%, respectively. These results indicate that CDF-06 can effectively inhibit lung metastasis of 4T1 breast cancer in mice.

[0040] 2.2 During the drug administration period, the body weight of mice in each group was measured every three days. At the end of the experiment, the spleen, liver, and kidneys of mice in each group were removed, weighed, and fixed, and the spleen index, liver index, and kidney index were calculated. The results showed that there was no significant difference in body weight between the groups and the solvent control group, and the spleen index, liver index, and kidney index of each group did not change significantly, with no statistically significant differences. Figure 3 The results indicate that CDF-06 had no effect on mouse body weight or organ index, and the safety profile at this dose was good.

[0041] 2.3 Mechanism study results showed that the proportion of M2-type TAMs in the lung tissue of the solvent control group was the highest (66%), and gradually decreased after CDF-06 administration. The proportions of M2-type TAMs in the CDF-06 2.5 mg / kg group, CDF-06 5 mg / kg group, and CDF-06 10 mg / kg group were 51.23%, 50.07%, and 28.33%, respectively. Figure 4 The proportion of M2 type TAMs in the positive drug IPI549 group was 56.60%. Figure 4 The inhibition rate results showed that the inhibition rates of CDF-06 2.5 mg / kg group, CDF-06 5 mg / kg group, and CDF-06 10 mg / kg group against M2 TAM polarization were 22.38%, 24.14%, and 57.07%, respectively; the inhibition rate of the positive control drug IPI549 was 14.24%, indicating that CDF-06 was more effective than IPI549 in inhibiting M2 TAM polarization.

[0042] At the same time, CD8 is labeled with CD8α. + T cell infiltration levels, experimental results showed that CD8+ in lung tissue of the solvent control group... + The proportion of T cells was 24.07%, and CD8 cell count was significantly increased after CDF-06 administration. + The proportion of T cells, CDF-06 2.5mg / kg group, CDF-06 5mg / kg group, CDF-06 10mg / kg group CD8 + The proportions of T cells were 27.67%, 28.80%, and 47.87%, respectively. The CD8+ level in the positive drug IPI549 group was... + The proportion of T cells was 29.53%. Figure 5 This indicates that CDF-06 adds CD8. + The T-cell infiltration effect is superior to that of IPI549.

[0043] The above results indicate that CDF-06 may inhibit the infiltration of M2 type TAMs in lung tissue and increase CD8+ in vivo. + The increased T-cell ratio activates the immune response, ultimately inhibiting breast cancer metastasis.

[0044] Example 3: Effect of CDF-06 on the migration ability of M2-type TAMs-mediated mouse breast cancer cells 1. Experimental Methods: Primary mouse bone marrow-derived macrophages (BMDM) in logarithmic growth phase and in good condition were induced with IL-4 (20 ng / mL) and IL-13 (20 ng / mL) for 72 h to polarize into M2 type TAMs.

[0045] The following groups were set up: negative control group (DMSO), IL-4 and IL-13 stimulation group, CDF-06 administration group (2.5 μM, 5 μM, 10 μM), and positive control group (IPI549 1 μM). After the cells were treated with the compound, they were cultured for another 24 h. The cell supernatant of each group was collected and filtered through a 0.22 μM filter membrane as conditioned medium.

[0046] 5 × 10⁶ mouse breast cancer 4T1 cells in logarithmic growth phase and good condition were collected per well. 5 Cells were evenly seeded in six-well plates and cultured overnight to allow them to adhere. A negative control group, a drug-treated group, and a positive control group were established, each receiving their respective conditioned medium and cultured continuously. When the cell density reached 95%, the original medium was discarded, and the cells were rinsed with PBS. A 10 μL pipette tip was used to streak the cells vertically into the wells. Cell debris was washed away with pre-cooled PBS. The control group received drug-free medium. The drug-treated groups received different concentrations of CDF-06 (2.5 μM, 5 μM, 10 μM), and the positive control group received 1 μM IPI549. Cells were cultured continuously. Images were taken under a microscope at the same location at 0 and 24 h. ImageJ software was used to calculate the scratch healing area and the healing rate and inhibition rate for each group.

[0047] 2. Experimental Results: The 24-hour cell migration rate in the negative control group was 26.43%. M2-type TAMs supernatant stimulated with IL-4 / 13 induced significant migration of breast cancer 4T1 cells, with a migration rate of 39.52%, demonstrating that M2-type TAMs promoted tumor cell migration. In the CDF-06 treatment groups, cell migration was significantly inhibited with increasing CDF-06 concentration. The cell migration rates in the 2.5 μM, 5 μM, and 10 μM CDF-06 treatment groups were 25.88%, 16.68%, and 9.39%, respectively. Figure 6 The inhibition rates were 34.53%, 57.79%, and 76.25%, respectively. These data indicate that CDF-06 significantly inhibits M2-type TAMs-mediated migration of mouse breast cancer cells.

[0048] Example 4: Inhibitory activity of CDF-06 against various PI3K kinase isoforms 1. Enzymes and kits: PI3Kα (p110α / p85α), PI3Kβ (p110β / p85α), PI3Kγ (p120γ), and PI3Kδ (p110δ / p85α) were all type I PI3K and were purchased from Promega; the PI3K activity assay kit was purchased from Echelon.

[0049] 2. Experimental Methods: The effect of CDF-06 on the activity of four PI3K isoform kinases was detected using a PI3K activity assay kit, following the kit's instructions. The specific method is as follows: A. Different concentrations of CDF-06 (0, 0.064, 0.32, 1.6, 8, 40, 200, 1000 μM) were incubated with each kinase (1.5 μg / ml) at room temperature for 15 minutes. An equal volume of DMSO was added to the solvent control group. 30 μL of 10 μM phosphatidylinositol diphosphate (PIP2) substrate and 30 μL of sample were mixed. The kinase reaction was sealed and allowed to react at 37°C for 2.5 hours. 90 μL of kinase was added to terminate each 60 μL kinase reaction. B. Preparation of PIP3 standards and controls: Take 30 μL of the previously prepared 3.6 μM phosphatidylinositol triphosphate (PIP3) stock solution and add it to 270 μL of standard curve buffer; perform four 3-fold serial dilutions from the 0.36 μM stock solution using standard curve buffer; transfer 60 μL / well of each standard solution in triplicate or triplicate to a culture plate (color); transfer 60 μL / well of each stopped kinase reaction to two wells of the culture plate to obtain replicate data points; add 60 μL / well of the above-diluted PIP3 assay solution to all control, standard, and stopped reaction wells of the culture plate; seal the culture plate and incubate at room temperature for 60 minutes; C. Transfer 100 μL of standards, controls, and reactants from the culture plate to the detection plate; seal the plate and incubate at room temperature for 60 minutes; discard the solution in the detection plate and wash the wells three times with 200 μL / well TBS-T; dilute the secondary detection solution with TBS-T at a ratio of 1:80, and add 100 μL of the diluted secondary detection solution to each well of the detection plate; seal the plate and incubate at room temperature for another 30 minutes; discard the solution in the detection plate and wash the wells three times with 300 μL / well TBS-T; completely discard the last TBS-T wash solution from the plate and immediately add 100 μL of room temperature TMB solution; develop for 5–30 minutes; when the color darkens, add 50 μL of 1N H2SO4 stop solution to each well to stop the color development; read the absorbance at 450 nm using a microplate reader.

[0050] 3. Experimental Results: CDF-06 can effectively inhibit the kinase activity of PI3Kγ, and its IC50 value is [missing information]. 50 The value was 0.84 μmol / L; however, it showed no inhibitory activity against the other three isoforms of PI3K (PI3Kα, PI3Kβ, and PI3Kδ), and its IC50 value was 0.84 μmol / L. 50 The values ​​were all greater than 1000 μmol / L (Table 1); the above experimental results indicate that CDF-06 is a novel, highly selective PI3Kγ inhibitor.

[0051]

[0052] Example 5: Effect of CDF-06 on phosphorylation of downstream proteins of the PI3Kγ pathway in M2 type TAMs.

[0053] 1. Experimental Methods: BMDM cells in the logarithmic growth phase and in good growth status were co-cultured with breast cancer 4T1 cells and induced with IL-4 (20 ng / mL) and IL-13 (20 ng / mL) for 72 h.

[0054] A negative control group (Control), a co-culture group of BMDM and breast cancer 4T1 cells, and a drug-treated group were set up. The drug-treated group was treated with different concentrations of CDF-06 (2.5 μM, 5 μM, 10 μM), while the positive control group was treated with the PI3Kγ inhibitor IPI549 (1 μM) and cultured for 24 h. Cells were collected by scraping, centrifuged to remove the supernatant, and RIPA lysis buffer was prepared according to the instructions. The cells were then lysed on ice for 30 minutes. Centrifugation was performed at 12,000 rpm for 15 minutes at 4°C, and the supernatant was the total protein. The total protein concentration was determined using a BCA protein concentration kit. Protein samples were denatured at 95°C for 5 minutes and then stored at -20°C. Western blot was used to detect the phosphorylation of downstream proteins in the PI3Kγ pathway and the total protein expression level.

[0055] 2. Experimental Results: Compared with the negative control group, the phosphorylation levels of key downstream proteins of PI3Kγ, including mTOR, S6K, S6, and 4EBP1, were significantly increased in the BMDM and breast cancer 4T1 cell co-culture group, indicating activation of the PI3Kγ-mTOR signaling pathway in M2-type TAMs. Treatment with different concentrations of CDF-06 significantly decreased the phosphorylation levels of these proteins. These experimental results further demonstrate that CDF-06 is a PI3Kγ inhibitor, capable of inhibiting the PI3Kγ-mTOR signaling pathway in M2-type TAMs by inhibiting PI3Kγ. Figure 7 ).

Claims

1. The use of o-piperidine cyclohexylamine ester compounds or their salts in the preparation of antitumor metastasis drugs, wherein the structure of the o-piperidine cyclohexylamine ester compounds or their salts is shown in Formula I: ， in, R1 is H, C1-C6 alkyl, or C1-C6 alkoxy.

2. The application of o-piperidine cyclohexylamine esters or their salts in the preparation of PI3Kγ kinase inhibitors, wherein the structure of the o-piperidine cyclohexylamine esters or their salts is shown in Formula I: ， in, R1 is H, C1-C6 alkyl, or C1-C6 alkoxy.

3. The use of o-piperidine cyclohexylamine esters or their salts in the preparation of medicaments for the prevention or treatment of diseases related to abnormal activation of PI3Kγ, wherein the structure of the o-piperidine cyclohexylamine esters or their salts is shown in Formula I: ， in, R1 is H, C1-C6 alkyl, or C1-C6 alkoxy.

4. The application as described in claim 1, characterized in that, The tumors mentioned are any one or more of the following: breast cancer, cervical cancer, ovarian cancer, lung cancer, leukemia, malignant lymphoma, multiple myeloma, thyroid cancer, nasopharyngeal carcinoma, meningeal carcinoma, pituitary adenoma, oral cancer, craniopharyngioma, thalamic and brainstem tumors, vascular tumors, intracranial metastases, liver cancer, gastric cancer, esophageal cancer, colorectal cancer, rectal cancer, colon cancer, pancreatic cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, bone cancer, malignant melanoma, glioma, and skin cancer.

5. The application as described in claim 1, characterized in that, The tumor metastasis mentioned is lung metastasis from breast cancer.

6. The application as described in claim 1, characterized in that, The aforementioned o-piperidine cyclohexylamine ester compounds or their salts exert their anti-tumor metastasis effect by inhibiting PI3Kγ kinase activity.

7. The application as described in claim 1, characterized in that, The aforementioned o-piperidine cyclohexylamine esters or their salts exert anti-tumor metastasis effects by inhibiting M2-type TAMs-mediated migration and invasion of breast cancer cells.

8. The application as described in claim 1, characterized in that, The aforementioned piperonylcyclohexylamine esters or their salts inhibit the infiltration of M2 type TAMs in lung tissue and increase CD8 levels. + The increased T-cell ratio activates the immune response and exerts an anti-tumor metastasis effect.

9. The application as described in any one of claims 1-8, characterized in that, The o-piperidine cyclohexylamine esters or their salts are selected from: 。 10. The application according to any one of claims 1-8, characterized in that, The aforementioned cyclohexylene ester compounds or their salts are prepared into pharmaceutical compositions with pharmaceutically acceptable carriers or excipients.

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