Application of FABP4 inhibitor in preparation of medicine for treating or preventing osteoporosis

Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to application of a fatty acid binding protein 4 inhibitor or pharmaceutically acceptable salt thereof in preparation of a medicine for treating or preventing osteoporosis, the in-vivo anti-osteoporosis activity of the fatty acid binding protein 4 inhibitor is similar to that of a clinical medicine alendronate sodium, but the chemical structure of the fatty acid binding protein 4 inhibitor does not belong to bisphosphate. Therefore, the composition is suitable for osteoporosis patients intolerant to bisphosphate drugs. The pharmacological action mechanism of the compound does not involve regulation and control of hormones and related pathways, and the risk of inducing hormone tumors does not exist, so that the compound is suitable for osteoporosis patients with high risk of hormone tumors.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to the use of a fatty acid binding protein 4 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating or preventing osteoporosis. Background Art

[0002] Osteoporosis is a bone disease characterized by a decrease in the density and mass of bone tissue, which makes bones fragile and prone to fractures. Under normal circumstances, bone tissue continuously undergoes bone formation and bone resorption to maintain the structure and strength of the bones. However, in osteoporosis, the bone resorption process is accelerated, while the rate of bone formation is relatively slow, resulting in osteopenia. The main effect is a decrease in bone density, which makes the bones more vulnerable to damage from external stress, especially in areas such as the spine, hips and wrists. Its pathogenesis is mainly related to overactive bone resorption, which accelerates the loss of bone tissue, resulting in a decrease in bone density and mass.

[0003] Treatments for osteoporosis typically involve drugs that inhibit bone resorption. Commonly used drugs include: bisphosphonates: alendronic acid, ibandronic acid, etc.; estrogen replacement therapy (HRT): a combination of estrogen and progesterone; and selective estrogen receptor modulators (SERMs): Raloxifene.

[0004] However, long-term use of bisphosphonates may cause osteonecrosis of the jaw and gastrointestinal discomfort, and their safety and effectiveness are still under investigation. Estrogen replacement therapy (HRT) increases the risk of breast cancer, uterine cancer, and cardiovascular disease and is therefore not suitable for all patients, especially women at risk for these conditions. While selective estrogen receptor modulators (SERMs) have a protective effect on bone density, they may increase the incidence of breast cancer when used in women at increased risk.

[0005] Therefore, the present invention aims to develop a new target for osteoporosis. Summary of the Invention

[0006] The purpose of the present invention is to provide a new target for osteoporosis and the application of the new target in the preparation of drugs for treating or preventing osteoporosis.

[0007] Fatty acid binding protein 4 (FABP4 in the present invention, unless otherwise specified) is highly expressed in both postmenopausal osteoporosis patients and elderly osteoporosis patients.

[0008] In the osteoporosis model mice, the expression of FABP4 is also increased, and inhibiting the activity of FABP4 can alleviate the symptoms of bone mass loss and bone density decrease of the osteoporosis model mice. Therefore, FABP4 is a new target for the treatment of osteoporosis.

[0009] Therefore, the fatty acid binding protein 4 inhibitor or the pharmaceutically acceptable salt thereof can be used for preparing a drug for treating or preventing osteoporosis.

[0010] Specifically, the FABP4 inhibitor described above is any one of the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (I), formula (II), or a pharmaceutically acceptable salt thereof,

[0011]

[0012] wherein R1R2 is any one of -H, -F; R is any one of -CH3, -CH2CH3 or -OCH2CH3; X is any one of -OCH2-, -OCH(CH2CH3)-, -CH(OH)CH2-, -CH2CH2-, / , -NHCH2-, -OCH(CH3)-;

[0013]

[0014] wherein X is any one of -O(CH2)4-, -m-Ph-O-CH2-;

[0015]

[0016] wherein X is any one of -OCH2-, -NHCH2-; R is any one of -H, -CH2CH3, -CH(CH3)2, -CH3, -CH2F, -CH2COOH;

[0017]

[0018] wherein R1 is any one of -Cl, -CF3; R2R4 is any one of -H, -F; R3 is any one of -H, -Cl;

[0019]

[0020] wherein X is any one of -O-, -NH-; R1R3 is any one of -H, -Cl; R2 is any one of -OCH3, -CH3, cyclopropyl-;

[0021]

[0022] wherein R1 is -Ph, ; R2 is ; R2 is

[0023]

[0024] wherein X is any one of -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-;

[0025]

[0026] wherein R1 is -H, -CH3, -CH3CONH-; R2, R4 are any one of -H, -CH3, -CH3O-, -F; R3 is any one of -H, -CH3, -CH3O-, -F, -Br; R5 is any one of -H, -CH3O-, -F;

[0027]

[0028] wherein R1 is any one of -F, -OCH3, -CF3, -CH3, -CONH2; n is any one of 0, 1, 2;

[0029]

[0030] wherein n is any one of 0, 1, 2;

[0031]

[0032] wherein R2 is any one of -H, -Ph, ; R3 is any one of -Ph,

[0033]

[0034] wherein R1 is any one of -H, -CH3, -CH2OH, -CH2OCH3; R2 is any one of -H, -CF3, -CH3, -C5H 11 ; R3 is any one of -H, -CH3; X is any one of -N=, -CH=; m is any one of 1, 2; n is any one of 0, 1;

[0035]

[0036] ​wherein X is any one of -CH3, -COOH, -N(CH3)CH2CH3, -N(CH2CH3)2, cyclopropy-, -CH(CH2CH3)2, Y is any one of -COOH, -CH(CH3)2, R1is any one of -H, -CH3, -Cl; R2is any one of -H, -F; R3is any one of -H, -CF3, -Cl; R4is any one of -H, -CH(CH3)2;

[0037]

[0038] wherein X is any one of R is any one of -H, -Cl.

[0039] Specifically, the above FABP4 inhibitors include BMS309403 (A1) and its derivatives, which are specifically shown in the following table. Unless otherwise specified, the compounds in the present application are represented by the numbers in the following table; A1 is BMS309403.

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053] Specifically, the above FABP4 inhibitors include BMS309403 (A1) and its derivatives, which are specifically shown in the following table. Unless otherwise specified, the compounds in the present application are represented by the numbers in the following table; A1 is BMS309403.

[0054]

[0055] Specifically, the osteoporosis is postmenopausal osteoporosis, senile osteoporosis and secondary osteoporosis.

[0056] Specifically, the osteoporosis is osteoporosis of patients who are intolerant to bisphosphonate drugs.

[0057] Specifically, the osteoporosis is osteoporosis of patients who are at high risk of hormone tumors.

[0058] The application further provides a pharmaceutical composition for preventing or treating osteoporosis, comprising a fatty acid binding protein 4 inhibitor or a pharmaceutically acceptable salt thereof.

[0059] Specifically, the pharmaceutical composition for preventing or treating osteoporosis further comprises a pharmaceutically acceptable carrier.

[0060] Compared with the prior art, the application has the following advantages and beneficial effects:

[0061] The fatty acid binding protein 4 inhibitor or the pharmaceutically acceptable salt thereof provided by the application can treat osteoporosis and delay the disease progression by inhibiting FABP4. The chemical structure of the fatty acid binding protein 4 inhibitor or the pharmaceutically acceptable salt thereof does not belong to bisphosphonate, and thus the fatty acid binding protein 4 inhibitor or the pharmaceutically acceptable salt thereof is suitable for patients with osteoporosis who are intolerant to bisphosphonate drugs. The pharmacological mechanism of the fatty acid binding protein 4 inhibitor or the pharmaceutically acceptable salt thereof does not involve regulating hormones and related pathways, and thus the fatty acid binding protein 4 inhibitor or the pharmaceutically acceptable salt thereof is suitable for patients with osteoporosis who are at high risk of hormone tumors.

[0062] The application will be further described in detail below with reference to the accompanying drawings. BRIEF DESCRIPTION OF DRAWINGS

[0063] Figure 1 is a result graph of in-vitro inhibition of bone resorption of FABP4 inhibitor compounds A1-A7 in the embodiments of the application.

[0064] Figure 2 is a result graph of FABP4 concentration in blood of osteoporosis model mice in the embodiments of the application.

[0065] Figure 3 is a result graph of FABP4 expression in bone tissue of osteoporosis model mice in the embodiments of the application.

[0066] Figure 4 is a result graph of improvement of bone mineral density of osteoporosis model mice by FABP4 inhibitor compound A1 in the embodiments of the application.

[0067] Figure 5 is a result graph of inhibition of bone resorption of osteoporosis model mice by FABP4 inhibitor compound A1 in the embodiments of the application.

[0068] Figure 6 is the sequencing result of FABP4 inhibitor compound A1 in the embodiments of the present application. DETAILED DESCRIPTION

[0069] The technical solutions in the present application will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Although the representative embodiments of the present application have been described in detail, those skilled in the art will understand that various modifications and changes can be made to the present application without departing from the scope of the present application. Therefore, the scope of the present application should not be limited to the embodiments, but should be defined by the appended claims and their equivalents.

[0070] The application effect of the fatty acid binding protein 4 inhibitor or the pharmaceutically acceptable salt thereof in preparing a drug for treating or preventing osteoporosis is studied below through specific embodiments.

[0071] Embodiment 1

[0072] In this embodiment, FABP4 inhibitor compounds A1-A7 are used to inhibit the function of FABP4, and then to inhibit bone resorption, and the specific steps are as follows:

[0073] 1. Animals: two 7-week-old C57BL / 6 ♀ mice.

[0074] 2. Experimental materials: DMEM (Corning Company, item number 10-013-CVRC), αMEM (Gibco Company, item number C12571500BT), FBS (Gibco Company, item number 10091148), P / S (Adamas life Company, item number C8021-100mL), PBS (Solarbio Company, item number G4200-500ML), culture dishes, high-pressure surgical instruments, M-CSF (PeproTech Company, item number 315-02-50), RANKL (PeproTech Company, item number 315-11-50), various animal bone marrow mononuclear cell separation kits (Solarbio Company, item number P6900), bovine bone pieces (Jiaxing Tuyuan Biotechnology Co., Ltd.), alendronate sodium (MACKLIN Company, item number A801267), compound A1 (MCE Company, item number HY-101903), and compounds A2-A7 are self-synthesized, and the synthesis route is shown in Embodiment 5.

[0075] 3. After the mice are sacrificed, the hind legs are dissociated from the hip joint and soaked in 75% alcohol for 5 minutes. Then, the legs are transferred to a clean bench, and the muscles and connective tissues are removed after three times of cold PBS. The complete tibia and femur are taken out. The tibia and femur are cut open with scissors to ensure that the ends are clean. The bone marrow cavity is washed repeatedly with a 1 mL syringe needle until the bone is completely white. The cells are filtered with a 70 μm cell screen, centrifuged at 200 g for 5 minutes, and resuspended twice with DMEM complete medium.

[0076] 4. The bone marrow cells are separated according to the instructions of the <Various animal bone marrow mononuclear cell separation kit>, and the bone marrow mononuclear cells (BMNCs) are collected and transferred to a 10 cm culture dish for overnight culture in αMEM complete medium (Gibco, special grade, inactivated).

[0077] 5. Two days later, the bovine bone pieces are seeded in a 96-well plate, and the BMNCs are inoculated on the bone pieces at a concentration of 5 x 10 4 per well in α-MEM complete medium with the addition of 50 ng / mL M-CSF for two days.

[0078] 6. Two days later, the medium is replaced with α-MEM complete medium with the addition of 50 ng / mL M-CSF and 100 ng / mL RANKL, and the culture is continued for two days.

[0079] 7. The drug administration groups are added with compounds A1-A7 and the positive control drug alendronate sodium (ALD) at a concentration of 10 μM based on the original induction medium, and the culture is continued for 11 days, during which the medium is replaced every 2 days.

[0080] 8. After the bone pieces are removed of cells by ultrasonic treatment, they are dried in a vacuum drying oven for 6 hours, and then subjected to scanning electron microscopy (SEM) scanning to count the lacunae area. The lacunae area of the blank control group is taken as 100%, and the relative lacunae area of each drug administration group is calculated to evaluate the activity of the drugs in inhibiting bone resorption.

[0081] The experimental results are shown in Table 1. Figure 1 As shown in Table 1, alendronate sodium (ALD) and compounds A1-A7 can all inhibit bone resorption in vitro. The relative lacunae area of the positive control alendronate sodium is 25.5%, while the relative lacunae area of compound A1 is 25.4%, which proves that the activity of the FABP4 inhibitor in inhibiting bone resorption in vitro is similar to that of the positive control.

[0082] Example 2:

[0083] This example uses an ovariectomized mouse model to verify the effect of compound A1 in an osteoporosis animal model.

[0084] Experimental procedure:

[0085] 1. Sterilize and dry the surgical instruments in advance.

[0086] 2. After weighing the C57BL / 6 ♀ mice, isoflurane (dose: 0.2-0.3 L / min) was used for anesthesia. When the mice's breathing, heartbeat, and toe pressing were stable and there was no pain reflex, it was indicated that the mice entered the surgical anesthesia period and the operation could be performed.

[0087] 3. After the mice were anesthetized, the animals were fixed, and the skin was prepared. The back was disinfected with iodine and 75% ethanol. A longitudinal incision was made at the lower 1 / 3 of the torso, 1-2 cm away from both sides of the spine, about 1 cm long. After separating the muscle layer, a light yellow fat mass was visible, and the ovary was in it. At this time, the fat mass was pulled out with a small forceps, and a group of irregular thread-like pink tissues were found, which were the ovaries. The lower end of the ovary was ligated, and the ovary and the remaining line were cut off. The tissue was pushed back into the abdominal cavity, and the incision was sutured.

[0088] 4. One week after the operation, the mice were divided into groups and given intragastrically administered water, the positive control drug alendronate sodium (ALD, 1.3 mg / Kg / day, MACKLIN company, item number A801267), and the FABP4 inhibitor (compound A1, 10 mg / Kg / day, MCE company, item number HY-101903) every day for one month. The mice were given regular diet instead of high-fat diet throughout the experiment. After the administration was completed, the mice were taken and the blood was taken to measure the content of FABP4 in the blood. At the same time, the left femur was scanned by Micro-CT and the bone density was analyzed, and the section was analyzed by histology. Trap staining was used to observe bone resorption, and FABP4 antibody staining was used to observe the distribution of FABP4 in the bone tissue.

[0089] The results are shown in Figure 2 The content of FABP4 in the blood of the osteoporosis model mice was higher than that of the blank group, which was consistent with the increase of FABP4 content in the blood of postmenopausal and elderly osteoporosis patients, indicating that the model mice simulated the pathological characteristics of postmenopausal and elderly osteoporosis.

[0090] The distribution of FABP4 in the bone tissue is shown in Figure 3 The expression of FABP4 in the bone tissue of the osteoporosis model mice was high, while the expression in the bone tissue of the blank group mice was less, indicating that under the condition of non-high-fat diet, the expression of FABP4 in the bone tissue of the osteoporosis model mice was increased, and directly participated in the pathological process of osteoporosis. Neither alendronate sodium nor compound A1 reduced the expression of FABP4 in the bone tissue, indicating that compound A1 inhibited the function of FABP4, not the expression of FABP4.

[0091] The results of FABP4 inhibitors against bone loss are as follows Figure 4 and Figure 5 As shown, compound A1 has the effect of increasing bone density and bone volume, increasing the number and thickness of trabeculae, reducing the distance between trabeculae, and inhibiting bone resorption. Its in vivo anti-osteoporosis efficacy is similar to that of the positive control alendronate sodium, and it has the potential to treat osteoporosis.

[0092] Example 3:

[0093] This example uses transcriptome sequencing to investigate the signaling pathway involved in the inhibitory effect of Compound A1 on bone resorption. The specific steps are as follows:

[0094] Experimental steps 1-5 are the same as those in Example 1.

[0095] 6) Two days later, the culture medium was supplemented with 50 ng / mL M-CSF and 100 ng / mL RANKL, with or without the addition of Compound A1 (10 μM), to allow differentiation into osteoclasts. The culture medium was changed every two days. On the third day of the experiment, the cells were harvested and sent to BGI for cDNA library preparation using the Illumina TruSeq RNA Library Prep kit for sequencing.

[0096] The raw sequencing data (fastq) were quality checked using fastQC (v0.11.3) and further aligned to the mouse genome using Tophat2 (v2.1.0) to generate bam files. Cuffquant (v2.2.1) was used to generate cxb files from the bam files. Cuffnorm (v2.2.1) was used to calculate FPKM values ​​using quartile normalization. Cuffdiff (v2.2.1) was used to identify differentially expressed genes between the control and mutants, and genes with FPKM > 1 were selected for further analysis. Cuffdiff was used to generate pre-ranked gene lists. Functional analysis and signaling pathway fitting of significantly altered genes were performed using DAVID.

[0097] The results are as follows Figure 6 As shown, the main signaling pathways affected by compound A1 on bone cells are cytokine receptor interaction pathway, IL-17 signaling pathway and chemokine receptor interaction pathway, and no hormone-related signaling pathway is involved, suggesting that the effect of FABP4 inhibitors on anti-bone resorption does not involve hormone regulation.

[0098] Example 4:

[0099] This example provides a method for synthesizing BMS309403 derivatives.

[0100] Because of the structural similarity of the target compounds, the synthesis method is general, and A5 is the best in vitro anti-osteoporosis activity among the derivatives. The following is an example of the synthesis of A5 to detail the experimental steps:

[0101] Step one:

[0102]

[0103] Under nitrogen protection, to the constantly stirring 2-bromophenylhydrazine hydrochloride (31.02 g, 0.139 mol) ethanol (500 mL) solution, add sodium acetate trihydrate (18.87 g, 0.139 mmol) and deoxybenzoins (30.96 g, 0.133 mol). Heat the mixture to reflux for 2 hours, then partially cool and evaporate. The residue is slurried in saturated sodium bicarbonate solution (300 mL), filtered, washed with water, and dried under vacuum at 60°C for 16 hours. The resulting solid is triturated in hot methanol (200 mL), filtered and dried to obtain white solid compound A, melting point 126-128°C, 36.84 g, yield 76%, [M+H]+: 366.28.

[0104] Step two:

[0105]

[0106] At room temperature and under nitrogen, to the stirring slurry of compound A (10.0 g, 27.4 mmol) in N-methylpyrrolidine (NMP, 25 mL), add propionic anhydride (4.6 mL, 35.9 mmol) to keep the reaction temperature below 35°C. Stir the reaction mixture for 2 hours, then quench with 5% potassium bisulfate solution, and extract with diethyl ether (100 mL) four times. Combine the ether extracts, wash with water twice, wash with brine once, dry (MgSO4) and evaporate to obtain 12.9 g of orange oil. Purify the crude product by flash chromatography on silica gel (1:4 ethyl acetate / hexane) to obtain compound B as a light yellow oil, 8.15 g, yield 71%, [M+H]+: 422.35.

[0107] Step three:

[0108]

[0109] To a solution of compound B (2.33 g, 5.53 mmol) in DMF (15 mL) was added sodium hydride (60% dispersion, 550 mg, 13.8 mmol) at room temperature under nitrogen for 1 minute. The reaction was heated to 50 °C for 20 minutes. The deep red reaction mixture was cooled in an ice water bath. The mixture was then acidified with 1 N hydrochloric acid to a pH of 2 and extracted with diethyl ether (50 mL) for 30 minutes. The combined organic extracts were washed with water twice, brine once, dried (MgS04) and evaporated. The crude product was purified by flash chromatography on silica gel (1 :3 ethyl acetate / hexanes) to give 1.63 g of the title compound as a light yellow amorphous solid in 73% yield, [M+H]+: 404.33.

[0110] Step Four:

[0111]

[0112] To a solution of compound C (5 g, 12.40 mmol), 3-aminophenylboronic acid (2.37 g, 17.29 mmol) and sodium carbonate (11 mL, 2 M, 22 mmol) in toluene (40 mL) and ethanol (15 mL) was added sequentially at room temperature under nitrogen for 30 minutes. Tetrakis(triphenylphosphine)- palladium(0) (508 mg, 0.43 mmol) was added and the reaction mixture was heated at 80 °C for 18 hours. The reaction mixture was cooled to room temperature and partitioned between diethyl ether and water. The organic layer was washed with water, brine, dried over anhydrous MgS04and concentrated. The crude product was purified by flash chromatography eluting with 1 :3 ethyl acetate / hexanes to give compound D as a light yellow foam (2.56 g, 50%), [M+H]+: 416.55.

[0113] Step Five:

[0114]

[0115] To dimethylformamide (20 mL) was added sequentially compound D (2.56 g, 6.16 mmol), potassium carbonate (918 mg, 6.60 mmol) and tert-butyl bromoacetate (975 pL, 6.60 mol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was extracted with diethyl ether and aqueous sodium bicarbonate solution, the organic layer was washed with water and brine, then dried over anhydrous MgS04and concentrated. The crude product was purified by flash chromatography eluting with 15:85 ethyl acetate / hexanes to give compound E as a foam (2.23 g, 70%), [M+H]+: 514.69.

[0116] Step Six:

[0117]

[0118] A solution of compound E (2.230 g, 4.34 mmol) in trifluoroacetic acid (15 mL) and dichloromethane (40 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated, the reaction was extracted with ethyl acetate and water, the aqueous layer was basified with IN NaOH and then the pH was adjusted to between 3-4 with 10% citric acid solution. The organic layer was separated, washed with water and brine, dried over anhydrous MgSO4 and concentrated. The crude product was purified by flash chromatography eluting with 7:93 methanol / dichloromethane to give compound F (1.69 g, 8.6%) as an oil foam, [M+H]+: 474.58.

[0119] In summary, the fatty acid binding protein 4 inhibitor or its pharmaceutically acceptable salt provided by the present application can treat osteoporosis and delay the disease progression by inhibiting FABP4, and thus can be used as a drug for treating osteoporosis. The fatty acid binding protein 4 inhibitor or its pharmaceutically acceptable salt provided by the present application is not structurally a bisphosphonate drug, and thus does not cause adverse reactions in the gastrointestinal tract, and thus can be suitable for osteoporosis patients who are intolerant to bisphosphonate drugs; does not regulate hormones and related pathways, and thus does not have the risk of inducing hormone tumors, and thus can be suitable for osteoporosis patients who are at high risk of hormone tumors.

[0120] The above examples are only illustrative of the present application, and do not constitute a limitation on the protection scope of the present application, and any design identical or similar to the present application falls within the protection scope of the present application.

Claims

1. Use of a fatty acid binding protein 4 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating or preventing osteoporosis.

2. Use according to claim 1, characterized in that: The fatty acid binding protein 4 inhibitor is any one of the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (I), and formula (II), or a pharmaceutically acceptable salt thereof, Wherein, R1R2 is any one of -H and -F; R is any one of -CH3, -CH2CH3 or -OCH2CH3; X is any one of -OCH2-, -OCH(CH2CH3)-, -CH(OH)CH2-, -CH2CH2-, / , -NHCH2-, -OCH(CH3)-; Wherein, X is any one of -O(CH2)4-, -m-Ph-O-CH2-; Wherein, X is any one of -OCH2- and -NHCH2-; R is any one of -H, -CH2CH3, -CH(CH3)2, -CH3, -CH2F, and -CH2COOH; Wherein, R1 is any one of -Cl and -CF3; R2R4 is any one of -H and -F; R3 is any one of -H and -Cl; Wherein, X is any one of -O- and -NH-; R1R3 is any one of -H and -Cl; R2 is any one of -OCH3, -CH3, and cyclopropyl-; wherein R1is -Ph, any of the following: R2is any of the following: Wherein, X is any one of -CH2-, -CH2CH2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-; Wherein, R1 is any one of -H, -CH3, and -CH3CONH-; R2 and R4 are any one of -H, -CH3, -CH3O-, and -F; R3 is any one of -H, -CH3, -CH3O-, -F, and -Br; R5 is any one of -H, -CH3O-, and -F; Wherein, R1 is any one of -F, -OCH3, -CF3, -CH3, -CONH2; n is any one of 0, 1, 2; Wherein, n is any one of 0, 1, and 2; wherein R2is -H, -Ph, ; R3is any of -Ph, ; wherein R1 is any one of -H, -CH3, -CH2OH, -CH2OCH3; R2 is any one of -H, -CF3, -CH3, -C5H 11 ; R3 is any one of -H, -CH3; X is any one of -N=, -CH=; m is any one of 1, 2; n is any one of 0, 1. wherein X is any of -CH3, -COOH, -N(CH3)CH2CH3, -N(CH2CH3)2, cyclopropy-, -CH(CH2CH3)2, Y is any of -COOH, -CH(CH3)2, R1 is any of -H, -CH3, -Cl; R2 is any of -H, -F; R3 is any of -H, -CF3, -Cl; R4 is any of -H, -CH(CH3)2; wherein X is any one of -H, -Cl.

3. The use according to claim 2, wherein the compound is ###0002### The fatty acid binding protein 4 inhibitor is selected from:

4. The use according to claim 3, wherein the compound is ###0002### The fatty acid binding protein 4 inhibitor is:

5. Use according to any one of claims 1 to 4, wherein the compound is of formula (I) ###0002### (I) or a pharmaceutically acceptable salt thereof. The osteoporosis includes postmenopausal osteoporosis and senile osteoporosis.

6. Use according to any one of claims 1 to 4, wherein Application in the preparation of drugs for preventing or treating osteoporosis in patients intolerant to bisphosphonates.

7. Use according to any one of claims 1 to 4, wherein the compound is ###0002### Application in the preparation of drugs for preventing or treating osteoporosis in patients at high risk of hormone-related tumors.

8. A pharmaceutical composition for preventing or treating osteoporosis, characterized by comprising the compound of claim 1 as an active ingredient. Includes a fatty acid binding protein 4 inhibitor or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition for preventing or treating osteoporosis according to claim 8, wherein the active ingredient is administered in an amount of 0.1 to 10 mg / kg. Also included are pharmaceutically acceptable carriers.

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