A class of deep-sea heteroterpenoid compounds and their use in preparing drugs for preventing or treating osteoporosis

Abstract

The present invention belongs to the field of biomedicine technology, and discloses a class of deep-sea heteroterpene compounds, a preparation method thereof, and an application thereof in the preparation of drugs for preventing or treating osteoporosis. The present invention provides a class of deep-sea heteroterpene compounds or pharmaceutically acceptable salts thereof, which have a structure of a hybrid compound of dumazane-type sesquiterpene and C7-C9 polyketone. The heteroterpene compounds of the present invention can be isolated and purified from Penicillium, and have the effect of simultaneously regulating osteoblasts and osteoclasts. Specifically, they inhibit osteoclastogenesis while promoting the mineralization of osteoblasts; and can simultaneously regulate osteoblasts and osteoclasts by targeting the TGFB1 protein. They are non-cytotoxic at effective concentrations and can be used in the preparation of bone disease drugs, especially drugs for preventing or treating osteoporosis. They are of great significance for the treatment of osteoporosis and the development of new drugs, and are expected to develop into a new generation of anti-osteoporosis drugs.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and particularly relates to a class of deep-sea heteroterpene compounds, a preparation method thereof, and an application thereof in preparing drugs for preventing or treating osteoporosis. Background Art

[0002] Osteoporosis is a common skeletal disease characterized by decreased bone density, osteoporosis, and increased risk of fractures, severely impacting patients' quality of life. With an aging population and changing lifestyles, the prevalence of osteoporosis is increasing year by year, making it a significant public health issue worldwide.

[0003] Bone maintenance and repair are regulated by two main cell types: osteoblasts and osteoclasts. Osteoblasts are responsible for generating new bone tissue, while osteoclasts are responsible for breaking down old bone tissue. Normally, a dynamic balance exists between osteoblasts and osteoclasts to maintain bone health. However, in patients with bone diseases, this balance is disrupted, leading to bone disorders such as osteoporosis and osteosclerosis. Therefore, one of the key treatments for osteoporosis and osteosclerosis is to restore the balance between osteoblasts and osteoclasts.

[0004] In osteoporosis, this imbalance manifests as increased osteoclast activity and decreased osteoblast activity, leading to substantial bone loss. Therefore, targeted approaches to promote bone formation and reduce bone loss are necessary. Currently, the main treatments for osteoporosis include both pharmacological and non-pharmacological approaches. Drug treatments often include anti-osteoporosis drugs, such as bisphosphonates and bone formation promoters, as well as calcium and vitamin D supplementation. These drugs primarily work by inhibiting osteoclast activity or promoting osteoblast activity to restore bone health. While these drugs can slow the progression of osteoporosis to some extent, they also have significant adverse effects and limitations. For example, long-term estrogen use may increase the risk of breast and endometrial cancer, while drugs that unidirectionally regulate bone homeostasis, such as bisphosphonates, may cause serious complications such as osteonecrosis of the jaw. Therefore, the search for novel osteoporosis treatments, particularly those with bidirectional effects on osteoblast and osteoclast activity, has become a hot topic. Summary of the Invention

[0005] To overcome the shortcomings and deficiencies of the aforementioned prior art, the primary objective of the present invention is to provide a class of heteroterpenoid compounds or pharmaceutically acceptable salts thereof. These heteroterpenoid compounds or pharmaceutically acceptable salts thereof have the property of acting simultaneously on both osteoblasts and osteoclasts, inhibiting osteoclastogenesis while promoting osteoblast mineralization, and can be used to prepare drugs for the prevention or treatment of osteoporosis.

[0006] Another object of the present invention is to provide the use of the above-mentioned heteroterpenoid compounds or pharmaceutically acceptable salts thereof in the preparation of drugs for preventing or treating osteoporosis.

[0007] The heteroterpenoid compounds or pharmaceutically acceptable salts thereof of the present invention can simultaneously regulate osteoblasts and osteoclasts by targeting the TGFB1 protein, which is of great significance for the treatment of osteoporosis and the development of new drugs.

[0008] The purpose of the present invention is achieved through the following solutions:

[0009] A class of heteroterpene compounds or pharmaceutically acceptable salts thereof, having a structure of a hybrid compound of a dumazane-type (drimane) sesquiterpene and a C7-C9 polyketone, wherein the sesquiterpene portion has a structural formula as shown in Formula I, and the C7-C9 polyketone portion has a structural formula selected from one of the structures shown in Formula II to Formula V:

[0010]

[0011] Among them, R1-R 15 are independently selected from one of H, halogen, hydroxyl, cyano, amino, nitro, carbonyl, carboxyl, ester, C1-C20 alkyl, C1-C20 alkylene, C1-C20 fluoroalkyl, C2-C20 alkenyl, C2-C20 alkenylene, C3-C20 alkynyl, C3-C20 alkynylene, C1-C20 alkoxy, and C6-C20 aryl; X is one of O, N or S.

[0012] Furthermore, R1-R 15 One or more hydrogen atoms in the group may be substituted by a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an oxygen atom, an alkenyl group, an alkynyl group, an aryl group, a hydroxyl group, an amino group, a carbonyl group, a carboxyl group, an ester group, a cyano group, a methyl group, an ethyl group, a methoxy group, a methylthio group, or a nitro group.

[0013] Furthermore, the above-mentioned aryl groups are C6-C20 aryl groups.

[0014] Furthermore, the heteroterpene compound of the present invention or a pharmaceutically acceptable salt thereof has a planar structure of the following formula VI or formula VII:

[0015]

[0016] Furthermore, the heteroterpene compound of the present invention or a pharmaceutically acceptable salt thereof has a structure as shown in Formula VIII or Formula IX:

[0017]

[0018] The present invention provides a method for preparing the above-mentioned heteroterpenoid compounds, which can be separated from Penicillium fermentation products.

[0019] The Penicillium allii-sativi has a preservation number of MCCC 3A00580 and is deposited in the China Marine Microbial Culture Collection Center.

[0020] The Penicillium fermentation product can be obtained by fermenting Penicillium in a fermentation medium.

[0021] The fermentation can be carried out at room temperature.

[0022] The fermentation time may be 25-35 days.

[0023] The composition of the fermentation medium, measured in parts by mass and parts by volume (g, mL), may be: 80-120 parts by mass of oats, 3.0-3.6 parts by mass of sea salt, and 80-120 parts by volume of water.

[0024] Furthermore, the separation method comprises the following steps:

[0025] The Penicillium fermentation product was extracted with ethyl acetate, dried, and then subjected to solid-phase extraction with petroleum ether, dichloromethane, and methanol. The dichloromethane fraction was dried to obtain an extract. The extract was passed through a normal phase column chromatography column using a petroleum ether / ethyl acetate gradient elution to obtain eight fractions (Fr.1-Fr.8). Fraction Fr.5 was separated using Sephadex gel chromatography (pure methanol) and ODS column chromatography (methanol-water gradient elution) to obtain subfractions Fr.5.1-5.11. Fraction Fr.5.9 was separated by HPLC to obtain the heteroterpenoid compounds of Formula VIII and Formula IX of the present invention.

[0026] The heteroterpenoid compounds or pharmaceutically acceptable salts thereof provided by the present invention act on osteoblasts and osteoclasts simultaneously, inhibiting osteoclastogenesis while promoting osteoblast mineralization, and can be used to prepare drugs for bone diseases, especially drugs for preventing or treating osteoporosis.

[0027] The present invention also provides use of the above-mentioned heteroterpenoid compounds or pharmaceutically acceptable salts thereof in the preparation of drugs for bone diseases.

[0028] The present invention also provides use of the above-mentioned heteroterpenoid compounds or pharmaceutically acceptable salts thereof in the preparation of drugs for preventing or treating osteoporosis.

[0029] The heteroterpenoid compounds or pharmaceutically acceptable salts thereof provided by the present invention can simultaneously regulate cellular osteogenesis and osteoclastogenesis by targeting the bone matrix protein TGFB1, which is of great significance for the treatment of osteoporosis and the development of new drugs.

[0030] Furthermore, the drug comprises a therapeutically effective amount of a terpenoid compound or a pharmaceutically acceptable salt thereof.

[0031] Furthermore, the drug can be prepared into various pharmaceutical dosage forms by conventional methods, including: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, lozenges, granules, granules, pills, pills, suspensions, wine preparations, tinctures, drops and other oral dosage forms and injections and other dosage forms for administration other than oral administration, such as injections.

[0032] Furthermore, the drug may also contain one or more pharmaceutically acceptable carriers or excipients.

[0033] Furthermore, the carrier or auxiliary material may include a diluent, a binder, a surfactant, a wetting agent, an adsorption carrier, a lubricant, a filler, a disintegrant, a preservative, and the like.

[0034] The present invention also provides a pharmaceutical composition for preventing or treating osteoporosis, comprising a heteroterpenoid compound or a pharmaceutically acceptable salt thereof.

[0035] Compared with the prior art, the present invention has the following beneficial effects:

[0036] The heteroterpenoid compounds of the present invention can be isolated and purified from Penicillium, and have the function of simultaneously regulating osteoblasts and osteoclasts. Specifically, they inhibit osteoclastogenesis while promoting the mineralization of osteoblasts. They are non-cytotoxic at effective concentrations and are expected to be developed into a new generation of anti-osteoporosis drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other relevant drawings can be obtained based on these drawings without paying any creative work.

[0038] Figure 1 The toxicity of Alliisativins AB to bone marrow mononuclear cells.

[0039] Figure 2 Effects of Alliisativins AB on RANKL-induced osteoclast formation.

[0040] Figure 3 Quantitative analysis of tartrate-resistant acid phosphatase-positive multinuclear cells.

[0041] Figure 4 The toxicity of Alliisativins AB to bone marrow mesenchymal stem cells.

[0042] Figure 5 Effects of Alliisativins AB on osteoblast mineralization of bone marrow mesenchymal stem cells.

[0043] Figure 6 Quantitative analysis of the Alizarin Red S staining area.

[0044] Figure 7 3D structure of the AlliisativinA-targeted TGFB1 (PDB ID: 4X2F) protein complex. DETAILED DESCRIPTION

[0045] The present invention will be further described in detail below with reference to the examples, but the embodiments of the present invention are not limited thereto. Unless otherwise specified, the materials involved in the following examples can be obtained from commercial channels. The methods described are conventional methods unless otherwise specified.

[0046] In one embodiment, a heteroterpene compound or a pharmaceutically acceptable salt thereof is a hybrid compound of a dumazane-type sesquiterpene and a C7-C9 polyketone, wherein the sesquiterpene portion has a structural formula as shown in Formula I, and the C7-C9 polyketone portion has a structural formula selected from one of the structures shown in Formula II to Formula V:

[0047]

[0048] wherein R1, R2, R3, R4, R5, R6, etc. are independently selected from one of H, halogen, hydroxyl, cyano, amino, nitro, carbonyl, carboxyl, ester, C1-C20 alkyl, C1-C20 alkylene, C1-C20 fluoroalkyl, C2-C20 alkenyl, C2-C20 alkenylene, C3-C20 alkynyl, C3-C20 alkynylene, C1-C20 alkoxy, and C6-C20 aryl; and X is one of O, N, or S.

[0049] Furthermore, one or more hydrogen atoms in R1, R2, R3, R4, R5, R6, etc. may be substituted by a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an oxygen atom, an alkenyl group, an alkynyl group, an aryl group, a hydroxyl group, an amino group, a carbonyl group, a carboxyl group, an ester group, a cyano group, a methyl group, an ethyl group, a methoxy group, a methylthio group, or a nitro group.

[0050] Furthermore, the above-mentioned aryl groups are C6-C20 aryl groups.

[0051] In a specific embodiment of the present invention, the heteroterpene compound of the present invention or a pharmaceutically acceptable salt thereof has a planar structure of the following formula VI or formula VII:

[0052]

[0053] In a specific embodiment of the present invention, the heteroterpene compound of the present invention or a pharmaceutically acceptable salt thereof has a structure as shown in Formula VIII or Formula IX:

[0054]

[0055] In one embodiment, a method for preparing the above-mentioned heteroterpenoid compounds can be separated from Penicillium fermentation products.

[0056] The Penicillium allii-sativi has a preservation number of MCCC 3A00580 and is deposited in the China Marine Microbial Culture Collection Center.

[0057] The Penicillium fermentation product can be obtained by fermenting Penicillium in a fermentation medium.

[0058] The fermentation can be carried out at room temperature.

[0059] The fermentation time may be 25-35 days.

[0060] The composition of the fermentation medium, measured in parts by mass and parts by volume (g, mL), may be: 80-120 parts by mass of oats, 3.0-3.6 parts by mass of sea salt, and 80-120 parts by volume of water.

[0061] Furthermore, the separation method comprises the following steps:

[0062] The Penicillium fermentation product was extracted with ethyl acetate, dried, and then subjected to solid-phase extraction with petroleum ether, dichloromethane, and methanol. The dichloromethane fraction was dried to obtain an extract. The extract was passed through a normal phase column chromatography column and gradient eluted with petroleum ether / ethyl acetate to obtain eight fractions (Fr.1-Fr.8). Fraction Fr.5 (fraction Fr.5 was obtained by elution with a ratio of 10:1) was separated by gradient elution using a Sephadex gel chromatography column (pure methanol) and an ODS column chromatography column (methanol-water system) to obtain subfractions Fr.5.1-5.11. Fraction Fr.5.9 (fraction Fr.5.9 was obtained by elution with a ratio of water:methanol = 4:120) was separated by HPLC to obtain the heteroterpenoid compounds of Formula VIII and Formula IX of the present invention.

[0063] The heteroterpenoid compound or its pharmaceutically acceptable salt provided by the present invention acts on osteoblasts and osteoclasts simultaneously, inhibiting osteoclastogenesis while promoting osteoblast mineralization, and can be used to prepare drugs for preventing or treating osteoporosis.

[0064] In one embodiment, the above-mentioned heteroterpenoid compound or a pharmaceutically acceptable salt thereof is used in the preparation of a drug for preventing or treating osteoporosis. The heteroterpenoid compound or a pharmaceutically acceptable salt thereof provided by the present invention can simultaneously regulate osteoblasts and osteoclasts by targeting the bone matrix protein TGFB1, thus having important implications for the treatment of osteoporosis and the development of new drugs.

[0065] In a specific embodiment of the present invention, the medicament comprises a therapeutically effective amount of a terpenoid compound or a pharmaceutically acceptable salt thereof.

[0066] In a specific embodiment of the present invention, the drug can be prepared into various pharmaceutical dosage forms by conventional methods, including: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, lozenges, granules, granules, pills, pills, suspensions, wines, tinctures, drops and other oral dosage forms and injections and other dosage forms for administration other than oral administration, such as injections.

[0067] In a specific embodiment of the present invention, the drug may further contain one or more pharmaceutically acceptable carriers or excipients.

[0068] In a specific embodiment of the present invention, the carrier or auxiliary material may include a diluent, a binder, a surfactant, a wetting agent, an adsorption carrier, a lubricant, a filler, a disintegrant, a preservative, and the like.

[0069] In one embodiment, a pharmaceutical composition for preventing or treating osteoporosis comprises a terpenoid compound or a pharmaceutically acceptable salt thereof.

[0070] Example 1: Structural Characterization of Terpenoid Compounds 1(VIII) and 2(IX) from Penicillium allii-sativi

[0071] The structural formulas of heteroterpene compound 1 (VIII) and heteroterpene compound 2 (IX) are shown below:

[0072]

[0073] Compound 1 (Alliisativin A)

[0074] Colorless oil; (c 0.20, MeOH); 1 H and 13 C NMR data, see Table 1; UV (MeOH) λ max (logε)206(4.13),270(2.81),289(2.74)nm; ECD(MeOH)Δ ε204 +9.01,Δε236 -2.44; HRMS (ESI) m / z: [MH] - Calcd for C 24 H 33 O7433.2226; Found 433.2213.

[0075] Compound 2(Alliisativin B)

[0076] Amorphous powder; (c 0.05, MeOH); 1 H and 13 C NMR data, see Table 1; UV (MeOH) λ max (logε)206(3.54),274(2.28),294(2.18)nm; ECD(MeOH)Δ ε204 -2.21,Δ ε248 +0.10,Δ ε340 +0.02; HRMS (ESI) m / z: [MH] - Calcd for C 24 H 35 O6419.2434; Found 419.2429.

[0077] The NMR data are shown in Table 1.

[0078] Table 1

[0079]

[0080]

[0081] a The solvent was DMSO-d6; b The solvent is CDCl3.

[0082] Example 2: Effects of Terpene Compounds 1 and 2 on Osteoclasts

[0083] (1) Extraction and culture of BMMs: 6-week-old C57BL / 6 mice were killed by cervical dislocation and completely immersed in alcohol for 3 minutes. Under sterile conditions, tweezers and tissue scissors (sterilized by high pressure) were used to remove the fur, muscle and other soft tissues of the lower limbs, and the femur was placed in a sterile culture dish. A 1 mL syringe was used to take α-MEM complete medium (containing 10% fetal bovine serum + 1% penicillin / streptomycin double antibody) containing 25 ng / mL MCSF to flush the bone marrow in the femoral bone marrow cavity. One mouse was placed in a 10 cm culture dish in a 37°C constant temperature incubator with 5% CO2 for 5-7 days to obtain BMMs, and primary cells were used for experiments.

[0084] (2) CCK-8 method to detect the toxic effects of heteroterpenoid compounds on BMMs: BMMS cells were seeded in 96-well plates at a density of 5000 cells. After overnight, basal culture medium containing or not containing compounds (Alliisativin A, Alliisativin B, 10 μM) was added. Three replicate wells were set up for each sample. After 48 hours, 10 μL of CCK-8 solution was added to each well and incubated at 37°C for 4 hours. The OD value at 450 nm was measured on a microplate reader. The results are as follows: Figure 1 As shown, the heteroterpenoid compounds of the present invention were not toxic to BMMs at a concentration of 10 μM.

[0085] (3) Effect of heteroterpenoid compounds on BMMs osteoclast formation: BMMs cells were digested and seeded in 96-well plates at a cell density of 5000 and cultured overnight. 100 μL of complete culture medium containing RANKL (25 ng / mL) was added to the negative wells, and 100 μL of complete culture medium containing RANKL (25 ng / mL) and M-CSF (25 ng / mL) was added to each well of the positive group and drug concentration group. The compound group was also intervened by adding different concentrations of compounds (Alliisativin A, Alliisativin B, 0, 1 μM, 5 μM, 10 μM). The cells were placed in an incubator and continued to be cultured, with the culture medium changed every 48 hours. On the 6th day, cells were observed to fuse under a microscope to form mature osteoclasts. TRAP staining was used to observe the effect of drugs on osteoclast formation. The results are shown in the figure below. Figure 2-Figure 3 As shown, the heteroterpenoid compounds of the present invention have a significant inhibitory effect on osteoclasts, and the effect of compound 1 (Alliisativin A) is particularly significant.

[0086] Example 3: Effects of terpenoid compounds on osteoblasts

[0087] (1) Extraction and culture of BMSCs: 3-week-old C57BL / 6 mice were killed by cervical dislocation and completely immersed in alcohol for 3 minutes. Under sterile conditions, tweezers and tissue scissors (sterilized by high pressure) were used to remove the fur, muscle and other soft tissues of the lower limbs, and the femur was placed in a sterile culture dish. A 1 mL syringe was used to take α-MEM complete culture medium (containing 10% fetal bovine serum + 1% penicillin / streptomycin double antibody) to flush the bone marrow in the femoral bone marrow cavity, and 10 mL of α-MEM complete culture medium was added to a 10 cm culture dish and mixed. The dish was placed in a 37°C constant temperature incubator with 5% CO2 and cultured for 7 days. Bone marrow mesenchymal stem cells were obtained by passage and expansion, and the P2 generation was used for the experiment.

[0088] (2) Toxic effects of heteroterpenoid compounds on BMSCs: BMSCs cells were seeded in 96-well plates at a density of 20,000 cells. After overnight, they were cultured with or without compounds (Alliisativin A, Alliisativin B, 0 μM, 1 μM, 5 μM, 10 μM). Three replicate wells were set up for each sample. After 48 hours, 10 μL of CCK-8 solution was added to each well and incubated at 37°C for 4 hours. The OD value at 450 nm was measured on a microplate reader. The results are shown in Figure 2. Figure 4 As shown, the heteroterpenoid compounds of the present invention have no toxicity to BMSCs at a concentration of 10 μM.

[0089] (3) Effect of compounds on BMSCs osteogenic mineralization: BMSCs were digested and 2×10 5 The cells were seeded at a density of 100 μg / L in 96-well plates and cultured overnight. The next day, osteogenic induction medium containing or not containing compounds was added. A blank control group, an induction group, a DMSO group, a compound group (AlliisativinA, Alliisativin B, 0, 1 μM, 5 μM, 10 μM), and a positive drug control group, Purmorphamine (PM, 1 μM), were set up. The drugs were administered once every 2 days for 10 consecutive days, and the cells were collected and stained with Alizarin Red S. First, the culture medium was removed, and the cells were fixed with 4% paraformaldehyde for 20 minutes, washed 3 times with 70% ethanol, and the ethanol was discarded and allowed to dry completely. 100 μL of 2% Alizarin Red S solution was added to each well to cover the cells and reacted at room temperature for 3-5 minutes; then 200 μL of 50% ethanol was added to each well to rinse 3 times, completely dried, and stored dry at room temperature. Pictures were taken and recorded using a microscope, and osteogenic mineralization was quantified using Image J. The results are shown in the figure below. Figure 5-Figure 6 As shown, the heteroterpenoid compounds of the present invention have a significant effect on promoting the mineralization of osteoblasts, and the effect of compound 1 (Alliisativin A) is particularly obvious.

[0090] Example 4: Effect of Compound 1 on the Dual-Target Regulatory Protein TGFB1

[0091] All molecular docking work was completed on the Yinfu cloud computing platform (https: / / cloud.yinfotek.com / ). The chemical structure of compound 1 was drawn using the JSME drawing board, then converted into a 3D structure and energy minimized under the MMFF94 force field. The platform automatically obtained the crystal of TGB1 protein (PDB number: 4X2F) from the RCSB Protein Data Bank database (http: / / www.rcsb.org / ). The protein structure was carefully processed through several steps, including: repairing residues, protonation, and adding partial charges under the AMBER ff14SB force field. The DMS tool was used with a radius of The protein surface was generated by using the probe. The binding pocket was defined by the crystal ligand, and the Sphgen module of UCSF Chimera was called to generate a small ball filling the site. The center of the box surrounding the small ball was set at (17.6, 69.657, 4.437) and the size was (37.265, 28.339, 36.549). The Grid module was used to generate grid points in the box, which were used for rapid scoring and evaluation. Finally, the DOCK 6.9 program was used for semi-flexible docking to generate 10,000 different conformational orientations. Cluster analysis was performed on the candidate conformations (RMSD threshold ), output the best scoring conformation. The result is as follows Figure 7 As shown, compound 1 binds to the 4X2F active pocket of the protein through hydrogen bonds with amino acid residues LYS213, ARG215, LYS335, and ASN338, as well as to VAL219, LYS337, and LEU340 through hydrophobic interactions. This binding was scored with a systematic score of -54.302063 kcal / mol, demonstrating the effectiveness of the docking.

[0092] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A heteroterpene compound or a pharmaceutically acceptable salt thereof, characterized in that: The heteroterpene compound has a planar structure of the following formula VI or formula VII:

2. The heteroterpene compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The heteroterpene compound has a structure as shown in the following formula VIII or formula IX:

3. A method for preparing the heteroterpene compound according to any one of claims 1 to 2, characterized in that: It is isolated from the fermentation product of Penicillium; the Penicillium is Penicillium allii-sativi, with the preservation number MCCC 3A00580, and is preserved in the China Marine Microbial Culture Collection Center.

4. A pharmaceutical composition for preventing or treating osteoporosis, characterized in that Comprising the heteroterpene compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2.

5. Use of a heteroterpene compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating osteoporosis, characterized in that Comprising the heteroterpene compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2.

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