New medical application of p-terphenyl derivative

Abstract

The invention discloses a new medical application of small molecular compounds for targeted inhibition of PHD2 activity to terphenyl derivatives, namely 6 '-demethylated candida B and 3'-demethoxy-6 '-demethyl-5'-methoxy candida B. The invention further discloses a preparation method of the small molecular compounds for targeted inhibition of PHD2 activity. The compound disclosed by the invention can be combined to an active site part of PHD2 and is used for preparing a medicine for preventing or treating PHD2-mediated diseases, and the PHD2-mediated diseases comprise acute kidney injury, chronic kidney diseases, renal anemia and the like.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and specifically describes the medical use of terphenyl derivatives 6'-demethyl candidatin B and 3'-demethoxy-6'-demethyl-5'-methoxy candidatin B. Background Art

[0002] Hypoxia inducible factor (HIF) is a type of oxygen-sensitive heterodimeric protein discovered by Semenza et al. in the early 1990s. It plays a key regulatory role in a series of physiological changes that occur in the body under hypoxic conditions. Studies have found that in tissue anemia (ischemia) and inflammatory diseases, the stable expression of HIF protein plays an important role in alleviating the disease. Proline hydroxylase domain (PHD), as the rate-limiting enzyme in the HIF degradation reaction, can hydroxylate HIF and promote the degradation of HIF protein, thereby affecting the treatment of related diseases mediated by HIF.

[0003] PHD belongs to 2-ketoglutarate and Fe 2+ PHD1 is a hydroxylation-dependent dioxygenase, including four subtypes: PHD1, PHD2, PHD3 and PHD4. PHD1 is distributed in the nucleus, PHD2 is distributed in the cytoplasm, PHD3 is distributed in both the nucleus and the cytoplasm, and PHD4 is mainly distributed in the endoplasmic reticulum. In the presence of oxygen, iron and 2-ketoglutarate, PHD can hydroxylate a variety of substrates, including HIF1α~3α, NF-κB, activated transcription factor 4, etc. PHD2 can recognize the proline residue Pro402 in the ODD region of HIF-1α and Pro564 in the N-TAD region, causing them to be hydroxylated and ubiquitinated for degradation. In the presence of hypoxia or PHD2 inhibitors, the hydroxylation activity of PHD2 decreases, which hinders the degradation of HIF-1α and causes HIF-1α to be stably expressed and accumulated.

[0004] HIF has been shown to be the major transcription factor responsible for increased erythropoietin production under hypoxic conditions. Although treatment with recombinant human erythropoietin has been shown to be an effective approach for the treatment of anemia, small molecule-mediated inhibition of PHD2 is expected to have advantages over treatment with erythropoietin. Specifically, the function of other HIF target gene products is essential for hematopoiesis, and modulation of these factors can improve the efficiency of hematopoiesis. Examples of HIF target gene products important for hematopoiesis include transferrin, transferrin receptor, and ceruloplasmin. Hepcidin expression is also inhibited by HIF, and small molecule inhibitors of PHD2 have been shown to reduce hepcidin production. Hepcidin is a negative regulator of iron availability, which is essential for hematopoiesis, and therefore a decrease in hepcidin production is expected to be beneficial in the treatment of anemia. PHD2 inhibition is also useful when used in combination with other anemia treatments, including iron supplementation and / or exogenous erythropoietin. Patients with dysfunctional mutations in the PHD2 gene exhibit increased erythrocytosis and elevated blood hemoglobin. At present, the focus of research on renal anemia drugs in the oxygen sensing pathway is inhibitors of hypoxia-inducible factor prolyl hydroxylase (PHD2), which can stably increase erythropoietin and hemoglobin, while downregulating hepcidin to increase iron transport, thereby improving anemia, local tissue ischemia and tissue damage-related diseases. Therefore, the development of PHD2 inhibitors has become one of the important strategies for the treatment of diseases such as acute kidney injury, chronic kidney disease and renal anemia.

[0005] At the same time, as a hypoxia regulatory factor, PHD2 can participate in angiogenesis and collateral vessel growth by regulating multiple signaling pathways, namely HIF-1 and non-HIF-1 pathways. Therefore, PHD2 may become an important therapeutic target molecule for ischemic diseases. PHD2 can be used as an important target factor for angiogenesis treatment, and inhibition of PHD2 is expected to become a new method for angiogenesis treatment of ischemic diseases.

[0006] In addition, inhibiting PHD2 can not only promote angiogenesis, but also protect cells. It has been found that transplanting PHD2-silenced adipose-derived stem cells into the myocardial infarction area of ​​mice can reduce cardiomyocyte apoptosis, myocardial fibrosis and infarction area, and play a role in protecting the myocardium. Studies have shown that these effects not only rely on the significant promotion of HIF-1 expression and the survival rate of transplanted adipose-derived stem cells in the myocardial infarction area after PHD2 silencing, but also rely on the increase in NF-κB-mediated IGF-1 (insulin-like growth factor 1) secretion promoted by PHD2 inhibition, thereby enhancing the protective effect on the myocardium. It can be seen that inhibiting PHD2 may protect the myocardium by improving the survival rate of adipose-derived stem cells and their paracrine function.

[0007] Recent studies have also shown that inhibiting PHD2 not only plays an important role in angiogenesis in ischemic diseases, but also affects tumor growth and metastasis in the tumor microenvironment by regulating the expression of genes related to tumor growth and metastasis. The hypoxic stress factor PHD2 plays an important regulatory role in the adaptation of tumors to the hypoxic microenvironment and tumor angiogenesis. Inhibiting PHD2 promotes the maturation of blood vessels in tumor tissues, that is, normalization, thereby inhibiting the rapid growth and metastasis of tumors; at the same time, it can also enhance the therapeutic effect of tumor chemotherapy drugs and reduce the toxic side effects of drugs. Therefore, inhibiting PHD2 may become an important new combined adjuvant therapy method in tumor treatment.

[0008] Given that current PHDs inhibitors lack specificity and targeting and produce a large number of toxic side effects, how to obtain highly efficient and specific inhibitors with excellent pharmaceutical properties that inhibit PHD2 activity has attracted much attention.

[0009] The 6′-desmethylcandidusin B and 3′-demethoxy-6′-desmethyl-5′-methoxycandidusin B involved in this patent are terphenyl derivatives. Literature reports that 6′-desmethylcandidusin B and 3′-demethoxy-6′-desmethyl-5′-methoxycandidusin B have strong inhibitory activity against α-glucosidase and acetylcholinesterase, but there is no report of their activity in inhibiting PHD2, let alone their use in the preparation of drugs for preventing or treating PHD2-mediated diseases. Summary of the invention

[0010] The purpose of the present invention is to provide a p-terphenyl derivative for targeted inhibition of proline hydroxylase (PHD2): 6′-desmethylcandidusin B and 3′-demethoxy-6′-desmethyl-5′-methoxycandidusin B, the structure of which is shown in the following formula:

[0011] (1) 6′-Demethylcandida B

[0012]

[0013] (2) 3′-demethoxy-6′-demethyl-5′-methoxycandidatin B

[0014]

[0015] The present invention provides use of 6'-demethyl candidatin B and 3'-demethoxy-6'-demethyl-5'-methoxy candidatin B in preparing medicines for preventing or treating diseases mediated by PHD2.

[0016] Furthermore, the drug can reduce the activity of proline hydroxylase.

[0017] Furthermore, the drug can increase the expression of HIF-1α.

[0018] Furthermore, the drug can increase the secretion of EPO.

[0019] The PHD2-mediated diseases of the present invention include, but are not limited to, acute kidney injury, chronic kidney disease, renal anemia and the like.

[0020] Beneficial effects of the present invention: The present invention discloses for the first time that 6′-demethylcandidacin B and 3′-demethoxy-6′-demethyl-5′-methoxycandidacin B can bind to the active site of PHD2, and molecular biological experiments confirm that they can inhibit the enzyme activity of PHD2, leading to increased expression of HIF-1α, thereby promoting the secretion of EPO. The present invention provides a new use of 6′-demethylcandidacin B and 3′-demethoxy-6′-demethyl-5′-methoxycandidacin B in the preparation of drugs for preventing or treating PHD2-mediated diseases.

[0021] Compared with the marketed drug roxadustat, 6′-demethylcandidiasis B and 3′-demethoxy-6′-demethyl-5′-methoxycandidiasis B exhibit comparable inhibitory activity in vitro. Therefore, these compounds are ideal candidates for developing highly effective and novel drugs for the treatment of diseases such as acute kidney injury, chronic kidney disease and renal anemia.

[0022] More specifically, the present invention relates to the use of the compound or pharmaceutical composition in the preparation of a drug, wherein the drug is used to protect, treat or alleviate HIF-related and / or EPO-related diseases in patients.

[0023] EPO-related diseases include any condition where increased EPO levels would provide a therapeutic benefit. EPO-related conditions include, but are not limited to, anemia, including anemia associated with diabetes, ulcers, renal failure, cancer, infection, dialysis, surgery, and chemotherapy; ischemic and hypoxic conditions, for example, arterial occlusive disease, angina, intestinal infarction, pulmonary infarction, cerebral ischemia, and myocardial infarction.

[0024] "HIF-related disease" refers to any condition associated with subnormal, abnormal or improper regulation of HIF. HIF-related conditions include any condition where increased levels of HIF would have a beneficial effect. HIF-related diseases include, but are not limited to, heart disease, stroke, peripheral vascular disease, ulcers, burns, chronic wounds, chronic ischemia, pulmonary embolism, ischemia-reperfusion injury, inflammation, and anemia.

[0025] HIF-related and / or EPO-related diseases include, but are not limited to, anemia, ischemia, vascular disease, angina pectoris, myocardial ischemia, myocardial infarction, metabolic disorders or wound healing, etc.

[0026] The PHD2-mediated diseases of the present invention refer to any disease caused by abnormal PHD2. PHD2-related diseases include, but are not limited to, anemia and ischemia, heart disease and tumors.

[0027] The present invention provides compounds, isomeric forms thereof, structural analogs thereof, pharmaceutically acceptable salts thereof and pharmaceutical compositions thereof that can be released to patients using various routes or modes of administration. Suitable routes of administration include, but are not limited to, inhalation, transdermal, oral, rectal, transmucosal, enteral and parenteral administration, and parenteral administration includes intramuscular, subcutaneous and intravenous injection.

[0028] The active compounds of the present invention may be administered per se or in the form of a pharmaceutical composition in which the active compound is mixed with one or more pharmaceutically acceptable carriers, excipients or diluents. Pharmaceutical compositions used in accordance with the present invention are usually formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants, which facilitate processing of the active compound into a pharmaceutically usable formulation. Suitable formulations depend on the chosen route of administration.

[0029] For oral administration, the compound is combined with a pharmaceutically acceptable carrier well known in the art. Such carriers enable the compounds of the present invention to be formulated into tablets, pills, lozenges, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral administration by the patient to be treated. Oral pharmaceutical preparations can be obtained by mixing with solid excipients, optionally grinding the resulting mixture, processing the mixture of particles, and adding suitable adjuvants if necessary to obtain tablets or lozenge cores. Suitable excipients are specifically fillers, such as sugars, including lactose, sucrose or mannitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP). If necessary, disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate, can be added.

[0030] The compound can be formulated for parenteral administration, by injection, such as bolus injection or continuous infusion. The injection preparation can be a unit dosage form, such as in an ampoule or a multidose container, to which a preservative is added. The composition can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and can contain a formulation agent, such as a suspending agent, a stabilizer and / or a dispersant, such as cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate.

[0031] Pharmaceutical preparations for parenteral administration include aqueous solutions of water-soluble active compounds. Oily injection suspensions of active compounds can be prepared as appropriate. Suitable lipophilic solvents or carriers include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes, and aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose dextran. Optionally, the suspension can also contain a suitable stabilizer or an agent that increases the solubility of the compound to prepare a highly concentrated solution.

[0032] The pharmaceutical composition may also comprise a suitable solid or gel phase carrier or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers, such as polyethylene glycol.

[0033] The choice of the mode of administration and the effective dose will vary, inter alia, depending on the disease to be treated. The choice of the mode of administration and the dose is within the capabilities of those skilled in the art.

[0034] The compounds of the invention can be used alone or, if necessary, in combination with other active compounds. The invention also provides a medicament comprising at least one compound according to the invention and one or more further active substances, in particular for the treatment and / or prevention of the diseases described in the invention. Suitable active substances in the combination that may be mentioned include: ACE inhibitors, angiotensin II receptor antagonists, beta-blockers, calcium antagonists, PDE inhibitors, mineralocorticoid receptor antagonists, diuretics, aspirin, iron supplements, vitamin B12 and folic acid supplements, statins, digitalis derivatives (digoxin), tumor chemotherapy drugs and antibiotics. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 The compound regulates the expression of HIF-1α ODD protein.

[0036] Figure 2 The compound regulates EPO secretion. DETAILED DESCRIPTION

[0037] The following specific examples are used to further illustrate the content of the present invention, but are not intended to limit the present invention in any way. The methods used in the following examples are all conventional methods unless otherwise specified.

[0038] The specifications and models of the instruments and equipment and some raw materials involved in the following embodiments are as follows:

[0039] Nuclear magnetic resonance instrument: Bruker 500 MHz (TMS as internal standard).

[0040] High performance liquid chromatography system (analysis): Waters, 2 515 pumps, 996 detector.

[0041] Analytical chromatography column: Nano-Micro Unisil ODS column (4.6× 250 mm, 10 µm).

[0042] High performance liquid chromatography system (preparation): LC3000 from Beijing Chuangxintongheng Company.

[0043] Preparative chromatographic column: Nano-Micro Unisil ODS column (21.2× 250 mm, 10 µm).

[0044] Chromatographic silica gel: 300~400 mesh, Qingdao Ocean Chemical Plant.

[0045] Hydroxypropyl dextran gel Sephadex LH20 chromatography medium: GE Company, USA.

[0046] Microplate reader: Victor2 1420 Multilabel Counter from Perkin Elmer.

[0047] Chromatographic grade methanol and acetonitrile were purchased from Merck, Germany, and other reagents were of analytical grade and purchased from Beijing Chemical Reagent Factory.

[0048] In the following examples, 6′-demethylcandidiasis B and 3′-demethoxy-6′-demethyl-5′-methoxycandidiasis B can be prepared by any existing technology. The preparation method is described in detail in GN, Belofsky, KB, Gloer, JB, Gloer et al. New p-terphenyl and polyketide metabolites from the sclerotia of Penicillium raistrickii. [J]. J Nat Prod, 1998, 61 (9): 1115-9.

[0049] The inventors prepared 6′-demethylcandidatin B and 3′-demethoxy-6′-demethyl-5′-methoxycandidatin B by the following method. The fungus NCC2114 was isolated from the soil collected from the Wulingshan National Nature Reserve in Hebei Province and preserved in the Strain Collection Center of North China Pharmaceutical Group New Drug Research and Development Co., Ltd.

[0050] Example 1. Preparation of fermentation culture of bacteria producing the compound of the present invention

[0051] (a) Preparation of seed solution: fungus NCC2114 was inoculated into seed culture medium, and cultured at 26°C and 220 rpm for 72 h to obtain seed solution. The preparation method of seed culture medium is as follows: 10.0 g corn starch, 40.0 g glucose, 14.0 g hot pressed soybean cake powder, 6.0 g malt powder, 1.0 g yeast powder, 1.0 g sodium chloride, 0.5 g magnesium sulfate heptahydrate, add tap water to dissolve to 1000 mL, pH value 7.0, and dispense into 1000 mL Erlenmeyer flasks, 150 mL per bottle, rubber stopper, sterilized at 121°C for 30 min.

[0052] (b) Preparation of solid fermentation culture: Inoculate the seed liquid with 5% inoculum into a 750 mL Erlenmeyer flask containing 150 g solid rice fermentation medium, and culture at 26°C for 14 days. The fermentation medium is prepared by mixing rice and water in a ratio of 4:1, soaking for 3-10 hours, and then adding 2.5% of the total weight of hot-pressed soybean cake powder. Then, the mixture is divided into 750 mL Erlenmeyer flasks, each containing 150 g, and sealed with rubber stoppers, and sterilized at 121°C for 30 min.

[0053] Example 2. Extraction and preparation of the compound described in the present invention

[0054] About 4 kg of NCC2114 fermentation product (solid fermentation) was added into 8 L of ethyl acetate for soaking and stirring. After 4 h, the filtrate was filtered and evaporated under reduced pressure to obtain 18.7 g of dark brown oil paste.

[0055] The ointment was dissolved in ethyl acetate, mixed with silica gel, evaporated, and roughly separated through a silica gel funnel (500 mL funnel, G3 pore size, 50% of the total volume), and the elution solvents were n-hexane, chloroform, chloroform-methanol (10:1, V:V), chloroform-methanol (1:1, V:V), and methanol, 750 mL each. HPLC detection was performed, and the fractions containing compounds with ultraviolet absorption at 278nm and 333nm were combined and concentrated under reduced pressure to obtain the concentrate 2114-3 (0.2g); the fractions containing compounds with ultraviolet absorption at 275nm and 331nm were combined and concentrated under reduced pressure to obtain the concentrate 2114-4 (0.1g).

[0056] The concentrate 2114-3 (0.2 g) was dissolved in methanol and separated by preparative reverse phase ODS HPLC. The mobile phase was 30% CH3CN-H2O (containing 0.05% trifluoroacetic acid) at 18.0 mL / min to obtain compound 2114-33: 29.1 mg (tR = 12.1 minutes).

[0057] The concentrate 2114-4 (0.1 g) was dissolved in methanol and separated by preparative reverse phase ODS HPLC. The mobile phase was 30% CH3CN-H2O (containing 0.05% trifluoroacetic acid) at 18.0 mL / min to obtain compound 2114-44: 21.5 mg (tR = 16.4 minutes).

[0058] NCC2114-33 (6′-demethylcandidatin B) is a light yellow oil, easily soluble in chloroform, acetone, methanol, ethyl acetate and dimethyl sulfoxide, UV (MeCN) λmax 278, 298, 333nm, 1 H-NMR (500MHz, Acetone-d6) and 13 C-NMR (125 MHz, Acetone-d6) data assignments are shown in Table 1.

[0059] NCC2114-44 (3′-demethoxy-6′-demethyl-5′-methoxy candidatin B) is a light yellow oil, easily soluble in chloroform, acetone, methanol, ethyl acetate and dimethyl sulfoxide, UV (MeCN) λmax 275, 307, 331 nm, 1 H-NMR (500MHz, Acetone-d6) and 13 C-NMR (125 MHz, Acetone-d6) data assignments are shown in Table 1.

[0060]

[0061] Chemical structure of 2114-33 (6′-demethylcandidatin B)

[0062]

[0063] Chemical structure of 2114-44 (3′-demethoxy-6′-demethyl-5′-methoxycandidatin B)

[0064] Table 1 2114-33 and 2114-44 1 H(500MHz) and 13 C(125MHz) NMR data

[0065]

[0066] Example 3. Determination of the inhibitory activity of PHD2 enzyme

[0067] The PHD2 recombinant protein was induced to express in Escherichia coli by genetic engineering method, and the recombinant human protein proline hydroxylase was obtained by affinity chromatography.

[0068] The method for determining the inhibitory activity is as follows: the compounds 6′-demethylcandidiasis B and 3′-demethoxy-6′-demethyl-5′-methoxycandidiasis B prepared in Example 2 were diluted and added to a 96-well plate, and 50 μL of reaction buffer containing 1 μM FITC-HIF1α (FITC-DLDLEMLAPYIPMDDDFQL) was added respectively. After incubation at room temperature for 5 minutes, 50 μL of 2 mM α-ketoglutaric acid and 2 μg of recombinant human PHD2 protein were added, and incubated at room temperature for 20 minutes. Roxadustat (FG-4592) was used as a positive drug, and the fluorescence polarization value was detected by an enzyme reader, using an excitation wavelength of 488 nm and an emission wavelength of 525 nm.

[0069] The inhibition rate was calculated according to the following formula:

[0070] Inhibition rate = (1-average fluorescence polarization value of the experimental group / average fluorescence polarization value of the blank control group) × 100%.

[0071] Evaluation criteria for inhibitory activity:

[0072] IC 50 The values ​​are the compound concentrations (μM) at which the inhibition rate is 50% as shown in Table 2.

[0073] Table 2 Inhibitory activity of compounds against PHD2 protease

[0074]

[0075] The above results show that the 6′-demethylcandidatin B and 3′-demethoxy-6′-demethyl-5′-methoxycandidatin B prepared by the present invention have significant PHD2 protease inhibitory activity, and their IC 50 The values ​​are 1.467 μM and 2.232 μM, and can be used to prepare drugs for preventing or treating diseases mediated by PHD2 protease.

[0076] Example 4. Detection of HIF-1α expression using the HIF-1α ODD-luc luciferase reporter system

[0077] The pTARGET™ HIF-1α ODD-luc fluorescent reporter plasmid was constructed using genetic engineering methods.

[0078] Hela cells were seeded into 96-well plates (1 × 10 4cells / well), the culture medium was high-glucose DMEM containing 50U / mL penicillin, 50U / mL streptomycin, and 10% FBS, and the culture conditions were 37°C and 5% CO2. After 12 hours of culture, the pTARGET™ HIF-1α ODD-luc luciferin reporter plasmid was transfected into Hela cells using Lipo8000™ transfection reagent. After 24 hours of transfection, different concentrations of compounds and positive drug roxadustat (FG-4592) were added to treat the cells for 16 hours. The Bio-Lumi™ Firefly Luciferase Reporter Gene Assay Kit was used to detect the effect of the compounds on the degradation of HIF-1α ODD in Hela cells.

[0079] The compounds 6′-demethylcandida B and 3′-demethoxy-6′-demethyl-5′-methoxycandida B of the present invention stabilize the expression of HIF-1α ODD by inhibiting the activity of PHD2 protein. Figure 1 As shown in the figure, at a concentration of 200 μM, the expression of HIF-1α ODD protein was upregulated by 3 times by compounds 6′-demethylcandida albicans B and 3′-demethoxy-6′-demethyl-5′-methoxycandida albicans B compared with the DMSO control group, which is close to the regulatory effect of the positive drug FG-4592, indicating that compounds 6′-demethylcandida albicans B and 3′-demethoxy-6′-demethyl-5′-methoxycandida albicans B can significantly upregulate the expression of HIF-1α ODD and inhibit its degradation.

[0080] Example 5. ELISA detection of EPO protein secretion in Hep3B cells

[0081] Hep3B cells were seeded into 96-well plates (1 × 10 4 cells / well), the culture medium was high-glucose DMEM containing 50U / mL penicillin, 50U / mL streptomycin, and 10% FBS, and the culture conditions were 37°C and 5% CO2. After 24 hours of adherent culture, the cells were treated with different concentrations of compounds 6′-demethylcandida B and 3′-demethoxy-6′-demethyl-5′-methoxycandida B for 6 hours, and roxadustat was used as a positive drug; the secretion of EPO in the cell culture medium was detected using the Boster human erythropoietin ELISA kit.

[0082] like Figure 2As shown: Compounds 6′-demethylcandidiasis B and 3′-demethoxy-6′-demethyl-5′-methoxycandidiasis B can increase the secretion of EPO in Hep3B cells. When Hep3B cells were treated with drugs at a concentration of 200 μM, the secretion of EPO in the cell supernatant was 6′-demethylcandidiasis B (43±6.2 mIU / mL), 3′-demethoxy-6′-demethyl-5′-methoxycandidiasis B (45±13.2 mIU / mL), positive drug roxadustat (48.6±7.7 mIU / mL), and DMSO control group (3.2±0.8 mIU / mL). The efficacy of 6′-demethylcandidiasis B and 3′-demethoxy-6′-demethyl-5′-methoxycandidiasis B was equivalent to that of the positive drug roxadustat.

[0083] The above experiments confirmed (Table 2, Figure 1 and Figure 2 ), compounds 6′-demethylcandida albicans B and 3′-demethoxy-6′-demethyl-5′-methoxycandida albicans B can bind to the active site of PHD2, and it has been confirmed that they can inhibit the enzymatic activity of PHD2 and promote the secretion of EPO in cells by increasing the expression of HIF-1α protein, and can be used to treat diseases such as acute kidney injury, chronic kidney disease and renal anemia.

Claims

1. Use of the terphenyl derivatives 6′-demethylcandidatin B and 3′-demethoxy-6′-demethyl-5′-methoxycandidatin B in the preparation of drugs for preventing or treating PHD2-mediated diseases.

2. The use according to claim 1, characterized in that The drug is capable of reducing the activity of PHD2.

3. The use according to claim 1, characterized in that The drug is capable of increasing the expression of HIF-1α.

4. The use according to claim 1, characterized in that The drug is capable of increasing the secretion of EPO.

5. The use according to claim 1, characterized in that: The medicine is used for preventing or treating HIF-related and / or EPO-related diseases.

6. The use according to claim 1, characterized in that: The PHD2-mediated diseases include acute kidney injury, chronic kidney disease, renal anemia and the like.

7. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.

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