Application of hypoxanthine derivative in preparation of medicine for treating peritoneal diseases

Abstract

The invention relates to the technical field of biological medicines, and discloses an application of an inoxanthine derivative in preparation of a medicine for treating peritoneal diseases, the pharmacological activity of the compound is tested in various animal disease models by detecting the pharmacological activity of the inoxanthine derivative subjected to structure modification and transformation in treatment of peritoneal diseases, and the application of the inoxanthine derivative in preparation of the medicine for treating peritoneal diseases is provided. The invention also provides data of activity of preventing and treating different types of peritoneal diseases, which proves that the compound has good activity, the effect is obviously superior to that of a clinically common drug nintedanib, and the effect is also obviously superior to that of hypoxanthine derivatives A, B and C and other hypoxanthine derivatives in the prior art. The hypoxanthine derivative provided by the invention can provide a novel skeleton for screening a novel compound for preparing a medicine for treating peritoneal diseases, and lays a theoretical foundation for developing a novel lead compound.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to the application of a hypoxanthine derivative in the preparation of drugs for treating peritoneal diseases. Background Technology

[0002] Peritoneal diseases are a complex group of conditions affecting the peritoneum, including peritonitis, peritoneal fibrosis, peritoneal ultrafiltration failure, peritoneal hypertransport, dialysate-related peritoneal diseases, and their complications. Peritonitis is an inflammatory disease involving the peritoneum (the thin membrane lining the abdominal cavity and internal organs). Its causes are diverse, including bacterial infections (such as secondary peritonitis caused by appendicitis perforation or gastrointestinal perforation), chemical irritants (such as the entry of corrosive substances like strong acids and alkalis into the peritoneal cavity), and physical injuries (such as peritoneal rupture due to abdominal trauma). Peritoneal hypertransport is a specific peritoneal transport characteristic in peritoneal dialysis patients, describing the rapid rate required for the transport of small molecule solutes (such as creatinine and urea) in the peritoneal dialysis fluid and plasma to reach equilibrium. Specifically, in patients with peritoneal hypertransport, the peritoneum rapidly absorbs glucose, leading to a rapid loss of the osmotic gradient, which may result in reduced or inadequate ultrafiltration. This hypertransport characteristic can affect the effectiveness of peritoneal dialysis and the patient's prognosis. Peritoneal dialysis rapid transporters or high transporters are usually defined as those whose creatinine-to-plasma ratio (D / P) is >0.8 after 4 hours of peritoneal dialysis, as shown by PET.

[0003] Currently, the pathogenic factors of peritoneal fibrosis are diverse. Long-term exposure of the peritoneum to non-biocompatible peritoneal dialysis fluid damages the peritoneal tissue and structure, causing peritoneal inflammation and angiogenesis, leading to peritoneal fibrosis. The main clinical pathological changes are extracellular matrix accumulation and mesothelial-mesenchymal transition, manifested as widespread mesothelial cell loss, thickening of the submesothelial matrix, inflammatory cell infiltration, increased angiogenesis, and alterations in peritoneal tissue structure and function. Peritoneal dialysis fluid often uses high-concentration glucose solutions, which irritate the peritoneum, causing damage to peritoneal mesothelial cells. Peritoneal mesothelial cells are a single layer of cells covering the peritoneal surface; their main functions are maintaining peritoneal structural integrity, participating in peritoneal defense, and transporting solutes and water across the peritoneum. When damaged, they secrete extracellular matrix and various pro-fibrotic factors such as TGF-β1, becoming important initiators of peritoneal fibrosis. The incidence of peritoneal fibrosis is extremely high, even higher than that of most tumors. Currently, there are only two anti-fibrotic drugs used in clinical practice, namely nintedanib and pirfenidone. However, since the pathogenesis of fibrosis in different organs is not the same, their efficacy against peritoneal fibrosis is not good. The FDA has only approved their clinical indication for pulmonary fibrosis. Pulmonary fibrosis is caused by type II epithelial cells secreting pro-fibrotic factors after injury, which mediates epithelial-mesenchymal transition, fibroblasts differentiate into myofibroblasts, secrete collagen, etc., resulting in excessive deposition of extracellular matrix, ultimately leading to pulmonary fibrosis and permanent loss of lung function [3].

[0004] Nintedanib has been approved for indications including idiopathic pulmonary fibrosis (IPF), non-small cell lung cancer (NSCLC), systemic sclerosis-associated interstitial lung disease (SSc-ILD), and progressive fibrotic interstitial lung disease (PF-ILD). Nintedanib is attempting to expand its indications to include endometrial fibrosis in a Phase II / III clinical trial (NCT05635071), but this has not yet been approved. Pirfenidone has been approved for indications including idiopathic pulmonary fibrosis (IPF). Pirfenidone is attempting to expand its indications to include liver fibrosis (NCT02161952), renal fibrosis (NCT04258397), post-acute myocardial infarction myocardial fibrosis (NCT05531955), and multiple sclerosis (NCT03109288) in a Phase I / II clinical trial, but none of these have yet been approved. Peritonitis, through repeated progression, eventually leads to peritoneal fibrosis. The recurring manifestation of interstitial peritonitis or other types of peritonitis is peritoneal fibrosis. Currently, there are no specific drugs for treating peritoneal fibrosis. Therefore, finding a drug that can prevent and treat peritonitis, peritoneal fibrosis, peritoneal ultrafiltration failure, peritoneal hypertransport, reduce inflammatory responses and changes in peritoneal structure, improve peritoneal function, and prevent the transformation of mild peritonitis into severe peritonitis and peritoneal fibrosis is crucial for the prevention and treatment of peritoneal fibrosis.

[0005] Hypoxanthine, also known as 6-hydroxypurine, is a naturally occurring purine compound and a precursor for the synthesis of purine nucleotides in nucleic acids. Currently, there are no reports of hypoxanthine derivatives blocking the development of peritoneal fibrosis or reversing pathological damage. Summary of the Invention

[0006] The purpose of this invention is to propose the application of a hypoxanthine derivative in the preparation of drugs for treating peritoneal diseases, thereby accelerating the development of new drugs for peritoneal diseases. The numerous technical effects of the preferred embodiment of this invention are detailed below.

[0007] To achieve the above objectives, the present invention provides the following technical solution:

[0008] The first aspect of this invention relates to the use of hypoxanthin derivatives in the preparation of drugs for treating peritoneal diseases, wherein the hypoxanthin derivatives have activity for treating peritoneal diseases, and wherein the hypoxanthin derivatives have one of the following structures:

[0009]

[0010] in:

[0011] R1 can be any of O, N, C, S or = O;

[0012] R2, R3, and R4 can be chosen as H and C1-C, respectively. 18 Alkyl or halogen-substituted C1-C 18 Alkyl, trifluoromethyl, sulfonyl, sulfonamide, sulfinyl, amino acid, 2-[bis(neopentyloxy)methoxy]phosphonomethoxyethyl, C1-C 18 Fatty acid group, C3-C 12 Heterocyclic groups, C1-C 18 Fatty acids; or C1-C atoms in which R2, R3, and R4 are optionally substituted with oxygen, sulfur, or nitrogen atoms. 18 The alkyl or fatty acid group; when R3 or R4 is substituted, the double bond is attached to the unsubstituted N position, and when all are substituted, there is no double bond.

[0013] The second aspect of this invention relates to compounds having the following structure:

[0014]

[0015] in:

[0016] R1 can be any of O, N, C, S or = O;

[0017] R2, R3, and R4 can be chosen as H and C1-C, respectively. 18 Alkyl or halogen-substituted C1-C 18Alkyl, trifluoromethyl, sulfonyl, sulfonamide, sulfinyl, amino acid, 2-[bis(neopentyloxy)methoxy]phosphonomethoxyethyl, C1-C 18 Fatty acid group, C3-C 12 Heterocyclic groups, C1-C 18 Fatty acids; or C1-C atoms in which R2, R3, and R4 are optionally substituted with oxygen, sulfur, or nitrogen atoms. 18 The alkyl or fatty acid group; when R3 or R4 is substituted, the double bond is attached to the unsubstituted N position, and when all are substituted, there is no double bond.

[0018] According to a preferred embodiment, the compound is selected from the group consisting of:

[0019]

[0020] A third aspect of the present invention relates to pharmaceutical compositions comprising the compounds of the present invention or pharmaceutically acceptable salts thereof.

[0021] According to a preferred embodiment, the pharmaceutical composition further comprises pharmaceutically acceptable excipients or auxiliary ingredients.

[0022] According to a preferred embodiment, the pharmaceutical composition is an oral formulation, an injectable formulation, or a nasal mucosal administration formulation.

[0023] The fourth aspect of the present invention relates to a method for treating peritoneal diseases by administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, to an individual in need.

[0024] According to a preferred embodiment, the peritoneal disease includes one or more of peritonitis, peritoneal fibrosis, peritoneal ultrafiltration failure, peritoneal hypertransport, and dialysate-related peritoneal disease.

[0025] According to a preferred embodiment, the drug for treating peritoneal diseases is a preparation made by adding pharmaceutically acceptable excipients or auxiliary ingredients, with hypoxanthine derivatives or their salts as the active ingredient.

[0026] According to a preferred embodiment, the formulation is an oral formulation, an injectable formulation, or a nasal mucosal administration formulation.

[0027] Terminology definition:

[0028] The compounds and derivatives provided by this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature systems.

[0029] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group. Examples of C1 to C3 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), and isopropyl (C3).

[0030] The term "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with receptors.

[0031] The term "pharmaceutically acceptable salt" refers to acidic and / or basic salts formed by the compounds of this invention with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the aforementioned compounds with appropriate (e.g., equimolar) amounts of an acid or base. These salts may form precipitates in solution and be collected by filtration, or be recovered after solvent evaporation, or be prepared by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compounds.

[0032] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0033] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with: (a) fillers or solubilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin wax; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0034] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0035] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0036] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0037] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0038] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0039] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers, such as nasal mucosal delivery formulations. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0040] The pharmaceutically acceptable excipients described in this invention refer to substances other than the active ingredient contained in the dosage form.

[0041] The pharmaceutically acceptable adjuvant component described in this invention possesses certain physiological activities. However, the addition of this component does not alter the dominant role of the aforementioned pharmaceutical composition in the disease treatment process; rather, it merely exerts an adjuvant effect. These adjuvant effects are simply the utilization of the known activity of the component, and are a commonly used adjuvant therapy method in the pharmaceutical field. If the aforementioned adjuvant component is used in combination with the pharmaceutical composition of this invention, it should still fall within the scope of protection of this invention.

[0042] The hypoxanthin derivatives provided by this invention have at least the following beneficial technical effects:

[0043] This invention relates to the application of hypoxanthin derivatives in the preparation of drugs for treating peritonitis. By testing the pharmacological activity of structurally modified and altered hypoxanthin derivatives in treating peritonitis, and by evaluating their pharmacological activity in various animal disease models, data on their activity in preventing and treating different types of peritonitis are provided. The results confirm that they all exhibit good activity, with effects significantly superior to the clinically commonly used positive control drug nintedanib, and also significantly superior to hypoxanthin derivatives A, B, and C, as well as other hypoxanthin derivatives in the prior art. This invention provides a novel framework for screening new compounds for the preparation of drugs for treating peritonitis and lays a theoretical foundation for the development of novel lead compounds. Brief description of the attached figures

[0044] Figure 1 Masson plots of peritoneum in different experimental groups in a glucose chlorhexidine-induced peritoneal disease model.

[0045] Figure 2 HE images of peritoneum in different experimental groups in a glucose chlorhexidine-induced peritoneal disease model.

[0046] Figure 3 Masson plots of peritoneum in different experimental groups in a peritoneal disease model induced by peritoneal dialysis fluid.

[0047] Figure 4 HE images of the peritoneum in each experimental group in a peritoneal disease model induced by peritoneal dialysis fluid. Detailed Implementation

[0048] To make the objectives, advantages, and technical solutions of this invention clearer, the technical solutions of this invention will be described in detail below. Obviously, the described embodiments are merely some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other implementations obtained by those skilled in the art without creative effort, including extended research on the treatment of peritoneal diseases using hypoxanthine derivatives of this invention, are within the scope of protection of this invention.

[0049] Through research on the medicinal chemistry and chemical processes of natural products, numerous plant endogenous compounds and derivatives have been developed. Modification and alteration of the structures of natural products have yielded many derivatives with excellent pharmacological and chemical activities. This invention provides the application of hypoxanthine derivatives in the preparation of drugs for treating peritonitis. By testing the pharmacological activity of structurally modified hypoxanthine derivatives in treating peritonitis, and by evaluating their pharmacological activity in various animal disease models, data on their activity in preventing and treating different types of peritonitis are provided, confirming that they all possess good activity, with effects significantly superior to the clinically commonly used positive control drug nintedanib, and also significantly superior to hypoxanthine derivatives A, B, and C, and other hypoxanthine derivatives in the prior art. This invention provides a novel framework for screening new compounds for the preparation of drugs for treating peritonitis, laying a theoretical foundation for the development of novel lead compounds.

[0050] The structures of hypoxanthine derivatives A (control 1), B (control 2), and C (control 3) are shown below:

[0051]

[0052] Hypoxanthine derivatives A (control 1), B (control 2), and C (control 3) were prepared according to the method for preparing compounds 2, 4, and / or 6 as follows.

[0053] The application of the hypoxanthin derivatives provided by the present invention in the preparation of drugs for treating peritoneal diseases will be described in detail below with reference to Examples 1 to 8.

[0054] Example 1: Preparation method of compounds 1-18

[0055] According to a preferred embodiment, compounds 1 to 12 are prepared by alkylation of hypoxanthin.

[0056] This embodiment provides preparation methods for 12 compounds, and the structures of all obtained compounds were determined by nuclear magnetic resonance spectroscopy and mass spectrometry.

[0057] Preparation of Compound 1 and Compound 5

[0058] The synthetic routes for compounds 1 and 5 are shown below:

[0059]

[0060] Reaction: (1) At 0℃, 3.45g NaH (4.5eq) was added to a 250mL four-necked flask. After evacuating the gas 3 times, 40mL (8V) of anhydrous THF was slowly added under N2 atmosphere; (2) 12.3mL of isopropanol (4.5eq) was slowly added dropwise to the system and the reaction was allowed to proceed for 30min; (3) Subsequently, 5g of compound 1 (1.0eq) was slowly added dropwise to a 100mL (20V) isopropanol mixture to the reaction system; (4) The temperature was raised to 80℃ and the system was allowed to react for 10h.

[0061] Post-processing: (1) After the reaction was complete, water was added to quench the reaction and acetic acid was added to neutralize the pH to 8-10; (2) Ethyl acetate was extracted 5 times and the organic phases were combined; (3) The organic phase was dried with anhydrous sodium sulfate, concentrated and then separated by rapid silica gel column chromatography to obtain a pale yellow solid; (4) TLC monitoring: developing solvent: dichloromethane / methanol = 10:1 Rf(compound 1) = 0.4.

[0062] The relevant spectral data for compounds 1 and 5 are as follows:

[0063] Compound 1: 1H NMR (400MHz, DMSO-d6) δ 13.33 (s, 1H), 8.44 (s, 1H), 8.32 (s, 1H), 5.55 (hept, J = 6.1Hz, 1H), 1.37 (d, J = 6.2Hz, 6H). HRMS (ESI-TOF) calculated for C8H10N4OH+[M+H+]: 179.09; found 179.10.

[0064] Compound 5: 11H NMR (400MHz, DMSO-d6) δ 13.37 (s, 1H), 8.47 (s, 1H), 8.35 (s, 1H), 5.57 (hept, J = 6.2Hz, 1H), 1.39 (d, J = 6.2Hz, 6H). HRMS (ESI-TOF) [M+H+]: 179.09; found 179.00.

[0065] Preparation of compounds 2, 4 and 6

[0066] The synthetic routes for compounds 2, 4, and 6 are shown below:

[0067]

[0068] The relevant spectral data for compounds 2, 4, and 6 are as follows:

[0069] Compound 2: 1found 179.30.

[0070] Compound 4: 1 H NMR(400MHz,Chloroform-d)δ8.58(s,1H),8.07(s,1H),5.63(hept,J=6.2Hz,1H),4.90(hept,J =6.7Hz,1H),1.59(d,J=6.8Hz,6H),1.44(d,J=6.2Hz,6H).HRMS(ESI-TOF)[M+H+]:221.27; found 221.20.

[0071] Compound 6: 1 found 179.30.

[0072] Preparation of compound 3

[0073] The synthetic route for compound 3 is shown below:

[0074]

[0075] The relevant spectral data for compound 3 are as follows:

[0076] Compound 3: 1 H NMR (400MHz, DMSO-d6) δ8.43 (s, 1H), 8.19 (s, 1H), 5.08 (hept, J = 6.9 Hz, 1H), 4.71 (hept, J = 6. 8Hz,1H),1.52(d,J=6.8Hz,6H),1.41(d,J=6.9Hz,6H).HRMS(ESI-TOF)[M+H+]:221.27; found 221.30.

[0077] Preparation of compounds 7 to 12

[0078] Compounds 7 through 12 were prepared by the same method used to prepare one of compounds 1 through 6 as described above.

[0079] The relevant spectral data of compounds 7 to 12 are as follows:

[0080] Compound 7: 1 found 193.10.

[0081] Compound 8: 1 H NMR(500MHz,Chloroform-d)δ8.55(s,1H),7.95(d,J=0.9Hz,1H),4.85(heptd,J=5.2,0.5Hz,1H) ,4.62(q,J=6.5Hz,2H),1.57(s,3H),1.50(t,J=6.5Hz,3H).HRMS(ESI-TOF)[M+H+]:207.12; found 207.10.

[0082] Compound 9: 1 H NMR (500MHz, Chloroform-d) δ8.51 (s, 1H), 7.57 (d, J = 0.3Hz, 1H), 4.57 (heptd, J = 5.0, 0.7Hz, 1H), 4.61 (t, J = 5. 4Hz,2H),1.90(qt,J=7.3,5.9Hz,2H),1.63(s,6H),1.15(t,J=7.4Hz,3H).HRMS(ESI-TOF)[M+H+]:221.13; found 221.10.

[0083] Compound 10: 1 H NMR(500MHz,Chloroform-d)δ8.37(s,1H),5.33–5.27(m,3H),4.74–4.64(m,2H),1.25 (d,J=6.2Hz,6H),1.17(dd,J=6.7,5.2Hz,12H).HRMS(ESI-TOF)[M+H+]:265.20; found 265.20.

[0084] Compound 11: 1H NMR (500MHz, Chloroform-d) δ7.99–7.88 (m, 2H), 4.83 (pd, J=5.6, 0.8Hz, 1H), 2.32 (s, 3H), 1.53 (s, 6H). HRMS (ESI-TOF) [M+H+]: 221.10; found 221.10.

[0085] Compound 12: 1 H NMR(500MHz,Chloroform-d)δ7.99–7.90(m,2H),4.85(heptd,J=5.2,0.5Hz,1H),2.54( q,J=7.7Hz,2H),1.55(s,3H),1.19–1.11(m,3H).HRMS(ESI-TOF)[M+H+]:235.10; found 235.10.

[0086] Preparation of compounds 13-18

[0087] Compounds 13 to 18 were prepared according to the method described above for compound 3.

[0088] The relevant spectral data of compounds 13 to 18 are as follows:

[0089] Compound 13: 1 H NMR(500MHz,Chloroform-d)δ8.54(s,1H),7.85(s,1H),4.65(s,1H),3.84(s,3H),1.23(s,6H).HRMS(ESI-TOF)[M+H+]:193.11; found 193.10.

[0090] Compound 14: 1 H NMR(500MHz,Chloroform-d)δ8.13(s,1H),7.56(s,1H),7.51(s,1H),5.83(s,1H),4.11(d,J=1.3H z,2H),4.11(s,1H),1.32(s,3H),1.23(s,3H),1.21(s,3H).HRMS(ESI-TOF)[M+H+]:209.14; found 209.14.

[0091] Compound 15: 1H NMR(500MHz,Chloroform-d)δ8.13(s,1H),7.81(s,1H),7.22(s,1H),5.91(s,1H),4.16(d,J=16.2Hz, 3H),1.84–1.71(m,2H),1.21(s,3H),1.10(s,3H),0.93(s,3H).HRMS(ESI-TOF)[M+H+]:223.16; found 223.16.

[0092] Compound 16: 1 H NMR(500MHz,Chloroform-d)δ8.41(s,1H),8.12(s,1H),7.82(s,1H),6.64(s,1H),3.91(s,3H),3.43(d,J=1.6Hz ,2H),1.72(d,J=12.1Hz,1H),1.72(d,J=12.3Hz,1H),0.91(s,3H).HRMS(ESI-TOF)[M+H+]:195.12; found195.12.

[0093] Compound 17: 1 H NMR(500MHz,Chloroform-d)δ8.41(s,1H),8.15(s,1H),7.84(s,1H),6.64(s,1H),4.20(d,J=2.4Hz,2H),3.44(d,J=1.6Hz,2 H), 1.74 (d, J = 12.1Hz, 1H), 1.72 (d, J = 12.3Hz, 1H), 1.34 (s, 3H), 0.91 (s, 3H). HRMS (ESI-TOF) [M+H+]: 209.14; found209.15.

[0094] Compound 18: 1 H NMR(500MHz,Chloroform-d)δ8.51(s,1H),7.95(s,1H),4.23(s,2H),4.14(s,2H),1.8 3(s,2H),1.78(s,2H),1.07(s,3H),0.93(s,3H).HRMS(ESI-TOF)[M+H+]:221.14; found 221.14.

[0095] Example 2: The activity of compounds 1-18 obtained in Example 1 against extensive peritoneal failure, high transport, and peritoneal fibrosis.

[0096] Experimental methods: A glucose chlorhexidine-induced peritonitis model was established. SPF-grade C57BL / 6 mice (weighing about 22-25g) were randomly divided into several groups, including a blank control group, a model group, and a hypoxanthine derivative and control drug intervention group, with 10 mice in each group. They were housed in an SPF-grade animal center for 7 days. At the start of the experiment, mice in each group were intervened by intraperitoneal injection of drugs. The blank control group received the same volume of physiological saline as the drug group based on body weight. The model group and drug intervention group received an appropriate volume of glucose chlorhexidine (0.1% / day, 10 mL / kg, administered every other day). The model group and drug intervention group received an appropriate volume of drug compound 1-18 (60 mg / kg / day), control group 1-3 (compounds A, B, and C, respectively), and control nintedanib (control group 4) based on body weight, administered twice daily. On day 22, mice were anesthetized with 0.8% tribromoethanol solution (10 mL / kg) and intraperitoneally injected with 4.25% dialysate. Four hours later, the peritoneum was incised along the midline of the abdomen, and the volume of peritoneal fluid was accurately measured. Ultrafiltration volume = (final outflow volume - intraperitoneal injection of 4.25% dialysate) mL. Peritoneal tissue was collected from the mice to evaluate the severity of peritoneal fibrosis. Paraffin sections of the peritoneal tissue were stained with MASSON stain. Figure 1 HE staining Figure 2 Peritoneal thickness was quantified (Table 1, Table 2), and pathological scores were performed. Data were analyzed using SPSS 19.0 statistical software. The results are expressed as mean ± standard deviation, and P < 0.05 was considered statistically significant.

[0097] Peritoneal function testing: Serum and peritoneal dialysis fluid were collected, and the glucose concentrations of serum, initial peritoneal dialysis fluid, and peritoneal dialysis fluid after 1 hour (D1) and initial peritoneal dialysis fluid (D0) were measured. Peritoneal equilibration test (PET) was performed: D1 / D0 was calculated as the ratio of glucose concentration in 1-hour peritoneal dialysis fluid to that in 0-hour peritoneal dialysis fluid. Since the 4-hour D / P creatinine ratio (D / PCr) is the most stable, it is currently used to assess the peritoneal transport characteristics of kidney patients (D: dialysate creatinine value, P: serum creatinine value). A 4-hour D / P creatinine ratio of 0.82-1.03 indicates high peritoneal transport, while a ratio of 0.65-0.81 indicates above-average transport.

[0098] Masson diagrams of the peritoneum in each group ( Figure 1 It can be seen that the peritoneal thickness of compound 1-18 was significantly reduced compared with the model group, and the Masson staining intensity was significantly reduced. Furthermore, it can be observed that the inflammatory infiltration in the compound 1-18 drug intervention group was significantly reduced, indicating that the hypoxanthine derivative 1-18 has a significant therapeutic effect on peritoneal fibrosis and is superior to the control group of hypoxanthine derivative 1-3 and control group of nintedanib.

[0099] Masson staining was used to detect peritoneal fibrosis and collagen fibrosis, and peritoneal thickness was quantified. The results showed that hypoxanthin derivative 1-18 could significantly reduce peritoneal thickness in glucose chlorhexidine-induced peritoneal fibrosis, and the effect was significantly better than the control group 4 nintedanib, and better than the control group 1-3 (hypoxanthin derivative AC) (Table 1).

[0100] Table 1. Analysis of Peritoneal Fibrosis Degree and Parietal Peritoneal Thickness Based on Masson Diagram

[0101] Group Peritoneal thickness (μm) Group Peritoneal thickness (μm) Blank control group 13±1 Compound 7 55±11 Model group 250±21 Compound 8 75±14 Control group 1 198±25 Compound 9 58±13 Control group 2 193±15 Compound 10 35±15 Control group 3 257±24 Compound 11 51±8 Control group 4 201±16 Compound 12 45±10 Compound 1 69±9 Compound 13 65±12 Compound 2 58±10 Compound 14 54±9 Compound 3 29±5 Compound 15 61±10 Compound 4 36±6 Compound 16 52±8 Compound 5 58±14 Compound 17 98±11 Compound 6 89±15 Compound 18 43±10

[0102] HE images of the peritoneum in each group ( Figure 2 It can be seen that the peritoneal thickness of compound 1-18 was significantly reduced compared with the model group, and the peritoneal inflammatory cell infiltration in the compound 1-18 drug intervention group was significantly reduced, indicating that the hypoxanthine derivative 1-18 has a significant effect on the treatment of peritoneal fibrosis, and is superior to the control group 1-3 (hypoxanthine derivative AC) and the control drug nintedanib.

[0103] As can be seen from the quantitative results of peritoneal thickness on HE images in Table 2, compound 1-18 significantly improved peritoneal fibrosis and was significantly better than control group 1-3 (hypoxanthin derivative AC) and control group 4 (nintedanib).

[0104] pass Figure 1 , 2 The data in Tables 1-3 clearly show that the degree of peritoneal fibrosis and peritoneal function in the glucose chlorhexidine-induced peritoneal fibrosis model mice were significantly improved under the action of compound 1-18 prepared in Example 1, indicating that compound 1-18 prepared in Example 1 has a significant anti-peritoneal fibrosis effect and a better improvement effect than control group 1-3 (hypoxanthin derivative AC) and control group 4 nintedanib.

[0105] Table 2. Analysis of peritoneal fibrosis degree and parietal peritoneal thickness based on peritoneal HE map.

[0106] Group Peritoneal thickness (μm) Group Peritoneal thickness (μm) Blank control group 12±2 Compound 7 51±13 Model group 243±23 Compound 8 32±10 Control group 1 268±15 Compound 9 61±11 Control group 2 233±11 Compound 10 42±16 Control group 3 241±21 Compound 11 47±10 Control group 4 223±11 Compound 12 52±13 Compound 1 52±6 Compound 13 58±15 Compound 2 48±12 Compound 14 43±12 Compound 3 57±4 Compound 15 52±10 Compound 4 69±8 Compound 16 56±14 Compound 5 74±12 Compound 17 63±13 Compound 6 56±12 Compound 18 49±10

[0107] Table 3. Results of peritoneal function tests in each group

[0108] Group D1 / D0 Group D1 / D0 Blank control group 0.61±0.05 Compound 7 0.52±0.04 Model group 0.14±0.01 Compound 8 0.56±0.05 Control group 1 0.15±0.02 Compound 9 0.54±0.05 Control group 2 0.16±0.02 Compound 10 0.56±0.04 Control group 3 0.17±0.01 Compound 11 0.51±0.05 Control group 4 0.21±0.01 Compound 12 0.53±0.04 Compound 1 0.51±0.04 Compound 13 0.55±0.04 Compound 2 0.54±0.05 Compound 14 0.52±0.03 Compound 3 0.58±0.04 Compound 15 0.57±0.05 Compound 4 0.56±0.04 Compound 16 0.56±0.03 Compound 5 0.54±0.04 Compound 17 0.53±0.05 Compound 6 0.51±0.05 Compound 18 0.54±0.03

[0109] Table 4. Ultrafiltration rate for each group

[0110] Group UF (mL) Group UF (mL) Blank control group 0.96±0.16 Compound 7 0.90±0.09 Model group 0.42±0.09 Compound 8 0.88±0.09 Control group 1 0.46±0.07 Compound 9 0.88±0.09 Control group 2 0.43±0.04 Compound 10 0.86±0.08 Control group 3 0.44±0.05 Compound 11 0.86±0.08 Control group 4 0.45±0.05 Compound 12 0.88±0.08 Compound 1 0.85±0.08 Compound 13 0.91±0.08 Compound 2 0.86±0.09 Compound 14 0.89±0.09 Compound 3 0.95±0.09 Compound 15 0.90±0.08 Compound 4 0.92±0.08 Compound 16 0.89±0.09 Compound 5 0.86±0.08 Compound 17 0.91±0.08 Compound 6 0.91±0.08 Compound 18 0.91±0.09

[0111] Table 5. Peritoneal transport function of each group: creatinine in peritoneal dialysis fluid at 4 hours / serum creatinine at 2 hours (4-hour D / P creatinine value)

[0112]

[0113]

[0114] Table 6. Serum inflammation-related indicators for each group

[0115] Group IL-6 (pg / mL) Group IL-6 (pg / mL) Blank control group 78±10 Compound 7 83±9 Model group 350±23 Compound 8 90±6 Control group 1 325±33 Compound 9 79±8 Control group 2 348±30 Compound 10 86±7 Control group 3 334±31 Compound 11 93±9 Control group 4 342±34 Compound 12 98±6 Compound 1 85±7 Compound 13 81±7 Compound 2 92±6 Compound 14 87±8 Compound 3 78±9 Compound 15 94±9 Compound 4 89±8 Compound 16 99±6 Compound 5 95±6 Compound 17 84±8 Compound 6 100±7 Compound 18 91±7

[0116] By comparing the peritoneal ultrafiltration volume, 4-hour D / P creatinine value, and serum inflammatory factor data in Tables 4, 5, and 6, the results showed that compounds 1-18 prepared in Example 1 significantly reduced peritoneal ultrafiltration failure, peritoneal hypertransport, and peritoneal inflammation levels induced in the model group. This indicates that the compounds prepared in Example 1 have a good therapeutic effect on peritoneal diseases, including peritonitis, peritoneal fibrosis, peritoneal ultrafiltration failure, peritoneal hypertransport, and other related peritoneal diseases and their complications.

[0117] Example 3: Compounds 1-18 obtained in Example 1 exhibit activity against peritoneal diseases induced by peritoneal dialysis fluid, peritoneal fibrosis, ultrafiltration failure, and high transport.

[0118] Experimental Methods: A peritoneal fibrosis model induced by 4.25% peritoneal dialysis fluid was established in vivo. SPF-grade C57BL / 6 mice (approximately 22–25 g) were randomly divided into several groups, including a blank control group, a model group, and compound 1-18 groups, with 15 mice in each group. These mice were housed in an SPF-grade animal center for 7 days. At the start of the experiment, each group underwent intraperitoneal injection of the drugs. Mice in the blank control group received the same volume of physiological saline as the drug groups based on their body weight. Mice in the model group received an appropriate volume of 4.25% peritoneal dialysis fluid (1 mL / g / d) based on their body weight. The model group and drug intervention groups received 60 mg / kg / d of compound 1-18, control groups 1-3 (compounds A, B, and C, respectively), and control group 4 (nintedanib) once daily. The drugs were dissolved in the peritoneal dialysis fluid and administered intraperitoneally. Forty-two days after drug administration, on day 43, mice were anesthetized with 0.8% tribromoethanol solution (10 mL / kg) and injected intraperitoneally with 4.25% peritoneal dialysis fluid (1 mL / g / d). Two hours later, the abdominal wall was cut along the linea alba, and peritoneal fluid was collected. Simultaneously, blood and peritoneal fluid samples were collected from each mouse at 0 h and 2 h after dialysis. Blood samples were centrifuged at 1000 rpm for 10 minutes, and peritoneal dialysis fluid samples were centrifuged at 1500 rpm for 5 minutes. Glucose concentration was determined using an automated biochemical analyzer. Peritoneal thickness was measured. After euthanizing the mice, parietal and visceral peritoneum were collected, embedded in paraffin, and serially sectioned for Masson staining. Peritoneal function was assessed: serum and peritoneal dialysis fluid were collected, and the glucose concentrations in serum, initial peritoneal dialysis fluid, and peritoneal dialysis fluid 1 hour later (D1) and the initial peritoneal dialysis fluid (D0) were measured. Peritoneal equilibration test (PET) was performed by calculating the ratio of glucose concentration in the 1-hour peritoneal dialysis fluid to that in the 0-hour peritoneal dialysis fluid (D1 / D0). Data were analyzed using SPSS 19.0 statistical software, and expressed as mean ± standard deviation. A p-value < 0.05 was considered statistically significant.

[0119] Masson diagrams of the peritoneum in each group ( Figure 3 It can be seen that the peritoneal thickness of compound 1-18 was significantly reduced compared with the model group, and the Masson staining intensity was significantly reduced. Furthermore, it can be observed that the inflammatory infiltration in the compound 1-18 drug intervention group was significantly reduced, indicating that the hypoxanthine derivative 1-18 has a significant therapeutic effect on peritoneal fibrosis and is superior to the control group 1-3 (hypoxanthine derivative AC) and the control group 4 nintedanib.

[0120] Masson staining was used to detect peritoneal fibrosis and collagen fibrosis, and peritoneal thickness was quantified. The results showed that hypoxanthin derivative 1-18 could significantly reduce peritoneal fibrosis and peritoneal thickness induced by peritoneal dialysis fluid, and the effect was significantly better than that of control group 1-3 (hypoxanthin derivative AC) and control group 4 nintedanib (Table 7).

[0121] Table 7. Analysis of Peritoneal Fibrosis Degree and Parietal Peritoneal Thickness Based on Masson Diagram

[0122]

[0123]

[0124] HE images of the peritoneum in each group ( Figure 4 It can be seen that the peritoneal thickness of compound 1-18 was significantly reduced compared with the model group, and the peritoneal inflammatory cell infiltration in the compound 1-18 intervention group was significantly reduced, indicating that the hypoxanthine derivative 1-18 has a significant therapeutic effect on peritoneal fibrosis, and is superior to the control group 1-3 (hypoxanthine derivative AC) and the control drug nintedanib. The quantitative results of peritoneal thickness in the HE images in Table 8 show that compound 1-18 significantly treats peritoneal fibrosis, and is significantly superior to the control group 1-3 (hypoxanthine derivative AC) and the control group 4 (nintedanib).

[0125] Table 8. Analysis of Peritoneal Fibrosis Degree and Parietal Peritoneal Thickness Based on Peritoneal HE Map

[0126]

[0127]

[0128] Table 9. Results of peritoneal function tests in each group

[0129] Group D1 / D0 Group D1 / D0 Blank control group 0.68±0.04 Compound 7 0.59±0.03 Model group 0.12±0.01 Compound 8 0.51±0.05 Control group 1 0.13±0.01 Compound 9 0.54±0.04 Control group 2 0.16±0.01 Compound 10 0.56±0.05 Control group 3 0.15±0.02 Compound 11 0.51±0.03 Control group 4 0.21±0.02 Compound 12 0.53±0.05 Compound 1 0.50±0.01 Compound 13 0.49±0.05 Compound 2 0.57±0.02 Compound 14 0.52±0.04 Compound 3 0.62±0.01 Compound 15 0.57±0.04 Compound 4 0.51±0.03 Compound 16 0.55±0.03 Compound 5 0.59±0.04 Compound 17 0.58±0.04 Compound 6 0.51±0.05 Compound 18 0.61±0.05

[0130] Table 10. Ultrafiltration rate for each group

[0131]

[0132]

[0133] Table 11. Peritoneal transport function of each group: creatinine in peritoneal dialysis fluid at 4 hours / serum creatinine at 2 hours (4-hour D / P creatinine value)

[0134] Group D / P Group UF (mL) Blank control group 0.61±0.05 Compound 7 0.69±0.05 Model group 0.94±0.09 Compound 8 0.70±0.06 Control group 1 0.90±0.08 Compound 9 0.71±0.05 Control group 2 0.91±0.09 Compound 10 0.63±0.06 Control group 3 0.92±0.08 Compound 11 0.64±0.05 Control group 4 0.93±0.09 Compound 12 0.65±0.06 Compound 1 0.63±0.05 Compound 13 0.66±0.05 Compound 2 0.64±0.06 Compound 14 0.67±0.06 Compound 3 0.65±0.05 Compound 15 0.68±0.05 Compound 4 0.66±0.06 Compound 16 0.69±0.06 Compound 5 0.67±0.05 Compound 17 0.70±0.05 Compound 6 0.68±0.06 Compound 18 0.71±0.06

[0135] Table 12. Serum inflammation-related indicators for each group

[0136]

[0137]

[0138] As shown in Tables 7-9, compounds 1-18 obtained in Example 1 significantly improved peritoneal fibrosis, peritoneal collagen deposition, and peritoneal function. This indicates that the compounds described in this application can effectively inhibit the increase in peritoneal thickness caused by peritoneal hyperplasia and improve peritoneal function, thus effectively preventing and reducing the tendency of peritoneal fibrosis and possessing a certain peritoneal protective function. This demonstrates that compounds 1-18 obtained in Example 1 have a significant anti-peritoneal fibrosis effect and a good improvement effect.

[0139] By comparing the peritoneal ultrafiltration volume, 4-hour D / P creatinine value, and serum inflammatory factor data in Tables 10-12, the results showed that compounds 1-18 prepared in Example 1 significantly reduced peritoneal ultrafiltration failure, peritoneal hypertransport, and peritoneal inflammation levels induced in the model group. This indicates that the compounds prepared in Example 1 have good therapeutic effects on peritoneal diseases, including peritonitis, peritoneal fibrosis, peritoneal ultrafiltration failure, peritoneal hypertransport, dialysate-related peritoneal diseases, and their complications.

[0140] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. The application of a hypoxanthin derivative in the preparation of a drug for treating peritoneal diseases, characterized in that, The hypoxanthin derivative has therapeutic activity for peritoneal diseases, and the hypoxanthin derivative has one of the following structures: in: R1 can be any of O, N, C, S or = O; R2, R3, and R4 can be chosen as H and C1-C, respectively. 18 Alkyl or halogen-substituted C1-C 18 Alkyl, trifluoromethyl, sulfonyl, sulfonamide, sulfinyl, amino acid, 2-[bis(neopentyloxy)methoxy]phosphonomethoxyethyl, C1-C 18 Fatty acid group, C3-C 12 Heterocyclic groups, C1-C 18 Fatty acids; or C1-C atoms in which R2, R3, and R4 are optionally substituted with oxygen, sulfur, or nitrogen atoms. 18 The alkyl or fatty acid group; when R3 or R4 is substituted, the double bond is attached to the unsubstituted N position, and when all are substituted, there is no double bond.

2. The application according to claim 1, characterized in that, The hypoxanthine derivatives mentioned are one or more of the following compounds:

3. The application according to claim 1, characterized in that, The peritoneal diseases include one or more of the following: peritonitis, peritoneal fibrosis, peritoneal ultrafiltration failure, peritoneal hypertransport, dialysis fluid-related peritoneal diseases, and their complications.

4. The application according to claim 1, characterized in that, The aforementioned drug for treating peritonitis is a preparation made by adding pharmaceutically acceptable excipients or auxiliary ingredients, with hypoxanthine derivatives or their salts as the active ingredient.

5. The application according to claim 4, characterized in that, The preparation is an oral preparation, an injectable preparation, or a nasal mucosal delivery preparation.

6. Compounds having the following structure: in: R1 can be any of O, N, C, S or = O; R2, R3, and R4 can be chosen as H and C1-C, respectively. 18 Alkyl or halogen-substituted C1-C 18 Alkyl, trifluoromethyl, sulfonyl, sulfonamide, sulfinyl, amino acid, 2-[bis(neopentyloxy)methoxy]phosphonomethoxyethyl, C1-C 18 Fatty acid group, C3-C 12 Heterocyclic groups, C1-C 18 Fatty acids; or C1-C atoms in which R2, R3, and R4 are optionally substituted with oxygen, sulfur, or nitrogen atoms. 18 The alkyl or fatty acid group; when R3 or R4 is substituted, the double bond is attached to the unsubstituted N position, and when all are substituted, there is no double bond.

7. The compound according to claim 6, selected from the group consisting of:

8. A pharmaceutical composition comprising the compound of claim 6 or 7 or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to claim 8, further comprising pharmaceutically acceptable excipients or auxiliary ingredients.

10. The pharmaceutical composition according to claim 8 or 9, wherein it is an oral formulation, an injectable formulation, or a nasal mucosal administration formulation.

11. A method for treating peritoneal diseases, characterized in that, Administer to an individual in need an effective amount of the compound of claim 6 or 7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claims 8-10.

12. The method according to claim 11, characterized in that, The peritoneal diseases include one or more of the following: peritonitis, peritoneal fibrosis, peritoneal ultrafiltration failure, peritoneal hypertransport, dialysis fluid-related peritoneal diseases, and their complications.

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