CN114588161A - Hypoxanthine derivative with effect of preventing and treating pneumonia - Google Patents
Hypoxanthine derivative with effect of preventing and treating pneumonia Download PDFInfo
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- CN114588161A CN114588161A CN202011438505.8A CN202011438505A CN114588161A CN 114588161 A CN114588161 A CN 114588161A CN 202011438505 A CN202011438505 A CN 202011438505A CN 114588161 A CN114588161 A CN 114588161A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
The invention relates to a hypoxanthine derivative with a pneumonia prevention and treatment effect, and belongs to the technical field of medicines. The invention provides application of a compound shown as a formula I or a salt thereof in preparing a medicament for preventing and treating pneumonia. Biological experiments prove that the hypoxanthine derivative can obviously improve pneumonia caused by bacteria, viruses and mycoplasma, reduce the number of inflammatory cells such as leucocytes and the like in pneumonia model blood, or reduce the levels of NF-kappa B, TNF-alpha, IL-1 beta and IL-6 in serum. The inventionProvides a new choice for the development and application of anti-pneumonia drugs.
Description
Technical Field
The invention relates to a hypoxanthine derivative with a pneumonia prevention and treatment effect, and belongs to the technical field of medicines.
Background
Pneumonia refers to the inflammation of the lung parenchyma including the terminal airways, alveolar spaces and pulmonary interstitium after the body is infected with pathogenic microorganisms such as viruses, bacteria and mycoplasma or after foreign matters such as dust and haze are inhaled. Pneumonia is the important cause of death and the first infectious disease cause of death of human beings, and is also the first cause of death of children under 5 years of age worldwide. Therefore, the search for a medicament which can prevent and treat pneumonia and reduce pulmonary inflammatory response is of great significance.
Inosine (1, 7-dihydro-6H-purin-6-one, Hypoxanthine), also known as "6-hydroxypurine" or "Hypoxanthine", is a naturally occurring purine compound that is a synthetic precursor of purine nucleotides. At present, no research finds a hypoxanthine compound which can block the development of pneumonia and reverse pathological injury.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art. Therefore, the invention aims to provide the hypoxanthine derivative with the effect of preventing and treating pneumonia.
The invention provides an application of a compound shown as a formula I or a salt thereof in preparing a medicament for preventing and treating pneumonia:
wherein R is1Selected from O, NH, CH2、S；
R2、R3Independently selected from H, substituted or unsubstituted C1-C3 alkyl, and R2、R3Not both can be H.
Further, R1Selected from O, S, NH.
Further, the substituted C1-C3 alkyl is a halogen substituted C1-C3 alkyl.
Further, R2、R3Independently selected from H or unsubstituted C1-C3 alkyl, and R2、R3Not both can be H.
Further, the compound is selected from:
further, the pneumonia is bacterial pneumonia, viral pneumonia and mycoplasma pneumonia.
Further, the bacterial pneumonia is pneumonia caused by streptococcus pneumoniae infection.
Further, the viral pneumonia is pneumonia caused by influenza virus and coronavirus infection.
Preferably, the influenza virus is influenza A virus or influenza B virus.
Preferably, the coronavirus is HCoV-OC43 or SARS-CoV-2.
Further, the mycoplasma pneumonia is pneumonia caused by mycoplasma pneumoniae infection.
Furthermore, the medicine is a preparation prepared by taking the compound shown in the formula I or the salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
Further, the preparation is an oral preparation, an injection preparation or a nasal mucosa administration preparation.
Definition of terms:
the compounds and derivatives provided by the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.
The term "alkyl" is a radical of a straight or branched chain saturated hydrocarbon group. C1～C3Examples of alkyl groups include methyl (C)1) Ethyl (C)2) N-propyl (C)3) And isopropyl (C)3)。
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.
The term "pharmaceutically acceptable salts" refers to acid and/or base salts of the compounds of the present invention with inorganic and/or organic acids and bases, and also includes zwitterionic salts (inner salts), and also includes quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound may be obtained by appropriately (e.g., equivalent) mixing the above compound with a certain amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.
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 the following ingredients: (a) fillers or solubilizers, for example, starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
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 nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The pharmaceutically acceptable auxiliary material of the invention refers to a substance contained in a dosage form except for an active ingredient.
The pharmaceutically acceptable auxiliary components have certain physiological activity, but the addition of the components does not change the dominant position of the pharmaceutical composition in the disease treatment process, but only plays auxiliary effects, and the auxiliary effects are only the utilization of the known activity of the components and are auxiliary treatment modes which are commonly used in the field of medicine. If the auxiliary components are used in combination with the pharmaceutical composition of the present invention, the protection scope of the present invention should still be included.
The invention provides a hypoxanthine derivative with a pneumonia prevention and treatment effect. Biological experiments prove that the hypoxanthine derivative can obviously improve pneumonia caused by bacteria, viruses and mycoplasma, reduce the number of inflammatory cells such as leucocytes and the like in pneumonia model blood, or reduce the levels of NF-kappa B, TNF-alpha, IL-1 beta and IL-6 in serum. The invention provides a new choice for the development and application of anti-pneumonia drugs.
Drawings
FIG. 1 is a graph of lung tissue HE in test example 1;
FIG. 2 is a graph of lung tissue HE in Experimental example 2;
FIG. 3 is a graph of HE in lung tissue in test example 4.
Detailed Description
The invention provides an application of a compound shown as a formula I or a salt thereof in preparing a medicament for preventing and treating pneumonia:
wherein R is1Selected from O, NH, CH2、S；
R2、R3Independently selected from H, substituted or unsubstituted C1-C3 alkyl, and R2、R3Not both can be H.
Structural modification and modification of natural products is one of the common approaches to obtain compounds with excellent pharmacological activity. The inventor of the invention screens a series of natural compounds and finds that the hypoxanthine has potential anti-pneumonia activity. Based on this, the inventors carried out structural modification using a hypoxanthine as a lead compound, and expected further optimization of the drug effect. By inspection, R2、R3The groups represented have important influence on improving the anti-pneumonia activity of the hypoxanthine: when electingWhen H or short-chain alkyl is used, the compound can play a remarkable anti-pneumonia effect; if the carbon chain of the alkyl group is extended or other functional groups with higher steric hindrance are used, the activity is reduced. Furthermore, R2、R3And when the content of the derivative is H (namely the hypoxanthine), the anti-pneumonia activity is not strong, and the anti-pneumonia activity is probably related to the solubility and the pH value of the compound. The efficacy of the compounds can be compared in the following biological experiments.
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
According to a preferred embodiment, the compounds 1-12 of the present invention are typically prepared by one or more steps of alkylation, sulfhydrylation, and imidization of inosine.
The following examples provide methods for the preparation of 12 typical compounds, each of which was structurally characterized by nuclear magnetic resonance spectroscopy (HNMR, CNMR) and mass spectrometry.
EXAMPLE 1 preparation of Compound 1, Compound 2
The preparation of compound 1 and compound 2 was as follows, starting from 1mmol of the main starting material for each reaction step below. Alkylation was carried out by reacting 1mmol of hypoxanthine and 1mmol of isopropyl iodide (2-iodopropane) in DMF (150mL) over NaH (0.5mmol) as catalyst for 3 h. Then adding hydrochloric acid to adjust the pH value to be neutral, decompressing and spin-drying the crude product, washing the crude product with methanol to remove the desalted product, then pressurizing and spin-drying the crude product to be desalted, and finally purifying the compound by a chromatographic column to obtain a compound 1 and a compound 2.
Compound 1:1H NMR(400MHz,DMSO)δ12.27(s,1H),8.19(s,1H),8.04(s,1H),4.79–4.65(m,1H),1.51(d,J＝6.8Hz,6H).13C NMR(101MHz,DMSO)δ156.73(s),147.81(s),145.15(s),138.19(s),124.27(s),46.91(s),22.25(s).HRMS(ESI-TOF)calc’d for C8H10N4ONa+[M+Na+]:201.0752；found201.0755.
compound 2:1H NMR(500MHz,Chloroform-d)δ8.26(d,J＝1.8Hz,1H),7.84(s,1H),4.34(heptd,J＝6.9,1.7Hz,1H),1.22(d,J＝6.8Hz,6H).13C NMR(125MHz,Common NMR Solvents)δ157.15,156.26,146.32,143.74,111.40,52.12,21.74。HRMS(ESI-TOF)calc’d for C8H10N4ONa+[M+Na+]:201.0752；found201.0831.
EXAMPLE 2 preparation of Compound 3
The preparation of compound 3 was as follows, starting from 1mmol of the main starting material for each reaction step below. Alkylation was carried out by reacting 1mmol of hypoxanthine and 5mmol of isopropyl iodide (2-iodopropane) in DMF (150mL) over NaH (0.5mmol) as catalyst for 3 h. Then hydrochloric acid is added to adjust the pH value to be neutral, the crude product is dried by spinning under reduced pressure, 2 is washed by methanol to remove the desalted product, then the crude product is dried by spinning under increased pressure to be desalted, and finally the compound is purified by a chromatographic column to obtain a compound 3.
Compound 3:1H NMR(600MHz,DMSO)δ8.47(s,1H),8.45(s,1H),5.58(hept,J＝6.2Hz,1H),4.81(hept,J＝6.8Hz,1H),1.54(d,J＝6.8Hz,6H),1.38(d,J＝6.2Hz,6H).13C NMR(151MHz,DMSO)δ159.58,151.67,151.09,141.55,121.06,69.29,47.01,21.98,21.78.HRMS(ESI-TOF)calc’d for C11H17N4OH+[M+H+]:221.1402；found221.13967.
EXAMPLE 3 preparation of Compound 4, Compound 5
The preparation of compound 4 and compound 5 was as follows, starting from 1mmol of the main starting material for each reaction step below. Taking 1mmol of the compound 2 (compound 1) and 3mmol of the Lawson reagent to react for 6h to obtain a compound 4 (or a compound 5).
Compound 4:1H NMR(500MHz,Chloroform-d)δ7.83(d,J＝6.4Hz,1H),7.62(d,J＝0.7Hz,1H),4.81(heptd,J＝4.6,0.7Hz,1H),1.82(s,6H).13C NMR(125MHz,Common NMR Solvents)δ176.34,151.47,145.89,143.12,141.73,48.32,22.13.
compound 5:1H NMR(500MHz,Chloroform-d)δ8.13(d,J＝6.8Hz,1H),6.82(d,J＝1.6Hz,1H),4.13(heptd,J＝7.2,1.8Hz,1H),1.24(d,J＝7.1Hz,6H).13C NMR(125MHz,Common NMR Solvents)δ185.23,150.82,146.53,145.42,124.71,54.13,21.72.
EXAMPLE 4 preparation of Compound 6
Taking 1mmol of hypoxanthine, 1mmol of iodo-isopropyl, 1mmol of NaH and 100mL of acetonitrile, stirring for 6h to obtain a crude product, and separating by a silica gel column to obtain an isopropyl substituted hypoxanthine product. Taking 1mmol of isopropyl substituted hypoxanthine product, 1mmol of methyl iodide, 1mmol of NaH and 100mL of acetonitrile, stirring for 6h to obtain a crude product, and separating by a silica gel column to obtain a compound 6.
Compound 6:1H NMR(500MHz,Chloroform-d)δ8.32(t,J＝0.9Hz,1H),7.93(d,J＝0.7Hz,1H),4.82–4.71(m,1H),3.61(d,J＝1.1Hz,3H),1.84(d,J＝4.6Hz,6H).13C NMR(125MHz,Common NMR Solvents)δ156.82,152.24,149.61,141.72,130.31,48.32,35.12,22.13.
EXAMPLE 5 preparation of Compound 7, Compound 8, Compound 9
1mmol of Compound 1 (or Compound 2 or Compound 3), 10mmol of ammonia water, 150mL of ethanol, and 2mL of acetic acid were placed in a 250mL flask and stirred at 78 ℃. TCL detects the reaction progress, the reaction is basically completed after about 6 hours, and the obtained compound 7 (or compound 8 or compound 9) is separated and extracted by a silica gel column.
Compound 7:1H NMR(500MHz,Chloroform-d)δ9.51(s,1H),7.81(s,1H),7.62(s,1H),4.85(heptd,J＝4.3,0.7Hz,1H),1.81(s,6H).13C NMR(125MHz,Common NMR Solvents)δ156.71,153.53,152.71,142.61,128.74,48.33,22.11.
compound 8:1H NMR(500MHz,Chloroform-d)δ8.11(s,1H),6.84(s,1H),3.32(heptd,J＝6.6,1.8Hz,1H),1.21(d,J＝6.5Hz,6H).13C NMR(125MHz,Common NMR Solvents)δ151.54,149.81,144.23,142.93,108.11,53.15,21.77.
compound 9:1H NMR(500MHz,Chloroform-d)δ7.63(s,1H),6.89(s,1H),4.80(heptd,J＝4.6,0.9Hz,1H),3.34(heptd,J＝6.6,1.8Hz,1H),1.82(d,J＝6.1Hz,6H),1.22(d,J＝6.5Hz,6H).13C NMR(125MHz,Common NMR Solvents)δ155.52,150.21,145.34,142.72,128.64,53.11,48.33,22.13,21.76.
EXAMPLE 6 preparation of Compound 10
Taking 1mmol of hypoxanthine, 1mmol of methyl iodide, 4mmol of NaH and 100mL of acetonitrile, stirring for 6 hours to obtain a crude product, and separating by a silica gel column to obtain a methyl substituted hypoxanthine product compound 10.
Compound 10:1H NMR(500MHz,Chloroform-d)δ8.31(s,1H),7.80(s,1H),3.61(s,3H),3.50(sHz,3H).13C NMR(125MHz,Common NMR Solvents)δ158.81,149.01,148.51,143.45,120.14,35.09,30.61.
EXAMPLE 7 preparation of Compound 11
Taking 1mmol of hypoxanthine, 5mmol of iodoethane, 4mmol of NaH and 100mL of acetonitrile, stirring for 6 hours to obtain a crude product, and separating by a silica gel column to obtain a methyl substituted hypoxanthine product compound 11.
Compound 11:1H NMR(500MHz,Chloroform-d)δ8.21(s,1H),7.80(s,1H),4.12(qd,J＝5.1,0.8Hz,2H),2.91(qd,J＝7.3,0.9Hz,2H),1.52(d,J＝10.3Hz,3H),1.12(t,J＝7.4Hz,3H).13C NMR(125MHz,Common NMR Solvents)δ156.31,154.32,150.21,142.33,123.02,42.14,40.23,15.32,14.03.
EXAMPLE 8 preparation of Compound 12
Taking 1mmol of hypoxanthine, 5mmol of iodopropane, 4mmol of NaH and 100mL of acetonitrile, stirring for 6h to obtain a crude product, and separating by a silica gel column to obtain a methyl substituted hypoxanthine product compound 12.
Compound 12:1H NMR(500MHz,Chloroform-d)δ8.21(d,J＝1.0Hz,1H),7.71(d,J＝1.0Hz,1H),4.13(td,J＝4.2,0.8Hz,2H),3.63(td,J＝6.5,0.9Hz,2H),1.84(qt,J＝7.3,4.2Hz,2H),1.82–1.71(m,2H),0.93–0.90(m,6H).13C NMR(125MHz,Common NMR Solvents)δ157.03,152.64,149.95,141.74,123.04,47.82,44.82,22.41,11.13,10.81.
the beneficial effects of the invention are demonstrated by biological experiments below. The structures of the hypoxanthine analogs (compound a, compound B, compound C) used for comparison in the test examples are as follows:
test example 1 Activity of typical Compounds 1 to 12 of the present invention against pneumonia induced by Streptococcus pneumoniae
Model of pneumonia caused by streptococcus pneumoniae in vivo: the SPF-grade C57BL/6J mice (25g) are randomly and evenly divided into a plurality of groups, including a blank control group, a model group, a methylprednisolone positive control group, a compound A group, a compound B group, a compound C group and a compound 1-12 group, wherein 9 mice in each group are raised for 7 days in a standard environment. Before the experimentThe mice are lightly anesthetized by ether inhalation, and then the mice of a model group, a methylprednisolone positive control group, a hypoxanthine analogue A, B, C group and a compound 1-12 group are respectively given 0.5mL/kg of bacterial liquid (the concentration is 1.0 multiplied by 10) by a nasal inhalation method except that a blank control group of mice is instilled with normal saline through the nasal cavity9CFU/mL), the bacterial liquid is slowly instilled into the nasal cavity of the mouse by using a syringe needle, and the instillation speed is about 0.05 mL/min. After the molding is finished, the mice of the blank control group and the model group are administrated with normal saline with the same dose of the drug group for intragastric administration at 12h and 24h, the mice of the positive control group are administrated with methylprednisolone (120mg/kg) by intragastric administration, the hypoxanthine analog A, B, C groups are administrated with the hypoxanthine analog A, B, C (120mg/kg/d) by intragastric administration, and the compounds 1-12(120mg/kg/d) of the invention are administrated by intragastric administration for the compounds 1-12 groups. The administration was performed twice a day for 7d, and 2 hours after the last administration, the mice were anesthetized with a 0.4% sodium pentobarbital solution (10mL/kg), blood was taken from the abdominal aorta and the blood routine change was examined. The results are shown in the following table:
TABLE 1
| White blood cells (10)9/L) | Neutrophils (10)9/L) | Lymphocyte (10)9/L) | |
| Blank group | 4.85 | 0.99 | 4.79 |
| Model set | 47.45 | 34.98 | 36.56 |
| Positive drug group | 38.15 | 25.49 | 25.25 |
| Compound A | 49.15 | 27.98 | 28.97 |
| Compound B | 39.35 | 27.57 | 31.14 |
| Compound C | 43.12 | 25.14 | 29.21 |
| Compound 1 | 4.83 | 0.93 | 4.71 |
| Compound 2 | 4.83 | 1.01 | 4.98 |
| Compound 3 | 4.81 | 0.95 | 4.68 |
| Compound 4 | 5.47 | 1.04 | 5.42 |
| Compound 5 | 5.12 | 0.98 | 5.12 |
| Compound 6 | 4.98 | 0.99 | 5.13 |
| Compound 7 | 4.94 | 0.99 | 5.31 |
| Compound 8 | 4.95 | 0.94 | 4.83 |
| Compound 9 | 4.89 | 1.02 | 4.79 |
| Compound 10 | 5.11 | 1.15 | 4.96 |
| Compound 11 | 4.99 | 1.14 | 5.12 |
| Compound 12 | 5.25 | 1.18 | 5.62 |
As can be seen from Table 1, the compound of the invention can significantly reduce the level of leukocytes, neutrophils and lymphocytes in blood, and shows that the compound has significant activity for resisting pneumonia caused by streptococcus pneumoniae and has better effect than methylprednisolone and hypoxanthine analogue A, B, C. Moreover, in the experiment, the compound 1-12 is found to interfere with the mice in the group, and the lung of the mice does not have fibrotic lesions.
As can be seen from figure 1, the compounds 1 to 12 of the invention can obviously reduce inflammatory infiltration and edema of lung tissues of pneumonia mice, and show that the compounds have obvious activity of resisting pneumonia caused by streptococcus pneumoniae infection, and the effect is better than that of methylprednisolone and hypoxanthine analogue A, B, C. Moreover, in the experiment, the compound 1-12 is found to interfere with the mice in the group, and the lung of the mice does not have fibrotic lesions.
Test example 2 Activity of typical Compound 1 to 12 of the present invention against influenza A Virus pneumonia
C57BL/6J mice (22-25g) were randomly divided into several groups, namely blank control group (Normal), Model group (Model), methylprednisolone positive control group, compound A group, compound B group, compound C group and compound 1-12 group. Influenza A virus was inoculated on day 1, except for the blank control group mice, the mice in each group were infected with influenza A H1N1 virus FM1 strain (30 μ L) by nasal drip, and after 24H, the mice were gavaged for 4 days of dry pretreatment, as follows: the mice of the blank control group and the model group are administrated by the same dose of normal saline for intragastric administration, the mice of the hypoxanthine analog A-C group are administrated by the same volume of hypoxanthine analog A, B, C120mg/kg/d for intragastric administration, the mice of the positive control group are administrated by the same volume of methylprednisolone 120mg/kg/d for intragastric administration, different compound groups are administrated by different intragastric administration respectively, and the doses are all 120 mg/kg/d. Mice were dosed for 4 consecutive days, and body weight and mortality were recorded daily. On the last day, blood was taken from the eyeball and the serum was immediately examined for expression levels of NF-. kappa. B, TNF-. alpha.IL-1 and IL-6. The results are shown in the following table:
TABLE 2
As can be seen from Table 2, the compound can obviously reduce the levels of NF-kappa B, TNF-alpha, IL-1 beta and IL-6 in serum, and shows that the compound has obvious activity for resisting influenza A virus pneumonia, and the effect is better than that of methylprednisolone and the inosine analog A, B, C.
As can be seen from figure 2, the compounds 1 to 12 of the invention can obviously reduce inflammatory infiltration and edema of lung tissues of pneumonia mice, and show that the compounds have obvious activity of resisting influenza A virus pneumonia, and the effect is superior to methylprednisolone and the inosine analog A, B, C. Moreover, in the experiment, the compound 1-12 is found to interfere with the mice in the group, and the lung of the mice does not have fibrotic lesions.
Test example 3 Activity of typical Compound 1 to 12 of the present invention against influenza B Virus pneumonia
C57BL/6J mice (22-25g) were randomly divided into several groups, namely blank group (Normal), Model group (Model), methylprednisolone positive control group, hypoxanthine analog group (compound A, compound B, compound C) and compound 1-12 groups. Influenza B virus was inoculated on day 1, and mice in each group were infected with influenza B H7N9 virus strain (30. mu.L) by nasal drip, except for the mice in the control group. After 24h, the gavage was continued for 4 days for intervention as follows: the mice in the normal group and the model group are administrated by the same dose of normal saline, the mice in the hypoxanthine analogue group are administrated by the compound A, B, C120mg/kg/d by the intragastric administration, the mice in the positive control group are administrated by the methylprednisolone with the same volume of 120mg/kg/d by the intragastric administration, the different compound groups are respectively administrated by the intragastric administration by the compound 1-12, and the dose is 120 mg/kg/d. Mice were dosed for 4 consecutive days, and body weight and mortality were recorded daily. On the last day, blood was taken from the eyeball and the serum was immediately examined for expression levels of NF-. kappa. B, TNF-. alpha.IL-1 and IL-6. The results are shown in the following table:
TABLE 3
As can be seen from Table 3, the compound can obviously reduce the levels of NF-kappa B, TNF-alpha, IL-1 beta and IL-6 in serum, and shows that the compound has obvious activity of resisting influenza B virus pneumonia, and the effect is superior to that of methylprednisolone and a hypoxanthine similar compound A, B, C. Moreover, in the experiment, the compound 1-12 is found to interfere with the mice in the group, and the lung of the mice does not have fibrotic lesions.
Test example 4 Activity of typical Compounds 1 to 12 of the present invention against Corona Virus pneumonia
Humanized C57BL/6J mice (22-25g) were randomly divided into several groups, blank (Normal), Model (Model), methylprednisolone positive control, inosine analog (compound A, B, C), and compound 1-12. Coronaviruses (HcoV-OC43) were inoculated on day 1, and mice in each group were infected with HcoV-OC43 coronaviruses (30. mu.L) by nasal instillation, except for the placebo group, in which normal saline was instilled into the nasal cavity. After 24h, the gavage was continued for 4 days for intervention as follows: the mice of the normal group and the model group are administrated with normal saline with the same dose for intragastric administration, the hypoxanthine analog is administrated with A, B, C (120mg/kg/d) for intragastric administration, the mice of the positive control group is administrated with methylprednisolone with the same volume of 120mg/kg/d for intragastric administration, the different compound groups are administrated with 1-12 for intragastric administration, and the doses are all 120 mg/kg/d. Mice were dosed for 4 consecutive days, and body weight and mortality were recorded daily. On the last day, blood was taken from the eyeball and the serum was immediately examined for expression levels of NF-. kappa. B, TNF-. alpha.IL-1 and IL-6. The results are given in the following table:
TABLE 4
As can be seen from Table 4, the compound can obviously reduce the levels of NF-kappa B, TNF-alpha, IL-1 beta and IL-6 in serum, and shows that the compound has obvious activity of resisting coronavirus pneumonia and has better effect than methylprednisolone and the hypoxanthine analog compound A, B, C. Moreover, in the experiment, the compound 1-12 is found to interfere with the mice in the group, and the lung of the mice does not have fibrotic lesions.
As can be seen from figure 3, the compounds 1 to 12 of the invention can obviously reduce the inflammatory infiltration and edema of the lung tissue of a mouse with coronavirus pneumonia, and show that the compounds have obvious activity for resisting the coronavirus pneumonia and have better effect than methylprednisolone and the hypoxanthine analogue A, B, C. Moreover, in the experiment, the compound 1-12 is found to interfere with the mice in the group, and the lung of the mice does not have fibrotic lesions.
Test example 5 Activity of exemplary Compounds 1 to 12 of the present invention against COVID-19
Humanized C57BL/6J mice (22-25g) were randomly divided into several groups, blank (Normal), Model (Model), methylprednisolone positive control, inosine analog (compound A, B, C), and compound 1-12. The day 1, the mice of the control group were inoculated with the novel coronavirus SARS-CoV-2, and the mice of each group were infected with SARS-CoV-2 virus strain (30. mu.L) by nasal instillation, except for the nasal instillation of physiological saline. After 24h, the gavage was continued for 4 days for intervention as follows: the normal group and the model group are administrated to the mice with the same dosage of normal saline for intragastric administration, the mice of the compound A-C group are administrated with the compound A-C with the same volume of 120mg/kg/d by intragastric administration, the mice of the positive control group are administrated with the methylprednisolone with the same volume of 120mg/kg/d by intragastric administration, different compound groups are administrated with the compounds 1-12 by intragastric administration respectively, and the dosages are all 120 mg/kg/d. Mice were dosed for 4 consecutive days, and body weight and mortality were recorded daily. On the last day, blood was taken from the eyeball and the serum was immediately examined for expression levels of NF-. kappa. B, TNF-. alpha.IL-1 and IL-6. The results are shown in the following table:
TABLE 5
As can be seen from Table 5, the compound of the invention can obviously reduce the levels of NF-kappa B, TNF-alpha, IL-1 beta and IL-6 in serum, and shows that the compound has obvious activity against COVID-19 and better effect than methylprednisolone and the inosine analog compound A, B, C. Moreover, in the experiment, the compound 1-12 is found to interfere with the mice in the group, and the lung of the mice does not have fibrotic lesions.
Test example 6 Activity of typical Compounds 1 to 12 of the present invention against Mycoplasma induced pneumonia
C57BL/6J mice were randomly and evenly divided into groups, namely blank control group, model group, methylprednisolone positive control group, hypoxanthine analog (compound A, B, C) and compound 1-12 groups. Before molding, the mice were anesthetized with ether, the nasal cavity was instilled with 100. mu.L of physiological saline in the normal group, and the MPFH strain solution (containing 1X 10 cells) was added to the other groups in the same volume7mL-1)The nasal cavity is slowly instilled, so that the nasal cavity is inhaled into the bronchus and continuously instilled for 3 days. Starting administration treatment after the infection day 2, and performing intragastric administration on the blank control group and the model group by using normal saline with the same dose; the dose of the hypoxanthine analog compound A, B, C is 120mg/kg, and the positive control group is administrated with methylprednisolone liquid medicine of 120mg/kg by intragastric administration; the compounds 1-12 were administered by gavage at a dose of 120mg/kg 2 times daily for 14 days in different groups. After the treatment is finished, the mice are sacrificed, blood is taken from the eyeballs, and the conventional indexes of the blood to be detected are stored at the temperature of minus 80 ℃. Meanwhile, the lung is irrigated with physiological saline, the irrigating solution is separated and collected, and the white blood cell count and classification are detected. The results are shown in the following table:
TABLE 6
| White blood cells (10)9/L) | Neutrophils (10)9/L) | Lymphocyte (10)9/L) | |
| Blank group | 6.43 | 17.41 | 71.77 |
| Model set | 83.35 | 183.21 | 411.69 |
| Positive group | 79.15 | 179.43 | 403.28 |
| Compound A | 78.12 | 182.94 | 395.32 |
| Compound B | 79.32 | 189.13 | 388.17 |
| Compound C | 78.94 | 184.15 | 399.12 |
| Compound 1 | 6.41 | 17.28 | 69.87 |
| Compound 2 | 6.38 | 16.84 | 70.24 |
| Compound 3 | 6.27 | 16.65 | 69.35 |
| Compound 4 | 6.32 | 17.32 | 70.31 |
| Compound 5 | 6.42 | 17.27 | 70.14 |
| Compound 6 | 6.40 | 17.21 | 69.67 |
| Compound 7 | 6.43 | 16.98 | 70.74 |
| Compound 8 | 6.35 | 17.12 | 70.52 |
| Compound 9 | 6.24 | 17.41 | 69.24 |
| Compound 10 | 6.35 | 18.12 | 69.69 |
| Compound 11 | 6.27 | 18.14 | 70.64 |
| Compound 12 | 6.24 | 19.34 | 70.38 |
As can be seen from Table 6, the compounds of the present invention were able to lower the level of leukocytes, neutrophils and lymphocytes in the blood, indicating that they have activity against pneumonia induced by Mycoplasma pneumoniae and are superior to methylprednisolone, and the hypoxanthine analog compound A, B, C. Moreover, the experiment shows that the compound 1-12 intervenes in the lung of mice without fibrosis lesion.
Test example 7 therapeutic Effect of the Compounds of the present invention on various inflammatory diseases
Inflammation is a fundamental biological response of the body to invasion by foreign bodies such as pathogenic microorganisms, and can promote repair of damaged cells and tissues. However, excessive inflammatory reactions can lead to damage and necrosis of tissue organs and even major organs throughout the body.
Pneumonia is a major respiratory disease with high morbidity and mortality. Severe pneumonia often causes respiratory failure and even death, and inflammatory cytokines play an important role in the pathogenesis, so that effective control of the levels is one of the important means for treating pneumonia. Viral, bacterial, mycoplasma, chlamydial infections are the main cause of pneumonia.
Gastritis refers to the inflammation of the stomach mucosa caused by various causes, and is one of the most common digestive diseases. The main cause of chronic gastritis and gastric ulcer is helicobacter pylori (Hp) infection. Research shows that 80-90% of gastric mucosa of gastritis patients is caused by Hp infection.
Autoimmune hepatitis is a chronic liver disease with an undefined etiology and an obvious autoimmune phenomenon. The transaminase in the serum of patients with autoimmune hepatitis is obviously increased, autoantibodies exist in the circulation, high gamma-globulinemia exists, and the deterioration of the disease condition can cause liver cirrhosis and liver failure.
Rheumatoid arthritis is an autoimmune disease mainly characterized by chronic destructive arthropathy, mainly damages articular cartilage and joint capsule, and can cause the consequences of joint deformity and function loss in severe cases.
The experimental example proves that the therapeutic effect of the hypoxanthine derivative on the pulmonary inflammation is obviously superior to that of the hypoxanthine derivative on pancreatitis, hepatitis and rheumatoid arthritis models.
Materials: influenza A virus mouse lung adapted strain FM1, TNF-alpha ELISA kit, animal interferon INF-gamma ELISA kit, formaldehyde and ethanol.
Grouping and molding: 72C 57BL/6J mice were randomly divided into 6 groups of 12 mice each, namely a Normal group (Normal), a Model group (Model), a pneumonia group, a gastritis group, a hepatitis group and a rheumatoid arthritis group, and inoculated and molded after 2 days of adaptive feeding.
And (3) pneumonia model: ketamine is used for anesthesia, 0.1ml of influenza A mouse lung adaptive strain FM1 is injected into the trachea through the puncture of the cricoid subchondral, the influenza A mouse lung adaptive strain FM1 directly enters the lung, the rat cage is returned after the inoculation is finished, the administration is started after one week,
a gastritis model: adding the identified and transferred H.pyri (SS1) strain into 10% FBS BHI culture solution to adjust to a bacterial solution with 0.1 McLee's concentration, placing the bacterial solution into a microaerobic environment at 37 ℃, and performing shake culture on a shaker at 120rpm for 16-18 h to enable the H.pyri to grow to a logarithmic phase. And taking out the bacterial liquid, and performing intragastric administration on 0.25mL of mice in the group infected by intragastric administration for 3 times, wherein the intragastric administration is performed once every other day, the mice are fasted for 12 hours before intragastric administration for each time, and the mice are fed after 2 hours after the intragastric administration. The infected mice were given 2% saline until the start of dosing to enhance bacterial infectivity, and dosing was started one week after the completion of the gavage infection.
Hepatitis model: the tail vein was injected with ConA solution (15mg/kg), and the control group was injected with an equal volume of physiological saline, and administration was started one week later.
Arthritis model: 10% chloral hydrate solution (3.5mL/kg) was injected intraperitoneally and fixed in the supine position after anesthesia was complete. 0.1mL of 1g/L sodium iodoacetate solution is injected into the knee joint cavity. Animals were driven daily for 30min from day 5, left free in their cages for the rest of the time, and dosing was started one week later.
The experiment selects intragastric administration uniformly, and the dosage is 120 mg/kg/d. The systemic responses including hair, activity, defecation, feeding, respiration, etc. were observed daily for each group of mice after infection with virus, and the daily body mass and death of the mice were recorded. After 14d administration, mice were sacrificed, weighed and evaluated for inflammatory cytokines TNF-. alpha.IL-6 and mortality.
Results of each group
1. Mortality rate
The normal group has no death, the model group has higher death condition, the death rate of the pneumonia group is 25 percent, the gastritis group is 20 percent, the hepatitis group is 25 percent, and the rheumatoid arthritis group is 25 percent. The mortality of each pneumonia model group can be reduced by the compound 1-12 intervention groups, wherein the mortality of the pneumonia groups of the compound 1-12 intervention groups is 0%, the mortality of the gastritis group is 20%, the hepatitis group is 25%, and the mortality of the rheumatoid arthritis group is 25%, which shows that the anti-pneumonia activity of the compound is more obvious compared with that of other anti-inflammatory groups.
2. Serum inflammatory factor IL-6
TABLE 7
As can be seen from Table 7, the compound of the invention has a particularly significant effect on pneumonia resistance, and can obviously reduce the level of IL-6 in blood of pneumonia model mice.
It should be appreciated that the particular features, structures, materials, or characteristics described in this specification may be combined in any suitable manner in any one or more embodiments. Furthermore, the various embodiments and features of the various embodiments described in this specification can be combined and combined by one skilled in the art without contradiction.
Claims (11)
1. The use of a compound of formula I or a salt thereof in the manufacture of a medicament for the prevention or treatment of pneumonia:
wherein R is1Selected from O, NH, CH2、S；
R2、R3Independently selected from H, substituted or unsubstituted C1-C3 alkyl, and R2、R3Not both can be H.
2. Use according to claim 1, characterized in that: r1Selected from O, S, NH.
3. Use according to claim 1, characterized in that: the substituted C1-C3 alkyl is halogen substituted C1-C3 alkyl.
4. Use according to claim 1, characterized in that: r2、R3Independently selected from H or unsubstituted C1-C3 alkyl, and R2、R3Not both can be H.
5. Use according to any one of claims 1 to 4, characterized in that: the compound is selected from:
6. use according to claim 1, characterized in that: the pneumonia is bacterial pneumonia, viral pneumonia and mycoplasma pneumonia.
7. Use according to claim 6, characterized in that: the bacterial pneumonia is pneumonia caused by streptococcus pneumoniae infection.
8. Use according to claim 6, characterized in that: the viral pneumonia is pneumonia caused by influenza virus and coronavirus infection; preferably, the influenza virus is influenza A virus or influenza B virus; preferably, the coronavirus is HCoV-OC43, SARS-CoV-2.
9. Use according to claim 6, characterized in that: the mycoplasma pneumonia is pneumonia caused by mycoplasma pneumoniae infection.
10. Use according to any one of claims 1 to 9, characterized in that: the medicine is a preparation prepared by taking a compound shown in a formula I or a salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
11. Use according to claim 10, characterized in that: the preparation is an oral preparation, an injection preparation or a nasal mucosa administration preparation.
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