CN109806255A - Diosmetin is in preparation for treating the application in pulmonary fibrosis disease drug - Google Patents

Abstract

The present invention provides a kind of diosmetins to prepare the application in the drug for treating pulmonary fibrosis disease, wherein shown in the structure of diosmetin such as following formula (I):It is experimentally confirmed, diosmetin has good effect to pulmonary fibrosis, has no adverse reaction, and can slow down the mouse pulmonary fibrosis of bleomycin induced, has a good application prospect in treatment, alleviation or in terms of improving pulmonary fibrosis disease.

Description

Diosmetin is in preparation for treating the application in pulmonary fibrosis disease drug

Technical field

The invention belongs to field of pharmaceutical chemistry technology, more particularly, to a kind of diosmetin in preparation for treating lung fiber Change the application in disease medicament.

Background technique

Pulmonary fibrosis is the last rank of a variety of interstitial lung diseases (interstitial lung diseases, ILDs) Section, it is characterized in that pulmonary parenchyma is destroyed and extrtacellular matrix deposition is in interstitial lung and alveolar space.This disease was once considered It is a kind of chronic inflammation processes, but current evidence shows that fiberization is the alveolar epithelial cells by abnormal activation (AECs) it drives.These cells generate medium, by reside mesenchymal cell proliferation, the attraction of Circulating fibrocyte and The formation of stimulation induced fibroblast and myofibroblast stove that epithelial cell changes to mesenchymal cell.Fibroblast Excessive extracellular matrix, mainly collagen are secreted with myofibroblast stove, lead to the cicatrization of lung structure and is broken It is bad.Idiopathic pulmonary fibrosis (idiopathic pulmonary fibrosis, IPF) is the most common diffusivity pulmonary fibrosis Disease, etiology unknown, pathogenesis are unclear so far, lack effective treatment means, median survival interval only 3-5.Traditional view Think that IPF is to be caused by chronic inflammation, however biopsy does not show obvious inflammation, in disease early stage also few protrusions Inflammatory signs, and clinically anti-inflammatory treatment produces little effect.The disease is apt to occur in 50~70 years old, especially there is the people of smoking history Group, male are higher than women.With the pollution of atmosphere, the deterioration of environment, disease incidence has in recent years for epidemiologic data report display Ascendant trend.The disease incidence of statistics IPF is 6.8-16.3/10 ten thousand at present, and illness rate is 14-42.7/10 ten thousand, in recent years illness people Group is on the rise.Number of patients whole world conservative estimation 50,000,000, it is contemplated that there is IPF patient 600,000 or so in China.Annual IPF Death is up to 40000.

It in recent years, include glucocorticoid, colchicin, ciclosporin A, half Guang of acetyl for the clinical test drug of IPF Amino acid, Bosentan, Etanercept, anti-coagulants, Nintedanib, pirfenidone and Imatinib etc., but IPF patient to hormone and The therapeutic response of various drugs is generally poor, there is no the drug that can definitely improve the final prognosis of patient, American Thoracic doctor at present Learning to point out in the IPF guide of (ATS), patient IPF must recommend and effectively treat just to be lung transplantation to state of an illness advanced stage unique value, But since expenses of surgical treatment is expensive, skill level is complicated, donor lung tissue source is in short supply, organ transplantation ethics and medical service law The presence for the factors such as Laws & Regulations are unsound, limits development of the lung transplantation as IPF patient treatment in China.

There are two the marketed drugs for being directed to the disease at present, is pirfenidone and the Buddhist nun of Boehringer Ingelheim of Roche respectively Da Nibu, but patient survival cannot be all effectively improved, medical expense is high, and clinical demand is far unmet.Therefore it illustrates The occurrence and development mechanism of pulmonary fibrosis explores new potential drug target, develops for the curative effect confirmation of pulmonary fibrosis, phase There is important social effect and medical significance to the drug of safety, reasonable price.

Diosmetin (Diosmetin) is one kind of natural flavonoid compound, is present in chrysanthemum, jatamans valeriana rhizome, spearmint In the equal fruits such as natural drugs and lemon, peanut, citrus, and there is multi-biological activity, it is such as anti-inflammatory antibacterial, anti-oxidant, anti-swollen Tumor etc. can be used to treat liver, lung, kidney, eye, the nervous system disease.Relevant report proves that diosmetin can be by inhibiting ROS's It generates and inactivation PI3K/Akt and MAPK access mitigates the EMT that TGF-β 1 induces, to reduce Airway Remodeling and at the mistake of fibrosis Journey.But it there is no diosmetin that can slow down the relevant report of special hair pulmonary fibrosis so far.

Summary of the invention

In view of this, the present invention is directed to propose a kind of substance suitable for treating specific pulmonary fibrosis disease drug.

In order to achieve the above objectives, the technical scheme of the present invention is realized as follows:

Diosmetin is in preparation for treating the application in pulmonary fibrosis disease drug, wherein the knot of the diosmetin Shown in structure such as following formula (I):

Preferably, the pulmonary fibrosis disease is idiopathic pulmonary fibrosis disease.

Preferably, the dosage of the diosmetin is 100mg/kg.

Preferably, form of administration is tablet, capsule, pill, suppository, aerosol, oral liquid, granule, dissipates Agent, injection, syrup, vina, tincture, distillate medicinal water or film.

The present invention also provides a kind of drugs for treating pulmonary fibrosis disease, including diosmetin and diosmetin are in medicine Acceptable auxiliary material on.

Preferably, the pulmonary fibrosis disease is idiopathic pulmonary fibrosis disease.

Preferably, pharmaceutically acceptable auxiliary material includes salt, ester and hydrate to the diosmetin, and wherein salt includes Organic salt and inorganic salts.

Preferably, the organic salt includes mesylate, formates, acetate, trifluoroacetate, maleate, winestone Hydrochlorate, succinate, fumarate, citrate, benzene sulfonate, toluenesulfonate, naphthalene sulfonate, lactate and benzene first One or more of hydrochlorate；The inorganic salts include one of hydrochloride, hydrobromate, sulfate and phosphate or It is two or more.

Preferably, the drug is one of oral, injection, implantation, external application, spraying or Sucked medicine form.

Compared with the existing technology, diosmetin of the present invention is in preparation for treating in pulmonary fibrosis disease drug Using having the advantage that

It is of the invention to have no adverse reaction studies have shown that diosmetin has good effect to pulmonary fibrosis, can slow down it is rich come The mouse pulmonary fibrosis of mycin induction has a good application prospect in treatment, alleviation or in terms of improving pulmonary fibrosis disease.

Detailed description of the invention

Fig. 1 is the changes of weight curve of each group mouse.Table 1 is the changes of weight table of each group mouse.

Fig. 2 is the collagen content of each group mouse lung.The collagen content table of 2 each group mouse lung of table.

Fig. 3 is each group mouse pulmonary fibrosis area；

Fig. 4 is each group mouse pulmonary fibrosis ratio column diagram.Table 3 is each group mouse pulmonary fibrosis ratio table.

Specific embodiment

In addition to being defined, technical term used in following embodiment has universal with those skilled in the art of the invention The identical meanings of understanding.Test reagent used in following embodiment is unless otherwise specified conventional biochemical reagent；It is described Experimental method is unless otherwise specified conventional method.

Below with reference to embodiment, the present invention will be described in detail.

The present invention provides a kind of diosmetins to prepare the application in the drug for treating pulmonary fibrosis disease, In, shown in the structure of diosmetin such as following formula (I):

Embodiment 1

Influence of the diosmetin to the mouse idiopathic pulmonary fibrosis of bleomycin induced

The preparation of pulmonary fibrosis animal model: C57BL/6J is taken, mass fraction is by (week old 8-10 weeks) wild-type mice 10% chloraldurate gives mouse peritoneal injecting anesthetic with 0.5mL/100g (weight), and it is mould that intratracheal invasive injection 2U/Kg wins Lay Element.

It is grouped situation: the physiological saline (mass fraction 0.9%NaCl) of normal group (sodium chloride group) injection same volume；Mould Type group is handled the 7th to 14 day according to the above modeling and in bleomycin, and it is fine to give mouse coordinative solvent carboxymethyl by stomach-filling daily Tie up plain sodium；It is fragrant that mouse 100mg/kg gives by stomach-filling when bleomycin is handled the 7th to 14 day, daily in diosmetin treatment group Leaf lignin, using coordinative solvent sodium carboxymethylcellulose as control.Each group Lung collagen is detected at the 14th day and fibrosis is tight Weight degree.The every day entry mouse weight of each group draws changes of weight curve.

Table 1 is the changes of weight table of each group mouse

Lung collagen detection (i.e. hydroxyproline content measurement): injecting the 14th day execution mouse in bleomycin, separates Mouse right lung, is put into 5mL amperes of bottles, and 120 DEG C of baking oven drying are added the hydrochloric acid that 3ml concentration is 12mol/L, hydrolyze 6 at 120 DEG C Hour, pH to 6.5-8.0 is adjusted with the NaOH that concentration is 10mol/L after hydrolysis, is filtered using the filter that aperture is 5 μm residual Slag obtains filtrate, and it is 10mL that PBS (phosphate buffer solution) adjustment total volume is added in filtrate, obtains sample A；Take 50 μ L samples 350 μ L deionized waters are added in A, and toluene-sodium-sulfonchloramide (Chloramine T) solution that 200mL concentration is 1.41%, incubation at room temperature 20 is added Minute, the perchloric acid solution that 200 μ L concentration are 18.9% is added, and (perchloric acid is incubated at room temperature 5 minutes, and 200 μ are added L concentration is paradime thylaminobenzaldehyde (P-DMAB) solution that concentration is 20%, and 65 DEG C are incubated for 20 minutes, obtains sample B；It takes 200 μ L sample B measure light absorption value of the sample B at 570nm wavelength into 96 orifice plates, utilize L- hydroxyproline standard product (Sigma) concentration and absorbance is transverse and longitudinal coordinate, draws standard curve, and the corresponding regression equation of establishing criteria curve calculates The concentration of institute's sample hydroxyproline.

The collagen content table of 2 each group mouse lung of table

Normal group (microgram/right lung)	Model group (microgram/right lung)	Diosmetin treatment group (microgram/right lung)
			19.92±14.07	133.98±32.6	70.41±16.65

Fibrosis area quantitative statistics are carried out to lung tissue section: mouse lung is fixed by paraformaldehyde, is routinely dehydrated, After paraffin embedding, slice, H&E (haematoxylin Yihong) dyeing, the processing of neutral gum mounting, dyed using microscope acquisition HE is just set Image data, every slice randomly select ten visuals field, using 6.0 software of Image-Pro Plus to pulmonary fibrosis area into Row statistics.

Table 3 is each group mouse pulmonary fibrosis ratio table

Model group (%)	Diosmetin treatment group (%)
		28.33±11.14	7.20±2.17

Shown in the following Fig. 1 to Fig. 4 of experimental result, as shown in Figure 1, mouse weight is kept after diosmetin treatment group self administration of medication Steadily, show that diosmetin can improve animal health condition；As shown in Figure 2, compared with the mouse of model group, diosmetin is controlled Hydroxyproline content is substantially reduced in the lung tissue for the treatment of group group mouse, shows that diosmetin can reduce what bleomycin was induced Collagen content inhibits the synthesis of collagen in the lung tissue of bleomycin induced, and p < 0.05, i.e., statistically have conspicuousness Difference；And as can be seen from figs. 3 and 4 H&E dyeing observation and statistical analysis show the mouse pulmonary fibrosis of diosmetin treatment group Degree is significantly lower than model group mouse, shows that diosmetin can effectively slow down the mouse pulmonary fibrosis of bleomycin induced.

To sum up, diosmetin has good effect to pulmonary fibrosis, has no adverse reaction, and can slow down the small of bleomycin induced Mouse pulmonary fibrosis has a good application prospect in treatment, alleviation or in terms of improving pulmonary fibrosis disease.

The above is only a specific embodiment of the invention, are not intended to limit the invention, all in spirit and original of the invention Within then, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.

Claims (9)

1. diosmetin is in preparation for treating the application in pulmonary fibrosis disease drug, wherein the structure of the diosmetin As shown in following formula (I):

。

2. application according to claim 1, it is characterised in that: the pulmonary fibrosis disease is idiopathic pulmonary fibrosis disease Disease.

3. application according to claim 1, it is characterised in that: the dosage of the diosmetin is 100mg/kg.

4. the form of administration of application according to claim 1 is tablet, capsule, pill, suppository, aerosol, oral solution Body preparation, granule, powder, injection, syrup, vina, tincture, distillate medicinal water or film.

5. a kind of drug for treating pulmonary fibrosis disease, which is characterized in that pharmaceutically including diosmetin and diosmetin Acceptable auxiliary material.

6. drug according to claim 4, it is characterised in that: the pulmonary fibrosis disease is idiopathic pulmonary fibrosis disease Disease.

7. drug according to claim 4, it is characterised in that: pharmaceutically acceptable auxiliary material includes the diosmetin Salt, ester and hydrate, wherein salt includes organic salt and inorganic salts.

8. drug according to claim 7, it is characterised in that: the organic salt includes mesylate, formates, acetic acid Salt, trifluoroacetate, maleate, tartrate, succinate, fumarate, citrate, benzene sulfonate, to methylbenzene One or more of sulfonate, naphthalene sulfonate, lactate and benzoate；The inorganic salts include hydrochloride, hydrogen bromine One or more of hydrochlorate, sulfate and phosphate.

9. drug according to claim 4 be oral, injection, implantation, external application, be sprayed or Sucked medicine form in one Kind.