CN106496169A - Alantolactone derivant and its salt - Google Patents

Abstract

Inulin derivatives and salts thereof provide a derivative of inulin as shown in formula (I); the acid forming the salt is an inorganic acid or an organic acid, and the inorganic acid is selected from hydrofluoric acid , hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, boric acid, selenous acid, phosphomolybdic acid, phosphorous acid, sulfurous acid, the organic acid is selected from citric acid, maleic acid, D- Malic acid, L-malic acid, DL-malic acid, L-lactic acid, D-lactic acid, DL-acid, oxalic acid, methanesulfonic acid, valeric acid, oleic acid, lauric acid, p-toluenesulfonic acid, 1-naphthalene Sulfonic acid, 2‑naphthalenesulfonic acid, phthalic acid, tartaric acid, malonic acid, succinic acid, fumaric acid, glycolic acid, thiol acid, glycine, sarcosine, sulfonic acid, niacin, picolinic acid, Isonicotinic acid, benzoic acid, or substituted benzoic acids.

Description

Inulin derivatives and their salts

Technical field:

The present invention relates to inulin derivatives and their salts and their application and preparation.

Background technique:

Inula helenium is a plant of the genus Inula in the family Compositae, a perennial herb whose roots are used for medicinal purposes. It has the functions of invigorating the spleen and harmonizing the stomach, regulating qi and relieving depression, relieving pain and preventing miscarriage. It is used for chest and flank, abdominal distension and pain, vomiting and diarrhea, chest and flank contusion, pain in the chest and flank, restless fetal movement and other diseases. Inulin volatile oil contains inulin, iso-inulin and other ingredients, its chemical structure is similar to Sandonian, it has anthelmintic effect on pigs, dogs, and cats, its curative effect is better than that of Sandonian, and its toxicity is lower.

Inulin (CAS: 546-43-0,) belongs to sesquiterpenoids, and is also the main active ingredient with high content in inulin. Its structure is as follows In recent years, studies have found that the sesquiterpene-inula lactone components in inulin have new effects such as anti-tumor cell proliferation and anti-mycobacterium tuberculosis. In 1999 and 2002 respectively, Charles and Konishi et al. proposed that α-methylene-γ-lactone may be the anti-tumor cell proliferation and anti-tumor effect of these compounds after studying the pharmacological effects of inulin compounds. Essential functional groups for Mycobacterium tuberculosis. However, due to the poor water solubility of inulin, it is difficult to act on the human body through conventional administration routes, and further experiments have found that inulin is more toxic.

Chinese patent CN2009100742161 discloses a derivative of xenocystolactone and its salt, and discloses that the 13-position methylene of xenoxystolactone is transformed into an amine group, so that it has better water solubility and oral bioavailability In terms of anti-tumor activity, its efficacy is higher than that of the original compound, and its toxicity is less. However, this document only discloses the data of in vitro tumor inhibition experiments on tumor cells. In animal experiments, we found that the oral toxicity of this compound is relatively high, it is difficult to be used in clinical practice, and its water solubility is not ideal. And the effect of antitumor experiment in animal body is all unsatisfactory, does not have the value of clinical application. Therefore, on the basis of the existing technology, the structure of inulin is modified, and a new derivative of inulin is provided to significantly improve its effect when used for the treatment of diseases such as cancer, and reduce its cytotoxicity, and By preparing the derivative into a derivative salt as a prodrug, it is an urgent problem to be solved in the prior art to overcome the disadvantages of poor water solubility, short half-life, and low bioavailability of the original drug.

Contents of the invention

In order to solve the foregoing problems, the present invention provides an inulin derivative and its salt, a pharmaceutical composition for treating cancer containing the inulin derivative salt as an active ingredient and at least one pharmaceutically acceptable carrier, and the formula (1) Application of inulin derivative salts in the preparation of drugs for treating cancer.

In order to realize the above-mentioned purpose of the present invention, the present invention provides following technical scheme:

A kind of inulin derivative shown in formula (I) is provided,

In formula (I), wherein Y is oxygen or a single bond;

R1 and R2 can be the same or different, and are _hydrogen , alkyl, cycloalkyl, hydroxy _- substituted alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, arylalkenyl, Arylalkynyl, heterocyclyl, trifluoromethyl, polyfluorosubstituted alkyl, nitrile, cyanomethyl, acyl, carbamoyl, sulfonyl, sulfonamido or aryloxyalkyl; R ₁ , R ₂ and N atoms form a ring structure, the ring is preferably a 3-9 membered ring, and the ring structure can be substituted by one or more substituents, including hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl , alkylaryl, arylalkyl, arylalkenyl, arylalkynyl, or heterocyclyl. Wherein R ₁ and R ₂ are preferably hydrogen or C ₁ -C ₆ alkyl or cycloalkyl. More preferably _R1 and R2 are _both methyl.

The present invention also provides an inorganic acid or organic acid salt of inulin derivatives as described in formula (I), wherein the inorganic acid is selected from hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, Sulfuric acid, nitric acid, phosphoric acid, carbonic acid, boric acid, selenous acid, phosphomolybdic acid, phosphorous acid, sulfurous acid, the organic acid is selected from citric acid, maleic acid, D-malic acid, L-malic acid, DL-malic acid Acid, L-lactic acid, D-lactic acid, DL-acid, oxalic acid, methanesulfonic acid, valeric acid, oleic acid, lauric acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, phthalic acid , tartaric acid, malonic acid, succinic acid, fumaric acid, glycolic acid, thiol acid, glycine, sarcosine, sulfonic acid, niacin, picolinic acid, isonicotinic acid, benzoic acid, or substituted benzoic acids. It is preferably a fumarate salt of inulin derivatives described in formula (I). More preferably a compound of formula (II) or formula (III)

The present invention also provides the application of the inulin derivatives described in the formula (I) and their inorganic acid salts or organic acid salts in the preparation of drugs for treating cancer. The inorganic acid salt or organic acid salt of the inulin derivatives described in the formula (I) is the compound of the formula (II) or the compound of the formula (III)

The present invention also provides the application of the inulin derivatives of formula (I) and their inorganic acid salts or organic acid salts in the preparation of anti-inflammatory drugs; the inulin derivatives of the formula (I) The inorganic acid salt or organic acid salt is a compound of formula (II) or formula (III).

The present invention also provides the application of inulin derivatives as described in formula (I) and their inorganic acid salts or organic acid salts in the preparation of medicines for treating thyroiditis; The inorganic acid salt or organic acid salt of compound is formula (II) compound or formula (III) compound.

The present invention also provides the application of inulin derivatives of formula (I) and their inorganic acid salts or organic acid salts in the preparation of medicines for treating inflammatory bowel disease; The inorganic or organic acid salts of ester derivatives are compounds of formula (II) or formula (III). The inflammatory bowel disease is ulcerative colitis or Crohn's disease.

The present invention also provides the application of inulin derivatives as described in formula (I) and their inorganic acid salts or organic acid salts in the preparation of medicines for treating pulmonary fibrosis; The inorganic acid salt or organic acid salt of the derivative is the compound of formula (II) or formula (III).

The present invention also provides a pharmaceutical composition, which is characterized in that it contains at least one compound of formula (II) or compound of formula (III) and at least one pharmaceutically acceptable auxiliary material as an active ingredient and at least one compound A medicinal excipient.

The present invention provides a novel inulin derivative and its inorganic acid salt or organic acid salt through structural transformation of inulin. In pharmacological experiments, we found that the novel inulin derivative and its Salt, on the basis of its high anticancer activity in vitro, has shown excellent performance in the tumor inhibition experiment of tumor-bearing mice. Especially preferred compound (I-II) of the present invention, compound (I-III) and compound (II), compound (II) as its prodrug, not only have higher tumor inhibition rate, more importantly large Increased the survival period of experimental animals by a large margin. Therefore, it can be applied in the preparation of anticancer drugs. At the same time, in other animal experiments, the inulin derivatives and salts thereof provided by the present invention also show good effects on autoimmune inflammatory diseases such as pulmonary fibrosis, inflammatory bowel disease, and thyroiditis.

detailed description

In order to understand the present invention, the present invention is further illustrated below with examples, but it is not intended to limit the protection scope of the present invention.

Example 1:

Preparation of compound (II)

1) Preparation of compound (I-II)

Inulin (300.0mg, 1.29mmol) was dissolved in dichloromethane (50mL), and dimethylamine hydrochloride (1.6g, 19.4mmol) and potassium carbonate (5.2g, 37.4mmol) were successively added to the above mixed system ), the system was heated to reflux for 3 hours, the solid was removed by filtration, the filtrate was washed with water, dried and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to obtain compound (I-II) (white solid, 236.0g, Yield: 50%).

2) Preparation of compound (II), dissolving compound (I-II) (200.0mg, 0.72mmol) obtained in step 1) in methanol (7mL), adding fumaric acid (86.7mg, 0.74mmol ), stirring and reacting for 0.5 hour, spin off the solvent, add ethyl acetate to dissolve, and filter to obtain compound (II) (white solid, 246.4mg, yield: 87.3%)

Molecular formula of compound (II) determined by elemental analysis: C ₂₁ H ₃₁ NO ₆

HMR data: ¹ HNMR (400MHz, CDCl ₃ ): δ6.69 (s, 2H), 5.25 (d, J = 2.8Hz, 1H), 3.56 (dd, J = 14.7, 6.9Hz, 1H), 3.41 (dd ,J=13.4,6.4Hz,1H),3.33–3.27(m,3H),2.91(s,6H),2.60–2.50(m,1H),2.12(dd,J=15.0,3.3Hz,1H), 1.90–1.77(m,1H),1.66–1.55(m,4H),1.44(m,1H),1.22(d,J＝8.8Hz,3H),1.17(t,J＝6.0Hz,4H); ¹³ C NMR (100MHz, CDCl ₃ )δ180.6, 173.7, 156.2, 138.7, 117.8, 82.0, 58.0, 46.8, 46.0, 45.9, 45.7, 42.6, 41.8, 36.7, 36.5, 31.7, 25.8, 20.4.

Example 2:

Preparation of compound (III)

1) Preparation of compound (I-III)

Inulin (2.0g, 8.6mmol) was dissolved in dichloromethane (10mL), and a solution of peroxybenzoic acid (2.1g, 10.3mmol) in dichloromethane (20mL) was slowly added dropwise to the above system. React for 3 hours, quench the reaction with saturated aqueous sodium thiosulfate solution, wash the organic layer with saturated aqueous sodium bicarbonate (20mL×3), dry and concentrate, and purify by column chromatography (petroleum ether: ethyl acetate = 5:2) to obtain the compound (I-III) (white solid, 2.0g, yield 94%)

2) Preparation of Compound (III)

The compound (I-III) (300.0mg, 1.29mmol) obtained in the previous step was dissolved in dichloromethane (50mL), and dimethylamine hydrochloride (1.6g, 19.4mmol) and carbonic acid were added to the above mixed system in turn. Potassium (5.2g, 37.4mmol), the system was heated to reflux for 3 hours, the solid was removed by filtration, the filtrate was washed with water, dried and concentrated, the obtained crude product was dissolved in methanol (7mL), and fumaric acid (130.1mg , 1.11mmol), stirred and reacted for 0.5 hour, the solvent was spinned off, dissolved in ethyl acetate, filtered to obtain compound (III) (white solid, 369.6mg, yield: 87.3%)

Molecular formula of compound (III) determined by elemental analysis: C ₂₂ H ₃₅ NO ₇

NMR spectrum data: ¹ HNMR (400MHz, CDCl ₃ ): δ6.26(s, 2H), 4.59–4.53(m, 1H), 3.06(dd, J＝14.7, 6.9Hz, 1H), 2.64(t, J＝12.5Hz, 1H), 2.46(d, J＝4.3Hz, 1H), 2.28(s, 6H), 2.60–2.50(m, 1H), 2.12(dd, J＝15.0, 3.3Hz, 1H), 1.90–1.77(m,1H), 1.66–1.55(m,4H), 1.09–1.01(m,4H), 0.89(d,J=8.8Hz,3H),0.88(s,3H); ¹³ C NMR ( 100MHz, DMSO) δ177.0, 167.6, 135.0, 75.4, 67.6, 57.1, 56.3, 45.0, 38.9, 38.0, 37.9, 35.7, 34.5, 32.0, 29.8, 24.1, 17.8, 16.6.

Example 3:

In vitro cancer cell inhibitory effect of inulin derivative salts

The inhibitory effect of inulin derivative salts on cancer cells was detected by tetramethylazolidine blue (MTT) colorimetric method.

MTT colorimetric method experimental steps: Inoculate cancer cells in the logarithmic growth phase into 96-well cell culture plates at a density of 5×104 cells per milliliter, and adjust the zero wells to normal culture medium without cells. After 12 hours, the medium containing inulin derivatives with different concentration gradients was replaced, and the normal medium was replaced in the zero-adjusted wells. Five replicate wells were set for each concentration gradient, and cultured in a 37°C, 5% CO2 incubator. After 24 hours, the cell state and growth changes were observed under a microscope. After 48 hours, add tetramethylazolazolium blue (KG Bio, 5 mg/mL) solution to each well, continue to cultivate at 37°C, 5% CO2 incubator, suck out the medium after 4 hours, and add 100 μL of DMSO to each well , using a microplate reader to measure the absorbance value at a wavelength of 570 nanometers, using Graphpad software for statistical analysis of data, and calculating the half effective concentration (IC50, unit: μM). The inhibitory effect is shown in Table 1.

Table 1 Inhibitory activity of inulin derivative salts on various cancer cells (IC ₅₀ )

Among them, MDA-MB-231, B16, Hela, A375, A549, Panc1, PLC, HepG2, MHCC-97H, C6, U937, Hep2, HCT-116, MGC-803, sk-ov-3 respectively represent human breast cancer cells, mouse melanoma cells, human cervical cancer cells, human lung cancer cells, human pancreatic cancer cells, human liver cancer cells, human highly metastatic liver cancer cells, rat glioma cells, lymphoma cells, human laryngeal cancer cells, human colon Cancer cells, human gastric cancer cells, human ovarian cancer cells.

It can be seen from Table 1 that the screened compounds all have a certain inhibitory effect on the tested cells.

Pharmacological Example 1: Tumor Inhibition and Animal Survival Prolongation Effects of Inulin Derivatives and Their Salts

Test object: The animal strain used in this test is C57BL/6 mice, female, 18-22 g, SPF level.

Test vaccination content: LLC solid tumor. Using the tumor secondary transplantation method, the solid tumor was cut into small pieces and inoculated one by one into the back axilla of the mice. After the obvious tumor was observed at the tumor site, regroup to ensure that the tumor size and body weight were evenly distributed in each group. After successful modeling, the tumor-bearing mice were divided into model control group and experimental group 1-6, and each group 20 mice, in which the model control group was given 0.1 mL of normal saline every day, and the experimental group 1 was the positive control group, with cyclophosphamide as the positive control drug at a dose of 20 mg/kg. The dosage of each compound in experimental groups 2 to 6 was 150 mg/kg, all of which were treated by intragastric administration, and the molecular formula of compound (IV) was The preparation method of compound (IV) is as described in Chinese patent application CN2009100742161, and the specific grouping and administration are shown in Table 2. The diameter of the mouse tumor was measured every day, the tumor volume of the mouse was calculated, and the body weight of the mouse was weighed every day.

Continuous administration for two weeks. After two weeks, 10 mice in each group were sacrificed and the tumors were stripped. After dissection, the tumor weight was weighed, and the tumor inhibition rate was calculated (means tumor, n=10). Then the remaining mice were bred until all died, and their average survival period was calculated (means bred, n=10).

Tumor inhibition rate = (average tumor mass of the control group - tumor mass of the experimental group animals) / average tumor mass of the control group × amount according to the group %

Table 2 Inhibitory effect of inulin derivative salt on tumor

Can know by table 2: compare with model control group (physiological saline group), compound (I-II), compound (I-III), compound (II) and compound (III) group all have inhibitory effect to tumor, and all Can significantly improve the survival period of tumor-bearing mice, among which compound (II) and compound (III) have higher water solubility and bioavailability after salt formation, and their tumor-inhibiting effect and the effect of prolonging the survival period of tumor-bearing mice are even better obvious. However, compound (IV) has no obvious effect of inhibiting tumor and prolonging the survival period of tumor-bearing mice.

Pharmacological Example 2: Treatment of Animal Models of Ulcerative Inflammatory Bowel Disease in the Acute Phase

1. Experimental method

The animal strain used in this experiment is C57BL/6 mice, female, 18-22 g, SPF level, 10 mice in each group. In the experiment, 3% DSS (dextran sodium sulfate) was used to induce the acute phase model of ulcerative inflammatory bowel disease. During the adaptation period, the mice were given free access to food and water. At the beginning of the experiment, the drinking water was replaced with 3% DSS solution (except for the normal control group), and the mice were given free access to drink. The daily water intake of each mouse was calculated as 6 mL, and a sufficient amount of DSS solution was added the next day, and the DSS solution was given for a total of 8 days. 24 hours after the initial administration of DSS, the mice with soft stools, diarrhea or bloody stools were used as the modeled animals, and then the mice were administered intragastrically. The mice in the positive control group were given 0.1 mL of sulfasalazine (SASP, 300 mg/kg) every day, and the mice in the drug group to be tested were given 0.1 mL (50 mg/kg) every day. The mice were sacrificed by cervical dislocation 7 days after administration.

During the administration period, the general living conditions, feces properties, diarrhea and bloody stools of the mice were observed every day, photographed and recorded, and the body weight of the mice was weighed every day. And carry out DAI (disease activity index) scoring after administration is finished, scoring standard is as follows

After the mice were sacrificed, the colorectum was dissected and dissected to measure its length. The colorectum was cut longitudinally along the direction of the mesentery, the feces were cleaned with normal saline, and fixed with 10% neutral formalin solution. Severe ulcers were taken for pathological examination, followed by dehydration, paraffin embedding, sectioning, and hematoxylin-eosin staining. The tissue lesions were observed under a microscope and scored. The tissue lesion score (HI) standard is shown in the table below (the score of the two indicators is added together to obtain the tissue lesion score)

The therapeutic effects of inulin derivatives and their salts on the acute phase of DSS-induced ulcerative inflammatory bowel disease are shown in Table 3 below (means±s, n=10)

It can be seen from Table 3 that the effect of compound (II) on the acute phase of DSS-induced Ulcerative Inflammatory Bowel Disease is more significant, and has a certain healing effect, which is significantly different from that of the model group. Compound (III), compound (I-II) and compound (I-III) have a certain relieving effect on ulcerative inflammatory bowel disease.

Pharmacological Example 3: Treatment of Hashimoto's Thyroiditis Model Animals Induced by High Iodine Water

1. Experimental method

SPF grade Kunming female mice were selected, weighing 28-32 g, and high iodine water (0.64 g of sodium iodide dissolved in 1 L of tap water) was used. Dissolve 100 mg of porcine thyroglobulin in 50 mL of sterilized double distilled water (2 mg/mL), take 10 mL and fully mix with an equal volume of complete Freund's adjuvant to form a water-in-oil state. After the skin was disinfected, 0.1 mL (100 μg) was given to the mice in the model group for multiple subcutaneous injections (subcutaneous on the toes, subcutaneous on the back, subcutaneous on the abdomen, subcutaneous on the neck) as the initial immunization. On the 12th day of the experiment, take 10mL (2mg/mL) of porcine thyroglobulin and 10mL of incomplete Freund's adjuvant and fully mix it into a water-in-oil state. After immunization, the modeling evaluation was carried out after immunization was carried out at intervals of 12 days. After successful modeling, the high iodine water was removed and normal water was given for drinking.

After the mice were successfully modeled, drug therapy was started (weighing before drug administration). The experimental animals that were successfully modeled were randomly divided into groups of 10, and another 10 normal mice were taken as the blank group. For grouping and drug administration, see The following table:

2. Experimental results

After the administration, the body weight of the experimental animals in each group was measured respectively, and the changes of TPOAb (anti-thyroid peroxidase antibody) and TGAb (thyroglobulin antibody) contents in the blood of the experimental animals were monitored.

The monitoring results are shown in the table below

Experimental group weight(g) TGAb (ng/L) TGAb (IU/ml) blank group 28.6±1.40 31.7±10.8 34.2±7.4 model group 19.9±1.99 80.7±17.9 65.5±24.8 Dexamethasone group 27.4±1.67 39.7±11.0 42.4±8.5 Compound (II) group 25.1±2.11 54.2±8.7 59.6±10.6 Compound (III) group 27.3±1.57 41.3±8.2 48.1±7.6 Compound (I-II) group 23.5±1.98 46.6±7.2 60.6±9.4 Compound (I-III) group 24.7±1.68 45.1±6.2 53.9±8.0

After the administration, compared with the blank group, the body weight of the mice in the model group decreased significantly; while the compound (II), compound (III), compound (I-II) and compound (I-III) groups had good body weight growth In the model group, it was shown that compound (II) and compound (III) could significantly improve the body weight of mice. Compared with the blank group, the TPOAb and TGAb of the model group mice were significantly increased, which were 255% and 192% of the blank group mice respectively, while the TPOAb and TGAb of the compound (II) group were 171% and 174% of the blank group respectively, The TPOAb and TGAb of the compound (III) group were respectively 130% and 141% of the blank group, and compared with the model group, the TPOAb and TGAb of the mice were significantly lower. Compared with the model group, the TPOAb and TGAb of the mice in the compound (I-II) and compound (I-III) groups also decreased.

The above results show that compound (II), compound (III), compound (I-II) and compound (I-III) all have a certain therapeutic effect on Hashimoto's thyroiditis.

Pharmacological Example 4: Treatment of Paraquat-induced Pulmonary Fibrosis in Mice

1. Experimental method

70 mice were randomly divided into two groups, 10 in the blank group and 60 in the modeling group, half male and half male. The mice in the modeling group were fasted for 16 hours before modeling, and were given a dose of 100 mg/Kg paraquat solution by intragastric administration, and the mice in the blank group were intragastrically administered with the same volume of normal saline.

On the 7th day (according to the exploration results of the modeling time in the pre-experiment, the mice had symptoms of pulmonary fibrosis after 7 days of modeling.) The 60 mice in the modeling group were randomly divided into 6 groups, respectively: 10 mice in the model group , 10 positive drug dexamethasone groups, compound (II) group, compound (III) group, compound (I-II) group, compound (I-III) group (10 in each group), half male and half male. On the 8th day, the mice were administered and treated (weighed before administration), and compound (II), compound (III), compound (I-II) and compound (I-III) were intragastrically administered at a certain dose for treatment; The dexamethasone group was treated by intragastric administration at a dose of 0.45 mg/Kg, and the mice in the blank group and the model group were intragastrically administered with corresponding volumes of normal saline according to body weight. The general state of the mice was observed once a day in the morning and afternoon, and the mice were weighed and administered once a day for 28 days.

2. Experimental results

After the experiment, the body weight, lung coefficient, hydroxyproline and collagen content of the experimental mice in each group were detected. The experimental results are shown in the table below (means±s, n=10)

2.1 Body weight monitoring results: After the administration, compared with the blank group, the body weight of the mice in the model group decreased significantly; while the body weight of compound (II), compound (III), compound (I-II) and compound (I-III) increased Situation is all better than model group, shows that compound (II), compound (III), compound (I-II) and compound (I-III) all can improve mouse body weight situation, wherein compound (II), compound (III) effect more obvious.

2.2 Effect of lung coefficient: Compared with the blank group, the lung coefficient of the mice in the model group was significantly increased, which was 124% of the lung coefficient of the blank group, and the lung coefficients of the mice in the compound (II) and compound (II) groups were respectively blank Compared with the model group, the lung coefficients of the mice in the model group were significantly reduced. The above results show that compound (II) and compound (III) can reduce the lung coefficient of paraquat-induced pulmonary fibrosis mice, can significantly improve the state of pulmonary fibrosis, and compound (I-II) and compound (I-III) can also be certain Reduce the lung coefficient to a certain extent and improve the state of pulmonary fibrosis.

2.3 Effect of hydroxyproline and collagen content: Compared with the blank group, the percentages of hydroxyproline and collagen in the lung tissue of the mice in the model group were significantly increased, and the contents of hydroxyproline and collagen were both 131% of those in the blank group. The lung tissue hydroxyproline and collagen percentage contents of the mice in the compound (II) group were 117% of the blank group, and the lung tissue hydroxyproline and collagen percentage contents of the compound (III) group mice were both in the blank group. Compared with the model group, the lung tissue hydroxyproline and collagen percentages of compound (II), compound (III), compound (I-II) and compound (I-III) were significantly reduced. The experimental results show that compound (II), compound (III), compound (I-II) and compound (I-III) can reduce the percentage content of hydroxyproline and collagen in paraquat-induced pulmonary fibrosis mice.

In summary: compound (II), compound (III), compound (I-II) and compound (I-III) can improve the collagen deposition in the lungs of mice with pulmonary fibrosis, and have a certain therapeutic effect on pulmonary fibrosis It is expected to be developed as a drug for the treatment of pulmonary fibrosis.

Claims (10)

1. alantolactone derivant of the one kind as shown in formula (I),

In formula (I), wherein Y is oxygen or singly-bound；

R₁And R₂Can be with identical or different, respectively hydrogen, alkyl, cycloalkyl, hydroxyl substituted alkyl group, thiazolinyl, alkynyl, aryl, alkyl Aryl, aryl alkyl, aryl alkenyl, aromatic yl polysulfide yl, heterocyclic radical, trifluoromethyl, polyfluoro replace alkyl, itrile group, itrile group methyl, acyl Base, carbamoyl, sulfonyl, sulfoamido or aryloxyalkyl group；R₁、R₂Circulus is formed with N atoms, ring is preferably 3-9 units Ring, can be substituted by one or more substituents in circulus, including hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, alkane Base aryl, aryl alkyl, aryl alkenyl, aromatic yl polysulfide yl or heterocyclic radical.

2. alantolactone derivant as claimed in claim 1, is characterized in that R₁And R₂For hydrogen or C₁-C₆Alkyl or cycloalkanes Base.

3. alantolactone derivant as claimed in claim 2, is characterized in that R₁And R₂It is methyl.

4. the inorganic acid salt or acylate of the alantolactone derivant as described in claims 1 to 3 is arbitrary, is characterized in that institute The mineral acid that states is selected from Fluohydric acid., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid, phosphoric acid, carbonic acid, boric acid, Monohydrated selenium dioxide, phosphorus molybdenum Acid, phosphorous acid, sulfurous acid, the organic acid is selected from citric acid, maleic acid, D-malic acid, L MALIC ACID, DL-malic acid, L- breasts Acid, D-ALPHA-Hydroxypropionic acid, DL- acid, oxalic acid, methanesulfonic acid, valeric acid, Oleic acid, lauric acid, p-methyl benzenesulfonic acid, 1-naphthalene sulfonic aicd, 2- LOMAR PWA EINECS 246-676-2, Phthalandione, tartaric acid, malonic acid, succinic acid, fumaric acid, glycolic, thiolic acid, glycine, sarcosine, sulfonic acid, nicotinic acid, methyl pyrrole Pyridine acid .gamma.-pyridinecarboxylic acid, benzoic acid or substituted benzoic acid.

5. the inorganic acid salt or acylate of alantolactone derivant as claimed in claim 4, is characterized in that inorganic acid salt Or acylate is fumarate,

6. the inorganic acid salt or acylate of alantolactone derivant as claimed in claim 4, is characterized in that the building The inorganic acid salt or acylate of fragrant lactone derivatives is formula (II) or formula (III) compound.

7. application of the alantolactone derivant as described in claims 1 to 3 is arbitrary in treating cancer medicine is prepared.

8. the inorganic acid salt or acylate of the alantolactone derivant as described in claim 4～6 is arbitrary is preparing treatment Application in cancer drug.

9. application as claimed in claim 8, it is characterized by the inorganic acid salt of the formula (I) the alantolactone derivant or Acylate is formula (II) compound or formula (III) compound.

10. a kind of pharmaceutical composition, is characterized in that containing at least one formula (II) compound as active component or formula (III) Compound and at least one pharmaceutically useful adjuvant.