Pulmonary fibrosis treatment agent

Abstract

The present invention addresses the problem of providing a therapeutic agent for pulmonary fibrosis that has high therapeutic effect. The present invention provides a therapeutic agent for pulmonary fibrosis that comprises a compound represented by formula (1) as an active ingredient. (In the formula, R represents linear or branched alkyl group having 1-30 carbon atoms, a linear or branched alkenyl group having 2-30 carbon atoms, or a linear or branched alkynyl group having 2-30 carbon atoms, each group optionally containing a cycloalkane ring or an aromatic ring. X and Y independently represent an oxygen atom or a methylene group, provided that X and Y do not represent a methylene group at the same time. M represents a hydrogen atom or an alkali metal atom.)

Description

Technical Field

[0001] The present invention relates to a therapeutic agent for pulmonary fibrosis containing cyclic phosphatidic acid or carbocyclic cyclic phosphatidic acid or a crystal form thereof as an active ingredient.

Background Art

[0002] Pulmonary fibrosis refers to a condition in which lung tissue becomes fibrotic due to the accumulation of excessive collagen and other extracellular matrices. Among pulmonary fibrosis, idiopathic pulmonary fibrosis is a chronic refractory disease with a poor prognosis, with an average intermediate survival period of 3 years and a 5-year survival rate of 20 to 40%. Despite being a disease with a poor prognosis, there are almost no recommended drug treatments for idiopathic pulmonary fibrosis. Conventionally, steroids and immunosuppressive drugs have been tentatively used, but in recent years, evidence has accumulated that they worsen the prognosis, and they have become treatments that are not recommended. Anti-fibrotic drugs such as pirfenidone and nintedanib have been introduced to the market after undergoing scientific verification tests and are beginning to be used as new therapeutic agents, but further development of more effective therapeutic agents is required.

[0003] The present inventors have found that specific cyclic phosphatidic acid derivatives and salts thereof have excellent preventive and therapeutic effects on arthropathies such as rheumatoid arthritis and osteoarthritis (Patent Document 1), atopic dermatitis (Patent Document 2), and suppression of cancer metastasis and invasion (Patent Document 3), etc.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0005] As mentioned above, it was known that certain cyclic phosphatidic acid derivatives and their salts exhibit certain pharmacological effects, but it was not known that cyclic phosphatidic acid derivatives and their salts have therapeutic effects against pulmonary fibrosis. The objective of this invention is to provide a highly effective therapeutic agent for pulmonary fibrosis. [Means for solving the problem]

[0006] As a result of diligent research to solve the above problems, the present inventors have found that cyclic phosphatidic acid and its derivatives have an effect in treating pulmonary fibrosis, and have completed the present invention.

[0007] The present invention provides the following: <1> A pulmonary fibrosis treatment agent containing the compound shown in the following formula (1) as an active ingredient. [ka] (In the formula, R is a linear or branched alkyl group having 1 to 30 carbon atoms, a linear or branched alkenyl group having 2 to 30 carbon atoms, or a linear or branched alkynyl group having 2 to 30 carbon atoms, and these groups may include a cycloalkane ring or an aromatic ring. X and Y each independently represent an oxygen atom or a methylene group, but X and Y cannot be a methylene group at the same time. M is a hydrogen atom or an alkali metal atom.) <2> In formula (1), one of X or Y is an oxygen atom and the other is a methylene group. <1> A pulmonary fibrosis treatment agent as described above. <3> The compound represented by formula (1) is 1-oleoylcyclic phosphatidic acid or 1-palmitoleoylcyclic phosphatidic acid and its derivative carbacyclic phosphatidic acid. <1> or <2> A pulmonary fibrosis treatment agent as described above.

[0008] The present invention further provides a method for treating pulmonary fibrosis, comprising administering a compound represented by formula (1) to a patient with pulmonary fibrosis. The present invention further provides a compound represented by formula (1) above for use in the treatment of pulmonary fibrosis. The present invention further provides the use of the compound represented by formula (1) above for the manufacture of a therapeutic agent for pulmonary fibrosis. [Effects of the Invention]

[0009] According to the present invention, it is possible to provide a highly effective therapeutic agent for pulmonary fibrosis. [Brief explanation of the drawing]

[0010] [Figure 1] Figure 1 shows the effect of 2cc PA on the wet weight of the right lung in a mouse model of bleomycin-induced pulmonary fibrosis. [Figure 2] Figure 2 shows the effect of 2cc PA on the dry weight of the right lung in a bleomycin-induced pulmonary fibrosis model mouse. [Figure 3] Figure 3 shows the effect of 2ccPA on hydroxyproline in the right lung of a bleomycin-induced pulmonary fibrosis model mouse. [Modes for carrying out the invention]

[0011] The present invention will be described in more detail below. The therapeutic agent for pulmonary fibrosis of the present invention can be used for the treatment of pulmonary fibrosis. Examples of diseases that cause pulmonary fibrosis include interstitial pneumonia, cystic fibrosis, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), inflammatory lung disease, pulmonary infection, radiation pneumonitis, drug-induced interstitial pneumonia, interstitial pneumonia associated with collagen disease, etc. Among them, idiopathic pulmonary fibrosis, which is idiopathic interstitial pneumonia with unknown cause, is particularly preferred. Idiopathic interstitial pneumonias (IIPs) include, as clinicopathological diseases, idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), idiopathic organizing pneumonia (COP / BOOP), acute interstitial pneumonia (AIP), desquamative interstitial pneumonia (DIP), interstitial lung disease associated with respiratory bronchiolitis (RB-ILD), lymphocytic interstitial pneumonia (LIP), etc.

[0012] The therapeutic agent for pulmonary fibrosis of the present invention contains cyclic phosphatidic acid or carbocyclic phosphatidic acid or salts thereof as an active ingredient. The cyclic phosphatidic acid or carbocyclic phosphatidic acid or salts thereof are not particularly limited as long as they exhibit the effects of the present invention. Preferably, a compound represented by the following formula (I) can be used.

[0013]

Chemical formula

[0014] (In the formula, R is a linear or branched alkyl group having 1 to 30 carbon atoms, a linear or branched alkenyl group having 2 to 30 carbon atoms, or a linear or branched alkynyl group having 2 to 30 carbon atoms, and these groups may contain a cycloalkane ring or an aromatic ring. X and Y each independently represent an oxygen atom or a methylene group, but X and Y do not simultaneously become a methylene group. M is a hydrogen atom or an alkali metal atom.)

[0015] In formula (I), specific examples of the linear or branched alkyl group having 1 to 30 carbon atoms represented by the substituent R include, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, eicosyl group and the like.

[0016] Specific examples of the linear or branched alkenyl group having 2 to 30 carbon atoms represented by the substituent R include, for example, allyl group, butenyl group, octenyl group, decenyl group, dodecadienyl group, hexadecatrienyl group and the like. More specifically, 8-decenyl group, 8-undecenyl group, 8-dodecenyl group, 8-tridecenyl group, 8-tetradecenyl group, 8-pentadecenyl group, 8-hexadecenyl group, 8-heptadecenyl group, 8-octadecenyl group, 8-icosenyl group, 8-docosenyl group, heptadeca-8,11-dienyl group, heptadeca-8,11,14-trienyl group, nonadeca-4,7,10,13-tetraenyl group, nonadeca-4,7,10,13,16-pentaenyl group, henicosa-3,6,9,12,15,18-hexaenyl group and the like.

[0017] Specific examples of the linear or branched alkynyl group having 2 to 30 carbon atoms represented by the substituent R include, for example, 8-decynyl group, 8-undecynyl group, 8-dodecynyl group, 8-tridecynyl group, 8-tetradecynyl group, 8-pentadecynyl group, 8-hexadecynyl group, 8-heptadecynyl group, 8-octadecynyl group, 8-icosynyl group, 8-docosynyl group, heptadeca-8,11-diinyl group and the like.

[0018] Specific examples of cycloalkane rings that may be contained in the alkyl, alkenyl, or alkynyl groups mentioned above include, for example, cyclopropane rings, cyclobutane rings, cyclopentane rings, cyclohexane rings, and cyclooctane rings. Cycloalkane rings may contain one or more heteroatoms, and examples of such rings include, for example, oxirane rings, oxetane rings, tetrahydrofuran rings, and N-methylprolysine rings.

[0019] Specific examples of aromatic rings that may be contained in the alkyl, alkenyl, or alkynyl groups mentioned above include, for example, benzene rings, naphthalene rings, pyridine rings, furan rings, and thiophene rings.

[0020] Therefore, specific examples of cases where the substituent R is an alkyl group substituted with a cycloalkane ring include, for example, a cyclopropylmethyl group, a cyclohexylethyl group, and an 8,9-methanopentadecyl group.

[0021] A specific example of a case where the substituent R is an alkyl group substituted with an aromatic ring is benzyl Examples include the phenyl group, phenethyl group, and p-pentylphenyloctyl group.

[0022] R is preferably a linear or branched alkyl group having 9 to 17 carbon atoms, a linear or branched alkenyl group having 9 to 17 carbon atoms, or a linear or branched alkynyl group having 9 to 17 carbon atoms. More preferably, R is a linear or branched alkyl group having 9, 11, 13, 15, or 17 carbon atoms, or a linear or branched alkenyl group having 9, 11, 13, 15, or 17 carbon atoms. Particularly preferably, R is a linear or branched alkenyl group having 9, 11, 13, 15, or 17 carbon atoms.

[0023] In the compound represented by general formula (1), X and Y each independently represent either an oxygen atom (-O-) or a methylene group (-CH2-), but X and Y cannot be methylene groups simultaneously. That is, there are three possible combinations of X and Y. (1) X is an oxygen atom, and Y is an oxygen atom. (2) X is an oxygen atom and Y is a methylene group. (3) X is a methylene group and Y is an oxygen atom.

[0024] In the cyclic phosphatidic acid derivative represented by formula (I), M is either a hydrogen atom or an alkali metal atom. Examples of alkali metal atoms include lithium, sodium, and potassium, with sodium being particularly preferred.

[0025] Specific examples of compounds represented by formula (1) used in the present invention include cyclic phosphatidic acids and carbacyclic phosphatidic acid derivatives having an oleoyl group (abbreviated as C18:1) where R is an alkenyl group with 17 carbon atoms, or a palmitooleoyl group (abbreviated as C16:1) where R is an alkenyl group with 15 carbon atoms, as the acyl group at position 1.

[0026] Compounds of formula (I) may have isomers such as positional isomers, geometric isomers, tautomers, or optical isomers depending on the type of substituent they have. All possible isomers, as well as mixtures containing two or more of these isomers in any proportion, are within the scope of the present invention.

[0027] Furthermore, the compound of formula (I) may also exist in the form of adducts (hydrates or solvates) with water or various solvents, and these adducts are also within the scope of the present invention. Moreover, any crystalline form of the compound of formula (I) and its salts is also within the scope of the present invention.

[0028] Examples of the crystalline form of the compound represented by formula (1) include the crystalline form of the cyclic sodium phosphonate salt described in Japanese Patent Publication No. 6736466. Japanese Patent Publication No. 6736466 describes the production of crystalline cyclic sodium phosphonate salt by the steps of reacting a cyclic phosphonate ester with sodium halide in an organic solvent to obtain 2cc PA, and then concentrating the solution containing the 2cc PA obtained in the above step under reduced pressure, or by cooling the solution containing the 2cc PA obtained in the above step to precipitate crystals. The crystalline form of the compound represented by formula (1) may be produced by the method described in Japanese Patent Publication No. 6736466, or by other methods.

[0029] Compounds represented by general formula (1) in which X and Y are oxygen atoms can be chemically synthesized, for example, by following the methods described in Japanese Patent Publication No. 5-230088, Japanese Patent Publication No. 7-149772, Japanese Patent Publication No. 7-258278, Japanese Patent Publication No. 9-25235, etc.

[0030] Furthermore, compounds represented by general formula (1) in which X and Y are oxygen atoms can also be synthesized by reacting lysophospholipids with phospholipase D in accordance with the method described in Japanese Patent Publication No. 2001-178489. The lysophospholipids used here are not particularly limited as long as they are lysophospholipids that can be reacted with phospholipase D. Many types of lysophospholipids are known, including those with different fatty acid species and molecular species with ether or vinyl ether bonds, and these are available commercially. Phospholipase D can be derived from higher plants such as cabbage and peanuts, or Streptomyces chromofuscus , Actinomadula sp. Microbial-derived reagents such as those listed above are available commercially, Actinomadula sp.The enzyme derived from No. 362 selectively synthesizes cyclic phosphatidic acid (Japanese Patent Publication No. 11-367032). The reaction between lysophospholipid and phospholipase D is not particularly limited as long as the conditions allow the enzyme to express its activity, but for example, it is carried out by reacting in an acetate buffer (pH 5-6) containing calcium chloride at room temperature with heating (preferably around 37°C) for about 1 to 5 hours. The resulting cyclic phosphatidic acid derivative can be purified by conventional methods such as extraction, column chromatography, and thin-layer chromatography (TLC).

[0031] Furthermore, compounds represented by general formula (1), in which X is an oxygen atom and Y is a methylene group, can be synthesized according to the method described in the literature (Kobayashi, S., et al., Tetrahedron Letters 34, 4047-4050 (1993)), and can also be synthesized by the method described in international publication WO2002 / 094286. An example of a specific synthesis route is shown below.

[0032] [ka]

[0033] In the above procedure, first, commercially available (R)-benzylglycidyl ether (1) is activated with BF3·Et2O, and then alcohol (2) is obtained by reacting it with the lithio compound obtained by reacting methylphosphonate dimethyl ester with n-BuLi. The resulting alcohol is reacted in toluene with an excess of the pyridinium salt of p-toluenesulfonic acid at 80°C to obtain a cyclized product (3). This cyclized product is hydrolyzed and debenzylated using 20% ​​Pd(OH)2-C under a hydrogen atmosphere (4). Using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride as a coupling agent, it is reacted with the fatty acid to obtain a coupling product (5). Next, using bromotrimethylsilane as a nucleophile, the methyl group is regioselectively removed to obtain a cyclic phosphonic acid (6). This is transferred to a separatory funnel using ether, and a small amount of 0.02N aqueous sodium hydroxide solution is added dropwise to perform a liquid-liquid extraction and purification of the target compound as a sodium salt (7).

[0034] Furthermore, compounds represented by general formula (1), in which X is a methylene group and Y is an oxygen atom, can be synthesized by the methods described in Japanese Patent Application Publication No. 2004-010582 or International Publication No. WO03 / 104246.

[0035] The pulmonary fibrosis treatment agent of the present invention is preferably provided in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable pharmaceutical additives and a compound represented by formula (1) which is an active ingredient.

[0036] The pulmonary fibrosis treatment agent of the present invention can be administered in various forms, but preferred forms of administration include oral administration and parenteral administration (e.g., intravenous, intramuscular, subcutaneous or intradermal injection, rectal administration, transmucosal administration, etc.). Suitable pharmaceutical compositions for oral administration include, for example, tablets, granules, capsules, powders, solutions, suspensions, and syrups, while suitable pharmaceutical compositions for parenteral administration include, for example, injections, infusions, suppositories, and transdermal agents, but the dosage form of the agent of the present invention is not limited to these. Furthermore, the pulmonary fibrosis treatment agent of the present invention may also be an inhalant. In the case of an inhalant, the route of administration may be oral administration or nasal administration. Moreover, a sustained-release formulation can be made by known techniques.

[0037] The types of pharmaceutical additives used in the manufacture of the pulmonary fibrosis treatment agent of the present invention are not particularly limited and can be appropriately selected by those skilled in the art. For example, excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, bases, solubilizers or solubilizers, dispersants, suspending agents, emulsifiers, buffers, antioxidants, preservatives, isotonic agents, pH adjusters, solvents, stabilizers, etc., can be used, and the specific individual components used for these purposes are well known to those skilled in the art.

[0038] For example, excipients that can be used in the preparation of orally administered formulations include: excipients such as glucose, lactose, D-mannitol, starch, or crystalline cellulose; disintegrants or disintegration aids such as carboxymethylcellulose, starch, or carboxymethylcellulose calcium; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin; lubricants such as magnesium stearate or talc; coating agents such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol, or titanium dioxide; and bases such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, or hard fat.

[0039] Pharmaceutical additives that can be used in the preparation of injection or intravenous formulations include: distilled water for injection, physiological saline, propylene glycol, surfactants, and other solvents or solubilizers that can constitute aqueous or dissolvable injection formulations; isotonic agents such as glucose, sodium chloride, D-mannitol, and glycerin; and pH adjusters such as inorganic acids, organic acids, inorganic bases, or organic bases.

[0040] The pulmonary fibrosis treatment agent of the present invention can be administered to mammals such as humans. The dosage of the pulmonary fibrosis treatment agent of the present invention should be appropriately increased or decreased depending on the patient's age, sex, weight, symptoms, and route of administration. Generally, the amount of the active ingredient per day for adults is in the range of 1 μg / kg to 1,000 mg / kg, preferably in the range of 10 μg / kg to 100 mg / kg. The above dosage of the drug may be administered once a day or divided into several doses (for example, 2 to 4 times).

[0041] The present invention will be specifically described by the following examples, but the present invention is not limited by these examples. [Examples]

[0042] <Materials and Methods> (1) Test substance and medium (1-1) Test substance 2-Carbacyclic phosphatidic acid (2ccPA): [ka]

[0043] (1-2) Medium Japanese Pharmacopoeia Physiological Saline Solution (Physiological Saline Solution)

[0044] (2) Examination System Mouse Crl:CD1(ICR), 45 males, purchased from Charles River Japan Co., Ltd. (11 weeks old at purchase)

[0045] (3) Preparation of the administration solution The test substance was divided into 28 vials of 6 mg each by the day of administration. The administration solution was prepared immediately before use. 6 mL of physiological saline was added to one vial (6 mg) of the pre-divided test substance and mixed by inversion. Warming (approximately 40°C) and sonication were performed until dissolution was visually confirmed (1 mg / mL solution). 0.5 mL of the 1 mg / mL solution was taken and 4.5 mL of physiological saline was added. Mixing was performed by inversion and dissolution was confirmed (0.1 mg / mL solution).

[0046] (4) Administration The administration route was intraperitoneal. To allow for acclimatization, the medium was administered intraperitoneally at a rate of 10 mL / kg once a day for a total of 7 days, starting from Day 7 (Day 0 being the first day of administration of bleomycin and the test substance). The drug was administered once a day for 28 days. During the creation of the pulmonary fibrosis model (Day 0 to Day 4), the drug was administered before bleomycin administration.

[0047] 10 mL / kg was administered intraperitoneally using a 1 mL syringe and needle (Terumo Corporation).

[0048] (5) Test group composition [Table 1]

[0049] (6) Experimental Method (6-1) Starting calculation method The first day of administration of bleomycin solution and physiological saline was designated as Day 0. (6-2) Weight measurement Measurements were taken daily from Day 0 to Day 4, and three times a week (including at the time of autopsy) from Day -7 to Day -1 and from Day 5 onward. (6-3) Creation of a pulmonary fibrosis model Bleomycin solution was administered intravenously to the tail vein of mice at a dose of 5 mL / kg (bleomycin dose: 15 mg / kg) once daily for 5 days. The amount of solution administered was calculated based on the most recent body weight, rounded to the nearest 0.01 mL (rounded to the third decimal place). Normal mice were administered physiological saline solution at a dose of 5 mL / kg. (6-4) Blood sample The procedure was performed on the day after the final dose (Day 28). Blood samples were taken from all surviving animals. The animals were laparotomyed under 2% isoflurane anesthesia, and total blood was collected from the abdominal vena cava using a heparinized syringe and needle. Subsequently, the animals were euthanized by bleeding through the abdominal aorta. The collected blood was centrifuged at 4°C, 1800 g, and 10 minutes to obtain plasma. The plasma was dispensed into two approximately 100 μL vials and the remainder into a total of three vials, and stored in a cryogenic freezer (tolerance range: -90 to -65°C). (6-5) Lung harvesting, right lung weight measurement and fixation After exsanguination, the right bronchial bifurcation was ligated, and only the right lung was removed. The wet weight of the removed right lung was measured. After weight measurement, the right lung was shredded. Subsequently, the right lung was dried in a dry heat sterilizer set to 72°C for approximately 72 hours, and the dry weight of the right lung was measured. After dry weight measurement, it was stored in a cryogenic freezer (tolerance range: -90 to -65°C) until the amount of hydroxyproline was measured. The left lung was ligated and fixed after inserting a cannula into the trachea, and a 10% phosphate-buffered formalin solution was injected through the cannula at a pressure of 15 cm H2O to expand and fix the lung tissue. Lung collection was performed on animals from which blood was collected. Pathological examination of the fixed left lung is currently underway.

[0050] (6-6) Measurement of Hydroxyproline (HYP) in the right lung Preparation of Hydroxyproline measurement samples The hydroxyproline content was measured in the right lung that had been cryopreserved in section (6-5). 2 mL of HCl for hydrolysis was added to the dried right lung, and hydrolysis was carried out in an autoclave at approximately 121°C for 30 minutes. The lung was then neutralized with 2.5 N NaOH (pH approximately 6-7; pH was confirmed using pH test strips). The tare weight was measured beforehand, and the sample volume (g) after neutralization was calculated by measuring the weight after neutralization. The neutralized sample was diluted appropriately with sterile water for injection, and 2 mL of this solution was used as the sample for HYP content measurement.

[0051] Calibration curve creation To 2 mL of HYP standard solution, 1 mL of chloramine T reagent was added and left at room temperature for 20 minutes. Then, 1 mL of perchloric acid reagent was added and left at room temperature for 5 minutes. 1 mL of p-dimethylaminobenzaldehyde reagent was added and the mixture was heated at 60°C for 20 minutes. The supernatant was filtered using a filter, and the absorbance at 557 nm was measured using a spectrophotometer to create a calibration curve.

[0052] Measurement of HYP content in a sample For each HYP content sample (2 mL), the absorbance was measured using the same procedure as in section 3.6.6.2. The HYP content (μg / mL) was then calculated from these measurements based on the calibration curve obtained in section 3.6.6.2. Each HYP content sample was diluted 20-fold for measurement. Single-spectrum measurements were performed. HYP amount (μg / mL) × Dilution ratio × Sample volume after neutralization (g) = HYP amount in the right lung (μg / Lung)

[0053] (7) Statistical analysis (USOP / STA / 1001) (7-1) Processing items Right lung wet weight, right lung dry weight, HYP amount in right lung, left lung histopathological examination (if performed) (7-2) Processing method The following combinations will be used for the test. Right lung wet weight, right lung dry weight, and HYP amount in the right lung Student's t-test: Test group 1 vs 2, Test group 2 vs 3, Test group 2 vs 4 Dunnett test: Test group numbers 2 vs 3, 4 Histopathological examination (if performed) Wilcoxon test: Test group number 1 vs 2 Steel certification: Exam group numbers 2 vs 3, 4 The significance level for each is set at 5%, and the results are displayed separately for 1% and 5%.

[0054] (7-3) Analysis software We will use SAS 9.4 [EXSUS Version 8.1.0, SAS Institute Japan Co., Ltd. (CAC Croa Co., Ltd.)].

[0055] <Result> Right lung weight and hydroxyproline dose are shown in Figures 1-3 and Table 2. In Figures 1 to 3, each value represents the mean ± SEM. ##: p<0.01; statistically significant difference from the normal group according to student's t-test. **: p<0.01; statistically significant difference from the control group according to student's t-test. *: p<0.05; statistically significant difference from the control group according to student's t-test.

[0056] [Table 2]

[0057] Each value represents the mean ± SEM. ##: p < 0.01; Significant difference from the normal group by Student's t-test. **: p < 0.01; Significant difference compared to the control group by Student's t-test. *: p < 0.05; statistically significant difference from the control group by Student's t-test.

Claims

1. A pulmonary fibrosis treatment agent containing the compound shown in the following formula (1) as an active ingredient. 【Chemistry 1】 (In the formula, R is a linear or branched alkyl group having 9 to 17 carbon atoms, or a linear or branched alkenyl group having 9 to 17 carbon atoms; X represents a methylene group; Y represents an oxygen atom; and M represents a hydrogen atom or an alkali metal atom.)

2. The compound represented by formula (1) 【Chemistry 2】 The pulmonary fibrosis treatment agent according to claim 1.

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