Capsaicin derivatives in the treatment of idiopathic pulmonary fibrosis.

Abstract

The present invention relates to the treatment of idiopathic pulmonary fibrosis. More specifically, the present invention provides compounds for use in the method for treating idiopathic pulmonary fibrosis, and compositions thereof. The present invention also relates to a method for treating idiopathic pulmonary fibrosis, and a method for inhibiting the activity of platelet-derived growth factor receptor (PDGF)-α and / or β in a subject in need thereof.

Description

[Technical field]

[0001] The present invention relates to the treatment of idiopathic pulmonary fibrosis. More specifically, the present invention provides compounds for use in the method for treating idiopathic pulmonary fibrosis, and compositions thereof. The present invention also relates to a method for treating idiopathic pulmonary fibrosis, and a method for inhibiting the activity of platelet-derived growth factor receptor (PDGF)-α and / or β in a subject in need thereof. [Background technology]

[0002] Idiopathic pulmonary fibrosis (IPF) belongs to a group of over 200 lung diseases known as interstitial lung diseases (ILDs) or diffuse parenchymal lung diseases (DPLDs) that affect the interstitium (the tissue and spaces surrounding the alveoli). IPF is a chronic, progressive, and ultimately fatal disease characterized by irreversible fibrosis of the lung parenchyma, which manifests in the usual interstitial pneumonia pattern, resulting in loss of lung function. Patients' alveoli become damaged, leading to increased scarring, stiffening of the lungs, and impaired gas exchange. Although the exact prevalence of IPF is unknown, it is estimated that approximately 5 million people worldwide suffer from IPF, with the disease occurring in approximately 12 new cases per 100,000 people annually. Symptoms typically include a dry cough, fatigue, clubbing, pain, weight loss, and increased difficulty breathing caused by reduced blood oxygen levels and stiffening of scar tissue.

[0003] With a variable and unpredictable clinical course, IPF has a worse prognosis than many cancers: progression of IPF is associated with an estimated median survival of only about 2.5–5 years after definitive diagnosis, with 5-year survival rates for IPF ranging from 20–40%. Some patients have a rapid decline in lung function that leads to death, whereas others experience a slower decline over time. Some patients exhibit periods of clinical stability interspersed with episodes of rapid respiratory deterioration, known as acute exacerbations, which can last from days to weeks and are devastating events from which recovery is extremely difficult. Acute exacerbations, although more common in patients with advanced lung dysfunction, can occur at any time in patients with IPF and are associated with an in-hospital mortality rate estimated to be greater than 50%.

[0004] In addition to respiratory failure, complications resulting from IPF include pulmonary hypertension, heart failure, pneumonia, and pulmonary embolism. Decreased health-related quality of life in patients with IPF is also associated with depression and anxiety.

[0005] There is currently no cure for IPF. Treatments aim to slow disease progression and prolong survival, relieve and reduce symptoms as much as possible, prevent acute exacerbations, and provide palliative care as the condition becomes more advanced. A small number of patients are suitable for lung transplantation, but donor lungs are in short supply. Symptom management and supportive care, including oxygen treatment and pulmonary rehabilitation, are also important components of the management of IPF. Some patients respond well to treatment, while others rapidly deteriorate or experience debilitating shortness of breath.

[0006] Two antifibrotic drugs, nintedanib and pirfenidone, have been approved for the treatment of IPF. They are recommended in the current (2015) treatment guidelines for IPF published by the American Thoracic Society, the European Respiratory Society, the Japanese Respiratory Society, and the Latin American Thoracic Association. The treatment guidelines also provide a conditional recommendation for the use of anti-acid therapy in patients with IPF and asymptomatic gastroesophageal reflux disease, but recommended against all other pharmacological therapies used in the treatment of IPF, including the antioxidant N-acetylcysteine. Side effects of nintedanib and pirfenidone are common and substantial. Gastrointestinal side effects (nausea, diarrhea, vomiting) are the most prevalent for both therapies, and additional side effects include rash with pirfenidone and liver function abnormalities with nintedanib. Neither pirfenidone nor nintedanib improve patient-perceived quality of life.

[0007] Thus, there is a need for new compounds and methods for the treatment of IPF. [Brief description of the drawings]

[0008] [Figure 1] 1 shows the results of a clonogenic survival assay for human corneal epithelial cell survival in the presence of PDGF. [Diagram 2] 1 shows results from a proliferation assay studying corneal epithelial proliferation stimulated by PDGF. [Diagram 3] 1 shows results from a clonogenic survival assay for human bronchial epithelial cell survival in the presence of PDGF. [Figure 4] 1 shows results from a proliferation assay investigating bronchial epithelial proliferation stimulated by PDGF. [Diagram 5]1 shows the results of the studies of Examples 3 and 4 testing clonogenic survival assays, phenylcapsaicin (2), capsaicin (1), controls and analogs. Summary of the Invention

[0009] The present inventors have discovered that capsaicin derivatives of formula I represent promising drug candidates for IPF.

[0010] In one aspect, the present invention relates to a compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, for use in a method for the treatment of IPF, [ka] During the ceremony, X is selected from oxygen and sulfur; Ar optionally contains one or more nitrogen, oxygen, or sulfur atoms and is selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, C 1 ~C 6 Linear and branched alkoxy, C 1 ~C 6 Sulfoxy, -SC 1 ~C 6 Alkyl, C 1 ~C 6 Straight and branched alkyl, C 2 ~C 6 Straight and branched alkenyl, C 2 ~C 6 Straight and branched alkynyl, C 1 ~C 6 Fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl, COO-C 1 ~C 6 Alkyl, N(C 1 ~C 6 Alkyl) 2 and CON(C 1 ~C 6 Alkyl) 2represents an aryl group optionally substituted with one or more identical or different substituents selected from the group consisting of: R' is hydrogen, C 1 ~C 6 Linear or branched alkyl, and C 3 ~C 6 selected from the group including or consisting of cycloalkyl; R is hydrogen; benzyl; C 1 ~C 18 Straight-chain and branched alkyl, alkenyl, and alkynyl; C 3 ~C 6 Cycloalkyl; acyl group COR 1 (In the formula, R 1 is C 1 ~C 18 Straight-chain and branched alkyl, alkenyl, and alkynyl, C 3 ~C 6 cycloalkyl, phenyl; and substituted phenyl (wherein the phenyl ring is selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, C 1 ~C 6 Linear and branched alkoxy, C 1 ~C 6 Sulfoxy, -SC 1 ~C 6 Alkyl, C 1 ~C 6 Straight and branched alkyl, C 2 ~C 6 Straight and branched alkenyl, C 2 ~C 6 Straight and branched alkynyl, C 1 ~C 6 Fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl, COO-C 1 ~C 6 Alkyl, and CON(C 1 ~C 6 Alkyl) 2 substituted with 1 to 5 identical or different substituents selected from the group consisting of sulfamic acid esters (SO 2NH 2 );Acyl groups of naturally occurring amino acids;Acyl groups of 5-membered ring amino acid esters (amino groups at 2- or 3-position);Acyl groups of 6-membered ring amino acid esters (amino groups at 2-, 3- or 4-position);CONR 3 R 4 (In the formula, R 3 and R 4 are each independently 1 ~C 18 Straight-chain and branched alkyl, alkenyl, and alkynyl groups and C 3 ~C 6 cycloalkyl); Ca 2+ , Na + , and K + A phosphate ester PO having a counterion selected from 3 2- ;Ca 2+ , Na + , and K + A phosphate ester PO having a counterion selected from 3 H - ;CO(CH) 2 COOH;CO(CH 2 ) 2 COOH; and CO(CH 2 ) 3 COOH, and The bond between the carbon atom alpha to the aryl group and the carbon atom beta to the aryl group is a single bond, a double bond, or a triple bond.

[0011] In one embodiment, the present invention provides a compound of formula II, or a pharma- ceutically acceptable salt or solvate thereof, for use in a method for the treatment of IPF: [ka] During the ceremony, X is selected from oxygen and sulfur; Ar optionally contains one or more nitrogen, oxygen, or sulfur atoms, and at any one or more positions, may be selected from the group consisting of nitro, trifluoromethyl, C 1 ~C 6Linear and branched alkoxy, C 1 ~C 6 represents an aryl group optionally substituted with one or more identical or different substituents selected from the group consisting of straight chain and branched alkyl; R' is hydrogen and C 1 ~C 6 Selected from the group including or consisting of straight chain or branched alkyl; R is hydrogen; C 1 ~C 6 Straight-chain and branched alkyl, alkenyl, and alkynyl; C 3 ~C 6 Cycloalkyl; acyl group COR 1 (In the formula, R 1 is C 1 ~C 6 Straight-chain and branched alkyl, alkenyl, and alkynyl, C 3 ~C 6 cycloalkyl and phenyl).

[0012] The inventors found that these compounds exhibited a dose-dependent inhibitory effect on human bronchial epithelial cell survival in the presence of PDGF (platelet-derived growth factor receptor), significantly reducing cell viability. These results are strong indicators of the compounds' utility in treating IPF.

[0013] In another aspect, the invention relates to a composition comprising such a compound, or a pharma- ceutically acceptable salt or solvate thereof, for use in a method for the treatment of IPF.

[0014] In another aspect, the invention relates to a kit comprising the compound or composition and an inhaler. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Unless otherwise defined, all terms, designations and other scientific or technical terms used herein are intended to have the meaning commonly understood by those skilled in the art to which the present invention belongs. In some cases, terms having a commonly understood meaning are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be interpreted as representing a substantial difference from what is commonly understood in the art.

[0016] The term "derivative" as used herein refers to a molecule that has a different chemical structure from that of a parent compound. Examples of derivatives include, but are not limited to, homologs that are incrementally different from the parent chemical structure, such as differences in the length of aliphatic chains; molecular fragments; structures that have one or more functional groups different from the parent compound, for example, can be created by converting one or more functional groups of the parent; changes in the ionization state of the parent, such as ionization of an acid into its conjugate base; isomers, including positional isomers, geometric isomers and stereoisomers; and combinations thereof.

[0017] As will be understood, any of the compounds described herein may be provided in the form of a pharma- ceutically acceptable salt or solvate thereof, such as a hydrate thereof. Procedures for the formation of salts and solvates are conventional in the art.

[0018] The terms "treating" and "treatment" and "therapy" (and grammatical variations thereof) are used interchangeably herein and refer to 1) inhibiting a disease; for example, inhibiting a disease, condition or disorder in a subject experiencing or exhibiting the pathology or symptomology of the disease, condition or disorder, including prevention of the disease (i.e., prophylactic treatment, preventing further onset of the pathology and / or symptomology), or 2) alleviating the symptoms of the disease, or 3) relieving a disease; for example, relieving a disease, condition or disorder in a subject experiencing or exhibiting the pathology or symptomology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomology). These terms may relate to the use and / or administration of a pharmaceutical, active pharmaceutical ingredient (API), food additive, food supplement, dietary supplement, nutraceutical, over-the-counter (OTC) supplement, medical food, and / or pharmaceutical grade supplement.

[0019] The early stages of IPF have long been thought to involve primarily chronic inflammation, and thus corticosteroids and other anti-inflammatory and / or immunosuppressive drugs were used to treat IPF. However, over the past few years, there has been a conceptual shift in the pathogenesis of IPF from an inflammation-driven process to a primarily fibrotic one, where fibrogenesis results from recurrent microinjury of alveolar epithelial cells followed by abnormal repair processes that lead to fibrosis. Thus, there has been interest in agents that target persistent fibrosis resulting from abnormal repair of alveolar epithelial damage, and the number of available anti-fibrotic treatment options has also increased, starting with pirfenidone and nintedanib. Pirfenidone helps to slow the development of scarring in the lungs by reducing the activity of the immune system. Nintedanib is a newer medication that may also help to slow lung scarring in some IPF patients. Both have been shown in clinical trials to slow the progression of mild to moderate idiopathic pulmonary fibrosis. However, as mentioned above, both drugs exhibit significant side effects. N-acetylcysteine ​​has also found some use in the treatment of IPF, with some studies suggesting it may reduce the amount of scar tissue in the lungs. Other studies have not shown any benefit, and N-acetylcysteine ​​is not currently widely recommended.

[0020] The pathogenesis and precise pathophysiological mechanisms of IPF remain incompletely understood. The prevailing theory is that IPF is caused by persistent alveolar epithelial cell microinjury combined with dysregulated repair processes.

[0021] The naturally occurring alkaloid capsaicin (1) as well as other structurally related compounds including synthetic phenylcapsaicin (2) (N-(4-hydroxy-3-methoxybenzyl)-7-phenylhept-6-ynamide) and its derivatives have found applications in a variety of areas. Phenylcapsaicin has been shown to have low systemic toxicity and to be safe with respect to gene mutations and chromosomal damage (Rage Paulsen et al., Toxicology Research and Application 2018, 2, 1), and has been tested and deemed safe by the European Food Safety Authority (EFSA NDA Panel et al., EFSA Journal 2019, 17(6), e05718). [ka]

[0022] Both capsaicin and phenylcapsaicin are known TRPV1 agonists. It is known that cough sensitivity to inhaled capsaicin is significantly increased in IPF patients because TRPV1 is overexpressed in IPF. Therefore, capsaicin has been used in the study of the pathogenesis of cough in IPF. The use of capsaicin has also been suggested for cough prevention in patients with chronic cough, or for symptom relief in various diseases, including respiratory diseases such as pulmonary fibrosis, but has not found widespread use.

[0023] The inventors have found that the compound of structure I is a very promising drug candidate for the treatment of IPF. In clonogenic cell survival assays of human bronchial epithelial cells (Examples 2 and 3), it was surprisingly found that phenylcapsaicin exhibited a dose-dependent inhibitory effect on the survival of human bronchial epithelial cells in the presence of PDGF (platelet-derived growth factor receptor), reducing the cell viability to only 35% after 14 days in the presence of 10 μM phenylcapsaicin. These findings strongly suggest that phenylcapsaicin is a useful drug against IPF and can delay or reduce scarring of lung tissue. Such reduction in scarring can result in a delay in the progression of IPF and / or relieve symptoms of IPF such as dyspnea and / or cough. Furthermore, in acute inhalation toxicity studies in rats (single exposure by inhalation, nose-only exposure), the LC 50 was found to exceed 5.65 mg / L in male and female rats based on active substance. This finding is an indication that the compounds of the present invention have low toxicity for use in IPF using inhalation as the administration route.

[0024] Interestingly, in the corresponding clonogenic cell survival assay (example 3), capsaicin showed little effect, with 10 μM capsaicin showing 95% viability, while phenylcapsaicin reduced viability to 83% at only 0.10 μM and only 32% at 10 μM. Other structurally similar compounds tested in the same assay show that the presence of an aromatic ring in the side chain is important: replacing the alkynylbenzene phenyl ring of phenylcapsaicin with a saturated cyclohexyl ring (compound 3) significantly reduced the activity (73% viability at 10 μM), while the tert-butyl derivative (compound 4) had only slight activity in this assay (91% viability at 10 μM). Moreover, derivatization of the hydroxy group of the vanillyl group to form an acetoxy group was found to improve the effect, with the acetoxy derivative of phenylcapsaicin (compound 5) reducing viability to only 20% at 10 μM. The corresponding acetoxy derivative of compound 3 (compound 6) also gave better results than compound 3, but introduction of an acetoxy group into compound 4 (compound 7) was unable to mediate the deleterious effect of the tert-butyl group. [ka]

[0025] Additionally, compound 10, a 4-nitrophenyl analog of phenylcapsaicin, and compound 12, a naphthalene analog of phenylcapsaicin, showed similar percent cell survival as the parent phenylcapsaicin. Compound 11, a 4-methoxyphenyl analog of phenylcapsaicin, showed a higher rate of decline in cell survival than lead phenylcapsaicin in cell survival studies. [ka]

[0026] Although not wishing to be bound by any theory regarding the mechanism of action, a possible explanation for the observed effects of the compounds of the present invention is that the compounds act as competitive inhibitors of platelet-derived growth factor receptors (PDGF)-α and β. PDGF has been shown in the literature to be a profibrotic mediator and plays an important role in the pathogenesis of IPF, and inhibition of platelet-derived growth factor signaling has been shown to attenuate pulmonary fibrosis. The effects of the compounds of the present invention on IPF can be explained by their being effective PDGF inhibitors, as shown by the results from Example 2, Example 3 and Example 4.

[0027] In one aspect, the present invention provides a compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, for use in a method for treating ILD, preferably idiopathic ILD and / or pulmonary fibrosis, more preferably IPF. In some embodiments, the present invention provides a compound of formula I, or a pharma-ceutically acceptable salt or solvate thereof, for use in a method for treating IPF. As used herein, the term "pharma-ceutically acceptable" means that the compound must be physiologically acceptable to the recipient and, when part of a composition, must be compatible with other components of the composition. [ka]

[0028] The dashed line indicates the optional presence of a bond, which means that the bond between the carbon atom alpha to the aryl group and the carbon atom beta to the aryl group (hereinafter referred to as the "α-β bond") can be a single bond, a double bond, or a triple bond.

[0029] In some embodiments, in the compound of formula I, the α-β bond is selected from a single bond, a double bond, and a triple bond; X is selected from oxygen and sulfur; Ar optionally contains one or more nitrogen, oxygen, or sulfur atoms and is selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, C 1 ~C 6 Linear and branched alkoxy, C 1 ~C 6 Sulfoxy, -SC 1 ~C 6 Alkyl, C 1 ~C 6 Linear and branched alkyl, C2-C6 linear and branched alkenyl, C 2 ~C 6 Straight and branched alkynyl, C 1 ~C 6 Fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl, COO-C 1 ~C 6 Alkyl, N(C 1 ~C 6 Alkyl) 2 and CON(C 1 ~C 6 Alkyl) 2 represents an aryl group optionally substituted with one or more identical or different substituents selected from the group consisting of: R' is hydrogen, C 1 ~C 6 Linear or branched alkyl, and C 3 ~C 6 selected from the group including or consisting of cycloalkyl; R is hydrogen; benzyl; C 1 ~C 18 Straight-chain and branched alkyl, alkenyl, and alkynyl; C 3 ~C 6 Cycloalkyl; optionally substituted phenyl; acyl group COR 1 (In the formula, R 1 is selected from the group consisting of linear, branched and cyclic alkyl; sulfamic acid esters (SO 2 NH 2);Acyl groups of naturally occurring amino acids;Acyl groups of 5-membered ring amino acid esters (amino groups at 2- or 3-position);Acyl groups of 6-membered ring amino acid esters (amino groups at 2-, 3- or 4-position);CONR 3 R 4 (In the formula, R 3 and R 4 are each independently linear, branched, and cyclic alkyl, alkenyl, and alkynyl; Ca 2+ , Na + , and K + A phosphate ester PO having a counterion selected from 3 2- ;Ca 2+ , Na + , and K + A phosphate ester PO having a counterion selected from 3 H - ;CO(CH) 2 COOH;CO(CH 2 ) 2 COOH; and CO(CH 2 ) 3 It is selected from the group consisting of or including COOH.

[0030] Preferably, in the compound of formula I, the α-β bond is selected from a single bond, a double bond, and a triple bond, most preferably a triple bond; Ar optionally contains one or more nitrogen, oxygen, or sulfur atoms and is selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, C 1 ~C 6 Linear and branched alkoxy, C 1 ~C 6 Sulfoxy, -SC 1 ~C 6 Alkyl, C 1 ~C 6 Linear and branched alkyl, C2-C6 linear and branched alkenyl, C 2 ~C 6 Straight and branched alkynyl, C 1 ~C 6Fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl, COO-C 1 ~C 6 Alkyl, N(C 1 ~C 6 Alkyl) 2 and CON(C 1 ~C 6 Alkyl) 2 represents an aryl group optionally substituted with one or more identical or different substituents selected from the group consisting of: R' is hydrogen, C 1 ~C 6 Linear or branched alkyl, and C 3 ~C 6 selected from the group including or consisting of cycloalkyl; R is hydrogen; benzyl; C 1 ~C 18 Straight-chain and branched alkyl, alkenyl, and alkynyl; C 3 ~C 6 Cycloalkyl; acyl group COR 1 (In the formula, R 1 is C 1 ~C 18 Straight-chain and branched alkyl, alkenyl, and alkynyl, C 3 ~C 6 cycloalkyl, phenyl; and substituted phenyl, where the phenyl ring is selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, C 1 ~C 6 Linear and branched alkoxy, C 1 ~C 6 Sulfoxy, -SC 1 ~C 6 Alkyl, C 1 ~C 6 Straight and branched alkyl, C 2 ~C 6 Straight and branched alkenyl, C 2 ~C 6 Straight and branched alkynyl, C 1 ~C 6Fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl, COO-C 1 ~C 6 Alkyl, and CON(C 1 ~C 6 Alkyl) 2 substituted with 1 to 5 identical or different substituents selected from the group consisting of sulfamic acid esters (SO 2 NH 2 );Acyl groups of naturally occurring amino acids;Acyl groups of 5-membered ring amino acid esters (amino groups at 2- or 3-position);Acyl groups of 6-membered ring amino acid esters (amino groups at 2-, 3- or 4-position);CONR 3 R 4 (In the formula, R 3 and R 4 are each independently 1 ~C 18 Straight-chain and branched alkyl, alkenyl, and alkynyl groups and C 3 ~C 6 cycloalkyl); Ca 2+ , Na + , and K + A phosphate ester PO having a counterion selected from 3 2- ;Ca 2+ , Na + , and K + A phosphate ester PO having a counterion selected from 3 H - ;CO(CH) 2 COOH;CO(CH 2 ) 2 COOH; and CO(CH 2 ) 3 It is selected from the group consisting of or including COOH.

[0031] In some embodiments, in the compound of formula I, The α-β bond is a triple bond; X is selected from oxygen and sulfur; Ar optionally contains one or more nitrogen, oxygen, or sulfur atoms and is selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, C 1 ~C 6 Linear and branched alkoxy, C 1 ~C 6 Sulfoxy, -SC 1 ~C 6 Alkyl, C 1 ~C 6 Linear and branched alkyl, C2-C6 linear and branched alkenyl, C 2 ~C 6 Straight and branched alkynyl, C 1 ~C 6 Fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl, COO-C 1 ~C 6 Alkyl, N(C 1 ~C 6 Alkyl) 2 and CON(C 1 ~C 6 Alkyl) 2 and more preferably, Ar optionally contains one or more nitrogen, oxygen or sulfur atoms and, at any one or more positions, nitro, trifluoromethyl, C 1 ~C 6 Linear and branched alkoxy, C 1 ~C 6 represents an aryl group optionally substituted with one or more identical or different substituents selected from the group consisting of straight chain and branched alkyl; R' is hydrogen, C 1 ~C 6 Linear or branched alkyl, and C 3 ~C 6 cycloalkyl, more preferably selected from the group consisting of hydrogen and C 1 ~C 6 Selected from the group of linear or branched alkyl; R is hydrogen; benzyl; C 1 ~C 18 Straight-chain and branched alkyl, alkenyl, and alkynyl; C 3 ~C 6 Cycloalkyl; acyl group COR 1 (In the formula, R 1 is C 1 ~C 18 Straight-chain and branched alkyl, alkenyl, and alkynyl, C 3 ~C 6 cycloalkyl, phenyl; and substituted phenyl, where the phenyl ring is selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, C 1 ~C 6 Linear and branched alkoxy, C 1 ~C 6 Sulfoxy, -SC 1 ~C 6 Alkyl, C 1 ~C 6 Straight and branched alkyl, C 2 ~C 6 Straight and branched alkenyl, C 2 ~C 6 Straight and branched alkynyl, C 1 ~C 6 Fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl, COO-C 1 ~C 6 Alkyl, and CON(C 1 ~C 6 Alkyl) 2 substituted with 1 to 5 identical or different substituents selected from the group consisting of sulfamic acid esters (SO 2 NH 2 );Acyl groups of naturally occurring amino acids;Acyl groups of 5-membered ring amino acid esters (amino groups at 2- or 3-position);Acyl groups of 6-membered ring amino acid esters (amino groups at 2-, 3- or 4-position);CONR 3 R 4 (In the formula, R 3 and R 4 are each independently 1 ~C 18Straight-chain and branched alkyl, alkenyl, and alkynyl groups and C 3 ~C 6 cycloalkyl); Ca 2+ , Na + , and K + A phosphate ester PO having a counterion selected from 3 2- ;Ca 2+ , Na + , and K + A phosphate ester PO having a counterion selected from 3 H - ;CO(CH) 2 COOH;CO(CH 2 ) 2 COOH; and CO(CH 2 ) 3 More preferably, R is selected from the group consisting of: COOH; 1 ~C 6 Straight-chain and branched alkyl, alkenyl, and alkynyl; C 3 ~C 6 Cycloalkyl; acyl group COR 1 (In the formula, R 1 is C 1 ~C 6 Straight-chain and branched alkyl, alkenyl, and alkynyl, C 3 ~C 6 cycloalkyl and phenyl).

[0032] In some embodiments, in the compound of formula I, the α-β bond is selected from a single bond, a double bond, and a triple bond; X is selected from oxygen and sulfur; Ar optionally contains one or more nitrogen, oxygen, or sulfur atoms and is selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, C 1 ~C 6 Linear and branched alkoxy, C 1 ~C 6 Sulfoxy, -SC1 ~C 6 Alkyl, C 1 ~C 6 Linear and branched alkyl, C2-C6 linear and branched alkenyl, C 2 ~C 6 Straight and branched alkynyl, C 1 ~C 6 Fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl, COO-C 1 ~C 6 Alkyl, N(C 1 ~C 6 Alkyl) 2 , and CON(C 1 ~C 6 Alkyl) 2 represents a phenyl or naphthyl group optionally substituted with one or more identical or different substituents selected from the group consisting of: R' is hydrogen, C 1 ~C 6 Linear or branched alkyl, and C 3 ~C 6 selected from the group including or consisting of cycloalkyl; R is hydrogen; benzyl; C 1 ~C 8 Straight-chain and branched alkyl, alkenyl, and alkynyl; C 3 ~C 6 Cycloalkyl; acyl group COR 1 (In the formula, R 1 is C 1 ~C 8 Straight-chain and branched alkyl, alkenyl, and alkynyl, C 3 ~C 6 cycloalkyl, and phenyl; sulfamic acid esters (SO 2 NH 2 );Acyl groups of naturally occurring amino acids;Acyl groups of 5-membered ring amino acid esters (amino groups at 2- or 3-position);Acyl groups of 6-membered ring amino acid esters (amino groups at 2-, 3- or 4-position);CONR 3 R 4 (In the formula, R 3 and R 4are each independently 1 ~C 8 Straight-chain and branched alkyl, alkenyl, and alkynyl groups and C 3 ~C 6 cycloalkyl); Ca 2+ , Na + , and K + A phosphate ester PO having a counterion selected from 3 2- ;Ca 2+ , Na + , and K + A phosphate ester PO having a counterion selected from 3 H - ;CO(CH) 2 COOH;CO(CH 2 ) 2 COOH; and CO(CH 2 ) 3 It is selected from the group consisting of or including COOH.

[0033] In accordance with the present invention, the α-β bond, X, Ar, R, and R′ may be varied and combined to provide a series of compounds all falling within the scope of general formula I, all of which may be useful in the treatment of IPF, either as such or as a pharma- ceutically acceptable salt or solvate thereof.

[0034] The aryl ring may be an aryl ring that does not contain any heteroatoms. Such a variation is shown in a1.

[0035] The aryl ring may be a phenyl or naphthyl ring that does not contain any heteroatoms. Such variations are shown in a2.

[0036] The aryl ring may also be a phenyl ring that does not contain any heteroatoms. Such a variation is shown in a3.

[0037] The aryl ring may be an aryl ring containing one or more nitrogen, oxygen, or sulfur atoms. Such variations are illustrated in a4.

[0038] The aryl ring may be a phenyl or naphthyl ring containing one or more nitrogen, oxygen, or sulfur atoms. Such variations are illustrated in a5.

[0039] The aryl ring may be a phenyl ring containing one or more nitrogen, oxygen, or sulfur atoms. Such variations are illustrated in a6.

[0040] The aryl ring may be substituted at one or all positions with fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, or C 1 ~C 6 Linear and branched alkoxy; C 1 ~C 6 Sulfoxy;-SC 1 ~C 6 Alkyl;C 1 ~C 12 Straight-chain and branched alkyl, alkenyl, and alkynyl; C 1 ~C 6 Fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl; COO-C 1 ~C 6 Alkyl;N(C 1 ~C 6 Alkyl) 2 ; and CON(C 1 ~C 6 Alkyl) 2 These may be substituted with the same or different substituents selected from the group consisting of: Such variations are shown in b1.

[0041] The aryl ring may be substituted at one or all positions with fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, or C 1 ~C 6 Linear and branched alkoxy; C 1 ~C 6 Sulfoxy;-SC 1 ~C 6 Alkyl;C 1 ~C 12Straight-chain and branched alkyl, alkenyl, and alkynyl; and C 1 ~C 6 They may be substituted with the same or different substituents selected from the group consisting of fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl. Such variations are shown in b2.

[0042] The aryl ring may be substituted at one to all positions with the same or different substituents selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, and trifluoromethyl. Such variations are shown in b3.

[0043] The aryl ring may be fluoro, chloro, bromo, iodo, or C 1 ~C 12 Straight-chain and branched alkyl, alkenyl, and alkynyl; N(C 1 ~C 6 Alkyl) 2 , and C 1 ~C 6 They may be substituted with the same or different substituents selected from the group consisting of or including straight chain and branched alkoxy. Such a variation is shown in b4.

[0044] The aryl ring may be fluoro, chloro, bromo, iodo, or C 1 ~C 6 Straight-chain and branched alkyl, alkenyl, and alkynyl; and C 1 ~C 4 They may be substituted with the same or different substituents selected from the group consisting of straight chain and branched alkoxy. Such variations are shown in b5.

[0045] The aryl ring may be substituted at one or all positions with nitro; 1 ~C 6 Straight-chain and branched alkyl, alkenyl, and alkynyl; N(C 1 ~C6 Alkyl) 2 , and C 1 ~C 4 They may be substituted with the same or different substituents selected from the group consisting of straight chain and branched alkoxy. Such a variation is shown in b6.

[0046] The aryl ring may be unsubstituted, such a variation is shown in b7.

[0047] In some variations, two of the substituents on the aryl ring are the same as each other. In some variations, three of the substituents are the same as each other. In some variations, four of the substituents are the same as each other. In some variations, five or more of the substituents are the same as each other. In other variations, all of the substituents are different from each other.

[0048] All variants a1 to a6 can be combined with all variants b1 to b7 to give a series of aryl groups, optionally containing heteroatoms and optionally substituted, to give the following Ar groups: ArI=a1+b1, ArII=a1+b2, ArIII=a1+b3, ArIV=a1+b4, ArV=a1+b5, ArVI=a1+b6, ArVII=a1+b7, ArVIII=a2+b1, ArIX=a2+b2, ArX=a2+b3, ArXI=a2+b4, ArXII=a2+b5 , ArXIII=a2+b6, ArXIV=a2+b7, ArXV=a3+b1, ArXVI=a3+b2, ArXVII=a3+b3, ArXVIII=a3+b4, ArXIX=a3+b5, ArXX=a3+b6, ArXXI=a3+b7, ArXXII=a4+b1, ArXXIII=a 4+b2, ArXXIV=a4+b3, ArXXV=a4+b4, ArXXVI=a4+b5, ArXXVII=a4+b6, ArXXVIII=a4+b7, ArXXIX=a5+b1, ArXXX=a5+b2, ArXXXI=a5+b3, ArXXXII=a5+b4, ArXXXIII= a5+b5, ArXXXIV=a5+b6, ArXXXV=a5+b7, ArXXXVI=a6+b1, ArXXXVII=a6+b2, ArXXXVIII=a6+b3, ArXXXIX=a6+b4, ArXXXX=a6+b5, ArXXXXI=a6+b6, ArXXXXII=a6+b7.

[0049] The letter-number combinations refer to the variables defined above, so that, for example, a1+b1 means that the aryl ring does not have any heteroatoms (a1) and can have from one to all positions: fluoro; chloro; bromo; iodo; cyano; nitro; trifluoromethyl; 1 ~C 6 Linear and branched alkoxy; C 1 ~C 6 Sulfoxy;-SC 1 ~C 6 Alkyl;C 1 ~C 12 Straight-chain and branched alkyl, alkenyl, and alkynyl; C 1 ~C 6 Fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl; COO-C 1 ~C 6 Alkyl;N(C 1 ~C 6 Alkyl)2 ; and CON(C 1 ~C 6 Alkyl) 2 and a6+b7 means a (b7) phenyl ring containing one or more nitrogen, oxygen, or sulfur atoms (a6) and is unsubstituted, and so forth.

[0050] R' is hydrogen, C 1 ~C 6 Linear or branched alkyl, and C 3 ~C 6 cycloalkyl; R is hydrogen; benzyl; C 1 ~C 18 Straight-chain and branched alkyl, alkenyl, and alkynyl; C 3 ~C 6 Cycloalkyl; acyl group COR 1 (In the formula, R 1 is C 1 ~C 18 Straight-chain and branched alkyl, alkenyl, and alkynyl, C 3 ~C 6 cycloalkyl, phenyl; and substituted phenyl (wherein the phenyl ring is selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, C 1 ~C 6 Linear and branched alkoxy, C 1 ~C 6 Sulfoxy, -SC 1 ~C 6 Alkyl, C 1 ~C 6 Straight and branched alkyl, C 2 ~C 6 Straight and branched alkenyl, C 2 ~C 6 Straight and branched alkynyl, C 1 ~C 6Fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl, COO-C 1 ~C 6 Alkyl, and CON(C 1 ~C 6 Alkyl) 2 substituted with 1 to 5 identical or different substituents selected from the group consisting of sulfamic acid esters (SO 2 NH 2 );Acyl groups of naturally occurring amino acids;Acyl groups of 5-membered ring amino acid esters (amino groups at 2- or 3-position);Acyl groups of 6-membered ring amino acid esters (amino groups at 2-, 3- or 4-position);CONR 3 R 4 (In the formula, R 3 and R 4 are each independently 1 ~C 18 Straight-chain and branched alkyl, alkenyl, and alkynyl groups and C 3 ~C 6 cycloalkyl); Ca 2+ , Na + , and K + A phosphate ester PO having a counterion selected from 3 2- ;Ca 2+ , Na + , and K + A phosphate ester PO having a counterion selected from 3 H - ;CO(CH) 2 COOH;CO(CH 2 ) 2 COOH; and CO(CH 2 ) 3 COOH or may be selected from the group consisting of: Such a variation is shown in c1.

[0051] R' is hydrogen, C 1 ~C 6 Linear or branched alkyl, and C 3 ~C 6 cycloalkyl; R is hydrogen; benzyl; C1 ~C 8 Straight-chain and branched alkyl, alkenyl, and alkynyl; C 3 ~C 6 Cycloalkyl; acyl group COR 1 (In the formula, R 1 is C 1 ~C 8 Straight-chain and branched alkyl, alkenyl, and alkynyl, C 3 ~C 6 cycloalkyl, and phenyl; sulfamic acid esters (SO 2 NH 2 );Acyl groups of naturally occurring amino acids;Acyl groups of 5-membered ring amino acid esters (amino groups at 2- or 3-position);Acyl groups of 6-membered ring amino acid esters (amino groups at 2-, 3- or 4-position);CONR 3 R 4 (In the formula, R 3 and R 4 are each independently 1 ~C 8 Straight-chain and branched alkyl, alkenyl, and alkynyl groups and C 3 ~C 6 cycloalkyl); Ca 2+ , Na + , and K + A phosphate ester PO having a counterion selected from 3 2- ;Ca 2+ , Na + , and K + A phosphate ester PO having a counterion selected from 3 H - ;CO(CH) 2 COOH;CO(CH 2 ) 2 COOH; and CO(CH 2 ) 3 COOH or may be selected from the group consisting of: Such a variation is shown in c2.

[0052] R' is hydrogen and C 1 ~C 3may be selected from the group including or consisting of straight chain or branched alkyl; R is hydrogen; benzyl; C 1 ~C 16 Straight-chain and branched alkyl, alkenyl, and alkynyl; C 3 ~C 6 Cycloalkyl; acyl group COR 1 (In the formula, R 1 is C 1 ~C 6 Straight-chain and branched alkyl, alkenyl, and alkynyl, C 3 ~C 6 cycloalkyl, phenyl; and substituted phenyl, where the phenyl ring is substituted at any one or more positions with 1 to 5 identical or different substituents selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, and trifluoromethyl; sulfamic acid esters (SO 2 NH 2 );Acyl groups of naturally occurring amino acids;Acyl groups of 5-membered ring amino acid esters (amino groups at 2- or 3-position);Acyl groups of 6-membered ring amino acid esters (amino groups at 2-, 3- or 4-position);CONR 3 R 4 (In the formula, R 3 and R 4 are each independently 1 ~C 6 Straight-chain and branched alkyl, alkenyl, and alkynyl groups and C 3 ~C 6 cycloalkyl); Ca 2+ , Na + , and K + A phosphate ester PO having a counterion selected from 3 2- ;Ca 2+ , Na + , and K + A phosphate ester PO having a counterion selected from 3 H - ;CO(CH) 2 COOH;CO(CH 2 ) 2COOH; and CO(CH 2 ) 3 COOH or may be selected from the group consisting of: Such a variation is shown in c3.

[0053] R' may be methyl or ethyl; R is hydrogen; benzyl; C 1 ~C 6 Straight-chain and branched alkyl, alkenyl, and alkynyl; C 3 ~C 6 Cycloalkyl; acyl group COR 1 (In the formula, R 1 is C 1 ~C 6 Straight-chain and branched alkyl, alkenyl, and alkynyl, C 3 ~C 6 cycloalkyl, phenyl; and substituted phenyl (wherein the phenyl ring is selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, C 1 ~C 6 Linear and branched alkoxy, C 1 ~C 6 Sulfoxy, -SC 1 ~C 6 Alkyl, C 1 ~C 6 Straight and branched alkyl, C 2 ~C 6 Straight and branched alkenyl, C 2 ~C 6 Straight chain and branched alkynyl, COO-C 1 ~C 6 Alkyl, and CON(C 1 ~C 6 Alkyl) 2 substituted with 1 to 5 identical or different substituents selected from the group consisting of sulfamic acid esters (SO 2 NH 2 );CONR 3 R 4 (In the formula, R 3 and R 4 are each independently1 ~C 6 Straight-chain and branched alkyl, alkenyl, and alkynyl groups and C 3 ~C 6 cycloalkyl;CO(CH) 2 COOH;CO(CH 2 ) 2 COOH; and CO(CH 2 ) 3 COOH or may be selected from the group consisting of: Such a variation is shown in c4.

[0054] X may be oxygen or sulfur. Such variations are shown in d1.

[0055] X may also be oxygen. Such a variation is shown in d2.

[0056] X may also be sulfur. Such a variation is shown in d3.

[0057] It is understood that each possible X, R, R', and Ar group selection disclosed herein should be construed as disclosed for use in any combination with one or more of any and all options of the possible X, R, R', and Ar groups disclosed herein.

[0058] Thus, in some embodiments, the present invention provides a compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, for use in a method for the treatment of IPF, wherein X, R, R′, and Ar are selected as listed below: ArI+c1+d1、ArI+c2+d1、ArI+c3+d1、ArI+c4+d1、ArI+c1+d2、ArI+c2+d2、ArI+c3+d2、ArI+c4+d2、A rI+c1+d3、ArI+c2+d3、ArI+c3+d3、ArII+c4+d3、ArII+c1+d1、ArII+c2+d1、ArII+c3+d1、ArII+c4+d 1、ArII+c1+d2、ArII+c2+d2、ArII+c3+d2、ArII+c4+d2、ArII+c1+d3、ArII+c2+d3、ArII+c3+d3、Ar II+c4+d3、ArIII+c1+d1、ArIII+c2+d1、ArIII+c3+d1、ArIII+c4+d1、ArIII+c1+d2、ArIII+c2+d2、 ArIII+c3+d2、ArIII+c4+d2、ArIII+c1+d3、ArIII+c2+d3、ArIII+c3+d3、ArIII+c4+d3、ArIV+c1+d 1、ArIV+c2+d1、ArIV+c3+d1、ArIV+c4+d1、ArIV+c1+d2、ArIV+c2+d2、ArIV+c3+d2、ArIV+c4+d2、Ar IV+c1+d3、ArIV+c2+d3、ArIV+c3+d3、ArIV+c4+d3、ArV+c1+d1、ArV+c2+d1、ArV+c3+d1、ArV+c4+d1 、ArV+c1+d2、ArV+c2+d2、ArV+c3+d2、ArV+c4+d2、ArV+c1+d3、ArV+c2+d3、ArV+c3+d3、ArV、+c4+d3 ArVI+c1+d1、ArVI+c2+d1、ArVI+c3+d1、ArVI+c4+d1、ArVI+c1+d2、ArVI+c2+d2、 ArVI+c3+d2、ArVI+c4+d2、ArVI+c1+d3、ArVI+c2+d3、ArVI+c3+d3、ArVI+c4+d3、 ArVII+c1+d1、ArVII+c2+d1、ArVII+c3+d1、ArVII+c4+d1、ArVII+c1+d2、ArVII+c2+d2、 ArVII+c3+d2、ArVII+c4+d2、ArVII+c1+d3、ArVII+c2+d3、ArVII+c3+d3、ArVII+c4+d3、 ArVIII+c1+d1、ArVIII+c2+d1、ArVIII+c3+d1、ArVIII+c4+d1、ArVIII+c1+d2、ArVIII+c2+d2、ArVIII+c3+d2、ArVIII+c4+d2、ArVIII+c1+d3、ArVIII+c2+d3、ArVIII+c3+d3、ArVIII+c4+d3、 ArIX+c1+d1、ArIX+c2+d1、ArIX+c3+d1、ArIX+c4+d1、ArIX+c1+d2、ArIX+c2+d2、ArIX+c3+d2、ArIX+c4+d2、ArIX+c1+d3、ArIX+c2+d3、ArIX+c3+d3、ArIX+c4+d3、 ArX+c1+d1、ArX+c2+d1、ArX+c3+d1、ArX+c4+d1、ArX+c1+d2、ArX+c2+d2、ArX+c3+d2、 <h2 style=";text-align:left;direction:ltr">ArX+c4+d2、ArX+c1+d3、ArX+c2+d3、ArX+c3+d3、ArX+c4+d3、ArXI+c1+d1、A rXI+c2+d1、ArXI+c3+d1、ArXI+c4+d1、ArXI+c1+d2、ArXI+c2+d2、ArXI+c3+ d2、ArXI+c4+d2、ArXI+c1+d3、ArXI+c2+d3、ArXI+c3+d3、ArXI+c4+d3、ArXI I+c1+d1、ArXII+c2+d1、ArXII+c3+d1、ArXII+c4+d1、ArXII+c1+d2、ArXII+ c2+d2、ArXII+c3+d2、ArXII+c4+d2、ArXII+c1+d3、ArXII+c2+d3、ArXII+c3 +d3、ArXII+c4+d3、ArXIII+c1+d1、ArXIII+c2+d1、ArXIII+c3+d1、ArXIII+ c4+d1、ArXIII+c1+d2、ArXIII+c2+d2、ArXIII+c3+d2、ArXIII+c4+d2、ArXI II+c1+d3、ArXIII+c2+d3、ArXIII+c3+d3、ArXIII+c4+d3、ArXIV+c1+d1、Ar XIV + c2 + d1 V+c3+d2、ArXIV+c4+d2、ArXIV+c1+d3、ArXIV+c2+d3、ArXIV+c3+d3、ArXIV+ c4+d3、ArXV+c1+d1、ArXV+c2+d1、ArXV+c3+d1、ArXV+c4+d1、ArXV+c1+d2、A rXV+c2+d2、ArXV+c3+d2、ArXV+c4+d2、ArXV+c1+d3、ArXV+c2+d3、ArXV+c3+ d3、ArXV+c4+d3、ArXVI+c1+d1、ArXVI+c2+d1、ArXVI+c3+d1、ArXVI+c4+d1、 ArXVI+c1+d2、ArXVI+c2+d2、ArXVI+c3+d2、ArXVI+c4+d2、ArXVI+c1+d3、Ar XVI+c2+d3、ArXVI+c3+d3、ArXVI+c4+d3、ArXVII+c1+d1、ArXVII+c2+d1、Ar ArXVII+c3+d1ArXVII+c4+d2, ArXVII+c1+d3, ArXVII+c2+d3, ArXVII+c3+d3, ArXVII+c4+d3 ArXVIII+c1+d1, ArXVIII+c2+d1, ArXVIII+c3+d1, ArXVIII+c4+d1, ArXV III+c1+d2, ArXVIII+c2+d2, ArXVIII+c3+d2, ArXVIII+c4+d2, ArXVIII+ c1+d3, ArXVIII+c2+d3, ArXVIII+c3+d3, ArXVIII+c4+d3, ArXIX+c1+d1 ArXIX+c2+d1, ArXIX+c3+d1, ArXIX+c4+d1, ArXIX+c1+d2, ArXIX+c2+d2A rXIX+c3+d2、RXIX+c4+d2、RXIX+c1+d3、RXIX+c2+d3、RXIX+c3+d3A rXIX+c4+d3, rXX+c1+d1, rXX+c2+d1, rXX+c3+d1, rXX+c4+d1, rXX+c 1+d2, ArXX+c2+d2, ArXX+c3+d2, ArXX+c4+d2, ArXX+c1+d3, ArXX+c2+d3 ArXX+c3+d3, ArXX+c4+d3, ArXX+c4+d2, ArXX+c1+d3, ArXX+c2+d3, ArXX+c 3+d3, ArXX+c4+d3, ArXXI+c1+d1, ArXXI+c2+d1, ArXXI+c3+d1, ArXXI+c4 +d1、ArXXI+c1+d2、ArXXI+c2+d2、ArXXI+c3+d2、ArXXI+c4+d2、ArXXI+c1+ d3, ArXXI+c2+d3, ArXXI+c3+d3, ArXXI+c4+d3, ArXXII+c1+d1, ArXXII+c 2+d1、ArXXII+c3+d1、ArXXII+c4+d1、ArXXII+c1+d2、ArXXII+c2+d2、ArXX II+c3+d2、ArXXII+c4+d2、ArXXII+c1+d3、ArXXII+c2+d3、ArXXII+c3+d3 、ArXXII+c4+d3,ArXXIII+c1+d1,ArXXIII+c2+d1,ArXXIII+c3+d1,ArXXI II+c4+d1, ArXXIII+c1+d2, ArXXIII+c2+d2, ArXXIII+c3+d2, ArXXIII+c4+d2, ArXXIII+c1+d3, ArXXIII+c2+d3 ArXXIV+c1+d1、ArXXIV+c2+d1、ArXXIV+c3+d1、ArXXIV+c4+d1、ArXXIV+c1+d2、ArXXIV+c2+d2、ArXXIV+c3+d2、ArXXIV+c4+d2、ArXXIV+c1+d3、ArXXIV+c2+d3、ArXXIV+c3+d3、ArXXIV+c4+d3、ArXXV+c1+d1、ArXXV+c2+d1、ArXXV+c3+d1、ArXXV+c4+d1、ArXXV+c1+d2、ArXXV+c2+d2、ArXXV+c3+d2、ArXXV+c4+d2、ArXXV+c1+d3、ArXXV+c2+d3、ArXXV+c3+d3、ArXXV+c4+d3、ArXXVI+c1+d1、ArXXVI+c2+d1、ArXXVI+c3+d1、ArXXVI+c4+d1、ArXXVI+c1+d2、ArXXVI+c2+d2、ArXXVI+c3+d2、ArXXVI+c4+d2、ArXXVI+c1+d3、ArXXVI+c2+d3、ArXXVI+c3+d3、ArXXVI+c4+d3、ArXXVII+c1+d1、ArXXVII+c2+d1、ArXXVII+c3+d1、ArXXVII+c4+d1、ArXXVII+c1+d2、ArXXVII+c2+d2、ArXXVII+c3+d2、ArXXVII+c4+d2、ArXXVII+c1+d3、ArXXVII+c2+d3、ArXXVII+c3+d3、ArXXVII+c4+d3、ArXXVIII+c1+d1、ArXXVIII+c2+d1、ArXXVIII+c3+d1、ArXXVIII+c4+d1、ArXXVIII+c1+d2、ArXXVIII+c2+d2、ArXXVIII+c3+d2、ArXXVIII+c4+d2、ArXXVIII+c1+d3、ArXXVIII+c2+d3、ArXXVIII+c3+d3、ArXXVIII+c4+d3、 ArXXIX+c1+d1、ArXXIX+c2+d1、ArXXIX+c3+d1、ArXXIX+c4+d1、ArXXIX+c1+d2、ArXXIX+c2+d2、ArXXIX+c3+d2、ArXXIX+c4+d2、ArXXIX+c1+d3、ArXXIX+c2+d3、ArXXIX+c3+d3、ArXXIX+c4+d3、ArXXX+c1+d1、ArXXX+c2+d1、ArXXX+c3+d1、ArXXX+c4+d1、ArXXX+c1+d2、ArXXX+c2+d2、ArXXX+c3+d2、ArXXX+c4+d2、ArXXX+c1+d3、ArXXX+c2+d3、ArXXX+c3+d3、ArXXX+c4+d3、ArXXXI+c1+d1、ArXXXI+c2+d1、ArXXXI+c3+d1、ArXXXI+c4+d1、ArXXXI+c1+d2、ArXXXI+c2+d2、ArXXXI+c3+d2、ArXXXI+c4+d2、ArXXXI+c1+d3、ArXXXI+c2+d3、ArXXXI+c3+d3、ArXXXI+c4+d3、ArXXXII+c1+d1、ArXXXII+c2+d1、ArXXXII+c3+d1、ArXXXII+c4+d1、ArXXXII+c1+d2、ArXXXII+c2+d2、ArXXXII+c3+d2、ArXXXII+c4+d2、ArXXXII+c1+d3、ArXXXII+c2+d3、ArXXXII+c3+d3、ArXXXII+c4+d3、ArXXXIII+c1+d1、ArXXXIII+c2+d1、ArXXXIII+c3+d1、ArXXXIII+c4+d1、ArXXXIII+c1+d2、ArXXXIII+c2+d2、ArXXXIII+c3+d2、ArXXXIII+c4+d2、ArXXXIII+c1+d3、ArXXXIII+c2+d3、ArXXXIII+c3+d3、ArXXXIII+c4+d3、 ArXXXIV+c1+d1、ArXXXIV+c2+d1、ArXXXIV+c3+d1、ArXXXIV+c4+d1、ArXXXIV+c1+d2、ArXXXIV+c2+d2、ArXXXIV+c3+d2、ArXXXIV+c4+d2、ArXXXIV+c1+d3、ArXXXIV+c2+d3、ArXXXIV+c3+d3、ArXXXIV+c4+d3、ArXXXV+c1+d1、ArXXXV+c2+d1、ArXXXV+c3+d1、ArXXXV+c4+d1、ArXXXV+c1+d2、ArXXXV+c2+d2、ArXXXV+c3+d2、ArXXXV+c4+d2、ArXXXV+c1+d3、ArXXXV+c2+d3、ArXXXV+c3+d3、ArXXXV+c4+d3、ArXXXVI+c1+d1、ArXXXVI+c2+d1、ArXXXVI+c3+d1、ArXXXVI+c4+d1、ArXXXVI+c1+d2、ArXXXVI+c2+d2、ArXXXVI+c3+d2、ArXXXVI+c4+d2、ArXXXVI+c1+d3、ArXXXVI+c2+d3、ArXXXVI+c3+d3、ArXXXVI+c4+d3、ArXXXVII+c1+d1、ArXXXVII+c2+d1、ArXXXVII+c3+d1、ArXXXVII+c4+d1、ArXXXVII+c1+d2、ArXXXVII+c2+d2、ArXXXVII+c3+d2、ArXXXVII+c4+d2、ArXXXVII+c1+d3、ArXXXVII+c2+d3、ArXXXVII+c3+d3、ArXXXVII+c4+d3、ArXXXVIII+c1+d1、ArXXXVIII+c2+d1、ArXXXVIII+c3+d1、ArXXXVIII+c4+d1、ArXXXVIII+c1+d2、ArXXXVIII+c2+d2、ArXXXVIII+c3+d2、ArXXXVIII+c4+d2、ArXXXVIII+c1+d3、ArXXXVIII+c2+d3、ArXXXVIII+c3+d3、ArXXXVIII+c4+d3、ArXXXIX+c1+d1、ArXXXIX+c2+d1、ArXXXIX+c3+d1、ArXXXIX+c4+d1、ArXXXIX+c1+d2、ArXXXIX+c2+d2、ArXXXIX+c3+d2、ArXXXIX+c4+d2、ArXXXIX+c1+d3、ArXXXIX+c2+d3, ArXXXIX+c3+d3, ArXXXIX+c4+d3, ArXXXX+c1+d1, ArXXXX+c2+d1, ArXXXX+c3+d1, ArXXXX+c4+d1, ArXXX X+c1+d2, ArXXXX+c2+d2, ArXXXX+c3+d2, ArXXXX+c4+d2, ArXXXX+c1+d3, ArXXXX+c2+d3, ArXXXX+c3+d3, ArXXXX+c4+d3, ArXXXXI+c1+d1, ArXXXXI+c2+d1, ArXXXXI+c3+d1, ArXXXXI+c4+d1, ArXXXXI+c1+d2, ArXXXXI+c2+d2, ArX XXXI+c3+d2, ArXXXXI+c4+d2, ArXXXXI+c1+d3, ArXXXXI+c2+d3, ArXXXXI+c3+d3, ArXXXXI+c4+d3, ArXXXX II+c1+d1, ArXXXXII+c2+d1, ArXXXXII+c3+d1, ArXXXXII+c4+d1, ArXXXXII+c1+d2, ArXXXXII+c2+d2, ArX XXXII+c3+d2, ArXXXXII+c4+d2, ArXXXXII+c1+d3, ArXXXXII+c2+d3, ArXXXXII+c3+d3, ArXXXXII+c4+d3.

[0059] The letter-number combinations refer to the variants defined above, so that, for example, ArI+c1+d1 is an aryl ring that does not have any heteroatoms (a1) and is selected from fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, C 1 ~C 6 Linear and branched alkoxy; C 1 ~C 6 Sulfoxy;-SC 1 ~C 6 Alkyl;C 1 ~C 12 Straight-chain and branched alkyl, alkenyl, and alkynyl; C 1 ~C 6 Fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl; COO-C 1 ~C 6Alkyl;N(C 1 ~C 6 Alkyl) 2 ; and CON(C 1 ~C 6 Alkyl) 2 (b1) an aryl ring substituted with the same or different substituents selected from the group consisting of: 1 ~C 6 Linear or branched alkyl, and C 3 ~C 6 R is selected from the group consisting of: hydrogen; benzyl; C 1 ~C 18 Straight-chain and branched alkyl, alkenyl, and alkynyl; C 3 ~C 6 Cycloalkyl; acyl group COR 1 (In the formula, R 1 is C 1 ~C 18 Straight-chain and branched alkyl, alkenyl, and alkynyl, C 3 ~C 6 cycloalkyl, phenyl; and substituted phenyl, where the phenyl ring is selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, C 1 ~C 6 Linear and branched alkoxy, C 1 ~C 6 Sulfoxy, -SC 1 ~C 6 Alkyl, C 1 ~C 6 Straight and branched alkyl, C 2 ~C 6 Straight and branched alkenyl, C 2 ~C 6 Straight and branched alkynyl, C 1 ~C 6 Fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl, COO-C 1 ~C 6 Alkyl, and CON(C 1 ~C 6 Alkyl)2 substituted with 1 to 5 identical or different substituents selected from the group consisting of sulfamic acid esters (SO 2 NH 2 );Acyl groups of naturally occurring amino acids;Acyl groups of 5-membered ring amino acid esters (amino groups at 2- or 3-position);Acyl groups of 6-membered ring amino acid esters (amino groups at 2-, 3- or 4-position);CONR 3 R 4 (In the formula, R 3 and R 4 are each independently 1 ~C 18 Straight-chain and branched alkyl, alkenyl, and alkynyl groups and C 3 ~C 6 cycloalkyl); Ca 2+ , Na + , and K + A phosphate ester PO having a counterion selected from 3 2- ;Ca 2+ , Na + , and K + A phosphate ester PO having a counterion selected from 3 H - ;CO(CH) 2 COOH;CO(CH 2 ) 2 COOH; and (c1) CO(CH 2 ) 3 For other combinations, X is O or S--, and the like.

[0060] For each of the combinations listed, the α-β bond may be a single bond. For each of the combinations listed, the α-β bond may be a double bond. For each of the combinations listed, the α-β bond is preferably a triple bond.

[0061] In some embodiments, the present invention provides a compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating IPF, wherein Ar, X, R, R′, and the type of α-β bond are selected as listed below: Ar: unsubstituted phenyl or naphthyl optionally containing one or more heteroatoms selected from N, O, and / or S. X:O or S. R': Hydrogen, C 1 ~C 6 Linear or branched alkyl, or C 3 ~C 6 Cycloalkyl. R: Acyl group COR 1 (In the formula, R 1 is C 1 ~C 18 Straight-chain and branched alkyl, alkenyl, and alkynyl, C 3 ~C 6 cycloalkyl, phenyl; and substituted phenyl, where the phenyl ring is selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, C 1 ~C 6 Linear and branched alkoxy, C 1 ~C 6 Sulfoxy, -SC 1 ~C 6 Alkyl, C 1 ~C 6 Straight and branched alkyl, C 2 ~C 6 Straight and branched alkenyl, C 2 ~C 6 Straight and branched alkynyl, C 1 ~C 6 Fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl, COO-(C 1 ~C 6 Alkyl, and CON(C 1 ~C 6 Alkyl) 2 and each is substituted with 1 to 5 identical or different substituents selected from the group consisting of: α-β bond: single, double, or triple bond.

[0062] In some embodiments, the present invention provides a compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating IPF, wherein Ar, X, R, R′, and the type of α-β bond are selected as listed below: Ar: at any one or more positions, fluoro; chloro; bromo; cyano, nitro, trifluoromethyl, COO-C 1 ~C 6 Alkyl, and C 1 ~C 6 Phenyl or naphthyl substituted with one or more identical or different substituents selected from the group including or consisting of fluoroalkyl, chloroalkyl, bromoalkyl. X:O or S. R': Hydrogen or C 1 ~C 4 Straight or branched alkyl. R: Acyl group COR 1 (In the formula, R 1 is C 1 ~C 8 Straight-chain and branched alkyl, alkenyl, and alkynyl, C 3 ~C 6 cycloalkyl, and phenyl. α-β bond: Triple bond.

[0063] In some embodiments, the present invention provides a compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating IPF, wherein Ar, X, R, R′, and the type of α-β bond are selected as listed below: Ar: iodine, C at any one or more positions 1 ~C 6 Linear and branched alkoxy, C 1 ~C 6 Sulfoxy, -SC 1 ~C 6 Alkyl, C 1 ~C 6Linear and branched alkyl, C2-C6 linear and branched alkenyl, C 2 ~C 6 Straight and branched alkynyl, C 1 ~C 6 Iodoalkyl, N(C 1 ~C 6 Alkyl) 2 and CON(C 1 ~C 6 Alkyl) 2 Phenyl or naphthyl substituted with one or more identical or different substituents selected from the group consisting of: X:O or S. R':C 1 ~C 6 Straight or branched alkyl. R: Acyl group COR 1 (In the formula, R 1 is C 1 ~C 6 Straight-chain and branched alkyl, alkenyl, and alkynyl, C 3 ~C 6 cycloalkyl, phenyl; and substituted phenyl, where the phenyl ring is selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, C 1 ~C3 straight chain and branched alkoxy, C 1 ~C 3 Sulfoxy, -SC 1 ~C 3 Alkyl, C 1 ~C 3 Straight and branched alkyl, C 2 ~C3 straight and branched alkenyl, C 2 ~C 3 Straight and branched alkynyl, C 1 ~C 3 Fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl, COO-C 1 ~C3 alkyl, and CON(C 1 ~C 3 Alkyl) 2 and each is substituted with 1 to 5 identical or different substituents selected from the group consisting of: α-β bond: Triple bond.

[0064] In some embodiments, the present invention provides a compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating IPF, wherein Ar, X, R, R′, and the type of α-β bond are selected as listed below: Ar: optionally containing one or more nitrogen, oxygen, or sulfur atoms, in any one or more positions, fluoro; chloro; bromo; iodo, cyano, nitro, trifluoromethyl, C 1 ~C 6 Linear and branched alkoxy, C 1 ~C 6 Sulfoxy, -SC 1 ~C 6 Alkyl, C 1 ~C 6 Linear and branched alkyl, C2-C6 linear and branched alkenyl, C 2 ~C 6 Straight and branched alkynyl, C 1 ~C 6 Fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl, COO-C 1 ~C 6 Alkyl, N(C 1 ~C 6 Alkyl) 2 and CON(C 1 ~C 6 Alkyl) 2 and more preferably the aryl group is nitro, trifluoromethyl, C 1 ~C 6 Linear and branched alkoxy, C 1 ~C 6 Optionally substituted with one or more identical or different substituents selected from the group of straight chain and branched alkyl. X:O or S. R': Hydrogen, C 1 ~C 6 Linear or branched alkyl, or C3 ~C 6 Cycloalkyl, more preferably hydrogen, C 1 ~C 6 Straight or branched alkyl. R: hydrogen; C 1 ~C 6 Straight or branched alkyl, alkenyl, or alkynyl; C 3 ~C 6 Cycloalkyl; acyl group COR 1 (In the formula, R 1 is C 1 ~C 6 Straight-chain and branched alkyl, alkenyl, and alkynyl, C 3 ~C 6 cycloalkyl and phenyl), more preferably H or acetyl. α-β bond: a double bond or a triple bond, more preferably a triple bond.

[0065] Non-limiting examples of compounds according to the present invention for use in methods for the treatment of IPF include: N-[(4-hydroxy-3-methoxyphenyl)methyl]-7-phenyl-6-heptynamide; (2) 2-Methoxy-4-[(6-phenyl-5-hexynylcarbonylamino)methyl]phenyl acetate (5); N-[(4-hydroxy-3-methoxyphenyl)methyl]-(E)-7-phenyl-6-heptenamide; N-[(4-hydroxy-3-methoxyphenyl)methyl]7-phenylheptanamide (8); N-[(4-hydroxy-3-methoxyphenyl)methyl]-7-(p-methoxyphenyl)-6-heptynamide (11); N-[(4-hydroxy-3-methoxyphenyl)methyl]-7-(p-nitrophenyl)-6-heptynamide (10); N-[(4-hydroxy-3-methoxyphenyl)methyl]-7-(1-naphthyl)-6-heptynamide (12); N-{[4-(benzyloxy)-3-methoxyphenyl]methyl}-7-(p-methoxyphenyl)-6-heptynamide; 3-{2-methoxy-4-[(6-phenyl-5-hexynylcarbonylamino)methyl]phenoxycarbonyl}propionic acid; 2-Methoxy-4-[(6-phenyl-5-hexynylcarbonylamino)methyl]phenyl hexadecanoate Examples include:

[0066] In some embodiments, the present invention provides a compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of IPF, the compound being selected from the group of phenyl-substituted 6-yne derivatives of capsaicin, often referred to as phenylcapsaicin, where Ar is unsubstituted phenyl or a substituted phenyl as defined above (variations ArXV-ArXXI), and R′ is hydrogen, C 1 ~C 6 linear or branched alkyl, R is H or C 1 ~C 6 Straight-chain or branched alkyl, alkenyl, and alkynyl; C 3 ~C 6 Cycloalkyl; acyl group COR 1 (In the formula, R 1 is C 1 ~C 6 Straight-chain and branched alkyl, alkenyl, and alkynyl; C 3 ~C 6 R is selected from the group including or consisting of cycloalkyl and phenyl, preferably R is H or an acyl group.

[0067] In some embodiments, the present invention provides a compound of formula I as disclosed above, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of IPF, wherein the α-β bond is a triple bond as shown in formula II. The Ar group is unsubstituted phenyl or substituted phenyl as defined above (variants ArXV-ArXXI). The R' and R groups are as defined above, more preferably R' is H, or C1 ~C 6 Linear or branched alkyl, R is H or C 1 ~C 5 It is a straight-chain or branched acyl group, and X is S or O. [ka]

[0068] In some embodiments, the present invention provides a compound of formula II, or a pharma- ceutically acceptable salt or solvate thereof, wherein Ar is unsubstituted phenyl or a substituted phenyl as defined above (variations ArXV-ArXXI), and R′ is C 1 ~C 3 is a straight or branched alkyl group, and R is H or C 1 ~C 5 It is a straight chain or branched acyl group, and X is O.

[0069] In some embodiments, the present invention provides a compound of formula II, or a pharma- ceutically acceptable salt or solvate thereof, wherein Ar is a substituted phenyl substituted with at least one alkoxy group and R′ is C 1 ~C 3 is a straight or branched alkyl group, and R is H or C 1 ~C 5 It is a straight chain or branched acyl group, and X is O.

[0070] In some embodiments, the present invention provides a compound of formula III, or a pharma- ceutically acceptable salt or solvate thereof, wherein Ph represents unsubstituted phenyl and R′ is C 1 ~C 3 is a straight or branched alkyl group, and R is H or C 1 ~C 5 It is a straight chain or branched acyl group, and X is S or O. [ka]

[0071] In some embodiments, the present invention provides a compound of formula III, or a pharma- ceutically acceptable salt or solvate thereof, wherein Ph represents unsubstituted phenyl and R′ is C 1 ~C 3 is a straight or branched alkyl group, and R is H or C 1 ~C 5 It is a straight chain or branched acyl group, and X is O.

[0072] In some embodiments, the present invention provides a compound of formula III, or a pharma- ceutically acceptable salt or solvate thereof, wherein Ph represents unsubstituted phenyl, R′ is methyl, and R is H or C, for use in the treatment of IPF. 1 ~C 5 and X is O. In one embodiment, R' is methyl and R is acetyl.

[0073] In some embodiments, the invention provides a compound of formula III, or a pharma- ceutically acceptable salt or solvate thereof, wherein Ph represents unsubstituted phenyl, R' is methyl, R is H or acetyl, and X is O, for use in the treatment of IPF.

[0074] The compounds of the present invention may contain one or more chiral centers and / or double bonds and therefore may exist in different stereoisomeric forms, such as double bond isomers (i.e., geometric isomers), enantiomers, and / or diastereomers. It is to be understood that both stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and stereoisomeric mixtures are encompassed by the present invention. It is believed that the present invention extends to diastereomers and enantiomers, as well as racemic mixtures.

[0075] The compounds described herein may be resolved into their geometric isomers, enantiomers and / or diastereomers using methods known in the art.

[0076] The compounds can be obtained commercially or by using any procedure known to those skilled in the art.Non-limiting examples of procedures for obtaining the compounds according to the invention are those disclosed by the applicant in European Patent No. 1670310 and Norwegian Patent Application No. 20200333.

[0077] Past and current smokers are more likely to develop IPF than those who have never smoked. Family history of IPF is also a risk factor, as are certain genes; approximately 1 in 20 people with IPF have a family member with the disease. IPF has also been linked to gastroesophageal reflux, certain viral infections, air pollution, and exposure to certain types of dust, such as metal or wood dust. It is not known whether any of these factors directly cause IPF. People in their 60s and 70s are most commonly affected, and the disease is rare in people under 50. Men are affected more frequently than women. One study estimated that in the United States, 1 in 200 adults over the age of 70 has idiopathic pulmonary fibrosis.

[0078] IPF has also been recognized in some breeds of both dogs and cats. Veterinary patients with the condition share many of the same symptoms as their human counterparts, including increased respiratory rate and eventual respiratory distress, and generally have a poor prognosis.

[0079] The patient group of the present invention includes patients diagnosed with or suspected of having ILD, preferably idiopathic ILD and / or pulmonary fibrosis, more preferably IPF. The patient group may consist of patients suffering from IPF, such as patients diagnosed with or suspected of having IPF. In a preferred embodiment, the subject is selected from this patient group. The subject may be a human or a non-human animal, such as a human or a non-human mammal, preferably a human patient. The subject may be male or female. In some embodiments, the subject is an adult (i.e., 18 years of age or older). In certain embodiments, the subject is an elderly person. In certain embodiments, the subject is not an elderly person. In some embodiments, the subject is a human over 50 years of age, such as a human over 60 years of age, such as a human over 70 years of age.

[0080] As used herein, "subject" means any human or non-human animal selected for treatment or therapy, and includes, and may be limited to, a "patient." None of these terms should be construed as requiring the supervision (regular or otherwise) of a medical professional (e.g., physician, nurse, nurse practitioner, physician's assistant, janitor, clinical trial investigator, etc.) or a scientific researcher.

[0081] Any of the compounds according to the present invention may be provided in the form of a prodrug. As used herein, the term "prodrug" refers to any compound that is converted into any of the compounds according to the present invention under physiological conditions. A prodrug may, but need not, be pharmacologically inactive until converted into an active compound. A prodrug can be obtained by derivatizing one or more functional groups in an active compound with a progroup, i.e., a group that masks the functional group in the active compound and undergoes a transformation to release said functional group under certain conditions of use, such as in vivo. The progroup should be non-toxic. A wide range of progroups and methods for providing prodrugs are known to those skilled in the art.

[0082] The compound for use in the treatment of IPF according to the present invention may be present as an active ingredient in a desired dosage unit formulation, such as a pharma- ceutically acceptable composition containing one or more conventional pharma- ceutically acceptable carriers.As used herein, the term "composition" refers to a mixture of one or more compounds according to the present invention and one or more additional chemical components in any formulation.

[0083] Thus, in another aspect, the invention provides a composition for use in a method for the treatment of IPF.

[0084] The composition for use in the method for treating IPF according to the present invention is prepared from the compound disclosed herein in substantially pure form.In some embodiments, the purity of the compound according to the present invention used to formulate the composition is at least about 95%, for example at least 96%, 97%, 98% or 99%.Preferably, the purity of the compound is at least 98%.

[0085] The composition may further comprise one or more of any conventional pharma- ceutically acceptable excipients and / or carriers, such as solvents, fillers, diluents, binders, lubricants, glidants, viscosity modifiers, surfactants, dispersants, disintegrants, emulsifiers, wetting agents, suspending agents, thickening agents, buffers, pH adjusters, absorption retarders, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweeteners, flavoring agents, and coloring agents.The composition may be formulated using conventional formulation techniques known in the art, such as conventional mixing, dissolving, suspending, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating, or compressing processes.

[0086] In some embodiments, the composition for use in the method for treating IPF is formulated for pulmonary, oral, and / or intravenous administration.In some embodiments, the composition is formulated for inhalation, for example in the form of an aerosol inhalation formulation.

[0087] The amount of the compound according to the invention present in the composition may vary. In some embodiments, the amount of the compound according to the invention present in the composition is 1-50% by weight, such as 1-30%, for example 20-50%. In other embodiments, the amount of the compound according to the invention present in the composition is 30-70% by weight, such as 40-60%. In yet other embodiments, the amount of the compound according to the invention present in the composition is 50-100% by weight, such as 50-70%, for example 50-80%, for example 60-98%, for example 70-95%, for example 80-99%, for example 95-100%.

[0088] Furthermore, the composition for use in the method for treating IPF according to the present invention is substantially free of contaminants or impurities.In some embodiments, the level of contaminants or impurities other than residual solvent in the composition is less than about 5% based on the total weight of the compound according to the present invention and other intended components.In certain embodiments, the level of contaminants or impurities other than residual solvent in the composition is less than about 2% or 1% based on the total weight of the compound according to the present invention and other intended components.

[0089] Advantageously, the compound or composition for use in the method for the treatment of IPF according to the present invention is sterile. Sterilization can be achieved by any suitable method, including but not limited to applying heat, chemicals, irradiation, high pressure, filtration, or a combination thereof.

[0090] A compound or composition for use in a method for the treatment of IPF, according to the present invention, is administered to a subject in a therapeutically effective dose. As used herein, the term "therapeutically effective dose" means an amount of a compound according to the present invention that is effective to produce a desired therapeutic effect in a subject at a reasonable benefit / risk ratio applicable to any treatment. A therapeutically effective dosage may vary depending on the route of administration and the dosage form. Appropriate dosages may vary depending on the compound used, the stage of the condition, the age and weight of the patient, etc., and may be routinely determined by one of ordinary skill in the art according to principles well known in the art. A suitable daily dosage of a compound according to the present invention may range from about 0.01 mg / kg body weight to 1.0 mg / kg body weight. For example, in some embodiments, the daily dosage may be 0.01 to 0.1 mg / kg body weight, such as 0.01 to 0.05 mg / kg body weight, such as 0.03 to 0.08 mg / kg body weight, such as 0.05 to 0.1 mg / kg body weight. In other embodiments, the daily dose may be 0.05-0.5 mg / kg body weight, such as 0.05-0.02 mg / kg body weight, for example 0.08-0.5 mg / kg body weight. In yet other embodiments, the daily dose may be 0.1-1.0 mg / kg body weight, such as 0.3-0.08 mg / kg body weight, for example 0.5-1.0 mg / kg body weight.

[0091] The therapeutically effective dose can be administered in a single dose or divided doses. The compound or composition according to the present invention can be administered once a day, more than once a day, once every two days, once every three days, twice a week or once a week, or as deemed appropriate by a medical professional. In certain embodiments, the compound or composition according to the present invention is administered once a day. In other embodiments, the compound or composition according to the present invention is administered twice a day. In some embodiments, the administration regimen is predetermined and is the same across a patient population. In other embodiments, the dosage and frequency of administration of the compound or composition according to the present invention treatment is determined by a medical professional based on factors including, but not limited to, the stage of the disease, the severity of symptoms, the route of administration, the age, weight, general health, sex and / or diet of the subject, and / or the subject's response to treatment.

[0092] In some embodiments, the therapeutically effective dose is administered at regular intervals. In other embodiments, the dose is administered as needed or sporadically. The compound or composition according to the present invention may be administered by a medical professional or by self-administration. The compound or composition according to the present invention may be administered with or without food, depending on factors such as the formulation and route of administration. In some embodiments, the compound or composition according to the present invention is administered at a specific time of day.

[0093] As used herein, the terms "administer," "administration," and "administering" refer to (1) providing, giving, administering, and / or prescribing a formulation, preparation, or composition according to the present disclosure by or under the direction of a medical professional or an agent approved by them, or by self-administration, and (2) introducing, ingesting, or causing a subject to consume a formulation, preparation, or composition according to the present disclosure.

[0094] The compounds or compositions for use in the methods for treating IPF according to the present invention may be administered locally or systemically. The compounds or compositions according to the present invention may be administered by any route of administration, including, but not limited to, pulmonary, oral, intravenous, intramuscular, sublingual, subcutaneous, buccal, nasal, and transdermal.

[0095] In a preferred embodiment, the compound or composition is administered pulmonary, orally, and / or intravenously.

[0096] In some embodiments, the compound or composition for use in the method for treating IPF according to the present invention is administered via the pulmonary route, for example by inhalation or insufflation of a powder or aerosol, such as by nebulizer, intratracheal, intranasal, epidermal and transdermal. In a specific embodiment, the compound or composition is administered by inhalation via the oral, nasal or bronchial route, for example by aerosol inhalation, for example by spray inhalation, for example using an inhaler known in the art. In a specific embodiment, the compound or composition according to the present invention is in the form of solid or liquid aerosol particles, preferably of respirable size. Such particles are small enough to pass through the mouth and larynx upon inhalation into the bronchi and alveoli of the lungs. Generally, particles with a particle size in the range of about 1 to 10 microns, preferably less than about 5 microns in size, are inhalable.

[0097] In some embodiments, the compound or composition is administered orally. In some embodiments, the compound or composition is administered with or before a meal.

[0098] In some embodiments, the compound or composition according to the present invention is administered intravenously.In these embodiments, water is a particularly useful excipient.Saline and aqueous dextrose and glycerol solutions can also be used as liquid excipients, particularly for injectable solutions.

[0099] A preferred unit dosage formulation is a formulation that contains a therapeutically effective dose or a suitable fraction thereof of the compound for use in the method for treating IPF according to the present invention as described hereinabove. The composition for use in the method for treating IPF may be provided in unit dosage form as a single dose in which all active and non-active ingredients are combined in a suitable system and do not need to mix the ingredients before administration. Alternatively, the composition may be provided as a kit in which the drug, excipients and carriers are provided in two or more separate containers (e.g., ampoules, vials, tubes, bottles or syringes) and need to be combined to form the composition to be administered. The kit may contain one or more compounds according to the present invention or the composition according to the present invention and all other ingredients in unit dosage form or in two or more separate containers, and may contain instructions for storing, preparing, administering and / or using the composition.

[0100] In some embodiments, the duration of use of the compound or composition for use in the method for the treatment of IPF according to the present invention is determined by clinical, physiological, and / or imaging information, such as pulmonary function tests. In some embodiments, the treatment is continued until no further improvement is expected based on clinical, physiological, and / or imaging information, such as pulmonary function tests. In certain embodiments, the duration of treatment with the compound or composition according to the present invention is at least 2 weeks, at least 1 month, at least 3 months, such as 3 months, 6 months, 9 months, 1 year, 3 years, 5 years. In other embodiments, the duration is determined by a medical professional based on factors including, but not limited to, the nature and severity of symptoms, the route of administration, age, weight, general health, sex and / or diet, and / or the subject's response to treatment. In other embodiments, the compound or composition is administered chronically, such as in a continuous mode as opposed to an acute mode, to maintain the initial therapeutic effect for a long period of time.

[0101] In certain embodiments, the compound or composition according to the present invention is administered alone. In other embodiments, the compound or composition according to the present invention is administered in combination with one or more other therapeutic agents. The one or more other therapeutic agents may be known to have an effect on IPF and / or may have an additive or synergistic mechanism of action for IPF treatment together with the compound or composition of the present invention. In some embodiments, the compound or composition according to the present invention is administered as part of a combination therapy. A combination therapy comprising a compound or composition according to the present invention may refer to a composition comprising a compound or composition according to the present invention in combination with one or more therapeutic agents, and / or the simultaneous administration of a compound or composition according to the present invention with one or more therapeutic agents, where the compound or composition according to the present invention and the other therapeutic agent(s) are not formulated in the same composition. When using separate formulations, the compound or composition according to the present invention may be administered simultaneously with, intermittently, alternately, before, after, or a combination thereof with the administration of another therapeutic agent.

[0102] In a further aspect, the present invention provides a method for producing a method for treating a cancer cell comprising the steps of: i) a compound of formula I, or any pharma- ceutically acceptable salt or solvate thereof; and ii) Inhaler A kit comprising:

[0103] In a further aspect, the present invention provides a method for producing a method for treating a cancer cell comprising the steps of: i) a composition comprising a compound of formula I, or any pharma- ceutically acceptable salt or solvate thereof, formulated for inhalation; and ii) Inhaler A kit comprising:

[0104] As used herein, the term inhaler encompasses all types of devices suitable for nasal and / or pulmonary administration of a compound or composition, such as to any part of a subject's lungs, including, but not limited to, mechanical metered dose inhalers (MDIs), such as pressurized MDIs, breath actuated MDIs, dry powder inhalers, inhalers with spacer devices, and nebulizers.

[0105] The embodiments and features described in the context of one aspect, e.g., for an aspect directed to a compound for use in a method for the treatment of IPF, also apply to other aspects of the invention, such as a composition for use in a method for the treatment of IPF, such as a method of treatment of IPF, such as a kit.

[0106] In a further aspect, the present invention provides a method of treating idiopathic pulmonary fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of formula I, or any pharma- ceutically acceptable salt or solvate thereof.

[0107] In some embodiments, the present invention provides a method of treating idiopathic pulmonary fibrosis, comprising administering to a subject in need thereof a composition comprising an effective amount of a compound of formula I, or any pharma- ceutically acceptable salt or solvate thereof.

[0108] In a further aspect, the present invention provides a method of treating idiopathic pulmonary fibrosis, comprising the step of administering to a subject in need thereof an effective amount of phenylcapsaicin, or any pharma- ceutically acceptable salt or solvate thereof.

[0109] In some embodiments, the present invention provides a method of treating idiopathic pulmonary fibrosis, comprising administering to a subject in need thereof a composition comprising an effective amount of phenylcapsaicin, or any pharma- ceutically acceptable salt or solvate thereof.

[0110] In yet a further aspect, the present invention provides a method for inhibiting activity of platelet-derived growth factor receptor (PDGF)-α and / or β in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I, or any pharma- ceutically acceptable salt or solvate thereof.

[0111] The present invention is not limited to the embodiments and examples shown. Although various embodiments of the present disclosure are described herein, it will be apparent to those skilled in the art that such embodiments are provided merely as examples. Numerous modifications and changes to the embodiments described herein, as well as variations and substitutions, will be apparent to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments described herein can be used in practicing the present disclosure.

[0112] It is to be understood that all embodiments of the present disclosure may be optionally combined with any one or more of the other embodiments described herein.

[0113] It is to be understood that each component, compound, or parameter disclosed herein should be construed as disclosed for use alone or in combination with one or more of any and all other components, compounds, or parameters disclosed herein. Each amount / value or amount / value range of each component, compound, or parameter disclosed herein should also be construed as disclosed in combination with each amount / value or amount / value range disclosed for any other component, compound, or parameter disclosed herein, and thus, it is to be further understood that any combination of amount / values ​​or amount / value ranges of two or more components, compounds, or parameters disclosed herein is also disclosed in combination with each other for the purposes of this specification. Any feature described herein, and combinations of such features, are included within the scope of the present invention, unless the features are mutually inconsistent.

[0114] It should be understood that each lower limit of each range disclosed herein should be interpreted as being disclosed in combination with each upper limit of each range disclosed herein for the same component, compound, or parameter. Thus, a disclosure of two ranges should be interpreted as a disclosure of four ranges derived by combining each lower limit of each range with each upper limit of each range. A disclosure of three ranges should be interpreted as a disclosure of nine ranges derived by combining each lower limit of each range with each upper limit of each range. Furthermore, a specific amount / value of a component, compound, or parameter disclosed in the specification or examples should be interpreted as a disclosure of either a lower or upper limit of a range, and thus can be combined with any other lower or upper limit or range or specific amount / value of that component, compound, or parameter disclosed elsewhere in this application to form a range for the same component, compound, or parameter.

[0115] example Example 1 - Reduction of PDGF-supported survival and proliferation of human corneal epithelial cells in the presence of phenylcapsaicin An assay was performed to study mediation of PDGF-supported survival and proliferation of human corneal epithelial cells in the presence of increasing concentrations of phenylcapsaicin.

[0116] method: Cell culture: Primary isolated human corneal epithelial cells; normal human cells (ATCC® PCS-700-010™) were cultured in serum-reduced (5% fetal bovine serum) modified promocell medium (MPM) supplemented with 4 ng / ml fibronectin (FN), 2 ng / ml human recombinant vascular endothelial growth factor (VEGF) and 4 ng / ml basic fibroblast growth factor (bFGF) at 37 °C for 24 h at 5% CO. 2 The cells were cultured and maintained at 37° C. with 5% CO and 95% humidity. This combination of FN, VEGF and bFGF has been shown to optimize growth and migration kinetics.

[0117] Clonogenic cell survival assay: Clonogenic cell survival assays determine the ability of cells to proliferate indefinitely. The effect of phenylcapsaicin (2) on the clonogenic survival of corneal epithelial cells was examined by incubating the cells at 25 cm 2 The effect of PDGF on the proliferation and proliferation of fibroblasts was investigated by seeding increasing numbers of cells (102-5x104) in flasks. SU9518, a known inhibitor of PDGF that has shown the ability to reduce radiation-induced fibroblast and endothelial cell activation, was used as a positive control. Cells were incubated separately with 0-10 μM phenylcapsaicin and SU9518 in the presence of 10 ng / ml PDGF-AB. Flasks were returned to the incubator for 14 days and then stained with crystal violet. Colonies were counted and viable ones were selected.

[0118] Proliferation assay: Corneal cells were harvested by trypsinization at 37°C and neutralized with trypsin neutralizing solution. A suspension of 50,000 cells in MPM / DMEM was added to a 25 ml flask. Cells were incubated with phenylcapsaicin or SU9518 for 1 h in cytokine-free medium in standard conditions and further incubated for 72 h in the presence of final medium (containing either 10 ng / ml PDGF-AB + 4 ng / ml FN or 2 ng / ml VEGF + 4 ng / ml bFGF + 4 ng / ml FN). Cells were then dispersed in trypsin, resuspended, and counted in a Coulter counter.

[0119] result: Clonogenic survival assay results: The results of the clonogenic survival assay are shown in Figure 1. In the clonogenic survival assay, the inhibitory effect of phenylcapsaicin showed a dose-dependent inhibitory effect on human corneal epithelial cell survival in the presence of PDGF (-AB isoform, 10 ng / ml). SU9518, a known inhibitor of PDGF signaling used as a control, also showed a dose-dependent decrease in cell survival.

[0120] Proliferation assay results: To further evaluate the specificity of phenylcapsaicin, its ability to inhibit corneal epithelial proliferation stimulated by PDGF was measured in comparison with its inhibitory potency against epithelial proliferation stimulated by VEGF+bFGF. As shown in Figure 2, phenylcapsaicin inhibited 10ng / ml PDGF-induced epithelial proliferation with an IC50 of approximately 1μM, whereas VEGF+bFGF-induced proliferation did not show an IC50 value up to the highest dose of phenylcapsaicin tested (10uM).

[0121] Discussion / Conclusion: PDGF inhibition is considered a viable mechanistic pathway for the treatment of fibrosis, especially pulmonary fibrosis. Inhibition of PDGF signaling in human corneal epithelial cells in the presence of phenylcapsaicin showed a dose-dependent decrease in endothelial cell viability. For example, at a concentration of 5 μM, phenylcapsaicin reduced epithelial cell viability to 27% versus 30% for the positive control SU9518. Thus, PDGF-mediated clonogenic survival of human corneal epithelial cells is significantly inhibited by administration of phenylcapsaicin in a dose-dependent manner.

[0122] Furthermore, phenylcapsaicin was shown to act selectively with respect to the PDGF pathway, since PDGF-induced proliferation was effectively blocked by phenylcapsaicin (IC50 of approximately 1 uM), whereas epithelial proliferation stimulated by VEGF and bFGF was barely inhibited (IC50>10 uM).

[0123] Example 2 - Phenylcapsaicin reduces PDGF expression in bronchial epithelial cells As mentioned above, PDGF has been shown in the literature to be a profibrotic mediator and play an important role in the pathogenesis of IPF, and inhibition of platelet-derived growth factor signaling has been shown to attenuate pulmonary fibrosis. Therefore, it seems reasonable to assume that blocking the PDGF pathway may be a way to treat IPF.

[0124] method Cell culture: Primary isolated human bronchial epithelial cells (NHBE) (normal, human (ATCC® BEAS-2B™) were cultured to passage 6. BEAS-2B cells were cultured in serum-free Ham's F-12 medium supplemented with 5 mg / ml insulin, 5 mg / ml transferrin, 20 ng / ml human EGF, 0.1 Mm dexamethasone, 20 ng / ml cholera toxin, 30 mg / ml bovine pituitary extract, and 1 mM retinoic acid.

[0125] Clonogenic cell survival assay: Clonogenic cell survival assays determine the ability of cells to proliferate indefinitely. The effect of phenylcapsaicin on clonogenic survival of bronchial epithelial cells was examined by incubating the cells at 25 cm 2 Increasing numbers of flasks (10 2 ~5×10 4 The effect of PDGF on the proliferation and proliferation of cells was investigated by seeding 1000 (1000) cells at 10 μM. SU9518, a known inhibitor of PDGF that showed the ability to reduce radiation-induced fibroblast and endothelial cell activation, was used as a positive control. Cells were incubated separately with 0–10 μM phenylcapsaicin and SU9518 in the presence of 10 ng / ml PDGF-AB. Flasks were returned to the incubator for 14 days and then stained with crystal violet. Colonies were counted and the percentage of survival determined for clonogenic survival after correcting for seeding efficiency.

[0126] Proliferation assay: Bronchial cells were harvested by trypsinization at 37°C and neutralized with trypsin neutralizing solution. A suspension of 50,000 cells in MPM / DMEM was added to a 25 ml flask. Cells were incubated with phenylcapsaicin or SU9518 for 1 h in cytokine-free medium in standard conditions and further incubated for 72 h in the presence of final medium (containing either 10 ng / ml PDGF-AB + 4 ng / ml FN, or 2 ng / ml VEGF + 4 ng / ml bFGF + 4 ng / ml FN). Cells were then dispersed in trypsin, resuspended, and counted in a Coulter counter.

[0127] result Clonogenic survival assay results: In clonogenic survival assays, the inhibitory effect of phenylcapsaicin showed a dose-dependent inhibitory effect on human bronchial epithelial cell survival in the presence of PDGF (-AB isoform, 10 ng / ml). SU9518, a known inhibitor of PDGF signaling, also showed a dose-dependent decrease in cell survival. The results are shown in Figure 3.

[0128] Proliferation assay results: To further evaluate the PDGF specificity of phenylcapsaicin, measurements were made of its ability to inhibit PDGF-stimulated bronchial epithelial proliferation compared to its inhibitory potency against epithelial proliferation stimulated by VEGF+bFGF. As shown in Figure 4, phenylcapsaicin inhibited 10 ng / ml PDGF-induced epithelial proliferation with an IC50 of approximately 1 μM. VEGF+bFGF-induced proliferation did not show an IC50 value up to the highest dose of phenylcapsaicin tested (10 uM).

[0129] Discussion / Conclusion PDGF inhibition is considered a viable mechanistic pathway for the treatment of IPF. Inhibition of PDGF signaling in human bronchial epithelial cells in the presence of phenylcapsaicin showed a dose-dependent decrease in endothelial cell viability, as seen in corneal epithelial cells. For example, at a concentration of 5 μM, phenylcapsaicin reduced epithelial cell viability to 35% versus 33% for the positive control SU9518. Therefore, it can be concluded that PDGF-mediated clonogenic survival of human bronchial epithelial cells is significantly inhibited by administration of phenylcapsaicin in a dose-dependent manner.

[0130] Furthermore, phenylcapsaicin was shown to act selectively on the PDGF pathway, albeit with less selectivity than in corneal cells: PDGF-induced proliferation was effectively blocked by phenylcapsaicin (IC50 of approximately 2 uM), whereas epithelial proliferation stimulated by VEGF and bFGF was moderately inhibited (IC75 of approximately 5 uM).

[0131] The results indicate that phenylcapsaicin is a potent inhibitor of PDGF in human lung (bronchial) tissue and is therefore a highly useful drug candidate for IPF.

[0132] Example 3 - Evaluation of capsaicinoids in reducing PDGF expression in bronchial epithelial cells Following the studies of Example 2, phenylcapsaicin (2) was tested along with capsaicin (1) and phenylcapsaicin derivatives 3-7 to evaluate the ability of each of these compounds to reduce PDGF expression in bronchial epithelial cells. [ka]

[0133] method Primary isolated human bronchial epithelial cells (NHBE) supplied by the American Tissue Culture Collection (Normal, Human (ATCC® BEAS-2B™) were used in this assay and cultured to passage 6. BEAS-2B cells were cultured in serum-free Ham's F-12 medium supplemented with 5 mg / ml insulin, 5 mg / ml transferrin, 20 ng / ml human EGF, 0.1 mM dexamethasone, 20 ng / ml cholera toxin, 30 mg / ml bovine pituitary extract, and 1 mM retinoic acid.

[0134] Clonogenic cell survival assay: Clonogenic cell survival assays determine the ability of cells to proliferate indefinitely. The cells were then placed in a 25 cm 2 Increasing numbers (102 to 5 x 104) were seeded into flasks of 100 x 10 cells. SU9518, a known inhibitor of PDGF that has shown the ability to reduce radiation-induced fibroblast and endothelial cell activation, and phenylcapsaicin were used as positive controls. Cells were incubated separately with 0-10 μM (3% in DMSO in water) phenylcapsaicin, SU9518, and compounds 1 and 3-7 in the presence of 10 ng / ml PDGF-AB (Sigma Aldrich). Flasks were returned to the incubator for 14 days and then stained with crystal violet (Sigma Aldrich). Colonies were counted and the percentage of survival determined for clonogenic survival after correcting for seeding efficiency.

[0135] result Clonogenic survival assay results: The results of the clonogenic survival assay are shown in Table 1 for each compound tested. [Table 1]

[0136] The results strongly indicate that the right side of the unsaturation of the molecule plays a major role in PDGF inhibition.

[0137] Discussion / Conclusion Inhibition of PDGF signaling in human bronchial epithelial cells in the presence of phenylcapsaicin again reduced endothelial cell viability in a dose-dependent manner.

[0138] Five derivatives were also assayed to learn about the structure-activity relationship of two important structural elements, the free hydroxy group of the vanillyl ring and the alkynylbenzene phenyl group. Importantly, no inhibition of PDGF was observed for capsaicin in this assay. This primarily indicates the importance of the alkynylbenzene group on the right side of the molecule for PDGF inhibitory activity. When this phenyl ring was replaced with a saturated six-membered ring (compound 3), the PDGF inhibitory activity was significantly reduced, whereas when the benzene ring was replaced with a bulky t-butyl group (compound 4), the PDGF inhibitory activity was completely lost. Furthermore, it was found that acetylation of the vanillyl hydroxy group of phenylcapsaicin (compound 5) significantly improved the PDGF inhibitory activity. More specifically, these results indicate that the unsaturated right side of the molecule plays a major role in PDGF inhibition. Capsaicin (1) and the t-butyl analogs of PheCap (4 and 7) did not show any PDGF inhibition. The cyclohexyl analogs of PheCap (3 and 6) showed some moderate activity, and the -OAc analog of PheCap (5) even showed greater PDGF inhibition than both the parent PheCap (2) and the positive control SU9518.

[0139] Example 4 - Phenylcapsaicin analogues - Reducing PDGF expression in bronchial epithelial cells The purpose of this third in-vitro assay was to follow up the positive results seen in the inhibition of PDGF expression in human bronchial epithelial cells by five new synthetic analogs of capsaicin and phenylcapsaicin. [ka]

[0140] method: Primary isolated human bronchial epithelial cells (NHBE) supplied by the American Tissue Culture Collection (Normal, Human (ATCC® BEAS-2B™) were used in this assay and cultured to passage 6. BEAS-2B cells were cultured in serum-free Ham's F-12 medium supplemented with 5 mg / ml insulin, 5 mg / ml transferrin, 20 ng / ml human EGF, 0.1 mM dexamethasone, 20 ng / ml cholera toxin, 30 mg / ml bovine pituitary extract, and 1 mM retinoic acid.

[0141] Clonogenic cell survival assay The effect of phenylcapsaicin (2) on clonogenic survival of bronchial epithelial cells was examined by incubating the cells at 25 cm 2 The efficacy of SU9518* and phenylcapsaicin was investigated by seeding increasing numbers of cells (102–5 × 104) in flasks of 100 μM each. SU9518* and phenylcapsaicin were used as positive controls. Cells were incubated separately with phenylcapsaicin, SU9518, and compounds 8–12 at 0–10 μM (3% in DMSO in water) in the presence of 10 ng / ml PDGF-AB (Sigma Aldrich). Flasks were returned to the incubator for 14 days and then stained with crystal violet (Sigma Aldrich). Colonies were counted and the percentage of survival was determined for clonogenic survival after correction for seeding efficiency. All synthetic analogs were calculated at 100% purity for molar concentrations.

[0142] result: The results of the clonogenic survival assay are shown in Table 2 for each compound tested. Figure 5 further illustrates the results graphically, including both compounds of Example 3 and Example 4. The X-axis gives the uM concentration and the Y-axis shows percent survival. The graphs obtained for each compound 1-12 are labeled as shown at the top of the figure. [Table 2]

[0143] Compound 8, a saturated side chain analog of phenylcapsaicin (2), and compound 9, a desphenyl analog of phenylcapsaicin, did not show any reduction in clonogenic cell survival.

[0144] Compound 12, a naphthalene analog of phenylcapsaicin, and 10, a 4-nitrophenyl analog of phenylcapsaicin, showed similar percent cell survival as the parent phenylcapsaicin.

[0145] Compound 11, a 4-methoxyphenyl analog of phenylcapsaicin, showed a greater reduction in this cell viability than lead phenylcapsaicin, and this reduction was comparable to the activity seen with the acetylated guaiacol analog 5 and the SU9518 positive control.

[0146] Inhibition of PDGF signaling in human bronchial epithelial cells in the presence of phenylcapsaicin again demonstrated a reduction in endothelial cell viability in a dose-dependent manner. Five analogs were also assayed to reveal SARs in two key structural elements, namely the free hydroxyl group on the guaiacol ring on the left side of the molecule and the alkynylbenzene on the right side. Importantly, no inhibition of PDGF was observed for capsaicin in this assay. This indicates primarily the importance of the alkynylbenzene group on the right side of the molecule for PDGF inhibitory activity. When the benzene ring was replaced with a saturated six-membered ring (cyclohexyl), the PDGF inhibitory activity was significantly reduced, whereas when the benzene ring was replaced with a bulky alkyl group ((t-butyl), the PDGF inhibitory activity was completely lost. Surprisingly, acetylation of the guaiacol hydroxy group in PheCap (5) resulted in a significant improvement in PDGF inhibitory activity, which was further improved by alkoxy group, e.g., 4-OMe substitution, on the side chain phenyl ring, as seen for compound 11.

[0147] Thus, it can be concluded that the inhibition of PDGF-mediated clonogenic survival of human bronchial epithelial cells is significantly increased by acetylation of the guaiacol hydroxy group and that the unsaturated ring at the right end of the PheCap structure also favors PDGF inhibition.

Claims

1. A composition for use in a method for the treatment of idiopathic pulmonary fibrosis (IPF), comprising a compound of formula II, or a pharma- ceutically acceptable salt or solvate thereof. 【Chemistry 1】 [In the formula, X is selected from oxygen and sulfur; Ar optionally contains one or more nitrogen, oxygen, or sulfur atoms, and at any one or more positions, nitro, trifluoromethyl, C １ ~C ６ Linear and branched alkoxy, C １ ~C ６ represents an aryl group optionally substituted with one or more identical or different substituents selected from the group of linear and branched alkyl; R′ is hydrogen, C １ ~C ６ Selected from the group of linear or branched alkyl; R is hydrogen; C １ ~C ６ Straight-chain and branched alkyl, alkenyl, and alkynyl; ３ ~C ６ Cycloalkyl; acyl group COR １ (In the formula, R １ is C １ ~C ６ Straight-chain and branched alkyl, alkenyl, and alkynyl, C ３ ~C ６ cycloalkyl and phenyl). A composition comprising:

2. The composition of claim 1 , wherein X is oxygen.

3. The composition of claim 1 , wherein Ar is an unsubstituted or substituted phenyl or naphthyl group.

4. Ar is a substituted phenyl, said one or more substituents being nitro and C １ ~C ６ The composition of claim 1 , wherein the alkoxy group is selected from the group of straight chain and branched alkoxy.

5. R' is H or methyl and R is H or an acyl group COR １ (In the formula, R １ But, C １ ~C ６ 2. The composition of claim 1, wherein the alkyl group is a straight chain or branched alkyl group.

6. 6. The composition of claim 5, wherein R' is methyl and R is acetyl.

7. A composition described in any of claims 1 to 6, wherein the method includes administering the composition to a subject by pulmonary, oral, and / or intravenous administration.

8. 7. The composition of any one of claims 1 to 6, formulated for inhalation.

9. The composition of any of claims 1 to 6, wherein the method comprises administering the composition to a subject by inhalation.

10. A kit comprising: i) a composition according to any one of claims 1 to 6; and ii) Inhaler Including the kit.

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